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OST Annual Report Fiscal Year 2000

• PREFACE
• Office of Science and Technology Staff
• OFFICE OF SCIENCE AND TECHNOLOGY PROGRAMS
• ARTIFICIAL ORGAN REPLACEMENTS AND ASSISTS
  • A New Flow Visualization System for Quantifying Flow in Artificial Organs
  • Ophthalmic Implants
  • Safety of High-Rate Nerve Stimulation
  • Examination of Mechanical Prosthetic Heart Valve Closing Sounds for High Frequency Acoustic Energy as a Signature of Cavitation
  • Simplified Bernoulli Relation and Artificial Heart Valves
  • Blood Flow and Pressure Transducer Protectors in Hemodialysis Machines
  • Neurological CSF Shunts
• BIOMATERIAL EFFECTS ON IMMUNE SYSTEM
  • Finalization of a Standard Practice for Testing for Alternative Pathway Complement Activation in Serum by Solid Materials
  • Complement Activation by Implanted or External Blood-Contacting Medical Devices
  • Analysis of Autoantibody Responses to Silicone Gel-Filled Breast Implants
• COMPUTATIONAL MODELING
  • MR Compatibility: Evaluation of Patient Heating
  • Calculation of Virus Transport through Barriers as a Function of Pore Geometry
  • Computational Studies of Vascular Grafts
• DEVICE PERFORMANCE ANALYSIS AND MODELING
  • Endovascular Stent Standards Development
• EMERGING ISSUES 2000: GENETIC TECHNOLOGIES
  • Development of an In Vitro P53 Human Gene Mutation Assay for Cancer Risk Studies
• FAILURE ANALYSIS OF ELECTRONICS IN MEDICAL DEVICES
  • Regulatory Support - Forensics
  • Premarket Support - Scientific Evaluations
  • Quality Management
  • Risk Management
  • Reliability
• MATERIALS AND DEVICE CHARACTERIZATION
  • Experimental Pathology: Cardiovascular Devices
  • Tissue Engineered Medical Products Standards (TEMPS)
  • Powder Measurement on Medical Glove through the Participation in ASTM Working Group
• MEDICAL IMAGING EVALUATION
  • Digital Image Display System Evaluation
  • X-ray Physics Laboratory Studies
  • Mammographic Dosimetry Studies
  • Imaging System Performance Evaluation
  • Ultrasound Bone Densitometry
• MEDICAL USES OF AND ENVIRONMENTAL EXPOSURES TO RADIATION
  • Optimization of Accelerator Targets for Neutron Capture Therapy
  • In vitro Biological Effects of Wireless Telephone Emissions
  • Parameters for Testing and Standardization of Skin Types and Skin Response to UV
  • Laboratory support for a revised risk assessment of skin cancer from UV-emitting devices
  • Biological Effects of Exposure to Electromagnetic Fields
  • Sunlamps and Sunbeds: Activities related to possible amendments to the Performance Standard for Sunlamp Products
• MINIMALLY INVASIVE TECHNOLOGIES
  • Determination of Tissue Properties Using Minimally Invasive Optical Techniques
  • Determination of Bone Density Using Minimally Invasive Optical Techniques
  • Evaluation of Endoscopes Used in Minimally Invasive Diagnostic and Therapeutic Procedures
  • Fibers and Waveguides Used for Minimally Invasive Surgery
  • Therapeutic Laser Devices Used for Tissue Ablation
  • Heat Transfer Issues in Catheter Ablation Devices
  • Measurement of Laser-Induced Acoustic Stresses
• PHYSIOLOGICAL SIGNAL ACQUISITION, ANALYSIS, AND CONTROL SYSTEMS
  • Laboratory Design/Staff Development
• PREDICTION OF MATERIALS STABILITY AND IDENTIFICATION OF DEGRADATION MECHANISMS
  • Abrasion Resistance of Medical Glove Materials
  • The Body's Response to Deliberate Implants: Phagocytic Cell Responses to Large Substrata versus Small Particles
  • Cleaning and Performance of Single Use Devices Project
  • Use of Physiologically-Based Pharmacokinetic Models (PBPK) in Risk Assessment
  • An In-Vitro Study of the Effect of In-Folds on Durability of Mammary Implants
  • Shelf-Life of Non-Latex Condoms
  • Shelf-Life of Medical Gloves
  • Shelf-Life of Cellulose Acetate Hemodialyzers
• RADIATION SAFETY
  • Ophthalmic Instruments – Fundus Cameras
  • Ultrasonic Characterization of Skin Following Ultraviolet Light Exposures
  • Laser Field Compliance Program
  • Microwave Oven Leakage Instrument Calibration
  • Laser Performance Standard
  • Sunlamp Performance Standard
  • CDER Sunscreen Monograph
• REUSE/STERILIZATION/DISINFECTION/INFECTIOUS DISEASE DIAGNOSTICS
  • Cleaning and Performance of Single-Use Devices
  • Standards for Sterilization and Cleaning Methods
  • Developing a PCR-PNA-ELISA Procedure for Rapid Detection of Antibiotic Resistant Strains of Mycobacterium Tuberculosis (MTB)
  • Isolation of High Molecular Weight DNA from Human Brain Tissue
• SOFTWARE ENGINEERING
  • Y2K Issue
  • Determining Best Practices and Establishing CDRH Software Policy
  • Implementation of CDRH Software Policy
• STATISTICAL ISSUES OF DIAGNOSTIC MODALITIES
  • Software development for Multivariate ROC Assessment of Diagnostic Modalities and Systems for Computer-Aided Diagnosis
  • Tissue Characterization
• TISSUE/MATERIAL INTERACTIONS
  • Evaluation of In Situ Polymers – Test Methods Development
  • Particulate Debris and Chronic Inflammatory Responses – In Vitro Methods
  • Particulate Debris and Chronic Inflammatory Responses – In Vivo Methods
  • Improvement of Natural Rubber Latex (NRL) Protein Quantitation Accuracy
  • Effects of Hospital Environmental Factors on NRL Allergy
  • Medical Glove Reclassification Rule
  • Molecular Biomarkers for Preclinical Evaluation of Medical Device Materials
  • Molecular Biomarkers for Endocrine Disruption by Medical Device Materials
  • DEHP Risk Assessment
  • Risk Assessment of Dioxin in Tampons
  • Tissue Engineering
• WIRELESS TECHNOLOGIES
  • Development of a Standardized Test Method for Evaluating Interference from Electronic Article Surveillance Systems
  • Measurement of Electromagnetic Energy Delivered to Models of Humans by Medical Devices
  • Laboratory Testing of Cardiac and Electrical Stimulation Devices
  • Wireless Medical Telemetry
• X-RAY INSTRUMENT CALIBRATION, FIELD SUPPORT, AND LABORATORY ACCREDITATION
  • X-ray Calibration Laboratory
  • Radiation Safety Standard for Personnel Security Screening Systems
  • Dosimetry Evaluations In Premarket Submissions
  • Technical Standards Development
  • Re-Engineering FDA’s Regulated Product Information System
• Appendix A – OST PUBLICATIONS
• APPENDIX B - OST PRESENTATIONS
• APPENDIX C - Academic Affiliations of OST Staff
• APPENDIX D - OST PATENTS
• APPENDIX E - OST- Sponsored Seminars
• APPENDIX F - Research Contracts, Interagency Agreements and Cooperative Research and Development Agreement
• APPENDIX G - Abbreviations and Acronmyms
• Appendix H
• Abbreviations and Acronyms

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PREFACE

The Office of Science and Technology (OST) is the laboratory of the Center for Devices and Radiological Health (CDRH) of the Food and Drug Administration.

