Report prepared by: Anastasiya Batrachenko, Semiconductor Research Corporation and Duke University Ralph K. Cavin, III, Semiconductor Research Corporation Daniel J.C. Herr, Semiconductor Research Corporation Celia I. Merzbacher, Semiconductor Research Corporation Victor Zhirnov, Semiconductor Research Corporation

Acknowledgements We thank the attendees at the 2nd Bioelectronics Roundtable held March 25-26, 2010 for their active participation and thoughtful contributions to this report. Comments of Drs. Herbert Bennett, Michael Gaitan, John Kasianowicz, Wentai Liu, Brian Nablo, Joe Reiner, Joey Robertson, David Seiler, and Lloyd Whitman are gratefully acknowledged. We also wish to thank the Howard Hughes Medical Institute (HHMI) for generously hosting the workshop at its Janelia Farm Research Campus in Ashburn, VA. In particular, we thank Kevin Moses and Janine Stevens for invaluable support. Stacey Shirland is thanked for her support of both the workshop and the preparation of this report. Table of Contents

Executive Summary 1

Introduction 3

High Impact Opportunities & Grand Research Challenges • Personalized Medical Diagnostics & Monitoring 9 • Implantable Medical Devices & Prosthetics 12 • Medical Imaging 15

Summary Message: Research Priorities & Key Recommendations 17

Appendices Appendix A | Influential Publications in Bioelectronics 20 Appendix B | Bioelectronics Research Resources 21 Appendix C | Agenda for 2nd Bioelectronics Roundtable Meeting 23 Appendix D | Attendee List for 2nd Bioelectronics Roundtable Meeting 24 Appendix E | Roundtable Participant Inputs on Potential Applications & Corresponding Research Needs 25 Appendix F | Proposed Framework for a Bioelectronics Research Initiative 36

Executive Summary: Convergent Bioelectronics Opportunities

Technological advances at the intersection of biology/medicine and semiconductor electron- ics — the area of “bioelectronics” — have the potential to transform healthcare, strengthen national and homeland security, and help protect our environment, food and water supplies. As semiconductor devices continue to become smaller yet more functional, we envision implantable prosthetics that restore quality of life, lab-on-a-chip tools that provide sensitive and selective identification of pathogens and biomarkers for disease, and imaging tools that are portable and less costly. Trends that are driving demand include aging populations in developed countries, rising health care costs, and lack of access to medical care in de- veloping countries and remote areas. Targeted bioelectronics research can provide signifi- cant societal and economic benefits.

This report follows a 2009 SRC report entitled Framework for Bioelectronics Innovation and Discovery, which outlined the range of bioelectronics related applications. Based on a work- shop in March 2010 that convened industry and government experts, this report updates the earlier report and identifies priority research opportunities that can advance discovery and enable innovation in the field. Workshop participants identified research opportunities within the broad categories of ex vivo, in vivo, and imaging applications that represented synergistic breakthrough opportunities for the semiconductor and biotechnology communi- ties. These identified opportunities exhibit significant commercialization, job creation and economic impact potential. Among the research opportunities that emerged, those that were given highest priority by the diverse workshop participants from industry and govern- ment fell into the following three areas in order of priority.

1. Personalized medical diagnostics and monitoring. Personalized medical diagnostics and monitoring represents the greatest near-term application opportunity. This area in- cludes multimodal (optical, chemical, electronic) single molecule detection systems that are capable of detecting low concentrations of molecules in “dirty” environments, such as blood. It also includes label-free detection, ideally with single molecule resolution, which could be realized using sensors that leverage semiconductor technology. Such ex vivo applications are more readily brought to market.

2. Implantable medical devices and prosthetics. The second highest ranked research area was neural-electronic interfaces and prosthetics-related research that would enable reliable and robust implantable devices. A key issue in this area is biotic-abiotic inter- faces that do not degrade over time.

1 3. Medical imaging. High impact research opportunities in medical imaging fall in two areas. One area is high-resolution in vivo imaging of small populations and clusters of cells, or even within a single cell. The second area is portable and affordable imaging systems that can be operated in settings outside the clinic, including remote, under- served regions.

Addressing the identified challenges requires targeted, application-specific research and advances in crosscutting areas, such as metrology in biological systems at sub-cellular to organ and system levels; understanding and controlling biotic/abiotic interfaces to insure biocompatibility and to manage biofouling; selective, sensitive and stable biosensors; compact imaging sources; and electronics (including for wireless communications) with low power requirements and enhanced signal to noise characteristics.

The synergistic, collaborative and interdisciplinary engagement of key stakeholders in the “innovation supply chain” will accelerate progress and facilitate the transition of university research to practical application and commercialization. Success requires strategic participa- tion, contributions and innovation from academia, clinicians, industry sectors, federal labo- ratories and other government funding and regulatory agencies. Semiconductor Research Corporation (SRC) has a proven track record for creating consortia that 1) catalyze innovative technology options through university research and transfer them to industry participants, 2) build public-private collaborative research enterprises involving all stakeholders and 3) estab- lish a pipeline of relevantly educated graduates who become the future industry workforce and technology leaders.

The time for creating a global consortium is now. Bioelectronics research is taking place around the world, with especially rapid growth in Asia. Those who wish to stay at the lead- ing edge — whether in government, industry or academia — can gain advantage by working together and synergistically leveraging their respective strengths.

2 Introduction

A confluence of scientific and technological advances at the intersection of semiconduc- tor electronics and biology points to novel applications in fields ranging from medicine and assistive technologies to homeland security and environmental protection. Innovation in the semiconductor industry has allowed the trend known as Moore’s Law to continue, produc- ing smaller and cheaper devices that provide better performance and greater functionality. At the same time, our understanding of biology and the biological basis of disease at the molecular, cellular, tissue and system levels is growing exponentially.

Combining knowledge and technology at the leading edge of biology and electronics—the area referred to as “bioelectronics” — can be part of the solution to challenges arising from a variety of trends, including aging populations, rising healthcare costs, the growing number of injured veterans, and the persistent lack of access to basic medical care in developing countries and remote areas. Beyond healthcare, there are many other applications of bio- electronics. For example, concerns are growing over safety, security and quality of the food supply. Various pathogens can be introduced at many points along the path from the ocean or field to the processing facility, market and table. And fraud in the food industry — from wine and olive oil to cheese and seafood — is a rapidly growing problem for the industry.

This report builds upon an earlier report entitled A Framework for Bioelectronics Discovery and Innovationa, which outlined the broad range of opportunities and challenges in this emerging area. Here we narrow and prioritize among the options, based on inputs from industry and government experts. The aim is to provide guidance for the development of basic research programs that will enable technological progress for synergistic bioelectron- ics applications that can have widespread social and economic impact, by creating new technologies, products, businesses and jobs.

Biomedical AND Within the broad spectrum of bioelectronics applications, this report focuses on those Healthcare Applications: in the area of medicine and healthcare, where progress will open the door for significant Primary Drivers advances in the ability to detect, diagnose and treat disease, while avoiding many adverse for Bioelectronics side effects. Ultimately, the goal is to prevent and treat illness early and affordably, and on a personalized basis. Moreover, bioelectronics holds the promise for enabling a range of prosthetics and other assistive technologies that can improve the lives of persons with disabilities. There are many examples of “smart” electronics that improve healthcare and

a www.src.org/emerging-initiative/bioelectronics/reports

3 quality of life, such as pacemakers, image-guided and robotic surgery, and programmable insulin pumps. But there are enormous opportunities yet to be addressed. While clinical applications represent large, high-impact markets, many advances will first be applied in biomedical research, where they can advance knowledge and understanding and be further developed for treating patients.

Although it is difficult to project the economic benefits at this early stage of research, the fol- lowing figures for some healthcare costs that could be impacted by bioelectronics provides a sense of the magnitude of potential markets and benefits to individuals and society.

• In 2010 an estimated 1.5 million new cases of cancer were diagnosed and over 570,000 cancer deaths were reported in the United States. The National Institutes of Health (NIH) estimates these cases cost nearly $100 billion in direct medical expenses and $160 bil- lion more in lost productivity.

• An estimated 22 million Americans suffer from heart disease and about 460,000 die from heart attacks each year (about 1 in 5 deaths). NIH estimates that in 2008, heart disease cost an estimated $172.8 billion in direct medical expenses and an additional $114.5 billion in indirect costs.

• An estimated 17.9 million Americans are diagnosed with Type 2 diabetes and millions more are undiagnosed. The American Diabetes Association estimates that medical costs associated with diabetes were $116 billion in 2007, with an additional $58 billion in indirect costs.

• According to the National Centers for Health Statistics, each year the number of Ameri- cans suffering from chronic pain is more than those who have diabetes, heart disease and cancer combined—over 75 million. NIH estimates the direct and indirect costs of chronic pain in the United States to be $100 billion annually.

Bioelectronics Research The 2009 Framework for Bioelectronics Discovery and Innovation report contains an analysis is a Global Enterprise of research activity in the area of bioelectronics based on publications. This report pro- vides updated data on the number of publications and citations, as well as the geographi- cal distribution of authors, as a tool to assess changes in regional publication momentum trends. As before, the Science Citation Index ExpandedTM (SCIE), available through the Web of Science®, was used to identify bioelectronic*-related publication trends, where the ‘*’ represents a wildcard search feature in the title or abstract. The total number of publications

2000 60 1800 1600 50 1400 40 1200 1000 30 800 20 600 10 400 200 0 0 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

Figure 1. Number of publications (left) and citations (right) with ‘bioelectronic*’ in the title or abstract by year (as of August 2010).

4 140 40 120 35 100 30 25 80 20 60 15 40 10 20 5 0 0 USA GERMANY CHINA S. KOREA JAPAN ITALY ENGLAND ISREAL FRANCE SPAIN SWEDEN CHINA USA S. KOREA GERMANY AUSTRALIA JAPAN ENGLAND FRANCE POLAND SPAIN 2000 60 1800 1600 50 1400 40 1200 1000 30 800 20 600 10 400 200 0 0 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

140 40 120 35 100 30 25 80 20 60 15 40 10 20 5 0 0 USA GERMANY CHINA S. KOREA JAPAN ITALY ENGLAND ISREAL FRANCE SPAIN SWEDEN CHINA USA S. KOREA GERMANY AUSTRALIA JAPAN ENGLAND FRANCE POLAND SPAIN

Figure 2. Number of publications with “bioelectronic*” in the title or abstract by country since 1991 (Ieft) and since January 2009 (right).

from 1912, when the first bioelectronics paper appeared, through August 2010 is 673, up from 548 as of January 2009. Since 1991 there has been a noticeable number of bioelec- tronics papers published each year, as shown in Figure 1. Because the term bioelectronics is not used universally to describe research at the intersection of biology and electronics, the actual number of publications in this field is much greater.

