Influence of Injectable Hyaluronic Acid Hydrogel Degradation Behavior on Infarction-Induced Ventricular Remodeling

Abstract

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 crosslinked, 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: 6.5mm, basilar: 7mm, high MeHA: apical: 7.0mm basilar: 7.2mm) than the hydrolytically degrading hydrogels (low HeMA-HA: apical: 3.5mm, basilar: 6.0mm, high HeMA-HA: apical: 4.1mm, basilar: 6.1mm); however, all hydrogel groups were improved compared to infarct controls (IC) (apical: 2.2mm, basilar: 4.6mm). 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.

Epicardial YAP/TAZ orchestrate an immunosuppressive response following myocardial infarction

“…CreERT2/+ Yap fl/fl Taz fl/fl R26 Tomato/+ mice using an HA polymer modified by hydroxyethyl methacrylate (HEMA-HA, 20% modification) to render it photopolymerizable and hydrolytically degradable (64). Hydrogel precursor solutions (25 μl per animal) consisted of HEMA-HA (6.0% weight) dissolved in a photoinitiator solution, as previously described (47), and contained either 1 μg recombinant IFN-γ (485-MI/ CF; R&D Systems) or no drug.…”

Targeted Injection of a Biocomposite Material Alters Macrophage and Fibroblast Phenotype and Function following Myocardial Infarction: Relation to Left Ventricular Remodeling

“…Although the basis for infarct expansion is likely to be multifactorial, local mechanical signals, such as increased stress and strain within the MI and border zones, likely promulgate this process. The injection of biomaterials within the MI region have been clearly shown to favorably alter these biomechanical factors and reduce adverse post-MI remodeling, and as such, translational studies regarding the underlying mechanisms and pathways by which these materials are operative have accelerated (Landa et al, 2008;Mukherjee et al, 2008;Pilla et al, 2009;Ifkovits et al, 2010;Morita et al, 2011;Rane et al, 2011;Tous et al, 2011Tous et al, , 2012Burdick et al, 2013;Johnson and Christman, 2013;Shuman et al, 2013). Using myocardial injections of a hyaluronic acid and poly (lactide-co-glycolide)-based microsphere (∼50 mm) formulation, it has been previously demonstrated that changing the degradation rates of the microsphere formulation (hydroxyethyl methacrylate) or the microsphere concentration (0-300 mg/ml) can be achieved, which in turn can alter tissue mechanical properties (Ifkovits et al, 2010;Tous et al, 2011Tous et al, , 2012.…”

“…These cell types, the macrophage and fibroblast, play a critical role in the post-MI remodeling process (Lindsey et al, 2001;Ertl and Frantz, 2005;Hohensinner et al, 2010;Frangogiannis, 2012;Freytes et al, 2013;Goldsmith et al, 2013). Past studies have provided functional evidence that the effects of injected acellular biomaterials, such as CHAM upon LV geometry and post-MI remodeling, are not entirely due to the biophysical effects of the material itself but rather to the localized cellular response evoked by these biomaterials (Ifkovits et al, 2010;Rane et al, 2011;Tous et al, 2011Tous et al, , 2012Burdick et al, 2013;Shuman et al, 2013). Therefore, understanding how macrophage and fibroblast form and function within the MI region are affected following targeted CHAM injections remains a critical issue if these biomaterials are to continue advancement as a possible therapeutic for post-MI remodeling.…”

Biomaterial‐Enhanced Cell and Drug Delivery: Lessons Learned in the Cardiac Field and Future Perspectives

“…(49,54) Similar results were found in studies by the Burdick group aimed at investigating the relative influence of mechanical properties using degradable and non-degradable hyaluronic acid based gels of low and high storage moduli (approximately 8 kPa and 40 kPa respectively). (55,56) In the acute infarct ovine studies, significant decreases in ejection fraction (EF) from baseline was seen in all groups, including control. (55,56) However, despite the decrease in EF, cardiac output (stroke volume) was only shown to be significantly lower in the control group, while increased infarct thickness and reduced infarct size was seen in both treatment groups.…”

“…(55,56) In the acute infarct ovine studies, significant decreases in ejection fraction (EF) from baseline was seen in all groups, including control. (55,56) However, despite the decrease in EF, cardiac output (stroke volume) was only shown to be significantly lower in the control group, while increased infarct thickness and reduced infarct size was seen in both treatment groups.…”