Delivery of Basic Fibroblast Growth Factor Using Heparin-Conjugated Fibrin for Therapeutic Angiogenesis
Delivery of Basic Fibroblast Growth Factor Using Heparin-Conjugated Fibrin for Therapeutic Angiogenesis
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DOI：
10.1089/ten.tea.2009.0673
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发表时间：
2010-06-01
影响因子：
4.1
通讯作者：
Kim, Byung-Soo
中科院分区：
文献类型：
--
作者：
Yang, Hee Seok;Bhang, Suk Ho;Kim, Byung-Soo
肝素结合的纤维蛋白（HCF，肝素结合的纤维蛋白原和凝血酶的混合物）被开发为用于长期递送成纤维细胞生长因子2（FGF2）的可注射载体，并通过评价小鼠后肢缺血模型中的新血管形成来研究HCF系统的治疗潜力。在体外，HCF释放FGF2的时间比含有游离肝素的正常纤维蛋白长得多。从HCF释放的FGF2是生物活性的，因为它刺激人皮肤成纤维细胞在体外血清耗尽培养基中的生长。相反，从正常纤维蛋白释放的FGF2不诱导显著的细胞生长，可能是因为其短期释放。将单独的HCF、负载有FGF 2的HCF和含有游离肝素和FGF 2的正常纤维蛋白植入小鼠缺血后肢中4周。组织学分析、蛋白质印迹分析和免疫组织学分析显示，用含有游离肝素和FGF 2的正常纤维蛋白治疗或仅用HCF治疗的缺血肢体显示严重的肌肉纤维化、炎症和低血管密度。相比之下，用FGF2负载的HCF治疗的小鼠显示出显著减少的肌肉纤维化和炎症，并显着增强的新血管形成。使用HCF的FGF 2递送可用于治疗性血管生成，因为HCF递送增强FGF 2的治疗功效。
Heparin-conjugated fibrin (HCF, a mixture of heparin-conjugated fibrinogen and thrombin) was developed as an injectable carrier for long-term delivery of fibroblast growth factor 2 (FGF2), and the therapeutic potential of the HCF system was investigated by evaluating neovascularization in a mouse hind limb ischemia model. HCF released FGF2 for a much longer period than normal fibrin containing free heparin in vitro. The FGF2 released from HCF was bioactive, as it stimulated growth of human dermal fibroblasts in a serum-depleted medium in vitro. In contrast, FGF2 released from normal fibrin did not induce significant cell growth, probably because of its short-term release. HCF alone, HCF loaded with FGF2, and normal fibrin containing free heparin and FGF2 were implanted into mouse ischemic hind limbs for 4 weeks. Histological analysis, Western blot analysis, and immunohistological analysis revealed that ischemic limbs treated with normal fibrin containing free heparin and FGF2, or treated with HCF only, showed severe muscle fibrosis, inflammation, and a low vasculature density. In contrast, mice treated with FGF2-loaded HCF showed significantly reduced muscle fibrosis and inflammation, and dramatically enhanced neovascularization. FGF2 delivery using HCF could be useful for therapeutic angiogenesis as HCF delivery enhances the therapeutic efficacy of FGF2.