Restoring the fixed charge density of damaged articular cartilage through synthetic aggrecan mimics

目前，没有持久的治疗方法来恢复骨关节炎患者退化的关节软骨。骨关节炎的许多治疗策略试图将细胞外基质（ECM）恢复到其天然硬度，但这些方法并不成功。相反，这个项目的重点是健康软骨膨胀的能力，这与ECM的刚度相结合，有助于支持负荷和降低摩擦。软骨膨胀的能力或其渗透压来自蛋白聚糖（聚集蛋白聚糖）的带负电荷的侧链。这些带负电荷的基团（糖胺聚糖）在骨关节炎中丢失。为了恢复渗透压，通常测量为固定电荷密度，我们建议开发由聚苯乙烯磺酸盐制成的合成聚集蛋白聚糖模拟物。结合这种治疗，我们将开发一个能够原位解决软骨肿胀的平台，这将有助于确定我们的治疗效果，同时也有助于软骨机械变化的时间轴。为了促进生理相关性，我们的平台将评估全堆叠马外植体的肿胀。该项目将首先确定典型的OA样过程，如酶消化，如何影响我们软骨外植体的原位肿胀。然后，我们将测试更多生理相关的OA前体，如机械损伤或炎症，如何导致异常肿胀行为。由于溶胀测量与标准机械测试的正交性质，我们将能够将软骨渗透压引起的机械变化与基质损伤引起的机械变化解耦。最后，在合成我们的聚合物聚集蛋白聚糖模拟物后，我们将测试我们的干预是否可以将受损软骨的肿胀行为恢复到天然软骨中所见的肿胀行为。这项工作的影响是一种基于软骨肿胀行为的新治疗策略：虽然肿胀对软骨的机械功能同样重要，但还没有看到类似水平的研究作为干预目标。我们假设，如果不恢复肿胀行为，目前的OA治疗策略不太可能长期成功。

Currently, there are no lasting treatments to restore degenerated articular cartilage in people with osteoarthritis. Many treatment strategies for osteoarthritis attempt to restore the extracellular matrix (ECM) to its native stiffness, but these approaches have not been successful. Instead, this project focuses on the ability for healthy cartilage to swell, which in conjunction with the stiffness of the ECM, helps support load and lower friction. The ability for cartilage to swell, or its osmotic pressure, is derived from the negatively charged sidechains of proteoglycans (aggrecan). These negatively charged groups (glycosaminoglycans) are lost in osteoarthritis. To restore the osmotic pressure, often measured as the fixed charge density, we propose developing synthetic aggrecan mimics made from polystyrene sulfonate. In conjunction with this treatment, we will develop a platform capable of resolving cartilage swelling in situ, which will help determine our treatment efficacy, while also contributing to a timeline of mechanical changes in the cartilage. To facilitate physiological relevance, our platform will evaluate swelling on full-stack equine explants. This project will first establish how typical OA-like processes, like enzymatic digestion, impact the in situ swelling in our cartilage explants. Then, we will test how more physiologically relevant OA precursors, such as mechanical injury or inflammation, lead to aberrant swelling behavior. Due to the orthogonal nature of swelling measurements to standard mechanical testing, we will be able to decouple mechanical changes derived by the osmotic pressure of the cartilage from those resulting from matrix damage. Finally, after synthesis of our polymer aggrecan mimics, we will test if our intervention can revert the swelling behavior of damaged cartilage into the swelling behavior seen in native cartilage. The impact of this work is a new treatment strategy based on the swelling behavior of cartilage: while swelling is equally important to the mechanical function of cartilage, it has not seen a similar level of research as an intervention target. We hypothesize that without restoring the swelling behavior, current OA treatment strategies are unlikely to be successful in the long term.