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«Directed By: Professor Srinivasa R. Raghavan & Professor Don L. DeVoe This dissertation focuses on applying droplet-based microfluidics to fabricate ...»

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Title of Document: Microfluidic Production of Polymeric Functional Microparticles

Kunqiang Jiang, Doctor of Philosophy, 2013

Directed By: Professor Srinivasa R. Raghavan & Professor Don L. DeVoe

This dissertation focuses on applying droplet-based microfluidics to fabricate new

classes of polymeric microparticles with customized properties for various applications.

The integration of microfluidic techniques with microparticle engineering allows for unprecedented control over particle size, shape, and functional properties. Specifically, three types of microparticles are discussed here: (1) Magnetic and fluorescent chitosan hydrogel microparticles and their in-situ assembly into higher-order microstructures; (2) Polydimethylsiloxane (PDMS) microbeads with phosphorescent properties for oxygen sensing; (3) Macroporous microparticles as biological immunosensors.

First, we describe a microfluidic approach to generate monodisperse chitosan hydrogel microparticles that can be further connected in-situ into higher-order microstructures. Microparticles of the biopolymer chitosan are created continuously by contacting an aqueous solution of chitosan at a microfluidic T-junction with a stream of hexadecane containing a nonionic detergent, followed by downstream crosslinking of the generated droplets by a ternary flow of glutaraldehyde. Functional properties of the microparticles can be easily varied by introducing payloads such as magnetic nanoparticles and/or fluorescent dyes into the chitosan solution. We then use these prepared microparticles as “building blocks” and assemble them into high ordered microstructures, i.e. microchains with controlled geometry and flexibility.

Next, we describe a new approach to produce monodisperse microbeads of PDMS using microfluidics. Using a flow-focusing configuration, a PDMS precursor solution is dispersed into microdroplets within an aqueous continuous phase. These droplets are collected and thermally cured off-chip into soft, solid microbeads. In addition, our technique allows for direct integration of payloads, such as an oxygen-sensitive porphyrin dye, into the PDMS microbeads. We then show that the resulting dye-bearing beads can function as non-invasive and real-time oxygen micro-sensors.

Finally, we report a co-flow microfluidic method to prepare uniform polymer microparticles with macroporous texture, and investigate their application as discrete immunological biosensors for the detection of biological species. The matrix of such microparticles is based on macroporous polymethacrylate polymers configured with tailored pores ranging from hundreds of nanometers to a few microns. Subsequently, we immobilize bioactive antibodies on the particle surface, and demonstrate the immunological performance of these functionalized porous microbeads over a range of antigen

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Advisory Committee:

Professor Srinivasa Raghavan, Chair Professor Don DeVoe,Co-Chair Professor Michael Zachariah Professor Daniel Falvey Professor Philip Deshong Professor Gregory Payne © Copyright by Kunqiang Jiang 2013 Dedication This dissertation is dedicated to my parents and my family for all their love, supports and sacrifices over the years. They give me the courage to be here today.

–  –  –

My four years of graduate study at Maryland have been always filled with learning, inspiration, and enjoyments. First I would like to thank my academic advisors, Professor Srinivasa Raghavan and Professor Don DeVoe, for providing the unique and wonderful opportunity to work in their groups and for their continuous guidance and encouragement over the years. I sincerely appreciate the unmatched dedication and patience they offer to their students and I am so blessed to have been one of them. They teach me valuable lessons on the importance of curiosity, determination and preservation through the journey of scientific research.

I want to give my sincere gratitude to my PhD committee members: Prof. Michael Zachariah, Prof. Daniel Falvey, Prof. Philip Deshong, Prof. Gregory Payne, for their guidance and mentorship throughout my graduate study. I am so thankful to have such an enriching experience working with them. In addition, I would like to thank Prof, Ian White for these insightful and fruitful discussions about ideas and projects.

I owe a lot of thanks to all of my peer colleagues in the labs of Complex Fluids and Nanomaterials Group and Maryland MEMS & Microfluidics Lab, for providing such a diverse, wonderful and always fun working environment. It has been a great pleasure to share thoughts with them and learn from them.

