INTRODUCTION TO MICROFLUIDICS

Introduction to Microfluidics
Patrick Tabeling
École Supérieure de Physique et de Chimie Industrielles, (ESPCI) Paris,
Paris Sciences et Lettres (PSL) University.
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To Isa
Preface

Microfluidics has progressed considerably over the last twenty years, and the time has
come to envisage a serious update of the first edition of Introduction to Microfluidics,
published in 2005. In fact, this second edition is more than an update. Compared
to the first one, it keeps the same structure, the same spirit, the same attempts to
explain things, on a physical basis, in depth and simply, whenever possible, but it is not
reducible to an update. The present edition results from complete rewriting of the first
one, nurtured by the considerable amount of information collected in the field over the
last two decades. So much information has been gathered in twenty years. So many
revisions of the visions of the field have been made. Things that looked impossible
in the 1990s gave rise to an important industry, ten years later. This is the case of
next generation sequencing (NGS). Things that looked revolutionary turned out to
be disappointing. The history of microfluidics is full of dreams that became real and
appealing evidence that became wrong. Let us return to the turn of the century. At that
time, the microfluidic market (i.e. without ink jet printing) was small, and scepticism
was floating around concerning the potential of the technology to find its feet in a
market, even though it was regularly announced, here and there, that microfluidics
would revolutionarize the twenty-first century. Common sense led to the theory, in fact
wrong, that driving flows through tiny channels, at an industrial scale, without leaks,
clogging, bubbles, or uncontrolled adsorption, was impossible. The opposite viewpoint
believing that it is straightforward to create a complex, functional, microfluidic device
was unrealistic. Still, successful microfluidic products emerged, while, in the meantime,
the technology penetrated into an increasing number of new domains. The market
steadily increased at a two-digit rate, reaching, today, seventeen billions dollars. At
the moment, hundreds of millions of devices are sold every year. For example, 1.2
million Illumina microfluidic flow cells, for gene sequencing, are shipped every single
year. In the meantime, fundamental phenomena, such as capillarity, wetting, slippage,
and nanofluidic transport have been better understood or, in a number of puzzling
cases, just understood. Over the years, the early vision of the domain, based on a
strict analogy with microelectronics, gradually shifted to a new paradigm, in which the
microfluidic tool box is no longer restricted to MOS-FET surrogates, but incorporates
a much broader palette of materials and mechanisms.
Since the first edition, twenty books on microfluidics have been published. Many are
good or very good. But some look more like galleries of cartoons exhibiting systems
supposed to work, with no data showing that they do. This is a style. I tried to avoid
this type of presentation. Other books, often engineering-oriented, describe basic phe-
nomena without much depth. In fact, caricaturing subtle mechanisms is a difficult
exercise. Sometimes, errors are made. Perhaps, we could content ourselves with this
viii Preface

level of description. After all, we can use a computer with no idea how a transistor
works. As P. Anderson stated, science is organized in hierarchical levels, built on top
of each other, the upper using concepts elaborated by the lower. Both operate inde-
pendently, elaborating their own laws and paradigms. Then, as just said, computing
researchers do not need to know what a transistor is, and there is no necessity for
fluid mechanicists to understand kinetic theory of gases. In the 1990s, it was thought
that soon, microfluidic researchers would no longer need fluid mechanics. Engineers
would design microfluidic machines, without noticing that fluids are running in them.
Perhaps, one day, microfluidics will reach this stage. But microfluidics has not reached
this level yet. And it is still valuable and probably important, to acquire a minimal
knowledge on the subtleties that the field relies upon, at least to know the limitations
that they induce. I attempted to provide this type of knowledge throughout this book.
Many calculations developed in the present book are elementary. Still, they allow us
to rationalize most of the physics involved in microfluidic flow and transport phenom-
ena. Physico–chemical processes, developing on surfaces or in bulks, so important in
microfluidics, are explained on an intuitive basis, without using the powerful machin-
ery of thermodynamics, whose exquisite concepts sometimes obscure the underpin-
ning physics. Emphasis is placed on modern applications, in which biology plays an
important part. Also, as in the first edition, a forty-page introduction to microfluidic
technologies is given. The book includes enough material to build up courses of various
formats, from a few to twenty hours or so.

Fig. 0.1: Ant playing microguitar (From M. Seiffert (2003)).

Acknowledgements
First, I would like to thank C. M. Ho, who hosted me in 2000, at the University of
California at Los Angeles (UCLA), at the time when the ’golden years’ of microfluidics
were just launching. Thanks to him, I discovered the field. On my return to Paris,
one year later, P. G. De Gennes offered me to create a microfluidic laboratory at
Ecole Supérieure de Chimie Industrielle (ESPCI), which I did with enthusiasm. Since
then, for twenty years, I have had the chance to meet extraordinary people, students,
postdocs, and colleagues, and to build strong friendships. Writing the second edition
is a sort of noetic journey through these exciting years.
Microfluidics is a broad field, and it is impossible to become, all of a sudden, a world
class expert on all the subjects it embraces. I was fortunate to receive help from many
colleagues, who kindly exchanged correspondance and, in many cases, corrected errors
and misconceptions. I acknowledge J. Ottino, who made numerous remarks on the
chaotic mixing section. In the strange atmosphere of the COVID confinement days, we
had long exchanges over the internet, evoking, sometimes, the years when we pertained
to the same community. This left the impression that writing a book is also a look
into the past, sometimes exposing the author to vertigo. I had the same feelings with
my friends Y. Pomeau, and J.P. Bouchaud, for their remarks concerning Brownian
motion and chaos, and K. Moffatt for his comments on Batchelor’s approach to fluid
mechanics. I had discussions with G. Whitesides and A. Manz concerning microfluidics,
its past and future. J. Eijkels and A. van den Berg expressed their enlightening vision
of nanofluidics which I refer to in the book. D.Lohse updated the poor knowledge I had
on nanobubbles, H. Stone made a detailed reading of my presentation of the Navier-
Stokes equations, F. Mugele gave precious remarks on electrowetting and J. Cossy on
surfactant chemistry. With my friend S. Quake, I had a long semantic dispute about
the word ‘vesicle’, not ended yet. Z. Z. Li, a former student, now professor at Beijing
Institute of Technology, performed experiments to obtain the useful (unpublished)
images shown in Chap 4, related to step emulsification technique. I also benefited
from great remarks from D. Quere, J. O. Fossum, T. Lecuit, V. Hessel, J. L Viovy,
J. Eggers, M. Bazant, R. Ismagilov, P. Doyle, H. Bruus, A. Strooke, F. Wyart, E.
Clement, A. Skjeltorp, E. Raphael, M. Tatoulian, Y. Tran, K. Jensen, S. Wereley, J.
Bibette, A. Griffiths and D. Weitz . I also acknowledge J. Mouly and C. Midelet, from
Yole Development, for their explanations of the microfluidic market. Deep thanks to C.
Rollard, for her description of the realm of spiders. I am also indebted to J.O. Fossum,
E. Torino, P.A. Netti, for great discussions and for their invitations to sabbatical
periods at Nordheim University and the Italian Institute of Technology, in Napoli. I
would also like to acknowledge A. Libchaber, from whom I learned a lot. Discussions
with my close colleagues, P. Nghe and J. Mc Graw were inspiring and exchanges in
my group provided a source of thinking and learning: thanks to P. Garneret, E. Coz,
E. Martin, U. Soysal, P. Nieckele, M. Russo, and I. Maimouni. I am also grateful to
M. Dhunnoo for her help and L. Dehove, for her appealing cover and the great figures
shown in this book.
Contents

1 Introduction 1
1.1 Astonishing microfluidic systems in nature 1
1.2 Exquisite microfluidic control in the human body 3
1.3 MEMS, the mother of microfluidics 6
1.4 The birth of microfluidics 9
1.5 The advent of soft technology 14
1.6 Diversification of the technology and broadening of the applica-
tions 16
1.7 MicroReaction Technology (MRT) 21
1.8 Nanofluidics 22
1.9 The microfluidic market 26
1.10 Future of microfluidics 30
1.11 Reviews and books 38
1.12 Organization of the book 39
References 40
2 Physics at the microscale 48
2.1 The scales of small things 48
2.2 Intermolecular Forces - basics 58
2.3 Nano-Micro and Millifluidics 71
2.4 The physics of miniaturization 73
2.5 Scaling laws in nature 77
2.6 Miniaturization of electrostatic systems 87
2.7 Miniaturization of electromagnetic systems 91
2.8 Miniaturization of mechanical systems - the vibrating microbeam 93
2.9 Miniaturization of thermal systems 95
2.10 Sampling and throughput 97
References 100
3 Hydrodynamics of microfluidics 1: channels 103
3.1 The flow equations and the boundary conditions 103
3.2 Slippage in gases 118
3.3 Slippage in liquids 121
3.4 Microfluidics at small Reynolds numbers 127
3.5 Resistances and capacitances in microfluidics 141
3.6 Inertial microfluidics and millifluidics 150
References 158
xii Contents

4 Hydrodynamics of microfluidics 2: droplets 162

4.1 Liquid–vapour interfaces 162
4.2 Laplace’s law 169
4.3 Surfactants 181
4.4 Wetting 188
4.5 Droplets advancing on a surface 198
4.6 The governing equations and the capillary number 202
4.7 The Landau–Levich and Bretherton films 205
4.8 The Rayleigh–Plateau instability 208
4.9 Washburn law and paper microfluidics 212
4.10 Production of microfluidic droplets and bubbles 215
4.11 Characteristics of microfluidic droplets and bubbles 225
References 240
5 Transport in microfluidics 245
5.1 The microscopic origin of diffusion 245
5.2 Advection-diffusion equation and its properties 253
5.3 Analysis of diffusion phenomena 257
5.4 Analysis of dispersion phenomena 263
5.5 Brief introduction to chaos and chaotic mixing 269
5.6 Mixing in microfluidic devices 276
5.7 Four applications of transport of matter in microfluidics 286
5.8 Transport of matter across interfaces 290
5.9 Particles and microfluidics 299
5.10 Particles in inertial regimes 307
5.11 Adsorption 308
5.12 Chromatography 312
5.13 Thermal transport by conduction 318
5.14 Convection-diffusion heat equation and properties 324
5.15 Heat transfer in the presence of a flow in microsystems 329
5.16 Evaporation and drying 336
5.17 Microexchangers for electronic components 340
References 344
6 Electrokinetics 350
6.1 Introduction 350
6.2 Basic notions of electrostatics of macroscopic media 350
6.3 The electrokinetic equations 356
6.4 The electrical double layer 359
6.5 Electro-osmosis 372
6.6 Electrophoresis 381
6.7 Microfluidic electrokinetic separation 393
6.8 Dielectrophoresis 400
6.9 Three illustrations/applications of dielectrophoresis 404
6.10 Electrowetting 406
 Contents xiii

References 412
7 An introduction to microfabrication 415
7.1 Introduction 415
7.2 Current situation of microtechnologies 415
7.3 The environment of microfabrication 417
7.4 Photolithography 419
7.5 Direct writing or maskless photolithography 424
7.6 Microfabrication methods for silicon and glass devices 425
7.7 PDMS-based moulding – soft lithography 437
7.8 Computer Numerical Control (CNC) Micromilling 449
7.9 3D Printing or Additive Manufacturing (AM) 449
7.10 Paper microfluidics 451
7.11 Other technologies 453
References 459
Index 462
1
Introduction

In the 1970s, it became possible to miniaturize electromechanical systems, down to

the micrometric scale. This gave rise to a new field, called Micro-ElectroMechanical
Systems (MEMS). Later, in the 1990s, the field expanded, creating all sorts of mi-
crodevices, in which fluids, driven under control, gave rise to new functionalities. This
prompted the birth of a new field – microfluidics – the central subject of this book.
Microfluidics can be defined as the science of manipulation of fluids in systems of
micrometric size. Fluids can be gases, liquids, Newtonian or not, mono or multiphasic
(e.g. oil and water). Systems can be devices with channels, patterned surfaces, or
paper sheets. Micrometric is an order of magnitude. In practice, microfluidic scales
range from 100 nm to 1 mm. The definition proposed here is currently used in the
field1 and we will adopt it throughout the book.2

1.1 Astonishing microfluidic systems in nature

Obviously, nature manipulates, with exquisite control, fluids at the microscale. Oth-
erwise no life would be possible. The tree is an example. In the tree of Fig. 1.1, tens
of thousands of leaves are nourished by a network containing thousands of capillaries
of diameters on the order of tens of micrometres (in the trunk and the branches) and
billions of pores of several tens of nanometres (in the mesophyll cell system, in the

1 In an influential paper [1], titled ‘The origins and the future of microfluidics’, G. Whitesides
defined microfluidics as ‘the science and technology of systems that process or manipulate small
(10−9 to 10−18 liters) amounts of fluids, using channels with dimensions of tens to hundreds of
micrometers’. The definition, although more restrictive about the scales, is essentially is the same as
ours.
2 Two remarks must be made at this level:
- Microfluidics should not be confused with microhydrodynamics. Microhydrodynamics is the study
of creeping flows, i.e. flows at low Reynolds numbers. In the definition of microhydrodynamics, ‘micro’
refers to the Reynolds number, not the system size. In microfluidics, ‘micro’ refers to the system size,
not the Reynolds number. One can have microhydrodynamic flows of decimetric sizes (e.g. honey
poured from a spoon) and microfluidic flows operating at substantially high Reynolds numbers (e.g.
inertial micromixers).
- ‘Microfluid’ is a word that sometimes appears in the literature. It is not a physical concept.
‘Fluid’ refers to a state of matter defined microscopically. In the bulk, gases and liquids circulating in
microchannels possess exactly the same microscopic structure as in large containers. There is no new
phase. In extremely confined systems, for instance, in carbon nanotubes, the liquid structure can be
affected by the walls. However, this concerns only nanometric scales.
2 Introduction

Fig. 1.1: This tree possesses a complex network of capillaries (xylem and phloem) that
supplies sap homogeneously to the tens of thousands of leaves that it carries on its branches,
and redistribute carbohydrates and other organic compounds between leaves, roots, and fruits
(credit: Johannes Plenio) [2].

leaf).3 In the pores, sap evaporates, through a process called transpiration, creating
interfaces that pull the sap from the roots to the top [3, 4]. Despite the complexity of
the network, the supply of sap is stable in time and homogeneous in space. The hy-
drodynamics of the tree is extremely subtle. For instance, large trees drive the sap at
negative pressures [5,6]. No hydraulic system made by humans functions like this. The
reason is that when the pressure is negative, bubbles nucleate and the flow is unstable
and becomes out of control. In trees, bubbles grow, but several mechanisms, including
mechanical, block their propagation, thereby preventing embolism and death [4].
We will come back to the trees in Chapter 4, when capillary phenomena are discussed.
Here, it is enough to observe that the tree provides an example of exquisite microflu-
idic control.. This control is achieved not for the pleasure of realizing a technological
performance, but to ensure survival.
A similar problematic holds for the spider. The spider produces4 long silken threads, a
few dozen micrometres in diameter, forming a complex pattern -the spider web-, each
thread developing a resistance to rupture that is twice as great as that of steel [7, 8].
How does the spider manage to produce this material? To make a long story short,
5
the silk solution is contained in the glands, which are highlighted in Fig. 1.2. In
most spiders, six glands produce different types of silks. The solution is driven in small
capillaries, several tens of µm in diameter. By actuating valves, or selecting the glands,

3 The mesophyll part is much more resistive than the other parts of the tree. This explains why
the tree distributes the sap among the leaves, in a remarkably homogeneous manner.
4 All spiders produce silk but only a fraction of them produce webs. Those which do not produce
webs use the silk wires to build cages protecting their eggs, or to pass from one leaf or one branch to
another to move more swiftly.
5 An excellent, description of the spider silk production is given by the Museum of Australia, in an
article named: ‘Silk: the spider’s success story’.
 Exquisite microfluidic control in the human body 3

the spider chooses the silk it wants to produce, for one part of the web or another.
Each gland works as part of a pair. In the capillary, one type of silk occupies the
central part of the channel, and the other the periphery. Thus, they form a concentric
system in which the two silks flow side by side. In their journeys, the silk solutions
deshydrate and, combined with the effect of the large deformation rate to which they
are subjected,6 tend to harden. At the end of these journeys, the soft material is
extruded at the back of the abdomen, through tens of submicrometric nozzles; it then
evaporates and solidifies. The spider thus controls a complex annular flow structure,
the dehydratation process along the capillary, and the final extrusion through many
nozzles. This technological tour de force allows it to catch insects to eat.

1.2: Two glands produce the silk of

the spider web, each gland secreting a
particular type of silk. The silk is in a
liquid state in the glands. During its
journey towards the outlet, the solu-
tion hardens under the effect of large
deformations, dehydrates, turns into
a soft material, exits the spider, evap-
orates, and solidifies.

1.2 Exquisite microfluidic control in the human body

Humans control flows at the microscale with a high level of precision, and for the
same reasons as animals and trees: to be viable. The examples are numerous and they
concern almost all parts of the body. Here, just a few are mentioned.
Blood circulation The blood network is formed by vessels of different types: arteries,
veins, and capillaries. Each of these plays a specific role in the circulation process.
The total length of the vessels is impressive: 100,000 km. Their diameters range
from 25 mm (the aorta) to 8 µm, i.e. the size of a red blood cell.7 Most of the vessels
are less than 100 µm in diameter, i.e. they have a microfluidic size. Fig.1.3 (A)
shows the vessel network of a lymph node. Its geometrical complexity is evident.
Blood itself is a complex fluid: it comprises a plasma, which includes a large variety
of solutes, and several types of cells -mostly red blood cells (erythrocytes)-. A
number of phenomena, described in the literature, alter the homogeneity of the
suspension. The Fahraeus effect [9] whereby, along microchannels whose diameter
decreases in the streamwise direction, the cell concentration decreases. The effect
is linked to the particular interaction that the cells develop with the walls. In
the blood network, different hydrodynamic regimes take place, depending on the
ratio of vessel diameter to blood cell diameter. Despite this complexity, the blood
circulation is precisely controlled. The averaged flow rate is tuned so as to be
6 It is considered that the silk solution behaves as a shear-thickening fluid.
7 Red blood cells are biconcave disks, 8 µm in diameter average
4 Introduction

Fig. 1.3: (A) Representation of a network of blood vessels. Gases and nutrients are exchanged
between the blood and surrounding tissue through the permeable walls of capillaries, the
smallest blood vessels(from Design cell, 2013). (B) Sketch of the gas transfers taking place
in the lungs. (C) Migration of a megakaryocyte in the bone tissue, penetration in the blood
vessel, and the subsequent platelet formation.

compatible with the metabolism. In the network, no clogging occurs, and the
pressure drops are kept small. Driving a suspension, under precise control, in such
a complex microfluidic system, represents a formidable challenge that evolution
has managed to meet.

Gas exchanges in lungs Lungs take in oxygen and eliminate carbon dioxide. The
gas transfer between blood and air, at the alveola level, is schematized in Fig.
1.3 (B). The membrane (made of cells) separating the alveola and the surround-
ing capillaries is one cell thick, i.e. about 1 µm. With such a small dimension,
gases pass quickly through the membrane into the blood. Oxygen-deficient, car-
bon dioxide-rich blood return to the heart. Although capillaries host only one
cell in their cross sections, no clogging occurs. Lungs typically contain 480 mil-
lion alveoli. The respiratory system provides an example where humans exert an
exquisite control of the blood circulation and gas exchanges, at the micron scale.

Platelet production : Platelets are cells measuring 2-3 µm and without nucleus.
They prevent haemorrhages. Without them, we would not survive. To carry out
this function, platelets, initially spherical, take the form of a star, adhere and
aggregate at a wound and trigger thrombin generation and fibrin formation to
create a clot, further strengthened by the accumulation of white blood cells [10].
Fig. 1.3(C) sketches the process of formation. Megakariocytes (30 µm large), are
produced in the bone marrow, then travel through the bone tissue and enter
the blood circulation, by migrating through the vessel wall. In the blood stream,
being tethered to the wall, they are stretched out by the shear flow and break up
to small vesicular blobs of micrometre size, called platelets [11]. The lifespan of
platelets is limited, and we must produce billions of functional platelets every day
to renew them. If the blood circulation were too fast, turbulence would develop
and the breakup process would become out of control. If the blood circulation
were too slow, the megakariocyte would not break up and no platelet would be
 Exquisite microfluidic control in the human body 5

produced. The process is thus finely controlled.

(a) (b) (c) Water channel

Evaporation
Tear film:
Mucous layer
Watery layer
+ Cell membrane
Oily layer Cell membrane
Skin +

Cornea Conjunctive
Sweat gland

Fig. 1.4: A - Sketch of a skin pore with its eccrine gland; B - Eye with its film: C - Aquaporin,
across which water molecules circulate.

Sweating Sweating cools down the body, during exercise, when the temperature is
hot or in case of fever [12]. Fig. 1.4 shows an eccrine gland, which produces sweat
and drives it through the microfluidic sudoral channel (50 µm in diameter), up
to the skin pore. The flow rate is determined by the kinetics of secretion of the
gland. Once at the skin level, sweat forms a film or a droplet, which evaporates
and, in turn, according to thermodynamics, cools down the blood circulating in
the region and thereby the body. Typical energy losses per unit of time are 350
watts, several times the basal metabolism, i.e. the energy, per unit of time, used
by a human at rest, as will be seen in Chap. 2. Should the sweat flow be too
large, the skin would be covered by a thick film, and, in the opposite case, there
would be no thermal regulation. Thereby, again in this case, evolution has led to
a fine control of microfluidic sweat flows, which plays an instrumental role in our
thermal stability.

Tears Tear film is essential for clear vision and eye health [13]. It protects the ocu-
lar surface with moisture, transports waste away, and provides a smooth optical
surface. This film has a micrometric thickness. After each blink, it re-forms. De-
ficiencies in the tear film causes blurred vision, burning, foreign body sensation,
and tearing. Flow control is instrumental to avoid these problems.

Aquaporin The preceding examples were concerned with micrometric scales. Hu-
mans also control flows at the nanometric scale. An example is aquaporin. The
function of this molecule is to transport water across cell membranes in response
to osmotic gradients [14]. Without cells could blow, as red blood cells do when
they are suddenly immersed in a salty solution. Typically, cells contain up to 30
aquaporins. As illustrated in Fig. 1.4(C), in the presence of an osmotic pressure
gradient, water molecules are forced to circulate through the aquaporin, in one
direction or the other, to cancel it. Aquaporins are extremely selective: only water
molecules pass through them. They never clog, due to the action of an anti-fouling
mechanism that is not yet understood. Their permeability is sufficiently high [15]
to enable fast equilibration, since if the equilibration process were too slow, cells
would be unstable. It has been suggested that the hourglass geometry of the
6 Introduction

molecule plays a role in this property. Aquaporin illustrates well the exquisite
control that humans have developed at the nanoscale to ensure their viability.

1.3 MEMS, the mother of microfluidics

As evoked in the first lines of the introduction, man has begun to create, in the seven-
ties, machines of micrometric sizes. These systems were called Micro ElectroMechanical
Systems (MEMS). MEMS sizes currently range between 1 µm and 500 µm. An excel-
lent example of a MEMS, hilglighted in [16], is shown in Fig. 1.5. This MEMS is a
microgear whose overall size is 200 µm. It is held by an ant. The figure illustrates the
intrusion of a man-made machine into the small animal realm. The entry into micro-
metric scales is not a new feat, however. Since the invention of the optical microscope
in the sixteenth century, the micrometric world has been scrutinized in detail. The mi-
croscope has allowed countless scientific discoveries to be made. However, before 1970,
humans did not act at a micrometric scale, which is precisely what MEMS allows. As
a result, when MEMS appeared on the scene, their potential of applications was clear.
The first example concerns airbags for cars.

1.5: Ant holding a nickel micro-gear,

made by LIGA technology (German
for ‘lithographie, galvanofomung, ab-
fomung’). This ant was metallized
and placed in a vacuum in order
to be photographed by electron mi-
croscopy. This image was provided by
the Karlsruhe group (Germany) [17].

MEMS for airbags, which first appeared in the 1980s, consist of an integrated system
on a silicon wafer that is just a few millimetres long. This is shown in Fig. 1.6. The
heart of the chip is made of two combs, one fixed and the other mobile; the capacitance
of these combs varies under the effect of an impact. As we will see in Chapter 2, the
miniaturization of the capacitor element allows the creation of a highly sensitive and
rapid detector. The industrial success of MEMS for airbag is not solely due to the
improvement in sensor response and sensitivity, but also to the ability to integrate
detection, information analysis, and signal processing all on one single chip. Just as
with integrated circuits, this chip can be reproduced by the million. The cost, which is
critical in the field of automobile manufacturing, becomes very advantageous compared
to traditional systems. For this reason, all modern automobiles now use MEMS for
their airbags, and tens of millions of these devices are produced each year.
The history of MEMS is interesting. The year 1959 is often considered to be the
beginning of the history of micro- and nanotechnology. In December of that year,
 MEMS, the mother of microfluidics 7

Fig. 1.6: A - SEM image of a part of a MEMS - accelerometer for airbag (Reprinted from Ref.
[18], with permission from IOP Publishing, Ltd, Copyright 2022); B principle of functioning
of the accelerometer.

a visionary speech was given by Richard P. Feynman during the American Physical
Society (APS) meeting at Caltech. This speech was entitled ‘There is plenty of room
at the bottom’ [19]. An early part of the speech is as follows:

I would like to describe a field, in which little has been done, but in which an enormous
amount can be done in principle. This field is not quite the same as the others in that it will
not tell us much of fundamental physics (in the sense of ‘What are the strange particles?’)
but it is more like solid-state physics in the sense that it might tell us much of great interest
about the strange phenomena that occur in complex situations. Furthermore, a point that is
most important is that it would have an enormous number of technical applications.

Feynman saw no physical reason why the 50 volumes of Encyclopedia Britannica could
not be inscribed on the head of a needle. One letter would only need to consist of less
than a dozen or so molecules. Confronted with the difficulty of working at micro-
metric scales, he suggested that we ‘train ants how to teach mites’ how to construct
miniaturized machines’.

How many times when you are working on something frustratingly tiny like your wife’s wrist
watch, have you said to yourself, ‘If I could only train an ant to do this!’ What I would
like to suggest is the possibility of training an ant to train a mite to do this. What are the
possibilities of small but movable machines? They may or may not be useful, but they surely
would be fun to make.

These suggestions or predictions did not remain just a fantasy; since three decades
later, in 1990, the word ‘IBM’ was spelled out with 35 xenon atoms [20] (see Fig.1.7).

1.7: IBM spelled out with 35 xenon

atoms, deposited on a cold (4K)
Nickel (110) surface. The atoms were
transferred from the sharp Scan-
ning Tunnelling Microscope (STM)
tip and imaged with the STM [20].
This image received a large echo.
8 Introduction

The first MEMS devices were created two decades after Feynman’s speech [21]. The
first microbeam was reported in 1982 (Fig. 1.8A), and the first microspring in 1988.
The first micromotor was created in 1988 [22,23] (Fig. 1.8B)8 . It consisted of an electro-
static motor, where the rotating electric field was generated by electrodes evaporated
onto polysilicon. One major difficulty was that stiction (the combined phenomena of
adhesion and friction), which tended to block the rotor was exacerbated by minia-
turization. The solution to this problem consisted of reducing the surface area of the
rotor/substrate contact, but this made microfabrication of this machine more difficult.

Fig. 1.8: (A) First microbeam (1982). (B) First micromotor, made at UC Berkeley by Tai
and Muller in 1989. This motor has been placed next to a human hair whose diameter is on
the order of 200 µm. (Courtesy of Professor Richard S. Muller, Berkeley Sensor & Actuator
Center, University of California, Berkeley).

Other examples are a microgripper, a hot-wire rake [21], and an astonishing microgui-
tar, shown in Chapter 7, with nanostrings 30 nm in size, vibrating at MHz frequencies.9
In addition, some unsubstantiated concepts were proposed: for instance, a MEMS con-
sisting of inclinable mirrors that permit communication between the ground and an
airborne micro-engine.10 The project failed, but the concept was appealing. Not all of
these objects were practical, but all of them stimulated the imagination.
Today, the MEMS market is estimated to be worth between US 10 and US 13 billions,
depending on the agencies. Examples of companies are ARM Holdings. Bosch, Cisco
Systems Inc., InvenSense, Knowles Electronics, MediaTek Inc. Microchip Technology
Inc., Samsung Developers, STMicroelectronics, and, Texas Instruments. MEMS pro-
duction includes a variety of products like MEMS for airbags, microgyroscopes for
mobile phones, micromirrors for digital projectors (Fig. 1.9), pressure sensors, to men-

8 We will see in Chapter 2 that this micromotor can comprise the base element of a microturbine
that converts chemical energy to electrical energy. It is also interesting to note that microgears,
fabricated using MEMS technology, are often used today in clock making.
9 The guitar, 10 µm long, with six 30 nm wide cords, will be shown in Chapter 7. It was realized
at Cornell, in 1997, in the group led by Prof Craighead.
10 This concerned a project, written by Kristofer S. J. Pister, Joe Kahn, and Bernhard Boser, the
University of California, Berkeley, in 1997, whose objective was to build wireless sensor nodes with a
volume of one cubic millimeter.
 The birth of microfluidics 9

Fig. 1.9: (A) Optical MEMS (MOEMS) made by Texas Instrument, used in digital projectors.
(B) An array of micro-mirrors used in a video-projector. The size of each mirror is 10 µm
[24](Creative Commons Attribution 4.0 Unported License).

tion a few. The applications are impressive, but there is still room at the bottom. For
instance, no MEMS is capable of flying and act, for instance, like a mosquito. Creating
a MEMS-mosquiito would necessitate developing an extremely lightweight and power-
ful energy source, that does not exist yet, and integrating an extraordinarily efficient
motor, along with ultraminiaturized micro-pumps. All this, today, looks impossible.

1.4 The birth of microfluidics

We now concentrate on microfluidics. As in the case in many fields, the birth of mi-
crofluidics, defined as ‘the science of manipulation of fluids at the microscale’, as said
above, has been preceded by precursors and even precursors of precursors. People have
succeeded, in many circumstances, in manipulating fluids at the micrometric scale, in
a controlled manner, with only their hands. To do this, they exploited hydrodynamical
laws that naturally provide a control of the micrometric scale. An example is painting.
Painters deposit micrometric layers on walls, whose thickness is controlled by the speed
of the brush. Another example is soap bubbles. The films, stabilized by surfactants,
are sub-micrometric. These examples show that without microtechnological toolbox,
the micrometric scale, in a number of cases, can be controlled.
Of much greater technological significance is a device producing submillimetric droplets.
It was invented in 1964 by R. G. Sweet [25, 26] (see Fig. 1.10).

~
18

16
14 12
24
HV+ 10
30 20
22
8
28
26

32
4

HV–

4 6 1.10: Sketch of the system used by R. G.

2
Sweet [25].
10 Introduction

The invention, with others, played an instrumental role in the field of ink-jet printing,
a major application of microfluidics. Here, droplets were emitted and deposited on a
moving sheet. A key point was the electrostatic control, which allowed large quantities
of nanoliter droplets to be produced, in a reproducible manner, opening an avenue
towards the fabrication of ink-jet printers.

1.11: First microfluidic sys-

tem (1975) [28]: a miniaturized
gas chromatographer, including
an injector, a 1.5 m long mi-
crochannel and a thermal detec-
tor.(Reprinted with the permis-
sion of IEEE, copyright 2022.)

In the 1970s, silicon-based MEMS technology was well advanced, many clean rooms
were available, and there were no difficulty in etching grooves on silicon wafers to
create microchannels. In this context, the first microfluidic device, invented by S.C.
Terry [27], appeared on the scene in 1975. Unlike Sweet’s invention, the manufacturing
and design of the device prefigured the silicon-based microfluidic devices that would
later develop, giving birth to microfluidics. The device made by Terry [27, 28] was a
miniaturized gas chromatographer. It is shown in Fig. 1.11.
Terry’s device circulated gas through a 1.5 m microchannel etched in a silicon wafer,
bonded to a glass plate. The system included a miniaturized electromagnetic injector
and a thermal detector. Separations of gaseous hydrocarbon mixtures were performed
in less than 10 s, without compromising the efficiency, which was an impressive feat
at that time.
Nonetheless, although the device was industrialized several years later, the techno-
logical jump remained isolated, because, during these years, the separation-science
community was not ready to adopt silicon technology [29]. It was only after 1990 that
the advantages of miniaturization were thrust into the spotlight, for its application to
electrokinetic liquid chromatography [30–32].
A seminal paper appeared in 1990 [30]. By reasoning on scaling laws, A. Manz et
al. argued that miniaturization enables the creation of performing separation systems,
combining portability, low cost, and high speed, without compromising the efficiency.11
We will describe these systems in Chapter 6. The paper introduced a new acronym,

11 The conclusion of the paper was: ‘A basic theory of hydrodynamics and diffusion indicates faster
and more efficient chromatographic separations, faster electrophoretic separations and shorter trans-
port times for a miniaturized TAS. The consumption of carrier, reagent or mobile phase is dramat-
ically smaller. A multi-channel device would allow the simultaneous performance of a large number
of measurements (under the same conditions).’
 The birth of microfluidics 11

1.12: First electrokinetic separation mi-

crosystem (1992). Overall dlmensions are
14.8 cm x 3.9 cm x 1 cm. (Reprinted rom
Ref. [31], with permission of Americal Chem-
ical Society. Copyright 2022.)

µTAS, which stood for Micro Total Analysis System. The term looks awkward. What
does it mean? A ‘Total Analysis System’ (TAS) refers to a system in which analyti-
cal instruments are transported on a cart, to perform the total analysis of a sample
(sampling, sample transport, chemical reactions, detection) in the field. Thanks to
miniaturization, no cart was needed, and the equivalent system was called µTAS. The
ideas were substantiated two years later, with the realization of the first electrokinetic
separation microsystem [30].12 This demonstrated performances in line with expecta-
tions, i.e. high speed of separation, and excellent efficiency, transportability, and low
cost. Microfluidics was born.

Later, all sorts of microfluidic systems were fabricated : electrophoretic separation as-
says [33, 34], electro-osmotic pumps [35], diffusive separation systems [36], micromix-
ers [37–42], DNA amplification systems [43–49], cytometers [50, 51], DNA separation
assays [98–102], centrifugal microfluidics (see review [103]) and chemical microreac-
tors [52–56], to cite a few examples. A number of these inventions were to play an
important role, a decade later, in the ramping up of the microfluidic market.

1.13: Cover of the pro-

ceedings of the first µTAS
conference organized by
A. van den Berg and
P. Bergveld in 1994, in
Enschede (the Nether-
lands). (Reproduced
with permission from the
Chemical and Biological
Microsystems Society
(CBMS), copyright 2022
CBMS.)

Up to 1994, the young microfluidic community gathered in different meetings, in par-

ticular in MEMS conferences (launched six years before, in 1988), in which one or
two sessions were devoted to microfluidics. The situation was not optimal. Controlling

12 In fact, the device was manufactured in 1988.

12 Introduction

fluid flows in microdevices required discussion of subtle hydrodynamic and physico-

chemical phenomena, and these were far from the focus of these meetings. Therefore, a
desire to organize specialized seminars emerged, in order to focus on these phenomena,
and, in the meantime, take the specific technological context into account, most often
overlooked in traditional academic meetings. The first µTAS conference was organized
by A. van den Berg and P. Bergveld in 1994, in Enschede (the Netherlands). The cover
of the proceedings is shown in Fig. 1.13. A total of 160 participants attended. Today,
µTAS conferences bring together 1,500 participants.13

In these early days, a ‘paradigm’, i.e. a set of concepts and practices that define a sci-
entific discipline at any particular period of time’, or, more simply, ‘what the members
of a scientific community, and they alone, share’ [57], emerged. It was thought that the
objective of microfluidics was to create basic microfluidic functions, or ‘bricks’, and
assemble them, in a way similar to microelectronics, so as to generate complex func-
tionalities, that could respond to unmet needs in biology and chemistry. The notion of
lab-on-a-chip was frequently put forward, and stunning cartoons designed to illustrate
the concept, such as those of Fig. 1.1414 , appeared in many broad-readership (for in-
stance Ref. [58]), augmenting the visibility of the field. But why did the community
not fabricate complex microfluidic systems, comparable to microelectronic processors,
as they envisioned? One bottleneck was valve integration. It appeared impossible, at
that time, with silicon, plastics or glass, to integrate more than a few valves on a
device. There was no chance to compete with the millions of transistors integrated, at
that time, on central processing units (CPUs).

In the same period, hydrodynamic experiments revealed unexpected phenomena; for

instance, large slippages, which apparently contradicted the no-slip dogma of hydro-
dynamics [59, 60]. In the meantime, microfluidic technology revealed the mechanical
behavior of single DNA molecules. The experiment was performed by Chu et al. [61]
in 1993, in cross-flow microchannels. This work laid down the foundations of a new
domain: the study of single molecules. It also showed that microfluidics could provide
new tools for investigating fundamental questions. Around that time, a number of
fundamental contributions allowed the physical role of the confinement to be clarified.
This concerned, for instance, electrohydrodynamics, electrowetting, chaotic mixing,
polymer dynamics, gas flows, or fluid interfaces. The list is long and we will return to
these subjects later. Molecular dynamics simulations, on the other hand, enlightened

13 The second meeting, µTAS 96, was held in Basel with 275 participants. The first two meetings were
held as informal workshops. By the time of the third workshop, µTAS 1998 (420 participants), held
in Banff, the workshop had become a worldwide conference. The number of participants continued
to increase in µTAS 2000 (about 500 participants) held in Enschede and µTAS 2001 (about 700
participants) held in Monterey. The number of submitted papers also dramatically increased in this
period from 130 in 1998, to 230 in 2000, to nearly 400 in 2001. From 2001, µTAS became an annual
symposium (text of presentation of µTAS 2002, held in Nara (Japan), and written by Yoshinobu
Baba and Shuichi Shoji).
14 Fig. 1.14(A) is stunning, but it is misleading in the sense that, in practice, the functionalities
shown on the figure are much more difficult to integrate than suggested. Perhaps inspired by this
unrealistic illustration, or understanding the analogy between microelectronics and microfluidics in a
too literal sense, several companies wasted much time and energy developing complex lab-on-a-chip
that had no chance of working
 The birth of microfluidics 13

Fig. 1.14: (A) Cartoon published in 1998 [58], showing an imaginary microfluidic device in-
tegrating several functionalities: electrophoretic separation, heating, driving, mixing, extrac-
tion, and polymerase chain reaction (PCR) amplification. (B) Image elaborated by Caliper,
around 2000, that illustrates well the lab-on-a-chip concept.

a number of phenomena, sometimes in conflict with the experiment. This concerned,

for instance, slippage, nanobubble dynamics, or electrowetting. Again, we will return
to these subjects later.

By the turn of the twenty-first century, many microfluidic devices were created in the
labs, some patented (one hundred or so) awaiting commercial developments, many
not. Before 2000, the global microfluidic market was a nano-market, worth less than
US$100 M.15 A number of microfluidic products, although elegant, did not meet any
market. This was the case of the microfluidic fountain pen [62]. Others did not function
with sufficient reliability: this was the case of the glucose watch, dedicated to monitor
glucose by sampling interstitial fluids. It will take years before this product finds its
place in the market [63]. Other inventions met considerable success: one developed
by i-Stat (created in 1983), of extremely simple construction, dedicated to glucose
measurements. In the 1990s, i-Stat company shipped several million cartridges every
year to hospitals. Two commercial products, whose production volumes were not as
important, but which promised an interesting future, must be mentioned: the Bioana-
lyzer, dedicated to DNA separation, made by Caliper Agilent, and the SmartCycler R
System, a Point of Care (POC) molecular system, developed by Cepheid (founded
in 1996). The two systems marked the entry of microfluidics in molecular biology.
Cepheid would become, years later, a major player in this field. In the meantime,
several microfluidic foundries, such as Micronit (founded in 1999), or ChipChop, and
later on, Dolomite (2005) for microfabrication, and Fluigent (2006) and Elvesys (2011)
for instrumentation, were created. They played an important role in the development
of microfluidics.

15 Although inkjet printing is a microfluidic system, by convention, it is not counted as part of this
market.
14 Introduction

Who first used the word microfluidics ?

Before 1993, the word microfluidics’ was essentially absent from the vocabulary of
the microsystem community It did not appear anywhere in the 857 pages of the
Microsystem technology 90 Proceedings [67], an important conference of the young
MEMS community. Instead, the words ‘micro liquid-handling’, ‘micro-hydraulics’,
‘micro fluid’, with or without hyphen, or micro-liquid flows’ were preferred [68]. ‘Mi-
crofluidics’ was also absent from Terry’s [28], and Manz’s [30,31] papers, published in
1979, 1990, and 1992. Why was this the case ? We may hypothesize that researchers
of that time, involved in what we now call ‘microfluidics’, were reluctant to use a word
that looked esoteric. The situation seemed to change in 1993, after the publication,
by P.Gravesen, of a survey titled ‘Microfluidics: A Review’ [65]. The paper acquired a
significant visibility. Although no etymologic study has been done, and probably will
never be done, one may hypothesize that the review strongly contributed to, if not
initiated, the spread of the word. Later on, although invisible in the MicroTas94 Pro-
ceedings, the word ‘microfluidics’ increasingly appeared in the literature. The word
was suitable since it represented, as pointed out by R. Zengerle [66], a ‘headline’ cov-
ering all types of actions involving fluids, and performed in microsystems. After 1997,
it frequently appeared and eventually acquired a prominent place in the language.
Finally, the community working on fluid manipulations at the microscale adopted it
to give a name to their field.

1.5 The advent of soft technology

An important step was taken in 1998, with the development, by G. Whitesides, of

soft technology [69–71].16 With soft technology, devices were no longer made in glass
or silicon, but in soft materials. From a technological perspective, this represented a
considerable shift. Two images, extracted from [69] and [70], are shown in Fig.1.15.

Fig. 1.15: (A) Scanning electron micrographs of a PDMS honeycomb structure, created by
molding the polymer against a photoresist mould (Reprinted from Ref. [69] with permission
from Wiley and Sons, copyright 2022 Wiley and Sons). (B) Double-T section of the network of
channels. The roughness in the side walls of the PDMS channels arises from the limited mask
resolution (Reprinted with permission from Ref. [70], copyright 2022 American Chemical
Society.).

16 Whitesides’ papers were preceded, in 1997, by two pioneering works [72, 73].
 The advent of soft technology 15

Figure 1.15(A) is taken from Ref. [69]. The paper explained the concept of soft technol-
ogy, and its two main facets, microprinting and micromoulding, which we will discuss
in Chapter 7.
Figure 1.15(B) shows microchannels made in PolyDiMethylSiloxane (PDMS) [70]. We
will hear much about PDMS in the book. It is almost a miraculous material. It has
properties that no other material possesses: deformable, transparent in the visible
range, insulating, hydrophobic, sticking to glass in a reversible manner. We will see, in
Chapter 7, that all of these properties make soft lithography possible. In Fig. 1.15(B),
the aqueous sample is introduced in the double T, then driven by electroosmotic
forces into a long microchannel (not shown), along which electrokinetic separation is
performed, in a manner similar to Manz’s work [31]. The walls are rough, due to the low
mask resolution. The authors achieved ionic separation in the system, with a resolution
and a speed comparable to silicon devices. The paper thus suggested, that, even though
surface chemistry is not as controlled as in glass or silicon, electrokinetic separation,
the major application of microfluidics at that time, is feasible. For chromatographic
experts, this was quite a surprise.
Nonetheless, the message received by many researchers was not about separation. It
was that PDMS microdevices were easy to create.17 Once the mould was fabricated,
the rest of the technological process could be made outside a clean room, without
specialized skills. A master student could learn it in one day. The simplification of the
technological process gave rise to a surge of activity. Many laboratories, interested in
microfluidics, but with limited access to clean rooms, came to the field and started
investigating new directions. One could compare this period to the transition from
centralized informatics to laptop computing.
Why did all the community not rush out to use soft technology, abandoning silicon?
Two reasons can be provided: the first is that PDMS surfaces are not stable, meaning
that performing accurate separations with such a material was impossible. For the
community of that time, composed, mostly, of analytical chemists, this represented a
serious limitation. Secondly, PDMS devices cannot be produced in large quantities.
Scaling up is not possible, while with silicon it is. These two arguments led most of
the microfluidic community of that time to keep working with silicon and glass. The
arguments were not unreasonable. Today, half of the hundreds of millions of devices
produced in the microfluidic market are made with glass and silicon.
Most researchers using soft technology were thus newcomers. In the same period, press-
ing needs appeared: examples are DNA sequencing, cell sorting, molecule screening,
single cell analysis, and proteomics. As mentioned earlier for the particular case of
DNA sequencing, all these applications conveyed big numbers: five billion cells to sort
for isolating 1-10 circular tumor cells (CTC) [76], hundred of thousands of compounds
for drug discovery [80], millions of fluid manipulations for performing gene sequenc-
ing [75]. How so many experiments could be carried out rapidly and in parallel, while
consuming little reagent [74]? This was the new challenge faced by microfluidics. The
17 The discovery of SU8, by IBM, in the 1990s, allowed thick moulds to be made in one photolitho-
graphic step, facilitating the fabrication of PDMS devices.
16 Introduction

challenge was not only intellectual. Today, the aforementioned domains represent the
largest share of the microfluidic market.18
In this context, a surge of innovations emerged. One landmark was the demonstration,
in 2002, that, by exploiting the deformability of PDMS [77], thousands of valves could
be integrated on the same device [78]. This is shown in Fig. 1.16. The valve problem,
raised in the previous decade, seemed to be solved. The technology gave birth to a
company, Fluidigm, whose valuation would soon reach US$1bn. With Cepheid and
Fluidigm, two microfluidic unicorns were born in the years 2000-2010.19

1.16: The device, whose channels are visu-

alized with dyes, contains 2056 microvalves.
The system performs distinct assays in 256
nl subreaction chambers. Each of them is
individually addressed, using a multiplexed
valve system,. With it, only 20 valves are
needed to control the assay. (Reprinted
from [78], with permission from the Ameri-
can Association for the Advancement of Sci-
ence. Copyright 2022.)

The device shown in Fig. 1.16 contains 2,056 microvalves. Each of the 256 chambers
on the chip is individually addressed. A multiplexer allows for reducing the number of
connections, from N (N being the number of chambers) to 2 log2 N [78]. It is impossible
to realize such a system with glass or silicon. For microfluidics, a new period opened.

1.6 Diversification of the technology and broadening of the

applications
In the years 2000-08, thanks to soft lithography, the microfluidic community had an
easier access to technology. The number of applications, including those involving large
numbers, increased, and growing public support raised momentum in universities. In
such conditions, the microfluidic community grew substantially, reaching thousands
of researchers worldwide. The stimulating atmosphere of that time was perceptible in
the µTAS conferences.
Droplet-based microfluidics appeared in the period 2000-2002. We will present the
technology in Chapter 4. At first glance, producing microdroplets under control did not
appear new. For instance, ink-jet printers and fluorescent active sorters (FACS) already
18 Before the advent of the COVID-19 pandemic.
19 At about the same time, Theranos, which promised to perform a hundred different tests with a
single drop of blood, reached much higher valuations. Ten years later, the company collapsed. Because
of the absence of peer-reviewed publications issued by the company, links between the microfluidic
community and this company were inexistent.
 Diversification of the technology and broadening of the applications 17

performed the task. The new idea was that, by playing with the device, droplets could
be filled with reagents, and thus operate as microreactors, being moreover well mixed,
thanks to vigorous recirculations developing inside them, as we will see in Chapter 4.
Millions of chemical reactions per hour could be run, using minute amounts of reagents
(less than one nanolitre or so per droplet). These performances allowed researchers to
work with large numbers, responding to the needs appearing at the turn of the century,
as mentioned earlier.

1.17: Two reagents A and B are

introduced in a T junction, in
a flux of oil, and form droplets.
By varying the flow rates, each
droplet can acquire different reagent
concentrations. This system allows
high throughput screening (kHz) of
biochemical reactions, using min-
imal quantities (nl) of reagents.
(Reprinted from Ref. [79], with per-
mission of John Wiley and Sons,
copyright 2022.)

Fig. 1.17, published in 2003 [79], illustrates well the situation. In short (this will be
explained in more detail in Chapter 4), the entry was composed of three channels: one
for reagent A, another for reagent B, and, in between a buffer. By varying flow rates,
the amount of reagent could be varied in each droplet. Then it was possible to screen
a chemical reaction, as a function of the phase ratio. With droplets being emitted
at kHz, the screening was orders of magnitude faster than could be achieved by any
robot.
In about the same period, it was demonstrated that more complex droplets, in the form
of double or multiple emulsions, could also be produced under control. This topics was
developed by D.Weitz (Harvard). This was an important step, because it established
the link between microfluidics and colloidal and material sciences.
Fig. 1.18 is extracted from a paper published in 2005 [84]. The device consists of three
glass tubes, one with a square, the others with circular cross sections, placed inside
each other. Along the tubes three liquids, immiscible or immiscible by pairs, are driven,
forming droplets inside droplets, i.e. double emulsions. The structures of the emulsions
depend on the flow rates, the nature of the phases and the formulation. The device
stood against the technological wind of the time: neither soft nor hard technology were
used.20 The work opened a route towards creating objects difficult or impossible to
make. Implications in various domains such as cosmetics, oil or food industries were
numerous.

20 Double emulsions have indeed also been created in microchannels, made with soft or hard tech-
nologies (see, for instance, [86]). The advantage of glass tube technique is its capacity to obtain well
defined hydrophilic and hydrophobic regions. Disadvantages are size limitations (double emulsions
below 30 µ are difficult to make), delicateness of the geometrical adjustment of the tube noses, and
limited parallelisation.
18 Introduction

Fig. 1.18: Microcapillary geometry for generating double emulsions from coaxial jets [84].
(A) Schematic of the coaxial microcapillary fluidic device. The geometry requires the outer
fluid to be immiscible with the middle fluid and the middle fluid to be in turn immiscible
with the inner fluid. (B to E) Double emulsions containing only one internal droplet. (F
and G) Double emulsions containing many internal drops with different size and number
distributions. (H) Double emulsion drops, each containing a single internal droplet, flowing
in the collection tube. The devices used to generate these double emulsions had different
geometries. (Reprinted from Ref [84], with permission of the American Association for the
Advancement of Science, copyright 2022).

Still in the same period, i.e. around the years 2000, digital microfluidics appeared
[87, 88]. The technology exploited a technique, called electroWetting on dielectrics
(EWOD), developed first by Berge [89]. EWOD consists of placing a conducting droplet
(such as salted water), polarized at some tension, over a thin hydrophobic insulating
layer, deposited on a metallic electrode. The electrical tension changes the apparent
contact angle. With this, the solid surface can switch, in a fast time (sub-millisecond)
from hydrophobic to hydrophilic state. Digital microfluidics exploits this functional-
ity, by displacing droplets over a surface patterned with addressable electrodes. In
the period 2000-10, several groups [88, 90–95] demonstrated impressive realizations:
rotating droplets, droplets moving on substrates in a complicated manner, interact-
ing together, mixing reagents, initiating chemical reactions and cutting droplets. The
technology substantiated well the concept of ‘lab-on-a-chip’. Some papers, written by
2010, promised the advent of another revolution [96].
Let us pause for a moment to consider the genome sequencing and its link to mi-
crofluidics. Sequencing illustrates two notions: big numbers and complexity without
valves. In the years 1990-2005, the human genome programme, in full development,
was exclusively based on Sanger sequencing [97]. Massive use was made of restriction
enzymes, which fragment the genome into small single-stranded pieces. This is where
big numbers came into play. Typically, ten fractionations per kilobase were needed
to determine primary sequences [104]. For the human genome, this represented no
fewer than ten million separations -a huge number-. The community thus invented
new separation technologies that were faster, more integrated, more automatized [58],
 Diversification of the technology and broadening of the applications 19

and more parallelized [98]. Impressive achievements were made. However, the sequenc-
ing community did not use this work. The most popular sequencer, ABI Prism 3700,
which, historically, sequenced the human genome, used a 96 parallel capillary configu-
ration [104]. There was not a single microfluidic chip in the machine. The penetration of
microfluidics came later, with the advent of Next Generation Sequencing (NGS). The
first NGS machine, the GS20, appeared in 2005 [104], and it could decipher 20 million
bases in 5.5 hours. The success of GS20 was due, in part, to the use of large microflu-
idic assays. Years later, methods, such as nanopore sequencing (Oxfore Nanopore) or
sequencing by synthesis (Illumina) also made full use of micro/nanofluidic technology.
This technology has clearly become core to genome sequencing.

These accomplishments demonstrated that a microfluidic device can perform millions

of different tasks without using a single valve. How to do that? By relying on molec-
ular actuators: enzymes (polymerases, recombinase, reverse transcriptase, helicase,
etc.), molecular motors, selective affinities (such as antibodies), and self assembly
processes (which spontaneously pattern molecular assemblies). In NGS microfluidic
devices, these processes, working synergistically, allowed extremely complex function-
alities to be developed. The same ideas will be used, later, in other fields of application,
such as the single cell.

Paper microfluidics came later, in the years 2005-07 [106]. The idea was to replace
standard microfluidic substrates (glass, silicon, plastics, or PDMS) with paper, much
cheaper (its cost is a few hundredths of a cent per sheet), and easier to source. Be-
ing burnable, it reduces the risk of contamination. This material is thus particularly
suitable for diagnostic applications in developing countries. Paper had been used for
decades for diagnostics, but the novelty brought by G. Whitesides’ group was paper
patterning [107]. Paper microfluidics appeared as a new branch of microfluidics, hold-
ing potential in several areas, while using a cheaper and more available substrate. We
will consider this further in Chapters 4 and 7.

1.19: Multiplexed analysis of a

model sample of urine (glucose so-
lution) [108]. The white is the pa-
per, the grey is the wax, defin-
ing channels. Two colorimetric de-
tections are performed in duplicate.
(Reprinted from Ref. [108], with
permission from American Chemical
Society, copyright 2022)

Later, in the period 2008-21, many inventions and discoveries were made. Thousands of
studies were published every year (today, about 5000). Obviously, reviewing them lies
beyond the scope of the book. We may nonetheless mention the appearance of new
technologies (3D printing, continuous flow lithography, Northland optical adhesive
20 Introduction

technology (NOA), hydrogel caging, etc.), raising the microfluidic tool box to a level
where a considerable number of microfabrication problems can be solved.
Special mention should be made to 3D printing, which has already impacted the way
in which microfluidic devices are built. This will be discussed in Chapter 7, but an
example is shown in Fig. 1.20.

1.20: An example of 3D microprinting.

Courtesy of Microlight3D, printed with
SmartPrint UV [109].

Another technology worth mentioning is organ on a chip (OOC). OOC creates systems
that mimick organs, in the hope of performing drug studies on representative models.
It has the potential to impact the pharmaceutical industry, by refining analysis, pro-
ducing large amounts of pertinent data, speeding up trials, accelerating early phases
of regulation processes, and, importantly, suppressing the use of animals. OOC was
the missing link between in vitro and in vivo drug trials. An early example of OOC,
mimicking lungs, is shown in Fig. 1.21, and was reported in 2010 [111].

(b)
Air Capillaries

Endothelium Membrane

Pip
Side chambers Diaphragm

Fig. 1.21: (A) Microfluidic model of a lung [111].(B) Real lung

In Fig. 1.21(A), a membrane, coated with epithelial cells, separates two microchannels:
one is for air circulation and the other filled with a liquid. This structure attempts
to mimick the real lung, shown in Fig. 1.21 (B). The gap is large, but the hope is
that, over the years, it will progressively shrink, reaching levels where drug testing
on animals becomes less representative than OOCs. Other OOCs, realized in the last
decade are intestines, kidneys, hearts, and vascularization networks [110].
 MicroReaction Technology (MRT) 21

In the meantime, fundamental questions such as slippage were clarified, albeit not
solved. After fifteen years of discussion, the nanobubble mystery was resolved in 2015
[85]. Different manners of handling fluids were proposed, sometimes counter-intuitively
(such as working at moderately high Reynolds numbers to reorder particles conveyed
by a flow, giving rise to ‘inertial microfluidics’), and progress in the ability to create
complex functionalities has been made (such as handling cells in droplets, barcoding
and processing them). The examples given are far from exhaustive.
Looking back on thirty years of microfluidics, it appears that most of the founding
microfluidic discoveries have been made in a surprisingly short period of time: be-
tween, roughly, 1998 and 2005. One could thus call this period the ‘golden years’ of
microfluidics.

1.7 MicroReaction Technology (MRT)

Microreaction technology (MRT) is part of a general approach called process intensi-

fication. The idea is that, as will be seen in Chapter 2, miniaturization enhances heat
exchange and facilitates temperature control, which in turn increases the specificity
of the reaction, by avoiding the formation of unwanted chemical species [112]. MRT
focusses on the millimetric and submillimetric scales, where better flow control can
be achieved, thanks to the absence of turbulence. Let us recall that turbulence mixes,
but also creates uncontrolled flow heterogeneities: for instance random eddies in the
corners, or behind the blades of a mixer. These eddies induce, in turn, heterogeneities
in temperature, concentration, and, eventually, product characteristics. The key point
of MRT is to operate below turbulence onset to avoid these phenomena21 and, in the
meantime, achieve throughputs of industrial relevance.
The first conference of MRT, international conference on microreaction technology
(IMRET), took place in 1997, three years after µTAS 1994. Since then, IMRET has
met annually.
From a technological viewpoint, because of high temperatures, and often high pres-
sures, MRT uses hard materials, such as slilicon, glass, ceramics, or metal. High
throughput and resistance to clogging impose larger microchannels than in microflu-
idics, typically in the milimetre range. An example of a MRT device, dedicated to the
chemical synthesis of carbamates, is shown in Fig. 1.22 [113].
With MRT, all kinds of synthesis have been performed over the years, starting with
quantum dot synthesis, which is better controlled with MRT than traditional tech-
niques [114]. Other applications are combinatorial chemistry and high throughput
screening.

21 The turbulence onset strongly depends on the flow geometry and is characterized by a Reynolds
number (see Chapter 3). Because of hysteresis phenomena, turbulence thresholds are difficult to define.
In the microfluidic literature, values ranging between 1000 and 3000 are taken without discussion.
This range is appropriate for most of the geometries of practical interest, such as straight pipes or
channels but does not apply for other geometries, such as converging or diverging flows.
22 Introduction

1.22: Multi-step microfluidic chemical

synthesis of carbamates starting from
aqueous azide and organic acid chlo-
ride using the Curtius rearrangement
reaction. The scheme involves three re-
action steps and two separation steps.
Reprinted from Ref. [113], with permis-
sion of John Wiley and Sons, copyright
2022.

By working in small rather than large microreactors, efficiency is increased and plant
sizes can be reduced. Concerning the throughput, parallelization allows volumes of
industrial interest to be reached. In this approach, safety and reliability are improved.
The first attempts to substantiate these ideas were made in the years 2005-10. An
example is shown in Fig. 1.23. Today, the global MRT market is around US$1bn [116].

1.23: Is it possible to miniatur-

ize a plant ? An example of a mil-
lifluidic plant (Reprinted from
[115], with permission of Wiley
and Sons, copyright 2022).

1.8 Nanofluidics

As will be discussed in Chapter 3, nanofluidics22 concerns the 1-100 nm range. Similarly

to microfluidics, nanofluidics can be defined as the science of manipulation of fluids at
the nanoscale.
Interestingly, humans have manipulated fluids at that scale long before clean rooms
were used. For instance, the study of Newton black soap films, 4 nm thick, traces
back to 1877 [120]. Ultrafiltration membranes designed by engineers have pore sizes

22 The word ‘nanofluidics’ appeared, for the first time, in a review written by H. Craighead [117] in
2000
 Nanofluidics 23

below 10 nm. Equilibrium films, created by A. Sheludko [121] in the 1960s, for mea-
suring disjoining pressures, had nanometric thicknesses [121, 122]. A landmark in the
domain was the invention of the force machine [123], in which fluids were confined in
nanometric (open) chambers for studying liquid behavior at the nanometric scale (a
detailed description of the instrument will be given in Chapter 2). Other examples can
be found in the review by J. Eijkel and A. Van den Berg [126].

In the 1990s, it was possible, with e-beam or optical lithography, to create nanochan-
nels less than 100 nm high, or holes less than 100 nm in diameter. In this context, sev-
eral contributions were made,23 such as the realization of a silicon membrane with 50
nm pore sizes in 1990 [118] and a 88 nm nanofluidic field-effect transistor in 1992 [119].
Later, in 1999, a nanofluidic device, built with the intent to develop a chromato-
graphic functionality, based on an original principle, was published by H. Craighead
et al [127].24 It is shown in Fig. 1.24.

Fig. 1.24: (A) Cell used in Ref. [127] (Reprinted from the preceding reference, with permission
of American Physical Society, courtesy of H. Craighead, copyright 2022.) (B) Numerically
designed single-walled nanotube 1.34 nm long with a diameter of 0.81 nm , solvated in a
water reservoir and simulated for 66 ns. Despite its strongly hydrophobic character, the
initially empty central channel of the nanotube is rapidly filled by water from the surrounding
reservoir, and remains occupied by about five water molecules during the entire simulation,
as shown in the figure [129].

The system was composed of a series of channels of different depths. Large’ channels
were 1 µm deep, and shallow ones had a depth of 90 nm, i.e. smaller than the gyration
radius of λ phage DNAs used in the experiments. Under the action of an applied
electric field, DNA strands periodically escape the chambers to migrate through the
shallow channels. In this process, they stretch out. Arguments based on entropy show
that the probability of escape is an exponential function of the DNA length. This was
the efficient size separation mechanism that the authors were seeking. It turned out
that the amplitude of the effect was much smaller than expected, for reasons explained

23 I am indebted to Jan Eijkel for bringing to my attention a number of contributions, along with
sharing his vision on the history of nanofluidics, consistent with that exposed here.
24 In the description we give, one may mention two studies, in which nanofluidic transport phenom-
ena were studied: DNA separation in a nanopillar array in 1998 [124], and mixing in a flow focusing
geometry in the same year [125]. These studies did not create nanochannels. They used microfluidic
systems to reach, through subtle physical mechanisms, the range of nanoscales
24 Introduction

by them.25 Later, in 2000, the system was modified and efficient DNA separation could
be demonstrated [128].
In about the same period (2001), Hummer et al. [129] simulated a single-walled carbon
nanotube (CNT), 1.34 nm long, 0.81 nm in internal diameter which was solvated in a
water reservoir and tracked for 66 ns. Despite its strongly hydrophobic character, the
nanotube was rapidly filled by water.26 We learned that water molecules circulated in
the CNT in single file, developing pulses with peaks of about 30 water molecules per
nanosecond.27 Soon after, CNTs were shown (numerically), to develop large slippages.
[132] The effect was directly measured twelve years later [134]. The phenomenon is
still not understood today.
The two studies, combined with other experimental [118, 119] (already mentioned)
and numerical [133,135,136] contributions, prompted the development of nanofluidics.
Soon after, nanofluidics swiftly expanded. An extremely short list of examples, far
from exhaustive, includes the observation of polarization concentration induced by
the overlapping of Debye layers [137], the invention of nanofluidic diodes and bipolar
transistors [138], DNA separation through arrays of nanopillars [139], and negative
capillary pressure studies [143]. Fundamental studies dedicated to slippage were also
performed, using surface force apparatus (SFA), nano or micro particle image ve-
locimetry (µ PIV), coupled or not to total internal reflection fluorescence (TIRF) or
pressure measurements in nanochannels and, more recently measurements through
single CNTs [134]. Of particular note is membranes made with aligned CNTs, realized
in 2004 [140] (see Fig. 1.25). By offering large permeabilities [141, 142]28 and high se-
lectivities, due to the extremely small pore sizes, they opened a new area in the field
of membrane technology.

(a) (b)

50 µm

Fig. 1.25: (A) A sketch of a CNT-based membrane structure. A polymer (PS) is embedded
between the CNTs; the pore size is their inner-tube diameter [141,142]. (B) Scanning electron
microscope (SEM) image of a vertically aligned array of CNTs produced using a Fe-catalysed
chemical vapor deposition (CVD) process [141]

25 The reason was [127]: ‘Bigger molecules escape faster simply because more monomers are facing
the thin slit, and are able to form a beachhead for escape’. This effect still led to a dependence of the
DNA mobility on the chain length, but it was much less strong.
26 The phenomenon was analyzed in [130]. It is attributed to liquid structuring effects, which reverses
the effective wettability of the tube.
27 Years later, other ’subcontinuum’ flow regimes will be discovered [131].
28 The permeability for the smallest CNTs (1 nm in inner diameter), is four orders of magnitudes
larger than no-slip hydrodynamics predicts
 Nanofluidics 25

In the last few years, a new era came with the advent of novel 2D and 3D materials:
functionalized CNTs, graphene, boron nitride (h-BN) and molybdenum disulphide
(MoS2) [149–151].

New phenomena were observed in ultra-confined systems (i.e., typically, of sub-2 nm

sizes): large slippages (already mentioned), strong decrease of water dielectric permit-
tivity (dead water’), non linear transport along with unexpected large shifts in the
freezing transitions [152]. These phenomena may call for a quantum description [149].
If confirmed, this would represent a major conceptual breakthrough. More strongly
than in the past, progress made in the domain showed that nanofluidics is not a mere
extension of microfluidics, but a distinct field, built on original physical effects and
using specific materials and techniques of investigation. The period also inspired new
applications, including energy harvesting, high flux membranes, water desalinization,
and nanoscale flow sensors.

Performing nanofluidic experiments is challenging, because several forces of various

origins, such as electrostatic, van der Waals, entropic or hydrophobic, coupled to the
effect of the confinement, come into play together and are uneasy to disentangle [148].
Therefore, when an unexpected phenomenon shows up, it is often difficult to determine
its origin. This may explain, for example, why it took fifteen years to understand the
origin of nanobubble stability (see Chapter 5). In addition, observation needs sophis-
ticated equipment and the dynamics, often in the nanosecond range, is challenging to
track. In this context, it was difficult to envisage the industrialization of a nanofluidic
product. This was nonetheless done by Pacific Bio, with zeroth mode cavities, and
Oxford Nanopore, with arrrays of nanoholes, both dedicated to sequencing DNA at
high speeds and large throughputs (see Fig. 1.26.).

Fig. 1.26: Oxford Nanopore technology. The purified sample is introduced in a chamber con-
taining arrays of nanopores. DNA strands, mobilized by an electric field, cross the arrays and
deliver molecular information on the sequence that they contain. The error rate is larger than
that of Illumina, but the compacity of Oxford Nanopore product is remarkable. (Courtesy of
Oxford Nanopore.)

The Oxford Nanopore system, shown in Fig. 1.26, includes a plate, pierced with
nanoholes, across which an electric field is applied. With the help of enzymes, single-
strand DNA (ssDNA) pass through the hole and each nucleotide is read, thanks to its
26 Introduction

electrical signature.

This section mentions a small fraction of the important work done, in nanofluidics,
since its birth, i.e. by the turn of the century. The reader may refer to reviews [126,144–
149] for detailed information. It should be noted that nanofluidics is part of a broader
world which includes, for example drug delivery, colloid science, membrane technology,
and nanochemistry. These domains, connected to nanofluidics provide opportunities
for developing fruitful synergies.

1.9 The microfluidic market

1.9.1 How to estimate the microfluidic market ?

The delicate task of defining microfluidic products. The microfluidic market inte-
grates microfluidic devices (raw chips), microfluidic products (cartridges with reagents
and packagings), and microfluidic instruments. Analysts often distinguish between two
segments: instruments and products. We will focus on the second one, which is by far
the most important.

How declare that a product pertains or not to the microfluidic market? Let us take the
example of dried blood spots (DBS), which store newborn blood samples. Collection is
achieved by imbibition and storage by drying. From a physical perspective, imbibition
can be viewed as a microfluidic process, because it drives flows, in a controlled man-
ner, through submillimetric pores. Lateral flow tests, such as pregnancy tests, urine
dipsticks, and glucose monitoring sensors [162], whose markets are several tens of bil-
lions of $, are in a similar situation. Should they be considered microfluidic products?
The answer is no. Analysts require a minimal level of technological functionalities, in
particular regarding fluid management, in order to decide whether a product pertains
or not to the microfluidic market. There is a blurred zone around this requirement,
which explains why market estimates may vary from one agency to another. Still, the
figures are, within 30%, consistent. Fig. 1.27 illustrates the discussion, for the case of
the diagnostic market. The figure is adapted from a recent report published by Yole
Development.

The diagnostic market gathers in vitro systems enabling the detection of contagious
diseases. It includes two types of products: molecular and immunoassay. Each category
is in turn divided into centralized (high throughput) and decentralized (point of care
(POC) systems). The centralized segment includes large systems, plates, tubes, cen-
trifuge equipment, etc. The machines manipulate µlitre volumes and they use standard
assays, which do not incorporate any microfluidic component. It is logical to exclude
them from the microfluidic market. By contrast, Cepheid products manipulate fluids
in microfluidic devices. The cartridges thereby pertain to the microfluidic market. Im-
munassays are excluded, for the reasons discussed above. All this leads to Fig. 1.27,
in which selected products are enclosed in oblong boxes.
 The microfluidic market 27

Fig. 1.27: Products of the diagnostic industry, declared belonging (inside oblongs) or not
belonging (outside the oblongs) in the microfluidic market. (Adapted from a recent report
from Yole Development.)

The case of inkjet printing. Ink-jet printers, for paper, are truly microfluidic systems:
droplets emitted by printers are typically 50 µm in diameter. Fig. 1.28 shows the
dynamics leading to the formation of droplets, on their way making contact with the
paper sheet. Paper inkjets exploit MEMS technology, in both versions (bubble or piezo-
injectors [154]) and manipulate microjets with high precision, producing monodisperse
droplets, under high throughput conditions. In fact, ink-jet printers represents one the
most remarkable achievement of microfluidics. An example is shown in Fig. 1.28.
According to several agencies (Mordor Intelligence, Future Market Insight) (FMI),
the overall 2021 market of ink-jet printers is on the order of US$50bn. This is more
than twice the rest of the microfluidic market, as will be seen below. Although it
could be legitimate to add them up for establishing a ‘total’ microfluidic market, it
is conventional to treat the ink-jet printing market separetly. The microfluidic market
that we present here therefore excludes ink-jet printers.

1.9.2 Today’s market

As mentioned above, before 2000, the microfluidic market (i.e. without ink-jet print-
ing) was insignificant and scepticism was floating around concerning the potential of
the technology to find its feet in a market, even though it was regularly announced,
here and there, that microfluidics would revolutionarize the twenty-first century [158].
Common sense led to the belief, in fact wrong, that driving flows through tiny channels,
at the industrial scale, without leaks, clogging, bubbles, nor uncontrolled adsorption,
was impossible. The opposite viewpoint - believing that it is straightforward to create
28 Introduction

(a) (b)
Piezo
tranducer

Nozzle

Droplets

Fig. 1.28: (A) Piezo acoustic inkjet printer of Ref. [156]; (B) Time series of jetted ink droplets,
stroboscopically recorded with single-flash photography. (Left to right) Multiple images of
single droplets with a delay of 3 µs between the individual droplets. Here the opening radius
of the nozzle is 15 µm and the diameter of the droplet 23 µm, which corresponds to a droplet
volume of 11 pL. The final velocity of the droplet is 4 m/s. The figure illustrates the imaging
quality and the absence of motion blur due to the use of the 8-ns iLIF (illumination by
laser-induced fluorescence) technique [155–157].
,

a complex, functional, microfluidic device - was unrealistic. To add to uncertainties,

the remark, occasionally made by prominent researchers, that microfluidic devices are
small, but, with the tubings and the pumps needed to operate the system, they more
often resemble a ‘chip in the lab’ rather than a ‘lab on a chip’, casted doubts about
the possibility of creating microfluidic devices of industrial relevance.
Despite all this, a number of successful microfluidic products emerged. Technical dif-
ficulties could be solved, circumvented, or just found irrelevant. Impressive industrial
challenges, previously considered out of reach, could be met, such as driving ssDNA
through nanoholes and collect genomic information from it. Finally, over the last two
decades, the microfluidic market steadily increased at a two-digit rate. Today, hun-
dreds of millions of devices are sold every year. For example, 400 million Illumina
microfluidic flow cells are shipped every year.
Let us analyse three examples, which, today, generate revenues between US$200mn–US$3bn
(see Fig. 1.29).
Quidel Triage In Fig. 1.29, the device is a microfluidic adaptation of the Elisa
test: the blood sample, in which targeted antigens are fluorescently labelled, is
driven, by capillarity, in a straight microchannel, with antibodies immobilized on
the walls. As in Elisa tests, antigens are captured by the antibodies, and, after
rinsing, fluorescence emission is analysed. With this test, levels of troponin, whose
elevation indicates heart muscle damage, can be measured, with a few nanograms
per litre sensitivity. This is a major application. Sales are on the order of US$200
mn.
Ilumina New Generation Sequencing (NGS) technology, developed by Illumina, is
based, as all NGS methods, on microfluidic technology. The cartridge contains
a patterned cell, with wells, called a flow cell, fabricated over a Complementary
 The microfluidic market 29

Fig. 1.29: Three examples of types of products, based on microfluidics, generating, in 2020,
turn overs in the range US$200mn–US$3bn: (A) Triage for cardiac control (Quidel); (B) DNA
sequencer (illumina HiSeq 2500); (C) Kindle (e-ink technology)
,

metal–oxide–semiconductor (CMOS) chip. In the cell, each well faces a photodi-

ode. In a nutshell, sequencing is performed by hybridizing sampled ssDNA on an-
chored probes, and monitoring, in real time, the light emitted during the process.
Microfluidics plays an instrumental role in this domain. Without microfluidics, no
NGS based sequencing could exist.29 Illumina revenues generated by the prod-
uct reached US$3.2bn in 2020. As noted above, the company ships 400 million
flow-cells each year.

e-ink The Pocketbook Inkpad Lite is based on microfluidic droplets (the technology
will be described in Chapter 4). Its price ranges between $200 -$300. The display
technology, commercialized by E-ink, generated US$530mn in 2021.

Who are the microfluidic players? Fig. 1.30 organizes them in three groups, each
corresponding to a range of revenues (the figure is adapted from Yole-Development).

Market estimates are given by several agencies: Yole Development, Market and Mar-
kets, Grand View Research, uFluidics, Research & Market, and BCC Research. On
average, the microfluidic market is estimated around 17 US$bn with a compound an-
nual growth rate (CAGR) around 15 - 20%. Should 20% be accurate, the market would
reach 100 B$ in 2030. A plot showing the evolution of the market over the years, again
made by Yole Development, is shown in Fig. 1.31.

Fig. 1.31 moreover provides information on the market segments. In decreasing order
(in terms of volume), we have: point of care, tools for pharmateutical and research,
clinical diagnostics, industrial diagnostics, optical actuation (liquid lenses), and man-
ufacturing.

29 NGS, compared to traditional sequencing, based on Sanger’s method, allowed to reduce sequenc-
ing prices along with increase speeds by orders of magnitude (see Chapter 5)
30 Introduction

Fig. 1.30: Microfluidic players organized in three groups, each corresponding to a range of
revenues [153]. (Adapted from Yole Development.)

Fig. 1.31: Microfluidic market and its evolution (Courtesy of Yole Development) [153]

1.10 Future of microfluidics

1.10.1 Microfluidics and Pasteur and Bohr quadrants

In 1997, D.Stokes proposed the ‘quadrant model [163, 164] (see Fig. 1.32). This model
classifies research activity into four quadrants. Three of them are defined in the fol-
lowing manner:
Bohr quadrant -pure basic research : N. Bohr’s efforts were entirely dedicated to
 Future of microfluidics 31

answer fundamental questions of physics. In 1913, he explained the origin of the

spectral lines of hydrogen, by representing the atom as a nucleus orbited by an
electron [159]. The Bohr atom model, which contributed to laying the foundations
of quantum theory, was conceived under the sole momentum of intellectual cu-
riosity, in a manner disconnected from applications. One paradox is that quantum
physics led to the invention of the transistor, and further to computing science,
internet -all inventions that, without exaggeration, revolutionized the world-.

Edison quadrant -applied research : Edison was a prolific inventor, with more
than thousand patents. Examples are the phonograph and the motion picture
camera. The electrical bulb lamp was not invented by him, but he managed to
increase its lifetime considerably, by using carbon filaments. Edison’s approach
was empirical, with no serious attempt to understand the physics involved in his
inventions.

Pasteur quadrant -use-inspired basic research : Pasteur discovered microbiol-

ogy by working on diseases of beer and wine, not understood at that time. His
discovery of the vaccine for rabies, made in 1885, was stirred up by the bite of
a 9 year old child by a rabid dog. Other examples, found when studying his life,
illustrate the synergy between societal/industrial inspiration and fundamental
discoveries.

The unamed fourth quadrant represents research motivated neither by intellectual

curiosity nor by applications. It is difficult to comment on this quadrant.

Pure basic Use-inspired

research basic research
High
Quest for fundamental

BOHR QUADRANT PASTEUR QUADRANT

understanding?

Applied
research

Low

EDISON QUADRANT 1.32: The four sectors of research:

Low High Bohr, Pasteur, Edison, and unnamed
Consideration of use? [163].

Regarding microfluidics, Pasteur’s quadrant is certainly the most relevant: microflu-

idics offers responses to industrial and societal needs, and, in the meantime, allows us
to address basic questions. Since the early days of microfluidics, the community has
worked mostly in the Pasteur quadrant.

However, it pays frequent visits to the Bohr quadrant. Often, along the lines of Feyn-
man’s talk, discoveries emerged from the excitation of realizing something that has
never been done before, or from efforts to understand strange phenomena occurring
at the microscale. For example, a precursor work done on microfluidic droplets was
32 Introduction

motivated solely by curiosity [165–167]. The objective of Ref. [165, 166], was to re-
port the outstanding monodispersivity of droplets produced in microjets, and that of
Ref. [167],was to describe droplet patterns observed in microchannels. No application
was mentioned. Later, it was realized that droplets could play an important role in
colloidal science, chemistry, material science, and biology. Another example is PDMS
soft technology, whose precursor studies were mostly motivated by technological chal-
lenges [168]. More striking is the case of nanofluidics, regarding which some of the
investigators, around the turn of the twenty-first century, had no idea about the ap-
plications that the technology could generate. Later, nanofluidics will become a core
technology for new genome sequencing. Today, the questions raised in this domain,
concerning, for example, the hydrodynamical behavior of carbon nanotubes, clearly
pertain to the Bohr quadrant. Other examples can be mentioned (nanobubbles, inertial
microfluidics), where research is mainly curiosity driven.

1.10.2 Promising areas of application

The advantages of microfluidics, put forward multiple times over the years, are as
follows: small quantities of reagents, small samples, high speeds of analysis, cost re-
duction, high sensitivity of separation, portability, exquisite flow control, functionality
integration, automatization, parallelisation, high level of compartmentalization, and
large information throughput. Disadvantages also exist (cleaning constraints for de-
vice fabrication, difficulty of producing large volumes of product, no standardization,
difficulty of scaling up for PDMS, and, for complex constructions, reliability below
industrial standards), but they are outweighted by the advantages offered by the tech-
nology.

The general vision is that, with such capabilities, microfluidics can resolve bottlenecks
hampering the development, sometimes the existence, of key industrial products (for
instance, NGS), or hindering the realization of industrial or research ambitions (for
instance, performing in-situ analyses on Mars, retrieving information stored in DNA
memories, or building representative models of the kidney). This is what microfluidics
has successfully done over three decades. Concerning the forthcoming years, since fluid
control at the submillimetric scale is increasingly required in a number of fields, and
many domains do not benefit yet from microfluidic technology, or even have no aware-
ness of it, conditions are met for the microfluidic field to keep growing at substantial
rate. This linear vision will be disturbed or disrupted by the emergence of new dis-
coveries in microfluidics or in related fields. Examples include the discovery of new
enzymes, that could simplify and reduce the cost of biological workflows, and the syn-
thesis of new materials, which could impact microfabrication techniques, as PDMS
did in the past. In addition, the priorities of the society, which support a major part
of microfluidic activity, may change. Yesterday, a priority was given to the human
genome programme. Today, energy production and the environment, are subjects of
major importance. All the problems of predicting the future lie in the unpredictable
advent of major discoveries and the extreme difficulty to visualize the evolution of
societal needs.
 Future of microfluidics 33

During the years 2000-05, institutions attempted to sketch the future. They produced
‘roadmaps’, or white papers’ for microfluidics, to structure the young field and to
reassure or stimulate funding agencies and investors, as Moore’s law did for microelec-
tronics. Today, on re-reading these roadmaps, the general impression is that they were
more concerned with platforms than with the future of the field [169]. This probably
shows how difficult it is to predict the future. The scientific literature was more per-
tinent. Reviews offering a vision of the future of microfluidics, or subfields pertaining
to it (see for instance [1, 74, 160, 223]), often pointed in the right directions.30
Here, we will look into the crystal ball by listing, without claim for completeness,
a number of promising areas of application of microfluidics, in a manner similar to
Ref. [161]. This is set out in Table 1.1.

Application Example
Diagnostics Perform low-cost SARS COV2 molecular testing
with paper microfluidics
Single cell Establish the transcriptome, at the single cell level,
of tumour cancer cells
Screening Discover antibiotics and enzymes by screening
large quantities of biochemical reactions
Delivery Produce lipid nanoparticles for nucleic acid delivery
(for example, for RNA-based vaccines)
Organ on a chip Create artificial liver, lung or intestine to test drugs
MRT Produce high-quality materials, benefiting from
high throughput and flow control
Cell culturing Produce, with high throughput and low cost, stem cells of high quality
Material Science Materials with novel functionalities
Membrane Science Membranes for energy harvesting or energy production
Cosmetics Cosmetic products and instrumentation
DNA storage Retrieve information stored in DNA matrices
Display technology Display images with microfluidic entities, such as droplets

Table 1.1 : Non-exhaustive list of promising areas of application for microfluidics and
nanofluidics

The table deserves few comments

Diagnostics: Today, therapeutic drugs are making rapid progress but common sense
says that, in order to cure a disease, one must first identify it. This is where di-
agnostic comes on stage. Tests pertain to two categories: antigen and molecular.
Antigen tests have limited sensitivities, but their costs are low and their usage
simple. To-day, molecular tests are mostly based on polymerase chain reaction
(PCR). In order to reach high sensitivities, these tests perform an extraction be-
fore amplifying the nucleic acids. The technology is thus more sensitive but more
30 It is amazing to note that, in some cases, authors did not predict the advent of technologies that,
later on, they invented [1].
34 Introduction

complicated and more costly than antigen tests. Since 2000, simpler methods of
amplification have been developed. An example is loop amplification (LAMP),
invented in 2000 [171], which operates under isothermal conditions, much simpler
to implement. It it is thus regrettable that PCR keeps dominating the molecular
market. It has been shown that paper microfluidics, described in Chapters 4 and 7,
and based on LAMP, performs molecular diagnostics, with integrated membrane
purification, with sensitivities and specificities comparable to those of PCR, much
lower cost, and with a minimal logistics [170,172–174]. There is no doubt, that, in
the future, paper microfluidics will represent an important technology for molec-
ular point of care (POC) diagnostics. At the moment, the problematic is linked
to business, not to technology.
Delivery: Delivery is about creation of particles, to be swallowed, inhaled, injected
into the blood circulation, or injected intracutaneously. These particles circu-
late or diffuse in the body and then, at the end of their journeys, deliver their
load, with a controlled kinetics. Words often used are ‘targeted drug delivery’
or ‘controlled drug release’. Delivery primarily concerns human health but also
agriculture: for example, pheromones are encapsulated and delivered at certain
periods of the year, in order to disrupt insect reproduction. Delivery methods are
diverse: physico-chemical (for instance hydrogel dissolution in tissues), acoustic
(bubble or droplet bursting) [175], thermal, or chemical. Delivery kinetics ranges
from fraction of seconds to months, and the sizes of the particle range from 100
nm to tens of micrometres. There is a natural coupling between delivery and
microfluidics [176]. Microfluidics allows, by reducing polydispersivity, improving
encapsulaton rates, suppressing of burst phenomena (too much delivery in a short
time, which can be lethal) and, more generally, optimizing delivery kinetics.
Let us pause for a moment to consider lipid nanoparticles (LNPs) (see Fig.
1.33(A)). We will see, in Chapter 5, that these objects gain considerably being
produced in microfluidic or millifluidic devices. LNPs are complex nanoparticles,
50 to 100 nm in diameter, formed through a self-assembly process that includes,
according to Ref. [178], three steps: discoidal cluster formation, aggregation of
clusters into larger patches, and vesicle formation.31 LNPs travel in the blood
circulation, attach to a cell thanks to their affinity, and penetrate into it. Hav-
ing penetrated the cell, LNPs deliver their passengers, designed to interact with
the cell machinery (see Fig. 1.33(B)). Molecules carried by LNPs can be DNA,
mRNA or siRNA. LNPs have been highlighted during the COVID-19 crisis. They
vectorized mRNA into cells and made possible mRNA-based vaccination [177].
There is little doubt that the domain of delivery, coupled to microfluidic technol-
ogy, will expand in the future.
Organ on a chip (OOC): As noted above, OOCs are biomimetic objects enabling
drug testing on representative models. One outcome of the technology is to ac-

31 LNP formulation includes, to control stability, electrostatic charge, and pH, reagents such as 1,2-
dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene
glycol-2000 (DMG-PEG2000), Citric acid, sodium citrate tribasic dehydrate and cholesterol
 Future of microfluidics 35

(a) (b) Cytoplasm

Nucleic acid
2

Endosome

Receptor

Endosome
Vesicle escape

Transitation
Polypeptide Nucleus

Lipids
ds

Ribosome

Fig. 1.33: (A) LNP structure: a ionizable lipiidic shell encapsulates vesicles, which encap-
sulate nucleic acids. (B) Nucleid acid delivery into the cell, including: endocytose, endosome
formation, endosome escape, and, for the case of mRNA, protein synthesis in the endoplasmic
reticulum (ER) and its finalization, prior to exocytose, in the Golgi apparatus (not shown).

celerate drug discovery, without animal testing. Mimicking in vivo conditions is a

challenge, for which microfluidics is instrumental. The OOC field is often reviewed
(see for instance [110]).

Microreaction technology (MRT): As noted earlier, MRT allows us to produce

materials under high throughput conditions with excellent control. It is probable
that MRT will progressively replace the traditional techniques, based on large
batches, in which turbulence tends to degrade the performances of the product
and, in a number of cases, raise safety issues. MRT devices, by working at high
throughput but below the turbulence onset, and, by working with smaller, paral-
lelized systems, avoid these problems. Broader discussion on the virtues of MRT
can be found in Ref. [187].

Single cell: Single cell domain concerns fundamental research and applications. For
more than decade, research has benefited considerably from microfluidic technol-
ogy [188]. In oncology, the challenge is to capture substantial amounts of cells
(typically 104 -105 ), barcode them and sequence their transcriptome, at the single
cell level, i.e. perform single cell RNA sequencing (scRNAseq). With this ap-
proach, cell expression heterogeneity can be mapped, guiding therapeutics. This
possibility would represent a breakthrough in cancer treatment. The task can be
performed in droplets, as shown by 10X Genomics, a fast-growing company [192].
It can also be performed in hydrogel cages [190, 191]. The domain was recently
reviewed [189].

Cell culturing: In cell culturing, microfluidics allows one to control or better con-
trol the environment, i.e. flow geometry, temperature, gas exchanges and nu-
trient fluxes (see for instance [193, 194]). The culture of mesenchymal stem cells
(MSCs) deserves particular interest. Several regenerative medicine treatments use
these cells. The treatments typically use 108 MSC cells, whose cost, at the mo-
ment, reaching several tens of thousands of dollars per dose, makes regenerative
medecine unaffordable [195, 196]. By using microfluidics, it can be argued that
costs will seriously significantly, while keeping production levels and quality high.
36 Introduction

It is thus probable that, in the future, microfluidics will play an important role in
the domain of regenerative medicine, and, more generally in cell therapy.
Materials: Microfluidics can produce all sorts of materials. These include nanopar-
ticles, too small to be directly controlled by the confinement, but still bene-
fiting from better-controlled environments. Micrometric particles gain consider-
ably from being produced in microfluidic systems [84, 179, 182]. Another area is
particle assemblies. Examples include clusters formed by hydrodynamic interac-
tions [180, 181], or bubbles assemblies, spontaneously forming crystals, leading,
after solidification, to microfluidic foams [183]. These foams may be used as scaf-
folds for cell culture, but also as complete photonic band gaps materials, [184,185]
an area called ‘phoamtonics’ [186]. This materials are interesting for infrared (IR)
communication applications. Other examples are tissues and organoids, obtained
by culturing cells.
Membrane technology: CNT-based membranes possess high permeabilities and
high surface charges densities. Based on these characteristics, a proposal was made
to use these membranes for converting osmotic energy into electrical energy [198].
Membranes separating salt water (from the sea) and fresh water generate osmotic
flows, which develop streaming electrical currents (See Chapter 6), and thus elec-
trical energy. In this manner, ‘blue’ energy can be produced. In the case of a
single boron nitride nanotubes (BNNT), performances are impressive [198]: the
maximum power density lies in the kW/m2 range, i.e. three orders of magni-
tude above that of standard membranes [199]. However, membranes formed with
nanotubes are subjected to a number of effects (in particular polarization concen-
tration), which considerably reduce their performances [199, 200]. This domain is
the subject of active research.
Cosmetics: There are opportunities to invent new cosmetic creams, perfumes, sprays
or nail polish and develop novel instrumentation, based on microfluidics [201,202].
DNA storage: DNA storage is a branch of DNA computing. DNA storage shows
impressive performances [203]. An assembly of DNA strands, packed in a container
of the size of a shoe box, contains all the internet information circulating in
the world. To retrieve the stored information, microfluidics and nanofluidics are
obviously needed . At the moment, this domain is still embryonic, but it should
grow considerably in the future.

1.10.3 Microfluidics and its interactions with other fields

Although possibly debatable, one may attempt to distinguish between microfluidic

technology and interactions between this technology and other fields. This leads to
the diagram in Fig. 1.34, which does not claim exhaustivity.
The upper part represents landmarks of the field. There is a range of years, extending
roughly, between 1997 and 2003, in which a large part of the foundations of microfluidic
science, as it looks today, have been established. These years may be called ’golden
years’. They are characterized by a high density of discoveries. The bottom part of
 Future of microfluidics 37

Fig. 1.34: Microfluidics and its coupling with other fields, giving rise to major applications.

the diagram shows successful couplings between microfluidics and other fields, from
which, in most cases, interesting applications emerge. They are numerous. Compared
to the upper part, the inventions are distributed in a more homogeneous manner. In
addition, more strongly than for the upper part, milestones often start off new areas
of activity, which expand further, sometimes considerably. This part conveys most of
the microfluidic market.

1.10.4 Microfluidics and complexity

In the field of microfluidics, there has been a continuous effort for increasing the
complexity of the devices, hoping to develop rich functionalities. For instance, PDMS
microvalves have.been used to create microfluidic devices of increasing complexity, that
were intended to represent analogs of CPUs. In fact, many mechanisms exist at the
bottom, that can be used to actuate the system, without technological effort: examples
are self assembly mechanisms [197] for which molecules spontaneously form patterns,32
amplification processes, selective chemistry, enzymatic activity, molecular motors, and
molecular conformational changes, induced by pH or temperature changes. At the
larger scale, we have, for instance, convection, Marangoni flows, and capillarity, which
can also be exploited to actuate the system. The question is how can we play with
all these natural actuators, how can we leverage them, to build up interesting func-
tionalities? How can we use this micro-nanoscopic toolbox? NGS, single cell studies,
organ-on-a-chip, and lipid nano-particles [177], provide examples in which the toolbox

32 A remarkable example, among many others, is DNA origamis.

38 Introduction

has been used to perform extremely complex tasks. In the future, microfluidics may
take inspiration from these examples to create new outstanding devices.

1.10.5 Microfluidics and Artificial Intelligence

Artificial Intelligence(AI) impacts science. Some domains, such as structural biology

or proteomics, will profoundly change their methodologies [204]. What about microflu-
idics? At the time of writing this book, no clear picture has emerged. Thoughts have
recently been published. For instance, Ref. [205] suggests that by incorporating AI
in chip designs and taking full advantage of feedback loops, along with data-driven
models, one could create systems generating large amounts of data useful for drug dis-
covery, organ modelling, or developmental biology. Thus far, as mentioned in a recent
review [71], progress has been slow and commercial adoption has been hampered by
issues with reliability, generalizability, and costs. It is probable that, for microfluidics,
the importance of AI will grow along the years, facilitating or perhaps enabling the
walk towards complexity mentioned in the previous section.

1.11 Reviews and books

1.11.1 Books

Today, around twenty books have been published on microfluidics.

The first book was Microflows: fundamental and simulation [206], published in 2002,
followed by Microflows and nanoflows, Fundamentals and Simulation, appeared in
2005. The book deals with gases, flow modelling and electrokinetics. In the same
period (2003), Fundamental and Application of Microfluidics, by N.T. Nguyen and S.
Wereley, was published [207]. It uncovered a broader part of the subject, mainly from
an engineering perspective. The book has been reedited three times. The first edition
of my book, in French, appeared in this period (Belin, 2003) [208], followed by the
english version, published in 2005, by Oxford University Press [209]. The focus was on
the physics of microfluidics. The books of S. Colin [210] (focusing on gases), H. Bruus
(Theoretical Microfluidics [211], 2007), and B.J. Kirby (Micro- and nanoscale fluid
mechanics : transport in microfluidic devices, [212], 2010) adopted a similar approach.
The book written by J. Berthier and P. Silberzan in 2009, Microfluidics for Bioengi-
neering [214], was instigated by a more engineering perspective. One may also cite
(without being exhaustive) Micro-Drops and Digital Microfluidics (2008) [215], The-
ory and Practice for Beginners [216], Introduction to BioMEMS [217], Laboratory
Methods in Microfluidics [218], and recently, Microfluidics and Lab on a Chip, by
Manz et al. [219].

1.11.2 Reviews

Reviews on the research carried out in the field of microfluidics are numerous. They
are often well cited, and over the years, they have certainly played a substantial role
 Organization of the book 39

in the spreading of information. Historically, the first microfluidic review was written
by P. Gravesen [65]. As mentioned in this chapter, the review certainly contributed to
introduce the word microfluidics’ into the community. Later on, in 1999, C.M.Ho and
Y. Tai [21] wrote a review on flow control with microfluidics, and M. Gad el Hak [220]
on gas dynamics. Reviews written in the same period of time by N. Giordano and J.T.
Cheng [221], H. Stone and S. Kim [222], and H. Stone et al [228] ,were centered on the
physics and the hydrodynamics of microfluidics. Later, in 2006, Todd et al [74] and
A.van den Berg et al in 2010 [229] reviewed the field along similar lines. D. Beebe et
al [223] published an early review on biomedical applications, as did G. Sanders and A.
Manz [224], E. Verpoorte [225] on biochemical analysis, J. Lichtenberg et al [226] on
sample pre-treatment, and P.A. Auroux et al [227] on analytical applications. In 2006,
a series of review appeared in a special issue of Nature, acquiring a large visibility, in
particular G.M. Whitesides’s paper ‘On the origin and future of microfluidics’.
After 2010, the field was too broad and diverse to review it in the format of an article.
Specialized reviews thus appeared, more and more frequently over the years. This
seems to be a general evolution. Sometimes, a topics is reviewed several times in a
row. These reviews are often of good quality, and are useful to acquire global views on
specific topics.

1.11.3 In which journals do microfluidic researchers publish ?

Research articles on microfluidics are dispersed in different journals. Lab-on-a-Chip

deserves particular attention because it accounts for about 40% of microfluidic publica-
tions. The journal contributed, in synergy with µTAS conferences, to identifying a com-
munity. Other journals are Analytical Chemistry, Sensors and Actuators, Microfluidics
and Nanofluidics, Journal of Micromechanical and Microengineering, Biomicrofluidics,
PNAS, Nature, Science, Physical Review Letters, Physical Review of Fluids, Journal
of Chromatography, Electrophoresis, BioMicrofluidics.

1.12 Organization of the book

This book consists of six chapters, in addition to this introductory chapter.
• Chapter 2 describes the physics of small systems is described
• Chapter 3 presents low Reynolds number flows.
• Chapter 4 presents droplet microfluidics
• Chapter 5 describes transport phenomena: diffusion, dispersion, mixing, adsorp-
tion, thermal exchanges and separation.
• Chapter 6 is about electrohydrodynamics of microsystems; electrophoresis, electro-
osmosis, and dielectrophoresis.
• Chapter 7 introduces microfabrication techniques : silicon technology, soft tech-
nologies, plastic moulding and 3D printing.
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2
Physics at the microscale

2.1 The scales of small things

2.1.1 The system of units for small quantities

Let us start with a question of vocabulary. The names used for describing small quan-
tities are shown in the following table:

Name Scale (m)

Milli 10−3
Micro 10−6
Nano 10−9
Pico 10−12
Femto 10−15
Atto 10−18
Zepto 10−21
Yocto 10−24
Table 2.1 Names of the small units.

These small units are frequently used, a few examples are presented below. Volumes
contained in microfluidic systems commonly range from about 10 to a few hundred
nanolitres. A biological cell has a size of 10 µm and it includes a volume of a few pL.
To take an example pertaining to the early days, Ref. [1] demonstrated a detection
threshold of 15 amole (i.e. 15 atto-mole) by coupling a microfluidic system to a mass
spectrometer. A zeptomole is around 600 molecules (often employed), and a yoctomole
0.6 molecules (rarely used).

2.1.2 Sizes of ions and small molecules

How can one measure the size of an ion or a small molecule, i.e. a molecule including
only a few atoms? Many techniques exist: X-ray, neutron diffraction, gas state equa-
tion, gas solubility, viscosity, self-diffusion measurements etc. An important notion is
the Van der Waals radius, obtained by using, for gases, the notion of Van der Waals
 The scales of small things 49

Ion Radius (nm) Ion/molec.Radius (nm)

Li+ 0.068 F− 0.136
Na+ 0.095 OH− 0.176
K+ 0.133 O2− 0.15
Fe2+ 0.076 CH4 0.20
Ca2+ 0.099 H2 O 0.17
Ar 0.188 He 0.2
Table 2.2 Van der Waals radii of some ions and molecules

excluded volume. The corresponding Van der Waals sphere is visualized as the smallest
sphere encapsulating the molecule. This notion applies to asymmetric molecules, such
as water. Some values of the Van der Waals radius are given in Table 2.2. For instance,
the Van der Waals radius of helium is around 0.2 nm. Water is 0.28 nm and methane
(CH4 ) 0.4 nm. Sizes of the simplest molecules are typically a fraction of a nanometre.

2.1.3 Complex molecules, DNA, proteins

Many molecules include a moderate number of atoms, and possess limited function-
alities, if none. Examples are alkanes, peptides, sugar, and glucose. Macromolecules,
by definition, are much larger: they include between a few hundreds and millions of
atoms. Macromolecules are also called ‘complex molecules’. Their behaviour is exceed-
ingly rich, and they may possess astonishing functionalities (for instance, aquaporines,
that we saw in the introduction, which filter water at the single molecule level, or anti-
bodies which bind to antigens in a highly specific manner). Depending on the solvent
in which they are immersed and the temperature, macromolecules can adopt different
conformations: helices, globules, sheets, stretched structures, etc. Examples are shown
in Fig. 2.1.

insulin (2hiu)

alcohol dehydrogenase (2ohx)

serum albumin (1e7i)
trypsin (2ptc)
10 nm antibody (1igt)

hemoglobin (4hhb)

atp synthase (1c17) hexokinase (1cza) rubisco (1rcx)

Fig. 2.1: Morphologies and sizes of a selection of proteins: insulin, trypsin, albumin, antibody,
deshydrogenase, synthase, haemoglobin, hexokinase, and rubisco. (From David Goodsell, un-
der public licence.)
50 Physics at the microscale

Different scales must obviously be used to characterize the geometry of these molecules.
An important notion is the radius of gyration Rg , defined as the standard type devi-
ation of the atom distances from the molecule centre (defined at the mean position
of the atoms). Should atoms be homogeneously p distributed inside the volume of a
sphere of radius R, Rg would be equal to ( 35 )R. The radius of gyration thus gives
an idea of the size of the molecule, as long as its shape is not too far from a sphere.
One advantage of this notion is that it can be directly related to small angle X-ray
scattering(SAXS) measurements.
The hydrodynamic radius RH is another estimate, which, for large molecules, can be
inferred from dynamical
p light scattering measurements. Theory provides the following
relation Rg = ( 35 )RH . There is a relation between these quantities and the molecular
weight Mw . The formula is RG ≈ 0.7Mw0.37 (with Mw expressed in kDa [2]. Table 2.3
gives a few gyration radii of proteins, including those of Fig. 2.1.

Molecule Contour length rG

Albumin 2.78 nm
Insulin 1.16 nm
Hemoglobin 23.8 nm
(Bovin) b-Trypsin 1.8 nm
Hexokinase 3.2 nm
ATP synthase 5 nm
Human chromosome 5 cm 1 µm
Human genome 2m
E. Coli DNA 1.5 mm 100 nm
Table 2.3 Geometric characteristics of some macromolecules.

