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FY 2009 OSEL Research Laboratories and Selected 2009 Accomplishments

Active Materials (Division of Chemistry and Materials Sciences)

Scientists in the Active Materials Laboratory investigate materials used in devices in which the time dependence of materials properties is a key component of how the device's mode of action is provided. This includes combination products in which medical devices incorporate some material-based mechanism for drug delivery, such as drug eluting stents. It also includes nano-materials, in which the properties of the nano-particles are critical to delivery of expected results. 

Accomplishments

  • Assessing the stability of nano-scale constructs.  The goal of this project is to elucidate and quantify how the physical, chemical, and electrical stabilities of nano-structures in medical devices, which are intrinsically different than their bulk counterparts, are impacted by structural geometry (e.g., size and shape) and environmental condition. Studies are underway through collaborations with the Division of Biology on in-vivo mouse studies of Nano-Ag toxicity and with the University of Maryland on the biological response of nano-scale features.  
  • Controlled RX delivery. The release of drug from coatings on implants such as drug eluting stents (DES) is affected by design and manufacturing variability. This project is about studying the mechanisms behind these relationships and developing methods of evaluating their effect on controlled drug delivery. Subsurface drug release from bioabsorbable coatings was studied by examining the combined effects of polymer degradation and water swelling the polymer. Relationships between swelling, degradation, drug microstructure and drug release will be used in DES reviews and future guidance and standards.

Laboratory studies and computer modeling of drug structure-processing-performance relations were quantitatively consistent, suggesting that these models may be used in reviews and guidance to reduce testing and improve the regulatory evaluation of medical devices. The code for these models will be shared with DES manufacturers in the future to improve design quality.

  • Impact of sex-based differences in atherosclerotic plaque on response to DES. To elucidate sex-based differences in plaque on DES efficacy, a two-pronged approach was employed: 1) create experimental systems to identify critical physiological sex differences and measure diffusion rates of a model drug, and 2) perform computational modeling of the same.

The studies indicate that drug diffusion and absorption depend on density and hydrophobicity of the release media. A computational model was developed that incorporates sex-based physiological differences. Predictions based on the model illustrate that drug release rate and distribution can vary significantly depending on the composition and morphology of the diseased vasculature. This research is currently being extended to the next generation, DES coated with bioabsorbable polymers such as poly(lactic-co-glycolic acid) (PLGA). The research provides evidence for a need within the DES community to account for sex-based differences in the design, manufacture, and regulation of these devices to ensure their safety and efficacy.

Biocompatibility and Risk Assessment (Division of Biology)

Risk assessment is the process of determining the extent of human health hazard relative to exposure conditions. Staff in the OSEL Laboratory of Biological Risk Assessment: 1) conduct research to address CDRH’s regulatory need for improved methods of detecting and quantifying risks associated with chemical compounds, microbial agents, and radiation released from medical device materials; and 2) conduct risk assessments to inform risk management decisions in the Center.  Research is focused the following areas:

  • Safety of reprocessed medical devices: Research in this area includes the assessment of the toxicity of residual disinfectants/sterilants and the efficacy of methods to remove residual bioburden on reprocessed devices.
  • Development of clinically relevant biomarkers and preclinical animal models: Research in this area was identified as being central to the FDA Critical Path Initiative.
  • Bioeffects of ultrasound and ultrasound contrast agents: Involves an assessment of the extent of the vascular endothelial and smooth muscle damage by microbubble-based ultrasound contrast agents and its role in the pathogenesis atherosclerotic changes. 

Accomplishments

  • Validated a method to measure the performance of liquid sporicides on hard nonporous surface. This method is used to validate claims of sporicidal activity on devices.
  • Provided quantitative endpoints (residual total protein and residual total organic carbon) that are being used for supplemental validation submissions on reprocessed single use devices from third party reprocessors.
  • Measured the disinfectant efficacy in multipurpose contact lens solutions against bacteria and fungi in the presence of various soft contact lens. These data are being used to support modification of international standard on testing antimicrobial efficacy of contact lens solutions.
  • Identified biomarkers of acute kidney injury (AKI) that are more sensitive than the tests currently used (e.g., BUN, creatinine) to detect renal damage. These data were used by the FDA Predictive Safety Testing Consortium to qualify new biomarkers for safety evaluations of FDA-regulated products.
  • Secured funding from the Chief Scientist Grant Program to begin a study to use the biomarkers of AKI to track the progression of kidney damage associated with hypertension.
  • Improved the clinical relevance and scientific basis of biocompatibility tests to evaluate the safety of medical devices.
  • Assessed the risk posed by patient exposure to BPA and DEHP released from medical devices and lead released from dental crowns.

Electromagnetic and Wireless Technologies (Division of Physics)

Research is focused on several issues associated with medical devices that utilize or are affected by electromagnetic (EM) fields. The primary concerns are as follows: (1) To address the safety and effectiveness issues associated with electromagnetic interference (EMI) of electronic medical devices, such as emissions from radiofrequency identification systems (RFID) that completely disrupt implanted cardiac pacemakers and defibrillators; (2) To address the rapid deployment of wireless technology around and into medical devices and their effect on medical device safety and effectiveness; (3) To evaluate the safety of medical devices in patients undergoing magnetic resonance imaging procedures (based on reports of many injuries and a few deaths due to heating from the intense fields emitted during clinical imaging procedures. Medical device manufacturers are submitting hundreds of requests for approval of their devices as MRI-compatible, e.g., devices allowed to be in or attached to the patient during MR imaging procedures); and (4) To develop methods to evaluate medical devices used for ablation of body tissues and the measurement and evaluation of EM heating and the evaluation of devices used intentionally to heat body tissues. A principle goal of this effort is to develop standard techniques for measuring and evaluating RF heating for both high and low frequency electromagnetic devices.

