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.

项目摘要 由于关节软骨的愈合能力有限，因此需要进行临床干预以防止 进一步的关节软骨损伤和退化性骨关节炎的早期发作。当前手术 程序导致维修不足，由于整合不良的透明软骨 并形成纤维网状，而不是正常的透明软骨。最常用的修复 膝盖关节软骨的小症状病变的治疗是微裂缝的，其中有多个 在软骨下骨中制成孔，使从骨髓中的干细胞迁移到关节 表面并促进修复。但是，从长远来看，此方法并不能替代 正常的透明软骨。这里描述的方法是结合手术治疗 微裂缝将提供能够为缺陷部位提供软骨发生的内源细胞， 在开发过程中模仿软骨细胞外基质的新型脚手架以促进 软骨发生和软骨组织形成。在软骨开发过程中，主要矩阵 成分是胶原蛋白和蛋白聚糖，其中主要的糖胺聚糖（gags） 蛋白聚糖是软骨素-6-硫酸盐和硫酸肝素。硫酸的模式和程度 这些和其他插科打在提供增长的必要功能/生物活性方面起着不可或缺的作用 软骨发育中的因子相互作用。典型的合成生物材料缺乏功能位点 启用这种互动。这项研究将研究纤维素的半合成衍生物，这是一个 最丰富的天然材料，用于软骨维修。纤维素硫酸钠（NACS）， 水溶性和模仿插科打结构的结构将被制成脚手架，并与 微裂缝是软骨修复的新型策略。 NACS是一种线性多糖，可以是 与不同程度的硫酸化合成，以改善天然插科打no的生物活性。在我们的研究中 日期，完全硫化的NACS在促进软骨发生和加速修复方面表现出了希望 骨软骨缺陷。我们假设NACS会赋予与 插科打，直接软骨发生和软骨组织形成。 AIM 1将捏造并表征NACS 构建并研究骨髓在体外衍生的间充质干细胞（MSC）软骨发生。 AIM 2将评估软骨组织形成和体内整合。这个目标的目的是 评估软骨组织的形成，并与周围宿主软骨的整合在兔缺陷中 模型。 AIM 3将在临床相关的，批判性的软骨缺陷中研究NACS构建体 模型。这项研究提出了一种新型的插科打模仿策略，其中含有NAC的脚手架可以是 结合微裂纹作为治疗软骨病变的有效且可翻译的策略。