Intramyocardial sustained delivery of basic fibroblast growth factor improves angiogenesis and ventricular function in a rat infarct model

Abstract

Recently we have demonstrated that the release of basic fibroblast growth factor (bFGF) from a biodegradable gelatin hydrogel carrier depends on the degradation of hydrogel in vivo. The purpose of our study was to assess whether bFGF-incorporating gelatin hydrogels induce myocardial angiogenesis and improve left ventricular function in the infarcted myocardium of rats. Studies were conducted in 22 Lewis rats after a 4-week ligation of the proximal left anterior descending coronary artery. The rats were randomized into the following two groups: the control group (n = 11) had an intramyocardial injection of saline alone, and the FGF group (n = 11) had gelatin hydrogel microspheres containing 100 microg of bFGF injected into the border zone of the infarct area after the repeat left thoracotomy. For visualization of the regional myocardial blood flow in the rat heart, (201)Tl images were taken just before and 4 weeks after the treatment using a 4-head single photon emission computed tomography scanner with pinhole collimators. Left ventricular function was also assessed with echocardiography and a micromanometer-tipped catheter. Finally, the extent of myocardial angiogenesis was evaluated quantitatively in the postmortem analysis. The (201)Tl defect score in the control group remained unchanged before and after the treatment, whereas it decreased significantly in the FGF group. Both regional and global left ventricular function was significantly better in the FGF group compared with the control group. The vascular density in the border zone of the infarct in the FGF group was significantly higher than that in the control group. In conclusion, intramyocardial injection of bFGF-impregnated gelatin hydrogels induces functionally significant angiogenesis and improves left ventricular systolic and diastolic function in the infarcted myocardium of rats.

Injectable Acellular Hydrogels for Cardiac Repair

“…Sustained release of fibroblast growth factor (FGF) from injectable hydrogels has been extensively explored to stimulate angiogenesis following MI [85][86][87][88][89][90]. FGF is a powerful angiogenic molecule, but has a very short half-life in vivo.…”

“…FGF is a powerful angiogenic molecule, but has a very short half-life in vivo. Sakakibara et al showed that radiolabeled FGF delivered to the myocardium via bolus venous injections, intracoronary injections, or intramyocardial injections is nearly undetectable 24 h after administration [88]. However, by using gelatin hydrogel microspheres as a carrier matrix, effective concentrations of radiolabeled FGF were sustained in the peri-infarct area of the myocardium 24 and 72 h after injection (all groups injected 4 weeks after induced MI in rats).…”

“…Upon evaluation at 4 weeks after injection, LV remodeling was significantly attenuated (echocardiography), and neovasculature was significantly increased (capillary density) compared to a control MI group. Other groups have also reported the efficacy of using gelatin microspheres to deliver FGF in the setting of MI [88,89]. In addition to gelatin microspheres, injectable chitosan hydrogels have been used to deliver FGF [85].…”

Hydrogels for Cardiac Tissue Repair and Regeneration

“…For example, it was reported that the bFGF-loaded gelatin microspheres tested on rat and pig models led to angiogenesis induction and improved left ventricle systolic and diastolic function in the infarcted myocardium [29][30][31]. In another study, by injecting bFGF -gelatin microspheres it was reported that the presence of bFGF in vivo increased from 3 to 15 days and also increases vessel density in infarcted and border zone myocardium [32].…”

Minimally invasive cell-seeded biomaterial systems for injectable/epicardial implantation in ischemic heart disease

“…For instance, targeted delivery of VEGF using encapsulating immunoliposomes into the MI zone has been shown to significantly enhance morphology and function of infarcted region. 220 Iwakura et al 221 delivered basic FGF via injectable gelatin microspheres and demonstrated improved angiogenesis and cardiac function. Delivery of a plasmid encoding the angiogenic growth factor pleiotrophin in fibrin glue also increased neovascularization in infarcted myocardium.…”