Biomaterial based cardiac tissue engineering and its applications

Abstract

Cardiovascular disease is a leading cause of death worldwide, necessitating the development of effective treatment strategies. A myocardial infarction involves the blockage of a coronary artery leading to depletion of nutrient and oxygen supply to cardiomyocytes and massive cell death in a region of the myocardium. Cardiac tissue engineering is the growth of functional cardiac tissue in vitro on biomaterial scaffolds for regenerative medicine application. This strategy relies on the optimization of the complex relationship between cell networks and biomaterial properties. In this review, we discuss important biomaterial properties for cardiac tissue engineering applications, such as elasticity, degradation, and induced host response, and their relationship to engineered cardiac cell environments. With these properties in mind, we also emphasize in vitro use of cardiac tissues for high-throughput drug screening and disease modelling.

Figure 1. Examples of in vivo studies

(A) Sections of left ventricle 3 weeks post MI (a) without and (b) with CDC graft, suggesting improved tissue repair with CDC graft. Masson’s Trichome staining of heart wall indicating collagen deposition (blue), and viable muscle cells (red). (d) Specimens with implanted grafts indicated more aligned collagen deposition and higher percentage of surviving muscle cells than (c) non-implanted specimens [43]. (B) (a) Sarcomeric organization in engineered heart tissue (EHT) four weeks post-implantation, stained for actin filaments (green) and nulcei (blue). (b) Putative blood vessel formation observed, with both endothelial and smooth muscle cells. (c) Pressure volume loop of healthy, infarcted, and grafted rat hearts suggest, hearts implanted with an EHT showed less left ventricle dilation and more similar function to normal hearts six weeks post-MI [40]. (C) Poly(2-hydroxyethyl methacrylate-co-methacrylic acid) hydrogel patch surrounded by collagen capsule (blue) and host myocardium (red) of a nude rat at 28 days after patch implantation. (a) Nonporous and (b) 60μm porous constructs had thicker and denser fibrous capsule than constructs with (c) 30μm and (d) 20μm pores, (e) this thickness was quantified. Neovascularization was more prevalent in the (f) 40μm pore construct, quantified by the presence of rat endothelial cell marker (RECA-1+) on lumen structures [38]. (D) (a) Hematoxylin and eosin stain of heart post MI (b) treated with chitosan-hyaluronan/silk fibronin patch compared to a post MI control presents reduction of left ventricle dilation with the patch treatment. (b) Masson’s Trichome stained heart wall at infarct zone; the dotted yellow line indicates the patch, and the dotted red line indicates the myocardium. The patch adhered strongly to the epicardial surface, and reduced fibrosis in the infarct zone [44].

Figure 2. Mechanism of hydrolysis for polyester polymer backbone

Water acts as a nucleophile, attacking and cleaving the ester linkage in the polymer backbone. Degradation is accelerated under acidic conditions.

Figure 3. Strategies for generating 2D and 3D cardiac tissue in vitro

(A) CM monolayers cultured on patterned MEA for guided action potential propagation [105]. (B) CM monolayers cultured on flexible elastomer films for contractile force measurement [108]. (C) High-throughput platform for monitoring contractile activity of an array of fibrin-based engineered heart tissues [113]. (D) Cardiac micro-tissues around micro-cantilevers to measure contractile properties [114]. (E) Cardiac biowire set-up with a suspended template to guide tissue formation and cell alignment. The phenotype of the CM was matured under external electrical stimulation and the drug candidates were applied by perfusion through micro-tubing within the biowire, providing improved physiological relevance [115].

Figure 4. Tissue-on-a-chip models

potentially allow for high-throughput screening of pharmaceuticals in vitro on human cell-based substrates in a relatively cost effective manner when compared to typical testing methods that involve extensive testing on explanted animal heart tissue slices and pre-clinical studies. These platforms can be tailored to specific diseases using cell lines from the affected patients, and exhibit the tissue response properties of the native cardiac tissue.