Integrative approaches in cardiac tissue engineering: Bridging cellular complexity to create accurate physiological models

Abstract

Recent innovations in cardiac tissue engineering (TE) have yet to fully harness integrative genomic mapping of cellular niches to replicate the spatially organized cellular communities and extracellular matrix (ECM) microniches of the heart. Bridging this gap will allow the development of robust platforms for cardiac regeneration and disease modeling. Recapitulating this complexity, including hierarchical vascularization, functional innervation, and immune integration, remains a fundamental challenge in precision cardiac tissue engineering. While iPSC-derived models, engineered biomaterials, and multi-scale 3D bioprinting have advanced creation of cardiac constructs, most of them still lack the optimal maturity and functional multicellular crosstalk. To address these gaps, this review critically evaluates our current understanding of cardiac cellular/ECM heterogeneity and synthesizes progress in recapitulating these features. By aligning challenges with emerging innovations, we provide a roadmap to drive cardiac tissue engineering innovations toward clinically transformative solutions.

Keywords: Bioengineering; Biomaterials; Cardiovascular medicine; Tissue engineering.

Graphical abstract

Figure 1

Dynamic cellular landscape of cardiac tissue microenvironment in states of homeostasis and injury (A) Various cell types in the heart, including cardiomyocytes, endothelial cells, fibroblasts, neurons, and tissue-resident macrophages, engage in active crosstalk to maintain a homeostatic myocardial niche and extracellular matrix integrity. (B) Following injury, interstitial fibroblasts enter a sustained activation state, accompanied by immune infiltration, cell death, and localized neurovascular inflammation. Cardiac injury signatures vary across cardiovascular pathologies, exhibiting distinct patterns of cellular and extracellular remodeling. Recapitulating the biochemical and biophysical interactions between cells and the extracellular matrix is essential for modeling native and pathological states of the heart.

Figure 2

Mimicking cellular heterogeneity in tissue-engineered cardiac constructs facilitates the creation of cardiac niches that promote cell-cell communication (A–D) This schematic summarizes key platforms and technologies that support static and dynamic cell-cell interactions in (A) microtissues, (B) engineered heart tissues, (C) microphysiological systems, and (D) bioprinted platforms. Employing facile biofabrication design strategies to integrate diverse cardiovascular cell types with functional innervation and vascularization is crucial for unraveling cell-cell interaction-mediated transitions during disease onset and in response to therapeutic interventions in disease modeling.

Figure 3

Roadmap for engineering a functional human heart via integrated biomanufacturing This schematic outlines the biofabrication pipeline for a human heart. First, iPSCs are differentiated into cardiomyocytes, vascular cells, fibroblasts, immune cells, and neuronal cells at clinical scale. These cells are embedded in extracellular matrix-based bioinks and assembled into an anatomically precise construct via multiaxial 3D bioprinting. The printed heart undergoes bioreactor conditioning with physiological pressure-volume cycles, electrical stimulation, and perfusion to achieve functional maturation in terms of stable vascular networks, native-like contractility, and tissue mechanics.