Label-free sensing with semiconducting nanowires

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Label-free sensing with semiconducting nanowires A Dissertation Presented to the Faculty of the Graduate School of Yale University in Candidacy for the Degree of Doctor of Philosophy by Eric Stern Dissertation
Label-free sensing with semiconducting nanowires A Dissertation Presented to the Faculty of the Graduate School of Yale University in Candidacy for the Degree of Doctor of Philosophy by Eric Stern Dissertation Director: Prof. Mark A. Reed May Abstract Label-free sensing with semiconducting nanowires Eric Stern 2007 Nanoscale electronic devices have the potential to achieve exquisite sensitivity as sensors for the direct detection of molecular interactions, thereby decreasing diagnostics costs and enabling previously impossible sensing in disparate field environments. Semiconducting nanowire-field effect transistors (NW-FETs) hold particular promise, though contemporary NW approaches are inadequate for realistic applications. We present here a novel approach using complementary metal-oxide-semiconductor (CMOS) technology that has not only achieved unprecedented sensitivity, but simultaneously facilitates system-scale integration of nanosensors for the first time. This approach enables a wide range of label-free biochemical and macromolecule sensing applications, including cell type discrimination through the monitoring of live, stimulus-induced cellular response, and specific protein and complementary DNA recognition assays. An important achievement is the introduction of real-time, unlabeled detection capability, allowing for fundamental studies of cellular activation, and specific macromolecule interactions at concentrations ( femtomolar) orders of magnitude lower than other commonly available techniques. 2 2007 by Eric Stern All Rights Reserved. 3 To Alan Stern, who taught me more about life, family, hard work and in turn myself over the past four years than I ever thought I d know 4 Acknowledgements There are more people than I can count who helped make this work possible. I owe a huge debt of gratitude to my advisor, collaborators, and coworkers, as well as to my family and friends (those categories are not mutually exclusive). And, of course, I am indebted to the agencies sponsoring the graduate fellowships I was fortunate enough to be awarded, the Department of Homeland Security and the National Science Foundation. First and foremost I thank Prof. Mark Reed, my boss, for keeping me in his laboratory at Yale for another four years and for being not only merely a truly exceptional mentor (and bill-payer) but also a good, trusted friend. My last four years have been one of the most spectacular periods of my life due primarily to the countless hours I spent in the Becton Center under his tutelage. I have had a truly unbelievable experience working in his laboratory and plan to maintain a close collaboration, at the very least, for a long time to come. I also thank all my committee members for their exceptional support for my work and for their advice and friendship. From the outset of my project, Prof. Fred Sigworth raised a number of critical concerns. Without accounting for his crucial observations, which required countless conversations throughout the course of the work, the project quite simply would not have worked. Also from the outset of my graduate career, I was fortunate enough to have a second laboratory, Prof. David LaVan s, opened to me. The chemical reactions and surface characterizations I performed in this second home, as well 5 as the conversations I had with Prof. LaVan, were critical at every step of my project. Although my interactions with Prof. Tarek Fahmy began later in the course of my work, this collaboration has proven to be the most fruitful of my life. Seemingly not a single experiment has been performed by me in the last year (many, incidentally, in his laboratory) without thorough discussions (generally after midnight) with Prof. Fahmy and I look forward to many more such conversations in the future as a postdoctoral researcher in his lab. Many of the current and former Reed group members have not only helped incredibly with my work but shaped me as a scientist as well. Professors Ilona Kretzschmar (City College of New York) and Guosheng Cheng (Suzhou University) were not only instrumental in teaching me to perform engineering research but also taught me the value of collaboration. Without them, much of the work presented here could not have even been started. James Klemic helped me through my work every step along the way not only scientifically but also has a good friend. Professor Takhee Lee (Gwangju Institute of Science and Technology) and Doctors Menno de Jong and Glenn Martin, though present for only a brief period during my thesis work, taught me an incredible amount about research and the required work ethic. Aleksandar Vacic, though only present at the tail end of the work, was