Office of Science and Engineering Laboratories 2009 Highlights
Controlled Drug Release Study (Active Materials Laboratory)
It is known that amount of drug released from DES coatings is not linearly related to the amount of drug in the coating, raising the following questions:
1. Was this related to manufacturing variability?
2. Would the release of drug vary from bath to batch?
3. Was this a phenomena common to drug/polymer mixtures?
4. Why is the drug release not linear to drug loading?
It was hypothesized that these questions could be addressed by examining relationships between materials, processing, and structure of the drug in the polymer coating matrix. In the Division of Chemistry and Materials Science (DCMS), coatings similar to those used in stents were manufactured under various processing conditions and drug loadings. The drug structure and the drug elution were then quantified. The amount of drug at the surface and the drug elution increased exponentially rather than linearly as drug loading increased. This is because during manufacture, drug particles formed preferentially at the surface of the coatings. Variation in the amount of drug at the surface and drug released were also related to variation in manufacturing parameters, such as evaporation rate. This helped to explain the data provided by the manufacturer and, as a result, different analytical and microscopic techniques were added to the DES (drug eluting stents) guidance document to better understand DES data. Computer modeling successfully simulated these results so that these models may be used in the future to reduce testing and improve the regulatory evaluation of medical devices. This scientific understanding significantly increased efficiency in processing a large number of submissions.
Intraocular Lenses. (Materials Performance Laboratory)
Intraocular lenses (IOLs) are medical devices used to replace the function of the natural crystalline lens after the onset of a cataract or other medical condition renders the natural lens opaque. For some classes of the materials used in IOLs, medical practitioners performing follow-up slit lamp examination noted “glistenings” within the IOLs that were caused by scattering from inclusions in the material not present at the time of implantation. While there have been few reports of clinical symptoms, there is concern that if the number and size of these defects (vacuoles) were to increase, the visual acuity of the patient would be impacted.
OSEL scientists began research to develop a general understanding of the physical phenomena underlying the formation of vacuoles (defects) in IOLs and to develop a laboratory test method for determining the propensity of IOLs to form vacuoles. They found that vacuoles are water-filled cavities, whose growth is driven by osmotic pressure differences between the aqueous solution within the cavities and the external media. The scientists developed models for both the rate and extent of cavity growth, and found that these models are consistent with the experimental observations and suggest that the impurity species responsible for cavitation and vacuolar growth are hydrophilic oligomers generated during polymerization.
A protocol framework has been developed for comparing the propensity for vacuolar formation in new IOLs with existing IOL materials, for which there is no available clinical experience. This method may be useful in determining the level of rigor needed for measuring the performance of IOLs in clinical trials. The scientific results of this project have been published as a peer-reviewed journal article, and regulatory results have been communicated to the Technical Review Committee and to relevant staff in the Office of Device Evaluation, CDRH.
Nonconforming Imported Titanium. (Active Materials Laboratory)
In the spring of 2009, a device manufacturer observed difficulties when attempting to process specific lots of a titanium alloy (Ti64) that is widely used in medical devices. These difficulties were attributed to microstructural anomalies present in the material that did not conform to the material specification. The impacted lots of material were all traced to Dalian Sunny Mill in China. In response to this information, a CDRH-wide team was assembled, led by the Office of Compliance, to assess the scope and potential ramifications of the affected material. Team members included OSEL engineers from both the Division of Solid and Fluid Mechanics and Division of Chemistry and Materials Science.
Based on their expertise and assessment of available data, the OSEL engineers helped draft a letter that was distributed to device manufacturers in September 2009 to inform them of the problem and offered guidance as to identifying any nonconformities in their material. The letter also outlined additional material evaluations that would assist the Center in identifying the potential risk to patients if nonconforming material was used to produce a device. Further, once details about the nonconforming titanium alloy became available publicly, OSEL engineers collaborated with the relevant stakeholders in the ASTM International metallurgical materials subcommittee to assess the cause. The consensus is that the root cause of the nonconforming material was due to lack of adequate process control during the melting of the alloy and that this is something that cannot realistically be evaluated by inspecting the material after it is produced; rather it needs to be addressed through the melter's Quality Systems and process control.
Semantic Analysis. (Software Engineering Laboratory)
The Center for Devices and Radiological Health (CDRH) maintains regulatory data in its archives, including data from pre-market submissions and post-market adverse event reports. Given this vast amount of historical data, FDA regulators would like to have the ability to analyze the various data repositories and identify signals or trends that may pose a risk to public health.
Scientists at the Division of Software and Electrical Engineering (DESE) have been investigating the use of semantic analysis to provide automated analyses of textual data contained in various regulatory documents. Semantic analysis is a novel data mining approach that provides the theory and methods for extracting and representing contextual-usage meaning of words by statistical computations applied to a large corpus of text.
