A Translational Approach Towards Ligament Regeneration

描述（由申请人提供）：前关键韧带（ACL）是膝关节最常见的韧带损伤。由于固有的较差的愈合潜力和有限的血管化，ACL破裂不能愈合，通常需要手术置换。目前的治疗方法包括自体移植物（通常使用髌骨肌腱或腘绳肌腱组织）或同种异体移植物。自体移植物使用的局限性包括第二次手术，这可能导致供体部位发病率和可用性有限。同种异体移植物可以潜在地传播疾病并引起宿主不利的免疫原性反应。组织工程已成为克服生物移植物局限性的一种替代策略。我们之前的研究导致了组织工程合成前交叉韧带支架的发展，模仿自然韧带的层次结构复杂性和力学。干细胞技术的最新进展表明，骨髓源性细胞和组织特异性细胞由于其表型可塑性，在促进结缔组织修复和再生方面具有巨大的潜力。本提案的目标是通过将仿生和生物功能支架与干细胞生物学的进展相结合，开发一种加速前关键韧带再生的转化方法。我们的目标将通过设计和优化一种细胞种子、三维（3D）可降解支架来实现，该支架具有与天然ACL相似的结构、机械和生物特性。3D编织结合表面修饰技术将用于制造具有优化孔隙结构和表面性能的支架，以促进细胞粘附、迁移、增殖和组织生长，并具有与天然ACL相当的力学性能。细胞支架结构将在体外和体内进行优化，以增强细胞性能和韧带生成。我们的总体假设是，细胞种子、可降解的纤维支架，其生物力学性能与天然前交叉韧带相当，具有适当的表面特性，可以促进和支持新前交叉韧带的加速再生。这种组织工程构建体的成功开发将为ACL修复提供一种替代方案。

DESCRIPTION (provided by applicant): The anterior crucial ligament (ACL) is the most commonly injured ligament of the knee. Due to inherently poor healing potential and limited vascularization, ACL ruptures do not heal and surgical replacement is often required. Current treatments include the use of autografts (usually with tissue from the patellar tendon or hamstring tendon) or allografts. The limitations associated with the use of autografts include a second surgery, which may cause donor site morbidity and limited availability. Allografts can potentially transmit disease and elicit an unfavorable immunogenic response from the host. Tissue engineering has emerged as an alternative strategy to overcome the limitations of the biological grafts. Our previous studies have led to the development of a tissue engineered synthetic ACL scaffold mimicking the hierarchical structural complexity and mechanics of natural ligament. Recent advances in stem cell technology have shown great potential of bone marrow derived as well as tissue specific cells in promoting the repair and regeneration of connective tissues due to phenotypic plasticity. The goal of this proposal is to develop a translational approach towards accelerated anterior crucial ligament regeneration by combining biomimetic and biofunctional scaffolds with advances in stem cell biology. Our goal will be achieved through the design and optimization of a cell-seeded, three- dimensional (3D) degradable scaffold with structural, mechanical and biological properties similar to natural ACL. 3D braiding in combination with surface modification techniques will be used to create scaffolds with optimized pore structure and surface properties to facilitate cell adhesion, migration, proliferation, and tissue in- growth, as well as mechanical properties comparable to natural ACL. The cell-scaffold constructs will be optimized for enhanced cellular performance and ligamentogenesis both in vitro and in vivo. Our overall hypothesis is that a cell-seeded, degradable, fibrous scaffold that s biomechanically comparable to natural ACL with appropriate surface properties can encourage and support the accelerated regeneration of a new ACL. The successful development of such tissue-engineered constructs will present an alternative to the currently available options for ACL repair.