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，费用超过50亿美元。前交叉韧带（ACL）是膝关节的主要稳定物，最容易因运动损伤引起的屈曲-旋转-外翻力而破裂或撕裂。组织工程可以潜在地为骨科医学提供改进的临床选择，通过在体外产生生物学基础的功能组织，以便在受伤或疾病时进行移植。组织工程化的前交叉韧带在重建时具有适当的生物和力学性能，将消除与当前外科技术相关的局限性，即不需要自体髌骨或腘绳肌腱采集和/或提供无限的同种异体韧带来源。消除目前治疗的主要衰弱副作用——供体部位发病率——将大大改善患者的预后。该项目的总体目标是设计可行的自体组织工程acl，消除目前自体腘绳肌或髌骨肌腱采集的需要。第二阶段的最终结果将是一个用于人体临床试验的工程韧带。组织再生公司（TRI）的初步研究和I期结果表明，一种创新的组织工程韧带有潜力在体内作为撕裂或破裂的acl的可行替代品。具体来说，一种新的基于丝纤维的基质已经被确定、设计和开发，当与人骨髓干细胞（BMSCs）一起播种时，它支持韧带组织的特定发育。该组织表达了预期ACL的生物相容性，生化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组织发育之间的关系（包括组织形态学和机械形态学）。本研究将阐明初始工程ACL特性（如基质线性刚度）与体内关节内重构级联之间的关键结构-功能关系。恢复前交叉韧带和膝关节功能的潜力将根据已建立的II期里程碑进行确定和评估，以达到III期（人体临床试验）和最终的商业市场的“成功/不成功”。

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.