C H A P T E R

4
Lab-on-a-chip: Systems integration
at the microscale
Vania Silverio and Susana Cardoso
Instituto de Engenharia de Sistemas e Computadores para os Microsistemas e as Nanotecnologias,
INESC-MN, Lisbon, Portugal
Department of Physics, Instituto Superior T
ecnico, Universidade de Lisboa, Lisbon, Portugal

Nomenclature Symbols
Acronym Fr Dimensionless Froude number
Pe Dimensionless Peclet number
CMOS Complementary metal-oxide-semiconductor Ph Dimensionless Phase number
COC Cyclic-olefin copolymer Re Dimensionless Reynolds number
CVD Chemical vapor deposition Tg Glass transition temperature
E-beam Electron beam μ Micro
FET Field effect transistor
IC Integrated circuit
LbL Layer-by-layer deposition 1 Introduction
LOC Lab-on-a-chip
PA Polyamide
PDMS Polydimethylsiloxane
Microfluidics provides a great opportunity to cre-
PEGDA Polyethylene glycol diacrylate
ate devices capable of outperforming classical tech-
PEM Polyelectrolyte multilayers
niques in biomedical and chemical research. [1]
PMMA Polymethyl methacrylate
PS Polystyrene Microfluidic devices integrating multiple
PU Polyurethane
functionalities on chip to enable fast and porta-
PVD Physical vapor deposition
RBC Red blood cells ble manipulation, synthesis or analysis of small
RBC Red blood cells volume samples of the order of some picoliters
RF Radio frequency are often called “lab-on-a-chip” devices or
SOI Silicon-on-insulator LOC. The high surface-to-volume ratio of their
SWM Surface wettability modification
microfluidic passages and their possibility of
TPE Thermoset polyester
UV Ultra-violet realizing controlled multiplexed testing make
WBC White blood cells these devices advantageous in comparison to
WBC White blood cells larger scale laboratorial equipment. Another
major advantage is that the operation and

Drug Delivery Devices and Therapeutic Systems 63 # 2021 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/B978-0-12-819838-4.00020-1
64 4. Lab-on-a-chip: Systems integration at the microscale

upkeep of LOC devices do not need skilled oper- metering and environment control, reaction, fil-
ators which, in addition to their small size, con- tration, separation, and sorting, etc. (Fig. 2).
tribute to LOC use in remote locations. In the following sections, these elements are
Over the past decades, much investment has addressed and their implementation in recent
been made toward understanding the physical, LOC technology is discussed.
chemical, and biological phenomena occurring
at such small fluidic passages to consolidate
the potential of LOC devices [2]. The scaling of 2 Materials for LOC fabrication
fully integrated and autonomous single or mul-
tiple lab processes down to chip-format raises Lab-on-a-Chip devices have been developed
new technological and scientific questions making use of the techniques described in
which calls for life scientists and engineers to Chapter 2. The choice of substrate relies on the
interact in a wide number of areas from material application but also on the substrate properties,
and system properties, microfabrication tech- the interaction fluid/substrate, the actuation
niques and strategies, system integration, mea- and sensing methodologies, the cost of the mate-
surement and analysis techniques, fluid rial and cost of production, or even the through-
transport, etc. (Fig. 1). put or the easiness of manufacture, among
The wide range of applications [3–6] has been others. The most used substrates for LOC
another factor leading to the fast development of devices were initially silicon and glass pro-
LOC devices. LOC are seen as the laboratories of cessed by fabrication techniques well estab-
the future not only because of size and simplicity lished in the Integrated Circuit (IC) Industry
to operate but also because they can integrate (e.g., lithography, deposition, etching) and
several elements such as fluid actuation, valves, bonded to a preformed polymer microfluidic
mixing elements, storage chambers, detection, network (e.g., via ozone plasma, corona) [7, 8],
but, with the advances in many areas and

FIG. 1 Multidisciplinary nature of LOC microfluidics devices.

I. Microfluidics
 2 Materials for LOC fabrication 65
Mixing:
Passive mixers
Active mixers
Piezo technology
Sample inlet: Surface waves Storage:
pipette tip Magnetic forces Lyophilized reagent
Luer connection Liquid storage (blister or pouch)
septum Metering and
enviroment control
Fluid actuation:
Peristaltic pump Micro valve technology
Syringe pump
Integrated system
Micropump Waste management
Active/passive valves
Capillary forces Detection:
Magnetic
Optical
Electrical
Filtration/Separation/Sorting Electrochemical
Integration of sensors

Storage: Reaction
Dry storage Bonding/Sealing:
Surface modification:
Oxygen plasma
Pressure Hydrophobic/liophobic
Hydrophilic/liophilic
Adhesives
Thermal compression

FIG. 2 Integrating elements on LOC devices. Adapted from https://www.thinxxs.com/main/thinxxs/mailing-california.html.

materials, new opportunities have thrived. Fig. 3 shows examples of the suitability of
Materials such as ceramics, metals, elastomers, materials to be used in the microfabrication of
thermoplastics, hydrogels or paper or the com- LOC devices based on the application. Silicon,
binations of two or more of these materials are glass, and thermoplastics such as Teflon are
becoming more attractive to safe and cost- inert to most chemicals while PDMS (polydi-
effective solutions for LOC microfluidics methylsiloxane) elastomer is easily and rapidly
devices [9–12]. prototyped, even for complex structures; ther-
moplastics (PA, COC, PMMA, etc.) on the other

Excellent

Good

Moderate
Silicon/glass
Elastomers
Poor
Thermoset
Thermoplastics
N/A Hydrogel
Paper

re is io
n n is R n
ltu re
s
at ctio he
s
PC atio
o cu ho rm e te nt liz
Bi
p
fo ld sy ta
tro et ic ys
ele
c
pl ica an cr
ro em rg ein
ry D ch O ot
illa ro Pr
ap ect
C El
FIG. 3 Suitability of materials for LOC microfabrication dependent on application [13].

