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Biomedical 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 Academic Press 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom © 2021 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN: 978-0-12-818791-3 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals Publisher: Mara Conner Acquisitions Editor: Fiona Geraghty Editorial Project Manager: Joshua Mearns Production Project Manager: Prem Kumar Kaliamoorthi Cover Designer: Mark Rogers Typeset by SPi Global, India To the love of my life, my beautiful wife Angela without whom this book would not have been possible. Michael R. Hamblin 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 laboratory 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 microfluidics, 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 microchannels. One chapter covers the basic principles of design and synthesis of the actual microchannels, and another covers the synthetic approaches to prepare the materials 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, however, 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 microfluidics 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 always 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 important 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 applications [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 reports. 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 biomedical research, with many more opportunities compared to traditional laboratory techniques [18, 22]. For instance, the integration between microfluidics and electrophoresis 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