Institute of Clinical Pharmacy and Pharmaceutical Sciences, National Cheng Kung University, Tainan, Taiwan; Department of Biochemistry and Molecular Biology, National Cheng Kung University, Tainan, Taiwan.
Institute of Clinical Pharmacy and Pharmaceutical Sciences, National Cheng Kung University, Tainan, Taiwan.
Eur J Pharm Biopharm. 2019 Feb;135:61-71. doi: 10.1016/j.ejpb.2018.12.007. Epub 2018 Dec 12.
Thrombomodulin (TM) is a type-I transmembrane glycoprotein expressed on the surfaces of endothelial cells and epidermal keratinocytes. It is known to regulate blood coagulation, inflammation, and cell-cell adhesion. A recombinant TM, which contains an epidermal growth factor-like domain and serine/threonine-riches domain, has been demonstrated to stimulate cell proliferation and migration of keratinocytes and wound healing. In this study, we developed the biodegradable hydrogels and evaluated the efficacy of sustained release of rhTM from the hydrogel for the treatment of diabetic wounds. The hydrogels were composed of gelatin with or without hyaluronic acid, and fabricated by chemical cross-linking followed by lyophilization. Gelatin-based hydrogels had porous structure, good swelling property, and were biodegradable with characteristics of slow rhTM release in a short term. The once every-3-day rhTM-loaded hydrogel (with hyaluronic acid) markedly promoted wound healing and were superior to rhTM solution, once daily rhTM hydrogel (without hyaluronic acid), hydrogel controls, and once every-3-day rhEGF hydrogel treatment groups. The rhTM hydrogels enhanced granulation tissue formation, re-epithelialization, collagen deposition, and angiogenesis in wound repair. The once every-3-day rhTM hydrogel was stable and drug release was maintained up to 11-month of storage at 4 °C. The developed rhTM hydrogels could meet the needs for clinical practice, and may have future medical applications for wound care in diabetic patients.
血栓调节蛋白（TM）是一种Ⅰ型跨膜糖蛋白，表达于内皮细胞和表皮角质形成细胞表面。它已知可调节血液凝固、炎症和细胞-细胞黏附。一种包含表皮生长因子样结构域和丝氨酸/苏氨酸丰富结构域的重组 TM 已被证明可刺激角质形成细胞的增殖和迁移以及伤口愈合。在本研究中，我们开发了可生物降解的水凝胶，并评估了从水凝胶中持续释放 rhTM 治疗糖尿病伤口的疗效。水凝胶由明胶（含或不含透明质酸）组成，通过化学交联后冻干制成。基于明胶的水凝胶具有多孔结构、良好的溶胀性能和可生物降解性，在短期内具有 rhTM 缓慢释放的特点。每 3 天一次 rhTM 负载的水凝胶（含透明质酸）显著促进了伤口愈合，优于 rhTM 溶液、每天一次 rhTM 水凝胶（不含透明质酸）、水凝胶对照和每 3 天一次 rhEGF 水凝胶治疗组。rhTM 水凝胶增强了肉芽组织形成、再上皮化、胶原沉积和血管生成，促进了伤口修复。每 3 天一次 rhTM 水凝胶在 4°C 下储存长达 11 个月时仍保持稳定，药物释放得以维持。所开发的 rhTM 水凝胶可满足临床实践的需求，可能在未来有应用于糖尿病患者伤口护理的医学用途。
