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New Technologies for Fabricating Biological Microarrays

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New Technologies for Fabricating Biological Microarrays NEW TECHNOLOGIES FOR FABRICATING BIOLOGICAL MICROARRAYS By Bradley James Larson A DISSERTATION SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY (MATERIALS SCIENCE) at the UNIVERSITY OF WISCONSIN – MADISON 2005 c Copyright by Bradley James Larson 2005 All Rights Reserved i New technologies for fabricating biological microarrays Bradley James Larson Under the supervision of Professor Max G. Lagally At the University of Wisconsin–Madison Microarrays, composed of thousands of spots of different biomolecules attached to a solid substrate, have emerged as one of the most important tools in modern biological research. This dissertation contains the description of two technologies that we have developed to reduce the cost and improve the quality of spotted microarrays. The first is a device, called a fluid microplotter, that uses ultrasonics to deposit spots with diameters of less than 5 µm. It consists of a dispenser, composed of a micropipette fastened to a piece of PZT piezoelectric, attached to a precision positioning system. A gentle pumping of fluid to the surface occurs when the micropipette is driven at specific frequencies. Spots or continuous lines can be deposited in this manner. The small fluid features conserve expensive and limited-quantity biological reagents. Additionally, the spots produced by the microplotter can be very regular, with coefficients of variability for their diameters of less than 5%. We characterize the performance of the microplotter in depositing fluid and examine the theoretical underpinnings of its operation. We present an analytical expression for the diameter of a deposited spot as a function of droplet volume and wettability of a sur- face and compare it with experimental results. We also examine the resonant properties of the piezoelectric element used to drive the dispenser and relate that to the frequencies at which pumping occurs. Finally, we propose a mechanism to explain the pumping ii behavior within the microplotter dispenser. The second technology we present is a process that uses a cold plasma and a sub- sequent in vacuo vapor-phase reaction to terminate a variety of oxide surfaces with epox- ide chemical groups. These epoxide groups can react with amine-containing biomolecules, such as proteins and modified oligonucleotides, to form strong covalent linkages be- tween the biomolecules and the treated surface. The use of a plasma activation step followed by an in vacuo vapor-phase reaction allows for the precise control of surface functional groups, rather than the mixture of functionalities normally produced. By maintaining the samples under vacuum throughout the process, adsorption of contami- nants is effectively eliminated. This process modifies a range of different oxide surfaces, is fast, consumes a minimal amount of reagents, and produces attachment densities for bound biomolecules that are comparable to or better than commercially available sub- strates. We show applications of these two technologies in the fabrication of protein microar- rays, enhancement of MALDI mass spectrometry, deposition of polymer electronics, di- rected growth of carbon nanotubes, and the chemical modification of carbon-containing materials. iii Acknowledgements I could not have performed any of the work that I describe here on my own. Therefore, I’d like to express my extreme gratitude to the following people for their help, in and out of the lab, during my time here at UW-Madison: In this document, I describe the development of a couple of cold-plasma-based chemical treatments. This was work that was performed in an equal-parts collabora- tion with Professor Ferencz Denes, whose excitement about the field of cold plasmas is contagious. A then-student of his, Emilio Cruz-Barba, performed the plasma treatments on carbon-containing materials. Jason Helgren did much of the experimental work in the development of the plasma treatment of oxides. I was able to get more done work- ing with Jason than with any other researcher I’ve met. I’d also like to thank Sorin Manolache for his advice and aid during the period that I worked on this and Albert Lau for performing analyses on some of our samples. My work on the fluid microplotter grew out of an early collaboration with Professor Amit Lal and Chung Hoon Lee, and I would like to thank them for giving me the op- portunity to learn about novel applications of ultrasonics. Anna Clausen and Albert Lau performed many of the experimental studies that allowed us to characterize the opera- tion of the microplotter. Avery Frey conducted the experiments that tested for protein activity in microplotter-exposed solutions. I would