For polymers, such as the plasmid shown in Fig. 2.2 [3], another dimension is needed:
the contour length Lc . It is the length of the macromolecule measured along its back-
bone. For a polymer made up of N monomers, each separated by a distance l, we
have:

Lc = N l

An important relation, established by Flory [4] in 1953, is the following:

Rg ∼ N ν ,

where N is the number of bond segments along the chain and ν is the Flory exponent.
ν is equal to 1/3 in poor solvents and 3/5 in good solvents. Another important length,
based on mechanics, is the persistence length, which tells us something about the chain
stiffness. For polymers shorter than the persistence length, the molecule behaves like
a rigid rod, while for longer polymers, the chain can bend and the molecule looks
 The scales of small things 51

2.2: DNA molecule imaged

with AFM. (Reprinted with
permission from [3]. Copy-
right 2022 American Chemi-
cal Society.)

like the trajectory of a three-dimensional random walker. To provide an example, a

strand of uncooked spaghetti has a persistent length of 1018 m [5], a strand of cooked
spaghetti 10 cm, and a double helical DNA 39 nm. Another length, the Kuhn length,
provides information on the distance within which molecules are correlated. Decades
of work have been dedicated to studying polymer conformation, and we will not go
further into the subject here.

2.1.4 Visualization of DNA strands in a microfluidic device.

Fig. 2.3: (Left) Microfluidic device used by [6], in which a functionalized PS bead is placed
at the centre of a cross-flow, at the stagnation point (black rectangle). (Right) Different
conformations of a DNA molecule tethered to the bead, subjected to a strain of 1 s−1 . The
DNA strand has a contour length of 22 µm. (Photo published with the permission of D.E.
Smith et al, Science, 283, 1999.) (Copyright 2003. American Association for the Advancement
of Science.).
.

In the 1990s, S. Chu et al [6] imaged the fluorescent labeled DNA of a bacteriophage
λ, subjected to the action of a straining field. The work1 prompted the development
of the field of single molecule study. In S. Chu’s experiments, the molecule is tethered
to a polystyren bead, and the bead is placed at the intersection of two microchannels
etched in silicon (Fig. 2.3, left)). Figure 2.3 (right) shows different conformations of
the DNA obtained in this type of system. The experiment revealed the considerable
richness of the conformational dynamics of DNA, and, in the meantime, demonstrated
that with microfluidic technology, it was possible to manipulate isolated molecules.

1 It was followed by a number of realizations, such as [7].

52 Physics at the microscale

2.1.5 Viruses, bacteria and cells

Virus sizes are on the order of 100 nm, and (prokaryotic) bacteria 1-2 µm. The sizes
of eukaryotic - i.e. possessing a nucleus - animal cells are much larger. They range
between 10 and 30 µm. There exist elongated eukaryotic cells ( neurons), eukaryotic
cells having lost their nucleus (red blood cells), but here, we concentrate on the vast
majority of the 3 1014 cells forming the human body, i.e. eukaryotic cells of spherical
shape, possessing a nucleus. A scheme of the principal cellular elements of these cells
is shown in Fig. 2.4 [8].

Nucleus Lysosome
Nucleolus
Smooth
Chromatin
Endoplasmic
Centrioles Reticulum

Golgi Apparatus

Cytoskeleton
Rough Endoplasmic Reticulum
Mitochondria

Plasma Membrane Cytoplasm Ribosomes

Fig. 2.4: Eukariotic cell, in which several elements are outlined

The cell includes different elements, which would need thick books with titles, such as
The Cell [8] to describe them. Here we content ourselves to mention basic entities:
• a nucleus of size between 3 and 10 µm. The nucleus itself is a complex object
that contains, among other elements, DNA folded into the form of a chromosome.
Chromosomes are objects of micrometric size;
• mitochondria, which are nucleated cells of micrometric size. Mitochondria have
the cellular function of supplying energy to the cell;2
• the endoplasmic reticulum, a collection of vesicles across which proteins are fab-
ricated and transported. The vesicles of the reticulum are micrometric objects;
• the cytoskeleton, containing actin, tubulin, and intermediate filaments. These
objects are between 10 and 30 nm in diameter, and a few micrometer in length.
They ensure the mechanical cohesion of the cell and
• the membrane, which has a thickness of a few tens of nanometres.

2 Mitochondria are reservoirs of ADP (acid diphosphate); the transformation of ADP to ATP (acid
triphosphate), outside the mitonchondria, supplies the cell with energy.
 The scales of small things 53

Table 2.4 presents the size of cellular elements.

Element Size
Nucleus 4 µm
Chromosome 3 - 5 µm
Ribosome 20 - 30 nm
Membrane thickness 10 nm
Microtubule diameter 25 nm
Lysosome 200 nm
Mitochondria 3 µm
Table 2.4 Sizes of cell components.

2.1.6 Single cells manipulated in microfluidic droplets

Fig. 2.5: Microfluidic device enabling the production of cells optimized for the secretion of
antibodies. Each cell is analysed, processed, selected, at individual level. The device mimicks
Darwin selection, but at a much faster rate. (Reprinted with permission from [10]. Copyright
2022. Springer Nature.).

Since the demonstration, in 2002 [9], that clone cells, i.e. possessing the same genome,
those can express different proteins, in different amounts and in a random manner, it
came as evidence that noise in the expression should be seriously taken into considera-
tion to understand the behaviour of living systems. The paper prompted the emergence
of a new domain, called ‘single cell’, for which microfluidics offered a powerful toolbox.
Figure 2.5 shows one of the most advanced systems in the domain [10].

Cells are encapsulated in droplets (see Fig. 2.5, left). The droplet sizes, 100 µm, is
suitable for hosting them. Cells, as they travel in their vehicle, may or not secrete
antibodies. Depending on their behavior, after incubation, they are sorted, the best
54 Physics at the microscale

performing ones are reinjected for further analysis [10]. The device mimics Darwin
selection, but at a much faster rate (hours instead of millions of years).

2.1.7 Multicellular organisms

An example, taken from the billions of multicellular organisms existing on earth, and
justified by its importance in neurobiology along with its link with microfluidics, is C.
Elegans. It is one of the most studied multicellular organisms. It was the first to have
its whole genome sequenced. The adult male has exactly 2,015 cells, all documented
phenotypically, genetically, transcriptionally, geographically and functionnally. Its ba-
sic anatomy includes a mouth, pharynx, intestine, gonad, and collagenous cuticle. It
has neither a circulatory nor a respiratory system. The life of the worm does not look
exciting: it solely consists of eating, moving, sensing, and reproducing.
The worm is on the order of one millimetre long and two hundred micrometres wide.
It can easily be introduced in microfluidic devices to study its behaviour. Several
experiments can be performed in parallel, as was done in Refs. [11, 13]. An example,
extracted from Refs. [12, 13], is shown in Fig. 2.6.

Fig. 2.6: C. elegans in a microfluidic device, designed for performing several experi-
ments in parallel. (Reprinted with permission from [13]. Copyright 2022. Elsevier.).

The goal of these experiments was methodological: it offered a platform for screening
the response of C. elegans to stimuli.

2.1.8 Mean free path in gases.

Let us discuss intermolecular distances in gases. In gases, contrarily to liquids, the

intermolecular distances are much larger than molecule sizes. A geometrical relation
relates the density n (i.e. the number of molecules per unit of volume) to the inter-
molecular distance d:

d = n−1/3
 The scales of small things 55

Gas λ(nm) τ (ns)

Air 61 0.18
Nitrogen 60 0.17
Argon 64 0.2
Helium 177 0.18
Table 2.5 Mean free paths and collision times in different gases.

Avogadro’s law stipulates that, at fixed temperature and pressure, all gases contain the
same number of molecules per unit volume At ordinary pressure, and at a temperature
of 273 K, this number is 2.69 × 1019 cm−3 . For nitrogen, taking a molecule diameter a
equal to 3 Å, we obtain a value of d equal, approximately, to 3 nm, then ten times a
(see Fig. 2.7).

2.7: A schematic view of the mean free

path for air in normal conditions. In this
case, λ is approximately 60 nm. The
molecule travels this distance before hit-
ting a partner

However, for gases, the fundamental scale involved in the establishment of the flow
equations is not d, nor a, but the mean free path λ. The reason is that λ is the
average distance travelled by a molecule between two successive collisions and, in
gases, momentum is exchanged through collisions. Geometrical considerations, coupled
to statistics, provide the following expression:
1 kT
λ= √ =√ (2.1)
2πna2 2πpa2

where T is the temperature, k is the Boltzmann constant, and p is the pressure.

Using the formula, and again for nitrogen, and in normal conditions, one finds a
mean free path of around 60 nm, This is twenty times the intermolecular distance d.
Therefore, a molecule succeeds in avoiding about 95% of their partners before hitting
a colleague, like a good rugby player (see Fig2.7.).
Several values of λ along with collision times τ (i.e. the mean duration of the molecule
journey between two successive collisions) are given, in normal conditions, in Table
2.5 [14].3

3 The values shown in the table, obtained from viscosity measurements, have been taken from [14].
Note that they vary by 10%, from one publication to the other
56 Physics at the microscale

Mean free paths for Nitrogen, Argon and air are similar because molecular sizes are
close. In the case of Helium, owing to its small size and efficient collision cross-sections,
the mean free paths are substantial .

2.1.9 Correlation length in liquids.

Three scales characterize a liquid: the molecular radius, the intermolecular distance
and the correlation length (see Fig. 2.8.).

2.8: Correlation function g(r) for liq-

uid argon at 90 K.

Fig. 2.8 shows the pair correlation function g(r), for argon at 90 K, plotted as a
function of the distance r from a molecule center, located at r = 0. g(r) represents the
probability of finding another dense entity at distance r from the centre. The molecule
radius is r ≈ 0.2 nm. Above this value, g(r) increases, up to r ≈ 0.4 nm, where
it reaches a maximum. This maximum marks the averaged position of the nearest
neighbor. We can infer that the intermolecular distance is ≈ 0.38 nm. g(r) oscillates,
but its amplitude decays with r. It is usually considered that the correlation length lc
corresponds to the value of r for which the decay has reached 10%. Then, in the case of
Argon, we find lc ≈ 1 nm. A similar order of magnitude hold for current liquids, such
as water and oil. The physical interpretation of lc is the length below which molecules
fluctuations remain correlated. This length will play an important role in the next
chapter, for the definition the fluid particle size.

2.1.10 Other scales

A few other scales often play an important role in the behaviour of small systems.
Some are illustrated in Fig. 2.9.
• Nucleation length. In homogeneous nucleation theory, molecules, subjected to
Brownian fluctuations, must form a cluster of radius larger than a critical value to
initiate crystallization. Nucleation length is twice this radius. The critical radius
is on the order of a few nanometres. It results from a competition between surface
and bulk energies. An Arrhenius-type statistic describes the nucleation probabil-
ity. In practice, this statistic holds, but nucleation is most often heterogeneous,
 The scales of small things 57

Fig. 2.9: Other scales: nucleation length lN (twice the nucleation radius), capillary length
lC , Reynolds length lRe and thermo-capillary length lCT .

i.e. controlled by impurities. These features, known for a long time [16], were con-
firmed in a microfluidic system performing hundreds of nucleation experiments in
parallel [17].
As the system size decreases, it becomes less probable to nucleate a supercritical
cluster. This explains why, in small systems, water can remain liquid at deeply
negative temperature. Altocumulus clouds, a common type of mid-altitude cloud,
are mostly composed of water droplets supercooled to a temperature of about
-15◦ C. These droplets often freeze on the airplane wings. In Ref. [18] (1953)),
it was found that, in droplets of 10 µm in diameter, the mean freezing temper-
ature of water was -38◦ C. The phenomenon was unsurprisingly re-observed in
microchannels [29]. In extreme confinements, such as sub 2 nm pores, ice never
forms [15].
• Capillary length Capillary length results from
q the competition between gravity
γ
and capillarity [19]. Its expression is lc = ρg and its order of magnitude is
one millimetre. As sketched in Fig. 2.9, lc provides an estimate for the meniscus
height developing along a wetting wall. We will return to this subject in Chap.
3. Compared to microchannel dimensions, lc is large, so that, in microfluidics,
gravity is often neglected in favour of capillarity.
• Reynolds length. As will be seen in this chapter, and in Chap. 3, the Reynolds
number is equal to Uνl , where U is a characteristic speed, l is the system size, and ν
is the kinematic viscosity. The Reynolds length that we introduce here, is another
manner of writing the Reynolds number.4 It is a manner to keep concentrated on
scales. We thus define the Reynolds length as lRe = Uν . With this definition, Re =

4 The Reynolds length we define here has the same expression as the Oseen length. Oseen length
concerns a very specific scale: for flows around obstacles, it tells at which distance Stokes equations
become inaccurate. This is not what we are interested in. In order to avoid confusion, we give this
scale a different name
58 Physics at the microscale

l l
lRe and lRe = Re . When the system is much larger than lRe , the Reynolds number
is large and turbulence develops. Small lRe (again compared to the system size)
correspond to small Reynolds and thus creeping flows. This feature is illustrated
in Fig. 2.9. In this case, the Reynolds length is smaller than the obstacle size.
Consequently, hydrodynamic instabilities leading to Karman vortices, typical of
large Reynolds number behaviour, develop. In terms of orders of magnitude, with
U equal to 1 mm/s, and for water, lRe is close to one millimetre.
• Thermo capillary length: We will see below that the cost of creating a new
interface, per unit of area, is equal to γ, the surface energy. Can we imagine a
situation for which this energy becomes comparable to thermal energy? The ratio
2
between them is given by γlkT , where l is the system size. This ratio is equal to unity
q
for l = lcT = kT γ . The order of magnitude of lcT is a few nanometers. As shown
in Ref. [20], for jets of diameters smaller than lcT , droplets become substantially
affected by noise lcT represent the cross-over between the two regimes. It also
represents the droplet size at this cross-over, as illustrated in Fig. 2.9. For larger
jets, thermal noise can be neglected.5

2.2 Intermolecular Forces - basics

2.2.1 Forces between molecules

Non-polar molecules in vacuum: Lennard-Jones potential. Most of the material shown

here is extracted from J. Israelachvili’s book titled Intermolecular and Surfaces Forces
[21].
Let us start with the forces existing between two neutral non-polar molecules, i.e.
whose barycentres of positive and negative charges overlap. When placed in a vac-
uum, these molecules develop forces, and thus interaction energies, made up of two
contributions.
• The first contribution is called ‘short range’, because, in all cases, the energy be-
comes negligible beyond a few Angstroms. This energy has a quantum-mechanical
origin that can be either attractive or repulsive. In the attractive case, the force
gives rise to the formation of a covalent bond. The force in the repulsive case is
known as hard-sphere repulsion, and it ensures the interpenetrability of atoms.
We will focus on the latter case.
• The second contribution is Van der Waals attraction. The term is called long
range, because, when molecules assemble, for instance, on a surface, the ener-
gies of attraction that they develop decay with an exponent smaller than the
dimension of space. In such geometries, one can observe the action of the Van der
Waals term, at distances on the order of ten nanometres. In the case of a pair of
5 Not completely: thermal noise is necessary for initiating the instability that breaks the jet into
droplets, but does not play a role in the determination of their characteristics, i. their shapes and
their sizes
 Intermolecular Forces - basics 59

molecules, this ‘long range’ reduces to one nanometre or so, but this is enough to
affect, in a crystal, the second and third nearest neighbours. As the molecule is
neutral and non-polar, the existence of a permanent attraction seems strange. So,
let us consider the Bohr model of the atom: the pair electron/proton produces
an instantaneous dipole. This dipole generates an electric field that deforms the
electronic cloud of a neighbouring atom. An induced dipole will thus form. This
dipole will in turn produce an electric field affecting the first dipole. This type
of interaction is called dipole-induced dipole’. It is attractive. Over the course of
time, atoms and their electron clouds fluctuate in position and in orientation, but
the attractive interaction remains. The reasoning, held for the Bohr atom, also
applies for molecules. The amplitude of the interaction energy is given by:

3α2 hν
w(r) = − (2.2)
4(4π0 )2 r6

in which h is the Planck constant, ν is the orbital frequency of the electron, α is the
polarisability, and 0 is the vacuum permittivity. The Planck constant comes into
play though the definition of the electron-nucleus radius. The interaction potential
w(r) is called ‘London’ or dispersion’ potential [22]. Its order of magnitude is
kT [21].

The two interactions, i.e. Van der Waals and hard sphere, form the basis of the
Lennard-Jones potential:
  
σ 12  σ 6
V (r) = 4 − , (2.3)
r r

where  is the cohesion energy and σ the hard sphere diameter’. For example, for
argon, σ = 3.045 Å and  = 1.67 10−21 J. σ is not exactly twice the Van der Waals
radius (which would lead to 3.76 Å - see Table 2.2 -), but both are comparable.6 In
Eqs. (2.3), the first term is the hard sphere repulsion, associated to the exponent −12.
This power law is used for mathematic convenience. The second term is the Van der
Waals attraction, of negative sign and associated to the exponent −6.

The Lennard Jones potential V (r) is also called ‘6-12’ potential, or shortened as ‘LJ
potential’. It is plotted in Fig.2.10. Two initially distant molecules will approach each
other and reach the equilibrium point, located at rm = 21/6 σ. At the end of their
journey, the couple acquires an energy −. Said differently, they will have reduced
their energy by a quantity equal to . This is Van der Waals bonding energy for
neutral molecule in a vacuum. It ensures the cohesion of Van der Waals solids and
liquids. As noted above,  is called the cohesion energy. On needs to bring  to the
pair to break the bond.

6 One should in fact, as will be seen later, compare 1 1/6

2
2 σ to the Van der Waals radius. The
difference is 10 %
60 Physics at the microscale

2.10: Lennard Jones potential.

The force between two molecules is the opposite of the gradient of the Lennard Jones
potential. We have the following expression:
  12   6 
dV σ σ
F (r) = − = 24 2 − .
dr r13 r7

The force is called cohesive force. The order of magnitude of this force is roughly, σ ,
10−21
which leads to 1.67
3 10−10 ≈ 5 pN. On must apply this force to break the pair. This
force can be converted in pressure by considering a sphere enclosing the molecule.
The corresponding cohesion pressure, negative, has the following order of magnitude:
− σ3 ∼ − bars. This negative pressure has a physical significance in solids. It cor-
responds to the stress engineers must apply to break them. We will return to this
question in Chap. 4.

Polar molecules in a vacuum. The above considerations can be extended to polar

molecules. Water and carbon dioxide are examples of such molecules. In these situ-
ations, there is always a hard-sphere repulsion (which has the same form as in the
non-polar case) and a London attraction. However, due to the polar character of the
molecules, the attraction term includes supplementary contributions, shown in Fig.
2.11.
So, as a whole, three long-range, attractive, interactions add up when molecules are
polar:
• London interaction, already described (see Eq. (2.2)).
• Keesom interaction, due to a dipole-dipole interaction. The corresponding poten-
tial is:
u2 u22
w(r) = −
3(4π0 )2 kT r6
in which u1 and u2 are dipolar momentums of molecule 1 and 2 respectively (the
other quantities are defined above).
 Intermolecular Forces - basics 61

Fig. 2.11: The three terms in the Van der Waals forces between polar molecules, in vacuum

• Debye interaction, due to a dipole-induced dipole interaction. The expression is:

u21 α
w(r) = −
(4π0 )2 r6

The electrostatic calculations that lead to the above formula are described in Ref.
[21]. The important result is that all these contributions decrease with 1/r6 . We have
reached the important conclusion that the Lennard Jones potential can represent not
only interactions between neutral molecules, but also those existing between polar
molecules in a vacuum. In general, for ordinary molecules, London, Keesom, and Debye
interactions have comparable orders of magnitude.

Molecules in a solvent. When two molecules are placed in a solvent, the solvent plays
the role of a third participant. Numerous phenomena develop, profoundly modifying
the situation described in the previous section. We will not describe them, and instead
refer to the work of Israelachvili [21] for a complete presentation of the subject. On
important step, that is in no way trivial, is to replace the molecule by a sphere of radius
a, characterized by a dielectric constant  and a refractive index n. To make a long
story short, the Van der Waals attraction potential w(r), for two identical molecules
(medium 1), separated by a solvent 2 , takes the followiing form:

√ !
1 − 2 2 3hνe (n21 − n22 )2 a6
w(r) = − 3kT ( ) + (2.4)
1 + 22 4 (n21 + n22 )3/2 r6

Here, 1 and 2 are the dielectric constants of the molecules and the solvent respectively,
and n1 , n2 are the corresponding optical refraction indices. The potential V (r) includes
the three contributions (Keesom, London, and Debye), which take a form different from
the case where the medium is a vacuum.
62 Physics at the microscale

What is the order of magnitudes of w(r) when the two molecules are at equilibrium
(r = a(1+21/6 )? Taking, as in the previous example, hνe =2.2 10−18 J, kT = 4.11 10−21
at 298 K, and considering n-Dodecan (1 = 20 and n1 = 1.41), with water as the
solvent, one finds -0.72 kT for the Keesom and Debye contributions and -1.4 kT for
the London contribution. Thus, the order of magnitude of the interaction energy is
roughly, in ampliitude, on the order of kT for Van der Waals materials.

Several remarks can be made:

• For two like molecules, i.e for the case we considered, Van der Waals interaction is
always attractive. However, when the molecules are different, the interaction can
be repulsive. There is no strangeness. Placed in vacuum, each molecule attracts its
partner. But when they are placed in a medium, for instance a liquid, the situation
changes. In particular, if medium 2 attracts molecule 1 more than molecule 3,
molecule 3 will feel a repulsion from its partner. We have here an equivalent of
Archimede principle. In a vacuum, a body is attracted by the earth, and falls
down. But, as soon as it is plunged in a heavier liquid, it rises, as if it were
repelled by the earth.

• Should the materials have the same dielectric constants, and the same refraction
index (often the former implies the latter), Van der Waals forces vanish. These
forces are thus ubiquitous, but sometimes they are cancelled.

2.2.2 Van der Waals forces between surfaces

We have examined the ranges of forces acting between two molecules, be they polar
or non-polar, isolated or placed in a solvent, simple or complex. Now, we consider
surfaces.

In this area, the major part of the experimental work has been carried out during the
years 1970-1990 [21, 23, 24]. Use was made of a remarkable device called surface force
apparatus’ (SFA), invented by C. Tabor, R. Winterton and J. Israelachvili [23]. SFA
allowed the approach of stages with a precision on the order of just a few angstroms,
and to measure the corresponding forces with great precision. One such device is shown
in Fig.2.12.

The stage on the device is displaced in an extremely precise manner, thanks to a system
of springs with varying stiffnesses, which act as a displacement divider. The space
between the stages is generally measured by Fabry Pérot interferometry. Information
obtained using this device is presented in the form of a force displacement curve.

In 1986, Atomic Force Microscopy (AFM), and its precursor, Surface Force Microscopy
(SFM), were invented [25]. AFM, commercialized in 1989, is now currently used to
investigate surfaces at the molecular level, providing remarkable images (an example
is given by Fig. 2.2), and enriching the body of information obtained by SFA, by
performing, for instance, measurements of the Hamaker constant [26, 27].
 Intermolecular Forces - basics 63

(a) (b) Quadrant

displacement
sensor

Lateral

Normal
Base
Light beam Strain ∆D0
Piezo
transducer
Cantilever
spring
displacements Cantilever
∆DC
Tip D Kc

Surface

Fig. 2.12: (A) Surface force apparatus (SFA) that enabled, in air and vacuum in 1972 and
later, in liquids, the measurement of intermolecular forces near interfaces [21, 23, 24]; (B)
Atomic force microscopy (AFM), invented by G. Binnig, C.F. Quate, and Ch. Gerber, in
1986 [25], enabling the analysis of surfaces at the molecular level

Let us return to theory: we saw that the Van der Waals force varies as 1/r7 for
molecules (where r is the distance between the molecule centres). In order to deter-
mine the forces between two plates, a sphere and a plate, or two spheres, we must
assume additivity, and sum up the pairwise forces of the molecules composing the
other medium. In this calculation, r becomes the gap between the objects, for in-
stance the distance between two plates. We do not take the bulk cohesive forces into
account, because we do not incorporate, in the summation, the molecule of the same
medium. So, the forces we calculate are those exerted by the partner, not by the object
on itself. It is then a matter of mathematics, well described in textbooks, to obtain
that the attractive forces varies as 1/r2 for sphere-plane and sphere-sphere7 systems,
and as 1/r3 for plane plane systems. The Van der Waals attraction force P (r), per
unit of area, between two identical plates along with the interaction energy, E(r) take
the following forms:
A A
P (r) = − and E(r) = − , (2.5)
6πr3 12πr2

where A is the Hamaker constant. Its expression is:

2
3hνe (n21 − n22 )2

3 1 − 2
A= kT + √ , (2.6)
4 1 + 2 16 2 (n21 + n22 )3/2

in which the involved quantities were defined previously (see Eq. (2.4)). In the above
formula, 1 represents the dielectric material forming the plate, and 2 the medium
between them. This expression was obtained by Lifschitz and is called Lifschitz theory
[28]. Its structure is close to Eq. (2.4), with, again, the first two terms summing up the
7 for the sphere-sphere case, the relation is valid when the gap r is much smaller than the sphere
radii. In the opposite case, we retrieve the r−7 law, holding between two molecules
64 Physics at the microscale

Keesom and Debye contributions, and the third one the London term. The Hamaker
constant given by Eq. (2.6), like for Eq. (2.4), is on the order of kT , for the most
common materials used in microfluidics.

The theoretical approach was confronted to experiments, performed with sphere plane
systems (in this geometry, the expression of Van der Waals forces is −A/6r2 ). The
experimental curve of Fig. 2.13, obtained with mica, confirms the formula.

Fig. 2.13: Measurement of the force between two crossed mica cylinders of radius ≈ 1 cm, in
water and electrolytes [21]. The solid line if −A/6D2 , with D replacing our gap r and A = 2.2
10−20 J. The notion of retarded is related to the fact that interactions between molecules are
not instantaneous. Corrections, taking this effect into account, are proposed in the literature.
The subject lies outside the scope of the book.

It also allowed us to measure Hamaker constants. Table 2.6 displays some results.

This table calls for several remarks:

• The values in the tables are obtained either from Lifschitz theory, when the ex-
periment is impossible to perform (the case of water/air/water is an example)
or when data is not available. In air and in all cases where comparison could be
done, theory and experiment were close, within 20 percent or so.

• A is 1-10 kT in air (recall that kT ≈ 4.11 10−21 J) and 0.1-1 kT in liquids.

• Hamaker constants in metals are much larger than in Van der Waals solids. This
is due to the fact that in metals, due to strong attraction between metal cations
and delocalized electrons (metallic bonds), cohesive forces are much stronger.

• Measurements of the Hamaker constant in liquids are delicate and results pub-
lished in the literature are, sometimes, inconsistent.
 Intermolecular Forces - basics 65

Material (1) Medium (2) A (10−20 J)

Water Air 3.7
Polystyrene Air 6.5
PTFE Air 3.8
Fused quartz Air 6.5
Si02 Air 6.50
Teflon Air 2.75
Silicon Air 18.65
Metals Air 25 -40
Fused quartz Water 0.63
Si02 Water 0.8
PTFE Water 0.29
Teflon Water 0.33
Silicon Water 9.75
Metals Water 30 -40
Fused quartz Octane 0.13
Table 2.6 Hamaker constants for different materials.

Microfluidic measurement of the Hamaker constant at high salt concentrations. A

microfluidic method for measuring the Hamaker constant at high salinities has recently
been reported [30]. The experiment is shown in Fig. 2.14.

Fig. 2.14: (left): Top: Microfluidic experiment enabling the measurement of Hamaker constant
at high salinity. bottom: fluorescent images of the 5 µm particles deposited on the walls, two
seconds after they have been injected in the channel.; (right) Evolution of the number N (t)
of particles deposited on the microchannel walls as a function of time, for two different flow
speeds [30].

A dilute suspension of polystyrene particles, 5 µm in diameter, is injected, in a rect-

angular, shallow, rectangular microchannel. Most particles circulate through it, from
the entry to the outlet, but a fraction of them deposit on the bottom and upper walls.
They are somehow captured by the channel. The number of these deposited particles
N (t) increases, proportionally to time (Fig. 2.14), right). Theory conducted at high
66 Physics at the microscale

saliniity (where electrostatic forces are screened - see below -) shows that the slope P
of these lines is equal to:

r φQ √
P = S
h/2 − r vp
,
in which φ is the mass fraction of the particles, vP is their volumes, Q is the flow rate,
h is the channel height, and S is given by:

A
S= ξL
kT

where A is the Hamaker constant, ξL = ULD rr

2 (in which L is the channel length, D the

diffusion coefficient of the particles, r their radius, and Ur the flow speed at a distance
r from the wall). By measuring the slope, one has access to the Hamaker constant A.
The value of A, estimated from Fig. 2.14, is equal to 8±0.4 10−21 J, which is close
to Lifschitz estimate (7.6 10−21 J) for a polystyrene/glass interface with water as a
medium.

2.2.3 Macroscopic manifestations of Van der Waals forces

Adhesion forces . When two planes come in contact, i.e. when the surface molecules
are separated by a molecular distance D0 , the force of attraction per unit of area, i.e.
the pressure P , called adhesion force, becomes:
A
P =−
6πD03

−21
Taking D0 = 0.3 nm, A = 6.5 10−20 J (fused quartz), one obtain P = 6π(31010−10 )3 ≈-
1280 bars. This is a huge (negative) pressure. In practice, the surfaces are rarely
atomically smooth and this estimate should be amended by several orders of mag-
nidude. Still, there is space, by optimizing the contact surface, to reach high pressures
of adhesion. This is what glues are doing. Glues do not possess adhesive virtues per
se, their functionality originates from the fact that they fill the vacant spaces between
two surfaces, in order, after solidification, to deploy the Van der Waals forces we just
calculated. Along this line of thought, one could imagine assembling plane wings to
the fuselage just by gluing them.8 Taking 10 m2 as the area of contact between the two
pieces, and using the previous Hamaker-based estimates, we would reach an adhesion
force of 100 kTons, a force sufficient to prevent the wings to detach during the flight, an
event that could scare the passengers. The task of improving the contact area between
two solids is well achieved by the gecko. For this purpose, the animal uses a complex

8 Words taken from Pierre Gilles de Gennes

 Intermolecular Forces - basics 67

system of setules, described in the literature [31, 32]. As a result, it suspends its own
weight above the floor by applying just one toe on a surface (see Fig. 2.15).

2.15: The gecko suspends his own

weight above the floor just by apply-
ing one finger on a surface (see the
arrow). Each finger possess structures
optimizing contact area, so as to take
advantage of the Van der Waals at-
tractive forces. (Reprinted from [32]
with permission of IOP Publishing,
Ltd. Copyright 2022.).

Surface tension. Surface energy γ is defined as the energy required to increase the
area of a liquid or a solid by one unit. Surfaces of solids can be increased in many ways,
such as by breaking them in two pieces. The corresponding energy cost is equal to the
work done by the Van der Waals forces to take the two pieces apart. Its expression is:
Z ∞
A A
E=− 3
dr = 2 = 2γ
D0 6πr 12πD 0

where γ is the surface energy, considering that the cost is shared between the two
surfaces. An energy, per unit of area, of 2γ is thus necessary to separate two planes
bound by Van der Waals adhesive forces. From this calculation, one concludes that
each surface possesses an energy density equal to γ, whose expression is:
A
γ=
24πD02

The system minimizes it by reshaping the interfaces, when interfaces are deformable.
Along this line of thought, a liquid blob will spontaneously become spherical, to min-
imize its exposed area.

Surface tension is a different concept: it is the tension that the solid or liquid elements
are subjected to at the surface. It is expressed as a force per unit of length. We will
see, in Chap 4, that in liquids, surface energy and surface tension are equivalent, and
they are often legitimately confused, while in solids, in general, they are not. Surface
tension gives rise to many spectacular phenomena, such as spontaneous reshaping of
68 Physics at the microscale

liquid blobs into spherical drops, as mentioned above, jet break-up, capillary rising,
and imbibition, which will be developed in Chapter 4.

2.2.4 Molecular Dynamic (MD) simulations of interfaces

Today, numerical simulations at the molecular level are important tools for under-
standing fluid behaviours. Most of them are based on Lennard-Jones potential (Eq.
2.3), to which random noise, mimicking the effect of temperature, is added. Two types
of simulations are carried out:
• Monte Carlo (MC) simulations calculate the evolution of the system, based on
Newton’s law, and reject the new state if it increases the total pairwise energy
of the system. MC allows the equilibrium state to be determined in an efficient
manner.
• Molecular dynamics (MD) simulations track the evolution of the system, whatever
the energetic direction it takes. This approach is often preferred in fluid physics,
because, although it takes a longer time to reach the equilibrium, it allows the
kinetics to be analyzed. Also, the notion of equilibrium does not apply to all
fluidic situations. A typical MD simulations involves thousands of particles. The
step is typically one fs, and the accessible range of time several ns, thus millions
of steps. In the present state of the technology, it would take more than the age
of the universe to calculate the dynamics of a microfluidic system for one second.
Systems computed with LJ potentials exhibit rich phase diagrams, including solid-
liquid, liquid-gas and solid-gas transitions, triple point, thus showing similarities with
the behaviour of real systems. Fig. 2.16 shows a case where parameters have been
tuned so that gas and liquid phases coexist.

2.16: Lennard-Jones simulation of a

nanobubble sitting on a surface patterned
with hydrophobic patches. Dark dots are
the liquid, grey dots are the gas. The liquid,
oversaturated in gas, is held at a pressure
of 26 bars. In these conditions, the bubble
remains stable for 45 ns, i.e. millions of
characteristic molecular times, without
any measurable change [33]. In Chapter 5,
arguments will indicate that this bubble
remains indefinitely stable. (Reprinted
with permission from [33]. Copyright 2022.
American Chemical Society.).

The simulation shows that, starting with a square distribution of particles, we end
up with a semi-spherical interface separating the liquid and the gas, i.e. a bubble.
We learn that even though bubbles are nanometric, they possess evident similarities
with their micro and millimetric equivalents. The simulation of Ref. [33] moreover
showed that, contrarily to naive arguments, nanobubbles pinned on a textured surface
do not dissolve in oversaturated liquids (see Fig. 2.16). In fact, the simulation helped
 Intermolecular Forces - basics 69

to end a long-term controversy (15 years). We will return to this point in Chapter
5. In many cases, simulations provide information on nanosystems, inaccessible to
experiment. Because of that, they have contributed considerably to the understanding
of nanofluidic phenomena, even though, as mentioned above, they are limited in time
to a few nanoseconds, and in size to a few nanometres.

Happy and unhappy molecules. One might ask why the interface found in Fig. 2.16
is semi-spherical. We will develop this point in detail in Chapter 4, but it is worth
discussing it here, from a microscopic viewpoint. Molecules in the bulk fluctuate in
position, but, on average, they feel the attractive forces exerted by their partners.
Let us consider an extremely simplistic model, in which molecules stay close to the
equilibrium point, i.e. at a distance equal to 21/6 σ from their nearest neighbours. This
model is that of a solid, and it will be criticized later, when capillary phenomena
are discussed in detail (see Chapter 4). Restricting ourselves to cubic structures and
immediate environments, the corresponding energetic level, associated to energy plot
minima, is −6. Bulk molecules cannot achieve a better energetic situation, and there-
fore, they feel happy’. At the interface, the molecules develop nine nearest-neighboring
bonds, and, thereby, the corresponding energy level9 is close to -4.5. These molecules
feel unhappy’. The system, being in a quest for an energy minimum, will minimize the
number of unhappy molecules, an objective it meets by adopting a spherical shape,
the sphere being the shape that minimizes, for a fixed volume, the exposed area.

2.2.5 Electrostatic forces between surfaces

When a dielectric is immersed in an electrolyte, a surface charge spontaneously ap-

pears. For example, a plate of glass immersed in a non-acidic aqueous solution, becomes
negatively charged. By preparing a pleasant beverage, such as an orange juice or mint
with water, we also cover the internal surface of the glass with charges. The origin of
this phenomenon comes from the fact that in aqueous solutions, the silane terminals
Si–O–H localized on the glass surface lose hydrogen ions in the presence of the aque-
ous solution; this protonation leaves Si–O− terminals on the surface, thus causing the
glass exposed to aqueous solution to become negatively charged. The electric potential
associated with these charges, for a pH of 7, is on the order of −30 mV. Protonation is
not the only cause of spontaneous charging of a surface in contact with water. Different
mechanisms exist. We will address this question in Chapter 6. They are described in
detail in the literature, for instance, in the text of Cabane and Hénon [34].
These surface charges are equilibrated in the fluid by a double layer of counter-ions,
as shown in Fig. 2.17 (A).
The first layer is fixed and is called the ‘Stern layer’. We shall discuss its structure
in Chapter 6. Although much remains to be learned regarding the Stern layer, its
thickness is considered to be on the order of the Bjerrum length, defined by:

9 Taking the full environment of the molecule into account, one finds -8.38 for molecules in the
bulk and -5.88 for molecules at the interface.
70 Physics at the microscale

(a) diffusse layer (b) 104

+ +100
0.1 M KNO3
+ – –
ΔΦSt + – F/R
+ – 103 104 M KNO3 0
Carbon matrix

+ –
+ – +
diffusse layer 104 M C8 (NO3)2 –100
+ 0 5 10
ΔΦd
+ – – + 102
–
Stern layer

+ – – Φ0
– +
+ – + –
+ – Φext 10
0 50 100 150
Distance D (nm)

Fig. 2.17: (A) Sketch of the Stern and Debye layers; (B) Measurement of force between two
crossed mica cylinders of R ≈ 1 cm in electrolytes. The forces of the double layer decrease ex-
ponentially with distance, and can extend over several tens of nanometres. The solutions used
for this experiment are KNO3 , and CaNO3 for the upper and lower curve, respectively. The
continuous lines are obtained from the Derjaguin-Landau-Verwey-Overbeck (DLVO) theory,
after [21]

e2
λB =
4πε kT

where e is the elementary charge. For water at room temperature λB ≈ 0.7 nm.

The second layer is diffuse. It results from a statistical equilibrium between thermal ag-
itation (which tends to homogenize the charge distribution) and electric forces (which
tend to displace charges of the same sign towards the surface, thus creating a charge
profile). We will describe it in detail in Chapter 6. The order of magnitude of the
thickness of the double layer, designated by λD (the Debye length), is given for a
binary symmetric electrolyte, by the following expression:

s
kT
λD = . (2.7)
2ρ∞ q

where ρ∞ is the ionic concentration (in C/m3 ) far from the walls and q is the ion
charge (q = e for monovalent ions, such as Na+ or Cl− ). The others quantities
have been defined in the previous sections. Debye layer is around ten nanometres
thick for an ionic solution of 1 mM of monovalent salt. As λD varies with the in-
verse of the square root of the charge concentration, it can in principle achieve high
values. However, practically speaking, because of the presence of charged impuri-
ties, the thickness of double layers does not exceed about a hundred nanometres.
This double layer is the origin of electrostatic forces, which had been measured in
force machines. Figure 2.17 (B) shows measurements of such forces, between mica
cylinders, for two different electrolytes.
 Nano-Micro and Millifluidics 71

The force of the double layer decreases exponentially, as theory predicts (we will return
to this point in Chapter 6). Fig. 2.17 (B) also indicates that the fluid feels’ the wall
at distances of several tens of nanometres.

2.2.6 Other forces.

When a liquid is confined between two surfaces separated by a few nanometers, the
liquid tends to structure itself. This structuration effect has important consequences
on the way how the fluid behaves, as we mentioned before, and the surfaces interact.
The field of forces developing in the tiny space becomes an oscillating function of the
distance from the wall [21]. The spatial period is on the order of the intermolecular
distance inside the liquid. This oscillatory behaviour plays a considerable role in the
behaviour of water in carbon nanotubes: for instance, it leads to a reversal of the
wettability or nonlinear behaviors. Other forces arise when surfaces are functionalized.
All these forces have given rise to a wealth of studies, well described in textbooks. We
will not develop the subject in this book, therefore.

2.3 Nano-Micro and Millifluidics

Fig. 2.18: Definition of the three fundamental domains involved in small-scale hydrodynam-
ics: nano-micro and millifluidics. Microfluidics, which covers four orders of magnitude, is the
focus of this book.

Fig. 2.18 and 2.19 show the three domains that define what we could call ‘small scale
hydrodynamics’: nanofluidics (between 0.1 and 100 nm), microfluidics (between 100
nm and 1 mm) and millifluidics (between 1 mm and 1 cm).
Nanofluidics Nanofluidics concerns fluidic systems whose sizes pertain to the 0.1
-100 nm range. It extends over three decades. Two subdomains can be defined:
• 0.1 -1 nm (subcontinuum nanofluidics): Molecular scale prevails. Ordinary
equations, such as the Navier-Stokes equations, based on a continuum as-
sumption (which we will discuss in Chap 3), are no more valid. This range of
scale is called subcontinuum.
• 1 -100 nm (continuum nanofluidics). Continuum hypothesis holds. Many
characteristic lengths pertain to the domain: thermo-capillary length, Debye
72 Physics at the microscale

length, mean free path, Bjerrum length, nucleation radius, slippage length, to
mention a few.10 They are shown in Fig. 2.19. These scales combine with the
confinement to give rise to interesting phenomena: unusual regimes of droplet
production in jets [35], non-hydrodynamic flow regimes [14], and transistor
effect [36]. The list is not exhaustive.

Fig. 2.19: Definition of the three fundamental domains involved in small scale hydrodynamics,
in which several characteristic scales are outlined. They are discussed in the text.

From a technological viewpoint, the methods employed in nanofluidics for fabri-

cating devices are based on UV photolithography (limited to sizes above10 nm)
or e-beam photolithography [37]. By the turn of the century, new materials ap-
peared, such as carbon nanotubes or graphene surfaces. This fostered the field
by enabling the creation of sub-10 nm devices, with unique properties. We have
developed the subject in Chapter 1, and will return to it in Chapter 3.

Microfluidics : Microfluidics concerns system sizes pertaining to the 100 nm - 1

mm range. The domain is vast: it extends over four decades11 . It represents the
central subject of this book. In terms of scales, the microfluidic domain looks
empty (see Fig. 2.19): not a single characteristic length pertains to it. In this
context, microfluidics possesses four outstanding properties:

• The behaviour of a microfluidic system is the same at all sizes. What happens
in a device, 100 nm in size, is the same as in a geometrically similar system,
ten thousand times larger.

10 The fact that thermo-capillary, nucleation and Bjerrum lengths are nanometric is true for Van
der Waals materials and water. There is a relation between these orders of magnitude and the fact is
that solid-liquid and liquid-vapor transitions of these materials take place in the 200-350 K range.
11 A proposal has been made to single out, within microfluidics, a sub-domain ranging between 100
nm and 1000 nm, called ‘extended nanofluidics’ [38].
 The physics of miniaturization 73

• Microfluidic scales being smaller than capillarity and Reynolds lengths (see
Fig. 2.19), gravity and inertia are negligible. By eliminating two parameters,
the systems are simpler to analyze and control.
• In the microfluidic domain, all microscopic and mesoscopic phenomena are
smoothed out, just as in macroscopic physics. This concerns, for instance,
thermal noise and the spatial structure of Van der Waals forces. This feature
considerably simplifies the control of microfluidic devices.
• Another important characteristics is geometric: the sizes of a number of in-
teresting objects fall in the microfluidic range. The most important example
is the human cell, 10 µm in size, which can be manipulated individually in
microfluidic devices. This gives rise to a considerable number of applications:
cell sorting, chemotaxis, single cell assays, and single cell -omics - (genomics,
transcriptomics, etc..) to mention but a few.
From a technological prospective, microfluidics is the realm of photolithography,
moulding, etching and deposition, which will be described in Chapter 7.
Millifluidics Millifluidics concerns fluidic systems whose sizes pertain to the 1mm -
1 cm range. It extends over one decade. This small domain hosts two important
characteristic scales: Reynolds and capillary lengths. This implies that in milliflu-
idics, inertia and gravity are generally important. The physics below and above
1 mm is therefore different. Technologywise, creating millifluidic devices requires
tools different from nano and microfluidics: for instance, low resolution 3D print-
ing, micromachining and injection moulding. Toolboxes below and above 1 mm
differ. We will develop the subject in Chap 7.

2.4 The physics of miniaturization

2.4.1 The Π theorem

The theorem of the product, called Π theorem, allows the number of variables of a
system to be reduced. The demonstration of the theorem is an elegant exercise of linear
algebra that the reader can find in fluid mechanics textbooks (see, for example, [39]).
The behaviour of a system is expressed by a function f , which relates an observable
A to n − 1 physical quantities, noted a1 , a2 ... an−1 .

A = f (a1 , a2 , . . . , an−1 )

These quantities possess k independent units (for instance three: metre, second, and
kilogram). The Π theorem states that the law f can be written in the following form:

Π = g(π1 , π2 , . . . πn−k−1 )

where the πs are independent dimensionless products formed from the initial quantities
and g, apart from a pre-factor, is equal to f , written in terms of the new dimensionless
74 Physics at the microscale

variables. We now only have a relation between n − k , instead of n variables. We

thus have reduced the number of variables by k. In many cases, this represents a
considerable simplification.
The origin of the Π theorem plunges deep in the history. In the fourth and third
millennia BC, the ancient peoples of Egypt, Mesopotamia and the Indus Valley in-
troduced units and homogeneity rules in order to trade. Lengths were measured with
the forearm, hand, or finger, and time was measured by the periods of the sun or the
moon. These were the units. If the outcome was a price, factors were introduced, such
as a price per unit of weight or length, to ensure homogeneity in the calculations.The
Π theorem, which formalizes, mathematically, this homogeneity rule, could be viewed
as a generalization of these antic practices.

Application 1: Pythagora’s theorem. More than one hundred demonstrations of Pythagora’s

theorem exist. This one is based on the Π theorem.

2.20: Triangle used to demonstrate

Pythagora’s theorem by using the Π
theorem.

The surface area S of the grey triangle shown in Fig. 2.20 is a function of φ and c, the
hypothenuse. It reads:
S = f (c, φ)
We have n = 3 variables and k = 1 dimension, a length. Using the Π theorem,
we conclude that the problem is governed by 3 − 1 = 2 independent dimensionless
variables. We choose them equal to cS2 and φ. Therefore, we can write the above
relation in the following form:
S = c2 g(φ)
where g is a function.12 The same law, with the same g and the same φ applies for the
subsurfaces S1 and S2 . Consequently, we have:

S1 = a2 g(φ).. and. S2 = b2 g(φ)

By using S = S1 + S2 , and elimination of g, we find:

a2 + b2 = c2

which is Pythagora’s theorem.

12 Function g is equal to 1
4
sin 2φ but we do not need to know this expression for demonstrating
Pythagora’s theorem.
 The physics of miniaturization 75

Application 2: Reynolds number. Let us consider the incompressible flow around an

object of characteristic dimension l (for instance, the sphere radius of Fig. 2.21).

2.21: Flow around an solid sphere.

The local velocity u (assumed to be stationary) must be written as a function of the

following parameters:

u = f (x, l, U, µ, ρ),

where x is the spatial coordinate, l is the sphere radius, U is the upstream speed, µ
is the viscosity, and ρ is the volumetric mass of the fluid. We have k = 3 and n = 6.
We deduce that we can form n − k = 3 independent dimensionless products, which we
choose to be equal to:
x u Ul
, and ,
l U ν
where ν = µ/ρ is the kinematic viscosity. The product U l/ν is the Reynolds number
Re. Thus, the preceding relation can be written in the form:

u/U = g(Re, x/l)

where gU is function f expressed in terms of the new dimensionless variables. We thus

have a much simpler expression than the initial expression.

From this expression, we can conclude that reducing l is equivalent to reducing U or

raising the kinematic viscosity ν. Without scrutinizing the flow equations, which we
will do in Chapter 3, we can infer that flows at small scales resemble extremely viscous
fluids circulating at creeping speeds. An example is the flow of honey around a spoon
gently displaced, at constant speed, in a pot. The empirical knowledge of these situa-
tions suggests that, in miniaturized devices, there will be no eddy, no hydrodynamic
instabilities, and no turbulence.

Comments.

• The two above examples illustrate the force of the Π theorem. By identifying
the relevant variables, exploiting the fact that each of them conveys a unit, and
units must be homogeneous, the theorem allows insightful conclusions to be drawn
without solving any equation.
76 Physics at the microscale

• Π theorem is powerful when the number of variables is small, but it is less oper-
ational when many variables come into play. In this case, several dimensionless
numbers must be defined, in one way or another, and the final relation, i.e the
equivalent of g, includes too many quantities to provide a clear vision of the situ-
ation. This often happens in physico-chemistry. In this field, the Π theorem rarely
helps in disentangling the inherent complexity of the phenomena.

2.4.2 The concept of scaling law

A ‘scaling law’ signifies a relation between an observable quantity and a measure of the
size of the system. The subject is long-standing. It was discussed by Galileo [40], Sir
D’Arcy Thomson [41], and many others. Table 2.7 presents a number of laws applying
for physical quantities, and pertinent to microfluidics.

Quantity Scaling law

Capillary force l1
Flow speed at fixed pressure gradient l1
Thermal flux at fixed temperature difference l1
Viscous force at fixed speed l1
Adhesion force l2
Electrostatic force at fixed electric field l2
Magnetic force at fixed magnetic field l2
Diffusion time l2
Muscular force l2
Mass l3
Force of gravity l3
Electrical motive power at fixed electric field l4
Inertia force at fixed pressure gradient l4
Centrifugal force at fixed rotation rate l4
Table 2.7 Scaling laws of different quantities.

Table 2.7 deserves a number of explanations and comments.

• For certain quantities, the scaling law is obvious. This is the case for mass where
we have the law:

M = ρV ∼ l3

where M is the mass of an object of size l, ρ its density and V its volume.
• The exponent of pressure driven flow speed is justified by the following formula,
resulting from orders of magnitude arguments made on Stokes equation, i.e in a
laminar regime (we will discuss this case in Chap 2):

h2 ∆P
U∼
µL
 Scaling laws in nature 77

where µ is the fluid viscosity, ∆P is the pressure difference applied along the
canal, L is the canal length, and h is its transverse dimension. At fixed pressure
gradient ∆P/L, considering there is a single geometric scale in the problem (which
is acceptable when the channel is square, the aspect ratio is large, or the cross-
section is circular), one obtains U ∼ l. Therefore, the scaling law exponent is equal
to one. Should the pressure gradient be a function of l, the scaling law would be
different.
• The scaling law for the electrostatic force Fe is obtained by using the following
relation:

Fe ∼ E 2 l2 ,

where  is the dielectric constant and E is the imposed electric field. With a
fixed electric field, the exponent is equal to 2. Similar considerations hold for
2
electromagnetic forces, equal to B 2
2µ l , where B is the imposed magnetic field and
µ is the magnetic permeability.
• Muscular force: The muscular energy is proportional to the volume of the body,
i.e. l3 . This energy is used to perform a work over a distance l (the only scale of
the problem). We infer that the muscular force scales as l2 .
In fact, the general rule of thumb is as follows: when two forces are present, it is the
force associated with the weaker exponent that becomes dominant in miniaturized sys-
tems. Thus, the equilibria we are used to in the human-scale world can be disrupted
at the micrometric scale. For example, gravity forces, being associated to a high expo-
nent, are most often negligible in the small world. This situation is the inverse of the
human-size world. Scaling laws have far-reaching implications, as will be seen later.

2.5 Scaling laws in nature

2.5.1 Mite clinging to a disk rotating at large speeds

2.22: Mite from New Mexico wan-

dering on a micromotor, before it
rotates (From Sandia Laboratories
(2005).).

Let us consider an animal of size l and density ρ, placed on a motor rotating at rate Ω
(see Fig. 2.22). In these conditions, the centrifugal force the animal is subjected to is:
xFc ∼ ρΩ2 l4
78 Physics at the microscale

We recover exponent 4 of Table 2.7. It is thus not difficult for a mite 100 µm large, to use
the adhesion forces (proportional to l2 , as we saw in the previous section and as shown
in Table 2.7), to cling to the motor, even though the latter rotates at large speeds, for
instance tens of rotations per seconds, as shown in a film by Sandia Laboratories in
2000 (not available today).

2.5.2 Kleiber’s law

The basal metabolic rate Wb is a central concept in animal physiology. It is the power
needed for an animal to live, when at rest. It involves all what is requested by the
organism to survive: breathing, blood circulation, heart beating, food digestion, etc.
Two main methods are used for measuring Wb :

• Insert the animal in an ice block and measure the melting rate.

• Place the animal in a confined environment and measure the rate of consumption
of the oxygen, assuming that this rate is proportional to Wb .

Both methods were used in 1784 by Lavoisier [42]. The basal metabolic rate Wb in
Watt) is represented in Fig. 2.23 in a function of the animal weight M .

103

102
Wb (watt)

101

100

10–1
10–2 100 103 104
Mass (kg)

Fig. 2.23: Kleiber’s law, relating the basal metabolic rate Wb to the animal mass M . The
line corresponds to the formula Wb = 3.45M 0.75 (best fit obtained excluding the whale, as
Kleiber did) [43].

The plot was obtained by Max Kleiber in 1947 [43]. Data are taken from the paper,
using modern units. It was a surprise to find that, despite the diversity of animals, Wb
follows so neatly, over five decades, a power law. Its expression is :

Wb ≈ BM 0.75
 Scaling laws in nature 79

where B ≈ 3.45W/kg 3/4 . Before Kleiber, a theory, called ’surface law’, proposed an
exponent 2/3. The idea was the following: suppose the thermal flux density, across
the body surface is the same for all animals, then we would have Wb = f (M, J),
which would imply, on using Π theorem, Wb ∼ M 2/3 . The surface law, which states
that animals produce heat proportionally to their surface areas, remained a dogma for
more than a century. It was based on a geometrically similar hypothesis. It was still
influential in the 1980s [47], although there was no justification for it. In the first part
of the last century, the amount of evidence that nature often obeys allometric laws (i.e.
that are not geometrically similar) increased, challenging the law. In fact the exponent
found by Kleiber in 1947, was not 2/3, but 0.75 ± 0.03. The difference seems small,
but it is significant, and has far-reaching consequences. It leads to different estimates
of life span, heart beating frequency, blood pressure, aorta diameter, etc...along with
a different vision of the circulation network of air and blood in the body [44].

Kleibler’s law remained mysterious for decades. In the nineties, an argument, based
on self similarity, emerged [54]. It led to conclude that the exponent should be exactly
3/4. The ingredients of the theory, very well explained in the course of T.Lecuit [45],
are sketched in Fig2.24.

2.24: Kleiber theory: blood and air cir-

culate through a self-similar hierarchical
network, with scales decreasing down to a
terminal scale, the cell size, the same for
all animals. The study of the optimization
of this network, from the point of view of
the power needed to drive fluids through
Mammal it, led to Kleiber’s law [45].

The system requires efficient delivery to ensure energy conversion at the cell level.
The evolution solved the problem by forming self similar structures, sketched in Fig.
2.24. Blood and air circulate through a self-similar hierarchical network, with scales
decreasing down to a terminal scale, the cell size, the same for all animals. The network
is space filling, because, in the body, cells occupy a substantial, homogeneous fraction
of the space. The study of the optimization of this network, from the point of view of
the power needed to drive fluids through it, led to Kleiber’s law. From the theory, we
3/4
may propose an estimate for the constant B; in the form B ∼ wc /mc , with wc the
−10
cell energy consumption and mc its mass. With wc ∼ 10 W and mc ∼ 1 pg, one finds
B ∼ 1W/kg 3/4 , which is consistent with the experimental estimate. The demonstration
of Kleiber’s law, which is quite elaborate, is well-explained in T. Lecuit’s lectures [45].
It stands outside the scope of this book.
80 Physics at the microscale

2.5.3 The short lifespan of small animals

Kleiber’s law has many consequences: for instance, it allows to establish the dependence
of the heart beating frequency f with the animal mass M. The argument as follows:
the time it takes to bring the oxygen from the lungs to the body is several 1/f . The
transported blood volume, per unit of time, is l3 f . This flow rate, conveying all the
oxygen needed to burn the energy used by the animal to stay alive, is proportional
to the metabolic rate. Taking Kleiber’s law, we conclude that heart beating frequency
scales as l−3/4 .

The calculation of the animal’s life span follows. It is based on a mysterious fact that,
whatever the animal size, the number of heartbeats during its entire life is the same:
about 1.5 billion. It is a sort of credit given to everyone, at its birth. So, based on that,
one infers that the lifespan T is:

T ∼ l3/4 ∼ M 1/4

This scaling is compared to the observation in Fig. 2.25 [45, 46].

2.25: Lifespans of mammals as a func-

tion of their weight [45, 46]. The 1/4
law can be taken to represent the lifes-
pans of all mammals (see the first line,
on the left of the graph), even though,
for extremely large animals, another
power law could be suggested, as is
done in [46]. (Reprinted from Ref. [46],
with permission from Wiley and Sons.
Copyright 2022.).

The spread is large, but the theoretical prediction is consistent with the observations
(see the first line, on the left of the graph), even though, for extremely large animals,
another power law could be suggested, as is done in [46]. The smallest mammal on
earth, the pygmy shrew, a few grams in weight, lives for 12-15 months. The largest
animals, the whales, one hundred tons or so, can live for 200 years. A human, with a
lifespan of 70 - 80 years, stands in between. To be able to live much longer, as Methuse-
lah (969 years [48]) or his son Lamech (777 years [49]) are said to have done, one would
have to drastically reduce one’s metabolism rate and, consistently, one’s heartbeat fre-
quency. The remaining problem to solve would be avoid falling into sluggishness, which
would be quite challenging.
 Scaling laws in nature 81

2.5.4 The running of animals

The running of animals, as a function of their size, is a more delicate subject. Naive
arguments suggest that the maximum speed is independent of the size. For instance,
it can be argued that, in order to acquire a kinetic energy of 12 M V 2 , the animal must
deploy a work equal to Fm l, where Fm is the muscular force. Fm scaling as l2 , this
would lead to V ∼ l0 ∼ M 0 . The measurements on a large collection of animals,
running on firm ground revealed the existence of an exponent, small but not equal to
zero. This is shown in Fig. 7.13. There is a large spread but it appears that, below a

2.26: Maximum speed V (in km/h)

of a variety of animals as a function
of their body mass M (in kilogram).
The line is the formula V ≈ 26 M 1/4
(Reprinted with permission from [52].
Copyright 2022. Springer Nature).

certain mass (on the order of 100 kg), a power law takes place, over nine decades, with
an exponent equal to 0.25 ± 0.1 (see Fig. 7.13). Theoretical arguments, based on an
optimization of the total power used by the animal, for struggling against air friction
and supplying the body oscillation during the run [53], suggest the following power
law :
V ∼ M 1/6
which leads an exponent 0.17, consistent with the measurements. In is interesting to
note, in the framework of the chapter, that the exponent 1/6 can be explained by
using Π theorem: considering that air friction and gravity play roles in the maximum
speed estimate, one can write:

V = f (ρa , ρ, g, l)

in which ρa is the air friction density, g is the gravity and ρ and l are the body density
and animal size. Applying Π theorem, we conclude that only two dimensionless number
drive the system. This leads to the following expression:
82 Physics at the microscale

ρa
V = g 1/2 l1/2 g( ) ∼ M 1/6
ρ

The detailed analysis leads to g(x) = x−1/3 . At the expense of some adaptation, it has
been shown that the 1/6 law also applies to birds and fishes [53].

Nonetheless, limits exist. To give a rough idea, should a global power law, such as
the one shown in the caption of Fig. 7.13, be true, we would infer that the elephant
runs at 211 km/h, which no one has ever seen, even when the animal has an urgency.
In fact, as shown in Fig. 7.13, there is a cross-over beyond which the animal speed
falls. This cross-over is linked to the kinetics of supply of the muscles in energy [52].
The existence of this cross-over implies, for instance, that the tyrannosaurus and the
mammoth, whose masses are around 6 tons, do not run at 228 km/h, as the empirical
scaling law of Fig. 7.13 would suggest, but at a speed on the order of 29 km/h [52].
More examples are shown in Table 2.8.

Animal Mass (kg) Scaling law (km/h)Phys. limited

Velociraptor 20 55 39
Allosaurus 1400 159 24
Thyrannosaurus 6000 228 29
Triceraptos 8500 250 26
Apatosaurus 28000 336 12
Braciosaurus 78000 434 18
Table 2.8 Name, mass, scaling law and physiology-limited speeds of several prehistoric an-
imals

For the brachiosaurus, whose weight is 78 tons, the scaling law of Ref. [52], would lead
to an impressive 434 km/h, faster than the french TGV.13 In the same line of thought,
is the drawing shown in Fig. 2.27 correct ?

2.27: Is it correct to sug-

gest that the tyrannosaurus
will catch these two helpless
struthiomimus dinosaurs? (Li-
cence Pixels Library - credit Mo-
hamad Haghani.)

13 TGV means ‘Tres Grande Vitesse’, i.e. very fast trains

 Scaling laws in nature 83

The flightless birds run, according to their mass (between 30 and 60 kg), at about
50 km/h. They would be easy preys for the tyrannosaurus, if he ran at 229 km/h.
However, with the physiological limitation just mentioned, his speed does not exceed
29 km/h. Then according to this estimate, the birds have a good chance to escape the
predator. It is interesting to add, in Jurassic Park, Spielberg was right to show the
tyrannosaurus outpaced by the Jeep, even though the car was not driving as fast as a
Ferrari.

2.5.5 The unpleasant life of the pygmy shrew

Before presenting the pygmy shrew, the smallest mammal on the planet, one must
discuss the question of thermal regulation.
Mammals are endothermal animals, i.e. they regulate their temperature internally, by
adapting the metabolism W , i.e. the production of heat, to the external conditions.
W is an adjustment variable, whose lower value is Wb the basal metabolism, and its
highest values are 4-5 Wb . Wb follows Kleiber law, as we saw in an earlier section. The
equation that expresses the thermal balance of mammals is [50, 51]:

W ≈ K(Tb − Te )l (2.8)

in which K is the ambient conductivity (for instance, the thermal conductivity of

water, for aquatic animals), l is the animal size, and Te and Tb are the exterior and body
temperatures, respectively. For the sake of simplicity, we assume K to be constant. In
order to keep the body temperature Tb constant, around 30 -37◦ C, W must compensate
for the variations of the environment. This is done by the hypothalamus, a gland which,
based on temperature sensors distributed in the body, regulates the blood flux, the
sugar content, among other variables. Fig. 2.28 shows how the animals (e.g. dogs)
adapt their metabolism to keep their temperature constant, in thermally changing
environments.
Fig. 2.28 is currently used in the field of thermal biology. It simplifies the problem: for
instance, there should not be such well-defined plateaus. We will nonetheless take this
diagram as a given to discuss the effect of miniaturization.
Let us start with the cold temperatures: on the left of Fig. 2.28(A) (bottom), between
0 and 20 ◦ , the metabolic rate W decreases linearly with the external temperature.
The linear decrease is imposed by Eq. (2.8), in which Tb is constant. In this range of
temperatures, the animal manages to keep its temperature at 37◦ . However, below 0◦ ,
this is no longer possible and the body temperature drops (see Fig. 2.28 (A), bottom).
Depending on the animal, this causes death (in the case of humans), hibernation, or
torpo (the case of hummingbirds at night). At higher temperatures, W reaches the
basal metabolism Wb . Above this temperature, called the lower critical temperature
LCT , W remains constant throughout a range of temperature called temperature neu-
tral zone (TNZ). In this range, the animal feels comfortable. The TNZ marks the
range of temperature in which the animal can live, although, in practice, it can endure
colder conditions. As the external temperature Te rises again, above a temperature
84 Physics at the microscale

Fig. 2.28: (A) : (Top) Evolution of the body temperature as a function of the external
temperature (see text); (bottom)Evolution of the metabolic rate, divided by the basal rate
Wb as a function of the ambient temperature. The graph corresponds to a dog. (B): Plots
similar to (A), for the case of small animals. (Top): Evolution of the body temperature with
the external temperature. (Bottom): Evolution of W/Wb with the exterior temperature.

called upper critical temperature UCT , the plateau ends. The animal has to struggle
against heat stresses (by sweating, or lapping). Unfortunately, above a certain tem-
perature, 40◦ or so, he no longer manages to keep its temperature constant and thus
dies. In humid environments, evaporation is slower, and, consequently, body cooling
is less efficient.

To discuss the consequences of miniaturization, it is useful to rewrite Kleibler’s law in

the form: Wb ∼ Al9/4 , where A ∼ ρ3/4 B, with ρ the animal density and B ∼ 1W/kg 3/4
(we work here with orders of magnitude). We thus have:

W/Wb ∼ KA(Tb − Te )l−5/4 (2.9)

The law is sketched in Fig. 2.28 (B). According to Eq. (2.9), with l small, the lower
critical temperature, defined by W/Wb =1, cannot be significantly different from the
body temperature, Tb . Consequently, the temperature neutral zone collapses. More-
over, because of the steepness of the slope given by Eq. (2.9), it would cost a great
deal of energy, for the small animal, to escape the neutral zone. In such circumstances,
it becomes difficult to find a place to live. From the plot of Fig. 2.28 (B), one can
estimate the sizes of the smallest mammals living on earth and in water. This size is
given by the following relation (for the ease of reading, we replace TNZ by ∆TN Z ):

l ∼ (KA∆TN Z )4/5 (2.10)

 Scaling laws in nature 85

In air, with ∆TN Z ∼ 1◦ , K ∼ 10−2 W m−1 K −1 and A ∼ 1W/m9/4 , one finds 3 cm. In
water, where K ∼ 1W m−1 K −1 , one finds 1 m. These estimates are rough, but their
orders of magnitude are consistent with the sizes of the smallest mammals living on
earth (the pygmy shrew, 2 g weight is 5 cm large (see Fig. 2.29)) and in the sea (the
sea otter is one metre big).

The pygmy shrew has an unpleasant life: it must eat all the time to keep the metabolic
rate high. During the night, it enters a state of torpor to preserve energy. This reduces
the chance to make beautiful dreams. When it awakes, in the morning, it must rush
out to eat. The animal hates heat, and prefers to live in the mid-northern part of
Europe and America. It also hates cold, and spends a part of its life in niches.

2.29: The pygmy shrew. Its heart

beats at 500-800 Hz. Its gestures are
fast (a few milliseconds.). The ani-
mal ingests its own weight in insects,
worms, and spiders on a daily basis.
A venom, located in its mouth, paral-
yses the prey (From Flickr library, Si-
mon Ward.).

Below l, mammals do not survive, but poikilotherm animals, called cold-blooded ani-
mals, such as insects, or reptiles, do. For them, temperature is not controlled internally,
but fixed by the environment. This looks clever but, on the other hand, as their tem-
perature is out of control, their biological complexity cannot compete with that of the
mammals.

2.5.6 Pro and cons being small

There are many advantages to being small:

• Adhesion forces, as we saw, scaling as l and gravity forces as l3 , insects will not
feel the effect of gravity as they climb a wall or wander on a ceiling.

• The same argument applies for walking on water, provided that foots are hy-
drophobic, which is the case.

• Small animals, like ants, must avoid entering bubbles (see Fig. 2.30): muscular
forces scaling as l2 and capillary forces as l, they would be unable to exit, and
their colleagues unable to free them.

• Everything goes fast: movements, heartbeats (when there is a heart). We could

say that, in the small world, size and time are miniaturized.
86 Physics at the microscale

• Small animals jump high. The argument is the following: the muscular energy
necessary to make a movement of amplitude l is thus proportional to l3 . This
quantity must be compared with the gravitational energy of the jump Ep :

Ep ∼ mgH ∼ l3 H.

Comparing the two energies, the height of the jump H scales as l0 . The height
attained is thus independent of the size of the animal. This implies that the flea
jumps just as high as a horse.14

2.30: This drawing, inspired by a fa-

mous animated drawing, represents
the significant effort it would take for
an ant to free a comrade imprisoned
in a bubble. At the scale of an ant,
capillary forces are very significant
with respect to the muscular forces
the animal can exert (after [55]).

If we lived in a submillimetric world, the principal phenomenon that would concern

us would be capillarity and not gravity or inertia. We would fear getting stuck to
the surface of liquids, but we would not risk being hurt by an impact. At this scale,
we would undoubtedly have invented (if our intelligence was still intact) numerous
machines driven by surface tension. It would seem natural that in our microworld,
automobile accidents would not be caused by collisions, but by drops of water left on
the road.

2.5.7 Three errors in ’Honey, I Shrunk the Kids’ (Walt Disney)

A comic sci-fi film showing life in a miniaturized world was released by Disney in 1989.
It met worldwide success. In the scenario, three kids fall into the beam of a shrinking
machine built by the dad. They suddenly shrink to a size of 6 mm. The size being
less than a pygmy shrew, they need to eat continuously to keep themselves in the
neutral temperature range (TNZ), as we saw above. Since the movie director let them
starve during a full day, they could not survive. There are several physical errors in
the movie, and they are instructive to point out, because they illustrate a number of
notions discussed in the book. Three examples are mentioned below:
A The children, who have been miniaturized, are thrown into the back of the garden.
They want to come back home. During their journey, the encounter a piece of
water, on which a dead insect is floating. The insect is hydrophobic, with a contact
14 fleas jump 30 cm and horses 1 metre. The jumps are thus comparable, in terms of order of
magnitude
 Miniaturization of electrostatic systems 87

angle on the order 100◦ (this notion will be developed in Chapter 4). Consequently,
there should be a meniscus a few millimetres high which, on the scale of the screen,
should neatly appear. Instead the water surface is flat.

B The children wander in the night, desperately trying to come back home. The
flame they carry less than 1 mm from their fingers, should cause severe burnings.
However, the children do not feel any harm. Later in this chapter, we will return
to the question of heat conduction in small systems.

C The children are now at home. The dad tries to speak to them. With their small
mouths (one hundred microns or so), the children speak with extremely acute
voices (in the 100 kHz range), which the dad should not be able to hear. Also,
what the dad says should not be captured by the small ears of the children. In
the film, they talk without difficulty. Later in this chapter, we will return to the
question of resonance frequencies in small systems.

2.6 Miniaturization of electrostatic systems

2.6.1 Dielectric breakdown is retarded in miniaturized systems

The phenomenon of sparks between two electrodes placed in a gas originates from
the fact that gas molecules, when subjected to an intense electric field, are ionized,
thus forming a plasma. Ionization is propagated through a cascade process, in which a
large number of electrons are liberated, and an intense electric current circulates. This
current is accompanied by a luminous emission that gives rise to the phenomenon of
the electric arc. In air, under normal conditions, the breakdown electric field strength
is on the order of 3.4 MV/m (34 kV/cm). This means that, under these conditions,
the voltage needed to arc a 1-metre gap is about 3.4 MV.

In miniaturized systems, much higher electric fields can be produced without the
generation of an electric arc. In gases, this effect is well-represented by the Paschen
curve, depicted in Fig. 2.31.
Breakdown voltage [V ]

104

103

2.31: Evolution of the dielectric breakdown

voltage for a parallel-plate capacitor as a func-
tion of a variable X equal to pressure times
10–2 100 distance between the plates, i.e X = P d; the
P.d [bar.mm] . curve is obtained in air, at 300 K
88 Physics at the microscale

The Paschen curve represents the dielectric breakdown voltage between two electrodes,
measured in air, at 300 K. This curve is traced as a function of X = P d, where P is
the pressure and d the distance between the plates. We see that at large values of X,
the slope being unity, the breakdown electric field strength Ed is proportional to the
pressure but does not depend on d. At one bar, we have:

Ed ≈ 3.4MV/m(= 34kV/cm).

At small values of X the breakdown electric field strength increases considerably The
cross-over between the two regimes takes place when d = λD , where λD is the mean
free path, as we saw in a previous section (see Eq. (2.1)). Physically, when the mean free
path becomes comparable to the distance between electrodes, the majority of molecular
collisions tends to take place between the gas and the electrodes, and not within the
gas itself. This situation inhibits the formation of the cascade process and consequently
makes it more difficult for an electric discharge to form in the gas. The effect is strong.
For instance, in a 5 µm channel, the breakdown voltage is on the order of 30 MV/m,
i.e. ten times the value at large X. In water, the physics of discharge is different.
It is suggested that the breakdown is initiated by field emission at the interface of
preexisting microbubbles [56]. In practice, the electric breakdown for millimetric gaps
is in the 10 -100 MV/m range.

2.6.2 Miniaturization of capacitors

In the field of micro electromechanic systems (MEMS), many devices use miniaturized
parallel-plate capacitors as actuators. We will consider the plane capacitor geometry to
establish scaling laws. The electrostatic energy We stored by a parallel-plate capacitor
reads:
1 0 SV 2
We = CV 2 = ,
2 2d
where C is the capacitance, S is the surface area of the plates, 0 is the dielectric
constant, V is the voltage applied on the edges of the capacitor, and d is the distance
between plates, whose lateral dimensions are supposed comparable to d. Here we in-
troduce a characteristic scale l, which is on the order of d and, in the meantime, on
the order of the lateral dimension of the plate, so that, for instance, their area S is
on the order of l2 . The forces used to displace one of the plates result in a gradient
of the energy W . For example, a displacement normal to the plane of the capacitor
necessitates a force equal to:

δWe 0 SV 2
F =− = ∼ 0 E 2 l 2
δz 2d2
(z being an axis perpendicular to a plate), where E is the electric field created in the
capacitor. In terms of scaling laws, and considering that the electric field is fixed, we
find that the energy varies as l3 , and the force as l2 . This is what was noted in Table
2.7. If E is the breakdown field, we have at our disposal an estimation of the maximum
 Miniaturization of electrostatic systems 89

forces that can release an electrostatic system of a given size. This electrostatic force
is dominant over gravitational forces and inertia (which vary as l3 ); there is thus no
difficulty in exerting rapid accelerations in microsystems. This fast speed is harnessed
in car accelerometers.

2.6.3 Electrostatic microactuators

The possibility of creating elevated electric fields has led to the creation of electrostatic
microactuators. Figure 2.32 shows an example [57].

V δ(L)
δ(x)
2.32: Cantilever beam, where the beam
and the substrate are conductive. The beam,
subjected to an electrical potential difference
x V , deflects and thus can form an actuator.

Here we have a beam and a base subjected to an electrostatic potential, thus forming
the two plates of a capacitor. f (x) is designated as the density of electrostatic attraction
force (per unit surface) evaluated at the position x.

The expression of the density of force f (x) can be obtained from the electrostatic force
given in the previous section. We obtain:
 2
0 V
f (x) = ,
2 d − δ(x)

where V is the applied voltage, 0 is the dielectric constant of the vacuum, d is the
distance between the beam and the plate for x = 0, and δ(x) the deflection of the
beam at the abscissa x (Fig. 2.32).

This force produces a deflection δ(x), which is controlled by a local elastic equilibrium,
given by the relation:

x2
dδ(x) = (3L − x)wf (x)dx
6EI
where E is the Young’s modulus of the beam, I is its moment of inertia, L is its length
and w is its width. We recall the expression of the moment of inertia of a beam of
width w and thickness h:
1
I= wh3
12

To determine the deflection at the end of the beam, one must integrate this equation.
The profile of the beam is governed by the equation:
90 Physics at the microscale

x
δ(x) ≈ δ(L).
L
This permits the determination of the relation between the total force F applied on
the beam, and its relative maximum deflection given by:

∆b = δ(L)/d

The calculation gives, in the limit of small deflections:

0 wL4 V 2 4∆b
F = 3
≈
2EId 3

In terms of scaling laws, we see that the relative deflection ∆ is expressed as:

V2
∆b ∼
l2
which shows that it is possible to obtain significant displacements by miniaturizing
while maintaining a fixed potential difference (assuming that the breakdown field is not
surpassed). This possibility, illustrated in the case of an extremely simple electrostatic
actuator, is actually used in a large number of MEMS.

2.6.4 The electrostatic micromotor

One of the first electrostatic micromotors made using MEMS technology is represented
in Fig. 2.33.

2.33: First micromotor created in 1988

by Fan et al. [58]. The rotor has a diame-
ter of 200 µm. (Photo courtesy of Richard
S. Muller.)

The principle of how this motor functions lies in the fact that the rotor will try to align
the region with the strongest dielectric constant with the regions with the strongest
electric field. Since the field is rotating, the rotor will tend to follow the maxima of the
field, and will thus begin to turn. To analyse the functioning of the motor, the forces
 Miniaturization of electromagnetic systems 91

in play must be averaged along the angular coordinate, taking into account the fact
that the electrostatic field produced by the stator is a rotating field.

Practically speaking, couples are produced on the order of nano- or piconewtonmeters,

powers on the order of the microwatt, for thousands or tens of thousands turns per
minute. One must envisage rapid rotations in order to produce significant power.
Impressive devices are currently being created, including ones that function at several
million turns per minute. One example is a micro-turbine developed at MIT which
functions at 2.4 million turns/minute and produces 20 W with a yield of a few tens
of per cent.A turbine like this, when put into rotation by combustion gases, allows
the conversion of chemical energy into mechanical and electric energy. However, in
practice, the turbine is complicate to realize.

2.7 Miniaturization of electromagnetic systems

2.34: Two circular coils of diameter

I, separated by a distance l, through
. which an electric current I circulates.

We consider two circular coils of diameter l, separated by a distance l, through which

a current I circulates (see Fig. 2.34). We also assume that the cross-section of the wire
carrying the electric current is on the order of l2 . This hypothesis may seem astonishing
: normally, electric wires have cross-sections much smaller than coil diameters. This
hypothesis is not unrealistic, however, for microcoils created with the microfabrication
techniques presented in Chapter 6. An example is given in Fig. 2.35.

2.35: Microcoil fabricated by H. Fujita et

al. [59]. The figure on the right shows a con-
ducting cross-section forming the microcoil.

Thus, the magnetic field B produced by the coil is

B ∼ µ0 jl
92 Physics at the microscale

where j is the current density, which we will consider as fixed. The magnetic energy
stored in the coil is:
B2 3
Em ∼ l ∼ j 2 l5
µ0
These expressions show that it is difficult to produce elevated magnetic fields with
miniaturizing coils. For a system with a size of 100 µm the maximum magnetic field
that can be produced, without excessive heating, is on the order of 100 mT, which
in a large number of situations would be considered to be a weak level of induction.
Concerning the interacting forces between coils, we have:

F ∼ jBl3 ∼ j 2 l4

We retrieve the exponent shown in Table 2.7. Consider also the case of a coil immersed
in a fixed magnetic field B, produced for example by a large electromagnet. In this
case, by using Laplace’s law, we obtain:

F ∼ IBl ∼ jBl3

We see here that the force varies as l3 for a fixed current density j. In all cases,
whether using a magnetic field produced locally or from the exterior, the exponents of
the electromagnetic forces are higher than those associated with electrostatic forces.15

To illustrate these calculations, we proceed to a comparison between electrostatic and

electromagnetic microactuators. We recall the expression for electrostatic forces for a
parallel-plate capacitor:

F ∼ 0 E 2 l 2

where E is the breakdown electric field. For an electric field of 30 kV/cm and a device
of 10 µm, we obtain:

F ∼ 10 nN

For an electromagnetic system containing N coils in series, we have the following order
of magnitude for the force:

F ∼ µ0 N j 2 l4

Taking N = 100 coils, j = 107 A/m2 and l = 10 µm, we obtain the following order of
magnitude for the force exerted between two microcoils:

15 We note that, in principle, it is possible to augment the current density in conductors, by main-
taining (as we will see later) intense thermal exchanges in miniaturized systems. A discussion can be
found in [57].
 Miniaturization of mechanical systems - the vibrating microbeam 93

F ∼ 100 pN

The force produced by the microcoils is less than capacitors. At which scale do elec-
trostatic forces become dominant with respect to electromagnetic forces? We consider
two ‘prototypic’ situations chosen arbitrarily: the case of the parallel-plate capacitor
and that of mutually coupled coils. Re-examining the expressions established above,
the scale that we find is on the order of a few hundred micrometers. More generally,
we allow that ten or so micrometres correspond to the physical limit beyond which
electrostatic forces begin to dominate over electromagnetic forces. Ref. [57] presents a
detailed discussion of the subject.

2.8 Miniaturization of mechanical systems - the vibrating

microbeam

A cantilever beam possesses a resonance frequency determined by the following rela-

tion:
hc
f≈ ,
2πL2
where h is the thickness of the beam, L is its length, and c is the speed of sound in
the beam. This expression is obtained by resolving the elasticity equation. In terms of
scaling laws, we have the relation f ∼ l−1 . This law can be directly obtained by noting
that an acoustic wave associated with the mechanical resonance has a wavelength on
the order of the size of the object. We thus have the relation:
c
f∼ ,
l
which corresponds to the expression deduced from the previous formula.

We find that the resonance frequency is proportional to the inverse of the size of
the system. In practice, the law implies that, in the film Honey, I shrunk the kids,
previously mentioned, the father and the son, contrarily to what the director imagined,
could not exchange together, which, in a family, is often problematic. The same scaling
law is used to create resonators working in the domain of radiofrequencies. These are
called ’RF MEMS’ [60]. Figure 2.36 shows an example of one.

2.36: Sketch of a mechanical resonator ex-

cited by an electric field. In practice, the ma-
. terial used is piezoelectric
94 Physics at the microscale

Figure 2.37 presents a SEM image of a silicon system, made with MEMS technology
[61]. In terms of orders of magnitude, we have:

c ≈ 7470m/s.

Thus, for a beam 1 µm thick and 3 µm long, the formula given above leads to:

f ≈ 100MHz.

2.37: A resonator functioning at

71.4 MHz, made with silicon at the
University of Michigan [61].

The resonance frequency of the sillicon beam of Fig. 2.37, 71.4 MHz, is consistent with
the estimate. Resonance falls in the radiofrequency range and therefore the device
can be used as an antenna. RF MEMS offer advantages, compared to traditional
technologies, in terms of cost, integration, linearity, packaging, power consumption
and weight. The domain is vast [60], and its presentation stands beyond the scope of
this book.

A note on quality factors. We recall the definition of a quality factor Q, for dampened
oscillators. These systems are traditionally modeled by the following equation:

d2 x dx
m 2
−b − kx = 0,
dt dt
where m is the mass of the spring, b is the attenuation coefficient, and k is the spring
constant. For this type of system, the quality factor is:
m
Q = ω0 ,
b
where ω0 is the resonance frequency defined by:
r
k
ω0 = .
m
In the Fourier domain, the resonance curve is given by the expression:
1
A(ω) = r 2 .
ω2 ω2
1− ω02
+ Q2 ω02
 Miniaturization of thermal systems 95

in which A is the (normalized) oscillation amplitude and ω the oscillation frequency.

The width of the resonance curve is directly related to Q: this width (calculated at
mid-height, i.e. for a value of A(ω) equal to 21 ), is on the order of the inverse of Q.
Thus, the higher the Q, the sharper the resonance. The factor that limits Q is the
friction represented by the coefficient b.

For a cantilever beam, the quality factor in a non rarefied gas is estimated by the
expression [57]:
√
Eρwh2
Q= ,
24νL2
where ν is the kinematic viscosity of the gas, E is the Young’s modulus of the beam
material, ρ is its density, w is the width, h is the height, and L is the length. This
law indicates that the quality factor decreases with the scale, which may suggest that
miniaturization, although interesting from an integration standpoint (all components
can be made in silicon, and fabricated with MEMS technology), degrades the sharpness
of the resonance. However, in practice, quality factors of current microresonators attain
values on the order of1,000. Operating in a vacuum leads to quality factors on the order
of 104 -105 .

2.9 Miniaturization of thermal systems

We will treat, in some detail, the miniaturization of thermal systems in Chapter 5.

Here, we focus on scaling laws, consistently with Table 2.7. Heat transfers by conduc-
tion are governed by the Fourier equation, which is written as follows:

q = −K∇T

where K is the thermal conductivity of the medium, T is the local temperature, and q
is the heat flux, i.e. the quantity of heat traversing a surface element per unit surface
(the units of q are thus energy per unit time and area, or power per unit of area).
The flux density varies as the inverse of the scale, at a fixed temperature difference.
A typical situation is a fluid at rest in a cylindrical container, thermally isolated on
the sides, and whose ends are in contact with thermostats that impose a temperature
difference ∆T = T2 − T1 (Fig. 2.38). Under these conditions, the heat flux going
through the fluid, along the cylinder axis, is written:
KS∆T
Q= ,
l
where S is the cross-sectional area of the cylinder, and l its length. The following
scaling law comes from this:

Q ∼ Kl∆T,
96 Physics at the microscale

which governs the heat flux. This law was displayed in Table 2.7, with the assumption
that the temperature difference is fixed.

2.38: Thermally isolated bar

carrying a heat flux Q, with
notations used in the text.

Another quantity of interest is the thermal resistance, defined as the ratio ∆T /Q.
According to the previous equation, this ratio is on the order of l. The smaller the
size, the smaller the thermal resistance. In the film Honey, I shrunk the kids, the
thermal resistance being small, children should burn, as in an horror movie. The
director preferred an unphysical and more pleasant scenario.

We now suppose that sources of heat exist, in the fluid: Joule heating or heating from
a chemical origin (if the fluid is the site of exothermic reactions). In both these cases,
we can consider that the heat produced by a volumetric source is:

Q v ∼ l3

which represents an exponent higher than that associated with heat evacuated by con-
duction. We can thus conclude that volumetric heat sources can be easily thermalized
in miniaturized systems.

It is interesting to consider this from a dynamic point of view: the heat flux associated
with a temporal variation of temperature dT and a time dt, is governed by the following
relation:
dT
q = ρCp
dt
where ρ is the volumetric mass, Cp is the specific heat at constant pressure, and t is the
time. Thus the order of magnitude of the time constant of thermalization associated
with an object of dimension l is written:

ρCp 2 l2
τ∼ l ∼
K κ

where κ is the thermal diffusivity of the environment. Consistent with the preceding
remarks, this expression shows that miniaturization considerably accelerates the re-
turn to thermal equilibrium of a fluid at rest subjected to a sharp temperature change.
In other words, miniaturization radically reduces thermal inertia. The preceding logic
shows that exo- or endothermic chemical reactions can in principle be finely thermal-
ized in microsystems. This characteristic is very useful for chemical engineering. In
 Sampling and throughput 97

general, temperature exchangers currently used by industrial reactors tend to develop

unwanted parasite reactions. These reactions limit the selectivity of the process. There
are also reactions, impossible to produce industrially in a safe manner, that miniatur-
ization allows to be controlled. For these types of systems, miniaturization offers a
source of important improvements. This led to the development, in the 1990s, of the
domain of micro reaction technology (MRT), presented in Chapter 1 to the book.

2.10 Sampling and throughput

2.10.1 Microfluidics and low concentration samples

For samples of low concentration, the number of molecules per unit of volume is
(by definition) small, and the question is raised whether a given microfluidic device
incorporate enough volume to be able to perform a detection. Let us consider a sample
of molar concentration Cs . The minimal volume containing at least one molecular
entity is given by:
1
v=
Cs NA
where NA is the Avogadro number. For a cubic microfluidic chamber of side 10 µm,
and thus a volume of 1 pL, the minimum concentration Cmin for which one molecule is
present in the chamber is on the order of 10−12 mol/L. Should the sample concentration
be lower, there would be no molecule in the chamber, and therefore nothing to detect.
In the field of diagnostics, a concentration of 1 pM/L is often encountered. For this
reason, the sensitivity of pregnancy tests is on the order of fM/L, i.e. three decades
below Cmin . In the molecular diagnostics of SARS COV2, the sensitivities are a few
RNA copies per µL. With such low viral loads, there is no chance to capture a single
RNA strand in the picoliter chamber.

The solution is obviously to increase the chamber size as much as possible. In practice,
typical volumes of detection are several microlitres or tens of microlitres, not picolitres
This covers most of the situations of interest. However, in some applications, this is not
enough. In the agricultural domain, it is requested to detect one bacteria (for instance
salmonella) per 25 ml. This is impossible with microfluidic devices. Then, in this case,
a preliminary amplification by culturing, called ‘enrichement’, is necessary. An early
discussion of this type of questions, in the context of the analytical applications of
microfluidics, was given by Manz et al [62].

2.10.2 Microfluidics and throughput

In the 1990s, microfluidic devices were considered as suitable for performing analytical
studies, but too small for producing materials in quantities of industrial interest. The
98 Physics at the microscale

question of the throughput can be formalized in the following manner: the quantity of
volume produced, per unit of time, by a device is:

Q ∼ U l2

in which U is the flow speed and l the characteristic cross-sectional size of the channel.
With U =1cm/s and l = 100 µm, one obtains a production of 10 ml per day. This is
far too small for industrial application. Over the years, progress has been made along
two lines:

Numbering up : By parallelizing 1000 times, the production reaches 10 litre per

day. This number is relevant industrially for high added value products. Number-
ing up is currently used for producing emulsions under litres per hour throughputs
(see, for instance, [63]). An example of a parallelized step emulsion device is shown
in Fig. 2.39.

2.39: A 40 fold parallelized device, produc-

ing droplets (white dots) in the 30 µm range,
at rates on the order of hundreds of µL per
minute. (MMN, IPGG, ESPCI.)

The highest parallelisation of droplet emitters, at the time of writing this book,
has been reported in Ref. [64] (see Fig. 2.40).

Using a silicon and glass device, 10260 droplet emitters could be placed in parallel,
producing trillions of monodisperse droplets per hour. The flow-rate is on the order
of liters per hour, and the mass of particles 2.4 ton per year, for a system that
could be held in the hand. We may imagine a factory, in which 1000 such systems
are put in parallel, leading to 2400 tons of particles produced per year. In many
domains (culture cells, functionalized particle,...), contrarily to current thinking,
microfluidic technology can respond, on the scale of the planet, to production
needs.
 Sampling and throughput 99

Fig. 2.40: (A) 10260 droplet emitters were placed in parallel, producing trillions of monodis-
perse droplets per hour. (B) The flow-rate is on the order of liters per hour, and the mass
of particles 2.4 tons per year [64]. (Licensed under a Creative Commons Attribution 4.0
International Licence.)

Millifluidics : By raising the dimensions by a factor of 30, we switch to millifluidics,

and can reach, by increasing the speed by a factor of 100, 1 m3 per day, i.e. 360
tons per year (assuming liquid densities equal to 1 ton/m3 ). These quantities
touch industrial levels. These orders of magnitude are those of micro reaction
technology (MRT). This led to realization of miniaturized’ industrial plants, as
we mentioned in Chapter 1 [65].
Today, one may consider that there is no incompatibility between micro/millifluidics
and industrial production of materials.
The question of the information throughput, i.e. the quantity of information produced,
per unit of time, by microfluidics, is entirely different. Microfluidics droplets are typi-
cally produced at a 1 kHz rate and each droplet conveys one information (for instance,
whether an enzyme is produced or not). We thus have the possibility to gather millions
of items of information per hour. Because of this large number, microfluidic technol-
ogy is currently used in domains requesting large screening capacities, such as cancer
research, combinatorial chemistry, genome sequencing and drug discovery. An example
is shown in Ref. [66].
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3
Hydrodynamics of microfluidics 1:
channels

3.1 The flow equations and the boundary conditions

3.1.1 The notion of fluid particle

How to establish the equations that govern fluid flows ? A natural approach would be
analysing the movement of the fluid molecules, and establish equations that describe,
from a probabilistic standpoint, their dynamics. This approach led, in 1872, to the
Boltzmann equations [1]. These equations are rigorous, but difficult to use in prac-
tice. Work has been done, over several decades, to derive approximate forms of these
equations. An example is the Burnett equations [2], established for gases in 1936.
In fact, fluid mechanics textbooks do not take the Boltzmann equation as a starting
point. Most often, they develop a mathematical approach, by considering an infinites-
imal cube, expressing the pressure and inertial forces it is subjected to, and using,
for the viscous contribution, a phenomenological law. In this presentation, the cube
remains an abstract object. Its size is never given and the role of thermal motion,
eliminated without justification, is never discussed. This led G. Batchelor to develop a
more physical approach, For this purpose, he introduced the concept of ’fluid particle’.
The notion is illustrated in Fig. 3.1. The figure is adapted from An Introduction to
Fluid Dynamics [3], published in 1967.
Let us imagine a sensor of arbitrary size measuring the instantaneous density of a gas.
The size of the probing volume is assumed to be comparable to the sensor size. This is a
thought experiment, because obviously, no density sensor can respond instantaneously,
nor be of arbitrary size. If the sensor size is on the order of the intermolecular scale,
the measurement will depend on whether one molecule visits or not, at the time of the
measurement, the probing volume. If no molecule shows up, density is zero and if one
visitor comes on stage, density suddenly bounces. For sensors of that size, the response
will jump from one value to another, as illustrated in Fig. 3.1. With such probes,
impossible to measure the density. Let us now consider the opposite situation, where
the sensor is so large that its size is comparable to the fluid container. In this case, the
sensor response will reflect global features, for instance, the presence of temperature
heterogeneities on the scale of the container, which will cause a dependence of the
measured density with the probing volume (see the right-hand part of Fig. 3.1). The
104 Hydrodynamics of microfluidics 1: channels

Molecular fluctuations

Measured density
System size variations

Fluid particle

Sensor size

Fig. 3.1: Plot shown in G. Batchelor’s textbook [3] representing the variation of the instanta-
neous measurement of the density made by a probe, as a function of its size. The plot allows
to introduce the notion of ’fluid particle’ (See text).

measurement performed by the sensor will obviously be non local. In the traditional
presentation of fluid mechanics, there is a plateau, extending over several decades,
that separates the two limits. In this context, the ‘fluid particle’ is defined as the
smallest probe volume that contains enough fluid molecules to smooth out the effect
of molecular fluctuations. Its size – several intermolecular scales – corresponds to the
lower edge of the plateau of Fig.3.1. We this notion, all quantities involved in the
description of the fluid behaviour, such as density, speed, or viscosity are defined as
spatial averages throughout the fluid particle. Gone the thermal fluctuations. They
have been eliminated by the averaging process.

h
3.2: Gas flowing in a sub-mean
free path channel. The sphere rep-
resents a Batchelor’s fluid particle,
i.e. a particle whose size is several
d. Sphere containing 5 d
However, when small systems are considered – i.e. the subject of the book –, Batchelor’s
definition of the fluid particle becomes problematic. Fig. 3.2 shows a gas flowing in a
small channel, of height h larger than the intermolecular scale d, but smaller than the
mean free path λ. In such a situation, by definition of the mean free path, molecules
most often, bounce off the walls, and rarely collide with each other. In this system,
we can define a fluid particle as Batchelor did (see the dashed circle in Fig. 3.2).
However, this particle cannot be representative of the local fluid behaviour, because
the molecules it contains mostly interact with the walls. Obviously, there is a problem
 The flow equations and the boundary conditions 105

in the definition.
One way to solve it is to declare that the fluid particle size is not several intermolecular
distances, but several mean free paths. In such circumstances, molecules forming the
fluid particle mostly interact with themselves, and consequently, this particle can be
representative of the local fluid behaviour. This is the new definition we propose. The
size of the new particle is always larger than Batchelor’s one, and, often, much larger:
as we saw in Chapter 2, for air, at normal pressure, λ is twenty times larger than d.
Similar arguments can be advanced for liquids. We saw in Chapter 2, that three scales
characterize the liquid: the molecular radius, the intermolecular distance and the cor-
relation length. For example, for liquid argon at 90 K, their values are, respectively:
0.2, 0.4 and 1 nm. In a channel, the correlation length is the length below which
molecules approaching a wall starts to ‘feel’ its presence. It can thus be taken as an
equivalent to the mean free path. We can therefore propose that, similarly to gases,
the liquid particle has a size on the order of the correlation length. A similar criteron
was proposed in Refs. [4, 5].
To conclude, it seems pertinent, in the context of small systems, to reconsider the
traditional definition of the fluid particle, given by G. Bathelor, and introduce a new
one. The size of the new fluid particle should be, in gases, several mean free paths,
and, in liquids, several correlation lengths.

3.1.2 The continuum hypothesis

The next step is to consider that the fundamental law of dynamics applies to each fluid
particle. A step further is to assume that the variables attached to the particle (density,
velocity, pressure) are continuous functions of their position. This assumption is called,
in Fluid Mechanics, the ‘continuum’ hypothesis. On this basis, by using the powerful
tools of continuum mechanics, it becomes possible, mathematically, to establish the
governing equations of the flow. Being based on the notion of fluid particle, previously
defined, these equations cannot describe phenomena on scales smaller than the mean
free path in gases or the correlation length in liquids, nor what happens close to the
walls, at distances smaller than these scales.

3.1.3 The Navier-Stokes equations

Having defined the continuum hypothesis, we adopt it. Let us consider a fluid element,
composed of several fluid particles. Transported by the flow, fluid particles enter and
exit the element. When fluid particles enter, the density raises and when they leave,
density decreases. The constraint that, throughout the process, mass is conserved is
expressed by the mass conservation or continuity equation:

∂ρ ∂ρui
+ =0
∂t ∂xi
106 Hydrodynamics of microfluidics 1: channels

where ρ is the density, xi, ui are the i components of position and velocity and t is
time. An approximation called ‘incompressibility approximation’, consists of taking ρ
as a constant, i.e. independent of space and time. Subsequently, the mass conservation
equation reduces to:

∂ui
=0 (3.1)
∂xi

The incompressibility approximation is justified when the fluid velocity is much lower
than the speed of sound. The reason is that density may vary from one point to another,
likewise pressure and velocity, but, well below the speed of sound, the corresponding
variations are so small that they can be neglected [3]. Thereby, density can be taken
as constant. As the speed of sound is more than one thousand metres per second in
liquids, and hundreds of metres per second in gases, it follows that in the vast majority
of microfluidic situations, we can consider the working fluids, whether gas or liquid,
as incompressible.
Now we come to dynamical considerations. Applying the fundamental relation of the
dynamics of the material point, we obtain the following equations for fluid motion:
Dui ∂σij
ρ = fi + (3.2)
Dt ∂xj

where fi is the volumetric force component the particle is subjected to (for instance,
gravity), and σij is the stress tensor representing the surface forces applying onto
the particle. In this equation, the operator D/Dt is the material derivative, whose
expression is written as follows:
D ∂ ∂
= + uj (3.3)
Dt ∂t ∂xj

∂
The left-hand term thus includes two contributions, called local acceleration ∂t and
∂
convective acceleration uj ∂xj . In practice, when we refer to inertial terms, we most
often include both. As mentioned above, the stress tensor σij represents the surface
forces the fluid particle is subjected to. Often, to express these forces, we consider a
cube , and σij represents the stresses applying on the six faces. Mathematically, if σij
∂σ
are those forces (per unit of surface), ∂xijj is the resulting volumetric force.
At this stage, additional assumptions are needed to move forward. A major assump-
tion, made in hydrodynamics, and justified for small deformations, leads to consider
that the stress tensor is linearly related to the deformation tensor. Its general form is
obtained by taking advantage of the symmetries of the problem and utilizing general
results of tensor theory:
 
2
σij = −pδij + µ 2eij − δij emm + ζδij emm (3.4)
3
 The flow equations and the boundary conditions 107

where p is the pressure, eij is the velocity gradient tensor, and δij is the Kronecker
symbol. The expression of the tensor eij is written as follows:
 
1 ∂uj ∂ui
eij = + (3.5)
2 ∂xi ∂xj

In Eq. (3.4), µ is the dynamic viscosity and ζ is the second viscosity or the volumetric
viscosity. Expression (3.4) represents a remarkable achievement of tensor theory, The
case where µ and ζ coefficients do not depend on the velocity gradient nor the flow
history corresponds to ‘Newtonian’ fluids (see the historical note below). As noted
earlier, we will concentrate ourselves on these fluids.

The above relations do not make any assumption about incompressibility. Here, for the
sake of simplicity, we will consider the fluid incompressible and, moreover, µ uniform
over the fluid. On using Eq. (3.4) and Eq. (3.2), we obtain a simplified form of the
Navier-Stokes equation, which will cover all the situations we will analyse in this book:

Dui ∂p ∂ 2 ui
ρ =− + µ 2 + fi (3.6)
Dt ∂xi ∂xj

A vectorial form of the Navier-Stokes equation is often more convenient to use:

Du
ρ = −∇p + µ∆u + f (3.7)
Dt
where we recall that f is the external force per unit volume. In the same notations,
the conservation of mass equation can be written as follows:

divu = 0 (3.8)

History of the Navier-Stokes equations

The first flow equations were obtained by L. Euler in 1757, assuming perfect
fluids, i.e. fluids with zero viscosity. The shortcoming of the equation was the
absence of dissipation. Without dissipation, fluids subjected to an imposed
pressure gradient, for instance, in a channel, or flowing downwards in a small
tube under the action of gravity, an example taken by Navier in his article [6],
accelerate indefinitely. This was obviously in conflict with the observation, and
the solution came by adding a term that dissipates energy, and, in turn allows
the flow to reach steady states in the same circumstances. This is what Navier
did in 1823 [6]. Amazingly, he used an incorrect phenomenological approach to
derive Eq. (3.6), which was correct. The formalization of the viscous term was
established in 1843 by Saint-Venant and in 1845, by Stokes, who introduced the
concept of viscous stresses. The equation is called the Navier-Stokes equations,
in honour of the two scientists but it could just as well have been called the
‘Euler Navier-Stokes’ equation or even the ‘Euler Navier Saint-Venant Stokes’
equation.
108 Hydrodynamics of microfluidics 1: channels

3.1.4 The concept of viscosity

What is the physical origin of viscosity, which we introduced in a formal manner? For
this, we need to return to the microscopic scale. The origin of viscosity is related to
the exchange of momentum between molecules moving, in the average, at different
speeds. The model was proposed by Maxwell in 1879 [7].

To reach an intuitive understanding of Maxwell’s theory, we may imagine, as in Ref.

[8]), two trucks, of total mass M (i.e. the vehicle plus the coal sacks, stacked on the
tub), circulating at different velocities u1 and u2 (see Fig. 3.3).

3.3: Two trucks moving at different veloci-

ties u1 < u2 and exchanging charcoal sacks.