OST supports the scientific basis for the Agency’s regulatory policies through the development of independent laboratory information for regulatory and other public health activities of CDRH. OST accomplishes this mission by managing, developing, and supporting standards used for regulatory assessments; performing laboratory evaluations and analyses in support of CDRH premarket and postmarket activities; developing data needed for current and future regulatory problems; and performing research, anticipating the impact of technology on the safety, effectiveness, and use of regulated products.

Specifically, OST develops and conducts research and testing programs in the areas of physical, life, and engineering sciences related to the human health effects of radiation and medical device technologies. OST develops specific scientific expertise for CDRH decision-making and analyses for health-risk assessments. The Office develops new or improved measurement methods, techniques, instruments, and analytical procedures for evaluating product performance and reliability. OST also provides innovative solutions to public health problems by developing generic techniques to enhance product safety and effectiveness. The Office prepares CDRH with the targeted science needed to ask the right questions early. The laboratory activities of the Office have four major focus areas: characterization of the constituents or components of products; measurement of product performance; bioeffects which derive from human exposure to radiation or medical devices; and radiation metrology in support of Agency regulation of radiation-emitting products.

The purpose of the OST Annual Report is to update our readers about OST's organization, staffing, and intramural science activities; provide a summary of our direct lab support for premarket review and compliance cases; and provide a bibliography of scientific publications, presentations, contracts, patents, and research seminars of the Office for fiscal year 2000. The Annual Report is an overview rather than a comprehensive accounting. For additional information, please contact us. The report might also be viewed as a source of information regarding areas in which Cooperative Research and Development Agreements (CRADAs) can be initiated with interested institutions. OST welcomes comments on the programs described in this report. We hope you find this report useful and informative, and we invite any comments you might want to offer.

Office of Science and Technology Staff

October 1, 1999 – September 30, 2000

OFFICE OF SCIENCE AND TECHNOLOGY PROGRAMS

ARTIFICIAL ORGAN REPLACEMENTS AND ASSISTS

Advances in the development of artificial organs will be driven by the continuing dearth of natural donor organs. The products in this category are among the most complex that the Center evaluates, and their public health significance is often profound. OST’s projects are directed toward elucidating the underlying mechanisms by which this technology interacts with the body so as to identify key questions early for CDRH. Projects also include development of meaningful test methods. In FY 2001, OST investigated a number of issues related to the successful use of artificial organs and organ assists including 1) cavitation damage to prosthetic heart valves, 2) damage to blood components following implant surgery, 3) test methods for implantable infusion pumps, 4) blood flow thru implants, and 5) issues related to neural stimulation. In each case, the goal is to develop information that will assist Center decision-making in the timely assessment of manufacturers' submissions. The on-going work in the areas of heart valves, blood damage, and hemodialysis is directly coupled into regulatory guidance and standards-setting activities. For example, there are on-going validation round-robin experiments involving both manufacturers and FDA in the area of heart valves. These experiments have grown out of the experimental work conducted in the area by OST over a number of years. This program also provided input to the development of ANSI and ISO standards on refractive implants and multifocal IOLs. Laboratory work on electrical stimulation was used to help formulate a guidance document for spinal cord stimulators, and in the revision process for national standards for nerve stimulators. Additionally, this research served as a basis for the premarket review of a number of investigational sense-organ replacement devices.

A New Flow Visualization System for Quantifying Flow in Artificial Organs
Key words: flow visualization, DPIV validation model, and standard test method

A new Digital Particle Image Velocimetry (DPIV) flow visualization system was developed this year incorporating a state-of-the-art dual pulsed YAG laser and fiber optic link. This new tool quantifies flow patterns from artificial organs such as heart valves, vascular grafts, artificial hearts, blood pumps, etc. It can identify aberrant flow patterns which may cause blood damage and device failure. When blood flow is too slow, dangerous blood clots can form; when blood flow gradients are too high, red blood cells are destroyed.

A block diagram of this system is shown in the figure below. The system uses two laser flashes to freeze the motion of particles seeded in the moving fluid. A high-speed digital camera captures the images produced by the laser pulses. A computer calculates fluid velocity by correlating particle positions in the two images.

Figure 1. This system was validated and used to measure flow through a
St. Jude mechanical heart valve. The figure below showsa sample
measurement obtained with the DPIV system that demonstrates
the tri-jet flow pattern for this triple orifice valve.

Figure 2

Ophthalmic Implants
Key words: intraocular lenses, refractive implants, standards, technical support

OST continues to participate in the Center's enforcement program for intraocular lens implants (IOL's) by developing and using test methods to assess IOL optical properties, such as refractive power and resolution. During FY 2000, several samples of IOLs were tested in the OST laboratory. Staff scientists are also participating in voluntary standards activities for IOLs on the ANSI Z80 subcommittees for optical engineering issues. The present ANSI Z80.7 standard for Intraocular Lenses is in the process of being harmonized with the ISO 11979 series. Additionally, there are two new IOL standards being developed in ANSI Z80 - Z80.12 (Multifocal Intraocular Lenses), and Z80.13 (Refractive Implants). These standards have also been accepted by the International Standards organization (ISO) for consideration as international standards. In the first half of FY 2001, OST will participate in a ring-test on Modulation Transfer Function (MTF) calculations (computer modeling) for a number of multifocal IOL designs.

Safety of High-Rate Nerve Stimulation
Key words: neuron, computer simulation, cochlear implant, spinal cord stimulator, brain

This project assesses the safety of rapid-rate nerve electrical stimulation at rates higher than nerve impulses can follow. This simulates the energy delivered by new-generation neurological implants. OST scientists examined the physiological effects of such stimulation in real and computer-simulated nerve cells. As pulse-rate is increased, nerve firing followed the stimulation. Then, as the rate increased further, the firing decreased, increased and finally (at highest pulse-rates) the nerve stopped firing and became refractory to stimulation. Even when pulses are subthreshold, rapid-rate pulses alter neural excitability. This work, for the first time, gives quantitative measures of nerve stimulation efficiency. It forms the basis of questions in regulatory reviews and improves the design of rapid-rate stimulation.

Figure 3: Action potential in real rabbit myelinated axon (left trace)
as compared to computer-simulated rabbit axon (right trace, the solid bar in each
trace represents a 2 millisecond, 0.2 nanoampere stimulation pulse).

Figure 4: Relationships between stimulation rate and action potential (A.P.) firing rate.

Examination of Mechanical Prosthetic Heart Valve Closing Sounds for High Frequency Acoustic Energy as a Signature of Cavitation
Key words: cavitation, acoustic, heart valves

Transient cavitation has been observed near operating mechanical heart valves. This cavitation, the formation and very rapid collapse of tiny bubbles, can cause valve damage or influence the hemolysis associated with these valves. FDA requires the manufacturers of mechanical heart valves under review to test for the presence of induced cavitation. OST is currently examining the available tests for cavitation. Previous studies to develop an acoustic technique detecting cavitation in and around mechanical prosthetic heart valves encountered a new problem. Not only does the collapse of cavitation bubbles causes high frequency noise; the mechanical action of valve closing, as well as the pump used to actuate the valves, also causes a broad band high frequency signal. In an attempt to distinguish cavitation noise from irrelevant sources, more data from different types of mechanical valves were taken. Spectra from time windows offset with varying time delays from valve closing were also captured to try to separate valve noise from cavitation noise. These data are currently being analyzed. Also, a new system using a sensor resonant at very high frequency (2 MHz) was put in place, and data will be taken at a higher frequency range for the universe of valves being studied.

Simplified Bernoulli Relation and Artificial Heart Valves
Key words: Bernoulli, heart valves, pressure drop.

