Table of Contents Table of Contents................................................................................................................ 1 Preface................................................................................................................................. 2 Regulatory Support Activities............................................................................................. 5 Office of Science and Engineering Laboratories 2011 Highlights ..................................... 7 Division Descriptions........................................................................................................ 23 Office of Science and Engineering Laboratories .............................................................. 29 Research Laboratories and Selected 2011 Accomplishments .......................................... 29 APPENDIX A – OSEL Publications ................................................................................ 50 APPENDIX B – OSEL Presentations............................................................................... 58 Breger J, Fisher B, Isayeva I, Baeva L, Wang N. Optimization of the 'click' reaction for therapeutic cell encapsulation utilizing RIN-5F cells. Biomedical Engineering Society 2011 Annual Meeting, Hartford, CT, October 12-15, 2011. ............................................ 60 Hitchins V. FDA’s perspective of “clean” for reprocessing medical devices. Association for the Advancement of Medical Instrumentation and FDA, AAMI/FDA Medical Device Reprocessing Summit, October 12, 2011. ........................................................................ 60 Choi J, Reipa V, Hitchins V, Goering P, Malinauskas R. Human blood biocompatibility of silver nanoparticles. AIChE (American Institute of Chemical Engineers), Annual Meeting of Chemical Engineers, October 16, 2011.......................................................... 60 Brown R. The basic elements of biocompatibility studies. FDA, Basic Nonclinical Bioresearch Monitoring, October 17, 2011. ..................................................................... 60 Elespuru RK, Rajani A. Evolution of colon cancer is reflected in DNA mutational sequence profiles. Environmental Mutagen Society 42nd Annual Meeting, Montreal, Canada, October 15-19, 2011. Elespuru RK, Rajani A. Miniaturization of a Salmonella Typhimurium genotoxicity assay. Environmental Mutagen Society 42nd Annual Meeting, Montreal, Canada, October 15-19, 2011. Fisher B. (Developmental) toxicity testing in the 21st century: Leveraging for alternative models. Middle Atlantic Reproductive and Teragology Association (MARTA), 2011 MARTA Meeting, October 20, 2011. ........... 60 Brown R. Biological effects of cobalt and chromium released from CoCr alloy: Research activities in the CDRH/OSEL Laboratory of Toxicology and Biocompatibility, National Institute of Standards and Technology, Failure of Metal-on-Metal Hip Implants Meeting, November 17, 2011........................................................................................................... 61 Wood S. Development of anti-Ebola MHC tetramers as a surrogate marker to evaluate cell-mediated immunity in vaccines:a computational approach, NIAID Research update, November 21, 2011........................................................................................................... 61 APPENDIX C – OSEL Academic Affiliations ................................................................ 70 APPENDIX D – OSEL Science Sharing Seminars .......................................................... 74 APPENDIX E – Laboratory Leaders................................................................................ 77 APPENDIX F – OSEL Organization Chart...................................................................... 79 Preface The Office of Science and Engineering Laboratories (OSEL), one of seven Offices within CDRH, contributes to the Center’s mission by providing laboratory data and consults. OSEL serves as the laboratory science nucleus for the Center. Specifically, OSEL helps provide a scientific foundation for the Agency’s regulatory decision- making by developing independent laboratory information for regulatory and other public health activities of CDRH. In addition to providing consultation to the Center’s regulatory experts, OSEL researchers are involved in mission-oriented science activities including test methods development, risk assessments, forensic investigations, product evaluations, and technology assessment. The research in OSEL is broad and cross-cutting, with research conducted in the physical, life, and engineering sciences as related to the effects of medical devices on human health. CDRH relies upon this work to support its efforts ensuring public safety in areas as varied as medical imaging, medical device software, breast implants, and drug eluting stents. OSEL laboratory science provides an important foundation for the regulatory mission of the Center and the Agency and in implementing the primary directive to protect the public health. Among the many accomplishments of OSEL: 1. The scientific research conducted in OSEL laboratories is significant, with great public