Acoustic evaluation of micro- and macro-steatosis in transplant livers

描述(由申请人提供)：肝移植是终末期肝病患者的主要治疗方法，美国每年进行超过6,000例肝移植。目前有近16,000人在等待名单上，尽管努力扩大捐赠者池，但这一数字预计还会增加。肥胖和糖尿病的流行增加了所需的肝脏移植数量和不使用供体器官，从而加剧了这一问题。脂肪性肝病(肝脏脂肪变性)是移植肝中最常见的不良情况，其中脂肪可分为大泡或微泡。巨泡状脂肪变性被认为是移植肝的主要危险因素，导致原发性无功能和功能障碍，因此可导致器官不使用。从历史上看，被判定脂肪含量高于30%的肝脏被拒绝移植。然而，由于迫切需要扩大捐赠者的群体，被认为是中等脂肪(30%-60%)的肝脏开始被使用。为了有效地利用这些肝脏，需要对脂肪含量进行准确的量化，以促进肝脏与受体的成功匹配。目前， 肝脂肪变性评估的金标准是活检和组织学评估。然而，这种方法是侵入性的，依赖于训练有素的人员，并产生主观结果。虽然已经出现了最先进的成像方法来确定脂肪含量，但这些方法昂贵、耗时长，并且无法区分大泡性和微泡性脂肪变性。为了填补现有诊断工具的空白，超声组织定征方法大有可为。这种方法利用超声波和组织之间的相互作用来识别机械组织属性。虽然这种方法已经被用来从总脂肪含量的角度来表征肝脏组织，但没有一种方法专注于区分微 和大泡囊成分。在这里，我们建议开发、实现和测试这种方法。我们的方法结合了成熟的技术：测量声速和非线性比率B/A预测总脂肪含量，而测量衰减作为频率的函数将使估计微泡脂肪和大泡脂肪的相对组成成为可能。第一个和第二个提议旨在建立一个在传输模式下运行的声学卡尺设备，实现测量和解释B/A、声速和衰减的先进方法，并基于对脂肪乳胶模体和肥猪肝脏的测量来完善这些功能。第三个目标是收集脂肪变性猪肝和拒绝移植的人类供体肝脏的体内和体外声学测量。这些测量的结果将通过与目前用于移植的黄金标准进行比较来进行评估，以证明原则的正确性。我们在华盛顿大学组建了一个声学、组织评估和肝移植领域的专家团队，以及更广泛的移植社区(LifeCenter Northwest)的合作伙伴，以实现提案目标并满足肝移植的主要临床需求。

DESCRIPTION (provided by applicant): Liver transplantation is the primary treatment for patients with end-stage liver disease, with over 6,000 liver transplants performed each year in the U.S. There are almost 16,000 people currently on waiting lists and this number is expected to increase despite efforts to expand the donor pool. The epidemic in obesity and diabetes has contributed to the problem by increasing both the number of liver transplants needed and donor organ nonuse. Fatty liver disease (hepatic steatosis) is the most prevalent adverse condition in liver grafts, wherein the fat can be classified as macrovesicular or microvesicular. Macrovesicular steatosis is considered a primary risk factor in transplanted livers for both primary non-function and dysfunction and can therefore result in organ nonuse. Historically, livers judged to have a fat content higher than 30% were rejected for transplantation. However, due to the dire need to expand the donor pool, livers that are considered moderately fatty (30-60%) are starting to be used. To effectively use these livers, an accurate quantification of fat content will be needed to facilitate successful matching of livers with recipients. At present, the gold standard for hepatic steatosis evaluation is biopsy and histological assessment. However, this method is invasive, relies on highly trained personnel, and produces subjective results. While state-of-the-art imaging modalities have emerged to determine fat content, these methods are costly, time intensive, and unable to differentiate between macro- and micro-vesicular steatosis. To fill this gap in available diagnostic tools, ultrasound tissue characterization methods have promise. Such methods utilize the interactions between ultrasound waves and tissue to identify mechanical tissue properties. While such approaches have been used to characterize liver tissue in terms of total fat content, none have focused on distinguishing micro- and macro-vesicular components. Here, we propose to develop, implement, and test such a method. Our approach comprises a combination of well-developed techniques: measurements of sound speed and the nonlinear ratio B/A predict total fat content, while measurements of attenuation as a function of frequency will enable estimates of the relative composition of micro- and macro-vesicular fat. The first and second proposal aims seek to build an acoustic caliper device operating in transmission mode, implement advanced methods for measuring and interpreting B/A, sound speed, and attenuation, and refine these functionalities based on measurements from lipid-emulsion phantoms and fatty pig livers. The third aim seeks to collect in vivo and ex vivo acoustic measurements from steatotic pig livers as well as human donor livers rejected for transplantation. Results of these measurements will be evaluated to demonstrate proof-of-principle by comparison with gold-standard metrics currently used for transplants. We have assembled a team of experts in the areas of acoustics, tissue evaluation, and liver transplantation at the University of Washington, as well as partners in the broader transplant community (LifeCenter Northwest) to accomplish proposal aims and address a major clinical need for liver transplantation.