Engineered Anterior Cruciate Ligaments

描述（由申请人提供）：2001年将有超过20万美国人需要ACL重建手术，价格超过50亿美元。前交叉韧带作为膝关节的主要稳定器，并且最容易由于与运动损伤相关的屈曲-旋转-外翻力而断裂或撕裂。组织工程可以通过在体外产生用于在损伤或疾病时移植的基于生物学的功能性组织来潜在地提供骨科医学中的改进的临床选择。具有在重建时可用的适当生物学和机械特性的组织工程化ACL将消除与当今手术技术相关的限制，即，消除了对自体髌骨或腘绳肌腱采集的需要和/或提供了无限的同种异体韧带来源。消除目前治疗的主要削弱性副作用-供体部位发病率-将大大改善患者的预后。本项目的总体目标是设计可行的自体组织工程化肌腱，消除当前自体腘绳肌或髌腱收获的需要。第二阶段的最终结果将是一个准备用于人体临床试验的工程韧带。组织再生公司，(TRI)初步研究和I期结果证明了创新的组织工程化韧带作为体内撕裂或破裂韧带的可行替代物的潜力。具体而言，已经鉴定、设计和开发了一种新型的基于丝纤维的基质，并且当与人骨髓干细胞（BMSC）接种时，支持韧带组织的特异性发育。该组织表达预期用于ACL的生物相容性、生物化学和生物力学相关特征。基于这些I期研究，我们建议进一步探索严格的体内关节内环境与ACL组织发育（组织形态学和机械学）之间的关系。本研究将阐明初始工程化ACL特性（例如，基质线性刚度）和体内关节内重塑级联。将根据已建立的II期里程碑确定和评估ACL和膝关节功能恢复的潜力，以达到III期（人体临床试验）和最终商业市场的“通过/不通过”。

DESCRIPTION (provided by applicant): Over 200,000 Americans will require ACL reconstructive surgery in 2001 with a price tag exceeding 5 billion dollars. The ACL serves as a primary stabilizer of the knee and is most often susceptible to rupture or tear resulting from a flexion-rotation-valgus force associated with sports injuries. Tissue engineering can potentially provide improved clinical options in orthopaedic medicine through the generation of biologically based functional tissues in vitro for transplantation at the time of injury or disease. A tissue engineered ACL with the appropriate biological and mechanical properties available at the time of reconstruction would eliminate the limitations associated with present day surgical techniques, i.e., eliminate the need for autologous patellar or hamstring tendon harvest and/or provide a unlimited source of allogenic ligaments. The elimination of the major debilitating side effect of current treatment--donor-site morbidity--would drastically improve patient outcomes. The overall goal of this project is to engineer viable autologous tissue engineered ACLs eliminating the need for current autologous hamstring or patellar tendon harvest. The final outcome of Phase II will be an engineered ligament ready for human clinical trials. Tissue Regeneration Inc., (TRI) preliminary studies and Phase I results demonstrate the potential of an innovative tissue engineered ligament to serve as a viable replacement for torn or ruptured ACLs in vivo. Specifically, a novel silk fiber-based matrix has been identified, designed and developed, and when seeded with human bone marrow stem cells (BMSCs), supports the specific development of ligament tissue. This tissue expresses biocompatible, biochemical and biomechanical relevant traits to be expected for an ACL. Based on these Phase I studies, we propose to further explore the relationship between a rigorous in vivo intra-articular environment and resulting ACL tissue development (both histomorphologically and mechanically). This study will elucidate key structure-function relationships between initial engineered ACL properties (e.g., matrix linear stiffness) and the in vivo intra-articular remodeling cascade. The potential to restore ACL and knee joint functionality will be determined and assessed in relation to established Phase II milestones in order to reach a "go/no go" for Phase III (human clinical trials) and eventual commercial markets.