The geographic location of bioelectronics research has shifted significantly in the 18 months since the last analysis. Figure 2 shows that the United States and Germany remain the two countries that have the greatest number of publications since 1991, while China has moved from sixth to third highest, overtaking South Korea, Italy and Japan. South Korea also moved past Italy and Japan into fourth place. The number of papers over the intervening 18 months is also shown in Figure 2, highlighting the dramatic surge in publica- tions from China. Figure 3 shows the distribution by region. The increased activity in China and South Korea led to an increase in the fraction of papers by Asian researchers from 23 percent 18 months ago to 28 percent today. The increased share of publications from Asia is paralleled by a decrease in the fraction from Europe, which went from 43 percent to 37 percent. The percentage from the United States and rest of the world has remained roughly steady. A list of highly cited bioelectronics publications is shown in Appendix A.

Another measure of the emphasis being placed on bioelectronics research is the large number of programs, centers and facilities at universities and other research institutions worldwide. Selections of these entities are listed in Appendix B.

USA OTHERS 14% 21%

Figure 3. Distribution of publications with ‘bioelectronic*’ in the title or abstract by region. ASIA 28% EU COUNTRIES 37%

5 A Coordinated, Realizing the potential of bioelectronics depends on the actions of diverse stakeholders. It Collaborative Approach requires collaboration among researchers in various disciplines, including the life and physi- cal sciences and engineering, along with clinicians and other practitioners. It also requires the involvement of technical experts from the semiconductor electronics and biomedical industries, who can translate research results into practical applications and useful prod- ucts. Government agencies — such as NIH, National Institute for Standards and Technology (NIST), National Science Foundation (NSF), Defense Advanced Research Projects Agency (DARPA), and Food and Drug Administration (FDA) — will play crucial roles in supporting and guiding this area of research and development. Ideally these efforts should be coordinated to expedite progress in both research and application. SRC is ideally equipped to coordi- nate such collaboration.

SRC is a recognized leader in managing collaborative research and has developed effi- cient, effective and proven mechanisms and processes for creating and managing industry consortia, setting direction, managing and coordinating the research, and disseminating the results. SRC’s primary objectives are to support the competitiveness of its company members (individually and collectively), explore new technologies, stimulate industry- relevant academic research, promote greater academic collaboration, and sustain a pool of experienced faculty and a pipeline of relevantly educated students. Since its inception in 1982, SRC has managed over $1.5 billion in basic academic research at over 198 universi- ties worldwide and supported over 8400 students, who have gone on to become the next generation of leading-edge researchers, technology innovators and industry leaders. Pro- cesses and infrastructure developed by SRC identify and communicate industry’s collective basic research needs, connect the academic faculty and student researchers with industry “users”, support university research with high impact potential, and deliver early results to members via online systems.

A first step in establishing a consortium-based research program is to develop consensus on research needs and opportunities. Two workshopsb — one in November 2008 and an- other in March 2010 — brought together experts from government, industry and academia to identify and prioritize research areas. The first workshop outlined the broad scope of bio- electronics applications and identified a number of high priority research topics. Expert input from that workshop is included in the Framework for Bioelectronics Discovery and Innovation. At that workshop the strategic drivers most frequently cited were disease detection, disease prevention and prosthetics. High priority research challenges were grouped into devices, measurements and analyses, and technologies and are listed in Figure 4 (next page).

At the second Bioelectronics Roundtable held in 2010, attendees from industry and gov- ernment agencies convened by invitation to discuss more specific research opportunities potentially worthy of joint investment. The workshop agenda and invited participants are shown in Appendices C and D. The 25 attendees included government representatives from DARPA, FDA, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute for Biomedical Imaging and Bioengineering (NIBIB), NIST and NSF, as well

b Details and presentations from the workshops are available at www.src.org/emerging-initiative/bioelectronics

6 APPLICATIONS Health care and medicine; Assistive technologies; Biodetection for homeland security; Food safety; Environmental monitoring, etc.

SYSTEMS TECHNOLOGIES Lab-on-a-chip; Molecular recognition; Implants; Imaging; Sensors MEASUREMENT Signal processing; Platforms: TOOLS & METHODS arrays, sequencing, etc. Sensitive; Selective; In situ; Real time; Noninvasive

Figure 4. Bioelectronics applications are driving broad areas of precompetitive research in systems & devices, technologies, and metrology.

as private sector representatives from The Bosch Group, GE Healthcare, Howard Hughes Medical Institute, IBM, Intel Corporation and Tokyo Electron Ltd.

Priority Research The following section of this report describes three categories of high-impact market and research opportunities discussed at the workshop: diagnostics (in vitro), implantable devices and prosthetics (in vivo), and imaging. In each category, a number of research topics that can have impact within five years are given. In the course of the workshop, a broad range of topics was considered based on the contributions of participants. Detailed descriptions of bioelectronics’ applications and associated research needs brought forward by workshop attendees, as well as the benefits over other technologies and metrics of prog- ress are listed in Appendix E. From these a set of priority research needs was developed.

In addition to the three categories, a fourth crosscutting area of research related to metrol- ogy was identified. There is a growing need to develop device characterization and testing methods that support each bioelectronics technology’s advancement through the innova- tion pipeline and its transition to commercial applications. A strategic collaborative invest- ment in relevant metrology research would enable access to appropriate characterization tools with the required sensitivity, reliability and traceability, in time to impact the research and development phases of emerging bioelectronics products. Examples of key character- ization research challenge topic areas include communication, fluidics and the integration of biomolecule sensors with chip-based platforms. This latter interdisciplinary topic inte- grates the specificity and sensitivity of biomolecules for analyte detection with the signal detection and processing power of semiconductors, etc.

LOOKING AHEAD Addressing the priority research outlined in this report will provide economic benefits, including jobs, and lead to better medical treatments, healthcare and quality of life — and doing so through a coordinated, collaborative approach can expedite progress. A potentially

7 powerful approach is for industry to: form a consortium that agrees upon technical goals and defines research needs; partner with aligned government agencies; and, through an in- dependent organization, fund university research. Such a Bioelectronics Research Initiative (BERI) delivers value to members in the form of research results and relevantly educated talent. Partnership with government agencies, including regulatory agencies, can further accelerate progress and ensure that research investments are in the most needed areas and that results are translated efficiently. A proposed organization for the new consortium- based initiative is shown in Appendix F. Such a collaborative approach leverages strengths of industry, academia and government, and maximizes value for all parties.

8 High-Impact Opportunities & Grand Research Challenges

PERSONALIZED MEDICAL An aging population, rising healthcare costs and increasing access are driving significant DIAGNOSTICS & MONITORING changes in the human diagnostics and monitoring technology market. In the United States the total market for personalized medicine, including diagnostics, monitoring and therapeu- tics, currently is estimated at $232 billion and is projected to grow 11% annually, nearly doubling in size by 2015 to a total of $452 billion, according to PricewaterhouseCoopers’ estimates.1 The core segment of the market — comprised primarily of diagnostic tests and targeted therapies — is estimated at $24 billion and is expected to grow by 10% annually to $42 billion by 2015.1

Early detection of disease or abnormality correlates with improved medical outcomes and lower cost. Can an individual know of the onset of a disease before symptoms even ap- pear? Can treatment be tailored for the individual’s specific condition, rather than an aver- age population response? Personalized medicine may revolutionize healthcare by leveraging knowledge of an individual’s biological information to guide the development of customized treatments and long-term health programs. And personalized medicine promises to en- able patients and healthcare providers to proactively predict, detect and prevent disease, optimize prevention and treatment strategies, and reduce inefficiencies that adversely impact patient care, clinical trials and healthcare costs. Examples of successful patient- specific diagnostics currently in use include genome-based molecular screening of drugs, and dosages for treating blood clots and certain types of colorectal and breast cancer. A broader emphasis on individualized diagnostic tools will improve the quality of healthcare by enabling the timely delivery of appropriate and customized therapies.

There is a growing need for multimodal, label-free, calibrated diagnostic tools that can detect single — or low concentrations of specific — molecules in a “dirty” environment, such as blood. This topic received the workshop participant consensus as the highest priority bioelectronics-related opportunity. Integrated chemical, optical and electronic detection systems using high-density arrays of sensors that leverage semiconductor technology could provide rapid, low-cost screening, risk-mapping and diagnostic capability. For example, a field-deployable screening tool using a protein microarray would facilitate the predictive and timely detection and diagnosis of autoimmune diseases, cancers, infectious diseases, drug resistance, bio-warfare agents, etc.

The state-of-the-art technology is improving, but is not yet sufficient. Current immunoassays in clinical use typically measure proteins at concentrations above 10−12 molar (M).2 However, for many cancers3, neurological disorders4,5 and early stage infections6 such as HIV, serum marker protein concentrations range from 10-16 to 10-12 M. Recent work demonstrates the feasibility of detecting 4*10-16 M concentrations of labeled prostate cancer-related proteins

9 in serum, using gold nano-particles and DNA barcodes7 or an enzyme labeled assay with ~10-19 M sensitivity.8

Label-free assays are more challenging. While label-free DNA assays with femtomolar (fM) sensitivity (10-15 M) have been demonstrated for some time, corresponding protein assays remained orders-of-magnitude less sensitive. More recently, new approaches using silicon nanowire devices and optical microcavities have pushed label-free protein assay sensitivities to the fM and attomolar (10-18 M) ranges, respectively, in non-serum samples.

These promising results suggest tremendous market opportunities for highly selective, real-time diagnostic and monitoring technologies. Targeted research is needed to explore emerging families of label-free diagnostics and monitoring devices for applications with high impact potential. The table below summarizes the workshop participants’ consen- sus on critical near-term (three years) and longer-term (five years) research challenges and objectives that would demonstrate a given technology’s commercialization and manufacturing potential.

Achieve sensor structure and response uniformity Control and characterize surface passivation, interfaces and chemistry: Control and characterize surface passivation, interfaces and chemistry • Selectively tune temporal absorption and affinity modulation

Standardize wireless sensing • Develop interface compatible anti-fouling technologies, i.e., for organic/organic, organic/inorganic and inorganic/inorganic Identify a low-cost solution for ensuring secure transmission interfaces to a network Selectively functionalize sensors for multiplexed applications Develop robust packaging and integration options for detection of at least 64 analytes Develop predictive models and guiding principles for Develop reliable, label-free single-molecule (5-yr) and managing biological variations and noise multi-molecule (5+ yrs) biosensor arrays Develop green technology options for manufacturing Explore new materials for sensor systems disposable devices that minimize environmental impact Integrate electronics, microfluidics and functionality Develop biocompatible semiconductor sensors that are designed for specific molecular structures Ensure protection of the underlying CMOS circuitry in the biological medium Develop Si-based peptide arrays for detecting multiple analytes, i.e., parallel peptide analyses Demonstrate manufacturing feasibility — rapid, flexible prototyping facilities needed Develop multiplexed, low-power platforms Develop benchmarks (3-yr) and a roadmap (5-yr) of projected Concurrently develop metrology standards parameter requirements that enable guiding principles for system design

10 References:

1. PricewaterhouseCoopers’ Health Research Institute (2009). [The new science of personalized medicine] http://www.pwc.com/personalizedmedicine and en.wikipedia.org/wiki/Personalized_medicine

2. Giljohann, D.A. & Mirkin, C.A., Drivers of biodiagnostic development, Nature 462 (2009), p. 461–464.

3. Srinivas, P.R., Kramer & Srivastava, Trends in biomarker research for cancer detection, Lancet Oncol. 2 (2001), p. 698–704.

