Mechanical Consequences of Focal Articular Defects

描述（由申请人提供）：局灶性关节缺损是最常见的关节病变类型之一，与骨关节炎和无症状膝关节的关节软骨进行性变性有关。先前对局灶性关节缺损的力学和软骨力学生物学的研究表明，局灶性缺损的存在会导致相邻和对面关节软骨的机械过载，这种过载对相邻和对面软骨的生存能力、机械能力和机械反应性有直接影响。因此，对局灶性缺损的力学环境的研究可以阐明这些缺损导致更大规模软骨损失和关节功能受损的生物学和生物力学机制。然而，关于关节缺损附近的组织内应变、应力、压力和流体速度的定量信息很少。本奖学金申请提出了一组初步研究，将表征局灶性关节缺陷的机械环境。这些研究是研究训练计划的核心组成部分，将拓宽PI在骨骼愈合力学生物学方面的背景，并促进PI过渡到关节软骨缺损修复的研究领域。提出的工作假设是，对于生理关节载荷，局部力学环境的局灶性关节缺损不同于完整的关节层；此外，缺陷的机械环境可以通过应用关节运动的定义改变来控制。提出了两个具体目标。目标1将在形成全层局灶性缺损之前和之后对相对的骨软骨切片应用压缩、滑动和滚动运动。在缺陷部位周围和对面的组织中诱导的菌株将通过荧光染色的软骨细胞核图像的数字相关来测量。Aim #2将使用特定于样本的有限元（FE）模型来估计在Aim #1的实验中软骨中发生的组织内压力、应力和流体速度。将FE计算的应变分布与Aim #1中测量的应变分布进行比较，从而验证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，这些研究旨在确定机械因素与缺陷进一步进展之间的关系，并为后续的机械生物学研究奠定基础，旨在操纵局部机械环境以增强愈合。综上所述，这项工作的发现将构成一个重要的初始里程碑，为软骨缺陷的生物力学和力学生物学的综合方法，应该引导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.