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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

基本信息

批准号：
8837570
负责人：
Julie C. Liu
金额：
$ 19.78万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-11 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8837570
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 Health 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 degradation cartilage regeneration cartilage repair cytokine design functional mimics improved in vivo joint function joint stiffness polysulfated glycosaminoglycan prevent research study scaffold stem cell differentiation tissue regeneration

项目摘要

DESCRIPTION: 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 applicaton 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 application 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 ste cells.

描述：骨关节炎（OA）是一种使人衰弱的疾病，根据关节炎基金会，影响超过2700万美国人。该疾病的特征是关节软骨细胞外基质（ECM）分子的破坏，包括II型胶原蛋白、聚集蛋白和透明质酸（HA）。随着ECM退化，出现疼痛和关节僵硬等症状。一旦胶原蛋白丢失，人们认为软骨独立再生的机会就丧失了。考虑到这一点，我们之前描述了将功能模拟的聚集蛋白与排列的软骨结合起来的协同效应，以防止基质降解并促进原代牛软骨细胞合成软骨ECM。然而，在人类中，我们的软骨细胞供应是有限的，原发性关节软骨细胞的收获可能导致供体部位发病率。成体间充质干细胞（MSCs）是一种很有前途的细胞来源，因为它们可以在没有损伤的情况下获得，具有高增殖能力，并且在适当的环境条件下可以分化成软骨细胞。然而，利用间充质干细胞的一个主要挑战是，以间充质干细胞为种子的移植物不能产生与分化软骨细胞为种子的移植物一样多的基质。因此，为有效的微分和随后的矩阵生成建立条件是至关重要的。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骨关节炎损伤的软骨。为了实现这一目标，我们的目标是创造一个环境，以抵抗OA软骨降解的破坏性循环，模拟天然软骨结构，并促进MSCs的软骨分化。为了解决这些问题，我们制定了以下具体目标。目的1：评估排列、聚集蛋白模拟浓度和BMP肽浓度对干细胞分化的影响。目的2：研究协同作用对软骨分化的影响。这一应用的结果将阐明影响干细胞分化的局部微环境的特性，从而增强基质的产生和机械性能。因此，这些研究将作为未来NIH R01申请的初步数据，该申请将在体内缺陷模型中评估这些结构。确定材料为基础的线索，导致改善软骨移植物是必要的，以发展安全有效的临床治疗涉及成人细胞。