A Novel Glycosaminoglycan Mimetic Scaffold for Cartilage Repair

项目摘要 由于关节软骨的愈合能力有限，临床干预是必要的，以防止 进一步的关节软骨损伤和退行性骨关节炎的早期发作。目前的外科 手术导致修复不充分，与周围的透明软骨整合不良 以及纤维软骨的形成而不是正常的透明软骨。最常用的修复方法 治疗膝关节软骨的小症状性损伤是微骨折，其中多个 在软骨下骨上打洞，使骨髓中的干细胞迁移到关节， 表面并便于修复。然而，从长远来看，这种方法并没有取代 正常的透明软骨本文所述的方法是将联合收割机的手术治疗 微骨折，这将提供能够软骨形成的内源性细胞到缺损部位， 在发育过程中模拟软骨细胞外基质的新型支架， 软骨发生和软骨组织形成。在软骨发育过程中， 成分是胶原和蛋白聚糖，其中主要的糖胺聚糖（GAG）在 蛋白聚糖是6-硫酸软骨素和硫酸肝素。硫酸化的模式和程度 这些和其它GAG在提供生长所需的功能性/生物活性方面起着不可或缺的作用 在软骨发育中的相互作用。典型的合成生物材料缺乏功能位点， 使这种互动。本研究将研究纤维素的半合成衍生物， 最丰富的天然材料，用于软骨修复。纤维素硫酸钠（NaCS）， 水溶性和模拟GAG的结构，将被制成支架，并与 微骨折作为软骨修复的新策略。NaCS是一种线性多糖， 用不同程度的硫酸化合成，以改善天然GAG的生物活性。在我们的研究中 迄今为止，完全硫酸化的NaCS已显示出促进软骨形成和加速修复的前景。 骨软骨缺损我们假设NaCS将赋予类似于 GAG，直接软骨发生和软骨组织形成。目标1将制造和表征NaCS 体外构建并观察骨髓间充质干细胞（MSC）向软骨细胞的分化。 目的2将评估体内软骨组织的形成和整合。这一目标的目的是 评估兔缺损中软骨组织形成和与周围宿主软骨的整合 模型目的3将研究NaCS结构在临床相关的临界尺寸软骨缺损中的应用 模型这项研究提出了一种新的GAG模拟策略，其中含有NaCS的支架可以 结合微骨折作为治疗软骨损伤的有效和可转化的策略。

Project Summary With the limited healing capability of articular cartilage, clinical intervention is necessary to prevent further articular cartilage damage and early onset of degenerative osteoarthritis. Current surgical procedures result in inadequate repair suffering from poor integration with surrounding hyaline cartilage and the formation of fibrocartilage instead of normal hyaline cartilage. The most frequently used reparative treatment for small symptomatic lesions of articular cartilage of the knee is microfracturing, where multiple holes are made in the subchondral bone allowing stem cells from the bone marrow to migrate to the joint surface and facilitate repair. However, in the long-term, this method does not result in the replacement of normal hyaline cartilage. The approach described here is to combine the surgical treatment of microfracturing, which will provide endogenous cells capable of chondrogenesis to the defect site, with a novel scaffold that mimics the cartilage extracellular matrix during development to promote chondrogenesis and cartilage tissue formation. During cartilage development, the major matrix components are collagens and proteoglycans, wherein the predominant glycosaminoglycans (GAGs) in the proteoglycans are chondroitin-6-sulfate and heparin sulfate. The pattern and degree of sulfation in these and other GAGs play an integral role in providing the necessary functionality/bioactivity for growth factor interactions in cartilage development. Typical synthetic biomaterials lack functional sites that would enable this interaction. This study will investigate a semi-synthetic derivative of cellulose, which is one of the most abundant natural materials, for cartilage repair. Sodium cellulose sulfate (NaCS), which is water soluble and mimics the structure of GAG, will be fabricated into a scaffold and combined with microfracturing as a novel strategy for cartilage repair. NaCS is a linear polysaccharide that can be synthesized with varying degrees of sulfation for improved bioactivity over native GAGs. In our studies to date, fully sulfated NaCS has shown promise in promoting chondrogenesis and accelerating the repair of osteochondral defects. We hypothesize that NaCS will impart functional qualities that are similar to GAGs, direct chondrogenesis and cartilage tissue formation. Aim 1 will fabricate and characterize NaCS constructs and investigate bone marrow derived mesenchymal stem cell (MSC) chondrogenesis in vitro. Aim 2 will evaluate cartilage tissue formation and integration in vivo. The goal of this aim is to evaluate cartilage tissue formation and integration with surrounding host cartilage in a rabbit defect model. Aim 3 will investigate NaCS constructs in a clinically relevant, critically-sized cartilage defect model. This study proposes a novel GAG-mimetic strategy where NaCS containing scaffolds can be combined with microfracturing as an effective and translatable strategy for treating cartilage lesions.