instrumental for the theoretical studies and I leave knowing the nanobars are in great hands with him and David Routenberg, who helped me through many of the rough spots and performed some of the most exciting and important device physics experiments. Additionally, Dr. Marleen van der Veen s infectious personality and work ethic helped reinvigorate me during the last months of the work and she should 6 join Alek and David as a member of a very high-flying Reed group team in the future. Doctors Jia Chen and Jeff Sleight, though graduated before I showed up, provided exceptional help with many experiments. Additionally, Doctors Elena Cimpoiasu, Nilay Pradhan, Wenyong Wang, Xiaohui Li, and Jie Su, in addition to Stan Guthrie, Ryan Munden, and Aric Sanders contributed to sample growth and device measurements. Matthew Phillips, though only present transiently, provided strong encouragement. I have been blessed with having some truly exceptional undergraduates working for me over time who have greatly contributed to the results. Daniel Turner-Evans began just as the work got exciting and his fingerprints are all over the work presented here. Robin Wagner single-handedly laid the groundwork not only for my final experiments but for much of the future work I hope to accomplish. Carl Dietz and Eric Steinlauf, though in lab just a bit too early to catch the most exciting work, contributed greatly to my original understanding of the sensors. Burt Helm, Elizabeth Broomfield, Shin Rong Lee, Jamie Capo, and Maria (Gaby) Oronchea (not under my direct supervision) also performed some interesting and critical experiments. As a very fortunate pseudo-member of the Fahmy group for the final semesters of my work, I have had the opportunity to work with his exceptional students and very much look forward to continuing these relationships. Erin Steenblock provided samples, a watchful eye, and good luck for some of my final experiments and traveled more miles with me than any other collaborator. Jason Park, Stacey Demento, Jason Criscione, and Tarek Fadel have provided great encouragement and much of the work we have recently 7 collaborated on will come to spectacular fruition under their direction. And the members of the Fahmy group undergraduate army, Michaela Panter, Karlo Perica, Karen Chen, Katie Allen, Gilbert Addo, Atu Agawu, Jeffrey Reitman, and Sean Mehra, have also contributed not only to the work but to making it fun. There are many professors in addition to my committee members whose advice and support was instrumental and who have helped make my Yale graduate experience exceptional. Yale Professors T. P. Ma, Jung Han, Jerry Woodall, Peter Kindlmann, Yiorgos Makris, Eugenio Culurciello, Hur Koser, and Robert Schoelkopf helped at many steps with device design and fabrication. Yale Professors Mark Saltzman, Michael Levene, Ron Breaker, Michael Snyder, Andrew Hamilton, Eric Dufresne, John Wood, Glenn Micalizio, Erin Lavik, and Dennis Spencer helped throughout my work with functionalization and sensing. I also enjoyed very fruitful collaborations with Professors Tadeusz Malinski of Ohio University and Chonwu Zhou of the University of Southern California, and Dr. Jack Yu of the Medical College of Georgia. Professors Jonathan Schneck (Johns Hopkins University), Herman Eisen (Massachusetts Institute of Technology), and Ruslan Medzhitov provided critical samples for cellular response measurements. Additionally, I am indebted to Profs. James Duncan, Fahmeed Hyder, Saltzman, and Fahmy for selecting me as a Teaching Assistant for their classes and to Prof. Levene for allowing me to be a guest lecturer in the Senior Seminar. There are countless Yale researchers in addition to my group memebers whose advise, assistance, and support was essential to my progress. I will try to name them all, but so 8 many people have been helpful throughout time that I apologize in advance if I forget some. In my eyes Thomas Boone and Robert Koudelka were always the ideal graduate students and have always been a great example for me and both workers and friends. Pauline Wyrembak single-handedly made functionalization possible by providing every molecule I needed. James Hyland helped minimize the drudgery of the Yale cleanroom and seemingly provided key suggestions every day and Christopher Tillinghast and Michael Young allowed that advice to be useful by keeping the cleanroom up and running (and also gave many critical suggestions themselves). Doctor Kathryn Klemic in addition to James Bertram, Steven Jay, Benjamin Boese, and Alexis de Kerchove assisted with (and oftentimes did) crucial studies that made some papers possible. Doctors Luigi Frunzio, Jun-Fei Zheng, Hironori Tsukamoto, George Cui, Zhenting Jiang, and Sharon Cui and Matthew Reese and David Schuster gave me many processing and metrology tips throughout the course of the work. Tania Henry, Manisha Gupta, Sara Hashmi, Joseph McManis, Yanxiang Liu, Weipeng Li, Chun-Chen Yeh, Joseph Schreier, Tolga Kaya, Dechao Guo, Bozidar