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OSEL 2007 Laboratory Accomplishments

Biological Risk Assessment (Division of Biology)

Optimize the technical assay conditions for the renal toxicity chip

Research indicates some initial success in developing a custom chip that can detect changes in gene expression in cells shed into urine following acute kidney injury. We hope to optimize the technical assay conditions in FY 08. This new scientific tool is likely to result in a product that will directly benefit patients.

Develop a guidance document on the use of renal biomarkers for preclinical evaluation of medical devices

One of the markers we evaluated last year with our collaborators at Harvard University, kidney injury molecule-1 (KIM-1), is found to have high prognostic value based on the statistical evaluation performed by the Preclinical Safety Testing Consortium (PSTC). This qualification effort is expected to play an important role in determining regulatory acceptance of this renal biomarker and others for use in preclinical studies evaluated by CDRH and CDER. Our goal in FY 08 is to expand this analysis to evaluate the ability of renal biomarkers other than Kim-1 to serve as indicators of acute renal injury in preclinical studies and to prepare a guidance document with colleagues in CDRH/ODE on how to use these data in preclinical biocompatibility assessment.

Biomolecular Mechanisms (Division of Biology)

There has been substantial progress in determining the effect of hyaluronic acid (HA) samples of different molecular weights on RAW 264.7 inflammatory nitric oxide response to specific amounts of endotoxin +/- gamma-interferon. Several samples of HA were assayed for their endotoxin levels using the kinetic chromogenic limulus lysate assay. No direct effect of HA on the macrophage cell line has been observed; however, the endotoxin response of RAW 264.7 is under some circumstances increased---and more so if interferon gamma is present. These early data in the project agree with preliminary pilot experiments that HA may be enhancing ongoing inflammatory responses but may not be directly causing inflammation.

Electromagnetic and Wireless Technologies (Division of Physics)

The Electromagnetic and Wireless Laboratory initiated new work on laboratory measurements and computer modeling of the currents induced in medical implants by the intense pulsed magnetic fields from gradient coils of MRI systems. The implants of interest are electrically conductive leads for implanted pacemaker/defibrillators and spinal or brain stimulators. The leads are in the bodies of patients who would be prescribed MRI imaging studies. This work is highly relevant since implanted device manufacturers are now developing MRI-compatible versions of their products and will seek pre-marketapproval from FDA. A literature search revealed that this work is unique and has not been studied or published by other organizations. It is completely different from the well-known MRI heating effect on implanted leads that is induced by RF fields of MRI systems.

  • Developed new or improved several techniques for assessing MR safety--specifically the RF-induced voltages at the tips of leads of implanted medal devices by the intense low frequency MRI gradient fields. This work included measurement techniques and computational modeling.
  • MRI RF induced heating. The findings of the FDA-directed international intercomparison demonstrated that ASTM and other standard test methods for MRI heating of medical implants are highly flawed. Heating depends on the specific MRI clinical system, the patient-simulating phantom, and the lead location.
  • Measured the magnetic field produced by iPod music players and attempted to detect any voltages these fields might produce within the protective “can” of a pacemaker placed inside a simulated human torso. Results of our tests concluded that no interference effects can occur in pacemakers exposed to the iPods. These results were published in the online journal Biomedical Engineering Online.

Electrophysiology and Electrical Stimulation (Division of Physics)

  • Established an in-vitro system for applying mechanical stretch at different phases of the cardiac excitation cycle. This system is being used to examine timing of cardiac electric pulses in relation to the mechanical cycle, and how arrhythmias are generated by these phase relationships.
  • Adopted porcine model of heart failure for gender-related studies. This is the initial part of our research for the Office of Women’s Health that is developing female-specific animal models for heart failure. We measure calcium signaling in this model and are in the process of establishing a transmural wedge preparation to examine arrhythmogenesis in this model.
  • Designed and tested, in collaboration with the Italian National Institute of Health, an arbitrary waveform defibrillator. This is being used to determine the maximum safe duration of biphasic shocks used in Automatic External Defibrillators (AEDs). It is to meet a specially requested objective to determine the safe limit of shock duration, which is in-preparation for device submissions for a new generation of defibrillators.
  • Published a journal paper that delineates the types of interactions that occur between cardiac stimulation devices and cardiac medications (Krauthamer, 2007). This paper points to important factors to consider during clinical trials during which all possible drug-device interactions cannot be tested.
  • Developed biomarkers for safe retinal stimulation and included anatomical markers (propidium iodide exclusion) and functional markers (ganglion cell firing). Also published reviews on methods for prosthetic stimulation of the human visual system.

