Injectable Cellular Composites for Cartilage Engineering

用于软骨工程的可注射细胞复合材料

• 批准号: 8289677
• 负责人: Fred Kurtis Kasper
• 金额: $ 32.08万
• 依托单位: RICE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8289677
• 关键词: Address; Adult; Autologous; Bone Regeneration; Cartilage; Cell Transplants; Cells; Chemicals; Clinical; Coupled; Culture Media; Defect; Degenerative polyarthritis; Dose; Drug Formulations; Encapsulated; Engineering; Environment; Foundations; Gelatin; Germ Cells; Goals; Growth Factor; Hydrogels; Implant; In Vitro; Injectable; Insulin-Like Growth Factor I; Kinetics; Mechanics; Mesenchymal Stem Cells; Modeling; Natural regeneration; Nature; Oryctolagus cuniculus; Pain; Population; Process; Progress Reports; Public Health; Research Project Grants; Staging; Stem cell transplant; Stem cells; Testing; Time; Tissues; Transforming Growth Factors; Translations; Transplantation; articular cartilage; bone; cartilage regeneration; combinatorial; density; experience; implantation; in vivo; in vivo Model; novel; novel strategies; oligo(poly(ethylene glycol)fumarate); osteochondral tissue; osteogenic; public health relevance; repaired; scaffold; tissue regeneration

DESCRIPTION (provided by applicant): The ultimate goal of this research project is to develop a novel injectable, bilayered, biodegradable hydrogel composite for the co-delivery of chondrogenic growth factors and mesenchymal stem cells (MSCs) to influence the degree and quality of cartilage tissue regeneration within osteochondral defects. We hypothesize that controlled dual delivery of transforming growth factor-21 (TGF-21) and insulin-like growth factor-1 (IGF-1) using optimal release kinetics and doses will induce chondrogenic differentiation of progenitor cells within the recipient to influence the regeneration of cartilage tissue in an osteochondral defect. Additionally, we hypothesize that the duration of exposure of MSCs to TGF-21 and osteogenic medium supplements during in vitro expansion will modulate the chondrogenic and osteogenic differentiation stages of the cells, respectively, which will in turn influence the degree and quality of osteochondral tissue regeneration when the cells are encapsulated within and transplanted with a hydrogel construct. Finally, we hypothesize that the co-delivery of growth factor(s) from hydrogel composites, coupled with the transplantation of progenitor cells encapsulated within the hydrogels will act cooperatively to promote regeneration of cartilage tissue in an osteochondral defect, with the initial cell seeding density influencing the degree and quality of the cartilage regeneration. To address these hypotheses, three Specific Aims are proposed. First, TGF-21 and IGF-1 will be loaded into OPF hydrogel constructs at different doses and released with different kinetics to determine the effect of these parameters on tissue regeneration in a rabbit osteochondral defect. Second, MSCs will be exposed to TGF-21 as a chondrogenic culture medium supplement or osteogenic medium supplements for various durations to result in cells of different chondrogenic and osteogenic differentiation stages, respectively, then they will be encapsulated within and transplanted with OPF hydrogel scaffolds (without loaded growth factors) into a rabbit osteochondral defect model to assess the effect of the differentiation stages of the transplanted cells upon osteochondral tissue regeneration. Third, cells of the optimal differentiation stages will be encapsulated for transplantation within OPF scaffolds corresponding to the optimal growth factor delivery formulation and will be implanted into rabbit osteochondral defects to determine the optimal seeding density of the progenitor cells for osteochondral tissue regeneration, which will be assessed post-implantation through histomorphometric analysis and mechanical testing. This novel strategy for the concurrent and spatially defined delivery of chondrogenic growth factors and in vitro expanded autologous progenitor cells to osteochondral defects presents tremendous potential for clinical translation and osteochondral tissue regeneration. PUBLIC HEALTH RELEVANCE: Due to the limited natural ability of cartilage tissue to repair itself, damage to articular cartilage and underlying bone often leads to significant clinical problems that afflict millions of people worldwide, including pain, limited mobility and osteoarthritis. No strategies currently exist that are consistently successful in treating cartilage defects of this nature. The project described in this proposal aims to develop novel injectable, bilayered, degradable materials that can be implanted as a vehicle for the concurrent delivery of bioactive molecules and adult derived stem cells to promote regeneration of damaged cartilage tissue.

描述(申请人提供)：本研究项目的最终目标是开发一种新型的可注射、双层、可生物降解的水凝胶复合材料，用于联合输送软骨生长因子和间充质干细胞(MSCs)，以影响骨软骨缺损区软骨组织再生的程度和质量。我们推测，使用最佳的释放动力学和剂量控制转化生长因子-21(TGF-21)和胰岛素样生长因子-1(IGF-1)的双重输送，将诱导受体体内的前体细胞向软骨分化，从而影响骨软骨缺损中软骨组织的再生。此外，我们假设，在体外扩增过程中，MSCs在转化生长因子-21和成骨介质补充剂中的暴露时间将分别调节细胞的软骨分化和成骨分化阶段，这反过来将影响细胞被包裹并与水凝胶构建物一起移植时骨软骨组织再生的程度和质量。最后，我们假设，从水凝胶复合材料中共输送生长因子(S)，再加上包裹在水凝胶中的祖细胞移植，将协同促进骨软骨缺损中软骨组织的再生，初始细胞种植密度影响软骨再生的程度和质量。为了解决这些假设，本文提出了三个具体目标。首先，将转化生长因子-21和胰岛素样生长因子-1以不同的剂量加载到OPF水凝胶载体中，并以不同的动力学方式释放，以确定这些参数对兔骨软骨缺损组织再生的影响。其次，将MSCs作为软骨细胞培养液或成骨细胞培养液分别作用不同时间，分别诱导成软骨和成骨分化阶段的细胞，然后将其包裹在OPF水凝胶支架内(不加载生长因子)，移植到兔骨软骨缺损模型中，评估移植细胞的分化阶段对骨软骨组织再生的影响。第三，将最佳分化阶段的细胞包裹在与最佳生长因子输送配方相对应的OPF支架内进行移植，并将其植入兔骨软骨缺损中，以确定用于骨软骨组织再生的祖细胞的最佳种植密度，并将通过组织形态计量学分析和力学测试来评估植入后的情况。将软骨生长因子和体外扩增的自体祖细胞移植到骨软骨缺损区的新策略在临床移植和骨软骨组织再生方面显示出巨大的潜力。 公共卫生相关性：由于软骨组织自我修复的天然能力有限，关节软骨和底层骨骼的损伤往往会导致严重的临床问题，这些问题困扰着全球数百万人，包括疼痛、活动受限和骨关节炎。目前还没有治疗这种性质的软骨缺损的持续成功的策略。该提案中描述的项目旨在开发新型可注射、双层、可降解的材料，这些材料可以作为载体同时输送生物活性分子和成人来源的干细胞，以促进受损软骨组织的再生。