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 Fisher 奖 ID：1264517 智力优点肌肉骨骼疾病和损伤通常会导致关节软骨损伤。这些软骨缺陷几乎没有固有的修复能力。目前的临床治疗不足，因为它们常常导致纤维软骨形成和关节疼痛。该提案的目标是开发专门用于浅层软骨再生的软骨细胞。这一策略的前提是为临床医生提供一种早期干预方法，同时也能防止形成更严重的缺陷。该小组最近证明了从原代间充质干细胞 (MSC) 中衍生出骨软骨祖细胞 (OPC) 的能力，并表明这些 OPC 对胰岛素样生长因子-1 (IGF-1)（一种与功能性关节软骨相关的合成代谢生长因子）有反应。研究表明，透明质酸 (HA) 可以导致浅层区蛋白 (SZP) 的软骨细胞表达上调，浅层区蛋白 (SZP) 是浅层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。据推测，在软骨形成培养基中动态培养人间充质干细胞将提供有利于软骨细胞快速分化的环境。具体而言，动态培养条件提供的增强的氧气和营养物质运输将促进 hMSC 活力和增殖，而 TGF-β3 输送和通过灌注软骨形成培养基赋予的剪切力将促进软骨细胞分化。为了检验这一假设，将开发动态培养参数以指导 MSC 分化为 OPC。其次，据推测，IGF-1 受控递送至骨软骨祖细胞将促进其成熟为分化的浅表区软骨细胞，如上调的 PRG4 和 II 型胶原蛋白表达所证明的那样。此外，据推测，工程浅表区软骨可以有效治疗大鼠模型中的浅表关节软骨缺陷。为了检验这些假设，将在 TPS 生物反应器环境中将外源 IGF-1 递送至骨软骨祖细胞，并评估它们向浅表区软骨细胞的成熟情况，如 PRG4 和 II 型胶原蛋白的产生所示，然后利用这种工程构建体在大鼠模型中再生浅表区软骨。 更广泛的影响 该项目的更广泛影响包括 工程组织的开发以及再生医学中新策略和技术的阐明。此外，加强多个教育层次的生物医学工程研究是该工作影响的一个关键方面。与该提案相关的关键活动将是开发和执行与马里兰大学工程世界健康 (EWH) 分会相关的一系列新项目。 EWH 旨在创造并向发展中国家传播易于实施的生物医学技术。 PI 在 2011-2012 年马里兰州 EWH 分会成立之初就与该分会合作，以实现这些目标。 PI 还将继续开展许多影响本科生和研究生教育的活动。例如，PI 目前教授本科生生理系统建模和实验室课程，以及本科生/研究生组织工程课程。自 2007 年以来，PI 负责指导本科生分子和细胞生物工程研究体验网站。迄今为止，分子与细胞生物工程 REU 网站已吸引了来自全国各地的约 60 名学生在费舍尔生物工程系相关教师的实验室工作。最后，PI 目前担任 Fischell 生物工程系的副系主任和本科生研究主任。在此职位上，PI 对在课程、项目和研究层面上促进本科生生物工程教育具有直接影响力。由生物医学工程 (CBET) 和生物研究仪器开发 (BIO 理事会) 联合资助