Table Of ContentBiomedical
Applications of
Microfluidic Devices
Biomedical
Applications of
Microfluidic Devices
Edited by
Michael R. Hamblin
Distinguished Visiting Professor, Laser Research Centre, University
of Johannesburg, South Africa
Mahdi Karimi
Cellular and Molecular Research Center, Iran University of
Medical Sciences, Tehran, Iran
Department of Medical Nanotechnology, Faculty of Advanced
Technologies in Medicine, Iran University of Medical Sciences,
Tehran, Iran
Oncopathology Research Center, Iran University of Medical
Sciences, Tehran, Iran
Research Center for Science and Technology in Medicine, Tehran
University of Medical Sciences, Tehran, Iran
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Contributors
Shahin Aghamiri
Student Research Committee, Department of Medical Biotechnology, School of
Advanced Technologies in Medicine; Cellular and Molecular Biology Research
Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Sepideh Ahmadi
Student Research Committee, Department of Medical Biotechnology, School of
Advanced Technologies in Medicine; Cellular and Molecular Biology Research
Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Samet Akar
Department of Mechanical Engineering, Çankaya University, Ankara, Turkey
Mojtaba Bagherzadeh
Department of Chemistry, Sharif University of Technology, Tehran, Iran
Nafiseh Baheiraei
Tissue Engineering and Applied Cell Sciences Division, Department of
Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran,
Iran
Sajad Bahrami
Department of Medical Nanotechnology, Faculty of Advanced Technologies in
Medicine, Iran University of Medical Sciences, Tehran, Iran
Beheshteh Khodadadi Chegeni
Oncopathology Research Center, Iran University of Medical Sciences, Tehran,
Iran
Arefeh Ebadati
Department of Medical Nanotechnology, Faculty of Advanced Technologies in
Medicine; Oncopathology Research Center, Iran University of Medical Sciences,
Tehran, Iran
Akbar Hasanzadeh
Department of Medical Nanotechnology, Faculty of Advanced Technologies in
Medicine; Advances Nanobiotechnology and Nanomedicine Research Group
(ANNRG), Iran University of Medical Sciences, Tehran, Iran
Iman Hashemzadeh
Department of Medical Nanotechnology, Faculty of Advanced Technologies in
Medicine; Advances Nanobiotechnology and Nanomedicine Research Group
(ANNRG), Iran University of Medical Sciences, Tehran, Iran
Masoumehossadat Hosseini
Faculty of Chemistry and Petroleum Sciences, Department of Chemistry,
Shahid Beheshti University; Soroush Mana Pharmed, Golrang Pharmaceutical
Investment Co (GPI), Golrang Industrial Group (GIG), Tehran, Iran
xv
xvi Contributors
Mahdi Karimi
Cellular and Molecular Research Center; Department of Medical
Nanotechnology, Faculty of Advanced Technologies in Medicine; Oncopathology
Research Center, Iran University of Medical Sciences; Research Center for
Science and Technology in Medicine, Tehran University of Medical Sciences,
Tehran, Iran
Saeid Maghsoudi
Department of Medicinal Chemistry, Shiraz University of Technology, Shiraz,
Iran
Mohammed Najafi-Ashtiani
Department of Physical Therapy, Faculty of Medical Sciences, Tarbiat Modares
University, Tehran, Iran
Negar Namaei Ghasemnia
Biomaterials Group, Department of Biomedical Engineering, Amirkabir
University of Technology, Tehran, Iran
Erdinc Naseri
Department of Cardiovascular Surgery, Park Hayat Hospital, Afyon, Turkey
Behzad Nasseri
Drug Applied Research Center, Department of Medical Biotechnology, Faculty
of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz,
Iran
Shirin Nour
Tissue Engineering Group, Biomedical Engineering Department, Amirkabir
University of Technology (Tehran Polytechnic), Tehran, Iran
Mohammad Rabiee
Biomaterials Group, Department of Biomedical Engineering, Amirkabir
University of Technology, Tehran, Iran
Navid Rabiee
Department of Chemistry, Sharif University of Technology, Tehran, Iran
Mehdi Razavi
Biionix™ (Bionic Materials, Implants & Interfaces) Cluster, Department of
Internal Medicine, College of Medicine, University of Central Florida, Orlando,
FL, United States
Azin Rostami
Biomaterials Group, Department of Biomedical Engineering, Amirkabir
University of Technology, Tehran, Iran
Preface
Not so many years ago, the term “microfluidics” was largely unknown amongst labo-
ratory scientists, and completely unknown amongst the general public. However, an
unstoppable trend for miniaturization has revolutionized technology in all aspects
of society and industry. Famously driven by Moore’s law stating that “the number
of transistors in an integrated circuit (computer chip) doubles every 2 years,” the
computer industry has become accustomed to producing ever more powerful devices
in ever-smaller formats. The same trend is now being applied to devices that require
a flow of liquids rather than a flow of electrons. So now we have a field called mi-
crofluidics, which can be regarded as an analogous development to microelectronics
but producing chip-based devices intended for different purposes. This remarkable
increase in broad interest in this subject has motivated us to compile this edited book
to assemble both basic knowledge and research advances in one place.
