Fibrous-Hydrogel Composites for Cartilage Repair in an Osteoarthritic Environment

描述(由申请人提供)：关节表面的损伤不会自发愈合，通常是临床上难以解决的问题，需要有症状地处理。关节软骨的进行性丧失是退行性关节疾病骨关节炎的病理特征。骨性关节炎是困扰人类的最常见的关节疾病之一，据估计，超过60%的美国人在55岁之前出现了骨性关节炎的放射学证据。考虑到美国人口老龄化和老年人体力活动的增加，随着时间的推移，这一估计可能会增加。这项建议的目的是设计和表征一种新型的纤维-水凝胶复合材料，以加强正常和骨关节炎环境下软骨缺损的修复。这项建议的目标是假设和设计驱动的，并将在以下具体目标中解决：目的1.开发和表征新型纤维-水凝胶复合材料以促进软骨修复。具体地说，我们将把三维电纺聚己内酯纤维网络结合到可光聚合的聚乙二醇水凝胶中。水凝胶中的纤维直径和密度将被调节，以优化复合材料的体积性能和软骨形成潜力。将对复合材料的物理性能进行评估。通过原代软骨细胞和骨髓间充质干细胞的包裹实验，体外研究软骨形成的潜力。这种材料的再生潜力将使用基于白介素1B暴露的体外骨关节炎模型进行研究。软骨的形成将根据细胞外基质的产生、基因表达和组织学进行评估。目的2.将纤维-水凝胶复合材料和基于细胞的修复策略转化为正常和骨关节炎关节的啮齿动物模型。来自Aim 1的合适材料将结合骨髓刺激程序应用于大鼠股骨滑车上的临界大小软骨缺损。在关节环境退化的大鼠手术失稳模型中，将用来评估这些材料的修复潜力。我们构建的软骨的发育和整合将通过大体损伤分级标准和组织学来评估。

DESCRIPTION (provided by applicant): Lesions of the articular surface do not heal spontaneously and are often intractable clinical problems that are managed symptomatically. The progressive loss of articular cartilage is a pathologic hallmark of the degenerative joint disease osteoarthritis (OA). OA is one of the most common joint disorders afflicting humans, and it is estimated that over 60% of the United States population develop radiographic evidence of OA by 55 years of age. Given the aging American population and increasing physical activity among the elderly this estimate is likely to increase over time. The objective of this proposal is to design and characterize a novel fibrous-hydrogel composite to enhance the repair of cartilage defects in a normal and OA environment. The goals of this proposal are both hypothesis and design driven and will be addressed in the following specific aims: Aim 1. Development and characterization of novel fibrous-hydrogel composites to promote cartilage repair. Specifically, we will incorporate a three dimensional electrospun poly(caprolactone) fibrous network into a photopolymerizable polyethylene-glycol hydrogel. Fiber diameter and density within the hydrogel will be modulated in order to optimize the bulk properties and chondrogenic potential of the composite. Physical properties of the composite will be evaluated. The chondrogenic potential will be studied in vitro through encapsulation experiments with primary chondrocytes and MSCs. The regenerative potential of this material will be investigated using an in vitro OA model based on Interleukin 1B exposure. Cartilage formation will be assessed on the basis of ECM production, gene expression, and histology. Aim 2. Translate the fiber-hydrogel composites and cell-based repair strategies to a rodent model of a normal and osteoarthritic joint. The appropriate material from Aim 1 will be applied to a critical sized cartilage defect on the rat femoral trochlea in combination with a marrow stimulation procedure. A rat surgical destabilization model of OA will be used to evaluate the repair potential of these materials in the context of a degradative joint environment. Cartilage development and integration of our constructs will be evaluated by gross lesion grading scales and histology.