Influence of injectable hyaluronic acid hydrogel degradation behavior on infarction-induced ventricular remodeling

Increased myocardial wall stress after myocardial infarction (MI) initiates the process of adverse left ventricular (LV) remodeling that is manifest as progressive LV dilatation, loss of global contractile function, and symptomatic heart failure, and recent work has shown that reduction in wall stress through injectable bulking agents attenuates these outcomes. In this study, hyaluronic acid (HA) was functionalized to exhibit controlled and tunable mechanics and degradation once cross-linked, in an attempt to assess the temporal dependency of mechanical stabilization in LV remodeling. Specifically, two hydrolytically degrading (low and high HeMA-HA, degrading in ~3 and 10 weeks, respectively) and two stable (low and high MeHA, little mass loss even after 8 weeks) hydrogels with similar initial mechanics (low: ~7 kPa; high: ~35-40 kPa) were evaluated in an ovine model of MI. Generally, the more stable hydrogels maintained myocardial wall thickness in the apical and basilar regions more efficiently (low MeHA: apical: 6.5 mm, basilar: 7 mm, high MeHA: apical: 7.0 mm basilar: 7.2 mm) than the hydrolytically degrading hydrogels (low HeMA-HA: apical: 3.5 mm, basilar: 6.0 mm, high HeMA-HA: apical: 4.1 mm, basilar: 6.1 mm); however, all hydrogel groups were improved compared to infarct controls (IC) (apical: 2.2 mm, basilar: 4.6 mm). Histological analysis at 8 weeks demonstrated that although both degradable hydrogels resulted in increased inflammation, all treatments resulted in increased vessel formation compared to IC. Further evaluation revealed that while high HeMA-HA and high MeHA maintained reduced LV volumes at 2 weeks, high MeHA was more effective at 8 weeks, implying that longer wall stabilization is needed for volume maintenance. All hydrogel groups resulted in better cardiac output (CO) values than IC.