Marinkovic, Ayse Kose, Jason Hoffman, Liyang Song, Miaomiao Wang, Chad Rigetti, Veronica Savu, Ning Li, and Sun Il Shim all look great in bunny suits and helped make working in the cleanroom almost fun. I also had many fruitful discussions that helped both the work succeed and time pass with Drs. Peter Fong, Jeremy Blum, and Hung Te Hsieh in addition to Millicent Ford, Jeffrey McCutcheon, Sara Royce-Hynes, Andrew Sawyer, Jennifer Saucier-Sawyer, Thomas Chia, Andrew Barthel, Richard Torres, Zai Yuan Ren, and Qian Sun. 9 Many researchers and companies outside Yale played significant roles in my project. Robert Ilic, Daron Westly, Meredith Metzler, and Vincent Genova of the CNF taught me real processing and their help and suggestions made the sensor fabrication possible. Doctor Ling Xie and John Tsakirgis of the Harvard Cleanroom provided much-needed fabrication assistance when the Yale Cleanroom was down. Doctors Emanuel Tutuc and Robert Klie made and measured samples, respectively, that added incredible dimensions to my work. Alec Flyer made some of the most critical functionalization suggestions that enabled the work to continue. Additionally, a number of companies routinely went well out of their way to help me meet my deadlines: CAD Art Servies, Benchmark Technologies, ntek, and Innovion. The support of Yale s staff also made the projects possible. Many of the apparatuses on or in which experiments were run were built by Vincent, Nick, or Russel Bernardo. No progress towards academic completion would ever occur without Cara Gibilisco and no reagents or supplies would ever show up without the dedication of Vivian Smart, Arlene Ciociola, Patricia Kakalow, Deanna Lomax, Elna Godburn, Senen Antunez and Susan Johns. And the company of the Becton custodial staff at all times of the day and night always helped to keep me going. Additionally, I owe a huge debt of gratitude to Dean Paul Fleury, Claudia Merson, and Bridget Calendo for making the Yale Engineering Futures in Science Research Fellowship (YEFSRF) a reality and to them and Prof. Levene, Dr. Joanna Price, and Steven Jay for continuing it. And I am very thankful to the students in my classes for 10 supporting me as a TA while I learned the ropes and for (mostly) doing great work that made my life incredibly easy. And since altruism isn t always the name of the game, I owe a huge debt of gratitude to all the Yale Office of Cooperative Research employees, especially James Boyle. Without the constant support of my family and friends I never could have dealt with the (constant) setbacks and the eventual success would mean nothing. Words truly can t express how lucky I feel to have had them there every step along the way. My Mom and Dad started me in this game and, man, do I love it and what other parents would also serve as the final evaluator of all papers? The constant love and support of (and interest in my work) my Grandma and Grandpa, my Uncle Don and Aunt Antje, and my cousins Bobby and Elizabeth, mean more than I can ever express. My brother, Alan, is the best brother a guy could ever ask for and my best friend and I can t wait to get to Boston in good part because he s there. My fill-in-something-here, Laura, was there every step along the way and made me who I am today as both a person and a scientist nearly every piece of data here was taken with her on the phone or in my office and most definitely in my heart; the last datafiles, named tnxljg say it all. And the friendship and support her parents, Mr. and Mrs. Greer, both means and has taught me more than I can explain. My best friends James, Steve, Mike, Rob, Park, Pauline, and Jen D, kept me going day-in and day-out and made grad school one of the best experiences of my life outside the lab as well as in it. And the friendship and support of Rachael and Sarah Mc, along with Jeremiah, Cutch, BD, Zak, Vip, Cogs, Fong, Tarek, Tom C, Andy, Rick, 11 Marc, Raul, Jan, Andy S, Dwayne, Chu, Rasika, Tom B, Rob K, Jimmy, Diego, Bill, Ashley, Elnaz, Tara, Carey, Julie, Sara, Rachel, Lauren H, Amy, Jen G, Jenny, Giggles, Vomit, Chillable, Stace, Erin, Vivian, Rutkow, Flyer, Cole, Moral, Dan, Jesse, Goldy, Lusty, the rest of the jellydonut crowd, and everyone else has made time fly. Thank you! And I also thank Gourmet Heaven for serving a spectacular sandwich just about every other night for the past two-and-a-half years, GPSCY and Thai Taste for Thursday nights, and Anna Liffey s and Solo cups for Fridays. 12 Contents List of Tables.. 15 List of Figures Introduction 18 References Theoretical Considerations Importance of Device Scaling on Sensitivity ph Response Functionalization and Molecular Binding Considerations Chamber Design and Solution Exchange Considerations Debye Screening Considerations Conclusions References Nanobar Fabrication and Characterization Nanobar Fabrication Nanobar Characterization Conclusions.. 