Intrasynovial soft tissue healing - a novel translational goal for mesenchymal stem cell therapy

肩部疼痛在人类中非常常见，其中最常见的原因是撕裂到被称为“肩袖”的肩部肌腱的复杂排列。症状包括肩部疼痛和无法将手臂举过头顶。这些损伤作为与年龄相关的退行性过程的一部分而发生，并且目前的治疗，经常涉及向该区域注射皮质类固醇，已被证明在长期内基本上无效，即使它们可以产生短期疼痛缓解。手术修复持续性和严重的肩袖撕裂是昂贵的，也经常失败。因此，需要改进治疗这种非常常见的病症的方法。提供这种额外动力以实现功能修复的主要候选者之一是使用干细胞治疗。我们最近已经表明，使用成体干细胞（称为间充质干细胞）在治疗马过度紧张肌腱损伤方面带来了明显的临床益处，因此我们建议从具有损伤的同一个体中提供活干细胞，从两种不同但临床上实用的来源制备-从骨髓或从肌腱所在的腔体内或内衬的滑膜细胞。这些细胞可以很容易地通过注射或在手术时输送。该项目测试的假设，即管理的干细胞将改善愈合的肌腱内的滑膜环境。该项目将使用一个与人类自然疾病相似的大型动物实验模型，以支持随后（如果项目成功）的申请，在项目结束后进行“首次人体”临床试验。该项目由两个互补但不相互依赖的项目阶段组成。第一项研究将在实验室中研究干细胞对培养皿中肌腱切片的影响。这将使我们能够确定最佳剂量，比较不同细胞类型的性能，并评估两种可能的作用机制-细胞“密封”受损肌腱表面并主动愈合的能力-这使我们能够限制研究第二阶段所需的动物数量。在这里，我们将在绵羊中使用一种新的、最近验证的、但相关性更高、更具成本效益的模型。该模型由锁孔手术造成的肌腱中可再现的手术缺损组成，该手术缺损不会导致术后明显不适，但确实会产生与肩袖疾病相似的愈合不足。“大型动物”模型的使用还使我们能够以与提议用于人类的方式相同的方式使用从同一动物制备的细胞，从而使其最相关地告知随后用于人类医学用途的技术的早期转化。

Shoulder pain in very common in humans, of which the most common cause is a tear to a complex arrangement of tendons in the shoulder known as the 'rotator cuff'. Signs include shoulder pain and an inability to raise the arm above the head. These injuries occur as part of an age-related degenerative process and current treatments, frequently involving the injection of corticosteroids into the area, have been shown to be largely ineffective in the long term, even though they can produce short-term pain relief. Surgical repairs of persistent and severe rotator cuff tears are expensive and also frequently fail. There is therefore a need to improve methods of treating this very common condition. One of the leading candidates to provide this extra impetus to achieve functional repair is the use of stem cell therapy. We have recently shown that the use of adult stem cells (known as mesenchymal stem cells) brings apparent clinical benefit in the treatment of equine overstrain tendon injuries and so we propose to deliver live stem cells from the same individual who has the injury, prepared from two different but clinically practical sources - from the bone marrow or from the synovial cells within, or lining, the cavity in which the tendon lies. These cells could be easily delivered either by injection or at the time of surgery. This project tests the hypothesis that the administration of stem cells will improve the healing of tendons inside a synovial environment. It will use a large animal experimental model with similarities to the natural disease in humans to support a subsequent (if the project is successful) application to undertake a 'first-in-man' clinical trial after the conclusion of the project.The project is composed of two complimentary, but not inter-dependent, project phases. The first will investigate, in the laboratory, the effects of stem cells on tendon sections in a culture dish. This will allow us to determine optimal dosages, compare the performance of the different cell types, and evaluate two possible mechanisms of action - the ability of the cells to 'seal' the surface of a damaged tendon and to actively heal it - which has enabled us to limit the number of animals needed in the second phase of the study. Here we will use a novel, recently validated, but more highly relevant, cost-effective model in the sheep. This model consists of a reproducible surgical defect in a tendon created by key-hole surgery which does not result in significant discomfort post-operatively but does produce a similar lack of healing to that seen in rotator cuff disease. The use of a 'large animal' model also enables us to use cells prepared from the same animal in a manner identical to that proposed for use in humans thereby making it most relevant to inform the early translation of the technology subsequently for human medical use.