Engineered Anterior Cruciate Ligaments

描述(由申请人提供)：2001年将有超过20万美国人需要花费超过50亿美元的前交叉韧带重建手术。前交叉韧带是膝关节的主要稳定器，最容易因运动损伤引起的屈曲-旋转-外翻力量而破裂或撕裂。组织工程学可能通过在体外产生生物功能组织来改善骨科医学的临床选择，以便在受伤或疾病时进行移植。重建时具有合适的生物学和力学性能的组织工程化前交叉韧带将消除与当今外科技术相关的限制，即不再需要自体髌腱或腿肌腱采集和/或提供无限的同种异体韧带来源。消除当前治疗的主要衰弱副作用--供体部位发病率--将极大地改善患者的预后。这个项目的总体目标是设计可行的自体组织工程化前交叉韧带，消除对目前自体腿筋或髌腱采集的需要。第二阶段的最终结果将是一种工程韧带，准备用于人体临床试验。组织再生公司(TRI)的初步研究和第一阶段结果表明，创新的组织工程韧带在体内作为撕裂或断裂的前交叉韧带的可行替代品的潜力。具体地说，一种新型的基于丝素纤维的基质已经被识别、设计和开发，当与人骨髓干细胞(BMSCs)种植时，支持韧带组织的特定发育。这种组织表现出与前交叉韧带预期的生物相容性、生化和生物力学相关的特征。在这些第一阶段研究的基础上，我们建议进一步探索体内严格的关节内环境与由此产生的前交叉韧带组织发育(包括组织形态和力学上的)之间的关系。这项研究将阐明最初设计的前交叉韧带特性(例如，基质线性硬度)和体内关节内重塑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确立的第二阶段里程碑进行确定和评估，以便达到第三阶段(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.