Abstract 20275: A Novel Engineered Hepatocyte Growth Factor Analog Released via a Temperature-Responsive, Shear-Thinning Hydrogel Enhances Post-Infarction Ventricular Function

Objective: Hepatocyte growth factor is cardioprotective, anti-apoptotic, and pro-angiogenic; yet, is limited in clinical translation due to its high manufacturing cost and low stability. We encapsulated an engineered HGF fragment (HGFf) in an engineered shear-thinning, temperature-responsive, injectable hydrogel (SHIELD). We hypothesized SHIELD would facilitate targeted, sustained intramyocardial delivery of HGFf, thereby attenuating myocardial injury and post-infarction remodeling. Methods: HGFf elution was tracked for 2 weeks via fluorophore conjugation. Cytoprotective effects of HGFf on rat cardiomyocytes were assessed with a WST-1 cell viability assay after a 48hr serum starvation. Adult male Wistar rats (n=21) underwent sham surgery or permanent ligation of the LAD followed by borderzone injection of 60μL PBS, SHIELD alone, or SHIELD encapsulating 10μg HGFf. Ventricular geometry and function, infarct size, and angiogenic response were assessed 4-weeks post-infarction. Results: HGFf elution was sustained for 14 days in vitro (Fig. 1A), remained active, and improved cardiomyocyte viability by 22% during serum starvation (Fig. 1B). SHIELD remained localized within the heart at day 16 following injection. Treatment with SHIELD-HGFf reduced infarct size and significantly increased ejection fraction compared to that of the controls (Fig. 1C and D). The improvements in function in SHIELD-HGFf treated animals were coupled with a significant increase in arterial density compared to that of the other study groups (Fig. 1E and F). Conclusions: Sustained delivery of a stable, protein engineered HGFf limits post-infarction adverse ventricular remodeling by increasing angiogenesis and reducing fibrosis. Combining HGFf with SHIELD improves clinical translatability by enabling catheter-based delivery and subsequent retention of this novel, potent angiogenic protein analog.