CTSA‐Enhanced Innovative Device Development

The key objective of the NIH Clinical and Translational Science Award (CTSA) is to more effectively translate basic science discoveries into new human therapies, diagnostics, and practices. Given the societal impression that we are in an unprecedented time of scientific and technologic acceleration in biomedical research, it can be disheartening to learn that it takes up to 15 years for discoveries to translate into treatments and that a large majority of medical research studies never reach the clinical trials or become widely available to patients.1 As part of the CTSA consortium, the University of New Mexico Clinical and Translational Science Center (CTSC) is a catalyst for more rapid translation within the pipeline of therapeutic development by encouraging innovation and high-risk projects, facilitating productive collaborations, assisting with study design, supporting clinical trials, and providing new mechanisms to more rapidly and effectively address regulatory requirements. CTSAs at comparatively smaller universities such as ours immediately transform the research landscape of their institutions, since support mechanisms for clinical and translational research would not otherwise exist. Now in its third year, the UNM CTSC was able to assist in the development of a point-of-care (POC) biosensor, which recently received an R&D Magazine Top 100 Technologies Award.2 Our biosensor project demonstrates the efficacy of the CTSA model in translating basic science conducted at universities into devices that will dramatically improve clinical practices. In order to expeditiously move discovery into clinical practice, CTSA-funded universities have established an intricate infrastructure that includes mechanisms for facilitating collaboration among disparate research groups and providing pilot funding for high-risk/high-impact ideas. The CTSA intervenes in customary operational modes of research to nurture new methodologies and networks; the effects have been exponential at our university in providing resources to carry out sophisticated translational projects. The POC biosensor was realized through a series of critical steps involving CTSA support mechanisms, including the facilitation of novel collaborations, pilot funding to conduct initial research, and help in developing private partnerships. The UNM CTSC also has a dedicated bioinformatics core and an extensive program for providing community-based research support, which coordinates researchers working in multiple departments and includes many community partners across the state. Moving forward, the CTSC will further aid the biosensor project with clinical trial support, bioinformatics, and assistance with regulatory processes. The idea for the biosensor grew from a unique process that has now become a commonplace method for executing innovative projects at the UNM CTSC. It begins with what we now call a "Madness Retreat." During these half-day events, investigators from various disciplines convene in directed brainstorming sessions. Participants include clinicians, biomedical researchers, public health researchers, engineers, biologists, chemists, and physicists. Through initial discussion, we developed an idea for a handheld sensor with the ability to rapidly diagnose viral or bacterial infection from saliva or blood. A group of scientists at Sandia National Laboratories (SNL), who participated in the discussions, were obvious partners given their national security-related interests in developing handheld diagnostic devices. They became our first collaborators on this project. Our team envisioned the potential to transform medical practice both during medical emergency situations, such as after a natural disaster when quick response is essential to avert the spread of infection, and also in routine situations, such as a doctor's appointment, when the device may allow for rapid and appropriate administration of antibiotics and antiviral therapy. Our expectation is for a device that will markedly increase patient satisfaction, reduce medical care costs, and lessen the development of antibiotic resistance. After our initial success with creating a collaborative team for the biosensor project, the UNM CTSC has held "Madness Retreats" focused on developing devices for brain trauma and prediabetes monitoring, which have resulted in ideas for novel devices currently under development. Given the variables and specialized skills needed to create biomedical devices, opportunities for collaborative thinking are critical to the mission of the CTSC to facilitate innovation of new medical technologies and practices. UNM's CTSA has provided the impetus for developed, coordinated collaborative activity on a scale previously unattainable at our institution. The initial proof-of-principle experiments demonstrated that our idea was feasible, so we applied for pivotal pilot funding from the UNM CTSC, a resource not readily available at our institution before the award, which allowed us to build a prototype. The biosensor operates on the basis of shear horizontal surface acoustic waves (SAWs) that are generated on the piezoelectric crystal lithium tantalate (LiTaO3) covered with a silicon dioxide (SiO2) waveguide. These materials form a chip that is used to detect the bio agent in the sensor. The surface contains interdigital transducers that are used to apply an alternating voltage at high frequency, in this case at 325 MHz, which in turn generate SAWs that are typical for the substrate wave velocity. While the team at SNL developed and manufactured the proof-of-concept surface of the chip, the team at UNM was able to functionalize the surface chemically with specific types of silanes, which allows the covalent attachment of specific ligands, such as monoclonal antibodies and peptides that bind specific organisms (Figures 1A and B). A surface wave is generated when a mass, such as a bacteria or virus is captured. When such specific binding occurs, the phase of the