Microfluidic Reactors for Polymer Particles E-Book

Eugenia Kumacheva

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 468

Veröffentlichungsjahr: 2011

Beschreibung

The manipulation of fluids in channels with dimensions in the range from tens to hundreds of micrometers – microfluidics – has recently emerged as a new field of science and technology. Microfluidics has applications spanning analytical chemistry, organic and inorganic synthesis, cell biology, optics and information technology. One particularly promising application is the microfluidic synthesis of polymer particles with precisely controlled dimensions, and a variety of shapes, morphologies and compositions.

Written as a comprehensive introduction for scientists and engineers working in microfabrication and microfluidics, Microfluidic Reactors for Polymer Particles covers topics such as:

• Applications and methods of generation of polymer particles
• Physics of microfluidic emulsification
• Formation of droplets in microfluidic systems
• High-throughput microfluidic systems for formation of droplets
• Microfluidic production of polymer particles and hydrogel particles
• Polymer capsules
• Synthesis of polymer particles with non-conventional shapes

This book is intended for a broad audience, including students, researchers and engineers in industry, with interests in physics, chemistry, materials science, engineering or biotechnology.

Leseprobe

Contents

Cover

Title Page

Copyright

Preface

Chapter 1: Applications of Polymer Particles

References

Chapter 2: Methods for the Generation of Polymer Particles

2.1 Conventional Methods Used for Producing Polymer Particles

2.2 Microfluidic Generation of Polymer Particles

References

Chapter 3: Introduction to Microfluidics

3.1 Microfluidics

3.2 Droplet Microfluidics

References

Chapter 4: Physics of Microfluidic Emulsification

4.1 Energy of the Interfaces Between Immiscible Fluids

4.2 Surfactants

4.3 Interfacial Tension

4.4 Laplace Pressure

4.5 Rayleigh–Plateau Instability

4.6 Wetting of a Solid Surface

4.7 Analysis of Flow

4.8 Flow in Networks of Microchannels

4.9 Dimensional Groups

References

Chapter 5: Formation of Droplets in Microfluidic Systems

5.1 Introduction

5.2 Microfluidic Generators of Droplets and Bubbles

5.3 T-Junction

5.4 Formation of Droplets and Bubbles in Microfluidic Flow-Focusing Devices

5.5 Practical Guidelines for the Use of Microfluidic Devices for Formation of Droplets

5.6 Designing Droplets

5.7 Conclusions

References

Chapter 6: High-Throughput Microfluidic Systems for Formation of Droplets

6.1 Introduction

6.2 Effects that Modify the Pressure Distribution

6.3 Hydrodynamic Coupling

6.4 Integrated Systems

6.5 Parallel Formation of Droplets of Distinct Properties

6.6 Conclusions

References

Chapter 7: Synthesis of Polymer Particles in Microfluidic Reactors

7.1 Introduction

7.2 Particles Synthesized by Free-Radical Polymerization

7.3 Polymer Particles Synthesized by Polycondensation

7.4 Combination of Free-Radical Polymerization and Polycondensation Reactions

7.5 General Considerations on the Use of Other Polymerization Mechanisms

7.6 Important Aspects of Microfluidic Polymerization of Polymer Particles

7.7 Synthesis of Composite Particles

References

Chapter 8: Microfluidic Production of Hydrogel Particles

8.1 Introduction

8.2 Methods Used for the Production of Polymer Microgels

8.3 Microfluidic Synthesis and Assembly of Polymer Microgels

8.4 Microfluidic Encapsulation of Bioactive Species in a Microgel Interior

References

Chapter 9: Polymer Capsules

9.1 Polymer Capsules with Dimensions in Micrometer Size Range

9.2 Microfluidic Methods for the Generation of Polymer Capsules

9.3 Emerging Applications of Polymer Capsules Produced by Microfluidic Methods

References

Chapter 10: Microfluidic Synthesis of Polymer Particles with Non-Conventional Shapes

10.1 Generation of Particles with Non-Spherical Shapes

10.2 Synthesis of Janus and Triphasic Particles

10.3 Other Particles with “Non-Conventional” Morphologies

References

Summary and Outlook

Color Plates

Index

This edition first published 2011

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Library of Congress Cataloging-in-Publication Data

Kumacheva, Eugenia.

Microfluidic reactors for polymer particles / Eugenia Kumacheva and Piotr Garstecki.

p. cm.

Includes bibliographical references and index.

ISBN 978-0-470-05773-5 (cloth) — ISBN 978-0-470-97923-5 (ePDF) — ISBN 978-0-470-97922-8 (obook) — ISBN 978-1-119-99028-4 (ePub)

1. Microreactors. 2. Microfluidic devices. 3. Emulsion polymerization. I. Garstecki, Piotr. II. Title.

TP159.M53K86 2011

668.9—dc22

2010042340

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

Print ISBN: 9780470057735

ePDF ISBN: 9780470979235

oBook ISBN: 9780470979228

ePub ISBN: 9781119990284

Preface

The manipulation of fluids in channels with dimensions in the range of from tens to hundreds of micrometers – microfluidics – has recently emerged as a new area of science and technology. Microfluidics has applications spanning the analytical chemistry, organic and inorganic synthesis, cell biology, optics, and information technology fields. Many of these applications have been demonstrated over the last two decades. During the past six or seven years, microfluidic synthesis has shown very promising applications in the continuous production of high value materials, including inorganic nanoparticles, polymers, organic compounds for positron emission tomography, and polymer particles. Microfluidic synthesis of micrometer-size polymer beads with precisely controlled dimensions and a variety of compositions, shapes and morphologies, has rapidly attracted great interest from scientists and technologists with very different backgrounds and occupations, ranging from polymer colloids to cell biology and drug delivery.

The motivation behind writing this book was that it would: (i) serve as a comprehensive introduction to this rapidly developing field, (ii) guide scientists and engineers working in the area of microfabrication and microfluidics toward new applications of microfluidic devices, in particular, microreactors for the synthesis of polymer particles, and (iii) serve as a source of information for the those wishing to join the field. This book is intended for a broad audience, including undergraduate and graduate students, postdoctoral research associates, and researchers and engineers in industry.