Clinicians utilize Doppler ultrasound devices to determine the blood velocity near heart valves. A theoretical relationship, the Simplified Bernoulli equation (P = 4V²), is then commonly used to calculate the transvalvular pressure gradient, an important indicator of valve performance. A study has begun in OST to determine how well this relation applies to currently marketed prosthetic heart valves, since prior studies have shown that the Bernoulli constant of 4 is not always appropriate. In vitro test data reported to the FDA by valve manufacturers shows a range of 1.5-8.0 for the constant. With data taken for the entire range of valves available for implantation, the current study is designed to resolve whether the variation is a real effect or primarily due to measurement error. The study comes as the ISO 5840 international heart valve standard and FDA heart valve guidance are under revision.

Blood Flow and Pressure Transducer Protectors in Hemodialysis Machines
Key words: hemodialysis, transducer protector, pressure

In May 1999, FDA issued a Safety Alert in conjunction with a manufacturer’s recall of hemodialysis blood tubing sets due to blood contamination within the tubing’s pressure line transducer protectors. Due to the large number of people undergoing hemodialysis in this country (approximately 250,000), OST began a study as to how blood contacts the pressure line transducer protectors in hemodialysis machines. Blood contact may prevent accurate pressure monitoring and lead to contamination of the machine’s internal tubing. The blood level may rise in the bubble traps due to air leaks in the pressure lines, air entrainment in the flowing blood, air-blood mixing causing foaming, and air compression due to increased flow resistance. Air leaks are especially serious since they can allow blood to contact the transducer protectors without activating the pressure alarms.

Neurological CSF Shunts
Key words: neurological shunts, CSF shunts, hydrocephalus, in vitro performance testing

Testing has been underway to address problems associated with neurological shunts used to treat hydrocephalus. Currently, there exists an ASTM standard for these devices. However, this standard has been criticized as not being predictive of in vivo performance. Preliminary test results from this shunt evaluation have shown variable performance that does not match data provided by the manufacturer. In order to further understanding of CSF shunt performance, several shunt models from different manufacturers have been acquired in larger numbers and will be evaluated using the ASTM standard. This will allow a better statistical determination of shunt performance in vitro and will enhance understanding of the suitability of the ASTM standard to currently marketed shunt designs. This may ultimately lead to the development of more appropriate test methodologies for CSF shunts.

Large Animal Models of Vascular Disease and Therapeutic Device Interventions
Key words: minimally invasive techniques, vascular disease, angioplasty, radiofrequency ablation, re-clinical animal models

CDRH has established a large animal cardiovascular research program to develop and study models of cardiovascular disease and therapeutic device interventions. OST scientists are studying the effects of gender and hormone state on the response of the coronary and carotid arteries to initial balloon angioplasty injury and then to subsequent re-intervention with angioplasty or stents for the treatment of restenosis. OST is also examining the biophysics of radiofrequency ablation for the treatment of hepatic tumors. The relationship of ablation volume to blood flow is being investigated along with the electrical properties of tissue. The research goals include improved understanding of both the mechanisms of action and the failure modes for these interventions.

BIOMATERIAL EFFECTS ON IMMUNE SYSTEM

A biomaterial in a medical device in contact with mucous membranes or blood may leach into tissue and initiate a local response such as inflammation. This normal inflammatory process can become pathologic under chronic conditions and result in unresolved granuloma formation. Chronic perturbation of the immune system characterized by episodes of inflammatory bursts can break biological tolerance. Immunological defense mechanisms such as those involving cellular elements of the inflammatory process, the complement cascade, and cell proliferation can (under chronic conditions) damage tissues. This occurs when the normal inflammatory process becomes pathologic and results in granuloma formation and arthritic-like symptoms.

From a regulatory perspective, immunotoxicity is defined as any effect on the structure or function of the immune system or on other systems as a result of immune system dysfunction. An effect is considered adverse or immunotoxic if it impairs humoral or cellular immunity needed by the host to defend itself against infections or neoplastic disease or causes unnecessary tissue damage. It is essential to clearly recognize that change in an immune function or level of immunological mediator may not necessarily appear as an adverse effect, but rather as immunostimulation. Decisions on whether a material/device is immunotoxic must rely on the available evidence from preclinical test results and clinical evaluation, as well as prior history of use. Because the available data will often be less than conclusive, good judgment will play an important part in evaluating immunotoxic risk.

A goal of the OST research program is to provide laboratory assessment of the types of testing available for evaluating potential adverse effect of biomaterials on the immune system and to provide a process for selecting appropriate test methods. OST aims to make it possible for reviewers to obtain adequate information to make confident regulatory decisions; to ask the appropriate questions when negotiating with manufacturers; and to generate independent data concerning immune responses to biomaterials in devices. The data should provide some level of assurance that immunotoxic reactions are unlikely.

OST scientists have served as members of ODE review teams for McGhan Gel-filled breast Implants, for Mentor Silicone Breast Implants; for gene kit components, PDP devices and humanitarian devices exemption submissions (including a request for a toxicological consult regarding the carcinogenicity of gluteraldehyde). Scientists contributed reviews of master files and guidance documents.

Staff developed and coordinated IMMUNOTOX, an online service available on FDA intranet/FIRST to enhance communication among FDA immunologists and immunotoxicologists and to provide online services. The goal of the service is to provide assistance on product-related regulatory review issues.

The regulatory impact of immunotoxicity was addressed in the Immunotoxicity Guidance for Reviewers and Industry, prepared by staff scientists. The guidance was derived, in part, from laboratory studies and literature review and is designed to provide assurance that immunotoxic reactions are unlikely.

Finalization of a Standard Practice for Testing for Alternative Pathway Complement Activation in Serum by Solid Materials
Key words: complement activation, alternative complement pathway, medical materials, standard

This Standard Practice was developed by OST scientists and has been accepted by ASTM as "Standard Practice for Testing for Alternative Pathway Complement Activation in Serum by Solid Materials." Complement activation by the alternative pathway is a potential hazard when a patient’s blood contacts medical device materials. Inappropriate complement activation by blood-contacting medical devices may have serious acute or chronic health effects. This practice provides a protocol for simple, inexpensive, rapid, in vitro screening for alternative pathway complement activating properties of solid materials used in the fabrication of medical devices that will contact blood. The practice is designed for use with other standards that assess the biocompatibility of materials, particularly a previous standard also developed by OST scientists: ASTM F1984-99 "Standard Practice for Testing for Whole Complement Activation in Serum by Solid Materials." The practice is composed of two parts. In the first part, serum from guinea pigs genetically deficient in the complement factor C4 (necessary for classical pathway complement activation) is exposed to a solid material, during which alternative pathway complement activation and depletion of key complement proteins may occur. In the second part, the remaining complement is assayed for its ability to lyse rabbit red blood cells via the alternative pathway. The unsuitability of using human serum depleted of C4 by column immunoabsorption is discussed. Data demonstrating the equivalence of guinea pig serum to human serum for detection of complement activation by biomaterials, such as beaded agarose (Sepharose), is presented. Whereas some assays identify the amount of individual complement proteins in the blood, this assay determines alternative pathway complement functional activity. Therefore, the standard practice examines the ability of complement to exert one of its primary functions: the lysis of target cells. Assessing in vitro alternative complement activation, as described here, provides one method for predicting potential complement activation by materials intended for clinical application in humans when the material contacts the blood. This in vitro test method is suitable for adoption in the specifications and standards used for screening solid materials used in constructing implantable medical devices or devices that come in contact with human blood outside of the body.

Complement Activation by Implanted or External Blood-Contacting Medical Devices
Key words: alternative pathway, complement activation, standards.

Complement is a series of serum proteins involved in mediating immune reactions. Complement activation is a tightly regulated process that, in addition to direct cell cytolysis, can have profound affects on the immune, vascular, and coagulation systems. Though complement activation is an important defense mechanism against microbial infections, inappropriate activation by implanted or external medical devices may result in serious acute or chronic reactions.