I. Microfluidics
66 4. Lab-on-a-chip: Systems integration at the microscale

hand are the most cost-effective for mass pro- reagents volume and reaction times; however, it
duction of simple microfluidics structures, may change the physical effects. The dynamics
hydrogels present themselves as more suitable of these microfluidics systems vary from the
for biorelated applications (e.g., bioculture) macroworld in the sense that interfacial forces
and paper is appealing to disposable bioassays. dominate over gravity and inertia (Eq. 1)
Of course, the use of these materials has draw-
backs either cost related, incompatibility surface forces ðviscous effectÞ l2

  3 ¼ l1 (1)
(biological, chemical), fabrication protocols, volume forces gravity, inertia l
etc., which can be overcome with the modifica-
tion of surface properties to meet the demands considering l to be a typical linear dimension
of the application [14]. and that all linear dimensions vary proportion-
ately to l.
Albeit not strictly defined where macroscale
2.1 Surface modification ends and microscale starts because these bound-
aries greatly depend on the property to be stud-
Some unique phenomena emerge at the microme- ied, the fact is that surface tension forces,
ter scale. For example, reactions are completed in a magnetic forces, or electrical forces at the sur-
shorter amount of time as the travel distances of mass face, which could be discarded in conventional
and heat are relatively small; the flows are usually
macrosystems, may become predominant in
laminar; and the capillary effect becomes dominant
owing to large surface-to-volume ratios. In the mean- LOC and need to be considered. Fig. 4 presents
time, the surface properties of the device material are the typical length and volume scales characteris-
greatly amplified, which can lead to either unique tic of LOC micro and nanosystems and fabrica-
functions or problems that we would not encounter tion techniques.
at the macroscale. [13]
Surface tension forces become dominant over
Reducing the scale unequivocally benefits the gravity forces and capillary effects are often
procedure through the reduction of sample and used to drive the flow. As such, the surface

FIG. 4 Length and volume scales of typical microsystems and microfabrication techniques.

I. Microfluidics
 3 Sample inlet and outlet 67
properties of the material often command the 2.2 Bonding and sealing
success of the application by granting the mate-
rial with either unique capacities or difficulties
In general, closing and connecting to the outside
that typically do not arise at the macroscale. world these miniature labs remain a challenge irre-
Hydrogen bonds and van der Waals forces are spectively of the type of application pursued. [43]
often sufficient to promote the adhesion of dif-
ferent materials, for example, PDMS and SU-8, Functional LOC microfluidic devices often
combined to microfabricate the LOC device rely on hybridization strategies in their fabrica-
[15, 16]. However, the adhesion of high and tion to assemble different parts into a final prod-
low solid surface free energy materials (e.g., uct. Bonding and sealing are critical steps of
glass and polymers) often requires surface microfabrication, which must be guaranteed
energy modification with reactive chemical without clogging the fluidic structures or with-
groups to promote strong covalent bonds [17, out changing their size or physical parameters.
18]. Moreover, the surface energy modification Often the material interfaces to be bonded are
may be tailored to inhibit or promote nonspeci- of a different kind, increasing the complexity
fic adsorption of analytes at the surface [19, 20], of the microfabrication. Parameters such as
to enable the fabrication of antistiction surfaces bonding strength particularly important for
[21], self-cleaning surfaces, or even enhanced high pressure devices, chemical and physical
capillary pumps [22–24]. compatibility to prevent unwanted interfacial
Common surface energy modification tech- reaction or stresses, optical properties to access
niques [19, 25, 26] rely on gas phase processing the flow or increase signal-to-noise ratio, high
(e.g., ultrasonic spray pyrolysis, calcination, temperature, or pressure fabrication, which
hydrothermal treatment, ultraviolet irradiation, can interfere with electric elements or device
microwave irradiation, plasma oxidation, UV dimensions, manufacturability, etc. are all cru-
irradiation, chemical vapor deposition, atomic cial to produce confined fluidic passages for
layer deposition, sputter coating of metal com- fluid manipulation [44]. Table 2 presents the
pounds), wet chemical methods (e.g., phase most common bonding and sealing techniques
inversion, interfacial polymerization, layer-by- available for LOC fabrication as well as the
layer deposition, sol-gel coatings, silanization, advantages and disadvantages of their
dynamic modification with surfactants, protein employment.
adsorption), or a combination of both (Table 1) After bonding the LOC device, it is time to
[27]. Electrochemical anodization, electrospin- connect the device to the world and infuse
ning, or others are described elsewhere [25, 26, medium, sample, reagents, etc.
39–42].
The description, advantages, and disadvan-
3 Sample inlet and outlet
tages of the main chemical and physical tech-
niques used for surface modification are
presented in the table below. Whether a relatively simple mixture of amino
Surface modification and chip bonding are acids or a more complex sample of DNA fragments
critical steps in the fabrication of microfluidic extracted and amplified on-chip, the ability to reliably
devices. Surface modification techniques are and reproducibly inject a representative sample is
arguably the most significant requirement for an elec-
usually suited to promote chemical bonds
trophoretic micro total analysis system (μTAS). [65]
between the modified surfaces, for the fabrica-
tion of LOC devices. Among the most used is The connection of the LOC to the world,
plasma treatment to seal PDMS to glass surfaces. denominated “world-to-chip” interface, “fluidic