The wireless technology revolution together with a flood of new medical devices incorporating sensitive microelectronics is leading to a highly unstable situation. Dangerous malfunctions and numerous patient injuries have been induced in medical devices via electromagnetic interference (EMI) from electromagnetic fields emitted by wireless equipment such as cellular phones, magnetic-field emitting security devices (such as airport metal detectors), radiofrequency identification (RFID) systems and other emitters. DP leads the FDA effort to make all electrically powered medical devices electromagnetically compatible (EMC) with the electromagnetic environment where they are used. In addition to EMC, the public and the news media continue to raise concerns about the possible harmful effects of exposure to radio frequency (RF) electromagnetic fields (also known as non-ionizing RF radiation) from hand-held wireless (cellular) telephones and other wireless personal communications devices.

Accomplishments

  • Published in a leading cardiac journal the results of laboratory tests demonstrating clinically significant disruption of a significant percentage of implanted cardiac pacemakers and defibrillators by RFID systems that are being widely deployed in public and the workplace.  
  • Performed a post-market study of the electromagnetic compatibility automated external defibrillators (AEDs) for radiated susceptibility. Preliminary results indicate potential problems in a few models and shortcomings in existing EMC test standards for AEDs. Developed an automated test system for the 10-meter FDA/CDRH anechoic chamber to enable testing to the predominant international medical device EMC standard (IEC 60601-1-2 and 61000-4-3).
  • Developed additional detailed computer anatomical models (four children) with 1 mm resolution in redefinable CAD format for computational assessment of electromagnetic field exposure of personnel in collaboration with the Foundation for Research on Information Technologies in Society (IT’IS), Switzerland. Published a paper describing this new medical CAD technology in a peer-reviewed journal. Also published a chapter in a handbook of anatomical models for radiation dosimetry (including electromagnetic non-ionizing).
  • Published detailed results of the first in-vitro method to assess MRI safety of passive and active implanted medical devices exposed to gradient fields from MRI systems in a peer-reviewed journal where it received widespread attention (highly accessed).
  • Laboratory staff participated in numerous workshops as invited speakers for wireless mobile health care, wireless technology and patient safety. Submitted invited paper on wireless health care and electromagnetic compatibility.

Electrophysiology and Electrical Stimulation (Division of Physics)

Medical devices that rely on electrophysiology and electrical stimulation for safety and efficacy cut across all medical specialties. The most important examples are devices that work in the heart and nervous system including the following: cardiac pacemakers, defibrillators, retinal stimulators for blindness, brain stimulators (for Parkinson’s disease, pain, motor function, hearing), electroconvulsive therapy, magnetic brain stimulation, cochlear implants, middle ear hearing devices, spinal cord stimulators, vagus nerve stimulators, and peripheral nerve stimulators (including those for locomotion, breathing, bladder and bowel control). The less obvious examples are devices for the electrical detection of cancer (from breast, colon and cervix), the transdermal electrical extraction of glucose for monitoring, and a number of “complementary and alternative medicine” devices. The scientific discipline of electrophysiology forms a unified basis for the scientific evaluation of all of these devices. The scientific issues involve the basic electrophysiology of a number of body systems and the biomedical engineering of the devices.

The work ranges from research directly applied to a single device type (the retinal stimulator), to broader work that is relevant to a class of devices (cardiac stimulators for treating arrhythmias and heart failure), to far-reaching work on the development of optical stimulation of excitable tissue (supported extramurally). In addition to these areas of research, this laboratory is heavily involved in direct regulatory activities with staff performing as lead reviewers, expert consultants, subject matter experts to FDA Advisory Panels, authors of guidance documents, and the revision of international medical device standards.    

Accomplishments

  • Developed arbitrary waveform defibrillator and test platform with perfused animal heart for defibrillator waveform safety and efficacy testing
  • Developed a cell-culture system to examine effects of mechanical and electrical dys-synchrony in cardiac tissue
  • Developed a test platform for cardiac ablation studies in animal heart
  • Produced analytic models to discern physiological sources of electrical currents in heart that are subject to different therapeutic modalities
  • Published journal articles on physiological measures of safe levels of acute retinal stimulation
  • Completed work on excitability model of retinal neurons
  • Developed impaired peripheral nerve model for safety testing
  • Published work on mechanism of near infra-red stimulation of nerve impulses
  • Initiated work on phantom development to calibrate and standardize functional magnetic resonance imaging measurements in clinical studies
  • Development of software infrastructure needed for computational models to be run in conjunction with experimental studies of magnetic resonance imaging

Fluid Mechanics (Division of Solid and Fluid Mechanics)

The Laboratory of Fluid Dynamics, located in the Division of Solid and Fluid Mechanics, maintains a research program focused on the fundamental factors governing the interaction of flowing fluids with medical devices and the development of test methodologies to objectively characterize such interactions and their consequences.

