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，临床干预是必要的。 进一步的关节软骨损伤和退行性骨关节炎的早期发病。当前外科手术 手术导致修复不充分，与周围透明软骨整合不良 纤维软骨的形成取代了正常的透明软骨。最常用的修复剂 膝关节软骨小症状性病变的治疗是微骨折，其中多发性 软骨下骨上会打洞，让骨髓中的干细胞迁移到关节上。 表面平整，便于维修。然而，从长远来看，这种方法并不会导致 正常的透明软骨。这里所描述的方法是结合手术治疗 微骨折，这将提供内源性细胞能够向缺损处形成软骨，具有 新型支架在发育过程中模拟软骨细胞外基质促进 软骨生成和软骨组织形成。在软骨发育过程中，主要基质 成分是胶原蛋白和蛋白多糖，其中主要的糖胺聚糖(GAG)在 蛋白多糖是软骨素-6-硫酸盐和硫酸肝素。硫酸盐化的方式和程度 这些GAG和其他GAG在为生长提供必要的功能/生物活性方面发挥着不可或缺的作用 软骨发育中的因素相互作用。典型的合成生物材料缺乏功能位点， 启用此交互。这项研究将研究一种半合成的纤维素衍生物，它是 最丰富的天然材料，用于软骨修复。纤维素硫酸钠(NaCS)，它是 可溶于水并模仿GAG结构，将其制成支架并与 微骨折作为一种新的软骨修复策略。NaCS是一种线性多糖，可以 用不同程度的硫酸盐化合成，以提高天然GAG的生物活性。在我们的学习中 目前，完全硫酸盐化的NAC在促进软骨生成和加速修复方面显示出了良好的前景 骨软骨缺陷症。我们假设NAC将提供与以下类似的功能特性 GAG、直接软骨生成和软骨组织形成。目标1将制造和表征NAC 构建并研究骨髓间充质干细胞(MSC)在体外的软骨形成。 目的2将评估体内软骨组织的形成和整合。这一目标的目标是 评价兔缺损区软骨组织的形成及其与周围宿主软骨的结合 模特。AIM 3将研究临床相关的临界大小的软骨缺损中的NACS结构 模特。本研究提出了一种新的模拟插嘴策略，其中包含支架的NAC可以 结合显微骨折是治疗软骨损伤的一种有效和可移植的策略。