William L. Kiser

Thermoacoustic molecular imaging of small animals.

We have designed, constructed, and tested a thermoacoustic computed tomography (TCT) scanner for imaging optical absorption in small animals in three dimensions. The device utilizes pulsed laser irradiation (680-1064 nm) and a unique, 128-element transducer array. We quantified the isotropic spatial resolution of this scanner to be 0.35 mm. We describe a dual-wavelength subtraction technique for isolating optical dyes with TCT. Phantom experiments demonstrate that we can detect 5 fmol of a near-infrared dye (indocyanine green, ICG) in a 1-microL volume using dual-wavelength subtraction. Initial TCT imaging in phantoms and in two sacrificed mice suggests that three-dimensional, optical absorption patterns in small animals can be detected with an order of magnitude better spatial resolution and an order of magnitude better low-contrast detectability in small animals when compared to fluorescence imaging or diffusion optical tomography.

Thermoacoustic CT of the breast

We have completed the design and testing of a thermoacoustic computed tomography scanner for whole-breast imaging. We report on the technical changes in this design form our previous TCT scanner, and how these design changes have improved image quality. Improvements to the design include: greater angular coverage of TCT measurements, increased sensitivity of the ultrasound detector array, and improved delivery of radio wave energy. These improvements resulted in higher fidelity 3D reconstructions, reduced scan time, and fewer image artifacts. These improvements were documented by imaging simple, 3D phantoms, formulated from salinated agar spheres. We confirmed improvements in breast image quality by comparing images of patient volunteers taken with our previous TCT scanner and this new TCT scanner.

Simulation, acquisition and analysis of passive millimeter-wave images in remote sensing applications

We report on the development of a passive millimeter-wave (MMW) imager for remote sensing, and the comparison of the experimentally acquired images with the theoretical images from our MMW scene simulator. The imager has an aperture diameter of 0.6m, and the detector and the imaging optics are mechanically raster-scanned over the scene to form an image. The angular resolution was experimentally found to be 0.4 degrees, which is close to the theoretical diffraction limit of 0.37 degrees, and the imager NEDT was measured to be 0.9 K. Qualitatively, simulated MMW imagery showed good agreement with an experimental MMW image.

Synthesis and Evaluation of Near-Infrared (NIR) Dye-Herceptin Conjugates as Photoacoustic Computed Tomography (PCT) Probes for HER2 Expression in Breast Cancer

We are evaluating PCT imaging in conjunction with NIR dye labeled Herceptin antibody for noninvasive assessment of HER2 expression in tumors. Herceptin was labeled with Alexa Fluor-750 amine reactive dye for characterization of photoacoustic and fluorescence signals. Measurements were performed in solution and after incubation in cultured cell lines that were positive or negative in expression of HER2. The dye to antibody ratio was controlled to achieve a broad range of degree of labeling (DOL = 2 to 15). Photoacoustic signal intensity of Herceptin-dye conjugates in solution increased with increases over the entire DOL range studied. In contrast, fluorescence exhibited significant quenching for higher DOL. In vitro PCT imaging of the labeled HER2 (+) and HER2 (-) cells revealed the targeting specificity of the NIR dye labeled Herceptin. In HER2 (+) cells lines, photoacoustic signal intensity gradually increased with increasing DOL and with increasing number of cells. These results demonstrate that PCT-based measurement of HER2 receptor binding using NIR dye labeled Herceptin is feasible. The absence of a quenching effect with increased DOL advantages this method over traditional methods based on fluorescence measurement.

Thermoacoustic CT of the breast: pilot study observations

In order to assess the potential clinical utility of using thermoacoustic computer tomography (TCT) to image the breast, we conducted a retrospective pilot study of 78 patients. We recruited patients in three age groups (<40,40-50,>50 years). The study population was further segregated into normal and suspicious based on the results of the previous x-ray mammography and ultrasound. Image quality was evaluated qualitatively by consensus of two trained mammographers using a 4-point scale. The appearance of normal anatomy, cysts, benign disease and cancer was noted. Patients were also asked to rate the comfort of the TCT exam and to indicate a personal preference for x-ray mammography or TCT. Analysis of the data indicated that TCT image quality was dependent upon both patient age and breast density, improving with both increasing breast density and decreasing patient age. Fibrocystic disease was well seen, cysts appearing as areas of low RF absorption. Fibroadenomas did not demonstrate contrast enhancement with the exception of one patient with associated atypical hyperplasia. Cancer displayed higher RF absorption than surrounding tissues in 4/7 patients in whom cancer was confirmed, including one patient with a 7-mm ductal carcinoma in situ (DCIS).