Accomplishments

Computational studies of fluid and chemical transport in vascular devices
In 2009, funding was renewed for the third year for our FDA Critical Path Initiative project (Standardization of computational fluid dynamic techniques used to evaluate performance and blood damage safety in medical devices. Computational fluid dynamics (CFD) is increasingly being used in the development of blood-contacting medical devices. However, the lack of reliable standardized techniques for assessing the validity of CFD models limits the use of this tool by industry and the FDA in the evaluation of new products. Through this project, 28 groups (from 6 countries) from academia, industry, and the FDA completed the first phase of an interlaboratory study on a benchmark flow model (nozzle design) to determine the applicability and limits of current CFD simulations in evaluating medical devices. The results of the computational simulations were compared to experimental velocity measurements made in three independent laboratories to help develop guidelines for performing and assessing CFD simulations.

Evaluation of Blood Damage Caused by Medical Materials and Devices
The Blood Damage Assessment Laboratory performed research in multiple areas in 2009, including developing, fabricating, and testing different models (e.g., orifice, nozzles) which simulate blood flow through medical devices to better understand the factors that affect blood damage and its in vitro assessment, evaluating platelet activation assays for applicability with animal and human blood, and testing the hemocompatibility of materials and nanoparticles. 

Flow visualization and characterization of selected medical devices or test models using optical measurement methods
OSEL scientists, in collaboration with Epicore Medical/St. Jude Medical Atrial Fibrillation Division, and the University of Cincinnati, developed a test method for characterizing high intensity focused ultrasound beams using measurements of the induced fluid streaming patterns. This technique was described in concept via U.S. patent 7,600,410 awarded to the group in 2009. Proof-of-concept research results for the measurement of ultrasound beam intensity via optical fluorescence were also presented conference papers. The group has previously published similar proof-of-concept results for the streaming technique.

Prosthetic Heart Valves (Cavitation and Percutaneous Delivery)
This group continues its work on artificial heart valves with the objectives of (1) improving the current test methodology for characterizing the hydrodynamic performance of prosthetic heart valves and (2) improving our understanding of factors that affect such performance. In 2009, a study looking at the use of acoustic methods for the detection of cavitation was published. This study found that an acoustic method can be adapted for detection of cavitation for in vitro; however, simple bandpass filtering of the acoustic signature did not provide separation of the cavitation from the noise generated by the leaflet closing. Further work is needed to fully specify reliable cavitation from acoustic measurements.      

Image Analysis (Division of Imaging and Applied Mathematics)

A wide variety of new digital imaging and display devices is under development by academia and industry, with a broad range of performance characteristics. The Center requires augmented support for the evaluation of such devices. To this end, OSEL scientists in this laboratory are developing a fundamental understanding of how these new devices operate and are developing a unified methodological approach for validating the applicability of these new diagnostic medical systems. The emphasis of the Image Analysis Laboratory is to understand the building block of computer software tools and develop assessment methodologies that appropriately estimate performance and improve clinical and non-clinical trial designs. Application areas include mammography, optical imaging, computed tomography, nuclear medicine, immunohistochemistry, and gene expression. This program is located within the Division of Imaging and Applied Mathematics (DIAM).

Accomplishments

  • Received Critical Path funding support for the project on Lung CT volumetry again in 2009.
  • Continued CT data collection. Data collection for non-spherical nodules was the focus in 2009. To date, over 4000 multi-detector CT (MDCT) scans have been collected across a range of imaging protocols for 7 different nodule configurations placed within our anthropomorphic phantom. Released an initial data set of over 1000 scans to the public in 2009. This data is being made available for direct download through NIH's National Biomedical Imaging Archive (https://imaging.nci.nih.gov).
  • Designed and commissioned the manufacture of multi-density synthetic nodules of known shape and size to support development and validation of quantitative tools for more complex and clinically realistic lung nodule phantoms.
  • Completed the development and assessment of our matched filter volume estimation approach for spherical nodules. This effort led to the submission of a non-peer reviewed and a peer-reviewed manuscript describing the technique and its performance.
  • Conducted a reader study, in conjunction with QIBA, using our phantom CT data comparing reader performance with either a 1D, 2D or 3D sizing techniques.
  • Published a paper presenting an automated method for the quantitative assessment of HER2 using digital microscopy. While the expression of the HER-2/neu (HER2) gene has been shown to be a valuable prognostic indicator for breast cancer, interobserver variability has been reported in the evaluation of HER2 with immunohistochemistry. This method has the potential for improving reader performance and increasing observer reproducibility. Improved accuracy and reproducibility in the interpretation of biomarkers such as this will build confidence in their clinical utility as prognostic/predictive factors and move the field a step further towards personalized medicine for breast cancer.
  • Developing methods for estimating the uncertainty in the performance measures, or endpoints, in a study evaluating medical imaging devices. Reader variability is being acknowledged and addressed more and more in studies evaluating medical image interpretations (imaging devices as well as CAD software tools, especially). A paper published by members of this laboratory allows for a large number of the methods to be compared in a concise and exact way and provides important information regarding the uncertainties that exist in the clinical imaging trials reviewed. In particular, this information is crucial for applying tests of significance when comparing imaging devices or CAD performance.
  • The leader of the Image Analysis Laboratory has been an active participant in an American College of Radiology Imaging Network (ACRIN) Trial 6681 (“Assessment of the Role of Computer-Aided Detection in Improving Observer Performance of CT Colonography”) protocol development team, serving along with the National Institutes of Health (NIH) Clinical Center. This effort has been designed to assess whether or not computer-aided detection (CAD) can improve radiologist performance in CT colonography. The ACRIN 6681 protocol was recently reviewed by the NIH Cancer Therapy Evaluation Program (CTEP) and was found acceptable for implementation on July 31, 2009. The development of this study design has been a 4-year effort from initial concept to CTEP approval. Final CTEP approval and funding will come after the protocol development team finalizes the study design for the specific commercial and academic CAD systems that will be utilized in the trial. This trial is a large-scale evaluation of CTC-CAD involving 26 radiologists retrospectively reading 78 CTC image sets both with and without CAD. This ACRIN study design and results could be used by CDRH as a basis for evaluating CTC-CAD devices submitted for regulatory review.
  • CDRH held a public panel meeting to discuss the assessment of radiological CAD algorithms in November 2009. The scientists on this project were contributors and presenters at this panel meeting.