We met in 2002 at Harvard University in the laboratory of Professor George Whitesides. The exploratory spirit of this remarkable research group inspired us to work, firstly, toward the fundamental understanding of two-phase microflows and, later, toward applications of microfluidic technologies. The Whitesides' laboratory strongly supports interdisciplinary collaboration, an attitude that was especially valuable to us, as we have very different backgrounds. We believe that we were able to combine and use our expertise in chemistry, physics and engineering, in order to develop microfluidic techniques for the formation of emulsions and of polymer particles.

The structure of this book is very straightforward. Our complementary backgrounds in polymer and materials science (E.K.) and in fluid mechanics and microfluidics (P.G.) helped us shape the book into a compehrensive review. From the applications of polymer particles and the current methods used for their synthesis (Chapters 1 and 2, respectively) we introduce the basics of microfluidics pertinent to the subject of the book (Chapter 3). The fundamental aspects of the physics of flow of immiscible liquids are covered in Chapter 4. From a detailed review of the current state-of-the-art for the methods of formation of droplets (Chapter 5) and a review of high-throughput microfluidic droplet and bubble generators (Chapter 6), we move to the synthesis of various types of polymer colloids (Chapters 7 8 9 10). The organization of the material in Chapters 7 8 9 10 is somewhat arbitrary. We believe that two separate chapters about the microfluidic synthesis of rigid polymer particles and gel microbeads (Chapters 7 and 8, respectively) provide important guidelines for the synthesis of these types of polymer particles. On the other hand, in Chapters 9 and 10 we did not make a distinction between the types of polymer colloids; instead, we discuss separately the microfluidic production of particles with capsular morphologies (Chapter 9) and particles with different shapes and structures (Chapter 10). The book is concluded with a brief summary of the future directions of research in the microfluidic production of polymer colloids.

We wish to thank Professor George Whitesides (Harvard University) for giving us the inspiration to work in this exciting field. While working at Harvard, we enjoyed the stimulating collaboration with the members of the research group and we wish to particularly thank Dr Michinao Hashimoto, Dr Michael Fuerstman, Dr Irina Gitlin, Dr Douglas Weibel (currently Professor at the University of Wisconsin-Madison), and Professor Shoji Takeuchi (currently at the University of Tokyo). We greatly appreciate scientific discussions with Professor Howard Stone (then at Harvard University now at Princeton University) and his assistance in the interpretation of experimental results. He contributed to our work with his unique knowledge and understanding of fluid hydrodynamics, and was an invaluable collaborator.

After completing research at Harvard University, the authors continued their work in their own laboratories. E.K. thanks her research group at the University of Toronto for the hard work in the area of continuous microfluidic synthesis of polymer particles. Rapid progress achieved in this fast developing field would not be possible without long hours spent in the laboratory, intensive discussions, fruitful collaborations and friendly competition within the research group. In the E.K. group, this work was pioneered by Dr Shengqing Xu (currently, a Senior Scientist at Dow Corning) and Dr Zhihong Nie, who has recently become an Assistant Professor at the University of Maryland. Patrick Lewis and Dr Minseok Seo have made the first steps toward the synthesis of copolymer particles and foam-templated materials, respectively. Dr Hong Zhang and Ethan Tumarkin paved the way for the microfluidic preparation of physically crosslinked microgels. Dr Wei Li and Jai Il Park worked on the microfluidic synthesis of particles with an interpenetrating network structure and bubble-templated particles, respectively. A large number of graduate students, postdocs, and undergraduate students participated in various research projects, including the synthesis of porous particles, particles for modeling the behavior of cells, the encapsulation of cells, microfabrication of microfluidic reactors, and characterization of monomer mixtures. The contributions of Jesse Greener, Stanislav Dubinsky, Neta Raz, Lindsey Fiddes, Lucy Siyon Chung, Chantal Paquet, Dinesh Jagadeesan, Raheem Peerani, Edmond Young, Danut Voicu, Monika Kleczek, Alexander Kumachev, and Micelle Mok are greatly appreciated. Fruitful collaborations with Professors Gilbert Walker, Peter Zandstra, Axel Guenther, Craig Simons, and Aaron Wheeler (all at the University of Toronto) helped to address the various aspects of microfluidic synthesis of polymer particles, which included fundamental fluid hydrodynamics and the applications of polymer particles. P.G. thanks the members of his research team, who continue to work on a wide range of fundamental and applied aspects of multiphase microflows. E.K. and P.G. are grateful to Anna Lee and Dr Neil Coombs for preparing the cover art for this book.

Finally, we are greatly indebted to our families who were always there for us. In particular, we thank our spouses, Boris Kumachev and Justyna Garstecka. They gave us their continuous support when we spent long hours at work and whilst we were writing this book. Without their patience and understanding the book would have never been written.

Chapter 1

Applications of Polymer Particles

Polymer particulate materials have important applications in fundamental research, in industry, biology, and medicine, and in the environmental sciences. The range of applications of polymer particles is so broad that it could be the subject of a separate book. Here we focus on the most important areas of science, technology, and medicine that currently use polymer colloids. The emphasis of the present section is on the application of polymer particles with a narrow size distribution.

The ability to synthesize monodisperse spherical polymer particles aids in the development of theoretical models for the mechanisms controlling the chemical and physical properties of particulate materials. Currently, only silica and polymer submicrometer-size microbeads can be synthesized with a truly narrow size distribution. A detailed investigation of the interactions of polymer colloids in aqueous and non-aqueous media contributed significantly to the current understanding of crystal nucleation and growth and to the mechanisms of phase transitions in colloid systems. In addition, studies of the rheology of concentrated dispersions of polymer particles and their sedimentation and self-assembly, chromatography, drug delivery and medical diagnostics, encapsulation of biologically active species (e.g., proteins or cells), and the utilization of electronic, optical, magnetic, electrokinetic properties, and film-forming properties of polymer microbeads are far from an exhaustive list of the applications of polymer colloid particles.

