Bio-enhanced ACL Repair as a Modular of Post-traumatic Osteoarthritis

描述（由申请方提供）：本次竞争性更新的总体目标是使用ACL损伤和“生物增强”ACL修复的新型大平移模型来鉴定创伤后骨关节炎（PTOA）的关键调节剂。在上一个资助周期中，我们用我们的实验模型证明了加速的PTOA发生在ACL损伤后，甚至在ACL重建后，目前的护理标准是用肌腱移植物代替受伤的韧带。我们确定，我们的“生物增强”ACL修复新技术，其中使用生物工程支架修复受伤的韧带以刺激愈合，不仅有效地愈合韧带，而且还防止ACL损伤后PTOA的发生。这种对软骨的治疗作用背后的机制是未知的，也是该提案的重点。随着上一个资助周期中开发的转化实验模型，我们现在准备使用差异系统生物学方法来比较未开发PTOA的受试者（即，用生物增强ACL修复治疗的那些）与用生物增强ACL修复治疗的那些（即，那些接受传统ACL重建治疗的患者），以确定发生PTOA的膝关节与未发生PTOA的膝关节之间的关键生物学、结构和生物力学通路。这项研究的具体目标是：1）鉴定在损伤后1、4、12、26和52周时，与经历ACL横断随后常规ACL重建的个体相比，经历ACL横断随后生物增强ACL修复的个体的关节中细胞因子、细胞外基质（ECM）相关蛋白质谱和步态不对称性的差异，和2）确定损伤后1、4和52周滑膜关节内细胞因子和ECM相关蛋白表达的来源。这两个目标都将利用我们的ACL横断、ACL重建和生物增强ACL修复的充分表征的实验模型。目标1（纵向评估）的主要结局指标是滑液中细胞因子、MMP、胶原蛋白和聚集蛋白聚糖片段的浓度，以及步态站立阶段期间地面反作用力峰值的比值。目标2（横断面评估）的主要结局指标是滑膜、韧带和关节软骨中细胞因子的基因表达测定以及软骨健康的宏观（改良外桥评分）和组织学评估。在这项研究完成后，我们将更好地了解生物增强ACL修复的软骨保护作用，为其他创伤性关节损伤的治疗干预建立上游目标，并准备将生物增强修复技术转移到临床使用。

DESCRIPTION (provided by applicant): The overall objective of this competitive renewal is to identify the key modulators of post-traumatic osteoarthritis (PTOA) using a novel large translational model of ACL injury and "bio-enhanced" ACL repair. In the last funding cycle we demonstrated with our experimental model that accelerated PTOA occurs following ACL injury and even after ACL reconstruction, the current standard of care in which the injured ligament is replaced by a tendon graft. We determined that our novel technique of "bio-enhanced" ACL repair, where the injured ligament is repaired using a bio-engineered scaffold to stimulate healing, not only effectively heals the ligament, but also prevents the onset of PTOA after ACL injury. The mechanisms behind this therapeutic effect on cartilage are unknown and the focus of the proposal. With the translational experimental model developed in the last funding cycle, we are now poised to use a differential systems biology approach to compare subjects that do not develop PTOA (i.e., those treated with bio-enhanced ACL repair) with those that do (i.e., those treated with conventional ACL reconstruction) to determine key biological, structural and biomechanical pathways that are different in knees which are developing PTOA from those that are not. The specific aims of the study are: 1) to identify differences in cytokine, extracellular matrix (ECM)-associated protein profiles and asymmetries in gait in the joints of individuals undergoing ACL transection followed by bio-enhanced ACL repair compared to individuals undergoing ACL transection followed by conventional ACL reconstruction at 1, 4, 12, 26 and 52 weeks after injury, and 2) to define the source of cytokine and ECM-related protein expression within the synovial joint at 1, 4, and 52 weeks after injury. Both aims will take advantage of our well- characterized experimental model of ACL transection, ACL reconstruction and bio-enhanced ACL repair. The primary outcome measures for Aim 1 (longitudinal assessments) are the concentrations of the cytokines, MMPs, and collagen and aggrecan fragments in synovial fluid, and the ratio of the peak ground reaction force during stance phase of gait. The primary outcome measures for Aim 2 (cross-sectional assessments) are the gene expression assays of cytokines in the synovium, ligament and articular cartilage and macroscopic (modified outerbridge score) and histological assessments of cartilage health. At the completion of this study we will better understand the chondroprotective effects of the bio-enhanced ACL repair, establish upstream targets for therapeutic intervention for other traumatic joint injuries, and be poised to transfer the bio-enhanced repair technology for clinical use.