The workers at the back of the trucks continually exchange sacks between the vehicles.
The new speeds of the trucks, u01 and u02 , after the sacks have been exchanged is:

m m
u01 = u1 + ∆u and u02 = u2 − ∆u
M M

in which m is the mass of the sacks that were exchanged, and ∆u = u2 − u1 > 0, taken
as positive for this discussion. We see that, due to sack exchange, truck 1 slows down
truck 2, while truck 2 speeds up truck 1, entraining each other, as if they exerted a
‘friction’ force on one another.

Following this line of thought, let us consider two gas layers, of surfaces S, located at
z and z + λ, in which molecules circulate, in the average, at different speeds, u(z) and
u(z + λ), as sketched in Fig. 3.4. A molecule situated on the plane z, jumps, at velocity
utherm , to the next layer, located at z +λ, and undergoes a collision. After the collision,
the new speed of the jumping molecule should be u(z +λ), because of flow stationarity.
The corresponding momentum transfer, during this event, is m(u(z +λ)−u(z)), where
m is the mass of the molecule. The time needed to perform the transfer is the collision
time τ , i.e. λ/utherm . In a volume Sλ, the total force F associated to this momentum
transfer will be F = λSρ(u(z + λ) − u(z))/τ ≈ Sρutherm ∂u ∂z . The corresponding stress,
σ = F/S is given by:

∂u
σ≈µ (3.9)
∂z

in which µ is given by:

µ ≈ ρutherm λ (3.10)
 The flow equations and the boundary conditions 109

where µ is the viscosity and σ is the viscous stress. Viscous stress acts against the
velocity gradient. To maintain the shear, one must apply an external force,. In channel
flows, this force is provided by the pressure gradient applied along the channel.

u (z+λ)
3.4: Two streamlines in a gas, sepa-
rated by the mean free path λ, and
u (z) moving at different velocities u(z)
and u(z + λ).

An important quantity is the kinematic viscosity ν ≈ µ/ρ. An estimate of utherm is

c, the sound speed. Therefore, we have ν ≈ cλ. The three dimensional theory, estab-
lished by Maxwell [7], incorporates a 1/3 prefactor. In practice, the expression without
prefactor provides an acceptable estimate for the kinematic viscosity of gases. For in-
stance, it leads to 1.6 10−5 m2 s−1 for air under normal conditions, while the measured
value is 1.5 10−5 m2 /s. Interesting is to note that, according to Maxwell’s theory, all
diffusivities (momentum, temperature, and mass) are equal.

For liquids, the situation is different and an excellent presentation is given in Ref. [8].
Liquids possess a crystalline order over short distances (a fraction of a nanometre)
while still remaining disordered over large distances. Molecules must cross an energy
harrier to leave the ‘cage’ formed by their immediate neighbors, and exchange mo-
mentum with a fluid layer moving at a different velocity. Statistical calculation leads
to the following form for the viscosity of Van der Waals liquids:
 
E
µ = A exp (3.11)
kT

where A is a constant and E is an activation energy.

Consistently with the previous discussions on the fluid particle, the notion of (bulk)
viscosity applies down to nanometric scales in liquids and a few mean free paths in
gas [28, 30].

3.1.5 Validity of the Navier-Stokes equations

The case of gases. We saw that in gases, the fluid particle size is on the order of
the mean free
√ path. Collision time and mean free paths are linked together by the
relation λ ∼ ντ . It is useful to recall the following formula:

1 kT
λ= √ =√ (3.12)
2πna2 2πpa2

where n is the density (the number of molecules per unit volume), T is the temperature,
k is the Boltzmann constant, p is the pressure and a is the size of the molecule. As noted
110 Hydrodynamics of microfluidics 1: channels

in Chapter 2, at atmospheric pressure, the mean free paths of usual gases, calculated
with the above formula, range between 60 and 160 nm. a and λ differ by more two
orders of magnitude. The intermolecular distance, of the order of 3 nm at atmospheric
pressure, lies in between.
For gases, the question of the validity of the Navier-Stokes equations has been in-
vestigated numerically, theoretically and experimentally for several decades (see, for
instance, [9–16]). Microfluidic technology has contributed to raise the accuracy of the
measurements and, in turn, the sharpness of the conclusions [15,17–19]. It is convenient
to define the Knudsen number, as the ratio λ/L, where L is the characteristic length of
the system (for instance, the height for a channel). To make a long story short, chan-
nels with heights larger than 2λ (i.e. Kn < 0.5) are governed by the Navier-Stokes
equations, with or without slip at the walls while, above this limit, they enter a new
regime, called ’transition regime’, where the Navier-Stokes equations no longer apply.
A pioneering experiment performed in microchannels [20], comparing Navier-Stokes
solution and measurements, supports this conclusion. It is shown in Fig. 3.5 [21].

3.5: Nondimensional flow rate as a

function of the Knudsen number for
rectangular microchannels. Squares are
the experiment, triangles the analytical
solution of the Navier-Stokes equation.
The line is a model of the Boltzmann
equations. Deviations between Navier-
Stokes and experiment are visible at
Kn > 0.5. (Reprinted figure with per-
mission from Ref. [21]. Copyright (2022)
by the American Physical Society.).

By comparing flow rate measurements with Navier-Stokes predictions (with slippage),

one sees that disagreements appear at roughly Kn > 0.5 (see Fig. 3.5). λ thus appears,
in terms of order of magnitude, as a cross-over for the validity of the Navier-Stokes
equations. If we consider that, at this cross-over, fluid particle and system sizes are
equal, we may confirm that the order of magnitude of the particle size is λ.

The case of liquids. Fig 3.6 shows examples of submicrometric systems, in which
the validity of the Navier-Stokes (NS) equations, for liquids, can be discussed, and,
consequently, a practical estimate for the liquid particle size can be obtained, if we
assimilate it again to the system size below which NS equations fail. Fig. 3.6(A) shows
a 100 nm high channel, fabricated with MEMS technology (described in Chapter 7).
In these systems, NS equations provide an accurate description of the flow. Flows in
nanocapillaries, such as that of Fig. 3.6(B) [22], are in a similar situation. Large carbon
nanotubes (CNT), or boron nitride nanotubes (BNNT), such as the one shown in Fig.
3.6(C) [23], can also be described using NS equations.
In carbon nanotubes larger than 1.4 nm in diameter, and again for water, numerical
simulations have shown that the Navier-Stokes equations remain accurate [24, 25].
Nonetheless, when diameters are smaller, complications arise. For CNTs smaller than
 The flow equations and the boundary conditions 111

Fig. 3.6: Examples of submicrometric channels or tubes: (A) Submicrometric channel, 100
nm high. (Courtesy of P. Joseph); (B) Nanocapillary, 30 nm in diameter. (Reprinted from [22],
with permission from the Royal Society of Chemistry; copyright 2022.); (C) Boron Nitride
Nanotube, 30 nm in diameter. (Reprinted from [23], with the permission from the American
Chemical Society; Copyright 2022.).

0.83 nm in diameter (2.4 times the water Van der Waals diameter), the liquid molecules
flow in single file.1 The phenomenon is shown in Fig. 3.7.

3.7: Molecular Dynamics (MD) simulation

snapshots of water structure inside carbon
nanotubes of different diameters, adapted
from [25]. In these simulations, speeds are
on the order of meters per seconds and the
pressure gradient is 4 1014 Pa/m (Reprinted
with permission from Ref [25]. Copyright
2022 by the American Physical Society).

The same simulation showed that when the CNT inner diameter is around 0.96 nm,
water molecules cease to structure in a single line; instead, they develop a pentagon
pattern. Other structures have been found at larger diameters. Above 1.39 nm, the fluid
eventually recovers its ordinary’ disordered bulk structure. The domain of diameters
below 1.39 nm is called the subcontinuum. It marks the end of Navier-Stokes validity.
1 This confirmed the pioneering work of Ref. [26].
112 Hydrodynamics of microfluidics 1: channels

In this domain, new, still unknown, equations are needed to describe the flow [27]. The
fact that in ultra-confined spaces, liquid molecules form structures (leading to force
oscillations), was known (see, for instance, [28, 29]). What we learned here was about
the dynamics, i.e. how water manages to flow in extremely confined conditions.
Not exactly in the same area, but linked to the question we discuss [5], Fig. 3.8 shows
a viscosity study peformed in extremely confined systems [30]. It was found that for
sub 2 nm water films squeezed between one cylinder and a flat plate, viscosity departs
from the bulk value, by up to five orders of magnitude. Above 2 nm, the bulk viscosity
is recovered.

3.8: Viscosity of water

versus gap d, measured
with SFA, for films
squeezed between mica
surfaces. Bulk water
viscosity is 10−3 Pa.s
(Reprinted with per-
mission from Ref. [30].
Copyright 2022 by
the American Physical
Society.)

Although it is difficult to disentangle bulk and surface contributions, one may consider
that 1–2 nm, i.e. 1–2 correlation lengths, marks the break-up of the NS equations and
therefore provides an estimate for the particle size in liquids. These considerations led
the community to distinguish between ‘subcontinuum’ and continuum’ nanofluidics,
with a frontier fixed at 1 nm. This distinction, which we showed in Chapter 2 of this
book without explanation, is now justified.

3.1.6 The Reynolds number

The Reynolds number was introduced in Chapter 2, using the Π theorem, and we did
not need the Navier-Stokes equations to establish it. The definition of this number
resulted from dimensional considerations, and there was no way to know what it
meant. This the strength and the weakness of the Π theorem. Now, we can answer the
question. Let us, thus, recall that stationary incompressible flows characterized by one
single spatial scale l are parametrically controlled by a single dimensionless number:
the Reynolds number. Its expression is:
Ul
Re = (3.13)
ν
where U is the characteristic velocity of the fluid and ν is its kinematic viscosity.
For stationary regimes ( ∂u
∂t = 0), inertia and viscous forces appearing in Eq. (3.6) can
be estimated in the following manner:
 The flow equations and the boundary conditions 113

ρU 2
Inertia forces ∼ (3.14)
l
µU
Viscous force ∼ 2 (3.15)
l

Therefore the Reynolds number can be written as:

Inertia forces
Re ∼ (3.16)
Viscous forces

The physical interpretation of the Reynolds number is thus the ratio of the inertial to
the viscous forces. Large Reynolds number flows are dominated by inertia, and small
Reynolds flows by viscous forces.

What is the value of the Reynolds number in microfluidic systems? In such systems,
fluid velocities do not exceed 1 cm/s and transverse channel dimensions are on the
order of 10 µm so that Reynolds numbers do not exceed 10−1 . In fact, in the domain
of microfluidics, and in the vast majority of situations, Reynolds number are low or
very low.

Still, there exists important exceptions. Devices dedicated to extract the heat gener-
ated by microprocessors, a subject that we will present later, need, in order to obtain
efficient heat transfer, to operate at substantially high Reynolds numbers. Substantial
Reynolds numbers are also involved in inkjet printers. High throughput mixers and
reactors, the two basic elements of micro reaction technology (MRT), also operate at
moderate or high Reynolds numbers (from ten to several thousands, typically). Last
but not least, for the sake of sorting particles or cells, it can be advantageous to work
at moderate Reynolds numbers. All these situations pertain to the domains of inertial
microfluidics or millifluidics. We will return to these subjects later. For the moment, we
assume low Reynolds numbers, which concerns, as mentioned above, the vast majority
of microfluidic situations.

3.1.7 The Stokes equation

The field of studying flows at small Reynolds numbers is known as microhydrodynam-

ics. As noted in this book, ‘micro’ refers to small Reynolds numbers, not to small sizes.
This domain is well-established in fluid mechanics, and we will review here some of
the essential results.

The flows of incompressible Newtonian fluids at small Reynolds numbers are governed
by the Stokes equation:

− ∇p + µ∆u + f = 0 (3.17)
114 Hydrodynamics of microfluidics 1: channels

To obtain the Stokes equation, we considered the inertial terms to he negligible with
respect to the viscous term, owing to the smallness of the Reynolds number. More
specifically:

• The first component involved in the inertial force is the acceleration term. It
has an order of magnitude of ρU/τ , where τ is the characteristic time of the
variation of velocity. One can imagine situations where the characteristic time of
the velocity variations is small (for instance, flow induced by the sudden movement
of a plate initially at rest, called the Rayleigh problem), and in this case, the
acceleration term cannot he neglected with respect to the viscous term. Here,
we consider different types of situations where the flow is quasi-steady. In those
cases, which cover a considerable number of practical situations in microfluidics,
the acceleration term can be neglected.

• The second component has an order of magnitude is ρU 2 /l, where U is a typical

velocity and l is the scale of the characteristic variation of the velocity. This term
must he compared to the viscous term, which is on the order of µU/l2 ; indeed,
the ratio of the first to the second term is precisely Re  1, as we showed before.

We will use the Stokes equations to describe, in most cases, microfluidic flows. The
domain of inertial microfluidics, which covers cases where the Reynolds reaches im-
portant values, a hundred or so, is obviously excluded from this framework. In such
cases, we will provide more qualitative descriptions.

3.1.8 The five virtues of Stokes equation

We recall here that in the framework in which we place ourselves, there are no free in-
terfaces and we assume no slippage at the walls. In such conditions, the flows governed
by the Stokes equation, which, as discussed above, is valid at small Reynolds numbers,
possess the following mathematical properties: linearity, reversibility, instantaneity,
uniqueness of solution, reciprocity, and minimum of dissipation.

1. Linearity: The Stokes equations are linear. This property permits the superpo-
sition of the elementary solutions of the equation to determine a given flow.

2. Reversibility: Changing t to −t does not modify the equations. This property

implies that, for stationary flows, a fluid particle moving in the forward direc-
tion, will move backwards on the same streamline when the flow conditions are
reversed. This implies that it is impossible to decide from the sole observation of
the streamlines, as an experiment will demonstrate later, in which direction the
flow circulates.

3. Instantaneity: Since t does not appear explicitly in the Stokes equations, the
response of the flow to an external change will be immediate. For instance, if
the pressure gradient driving the fluid is suddenly changed, the fluid will react
immediately, by setting up a new flow profile.
 The flow equations and the boundary conditions 115

Fig. 3.9: Water flow in a Tesla geometry, in a Silicon glass microsystem. flow rate is 600
µl/min, channel height is 20 µm, channel width 200 µm on average. Speeds are on the order
of metres per second In the top photo, the flow is oriented from left to right, and in the bottom,
the orientation is inverted. Experiment carried out at the MMN laboratory, at ESPCI (coll.
O.Francais [31]).

4. Minimum of dissipation: The flow resulting from the solution to the Stokes
equation minimizes the kinetic energy dissipation with respect to all kinematically
admissible fields compatible with the boundary conditions.
5. Uniqueness: The solution to the Stokes equation is unique. This is an important
property, because it implies that flow instabilities cannot occur. The reason is that,
according to theory, instabilities are associated to bifurcations, i.e. the existence,
in the same conditions, of a multiplicity of solutions to the governing equations.
This possibility cannot be envisaged with Stokes equations.
Reversibility is illustrated in Fig. 3.9. The geometry of the microchannel is that of the
‘Tesla valve’ (1920). This valve is made up of a series of hydrodynamic circuits, one
unit of which is shown in Fig. 3.9. The flow is driven from left to right in Fig. 3.9 (left)
and from right to left in Fig. 3.9 (right). At high Reynolds numbers, the direction of
circulation matters, because the positions of the vortices detaching from the boundary
layers differ depending on the direction of flow. At low Reynolds numbers, however,
the reversibility of the Stokes equation makes the two directions of circulation, with
exactly the same streamline pattern, dynamically possible. This is why, from the sole
inspection of the streamlines of Fig. 3.9, it is impossible to decide in which direction
the liquid circulates.
The reversibility of the Stokes equation has important consequences in the case we
examine. It signifies that, unless pushing the fluid at considerable speeds2 it is not
possible to fabricate a ‘microfluidic diode’, which would present a weak resistance to
flow in one direction, and a high resistance in the other direction. This hope, expressed
by some investigators in the early days of microfluidics, was rapidly abandoned.
The properties listed above can be viewed as virtues in the sense that they enable
to reach an exquisite level of flow control, by inhibiting hydrodynamic instabilities,
2 We note that in this case, although the speed is several metres per seconds, the Reynolds number,
based on the height of the channel, is less than ten. This suggests that the range of validity of Stokes
equations may, for some flow geometries, be larger than simple order of magnitude argument may
suggest
116 Hydrodynamics of microfluidics 1: channels

Fig. 3.10: Different flow configurations, at low and high Reynolds numbers. From H. Stone
(Cours les Houches, 2009)

responding instantaneously to external changes of flow conditions, adding contribu-

tions in a linear manner, which simplifies the design and understanding of the flow
behaviours. Also, reversibility can facilitate the operation of microfluidic devices, when
rinsing or other operations are required. Figure 3.10 stresses this point. It contrasts
the behaviour of low Reynolds number flows, governed by Stokes equations, to that of
high Reynolds number flows, governed by the Navier-Stokes equations, for a variety of
geometries. In the former case, flows are laminar, reversible, while in the latter, detach-
ment phenomena (which we will present later), instabilities, and turbulence develop,
jeopardizing fine control over the flow.

3.1.9 The Navier boundary condition

Figure 3.11 allows us to introduce the Navier boundary condition. Here, a fluid is
flowing along a plate at rest, with a speed u(z), z being the coordinate normal to the
wall, the system being invariant along the other directions of space.
In the same article in which he derived the Navier-Stokes equations ( [6]), Navier
stipulated that, at the wall, the speed u(0) adopted by the fluid, i.e. at z = 0, is not
zero, but is given by:

 
∂u
u(0) = b (3.18)
∂z
where b is the Navier length, or the slip length. In the above expression, the derivative
is calculated at z = 0.
 The flow equations and the boundary conditions 117

(a) (b)
z u(z)

0
u(0)

–b 0 z

Fig. 3.11: (A) Flow over a plate, with the system of coordinates.(B) Geometrical illustration
of the Navier length. The tangent at the origin crosses the z axis at z = −b.
.
A geometrical illustration of the Navier boundary condition, for b > 0, is provided in
Fig. 3.11. The tangent to the velocity profile at the origin crosses the z axis at z = −b.
Note that b can be positive or negative. In ordinary fluids, it is positive, but in complex
fluids, such as polymer solutions, where adsorption of the chains leads to the build-up
of a solid wall inside the fluid, the flow speed can vanish at z > 0, yielding a negative
value for b.

At the time Navier wrote his’ boundary condition, there was no support for it. Sixty
years later, Maxwell provided a justification for the case of the gases [7], by showing
that b is proportional to λ. The result was published in the same paper as that es-
tablishing an expression for the gas viscosity. In short, momentum is exchanged by
collision between the walls and molecules located at a distance λ from it. On transpos-
ing the relations used in the gas kinetic model for viscosity, to the case of molecules
colliding diffusively with a wall, one obtains b = λ. In fact, in Ref. [7], Maxwell treated
the general case where a fraction σ of molecules undergo diffusive reflection, the others
reflecting the walls in a specular manner. Calculations lead to b = Cλ, where C = 2−σ σ .
For the purely diffusive case, σ = 1 and thereby C = 1 while, for pure specular re-
flection, σ = 0 and C is infinite. In this case, the wall behaves as a free surface. For
liquids, as will be seen later, things are more complicated.

Decades of controversies on the existence of slippage

The question of whether b is non zero has been much debated in the fluid mechanics com-
munity. Navier, Stokes, Rayleigh, Kelvin, and Taylor participated in the discussion [32]. H.
Lamb, after having advocated the idea that fluids slip over rigid surfaces [32], later argued
that b should be strictly equal to zero. The argument was formulated for the case of rectilin-
ear channel flows. In the continuum framework, if fluids slipped at the wall, the wall shear
stress would be infinite, which would contradict the experiment. Taking the words of Huh
and Shih, pronounced in another context [33], even Heracles would not be able to push a
fluid in a tube. This reasoning, supported by a multitude of experiments carried out over
one century, was so well-accepted that textbooks never questioned it. Now, we know that it
is physically wrong: liquids, in almost all situations, slip at the wall.
118 Hydrodynamics of microfluidics 1: channels

3.2 Slippage in gases

3.2.1 The different gas flow regimes

As the mean free path is a central quantity in gases, it is natural to introduce a

dimensionless number defined by:

λ
Kn = (3.19)
l

in which l is the system size. This number is called the Knudsen number, in honour
of Martin Knudsen [12, 34, 35]. Following Schaaf and Chambre [10], four regimes can
be defined. They are shown in Fig. 3.12.

Hydrodynamic Slip regime Transition Rarefied gas

regime regime regime

Kn
0.1 0.6 20

Microfluidics

Fig. 3.12: Different gas flow regimes, depending on the Knudsen number. The values indicated
on the diagram represent rough estimates of the Knudsen numbers determining the ranges
of existence of each regime. The grey zone represents current values of the Knudsen numbers
found in microfluidic devices.

The four regimes are:

• For Knudsen numbers smaller than 0.1, the fluid particle is much smaller than
the system size, and the flow is described by the Navier–Stokes equations. At the
wall, Knudsen layers, of thickness λ, occur, but they can be neglected. Slippage
exists, but is negligible. This is the hydrodynamic regime.
• For Knudsen numbers between 0.1 and (roughly) 0.5, especially in the lower range
of this domain, Knudsen layers are thin, so that most of the fluid volume is
governed by the Navier-Stokes equations. At the wall, slippage is significant. The
flow is described by the Navier-Stokes equations with slippage at the wall, which
defines the ‘slip regime’.
• For Knudsen numbers between 0.5 and 10, the ‘intermediate’ or transition’ regime
holds: gas molecules more often undergo collisions with the walls than with their
colleagues. Rarefaction effects are significant, both in the bulk and at the wall.
Continuum hypothesis breaks down and the Navier-Stokes equations no longer
apply. To take rarefaction into account, the Burnett equations, derived from the
Boltzmann equations were established in 1936 [2]. In practice, they are rarely used
because of their complexity. One sometimes defines an early transition’ regime, for
 Slippage in gases 119

Kn around unity, in which rarefaction effects take place, but with small amplitude
[9].
• Finally, for Knudsen numbers greater than 10, the system is in the ‘rarefied’
regime. The flow is described by the Boltzmann equations.
As indicated by the grey zone in Fig. 3.12, is not rare to find microfluidic flows in
the slip regime. Examples are micro- or submicrometric-sized channels, working at
atmospheric or sub-atmospheric pressures.

3.2.2 Gas flows in channels in the slip regime

We consider here the case of gas flows in microchannels, where the Knudsen numbers
fall in the slip regime. In such conditions, the gas is governed by the Navier-Stokes
equations. As mentioned above, we may consider that the Navier boundary condition
applies at the wall:  
∂u
u(0) = Cλ (3.20)
∂z
in which u(0) is the velocity at the wall and ∂u


∂z is the deformation rate at the wall.

There is no space here to develop the calculations of the flow in the channel. This was
done in a number of papers [17–19], and in the first edition of the present book [36].
The following relation between mass flow rate and pressure, was obtained:

∆P Pm wh3
Qm = (1 + 6CKn) (3.21)
12µRT L

where Pm is the average pressure in the channel and ∆P the difference between pres-
sure at the entrance P (0) and the exit P (L), for a channel of length L. Here, the
Knudsen number reads Kn = λh , where λ is the mean free path, calculated at Pm . A
dimensionless quantity facilitating the discussion on the slip is the slip coefficient S,
defined by the expression:
12µPm Qv L
S= (3.22)
P (0)∆P wh3
where Qv is the volumetric flux at the exit of the canal x = L. The calculation shows
that S satisfies the following equation:

S = 1 + 6CKn (3.23)

The evolution of S with the Knudsen number, obtained for nitrogen, in various exper-
iments, is shown in Fig. 3.13.
Should there be no slip, we would have S = 1. The curve of Fig. 3.13 shows that slip
exists, and that if neglected, the flow rate would be underestimated by one order of
magnitude. The effect of slippage, which enhances flow rates, is thus considerable in
this case. From the data, by looking at the slope at the origin, one finds C ≈ 0.92,
120 Hydrodynamics of microfluidics 1: channels

3.13: Evolution of slip coefficient S

as a function of the Knudsen num-
ber, for a microcanal of rectangu-
lar cross-section [19] (empty triangles).
The dashed line shows the expression
3.23 with C = 1 and the continuous
line a polynomial fit of degree 2 .The
plot also shows data from [17, 18]. A
similar plot, up to Kn = 0.8 was ob-
tained with helium. .
in agreement with hard sphere model with purely diffusive wall reflection [38]. It is
interesting to note the existence of the small positive curvature in the S − Kn plot.
This small curvature, called ‘second order effects’, indicates that as Kn increases above,
roughly, 0.3, Navier boundary condition must be modified [18,37,39]. The experiments
of Ref. [19], as well as others (see, for instance, [15]) showed that slip regime may be
extended, as far as flow ratemeasurements are concerned, to a Knudsen number of 0.8.

What happens at larger Knudsen numbers ?

Microfluidics has contributed to make progress in the field of rarefied gas dy-
namics, by providing techniques allowing to perform measurements of unprece-
dented accuracy in a large range of Knudsen numbers. The plot of Fig. 3.14
shows an example. On this plot, the dimensionless
√
mass flow rate G (see [15]
for its expression) is plotted against δm = 2π Kn−1 . The experiments, per-
formed in helium, allowed three orders of magnitude of variation in Knudsen
number to be spanned.

Fig. 3.14: Evolution of the dimensionless mass flow rate G with δm , in a

channel, for three different pressure ratios (between the entry and the out-
let). Dashed and full lines are theoretical curves (From [15], reprinted with
permission from Cambridge University Press.)
What we learn from this plot is, among other things, the confirmation of the
existence of a minimum (known as the Knudsen paradox), the pertinence of
the Boltzmann equations, and that of various models attempting to simplify
them. This plot is taken as a reference in the field of rarefied gas dynamics.
 Slippage in liquids 121

3.3 Slippage in liquids

3.3.1 The friction model

The structure of water close to a hydrophobic surface has been calculated by several
authors [40–43]. An example is shown in Fig. 3.15 [43].

3.15: Molecular simulation of wa-

ter over an hydrophobic surface
(Reprinted by from [43], by permission
from AIP. Copyright 2022).

Close to the wall, holes form, depleting the local fluid density. The physical origin of
these holes lies in the fact that water molecules are more attracted by the bulk than by
the wall. Then, they frequently bounce off the wall to join the bulk. In the hydrophilic
case, no such holes form, because molecules, most of the time, stick to the wall [44].

In the presence of a flow, and in the hydrophobic case, it is conceivable that water
molecules, being frequently captured by the bulk, are entrained by it. Slippage origi-
nates from this effect. In the hydrophilic case, since molecules remain at the wall most
of the time, where they are held by Van der Waals forces, there is no slippage.

How can we formulate a boundary condition that could represent the situation? In
fact, boundary conditions are like trees hiding forests. In our case, the trees hide a
complex physical situation, in which roughness, crystallography, the possible presence
of a vapour phase, Van der Waals force field, flow dynamics, and thermal motion
presumably play roles. Incorporating these aspects in the expression of the boundary
condition is challenging.

According to [45,46], the simplest manner to address the problem, from a phenomeno-
logical viewpoint, is to assimilate slippage to a friction process with a friction coefficient
independent of the slip velocity. In [45], the following relation between the frictional
stress and the hydrodynamic shear stress σw (which forces the fluid molecules to slip
at the wall), was proposed:
122 Hydrodynamics of microfluidics 1: channels

 
∂u
σw = µ = λw u(0) (3.24)
∂z

where µ is the fluid viscosity and λw is the friction coefficient.3 The above relation has
exactly the form of the Navier boundary condition, with a slip length defined by:

µ
b= (3.25)
λw

What is this λw and how large is b? The calculation, performed in [45], lies outside
the scope of this book. The following expression was obtained:

kT µD b0
b∼ ≈ (3.26)
Cρσ2 (1 + cos θ)2

in which D, k, T, C, ρ, σ and  are parameters4 and whose detailed expressions can

be found in Refs. [5, 45, 46]. The formula on the right includes the phenomenological
constant b0 . Interestingly, the formula states that, in the case of perfectly smooth walls,
slippage is infinite. Molecular roughness, along with crystal anisotropy, neglected in
fluid mechanics, plays a crucial role here. In practice, assuming pre-factors on the order
of unity, Eq. (3.26) provides slip lengths that increase with the contact angle, up to
tens of intermolecular distances, i.e. several nanometres. These values are consistent
with the numerical simulations (see Fig. 3.19 in the next section). The slippage we
discuss here is often called ‘intrinsic slippage’.

3.3.2 Hydrodynamics of liquid flows with slippage

We now analyse the hydrodynamical consequences of the presence of slippage in liquids,

using again the Navier boundary condition:
 
∂u
u=b (3.27)
∂z

We assume a stationary pressure-driven flow between two infinite plates, and consider
that the flow has only one component, u, directed along the direction x along which
the pressure gradient is applied (see Fig. 3.16). With the symmetries, u only depends
on the coordinate z, normal to the walls. To calculate the flow profile, we project
the Stokes equation onto the x axis. The projection imposes the pressure gradient
3 Here, the frictional force is proportional to the speed, not to the speed gradient (i.e. the speed
divided by an intermolecular distance). This where Lamb’s argument is objectionable. In fact, Lamb’s
argument is based on the hypothesis that liquid/solid interfaces behave as fluid/fluid interfaces. The
assumption is acceptable for gases, as we saw, but, for liquids, it has no theoretical justification, and
leads to conclusions in conflict with molecular dynamical simulations and experiment.
4 D is the fluid diffusion constant, k the Boltzmann constant, T the temperature, C a constant
characterizing the molecular roughness, ρ the density, σ a microscopic length scale and  a fluid-solid
energy.
 Slippage in liquids 123

∂p
G = − ∂x , in which p is the pressure, to be constant, i.e. independent of x and z. With
that, the equation to solve is an ordinary differential equation of the second order,
coupled to the boundary conditions (3.27). The solution is:

h2
 
Ghb G
u(z) = − z2 − (3.28)
2µ 2µ 4

3.16: Flow between two in-

finite plates, located at z =
± h2 , driven by a pressure
gradient applied along x,
with slip

The velocity profile with slip is a superposition of a plug flow (uniform velocity of
magnitude Ghb 2µ ) and a Poiseuille flow. To illustrate this, the velocity profile without
slip is represented in Fig. 3.17. Obviously, at fixed ∆P , the presence of slip increases
the flow rate. We can describe the profile, as is often done, as a Poiseuille profile, but
with a wall located at z < −h/2 in the negative part and z > h/2 in the positive one.
For b << h, the (virtual) wall is located at:
 
h
z=± +b (3.29)
2

The pressure drop ∆P can be calculated by integrating the Eq. 3.28 along z:
12µLQ
∆P = (3.30)
wh2 (h + 6b)

in which w is the channel width (assumed, in practice, much larger than h in order
to consider that u only depends on z). The above relation again shows that slippage
reduces the pressure drop needed to drive the fluid.
An interesting case occurs when b is much larger than h. This happens in carbon
nanotubes a few nanometres in diameter. In this case, slippage dominates the right
124 Hydrodynamics of microfluidics 1: channels

3.17: Velocity profiles, with slip-

page (full line) and without slip-
2
page(dashed line). u0 = Gh 8µ
and,
for the slippage case, b = h/10.

hand side r.h.s.) of Eq.(3.28) and the flow profile is flat. On the other hand, again in
the limit of large b/h, for a given Q, ∆P becomes extremely small. Walls behave as free
surfaces and no pump is needed, in principle, to drive the flow. These considerations
raised hope, in membrane technology, to develop large permeabilities, which could
facilitate energy production (see Chapter 6).

We give here another formula, equivalent to Eq. (3.32), and valid for tubes. It can be
obtained by performing the same task as above, in cylindrical coordinates. We find:

128µLQ
∆P = (3.31)
πd4 (1 + 8b/D)

in which D is the (inner) tube diameter, and L its length.

In microfluidic channels, Q and ∆P can be measured. This led experimentalists to use

Eqs. (3.32) or (3.31) for determining slip lengths [47]. For instance, in the rectilinear
case, one has:

 
h 12µLQ
b= −1 (3.32)
6 ∆P wh3

which shows how b can be inferred from pressure and flow rate measurements carried
out in a microchannel. Although the method seems straightforward, the main difficul-
ties of the approach are that, since, in microfluidic channels, b lies on the nanometre
or decananometre range, great accuracy on flow rate and pressure measurements are
needed. Moreover, the presence of minute leakages, difficult to detect, may introduce
biases in the flow rate measurements and affect the slip length determination. Nonethe-
less, a number of experimentalists have resolved the issues and obtained plausible (but
moderately accurate) measurements of slip lengths with this method [86].
 Slippage in liquids 125

3.3.3
. Slippage measurements in liquids over smooth walls

The measurements of slip lengths, in liquids, over smooth walls5 have long been con-
troversial (see the review of E. Lauga, M. Brenner and H. Stone [47], who discussed
the fifty or so slip measurements performed between 1920 and 2005). By the turn of
the century, the confusion increased even more, after three modern’ measurements re-
vealed surprisingly large slip lengths [49–51] (on the order of 200 nm -2.5 µm), further
unconfirmed by other investigators. In the meantime, numerical studies consistently
reported much smaller slip lengths, on the order of a few nanometres, while a sec-
ond generation of experiments ( [52, 53, 84, 86, 87]), using improved instrumentation,
and, in the case of the force machine, analysing biases and artefacts in depth ( [52])),
consistently led to slip lengths at most in the deca-nanometre range.6 An example of
experimental study, performed in 2010, in which the flow profile close to the wall could
be resolved down to 100 nm, is shown in Fig. 3.18 [87]. .

Fig. 3.18: (Left) Experimental setup, showing a microchannel low, with an objective mounted
on a piezo-electric transducer, allowing the focal plane to span the near-wall region. Evanes-
cent waves illuminate the fluid and fluorescent nanoparticles seed the flow.(Right) Velocity
profiles obtained in this system, for hydrophobic walls, showing, by extrapolation, wall slip-
page [59, 87].

The ensemble of results, numerical and experimental, were summarized, for water -
used in the vast majority of studies - in Ref. [5]. The data are shown in Fig. 3.19. Nu-
merics and experiments show that slip lengths, are indistinguishable from zero when
the fluid fully wets the surface. Concerning numerics, slip lengths increase with the
contact angle, reaching several nanometres for the largest contact angle, consistently

5 Smoothness is molecular on bare surfaces of silicon and mica. With hydrophobic layers deposited
onto them, the roughness, measured with Atomic Force Microscopy AFM), raises up to a few nanome-
ters. This parameter is systematically measured in the controlled experiments performed on the sub-
ject
6 Stimulated by preliminary observations of nanobubbles at the water/solid interfaces ( [57]), it was
proposed that a nanometric gas layer, confined between the wall and the fluid, could play the role of
a lubrication film, allowing the fluid to slip at substantial speeds and thus develop large slip lengths
( [58]). However, series of studies made with X-ray and neutrons, could not confirm the hypothesis.
126 Hydrodynamics of microfluidics 1: channels

with intrinsic slippage theory7 . A similar trend is observed in the experiments. How-
ever, a discrepancy exists between the two sets of data (numerical and experimental),
unresolved at the time the book was written.

3.19: Experimental and numerical

measurements of slip length b as a func-
tion of the contact angle θ (adapted
from Ref. [5]). The full line on the right
is given by b = 0.3(1 + cosθ)−2 . The
dashed line provides a guide for the
eyes; it has no theoretical significance.

7 Note that one parameter has been tuned in the theory to match the simulations.
 Microfluidics at small Reynolds numbers 127

Slippage in small carbon canotubes: a puzzling situation

At the moment, regarding the question of slippage in CNTs, the situation is puzzling.
The subject stands at the cutting edge of research and, even though important issues
are still unresolved, it is interesting, in the context of the book, to provide information
on the situation. Fig. 3.20, established in [60], collects data reported in the period
2000- 2017. The reader should pay attention to the fact that a double logarithmic
scale is used to represent the data. Water flows extremely fast in CNTs, but the
measured flow rates, compared to classical hydrodynamics predictions, are scattered
over five orders of magnitude. Slip lengths of 1 to 500,000 nm, resulting in almost zero
to 500,000 flow enhancement factors, are reported for water in CNTs with diameters
of 0.8 to 10 nm.

Fig. 3.20: Slip length of water in carbon nanotubes. The graph gathers data obtained
from experiments and simulations [60]. Details can be found in the reference. The
figure reveals a puzzling situation (Reprinted from Ref. [60] with permission from
Materials Research Society. Copyright 2022.).
Why is it so scattered ? There is no response yet and the discussion of this graph
stands outside the scope of the book. The reader may refer to recent reviews for more
information. See, for instance, [61].

3.4 Microfluidics at small Reynolds numbers

3.4.1 Flows in channels with rectangular cross-sections

We now concentrate on bulk phenomena and proceed to the calculation of unidirec-

tional flows through channels of rectangular cross-section, as sketched in Fig. 3.21,
using the Stokes equation, which are valid, as discussed above, at small Reynolds
numbers. This geometry is fundamental in microfluidics. Microfabrication techniques
naturally create microchannels of this geometry. An example, shown in Fig. 3.21 (right)
was taken in Ref. [62]. Much ingenuity is required to build channels of circular cross-
sections, and in practice, they are rarely used. This justifies us bringing particular
attention to the rectangular case.
Here we assume a slip length b = 0 and hypothesize that the flow reduces to a sin-
gle velocity component along x. This assumption is crucial. By projecting the Stokes
128 Hydrodynamics of microfluidics 1: channels

Fig. 3.21: (A) Model: Straight channel of rectangular cross-section, with the system of coor-
dinates.(B) Real PDMS channel. (Reprinted from Ref. [62]).

equation onto the z and y axis, one infers that pressure p depends only on x (other-
wise, transverse velocity components would develop). Then, by projecting the Stokes
∂p
equations along x, we further infer that the pressure gradient G = − ∂x should be a
constant (otherwise, the flow would depend on x). Using G, the flow equation reads:

G
∆u = − (3.33)
µ
∂2 ∂2
where ∆ = ∂y 2 + ∂z 2 . The boundary conditions are:

w h
y=± and z = ± , u = 0 (3.34)
2 2
In the mathematical language, we have a Poisson equation with Dirichlet boundary
conditions. Several methods exist to solve it. Fourier series expansion is particularly
efficient in this case. In practice, the velocity is expanded into Fourier series expansion
along y or z. After some calculations, we obtain the following expression of the velocity
u(y, z) (the expansion is made along y):

∞
!
4G X (−1)n+1 chβn z
u(y, z) = 1− cos βn y (3.35)
µw n=1 βn3 chβn h2
where βn is defined by:
π
βn = (2n − 1) (3.36)
w

The iso-velocity contours, in the case of a shallow channel r = h/w = 0.125 is shown
in Fig. 3.22. Except close to the sidewalls y = ±w/2 (i.e. y/h = ±4), the velocity is
independent of y. A misconception of hydrodynamics sometimes leads to think that
the velocity profile should be doubly parabolic, i.e. parabolic along y and z. This is
not the case.

The volumetric flux Q is defined by:

 Microfluidics at small Reynolds numbers 129

Fig. 3.22: Flow contours and profiles in a rectangular channel of aspect ration h/w = 0.125.
On the top left, iso-velocity contours. On the right velocity profile u(z), for y = 0; at the
bottom, velocity profile u(y), for z = 0 Except close to the side-walls y = ±w/2, the velocity
u depends on z, but not on y. A misconception of hydrodynamics sometimes leads scientists
to think that the velocity profile should be parabolic along y and z. This is not the case.
Z w/2 Z h/2
Q= u(y, z)dydz (3.37)
−w/2 −h/2

satisfies the following relation:

∞  
8Gh X 1 2 h
Q= 1− thβn (3.38)
µw n=1 βn4 βn h 2

A close estimate (up to about 10%) of Q, valid for h ≤ w, is given by the following
expression :

wh3 G 6 × 25 h wh3 G
   
h
Q≈ 1− ≈ 1 − 0.63 (3.39)
12µ π5 w 12µ w

In the limiting case h/w << 1, the flow rate is:

wh3 G
Q0 = (3.40)
12µ

We plotted Q/Q0 , with Q given by Eq. (3.38), as a function of the aspect ratio r = h/w.
The result is shown in Fig. 3.23:

For completeness, Table 3.1 displays values of the ratio Q/Q0 = f (r) as a function of
r = h/w.
130 Hydrodynamics of microfluidics 1: channels

3.23: Evolution of Q/Q0 (Q is given

by Eq. (3.38), and Q0 by Eq. (3.40) as
a function of the aspect ratio r = h/w.

r = h/w Q/Q0
0.01 0.994
0.25 0.843
0.5 0.686
1 0.422
2 0.172
4 0.0527
6 0.0249
10 0.0094
Table 3.1 Various values of Q/Q0 = f (r) as a function of aspect ratio r = h/w. One may
check that f ( r1 ) = r2 f (r).

3.4.2 Flow around a sphere - the Stokes law

The Stokes law is one of the most remarkable achievement of hydrodynamics. Let us
consider Fig. 3.24, in which a sphere of radius a, is held in a homogeneous stream,
coming from the left, with speed U∞ oriented along x.

Fig. 3.24: Flow around a sphere.

The flow is perturbed by the sphere. In a spherical system of coordinate, the flow is
independent of the azimuthal coordinate. It only depends on r, the distance from the
sphere centre, and θ, the polar coordinate. The flow field has two components, ur and
 Microfluidics at small Reynolds numbers 131

uθ . The Stokes equation reads:

− ∇p + µ∆u = 0 (3.41)

in which p is the pressure. Here, we neglect slippage, so that the boundary conditions
are:

u = 0 for r = a and u = U∞ , p = P∞ for r = ∞ (3.42)

in which P∞ is the (constant) pressure at infinity. To calculate the flow, we need to

express Eq. (3.41) in a spherical system of coordinates. The strategy, for figuring out
the solution, consists in determining the pressure field p(r), by taking the divergence
of Eq. 3.41 and calculate u(r, θ) by taking the curl. This is not a straightforward
calculation. We recommend Ref. [8], which explains well the steps of the calculation.
Here, we skip this technical part and directly provide the solutions. It can found in
many fluid mechanics textbooks (see, for instance, [3, 8, 63]):

3µaU
p(r, θ) = P∞ − cos θ (3.43)
2r2
a3
 
3a
ur (r, θ) = U∞ cos θ 1 + 3 − (3.44)
2r 2r
3
 
a 3a
uθ (r, θ) = U∞ sin θ −1 + 3 + (3.45)
4r 4r
a3
 
U∞ 3a
ψ(r, θ) = sin2 θ r2 − r + (3.46)
2 2 2r

The streamfunction ψ and the iso-pressure lines p are plotted in Fig. 3.25.

Pressure develops lobes which are positive on the left-hand side of the figure and
negative on the right. There is a streamwise pressure gradient that tends to push the
sphere downstream. It is called pressure drag’. Flow streamlines develop around the
sphere. Far from the sphere, they stack with an increasing density. This is due to the
spherical geometry.

One extremely important outcome of the calculation is the determination of the drag
exerted by the flow on the sphere. The drag includes two components: a pressure
drag (mentioned above), and a viscous drag, associated to the tangential stress τrθ =
3
− 3µa U ∞ sin θ
2r 4 . Stresses developed by the two components must be integrated over the
sphere surface to determine the force. As expected from symmetry, one finds zero in
the direction normal to the upcoming flow. Along x, the calculation leads to:

F = 6µaU∞ (3.47)
132 Hydrodynamics of microfluidics 1: channels

Fig. 3.25: (A) Iso-pressure levels around a sphere, in unit of µU∞ /a , given by Stokes’s
solution (3.43), with P∞ =0. Levels are separated by 0.1.(B) Flow streamlines around a sphere,
given by the Stokes solutio (3.46), in unit of U∞ a2 . The minimum level is 0.1; the other levels
are separated by a dimensionless quantity equal to 0.5.

This is the famous Stokes law, established in 1851 by George Gabriel Stokes. It is valid
at small Reynolds number, for all sphere sizes. We will use the law several times in
the book (in Chapter 5, for Brownian motion and particle deposition phenomena, and
in Chapter 6 for dielectrophoresis and electrophoresis). Note that in the Stokes law,
2/3 of the force come from the shear stress and 1/3 comes from the pressure difference
between the fore and the aft surfaces of the sphere.

3.4.3 Flow around bubbles and droplets

The same approach can be taken for droplets and bubbles. General formula exist,
depending on the viscosity ratio between the inner and outer fluids. Let us consider
the case of bubbles. In bubbles, the boundary condition, at the liquid-gas interface,
is stress-free, i.e., on the liquid side, the tangential stress is equal to zero. There is a
non-zero velocity at the interface, but no stress. In such conditions, by applying the
same method as before, one obtains the following streamfunctions:

a
r > a : ψ(r, θ) = U∞ ar sin2 θ(1 − ) (3.48)
r
U∞ r 2
r < a : ψ(r, θ) = sin2 θ(r2 − a2 ) (3.49)
2a2

These streamfunctions are represented in Fig. 3.26.

It is important to note that two counter-rotating eddies develop inside the bubble.
These circulations also exist in droplets. We will see, in Chapter 5 that they allow
reactants to mix inside the droplet, which is critical for the biochemical applications
 Microfluidics at small Reynolds numbers 133

3.26: Flow around and inside a bub-

ble. Two counter-rotating eddies de-
velop in the bubble. A. similar pat-
tern holds in droplets (i.e. for which
the fluid inside the sphere is a liquid.)

of microfluidics. Interestingly, the drag exerted by the flow on the bubble is equal to
F = 4µaU∞ (the factor 6 has changed).

3.4.4 Flows in Hele–Shaw cells

Returning to flows in channels of rectangular cross-section, the particular case h << w

deserves particular attention, because it is frequently encountered in microfluidics.8
The reason is that, because of the limitation of photosensitive resins, it is uneasy to
realize channels with heights above 200 µm. On the other hand, it is often tempting,
for throughput reasons, to enlarge the channel, which leads to h << w. This type
of geometry is called, in the hydrodynamic literature, Hele–Shaw cells, in celebration
of Henry-Selby Hele-Shaw, who introduced it in 1898, to investigate the origin of the
liquid/solid friction. A Hele-Shaw cell is shown in Fig. 3.27. In general, the channel
is not straight; it varies along x, keeping the height h constant, but allowing for slow
variations of w. As w is a function of x, velocity u will also depend on this coordinate.
Here we perform the calculation in the case we just mentioned, i.e. the variations of
w along x involve a scale much larger than h. Also, as repeatedly said, the Reynolds
number is vanishingly small. Despite the apparent complexity of the situation, simple
formulas can be obtained.

Fig. 3.27: Geometry of Hele–Shaw flows, with the system of co-ordinates.

A fundamental remark is that, in the framework of these approximations, the flow

component normal to the plates is negligible. This can be shown by analysing the

8 We showed an example in Fig. 3.6

134 Hydrodynamics of microfluidics 1: channels

mass conservation relation div u = 0.9 This implies, still taking the Stokes equations,
that p does not vary with z, i.e. is a constant along the vertical dimension. Based on
∂2
that, taking again the Stokes equations, and approximating the operator ∆ by ∂z 2

(because velocity varies only slowly with x and y), U (x, y, z) is found to have the
following expression:

3 4z 2
U(x, y, z) = (1 − 2 )V(x, y) (3.50)
2 h

where V is a horizontal vector function of x and y. It should be noted that V represents

the average of U across the channel height. In most cases, rather than U, V is used to
discuss flow phenomena in Hele-Shaw cells. This is what we shall do here. The relation
of V to pressure is:
h2
V(x, y) = − ∇P (3.51)
12µ
where P is the pressure and, as in the rest of this chapter, µ is the dynamic viscosity.
This analysis is valid as long as the velocity varies slowly with x and y, i.e. far from
the vertical boundaries.

Eq. (3.51) is the equivalent of Darcy’s law in porous media. The velocity field is poten-
tial, implying that vorticity is everywhere zero. There cannot be closed circulations,
i.e. eddies, in Hele-Shaw flows. An interesting relation on the pressure, obtained by
applying mass conservation div u = 0, is the following:

∆P = 0 (3.52)
showing that pressure is an harmonic function. Looking at the function current Ψ(x, y),
defined by curl(Ψ ez ) = V(x, y), in which ez is the unit vector normal to the (x,y)
plane, one gets ∆Ψ = 0. These properties characterize Hele-Shaw flows, and in many
cases allow the determination of their structure using, for instance codes available in
MatLab that are dedicated to electromagnetic or thermal calculations.

Flow around a cylinder in Hele-Shaw cells. To illustrate the previous discussion, let us
consider a flow around a cylinder, in a Hele Shaw cell, produced by an upstream speed
U∞ . By solving the equation ∆Ψ = 0, associated to zero normal speed component at
the surfaces (i.e. Ψ = 0 at the cylinder and Ψ = Cst at the walls ), one finds that the
stream function Ψ(r, θ) is given, in cylindrical coordinates, by the following expression:

R2
 
Ψ(r, θ) = U∞ r 1 − 2 sin θ (3.53)
r

9 If u is the vertical component of the velocity, mass conservation equations tells us that u ∼
z z
h/wU , where U is a typical horizontal speed. As h/w is small, uz can be neglected.
 Microfluidics at small Reynolds numbers 135

where r is the distance from the center and θ the polar angle. Fig. 3.28 (A) shows the
calculated streamlines and Fig. 3.28 (B) those observed in a Hele-Shaw experiment.
The patterns agree well.

Fig. 3.28: (A) Theoretical stream function.(B) Observed flow pattern, developing around a
cylinder, embedded in a Hele-Shaw cell, 1 mm high. The cylinder is several cm in diameter
and U∞ is 1 mm/s(Photo D. H. Peregrine)

Note that solution (3.53) slips at the wall. This is physically possible, independently of
the material wall properties, because of the presence of thin fluid boundary layers, of
thickness h, in which velocity decreases to zero. These layers are neglected in the Hele-
Shaw approximation. Interestingly, the flow streamlines of Hele-Shaw flows, obtained
at small Reynolds number, are identical to those of a perfect fluid, i.e. a fluid of zero
viscosity slipping over the cylinder surface.

3.4.5 Flow along cavities - Moffatt eddies

Microchannels with cavities or holes are frequently encountered in microfluidics and it

is interesting to present the flow patterns developing in such geometries. The stream-
lines are shown in Fig. 3.29, in a geometry where the flow is two-dimensional, i.e.
invariant along the coordinate normal to the plane of the figure. (This geometry is
fundamentally different from that of Hele-Shaw, in which the flow is confined along
the same coordinate.)
Calculations and mathematical analysis show that when the depth of the cavity in-
creases, a larger number of vortices forms inside. This phenomenon was explained by
Moffatt in 1964 [64], for wedges of arbitrary angles. In the rectangular cavities we
consider, the inner corners correspond to Moffatt wedges of ninety degrees angle. In
practice, recirculations inside the cavities are much weaker than the main stream.

3.4.6 Flow over patterned surfaces

To enhance slippage, one idea is to pattern the wall surfaces, by including zones, called
no shear zones’, that possess infinite slip lengths. In this manner, one may hope that,
if the proportion of such zones is important, the walls will expose, globally, a large
136 Hydrodynamics of microfluidics 1: channels

Fig. 3.29: Different flow structures in cavities at small Reynolds numbers. Here, the system
is invariant along the direction normal to the plane of the figure. Eddies appear in the cavity.
They are due to a mechanism explained by Moffatt [64], which gives rise to the so-called
Moffatt eddies. (The figures originate from Ref. [65].)

slip length to the fluid. In practice, the zones with infinite slip lengths are created
by cavities trapping gas bubbles, forming a Cassie state, which we will describe in
Chapter 4. Two geometries are currently considered [66]. They are shown in Fig. 3.30,
for tubes, but equivalents also exists for planes:

Fig. 3.30: Schematic views of the elementary models used: pressure-driven flow in a pipe of
radius R with distribution of no-shear regions of width h and separation H; λ denotes the
microscopic slip length.(A) The no-shear regions are transverse to the flow direction.(B) The
no-shear regions are parallel to the flow direction. [66]
.

In Fig. 3.30, the inner tube walls include no slip and infinitely slipping (called ‘no-
shear’) zones. In most cases, in such geometries, whether cylindrical or planar, no exact
solution exists. Nonetheless, the case of Fig. 3.30 (b) could be analytically solved by
Philip in 1972 [67, 68]. The solution is quite complicated and we do not present it in
the book. The reader can refer to Refs [66, 67] for detail. Instead, we focus on the slip
length, whose expression is given by the formula:

!
H 1
b = ln hπ
π cos( 2H )
 Microfluidics at small Reynolds numbers 137

in which the definitions of h and H are the stripe width and inter distance, respectively
h
(see Fig. 3.30). When the area fraction of no-shear bands equals unity, i.e. H = 1, slip
length b becomes infinite. There is thus a manner, in principle, to produce low pressure
loss systems, if these no-shear regions could be realized experimentally.

Unlike the case of longitudinal bands, the case of transverse bands, shown in Fig. 3.30
(A) has no exact solution in the general case. Nonetheless, as expected intuitively, as
the fraction of no-shear fraction reaches unity, one finds that, in this system, slip also
becomes infinite.

Slippage over CNT forests. Since 2003 and later, a number of theoretical, numerical
and experimental studies have been carried out on the subject (see for instance [69–
74]). Confirmation was given that large effective slip lengths can be obtained when
the solid area exposed to the fluid is minimal. Ref. [74] provides an example of an
experiment, in which a forest of hydrophobic CNTs covers the wall surface (see Fig.
3.31).

Fig. 3.31: (A)SEM images of superhydrophobic CNT forests, after functionalization with
thiols: L: 1.7, 3.5 and 6 µm (pictures b, c and d). B - Velocity profile in the region close to the
CNT surfaces, normalized by the velocity in the centre of the channel v0 (v0 = 360 µm/s).
Inset: the three different profiles correspond to CNT surfaces with different roughness length
scale L. From bottom to top, L = 1.7, 3.5, 6 µm, and v0 = 550; 760; 360 µm/s [74].

Slip lengths found in these experiments were in the micrometre range, i.e. two orders of
magnitude above smooth walls. The slip lengths were also found to be proportional to
the distances between nanotubes, similarly to the case of longitudinal bands, discussed
above, a result justified by theoretical arguments [74]. In other experiments, impressive
slip lengths of up to 400 µm were reported on surfaces patterned with submicrometric
pillars or bands [73, 75–77].10

10 These large slip lengths hardly enter the theoretical framework discussed above. See [75, 76].
138 Hydrodynamics of microfluidics 1: channels

3.4.7 Micro and nanofluidic Landau Squire jets

The Landau–Squire flow is a jet emerging from a narrow tube into a large reservoir.
The flow was first solved by Landau and Squire in two independent works (Landau &
Lifshitz [63], Squire [78]). The flow is controlled by the rate of momentum transferred
from the tube into the reservoir, i.e. a force, not a flow rate. The solution for the flow
produced in the reservoir is given by [63]:

F cosθ F sinθ
vr = and vθ = −
4πµ r 8πµ r

in which r, θ are the radial and orthoradial components of a spherical system of

coordinate, centered at r = 0, F is the force driving the flow at the tube orifice, i.e.
the pressure divided by the jet nozzle area, the reference pressure being zero at infinity.
The Landau-Squire solution is one of the rare solutions of the nonlinear Navier-Stokes
equations.

Fig. 3.32: Velocimetry measurements of Landau–Squire jet flows in submicrometric capillaries

[79].(A) Tracer trajectories around the nanocapillary, 200 nm in diameter, obtained
√ at ∆P
= 140 mbar.(B) Particle velocity v as a function of the parameter r0 (θ) = 2r 1 + 3 cos2 θ
for various ∆P , for a capillary, 320 nm in diameter. From bottom to top, ∆P = 20, 60,
100, 140 and 180 mbar. Landau Squire theory predicts proportionality between v an 1/r0 (θ).
(Reprinting of Figure from Ref. [79] by permission from J. Fluid. Mech.).

Figure 3.32 shows the flow streamlines, obtained by tracking fluorescent particles, for a
nozzle of 200 nm in diameter, pressurized at 140 mbar [79]. As the fluid is ejected from
the tube, it forms a jet, which entrains the fluid of the reservoir. This gives rise to the
pattern observed in Fig. 3.32 (A). The same figure shows the velocity intensity field,
along with measurements of the speed intensity as a function of variable 1/r0 (θ) (see
caption), showing proportionality, as expected. With additional measurements and
theoretical developments it is possible to estimate the flow rate in the nanocapillary
or the nanotube [79, 80],11 and in turn, determine the slip length. This was done
in [79]. Measurements indicated hundreds of nanometres for carbon nanotubes and,
surprisingly, no slippage for the case of boron nitride nanotubes (BNNTs), despite the
11 The task needs a separate information, because, in the theory, the jet nozzle has no size and
Q=0
 Microfluidics at small Reynolds numbers 139

fact that the crystallographic structures of the two materials are close. At the time of
writing of this book, as underlined in a previous section, the levels of slippage observed
in this experiment, and in general in CNTs, is not understood.

3.4.8 Miscible fluids flowing side by side in a Hele-Shaw cell

Here, two miscible fluids are injected in a Hele-Shaw cell. Far from the entry, where
the two fluids meet, the flow reaches a steady state, where the fluids flow side by side.
The flow structure shown in Fig. 3.33 assumes that mass diffusion is negligible.

Fig. 3.33: Miscible liquids flowing side-by-side, for which mass diffusion between the two
fluids are neglected.

Recall that in a Hele-Shaw cell, the flow is governed by Darcy’s law. We thus have:

h2 ∆P h2 ∆P
V1 = − V2 = − (3.54)
12µ1 L 12µ2 L
.

which implies that, as long as µ1 6= µ2 , the two speeds V1 and V2 are different. The
ratio of the two speeds is given by:

V1 µ2
= (3.55)
V2 µ1
.

Let us take the particular case where the flow rates of the two fluids are the same. We
have Q = w1 hV1 = w2 hV2 , where Q is the flow rate of each fluid. Finally, we arrive at
the following relation:

w1 µ1
= (3.56)
w2 µ2
.
140 Hydrodynamics of microfluidics 1: channels

The fact that velocity is discontinuous at the interface does not violate any law. In
fact, there is a thin layer, on the order of the channel height, in which the velocity
passes gradually from V1 to V2 .12
Eq. (3.56) also applies to non-miscible fluids, as long as instabilities, droplet formation,
or wetting phenomena, do not affect the flow. The system shown in Fig. 3.33 has been
used in [81, 82] for measuring viscosities, converting a dynamical measurement into a
geometrical one, that of the position of the interface in the channel. In Ref. [81], the
sample was less 300 µL and the viscosities ranged from 10−3 to 70 Pa·s.

Progress in local velocity measurements

Particle imaging velocimetry (PIV) consists in seeding flows with microparticles and
infer, from the analysis of image cross-correlations, the speeds of particle patches.
The resolution is on the order of several hundreds µm. With such a resolution, it is
impossible to investigate flows in microchannels. Improvements were made in 1999
with the advent of micro particle Imaging velocimetry (µPIV) technique [83]. As
in PIV, cross-correlations are calculated, but micro or sub-micrometric fluorescent
particles are used. Moreover, the flow is placed under a microscope, with a high
aperture objective, and thus small field depths, in order to localize particles. An
example is shown in Fig. 3.34 A [84].

Fig. 3.34: A - MicroPIV measurements of a Poiseuilles flow in a microchannel, with

wetting walls [84] ; B - TIRF based measurement of a pressure driven flow profile
carried out, in a 18 µm channel high, at less than 1µm from the wall (see [85] for
detail). The profile is parabolic, but, close to the wall, it is undistinguishable from a
linear profile, i.e. a pure shear flow
Fig. 3.34 (A) shows µPIV measurements of a Poiseuille flow, in a microchannel, using
500 nm particles. With such particles, the wall cannot be approached by less than 1
µm. Decreasing particle sizes to improve the situation is difficult, because of Brownian
motion, which tends to cancel correlations and make particle localization inaccurate.
Later, investigators coupled smaller particles (typically 100 nm in diameter), and
total internal reflection fluorescence (TIRF) [86, 87]. They improved, by one order
of magnitude, the spatial resolution of the velocity measurements. Fig. 3.34 B [85]
shows that with 100 nm particles, the wall could be approached down to 200 nm.
Microfluidics has stimulated progress in velocity measurements.

12 This is specific to the Hele Shaw geometry. It would not happen in a 2D geometry, i.e. invariant
normally to the plane of the figure. In this case, momentum would diffuse and, beyond a certain
distance, the velocity would be homogeneous.
 Resistances and capacitances in microfluidics 141

3.5 Resistances and capacitances in microfluidics

3.5.1 Flow generators in microfluidics

To drive fluids, we need flow generators. Those mostly used in microfluidics are shown
in Fig. 3.35.

3.35: Microfluidic flow gen-

erators. (Left) Syringe pump
imposing a fixed flow rate
Q;(Right) Pressure source that
impose a fixed pressure p up-
stream.

The syringe pumps include a piston that pushes the fluids inside a cylinder. The flow
control can be excellent, and the flow rate oscillations low.13 The pressure controllers
impose a gas pressure in reservoirs partially filled with the working fluid. This system
allows liquids in the microfluidic device to be driven by acting on the gas pressure.
Pressure controllers impose well-controlled pressures, down to tens of microbars.

Over the years, the field benefited from improvements in the instrumentation, genera-
tors, and flowmeters. This progress allowed carrying out of delicate experiments, and
undoubtedly, contributed to the development of the field. Fluid columns, imposing a
gravitational pressure, were used in the early days of microfluidics. They are much less
convenient to operate, but offer a degree of accuracy.

3.5.2 The hydrodynamic resistance

Definition. Microfluidic circuits can have a complex geometry, and, very early, the
community sought to harness the concept of hydrodynamic resistance to determine the
flow in each of their branches. Contrarily to electrokinetics, where Ohm’s law is local, in
microfluidics, except in the Hele-Shaw limit,14 the notion of hydrodynamic resistance
is global, i.e. it is attached to a particular geometry. In an earlier section, we saw that,
for channels of rectangular cross-section, the pressure drop ∆P is proportional to the
flow rate Q (see Eq. (3.38). We thus have the relation:

13 For low cost syringe pump, a few % is a plausible number. The highest-quality syringe pumps
reach 1% fluctuation, roughly
14 Eq. (3.51) represents a local relation between speed and potential gradient, analogous to local
Ohm’s law
142 Hydrodynamics of microfluidics 1: channels

∆P = RQ (3.57)

where R is called the hydrodynamic resistance. In the case of a shallow channel, where
h << w, the expression of R is:

12µL
R= (3.58)
h3 w
.

Eq 3.57 points to an analogy with electrokinetics, in which pressure would correspond

to electrical voltage, and flow rate to electrical current intensity. At large Reynolds
numbers, we can still write a relation of this type, but the resistance is no longer an
intrinsic property of the fluids and the geometry, it depends on the flow itself, which
reduces the interest of the concept. Going further into the analogy, one can define an
hydrodynamic resistivity equal, in the case of shallow channels, to 12µh2 . This resistivity
increases as the inverse of the second power of the height, indicating that there is a
‘price’ to pay, in terms of pressure drop, for miniaturizing microfluidic devices. The unit
of hydrodynamic resistance is P asm−3 . This unit does not have a particular name. To
provide an order of magnitude for R, it is useful to know that for water (µ ≈ 10−3 Pas),
and a square channel of 100µm side, 1 mm long, we have R ≈ 1011 P asm−3 .

Several geometries, with an without slippage at tha walls, are displayed in Table 4.4.

Shape Rhyd

12µL
Shallow . h3 w

12µL 1
Rectangle . ≈ h3 w (1−0.63 w
h
)
(h/w < 1)

28µL
Square . ≈ h4

8µL
Circular . πr 4

12µL
Shallow with slip . b
h3 w(1+6 h )

8µL
Circular with slip . πr 4 (1+4 rb )

Table 3.2 Formulas of various resistances for channels of circular and rectangular cross-sec-
tions, with and without slip.

Resistances in series and parallel. There are laws for nodes and branches, just as in
electrokinetics. For a node, the sum of the flow rates is cancelled out. We thus have
the following equation:
 Resistances and capacitances in microfluidics 143

n
X
Qi = 0
i=1

in which Qi is the flow rate entering or exiting the node. On the other hand, along
each closed branch, we have:

n
X
∆Pi = 0
i=1

in which ∆Pi is the pressure difference between two points of the closed branch. The
two relations form the equivalent of Kirchoff’s law in electrokinetics. It follows that
hydrodynamic circuits can be treated as electrokinetic circuits. For example, two re-
sistances R1 and R2 placed in series are equivalent to a resistance R = R1 + R2 . Such
a situation is shown in Fig. 3.36. The series of relations leading to this result is the
following:

∆P1 = R1 Q (3.59)
∆P2 = R2 Q (3.60)
∆P = ∆P1 + ∆P2 = (R1 + R2 )Q = RQ (3.61)

In this calculation, we assumed that the transition region between R1 and R2 , in which
the streamlines develop a curved pattern to match the two resistances, has a negligible
size. It could be possible to attach a resistance to this region. All this complicates the
analysis, however. In practice, when transition regions take a substantial part of the
circuit, the notion of resistance is no longer interesting to use. Electrical circuits have
the same problem, but, in practice, the transition regions are extremely small and they
can always be neglected.
The case of two resistances in parallel are equivalent to a resistance whose expression
is:
R1 R2
R// = (3.62)
R1 + R2

We can formulate the same remarks as previously, concerning the transition regions lo-
cated upstream and downstream of the two branches. All these analogies are extremely
useful when dealing with microfluidic circuits with several well-identified branches,
which is most often the case.

3.5.3 Two examples of microfluidic resistance networks

144 Hydrodynamics of microfluidics 1: channels

Fig. 3.36: Two hydrodynamic resistances placed in series (left) and in parallel (right).

Example 1: The hydrodynamic focusing geometry. A paper published in 1998 [88]

reported a micromixer with a mixing time in the µs range. The work received a large
echo, because this mixing time was three orders of magnitude faster than the most
rapid mixers used at that time. The experiment is shown in Fig. 3.37. The geometry is
the intersection of two microchannels. On the left, an aqueous solution of fluorescein,
is injected at pressure Pi , while on the sides, pure water is introduced at pressure
αPi . The idea is that the side flows squeezes the fluorescein stream, down to deca-
nanometric dimensions [88]. Now, this type of geometry is frequently used to form
droplets, as will be explained in the next chapter. Its name is ‘hydrodynamic focus-
ing’.15
Fig. 3.37 (right) shows the equivalent electrical circuit.

On resolving the currents and pressure drops in the network, one is led to the following
expression for the ratio of the injected current in the central branch Ii to the total
current I0 .

Ii 1 + 2σ − 2ασ
=
I0 1 + 2αγ

in which the meanings of the variables are displayed in Fig. 3.37. For α > 1+2σ 2σ (for
instance, the main branch highly resistive, and large side pressures), Ii is negative. In
such a case, the flow in the main branch is inverted. Before inversion, a weak stream of
fluorescein, strongly squeezed by the side-flows, penetrates into the collecting channel,
as shown in Fig. 3.37. In the experimental work, the authors succeeded to reduce its
width down to less than 100 nm, which led to diffusive times lying in the tens of µs
range. These were the conditions for which an extremely fast dilution of fluorescein
with water could be obtained.

15 Sometimes it is called ‘X cross-channel’

 Resistances and capacitances in microfluidics 145

Fig. 3.37: Hydrodynamic focusing is a geometry for which fluids penetrate the device through
three entries, and, depending on the flow conditions, are collected or not by a main chan-
nel. The left figure was taken from [88]. In the reference, the flow was visualized by using
fluorescein. On the right, the equivalent hydrodynamic circuitry, with the original notations,
that we keep for the calculation. (Reprinted figure with permission from Ref. [88] Copyright
(2022) by the American Physical Society with permission of R. Austin.)

Example 2: The 10-fold log levels solute distributor. G. Whitesides developed a device
enabling the distribution of tracers in multiple levels. Years later, Furlani et al. [89] in-
vented a device, in which a solution can be distributed with 10-fold dilutions, spanning
two decades in the solute concentration (see Fig. 3.38).

Fig. 3.38: The ten-fold dilution device [89]. (Left) Design of the network, incorporating
branches of different lengths, so as to implement the set of resistances calculated by the
theory; (right) Detail of the network, with the definitions of the lengths and flow rates in
each branch. The calculation leads to: Q1 = Q2 = Q3 = Q4 = 1 µl /min; Q5 = 0.9; Q6 =
0.1; Q7 = 1.2; Q8 = 2.9; Q9 = 0.99; Q10 = 0.11; Q11 = 1.11 µl/min; L1 = 25.2; L2 = 10; L3 =
10.2; L4 = 21.4; L5 = 16.8; L6 = 2; L7 = 10; L8 = L11 = 2; L9 = 4; L10 = 2 mm.
.
146 Hydrodynamics of microfluidics 1: channels

Here, one has two entries, with two colors, and four outlets, that redistribute the colour
levels in a series of 10-fold log levels. The authors succeeded in designing the circuit,
i.e. determining the lengths of each branch, to obtain this remarkable result. The right
part of Fig. 3.38 shows the various flow rates circulating in each branch. For detail,
see [89].

3.5.4 Hydrodynamic capacitance

In the same way as for resistance, the notion of hydrodynamic capacitance of an

element can be introduced with the relation:
dP
Q=C
dt
where Q is the volumetric flow rate, C is its capacitance, and P is the pressure drop
across the element in question. The idea of hydrodynamic capacitance is interesting
when the channels are deformable. An example is the soft plastic tubing that conveys
the fluids into the device. In all cases, under the action of the pressure, the volume
changes, generating additional flow rates, which are precisely accounted for in the
definition of the capacitance. The unit of hydrodynamical capacitance is m3 P a−1 ,
which, as for the resistance, does not have a specific name.

Fig. 3.39: (Left)Flow in a microchannel, with a piston-spring system. (Right) Elec-

trokinetic model representing the flow.

To illustrate the notion of capacitance, consider a case where the flow is driven in an
elastic tube. Suppose that, in a lapse of time δt, the global pressure in the tube is
suddenly changed by an increment δP > 0. The fluid volume V will expand by an
amount δV , generating an additional flow rate q that fills the new available space. Let
us calculate q. One has:

δV
q=
δt
 Resistances and capacitances in microfluidics 147

On the other hand, the tube is made in elastic material, with a Young modulus E, a
thickness e and a diameter φ. We have:

2e δV
δP = E
φ V

Then, combining the two equations, we end up with the relation:

δP φV
q=C . with C =
δt 2eE

This important example, which will be used later, illustrates the concept of capaci-
tance.

3.5.5 Two examples of applications of the concepts of resistance and

capacitance

Example 1: The long transients caused by trapped bubbles. In the preceding ex-
ample, the capacitance was not localized, but distributed along the tube. Take the
case, now, where the tube deformation is localized. Figure 3.39 shows a piston, held
by a spring of stiffness k, placed on the side of a channel (see Fig. 3.39). The equiv-
alent circuit of this system is shown on the same figure. One has a first resistance R
along which the fluid is driven. Then there is a node, at which the flow separates in
two branches, one pushing or pulling the piston, the other flowing through another
resistance R. Calculations show that the capacitance C is given by the expression:

S2
C=
k
in which S is the piston area.
By resolving the circuit of Fig. 3.39), one finds the following equation for the current
i(t) circulating in the branch of the second resistance:

∆P di
= i + RC
R dt

From this equation, one concludes that the time needed to reach a stationary state
is RC. This type of calculation can be repeated to determine the behaviour of a
device in which a bubble is trapped. By replacing the piston/spring system by a
bubble, one finds, for the expression of the capacitance, C = PV00 , where V0 is the
148 Hydrodynamics of microfluidics 1: channels

volume bubble. On considering typical microfluidic values, one concludes that, with
trapped bubbles, the time constant RC, which controls the time it takes to reach
a stationary state, is large: let us take a resistance of 1011 P a.sm−3 (see Section
3.57) and a bubble of 100 µm in diameter. One finds a time constant RC of 1000
s. It will thus take 15 mins to reach a steady state after a change in the oper-
ating conditions. If there are several bubbles, in the device, which evolve, for in-
stance, dissolve or reform, one may never reach a steady state. It can be concluded
that the presence of trapped bubbles in a microfluidic device is extremely detri-
mental to its functioning. Trapped bubbles are the ‘enemies’ of microfluidics.16 .

In practice, bubbles are more likely to appear when there is a leak, and during the filling
of the device. In order to avoid bubble trapping, one usually works with hydrophilic
materials (if aqueous solutions are the working fluids), and avoid geometrical dead
zones, corners, intersections. Evacuating before filling, or pre-wetting with short-chain
alcohols, can also be strategies. It is interesting to note, working with a material
permeable to gas, such as polydimethylsiloxane (PDMS), facilitates the removal of
bubbles, enabling it to work more easily with complex designs.

Example 2: The long transients induced by syringe pumps. There is an important

effect, in microfluidics, that I called ‘bottleneck effect’ in the first edition of this book,
and which must be known to avoid long transient in microfluidic devices. The situation
is shown in Fig. 3.40.
A syringe pump pushes a liquid in a microfluidic devices, represented as a simple
microchannel. The source of flow includes the syringe pump, the tubing, which is
deformable and possesses a low resistance. On the microdevice side, the system is
rigid and highly resistive. Since the device is highly resistive, the piston must build
up a substantial pressure in the chamber and the tubing for pushing the liquid. The
equivalent circuit is shown in the left-hand part of Fig. 3.40. The source of flow includes
a current source, that delivers a flow rate Q in parallel with a capacity C that takes
into account the fact that part of the flow rate produced by the piston is sucked by the
volume increase of the tubing. The two contributions, Q and the capacity flow rate
add up to enter the device, characterized by R.
Replacing R by its expression for channels of square cross-section (see Table 4.4) and C
by its expression for an elastically deformable tube, one obtains, for the time constant
τ = RC of the circuit:

3.6πµlφ3 L
τ = RC =
Eeh4
16 In the blood circulation of the body, micrometric bubbles dissolve rapidly, and thereby do not
generate problems. On the other hand, it is accepted that bubbles greater than 7 µ m in diameter
may cause embolisms. One may have sorts of embolisms in microfluidic devices, when, for instance,
because of a leak, trapped bubbles are so large that they block the main channel.
 Resistances and capacitances in microfluidics 149

Fig. 3.40: When a syringe pump is used for driving a fluid in a microfluidic device, the
deformability of the tubes may generate long transients. This was called bottleneck effect in
the first version of the book, because, during the transient regime, no liquid penetrates in
the microfluidic channel, even though the piston keeps advancing. Somewhere, a bottleneck
needed to be unlocked to feed the device The right figure shows the hydrodynamic circuitry
equivalent to the syringe/microchannel system.

in which φ and L are the diameters and lengths of the tubing, l and h are the lengths
and side of the microchannel, and K is the Young modulus of the tube material. In
practice one obtains a time constant on the order of 20 min, for a 5x5 µm square
microchannel, 1 cm long, a tube of 1 mm diameter, 0.5 m long, 0.1 mm thick plastic
tubing (1 GPa of Young modulus), and water (0.9 10−3 Pa.s). This means that when
we start operating a microfluidic device of that size, one must wait for 10 min for
reaching a steady state, which is obviously a long time. There are ways of improving
the situation, by working with larger channels, using more rigid tubes, or with smaller
diameters. However the most elegant way to resolve the problem is to replace the
syringe pump by a pressure controller, i.e. to work at fixed pressure, not at fixed flow
rate. The explanation is provided by Fig. 3.40, where we see that, by replacing the
current source by a pressure source, the device is submitted, without any transient
regime, to a fixed pressure. Indeed, the source will have to deliver a current in the
capacitance to compensate for the inflation of the tubes. But this derivation will not
affect, in any respect, the fact that the device R will be submitted immediately by the
pressure imposed by the source. In this manner, we completely suppress the transient
state.17 Accurate measurements of the effect are shown in Ref. [91].

17 This type of idea is developed in other domains. For instance, in hot wire anemometry, the probe
is operated at fixed resistance and thus fixed temperature, and not at fixed electrical current, in order
to eliminate long transient regimes related to the thermal inertia of the probe [90].
150 Hydrodynamics of microfluidics 1: channels

3.6 Inertial microfluidics and millifluidics

3.6.1 Introduction

We have noted that, due to scaling laws, the Reynolds number is inherently small
in microsystems, and, as a consequence, flows developing in them are governed by
the Stokes equations. However, it is necessary to qualify this line of thought. Many
microsystems do not work at small Reynolds numbers. This is the case micro of heat
exchangers. We will see, in Chapter 5, that they operate at moderate or high Reynolds
numbers to achieve high efficiencies. Moderate Reynolds numbers are also involved in
inkjet printers, which were presented at the beginning of this book. In such devices,
moderately high Reynolds number are needed to achieve large throughputs without
triggering hydrodynamic instabilities. In other microdevices, divergent channels func-
tion at high Reynolds numbers to generate flow irreversibility and give rise to pumping.
In other microsystems, eddies are produced at moderate Reynolds numbers to favour
mixing, without developing turbulence. These examples show that, in a number of
cases, moderate or high Reynolds numbers are used in miniaturized systems, and,
consequently, they must be considered in this book.
Another topics, which surged in the last decade, associates high or moderate Reynolds
numbers to particle or cell transport. This domain has been called ‘inertial microflu-
idics’. In this book, we will not adopt this definition. We will consider that ‘ı̀nertial
microfluidics’ covers all situations where, in a micro or millifluidic system, inertia forces
are important, i.e. the Reynolds number is well-above unity.

3.6.2 The phenomenon of boundary-layer separation

Fig. 3.41: (A) Convergent geometries are favourable, in the sense that they keep the boundary
layer ‘attached’ to the wall, and are associated to small hydrodynamic losses.(B) Divergent
flow cause substantial hydrodynamic losses, due to the development of detachment eddies
triggering turbulence. This case is called unfavourable.

Laminar boundary layers form a classical topics in fluid mechanics, and one can find
detailed descriptions in many textbooks. We consider here a laminar boundary layer
developing over a wedge of small angle (see Fig. 3.41). This situation could be, for
example, the flow along the walls of a convergent or divergent microchannel. We can
 Inertial microfluidics and millifluidics 151

distinguish two situations often called ‘favourable’ and ‘unfavourable’. The favourable
case is sketched in Fig. 3.41 (A).
Here we have the following two conditions:

dU dP
>0 and < 0,
dx dx

where U (x) represents the flow external to the boundary layer (which mainly depends
on the streamwise direction x because the wedge angle is small), and P (x) is the
corresponding pressure. The flow U (x) increases along x because of mass conservation.
On the other hand, Bernoulli’s theorem, which is valid at high Reynolds numbers
(which we consider here) and for stationary flows, stipulates that P (x) + 12 ρU (x)2
is constant along a fluid trajectory. This implies that P (x) decreases downstream.
Pressure P (x), which also holds in the boundary layer, thus tends to accelerate the
flow therein. In this configuration, the boundary layer remains ’attached’ to the wall.
Also, for reasons that we have no space to develop here, the flow is stabilized. This
case is considered as ‘favourable’.
The unfavourable case is shown in Fig. 3.41(B), corresponding to a divergent channel.
In this case, the velocity U (x) decreases (where we recall that x is the streamwise
coordinate), implying (due to Bernoulli theorem) that the pressure P (x) increases
downstream. Consequently, pressure acts against the flow. There is thus the possi-
bility to trigger the appearance of an internal recirculation, i.e. an eddy, within the
boundary layer. The formation of this eddy is called boundary-layer detachment, be-
cause, in such a situation the streamlines emitted from the apex seem to detach from
the wall. It is also called boundary layer separation, because, as sketched in Fig. 3.41
(B), the boundary layer splits into two regions. In geometries like that of Fig. 3.41
(B), detachment of the boundary layer is unstable, so that separation generally trig-
gers turbulence, which considerably increases the hydrodynamic losses. In the case
where the detachment point is anchored at a corner, like in Fig. 3.42 [92], there is
no turbulence triggering, but hydrodynamic losses are still substantially more impor-
tant than in the favourable case. This feature was exploited in the 1990s to fabricate
micropumps. Eddies frequently occur in diverging geometries [92].
These eddies have also been used in Ref. [92] to separate particles.

Pumps working at moderate Reynolds number. Separation can intervene in microsys-

tems functioning at moderate Reynolds numbers it the geometry includes edges, di-
vergent parts, or ruptures. An example is shown in Fig. 3.43 [93].
The principle consists of pushing and pulling the fluid with an electrostatically driven
membrane, in an asymmetric chamber. When the fluid is sucked by the membrane,
separation of the boundary layer occurs at the right because there is an abrupt opening
of the geometry. On the left, thanks to the divergent, the speed is decreased before
the flow arrives at the rupture, weakening the nonlinear phenomena associated to
152 Hydrodynamics of microfluidics 1: channels

Fig. 3.42: Eddy pair developing in a rectangular cavity crossed by a flow at moderate
Reynolds numbers [92]. The pair appears at the entry, i.e. where geometry is diverging, not
close to the outlet, where geometry is converging. (Reprinted from Ref. [92], with permission
from the Royal Chemical Society. Copyright 2022.)

3.43: Micropump working at moder-

ate or high Reynolds numbers, exploit-
ing a geometrical asymmetry between
the left and the right, to produce a
net flow towards the right (see expla-
nations in the text) [93].

it, so that the rupture of the geometry generates smaller losses. Similar phenomena
occur when the movement of the membrane is inverted, i.e. from pulling to pushing,
so that eventually, as indicated in Fig. 3.43, a net flux, from left to right, develops.
One limitation of such pumps, beyond the difficulties of microfabrication, and their
cost, is their low efficiency, meaning that hey are rarely used in practice.

3.6.3 Centrifugal microfluidics

Centrifugal microfluidics has a long history [94–96]). It started in the 1970s and was
reexpanded in 1998, fostered by contributions from M. Madou and G. J. Kellogg, along
with industrial involvements of Abaxis and Gyros [94]. The field is now considered to be
moving towards a mature technology. The idea is to exploit centrifugal forces to move
fluids radially outwards on a disk. In practice, microchannels are moulded in plastic
cartridges, which look like CD disks [94]. Even though the scaling laws associated with
inertial terms are unfavourable in microsystems, the high rotation speeds allow the
development of appreciable centrifugal forces, permitting the controlled movement of
fluids. The rotation speeds used here are on the order of 3,000 turns per minute. The
principle of the functioning of such a system is represented in Fig. 3.44.
 Inertial microfluidics and millifluidics 153

3.44: Microfluidic system using cen-

trifugal forces to drive fluids on a disk.
The system shown here was developed
by the company Gyros, about twenty
years ago.

In the figure, we see a dispenser supplying fluid to a rotating disk. The details of these
canals and reservoirs in the disk are shown in Fig. 3.45.

Fig. 3.45: Detail of a rotating disk, showing a valve formed by a hydrophobic restriction,
in which a meniscus is held by capillary forces.(Left) At small rotation speeds, the meniscus
is immobile, and the white fluid is blocked. (Right) At larger speeds, the meniscus cannot
sustain the centrifugal pressure, and the (white) fluid flows radially outwards.

Each reservoir is separated by an hydrophobic restriction, which plays the role of a

valve. They are successively filled using an incremental augmentation of the rotation
speed of the disk.
The following relation, which provides the expression of the centrifugal forces f driving
the fluid, allows to describe, schematically, how a centrifugal valve functions. Let us
consider a fluid volume v, enclosed in a chamber, it will be able to flow outwards if
the following condition is satisfied:

f = ρvΩ2 R > fcap

where Ω is the rotation velocity, R is the radial position of the valve, and fcap is the
capillary forces that holds the fluid meniscus. This inequality thus compares capillary
forces, which retain the fluid meniscus, with the centrifugal forces, which pushes the
fluid towards the periphery of the disk. The valve is open if centrifugal forces are higher
than the capillary forces, which is expressed by the inequality above. The capillary
force can be controlled by adjusting the dimensions of the canal connecting the two
reservoirs, or the properties of the surfaces exposed to the fluid, or both. The smaller
the channel, the larger the forces keeping the liquid on the disk must be. By increasing
the rotation speed, fluid volumes are drivent outwards to fill new reservoirs.
154 Hydrodynamics of microfluidics 1: channels

Thus, centrifugal microfluidics elegantly resolves the delicate problem of pumps and
valves, despite unfavourable scaling laws.
Over the last two decades, an important number of functionalities has been developed
by the centrifugal microfluidic community (mixing, separation, aliquoting, RNA ex-
traction, amplification, etc.) [94]. The integration of these functionalites on centrifugal
devices enabled to reach a certain level of complexity, attracting, in the recent years,
the interest of companies, including major ones such as Abbott and Samsung. An
example of application of the technology to the diagnostic field is shown in Fig. 3.46.

3.46: An integrated ELISA on a disc from

Samsung.

The future will tell whether the technology will give rise to major microfluidic appli-
cations.

3.6.4 Dean vortices in curved channels

When a flow is driven in a curved rectangular channel, as shown in Fig. 3.47, recir-
culating flows appear. They superimpose to the mean motion, so that fluid particles
spiral out, as they move downstream. This is what J. Eustice [97] discovered in 1911,
by injecting ink in water flows driven in curved tubes. The secondary motion was cal-
culated sixteen years later, by W. R. Dean [98], for the case of small Reynolds numbers
and circular tubes of small curvature.
A flow driven in a curved channel of rectangular cross-section is subjected to centrifugal
forces, whose radial component fr is given by:

ρUθ 2
fr =
r

in which Uθ is the orthoradial (or circumferential) flow component. The problem is

that, because of the presence of horizontal walls (see Fig. 3.47), Uθ varies with the
vertical coordinate z. This implies that this force cannot be balanced by a pressure
gradient. One way to show that is to calculate the rotational of the centrifugal force,
2
aligned along θ, and equal to 1r ∂z
∂
Uθ,r (z) which is not null, precisely because of the
presence of these walls. This implies that it cannot be balanced by a pressure gradient
 Inertial microfluidics and millifluidics 155

(whose rotational is zero), and, therefore a motion within the fluid, develops. Due
to the fact that the rotational of the driving force is along θ, a recirculating flow will
develops in the (r, z) plane, as sketched in Fig. 3.47. This flow is called Dean flow’ after
the pioneering paper written by him. Physically, the flow is pushed radially outwards
by the centrifugal forces, more strongly in the center than on the top and bottom parts
of the channel, forcing the flow to recirculate.

Fig. 3.47: Dean flows are recirculating flows that superimpose to a mean flow driven through
a curve tube. At the lowest Dean numbers, they take the form of two symmetric eddies,
as sketched in the lefthand part of the figure. The existence of these eddies was confirmed
experimentally (right).(Reprinted from [99] under Creative Commons licence.)

The order of magnitude of the Dean flow can be estimated by using the Navier-
Stokes equations, that must be written in cylindrical coordinates for this purpose
(expressions can be found in [3]). Assuming the secondary flows to be weak, and
balancing centrifugal forces and viscous terms, one finds, for the r and z component
of the secondary flow:

ρUθ 2 h2
ur , uz ∼
µr

The Dean number De is constructed as a Reynolds number based on the secondary

flow components:

r
h Uh
De = Re in which Re =
2r ν

This number provides an indication on the Dean flow intensity along with the inertia
forces associated to it. In the years 1990–2000, it appeared that the primary Dean
flow structure, sketched in Fig. 3.47 is replaced, as the Dean numbers was increased,
by more complex vortical structures, including larger number of vortices. Describing
these structures would lie outside the scope of this book.
156 Hydrodynamics of microfluidics 1: channels

In practice, in microfluidics, the secondary flows are exploited mostly for mixing and
separation. An example is shown in Fig. 3.48 [100]. Blood cells are separated from
circulating tumor cells (CTC ) under high throughput conditions. As cancer cell sizes
are larger, it is considered that they separate under the action of the Dean vortices
and centrifugal forces. As the CTCs are rare (1–10 per ml), important blood volumes
need to be screened.

Fig. 3.48: The spiral microfluidic chip, exploiting the action of centrifugal forces and Dean
recirculations, enables an efficient, size-based separation and isolation of circulating tumor
cells (CTCs) from whole blood [100].

3.6.5 Millifluidics and micro reaction technology (MRT)

Micro reaction technology was mentioned in Chapter 1. The domain develops reactors
working at large throughput. Therefore, they need to function at moderate or large
Reynolds numbers.18 Channel dimensions pertain to the millimetre range, and flows
developing in these systems can be qualified as ‘millifluidic’. An example is given in
Fig. 3.49 [101].
The flow direction is signaled by the arrow shapes of the channel structures. The
geometry favors the development of eddies at the edges of the (white) end of the arrow,
inducing mixing. Typical flow rates are milliliters per minute, and typical speeds are
metres per second.

18 In these systems, it is preferable to work below the turbulence onset. We often hear, in the mi-
crofluidic community, that below a Reynolds number of 2,000 or so, there is no turbulence. This
statement is not accurate. The onset of turbulence depends on the flow geometry, and for subcritical
bifurcations (for instance a pipe), on the initial level of perturbation. The example of pipe flows
illustrates this point. In linear instability theory, the flow is stable at all Reynolds numbers. A per-
turbation of substantial amplitude is needed to trigger turbulence. In practice, turbulence appears at
Reynolds numbers of 3,000 - 10,000. For flows behind blunt bodies, the critical Reynolds numbers are
typically a few hundreds or less. These examples show that the onset of turbulence strongly depend
on the geometry. A critical Reynolds number of 2,000 provides a general estimate, valid within a
factor ten or so, of the onset of turbulence.
 Inertial microfluidics and millifluidics 157

3.49: Mixer commercialized

by Corning, functioning at
moderate and high Reynolds
numbers (Reprinted from Ref.
[101], under Creative Com-
mons licence). The channel
widths are millimetric.
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4
Hydrodynamics of microfluidics 2:
droplets

4.1 Liquid–vapour interfaces

4.1.1 Microscopic phenomenology

Interfacial phenomena often defy intuition, and it has proved useful, along the years,
to use molecular dynamic (MD) simulations to get a better sense of the physical
mechanisms at work. Figure 4.1 shows a molecular simulation of water in equilibrium
with its vapour [1] A. At the interface, molecules leave the liquid by evapouration and
vapour renews the population through condensation. A permanent layer takes place,
whose properties are different from the bulk because the density is neither that of
the gas nor the liquid, and the molecules pertaining to the layer develop less cohesive
bonds than in the bulk.

Fig. 4.1: Simulations of water vapour interfaces.(A) The interface layer is underlined with
darker molecules. Molecules in this layer develop less cohesive bonds than their colleagues
in the bulk.(Reprinted from [1], with permission from Springer Nature. Copyright 2022.)
(B) A 10 nm thick argon film suspended with 7.5 nm thick vapour on both sides along the
z direction. The different curves correspond to different scales characterizing the pairwise
interaction energy. (Reprinted from [2], with permission from Elsevier. Copyright 2022.)

Fig. 4.1 (B) represents another MD simulation, modelling a 10 nm thick liquid argon
film, in the presence of its vapour [2]. The curve shown in the figure reveals that the
 Liquid–vapour interfaces 163

interfacial layer is extremely thin, a fraction of nanometre or so, i.e. a few intermolec-
ular distances. How can we describe these systems? Here, we will limit ourselves to
energetical and mechanical approches.1

4.1.2 Liquid vapour interfaces: energetical approach

In Chapter 2, we learned that Van der Waals liquids and solids are materials composed
of molecules interacting through Lennard–Jones (LJ) potential V (r), whose expression
is:

  
σ 12  σ 6
V (r) = 4 − (4.1)
r r

where  is a cohesion energy and σ is the molecule size. We recall that the attractive
part is associated to the negative term and the repulsive part, which ensures the non
interpenetrability of the molecules, to the positive one. For the example of argon,
which we considered in Chapter 2, σ = 3.045 Å and = 1.67 10−21 J.

4.2: Lennard Jones potential, indicating the

range of scales explored by the molecules,
at ambient temperature, in different states
of matter: solid, liquid, and gas. In solids,
apart from small fluctuations, molecules re-
main at the minimum. In liquids, positions
fluctuates (see the grey zone). In gases, the
mean intermolecular distance, indicated by
the horizontal arrow, and not shown here, is
typically ten σ.

Pairs of molecules will tend to place themselves at the minimum of the LJ potential,
i.e. at the equilibrium point given by rm = 21/6 σ, and V (r) = −. In solids and liquids,
molecules have several neighbours and energies must be added up to characterize the
equilibrium state. For example, in a simple cubic structure, the energy associated to
the equilibrium state will not be –, as in Fig. 4.2, but −8.38. This is the energy that
we must provide to extract one molecule from the material. With this reasoning, one
sees that molecules located at the surface are energetically at a higher level than in
the bulk. This leads to the metaphor of ’happy’ molecules (in the bulk) and ’unhappy’
molecules (at the surface), often taken in Ref. [4], and which we will also use in this
book. Taking the example of the simple cubic structure, as just said, a molecule in
the bulk ‘feels’ attractive forces corresponding to an energy of –8.38, while, at the
1 The question was discussed in depth by J. S. Rowlinson and B. Widom [3]. Their book, which
includes an interesting account of the controversies held on the subject, in the nineteen century,
analyses the question from different prospectives: mechanical, thermodynamical, and statistical.
164 Hydrodynamics of microfluidics 2: droplets

interface, the corresponding energy is smaller (–5.88). There is thus an excess of

energy of 3.5 for molecules located at the surface. The corresponding energy, per unit
of area, is called γ. For Van der Waals materials, γ is on the order of a few tens of
mN/m.

4.3: Herge’s drawing showing that, in

the absence of gravity, liquids spon-
taneously adopt a spherical shape. A
question that could be addressed is
that of the initial conditions, i.e. filling
the cup in the absence of gravity. An-
other question concerns the material.
Should it be glass, whisky, which wets
it, would perhaps prefer to stay in-
side. (Reprinted with permission from
Moulinsart SA.) .

Interfaces will adopt a shape that minimizes the number of ’unhappy’ molecules. This
leads to spectacular phenomena in liquids. An illustration is given by Captain Had-
dock, in ’On a marché sur la lune’ [8]. In the microgravity environment of the rocket
the captain was flying in, the whisky poured in the cup spontaneously reshapes into
a sphere floating in the air. Again, we recover the fact that fluids seek to reduce
their exposed surface area, the sphere representing the minimum exposed area for a
given volume. On earth, gravity inhibits the process, and we can swim in lakes, for
instance, without fearing that the water level suddenly jumps to form a huge drop.
In microfluidic systems, gravity forces, as we saw in Chapter 2, are negligible against
the interfacial forces we discuss here. We will thus be exposed to phenomena similar
to those observed by Captain Haddock.2

4.1.3 The liquid–vapour interface: mechanical approach

To describe the interfacial region from a mechanical viewpoint,3 we use the illuminating
paper published by M. Berry in 1971 [5].4
In gases, molecules are far apart and pressure is only kinetic. In liquids, because
molecules are agitated and remain extremely close to each other, the pressure has two
components: one is ‘kinetic’, as in gases and the other one, due to Van der Waals
cohesive forces, is ‘static’. These two contributions must be taken into account for
understanding the mechanics of the interfacial layer. So, let us consider the system of
Fig. 4.4), and call ‘T’ the coordinate parallel to the interface and ‘N’ the one normal

2 The search for a minimum of the exposed area often represents a mathematical challenge. Ref. [4]
provides a nice presentation of the subject
3 In fact, the mechanical description of liquid vapour interfaces is subtle, and in almost all cases,
on the web, and in textbooks, it is incorrectly presented. In fluid mechanical textbooks, the problem
is eluded by taking a mathematical membrane model [39], which is abstract.
4 The work was well–explained by B. Andreotti [6, 7]. I am indebted to him for his critical remarks
on a first version of this Section.
 Liquid–vapour interfaces 165

to it. The components of the forces (per unit of area) exerted on the faces of the cube
shown in the figure are pT (along T) and pN (along N) (see Fig. 4.4).

4.4: Representation of the components pT

and pN , in which coordinates are indexed by
T (parallel to the interface) and N (normal to
.. it).

Let us first consider the bulk, and note the pressure components by pN T
L and pL . These
quantities decompose into kinetic and static components as follows:

pN N N N T T T T
L = pk + ps = nL kT + ps and pL = pk + ps = nL kT + ps (4.2)

in which the indices k and s mean ‘kinetic’ and ‘static’, and nL is the number density
of molecules (i.e.the number of molecules par unit of volume). In the above equations,
we have considered that the kinetic terms obey Mariotte’s law, even though we are in a
liquid. Since the system is at equilibrium, pTL and pNL are equal to P0 , the atmospheric
pressure, that we take equal to 1 bar. Let us look at the orders of magnitude: the kinetic
term is, roughly, 1000 bars,5 while the static components is –1000 bars. Remarkably,
the two terms almost compensate each other, so that their sum is equal to P0 . If the
compensation was not possible, the liquid/gas system would not be stable. In such a
case, the liquid would solidify or evaporate.
In gases the situation is much simpler. There is no static terms. Pressure is only
kinetics. It is given by the relation:

pG = nG kT

where nG is the number density of molecules in the gas. This is again Mariotte’s law.
Gases being one thousand times less dense than in liquids, the kinetic term will be
one thousand times smaller, which leads again to 1 bar, i.e. P0 .
What happens at the liquid–vapour interface? The response, given by M. Berry [5], is
schematized in Fig 4.5.
In the interfacial region, normal pressure component pN keeps being equal to P0 .
Indeed, pN N
k and ps change, because the fluid density decreases, and there are less

5 n kT , with n ∼ 3 1028 molecules/m3 (for water) and kT ∼ 4 10−21 J (at ambiant temperature)
L L
is on the order of 1000 bars
166 Hydrodynamics of microfluidics 2: droplets

4.5: (A) Normal pressure com-

ponents in the interfacial layer
(black arrows: kinetic; dashed
grey arrows: static). (B) Tan-
gential pressure components in
the interfacial region, with the
same symbols.

molecules to interact with, but the sum must remain the same, otherwise mechanical
equilibrium would not be achieved (see Fig. 4.5 (A)). This is possible because the
kinetic term pN N 6
k and the static term ps are proportional to the density. Therefore,
as the density decreases, they can compensate, as they do in the bulk. In the other
direction, i.e. along the tangential direction T, things are different. Concerning the
static part of the tangential pressure component pTs , we note that the edges of the
rectangle of Fig. 4.5 are pulled by the liquid nearby. If we assimilate this situation
to a sphere-plane system, the Van der Waals forces that pull these edges vary as the
fluid density to the power 2/3.7 Concerning the kinetic term pTk , the pressure it exerts
onto the rectangle edges varies as the fluid density. Therefore, as the fluid density
decreases, the static term decreases less rapidly than the kinetic term. Consequently,
the sum pT = pTk + pTs becomes negative in the interfacial region (see Fig. 4.5 (B)).
As a result, a tension appears, which is the surface tension we introduced before. This
conclusion was formulated by M. Berry [5] without calculation, noting that static forces
are long range and kinetic ones short range and taking the geometry of the problem
into account. Complete discussion is given in [5, 7]. Surface tension thus results from
a subtile mechanism. Note that, in the interfacial layer, surface tension is dominated
by Van der Waals forces. It is thus legitimate to neglect the kinetic contribution. This
is done in the literature, without justification, as we did in the previous section.
Numerical simulations confirm Berry’s analysis (see Fig.4.6) [7].
The evolution of the density across the interface is shown in Fig. 4.6 (a) and (b) [7].
As in Fig. 4.1, the interfacial region is two or three molecular thick. Much information
is conveyed by the generalized’ pressure Π(z), defined by:

Π(z) = pN T
L (z) − pL (z)

where z is the normal to the interface. Π(z) is also (minus) the extra stress developed in
the interfacial region. It allows to calculate the surface tension γ through the relation

Z +∞
γ= (pN T
L − pL )dz
−∞
.
6 In fluids, the Van der Waals force between two planar surfaces varies as their separation to the
power −3, i.e. as the fluid density.
7 In fluids, the Van der Waals force between a sphere (representing the edge), and a planar surface
varies as the separation to the power −2, i.e. as the fluid density to the power 2/3.
 Liquid–vapour interfaces 167

Fig. 4.6: (a) Numerical simulation of the water vapour interface [7]; Evolutions of the density
(b) and generalized pressure Π(z) (c) across the interface, in dimensionless units (Reproduced
from Ref. [7], with permission of American Association of Physics Teachers. Copyright 2022
AIP Publishing.)

Π(z) is represented in Fig 4.6(c). In the gas, Π(z) is zero, In the liquid bulk, pN T
L and pL
are equal to the vapour pressure P0 and therefore Π(z) vanishes too. In the interfacial
region, Π(z) is found positive (see Fig. 4.6 (c)) and its magnitude is a fraction of /σ 3 ,
i.e. hundreds of bars. This implies that pTL is negative and larger than pN L . We may
thus conclude that the fluid layer is under tension. It is like a stretched skin, an image
often taken in the literature. Should we sample out an element, it would immediately
retract. According to Formula 4.1.3, the surface tension would be on the order of 0.25
/σ 3 , which, for ordinary fluids, leads to a range of 10–30 mN/m for γ. We see that
the numerical results are in excellent agreement with Berry’s description.

A misleading presentation of the molecular origin of surface tension

A presentation of the molecular origin of surface tension, often given on the web, in textbooks
and, sometimes, in scientific reviews, is shown in Fig. 4.7. In these presentations, pressure
is only static (there is no kinetics). Accordingly, a force appears at the interface, oriented
towards the interior of the liquid. The problem is that there is no way to balance this force.
With such an unbalanced force, either the fluid is pressurized above the atmospheric pressure
or the interface moves; This would contradict the hypothesis of equilibrium. The error here
is the omission of the kinetic contribution to the pressure.

Fig. 4.7: Misleading presentation of the molecular origin of surface tension.

168 Hydrodynamics of microfluidics 2: droplets

4.1.4 Experiments

Liquid film retracting in a rectangular frame. We now have tools for understanding
simple, or apparently simple, experiments. The one shown in Fig. 4.8 is subtle, and
offers an elegant illustration of the notions previously discussed.8 It is borrowed from
Ref. [4].

