Mechanical Consequences of Focal Articular Defects

描述(申请人提供)：局灶性关节缺陷是最常见的关节损害类型之一，与骨关节炎和无症状膝关节的关节软骨进行性退行性变有关。以往对局灶性关节缺损力学和软骨力学生物学的研究表明，局灶性缺损区的存在会导致邻近和对侧关节软骨的机械过载，这种过载直接影响相邻和对侧关节软骨的生存能力、机械能力和力学反应能力。因此，对局灶性软骨缺损区的力学环境的研究可以阐明这些缺损区可导致更大范围的软骨丢失和关节功能受损的生物学和生物力学机制。然而，关于关节缺损区附近的组织内应变、应力、压力和流体速度的定量信息很少。这项奖学金申请提出了一套初步研究，将表征局灶性关节缺陷的机械环境。这些研究是研究培训计划的中心组成部分，将拓宽PI在骨骼愈合机械生物学方面的背景，并促进PI过渡到关节软骨缺损修复研究领域。这项工作的假设是，对于生理关节载荷，局灶性关节缺损处的局部力学环境不同于完整关节层的局部力学环境；此外，通过施加关节运动的限定改变，可以控制缺陷的力学环境。提出了两个具体目标。目的#1将压缩、滑动和滚动运动应用于创建全层局灶性缺损区之前和之后的相对骨软骨片。通过软骨细胞核被荧光染色的图像的数字相关来测量在缺损处周围和相反的组织中诱导的应变。AIM#2将使用特定于标本的有限元(FE)模型来估计在AIM#1中的实验期间发生在软骨中的组织内压力、应力和流体速度。将通过将有限元计算的应变分布与在AIM#1中测量的应变分布进行比较来验证FE结果。这些研究的方法和结果将为后续的生物力学研究奠定基础，这些生物力学研究试图确定机械因素与进一步的缺陷进展之间的关系，以及随后旨在操纵局部机械环境以促进愈合的机械生物学研究。综上所述，这项工作的发现将成为软骨缺陷的生物力学和机械生物学综合方法的一个重要的初始里程碑，这将引领关节软骨修复的新治疗方法。 公共卫生相关性：关节软骨损伤很常见，并与进行性软骨退化和关节功能丧失有关。虽然先前的研究结果表明，关节软骨中存在的缺陷会通过周围组织的机械过载而加速软骨的破坏，但对这些缺陷的力学环境知之甚少。这项拟议的研究将量化这种机械环境和关节负荷/运动之间的关系，长期目标是开发关节软骨修复的新治疗方法。

DESCRIPTION (provided by applicant): Focal articular defects are one of the most common types of articular lesions and are associated with progressive degeneration of articular cartilage in both osteoarthritic and asymptomatic knees. Prior investigations on the mechanics of focal articular defects and on cartilage mechanobiology suggest that the presence of a focal defect causes mechanical overload of the adjacent and opposing articular cartilage, and that this overload has direct consequences for the viability, mechanical competence, and mechano- responsiveness of the adjacent and opposing cartilage. Study of the mechanical environment of focal defects may therefore elucidate the biological and biomechanical mechanisms by which these defects can lead to larger scale cartilage loss and compromised joint function. However, little quantitative information is available on the intra-tissue strains, stresses, pressures, and fluid velocities in the vicinity of articular defects. This fellowship application proposes a set of initial studies that will characterize the mechanical environment of focal articular defects. These studies are the central component of the research training plan that will broaden the PI's background in the mechanobiology of skeletal healing and facilitate the PI's transition into the research area of articular cartilage defect repair. The hypothesis of the proposed work is that for physiologic joint loading, the local mechanical environment of a focal articular defect differs from that of the intact articular layer; moreover, the mechanical environment of the defect can be controlled through defined alterations in the applied joint motions. Two specific aims are proposed. Aim #1 will apply compression, sliding, and rolling movements to opposing osteochondral slices both before and after creation of a full-thickness, focal defect. The strains induced in the tissue surrounding and opposing the defect site will be measured via digital correlation of images in which the chondrocyte nuclei have been fluorescently stained. Aim #2 will estimate, using specimen-specific finite element (FE) models, the intra-tissue pressures, stresses, and fluid velocities that occur in the cartilage during the experiments in Aim #1. Validation of the FE results will be performed by comparing the FE-computed strain distributions with those measured in Aim #1. The methods and results from these studies will lay the foundation for subsequent biomechanical investigations that seek to define relationships between mechanical factors and further progression of defects, and for subsequent mechanobiological investigations aimed at manipulating the local mechanical environment in order to enhance healing. Taken together, the findings from this work will constitute an important initial milestone for an integrated approach to the biomechanics and mechanobiology of cartilage defects that should lead the way to new treatment approaches in articular cartilage repair. PUBLIC HEALTH RELEVANCE: Injuries to articular cartilage are common and are associated with progressive cartilage degeneration and loss of joint function. Although results of prior studies have suggested that the presence of a defect in articular cartilage leads to accelerated cartilage destruction through mechanical overload of the surrounding tissue, little is known about the mechanical environment of these defects. The proposed research will quantify relationships between this mechanical environment and joint loads/motions, with the long-term goal of developing new treatment approaches in articular cartilage repair.