Complement activation can occur by two main pathways. The classical pathway is triggered by antibodies bound to a cell surface. The alternative pathway is triggered by free hydroxyl or amino groups, such as are present on microbial organisms. Medical device materials generally activate complement by the alternative pathway. Complement activation by a candidate material via the alternative pathway in vitro indicates the material’s potential to trigger inappropriate complement activation when implanted in a patient or placed in contact with the patient’s blood outside the body.

OST scientists finalized a Standard Practice, accepted by ASTM, which screens specifically for alternative pathway complement activation by solid materials used in manufacturing medical devices. This supplements ASTM Standard Practice F1984-99, also developed by OST scientists, which screens for complement activation but does not specify which pathway is activated.

Examples of devices whose materials might activate complement by the alternative pathway include perfusion devices (such as dialysis membranes, cardiopulmonary assist systems, biosensor membranes, liver-assist perfusion devices, and columns for removing antibodies and other factors from patient blood), indwelling artificial vascular grafts, encapsulated drugs or cells, and vascular shunts/stents/catheters. OST is conducting research to acquire baseline information related to assessing risk from complement activation, particularly via the alternative pathway, by these devices.

In particular, complement activation by cardiovascular devices is being studied in a pig model. OST scientists are developing standardized methods to study complement activation by cardiovascular shunts, catheters, guide wires, and stents. The serum taken from pigs has been assayed before and after balloon angioplasty, and the scientists have documented a small but significant decrease in systemic whole complement levels, suggesting that complement activation does indeed occur during the procedure. The possible association of device-mediated complement activation in reblockage (restenosis) of unblocked cardiac arteries is also a concern.

Since damage by cardiovascular devices to the endothelial cells lining the inside of the blood vessels is known to be a critical step in subsequent restenosis, methods were developed for determining the effect of complement on pig and human endothelial cells via flow cytometry and fluorescent dyes. OST data demonstrated that complement activation by the classical and alternative methods both produce significant lysis of endothelial cells. OST researchers are now developing methodologies to extend the data to intact monolayers of pig and human endothelial cells, as a model of the interior of device-disturbed blood vessels.

Analysis of Autoantibody Responses to Silicone Gel-Filled Breast Implants
Key words: autoimmune disease, autoantibodies, silicone breast implants, silicone gel

Autoimmune diseases have been reported in women with silicone breast implants. The presence of autoantibodies in some of the women, as well as studies in experimental animals, suggest that silicone may play a role in these adverse effects on the immune system. Earlier OST studies have shown that silicone gel/oil can promote autoantibody production against the connective tissue proteins, collagen, and can migrate from the implant site to other parts of the body. The current project is a confirmation study. There were 240 rats from 2 different strains used in this study: Dark Agouti and Sprague Dawley. Rats were divided into six groups: immunized with Dow Corning oil, silicone oil with/without rat collagen type I/II, Dow Corning gel, silicone gel with/without collagen type I/II, incomplete adjuvant with collagen type I/II, and rat collagen I/II. Rats were pre-bled before the immunization and every 4 weeks after the initial immunization. Sera were tested for antibodies against rat collagen type I, and rat collagen type II using ELISA technique.

COMPUTATIONAL MODELING

Continuing advances in computer power are now making computational modeling a powerful tool for evaluating new devices. Product designers are making increasing use of such modeling in the development and evaluation of new technologies and products. These techniques allow both designers and FDA scientists to manipulate a wide range of variables without having to construct a laboratory bench test mechanism for each possibility. Moreover, a well-optimized complementation of clinical trials with computer modeling holds excellent promise for both reducing costs and increasing the informational value of such trials. In FY 2000, OST investigated these modeling techniques with the goal of assisting manufacturers in the analysis their products through the use of computation methods where cost/benefit advantages exist. Sponsors are increasingly turning to computational modeling to provide answers to problems not answerable by other techniques, and this is particularly true for heart valve technology. In FY00, OST scientists reviewed a number of applications where computational modeling provided the best available estimate of the large transient stresses induced in mechanical heart valves when the valve slams shut. This program also contributed to the development of the ASTM Standard Test Method for Measurement of Radio Frequency Induced Heating near Passive Implants in the Magnetic Resonance Imaging (MRI) Environment and to the review of device applications with claims of MRI compatibility and safety.

MR Compatibility: Evaluation of Patient Heating
Key words: magnetic resonance imaging radiofrequency MRI safety, Implants, SAR, magnetic fields

This project is investigating the use of computer modeling to evaluate the undesirable heating of certain patients undergoing magnetic resonance imaging (MRI) examinations. This heating occurs because of the interaction of metallic implants with the strong radio frequency (RF) magnetic field produced by a MRI device. Commercially available software XFDTD was adapted to model and calculate the rate of RF energy absorption (Specific Absorption Rate or SAR) and the SAR distribution in a realistic model of the human body. The body model contains a metallic implant and is placed in a model of birdcage body coil of a 1.5 Tesla MRI (RF magnetic fields at 64 MHz). The result of extensive computations show that the magnitude of the increased tissue heating due to the presence of the metallic implant depends on the dimensions, the orientation, the shape of the metallic objects, and the location of the metallic implants in the patient. The increased heating of surrounding tissues primarily concentrates in a small volume near the tip of the metallic wire. Scientists obtained a calculated maximum SAR value of 41 W/kg (averaged over one gram of tissue) at this location. However, a maximum value of 310 W/kg was calculated when the absorption is averaged over 0.125 gram of tissue.

Calculation of Virus Transport through Barriers as a Function of Pore Geometry
Key words: virus transmission, transport modeling, computational fluid dynamics, barrier evaluation

When stressed during use, synthetic barriers such as surgical gloves can develop tears that are undetectable by the user. While post-operation tests can detect the presence of holes in the glove, they provide little information regarding how much virus may have been transmitted during use. OST scientists employed a mathematical model to predict levels of virus transmission through a compromised barrier as a function of pore geometry and trans-membrane pressure. It was found that during conditions modeling the manipulation of surgical instruments, up to 300 hepatitis B viruses per second are transmitted through a slit 1 micron high and 4 microns wide. The calculations help CDRH to meaningfully quantify the risk associated with barrier failure.

Computational Studies of Vascular Grafts
Key words: vascular grafts, blood flow, modeling methods

A computational study has begun to determine how vascular prostheses affect blood flow and the concentration of chemicals activated by the prosthetic material. Earlier studies have shown trapped particles at the downstream junction between a graft and artery, which correlates well with the clinical finding of increased tissue overgrowth there. Preliminary computational studies also show an enhanced concentration of dissolved species at this site. This study aims to elucidate factors leading to clinical graft failure and to provide expertise in modeling methods likely to be used in future applications of endovascular grafts, stents, and other cardiovascular devices.

DEVICE PERFORMANCE ANALYSIS AND MODELING

The development of test methodologies and performance requirements for devices and materials are vital for industry’s consensus standards. OST’s program has two areas of focus. The first is developing chemical test methods that determine the accuracy and precision of analytical instruments or the performance of devices that rely on mass transfer. The second is developing test methods for devices and materials involving performance requirements such as strength, durability, abrasion resistance, puncture resistance, etc. This program area allowed OST to participate in the technical reviews of numerous new products such as bioprosthetic heart valves and tissue adhesives.

Endovascular Stent Standards Development
Key words: stents, standards, test methods

OST laboratory personnel, in collaboration with ODE and industry and under the auspices of ASTM, are continuing to develop detailed test procedures for clinically relevant engineering attributes of endovascular stents. The ASTM Interventional Cardiology Task Group, co-chaired by OST and supported by data generated by the OST laboratory effort, has completed work on two standards. The data to support precision and bias statements for these methods are being developed. Significant effort was spent evaluating the details of stent dimensional characterization, including the diameter measurements used for the calculation of recoil. The stents on hand were characterized by a variety of methods (profile projection, pin gages, laser micrometer, calipers) with a view toward quantifying both the precision of the method and the variation in dimension across the stent. Preliminary data indicate that further development of the methodology is necessary if the precision goals for the standard test methods are to be met.

