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Cardiovascular diseases are the number one killer in the world. 1 , 2 Currently, there are no clinical treatments to regenerate damaged cardiac tissue, leaving patients to develop further life-threatening cardiac complications. Cardiac tissue has multiple functional demands including vascularization, contraction, and conduction that require many synergic components to properly work. Most of these functions are a direct result of the cardiac tissue structure and composition, and, for this reason, tissue engineering strongly proposed to develop substitute engineered heart tissues (EHTs). EHTs usually have combined pluripotent stem cells and supporting scaffolds with the final aim to repair or replace the damaged native tissue. However, as simple as this idea is, indeed, it resulted, after many attempts in the field, to be very challenging. Without design complexity, EHTs remain unable to mature fully and integrate into surrounding heart tissue resulting in minimal in vivo effects. 3 Lately, there has been a growing body of evidence that a complex, multifunctional approach through implementing scaffold designs, cellularization, and molecular release appears to be essential in the development of a functional cardiac EHTs. 4. , 5. , 6. This review covers the advancements in EHTs developments focusing on how to integrate contraction, conduction, and vascularization mimics and how combinations have resulted in improved designs thus warranting further investigation to develop a clinically applicable treatment.

Regenerative medicine technologies rely heavily on the use of well-designed biomaterials for therapeutic applications. The success of implantable biomaterials hinges upon the ability of the chosen biomaterial to negotiate with the biological barriers in vivo. The most significant of these barriers is the immune system, which is composed of a highly coordinated organization of cells that induce an inflammatory response to the implanted biomaterial. Biomimetic platforms have emerged as novel strategies that aim to use the principle of biomimicry as a means of immunomodulation. This principle has manifested itself in the form of biomimetic scaffolds that imitate the composition and structure of biological cells and tissues. Recent work in this area has demonstrated the promising potential these technologies hold in overcoming the barrier of the immune system and, thereby, improve their overall therapeutic efficacy. In this review, a broad overview of the use of these strategies across several diseases and future avenues of research utilizing these platforms is provided.

Structural cardiac defects, such as Tetralogy of Fallot, often requires surgical placement of a patch to expand the right ventricular outflow tract (RVOT) in an area normally consisting of contractile myocardial tissue. Current cardiac patch materials are biologically inert and will not grow with a pediatric patient, often requiring reoperations. In this study, novel multi-layered scaffolds with a polycaprolactone core, a chitosan-based scaffold, and either gelatin or decellularized porcine heart matrix were implanted into a full thickness rat right ventricle defect for up to 8 weeks. The results show that engineered scaffolds were biodegradable and promoted tissue remodeling. Histological analysis of control fixed pericardium patches showed little to no cellular infiltration, while engineered scaffolds had significant muscular and vascular cell remodeling. Quantitative MRI revealed that left ventricular ejection fractions were stabilized in all patched hearts after 8 weeks, and the right ventricular ejection fraction in hearts with engineered patches was significantly greater than hearts with control pericardium patches. In addition, patches with heart matrix promoted a denser vascular network and a higher M2/M1 inflammatory macrophage ratio when compared to patches containing only gelatin. Collectively, these results show that these multi-layered patches are capable of full thickness defect repair and regeneration.