Establishing Treatments and Diagnostic Tools for Post-Traumatic OA in Vivo

本项目旨在建立新的治疗方法，以降低睑下垂的风险，并研究新的诊断工具，以确定高风险的睑下垂患者。目标是提供有效的即时临床前信息，以支持这些治疗和诊断工具的临床应用。相关的治疗方法有：1)细胞保护治疗，防止急性软骨损伤部位或附近立即坏死和急性凋亡的软骨细胞死亡；2)软骨细胞代谢增强治疗，通过调节损伤相关的急性炎症反应，改善软骨细胞能量产生，恢复合成代谢功能，抑制分解代谢活动。这些治疗方法将在存活的兔子模型上进行试验。在该模型中，经过可控的手术损伤，复制了导致关节损伤后人类上睑下垂发病的主要因素（即急性关节损伤和对受伤软骨的过度累积机械应力），在相对较短的时间内（8周），实验关节（膝盖）可预见地发生进行性软骨损失。利用这种快速进展性上睑下垂动物模型，我们将测试上述治疗是否能够在体内减轻早期生物介导的上睑下垂疾病过程，以及这些治疗是否能有效减少随后的软骨损失。

This project is designed to establish novel treatments to decrease the risk of PTOA, and to investigate new diagnostic tools to identify patients at high risk of PTOA. The goal is to provide effective immediate preclinical information to support clinical application of these treatments and diagnostic tools. The treatments of interest are: 1) cytoprotective treatment that prevents immediate necrotic and acute apoptotic chondrocyte death at/near a site of acute cartilage injury, and 2) chondrocyte metabolic enhancement treatment developed to improve chondrocyte energy production, to restore anabolic function, and to suppress catabolic activities, by modulating the injury-related acute inflammatory response. These treatments will be piloted using a survival rabbit model. In this model, after controlled surgical insults that replicate major factors contributing to pathogenesis of human PTOA following joint injuries (i.e., acute joint injury and excessive cumulative mechanical stress to the injured cartilage), progressive cartilage loss predictably develops in the experimental joints (knees) in a relatively short period (8 weeks). Using this animal model of rapid-progression PTOA, work is proposed to test if the above treatments are capable of mitigating the early biologically mediated disease process of PTOA in vivo, and whether the treatments effectively decrease subsequent cartilage loss. The diagnostic tools of interest are: 1) MR imaging that visualizes/measures inflammatory anatomical changes and early intra-cartilage degenerative changes prior to cartilage loss, and 2) molecular biomarker analysis that measures whole-joint inflammation and whole-joint cartilage metabolic activity. The diagnostic power of these clinically applicable non- or minimally-invasive tools will be tested in a goat survival model of acute cartilage injury (created by means of precisely controlled blunt impaction insult). Work is proposed to test if these tools are capable of characterizing the severity of acute joint injury in vivo (particularly focusing on cartilage damage), and to test if subsequent progression of cartilage loss in these joints is reliably predictable using the early (< 1 month) information provided by these diagnostic tools.