EMERGING ISSUES 2000: GENETIC TECHNOLOGIES

The revolution in human genetics and the sequencing of the human genome will create new opportunities for public health and new challenges for FDA. CDRH is preparing for the capability of assessing and regulating genetic testing devices within the near future. OST organized meetings with ODE senior staff to assess the role of genetic testing in CDRH. Staff presented grand rounds and updates on emerging science issues. The FDA Science Forum was organized. OST scientists served as members of scientific advisory committees for other FDA Centers, and taught courses on biocompatibility to update review staff. Information sessions, including presentations by developers of genetic and genomic technologies, have been organized by ODE’s Division of Clinical Laboratory Devices. Scientists in OST’s Division of Life Sciences have aided the recruitment of speakers and contributed actively to the discussions. OST is also involved in the FDA Genomics/Proteomics working group, organized by the Commissioner’s Office. This group is developing priorities for action related to FDA readiness in assessing new genetic technologies.

OST scientists are developing laboratory projects to develop hands-on readiness for the emerging technologies. These projects will provide a base for keeping up with the technologies as they evolve. It is also expected that they will demonstrate some of the ways in which new genetic approaches can enhance human health. There are two quite different types of devices representing the new technology expected to come to CDRH for review: genomic or genetic testing devices.

Laboratory projects in genetics testing and genomics are developed to enhance the reviewer readiness for emerging technologies involving the genome revolution. Models derived from these studies are useful to derive standards related to identification of genotoxic components of medical devices (including dyes in sutures, surgical sealants, etc.) and assessment of genetic testing components.

The genomic type involves gene expression, often in comparison to a reference population. This involves analyzing many hundreds or thousands of genes that are up-regulated or down-regulated in response to a stimulus. The result is a pattern of gene expression that is designed to be diagnostic or characteristic of a particular subset of the population. For this type of device, data organization and assessment, i.e., bioinformatics, are important. Examples would be a pattern of gene expression related to toxic responses and other adverse events.

The second type of assessment is a genetic test to determine the presence or absence of a particular DNA sequence already known to be related to a health outcome. In practice, this is a yes or no question, independent of signal size. Examples are mutations in the cystic fibrosis gene (human genetic disease), in a drug metabolizing gene (adverse event from a particular class of drug), in the p53 gene of a tumor (diagnostic for cancer), or in genes related to susceptibility to cardiovascular disease. Pharmaceutical companies are planning to submit genetic testing devices along with drugs in order to stratify a clinical trial population, or to include or exclude a certain segment of the population, resulting in a customized therapy. The goal is to identify a smaller and more appropriate clinical trial population.

The technological issues in insuring the safety and efficacy of these two different types of genetic testing devices are different. It is important to address both sets of issues.

OST has developed projects in each area that can be used as a basis for investigations into the issues affecting the safety and efficacy of genetic and genomic devices.

Genomic devices. A project to develop a gene expression pattern characteristic of latex sensitivity is being developed in collaboration with the CDRH Offices ODE and OSB, with CBER, and with a small biotech company. This project allows OST to gain data and experience. OST scientists expect to establish gene chip technology in the future. The gene expression model could be used to develop methods for evaluating new biomaterials, such as those resulting from tissue engineering. With an in-house system, OST could offer to partner with ODE in identifying technological sources of error in chip devices (e.g., reproducibility of oligonucleotide sequence and quantity deposited). These issues could then be addressed in standards and guidelines for approval of these devices. Collaboration between OST’s Division of Life Sciences and Division of Electronics and Computer Science could be established in the area of data management, bioinformatics, and pattern recognition.

Genetic devices. Genetic testing and genetic susceptibility testing involve the resolution of single-base pair differences in DNA, usually by hybridization to specific oligonucleotides. OST has a project in this area utilizing the human p53 gene. The project involves assessing sequence changes in the p53 gene using both conventional and microarray technologies. This project serves as a model for genetic testing related to diagnosis, prognosis, and therapy of many types of cancer. It may also be used as a model for standards development related to identification of genotoxic components of medical devices. These include dyes in sutures and other products, components of surgical sealants, and some types of breast implants.

Development of an In Vitro P53 Human Gene Mutation Assay for Cancer Risk Studies
Key words: p53, cancer risk, mutation, genetic testing, genetic devices

There is a great need for more relevant tests for evaluating the cancer risk of medical devices and low frequency radiation. This includes assessing the genotoxic constituents of medical device materials, e.g., those in surgical sealants and bone cement (t-butylhydroperoxide and hydroquinone), as well as implants (toluenediamines). Dyes associated with medical devices can be genotoxic. Assessing the long-term risk of devices emitting low frequency radiation, including cellular phones, is also problematic. Recent findings in cancer research have shown that a substantial proportion of human tumors has mutations in the p53 tumor suppressor gene, 50% on average, but varying by tumor type. These mutations cause loss of genome integrity and cellular growth control; evidence is accumulating that these mutations are directly related to cancer development in humans. Among the most compelling data are the cases in which p53 signature mutations, characteristic of the environmental agents to which a population has been exposed, are found in their tumors.

In assessing human cancer risk, therefore, one important question is whether a biomaterial, breakdown product, impurity, or other relevant substance or device has the capability of causing mutations in critical regions of the p53 gene. There are no currently available practical means of determining this. Therefore, OST has worked to develop a standardized screening assay for measurement of mutation induction in the p53 gene. Until recently, it has not been technically feasible to easily identify and select p53 mutations. However, several laboratories have developed methods for identifying p53 mutations introduced into yeast. A recently constructed version of the yeast, created at MIT, carries a plasmid carrying p53 cDNA and two genes that are transactivated by wild-type p53 protein. The strain is engineered such that p53 mutants have a double mutant phenotype allowing mutant identification by color and mutant growth advantage on selective media. OST acquired this strain and have made progress in developing a p53 mutagenicity assay for routine screening purposes. By varying conditions of culture growth, temperature, media components, concentration (the chemical used in the p53 mutation assay), age of plates, and incubation time, scientists established conditions for optimum selection of yeast having p53 mutations. In a reconstruction experiment, OST scientists demonstrated the recovery of 10 mutants in a background of 10⁵ or 10⁶ non-mutants. Scientists determined that several variables are critical in reproducible selection of mutants (temperature, plate age). By selecting for linked markers, OST developed simple tests to monitor for loss of the two plasmids. Other experiments have studied the role of media, temperature, growth stage, and expression time on mutation generation and recovery. Initial experiments with UV radiation were successful in generating p53 mutants, although the doses have not been optimized. OST explored ways of accomplishing mutant expression and selection on one plate, to make the assay as functionally simple as the Ames Salmonella plate assay; but this has not yet been achieved. There has been good progress in developing a more relevant tool for assessing cancer risk.

FAILURE ANALYSIS OF ELECTRONICS IN MEDICAL DEVICES

OST applies readily available tools and methods to the laboratory evaluation of medical device performance. OST also applies analytical tools to problems of medical device reliability. These programs are directed at identifying generic device electrical engineering problems and their solutions. The principal laboratory activities are to design and develop specialized test equipment, evaluate failed medical devices, and develop test methods. Areas of particular laboratory interest include microcircuits, batteries, and electrical fires.