Imaging Physics (Division of Imaging and Applied Mathematics)

A wide variety of advanced imaging systems with solid state detectors and digital display devices are under development by academia and industry, with a broad range of performance characteristics. To support the Center’s need for assistance evaluating such devices, OSEL scientists are developing evaluation methodologies for diagnostic medical imaging systems such as mammography and fluoroscopy, computed tomography, nuclear medicine, diagnostic ultrasound, and magnetic resonance imaging, as well as for novel soft-copy display devices for viewing medical images. This program is located within the Division of Imaging and Applied Mathematics (DIAM).  

Accomplishments

  • Developed the facilities in the display laboratory to evaluate color, 3D, and mobile devices. Acquired a number of display systems, calibration tools, luminance and color measurement devices, programming tools for robotic arm for the mobile study, cameras and software for gaze-tracking, and test targets for absolute color measurement and 3D shape recognition in 3D displays.
  • Published a paper on an analytical model for CsI screens in indirect x-ray detectors, which facilitates the modeling and understanding of this receptor technology.
  • Received first prize award for the best presentation at the High Performance Medical Imaging (HPMI) workshop held during the IEEE Medical Imaging Conference in October 2009. A related manuscript on the use of graphical processing units (GPUs) for simulation of medical imaging systems was the subject of a publication in Medical Physics. Members of this laboratory are using GPUs to accelerate the group’s Monte Carlo package for simulating medical imaging systems -- which can be applied to mammography, CT, and even nuclear medicine modalities. The publicly available software allows the comparison of different imaging geometries and acquisition protocol choices in terms of image quality and dose. 
  • Developed theory for advanced methodology for measurement of attenuation and sound speed in bone; validated theory with measurements in bone-mimicking phantoms.
  • Developed theory for phase measurements in Time Domain Spectroscopy; validated theory with measurements on electric circuits.

Ionizing Radiation Metrology Laboratory (Division of Imaging and Applied Mathematics)

The DIAM Ionizing Radiation Metrology Laboratory was assessed by NVLAP in July 2009. The on-site review was completed on August 24, 2009, and the calibration laboratory met all on-site assessment requirements. The laboratory performed the following calibration services for FY 09:

  • 125 radiation calibrations of general diagnostic instruments
  • 22 radiation calibrations of mammographic instruments
    • 93 electrical calibrations of radiation monitors
    • 11 calibrations of non-invasive kVp meters
    • 7 calibrations of light meters

Materials Performance Laboratory (Division of Chemistry and Material Sciences)

Scientists in Materials Performance Laboratory investigate materials used in devices in which the physico/chemical properties of a material impact its performance and the long-term behavior of these properties affect the device's safety or effectiveness. The goal of these efforts is to improve the review of pre-market submissions, establish materials test method and standards, assess post-market issues in light of materials performance or failure, and communicate information through publications and presentations regarding the public health impact of device materials selection, design, and processing.

Accomplishments

Hermiticity in Active Implantable Medical Devices

  • Conducted experiments using time-resolved Fourier transform infrared-attenuated total reflectance (FTIR-ATR) spectroscopy, differential scanning calorimetry (DSC), and X-ray scattering). Found heating-induced structural changes in the polymers can change the ability of the polymers to resist water permeation.
  • Developed mathematical models to determine the extent to which changes in structure affect water permeation.

Hydrogels Project
Devised a protocol to examine wetting and dewetting behavior of a model soft viscoelastic polymer system from a well-defined surface and determined key variables in wetting behavior.

Intraocular Lens Project
Published final results and findings in the following journal article: (Saylor DM, Coleman Richardson D, Dair BJ, Pollack SK. “Osmotic cavitation of elastomeric intraocular lenses.” Acta Biomaterialia. Published online Aug 25, 2009. (Print version: 2010 March; Vol 6 Issue 3, pages 1090-8.) )

Optical Diagnostic Devices Laboratory (Division of Physics)

The rapid proliferation of novel diagnostic medical devices employing minimally or noninvasive optical technology is revolutionizing modern health care. These devices now perform a variety of critical in vivo tasks in the clinic, such as oximetry monitoring, atherosclerotic plaque assessment, high resolution retinal imaging, and early detection of lung, cervical and gastrointestinal cancers. These systems are based on a variety of optical mechanisms including fluorescence, reflectance and coherence-domain imaging.  Furthermore, next-generation technologies currently in advanced stages of development hold promise for applications such as early breast cancer detection and noninvasive glucose sensing.