The principal property that characterizes microfluidics devices, is the use of mi-
crochannels. One chapter covers the basic principles of design and synthesis of the
actual microchannels, and another covers the synthetic approaches to prepare the ma-
terials themselves. It discusses how the devices are coupled to signal read-outs and
calibrated. Some broad areas of application in the basic science areas of analytical
chemistry and synthetic organic chemistry are covered. The major emphasis, how-
ever, is on biomedical engineering and biomedical science applications. These areas
include tissue engineering, organ-on-a-chip devices, pathogen identification, and
drug/gene delivery. Special chapters cover microarrays and paper-based microfluidic
devices. To keep the coverage up-to-date one chapter addresses smartphone-based
microfluidics devices, which have clear applications in less-developed countries for
disease diagnosis and screening. Moreover, the rapidly expanding fields of genetic
engineering and nucleic acid-based therapeutics are ideally suited for the use of mi-
crofluidics approaches, due to the highly-specific recognition system being able to
occur in very small volumes of liquid.
The reader will notice that many of the authors of the chapters are based in Iran.
This is an example of the remarkable rise in high-technology science that has taken
place in Iran. Iran was ranked 4th in the world, behind China, United States, and
India in terms of the number of nanotechnology publications. Microfluidics has al-
ways been closely associated with nanotechnology, although they are not necessarily
the same thing.
The arrival of the COVID-19 pandemic in 2020 has made microfluidics even
more relevant than it otherwise might have been. The requirement for inexpensive,
rapid, and accurate tests for the presence of SARS-CoV-2 in biological samples is
ideally suited for a microfluidics-based solution. Although the timing of this book
did not allow us to have a chapter specifically dedicated to COVID-19 testing, there
will undoubtedly be reports of microfluidics-based systems designed to solve this
challenge to the whole world.
xvii
xviii Preface
The commercial introduction of microfluidics devices, that are now manufac-
tured by several major multinational companies as detailed in the book, augurs well
for the wider dissemination of this approach in the years to come. Readers are en-
couraged to stay up-to-date as the very nature of the subject implies that advances in
both basic science and biomedical applications of microfluidics will continue to be
made, and may even increase exponentially in the years to come.
Michael R. Hamblin, Editor
Mahdi Karimi, Editor
CHAPTER
1
An overview of microfluidic
devices
Saeid Maghsoudia, Navid Rabieeb,∗, Sepideh Ahmadic,d, Mohammad Rabieee,
Mojtaba Bagherzadehb, and Mahdi Karimif,g,h,i
aDepartment of Medicinal Chemistry, Shiraz University of Technology, Shiraz, Iran
bDepartment of Chemistry, Sharif University of Technology, Tehran, Iran
cStudent Research Committee, Department of Medical Biotechnology, School of Advanced
Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
dCellular and Molecular Biology Research Center, Shahid Beheshti University of Medical
Sciences, Tehran, Iran
eBiomaterials Group, Department of Biomedical Engineering, Amirkabir University of
Technology, Tehran, Iran
fCellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
gDepartment of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine,
Iran University of Medical Sciences, Tehran, Iran
hOncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
iResearch Center for Science and Technology in Medicine, Tehran University of Medical Sciences,
Tehran, Iran
*Corresponding author. E-mail: [email protected]
1.1 Introduction
In the 21st century, the development of a new approach for the analysis and detection
of many different biomolecules could address some insurmountable dilemmas. One
judicious choice could be an innovative technology that can overcome these impor-
tant issues in the life sciences. But which technology could break these barriers?