Polymer particles can be used as stable suspensions in polar or non-polar liquids or as solid materials, such as close packed arrays or films. Both systems find a broad range of applications due to the presence of functional groups on the particle surface. Surface functional groups can be introduced during particle synthesis with an initiator, a monomer, or with a chain-transfer agent. Examples of surface functional groups include –SO3−, –CHO, –OH, or COOH groups. Post-synthesis reactions of surface groups may occur inadvertently or with the objective of chemical modification of the surface of the polymer colloids. For instance, in poly(vinyl acetate)-based particles, hydrolysis of surface acetate ester groups transforms them into hydroxyl and acetic acid groups. Derivatization of surface functional groups is driven by the targeted application of polymer particles: heterogeneous catalysis, such as acid-catalysed hydrolyses, decarboxylation, chemical analysis, or biomedical applications. Examples of derivatization of surface functional groups include reactions of benzyl chloride groups with ammonia to produce surface amino groups, or redox reactions of surface aromatic groups to reduce them to amine groups.

Colloidal polymer catalysts have been used for organic chemical transformations, for example, hydrolysis, substitution, oxidation, hydrogenization and C–C bond formation (Ford and Miller, 2002; Arshady et al., 2002). Catalytic groups on the surface of particles include quaternary ammonium, pyridine, carboxylic and sulfonic acids, and transition metal chelates. Polymer particles typically used for heterogeneous catalysis are either relatively large microspheres (with a diameter of 40 μm and larger), or submicrometer-size latex particles. Polymer catalytic supports can be rigid (e.g., polystyrene microbeads) or soft (e.g., polysaccharide or polyacrylamide microgels).

Polymer particles find important applications in medical diagnostics, cell separation, and drug delivery (Arshady et al., 2002). Most of the biomedical applications of polymer particles exploit the binding of biological molecules, for example, proteins, DNA fragments, or antibodies, to the polymer surface when it carries specific functionalities such as aldehyde, amine, thiol, epoxy, or acid groups. For example, surface epoxy groups readily react with thiol or amine groups in biomolecules. Alternatively, carbodiimide coupling includes activation of surface carboxyl groups, which is followed by a rearrangement reaction and the formation of a covalent bond between the particle surface and a biological molecule. Chemical attachment of biomolecules ensures high specificity and irreversible adsorption, and it can be used for the sensing or separation of biological molecules.

Polymer particles have been used for immunospecific, that is, immunomagnetic or immunofluorescent, cell separation. In the first method, magnetic latex particles coated with a layer of a hydrophilic gel carry surface-attached antibodies, and thus they can attach only to the cells carrying a complementary antigen. Following the attachment, particle-coated cells are removed from the system by applying a magnetic field. In the second method, immunospecific latex particles are labeled with a fluorescent dye. Subsequent to the attachment of the particles to the cells, the cells are removed using flow cytometry.

Cell separation based on immunospecificity can be used in the therapy of cancer of the nerve cells, lymphoma, and leukemia. For example, in clinical treatment of a cancer of the nerve cells, a large sample of bone marrow is mixed with polymer magnetic particles that are immunospecific for the cancer cell surface. The separation of cancer cells is achieved by applying a strong magnetic field, then a suspension of healthy cells is introduced to the patient's bones. This step is followed by chemotherapy and radiation.

Clinical diagnostics applications of polymer particles also rely on interactions of polymer particles carrying antibodies and proteins that are characteristic of certain diseases. The detection may be in the form of coagulation (or “agglutination”), which is monitored visually or by turbidimetry, fluorescence, or colorimetrics. Other diagnostic applications are based on interactions of particles with DNA molecules or their fragments to obtain information about inherited diseases, viruses, and bacteria.

Radiolabeled polymer particles find applications in nuclear medicine, in imaging, therapy, and laboratory studies (Arshady et al., 2002). Particle size in these applications varies from several nanometers to tens of microns. Examples of radiolabeled particles are 99mTc-labeled albumin microspheres, -polylactide microspheres or -polystyrene nanospheres. The advantage of radiolabeled particles versus molecularly soluble radiolabeled species is that they maintain the radiolabel in a specific body location for diagnostic or therapeutic purposes. This can prevent or substantially reduce the spreading of radioactivity to other body parts. Another important feature of radiolabeled particles is the size selectivity of sequestering of these particles by various organs. For example, 10–90 μm-diameter radiolabeled albumin particles will be trapped in the lungs, thereby providing the ability to image this organ.

Nanometer-size and submicrometer-size polymer colloids – lyposomes, polymer microgels, polymersomes, capsules, and solid polymer particles – can also be used for drug delivery, and, in particular, targeted, site-specific drug delivery (Oupicky, 2008). A drug can be loaded in the particle interior, be a part of the particle, or it can be attached to the particle surface. The site-specific delivery of the drug is achieved by attaching biological molecules to particle surfaces, as discussed above. The problem of clearing the particles by the reticulorendothelial system is partly solved by coating them with poly(ethylene oxide).

The encapsulation of cells in polymer particles with dimensions in a range of from tens to several hundred micrometers was proposed in the early 1960s as a method of reducing the effects of immune rejection, thereby forming the basis of “cell therapy” for the treatment of various diseases. The encapsulation of cells and other biological molecules such as peptides and proteins in microgels has led to the development of systems for the study and treatment of hormone or protein deficiencies (Ross et al., 2000), hepatic failure (Liu and Chang, 2006), cancer (Cirone, Bourgeois, and Chang, 2003), and diabetes (Lim and Sun, 1980). Typically, polymer microgels encapsulating cells are prepared from biological polymers, such as alginate or agarose.

Polymer particles find applications in size-exclusion chromatography (SEC), or gel-permeation chromatography (GPC), a chromatographic method in which polymer molecules in solution are separated and analyzed based on their hydrodynamic volume. This method is generally used for the purification and analysis of synthetic and biological polymers. Polymer chemists typically use either silica, or crosslinked polystyrene particles.

