Intra-articular TSG-6 delivery from heparin-based microparticles reduces cartilage damage in a rat model of osteoarthritis†,Biomaterials Science

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Intra-articular TSG-6 delivery from heparin-based microparticles reduces cartilage damage in a rat model of osteoarthritis†
Biomaterials Science ( IF 5.8 ) Pub Date : 2018-03-14 00:00:00 , DOI: 10.1039/c8bm00010g
Liane E. Tellier _{1,

2,

3,

4} , Elda A. Treviño _{1,

2,

3,

4} , Alexandra L. Brimeyer _{1,

2,

3,

4} , David S. Reece _{1,

2,

3,

4} , Nick J. Willett _{1,

2,

3,

4,

5} , Robert E. Guldberg _{3,

4,

6,

7,

8} , Johnna S. Temenoff _{1,

2,

3,

4,

6}

Affiliation

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.

中文翻译：

从基于肝素的微粒关节内TSG-6的递送减少了骨关节炎大鼠模型的软骨损伤†

作为骨关节炎（OA）的潜在治疗方法，我们已经开发出可注射和可水解降解的基于肝素的生物材料，具有可调节的硫酸化作用，可在关节内递送肿瘤坏死因子-α刺激基因6（TSG-6）。抑制纤溶酶可能会降解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，发现虽然完全硫酸化（Hep）和肝素仅在N位脱硫（Hep ^-N）可以显着增强体外TSG-6的生物活性，但完全脱硫的肝素（喉癌^-）没有任何影响，表明肝素硫酸在调节TSG-6生物活性的显著作用。接下来，负载TSG-6，可降解10 wt％Hep ^-N在大鼠半月板内侧横切（MMT）损伤后第1、7和15天，通过关节内注射将微粒（MPs）输送至膝盖。21天后，可溶性TSG-6使软骨厚度，体积和衰减显着增加，表明退行性改变。相比之下，TSG-6载脂蛋白治疗未观察到显着差异，表明TSG-6载脂蛋白减少了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抗纤溶酶的活性，并且基于Hep ^-N的生物材料可能是TSG-6递送治疗OA的有效方法。

更新日期：2018-03-14

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