Given their increasing complexity, optical technologies represent a significant new regulatory challenge to FDA. There are distinct gaps in understanding the biophysical mechanisms of action, device- and tissue-specific light propagation effects, and tissue damage by ultraviolet, visible and infrared radiation. As a result, guidance documents and standardized test methods are currently not available for most optical diagnostic device classes. Basic mechanism studies are needed to facilitate the development of relevant evaluation criteria early in the regulatory process, thus enabling thorough and swift reviews of cutting edge optical technologies. The Optical Diagnostic Devices laboratory works to generate fundamental data through studies of light-tissue interaction mechanisms, device performance and tissue safety for a variety of optical technologies. Furthermore, the laboratory is developing bench-top performance test methods and advanced computational models of light propagation in tissue to elucidate device working mechanisms and facilitate the device review process. This program is located within the Division of Physics (DP).

Accomplishments

  • Published an article on a post-market study of cutaneous transilluminators performed in collaboration with the Office of Surveillance and Biometrics (CDRH) [Pfefer TJ, et al. Phys Med Biol 54:6867-6880, 2009]. A follow-up study was also performed on the potential for retinal injury in adults and neonates based on spectral measurements of transilluminator output.
  • Developed fabrication, imaging, and data analysis techniques for a novel, phantom-based performance test method for optical coherence tomography (OCT) devices. Initial assessment of this approach is currently underway. A Fourier domain OCT system for ophthalmic imaging was installed, training was completed, and initial measurements were performed. A material transfer agreement was established with National Physical Laboratory (United Kingdom) to facilitate collaborative research towards the development of bench test methods for OCT systems.
  • A condensed Monte Carlo model for rapid computation of reflectance from a fiberoptic probe was developed and used to generate simulated reflectance spectra based on normal and cancerous breast tissue. This study represents a significant step towards development of numerical models that can be used to elucidate the working mechanisms and performance of minimally invasive, fiberoptic-based optical diagnostic devices submitted to CDRH.
  • Developed and validated an approach for in situ, fiberoptic-based measurement of layered tissue optical properties. Quantitative assessment of optical property measurement accuracy was evaluated experimentally using layered phantoms simulating the optical characteristics of mucosal tissues. This study represents a significant step towards determining fundamental optical properties in ultraviolet A and visible regimes – data that is critical for establishing a quantitative understanding of light-tissue interactions in optical spectroscopy devices for early cancer detection in gastrointestinal, cervical and oral tissues.
  • Studied the effect of ultraviolet-B radiation on DNA damage induced in in vitro samples of living artificial tissue samples. New multi-labeling techniques were used to enable accurate digital image-based quantitative analysis of DNA-damaged cells. Organized symposium on Light and Internal Tissues in Rockville, Maryland, co-sponsored by FDA and the American Society for Photobiology.  Reported the initial results of the UV damage study at this meeting.

Optical Therapeutics and Medical Nanophotonics Laboratory (Division of Physics)

Minimally invasive biophotonics techniques and devices have been recently developed as potential alternatives to conventional medical methods for diagnostics, monitoring and treatment of a variety of diseases, drug discovery, proteomics, and environmental detection of biological agents. These technologies offer a non-contact, effective, fast and painless way for sensing and monitoring various biomedical quantities. Medical devices utilizing minimally invasive biophotonics technology are rapidly finding their way into the mainstream for early disease diagnosis and improved patient acceptance and comfort. Optical therapeutics approaches are being proposed that use high-intensity ultra-short laser radiation, precise delivery fiber optics and near/mid-infrared biosensing and monitoring. Currently, CDRH is faced with the need to prepare for evaluating devices being developed to optically diagnose and treat various diseases, including pre-cancerous and cancerous conditions.

However, despite recent research efforts to address this need, there is still a fundamental lack of understanding of the working mechanisms of light-tissue interactions involved with various optical therapeutics techniques and devices. These mechanisms need to be understood at cellular and intracellular levels in order to identify factors that are determinative for effectiveness and that ensure the safety of laser therapy, photodynamic cancer treatment, precise laser tissue manipulation, ophthalmic therapeutics, pain relief, light-assisted cellular and tissue repair. Furthermore, recent research efforts and developments in the area of biophotonics technology have confirmed its compatibility with the modern nanotechnology trends. These have opened new horizons for developing alternative technologies that provide unprecedented, ultrahigh-nanoscale resolution for single cell and intracellular monitoring and manipulations, as well as nanobiosensing of specific target molecules and intracellular analytes. Thus, exploiting the nanophotonics approach in the optical therapeutics field will provide new quantitative knowledge of the molecular and cellular mechanisms of light-tissue interactions for optimizing the effectiveness and critical parameters of recently developed optical therapeutic techniques and devices.