health impact. One such example is the Huber needle investigation. Huber needles are used to access ports that are implanted under the skin of chronically ill patients for continued access to the veins for blood withdrawal and for delivering medication, nutritional solutions, blood products, and imaging solutions. These needles should be designed to penetrate the port without cutting and dislodging any silicone cores (or slivers) from the ports into which they are inserted. When FDA received reports of leakage after accessing a port with a Huber needle (labeled to be non-coring), OSEL scientists assisted the Agency by conducting laboratory testing of Huber needles from multiple manufacturers. The testing showed that certain Huber needles produced cores when inserted into ports. 2. OSEL created a new laboratory, the Functional Performance and Device Use Laboratory, to assess the needs of medical device users in varied-use environments, using multiple-device user interfaces to expand understanding of how medical device design influences use errors and physical performance. The creation of this laboratory was in response to the adverse events data showing that 2 as many as one-third of medical device failures causing patient harm and reported to the FDA appear to be failures of medical device use rather than failure of the device itself. One priority discussed in the CDRH 2011 report, “A Vital Framework for Protecting and Promoting Public Health,” was improving medical device safety. A key approach to this laboratory’s research would be “to help reduce use error, enhance patient and user safety, improve product usability and efficiency, and enhance user satisfaction with medical devices.” 3. All Centers in FDA continue to receive products containing nanotechnology and nanomaterials. The FDA Nanotechnology Taskforce recognized that characterization of nanomaterials is a key component of FDA research; and there is a need to establish a core laboratory facility accessible to all of the Centers, and whose primary function is to provide specialized equipment and tools that are basic to all nanomaterial-related research projects. The Core facility was established in OSEL/CDRH in 2011 with the purchase of three pieces of equipment: OSEL continues its outreach to the scientists and engineers of tomorrow. Since first begun in 2003, the OSEL student science poster exhibit has become a much-anticipated annual event. What began as an in-house event to provide a forum for young future scientists in OSEL to discuss their work with one another has now become a symposium for collaboration among interns from other FDA components, federal agencies, and various academic institutions—both at the high-school, and college and university levels. The annual exhibit continues to expand and draw interest from non-FDA science and health-care professionals. The OSEL Annual Report offers timely information about the Office’s organization and intramural science activities; provides a summary of the Office’s direct laboratory support for pre-market review and post-market evaluation; and provides a bibliography of scientific publications, presentations, and research seminars for the fiscal year reported. The information is within the framework of OSEL’s organization structure: divisions are first described, followed by descriptions of the research laboratories. The section on 2011 highlights lists examples of specific successful OSEL research projects and laboratory accomplishments. This report also cites a few examples of the regulatory support work that OSEL provides to the Center’s post-and pre-market offices. We hope you find this document useful and informative. We welcome your comments on the programs described in this report. For additional information, please visit the OSEL web site at http://www.fda.gov/cdrh/osel or contact us at 301-796-2530. 3 Steven K. Pollack, Ph.D. Director Office of Science and Engineering Laboratories Center for Devices and Radiological Health, FDA Disclaimer: Please note that the mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the Department of Health and Human Services. 4 Regulatory Support Activities Research conducted in the OSEL supports the regulatory activities of the Agency as follows: · Strategically manage research with the aim of providing a scientifically sound basis for responding to current needs and anticipating future regulatory challenges; and · Provide technical consults in support of the Center’s pre-market, post-market, and compliance activities. Both activities are coordinated within OSEL in an effective manner so as to best meet Center’s regulatory science needs. Laboratory research is the cornerstone upon which the Office provides the regulatory support function. (The research is described in subsequent sections.) It is largely based on investigations related to the mechanistic understanding of device performance or test procedures, enabling the Center and device manufacturers to gain an improved understanding of issues related to safety and efficacy. In general, although the research is directed toward issues identified at the pre-market approval level, the reality is that the research has the largest