Porous polymer particles are also used as ion-exchange resins (Okay, 2000). The beads have a highly developed network of pores on the surface and can easily trap and release ions, with a simultaneous release of surface-bound ions. Ion-exchange resins are widely used in separation, purification, and decontamination technologies. Water softening and purification are the most common examples of such processes. Typically, ion-exchange resins are based on crosslinked polystyrene beads. Crosslinking prolongs the time needed to accomplish ion exchange; however, crosslinked polymer particles are mechanically stronger and are more stable. The required functional groups can be introduced during or after polymerization, as discussed above. Typical groups include strongly acidic, weakly acidic, strongly basic, and weakly basic functionalities. Particle dimensions and pore size distribution strongly impact the performance of ion-exchange resins: smaller, highly porous particles have a larger surface area available for ion exchange.

Solid particle-derived materials can be formed by randomly organized particles, or by particles assembled in highly periodic, crystalline arrays. A typical example of the first system includes latex films and coatings. The need for environmentally friendly organic coatings has sparked a lot of interest in water-borne paints based on polymer latex particles. The formation of films from latex particles in the coating industry is one of the most important practical applications of polymer colloids. A broad range of specific applications includes the production of printing inks, adhesives, varnishes, and water-borne paints. Coatings are formed by applying a liquid dispersion of the polymer particles onto the substrate. Other than polymer particle additives, paints typically contain pigments, particle stabilizers, and photo- and corrosion protection agents (Ottewill and Rowell, 1997 and references therein).

The ability of monodisperse polymer colloids to assemble into regular arrays in concentrated dispersions has been known for a long time (Pieranski, 1983; van Megan, 1984; Gast and Russel, 1998). The formation of liquid colloid crystals was driven by the balance of electrostatic forces acting between the particles. Therefore the presence of surface-charged groups in polymer colloids and the ionic strength of the dispersion medium had a great influence on the ability of polymer colloids to crystallize. Recently, Geerts and Eiser (2010) reported spontaneous crystallization of micrometer-diameter polystyrene particles coated with long double-stranded DNA molecules. The DNA was weakly attracted to the oppositely charged substrate and, as a result, these two-dimensional colloidal crystals floated several microns above the surface.

Liquid colloid crystals are iridescent owing to constructive interference of light beams reflected from regularly spaced rows of particles at the Bragg angle. For a particular system the spectral position of the diffracted light depends on the crystal lattice constant, which, in turn, is determined by the properties of the continuous phase. Thus colloid crystalline arrays have found applications as diffraction gratings and chemical and biochemical sensors (Ottewill and Rowell, 1997). For example, the change in the concentration of analytes in the dispersion medium was monitored by the change in the position of diffraction peak (Weissman et al., 1996; Holtz et al., 1998). Other applications of fluid colloid crystal arrays include photothermal nanosecond light-switching devices, which change their properties in response to electric fields, and sensors to mechanical deformation (Ottewill and Rowell, 1997 and references therein).

The ability to preserve the regularity of liquid colloid crystals in the solid state has led to the development of a new class of organic and inorganic materials with properties that originated from their periodic structure, and from chemical composition (Xia et al., 2000; Paquet and Kumacheva, 2008). Two-dimensional hexagonal lattices of polymer colloidal spheres have been used as ordered arrays of optical microlenses in image processing (Hayashi et al., 1991), as masks for fabricating periodic micro- or nanostructures (Roxlo et al., 1987; Hulteen and Duyue, 1995; Hulteen et al., 1999), and as relief structures to cast elastomeric stamps (Xia et al., 1996). Three-dimensional colloid crystals of polymer particles have also been utilized as templates for the fabrication of ordered macroporous materials (Park, Qin and Xia, 1998, Yan et al., 1999; Velev et al., 1999), as filters, switches, and photonic band gap (PBG) materials.

To summarize, an expanding range of applications of polymer colloids imposes requirements on the synthesis and assembly of particles with multiple functionalities and precise control of particle size, shapes, and morphologies. Development of new methods or modification of conventional methods of particle production are required to address these requirements in the most effective and cost-efficient way.

References

Arshady, R., Corain, B., Zecca, M., Jayakrishnan, A., and Horak, D. (2002) Amphiphilic Functional Microgels. In: Functional Polymer Colloids & Microparticles, Vol. 4 (eds. R. Arshady and A. Guyot), The MML Series, Citus Books, London, pp. 203–251.

Cirone, P., Bourgeois, J.M., and Chang, P.L. (2003) Hum. Gene Ther., 14, 1065–1077.

Ford, W.T., and Miller, P.D. (2002) Functional Polymer Colloids as Catalysts. In: Functional Polymer Colloids and Microparticles, Vol. 4 (eds. R. Arshady and A. Guyot), The MML Series, Citus Books, London, pp. 171–202.

Gast, A.P., and Russel, W.B. (1998) Phys. Today, 24.

Geerts, N., and Eiser, E. (2010) Soft Mat., 6, 664–669.

Hayashi, S., Kumamoto, Y., Suzuki, T., and Hirai, T. (1991) J. Colloid Interface Sci., 144, 538.

Holtz, J.H., Holtz, J.W., Munro, C.H., and Asher, S.A. (1998) Anal. Chem., 70, 780–790.

Hulteen, J.C., and Duyue, R.P.V. (1995) J. Vac. Sci. Technol., A13, 1553–1558.

Hulteen, J.C., Treichel, D.A., Smith, M.T., Duval, M.L., Jensen, T.R., and Duyne, R.P.V. (1999) J. Phys. Chem., B, 103, 3854–3863.

Lim, F., and Sun, A.M. (1980) Science, 210, 908–910.

Liu, Z.C., and Chang, T.M.S. (2006) Liver Transplant., 12, 566–572.

Okay, O. (2000) Prog. Polym. Sci., 25, 711–779.

Ottewill, R.H., and Rowell, R.L. (1997) Order–Disorder Phenomena. In: Polymer Colloids: A Comprehensive Introduction, Academic Press, San Diego, pp. 250–275.

Oupicky, D. (2008) Adv. Drug Delivery Rev., 60, 957.

Paquet, C., and Kumacheva, E. (2008) Mater. Today11, 48–56.

Park, S.H., Qin, D., and Xia, Y.X. (1998) Adv. Mater., 10, 1028–1032.

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Ross, C.J.D., Bastedo, L., Maier, S.A., Sands, M.S., and Chang, P.L. (2000) Hum. Gene Ther., 11, 2117–2127.

