Basic Science of Tendon To Bone Healing

描述（由申请人提供）：各种重建外科手术，如膝关节前交叉韧带（ACL）重建和肩袖修复，需要肌腱和骨骼之间的愈合。先前的动物研究发现，在愈合过程中没有形成正常的骨-肌腱附着部位形态，导致机械界面较差。对于启动和调节愈合过程的细胞和分子事件以及机械刺激如何影响这些事件知之甚少。理想情况下，肌腱和骨骼之间的愈合应该再现胚胎发育过程。这项研究的长期目标是了解控制肌腱-骨附着部位愈合的细胞和分子事件，以便我们最终可以开发出改善愈合过程的新方法。我们将测试关于肌腱到骨愈合的假设，这些假设来自于目前关于插入部位胚胎发生和炎症在组织愈合中的作用的知识。尽管关节结构的形成和维持依赖于肌肉活动，但胚胎关节发育过程中的初始定位和细胞变化似乎是在肌肉活动之前被指定的，因此与肌肉活动无关。因此，我们的总体假设是，最佳的附着部位愈合是由遗传（内在）和机械（外在）因素控制的。具体来说，我们假设机械载荷引起肌腱-骨界面的相对运动（剪切），只有在初始固定期后施加，才能改善愈合，从而解决急性炎症并开始早期愈合（即早期与延迟活动）。为了验证这一假设，我们将：(1)评估运动的时间和大小对肌腱到骨愈合的影响，(2)评估机械刺激影响愈合的机制，(3)通过评估巨噬细胞消耗对愈合的影响来确定巨噬细胞在肌腱到骨愈合中的作用。了解影响肌腱-骨愈合的内在和外在因素可能对改善前交叉韧带重建和肩袖修复的结果产生巨大影响，这是当今最常用的两种矫形手术。基于对肌腱到骨愈合的更好理解，改变术中技术或术后康复方案可以直接显著改善长期临床结果。

DESCRIPTION (provided by applicant): Various reconstructive surgical procedures, such as anterior cruciate ligament (ACL) reconstruction in the knee and rotator cuff repair, require healing between a tendon and bone. Previous animal studies found that normal bone-tendon attachment-site morphology is not formed during healing, resulting in a mechanically inferior interface. Little is known of the cellular and molecular events that initiate and regulate the healing process, and how mechanical stimuli affect these events. Ideally, healing between tendon and bone should recapitulate the process that occurs during embryonic development. The long-term objective of this research is to understand the cellular and molecular events that control healing at the tendon-to-bone attachment site, so that we may eventually develop novel methods for improving the healing process. We will test hypotheses about tendon-to-bone healing drawn from current knowledge of insertion site embryogenesis and the role of inflammation in tissue healing. Although formation and maintenance of joint structures is dependent on muscular activity, the initial positioning and cellular changes during embryonic joint development appear to be specified prior to and therefore independent of muscle activity. Thus, our global hypothesis is that optimal attachment-site healing is controlled by both genetic (intrinsic) and mechanical (extrinsic) factors. Specifically, we hypothesize that mechanical load causing relative tendon- bone interface motion (shear) will improve healing only if applied after an initial period of immobilization to allow resolution of acute inflammation and initiation of early healing (i.e., early vs delayed mobilization). To test this hypothesis, we will: (1) Evaluate the effect of the timing and magnitude of motion on tendon-to- bone healing, (2) Evaluate the mechanism(s) by which mechanical stimulus affects healing, and (3) Determine the role of macrophages in tendon-to-bone healing by evaluating the effect of macrophage depletion on healing. Understanding the intrinsic and extrinsic factors that influence tendon-to-bone healing could have a tremendous impact on improving the outcomes of ACL reconstruction and rotator cuff repair, two of the most commonly performed orthopaedic procedures today. Altered intraoperative techniques or postoperative rehabilitation protocols that are based on a better understanding of tendon to bone healing could directly and significantly improve long-term clinical outcomes.