The Optical Therapeutics and Medical Nanophotonics Laboratory of CDRH/OSEL’s Division of Physics is responsible for providing and maintaining state-of-the-art knowledge and expertise in the biophotonics, nanobiophotonics, biomedical optics and medical laser field to assist the Center and Agency in the evaluation of new medical therapeutics devices that employ the latest minimally invasive optical technologies. The OTMN Laboratory also assists with the regulation of hazardous optical and laser radiation emissions harmful to the unaware population, and with the latest measurement devices to evaluate new optical therapeutics products. OTMN Laboratory research and regulatory-related projects are focused in the following major areas:

  • Evaluating safety and effectiveness of new optical therapeutics technologies and devices concerning critical optical parameters and safety issues related to various medical therapeutic lasers, fiber-optic technologies, and new therapeutic monitoring and biosensing systems
  • Developing standard test methods and test protocols for laboratory evaluation of fundamental optical radiation characteristics including spectral (from the ultraviolet to mid-infrared), timescale (from millisecond to femtosecond) and spatial parameters of key coherent (lasers) and non-coherent light sources, and fiber-optic components used in recently developed optical therapeutics devices
  • Studying working light-tissue interaction mechanisms for optimizing effectiveness and safety of new optical therapeutics devices, which includes studying light-tissue interaction mechanisms at cellular/intracellular levels using state-of-the-art nanobiosensing, nanoimaging and therapeutics techniques

Accomplishments

  • Developed, experimentally tested and published an independent standard test method, based on a new fiber-optic confocal laser design, for precise pre-clinical evaluation the dioptric power of various intraocular lens (IOL) designs such as multifocal, toric and exact-labeled-power IOLs.
  • Developed and experimentally tested alternative standard methods for pre-clinical evaluation of fundamental optical properties of IOL such as refractive index, scattering characteristics, geometrical topography and dimensions.
  • Developed a novel combined sensing and imaging method for noninvasive, three-dimensional volumetric evaluation of tissue and IOL samples using a common-pass optical coherence tomography (CP-OCT) technique.
  • Implemented and published a simple and effective CP-OCT-based method for optical nerve stimulation that provides significantly improved precision and safety of stimulation laser power.
  • Established a collaborative agreement with the Wilmer Eye Institute at Johns Hopkins University to investigate the safety and effectiveness of non-invasive optical methods for in vivo monitoring and diagnostics of corneal inflammations. Performed study on post-surgical volumetric evaluation of the quality of corneal incisions and wound healing using a CP-OCT-based imaging approach.
  • Investigated working light-tissue interaction mechanisms for optimizing effectiveness and safety of new optical therapeutics devices, which includes studying the functional role of laser-induced hydrogen peroxide from human brain cancer, in-vitro.
  • Tested optical properties of new up-conversion nanoparticles for use in medical therapeutics (such as photodynamic therapy) and devices.
  • Designed and established a state-of-the-art laboratory facility for performing systematic experimental and theoretical research on evaluating the safety and effectiveness of various laser spectroscopy approaches (such as for Raman, FTIR, infrared and fluorescence spectroscopy) for non-contact sensing and analyzing chemical and biological contamination at medical device surfaces.

Solid Mechanics Laboratory (Division of Solid and Fluid Mechanics)

The goal of the Solid Mechanics Laboratory is to help CDRH understand the response of medical devices and their constituent materials to applied stress for both pre-market evaluations and post-market reported adverse events. The materials of interest include traditional engineering materials such as metals and polymers, but also extend to biological materials and those used in tissue engineered scaffolds. Though the spectrum of relevant materials is broad, common stress analysis principles can be applied to evaluate their behavior. 

Effects of Mechanical Stimulation on Chondrocyte Phenotype and Adhesion for the Production of Tissue Engineered Products
Approximately 640,000 cartilage repair procedures are performed each year in the U.S.  Cadaveric sources initially used to repair or replace damaged cartilage present public health concerns in the areas of microbial contaminants, disintegration and disease transmission. The ability to use tissue engineered medical products (TEMPs) in place of cadaveric sources would reduce these safety concerns. But, the development of products intended for cartilage repair using TEMPs containing chondrocytes and/or growth factors has been difficult, based in part on inefficient and expensive biomarkers for the chondrocyte phenotype as well as limited understanding of the effects of manufacturing parameters on the chondrocyte biology. Within this project, researchers in the Solid Mechanics laboratory have chosen to address the effects of altered culture conditions on the maintenance of the chondrocyte phenotype by evaluating physical and biological markers, including cell adhesive strength to a 2D substrate, chondrocytic gene expression, protein expression and quantitative histomorphometry.

Investigations this year have focused on the correlation between different phenotype tracking assays (e.g., cell adhesion, gene expression) for chondrocytes and L929 fibroblasts grown in 2D in monolayer cultures. Methods were developed to identify, isolate and reduce the sources of variability in the shear force assay. The sources of variability proved extremely difficult to reduce. Therefore, the assay system was restructured using a centrifugal force assay in place of a shear stress assay. Studies are ongoing to optimize the parameters for the centrifugation assay cell adhesion system.

Fatigue Testing of PMMA Bone Cement  
PMMA bone cement is considered the gold standard for use in arthroplastic procedures of the hip, knee, and other joints to fix metallic and polymeric prosthetic implants to living bone. Recently, new bone cement formulations have been used to stabilize painful osteoporotic compression fractures of the spine. Because fatigue failure has been identified as a clinical mode of failure, ASTM International developed and published a standard test method for fatigue testing of PMMA bone cement, F2118. Results from round robin testing for F2118 showed that specimen preparation methods can affect mechanical behavior of the bone cement. Scientists are currently working to identify a method to reduce variability in measured bending strengths of bone cement using different mold materials and finishing methods. The ultimate goal is to facilitate comparison of mechanical properties of bone cements by identifying a reproducible and consistent sample preparation method. 

