Flexor tendon intrinsic healing and intervention strategy development

摘要 手部屈肌腱损伤很常见，并且经常发生在年轻的工作年龄人群中，导致相当大的伤害。 残疾和经济影响。肌腱损伤后立即进行手术直接修复是实践中的临床标准。 然而，由于限制性粘连和肌腱修复后的临床和功能结果仍然不令人满意。 手指运动不良，通常会导致多次手术修复，例如肌腱松解术或肌腱移植术。据了解 屈肌腱愈合涉及内在和外在愈合机制。内在治愈已完成 通过肌腱内细胞的细胞生产力，导致更少的粘连和更好的功能。相比之下， 外在愈合依赖于外部组织的愈合，导致与组织结合的粘连和疤痕形成 肌腱与周围组织的接触，削弱手部功能。因此，改善临床结果的研究策略 专注于增强内在治愈或消除外在治愈，或两者的结合。这也是 认识到一些内在愈合元素（IHE）涉及肌腱内在愈合能力，包括屈肌 肌腱内的腱细胞（EC）和腱细胞（EC）用于肌腱再生。然而，它 目前尚不清楚这些 IHE 是否以及如何影响内在愈合能力。由于 IHE 可能会在 肌腱损伤，更好地了解与 IHE 相关的内在愈合至关重要，这不仅有助于弥合 该领域临床与研究之间的科学差距，也提高了干预策略的制定。 最近，我们成功开发了一种新型火鸡动物模型，该模型类似于人类屈肌腱 大小、解剖结构、结构、功能，以及最重要的内在愈合能力。这种独特的动物模型提供了 这是研究 IHE 对肌腱内在愈合影响的理想机会。此外，我们最近还 探索了梅奥再生医学中心在 ISO-5 Good 中开发的纯化外泌体产品 (PEP) 制造实践 (GMP) 设施可改善肌腱内部愈合，并取得可喜的结果。我们还有 使用碳二亚胺衍生滑液加明胶（cd-SF-G）开发了一种润滑屏障材料，以减少 肌腱移植物粘连；但尚未在屈肌修复模型中进行测试。因此，本提案的目标 1 是 确定 IHE 的两个主要因素（包括 FV 和 EC）对肌腱愈合和功能恢复的作用 我们的新型火鸡屈肌腱损伤模型。这一具体目标如果成功，我们将解决一个关键障碍 了解屈肌腱内在愈合机制并推进当前手外科知识。目标2 将定义我们使用 PEP 增强内在愈合能力和 cd-SF-G 的新型干预措施的有效性 使用我们的新火鸡动物模型防止外在愈合，以减少疤痕和粘连形成。如果成功的话，我们 将开发并验证临床转化干预措施，以改善以下功能结果 屈肌腱修复，因为我们的治疗方法（GMP 级 PEP 和天然 SF 基材料）已接近实现 临床试验。因此，该提案对基础科学研究和临床转化都具有重大影响。

ABSTRACT Hand flexor tendon injuries are common and often occur in a young working-age population resulting in considerable disability and economic impact. Surgical direct repair immediately after tendon injury is the clinical standard in practice. However, clinical and functional outcomes following tendon repair remain unsatisfactory due to restrictive adhesions and poor digital motion, often resulting in multiple surgical revisions, such as tenolysis or tendon grafting. It is known that both intrinsic and extrinsic healing mechanisms are involved in flexor tendon healing. Intrinsic healing is accomplished by cellular productivities from the cells within the tendon resulting in fewer adhesions and better function. In contrast, extrinsic healing relies on the healing from outside tissues, leading to adhesion and scar formations that bond to the tendon with surrounding tissues and diminish hand function. Therefore, research strategies to improve clinical outcomes have focused on either enhancing intrinsic healing or eliminating extrinsic healing, or a combination of both. It is also recognized that some intrinsic healing elements (IHE) involve tendon intrinsic healing capacity including flexor vinculum (FV) for tendon blood supply and epitenon cells (ECs) within the tendon for tendon regeneration. However, it is still unknown if and how these IHEs would affect the intrinsic healing ability. Since the IHEs can be damaged during tendon injury, it is critical to better understand the intrinsic healing associated with IHEs, which not only help to bridge the scientific gap between clinic and research in this field, but also improve the intervention strategy development. Recently, we have successfully developed a novel turkey animal model, which is similar to the human flexor tendon in size, anatomy, structure, function, and most importantly the intrinsic healing capacity. This unique animal model provides an ideal opportunity to investigate the effects of the IHE on tendon intrinsic healing. Furthermore, we have recently explored a purified exosome product (PEP) developed by Mayo Center for Regenerative Medicine in the ISO-5 Good Manufacturing Practice (GMP) Facility to improve tendon intrinsic healing with promising results. We have also developed a lubricating barrier material using carbodiimide derivatized synovial fluid plus gelatin (cd-SF-G) to reduce adhesions in the tendon graft; but it has not been tested in flexor repair model. Therefore, Aim 1 of this proposal is to determine the role of two major factors of IHEs including FV and ECs on tendon healing and functional restoration using our novel turkey flexor tendon injury model. This specific aim, if successful, we will address a critical barrier for the understanding of flexor tendon intrinsic healing mechanism and advance the current knowledge in hand surgery. Aim 2 will define the effectiveness of our novel interventions using PEP for enhancing intrinsic healing ability and cd-SF-G for preventing extrinsic healing to reduce scar and adhesion formations using our new turkey animal model. If successful, we will have developed and validated the clinically translational interventions to improve functional outcomes following flexor tendon repair, since both our therapeutics, GMP grade PEP and native SF based material, are one step close to a clinical trial. Thus, the proposal has a significant impact on both basic science research and clinical translation.