Roxlo, C.B., Deckman, H.W., Gland, J., Cameron, S.D., and Chianelli, R.R. (1987) Science, 235, 1629–1631.

van Megan, W., and Snook, I. (1984) Adv. Colloid Interface Sci., 21, 119.

Velev, O.D., Tessier, P.M., Lenhoff, A.M., and Kaler, E.W. (1999) Nature, 401, 548.

Weissman, J.M., Sunkara, H.B., Tse, A.S., and Asher, S.A. (1996) Science, 274, 959–960.

Xia, Y., Tien, J., Qin, D., and Whitesides, G.M. (1996) Langmuir, 12, 4033.

Xia, Y., Gates, B., Yin, Y., and Lu, Y. (2000) Adv. Mater., 12, 693–713.

Yan, H., Blanford, C.F., Holland, B.T., Parent, M., Smyrl, W.H., and Stein, A. (1999) Adv. Mater., 11, 1003–1006.

Chapter 2

Methods for the Generation of Polymer Particles

2.1 Conventional Methods Used for Producing Polymer Particles

This chapter describes the methods that are currently used to generate polymer particles, with a particular focus on microbeads in the micrometer-size range. Particle-forming processes occur in two-phase systems, in which the starting reagent(s) and/or the resulting polymer(s) are in the form of a fine dispersion in an immiscible fluid. Classification of processes used for producing polymer particles relies on: (i) the initial state of the system (e.g, single-phase state versus a multi-phase state); (ii) the mechanism of particle formation, including chemical and physical methods; and (iii) the size of the resulting polymer particles. We will focus on the first and the second features of the classification, with emphasis on the polymerization methods.

Based on the initial state of the system, the polymerization methods can be divided into two groups. In the first group of methods, particle synthesis begins in a one-phase solution that contains molecules of monomers or reactive pre-polymers, initiators, and stabilizers. In the course of the polymerization, the system becomes heterogeneous, due to the nucleation of seed particles. Growth of primary particles occurs through the attachment of molecules or their clusters to the seeds. A classical example of this process is dispersion polymerization, in which the monomer and the initiator are soluble in the polymerization medium, but the medium is a poor solvent for the resulting macroradicals and macromolecules (Barret, 1975; Ober, Lok, and Hair, 1985; Arshady, 1992). Phase separation leads to the formation of primary particles that are swollen by the polymerization medium and/or the monomer. Polymerization proceeds largely within the particles, leading to the formation of spherical particles in a size range of from 0.1 to 10 μm. Dispersion polymerization is typically used for the synthesis of vinyl monomers, such as styrene, and acrylic monomers in hydrocarbons or in alcohol–ether or alcohol–water mixtures.

Precipitation polymerization resembles dispersion polymerization in the initial state of the reaction mixture: it is also a homogeneous solution of the monomer, initiator, and stabilizer in the polymerization medium. However, in contrast with dispersion polymerization, primary particles are not in the swollen state. A sharp distinction between dispersion and precipitation polymerizations may not always exist, however the quality of the medium as a solvent serves as a useful guide: in precipitation polymerization both initiation and polymerization processes occur largely in the homogeneous medium. Continuous nucleation and coagulation of the resulting nuclei (primary particles) lead to the formation of larger polymer particles. Examples of precipitation polymerization include the synthesis of tetrafluoroethylene in water (Suwa et al., 1979) or the preparation of poly(N-isopropylamide) microgels by polymerizing N-isopropylamide monomer dissolved in water in the presence of a chemical crosslinker (Pelton, 2000).

In classical emulsion polymerization a monomer that is scarcely soluble in the polymerization medium is emulsified in it using a surfactant (Gilbert, 1996), thus the synthesis begins in a heterogeneous system. The initial diameter of the monomer droplets is in a range of from 1 to 20 μm or larger. Excess surfactant creates micelles. The initiator is soluble in the medium, and not in the monomer. A small amount of monomer diffuses through the medium to the micelles where it reacts with the monomer, and the monomer-swollen micelles become the main loci of polymerization. In the next stage, more monomer molecules from the droplets diffuse to the growing particles and react with initiator molecules. Eventually, the monomer droplets disappear and all remaining monomer is localized in the particles where polymerization continues, until all monomer is polymerized. Typically, the final product is a dispersion of polymer particles in water, known as latex particles. The size of the latex particles thus produced is usually in the range 50–500 nm. Larger particles are generated via a multi-step polymerization process (see later in this chapter).

Microemulsion polymerization begins in a thermodynamically stable emulsion of nanometer-size monomer droplets. Microemulsions are spontaneously formed in the presence of high concentrations of surfactants, which reduce the value of interfacial tension at the monomer–continuous phase to close-to-zero values. Polymerization yields small (in the order of 5–50 nm in size) polymer particles that coexist with empty micelles formed by surfactant molecules (Chang et al., 1998); Candau, Pabon, and Anquetil, 1999.

Miniemulsion and suspension polymerizations occur in monomer droplets containing a monomer-soluble initiator (Hopff, Lussi, and Hammer, (1965); Yuan, Kalfas, and Ray, 1991; Landfester, 2006). Nucleation occurs in the monomer or droplets of a monomer solution, so that each droplet behaves as an individual small reactor. After polymerization, the original droplets are converted directly into polymer particles of approximately the same dimensions. The differences between the suspension and miniemulsion polymerizations include the size and stability of the droplets. Suspension polymerization takes place in large (from 1 μm to 1 mm diameter) droplets, whereas miniemulsion polymerization occurs in significantly smaller, typically, submicrometer-size droplets. In suspension polymerization, droplets are generally stabilized against coalescence using polymeric stabilizers such as polyvinylpyrrolidone and poly[(vinyl alcohol)-co-(vinyl acetate)] or using biopolymers, for example, natural gums or cellulose ethers. In miniemulsion polymerization, the instability of the system is dominated by Laplace pressure in the droplets, which governs monomer diffusion from the droplets, and the growth of larger droplets at the expense of the smaller ones in the process of Ostwald ripening (Ostwald, 1900; Higuchi, 1962). Stabilization is achieved by adding to the monomer phase a substance with a very poor solubility in the continuous phase, thereby exploiting stabilization based on building a counteracting osmotic pressure in the system. For oil-in-water miniemulsion polymerization, the addition of hydrophobic solvents, such as hexadecane, or strongly non-polar monomers results in greatly increased stability of the droplets (Lowe, 2000).

