A Novel Glycosaminoglycan Mimetic Scaffold for Cartilage Repair

用于软骨修复的新型糖胺聚糖模拟支架

• 批准号: 10558632
• 负责人: Treena Lynne Arinzeh
• 金额: $ 34.09万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-16 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10558632
• 关键词: Acceleration; Address; Adult; Affect; American; Binding; Biochemical; Biocompatible Materials; Biological; Bone Marrow; CSPG6 gene; Cartilage; Cartilage Matrix; Cell Aggregation; Cell Communication; Cell-Matrix Junction; Cells; Cellulose; Chondrocytes; Chondrogenesis; Clinical; Collagen; Data; Defect; Degenerative polyarthritis; Development; Encapsulated; Event; Extracellular Matrix; Fibrocartilages; Gelatin; Glycosaminoglycans; Goals; Growth; Growth Factor Interaction; Heparin; Histologic; Human; Hyaline Cartilage; Imaging Techniques; In Vitro; Intervention; Joints; Knee; Lesion; Mechanics; Mediating; Mesenchymal; Mesenchymal Differentiation; Mesenchymal Stem Cells; Methods; Miniature Swine; Modeling; Molecular Biology Techniques; Morphology; Operative Surgical Procedures; Oryctolagus cuniculus; Pattern; Phenotype; Physical condensation; Play; Polysaccharides; Proteoglycan; Publishing; Role; Site; Sodium; Structure; Sulfate; Surface; Techniques; Testing; Thick; Tissues; Water; age effect; articular cartilage; bone cell; bone marrow mesenchymal stem cell; cartilage development; cartilage repair; cellulose sulfate; clinically relevant; early onset; healing; improved; in vivo; microbicide; migration; mimetics; novel; novel strategies; osteochondral repair; osteochondral tissue; prevent; repaired; scaffold; stem cells; subchondral bone; translatable strategy

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.

项目概要 由于关节软骨的愈合能力有限，需要临床干预来预防 进一步的关节软骨损伤和退行性骨关节炎的早期发作。目前手术 手术导致修复不充分，与周围透明软骨融合不良 并形成纤维软骨而不是正常的透明软骨。最常用的修复方法 膝关节软骨小症状病变的治疗方法是微骨折，其中多个 在软骨下骨上打孔，使骨髓中的干细胞迁移到关节 表面并便于修复。但从长远来看，这种方法并不能取代 正常的透明软骨。这里描述的方法是将手术治疗结合起来 微断裂，这将为缺损部位提供能够软骨形成的内源性细胞， 新型支架在发育过程中模仿软骨细胞外基质，以促进 软骨发生和软骨组织形成。在软骨发育过程中，主要基质 成分是胶原蛋白和蛋白聚糖，其中主要的糖胺聚糖（GAG） 蛋白多糖是6-硫酸软骨素和硫酸肝素。硫酸化的模式和程度 这些和其他 GAG 在提供生长所需的功能/生物活性方面发挥着不可或缺的作用 软骨发育过程中因素的相互作用。典型的合成生物材料缺乏功能位点 启用此交互。这项研究将研究纤维素的半合成衍生物，它是一种 最丰富的天然材料，用于软骨修复。纤维素硫酸钠（NaCS）， 水溶性并模仿GAG的结构，将被制作成支架并与 微骨折作为软骨修复的新策略。 NaCS是一种线性多糖，可以 合成时经过不同程度的硫酸化，以提高比天然 GAG 的生物活性。在我们的研究中 迄今为止，完全硫酸化的 NaCS 在促进软骨形成和加速修复方面表现出了希望 骨软骨缺损。我们假设 NaCS 将赋予类似于 GAG，直接软骨形成和软骨组织形成。目标 1 将制造 NaCS 并对其进行表征 体外构建并研究骨髓间充质干细胞 (MSC) 软骨形成。 目标 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的形成以及与周围宿主软骨的整合 模型。目标 3 将研究临床相关的临界尺寸软骨缺损中的 NaCS 结构 模型。这项研究提出了一种新颖的 GAG 模拟策略，其中含有 NaCS 的支架可以 与微骨折相结合作为治疗软骨损伤的有效且可转化的策略。