impact on the post-market end of the Center’s business because most often the research is anticipatory in terms of potential issues of medical devices identified at the pre-market level. The regulatory support function of the Office is provided through consults supporting both pre-market decisions and post-market actions using expertise developed in the laboratory. A consult is a request for expert advice or information of a specific nature, and provides information that contribute to sound regulatory decisions. Consults are often based on acknowledged scientific/engineering principles or on independent data generated in OSEL laboratories. In 2011 OSEL provided the following: Number of consults on pre-market issues 1780 Number of consults on post-market issues 142 The information provided by a consult is used in some of the following ways: · Evaluate a pre-market submission (IDE, HDE, PMA, 510(k)); · Support a compliance action (regulatory case support/development, Health Hazard Evaluation, Health Risk Assessments, etc.); · Assist scientific collaboration; 5 · Respond to a consumer inquiry; · Provide feedback on guidance documents; · Provide revisions to one-pagers for the new device approval page; · Support health hazard evaluation/health risk assessments in device determinations/classifications. For many post-market as well as pre-market regulatory issues, the consults/reviews and investigations conducted by OSEL independently assess the claims made by manufacturers or other parties concerning safety or effectiveness. In other cases, OSEL reviews may assess the adequacy of a design, a failure investigation, a production process, or a quality process employed by the manufacturer. These reviews and analyses rely on in-house expertise and are often augmented by expertise solicited from colleagues in academia, other government laboratories, or even other industry sectors. OSEL laboratory investigations may be undertaken in instances where the veracity of a performance claim needs to be independently verified by testing or when the claimant lacks the resources to conduct the investigation. OSEL also provides analytical support to post-market regulatory activities in a variety of ways: · Provide scientific and engineering reviews and analyses; · Conduct laboratory investigations of product performance; · Participate in inspections of medical device establishments; · Conduct forensic reviews and investigations; · Identify device safety and performance issues; · Provide training to FDA and industry; and · Contribute to Center-wide Matrix teams on issues identification as well as science-based analysis of post-market device performance. Finally, developing standards and measurements methods is a significant activity of this office. OSEL continues to provide innovative solutions to public health problems by constructing generic techniques that lead to the creation of national and international standards that will enhance product safety and effectiveness. OSEL staff actively participate in developing standards at the national and international levels by performing research to establish standard procedures, and by shouldering standards committees responsibilities to manage, develop and support standards development. 6 Office of Science and Engineering Laboratories 2011 Highlights Development of a Nanoparticle-based Phantom for Assessment of Retinal OCT Device Performance (Optical Diagnostic Devices Laboratory, Division of Physics) Optical coherence tomography (OCT) is an FDA-cleared imaging modality now being used 16 million times annually to image the eye with devices from at least 6 different manufacturers. Although OCT is extensively used, there are no standardized test methods that ensure the accuracy and consistency of OCT data. Controlled test objects known as phantoms can fill this gap by serving as a stable, well-characterized reference, which is imaged for preclinical assessment as well as periodically during clinical use for quality assurance. Optical Diagnostic Devices Laboratory (ODDL) researchers have recently designed, fabricated and validated a novel nanoparticle-based phantom specifically for benchmarking the performance of retinal OCT devices. The phantom comprises a precisely shaped transparent polymer with embedded gold nanoshells placed at the retinal plane of a model eye that realistically replicates the focusing characteristics of the human eye. The nanoparticles reflect light from the OCT scanner beam, enabling accurate measurement of the device's point spread function. This provides a detailed representation of the device’s spatial resolution and its variation throughout the imaging volume. The phantom, which is easy to use and portable, has been evaluated on a research-grade retinal OCT device in ODDL. The fabrication methods and evaluation results form the basis of a manuscript that has recently been submitted for publication in a scientific journal. Through its research on novel, phantom-based test methods for optical imaging, ODDL is facilitating science-based evaluation and regulatory clearance of innovative, minimally invasive devices with the potential to impact public health. Brain Computer Interfaces (Biophysics Laboratory, Division of Physics) Dr. Cristin Welle and staff of the Biophysics laboratory developed a platform to assess physiological, anatomical, chemical and behavioral responses to invasive recording electrodes in the brain. This is an important development because of the need to improve and assure the long-term safety and reliability of these novel implants. Neural implants have the potential to provide an unparalleled capability for individuals using prosthetic devices to interact with their external environment. Currently, these devices have fallen short of their potential due to a longitudinal decline in their ability to detect neural signals. This failure may result from biological reactions that result from inserting a foreign object into the brain, or from gradual decay of the electrode materials, although 7 the precise failure mechanisms have yet to be determined. The Division of Physics entered into a collaborative research endeavor with DARPA’s (Defense Advanced Research Projects Agency) Reliable Neural Interface Technology (RE-NET) program based on a common interest in the long-term safety and reliability of neural implants. Dr. Welle’s expertise in cortical electrophysiology, two-photon imaging and small animal survival surgery has been leveraged to develop innovative test platforms to identify biomarkers predictive of long-term implant success. The DP platform to identify physiological markers that are predictive of failure will see several types of neural electrodes implanted in a genomically controlled mouse model. Single-unit and local field potential electrophysiological data will be recorded weekly for 12 months. Additionally, in-vivo two-photon imaging on a weekly basis from individual animals will observe neural death and morphological changes, and automatic computerized detection of freely moving behaviors will be correlated with the electrophysiology to link features important to motor control. In parallel, DP researchers will perform accelerated aging protocols in an artificial brain to assess chronic electrode integrity and function through electrochemical analysis. These investigations identify the factors that are critical to electrode longevity and establish test platforms that can be used to aid the regulatory decisions regarding penetrating neural interfaces. CDRH-Transportation Security Laboratory Interagency Project on Electromagnetic compatibility (EMC) (Electromagnetic and Wireless Technologies Laboratory, Division of Physics) The Transportation Security Laboratory (TSL), Department of Homeland Security (DHS) sought the expertise of OSEL’s Division of Physics to assess the potential electromagnetic interference (EMI) risks for airline passengers with personal electronic medical devices (PMEDs) screened with new advanced imaging technology (AIT) systems. This project is being performed under an interagency agreement between FDA and TSL/DHS. It follows previous interagency agreements with TSL in such areas as the study of the potential effects on personal medical devices (PMEDs) from exposure to magnetic fields from metal detector security systems. The present project involves testing and research centered on the potential effects on PMEDs from exposure to the emissions from new millimeter wave body scanner systems. This technology operates by emitting very low levels of electromagnetic fields at very high frequencies (millimeter waves) to create an image of the subject to search for contraband. Because of the dearth of information about medical device exposures to such high-frequency emissions, the OSEL laboratory research project developed novel methods to test and assess effects on PMEDs. The PMEDS included implantable cardiac pacemakers and implantable cardioverter defibrillators, implantable neurostimulators, and drug infusion pumps such as body-worn insulin pumps. The test methods were adapted from earlier OSEL studies involving use of a simulated human body torso. A new simulated torso had to be made 8 for the present study because of the nature of the millimeter wave fields, since they can be more highly attenuated in the body than fields at lower frequencies. To assess the exposures, measurements were made of the emissions at several locations in and around the millimeter wave AIT system. These measurements help in developing a unique system to simulate the emissions from the AIT that was used to develop a simple and more easily implemented way to reproduce the AIT exposure. Using the novel testing methods and materials, testing was performed over a range of different makes and models of the implantable and body-worn PMEDs at various positions and orientations in and around the AIT unit. The programming and functioning of each PMED was carefully monitored during these tests. Findings indicated no effects on the functioning of any PMEDs at any of the locations or orientations. The risks for effects on the PMEDs studies for this AIT were assessed to be very low. In addition to the PMED study, the emissions measurements were assessed for radiation safety in reference to the American National Standards Institute (ANSI) Institute for Electrical and Electronics Engineering (IEEE) C95.1 