Alternatively, polymer particles can be formed by physical means. For example, heat-induced phase separation of the solution of linear poly(N-isopropylamide) leads to the loss in solubility of this polymer and the association of polymer molecules into particles (microgels) (Deng, Xiao, and Pelton, 1996; Chan, Pelton, and Zhang, 1999). In another approach, emulsification of polymer solutions and subsequent removal of the solvent from the droplets by extraction or evaporation also produces polymer particles (Gañán-Calvo et al., 2006). In this method, the size of the particles is precisely controlled by tuning the concentration of the initial polymer solution; however, using a high polymer content (and hence, generating large, micrometer-diameter polymer beads) is problematic because of the high viscosity of such solutions and the difficulties in their emulsification.

Among the synthetic methods, three types of polymerization can be used to produce polymer particles with dimensions exceeding 10 μm, namely: the multi-stage interfacial polymerization, the swelling (Ugelstad) method, and the suspension polymerization described above. (Dispersion polymerization is generally used for the synthesis of particles with dimensions of up to approximately 10 μm.)

The swelling method can be combined with the particle polymerizations described above (Ugelstad et al., 1980, 1985, 1999; Jorgedal, 1985). In this method, relatively small monodispersed seed particles prepared by, for example, emulsion polymerization, undergo swelling with a monomer or a monomer mixture. This step is followed by polymerization of the monomer(s) taken up by the seeds. To grow large polymer particles with dimensions of up to tens of micrometers, the procedures of swelling and polymerization may be repeated several times. The method yields large polymer particles with a narrow size distribution. The multi-stage Ugelstad method can produce monodipersed polymer particles with dimensions of up to 100 μm; however this method is time consuming and material specific. It is challenging to generate particles loaded with low molecular weight molecules or nanoparticles, and microbeads with complex morphologies and non-spherical shapes.

Multi-stage interfacial polymerization also exploits polymer seed particles synthesized by, for example, emulsion polymerization (O'Callaghan, Paine, and Rudin, 1995a, 1995b). Interfacial polymerization on the surface of seeds results in increasing microbead diameter. Typically, the particles are grown to a certain size, after which they serve as seeds in a subsequent stage, and the dimensions of polymer beads gradually increase with the number of polymerization stages. This process may be complicated by the secondary nucleation process in which a monomer polymerizes in the continuous phase rather than on the surface of seeds, thereby leading to the nucleation of secondary small particles. Typically, this complication, as well as possible aggregation of the large particles, is overcome by diluting the dispersion of the particles in each subsequent stage and by using a mixed initiator approach, that is, a combination of the oil-soluble and water-soluble initiators (O'Callaghan, Paine, and Rudin, 1995a; O'Callaghan, Paine, and Rudin, 1995b; Kalinina and Kumacheva, 1999). The process is time-consuming, and generally, it is not used for the synthesis of polymer microbeads with dimensions exceeding several micrometers.

Suspension polymerization is a straightforward, simple, and cost-effective method, however, generally, it produces polymer particles with a broad distribution of sizes. This drawback originates from the limited ability to emulsify monomers in monodispersed droplets and to suppress subsequent coalescence of these droplets prior to their polymerization. As a result, fractionation is used to narrow the distribution of the sizes of the resulting particles. This step is time-consuming and it results in the loss of material. The polydispersity of polymer microbeads produced by suspension polymerization can be significantly improved (i) by generating monomer droplets with a narrow size distribution and (ii) by minimizing coalescence between these droplets before they solidify or gel.

We leave a detailed discussion of the emulsification to Chapter 4. Here we note that conventional emulsification methods, such as sonication, stirring, or ultra-turrax, do not yield droplets with a narrow size distribution; however, several promising methods exist that produce relatively monodisperse “precursor” droplets for suspension or miniemulsion polymerization.

Firstly, membrane emulsification has proved effective in preparing droplets of monomers with dimensions in the micrometer-size range and polydispersity close to 10% (Yuyama et al., 2000). Emulsification of monomers in the immiscible continuous phase occurs by pressing a liquid monomer or a crude pre-emulsion through membranes with a particular, well-defined size of pores. The size of the droplets is determined by the size of the pores in the membrane, the pressure, the viscosity of the continuous and droplet phases, and the value of the interfacial tension between the liquids. The subsequent polymerization step is similar to conventional suspension polymerization. Examples of particles produced by using membrane emulsification include polystyrene microbeads (Omi et al., 1994; Omi et al., 1995) or biodegradable polylactide microbeads (Ma, Nagai, and Omi, 1999).

Emulsification in the Bibette process is achieved by shearing a polydisperse emulsion at a well-defined low shear rate in a narrow gap between the two vertical, coaxial cylinders in a Couette apparatus (Mason and Bibette, 1997; Mabille et al., 2000). At the optimized viscosity of the initial emulsion, controlled dissipation of mechanical energy yields droplets with a relatively narrow distribution of sizes. The final dimensions of the droplets are determined by the applied shear rate, the viscosity of the original emulsion, and the interfacial tension between the droplet and the continuous phases. The distribution of droplet sizes narrows with a reducing width of the gap in the Couette apparatus.

Emulsification can be also achieved by forcing fluids into the bulk continuous medium through a nozzle (Berkland, 2001; Loscertales, 2002) or a vibrating orifice (Partch, 1985; Esen and Schweinger,). For example, photopolymerization of aerosol droplets of acrylate monomers, which were generated using a vibrating-orifice droplet generator, was utilized to generate spherical microbeads (Esen and Schweinger, 1999).

Generally, following emulsification, micrometer-size droplets are transferred into the reactor and polymerized or gelled in a batch process. Polymerization takes from tens of seconds to several hours, depending on the type of monomer. During this process, droplets collide and coalesce, especially, if their concentration in the emulsion is high. As a result, polydispersity of the resultant polymer particles is typically substantially higher than that of the original precursor droplets, even if the latter were produced under optimized conditions. Continuous polymerization of droplets under unbound conditions narrows particle polydispersity; however, in comparison with a batch process, it does not completely suppress coalescence of droplets.