4.8: A soap film is enclosed in a rect-

angular metallic wire, with a mobile
side. The mobile bar spontaneously
moves in the direction of the soap
film [4, 9].

A soap film is held in a metallic rectangular frame. There is a mobile bar, forming one
side of the rectangle, also metallic (see Fig. 4.8). One observes that the bar sponta-
neously moves inwards, reducing the film area.9 The experiment brings evidence that,
in this configuration, a pulling force exists, directed normally to the bar, and parallel
to the plane of the film, which works at reducing the soap film area. This is the surface
tension we previously discussed.
One can play with this observation and establish an equivalence between surface energy
and surface tension (in liquids). The work dW done during an infinitesimal displace-
ment of the bar is dx is 2γLdx (with L the bar length), the factor 2 being due to the
fact that the soap film is composed of two surfaces. This work is equal to the force 2F
exerted by each interface onto the bar. We thus have:

dW = 2γLdx = 2F dx (4.3)

In these expressions, γ can be viewed as the energy needed to increase the area by one
unit, or the tension per unit of length needed to perform the same task. Since we have

8 An infinitely thin membrane is often taken, in mechanical textbooks, to expose the concept of
surface tension. But this is quite abstract. How to suspend a monomolecular layer in the air? Where
would the tensile force apply ? On the molecules forming the edges? Soap films can be used to illustrate
the concept, but the experiment is more complex than it looks. Soap films are composed of two
surfactant monolayers sandwiching a water film. How can the concept be connected to this complex
structure? In practice, the soap film experiment is never presented or discussed. The consequence
is that students have no idea about the physical origin of surface tension, and are left with elegant
equations describing a strange physical phenomenon.
9 As the film contracts, where do the soap and the liquid of the film, escape? The answer is inside
the menisci attached to the frame and the moving bar. These regions contain most of the liquid
volume, and their exposed area is small compared to the planar part. They can be filled and emptied
without consuming volumetric (if we neglect viscous losses) nor surface energy. In this manner the
film can freely reduce its surface area and therefore decrease its energy without cost.
 Laplace’s law 169

F/L = γ, the system can be used as a tensiometer for bilayers. In practice, however,
it is delicate to use.

Thread spontaneously forming a circle in a soap film. Another spectacular manifes-

tation of surface tension is shown in Fig. 4.9. Here again, a soap film is held in a
rectangular frame. This time, all the sides are fixed and a thread of arbitrary shape is
introduced in the film (see Fig. 4.9 (A). The thread does not move because, whatever
its shape, the total surface area of the soap film, and then the surface energy, remains
the same. In other words, no gain of energy is obtained by changing the shape. Now,
the film inside the thread is pierced by a needle (see Fig. 4.9( B)). It bursts and dis-
appears, leaving a hole. Suddenly, the thread adopts a circular shape. The simplest
explanation is based on forces: as shown above, each thread element is subjected to the
same force. This force applies in the plane of the film, normally to the thread, towards
the liquid. These forces work at reducing the soap film area. The system reaches an
equilibrium state by adopting a circular shape, where all forces balance each other. If
we look at this system from an energetic standpoint, we may suggest that in 2D, the
biggest area enclosed in a loop of fixed length is obtained with the circle. Alternatively,
the shortest loop enclosing a fixed area forms a circle.

4.9: A: A closed thread is in-

serted in the soap film. B: With
a metallic piece, the film inside
the thread is burst. In a fraction
of second, the thread adopts a
circular shape (vertical scale ad-
justed). (Courtesy of Leo Boulot
(Amaco). Reprinted from [4] un-
der Creative Commons licence.

4.2 Laplace’s law

4.2.1 Establishment of Laplace’s law

Laplace’s law stipulates that, in order to maintain a curved fluid interface in mechanical
equilibrium, it is necessary to exert a higher pressure on the convex side, as for a
balloon we would blow inside to keep it spherical. Two methods exist for establishing
Laplace’s law, one based on surface tension, the other on energy.

Method based on surface tension for a bubble. Let us consider a bubble pressurized
at pressure ∆P , surrounded by a liquid. Our hypothesis is that, in order to maintain
the bubble in mechanical equilibrium, one must pressurize it. Let us define a sub-
system, formed by half of the bubble. According to the Euler–Cauchy principle, one
must replace the missing part by the forces it exerted on the subsystem, before the
separation. Let us consider the equator: it is pulled by a surface tension equal to γ.
The corresponding pulling force is equal to 2πRγ. On the other hand, the equatorial
170 Hydrodynamics of microfluidics 2: droplets

plane is pushed by pressure ∆P . The corresponding force is πR2 ∆P . The subsystem

being in equilibrium, one must have:

2γ
∆P =
R

This is Laplace’s law for a bubble.

4.10: In a spherical droplet

at rest, half of the structure is
subjected to tensile forces ex-
erted by the other part.

Method based on energy for a sphere. Let us now use the energetic method, and, for
this purpose, reuse our bubble, still pressurized at ∆P (Fig. 4.11). Here, we do not cut
it in two parts, but increase its radius by δR, for instance with δR > 0. In this process,
we assume that the volume of the continuous phase (i.e. the liquid surrounding the
bubble), along with its pressure, does not change.

4.11: Geometry used for the

derivation of Laplace’s Law,
for a sphere. Pressure ∆P is r
larger inside the bubble, in
order to maintain mechanical
equilibrium. The correspond-
ing pressure jump, across the
interface, is called Laplace
pressure, or capillary jump.

By swelling, the bubble creates a new interfacial area δS. This costs energy. This
energy is, by definition of γ:

δES = γδS = 8γπRδR

By increasing the volume, we develop a negative work, inside the bubble equal to
δEV = −∆P δV , whose expression is:

δEV = −∆P δV = −4πR2 ∆P δR

 Laplace’s law 171

When the bubble swells, it displaces the liquid around it. This displacement, nonethe-
less, does not cost any energy because, as observed above, liquid pressure is fixed it is
performed at fixed volume of the continuous phase. The system being at equilibrium,
the variation of the total energy δES + δEV should be zero. This implies:
2γ
∆P =
R

The result is identical to the one obtained with the forces. The law, established for
bubbles, applies for any pair of immiscible fluids, i.e. for droplets.

General expression of Laplace’s law in 3D. It is a matter of mathematics to generalize

the results obtained above, to the case of an arbitrarily curved interfacial element in
3D (see for instance Landau’s textbook on fluid mechanics [137] or Refs. [12, 24]).
For this purpose, one must introduce the two principal radii of curvature, R1 = κ−1 1
and R2 = κ−1 2 , where κ1 and κ2 are the principal curvatures, i.e. the maximum and
minimum values of the curvature at point P of a surface (see Fig. 4.12).

4.12: At point P , the two

principal curvatures κ1 and
κ2 are the maximum and
minimum values of the curva-
ture. On the figure, a plane,
normal to the surface, with
its normal and tangential
vectors, is shown.

At point P , in each principal plane, surface tension develops a force directed inwards,
equal to κγδS, where δS is a surface element and κ the curvature. To reach equilib-
rium, a pressure ∆P must build up in he fluid. Since we have two principal planes of
curvature, we must have:
 
1 1
∆P = γ + .
R1 R2

γ
This is Laplace law. For 2D systems, Laplace’s law reduces to ∆P = R, in which R is
the local curvature radius.

In terms of order of magnitude, the Laplace jump for a bubble of 1 µm in radius, in

water, is 70 kPa. In microfluidics, and in small systems in general, Laplace pressure
gives rise to important and sometimes spectacular phenomena.
172 Hydrodynamics of microfluidics 2: droplets

4.2.2 Is Laplace’s law valid at the nanoscale?

Considering that the interface has a finite thickness (of nanometric size, as observed
in numerical simulations), it has been argued that surface tension is not a constant,
but some function of the geometric characteristics of this layer, for instance its mean
curvature, or its thickness. The argument indeed impacts Laplace law. In 1949, J.
Tolman [15] proposed the following formula:

γ = γ∞ (1 − δ/R) (4.4)

in which R is the mean curvature radius of the interface, γ is the true’ surface tension,
γ∞ is the value of γ for R infinite and δ is the Tolman length. The latter can be
positive or negative. How large is δ? The question has been discussed for decades.
Recent simulations [16], based on molecular dynamics (MD), have shown that the
Laplace relation is valid down to 1.3 nm; therefore, δ is smaller than this limit. The
geometry is shown in Fig. 4.13.

4.13: (A) Molecular simula-

tion of a liquid held through
a hole by capillary forces.(B)
Measured surface tension
(Reprinted from [16], under
Creative Commons Attribution
4.0 International License.)

Thousands of molecules, interacting through a Lennard Jones potential, are placed

below a plate pierced by a nanohole. The fluid develops a semi–spherical dome. A
subtle feature is that the angle formed at the intersection between the semi–sphere
and the horizontal plane is constrained by the dome curvature and not by the wetting
properties of liquid/solid system. This is due to the extreme thinness of the plate. In
the molecular dynamics simulation, pressure P is monitored, and the dome radius R
γ
is measured. It was observed that the Laplace relation, i.e. P = R , holds in a range
of hole radii down to 1.3 nm, i.e. several intermolecular scales, with the same γ (see
Fig.4.13 (B)).

The work thus shows that Laplace law is valid down to 1.3 nm. Series of numerical
simulations, performed in recent years, suggested δ on the order of 0.1 nm. Recent
experimental investigations, studying nucleation in water [21], or measuring curvatures
of nanometric menisci [20], provide a similar order of magnitude.10

10 This does not imply that Tolman length should always be neglected. For instance, it plays a
considerable role in bubble nucleation [21].
 Laplace’s law 173

4.2.3 Manifestations of Laplace’s law

Capillary adhesion. A first example is capillary adhesion (see Fig. 4.14).

4.14: Capillary adhesion, in which a wa-

ter droplet, held between two glass plates,
develops an attracting force which tends to
. squeeze them.

In this case, a small volume of water is trapped between two plates (for instance clean
glass). Because water wets clean glass (we shall discuss later the general question of
wetting), the meniscus is oriented in the direction shown in Fig. 4.14. On calculating
the Laplace pressure jump across the menisci, and therefore the pressure P inside the
water film, one finds the following expression:
γ
P = P0 −
R

where P0 is the atmospheric pressure. As P is below P0 , a force of attraction develops

between the two plates. It is equal to 2γh S, h being the separation distance between
the plates and S being the wetted area by the liquid. A film of 1 µm, with a wetted
area of 10 cm2 , can hold a weight of 7 kg. The effect is thus important.

Capillary collapse. Capillary adhesion raises issues for the fabrication of suspended
microstructures, such as (micro) bridges or (micro) cantilevers. It can lead to capillary
collapse. Illustrations are shown in Fig. 4.15 [17]. Droplets or films are often present on
the wafers, during microfabrication, such as after rinsing. These droplets or films may
establish a liquid bridge between the cantilever beam and the substrate, as sketched
in Fig. 4.15 (left). Owing to the small sizes, Laplace adhesion is substantial and can
trigger the collapse of the structure. Fig. 4.15 (right), shows a situation where, due
to the phenomenon, the teeth of a micro–comb stick together, which was not the
objective.11

(a) (b)
4.15: (A) Capillary collapse
Cantilever beam of a microcantilever beam
Capillary force (Reprinted from Ref. [17] with
permission from IOP Publish-
Fluid ing.).(B) Capillary collapse of
Substrate an array of micropillars [17].

11 To realize such a structure, one needs to perform several lithographic steps, the final step involving
Deep Reactive Ion Etching (DRIE), a long process, which usually takes one night to be performed.
These teeth therefore take much labour and time to fabricate.
174 Hydrodynamics of microfluidics 2: droplets

4.16: Leaf and the structure through

which water evapourates.

Capillary pumping in trees. Giant trees, like sequoias, possess the capacity of lifting
sap at heights above 100 m. This fact indicates that somewhere, there is a pump
delivering a pressure drop of, at least –10 bars between the top of the tree and its
roots. This is precisely what Laplace’s law provides. Sap is driven along microchannels
(called xylems), in the trunk and the branches (see Fig. 4.16). At the end of the
journey, which takes a week, sap penetrates in the leaves. The journey ends with the
imbibition of a porous region, formed by the packing of spongy mesophyll cells, within
which sap evapourates (the phenomenon is called transpiration). In this process, the
spongy medium encloses a large number of menisci. Since the pores are 10 –50 nm
in diameter, the Laplace pressure in the sap, just behind the menisci, will be on the
order of –20 to –100 bars. With such pressure differences, between the roots and the
top, there is no difficulty for the tree to lift sap up to 100 m, which corresponds to the
height of the highest trees on earth.12

Bird drinking water. How do birds drink? How do they manage to drag water drops
along their beak, against gravity, without tongues?13 The answer is provided by Fig.
5.79. In the beak, the droplet possesses two different curvatures. Close to the head, the
meniscus is more curved than at larger distances. Consequently, because of Laplace’s
law, the pressure, inside the water drop, is smaller close to the head. The droplet will
thus move towards the throat and the bird will be able to drink. We will see later that
as wetting is partial, drops can get pinned at the beak surface. The bird solves the
problem by developing more complex movements of its beak [13, 14].

4.2.4 Methods of measurement of interfacial tension

Static surface tension measurements in liquids. Measuring surface tension of liq-

uid/gas and liquid/liquids interface is performed using a variety of methods that are
well–described in textbooks (see [4] and references therein). We will thus succinctly

12 One difficulty, however, is to operate liquids at negative pressures. Liquids at negative pressures
are unstable. Bubbles (positive pressure) grow and provoke embolism. Trees have thus developed
networks of mechanical valves, which isolate bubbles as soon as they appear
13 Some birds, like the hummingbird, possess a tongue. In this case, the drinking process must be
explained differently [13]. Others, like phalaropes, studied in Ref. [111], do not have tongues
 Laplace’s law 175

4.17: Bird drinking water. It exploits the

wedge geometry of its beak to swallow the
droplet.

summarize the topics. Figure 4.18 shows the most current techniques used in the lab-
oratories.
rc
Fcapillary
l
d h P
l a
ω
d
θc
p

Wilhelmy plate Maximum bubble pressure Spinning drop

rc
rc
Fmax
θc

h
V R0

Du Noüy ring Capillary rise Pendant drop

Fig. 4.18: Current methods of measurements of the surface tension

– Whilelmy plate technique consists of immersing a thin plate into the liquid, and
measuring both the contact angle θ formed with the interface and the interfacial force
exerted by the fluid onto it. In the wetting case, the interfacial force has an expression
similar to that involved in the rectangular frame experiment (see above), i.e. γl, in
which l is the plate length. By measuring this force, γ can be determined.
– The ring method is based on the same principle, but in a circular geometry.
– The maximum bubble pressure technique consists of blowing a bubble up to the point
where the bubble radius becomes equal to the capillary radius. In such circumstances,
the internal pressure reaches a maximum Pmax = 2γ/r in which r is the capillary
radius. From this expression, γ can be determined.
– The pinning drop exploits the Rayleigh–Plateau instability. This will be described
later.
– Capillary rise represents the first experiment ever made on capillarity, with the ex-
176 Hydrodynamics of microfluidics 2: droplets

perimentalist being Leonard de Vinci (see [4]). We will demonstrate later the following
expression: h = 2γcosθ
ρgr , in which h is the column height, ρ is the fluid density, θ is the
contact angle, and r is the capillary radius. In the expression, all quantities are known,
except γ. This parameter can thus be determined.
– Finally, the pendant drop method, used in many laboratories, is based on the
analysis of the droplet shape, which depends on γ.

A number of these techniques are commercially available, offering a catalogue of mea-

surement methods accessible to laboratories. Most of them can be used with two
fluids, allowing the measurement of surface tension of liquid–liquid interfaces. Table
4.1 shows a selection measurements of γ reported in the literature, often relevant to
microfluidics.

Name Surface energy (mN/m)

Acetone 23
Ethanol 22
Glycerol 92
Water 72
Toluene 28
Silicon oil 22
Hexadecane 28
Mercury 474
Table 4.1 Surface tensions of a selection of liquids.

Dynamical surface tension measurements in microchannels. What about dynamical

measurements of surface tension? In microfluidic devices, surface tension may suddenly
change, induced by changes in surfactant concentrations (see the next section). The
time scale of change is below 1 s, and the methods described previously are too slow
to follow the dynamics. The system of Fig. 4.19 takes advantage of miniaturisation for
measuring sub–second dynamical changes of the surface tension.

4.19: Droplets are produced by fo-

cusing a stream of water (Qw )in a
stream of fluorinated oil–surfactant
solution Qoil and spaced by a sep-
aration stream Qsep . Droplets flow
in a series of expansions where the
droplet shape is recorded and inter-
facial properties are measured. The
white scale bar has a length of 100
mm. (Reprinted from [22] under Cre-
ative Commons Attribution 3.0 Inter-
national License.) .

Droplets produced in a flow–focusing junction flow in a series of expansions/contractions

 Laplace’s law 177

where the droplets, driven at constant speeds, and subjected to a known pressure gra-
dient, undergo sequences of deformations, during which the surfactant concentration,
and therefore the surface tension, changes. From the analysis of the droplet defor-
mation, the dynamical evolution of the surface tension was measured [22, 23]. The
temporal resolution of the method is on the order of fractions of a second.

Micropipette interfacial area–expansion method. The method for measuring dynam-

ical interfacial tension reported in Ref. [24] uses systems whose sizes pertain to the
microfluidic range of scales. The device, based on micropipettes, is shown in Fig 4.20.

Fig. 4.20: (A) Dynamical surface tension (DST) measurement using the micropipette
interfacial–area expansion method. (1) The micropipette is inserted into the solution
under high positive applied pipette pressure. The interfacial area was quickly expanded
200–fold by decreasing the applied pipette pressure.(B) Measurements of the temporal
evolution of the surface tension, at different surfactant concentrations. (Reprinted with
permission from [24]. Copyright 2022, Elsevier.)

The micropipette is inserted into the solution by applying pressure. The interfacial
area, inside the pipette, is quickly expanded 200–fold by rapidly (0.1– 0.3 s) decreasing
the pressure. The measurements shown in Fig. 4.20 involves time constant larger than
the temporal resolution of the method. We learn from the experiment that for interfaces
whose size and curvature radius are in the 10 µm range, the time required to re–
establish the equilibrium interfacial tension lies in the second range.

Surface tension measurements in solids. The measurement of surface energy in the

cases of solid/liquid or solid/gas interfaces is much less straightforward, because (ex-
cept with soft solids) surface–tension–induced deformations are not measurable. Many
of the methods used for solids are thus indirect. They are often based on contact angle
measurements made with series of fluids, using the Zisman plot [18], or on detailed
models of intermolecular forces. Other techniques are based on working at high tem-
peratures, or analysing heat sublimation. Direct methods nonetheless exist, based on
measuring the force needed to open a crack in the material. The case of soft solids de-
serves particular attention because the measurement could be made more directly, with
178 Hydrodynamics of microfluidics 2: droplets

excellent accuracy, by analysing the deformation of polydimethylsiloxane (PDMS) in-

terfaces placed in contact [19]. Describing the techniques would lie beyond the scope of
this book. Table 4.2 shows a selection of surface energies obtained with one or another
approach, for materials currently used in microfluidics.

Abbreviation Name Surface energy (mN/m)

PC Polycarbonate 46
PMMA Polymethylmethacrylate 41
PVA Polyvinyl alcohol 39
PS Polystyrene 34
PDMS Polydimethylsiloxane 23
Co Copper 2450
Au Gold 1500
C Carbon (graphite) 68000
Glass (Clean) glass 4400
Table 4.2 Surface energies of a selection of solids.

Consistently with the preceding discussion on the order of magnitude of surface tension
of solid/air interfaces, Table 4.2 shows that plastics, close to Van der Waals materials,
have low surface energies, on the order of 20– 30 mN/m, much lower than metals.
Clean glass also has a large surface energy, which decreases by a factor of 2 or so,
when exposed to an ambient atmosphere. This is due to the deposition of wetting
films (water, for instance) or dust, which work at decreasing surface energies. Dust,
made of low–energy organic materials, floating in the air and being deposited on high
energy surfaces, is happy to stay on these.

4.2.5 Surface tension and gravity

Capillary length. Dimensional analysis allows an interesting scaling law for capillary
phenomena to be established, which has important implications in microfluidics. The
question is: what is the typical length lc for which gravity and capillarity balance?
Such a length would be determined by the following condition:

lc = f (γ, ρ, g) (4.5)

where f is a function. Here, we have four physical quantities, with three units (masse,
time and length). Using the Π theorem, we conclude that the above expression reduces
to:

r
γ
lc = (4.6)
ρg
 Laplace’s law 179

lc is called the capillary length. Another manner to obtain the same result is to note
that gravitational forces are on the order of ρgl3 , and capillary forces on the order of
γl. Systems of size lc achieve the balance between the two forces. As lc is on the order
of a few millimetres (2.6 mm for water), we can also infer, from this order of magnitude
reasoning, that in microfluidics, gravity is negligible against surface tension.

Shape of the meniscus. In contact with a smooth vertical plane, partially wetting
liquids form a meniscus that matches the plane with a contact angle θ, assumed here
to be acute (see Fig. 4.21).

4.21: Profile z(x) of a meniscus

taking place on a vertical plate,
with an angle θ.

Since the fluid is at rest, capillary pressure (which elevates the fluid), must balance
the hydrostatic pressure ρgz(x), where z is the liquid elevation and x is the horizontal
coordinate. We thus have:

γ
= ρgz(x) (4.7)
R

Using a known mathematical relation between R and z 0 (x), z 00 (x), the relation reads:

ρg z 00 (x)
z(x) = (4.8)
γ (1 + z 0 (x)2 )3/2

There is no general analytical solution to this equation. Let us thus simplify the prob-
lem, by considering the case where θ is close to π/2. In this case, we can assume that
the slope of the water/gas surface is small everywhere. Under such an assumption, the
differential equation becomes:

z = lc2 z 00 (4.9)

With the boundary conditions z → ∞, z = 0, and z = 0, dz/dx = − cot θ, the solution

reads:

x
z(x) = lc cot θ exp(− ) (4.10)
lc
180 Hydrodynamics of microfluidics 2: droplets

The formula shows that the height of the meniscus, i.e. the elevation z(x) at x = 0,
equals lc cot θ. This result underlines the role of lc , which naturally emerges as the
characteristic length of the problem. The fact that for θ = 0, z(0) is infinite signals that
at small contact angles, the surface is strongly curved; consequently, the approximation
we used is no longer acceptable. The rigorous calculation provides, for the maximum
elevation h of the meniscus at z = 0, the following expression:

p
h= (2)lc (1 − sin θ)1/2 (4.11)
p
There is no more divergence at θ = 0. In this situation,i.e.complete wetting, h = (2)lc
For clean water, this leads to h ≈ 3.7 mm. This small elevation requires careful visual
observation to be observed, but it is much larger than the size of a microchannel.
As noted in the precedent subsection, the fact that lc (and thus, h) is much larger
than a microchannel, implies that in microfluidics, gravity can be neglected against
capillarity.

Jurin’s law. This law is the oldest law of capillarity. (The fascinating history of the
law is told in [4].) For acute contact angles, a circular capillary of internal radius r
placed in contact with a liquid bath spontaneously forms a column in the tube. Its
height h is given by the relation:

2γ cos θ l2
h= = 2 cos θ c (4.12)
ρgr r0

Fig. 4.22: On the left, the situation for which Jurin’s law applies, with the definitions of the
geometrical parameters. On the right, an experimental realization (courtesy by D.Quere).

This law results from the balance between the hydrostatic pressure ρgh and the
capillary pressure 2γ rcos
0
θ
, the principal radius of curvature of the meniscus r being
14
r0 /2 cos θ. ). In most situations, liquids in contact with high energy surfaces (such as

14 The geometrical calculation is done by determining the radius of the sphere for which, in the
vertical plane, the meniscus forms an arc
 Surfactants 181

glass) develop acute contact angles and therefore rise. Mercury on glass is a counter–
example. The contact angle is 135◦ , and the meniscus moves downwards.

4.3 Surfactants

4.3.1 What is a surfactant?

Surfactants15 are molecules made of two parts: a hydrophilic part which ‘likes’ water
(energetically speaking), and a hydrophobic/lipophilic part which ‘dislikes’ water and
likes’ oil. These molecules are called amphiphilic, because they like simultaneously
being in one phase and out of that same phase. Their names come from the Greek
‘amphi’, meaning double. Chemistry has synthesized and is still synthesizing many
surfactants [25,26]. The domain is considerable. There are numerous applications, such
as in cosmetics, the food industry, biology, the oil industry, etc. with a multi–billion
dollar market. Research started more than a century ago, and is still extremely active.
Obviously, without surfactants, the domain of droplet–based microfluidics would not
exist.
Surfactants are classified in a number of ways; one of these, established according to
the charges they convey, is shown in Fig. 4.23.

4.23: Classification of the surfac-

tants, according to the charges they
convey: non ionic, anionic, cationic
and amphoteric

Often, the hydrophilic part of the surfactant is an ion forming a polar or charged head,
and the hydrophobic part is one aliphatic chain (or several) CH3 (CH2 ) n forming a hy-
drophobic (lipophilic) tail. The hydrophobicity of the aliphatic chains originates from
the fact that they force water molecules to reorganize around them in an entropically
unfavourable manner. In ionic and amphoteric surfactants, the hydrophilicity of the
head is linked to its polarization, or charge, which, for water, leads to the creation of
hydrogen bonds and therefore strong attractive forces. For non–ionic surfactants, the
hydrophilic part is a short chain of neutral units soluble in water. Examples of surfac-
tants, frequently used in microfluidics, are: Span 80, Tween 20 and Krytox (non ionic),
SDS (anionic), and CTAB (cationic). Table 4.3 shows the hydrophilic and hydrophobic
groups of several surfactants.
Because the molecules are amphiphilic, i.e. their hydrophobic part likes oil, and the
hydrophilic part likes water, it is argued that the best energetical solution for them
is to stay at the interface (we will return to this point later). We have experimental
15 Surfactant is a blend of two terms: surface and active agent.
182 Hydrodynamics of microfluidics 2: droplets

Abbreviation Hydrophobic part Hydrophilic part

SDS CH3 (CH2 )11 SO4 −−
SPAN80 CH3 (C18 H38 )C5 H3 O6 C6 H11 O5
KRYTOX C2 F5 (C3 F6 )O)n OC2 F4 COOH
CTAB CH3 (CH2 )15 N+ (CH3 )
Table 4.3 Chemical formulas of surfactants currently used in microfluidics, along with hy-
drophobic and hydrophilic groups.

evidence for this, for instance by observing, in a bathtub, the propagation of soap at
the water’s surface. The same experiment can be carried out in a dish, using pepper
to visualize the surface flow, as will be discussed later. The numerical simulation of
Ref. [27] confirms this feature. Figure 4.24 represents a water/dodecane interface, with
sodium dodecyl sulfate (SDS) as a surfactant.

4.24: Dodecane– water interface with SDS

simulation. Water and dodecane molecules
are drawn as lines, and surfactant molecules
are drawn as ‘balls–and–sticks’. (Reprinted
from [27] with permission from John Wiley
and Sons. Copyright 2022.)

The simulation shows that surfactant molecules form a layer, approximately 20 nm

thick. By populating the interfaces in this manner, they change their surface properties,
in particular their surface tension.

4.3.2 Surfactant and solubility

Fig. 4.25 shows a container filled with water and oil, in which surfactant molecules, at
low concentrations, have been introduced. What happens?

4.25: Surfactant
introduced at low
concentration in a
water/oil system,
in a container.

As we previously saw, most of the surfactants adsorb at the interface. However, some
are dispersed in the bulk, in oil and in water, in proportions that depend on their solu-
 Surfactants 183

bility. This is partitioning. An equilibrium takes place, characterized by a distribution

factor K, which reads:

Cw
K= (4.13)
Co

in which Cw and Co are the bulk surfactant concentrations in water and oil, respec-
tively. Instead of using K, it is usual, in the domain, to use Hydrophilic Lipophilic
Balance (HLB). The definition of HLB is:

HLB = 7 + Σ(hydrophilic groups number) − Σ(hydrophobics group number) (4.14)

in which the group (for example, hydroxyl or methyl groups) numbers involved in
the definition are determined empirically. More detail can be found in [4]. The idea
behind this definition is to establish a link between solubility and molecular structure.
Long hydrophobic chains are associated to small HLB. In this case, the surfactant
will be poorly soluble in water. In the opposite case (large HLB), the chain is short
and solubility in water will be substantial. The knowledge of HLB also allows us to
determine whether an emulsion will be direct (oil droplets in water) or inverse (water
droplets in oil). This is Bancroft rule, which states: ‘The phase in which an emulsifier
is more soluble constitutes the continuous phase’ [28, 29]. Other properties, such as
foaming, spreading or solubilization are also correlated with HLB. Table 4.4 below
lists HLB values, and some properties to which these values correlate.

HLB Properties Examples

<10 Lipid–soluble (water–insoluble) Span 80
>10 Water–soluble (lipid–insoluble) Tween, SDS
3– 6 W/O (water in oil) emulsifier
13– 16 Detergent Span 80
8– 16 Oil in water
Table 4.4 HLBs of a selection of surfactants, with their current usages.

In the field of microfluidics, HLB is not frequently used because channel walls largely
control the system behaviour. The occurrence of water–in–oil or oil–in water droplets
depends on the wettability of the walls with respect to the working fluids, not on the
HLB. For example, in microfluidic devices, one can produce water–in–oil emulsions
with HLB values indicating that oil in water emulsions should form. An example is
shown in Ref. [30]. In these experiments, SPAN 80 was used. Instead of obtaining oil
droplets, the authors observed stable water droplets. The reason was that, in this case,
microchannel walls being lipophilic, oil wetted the walls, and therefore was selected
as the external phase, against Bancroft rule. We will return later to this type of
phenomenon. In general, in droplet based microfluidics, Bancroft rule is irrelevant.
184 Hydrodynamics of microfluidics 2: droplets

4.3.3 Surfactants and surface tension

Fig. 4.26: As more surfactant is introduced in the container (centre), the surface saturates
and, on further increase (right), above a threshold called critical micellar concentation (CMC),
micelles appear. A typical image of a spherical micelle, several tens nanometre in size, is shown
on the right

The case of liquids. Let us take again Fig. 4.25 and add surfactants (see Fig. 4.26).
Indeed, as more surfactant is added, the interface tends to saturate. At C = CS , satu-
ration is achieved. As the amount of surfactant is increased further, the concentration,
in the bulk, increases. But we have to reach a new threshold, called critical micellar
concentration (CMC), to see micelles appearing in the solution.

(a) (b) (c)

(d) (e)
4.27: Five types of micelles, as interpreted
from experimental data: (A) spherical; (B)
lamellar; (C) inverted (or reversed); (C)
disk; (E) cylindrical or rodlike. (From [26].)

Micelles are self–assembled nanometric structures that protect the hydrophobic tails
from the aqueous environment. They are energetically advantageous but they need to
jump over a nucleation barrier to form. Often, micelles are represented as spherical
objects, but as shown in Fig. 4.27, a variety of morphologies exist16 [26].
So, how does the system respond energetically to the addition of surfactants and the
formation of micelles ? Fig. 4.28 show the evolution of the water–oil interfacial tension
γ as a function of the surfactant concentration CS . γ decreases as the surfactant
concentration CS increases [30]. Why is this the case ? The argument is that, when

16 Each being associated to specific CMCs. The same system can thus have several CMCs.
 Surfactants 185

Fig. 4.28: Evolution of the water/hexadecane interfacial tension as a function of the surfac-
tant concentration CS , the surfactant being SPAN 80. The concentration axis has units of
%w/w (w for weight) of solute in solvent. To convert in mMole/litre, a unit often used in
the literature, one must multiply by 103 /M where M is the molar mass of SPAN 80 (429
g/mole). In this case, we have a CMC of 3 10−4 w/w, then 0.6mM/l. (Taken from [30].)

surfactants absorb at the surface, they replace the air/water interface by an organic
phase/air interface, whose cohesive (between themselves) and adhesive (with water)
energies are weaker than for water/water interfaces. The interface is thus less energetic.
Therefore, surface tension decreases. Measurements show that above a concentration
called Csat (see Fig. 4.28), for which the interface is saturated in surfactant, γ decreases
linearly with the logarithmic of CS , consistently with Gibbs theory [25]. As CS reaches
the CMC, γ levels off. 17 The plateau is the energetic signature of micelle formation
(see Fig. 4.26).

The explanation of this behaviour is subtle. The approach that is usually taken is
macroscopic and is based on the concept of chemical potential, that we do not develop
in the book. We recommend Ref. [4] to readers for a pedagogical presentation. We may
nonetheless envisage that micelle creation does change much the energy of the system.
Micelles do not perturb the bulk properties, because, in the range of CS we address,
their concentration is low. Neither do they perturb the interface, which is saturated.
Therefore, we may understand, at least intuitively, that in Fig. 4.28, a plateau forms
above CMC.

In practice, the knowledge of CMC is fundamental. Depending on the surfactant, in

particular the length of the chain (the longer the chain, the higher the free energy gain,
the smaller the CMC), CMC can vary over several decades, [26]. For SDS, SPAN 80,
and CTAB, in water/alkane systems (tetradecane, hexadecane, etc.), CMC is on the
order of one or several mM/L, or 10−4 w/w (surfactant mass over liquid mass in the
same volume). It is approximately 4 µML, i.e. three orders of magnitude smaller, for

17 Often,C and CMC are considered as identical, which is incorrect

sat
186 Hydrodynamics of microfluidics 2: droplets

Surfactant Liquid 1 Liquid 2 CMC (M/l)

SDS Water Air 8 10−3
SPAN 80 Water Hexadecane 6.10−4
Krytox Water PFC 4.10−6
CTAB Water air 9.10−4
Tween20 Water Air 10−5
Table 4.5 CMC at 20◦ C for a surfactants currently used in microfluidics.

Krytox in water/PFC systems (i.e. perfluorinated oil), frequently used in microfluidics,

for their compatibility with PDMS (no swelling). Table 4.5 lists a few values.
In practice, working at several CMC guarantees that we stand on the plateau of Fig
4.28 and therefore γ is constant. Around CMC, the surfactant concentration is low
and viscosity is essentially that of the solvent. At much larger CS , this ceases to be
true, and non–Newtonian behaviour takes place. We will not address this type of
situation, for which, interestingly, microfluidics provided accurate data and proposed
novel concepts [31, 32].

4.29: Evolution of the interfacial ten-

sions of PDMS in water (closed cir-
cles), and water in air (open circles),
with surfactant (heptaethylene glycol
mono–n–dodecyl ether) concentration
Cs . The units here are expressed in the
old system CGS (erg/cm2 ). One has
1 erg/cm2 =1 mJ/m2 . (Reprinted with
permission from [33]. Copyright 2022
American Chemical Society.)

The case of solids. For reasons similar to those presented above, surfactants adsorb
at the walls. They form mono layers, or multilayers, that affect the surface tension γLS .
The effect was demonstrated by Chaudhury [33], who exploited the deformability of
PDMS to measure surface tensions as a function of bulk surfactant concentrations. Fig.
4.29 show the existence of a critical micellar concentration, above which, similarly as
for liquid/gas interfaces, surface tension reaches a plateau. Interesting is to note that
the CMC of the liquid/solid interface is different, but of the same order of magnitude as
that of the liquid–vapour interface (see Fig. 4.29). On the right–hand side of the figure,
attempts of the authors are made to figure out the molecular structures adsorbed at
the interface [33].

4.3.4 Marangoni flow

When one deposits a small drop of liquid soap (for dish cleaning; for instance) on a
water surface, almost immediately, the surface gets covered with a soap film (see Fig.
 Surfactants 187

4.30). In the experiment shown in Fig. 4.30 pepper powder was used to visualize the
phenomenon [34]. One observes that the speed of the water/soap front is on the order
of 1 m/s. So, what happened?

Fig. 4.30: Pepper experiment: water is covered by pepper (for the sake of visualization).
A drop of soap, introduced in the system, spreads at fast speed, pushing the pepper [34].
(Credits: Chirag Kalelkar, Abhijeet Kant Sinha.)

The theory of Carlo Marangoni, built in the nineteenth century, allows us to explain
the phenomenon [35]. In the presence of a gradient of surface tension (here, the gradient
is produced by the soap patch initially deposited on a fresh water surface), similarly
as the soap film confined in a rectangular frame, the system searches to decrease its
energy. A flow starts over, in order to spread the surfactant over the surface, since, as
explained above, soap reduces surface tension. The phenomenon can be modelled by
noting that the continuity of the tangential stress at the interface imposes the following
relation:

∂U ∂γ
µ =
∂z ∂r

in which µ is the fluid viscosity, U is the flow speed at the surface z = h, with z
the vertical dimension, γ is the surface tension and r is the radial coordinate. For
uniform γ we have the usual boundary condition for a free surface, i.e. µ ∂U ∂z = 0.
However, in the pepper experiment, with the addition of the soap, γ is no longer
homogeneous. The problem is a century old, but it was analyzed comprehensively only
recently [36]. The stress, driven by ∇γ, generates a flow in the bulk, which pushes the
pepper radially outwards. A hole (i.e. a surface without pepper)thus grows at speed
U . As the patch radius r grows,q the momentum diffuses in the depth of the water
U
bath, down to a distance δ ∼ νr from the free surface, in which ν is the kinematic
viscosity. By equating the viscous stress µ Uδ , where ∆γ = γw − γs (here γw is the
water surface tension and γs the surface tension with soap) with the surface tension
gradient ∂γ ∆γ
∂r ∼ r , one obtains the following expression for U :
188 Hydrodynamics of microfluidics 2: droplets

∆γ µ2
U∼ Oh1/3 , with Oh = the Ohnesorge number
µ ∆γρr

For soap spreading on water, the expression leads to U ∼ 1m/s, which is consistent
with the observation.
We will see that the Marangoni effect plays in important role in microfluidics, for the
questions of droplet stability and coalescence.

4.4 Wetting

4.4.1 The three fundamental cases of wetting

There exist three basic cases of wetting: complete (or full) wetting, partial wetting,
and dewetting [37, 48]. The first two cases, complete and partial wetting are shown in
Fig. 4.31.

Fig. 4.31: Two fundamental cases of wetting: (A) complete and (B) partial.

In the case of complete wetting (Fig. 4.31 (A)), a droplet deposited on the surface
spontaneously spreads and forms a film. Using a vocabulary employed before, this
behaviour suggests that the liquid likes’ the surface.
The second case is partial wetting (Fig. 4.31 (B)). Here, the droplet does not spread
and a contact angle appears.
In the literature, one distinguishes between two sub–cases: contact angle smaller than
90◦ or larger than 90◦ (see Fig. 4.32). In the former case, the fluid is declared ‘wetting’
(a name which must not be confused with ‘complete wetting’), and, in the latter,
’non–wetting’.

4.32: (A) An acute con-

tact angle corresponds
to ‘wetting’, while an ob-
tuse one (B) corresponds
to ‘non–wetting’.
 Wetting 189

We will see that, from an energetic perspective, there is no reason to single out the 90◦
angle. However, from a dynamical perspective, the two situations are fundamentally
different. A wetting fluid introduced in the entry of a capillary tube, or a microchannel,
will develop a convex meniscus (i.e. whose curvature is oriented against the fluid) and
consequently, as was seen earlier, the Laplace pressure will work to generate a flow
that pushes the meniscus further into the device. In such circumstances, filling is
spontaneous. In the other case (non–wetting), the meniscus will recede backwards,
against filling. We will return to this behaviour later.

An important case is when the contact angle is 180◦ (Fig. 4.33). In this case, called
dewetting, the droplet minimizes its contact with the surface. This suggests that in this
case, the liquid hates’ the surface. In air, it never happens. In liquid–liquid systems,
dewetting can be achieved by using surfactants. This is detergence. We will describe
this situation later.

4.33: Dewetting: in this case, a

droplet sitting on a surface devel-
ops a contact angle equal to 180◦ .

4.4.2 The spreading coefficient

How can we describe the two situations shown in Fig. 4.31? We again use reasoning
based on energy [37]. We have here three interfaces: solid/gas, liquid/solid, and liq-
uid/air. An interfacial energy corresponds to each of these interfaces. To describe the
system, we will make use of a fundamental parameter: the spreading coefficient S,
which is defined by:

S = γSG − γSL − γ

in which γSG , γSL are the energies of the solid–gas and solid–liquid interfaces respec-
tively, and γ, as usual, is the energy of the liquid–vapour interface. There is a subtlety
here: γSG assumes the exposed surface to be in equilibrium with the vapour, which
in turns implies that, owing to volatility, a few molecules adsorb to the surface. The
surface is thus moist. The difference between a dry and a moist surface can be large.
Ref. [37] mentioned the case of metallic oxides: in such a case, the moist surface is on
the order of 60 mN/m, while the dry one is ten times larger. In the case of organic
materials, liquids and solids, or non–volatile liquids, the difference is smaller.
190 Hydrodynamics of microfluidics 2: droplets

The spreading parameter S allows us to quantify the two situations outlined in the
preceding section. We will assume that the fluid is not volatile, and consequently SLG
represents the surface energy of a dry solid.

• S > 0: complete wetting. We may view S as representing the difference between

the surface energy of the dry surface (γSG ), and the energy of the surface covered
by a film (γLG + γSL ). S > 0 means that a surface entirely covered by a liquid
film is energetically more favourable than a dry surface. Solid gas interfaces ‘cost’
too much. To reduce the price to pay, liquid blobs placed on dry surfaces spread
spontaneously.

• S < 0: partial wetting or dewetting. In partial wetting, film spreading is not

energetically favourable, and a droplet, characterized by an equilibrium contact
angle θ, forms on the surface. When S is strongly negative, for instance when
γSL is large, a gas layer, sandwiched between the liquid and the solid, tends to
form, in order to avoid contact between the two phases. This configuration could
physically occur in microgravity. On earth, liquids do not spontaneously levitate
and dewetting corresponds to a situation where the contact angle is equal to 180◦ .
This discussion shows that complete wetting and dewetting are the two faces of
the same coin. If the dispersed phase (the droplet) is dewetting with respect to a
surface, then the continuous phase (the fluid exterior to the droplet) is completely
wetting with respect to the same surface. We will study these situations in more
detail below. For that, we need to establish Young’s equation.

4.4.3 Young’s equation

Let us concentrate on partial wetting, again with non volatile liquids, so that γSG
corresponds to a dry surface exposed to gas. We take here the demonstration made in
Ref. [37]. To express the equilibrium, we again use the method of virtual displacements,
considering that, in the process, liquid and gas volumes do not change. This implies
that the only energies that matter are surface energies. Let us assume that the fluid
interface is flat down to the wall, an hypothesis we will comment later, and calculate
the variation in interfacial energy produced by a displacement δx of the contact line
on the solid surface (Fig. 4.34(A)). During this displacement, in the case shown in the
figure (displacement on the right), the solid liquid interface looses a length δx, while
the solid gas interface gains δx. On the side of the liquid–vapour interface, there is a
gain δx cos θ, in which θ is the contact angle. Why is it the case? One may think that,
far from the wall, the liquid interface is held at a fixed point. Then, a geometrical
calculation shows that the length of the liquid–vapour interface must increase by a
quantity equal to δx cos θ in order to displace the contact line by a quantity equal to
δx.

The work δW associated to the contact line displacement is:

δW = (γSG − γSL )δx − γ cos θδx (4.15)

 Wetting 191

Fig. 4.34: Solids are in dark grey, liquid in light grey, and gas in white.(A) To demonstrate
Young’s equation, the contact line is displaced by δx [39].(B) Young’s equation can also be
established by considering a droplet placed on a solid and minimizing the surface energy of
the system [38].(C) Mechanical demonstration of Young’s equation. The tension γSG − γSL
applies to the liquid/solid interface, close to the contact line [5, 7].

At equilibrium, this incremental work must be equal to zero. On expressing this con-
dition, we obtain Young’s equation [39]:

γSG − γSL = γ cos θ (4.16)

or:
S
cos θ = +1 (4.17)
γ

In this demonstration, the liquid–vapour interface can curve in as we approach the

contact line, but this does not change the result as long as the curved region occupies
a negligible fraction of space.
Young’s equation can also be demonstrated by considering a droplet, deposited on a
flat surface, and minimizing, at fixed volume, the surface energy of the system [38] (see
Fig.4.34 (B)). The mathematics are not complicated, but it takes one page to perform
the calculation. It allows us to avoid handling infinite volumes of fluid, infinite surface
energies, seen from a point located at infinity. The approach is thus less abstract than
in Ref. [37], but less elegant.
Young’s equation can also be established by reasoning with line tensions, but the
demonstration is more delicate.18 According to Refs. [5,7], the force (per unit of length)
exerted by the liquid/solid interface on the contact line is found equal to γSG − γSL
18 Reasoning with energy allows to avoid asking questions, such as: where do forces apply? In which
directions do they point? How to incorporate kinetic pressure? The reason is that energy is a global
quantity, which integrates all these questions.
192 Hydrodynamics of microfluidics 2: droplets

(see Fig. 4.34 (C), for the case γSG − γSL > 0). On the other hand, the liquid pulls
the contact line with a tension γ. The system being at equilibrium, these forces must
equilibrate. By projecting the equilibrium condition onto the horizontal axis, one ob-
tains Young equation (4.16).19 The projection on the vertical axis yields a pulling
force normal to the wall, oriented upwards, which is balanced by the elasticity of the
material. This gives rise to a slight deformation of the substrate. This deformation is
extremely small in hard solids and, consequently, is difficult to measure. The task is
easier in soft solids, such as rubber, PDMS, or fresh paint [4].
Whether obtained energetically or mechanically, Eq. (4.17) stipulates that if the spread-
ing coefficient S is positive or less than −2γ, there is no solution, and, consequently,
there is no contact line. For positive S, the system forms a film completely covering the
solid. This is the case of oil on clean glass (see the discussion below). For S ≤ −2γ,
the liquid adopts a shape that minimizes contact with the solid, for instance a gas
layer sandwiched between the solid and the liquid. This is dewetting. As said above,
between these two extremes, the contact angle is prescribed by Eq. (4.17).

The link between θ and the material characteristics. This is also a long story and
we will content ourselves to summarize an important conclusion [37]. There is a link
between θ and polarizability, which, as we saw in Chapter 2, controls the intensity
of the Van der Waals interactions. The more polarizable the solid, the more wetting
the surface. This statement, justified in [37], rests on a number of simplifications
and hypotheses that restrict its domain of validity. Nonetheless, from this, it can be
considered that poorly polarizable liquids, such as oil, wet highly polarizable materials,
such as glass, and metals. The intuitive notion that fluids with low surface tensions
wet high energy surfaces, is a consequence of this result.

4.4.4 Experimental validation of Young equation

In the spirit of this book, which emphasizes real measurements, and due to its impor-
tance, it is interesting to mention a direct experimental validation of Young’s equa-
tion, established for the particular case of soft solids. This was done by Chaudhury
and Whitesides in the 1990s [19]. Data is shown in Fig.4.35. Verification of Young’s
equation achieved with mixtures of water and methanol on PDMS. The graph shows
the evolution of γ cos θ with γSL , for advancing and receding angles (two different
symbols), which are barely distinguishable, within experimental error. All quantities
are measured independently, using standard techniques for the liquid/vapour interface,
and, at that time, a novel method, already mentioned in this chapter, based on the
analysis of the deformation of PDMS, for the γSL measurement. The data shows that
γ cos θ varies with γSL linearly, with a slope −1, in excellent agreement with Young’s
equation.
19 Fig 4.34 (C) differs from the figures shown in textbooks. In the traditional approach, each interface
is associated to a tension that pulls the contact line. In Berry’s theory, only liquid/vapour and
liquid/solid interfaces pull the contact line.
 Wetting 193

4.35: Verification of Young’s equa-

tion, made with mixtures of water
and methanol on PDMS. The graph
shows the evolution of γ cos θ with
γSL , for advancing and receding an-
gles (two different symbols), which
are barely distinguishable, within ex-
perimental error. All quantities are
measured independently. The data
shows that γ cos θ varies with γSL
linearly, with a slope −1, in excel-
lent agreement with Young’s relation
(Reprinted (adapted) with permission
from [19]. Copyright 2022 American
. Chemical Society).

4.4.5 Is Young’s equation valid at the nanoscale?

We saw that, in the case of partial wetting, the region where gas, solid and liquid meet
defines a line, the contact line. Physically, the contact line has some thickness, and
a legitimate question is raised as whether the corresponding region has some special
properties, different from the bulk and the interface, which should be incorporated,
in some way, in Young’s equation. Gibbs suggested long ago [40], that this line is
subjected to a tension τ , which must be directly introduced in Young’s equation as
a force applied onto the contact line, that prevents, or favour its displacement.These
considerations led to the proposal of a modified Young’s equation, which reads:

τ
γSG − γSL − = γ cos θ
γR

in which τ is the tension of the contact line (which can be stretched or compressed,
depending on the sign of τ ), and R is its curvature radius of the same line. If the drop
is cylindrical, the contact line is straight and the correction vanishes out. Only curved
contact lines are concerned by the correction. When τ is positive, the ’true’ contact
angle is larger than the Young angle. One century of discussion has been conducted
on the value of τ , but, today, there is a consensus, essentially based on numerical
simulations, that the correction is extremely small. It was found that the length scale
l= γτ does not exceed a fraction of nanometres, so that the ratio l/R is negligible in all
cases of practical interest.

4.4.6 Dewetting induced by surfactants – detergence

We learned that surfactants decrease the surface tension of liquid/air interfaces. We

will see here that this feature generates spectacular effects. An example is detergence,
a phenomenon that laundry companies exploit for cleaning clothes and that turns out
to be extremely important for microfluidics.
194 Hydrodynamics of microfluidics 2: droplets

Fig. 4.36: Dewetting in a water–tetradecane system, in which a water droplet, 100 µm in size,
sitting on a smooth glass surface, is created. On increasing the SPAN 80 concentration (up
to several CMCs), the system shifts from left to right, i.e. from partial wetting to dewetting.

The photo on the left of Fig. 4.36 represents a droplet of water in tetradecane, without
surfactant. We have here a situation of partial wetting. On the right, we introduced
SPAN 80 at a concentration three times above CMC. Data on this surfactant were
shown in Fig 4.28. The effect of Span 80 is spectacular: it brings the system from a
state of partial wetting to dewetting.

Why this is the case? In fact, the phenomenon is a spectacular consequence of Young’s
equation, which we recall here (in the case of a smooth surface):

γSW − γSO = γ WO cos θ

where the symbols S, W, and O signify solid, water, and oil, respectively, and θ is the
contact angle formed between the solid and water, defined, by convention, inside the
droplet. Without surfactant, this angle is about 110 degres. Adding a surfactant above
CMC, as we have seen (see Fig. 4.28), reduces the interfacial tension γ by a factor
of 20. Indeed, surfactant molecules will adsorb at the solid interfaces, and change
interfacial tensions (see Fig. 4.29). However, Span 80 is almost insoluble in water.
Therefore, we have γSO decreasing, and γSW approximately constant. Consequently,
with γ decreasing, Young’s relation imposes cos θ, initially negative, to become more
negative. As it reaches −1, θ adopts a value of 180◦ and dewetting occurs. At this stage,
the contact line vanishes and Young’s equation no longer holds. The system is locked
in this state. This is detergence.

Laundry products harness this effect: the droplet is an oil stain initially adsorbed onto
a piece of clothing. The surfactant transforms the stain to a drop, then the hydro-
dynamic currents of the washing machine remove these droplets from the clothing.
In a microfluidic device where flows develop, forced by syringe pumps or pressure
controllers, as explained in Chapter 3, droplets are kept away from the walls in a sim-
ilar manner. In permanent regimes, a lubricating film covers the walls, preventing the
droplets to establish direct contact with them.
 Wetting 195

4.4.7 The effect of surface roughness on the contact angle

4.37: Typical image of a glass etched

surface, imaged by Atomic Force Mi-
croscopy (AFM). Vertical axis unit is
nanometre and horizontal units are mi-
crometres(Reprinted from [41] by per-
mission of Springer Nature.)

Thus far, we have assumed smooth surfaces. In reality, surfaces are rough. Silicon sur-
faces are atomically rough and glass or polymers (such as PDMS), more frequently
used than silicon, have surfaces with roughnesses in the nano– or deca–nanometre
range. When the surface is coated, with a hydrophobic layer for instance, the rough-
ness increases up so several tens of nanometres. Figure 4.37 shows an AFM image of a
glass surface that has been etched, without particular effort deployed for minimizing
roughness [41]. One can see a roughness in the order of 10–20 nm, with a wavelength
of 100 nm. The parameter r, also called roughness’, defined as the surface area over
the projected area, will be on the order of 1.1. Although small, this roughness must
be seriously taken into account.

Discussing the effect of roughness on wetting is a complex task. Decades of discussion

have been conducted on the subject. Over the years, progress in theory, simulation
and surface observation and control, allowed a consensus of knowledge to be built up.
In the domain, one usually distinguishes between two types of roughness: geometrical
roughness and chemical heterogeneities (see Fig. 4.38). Each type needs a specific
model.

Fig. 4.38: Two types of roughness: geometrical (left) and induced by chemical heterogeneities
(right).
196 Hydrodynamics of microfluidics 2: droplets

Geometrical roughness: Wentzel model. The Wentzel model is well reviewed in the
literature, and we content ourselves with discussing the most important outcome. R.
N. Wentzel [43,44] showed that the apparent contact angle θ∗ (see Fig. 4.38) is related
to the equilibrium contact angle θE and the roughness r, as given by the following
relation:

θ∗ = r cos θE (4.18)
in which θ∗ is the apparent contact angle, θE is the Young angle and r is the roughness.
As shown in Fig. 4.39, since r > 1, the roughness always accentuates the wettability
or non wettability of the material. therefore, for wetting surfaces, the base of drop, at
the molecular scale, develops an averaged contact angle smaller than the macroscopic
equilibrium contact angle. For small roughnesses, θ∗ will differ from θE by a quantity
≈ −(r − 1) tanrθE . For r ∼ 1.1 and a contact angle of 60◦ , the deviation is on the order
of 10◦ .

Fig. 4.39: (A)Smooth wetting surface, characterized by a contact angle θE .(B) Same material,
but rough. The averaged contact angle θ∗ is smaller than θE .

Chemical heterogeneity: Cassie–Baxter model. In the Cassie–Baxter model [45], we

have the following relation:

cosθ∗ = f1 cos θ1 + f2 cos θ2 (4.19)

in which f1 and f2 are the fractions of the surfaces of chemical type 1 and 2, respec-
tively, and θ1 and θ2 are the corresponding Young angles. The apparent angle is thus
the outcome of an average on the cosinus. If we mix a fully wetting material with an
hydrophobic one (for instance, a contact angle of 120◦ , in equal proportions, the result
will be a wetting surface with an angle of 75◦ (and not 60◦ ).

Pinning. We saw before that microfluidic surfaces are rough. We recall that their
typical roughness factors are on the order of 1.1 and their maximal amplitudes are 10
– 30 nm. Here, we shall see that, even though r looks small, and amplitudes lie in the
nanometre range, roughness considerably affects the dynamics of the droplet.
Fig. 4.40 shows the mechanism of pinning. In order to move forward, the contact line
must travel in a landscape composed of hills and valleys. During the journey, the
 Wetting 197

Fig. 4.40: (A) An example of a rough surface [42].(B) Zoom of the contact line region over
a rough surface.

contact angle departs from its equilibrium value θ shown in the figure, by an amount
∆θ ∼ (r−1), for r−1 small and tan(θ) ∼ 1. The force working at bringing the meniscus
back to equilibrium is ∆θσh, where h is the side length of the square cross–section and
σ is a representative of the surface forces. On the other hand, the fluid is subjected to
an overpressure ∆P , which pushes the interface downstream with a force ∆P h2 . For
the interface to advance, one must have:

∆P h2 > ∆θσh (4.20)

Let us estimate, naively, the various terms of this inequality. Overpressures developed
in microfluidic flows are on the order µU L/h2 in which U is a typical speed, L is the
channel length, and µ is the fluid viscosity. On the other hand, for Van der Waals
materials, σ ∼ γ, γ being a typical surface tension for such systems (we estimated on
the order of 20 mN/m). As a consequence, in order for the meniscus to move forward,
one must have:

µU L
∆θ < (4.21)
γh

We shall see later that the group µU/γ plays an important role in droplet–based
microfluidics. It is called capillary number and its value is on the order of 10−5 . With
L ∼ 1 cm and h ∼ 100µm, one gets ∆θ < 10−3 , which in practice is impossible to
achieve with current materials, such as polymers or glass.
To summarize, the naive model developed here indicates that even though roughness
is small, the meniscus remains trapped in valleys and the droplet stops. In order to
avoid this problematic situation, one needs to work in completely wetting conditions
(or dewetting conditions for the dispersed phase).

Hysteresis. Let us make another remark on Fig. 4.40. As the contact line advances,
it floods a dry landscape, while when it recedes, the landscape is already wetted by
itself. Liquid is adsorbed on the surface, or trapped in valleys, so that surface energy
is different from the dry state. This asymmetry is at the origin of the hysteresis of the
198 Hydrodynamics of microfluidics 2: droplets

contact angle. The hysteresis must be taken into account carefully in the measurement
of contact angles. Hysteresis of several degrees, is frequently encountered on unpre-
pared surfaces. Smaller hysteresis, of a fraction or degree or so, is currently achieved
in wetting studies.

Superhydrophobicity. In reality, surfaces must be viewed, in general, as including

both chemical heterogeneities and geometrical roughness. For hydrophobic rough sur-
faces, air bubbles can be trapped in the valleys, giving rise to superhydrophobicity.
The subject of superhydrophobicity has been studied for decades (see, for instance,
Ref. [46]). It has given rise to many interesting applications, such as in textile indus-
try, with repelling tissues. We saw in Chapter 3 that, with these surfaces, slip lengths
could be enhanced by one or several orders of magnitude. Superhydrophobic surfaces
have first been created by using microfabrication techniques but, over the years, much
simpler techniques have been invented [47]. Even simplified, these techniques represent
serious microfabrication constraints, which must be balanced with the gain obtained
from working with superhydrophobic walls. Today, in the specific context of microflu-
idics, superhydrophobicity is still awaiting applications.

4.5 Droplets advancing on a surface

4.5.1 The physics of displacement

What happens when a drop is in motion over a plate? It took decades to answer this
apparently simple question [37,48,49]. Electro wetting on dielectrics (EWOD) technol-
ogy [50], which now is an important component of microfluidics, added a technological
facet to the subject. A droplet moving over a surface seems a simple phenomenon.
Actually, it uncovers considerable complexity.
A now well–accepted representation of the structure of the region around the contact
line (the ‘foot’) of an advancing droplet is shown in Fig. 4.41.

Fig. 4.41: The three regions appearing when a droplet advances over a smooth flat plate:
microscopic, mesoscopic, and far region. In the microscopic region, roughness is represented
by an apparent acute contact angle θ∗ smaller than the equilibrium angle θE (see above).
 Droplets advancing on a surface 199

Close to the contact line, the interface for smooth wetting surfaces can be divided into
three regions:
Microscopic region : concerns scales comparable to the microscopic, or nanometric
roughness. As seen above, the averaged contact angle is smaller than the equilib-
rium angle.
Mesoscopic region : intermediate region, of size Ca ∼ R/θE (where R is the system
size (for instance, the droplet radius) and θE the Young angle), between the
microscopic and the far region.
Far region : region whose size is comparable to the system size.
With droplets of centimetric sizes, the three regions embrace seven decades of scale.
At the smallest (nanometric) level, the surface is rough and an apparent contact angle,
θ∗, given by the Wentzel model, develops. This angle is different from the equilibrium
contact angle θE , not shown on the figure. The far region is characterized by an appar-
ent angle θa which depends on the droplet speed. This angle concerns submillimetric,
millimetric, or centimetric dimensions, and is thus accessible to the measurement.
The relation between the two angles is given by the Cox–Voinoi law [51, 52]. The
demonstration uses matched asymptotic expansions, balancing viscous and capillary
forces in each of the three regions, and matching them. It is well described in several
places [4, 37, 48, 49], and lies beyond the scope of the book:

αl0
θa3 = θ ∗3 +9Ca log (4.22)
li

in which Ca = Uγµ (in which U is the droplet speed, and µ is the fluid viscosity), α is
a geometry dependent factor, l0 a length characterizing the droplet size (on the order
of R, its radius), and li is a microscopic scale. The formula tells us that the faster the
droplet, the more obtuse the apparent contact angle. In terms of order of magnitude,
for a water droplet 100 µm of radius, moving at 100 µm/s, which is quite fast, the
difference between the static and the apparent dynamical contact angles do not exceed
a few degrees. The size of the mesoscopic region, roughly estimated to be ∼ Ca R/θE ,
is, in practice, on the order of tens of nanometres.
The structure was challenging to establish, because of considerable experimental diffi-
culties (the regions to analyse are extremely small and roughness is difficult to quantify
and control) along with the limitation of numerical simulations, which cannot fully ad-
dress the multi–scale nature of the problem. Now, the structure is well–accepted. One
conceptual difficulty that the community had to face, and which is reflected by the
existence of a phenomenological microscopic length li in the Cox–Voinoi formula, is
the slippage of the contact line. The droplet advances as a caterpillar [53], thus with-
out slippage, but the contact line must slip. Because of the logarithmic dependence in
Eq. 4.22, different phenomenological estimates of slip lengths work equally well, as far
as the global movement of the droplet is concerned [4, 48, 49]. We will not discuss this
point any further as it stands well beyond the scope of this book.
200 Hydrodynamics of microfluidics 2: droplets

4.5.2 Displacing droplets by patterning surfaces

One way to move a liquid drop placed on a plate is to pattern the wettability of
the surface. Figure 4.42 shows an example where, on the left–hand side, the surface
is hydrophilic, and, on the right–hand side, it is hydrophobic. This pattern can be
obtained on plastic or PDMS surfaces, for instance, by exposing them to deep UV
through a quartz mask, before closing the device. We will discuss the delicate question
of surface patterning later, in Chapter 7.

γLsl γRsl

Hydrophilic Hydrophobic

Fig. 4.42: Difference between the contact angles of two sides of a drop produced by a gradient
in the surface chemistry. Due to Laplace pressure, the drop will move to the side where the
contact angle is smaller.

As shown in Fig. 4.42, Young’s equation imposes different contact angles at the left
and the right of the drop, creating a pressure difference inside the drop, from the right
to the left. The drop will advance towards the hydrophilic region, which it ‘likes’ most.
At some point in its journey, the contact line, initially located on the hydrophobic part,
touches the hydrophilic zone. Then, the meniscus inverts its curvature, the pressure
difference disappears, and the drop stops. To obtain a continuous movement, one
must renew permanently the surface energies of the substrate. This cannot be done
mechanically, nor chemically, but thanks to the phenomenon of electrowetting, coupled
to electro wetting on dielectrics (EWOD) technology, that we will discuss in Chap. 6,
the task is feasible.

4.5.3 The important role of pinning and dewetting in droplet

microfluidics

A microfluidic experiment carried out in 2003 illustrates two phenomena discussed

above: pinning of the contact lines and dewetting [30]. Experiments involved injecting
tetradecane and water into a hydro–focusing junction made in glass (see Chapter 3),
with tetradecane in the centre and water on the sides. Two cases are considered: with
surfactant (SPAN 80 above CMC) and without surfactant. With surfactant, water
dewets the wall (see Fig. 4.36, right). In this case, well–defined morphologies are ob-
tained (see Fig.. 4.43 (left)): isolated drops, drop pairs, necklaces. Note that the system
produces water droplets, not oil droplets (as would be expected from Bancroft’s rule).
This is because channel wall wettability controls the type of droplet that is obtained,
through the detergence effect.
 Droplets advancing on a surface 201

Fig. 4.43: Different regimes observed in a microcanal 20 µm deep and 200 µm wide, for
tetradecane–water systems, with a surfactant (Span 80) whose concentration is over the
CMC [30].

In the absence of surfactant, wetting is partial (see Fig.4.36). For the same flowrates as
in the preceding case, different morphologies and dynamical behaviours are obtained
(Fig. 4.43). Featureless water blobs, and sticking intermittently to the walls, are ob-
served. The flow produced is therefore meandering, and its structure is erratic and
uncontrolled. The reason is that in this case, as mentioned above, contact lines de-
velop and, from time to time, are pinned by the roughness of the glass walls, however
small it is (on the order of 10 nm). Varying flowrates by four orders of magnitude does
not modify the situation in any respect.
These observations can be illustrated in Fig. 4.44. Fig 4.44 (A) shows a stable sit-
uation: a water droplet circulates in a microchannel filled with oil, in which walls
are hydrophobic. Since oil completely wets the walls, the oil film, which separate the
droplet from the walls is stable and the droplet can steadily move downstream.

Fig. 4.44: (A) Water droplet in a channel, with hydrophobic walls, i.e. fully wetting with
respect to oil. The system is stable.(B) The same system, but with hydrophilic walls, i.e. fully
wetting with respect to water. The system is unstable
202 Hydrodynamics of microfluidics 2: droplets

Fig 4.44 (B) shows the opposite situation, in which we assume water droplets in oil,
but the microchannel walls are hydrophilic. In this case, the system is unstable. If the
droplet touches the wall, water will spread over it and destroy its structure. After some
time, phase inversion will take place, in which oil droplets, instead of water droplets,
will form. This sequence of events illustrates that wall wettability imposes the type of
emulsion that can be produced in microfluidic channels.

4.6 The governing equations and the capillary number

4.6.1 Dimensional reasoning and physical interpretation

In Chapter 3, we showed that, at small Reynolds numbers, the flow pattern only
depends on the geometry. We could arbitrarily change the flow rate without changing
the flow pattern. Now, what happens when capillarity comes into play?
Let us consider a flow in a system including two immiscible fluids 1 and 2, charac-
terized by their viscosities µ1 and µ2 , and the interfacial tension γ. The geometry
is characterized by a single scale l and it is driven by a speed U . In this problem,
inertia is negligible (because the Reynolds number is small), and therefore the fluid
density ρ does not play any role. On applying the Π theorem (with local velocity u
and position x, the two viscosities, the characteristic length and the surface tension,
we have six physical variables and three units. Therefore, three dimensionless numbers
characterize the flow. Consequently, local velocity u can be written as follows:

x
u(x) = U f ( , λ, Ca) (4.23)
l
µ1
in which λ = µ2 is the viscosity ratio and Ca is the capillary number, defined by:

µ1 U
Ca = (4.24)
γ

When the system is characterized by a single scale, the physical meaning of Ca is the
ratio of the viscous forces (µ1 U l) over the surface forces (γl).

Viscous forces
Ca ∼ (4.25)
Capillary forces

The larger the capillary forces, the smaller the capillary number. Despite this disturb-
ing construction, Ca is the undisputed reference dimensionless parameter for describing
capillary phenomena.

The equations that govern capillary flows are the Stokes equations for each phase, sup-
plemented by boundary conditions. One is kinematical, prescribing where the interface
goes. The others include velocity and tangential stress continuity, along with pressure
 The governing equations and the capillary number 203

discontinuity, caused by the Laplace jump. This system becomes nonlinear, and, as
a consequence, all the virtues’ of Stokes equations, established with rigid boundaries,
vanish. The stability of the solutions, their unicity, the flow reversibility are gone. In-
stabilities are now allowed, along with irreversibility. The presence of free interfaces
changes profoundly the dynamics of the system.

4.6.2 Application to droplet break–up

The preceding discussion is well–illustrated by the problem of droplet break–up in a

shear flow at low Reynolds numbers [54]. Figure 4.45 shows the situation.

µ1 αR
Fig. 4.45: Grace curve: Ca vs λ diagram, in which Ca = γ
,
where R is the initial droplet
µ1
radius and λ = µ2
the viscosity ratio, with µ1 that of the dispersed phase (e.g. gas if there
are bubbles), and µ2 that of the continuous phase (for instance air for rain).

Under the action of the shear, the droplet rotates and elongates. As noted above, the
process depends only on Ca and λ, with λ the ratio of the viscosity of the dispersed
phase over the continuous phase. Fig. 4.45 is a Ca vs λ diagram, in which Ca = µ1γαR ,
where R is the initial droplet radius. Below a certain curve called the Grace curve [56],
the system reaches a steady state, for which the droplet undergoes steady elongation.
Above the Grace curve, the droplet increasingly elongates and eventually breaks up.
Physically, in this regime, capillary forces can no longer preserve the integrity of the
droplet, against the viscous forces which work at tearing it off. It is easier to break–up
a droplet when the two fluids have comparable viscosities. Above a critical λ ≈ 3.5,
no break–up is possible. This is the case of rain drops. Their λ is on the order of 103 .
However large their speed may be, rain drop do not break up.
The phenomena are many and it is remarkable that two numbers suffice to describe
them, throughout a considerable range of scale, from R (let us say 1 cm) to the nano-
204 Hydrodynamics of microfluidics 2: droplets

metric scale (filament thicknesses preceding break–up20 ). We thus have here an illustra-
tion of the capacity of the capillary number to characterize the wealth of phenomena.
Droplet break–up moreover illustrates three properties of the governing equations:
nonlinear behaviour (droplet deformation varies nonlinearly with the shear), presence
of instabilities (break–up) and irreversibility (coalescence and break–up are not sym-
metric).

4.6.3 What happens at large capillary numbers ?

In microfluidics, as we saw, capillary numbers are small. Typical values range in the
domain 10−6 to 10−4 . This result was anticipated in Chapter 2, when we pointed out
the prevalence of capillary forces in small systems.

Fig. 4.46: Different flow regimes. The vertical pipe diameter is 0.20 m and allows speed of
several metres per seconds. The main regimes are, from left to right: bubbly, plugs or slugs,
churn, annular and wispy annular. Many subregimes exist.

Imposing small Reynolds numbers and, in the meantime, large capillary numbers is
difficult. For the capillary number to be large, U must be larger than a speed Uc ∼ γ/µ.
With typical surface tensions (say, 10 mN/m), and ordinary fluids(µ ≈ 10−−3 Pa.s),
one has Uc ∼ 10 m/s. At such speeds, in most situations of practical interest, the
Reynolds number is large, and the flow is turbulent. Systems with extremely small
surface tensions exist, but they are used in very specific contexts.
Here, we consider gas–water flows at high capillary and large Reynolds numbers. Such
a situation is often encountered in the oil and nuclear industries [58]. We use it to

20 The statement is reinforced by an additional complexity of the phenomenon, revealed by studes

carried out in the 1990s. To achieve break–up, one needs to break Van der Waals bonds inside the
fluid. How can this be done The response is through a cascade of instabilities, taking place in the
filaments that join, in the last moments preceding break–up, the daughter droplets together [57].
 The Landau–Levich and Bretherton films 205

illustrate the idea that at large capillary numbers, interfaces are strongly deformed
by the flow. Fig. 4.46 thus shows different regimes for water/air flows circulating at
high Reynolds and capillary numbers. In this case, Reynolds numbers and capillary
numbers are on the order of 105 and 1–10, respectively. One can see that the dynamics
of the system is extremely rich and the interface shapes between water and gas adopt
a considerable variety of time dependent shapes, undergoing turbulent behaviour. In
microfluidics, these numbers are small, there is no hydrodynamic turbulence, and the
droplets that form, owing to the prevalence of capillarity, are spherical or (due to the
confinement) oblong, unless some specific process forces them to depart from these
two basic morphologies.

4.7 The Landau–Levich and Bretherton films

4.7.1 The Landau–Levich film

When a plate (e.g. glass) is pulled upwards, from a bath filled with a completely
wetting fluid (e.g. oil), the fluid is entrained by the solid and gives rise to a film of
constant thickness that covers its surface. In 1942, L. Landau and B. Levich provided
a rigorous explanation of the phenomenon [59], giving their names to the film.21 The
situation is sketched in Fig. 4.47.

4.47: Landau levich film, with the

definition of the four regions that
must be introduced to solve the flow
equations

The flow can be divided into four zones:

• the film of constant thickness h∞ , where the interface is flat
• the dynamical meniscus, in which the interface starts to curves in
• the static meniscus, whose shape is identical to the one in the absence of flow
• the horizontal free surface
21 The name of Derjaguin [60], who made the calculation in 1943, is also often linked to the discovery.
206 Hydrodynamics of microfluidics 2: droplets

Of particular interest is the film thickness h∞ developing over the plate. Its expression
is:

h∞ ≈ 0.95 lc Ca2/3 (4.26)

where Ca = µU γ and lc is the capillary length, introduced in this Chapter. Typical

thicknesses of the deposited layer is a few µm. To get a sense of the orders of magnitude,
suppose you swim in a lake. If you decide to leave the lake leisurely and walk, you will
have to support a water film of 100 µm thick over your body, increasing your weight
by 100 g, until it dries out. If you rush, the weight will be larger.
Formula 4.26 thus shows that the film thickness is controlled by the speed and the fluid
properties. We may infer that an entity of micrometric size (the film) can be obtained,
in a simple manner, by utilizing large objects (plate, container), while achieving ex-
cellent control. An important utilization of this capacity, which we will describe in
Chapter 7, is spin coating.

4.7.2 The Bretherton film

We will not analyse the way in the which Landau–Levich film equations are resolved.
The reader can refer to Refs. [3, 59, 60], for detailed analysis (Ref. [3] provides an
excellent tutorial). Instead, we pay more attention to the Bretherton film [62], which
is more relevant to microfluidics. Bretherton extended the Landau–Levich analysis to
the case of a bubble moving in a tube at a constant speed22 [62].

4.48: Bretherton film deposite

by a bubble moving at constant
speed in a tube

The constant thickness δ∞ of the film, far from the finger nose (i.e. the interfacial
region, approximately circular, around the symmetry axis of the channel), can be
found by orders of magnitude arguments [63, 64]. Similarly as for the Landau Levich
film, several regions can be outlined: the nose, a transition region, of length λ and
thickness δ, and the film, far from the nose, of constant thickness δ∞ (see Fig. 4.48).
First, the curvature of the transition region must match that of the nose, implying:
22 In fact, Bretherton neglected the curvature of the tube, and thus carried out the calculation as if
the film developed on a plane.
 The Landau–Levich and Bretherton films 207

δ 1
2
∼
λ r
√
and therefore λ ∼ rδ. On the other hand, as the bubble moves downstream, a flow
develops in the transition region to keep the film supplied with fluid. In this region,
on employing the Stokes equation, we have, in terms of order of magnitude:

µU 1γ
2
∼
δ λr

By combining the two equations, we end up with:

δ ∼ rCa2/3 ; λ ∼ rCa1/3

A detailed analysis of the governing equations led Bretherton to the following result:

δ∞ ≈ 0.66 r Ca2/3

We may conclude that the micrometric film thickness can be controlled accurately. An
important point is the asymmetry between the front and the rear of the bubble, which
represents another example of irreversibility of the flow equations. This asymmetry
was also analysed by Bretherton [62] (see Fig. 4.49). The physical origin is that, at the
front, the capillary flow in the transition region develops against the flow, reducing
the curvature, while the situation is opposite at the rear. We thus have a larger local
curvature in the transition region in the rear than in the front. This effect translates
into a larger nose radius at the rear than at the front. The dynamical consequence of
this asymmetry is the existence of a pressure drop ∆P along the channel, which will
play an important role later. The amplitude of ∆P is not straightforward to calculate.
The result found by Bretherton, in terms of order of magnitude, is:

γ 2/3
∆P ∼ Ca .
r

4.7.3 An application of the Landau–Levich film: dip coating technology

An application of Landau–Levich film is dip coating technology.

An object is immersed in a formulated bath, then lifted at constant speed, and even-
tually dried out (Fig. 4.50). This technology is used in the industry, for coating glass
208 Hydrodynamics of microfluidics 2: droplets

4.49: Bretherton bubble asymmetry:

because of the film, the nose of the
bubble is different from the rear. This
difference, calculated by Bretherton
in a tube, also exists in a microchan-
nel, as shown in the bottom picture,
in which a water droplet circulates in
a 100 µm square microchannel at 1
mm/s. (Courtesy of O.Caen.)

4.50: Dip coating technology. An ob-

ject is immersed in a solution contain-
ing nanoparticles, and pulled upwards
at constant speed, forming a Landau–
Levich film. As the film dries, the par-
ticle agglomerates and form a solid
coating. Different formulations can be
used (monomers, polymers with cross–
linkers, etc.)

fibres for instance, but it also belongs to the catalogue of microfluidic technologies. Dip
coating is helpful, for instance, for depositing micrometric gel structures onto surfaces.

4.8 The Rayleigh–Plateau instability

4.8.1 Physical mechanism

A column of liquid ejected from a nozzle spontaneously creates droplets. This happens
when we turn on a tap: the jet spontaneously breaks up into droplets (see Fig. 4.51).

The same break–up instability develops in microfluidics. An example is shown in Fig.

6.50 [68].

In this case, a droplet is transported at a T–junction. Along the side and the main
channels, the liquids are pumped. The droplet splits in two parts, one advancing in
a first channel and the other in the second. At some point, the droplet builds up a
bridge which thins out and eventually breaks up, giving birth to two droplets.

All this is due to an ubiquitous instability: the Rayleigh–Plateau instability [65, 66].
Its physical origin can be explained with a reasoning based, as usual, on interfacial
 The Rayleigh–Plateau instability 209

4.51: Tap produc-

ing drops. (Courtesy
of L. Bocquet, T.
Maimbourg.)

Fig. 4.52: break–up of a droplet at a T–junction. The droplet give rise to a daughter droplet,
which will further move downstream in the side channel [68].(Courtesy of L. Menetrier-
Deremble.)

energy. Let us consider the interfacial excess energy E of a column of fluid of volume
V . One has:
2πV γ
EC = 2πRLγ =
R
We now consider the excess energy associated with a collection of N drops of radius
R0 :
3γV
E = 4πR02 N γ =
R0
We thus see that the droplets with radii:
3
R0 ≥ R
2π
are less energetic than the column. The column thus ‘prefers’ to form a string of drops.

We now give more detail on this instability, in 3D and 2D.

Rayleigh–Plateau instability in 3D. The calculation of the instability is traditionally

presented in the limit where the fluid is perfect, i.e. with zero viscosity. Although
microfluidics is dominated by viscosity, the inviscid calculation is interesting because
it allows us to figure out the mechanism of instability. Details can be found in the
original papers and in reviews such as Refs. [54, 67, 115]. Calculation shows that the
210 Hydrodynamics of microfluidics 2: droplets

column is destabilized by infinitesimal perturbations of wavelength λ, subjected to the

following condition (see Fig. 4.53): :

λ ≥ 2πR

Why is it the case? In the presence of a perturbation (see Fig. 4.53), the radii of curva-
ture of the column, in the radial and longitudinal directions, R1 and R2 , respectively,
vary, in opposite manners. As R1 increases, R2 decreases, and vice versa. For wave-
lengths above ≥ 2πR, the Laplace pressure field induced by the disturbance generates
a flow that amplifies the perturbation. Crests and dips grow. This is the mechanism.
It provides a dynamical pathway for decreasing the interfacial energy. Now, among all
the unstable
√ wavelength, which grows the fastest? The most unstable wavelength is
λc = 2πR 2. The radius R0 of the droplets produced in this manner is given by the
relation:
1/3
R0

3π
= √ implying R0 ≈ 1.85R
R 2
The same calculation provides the length L of the column above which drops will
appear:
1/2
8ρR3

L=U
γ

where U is the jet speed. This length can also be found by the Π theorem, considering
that it is only function of ρ, U , and R. For inkjet printers, speeds are large, and the
distance of formation of droplets may be problematic. In such situations, we typically
have R ≈ 25µm (for the jet radius), U = 10m/s, so that droplets are about 50 µm in
radius. The length of formation of the droplets is ≈ 3 mm. The formula indicates that,
increasing the printing speed may lead the ink be splashed too early onto the paper,
before a droplet can be formed, which is not desirable.

Now, what happens when viscosity comes into play ? Rayleigh [65] also resolved the
viscous case in his seminal paper. As expected, viscosity slows down the instability in a
manner that depends on a dimensionless number, the Ohnesorge number, introduced
before. In microfluidics, viscosity and confinement come into play and modify the
conditions of development of the disturbance. It may be suggested, although in a very
naive manner, that in such a constrained geometry, the time of droplet formation τD
depends on µ, the viscosity, the channel transverse dimension l, and γ. Using the Π
theorem, one obtains:

µR
τD ∼
γ

Guillot et al [69] solved the problem analytically, in the case of the co–flow, and in a
 The Rayleigh–Plateau instability 211

cylindrical geometry. We will come back to this calculation later. It led, for the so–
called dripping regime, to an estimate for τD consistent with the preceding reasoning.
In reality, the situation is more complicated. The flow may entrain the perturbation
and inhibit the instability; both of these actions increase the length of appearance of
the droplet, giving rise to the ‘jetting’ regime, or, taking the words currently used in
hydrodynamics, convective instability’. We will return to these phenomena later on.

4.53: Perturbed interface giving rise, in 3D,

i.e. for a fluid column, to the Rayleigh–
Plateau instability, the source of droplets. In
2D, the same perturbation does not amplify
and consequently does not lead to the for-
mation of a droplet.

No Rayleigh–Plateau instability in shallow microchannels. In 2D, the same calcula-

tion shows that a straight band (the equivalents of a jet) is stable. The result can be
understood from Fig. 4.53. Surface tension will always tend to kill small perturbations,
because they increase the interfacial area. Consequently, the interface will return to
rest. This does not imply that the band is the least energetic structure. For instance,
a disk (the equivalent of a drop) is less energetic than a band. The problem is that,
if we restrict ourselves to small perturbations, there is no dynamical pathway that
would reshape a band into a disk. The band is in a metastable state. This result has
important implications for microfluidics. It implies that, in shallow channels, which
achieve conditions close to two–dimensionality, immiscible fluids flow side by side in a
stable manner [55].

4.8.2 The break–up of nanojets

What happens when the jet becomes nanometric? Numerical simulations based on
molecular dynamics [70], discussed by [71] have addressed this question (see Fig. 4.54).
The simulations show that at the nanometre scale, instead of capillarity, thermal noise
is responsible for the breaking up of the jet. To quantify this, a fundamental scale
of the problem, the so–called thermal–capillary’ scale lCT , for which the orders of
2
magnitude of thermal energy (given by kT ), and capillary energy (given by γlTC ) are
comparable, can be introduced. The scale is defined by the following relation:
s
kT
lTC =
γ

For ordinary fluids (oil, water, etc.) lTC is a few nanometres. Therefore, for jet diam-
eters much larger than this length, Rayleigh instability dominates, while for smaller
jets, on the order of tens of nanometres or less, thermal noise prevails. Incidentally, it
212 Hydrodynamics of microfluidics 2: droplets

4.54: Nanojet emitted by a noz-

zle of 6 nm. (Reprinted from Ref.
[70] with permission from Ameri-
can Association for the Advance-
ment of Science. Copyright 2022.)

is interesting to note that, from a flow control perspective, microfluidics operates in

an optimal range of scales: small enough to suppress turbulence, and large enough to
smooth out the effect of thermal noise.

4.9 Washburn law and paper microfluidics

4.9.1 Washburn law

A meniscus is pushed in a capillary, as depicted in Fig. 4.55.

4.55: Washburn law. A fluid is pushed

from a reservoir, and fills a capillary.
The zoomed view shows a meniscus
with a contact angle equal to zero.

The reservoir, on the left, is pressurized at pressure P above the atmospheric pressure
P0 . The overpressure ∆P = P − P0 , which drives the fluid in the capillary tube at a
mean speed U , is equal to (see Chapter 3):

r2 ∆P
U= (4.27)
8µ l
 Washburn law and paper microfluidics 213

in which r is the tube radius, µ the fluid viscosity and l(t) the position of the meniscus
dl
in the capillary. Noting that U = dt , and assuming full wetting of the fluid with respect
to the capillary (for instance, oil in glass), one obtains, after integration, the position
of the meniscus in the capillary, at time t.

r
γrt
l(t) = (4.28)
2µ

This is Washburn law [72]23 The square–root law comes from the fact that, as the
meniscus advances, the hydrodynamic resistance of the system increases. In practice,
with liquids like water, and capillary 20 µm in radius, it takes 10 s to push the fluid
8 cm.

The calculation can be generalized to the case where the contact angle between the
fluid and the tube walls, is arbitrary, say θ. In this case, assimilating the meniscus to a
spherical cap, the tube radius r must be replaced by r/cosθ. With this generalization,
we conclude that, for θ > 90◦ , a situation we previously called non wetting’, the
meniscus recedes. Then filling a small tube is possible only if one applies a pressure, at
the tube entry, working against capillarity. For tubes or in a straight microchannels,
this is possible. However, in practice, in geometries with a minimum of complexity,
working with non wetting fluids unavoidably leads to bubble trapping. As we saw in
Chapter 3, these bubbles perturb the functioning of the system considerably. This is
why it is highly preferable to work with wetting fluids, which spontaneously fill or tend
to fill cavities and branched channels, owing to the action of capillarity.

4.9.2 Paper microfluidics

The domain of paper microfluidics was initiated by G. Whitesides [73, 74]. The first
paper–based microfluidic device, developed by his group in 2007, simultaneously de-
tected protein and glucose via colour–change reactions. In paper microfluidics, the
substrate is paper, the motor is capillarity, and the underlying law that controls the
flows is Washburn law. Because paper is inexpensive and widely available, it is possi-
ble to create inexpensive diagnostic devices, reducing health–related cost in general,
along with providing testing accessibility to low–resources countries, which cannot
afford glass or PDMS. The philosophy of paper microfluidics is similar to low–cost
immunoassays, also made in paper. However, with paper microfluidics, it becomes
possible to increase the complexity of the test (for instance, by integrating different
elements on the same device) [75].

Fig. 4.56 shows a scanning electron micrograph (SEM) image of an enlarged part of a
paper sheet.

23 E. W. Washburn established his law date in 1921, but several researchers established it before:
L. Lucas in 1918 and J. M .Bell, F. K. Cameron in 1906. Nonetheless, the name of the law was given
to Washburn.
214 Hydrodynamics of microfluidics 2: droplets

4.56: SEM of Indian print paper surface

with cellulose fibres. Cellulose or cellulosic
fibres are fibres structured from plant cel-
lulose, a starch–like carbohydrate. They
are created by dissolving natural materials
such as cellulose or wood pulp, which are
then regenerated by extrusion and precip-
itation. Magnification: x130 when short-
est axis printed at 25 millimetres. (Science
Photo Library.)

This type of paper comprises pores of 20–50 µm transverse dimensions, which is a

typical range of values for paper, although filtration paper may have much smaller
pores. It is possible to confine liquids inside boundaries by using wax technology [74].
The technology consists in depositing, with a wax printer, wax droplets on one side
of the paper, heating up the sheet at 60◦ C or so, and melting the wax to force it to
cross the paper thickness. In this manner, the wax, which is hydrophobic, forms a
barrier allowing, in a way similarly as in microfluidic channels, aqueous solutions to be
confined in a restricted space, within the paper. Fig. 4.57 shows a fluorescein solution
confined in the tree, without leaks, so that the other parts of the sheet remain dry.

Fig. 4.57: Paper tree, patterned with green ink (grey on the figure), imbibed by a small water
drop, coloured with fluorescein. (Courtesy of L. Magro (MMN, 2010)).

The experiment shows that fluoresceinspeed decreases in time, consistently with Wash-
burn law.
A remarkable feature is that, despite the complexity of the paper matrix, which could
have given birth to a wealth of different regimes24 , Washburn law applies over a broad
range of time and conditions, semi–quantitatively. This was shown by P. Yager et al.
(see Fig.4.58) [76].
In the experiments of Ref. [76], paper sheets are cut in channels of different geometries.
Sheets are dipped in a coloured water bath. Imbibition starts over, and one observes
24 This wealth of regimes appears in the drainage case, i.e. when the fluid is non–wetting with
respect to the paper. We will not discuss them in this book.
 Production of microfluidic droplets and bubbles 215

4.58: Series of experiments

made in the same paper, thus
with the same pore size r, cut
in different forms, showing that
in all cases, Washburn law ap-
plies with the same pre-factor,
which turns out to be close to
the theory (see Ref. [76]) for de-
tails on the relative time s def-
inition. (Reprinted with permis-
sion from [76]. Copyright 2022.
Springer Nature.)

that all water fronts penetrate the channels at the same speed, independently of their
geometries. The observation confirms Washburn’s law, which stipulates that l(t) only
depends on the pore size r, and not on the channel width. Figure 4.58 (right) also
shows that the front dynamics agrees with Washburn law, at a semi–quantitative level,
despite the fact that the paper internal structure, including pores of different sizes,
geometries and spatial organizations, is incomparably more complex than a cylindrical
capillary.

4.10 Production of microfluidic droplets and bubbles

4.10.1 Early experiments

The domain of droplet–based microfluidics took off at the beginning of the twenty–
first century, after precursor experiments (See, for instance, [77, 78]) suggested the
potential of the coupling between droplets and microfluidic technology. In particular
its capacity to produce large numbers of droplets with unprecedented size control.
Among the few pioneering contributions made at that time, two experiments turned
out to be particularly inspiring (see Fig. 4.59).
In S. Quake group’s experiment [79] oil and water meet at a T–junction. Wetting
was perhaps not optimal (this could explain the strange shape of the interface at the
junction). Nonetheless, the experiment showed that large quantities of monodisperse
droplets could be produced under excellent control, either well separated from each
other, or forming regular patterns.25 Another series of experiments, performed in H.
Stone’s lab [81], revealed the same type of phenomena.
25 A curious situation occurred here. The paper was titled ‘Dynamic pattern formation in a vesicle–
generating microfluidic device’. If we consider the usual definition of vesicles (i.e. a lipid layer forming a
topologically closed structure in the same medium), there was not a single vesicle in the experiment.
The author notes that another definition of the word vesicle’, given in Oxford English dictionary,
may be more compatible with the title given to the article: ‘A minute bubble or spherule of liquid or
vapour, esp. one of those composing a cloud or fog’ [80].
216 Hydrodynamics of microfluidics 2: droplets

Fig. 4.59: Two early experiments that prompted the development of droplet–based microflu-
idics.(A) Production of droplets in a T-junction. (Reprinted figure with permission from [79].
Copyright (2022) by the American Physical Society.).(B) Production of droplets in a hydro-
focussing geometry. (Reprinted figure with permission from [81]. Copyright (2022) by the AIP
Publishing.)

The take–off of the domain came soon after, when it was realized that these droplets
could be used as microreactors and material templates, opening new avenues for biol-
ogy, chemistry, and material science.

4.10.2 General behaviours

Although emitter geometries are diverse, it is possible to figure out common be-
haviours, imposed by the hydrodynamical and geometrical constraints all systems
are subjected to. We use Ref. [82] to classify the different cases, adopting the same
vocabulary.

Fig. 4.60: The three basic regimes, omnipresent in microfluidic droplet emitters, as flow
rates are raised up: from left to right, dripping, jetting, and stable co–flow. (Reprinted from
Ref. [82] with permission from IOP Publishing.)

The three basic flow regimes are sketched in Fig. 4.60. They are shown for the case
of flow focusing, but they hold for all emitters. As the flow rates of the phases are
 Production of microfluidic droplets and bubbles 217

increased, we successively have:

1. Dripping regimes. The fluids form droplets where they meet. We shall stick to
this definition, which is slightly different from Ref. [82]. It helps simplifying the
descriptions of the various regimes holding in microfluidic emitters. In such con-
ditions, an excellent control of the droplet characteristics can be reached.
2. Jetting regimes. As speeds increase, the disturbance giving rise to the droplet is
transported downstream. The fluids flow side by side, up to a certain distance,
largely uncontrolled, where a droplet forms. Although interesting from the view-
point of the throughput, this regime is not used for producing droplets, because
of the poor control of the droplet characteristics.
3. Stable co–flow regimes. At higher speeds, fluids flow side by side and no droplet
forms in the device.
As discussed in Ref. [82], these behaviours are general because they all result from
the competition between capillary and shear forces, in contexts where, because of the
confinement, a single characteristic scale emerges. Crudely, at small speeds, capillary
prevails, imposing a formation of the droplet close to the entry, giving rise to dripping
regimes, while at large speeds, transport phenomena come into play, the instability
is transported downstream, which leads to jetting regimes. This naive reasoning may
help us to understand, intuitively, why the sequence of regimes presented above is
so generic. In Ref. [82], general estimates for the cross–overs, expressed as capillary
numbers, between different regimes, are suggested. In practice, geometry must be taken
into account to estimate these numbers.
There can exist sub–regimes, within dripping or jetting regimes, or regimes related to
them, giving rise to rich phase diagrams. However, these subregimes organize them-
selves around the general trends we presented. It is interesting to note that the notions
of dripping and jetting regimes resonate with those of absolute and convective instabil-
ities, which are well–documented in fluid dynamics [83], and for which, depending on
the flow conditions, the perturbation giving rise to the instability (here, the droplets)
grows locally (dripping) or is transported downstream (jetting).

4.10.3 The T–junction

The T–junction represents the most documented geometry. The principle is shown in
Fig. 4.61.
Let us start with the dripping regime (also called shearing’ or ‘squeezing’ regime,
names we do not use herein). A fluid (the continuous phase) is driven along the main
channel (horizontal on the figure), at a flow rate Qc . The other, non miscible, fluid (the
dispersed phase) is driven along the side–channel, at a flow rate Qd . The two fluids
meet at the junction and form droplets. The dripping regime has not received a first
principle–based theoretical analysis, owing to the complexity of the hydrodynamics.
Garstecki et al. [84] proposed a physical model. Schematically, the idea is to divide
the process of formation of the droplet into three steps:
218 Hydrodynamics of microfluidics 2: droplets

Fig. 4.61: Formation of droplets in T-junctions

1. penetration of a tongue into the main channel until obstruction;

2. transportation of the rear interface towards the right–hand corner of the junction;
and
3. break–up at the corner, droplet formation, and return to step 1;
These steps are schematized in Fig 4.62 [84].

Fig. 4.62: The formation of the droplets can be divided into three steps: penetration, advec-
tion, and break–up [84].

Step 1 takes a time τ1 equal to w/Ud to be completed, in which w is the side–channel

width, and Ud = Q w2 is the mean speed of the dispersed phase, called, in the jargon
d

of two–phase flow, superficial speed’. Step 2 takes a time τ2 equal to w/Uc to be

completed, where Uc = Q w2 is the mean speed of the continuous phase. The volume of
c

fluid collected by the droplet, during the two steps is:

Qd
V = Qd (τ1 + τ2 ) = w3 (1 + ) (4.29)
Qc

This is Garstecki’s relation. As usual, corrections are needed to adapt the simple model
to the experiments. The measurements of the droplet lengths as a function of the flow
rates, carried out for channels of square cross–sections [84], could be accurately fitted
by the expression: Lwd ≈ 1 + 2 Q Qc which is exactly the structure of the model. The
d
 Production of microfluidic droplets and bubbles 219

law holds for liquid and gases as well. Since the theory relies on transport only, there
is no evolution of Ld with the capillary number. This is one of the most remarkable
features. With rectangular cross–sections, the structure of the relation remains valid,
but the constants must be changed.

As stated in the preceding section, at larger flow rates, the jetting regime takes place.26
This is shown in Fig. 4.63 (see [82]).

4.63: Jetting regime in T junction: liq-

uids flow side by side and, at some dis-
tance from the junction, they form a
droplet (Reprinted from Ref. [82] with
permission from IOP Publishing.)

The disturbance giving rise to the droplet is transported downstream. At a certain

distance, largely uncontrolled, a droplet forms. As explained above, this regime is
not used for producing droplet, because of the poor control of the droplet formation
mechanism. As speeds are increased further, the droplet forms at larger and larger
distances, and we enter a stable co–flow regime.

Fig. 4.64: Formation of droplets in shallow T–junctions [89].

T–junction in shallow channels. It is tempting to consider shallow geometries, for

which, as explained in Chapter 3, the equations take a much simpler form. This was
done very recently [89]. As compared to square channels, a new regime, called ’tearing
regime’, dominates the system: droplets move along the lower channel side, being, in
the meantime, torn off by the shear developed at the junction (see Fig.4.64)). Further
downstream, the droplet is only weakly distorted. The length Ld of these tears follows
a power law, in the form Lwd ≈ 0.3 ± 0.1Ca−−1/3 , in which w is the channel width,
and Ca is the capillary number, based on the droplet speed and the continuous phase
viscosity. Theoretical analysis [89] provided justifications for this law.

26 In the T–junction, our jetting regime is called ‘dripping’ in Ref. [82]. In the jetting regime, the
droplet forms far from the entry. Therefore, it is preferable not to call it ‘dripping’. Jetting is the
appropriate word because the disturbance is transported downstream before forming a droplet. All
this is somewhat confusing indeed.
220 Hydrodynamics of microfluidics 2: droplets

Phase locking of V–junction emitters. V–junctions are variants to T–junctions. On

Fig 4.65, two V–junctions are placed in parallel, producing alternatively red (shown
in dark grey) and droplets with no dye (shown in white).

4.65: Two V–junctions

placed in parallel, produc-
ing alternated droplets.
(Courtesy of MMN team
(ESPCI)).

The emitters are phase–locked in an out–of–phase regime. When one droplet is pro-
duced in the upper V–junction, no droplet is produced below, and vice versa. The
synchronization of the emitter is stable. It results from the hydrodynamic interactions
building up between the two injectors, leading to resonance phenomena, in a manner
shown, in other contexts, by Refs. [85, 86].

4.10.4 Flow focusing

Flow focusing geometry was discussed in Chapter 3 and its capacity to focalize fluid
streams was underlined. Here, the same geometry is considered, but, this time, for
producing droplets. Now, flow focusing represents the most currently used droplet
emitter. The way in which it functions is shown in Fig. 4.66.

Fig. 4.66: Flow focusing geometry. Droplets of aqueous solutions are produced at 10 kHz in
PFC oil, using Krytox surfactant for working in dewetting conditions. The device material is
PDMS. (Courtesy of O.Caen.)

Oil is injected at the sides, and water at the centre. The organic phase focusses the
aqueous stream in the restriction (see Fig.4.66). The elongated shape of the stream
favours break–up. In such circumstances, droplets form. In the experiment of Fig. 4.66,
the continuous phase is fluorinated oil (PFC). A surfactant (Krytox) is added to the
external phase to force water droplets to dewet the channel walls and avoid pinning
phenomena, as explained earlier.
 Production of microfluidic droplets and bubbles 221

As mentioned in the previous subsection, there exist several regimes. They are shown
in Fig 4.67 [82]. In the dripping regime, break–up of the water stream occurs at the
restriction. At higher flow rates, break–up occurs downstream, marking the advent of
the jetting regime. At higher flow rates, water and oil flow side by side.

4.67: Regimes in the flow focusing ge-

ometry. From bottom to top: dripping,
jetting, and stable co–flow (Reprinted
figure with permission from [87]. Copy-
right (2022) by AIP Publishing.)

Despite its apparent simplicity, there is no general model expressing, for instance, the
droplet sizes as a function of the flow rates, partly because of the many aspect ratios
involved in the problem. Empirically, it is observed that flow focusing gives rise to
substantial, even large, throughputs. Typical frequencies lie in the range 1– 50 kHz,
i.e. more than one order of magnitude higher than the T–junction. This range is typical
for droplets, and, for bubbles, it can reach several MHz (an exemple at 300 kHz, 5
µm bubbles, is shown in Fig. 4.68 [88]). Typical bubble sizes are 10– 200 µm and the
volumes are typically a few picolitres.

4.68: 5 µm in diameter bubbles pro-

duced at 300 kHz in a flow focus-
ing device. (Left) Snapshot of the
production.(Right) Harvested bubbles,
showing excellent monodispersity. [88].
(Courtesy of T. Segers.)

4.10.5 Step emulsification

Using a geometrical rupture to produce droplets in microdevices was demonstrated by

the turn of the century [90] and developed later on by a number of contributors [91,92].
The principle of this technique, called ‘step emulsification’, is shown in Fig. 4.69.

Two immiscible fluids are injected at the entries of a shallow flow focusing geometry
and penetrate in a deeper channel after having passed an abrupt step. As mentioned
previously, in shallow channels, immiscible fluids flow side by side without developing
Rayleigh–Plateau instability. The pair of immiscible fluids thus arrives at the step as
a stable co–flow. At the step, the interface is destabilized, and droplets form.
222 Hydrodynamics of microfluidics 2: droplets

4.69: Geometry of step mulsification. Two

immiscible fluids are injected in a shallow
flow focusing geometry and penetrate in a
deeper channel after having passed the step.

Fig. 4.70: (Left) Step emulsification (top) and balloon (bottom) regimes. (From X. Ge and
Z. Li [94]) (Right) Phase diagram showing the domains of existence of the two regimes. [93]

The mechanism of droplet formation was figured out by Leshansky et al. [93]. Its
description lies beyond the scope of this book. The analysis showed that two regimes
exist (Fig. 4.70): the step emulsification regime, in which droplets (or bubbles) are
produced at the step, and the balloon regime, where the incoming fluids fill the deeper
channel, as if one would inflate a balloon in a cavity. The two regimes represent the
equivalents of the dripping and jetting regimes, respectively. The following formula for
the droplet diameter d, in the step emulsification regime, was established:

 −1
d (1 + k)
≈3 1+ (4.30)
h w/h

in which h is the inlet channel height, w its width, and k = µ1 Q1 /µ1 Q1 , where µ and
Q stand for fluid viscosity and flow rates, and 1 and 2 for the dispersed and continuous
phases, respectively.
In practice, d/h lies in the range 3 – 5. We will see, in Chapter 7, that there is not
much difficulty microfabricating channel heights ranging from 500 nm to 200 µm.
 Production of microfluidic droplets and bubbles 223

4.71: Droplets of 33, 2, and 0.4 fem-

tolitres (i.e. 4, 1.5, and 0.9 µm in di-
ameter respectively), obtained with
the step emulsification emitter. The
smallest size obtained in the experi-
ment is 900 nm in diameter [91]. The
world record is 400 nm [95].

