Novel Strategies in Cartilage Tissue Engineering: Enhancing Cartilage Stability Using Muscle-Derived Factors and Scaffold Selection

ZengCartilage是一种自我修复能力较差的组织。目前的组织工程策略旨在通过将软骨细胞或软骨细胞种植到三维支架中来替换受损组织。在支架内，这些软骨细胞增殖并分泌细胞外基质，导致再生软骨的形成。然后，这些再生的软骨将被移植到宿主体内，目的是承担本地软骨的功能。工程化软骨的生物力学强度与软骨细胞产生的细胞外基质的量直接相关。然而，即使具有良好力学性能的再生软骨也可能被宿主部位存在的促炎细胞因子破坏，从而影响再生软骨的稳定性。因此，迫切需要工程化软骨能够抵抗促炎细胞因子诱导的降解。这项跨学科的研究结合了发育生物学(曾博士)和组织工程学(卡普兰博士)的专业知识。它旨在通过验证肌肉细胞和支架选择可以从软骨基质产生和抗炎性细胞因子方面增强再生软骨的稳定性这一中心假设来解决软骨组织工程技术中的关键问题。计划进行一系列全面的生化和生物力学分析来验证这一假说。关于肌肉细胞调节软骨基因表达的机制知之甚少，肌肉细胞或支架材料对细胞因子反应的作用也从未报道过。因此，除了推进软骨组织工程技术的发展外，完成这项研究也将使人们对软骨调控的生物学有更深入和更完整的了解。本建议中描述的策略受到动物发育概念的启发，当组织(如软骨和肌肉)同时发育时，在相邻组织之间的细胞-细胞信号传递以及随后的分化和增殖中发挥关键作用。因此，软骨的形成不仅涉及软骨细胞，还涉及周围多个组织的细胞。因此，我们模仿胚胎发育的想法可能会启发我们创造新的策略，来设计其他组织类型的工程。更广泛的影响。这项拟议的研究试图在科学知识之外促进教育和学习。两个新的模块被设计成两门课程(即生物材料与组织工程和发育生物学)，重点是利用发育生物学的概念和方法加强软骨组织工程，并使用组织工程方法总结和研究发育过程。课程将分为课堂讲课、学生陈述和文学阅读。曾博士和卡普兰博士都参加了各种教育项目，如TAHSS(教师和高中生)和BDBS(建立生物医学科学的多样性)。这些计划招收少数族裔或经济上处于不利地位的学生，否则他们可能没有机会接触研究。研究计划的教育方面经过仔细研究，使不同水平的学生能够在两个实验室进行跨学科的研究。拟议的研究活动也将加强科学界的基础设施。首先，这项工作将直接惠及塔夫茨大学的当地社区。特别是，它将为塔夫茨生物工程和生物技术中心的基础设施做出贡献。通过其教育和培训计划，该中心将学术界内的成员(学生、博士后和教职员工)以及学术界和产业界之间的成员联系起来。此外，这项研究的成果将通过出版物以及全国各地的会议和研究研讨会与其他科学家分享。因此，这项研究产生的活动也将对广大科学界产生积极影响。

0966920ZengCartilage is a tissue that has a poor capacity for self-repair. Current tissue engineering strategies aim to replace damaged tissue by seeding cartilage cells or chondrocytes into three-dimensional scaffolds. Within the scaffolds, these chondrocytes proliferate and secrete extracellular matrix, leading to the formation of regenerated cartilage. This regenerated cartilage will then be transplanted into the host, with the goal of assuming the function of native cartilage. The biomechanical strength of engineered cartilage is directly correlated to the amount of extracellular matrix produced by cartilage cells. Yet, even regenerated cartilage with good mechanical properties may be damaged by pro-inflammatory cytokines present in the host site, compromising the stability of the regenerated cartilage. Thus, there is a critical need for engineered cartilage to be resistant to pro-inflammatory cytokine-induced degradation.Intellectual merit.This interdisciplinary research combines the expertise of developmental biology (Dr. Zeng) with tissue engineering (Dr. Kaplan). It aims at solving key issues in the technology of cartilage tissue engineering by testing the central hypothesis that muscle cells and scaffolding selection can enhance the stability of regenerated cartilage in terms of cartilage matrix production and inflammatory cytokine resistance. A comprehensive battery of biochemical and biomechanical analyses are planned to test this hypothesis. Very little is known regarding the mechanism by which muscle cells regulate cartilage gene expression, and the role of muscle cells or scaffolding materials on cytokine response has never been reported. Thus in addition to advancing cartilage tissue engineering technology, completing this research will also lead to a deeper and more complete understanding of the biology of cartilage regulation.The strategy described in this proposal was inspired by concepts from animal development, when tissues develop alongside each other (such as cartilage and muscle) play crucial roles in cell-cell signaling between adjacent tissues and their subsequent differentiation and proliferation. Thus, cartilage formation involves not just cartilage cells, but cells of multiple surrounding tissues. Thus our idea of mimicking embryo development may inspire the creation of novel strategies to engineer other tissue types as well.Broader impacts.This proposed research seeks to advance education and learning in addition to the knowledge of science. Two new modules are designed to build into two courses (i.e. Biomaterial and tissue engineering and Developmental Biology), which will focus on enhancing cartilage tissue engineering using the concepts and approaches in developmental biology, and using tissue engineering approaches to recapitulate and investigate developmental processes. The courses will be divided into classroom lectures, student presentations and literature reading. Both Dr. Zeng and Dr. Kaplan belong to a variety of educational programs, such as TAHSS (Teachers and High School Students) and BDBS (Building Diversity in Biomedical Sciences). These programs recruit minority or economically disadvantaged students who otherwise may not have the opportunity to be exposed to research. The education aspect of researchplan has been carefully developed to enable students of different levels to perform interdisciplinary research in both laboratories.The proposed research activity will also enhance the infrastructure of the scientific community. First, this work will directly benefit the local community of Tufts University. In particular, it will contribute to the infrastructure of the Tufts Bioengineering and Biotechnology Center. Through its education and training programs, the center connects members within the academia community (students, postdocs and faculty) and between academia and industry. Moreover, the results obtained from this research will be sharedwith other scientists through publications, and in conferences and research seminars throughout the nation. Thus, the activities resulting from this research will have a positive impact on the broad scientific community as well.