I. Microfluidics
68 4. Lab-on-a-chip: Systems integration at the microscale

TABLE 1 Main surface modification techniques, their advantages, and disadvantages [25].
Surface modification technique Advantages Disadvantages

Plasma treatment/vacuum plasma Plasma treatment occurs at near- Plasmas are thermodynamically
treatment ambient temperature, minimizing unfavorable—plasma-processed
Partially ionized gas (e.g., oxygen, the risk of damage to heat-sensitive surfaces may lack uniformity
nitrogen, hydrogen), which materials Gas ionization efficiency can
dissociate and react with the Short processing times decrease the power efficiency more
substrate surface, creating chemical No drying stage than tenfold depending on the carrier
functional groups [25, 27–30] Low energy consumption plasma and substrate
Low chemical consumption High operation costs of vacuum
More environmentally friendly and requirements
cost-effective compared to
alternative methods—no need for
waste disposal of harmful chemicals
Chemical vapor deposition (CVD) Vapor molecules conform to the High temperatures are usually required
Deposition of gaseous molecules on geometry of the substrate at relatively Depends on the properties of
the substrate to produce a high deposition rates only requiring chemical precursors
chemically reactive thin film at the rough to process vacuum regimes Precursors are usually toxic,
surface [27, 31–35] Easiness of process explosive, or corrosive
Small amounts of chemicals Reaction byproducts can be
Highly reproducible hazardous
Stable modification over time
Relatively high deposition rates
Vapor phase does not transport
impurities present in the liquid
(compared to wet chemistry
methods)
Ultraviolet irradiation Simplicity Instability of the coated surface
UV radiation is applied to induce Cost-effectiveness Surfaces prone to degradation
photochemical reactions at the Can operate under mild reaction
surface [15, 36] conditions
Layer-by-layer deposition (LbL) Simplicity Time-consuming
Alternating adsorption of Environmentally benign
polyanions and polycations that can Potentially cost-effective Large amounts of precursors for each
be accomplished on virtually any deposition step
substrate surface to produce
polyelectrolyte multilayers (PEMs) Difficult to define and establish a
[27, 37, 38] priori the best assembly features for
achieving a desired target

interconnection” or “macro-to-micro” interface is integration of interconnects is often not readily

an important component in a LOC microfluidic compatible with available LOC fabrication tech-
device. Somewhat neglected in microfluidics inte- niques, as are examples the Luer Locks or the
gration, these interfacing elements can typically be syringe tips, and are of materials differing from
the most unreliable elements of a LOC device, fre- that of the LOC device, significantly increasing
quently limiting their efficiency. Additionally, the the complexity and the overall cost of the device.

I. Microfluidics
 3 Sample inlet and outlet 69

TABLE 2 Summary of typical bonding and sealing microfabrication techniques.

Bonding strategy Common materials Advantages Disadvantages

Fusion bonding Silicon-silicon Easily scalable for mass Material specific

High-temperature annealing from 300 to Silicon-silicon oxide production
800˚C in oxygen or nitrogen atmosphere SOI-SOI
[45] Silicon-silicon
Nitride-silicon
Anodic bonding, field-assisted bonding or Silicon-glass High bonding yields Material specific
electrostatic Excellent capability in Glass must
Wafer bonding process to seal glass, alignment contain high
containing a high concentration of alkali Large process windows concentration of
ions to either silicon or metal using an alkali ions
electric field and elevated temperature
without introducing an intermediate layer
sealing [46]

Adhesives Any combination of: Versatile Large thermo-

Make use of an interfacial layer of resin, Polymer Substrate independent mechanical
UV curable material, thermally activated Thermoplastic Simple and cost- stresses
materials Metal effective Localized
[47–50] Composite deformation of the
Ceramic device
Inhomogeneities
in the interfacial
layer thickness
Microvoids
between the
bonded surfaces
Solvent bonding Thermoplastic- High throughput Contamination of
Uses chemical reagents (solvents) to Thermoplastic Easily scalable for mass samples and
achieve a solvated surface production surfaces
[51]
Oxygen plasma PDMS-PDMS The Si-O-Si bond is Surface must have Si
Surface treatment to produce Si-OH PDMS-silicon sufficiently strong to content in their
groups at the surface [52–54] PDMS-glass impede the two layers composition
to be peeled Chemically
reactive
Can damage
organic molecules
Electrical discharge (Corona) PDMS-PDMS Simple and cost-effective Nonuniform
Corona plasma is established in room air PDMS-glass treatment
at atmospheric temperature to oxidize the Can interfere with
surfaces [55, 56] electrical elements

Continued

I. Microfluidics
70 4. Lab-on-a-chip: Systems integration at the microscale

TABLE 2 Summary of typical bonding and sealing microfabrication techniques—cont’d

