Microfluidics for Medical Applications: Volume 36 - Rilegato

Rilegato

ISBN 10: 1849736375 ISBN 13: 9781849736374

Casa editrice: Royal Society of Chemistry, 2014

Riassunto

Lab-on-a-chip devices for point of care diagnostics have been present in clinics for several years now. Alongside their continual development, research is underway to bring the organs and tissue on-a-chip to the patient, amongst other medical applications of microfluidics.

This book provides the reader with a comprehensive review of the latest developments in the application of microfluidics to medicine and is divided into three main sections. The first part of the book discusses the state-of-the-art in organs and tissue on a chip; the second provides a thorough background to microfluidics for medicine, and the third (and largest) section provides numerous examples of point-of-care diagnostics.

Written with students and practitioners in mind, and with contributions from the leaders in the field across the globe, this book provides a complete digest of the state-of-the-art in microfluidics medical devices and will provide a handy resource for any laboratory or clinic involved in the development or application of such devices.

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Informazioni sull?autore

Albert van den Berg received his MSc in applied physics in 1983, and his PhD in 1988 both at the University of Twente, the Netherlands. From 1988-1993 he worked in Neuchatel, Switzerland, at the CSEM and the University (IMT) on miniaturized chemical sensors. From 1993 until 1999 he was research director Micro Total Analysis Systems (µTAS) at MESA, University of Twente. In 1998 he was appointed as part-time professor “Biochemical Analysis Systems”, and later in 2000 as full professor on Miniaturized Systems for (Bio)Chemical Analysis in the faculty of Electrical Engineering. He received several honors and awards such as Simon Stevin (2002), ERC Advanced (2008) and ERC Proof of Concept (2011, 2013) grants, Spinoza prize (2009), Honorary University Professorship (Twente, 2010), and Distinguished Professor at SCNU (Guangzhou, 2012). He has co-authored over 250 papers (H=44) and over 10 patents, and has been and is involved in 6 spin-off companies. He is member of the Dutch National Health Council and became a board member of the Royal Dutch Academy of Sciences (KNAW) in 2011. He has been co-initiator and chairman of the international Micro Total Analysis Conference. His current research interests focus on microanalysis systems and nanosensors, nanofluidics and single cells, tissues and organs on chips, especially with applications in personalized health care, drug development and development of sustainable (nano)technologies.

Dalla quarta di copertina

Lab-on-a-chip devices for point of care diagnostics have been present in clinics for several years now. Alongside their continual development, research is underway to bring the organs and tissue on-a-chip to the patient, amongst other medical applications of microfluidics.

This book provides the reader with a comprehensive review of the latest developments in the application of microfluidics to medicine and is divided into three main sections. The first part of the book discusses the state-of-the-art in organs and tissue on a chip; the second provides a thorough background to microfluidics for medicine, and the third (and largest) section provides numerous examples of point-of-care diagnostics.

Written with students and practitioners in mind, and with contributions from the leaders in the field across the globe, this book provides a complete digest of the state-of-the-art in microfluidics medical devices and will provide a handy resource for any laboratory or clinic involved in the development or application of such devices.

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Microfluidics for Medical Applications

By Albert van den Berg, Loes Segerink

The Royal Society of Chemistry

Copyright © 2015 The Royal Society of Chemistry
All rights reserved.

