A Translational Approach Towards Ligament Regeneration

描述(申请人提供)：前关键韧带(ACL)是膝关节最常见的损伤韧带。由于固有的较差的愈合潜力和有限的血管形成，前交叉韧带断裂无法愈合，经常需要手术置换。目前的治疗方法包括使用自体移植(通常使用来自膝盖腱或腿筋腱的组织)或同种异体移植。与使用自体移植物相关的限制包括第二次手术，这可能会导致供区并发症和可获得性有限。同种异体移植物可能会传播疾病，并引发宿主不利的免疫原性反应。组织工程已经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一种组织工程化合成前交叉韧带支架的开发，该支架模仿了自然韧带的层次结构复杂性和力学特性。干细胞技术的最新进展表明，由于表型可塑性，骨髓来源的细胞以及组织特异性细胞在促进结缔组织的修复和再生方面具有巨大的潜力。这项建议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翻译方法。我们的目标将通过设计和优化一种细胞种植的三维(3D)可降解支架来实现，该支架具有类似于自然前交叉韧带的结构、力学和生物学特性。三维编织结合表面改性技术将被用来创造具有优化的孔结构和表面特性的支架，以促进细胞黏附、迁移、增殖和组织内生长，以及与自然前交叉韧带相当的机械性能。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形成。我们的总体假设是，一种细胞种植的、可降解的纤维支架，具有与自然前交叉韧带相似的生物力学性能，并具有适当的表面特性，可以鼓励和支持新前交叉韧带的加速再生。这种组织工程化结构的成功开发将为目前可用的前交叉韧带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.