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肩部肌腱撕裂，这种复杂的排列被称为‘肩袖’。症状包括肩痛和无法将手臂举过头顶。这些损伤是与年龄相关的退化过程的一部分，目前的治疗通常涉及到向该地区注射皮质类固醇，从长期来看基本上是无效的，尽管它们可以产生短期的疼痛缓解。手术修复持续性和严重的肩袖撕裂费用昂贵，而且经常失败。因此，有必要改进治疗这种非常常见的疾病的方法。提供这种额外动力以实现功能修复的主要候选方法之一是干细胞疗法的使用。我们最近已经证明，使用成人干细胞(称为间充质干细胞)在治疗马腱过度劳损中带来明显的临床益处，因此我们建议从同一个损伤患者身上移植活干细胞，这些干细胞来自两个不同但具有临床实用价值的来源--来自骨髓或来自肌腱所在腔内的滑膜细胞或衬里。这些细胞可以很容易地通过注射或在手术时输送。这个项目测试了这样一种假设，即干细胞的使用将改善滑膜环境中肌腱的愈合。它将使用一个与人类自然疾病相似的大型动物实验模型来支持后续(如果项目成功)的申请，在项目结束后进行第一个人的临床试验。项目由两个相互补充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‘封闭’受损肌腱表面并主动修复它的能力--这使我们能够限制第二阶段研究所需的动物数量。在这里，我们将在绵羊身上使用一种新奇的、最近得到验证的、但更具相关性的成本效益模型。这一模型包括由锁孔手术造成的肌腱可复制的手术缺陷，这种缺陷不会导致术后明显的不适，但确实会导致类似于肩袖疾病的愈合不足。大动物模型的使用还使我们能够以与建议用于人类的方式相同的方式使用从同一动物中制备的细胞，从而使其与随后用于人类医学的技术的早期翻译最相关。

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.