Ultrasound-Based Device to Guide Treatment of Graft-Versus-Host-Disease using Skin Elasticity as a Biomarker 1 ABSTRACT Sclerotic chronic graft versus host disease (cGVHD) develops in 30 - 70% of allogenic Human Stem Cell Transplant (HCT) recipients and is associated with significant morbidity and mortality. GVHD is treated with immunosuppression, which puts patients at severe risk of infection. Immunosuppression must therefore be delivered judiciously to obtain the therapeutic effect while minimizing dose, but current clinical instruments for quantifying cGVHD provide an incomplete picture and are not sensitive enough to predict outcome or response to therapy[1], [2]. Currently, there is no standard device used to measure skin sclerosis in clinical practice. Indeed, the NIH Chronic GVHD Working Group has stated that: ?There is an urgent need for the development of more quantifiable and reproducible measurements or imaging methods that could be used in patients with sclerotic skin manifestations of chronic GVHD?[3] Our team includes the inventors of ultrasound-based methods for measuring the elasticity of tissue[4], which we have demonstrated to distinguish healthy skin from sclerotic in preliminary clinical studies using our research platform[5]. We have invented a specific type of elasticity measurement called Constructive Shearwave Interference (CSI), optimized for use in portable, point-measurement systems without the complexity and cost of full-scale clinical imaging systems, and with features to improve estimates in highly sclerotic skin over previous methods. In Phase I, we built the first dedicated CSI transducers and systems, developed the software and algorithms to quantify the elasticity of thin-layered media, and characterized their performance in tissue-mimicking elastic phantoms. We demonstrated that all of the necessary ultrasound electronics could be built into a single device, controlled by USB. We have benchmarked the performance of these devices with simulations and experiments and designed and built a system for assisting with positioning the transducer a fixed distance from the skin and detecting proper alignment. In summary, the progress we have made in Phase I to answer critical feasibility questions has us well-positioned for success in Phase II. In Phase II, we propose to prepare our prototype devices for use in a clinical study by developing important features and performing critical safety analysis and testing, both in the context of this study, and in preparation for submission to the FDA. Based on findings of the simulations and experiments, we also propose to develop advanced algorithms for robust estimation of skin properties, including automatic detection of skin thickness. This leads up to our major goal, which is to perform a clinical study to test our technology?s reliability at identifying disease severity in comparison to invasive gold-standards. With successful completion of the tasks proposed in Phase II, we will be prepared to launch the device onto the market in Phase III, paving the way for precision delivery of immunosuppression to cGVHD patient, and establish a platform for further research and commercialization efforts across a broader range of applications. 1
Current methods of evaluating sclerotic skin manifestations of chronic Graft-Versus-Host-Disease (cGHVD) are insufficient for staging the disease and monitoring treatment response, impacting clinical care for allogenic stem cell transplant recipients. We have developed a novel ultrasonic method of characterizing skin elasticity noninvasively, which early work indicates could be used to quantify the onset and progression of cGVHD. In phase I, we built the first integrated prototype device to use this technology and tested its performance in tissue-mimicking phantoms. In phase II, we propose to continue development of the hardware and software, and to test our enhanced device in a clinical study with patients who have cGHVD and other sclerosing skin disorders. 2
