Biologically Enhanced Healing of Autograft ACL Reconstruction

描述(申请人提供)：这项研究的目的是通过使用胶原-血小板复合材料来促进移植物的生物结合，以改善前屈指韧带重建(ACLR)的功能愈合。目前治疗前十字韧带(ACL)撕裂的“标准护理”是使用自体肌腱移植的ACLR。尽管ACLR在短期内取得了成功，但术后关节松弛程度增加，这可能会使膝关节面临后续损伤和早期骨关节炎(OA)的风险。因此，加强移植物愈合以减少松弛、保护关节和保留关节软骨的技术将为前交叉韧带损伤患者提供更好的长期结果。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来刺激关节内韧带的愈合。我们假设它们也会促进移植物的愈合。我们已经开发出一种方法，使用胶原海绵来控制移植物周围的血小板。在母公司R01资助的工作中，我们发现在15周愈合后，移植物性能显著改善(弹性系数增加300%，屈服应力改善250%)，膝关节松弛显著减少。由于随访评估相对较短(15周)，我们一直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。在这项竞争性修订中，我们建议纳入存活6个月和12个月的两组长期动物(胶原-血小板复合材料重建前交叉韧带与传统前交叉韧带重建)。这些小组将扩展我们最初的建议，并提供信息，说明胶原蛋白-血小板复合材料在短期内显著改善移植物质量和膝关节松弛，是否将长期持续并防止过早的骨关节炎的发展。如果成功，这些数据将为后续的临床研究提供基础，进一步阐明生物支架在促进移植物愈合、促进关节长期稳定和关节软骨健康方面的作用，从而减少ACLR后的骨关节炎。 公共卫生相关性：在美国每年有250,000名前交叉韧带(ACL)重建患者中，使用带有自体血小板的胶原支架(一种胶原-血小板复合材料)来改善前交叉韧带(ACL)自体移植物的功能愈合，可以缩短康复时间，促进膝关节更稳定，并显著降低过早发生骨关节炎的风险。我们希望这项研究的结果将激发基于细胞的治疗关节内愈合的新领域的探索，并可能导致范式的转变，从使用单一的生长因子到使用能够随着时间的推移提供多种生长因子和细胞因子的细胞作为关节内愈合的辅助工具。

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.