As demonstrated in Fig 4.71 [91], forming submicrometric droplets, i.e. femtoliter

droplets, is therefore feasible with the step emulsion emitter. In this category, the
world record is, at the time of writing, 400 nm in diameter [95]. Step emulsification
is moreover favourable for the obtention of large throughputs, for dynamical reasons
(the large depth of the collecting channel, just after the step, associated to a small
hydrodynamic resistance, facilitates the application of large flow rates). Frequencies
in the range 10–100 kHz are common for this type of system. Double emulsions have
also been obtained, with three different fluids [91], and, very recently, with extra–thin
shells [96].

4.10.6 Producing droplets in glass capillaries

Fig. 4.72: Schematic of a co–flow microcapillary device for making droplets. Arrows indicate
the flow direction of fluids and droplets.

An unconventional approach emerged in 2005 [96]. The device was microfluidic, in the
sense that microfluidics manipulates fluids in small volumes, but, unlike the preceding
devices, it did not use any microfabrication technique. The geometry is shown in Fig.
4.72. The internal cross–section of the large capillary tube is square. The design thus
centers the smaller tube in the larger one, with a precision of 50 – 100 µm or so.
Fluids are injected in the two capillaries, and meet at the end of the smaller one,
forming a co–flow that destabilizes into a droplet stream. The technology is suitable
for producing submillimetric droplets (i.e. above 50 µm), at moderate throughputs (10
–100 Hz). Even though manual skills are needed to operate it, glass capillary technology
is attractive, because it does not require any clean room equipment. Important to note,
since each tube has its own wettability, complex multiple emulsions can be produced
much more easily than in microfabricated channels.
224 Hydrodynamics of microfluidics 2: droplets

Fig. 4.73: A – Different flow regimes. From top to bottom: dripping, jettting and ’balloon’
regimes (not described here); B – Comparison between theory [69] and experiment: grey
points: dripping (experiment); black points: jetting (experiment); the full line is the theory
(reprinted from [69] with permission of American Physical Society. Copyright 2022.

Different flow regimes exist, as shown in Fig. 4.73(A). From top to bottom, the dripping
regime, jetting regime, and, at larger flow rates, a balloon regime. An analytical theory,
based on a number of approximations, succeeded to describe the onset of droplet
formation, along with the transition between the dripping and jetting regimes [69].
This is the only case where microfluidic droplet formation is described analytically. The
formulas for the growth rate of the perturbations are complicate and not particularly
inspiring, and it is out of the scope of this book to present them. A comparison between
theory and experiment is shown in Fig. 4.73. The frontier, between the dripping and
jetting regimes, takes the form of an inverted L, indicating that flow rate increases
of any of the two liquids brings us outside the dripping regime. Agreement between
theory and experiment is excellent. From a practical perspective, it is noteworthy that
the most interesting regimes for droplet production (dripping regime) occupies a broad
space, extending over roughly two orders of magnitudes in flow rates.

4.10.7 Other methods of droplet production

Since 2000, several methods of droplet production have been invented and there is
not enough space here to review them. We mention here a technique, that exploits a
gradient of confinement along the flow. We already discussed the effect of a gradient
of confinement when discussing bird drinking. This gradient induces a pressure drop,
which drives the droplet into the throat of the animal. In the droplet emitter we discuss
here, the same physics is at work. The system is shown in Fig. 4.74 [99].
The dispersed phase is pushed through the inlet channel into a reservoir, whose top
wall is inclined, with respect to the floor. A capillary pressure drop, generated by
 Characteristics of microfluidic droplets and bubbles 225

Fig. 4.74: (A) Sketch of the droplet emitter. The dispersed phase is pushed through the
inlet channel into a reservoir, whose top wall is inclined with respect to the floor. (B) The
capillary pressure drop, generated by the inclination, drives the flow and produces break–up.
(Reprinted from [99] with permission of PNAS. Copyright 2022.)

the inclination, drives the dispersed phase into the continuous phase, and, for subtle
reasons explained in Ref. [99], produces break–up, giving rise to a droplet. With this
mechanism, no pressure source is needed to produce droplets.

4.11 Characteristics of microfluidic droplets and bubbles

4.11.1 Obstructing and non–obstructing droplets

The structures that can be produced, in typical microfluidic conditions, are droplets
or bubbles in a liquid phase. We recall here a question of vocabulary: droplets are
liquid and bubbles are gaseous, notions that are often mixed up by beginners.
Bubbles and droplets are most often treated in the same manner. Nonetheless, in a
limited number of situations, a distinction is made between droplets and bubbles that
takes into account gas compressibility (negligible in droplets), or internal pressure
drops (negligible in bubbles).
In typical microfluidic conditions, it is impossible to envisage droplets as the dispersed
phase, and gas as the continuous one.The reason is related to wetting. A droplet
confined in a microfluidic channel, moving in a gas flux, would be unstable. Should
the droplet touch the wall, it would immediately stick to it. As explained earlier, in
solid–liquid–gas systems, the droplet never dewets the wall. In such circumstances,
after the droplet has touched the surface the contact line sticks to it. Entrained by
the flow, the structure moves downstream, in an erratic and uncontrolled manner, in
a way similar to that shown in Fig. 4.43. No stable droplet could be formed in such
conditions. Indeed, at very large speeds, the droplet may detach and return to the
flux. However, this situation is not representative of microfluidic conditions.
This being said, Fig. 4.75 shows the two types of droplets or bubbles that can be pro-
duced, in a stable manner, in microfluidic channels: they are either ‘non–obstructing’
or ‘obstructing’. As just noted, they can be droplets or bubbles, but in all cases, they
are immersed in a liquid. In the non–obstructing case, the droplet (or bubble) size is
226 Hydrodynamics of microfluidics 2: droplets

smaller than the channel transverse dimensions. In this case, the droplet is spherical; it
travels downstream, at an uncontrolled distance from the walls and a poorly controlled
speed, because its velocity depends on its distance from the walls.

Fig. 4.75: Non obstructing and obstructing microfluidic droplets

The other case (obstructing) is more interesting, from the viewpoint of control: the
droplet position with respect to the walls is fully controlled, along with its speed, fixed
by the flow rate. The three–dimensional structure of such a droplet (or bubble) was
established in the 1990s [100]. It is shown in Fig. 4.76.
In Ref. [100], the bubble is at rest. The front and the rear form a nose which is almost
spherical. At the channel corners, gutters form, leaving a small – but often dynamically
important – space filled with the continuous phase. The bubble is separated from the
walls by a thin film, whose shape and thickness evolves slowly over time. This film
is composed of a dome at the centre and a convex film closer to the gutters, both
evolving extremely slowly over time, due to the action of capillarity.
How can we understand the structure of this bubble? Again, by invoking Laplace’s law.
The bubble is pressurized, because of the curvature at the nose and at the corners.
At the nose, assuming a spherical shape, the internal overpressure is ≈ 4γ h , in which
γ is the surface or interfacial tension and h is the height of the square cross–section
of the channel. To ensure mechanical equilibrium, the pressure in the bubble must be
homogeneous. This implies that the curvature radius r of the interface at the corners

4.76: Most frequently used type

of droplet : the obstructing
droplet
 Characteristics of microfluidic droplets and bubbles 227

should be ≈ h4 . With such a curvature, and in the case where the liquid fully wets the
solid, the meniscus matches the wall, or the film at a distance ≈ h/2 from the channel
mid–plane. The corresponding bubble shape is shown in Fig. 4.76.27 The corner region,
outside the bubble is called gutter’. It sometimes plays a role in the bubble dynamics.
The arguments given here also apply for droplets.

4.11.2 The excellent monodispersity of microfluidic droplets

A striking feature of microfluidic droplets is their high monodispersity. Millions of

droplets per hour, departing only slightly from their mean sizes, are currently produced
in microdevices. An example is shown in Fig. 4.77 [102].

Fig. 4.77: monodispersity of microfluidic droplets. (Left) Typical oil in water droplet popula-
tion obtained in microfluidic devices. (Right) Typical size distribution of microfluidic droplets
(dodecane in water). In this case, the mean value is 26.6 µm and the standard deviation is
around 1.5% [102].

Typical standard deviations of droplet sizes are less than 5%. This small number
reflects the excellent control of the hydrodynamic flows in microfluidic systems. The
break–up process, like all instabilities, is triggered by noise, which can be a source of
polydispersity. However, this noise concerns only the ultimate times preceding break–
up, when the structure of the droplet is already established. Consequently, it does not
impact the characteristics or the droplet that is emitted.
Monodispersity and high throughput are critical for applications. For example, millions
of identical reactors, where reactions take place under the same conditions, can be
created, enabling massive screening. Another example concerns the production of solid
particles with uniform properties, as shown in Fig. 4.78.
Most often, industrial emulsions are highly polydisperse. An example is shown in Fig.
4.79.
Broad size distributions, 100 % or more, are common. When comparing microfluidic
to standard emulsions, the question that is most often raised concerns the throughput.
27 If the liquid partially wets the solid, the meniscus must find a shape that satisfies Young Equation
and pressure homogeneity condition
228 Hydrodynamics of microfluidics 2: droplets

Fig. 4.78: Optical microscopy images of polyTPGDA particles: (A) microspheres, (B) crystal
of microspheres, (C) rods, (D) disks, and (E) ellipsoids. Optical microscopy images of (F)
agarose disks and (G) bismuth alloy ellipsoids produced using thermal solidification; inset:
micrograph of the bismuth alloy ellipsoids at higher magnification. (Reprinted from [101] with
permission of John Wiley and Sons. Copyright 2022.)

Fig. 4.79: A typical emulsion produced in the industry, showing a large polydispersity, with
typical standard type deviations on the order of 100%. (Reprinted from [103] with permission
of John Wiley and Sons. Copyright 2022.)

Producing thousands of droplets per seconds, hundreds of micrometres in diameter,

leads to a mass production of, roughly, 30 kg per year, while industry currently pro-
duces tons in the same period of time. The gap seems large, but one must emphasize
that progress is made on parallelization. Sometimes, the fabrication of complex, frag-
ile, objects needs microfluidics or millifluidics to be produced. This is the case of the
lipid nano particles (LPN) involved in the COVID vaccine, which must be produced
in huge quantities. Today, use is made of millifluidic technology. We may envision that
micro or millifluidic technology will progressively compete with traditional emulsion
techniques, even in domains currently inaccessible to them.
 Characteristics of microfluidic droplets and bubbles 229

4.11.3 How fast obstructing droplets move ?

The behaviour of obstructing droplets is surprising: in cylindrical tubes and in 2D,

they move faster than the mean flow, while in square channels, it is the opposite. How
can we understand this behaviour?

4.80: 2D calculation, showing

the evolution of the relative
speed excess X = (U − −V )/U ,
where U the droplet speed and
V the mean flow speed, versus
the capillary number, for differ-
ent viscosity ratios .(Reprinted
from [104] with permission from
the American Physical Society.
Copyright 2022.)

Let us start with Fig. 4.80, which shows numerical results obtained in a 2D geometry
[104], representative, for the problem we address, of the cylindrical geometry, i.e. the
geometry of the tube. In this case, the droplet speed U is larger than the mean flow
V and its expression is given by:

U = V (1 + βCa1/3 ) (4.31)

in which Ca = µU γ is the capillary number, and β is a coefficient depending on the

viscosity ratio between the disperse and the continuous phase. Gas bubbles slide at
faster speed than viscous droplets. The excess speed, U − −V , is substantially above
the mean velocity. The phenomenon can be explained by invoking mass conservation:
as the fluids are incompressible, the volumetric flow rate is conserved along the chan-
nel. Far from thee droplet, and in 2D, it is V h (with h the channel height) while at the
droplet level, it is U (h − −2δ) considering that the drained film, of thickness δ, is prac-
tically at rest. This quantity can be calculated, using the law we established earlier for
the Landau–Levich film. We have δ ∼ Ca1/3 . By applying flow rate conservation, and
proceeding to a development at small Ca, one obtains the observed relation between
U and V . The origin of the excess speed is thus related to the presence of a Bretherton
film at rest.
In square microchannels, the presence of gutters, at the corners, not taken into account
in the previous reasoning, inverts the conclusion. These gutters act as resistances
placed in parallel with the bubble. This resistance is much lower than the Bretherton
film. The consequences are important: Wong et al. [107] showed that at small capillary
230 Hydrodynamics of microfluidics 2: droplets

numbers, and for moderate lengths, bubble speeds are on the order of V Ca1/3 , i.e.
significantly below the mean flow speed V .

4.11.4 Internal mixing of microfluidic droplets

As droplets move downstream, they generate internal recirculations [108, 109]. This is
shown in Fig. 4.81:

Fig. 4.81: (A) Numerical simulation of the recirculations developing inside and outside the
droplet, in its own frame of reference, as it moves rightwards in a square microchannel.
(Reprinted from [109] with permission of John Wiley and Sons. Copyright 2022.) (B) Visual-
ization, with rhodamine initially introduced in droplets, of the recirculations. External phase
is octanol and dispersed phase (droplets) is water [110].

The origin of the recirculations is purely kinematical. In the frame of reference of

the droplet, walls move in the opposite direction, all around. These walls entrain the
fluids and give rise to the internal recirculations shown in the figure. Depending on the
aspect ratio of the channel cross–section, the speed, the droplet can include different
numbers of eddies. In Fig. 4.81, four eddies are shown.
Those recirculations are extremely important for the applications. The eddies mix the
fluids contained in the droplets. Being purely kinematical, they do not depend on thee
physico–chemistry of the system, and therefore are robust. They are vigorous. Their
turn–over time is typically h/U , in which h is the channel height and U the droplet
speed. A droplet moving at U = 1 mm/s, in a channel of 100µm high, will produce
a recirculation time of 0.1 s, which is comparable to the best conventional (i.e. non
microfluidic) mixers. If two reactants are present in the droplet, a homogeneous reac-
tion can take place, in a fast time. This property, coupled to others (monodispersity,
throughput) opened, for microfluidics, avenues in the fields of chemistry and biology.

4.11.5 Large pressure drops generated in channels by microfluidic

droplets or bubbles

As droplets or bubbles circulate in microchannels, they develop a pressure field. A

counter–intuitive result is that in typical microfluidic conditions (i.e. small Reynolds
numbers, small capillary numbers), even though droplets occupy a small fraction of
the channel, however small the viscosity can be (e.g. gas for bubbles), the pressure
 Characteristics of microfluidic droplets and bubbles 231

∆Pplug ∆Pdrop ∆Pplug ∆Pdrop ∆Pplug

P
λ~1

4.82: Pressure drops induced

by droplets along a microchan-
nel (from [65]).

drop induced by them dominates the other contributions. In other words, the cost, in
terms of pressure, of driving droplets or bubbles in microchannels is high. This feature
was analysed in [106] and reviewed in [65]. It is represented in Fig. 4.82.
The pressure decreases downstream, as in any channel, but in a complicated manner.
In between the two droplets, the pressure ∆Pc (c for continuous) decreases linearly,
at a rate controlled by the hydrodynamic resistance of the channel. The same remark
holds for ∆Pd , the pressure drop inside the droplets (d for the interior of the dispersed
phase). Droplets move over a Bretherton film, which is at rest. Figure 4.82 shows that
between the film and the droplet nose regions, there is a sudden pressure change. This
feature was discussed earler. We saw that the pressure drop ∆Pi (i for interface) is on
the order of hγ Ca2/3 . It is positive in the rear of the droplet and negative at the front.
Should the droplet be perfectly symmetric, these pressure jumps would add up and
cancel each other. But they are not. The interface at the front is distorted differently
than in the rear, for subtle reasons discussed in Ref. [62]. Eventually, the imbalance
between the front and the rear cause a net pressure drop.
All this can be quantified in terms of order of magnitude. Let us take the case of a
channel of length L including one bubble of length Ld , so that the remaining channel
length is Lc = L − −Li (see Fig. 4.82). The expression of the pressure drop along the
channel reads:

∆P = ∆Pc + ∆Pi (4.32)

in which we put ∆Pd = 0, because here, we consider a bubble. The two terms can be
developed:

γ 2/3
∆P = Rc Q + Ca (4.33)
h

where Rc is the resistance of the continuous phase and Ca = µU γ is the capillary

number. In Eq. 4.34, for the sake of simplicity, we assume that the coefficient in front
of the interfacial contribution is unity. Rc was established in Chapter 3. Its expression
reads, without considering the pre-factor, Rc ∼ µL h4 . Eq. 4.34 can be rewritten in the
c

following manner:
232 Hydrodynamics of microfluidics 2: droplets

µU Lc
∆P ∼ ( + Ca−−1/3 ) (4.34)
h h

With capillary numbers on the order of 10−−6 , one sees that, for channels where
Lc
h is a few units, the interfacial contribution dominates the pressure drop. In other
words, we need a channel length one hundred times its height to overcome the bubble
contribution. The conclusion that we can draw from this order of magnitude analysis
is that, in general, pressure drops are dominated by the droplets contributions.28

Boolean algebra with droplet microfluidics. An amazing application of droplet–based

microfluidics is Boolean algebra [111]. The principle is shown in Fig. 4.83.

4.83: Boolean algebra

with droplet microflu-
idics (see text)

Let us examine Fig. 4.83 (right). Assume a bubble comes from the left, entry A, i.e.
A = 1 and B = 0. The bubble will join outlet A+B, because the channel is wider, and
therefore its resistance is smaller. We thus confirm that this outlet is A + B (0 + 1 = 1)
and the other is A ∗ B, because, in this case is 0 ∗ 1 = 0. The same reasoning for the
case where a bubble is introduced at entry B, i.e. A = 0 and B = 1. Now, assume that
A = 1 and B = 1; In this case, the two bubbles are just behind each other. The first
will join the outlet A + B. However, by doing this, it increases the resistance of the
channel, as we saw previously. Consequently, the second droplet will joint the outlet
A ∗ B. We show, then, that the device works as a Boolean operator, as summarized in
Fig 4.83 (left).

4.11.6 How do droplets break up?

In the first years of the development of droplet microfluidics, i.e. at the beginning of
this century, investigators desired to build up a toolbox that would include all the
operations needed to manipulate droplets. One operation that came to their attention
was droplet break–up. But how can this be done? At first sight, this seems impossible.
Small pearls at the dew are very difficult to break up. So, how could it be possible
to break up even smaller droplets? How to reproduce the Grace break–up conditions,

28 The analysis made here neglects the gutters, which, as we saw earlier, may play a substantial
role. For short bubbles, the gutters tend to reduce the bubble speed, and,consequently the pressure
drop induced by them. However, this effect tends to become negligible in long bubbles.
 Characteristics of microfluidic droplets and bubbles 233

which require capillary numbers on the order of unity, impossible to achieve in mi-
crofluidic devices? In fact, in microfluidics, droplets break up in many circumstances.
So, how to explain this feature?

The simplest geometry in which the problem can be addressed is the T–bifurcation
(see Fig.4.84) [112]:

Fig. 4.84: Droplet break–up in a T-bifurcation. (Top) Typical situation at small flow rates:
no break–up.(Bottom) Typical situation at large flow rates: breakup [112].

A water droplet is driven along a channel and arrives at a T–bifurcation. At small flow
rates (see Fig.4.84 (top)), the droplet elongates and takes the shape of a dumbbell.
This dumbbell is symmetric. The dumbbell stays there for some time, a few seconds or
so, and, suddenly, it looses its symmetry, moves on the left branch, adopts an oblong
shape, and is evacuated by the flow. At larger flow rates (see Fig.4.84 (bottom)), the
sequence of events is different: as previously, a dumbbell forms in the junction, but,
instead of adopting a stationary shape, it keeps elongating and eventually breaks up,
forming two daughters that further on, are advected downstream.

Why is it so? The answer was given by A. Leshansky and L. Pismen [113].

4.85: Sketch of a droplet arrived at the T–

junction. A thin Bretherton film confined be-
tween the droplet bulges and the walls con-
trols the dynamics of the system
234 Hydrodynamics of microfluidics 2: droplets

The analysis relied on the presence of Bretherton films, confined between the bulges
and the lateral walls (see Fig.4.85).29 In this geometry, when the speed U is im-
posed, the flow is forced to pass through small gaps. Large viscous stresses develop,
which, above a critical speed, entrain the bulge downstream. In such circumstances,
the droplet elongates and eventually breaks up. This explains why droplet break–up
occurs in microfluidic devices even though the capillary number is small. The paradox
is thus solved. In Ref. [113], it was shown that, when l/w >∼ Ca0.2 (where l is the
droplet length, w is the channel width, and Ca is calculated by using U , w and the
interfacial tension), break-up occurs.
The T–bifurcation can be asymmetric, as in Fig. 4.86 (see Ref. [117], from which the
image is taken).

4.86: Non–symmetric T–bifurcation, gen-

erating small droplets. The size reduction
can be increased by placing several T–
bifurcations in cascade [114]. The process
is limited by the lithographic resolution. In
practice, the smallest droplet size obtainable
with such a process is a few micrometres

By placing several T–bifurcations in cascade, smaller and smaller droplets can be

produced [114]. However, the smallest size is limited by the smallest channel that can
be made, i.e. by the lithographic resolution – in practice, several micrometres –.

4.11.7 Coalescence of microfluidic droplets

Physics of coalescence. Droplet merging or coalescence has been studied for decades
[67,115]. Today, although considerable progress has been made, questions remain. It is
difficult to describe the various regimes occurring at the early times of the coalescence
process. Even more difficult is the incorporation, in the analysis, of a surfactant. It
is challenging to carry out experimental studies, owing to the fast times and small
scales involved, along with numerical simulations, due to the multiscale nature of the
problem. We shall thus restrict ourselves to basic ideas.
We learned that surfactants control wettability. We will see here that they also stabilize
the droplets. The stabilization mechanism is shown in Fig. 4.87.
Surfactants prevent coalescence by raising electrostatic and steric barriers. Therefore,
to merge two droplets, holes must be made in the surfactant layers. This is precisely
what happens when two droplets approach. As sketched in Fig. 4.87, the displacement
generates a recirculating flow that tends to deplete the surfactant concentration locally.
The surfactant film is drained by the flow, fresh surface is created, and again, due to
energy minimization, coalescence may occur. However, Marangoni effect counteracts
the process by swiftly rehomogenizing the surfactant at the interface, in a manner
29 The idea was new: previous studies overlooked the role of the Bretherton film [114].
 Characteristics of microfluidic droplets and bubbles 235

4.87: In an infinite medium, when two

droplets approach, they generate a flow that
tends to deplete the surfactant in the contact
region, thus exposing fresh surfaces. How-
ever, Marangoni stresses counteracts this
effect, generating flows that prevents coa-
lescence (adapted from [23]). In microflu-
idic systems, these flows are damped by the
walls. Therefore, conditions for obtaining co-
alescence are easier to achieve.

similar to the pepper experiment. This is, in short, the mechanism invoked in reviews
and books to explain that emulsions are stabilized by surfactants (see, for instance,
Ref. [23]). So, how droplets can be coalesced in microfluidic systems, in which, most
often, surfactants are present? This looks difficult.

The answer is that in microfluidic channels, confinement inhibits the Marangoni restor-
ing mechanism. No large flows can develop, and we are left with diffusion for rehomog-
enizing the surfactant at the droplet interface. A reasoning, presented in Ref. [116],
allows to characterize the dynamics of the process: to fill a fresh interface, just de-
pleted in surfactant, one must recruit the molecules located around it. Their bulk
concentration is cs while, at the interface, at saturation, the area per molecule is as .
The size l of the recruitment volume is then l ∼ (as cs )−1 . In typical conditions, well
l2
above CMC, this length is tens of micrometres. The diffusive time τ = D , in which
D is the diffusion coefficient of the surfactant, will thus be τ ≈ 1 s. Therefore, if the
droplet approach process is faster than this time, coalescence has a chance to occur.
With such times, one may conclude that coalescence is possible. One must nonetheless
add that flow transport, due to the presence of local pressure differences, induced by
shape change, may also play a role. The conclusion is that we have, at the moment,
a qualitative picture of the coalescence process, which helps in the design of devices
dedicated to this task, but no comprehensive description.

Microfluidic strategies for coalescing droplets. In practice, the strategies used for
coalescing droplets consist of forcing them to collide in constrictions, openings, or
combs. The various solutions proposed in the literature were reviewed by Seeman et
al. [117], from which Fig. 4.88 and its caption are sourced.

A practical remark should be made here: the strategies shown in Fig. 4.88 are some-
times difficult to integrate in a device because they perturb the pressure field, the
flow conditions and, sometimes, need fine tuning to operate efficiently. Therefore, in
a number of cases, in order to circumvent these difficulties, electric fields are used for
achieving merging (an example is Ref. [119]). We will return to this subject in Chapter
6.
236 Hydrodynamics of microfluidics 2: droplets

Fig. 4.88: Schematic of different geometries to coalesce droplets by (A) stopping a droplet
at a narrowed channel, (B) stopping a droplet in a widened channel, (C) slowing down the
drop movement in a widening channel, (D) slowing down a droplet in a comb geometry, and
(E) slowing down a droplet by a controlled bypass. (From [117].)

4.11.8 Microfluidic multiple emulsions

Double emulsions (one droplet engulfed in another one, often called a globule’), are a
century–old subject. The domain is involved in many industrial applications, and the
reader may refer to [120, 121] for general presentations. Here, we define two types of
double emulsions: (i) with three different liquids, and (ii) with two different liquids
(oil and water).

(i) Double emulsions with three different liquids. When three different immiscible
liquids are put together, they spontaneously form structures. The structures can be
Janus, separated droplets or double droplest (see Fig.4.89).

4.89: Janus, separated

droplets, or double droplet.

These structures are controlled by spreading coefficients [120–122]. In the domain of

microfluidics, the first double emulsions appeared soon after droplet–based microflu-
idics took off. One example is shown in Fig. 4.90 (A).
In the experiment of Ref. [122], TPGDA, tetradecane and water/SDS are used. The
channels are hydrophilic. The system was stable because TPGDA wets the walls
more than tetradecane and, further downstream, water/SDS wets the walls more than
TPDGA. Moreover, for the tetradecane/TPGDA/water system, double droplets rep-
resent an energetically favourable state.
 Characteristics of microfluidic droplets and bubbles 237

Fig. 4.90: (A) Tetradecane droplets in TPGDA are produced at the first junction. At the
second junction, water/SDS engulfs the droplets. The structure further moves into a reser-
voir [122].(B) Water/oil/water (W/O/W) double emulsion produced in the step emulsion
geometry [96]

(ii) O/W/O and W/O/W emulsions. The second type of double emulsion uses only
two fluids: oil, or, more generally, a lipophilic phase, and water. An example is an
oil droplet engulfed in a water droplet, in an oil medium (O/W/O emulsions) or the
opposite, i.e. water encapsulated in oil, in water (W/O/W emulsions). These double
droplets are metastable (the lowest energy state would be an oil or a water droplet).
They survive because they are stabilized by surfactants, as previously noted.

Let us now revisit the strategy of Fig. 4.90. To fabricate a W/O/W emulsion (water
in oil in water), a water droplet in oil must first be created. Further downstream, the
droplet must be encapsulated in an oil droplet, immersed in water. The problem is that,
in the upstream part, water droplets must circulate in hydrophobic channels, other-
wise they are unstable, while, downstream, the oil droplet engulfing the water droplet
must circulate in hydrophilic channels, for exactly the same reason. The conclusion is
that wetttability must be patterned inside the device to operate in stable conditions.
Today, wettability patterning remains challenging despite a number of efforts (see, for
instance, Ref. [124]). This is one of the bottlenecks that today, microfluidic technology
is facing. These difficulties could be circumvented in Ref. [96] by transporting the three
fluids in a co–flow regime at high speeds, in order to reduce the detrimental effect of
inappropriate wetting conditions (see Fig.4.90 B).

With glass capillary technology, there is no difficulty to solve the wettability problem,
by using bare glass in hydrophilic regions and silanized glass in hydrophobic zones.
Moreover, droplets are formed in the center of the capillaries and they do not touch
the walls. This prevents complications from arising close to the nozzles. These features
considerably facilitate the creation of multiple emulsions. D. Weitz’s group succeeded,
in this manner, by using combinations of tubes of different wettabilities, to produce
impressive multiple emulsions [123]. An example is shown in Fig. 4.91.
238 Hydrodynamics of microfluidics 2: droplets

Fig. 4.91: Fabrication of triple emulsions in a capillary device. (A) Schematic of the device.
(B)–(D) Optical micrographs taken with a high–speed camera displaying the (B) first, (C)
second, and (D) third emulsification stages. (E) Optical micrographs of triple emulsions that
contain a controlled number of inner and middle droplets [123].(Reproduced with permission
of Wiley and Sons (2007).)

4.11.9 The microfluidic droplet toolbox

We saw that droplets can be used as microreactors, and these reactors can be manip-
ulated in a number of ways: for instance, droplets can be split or merged, or put at
rest to serve as micro–incubators or storage units, awaiting further processing. One
may imagine a tool box, which gathers all droplet functionalities, and provides bricks
for building miniaturized chemical factories, capable of running complex chemical or
biochemical processes in a continuous and automatized manner. An example of such
a toolbox, imagined by Ref. [125], is shown in Fig. 4.92.

In the tool box, we have: coalescence, generation, mixing, storage, detection, sorting,
re–injection, splitting, and off–chip incubation. To this list, one may add droplet con-
tent modification, in which a reagent is added in the droplet (this will be explained
in Chapter 6), diluting, heating (e.g. for polymerization), or thermal cycling (for am-
plifying DNA, using PCR). The list is long; therefore, in principle, a high level of
complexity can be achieved by assembling these functionalities in the manner of Lego,
as suggested by Fig. 4.92.
 Characteristics of microfluidic droplets and bubbles 239

Fig. 4.92: Droplet microfluidic toolbox: coalescence, generation, mixing, storage, detection,
sorting, re–injection, splitting, and off–chip incubation. (Reprinted from Ref. [125], under
Creative Commons licence 4.0.)

In practice, so far, the number of functionalities that have been successfully integrated
on the same device has remained limited. This is because, as the device becomes more
complex, it is increasingly difficult to control its behaviour. Unlike with electronics, all
elements are coupled to the others, via the pressure field, which propagates hydrody-
namic perturbations across the system at the speed of sound. Local pressure changes,
for instance, due to the formation of a new droplet at a T-junction, are felt every-
where in the device. This fact, inherent to hydrodynamics, represents a bottleneck tor
integrating a large number functionalities. Although the number of fluidic operations
that can be integrated on a single device is limited, the capacity of performing com-
plex operations in microfluidic droplets remains considerable, so that, over the years,
droplet–based microfluidics has become a major component of the field, as shown in
Chapter 1.
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5
Transport in microfluidics

5.1 The microscopic origin of diffusion

5.1.1 Brownian motion

The idea that diffusion of small objects in liquids results from numerous collisions
with molecules’ was expressed by Robert Brown in 18271 [1]. He noticed that pollen
grains do not stay immobile on the surface of water, but undergo spontaneous erratic
movements, as in Fig. 5.1. After having thought that this could be the expression of life,
Brown hypothesized that the origin of the phenomenon was due to collisions between
pollen grains and extremely small particles that he called ‘molecules’. This was an
important step, because his work allowed, for the first time, a bridge to be established
between the molecular structure of matter and a macroscopic phenomenon. Brown’s
experiment generated passionate discussions for more than a century.

The theory of molecular diffusion, anticipated by Brown, was established 180 years
later, by Einstein [4], Langevin [5], and Smoluchowski [6].2 Soon after, in 1909, Perrin
[3] confirmed the theory, also reporting the first estimate of the Avogadro number
(Fig. 5.1).

5.1: Trajectories of particles ob-

tained in Perrin’s experiment (1909)
[3].

1 Credit for the discovery of Brownian motion should probably be given to dutch doctor Jan
Ingenhousz: in 1785, he noticed the erratic movement of charcoal powder on the surface of an alcoholic
solution. Concerning the notion of molecules, it traces back to Lucrece (see a discussion by Y. Pomeau
and J. Piasecki [2]).
2 The work of Sutherland [7], performed at the same time, is commented in [2].
246 Transport in microfluidics

To develop an intuitive understanding of the phenomenon, let us consider a walker on

a line, taking steps of length ±l in a random manner, like a drunken sailor who decides
to pay a visit to the bars on his street, starting from home X = 0 at t = 0, where t is
time (see Fig. 5.2). Assume the bars are distributed homogeneously along the street
and the drunkard has no memory of what he did before. We also assume that he walks
at a constant speed V and the time for which he stops in the bars is negligible, being
invited to leave the establishments promptly (Fig. 5.2).

5.2: Brownian walker performing random

steps of lengths l, along a line.

A Brownian walker like this occupies a position X(N ) that is equal to the sum of the
N steps that it has made:
XN
X(N ) = li
1

where li is a random variable that can take two values: +l or −l. Over time, the
drunkard seems barely to depart from the home position X = 0, because he walks,
with equal probabilities, on the right and on the left. Still, over time, he explores
larger and larger distances, given by the variance of X, i.e. the sum of the squared
displacements. We have :

N
X
X 2 (N ) = li2 = N l2
1

Since N ≈ V t/l, we have:

X 2 (N ) ≈ 2Dt
where D = 21 V l is the diffusion coefficient . The result is important: it shows that the
drunkard is governed by a diffusive law.
Now, suppose that the drunkard has many colleagues, who decide to visit the same
bars, but in an uncorrelated manner, i.e. without being influenced by each other.
How can we describe their distribution along the line ? Said differently, how can we
calculate p(X, t), the distribution of distances travelled by the walkers ? This is where
a fundamental statistical theorem comes into play: the central limit theorem, which
stipulates that at late times, the spatial distribution of the walkers is Gaussian. For
a spot of dye initially injected in a fluid at rest, this signifies that at long times, the
concentration field of the dye adopts a Gaussian profile. Later, we will establish the
same result in a different manner.
With such populations of walkers, Fick’s law, i.e. proportionality between matter flux
and concentration gradients, can be demonstrated. Take N walkers located on the
same site, and assume that the next site, located on their right, is empty. Half of the
 The microscopic origin of diffusion 247

population will move to the empty site, so that the flux J, defined as the number of
walkers that jump to the empty site per unit of time, will be:
1
J= NV
2
On the other hand the gradient of walker number G is −N/l. With D = 12 V l, we have:

J = −DG

which is Fick’s law3 .

5.1.2 Normal and anomalous diffusion

The notion of anomalous diffusion

The limits of the preceding theory, called ‘normal diffusion’, were discussed by Levy in
the 1930s [8,9] (see the review by JP. Bouchaud and A. Georges [10]). Normal diffusion
assumes the absence of correlations between the walker jumps, and narrow distribu-
tions of their characteristics (for instance, step lengths, or waiting times between two
successive steps). However, in a number of cases, such assumptions do not hold. Take
a traveller who walks to the taxi station, reaches the airport by car, takes a flight
from Paris to Chicago, then takes another taxi and, eventually, reaches the hotel by
walking to the lobby. The total travelled distance, which is the sum of all the steps
he made, is dominated by one single event: the flight. We could neglect the others,
this will not change the result significantly. The example illustrates the case where
the distribution of the walker’s steps is broad. In such cases, averaged quantities are
dominated by a few large events. In the example of the preceding section, the step
distribution was narrow and averages result from the contributions of many events.
The existence of broad distributions may completely change the statistical behaviour
of the system, leading to ’anomalous’ diffusion. In anomalous diffusions,
√ the central
limit theorem no longer applies and walkers do not disperse as t, but in a different
manner, no longer universal, but dependent on the particular process at work. This
is not just abstraction. Many physical situations, relevant to microfluidics, involve
anomalous diffusion.
Hyperdiffusion in the presence of a shear
An important case of anomalous diffusion is hyperdiffusion. A model is shown in Fig.
5.3.
The walker moves in a 2D space, in the presence of a shear flow U (y) = γy, where U
is the flow component along x. Let us assume that it makes leaps in the y direction,
and, in the meantime, is transported in the x direction by the shear flow . We have
here a coupling between a diffusive and a ballistic process, and there is no reason that
3 Note that the law can also be obained by using Π theorem: writing J = f (D, G), we have a
number of units equal to 2 and a number of variables equal to 3. With that, only 3-2=1 expression is
possible, J ∼ DG
248 Transport in microfluidics

5.3: An example of hyperdif-

fusion: walker wandering in the
plane in the presence of a shear
flow.

the walk would be diffusive. The walker trajectory (x(t), y(t)) can be estimated with
the following equations:

√
x(t) ∼ γyt; y ∼ Dt

in which D is the diffusion coefficient. From this equation, we find:

x(t) ∼ γD1/2 t3/2

An assembly of such walkers thus spreads, along the flow streamlines, as time to the
power of 3/2. This is ‘hyperdiffusion’. It is interesting to note that x and y are linked
by the relation y ∼ ( D
γ)
1/3 1/3
x . With this relation, one may infer that the cloud of
particles adopts an S shape. If the shear was zero, the pattern formed by the particles
would be a disk.
The hyperdiffusive behaviour of the walkers, in the presence of the shear, originates in
the existence of correlations: the movement of the walker in the x direction is coupled
to the leaps in the y direction. This correlation breaks the assumption of independency
of the events, under which the central limit theorem can be established. Later, we will
encounter several cases of anomalous diffusion.4

5.1.3 The Stokes-Einstein law

Langevin equation. Einstein established the Stokes-Einstein law in 1905 [4]. To ob-
tain this law, he applied a concept introduced in 1883 by J.H. Van’t Hoff [12] – the
osmotic pressure – to particle suspensions.5 A simpler demonstration was given later,
in 1908, by P. Langevin [2, 5, 11]. In his demonstration, P. Langevin introduced, for
the first time, the notion of stochastic equations, which later had a deep influence on
contemporary physics, as underlined in Ref. [2]. We shall take his approach.
In Langevin’s theory, a spherical particle of mass m, radius r, immersed in a fluid of
viscosity µ, is subjected to a random force f (t) that drives it in an erratic manner.
With u = dxdt its speed, we have the relation:

4 In the context of microfluidics, due to confinement, after some time, another regime takes place,
which is, most of the time, diffusive.
5 In fact, in the period 1905-1910, Einstein produced three demonstrations of his law [11]
 The microscopic origin of diffusion 249

dx 2
< m( ) >= kT (5.1)
dt

in which the brackets mean ‘statistical averaging’, i.e. averaged over many particles.
This is the equipartition theorem. At equilibrium, the kinetic energy of the particles
must be equal to the thermal energy of the liquid around, i.e. 1/2 kT per degree of
freedom.

Applying the fundamental law of mechanics, we have:

du
m − βu = f (t) (5.2)
dt

for which we will assume, for simplicity, the following initial conditions: at t = 0, x = 0
and v = 0.

In Eq. 5.2, β = 6πµr (where r is the particle radius and µ the fluid viscosity) is
the Stokes friction coefficient (determined in Chapter 3). f (t) is a stochastic force. In
the traditional presentation of Langevin equations [2], f (t) represents the momentum
transferred by fluid molecules hitting the particles, and pushing them in an erratic
manner. The time of variation of f is molecular. To provide an idea, we show, in
Fig. 5.4 an approximate mathematical model of f (t). The graph represents a function
which adopts, at each increment of time, a random value comprised between -1/2 and
1/2.

5.4: An example of f(t).

In the simplest situation, the random forces exerted against the particles are considered
instantaneous, of zero statistical average, and without memory. These properties are
expressed by the following relations:

< f (t) > 0 and < f (t)f (t + τ ) >= F δ(τ )

in which F is a force which we will determine later. In the above equation, the Dirac
function is a generalized function whose properties are: δ(τ ) = 0 for τ 6= 0 and
R +∞
−∞
δ(τ )dτ = 1. The mathematical function shown in Fig. 5.4, divided by its standard
type deviation, and applied to a population of particles, possesses such properties in
the limit where the time increment is zero.
250 Transport in microfluidics

One might think that, since f (t) is impossible to express analytically, it will be difficult,
by working out Eq. (5.2), to gain valuable information on v(t). P. Langevin [5] solved
it by postulating, without much explanation, zero correlation between the particle
position x and the fluctuation force f . Here, we take the modern’ approach, which
requires a more elaborate mathematical formalism, but does not need this assumption
(see comments in [2,11]). To perform the calculation, we follow the presentation given
in ‘colloidal dispersion’, by W. B. Russel et al. [13].

By integrating Eq. 5.2 with the boundary conditions, we find:

Z t
1
v= f (t0 )exp(−β(t − t0 )/m)dt0
m −∞

By multiplying the equation by v(t + τ ) and taking the statistical average, one obtains
the relation6 :

F β
< R(τ ) >=< v(t)v(t + τ ) >= exp(− τ ) (5.3)
2βm m

2
m
In liquids, the viscous time τv = m/β = 6πµr ≈ 2ρr
9µ , with ρ the fluid density, is for
water, and for particles 1 µm in diameter, approximately 200 ns. After a few τv , the
self correlation of v vanishes out, which means that, after this time, particles forget
the speed at which they moved. Further, on comparing, for τ = 0, Eq. (5.5) to Eq.
(5.1), we find:

F = 2βkT

1
Bu using Eq. (5.3), it is not difficult to calculate the product 2 < x(t)x(t) >. We find:

Z t
1 d kT β
< x(t)x(t) >=< x(t)v(t) >= R(τ )dτ = (1 − exp(− τ ))
2 dt 0 β m

Therefore, by restricting ourselves to times much larger than τv , which defines the so-
called overdamped approximation’, we obtain, after integration, the following relation:

2kT
< x2 > (t) = t (5.4)
β

which is the Stokes–Einstein law. Particles, animated by uncorrelated impulsions, un-

dergo a diffusion process, characterized by a diffusion constant equal to:
R +∞
6 To perform the calculation, we use the identity −∞ δ(t0 )g(t0 )dt0 = g(0).
 The microscopic origin of diffusion 251

kT
D= .
6πrµ

The law was used by Perrin in 1914 to estimate the Avogadro number [3]. The obser-
vation he made is shown in Fig. 5.1. This shows three trajectories of particles placed
at the surface of a water tank. Perrin could provide an estimate of D by analyzing
them. From the knowledge of D, kT and therefore the Avogadro number NA = R/kT
(where R is the ideal gas constant) could be estimated. Perrin found 6.8 1023 , which
is close to the modern value. It was the first time that a quantitative link could be
established between molecules and a macroscopic phenomenon.

Calculating dispersion phenomena in the presence of a flow on a computer. To cal-

culate trajectories of Brownian particles, in the presence of a flow, one should, in
principle, use Langevin equations and add terms representing the flow. In this ap-
proach, it is tempting to neglect the acceleration term, which, in fine is neglected
in the last part of the resolution of the problem, the justification being that we are
not interested in times smaller than τv , i.e. extremely short times. However, if we set
m = 0 at the beginning of the problem, owing to the equipartition theorem, there is
no particle agitation. So, how to proceed?
What is done in practice is to suppress the inertial term and, in the meantime, adjust
the forcing so as to keep molecules agitated. In this spirit, by assuming that particle and
flow speed are equal (an hypothesis we will return to later), the equations governing
particle speed v reads:

v = g(t) + U(x, t) (5.5)

in which g(t) is an effective random forcing and U(x, t) is the local flow speed. In the
equations, g(t) is such that for a fluid at rest, particles are subjected to the Stokes–
Einstein law. This approach raises a number of subtle questions that we do not address
here.
Let us now go to the computer and decompose the trajectories in n steps. In the
computation, gn is a random, uncorrelated function whose variance is < gn2 >= 2Dτ ,
in which τ is the temporal increment used in the computation. Defined in this manner,
gn guarantees that in the absence of flow, particles are subjected to Stokes Einstein
law.
To take an example, let us consider an ensemble of particles immersed, in a two-
dimensional space, in a shear flow. Defining xn and zn as the particle position at step
n and setting U = (γzn , 0) (with γ the shear rate), we have:

xn+1 = xn + γzn τ + gxn (5.6)

yn+1 = yn + gyn (5.7)
252 Transport in microfluidics

Pn 2
Pn
From Eq. (5.27), we infer that zn+1 = 1 gyn and thus < yn+1 >= 1 < gy2n >=
2Dnτ = 2Dt, where t = nτ . Thereby, the movement of the particles, in the direction
normal to the shear, i.e. along y, is brownian. In the absence of the shear, i.e. with
γ = 0, the same property holds for the movement along the shear, i.e. along x. These
results confirm the choice of g we made. The left plot of Fig. 5.5 shows a superposition
of 100 trajectories, obtained without shear, all with the same initial conditions, i.e.
x = y = 0 for t = 0, and after 1,000 steps. They are calculated with D = 21 < g 2 >=
0.0424, One sees
√ that the trajectories develop isotropically. The cloud’ width can be
estimated by 2Dt ≈ 9.

Fig. 5.5: Two simulations, conducted with the same initial conditions. In one case, the fluid
is at rest (γ = 0) and in the other case, a shear flow is present (γ = 1).

When the flow is present (see Fig. 5.5, γ=1), the movement of the particles along y
remains the same, as we saw, but that along x changes. Trajectories spread orders
of magnitude faster along the flow, than normally to it, developing an S shape. The
movement is no longer isotropic.

5.6: Width σx , along x, of the particle

cloud, formed by particles injected at the
origin x = z = 0, as a function of the cloud
width σy , along y. Averaging is performed
over 100 trajectories. The dashed line rep-
1/3
resents a fit given by σy = 0.54σx

The simulation leads, in the case γ=1, to the following relations:

< x2 >≈ 0.025 t3 and < y 2 >≈ 0.085 t

 Advection-diffusion equation and its properties 253

The fact that < x2 > varies more rapidly than t indicates the hyperdiffusivep character
of the regime. Fig. 5.6 represents
√ the standard type deviations of y, i.e. σy = < y 2 >,
2
as a function of σx = < x >. These standard deviations provide estimates for the
1/3
widths of the ’clouds’ shown in Fig. 5.5. The empirical law we found is σy ≈ 0.54σx .
As said above, the tracer spreads rapidly along the flow, and slowly normally to the
flow, adopting a S shape. The exponent we find is consistent with the walker model
we developed earlier, which led to y ∼ ( D γ)
1/3 1/3
x ≈ 0.36x1/3 .
The concept of mobility
A force present in the system, for instance a Coulomb force produced by an electric
field on charged particles, can affect the particle movement. How to introduce such a
force theoretically? This is achieved by using the notion of mobility, i.e. a parameter
µm defined by:
F = µm v
An example of mobility is the Stokes factor β which we used earlier. With this notion,
forces, translated into speed (with the relation v = F/µm ), can be directly introduced
in the equations of the problem.

5.2 Advection-diffusion equation and its properties

5.2.1 Fick law

Here, we are no longer interested in determining the trajectories of each tracer particle.
We work in a continuum framework, characterize the particle population by its mass
concentration C(x, t), and attempt to determine the evolution of C. The massic flux
J(x, t) is, by definition, a vector oriented along the mass flux of particles, i.e. along
their speed, and whose intensity is defined by the ratio δm crossing, per unit of area
and time, a surface δS, placed normally to J, during a time δt. It is thus defined by
the relation:

δm
J.n =
δt δS

in which n is the unit vector normal to the surface element δS. Fick’s law relates J to
the local concentration gradient D∇C. Its expression is:

J = −D∇C
where D is the coefficient of diffusion. For reasons similar to those given in Chapter
3, the domain of validity of this law concerns, for gases, systems larger than the
mean free path, and for liquids, systems roughly larger than 1 nm. In a number of
situations, the system may be anisotropic, i.e. the diffusion constant may be different
in different directions. This happens close to a wall. In this case, D is a diagonal
tensor with two components, one normal and the other parallel to the wall. We will
254 Transport in microfluidics

describe this situation later. For the moment, unless specified, we will consider only
isotropic situations, where the diffusion process is characterized by a single parameter,
the diffusion constant (or coefficient) D.
The units of the diffusion coefficient are m2 /s. Table 5.1 shows a selection of values.

Diffuser Medium Diffusion constant (m2 /s)

Fluorescein Water 4 10−10
Sucrose Water 5 10−10
Albumin Water 6 10−11
20 bp DNA strand Water 5 10−12
6 Kbp DNA strand Water 8 10−13
Table 5.1 Diffusion constants of a selection of molecules in water.

The orders of magnitude of the diffusion coefficients, for small molecules in simple
liquids (e.g. alcanes, alcohol), are on the order of 10−10 m2 /s. The diffusion coefficients
found for albumin and DNA strands in water are smaller because of the larger sizes of
the molecules, which is consistent with the Stokes–Einstein law. More generally, the
values of Table 5.1 agree, within 30% or so, with the Stokes-Einstein equation, which
we rewrite here:
kT
D=
6πRµ

5.2.2 Advection-diffusion equation

The advection-diffusion equation expresses mass conservation. In a fixed frame of

reference, the local flux of matter includes two components: one, uC, where u is
the local velocity, is the advective part – sometimes called ’convective’ –, and the
other, −D∇C, is the diffusive one. By using the divergence formula, one finds that
the mass change δm, in a volume δV , caused by these fluxes, is equal to div(−D∇C +
uC)δV . With this, by noting that mass change of the control volume is also ∂C
∂t δV , and
that mass is conserved, one obtains, for incompressible fluids, the advection-diffusion
equation:

DC ∂C
= + u∇C = D∆C (5.8)
Dt ∂t

The phenomenon described by this equation is called dispersion’. In the case where
a source or a sink is present in the system, additional terms must be incorporated
in the right–hand side of the equation. This possibility, however, is difficult to realize
experimentally. Thus, for the sake of simplicity, we will not consider these cases. The
boundary conditions are:

C = 0 for adsorbing walls and ∇C = 0 for impermeable walls

 Advection-diffusion equation and its properties 255

In a closed system, with impermeable walls, Eq. (5.8) possesses a trivial solution, in
which concentration C is uniform and stationary. The system always tends to this so-
lution. This intuitive statement is justified mathematically by considering the variance
of the concentration field, defined by:
Z
Θ = C 2 dx

where dx is the elementary volume and the integral is taken over the total space
occupied by the fluid. By multiplying each term of Eq. (5.8) by C, with the boundary
conditions indicated above, and integrating, one obtains the folllowing equation for Θ
:

Z
∂Θ
= −D (∇C)2 dx
∂t

The
R equation states that the variance always decreases with time. In the ultimate state,
(∇C)2 dx = 0, which implies that C is uniform. The tracer is said to be ‘completely
mixed’ with the fluid. In closed systems, dyes and tracers, will thus always tend to get
completely mixed with the fluid. The question is: how much time do we need to reach
this state? This important question will be the focus of the next sections.

When D = 0, we have:
DC
= 0.
Dt
The equation states that the local concentration C(x, t) is conserved along the fluid
trajectories. In practice, this property holds for short times, i.e. during an interval of
time well below the diffusion time l2 /D, in which l characterizes the system size. As
discussed earlier, we need to allow this time for diffusion to come into play.

Fig. 5.7: Microfluidic experiment in which seven aqueous solutions flow side by side in a
microchannel with several entries. The experiment shows that, over short times, dye parti-
cles follow, in practice, the flow trajectories, or equivalently, dye concentration is conserved
along the flow streamlines. (Reprinted from [14], with permission from American Association
Advanced Science. Copyright 2022.)
256 Transport in microfluidics

Figure 5.7 illustrates such a situation: seven aqueous solutions are driven, from right
to left, in a system including six bifurcations [14]. Dyes remain in the device only
a fraction of second, so diffusion did not have time to act. In such conditions, the
aqueous solutions flow side to side, keeping sharp interfaces between them. The dye
particles follow the flow trajectories, or equivalently, dye concentration is conserved
along the flow streamlines. Should diffusion come into play, the interfaces between the
streams would blur substantially.
The opposite limit, u = 0 is pure diffusion. In this case, Eq. (5.8) reduces to:

∂C
= D∆C (5.9)
∂t

and the system behaves as if the fluid were at rest.

5.2.3 The Peclet number

One fundamental dimensionless number is the Peclet number. Its definition is:

Ul
Pe =
D

where U is a characteristic flow velocity, l is a characteristic scale of the system (e.g.

the channel height), and, as we saw above, D is the diffusion coefficient. The order
of magnitude of the advection terms is U δC/l (where δC is a typical variation of the
concentration over a distance l), and the order of magnitude of the diffusion terms is
DδC/l2 . The Peclet number represents the ratio of the first term with the second. It
thus estimates the relative importance of advection with respect to diffusion. Using
minimal wording, we could write:

Advection
Pe ∼
Dif f usion

The higher the Peclet number, the higher the contribution of the flow to the transport
process. If we applied directly the scaling lows given in Chapter 2, we would get follow-
ing relation for the Peclet number: P e ∼ l2 . We would conclude that in microfluidics,
only diffusion matters, and the advection terms are negligible. This would imply that
in microsystems, it is useless to stir two fluids to mix them.
However, these conclusions would be erroneous: in fact, diffusion coefficients D are
typically on the order of 10−10 m2 /s for molecular tracers in water for instance (see
Table 5.1). Thus, with velocities on the order of 1 mm/s, in a canal 100 µm high, the
Peclet number is on the order of 1, 000. We could envision a situation where the Peclet
number is small. However, this would concern channels much smaller, for instance,
a micrometre in size, which is not current in microfluidic. In nanofluidic devices, the
 Analysis of diffusion phenomena 257

situation is different. The Peclet number is small and diffusion prevails.

5.3 Analysis of diffusion phenomena

5.3.1 Diffusion of a tracer in an infinite medium

Let us place ourselves in a one-dimensional space, and inject a tracer, a solute, or a

dye spot in a liquid tank (i.e. a line), ‘filled’ with a liquid at rest. In such conditions,
Eq. (5.8) reduces to:

∂C ∂2C
=D 2 (5.10)
∂t ∂x

In order to simplify the mathematics, we will consider that, initially, the concentration
profile C(x, t) is represented by the following function:

t = 0, C = C0 δ(x) (5.11)

where δ(x) is the Dirac function and C0 is the total mass of tracer enclosed in the
spot. We already used the Dirac function. It is a generalized function that is zero
everywhere except at the origin, where it is infinite. Its integral over space is unity.
It is important to note that the unity of C(x, t) is a mass per unit of length. In our
one-dimensional world, it represents a mass concentration.
The fact that, at t = 0, the spot is of zero size and has infinite concentration may
look unphysical. In fact, it is possible to argue that taking this initial condition is
acceptable at late times, i.e. when the dye has spread so much that its size is much
larger than the initial spot. With the initial condition given by Eq. (5.11), the solution
to Eq. (5.10) is a gaussian function, whose expression is:

x2 x2
   
C0 C0
C(x, t) = √ exp − =√ exp − 2 (5.12)
4πDt 4Dt 2πσ 2 2σ

in which σ is the standard type deviation, defined by:

Z ∞
1
σ2 = x2 C(x, t)dx = 2Dt
C0 −∞

For completeness, let us add two identities

Z ∞ Z ∞
C0 = C(x, t)dx, xC(x, t)dx = 0
−∞ −∞
258 Transport in microfluidics

The solution C(x,t)

C(0,t) , plotted as a function of x/σ, is shown in Fig. 5.8. With the
dimensionless coordinates we used, the plot is universal, i.e. the same at all times, and
independent of C0 and D.

5.8: Universal representation of the gaus-

sian function. For x = σ, one has
C(x, t)/C(0, t) ≈ 0.607.
R ∞ Mass conservation
is satisfied because −∞ C(x, t)dx = C0 at
all time.

Figure 5.8 can also be viewed as the distribution of concentration levels, at fixed time.
This is the so-called Gaussian or normal distribution. The way in which the solution
to Eq. (5.12) is obtained is not straightforward. In short, the approach consists of
guessing a form of the solution compatible with the boundary conditions. For this
task, theorem Π is extremely useful. Owing to linearity of the equation, one must
have: C(x, t) = C0 F (x, t) with F is an unknown function, whose dimension is the
inverse of a length. Theorem Π tells us that two forms are possible and, among them
only one is compatible with the initial condition. This leads to write F in the form:
F (x, t) = √1Dt G(ξ), in which ξ = x2 /2Dt.. This being written, the rest is (tedious)
calculation for determining F .

It is usual to take, for simplicity, the standard deviation σ as an estimate of the spot
size. A one-dimensional spot of uniform concentration C(0, t) and size σ would includes
80% of the total mass of the tracer. It may therefore represent a model for schematizing
the spot. Let us thus write,
√ for the spot size l, in terms of order of magnitude, the
following relation: l ∼ Dt. This estimate is indeed consistent with our drunkard
model. The same relation can also be√obtained by using theorem Π: l depending only
on D and t, theorem Π imposes l ∼ Dt.

Similar Gaussian solutions hold in two and three dimensions, in Cartesian, cylindrical
and spherical geometries. Analytical expressions can be found in textbooks and online.

5.3.2 Diffusion of a tracer in a box

Gaussian solution concerns infinite spaces. When a tracer diffuses in a bounded space,
for instance, a one-dimensional box, gaussian solution no longer holds. In this case, a
solution can still be found, but in the form of developments in Fourier series, as seen
in Chapter 3, for the case of flows developing in channels of rectangular cross-sections.
 Analysis of diffusion phenomena 259

Let us consider a tracer, initially injected, as in the previous subsection, in an infinitely

small spot, but now inside a box bounded by two impermeable walls, located at x =
±L. The boundary conditions are thus:
∂C
t = 0, C = 2LC0 δ(x) ; x = ±L, =0 (5.13)
∂x

in which C0 is the mass of tracer localized in the spot, divided by 2L. The units of
C0 and C are mass per unit of length, i.e. in this one-dimensional geometry, mass
concentrations. The solution to Eq. (5.10) reads:
∞
!
X
2 2 2
C(x, t) = C0 1 + 2 exp(−Dn π t/L ) cos(nπx/L) (5.14)
1

It is represented in Fig. 5.9.

5.9: Concentration profiles cal-

culated in a box, at different
times. The curved arrow indi-
cates increasing times. The dif-
ferent times are, in units of τD =
L2 /2D: 0.043, 0.086, 0.13, 0.17,
0.21, 0.26, and 0.3.

According to Eq. (5.9), t does not act individually, but through the product Dt/L2 .
It is thus natural to introduce a characteristic time τD = L2 /2D and describe the
behaviour of the solution in terms of the ratio t/τD . At short times (e.g. for t=0.03
τD ), we recover the Gaussian solution, because, at those times, the concentration field
has spread over lengths much smaller than the box size. The spot, still localized, does
not ’see’ the walls. At longer times, the concentration field broadens, and, eventually,
tends form a plateau located C = 1, which is the mean concentration. We need to wait
a time on the order of τD to reach a state close to homogeneity. In the process, the
total mass of the tracer is conserved, because walls are impermeable. Should we have
taken, as the initial condition, C = 0, a flux across the wall would develop and, along
time, C would decrease to zero.
260 Transport in microfluidics

5.3.3 Interface broadening

Here we return to infinite media, and again, limit ourselves to one dimension. Let us
consider that, initially, a front separates two regions: one with a uniform dye concen-
tration C0 and the other without dye (see Fig. 5.10).

5.10: Initial conditions: the tracer is lo-

cated on the right, i.e. x > 0.

We thus have:

t = 0, C = 0 for x < 0, and C = C0 for x > 0 (5.15)

With such initial conditions, the exact solution to diffusion Eq. (5.9) reads:

  
1 x
C(x, t) = C0 1 + erf √ (5.16)
2 2 Dt
where the error function, called erf , is defined by:
Z z
2
erf(z) = √ exp(−v 2 )dv .
π 0
√
The solution, represented by using dimensionless coordinates x/σ (with σ = 2Dt),
and C/C0 , is shown in Fig. 5.11. As in the preceding section, the plot is universal, i.e.
it is valid at all times, and is independent of √
C0 and D. The thickness of the front is
given by the width of the error function, i.e. 2Dt. The front thus broadens propor-
tionally with the square root of time.

For a long time, the phenomenon was challenging to investigate experimentally. This
was due to the presence of uncontrolled flows, linked to thermal convection or buoy-
ancy, or both, which considerably perturbed the diffusive process. With the advent
of microfluidics, it became possible to eliminate these perturbations. The experiments
of Refs. [15–17], performed in shallow T-shaped microchannels, called T-sensors’, ex-
ploited this possibility. The system is shown in Fig. 5.12.
In the experiment of Ref. [15], two miscible fluids are injected in a T-junction and
circulate side by side in the main channel. One is a buffer; the other is an albumin
 Analysis of diffusion phenomena 261

5.11: Universal concentration profile given

by Eq (5.16).

Fig. 5.12: Sketch of the device (T sensor) used in Ref. [15] for carrying out diffusion studies.
Two miscible fluids, injected in the device, circulate side by side towards the right. The upper
fluid transports a (black) solute, of concentration C0 , and the other is a buffer. Downstream,
the system builds up a conical zone, within which the black solute diffuses.

blue solution (AB580). Downstream of the junction, the system builds up a conical
zone, within which albumin blue diffuses. How can we model the phenomenon ?
The concentration gradients are mainly along y, i.e. transverse to the flow, in the hor-
izontal plane. There is indeed a variation of the concentration field along x, evidenced
by the presence, mentioned above, of a cone of concentration; however, this is weak,
and we will neglect it. In the theory, we consider that the flow is 2D. In the experiment,
the flow is driven in a shallow channel and develops a parabolic profile in the vertical
direction (i.e. normally to the plane of Fig. 5.12), and is uniform horizontally; its mean
speed equal to U . As the channel is shallow, we assume that the concentration is ho-
mogeneous vertically. We will discuss these approximations later. In these conditions,
the stationary diffusion-advection Eq. (5.8) reduces to:

∂C ∂C
U ≈D 2
∂x ∂y

with the initial conditions:

262 Transport in microfluidics

x = 0, C(0, y) = 0 for y ≤ 0, and C = C0 for y ≥ 0.

For y << w, the problem is identical to the one discussed above, with t replaced by
x/U . Time is translated into a spatial variable x/U . In such conditions, the solution
reads:

r !
1 y U
C(x, y) = C0 1 + erf( ) (5.17)
2 2 Dx

Remembering that x = t/U , Eq. (5.17) tells us that the temporal evolution of C, along
the flow streamlines, can be analysed by looking at the stationary dye field in the main
channel. Equation (5.17) also √yields the equations of the iso-concentration lines. We
find x = k D y , in which k ≈ 2π ( 2C
U 2
C0 − 1), with Cl the concentration level. The cone
l
√
is thus a parabola of equation x ≈ 4π D
U
y 2 (here we took Cl = C20 to define the cone
boundaries). The greater the speed, the narrower the width of this parabola, and thus
the more acute the cone.

The concentration measurements made in Ref. [15] are shown in Fig. 5.13.

5.13: Fluorescence intensity

profiles for the distribution of
AB580 across the y dimension
at a distance of 5000 µm down-
stream. Flow rates are 83.3 nl/s
(circle), 416 nl/s (square), and
833 nL/s (triangle). Solid lines
are analytical fits using D=4.55
10−10 m2 /s (Reprinted with
permission from [15]. Copy-
right 2022 American Chemical
Society.)

Theory agrees well with experiment. In Ref. [15], the system was used for measuring
the diffusion constant of Albumin blue.

The butterfly effect. We just mentioned the good agreement between theory and
experiment, but did not discuss the three–dimensional aspects of the problem. In the
theory, as noted, we assumed that the concentration is homogeneous in the vertical’
direction z, i.e. normal to the flow plane, and that the speed can be replaced by
its average along z. In reality, along the vertical axis, the flow is parabolic and the
concentration field develops a ‘butterfly’ structure. This feature was revealed by [15]
and analysed by Ismagilov et al. [18] (see Fig. 5.14).
 Analysis of dispersion phenomena 263

5.14: Butterfly effect. The

tracer develops ‘wings’ close
to the floor and the ceil-
ing of the channel, in re-
gions where speeds are low.
The phenomenon, revealed in
Ref. [15] was analysed by Ref.
[18], from which the images are
taken. (Reprinted with permis-
sion from [18]. Copyright 2022
AIP Publishing.)

Figure 5.14 (left) shows that, in the central part of the channel, the concentration
of the fluo-3 complex, at the origin of fluorescence emission, is homogeneous along z.
Nonetheless, at the bottom and the top, i.e. close to the horizontal walls, two ‘wings’
develop. This is the ‘butterfly’ effect. The phenomenon was explained in Ref. [18]. In
short, low speeds close to the walls favour the broadening of the concentration field,
compared to the central region, where speeds are greater. This leads to wing formation.
Fig. 5.14 obtained a spectacular image of the phenomenon.

5.4 Analysis of dispersion phenomena

5.4.1 Plug flows, pure shear flows, and straining flows

Here, we present three important examples in which tracers are dispersed by flows.

Fig. 5.15: (A) Band of tracer transported by a plug flow at different times (top: initial state;
bottom: later times).(B) Band of tracer transported by a shear flow at different times (top:
initial state; bottom: later times)

Example A: Dispersion in plug flows. A band of dye is transported by a uniform

speed U (see Fig. 5.15 (A)). To solve the governing equations (5.8), one must place
ourselves in the frame of reference of the flow. By posing x0 = x − U t, in which x is
the streamwise coordinate in the laboratory frame, and x0 in the moving frame, one
obtains:
264 Transport in microfluidics

∂C ∂2C
= D 02 (5.18)
∂t ∂x

In the limit where the band width is initially small, the solution is:

(x − U t)2
 
C0
C(x, t) = √ exp − .
4πDt 4Dt

In the frame of reference of the flow,

√ the band width δ (the standard type deviation of
the gaussian function) varies as 2Dt. The flow transports the dye without changing
the dynamics of spreading.

Example B: Dispersion in pure shear flows. A band of dye is transported by a shear

flow U (y) = U0 + 12 αy, in which y is the coordinate transverse to the mean flow (see
Fig. 5.15 (B)). The equation of diffusion advection reads:
 
∂C 1 ∂C ∂C ∂C
+ (U0 + αy) =D 2
+ 2
∂t 2 ∂x ∂x ∂y

The solution, in the limit where, initially, the band width is infinitely small, can be
found in [20].7 It reads:

(x − U0 t − 21 αyt)2 y2
 
C0
C(x, y, t) = exp 2
− 2
2πσx σy 2σx 2σy

in which:  
1
σx2 = 2Dt 1 + α2 t2
12
and:
σy2 = 2Dt

The solution shows that, along y, the spreading of the dye is diffusive. However, in
the flow direction, i.e. along x, at long time, the spreading is hyperdiffusive because
the standard type deviation varies as t3/2 . This finding echoes the anomalous diffusion
model we presented at the beginning of the chapter.
Two remarks can be made:
2
1 After a time τy = wD , where w is the channel width, the tracer becomes homoge-
neous in the y direction. Then, a new regime takes place; this is the Taylor regime,
that we will discuss later.
2 In practice, pure shear flows are difficult to realize experimentally, and, so far, no
serious attempt has been made to confront theory with experiment. This would
necessitate a moving wall, which is challenging to realize in microfluidic devices.
7 The problem was independently solved, in about the same years, by J. Ottino [21]
 Analysis of dispersion phenomena 265

Example C: Dispersion in a straining field. Here, we analyse the filamentation and

reorientation processes that concentration fields are subjected to in straining flows.
For the calculation, as before, we use the notations of Rhines and Young [20]. Let us
consider a pure straining velocity field, defined by:

U = (αx, −αy) α > 0 .

Initially, we have:
t = 0, C(x) = A0 sin M · x
where C is the concentration field of a tracer, C0 is a constant, and M is a vector with
components (M1 , M2 ) (see Fig. 5.16).

Fig. 5.16: Periodic concentration field immersed in a straining field, undergoing reorientation,
filamentation and diffusion.

This initial condition represents a series of bands of dye oriented perpendicularly to

M, with ‘colours’ labelled with positive and negative levels. In order to discuss the
different regimes, it is interesting to introduce a Peclet number. The band width is on
the order of λ = 1/M and a typical speed of the flow field is α/M . We thus define the
Peclet number as:
α
Pe =
DM 2
Large Peclet numbers are associated to large straining rates, large bands, or small
diffusion constants D. We postulate the following solution:

C(x, t) = A(t) sin(m(t) · x)

where m(t) = (m1 (t), m2 (t)) is a time dependent vector. By inserting it into the
advection diffusion equation, we find:
dm1 dm2 dA
= −αm1 (t); = αm2 (t) and = −Dm2 (t)A
dt dt dt
The solution to these equations reads:
266 Transport in microfluidics

Z t
m1 (t) = M1 exp(−αt) , m2 (t) = M2 exp(αt) and A(t) = A0 exp(−D m2 dt)
0

Without flow, the bands keep their orientation, positions, and wave-numbers, while
their concentration levels decays, with time, as exp(−DM 2 t). The time constant of
1
this decay is τD = DM 2 . At times well above τD , A(t) becomes vanishingly small,

and the concentration is homogeneous. This is complete mixing. Taking a width λ =

1/M = 100µm, and D = 10−11 m2 /s, one obtains τD = 103 s. This is a long time. This
indicates that in microfluidic systems, diffusion can be slow.

Let us now analyse the solution when the flow is present. Several conclusions can be
drawn out:

• With m1 (t) decreasing, the vector m tends to align along y, the principal axis of
the strain. As sketched in Fig. 5.16, the bands rotate and align along y. This is
the reorientation process. At large strains, the process is vigorous, because m1 (t)
decreases exponentially, with a time constant equal to α−1 .

• In the meantime, m2 (t) increases. Thereby, bands become thinner and thinner,
while their density, i.e. their number per unit of length in the m direction, being
proportional to m2 (t), also increases. This is the filamentation process, sometimes
called striation. At large strain rates, it is vigorous, because m2 (t) increases ex-
ponentially in time, with a time constant equal to α−1 . After several α−1 , the
bands takes the form of closely packed filaments, as sketched in Fig. 5.16.

• With m2 increasing, the amplitude of the concentration levels decrease. Bands

blur. In order to analyse the process, we note that, after several α−1 , m1 (t) is
vanishingly small, and, therefore, A(t) can be approximated by:

DM22
A(t) ≈ A0 exp(− exp(2αt))
2α
We find a surprising result: the concentration levels decrease at an exponential of
exponential rate. This is fast. With α=1 s−1 , we find, after 3 s, a decay of A(t)
by a factor of 2,400. And after 10 s, the factor becomes 1010 . Instead of taking
1000 s, without flow, the mixed state – associated to small A – is reached in a
few seconds. It is remarkable that the process is controlled by the strain rate α,
independently of the diffusion constant; D influences the process only through a
logarithmic correction (this does not mean that D can be replaced by zero).

To conclude, the model shows that, at large strains, mixing is achieved at a rate much
faster than diffusion and, in practice, independent of it. The entire process is controlled
by the strain, diffusion just ’completing’ the homogenization process in a negligible
time. These properties will be used to design efficient micromixers.
 Analysis of dispersion phenomena 267

5.4.2 Taylor dispersion in microchannels

Taylor dispersion, also called Taylor-Aris dispersion [22,23], provides another example
for which diffusion is accelerated by the shear. Let us consider a tracer injected in a
Poiseuille flow driven between two plates separated by h, at small Reynolds numbers.
Fig. 5.17 schematizes the situation. At large Peclet numbers, as discussed earlier, two
ranges of time can be defined: at short times, the tracers follow the streamlines, forming
an arch, advected downstream. At times greater than h2 /D (where D the diffusion
constant of the tracer in the liquid), diffusion will come into play and C will tend to
homogenize. As schematized in Fig. 5.17, the concentration field will take the form of
a patch of dye, approximately rectangular. How can we describe such a structure ?
For this, we again take the diffusion advection equations:

5.17: A dye is injected in a Poiseuille

flow, at high Peclet number. First, the
dye particles follow the fluid trajec-
tory. Later, the dye spot tends to adopt
a rectangular shape, whose spreading
rate, in the streamwise direction, is
given by the Taylor dispersion equa-
tion.

DC ∂C ∂C
= + U (z) = D∆C (5.19)
Dt ∂t ∂x

where C(x, z, t) it the concentration field, x, z the coordinates, and U (z) the parabolic
Poiseuille profile across the channel. We consider here the calculation made by Aris [23],
based on a decomposition of the concentration field into two components:8

C(x, z, t) = C̄(x, t) + c0 (x, z, t)

in which C̄(x, t) is the concentration averaged across h and c0 = C − C̄. This decompo-
sition, introduced in Eq. 5.19, generates several terms. There is no analytical solution
to it, but over long times, when C is nearly homogeneous in the cross-section, an
approximate solution can be found. In such circumstances, c0 (x, z, t) is much smaller
than the averaged concentration and can be expressed in function of C̄(x, t) and its

8 The phenomenon is often called ‘Taylor-Aris dispersion’.

268 Transport in microfluidics

gradients. The calculation is quite long. It can be found in textbooks (see for exam-
ple, [24] or the original work of R. Aris [23].). The calculation reveals that the terms at
0
the origin of the enhancement of diffusion is the coupling between U (z) and ∂c ∂z , and
more specifically the (spatial) average of the product U (z) ¯ ∂c0 . The calculation leads
∂z
to the following equation:

∂ C̄ ∂ C̄ ∂ 2 C̄
+ Ū ≈ Def f .
∂t ∂x ∂x2

with  2 !
Uh
Deff = D 1 + β
D

1
where β = 210 . For a capillary tube with circular cross-section, the calculation leads
1
to β = 48 . The above expression can be written by using the Peclet number:

Deff = D 1 + βP e2

Uh
where P e = D is the Peclet number.

At high Peclet numbers, the effective diffusion constant thus increases, approximately,
as the square of this parameter. In this range, the spreading of tracers is thus much
faster than with diffusion alone. The effect is called ‘shear augmented diffusion’. In
microfluidics, the effect is considerable. Taking a Peclet number of 100, which is typi-
cal, the shear augmented term reaches three orders of magnitude.

We conclude this subsection with four remarks:

• The expression of the effective diffusion constant leads to a counter-intuitive re-

sult: the smaller D is, the faster the diffusion is. Thus, without diffusion, the
tracer diffuses infinitely fast. On the other hand, in this limit, it takes an infinite
time to reach the Taylor regime. To summarize, it takes an infinite time to be
infinitely fast.

• Relevant to microfluidics, the calculation of Taylor–Aris has been generalized to

arbitrary shapes (triangular, elliptic, etc.), using lubrication approximation [25].

• In practice, Taylor dispersion is difficult to observe. We need to wait a time

τ ∼ h2 /D to reach the Taylor regime. With a 100 µm channel, and a diffusion
constant of 10−11 m2 /s, the waiting time is 1000 s. In the meantime, if the flow
speed is 1 mm/s, the liquid will have travelled a distance of 1 m. Thus, in practice,
Taylor dispersion rarely holds. This remark is often overlooked by researchers, who
often assume that the Taylor dispersion regime is reached, while the system is still
in a transient regime. The phenomenon is nonetheless valuable to know, because
 Brief introduction to chaos and chaotic mixing 269

it treats, in a neat mathematical manner, an example where diffusion is strongly

augmented by the shear. It thus provides an important reference.
• Because of Taylor dispersion, and, more importantly, the action of the regimes
which precede, it is impossible to transport solutes in a microfluidic device without
diluting them. We will see later that the solutions to this problem are droplets
and electroosmosis.

5.5 Brief introduction to chaos and chaotic mixing

5.5.1 Chaos

Chaos is an important concept, which deserves a thorough treatment, but this would
take us well beyond the scope of this book. We can mention [26,27,29] for descriptions
of the subject. We will thus content ourselves with highlighting a few notions, that
we consider useful for understanding phenomena important for microfluidics, such as
chaotic mixing.
To start, let us introduce the notion of dynamical systems, not in general, but in the
context of fluid dynamics. Take the fluid velocity u(x, t), with the position x(t) of a
fluid particle. By definition, we have:
dx
= u(x, t) (5.20)
dt

These equations define a dynamical system. One way to describe the behaviour of the
solutions is to visualize the particle trajectories x(t) in the phase space, i.e. in our
case, the real space.
Before discussing the nature of the solution to Eq. (5.20), let us comment on flow
streamlines and fluid particle trajectories. In stationary 2D flows, streamlines and
trajectories are the same. In an (x,y) plane, streamlines are governed by a stream
function ψ, defined by:
∂ψ ∂ψ
ux = − , uy =
∂y ∂x
By noting that DψDt = 0, one infers that ψ is constant along the trajectory, and, thereby,
ψ describe both streamlines and trajectories. One consequence is that, in steady 2D
flows, trajectories never cross, because, this would mean that at the same point, one
could define two different speeds, which is mathematically not possible. There exist
singular points, called hyperbolic or saddle points, where streamlines cross. However,
these points are inaccessible to fluid particles because all velocity components are zero.
Therefore, even at these singular points, particle trajectories do not cross.
If the flow is time-dependent, things change. Streamlines and trajectories are generally
different. An example is shown in Fig. 5.18. Here, we have a time varying field, defined
by ux = sin t; uy = cos t. The calculation shows that streamlines are lines, and fluid
trajectories are circles. In stationary 3D flows too, streamlines and trajectories can
270 Transport in microfluidics

be different. This depends on the flow structure. For some flow structures, however
counter-intuitive it looks, streamlines can be steady and fluid trajectories chaotic. We
will return to this point later.

Fig. 5.18: (A) Ten streamlines and (B) five trajectories (circles), associated to the time
dependent field defined by: ux = sin t; uy = cos t.

This being said, a solution x(t) is said to be ‘chaotic’ if it possesses the property
of sensitivity to initial conditions: more precisely, if two nearby trajectories are per-
turbed, the perturbation grows at an exponential rate. This situation is represented
schematically in Fig. 5.19.

5.19: Divergence of trajectories.

Then, let us consider a point x placed on a trajectory at time t0 that we choose

as the origin of time. We designate by x + δx the vector located at a point near
x, at (now) t = 0. Over the course of time, the two points evolve on neighbouring
trajectories. They can move away from one another, or not. In a chaotic system,
a direction must exist for which the two points separate exponentially. The word
‘exponentially’ is important. Should the divergence be algebraic (for instance, in pure
shear flows, separations increase linearly with time), the system would be non–chaotic.
Often, in chaotic systems, two directions are diverging, and one is converging. This
occurs in the Lorenz model, presented below.

Thus, with this definition, we can write:

 Brief introduction to chaos and chaotic mixing 271

δxi (t) ≈| δx0i | eσi t

where δx0i the initial perturbation in direction i, δxi is the modulus of the separation
vector at time t, associated to δx0i , and σi is the exponential rate. From the preceding
formula, one has:  
1 δxi (t)
σi = log .
t | δx0i |

We can repeat this analysis along the trajectory x(t) and come up with a collection
of parameters σi , which depend on the position x(t) on the trajectory. If there ex-
ists a direction i along which the exponent is, on average (i.e. by averaging along the
trajectory) positive, the system is chaotic. The corresponding value is known as the
Lyapunov number along the direction i, or, if there is only one direction of divergence,
the Lyapunov number. If there exist several positive σi , the Lyapunov number corre-
sponds with the direction along which σi is maximal, i.e. along which the divergence
is the most rapid. We can say, to simplify, that a system is chaotic if, on average, tra-
jectories separate from one another at an exponential rate. An example of a chaotic
trajectory, obtained in the Lorenz model, is shown in Fig. 5.20.

5.20: Lorenz chaotic attractor. The

attractor has a fractal dimension of
2.04( [32]), so that trajectories evolve
on surfaces similar to that of the fig-
ure, forming a layer of volume equal to
zero. Figure taken from Wikimedias

The Lorenz system was devised to model convection in the atmosphere [30]; at that
time, it came as a surprise that erratic trajectories could emerge from apparently
simple differential equations (that we call here dynamical system).9 This numerical
discovery put on the scene mathematical ideas developed at the end of the nineteen
centuries, in particular by H. Poincaré [31]. It also gave birth to the field of chaos. In
Fig. 5.20, a chaotic trajectory of a fluid particle, obtained with the ’classical’ values
of the parameters of the model, is shown. The Lyapunov number is positive along two
directions of space, and negative along the third one. Particles are thus trapped in
surfaces, forming layers, characterized by a fractal dimension of 2.04 [32]. This is the
Lorenz attractor, which was later called ’strange’ by Ruelle [33].

9 The hypothesis that computers (the work was performed in 1963) were provoking the phenomenon
was seriously considered. After some time, it could be ruled out
272 Transport in microfluidics

In practice, the perturbations giving rise to the divergence of the trajectories are, in
the experiments, the thermal noise and, in the computations, the numerical noise.
We may infer that chaotic systems amplify noise. This property is at the origin of
the so-called butterfly effect’, in which the flapping of a butterfly’s wing in Brazil,
being amplified by the chaotic dynamics of the atmosphere, can set off a tornado in
Texas [34]. It also leads to the counter-intuitive notion that, although chaotic systems
are governed by deterministic equations, their behaviour is erratic.

5.5.2 Horshoe tranform, baker’s transform

There is an equivalent way to define chaos. In chaotic systems, sets of particles (for
instance blobs of dye), undergo an infinite succession of foldings and stretchings. In
chaos theory, this process associated to the presence of a horseshoe transform [35],
which repeats indefinitely over time, transforming the blob of particles in a dense,
striated, manifold. One example of an horseshoe transform is the baker’s transform,
which the artisan uses when making mille-feuilles. Initially, we have an object (a
segment of some width, as shown in Fig. 5.21). We stretch and fold it, giving rise to a
new object, twice as long and half as wide. By repeating the process, we obtain thinner
and thinner segments, folded and packed in a multilayered sandwich.

Stretching

Folding

Stretching
5.21: An example of the horshoe
transform: the baker transform, in
which a rectangular patch of fluid Folding

particles is stretched and folded. At

each step the distance separating two
neighbour points is multiplied by 2.

The two definitions of chaos, exponential separation, and horseshoe transform, are
equivalent. Taking two neighbouring points placed in the initial segment in Fig. 5.21,
their distance along the stretching direction is multiplied by two at each step of the
process. There is thus an exponential growth of the separations, along one direction,
indicating an equivalence between the two definitions.
With the horseshoe transform, material lines extend exponentially and, in the mean-
time, they fold. This naturally leads to the formation of motifs such as those in
Fig. 5.22. One consequence of the process is the exponential growth of the surfaces of
exchange and, in the meantime, the exponential increase of the concentration gradi-
ents. The two effects, which are linked by a conservation law, intensify the diffusive
exchanges. Chaotic mixing can thus be effective for mixing fluids or reagents.
 Brief introduction to chaos and chaotic mixing 273

Fig. 5.22: Series of foldings and stretchings produced by the oscillatory movement of one of
the container walls [27].

5.5.3 Impossibility of generating chaos in 2D steady flows

Is it possible to know a priori if a system is chaotic or not? On this point, several

powerful theorems exist [26, 27, 29]. Here, we will restrict ourselves to the case of
bounded flows.
An important theorem, called ’Poincaré-Bendixson theorem’, stipulates that two di-
mensional autonomous dynamical systems cannot give rise to chaos. In other words,
a steady two dimensional flow cannot generate chaotic trajectories. To obtain chaotic
behaviour, one must escape the plane. This can be achieved in two ways:
• Work with stationary three-dimensional flows. In this case, chaotic trajectories
can develop. This statement is subtle and it contradicts current thoughts on flow
reversibility at small Reynolds numbers. These thoughts often result from a mis-
interpretation of a spectacular experiment, carried out by G. I. Taylor, in the
1950s [37], and frequently presented to students in fluid dynamic courses. The
experiment demonstrated that in a fluid driven between coaxial cylinders, whose
inner cylinder is rotated several turns, one observes that, as when the cylinder
is rotated backwards, tracer particles return to their initial positions. This was
Taylor’s reversibility experiment [37]. As strange as it seems, in 3D, particles may
not return to their initial locations when the flow is inverted [38]. This depends,
for instance, on whether or not the flow contains hyperbolic points. In such a case,
speed is reversible, with respect to flow inversion, but not trajectories. In Taylor’s
experiment, the flow was regular’, i.e. it did not contain hyperbolic points. In such
circumstances, the fluid trajectories were reversible.
• Work in two dimensions, but with velocity u depending on time t. For instance,
a flow generated by a wall moving periodically in time. Let us take x and y as
the plane coordinates and, just to show, formally, how a third dimension can be
introduced, let us define a variable z by the following equation:
274 Transport in microfluidics

dz
=1
dt

By replacing t with z in the original 2D dynamical system, we create an au-

tonomous three–dimensional system. In this way, we escape the Poincaré-Bendixson
theorem.
Working in three dimensions, in one way or another, i.e. using a 3D geometry or a
time dependent excitation, is a necessary but not sufficient condition for developing
chaotic trajectories. The flow must possess certain features. We present two of them
in the next section.

5.5.4 Trajectories crossing at different times lead to chaos

A necessary condition for obtaining chaotic trajectories in unsteady 2D flows was

proposed in Refs. [39, 40]. The demonstration is technical and we content ourselves
with formulating the conclusion: to develop chaotic trajectories, ’the flow pattern must
change with time so that a streamline in one pattern crosses a streamline in a later
times’ [40]. This condition is illustrated in the blinking vortex flow, introduced by H.
ARef. [41],and shown in Fig. 5.23.

Fig. 5.23: Numerical simulation showing the positions, at different times, in the blinking
vortex flow, of particles initially confined in a square. (Reprinted from [41] with permission
of Cambridge University Press. Copyright 2022.)

The blinking vortex is a vortex, placed in a tank, that jumps from one position to
another in a periodic manner (see Fig. 5.23). Within each period, the vortex develops
steady circular streamlines and, thereby, circular trajectories. However, by jumping
 Brief introduction to chaos and chaotic mixing 275

from one position to the other, fluid trajectories become chaotic. This was shown by
H.Aref in 1984 [41], and it came as a surprise, at that time, that abstract concepts
could be substantiated in such a simple manner. The paper triggered the discovery of
a new domain, called ’chaotic mixing’. This domain provided the conceptual tools to
design, one decade later, microfluidic mixers.

5.5.5 Chaotic mixing in time dependent flows with hyperbolic points

It is important to present a less general condition for creating chaotic behaviour,

often described in detail in reviews and textbooks, and whose implementation, in
microfluidic devices, turns out to be easier. It is based on the temporal displacement
of hyperbolic points.

5.24: Hyperbolic point in a two–

dimensional flow.

As evoked before, in 2D, a hyperbolic (also called saddle) point is a point where, along
one axis, fluid particles converge and along the other, they diverge (see Fig. 5.24). The
two axes define separatrices that delineate regions, from where, in a steady regime, fluid
particles cannot escape. Close to the hyperbolic point, streamlines are hyperbolas. One
key remark is that, in the vicinity of the saddle point, small perturbations can push
particles across a separatrix, and expedite it in a different region. Small perturbation,
large consequences. This sensitivity is a source of chaos. Poincaré showed that, by
periodically perturbing the position of a saddle point, homoclinic orbits (i.e. joining
hyperbolic points to themselves), develop complex patterns, which, decades later, were
called ‘chaotic’ [35, 36]). The mechanism is subtle and a number of tools of dynamical
system theory are needed to describe it. Let us nonetheless attempt to provide hints.
Fig. 5.25 (extracted from J. Ottino [28]), shows what happens when a hyperbolic
point is forced to move, at constant speed, along a small loop (shown by a dashed
line). In this case, the homoclinic orbit develops a complex pattern. Lobes form, whose
number grows in time and thicknesses shrinks. In such conditions particles placed on
the orbit jump from one region to another, in a manner increasingly sensitive to noise.
In this process, after some time, particles initially placed on the orbit pay visits to
different flow regions, in an erratic manner. Particles located close to it will manifest
similar trends. This is how, though described in an oversimplified manner, chaotic
behaviour may develop close to erring saddle points. We refer readers to specialized
books (see [26, 27, 29]) for thorough presentations on the subject.
276 Transport in microfluidics

5.25: (A) steady homoclinic orbit,

with a fixed hyperbolic point;(B) the
hyperbolic point moves along a loop
(dashed line);(C) sketch of streaklines
produced by the saddle point move-
ment (From J. Ottino [28].)

In practice, modulating in time the positions of hyperbolic points is an efficient strategy

for producing chaotic trajectories, and, thereby, mix tracers in reservoirs. Fig. 5.26
shows a numerical example, which is easy to implement (15 lines of Matlab code),
that illustrates this feature. We have here a line of periodic counter-rotating vortices
defined by the stream function:

Ψ = sin πx cos πy

where x, y are the plane coordinates. Fig. 5.26(A) shows two eddies, with centres
located at x = 0 and x = 1. The hyperbolic points are located at the walls y = ±0.5;
two of them are denoted by S and S 0 . In Fig. 5.26(B), the positions, along the x axis,
of the two eddy centres are modulated in time (in the simulation, the perturbation is
0.4 sin(ωt), with ω = 0.3). Indeed, the modulation also affects the hyperbolic points.
In such circumstances, fluid particles undergo chaotic behaviour. They visit one eddy
then the other, in a random manner, tending to cover the entire space. Interestingly, an
island seems to resist.10 Fig. 5.26(B) thus suggests that modulating hyperbolic points
represents an efficient method for mixing fluid particles.

5.6 Mixing in microfluidic devices

5.6.1 How to characterize mixing ?

Complete or full mixing is defined as a state where the concentration field C(x) is
homogeneous. But how to characterize mixing when it is not complete? There exist
an infinity of measures of mixing. The most widely used, often called ‘mixing index’,
is given by the expression:

1/2
(C(x) − Cmean )2 dx
R
V
I =1− 2
V Cmean

10 This is related to KAM theorem, whose description lies beyond the scope of the book (we refer
the reader to Refs [26, 27, 29] for presentations)
 Mixing in microfluidic devices 277

Fig. 5.26: Matlab simulation showing the trajectories of two particles, in (A) steady and
(B) modulated counter-rotating vortex flows. S and S’ are two saddle points. In both cases,
the initial conditions are the same (x = 0.9; y=0.3 and x=1.9, y=0.3 – indicated by dots
–).(A) Steady vortex flow: the particles remain on closed streamlines, which reveal the flow
structure.(B) Modulated vortex flows: here, the positions of the vortex centers, and thereby
those of the hyperbolic points vary periodically in time, along the x axis. In such conditions,
the trajectories of the two particles display chaotic behaviour.

in which V is the fluid volume, dx is the elementary volume of integration, and Cmean
is the concentration averaged over V . As the system gets more an more mixed, the
index approaches unity. In the opposite case, where C is a Dirac function, I = 0.
The definition of the mixing index is arbitrary. One could have imagined a criterion
based on the concentration gradients, or the derivatives of the concentration gradients,
in view of highlighting the presence of strong gradients in the system. Alternatively,
one could use an index defined by I 0 = 1 − max(C − Cmean )/Cmean . However, for
the sake of conceptual and computational simplicity, and to be able to compare with
published data, it is now current to use I. There is no general rule to appreciate
whether the mixing is satisfactory or not, it depends on the application, although 90%
is often termed, in the literature, as satisfactory, good, excellent, or of high quality.

5.6.2 Mixing index in a box.

Let us take the example of a spot diffusing in a one dimensional box of size 2L, and
calculate the mixing index. We recall the expression of the concentration field for this
case (see Eq. (5.9))

n
!
X
2 2 2
C(x, t) = C0 1+2 exp(−Dn π t/L ) cos(nπx/L) (5.21)
1

in which D is the diffusion coefficient, C0 is the mean concentration and t is time. In

our geometry, the expression of the mixing index is:
278 Transport in microfluidics

RL !1/2
−L
(C(x, t) − C0 )2 dx
I =1−
2LC02

The mixing index is represented in Fig. 5.27 as a function of the dimensionless time
2tD/L2 .

5.27: Evolution of the mixing index

with time in a one-dimensional box,
in which, at t = 0, a small spot of
tracer has been injected.

I indeed depends on time. The longer we wait, the more mixed the system is, and
the larger I is. At late times, the first term of the series of Eq. (5.21) dominates the
others. Thereby, in this range of time, the index factor is approximately given by :

I ≈ 1 − exp(−Dπ 2 t/L2 )

The approximation shows that complete mixing is approached at an exponential rate,

the time constant being L2 /π 2 D. Thereby, as seen in Fig. 5.27, if we wait a time equal
to τD = l2 /2D, we obtain a mixing index of 1-exp(−π 2 /2) ≈ 99.3%, which is high.
Thus, in this problem, τD appears as a time above which mixing is excellent’. Further-
more, although counter–examples may be found, we will consider that, in general, by
waiting for a time τD , high mixing is achieved.

5.6.3 The problem of the slowness of diffusion.

As suggested above, in the case of pure diffusion, waiting a time equal to l2 /D (where
l is a characteristic length and D the diffusion coefficient) guarantees that mixing is
achieved. Table 5.2 provides orders of magnitude for such a time.

Sugar in water in a 10 cm high glass 200 days

Fluorescein in water, in a microwell of 1 µm 2.5 ms
Fluorescein in water, in a microwell of 200 µm 100 s
Albumin in a microreactor of 200 µm 2, 000 s
20 bp DNA strand in a microreactor of 500 µm 14 h
Table 5.2 Diffusion times for various systems.
 Mixing in microfluidic devices 279

The table 5.2 indicates that mixing is rapid in micrometric-sized systems (see the
example of the one-micron well). In this case, we can ‘laisser-faire’ to achieve mixing.
This remark applies well to nanofluidics. By contrast, for typical microfluidic reactors,
hundreds of µm in size or so, depending of the molecule, the mixing time can reach
hours. Moreover, in most situations, fluids move. With speeds of 1 cm/s, translating
100 s into a travel length leads to 1 m. This generates obvious constraints for the
design of the device. It thus appeared evident, in the early years of microfluidics, that
new ideas for accelerating mixing were needed. A bottleneck had to be resolved. This
brings us to the question of micromixing.

5.6.4 A tour in the world of micromixers

When the first (French) edition of this book was written, in 2002, about ten or so
micromixers had been invented. Today, more than a hundred exist. Several reviews
have been published (see, for instance, [42–44]).

Micro– and milli–mixers can be represented as functions of their Peclet and Reynolds
numbers, as was done in Ref. [43] (See Fig.5.28).

Fig. 5.28: Representation of micromixers and milimixers, for gases and liquids, in a Reynolds–
Peclet diagram (Reprinted from Ref. [43], with permission of Institute of Physics Publisher.
Copyright 2022).

Peclet and Reynolds numbers are defined, respectively, by P e = UDl and Re = Uνl ,
where U is a characteristic speed, l is a characteristic scale, and D and ν are, respec-
tively, the diffusion constant of the tracer and the kinematic viscosity. The ratio:
ν
Sc =
D
280 Transport in microfluidics

is the Schmidt number. It is on the order of unity for gas and around 1000 for the
liquids. The two lines, one for gas, the other for liquids, drawn on Fig. 5.28, correspond
to these values.

Restricting ourselves to liquids, one can distinguish low Reynolds numbers micromix-
ers, working up to Re = 10 or so, and moderate Reynolds numbers micromixers or
millimixers, which operate at Re > 10, and exploit, most of the time, eddies generated
by the fluid inertia, as we saw in Chapter 3. These can be called ’inertial micromixers’.
In Fig. 5.28, mixers have also been classified in several categories: passive or active,
chaotic or not. We now look at particular cases, which will illustrate the different types
of mixers published in the literature.

5.6.5 Reducing sizes to speed up mixing

In order to mix, one could think of shrinking the system size so as to decrease the
diffusive time, and thereby mix at a faster speed. Fig. 5.29 shows an example of a
naive device that would make use of this idea.

5.29: T–junction followed by a restric-

tion, added to facilitate mixing.

Two fluids, A and B, enter a T-shaped intersection. We previously studied this geom-
etry, called T-sensor. Downstream of the T-junction, assume the cross section of the
channel is reduced. For instance, its width w0 is reduced to w < w0 . The corresponding
diffusive time τ in this part of the channel is given by the relation :

w2
τ∼
D

This looks easy. Just reduce the size, and the mixing time is reduced by a factor
(w0 /w)2 . The problem is the mixing length. In the same channel, the two fluids have
a speed Q/wh, where Q is the flow rate and h is the channel height, which is the same
before and after the restriction. Thus, the length necessary to achieve mixing is :

Qw
L∼
hD
 Mixing in microfluidic devices 281

It increases by a factor (w/w0 ). Let us take orders of magnitude: with w and h equal
to 100 µm and a flow rate equal to 100 µL/s, L is 100 m. This is far too large. One
method is to parallelize the entries. Topological constraints force to escape from the
plane, i.e. design a three–dimensional system. An example is shown in Fig. 5.30.

Fig. 5.30: Micromixer built by Upchurch. (Left) SEM image of the micromixer. (Right)
Integration of the micromixer at the entry of a microfluidic device.

The two fluids A and B enter from the sides of the left–hand image in Fig. 5.30. Each
flow rate is divided into 24 =16 branches. Branch widths are substantially smaller, a
factor or 4 or so. Divided as such, A and B meet in the central part of the left-hand
image of Fig. 5.30. They exit normally to the plane of the device (see the tubes of Fig.
5.30, right). Using the above formula, mixing length is decreased 64 times, which is
progress.

5.6.6 The herringbone micromixer

The herringbone mixer [45] is shown in Fig. 5.31.

The bottom wall of the channels is structured: oblique grooves, asymmetric with re-
spect to the channel width, are built along it. This is the ‘herringbone’ structure. They
force the flow to develop recirculations along the mean stream, or, said differently, they
cause fluid particles to spiral out. Every five grooves, the centres of the two eddies,
are displaced. In the frame of reference of the mean flow, the saddle point positions
are modulated in time, inducing chaotic behaviour, according to the mechanism men-
tioned earlier. The following expression for the mixing length Lm was found consistent
with the experiments:

Lm ≈ w log(P e)

where w is the channel width and P e is the Peclet number (calculated with w, the
average flow and the fluorescein diffusion coefficient). This expression reflects the expo-
nential increase of trajectory separations, discussed in the previous section. In practice,
Lm is a few millimers for Peclet numbers on the order of 105 . [45]. The herringbone
282 Transport in microfluidics

Fig. 5.31: Herringbone micromixer. Structuration of the microchannel bottom wall with
grooves, forcing the flow to swirl (see the bottom figure). Mixing of fluorescein in water
is obtained after a few microchannel widths. (Reprinted from [45] with permission from
American Association for Advanced Science. Copyright 2005.)

mixer, due to its simplicity and efficiency, is frequently used in laboratories. Its limi-
tation, common to practically all micromixers, is the small throughput.

5.6.7 The rotary micromixer

We now consider active mixers. Using polydimethylsiloxande (PDMS) valve technol-

ogy, S. Quake [46] developed a circular micromixer (see Fig. 5.32). A peristaltic pump,
activated by three microvalves (we will describe the technology later), transports DNA
and cells in an annular channel, along the curved arrow shown in Fig. 5.32).
The two entities are transported at the mean flow speed, but, in the meantime, velocity
gradients disperse the spots along the flow streamlines, We discussed this phenomenon
earlier. The tracers form arches, which, over time, because of the confinement, stack
onto each other. After a few rotations, thin striations appear. As their widths decreases
in time and their number increases, mixing is rapidly achieved. This phenomenon was
discussed in detail in Ref. [25]. In practice, mixing is achieved in a few seconds, well
before the Taylor dispersion regime establishes.

5.6.8 The cross-channel micromixer

The cross-shaped micromixer is another active mixer. It consists of a principal channel,

along which a stationary flow is imposed, which intersects with side channels, along
 Mixing in microfluidic devices 283

Fig. 5.32: Rotary micromixer: fluids or suspensions are introduced in the annulus and
driven by a peristaltic pump, activated by valves (channels transverse to the ring); 5 nl
of a micromixer before (a) and after (b) mixing. DNA and cells are mixed in a few seconds.
(Reprinted from [46] with permission from IOP. Copyright 2022.)

which a time-periodic flow is imposed (see Fig. 5.33). The velocity field is thus time-
dependent, and then, according to the preceding discussion, the development of chaotic
trajectories is possible. It has been shown in this system that, at the intersection, a
material line is subjected to a succession of folding and stretching [47–51]. This is due
to the fact that, by superimposing a time-dependent side flow onto the mean motion,
one creates modulated hyperbolic points (located at the junction corners [49]), which
induce, as explained in the preceding section, stretching and folding of the material
lines.

5.33: Cross–channel mi-

cromixer: fluids (water and
fluorescein solution) penetrate
the junction from the left,
and are subjected to the time
periodic action of a side flow,
activated by a pump [49].

In practice, depending on the flow conditions, stretching and folding intervene 1– 3

times in the intersection. A phenomenon of resonance has been uncovered, for which,
in certain conditions, lobes develop at the intersection and allow us to achieve high
mixing indices [50,51]. Fig. 5.33 illustrates this feature. The length of mixing Lm is, in
practice, several w, where w is the channel width. The range of conditions for which
mixing is achieved can be broadened by placing several cross-channels in series [49,52]).
284 Transport in microfluidics

5.6.9 Mixing in droplets

As we saw in Chapter 4, as droplets move downstream, they generate internal recir-

culations [53]. The detail of the corresponding mixing process is shown schematically
in Fig. 5.34 [54].

5.34: Mixing in droplets.

(Reprinted from [54, 55] with
permission from AIP Publish-
ing. Copyright 2022.)

After the T-junction, the dye concentrations, in each half of the droplet, are homo-
geneous and thus a strong gradient exists across the two regions. The role of the
turnings is to vary, in time, the recirculation pattern, so as to develop, in a process
discussed in the preceding section, stretchings and foldings of the material lines. Fig.
5.34 shows that after two turnings, striations appear. As the turnings are repeated,
chaotic behaviour takes place, leading to mixing. This process, modelled as a baker’s
transform in [55], allows mixing to occur ’for free’. The process is crucial for biological
and chemical applications. Allowing droplets to be treated as chemical microreactors,
it has played a major role in the development of droplet–based microfluidics.

