Genetically Designed Materials for Cartilage Repair

描述(申请人提供)：软骨修复的组织工程学策略因其促进受损组织功能恢复的潜力而颇具吸引力。然而，软骨功能的恢复是一个定义不明确且具有挑战性的设计目标，因为软骨具有重要的机械、生化和生物行为，很难用任何一种策略同时针对这些行为。我们建议设计一种基因工程支架，用于恢复关节软骨和半月板特有的组织功能，其中包括创建一套新的“成功结果”的定义。弹性蛋白样多肽(ELP)通过对氨基酸序列、相对分子质量和受控的交联点进行遗传编码，对具有广泛物理行为的生物相容材料进行基因工程。ELP作为软骨修复的多功能支架也很有吸引力，因为它们是肌肉骨骼组织固有的，没有抗原反应，可以设计成原位聚合形成完整的3D支架。在这个项目中，我们将设计和优化交联ELP水凝胶支架，用于两种不同组织-关节软骨和半月板的功能修复。我们还将探索两种不同的方法来交联ELPs-酶交联系统和光引发的交联系统。最后，我们将为软骨修复支架的合理设计开发一种新的框架。我们计划根据重要的机械、扩散和降解行为以及修复组织生化、组织化学外观和细胞增殖的可量化参数来定义每种支架的结果。选择的参数将通过使用ELP水凝胶支架进行的体外实验(特定目标1和2)或体内实验(特定目标3)确定。神经网络模型将被用来构建ELP支架成分和结构的遗传编码特征与描述“结果”的变量之间的关系，以确定这些复杂和不同的变量之间的模式(具体目标1和2)。这一努力将产生新的信息，说明测量的参数如何关联来定义特定的“结果”，从而实现定义跨越物理、生化和生物边界的支架成功的目标。这项工作的结果将是：(1)一个或多个适合修复软骨和半月板缺陷的交联型ELP；(2)一个合理量化和解释组织修复策略结果的框架；以及(3)一个训练有素的网络模型，可用于为各种软骨组织修复方案定制设计基于ELP的支架。

DESCRIPTION (provided by applicant): Tissue-engineering strategies for cartilage repair are attractive for their potential to promote functional restoration of the damaged tissue. Restoration of cartilage "function is a poorly defined and challenging design goal, however, as cartilage has important mechanical, biochemical and biological behaviors that are difficult to simultaneously target with any one strategy. We propose to design a genetically engineered scaffold for restoration of tissue function specific to articular cartilage and the meniscus, which includes the creation of a novel set of definitions of a "successful outcome". Elastin-like polypeptides (ELP) are useful for genetically engineering biocompatible materials with a broad array of physical behaviors through genetic encoding of amino acid sequence, molecular weight, and sites for controlled cross linking. ELPs are also attractive as a versatile scaffold for cartilage repair, as they are native to musculoskeletal tissues and present no antigenic response and may be designed to polymerize in situ to form an integrated 3D scaffold. In this project, we will engineer and optimize cross linked ELP hydrogel scaffolds for functional repair of two different tissues - articular cartilage and the knee meniscus. We will also explore two distinct approaches to cross linking ELPs - an enzymatic cross linking system and a photo-initiated cross linking system. Finally, we will develop a novel framework for the rational design of scaffolds for cartilage repair. We plan to define"outcomes for each scaffold based on quantifiable parameters of important mechanical, diffusion and degradation behaviors, as well as repair tissue biochemistry, histochemical appearance, and cell proliferation. Select parameters will be determined from experiments conducted with the ELP hydrogel scaffolds in vitro (Specific Aims 1 and 2) or in vivo (Specific Aim 3). Neural network models will be used to construct relationships between genetically encoded features of ELP scaffold composition and structure, and variables describing "outcome", to identify patterns amongst these complex and dissimilar variables (Specific Aims 1and 2). This effort will yield novel information on how measured parameters associate to define a particular "outcome", towards the goal of defining scaffold success across physical, biochemical and biological boundaries. The results of this effort will be: (1) one or more cross linked ELPs that are suitable for repair of cartilage and meniscal defects; (2) a framework for the rational quantitation and interpretation of results from tissue repair strategies; and (3) an extensively trained network model useful for the custom-design of an ELP based scaffold for a variety of cartilaginous tissue repair scenarios.