Flexor tendon intrinsic healing and intervention strategy development

屈肌腱内在愈合和干预策略的制定

• 批准号: 10436789
• 负责人: Chunfeng Zhao
• 金额: $ 50.8万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10436789
• 关键词: Address; Adhesions; Affect; Anatomy; Animal Model; Antibodies; Area; Autologous; Basic Science; Biological; Biological Products; Canis familiaris; Carbodiimides; Cells; Chickens; Chondrocytes; Cicatrix; Client satisfaction; Clinic; Clinical; Clinical Trials; Data; Development; Domestic Fowls; Economic Burden; Effectiveness; Elements; Fibrocartilages; Flexor; Future; Gelatin; Genetic Markers; Glues; Gold; Hand; Hand functions; Human; Injury; Intervention; Intrinsic factor; Knowledge; Lead; Leg; Meleagris gallopavo; Minerals; Modeling; Molecular; Motion; Natural regeneration; Necrosis; Operative Surgical Procedures; Outcome; Patients; Play; Postoperative Period; Productivity; Recovery of Function; Regenerative Medicine; Reporting; Research; Rodent; Role; Rupture; Second Look Surgery; Structure; Surface; Synovial Fluid; Techniques; Tendon Injuries; Tendon structure; Testing; Therapeutic; Time; Tissues; Vascular blood supply; Work; aging population; base; cDNA Library; cell type; clinical application; clinical practice; clinical translation; clinically relevant; crosslink; digital; disability; disability impact; economic impact; exosome; foot; functional outcomes; functional restoration; genome sequencing; healing; improved; molecular marker; novel; prevent; progenitor; regeneration potential; repair model; repaired; response; severe injury; stem cells; tendon graft; therapy development; tool

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.

抽象的 手屈肌腱受伤很常见，经常发生在年轻的工人年龄中，导致相当多 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。 但是，由于限制性粘连和 数字运动不佳，通常会导致多次手术修订，例如借方或肌腱移植。众所周知 屈肌肌腱愈合涉及固有和外在的愈合机制。内在的康复已完成 通过肌腱内细胞的细胞生产力，导致粘附较少和功能更好。相比之下， 外在的愈合依赖于外部组织的愈合，导致粘合和疤痕形成与 肌腱周围组织并减少手部功能。因此，改善临床结果的研究策略 专注于增强内在的愈合或消除外部愈合或两者的组合。也是 认识到某些内在的愈合元素（IHE）涉及肌腱内在的愈合能力，包括屈肌 肌腱再生的肌腱血液供应和上皮细胞（ECS）的尾cul（FV）。但是，它 这些IHS是否以及如何影响固有的愈合能力仍然未知。由于ihes在 肌腱受伤，至关重要的是要更好地了解与IHES相关的内在康复，这不仅有助于桥接 该领域的诊所与研究之间的科学差距，但也改善了干预策略的发展。 最近，我们成功地开发了一种新型的火鸡动物模型，该模型类似于人类屈肌肌腱 大小，解剖学，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 研究IHE对肌腱固有愈合的影响的理想机会。此外，我们最近有 探索了由Mayo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）设施可改善肌腱固有的愈合，并有令人鼓舞的结果。我们也有 使用碳二二胺衍生化的滑液加明胶（CD-SF-G）开发了润滑屏障材料以减少 肌腱移植的粘附；但尚未在屈肌维修模型中进行测试。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）在使用肌腱愈合和功能恢复中的作用 我们的新型火鸡屈肌肌腱损伤模型。这个具体目标，如果成功，我们将解决一个关键的障碍 了解屈肌肌腱固有的愈合机制，并提高当前手术方面的知识。目标2 将使用PEP来确定我们新颖干预措施的有效性，以增强内在的愈合能力和CD-SF-G 防止外部愈合，以减少我们的新火鸡动物模型减少疤痕和粘附地层。如果成功，我们 将开发并验证临床翻译干预措施，以改善功能结果 屈肌肌腱修复，因为我们的治疗剂，GMP级PEP和基于天然SF的材料都接近一步 临床试验。因此，该提案对基础科学研究和临床翻译都有重大影响。