Engineering functional anisotropy in chondrocyte- and MSC-laden hydrogels

负载软骨细胞和 MSC 的水凝胶中的工程功能各向异性

• 批准号: 7354123
• 负责人: Robert L Mauck
• 金额: $ 7.72万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-02 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7354123
• 关键词: Address; Adolescence; Adult; Anabolism; Animals; Anisotropy; Bioreactors; Birth; Cartilage; Cell Differentiation process; Cells; Chondrocytes; Chondrogenesis; Collagen; Collagen Fiber; Complex; Cultured Cells; Degenerative polyarthritis; Deposition; Development; Engineering; Environment; Excision; Exhibits; Exposure to; Extracellular Matrix; Fiber; Gel; Gene Expression; Growth; Healed; Hydrogels; Incidence; Joints; Lead; Location; Longitudinal Studies; Mechanics; Mesenchymal; Mesenchymal Stem Cells; Monitor; Numbers; Pattern; Peptides; Phase; Play; Positioning Attribute; Process; Property; Protocols documentation; Relative (related person); Role; Sepharose; Signal Transduction; Slide; Stimulus; Surface; Swelling; System; Testing; Time; Tissue Engineering; Tissues; Transforming Growth Factors; Weight-Bearing state; articular cartilage; base; cartilage development; clinically relevant; concept; day; design; healing; in vivo; insight; novel; repaired; scaffold

DESCRIPTION (provided by applicant): Articular cartilage lines the surfaces of joints and functions to transmit the forces associated with joint loading. Limited by its poor healing capacity, there exists a growing demand for cell-based strategies for repair. Given the mechanical role of the native tissue, the successful replacement of articular cartilage using engineered constructs will require grown tissue possessing functional mechanical properties. In this study, we propose the combination of chondrocytes or mesenchymal stem cells (which can undergo chondrogenic differentiation) in a hydrogel environment (agarose and self-assembling peptide hydrogels), and focus on the development of compressive and tensile properties of these constructs. Tensile properties in mature cartilage are anisotropic, particularly in the superficial zone, and emerge during adolescence as maturation occurs with joint loading. Borrowing from this developmental concept, we suggest a novel bioreactor system designed to recapitulate the sliding contact that occurs between two contacting articular cartilage layers. Using this bioreactor, chondrocyte biosynthesis and chondrogenic differentiation of MSCs will be valuated as a function of pre-incubation period and duration and intermittency of sliding. It is hypothesized that the patterns of gene expression and differentiation will be dictated by the relation of the position in the gel to the applied contact, with enhancements occurring beneath and along the line of contact, particularly in the superficial layer. Subsequent long-term studies will utilize these optimized loading protocols to direct the increase the compressive and tensile (in the direction of sliding) mechanical properties of MSC- and chondrocyte-laden hydrogel constructs. Furthermore, it is hypothesized that these constructs will exhibit enhanced collagen content as well as a parallel collagen fiber orientation in the direction of sliding contact. This application examines the ability of chondrocyte- and MSC-laden hydrogels to achieve cartilage-like tensile properties, and to instill anisotropy in these constructs via culture in a novel sliding contact bioreactor system. These studies will provide insight into the mechanisms of cartilage differentiation and maturation. If realized, the specific aims of this proposal will further our efforts to produce clinically relevant chondrocyteand MSC-laden functional cartilage replacements that exhibit the complex material properties and anisotropies that define the native tissue and are necessary for its mature function.

描述（由申请人提供）： 关节软骨线的关节表面和功能表面以传递与关节载荷相关的力。受其治疗能力不佳的限制，对基于细胞的维修策略的需求不断增长。鉴于天然组织的机械作用，使用工程结构的成功更换关节软骨将需要具有功能性机械性能的生长组织。在这项研究中，我们提出了软骨细胞或间充质干细胞（可以在水凝胶环境（琼脂糖和自组装肽水凝胶）中进行软骨分化）的组合，并着重于这些构建体的压缩和拉伸特性的发展。成熟软骨中的拉伸特性是各向异性的，尤其是在浅表区域，并且随着关节载荷的成熟而出现在青春期。从这个发展概念中借用，我们建议一种新型的生物反应器系统，旨在概括两个接触的关节软骨层之间发生的滑动接触。使用该生物反应器，MSC的软骨细胞生物合成和软骨分化将被评估为固定期和滑动的持续时间和间歇性的函数。假设基因表达和分化的模式将取决于凝胶中的位置与所施加的接触的关系，并在接触线下和沿着浅表层中发生增强。随后的长期研究将利用这些优化的载荷方案来指导MSC和含有软骨细胞水凝胶构建体的机械性能增加压缩和拉伸（朝着滑动的方向）。此外，假设这些构建体将表现出增强的胶原蛋白含量以及在滑动接触方向上的平行胶原纤维方向。该应用研究了软骨细胞和含MSC的水凝胶实现软骨状拉伸特性的能力，并在新型的滑动接触生物反应器系统中通过培养物在这些构建体中灌输各向异性。这些研究将洞悉软骨分化和成熟的机制。如果意识到，该提案的具体目的将进一步努力产生与临床相关的软骨细胞替代软骨软骨替代品，这些功能软骨替换表现出具有复杂的材料特性和各向异性的定义定义天然组织，并且是其成熟功能所必需的。