Repair and regeneration of osteochondral defects in mouse articular joints

小鼠关节骨软骨缺损的修复与再生

• 批准号: 1133883
• 负责人: Mei Wei
• 金额: $ 31.11万
• 依托单位: University of Connecticut
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1133883&HistoricalAwards=false
• 关键词: Repair; regeneration; osteochondral; defects; mouse

1133883WeiIn a high percentage of patients, damages to the articular cartilage surface and the underlying subchondral bone can easily progress to joint degeneration, especially osteoarthritis which is the main cause of chronic disability in US. Extensive efforts have been made in osteochondral defect treatment, but there is still no widely accepted method which produces consistent satisfactory results. The regenerated cartilage is inferior to the original cartilage morphologically, biochemically, and biomechanically. Instead of forming articular cartilage, fibrocartilage is normally generated, which lacks of the long-term stability and cannot withstand prolonged stress to the joint. Thus, there is a need for a new approach that outperforms currently used methods. In this study, we propose to develop a graded scaffold with structure and mechanical properties mimicking those of natural cartilage, load the scaffold with articular-specific chondroprogenitor cells identified by GFP reporters, and then implant the cell-loaded scaffold into a novel transgenic mouse cartilage model to test for osteochondral repair and regeneration. It is expected that an optimum cell-scaffold construct will be determined which effectively regenerates osteochondral cartilage with excellent functionality and long-term stability.Intellectual merits: The novelty of the current proposal includes: (1) the development of a graded scaffold with structure, orientation, composition and mechanical properties mimicking those of natural cartilage and subchondral bone; (2) the development of an in-depth understanding of chondrocytes differentiation pathways and establishment of their lineage interrelationships; (3) the identification of articular-specific chondroprogenitor cells using a series of cartilage GFP reporters; (4) the development of an informative transgenic murine cartilage model to assess osteochondral repair and its integration with host tissues at a relatively low cost.Broader impact: The proposed project has a broader impact on various scientific disciplines. The results of the proposed research will contribute to our understanding of the cell-scaffold interactions, chondrocyte differentiation pathways, and host/donor cell contribution to the articular cartilage restoration for the first time. The information gained here will be an essential ingredient in developing and interpreting tissue engineering strategies to determine the optimal scaffold design and source of progenitors, and whether a repair process is initiated from the host or donor. Distinguishing the completeness of the repair in terms of the composition of cells that fill the repair region will be another measure of success of a repair strategy. The proposed research will be transformative to the tissue engineering field as it directly addresses the existing problems of the osteochondral cartilage repair and its approach may provide an effect solution to these problems.This project will result in the training of a graduate student and a number of undergraduate students in areas of tissue engineering, while exposing them to a multidisciplinary working environment. Efforts will be made to recruit female and minority students by integrating our research activities with existing recruiting efforts at the Department, the School and the University levels as well as participating in activities organized by various professional societies dedicated to underrepresented minorities. In addition, we will perform K-12 outreach to get high school students, especially female and underrepresented minorities, excited about engineering research. The results obtained from the project will be disseminated broadly via publishing in scientific journals, presenting in conferences and publicizing to general public via a website. We will make sure that all data will be kept for at least three years after conclusion of the award or three years after public release, whichever is later. We will also make our transgenic mice available to the tissue engineering community so that more researchers can use them to optimize their repair strategies.

1133883Weiin很大一部分患者，关节软骨表面的损害和下面的下骨可以很容易地发展为关节变性，尤其是骨关节炎，这是美国慢性残疾的主要原因。在骨软骨缺陷治疗中已经做出了广泛的努力，但是仍然没有广泛接受的方法可以产生一致的令人满意的结果。再生软骨在形态，生物化学和生物力学上都比原始软骨不如原始软骨。通常会产生纤维球杆菌，而不是形成关节软骨，而是缺乏长期稳定性，无法承受对关节的延长应力。因此，需要一种新方法，该方法当前使用了当前使用的方法。在这项研究中，我们建议开发一个具有模仿天然软骨的结构和机械性能的分级支架，并用GFP记者确定的关节特异性软骨元素细胞加载支架，然后将细胞加载的脚手架植入新型的转基因小鼠模型，以测试一种新型的转基因软骨模型，以进行骨质修复和注射量。可以预期，将确定最佳的细胞支撑构建体有效地再生骨软骨，具有出色的功能和长期稳定性。智能优点：当前提案的新颖性包括：（1）开发具有结构，方向，方向，组成和机械性能的级分脚手，模仿自然Cartilage and Subschondral bornal bornal bornal bornal bornal bornal bornal； （2）对软骨细胞分化途径的深入理解和建立其血统相互关系； （3）使用一系列软骨GFP记者鉴定关节特异性软骨元基因细胞； （4）开发信息丰富的转基因鼠软骨模型，以评估骨软骨修复及其与宿主组织的整合，其成本相对较低。BRODER的影响：拟议的项目对各种科学学科都有更广泛的影响。拟议的研究的结果将有助于我们首次对关节软骨恢复的细胞 - 伴侣相互作用，软骨细胞分化途径以及宿主/供体细胞的贡献。这里获得的信息将是制定和解释组织工程策略的重要组成部分，以确定最佳的脚手架设计和祖细胞的来源，以及是否从宿主还是供体开始修复过程。从填充修复区域的细胞组成方面区分修复的完整性将是修复策略成功的另一个量度。拟议的研究将对组织工程领域进行变革，因为它直接解决了骨软骨软骨修复的现有问题，其方法可能会为这些问题提供效果解决方案。该项目将导致研究生培训研究生和许多本科生在组织工程领域的本科生，同时将它们公开为多学科工作环境。将通过将我们的研究活动与部门，学校和大学级别的现有招聘工作以及参与专门用于代表性不足少数群体组织的各种专业社会组织的活动进行努力来招募女性和少数族裔学生。此外，我们将进行K-12外展活动，以吸引高中生，尤其是女性和代表性不足的少数民族，对工程研究感到兴奋。从该项目获得的结果将通过在科学期刊上发表广泛传播，并在会议上介绍并通过网站向公众宣传。我们将确保在奖励结束后或公开发布后三年后至少保存所有数据，以较晚者为准。我们还将使我们的转基因小鼠可用于组织工程社区，以便更多的研究人员可以使用它们来优化其维修策略。