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Published by
Jenny Stanford Publishing Pte. Ltd.
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3 Temasek Avenue
Singapore 039190

Email: [email protected]
Web: www.jennystanford.com

British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library.

Microfluidics and Bio-MEMS: Devices and Applications

c 2021 Jenny Stanford Publishing Pte. Ltd.
Copyright 

All rights reserved. This book, or parts thereof, may not be reproduced in any
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required from the publisher.

ISBN 978-981-4800-85-3 (Hardcover)

ISBN 978-1-003-01493-5 (eBook)
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Contents

Preface xv

1 Microfluidic Technologies for Cell Manipulation,

Therapeutics, and Analysis 1
Amogh Kumar, Pallavi Shinde, Loganathan Mohan,
Pallab Sinha Mahapatra, and Tuhin S. Santra
1.1 Introduction 2
1.2 Microfluidic Cell Capture Techniques 3
1.2.1 Microdroplet-Based Cell Trapping 4
1.2.2 Cell Trapping through Microarray Devices 9
1.2.3 Cell Trapping through Hydrodynamic Systems
and Microvortices 11
1.2.4 Miscellaneous Techniques for Cell Trapping 13
1.3 Microfluidic Single-Cell Therapy and Analysis 17
1.3.1 Electroporation 17
1.3.2 Mechanoporation 21
1.3.3 Optoporation 22
1.4 Microfluidic Cell Diagnosis and Analysis 24
1.4.1 Cell Diagnosis 24
1.4.2 Cell Analysis 28
1.4.2.1 Droplet-based analytical techniques 28
1.4.2.2 Microfluidic devices for massively
parallel cell analysis 32
1.4.2.3 Miscellaneous analysis employing
microfluidic devices 35
1.5 Future Prospects 38
1.6 Conclusions 39
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2 Optical Manipulation of Cells 49

Srabani Kar, Pallavi Shinde, Moeto Nagai, and
Tuhin S. Santra
2.1 Introduction 50
2.2 Photodynamic and Electrokinetic Phenomena 51
2.2.1 Dielectrophoresis 51
2.2.2 AC Electro-osmosis 53
2.2.3 Electrothermal Effect 54
2.3 Optical Trapping 56
2.3.1 Working Principle 56
2.3.2 Configurations of Optical Traps 59
2.3.2.1 Single-beam optical trap 60
2.3.2.2 Dual-beam optical trap 60
2.3.2.3 Multiple optical traps 61
2.3.3 Applications of Optical Trapping in Biology 63
2.3.3.1 Cell manipulation 63
2.3.3.2 Studies of cell-to-cell interactions 65
2.3.3.3 Robot-tweezer manipulation system 66
2.3.3.4 Manipulation of subcellular
organelles 66
2.4 Optoelectronic Tweezers 67
2.4.1 Device Design, Working Principle, and
Developments 68
2.4.2 Applications of an Optoelectronic Tweezer 73
2.4.2.1 Cell lysis 73
2.4.2.2 Cell trapping, alignment, and
patterning 74
2.4.2.3 Electroporation 74
2.4.2.4 Cell selection, identification, and
separation 75
2.4.2.5 Cellular intrinsic properties 76
2.5 Rapid Electrokinetic Patterning 77
2.5.1 Setup and Working Principle 78
2.5.2 Biological Applications of REP 81
2.5.2.1 Patterning, translating, and
sorting 81
2.6 Conclusions 83
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Contents vii

3 Micro-Robots/Microswimmers for Biomedical Applications 95

Naveen Kumar Agrawal, Pallab Sinha Mahapatra, and
Tuhin S. Santra
3.1 Introduction 96
3.2 Propulsion Mechanism 98
3.2.1 Magnetic Propulsion 99
3.2.2 Bubble Propulsion 105
3.2.3 Biological Propulsion 109
3.2.4 Self-Thermophoresis 113
3.3 Materials and Fabrication Techniques 114
3.3.1 Tubular Micro-Robots 115
3.3.1.1 Rolled-up technology 116
3.3.1.2 Template synthesis 118
3.3.2 Helical Micro-Robots 119
3.3.3 Flexible Tail Micro-Robots 122
3.3.4 Janus Micro-Robots 124
3.4 Biomedical Applications 125
3.4.1 Delivery 127
3.4.2 Surgery 130
3.4.3 Sensing and Diagnosis 132
3.5 Discussion and Future Scope 136