The research performed involved developing a prototype search and retrieval framework for semantic analysis of regulatory data. The aim of the research was to provide signal detection, relational analysis and predictive analysis for analysts in CDRH. The prototype framework comprised of three distinct functionalities: an indexing utility to extract text from various documents and store them in a local repository; a set of heuristics and rules to mine the data stored in the repository; and a user interface front-end for searching and reporting the results of data analyses. A major challenge here was to extract data in a meaningful consistent manner from across different document formats, including PDF, Microsoft Word, rich text, HTML and XML.
As a pilot study, the prototype framework was used to mine adverse events related to a device failure involving a specific product. The root cause of the failure pointed to tears in a key component fabricated from a proprietary nylon material. Investigators wanted to quickly determine other medical devices that might incorporate the same material. Our application searched over 3.25 million documents across various databases, and identified 18 documents that indicated the use of the same material in other products. On the basis of this finding, a more detailed analysis was carried out by CDRH analysts to assess the risks of using this material in the products identified.
Following on the success of the pilot application, OSEL/DESE scientists are working on extending the prototype framework to provide an automated semantic analysis capability to CDRH analysts. Efforts are currently underway to scan, index, and store an ever-growing corpus of millions of documents on a daily basis.
Study of the Reliability of Computational Fluid Dynamics for Regulatory Decisions. (Fluid Dynamics Laboratory)
Computational fluid dynamics (CFD) is routinely used to develop complex blood-contacting medical devices, such as ventricular assist devices, or VADs. Current computer software is able to simulate both the solid and fluid mechanics of a device, the transport of blood elements, and the transport and reactions of chemical species. New methods are also being developed to compute levels of hemolysis and thrombosis from the local fluid dynamics derived from simulations. The advantages of computations are that they are cheaper and easier than bench measurements, especially those using blood. However, using CFD to demonstrate product safety in FDA pre-market device applications and post-market investigations has not been adequately validated.
To advance the use of CFD in medical device evaluations and to assess its limitations, researchers initiated an inter-laboratory project among academia, industry, and the FDA. OSEL staff formed a technical steering committee to guide the CPI blood-damage project, comprised of researchers experienced in both CFD and bench experiments. In collaboration with this committee, a nozzle model was developed having features common to medical devices that was, nevertheless, simple enough where CFD analyses could be readily performed and meaningful comparisons could be made. Participants from 28 different groups from 6 countries submitted velocity and blood damage predictions. These results were validated against measurements made using quantitative flow visualization on physical models in three independent laboratories.
OSEL provided the experimental data to the participants so that they could replicate part of the study to help identify best practice guidelines for using CFD. A second inter-laboratory study performed on a simplified VAD model will also be conducted soon. These studies will provide benchmark flow data for developing and improving guidelines and standards for the use of CFD in the evaluation of medical devices.
Image Acquisition and Analysis (Imaging Analysis Laboratory)
OSEL/DIAM scientists, funded by the FDA Critical Path program, have been evaluating image acquisition and image analysis procedures to facilitate the use of CT imaging for lung cancer screening and tumor therapy evaluation by quantifying the impact of numerous CT acquisition parameters and data analysis approaches on the accuracy and precision of tumor size estimates. As part of this project, numerous CT scans of an anthropomorphic thorax phantom have been collected. This anthropomorphic phantom contains realistic anatomy including vasculature structures within the lung region. Simulated lung nodules of various shapes, sizes, and densities have been embedded within the phantom's lung vasculature to allow for the collection of CT scans of lung nodules within realistic lung backgrounds.
One of the goals of this project is to make this CT data available to the public for other research. To date, over 4000 multi-detector CT (MDCT) datasets have been collected across a range of imaging protocols for multiple nodule configurations placed within the anthropomorphic phantom. An initial data set of over 1000 scans was released 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
). This FDA CT phantom data has already been utilized in a number of outside projects including a study conducted by the Quantitative Imaging Biomarker Alliance (a collaborative group of the Radiological Society of North America), NIST's Biochange challenge and the Volcano '09 (Volume Change Analysis of Nodules) effort. OSEL/DIAM expects the utility of this data set and its public use to grow further in 2010, especially after the release of additional CT data of more complex non-spherical nodules in early 2010. This new data will also be available for direct download through the National Biomedical Imaging Archive.