5.6.10 Mixing at moderate Reynolds numbers

Mixing with Dean vortices. We saw in Chapter 3 that when a flow is driven in a
curved channel, Dean vortices develop, with speeds increasing with the square of the
flow rate. These vortices have been exploited to mix fluids. An example is shown in
Fig. 5.35 [56].

1.0
Re = 20

0.8
Re = 20
Mixing index

0.5
Re = 1
0.4 Mixing
unit 2
0.2

0.0
Mixing Mixing Mixing Mixing
Inlet Outlet
unit 1 unit 2 unit 3 unit 4

Fig. 5.35: Dean mixer in a serpentine. (Right) Mixing index along the serpentine, at different
Reynolds numbers [56]. (Creative Commons Attribution (CC BY) licence.)
 Mixing in microfluidic devices 285

In this case, the curved channel, by developing Dean recirculations, mixes the two
dyes injected at the entry. Fig. 5.35 shows that, after four turns, for a Reynolds num-
ber of 100, the mixing index is almost equal to unity. At smaller Reynolds numbers,
Dean vortices are weak and mixing is poor. Dean micromixers thus operate at mod-
erate and large Reynolds numbers, below turbulence onset. In practice, a range of
Reynolds numbers ranging between 50 and 500 is frequently used. This range favours
high throughput and, in the meantime, keeps the flow under control. However, mixing
frequently occurs before the fluids penetrate in the curved part of the system. This
is because, since the Reynolds is high or moderately high, eddies naturally appear
at the entry. This indeed depends on the design of the entry channels. Eddies may
also nucleate at corners, when the serpentine has a crenel shape. High mixing indexes
are favoured by the presence of temporal instabilities, triggering the onset of chaotic
trajectories, as shown recently [61].

Mixing in T junctions at moderately large Reynolds numbers. At moderately large

Reynolds numbers, typically above 20-100, microfluidic flows enter a domain in which
eddies naturally appear: close to corners, in diverging sections (see Chapter 3), or
around curved boundaries. These eddies may, in turn, trigger temporal instabilities.
There are various contributions on the subject, focusing, most often, on the flow struc-
tures and their connections to mixing. They are periodically reviewed (see, for in-
stance, [62]).

Fig. 5.36: Fluids introduced in a T–junction and developing eddies. (a) Re=186; (b) Re =
600. (Reprinted from Ref. [63], with permission of Elsevier. Copyright 2022.)

In the example we take here, two miscible fluids are injected in a T–junction and are
further collected in a rectangular channel. Numerical simulations show that eddies
develop right at the entry (see Fig. 5.36). These eddies, being induced by the cur-
vature of the streamlines, are similar to Dean vortices. Here, the Reynolds number
Re is defined by Uνd in which U is the ‘superficial‘ speed (i.e. the flow rate of each
branch divided by the cross section area), d is the hydraulic diameter, and ν is the
kinematic viscosity of the (identical) fluids. For Re comprised between ≈ 20 and 150,
two stationary symmetric vortices appear at the entry. Above 150, the flow pattern
undergoes a bifurcation towards asymmetric eddies. Above 400, a new regime takes
286 Transport in microfluidics

place, in which these vortices become time–dependent. Simulations show that in such
conditions, substantial mixing between the two fluids takes place at a few hydraulic
diameters from the entry (see Fig. 5.36 (B)). The simulation was found to be in good
agreement with the experiment [64]. Here again, the modulation of the saddle point
is probably at the origin of mixing11 .

5.7 Four applications of transport of matter in microfluidics

5.7.1 Example 1: measurement of fast reaction kinetics in Y–junctions

In principle, fast reaction kinetics can be measured in T– or Y–junctions. A flow

driven at speed U , in such a system, can resolve kinetics on the order of δ/U , where
δ is the spatial resolution. With δ = 10µm, and U =10 cm/s, a kinetics of 0.1 ms can
be resolved. This is two orders of magnitude faster than conventional systems, such
as the stop-flow’, which consists in pushing, with a syringe, two reagents in a tank, as
fast as possible, and stopping brutally. Such systems have temporal resolutions on the
order of 20 ms.
The interpretation of the chemical phenomena taking place downstream of T or Y
junction is nonetheless not straightforward to analyse [19, 65, 66]. Fig. 5.37(A) shows
an example of the fluorescence field produced by two reagents introduced in a Y–
junction.

Fig. 5.37: Measurement of the kinetics of a protonation reaction, in which a fluorescent dye
(acidic coumarin) is produced. (Upper left) Design of the microfluidic device. (Lower left)
Typical stationary field of fluorescence measured in the collecting channel. (Right) Plot of
the maximum fluorescence intensity as a function of the streamwise coordinate, converted in
time by the relation τ = X/U (see text) [66].

The solutions driven in the Y-junction of Fig. 5.37 are acetronitrile solutions, one
containing basic coumarin and the other triflic acid. The reaction produces acidic
11 This is an hypothesis. The point is not discussed in the cited paper.
 Four applications of transport of matter in microfluidics 287

coumarin, which is fluorescent. Fig. 5.37 shows the field developed by the reaction.
Owing to the kinetics of the reaction, which depends on the local concentrations of the
reagents, the fluorescent field is asymmetric. The concentration fields of the reactants
are symmetric (they have the error function shapes described earlier), but the product
concentration profile is not. A plot of the fluorescence maximum as a function of time
τ = X/U , where X is the downstream coordinate, and U is the mean speed, is shown
on the right of the figure. The graph shows that, with microfluidics, the kinetics of
fast reactions can be measured. In Ref. [66], a detailed theoretical/numerical analysis
was performed.

5.7.2 Example 2 :measurement of fast reaction kinetics in droplets and

screening of chemical reactions

A droplet-based method for measuring reaction kinetics was proposed in 2003 [53]. As
shown above, in droplets, because of the internal recirculations, mixing time are small.
For example, with droplets moving at 10 cm/s in a 100 µm side square channel, the
mixing times are on the order of 1 ms. Fast reaction kinetics are thereby accessible to
the measurement. The demonstration is shown in Fig. 5.38 [53].

Fig. 5.38: The upper figure shows the droplets formed in the system. In the lower figure Fluo4
and CaCl2 solutions are injected in the T-junction. The increase in the fluorescence signal
shows the development of the complexation reaction as droplets are moving downstream.
(Reprinted from [53] with permission of Wiley and Sons Eds. Copyright 2022.)

In the experiment, Fluo–4 and CaCl2 solutions are injected in the T–junction. They
form, with a separation buffer, the content of the droplets. Fluo–4 is weakly fluorescent,
but, in the presence of calcium ions, it forms a highly fluorescent complex. With speeds
on the order of tens of centimetres per second (see Fig. 5.38), it was possible to resolve
submillisecond kinetics [53].
The same geometry was used to mix chemical reagents, and screen the characteristics
of the products at various concentrations ratios [53]. This screening was achieved by
varying the flow rates. In this manner, the amounts of reagent could be varied in each
droplet. Droplets are emitted at kHz and the screening is fast – orders of magnitude
faster than any robotic equipment –. In the meantime, the quantity of reagents used
in each reaction is orders of magnitude smaller than traditional technique: a droplet
288 Transport in microfluidics

encloses, typically, one nanoltre, while a well, in a 96 or 384 well plate, uses one millil-
itre or so. The work prompted new ideas that today, are harnessed in a number of
successful biotechnological companies.

5.7.3 Example 3: shaping concentration fields

With microfluidics, it is possible to shape concentration fields [67]. The principle is

shown in Fig. 5.39.

Q Q
C1 C2

2Q/3 2Q/3 (C1+C2)/2 2Q/3

C1 C2

5.39: Principle of the concentration gradi-

ent generator.

Two dyes, of concentration C1 and C2 are introduced at the top of Fig. 5.39. Four flow
streamlines are sketched on the figure. Due to the large Peclet numbers at work, and
the short travel times, dye 1 is transported directly in the left channel, dye 2 in the
right one, and both of them penetrate, in equal proportions, in the central channel.
Further downstream, if the channel is sufficient long, they mix. Then, starting with
two concentration levels, one generates a third one, intermediate between the two.
Thus, if the two dyes are red and blue, we will create an additional colour, violet. By
repeating the process, more colours can be created. The network of Fig. 7.23 shows
that nine colours (i.e. nine distinct levels of solute concentration) can be obtained.
In the experiment, the nine concentration levels were recombined in a collecting chan-
nel, in order to produce a constant concentration gradient (See Fig.7.23). This system
was used in chemotaxis studies: the migration of neutrophils, placed at the bottom
of the collecting channel, and subjected to nutrient gradients was analysed [68]. The
10-fold log levels solute distributor [69], presented in Chapter 3, was inspired by this
work.

5.7.4 Example 4: Lipid Nano Particles production in inertial

micromixers

Lipid Nano Particles (LPN), sketched in Fig. 5.41 (A), are complex nanoparticles, 50
– 100 nm in diameter, formed through a self–assembly process, including, according
 Four applications of transport of matter in microfluidics 289

5.40: Image taken from [68], in

which a nine–channel gradient gen-
erator is demonstrated.

(a) (b) Cytoplasm

Nucleic acid
2

VT mRNA nanosystem
complex
Endosome

Receptor

Endosome
escape
3
Vesicle Transitation
Polypeptide Nucleus

Lipids
Ribosome

Fig. 5.41: A: LNPs structure: a ionizable lipiidic shell encapsulates vesicles, that encapsulate
nucleic acids. B - Nucleid Acid delivery into the cell, including: endocytose, endosome forma-
tion, endosome escape and, for the case of mRNA, protein synthesis in the ER (endoplasmic
reticulum) and its finalization, prior to excocytose, in the Golgi apparatus (not shown)

to Ref. [57], three steps: discoidal cluster formation, aggregation of clusters into larger
patches, and vesicle formation. LNPs are used as vectors for nucleic acids. They migrate
in the tissue, attach to the cells, and penetrate into them, thanks to their affinity with
the cell membrane. Having penetrated the cell, LNPs deliver their passengers, which
are designed to interact with the cell machinery (see Fig. 5.41(A)) . Nucleic acids
carried by LNPs can be DNA, mRNA, or siRNA. LNPs have been highlighted during
the COVID crisis. They vectorized mRNA into cells and made possible mRNA–based
vaccination [58].

How to create LNPs ? In order to assemble the elements forming the LNPs, mix-
ing is required. In large mixers, because of turbulence, size polydispersivity is large
and encapsulation efficiency is low. Post–processing steps, such as filtration, extru-
sion and centrifugation, are needed to produce functional LNPs in this manner. Using
microfluidic mixers, in particular inertial milli/micromixers, in view of reaching high
throughputs, is an option [59–61]. Fig. 5.42 shows a four–ring micromixer, producing
290 Transport in microfluidics

functional LNPs, under flow rates on the order of several tens of ml/min.

Fig. 5.42: Three–dimensional view of the device, in which the aqueous phase containing the
nucleic acid (plasmid DNA (pDNA)) diluted in an acidic buffer is injected on one side, and an
ethanol-lipid solution on the other. The mixing of the two constituents lead to the formation
of LNPs. The process is well controlled [61].

In Fig. 5.42, a three dimensional view of the four-ring system is shown. The aqueous
phase containing the nucleic acid diluted in an acidic buffer is introduced in one branch,
and ethanol phase containing the lipids in the other. As they mix together, lipids,
exposed to water, form vesicles, encapsulating their partners, in a process called‘’self
assembly’. LNPs thus form. An image of a LNP, obtained in the system of Fig. 5.42,
100 nm in size, transporting plasmid DNA (pDNA) with an excellent encapsulation
yield, is shown [61]. With the progress made in the domain over the recent years, and
the numerous applications of nucleic acid vectorization to the fields of vaccination and
therapeutics, it seems obvious that inertial micromixers will be increasingly used in
the forthcoming years.

5.8 Transport of matter across interfaces

5.8.1 Basics

Transport across interfaces occurs in many systems: for instance, osmotic membranes,
liquid-liquid extraction, or droplets. The subject is well described in classical textbooks
[70, 113]. When two solutions 1 and 2, incorporating solutes of concentrations C1 and
C2 , respectively, are separated by a permeable interface, equilibrium takes place if the
following condition is satisfied
K = C1 /C2
in which K is the partition coefficient. If the concentration ratio is not equal to K,
then fluxes develop across the interface, in order to restore equilibrium. In the chemical
engineering literature, a convenient notion – the mass transfer coefficient (we call it
here hm ) – is often used to quantify the process. It is schematized in Fig. 5.43..
Here a volume, assumed to be perfectly mixed at all times, is filled with a solution,
that includes a solute of concentration Cbody . Outside, the concentration, also perfectly
 Transport of matter across interfaces 291

5.43: Body exchanging matter with a

fluid. The mass transfer coefficient is
a convenient tool allowing the process
to be characterized without solving the
equations of the problem (see text).

mixed, is equal to Cext . Although different proposals exist in the literature, we consider
here the following definition of the mass transfer coefficient [70]:

J
hm =
A(Cbody − KCext

in which J is the mass flux across the exchange area A and K is the partition coefficient.
We saw that Fick’s law impose fluxes proportional to the concentration gradient.
We may thus expect that, at low Reynolds numbers, and in regimes where diffusion
prevails, hm will be proportional to the inverse of the system size. By reducing system
sizes, we thus accelerate the transport, and reduce the time needed to achieve processes
based on mass transfers. This is where microfluidics can be advantageous.

5.8.2 Microfluidic liquid–liquid extraction

Liquid–liquid extraction in channels. The idea was harnessed in liquid-liquid extrac-

tion systems, schematized in Fig. 5.44 [71]. In this work, the wall wettability of the glass
microchannel is textured, so that one side is hydrophilic and the other hydrophobic. In
such conditions, a stable countercurrent flow of an organic phase could be driven along
an aqueous phase, itself driven in the opposite direction. In this system, extraction of
a cobalt complex from toluene into water could be achieved in a few seconds, with an
efficiency (the ratio of the extracted phase concentration over its initial concentration)
of up to 98% [71].

Droplet–based liquid–liquid extraction. This time, extraction is performed with mi-

crofluidic droplets. As shown in Fig. 5.45, droplets are formed in a hydrodynamic
focusing junction [72]. The droplets are composed of water or water/glycerol mixtures
and the external phase is octan-1-ol, to which fluorescein was added. The choice of
ethanol was motivated by its high partition coefficient, with respect to a number of
solutes, including fluorescein and rhodamine. Droplets move downstream, at a speed
of 10 mm/s.
292 Transport in microfluidics

5.44: A stable flow of toluene is driven

along an aqueous phase, itself driven
in the opposite direction. The config-
uration is called ‘counterflow’. In this
system, extraction of a cobalt com-
plex from toluene to water could be
achieved in a few seconds with a high
efficiency.

Fig. 5.45: Droplets are composed of water/glycerol mixtures and the external phase is octan-
1-ol, to which fluorescein is added. Their mean diameter is 195 µm. Channel height h is 95
µm and width 205 µm. Droplets move downstream, i.e. towards the right, at speeds of 10
mm/s. The left figure shows the system, just after droplet formation, and the right figure,
further downstream, at 1 cm from the entry. .

The experiment showed that, after a few seconds, almost all fluorescein is transferred
from the external phase (octanol) to the aqueous droplets (See Fig. 5.45, right). In
Ref. [72], this was called extraction, considering fluorescein is extracted’ from octanol.
The authors also investigated the inverse case, i.e. rhodamin transferred from the
droplet to the external phase. This case can be called ‘delivery’. In all cases, they
found that, depending on the flow rate, the extraction times vary between 0.2 and 0.8
τD , where τD is the diffusive time h2 /D, where D is the diffusion constant of the solute
in octanol (the other diffusion constants being comparable) and h the channel height.
The dependence of the extraction time with the flow speed, is linked to the presence
of eddies inside and outside the droplets, as we saw in Chap 3. Using a constant mass
transfer coefficient, in this case, would be erroneous.

5.8.3 Bubbles and droplet dissolution: the Epstein-Plesset theory

A bubble immersed in an undersaturated liquid dissolves. As sketched in Fig. 5.46, gas

around the bubble diffuses away, depleting the interfacial region, forcing the bubble
to transfer gas in the liquid, in order to maintain the interface at equilibrium. In this
process, the bubble shrinks. But even in saturated and oversaturated liquids, bubbles
may shrink, owing to the action of capillarity, as will be seen later. Since diffusion and
interfaces are involved in these situations, one may think that miniaturization will con-
siderably affect the behaviour of the systems. We may expect, for example, that small
 Transport of matter across interfaces 293

bubbles will dissolve faster, because mass transfers are accelerated by miniaturization.
Depending on the case, this acceleration may be problematic or advantageous.
The problem of bubble dissolution, in a fluid at rest, was described theoretically, in
a comprehensive and concise manner, by Epstein and Plesset [73], leading to the so-
called Epstein-Plesset theory. Fig. 5.46 sketches the geometry of the problem.

P0

P0+2γ/R(t)
5.46: Epstein–Plesset theory. In
non–saturated liquids, gas diffuses in
the liquid phase to maintain equi-
librium at the interface, dictated by
Henry’s law.

In the liquid phase, gas concentration C(r, t) (where r is the radial coordinate and t
the time), is governed by diffusion equation. In spherical coordinates, taking angular
invariances into account, the equation reads:

∂C 1 ∂C 2 ∂C
= D∆C = D 2 (r ) (5.22)
∂t r ∂r ∂r

in which D is the diffusion coefficient of gas in liquid. Here we consider two cases (we
use D. Lohse’s review [79] for the presentation).

Large bubbles. .
For large bubbles, capillarity can be neglected. In such conditions, the boundary con-
ditions are:

C(r, 0) = C∞ . and C(R, t) = Cs

where C∞ is the gas concentration far from the bubble, Cs is the saturation con-
centration, also called solubility, and R(t) is the bubble radius. Cs is the maximum
gas concentration that a liquid, at equilibrium, can solubilize. It depends on pressure
and temperature. The warmer the liquid, the smaller the solubility. This dependence
explains why, when a glass of water warms up, bubbles spontaneously nucleate at
the surface. Forming bubbles is a way, for the liquid to degas, i.e. to decrease its gas
content so as to match a smaller Cs .
Let us return to Eq. 5.22. In the limit where the process is slow, ∂C
∂t can be neglected,
and the solution to Eq. 5.22, together with the boundary conditons, read:
294 Transport in microfluidics

R
C(r) = C∞ + (Cs − Ci )
r
Except when C∞ = Cs , a flux J = D( ∂C ∂r )r=R develops across the interface, in one
direction or another, depending on the sign of C∞ − Cs . An important parameter here
is the oversaturation, defined by

C∞
ζ= −1
Cs

ζ can be positive (oversaturated solution) or negative (undersaturated solution). From

the previous relations, one can determine the mass exchange rate across the interface.
It is given by

dm ∂C
= 4πR2 D( )r=R = 4πRDζCs (5.23)
dt ∂r

in which m = 43 πR3 ρG , in which ρG is the gas density, is the bubble mass. We can
establish the following relation:

dR D D
= (C∞ − Cs ) = ζ Cs
dt ρG R ρG R

After integration, we find:

2DζCs
R(t)2 = R(0)2 + t (5.24)
ρG

where R(0) is the initial bubble radius. When ζ < 0, the bubble shrinks and when
ζ > 0, it grows. In the former case, the bubble lifetime, in a pure liquid (ζ = −1), is
given by:

ρG R02
τ= (5.25)
2DCs

Table 5.3 provides a few values of Cs and τ , for a bubble of 100 µm in radius and
three gas/liquid systems.
The formulas we just established have interesting consequences for microfluidics: when
bubbles are trapped in a microfluidic device, it is often difficult to remove them, be-
cause, most of the time, as explained in Chapter 4, they are anchored by the roughness
of the wall surface, trapped by wetting heterogeneities, or captured in dead zones. A
strategy currently used in the laboratories is to evacuate the liquid, before filling.
Then, according to the theory, trapped bubbles will dissolve. However, theory also
tells us that this strategy is not efficient with air, because, according to Table 5.3,
significant waiting times would be needed. For instance, for an air bubble, 100 µm in
 Transport of matter across interfaces 295

Gas Medium Solubility C*(w/w) τ (s)

CO2 Water 1.7 10−3 6
N2 Water 10−5 1200
O2 PFC ∼2 10−4 60
Table 5.3 Solubilities of various gases in liquids, and dissolution times estimated for a
bubble of 100 µm in radius, and pure liquids (see Eq.5.25). The relation between C* and Cs
is Cs = ρL C*, where ρL is the liquid density

radius, one must wait 20 min before it disappears. By using carbon dioxide, whose
solubility is much higher, this time is reduced to 6 s. This is why devices are often
pre-filled with this gas. In the field of microfluidics, researchers easily understand that
solubility favours rapid dissolution, but they rarely pay attention to Epstein–Plesset
theory.

Small bubbles. .

The calculation we made neglected surface tension. As noted, it applies to large bub-
bles. When a large bubble shrinks, at some point, it becomes small and capillarity
ceases to be negligible. To describe the shrinking process fully, we thus need to take
capillarity into account. The problem was solved by Epstein and Plesset [73]. The
calculations are elaborate, and we give here a summary of the results, using again D.
Lohse’s review [79].

With capillarity, the situation changes: pressure Pg inside the bubble is above that in
the liquid. We have:

2γ
Pg = P0 +
R

in which P0 is the ambient pressure and γ the surface tension. This is Laplace’s law,
which we discussed in Chapter 4. The law is interesting, because it provides a crite-
rion for distinguishing between what we called ‘small’ and ‘large’ bubbles. From the
formula, we may consider that ‘small’ bubbles have radii below P2γ0 and large bubbles
have radii larger than this. For clean water and air, the cross-over between the two
cases, i.e. P2γ0 , is 1.4 µm.

The gas concentration at the interface, on the liquid side, is given by Henry’s law:

CS
C(R, t) = Pg
P0

With this, calculations similar to those carried out previously allow us to determine the
temporal evolution of R. We will concentrate on the case where capillarity dominates
the problem, i.e. R << P2γ0 A calculation carried out in this limit leads to the formula:
296 Transport in microfluidics

dR 3DCs
=−
dt 2ρG R

The bubble shrinks, according to a law given by:

3DCs
R2 (t) = R2 (0) − t
ρG

Now, the life time of the bubble is as follows:

ρG R2 (0)
τ=
3DCs

Note that, despite the fact that the regime is dominated by capillarity, the bubble
lifetime is independent of surface tension. For a nitrogen bubble measuring 1 µm in
radius, in water, the survival time is 1 ms. Micrometric bubbles dissolve extremely
fast.
As noted, the full determination of the bubble dynamics, for arbitrary values of ζ and
R(0), including saturation and capillarity, was performed by Epstein and Plesset [73].
In all cases, it was found that for ζ < 0, the bubble always shrinks while for ζ > 0, it
may shrink or grow, depending on the parameters of the problem. A stationary state
exists, for which the oversaturation ζ compensates the action of capillarity, but it is
unstable [79]. The theory, applied to nanobubbles, concludes that in practice, bubbles
of that size always disappear, in 1 ms or so [79].

5.8.4 The long lifetime of surface nanobubbles

According to Epstein–Plesset theory, one must be fast to see submicrometric bubbles.

They dissolve so rapidly that a standard camera (with a frame rate of 100 images/s)
coupled to a high magnification microscope would be too slow to image them. Early
observations, made in 2000–2001 by three groups [75–77] indicated that in oversatu-
rated water and over hydrophobic surfaces, nanobubbles survive for hours. An example
of long–lived nanobubbles [77], observed with the atomic force microscopy (AFM), is
shown in Fig. 5.47 (A).
The observations made by the three groups challenged our understanding of the liq-
uid/vapour interfaces, and, for this reason, they attracted much interest. However, for
years, the situation remained confusing. The existence of long–lived nanobubbles was
confirmed by a number of investigators and rejected by others.12 Eventually, based on
theory, numerics, along with considerable experimental effort, the community came to
12 In the confusion, some companies proposed to sell bulk nanobubbles in bottles, arguing that they
enhance the growth of plants, improve the life of oysters, and reduce the occurrence of heart or cancer
problems. What we can say today, is that there is no indication that, if these nanobubbles exist, they
are not trapped by impurities, and should be seen as surface nanobubbles [80]. Whether they can
heal something is another subject.
 Transport of matter across interfaces 297

Fig. 5.47: (A) AFM image of a single large surface nanobubble on a hydrophobized gold
surface. (Reprinted from [77], with permission of the American Physical Society. Copyright
2022.) (B) Shrinking process of a pinned surface nanobubble with footprint diameter L and
initial contact angle θi > θe towards the equilibrium contact angle θe [74].

the conclusion that these bubbles exist [78, 79]. There is a diversity of cases, but, in
most of them, long–lived nanobubbles are several tens of nanometres in size, contain
hundreds of molecules, and have semi-spherical shapes, with contact angles substan-
tially more acute than Young angle.
How can we reconcile these observations with Epstein–Plesset theory? One notes first
that Epstein-Plesset theory concerns bulk bubbles, not surface bubbles. The point
raised by [74] is that nanobubbles are stabilized by the pinning of their contact line
at the surface. As we explained in Chapter 4, when wetting is partial, roughness and
wetting heterogeneity generate pinning. Pinned nanobubbles, as they shrink, decrease
their contact angle, because they keep the same footprint (see Fig. 5.47 (B)). To
understand nanobubble stability, we may reproduce the argument of Ref. [74].13 The
kinetics of the bubble mass M derives from an equation similar to Eq(5.23). It is given
by:
 
dM π 4γ sin θ cs Lc
= − LD (P0 + ) − c∞ f (θ) ∼ K( sin θ − ζ)
dt 2 L P0 L

in which f (θ) is a geometric function characterizing the bubble geometry [74, 81], and
K is a factor. The key point is that, for ζ > 0, and for a certain range of L, this
equation admits a stationary solution, characterized by a contact angle θe given by:

L
sin θe = ζ
Lc

in which Lc = 4 Pγ0 ≈ 2.84 µm. At equilibrium, and for bubbles smaller than Lc /ζ,
Laplace pressure counteracts the gas influx induced by the oversaturation. Large sur-
face bubbles, i.e. larger than Lc /ζ cannot reach an equilibrium: they swell and detach
from the surface, by buoyancy. The equilibrium, found for small bubbles, is stable.
Should the bubble swell, Laplace pressure increases, gas crosses the interface, and the
bubble shrinks. A similar reasoning can be made for negative volume perturbations.
13 Amazingly, the work extended a theory made by Y. Popov, concerning the coffee ring effect. [81]
298 Transport in microfluidics

In all cases, the system is stable. The theory also explains that θe is uncorrelated
with the Young angle. The theory was well–supported numerically [82]. As a whole,
one may conclude that nanobubbles can survive. Interestingly, the theory resolved a
fifteen–year puzzle.14

Microfluidic contrast agents.

It is possible to delay bubble dissolution by coating them with a polymerized shell
and filling them with a heavy gas (for instance, perfluorohexane C6 F14 ). The shell
being porous, the bubble still dissolves, but the process takes a much longer time,
tens of minutes or so, in water, for 5 µm diameters. These bubbles, possessing a high
echogenicity, can be used as ultrasonic contrast agents (UCAs). With an echograph,
it is possible to visualize the bubbles and see where in the body they travel, and at
what speed. These bubbles are used to analyse, for instance, the presence of leaks
at the level of the heart valves. In the USA each year, this technology is used on
30,000 patients. It is possible to image different parts of the body without contrast
agents, but, in this case, the image quality is reduced, and, sometimes, crucial details
are impossible to detect. It has been shown that, with microfluidics, one can create
highly monodisperse contrast agents [83,100]. An example is shown in Fig. 5.48 [100].

Fig. 5.48: Microfluidic contrast agents, coated with polyvinyl alcohol (PVA), along
with their size distribution [100]. (Courtesy of Ugur Soysal and Pedro Azevedo.)
.
Monodisperse contrast agents are advantageous for obtaining more intense acous-
tic responses (all bubbles resonate and produce strong signals). They are interest-
ing for drug delivery applications (the optimisation of the delivery process, based
on bubble bursting, is sensitive to the size), and for performing non invasive pres-
sure measurements (bubbles emit echos depending on the local pressure and the
size) [84–86, 100]. At the moment, microfluidic monodisperse UCAs are awaiting
commercialization [100]. Note that the coupling between microfluidics and acous-
tics has been explored long ago, in the years 2003–2010, in particular for particle
sorting [24, 87].

14 The theory seems simple. Then why did we have to wait for fifteen years to formulate it ?
This is hows science proceeds. Situations may be blurred by experimental confusion, induced by the
considerable difficulties experiments had to face. Also, elaborating the correct vision of a complex
problem, involving unsettled questions, takes time. In a private communication, D. Lohse told that
he discovered the argument during a Taipeh–Amsterdam flight. One may perhaps infer that flying
above continents stimulates inspiration.
 Particles and microfluidics 299

5.9 Particles and microfluidics

5.9.1 How do small particles diffuse close to a wall?

We saw that small particles diffuse with a diffusion coeffient given by the Stokes–
Einstein law. We recall here the expression of the law:

kT
D=
6πRµ

This law was established in an infinite medium. Close to a wall, the movements of the
particle are slowed down, and the diffusion constants decrease. This is called hindered
diffusion’. How can we describe the phenomenon? Faxen in 1922 [88] and Brenner in
1961 [89] carried out the calculation. The coefficient of diffusion is no longer a single
number, but a diagonal tensor, with two components, one parallel to the wall, D// [88]
and the other normal to the wall [89, 90], D⊥ . The corresponding formulas are:

D// ≈ (1 − 9r/16z + r3 /8z 3 − 45r4 /256z 4 − r5 /16z 5 )D

and:
6(z − r)2 + 2r(z − r)
D⊥ ≈ D
6(z − r)2 + 9r(z − r) + 2r2

in which r is the particle radius, z the distance of the particle centre to the wall, and
D is the bulk diffusion coefficient.

Fig. 5.49: Hindered diffusion correction factor D// /D, D⊥ /D vs nondimensional gap size
between particles and glass surface (z − r)/r, where r is the particle radius and z is the
centre distance to the wall. D is the diffusion coefficient measured in the bulk. The full
line corresponds to the theoretical models discussed in the text. (Reprinted from [91], with
permission of AIP. Copyright 2022.)

Figure 5.49 shows measurements, based on evanescent waves, of the two diffusion
coefficients as a function of the distance to the wall (z − r)/r, in which z, as we
said, is the distance of the particle centre to the wall, i.e. its ‘altitude’ [91]. Similar
measurements were obtained by Ref. [92]. As we approach the wall, D// /D decays to
300 Transport in microfluidics

a value close to the theoretical expectation, i.e. 0.32, while D⊥ decays to zero. The
effect of the wall is thus important at distances comparable to the particle radius.

5.9.2 Particles deposition at low Reynolds numbers

We just saw how walls affect the diffusion constants of particles. More generally, close
to a wall, and at small Reynolds numbers, the particle is subjected to a number of
effects, sketched in Fig. 6.37.

Fig. 5.50: Spherical particle moving close to a wall. Van der Waals force Fvdw (z), repulsive
electrostatic force Fe (z), and viscous drag γU (z) are represented.

The effects include brownian agitation (that we analysed earlier), viscous forces (due
to particle displacement and rotation), Van der Waals forces (attracting the particles
towards the wall (see Chapter 2), and electrostatic forces (due to the presence of
surface charges, as will be seen in Chapter 6). Depending on the conditions, these
effects carry the particles away from the wall or bring them to it, onto which, in most
situations, they stick.

The problem looks complicated, but recently, a comprehensive analysis of the different
cases has been carried out [93–95]. Here, we consider the case where electrostatic forces
are negligible and the particle is located close to the wall, at distances z − r << r
(where z is the distance to the wall and r is the particle radius). In such conditions,
the equations governing the particle trajectory x(t), z(t), are [93]:

ẋ(t) ≈ γU (z) + fx (t) (5.26)

dD⊥ D⊥
ż(t) = fz (t) + + FvdW z (5.27)
dz kT

in which
Ar
FvdW z = − (5.28)
6(z − r)2
 Particles and microfluidics 301

where A is the Hamaker constant of the wall/solution/particle system (see Chapter

2).15 γ is a constant (on the order of 0.7), modelling the action of the shear on the
particle speed [93], and Ur is the local velocity, i.e. the flow speed calculated at a
distance z = r from the wall. fx (t), fz (t) are the components of the Brownian forcing,
discussed earlier. We further focus on the case where the particle are so large (typically
above 1 µm) that Brownian motion can be neglected.16 This regime is called ‘Van der
Waals 1’ in Ref. [94]. In this case, the equations simplify into the following:17

ẋ(t) ≈ γUr (5.29)

A D
ż(t) ≈ − (5.30)
6kT (z − r)

On solving Eqs. (5.29) – (5.30), one finds:

ADt
(z(t) − r)2 = (z0 − r)2 − and x = γUr t
3kT
where z0 is the particle position for t = 0, assuming that initially, the particle is located
at x = 0. As sketched in Fig. 5.51, particles, attracted by Van der Waals forces, falls
towards the walls while being transported
q by the flow. Particles injected at an altitude
ADL
z0 < zc , with zc − r = δc = 3γkT Ur , are caught by the channel, while the others
escape. This is the deposition mechanism.

5.51: In the Van der Waals 1 regime,

the non–Brownian particle, injected at
the ‘altitude’ z0 , is transported by the
flow and, in the meantime, attracted
by the wall. For a given channel length
L, below a critical altitude z0 = zc , the
trajectory hits the wall, and the parti-
cle is captured. Above zc , the particle
escapes the channel.

In practice, particles are injected in the system, at a rate J = ϕQ vP , in which ϕ is

the volumetric concentration, vp is their volume, and Q is the volumetric flow rate.
J is the number of particles that penetrate, per unit of time, the channel. Its unit is
T −1 . Using the previous results, it is not difficult to show that the number of particles
NA (t), deposited at time t on the lower channel wall, is equal to:

δc
NA (t) ≈ J t (5.31)
h
15 We take here the expression for the plane-plane case. This is appropriate because the particle is
close to the walls, at distances so small that its surface looks planar.
16 It is considered, in colloidal science, that particles with diameters larger than 1 µm smooth out
the effect of thermal agitation.
17 In practice, for plastic material, A/kT ∼ 1, so that, close to the wall, the term dD⊥ is negligible.
dz
302 Transport in microfluidics

with:

 1/2
δc A LD
=S= ξL with ξL = (5.32)
r 3γkT Ur r2

NA (t) is the number of particles that are collected, at time t, by the lower wall, in
a channel of length L. Replacing L with x, N a(t) becomes N a(x, t), i.e. the number
of particles collected by the same channel at time t, but up to a distance x from the
entry. With that, we can define the particle density p(x, t) by the following relation:

∂NA δ0
p(x) = = 3/2 Jx−1/2 t (5.33)
∂x 4h

p(x, t) decreases along the channel. This is the so-called ‘retention profile’, systemati-
cally observed when particles are injected in narrow channels, for instance, in porous
media. At all time, the maximum particle density is located at the entry of the chan-
nel, i.e. in the framework of our analysis, for x = h. Eqs. 5.31 and 5.32 also show that
the larger the Hamaker constant A is, the stronger the deposition rate is. This implies,
for instance, that deposition of polystyrene particles, as used in Ref. [93], is stronger
with hydrophobic walls than with hydrophilic walls.

The experiments of Ref. [93], conducted with high salt concentrations for screening
the electrostatic forces, and polystyrene particles, 5 µm in diameter, has confirmed
these predictions, along with the scalings given by Eqs. (5.31), (5.32) and (5.33).
Figure 5.52 shows an example of comparison between theory and experiment. From
this work, proposal was made to measure the Hamaker constant [93].

Fig. 5.52: (Left) Number of particles collected by the lower channel wall, as a function of
time, for hydrophilic and hydrophobic walls. The lines correspond to Eq. (5.31). (Right)
Probability of finding a particle collected by the wall, at a given time, at distance x from
the entry. The line is p(x) ∼ x−1/2 . This plot is called ’retention’ profile by the filtration
community [93].
 Particles and microfluidics 303

5.9.3 Clogging

Often, the first impression that one may have, on looking at a microfluidic device, is
that channels are so small that they will always clog. Consequently, they will never
be used industrially. It turns out that this is wrong: today, as we saw in Chapter 1,
hundreds of millions of microfluidic devices are shipped every year. Still, it remains true
that clogging is an issue. Any impurity of size comparable to the channel transverse
dimensions, or a fraction of it, often present in systems of practical interest, or even
generated by the device itself (for instance, PDMS debris), may close channels partially
and eventually clog the system. However, over the years, progress has been made and
today, many microfluidic devices are used in the industry in a reliable manner, without
clogging. In most cases, clogging can be avoided by working with filtered liquids and,
most importantly, placing filters with submicrometric pores in line with the device.
How does clogging occur? Fig. 5.53 shows an example.

5.53: Clogging in a PDMS microchan-

nel.(A) Several particles deposit at the walls,
forming a precursor that partially obstructs
the channel.(B) After arches have formed
across the channel, the clog appears.The
dashed arrow represents the small flow
traversing the porous clog, bringing new par-
ticles that increase its size. In this experi-
ment, speeds are fractions of mm/s, particles
are 5 µm in diameter, and the clog forms in a
few seconds. (Courtesy of C. Cejas (2018).)

In Fig. 5.53 (A), particles first deposit at the walls, then accumulate locally, form-
ing arches across the channel, which eventually clogs it (Fig. 5.53 (B)). Today, there
is no established description of the phenomenon, and consequently no formula that
could characterize the clogging conditions. It is nonetheless possible, using Eq. 5.31,
to suggest a criterion. Let us assume that clogging takes place when several particles
are adsorbed at the same place, forming a cluster, that develops arches and provokes
clogging. Let us further assume that this event will occur first close to the channel
entry, i.e. for x ∼ h (because p is maximal there). A cluster can be associated to a
local full coverage, i.e. p(x) on the order of rh2 .18 Based on this, using Eq. (5.33), we
find the following expression of the clogging time:

h3
tc ∼
r2 δ 0J

Applied to the experimental conditions, of Fig. 5.53, we find seconds, which is con-
sistent with the observations. The formula indicates that the smaller the Hamaker
18 For a channel of width h, this event will occur with a probabiliy r p(x). We can also say that, at a
h
distance h from the entry, one must have full coverage, i.e. for a channel of width h, NA (h, t) ∼ ( h
r
)2 ;
then, p ∼ NA (h)/h ∼) rh2
304 Transport in microfluidics

constant, the larger the clogging time, which agrees with the experiment. This implies
that is preferable to use hydrophilic channels to transport polystyrene particles (rather
than hydrophobic ones).

5.54: Clogging in an array of

square PDMS microchannels,
20 µm side, in which 5µm par-
ticles have been introduced,
by driving a flow from left to
right. The image is taken a
few seconds after the particles
have penetrated the channel.
Most of the clogs appear close
to the channel entries. (Cour-
tesy by C.Cujas (2018).)

One can also show that tc is proportional to h (since δ0 ∼ h2 ), so that the larger h
is, the later the channel clogging. From this remark, one may infer that in a channel
including restrictions, clogging will most probably occur in the narrowest parts of the
channel. The reasoning we present for the Van der Waals regime 1 can be extended to
the other deposition regimes analysed in Ref. [94]. Although this approach may provide
interesting clues on the clogging conditions, in particular a link with the material prop-
erties, it is based on hypotheses and simplifications that need to be confirmed. Other
approaches have been proposed [96–99], emphasizing kinetic and statistical aspects.19
To summarize, much remains to be understood in the domain.
In practice, if neither surface properties, nor dimensions can be tuned, what can be
done? The first idea is filtering. Filtering prior to injecting the (liquid) sample in the
system through submicrometric pores (200 nm pore sizes are often used), along with
care in the microfabrication process, are rules, respected by microfluidic laboratories,
to ensure long–term functioning of microfuidic devices. Another approach consists, for
instance, in introducing anti-clogging systems, such as the ‘rivers’ shown in Fig. 5.55.
Here, small bubbles (5 µm in diameter) are produced at several kHz. Gas is introduced
in a central channel, and liquids in side channels. To avoid clogging, two large channels,
called ‘rivers’, are added on the sides. Most of the liquid phase (water) circulates in
the rivers, only a small part of it penetrate into the flow focusing device. Rivers sweep
away dust particles that could enter the system. In the filtration language, this is
called ‘tangential filtering’. The liquid can be recycled.
For microfluidic systems dedicated to handle particles, the problem is more delicate,
because particle must circulate in the system. Once the clogs appear, it is difficult, in
practice to remove them, and in most cases, the device is lost. The most obvious rule to
avoid the problem is to enlarge the channels and minimize the attractive interactions
between the particles and the walls. Another approach is to use droplets to transport

19 These aspects have been overlooked in the model described above

 Particles and microfluidics 305

5.55: Anti–clogging system allowing

us to produce bubbles without clog-
ging: air is injected in a channel, in
the lower part of the figure, and liq-
uid (water) is injected on the sides,
through two small channels (barely vis-
ible). These small channels are con-
nected to a ‘river’, i.e. a much larger
channel, which carries most the liq-
uid phase. This system represents a
tangential filtering configuration [100].
(Courtesy of U. Soysal and P. Nieck-
ele.)

the particles or to work at large speeds, which may be impractical in a number of

cases.

5.9.4 Three methods of sorting particles

The H filter. The H filter was invented in the late 1990s [101]. The principle is shown
in Fig. 5.56.

5.56: The H–Filter [101]: two mis-

cible fluids, one including particles,
and the other not, form an inter-
face across which particles diffuse, at
a speed depending on their sizes. In
this way, particles can be sorted in
function of their sizes.

The incoming fluids are miscible and their flow rates are equal. Therefore, as we saw
in Chapter 3, a diffuse interface establishes in the system. Particles are injected in
the left part of Fig. 5.56, in the lower branch. Large particles follow the streamlines.
They travel in the central channel, bifurcate to the right, and exit. Small particles
diffuse, and consequently, they visit different streamlines during their journey. Part of
them cross the interface and jump in the upper branch of the H–filter. By repeating
the operation, it is possible, in theory, to sort particles with a large yield. In practice,
in order the diffusive process to be efficient, the central channel of the H–filter must
be long, and speeds must be low. As a consequence, throughputs are low. Therefore,
although conceptually appealing, over the years, other methods have been preferred .
306 Transport in microfluidics

Sorting by confinement (particle flow fractionation (PFF). Different sorters use the
effect of the confinement to place particles of different sizes on different streamlines.
This gave rise to the acronym PFF’ (particle flow fractionation) [102]. An example is
shown in Fig. 5.57.

5.57: System enabling particle

separation.

By passing trough the restriction, large particles are forced to circulate along the cen-
terline, even though they were injected sideward, as in Fig. 5.57. Further downstream,
these particles will stay on the same streamline and, consequently, travel distantly
from the walls. By contrast, small particles, also injected sideward, will stay close to
the wall in the collecting channel. Thereby separation according to size is achieved.
Since diffusion is irrelevant, the device can be operated at fast speeds, as long as the
flow does not develop detachment eddies induced by the divergent channel. This con-
straint restricts the operating speed. In practice, non–Brownian particles and cells, i.e.
with sizes above 1 µm, can be efficiently sorted with this method.

The pillar array. The idea was proposed in 2004 [103], giving rise to the acronym DLD
(deterministic lateral displacement). The principle is shown in Fig. 5.58 (borrowed from
Ref. [104]):

Fig. 5.58: Deterministic lateral displacement (DLD) [104]. Large particles are conveyed along
oblique trajectories, while small particles can pass from one row to the other, transported
by transverse fluid streamlines.(A) Inclined array.(B) ‘Vertical array’, in which cells (red and
white blood cells) are separated from platelets [104]. (Creative Commons licence.)
 Particles in inertial regimes 307

Large particles, whose centres are maintained at some distance from the disks, are
forced to follow oblique trajectories, into which they are continually displaced at each
successive pillar (this justifies the acronym). By contrast, a fraction of small particles
follow fluid streamlines passing from one row to another one [104]. Thanks to this
process, separation between small and large particles can be achieved. Being based on
hydrodynamic transport, separation is much faster than diffusion. Fig. 5.58 (B) shows
that the principle works for separating blood cells from platelets. The idea also works
for separating long DNA fragments, but with limited resolution.

5.10 Particles in inertial regimes

Although the Segre-Silberg effect was discovered in 1961 [105], it came as a surprise, in
the microfluidic community, that it was possible to reorder particles in a microchannel,
just by increasing the Reynolds number. The rediscovery of the Segre-Silberg effect,
made by Di Carlo et al. in 2006 [106], stimulated the growth of a new topic, called
‘inertial microfluidics’ . In fact, as we noted in Chapter 3, the term ‘inertial microflu-
idics’ encompasses a much broader domain. This concerns moderate Reynolds number
flows, driven in inertial regimes, i.e. regimes in which inertia forces come into play, in
microfluidic or millifluidic systems, incorporating or not particles or interfaces.
We thus present the behaviour of particles transported in flows driven at moder-
ate Reynolds numbers, i.e. typically 10–100. Above these numbers, time–dependent
phenomena develop, giving rise, as we previously saw, to chaotic behaviour. In such
regimes, it is impossible to reorder anything. We restrict ourselves to rigid particles.
Soft particles, such as blood cells, although important for the applications, are nonethe-
less too complex to be discussed here. For such particles, membrane elasticity along
with deformability generate a plethora of effects that are too extensive to present here.

5.59: From Ref. [107]: in a cylindrical

pipe, at moderate Reynolds numbers,
randomly distributed particles focus to
an annulus located between inside the
pipe.

The Segre–Silberberg effect [105] is sketched in Fig. 5.59. In dilute suspensions of neu-
trally buoyant particles, driven in a tube, particles tend to collect on an annulus, whose
radius is 0.6R . Why this is the case? The subject is rich and subtle. To make a long
story short, one may first note that, in inertial microfluidics, particles are subjected
to viscous drag forces and inertial lift forces. The drag forces drive particles along
308 Transport in microfluidics

the flow streamlines, whereas inertia forces drive particles across the flow streamlines.
There are several inertial forces, induced by the particle rotation, their speed deficit,
with respect to the flow, the wake generated by this deficit, and the coupling of all
these effects to the wall. In straight channels, the most important forces are a lift di-
rected away from the wall and a shear gradient lift directed down the shear gradient,
i.e. towards the wall (Saffman force). The combination of the two forces gives rise to
equilibrium positions towards which particles migrate as they travel downstream. In
channels of rectangular cross-section, the equilibrium positions are surfaces parallel to
the walls. Ref. [108] provides detailed analyses of these forces. In practice, one needs
long channels to observe the Segre–Silberberg effect.

5.60: Inertial separation in a

multi-orifice microchannel ac-
cording to the size-dependent
lateral migration termed as
multi–orifice flow fractionation
[108–110]. Such images are ob-
tained for Reynolds numbers
ranging between 20 and 100.
(Reprinted from Ref. [108] with
permission of the Royal Chemi-
cal Society. Copyright 2022.)

Over the years, the effect has been exploited in different geometries to reorder or sort
particles and cells. We mentioned an example, in Chapter 3, in which Dean vortices,
probably coupled to Segre-Silberberg effect, allowed to isolate Circulating Tumor Cells
(CTC) [111]. Another example of the reordering effect which is quite spectacular was
demonstrated in Refs. [109, 110]; this is shown in Fig. 5.60 (images taken from Ref.
[108]). Some of these systems are commercialized. Their advantages are their simplicity
and high throughput.

5.11 Adsorption

5.11.1 Generalities

Due to the presence of attractive forces and thermal motion, molecules located near
a wall may be captured by the surface for some time (adsorption) until a thermal
fluctuation re-expedites it in the bulk (desorption). The field of adsorption is vast
(see, for instance, Ref. [112, 113]), we give here an extremely brief account, motivated
by the fact that microfluidics exacerbates the role of the surfaces; therefore, it makes
sense, in the context of this book, to introduce a few notions. Adsorption concerns
 Adsorption 309

surfaces, while absorption concerns volumes. A simple illustration of the difference is

shown in Fig. 5.61.

5.61: Difference between ad-

sorption and absorption. (from
L. Dehove.)

Adsorption/desorption concerns molecules, macromolecules, and clusters of molecules,

small enough to be sensitive to thermal fluctuations. For larger objects (colloids, par-
ticles), the terms used most often are sticking, adhesion or deposition. Direct evidence
of adsorption is brought by various methods, such as atomic force microscopy (AFM),
spectroscopy, or electronic microscopy. An example based on AFM is shown in Fig.
5.62 [114].

5.62: AFM image of adsorbed al-

bumin molecules on a flat surface.
(Reprinted from [114] with permis-
sion of Elsevier. Copyright 2022.)

There exist two types of adsorption: physisorption, where the adsorbate (i.e. the ad-
sorbed molecules) is retained by intermolecular forces, and chemisorption, where the
adsorbate undergoes a chemical reaction to reside, for some time, or irreversibly, at the
interface. One example of physisorption concerns the already mentioned amphiphilic
molecules, and one example of chemisorption is oxygen molecules adsorbing and ox-
idizing a metal surface. The former process is reversible, and the latter process is
generally not. Microfabrication often uses one or the other of these two mechanisms
for depositing films or layers on silicon wafers or glass plates. We will see examples of
310 Transport in microfluidics

this in Chapter 7.
Adsorption and desorption phenomena are crucial for microfluidics. Adsorption can
be favourable or unfavourable. A favourable example, is the extraction of nucleic acids
in membranes, a technique invented in the 1990s by Boom [115]. Here, by varying
the salt concentration, it is possible to change the sign of the forces developed at
silicon membrane surfaces, so as to adsorb (capture) or desorb (release) RNA. An
unfavourable example is non–specific adsorption (NSA) at the microchannel walls,
that often leads to the loss of the biological sample before it can be processed, or,
in an electrochromatographic context, can lead to undesirable electrosmotic flows. In
order to block NSA, an albumin or PEG coating, prior to sample injection, is currently
used.

5.11.2 Langmuir isotherm

In 1916, Langmuir proposed a theory of adsorption [70,113,116–118]. It is schematically

represented in Fig. 5.63.

Adsorption
5.63: Langmuir model of adsorp- Desorption
tion, in which a single layer ex-
changes with the bulk, through ad-
sorption/desorption events.

Molecules adsorb on the surface for a certain interval of time. Even though they are
energetically ‘happy’, they do not stay anchored to the surface. Subjected to thermal
fluctuations, they desorb. In stationary regimes, one may assume that an equilibrium
holds between adsorption and desorption fluxes, towards and from the surface.
The theory of Langmuir relates the flux J1 of molecules adsorbing on the surface and,
for liquids, their bulk concentration C. For gas, C is replaced by partial pressure.
Let us assume a liquid. In Langmuir theory, one single molecular layer is adsorbed:
molecules are retained on the bare areas of the surface, but are warded off by areas
that are already covered. The flux J1 of incident molecules is proportional to the local
concentration C and to the area uncovered by the adsorbed monolayer. Calling φ the
fraction of surface covered by the adsorbate, we can write:

J1 = k1 C(1 − φ)

where k1 is a coefficient. On the other hand, the flux of desorbed molecules, represented
by J2 , is proportional to the covered area:

J 2 = k2 φ

where k2 is a second coefficient. At equilibrium, the two fluxes are equal. We deduce:
 Adsorption 311

KC
φ=
1 + KC
where K = k1 /k2 is often called the Langmuir constant. The quantity of material
adsorbed at the surface, as a function of the bulk concentration C, is thus:
F0 KC
F =
1 + KC
where F0 is a constant. This is the Langmuir isotherm.20 . It is called ‘isotherm’ to
underline that, in the theory, the temperature is maintained constant.21 At high
concentrations, φ tends to unity. In this limit, the surface is entirely covered by a
monomolecular film.

Langmuir theory is generally found in good consistency with the experiment. One
example is shown in Fig. 5.64, for protein adsorption on silica surfaces [119]. The
numbers on the axes are typical: a few milligram per m2 at ambient temperature for
full surface coverage, at concentrations on the order of 10 g/l.22

5.64: Comparison, in liquid, between Lang-

muir isotherm theory and experiment (pro-
tein adsorption on silica surfaces.) [119]
(Creative Commons licence.)

Other demonstrations of Langmuir’s law, using thermodynamics or statistical physics,

have been established. The main limitations of this law are that a single layer is
assumed and interactions inside it are neglected. For these reasons, and in an attempt
to generalize the Langmuir isotherm, different laws have been proposed over the years,
such as the Brunauer–Emmett–Teller (BET) isotherm [120]. There also exist purely
phenomenological relations, such as Freundlich’s law. This law, which reads F = KC a ,
where a and K are empirical constants, is widely used. It was written in 1909, by
Herbert Freundlich [121], seven years before Langmuir.

20 For gases, the same law applies, but C is replaced by partial pressure
21 Heat is released in the adsorption process and absorbed by desorption. In the framework of Lang-
muir theory, the temperature is held constant during the entire processes. Otherwise, the temperature
would evolve unboundedly, and the model would be unphysical.
22 It is often noted, in the field, that the excellent agreement between Langmuir theory – with a
free parameter – and the experiment does not demonstrate that theory is valid. It just shows that
the theory provides a possible description of the adsorption phenomenon, consistent with the data.
312 Transport in microfluidics

It is usual, in the field of chromatography, to distinguish between two cases of adsorp-

tion
• If the function F = f (C) is concave, adsorption is said ‘favourable’. Concentration
fluxes being the derivative of the curve, it is large at the origin, i.e. at same C.
Thus, in the domain of chromatography, it will be possible to detect traces of
substances in a sample by capturing them on a surface and, after elution, proceed
to their analysis.
• If F = f (C) is convex, the situation is opposite: fluxes are small at small C and
adsorption is said ‘unfavourable’.

5.12 Chromatography

5.12.1 Principle of chromatography

Chromatography is described in a number of textbooks [122–126] papers and lectures

(see, for instance, [127–129]).
The general principle (for column chromatography), is represented in Fig. 5.65.

Fig. 5.65: Principle of chromatography (see text).

The column is filled with a porous medium, beads, or a gel, forming the stationary
phase (the matrix). The mobile phase is the solution (i.e. the solute and the solvent)
that circulates through the column. The sample is deposited at the top of the column;
it separates into components as it travels through it.
 Chromatography 313

During its journey, the sample is subjected to adsorption/desorption processes, which

depends on the affinities of the molecular species contained in the sample and the
matrix. The transport velocity will thereby vary from one species to another. In this
way, distinct bands will appear progressively along the column over time, each band
containing species with the same partition coefficient. As time goes by, a detector
placed at the bottom of the column records a temporal signal (see Fig. 5.66).

5.66: Typical temporal signal ob-

tained by the detector.

The signal is made up of a series of peaks. It allows the measurement of the time of
passage of each band in before the detector (called the ‘retention time’). From this
are deduced the migration velocities, the corresponding partition coefficients, and, ex-
ploiting the calibration data or other associated information, the different components
of the sample. The chromatographic signal can also, from the measurement of the area
under each peak, determine the concentrations for each component. It is remarkable
that the method’s efficacy is based on the amplification of small differences: small
disparities in the partition coefficients of different constituents of the sample were
effectively amplified by repeated passages through the grains forming the matrix.

Once the bands have migrated to the base of the column, we proceed to the detection
phase. In chromatographic systems, this problem is crucial, especially when the com-
ponent in question exists only in trace amounts (this is frequently the case in biiology
and the environmental sciences). Nevertheless, there are a wide variety of detectors
available that use for example fluorescence (an extremely sensitive method), thermal
conductivity, electrical conductivity, photon adsorption, etc.

Let us indicate a few orders of magnitude: for liquid phase chromatography (LPC),
columns are typically 20 cm long and 4 mm in diameter, with particles of 20 µm
and applied pressures increasing to several bars or tens of bars. The quantities being
analysed are on the order of the milligram, and the efficacy varies between 100 and
1 000 theoretical plates. The typical minimum detection for this type of column is on
the order of the picogram. The retention time obviously depends on several parameters,
but to illustrate, we can say that they are typically on the order of ten or several tens
of minutes. The versatility and the richness of chromatographic methods allows us to
believe that it is possible to find a solution to whatever analytical problem may arise.
314 Transport in microfluidics

5.12.2 Different types of chromatography

The main types. Without entering into the details, the most common methods of
liquid-phase chromatography are described below (see Fig. 5.67).
• Adsorption chromatography: : the sample components interact differently with
the matrix of the column, leading to different travel times.

• Partition chromatography: the column contains a liquid film covering each sphere
making up the stationary phase. Certain components of the sample dissolve in this
film.

Fig. 5.67: Types of chromatographies.

• Ion-exchange chromatography: the matrix is made up of charged spheres that

retard the displacement along the column of ions of the opposite sign. The most
common matrices are gels of cellulose. The effect of the retardation of the displacement
can be controlled and optimized by modifying the pH of the solution.

• Exclusion chromatography: the matrix is made up of porous spheres. Small

molecules frequently visit the interior of these spheres by diffusion. and thereby progress
along the column more slowly than large molecules do: this is the effect of separation
by exclusion. The spheres used are, for example, agarose beads, which possess a large
diversity of porosities.
• Affinity chromatography: in this case, the matrix shows high affinity for certain
components of the solute (for example, antibodies specific to antigens). The molecule
 Chromatography 315

is captured by the matrix, and is further eluted by circulating a solvent.

High performance liquid chromatography (HPLC). Over the years, the reduction of
the grain sizes, along with the augmentation of the column length, have considerably
improved the performances of the columns. This gave birth to a new acronym HPLC
(high performance liquid chromatography). HPLC is not a specific type of chromatog-
raphy, but a refinement of preceding techniques, resulting in highly resolved separa-
tions. Typically, the matrices of HPLC systems are made of pores between 1 and 5 µm.
Columns are long and operates at high pressure (hundreds of bars). With this type
of system, as will be shown in the next section, hundreds of thousands of theoretical
plates can be obtained.

5.12.3 Performances of the columns

The characterization of a separation process is based on a number of quantities [123–

125, 129]. The first one is the retention time tR , defined in Fig. 5.66. This is the time
a component of the sample takes to traverse the column and pass before the detector.
The second quantity is the standard deviation of the peak corresponding to a given
component (Fig. 5.66). It is advantageous to reduce this quantity as much as possible.
This quantity is notated as σ. The column efficiency is characterized by a number N ,
the number of theoretical plates23 . This number is defined by the following expression:

t2R
N= (5.34)
σ2

The larger N is, the higher the column efficiency is. A related quantity is the plate
height, defined by.

L
H= (5.35)
N

The smaller H is, the higher the efficiency is. Over the course of time, the different
bands (corresponding to each species present in the sample) spreads. A well–accepted
model, obtained on a semi–empirical basis, is due to J. J. van Deemter (1956) [130]:

B
H =A+ + CU
U
in which A, B and C are empirical constants. Physically, A represents the effect of het-
erogeneities across the column, B is the effect of longitudinal dispersion, that spreads
the solute band, according to mechanisms we presented earlier, and C covers different
adsorption phenomena at the pore scale. A thorough discussion of the van Deemter
equation, along with other models can be found in C. F. Poole [125]. Chromatography
optimizes H by reducing A, B and C, and working in a region close to the minimum
23 A word borrowed from the domain of distillation
316 Transport in microfluidics

of the function H(U ). In HPLC, pores or bead sizes are in the micrometric range, and
arguments and experiments indicate that, for the speeds currently used in the domain
(a few mm/s), the first term, i.e. constant A, is dominant [125]. Although this term
deserves discussion, one may have a rough idea of its amplitude by taking d, the pore
size. We thus have:

L
H ∼ d and N ∼ (5.36)
d

The plate number thus can reach high levels, 105 or so, for columns of several cen-
timetres size. An example [131] with a number of plates of 106 is shown in Fig. 5.68.

5.68: An example of HPLC

with N ≈ 106 [131]. (Creative
Commons licence.)

5.12.4 First miniaturization of a gas chromatographic column: Terry

(1975)

As noted in the introduction, the first miniaturized chromatographic column was made
in 1975 [132]. Fig. 5.69 again shows the device. The system, made in silicon, included
an injection valve and a separation column, 1.5 m long. Detection was based on a
thermal sensor, fabricated on an external silicon wafer, and fixed to the chip. The
design can be understood by using the notions we previously introduced. Here, the
chromatography is based on adsorption. The carrier gas and the sample adsorb to
the walls with a different kinetics, so that , at the end of the column, one recovers
two separate peaks. The column must be long, in order to obtain a high efficiency,
and it was challenging to pack a channel 1.5 m long in a miniaturized device. The
valve must be small and quick, to work with small samples, favouring resolution. It
was fabricated on a separate wafer. The number of plates we could estimate was on
the order of several tens of thousands. The authors emphasized the small quantity of
carrier gas used to perform the separation and the speed (less than 10 s) [132].

As discussed by Reyes et al. [127], this work is historically important, but it did not
generate a surge of activity in what we now call microfluidics. At that time, neither
 Chromatography 317

researchers in biology, physics, or chemistry expressed interest in the invention. In the

1980s, the visibility of microfluidics was extremely modest.24

Fig. 5.69: Gas Chromatographer described by Terry et al [132]. The device consists of a
1.5 m long, spiral channel, etchec in silicon, with input (top right) and output (right) for
gas sample Channel dimensions are 40 µm depth, 200 µm wide. Flow within the device is
controlled with a valve(top left) before the coil; the thermal detector is located on the right
of the device. B - Shematic showing the components housed on the silicon. wafer (Reprinted
from Ref. [132] with permission of IEEE. Copyright 2022).

Today, miniaturized gas chromatographs are commercially successful. They serve dif-
ferent industries, for instance oil industry interested in on-site analyses, and for which
the compactness of the system, coupled to the quality of the analyses, is unique.
However, this is a niche. The start-up of microfluidics, which addresses much broader
applications, began twenty years later, around 1990, with the coupling of microfabri-
cation technology and capillary electrophoresis [133]. We will develop the subject in
Chapter 6.

5.12.5 Is it worth miniaturizing chromatographic columns ?

Why miniaturizing chromatographic columns? Four arguments can be advanced:

• Sample volumes are reduced.
• Compactness is increased. The system becomes transportable.
• The cost is lower.
• By parallelizing several columns, throughput can be increased.
These advantages must, however, be taken alongside a certain number of limitations:
• In conventional HPLC, matrix particles or gel/porous pores are micron-size. As
previously explained, these small sizes, coupled to the substantial length of the
columns, allow high efficiencies to be reached. By contrast, transverse dimensions
of microfluidic channels are, typically, 10 µm, while device lengths are a few
centimetres long. This leads to a loss of four orders of magnitude in terms of
efficiency, compared to conventional HPLC.
24 The word ‘microfluidics’ appeared later, in the 1990s (see Chapter 1).
318 Transport in microfluidics

• To improve the situation, a number of investigators proposed to integrate gels

or particles on the device, or reduce the channel dimensions. Even with these
improvements, a substantial loss of performances persisted, in comparison with
traditional HPLC.
In conclusion, miniaturization of chromatographic columns can be interesting for prac-
tical reasons (this is the case for gas chromatographers), but performances are in-
herently limited. In Chapter 6, we will see that miniaturization becomes extremely
advantageous when electrokinetics is used.

5.13 Thermal transport by conduction

5.13.1 Conduction of heat in gases, liquids, and solids

Heat-conduction phenomena have been studied a great deal over the last century;
excellent books exist and we will give an extremely brief account here of the domain.
• For gases, the origin of thermal conduction stems from the random movement
of molecules. For systems much larger than the mean free path λ (which, as
the reader may recall, is about a hundred nanometers at ambient temperature),
kinetic theory gives the following estimate for the thermal diffusivity κ:
K
κ= ∼ λc, (5.37)
ρCp

where K is the thermal conductivity, ρ is the gas density, Cp is the heat capacity,
and c is the sound speed. This expression is valid for perfect gases. For systems
that are about the same size or smaller than the mean free path λ, molecules
collide more often the walls than their partners, and the expression of thermal
diffusivity must be amended. More generally, the hypotheses leading to the estab-
lishment of the macroscopic laws of heat transport (such as Fourier’s law) must
be re-examined. This problematic is similar to that concerning the validity of the
Navier–Stokes equations in small systems, discussed in Chapter 3.
• For solids and liquids, it is necessary to distinguish between metals and insulators
(see Kittel [135] for a thorough presentation of the subject). For insulators, heat is
transported by the internal modes of vibration in the crystal lattice [134]. These
modes are quantized, and one can treat them as quasi-particles known as phonons
(quasi indicates that they do not have an autonomous existence independent of
the crystal lattice that supports them). These quasi-particles undergo collisions,
producing an erratic agitation that resembles that of gas molecules. Just as for
gases, a mean free path λp can be defined. It ranges between 1 and 100 nm at
ambient temperature.
For insulators larger than λp , the thermal conductivity Kp can be estimated in a
manner similar to the kinetic theory of gases. We obtain:
 Thermal transport by conduction 319

Fig. 5.70: Calorimetry experiment on a 40-nm wide silicon wire. The wire was used to
study deviations from Fourier’s law of heat conduction, which makes up part of macroscopic
heat transport theory. (Reprinted with permission from Cahill et al. [134]. Copyright 2003,
American Institute of Physics.)

1
Kp ≈ ρCph λp up , (5.38)
3

where Cph is the heat capacity of phonons and up is the speed of sound. For
systems smaller than λp , the calculation is more complicated. It would take us
far beyond the scope of this book.

• For pure metals, electrons are the principal thermal carriers. At ambient tem-
perature, their mean free paths and speeds are on the order of 100 nm and 103
km/s, respectively. Although electrons have tiny mass, owing to their speeds, the
kinetic energy exchanged during electron-phonon collisions is greater than that
exchanged between phonons, which is why they are the principal carriers of heat
in metals. Just as for insulators, the conduction of heat in nanometric metallic
systems is currently an active area of research. One example is an experiment
carried out with wires, a few nanometres in diameter (see Fig. 5.70) [134].

To conclude, macroscopic theories are no longer valid at scales below a mean free path,
i.e. roughly 100 nm or so in solids and gases. These scales lie on the lower edge of the
microfluidic domain (see Chapter 2) and we will not address them. In smaller systems
(pertaining to the nanofluidic range), the investigation of thermal phenomena, and
their coupling to flow phenomena, is a domain of active research.

5.13.2 Fourier’s Law

As observed above, the mean free paths of the particles ensuring heat conduction
(molecules, phonons, or electrons) are much smaller than the size of the systems we
320 Transport in microfluidics

System K (W m−1 K−1 ) κ (m2 /s) × 10−6 Cp (kJ/kg/K)

Water 0.6 0.14 4.2
Silicon 150 80 0.70
Glass 1.4 0.34 0.83
PDMS 1.5 0.1 1.4
Copper 401 113 0.38
Air 2.41 10−2 22 1
Table 5.4 Thermal conductivities, diffusivities, and specific heats for a selection of materials.

will consider. The heat fluxes q will thus be related, as in ordinary size systems, to
the temperature gradients ∇T by Fourier’s law, which reads as follows:

q = −K∇T (5.39)

where K is the thermal conductivity. The units of K are W m−1 K−1 . An important
quantity, altready introduced, is the thermal diffusivity, denoted by κ. We recall its
definition:
K
κ= , (5.40)
ρcv
where ρ is the density of the fluid and cp is its specific heat. The unit of thermal
diffusivity is the same as for the kinematic and mass diffusivities: m2 /s. A few values
of K and κ, along with Cp for different liquids, solids and a gas (air) are given in Table
5.4:
Consistently with common knowledge, metals and semi-conductors are excellent con-
ductors. Gas is an insulator and materials, such as pure water and glass, are in be-
tween. This hierarchy reflects the existence of different physical mechanisms for the
conduction of heat, as discussed in the preceding section.

5.13.3 The heat diffusion equation

The heat equation can be derived in the same manner as the diffusion equation for
mass transport, and we refer the reader to textbooks such as [136] for its derivation.
With a constant thermal conductivity K, the heat diffusion equation reads:

∂T
ρCp = K∆T + s(x, t), (5.41)
∂t

where T (x, t) is the local temperature ρ is the fluid density, and s(x, t) ( in Wm−3 ),
is a rate of heat production or absorption per unit of volume, due to a source or a sink.
s can be positive or negative. For instance, if the fluid is conducting and an electrical
2
current is applied through it, we will have s = EρE , in which ρE is the electric resistivity,
and E the applied electric field. If the fluid develops an exothermal reaction, s will be
the enthalpy produced by this reaction, per unit of volume and unit of time.
 Thermal transport by conduction 321

Another form of the heat diffusion equation, frequently used, is:

∂T s
= κ∆T + (5.42)
∂t ρCp

With a temperature Tw and a flux qw at the walls, the boundary conditions are:

∂T
T = Tw or K = qw (5.43)
∂z

These boundary conditions satisfy temperature and thermal flux continuity.

5.13.4 Three examples

Example 1: Temperature field in a sandwich. To begin, let us say that a slab of height
h, whose top and bottom, located at z = ± h2 (where z is the coordinate normal to
the slab), have temperatures equal, respectively, to T2 and T1 , Eqs. 5.41 reduce, in the
2
steady state, to ∂∂zT2 = 0. Thereby, in such a geometry, the temperature profile T (z),
reads:

1 z
T (z) = (T1 + (T2 ) + (T2 − T1 )
2 h

Let us now consider, instead of one slab, three slabs, represented in Fig. 5.71. The
lower face of the system is cooled down at T0 and the upper one is kept at Ta (‘a’ for
atmosphere). We examine two cases, often encountered in microfluidics:
a stack of glass, water, and PDMS and
b stack of glass, air, and PDMS.
With our notations, the boundary conditions, at the slab interfaces, reads as follows:
∂T1 ∂T2
T1 = T2 , K1 = K2 (5.44)
∂z ∂z

With this, it is possible to calculate, in each slab, the temperature profiles. We do no

write the expression of the temperature profiles, but show their shapes in Fig. 5.71.
Depending whether the medium layer is air or water, we have different temperature
profiles: in case (a), PDMS and glass have similar conductivities, but water is 2.5 less
conductive (see Table 5.4). We thus have a higher slope in the water channel. In case
(b), air has a much smaller conductivity than water. Consequently, the temperature
slope, in the microchannel, compared to water, is much steeper, while inside PDMS
and glass, temperatures are almost uniform. In this system, air plays the role of a
322 Transport in microfluidics

5.71: Temperature profiles

in a three–layer system, sub-
mitted to the same temper-
ature difference Ta − T0 > 0:
(A) PDMS–water–glass; (B)
PDMS–air–glass.

thermal insulator, while PDMS and glass thermalize at the temperatures to which
they are exposed.

Example 2: Temperature field in a microchannel with internal heating. Now, we

consider the microchannel represented in Fig. 5.72 and assume that the liquid is heated
by a thermal source s.

5.72: Temperature profile in

a microcanal filled with a mo-
tionless fluid, subjected to in-
ternal heating, characterized by
a source s.

The two plates that confine the liquid are located at ±h/2 and are held at tempera-
ture Tw . In the problem, temperature T only depends on z. Therefore, the equation
governing the temperature profile, in the fluid, and for the steady state, reads:

∂2T
0=K +s (5.45)
∂z 2

The thermal boundary conditions for walls maintained at fixed temperature Tw are:

h
z=± , T = Tw (5.46)
2
 Thermal transport by conduction 323

After integrating, we find:

h2 z2
 
s
T (z) = Tw + −
K 8 2

The maximum heating is located at z = 0. The temperature difference ∆Tmax , between

the channel centre and the walls, is given by:

sh2
∆Tmax = . (5.47)
8K

Just as the scaling laws predicted, ∆Tmax increases with the square of the transverse
dimension of the canal. We can thus expect, in miniaturized system, and for standard
heat sources, an extremely limited increase (or a decrease if s is negative) of the fluid
temperature. Let us take two examples:

1 – Joule heating in electrolytes. . Let us consider an electrolyte of resistivity

ρE enclosed in a microchannel of length L, subjected to a voltage V . An example
2
is an electrophoresis separation channel. We will have s = ρEV L2 . With V = 1 kV,
ρE ∼ 1 Ohm-m, h=10 µm, L = 1 cm, we find ∆T ≈ 10−1 ◦ C, a small quantity.
The channel can thus easily be maintained at constant temperature. By con-
trast, standard electrophoresis gels, for DNA separation, are several millimetres
in height, and 10 cm long. The same calculation leads to an increase in temper-
ature by tens of ◦ C. Heating represents the main source of resolution limitation
and low speed of the technique.

2 – Exothermal reactions. In exothermal reactions, s = QU , where Q is the heat

per unit of volume produced by the reaction and U is the flow speed. Rough orders
of magnitude, for reactions producing 100 kJ/mole, indicate that, in microsystems
similar to the preceding example, temperature increases does not exceed 1◦ . How-
ever, for industrial systems, designed for high throughput and therefore, having
higher dimensions, typically millimetres in size, and larger speeds, typically cm/s,
the increase can be several or several tens of ◦ C. Heat must be extracted to keep
the temperature constant. This brings us to the topic of microexchangers, which
we will return to later.

Example 3: Plate suddenly raised at temperature Tw . In a fluid initially held at

temperature T∞ , a thin plate, located at x = 0 is suddenly heated at temperature Tw .
For instance, a hot knife we would have quickly immersed in a cold liquid to cool it
down. The plate has a thickness e. The situation is sketched in Fig. 5.13.4.

In the limit of small e, we can model the initial condition by the expression:

t = 0, T (x, 0) = e(Tw − T∞ )δ(x)

in which δ(x) is the Dirac function, that we saw earlier.

324 Transport in microfluidics

T(x)

5.73: A thin hot plate is suddenly T∞ x

raised at temperature Tw . The solu-
tion to the problem, in the limit where
e tends to zero, is a gaussian

The system is governed by the following equation (see Eq. (5.42)):

∂T
= κ∆T (5.48)
∂t

The solution is Gaussian. Its expression is:

x2
 
e(Tw − T∞ )
T (x, t) = T∞ + √ exp − 2 (5.49)
2πσ 2 2σ
√
with σ = 2κt. The plane cools down and eventually reaches the bath temperature
T∞ . To have a sense of the orders of magnitude, suppose you plunge the knife in cold
water, held at T∞ ≈ 10◦ .Taking e = 3 mm, κ = 0.14 m2 /s, and Tw = 90◦ C, the
calculation shows that you need a time of ≈ 8 s to bring it back to a temperature of
30◦ C. At this temperature, at least from a thermal prospective, the knife no longer
causes any harm.

Note that the solution (5.49) can be found in the Landau-Lifchitz textbook on fluid
mechanics [137]. In this reference, the general problem of the temporal evolution, in
a fluid at rest, of a temperature field T0 (x) is solved. The case we considered here is
also discussed in Ref. [137].

5.14 Convection-diffusion heat equation and properties

5.14.1 The notion of heat transfer coefficient

A quantity central in the engineering literature, is the thermal exchange coefficient,

denoted by h. This coefficient, illustrated on Fig. 5.74., was invented by Newton. It is
similar to the mass exchange coefficient’, introduced earlier. Take a body of uniform
temperature Tbody , immersed in a flow, whose upstream temperature is T∞ . Depending
on the sign of ∆T = Tbody − T∞ , heat flux Q is oriented towards the body or the fluid.
 Convection-diffusion heat equation and properties 325

Fig. 5.74: Definition of the heat transfer coefficient.

Newton assumed a relation of proportionality between Q and ∆T . The coefficient h is

defined by the relation:
Q
h= ,
A∆T
where A is the surface body area, is known as the heat transfer coefficient. One ex-
ample is a radiator functioning at fixed temperature heating up a room: in this case,
the temperature difference is defined as the difference between the radiator and room
temperatures, A is the area of the radiator and Q is the thermal power output. The
units of the coefficient h are W m−2 K−1 . This incorporates all the mechanisms (natu-
ral convection, forced convection, radiation, conduction) participating in the thermal
exchange. The higher h is, the greater the thermal exchange is. Table 5.5 shows some
values of h, useful for characterizing the performances of common systems.

Type of transfer Fluid or process h (W m−2 K−1 )

Natural convection Gas 5 – 30
Water 100 –1,000
Forced convection Gas 10 – 300
Water 300 – 12 000
Phase transition (water) boiling 3,000 – 60,000
condensation 5,000 – 110,000
Table 5.5 Typical values of the thermal exchange coefficient h.

Heat transfer coefficient is a clever engineering concept: it allows us to have orders of

magnitude of heat exchanges without solving any equation, and, moreover, by con-
sidering it as a constant, to establish simplified equations. For instance, how long a
time is needed to cool down the body of Fig. 5.74? With h constant, the heat transfer
between the body and its environment is governed by the following equation:
326 Transport in microfluidics

dT
mCV = hA(T − T∞ )
dt

in which m is the body mass, and CV is its specific heat. The solution to this equation
is:
t
T (t) = T∞ + (T0 − T∞ ) exp(− )
τ
where T0 it the initial body temperature, and
mCV
τ=
hA
is a time characterizing the dynamics of the process (cooling or heating). With h= 100
W m−2 K−1 , it takes 100 seconds to cool down a body of centimetric size, and a fraction
of second or so for an object 10 µm in size.25 Indeed, in many cases, temperature is not
uniform and it is erroneous to assume that h is time – and temperature – independant.
Still, taking h as constant, allows us, with the help of Table 5.5, to have a sense of the
orders of magnitude involved in a given system, which is extremely useful.

So far, we discussed global heat transfer coefficients, i.e. averaged out over the body
surface area. There is also a local version of h. In this case, we have:

q = h(T − T∞ )

in which q is the local heat flux density crossing the interface, normally to it, and T
is the local interfacial temperature. h, then, is the local heat transfer coefficient. This
relation will allow us to define thermal boundary conditions.

5.14.2 Convective heat transfer

Convection–diffusion equation. The convection-diffusion equation can be derived from

the heat diffusion equation, by placing ourselves in a Lagrangian frame of reference.
The reader may refer to Batchelor’s and Landau–Lifschitz textbooks for a detailed
derivation of this equation [136, 137]. We obtain:

 
DT ∂T
ρCp = ρCp + u∇T = K∆T + s(x, t), (5.50)
Dt ∂t

in which, s includes external heat sources or sinks and the heat generated by viscous
dissipation. As in the preceding section, depending whether a temperature Tw or a
flux qw is fixed at the walls, the boundary conditions are:

25 Here, for the sake of simplicity, we took the same h for the two cases. We will see later that h
increases with the inverse of the system size.
 Convection-diffusion heat equation and properties 327

∂T
T = Tw or K = qw (5.51)
∂z

When qw = 0, these conditions can be expressed in a more compact form by using the
local heat transfer coefficient h :
∂T
K = h(T − Tw )
∂z

The preceding boundary conditions correspond to h = ∞ and h = 0, respectively.

These equations, coupled to the boundary conditions, encompass a considerable vari-

ety of phenomena: natural convection, forced convection, heat diffusion, and heating
due to the presence of heat sources. In the framework of miniaturized systems, this
diversity can be reduced by exploiting the scaling laws presented in Chapter 2. Phe-
nomena like internal heating with viscosity, buoyancy (giving rise to convection), and
radiation emitted by the fluid, are negligible in microfluidics, in the most common
situations. These estimates will allow us to concentrate on specific situations, relevant
to microfluidics.

The Biot number. The Biot number Bi characterizes heat transfers at the boundaries.
It is currently used in the engineering literature. Its definition is:

hl
Bi =
K

where l is a characteristic scale. In miniaturized system, since h depends on the system

size, it is difficult to estimate, in general, an order of magnitude for the Biot number.

Thermal Peclet, Nusselt, and Prandtl numbers. Let us first define the thermal Peclet
number. In a system of size l subjected to a temperature difference ∆T , with a flow
U , heat transfers, characterized by Q, take place. An example is the body immersed
in a cold (or hot) fluid moving around it, which we represented in Fig. 5.74. In such a
situation, one can write:

Q = f (κ, U, l, ∆T, ρ, cp ).

We have here 7 variables and 4 dimensions. We can thus write this equation in the
form:
 
Q U l cp ∆T
=f , .
Kl∆T κ U2

At small ∆T , we may neglect the second term in the parenthesis of the right hand
size. Under this approximation, we obtain:
328 Transport in microfluidics

 
Q Ul
≈f ,
Kl∆T κ

which can be written in the form:

N u = f (P e th ),

where P e th is the thermal Peclet number, defined by:

Ul
P e th = ,
κ
and Nu is the Nusselt number defined by:
Q
Nu =
Kl∆T
.

The thermal Peclet number can also be introduced by using Eqs. (5.50). The approach
is similar to that leading to the definition of the Reynolds and (massic) Peclet numbers.
It provides the physical following physical interpretation of P e th :

Transport by convection
P eth =
Transport by diffusion

At small thermal Peclet numbers, heat is mostly transported by the materials (solid
parts and fluids taken at rest) and at large Peclet numbers, mostly by the flow. Heat
exchangers, which use flows to enhance thermal transport, must obviously operate at
large Peclet numbers. The Nusselt number has a long history in thermo-fluidics. It
allows to quantify, in a dimensionless form, the heat exchanges developed in a system.
In the literature, it is often derived from the heat transfer coefficient h, using the
formula:
hl
Nu =
K

How large is the thermal Peclet number? As the velocity varies with l (at fixed pressure,
see Chap 1), the thermal Peclet number varies as l2 : this suggests that it is small in
microsystems, which might tempt us to neglect the flow contribution to the heat
transport. This remark is illustrated by Fig. 5.75.

In these experiments, a heat source is placed on the right of the figure, on the side
of a microchannel, along which a flow is driven. The Reynolds numbers vary from 7
to 91. The local heat source (a resistance) develops a thermal field, which crosses the
flow. The Peclet number, in this case vary from 1.1 to 13. One sees that, for a Peclet
number of 1.1, the thermal field is unaffected by the flow. At the largest speed, where
the thermal Peclet number reaches a value of 13, an effect of entrainment of heat by
the flow is visible.
 Heat transfer in the presence of a flow in microsystems 329

Fig. 5.75: Effect of the thermal Peclet number, shown by placing a heat source close to a
microfluidic channel. At the highest Peclet number, heat is transported by the flow, erasing
the thermal field. (A)10 µl/min. (B) 120 µl/min. (Reprinted from [138], with permission of
Royal Chemical Society. Copyright 2022.)

In most cases, microfluidic devices, dedicated to chemical or biological analysis, operate

at small thermal Peclet numbers, leaving the thermal field unaffected by the presence
of a flow. By contrast, microfluidic heat exchangers must interact with the thermal
field, and thereby operate at high thermal Peclet numbers. The problem is that, in
order to obtain significant Peclet numbers, we need to operate at high or moderately
large Reynolds numbers. In effect, the ratio of the two numbers is:

P eth ν
= = Pr
Re κ

in which Pr is the Prandtl number. For usual gases, this number is close to unity. For
water, most currently used in heat exchangers, because of its low viscosity and high
capacity, the Prandtl number is seven. It is thus impossible, with water, to reach large
Peclet numbers and, in the meantime, work at small Reynolds numbers. This raises
a constraint on the design of micro heat exchangers. In practice, in order to achieve
Reynolds numbers up to 1000, typical channel transverse dimenstions are 100 µm -
1 mm and velocities are on the order of m/s. In such conditions, the thermal Peclet
numbers range between 10 and 100.
One may conclude that, in practice, in efficient micro heat exchangers, thermal Peclet
and Reynolds numbers must be substantial. In fact, these systems operate in inertial
regimes. This represents a major difference between microfluidic heat-exchangers and
lab-on-a-chips. In practice, the two communities, although sharing the same microfab-
rication toolbox, most often work along separate pathways.

5.15 Heat transfer in the presence of a flow in microsystems

5.15.1 The laminar thermal boundary layer

When a flow is driven over a surface maintained at a temperature different from the
upstream fluid, a thermal boundary layer develops. There is a vast literature on the
330 Transport in microfluidics

subject, which analyses heat transfers in laminar and turbulent regimes, examines
the coupling between velocity and thermal fields, and calculate heat transfers and
exchanges coefficients. Here, we restrict ourselves to an elementary situation, whose
analytics is simple and which is relevant to microfluidics.

The geometry we consider is shown in Fig. 5.76. The plate is maintained at fixed
temperature Tw . The velocity field is supposed uniform, which can be justified at small
Prandtl numbers or at large slippages.26 Far from the plate, the fluid is at temperature
T∞ . In such conditions, a temperature field develops. Assuming stationarity, the field
T (x, z) is governed by the equation:

∂T ∂2T
U =κ 2 (5.52)
∂x ∂z

where U is the fluid velocity The boundary conditions are:

T (x, 0) = Tw and T (x, ∞) = T∞ . (5.53)

Equation (5.52) is a diffusion equation. We already solved this type of equation. The
solution is:

√
z U
T (x, z) = Tw + (T∞ − Tw ) erf( √ )
2 κx

A boundary layer, sketched in Fig. 5.76 develops. Its width δBL is given by:
r
2κx
δBL (x) = (5.54)
U

Thus, the thickness of the thermal boundary layer grows with the square root of the
distance from the edge of the plate.

In terms of orders of magnitude, taking x =100 µm, κ = 0.14 10−6 m2 /s (for water),
and U0 = 1 mm/s, one finds δBL ≈ 170µm. The boundary layer grows rapidly in the
cross-stream direction. We will return to this point in the next subsection.

26 At small Prandtl numbers, the hydrodynamic boundary layer is much thinner than the thermal
boundary layer and, from the viewpoint of the thermal field, it can be neglected.
 Heat transfer in the presence of a flow in microsystems 331

5.76: Thermal boundary layer

over a plate, with a uniform flow
U.

5.15.2 How long does it take to thermalize a fluid entering a

microdevice?

To answer this question, it is convenient to define the thermal length L e as the distance
beyond which the thermal boundary layer ‘hits’ the walls, i.e. its width equals the
microchannel height. This image, although approximate and schematic, leads us to
consider that, beyond L e , the fluid is thermalized at the device temperature, forgetting
its thermal history. The expression of this length can be established by using the
definition of the thermal boundary layer thickness δBL (see above). By imposing δBL =
h/2, we obtain:

1 U h2
Le ≈
8 κ
Another way to obtain the same result is to note that the temperature field takes a
time equal to h2 /8κ to diffuse more than half the height of the canal. During this time,
the field is transported by the flow, at a distance equal to U h2 /8κ. This leads to the
expression of Le .

The thermal length L e can be rewritten in the following form:

Le 1
≈ P e th
h 8
where the thermal Peclet number is defined by:
Uh
P e th =
κ

By taking the same numbers in the previous subsection, with h = 100 µm, one finds
Le ≈ 9 µm. In practice, with current fluids, typical speeds and channel sizes, Le
does not exceed the height of the canal. Indeed, these estimates neglect entry effects
related to flow momentum. In fact, at small Reynolds numbers, the entry length for
the establishment of a Poiseuille flow profile is also on the order of h (this point is not
332 Transport in microfluidics

discussed in this book). From this estimate, we may confirm the conclusion we just
drew out for the temperature field.

5.15.3 Application: microfluidic polymerase chain reaction (PCR)

5.77: Fast PCR: device performing

a 20-cycle PCR amplification of a
176-base pair fragment in 90 seconds
[139]. Traditional technique takes 2 h
for achieving the same task.

Small thermal lengths allow the time required for amplifying nucleic acids to be short-
ened [139]. Fig. 5.77 shows a system in which polymerase chain reaction (PCR) is
performed along a microfluidic serpentine [139]. Driven by a syringe pump, the DNA
sample visits different temperature zones on a glass plate. For performing PCR, three
temperatures are needed: 60◦ C (annealing), 70◦ C (extension), and 95◦ C (denatura-
tion). With microfluidics, a 20-cycle PCR amplification of a base pair fragment can be
achieved in a pair of minutes, to be compared to 2 h in non miniaturized setups [139].
The key feature here is the rapid thermalization of the biological mix (i.e. primers,
sample, enzymes, nucleotides, buffer) as it is transported downstream. In practice, the
continuous flow format is not used today because of hydrodynamic dispersion, which
tends, as explained earlier, to dilute the sample along the serpentine. We will see, in
Chapter 6, that this effect can be suppressed by using electrokinetics.

5.15.4 Heat transfer in microchannel flows far from the entry (developed
region)

We consider a microchannel, subjected to a heat flux q0 applied normally to the walls.

The geometry is shown in Fig. 5.78.
To model the situation, we consider that the fluid is confined between two infinite
planes separated by h, with the flow developing along x. The Poiseuille profile, which
characterizes the flow, is given by the expression:

U (z) = U0 (1 − 4z 2 /h2 ),
 Heat transfer in the presence of a flow in microsystems 333

Fig. 5.78: Flow in the presence of a fixed thermal flux q0 .

where U0 is a speed and z is the co-ordinate normal to the planes. The temperature
field, assumed stationary, only depends on x and z. In such conditions, the convection-
diffusion equation reads:

∂T ∂2T
U0 (1 − 4z 2 /h2 ) =κ 2. (5.55)
∂x ∂z

The thermal boundary conditions at the walls z = ± h2 are given by the equations:

h ∂T
z=± , K = ∓q0 , (5.56)
2 ∂z
where K is the fluid thermal conductivity. We look for a solution of the form:

T (x, z) = Ax + F (z),

where A and F (z) are unknown quantities. By identification, we find the following
expression for the function F (z):

AU0 z 2 z4
 
F (z) = − 2 + B,
κ 2 3h

where B is a constant. Then, considering the boundary conditions (5.56), we obtain

the relations:
3q0 h z 2 z4
 
F (z) = − 4 + B, (5.57)
K 2h2 3h

Now we must determine B. For this purpose, we introduce a temperature Tb , called

the ‘bulk’ temperature, or the ‘mixing cup’ temperature, which will be later taken for
the calculation of the coefficient of heat transfer hc (c’ for channel, to avoid confusion
with the height h). By definition, Tb is:
334 Transport in microfluidics

R h/2
−h/2
U (z)T (x, z)dz
Tb = R h/2
−h/2
U (z)dz

This temperature is extremely important. It represents the temperature of a sam-

ple, taken out of the channel, and mixed in a cup’.27 By identification, after some
calculation, one finds the following formula for the temperature field:

z2 2z 4
 
3q0 h 39 q0 h
T (x, z) − Tb (x) = 2
− 4 − (5.58)
K h 3h 280 K

Let us calculate global values. The temperature difference ∆T along the microchannel
is equal to:

3q0
∆T = Ax = x (5.59)
ρCp hU0

Then the exit temperature Te is related to the inlet temperature Ti by the relation:
3q0
Te = L + Ti . (5.60)
ρCp hU0

The following observations can be made about this formula:

• The smaller the height, the larger the temperature difference between the entry
and the exit. This behaviour is intuitive.

• The higher the speed, the smaller the temperature difference between the en-
try and the exit. According to Eq. (5.60), should the fluid be at rest, the exit
temperature would be infinite. To suppress this unphysical behaviour, one must
incorporate, in the analysis, thermal inertia, represented by the term ρCp DT Dt .
With this term, the temperature is no more infinite, but increases with time.
Here, the presence of the flow, however small it is, allows a stationary regime to
be achieved.

Let us now calculate the heat transfer coefficient hc . One obtains:28

27 This sampling temperature is not the average, along z, of the fluid temperature in the channel,
which could be tempting to take instead of Tb . The reason is that when we take a fluid sample out of
the system, the fast regions are more represented than the slow ones. This fact is not accounted for
in spatial averaging.
28 The factor 4 in the expression of h comes from that fact atht, by convention, the hydraulic
c
diameter 2h is used as the characteristic scale, and the total heat flux across the walls is 2q0
 Heat transfer in the presence of a flow in microsystems 335

4q0 140K
hc = = (5.61)
Tw − Tb 17h

in which Tw is the wall temperature, i.e. the temperature at z = ±h/2. The result
deserves four remarks:
1. There is an apparent paradox: the heat transfer coefficient, being independent
of flow speed, would be the same if the fluid were at rest. To understand this
behaviour, one must note that, according to Eq. (5.58), temperature gradients
across the channel (then along z) do not depend on x or the flow speed. Therefore,
temperature differences, between the wall and a reference such as Tb , only depend
on the channel height, the fluid thermal conductivity, and the heat flux at the wall.
Because of that, the heat transfer coefficient hc , which quantifies the heat fluxes
normal to the channel wall, is flow independent, however strange it may look at
a first glance. This does not mean that we can stop the flow: in this problem,
the flow has two functions: the first is to maintain a stationary state in which
a permanent heat transfer across the wall can develop. Without flow, no steady
state. The second function is to keep the fluid temperature low (see below).
2. The Nusselt number is N u = hc h/K. Its value is 140
17 , a number difficult to guess
without carrying out the full and quite lengthy calculation. In a tube, a similar
calculation leads to a Nusselt number equal to 48
11 .

3. If the heat transfer coefficient does not depend on the flow rate, why are large
thermal Peclet numbers and large Reynolds number used? In fact, heat must be
transported along the flow, and released outside the system, in order to avoid
working at elevated temperatures, leading to boiling. To satisfy this condition,
Peclet numbers must be large. To stress this point, one may rewrite Eq. (5.60) in
the form: Te = 3qK0 L P e−1 U0 h
th +Ti , in which P eth = κ . The formula shows that large
P eth prevent temperatures to reach high levels. In terms of order of magnitude,
let us take, with water, U0 = 10 mm/s, q0 = 1 kW/m2 , L = 0.1 m and h = 100µm.
We obtain: P eth ≈ 7, 3q ◦ ◦
K ≈ 167 and consequently, Te − Ti ≈ 23 . Working with
0

a thermal Peclet number of 0.1 would lead to a temperature elevation of 1670◦ ,

i.e. above the melting temperature of silicon.
4. Result 5.61 shows that, as announced previously, the exchange coefficient is in-
versely proportional to the characteristic size of the system, i.e. the channel height.
In the system we discuss here, we can produce thermal exchange coefficients on
the order of 105 - 106 W m−2 K−1 . This is much larger than with non miniaturized
systems (see Table 5.74)).

5.15.5 Why do bird legs not freeze in winter?

Small bird legs are several millimetres in diameter (see Fig. 5.79). A naive reasoning,
based on thermal diffusion, would lead us to conclude that they should freeze in winter.
336 Transport in microfluidics

However, they do not. The explanation is provided on the right–hand part of the figure.

Fig. 5.79: Small bird in the snow. Why do its legs not freeze ? The explanation, based on
the right–hand figure, is given in the text.

In the legs, veins and arteries are located close to each other. Consequently, due their
small sizes, they develop substantial thermal exchanges between them. Therefore, the
hot channel (35◦ C) can keep the other at above-zero temperatures, avoiding freezing.
This mechanism also holds for larger birds, such as ducks, in which veins and arteries
are also placed close to each other. Moreover, they are placed distantly from the outer
surface. In this manner, evolution has helped the small and medium–sized birds to
survive in winter.

5.16 Evaporation and drying

5.16.1 Generalities

When a liquid/vapour system is heated, the liquid is transformed into gas until a
new equilibrium state is reached. This is evaporation. Evaporation occurs when the
saturation pressure is larger than the partial pressure but smaller than the ambient
pressure. This is the case of a puddle evaporating under the sun. When no equilibrium
is found, the liquid disappears or, if it contains non–volatile components, precipitates.
This is drying. Boiling is different from evaporation. It occurs when the saturation
pressure is larger than both. This is the case when water is heated above 100◦ C. We
focus here on evaporation.
Let us consider the heated droplet shown in Fig. 5.80.
The droplet being hotter, the vapour concentration close to the interface will be larger
than in the far region, where the temperature is kept cold. Thereby, a diffusive profile
 Evaporation and drying 337

5.80: Sketch of the evaporation of

a hot droplet in a cold gas. A flux
of matter develops from regions rich
in vapour, close to the interface, to-
wards regions poor in vapor, far from
the interface. In this process, the
droplet shrinks.

develops, that maintains a flux of matter from regions rich in vapour, close to the
interface, towards regions poorer in vapour, far from it. In this process, the droplet
shrinks.

The phenomenon looks simple, but in practice, it is complex [140]. In many cases, it
involves capillarity, hydrodynamics and heat transfer, that couple together to induce
convection, Marangoni flows [141], crystallization, or precipitation.29 Efforts have been
expended for decades to investigate these situations. Some aspects have been reviewed
[140, 144, 145].

In microfluidics, evaporation is an important phenomenon. It can be detrimental. For

instance, small samples exposed to atmosphere can evaporate fast and get lost. It can
also lead to the realization of new structures, impossible to create in non–miniaturized
systems. An example shown in Fig. 5.81 is monodisperse micrometric solid foams [147]
(see also [150]). These foams are obtained from an assembly of microfluidic bubbles,
for which the continuous phase, a chitosan solution, was polymerized, cross-linked, and
dried.30 This ability to create new objects, by controlling drying, opens opportunities in
material science. In the case of the foams, applications to photonic band gap materials
and stem cell expansion were proposed [147–149].

5.81: Scanning electron microscopy (SEM)

image of a solid structure obtained by cross-
linking an assembly of monodisperse mi-
crofluidic bubbles. In this system, the liquid
phase, a chitosan solution, was polymerized,
cross-linked and dried [147]. (Courtesy of
M. Russo, I. Maimouni.)

29 In addition, surprising phenomena have been reported, such as a temperature jump at the inter-
face, in apparent violation with thermodynamics [143]
30 During the drying process, the thin films located between each bubble burst and disappear,
leaving the pores open.
338 Transport in microfluidics

5.16.2 How long does it take for an isolated spherical droplet to dry?

The first and simplest theory of droplet evaporation is due to Maxwell [151]. He suc-
ceeded in solving the equations of the problem, by assuming vacuum, no internal
convection, and no latent heat. Some assumptions are probably questionable – in par-
ticular the neglect of latent heat, which cools down the droplet as it evaporates, and
giving rise to Stefan flows [141, 142, 152] –. Maxwell theory nonetheless provides an
important starting point, which turns out, in many cases of practical interest, to be
extremely useful for interpreting the experiments. Maxwell theory shares features with
the Epstein-Plesset theory of dissolving bubbles [73], mentioned previously. The cal-
culation is lengthy but not difficult and the interested reader will find it described in
Ref. [144]. The main outcome of the Maxwell model is the determination of the evolu-
tion of the droplet radius a(t), which is given by a formula similar to Epstein-Plesset
theory (see Eq. (5.24)).

8DM psat
a2 = a20 − t (5.62)
ρL RT

in which a0 is the droplet initial value, D is the diffusion constant of the liquid vapour
in the gas medium, M is the molar mass of the liquid, ρL is its density, R is the
gas constant and TL is the liquid temperature.31 The theory compares well with the
experiment. An example is shown in Fig. 5.82, in which droplets were levitated elec-
trostatically.

5.82: Radius evolution, with time,

of water and ethanol microdroplets
at different temperatures and 0%
relative humidity. Symbols: exper-
imental; solid lines: Stefan-Fuchs
model; dashed lines: Maxwell model
(Reprinted from [154], with permis-
sion of Springer Nature. Copyright
2022.)

The authors also compared the measurements to the Stefan-Fuchs model [153], in
which Stefan flows are taken into account. It turned out that in the experimental
conditions that were considered, there is little difference between the two models. This
suggests that latent heat can be neglected in this case. From a(t), one can calculate
the lifetime τ of the droplet:

31 Maxwell and Epstein-Plesset formulas have the same form. This can be seen by replacing c
sat by
psat M/RT (using the law of perfect gases).
 Evaporation and drying 339

a20 ρL RT
τ= (5.63)
8DM psat

This time decreases with the droplet size to the square, indicating that the smaller
the droplet, the shorter its lifetime. In practice, 1 µm diameter droplets survive for 1
ms, and 100 µm droplets live for 10 s.

5.16.3 How long does it take for a surface droplet to dry?

When the droplet is deposited on a plane substrate, we can anticipate, from reading
Chapter 4, that complications will arise, due to the presence of a contact angle, rough-
ness, and wetting heterogeneities. In fact, two situations can be defined [155]: (a) the
contact angle is constant or (b) the droplet radius is constant (see Fig. 5.83).

5.83: Two situations for the evap-

oration of a droplet on a substrate:
(A) free contact line. Contact an-
gle is locked at the Young value, as
the droplet evaporates.(B) Droplet
pinned on the surface, with a con-
stant footprint and a free contact an-
gle.

Typically, contact angles are constant on high energy surfaces, and they vary on low
energy surfaces, because, again, of contact line pinning. Note that our droplet can
decide to jump from one state to the other during the evaporation process, or get
pinned only partially, developing a footprint evolving in a complicated manner.

Let us restrict ourselves to case (b), i.e. a variable contact angle and a constant foot-
print, characterized by radius a0 . Different authors succeeded in solving the problem,
within slightly different frameworks of approximation [156–160]. These theories essen-
tially agree with each other. We use Ref. [160] which provides a simple approximate
formula for the temporal decay of the droplet mass:

m(t) ≈ m0 − 4D(1 − H)csat a0 t (5.64)

in which m is the droplet mass at time t, m0 is its initial value, H is the relative
humidity, D is the diffusion coefficient of liquid vapor in the ambient gas, csat is the
saturation gas concentration far from the droplet and, again, a0 is the footprint radius.
The evolution of a(t), given by Eq. (5.64), and compared to the experiment, is shown
in Fig. 5.84.
340 Transport in microfluidics

5.84: Measured droplet profiles at dif-

ferent times, for water evaporating from
a droplet of initial radius a0 = 0.85 mm
and initial height 0.329 mm. The sym-
bols show the locations of fluorescent
particles on the droplet surface, and the
lines are the fittings of circular arcs to
these data. (Reprinted from [160] with
permission of the American Chemical
Society. Copyright 2022.)

Fig. 5.84 shows that the Hu and Larson formula reproduces well the experimental
observations. From Eq. (5.64), the droplet’s lifetime τ is:

m0
τ≈
4D(1 − H)csat a0

Here again, it is instructive to estimate orders of magnitude.32 For a 1 µm-sized droplet

in a dry environment – so, roughly, a volume of 1 f l. – the droplet survives for 1 ms.
For 100 µm-sized droplets, the life time is 10 s. This time can be increased considerably
by raising H.