Regulatory Support - Forensics
Key words: electronics, forensics, regulatory support, fire

OST provided laboratory forensic support for several FDA regulatory actions. In one, an OST engineer played a significant role in a case involving the explosion of a lithium sulfur dioxide battery in a portable defibrillator. The battery in question used a newly emergent technology. This technology offers significant performance advantages over more established battery chemistries, but hazards associated with the new product were not well understood by the manufacturer. OST's investigation revealed that at least one other manufacturer of portable medical devices has grappled with these issues.

In another compliance case, one involving an infusion pump, it was determined that defective battery "gas gauge" software caused a rechargeable battery to be depleted to the point that physical damage occurred in one or more cells, resulting in premature failure of the battery. An OST engineer participated in an on-site inspection of the firm, which prompted a product recall.

OST engineers provided regulatory support in several other cases involving electrical safety. In one case, OST developed a test apparatus for assessing the compliance of medical device connectors with the CDRH Standard for Electrode Test Leads and Patient Cables. In another case, cable assemblies from a surgical device were tested for compliance to IEC 60601-1. In a third case, OST investigated a recall situation involving a neurological testing device that was manufactured by both a U.S. and Canadian firm under a license agreement. The U.S. firm determined that the design was not compliant with electrical safety provisions of IEC 60601-1 and instituted a recall on that basis. The Canadian firm disagreed with this assessment and declined to recall. OST determined that the product was indeed non-compliant. A fourth case involved a complaint brought by a competitor against a cardiac assist device, in which it was alleged that the device violated an electrical safety standard to which compliance was claimed. OST determined that the design did not violate the standard and the manufacturer was exonerated. In a fifth case, OST assisted in the field investigation of an implantable defibrillator. Capacitor quality and aging issues were addressed.

Premarket Support - Scientific Evaluations
Key words: electronics, forensics, regulatory support, fire, standards/guidance

OST engineers consulted on a premarket review case, involving a novel technique for securing bone staples. The staple was designed to be inserted into pre-drilled holes in the bones to be fastened. The device in question passes electrical current though the staple, causing it to become hot. The tines of the staple are designed to deflect inward when heated, permanently securing the staple and fixing the joint. OST was to assess whether UL Standard 2601-1 was adequate to assure safety of this device. It was determined that UL 2601-1 did indeed apply to this device, and that the device appeared to be compliant. However, the issue of possible tissue necrosis due to heating of the staple is a clinical issue and thus outside the scope of the standard. OST staff carefully explained the limits of applicability of the standard and suggested how the clinical issues could be clarified.

Quality Management
Key words: quality systems

An OST engineer has worked with senior CDRH management to begin implementing a Center-wide quality plan. OST has advocated applying the concepts of design control, quality systems, and risk management to a variety of regulatory problems. Positive impact by OST on the direction and outcome of several reengineering efforts, on the science review, and on several premarket guidance documents has been achieved. Specific examples include the following:

• A tutorial was presented on the principles of design control in the Staff College Quality Lecture series. Part of this presentation focused on the need for organizations to develop an integrated system of quality management processes that encompasses product quality, risk management for safety, environmental management, regulatory requirements, and business decision-making;
   
• Technical support was provided to the FDA Laboratory Accreditation Committee on a number of issues, including estimating the cost of implementation and formulating a training plan;
   
• A consultation was provided to the Office of Regulatory Affairs on implementing a document control system;
   
• Consultations were provided to various field investigators on a variety of quality system issues involving design controls, corrective and preventive actions, and calibration of test and measuring equipment. The focus of OST's contribution in these cases is reconciling the general requirements of the quality system regulation with the specific practices of the electronics industry;
   
• OST provided consultation to several CDRH reengineering committees to help them to validate reengineered processes. Most notably, work with the QSIT Reengineering Team has helped to ensure broad acceptance of the Quality System Inspection technique; and
   
• Design control concepts were incorporated into a new guidance document covering home uterine activity monitors. This guidance document describes a means by which manufacturers can establish substantial equivalence to a predicate device. Designating this guidance document as a "special control," in the language of the Safe Medical Device Act of 1990, permitted home uterine activity monitors to be downgraded from Class III to Class II. By following the guidance, manufacturers can minimize the effort required to prepare the premarket submission and significantly streamline the Agency’s review. In response to this request for assistance, OST developed plain language clarifying the distinction between a premarket review of design information and a quality system review of the same or similar information. Now that design controls are firmly ensconced in the quality system inspection, premarket reviewers may avoid covering the same ground as covered by quality system investigators.

Additionally, OST engineers led an effort to lay the groundwork for a quality management system within the Office of Science and Technology. This included preliminary training for managers in quality management system concepts, performing a gap analysis to assess the degree to which the Office’s existing management systems satisfy the requirements of ISO 9001, and developing a detailed plan and cost estimate to implement a compliant quality management system.

Risk Management
Key words: risk management, training

OST developed a plan for training Center staff in the principles and practices of risk management, how those principles and practices are applied by device manufacturers, and how risk management information can be used to expedite the review process. This has been a major undertaking affecting ORA, OC, and ODE. First, OST staff worked with ORA in developing a set of computer-based training modules in technical risk management for field personnel. OST developed the outline for the first training module, identified CDRH experts in human factors and software hazard analysis to work on modules, and has provided an expert to write the module on risk management and the Quality System Regulation. In addition, OST participated in the ISO/IEC 14971 Joint Working Group on Risk Management for Medical Devices.

Reliability
Key words: reliability, dependability

For the past several years OST has provided the representative to the IEC TC 56 on Dependability. This work has resulted in the FDA recognition of IEC 61812 Analysis Techniques for Reliability - Failure Mode and Effects (FMEA). FMEA is the primary risk analysis technique used by medical device manufacturers, and recognition of IEC 61812 will promote harmonization in this important area with regulatory organizations in other countries. IEC TC 56 has now moved on to revising IEC 60300-3-1 on Dependability Analysis Techniques, the purpose of which is to increase its relevancy to modern dependability programs of the type used by the vast majority of medical device manufacturers. Issues in medical device reliability and dependability have pointed to the need for a new laboratory in OST concerned with issues of reliability -- a laboratory capable of analyzing data coming from a variety of sources and generated under a variety of test conditions. OST tested the concept of a Reliability Laboratory when, in support of DCRND in the review of an IDE and PMA for two Left-Ventricular Assist Devices (LVADs), it provided technical analyses of the company's reliability programs and evaluation of reliability data.

MATERIALS AND DEVICE CHARACTERIZATION

The focus of this program is to develop and assess suitable characterization methods and the generation of baseline data of the chemical, physical, and mechanical properties of medical devices and their materials. The effects of devices, drugs, radiation, etc. on the physical properties of tissue, as well as research into the determination of specific exposure limits are included in this area of study. By undertaking work in this program area, OST will help CDRH with its regulatory mission by participating in the development of consensus standards and characterization techniques that allow for the timely review of many diverse products, including absorbable sutures and vascular grafts. With OST’s extensive expertise in materials, the Office drafted standards that assist manufacturers in assessing the MRI compatibility of their devices by evaluating the potential for soft tissue damage by either torque or unbalanced linear forces in the presence of large magnetic fields. The work described below on the development of a standard methodology for the measurement of powder on gloves aided in the drafting of regulations concerning the allowable limits of powders on gloves.

Experimental Pathology: Cardiovascular Devices
Key words: pathology, valves, grafts

The objective of the experimental pathology program is to identify potential failure modes associated with the use of implantable cardiovascular devices as well as the elucidation of pathologic mechanisms responsible for their failure. Studies of explanted replacement heart valves, vascular grafts and angioplasty-injured coronary arteries are ongoing. Studies completed this year include 1) the development of experimental pathology methods for the evaluation of tissue engineered replacement heart valves and small diameter vascular grafts; 2) a morphologic study of decellularized carotid artery vascular grafts; and 3) the evaluation of a swine model to assess the preclinical safety of mechanical heart valves.