Researchers developed a molding fixture for simultaneous preparation of five bone cement specimens per ISO 5833-02 and also developed a four-point bending fixture per ISO 5833-02. Specimens were then prepared using several different mold materials, measured specimen surface roughness and tested them in accordance with ISO 5833-02 to determine bend strength. Preliminary results on the effects of surface roughness on bend strength were presented at the 2009 Annual Meeting of the Society for Biomaterials and at the ASTM F04 Committee week meetings. Work continues investigating the effects on bending strength of sanding samples produced with different mold materials.
 

Development of a standard test method for compatibility of personal lubricants with condoms 
A test protocol was developed for determining compatibility of a personal lubricant and non-lubricated latex condoms. The protocol was incorporated into an ASTM International interlaboratory study, which was conducted in nine laboratories (three domestic, five foreign), including FDA. Tensile and airburst data from the nine participating laboratories underwent preliminary analyses at FDA prior to statistical analyses performed jointly by FDA and others. This preliminary work was presented to the ASTM Condom Task Group in December 2009. Further analyses are currently underway to better understand the reliability of these tests to screen for undesired latex deterioration from potential lubricants.

Strength retention of bioabsorbable polymers subjected to load
Bioabsorbable polymers are currently being used as raw materials for new orthopaedic and cardiovascular medical devices. The FDA expects increased regulatory submissions using bioabsorbable polymers in devices that experience complex mechanical loading such as stents, spinal cages, and tissue engineered products. One of the emerging device areas that receives continued attention is the fully bioabsorbable stent. Key pre-clinical questions in bioabsorbable stent development are related to adequacy of test methods for evaluating stent degradation and long term creep. Despite the increased use of these bioabsorbable materials in medical devices, a lack of substantial information is available on the effects of physiologic factors on the degradation of bioabsorbable medical devices, particularly for emerging applications. Within this project, researchers have chosen to concentrate on bioabsorbable polymer degradation during exposure to mechanical load and its relevance to fully bioabsorbable cardiovascular stents.

This year initial experiments were performed to evaluate the effect of static mechanical loading on the degradation and strength retention behavior of the bioabsorbable polymer, PLGA. This is an amorphous polyester that is used in low load-bearing applications such as sutures and craniofacial repair. Emerging devices using this polymer are being developed for articular cartilage repair. These experiments identified a significant creep behavior of PLGA under static loading at physiologic conditions due to plasticizing of the material and the amorphous molecular structure. The creep behavior of the polymer produced more than 200% elongation in the specimen over a very short 2-week time frame and a reduction in the strain to failure as compared to non-loaded devices. While the creep properties were significant, the short time frame of the experiment did not allow for chemical degradation. 

Since the project objective is to evaluate the combined effect of physiologic conditions and mechanical loading on the degradation of the material, the experiment goals have been revised to the following items:

  • Measure the short term static and dynamic creep properties of relevant bioabsorbable polymers, including those with amorphous and crystalline structures, and
  • Evaluate the effects of dynamic loading on the degradation and strength retention properties of relevant polymers. Due to these revisions, we are currently developing a new in vitro dynamic loading system to expose polymers to both mechanical loading and physiologic conditions for several months. 

Toxicology Laboratory (Division of Biology)

This is an interconnected program of laboratory research, risk assessment, and standards development activities designed to provide a scientific basis for regulatory decision making in CDRH. Researchers evaluate the potential adverse effects of medical device materials and chemicals, including nano-sized particles, using in vivo and in vitro experimental models and approaches. Scientists use data to reduce uncertainties in assessing risks to patients exposed to physical and chemical exposures, and ultimately protect their health. 

Accomplishments

  • Gold nanoparticles have applications in biomedical imaging and cancer therapies.  NIST standard reference gold nanoparticles were subjected to a repertoire of in vitro biocompatibility tests to examine potential cytotoxic and inflammatory responses. The particles were shown to interfere with a common biocompatibility test method used to determine cell viability. The results of the study contributed to the recommendation to use cell-free controls in cytotoxicity assays in the draft CDRH guidance document on the biological evaluation of nanoparticle-containing medical devices.
  • Silicon nanoparticles have applications in biomedical imaging. NIST silicon particles were used to address the question of whether current ISO and ASTM biocompatibility standards adequate for evaluating engineered nanomaterials. The biological responses of silicon nanoparticles and micron-sized particles were evaluated using several biocompatibility tests to examine potential cytotoxic and inflammatory responses. Nanoparticles were shown to be more cytotoxic than micron-sized silicon, and differences in cytotoxicity potency were observed for two standard cytotoxicity tests in response to silicon nanoparticles. The results contributed to the recommendation in the draft CDRH guidance document to use more than one method to assess same endpoint, e.g., cytotoxicity, inflammatory mediators.
  • Completed an animal study evaluating the potential transfer of nanosilver, a nanomaterial used in medical and consumer products, from pregnant mothers to the embryos.