4. Galasko, D., Biomarkers for Alzheimer’s disease – clinical needs and application, J. Alzheimers Dis. 8 (2005), p. 339–346.

5. de Jong, D., Kremer, B.P.H., Olde Rikkert, M.G.M. & Verbeek, M.M., Current state and future directions of neu- rochemical biomarkers for Alzheimer’s disease, Clin. Chem. Lab. Med. 45 (2007), p. 1421–1434.

6. Barletta, J.M., Edelman, D.C. & Constantine, N.T., Lowering the detection limits of HIV-1 viral load using real- time immuno-PCR for HIV-1 p24 antigen, Am. J. Clin. Pathol. 122 (2004), p. 20–27.

7. Thaxton, C.S. et al., Nanoparticle-based bio-barcode assay redefines “undetectable” PSA and biochemical recurrence after radical prostatectomy, Proc. Natl. Acad. Sci. USA 106 (2009), p. 18437–18442.

8. Rissin, D., Kan, C., Campbell, T., Howes, S., Fournier, D., Song, L., Piech, T., Patel, P., Chang, L., Rivnak, A., Fer- rell, E., Randall, J., Provuncher, G., Walt, D., & Duffy, D., Single-molecule enzyme-linked immunosorbent assay detects serum proteins at subfemtomolar concentrations, Nature Nanotechnology, 28, 6 (2010), p. 595-599.

9. Nagel, M., Bolivar, P., Brucherseifer, M., et al., Integrated THz technology for label-free genetic diagnostics, Applied Physics Letters, 80, 1 (2002), p. 154-156.

10. Arntz, Y., Seelig, J., Lang, H., et al., Label-free protein assay based on a nanomechanical cantilever array, Nanotechnology, 14, 1 (2003), p. 86-90.

11. Patolsky, F., Zheng, G., Lieber, C., Fabrication of silicon nanowire devices for ultra sensitive, label-free, real-time detection of biological and chemical species, Nature Protocols, 1, 4 (2006), p. 1711-1724.

12. Armani, A., Kulkarni, R., Fraser, S., et al., Label-free, single-molecule detection with optical microcavities, Science, 317, 5839 (2007), p. 783-787.

11 Implantable Medical Innovations in integrated circuit technologies are spurring a revolution in in vivo health- Devices & Prosthetics care, thereby catalyzing significant growth in the ~$40 billion implantable medical device market.1 Ideally, medical implants and prosthetics allow the recipient to be able to carry out many daily activities unassisted — and with devices such as pacemakers, without even thinking about the device once implanted.

A variety of conditions and disabilities have the potential to be addressed by medical im- plants and prosthetics. Approximately 67 million Americans are afflicted with arthritis2 and 24 million have diabetes.3 Ten percent of the U.S. population (i.e., ~30 million people) will experience a seizure in their lifetime.3 And several million individuals suffer from limb loss or other orthotic impairments that require prosthetics, due to the impact of cardiovascular disease, diabetes, traumatic injury, infection, tumors, nerve damage and congenital anoma- lies.2 As the population ages over the next few decades, there will likely be an increase in spinal injuries and paralysis, and a growing demand for associated orthotic services.4 Ad- ditionally, each year, approximately 75 million Americans report suffering from pain lasting more than 24 hours4. For the broader population, in vivo health monitoring, diagnostic and automated drug delivery devices promise to sustain a person’s health by proactively ad- dressing the early onset of infections and diseases and managing pain. These health and demographic statistics paint a picture of the significant and growing need for robust and reliable in vivo and integrated devices.

Key application opportunities for implantable bioelectronic devices include artificial organs, prosthetics, health monitors, and automated drug and metabolite delivery devices. Given the large and growing number of people with diabetes, and the disease’s potential for debilitat- ing effects including blindness and limb loss, the artificial pancreas is among the highest impact artificial organs. In prosthetic systems, long-term sensitivity, reliability and functionality of biotic/abiotic interfaces is vital. In particular, controlling and quantitatively monitoring the chemical, electrical and optical interfaces between neural and engineered systems is critical to the performance of neural implants and prosthetics.5

Implantable or wearable healthcare monitors have the potential to continuously assess mul- tiple conditions and biomarkers and network to the appropriate service providers for real-time personal care. The following implantable monitoring devices appear to exhibit the highest impact potential: glucose monitor, cardiac blood flow and composition monitors, monitors for detecting human brown adipose tissue, integrated optical electrical neurophysiology probes, and selective biosensors, e.g., for early cancer detection. Such technologies promise to speed diagnosis and reduce the need for costly lab tests.

Finally, integrated, automated drug and metabolite delivery devices could be tailored to an individual’s specific needs to offer optimal dosing with minimal side effects. This latter set of applications could revolutionize personal medicine by providing timely, targeted thera- peutics to alleviate symptoms and pain in persons with infections, chronic diseases such as cancer and malaria, physical and psychological trauma, and genetic disorders such as cystic fibrosis, sickle-cell disease, Tay-Sachs disease, Niemann-Pick disease, spinal muscu- lar atrophy, Roberts Syndrome, etc.

12 While the potential benefits of implantable bioelectronic devices are significant, the risk of trauma and chronic side effects must be addressed for these technologies to be widely adopted. Ensuring that the implanted device is highly biocompatible can minimize some adverse consequences. According to one definition, “An implant can be considered to be biocompatible if 1) it does not evoke a toxic, allergic or immunologic reaction, 2) it does not harm or destroy enzymes, cells or tissues, 3) it does not cause thrombosis or tumors, and 4) it remains for a long term within the organism without encapsulation or rejection.”6 In general, the interfaces between the biomatter and the sensing surfaces are critical. For ex- ample, in some prosthetic devices actuation and control functionality degrades significantly during the first two years of use largely due to biofouling and biodegradation.7 The ability to form stable, immobilized, micro-scaled interfaces that contact individual nerves with minimal tissue damage, immune response and signal noise, would significantly reduce the variability, degradation and functional attenuation of heterogeneous biotic-abiotic systems. If stability is not feasible, embedded nanosensors might allow for compensation over time. Other challenges include power generation, storage and management, hermetically sealed packages, and maximizing the functionality of embedded microsystems, i.e., sensing, sig- nal processing, multiplexing, communication and actuation.

The table on the following page summarizes a set of critical near- and longer-term research opportunities that would address many of the strategic research challenges facing implant- able bioelectronic devices with significant market potential.

13 Materials: Robust, reliable biotic/abiotic interfaces Coatings for implantable devices, including large-area thin Interface-compatible cleaning technology, i.e., for organic/organic, films and hermetically sealed packages organic/inorganic and inorganic/inorganic interfaces Biocompatible organic electronic materials and biotic/abiotic Novel, adaptable, biocompatible and biomimetic materials interfaces that minimize rejection and immune response and maintain cell viability Artificial bioelectronic [nanomorphic] cells for in vivo sensing, monitoring, diagnosis, etc. Devices: Sensors using organic semiconductors Additional long-term challenges:

Biocompatible devices designed to sense specific molecular Soft-case approach (thin film coating) for hermetic sealing structures/biological targets and packaging

Devices for concurrent assessment of multiple biological Close-loop architecture for hybrid integration of chemical parameters and electrical sensing and stimulation

Adaptable algorithms for designing new devices High energy efficiency power source

Systems: Architectures

Wireless communication

Hardware/software trade-offs

Fabrication: High accuracy patterning of printable, degradable organic electronics

References:

1. Biocompatible Materials Drive the Success of Implantable Medical Devices | ECN: Electronic Component News

2. http://www.aboutonehandtyping.com/statistics/, accessed August 13, 2010.

3. http://www.diabetes.org/diabetes-basics/diabetes-statistics/, accessed August 13, 2010.

4. http://www.painfoundation.org/newsroom/reporter-resources/pain-facts-figures.html, accessed August 13, 2010.

5. M. P. McLoughlin, DARPA Revolutionizing Prosthetics 2009, http://www.dtic.mil/cgi-bin/GetTRDoc?Location=U2&d oc=GetTRDoc.pdf&AD=ADA519193/(January 2009), accessed August 13, 2010.

6. http://www.opcareers.org/assets/pdf/TrendsFINAL.pdf, accessed August 13, 2010.

7. S. Thanos and P. Heiduschka, Implantable bioelectronic interfaces for lost nerve functions, Progress in Neurobiology, 55(5), pp. 433-461 (Aug 1998).

14 Medical IMAGING Medical imaging is a powerful means of disease detection and diagnosis. There are many modalities to chose from, including conventional radiography (x-rays), dual x-ray absorptiom- etry (DXA), computed tomography (CT), ultrasound (US), magnetic resonance imaging (MRI), positron emission tomography (PET), single photon emission tomography (SPECT), opti- cal coherence tomography (OCT) and microscopy. Optical microscopy is usually applied to pathological analyses. Clinical scans also often rely on chemical contrast agents to selec- tively change tissue properties for easier biological characterization of any potential abnor- malities. Each of the existing imaging techniques has its own strengths and deficiencies, and a combination of scans can greatly improve diagnostic accuracy. Yet every additional scan contributes to the cost of patient care, and the use of contrast agents may result in undesired side effects. A single diagnostic imaging procedure can cost $3000 or more for CT and MRI modalities1. Yet, CT and MRI are currently some of the more informative and widely used imaging tools in the clinic, with over 68 million CT scans performed in the United States in 2008, an increase of 10 percent from 20072. Even if cost is not an issue, the frequency and number of possible imaging procedures is limited for each patient by fed- eral and state safety regulations in order to keep the radiation exposure within biologically tolerable levels. Therefore, effective yet low-maintenance and low-risk imaging tools are a very strong need for successful medical care.

A primary driver of medical imaging is early detection of cancer. The ultimate goal is catch- ing the disease before it even fully develops, i.e., identifying the troublesome cells before they become cancerous. Current imaging technology is capable of reliably distinguishing le- sions down to ~1 mm3 in size3. Unfortunately, such a lesion size is achieved long after the initiation of the angiogenic switch, which supplies the tumor with its own blood vessels and allows the disease to metastasize. An imaging method that could detect malignant cells before the angiogenic switch stage would be a key to avoiding progression and effectively eliminating illness from cancer.

