Inducing Endogenous Cardiac Regeneration: Can Biomaterials Connect the Dots?

Abstract

Heart failure (HF) after myocardial infarction (MI) due to blockage of coronary arteries is a major public health issue. MI results in massive loss of cardiac muscle due to ischemia. Unfortunately, the adult mammalian myocardium presents a low regenerative potential, leading to two main responses to injury: fibrotic scar formation and hypertrophic remodeling. To date, complete heart transplantation remains the only clinical option to restore heart function. In the last two decades, tissue engineering has emerged as a promising approach to promote cardiac regeneration. Tissue engineering aims to target processes associated with MI, including cardiomyogenesis, modulation of extracellular matrix (ECM) remodeling, and fibrosis. Tissue engineering dogmas suggest the utilization and combination of two key components: bioactive molecules and biomaterials. This chapter will present current therapeutic applications of biomaterials in cardiac regeneration and the challenges still faced ahead. The following biomaterial-based approaches will be discussed: Nano-carriers for cardiac regeneration-inducing biomolecules; corresponding matrices for their controlled release; injectable hydrogels for cell delivery and cardiac patches. The concept of combining cardiac patches with controlled release matrices will be introduced, presenting a promising strategy to promote endogenous cardiac regeneration.

Keywords: biomaterials; cardiac patch; cardiac regeneration; drug delivery; myocardial infarction; tissue engineering.

FIGURE 1

Biomaterial-based applications for cardiac tissue engineering. (A) Biomaterials can be injected alone into the infarcted regions in order to attenuate scar formation, (B) cell-delivery using injectable hydrogels can improve cell retention and survival after transplantation; (C) three-dimensional matrices can be fabricated with or without cells, then implanted as cardiac patches to improve cardiac function; and (D) biomaterials designed to release drugs and bioactive molecules may induce cardiac regeneration in a sustained effective manner.

FIGURE 2

Biomaterial-based applications for cardiac regeneration. (A) Natural or synthetic polymers can be used as nano-carriers for the delivery of cardiac inducing agents. This will assist their bioavailability, allow specific targeting to the infarcted region or destination cell population, and increase their half-life in the tissue, eventually improving treatment efficacy; (B) hydrogel systems can be utilized to protect transplanted cells from the hostile post-MI microenvironment. This strategy can improve cell retention and provide the transplanted cells and the infarcted tissue the mechanical support lost as a result of massive loss of muscle tissue; (C) biomaterials can be used to fabricate cellular or acellular cardiac patches, providing cell with ECM interactions, mechanical and electrical stimuli. Depending on their size and mechanical properties, cardiac patches can perform as temporary or permanent replacements for damaged tissue; (D) regeneration-inducing agents can be encapsulated or bound to biomaterial-based delivery platforms, allowing effective release of these agents in a spatial–temporal manner. Plus sign indicates benefits of the application, arrow indicates an attribute that improves.

FIGURE 3

Cardiac patch after explant. (A) Representative image of a dissected rat heart, 30 days post-implementation of an alginate cardiac patch. The cardiac patch consists of a macroporous alginate scaffold, incorporated with magnetic nanoparticles. The construct was seeded with human embryonic stem cell-derived cardiomyocytes, and cultivated for 24 h prior to implementation on top of an infarcted rat heart. Dashed line denotes cardiac patch borders; (B) photomicrograph of Masson’s trichrome-stained section of the interface between implanted cardiac patch and host myocardium, 30 days post-transplantation. CP, cardiac patch; FS, fibrotic scar; HCM, host cardiac muscle. Scale bar is 100 μm. Images are courtesy of Mr. Edan Elovic.

FIGURE 4

Challenges in cardiac patch implementation. Cardiac patches must integrate properly with host myocardium to properly improve cardiac function. For cell-seeded patches, sufficient nutrient supply by blood vessels is crucial for cell survival; biomaterials, as foreign objects, induce immunogenic response immediately after their introduction, impairing integration and leading to patch rejection; improper electrical coupling of the patch with host myocardium may result in arrhythmias; and cellular continuum, translated into biomechanical integrity, is also important for patch assimilation.