4 Microfluidics in Neuroscience 149

Pallavi Gupta, Nandhini Balasubramaniam, Kiran Kaladharan,
Fan-Gang Tseng, Moeto Nagai, Hwan-You Chang, and
Tuhin S. Santra
4.1 Introduction 150
4.2 Traditional Microfluidic Devices 152
4.3 Current Approaches 153
4.3.1 Compartmentalized Microfluidics 154
4.3.2 Single-Cell Monitoring 156
4.3.3 Co-culturing 162
4.3.3.1 Types of co-culture systems 162
4.3.3.2 Blood–brain barrier 163
4.3.3.3 Co-culturing of neural cells 164
4.3.4 Integrated Microfluidic/Microelectrode Array 166
4.3.5 Hydrogel Gradients 169
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viii Contents

4.4 Applications 171

4.4.1 Neuron Differentiation and Polarity 172
4.4.1.1 Axon guidance 173
4.4.1.2 Patterned substrates 173
4.4.2 Biochemical Gradients 175
4.4.3 Electrophysiological Recordings 177
4.4.4 Dendritic Signaling and Synapse Formation 180
4.4.5 Developmental Study at Cell
Population/Tissue/Organ-on-a-Chip
(Brain-on-a-Chip) Level 184
4.4.6 Neurodegenerative Studies 188
4.5 Future Prospects 194
4.6 Summary 196

5 Vascularized Microfluidic Organ on a Chip and Its

Applications 213
Qiyue Sun, Jianghua Pei, Qinyu Li, and Xiaolin Wang
5.1 Introduction 214
5.2 In vitro Vascularization Strategies 215
5.2.1 EC Lining–Based Methods 216
5.2.1.1 Microneedle-based removable method 217
5.2.1.2 Micropatterned planar hydrogel slab
bonding method 218
5.2.1.3 Dissolvable material–based sacrificial
micromolding method 218
5.2.1.4 EC lining inside a PDMS-based
microfluidic channel 219
5.2.2 Vasculogenesis- and Angiogenesis-Based
Methods 221
5.2.2.1 Vasculogenesis 221
5.2.2.2 Angiogenesis 222
5.2.2.3 Hybrid methods 223
5.3 Vascular-Inducing Factors 226
5.3.1 Biomechanical Factors 226
5.3.2 Extracellular (or Diffusible) Signaling
Molecules 228
5.3.3 Cell Source and Cell–Cell Interaction 230
5.4 Selective Vascular Barrier 230
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Contents ix

5.5 Application of Engineered Microvascular Networks

to Cancer Biology 234
5.5.1 Tumor Angiogenesis 235
5.5.2 Tumor Intravasation 237
5.5.3 Tumor Extravasation 237
5.5.4 Tumor Microenvironment 238
5.5.5 Application of Vascularized Tumor on a Chip 239
5.5.5.1 Anticancer drug screening 239
5.5.5.2 Different tumor therapies 240
5.6 Conclusions and Future Perspectives 241

6 DNA Gene Microarray Biochip and Applications 255

Jian-Chiun Liou
6.1 Introduction 256
6.2 Combining Nanotechnology’s Biochips 259
6.3 Simulation of the Injection Performance of a
Single-Channel Injection Chamber 260
6.4 Experiment and Results 266
6.5 Conclusions 271

7 Microneedles: Current Trends and Applications 275

Hima Manoj, Pallavi Gupta, Loganathan Mohan,
Moeto Nagai, Syrpailyne Wankhar, and Tuhin S. Santra
7.1 Introduction 276
7.2 History of Microneedles 278
7.3 Mechanism of Drug Delivery via Microneedles 279
7.4 Types of Microneedles 283
7.4.1 Solid Microneedles 283
7.4.1.1 Solid, durable microneedles 283
7.4.1.2 Solid, degradable microneedles 283
7.4.2 Hollow Microneedles 284
7.4.3 Polymer Microneedles 287
7.4.3.1 Dissolving microneedles 288
7.4.3.2 Biodegradable polymers 291
7.4.3.3 Swellable polymers 293
7.5 Microneedle Material and Its Properties 295
7.5.1 Silicon 295
7.5.2 Metal 295
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x Contents

