A pro-angiogenic degradable Mg-poly(lactic-co-glycolic acid) implant combined with rhbFGF in a rat limb ischemia model
A pro-angiogenic degradable Mg-poly(lactic-co-glycolic acid) implant combined with rhbFGF in a rat limb ischemia model
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DOI：
10.1016/j.actbio.2017.09.033
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发表时间：
2017-12-01
影响因子：
9.7
通讯作者：
Liu, Tianjun
中科院分区：
文献类型：
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作者：
Bao, Hanmei;Lv, Feng;Liu, Tianjun
外源性血管生成生长因子如重组人碱性成纤维细胞生长因子（rhbFGF）的位点特异性控制释放已成为改善外周血管疾病的有希望的方法。在这里，我们已经开发了一种植入物组成的螺旋镁（Mg）和涂层使用聚（乳酸-羟基乙酸）（PLGA）与封装rhbFGF（Mg-PLGA-rhbFGF）。包封后的蛋白可持续释放4周，生物活性保持良好。我们比较了Mg-PLGA-rhbFGF和载有rhbFGF的PLGA植入物（PLGA-rhbFGF）的血管生成效果。植入物中Mg的掺入提高了聚合物中的微气候pH值，从而保持了rhbFGF的稳定性。Mg-PLGA-rhbFGF在细胞相容性评价方面优于PLGA-rhbFGF植入物。体内血管生成试验进一步证实了释放的rhbFGF的功效。HE、CD 31和α-SMA染色结果显示，Mg-PLGA-rhbFGF植入物的缓释效果优于PLGA-rhbFGF植入物，具有上级促血管生成作用。植入4周后，Mg-PLGA-rhbFGF组的毛细血管密度明显高于PLGA-rhbFGF组、对照组和正常组（分别为p < 0.05、p < 0.01和p < 0.01）。此外，Mg-PLGA-rhbFGF和PLGA-rhbFGF组的肢体血液灌注率显著增加，分别为99.1 +/- 2.9%和80.7 +/-3.2%，而对照组的缺血肢体没有恢复。还评价了植入物的生物相容性。总之，基于Mg-PLGA的rhbFGF持续局部递送促进缺血后血管生成和血流恢复。结果提示Mg-PLGA-rhbFGF对组织缺血具有潜在的治疗价值。意义声明镁基植入物已用于严重肢体缺血患者。重组人碱性成纤维细胞生长因子（rhbFGF）的靶向控释治疗已成为改善外周血管疾病的一种有效方法。我们在这里报告了一种新型的组合植入物组成的螺旋镁和涂层使用聚（乳酸-羟基乙酸）（PLGA）与封装rhbFGF（Mg-PLGA-rhbFGF）。该制备方法不涉及任何复杂的过程，并导致高包封率（约100%）。金属镁的降解提高了PLGA聚合物中的微环境pH值，使rhbFGF在植入体中的生物活性得到很好的保持。Mg-PLGA缓释rhbFGF促进大鼠肢体缺血后血管生成和血流恢复本工作标志着第一次报告的控制释放rhbFGF与金属镁，并建议潜在的治疗组织缺血Mg-PLGA-rhbFGF的有用性。(C)2017 Acta Materialia Inc.由爱思唯尔有限公司出版。保留所有权利。
Site-specific controlled release of exogenous angiogenic growth factors, such as recombinant human basic fibroblast growth factor (rhbFGF), has become a promising approach to improve peripheral vascular disease. Here, we have developed an implant composed of spiral magnesium (Mg) and a coating made using poly(lactic-co-glycolic acid) (PLGA) with encapsulated rhbFGF (Mg-PLGA-rhbFGF). The encapsulated protein could release continually for 4 weeks with well preserved bioactivity. We compared the angiogenic effect produced by Mg-PLGA-rhbFGF with that of a PLGA implant loaded with rhbFGF (PLGA-rhbFGF). The incorporation of Mg in the implant raised the microclimate pH in the polymer, which preserved the stability of rhbFGF. Mg-PLGA-rhbFGF exhibited advantages over PLGA-rhbFGF implant in terms of a cytocompatibility evaluation. An in vivo angiogenesis test further confirmed the efficacy of released rhbFGF. HE, CD31 and alpha-SMA staining revealed that the controlled release of rhbFGF from the Mg-PLGA-rhbFGF implant was superior in promoting angiogenesis compared with that of the PLGA-rhbFGF implant. Four weeks post-implantation, the capillary density of the Mg-PLGA-rhbFGF group was significantly higher than that of the PLGA-rhbFGF, control and the normal group (p < 0.05, p < 0.01 and p < 0.01, respectively). Furthermore, the limb blood perfusion ratios of the Mg-PLGA-rhbFGF and PLGA-rhbFGF groups were dramatically increased, at 99.1 +/- 2.9% and 80.7 +/- 3.2%, respectively, whereas the ischemic limb did not recover in the control group. The biocompatibility of the implants was also evaluated. In conclusion, Mg-PLGA-based, sustained local delivery of rhbFGF promotes post-ischemic angiogenesis and blood flow recovery. The results suggest potential therapeutic usefulness of Mg-PLGA-rhbFGF for tissue ischemia.Statement of SignificanceMagnesium (Mg)-based implant has been already used in patients with critical limb ischemia. Site specific controlled release of recombinant human basic fibroblast growth factor (rhbFGF), has become a promising approach to improve peripheral vascular disease. We report here on a novel combination implant composed of spiral magnesium and a coating made using poly(lactic-co-glycolic acid) (PLGA) with encapsulated rhbFGF (Mg-PLGA-rhbFGF). The preparation method does not involve any complex processes and results in a high encapsulation efficiency (approximately 100%). The degradation of metal Mg raise the microclimate pH in the PLGA polymer, which could well preserve the bioactivity of rhbFGF incorporated in the implant. Mg-PLGA-based, sustained local delivery of rhbFGF promotes post-ischemic angiogenesis and blood flow recovery in rat limb ischemic model. This work marks the first report for controlled release of rhbFGF in combination with metal Mg, and suggests potential therapeutic usefulness of Mg-PLGA-rhbFGF for tissue ischemia. (C) 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.