ISBN: 978-1-84973-637-4

Contents

Chapter 1 Microtechnologies in the Fabrication of Fibers for Tissue Engineering Mohsen Akbari, Ali Tamayol, Nasim Annabi, David Juncker and Ali Khademhosseini, 1, 
Chapter 2 Kidney on a Chip Laura Ha, Kyung-Jin Jang and Kahp-Yang Suh, 19, 
Chapter 3 Blood-brain Barrier (BBB): An Overview of the Research of the Blood-brain Barrier Using Microfluidic Devices Andries D. van der Meer, Floor Wolbers, Istvãn Vermes and Albert van den Berg, 40, 
Chapter 4 The Use of Microfluidic-based Neuronal Cell Cultures to Study Alzheimer's Disease Robert Meissner and Philippe Renaud, 57, 
Chapter 5 Microbubbles for Medical Applications Tim Segers, Nico de Jong, Detlef Lohse and Michel Versluis, 81, 
Chapter 6 Magnetic Particle Actuation in Stationary Microfluidics for Integrated Lab-on-Chip Biosensors Alexander van Reenen, Arthur M. de Jong, Jaap M. J. den Toonder and Menno W. J. Prins, 102, 
Chapter 7 Microfluidics for Assisted Reproductive Technologies David Lai, Joyce Han-Ching Chiu, Gary D. Smith and Shuichi Takayama, 131, 
Chapter 8 Microfluidic Diagnostics for Low-resource Settings: Improving Global Health without a Power Cord Joshua R. Buser, Carly A. Holstein and Paul Yager, 151, 
Chapter 9 Isolation and Characterization of Circulating Tumor Cells Yoonsun Yang and Leon W. M. M. Terstappen, 191, 
Chapter 10 Microfluidic Impedance Cytometry for Blood Cell Analysis Hywel Morgan and Daniel Spencer, 213, 
Chapter 11 Routine Clinical Laboratory Diagnostics Using Point of Care or Lab on a Chip Technology Gábor L. Kovács and István Vermes, 242, 
Chapter 12 Medimate Minilab, a Microchip Capillary Electrophoresis Self-test Platform Steven S. Staal, Mathijn C. Ungerer, Kris L. L. Movig, Jody A. Bartholomew, Hans Krabbe and Jan C. T. Eijkel, 259, 
Subject Index, 289, 

CHAPTER 1

Microtechnologies in the Fabrication of Fibers for Tissue Engineering

MOHSEN AKBARI, ALI TAMAYOL, NASIM ANNABI, DAVID JUNCKER AND ALI KHADEMHOSSEINI

1.1 Introduction

Tissue engineering is a multidisciplinary field that brings together researchers with backgrounds in engineering, biology, medicine, and chemistry to build tissue-like constructs for patient treatment or research. The ultimate goal of many research efforts in tissue engineering is to create biological replacements for diseased and damaged organs in the human body. Such constructs should mimic the physiological environment including the structural and physicochemical features of native tissues. Therefore, fabrication tools that allow for the creation of biocompatible complex 3D structures with controlled internal architecture and cell distribution and an effective vascular network are required.

Fiber-based techniques, which include textile technologies (i.e. weaving, braiding, knitting, embroidering), electrospinning, and direct writing, hold great promise for engineering 3D biomimetic tissue-like constructs. These techniques enable tuning the mechanical and structural properties of the fabricated constructs with interconnected pores and controlling the distribution of different cell lines in the constructs. Creating biopolymeric fibers with topographical properties that vary spatiotemporally on the micro- or nanoscale is the initial step for any fiber-based tissue engineering approach. In addition, fibers can serve as carriers for biomolecules and microorganisms. The biological and mechanical properties of the fabricated fibers are essential for the functionality of the resultant tissue constructs. Surface topology of the fibers also plays an important role in directing cell growth within the tissue construct.

Recent developments in microtechnologies along with the fast pace of growth of biopolymer science have allowed for the fabrication of fibers with amenable biomechanical properties for tissue engineering. In this chapter, we describe fiber fabrication techniques used in tissue engineering while emphasizing the role of microfluidics and microtechnologies. We categorize current fiber formation techniques into four methods: i) co-axial flow systems, ii) wetspinning, iii) meltspinning (extrusion), and iv) electrospinning. These methods are popular and have been enhanced by microtechnologies. We discuss the operational principles of these techniques and explore their advantages and limitations in tissue engineering.

1.2 Fiber Formation Techniques

1.2.1 Co-axial Flow Systems

Co-axial flow in microsystems is achieved by creating two or more flow streams in parallel. Due to the laminar nature of the flow in micro-channels, the interface of fluids remains stable and mixing only occurs due to molecular diffusion across the interface between the fluids. As a result, fibers with uniform cross-section can be fabricated. Co-axial flow-based micro-fluidic systems have been recently used for creating micron-size fibers featuring different shapes and sizes and containing different cell types and chemicals. This section describes the principle and theory of co-axial fiber fabrication and explores the current state-of-the-art in creating hydrogel fibers using microfluidic systems.

