Biomechanical Simulations of Progressing Osteoarthritis to Advance Understanding and Therapies

该项目的目的是通过利用新的力学和成像实验、体内虚拟人类软骨进化的新模拟以及NIH资助的骨关节炎倡议(OAI)数据库中的多幅膝关节图像，了解组织内应力分布对人类软骨骨关节炎(OA)进展的影响。骨性关节炎是一种滑膜关节疾病，关节软骨变性和丢失是其显著变化。机械应力在疾病的破坏性演变中起着关键作用。软骨的过载(例如创伤)和减少的负载(例如制动)都会导致分子和微观结构的变化，从而导致机械软化、纤颤和侵蚀。最重要的是，目前还没有直接的方法可以将组织内应力的空间分解与个体患者的骨性关节炎进展联系起来。康涅狄格州科学中心女性参与科学倡议的活动将激发STEM对女中学生的兴趣。高中生、本科生和研究生将进行新的实验并建立模拟。主要假设是，组织内应力(例如最大剪应力)与结构定义的骨性关节炎进展的相关性更强，这是通过胶原纤维网络(组织和密度)和总组织体积的变化衡量的，而不是相应的应变。目的1通过测量骨性关节炎人软骨的大剪应力-应变响应，成像相应的细胞活性、成分和微结构，建立描述结构上重要的软骨成分周转的函数，并将这些功能整合到定制的模拟框架中，从而建立体外进化骨性关节炎的化学-生物力学本构关系。目标2通过使用OAI数据建立特定于患者的模型；训练模拟以产生测量的时间进程结果；执行敏感性和统计分析；以及使用更多的OAI患者执行验证研究，来建立和验证体内虚拟人类软骨进化的模拟。这些研究将把身体活动和由此产生的机械刺激与骨性关节炎的进展和软骨功能的丧失联系起来。

The objective of this project is to understand the influence of intra-tissue stress distributions on the progression of osteoarthritis (OA) in human cartilage by leveraging new mechanical and imaging experiments, novel simulations of evolving virtual human cartilage in vivo, and multiple images of the knee from the NIH-funded Osteoarthritis Initiative (OAI) database. OA is a disease of the synovial joint, with degeneration and loss of articular cartilage as one hallmark change. Mechanical stresses play a key role in the destructive evolution of the disease. Both overloading (e.g. trauma) and reduced loading (e.g. immobilization) of cartilage induce molecular and microstructural changes that lead to mechanical softening, fibrillation, and erosion. Crucially, there is currently no direct method to correlate spatially resolved intra-tissue stresses with progression of OA in individual patients. Events with the Connecticut Science Center's Women in Science Initiative will spark STEM interest in female middle school students. High school, undergraduate and graduate students will perform new experiments and establish simulations.The primary hypothesis is that intra-tissue stresses (e.g. maximum shear stresses) will more strongly correlate with structurally defined OA progression measured by changes in both the network of collagen fibers (organization and density) and gross tissue volume, than with corresponding strains. Objective 1 establishes chemo-biomechanical constitutive relations for evolving OA ex vivo by measuring the large-shear stress-strain response of OA human cartilage; imaging the corresponding cell viability, composition, and microstructure; establishing functions describing the turnover of structurally significant cartilage constituents; and incorporating these within a custom simulation framework. Objective 2 establishes and validates simulations of evolving virtual human cartilage in vivo by establishing patient-specific models using the OAI data; training simulations to produce measured time-course outcomes; performing sensitivity and statistical analyses; and performing validation studies using additional OAI patients. The studies will link physical activity, and the resulting mechanical stimuli, to progression of OA and loss of cartilage function.