Intracoronary Injection of In Situ Forming Alginate Hydrogel Reverses Left Ventricular Remodeling After Myocardial Infarction in Swine

ObjectivesThis study sought to determine whether alginate biomaterial can be delivered effectively into the infarcted myocardium by intracoronary injection to prevent left ventricular (LV) remodeling early after myocardial infarction (MI).BackgroundAlthough injectable biomaterials can improve infarct healing and repair, the feasibility and effectiveness of intracoronary injection have not been studied.MethodsWe prepared a calcium cross-linked alginate solution that undergoes liquid to gel phase transition after deposition in infarcted myocardium. Anterior MI was induced in swine by transient balloon occlusion of left anterior descending coronary artery. At 4 days after MI, either alginate solution (2 or 4 ml) or saline was injected selectively into the infarct-related coronary artery. An additional group (n = 19) was treated with incremental volumes of biomaterial (1, 2, and 4 ml) or 2 ml saline and underwent serial echocardiography studies.ResultsExamination of hearts harvested after injection showed that the alginate crossed the infarcted leaky vessels and was deposited as hydrogel in the infarcted tissue. At 60 days, control swine experienced an increase in left ventricular (LV) diastolic area by 44%, LV systolic area by 45%, and LV mass by 35%. In contrast, intracoronary injection of alginate (2 and 4 ml) prevented and even reversed LV enlargement (p < 0.01). Post-mortem analysis showed that the biomaterial (2 ml) increased scar thickness by 53% compared with control (2.9 ± 0.1 mm vs. 1.9 ± 0.3 mm; p < 0.01) and was replaced by myofibroblasts and collagen.ConclusionsIntracoronary injection of alginate biomaterial is feasible, safe, and effective. Our findings suggest a new percutaneous intervention to improve infarct repair and prevent adverse remodeling after reperfused MI

Micropatterning Alginate Substrates for In Vitro Cardiovascular Muscle on a Chip

Soft hydrogels such as alginate are ideal substrates for building muscle in vitro because they have structural and mechanical properties close to the in vivo extracellular matrix (ECM) network. However, hydrogels are generally not amenable to protein adhesion and patterning. Moreover, muscle structures and their underlying ECM are highly anisotropic, and it is imperative that in vitro models recapitulate the structural anisotropy in reconstructed tissues for in vivo relevance due to the tight coupling between sturcture and function in these systems. We present two techniques to create chemical and structural heterogeneities within soft alginate substrates and employ them to engineer anisotropic muscle monolayers: (i) microcontact printing lines of extracellular matrix proteins on flat alginate substrates to guide cellular processes with chemical cues, and (ii) micromolding of alginate surface into grooves and ridges to guide cellular processes with topographical cues. Neonatal rat ventricular myocytes as well as human umbilical artery vascular smooth muscle cells successfully attach to both these micropatterned substrates leading to subsequent formation of anisotropic striated and smooth muscle tissues. Muscular thin film cantilevers cut from these constructs are then employed for functional characterization of engineered muscular tissues. Thus, micropatterned alginate is an ideal substrate for in vitro models of muscle tissue because it facilitates recapitulation of the anisotropic architecture of muscle, mimics the mechanical properties of the ECM microenvironment, and is amenable to evaluation of functional contractile properties