Co-delivery of FGF-2 and G-CSF from gelatin-based hydrogels as angiogenic therapy in a murine critical limb ischemic model
Co-delivery of FGF-2 and G-CSF from gelatin-based hydrogels as angiogenic therapy in a murine critical limb ischemic model
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DOI：
10.1016/j.actbio.2008.07.024
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发表时间：
2009-01-01
影响因子：
9.7
通讯作者：
Andreopoulos, Fotios M.
中科院分区：
文献类型：
--
作者：
Layman, Hans;Sacasa, Marianne;Andreopoulos, Fotios M.
在美国，由于老年人口的增加以及肥胖和糖尿病的流行，外周动脉疾病和严重的肢体缺血已成为普遍的健康风险。尽管高侵入性动脉内膜切除术是最流行的治疗方法，但基于生长因子注射的血管生成疗法正迅速成为一种流行的替代疗法。这些因子在体内的酶降解可以通过将它们加入到传递载体中来避免，在传递载体中，生长因子的释放速度可以通过改变载体的性质(即交联密度、材料选择、生物降解等)来控制。在此，我们报道了从离子明胶水凝胶支架中固定化和控制释放人重组碱性成纤维细胞生长因子(FGF-2)和人重组粒细胞集落刺激因子(G-CSF)以重建灌流。并在小鼠后肢缺血模型中诱导毛细血管生长。体外研究表明，血管内皮细胞的增殖高度依赖于成纤维细胞生长因子-2，而G-CSF则刺激内皮细胞迁移和形成肾小管网络。联合应用成纤维细胞生长因子-2和粒细胞集落刺激因子时，内皮细胞分支点的形成比对照组增加82%。用激光多普勒血流成像评价小腿再灌注，用CD31(+)和α-SMA免疫染色评价缺血小腿的毛细血管生长。明胶水凝胶中联合应用G-CSF(1000 ng m l(-1))和FGF-2(1000 ng m l(-1))后，血管灌注量增加了3倍，毛细血管密度和α-SMA阳性血管数增加了2倍。综上所述，联合应用成纤维细胞生长因子2和粒细胞集落刺激因子在促进再灌注和成熟血管形成方面优于单用或单独应用。(C)2008 Acta Materialia Inc.由爱思唯尔有限公司出版。版权所有。
Peripheral artery disease and critical limb ischemia have become prevalent health risks in the United States due to an increasing elderly population and the prevalence of obesity and diabetes mellitus. Although highly invasive endarterectomy is the most popular method for treatment, angiogenic therapies based on growth factor administration are quickly becoming a popular alternative. Enzymatic degradation of these factors in vivo may be avoided by their incorporation in a delivery vehicle where the growth factor's release rate can be controlled by altering the vehicle's properties (i.e. cross-linking density, material selection, biodegradation, etc.). Herein, we report on the immobilization and controlled release of human recombinant basic fibroblast growth factor (FGF-2) and human recombinant granulocyte colony-stimulating factor (G-CSF) from ionic, gelatin-based hydrogel scaffolds to re-establish perfusion. and induce capillary outgrowth in a murine hindlimb ischemic model. In vitro studies showed that endothelial cell proliferation was highly depended on FGF-2, whereas G-CSF stimulated migration and formation of a tubular network. When FGF-2 and G-CSF were used in combination there was an 82% increase in endothelial branch point formation compared to control groups. Leg reperfusion was assessed with laser Doppler perfusion imaging, while capillary outgrowth in the ischemic leg was evaluated using CD31(+) and alpha-SMA immunostaining. The co-delivery of G-CSF (1000 ng ml(-1)) and FGF-2 (1000 ng ml(-1)) from the gelatin hydrogels resulted in a 3-fold increase in the perfusion levels and a 2-fold increase in capillary density and positive a-SMA vessels compared to the empty vehicle group. In conclusion, the co-delivery of FGF-2 and G-CSF was superior to bolus administration or the delivery of either factor alone in promoting reperfusion and mature vessel formation. (C) 2008 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.