Shear Force Effects on Superficial Cartilage Regeneration

剪切力对浅层软骨再生的影响

• 批准号: 1264517
• 负责人: John Fisher
• 金额: $ 30.98万
• 依托单位: University of Maryland, College Park
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1264517&HistoricalAwards=false
• 关键词: Shear; Force; Effects; Superficial; Cartilage

PI: John P FisherAward ID: 1264517Intellectual MeritMusculoskeletal disease and injury can commonly result in damage to articular cartilage. These cartilage defects have little inherent ability to repair. Current clinical treatments are inadequate as they often lead to fibrocartilage formation and joint pain. The goal of this proposal is to develop chondrocytes specifically for superficial zone cartilage regeneration. The premise of this strategy is to provide clinicians with an early stage intervention approach, and one that would also prevent the formation of more debilitating defects. This group has recently demonstrated the ability to derive osteochondroprogentior cells (OPCs) from primary mesenchymal stem cells (MSCs) and shown these OPCs to be responsive to insulin-like growth factor-1 (IGF-1), an anabolic growth factor associated with functional articular cartilage. It has been shown that hyaluronic acid (HA) can lead to up-regulate chondrocytic expression of superficial zone protein (SZP), a key phenotypic marker for superficial zone chondrocytes. These results led to the development of the following hypotheses. It is hypothesized that the dynamic culture of human mesenchymal stem cells within chondrogenic media will provide an environment conducive for rapid chondrocytic differentiation. Specifically, enhanced oxygen and nutrient transport, provided by the dynamic culture conditions, will promote hMSC viability and proliferation, while TGF-beta3 delivery and shear forces imparted the by perfusing chondrogenic media will promote chondrocytic differentiation. To examine this hypothesis, dynamic culture parameters will be developed so as to direct MSC differentiation into OPCs. Second, it is hypothesized that controlled delivery of IGF-1 to osteochondroprogenitor cells will encourage their maturation to differentiated superficial zone chondrocytes, as demonstrated by up-regulated PRG4 and type II collagen expression. In addition, it is hypothesized that engineered superficial zone cartilage can effectively treat superficial articular cartilage defects in a rat model. To examine these hypotheses, delivery exogenous IGF-1 to osteochondroprogenitor cells within the TPS bioreactor environment will be performed and their maturation into superficial zone chondrocytes will be assessed as well, as indicated by PRG4 and type II collagen production, and then utilize this engineered construct to regenerate superficial zone cartilage in a rat model.Broader ImpactsThe broader impacts of this project include the development of an engineered tissue and the elucidation of new strategies and technologies within regenerative medicine. In addition, enhancing biomedical engineering research at multiple education levels is a key aspect of the work's impact. The key activity related to this proposal will be the development and execution of a new series of projects associated with the Engineering World Health (EWH) chapter at the University of Maryland. EWH aims to create and distribute readily implementable biomedical technologies to developing countries. The PI has worked with the EWH chapter at Maryland during it inaugural year in 2011-2012 to realize these goals. The PI will also continue many activities that impact undergraduate and graduate education. For example, the PI currently instructs an undergraduate Modeling Physiological Systems and Laboratory course, and an undergraduate / graduate Tissue Engineering course. Since 2007, the PI has directed the Molecular & Cellular Bioengineering Research Experiences for Undergraduates Site. To date, the Molecular & Cellular Bioengineering REU site has brought approximately 60 students from around the country to work in the laboratories of faculty associated with the Fischell Department of Bioengineering. Finally, the PI currently acts as the Associate Chair and Director of Undergraduate Studies in the Fischell Department of Bioengineering. In this position, the PI has a direct influence in fostering undergraduate bioengineering education at the curriculum, program, and research levels.Jointly funded by Biomedical Engineering (CBET) and Instrument Development for Biological Research (BIO Directorate)

PI：John P Fisheraward ID：1264517Intlectual firitmusculoskleoskeletal疾病和损伤通常会导致关节软骨的损害。这些软骨缺陷几乎没有固有的维修能力。当前的临床治疗不足，因为它们通常会导致纤维球杆菌形成和关节疼痛。该提案的目的是开发专门针对浅表软骨再生的软骨细胞。该策略的前提是为临床医生提供一种早期干预方法，这也将阻止形成更多令人衰弱的缺陷。该组最近证明了从原发性间质干细胞（MSC）中得出骨软质细胞（OPC）的能力，并证明这些OPC对胰岛素样生长因子1（IGF-1）有反应，这是一种与功能关节软骨相关的合成代谢生长因子。已经表明，透明质酸（HA）可以导致表面蛋白（SZP）的软骨细胞表达（SZP），这是浅表软骨细胞的关键表型标记。这些结果导致了以下假设的发展。假设软骨培养基中人间充质干细胞的动态培养将为快速软骨细胞分化提供一个环境。具体而言，由动态培养条件提供的增强的氧气和养分传输将促进HMSC的活力和增殖，而TGF-BETA3的递送和剪切力通过完美的软骨源会促进软骨细胞分化。为了检验这一假设，将开发动态培养参数，以将MSC分化为OPC。其次，假设由上调的PRG4和II型胶原蛋白表达所证明的，受控递送IGF-1向骨软骨元素细胞的递送将鼓励它们成熟到分化的表面软骨细胞。此外，假设工程的表面软骨可以有效地治疗大鼠模型中的浅表关节软骨缺陷。为了检查这些假设，将进行TPS生物反应器环境中的外源IGF-1向骨软骨生殖器细胞的递送，并将评估它们成熟成浅层软骨细胞，如PRG4和II型胶原蛋白产量所示，然后利用这些工程构造的影响范围，并将其构建为构建范围。开发工程组织，并阐明再生医学中新的策略和技术。此外，在多个教育水平上增强生物医学工程研究是工作影响的关键方面。与该提案相关的关键活动将是与马里兰大学的工程世界卫生（EWH）分会相关的一系列新项目的开发和执行。 EWH旨在为发展中国家创建和分发易于实施的生物医学技术。 PI在2011 - 2012年就职期间与马里兰州的EWH分会合作，以实现这些目标。 PI还将继续进行许多影响本科和研究生教育的活动。例如，PI目前指导本科生建模生理系统和实验室课程，以及本科 /研究生组织工程课程。自2007年以来，PI指导了本科生部位的分子和细胞生物工程研究经验。迄今为止，分子和蜂窝工程REU网站已将来自全国的大约60名学生带到了与Fischell生物工程系相关的教师实验室工作。最后，PI目前是Fischell生物工程系的副主席兼本科研究主任。在这个职位上，PI在课程，计划和研究级别培养本科生物工程教育方面具有直接影响。由生物医学工程（CBET）（CBET）和生物学仪器开发（Bio Direction）资助。