5.17 Microexchangers for electronic components

5.17.1 The considerable needs of cooling of data centres

Since the invention of the integrated circuit, the course of the integration of transistors
onto Central Processing Unit( CPU) has proceeded with impressive speed. In 1971, the
operating units of computers contained around 2,000 transistors. In 2002, this number
had multiplied by 25,000, approaching 60 million transistors for the 3 GHz Pentium
IV. At the time of writing (2022), 50 billion transistors are currently integrated on
microprocessors.
This evolution is accompanied by an increase in the number of commutations and,
consequently, a raise in the quantity of heat produced by the unit. It is critical to
extract this heat for the transistors to function at a stable temperature, between 80◦
C and 95◦ C.
Today, in the USA alone, data centers consume 24 TWh of electricity and 100 billion
litres of water to cool them down [161]. This represents the residential needs of a
32 Maxwell and Hu-Larson formula have the same form. This can be seen by replacing c
sat by
psat M/RT and developing m0 . The two formulas therefore provide, for the droplet lifetime, compa-
rable orders of magnitude.
 Microexchangers for electronic components 341

city of the size of Philadelphia. In 2027, the needs will account for 31% of Ireland’s
electricity [161].
Traditionally, processors are cooled down with radiators. These radiators are fabricated
with a good thermal conductor (copper), ventilated, or traversed by cooling channels.
In some case, the entire CPU is immersed in an insulating fluid. The seminal work of
Tuckerman and Pease [162] showed that the usage of microcanals placed directly on
or in good thermal contact with the processor allows to reach exchange coefficients
much higher than traditional methods.33 This is where micro and millifluidics come
on the stage.

5.17.2 Old method

The traditional method consists, thus, in installing a radiator cooled by forced or nat-
ural convection (i.e. with or without a fan). Nature has used this solution to cool down
the stegosaurus. This dinosaur, a peace-loving herbivorous animal, shown on Fig. 5.85,
grew large plates on its back, to thermoregulate its body and, in the meantime, scare
predators.

5.85: A traditional radiator, possess-

ing cooling fins increasing the surface
area of exchange with the cooling source
(air). The animal (stegosaurus) bears
the radiator on his back. (iStock image,
Credit MR1805 Bochum, Germany.)

In all cases, including our stegosaurus, the heat flux q extracted by the radiator is
given by:
P
q= = hc ∆T (5.65)
A
where hc is the exchange coefficient, ∆T is the temperature difference between the
component and the exterior, P is the power produced by the component, and A is
the exchange surface. For a radiator cooled by natural convection, the exchange coeffi-
cient is on the order of ten or so W m−2 K−1 (see Table 5.5). In such conditions,
33 We may quote, from Tuckerman and Pease (1983 Symposium on VLSI Technology): ’The widely
held belief that a VISI circuit (VLSIC) must not use more than a few watts of power due to thermal
limitations has led to major constraints on the performance of VLSI systems. There is, however, no
fundamental justification for this belief.
342 Transport in microfluidics

with a produced heat q is on the order of 103 W m−2 , it is possible to maintain the
microprocessor at a temperature between 80 and 90◦ C. The usage of fans, by improving
h up to an order of magnitude, allows us to work at larger q. However, for heat densities
currently required in data centres, such radiators are no longer able to thermoregulate
the system.

5.17.3 Optimizing microexchangers

We recall that in microchannels, the thermal exchange coefficient hc is given, in term

of order of magnitude, by the relation hc ∼ h−1 , in which h is the channel height
(see Eq. (5.61)). By miniaturizing the system, higher exchange coefficients can thus be
obtained. In terms of orders of magnitude, for water in a microchannel, 100 µm high,
one achieves coefficients hc on the order of 105 W m−2 K−1 . As noted, this represents
an improvement of two orders of magnitude compared to the passive radiator. This
point was stressed by Tuckerman and Pease [162]. In their experiment, they achieved
a heat transfer coefficient on the order of 105 W m−2 K−1 , so that they could extract
a power density equal to 7.9 MW/m2 , keeping the temperature rise below 71◦ C.
A simplified view of a microexchanger, of the type discussed by Tuckerman and Pease,
is formed by stacking microchannels (see Fig. 5.86).
The channels have a width w, a height h, and a total length L. They are placed in
parallel, along a serpentine (not represented), located just beneath, and in excellent
thermal contact with a CPU, idealized by a rectangular plate. We assume that the
solution obtained in Section 4.14.4 can be transposed, in terms of order of magnitude,
to our case. The processor produces a thermal power P , and the heat flux q that the
microexchanger extracts is:
P
q∼
wL
In Section 4.14.4, we calculated the temperature differences developing in the fluid,
along the streamwise direction (∆Tx ) and the cross-stream direction (∆Tz ). We found:

q0 h q0 L
∆Tz ∼ and ∆Tx ∼ (5.66)
K ρU Cp b

in which U is the flow speed, ρ is the fluid density, and Cp is the thermal capacity.
∆Tz increases with h, while ∆Tx decreases with it. In an optimal microexchanger, the
two temperature rises must be minimized, in order to work in thermally acceptable
conditions. The optimal conditions, obtained by equating ∆Tz and ∆Tx , are defined
by the following expression:

r
U0 h L Lκ
P e th = = and then h ∼ (5.67)
κ h U
 Microexchangers for electronic components 343

5.86: Example of an oversim-

plified microexchanger using
several microchannels in par-
allel, placed along a serpen-
tine.

Ideally, it would be interesting to increase U , so as to decrease h and increase the ther-

mal exchange coefficient. However, in this approach, the power of the pump assuring
fluid circulation must be raised. Let us recall the formula for the pressure drop along
a microchannel, established in Chapter 3:
µLU
∆P ∼ (5.68)
h2
where µ is the fluid viscosity. Increasing U and, in the meantime, decreasing h implies
increase ∆P . This brings us to the question of the pump. Excellent pumps are needed
to drive, in a compact design, flows at substantial speeds in narrow channels. In the
early days of microfluidics, electro–osmotic pumps were proposed [163]. Today, the
subject is an active area of research.
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6
Electrokinetics

6.1 Introduction
In the years 1980s, stimulated by the surge of micro–electromechanical systems (MEMS)
technology, and in the hope of creating performing, miniaturized, electro-mechanical
actuators, researchers worked at integrating, in microsystems, electrodes with ex-
tremely small separations. In this manner, they could produce high electric fields, and
thus large electromotive forces. The idea came to a small group, based in Europe, to
exploit these large fields for separating ions, sorting particles and driving electrolytes.
In 1992, Manz and Widmer [1] invented the first miniaturized electrokinetic system
of separation based on MEMS technology. They demonstrated that, by working in
microchannels, ions can be separated in seconds, with excellent efficiency, while tra-
ditional methods needed heavy equipment and hours to perform the same task. The
concept was appealing, and, in a visionary impetus, it gave rise to the notion of lab
on a chip, i.e. a device performing all operations carried out in laboratories, but in a
centimetric system, using small amounts of reagents and short times.1 Microfluidics
was born.

6.2 Basic notions of electrostatics of macroscopic media

6.2.1 Governing equations

Here, we briefly review some basic results of electrostatics. For further reading, we
recommend two excellent textbooks [2, 4]. In the field of electrostatics, by definition,
there is no magnetic field and Maxwell equations, in a vacuum, reduce to:

div 0 E = ρe (6.1)
curl E = 0 (6.2)

in which E is the electric field, ρe is the charge density (C/m3 ), and 0 = 8.8410−12
F/m is the vacuum permittivity. The first equation leads to the Gauss theorem (the
1 We may quote a sentence in the conclusion of Ref. [18]: Such systems could lead to laboratories on
a chip that offer rapid, sophisticated analyses in a mobile package that is free to leave the laboratory.’
 Basic notions of electrostatics of macroscopic media 351

flux of E across a surface enclosing a volume is equal to the charge contained in it)
and the second one to electric field circulation along a closed line equal to zero. From
Eq. (6.2), one introduces an electric potential φ given by:

E = −∇φ

Combining this with Eq. (6.1), on obtains ::

ρe
∆φ = − (6.3)
0

In purely dielectric media, i.e. with zero conductivities, and in the presence of an
electric field, charges of opposite sign, electrons or protons, separate, so that dipoles,
aligned along the field line, emerge from the background. On the other hand, the
permanent molecular dipoles (for instance, water) reorient and align along the field
direction. All these molecular contributions sum up to develop a macroscopic polar-
ization P (see below). The phenomenon is illustrated in Fig. 6.1.

6.1: A dielectric volume δV , sub-

jected to an electric field E, polarizes.
Microscopic dipoles pi form, giving
rise to a local, macroscopic, polariza-
tion vector P, which sums up all of
them.

Determining the consequence of the presence of a polarization field is nothing but

straightforward. First, let us recall that for a dipole formed by two opposite charges
q, separated by a vector di , the polarization vector is equal to qdi . In vacuum, and
at distances large compared to di , this dipole develops, at location r (with the origin
taken at the dipole centre), an electric potential φi (r), given by:

pi .r
φi = (6.4)
4π0 r3

In a dielectric medium, a polarization vector par unit of volume, P, builds up by

summing up, in the elementary volume δV , all the molecular dipoles i induced by
the presence of the local electric field (see Fig. 6.1). Without electric field, no charge
separates, then no polarization appears. P is therefore a function of E. In linear,
isotropic materials, which will be considered all along the chapter, P = 0 χE, where
χ is the dielectric susceptibility.
It has been a mathematical achievement to demonstrate that, for these materials, the
effect of polarization is fully taken into account by replacing, in Maxwell equations, and
352 Electrokinetics

in the boundary conditions, the vacuum permittivity 0 by the medium permittivity

 = 0 (χ + 1). In other words, the effect of polarization is to replace the displace-
ment field 0 E by 0 E + P. We will admit this result, which is not straightforward to
demonstrate, and is well–presented in textbooks.2 Often, a physical picture is offered,
in which a dielectric material is shown to be equivalent to a non–dielectric material
with a charge distribution at its surface, called ‘bound charges’. This representation
allows us to visualize the effect of the polarization, but it is not useful for calculat-
ing the electrostatic field, because the charge distribution is, in fact, most often, an
unknown of the problem.

In microfluidic systems, where oils, poydimethylsiloxane (PDMS), plastic, and glass

are used, the dielectric materials are isotropic and linear, and  is typically a few times
the vacuum permittivity. Water is extremely polarizable: its permittivity is 80 0 (at
20◦ C).

6.2.2 Boundary conditions

Having stated that, formally, the effect of polarization is absorbed in , called ‘dielectric
constant of the medium’, it becomes possible to establish, in a simple manner, the
boundary conditions. At the frontier between two media of permittivities 1 , and 2 ,
with E1 on one side and E2 on the other, one has (see Fig. 6.2):

6.2: Boundary conditions on the

electric field at the frontier between
two dielectric materials.

Et1 = Et2 and. 2 En2 − 1 En1 = σS (6.5)

in which σS is the surface charge and t and n represents the tangential and normal
coordinates, respectively, with respect to the interface. The condition on the electrical
potential is the continuity at the interface, along with a relation, similar to that shown
in Eq. (6.5) on the normal derivatives. In conducting materials, charges can move
towards the interfaces, building up surface charges. But here, we restrict ourselves to
pure dielectric material, in which charges are fixed, so that, in most cases, σS will be
taken as equal to zero.

2 And also, at the time this book is written (February 2021), Wikipedia
 Basic notions of electrostatics of macroscopic media 353

6.2.3 Electric field in dielectric slabs

In microfluidic systems, electric fields are produced by electrodes integrated in the

device. Obviously, in the exceedingly important case of water, in order to avoid elec-
trochemical interactions, electrodes cannot touch the fluid. Then, an insulating layer
must be placed between it and the electrodes, as sketched in Fig. 6.3. How does the
electric field behave in such a situation? Is it screened by this layer? The question can
be answered by using Eqs. (6.1), (6.2), (with ρe = 0), together with the boundary
conditions (6.5) (with σS = 0).

6.3: Two electrodes, held at a poten-

tial difference V , developing an electric
field E, across a channel of permittiv-
ity c , separated from the electrodes by
a layer of permittivity w .

One finds that the electric field E, oriented normally to the electrodes, is constant
in each domain, i.e. in the layers and the channel (see Eq. 6.1). Applying further the
boundary conditions (6.5), one finds, for the channel region:

w V
Ec = (6.6)
hw w + hc

The calculation shows that if the working fluid is more polarizable than the walls, for
instance, water for the liquid and PDMS for the walls, the electric field is screened by
them. It is somehow lost in the walls. In the case where the walls have comparable
or larger permittivities, than the working fluid, there is no screening effect. In such
cases, an intense electric field can be applied within the channel. To fix orders of
magnitudes, with PDMS channels of 100 µm high, a layer of 10 µm and silicone oil as
the working fluid, by applying tensions of 300 V across the pair of electrodes, electric
fields of 27 kV/cm can be imposed inside the fluid. Note that this level approaches
the electrical breakdown. In air, for instance, the electrical breakdown is 30 kV/cm; in
silicone oil, it ranges, roughly, between 30 and 100 kV/cm. There is not much difficulty,
in microfluidic systems, to work with high electric fields.
The microfluidic device shown in Fig. 6.4 provides an interesting example, in which
Eq. 6.6 can be used.
Here, water droplets are driven in oil. An electric field is produced by two electrodes,
integrated in the PDMS walls. Owing to the dielectric constants of the channel and the
walls are comparable, one may estimate that droplets will see’ an electric field on the
order of V /d, where d is the distance between the two electrodes. Should the emulsion
be direct (oil droplets in water), the application of a voltage would be inefficient. The
354 Electrokinetics

6.4: Microfluidic sorter of aqueous droplets,

transported in an oil phase. The electric field
inside the droplets is substantial and it is
possible to exploit it to deflect their trajec-
tories and sort them. Should the continuous
phase be water instead of oil, the electric
field inside the droplets would be small and
it would be impossible to perturbe their tra-
jectories.

electric field would develop in the continuous phase and would be extremely weak in
the droplet.

6.2.4 Dielectric sphere in an uniform electric field

Here we consider the important problem of a dielectric sphere of radius R, permittivity

s immersed in a medium of permittivity m , and subjected to a uniform electric field
E0 , applied along z axis. Here again, the medium is a pure dielectric material, and
there is no permanent volumetric nor surface charge. Therefore, both ρe and σS are
zero. Coordinates (r,θ) are shown in Fig. 6.5.

6.5: Sphere immersed in a uniform electric

field, showing the spherical coordinate sys-
tem, with radius r and polar angle θ as the
variables (the system is independent of the
azimuthal angle).

The problem can be exactly solved, using a spherical system of coordinates and noting
that the solution is independent of the azimuthal coordinate.(see, for instance, Ref. [2]).
Quantities depend only on r, the distance from the sphere centre, and θ, the polar
angle. One finds, for the potential φ:

r < R : φ = −E0 (1 + K0 )r cos θ. (6.7)

R3
r > R : φ = −E0 (r + K0 2 ) cos θ (6.8)
r

in which:
1 − r
K0 =
r + 2
 Basic notions of electrostatics of macroscopic media 355

and r = ms . K0 is the equivalent of minus the Clausius–Mossoti factor for steady
fields. It plays a crucial role in the phenomenon of dielectrophoresis, as will be seen
later. Let us write the expressions, still in spherical coordinates, of the electric field:

r < R : Er = E0 (1 + K0 ) cos θ and Eθ = −E0 (1 + K0 ) sin θ (6.9)

R3 R3
r > R : Er = E0 (1 − 2K0 3 ) cos θ and Eθ = −E0 (1 + K0 3 ) sin θ (6.10)
r r

Expression (6.9) includes two terms: the first term is the applied field, while the second
is the field developed by the sphere. This field has a pure dipolar structure (see Eq.
(6.4)), with a dipole moment p, located at r = 0, aligned along E0 , and equal to:

p = −4π1 K0 R3 E0

For the external medium, as far as the electric field is concerned, the dielectric sphere
is equivalent to a dipole of moment p, located at the particle centre. Equation (6.9)
tells us that, in the sphere, the electric field is constant, and oriented along x. Its value
is E0 (1 − K0 ). Thus, for a highly dielectric sphere, the electric field inside the sphere
is zero, while in the opposite case, it is 23 E0 , i.e. larger than the applied field. The
field patterns are shown in Fig. 6.6, in two extreme cases: (a) a sphere much more
polarizable (r >> 1) and (b) one much less polarizable than the medium (r << 1 ).

Fig. 6.6: A dielectric sphere immersed in a uniform electric field. The sphere deforms the
electric field lines. (A) Sphere of large permittivity (compared to the medium).(B) Sphere of
small permittivity.

In case (b), the field lines enter the sphere normally to its surface, as if they were
attracted by it. In case (b), the field lines tend to be tangential to the sphere, as if
356 Electrokinetics

they seek to avoid it.

Is it possible to understand why this is the case? Let us write again the boundary
conditions across two dielectric media:

Etm = Ets and. m Enm − s Ens = 0 (6.11)

In the case of large permittivity (case (a)), the boundary conditions impose Ens ≈ 0,
at the interface, inside the sphere. This relation suggests that E = 0 inside the sphere,
and then Etm = 0 at the interface. This leads to electric field lines normal to the
interface, as shown in Fig. 6.6 (A). In the case of a sphere of low dielectric constant
(case (b)), Eq. (6.11) implies Enm ≈ 0, so that the electric field is, in the medium,
tangential to the sphere. This explains the pattern shown in Fig. 6.6 (B).

6.2.5 The analogy between dielectric and conducting systems

Conducting materials are physically different from dielectric materials. In the former,
ions or electrons are mobile, while in the latter, they are fixed. Nonetheless, there exists
an analogy between conducting systems, in which the conductivity σ is constant (for
example, homogeneous metals), and homogeneous dielectric systems: if we neglect
charge diffusion, the relation J = σE, in which J is the electric current density, holds.
Electric and current lines are therefore undistinguishable. Restricting ourselves to the
steady–state, the boundary conditions are, for the normal component of the electric
field, σ1 En1 = σ2 En2 and, for the tangential one, Et1 = Et2 . They are analogous to
Eqs (6.5), if we replace permittivities by conductivities. There is thus an equivalence
between the steady–states of electric and current density fields. Formally, solving the
equations for the former case provides the solution for the latter.
This analogy applies well for system composed of different metallic materials, for
instance, metallic particles immersed in mercury, but is not a very interesting system
in practice. It does not apply to systems of metallic particles suspended in electrolytes.
In this case, because ions, which transport the current, cannot penetrate the particles,
charge accumulation occurs, and the analogy, which is about steady–states, ceases to
be valid. We will return to this situation later.

6.3 The electrokinetic equations

6.3.1 Charge density, conductivity, diffusion constant,...

We concentrate on electrolytes. Before proceeding to the establishment of the governing

equations, it is useful to define several quantities.
Charge density: the charge density, denoted by ρe is the electrostatic charge per
unit of volume. It is related to the ionic mass concentration C by the relation
q
ρe = m C, where q is the ion charge and m is its mass.
 The electrokinetic equations 357

Ionic mobility: In the presence of an electric field E, an ion migrates at speed v,

according to the law: v = µe E, in which µe is the ionic mobility. This mobility
can be estimated by using the Stokes-Einstein law. One finds:
q qD
µe = =
6πµa kT

in which µ is the fluid viscosity, a is the ionic radius (or ionic complex radius) and
D is the diffusion coefficient. a includes the presence of a hydration shell bound
to it, and moves with it. For instance, for sodium ions, for which the hydration
shell is formed with three water molecules, a is 0.25 nm, i.e. 2.5 times its ionic
radius. For potassium ions, there is no hydration shell, and a is equal to the ionic
radius (0.14 nm).
Ionic conductivity: The relation between the mobility µe and the conductivity σ
reads:
qD
σ = ρe µe = ρe
kT
.The important fact here is that, unlike with metals where conductivities are con-
stant, σ is proportional to the ionic density. We will see later that this dependence
has considerable implications on the electrokinetics of the electrolyte.

6.3.2 The electrokinetic equations for a single ion species

Electrolytes include several species of ions, positive and negative, of different masses
and charges. However, here, for simplicity, we assume that the ions contained in the
solution have the same mass m, diffusion constant D, and charge q. This electrolyte
could be called ‘mono-ionic’. Later we will return to realistic cases, where several types
of ions, with different characteristics, compose the solution. At this stage, introducing
several species would make the equations opaque.
Within the electrolyte, electric currents develop, due to ion displacements, develop.
Their origin, schematized in Fig. 6.13, is threefold:

6.7: Three origins of the electric cur-

rent in electrolytes. With the vector
orientations shown on the figure, Eq.
(6.13) tells us that the charge density
ρe will decrease.

• Diffusion. This process is analogous to the ordinary diffusion process, and is gov-
erned by Fick’s law, which we saw in Chapter 5. Let us recall the expression of
this law:

J m = −D∇C
358 Electrokinetics

where J m is the mass current (i.e. the mass crossing a surface element per unit
time) and C is the mass concentration. Dividing the two sides of the equation by
q/m, we obtain the relation:

J D = −D∇ρe (6.12)

where J D is the current with a diffusive origin, and ρe is the charge density, i.e. the
electric charge per unit volume. Indeed, in our model, ρe is everywhere positive
or negative, depending on the sign of q.
• Transport by the flow u. The current induced by this effect is written:

J T = ρe u,

where u is the fluid velocity. This term is the equivalent of the flux of matter uC
in Chapter 5.
• Migration in the presence of an electric field E. The corresponding flux is given
by Ohm’s law:

J e = σE

where σ is the ionic conductivity.

Adding up these three contributions, we arrive at the equation:

J = −D∇ρe + ρe u + σE. (6.13)

The relation is valid for electrolytes, where, as noted above, currents are conveyed by
ions. In liquid metals (such as mercury), where currents are transported by electrons,
the physics is different, and the first two terms are absent. In practice, as noted above,
electrolytes include several types of ions, and several equations of this type should be
written, one for each species. We will come to this point later.
The equation for the conservation of the electric charge is similar to the conservation
of mass:

∂ρe
+ div J = 0 (6.14)
∂t

As in the preceding section, Maxwell equations constrain the electric field with two
relations:
 The electrical double layer 359

div E = ρe and curl E = 0 (6.15)

in which  is the homogeneous dielectric permittivity of the medium.  incorporates,

in a single parameter, the polarization of the medium induced by the electric field.
Equations (6.13), (6.14), and (6.15) must be completed by the Navier-Stokes equation,
to which Coulomb forces are added. Coulomb forces apply to the ions, but on the scale
of the fluid particle, owing to fast momentum exchange, these ions drag the neutral
elements. Consequently, Coulomb forces, weighted by the ionic density ρe , apply to the
fluid element as a whole. With  homogeneous, there are no other forces to consider.
The flow equation thus read;

Du
ρ = −∇p + µ∆u + ρe E (6.16)
Dt

where u is the fluid velocity. In the context of microfluidics, as emphasized in Chap-

ter 3, we can eliminate inertial terms, and restrict ourselves to the following form:

−∇p + µ∆u + ρe E = 0 (6.17)

Equations (6.13), (6.15), and (6.17) define the system of equations governing electrolyte
flows. They must be completed by boundary conditions. Compared to the preceding
section, where the media were not conducting and therefore charges did not move,
here the situation is more complex. Electrical currents flow, covering interfaces with
charges, which in turn affect the electric field distribution. The boundary conditions
thus must include several relations, including speed, electric fields, currents, charges.
We will not develop the subject here, but content ourselves, in the next sections, with
considering elementary situations for which the boundary conditions take a simple
form.
Because of the dependence of the electric conductivity on the ionic density, the equa-
tions are non–linear. This feature gives rise to complex phenomena, such as instabili-
ties, chaotic behaviour, and turbulence. We will not discuss this subject, but restrict
ourselves to the description of important cases, pertinent to microfluidics.

6.4 The electrical double layer

6.4.1 Origin of the surface charges

The appearance of charges at interfaces is a general phenomenon. Two major causes

exist.
Ionization or dissociation of surface groups A glass immersed in an aqueous so-
lution becomes negatively charged, because the silane terminals SIOH, located at
360 Electrokinetics

the surface of the glass, are deprotonated, i.e. they loose their H + . The electrical
potential associated with these charges at a pH of 7 is on the order of −100 mV.
The process is general: many chemical groups can dissociate in water, conferring
the surface with a net charge. Examples are carboxylic and sulphate groups.
Ion adsorption As we saw in Chapter 3, ions can develop an affinity with the sur-
face and get adsorbed, in a process similar to Langmuir adsorption, described
in Chapter 5. An important example for microfluidics is hydroxyl group on hy-
drophobic surfaces. The phenomenon, unexplained until the year 2000, is due to
the enhanced autolysis of water on these surfaces (see [5]).

6.4.2 Gouy Chapman and Stern models

General structure:. The study of electrokinetics close to charged surfaces has a long
history. The first model was proposed by Helmholtz [6], in 1879. Immersed in an
electrolyte, charged surfaces adsorb a fixed layer of counter-ions that neutralizes the
charge. This model had drawbacks, in particular a capacitance independent of the ionic
concentration, which contradicted the experiment. We will return to this point later.
Also, physically, it was not clear why, in the presence of thermal agitation, all counter–
ions would condensate or adsorb at the walls. This led Gouy (1910) [7] and Chapman
(1913) [8] to propose another model where, unlike the previous one, all counter–ions,
whatever their distance to the wall, are mobile. Later, a two-layer model, combining
the two preceding ones, was proposed by Stern [9], in 1924. The first layer, which is
fixed (see Fig. 6.8), is called ‘Stern layer’. At its edge, there is a plane, called ‘slip
plane’, associated to a potential ζ, beyond which ions are mobile (see the dashed line).
This is the ‘diffuse layer’. The model is called ’double layer’ (DL or EDL for electrical
double layer), because it is composed of two layers: one fixed and the other diffuse.

compact stern diffuse charge

layer layer

+
– +
– +
– neutral
solid
+ – + bulk
+ + +
+ electrolyte

– –
+ – + – +

Fig. 6.8: Stern model: a fixed layer, composed of a featureless accumulation molecules,
charged or not, and a diffuse layer, in which ions are mobile. There is a plane, called slip
plane’, associated to a potential ζ, whose location is not precisely defined, supposed to mark
the separation between the two layers.

Structure of the Stern layer. For a long time, the structure of the Stern layer remained
inaccessible to measurements. Theoretical considerations led researchers to think that
 The electrical double layer 361

its content is a dense mixture of molecules, ions, and counter-ions, as sketched in

Fig. 6.8. Its thickness is on the order of the Bjerrum length, which represents the
separation distance between two elementary charges storing an electrostatic cohesion
energy equal to kT. We may suggest that the Stern layer, storing such an energy, will
form a condensed phase. The expression of the Bjerrum length is:

e2
λB =
4πε kT

where e is the elementary charge. For water at room temperature, λB ≈ 0.7 nm.
In recent years, thanks to progress in spectroscopy, along with indications provided
by numerical modeling (see [10], for instance), a number of information has become
accessible. In the work of Ref. [11], performed with a glass surface exposed to an NaCl
solution, the authors concluded that the chemical content of the Stern layer includes a
first layer of hydrated sodium ions, linked to the surface, above which hydrating water
molecules, forming either part of the first layer, or a second or third layer, in contact
with the fluid. Fig. 6.9 shows measurements carried out on this system.

Fig. 6.9: A variety of measurements characterizing the Stern layer: (Left) Quantities charac-
terizing the Stern layer. (Right) Evolution of the Stern layer thickness, in function of the NaCl
concentration. (Reprinted from [11] with permission of Wiley and Sons. Copyright 2022.)

Different quantities could be measured: the surface potential, ΦS , inferred from X–

ray photoelectron spectroscopy, the charge surface, measured by Fourier transform
Infrared (FTIR) spectroscopy, and the ζ potential, inferred from electrophoretic mea-
surements. Φsurf is on the order of -300 mV, i.e. one order of magnitude larger than
ζ. There is a strong drop across the Stern layer, leading to electric fields on the order
of 300 MV/m, well above the breakdown field.3 From the knowledge of the electrical
potentials, and that of the surface charge, the thickness of the Stern layer dStern can
be estimated. It is represented in Fig. 6.9 (right). dStern was found on the order of
a few Angstroms, in agreement with estimates based on Bjerrum length. There is a
decrease of dstern , with the NaCl concentration, consistent with the evolution of the
ζ potential with this parameter. Much remains to be learned in this area.

3 The breakdown field in common materials is below 10 MV/m.

362 Electrokinetics

6.4.3 The electric field in the diffuse layer

Let thus concentrate on the diffuse layer, and take z as the coordinate normal to the
wall (see Fig. 6.10). In the presence of a surface charge, the mobile ions located close
to the surface feel an attractive forces that drive them towards the wall, while thermal
agitation works at suppressing concentration gradients. The analysis of this situation
can be carried out by using statistical or thermodynamical arguments (as currently
done in textbooks). Here we investigate the problem with the electrokinetic equations
presented previously.

Fig. 6.10: Gouy-Chapman model, in which, close to the surface, all ions are mobile.

Let us assume, as Debye and Huckel did, that the solution includes two types of
ions, one positive, of charge +q (q > 0), of density ρ+e and conductivity σ
+
and the
− −
other of charge −q, density ρe and conductivity σ . This electrolyte is called binary
symmetric’. The flow is at rest and quantities depend on z only. This implies that E
and J have one single component, oriented along z. We look for a stationary solution.
Equation 6.14 imposes Jz = Cst. We assume here that the wall is insulating, implying
the constant is zero. Based on this, Eq. 6.13 simplifies into:

dρ+ dρ−
0 = σ + Ez − D + e
and 0 = σ − Ez − D− e
dz dz

Conductivity σ depends on charge densities, and we need to take this dependence into
account to go further. This is done by using the expressions shown in the last section:

qD+ qD−
σ + = ρ+
e and σ − = −ρ−
e
kT kT
With this relation, and using the electrical potential φ defined by:
dφ
Ez = −
dz
the previous equation can be rewritten as follows:
 The electrical double layer 363

q dφ dρ+
D+ (−ρ+
e − e )=0 (6.18)
kT dz dz

q dφ dρ−
D− (ρ−
e − e )=0 (6.19)
kT dz dz

On integrating them, and taking into consideration that, far from the wall, ρ±e tend to
±ρ∞ , one obtains the following relations between the ionic densities and the potential:

qφ
ρ+
e = ρ∞ exp(− ) (6.20)
kT

qφ
ρ−
e = −ρ∞ exp( ) (6.21)
kT

These expressions are the Boltzmann distributions of the ionic charges.

−
With this, using ρe = ρ+
e + ρe , adding up Eqs. (6.20) and (6.21), one obtains:

q
ρe = −2ρ∞ sinh( φ) (6.22)
kT

and using
d2 φ ρe
=−
dz 2 
we get:
d2 φ ρ∞ q
=2 sinh( φ)
dz 2  kT

This equation is called the Poisson-Boltzmann equation. Together with the boundary
conditions φ = ζ at z = 0 and φ = 0 at z = ∞ (neutrality condition), it can be solved.
The solution is:
4kT
φ= tanh−1 (tanh(qζ/4kT )exp(−z/λD )) (6.23)
q

where λD is the Debye length, defined by the relation:

s
kT
λD = (6.24)
2ρ∞ q

It is timely to introduce a parameter, called κ, equal to the inverse of the Debye length.
Its definition is thus:
364 Electrokinetics

κ = 1/λD

This parameter is often used in the literature. It facilitates the writing of the equations.
We will also use it.

A most useful approximation is the Debye approximation, which consists in assuming

qφ
that kT is small. Physically, this condition means that the potential energy qφ , which
tends to concentrate the counter-ions close to the wall, is weaker than the thermal
energy kT , which tends to disperse them. In this context, one may expect almost flat
counter–ions density profiles and therefore small deviations of ρe from its bulk values.
qφ
With kT small, Eq. (6.23) becomes:

d2 φ 2ρ∞ q
2
≈ φ (6.25)
dz kT

The solution is:

φ(z) = ζe−z/λD , (6.26)

where ζ and λD have the same meaning as before. Figure 6.11 (A) represents the
evolution of the potential φ(z), obtained in the framework of the Debye approximation.

Fig. 6.11: (A) Electrical potential profile φ(z)/ζ in the Debye layer, obtained in the framework
of the Debye approximation.(B) Density charge profiles, ρ+ , −ρ− , and −ρe , with the same
approximation, with Θ = 1 (see text).

The potential decays over a scale on the order of λD . Above 2 λD , the potential and
the electric field strength are less than 10% of their values at the wall. This is called,
in the jargon of the domain, ‘Debye screening’ λD is thus a crucial parameter. In the
literature, it is often expressed in terms of massic rather than ionic concentrations, as
 The electrical double layer 365

we did. We can thus reformulate Eq. (6.24) in terms of C∞ , the concentration of ions
in mole per unit of volume.
s
kT
λD = (6.27)
2NA C∞ q 2

in which NA is the Avogadro number. A practical formula, for monovalent ions (i.e.
q = e, the electron charge) and binary electrolytes, is
p
λD ≈ 0.304nm/ C∞

in which C∞ is the concentration in moles per litre, more commonly used in physico-
chemistry. For instance, for an electrolyte of concentration of 1 mM/l, the Debye length
is 9.6 nm.

Two remarks can be made:

• In practice, it is difficult to obtain Debye lengths much larger than several hun-
dreds of nanometres. In the limiting case of pure water, C∞ is 10−7 M/l; therefore,
λD is approximately 0.96 µm. This is the highest Debye length that can be ob-
tained in aqueous solutions. However, the unavoidable presence of dissolved ions
delivered by walls in contact with the fluid raises the ionic concentration and
consequently decreases the Debye length.

• It is not difficult, on the other hand, to obtain a Debye length comparable to the
molecular scale. With a concentration of 1 M/l, the Debye length is 0.3 nm. So,
what happens, physically? Surprising observations have been made recently [12].
As the Debye length decreases below the ionic size, a new regime occurs, where
the screening length, i.e. the distance within which the electrolyte ‘feels’ the ζ
potential, drastically increases with the concentration, reaching values orders of
magnitude larger than λD . Much remains to be learned on the subject.
−
From Eqs. (6.26), (6.20), and (6.21), along with ρe = ρ+
e + ρe , one obtains the expres-
sions of the charge densities:

z z
ρ+ = ρ∞ (1 − Θ exp(− )), ρ− = −ρ∞ (1 + Θ exp(− ))
λD λD
ρe (z) = −2Θρ∞ exp(−z/λD )

in which Θ is defined by:

qζ
Θ=
kT
Θ is an important dimensionless number. It could be called dimensionless thermal
voltage, but has no official name. Θ << 1 defines the condition for which the De-
366 Electrokinetics

bye approximation can be made. The opposite case, Θ >> 1, defines the domain of
nonlinear electrokinetics, in which a rich variety of interesting phenomena exists.
The above equations confirm a statement made previously, i.e. Θ being small, the
deviation of the positive and negative charges, from their bulk values ±ρ∞ , are small.
Fig. 6.11 (B) represents the positive and negative charge density profiles, along with
the total density charge −ρe , in the case Θ=1, i.e. in the case where the wall charge,
and then the potential ζ, are positive. Even though Θ is slightly too large, in amplitude,
for the Debye approximation to strictly apply, Fig. 6.11 (B) provides an acceptable
representation of the structure of the charge density profiles. We see that the total
charge ρe is negative. Its maximum value, at the wall, in this particular case, is −2ρ∞ .
The present analysis was found to be in agreement with Israelachvili’s experiments [13],
described in Chapter 2, and, later, with molecular simulations. In 2008, the theoretical
expression of φ could be compared more directly with the experiment (see Fig. 6.12)
[14]. The difficulty was to resolve the Debye layer, i.e. scales in the range 5-100 nm.
This was achieved by using total internal reflection fluorescence (TIRF) microscopy
technique.

6.12: Potential profile φ(z) inferred

from the measurement of distributions of
nanoparticles close to a glass wall, in a
microfluidic channel. The TIRF technique
was used to resolve sub-100 nm scales and
obtain profiles along z. The dashed line
is Eq. (6.23) in which λD and the group
qζ/4kT are free parameters [14].

The potential was inferred from the measurement of distributions of nanoparticles

suspended in the fluid, and located close to the wall. The particles, negatively charged,
are repelled by the negatively charged wall, and their distributions, given by Boltzmann
theory, depend on the potential φ(z). In this manner, the potential could be measured,
providing an additional confirmation of the theory (see Fig. 6.12).

6.4.4 Divergence of the charge density

Let us calculate the ionic density ρe at the edge of the Stern layer, i.e. for z=0. Using
Eq. (6.22), we obtain:

ρe (z) = −2ρ∞ sinh(Θ) (6.28)

 The electrical double layer 367

At the wall, there is an amplification, by a factor 2 sinh Θ of the ionic bulk concen-
tration. This factor can reach several orders of magnitude. With ζ = −120 mV, the
amplification factor is equal to 54. Therefore, if we take an electrolyte with an ionic
concentration of 1 M/l, the concentration on the slip plane would reach three ions per
nanometre. With such a concentration, potassium ions would be close–packed, and
sodium ions, with their hydration shell, would overlap. This example shows that, for
a given concentration, the magnitude of Θ and thus ζ cannot be arbitrary large.

Let us make the argument more precise: for a monovalent electrolyte, the close-packing
limit is given by:
e
ρe ∼ 3
a
in which a is an ion size. Using Eq. (6.28), the corresponding zeta-potential limit ζmax
is equal to:
kT e
ζmax ∼ ln 3
e a ρ∞
kT /e is the thermal potential, equal to 25 mV. The multiplication by the logarithmic
term does not change this order of magnitude. In practice, for a millimolar solution
of monovalent salt, such as NaCl, the maximum zeta potential values is on the order
of 100 mV. This argument provides an explanation why, in practice, the ζ potentials
range typically, for non–metallic materials, between -100 and +100 mV.

6.4.5 Debye layers in microchannels

So far we have considered one isolated surface immersed in a liquid. The calculation
can easily be extended to the case of two walls, forming, for instance, a shallow channel,
again by using Debye approximation. One finds:

cosh(κz)
φ(z) = ζ (6.29)
cosh(κh/2)
qζ cosh(κz)
ρe (z) = −2ρ∞ (6.30)
kT cosh(κh/2)

in which h is the distance between the two walls. Several profiles of φ(z) are shown on
Fig. 6.13, for different values of κh.

For κh = 20, two thin Debye layers are established close to the walls z = ±h/2. In the
main part of the channel, the electric potential, along with the charge density ρE , are
extremely small. In this case, close to each wall, the Debye profile given by Eq. (6.26)
is recovered. As κh decreases, the Debye layers overlap. This situation is interesting,
because, in such cases, the whole fluid acquires a charge density. The feature has been
used to filter charged particles in function of their sign. In practice, overlap of the
Debye layers occurs only in nanofluidic channels, with heights smaller than 100 nm.
368 Electrokinetics

6.13: Potential profiles φ(z) for three

values of κh: 1, 4, and 20.

6.4.6 The Debye layer around a sphere

The mechanism discussed for the case of charged surfaces also holds for charged
spheres. The charge attracts counter-ions, which distribute around the sphere in a
manner similar to the case of the plane. The situation is sketched in Fig. 6.14.

6.14: Sphere immersed in an elec-

trolyte, with a potential ζ at its sur-
face.

We suppose here that the surface of the sphere is held at a potential ζ. This potential
gives rise, in the fluid, to a charge distribution, which is governed, in the Debye approx-
imation, by the same equation as for plane surfaces (see Eq. (6.25)) but in spherical
coordinates. We thus have:

1 d 2 dφ
∆φ = (r ) = κ2 φ (6.31)
r2 dr dr

This leads to the following expressions:

 The electrical double layer 369

R
exp(−κ(r − R))
φ(r) = ζ (6.32)
r
1 ∂ ∂φ
ρe (r) = − 2 ( r2 ) = −κ2 φ (6.33)
r ∂r ∂r
R∞
ζ is linked to total amount of counter–ions Q = R
4πr2 ρe dr, generated, in the liquid,
by the charged surface, through the relation:

Q
ζ=− (6.34)
4πR(1 + κR)

in which, as said before, κ = 1/λD the inverse of the Debye length. The particle thus
creates, in the fluid, a charge distribution, whose net charge is Q. As the system is
neutral, the charge of the particle should be −Q.
Two cases can be singled out:
• λD >> R (κR << 1): In this case the counter-ion density around the sphere is
small, and the fluid around it is weakly charged. The field thus extends over sub-
stantial distances, repelling partners conveying charges of the same sign, thereby
preventing aggregation.
• λD << R (κR >> 1): In this case, a thin charged layer builds up around the
sphere, screening the electrical field developed by the surface charge. This situ-
ation can be created by adding salt in the solution (with salt, ρ∞ is increased,
and thereby λD is decreased (see Eq. (6.24)). In such conditions, particles can
approach each other at distances so small that Van der Waals forces come into
play, leading to aggregation.
These notions are critical for the stability of colloidal suspensions. Working with
κR << 1 allows the suspension to be stable, as sketched in Fig. 6.15. In the opposite
case, the electric field developed by the particles is screened; clusters form, breaking
the suspension (see Fig. 6.15).

compact stern diffuse charge

layer layer

+
– +
– +
– neutral 6.15: In the case κR << 1, an electric
solid
+ – + bulk field develops, preventing aggregation,
+ + + thus ensuring colloidal suspension sta-
+ electrolyte
– bility; in the other case (κR << 1, the
+ – + – electric field is screened, and aggrega-
– + tion takes place.

Colloidal aggregation plays important roles in different domains, such as paper produc-
tion, cheese fabrication, and water treatment. A spectacular example, well–connected
to the situation that we discuss here, is the formation of deltas. The Mississippi delta,
schematized in Fig. 6.16, is the largest delta of the world. Its formation is due to the
370 Electrokinetics

sedimentation of fine particles, carried by the river’s freshwater, which precipitate as

they meet the sea water. The sedimentation rate is extremely large: 90 millions tons
each year, leading to the continous creation new lands. Hope is raised using this huge
quantity of mud to elevate the level of the existing lands, so as to resist the general
rise of the sea level.

6.16: Schematic representation of the

Mississipi delta.

6.4.7 The diffuse layer capacitor

So far, we have adopted a local point of view to describe the electrokinetics of elec-
trolytes. Let us now consider a circuitry viewpoint. Fig. 6.17 shows an electrolyte
confined between two blocking electrodes, i.e. two electrodes capable of imposing an
electrical voltage, but unable to support a Faradaic current, owing to the fact that
no chemical reactions develops at the interface, and no ion penetrates the electrodes.
The situation was discussed in depth in [15]. As mentioned in this paper, the naive
picture would be that in the device shown in Fig. 6.17, once the voltage is applied, a
homogeneous electric field E = V /L develops immediately across the electrolyte.

–V +V

+ – –
+
– + +
–
–
+ – +

6.17: Circuit including an elec- + +

–
–
trolyte between two blocking elec- – +

trodes, i.e. that do not support a

X
Faradaic current(inspired from [15]). –L 0 L

In fact, during the process, opposite charges move towards the electrodes and develop
double layers at each side.4 After some time, a steady–state is reached. The process is
similar to a capacitor and the name given to it is differential capacitance CD (taken

4 We will see later that in such a geometry, electro-osmotic flows develop along the walls parallel
to x. We will neglect these flows, or consider that the fluid boundaries, parallel to the x axis, are free
surfaces (which is not particularly realistic)
 The electrical double layer 371

per unit of the electrode exposed area). By differentiating Eq. (6.22), using the relation
dρe ≈ CD λD dφ, along with the definition of λD (see Eq. (6.24)), this capacitance, first
calculated by Chapman in 1913 [8], is found equal to:

 q
CD = cosh( ζ)
λD kT

An electrolyte confined between two blocking electrodes is thus equivalent to a resis-

λ2D L
tance per unit of electrode area (that of the bulk electrolyte), equal to D [15], in
series with a capacitor. A rigorous analysis, including historical notes and a review of
the topics, with far-reaching insights, can be found in Ref. [15].

6.4.8 Dependence of the ζ potential with pH and ion concentration

We shall see later how the potential ζ is measured. The question we address here is how
it varies with important parameters, such as the pH and the ionic concentration of the
electrolytes. The question was reviewed in [16] and a compilation of data, extracted
from the reference, is shown in Fig. 6.18). The data concerns naked silica surfaces and
different electrolytes.

Fig. 6.18: (A) Series of ζ measurements, obtained on silica surfaces, with different elec-
trolytes, as a function of pC = −log10 (C), where C is the massic concentration of ions.(B)
A compilation of ζ/pC as a function of the pH of the electrolyte. (Reprinted from [16] with
permission of Wiley and Sons. Copyright 2022.)

Dependence with the ionic concentration: Fig. 6.18 (A) shows that ζ varies lin-
early with the logarithm of the bulk concentration C (i.e. the ionic concentration,
expressed in M/l), noted by pc = − log10 (C). Why is it the case ? The argument,
discussed in [16], is the following: at large Θ, the total charge, per unit of area,
Q, stored in the Debye layer, is equal to:
Z ∞
qζ
Q= ρe (z)dz ≈ 2ρ∞ λD exp( )
0 2kT
372 Electrokinetics

Because of the neutrality condition, Q is also the charge stored in the Stern layer.
If we assume that the structure of the Stern layer and the charge it contains are
independent of the bulk concentration of the electrolyte, Q will not depend on ρ∞ .
This heuristic reasoning [16], which needs to be confronted with the knowledge
gained recently on the Stern layer, leads to the linear dependence of ζ with log ρ∞
(and thus pc), consistent with Fig. 6.18.
Dependence with the pH For the same series of ions as above, Fig. 6.18 (B) shows
that the ζ potential decreases as the pH increases. Interestingly, the sign of ζ
changes as the pH decreases below 3. This behaviour is inherent to the reaction
of deprotonation of silanol groups on the silica surface. The point where ζ = 0 is
called isoelectric point. In general, the possibility to invert the sign of ζ potential
by varying the electrolyte ionic concentration (for instance, of chaotropic salts) is
interesting for capturing, and releasing molecular species such as nucleic acids [17].

6.5 Electro-osmosis
6.5.1 Electro-osmotic flows in channels

Historically, the term electro-osmosis was introduced by H. Dutrochet [19], in 1826,

after the experiments of F. F. Reuss [20] and Porrett [21], to evoke an analogy between
their observations and the phenomenon of osmosis, i.e. the spontaneous movement of
solvent molecules through a semi-permeable membrane, induced by a concentration
gradient (a historical account of electro-osmosis can be found in [37]). The analogy
was abandoned by the author, but the word ‘electro-osmosis’ survived. The simplest
geometry in which electro-osmosis takes place is a straight channel, with charged walls
located at z = ±h/2, submitted to a longitudinal electric field (see Fig. 6.19).

6.19: Geometry of electro-osmosis: a

channel with charged walls, submitted
to an electric field along x

The electric field is applied in the x direction, with component Ex . This electric field
is superimposed on that induced by the walls. The corresponding electrical potential
is φT = −Ex x + φ(z), in which φ is the potential induced by the walls. In the previous
section, we calculated the density of charges appearing in an electrolyte at rest, con-
fined between two charged walls. When the electrolyte flows in a direction parallel to
the walls, and an electric field is applied in the same direction, the calculations remain
valid, because the electric field along x does not modify the charge distribution. In
the framework of the Debye approximation, φ is thus given by the following (see Eq.
6.29):
 Electro-osmosis 373

cosh(κz)
φ(z) = ζ (6.35)
cosh(κh/2)

The movement of the electrolyte is governed by the following equation:

0 = −∇p + µ∆u + ρe E, (6.36)

where p is the pressure, u is the velocity of the fluid (assumed along x), µ is the
fluid viscosity, ρe , as previously, is the electrical density of ionic charges, and E is the
electric field. The projection of Eq. (6.36) along x reads:

∂p ∂2u d2 φ
0=− + µ 2 − Ex 2 (6.37)
∂x ∂z dz

On the other hand, since there is no flow component along z, the projection along this
direction reduces to:

∂p 1 dEz2
0=− +  (6.38)
∂z 2 dz

These equations are associated to the no-slip conditions u = 0 at z = ± h2 .

From these equations, one infers:

∆P 1
P (x, z) = − x + Ez2
L 2

in which L is the channel length and ∆P is the pressure along it. The expression
shows that a pressure, 12 Ez2 , builds up in the channel. This electrostatic pressure has
no dynamical consequence. It just pressurizes the fluid, and exert forces on the walls,
without producing any motion.

Where does this ∆P come from? A pump can deliver it. However, one can imagine
to force ∆P = 0, by imposing the same pressure at the inlet and the outlet of the
channel (for instance, leaving them exposed to the ambient atmosphere). Still, there
will be a flow, because, in order to balance the electrostatic term in Eq. (6.37), one
needs viscous forces, and therefore a flow.

We thus consider two cases.

No applied pressure gradient (pure electro-osmotic flow). Here, we have ∆P = 0. Eq.

(6.37) can be integrated and, in the framework of Debye approximation, one obtains
(assuming no slippage at the walls):
374 Electrokinetics

 
Ex ζ cosh(κz)
u(z) = (φ − ζ) = − Ex 1 − . (6.39)
µ µ cosh(κh/2)

Two profiles, for two values of κh, are shown in Fig. 6.20.

6.20: electro-osmotic profiles for two

values of κh: 2 and 25.

At large κh, there is a plateau, which occupies most of the channel space. The plateau
speed is:

ζ
u(z) = uc = − Ex . (6.40)
µ

This velocity uc is called the Helmholtz-Smoluchowski velocity. Close to the wall,

i.e. within the Debye layer, the velocity decreases to zero so as to match the no-slip
boundary conditions. Physically, Debye layers, which are charged, are dragged by the
electric field, and in turn mobilize the rest of the flow, in a manner similar to walls
moving at speed uc . Tthis flow exerts an mechanical stress on the walls equal to µu
λD .
c

Over the years, a considerable amount of experimental measurements have confirmed

Debye Huckel theory. Recently, velocity profiles could be measured directly in the
Debye layer in two cases: hydrophilic and hydrophobic walls (see Fig. 6.21) [14].

6.21: Electro-osmotic flows close to hy-

drophilic glass (disks) and hydrophobic OTS
(octadecyltrichlorosilane) (squares). The im-
posed electric field is 500 V/m. Dashed lines
are fits to the theoretical predictions. The
velocity profile in the hydrophobic case re-
veals slippage amplification [14].
 Electro-osmosis 375

In the hydrophilic case, for which there is no slippage at the wall, good agreement was
found with the theory (see disks and dashed line in Fig. 6.21).
In the literature, an important notion is the electro-osmotic mobility µEOF . It is defined
by the expression:

uc = µEOF Ex

Using Eq. (6.40), we obtain:

ζ
µEOF = −
µ

In terms of order of magnitude, with an electric field of 100 kV/m, and a ζ potential
of 100 mV, the Helmholtz–Smolukowski speed is on the order of 1 cm/s, which is
substantial. One remarkable consequence of Eq. (6.40) is that the speed is independent
of the channel size, as long as the Debye layers are thin. Miniaturization does not cost
anything, in terms of flow speed. This appeared, in the early times of microfluidics,
with an excess of optimism, as a definitive solution to the problem of liquid pumping
at the microscale. We will return to this question later.

Electro-osmotic flow with walls of different ζ potentials. It often happens that mi-
crochannel walls are made in different materials: for instance, a PDMS channel bonded
to a glass plate. In such circumstances, there is no reason that the ζ potentials of the
walls are the same, and thereby, the solution in Eq. (6.39) that we obtained is no more
valid. So, what happens? Intuitively, we expect that with each Debye layer playing
the role of moving walls, due to the speeds being different, a Couette flow profile will
develop in the central part of the channel. The answer is given by resolving Eqs. 6.37.
The solution reads:

sinh κ(h/2 − z) sinh κ(h/2 + z)

φ(z) = ζ1 + ζ2
 sinh κh sinh κh 
 z 1 sinh κ(h/2 − z) sinh κ(h/2 + z)
u(z) = − Ex (ζ2 − ζ1 ) + (ζ1 + ζ2 ) − ζ1 − ζ2
µ h 2 sinh κh sinh κh

in which ζ1 and ζ2 are, respectively, the wall potentials located at z = −h/2 and
z = h/2. The solution u(z), calculated with − µ Ex = 1 V −1 , is shown in Fig. 6.22, for
κh = 25, ζ1 = 80 mV and ζ2 = 20 mV.
As expected, outside the Debye layer, we have a Couette profile. Using asymmetric
walls could be viewed as an elegant method for producing Couette flows in a microflu-
idic channel. On the other hand, as we saw in Chapter 5, Couette flows are associated
376 Electrokinetics

6.22: electro-osmotic profile calculated with

κh = 25, − µ Ex = 1 V −1 , ζ1 = 80 mV and
ζ2 = 20 mV.

to large longitudinal dispersion, leading, as we saw in the same chapter, to dilution

and loss of the sample transported in the microfluidic device. The plot of Fig. 6.22
can thus also be viewed as a regime to avoid, by equalizing, as much as possible the ζ
potentials of the walls.

Pressure gradient combined with electro-osmotic flow. The mixed case corresponds to
the situation where walls are identical, and a constant pressure gradient G = −dp/dx
is applied, or induced (for instance, when the flow develops in a closed cavity). In such
conditions, the expression of the flow profile reads :
 2 !
∆P h2
 
2z ζ cosh(κz)
u(z) = 1− − Ex 1 − (6.41)
8µL h µ cosh(κh/2)

In the central part of the channel, the flow is no longer a plug flow, but a superposition
of a parabolic Poiseuille profile and a plateau. The total flow rate is given by the
expression:

wh3
 
ζwh 2
Q= ∆P − Ex 1 − tanh(κh/2)
12µL µ κh

in which ∆P is the applied pressure, L is the channel length, and w is the channel
width. Q can be positive or negative. The profile is sketched on Fig. 6.23, in the case
where the liquid is confined in a cavity, so that Q=0.

Flow due to induced Flow due to

back pressure gradient electroosmosis

+V 0

Blocking Blocking
Electrode Electrode
6.23:
Flow pro- z
file when
Q=0. Zero velocity line
x
 Electro-osmosis 377

The figure shows that a flow is created, and recirculates within the cavity. Wrong
reasoning would be: by closing the channel, the liquid stays at rest. This would not be
true. In fluid dynamics, an external force f can be balanced by a pressure gradient, and
thus maintain the fluid at rest, only if curl f = 0. Otherwise, no static equilibrium
is possible, and a flow develops. In the present case, the electrostatic force f has a
x component fx = ρe (z)Ex , where Ex = ∆V L is constant. The other component, fz ,
being equilibrated by a pressure gradient, can be discarded. The curl of f has only one
component, normal to the plane, equal to −Ex ∂ρ ∂z . As this component is non–zero, a
e

flow must develop.

6.5.2 The similarity principle

In an insulating channel, as we saw, the speed u is given, at the edge of the Debye
layer, by the Helmholtz-Smoluchowski relation (6.40). It is thus proportional to the
applied field E. This relation, obtained for a straight channel can be generalized to
any curved bodies as long as their characteristic scale is much larger than λD . This
is because, in such a case, the liquid/solid interface looks flat; therefore, we can apply
the results obtained for a straight channel. For instance, in Fig. 6.24 this condition
would hold if the obstacles developed gently curved shapes, with curvatures much less
than κ.

6.24: When Debye layers are small com-

pared to the characteristic size of the ob-
jects, and in the absence of pressure gra-
dient, the electric field lines and the flow
streamlines are undistinguishable.

We thus have, at the edge of the Debye layer, the following relation:

ζ
u(x) = − E(x). (6.42)
µ

The similarity principle consists in considering that, in the absence of imposed pressure
gradient, the velocity field given by Eq. (6.42) represents, for infinite spaces, a solution
to the problem. This is not just at the edge of the Debye layer, but in the entire outer
region, i.e. outside the Debye layers. This statement is justified by two arguments:
• Outside the Debye layers, ρe = 0, and therefore, the velocity field given by Eq.
(6.42), associated to a uniform pressure field (p constant), satisfies the Stokes
equations (see Eq. (6.17)).5
5 Because, in a neutral medium, ∆E = −curl(curlE) + graddiv(E) = 0.
378 Electrokinetics

• Inside the Debye layers, the electro-osmotic velocity decreases exponentially to

zero. Therefore, the velocity field given by Eq. (6.42), associated to the Debye
layers, satisfies the no–slip boundary conditions at the liquid–solid interfaces.
The solution we constructed is thus proportional to the electric field. The flow we found
is ‘similar’ to the electric field, in the same manner as in mathematics, two triangles
are similar. However surprising it may look, the flow is potential, as it would be at
infinite Reynolds numbers. We met the same paradox, in Chapter 3, in the section
dedicated to Hele–Shaw cells. We may infer that, in microfluidics, this type of paradox
does not appear infrequently.
The similarity solution develops a uniform flow at infinity. This looks surprising. Hold
firmly an insulating object in a tank, apply an electric field and suddenly, the whole
fluid is put into motion. This kind of situation is not specific to electro-osmosis. It
also occurs in hydrodynamics. Move an infinite plate in a fluid initially at rest. After
some time (neglected in the Stokes equation, due to the instantaneity principle, seen
in Chapter 3), the fluid, in the entire space, is put into motion. Do the same in a
cylindrical geometry. Rotate a cylinder in a fluid, again in an infinite space. Even far
from the cylinder, fluid molecules feel a stress induced by the cylinder rotation. In
response, they move at the same rotation rate. Eventually, the entire fluid will rotate
as a solid object. Thus we are led to the statement that a long spaghetti, plunged in
the Atlantic, and rotating at a constant rate, puts the whole ocean into rigid rotation.
These statements are correct, as long as there is no wall. A rotating hair has the
capacity to put an ocean in rotation, but, for similar reasons, a wall can entirely stop it.
In our case, if we insert a wall in the system, the uniform flow is blocked, the solution
can no longer be represented by (6.42) and, consequently, the similarity principle
breaks down. In these circumstances, the electro-osmotic flow remains confined in a
region of limited extent, around the objects.
In applying the similarity principle, the question that must be addressed is whether
the similarity solution is physically admissible, i.e. compatible with the geometry of
the system. On might think that the similarity solution is mathematically elegant,
but physically unrealistic, because there are always walls somewhere. In fact, this
criticism can be circumvented. We will see later that the similarity principle does
yield a physically admissible solution, that we will exploit to determine electrophoretic
mobilities.

6.5.3 Slippage amplification

A surprising phenomenon exists when the electrolyte slips at the wall. Let us solve
again Eq. (6.37), in the framework of the Debye approximation, but now with slippage
conditions at the wall, i.e:
h ∂u
u(± ) = ∓b
2 ∂z
.
where b is the slip length (see Chap 2). We obtain:
 Electro-osmosis 379

 
ζ cosh(κz)
u(z) = − Ex 1 + bκ tanh(κh/2) − (6.43)
µ cosh(κh/2)

An important feature of Eq. (6.43) is that, for κh >> 1, the slip length enters the
profile through the dimensionless product bκ, i.e. b/λD . The effect of slippage is thus
not on the order of b/h, as in Chapter 3, but on the order b/λD , which is much larger.
The Debye length plays somehow the role of an effective channel height. There is thus
an amplification of the manifestation of slippage on the flow, as compared to ordinary’
hydrodynamics. We can return to the velocity profiles shown precedently (see Fig.
6.21), and discuss the two cases: hydrophilic (lower curve) and hydrophobic (upper
curve) walls. One sees a neat effect of the slippage: it accelerates the plug speed by a
factor of 2. By comparing the experimental profiles to the theory, b was found on the
order of 40 nm, consistently with the slip length measurements shown in Chapter 3.

6.5.4 Three microfluidic applications or implications of electro-osmosis

Transport of solutes in microchannels. In the case of pure electro-osmotic flows,

whose velocity profile is given by Eq. (6.39), solutes are transported along the channel,
as in a plug flow. The deviation, due to the presence of Debye layers close to the walls,
is on the order of ( uD
c λD 2
s
) , in which Ds is the solute diffusion coefficient. In microchan-
nels, this is negligible. These considerations have been confirmed experimentally, as
shown in Fig. 6.25 [22, 23].

Fig. 6.25: Fluorescence imaging of a fluorescence spot, injected in a microchannel, and tracked
at different times (given in seconds), for two cases. (Left) Poiseuille flow (viewed region 100
by 200 µm). (Right) Electro-osmotic flow in a glass capillary (viewed region 75 by 188 µm).
(Reprinted from Ref [23] with permission from American Chemical Society. Copyright 2022.)

The figure shows the striking difference between Poiseuille and electro-osmotic flow.
Being able to transport solutes with a minimal dispersion is key to the success of
electrokinetic separation techniques, as will be seen later.
380 Electrokinetics

Electro-osmotic pump. The calculations developed in Section 5.5.1 naturally lead to

the notion of electro-osmotic pumps. A general diagram is shown in Fig. 6.26 (A).

(a) Glass wall (b)

1
Low High
pressure Pressure 0.8
+ –

∆P/∆Pmax
0.6

0.4

0.2
+
0
0 0.2 0.4 0.6 0.8 1
Q/Qmax
Electroosmotic Pressure
Flow Drived flow

Fig. 6.26: (A) Principle of the electro-osmotic pump. (B) Universal characteristics of the
electro-osmotic pumps (Reprinted from [24] with permission from Wiley and Sons. Copyright
2022.)

Two electrodes impose an electric field along a channel Ex = ∆V /L, where ∆V is the
voltage drop and L the channel length, in the presence of a pressure gradient ∆P/L.
The flow is the combination of a planar Poiseuille and an electro-osmotic flow, as
sketched in Fig. 6.26(A). Let us take Eq. (6.41) in the limit κh >> 1:

wh3 ζwh
Q≈ ∆P − Ex (6.44)
12µL µ

The pressure gradient results from the existence of a hydrodynamic resistance to which
the electrokinetic channel is connected, through which the flow rate is Q established.
The characteristics of this pump can be represented by the formula:
Q ∆P
=1−
Qmax ∆Pmax

in which Qmax = − ζwhµ Ex and ∆Pmax =

12Lζ∆V
h2 , independent of the viscosity and
the channel length. The formula agrees with the experiment (see Fig. 6.26 (B)) [24].
In practice, typical maximum pressures, obtained with such pumps are on the order of
0.3 bar for 10 µm channels. Note that this pressure rises to 30 bars for 1 µm channels.

6.5.5 Streaming potential

Streaming potential is the opposite of the electro-osmotic pump: instead of imposing

an electric field to obtain a flow rate, we impose a flow rate to produce an electric
field. The principle is sketched in Fig. 6.27
The electric potential produced in this system can be inferred from Eq. (6.5.5).
 Electrophoresis 381

6.27: A pressure difference

∆P generates a flow. This
flow, by entraining the pos-
itive charges of the Debye
layer, gives rise to an elec-
trical current and induces a
‘streaming potential’.

ζwh wh3
Ex ≈ Q + ∆P
µ 12µL

The flow entrains the charges of the Debye layer, giving rise to an electrical current,
called streaming current’. This mechanism has been proposed to produce electric-
ity across membranes made of aligned carbon nanotubes (CNTs) [25, 26]. As we saw
in Chapter 3, these membranes exhibit large slippage velocities and thus reduce the
hydrodynamic losses. A configuration for producing energy is a semi-permeable mem-
brane separating brine from fresh water, giving rise to an osmotic flow inside the CNTs,
which dilute the salt. This flow transports charges and produces a current, which, af-
ter collection at electrodes, converts osmotic into electrical energy, with interesting
performances [26].

6.6 Electrophoresis

6.6.1 The physics of electrophoresis

Electrophoresis is defined as the phenomenon for which ions, particles, bacteria, macro-
molecules, or, more generally, charged objects, distributed in a solution, move in the
presence of an imposed electric field. The phenomenon is characterized by an elec-
trophoretic mobility, defined by the relation

U = µe E∞

in which U is the particle speed and E∞ the applied field, i.e. its value far from
the particle. The question is: what is the expression of µe ? To answer this question,
different elements must be taken into account (see Fig. 6.28).
The particle is surrounded by a counter ionic cloud, i.e. a ‘ionosphere’. The applied
field E∞ is deformed by the presence of the particle, giving rise to a spatially dependent
field E, This field exerts a force on the ionosphere. A pressure field develops, exerting,
in turn, a force on the particle. In the meantime, the ’ionosphere’ is put into motion.
This flow drags the particle. Figure 6.29 shows an example of a velocity and a pressure
field, calculated for a particle as conducting as the fluid, for κR = 1. The calculation
is based on Henry’s solution [29].
382 Electrokinetics

Fig. 6.28: Physics of electrophoresis. (A) The particle, associated to a potential ζ > 0,
develops a cloud of counter-ions around it, forming an ‘ionosphere’. The system is subjected
to an electric field E. (B) E exerts a force on the cloud. These forces build up a pressure in
the fluid and drive a flow, which, in turn, exert a drag on the particle, and a Coulomb force
onto the fixed charges of the particle (surface and dipolar)

Fig. 6.29: (A) Pressure field developing around a particle, characterized by a positive ζ
potential and a conductivity equal to the fluid. Here, κ = 1. The calculation is based on
Henry’s solution [29]; the numbers shown on the figure correspond to pressure levels, in
dimensionless (arbitrary) units.(B) Streamlines obtained in the same conditions.

The pressure field develops lobes, with negative levels on the left side of the sphere and
positive levels on the right (see Fig.6.29(A)). There is therefore a force pushing the
particle leftwards. The electrolyte flow works in the same direction: it is directed to the
left of the figure, dragging the particle leftwards (see Fig. 6.29(B)). At large distances,
this flow decays as the inverse of r. It is thus confined in a region surrounding the
sphere. The particle has a fixed charge. It will therefore be subjected to a Coulomb
 Electrophoresis 383

force, pointing to the right of the figure. In principle, in order to solve the problem,
one should determine pressure and velocity fields, and, by integrating stresses over the
particle surface, determine the forces exerted on it, and thereby, after adding the force
due to the fixed particle charge, establish the electrophoretic mobility.

This calculation is not straightforward. In principle, it should take into account that,
due to the applied electric field, the ionosphere adopts an elliptic shape, because neg-
ative charges, in the bulk, are pulled by the electric field [30,31]. In practice, the effect
is significant at large ζ. For small ζ (for instance, on the order of 10 - 20 mV), the
cloud deformation can be neglected.

By assuming a symmetric ionosphere, Henry performed, in 1931, the calculation of

the electrophoretic mobility, for arbitrary conductivities and arbitrary κ [29]. The
calculation takes eight pages. Henry’s work solved a controversy between Smoluchowski
[27] and Huckel [28], who proposed different formulas for µe . Later, Russel, Saville
and Schowalter [2] obtained the same result in a simpler manner. We will start by
considering two limiting cases:

• (a) λD >> R (or equivalently κR << 1). The Debye layer much thicker than the
sphere radius

• (a) λD << R (or equivalently κR >> 1). The Debye layer much thinner than the
sphere radius.

We shall moreover focus on the case of insulating spheres. The reason for this is that in
electrolytes, ions cannot penetrate the sphere. Therefore, at the sphere interface, the
normal component of the ionic current, and therefore that of the electric field, must
be zero, as for insulators. Thus, as strange as it looks, the conducting sphere behaves
as an insulator. In fact, things are more complicated. When the sphere is conducting,
ions, driven by field components pointing normally to the surface, accumulate. This
gives rise to transient regimes, where the sphere starts to behave as a conductor,
and eventually behaves as an insulator. This will be described later. For insulating
particles, there is no component of the applied electric field normal to the surface and
therefore, no accumulation.

6.6.2 Case (a): Debye length much larger than the particle (κR << 1)

Let us recall the general expression of the potential φ and charge density ρe around a
sphere, induced by a surface charge on the particle, characterized by a potential ζ:

R
φ(r) = ζ exp(−κ(r − R)) (6.45)
r
1 ∂ ∂φ
ρe (r) = − 2 r2 = −κ2 φ (6.46)
r ∂r ∂r
384 Electrokinetics

When κR is small, the charge density ρe (r) is small; consequently, the flow and the
pressure, generated by the coupling between the applied field and the charge density
are small. When κ tends to zero, ρe (r) tends to zero. In limit, the electrostatic pressure
and viscous stresses become negligible. We are thus left with the Coulomb force QE∞ ,
for which we recall that Q is the fixed particle charge and E∞ the applied field, far
from the particle. From this result, and on using Stokes relation, the mobility can be
determined. This leads to the following formula:

Q
µe = . (6.47)
6πRµ

The expression is called the Huckel formula [28]. Expressed differently, if we use the
Q
potential ζ given by the Gauss theorem (ζ = 4πR when κR tends to zero), we obtain:

2ζ
µe = (6.48)
3µ

Eqs. (6.55) and (6.48) are valid for particles of arbitrary shapes, as the reasoning
suggests.

6.6.3 Case (b): Debye length much smaller than the particle κR >> 1

As the Debye length decreases (then κR increases), as in the straight channel, the
highest flow gradients tend to concentrate in a thin Debye layer. In fact, at large κR,
and in the case of insulating particles, the mobility can be elegantly determined by
applying the similarity principle. The principle tells us that outside the Debye layer,
in an infinite medium in which no pressure gradient is applied, the flow field is given
by the expression:

ζ
u=− E
µ

in which, again, E is the applied field. This leads to the following formulas:

ζ R3 ζ R3
ur = − E∞ (1 − 3 ) cos θ and uθ = E∞ (1 + 3 ) sin θ.
µ r µ 2r

This flow is sketched in Fig. 6.30, again in the case ζ > 0.

The flow is potential. It is associated to a constant pressure field, i.e. an absence of
pressure gradient. The flow is oriented leftwards, because Smoluchowski speed, at the
edge of the Debye layer, points in that direction. A large distance from the sphere,
the flow is uniform. Thus, what we have here is a particle at rest, immersed in a
uniform flow, oriented from the right to the left. This solution can also be viewed as
a particle moving at speed U = + ζ µ E in a motionless fluid. An example is a particle
 Electrophoresis 385

6.30: Flow around the sphere, ob-

tained by applying the similarity prin-
ciple. The flow is potential, and is asso-
ciated to a uniform pressure field. This
solution corresponds to a particle trav-
elling at speed U = + ζ µ
E in a quies-
cent fluid.

moving in a large container, in which the fluid is quiescent. The fact that, viewed
in this manner, the fluid is at rest at large distance from the sphere warrants that
the boundary conditions at infinity are satisfied and, consequently that the similarity
solution is physically admissible. Note that the similarity flow, which is potential, is the
superimposition of a non–potential Stokes flow generated by the displacement of the
particle, and another non–potential flow, produced by the movement of the ionospheric
charges, discussed in a previous section.

We thus have succeeded in working out, without calculation, the solution to the prob-
lem. These considerations allow us to calculate the electrophoretic mobility. It is given
by the formula:

ζ
µe = (6.49)
µ

Eq. (6.49), obtained by Smoluchowski [27], is called ’Smoluchowski approximation’ or

’Smoluchowski formula’.

It is possible to examine the problem from the viewpoint of the forces, as Henry did.
The exercise is much more complicated than applying the similarity principle. We
may content ourselves to check that forces acting on the sphere are equilibrated. With
the flow described above, the pressure forces are cancelled, and the remaining stress
acting on the particle, integrated over the sphere, is 4πR2 µκUS , in which US is the
Smolukowski speed. We can check that this force balances Coulomb forces, whose
expression is, at large κR, Fe = QE∞ ≈ 4πζκR2 (see (6.34)).

The arguments we used apply to insulating particles of arbitrary shapes. The Smolu-
chowski speed thus concerns any object of size l, provided it is insulating and κl is
large. If the particle is conducting, things change. For instance, according to Henry’s
calculations, metallic particles have no electrophoretic mobility.
386 Electrokinetics

6.6.4 The Henry function

As noted above, by neglecting the ionosphere ovalization, Henry solved the general
case, i.e. κR arbitrary and arbitrary conductivities. Further, assuming the Debye ap-
proximation, Henry expressed, for the case of insulating particles, the mobility in terms
of a dimensionless function f (κR), defined by:

ζ
µe = f (κR) (6.50)
µ

where f is given by:

f (x) = 1 − exp(x)(5E7 (x) − 2E5 (x)) (6.51)

in which En is the exponential integral of order n.6 ) The function is called the ‘Henry
function’. It is plotted in Fig.6.31.

6.31: The Henry function [29].

At small κR, the function is close to 2/3, and at large κR, it tends to unity. The
Henry function thus fills the gap between the two limiting cases we considered. In
practice, f (x) is currently used in the colloid industry, to infer the ζ potential from
the measurement of the electrophoretic mobility. It is often called the ‘Henry factor’.

6 E (x)
R∞ exp(−xt)
n = 1 tn
dt
 Electrophoresis 387

Why is the electrical force, exerted by the applied electric field on the
particle QE∞ ?

We considered that the force F applied on a particle of charge Q immersed, in an

uncharged fluid, in an electric field E∞ , is equal to QE∞ . This result is independent
of the sphere permittivity, while, as we saw in this Chapter, the electric field pattern
strongly depends on it. So where does this independency come from? The result is
often presented as straightforward, but it is not. The demonstration can be found
in [2]. The starting point is well explained in [3]: in a solid immersed in a fluid, the
local force exerted by the applied field is given by the divergence of the Maxwell stress
tensor Tij , defined by:
1 2
Tij = (Ei Ej − Eii )
2
in which Ei and Ej are the electric field components, in the fluid [3]. The force applied
on the particle is given by the integral of DivTij over a volume V around the sphere.
Since the fluid around the sphere is uncharged, we may integrate throughout a sphere
of large radius containing the particle. Owing to the divergence theorem, this force is
also equal to: Z Z
1 2
F = Tij dV = (Ei Ej − Eii ) dS
V S 2
in which S is the surface or the large sphere. Further, by noting that, far from the
sphere, the field reduces to E∞ , the integral can be calculated. In the calculation, on
using the Gauss theorem, one obtains the classical result F = QE∞ . The expression
of the force is consistent, as it should be, with Coulomb law.

6.6.5 The case of perfectly conducting spheres

Fig. 6.32: (Left) Electric field lines, just after the electric field E is applied. (Right) After
some time, charges accumulate, expelling the field lines from the interior of the particle. In
such circumstances, the object behaves as an insulator. (From [32]).

The case of uncharged particles. The case of perfectly conducting spheres is rich and,
sometimes, counter-intuitive. We refer here to the work of Ref. [32]. Let us immerse
a perfectly conducting sphere in an electric field E. Initially, there is no volumetric
nor surface charge, and the sphere permittivity is infinite. Consequently, the electric
field pattern will take the form shown in Fig.6.32(B), i.e. with field lines penetrating
normally into the sphere and, inside, an electric field equal to zero. In the electrolyte,
the solution thus reads:
388 Electrokinetics

R3
 
φ = −Er cos θ 1 − 3 (6.52)
r

A ionic current thus develops, conveying charges to the surface. Because ions can-
not penetrate into the sphere, they will accumulate. After some time, estimated to
λ2D /D [32], a charge distribution establishes, expelling the electric field lines (see Fig.
6.32). The positive charges accumulate at the bottom of the particles (the south hemi-
sphere), while the negative charges, moving against the electric field, gather in the
north hemisphere. Eventually, a steady–state is reached, for which the accumulation
process is complete, implying the current normal to the sphere has vanished. The corre-
sponding electric field line pattern is shown in Fig. 6.32. The electrical field lines being
tangential to the surface, the perfectly conducting sphere behaves as an insulator. The
expression of the steady–state potential, in the electrolyte, now reads:

R3
 
φ = −Er cos θ 1 + 3 (6.53)
2r

6.33: A metallic particle develops a

quadripolar flow around it. (From [32].)

The corresponding ζ potential, φ(R) is equal to − 23 Er cos θ. It gives rise to a quadripo-

lar electro-osmotic flow pattern, shown in Fig. 6.33. The electrophoretic mobility is
zero, and therefore the particle remains immobile, but the fluid moves around it.
The phenomenon gives rise to interesting applications: examples are mixing, particle
handling, etc. Just insert a metallic particle in a microwell, with two electrodes, and
mixing is achieved. This is conceptually very elegant. In practice however, controlling
the oxidation of the particle surface is difficult, so that, in general, mixing takes place
only for a limited time.

The case of charged particles with κR >> 1. Let us now assume a thin Debye layer,
q0
and charge the particle with a surface charge q0 = Q/4πR2 , or a zeta potential, ζ0 ≈ κ
 Electrophoresis 389

(see Eq. (6.34)). After the system has reached a steady–state, due to the linearity of
the equations, we will have:
3
ζ = ζ0 − Er cos θ
2
In the presence of the electric field, whose pattern is shown in Fig. 6.32 (right), the
counter–ions in the Debye layer will be dragged and give rise to an electro-osmotic
velocity around the sphere. As in the previous case, the similarity principle can be
applied, leading to a mobility equal to:

ζ0
µe = (6.54)
µ

We thus recover, in this case, the Smoluchowski result for insulating spheres.

6.6.6 The electrophoretic mobility of ions

Ions are much smaller than the Debye length, and, if they are viewed as a sphere of
radius a, the results of the preceding sections in the case κa << 1 apply, leading to:

Q
µe = . (6.55)
6πaµ

in which a is the hydrodynamic radius’. As mentioned in Chapter 2, depending on the

level of hydration, and for small ions, a ranges between 0.1 and 0.5 nm.

6.6.7 The electrophoretic mobility of DNA

With the buffers used in DNA studies or DNA electrophoresis systems, ionic strengths
are of the order 10 –100 mM and Debye lengths are on the order of 1–2 nm. These
lengths are comparable to the sizes of the molecular entities pertaining to the DNA
chain. Therefore, we may use Smoluchowski’s formula to estimate their mobilities.
Since the ζ potentials for each molecular entity are comparable, they will travel at the
same speed. The unfortunate consequence is that the electrophoretic speeds of DNA
strands or double strands are independent of their length. In free solutions, no way to
‘fractionate’ DNA fragments, i.e. to separate them in function of their sizes.7
The argument has naturally led the community to use gels. Much work has been done
on the subject, in particular during the period 1970–2010. The work has been well
reviewed by J. L. Viovy [34] and, more recently, by K. Dorfman [35]. When a DNA
chain migrates in a gel, it undergoes different regimes. They are sketched in Fig. 6.34.
7 This is the argument. Looking in more detail, without gel, end effects and differences in chain
flexibilities induce measurable differences in mobilities, between long (above 100 bp) and short chains
(10 bp or so) (see [33]). However, the separation efficiencies are much smaller than in gels.
390 Electrokinetics

6.34: Different regimes of mi-

gration in constant-field elec-
trophoresis: (A) Ogston sieving;
(B) reptation without orienta-
tion; (C) reptation with orien-
tation [34].

Ogston sieving [37] corresponds to the case where the DNA coil is smaller than the
pore (see Fig. 6.34 (A)). Its migration is slowed down by the gel matrix. Reptation,
with and without orientation, occurs when the molecule size is larger than the pore
(see Fig. 6.34 (B) and (C)). These regimes give rise to a dependence of the mobility
with the chain length [34, 35]. They were revealed experimentally in the 1990s (see
Fig. 6.35) [36].

Fig. 6.35: (A) Electrophoretic mobility of different sized DNA in a 1.5% agarose gel as a
function of the electric field [36].(B) Typical DNA separation images obtained in agarose
gels, for three different gel concentrations. Often (this is not the case here), gels include a
reference ladder, showing several DNA fragments with known sizes (Reprinted from Ref [36]
with permission of John Wiley and Sons. Copyright 2022.)

Fig.6.35 A shows the evolution of the mobility of DNA duplexes with the electric field,
for different DNA lengths. In practice, DNA was visualized with fluorophores, giving
rise to an image such as Fig. 6.35 (B), utilizable for measuring mobilities. Within some
range of electric field, the mobility depends on the length and is independent of the
applied field. In these regimes, fractionation is possible. At larger electric fields, the
 Electrophoresis 391

dependence with the length collapses and no fractionation is possible.

In the years 2000–2010, new systems, attempting to produce gel-like structures with
microfabrication techniques, flourished: examples are microfabricated posts with DRIE
(see Chapter 7) [40], self assembled functionalized magnetic columns [38], or mi-
crochambers forming entropic traps [39]. These systems, which offered alternatives
to standard gels, are reviewed in Dorfmann [35].

Electronic Paper
An interesting application of electrophoresis is electronic paper (e–paper). This cur-
rently uses hydrocarbon oil droplets, in which pigments of opposite signs are sus-
pended (see Fig. 6.36(A)). Typically, TiO2 pigments, negatively charged, are used for
the white colour. Depending on the orientation of the electric field, black or white
pigments migrate at the bottom or the top of the droplet. Observed in reflection, the
colour will be either black or white. Droplets are several tens of micrometre in diam-
eter. The electrodes, which impose the electric field, can be addressed individually.
In this way, it is possible to display any pattern.

Fig. 6.36: (A) Principle of the electronic paper: under the action of the electric field,
white pigments migrate upwards, and black pigments downwards. Seen from above,
and in reflection, the droplet looks white. By inverting the electric field, the droplet
looks black.(B) An example of an electronic paper, the Kindle reader.
This looks simple. There exist limitations. One of them is the commutation speed, too
slow to display movies. E–paper technology possesses important advantages compared
to standard electronic display technologies. E–paper consumes much less energy. Also,
eye fatigue is reduced. Since 2007, Kindle (Amazon) has sold more than 30 millions
e–books.

6.6.8 Particle deposition in microchannels with electrically charged

walls

We described, in Chapter 5, based on Ref. [41], how particles, entrained in a channel,

deposit on the walls. The analysis can be extended to the case when a surface charge
is present, giving rise to a potential ζ, which in turn develops an electric field repelling
or attracting the particle, depending on the signs of the ζ potentials. The situation is
depicted in Fig. 6.37.
In Chapter 5, we considered the case where Van der Waals forces, drag forces, and
Brownian movement are present. Here, we add an electric field, produced by the wall
392 Electrokinetics

Fig. 6.37: Particle moving in a channel, close to a wall. Channel walls and particles have
zeta potentials ζw (wall) and ζp (particle) [42].

charges. The general situation is rich. It was treated in Ref. [42] and compared with
experimental measurements performed in microchannels. Let us take a part of this
analysis, by considering the case where particles are non Brownian and the forces
developed by the charged walls are much larger than the Van der Waals forces. We
also assume that zeta potentials are negative, and thereby, wall and particles repel
each other. In such a case, the equations governing the particles trajectories are:

κD
ẋ(t) ≈ γUr (z) and ż(t) ≈ βz χ exp(−κ(z − r) (6.56)
kT

in which χ = 4π0 ζw ζp R
Here, , 0 are the dielectric constant of the fluid transporting the particles and the
permittivity of vacuum, respectively, and ζw and ζp are respectively the zeta potentials
of the channel wall and the particle. γ is a factor taking particle rotation and shear
effect into account and βz is the hindered diffusion factor (see Chapter 5), D the
particle diffusion constant, kT the thermal energy, z the distance of the particle center
from the wall, and r the particle radius. κ has been defined in this chapter. From
equation 6.56, we infer ż > 0. This implies that particles move away from the wall.
Thereby, no particle sticks to the wall. Indeed, when Van der Waals forces are added,
the situation changes. Ref [41] showed that, in this case, deposition rates depend on the
ratio between electric and Van der Waals forces. Figure 6.38 shows a general diagram,
where the complete analysis of the situation, incorporating Brownian, Van der Waals,
drag, and electrical forces,is carried out.
The diagram has a form of a shoe. The abscissa is the salt concentration (which controls
the Debye length), ξL , an inverse of the Peclet number, which controls the ratio of
diffusion over advection terms. The larger ξL , the more important the diffusion. The
ordinate involves the parameter S, which measures the amount of particle, per unit of
time, captured by the wall. One learns, from this diagram, that below a ionic strength
of 100 mM, no particle deposits in the channel. When the electric field is screened
(Csalt > 100mM ), deposition occurs. In this range, depending on ξL , two different
regimes of deposition occur: at small ξL (for instance, with small particles, the regime
is Brownian, while, at large ξL (for instance, large particles) as we saw in Chapter 5,
 Microfluidic electrokinetic separation 393

Fig. 6.38: Universal diagram showing the (non-dimensional) rate of deposition S, as a func-
tion of the salt concentration and a parameter, ξL , representing the ratio between the diffu-
sive and advective terms, for the particle. The points represent measurements performed in
microchannels. Below 100 mM, no deposition occurs. In practice, above this concentration
deposition occurs, dominated either by Van der Waals forces (Van der Walls 2 regime), or
by Brownian motion (Diffusive 1 regime). (From [42].) The various regimes, along with their
frontiers, are well accounted for by the theory.

the regime is dominated by Van der Waals forces. The latter regime is the most prone
to cloggingl.

6.7 Microfluidic electrokinetic separation

6.7.1 Acronyms

Electrokinetic methods of separation are numerous and the non–specialist may get
confused between the different acronyms used in the field. Before going further, it is
useful to list the full names of some of them, and the type of interactions they rely on.

6.7.2 Free solution capillary electrophoresis (FSCE)

In free solution capillary electrophoresis (FSCE), the sample is injected in a capillary,

in a free solution, i.e. without gel, and subjected to an electric field, imposed by two
electrodes submerged in external reservoirs (see Fig. 6.39).
As we saw above, the field has two effects: it induces an electro-osmotic flow that
displaces the whole fluid as a plug flow, and it separates ions. Those migrate at different
velocities, according their charge over mass ratios, as expressed by Eq. 6.55. We have:
394 Electrokinetics

Method Acronym Interaction

Zone electrophoresis ZE Charge
Capillary zone electrophoresis CZE Charge
Capillary electrophoresis CE Depends on case
Free solution capillary Electrophoresis FSCE Charge
Capillary gel electrophoresis CGE Sieving
Micellar electrokinetic chromatography MEKC Charge+affinity
Micellar electrokinetic capillary chromatography MECC Charge+affinity
Microfluidic electrokinetic separation method MESM Case dependent
Capillary electro chromatography CEC Charge+matrix interation
Isoelectric focussing CIEF Isoelectric Point

Table 6.1 Different electrokinetic separation methods, with acronyms

Data Acquistition

Sample Zone
UV Detector
Capillary Capillary
Inlet Outlet

+ –

Buffer Reservoir Buffer Reservoir

for Anode for Cathode
High Voltage
Power Source

Fig. 6.39: Typical setup of capillary electrophoresis.

Ub = UEOF + Uq ,

where UEOF and Uq are the electrosmotic and electrophoretic velocities, respectively.

In CE, the electro-osmotic velocity dominates the electrophoretic one, so as bands of

analytes pass under the detector at different instants without overlapping. Detection
is more often based on fluorescence, conductivity, or absorption.

An example is shown in Fig. 6.40.

Each peak corresponds to the passing of ions that have the same electrophoretic mobil-
ity. From the analysis of Fig. 6.40, and using calibration, we can deduce the migration
velocities, and can then identify the different solutes present in the sample. In the case
of the figure, the analytes were methylanthracene and perylene. The sharpness of the
peaks indicates an excellent resolution of the method.
 Microfluidic electrokinetic separation 395

6.40: Early electropherogram of

n-alkylamines as fluorescamine
derivatives. demonstrating the
high resolution of free solution
capillary electrophoresis (FSCE).
Peaks: A = octyl; B = heptyl; C
= hexyl; D = pntyl; E = butyl; F
= unknown impurity; G = propyl.
Approximately 7 pmoles of each
derivative, except for propylamine.
(Reprinted from [45], with per-
mission of Elsevier. Copyright
2022.)

6.7.3 The performance of free solution capillary electrophoresis

What are the performances of free solution capillary electrophoresis? The high perfor-
mances of the technique were pointed by Jorgenson et al. in 1981 [45]. Because solutes
are transported by a plug flow, there is no shear and thereby the spreading δX of the
spots is controlled solely by molecular diffusion. δX can be estimated by the following
expression:
√
δX ∼ Dt

where D is the diffusion coefficient of the ions forming the spot, and t is the time. At
the end of the capillary tube, i.e. at a time equal to L/UEOF , where L is the capillary
length, the band has acquired a width W equal to:
r
DL
W ∼
UEOF

Then the number of theoretical plates reads:

UEOF L
N∼
D

The previous formula shows that in order to obtain large number of theoretical plates,
it is advantageous to work with strong electric fields and long capillaries. In typical
systems, the capillary is a silicon tube with a circular section, from 25 to 50 µm in
diameter, and 20 or so cm long. In terms of orders of magnitude, the applied voltages
in capillary electrophoresis are of several thousand volts and speeds are on the order of
1 mm/s. Taking UEOF = 1 mm/s, D = 10−9 m2 /s and L =0.1 m, one finds N ≈ 105 ,
which is a number comparable to the best performing separation techniques, such as
high performance liquid chromatography (HPLC), as we saw in Chapter 5.
396 Electrokinetics

6.7.4 Miniaturizing free solution capillary electrophoresis

Why miniaturize CE? There are several advantages:

• manipulate small volume samples;

• integration (favouring automation);

• parallelization (allowing high-throughput analysis);

• short analysis times; and

• high performances.

The first three advantages are applicable to miniaturization in general. The fourth
advantage is justified in the following manner: we take the expression of the number
of theoretical plates given above. We have:
µEOF EL
N∼
D
where µEOF is the electro-osmotic mobility, L is the capillary length (the micro-column
length), and D is a representative diffusion coefficient of the ions. The formula shows
that it is advantageous to work at elevated electric fields. The electric field strength is
limited by Joule heating, due to the electric current developing in the electrolyte. We
have the following equality, in terms of order of magnitude:

Q ∼ σe E 2 Ld2 ∼ K∆T L

where d is the capillary diameter, Q is the heat produced by the Joule effect in the
microsystem, K is the conductivity, and ∆T is the temperature difference between
the fluid contained in the capillary and the exterior. From this equality, we obtain the
following estimate for the electric field :
p
E ∼ K∆T /σe d−1

Thus, at fixed ∆T , the smaller d is, the higher E will be. Miniaturization thus allows
us to work at an elevated electric field. We are thus led to the following scaling relation:

N ∼ L/d

Even though L is in the decimetre range, the ratio can be large. With the pre-factor
in front of this relation(not shown), one can have high N . Thus, miniaturization does
not degrade the resolution of the separation process. The scaling of the retention time
in the micro–column is given by:

tr ∼ Ld
 Microfluidic electrokinetic separation 397

As the retention time is proportional to miniaturized quantities (L and d), it can be

small. In practice, compared to standard columns, working in a microfluidic format
allows us to reduce the separation time by orders of magnitude.

6.7.5 The first microchip capillary electrophoresis (MCE) system (1992)

As said in the introduction to this chapter, the first proof of concept of a miniaturized
free electrophoretic separation system was obtained by Manz’s group, in 1992 [1]. This
gave rise to the acronym MCE, which means: microchip capillary electrophoresis. The
device is shown in Fig. 6.41.

Fig. 6.41: First proof of concept showing that capillary electrophoresis can be performed in
a microfluidic channel (1992) [1]. (A) Microscope image of the chip. (B) Electropherogram
showing the fast (a few minutes) separation of fluorescein and calcein. (Reprinted from Ref. [1]
with permission of the American Chemical Society. Copyright 2022.)

The separation channel, of rectangular cross-section, is 10 cm long, 20 µm high, and

30 µm wide. Compared to standard capillary electrophoresis (CE), the column length
is five time shorter. Sample injection has been miniaturized, in order to keep the
resolution high [44]. In the system of Ref. [1], the sample injection is performed with
the cross-channel shown in Fig. 6.41. The sample is transported in the column by an
electro-osmotic flow developing sideway. After the sample has reached the intersection,
an electric field is applied along the ’column’, i.e. the main channel. A plug flow
develops and the sample decomposes into bands. The electropherogram reported in [1]
is shown in Fig. 6.41. Plateau numbers rangis between 104 and 105 were obtained.
Developments of this approch can be found in Ref. [43].
In practice, MCE requires an excellent control of the pressures applied at the system
entries, in order to avoid back–flows. High hydrodynamic resistances are often used
to reduce parasite flows, for instance, induced by capillarity. Such flows disperse the
bands and degrade the resolution.

Separating ions in 800 µs. In 1998, Jacobson et al. [47] separated the components of
a sample in 800µs (see Fig. 6.42).
398 Electrokinetics

Fig. 6.42: Demonstration that, with microfluidics, samples can be separated in less than
one millisecond. (A) Design of the MEC system.(B) Electropherogram demonstrating large
speeds of separation. (Reprinted from [47], with permission of the American Chemical Society.
Copyright 2022.)

To perform the same task, traditional gel-based methods would take hours or fractions
of hour. The success of the demonstration was due to the miniaturization of the device
and a careful design of the injection section (see Fig. 6.42) [47].

6.7.6 Micellar electrokinetic chromatography (MEKC)

With CE and MCE, impossible to separate neutral species. This is where micellar
electrokinetic chromatography (MEKC) comes on stage. With MEKC, charged and
uncharged molecules can be separated, by exploiting, in addition to electrophoretic
properties, the affinity of hydrophobic species with micelles Thus, two criteria add
up to achieve the separation, providing denser electropherograms. In practice, charged
micelles are introduced in the system, by mixing the sample with ionic surfactants, such
as Sodium Dodecyl Sulfate (SDS), above the Critical Micellar Concentration (CMC
– see Chapter 5 –). Hydrophobic molecules, which hate water, are happy to embark
on micelles. They travel together along the column, i.e. the separation channel, at a
speed determined by the micelle mobility, with its passengers. Further downstream,
the molecule can be detected.
MEKC was carried out in a microdevice, for the first time, in 1995 [48] and 1996 [49].
The electropherogram shown in Fig. 6.43 was obtained in 2000 [50].
In Fig. 6.43, the 19 peaks result from the separation of tetramethylrhodamine-labeled
amino acids. Separation was accomplished in 165 s, with an average plate number of
280,000.

6.7.7 Capillary electrochromatography (CEC) and DNA separation

With the preceding techniques, one can separate ions and organic species, but not
DNA fragments. A first reason was given previously: the mobility of DNA fragments
does not depend on their sizes. Thereby, electrophoresis, whether CE or MEC, cannot
 Microfluidic electrokinetic separation 399

Fig. 6.43: (A) Image of the MEKC microdevice. (B) MEKC separation of 19 TRITC-labelled
amino acids in a 10 mM sodium tetraborate/50 mM SDS buffer with 10% (v/v) 2-propanol.
The field strength was 770 V/cm, and the detection point was 11.87 cm from the injection
cross. The peak locations of the amino acids are indicated by their standard one-letter abbre-
viations (Reprinted from [50] with permission of the American Chemical Society. Copyright
2022).

fractionate them. The second reason is physico-chemical: DNA, soluble in water, feels
‘happy’ in aqueous environments. Therefore, it does embark on organic micelles. This
excludes MEKC from the list. Therefore, none of the preceding techniques allows us
to fractionate DNA.

This is where capillary electro chromatography (CEC) comes on stage. The technique
combines chromatography (i.e. separation in a matrix) and capillary electrophoresis.
A typical CEC system consists of a capillary filled with a matrix (e.g. silicon particles
or a gel) and electrodes imposing a longitudinal electric field. A sample placed at the
head of the capillary will be fractionated, because, as discussed earler, during their
journey, DNA fragments interact differently with the matrix, and consequently migrate
at different speeds.

The first commercial CEC product was launched by Caliper Technologies around the
turn of the century [51]. The channels were etched in glass. Detection was based on
fluorescence. The electric field was about 1 kV/cm and the column length was a few
millimeters. In this device, the separation time took tens of seconds, with a resolution of
several thousand theoretical plates. The technology offered important advantages over
gel slabs, for which fractionation takes hours. By marking the entry of microfluidics
in biology, the Caliper system represents a landmark for the field.

In the meantime, the genome programme was blooming. The genome sequencing was
exclusively based on Sanger method [53]. The method used restriction enzymes, frag-
menting the genome into small single-stranded pieces. A crucial step was the deter-
mination of their sizes. Typically, ten fractionations per kilobase were needed to de-
termine primary sequences [56]. For the human genome, this represented no less than
ten millions separations. This number is huge. In this context, researchers invented
new CEC configurations, faster, more integrated, more automatized [57], and more
parallelized [52]. One example is shown in Fig. 6.44 (B) [55]. DNA samples are placed
400 Electrokinetics

Fig. 6.44: (A) CEC device, commercialized by Caliper Technologies Corp. (Now Agilent
Technologies) [51]; (B) 384 well systems for DNA fractionation. (Reprinted from Ref. [55],
with permission of the American Chemical Society. Copyright 2022.)

in 384 wells, situated at the periphery of the system. The number of theoretical plates
was 4 × 106 and complete analysis of 384 samples took about 6 min.8
It turned out that the most popular sequencer, ABI Prism 3700, that sequenced the
human genome, did not use this work. To increase the throughput, the machine placed
many glass capillaries in parallel. No microfluidic chip was on stage, so to speak. The
penetration of microfluidics came later, with the advent of Next Generation Sequencing
(NGS). NGS, less accurate than Sanger’s method, but much less expensive, no longer
needed fractionation. The first NGS machine, the GS20, produced by 454 Sequencing,
appeared in 2005. The success of GS20 was due in part to the use of large microfluidic
assays. More recent methods [58], such as nanopore sequencing [59], or zeroth mode
cavity [60], also made full use of microfluidic or nanofluidic technology. Since then,
micro–nanofluidics have become, clearly, a core technology for genome sequencing.

6.8 Dielectrophoresis

In a previous section we calculated the force exerted by a homogeneous electric field

on a charged sphere. This led to electrophoresis. When the sphere is neutral, the
force is zero. But this is not the end of the story. We saw, in this chapter, that, in a
purely dielectric system (not conductive), a sphere subjected to a uniform electric field
develops a dipolar field. The corresponding dipolar moment p is equal to the following
(see Eq. (6.45)):

 
r − 1
p = 4π1 R3 E
r + 2

8 In the extension of this work, architectures with higher throughputs were proposed [54].
 Dielectrophoresis 401

A question we may ask is whether the interaction between this dipole and the applied
electric field gives rise to a global force. The answer is no, for symmetry reasons. By
replacing the sphere by bounded charges at its surface, of opposite signs, and located
symmetrically with respect to the sphere centre, one sees that the global Coulomb force
exerted on the system is zero. An electric field does not behave like a wind pushing
the sphere. However, should the field be non–uniform, there is a possibility that, the
symmetry being broken, a net force develops.

Let us investigate this possibility by considering an elementary dipole, shown in Fig.

6.45.

6.45: Dipole immersed in a non

homogeneous electric field.

The dipole is formed by two charges of opposite signs, separated by d. E is the applied
field. In the limit where d is much smaller than the characteristic scale of variation of
E, the Coulomb force exerted on the dipole is:

F = q(E(r + d) − qE(r)) ≈ p∇E

in which p = qd is the dipolar moment. Applying this result to the case of the sphere,
where the corresponding dipolar moment is given by Eq. (6.45), one finds:

 
3 r − 1
F = 2πm R ∇E2 (6.57)
r + 2

in which m is the medium permittivity, and r = ms is the relative permittivity (in
which s the sphere permittivity). The formula shows that a force appears when the
particle is immersed in an electrical field gradient. This force is called dielectrophoretic
[61]. In the literature, it is abbreviated as DEP. The origin of the force is sketched in
Fig. 6.46.

When the particle is more polarizable than the medium, the factor rr −1 +2 is positive,
and, according to Eq. (6.57), the force points towards the field maxima (see Fig. 6.46
A). In the opposite case, i.e. when the liquid is more polarizable than the particle, the
particle is attracted towards the minima of the electric field (Fig. 6.46B).
402 Electrokinetics

(a) (b)

FDEP FDEP

Fig. 6.46: Physics of dielectrophoresis (DEP).(A) Positive DEP: the particle is attracted by
field maxima.(B) Negative DEP: the particle is repelled by them.

This conclusion can also be drawn out from an energetic point of view. To create a
dipole, one must bring two charges ±q at a distance d from each other. The corre-
sponding energy cost is −qE.d = −pE. Applying this formula to the case of the sphere
leads to:
 
3 r − 1
W = −pE = −4π1 R E2 (6.58)
r + 2

The formula tells us that a particle more polarizable than the environment (r > 1)
always reduces the electrostatic energy of the system. It will thus be attracted by
regions rich in electric field. In the opposite case ( r < 1), the particle will feel
repelling forces.

An important remark is that the force does not depend on the sign of the field. Should
the field be oscillatory, the force would keep the same sign because it is proportional
to the gradient of the square of the electric field.

This remarks calls for addressing the case of an oscillatory electric field, i.e. an electric
field given by the expression:
E = E(x) cos(ωt)
in which ω is the pulsation. As is currently done in the literature, we will generalize
our presentation to the case where the particles and the medium are both dielectric
and conducting. The establishment of the expressions of the forces, in such a case, is
available in Refs. [67,76]. This consists in introducing the expression of the electric field
in Eq. (6.57), averaging out, replacing the permittivities by their complex expressions,
and taking the real part. By doing this, the expression of the DEP force F becomes:

F = 2πrm R3 Re(K)∇Erms
2
(6.59)
2
where Erms is the average quadratic value of the applied electric field, Re denotes the
real part, and K is the complex Clausius–Mosotti factor. This factor is defined by the
 Dielectrophoresis 403

following formula:

 
p − m
K= .
p + 2m

in which:

σm σp
m = rm − i and p = rp − i
ω ω

where rm , σm and rp , σp are the dielectric constant and electric conductivities of the
medium and the particle, respectively. The dielectrophoresis is ‘positive’ is Re(K) is
positive and ‘negative’ in the opposite case. K varies considerably with the frequency.
An example, for water and dielectric particles, is shown in Fig. 6.47.