Standard for human exposure to non-ionizing electromagnetic radiation. The emissions measurements revealed very low exposures for the person being scanned or nearby security personnel. Exposures were found to be at least 1000 times below the limits of the human exposure standards. Comparative Study of Temperature Measurements in Ex-vivo Swine Muscle and a Tissue- Mimicking Material during High Intensity Focused Ultrasound Exposures (Ultrasonics Laboratory, Division of Solid and Fluid Mechanics) High-intensity focused ultrasound (HIFU) is a leading-edge, minimally invasive technology for surgery without incisions. Dozens of active development efforts are underway around the globe for applications such as ablating pathologic tissue and stopping internal bleeding. As with many emerging technologies, HIFU has a need for reliable standardized test methods. Existing test methods have been complicated, poorly characterized, and often unreliable. To enable meaningful testing by sponsors and developers, Ultrasonics Laboratory scientists within the Division of Solid and Fluid Mechanics have developed tissue-mimicking materials (TMMs) for characterizing new HIFU products. When TMMs containing thermal sensors are used to measure ultrasound- induced temperature rise, it is important that measurement results reasonably represent those that occur in biological tissue. Therefore, the thermal behavior of the TMM under HIFU exposure was compared to that of ex vivo tissue (freshly excised swine muscle). Temperature traces obtained at various pressure levels demonstrated similar types of heating profiles in both the tissue and TMM, the exact nature of which depended on whether bubbles formed during the HIFU exposure. Knowledge gained from this research will facilitate the evaluation of preclinical data submitted by device sponsors, and will aid in developing bench testing guidance and standards. A peer-review paper describing the methodology and results was published recently in Physics in Medicine and Biology. 9 Contact Lens Contamination Project (Division of Chemistry and Materials Science) In 2006-2007, a series of widespread Fusarium and Acanthamoeba outbreaks threatened contact lens users in the United States and abroad, making public health authorities increasingly aware of the need for better pre-market testing methods to evaluate contact lens product safety. Experts advised that a single grouping for silicon hydrogels was not adequate to predict potentially harmful lens-solution interactions. Scientists in the Division of Chemistry and Materials Science were charged with performing scientific testing of various physical properties of conventional and silicon hydrogel lenses to determine how they could be grouped to safely predict solution interactions. DCMS staff worked with staff within the Office of Device Evaluation (ODE) to devise a laboratory research strategy that would target some of the most important properties of polymer materials that affect material-solution interactions. This served to familiarize them with both DCMS research capabilities and proposals of analytical methods to answer key questions. The team mapped their strategy based on the hypothesis that silicon hydrogels could be grouped with most of the same properties (water content and charge) as conventional hydrogels, with the exception of one property (hydrophobicity). The work done by DCMS involved five different research areas: water states, pore sizes, hydrophobicity, and protein and lipid uptake. In each of these areas, DCMS staff used their extensive research experience and scientific knowledge to devise experimental strategies to answer the questions that the team had about silicon contact lens properties and interactions. DCMS researchers also relied heavily on a number of advanced instruments available in OSEL for research, including microscopy, thermogravimetric tools and wet laboratory resources. When combined with results from additional studies being done by staff in the Division of Biology, the results of these experiments allowed the team to devise an improved grouping strategy to help predict interaction of current and future care product components with wide-ranging contact lens materials. ODE will be proposing the new grouping strategy to the contact lens industry and other regulatory bodies as a new standard grouping system that can be used to predict potential harmful lens-solution interactions. The use of this grouping system will greatly simplify lens testing for manufacturers; and as more and more silicon hydrogel lenses and lens care products come to market, it will help ensure consumer safety by preventing harmful lens- solution combinations. Labeling changes can also be made to warn about specific care product interactions where depletion of preservative might allow microbial contamination, or otherwise harmful interactions might occur. The work has not only resulted in several submitted scientific publications and an invited presentation to the Contact Lens Association for Ophthalmology (CLAO) conference, but it is also being used at FDA to help develop improved guidance and standards documents for contact lenses and care products. 10