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，可润滑和重新分配关节中的压缩载荷。这两种功能在软骨疾病和损伤如骨关节炎（OA）中受到损害。关节软骨润滑的一个关键成分是表浅区蛋白（SZP），其在早期和晚期OA的动物模型中显示出改变的水平。SZP的合成在体内受到机械调节，通过机械刺激，其表达已在体外成功操纵。将这些发现与先前在操纵工程软骨的机械特性方面的成功相结合，研究人员的长期使命是关节中关节软骨的完全再生，以恢复该组织的润滑和机械功能。为了实现这一目标，该提案的假设是，使用生长因子、细胞骨架调节和机械信号的组合，用边界润滑和机械特性工程化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）确定静水压力对关节软骨组织外植体中SZP mRNA和蛋白质表达的生物力学信号传导的影响和机制，2）使用生长因子、细胞骨架调节和机械信号传导的组合将润滑工程化到组织工程化软骨中，和3）确定润滑的完整性和稳定性，利用SCID小鼠模型体内组织工程化软骨。在小鼠模型中成功验证润滑的组织工程结构功能将导致更大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.