Advancing Cardiomyocyte Maturation: Current Strategies and Promising Conductive Polymer-Based Approaches

Abstract

Cardiovascular diseases are a leading cause of mortality and pose a significant burden on healthcare systems worldwide. Despite remarkable progress in medical research, the development of effective cardiovascular drugs has been hindered by high failure rates and escalating costs. One contributing factor is the limited availability of mature cardiomyocytes (CMs) for accurate disease modeling and drug screening. Human induced pluripotent stem cell-derived CMs offer a promising source of CMs; however, their immature phenotype presents challenges in translational applications. This review focuses on the road to achieving mature CMs by summarizing the major differences between immature and mature CMs, discussing the importance of adult-like CMs for drug discovery, highlighting the limitations of current strategies, and exploring potential solutions using electro-mechano active polymer-based scaffolds based on conductive polymers. However, critical considerations such as the trade-off between 3D systems and nutrient exchange, biocompatibility, degradation, cell adhesion, longevity, and integration into wider systems must be carefully evaluated. Continued advancements in these areas will contribute to a better understanding of cardiac diseases, improved drug discovery, and the development of personalized treatment strategies for patients with cardiovascular disorders.

Keywords: cardiomyocyte maturation; cardiovascular research; conductive polymers; human induced pluripotent stem cells; physiological stimuli.

Figure 1

A) Morphological differences in proliferating and hypertrophied cardiac cells. B) Action potential curve of cardiac cells. C) Excitation‐contraction coupling and relaxation in cardiac muscle. Created with BioRender.com.

Figure 2

A) CMs undergoing polyploidy. B) The hypertrophy, multinucleation, and endoreduplication of neonatal CMs in comparison to the embryonic regeneration process in mice. C) Cell cycle regulation by transcription factors, cyclins, cyclin‐dependent kinases (CDKs), and CDK‐ inhibitors CKIs. Created with BioRender.com.

Figure 3

Schematic summary of topographical and biochemical cues for iPSC‐CM maturation. Created with BioRender.com.

Figure 4

Tissue engineering strategies for cardiac maturation. A) Electrically controllable 3D biohybrid actuator of neonatal rat CMs. B) Cardiac biowire under 3D culture, ECM modification, and E‐stimulation. C) Cardiac tissue sheets resembling torsade de pointes arrhythmias. Created with BioRender.com.

Figure 5

Schematic representation of cardiac regeneration strategies using M‐, E‐, or EM‐stimulations. Created with BioRender.com.

Figure 6

A) Schematic diagrams demonstrating the synchronization of cell beatings following E‐stimulation of cells seeded on aligned conductive nanofibrous mesh. Reproduced with permission.^{[ 191 ]} Copyright 2013, Elsevier. B) A schematic diagram and an immunofluorescence image showing the direct E‐stimulation and optical imaging of neonatal CMs stained for DAPI (blue), α‐Actinin (green), and connexin 43 (red) with a scale bar of 100 µm. Reproduced with permission.^{[ 204 ]} Copyright 2018, Springer Nature. C) Schematic representation of the E‐stimulation of CVD‐specific hiPSCs in a unidirectional and multidirectional manner. Reproduced with permission.^{[ 205 ]} Copyright 2017, American Chemical Society.

Figure 7

A) Schematic representation of the chemical mechanism responsible for PPy actuation. B) Schematic representation of the design and fabrication of an M‐stimulation chip using PPy microactuators resulting in a cellular Ca²⁺ response induced by autocrine ATP signaling. Reproduced with permission.^{[ 216 ]} Copyright 2011, The Royal Chemical Society. C) SEM image of the cross‐sectional view of the PLGA core coated with PPy (scale bar = 500 nm) and microscopic images of iPSCs cultured electromechanically stimulated and unstimulated scaffolds stained for i,ii) live/dead and iii,iv) actin filaments. Reproduced with permission.^{[ 130 ]} Copyright 2016, Wiley‐VCH GmbH.