The complete dispersal and dissolution of samples in a liquid is a requirement
for significant improvement in analytical detection approaches. The optimal solution
may be to manufacture systems based on very small quantities (microliter or nanoli-
ter) of fluids (liquid or gas), along with reducing the reaction time to mere seconds,
together with miniaturized analytical technology for biomedical and chemical ap-
plications [1–3]. In the early 1950s, to get to grips with the issue of liquid sampling,
microfluidics became an interdisciplinary field using micrometer-scale channels.
According to George Whitesides [4], acknowledged to be the father of microfluidics,
microfluidics is “the science and technology of systems that process or manipulate
small (10− 9 to 10− 18 liters) amounts of fluids, has taken advantage of channels with
Biomedical Applications of Microfluidic Devices. https://doi.org/10.1016/B978-0-12-818791-3.00005-X 1
© 2021 Elsevier Inc. All rights reserved.
2 CHAPTER 1 An overview of microfluidic devices
dimensions of tens to hundreds of micrometers.” The development of microfluidics
has revolutionized the science of chemistry [5], biology [6], analytical biochemistry
[7], biotechnology [8], tissue engineering [9], and medicine [10] by allowing the
flow and manipulation of minute quantities of liquids in a network of channels
[11, 12]. Microfluidic devices have high reproducibility and robustness [13], use
high surface-to-volume ratio (m2/m3) microchannels [14], with identical fabrication,
good handling of droplets [15], improvement of mass and heat transfer, and minimal
reagent consumption during optimization [16], as well as rapid analysis, high sensi-
tivity, and good portability [8].
The history of microfluidics dates back to the mid-20th century when two scientists
Golay and Van Deemter worked on gas chromatography and liquid chromatography,
respectively. They figured out that for maintaining a high level of performance, the
diameter of the open column and the packed column particle size should be reduced;
hence columns began to be fabricated in the micrometer range. As a consequence,
capillary electrophoresis became popular for the separation of diverse biomolecules
[17]. Following these innovative studies, many groups of scientists put large amounts
of time and energy into developing microfluidic devices for fluid transport, fluid meter-
ing, fluid mixing, for the concentration and separation of molecules within minuscule
volumes of fluids [18]. These techniques were first performed in planar substrates sur-
rounding channels with lengths, widths, and depths of approximately 10 mm, 100 μm,
and 10 μm, respectively. In comparison to traditional devices that only focused to a lim-
ited extent on the physical properties, in microfluidic technologies, the focus is on vis-
cosity, surface tension, and diffusion which becomes a matter of the utmost importance
[19]. Surface tension in microfluidics is involved with: (i) passive pumping of fluids
into the devices; (ii) user-defined patterned surfaces; and (iii) filtering of undesirable
products. It is worth mentioning that gravitational forces are considered to be insignifi-
cant in microfluidic devices, due to the small overall dimensions of the devices [20].
This blooming field has been making great progress based on development re-
ports. Its market value was approximately $2.5 billion in 2017 and is projected to
increase dramatically to $5.8 billion by 2022 [21]. Microfluidic science has triggered
a renaissance in the fields of drug discovery, drug delivery, biomedical engineering,
and other lab-on-chip (LoC) applications, to which many studies have been devoted
during recent decades. Due to the intrinsic ability of microfluidics to be beneficially
coupled with a wide variety of devices onto a single chip in a straightforward, flex-
ible, and ideally monolithically manner, they are becoming highly versatile for bio-
medical research, with many more opportunities compared to traditional laboratory
techniques [18, 22]. For instance, the integration between microfluidics and electro-
phoresis in several publications has been reported. In this regard, Li et al. published
many important papers that incorporated multiple fluidic, electronic, and mechanical
devices or chemical processes onto a single chip-sized substrate [23]. Importantly,
microfluidic devices open doors for the generation of micro- and nanoparticles with
excellent size control, composition, morphology, and size distribution. Furthermore,
in microfluidic devices, the low reaction volumes needed to be combined with the
high heat and mass transfer rates, together make a variety of chemical reactions