Tissue Engineered Medical Products Standards (TEMPS)
Key words: standards, tissue engineering

Division IV of ASTM F04 has established itself as the recognized leader, both nationally and internationally, in the development of TEMP standards. International liaisons have been established with other standards organizations that have expanded international involvement with the consensus process.

An important initiative is an ASTM International Symposium for Tissue Engineered Medical Products Standards to be held in Miami Beach, Florida, November 4-5, 2002, in conjunction with Committee Week and proposed as a "back-to-back" meeting with the Tissue Engineering Society International biannual meeting. The goals for the symposium are to review the technology, the use of standards, and the need for standards.

Powder Measurement on Medical Glove through the Participation in ASTM Working Group
Key words: powder measurement, powdered glove, powder-free glove

Prior to the present work, ASTM D 6124 – 97 was the standard test method for residual powder on medical gloves described as powder-less, powder-free or no powder. Due to the proposed powder limit on "powdered" gloves by FDA, there was a need to modify how larger amounts of powder were measured. The Division of Mechanics and Materials Science laboratory in OST participated in the ASTM D 11.40 round robin method development. By changing to a larger filter paper size, using the multiple fresh water washes per glove, minimizing extractions/filter, preconditioning of the filter, and agitating during the wash, a new Standard Test Method D 6124 - 00 was established. This method can be used for quantitation of powder on both powdered and powder-free gloves.

MEDICAL IMAGING EVALUATION

OST scientists develop consensus evaluation methodology for diagnostic medical imaging systems such as mammography and other film-screen x-ray systems, computed tomography, nuclear medicine, diagnostic ultrasound, magnetic resonance imaging, and digital imaging including fluoroscopy and digital mammography. The goal of the program is to characterize and optimize medical imaging systems and components through the application of quantitative measures of imaging performance and dose. This program also supports development of mammography equipment standards and special procedures and test equipment for MQSA. During 2000, this program contributed to the soft-copy aspects of the premarket guidance document "Information for Manufacturers Seeking Marketing Clearance of Digital Mammography System."

Digital Image Display System Evaluation
Key words: digital radiography, soft-copy display

The purpose of this project is to develop measurement and analysis procedures to evaluate the performance of image display devices for digital diagnostic imaging systems. Currently, the primary technologies used for the display of digital medical images are laser film printers (hardcopy) and CRT-based video monitors driven by computer-controlled digital frame buffers (softcopy). This study provides the scientific basis for regulatory decisions regarding the display subsystems of a variety of digital diagnostic imaging devices. The research will lead to a more efficient review of applications submitted for clearance to market products containing such display systems.

During FY 2000, scientists were limited to setting up display hardware and software, and establishing various display measurement capabilities. Existing display hardware and workstation software were supplemented by an additional display system and software upgrades. These elements were reconfigured to provide two dual-monitor display workstations, one of moderate resolution (1728 x 2304), and one of high resolution (2048 x 2560). Both systems were equipped with photometric calibration sensors and software produced by the manufacturers of their respective frame buffers, and both are equipped with a third-party calibration package that can provide independent verification of photometric performance. At the end of FY 2000, a scientific-grade camera and computer-controlled positioning equipment were acquired.

X-ray Physics Laboratory Studies
Key words: x-ray spectroscopy, mammographic grids

The purpose of this project is to evaluate equipment and materials used in medical radiography and in the quality assurance of medical radiography systems; and to support OST research efforts, other Center programs, and the general radiology community, when appropriate. Conducting this project requires establishing and maintaining the capability to generate x-ray beams typical of those used both for mammography and for general diagnostic radiography, as well as state-of-the-art capability for x-ray measurements, including high-resolution x-ray spectroscopy. OST provided technical consultations to the Office of Compliance on questions related to mammography field limitation/primary barrier and "mini C-arm" fluoroscopy systems. The Diagnostic X-ray Standard was extensively revised to address radiation safety during interventional fluoroscopy.

The medical imaging physics community has noted an increasing use of higher-voltage spectra in digital mammography. In response to publication from the University of California, Davis, of Monte Carlo calculations of mono-energetic, mammographic exposure-to-dose conversion factors for an extended range of x-ray energies, OST planned and initiated a series of spectral measurements for the three anode materials used in mammography--molybdenum, rhodium, and tungsten--at tube voltages up to 50 kVp. The measurements are being made at two field positions to allow for inclusion of the influence of the "heel effect" on patient dose in theoretical calculations.

X-ray spectroscopic measurements were employed to evaluate the performance of small-size prototype grids produced using microlithographic techniques. It is expected that such grids will soon be commercialized.

Mammographic Dosimetry Studies
Key words: mammography, dosimetry, optimized mammography system

The purpose of this project is to experimentally verify Monte Carlo predictions of the exposure-to-dose conversion factors for new x-ray sources such as rhodium anode with rhodium filter and tungsten anode with various K-edge filters. This project supports the MQSA mission to promote and maintain minimum dose levels in mammography, and may result in changes to the dose determination procedure for systems using newer x-ray source options. OST scientists began the spectral measurement program described above to extend the range of tube voltages for which experimentally measured spectra are available for the three anode materials used in mammography: molybdenum, rhodium, and tungsten. The scientists performed a small study to estimate phantom doses from the optimized mammography system for several screen-film combinations being considered as replacements for the discontinued products that had been used in earlier experiments.

Imaging System Performance Evaluation
Key words: digital radiography, flat panel detector, CCD-based x-ray imager

OST scientists are extending the quantitative assessment of dose and imaging performance from the analog to digital imaging domain. OST scientists have played a significant role in developing consensus measures of imaging performance that form the basis of the nonclinical device description now required in marketing clearance applications for a variety of imaging devices, and they are now extending these measures to digital imaging systems. Several important measures of imaging performance that are now routinely applied to analog imaging systems are based on assumptions that are violated to one degree or another by digital systems. OST is investigating the validity of these measures for digital systems and is investigating alternate performance measures that are rigorously valid for digital systems.

In one laboratory initiative, the impact of violation of the analog-system assumptions on consensus measures for digital systems was explored through a series of computer simulations. To supplement this work, OST has acquired a flat panel digital detector for experimental verification of the simulation results. In the future, actual human observer data will be compared with predicted results, derived from quantitative measurements on the digital detector, for reading imaging phatoms. It is hoped that this work will help to bridge the gap that currently exists between subjective evaluations using imaging phantoms and objective measures of imaging performance. In the area of analog x-ray devices, OST scientists are evaluating inefficiencies in imaging performance using laboratory measurements. To address the issue of optical coupling inefficiency in the image formation process, which arises in the premarket approval of, some digital imaging devices, OST set up a lens-coupled CCD-based digital imaging system and investigated the effects of system design on overall radiation use efficiency.

Ultrasound Bone Densitometry
Key words: ultrasound, bone density, osteoporosis

OST plays a significant role in the approval of PMAs for ultrasound bone densitometers. This is a new technology that is likely to undergo much technological evolution and regulatory activity in the near future. Currently there is a considerable lack of standardization among devices. Preclinical experiments, clinical trials, and theoretical analysis are important to develop understanding of this technology and to anticipate future trends. This project provides an independent source of data in OST in support of regulatory decision making. OST has explored fundamental mechanisms underlying the interaction between ultrasound and bone. These investigations increase understanding of how and why ultrasound bone densitometry is effective and therefore lead to better and more thorough reviews of these devices. OST contributed a section to a CDRH guidance document on submissions for bone sonometers.

MEDICAL USES OF AND ENVIRONMENTAL EXPOSURES TO RADIATION

This program encompasses a collection of biological research projects needed to ensure that the public enjoys the benefits of modern medical and consumer technology without undue harm due to associated radiation exposures. Another goal of the program is to prevent unnecessary exposure of the population to radiation emitted from electronic products and to establish the scientific basis for regulatory decisions involving electronic product radiation.