7.5.3 Ceramic 295

7.5.4 Silica Glass 297
7.5.5 Carbohydrate 297
7.5.6 Polymer 297
7.6 Microneedle Patch Design Parameters and Evaluation 298
7.6.1 Microneedle and Patch Geometry 298
7.6.2 Drug and Vaccine Stability in Microneedles 299
7.6.3 Mechanical Strength of Microneedles 300
7.6.4 Characterization of Penetration 300
7.6.5 In vivo Animal Model Studies 301
7.7 Applications of Microneedles 301
7.7.1 Delivery to the Skin 301
7.7.2 Cosmetology 302
7.7.3 Microneedles for Ocular Drug Delivery 304
7.7.4 Insulin Delivery 309
7.7.5 Oral and Gastrointestinal Drug Delivery 312
7.7.6 Protein and Vaccine Delivery 316
7.7.7 Miscellaneous Applications 319
7.8 Drawbacks of Microneedles 321
7.9 Future Scope 323
7.10 Summary 324

8 Microfluidic Electroporation and Applications 343

Koyel Dey, Srabani Kar, Pallavi Shinde, Loganathan Mohan,
Saumendra Kumar Bajpai, and Tuhin S. Santra
8.1 Introduction 344
8.2 Brief Overview of Electroporation 345
8.3 Recent Advancement in Electroporation 348
8.3.1 Gold Nanoparticle–Enhanced Electroporation 349
8.3.2 Carbon Nanotube–Based Electroporation 351
8.4 Recent Advancements in Single-Cell Electroporation 351
8.4.1 Single-Cell Trapping and Electroporation 352
8.4.1.1 Mechanical trap 353
8.4.1.2 Optical tweezer 353
8.4.1.3 Droplets microfluidics 354
8.4.1.4 Magnetic trap 355
8.4.2 Micro-/Nanochannel-Based Single-Cell
Electroporation 357
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Contents xi

8.4.3 Magnetoelectroporation 363

8.4.4 Optoelectronic Tweezer for Electroporation 365
8.4.5 Waveguide-Based Electroporation 368
8.4.6 Microcavity-Based Electroporation 370
8.4.7 Electrofusion 371
8.5 Applications 375
8.5.1 Imaging Based on Electrical Properties 375
8.5.2 Cell Reprogramming 377
8.5.3 Tissue Engineering and Regenerative Medicine 378
8.5.4 Intracellular Recording 378
8.5.5 Cancer Studies 379
8.5.6 Gene Transfer and DNA Vaccination 380
8.6 Limitations and Future Directions 380
8.7 Conclusions 381

9 Electrical Cell Lysis on Microfluidic Devices 401

Bashir I. Morshed
9.1 Cell Membrane and Electrical Lysis 402
9.2 Mechanism of Pore Formation and Electrical Lysis 405
9.2.1 Theories 405
9.2.2 Transmembrane Potential and Pore Formation 406
9.2.3 Transition States and Dynamics 408
9.3 Microfluidic Devices for On-Chip Electrical Lysis 412
9.3.1 On-Chip Electrical Lysis 412
9.3.2 Microchannel and Electrode Geometry 413
9.4 Electrical Lysis Parameters and Considerations 417
9.4.1 PEF Parameters 417
9.4.2 Critical Pore Formation Time 418
9.4.3 Excitation Type 418
9.4.4 Fluidic Medium 419
9.4.5 Cell Line 419
9.5 EL-Associated Phenomena 420
9.5.1 Secondary Effects 420
9.5.2 Cellular Spin Resonance 420
9.5.3 Electrofusion 420
9.5.4 Electroinsertion 421
9.5.5 Electroactivation 421
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xii Contents

9.6 On-Chip Electrical Lysis Applications 421

9.6.1 Advantages of On-Chip Electrical Lysis 421
9.6.2 Bioanalysis Device 422
9.6.3 Biofouling Treatment 422
9.6.4 Single-Cell Analysis 422
9.6.5 Cancer and Tumor Treatment 423
9.7 Summary 423