also like to acknowledge Professor Robert Blick’s research group for allowing me free access to their laboratories in order to perform the impedance-based studies of piezoelectric resonances. As far as the other applications of these two technologies, all of the nanotube work iv was either performed by members of Professor Mark Eriksson’s research group or was done with their assistance. Matt Marcus of the Eriksson Group and Todd Narkis of the Lagally Group did all of the research involving the spotting of nanotube catalyst. Jason Simmons and Matt Marcus provided the nanotubes used for the nanotube plasma func- tionalization experiments and helped with the experiments themselves. In addition to being excellent researchers, these guys could always make me laugh. The MALDI mass spectrometry experiments were done in collaboration with Professor David Barnes, who suggested the experiments to begin with, and Dr. Martha Vestling, who ran the MALDI equipment for these studies. The deposition of conducting polymers for the fabrication of LEDs was done in active collaboration with Professor Michael Winokur and his stu- dent, Hyunseok Cheun. I didn’t always understand what Professor Winokur was talking about, but I knew it was important. The folks over at Professor Lloyd Smith’s research group were kind enough to let me use some of their equipment and take part in their weekly group meetings, where I learned quite a bit about surface chemistry. I also picked up quite a few useful tips and techniques from hanging around their labs. You couldn’t find a better group of people to surround yourself with than those in the Lagally Group (including our honorary member, Charles). Our group meetings could be brutal, but what doesn’t kill you makes you stronger. I’d like to single out one of those people for special recognition. Susan Gillmor took me under her wing when I started graduate school and taught me most of the skills I would need. Not only that, she also introduced me to the research that would later become the basis for what I describe here. Thanks again, Susan. I also would like to thank Diana Rhoads for all the ways that she has helped me v (and other Materials Science Program students) over my time here. The MSP would fall apart if she wasn’t there to hold it together. The final person at the University of Wisconsin that I would like to thank is my advisor, Professor Max Lagally. He has given me the opportunity to do the research that I wanted to do, something that few others would allow. His criticisms have always been constructive and he has always fiercely defended me when he felt that I was getting the short end of the stick. Unfortunately, I still haven’t learned how to be concise, with the size of this dissertation as proof. It would take a document longer than the one in your hands to adequately describe what my family means to me. The work ethic and focus that I needed to make it this far I learned entirely from my parents. That, and I could always drive home and get them to do my laundry when I couldn’t find the time to do it myself. My brother is now headed down this same road, so I wish him the best of luck in his own research even though I know he won’t need it. I haven’t thanked any of them nearly enough for what they have done, and continue to do, for me. Thank you all again for making this possible. vi Contents Abstract i Acknowledgements iii 1 Introduction 1 1.1 Microarrays . 1 1.1.1 DNA microarrays . 4 1.1.2 Protein microarrays . 10 1.2 Fluid deposition . 14 1.2.1 Existing technologies . 15 1.2.2 Non-microarray applications . 22 1.3 Surface treatments . 24 1.4 Cold plasmas . 31 1.5 Structure of the dissertation . 35 2 Controlled deposition of picoliter amounts of fluid using an ultrasonically driven micropipette 37 2.1 Introduction . 37 2.2 Fluid microplotter design . 40 2.3 Deposition process . 42 2.4 Performance tests . 47 2.5 Discussion . 50 vii 2.6 Acknowledgements . 53 3 Theoretical and experimental studies of microplotter operation 54 3.1 Spot diameter as a function of surface wetting . 55 3.1.1 Theory . 55 3.1.2 Experimental results . 60 3.2 Spot diameter as a function of viscosity . 62 3.3 Spot diameter as a function of dispenser settings . 65 3.4 Evaporation . 66 3.4.1 Evaporating droplets . 66 3.4.2 Evaporating solvent within a dispenser . 70 3.5 Conclusion . 74 4 Acoustic pumping and spraying 75 4.1 Measuring resonances . 75 4.2 Spraying . 89 4.3 Acoustic pumping . 94 4.3.1 Longitudinal vibrations . 95 4.3.2 Transverse vibrations . 115 4.4 Conclusion . 116 5 Cold-plasma modification of oxide surfaces for covalent biomolecule attach- ment 117 5.1 Introduction . 118 5.2 Materials and methods . 119 viii 5.2.1 Plasma treatment . 119 5.2.2 X-ray photoelectron spectroscopy . 121 5.2.3 Contact angles . 122 5.2.4 Atomic force microscopy .
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