Special thanks go to all my friends at Maryland for these foods, movies, sports, as well as friendship and supports. I am grateful to have met each one of you.

To my parents and my family members, you are the people I owe the most.

Thanks for all your love and encouragements that keep me brave and warm even I ran off thousands of miles away.


Table of Contents



Table of Contents.........…

List of Tables.........…

List of Figures.........…

Chapter 1. Introduction and Overview

1.1. Problem Description and Motivation

1.2. Proposed Approach

1.2.1. Hydrogel Microparticle and Their Assembly…

1.2.2. Polydimethylsiloxane (PDMS) Microparticles

1.2.3. Macroporous Microparticles

1.3. Significance of This Work

Chapter 2. Background

2.1. The Science of Microparticles

2.2. Parameters to Characterize Microparticles

2.2.1. Composition………

2.2.2. Particle Size and Particle Size Distribution

2.2.3. Geometric Shape

2.2.4. Functional Properties

2.3. Microfluidic Production of Microparticles

2.3.1. T-Junction

2.3.2. Flow-Focusing

2.3.3. Co-Flow

2.4. Factors that Control Droplet Generation

2.4.1. Capillary Number

2.4.2. Flow Rate Ratios

2.4.3. Liquid Viscosities

2.4.4. Sidewall Wettability

2.4.5. Effects of Surfactants

2.5. Polymerization of Droplet Precursors

2.5.1. Thermal Curing

2.5.2. UV Crosslinking

2.5.3. Chemical Crosslinking

2.6. Fabrication of Microfluidic Devices

2.6.1. PDMS Soft Lithography

2.6.2. Thermoplastic Microfabrication

2.6.3. Capillary Assembly

iv Chapter 3. Microfluidic Production and Assembly of Chitosan Microparticles………....25

3.1. Introduction

3.2. Experimental Section

3.3. Results and Discussion

3.3.1. Droplet Generation and Conversion to Robust Microparticles........... 31 3.3.2. Linking Microparticles into Microchains

3.3.3. Magnetic Chains of Varying Flexibility

3.3.4. Future Outlook

3.4. Conclusions

Chapter 4. Monodisperse PDMS Microbeads as Discrete Oxygen Sensors

4.1. Introduction

4.2. Experimental Section

4.3. Results and Discussion

4.3.1. Microfluidic Production of PDMS Microparticles

4.3.2. Performance as Oxygen Sensors

4.4. Conclusions

Chapter 5. Microfluidic Synthesis of Macroporous Polymer Immunobeads…….


5.1. Introduction

5.2. Experimental Section

5.3. Results and Discussion

5.3.1. Macroporous Microsphere Synthesis

5.3.2. Immunobead Functionalization

5.3.3. Immunobead Performance

5.4. Conclusions

Chapter 6. Conclusions and Recommendations

6.1. Project Summary and Principal Contributions

6.2. Recommendations for Future Work

6.2.1. Chitosan Microparticle Assembly

6.2.2. PDMS Microparticles: Synthesis and Other Applications.................. 80 6.2.3. Macroporous Microparticles: Other Applications

References……………….………………………………………………………………. 83

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Table 2.1.

Brief summary of important aspects in the production of microparticles…….. 9 Table 2.2.

General considerations for microfluidic production of microparticles…..……12 Table 6.1.

Brief summary of polymeric functional microparticles developed in this thesis……………………………………………………………………………………...76

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Figure 1.1.

A new approach to “micro-manufacturing”: microfluidic fabrication of magnetic and fluorescent chains using chitosan microparticles as building blocks……… 2 Figure 1.2.

Schematic illustration of the production process of PDMS microparticles on a flow focusing thermoplastic device. These produced PDMS microparticles can be further functionalized with various encapsulants………………………………………………… 3 Figure 1.3.

Uniform polymer microparticles with macroporous textures. The surface of these microparticles has been modified with bioactive species so that they can serve as high performance immunobeads…………………………………………………………. 4 Figure 2.1. Dimensional scale for various types of natural and synthetic objects. The scope of microparticle research focuses on the size scale ranging from 500 nm to 500 m.

