W. H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA and Department of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.
Biomater Sci. 2018 May 1;6(5):1159-1167. doi: 10.1039/C8BM00010G.
As a potential treatment for osteoarthritis (OA), we have developed injectable and hydrolytically degradable heparin-based biomaterials with tunable sulfation for the intra-articular delivery of tumor necrosis factor-alpha stimulated gene-6 (TSG-6), a protein known to inhibit plasmin which may degrade extracellular matrix within OA joints. We first assessed the effect of heparin sulfation on TSG-6 anti-plasmin activity and found that while fully sulfated (Hep) and heparin desulfated at only the N position (Hep-N) significantly enhanced TSG-6 bioactivity in vitro, fully desulfated heparin (Hep-) had no effect, indicating that heparin sulfation plays a significant role in modulating TSG-6 bioactivity. Next, TSG-6 loaded, degradable 10 wt% Hep-N microparticles (MPs) were delivered via intra-articular injection into the knee at 1, 7, and 15 days following medial meniscal transection (MMT) injury in a rat model. After 21 days, cartilage thickness, volume, and attenuation were significantly increased with soluble TSG-6, indicating degenerative changes. In contrast, no significant differences were observed with TSG-6 loaded MP treatment, demonstrating that TSG-6 loaded MPs reduced cartilage damage following MMT injury. Ultimately, our results indicate that Hep-N can enhance TSG-6 anti-plasmin activity and that Hep-N-based biomaterials may be an effective method for TSG-6 delivery to treat OA.
作为骨关节炎（OA）的一种潜在治疗方法，我们开发了可注射和可水解的基于肝素的生物材料，其硫酸化程度可调，用于关节内递送肿瘤坏死因子-α刺激基因-6（TSG-6），这种蛋白质已知可抑制纤溶酶，而纤溶酶可能会降解 OA 关节内的细胞外基质。我们首先评估了肝素硫酸化对 TSG-6 抗纤溶酶活性的影响，发现完全硫酸化的肝素（Hep）和仅 N 位去硫酸化的肝素（Hep-N）显著增强了 TSG-6 的体外生物活性，而完全去硫酸化的肝素（Hep-）则没有作用，表明肝素硫酸化在调节 TSG-6 生物活性方面起着重要作用。接下来，通过关节内注射，将负载 TSG-6 的可降解 10wt% Hep-N 微球（MPs）递送到内侧半月板横断（MMT）损伤后的大鼠模型膝关节中，在 1、7 和 15 天分别进行注射。21 天后，与可溶性 TSG-6 相比，软骨厚度、体积和衰减显著增加，表明发生了退行性变化。相比之下，负载 TSG-6 的 MPs 治疗组没有观察到显著差异，表明负载 TSG-6 的 MPs 减轻了 MMT 损伤后的软骨损伤。最终，我们的结果表明，Hep-N 可以增强 TSG-6 的抗纤溶酶活性，并且基于 Hep-N 的生物材料可能是一种有效递送 TSG-6 以治疗 OA 的方法。