10 Microfluidics-Based Metallic Nanoparticle Synthesis and

Applications 429
Kavitha Illath, Ashwin Kumar Narasimahan, Moeto Nagai,
Syrpailyne Wankhar, and Tuhin S. Santra
10.1 Introduction 430
10.1.1 Nanoparticle Formation 432
10.1.2 Metallic Nanomaterials 434
10.2 Microfluidics 435
10.2.1 Single-Phase Microfluidics 436
10.2.2 Multiphase Microfluidics 437
10.3 Microfluidic Devices for Metallic Nanoparticle
Synthesis 438
10.3.1 Continuous-Flow Microfluidics 439
10.3.2 Segmented-Flow Microfluidics 439
10.3.3 Mixing Strategies in Microfluidics 440
10.3.4 Controlling Parameters in Metallic
Nanoparticle Synthesis 446
10.3.5 Synthesis of Gold Nanoparticles 461
10.3.6 Synthesis of Silver Nanoparticles 467
10.3.7 Synthesis of Other Metallic Nanoparticles
for Biomedical Applications 472
10.4 Biomedical Applications 475
10.4.1 Bioimaging 475
10.4.2 Biosensing 481
10.4.3 Photothermal Therapy 487
10.5 Future Prospects 490
10.6 Conclusions 491
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Contents xiii

11 Microfluidic Particle Separation and Biomedical

Applications 503
Ida Laila Ahmad and Mohd Ridzuan Ahmad
11.1 Introduction 504
11.1.1 Theory and Mechanism 506
11.1.2 Flow Resistance 508
11.2 Materials and Methods 509
11.2.1 Flow Streamlines Simulation 511
11.2.2 Microparticle Separation Simulation 512
11.2.3 Microparticle Separation Technique 513
11.3 Results and Discussions 518
11.3.1 Separation of Polystyrene Microbeads 518
11.3.2 Separation of Polydisperse Samples 520
11.4 Conclusions 524

Index 531
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Preface

Microelectromechanical systems (MEMS) are defined as miniatu-

rization of the mechanical as well as electromechanical components
(devices and structures) at the microscale level. The past two
decades have seen rapid development of MEMS technology, with
the integration of chemical engineering, biomedical engineer-
ing, chemistry, and life sciences, generating a new branch bio-
microelectromechanical systems (bio-MEMS). Bio-MEMS, or lab-on-
chip devices or micro–total analysis systems (μTAS), have proven
to be powerful and inevitable tools for cellular analysis in a
complex micro-/nanofluidic environment with their strengths of
minimum sample consumption and contamination. These devices
can potentially manipulate and detect biosamples, reagents, or
biomolecules in a micro-/nanoscale environment and precisely
perform cellular analysis because of their real-time operations,
range of designing, easy fluid control, monitoring, and programmatic
switching. The devices are not only useful for optical, mechanical,
electrical, and biochemical characterization at the cellular and
subcellular levels but also capable of cell trapping, manipulation,
isolation, separation, and lysis. Even the cellular structure and
function can be analyzed in detail with the aid of induced flow fields,
such as shear stress, by employing micro-/nanofluidic devices.
This book compiles details of cutting-edge research, including
the techniques of cell trapping, manipulation, separation, and
analysis, utilizing advanced microfluidic and bio-MEMS devices.
It encompasses several aspects of micro-/nanofluidic devices,
including neuronal cell activity in the microfluidic compartment,
vascularized microfluidic organs-on-a-chip and their implemen-
tation, different physical techniques for drug delivery, micro-
arrays for gene patterning, micro-/nanoparticle preparation and
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xvi Preface