Boron Neutron Capture Therapy (BNCT) promises the potential of becoming a major new modality for the treatment of brain tumors, whose therapy is currently problematic. Its clinical investigation and commercialization will raise a number of new medical device and drug-device issues for CDRH and CDER. OST has worked toward developing computational capabilities to verify dosimetric data submitted in IDEs and PMAs. One of the current challenges to bringing BNCT to the clinic is the design of epithermal neutron beams which will result in safer and more effective therapy by maximizing tumor dose while minimizing normal tissue dose. Since reactor neutron sources are unsuitable for siting in hospitals, there is a need for computational design of beam generators employing particle accelerators. This requires extensive modeling of combinations of charged particle neutron sources, moderators, and reflectors to optimize the dose delivered to a tumor mass. Variables to be considered include tumor dose for various tissue depths and dose to normal tissues from boron capture, as well as proton recoil and nitrogen capture reactions and capturing gamma rays from the target structure. These calculations will provide guidance on desirable properties of neutron beams proposed for IDE's and can serve as a basis for the design of a future experimental facility. Until recently, powerful neutron sources were limited to a very few locations at existing nuclear reactors and thus not generally available for patient treatment. The marketing of a new generation of powerful nuclear particle accelerators, comparable in price to the accelerators currently used for radiation therapy, will soon make clinically useful neutron sources available for therapeutic applications.

Currently over 100 million Americans use wireless phones. This exposure of large numbers of people to radio frequency radiation (RFR) is unprecedented. Data relating to the safety of wireless phones is currently inadequate to determine whether adverse health effects are likely to result from these exposures. A small number of chronic rodent exposures have been conducted which show no evidence of cancer in exposed animals; but one of these studies did indicate an increased number of lymphomas in susceptible transgenic mice. In addition, in vitro studies have been reported to show changes in enzyme activity that are suggestive of cancer-promoting effects. Another in vitro study showed an increase in micronucleus formation, a possible marker for epigenetic effects on DNA synthesis, in human cells exposed to wireless phone emissions. Research into the bio-effects and effects on medical electronics of cell phone use continues. OST developed and established a cooperative research agreement allowing FDA to better assess the possible health risks associated with mobile phone technology. Once the mobile phone industry has initiated this research, FDA will provide ongoing scientific and technical oversight of the research programs. OST research investigated some of the reported in vitro effects using an exposure system calibrated in terms of specific absorption rate. This research, along with extensive involvement in research with other laboratories, aids assessing published data that suggest the biological effects of exposure to radio frequency radiation at levels relevant to wireless phone use.

OST studies of the utility of novel noninvasive and biomarker methods to test and standardize skin responses to ultraviolet radiation (UV) can provide data needed for revising the national and international standards in the area. Such research supports CDRH policies for ultraviolet lamps used in medicine and cosmetology, CDER policies related to sunscreens and photosensitizing drugs, and CFSAN policies in the area of cosmetics. FDA’s policies regarding sunlamps has been repeatedly questioned by the consumers, the industry, and the medical community. OST research will include the collection of data on human subjects representing skin types I-VI and racial ethnic groups of (1) American Indians or Alaska Natives, (2) Black or African Americans, (3) Asians, (4) Hispanic or Latinos, (5) Native Hawaiians or Other Pacific Islanders, and (6) Whites. These data include changes in the skin properties following UV exposure assessed using two mechanical methods, four optical methods, one ultrasound method, and several biomarkers measured in the biopsies. OST data provide a solid scientific basis for improving the classification and testing of human skin sensitivity to UV.

Some UV-exposed skin cells do not die. Rather they acquire genetic mutations that can lead to skin cancer. Inhibition or failure of cells to die when too many genetic mutations have been acquired has recently been implicated as a mechanism for initiation and promotion of skin cancer by UV. In vitro laboratory data from cell exposure to UVA and UVB wavelengths separately, which are both emitted to different degrees from tanning lamps and, together, can be used to establish adjustments that should be made to existing UV risk assessment equations. Until recently, no risk assessment of tanning lamps for skin cancer could be accurately performed because only the action spectrum, i.e., data for the individual UV wavelengths, was known. The combined output effect on skin cancer from tanning lamps, i.e., UVA and UVB wavelengths, could not be established because a definitive biological endpoint to monitor in human cells was not established. OST data can be used to see if an additive, synergistic, or antagonistic effect occurs when UVA and UVB are combined together, as they are in tanning device emission. With this data, scientists will be able to complete a risk assessment because they will know the appropriate approach and equations to use in this tanning lamp situation.

Radiation scientists are assessing the utility of several testing methods for charcterizing the effects of UV radiation on skin for potential use in the regulation of products such as sunlamps, tanning booths, sunscrenns, and photosensitizing drugs. In addition, a cross agency effort to estimate the effect of exposure to ultraviolet radiation and implement efforts to reduce exposures. The studies, initially funded by grants from the FDA Office of Science have begun to yield results that are useful in developing standards for determining UV exposures and for validating predictive models of tissue behavior when exposed to UV.

The projects described below are complimented by standards development activities, particularly in the areas of nonionizing radiation exposures. The OST scientists responsible for this research are active in the revision of international standards and guidelines for ultraviolet, radio frequency, and extremely low frequency radiation.

Optimization of Accelerator Targets for Neutron Capture Therapy
Key words: cancer therapy, boron, neutrons

Boron Neutron Capture Therapy (BNCT) remains a promising investigational therapy for brain tumors, and it uses boron-10 and a neutron beam to selectively produce highly ionizing helium nuclei (alpha particles) in a tumor while only producing minimal damage to the surrounding brain tissue. A variant of BNCT, capture synovectomy, has been proposed and patented for ablation of pathological synovium in rheumatoid arthritis refractory to medical treatment. Since there is currently inadequate information about the optimal performance characteristics of devices that would be used to deliver these therapeutic neutron beams, OST has initiated a project to investigate issues of potential regulatory significance using computational modeling. OST developed a computational model of the moderator which must be placed in a fast neutron beam to slow the neutrons to therapeutic energies. Moderators of deuterium oxide, carbon, Teflon, aluminum oxide, lithium fluoride, iron fluoride and an aluminum-aluminum fluoride composite were modeled. The neutron source was a lithium accelerator target bombarded by 2.5 MeV protons. Comparisons of the computed spectra of neutrons emerging from the moderators indicates that aluminum oxide, a cheap and readily available material, gave the highest fraction of epithermal neutrons and lowest contamination by fast and thermal neutrons. OST also collaborated with a local accelerator facility that will allow experimental confirmation of these results as well as in vitro studies of lethality for brain tumor cells.

In vitro Biological Effects of Wireless Telephone Emissions
Key words: wireless communications, cancer

Due to the continuing interest in possible adverse health effects in wireless phone users, OST developed an exposure system utilizing radio frequency (RF) radiation from wireless phones to permit investigation of some of the reported in vitro effects of this radiation. A series of experiments was conducted to calibrate the RF exposure system for exposure of cultured cells to radiation emitted from wireless phones and to characterize the effects of this radiation on the enzyme ornithine decarboxylase (ODC). Precision calorimetry was used to measure the amount of RF energy deposited in cultured cells for both analog and digital phone signals. Experiments were then conducted to verify reports that wireless phone radiation increased the activity of ODC, a marker for tumor promotion, in cells. Exposure to a wide range of RF power levels from wireless phones did not increase ODC activity, although at higher power levels a decrease in activity was observed. This decrease was demonstrated to be due to heating of the cells by the RF radiation. These results are consistent with a large number of experiments conducted by OST, which did not confirm reports from other laboratories that electromagnetic fields enhance ODC activity in mammalian cells