In addition to sensitivity and safety, ease and cost of maintenance and accessibility (both geographic and economic) are crucial factors for any successful imaging technology. Impressive advances have been made in making some modalities more compact, e.g., x-ray gear that fits into an army backpack and ultrasound modules the size of a laptop. However, other versatile clinical diagnostic tools, such as PET/CT and MRI scanners, still remain quite bulky and expensive to support. A new MRI scanner may cost $2-3 million dollars and annual follow-on servicing and technician costs may approach $1 million per year4. Currently, CTs and MRIs are the most capable tools for evaluating and tracking a wide range of medical abnormalities, such as cancerous lesions, cardiovascular abnormali- ties or neuronal degeneration. Yet their high construction costs and extensive maintenance requirements strongly limit the accessibility of these potent imaging modalities at smaller hospitals and private points of care, not to mention in remote, underserved areas.

Much research and development work remains to be done in designing accurate, acces- sible and safe imaging tools. In particular, there is a growing need for high sensitivity, high resolution, low-maintenance macroscopic imaging devices, as well as for in vivo single cell

15 and single molecule imaging capabilities. Additional high priority opportunities include the detection of rare small populations of cells below the resolution of conventional techniques (such as the detection of small clusters of pancreatic beta cells), and the design of highly portable ultrasonic and MRI scanners. There are also novel opportunities to explore cur- rently underused parts of the electromagnetic spectrum. Terahertz imaging systems, for example, have potential to expand even further the available technological arsenal to aid security screening and early skin cancer detection. Currently, biopsy is still used as the gold standard for the clinical evaluation of skin tissue lesions, even though its diagnostic accuracy is far from absolute. This procedure also may cause the patient unnecessary pain and emotional discomfort. Hence, the ability to accurately identify anatomical and metabol- ic abnormalities at the single-cell level, or at least at the level of a microscopic cell cluster, holds significant promise for effective and painless disease monitoring and treatment. In the longer-term, bioelectronic—or nanomorphic—cells are envisioned that are capable of a wide variety of health-related actions, from gene sequencing to the characterization of local environments inside the body.

The success of diagnostic imaging relies on technological advances in data acquisition, analysis, reconstruction and processing efficiency. Miniaturizing detection electronics and the primary radiation sources, while accelerating reconstruction software capabilities, will improve a scanner’s diagnostic capabilities and its portability and ease of maintenance. A strategic, collaborative investment in imaging research would catalyze the creation of new high performance and portable biomedical imaging technologies.

The following table highlights several of the key identified bioelectronics imaging-related research challenges and opportunities.

Identify novel parallel-signal acquisition paradigms, together with enhanced data reconstruction and storage software and hardware

Design ultra-low power mixed-signal integrated circuits for high performance imaging equipment applications and operation

Develop novel materials for terahertz wave sources/receptors and lighter imaging magnets

Develop unique molecular marker-sensing techniques for nanoscopic detectors

Understand the radio and thermal deposition effects of THz radiation on tissue

References:

1. , accessed on August 24, 2010

2. American Consumer News , accessed on August 24, 2010

3. Wolbarst and Hendee. “Evolving and experimental technologies in medical imaging”. Radiology. 238:1, January 2006

4. , accessed on August 24, 2010

16 Summary Message Research Priorities & Key Recommendations

The field of bioelectronics includes a range of diverse applications areas, each of which has the potential for significant societal and economic impact. Experts at the workshop identified research opportunities within the broad categories of ex vivo, in vivo and imaging applications that had potential for high impact. Among the 20 research opportunities that emerged, those that were given highest priority by the diverse workshop participants from industry and government fell into the following three areas in order of priority.

1. Personalized medical diagnostics and monitoring. Personalized medical diagnostics and monitoring represents the greatest near-term application opportunity. This area in- cludes multimodal (optical, chemical, electronic) single-molecule detection systems that are capable of detecting low concentrations of molecules in “dirty” environments, such as blood. It also includes label-free detection, ideally with single-molecule resolution, for example using sensors that leverage semiconductor technology. Such ex vivo applica- tions are more readily brought to market.

2. Implantable medical devices and prosthetics. The second-highest ranked research area was neural-electronic interfaces and prosthetics-related research that would enable reliable and robust implantable sensors and devices. A key issue in this area is biotic- abiotic interfaces that do not degrade over time for high-impact applications, such as functional prosthetics and diabetes management.

3. Medical imaging. High-impact research opportunities in medical imaging fall in two areas. One area is high-resolution in vivo imaging of small populations and clusters of cells or even within a single cell. The second area is portable and affordable imaging systems that can be operated outside the clinical setting, including in remote, under- served regions. Wearable electronics, especially for cognition monitoring and the gaming industry, is within this category.

Other research opportunities that were discussed (and which are detailed in Appendix E) include:

• Artificial pancreas

• Terahertz imaging systems

• Neurophysiology probes

17 • Single-molecule diagnostics

• Digital point-of-care diagnostics

• Degradable, implantable bioelectronics chips, e.g., blood flow monitor

• Human brown adipose tissue detection

• Biosensors with high sensitivity, reliability and traceability

• Integrated chemical-optical-electrical-neurophysiology probes

• Multiplexed biomarker detection

• Stochastic sensing

• High-performance bio-signal/information processing

• Nanomorphic cell

• Measurements and standards for quantitative medical imaging

• Cell integration platform

• Power sources, such as rechargeable batteries

Many of these opportunities align with one of the top-ranked areas listed above. For ex- ample, single-molecule and digital point-of care diagnostics, biosensors and multiplexed biomarker detection align with personalized medical diagnostics and monitoring. Implant- able medical devices include artificial pancreas, neurophysiology probes (including inte- grated electro-optical devices), and degradable and implantable bioelectronic chips. Finally, research on terahertz imaging systems and human brown adipose tissue detection could be associated with opportunities in high-resolution imaging technologies.

In addition to these focused topics, there is a crosscutting need for characterization and testing methods that support advancement of bioelectronics in general through the innova- tion pipeline and transition to commercial applications.

These topics lay the foundation and provide a framework for more detailed discussions on specific high-value collaborative research projects between the semiconductor electronics and the biotechnology communities. The top-three ranked research topics, while highly rat- ed, may represent different grades of potential commercial opportunity for each community. For example, low volumes of high-margin devices and systems may enable some strategic, high-value market opportunities, such as enhanced MRI technology, for the biomedical community. Similarly, this community also realizes the commercial potential for low-cost point-of-care or home diagnostic devices, which represent high volume, but lower margin products. Correspondingly, a traditional commercialization success factor for the semicon- ductor community is its ability to achieve high yields of high-volume products. Smaller runs of high-margin products are possible, but may require new business models and innovative fabrication methods. Given these considerations, personalized medical diagnostics and monitoring appears to represent a clear and immediate initial point of traction between the semiconductor electronics and biomedical technology communities. The other two high-

18 priority topics also warrant consideration. However, further discussions may be needed to clarify the synergistic win-win for both communities.

Based on input of workshop participants and recognizing the strengths and concerns of both the semiconductor and biomedical industries, the following findings and recommenda- tions are offered as a means of strengthening the value of university research in the area of bioelectronics — for both industry and government stakeholders.

Findings:

1. Advances in semiconductor electronics and biology/medicine are creating an opportuni- ty for bioelectronic technologies that provide societal and economic benefits. With grow- ing research activity worldwide, now is the time for academia, industry and government to work together to achieve the research, education and development goals of each and to overcome barriers to realizing these benefits.

2. A Bioelectronics Research Initiative based on SRC’s consortium model for the support of collaborative, precompetitive research can facilitate and accelerate development of future bioelectronics products.

3. For the Bioelectronics Research Initiative to succeed, the biomedical community has a role to play in defining credible bioelectronics research targets and insertion metrics, and in supporting clinical and regulatory infrastructure for testing selected application opportunities. The semiconductor community provides infrastructure for designing and fabricating high volume, nanoscaled and complex information processing technologies for healthcare applications.

4. Each of the top-three priority topics listed above represents a multimillion dollar three- to five-year initiative.

Recommendations: The research opportunities identified and prioritized in this report represent a consensus of diverse stakeholders from industry and government. The next step is to define, with key stake- holders, the detailed research directions and specific research targets for each of the top-rated synergistic research opportunities. The first focus group will clarify a set of research tasks that would enable advancement in personalized medical diagnostics and monitoring, which is the area of bioelectronics with the greatest impact potential in the five-year timeframe.

In addition, further consideration will be given to research needs in the area of neural-elec- tronic interfaces, implantable devices, imaging small populations of cells, and portable high- resolution imagers, which also represent areas that can benefit from greater collaboration. Subsequent stakeholder discussions will clarify the specific research directions and research targets for these additional high-priority opportunities.The goal is to launch well-targeted, coordinated university research that leverages individual investments and provides high value to both the electronics and biomedical industries by enabling new market opportunities and creating jobs, and at the same time improving healthcare in a cost effective manner.

19 Appendix A: Influential Publications in Bioelectronics

Publication Author(s) Citations

“Integration of layered redox proteins and conductive supports for bioelec- I. Willner and E. Katz 486 tronic applications”, Angew. Chem.-Int. Ed. 39 (7): 1180-1218, 2000 Hebrew University, Jerusalem, Israel

B. Kasemo “Biological surface science”, Surface Science 500 (1-3): 656-677, 2002 Chalmers University Technology, 364 Gothenburg, Sweden

“Probing biomolecular interactions at conductive and semi-conductive surfaces by impedance spectroscopy: Routes to impedimetric immuno- E. Katz and I. Willner 354 sensors, DNA-Sensors, and enzyme biosensors”, Electroanalysis 15 (11): Hebrew University, Jerusalem, Israel 913-947, 2003

C. Richard, et al. “Supramolecular self-assembly of lipid derivatives on carbon nanotubes”, University Strasbourg, France 289 Science 300 (5620): 775-778, 2003 Illkirch Cedex, France

“Control of the structure and functions of biomaterials by light”, Angew. I. Willner and S. Rubin 219 Chem.-Int. Ed. 35 (4): 367-385, 1996 Hebrew University, Jerusalem, Israel

“Toward bioelectronics: Specific DNA recognition based on an H. Korri Youssoufi, et al. oligonucleotide-functionalized polypyrrole”, J. Am. Chem. Soc. 119 (31): 207 CNRS, France 7388-7389, 1997

KD Hermanson, et al. “Dielectrophoretic assembly of electrically functional microwires from University Delaware, Newark, DE 196 nanoparticle suspensions” Science 294 (5544): 1082-1086, 2001 NC State University, Raleigh, NC

“Preparation and hybridization analysis of DNA/RNA from E-coli on J. Cheng, et al. microfabricated bioelectronic chips”, Nature Biotechnology 16 (6): 174 Nanogen, Inc., San Diego, CA 541-546, 1998

“Nanomaterial-based electrochemical biosensors” Analyst 130 (4): 421- J. Wang, UCSD [Formely with NM 173 426, 2005 State University, Albuquerque, NM]

“Towards genoelectronics: Electrochemical biosensing of DNA hybridiza- J. Wang, UCSD [Formely with 166 tion”, Chemistry-Eur. J. 5 (6): 1681-1685, 1999 NM State University, Albuquerque, NM]

“Chip and solution detection of DNA hybridization using a luminescent zwit- KPR Nilsson and O. Inganas 151 terionic polythiophene derivative”, Nature Materials 2 (6): 419-U10, 2003 Linkoping University, Sweden

“Biomolecular electronics: Protein-based associative processors and RR Birge, et al. 132 volumetric memories”, J. Phys. Chem. B 103 (49): 10746-10766, 1999 Syracuse University, Syracuse, NY

“The Application of Conducting Polymers in Biosensors”, Synthetic Metals PN Bartlett and PR Birkin 132 61 (1-2):15-21, 1993 University Southampton, England

“Electrical contact of redox enzyme layers associated with electrodes: I. Willner, et. al. Routes to amperometric biosensors”, Electroanalysis 9 (13) 965-977, 131 Hebrew University, Jerusalem, Israel 1997

“Biocatalyzed amperometric transduction of recorded optical signals I. Willner, et. al. using monolayer-modified Au-electrodes”, J. Amer. Chem. Soc. 117 (24): 111 Hebrew University, Jerusalem, Israel 6581-6593, 1995

20 Appendix B: Bioelectronics Research Resources

The following list includes centers, funding organizations and other resources related to bioelectronics research; it should not be considered comprehensive.