Fluid Dynamics (Division of Solid and Fluid Mechanics)

  • Formed a collaboration with three universities to help design and fabricate the necessary flow models; performed preliminary computational simulations and flow visualization on the models; developed an FDA website to publicize the project; and worked with scientific organizations (e.g., the American Society for Artificial Internal Organs and the American Society of Mechanical Engineers Biofluid’s Group) to recruit participants for the round-robin evaluation.
  • Received approval from FDA’s Human Use Committee and NIH’s Blood Research Donor Program to begin blood damage testing using human blood. A single-pass orifice system was used to investigate the fragility of human blood for comparison to that of bovine blood. This is important since most in vitro testing is performed on animal blood and the relationship to human blood is not established.The geometry of the single-pass orifice system was reproduced in a computational fluid dynamic simulation program to meet the program objective of correlating shear force exposure to actual blood cell damage (hemolysis and platelet activation).
  • Established experimental protocols for assessing platelet activation with flow cytometry, whole blood aggregometry, platelet counting, and ELISA analysis.
  • A CRADA (#128-07) was completed and signed by Epicor St. Jude Medical and FDA in April 2007.
  • Epicor heart ablation transducer (HAT SN GGDY) was characterized for velocity profiles at 10, 15, 20, 30, and 40 V rms and for several transducer locations of midline, rear line, and frontline. The new differentiation numerical algorithm will be used on this data to predict the 3D acoustic intensity distribution.

Image Analysis (Division of Imaging and Applied Mathematics)

  • IHC sub-project: IHC sub-project: Finished the first stage of the HER2 CAD algorithm development. This study has been submitted for publication, and the work will be presented at ISBI 2008.
  • IHC sub-project: Defined protocol for reader study experiment to assess both intra- and inter-reader variability
  • Investigated the impact of patient-based and location-based assessment methods on the impact of reading mode on clinical utility. This study showed that selecting different assessment methodologies can lead to conflicting study conclusions. This work was presented at SPIE 2008.
  • Completed data collection for all of the attached spherical nodules of densities -800 HU, -630HU and +100HU and are receiving requests for use of the data by outside groups.
  • Completed initial assessment of a single software tool for measuring nodule volume and presented at SPIE 2008.

Imaging Diagnostics (Division of Imaging and Applied Mathematics)

  • Extended computer simulation activity via the incorporation of the PENELOPE code, through collaboration with one of the developers of this code, Dr. Josep Sempau of the Institut de Tecniques Energetiques, Universitat Politecnica de Catalunya in Barcelona, Spain. This accomplishment enables the combined x-ray/electron/optical simulation of radiation detection at the full energy range of interest in radiological imaging.
  • Developed methods for the automated, quantitative evaluation of imaging phantoms for use in the objective assessment methods for digital radiography. These methods were validated using both a laboratory imaging system in DIAM as well as a clinical mammography unit at USUHS.
  • Developed method and graphical interface software to run viewing angle observer studies using Tcl/Tk.
  • Conducted experimental and computational observer studies of viewing angle effects.
  • Developed a feature extraction method for a linear imaging system for use in efficient computation of ideal-observer performance.
  • Developed efficient computation tools for ideal-observer based performance metrics in detection tasks involving non-Gaussian, randomly varying backgrounds.
  • Developed the first set of physical breast phantoms that consist of PMMA balls with different sizes and different densities for use in validation of simulation tools and evaluation of 3D breast imaging systems.

Optical Diagnostics (Division of Physics)

  • Validated a novel multi-wavelength optical property measurement system.
  • Performed extensive measurements in porcine mucosal and liver tissues with fiberoptic probe.
  • Analyzed results to identify the site quantifying the level of natural variations in optical properties and identify significant light absorption components as a function of wavelength.
  • Modification of the OCT system to perform measurements on nanoshell-based phantoms is underway, with measurements to begin in the next few months.
  • Performed initial round of artificial human skin and mucosal tissue. Initial results have not shown significant consistency or expected damage levels.
  • Revised methodology for irradiation, biopsy, and fixation. Results from second round of sample measurements are currently being processed.

