Establishing Design Criteria and Large Animal Model for Evaluation of ACL Repair

描述（由申请人提供）：在患者中，前交叉韧带（ACL）是一种常见的膝关节损伤结构，手术后重建失败率高达27%。失去ACL功能可显著改变关节运动学，在短期至中期内对次级韧带约束造成不利负荷，在长期内造成软骨损伤、退行性关节疾病和骨关节炎。研究人员现在开始准确地描述正常膝关节的三维运动学特征。然而，控制这些运动学的至关重要的3-D组织力仍然不可能在患者中直接测量，只能通过记录韧带表面应变来推断。韧带力可以在动物模型中确定，但前提是：a）关节运动和组织力传感器输出在体内同时记录，用于日常生活活动（ADL）;以及B）然后在实验室中模拟这些体内运动期间校准这些装有仪器的肢体。在这项资助中，我们建议这样做：测量正常和受伤成年绵羊膝关节中多个ADL的体内膝关节运动，然后使用机器人技术在实验室中模拟这些ADL，以确定3D ACL力。这些结果将在一个大型的相关临床前模型中提供为现有和新型ACL治疗策略（如组织工程修复）设定设计标准和评估基准的能力。为了满足这些需求并建立在我们的初步数据基础上，我们现在提出在绵羊模型中进行研究，以检查受控内侧副韧带（MCL）损伤和/或内侧韧带切除术（MM）前后垂直地面反作用力（VGRF）、膝关节运动以及全膝关节和ACL力的活动相关变化。我们目前的研究旨在回答五个重要的研究问题：1）如何改变正常绵羊膝关节步态表面倾斜影响这些反应措施（VGRF，膝关节运动，膝关节和ACL的力量）？2）MCL损伤或3）内侧韧带切除术如何影响这些措施？4)MCL损伤和内侧半月板切除术的结合如何影响这些措施？5)与两种单独伤害相比，这两种伤害的组合如何改变这些反应措施？目标1：检查与水平和上坡表面相比，在下坡步态表面上行走绵羊如何改变正常的膝关节VGRF、三维膝关节运动、ACL力和总膝关节力。目标二：确定MCL损伤或内侧半月板切除术如何影响术后12周时三种步态表面倾斜度和一种速度的所有反应指标。目标3：确定MCL损伤和内侧半月板切除术联合如何影响我们在术后12周时对相同步态表面倾斜度的反应措施。将这些结果与个体损伤的结果进行对比。 公共卫生相关性：在大型动物模型中测量不同ADL的韧带力和运动将使我们能够研究ACL重建的现有和新的治疗策略。本研究为ACL损伤和重建的后续研究提供了平台，因此我们可以为常见的骨科损伤制定更合理的重建策略。

DESCRIPTION (provided by applicant): In patients, the anterior cruciate ligament (ACL) is a frequently injured knee structure and its reconstructions after surgery can fail in up to 27% of cases. Losing ACL function can dramatically alter joint kinematics, causing adverse loading on secondary ligamentous restraints in the short to intermediate term and cartilage damage, degenerative joint disease and osteoarthritis in the longer term. Investigators are now beginning to accurately characterize 3-D kinematics in the normal knee. However, critically important 3-D tissue forces that control these kinematics remain impossible to directly measure in patients and can only be inferred by recording ligament surface strains. Ligament forces can conceivably be determined in animal models, but only if: a) joint motions and tissue force transducer outputs are simultaneously recorded in vivo for activities of daily living (ADLs); and b) these instrumented limbs are then calibrated during simulations of these in vivo motions in the laboratory. In this grant, we propose to do just this: to measure in vivo knee motions for multiple ADLs in the normal and injured adult sheep knee and then use robotics to simulate these ADLs in the laboratory in order to determine the 3-D ACL force. These results will provide, in a large and relevant preclinical model, the ability to set design criteria and evaluation benchmarks for both existing and novel ACL treatment strategies such as tissue engineered repairs. To address these needs and build on our preliminary data, we now propose studies in the sheep model to examine activity-related changes in vertical ground reaction forces (VGRFs), knee motions, and total knee and ACL forces before and after controlled medial collateral ligament (MCL) injury and/or medial meniscectomy (MM). Our current studies are designed to answer five important research questions: 1) How does altering gait surface inclination in the normal sheep knee affect these response measures (VGRFs, knee motions, and knee and ACL forces)? How does 2) MCL injury or 3) medial meniscectomy affect these measures? 4) How does combining MCL injury and medial meniscectomy affect these measures? 5) How does combining these two injuries alter these response measures compared to those for both individual injuries? Aim 1: Examine how, compared to level and uphill surfaces, walking a sheep on a downhill gait surface alters normal knee VGRFs, 3-D knee motions, ACL force, and total knee force. Aim 2: Determine how MCL injury or medial meniscectomy influences all response measures for three gait surface inclinations and one speed at 12 weeks post surgery. Aim 3: Determine how combined MCL injury and medial meniscectomy influence our set of response measures for identical gait surface inclinations at 12 weeks post surgery. Contrast these results with those of the individual injuries. PUBLIC HEALTH RELEVANCE: Measuring ligament forces and motions for different ADLs in a large animal model will permit us to study existing and novel treatment strategies for ACL reconstruction. This proposed research serves as the platform for subsequent investigation into ACL injury and reconstruction so we can develop more rational reconstruction strategies for common orthopaedic injuries.