Bonding strategy Common materials Advantages Disadvantages

Thermal compression Thermoplastic- Simple technique Thermal

Substrates in contact are heated close to thermoplastic (with deformation of the
their glass transition temperature (Tg) similar Tg) fluidic features
while submitted to compression [57–59] Intermediate layer
of polyolefin to
decrease bonding
temperature
Localized welding Thermoplastic- Can be used to perform Increased
Use of ultrasounds, microwaves or thermoplastic localized bonding complexity
infrared lasers to heat and soften the Thermoplastic-
interface of the mating parts [60–62] metal
Pressure clamping or screwing Thermoplastics, Reversible Usually needs
Make use of clamps or screws to maintain elastomers, metal Provides easy access to additional sealing
two surfaces in contact [63, 64] samples after elements such as
experiments o-rings
Mechanical
strength is
difficult to
reproduce

Three review papers [44, 65, 66] cover some One important aspect to have in mind is the
examples of the most used microfluidic interfaces input of contractions and expansions usually
integrated in LOC devices, which include one of but not exclusively related to inlets and outlets
each four main characteristics pointed in Table 3. and characteristic curves of the total kinetic
To be suitable to be integrated in a LOC energy contribution. The pressure drop Δ p in
device for a given application, World-to-chip the flow circuit includes the contributions of
interfaces should ideally: be simple, easy to the kinetic (Ek) energy determined from the iner-
assemble, to replace and to reuse; be reliable tial forces, potential (Ep) energy and the pressure
over a range of pressures and/or temperatures; loss Δ pfriction due to friction (Eq. 2).
be (bio)chemically compatible and/or inert; be
Δp ¼ pinlet  poutlet ¼ ΔpEk + ΔpEp + Δpfriction (2)
affordable and easily available; have minimal
dead volume and pressure drop; avoid cross- In the example presented in Fig. 5, the fluid passes
contamination; their size and positioning should through position i with average velocity vi, and
not compromise high density of connections or flows across a sudden contraction into the straight
field of view; be compatible with commercial channel to position ii experiencing acceleration
tubing, fittings and equipment. Although there believed to be approximately isentropic. The
is not yet a universal fluidic connector for LOC entrance pressure drop is owed to combined
microfluidic devices, efforts are being made on effects of fluid acceleration toward the entrance
the standardization toward an open architecture and wall shear stress. The fluid subsequently
of interconnection [67–71] as a means to facilitate leaves the flow circuit after a sudden expansion
the compatibility between devices and instru- to position iv, where fluid deceleration takes place
mentation independently of the vendor. together with mechanical energy loss [72].

I. Microfluidics
 3 Sample inlet and outlet 71

TABLE 3 Examples of typical fluidic interconnects and relevant interconnection characteristics for sample injection in
LOC devices.
Fluidic interfacing
Connector type Plugging orientation Material technique

Pipette Top connect or out of plane Silicon Insertion coupling

Microneedle interconnection Glass Interfacial
Luer connector Side connect or in-plane Ceramic adhesion
Septum connector interconnection Elastomers Compression
Tube sealing
Loading pad Monolithic
Reservoir PDMS, thermoset polyester (TPE) integration
Port interface Thermoplastics
Injection-molded
coupler Polystyrene (PS), polycarbonate, poly-
Press-fit connector methyl methacrylate (PMMA), poly-
Ferrule ethylene glycol diacrylate (PEGDA)
Solder based connector Teflon
Polyurethane (PU)
Cyclic-olefin copolymer (COC)
Dry adhesive films

The total pressure drop across the fluid occurring due to flow area change without fric-
circuit is obtained by correcting the inertia term tion and the pressure drop due to irreversible
accounting for flow acceleration in constricted free expansion that follows the abrupt contrac-
entrances, flow deceleration after expansions, tion (vena contracta) and consequent pressure
change in flow direction in bends, elbows, tees, variation due to the variation in the flow velocity
and other fittings and losses due to open or profile downstream from the vena contracta.
partially closed valves.
"  2 #
ΔpEk ¼ Δpsuddenconstriction + Δpprogressiveconstriction Acs, ii G2ii G2
+ Δpsuddenexpansion + Δpprogressiveexpansion Δpsc ¼ 1  + Ksc ii (4)
Acs, i 2ρL 2ρL
+ Δpbends + Δpelbows + …
(3)
Acs is the cross-section area, G is the mass flux
The abrupt contraction pressure drop, Δ psc, can given in kg m2 s1, and Ksc is the abrupt con-
be expressed as a sum of the pressure drop traction coefficient given by

FIG. 5 Length and volume scales of typical

microsystems and microfabrication techniques.

