The Influence of Macromolecule Accumulation on Cartilage Mechanics and Chondrocyte Health

这个项目将研究关节软骨的力学。关节软骨覆盖并保护长骨的末端，使关节运动平稳无痛。软骨被滑液包围，这是一种粘稠的液体，为组织提供润滑和营养。由于滑液是由过滤后的血浆形成的，因此它含有血浆蛋白，如白蛋白。有趣的是，受骨关节炎影响的关节中白蛋白和其他血浆蛋白的浓度显著增加，骨关节炎是一种破坏性疾病，其最显著的特征是软骨进行性破坏。这些大分子（大分子）可以通过组织内的孔隙进入软骨，但尚不清楚它们的存在是否会改变软骨抵抗机械力和保护关节免受损伤的能力。为了解决这一知识差距，这项工作将测试溶质积聚如何改变软骨功能。这项研究的结果可能有一天会影响骨关节炎的临床护理，因为它揭示了滑液的分子组成是如何影响软骨力学性能和健康的——这可能会通过临床干预来改变。除了科学和临床影响之外，这项研究还将影响更大的罗切斯特纽约社区，因为它将与一个教育项目一起进行，该项目为当地高中生提供研究经验，指导和指导他人的机会。该项目旨在确定关节软骨对机械负荷的反应如何受到其孔隙内大可溶性分子积聚的影响，尽管软骨力学研究已经进行了数十年，但这一现象之前尚未被描述。基于我们的初步工作，当前研究将验证的中心假设是，积累大于临界尺寸的可溶性分子的临界浓度对软骨健康有害，因为吸收的分子增加了组织的渗透性，导致改变的随时间变化的机械反应。此外，随着寿命的延长，大量溶质的积累会增加，这可能会导致关节疾病的发病。这项工作将通过分析建模、计算建模和独特的软骨外植体模型相结合进行，该模型完全保持软骨完整性和原生边界条件，使流体仅通过关节表面吸收和渗出，从而可以评估溶质吸收的真实影响。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

This project will study the mechanics of articular cartilage. Articular cartilage covers and protects the ends of long bones to enable smooth and pain-free joint motion. Cartilage is surrounded by synovial fluid, a thick and viscous liquid that provides lubrication and nutrients for the tissue. Since synovial fluid is formed from filtered blood plasma, it contains plasma proteins such as albumin. Interestingly, concentrations of albumin and other plasma proteins are markedly increased in joints affected by osteoarthritis, a devastating disease whose most prominent feature is progressive cartilage breakdown. These large molecules (macromolecules) can enter cartilage through pores within the tissue, but it is not known whether their presence alter cartilage’s ability to resist mechanical forces and protect joints from damage. To address this knowledge gap, this work will test how solute buildup modifies cartilage function. The results of this study could one day impact clinical care for osteoarthritis by shedding light on how the molecular composition of synovial fluid – which may be modifiable through clinical interventions – affects cartilage mechanical properties and health. In addition to its scientific and clinical impacts, this study will also impact the greater Rochester NY community, as it will be carried out in conjunction with an educational program that provides local high school students with research experience, mentoring, and opportunities to mentor others. This project seeks to define how the response of articular cartilage to mechanical load is influenced by the accumulation of large soluble molecules within its pores, a phenomenon that has not been described previously despite decades of cartilage mechanics research. Based on our preliminary work, the central hypothesis that will be tested in the current study is that accumulating a critical concentration of soluble molecules larger than a critical size is detrimental to cartilage health because the absorbed molecules increase tissue permeability, leading to an altered time-dependent mechanical response. Moreover, accumulation of large solutes increases over the lifespan, potentially contributing to joint disease pathogenesis. This work will be conducted through a combination of analytic modeling, computational modeling, and a unique cartilage explant model that completely maintains cartilage integrity and native boundary conditions such that fluid is imbibed and exuded only through the articular surface and the true impact of solute absorption can be evaluated.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.