size-based separation in a micro-/nanofluidic environment, and

their feasible biomedical applications. The chapters describe the
recent advancements in single-cell analysis (SCA), including single-
cell manipulation, separation, lysis, omics analysis, therapeutics, and
diagnostics. These SCA techniques are more beneficial compared
to cellular bulk analysis. SCA facilitates an in-depth understanding
of several fundamental characteristics at cellular and subcellular
levels, such as cellular heterogeneity characteristics and molecular
dynamics; a precise biological context, such as functional mutation
and copy number variation of cells; cell–cell interactions; and
cellular responses to the environment, and all of this knowledge is
critical for therapeutic and diagnostic purposes.
This book comprises 11 chapters broadly covering several
aspects of microfluidics and bio-MEMS-based devices for cellular
analysis. Each chapter, written by the experts, provides in-depth
analysis, potential problems, limitations, and future prospects.
Chapter 1 discusses cell manipulation, therapy, and their feasibility
for clinical applications using various microfluidic devices. It mainly
focuses on high-throughput cell capture or trapping and therapeutic
analysis at the single-cell level and discusses the advantages
of this method compared to conventional techniques. Chapter 2
demonstrates the optical manipulation of cells, including advanced
opto-electrokinetic technology for biological cell manipulation
with their different sizes, shapes, and properties. A different
optophysical mechanism has been demonstrated, including the
light control electric field, optothermal effect, optical radiative
force, and light-driven vortices. Chapter 3 discusses different
types of micro-robots or microswimmers and microswimmer-based
devices for biomedical and health care applications, with their
existing challenges and future prospects. Chapter 4 demonstrates
neuronal cell activity in a microfluidic environment. Microfluidic
devices can provide a microenvironment with fluid control, which
is an essential requirement for neuroscience research. The re-
creation of neurodegenerative disorders and neural stem cell (NSC)
behavior using microfluidic and bio-MEMS platforms with their
advantages and limitations has been discussed in this chapter,
and their processes can be used as a basis to construct brain-
on-a-chip devices. Chapter 5 elaborates on different strategies of
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Preface xvii

on-chip vascularization to create organ-specific models encompass-

ing healthy as well as pathological vascularized microtissues by
using microfluidic technologies. The chapter describes how the inte-
gration of tumor cells/spheroids into engineered microvasculature
can model vascularized tumors on a chip, which is potentially ben-
eficial for studying cancer metastasis or anticancer drug screening.
Chapter 6 discuss the formation of DNA gene microarray biochips
that can help us analyze DNA sequences, gene expression profiles,
and diseases and perform embryogenesis studies; search for tissue-
specific genes; and analyze toxicity of drugs. Chapter 7 discusses
the advanced transdermal drug delivery system using microneedles.
This chapter emphasizes in detail on the microneedle history, types,
fabrications, and working mechanism for drug delivery. It also
highlights therapeutic agent delivery using various shapes, sizes,
and composition-based microneedles. Chapter 8 focuses on recent
cutting-edge technologies for bulk and single-cell electroporation,
with their advantages, limitations, potential clinical applications,
and future prospects. In continuation, electrical cell lysis using
microfluidic and bio-MEMS devices is demonstrated in Chapter
9. The chapter briefly discusses recent on-chip electrical lysis, its
related theory and dynamics, and applications for cellular analysis.
Chapter 10 demonstrates different metallic nanoparticle synthesis
using microfluidic devices and potential biomedical applications
such as therapeutics and diagnostics, sensing and imaging, etc.
The advantages, limitations, and future challenges in nanoparticle
preparation using microfluidic devices are also discussed. Finally,
Chapter 11 emphasizes on microfluidic particle separation and
its potential biomedical applications, such as for point-of-care
diagnosis and μTAS.
This book will be interesting to the readers, especially under-
graduate and graduate students, and it will be useful for scientists
performing academic and industrial research.

Tuhin S. Santra
2021
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Chapter 1

Microfluidic Technologies for Cell

Manipulation, Therapeutics, and
Analysis

Amogh Kumar,a Pallavi Shinde,a Loganathan Mohan,a

Pallab Sinha Mahapatra,b and Tuhin S. Santraa
a Department of Engineering Design, Alumni Ave, Indian Institute of Technology,

Chennai, Tamil Nadu 600036, India

b Department of Mechanical Engineering, Indian Institute of Technology, Chennai,

Tamil Nadu 600036, India

[email protected], [email protected]

Biological cell studies commonly involve thousands or millions of

cells together, especially in the case of clinical applications. Toward
this end, conventional techniques used for research, diagnostic, and
therapeutic purposes in cellular biology fall short due to their low
throughput and inability to provide information about individual
cells. In recent years, microfluidic technologies have come to the
frontiers of research due to their seemingly vast applications and
adaptability to various requirements for conducting comprehensive
cell studies on chip. On the other hand, microfluidic-based single-
cell analysis has emerged over the past two decades owing to
high throughput combined with the ability it provides to study

Microfluidics and Bio-MEMS: Devices and Applications

Edited by Tuhin S. Santra
Copyright c 2021 Jenny Stanford Publishing Pte. Ltd.
ISBN 978-981-4800-85-3 (Hardcover), 978-1-003-01493-5 (eBook)
www.jennystanford.com