Total Joint Resurfacing

全关节表面重修

• 批准号: 8118205
• 负责人: JAMES E DENNIS
• 金额: $ 12.27万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8118205
• 关键词: Adhesives; Animals; Area; Arthritis; Autologous; Biomechanics; Bioreactors; Carbodiimides; Cartilage; Cell Culture Techniques; Cells; Chondrocytes; Collagen; Defect; Degenerative polyarthritis; Engineering; Ensure; Failure; Fibrin Tissue Adhesive; Follow-Up Studies; Goals; Goat; Growth Factor; Harvest; Histology; Hyaluronan; Image; Immunochemistry; Implant; In Vitro; Joints; Lateral; Length; Life; Magnetic Resonance Imaging; Maps; Measures; Mechanics; Mesenchymal Stem Cells; Methods; Modeling; Nude Mice; Omega-3 Fatty Acids; Operative Surgical Procedures; Organ; Oryctolagus cuniculus; Outcome; Paste substance; Pre-Clinical Model; Procedures; Production; Property; Prosthesis; Replacement Arthroplasty; Sheep; Site; Surface; Testing; Thick; Tissue Engineering; Tissues; Variant; Wound Healing; adhesive polymer; alternative treatment; articular cartilage; base; bone; calcium phosphate; density; design; implant material; implantation; in vivo; in vivo Model; repaired; scaffold; sound; stem

Total Joint Resurfacing Previous attempts to repair articular cartilage have focused on the repair of focal defects. One of the main complications of focal defect repair is that integration of the repair tissue with the surrounding native cartilage is inconsistent and generally poor, which renders the repair site biomechanically unstable not clinically efficacious. In the case of severe osteoarthritis where the entire joint surface has deteriorated, the procedures for repair of focal cartilage defects are no longer applicable. For severe arthritis, total joint replacement is the final option which, although it has a generally good outcome, there are still long-term complications including, erosion of the articulating surface of the prostheses, and breaking or loosening of the prosthetic stem. These problems necessitate revision surgery which is progressively more difficult and complicated. To obviate this problem, we propose to design and test a tissue engineered cell-matrix composite for the total resurfacing of a joint or joint compartment, which is designed to eliminate cartilage-tocartilage integration problems and provide a cell-based option for totally resurfacing joints without totally replacing them. The primary challenges for tissue engineering the total cartilage resurfacing of a joint are to produce viable cartilage tissue of sufficient thickness and surface area to cover an entire joint, to produce cartilage that has appropriate mechanical properties to support the in vivo mechanical demands, and to ensure the integration of the construct with underlying bone. The goal of this proposal is to produce functional autologous cartilage constructs using tissue engineering principles wherein autologous cells, such as Mesenchymal Stem Cells (MSCs), auricular or articular chondrocytes are used to produce full-thickness replacement cartilage and that is then fused and allowed to integrate onto sub-chondral bone, thus totally replacing the deteriorated cartilage with autologous engineered cartilage. This approach is based on the hypothesis that the production of full-thickness cartilage implants obviates the intractable difficulty of lateral cartilage integration, and functional long-term repair will be accomplished by producing biomechanically sound autologous cartilage. The specific aims of this proposal are: 1. To produce implantation-ready tissue engineered cartilage constructs: In a rabbit model, MSCs and culture-expanded chondrocytes will be used to produce full-thickness (300 um) cartilage constructs of sufficient area to cover an entire humeral condyle. Variables to be tested include the use of auricular or articular chondrocytes or MSCs; hyaluronan- or collagen-based scaffolds; and variations in culture conditions such as cell seeding density, medium flow rate, and the addition of growth factors such as TGF-p1, TGFpS, BMPs, and omega-3 fatty acids. 1. To test implantation-ready constructs in an ex vivo model for cartilage resurfacing: Implant materials synthesized to the proper thickness and surface area will be fixed onto explanted rabbit humeral condyles using four adhesive methods: a calcium phosphate paste, fibrin glue, a final using the zero-length cross-linker1-Ethyl-3-{3-dimethylaminopropyl} carbodiimide, and APTMS-MBA (aminopropyltrimethoxysilanemethylenebisacrylamide), a non-toxic polymer adhesive. These adhesive materials will be tested for their biomechanical properties in vitro, in organ culture, and after implantation into athymic mouse hosts for up to 6 weeks. Biomechanical properties to be tested include a map of surface stiffness, and measures under uniaxial tension and horizontal shear (to failure). MRI imaging, histological examination, and immunochemistry will be used to determine the consistency of cartilage thickness and integration into subchondral bone. 2. To test constructs in an in vivo model of cartilage resurfacing in rabbits: Autologous engineered cartilage constructs will be used to resurface entire humeral condyles in rabbits. The implants will be harvested and examined for biomechanical properties and histology at 4, 12, 24 and 48 weeks post-implantation. Through the use of the Cell, Bioreactor and Imaging Cores, the goals of this proposal will be more easily and efficiently accomplished. The Core components are very appropriate for this project as there is a high demand for cells (chondrocytes and MSCs), bioreactors are need to fabricate cartilage tissue, and imaging is needed for outcome analysis. If these studies are successful, the follow-up study would be to reproduce these results in a large animal pre-clinical model such as in sheep or goats. The long-term objective of this study is to provide an alternative treatment for severe arthritis of diarthrodial joints that is composed of living autologous tissue which, hopefully, will provide many years of functional use before the need for total joint replacement.