0.8
Re (CM)

0.4
Positive DEP
0
Negative DEP
–0.4
6.47: Typical evolution of the real part
2 4 6 8 10 of Clausius-Mossotti factor Re[K(x)] versus
Log(Frequency) frequency for dielectric particles in water.

At low frequencies, K is dominated by conductivity effects, and, at large frequencies,

by dielectric effects. Fig. 6.47 shows that in the former range, the DEP is positive,
while it is negative in the upper range. The cross-over frequency is typically on the
order of 1 MHz, again for dielectric particles in water. Varying frequency is a method
for changing the sign of the forces.

Let us now analyse the movement of the particles put in motion by DEP forces. In
microfluidics, the viscous force acting on a particle of radius R, as we saw in Chapter
3, is given by the Stokes law:

F v = 6πRµU ,

where µ, as usual, is the fluid viscosity, U the particle speed, and R its radius. Using
Eq. (6.59), we obtain:

R2 rm 2
U= Re(K(ω))∇Erms
3µ
404 Electrokinetics

With an excitation of 1 kV/cm, and a particle of 10 µm in size, the forces and speeds
are of the order of tens of pN and µm/s. DEP forces are limited by the electrical
breakdown of the material (see Chapter 2). Still, as will be seen later, the forces
deployed by DEP technology are large enough to develop interesting functionalities.
An experimental evidence of the DEP forces is shown in Fig. 6.48.

6.48: Laboratory experiment

demonstrating the effect of
DEP forces on polystyrene par-
ticles immersed in water, with
electrodes held at 300 v (MMN,
J. Goulpeau, 2003.)

The left-hand part of the figure shows polystyrene particles in water, above 1 MHz.
They are repelled by the electrodes. On the right-hand part, the frequency is below
1 MHz and the particles tend to accumulate at the electrodes, where the field is
maximum. In the first case, DEP is positive and in the second, it is negative.
The important advantage of using oscillatory electric fields rather than continuous ones
is that all forces linear in the electric field are eliminated. In microfluidic devices, these
forces are ubiquitous. They originate, for instance, from ζ potentials, charges or ions
adsorbed at the walls, or conveyed by impurities, particles, bubbles or droplets. They
are, in practice, largely uncontrolled. By working with oscillatory fields, we capture
the dielectrophoretic part of the electric forces and neutralize the others. Important
to note, dielectrophoretic forces are volumetric and not surfacic. More information on
dielectrophoresis can be found in Refs. [64, 68, 76, 81].

6.9 Three illustrations/applications of dielectrophoresis

6.9.1 Capturing submicrometric particles

6.49: Dielectrophoretic trap local-

ized between four polynomial elec-
trodes. At the centre, where the elec-
trical field is minimal, a 557 nm par-
ticle is captured with negative DEP
(Reprinted from Ref. [62] with per-
mission of the American Chemical
Society. Copyright 2022.)

An early demonstration of the capacity of dielectrophoresis to trap sub–micrometric

particles is shown in Figure 6.49 [62, 63] . The figure shows a 557 nm in diameter
 Three illustrations/applications of dielectrophoresis 405

particle captured in the region where the electric field, produced by four polynomial
electrodes, is minimal [62]. DEP is negative in this case.

6.9.2 Droplet becoming rectangular in an AC electric field

A water droplets is produced at a T-junction and moves rightwards along the main
channel (see Fig. 6.50). As it penetrates in the inter-electrode region, the flow is
stopped and a voltage V is applied.

6.50: Water droplet at rest,

subjected to an electric field, in
a channel 100 µm wide and 30
µm high, filled with oil. (MMN,
L. Menetrier Deremble (2010).)

Droplet shapes are shown in Fig. 6.50. At V = 0, we find the usual shape of the
obstructing droplet, dictated by surface tension and confinement, with a round nose
and an elongated part (see Chapter 4). As the voltage is raised to 900 V, the water
droplet becomes rectangular. Why this is the case? As often in interface problems, it is
more convenient to think in terms of energy rather than forces. As water is polarizable,
the droplet will reshape itself to place water, as much as possible, in the highest field
regions. It will thus tend to become rectangular.
One may suggest that the effect become important when electrical energy E 2 becomes
larger than capillary energy γ/w, in which E is the electric field in the channel, γ is
the interfacial tension water/oil, and w is the channel width. A dimensionless number
can be constructed:
wE 2
J=
γ
In the experiment of Fig. 6.50, with w= 100 µm, and E= 9 MV/m, one has J ≈ 1
indicating that according to the argument just given, above this tension, electric forces
control the droplet shape, as observed in the experiment.

6.9.3 Sorting droplets with DEP

Figure 6.51 shows the concept [69]: droplets of different colours (black and white)
are driven towards a Y junction. When the electrodes are not polarized, droplets,
406 Electrokinetics

arriving at the junction, choose the upper branch, because its hydrodynamic resistance,
compared to the lower one, is smaller. When an AC electric field is applied, droplets
are attracted, by positive DEP forces, towards the electrodes. Their trajectories bent
downwards, so that, at the junction, they chose the right branch. Then, by activating
the electrodes in function of the droplet colour (identified by a laser), the device
operates as a droplet sorter.

Fig. 6.51: Droplet–based sorting device. (Reprinted from [69] with permission of PNAS.
Copyright 2022.)

The sorting rate is typically thousands of droplets per second. To increase this rate,
higher electric fields would be needed. This is not possible because of the dielectric
rupture limit. Therefore, in practice, microfluidic DEP sorters are limited to several
kHz. Although the rate is well below the fluorescence-activated cell sorting (FACS),
microfluidic DEP sorters are extremely useful. They were used in Ref [69], to identify
new functional mutants of the enzyme horseradish peroxidase. From an initial pop-
ulation of 108 enzymes, 100 variants were selected in less than 10 h, using less than
150 µL of total reagent volume. Compared with the state of the art, the microfluidic
screening assay represents a 1,000-fold increase in speed and a 1-million-fold reduction
in cost [69].

6.10 Electrowetting
Let us consider a conducting droplet (for instance, salted water), polarized at tension
V , placed over a thin hydrophobic insulating layer, deposited on a metallic electrode
(see Fig. 6.52).9 .
The configuration of Fig. 6.52 is called electrowetting on dielectrics (EWOD). It was
popularized by B. Berge [73]. Without an insulating layer, electrochemical reactions
develop at the liquid–electrode interface, imposing to work at small voltages. In such
circumstances, the droplet does not depart much from its shape at zero voltage. With
the insulating layer, as we saw in this chapter, the electric field strength is reduced,
but this reduction is outweighed by the possibility to apply large voltages. In practice,
by applying voltages ranging between 50 and 1000 V, in the configuration of Fig.
9I am much indebted to F. Mugele for the writing of this section
 Electrowetting 407

Fig. 6.52: Electrowetting on dielectrics (EWOD): a conducting droplet is placed on an in-

sulating layer of thickness d, below which a metallic electrode represents the ground.(A) No
voltage is applied; the contact angle is equal to the Young angle θY .(B) V > 0, the contact
angle is decreased.

6.52, one significantly modifies the droplet morphology, in a stable and reproducible
manner.

Fig. 6.52 defines a capacitor. When a voltage is applied, a charge Q appears at the
droplet/insulator interface (see Fig. 6.52). This charge is given by Q = CV S, in which
S the droplet footprint and C = d is the capacity per unit of area (here d is the layer
thickness). In the droplet, counter–ions, attracted by the surface charge, build up a
Debye layer at the solid–liquid interface. In the meantime, charges of the same sign
populate the liquid–vapor interface, essentially close to the contact line, as will be seen
later. The question is: how to describe the situation?

Several descriptions can be found in the literature. Here, we use the description of
Refs. [72, 74]. For the sake of simplicity, let us assume that the droplet conductivity
is large and, consequently, Debye layers are thin and there is almost no electric field
in the liquid bulk. Let us take an energy viewpoint, as we did in in Chapter 4, in the
section dedicated to Young equation. In our problem, two energies must be considered:
surface and electrostatic energies. Suppose that we move, on Fig. 6.53, the contact
line by dx > 0 (flooding the surface). This displacement increases the capacity of the
system by a quantity, per unit of length, equal to Cdx. This in turn decreases the
electrostatic energy Ee of the system, by an amount, still per unit of length, equal to
dEe = 12 CV 2 dx.10 ) In this displacement, the contact angle changes and the surface
energy of the system, ES , varies by a quantity equal to:

dES = (γSL − γSG + γ cos θ)dx = γ(cos θ − cos θY )dx

where γSV , γLS and γ are the solid-vapor, solid-liquid and liquid-vapour surface ten-
sion, respectively, θY is the Young angle, and θ is the contact angle adopted by the

10 The word ‘decrease’ is important. Two condensator plates attract each other, because their
charges are of opposite sign. Should they be free to move, they would approach each other. By
approaching, from infinity, at a distance d, their energy decreases by an amount equal to 12 CV 2 S
(where C = /d), like a mass m falling on earth, whose gravitational energy decreases by a quantity
equal to mgh, where h is its initial altitude and g the gravity. Similarly, if the capacity, per unit of
length, increases by Cdx, the energy will decrease by an amount equal to 12 CV 2 dx.
408 Electrokinetics

system when the voltage is applied. As the system is at equilibrium, the sum dEe +dES
must be equal to zero. We thus obtain:

V 2
cos θ = cos θY + (6.60)
2dγ

This equation is called the Young-Lippman equation (YL) [70]. To summarize, the
droplet spreads, as much as it can, to augment the capacitance of the system and then
decreases its energy. This decrease is balanced by an increase in surface energy. The
outcome is the YL equation.
Then, droplets flatten out to satisfy YL equation. Where do the forces come from? Why
does the droplet spread out ? As we said, inside the droplet, counter–ions, attracted
by the charges embedded in the dielectrics, build up two charged layers. One at the
horizontal surface, and another one, at the liquid–vapour interface, near the contact
line, covering only a part of it. Let us assume, as above, that the liquid conductivity
is large, and, consequently, these layers are thin. Within each layer, charges repel
themselves, and thus work at spreading the droplet over the solid surface. This where
the forces originate from. Their calculation requires some technique. The most efficient
method for carrying out the calculation is using Maxwell stresses. This was done by
Jones, in 2002 [74, 76]. The calculation showed that the corresponding line tension,
2
which pulls the contact line outwards, is V 2d . The result is, as expected, equivalent to
the energetical approach. Charges and stresses are localized at the contact line [75,77].
The reason is geometrical: interfaces form a wedge, and, by approaching the apex, each
charged layer gets closer to each other. Consequently, the local electric field increases.11
A singular behaviour takes place there. In fact, calculations show that, at the contact
line, electric field and pressure are infinite [75,77]. Still, despite this singular behaviour,
the tension (per unit of length) exerted on the contact line, by electrostatic forces, is
2
the one calculated by Jones, i.e. V 2d [77].

Several remarks can be made:

• Lippman angle is an apparent contact angle. At distances comparable to the
insulating layer thickness, i.e. d, the interface bends so as the contact angle, at
the surface, its equal to the Young angle [80]. This is sketched in Fig. 6.53
The reason is that, as shown in Ref. [72, 74], the Maxwell stress is zero at the
contact line. Thereby, surface tension forces prevail and the Young angle is re-
covered. Then, if we look the system at a scale comparable to d, we see that the
electric field affects the droplet shape, but not the contact angle, unlike what the
term ‘electrowetting’ might suggest.
• The Debye layer has its own capacitance. It is placed in series with the dielec-
tric/electrode capacitor. Since the Debye layer capacitance is large, it can be ne-
glected. More accurate formulas, taking the Debye layer into account, have been
established in the literature [74].
11 In the calculation, Kang assumed charged layer thicknesses on the order of the Debye length
 Electrowetting 409

6.53: Droplet shape, close to the

solid surface. At point A, the appar-
ent contact angle, characterizing the
slope of the liquid interface, is given
by the Young-Lippman equation. At
point B, i.e. at the surface, the con-
tact angle is θY . (From Ref [74]).)

• Switching between hydrophobic and hydrophilic states takes, typically, 1 ms. From
an engineering prospective, this high speed is interesting.

Early measurements of the evolution of the contact angle with the applied tension,
carried out with salt water in air, are shown in Fig. 6.54 [75].

6.54: Early measurement of the cosinus of

the contact angle θ as a function of the ap-
plied tension V , for a PTFE film in air, 50
µm thick, using salted water. The full line
– a parabola – represents Young–Lipmann
equation (6.60). (Reprinted from [75] with
the permission of Springer Nature. Copy-
right 2022.)

Fig. 6.54 shows that the contact angle varies from 102◦ to 27◦ , as tension V is increased
from 0 to 1000 V [75]. The full line – a parabola –represents YL Eq. (6.60). The work
showed that theory is in excellent agreement with experiment, in a broad range of
voltages. At larger V , the contact angle levels off, a phenomenon called ‘contact angle
saturation’, still not fully understood [74, 79].

Electrowetting is exploited in ’digital droplet technology’, also called ’digital microflu-

idics’ (DMF) [81–83]. The concept is shown in Fig. 6.55.

Fig. 6.55: A droplet, initially at rest, feels the action of the right electrode, and, in response,
decreases its contact angle. Laplace pressure moves it rightwards. At the end of the journey,
it adopts a symmetric shape and returns to rest. The process can be repeated to displace the
droplet over an array of electrodes addressable individually.
410 Electrokinetics

Let us consider a droplet placed between two plates, with the lower surface patterned
with two electrodes. When the electrodes are not polarized, the two contact angles,
on the right and on the left are equal, and the droplet stays at rest. When the right
electrode is activated, the right contact angle decreases, the interface tends to inverse
its curvature, and consequently, due to the action of Laplace pressure, the droplet
moves to the right. At the end of its journey, it adopts a symmetric shape and stops.
The process can be repeated to displace the droplet on a plane. This is the idea of
digital droplet technology.

Fig. 6.56 shows a system where a water droplet is moved at will, over a surface pat-
terned with addressable electrodes [85].

6.56: An EWOD system, in which droplet

move on a patterned plate, driven by suc-
cessive activations of addressable electrodes
(Reprinted from [89] with the permission of
John Wiley and Sons. Copyright 2022.)

Over the last two decades, several research groups [79, 82, 84–88] have demonstrated
impressive realizations: rotating droplets, droplets moving on a substrate in a com-
plicated manner, interacting together, mixing reagents, initiating chemical reactions,
cutting droplets. The technology substantiated well the concept of lab on a chip’. This
was clearly a groundbreaking technology and some papers promised the advent of a
revolution [89].

Several remarks can be made: DMF requires precise microfabrication. Electrodes must
be placed close to each other, so as, at any time, droplets feel’ the electric field. Typical
inter electrode distances range between 5 and 10 µm. With voltages on the order of
100 V, the local electric field is 10 kV/cm. Therefore, DMF does not operate far
from dielectric rupture. In fact, today, this constraint does not raise technological nor
economical issue. The real practical issue is the long term stability of the coatings
over thousands (or millions for displays) of actuation cycles, and for bio-applications,
fouling onto the hydrophobic coatings [90].

Today, digital microfluidics remains an important branch of microfluidics, but its com-
mercial success is still concentrated on niches. The situation has recently been ana-
lyzed [91]. Commercial EWOD systems are used in two areas: optical (e.g. liquid lenses
– see above –) and biomedical, the important example being sample preparation for
DNA sequencing.12 By automatizing sample preparation steps, EWOD allows us to
complete sample preparation in ∼30 min instead of the 4–5 hours of manual operation.
This example illustrates the impressive capabilities of the technology.

12 Although, today, other systems are preferred

 Electrowetting 411

Lenses controlled by electrowetting

Electrowetting is used in optics to control the focus of liquid lenses. The prin-
ciple, pioneered by Berge [73], is shown in Fig. 6.57. An oil layer, forming a
concave lens, is confined in a system filled with water. The oil/water contact
line touches an electrode. By varying the voltage, the contact angle changes, as
does the focal length. This approach allows for faster focusing. It also makes
the lens less susceptible to shock. Mechanical autofocus systems achieve focus
in around 500 milliseconds. Fluidic lenses are expected to achieve this in only
a couple of milliseconds. The technology may thus substantially impact the
mobile phone market.

Fig. 6.57: Principle of a liquid lens, controlled by electrowetting. This type of lens
can be used on mobile phones.
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7
An introduction to microfabrication

7.1 Introduction

In the chapter, we will briefly describe the most common microfabrication techniques
used in microfluidics today. We will start with silicon technology. The reasons are the
followings: the possibilities offered by this technology are considerable, it represents an
immense resource of knowledge, and it is used in many commercial devices. Addition-
ally, up until the turn of the century, microfluidics was primarily a silicon or glass-based
technology. In a second part of the chapter, we will describe soft technology, which
is currently most frequently used in the laboratories. We may give tribute for this
to G. Whitesides, whose papers, published in 1998, induced a change of paradigm in
the field [1]. Before the advent of soft technology, many scientists believed that mi-
crofluidics could be extremely useful in biology and chemistry. However, they were
hindered by the clean room barrier. G. Whitesides played a crucial role in lowering
this barrier and opening a box of innovations. We will devote significant attention to
this technology in this chapter.
This chapter does not intend to be exhaustive. For more detail, the reader can refer
to books, such as Fundamentals of Microfabrication [2], Handbook of Microlithogra-
phy, Micromachining and Microfabrication [3], or Fundamental and Applications of
Microfluidics [4].

7.2 Current situation of microtechnologies

7.2.1 Hard, plastic and soft technologies

From a material prospective, one can classify the microfluidic technologies into several
categories: hard materials (silicon, glass), plastic materials (COC, PMMA, etc.) and
soft materials (PDMS, PUV, hydrogels, etc.).
Hard materials: these include silicon and glass. The technologies are based on etch-
ing/lithography/deposition. The typical dimensions associated to hard materials
range between 20 nm and 500 µm.
Plastic materials: these materials allow channels to be created with sizes that
mainly range between 20 µm and several milimiters, i.e. embracing micro– and
416 An introduction to microfabrication

millifluidic scales. A large variety of materials are used, with different surface prop-
erties, e.g.. hydrophobic and hydrophilic. Examples are polymethylmethacrylate
(PMMA), Cyclic olefin copolymer (COC) or SU8, a photoresist. Plastic devices
are made using different technologies, such as micromilling, laser ablation, or in-
jection. Plastics are extremely important for the industrialization of microfluidic
devices, due to their low cost. With the development of 3D printing, they are
being increasingly used in research laboratories.
Soft materials: these materials are mostly used for creating channels (or other
structures) between 0.5 and 500 µm of characteristic sizes. PDMS is by far the
most used one.

7.2.2 Tolerances

Figure 7.1 represents the dependence of the relative tolerance with the size of the
objects to be created.

7.1: Relative tolerance at which several ob-

jects, characterized by their dimensions, are
fabricated.

A number of comments can be made:

• In the construction domain, houses are built with a tolerance of 1%. For instance,
for a vertical wall, a tolerance of 8 mm for a height of 1 m is recommended by
the agencies. This represents a relative uncertainty of 0.8 %.
• Traditional machining (milling machine, lathe, etc.) creates objects between 1
mm and a few decimetres. The technique has a precision on the order of tens of
µm. The relative tolerance is thus high, up to 10−6 (upper grey area of Fig. 7.1).
Over the last decades, the resolution has been improved. The extreme case is
the Robonano machine, which creates metallic objects with a precision of tens
of nanometres [5] (see Fig. 7.2 (A)). The machine has five degrees of freedom (3
in translation, 2 in axial rotation). Its displacement precision is of 1 nm, and its
angular precision is (10−5 )◦ . Fig. 7.2 (B) shows a Boudda micromask made with
such a machine.
 The environment of microfabrication 417

Fig. 7.2: (A) Machine ROBOnano-Ui. It has 5 degrees of freedom (3 in translation, 2 in

axial rotation). The displacement precision is of 1 nm, and its angular precision is of (10−5 )◦ .
(B) Bouddha micromask fabricated with Robonano. (photos by Pr Takenchi, University of
Electro-Communications, Osaka.)

Robonano has not penetrated the laboratories for obvious reasons: it can only be
used with metals, it is extremely expensive and slow. On may appreciate these
machines as great technological feats, the crowning achievement of traditional
methods, but with very limited usage in practice.
• The domain of microfabrication involves scales spanning between one micrometre
and a millimetre. The absolute tolerance is 1–10 µm and the relative tolerance 1–
10 percents. It is amazing to note that microfluidics is less accurate than masonry.
• The fabrication of nanometric objects (between 1 and 100 nm) embraces a large
variety of techniques (silicon technology, carbon nanotubes (CNTs), etc.). They
are associated to high absolute precision, and relative tolerances typically low or
extremely low.

7.3 The environment of microfabrication

7.3.1 The environment of microfabrication

Dust particles erring in laboratories have sizes ranging, roughly, from a few tens
nanometres to tens of micrometres. They wander in the air and deposit onto sur-
faces. In a standard environment, there exist millions of dust particles per feet cube.
This dust does not perturb human activity, but, considering the scales used in mi-
crofabrication, they may jeopardize the fabrication of microfluidic devices. Figure 7.3
shows a pollen dust particle stuck on a microelectronic circuit. It is not difficult to
imagine that such particles can clog microchannels or affect the surface properties
of the material. Microelectronics faced this problem for years, until Willlis Whitefield
from SANDIA Laboratories invented, in 1962, the concept of ’clean room’, i.e. isolated
spaces permanently cleaned by air fluxes. In clean rooms, air circulates from the ceiling
to the floor, where it is extracted. This configuration forces the particles produced by
418 An introduction to microfabrication

the users – the most abundant origin – downwards, preventing benches, equipments,
etc.. from dusting. This invention represented a milestone in the field.

7.3: Pollen on a microelec-

tronic circuit [2].

What is a clean room? It is an environment thermally regulated (around 20 ◦ C), in

which humidity is controlled, and which is permanently traversed by filtered air fluxes.
The quality of the clean room is measured by counting the number of particles of a
size less than 4 µm contained in one cubic inch1 . Typical clean room classes for MEMS
microfabrication are 1000 to 10000. Now, more and more frequently, ISO classification
is preferred to the notion of clean room classes. A clean room of class 1 is ISO3, of
class 1000 is ISO6, etc.. Inside laminar hoods, classes are typically between 10 and
100. In microelectronic industry, it is not rare to find large rooms classed at 10 or 1
to reduce failure rates. For a class of 1000 to 10000, it is necessary to wear specialized
clothing, to cover hair, and to put on gloves and shoe–covers. These precautions are
not necessary for rooms of higher classes (i.e. less ‘clean’).

An example of microfluidic facilities, located in the Pierre GIlles de Gennes Institute

in Paris, includes a 200 m2 ’grey room’ (class 10000) and a 100 m2 clean room (class
1000). It is shown in Fig. 7.4.

7.3.2 Using or not using clean rooms for microfluidics

Figure 7.5 shows two extreme cases: a sophisticated submicrometric device (Fig. 7.5 (A))
and a crude millichannel (Fig. 7.5 (B)). In the first case, the device would be impos-
sible to create outside a clean room. In the other case, a photocopyer and a modest
amount of PDMS were enough to create the milli–channel.2 The cross-section of the
canal is not geometrically well defined and the walls are rough. Nonetheless, the device
was functional.

Microfluidics stands between these two extremes: sophisticated technologies, most of-
ten associated to high costs and long processes, and low technologies, most often
associated to low costs and speed.

1 Recall that an inch equals 2.56 cm.

2 The idea was proposed in Ref. [8].
 Photolithography 419

Fig. 7.4: Institut Pierre Gilles de Gennes (IPGG) platform, in Paris, including a 200 m2 grey
room (class 10000) and a 100 m2 clean room (class 1000). (Drawn by Ecart Fixe.) The grey
room includes oxygen plasmas, nanoimprint apparatus, ovens, benches, an actinid room and
the clean room an electronic microscope, profilometers, deposition equipment, aligner, spin
coater, ellipsometer, and ovens. .

Fig. 7.5: (A) Submicrometric structure( Courtesy of P. Joseph). (B) Channel made with a
photocopyer (From T. Jues, R. Prunieres, E. Brunet, P. Tabeling (2002).)

7.4 Photolithography

7.4.1 Introduction

A process playing a central role in microfabrication, is photolithography. The term

photolithography’ includes the word ‘litho’, which means stone’. The term refers to
the first photolithography, made on a limestone, by Alois Senefelder, in 1798 [37].
We will see that photolithograpy uses collimated sources. Today, different types of
420 An introduction to microfabrication

sources are available: X-ray, electron, and photon. In practice, microfluidics uses optical
lithography, with wavelengths between 200 and 450nm. Using X-rays has been done,
giving rise to a technology called ‘lithographie, galvanoformung, abformung’ (LIGA).
LIGA conveyed the hope that, by scaling down microfluidic devices, new valuable
systems could be created, as in microelectronics. Despite its potential usefulness, it
has not been widely used due to the challenges posed by its complexity. Electron
lithography is essentially used for making precision masks. Lithography in the optical
range, widespread in microfluidic laboratories, will be the focus of the chapter.

7.4.2 Photolithography masks

Masks are of two types (see Fig. 7.6): high resolution (plates of quartz on which
deposits of chrome forming a pattern are made) and low resolution (5 µm or so, made
by ink printing on a plastic sheet, most currently used in the labs, owing to its low
price and availability). High precision masks are made by using electron beams with a
precision on the order of a fraction of a micrometre. We will not describe the technique
in this book.

Fig. 7.6: (A) High resolution mask, made by depositing chromium on quartz (submicrometric
resolution). (B) Low resolution mask (5 µm or so), using a transparent sheet.

7.4.3 Deposition of the photoresist

The photosensitive polymer is deposited in a thin layer on a solid substrate of silicon or

glass, usually a wafer. The deposit is made using a spincoater, as depicted in Fig. 7.7.
This system consists of a disk, that maintains the wafer on it by evacuating air. The
wafer rotates at rotation speeds ranging between 1000 rpm and 10000 rpm. While the
resist spreads on the substrate, the solvent evaporates, and the film thickness saturates.
The material thus formed resembles a soft solid. It is remarkable that the thickness h
of a film obtained in this way is extremely uniform (to about 20 nm). The evolution of
the thickness h of the film is described in [10]. It is governed by the following equation:

dh/dt = −2Kh3 − E
 Photolithography 421

2
in which t is time, K = ω3ν , where ω is the angular velocity, ν is the kinematic
viscosities, and E is the evaporation rate. Two regimes can be singled out, with a
cross–over time τ = 2π/33/2 (2E 2 K)−1/3 . At small t/τ , the evaporation is negligible,
and the solution spreads, under the action of the centrifugal forces. At late times,
evaporation comes into play, the solution concentrates, its viscosity increases, and h
levels off. Eventually, the limiting height is given by the following expression:
 µ 1/3
h = kC
ω2

where C is the initial concentration of polymers in solution, and k is a constant (cur-

rently on the order of 0.8). In practice, it takes seconds or tens of seconds to reach the
equilibrium thickness.

Fig. 7.7: Deposition of the resist on a spincoater).

Depending on the polymer used, film thicknesses vary between a fraction of a mi-
crometre to 200 µm. Once the spreading is completed, the resist still typically consists
of about 15 % solvent. If this solvent is not removed, cracks or fissures appear once the
film is completely reticulated. To eliminate the solvent completely, the resin is heated
slightly (at 70 ◦ C for a few minutes).

7.4.4 Exposure

After spin coating, the photosensitive polymer and its substrate are placed in an
aligner. The film is thus exposed to a luminous flux produced by a source crossing the
photolithographic mask. The source is most often a mercury vapour lamp that delivers
substantial luminescent power (10 to 20 mW), in wavelengths between 300 and 450
nm. 3 The luminous flux initiates physico-chemical reactions in the polymer, which
modify its solubility. There are two types of resists: positive and negative.

3 g- and i-lines are used at 436 nm and 365 nm, respectively.

422 An introduction to microfabrication

Fig. 7.8: Principle of photolithography. In practice, in lithographic machines (called aligners),

beams are collimated, which is not shown here.

• Positive resist: the insolated zones become soluble (in some solvent), and the
others remain insoluble.

• Negative resist: the insolated zones become insoluble and the others remain
soluble.

Thus, for positive resists, insolation across a photolithographic mask defines the zones
that will, after development (that is, after immersion in a solvent), form holes in the
resist film. For negative photoresists, this is the opposite. The resist must be sufficiently
transparent to allow the illumination of the whole thickness of the deposited layer, and
sufficiently sensitive for the light to develop the appropriate chemistry. In practice, the
thickness of a positive resist films does not exceed 10 – 20 µm. The invention of SU8
– a negative photoresist.–, by IBM, in the 1990s, constituted a small revolution in the
field. With SU8, it is possible to deposit thick films (hundreds of micrometres).

Several phenomena alter the resolution of the photolithography. One is diffraction at

the edges of the mask openings. As in microscopy, this effect limits the resolution to
a quantity close to the diffraction limit, i.e. λ/N A, in which N A is the numerical
aperture of the collimating lens. In practice, resolutions are on the order of 1 µm.

Another limitation is linked to the penumbra effect: as shown in Fig. 7.9, a collimated
beam crossing a mask, and projected onto a screen, produces lit and dark regions. In
between, there is a penumbra. Another phenomenon limiting the precision is diffrac-
tion. The size δ of the diffraction zone is given by the following formula:
 Photolithography 423

Fig. 7.9: Penumbra effect, degrading photolithography resolution. The effect is reduced by
approaching the mask close to the wafer.
√
δ ≈ 3 λh,

where λ is the light wavelength and h is the thickness of the polymer film.4 Inserting
typical values, we obtain that δ is on the order of 2–3 µm. This steers researchers to
work with resists of limited thicknesses and short wavelengths.

An example of a protocol for the fabrication of an SU8 mold

Suppose that the resist, the optical aligner, spincoater, and a silicon or glass substrate
are all available. The substrate must be cleaned and dried, which is achieved in
two steps. The first step consists of immensing the wafer in acetone (to dissolve
organic residue), in an ultrasound bath, and then drying. The second step consists of
performing the same operation but with alcohol. The substrate must then be placed
on a hotplate at 120◦ C for 5 min for dehydration. It is necessary to have a substrate
with no traces of contaminant whatsoever. Then the resist is spread on the wafer with
a spincoater. The system is then heated to 65◦ C for 60 s, then at 95◦ C for 180 s, which
serves both to eliminate the violent nature of the residual solvents and also as a first
hardening step. It is after the exposure step that the baking step known as post bake
(PBM) takes place. To encourage the progressive rearrangement of material during
thermal deformation, heating is achieved in two steps: the wafer is heated to 65◦ C
for 60 s, and then to 95◦ C for 120 s. The system is now ready for the development
step. The system is dipped in a developing solution for 180s. The SU8 is a negative
resist, so the exposed motives stay, and the non-exposed motives are dissolved. The
whole system is then rinsed with alcohol and dried with nitrogen gas. To finish the
protocol and obtain a stable mold, the whole system is heated to 200◦ C for 2 h.

4 Mask aligners generally have two positions: contact (the mask is in contact with the resist) and
proximity (the mask is 10 µm above the resist). The second mode is more often favourable because
the first carries the risk of the resist, which is still in a sticky state, adhering to the mask.
424 An introduction to microfabrication

7.4.5 Commonly used resists and the development step

We now properly discuss resists. Resists used for photolithography must possess the
following characteristics:
1. a large contrast between the solubilities of the exposed and unexposed parts;
2. high photosensitivity; and
3. high resistance to certain classes of chemical agents.
The solutions used for photolithography are composed of a photosensitive resist, a
solvent (that reduces the viscosity of the solution, allowing the spreading on a spin-
coater), and an additive (in order to control the kinetics of the photoreaction). For
positive resists, the light breaks or weakens the internal bonds of the resist, and in-
duces a rearrangement of the molecule to a more soluble form. For negative resists, the
action of the light is to induce the formation of covalent bonds between principal or
secondary chains, making them soluble by a process we will not describe here. Exam-
ples of ‘positive’ resists include DQN (a mix of diazoquinone with the resist phenoline
novolak), and AZ. These resists are soluble in highly basic solutions such as KOH,
TMAH, ketones, and acetates. As an example we cite the negative resists KTFR (a
polyisoprene elastomer produced by Kodak), and most importantly, SU8, which we
already mentioned. SU8 can be used as a mould, but can also form structures with a
high aspect ratio.

With regard to microfabrication, the choice between positive and negative resists is not
trivial: negative resists adhere better to the substrate than positive resists, and tend to
be more chemically resistant. However, the contrast of the photosolubility of negative
resists is weaker than those of positive resists. These characteristics are all factors in
the refinement of the microfabrication process. After the insolation step comes the
development step. This step consists of immersing the system in a solvent. This step
must be carried out at a carefully controlled temperature. It is necessary to remember
that the relevant processes during the development phase have a high temperature
dependence. Then, either the exposed part (for positive resists) or the unexposed part
(for negative resists) is eliminated. The photolithographic process concludes by the
reinforcing of the cross-linking of the resist, incubating the system well above the
glass transition temperature typically for tens of minutes.

7.5 Direct writing or maskless photolithography

Direct writing (also known as maskless lithography) refers to any technique or pro-
cess capable of altering the chemistry, depositing, removing, dispensing, or processing
various types of materials over different surfaces following a predetermined layout or
pattern. There are various means to achieve the desired patterns and they can be
broadly classified into additive and subtractive techniques. Additive techniques such
as ink jet printing, dip pen nano-lithography (DPN), and micropens add material to
a substrate based on a CAD layout. Subtractive techniques such as focused-ion beam
 Microfabrication methods for silicon and glass devices 425

(FIB), and laser micromachining selectively remove material from a substrate using
an ion beam and laser source, respectively.
Fig. 7.10 shows an example of direct writing technology, called laser direct writing
(LDW).

Fig. 7.10: (Left) Principle of direct writing: a spot is illuminated, translated so as the whole
surface is exposed. (Right) Example of the direct writing of a photosensitive hydrogel struc-
ture [12]. It was obtained with Dilase 650 Kloe, using a 266 nm wavelength and 50 mW
output-power source.

In this case, a laser beam illuminates a photo-sensitive polymer layer, which, in a

same manner as negative photo-resists, cross-links under illumination. After washing,
a structure in form of parallel rails is formed. The figure shown on the left shows an
example of a structure obtained with a photo-curable PNIPAM hydrogel. Dimensions
indicated on the figure illustrates the fact that the resolution of LDW is comparable to
standard photolithography, the limit being again linked to diffraction. LDW is more
flexible than standard lithography, but slower, owing to the fact that, in the former
case, one small spot is exposed one after the other, while in the latter case, the whole
object is illuminated. In the former case, the process is serial, and in the other, parallel.

7.6 Microfabrication methods for silicon and glass devices

7.6.1 Silicon as a microfabrication material

The use of silicon is justified for the following reasons:

• the ready availability of the material, and the considerable documentation of its
properties;
• the large number of well-established microfabrication processes, which allow for
the fabrication of devices with greater than submicrometric precision;
• the possibility of integration with electronic circuits;
• its anisotropy, advantageous for microfabrication; and
• its physico-chemistry, compatible with many processes.
426 An introduction to microfabrication

Germanium is not a viable alternative to silicon because the native dioxide GeO2 is
soluble in water, making it inconvenient for photolithography. Silicon is delivered in
the form of wafers that constitute a monocrystal. Silicon is produced by crystalline
growth, process carried out in a very clean environment (around class 1 or 10). The
growth process, developed by Czochralski, consists of slowly pulling a crystal from
an ultrapure bath of silicon while the whole ensemble rotates. A cylindrical crystal is
obtained, from which slices hundreds of micrometres thick are cut. This is followed
by the atomic polishing phase. All this leads to the fabrication of a wafer, atomically
smooth on the polished surface, whose crystallographic orientation is identified by
marks on the wafers.

From a crystallographic point of view, silicon is a cubic crystal, whose structure is the
same as that of diamond (Fig. 7.11). We recognize two cubic networks with overlapping
centres, resulting in a two interpenetrating face-centered cubic structure. The side of
one cubic face is 5.43 Å. Each tetravalent silicon atom belonging to a given network is
at the centre of a tetrahedron, whose points are made of atoms of the partner network,
as shown in Fig. 7.11. The highest-density planes are the (111) planes, which form an
angle of 54.74◦ with respect to the (100) planes.5 We will later see that these planes
play an important role in the wet-etching process.

Table 7.1 displays a number of mechanical, electrical, and thermal properties of silicon.

7.11: Silicon structure. Two cubic networks

with overlapping centers, resulting in a two
interpenetrating face-centered cubic struc-
ture. The side of one cubic face is 5.43 Å.
.

The Young’s modulus of silicon is comparable to stainless steel. A similar statement

can be made for polysilicon (composed of silicon atoms in a structurally disordered
state) (160 MPa).6 Silicon is a fragile material, as is glass. This signifies that there is
no plastic zone. The stress rupture is on the order of 7 GPa, with a maximal strain
of 3.5 percent. Silicon is an insulator at ambient temperature. It is an excellent piezo-
resistor, a poor piezoelectrics, and an excellent thermal conductor (comparable to a
metal). Thermal expansion of silicon is small: in the range of temperatures around
300 K, the corresponding coefficient is equal to 2.33 × 10−6 , a value comparable to
glass. The coefficient decreases with temperature, and becomes negative around 100
K. Native silicon dioxide SiO2 adheres well to the substrate, is thermally stable, has
an excellent chemical resistance and is insoluble in water (unlike germanium dioxide).

5 Examining
√
the elementary cell, this angle is seen to be arctan 2.
6 Polysilicon is the structure adopted by silicon, when deposited on a substrate to create microstruc-
tures.
 Microfabrication methods for silicon and glass devices 427

Physical size Value Units

Rupture strength 7 GPa
Young’s modulus 190 GPa
Density 2.33 g/cm3
Thermal conductivity 2.33 W/cm K
Thermal dilation 2.33 × 10−6 K −1
Electrical permittivity 11.9 F/m
Electrical field breakdown 3 × 105 V/cm
Electrical resistivity 2.3 × 105 Ω cm
Thermal diffusivity 0.9 cm2 /s
Specific heat (at constant pressure) 0.7 J/g K
Fusion temperature 1415 K
Table 7.1 Physical characteristics of silicon.

Currently, silicon wafers are delivered with one or both sides polished, the location
of the crystallographic orientation (defined by two planes) marked, and with different
diameters and thicknesses. To get an idea of typical sizes, the 4-inch wafer is frequently
used because current machines in the field of MEMS have adopted this format, though
the trend is going towards increasing these sizes. The reason for this is practica: the
larger the wafer, the more microsystems can be created in a single batch. There is a
disparity between microelectronics, which often uses 8-inch and 12-inch wafers, and
microfluidics, which uses smaller wafers. A typical wafer thickness is 500 µm. It is
interesting to mention SOI wafers (silicon on insulator), which possess three layers,
two made from silicon and one made from silicon dioxide. They facilitate the fabrication
of a certain number of devices, notably those using sacrificial layers.

7.6.2 Wet etching of silicon and glass

Wet etching consists of exposing an object, on which certain parts have been protected
by a mask, to a chemical reagent, in a liquid, whose action leads to material removal.
This process was in use as early as in the fifteenth century to decorate armours. To
accomplish this, the armour was covered with wax, the parts destined for exposure to
reagents were cut out, and then it was all dipped into a reactive bath for a determined
period of time. When the armour was taken out of the liquid bath and the wax was
eliminated by heating, an etched or hollowed-out pattern was obtained. The discov-
ery of photosensitive materials by Niépce, the inventor of photography, represents an
important milestone in the history of this technique. Later, the microelectronic revo-
lution of the 1950s caused an extraordinary refinement of wet etching. We now have
a large amount of data on etching velocities in different conditions, which allow us to
control the geometry of the etched object to just a few micrometres.
An important distinction must be made between isotropic and anisotropic etching.
Isotropic etching is carried out equally in the three spatial directions, and can be used
for forming structures such as spherical cavities; examples include fluoric acid in glass
428 An introduction to microfabrication

and EDP in silicon. Anisotropic etching consists of a chemical attack that is carried out
preferentially along one of the crystallographic planes. It is possible to create cavities
that have facets, which can be useful. This type of etching is not possible in glass,
since it is an amorphous solid. Figure 7.12 illustrates these two types of etching for
silicon. In the first case (left-hand figure), EDP is used for isotropic etching, while
in the second case (right-hand figure), the base KOH is used to etch anisotropically,
which is carried out along the planes (111).

Fig. 7.12: (Left) Isotropic wet etching using EDP in glass. (Right) anisotropic wet etching
using KOH in silicon.

Isotropic etching of silicon and glass. Isotropic etching generally implies the use of
acids: a commonly used system for silicon is composed of HNA, which is a mix of
HF/HNO3 /CH3 COOH. For glass, a commonly used system is fluoric acid. In these
two cases, the etching is carried out at ambient temperature, with etching velocities of
tens of micrometres per minute. The attack is accomplished in four steps: the trans-
port of the reactant towards the surface, the local development of chemical reactions,
the formation of a cavity, then the evacuation of the product. The transport steps
are controlled by the mixing of the reactants in the bath in which the material is
submerged. As the etching velocities are high (in comparison to the velocities of the
evolution of the diffusion fronts), it is important to mix well to ensure the homogeneity
of the concentrations of reactive chemicals in the volume of the system. Chemically
speaking, the attack of the reactant is in fact a subtle process. For example, the action
of HNA on silicon makes use of the following global reaction:

Si + HNO3 + 6HF −→ H2 SiF6 + HNO2 + H2 O + H2 (gas).

Simplifying the reaction model, we can consider the action of HNA to essentially consist
of breaking the covalent bonds of the crystal, and producing a fluoride compound of
silicon (H2 SiF6 ) that is soluble in fluoric acid. The reader can refer to the work of
Marc Madou [2] for a detailed presentation of this process.

Since we are dealing with a chemical reaction, the temperature of the bath must be
maintained constant in order to control the depth of the etching. Typically, regulation
to a few tenths of a degree is necessary to guarantee precision on the order of 10 per-
 Microfabrication methods for silicon and glass devices 429

cent of the depth. The state of the surface is also an important issue: physically, to
obtain smooth surfaces, it is useful to place the system in the regime where diffusive
processes (which tend to make reactive concentrations uniform) are quicker than the
chemical kinetics. This regime is chosen by controlling the temperature of the system.
The corresponding conditions are now known, and are just one of several parameters
defining microfabrication protocols. It is useful here to refer to the specialized liter-
ature. In an ideal situation, the mask is not attacked by the reactant. In practice,
however, there is a chemical attack of rates on the order of a few per cent of those in
the intended process itself. For example, silicon is used as a mask for HNA, but it itself
is also attacked by HNA, although at a rate 80 times slower than that of silicon. It
is thus important to work with thick masks (hundreds of nanometres) to ensure that
the masked part remains covered during the entire etching step. However, it has also
been shown that the thicker the mask, the less geometric precision is achieved when
the pattern is transferred from the lithographic mask to the photosensitive resist. A
compromise must thus be reached. As a final point, it is important to note that the
chemical reactant etches not only the volume of the exposed part, but also under the
mask. This phenomenon can be elegantly used to form original structures, such as
planes fixed on rounded supports, or to make tips for atomic force microscopy (AFM).

Anisotropic etching of silicon. Anisotropic wet etching of silicon is a very common

technique in the field of MEMS because it allows the formation of flat surfaces, such
as wells or canals with flat walls (but with a trapezoidal cross-section, as we will later
see). Here, the reactants that are used are alkanes at high concentrations (several moles
per litre); unlike isotropic etching that uses acids, the medium in which the object to
be etched is immersed is strongly basic.

7.13: The evolution of the etching

speed with respect to temperature
for different crystallographic orienta-
tions (anisotropic etching). The low-
est velocities seem to correspond to
the densest planes. The contrast be-
tween slow and fast orientations is
one order of magnitude [2].

The principle of anisotropic etching is based on the diagram shown in Fig. 7.13.

The etching rate depends on the crystallographic orientation that the chemical attack
430 An introduction to microfabrication

follows. The velocity of etching is slow along the planes (111) (on the order of 13 µm per
hour), and faster along other orientations. The corresponding ratio of etching velocities
is on the order of 60. The consequence of such a contrast is that the silicon crystal
immersed in base will make the cut-out forms appear spontaneously along the planes
where the etching is the slowest, i.e. along the planes (111). An analogous process
occurs during the phenomenon of faceted growth, where the visible facets are those
associated with the slowest growth velocities, which also happen to be the highest-
density planes. It is this process that causes cubic crystals such as salt to have an
orthorhombic structure (constructed from the planes (111)). Unlike isotropic etching,
the process of anisotropic etching is not completely understood in all its detail today.
There are several concurrent models that describe the various mechanisms in play. The
reader can refer to specialized literature for a description of these models. As for the
state of the surface, anisotropic etching theoretically allows for the production of an
atomically smooth surface formed from terraces. In fact, in the common case of silicon
etching by KOH, the production of hydrogen bubbles introduces local fluctuations
in concentration of the chemical reactants, inducing inhomogeneities in the etching
velocities, and thus leading to more roughness in the surfaces. These perturbations
can be reduced by using moderately elevated temperatures (thus reducing the flux
of bubbles, which raises the temperature), and thorough mixing of the bath. In a
standard well-tuned process, the surfaces have a local roughness on the order of 20
nm.

It is not always simple to guess the shape produced by anisotropic etching. Figure 7.14
illustrates this point.

7.14: Structure (black line) obtained

with anisotropic etching [2].

7.6.3 Dry etching of silicon

Dry etching is the removal of a substrate exposed to ionic species contained in a

gaseous or plasma phase. Depending on the conditions, the shapes obtained can be
anisotropic or isotropic. Here, we will limit ourselves to a very brief presentation of
the methods and principles of dry etching. The interested reader can find a detailed
presentation of the technique in Ref. [2].

We begin by a general classification: Fig. 7.16 represents the four most common types
of dry etching.
 Microfabrication methods for silicon and glass devices 431

Fig. 7.15: Different types of dry etching for silicon (from top to bottom): physical, chemical,
physico-chemical, and physico-chemical with inhibitor [2].

• Physical etching: here, ions are accelerated in an electric field and bombard the
surface of a target (the object to be etched). An etching effect is produced by the
physical action of the flux of incident ions. Physical etching is anisotropic and not
selective.
• Chemical etching: chemical species migrate towards the surface of the target
under the action of an electric field, and chemical reactions occur on the surface,
thus producing volatile species and holes.
• Physico-chemical etching: the two preceding actions are combined. This type
of etching is commonly used.
• Physico-chemical etching with inhibitor: the process consists of depositing
a protective layer along the sides of the etched cavities during the process. This
technique allows to create structures with high aspect ratios (e.g. 1:30).
We describe in this section four important techniques used in microfluidics.

Physical dry etching:. The action of a plasma on a target placed at the cathode
(Fig. 7.16) depends on the kinetic energy of the ions accelerated toward the target. For
kinetic energies less than 10 eV, nothing happens: the ions are not sufficiently energetic
to eject material. For energies between 10 eV and 5000 eV, ejection of material occurs,
resulting in physical etching. For energies between 10 and 20 keV, ions penetrate the
target in depth. This enables ionic implantation, used in semiconductor technology.
Physical dry etching is carried out at low pressures (typically a few mTorr). using
ballistic ions. The simplest configuration (Fig. 7.16) is known as sputtering.

Reactive ion etching (RIE). In reactive ion etching (RIE), the object to be etched is
in contact with reactive components contained in a gas or a plasma. The principle of
this method can be decomposed into six steps:
Chemical etching consists of the following steps.
1. Generation of chemical reagents;
432 An introduction to microfabrication

7.16: Plasma etching of silicon.

2. Diffusion of reactive species towards the target;

3. Adsorption;
4. Reaction with the target and the formation of a volatile component;
5. Desorption of the component; and
6. Diffusion in the gas or plasma.
An example is CF4 . This component does not react with silicon, while CF3 radicals
and F − ions, created by the plasma, do. Several phenomena, not discussed here, are
involved in the chemical etching (charge effect of charge, ‘bullseye’ effect, etc.). For
details, the reader can refer to Ref. [2].

Physico-chemical etching with inhibitor: deep reactive ion etching (DRIE). RIE can
be used with an inhibitor, whose function is to form a polymerized film that protects
the vertical walls from etching.

Fig. 7.17: Two microfabricated structures obtained by DRIE. (Left) Forest of pillars
(Reprinted from [11], with permission from Wiley and Sons. Copyright 2022.). (Right) Spring
attached to a small mass.
 Microfabrication methods for silicon and glass devices 433

The technique is known as deep RIE (DRIE). It allows to make structures with large
aspect ratios (e.g. 30:1). Two spectacular examples are given in Fig. 7.17.

7.6.4 Techniques of deposition onto silicon and glass

Deposition is a process that plays a crucial role in microfabrication. Today, a large

variety of techniques allows to deposit all sorts of materials: metals, insulators, semi-
conductors, polymers, or proteins. We will present here the principles without delving
into the detail. Most vapour deposition techniques fall into two categories:
1. PVD: physical vapour deposition. The object (or target) is exposed to a vapour
containing molecules to be deposited. These molecules adsorb on the substrate
and form a layer.
2. CVD: chemical vapour deposition. Vaporized species, in contact with the target,
react with the surface, forming components chemically bonded to it.

Thermal evaporation. In this case, the material to be deposited faces the target, in
a chamber maintained at a low pressure. Next, the material is heated and sublimated.
The molecular flux created in this way adsorbs on the target surface. The working
pressures are on the order of 10−8 Torr). Due to its simplicity, thermal deposition is
commonly used in laboratories. Speeds of deposition are slow (a few Å per second);
the method is mostly used for metallic deposits.

Sputtering. Here, a cold plasma is created. A cathode is subjected to a ionic flux (for
instance, Ar+ ), which ejects the anodic material. The ejected material then deposits on
the target. In practice, ionic kinetic energies are in the range of 0.3 – 2keV. Sputtering
is interesting because it allows to deposit a large variety of materials with a strong
adhesion.

CVD: chemical vapor deposition. The substrate is exposed to a gas containing reac-
tive species. There are two possibilities:
• the reaction takes place in the gas and the products of the reaction are adsorbed
onto the target;
• the reaction takes place at the surface of the target.
Most CVD equipments are based on heterogeneous reactions, since the adherence of
the film produced is superior to that of the homogeneous case. Figure 7.18 roughly
represents the mechanism in the heterogeneous case.
CVD allows for the deposition of insulators (for masks or electric insulation), and of
polysilicon (for surface micromachining). The deposition rates in all cases are slow
(on the order of µm per hour), and this is a problem for the microfabrication of thick
structures. Because of this slow deposition speed, many polysilicon structures (e.g.
motors, beams) reproduced in the literature are only a few micrometres high.
434 An introduction to microfabrication

Fig. 7.18: Succession of steps involved in CVD: production of species in the plasma, ad-
sorption, surface reaction, diffusion, aggregation, desorption of volatile components, and film
formation.

Here the CVD techniques most commonly used for MEMS and microfluidics are de-
scribed briefly. There are basically three types of techniques:
• LPCVD (Low-pressure chemical vapor deposition): deposition takes place
at low pressure (1 Torr). This is used for polysilicon, a fundamental material for
MEMS. Deposition speeds are in the order of 1µm/hour.
• APCVD (Atmospheric-pressure chemical vapor deposition): in this case,
deposition takes place at atmospheric pressure.
• PECVD (Plasma-enhanced chemical vapor deposition): this technique
deals with systems for which thermal activation is not sufficient to allow hetero-
geneous chemical reactions. A plasma is thus used, whose role is to activate chemical
reactions at the target surface using ionic bombardment.
Evaporating a material on a pre-existing relief does not necessarily lead to uniformly
thick layers. We may have conformal and non-conformal deposition. The two cases are
shown in Fig. (7.19):
• Conformal deposition: the deposited film has a constant thickness. This is achieved,
typically, by working with highly energetic particles.7
• Non–conformal deposition: the film thickness is not uniform. This situation is gen-
erally avoided, although, in some cases, it can be useful for closing submicrometric
channels.

7.6.5 Bonding

Once the etching step is completed, we have grooves carved onto a wafer, and must
now cover them in a watertight manner, in order to create functional microfluidic
devices. Sealing is not an easy procedure. If it is poorly done, leaks obviously appear.

7 These particles reach all parts of the target before forming chemical bonds with the substrate
 Microfabrication methods for silicon and glass devices 435

Fig. 7.19: Conformal and non-conformal deposition. Conformal deposition (left) takes the
form of the substrate, while non-conformal deposition (right) develops forms different from
the substrate (From [2])

To make seals between glass-silicon, glass-glass, or silicon-silicon, fusion techniques are

used, with or without an electric field. We describe these techniques below.

Anodic bonding. Anodic bonding allows for the sealing of glass onto a metal or semi-
metal such as silicon, in the presence of an electric field. The electric field induces
the migration of Na+ ions in the glass to the interface. Trapped at the interface, they
produce an intense local electric field. Sealing is assured by the interpenetration of
atoms at the interface. For glass–silicon, this mix of atoms is made possible by an
elevated temperature (400◦ C) to which the system is raised, and by the intense local
electric field reduced the sodium trapped for the interface.Typical voltages used to
ensure anodic sealing are on the order of 1 kV.

Fusion Bonding. It is possible to seal two pieces of silicon or glass by fusion bonding.
Physically, thermal agitation causes the reorganization of silicon atoms at the interface,
establishing a small amount of interpenetration that ensures bonding. Depending on
the material, temperatures used a range between 600 and 1100◦ C.

7.6.6 Application: fabrication of a silicon membrane

To apply the previous ideas, the steps leading up to achieving a membrane on a silicon
wafer are presented in Fig. 7.20.

The first step consists of depositing a silicon dioxide layer (SiO2 ) on a silicon wafer.
For that, an oven is used. Then, a layer of photosensitive positive resist is spin-coated.
After this comes the photolithographic step, which creates a hole in the resist layer. In
the hole, the SiO2 layer is etched with RIE technique. Further, by using wet etching,
a cavity, with oblique walls, is formed in the wafer, with a detph close to its thickness
In this way, a silicon membrane is created.
436 An introduction to microfabrication

Fig. 7.20: Process of fabrication of a silicon membrane, involving oxydation, spin coating,
photolithography, RIE, and wet etching. For achieving the task, seven steps and one mask
are needed.

7.6.7 Micropump for insulin injection

The insulin pump, made by Debiotech, is shown in Fig. 7.21 [13]. This micropump can
be held on the tip of a finger as shown in Fig. 7.21 (right). The structure includes a
polysilicon membrane, called a ‘pump diaphragm’, a few micrometres thick, made by
deposition. Note that silicon is not piezo-electrical but polysilicon is. This membrane
is actuated by an electrical field provided by a circuit (not shown in the figure).

actuation chamber pump diaphragm

counterelectrode pump chamber
isolation
layer
actuation
unit

valve unit

inlet outlet
A. Richter – Drawing by G. Kovacs (Stanford)

Fig. 7.21: Micropump made by Debiotech [13], which benefited from a large echo in the
1990s.

When the diaphragm raises, fluid is pulled, and when it come back to the rest, it pushes
the same fluids out of the chamber. Pumping is possible with the action of two valves,
which open and close, in function of the movement of the diaphragm, preventing the
captured liquid from flowing out of the chamber when the membrane returns to its
rest position. With this system, flow rates in the range of microlitres per minute are
 PDMS-based moulding – soft lithography 437

obtained. The pump adapts well to the problem of insulin delivery, with its small size,
along with the flow rate. In practice, the pump is placed on the skin, at the liver level,
and actuated with a battery. It is often called ‘skin pump’. The fabrication is delicate,
the most critical part being the valves, and it can be achieved using the technological
tools shown above.

7.6.8 Electron beam lithography - Nanoguitar

A nanoguitar is not exactly a microfluidic object, but it illustrates, in an amazing

manner, the capabilities of MEMS technology, although extended to the nanometric
scale. The silicon guitar shown in Fig. 7.22 was made in 1997, in Cornell Laboratory, by
the group led by Craighead, using technological ideas presented in the chapter. Its size
is ten µm, it includes six chords, as in standard guitars. There sizes are submicrometric.

Fig. 7.22: The world’s smallest guitar is 10 µm long, with six strings each about 50 nm wide
(i.e. 100 atoms). Made by Cornell University researchers from crystalline silicon, it announced,
at that time (in 1997) a new generation of electromechanical devices.

The guitar was made by using electro beam lithography, which uses the same ideas
as photolithography, but with an access to much smaller scales, owing to the use of
electrons (whose wavelengths are in the amstrong range) and not photons (for which
200 – 300 nm wavelengths are typically used, as we saw in the chapter). Difficult to
play the Albidoni concerto with this guitar. Should it be possible, the sound would be
difficult to hear. Considering that the vibration frequency is inversely proportional to
the length, we would need ears able to hear sounds in the MHz range, i.e. ultra-sounds,
while the acoustic range of human ears do not exceed 20 kHz.

7.7 PDMS-based moulding – soft lithography

7.7.1 Historical note

Two papers, published in 1998, represent landmarks in the field. The first one [1] intro-
duced the concept of ’soft lithography’, i.e. microfabrication based on lithography and
soft materials. The second one [15], titled Rapid Prototyping of Microfluidic Systems
438 An introduction to microfabrication

in Poly(dimethylsiloxane)’, made it possible ’ to design and fabricate’ microfluidic

systems in an elastomeric material – poly(dimethylsiloxane) (PDMS)– in less than
24 h’. The work was preceded by two precursor papers reporting the fabrication of
PDMS channels and stamps, with a sensibly different approach [16, 17]. Two figures
of Ref. [15] are shown in Fig. 7.23.

Fig. 7.23: (Left) One of the first PDMS microfluidic devices, made in 1998, and dedicated
to separate nucleotides. [15]. (Right) Electropherogram demonstrating the separation of nu-
cleotides in a PDMS device. (Reprinted from [15], with permission of the American Chemical
Society. Copyright 2022.)

The left–hand part of Fig. 7.23 represents a PDMS device designed to separate ionic
species.8 Widths and heights are on the order of 50 µm. The right-hand figure shows
an electropherogram. Ions are separated in few minutes, with a resolution comparable
that of early silicon devices [18] (see shapter 6). Although chromatography is not
the most important application of PDMS, the work demonstrated that performing
chromatographic studies with this material is possible. At that time, this appeared
quite as a surprise: as PDMS surface chemistry is poorly controlled, the efficiency of
the separation process could have been compromised.

The message taken away by many scientists was not about chromatography. It was that
PDMS technology was an easy-to-use microfabrication method capable of producing
a wide range of interesting devices A master student can learn it in one day. The
simplicity of the technological process gave rise to a surge of creativity. One could
compare it to the transition from centralized informatics to lab–top computers. Many
laboratories, interested in microfluidics, but hindered by the complexity of silicon and
glass technology, or with little access to clean rooms, adopted PDMS technology and
developed new directions that paved the way for outstanding innovations.

8 See Chapter 5
 PDMS-based moulding – soft lithography 439

7.7.2 PDMS Characteristics

Polydimethylsiloxane (PDMS) belongs to a large family of polymers. Low molecular

weight PDMS is a liquid used in lubricants, antifoaming agents, and hydraulic fluids.
At higher molecular weights, PDMS is a soft, compliant rubber or resin. Among the
commercially available forms, Sylgard 184 (Dow Corning) and RTV 615 (GE Bayer
Silicones) are the most widely used.

The formula of PDMS is (–Si(CH3 )2 O)–. The semi-structural fomula is shown in

Fig. 7.24. The siloxane chains are substantially separated by hydrophobic methyl
groups (CH3 ), leading to high flexibility of the material. The same methyl groups
are responsible for the hydrophobicity of the material.

PDMS mixed with a cross-linker, and heated, forms an elastomer whose principal
properties are shown in Table 7.2 (from [14]).

Fig. 7.24: Left: Semi-structural fomula of PDMS; Right: Manipulation of a PDMS cross-
linked material. (Courtesy of uFluidix.).

Most, if not all, properties listed in Table 7.2 are extremely important: optical trans-
parency is obviously critical for imaging, electrical insulation for the establishment of
electric fields, low Young moduli for valving, gas permeability for liquid filling, absence
of reactivity for chemistry and biology. In practice, not all chains are cross-linked. In
the material, free short chains migrate to the surface and accumulate. This process is
responsible for the time-dependency of the surface properties of the material.

PDMS is unique. There have been several attempts to explore other elastomers for
microfluidic applications, with the goal of finding materials that could offer advantages
over PDMS. All failed. For instance, in the case of polyurethane, degassing was difficult,
due to a high surface tension, and demoulding was challenging due to a stronger
440 An introduction to microfabrication

Property Characteristics
Density Around 0.9 kg/m3
Optical Transparency between 300 nm and 2200 nm
Electrical Insulating with breaking field 20 kV/cm
Mechanical Elastomeric with Young’s modulus ∼ 350–800 kPa
Thermal Insulating; thermal conductivity ∼ 0.2 W/m/K
Interfacial Low surface energy (∼ 20 mN/m)
Permeability Permeable to gas, apolar organic solvents, small permeability to water
(pervaporation speeds in the nm/s range)
Reactivity Inert, oxidizable by a plasma
Toxicity Non-toxic
Table 7.2 Cross-linked PDMS properties, using a cross-linker in the 1:10–1:5 concentration
range

adhesion [19]. To these constraints, one must add the difficulty of realizing connections
without leakage.

7.7.3 How to make PDMS channels ?

To create a microchannel, four steps are needed (see Fig. 7.25). To start, we need a
mould made of a hard material which, often, is SU8 or plastics. The mould fabrication
is made in a clean room. When carried out in an ordinary environment, the risk of
failure is high. The next step is to pour a mix of PDMS and cross-linker onto the
mould. Then, the temperature is raised at about 70◦ C. During this phase, PDMS
cross-links, and becomes solid. After peeling off the PDMS, an object representing the
negative of the mould is obtained. This object is placed onto a substrate, often a glass
slide, on which it weakly adheres. Most often, this adhesion is reinforced by exposing
the surfaces to an oxygen plasma.
The precision of the structures obtained this way is surprisingly high. Whitesides et
al. [6] demonstrated a submicrometric precision. In practice, owing to various uncer-
tainties entering the process, the microchannel transverse dimensions lie between 2
and 200µm.

7.7.4 Remarks on PDMS

The properties of PDMS deserve a number of remarks:

• Transparency in the visible spectrum enables flow visualization, which is often
crucial in microfluidic studies. Nonetheless, its opacity to hard UV (below 300 nm)
leads, in some case, to limitations. For instance, it is difficult to cure materials
embedded in PDMS structures.
• The Young’s modulus of reticulated PDMS lies in the range 300–850 kPa. It
increases with the cross–linker concentration, the largest values leading to ‘hard
PDMS’, which is no longer deformable. The deformability of PDMS allows valves
 PDMS-based moulding – soft lithography 441

Fig. 7.25: Fabrication of a PDMS microchannel.

to be made, as will be shown later. Under pressure, microchannels deform, and,

consequently, their hydrodynamic resistance decreases. An example is shown in
Fig. 7.26 [23].

7.26: Flow rate (Q) evolution in a

channel (227 µm wide, 24.2 µm high,
2.8 cm long),as a function of pres-
sure ∆P . The straight line is the for-
mula ∆P = 12µL
h3 w
Q in which µ is the
viscosity, and L, h, and w are the
channel length, height, and width
[20] (Courtesy of J. Goulpeau.)

In the experiment of Ref. [20], at 1 bar, the channel cross-section increases by

30% and the resistance by 100%. Consequently, the flow rate increases by a factor
of two.

An important phenomenon, which is the opposite of the previous one, is the ‘roof
collapse’, i.e. the fact that the roof of a microchannel can collapse and stick to
the floor, obstructing the channel. A criterion, calculated by Huang et al [21], for
the case of shallow channels, reads:
wγ
> 0.13
Eh2
in which w is the width, h is the height, E is the Young modulus, and γ is the
442 An introduction to microfabrication

surface tension. In practice, it is wise to restrict ourselves to aspect ratios w/h

below 10.
• The elastomeric character of PDMS enables the watertightness of microfluidic
connections, which is crucial. The elasticity of the material also allows the fabri-
cation of valves and pumps using membranes, as noted above.
• Untreated (native) PDMS is hydrophobic, and becomes hydrophilic (temporar-
ily) after the oxidation of the surface by oxygen plasma or after immersion in a
strong base. The plasma breaks Si–CH3 bonds, and replaces the methyl groups
by hydroxyl groups, which, immersed in water, builds up hydrogen bonds. With
this mechanism, the surface, initially hydrophobic, becomes hydrophilic. On the
other hand, the formation of reactive silane groups at the surface allows covalent
bonding of the PDMS with the silanol groups of other oxidated surfaces. PDMS
surfaces can thus strongly bond to different materials, such as glass, silicon, or
plastics. Being able to seal PDMS onto substrates represents an extremely impor-
tant feature, which is instrumental for the creation of functional devices.
• Its permeability to gas facilitates filling in open and blind channels.9 PDMS per-
meability is also interesting for cell culturing. On the other hand, its solubility to
non-polar organic solvents makes PDMS unsuitable for many chemistry applica-
tions.
• Its weak surface energy facilitates the process of peeling off the mold from the
substrate. This property plays a key role in the technology.
• The properties of PDMS evolve with respect to time, owing to the diffusion of
small free chains in the materials, migrating to the surface. Typically, an oxi-
dized surface remains hydrophilic for thirty minutes, and then evolves towards
hydrophobicity. In general, because of the difficulty of controlling surface chem-
istry, patterning PDMS surfaces remains challenging. Efforts conducted during
the past decade in this area have turned out, despite a number of temporary
successes, to be unconvincing.
• It is not possible to deposit metallic electrodes on PDMS because of poor ad-
herence and the elevated temperatures involved in the process. PDMS structures
can nevertheless be placed on a glass or silicon wafer, on which electrodes were
deposited.

7.7.5 Flow lithography

Flow lithography is one of the many applications of soft lithography. The principle is
shown in Fig. 7.27 (A), and the presentation of the technology is taken directly from
Ref. [30]. A stream of a photosensitive initiator is passed through the rectangular,
PDMS microfluidic device shown in the figure. Particle arrays of mask-defined shapes
are formed by exposing the flowing oligomer to controlled pulses of ultraviolet (UV)

9 Air bubbles trapped during filling escape by migrating through PDMS, which is porous to gas.
 PDMS-based moulding – soft lithography 443

light. Rapid polymerization kinetics permits the particles to form quickly (∼ 0.1 s),
and oxygen-aided inhibition near the PDMS surfaces allowed for particle flow without
wall attachment and clogging (oxygen, which diffuses through the PDMS surfaces
leaves a non-polymerized lubricating layer near the PDMS walls).

An extension of the technique was made in [31], leading the production of multifunc-
tional particles bearing more than a million unique codes (see Fig. 7.27 (B)).

(a) (b)

Fig. 7.27: A - Schematic depicting the experimental setup used in flow lithography [30]
(Caption taken from the reference). A mask containing the desired features is inserted in the
field-stop plane of the microscope. The monomer stream flows through the all-PDMS device in
the direction of the horizontal arrow. Particles are polymerized, by a mask-defined UV light
beam emanating from the objective, and then advect within the unpolymerized monomer
stream. The side-view of the polymerized particles can be seen in the inset shown on the
right (Reprinted from Ref. [30] with permission from Springer Nature. Copyright 2022). B
Typical image of multifunctional particles made with the technology. The scale bar is 100 µm
(Reprinted from Ref. [31] with permission of the American Association for the Advancement
of Science. Copyright 2022.)

7.7.6 Microcontact printing

This technology represents another application of soft photolithography. The principle

is represented in Fig. 7.28 (Left).

We start with a PDMS stamp. The stamp is the negative of a mould made in hard
material, as we explained in this chapter. Inking of the stamp is performed by im-
mersion. The PDMS stamp absorbs the ink. After drying out, the stamp is brought
into contact with a hydrophilic substrate, and immersed in a buffer. The molecules
captured by the stamp migrate towards the substrate, and form a hydrophobic self-
assembling monolayer (SAM). This technology allows surfaces to be patterned with
all sorts of molecules. An example is shown in Fig. 7.28 (Right). The figure shows a
L pattern of fibronectin, deposited onto a glass surface. The system is immersed in a
suspension of Hela cells, whose membranes bind to fibronectin [32]. This experiment
allowed to visualize the behaviour of these cells in the presence of constraints imposed
by the patterning. The work enlightened the question of the influence of the extra-
cellular matrix on the cell structure, in various situations, e.g. during cell division.
444 An introduction to microfabrication

Fig. 7.28: (Left) Principle of microcontact printing technology. From top to bottom, inking,
drying, contact, and separation; (Right) Hela cell deformed by a fibronectin patch in form
of a L, created by contact photolitography. (Reprinted from Ref. [32], with permission from
Springer Nature; Copyright 2022.)

Microcontact printing is used industrially, to carry out high content screening (HCS)
of pharmaceutical drugs.

7.7.7 PDMS valving and pumping

As mentioned above, the elasticity of PDMS makes possible the creation of microvalves.
The idea developed by S. Quake [22] is shown in Fig. 7.29.

(a) Actuation channel at ambient pressure (b) Actuation channel under pressure

Working channel open Working channel closed

Fig. 7.29: Principle of functioning of PDMS valves, often called ‘Quake’s valves’, shown in
the case of a ‘push-down’ valve (see below). (A) Actuation channel at ambient pressure: the
working channel (below) is open.(B) Actuation channel pressurized: the working channel is
closed. Owing to the round shape of the working channel, leakage is extremely weak.

The figure can be misleading because the two channels shown on the figure are normal
with respect to each other, not parallel. Nonetheless, we will use it for explaining how
valves work. The valve of Fig. 7.29 is thus composed of two layers, one above the other.
This superposition of layers refers to ‘multilayer soft lithography’. In the upper layer, a
microchannel, called ‘actuation channel’, is filled with a liquid called ‘actuation fluid’.
Below it, there is a second channel, called ‘working channel’, through which the working
fluid flows. In between, the separating wall is thin enough to be deformed under a
 PDMS-based moulding – soft lithography 445

fraction of bar. This thin wall forms a membrane of typically 5-10 µm in thickness.
Thus, as the actuation channel is pressurized, it deflects the membrane and obstructs
the working channel. Owing to the round shape of the working channel, the valve is
tightly sealed.10 In early versions, air was used to pressurize the actuation channel.
However, due to PDMS permeability, bubbles formed. This option was abandoned,
and, even though some presentations still mention that gas is the actuation fluid,
gases are no longer used. Two types of valves exist (see Fig. 7.30):

Fig. 7.30: (A) Push-up valve. (B) Push-down valve.

One is push-up and the other push-down; in the former, pressure is applied on the
lower channel, to push the membrane up, while in the latter, pressure is applied on
the upper channel. The characteristics of the valves have been analysed in several
papers [23, 24, 26]. In an optimized design, the dead-volume is indistinguishable from
noise.Valves sustain pressures up to several bars. Dynamically, Quake’s valves behave
as low pass band filters, with a characteristic frequency on the order of 100 Hz.11 This
frequency, which decreases as the system size increases, is large enough for biological
applications. The pressures needed for closing the valve are on the order of a fraction
of bar. Attempts to miniaturize the valves have been made12 . Thus far, valves smaller
than 6 x 6 µm2 have not yet been reported [26].

The push-down valve was modeled by J. Goulpeau et al. [23]. This led to the circuit
shown in Fig. 7.31.

7.31: Electrical circuit pro-

posed in [23] for modelling
PDMS valves. C is the capac-
itance characterizing membrane
deformability, r a resistance de-
pending on the valve state (open
or closed), and R is the resis-
tance of the external circuit.

10 The round shape is obtained by using a positive photo-resist, for instance, AZ100, which, when
heated in a certain range of temperatures, rounds off.
11 There is another characteristic frequency, much higher, linked to the channel deformability, which
we do not discuss here [23].
12 In this approach, a Moore’s law has been suggested [25, 26]
446 An introduction to microfabrication

The capacity expresses the deformability of the membrane, as discussed in Chapter 4.

The resistance R is the circuit resistance and r, the valve resistance, depends on the
actuation pressure Pa . Its expression is:
r0
r=
1 − ((Pa − Pm )/Pc )3

in which Pa is the actuation pressure, Pm is the pressure in the channel, Pc is the

closure pressure, i.e. the pressure at which the valve is closed, and r0 is the value
of r when Pa = Pm , i.e. when the membrane is flat. The exponent 3 in the formula
is obtained by using the Reynolds model for a piston approaching a surface, in the
framework of lubrication approximation. When Pa − Pm = Pc , r is infinite, and the
valve is closed. The theory agrees well with the experiment [23].

With at least two valves actuated in a periodic manner, one realizes a peristaltic pump.
A three-valves pump is shown in Fig. 7.32.

7.32: By actuating three valves

sequentially, a net flow along
the working channel can be ob-
tained.

These peristaltic pumps provide flows on the order of one µL/min, and sustain counter-
pressures on the order of one bar or so. The maximum flow rate obtained in Ref. [23]
is:
Pc
Qmax ≈ 0.4
R
This maximum was found close to 7.5 µL/min, for a 44 µm micropump. These figures
represent well the highest performances one can obtain with these pumps. Technology–
wise, these miniaturized pumps represent a leap, in term of simplicity and cost, com-
pared to hard material pumps.

Thus, due to the simplicity of the design, their small sizes, and their natural integrabil-
ity, thousands of valves, along with many pumps, can be integrated on a device. This
opened a route towards the implementation of complex functions on microfluidic de-
vices, suggesting an equivalence between MOS–FETs and valves, i.e. microelectronics
and microfluidics. The concept has represented a conceptual jump of the field, giving
rise to an important number of innovations.

Illustration 1: Controlling droplet formation with PDMS valves

 PDMS-based moulding – soft lithography 447

Fig. 7.33: (A) Top view of the experiment of Ref. [27]. Tetradecane (black) and water with
fluorescein (white) meet in the T–junction, emitting droplets.(B) Sketch of the actuation
system; (1) working channel; (2) actuation channel; (3) PDMS; (4) glass substrate.(C) Fourier
power spectrum for a T–junction producing droplets without modulation, i.e. with the valve
permanently open.

An experiment [27] performed in 2006 showed that PDMS valves can control droplet
emitters. In Fig. 7.33 (A) and (B), a push-up valve has been inserted in the entry
channel of a T–junction, in which oil (black) and water (white) are introduced, for
the purpose of producing water-in-oil droplets. The valve is periodically opened and
closed, thus modulating the flow rate of the dispersed phase. Droplet production is a
nonlinear process characterized by an internal frequency shown in Fig. 7.33 (C). The
coupling between this frequency and the modulation frequency of the valve give rise to
complex behaviour. In the experiment, Arnold tongues were observed. In practice, by
working in resonant tongues, i.e. in conditions where the internal frequency resonates
with the modulation frequency, the emission frequency and the droplet size can be
finely tuned.
Illustration 2: Automatized nanoliter DNA purification
Figure 7.34 shows a biological application of PDMS valve technology [28].
The sample is introduced and mixed with reagents in the ring micromixer. After mixing
is completed (a few seconds), the mixture is brought in contact with functionalized
beads, which capture DNA. After rinsing, and elution, purified DNA is retrieved. The
entire process is carried out automatically.
Illustration 3: Large scale integration
An influential contribution [29], appealing from a conceptual viewpoint, is shown in
Figure 7.35.
The device contains 2056 microvalves. Two different reagents can be separately loaded,
mixed pairwise, and selectively recovered, making it possible to perform distinct assays
in 256 subnanolitre reaction chambers and then recover a reagent. The microchannel
layout consists of four central columns in the flow layer consisting of 64 chambers per
column, with each chamber containing 750 pL of liquid after compartmentalization
448 An introduction to microfabrication

Fig. 7.34: Cell isolation, cell lysis, DNA purification, and recovery, are carried out on the mi-
crofluidic chip in nanolitre volumes without any pre– or postsample treatment. Measurable
amounts of DNA are extracted in an automated fashion from as little as a single mam-
malian cell and recovered from the chip. The right-hand figure is an image of the device,
using coloured fluids for visualization, in a mutliplexed version (three systems in parallel).
(Reprinted from Ref. [28], with permission from Springer Nature. Copyright 2022.)

7.35: The device, whose channels are

visualized with dyes, contains 2056 mi-
crovalves. The system performs distinct
assays in 256 nl subreaction chambers.
(Reprinted from [29], with permission
from the American Association for Ad-
vancement of Science. Copyright 2022.)

and mixing. Liquid is loaded into these columns through two separate inputs under
low external pressure (20 kPa), filling up the array in a serpentine fashion. Barrier
valves on the control layer function to isolate the sample fluids from each other and
from channel networks on the flow layer used to recover the contents of each individual
chamber. These networks function under the control of a multiplexor and several other
control valves. Each of the 256 chambers on the chip can be individually addressed
and its respective contents recovered for future analysis using only 18 connections to
the outside world.
 Computer Numerical Control (CNC) Micromilling 449

Fig. 7.36: CNC (Computer Numerical Control) micromilling. On the left, a drawing showing
the principle of the technology, and, on the right, an example of a microchannel made with
it (Reprinted from Ref. [36], with permission from Royal Society of Chemistry. Copyright
2022).

7.8 Computer Numerical Control (CNC) Micromilling

Computer numerical control (CNC) micromilling is an extension of milling (see Fig.

7.36). 13 The technique creates microscale features via cutting tools removing the
material. It is mostly used for creating micro and millichannels in plastic materi-
als (COC, PMMA,...). Endmills – the most common cutting tool for milling – are
available in many profiles, in a variety of materials (titanium nitride, titanium carbo-
nitride,titanium aluminium-nitride), and with different coatings [36]. The diameter of
the cutting tool can be as small as 25 µm. An example of a device is shown in Fig.
7.36. A trained machinist can realize the device in thirty minutes. There exist limita-
tions. With micromilling, it is difficult to create a microchannel smaller than 100 µm
width. The surface roughness is quite large (on the order of five hundred nanometres
- in practice, tool traces are visible on the surfaces -). Still, micromilling is extremely
useful. It complements well the techniques based on photolithography, described in
the chapter. Today, micromilling is widespread in microfluidic platforms.

7.9 3D Printing or Additive Manufacturing (AM)

Over the last two decades, three dimensional printing (also called Additive Manufac-
turing (AM)), has undergone significant growth and diversification in terms of applica-
tions, materials, and capabilities.This gave rise to a multitude of acronyms, sometimes
puzzling the reader. The presentation given here is extremely brief, and we refer the
reader to Refs. [39, 40] for detailed information.
Digital light processing stereolithography (DLP-SLA)

13 Milling was invented in 1818 [37]

450 An introduction to microfabrication

DLP-SLA (Digital Light Processing Stereolithography) technique is illustrated in Fig.

7.37. A 365 nm light is projected onto a build platform, i.e. a flat surface that can
move in multiple directions as commanded by the printer’s software. Following each
exposure, the build platform is raised then lowered back into the resin bath for the
next 50 µm layer [40].

Fig. 7.37: DLP-SLA method, in which 365 nm light was projected onto a build platform, i.e.
a flat surface that can move in multiple directions as commanded by the printer’s software.
Following each exposure, the build platform is raised then lowered back into the resin bath for
the next 50 µm layer (Reprinted from Ref. [40] with permission from the American Chemical
Society. Copyright 2022.)

Fig. 7.38: Polyjet method, where two sets of four-micronozzle arrays (build and support
material, respectively) are spraying microdroplets of polymer to form the device. Following
each pass, UV lamps polymerize the material before the layer is leveled by a roller and scraper
(Reprinted from Ref. [40] with permission from the American Chemical Society. Copyright
2022.)

Polyjet (photopolymer inkjet printing)

As sketched in Fig. 7.38, polyjet printing consists in jetting a photopolymer through an

array of nozzles, which spray microdroplets onto the build surface, where the material
is polymerized using an integrated UV light source.

FFF (Fused filament fabrication) or FDM (fused deposition moulding)

FFF (Fused filament fabrication) or FDM (fused deposition moulding) printing con-
sists in extruding thermal plastic through a heated nozzle, controlled by two precision
 Paper microfluidics 451

stepper motors (see Fig. 7.39).

Fig. 7.39: FDM method, in which molten plastic is extruded through a heated nozzle. The
features are formed by moving the nozzle in the XY-plane until the current layer is complete,
before moving to the next layer. (Reprinted from Ref. [40] with permission from the American
Chemical Society. Copyright 2022.)

7.10 Paper microfluidics

7.10.1 Background

Paper microfluidics appeared in the years 2005–2007 [33]. The idea was to replace the
standard microfluidic materials (glass, silicon, plastics, or PDMS) by paper. Paper is
much cheaper (its cost is a few hundredths of a cent per sheet), is more availalbe, and is
burnable (reducing risks of contamination). This material is thus particularly suitable
for diagnostic applications in developing countries. Paper has been used for decades
for diagnostics, but the novelty brought by G. Whitesides’ group was patterning. By
using a wax printer [34], it is possible to design channels along which liquids flow in a
way similar to microfluidic devices. With this possibility, paper microfluidics appeared
as a new branch of microfluidic technology, holding several of its promises, while using
a cheaper and more available substrate. Figure 7.40 shows the patterning technique
allowing to create a paper microfluidic device.

What about chemistry ? The cellulose fibers, which form the paper, are supramolecular
assemblies of polymer chains of glucose [42]. These chains include hydroxyl groups,
which are potentially reactive. Although, in many cases, this reactivity does not hinder
the functioning of the paper devices, it must be discussed when paper used is as a
chemical or biological assay.

7.10.2 Paper microfluidics functionalities

Paper naturally integrates several functionalities [42]:

452 An introduction to microfabrication

Fig. 7.40: Paper technology using wax printing. The tree is wax–printed. The paper sheet
is heated, so as to melt the wax. By melting, the wax diffuses across the sheet and form
a physical hydrophobic barrier. Fluorescein is then injected at the bottom of the tree. It
spontaneously fills the trunk, the branch and the leaves. (From L. Magro, MMN Lab, IPGG
(2015).)

1. Solute transport without pump: as we saw in Chapter 4, Washburn law ap-

plies in paper [41], i.e. the flow speed decreases as the inverse of the square root of
time. No pump is required. The work is done by capillarity. Note that this is not
specific to paper: in microchannels, spontaneous filling is also achieved, thanks to
the action of capillarity (see Chapter 4).

2. Filtration: pores are between 5 and 50 µm in size, and therefore they can block
objects bigger than these dimensions.

3. Storage: paper can store dried or freeze-dried entities, like blood in dried blood
spots (DBS).

4. Valving: . valving can be achieved by folding and unfolding the paper sheet. An
example is shown in Fig. 7.41 [43].

5 Multiplexing: in multiplexed assays, several diseases can be diagnosed at the same

time, on the same device. An example, using a model of urine, illustrates this point
(see Fig. 7.42).

6. Sample to answer devices: with paper technology, is it possible to create fully

integrated systems, often called ’sample to answer’ devices ? The first example,
proposed to commercialization, was realized by Diag4All. It was called ‘paper
machine’ [44]. Recently, several fully integrated devices were proposed [43], some
of them motivated by the COVID pandemy [43,45]. Fig. 7.43 shows an integrated
device, called ‘Covidisc’, which performs nucleic acid extraction, followed by loop
 Other technologies 453

Fig. 7.41: Paper-folding steps for fluidic manipulation. Schematics of how the paper strip in
the microfluidic device is folded for each step. The arrows indicate the direction of folding.
(A) The layout of the multiplex paper device. (B) The magnetic beads and the DNA in the
sample are mixed and added to the sample zone. (C) The second (sample zone) and third
panels are then folded to come into contact with each other, forming a distributing channel for
DNA elution. (D). The distributing channel is then folded onto the remaining square, which
is then placed against the plastic device to cover the three LAMP chambers [43] (Creative
Commons License 4.0.)

7.42: Multiplexed analysis of a

model sample of urine (glucose solu-
tion) [34]. The white is the paper, the
brown is the wax, defining channels.
Two colorimetric detections are per-
formed in duplicate (reprinted from
Ref. [34] with permission of American
Chemical Society. Copyright 2022).

amplification (LAMP), with all reagents freeze–dried on it. The system showed
performances, in terms of sensitivity and specificity, equivalent to PCR [45].

7.11 Other technologies

7.11.1 Casting

The principle of casting is illustrated in Fig. 7.44 [47].

It includes three steps: heating, embossing, and de–moulding. The most commonly
used material for this technology is polymethylmethacrylate (PMMA). When raised
to a temperature on the order of 170 ◦ C and pressurized at several tens of bars, it
become deformable. In this way, it is possible to create structures by using a press
and a mould, as indicated in Fig. 7.44. In general, the mould is made of silicon or
metal. The materials used in this technology are not limited to PMMA. They include
454 An introduction to microfabrication

Fig. 7.43: Description (A) and photograph (B) of the COVIDISC. The device, based on
paper microfluidics, performs a molecular detection of pathogens, i.e. a detection based on
their nucleic acids. It includes an extraction membrane, and a section enabling LAMP am-
plification. To pass from the extraction to the amplification zone, the upper disk is rotated.
Clinical test carried out on 99 COVID samples, with charges distributed in a broad range
(from a fraction to hundreds of copies per millilitre), has led to 97 % sensitivity and a 100 %
specificity [45, 46].

7.44: Casting technology. The process con-

sists in heating, embossing, and demoulding.

plastics such as PC, PI, PE, PET, PVC, or PEEK. The absolute precision of casting
is impressive: it is on the order of tens of nanometres [47].

7.11.2 Microinjection

7.45: Plastic moulding injection technology.

A plastic material is injected at high temper-
atures in a mould It is further cooled down
to solidify the object
 Other technologies 455

Microinjection is a technique issued from plasturgy. It is shown schematically in

Fig. 7.45.

The method can be broken down into three phases:

• The liquid plastic material is injected into a mold under a vacuum and pressure,
at a temperature above the glass transition temperature Tg of the plastic.

• The system is cooled down below the glass transition temperature.

• After taking off the mould, a structure is obtained.

The moulds are delicate to make and expensive but, once they are realized, they can
give rise to considerable throughputs (milions of device per year are currently made).
The technique is interesting for the production of microfluidic devices at low cost.

7.11.3 Laser ablation

Here, plastic is sublimated by the application of an intense laser beam. Examples are
shown in Fig. 7.46.

7.46: Micro-trenches made by

laser ablation.

UV and femtosecond lasers are used for this technique. The micromachining precision
is mediocre (a few micrometres), and the roughness of the surfaces is on the order of
200 to 500 nm. The technique is extremely useful for digging small holes in glass, so
as to inject fluids in microfluidic devices.

7.11.4 Sticker technology

A technology, called ‘sticker’, exploiting the permeability of PDMS to control cross-

linking, was developed in 2008 [38]. The process is shown in Fig. 7.47.

A PDMS mould is applied on a photopolymerisable acrylate droplet. After UV illu-

mination, the droplet is cross-linked, but not entirely (see Fig. 7.47 (A)). As oxygen
diffuses through the mould, cross-linking is inhibited close to the walls, which enables
demoulding. The residual liquid layer allows to seal the system to a glass substrate
(see Fig. 7.47 (B)). Owing the large Young modulus of the cross-linked material, the
device can sustain high pressures. One limitation is the reactivity of acrylates, which
may raise biocompatibility issues.
456 An introduction to microfabrication

A μPS
1

7.47: (A) Structuration of a mi- 2

crofluidic device: a PDMS mould is
placed on an photocuring droplet. Af-
ter cross-linking, the structure is re- uv
moved from the mould. (B) Sealing uv
3
of the structure onto a glass slide, us-
ing the residual liquid layer to achieve
bonding [38].

7.11.5 Actuators based on responsive hydrogels

In the vast family of polymers, some are responsive to stimuli, such as temperature, pH
or light. This is the case of PNIPAM (Poly(N-isopropylacrylamide)).14 When cross-
linked with an acrylamide, it forms an hydrogel, which is hydrophilic below a temper-
ature called ‘low solubility critical temperature’ (LCST) and hydrophobic above. For
PNIPAM, the transition temperature is 32◦ C. Why is it so? This is explained in Fig.
7.48 (taken from [48]).
(a) CH2 (b) PNIPAM

CH > 32ºC
n
H2O
C

Amine group O NH
< 32ºC
(hydrophilic)

CH
Hydrophilic Hydrophobic
CH3 CH3
isoprophyl group
(hydrophobic)

Fig. 7.48: (A) Developed formula of PNIPAM, showing the amine group (hydrophilic) and the
isopropyl group (hydrophobic). (B) At low temperature (i.e. below 32 ◦ ), energy prevails, and
the molecule adopts a linear structure, to expose the hydrophilic group to water and decrease
energy. This is the swollen state. At larger temperature, entropy prevails and the molecule
collapses to protect the amine group from water. Only hydophobic groups are exposed, and,
consequently, the molecule becomes hydrophobic.

At low temperature (i.e. below 32◦ C), energy prevails, and the molecule adopts a lin-
ear structure to expose the hydrophilic group to water and, consequently, decrease the
energy of the system.This is the swelling state, in which the molecule is hydrophilic.
At larger temperature, entropy prevails and the molecule forms a compact structure to
protect the amine group from water. This is the collapsed state. As only hydrophobic
groups are exposed, the molecule is hydrophobic. Exploiting this property, the com-
munity has elaborated microfluidic actuators. The first demonstration was made in
2000 [49] (see Fig. 7.49).

14 The molecule is quite recent: it was synthesized in 1968.

 Other technologies 457

Fig. 7.49: First hydrogel microvalves, based on in-situ photocuring of PNIPAm around pillars
(Reprinted from [49] with permission of Springer Nature. Copyright 2022).

Here the excitation which provokes the swelling and the collapse of the hydrogel is
not the temperature, but the pH. In Fig. 7.49, the polymer is cross-linked around
three pillars, forming annular layers, which swell or collapse, thus close and open
the channel, depending on the pH of the solution. The technology had a number of
limitations, concerning the control, the presence of cross-linked residues in the channel,
and the slow response time, so that it did not spread out in the community. Over the
years, progress has been made [50]. Recently, a breakthrough was made [12, 51]. Fig.
7.50 shows a system of 25 cages, that can open and close, in less than one second,
under excellent control.

Fig. 7.50: Sequence of fluid manipulations for a system of 25 hydrogel cages, 200 x 200 µm
in size with 10 µm thick walls, in a microfluidic chamber. (i) the system is initially filled with
a fluorescein solution at 50◦ C, i.e. with the cages open; (ii) then, temperature is decreased
to 25◦ C. The hydrogel swells and the cages close. (iii) the system is further rinsed with DI
water, leaving fluorescein captured in the cages [12].

The device of Fig. 7.50 is initially filled with a fluorescein solution at 50◦ C, i.e. with
the cages open. Then, temperature is decreased to 25◦ C. The hydrogel swells and the
458 An introduction to microfabrication

cages close. Finally, the system is rinsed with DI water, leaving fluorescein captured
in the cages [12]. The technology allows to trap cells, analyse and process them.
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Index

Π theorem, 73 Capillarity, 37
µTAS, 11 Capillary collapse, 173
ζ potential, 361 Capillary length, 57, 179
3D printing, 19, 449 Capillary number, 202
Capillary pumping, 173
Actin, 52 Carbon Nanotube (CNT), 24
Actuator, 37 Cassie–Baxter model, 196
Adsorption, 308 Casting, 453
Advancing droplet, 198 Cell membrane, 52
Advection-diffusion equation, 253, 254 Centrifugal microfluidics, 152
Airbag, 6 Chaos, 269
Amphiphilic, 182 Chaotic mixing, 269
Amplification, 37 Chemical etching, 431
Anomalous diffusion, 247 Chemical vapor deposition(CVD), 433
Ant, viii Chemisorption, 309
APCVD, 434 Chromatography, 312
Aquaporin, 5 Adsorption, 314
Artificial Intelligence, 38 Exclusion, 314
Atomic Force Microscopy (AFM), 62 Partition, 314
Atto, 48 Affinity, 314
High Performance Liquid Chromatography
Bacteria, 52 (HPLC), 315
Baker’s transform, 272 Ion exchange , 314
Beam, 89 Clean room, 418
Bernoulli theorem, 151 Clogging, 303
Biot number, 327 CMC(Critical Micellar Concentration, 186
Bird drinking water, 174 CNT forest, 137
Bird in winter, 335 Co–flow regime, 217
Bjerrum length, 361 Coil (electric), 91
Blood, 3 Colloidal aggregation, 369
Boltzmann equations, 103 Conducting sphere, 387
Bonding, 434 Conducting systems, 356
Fusion, 435 Conformal deposition, 434
Anodic, 435 Continuous Flow Lithography, 19
Boolean algebra, 232 Continuum hypothesis, 105
Boundary conditions, 103 Contour length, 50
Boundary layer, 150 Convection-Diffusion heat equation, 324
Braciosaurus, 82 Correlation length, 56, 105
Bretherton film, 205 CPU, 37
Brownian motion, 245 Cytoskeleton, 52
Bubble and droplet dissolution, 292
Bubble production, 215 Dean vortices, 154
Butterfly effect (chaos), 272 Debye layer, 70, 362
Butterfly effect (in T-junctions), 262 Around a sphere, 368
Debye length, 70, 363, 365
C Elegans, 54 Deep reactive ion etching (DRIE), 432
Cantilever beam, 93 Deposition, 66
Capacitance, 141 Deposition techniques, 433
Capacitor, 88 Detergence, 193
 Index 463

Dewetting, 200 Flory exponent, 50

Diagnostics, 26 Flow around cylinders, 134
Dielectric, 69 Flow equations, 103
Constant, 352 Flow focusing, 220
Material, 352 Flow lithography, 442
Sphere, 354 Fluid particle, 103
Dielectric breakdown, 87 Fluids flowing side-by-side, 139
Dielectrick Fusion Bonding, 435
Permittivity, 354 Future, 30
Dielectrophoresis (DEP), 400
Diffuse layer, 362 Gas, 103
Diffusion, 245 Gas chromatography, 316
Diffusion coefficient, 246 Gas flow regime, 118
Digital droplet technology (DMF), 409 Gauss theorem, 350
Digital microfluidics (DMF), 409 Generalized pressure, 166
Dip coating technology, 207 Gouy Chapman model, 360
Dipole, 351 Grace curve, 203
Direct writing, 424
Dispersion Hamaker, 63
in plug flows, 263 Hamaker constant, 62
in straining fields, 265 Happy molecule, 69
Dispersion in shear flows, 264 Hard sphere, 59
Distributor of solutes, 145 Heat diffusion equation, 320
Double emulsions, 237 Heat transfer, 329
Dripping regime, 217 Heat transfer coefficient, 324
Droplet break–up, 203, 232 Hele-Shaw cell, 133
Droplet coalescence, 234 Henry function, 386
Droplet production, 215 Hindered diffusion, 299
Droplet toolbox, 238 HLB (Hidrophilic Lipophilic Balance, 183
Dry etching, 430 Horshoe transform, 272
Drying, 336 Hydrodynamic flow focusing, 143
Dynamical surface tension, 176 Hydrogel, 20, 456
Dynamical system, 269 Hydrogel caging, 20
Hydrogen ions, 69
Electrical double layer, 359 Hydrophobic, 121
electro-osmosis, 372 Hyperbolic point, 269
Electrokinetic equations, 356 Hysteresis of the contact angle, 197
Electrokinetic Separation
Incompressibility approximation, 106
Capillary Electrochromatography(CEC),
Inkjet printing, 27
398
Instantaneity, 114
Free Solution Capillary Electrophoresis,
Instrinsic slip, 121
393
Intensification, 21
Micellar Electrokinetic
Isotropic and anisotropic wet etching, 427
Chromatography(MEKC), 398
Electrokinetics, 350 Jetting regime, 217
Electrolyte, 69 Joule heating, 323
Electromagnetic systems, 91 Jurin’s law, 180
Electron beam lithography, 437
Electronic paper, 391 Keesom interaction, 60
Electrophoresis, 381 Kleiber’s law, 78
Electrostatics, 350 Knudsen number, 118, 119
Electrowetting, 406 Kuhn length, 51
Electrowetting On Dielectrics (EWOD), 18,
407 Lab on a Chip, 350
Elementary charge, 70 Landau Squire jet, 138
Endoplasmic reticulum, 52 Landau–Levich film, 205
Epstein-Plesset theory, 292 Langmuir isotherm, 310
Eukariotic, 52 Laplace’s law, 169
Evaporation, 336 Lennard Jones, 68
Lennard Jones potential, 59
Fick law, 253 Lens (based on Electro Wetting), 411
464 Index

Levy’s walk, 247 Nanochannel, 24

Lifespan of small animals, 80 Nanohole, 25
Lifschitz theory, 63 Nanojet, 211
Linearity, 114 Navier boundary condition, 116
Lipid Nano Particle (LNP), 288 Navier length, 116
Liquid liquid extraction, 291 Navier-Stokes equations, 105
Liquid–vapour interface, 162 NGS (Next Generation Sequencing), 19, 37,
LNP (Lipid Nano Particle), 37 400
London interaction, 60 NOA technology, 20
Lorenz system, 271 Non–conformal deposition, 434
LPCVD, 434 Normal diffusion, 247
Lung, 4 Nucleation length, 56
Number of theoretical plates, 315
Macromolecule, 49 Nusselt number, 327
Magnetic field, 92
Mammal, 85 Obstructing droplet, 225
Mammoth, 82 Organ on a Chip, 20
Marangoni, 37 Organ on a chip (OOC), 37
Marangoni flow, 186
Market, 26 Paper microfluidics, 19, 451
Masks (for photolithography), 420 Paper microfluiidics, 213
Maxwell Equations, 350 Particle and microfluidics, 299
Maxwell stress, 408 Particle deposition, 300
Mean Free Path, 54 Particle sorting, 305
Mean free path, 105 Partition coefficient, 290
Membrane, 24 Pattened surfaces, 135
MEMS, 1, 6, 8, 27 Patterned surface, 200
Meniscus, 179 PDMS, 15
Micelle, 184 PDMS (PolyDiMethylSiloxane, 437
Micro Reaction Technology (MRT), 156 PDMS valve, 444
Micro-pump, 151 Peclet number, 256
Microactuator, 89 PECVD, 434
Microbeam (vibrating), 93 Photolithography, 419
Microcontact printing, 443 Photoresist, 420
Microexchanger, 340 Physisorption, 309
Microfabrication, 415 Pinning, 196
Microfluid, 1 Plasma etching, 431
Microguitar, viii, 437 Platelet, 4
Microhydrodynamics, 1, 113 Poı̈kilotherms, 85
Microinjection, 454 Poincaré-Bendixson theorem, 273
Micromilling, 449 Point of Care (POC), 26
Micromixer, 279 Polar molecule, 60
Micromotor, 90 Polar molecules, 60
Micropump, 436 Polarization, 351
MicroReaction Technology(MRT), 21 Polymerase Chain Reaction (PCR), 332
Microreactor, 22 Positive resist, 422
Microtechnology, 415 Prandtl number, 327
Miniaturisation, 73 Pressure drop induced by droplets, 230
Minimum of Dissipation, 115 Principal radius of curvature, 171
Mite, 77 Probing volume, 103
Mixing, 276 Pygmy shrew, 80, 83
Mixing in droplets, 230, 284 Pythagoras theorem, 74
Mobility, 253
Moffatt eddies, 135 Quality factor, 94
Molecular Dynamics simulations (MD), 68
Molecule, 61 Radius of gyration, 50
monodispersity of droplets, 227 Rayleigh–Plateau instability, 208
Monte Carlo, 68 Reaction kinetics measurements, 286
Resistance, 141
Nanobubble, 21, 296 Reversibility, 114
 Index 465

Reynolds length, 57 Surface tension, 67

Reynolds number, 75, 112, 150 Surface tension in solids, 177
RF MEMS, 93 Surface tension measurement, 174
Roughness, 195 Surfactant, 181
Running of the animals, 81 Sweat, 5

Saddle point, 269 T–junction, 217

Sampling, 97 Taylor dispersion, 267
Scaling law, 76 Taylor’s reversibility experiment, 273
Schmoluchowski approximation, 385 Thermal
Screening of chemical reaction, 287 Peclet number, 327
Segre-Silberberg effect, 307 Thermal boundary layer, 324
Self Assembly, 37 Thermal conductivity, 320
Shapiing of the concentration field, 288 Thermal diffusivity, 320
Silane, 69 Thermal neutral zone (TNZ), 83
Silicon, 425 Thermal regulation of mammals, 83
Similarity principle, 377 Thermal system, 95
Single Cell, 53 Thermal transport, 318
Single cell, 37 Thermo Capillary length, 58
Slip regime in gas, 119 Throughput, 97
Slippage, 25 Trajectory crossing (leading to chaos), 274
Slippage amplification, 378 Trapped bubble, 147
Slippage in gas, 118 Tree, 1, 173
Slippage in liquids, 121 Tubulin, 52
Soap film, 22, 168 Tyrannosaurus, 82
Soft lithography, 437
Soft Technology, 415 Uniqueness, 115
Soft technology, 14
Solubility, 182 Valve, 37
Solvent, 61 Van der Waals, 58
Specific heat, 320 Van der Waals attraction, 58
Spider, 2 Van der Waals radius, 48
Spincoater, 420 Virus, 52
Spreading coefficient, 189 Viscosity, 108
Stegosaurus, 341
Step emulsification, 221 Walker, 248
Stern layer, 69 Washburn law, 212
Stern model, 360 Wentzel model, 195
Sticker technology, 455 Wet etching, 427
Stokes equation, 113 Wettability, 71
Stokes law, 132 Wetting, 188
Stokes-Einstein, 248
Stokes-Einstein law, 248 Yocto, 48
Straining fleld, 51 Yoctomole, 48
Structuration force, 71 Young equation, 190
SU8, 424 Young Lippman equation, 408
Superhydrophobicity, 198
Surface charge, 359 Zepto, 48
Surface Force Microscopy (SFM), 62 Zeptomole, 48