Engineering Lubrication in Tissue Engineered Cartilage

描述（由申请人提供）：关节软骨是一种持久、耐用的组织，可以润滑和重新分配关节中的压缩载荷。在软骨疾病和骨关节炎（OA）等损伤中，这两种功能都受到损害。关节软骨润滑的一个关键组成部分是浅带蛋白（SZP），在早期和晚期OA动物模型中显示出改变的水平。SZP的合成在体内受机械调控，通过机械刺激在体外成功地调控了SZP的表达。结合这些发现和先前在操纵工程软骨机械性能方面的成功，研究人员的长期任务是在关节中完全再生关节软骨，以恢复该组织的润滑和机械功能。为了实现这一目标，本提案的假设是，使用生长因子、细胞骨架调节和机械信号的组合来设计具有边界润滑和机械性能的软骨，可以通过维持其生物稳态和结构完整性来恢复小鼠模型中的关节软骨。提出了三个具体目标：1)确定静水压力生物力学信号对关节软骨组织外植体中SZP mRNA和蛋白表达的影响及其机制；2)利用生长因子、细胞骨架调节和机械信号的组合对组织工程软骨进行润滑；3)利用SCID小鼠模型确定润滑的组织工程软骨的完整性和稳定性。成功验证润滑组织工程构建功能的小鼠模型将导致更大规模的动物研究和潜在的临床转化。

DESCRIPTION (provided by applicant): Articular cartilage is a long-lasting, durable tissue that lubricates and redistributes compressive loading in joints. Both of these functions are compromised in cartilage diseases and injuries such as osteoarthritis (OA). A key component of articular cartilage lubrication is superficial zone protein (SZP), which displays altered levels in animal models of early- and late-stage OA. SZP synthesis is mechanically regulated in vivo, and through mechanical stimulation its expression has been manipulated successfully in vitro. Combining these findings with previous successes in manipulating the mechanical properties of engineered cartilage, the long- term mission of the investigators is the complete regeneration of articular cartilage in the joint to restore both the lubrication and mechanical functionality of this tissue. Toward this goal, the hypothesis of this proposal is that cartilage engineered with boundary lubrication and mechanical properties using a combination of growth factors, cytoskeletal modulation, and mechanical signaling can restore articular cartilage in a murine model by maintaining its biological homeostasis and structural integrity. Three specific aims are proposed: 1) to determine the influence and the mechanism of the biomechanical signaling of hydrostatic pressure on SZP mRNA and protein expression in articular cartilage tissue explants, 2) to engineer lubrication into tissue engineered cartilage using a combination of growth factors, cytoskeletal modulation, and mechanical signaling, and 3) to determine the integrity and stability of lubricated, tissue engineered cartilage in vivo utilizing a SCID mouse model. The successful validation of lubricated, tissue engineered construct functionality the mouse model would lead to larger animal studies and potential clinical translation.