72 References Functionalization Techniques for Protein and DNA Conjugation Introduction Oxidative Electropolymerization-Based Functionalization Electrically-Directed Silicon Functionalization Silicon-Specific, Non-Electrically Directed Functionalization Non-Silicon-Specific, Non-Electrically Directed Functionalization Conclusions.. 92 References 5 Nanobar Sensing Introduction Unfunctionalized NB Sensing Unfunctionalized NB Sensing of Specific Cellular Responses Silicon-Specific NB Functionalization Nanobar Sensor Characterization Nanobar Sensing of Unlabeled Proteins and DNA Conclusions References Conclusions. 139 References Appendix I: Functionalization Methods Appendix II: Sensing Methods Appendix III: Nanowire-Field Effect Transistors List of Tables Table Table List of Figures Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Chapter 1: Introduction The importance of sensing chemicals and biochemicals in disparate field environments cannot be underestimated in today s world [1-13]. Sensing small numbers of molecules exactly, effectively, and expeditiously is paramount for army defense and homeland security [1-3], clinical screening and diagnoses [4-8], drug discovery [9,10], and basic research assays [7,8,10,11]. For each of these applications, it is highly desirable that an ultrasensitive, small, versatile, robust, low-power, easy-to-use, inexpensive, variablesensitivity sensor be created [1,4,11-13]. In spite of the critical demand for such a sensor, no single technology has yet shown the capability to meet all of these requirements [11-29]. Sensors can be roughly grouped into two major categories: those that identify molecules spectroscopically [30-35], or those that use a direct or indirect means of sensing a specific molecule [36-47]. The detection of small molecules is readily achieved with sensors in the first category and, due to the success of such technologies, many are now being scaled down. In spectroscopic approaches, the aforementioned desirable requirements have stimulated the development of miniaturized gas chromatographs [32], Fourier transform infrared spectrometers [33], mass spectrometers [32,34], and solid-state gas-phase sensors [37,40,41]. However, many of these techniques face lower limits on size due to scaling limitations and lower limits on power dissipation because of the fundamental physical phenomena by which they operate [12]. Furthermore, these 18 methods are generally incapable of sensing large molecular species, such as proteins and viruses [11-16]. In contrast, the macromolecular sensing required for biological research and clinical applications is predominantly achieved by specific-molecule detection methods [39-44] because these molecules are often too complex for spectroscopic recognition [11-16]. Specific-molecule detection techniques can be further divided into those solely reliant upon chemical means for detection [43,44], and those that convert the chemical signal into an electrical one [39-42]. Methods in the former category such as enzyme-linked immunosorbent [43] and immunoblotting [44] assays, or fluorescence/radioisotope/dye labeling [45] are significantly more sensitive but are of marginal utility outside the laboratory environment (with some exceptions, such as home pregnancy tests) [11-16]. As sensing in disparate field environments becomes increasingly critical, development has begun on a number of label-free, specific-molecule technologies for converting chemical signals to electrical ones without the need for complex sample preparation [17-29]. The most established approaches are metallic potentiometric [46] and amperometric [24] sensors, which sense ions electrochemically in solution; solid state [37,47] conductance sensors, which sense gas-phase ions and small molecules by measuring the absorption-induced conductance change of a material; and chemical field effect transistors (chemfets; a type of ion sensitive field effect transistor, ISFET), which sense ions in solution by charge modification of the gate of a FET [42,48]. Though each of these techniques has been successful for various applications metallic potentiometric 19 and amperometric sensors for small molecules and ions [48,49], solid-state gas sensors for chlorine and fluorine [37], and chemfets for glucose and other small molecules [48,50,51] none are very sensitive (detection limits are generally parts per million). One method that has successfully overcome this sensitivity barrier and currently serves as the standard for unlabeled sensing is surface plasmon resonance [52]. In this approach, an antibody of the protein to be sensed is attached to a thin gold film. The angular reflection of a laser beam off the backside of the gold is dependent on the local dielectric constant; binding of the protein changes the dielectric constant, and thus deflects the laser beam. However this technique has not met with success outside research environments due to its price, size, high-power, and mechanical alignment issues. The lack of a scalable, inexpensive, label-free sensing technol
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