Research Centers

Agency for Science, Technology and Research (A*STAR) – Institute for Microelectronics http://www.ime.a-star.edu.sg

Arizona State University – Center for Bioelectronics and Biosensors http://www.biodesign.asu.edu/research/research-centers/bioelectronics-and-biosensors

Clemson University – Center for Bioelectronics, Biosensors and Biochips http://www.clemson.edu/c3b

Duke University – Center for Neuroengineering http://www.duke.edu/~ch/Neuroeng/Neuro.htm

Fraunhofer Institute for Biomedical Engineering – Molecular Bioanalytics and Bioelectronics http://www.ibmt.fraunhofer.de/fhg/ibmt_en/biomedical_engineering/molecular_bioanalyt- ics_bioelectronics/index.jsp

Janelia Farm – Howard Hughes Medical Institute http://www.hhmi.org/janelia

Seoul National University – Nano-Bioelectronics & Systems Research Center http://nanobio.snu.ac.kr

University of California-Santa Cruz – Integrated Bioelectronics Research http://ibr.soe.ucsc.edu/?file=kop1.php

University of Michigan – Center for Wireless Integrated Microsystems http://www.wimserc.org

University of South California – Biomimetic MicroElectronic Systems Research Center http://www.erc-assoc.org/factsheets/15/15-Fact%20Sheet%20Save%20as%20Webpage.htm

University of Utah – Center for Advanced Imaging Research http://www.ucair.med.utah.edu

Government Programs

The Department of Energy has within its Office of Basic Energy Sciences multidisciplinary programs that fund projects at national laboratories and universities. http://www.science.doe.gov/Program_Offices/BES.htm

The Food and Drug Administration (FDA) has programs related to the multidisciplinary aspects of applying bioelectronics to protecting the environment. The FDA Office of Science

21 and Engineering Laboratories has several divisions that contribute to bioelectronics. http://www.fda.gov/cdrh/osel/researchlabs

The National Institutes for Health (NIH) has many intramural and extramural programs involving bioelectronics. Examples include:

National Institute for Biomedical Imaging and Bioengineering http://www.nibib.nih.gov/Research/Intramural http://www.nibib.nih.gov/Research/ProgramAreas

National Cancer Institute Network for Translational Research http://proteomics.cancer.gov

National Institute of Diabetes and Digestive and Kidney Diseases http://www2.niddk.nih.gov

National Institute of Standards and Technology (NIST) has bioelectronics projects in many of its laboratories, such as those involved with electronics and electrical engineering, chem- istry, physics, materials research and information technologies. Examples include: http://www.nist.gov/pml http://www.nist.gov/mml http://www.nist.gov/itl http://www.nist.gov/msel/biomaterials.cfm/

The National Science Foundation currently supports bioelectronics research in the Electron- ics, Photonics and Device Technologies (EPDT) program. http://www.nsf.gov/funding/pgm_summ.jsp?pims_id=13379/

Books

Willner, I. and E. Katz (eds.), Bioelectronics: From Theory to Applications, Wiley-VCH, Wein- heim, Germany, 2005. http://www.amazon.com/Bioelectronics-Theory-Applications-Itamar Willner/dp/3527306900/ ref=sr_1_1?ie=UTF8&s=books&qid=1229293104

Market Reports

SRI Consulting Business Intelligence – Next-generation technologies: Bioelectronics http://www.sric-bi.com/Explorer/NGT-BE.shtml/

Venn Research, Inc. -- Worldwide Biosensor and Bioelectronic Market http://www.marketresearch.com/map/prod/1343053.html

BCC Research – Biotechnology: Biosensors and Bioelectronics http://www.bccresearch.com/report/BIO039B.html

22 Appendix C: Agenda for 2nd Bioelectronics Roundtable Meeting

AGENDA 2nd SRC Bioelectronics Roundtable (BERT2) Howard Hughes Medical Institute (HHMI) Janelia Farm Research Campus March 25-26, 2010

Thursday, 8:30 – 8:45 Welcoming Remarks March 25, 2010 Kevin Moses, Janelia Farm

8:45 – 9:00 Roundtable Program and Goals Celia Merzbacher, SRC

9:00 – 11:30 Session 1. Ex Vivo Systems Overview by Madoo Varma, Intel Corp. Session Moderator – Lloyd Whitman, NIST

Breakout Discussion

12:30 – 3:00 Session 2. In Vivo Systems Overview by Jack Judy, DARPA Session Moderator – William Heetderks, NIBIB

Breakout Discussion

3:20 – 5:50 Session 3. Imaging Overview by Jonathan Murray, GE Healthcare Session Moderator – Sankar Basu, NSF

Breakout Discussion

6:30 – Dinner/Informal Networking

Friday, 8:00 – 8:20 Bioelectronics Research and Development at A*STAR Institute March 26, 2010 for MicroElectronics Tushar Bansal (A*STAR IME, Singapore)

8:20 – 8:30 Overview of Day 2 Goals

8:30 – 10:00 Breakout Group Discussions on Challenges

10:00 – 10:30 Session Summaries

10:30 – 10:45 Prioritization of Identified Opportunities

11:00 – 12:15 Session 4. Wrap-up: Summary/Discussion of Prioritization and Next Steps

12:15 Adjourn

12:15 – 1:15 Lunch Tour of Janelia Farm Research Center [optional]

23 Appendix D: Attendee List for 2nd Bioelectronics Roundtable Meeting

Roundtable Participants 2nd SRC Bioelectronics Roundtable (BERT2) Howard Hughes Medical Institute (HHMI) Janelia Farm Research Campus

Participant affiiation

Guillermo Arreaza-Rubin National Institute of Diabetes and Digestive and Kidney Diseases

Tsunetoshi Arikado Tokyo Electron Ltd.

Tushar Bansal A*STAR Institute of Microelectronics, Singapore

Sankar Basu National Science Foundation

Anastasiya Batrachenko Semiconductor Research Corporation

Michael Gaitan National Institute of Standards and Technology

Timothy Harris Janelia Farm/Howard Hughes Medical Institute

William Heetderks National Institute of Biomedical Imaging and Bioengineering

Daniel Herr Semiconductor Research Corporation

William Joyner Semiconductor Research Corporation

Jack Judy Defense Advanced Research Projects Agency

Sam Kavasi The Bosch Group

Maren Laughlin National Institute of Diabetes and Digestive and Kidney Diseases

Celia Merzbacher Semiconductor Research Corporation

Kevin Moses Janelia Farm/Howard Hughes Medical Institute

Jonathan Murray GE Healthcare

Steve Pollock Food & Drug Administration

Dave Seiler National Institute of Standards and Technology

Stacey Shirland Semiconductor Research Corporation

Dorel Toma Tokyo Electron Ltd.

Madoo Varma Intel Corporation

Usha Varshney National Science Foundation

Lloyd Whitman National Institute of Standards and Technology

Sufi Zafar IBM

Victor Zhirnov Semiconductor Research Corporation

24 Requirements Estimated Resource eople: P 5 PhD students TBD $0.5M A nnual C osts: Metrics of Progress ear G oal(s): ear G oal(s): ear G oal(s): ear G oal(s): ear G oal(s): b) Photolighographic peptide 5- Y Multi-molecule biosensor array Develop silicon-based peptide Develop 3- Y 10- Y 3- Y Commercial Prototype Concept Demonstration Single molecule biosensor array clinical diagnostics c) Array performancec) Array testing; arrays for drugarrays discovery and a) Wafer surface derivatization a) Wafer d) Application development synthesis; 7- Y Advantages biology/immunology includes high-resolution, includes high-resolution, Benefits/advantages for Research time/cost Enable multi-dimensional field deployable highly field deployable massively parallel cost- multi-analyte analyses reduction by better reduction by cell study platforms effective tools, discrete effective tools, answer integration for answer system-wide analyses, system-wide analyses, specific and sensitive sensors – ease of use, sample-to- – ease of use, otential A pplications & C orresponding Research N eeds edical a n d D ia gn ostics P erso n ali z ed M edical Research Need Research b) Designing for manufacturabil - ing surface interactions at the intersection of biology and ity – compatibility with standard Miniaturization of platforms requirements. CMOS fabrication methods; Chemical Delivery/Detection c) Cost/volumes for intended a) Biocompatibility – Understand - and relatively unknown biology; applications – modularity; and and packaging d) Low power silicon, limited starting silicon, material, Alternative Solutions articipant Inputs on P

Applications of Interest D river(s): D river(s): bodies using auto antigen micro M arket need: M arket size: Point of care/$3B] Point M arket need: infectious diseases, drug resis - infectious diseases, Benchtop cells interrogation tance, bio-warfare agents bio-warfare tance, throughput flow cytometry research for autoimmune Screening & profiling auto anti - platforms to compliment high Over the counter/$5B, care costs, healthcare delivery care costs, array can diagnose and predict array autoimmune diseases; cancer, access, singularity push access, applications diseases, cancer, etc. cancer, diseases, $32B [Central Lab/$24B, Aging population, rising health - Aging population, Addresses the need for biology A ppendix E : Roundtable P Human Diagnostics – Label-free Low Cell Interrogation Platforms and High Density Electronic Arrays Research Opportunity