The fabrication of single layer hydrogel fibers in a co-axial flow format is shown in Figure 1.1a. The microfluidic system contains a central channel that delivers a pre-polymer solution (core) into a main channel. The delivered solution from two side-channels forms a sheath flow around the core stream. Polymerization of the core solution (hydrogel formation) occurs downstream of the flow either by cross-linkers directly from the neighboring fluids or by light irradiation. The core solution can be loaded with cells or chemicals for different biomedical applications. The sheath flow acts as a lubricant and facilitates fiber formation by preventing channel clogging during the hydrogel formation. Moreover, due to the short length of microchannels containing the co-axial flow, cells are only exposed to a high shear stress and cross-linking reagents for a short time; this property helps the formation of hydrogel fibers containing viable and functional cells.

Fiber dimensions can be tuned by changing the ratio between the core and sheath flow rates and their relative viscosities. The fiber diameter, when the sheath and core viscosities are identical, is obtained from the following relationship:

[MATHEMATICAL EXPRESSION OMITTED] (1)

where Dfiber is the fiber diameter, Dchannel is the main channel diameter, and Qsh and Qcore are the sheath and core flow rates, respectively. Jeong et al. for the first time fabricated fibers using co-axial flow in a microfluidic system. Their microfluidic device was similar to the schematic shown in Figure 1.1a and comprised of a pulled glass capillary inserted in a polydimethylsiloxane (PDMS) substrate with feeding tubes, which were connected to syringe pumps. They used a photopolymerizable pre-polymer (4-hydroxybutyl acrylate (4-HBA)) as the core fluid and a mixture of 50% (v/v) polyvinyl alcohol (PVA) and 50% (v/v) deionized water (DI). They exposed the outlet channel to ultraviolet (UV) light in order to photopolymerize the core solution "on-the-fly". They showed that eqn (1) can be used for predicting the diameter of the fabricated fibers within [+ or -] 8%. In an attempt to create a glucose sensing microfiber, they mixed two enzymes, i.e. glucose oxidase (GOX) and horseradish peroxidase (HRP) in the core solution. Fibers containing enzymes responded to the glucose existing in the solution by emitting a fluorescent signal. No response was detected in the fibers without enzymes.n

In another study, Hwang et al. used a similar microfluidic device and created microfibers from poly(lactic -co-glycolic acid) (PLGA) to investigate the effects of the microfibers' diameter on the orientation of mouse fibro-blasts of L929 cells. The core solution was 10% (w/v) PLGA dissolved in dimethyl sulfoxide (DMSO) and the sheath solution was a mixture of 50% (v/v) glycerine in water. The exchange of DMSO and water at the interface between the core and sheath solution solidified the PLGA and fibers in the range of 10-242 µm were collected at the device outlet on a motorized rotating glass slide. Hwang et al. showed that cells tend to orient themselves along the long axis of these fibers more as the fiber diameter decreases.

Shin et al. created alginate fibers using a microfluidic device, schematically shown in Figure 1.1a. They used sodium alginate as the core and calcium chloride (CaCl2) as the sheath solutions. Consequently, Ca2+ ions diffused from CaCl2 into the alginate central stream along the flow direction, forming calcium alginate cell-laden fibers before exiting the microfluidic device. They showed that for a constant sheath flow rate, the fiber diameters increased as the core flow rate was increased. However, as the core flow rate increased, instability in the flow occurred and spiral curls were formed. To assess the potential use of the alginate fibers fabricated by co-axial flow configuration, Shin et al. loaded the fibers with protein and mammalian cells by mixing bovine serum albumin (BSA) and human fibroblast cells (L292) in sodium alginate, respectively. The in vitro cell viability assay confirmed that the fabrication process was not harmful to the cells.

