Biologically Enhanced Healing of Autograft ACL Reconstruction

描述（由申请人提供）：本研究的目的是通过使用胶原-血小板复合材料增强移植物的生物结合来改善前库韧带重建（ACLR）的功能性愈合。目前治疗前交叉韧带（ACL）撕裂的“标准护理”是使用自体肌腱移植的ACLR。尽管ACLR短期成功，但术后关节松弛增加，这可能使膝关节面临后续损伤和早期骨关节炎（OA）的风险。因此，增强移植物愈合、减少松弛、保护关节和保留关节软骨的技术将为ACL损伤患者提供更好的长期预后。该研究小组最近开发了一种胶原-血小板复合材料，以增强ACLR移植物的愈合反应。众所周知，血小板可以释放各种生长因子和细胞因子，刺激关节内韧带愈合。我们假设它们也会促进移植物愈合。我们已经开发出一种方法，使用胶原蛋白海绵来控制移植物周围的血小板。在由母公司R01资助的研究中，我们发现移植物的性能有了显著的改善（模量增加300%，屈服应力改善250%），并且在愈合15周后，膝关节松弛明显减少。由于随访评估相对较短（15周），我们无法检测这些改善是否会显著影响前交叉韧带重建后的软骨健康。在这一竞争性修订中，我们建议纳入两组较长期的动物（胶原-血小板复合ACL重建与传统ACL重建），存活时间分别为6个月和12个月。这些小组将扩展我们最初的建议，并提供关于胶原-血小板复合材料是否能在短期内显著改善移植物质量和膝关节松弛的信息，是否能长期持续并预防过早骨关节炎的发展。如果成功，这些数据将为后续的临床研究提供基础，进一步描述生物支架在改善移植物愈合和促进长期关节稳定性和关节软骨健康方面的作用，从而减少ACLR后的OA。

DESCRIPTION (provided by applicant): The objective of this study is to improve the functional healing of an anterior curiae ligament reconstruction (ACLR) by using a collagen-platelet composite to enhance the biologic incorporation of the graft. The current "standard of care" for an anterior cruciate ligament (ACL) tear is ACLR using an autograft tendon. Despite short-term success of ACLR, increases in joint laxity occur after surgery, which may place the knee at risk for subsequent damage and early osteoarthritis (OA). Thus, techniques to enhance graft healing which reduce laxity, protect the joint, and preserve articular cartilage would provide better long-term outcome for the ACL injured patient. A collagen-platelet composite was recently developed by this research team to enhance the healing response of the ACLR graft. Platelets are known to release various growth factors and cytokines that stimulate intra-articular ligament healing. We hypothesized that they will improve graft healing as well. We have developed a method to contain the platelets around the graft using a collagen sponge. In the work funded by the parent R01, we have found significant improvements in both graft performance (300% increases in modulus and 250% improvement in yield stress) as well as significant reductions in knee laxity after 15 weeks of healing. Due to the relatively short follow-up evaluation (15 weeks), we have been unable to detect whether these improvements will significantly impact cartilage health after an ACL reconstruction. In this competitive revision, we propose to include two longer-term groups of animals (ACL reconstruction with collagen-platelet composite vs traditional ACL reconstruction) with survivals of 6 and 12 months. These groups will expand our original proposal and provide information as to whether the collagen-platelet composite, which significantly improves graft quality and knee laxity in the short-term, will continue in the long term and prevent the development of premature osteoarthritis. If successful, these data will provide the foundation for subsequent clinical studies to further delineate the role of biologic scaffolds in improving graft healing and promoting long- term joint stability and articular cartilage health, thus reducing OA after ACLR. PUBLIC HEALTH RELEVANCE: The use of a collagen scaffold with autologous platelets (a collagen-platelet composite) to improve the functional healing of an anterior cruciate ligament (ACL) autograft could decrease rehabilitation time, promote a more stable knee and significantly reduce the risk of premature osteoarthritis for 250,000 ACL reconstructed patients in the US annually. We are hopeful that the results of this study will inspire new fields of inquiry into cell-based therapies for intra-articular healing, and may result in a paradigm shift from use of a single growth factor toward the use of cells that can deliver multiple growth factors and cytokines over time as adjuncts to intra-articular healing.