Terahertz imaging of burned tissue

There are over 2 million reported burn injuries each year in the United States with 75,000 of these incidents resulting in hospitalization. Current medical imaging modalities have limited capabilities to assess initial burn damage and monitor healing progress. Some of these limitations can be attributed to modality occlusion from bandages, dried tissue and/or blood and inflammation. Since terahertz radiation can see through textiles and bandages1, previous studies2,3 suggested that terahertz radiation, in a reflectance configuration, could be used for non-invasive analysis of tissue thermal damage and healing status. In this study, we perform an analysis of the terahertz absorption and reflection properties of the tissue constituents comprising a wound area, and provide a feasibility assessment of the capabilities of terahertz imaging to provide a clinical tool for initial burn analysis and healing progress.

Modeling passive millimeter wave imaging sensor performance for discriminating small watercraft.

Passive millimeter wave (pmmW) imagers are quickly becoming practical sensor candidates for military and nonmilitary tasks. Our focus was to adapt the Night Vision [U.S. Army Research Development and Engineering Command, Communications and Electronics Research Development and Engineering Center, Night Vision and Electronics Sensors Directorate (NVESD)] passive thermal infrared imager performance models and apply them to pmmW imaging systems for prediction of field performance for the task of small watercraft and boat identification. The Night Vision Labs infrared sensor model has been evolving since the 1950s, with the most current model being NVThermIP [Night Vision Thermal and Image Processing (NVThermIP) Model Users Manual, Rev. 9 (U.S. Army RDECON, CERDEC, NVESD, 2006)]. It has wide recognition as an engineering tool for sensor evaluation. This effort included collecting pmmW signatures for a representative set of targets, conducting an observer perception experiment, and deriving the task difficulty criteria that can be used in NVThermIP for identification of boats. The task difficulty criteria are used by designers and managers to create systems capable of meeting specific performance criteria in the field.

Thermoacoustic in vivo determination of blood oxygenation

We have utilized a prototype Thermoacoustic Computed Tomography Small Animal Imaging System to acquire images of athymic mice with bilateral tumors implanted in the cranial mammary fat pads. The breast tumor cell lines used in the study, which are MCF7, and MCF7 transfected with Vascular Endothelial Growth Factor (VEGF), exhibit distinctly contrasting levels of vascularization. Three dimensional images of the mice, acquired using pulses of NIR stimulating light, demonstrate the ability of the system to generate high resolution images of the vascular system up to one inch deep in tissue, and at the same time, differentiate tissue types based on the infrared absorption properties of the tissue; a property related in part to blood content and oxygenation levels. We have processed images acquired at different stimulating wavelengths to generate images representative of the distribution of oxygenated and deoxygenated hemoglobin throughout the tumors. The images demonstrate the in vivo capabilities of the imaging system and map system structure as well as the total, oxygenated and deoxygenated hemoglobin components of the blood.

Millimeter wave sensor requirements for maritime small craft identification

Passive millimeter wave (mmW) imagers have improved in terms of resolution sensitivity and frame rate. Currently, the Office of Naval Research (ONR), along with the US Army Research, Development and Engineering Command, Communications Electronics Research Development and Engineering Center (RDECOM CERDEC) Night Vision and Electronic Sensor Directorate (NVESD), are investigating the current state-of-the-art of mmW imaging systems. The focus of this study was the performance of mmW imaging systems for the task of small watercraft / boat identification field performance. First mmW signatures were collected. This consisted of a set of eight small watercrafts; at 5 different aspects, during the daylight hours over a 48 hour period in the spring of 2008. Target characteristics were measured and characteristic dimension, signatures, and Root Sum Squared of Targets Temperature (RRSΔT) tabulated. Then an eight-alternative, forced choice (8AFC) human perception experiment was developed and conducted at NVESD. The ability of observers to discriminate between small watercraft was quantified. Next, the task difficulty criterion, V50, was quantified by applying this data to NVESDs target acquisition models using the Targeting Task Performance (TTP) metric. These parameters can be used to evaluate sensor field performance for Anti-Terrorism / Force Protection (AT/FP) and navigation tasks for the U.S. Navy, as well as for design and evaluation of imaging passive mmW sensors for both the U.S. Navy and U.S. Coast Guard.

Electro-optic polymer modulators as passive mm wave detectors

We have developed a first generation of electro-optic polymer modulators, designed specifically for passive millimeter-wave detection. The advantages of utilizing electro-optic polymers for modulator fabrication are their economical and simple fabrication, potential for large scale array fabrication, and well matched RF and optical indices, which provide the potential for an excellent high-frequency response. The current drawbacks of these devices include long term device stability due to oxidation and the relative immaturity of the RF designs for the modulator and interconnects, which lead to unacceptable internal losses and low sensitivity. These are both items we expect remedied in the upcoming year. We provide a brief overview on the opto-electronic method of detecting millimeter waves and our design and fabrication of the polymer modulator. Current measured results for the modulator response at 95GHz are presented and an analysis of the required performance for imaging is presented.