Synovium-based articular cartilage tissue engineering

基于滑膜的关节软骨组织工程

• 批准号: 7095552
• 负责人: ERNST B. HUNZIKER
• 金额: $ 17.6万
• 依托单位: UNIVERSITAT BERN
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7095552
• 关键词: articular cartilage; bone; cartilage; joints; stem cells; synovial membrane; tissue engineering; tissues

DESCRIPTION (provided by applicant): Osteoarthritis is one of the most common diseases suffered by elderly persons in Western countries. This disabling joint disorder is usually multifactorial in nature and thus of unknown origin in individual cases. During the early stages of osteoarthritis, localized lesioning of the articular cartilage layer is a characteristic occurrence. Once initiated, this lesioning process is progressive, and no prophylactic measures are available to arrest it. Likewise, no established biologically-based treatment strategies are available to induce the healing of these structural defects. Endeavours are now being made to adopt a more biologically rational approach to the repair of articular cartilage lesions using tissue-engineering principles. We have recently developed a growth-factor-based strategy which induces the healing of small articular cartilage defects. But when applied to very large defects in experimental animals (goats), the same strategy is unable to induce their repair within a short period of time. - We postulate that by introducing an adult stem cell population directly into the defect space by the autotransplantation of synovial membrane flaps, the difficulties can be overcome and the repair of large defect areas and volumes induced. We hypothesize that a "layered synovioplasty" performed in a single intervention (surgery or arthroscopy) can form the basis for the repair of bulk volume articular cartilage defects. Layers of synovial flaps will be interposed with a matrix containing growth factors in a controlled release system, which will assure their transformation. - We will first optimize the transformation conditions using a tissue-culture system based on the availability of fresh synovial bovine tissue (from young adult cows). - We also hypothesize that adult stem cell populations within different synovial joints of the body contain positional information respecting their differentiation potential into joint- specific articular cartilage. This being the case, the local recruitment of adult synovial stem cells would be a great advantage, in that the cells would carry local positional information to form the same type of joint-specific articular cartilage. We will test this hypothesis using articular cartilage tissue as well as synovial tissue from three different bovine joints that differ significantly both structurally and functionally, i.e., from the shoulder joint, from the knee joint and from the metatarsal joint of bovine origin. - Following fine-tuning, the optimized protocols will be cross- checked in vitro using adult goat material derived from the knee joint. The finalized protocols will be tested at mid- term (5 weeks post-operatively) and long-term (6 months post-operatively) junctures in adult goats. The repair tissue will be analyzed quantitatively with respect to mRNA expression profiles and the post-translational expression of cartilage matrix components, as well as morphometrically, ultrastructurally and biomechanically. We believe that this project is highly innovative and that the results of this research will have a significant impact on the future treatment of osteoarthritic lesions and on improvement of the health status of the US population.

描述（申请人提供）： 骨关节炎是西方国家老年人最常见的疾病之一。这种致残性关节疾病本质上通常是多因素造成的，因此个别病例的起因不明。在骨关节炎的早期阶段，关节软骨层的局部病变是一个特征性的现象。一旦开始，这种损害过程就会进行性发展，并且没有预防措施可以阻止它。同样，没有既定的基于生物学的治疗策略可用于诱导这些结构缺陷的愈合。现在正在努力采用一种更加生物学合理的方法，利用组织工程原理来修复关节软骨损伤。我们最近开发了一种基于生长因子的策略，可诱导小关节软骨缺陷的愈合。但当应用于实验动物（山羊）的非常大的缺陷时，相同的策略无法在短时间内诱导其修复。 - 我们假设，通过滑膜瓣自体移植将成体干细胞群直接引入缺损空间，可以克服困难并诱导大缺损区域和体积的修复。我们假设在单次干预（手术或关节镜检查）中进行的“分层滑膜成形术”可以构成修复大量关节软骨缺陷的基础。滑膜瓣层将在受控释放系统中插入含有生长因子的基质，这将确保它们的转化。 - 我们将首先根据新鲜滑膜牛组织（来自年轻成年奶牛）的可用性，使用组织培养系统优化转化条件。 -我们还假设身体不同滑膜关节内的成体干细胞群包含关于其分化为关节特异性关节软骨的潜力的位置信息。在这种情况下，成体滑膜干细胞的局部募集将是一个很大的优势，因为这些细胞将携带局部位置信息以形成相同类型的关节特异性关节软骨。我们将使用来自三种不同牛关节的关节软骨组织和滑膜组织来检验这一假设，这些关节在结构和功能上都显着不同，即来自牛起源的肩关节、膝关节和跖关节。 - 微调后，将使用源自膝关节的成年山羊材料在体外对优化方案进行交叉检查。最终确定的方案将在成年山羊的中期（术后 5 周）和长期（术后 6 个月）阶段进行测试。将对修复组织的 mRNA 表达谱和软骨基质成分的翻译后表达进行定量分析，以及形态测量、超微结构和生物力学分析。我们相信这个项目具有高度的创新性，这项研究的结果将对未来骨关节炎病变的治疗以及美国民众健康状况的改善产生重大影响。