25 Requirements Estimated Resource eople: P $1M A nnual C osts: TBD 10 PhD students Metrics of Progress ear G oal(s): ear G oal(s): ear G oal(s): ear G oal(s): b) Novel assay + fluidic detection assay b) Novel 5- Y 5- Y Development of array of highly of array Development 3- Y 3- Y Integration of the sensors on fluidics and assays for automated sample delivery, data for automated sample delivery, multi-functional, low power platform low power multi-functional, reliable & sensitive label free sensors System demonstrations using existing combination a) Commercial Prototype acquisition & transmission neural Advantages Reduced development/ Reduced development/ - leading to better preven Huge healthcare cost Important research tool cancer viral infection, tion methods neglected markets prosthetics proteins providing new insight into new providing enable early diagnostics can also be applied for and prevention at point- and prevention cost for approval detecting opening of-care saving & closing of ion channel & other illnesses, thus & other illnesses, This technology can The sensor technology Research Need Research edical a n d D ia gn ostics (continued) P erso n ali z ed M edical Bioelectronics to relax Biomarker discovery FET sensor design & fabrication Detection System Demonstration in the field Functionalization of sensing Demonstration of sensitivity & Integration with low-cost fluidics the sample preparation micro-fluidics for sample delivery reliability for bio-sensing in an Coupling sensor array with Coupling sensor array evaluation of bio-fouling evaluation aqueous environment, including aqueous environment, steps/modules optimization surface detection Applications of Interest D river(s): D river(s): bio-sensing platform using M arket size: M arket need: M arket size: Low-cost complete detection + Improve availability of point- availability Improve tor (FET) devices such as virustor (FET) devices fluidic + radio + power integration fluidic + radio power for under $0.50 miniaturized field effect transis - USA > $200 Billion USA > $150 Billion cancer screening detection (e.g. influenza, HIV) detection (e.g. influenza, including and protein detection, of-care diagnostics A highly sensitive & automated > number of cell phones •Annual influenza cost in •Annual cancer costs in

Label Free BioSensing Digital POC Dx using FET-Based Sensors Research Opportunity

26 Requirements eople: 10-15 Estimated Resource Facilities: E st. A nnual costs: P Interdisciplinary teams with access nano - to CMOS, fabrication and facilities. clinical test electronics TBD ~$5M/year; Metrics of Progress ears G oal(s): ear G oal(s): ear G oal(s): Prioritization of needs 5- Y Development of standards Development Demonstrate multipexed Demonstrate multiplexed, Demonstrate multiplexed, 3- Y Identification of metrology to support cross cutting 3- Y measurement needs month operation in vivo. matrices with off-chip signal needs road-mapping planning work, facilities planning work, processing and 1 (one) processing. Guidance for federal agen - cies, such as NIST, for such as NIST, cies, ces with on-chip signal and/or precompetitive and external investment analytes in biological matri - analytes in biolocial stochastic sensing of 64 stochastic sensing of 8 Technology and metrology Technology Advantages enefits/advantages over cur - B enefits/advantages in vitro and in vivo. With few in vitro and vivo. With few rent capabilities or technology: Would create a totally new ap - create a totally new Would Early awareness of standards Early awareness Enables the accurate compari - the same systems to be used tory agencies, such as FDA, etc. tory such as FDA, agencies, that industrial needs are met in the need for microarrays and the need for microarrays - for the coordination and devel multi-step labeling assays. research groups. reagents and broad-spectrum proach to biosensing, allowing proach to biosensing, protocols with federal regula - capabilities, may be low enough may capabilities, countries cost for developing device technologies and device and calibration requirements so advance. opment of test and certification son of performance between son of performance between This knowledge will be needed This technology would eliminate Research Need Research b) Standards for defining the identified or under consider - Bioinformatics to interpret Biocompatible packaging to Development of new test of new Development Determine needs for calibration performanceDevice testing Examples of current needs the device Instrumentation development tion of separations frequency. facilities methods resolution retic flow properties Sensing surface potential bio-encapsulation of prevent changes with single-molecule c) Propertiese.g. database(s), conductivity and permittivity vs. electroosmotic and electropho - detector sensitivity and resolu - ation by SEMI include: ation by a) Standard test method for stochastic signals edical a n d D ia gn ostics (continued) P erso n ali z ed M edical Applications of Interest D river(s): binding events and providing the signal and providing binding events M arket need: D river(s): M arket size: M arket need: in vitro, broad-spectrum detection in vitro, Needs for test methods and instrumenta - Label-free, real-time, in vivo or real-time, Label-free, takes time. Standards organizations such takes technologies should be accompanied with prioritized and tion should be identified, facilities and standard reference materials facturing methods. metabolomics, proteomics, genomics proteomics, metabolomics, road-mapped. Vast application space in biomarkers, IVD, IVD, application space in biomarkers, Vast processing to translate the binding properties, performance and reliability, properties, performance and reliability, cies such as NSF, can work with academic cies such as NSF, cutting and precompetitive needs. as SEMI, ASTM and NIST, and other agen - ASTM and NIST, as SEMI, and industrial groups to identify cross of monitoring stochastic bind and un- advances in methods for testing device advances in methods for testing device and their relationship to optimizing manu - signatures. An integrated chip-based system capable The development and advancement of new and advancement of new The development calibration of standards, The development

Characterization Methods for Stochastic Sensing Bioelectronic Devices Research Opportunity

27 Requirements Estimated Resource eople: eople, time and eople, Facilities: P facilities: TBD bio-abiotic interface P Interdisciplinary teams with access to nano-electronics facilities robust and reliable 3-4 Faculty 3-4 Faculty and clinical test $3M – $13M A nnual cost: A high-performance, A high-performance, & MEMS fabrication ~$700K/year; Metrics of Progress ear G oal(s): ear G oal(s): ear G oal(s): ear G oal(s): ear G oal(s): 5- Y implantable, wireless multi-parameter implantable, in human bodies Reliable and robust control of one-bit Demonstrate the feasibility of Demonstrate the feasibility of an 3- Y 10- Y 10- Y 3- Y wireless cardiac monitoring system flow system reliable bio-abiotic interface Successful demonstration of the cardiac measuring system with bio- compatible packaging an implantable wireless blood applications switches for neural-electronic interface A high performance, robust, and robust, A high performance, Advantages benefit the lives of Impact, if successful: Impact, improve the quality of life improve impacts of pain and cost. Neural Prosthetics Reliable Brain-Controlled Higher-Performance and Higher-Performance millions of people with peripheral-vascular cardiovascular or cardiovascular and prevent complicated and prevent disease. surgery and associated This technology would This technology could n d P rost h etics a b le D evices I mpla n ta Research Need Research Physical Reliability C hallenge 1: Physical Fast and Reliability C hallenge 2: Fast has yet to be controlled reliably. has yet to be controlled reliably. Nano wire sensors, wireless Nano wire sensors, vascular system or graft Implantable device on to the Implantable device typically decays to zero in < 1 2 typically decays often much sooner. years, neural-electronic interface or BMI neural-electronic interface. Signal-to- noise ratio of single-unit potentials Software and system control Software powering and measurement, powering Currently long-term (years) reliable patient acceptance of prostheses. precision/speed control of many- presently out of reach. correct operation (>>99%) required; and management algorithms does not exist. Even a one-bit switch degree-of-freedom systems are Applications that call for high- Applications of Interest D river(s): D river(s): M arket need: M arket size: M arket need: hand-held monitoring device hand-held monitoring device Regain function needed to High performance, robust High performance, vascular or peripheral Improve the health and quality Improve for the patient flow measuring system that return to duty, maintain quality return to duty, provides a simple real-time provides and reliable prosthetics for amputees disease. of life people with cardio - of life (rotation/post service) As many as 1 billion people As many An automated wireless blood

Higher-Performance and Reliable Implantable Cardiac Brain-Controlled Neural Prosthetics Blood Flow Monitor Research Opportunity

28 Requirements Estimated Resource eople: ~10 eople: Facilities: Facilities: P P Funded core facilities, Funded core facilities, with access to relevant operational relevant Chemistry and engineering teams environments $2M A nnual C osts: A nnual costs: surface chemistry services 15 PhD students ~$4M/year

Metrics of Progress ear G oal(s): ear G oal(s): ear G oal(s): ear G oal(s): ear G oal(s): b) Prototypes developed and demon - b) Prototypes developed Prototypes in clinical trial Products on the market Prototyped micron-scale system 5- Y 5- Y 10-year G oal(s): 10-to-12- Y 3- Y 3- Y Sub-mm size energy source Subsystems demonstrated (power communication) demonstrated a) Interface between semiconductors a) Interface between and biochemistry is better understood strated for life sciences supply, microcontroller, sensors, microcontroller, supply,

Advantages b) Synergistic with Impact, if successful: Impact, high-selectivity healthcare cost and increase quality of life. trends (scaling, func - trends (scaling, tional diversification) In vivo diagnostics and to affordable and repeat - therapeutics at the level therapeutics at the level will lower the overall the overall will lower real-time, high-resolution, high-resolution, real-time, current semiconductor early detection of chronic able technology for therefore, disease and, a) Non-invasive, of individual cells A dvantages: This approach will lead Research Need Research n d P rost h etics (continued) a b le D evices I mpla n ta semiconductor device between b) creating closed control loops increasing selectivity and sensitiv - using ity of biomarker detection by is enabler. Micro-scale system assembly low-cost chemistry cost is — overall face of biochemistry and semicon - Ultra-compact energy sources Communication with an external Semiconductor technology for chemistry and semiconductor device. ductor technology has to be done: a) understanding interaction and biochemistry, bio - around the interface between and packaging still low; semiconductor technology station To achieve this, research at the inter - this, achieve To Applications of Interest D river(s): D river(s): M arket size: M arket need: M arket size: Potential for widespread use Potential home. The devices have to be have home. The devices Extreme Capsule Endoscopy Examples of unmet bio/ to detect biomarkers and the level of cell physiology the level monitor multiple biomarkers multiple biomarkers understand the biological medical need: early detection Currently research is underway Currently research is underway pathways associated with pathways Several billion Several Semiconductor-based chronic diseases at an early ers. This will set the stage for easy to use and robust. diseases and their biomark - that will quantitatively devices done at a doctor’s office or at done at a doctor’s quantitative diagnostics of over time in order to detect over stage. These tests will be of cancer; active imaging at

Multiplexed BiomArker Detection NanoMorphic Cells Research Opportunity

29 Requirements Estimated Resource TBD TBD Metrics of Progress ear G oal(s): ear G oal(s): ear G oal(s): ear G oal(s): human body 5- Y Development of algorithms for Development Development of integrated chip Development 3- Y 3- Y Identify sensors responsible to electronics and Interface between close-loop automation consisting of sensor and pumps specific antibodies 7- Y Advantages blood pressure and Provide new scien - new Provide Impact, if successful: Impact, Reduced healthcare Low-cost diagnoses, Low-cost diagnoses, Huge amount of people Improved diabetic care Improved temperature sensors for tific understanding of would have cancer would have further improvement method(s) for prevention rapid and high-sensitivity, rapid and high-sensitivity, Can be integrated with check every year. Cancer check every year. could be detected at costs early stage. early-stage detection. diabetes to food intake and lifestyles – a better Research Need Research n d P rost h etics (continued) a b le D evices I mpla n ta between sensors & deliverybetween pumps blood sugar Parasitic interface parameters Parasitic Whole blood analysis with no - devel Based on human physiology, Development of database based Development Develop non-invasive glucose sensor non-invasive Develop of insulin pumps Development Identify sensor responses to that provides real-time measure of that provides (R;C;H) between electronics, sen - electronics, (R;C;H) between pretreatments dramatic sensitivity. diagnose precisely. accurate close-loop automation on race, region and nation to on race, opment of algorithms that provide opment of algorithms that provide sors and antibodies can be a “show reducing by stopper” in investigation specific antibody sensors and electronics & sensors interface between develop To Applications of Interest D river(s): D river(s): M arket size: M arket need: M arket size: in the number of people with in the blood, thus providing thus providing in the blood, Enhance early identification for monitoring and screening. 500 million people worldwide monitors and controls glucose uted to diabetic care; growth Cancer detection chip not 250 million by the year 2025. 250 million by also with low cost. In addition, also with low cost. In addition, diabetes is expected to reach diabetic care of cancer and other disease only with high sensitivity but short cycle time is essential An artificial pancreas that 1/3 healthcare costs attrib -