I. Microfluidics
72 4. Lab-on-a-chip: Systems integration at the microscale

  in Refs. [77–79], is fairly dependent on the valve

Acs,ii 2 2
1  Keb Cc  2Cc + 2Kd Cc 2 design whereas gradual expansions and con-
Acs,i
Ksc ¼ tractions largely depend on their expansion or
C2
 2 ! c contraction angle [78, 79].
Aii The friction contribution to pressure drop is
 1 (5)
Ai dependent on the average flow velocity vavg
and the dimensionless friction factor f
Cc is called the jet contraction ratio, which relates
L ρ vavg
to the vena contracta area and the contraction 2
A
area. It is a function of Acscs, i,+i 1 . Kd is the velocity Δpfriction ¼ f (10)
Dh 2
distribution coefficient as
ðA Here, L is the channel length and Dh is the
1 hydraulic diameter defined as Dh ¼ 4 PA cs
.
Kd ¼ 2 v2 dA (6) wetted
Avavg 0 For short channels, these entrance effects are
Here, v is the velocity of the fluid. The average even more pronounced. Entrance and exit losses
flow velocity is defined as vavg ¼ Q/A can, according to Webb [80], account for as much
Ð cs where as 30% of the total pressure drop. The hydrody-
the volumetric flow rate is Q ¼ v dA over
the cross section and Keb is the kinetic energy namic developing region is expected to occur
correction factor over part or all of the microchannel flow length
and is more significant at higher laminar Reyn-
ðA
1 olds numbers.
Keb ¼ 3 v3 dA (7) The fully developed hydrodynamic length
Avavg 0
yfd,h, defined as the length from the channel inlet
The abrupt expansion pressure rise, Δ pse consists at which the flow is 99% fully developed is char-
of the pressure rise occurring due to area change acterized by the dimensionless hydrodynamic
combined with the pressure loss associated with y ,h
entry length y + ¼ DfdhRe given by [81]
the irreversible free expansion and momentum
changes following an abrupt expansion. y + ¼ 0:019 + 0:0783α∗  0:0384α∗ 2 (11)
"  #
Acs,iv 2 G2 G2 α ¼ short
long is the channel aspect ratio.
Δpse ¼ 1   Kse (8) More complex devices go beyond the inlet—
Acs,iii 2ρL 2ρL
straight channel—outlet. They often integrate
Kse is the abrupt expansion coefficient actuation and manipulation elements, used to
    pump the liquids or to sort cells from growth
Acs,iv Acs,iv 2 medium, along the flow path.
Kse ¼ 1  2Kd + ð2Kd  1Þ (9)
Acs,iii Acs, iii
Ksc and Kse are functions of the contraction and
expansion geometry [72]. 4 Actuation and manipulation
The pressure drop resulting from losses due
to the change in flow direction is usually
expressed by the bend-loss coefficient Kb. This … microfluidic devices offer the unrivalled ability
to precisely control and perturb the environment of
coefficient depends on the channel bend angle
single cells … [82]
and curvature ratio and is usually listed in
tables, for turbulent flow [73–76]. For valves, Efficient LOC devices often rely on actuation
the head loss coefficient, Kv, found for example (mixing, pumping, atomizing, nebulizing, etc.)

I. Microfluidics
 4 Actuation and manipulation 73
and manipulation (separation, sorting, trapping, [127], flap valves [128], diaphragm valves [129])
concentration, merging, patterning, aligning, accomplish flow rectification by deforming and
focusing, etc.) of fluids, particles, droplets, cells, are either passive (the actuation is due to pressure
nanotubes, among others [83–85]. The integration difference) or active (actuated by external forces).
of LOC devices with up to thousands of actuation These valves usually withstand high operating
and manipulation elements has been made possi- pressures and are more precise imposing flow
ble by the adaptation of standard microfabrica- directionality. Because they are usually exposed
tion methods to nonconventional materials and to high pressures and high-pressure differences,
their combination with multilayer soft lithogra- material fatigue is an important aspect to consider
phy [86–88]. Valves and mixing in LOC devices [130]. Conversely, static valves (e.g., diffusers
take advantage of actuation and manipulation [131] nozzles [132], Tesla valves [133]) have fixed
methodologies presented in Table 4. The most geometry with no moving parts or boundaries.
common for flow rectification is to use valves that This results in reduced mechanical and fatigue
force the flow only in one direction [125]. failure and wear and absence of fluid contamina-
Dynamic valves (check valves [126], ball valves tion because there is no requirement for

TABLE 4 Actuation and manipulation strategies at the microscale.

Mechanical displacement Dynamic

• The fluid delivery and suction modes are imposed through volume variation by • Add momentum to the fluid by
a moving boundary external forces
• Independent of fluid properties • Usually provide higher flow rate
• Pneumatic and hydraulic deliver higher force and power densities at the • Usually much steadier discharge
microscale • Ineffective in handling high
viscosity fluids
Bimetallic [89] Bubble type [90]
Electromagnetic [91, 92, 93] Centrifugal (rotating disk) [94–96]
Electrostatic [97] Electrohydrodynamic (EHD) [98]

Ion conductive polymer film (ICPF) [99] Electrochemical [100, 101]

Phase change type [102] Electroosmotic [90]
Piezoelectric [103] Electrowetting [104, 105]
Pneumatic [106–108] Evaporation type [109]
Shape memory alloy (SAM) [110] Flexural plane wave (FPW) [111]
Thermopneumatic [112] Magnetohydrodynamic (MHD) [92,
113]
Ferrofluid displacement [114] Optical [115]
Rotating gear [116] Capillary [117, 118]

Rotary viscous force [119] Hydrostatic pressure [120]

coustic standing wave (ASW) [121–123] Ultrasonic vibration [124]

Adapted from M. de Volder, D. Reynaerts, Pneumatic and hydraulic microactuators: a review, J. Micromech. Microeng. 20 (4) (2010) 043001, https://doi.org/
10.1088/0960-1317/20/4/043001.

