Injectable Shear-Thinning Hydrogels for Minimally Invasive Delivery to Infarcted Myocardium to Limit Left Ventricular Remodeling

Abstract

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.

Methods To Assess Shear-Thinning Hydrogels for Application As Injectable Biomaterials

“…Here, hydrogels are used for mechanical bulking, 3,4,35 modulating remodeling, 7,17 or therapeutic delivery (cells, small molecules, RNAs) after infarction. 6,15,45 An additional advantage of injectable hydrogels in cardiac disease is the potential to deliver material through minimally invasive approaches, such as percutaneously through a catheter.…”

“…34,35 For tissue regeneration, the encapsulation of cells within hydrogels also requires specific injection parameters that can influence viability. 6,36 For bioprinting applications, injection parameters are also important in modulating both the resolution and stability of printed structures, as well as cellular viability.…”

Computational sensitivity investigation of hydrogel injection characteristics for myocardial support

“…The size and shape of the hydrogel injections (Figure 1, Table 1) were based on MRI reconstruction of injected explant tissue from a previous study. For more detail related to that experimental data, please see the Supplemental Material section in (Rodell et al, 2016). The geometry of the LV wall was based on experimental measurements from ovine hearts (Rodell et al, 2016).…”

“…Several formulations of injectable biomaterials have been studied in order to evaluate the impact on wall thickness and global LV function (Dorsey et al, 2015; Ifkovits et al, 2010; Morita et al, 2011; Tous et al, 2011). These in vivo studies have demonstrated that injectable hydrogel injections can mitigate the adverse effects of MI (Dorsey et al, 2015; Rodell et al, 2016). …”

“…Specifically, experimental studies with large animal models were conducted to investigate different hydrogel injections with altered stiffness characteristics, namely, one with a higher stiffness and another with a lower stiffness (Ifkovits et al., 2010; Rodell et al, 2016). The results showed a better ability to limit infarct expansion and remodeling with the higher stiffness hydrogel injection.…”