Materials science and tissue engineering: repairing the heart

Abstract

Heart failure after a myocardial infarction continues to be a leading killer in the Western world. Currently, there are no therapies that effectively prevent or reverse the cardiac damage and negative left ventricular remodeling process that follows a myocardial infarction. Because the heart has limited regenerative capacity, there has been considerable effort to develop new therapies that could repair and regenerate the myocardium. Although cell transplantation alone was initially studied, more recently, tissue engineering strategies using biomaterial scaffolds have been explored. In this review, we cover the different approaches to engineering the myocardium, including cardiac patches, which are in vitro-engineered constructs of functional myocardium, and injectable scaffolds, which can either encourage endogenous repair and regeneration or act as vehicles to support the delivery of cells and other therapeutics.

Keywords: ECM; EHT; ESC; HA; LV; MI; MeHA; PSC; VEGF; bFGF; basic fibroblast growth factor; embryonic stem cell; engineered heart tissue; extracellular matrix; hESC; human embryonic stem cell; hyaluronic acid; iPSC; induced pluripotent stem cell; left ventricular; methacrylated hyaluronic acid; myocardial infarction; pluripotent stem cells; vascular endothelial growth factor.

Figure 1. Pluripotent stem cell derived cardiac patches

A) Vascularization of cardiac patches based on cardiomyocytes (CM) derived from human embryonic stem cells (hESC) can be enhanced by co-culture with endothelial cells (EC) and either mouse embryonic fibroblasts (MEFs) or mesenchymal stem cells (MSC). B) Human iPSC based cardiac patch can be implanted onto the heart of an athymic rat and persist for one week. Top β-myosin heavy chain staining; bottom, α-actinin, showing the graft–host interface. From Circ Res, with permission. CM= cardiomyocytes; EC = endothelial cells; MEFs = mouse embryonic fibroblasts; MSC = mesenchymal stem cell.

Figure 2. Cardiac patches derived from mouse parthenogenetic cells

A) Patches were conditioned by mechanical stimulation. B) They were used to repair infarcted myocardium of the mouse donors. C) Patch implantation resulted in the improvement of anterior wall thickening at diastole. From J Clin Invest, with permission.

Figure 3. Engineering of vascularized myocardium by the control of topography and presentation of angiogenic growth factors

A) A polydimethylsiloxane stamp with topographical cues (grooves and ridges) is coated with collagen:chitosan hydrogel desired for controlled release of an angiogenic factor thymosin b4. The topographical cues guide the outgrowth of capillaries from an artery and vein, resulting in a microvessel bed around which cardiomyocytes are seeded. B) Microvascular outgrowths are connected by Day 21. C) Confocal micrographs indicate the presence of open lumens. D) Vascularized cardiac tissue. From PNAS, with permission.

Figure 4. Delivery approaches for injectable biomaterial scaffolds

Similar to cell injections, biomaterial scaffolds can be delivered via transcoronary infusion (A), which involves infusion of the material across the leaky coronary vessels acutely post-MI, transendocardial injections (B), which involves catheter placement inside the chamber of the left ventricle and injection across the endocardium, or direct epicardial injection (C), which requires a surgical approach to access the epicardium. Both transendocardial and direct epicardial injection involve puncture with a needle and targeted injection into the infarct area. From Heart Lung Circ, with permission.

Figure 5. Transcoronary delivery of alginate

Alginate, which is crosslinked with Ca²⁺, was delivered via a catheter-based transcoronary infusion in a porcine MI model. Given the leaky vasculature and high extracellular Ca²⁺ in an acute MI, the material is able to pass through the vasculature and gel once inside the tissue. The white material is visible on the epicardial surface of the infarct (A) and in tissue slices (B). From JACC, with permission.

Figure 6. Increased cardiac muscle using an acellular myocardial matrix hydrogel

In a porcine myocardial infarction model, percutaneous transendocardial injections of a decellularized myocardial extracellular matrix based hydrogel were performed 2 weeks post-MI. Three months following injection, there was significantly more cardiac muscle (*) found at the endocardium following matrix treatment (A) compared to controls (B). Images are of trichrome stained heart sections, where muscle is stained red and collagen is stained blue. From Science Translational Medicine, with permission.