New International Standard for Testing Image Display Systems. (Imaging Physics Laboratory)
A new international Standard providing evaluation methodologies for testing image display systems in medical diagnostic imaging equipment was published in December 2009 through IEC (62563-1). This document provides the first standardized set of test methods for assessment of display image quality in the area of diagnostic imaging, as well as for the specifications of the instrumentation required to perform the tests. This Standard will allow FDA Sponsors to describe the properties of display devices associated with imaging equipment with consistent and well-defined methodologies. An OSEL scientist in the Division of Imaging and Applied Mathematics designed and wrote several of the test methods in the Standard, contributed the section related to instrumentation required to test displays, and evaluated most of the proposed test methods in his laboratory as part of the consensus development effort. The scope of this document is restricted to display systems for grayscale images. An amendment for the display of color images is now being formulated, led by the author of the test methods.
Postmarket Study of Cutaneous Transilluminators (Optical Diagnostics Laboratory)
Office of Surveillance and Biometrics (OSB) staff noted that several reports to MedSun identified skin burns produced by neonatal and adult transilluminators. In order to better understand the cause of these burns and the potential risk of these devices, OSB staff requested OSEL perform a bench study on the levels of heat produced by commercially available devices. OSEL staff performed a study of the optical and thermal output of six transilluminator models based on various types of light-emitting diodes (LEDs). Due to a lack of established test methods, OSEL Division of Physics (DP) and Division of Electrical and Software Engineering (DESE) staff performed measurements adapted from consensus standards for similar devices, with some necessary modifications.
Broadband and spectrally resolved radiometric measurements were performed as well as transient temperature-rise measurements with thermocouples. The findings of these investigations indicated that devices based on red and orange LEDs tended to produce levels of heat and light that were well below safety limits. White light LEDs, however, tended to produce significantly greater levels of heat and light. The predominant source of temperature rise was found to be heat generation within the transilluminators rather than absorption of emitted light by tissue. Although optical and thermal outputs of two white light LED-based BPTs were significant, they were not found to exceed levels expected to cause injury under normal conditions.
The conclusion of this study was that the MedSun reports were due to malfunctioning devices and that properly functioning devices would not be expected to cause burns during typical short-exposure use. However, this research brought to light potential safety risks associated with new LED-based devices that have increasingly high power levels and indicates the need for improved knowledge regarding burn susceptibility in neonates and other potentially “at-risk” groups. This study was recently accepted for publication in a peer-reviewed journal, which will help to increase awareness of these issues in the biomedical engineering community [Pfefer et al., Physics in Medicine and Biology, 54:6867-6880, 2009].
Infection Control (Biological Risk Assessment Laboratory)
Two different multipurpose contact lens solutions (MPS) for soft contact lens have been implicated in ocular infections (Fusarium and Acanthamoeba) in users of soft contact lens and were recalled and removed from the market. These infections are serious as they can lead to blindness. The present ISO standard 14729 to test the microbicidal efficacy of MPS against bacteria and fungi does not require the presence of the lens in a case with the MPS. Earlier studies (Warburton et al. 2007) showed that the concentration of the disinfectant Alexidine in MPS was reduced by the presence of a soft contact lens and hence less microbicidal efficacy against Fusarium. In 2009, in collaboration with WEAC, researchers in the Biological Risk Assessment laboratory presented a poster that illustrated that one type of lens reduced the concentration of polyhexamethylene biguanide (PHMB) in MPS and also had reduced microbicidal efficacy against S. aureus (Clavet et al. 2009). The work also entailed developing a new method to measure very low concentrations (less than 1 ppm) of PHMB in MPS (Lucas et al. 2009). Researchers have continued examining four new types of soft contact lens and observed that the concentration of PHMB decreases, in some instances significantly, over time when a contact lens is added to a polypropylene lens case filled with MPS + PHMB. Microbicidal efficacy against S. aureus decreases over time in the presence of some lens as early as 6 hours after soaking, compared to controls. The results of these studies on seven soft contact lens and one conventional hydrogel lens will contribute to the revision of ISO 14729 and the FDA 510(k) Guidelines for Contact Lens Care Products, May 1, 1997, for contact lens.
Analysis of polyhexamethylene biguanide (PHMB) in Multipurpose Contact Lens Solution (Biological Risk Assessment Laboratory)
PHMB has been approved for use by the U.S. Environmental Protection Agency and has been declared a low-risk product, except for workers in the drilling industry who handle drilling muds and work-over fluids. It has been applied to swimming pool water and used in many products such as personal care, cosmetics, fabric softeners, and contact lens solutions, to name a few. It is also applied to medical utensils and equipment as a disinfectant. For the general public at the levels normally encountered, it is a safe chemical.
