Basic Science of Tendon To Bone Healing

描述(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，需要肌腱和骨之间的愈合。以前的动物研究发现，正常的骨-肌腱附着点形态在愈合过程中不会形成，导致力学上较差的界面。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，人们知之甚少。理想情况下，肌腱和骨骼之间的愈合应该重述胚胎发育过程。这项研究的长期目标是了解控制肌腱与骨连接部位愈合的细胞和分子事件，以便我们最终可能开发出改进愈合过程的新方法。我们将检验关于肌腱到骨骼愈合的假说，这些假说来自于目前关于起止点胚胎发生和炎症在组织愈合中的作用的知识。虽然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指定的，因此与肌肉活动无关。因此，我们的总体假设是，最理想的附着部位愈合是由遗传(内在)和机械(外在)因素控制的。具体地说，我们假设引起肌腱-骨界面相对运动(剪切)的机械负荷只有在最初的制动阶段后才能改善愈合，以允许急性炎症的消退和早期愈合的启动(即早期活动与延迟活动)。为了验证这一假说，我们将：(1)评估运动的时机和大小对肌腱到骨的愈合的影响，(2)评估机械刺激影响愈合的机制(S)，以及(3)通过评估巨噬细胞耗尽对愈合的影响来确定巨噬细胞在肌腱到骨的愈合中的作用。了解影响腱-骨愈合的内在和外在因素对改善ACL重建和肩袖修复的结果有巨大的影响，这两种手术是当今最常见的骨科手术。改良术中技术或基于对肌腱到骨愈合的更好了解的术后康复方案可以直接和显着地改善长期临床结果。

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.