frequency shifts, which can be measured using specific software. Figure 1C shows representative examples for the detection of Francisella tularensis. To date, we have generated data on two different bacteria, that is, Anthrax spp. and F. tularensis, and at least four different viruses, that is, Coxsackie, Sin Nombre Virus, HIV-1, and HIV-2. These data are highly supportive of the capability of the biosensor, and the commercialization potential to develop a clinically applicable device is evident. (A) Portable set up of biosensor. Detection board (thin arrow) with fluidic chamber (sensor chip is inside [asterisk]), and PDA (thick arrow) and battery (arrowhead) are shown. (B) Functionalization of biosensor surface consisting of the piezoelectric lithium tantalate (LiTaO3), silicon oxide (SiO2), and silane to bind specific ligands, including monoclonal antibodies, nucleic acids, and peptides. (C) Detection of F. tularensis using a monoclonal antibody against surface lipopolysaccharide (LPS). Quadruplicate measurements (mean ± standard deviation) were taken at 5 minutes after addition of bacteria. The x-axis and y-axis indicate viral load (logarithmic scale; CFU = colony forming units) and phase shifts (Δϕ), respectively. The solid line represents the best-fitting model and coefficient correlations (R2) for Δϕ as a function of bacterial load. The horizontal dotted line represents the background signal obtained with buffer without bacteria. Regardless of the organism under investigation, whether it is a pathogen of interest to biodefense or to medical healthcare, the strongest advantages of this technology include: (i) Time of detection: Our biosensor provides responses within minutes.3 In fact, the detections for bacterial and viral organisms shown in Figure 1C were performed under 5 minutes, without any preprocessing of the blood samples. In comparison, the gold standard of unambiguous tularemia detection by culture takes up to 24 hours. 4 (ii) Limit of detection and linearity: To date, these important parameters have given results superior to or comparable to current gold standard techniques such as culture and nucleic acid amplification. For example, Figure 1C indicates the detection of 10–30 F. tularensis organisms and a linearity of detection R2 of >0.9; these values are comparable with the most sensitive, yet expensive and equipment-savvy technology reported to date, nucleic acid amplification.5–7 (iii) Insensitivity to interferents: We have performed experiments in blood, buffer, river water, and sewage water that have yielded similar bioagent detection capabilities regardless of matrix.3 (iv) Cost-effective and portable: All components of the biosensor, especially when developed into a commercially viable product, can be manufactured at competitive costs and the easy "sample-to-readout" format requires only limited technical skill. As a consequence, the physical scale of the biosensor is small, light, and thus highly portable (Figure 1A).3 Among others, these characteristics make this device an ideal POC diagnostic device. Once we created a prototype, the UNM CTSC provided essential support in helping us to f nd a commercial or private industry partner. We felt that the translational applications and widespread health implications of this POC biosensor technology made it a compelling project for rapid development into a widely available healthcare device. The CTSC, through a unique program designed to facilitate private partnerships (Larson, CTSA Consortium Steering Committee Meeting, October 2011), assisted us in working with the New Mexico Angels, a local investment group, and Adaptive Methods, Inc., which will deliver a manufacturable device that will ultimately proceed through FDA clearance as a rapid and portable POC diagnostic instrument. The CTSA has created an environment for fostering innovation that made it possible for our team to overcome some of the hurdles we faced in developing the POC biosensor. Our network of collaborators has enabled us to immediately address issues as they emerge during this translational project. Technical challenges required facilitated discussion to cross the natural perspective and language barriers used by scientists of different disciplines. For example, the physical parameters of the biosensor chips had to be changed to address the initial inconsistencies of detection of different analytes; this necessitated an iterative process for redesigning the chip fabrication between SNL and researchers at UNM. Also, innovative approaches had to be taken relative to the attachment of specific ligands to the surface of the biosensor chips to increase the sensitivity of detection (the silane chemistry approach resulted from these efforts). The UNM CTSC has provided pilot funding, facilities, and other resources to the research and development of our POC biosensor. As we further develop the biosensor, we will continue to use other CTSC resources, such as the biostatistics, clinical research unit, and regulatory support cores. Perhaps more importantly, the culture of collaboration, and specific mechanisms for creating novel research teams and addressing regulatory requirements, has provided a structure and set of values that support and sustain this project, as our device moves from idea to development to commercial production. This clinical and translational project would not have been possible without the existence of a CTSA at our university to provide the needed resources and infrastructure to transform our collective vision for the POC biosensor into a reality. Pathologists, engineers, physicists, biologists, and chemists continue to collaborate to develop a device that may have substantial impact on healthcare. This work was supported by the following grants from the National Science Foundation (NSF IIS-0434120) and the National Institutes of Health (UCD-POCTC-08 and 8 UL1TR000041-3/ U54 RR026083). We would like to gratefully acknowledge Emily Morelli and Kara McKinney for their administrative and editing support.