Scientists in the Biological Risk Assessment laboratory published the results of their research on developing a method based on High Performance Liquid Chromatography (HPLC) with evaporative light scattering detection (ELSD), which overcomes the sensitivity limitations of other methods. The researchers examined commercial multipurpose contact lens solutions bought locally. Six contained PHMB, two contained hydrogen peroxide and one contained the preservative Polyquad, a polymeric quaternary ammonium compound. The HPLC-ELSD method for measuring PHMB in multipurpose contact lens solutions was found to be simple and reliable and has an adequate detection limit for this medium. The detailed article can be found in the publication Talenta 2009, 80:1016-1019.
Investigation of Coring Huber Needles (Solid Mechanics Laboratory)
CDRH’s device reporting system received reports that Huber needles were coring an implanted port. The OSEL Division of Solid and Fluid Mechanics (DSFM) engineers examined the report and concluded that that there was a potential public health concern. DSFM tested and examined the reported needles and found inconsistencies; then expanded the laboratory investigation to determine if these inconsistencies were limited to a single manufacturer, a single lot, or if there was a common issue across the market for this product.
Huber needles from 10 manufactures were bench-tested for coring using intravascular access ports from 5 manufacturers. The majority of the tested needles performed as they should; that is, they perforated the port septa without creating cores. The coring tests and the subsequent cross-sectional microscopic analysis revealed that the most important needle characteristic associated with coring is the rear cutting edge of the lumen at the bevel, better known as the heel edge of the needle. Heel edges that are plastically deformed towards the lumen, providing a dull heel edge, resulted in non-coring behavior. Manufacturing processes which dulled or rounded the heel prevented coring. In contrast, omitted or inadequate steps to alter the sharp heel after bevel grinding produced a sharp heel that cut cores during the testing. DSFM noted inconsistencies in the degree of dulling or rounding of the heel among the products tested. For one manufacturer’s product, all the Huber needles tested had sharp heels and produced cores. For another, some of the needles tested had sharp heels that were associated with cores. OSEL engineers and other FDA personnel have worked with the manufacturers to resolve these problems. FDA also issued a Class 1 recall of more than 2 million Exel Huber needles after the manufacturer’s testing showed that between 60% and 72% of the needles from affected lots produced cores.
To prevent coring needles from entering the market as a result of manufacturing flaws, optical inspection of the heel edge and coring testing should be performed as part of routine quality control. Optical microscopic inspection of the heel edge should verify that the edge has been plastically deformed or dulled. The coring test should minimally include an optical microscopic inspection of the needle lumen to determine coring after septum puncture. Additionally, the material properties of the septum used for the coring test should represent those material used for port septa, with which the needles are intended to be used.
Progress in Developing the Scientific Infrastructure for Evaluating High Intensity Ultrasound Devices (Ultrasonics Laboratory)
CDRH is seeing an increasing number of submissions for high intensity focused ultrasound (HIFU) devices, an emerging technology that holds promise for non- or minimally invasive surgery to ablate benign or malignant masses without damage to surrounding tissue. In the absence of guidance and standards documents for these devices, the Ultrasonics Laboratory has undertaken several studies to help expedite the regulatory reviews, especially in the pre-clinical phase.
1. Cavitation, the formation and collapse of small gas bubbles, 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 treatment time. So, the occurrence and effect of cavitation needs to be well understood in order to evaluate the safety and effectiveness data generated in pre-clinical studies. OSEL scientists in the Division of Solid and Fluid Mechanics monitored cavitation behavior using several different techniques, including B-mode imaging and hydrophones, and determine its effect on temperature rise in a HIFU tissue-mimicking material (TMM) containing an embedded thermocouple. The results of this investigation were presented at the 9th International Symposium on Therapeutic Ultrasound in September 2009.
2. In clinical applications of HIFU, the absorption of acoustic energy by bone is an important safety factor. The high acoustic absorption of bone can lead to large temperature rises near the surface of the bone and potential damage to nearby sensitive tissues. Therefore, a study was performed 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. A paper describing this work was published in the Journal of the Acoustical Society of America.
3. An important component of the pre-clinical review process is evaluating the sponsor's computational models and results for tissue heating. Therefore, laboratory scientists have developed an analytic temperature-mode model for computing the temperature rise in tissue under conditions when nonlinear propagation generates significant higher harmonics, as can occur in HIFU procedures. They also have performed computations to define the threshold at which nonlinear models are required in acoustic propagation simulations. A paper describing this work was published in the Journal of the Acoustical Society of America.
These investigation results are being used by Center staff in evaluating pre-clinical studies of the heating capabilities of HIFU devices and also in setting treatment protocols. Further, the findings of the nonlinear study will be useful in guiding manufacturers as to when nonlinear (and typically more complicated and expensive to use) models are required and when linear models are adequate for evaluating pre-clinical designs and establishing clinical procedures.