Background Injectable, acellular biomaterials hold promise to limit left ventricular (LV) remodeling and heart failure precipitated by infarction through bulking and/or stiffening the infarct region. A material with tunable properties (e.g., mechanics, degradation) that can be delivered percutaneously has not yet been demonstrated. Catheter deliverable soft hydrogels with in vivo stiffening to enhance therapeutic efficacy achieve these requirements. Methods and Results We developed a hyaluronic acid hydrogel that utilizes a tandem crosslinking approach, where the first crosslinking (guest-host, GH) enabled injection and localized retention of a soft (<1kPa) hydrogel. A second crosslinking reaction (dual-crosslinking, DC) stiffened the hydrogel (41.4±4.3kPa) after injection. Posterolateral infarcts were investigated in an ovine model (n≥6 per group), with injection of saline (MI control), GH, or DC. Computational (day 1), histological (1 day, 8 wk), morphological and functional (0, 2, 8 wk) outcomes were evaluated. Finite element modeling projected myofiber stress reduction (>50%, P<0.001) with DC but not GH injection. Remodeling, assessed by infarct thickness and LV volume, was mitigated by hydrogel treatment. Ejection fraction was improved, relative to MI at 8 weeks, with DC (37% improvement, P=0.014) and GH (15% improvement, P=0.058) treatments. Percutaneous delivery via endocardial injection was investigated with fluoroscopic and echocardiographic guidance, with delivery visualized by MRI. Conclusions A percutaneous delivered hydrogel system was developed, and hydrogels with increased stiffness were most effective in ameliorating LV remodeling and preserving function. Ultimately, engineered systems such as these have the potential to provide effective clinical options to limit remodeling in patients after infarction.

Background-Left ventricular remodeling after postero-basal myocardial infarction can lead to ischemic mitral regurgitation. This occurs as a consequence of leaflet tethering due to posterior papillary muscle displacement.

Infarcted regions of myocardium exhibit functional impairment ranging in severity from hypokinesis to dyskinesis. We sought to quantify the effects of injecting a calcium hydroxyapatite-based tissue filler on the passive material response of infarcted left ventricles. Three-dimensional (3D) finite element models of the left ventricle were developed using 3D echocardiography data from sheep with a treated and untreated anteroapical infarct, in order to estimate the material properties (stiffness) in the infarct and remote regions. This was accomplished by matching experimentally determined left ventricular volumes, and minimizing radial strain in the treated infarct, which is indicative of akinesia. The nonlinear stress-strain relationship for the diastolic myocardium was anisotropic with respect to the local muscle fiber direction, and an elastance model for active fiber stress was incorporated. It was found that the passive stiffness parameter, C, in the treated infarct region is increased by nearly 345 times the healthy remote value. Additionally, the average myofiber stress in the treated left ventricle was significantly reduced in both the remote and infarct regions. Overall, injection of tissue filler into the infarct was found to render it akinetic and reduce stress in the left ventricle, which could limit the adverse remodeling that leads to heart failure.