Matrix Mechanobiology of Ligament Repair

韧带损伤导致关节不稳定，并可能导致慢性关节疾病。这些功能缺陷的根本原因是修复基质的结构质量差。临床结果的改善需要对指导基质结构和功能恢复的物理机制的机械理解。机械模型的开发和验证将支持有针对性的干预措施的应用和设计，如软组织动员，将机械刺激直接应用于重塑基质。本研究的主要目的是描述韧带伤口愈合过程中基质重塑的物理机制。中心假设是伤口愈合期间的机械刺激可以通过增强基质组成和组织来改善韧带修复。为了验证这一假设，将采用实验和计算方法来测量和预测机械刺激对韧带修复组织的结构和功能影响。在目标1和2中，将开发一个计算框架，以预测使用组织等效材料进行机械刺激后的基质重塑。在目标3中，体内实验将验证这种新模型在三维有限元模拟中的预测能力。这项工作产生的两个潜在项目包括设计用于人类受试者的软组织动员方法（临床试验）;以及制定修复过程中机械传导机制的新假设。这可能会提高我们在组织修复过程中指导信号通路的能力，并有助于进一步实现我们的长期目标，即开发用于损伤后快速和完全恢复软组织功能的治疗方法。作为矩阵生物学COBRE的初级研究员，我将与我的科学导师一起完成科学目标，并为未来的R 01资金制定拨款提案。

Ligament injuries cause joint instability and can lead to chronic joint disorders. The underlying cause of these functional deficits is the poor structural quality of the repaired matrix. Improvements to clinical outcomes require a mechanistic understanding ofthe physical mechanisms that instruct the restoration of matrix structure and function. The development and validation of mechanistic models would support the application and design of targeted interventions, such as soft-tissue mobilization, that apply mechanical stimuli directly to the remodeling matrix. The primary objective of this research proposal is to characterize physical mechanisms for matrix remodeling during ligament wound healing. The central hypothesis is that mechanical stimulation during wound healing can improve ligament repair by enhancing matrix composition and organization. To test this hypothesis, an experimental and computational methodology will be employed to measure and predict the structural and functional effect of mechanical stimulation on ligament reparative tissue. In Aims 1 and 2, a computational framework will be developed to predict matrix remodeling from mechanical stimulation using tissue-equivalent materials. In Aim 3, an in-vivo experiment will validate the predictive ability of this new model in a three-dimensional finite element simulation. Two potential projects stemming from this work include the design of soft tissue mobilization methods for use in human subjects (clinical trial); and the formulation of a new hypothesis on mechanotransduction mechanisms during repair. This may improve our ability to instruct signaling pathways during tissue repair, and help further our long-term goal of developing therapies for fast and full restoration of soft-tissue function after injury. As a Junior Investigator in the COBRE in Matrix Biology, I will work with my scientific mentor to complete the scientific aims and to develop a grant proposal for future R01 funding.