Inspired by the work of Shin et al., Ghorbanian et al. developed a microfluidic direct writer (MFDW) to construct 3D cell-laden alginate structures containing interconnected pores. The MFDW was mounted on a motorized stage and was automatically controlled and moved at a speed synchronized with the speed of fiber fabrication. To avoid channel blockage, they designed a declogging mechanism that injected a degelling agent (e.g. ethylenediaminetetraacetic acid) to dissolve the clogged gel. They formed a simple 3D construct by layer-by-layer deposition of these cell-laden alginate fibers on a glass slide. Using a standard live/dead assay, they showed that the writing process was not harmful to mammalian cells.

To improve cell adhesion properties of alginate for tissue engineering applications, Lee et al. used a co-axial flow microfluidic system to create chitosan-alginate composite fibers. They used water-soluble chitosan and sodium alginate mixture as the core and CaCl2 as the sheath streams. It was found that the bi-component fibers offer a superior cell viability over pure alginate fibers, evidenced by their live/dead assay results for human hepa-tocellular carcinoma (HepG2) cells over 7 days of incubation. Although water-soluble chitosan is mechanically weak, the mechanical strength of the composite fibers did not change significantly.

Multiple-layer fibers can be fabricated by adding more streams to the microfluidic device. For example, Figure 1.1b shows the process of creating a two-layer composite fiber. First pre-polymer (core 1) surrounded by the second pre-polymer (core 2) enters the main channel and a sheath solution is formed around them. Cross-linking of the pre-polymers occurs downstream of the main channel either chemically or optically. The diameter of the created two-layer composite fiber can be estimated using the following relationship:

[MATHEMATICAL EXPRESSION OMITTED] (2)

where Qcore1 and Qcore2 are the volumetric flow rates of the first and second pre-polymer solutions, respectively.

Lee et al. fabricated a microfluidic device, similar to the schematic shown in Figure 1.1b, to create hollow alginate fibers. They used CaCl2 as core 1, sodium alginate as core 2, and another stream of CaCl2 as the sheath stream. They encapsulated HIVE-25 cells in the hollow fibers and implanted them in a composite hydrogel (mixture of agar, gelatin, and fibronectin). The composite hydrogel was loaded with human smooth muscle cells (HIVS-125) to closely mimic a tissue with a stable microvessel network.

In another study, Hu et al. devised a triple-orifice spinneret to create co-axial flow of three different types of hydrogels. They used a wide range of hydrogel materials including enzymatically cross-linking gelatin-hydroxyphenylpropionic acid (Gtn-HPA), alginate, poly-(JV-isopropyl acrylamide) (poly(NIPAAM)), and polysulfone. With their triple-orifice spinneret, Hu et al. fabricated hollow and multilayer composite cell-laden fibers. The ability to change the flow rate of each stream during the fiber fabrication process enabled them to change the total fiber diameter and thickness of each layer "on the fly".

The morphology of the fabricated fibers can be determined by changing the cross-sectional shape of the main channel. For example, Kang et al. used a grooved round channel to fabricate artificial tubuliform fibers with grooves on their surfaces (Figure 1.1c). They showed that the number of grooves and their sizes could be tuned by changing the shape of the channel and adjusting the flow rates. The grooved fibers were then used to investigate the effect of mechanical cues on rat embryonic neurons (Figure 1.1d). It was shown that the neural cells aligned themselves along the ridges of the nanogrooved fibers, indicating that the surface morphology of fibers played an important role on the cellular behaviour of the neurons.

Hydrogel fibers that are heterogeneous in chemical and physical microstructure are of interest to better mimic the microenvironment of natural tissues. Yamada et al. fabricated a PDMS-based microfluidic system to continuously synthesize chemically and physically anisotropic calcium–alginate fibers. Their device comprised a main core stream (propylene glycolþalginateþcells) co-axed with three streams of propylene glycolþalginate, buffer solution, and CaCl2 solution. Cell-laden fibers were collected by a rotating roller that was partially dipped in a bath of CaCl2. They added polyglycolic acid (PGA) to the alginate solution to adjust the stiffness of the local region of the alginate fibers and form sandwich-type solid-soft-solid structures. They showed that these structures provided better control of the cellular proliferation and networking. Inspired by the silk-spinning process in spiders, Kang et al. developed a microfluidic chip consisting of six hydrogel streams and one sheath flow (Figure 1.2a). They used sodium alginate solutions loaded with different chemicals and cell types and CaCl2 as the curing agent. The composition of the fabricated fibers was controlled using pneumatic valves. With this configuration, they controlled the spatial topography and chemical composition along the fibers. For example, they coded their fibers in serial (Figure 1.2b) and parallel (Figure 1.2c) configurations. They used the parallel coding feature to co-culture hepatocytes and fibroblasts on a single fiber. This shows the robustness of using microfluidic platforms for fabrication of cell-laden fibers for tissue engineering applications.