BIOSENSORS ARTIFICIAL PANCREAS Research Opportunity

30 Requirements eople: 10-15 Estimated Resource Facilities: E st. A nnual costs: P FTE plus MEMS through several through several Interdisciplinary teams with access nano - to CMOS, ties. fabrication cost fabrication and cycles of design clinical test facili - and test electronics ~$0.5-1/yr, 2 ~$0.5-1/yr, ~$5M/year; TBD TBD

Metrics of Progress ear G oal(s): ear G oal(s): ear G oal(s): ear G oal(s): ear G oal(s): b) Multi-shank versions b) Low-loss coupling of an b) Switchable emission site Project completion b) Head-mounted electron - Project completion: 5 integrated emitter 5- Y ics to multiplex up 5000 1- Y 3- Y 3- Y 2- Y waveguide fabrication waveguide fabricated 500-1000 sensor sites probes, 10 shanks each, 10 shanks each, probes, per shank a) Low-loss polymer planar a) Integration of multicolor a) Switchable emitter color at coupling, a) Integrated single shank with 500-1000 ad - devices dressable sites per shank, on probe sources with electrical probe, sources with electrical probe, signals ear G oal(s): ear G oal(s): ear G oal(s): ear G oal(s): human body 5- Y Development of algorithms for Development Development of integrated chip Development 3- Y 3- Y Identify sensors responsible to electronics and Interface between close-loop automation consisting of sensor and pumps specific antibodies 7- Y Advantages Far more complete data sets Far Resolution of closely spaced Flexibly programmed optical Flexible modular design and tion with minimal perturbation fabrication platform neurons resolving current ambiguities of regions at the same time Current fiber-coupled devices perturbation. Wireless (battery or thin flexible pow - powered) preferred. cause considerable animal excitation and electrical detec - ered devices would be much ered devices active neuron count of animal behavior. Ability to monitor multiple brain blood pressure and Provide new scien - new Provide Impact, if successful: Impact, Reduced healthcare Low-cost diagnoses, Low-cost diagnoses, Huge amount of people Improved diabetic care Improved temperature sensors for tific understanding of would have cancer would have further improvement method(s) for prevention rapid and high-sensitivity, rapid and high-sensitivity, Can be integrated with check every year. Cancer check every year. could be detected at costs early stage. early-stage detection. diabetes to food intake and lifestyles – a better Research Need Research head-mounted amplifiers ing and amplification on shank integrated onto ~20-um thick, integrated onto ~20-um thick, inserted into the brain of mice integrated onto ~20-um thick, inserted into the brain of mice Brain immersed high sensor with just above brain program - with just above 60-um wide probes, to be 60-um wide probes, to be 60-um wide probes, 5-10-mm long low loss (0.5 dB) 5-10-mm long low loss (0.5 dB) mable multiplexing multiplexing and amplifying multimode optical waveguides multimode optical waveguides multimode optical waveguides Very lightweight head-mounted lightweight Very 32-64 5-10-um diameter metal electronics and/or multilayer metallization and/or multilayer device, with conductors into the device, site “shanks” with multiplex - sites integrated into this same n d P rost h etics (continued) a b le D evices I mpla n ta between sensors & deliverybetween pumps blood sugar Parasitic interface parameters Parasitic Whole blood analysis with no - devel Based on human physiology, Development of database based Development Develop non-invasive glucose sensor non-invasive Develop of insulin pumps Development Identify sensor responses to that provides real-time measure of that provides (R;C;H) between electronics, sen - electronics, (R;C;H) between pretreatments dramatic sensitivity. diagnose precisely. accurate close-loop automation on race, region and nation to on race, opment of algorithms that provide opment of algorithms that provide sors and antibodies can be a “show reducing by stopper” in investigation specific antibody sensors and electronics & sensors interface between develop To Applications of Interest D river(s): D river(s): D river(s): M arket size: M arket need: Monitoring activity of M arket need: M arket size: D river(s): M arket size: M arket need: M arket size: individual neurons is a common and basic individual neurons in genetically modified in awake, freely moving research mice. freely moving in awake, induced with light. in the number of people with in the blood, thus providing thus providing in the blood, Enhance early identification vices compatible with mice and rats have vices compatible with mice and rats have thousands of sites are needed. with human clinical brain implants. for monitoring and screening. 500-1000 research groups worldwide, 500-1000 research groups worldwide, 500 million people worldwide neurons in mouse and rat brains to under - mice. Selected neurons are made optically monitors and controls glucose uted to diabetic care; growth Sensing activity of large numbers of Controlling and monitoring activity of Cancer detection chip not part of neurobiology research. Current de - Sensing and controlling activity of neurons 250-500 research groups worldwide, 250-500 research groups worldwide, 250 million by the year 2025. 250 million by at most 64 sensing sites. Systems with also with low cost. In addition, also with low cost. In addition, diabetes is expected to reach diabetic care stand basic brain function. overlap with human clinical brain implants. spending. Substantial long-term overlap spending in the area. Some long-term of cancer and other disease only with high sensitivity but sensitive so that neuron firing can be short cycle time is essential An artificial pancreas that 1/3 healthcare costs attrib - ~$50-150K per group year annual ~$50-150K per group year annual

Integrated Optical & Electrical Neurophysiology Probes Neurophysiology Probes Research Opportunity

31

Requirements eople: Estimated Resource Facilities: P bio/medical). Primarily physics, Primarily physics, Need interdis - with access to 5 years. materials science, materials science, (technical and relevant operational relevant chemistry & ciplinary teams engineering teams environments. A nnual cost: A nnual C osts: ~$4M/year; ~10 Faculty ~1M/year for

ear G oal(s): ear G oal(s): Metrics of Progress ear G oal(s): ear G oal(s): ear G oal(s): b) Study large clinical b) Test in animals and b) Test Prototyped micron-scale 5-to-10- Y 6- Y 3- Y 12- Y 1-to-5- Y robustness Sub-mm size energy source Subsystems prevalence in population prevalence populations to prove people c) Use in clinical trials demonstrated (power a) Detect hBAT mass a) Detect hBAT a) Determine hBAT supply, microcontroller, supply, communication) sensors, system demonstrated of obesity drugs & activity

Advantages b) Non-invasive, real-time, b) Non-invasive, b) Measure contribution of high-resolution, high-selectivity high-resolution, hBAT to energy balance/ hBAT individual cells therapeutics at the level of therapeutics at the level functional diversification) radiation exposure, nonspecific) radiation exposure, protection from obesity, protection from obesity, c) Synergistic with current c) Improved endpoints for c) Improved a) In vivo diagnostics and a) Identify conditions that activate hBAT, d) 18F-Deoxyglucose PET is semiconductor trends (scaling, semiconductor trends (scaling, A dvantages include: obesity clinical trials to monitor (expensive, only way Research Need Research have hBAT have Novel tissue only recently Novel obese Not clear if elderly, Micro-scale system assembly Few non-invasive approaches to non-invasive Few found in neck, below clavicles, below clavicles, found in neck, Ultra-compact energy sources. measuring mass and function nal station. Communication with an exter - and packaging. along spine in lean, young along spine in lean, adult humans. of this tissue exist. Activated by cold Activated by n d P rost h etics (continued) a b le D evices I mpla n ta Applications of Interest D river(s): M arket size: M arket needs: M arket need: Potential for widespread use Potential M arket size: identify people that would benefit from Extreme Capsule Endoscopy Examples of unmet biomedical needs are to monitor hBAT mass/activity would help to monitor hBAT therapies aimed at activating it. which burns calories; activating molecules may be good obesity drugs. may Obesity/overweight affects >2/3 of Obesity/overweight early detection of cancer; active imaging at the level of cell physiology at the level A pplication D river: Americans, creating high health costs Americans, safe way quantitative, reliable, A cheap, Adults have brown adipose tissue (hBAT) brown adipose tissue (hBAT) Adults have

Human Brown Adipose Nanomorphic Cell Tissue Detection Research Opportunity

32 Requirements eople, time eople, eople: Estimated Resource P Facilities: P i.e. CT, X-ray, and X-ray, i.e. CT, MR Interdisciplin - with access to fabrication and facilities micro-electronics and facilities: 3-6 Faculty clinical test across 3 areas, across 3 areas, ary teams $1B over 5 years $1B over A nnual cost: TBD

Metrics of Progress ear G oal(s): ear G oal(s): ear G oal(s): ear G oal(s): C battery-powered operation battery-powered operation 5- Y 5- Y Metabolic MR with Hyperpolarized Demonstrate feasibility of a Demonstrate feasibility of Demonstrate feasibility of a 3- Y 10- Y 13 palm-sized 3D ultrasonic imager palm-sized 3D ultrasonic imager capable of three hours of continu - capable of 8 hours of continuous capable of 2 days of continuous capable of 2 days a laptop-sized 3D ultrasonic imager ous battery-powered operation Advantages B enefits/advantages: Impact: improved staging and improved influence treatment Measure biochemical tests using MR It would also enable tion, diagnosis, treat - diagnosis, tion, to ultrasonic imaging for earlier diagnosis, for earlier diagnosis, ment and monitoring. reduce the cost of Significantly faster prostate cancer. Stay healthier longer by healthier longer by Stay gency situations cost exam than current enabling earlier predic - decisions starting w/ - especially in the devel effectively. and expand access and quick treatment decisions in emer - oping world on-site diagnostics This technology would “fingerprint” of tissue C 13 MEDICAL IMA G I NG Research Need Research S cientific problems hyperpolarized within hyperpolarized imaging algorithms ity of MR through injection of the agent labeling of endogenous Energy-efficient ultra - Increasing the sensitiv - the MRI department. I.V Ultra-low-power mixed- Ultra-low-power (milliwatt) mechanism and signal metabolic product Software and Software and barriers: compounds that are detection and imaging of several and imaging of several sonic transduction signal integrated circuits

