Multiscale simulation and measurement of knee joints biomechanics under physiological loading conditions

膝关节软骨（AC）衰竭的直接经济负担是100亿美元，预计在未来十年还会增长。由身体活动引起的机械刺激，如应力和应变，是AC稳态的调节器。然而，临床医生和研究人员仍然不知道什么类型和水平的机械负荷是安全有效的，以减少AC变性的风险。提出的研究计划将解决这一领域的两个主要局限性，在研究软组织力学方面具有广泛的应用。首先，我们没有足够的工具来测量和预测关节水平的体育活动如何在细胞水平上使AC软骨细胞变形。目前关于软骨细胞力学的许多信息都是通过在静载荷下的嵌入凝胶中软骨细胞的实验获得的，这提供了一个受控的机械和生化环境。在本研究中，我们将开发一种实验装置，并采用新颖的显微镜技术来测量动态加载条件下天然AC不同区域的软骨细胞和细胞外基质（ECM）的局部变形。我们将研究促进细胞生物合成的联合力量水平，从简单的循环负荷开始，最终在生理负荷条件下结束。此外，我们将研究微尺度裂纹附近ECM的微尺度变形，以阐明ECM中裂纹扩展的机制。其次，我们缺乏一个完整膝关节的有限元（FE）生物学模型，该模型包括关节功能中的软骨细胞反应。传统的膝关节有限元模型是纯力学的，研究的是AC对机械干扰（如损伤）的急性反应。然而，软骨衰竭是一种慢性疾病，涉及组织退化和裂纹随着时间的推移而扩展。本提案旨在开发纤维增强软骨模型，并将其应用于包括肌肉和骨骼（组织水平）以及软骨细胞（细胞水平）的全3D膝关节有限元模型。提出的多尺度膝关节有限元模型的新颖性在于将组织尺度的软骨变形与细胞尺度的软骨细胞生物活性联系起来的独特方法，而细胞尺度的软骨细胞生物活性解释了软骨生长的速度。这样一个生物学信息的多尺度有限元模型将确定施加载荷对交流功能的长期影响。这项工作的预期结果是勾勒出确定促进软骨细胞功能和软骨生成有利条件的体育活动的途径，以建立信心。这为社会（防止关节损伤）和经济（减少膝关节衰竭治疗的负担费用）提供了许多好处。除了技术进步，我的研究小组还培训了至少9名HQP，他们帮助满足加拿大对工程师的需求，并将为加拿大的经济成功做出贡献。

The direct economic burden of knee articular cartilage (AC) failure is $10 billion and is expected to grow over the next decade. Mechanical stimuli, such as stresses and strains, induced by physical activities, are a regulator of AC homeostasis. However, clinicians and researchers still do not know what type and level of mechanical loads are safe and effective to reduce the risk of AC degeneration. The proposed research program will address two primary limitations in this field, with broad applications for studying soft tissue mechanics in general. First, we do not have adequate tools to measure and predict how physical activities at the joint level deform AC chondrocytes at the cellular level. Much of the information currently available on chondrocyte mechanics were obtained from experiments on chondrocytes in embedded gel under static loads, which provides a controlled mechanical and biochemical environment. In the proposed research, we will develop an experimental apparatus and employ novel microscopy techniques to measure the local deformations of chondrocyte and extracellular matrix (ECM) at different zones in native AC under dynamic loading conditions. We will study the level of joint forces that promote cell biosynthesis, beginning with simple cyclic loadings and culminating in physiological loading conditions. Moreover, we will study the microscale deformations of ECM near a microscale crack in AC, to elucidate the mechanism of crack propagation in ECM. Second, we lack a biologically informed finite element (FE) model of the full knee joint that includes the chondrocyte response in the joint function. Traditional knee FE models are purely mechanical and study the acute response of AC to mechanical disturbances, such as injuries. However, cartilage failure is a chronic condition that involves tissue degeneration and cracks propagation over time. This proposal aims at developing a fiber-reinforced cartilage model and applies it into a full 3D knee FE model that includes muscles and bones (tissue level) as well as chondrocytes (cellular level). The novelty of the proposed multiscale knee FE model lies in the unique approach in linking the tissue-scale cartilage deformations to the cellular-scale chondrocyte bioactivity that accounts for the rate of cartilage growth. Such a biologically informed multiscale FE model would identify the long-term effects of applied loads on the AC function. The expected outcome of this work is to outline pathways to establish confidence in identifying physical activities that promote favorable conditions for chondrocyte function and cartilage production in cartilage. This offers a number of benefits to the society (prevented joint injuries) as well as the economy (reduced burden costs of knee joint failure treatments). In addition to technical advancements, my research group trains at least 9 HQP who help meet Canada's demand for engineers and will contribute to its economic success.