Flexor tendon intrinsic healing and intervention strategy development

摘要 手屈肌腱损伤是常见的，经常发生在年轻的工作年龄人口，导致相当大的 残疾和经济影响。肌腱损伤后立即手术直接修复是临床实践的标准。 然而，肌腱修复后的临床和功能结果仍然不令人满意，因为限制性粘连， 手指活动不良，通常导致多次手术翻修，如肌腱松解或肌腱移植。已知的是 屈肌腱愈合涉及内在和外在愈合机制。内在愈合完成 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。与此相反， 外在愈合依赖于外部组织的愈合，导致粘连和瘢痕形成， 肌腱和周围组织，并削弱手功能。因此，改善临床结果的研究策略 集中在增强内在愈合或消除外在愈合，或两者的组合。也是 认识到一些内在愈合要素（IHE）涉及肌腱内在愈合能力，包括屈肌 腱内的腱外膜细胞（EC）用于肌腱再生。但 目前还不清楚这些IHE是否以及如何影响内在的愈合能力。由于IHE可能在 肌腱损伤，更好地了解与IHE相关的内在愈合至关重要，这不仅有助于桥接 该领域的临床与研究之间的科学差距，也改善了干预策略的制定。 最近，我们成功地开发了一种新的火鸡动物模型，它类似于人类屈肌腱， 大小、解剖结构、结构、功能，最重要的是内在的愈合能力。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 探索了由马约再生医学中心开发的纯化的外泌体产品（PEP）， 制造规范（GMP）设施，以改善肌腱内在愈合与有前途的结果。我们还 开发了一种使用碳二亚胺衍生的滑液加明胶（cd-SF-G）的润滑屏障材料， 肌腱移植物中的粘连;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， 我们新的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的障碍， 了解屈肌腱的内在愈合机制，促进手外科的现有知识。目的2 将确定我们的新干预的有效性，使用PEP增强内在愈合能力和cd-SF-G， 使用我们新的火鸡动物模型，防止外部愈合以减少疤痕和粘连形成。如果成功，我们 将开发并验证临床转化干预措施，以改善以下功能结局 屈肌腱修复，因为我们的治疗，GMP级PEP和天然SF基材料，是一个步骤接近 临床试验因此，该提案对基础科学研究和临床翻译都产生了重大影响。

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.