Engineering cartilage: an approach to joint repair

描述(由申请人提供)： 骨性关节炎的关节软骨退化是影响美国4300多万人生活的主要残疾原因。受损的软骨无法愈合。基于间充质干细胞(MSC)技术的软骨组织工程提供了可制造的可制造的任意大小和形状的自体组织替换，使用来自骨髓活检的细胞。这项生物工程研究资助提案是由软骨组织工程的需求推动的，以过渡到可重复的临床治疗。要做到这一点，必须彻底了解所涉及的过程，并且必须建立标准化的协议。支持这一建议的全球假设是，通过将受控的体外环境中的细胞支架结构暴露在有利于软骨分化的条件下，这些结构将在植入关节后发展出生存所需的特定特性。在组织工程学成为软骨缺损的常规治疗方法之前，必须解决两个主要问题：营养物质和废物在支架内细胞之间的运输，以及支架的机械调节，使其能够在原位发挥作用。我们提出了五个具体目标，解决与质量运输和机械条件作用相关的具体问题，以及它们对体内构建功能的影响。具体目标1：评价软骨组织工程中的传质问题。这将导致更好地理解结构内的传质，并将用于评估提出的改善传质的反措施。具体目标2：开发软骨生物反应器监测与过程控制系统。我们将利用这项技术来识别和表征软骨组织工程系统中的过程控制参数。具体目标3：针对具体的大众运输限制制定对策。在这个特定的目标中，我们将研究改善结构中质量传递的策略。具体目标4：实施和评估复合材料的机械刺激，使用一种可以施加受控的生理相关载荷的系统，并确定提高结构力学性能的载荷参数。具体目的5：在体内评价复合构建物，因为人工构建物在关节中的存活和整合决定了组织工程过程的成功。这项拟议研究的实用价值在于，它将为围绕软骨组织工程和软骨修复的技术问题以及关节的复杂生物学提供新的见解。如果成功，这些研究将为关节软骨损伤的成功治疗提供新的原则和指导方针。

DESCRIPTION (provided by applicant): Articular cartilage degeneration in osteoarthritis is a major cause of disability affecting more than 43 million lives in the US. Damaged cartilage does not heal. Cartilage tissue engineering based on mesenchymal stem cell (MSC) technology offers the promise of manufacturable autologous tissue replacements of arbitrary size and shape, using cells from a bone marrow biopsy. This Bioengineering Research Grant proposal is driven by the need for cartilage tissue engineering to make the transition to a reproducible clinical therapy. To accomplish this, the processes involved must be thoroughly understood, and standardized protocols must be established. The global hypothesis underlying this proposal is that by exposing the cell scaffold constructs in a controlled, in vitro environment to conditions that favor chondrogenic differentiation, these constructs will develop the specific properties required for survival after implantation in the joint. Two major problems must be solved before tissue engineering can become a routine treatment for cartilage defects: transport of nutrients and waste products to and from the cells within the construct, and mechanical conditioning of the constructs to allow function in situ. We propose five Specific Aims, which address specific issues related to mass transport and mechanical conditioning, and their impact on construct functionality in vivo. These are: Specific Aim 1: To assess the mass transfer problem in cartilage tissue engineering. This will lead to better understanding of mass transfer within the constructs and will serve to evaluate the counter-measures proposed to improve mass transfer. Specific Aim 2: To develop a cartilage bioreactor monitoring and process control system. We will implement this technology to identify and characterize process control parameters in cartilage tissue engineering systems. Specific Aim 3: To develop countermeasures to specific mass transport limitations. In this Specific Aim, we will examine strategies to improve mass transfer in the constructs. Specific Aim 4: To implement and assess mechanical stimulation of the composites, using a system in which controlled, physiologically relevant loads can be applied, and identifying loading parameters that improve the mechanical properties of the construct. Specific Aim 5: To evaluate the composite constructs in vivo, as survival and integration of the manufactured construct in the joint defines the success of the tissue engineering process. The practical value of the proposed research is in the new insights it will provide into the technical issues surrounding cartilage tissue engineering and cartilage repair, and into the complex biology of the joint. If successful, these studies will provide novel principles and guidelines for the successful management of articular cartilage injuries.