Optical Therapeutic and Medical Nanophotonics (Division of Physics)

  • Developed a standard test method for evaluating glare from IOLs to determine which methods can be used to characterize and pinpoint the source of extraneous glare images from intraocular lens implants from point light sources [Landry, RJ, Ilev, IK, Pfefer, TJ, Wolffe, M, and Alpar, JJ, Eye, 21, 1083-1086, 2007, Nature Publishing Group] . The haptic insertion in the optic of three-piece IOL’s has been identified as a source of line glare images. These test methods will be considered for manufacturer and reviewer guidance and for incorporation into national and international IOL standards. This project will also provide laboratory testing to evaluate IOLs and new IOL designs as needed by ODE.
  • Determined in cell culture work the importance of hydrogen peroxide produced inside the cells by the mitochondria. This production of hydrogen peroxide is able to escape the cell producing it and enter other cells thus acting deeper into tissue than just those cells penetrated by light. Understanding biological response to non-ionizing radiation for various light therapeutic devices is important to CDRH. There is growing evidence in the literature showing that “low-level light” exposures can produce positive therapeutic responses to many illnesses, diseases, and injuries. Further investigations have confirmed that catalase, an enzyme reducing hydrogen peroxide to water and oxygen, can scavenger hydrogen peroxide outside the cell and reduce its interaction with other cells. Additionally, we have measurements that show that cell proliferation or inhibition is directly related to the dose of light given.

Software (Division of Electrical and Software Engineering)

Collected usage model state data with the help of a sole-source contractor, in consultation with domain experts. The usage model state transition probabilities were defined and corroborated. The model was implemented with the help of MATLAB Simulink/Stateflow suite, and exhaustively verified for anomalies and inconsistencies. Test scripts were derived for the generic pump model, to be used as a basis for manufacturer software validation.

Toxicology (Division of Biology)

  • Characterized TiO2 particles by dynamic light scattering spectrometry prior to experimental use, and by electron microscopy and energy dispersive X-ray scattering to visualize particles (or aggregates) in tissues after exposure.
  • In vivo studies – Determined the tissue distribution of aggregates, histopathology, the time course of distribution, blood cell changes, and production of inflammatory cytokines. Specific results: 1) route of administration (intravenous vs. subcutaneous) affects tissue distribution; 2) observed a re-distribution but no clearance of clumps of nanoparticles up to 6 months post-exposure; and 3) observed minimal toxic responses to titanium nanoparticles after 6 months exposure.
  • In vitro studies - Increased production of reactive oxygen species and loss of cell membrane integrity was observed at higher TiO2 doses and longer exposure times in cultured J774 macrophage cells. Cytokines released from cells included TNF-a, IL-1b, IL-6, and GM-CSF with increasing dose and exposure time to TiO2. These data suggest macrophage accumulation of TiO2 aggregates may result in cytokine release and potential cytotoxicity in cells and tissues responsible for TiO2 clearance from circulation.
  • Established working collaborations with the University of Florida (tissue silver analysis via ICP-MS) and The George Washington University. Initiated studies of placental transport of silver nanoparticles into mouse embryos after exposure of pregnant dams have been initiated. We have detected silver from treated mice in embryonic tissues and adult tissues.
  • Established working collaborations with University of Maryland and NIST to produce well characterized, sterile, endotoxin-free silicon nanoparticles. Observed apparent intracellular uptake of fluorescent silicon (4-nm) particles by murine macrophage cells, a cell line relevant to measure potential inflammatory responses to particles. Studied effect of particle size on biological effects. Measured tumor necrosis factor-α, interleukin-6, and nitric oxide production by macrophages in the presence of silicon nano- and micro-sized particles.

Ultrasonics (Division of Solid and Fluid Mechanics)

  • Continued collaboration with NIST to provide calibrated transducers and customized radiation force balance (RFB) targets with which we can further calibrate and characterize the RFB system.
  • The Epicor-St. Jude Medical/FDA CRADA (# 128-07) was signed and executed on May 1, 2007. Additionally, a final non-provisional patent was submitted to U.S. Patent office on March 12, 2007, by Epicor-St. Jude Medical. The acoustic streaming characteristics of an experimental heart ablation HIFU transducer (Epicor-St. Jude Medical) were measured in support of the CRADA.
  • Developed measurement protocol for characterizing acoustic intensity distribution from HIFU transducers at high intensities, using acoustic streaming and numerical differentiation methods. Unlike the previous streaming technique, these “direct” methods do not involve iterative numerical algorithms, and are much faster. The direct methods have been validated using the iterative streaming technique as well as hydrophone scanning.
  • Designed, implemented, tested, and documented a general axisymmetric HIFU simulation package for in-house and possibly external use. The package is easy to use and runs in Matlab. It computes pressure, intensity, heating rate, temperature rise, and thermal dose for a broad range of HIFU systems. This is a frequency-domain code suitable for continuous beams and complements the existing short pulse, time-domain “ Texas code.”
  • Initiated efforts to develop analytical models that will characterize the heat source resulting from propagation of acoustic waves in visco-elastic solids. These models will be used in conjunction with acoustic field data from the validated linear wave propagation code (WavePro) and from a nonlinear wave propagation code (KZK) to compute the heat source terms that will be used in the future heat-transfer simulations of HIFU sonications in bone-tissue models.