Fiber fabrication using co-axial flow in microfluidic systems holds great promise as it enables continuous fabrication of fibers with tunable morphological, structural, and chemical features. Various hydrogels including chemically and optically cross-linkable materials can be used in the co-axial format. Moreover, the incorporation of cells and chemicals in single- and multilayer fibers during the manufacturing process is possible. However, the biopolymers that are currently in use cannot form mechanically strong fibers to be easily manipulated. Furthermore, the process of fiber fabrication is relatively slow, which makes creating 3D structures a time-consuming process.

1.3 Wetspinning

In wetspinning, polymer fibers are formed by continuously injecting a pre-polymer solution into one or multiple coagulation baths to polymerize and form long fibers. The system is usually simple and includes a reservoir for the pre-polymer, a spinneret, and a coagulation bath (Figure 1.3a). Pre-polymers can be injected manually, gravitationally, using a syringe pump, or using pressurized air. To achieve chemically and mechanically stable fibers, the pre-polymer and the final polymer should be insoluble in the coagulation solution. Fibers fabricated by this method can be deposited randomly or in a predefined pattern in the coagulation bath to form a porous scaffold or can be collected on a motorized spool and assembled in a consequent process. Wetspinning has been widely used for fabrication of fibers from various biocompatible materials including alginate, collagen-alginate composite, collagen, chitosan, poly ε-caprolactone (PCL), starch-PCL composite, chitosan-tripolyphosphate composite, and calcium phosphate cement-alginate composite. Fiber diameter can be adjusted by controlling the polymer composition and viscosity, the injection flow rate, and the diameter of the spinneret.' In general, wetspun fibers have been fabricated with a wide a range of diameters from ~30 to 600 µm. In addition, the velocity of the pre-polymer jet entering the coagulation bath and the relative viscosity of both solutions should be optimized to prevent instability in the fiber (polymer) stream, which can affect the quality of the fabricated fibers.

For example, Tuzlakoglu et al. created chitosan fibers using the wetspinning process for bone tissue engineering. They dissolved chitosan in acetic acid and injected the solution in a bath of 30% 0.5 M Na2SO4, 10% 1 MNaOH, and 60% water and created randomly deposited fibers. They kept fibers in the coagulation bath for 1 day to fully cross-link. Tuzlakoglu et al. seeded the scaffolds with osteoblast-like cells, which proliferated (Figure 1.3b,c). In another work, Neves et al. created chitosan/PCL composite fibers by injecting the pre-polymer solution into a methanol bath, which formed fibers. They formed randomly deposited 3D scaffolds with porosity in the range of 64% to 83%. The scaffolds were seeded with bovine chondrocytes for cartilage tissue engineering. They showed that the presence of PCL resulted in rough fiber surface, which led to better cell attachment. Pati et al. formed fibers by adding chitosan to two different coagulation baths containing sodium triphosphate and NaOH to form chitosan-TPP and regular chitosan fibers, respectively. Fibers were deposited over each other to form a scaffold with porosities up to 89%. Chitosan-TPP scaffolds had a higher degradation rate than chitosan scaffolds. Chitosan-TPP scaffolds also offered a better cell viability and a faster degradation rate.

(Continues...)

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Dettagli dell'edizione

• Editore: Royal Society of Chemistry
• Data di pubblicazione: 2014
• Lingua: Inglese
• ISBN 10: 1849736375
• ISBN 13: 9781849736374
• Rilegatura: Copertina rigida
• Numero di pagine: 303
• Redattore: Van Den Berg Albert, Segerink Loes
• Contatto del produttore: non disponibile
• Persona responsabile: non disponibile