I. Microfluidics
74 4. Lab-on-a-chip: Systems integration at the microscale

lubrication. But reverse flow in this type of valves The use of biocompatible and versatile elasto-
is often a challenge specially penalizing biomed- meric materials such as PDMS (polydimethylsi-
ical applications. Another important factor is the loxane) in the fabrication of microfluidic devices
dead volume, which can become large in compar- has opened the way to the development of inge-
ison with the total sample volume [134]. nious solutions in addition to fluid actuation
Valves are often used for sample prepara- and manipulation. To study cells and cellular
tion and mixing purposes in microfluidic behavior, LOC microfluidic devices often inte-
devices. Such as valves, mixing can also be grate mechanical stimulation of living cells,
divided into passive or active depending on which mimic the conditions and stress that cells
the forces actuating in the flow. Passive mixing naturally undergo in their physiological envi-
relies on the diffusion of the mixing phases ronment [140–142]. Sample preparation is
usually promoted by increasing their contact another important step to isolate the analyte of
surface and time of contact or on the chaotic interest from other components in the sample.
advection of species fostered by specific geom- On-chip sample preparation reduces processing
etries in the fluidic path (obstacles in the wall time and requires smaller amounts of samples to
or flow channel, zig-zag configuration, etc.) process, but has challenges associated [143].
[135, 136]. Although turbulence is difficult to Typical preparation protocols are filtration
achieve in passive mixers, mixing is enhanced [144, 145], preconcentration [146], purification
by secondary flow, swirling flow [137], and [147], cell lysis [148], or derivatization [149].
vortices [138]. On the other hand, active mixing Based on cell size, shape, and stiffness, Brás
is achieved when external energy input is et al. [150] used soft lithography to devise a
applied to the system to stimulate flow distur- microfluidic cell trap to study the continuous
bance [139]. Active mixers are usually more controlled cell growth and continuous culture
expensive and complex to integrate into LOC of Saccharomyces cerevisiae and the extracellular
but offer faster mixing than passive mixers. protein invertase. The authors used modified
Table 5 presents 6 types of active micromixing Reynolds (Ref), P
eclet (PeL), axial Froude (Fra),
approaches and relevant parameters for their and Phase (Ph) dimensionless numbers defined
implementation. in Ref. [151] to compare between micro and

TABLE 5 Evaluation of active micromixing approaches.

Mixing mechanisms Acoustic Cavitation Electroosmotic Magnetic Pressure Temperature

Applicable for stagnant flows Yes Yes Yes Yes Yes No

Applicable to very low Re numbers Yes Yes Yes Yes Yes Yes
Compatible with biological No No No Yes Yes No
components
Easy to fabricate No No No Yes No Yes
Low-cost fabrication No No No Yes No Yes

Readout visibility Yes Yes Yes No Yes Yes

Sample preparation needed No Yes Yes No No No

Adapted from E.-S. Shanko, Y. van de Burgt, P. D. Anderson, J. M. J. den Toonder, Microfluidic magnetic mixing at low Reynolds numbers and in stagnant
fluids, Micromachines, 10 (2019) 731; https://doi.org/10.3390/mi10110731, with permission from MDPI.

I. Microfluidics
 4 Actuation and manipulation 75
macroscale reactors for both batch and continu- tool to predict the breakup modes of droplet
ous modes. With these structures, the authors generation directly related to the precise and
achieved productivity higher than their macro- effective control of droplets [162]. Table 6 sum-
scale counterparts for at least 32 h. marizes the most important dimensionless num-
Such strategies are employed to evaluate the bers used to classify and compare bubble
nature of complex physical processes. As in the generation and dynamics in LOC devices.
example above, scaling analysis and dimension- ρ is the volumetric mass density and U0 is the
less numbers are often used to quickly estimate characteristic velocity. It is common practice to
the values and orders of magnitude of variables use the molar average velocity for dilute gases
relevant to the problem [152–157]. According to and the mass average velocity for liquids [166].
Suea-Ngam and coworkers, in the last 8 years, In LOC devices, L0, which is called the character-
droplet-based microfluidics in LOC has had an istic dimension, is typically assumed to be the
enormous impact in single cell experimentation, hydraulic diameter Dh. μ is the dynamic viscos-
in which droplets are used to house, probe, ity of the fluid, γ is the surface tension of the
manipulate, and sort cells [158–161]. The use fluid, and g0 is the standard acceleration due
of dimensionless numbers has been a powerful to gravity.

TABLE 6 List of relevant dimensionless numbers commonly used in bubble generation and dynamics [139, 163–165].
Name Symbol Definition Interpretation

Reynolds Re ρ U0 L0 Ratio of inertial to viscous forces. Identifies the nature of fluid flow as Creeping
number μ flow Stokes flow (Re << 1), Laminar flow (Re < 2300), Transition flow
(2300 < Re < 10000) or Turbulent flow (Re > 10000)
Weber We ρ U02 L0 Ratio of inertial forces to surface tension forces. It can be used to distinguish
number γ between regimes of droplet formation

Froude Fr U0 Ratio of inertial forces to gravitational forces (in a horizontal rectangular

pffiffiffiffiffiffiffiffiffiffi
number g0 L0 channel). Can be used to characterize the path and shape deformation of
bubbles
Bond Bo 4ρ g0 L20 We Ratio of gravitational to surface tension forces. When Bo 103, gravity effects
¼
number γ Fr are found negligible

Capillary Ca μ U0 We Ratio of viscous forces versus surface tension acting across an interface between
¼
number γ Re a liquid and a gas. When Ca < 106, the flow is dominated by capillary forces

Ohnesorge Oh μ
Re pffiffiffiffiffiffiffiffi
1=2
¼ WeRe Ratio of internal viscosity dissipation to surface tension * inertial forces. Low Oh
ρ γ L0
number represents small friction losses due to viscous forces, hence, most of the
energy converts into surface tension energy and droplets are formed.
Peclet Pe Re UD
0 L0
¼ Re Sc Ratio of convective (hydrodynamic) transport to diffusive transport. For small
number Re, typical of microfluidics, mixing by diffusion becomes more important
than mixing by convection.

