Abstract
Heart failure has a five-year mortality rate approaching 50%. Inducing angiogenesis following a myocardial infarction is hypothesized to reduce cardiomyocyte death and tissue damage, thereby preventing heart failure. Herein, a novel nano-in-gel delivery system for vascular endothelial growth factor (VEGF), composed of star-shaped polyglutamic acid-VEGF nanoparticles in a tyramine-modified hyaluronic acid hydrogel (nano-VEGF-HA-TA), is investigated. The ability of the nano-VEGF-HA-TA system to induce angiogenesis is assessed in vivo using a chick chorioallantoic membrane model (CAM). The formulation is then integrated with a custom-made, clinically relevant catheter suitable for minimally invasive endocardial delivery and the effect of injection on hydrogel properties is examined. Nano-VEGF-HA-TA is biocompatible on a CAM assay and significantly improves blood vessel branching (p < 0.05) and number (p < 0.05) compared to a HA-TA hydrogel without VEGF. Nano-VEGF-HA-TA is successfully injected through a 1.2 m catheter, without blocking or breaking the catheter and releases VEGF for 42 days following injection in vitro. The released VEGF retains its bioactivity, significantly improving total tubule length on a Matrigel® assay and human umbilical vein endothelial cell migration on a Transwell® migration assay. This VEGF-nano in a HA-TA hydrogel delivery system is successfully integrated with an appropriate device for clinical use, demonstrates promising angiogenic properties in vivo and is suitable for further clinical translation.
Highlights
Heart failure causes severe patient morbidity and has a five year survival rate of approximately 50% [1,2,3,4,5,6,7]
While initially a necessary and protective response, this scar formation increases the risk of cardiac arrhythmias and reduces the pumping capacity of the heart leading to heart failure
We have previously reported on the successful complexation of vascular endothelial growth factor (VEGF) with a star-shaped polyglutamic acid polypeptide to form nanoparticles [19]
Summary
Heart failure causes severe patient morbidity and has a five year survival rate of approximately 50% [1,2,3,4,5,6,7]. The most common causative factor is ischemic heart disease. Despite revascularization and current pharmacological therapy approaches aimed at restoring blood supply to the affected cardiac tissue, tissue damage tends to spread from the original area of infarct over time to take up more of the previously healthy tissue [11]. This persistent spread in damage causes loss of beating heart muscle and formation of akinetic, fibrotic scar tissue [12]. While initially a necessary and protective response, this scar formation increases the risk of cardiac arrhythmias and reduces the pumping capacity of the heart leading to heart failure
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