Molecular engineering of HA-based lubricants for articular cartilage

摘要 关节损伤后关节软骨的润滑改变增加了滑动软骨之间的摩擦力 表面，导致软骨退化，并加速骨关节炎（OA）的发展。关节致OA 损伤，称为创伤后骨关节炎（PTOA），估计占所有OA病例的至少12 在美国，大约一半的前交叉韧带（ACL）损伤患者 无论ACL重建与否，均发生PTOA。补充滑液，从而恢复 关节软骨润滑已被证明对关节有益。拟议的总体目标 这项研究是为了研究软骨粘附，自我修复的透明质酸分子的潜力，以防止或 延缓损伤或创伤后关节软骨的退化，从而延缓骨关节炎。的 分子工程HA基润滑剂被设计成整合透明质酸和 润滑素，滑液的两个关键组成部分，同时表现出自我修复能力。自愈 性能的结合，以确保长期保留和适应性的润滑剂内， 机械活性关节，而软骨粘附性能预计将改善边界润滑。 我们假设，整合HA分子特征的动态软骨粘附分子， 润滑素并同时表现出自愈特性将保护关节软骨， 降低PTOA的进展。为此，我们将：（i）开发软骨粘附，自我愈合的HA分子 并确定分子结构的影响-润滑功能的关系，（ii）确定的影响， 所提出的新型HA基润滑剂对软骨保护的分子结构， 平台，和（iii）确定这些润滑剂对减轻创伤后发展的影响 骨关节炎拟议的研究将使一个新的范例，其中关节内注射的自我愈合 HA瓶刷分子可能是急性损伤后改善或延迟PTOA的重要治疗方法， 或在手术修复后作为辅助手段，以改善预后。

ABSTRACT Altered lubrication of articular cartilage following joint injury increases friction between the sliding cartilage surfaces, leads to deterioration of cartilage, and hastens the development of osteoarthritis (OA). OA due to joint injury, termed as post-traumatic osteoarthritis (PTOA), is estimated to account for at least 12% of all OA cases in the United States and approximately half of the individuals with an anterior cruciate ligament (ACL) injury develop PTOA regardless of the ACL reconstruction. Replenishing the synovial fluid and thereby restoring the articular cartilage lubrication has been demonstrated to benefit the joint. The overarching goal of the proposed study is to investigate the potential of cartilage-adhering, self-healing hyaluronic acid molecules to prevent or delay the degeneration of articular cartilage, and thereby osteoarthritis, following injury or trauma. The molecularly engineered HA-based lubricants are designed to integrate the function of both hyaluronic acid and lubricin, two key components of the synovial fluid, while exhibiting self-repairing ability. The self-healing properties are incorporated to ensure both long-term retention and adaptability of the lubricant within the mechanically active joint, while the cartilage adhering properties are expected to improve boundary lubrication. We hypothesize that the dynamic cartilage-adhering molecules that integrate the molecular features of HA and lubricin and simultaneously exhibit self-healing properties will protect the articular cartilage and prevent or slow down the progression of PTOA. Towards this, we will: (i) develop cartilage-adhering, self-healing HA molecules and determine the effect of molecular architecture-lubrication function relationship, (ii) determine the effect of the molecular architecture of the proposed novel HA-based lubricants on chondroprotection by using a joint-on-chip platform, and (iii) determine the effect of these lubricants on mitigating the development of post-traumatic osteoarthrits. The proposed studies will enable a new paradigm in which intra-articular injection of self-healing HA-bottle brush molecules could be an important treatment following acute injury to ameliorate or delay PTOA, or they could be used as an adjunct after surgical repair to improve the outcome.