Control over particle size, composition, geometry and functionality is the main focus in microparticle research……………………………………………………………………. 8 Figure 2.2.

Schematic illustration of different types of droplet generators including T-Junction, Flow Focusing and Co-Flow configurations……………………………….. 13 Figure 2.3.

Schematic illustration of typical fabrication procedures for microfluidic devices via PDMS soft lithography……………………………………………………... 21 Figure 2.4.

Schematic illustration of the fabrication routes of thermoplastics microfluidic devices. Top route: hot embossing method; bottom route: direct micro-machining…… 23 Figure 2.5.

Schematic illustration of procedures for droplet generator assembled from capillaries. (a) capillary pulling under heat; (b) breakage of the pulled tip via microforging; (c) assembled microdroplet generator; (d).microscopic image of such a device……………………………………………………………………………………. 24 Figure 3.1. Microfluidic generation of chitosan microparticles. The channels have a rectangular cross-section (125 m height and 100 m width). At the T-junction, the dispersed phase (an aqueous chitosan solution) is contacted with the continuous phase (a solution of the detergent, Span 80 in hexadecane), and in turn, discrete aqueous droplets are formed. These droplets travel down the channel and meet the flow of the incubation phase, which consists of glutaraldehye (GA) emulsified in hexadecane using Span 80.

The GA crosslinks the droplets as they travel through the long, serpentine channel segment. Ultimately, the droplets are converted into particles and these are collected in the reservoir at the end. The inset shows a single microparticle: note that the chitosan chains are covalently linked by GA and the particle is stabilized in hexadecane by detergent molecules.

vii Figure 3.2.

Optical micrographs of: (a) spherical chitosan-bearing aqueous droplets in hexadecane (these were not contacted with GA); (b) plug-like microparticles formed by crosslinking the above droplets with GA; (c) the above microparticles transferred from hexadecane to deionized water, and (d) close-up of a single microparticle in water. Note that the droplets/particles contain MNPs, and the black spots in the images correspond to aggregates of these MNPs.

Figure 3.3.

(a) Schematic depiction of the on-chip process for linking individual particles into chains. (1) A stainless steel wire is used as a valve to block the channel outlet, (2) the wire is held until the desired number of subunits has been accumulated on the chain, and (3) the wire is then removed and the chain is flushed into the reservoir. (b) Optical micrograph showing a close-up of the assembled chain inside the microchannel.

Figure 3.4.

(a) Schematic of the modified chip design used to prepare chains of alternating particles. The chip has two T-junctions, corresponding to two dispersed phases. One dispersed phase has 0.1% of the fluorescent dye, sodium fluorescein while the other does not contain dye. When the flow rates of the two dispersed phases are set equal, an alternating sequence of drops with and without the dye travel down the channel, where they are fixed into chains as described in Figure 3.3. (b) Fluorescence micrograph showing a particle chain with alternating fluorescent and non-fluorescent subunits........ 36 Figure 3.5. Rotation of a rigid magnetic chain when a bar magnet is rotated above the holding container. The chain is formed by extensive fusion of three chitosan particles bearing MNPs and a fluorescent dye. (1) to (3) represent successive images taken using a fluorescence microscope. Arrows indicate the direction of the net (induced) magnetic dipole at each instant.

Figure 3.6.

Undulating or “beating” motion of a semiflexible magnetic chain when a magnet is swayed on top of the holding container. (1) to (6) represent successive images obtained using a bright-field optical microscope. Scale bars in all images are 200 m.... 39 Figure 4.1.

Illustration of the scheme for producing PDMS microbeads that can be used as oxygen sensors. (a) Microfluidic generation of PDMS droplets bearing a phosphorescent dye by flow-focusing on a PMMA microfluidic device; (b) Off-chip curing of the PDMS droplets at 70C; (c) Rinsing and harvest of the resulting dyebearing microbeads; (d) Use of these microbeads for oxygen sensing.

Figure 4.2.

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