总关节重铺 以前修复关节软骨的尝试集中在修复局灶性缺陷上。中的一个 局灶性缺陷修复的主要并发症是修复组织与周围天然的整合 软骨不一致，通常很差，这使维修部位在生物力学上不稳定不稳定 临床有效。在整个关节表面恶化的严重骨关节炎的情况下， 修复焦点软骨缺陷的程序不再适用。对于严重关节炎，总关节 替换是最终选择，尽管它的结果总体好，但仍有长期的选择 并发症，包括侵蚀假体表面的侵蚀以及破坏或松动的并发症 假肢。这些问题需要修改手术，这逐渐变得更加困难，并且 复杂的。为了消除此问题，我们建议设计和测试组织工程的细胞矩阵 关节或关节隔室的总重铺的复合材料，旨在消除软骨 - 区域 集成问题，并提供基于单元的选项，用于完全重新铺面没有完全重新铺面 更换它们。 组织工程的主要挑战是关节的总软骨重新铺面是生产 有足够厚度和表面积的可行软骨组织覆盖整个关节，以产生软骨 具有适当的机械性能来支持体内机械需求，并确保 将构建体与潜在的骨骼整合。该提议的目的是产生功能 使用组织工程原理的自体软骨结构，其中自体细胞，例如 间充质干细胞（MSC），耳塞或关节软骨细胞用于产生全厚度 替换软骨，然后融合并允许整合到下软骨上，因此完全 用自体工程软骨代替恶化的软骨。 这种方法基于以下假设：全厚软骨植入物的产生 消除了横向软骨整合的棘手难度，功能性长期修复将是 通过产生生物力学声音自体软骨来完成。 该提案的具体目的是： 1。生产植入的组织工程软骨结构：在兔子模型中，MSCS 和培养的软骨细胞将用于产生全厚度（300 um）软骨的构建体 足够的区域覆盖整个肱骨con。要测试的变量包括使用耳或 关节软骨细胞或MSC；透明质酸或胶原蛋白的支架；和培养条件的变化 例如细胞播种密度，中等流速和添加生长因子，例如TGF-P1，TGFPS， BMP和Omega-3脂肪酸。 1。在体内模型中测试植入就绪的构造，用于软骨重新铺面：植入物 合成的厚度和表面积合成的材料将固定在外植物兔肱骨上 使用四种粘合剂方法：磷酸钙糊，纤维蛋白胶，最终使用零长度 交叉链接1-乙基-3- {3-二甲基氨基丙基}碳二酰亚胺和APTMS-MBA（氨基丙基三甲氧基甲基甲基甲基二酰胺） 一种无毒的聚合物粘合剂。这些粘合剂材料将经过测试 体外生物力学特性，器官培养和植入无胸腺小鼠宿主之后 6周。要测试的生物力学特性包括表面刚度图和措施 单轴张力和水平剪切（失败）。 MRI成像，组织学检查和 免疫化学将用于确定软骨厚度的一致性和整合到 软骨下骨。 2。在软骨的体内模型中测试构造中的兔子：自体 工程软骨构建体将用于兔子的整个肱骨con。植入物 在植入后4、12、24和48周时，将收获并检查生物力学性质和组织学。 通过使用细胞，生物反应器和成像核，该提案的目标将更多 轻松有效地完成。核心组件非常适合该项目，因为有一个 对细胞（软骨细胞和MSC）的需求很高，需要制造软骨组织，并且需要生物反应器 结果分析需要成像。 如果这些研究成功，那么后续研究将是在大量中重现这些结果 动物临床前模型，例如绵羊或山羊。这项研究的长期目标是提供 由活体组织组成的腹膜关节严重关节炎的替代治疗 希望在需要全部置换之前，它将提供多年的功能用途。