时空传递碱性成纤维细胞生长因子直接并同时减轻心肌纤维化并促进心肌梗塞后心脏组织血管化。,Journal of Controlled Release

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时空传递碱性成纤维细胞生长因子直接并同时减轻心肌纤维化并促进心肌梗塞后心脏组织血管化。
Journal of Controlled Release ( IF 10.5 ) Pub Date : 2019-09-12 , DOI: 10.1016/j.jconrel.2019.09.005
Zhaobo Fan ₁ , Zhaobin Xu ₁ , Hong Niu ₂ , Yang Sui ₂ , Haichang Li ₃ , Jianjie Ma ₃ , Jianjun Guan ₄

Affiliation

心肌梗塞（MI）后，梗死心肌的脉管系统破坏和心脏纤维化的进展导致心脏功能恶化。受损组织的血管化和心脏纤维化的预防代表了改善心脏功能的有前途的策略。本文中，我们开发了具有合适释放动力学的bFGF释放系统，以同时实现两个目标。释放系统基于可注射，热敏和快速凝胶化的水凝胶和bFGF。水凝胶的胶凝时间＜7s。它可以在注射入组织后迅速固化，从而增加药物在组织中的滞留率。水凝胶复合物模量可通过水凝胶溶液浓度来调节。176.6 Pa及更低的复数模量可使心脏成纤维细胞保持其表型。具有生物活性的bFGF能够逐渐从水凝胶中释放4周。在模拟梗死心脏的缺血条件下，释放的bFGF促进了心脏成纤维细胞的存活。当在3D胶原蛋白模型（类似于bFGF释放系统注入心脏的情况）中进行测试时，在存在TGFβ的情况下，它还能使心脏成纤维细胞分化为成肌纤维细胞。此外，释放的bFGF刺激人脐带内皮细胞形成内皮管腔。植入梗死心脏4周后，bFGF释放系统显着增加了血管密度，降低了成纤维细胞密度和胶原蛋白含量，增强了心肌细胞的存活/增殖，并降低了巨噬细胞密度。此外，bFGF释放系统显着增强了心脏功能。

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Spatiotemporal delivery of basic fibroblast growth factor to directly and simultaneously attenuate cardiac fibrosis and promote cardiac tissue vascularization following myocardial infarction.

Following myocardial infarction (MI), the destruction of vasculature in the infarcted heart muscle and progression of cardiac fibrosis lead to cardiac function deterioration. Vascularization of the damaged tissue and prevention of cardiac fibrosis represent promising strategies to improve cardiac function. Herein we have developed a bFGF release system with suitable release kinetics to simultaneously achieve the two goals. The release system was based on an injectable, thermosensitive, and fast gelation hydrogel and bFGF. The hydrogel had gelation time <7 s. It can quickly solidify upon injection into tissue so as to increase drug retention in the tissue. Hydrogel complex modulus can be tuned by hydrogel solution concentration. The complex modulus of 176.6 Pa and lower allowed cardiac fibroblast to maintain its phenotype. Bioactive bFGF was able to gradually release from the hydrogel for 4 weeks. The released bFGF promoted cardiac fibroblast survival under ischemic conditions mimicking those of the infarcted hearts. It also attenuated cardiac fibroblasts from differentiating into myofibroblasts in the presence of TGFβ when tested in 3D collagen model mimicking the scenario when the bFGF release system was injected into hearts. Furthermore, the released bFGF stimulated human umbilical endothelial cells to form endothelial lumen. After 4 weeks of implantation into infarcted hearts, the bFGF release system significantly increased blood vessel density, decreased myofibroblast density and collagen content, augmented cardiac cell survival/proliferation, and reduced macrophage density. In addition, the bFGF release system significantly increased cardiac function. These results demonstrate that delivery of bFGF with appropriate release kinetics alone may represent an efficient approach to control cardiac remodeling after MI.

更新日期：2019-09-12

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