Ultrasonics Laboratory (Division of Solid and Fluid Mechanics)

The Ultrasonics Laboratory continues to develop test methods and computational techniques for analyzing the safety and effectiveness of ultrasound ablation devices known as high intensity focused ultrasound (HIFU). Current accomplishments include developing two techniques for non-invasive measurement of high intensity fields to avoid sensor damage; formulating a coagulating blood mimicking fluid for use in HIFU in vitro phantoms; characterizing the occurrence of cavitation in a tissue mimicking material during HIFU exposures and assessing its effect on temperature measurements; determining the thermal effects when ultrasound is incident on bone; and utilizing computational techniques to evaluate the effects of nonlinear propagation characteristic of HIFU beams on acoustical and thermal measurement endpoints. Further, the laboratory has begun studies into the neurological effects of blast waves. 

Accomplishments

Characterization of ultrasonic intensity output of HIFU transducers  
To circumvent the problem of sensor damage at the high intensities produced by HIFU devices, two non-invasive techniques were developed for measuring the intensity field.  In one, under a CRADA with St. Jude Medical and the University of Cincinnati, laboratory scientists developed a system for optical characterization of an acoustic beam via particle image velocimetry. A patent was issued for this system. The second technique comprised a method for infrared (IR) thermographic imaging of an ultrasound-induced temperature distribution on a membrane. The ultrasonic intensity field giving rise to this temperature distribution was computed via an inverse technique. 

Development and use of tissue mimicking materials (TMMs) for assessment of HIFU devices 
Cavitation in clinical HIFU procedures generally is to be avoided because of its unpredictable effect on the tissue heating pattern. However, in some cases, controlled cavitation is being employed to enhance heating of the target tissue and thus shorten the treatment time. The occurrence and effect of cavitation in TMMs needs to be well understood in order to evaluate the safety and effectiveness data generated in pre-clinical studies. Therefore, an investigation was undertaken to monitor cavitation behavior using several different techniques, including B-mode imaging and hydrophones and determine its effect on temperature rise in a HIFU TMM containing an embedded thermocouple. Temperature traces obtained at various pressure levels demonstrated a wide range of heating profiles in the TMM due to the occurrence of cavitation. There was good correlation between the various methods to detect the occurrence of cavitation.

Related accomplishments:

  • Conducted a study to determine the thermal effects arising from absorption of ultrasound beams incident upon bone. The safety of simulated HIFU procedures was assessed as a function of transducer/bone separation.
  • Completed an analysis of data acquired in a TMM containing a simulated vessel. Experimental results confirmed computational predictions of a cooling effect due to blood flow through the large vessel, when a HIFU procedure is targeted within about one beam width of the vessel.
  • Developed two blood mimicking fluids (BMFs) that can serve as a blood coagulation surrogate in phantoms for bench studies of devices such as those designed to control blood loss in injured vessels. One is based upon the existing BMF by adding a thickening agent, and the other is based upon an egg white solution. Evaluation of the BMFs included characterization of the coagulation temperature, viscosity, temperature-dependent attenuation, sound speed, thermal properties, and backscatter coefficient.

Computational techniques for evaluating HIFU safety and effectiveness
Computational methods play an important in assessing the safety and effectiveness of HIFU devices. In collaboration with the University of Washington (UW), OSEL researchers investigated the time to boil for highly nonlinear ultrasound beams using simulations, comparing with experimental results. Bandwidth limitations in the waveform measurements result in underestimation of heating rates; therefore, a validated numerical model can be an effective tool in the laboratory and clinical settings.

A generalization of the standard model of ultrasound propagation and thermal heating was developed to account for changing absorption of tissue as it is cooked. Simulations predicted this change in absorption can have a very strong effect, resulting in peak temperatures as much as 70% higher than assuming static tissue properties as is often done in practice. Further, laboratory staff developed an analytic temperature-mode model for computing the temperature rise in tissue under conditions when nonlinear propagation generates significant higher harmonics, and they performed computations to define the threshold for when nonlinear models are required in acoustic propagation simulations. The outcome of this latter study will be useful in guiding manufacturers on when nonlinear (and typically more complicated and expensive to use) models are required and when linear models are adequate. 

Blast Waves
The work in thermal safety described above has been complemented by a study into the neurological effects of blast waves. In collaboration with the Uniformed Services University of Health Sciences (USUHS), Center for Neuroscience and Regenerative Medicine, laboratory researchers have developed a HIFU-based shock-wave generator to produce blast conditions on a small scale. Preliminary experiments using HIFU to simulate blast conditions produced neurological damage in mice, but the number of pulses required was more than desired. More recently, a higher-pressure “amplitude modulated” blast simulator that operates at 1 MHz but has an envelope of roughly 1 millisecond was developed. The bioeffects of the amplitude-modulated blaster will be examined in early 2010. Further, a study was initiated to determine the effect of blast waves on the conduction of electrical signals in neurons, using an earthworm as the first neural model. This work was begun to better understand and possibly control blast-induced brain injury.

Standards Management Staff 

The current status of the CDRH Standards program includes the following: 834 recognized voluntary consensus standards; and 263 FDA staff serving as liaison representatives participating in 547 standards committees revising or developing new medical device relevant standards. Fifteen designated CDRH liaison representatives come from other Agency components such as the Center for Biologics and Evaluation Research (CBER), the Center for Drug Evaluation Research (CDER), and the Office of Regulatory Affairs (ORA).