One of the main advantages of microfluidic synthesis of polymer particles, as will be discussed in Chapters 7 8 9 10, is the ability to generate droplets with a very narrow size distribution and to avoid coalescence between them, by solidifying or gelling droplets as they flow through microchannels and are separated by the well-defined gap of the continuous phase. Frequently, microfluidic synthesis is limited to the emulsification step, so that subsequent to emulsification, precursor droplets are polymerized or gelled in a batch process, where their coalescence is unavoidable.

2.2 Microfluidic Generation of Polymer Particles

Microfluidic synthesis and assembly of polymer particles is described in details in Chapters 7, 8, 9, 10. Here we explain the most important general features of the microfluidic production of polymer microbeads. Particles can be generated via a continuous single phase (Dendukuri et al., 2006) or a multiphase microfluidic synthesis (Xu et al., 2005; Dendukuri et al., 2005). Currently, the latter synthesis dominates the field; therefore here we focus on the mutiphase microfluidic reactors. Typically, a microfluidic reactor for the multiphase synthesis of polymer particles contains two or three parts (corresponding to the stages of the synthesis), as shown in Figure 2.1: a mixing compartment, a droplet generator, and a compartment for polymerization, gelation or solvent withdrawal. A mixing compartment is required when reagents have a high reactivity, in order to avoid chemical changes in the tubing supplying the liquid mixture to the reactor. In the droplet generator, two immiscible liquids – the droplet phase and the continuous medium – are introduced into the separate microchannels or capillaries. The stream of the liquid that is to be dispersed periodically breaks up into droplets, which are emulsified in the continuous phase. The droplets move to the extension channel in which they are subjected to irradiation, heating, addition of chemical agents, or solvent extraction.

Figure 2.1 Schematic of the microfludic reactor for multiphase synthesis of polymer particles. The monomers are supplied to the mixing compartment through inlets 1–3. A continuous phase is supplied to inlets 4 and 5. Droplets of the monomer mixture move to the polymerization zone where they are exposed to UV-irradiation to initiate photopolymerization. Adapted with permission from Li, W., et al., Multi-Step Microfluidic Polymerization Reactions Conducted in Droplets: The Internal Trigger Approach, J. Am Chem. Soc., 130, 9935–9941. Copyright (2008) with permission from American Chemical Society.

Microfluidic emulsification can be carried out in droplet generators with varying geometries, such as T-junctions, co-axial capillaries, flow-focusing geometry, and terrace-like microchannels. A detailed discussion of existing microfluidic droplet generators is given in Chapter 5. Regardless of the type of droplet generator, for a particular combination of continuous and droplet phase liquids, the size of the droplets depends on the dimensions of the microchannels or capillaries and the flow rates of the liquids. A highly periodic manner in which the stream of the droplet phase (a monomer, an oligomer, or a polymer solution) breaks up, determines the narrow size distribution of the “precursor” droplets and a well-defined distance between them when they are moving in the downstream channel.

The transformation of precursor droplets into polymer particles is achieved by either chemical or physical mechanisms, such as polymerization, crosslinking, thermally induced gelation, self-assembly, evaporation of the solvent from the droplets, or phase separation. Currently, free-radical and condensation polymerization are the two methods that are most frequently used to generate rigid polymer particles with a uniform or a capsular structure (see Chapters 7–10).

As in conventional suspension polymerization, in microfluidic synthesis every droplet performs as a small isolated reactor with a volume in the range of from pico- to nanoliter. Therefore, in addition to the synthesis of polymer particles, droplets generated by microfluidic emulsification can be used for solution-based synthesis. Such an application of droplets can be useful for polymer synthesis, which is difficult to perform in a single-phase microfluidic format due to the gradual increase in the viscosity of the liquid with the increasing molecular mass of the polymer.

Continuous microfluidic synthesis and assembly of polymer particles offer several beneficial and, in some ways, unique features, which are listed below and described in detail in Chapters 7–10:

The ability to generate polymer particles with polydispersity below 5% (and under particular conditions, below 1%).The capability to generate polymer particles with non-conventional, non-spherical shapes. One of the methods utilizes solidification or gelation of droplets confined by microchannels with dimensions smaller than the unperturbed droplet diameter. Another method uses multiphase droplets with non-symmetric morphologies, from which, following polymerization, one of the phases is removed (Nie et al., 2005) A powerful, although less frequently used method exploits one-phase polymerization using projection lithography, in which the shape of the particles is determined by the features of the mask.The capability to produce polymer particles with complex architectures, which originates from the ability to control the morphology of precursor droplets by hydrodynamic means. Examples of such particles include core-shell particles (capsules), Janus particles, or photonic balls.Control of internal structures of polymer particles realized by the uniform supply of energy e.g., UV radiation to precursor droplets.For multiple reactions or physical processes leading to the transformation of droplets into particles, microfluidics allows control of the location and timing of a particular chemical or physical process by using a “time-to-distance” transformation. This feature allows control of particle composition and internal structure.Shear imposed on precursor droplets can play an important role in controlling their shape and architecture, thereby influencing the shape and structure of the resulting polymer particles.Owing to the narrow distribution of sizes of particles generated by the microfluidic methods, they can be used for the controlled encapsulation of cells. The average number of cells per particle is accurately described by the Poisson distribution.

Along with the advantages, successful production of polymer particles has several requirements. These requirements include: (i) efficient microfluidic generation of precursor droplets from liquids with well-defined macroscopic properties such as interfacial tension and viscosity (this requirement being important in multiphase polymer synthesis); (ii) fast transformation of precursor droplets into polymer particles; and (iii) the ability to scale-up the microfluidic production of the particles by using multiple parallel microfluidic reactors.

In the following chapters we describe the characteristic features of the continuous microfluidic production of polymer particles: the basics of microfluidic emulsification, the production of rigid and soft polymer particles with controlled shapes and morphologies, and the generation of polymer particles with various compositions.