Applications of Interest D river(s): D river(s): M arket size/need: M arket size: M arket need: S taging: Localize where and the size of prostate Differentiate BPH & chronic prostatitis from cancer – Enhance ability of clinicians to quickly perform diag - the index tumor is (index largest lesion that will solve many diagnostic problems easily that will solve many with the highest Gleason score), determine spread with the highest Gleason score), useful in all patients. If patients have a previous a previous useful in all patients. If patients have negative biopsy but still high clinical suspicion they nosis and reach treatment decisions personalized and actionable information Guide from where in the prostate to take the sample – Guide from where in the prostate to take could get a 13C scan instead of a new biopsy. biopsy. could get a 13C scan instead of new avoid biopsies in these patients. avoid disease assessment/prevention/treatment, access, access, disease assessment/prevention/treatment, quality, and cost; and integrated, accessible, and cost; integrated, quality, outside prostatic capsule and involvement of other outside prostatic capsule and involvement structures of people. solved by imaging is needed. solved by Aging demographics; productivity, i.e., simultaneous i.e., Aging demographics; productivity, An accurate, highly-mobile and safe imaging system An accurate, This technology would benefit the lives of millions

Highly Mobile Metabolic Magnetic Resonance Ultrasonic Imager Research Opportunity

33 Requirements Estimated Resource eople: P Primarily physics and Primarily physics interdisciplinary facilities Needed are dedicated test sites with imaging and diabetes researchers. components and clinical engineering teams with access to MRI equipment and European funding agencies is about $75M over 10 years. over A nnual cost: Total spent to date by US spent to date by Total 4-6 Faculty ~$1-2M/year ear G oal(s): ear G oal(s): ear G oal(s): Metrics of Progress ear G oal(s): ear G oal(s): b) Explore biology of Performance optimization Performance 5- Y 5-to-10- Y imaging approach is in large clinical popula - MRI units 10- Y 3- Y 10- Y tions to prove robustness tions to prove with stationary clinical (~1.5-3T), yet low-mainte - (~1.5-3T), scanner magnet, market/ligand to prove market/ligand to prove nance portable magnet Construction of the people Study imaging approach c) Test in animals and c) Test assessment of a strong assembly and competitiveness a) Identify cell markers and specific ligands quantitative and specific Theoretical design

Advantages B enefits/advantages Impact: healthcare sites and improved endpoints for improved increase availability to increase availability Full-body 3T MRI scanners Reduce costs/safety Explore natural history to wider population of measure of function and room to be well-shielded & room to be well-shielded require less electric power, risks of MRI maintenance, risks of MRI maintenance, Currently, measure Currently, per month. Installation patients over current over capabilities: currently require ~50-100L clinical trials which is a poor c-peptide, cannot report on cell mass electronics. Smaller in size, electronics. Smaller in size, early detection of disease; of liquid helium for cooling of diabetes; potential for only glucose or insulin separate from the control cooling. shielding, MEDICAL IMA G I NG (continued) Research Need Research beta cell and islet. imaging difficult Motion and location Magnet stability Beta cells are only Relatively little is known Few unique markers for Few Long cell half-life, little Long cell half-life, Data reconstruction and turnover or growth molecular imaging power supply/control power Sufficient field strength Gradient and RF coil- cooling mechanisms electronics deep in gut make about the biology of the and homogeneity storage. Temperature stability/ Temperature ~1% of pancreas Applications of Interest D river(s): D river(s): M arket need: M arket size: M arket size: M arket needs: Emerging therapies are focused on beta cell Diabetes/pre-diabetes affects >26M Existing tests of beta cell function in diabetes Easy portability and assembly units at sites technology for central nervous system and soft tissue imaging fail to distinguish between altered mass and fail to distinguish between worldwide magnetic resonance imaging preservation, expansion, regeneration or re - preservation, expansion, but are hard to explore without placement, altered function. a measure of cell mass. of need will improve availability and safety of availability of need will improve Americans. To improve utility of magnetic resonance improve To Thousands of hospitals; millions people

Imaging the Pancreatic High-ResOLUTION Portable MRI Scanner Beta Cell Mass Research Opportunity

34

Requirements Estimated Resource eople: eople: Facility: Facility: P P NIST Neutron Center, NIST Neutron Center, nano-electronics fabrication nano-electronics fabrication ary teams with access to ary teams with access to $4M/year A nnual costs: $4M/year A nnual costs: & clinical test facilities & clinical test facilities 12 scientists, interdisciplin - 12 scientists, 12 scientists, interdisciplin - 12 scientists, ear G oal(s): ear G oal(s): ear G oal(s): Metrics of Progress ear G oal(s): ear G oal(s): ear G oal(s): 5- Y 5- Y Nanopore based metrol - RNA, DNA, proteins, an - proteins, DNA, RNA, Develop multiple unique Develop Demonstrated integrated 1-to-5- Y 10- Y 10- Y thrax toxins; single-mole - than 1.5 Angstroms 3- Y tronic chips fluidic structures & elec - medical imaging and medicine & HLS nanopores (solid state Competitive tools for Compact and efficient cule mass spectrometry can discriminate to better applications ogy: detect/characterize system security screening selectivity. Coupling to selectivity. A device for personalizedA device & biological) for greater THz sources and optics

Advantages b) Highly scabale b) On-site rapid detection Powerful imaging & screen - Powerful enefits/advantages over B enefits/advantages Impact, if successful: Impact, Impact, if successful: Impact, in a haystack capability) in a haystack ing technology, availability availability ing technology, to health care sites and trends wider population of patients (detect ~ 1000 unique molecules/chip) medicine remediation real-time, high-resolution, high-resolution, real-time, remote “materials finger - printing”, synergistic with printing”, current capabilities: c) Low-cost (e.g., current semiconductor a) Highly selective (needle d) Electrical detection with and bio-warfare agent and bio-warfare a) Affordable personalized single-molecule sensitivity Non-invasive, A dvantages: Non-invasive, < $1k per genome), MEDICAL IMA G I NG (continued) Research Need Research biomolecules is enor - them requires between by 19th & early by 20th highly-selective, single- highly-selective, ics into electronic chips Most commercial Data reconstruction Integrating nanoscale ments’ fundamental mous. Discriminating molecule detectors. Compact and efficient physical basis physical century technologies. and storage devices are limited devices optics sensors, micro/nanofluid - sensors, standing of the measure - A quantitative under - THz components e.g. for THz materials, THz detector arrays The number of unique

Applications of Interest D river(s): biometrics; security; detection of explosives b) Real-time on-the-fly detection of explosives M arket size: M arket needs: D river(s): based on an individual’s biochemistry as de - based on an individual’s metabolites, proteins, RNA, biosignature (DNA, M arket size: M arket need: New methodologies for faster, cheaper & better & cheaper faster, for methodologies New Real-time, label-free detection, identification, label-free detection, Real-time, Healthcare accounts for 14% ($2T) of the US GDP; fastest growing sector in the economy termined from measurements of the patient’s agents therapeutics against biowarfare for security comparable to e.g. X-ray; Growing demand comparable to e.g. X-ray; a) Early detection of skin cancer and narcotics etc.), identify bioterrorism threats, & develop & develop identify bioterrorism threats, etc.), diagnostics will enable personalized medicine Accessible, lower-cost medical imaging lower-cost Accessible, & narcotics, etc. & narcotics, & quantification of biological molecule T-ray imaging for cancer diagnostics; T-ray

Single Molecule Bioelectronics for Terahertz Imaging Systems Healthcare & SECURITY APPLICATIONS Research Opportunity

35 Appendix F: Proposed Framework for a Bioelectronics Research Initiative

The primary goal of the Bioelectronics Research Initiative (BERI) is to enable and advance high-impact opportunities at the intersection of two industry sectors — biomedical technol- ogy and electronics. Initially, BERI will focus on personalized medical diagnostics [PMD] and monitoring, implantable devices and prosthetics [IDP], and medical imaging [MI]. The approach will be modeled on existing successful SRC research programs and will comprise a member-directed, inter-industry consortium to fund relevant university research in bioelec- tronics. BERI will transfer or make rights available to such technology to its members.

BERI Attributes and Objectives:

• Support foundational collaborative university research that bridges fundamental pre-com- petitive research and targeted application opportunities

• Identify a common set of critical challenges and metrics that focus on and accelerate pre-competitive research

• Coordinate with and synergistically leverage other strategic initiatives, such as relevant federal agency programs

Participating/Contributing Organization Benefits:

• Early and easy access to supported research results

• Access to BERI-funded faculty experts and relevantly educated students

• Royalty-free access to the results from the selected projects

• Easy archival access to supported research results

• Voting rights on the BERI Technical Advisory Boards

Participating/Contributing Organizations Responsibilities:

• People: Assign Governing Council and Technical Advisory Board representatives

• Management: Exercise and leverage SRC’s research management processes

• Stewardship: Provide strategic input on research scope, priorities and direction

• Funding: Assist in securing necessary support to ensure sustained effort

BERI Organizational Structure

• A Governing Council will provide administrative oversight of the BERI program, and each participating member will designate one primary and one alternate representative

• Technical Advisory Boards will provide technical guidance and facilitate technology trans-

36 fer, and each Governing Council member shall designate one primary and one alternate for each Board, i.e., PMD, IDP and MI, as warranted.

• As agreed-upon by members, funds may be directed to individual investigators or to large, multi-university centers. SRC will ensure coordination among university researchers.

SRC serves as the liaison between consortium members and university researchers, and is responsible for managing the overall program in terms of budget, research agenda/timelines, IP management, technology transfer and internal/external communications.

Governing Council Roles and Responsibilities

• Provide administrative oversight of overall program and serve as primary point-of-contact for their respective companies

• Set high-level strategic direction and corresponding budget allocation

• Approve and help recruit new members

• Review and approve new research initiatives and funding opportunities

• Appoint Technical Advisory Board representatives from their respective companies and direct technical interactions

• Provide periodic feedback on overall program quality and opportunities for improvement

• Serve as executive advocates for BERI program within their respective companies

Technical Advisory Board Roles and Responsibilities

• Provide technical oversight of the PMD, IDP or MI program and serve as the primary point-of-contact for technology transfer at their respective companies

• With SRC, develop a compelling strategic plan

• Review new research initiatives and projects

• With SRC, select projects for funding

• Provide periodic feedback on overall program quality and opportunities for improvement

• Serve as advocates for the BERI program within their respective companies, as well as externally

37 BERI Business Processes

• SRC solicits white papers based on member-identified research needs and priorities.

• Technical Advisory Board members review the submitted papers and select projects for funding.

• SRC executes contracts with universities; projects will include deliverables and mile- stones to measure progress.

• Research results are presented at annual reviews and periodic e-seminars.

• Deliverables, including reports, seminar presentations and pre-publications will be made available on the SRC website to BERI members.

• Facilitate access to students via networking events at reviews and other forums, and via electronically accessible resumes.

• Governing Council and Technical Advisory Boards will meet periodically to review the over- all progress and discuss opportunities for improvement.

38

Pioneers in Collaborative Research®

P.O. Box 12053 1101 Slater Road RTP, NC 27709-2053 Brighton Hall, Suite 120 919 941 9400 Durham, NC 27703

On the Web at www.src.org.