Engineering cartilage: an approach to joint repair

描述（由申请人提供）： 在美国，骨关节炎中的关节软骨退化是影响超过4300万人的残疾的主要原因。受损的软骨不会愈合。基于间充质干细胞（MSC）技术的软骨组织工程提供了使用来自骨髓活检的细胞制造任意大小和形状的自体组织替代物的希望。这项生物工程研究资助提案是由软骨组织工程的需要驱动的，以过渡到可重复的临床治疗。为了实现这一点，必须彻底理解所涉及的过程，并建立标准化的协议。这一提议背后的总体假设是，通过将细胞支架构建体在受控的体外环境中暴露于有利于软骨形成分化的条件下，这些构建体将发展出植入关节后存活所需的特定性质。在组织工程成为软骨缺损的常规治疗之前，必须解决两个主要问题：将营养物质和废物运输到构建体内的细胞和从构建体内的细胞运输，以及对构建体进行机械调节以允许原位功能。我们提出了五个具体目标，解决了与质量传输和机械调节相关的具体问题，以及它们对体内结构功能的影响。具体目标1：研究软骨组织工程中的传质问题.这将导致更好地了解结构内的传质，并将有助于评估提出的改善传质的对策。具体目标2：开发软骨生物反应器监测和过程控制系统。我们将实施这项技术，以确定和表征软骨组织工程系统的过程控制参数。具体目标3：针对具体的大众运输限制制定对策。在这个具体目标中，我们将研究改善结构中传质的策略。具体目标4：为了实施和评估复合材料的机械刺激，使用可以施加受控的生理相关载荷的系统，并确定改善结构机械性能的载荷参数。具体目标五：评价体内复合结构，因为关节中制造结构的存活和整合决定了组织工程过程的成功。拟议研究的实用价值在于它将为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，这些研究将为成功治疗关节软骨损伤提供新的原则和指南。

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.