Biomimetic Scaffolds to Promote Stem Cell Differentiation for Cartilage Engineeri

仿生支架促进软骨工程干细胞分化

• 批准号: 8617559
• 负责人: Julie C. Liu
• 金额: $ 16.42万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-11 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8617559
• 关键词: Address; Adult; Affect; American; Arthritis; Biomimetics; Cartilage; Cartilage Matrix; Cattle; Cells; Chondrocytes; Chondrogenesis; Chondroitin Sulfates; Clinical; Collagen; Collagen Type II; Coupled; Cues; Data; Defect; Degenerative polyarthritis; Development; Disease; Environment; Enzymes; Extracellular Matrix; Foundations; Future; Gene Expression; Glycosaminoglycans; Goals; Harvest; Human; Hyaluronic Acid; Hyaluronidase; Inflammation; Injury; Interleukin-1; Joints; Lead; Matrix Metalloproteinases; Mechanics; Mediating; Mesenchymal Stem Cells; Mind; Modeling; Morbidity - disease rate; Oryctolagus cuniculus; Pain; Peptides; Process; Production; Property; Site; Source; Structure; Symptoms; Technology; Testing; Tissue Engineering; United States National Institutes of Health; adult stem cell; aggrecan; aggrecanase; articular cartilage; base; bone morphogenetic protein 2; cartilage regeneration; cartilage repair; cytokine; design; functional mimics; improved; in vivo; joint function; joint stiffness; polysulfated glycosaminoglycan; prevent; public health relevance; research study; scaffold; stem cell differentiation; tissue regeneration

Summary Osteoarthritis (OA) is a debilitating disease that, according to the Arthritis Foundation, affects over 27 million Americans. The disease is characterized by a breakdown of articular cartilage extracellular matrix (ECM) molecules, including collagen type II, aggrecan, and hyaluronic acid (HA). As the ECM degrades, symptoms appear including pain and increasing joint stiffness. Once loss of collagen occurs, it is believed that the opportunity for unaided cartilage regeneration is lost. With this in mind, we previously described synergistic effects of combining a functional mimic of aggrecan with aligned cartilage to prevent matrix degradation and promote cartilage ECM synthesis by primary bovine chondrocytes !"#. However, in humans, we are limited in our supply of chondrocytes, and harvest of primary articular chondrocytes can lead to donor site morbidity. Adult mesenchymal stem cells (MSCs) are a promising cell source because they can be harvested without injury, have a high proliferation capacity, and can differentiate into chondrocytes under appropriate environmental conditions. One major challenge of utilizing MSCs, however, is that grafts seeded with MSCs do not produce as much matrix as grafts seeded with differentiated chondrocytes !$%&#. Thus, it is vital to establish conditions for effective differentiation and subsequent matrix production. Our long-term goal is to use MSCs in tissue-engineered cartilage to replace cartilage damaged by osteoarthritis. To achieve this goal, our objective is to create an environment that resists the destructive cycle of cartilage degradation from OA, mimics the native cartilage structure, and promotes chondrogenic differentiation of MSCs. To address these issues, we have developed the following specific aims. Aim 1: Evaluate the effects of alignment, aggrecan mimic concentration, and BMP peptide concentration on stem cell differentiation. Aim 2: Investigate the effect of synergistic interactions on cartilage differentiation. The results from this proposal will elucidate properties of the local microenvironment that affect stem cell differentiation, resulting in enhanced matrix production and mechanical properties. These studies will thus serve as preliminary data for a future NIH R01 proposal that will evaluate these constructs in an in vivo defect model. Identification of material-based cues that result in improved cartilage grafts is essential in the development of safe and effective clinical therapies involving adult stem cells.

概括 据关节炎基金会称，骨关节炎 (OA) 是一种使人衰弱的疾病，影响超过 2700万美国人。该疾病的特点是关节软骨细胞外破坏 基质 (ECM) 分子，包括 II 型胶原蛋白、聚集蛋白聚糖和透明质酸 (HA)。作为 ECM 退化，出现包括疼痛和关节僵硬增加等症状。一旦胶原蛋白流失 一旦发生这种情况，人们相信就会失去无辅助软骨再生的机会。考虑到这一点， 我们之前描述了聚集蛋白聚糖的功能模拟物与对齐的组合的协同效应 软骨防止基质降解并促进原代牛软骨ECM合成 软骨细胞！”#。然而，在人类中，我们的软骨细胞供应和收获是有限的 原代关节软骨细胞可导致供体部位发病。成体间充质干细胞 （间充质干细胞）是一种很有前途的细胞来源，因为它们可以在无损伤的情况下收获，具有很高的 具有增殖能力，在适当的环境下可分化为软骨细胞 状况。然而，利用 MSC 的一大挑战是，接种 MSC 的移植物不会 产生与接种分化软骨细胞的移植物一样多的基质！$%&#。因此，至关重要的是 为有效分化和随后的基质生产创造条件。 我们的长期目标是在组织工程软骨中使用间充质干细胞来替代因软骨损伤而受损的软骨。 骨关节炎。为了实现这一目标，我们的目标是创造一个抵抗 OA 软骨退化的破坏性循环，模仿天然软骨结构，并且 促进 MSC 的软骨分化。为了解决这些问题，我们开发了 遵循特定目标。目标 1：评估对齐、聚集蛋白聚糖模拟浓度和 BMP 肽浓度对干细胞分化的影响。目标 2：研究协同效应 软骨分化的相互作用。 该提案的结果将阐明影响干细胞的局部微环境的特性 细胞分化，从而增强基质生产和机械性能。这些研究 因此，将作为未来 NIH R01 提案的初步数据，该提案将在 体内缺陷模型。识别基于材料的线索，从而改善软骨移植 对于开发涉及成体干细胞的安全有效的临床疗法至关重要。