Schmidt Sc μ Ratio of momentum diffusivity to mass diffusivity. Is used to characterize fluid

¼ Re Sc
number ρD flows in which momentum and mass diffusion convection processes are
occurring simultaneously
Galilei Ga g0 L30 ρ2 Re2 Ratio of gravity to viscous forces. Can be used to characterize the path and shape
number ¼ deformation of bubbles
μ2 Fr

I. Microfluidics
76 4. Lab-on-a-chip: Systems integration at the microscale

The scaling analysis and the dimensionless • if the flow is incompressible, then r ∙ v ¼ 0
numbers ease the mathematical analysis and • if the flow is steady state, then ∂t∂ ¼ 0
numerical simulations of the basic equations of • if the flow is unidirectional in y, then v ¼ vy(x, z)
fluid dynamics. The most complete and accurate • if the flow is fully developed in y, then ∂v ∂y ¼ 0
description of fluid motion comes from the par- • if the gravitational effects are negligible, then
tial differential equations [167]. In the case of iso- Fg ¼ 0
thermal flow, the flow field is characterized by • if there is slip flow, then τij ¼ 0
the balance of mass, momentum, and total
energy described by the conservation of mass Exact solutions of the flow field are obtained
or continuity equation (Eq. 11), linear momen- by imposing boundary conditions, usually based
tum or Navier-Stokes equations (Eq. 12), and on physical observation or theoretical analysis.
total energy equation (Eq. 13) The no-slip boundary condition is an example of
boundary condition widely used for microfluidic
∂ρ flow of Newtonian fluids. It states that the three
+ r∙ðρvÞ ¼ 0 (11)
∂t components of the velocity of the fluid on the
where t is the time, v is the velocity vector field, solid surface (boundary) are equal to the respec-
and r is the nabla vector differential operator. tive velocity components of the surface.
The linear momentum equation is • no-slip boundary condition, v ∙ n 5 0, here n
∂ðρvÞ is the normal to the surface, directed into the
+ ðv∙rÞðρvÞ ¼ rp + r∙τ ij + F (12) liquid
∂t
p is the pressure, τij is the viscous stresses tensor, From the simplifications above arise simplis-
and F are the external forces. The rate of change tic relations such as the Bernoulli’s principle
of the total energy of a body, equal to the sum of
the rate at which heat is transferred from the p1 1 2 p2 1 2
body and the rate at which work is being done + U + g0 z1 ¼ + U0,2 + g0 z2 ¼ constant
ρ 2 0,1 ρ 2
by the body is given by total energy equation
(14)
in its differential form:

∂ considering the flow is steady state and incom-

_ W
ðρeÞ + ðv∙rÞðρeÞ + v∙rp ¼ Q _ (13) pressible along one current line, there is no work
∂t
in altitudes z1 and z2, there is no heat being
exchanged between altitudes z1 and z2 and there
Here, e is the energy of the system per unit mass
is slip. Consequently, Bernoulli’s principle is not
and can include internal energy, kinetic energy,
valid along a current line close to the wall where
potential energy, energy from chemical reac-
no-slip condition applies.
tions, nuclear reactions, and electrostatic or
_ is heat rate and W _ is When diminishing the scale, the common
magnetic field effects. Q
simplifications found in the literature may not
the work rate. The work can be that of pressure,
directly apply because the components consid-
viscous stresses, electromagnetic forces, etc. The
ered negligible to obtain these simplifications
work of gravitational forces is included in e in
may now need to be included in the analysis.
the form of potential energy. The dot designates
Examples are:
time derivatives.
Based on the physics of the phenomena, sim- • entrapped gas in the liquid flow can originate
plifications can be made to these equations. For unwanted or unexpected compressibility
example: effects [168];

