Ultrasound-Based Device to Guide Treatment of Graft-Versus-Host-Disease using Skin Elasticity as a Biomarker

基于超声的引导装置 移植物抗宿主病的治疗 用皮肤弹性作为生物标记物 1摘要 硬化性慢性移植物抗宿主病(CGVHD)发生在30-70%的同种异体人类干细胞中 与移植(HCT)接受者有关，并与显著的发病率和死亡率有关。GVHD的治疗方法是 免疫抑制，使患者面临严重的感染风险。因此，免疫抑制必须是 明智地给予，以获得治疗效果，同时最大限度地减少剂量，但目前的临床仪器 量化cGVHD提供了一幅不完整的图景，而且不够敏感，无法预测结果或反应 治疗[1]、[2]。目前，临床上还没有用于测量皮肤硬化度的标准仪器。 练习一下。事实上，美国国立卫生研究院慢性GVHD工作组已经表示：“迫切需要 开发更可量化和可重复性的测量或成像方法，可用于 慢性移植物抗宿主病皮肤硬化症患者“[3] 我们的团队包括基于超声波测量组织弹性的方法的发明者[4]，这 我们已经在初步的临床研究中展示了区分健康皮肤和硬化皮肤的方法 研究平台[5]。我们发明了一种特殊类型的弹性测量方法，称为建设性 横波干扰(CSI)，优化用于便携式、点测量系统，无需 全尺寸临床成像系统的复杂性和成本，并具有显著改善估计的功能 硬化性皮肤优于以往的方法。 在第一阶段，我们构建了第一个专用的CSI换能器和系统，开发了软件和算法来 量化薄层介质的弹性，并表征它们在模拟组织弹性方面的性能 幻影。我们证明了所有必要的超声电子设备都可以内置到一个设备中， 由USB控制。我们已经通过模拟和实验对这些设备的性能进行了基准测试 并设计和构建了辅助将换能器定位到与皮肤固定距离的系统 正在检测正确的对准。总而言之，我们在第一阶段回答关键可行性方面取得的进展 问题为我们在第二阶段取得成功做好了准备。 在第二阶段，我们建议准备我们的原型设备用于临床研究，通过开发重要的 在本研究的背景下和准备工作中，进行关键的安全分析和测试 提交给FDA。基于模拟和实验的结果，我们还建议开发 用于稳健估计皮肤属性的高级算法，包括皮肤厚度的自动检测。 这导致了我们的主要目标，即进行一项临床研究，以测试我们技术的可靠性 与侵袭性黄金标准相比，确定疾病严重程度。 在成功完成第二阶段建议的任务后，我们将准备将该装置发射到 第三阶段的市场，为向cGVHD患者精确输送免疫抑制药物铺平道路，以及 为更广泛的应用领域的进一步研究和商业化努力建立一个平台。 1

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