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Chapter 3

Introduction to Microfluidics

In Chapter 2 we gave an overview of the applications of polymeric microparticles and their methods of formation. These include the classical and industrially implemented methods and the microfluidic techniques that are the focus of our book. Microfluidics itself is a relatively young branch of chemical engineering, spanning only the last 20 years. The use of microfluidic systems for the formation of droplets is even younger, as it has only been of interest for the last few years. The rapid development of the understanding of multiphase microflows and of the wide range of applications of these systems to the generation of droplets and polymeric particles forms the basis of commercial implementations. However, as it stands, this set of techniques does not yet constitute a technology. There are important scientific and engineering problems that still need to be tackled. We will give an overview the current state-of-the-art academic achievements, and demonstrate their strengths and potential, along with the remaining challenges.

3.1 Microfluidics

Microfluidics is a branch of chemical engineering that studies the design, fabrication, and operation of systems of microscopic channels that conduct fluids. If compared with standard fluidic systems, the microfluidic channels are typically small, having widths (or diameters) ranging from single micrometers to tens or hundreds of microns. The pumping of liquids and gases through microducts typically occurs at small speeds. In this context “small” means that the viscous forces dominate over the inertial ones. As a result, the flow of liquids at the microscale can most often be described by equations of flow based on a simple proportionality between the speed of the flow and the magnitude of the force that drives the flow (Squires and Quake, 2005). The resulting flow is laminar, i.e. the sub-volumes of liquid flow side-by-side, following the field of the gradient of pressure, and the streamlines never cross each other (Figure 3.1). This characteristic of the flow provides for extensive control: the speed of flow obeys the simple Hagen–Poiseuille equation, which predicts the speed of flow as a quotient of the pressure drop through the particular capillary and its hydraulic resistance. Importantly, the resistance to flow is a function of the dimensions of the channel and the viscosity of the fluid. This allows networks to be designed that distribute the flow of liquids in accordance with the desired pattern. This property, when combined with typically large values of the Peclet number (Stone, Stroock, and Ajdari, 2004), reflecting the fact that diffusional transport is typically slow in comparison with the flow, makes it possible to control the profiles of the concentration (Jeon et al., 2000) of chemicals and also the profiles of the temperature (Lucchetta et al., 2005) in the channels, all with minute consumption of the fluids.

Figure 3.1 A micrograph by Felice C. Frankel of laminar streams of aqueous dyes in microchannels. Photograph by Felice C. Frankel, reproduced with permission.

A crucial contribution to the explosion of the research activity in the field of microfluidics was the development of accessible procedures for microfabrication (Whitesides, 2006). A judicious choice of the microfabrication techniques – either lithography, milling or etching – allows for the facile preparation of both planar and truly three-dimensional systems of microchannels (Becker and Locascio, 2002; Becker and Gartner, 2008; Desai, Hansford, and Ferrari, 2000; Tseng, 2004; Voldman, Gray, and Schmidt, 1999; Weibel, DiLuzio, and Whitesides, 2007). In the planar systems, all the ducts share a common plane and all have the same height, while the dimensions in the plane can vary across the system. Spincoating allows for the tuning of this height across the lengthscales: from single nanometers, through micrometers to fractions of a millimeter. It is also possible to form systems in which the heights of the channels change along the line of flow of the fluids (the so-called 2.5-dimensional systems) (Tseng, 2004), or to prepare systems that are truly three-dimensional, such as the axi-symmetric systems (Ganan-Calvo, 1998). The technique that has probably played the most important role in expanding academic interest in microfluidics is fast prototyping via lithography and replication of the masters in polydimethylosiloxane. This technique -- often referred to as soft-lithography--makes it possible to go from the idea to the fabricated chip within a day, with facile reproduction of the existing masters for multiple experiments (Duffy et al., 1998). The extensively developed techniques of fabrication of micro-electro-mechanical systems (MEMS) provide a vast and readily available set of tools for integration of actuators, electrodes, and waveguides with microfluidic channels (Verpoorte and De Rooij, 2003). Such integration opened the vistas to systems based on electrostatic forcing of flow, such as via electro-osmosis or electrophoresis, and for the simultaneous readout of the results of on-chip separations and reactions (Dittrich, Tachikawa, and Manz, 2006).

The character of flow, the small volumes of liquids used in experiments, and the facile access to microfabrication, all prompted a vision of the development of microfluidic chips for use in analytical chemistry and diagnostics. In the 1990s, some of the existing technologies of chemical analysis – chromatography and electrophoresis – which already took advantage of guiding fluids in channels with small cross-sections, inspired construction of more integrated devices (in the form of chips) for sensitive assays with high resolution and operating on small samples of fluids (Whitesides, 2006). The intense interest in in-field analytics for defense against bio- and chemical-terrorism and warfare, and the exploding interest in high-throughput tools for biochemistry, meant that the necessary funding for research on microfluidic systems was provided (Whitesides, 2006).

One of the most important aspects of the visions that has driven progress in the area of microfluidics is integration. Already the first demonstrations of electrophoresis on a chip (Harrison et al., 1993) have suggested that complicated protocols for chemical analyses will be feasible, which have now been shown by a number of groups (Erickson and Li, 2004). In the almost 20 years since the first demonstrations (Harrison et al., 1993), the field has generated thousands of academic reports on analytical techniques performed on-chip, including highly integrated systems (Thorsen, Ismagilov, and Zheng, 2002) and commercial applications. The area of microfluidics has gone through a phase of rapid expansion and is now maturing (Figure 3.2). The exponential explosion of interest has slowly saturated the field, which is now transiting into the phase of research more oriented towards appliations. This is possible because the fundamental concepts and understanding, although still being areas of active investigation, have already been laid.

Figure 3.2 Number of scientific articles related to microfluidics (citing the word “microfluid” ) and of those pertaining to droplet microfluidics (citing both of the words “microfluid” and “drop” ) plotted as a function of the year of publication (extracted from the ISI Web of Knowledge database). One can clearly see the exponential growth of the number of publications up to approximately 2005, and then the slow saturation of the increase in the number of articles

3.2 Droplet Microfluidics

At the beginning of this century Thorsen et al