I. Microfluidics
 5 Storage and reaction 77
• unanticipated pulsation and flow oscillation, may not be fully inclusive as they usually con-
typically obtained from pumping systems sider input parameters, mathematical assump-
such as syringe pumps, result in nonuniform tions, and approximations not always valid at
flow with time, more pronounced for small the microscale, thus misleading authors and
flow rates [169]; readers into incorrect methodologies and
• viscous dissipation in incompressible flow conclusions.
with no heat transfer gives rise to the
variation of fluid properties over time and
channel length [170]. These effects become
more pronounced the smaller the scale and 5 Storage and reaction
the higher the Re number.
• poor-resolution microfabrication processes
The number of methods used for integrating and
generate ill-defined channel geometrical
releasing reagents is surprisingly large and involves
shape or cross sections, adversely turning the reagents in dry and liquid forms, directly-integrated
flow multidirectional; reagents or reagents linked to carriers, as well as
• the increase in pressure inside a soft-walled active, passive and hybrid release methods [134]
channel or tubbing can be sufficiently high to
LOC devices with integrated storage for
lead to the mechanical variation of channel/
reagents, usually liquid, dried, lyophilized, or
flow circuit dimensions, and the velocity of
immobilized, to enable pretreatment of the sam-
the flow may vary along the flow path [171];
ple [173], washing and incubation steps [174],
• the forces acting on the flow need to be
reactions [175], etc., are already on the market
evaluated concerning the properties of the
[123, 176]. The minute amounts of reagents to
fluids and the surfaces and their interaction.
be used, either chemicals, biomolecules (anti-
As example, gravity forces, which can be
bodies, proteins, enzymes, DNA, etc.), buffers,
neglected when fluid 1 is flowing in a channel
surfactants, nanoparticles, stabilizers, etc., de-
of a given material and micrometric
fine the storage requirements such as pH, tem-
dimensions, may become important if fluid 2
perature, concentration, humidity, protective
with different properties is used instead;
atmosphere, material opacity. Reagents can be
• the small-scale interaction of liquid and solid
deposited directly on the surface or immobilized
may occur with slip in particular conditions,
in carriers (e.g., beads, nanoparticles, carbon
depending on several factors such as the
nanotubes) or hydrogels. The latter is more ver-
surface wettability, charge, roughness or
satile in the sense that it is independent on the
impurities, the shear rate, the pressure or the
microfluidic device and can take advantage of
presence of dissolved gas, or impurities in the
the large surface-to-volume area of the carrier
liquid. Lauga and coworkers [172] discuss the
for reaction, capture, binding, etc.
no-slip boundary condition in microfluidics
Pipetting robots, sprayers, screen printing,
and the possibility of its violation resulting in
piezoelectric inkjet printing, usually named non-
molecular, apparent, or effective slip.
contact methods, are preferred when the integra-
A critical assessment of the correct compo- tion needs working distances of a few millimeters
nents and physical phenomena in microflows and deposition of multiple reagents on the same
can be very complex. When not properly position without cross-contamination, whereas
addressed, the resulting scientific literature on contact methods (screen printing, flexographic
this topic wrongly reports anomalies or devia- printing, microcontact printing), as the name
tions from macroscale predictions. These works indicates, rely on the physical contact between

I. Microfluidics
78 4. Lab-on-a-chip: Systems integration at the microscale

the deposition method and the surface, conse- of operation and cross-sensitivity can become dif-
quently enabling much smaller spots, down to ficult to quantify. On the other end, offline meter-
50 nm resolution [177]. Reaction is predomi- ing and/or monitoring is more versatile mainly
nately diffusion or dissolution controlled and because of mature analytical tools in the market,
less often osmotic controlled [178–182]. with proven high selectivity and accuracy. The
The reagents can be actively released inside the main setbacks are contamination through sam-
microfluidic device from storage positions (e.g., pling, sample degradation, no real-time measure-
blisters [183], chambers [184], ampoules [185], ments and bulky instrumentation.
scaffolds [186–188], actuated release [189]) into The ability to meter and monitor process vari-
the flow or the samples penetrate these elements ables in an online test, in a noninvasive and non-
for reaction. However, the most common strate- destructive manner, has led to the integration of
gies to supply reagents to the microfluidic device sensing and control elements in lab-on-a-chip
are through inlet ports, loading pads, or car- devices. Integration on-chip has greatly been
tridges, requiring peripheral equipment, increas- made possible through the advances in micro-
ing the chance of contamination, leakage and air electronics and micro/nanofabrication and the
bubbles in LOC devices. Likewise, the accumula- solutions for compatibility between sensor and
tion of waste products, which can be very fast in substrate materials, miniaturization of different
microfluidic devices, often recurs to the strategies types of sensors (magnetoresistive, optical, ther-
used for reagent management [190–192]. mal, CMOS, electrochemical, FET, RF, and
mechanical), increased detection level, etc.
And although technologically challenging, inte-
6 Metering, monitoring, and detection
grated sensing and control elements are contrib-
uting to set the pace to the development of self-
Current demands for affordable integrated health- contained portable laboratories. Examples of
care systems providing monitoring, diagnosis and sensor integration in LOC devices are further
therapy are leading to an increase in the development detailed in [90, 193, 195–204]. Moreover, LOC
of integrated systems for lab-on-a-chip (LOC) portability is being further trailed by the rapid
devices. [193] replacement of conventional electronics and
Key variables of chemical or biological tests electrical read-out systems by open-source
such as oxygen, CO2, glucose, temperature, and microcontrollers, that have easy-to-use develop-
pH provide essential information for sample char- ment environments to enable faster and simpler
acterization [194]. These can be metered and/or development of fully integrated LOC devices
monitored either online or offline. In online meter- onto the market [205].
ing and/or monitoring, the sensing elements are
in direct contact with the sample, usually inte-
grated into the fluidic path, and signals are contin- 7 Standardization
uously acquired in real time and in an automated
manner. Because no manual or automatized sam-
pling is required in this mode, the flow is undis- Micro-flows are growing more important and use-
rupted and measurements are made at real-time ful for a wide variety of scientific and engineering fields
such as bioanalysis, drug development and administra-
conditions, lessening the risk of contamination.
tion, Organ-on-a-Chip, etc., but accurate and reliable
Of course, the possible interaction of the sensing measurements traceable to the International System
elements with the sample can limit the LOC device of Units can be challenging in micro-to-femto flow
to a specific analytical problem, under strict ranges operating ranges. [169]

I. Microfluidics
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