Metabolic control of cartilage growth and chondrogenesis

关节软骨是一种致密的、承重的结缔组织，它提供了滑膜关节的滑动表面。由于天然软骨相对不能自我修复，因此已经在工程化（或实验室生长）软骨的开发上投入了大量的努力。尽管这种方法具有软骨修复的潜力，但主要缺点是软骨细胞（软骨细胞）产生大量适合关节表面置换的组织的能力低。虽然已经研究了不同的策略，但一种新的方法是控制营养代谢。虽然已知它们的厌氧代谢，软骨细胞合成更多的组织条件下，引起混合有氧-厌氧代谢。最近，我们已经证明，这种代谢开关可以诱导特定的信号通路，从而改善组织生长。 这项NSERC资助的研究计划的长期目标是开发改善功能性工程软骨生成的方法。在这个框架内，该研究计划未来五年的直接目标是利用这些新发现的代谢信号通路来开发可扩展的过程，以产生组织工程软骨。为实现这一目标，将通过以下四个平行但相关的目标，采用实验和计算相结合的方法：（i）ATP-嘌呤能受体途径的生物反应器控制，（ii）HIF-1 α途径的生物反应器控制，（iii）离散代谢状态之间的转换对组织生长的影响，和（iv）开发用于软骨形成干细胞分化的无生长因子方法。拟议的研究预计将通过创建组织工程软骨开发的有效过程以及进一步了解软骨细胞代谢-一个通常很少受到关注的领域，为材料和化学工程学科（ENC 04：生物材料工程; ENC 02：过程工程）做出重大贡献。虽然需要改进的方法来产生适合于软骨修复和重建的功能性组织，但用于软骨组织工程和软骨干细胞分化的可扩展方法的开发具有直接的工业应用。在接下来的五年里，该研究计划还将为生物化学/生物医学/生物材料工程的职业生涯准备8名HQP（4名博士和4名本科生）。从事这些项目的HQP将有机会参与跨学科研究，并获得组织工程，代谢组学和代谢建模以及生物反应器控制策略等领域的基础知识和实践经验。

Articular cartilage is a dense, load bearing connective tissue that provides the sliding surfaces of synovial joints. Due to native cartilage's relative inability for self-repair, substantial efforts have been placed on the development of engineered (or lab grown) cartilage. Despite the potential of this approach for cartilage repair, a major shortcoming is low capacity of cartilage cells (chondrocytes) to generate significant quantities of tissue suitable for joint resurfacing. While different strategies have been investigated, a novel approach is to control nutrient metabolism. Although known for their anaerobic metabolism, chondrocytes synthesize more tissue under conditions that elicit mixed aerobic-anaerobic metabolism. Recently, we have demonstrated that this metabolic switch can induce specific signaling pathways that result in improved tissue growth. The long-term goal of this NSERC funded research program is to develop methods to improve the generation of functional engineered cartilage. Within this framework, the immediate goal over the next five years of this research program is to exploit these newly identified metabolic-signaling pathways to develop scalable processes to generate tissue engineered cartilage. To achieve this goal, a combination of experimental and computational approaches will be carried out through four parallel, but related objectives, as follows: (i) bioreactor control of the ATP-purinergic receptor pathway, (ii) bioreactor control of the HIF-1a pathway, (iii) effect of switching between discrete metabolic states on tissue growth, and (iv) development of growth-factor free approaches for chondrogenic stem cell differentiation. The proposed research is expected to make significant contributions to the discipline of Materials and Chemical Engineering (ENC04: Biomaterial Engineering; ENC02: Process Engineering) by creating effective processes for development of tissue engineered cartilage as well as furthering our knowledge of cartilage cell metabolism - an area which has generally received little attention. While improved methodologies are needed to create functional tissues suitable for cartilage repair and reconstruction, the development of scalable processes for cartilage tissue engineering and chondrogenic stem cell differentiation have direct industrial applications. Over the next five years, this research program will also prepare 8 HQP (4 PhD and 4 undergraduates) for professional careers in biochemical/biomedical/biomaterials engineering. HQP working on these projects will have the opportunity to be involved in interdisciplinary research and to acquire fundamental knowledge and practical experience in the areas of tissue engineering, metabolomics and metabolic modeling, and bioreactor control strategies.