Challenges and opportunities for the next generation of cardiovascular tissue engineering

Abstract

Engineered cardiac tissues derived from human induced pluripotent stem cells offer unique opportunities for patient-specific disease modeling, drug discovery and cardiac repair. Since the first engineered hearts were introduced over two decades ago, human induced pluripotent stem cell-based three-dimensional cardiac organoids and heart-on-a-chip systems have now become mainstays in basic cardiovascular research as valuable platforms for investigating fundamental human pathophysiology and development. However, major obstacles remain to be addressed before the field can truly advance toward commercial and clinical translation. Here we provide a snapshot of the state-of-the-art methods in cardiac tissue engineering, with a focus on in vitro models of the human heart. Looking ahead, we discuss major challenges and opportunities in the field and suggest strategies for enabling broad acceptance of engineered cardiac tissues as models of cardiac pathophysiology and testbeds for the development of therapies.

Fig. 1 |. A scatterplot depicting the trade-off between throughput and maturity in cardiac tissue engineering.

a–f, Models reported to date can be broadly categorized based on the fundamental methodologies: (a) traditional 2D models and hydrogel-based systems; (b) spheroids that rely on self-aggregation of differentiated cells or organoids generated by spontaneous co-differentiation of cells in 3D aggregates^,,,,, (red); (c) early methods that have focused primarily on 3D biomaterial scaffolds for cell seeding (blue); (d) engineered tissues of varying geometries and sizes that provide exogenous structural and/or electromechanical maturation cues to promote physiological tissue architecture^– (yellow); (e) miniaturized microphysiological systems and microtissues^,,, (green); and (f) 3D bioprinting-based methods that enable arbitrary structural control at the macroscale^,– (purple). The most common and relatively recent categories of techniques are highlighted in black boxes with an accompanying illustration. Note that ‘tissue maturity’ shown on the x axis is meant to be an abstract, qualitative representation, placing more weight on the structural, mechanical and electrophysiological maturity of the tissue as it pertains to the organ’s primary function (that is, contractile beating), than on ‘biological complexity’, which takes into consideration how many physiological features are recapitulated by the model (for example, the number of cell types incorporated and the extent of vascularization). MPS, microphysiological system; μHM, micro-heart muscle; CMT, cardiac microtissue; dynEHT, dynamically loaded EHTs; dECM, decellularized ECM; FRESH, freeform reversible embedding of suspended hydrogels; SWIFT, sacrificial writing into functional tissue.

Fig. 2 |. Illustration of tissue maturity levels that can be achieved by current tissue engineering models.

a–h, The levels of maturity are categorized based on major readouts: gene expression profiles (a), tissue structure and morphology (b), ECM composition and mechanics (c), contractility (d), electrophysiological properties (e), calcium handling (f), metabolism (g) and vascularization (h). Cones and faded gray arrows are abstract representations of current roadblocks and how far the best-available tissue models today are from reaching adult myocardium-like maturity levels for each category. Many of the readouts are inherently intertwined (for example, metabolism can directly regulate gene expression and vice versa), suggesting major advancements in one area can indirectly contribute to overcoming obstacles in another. Gluc, glucose metabolism; FAO, fatty acid oxidation; NA, not applicable.

Fig. 3 |. Major obstacles and opportunities in cardiac tissue engineering.

a, Enhancing tissue maturation to near-adult myocardium levels without substantially compromising throughput. b, Efficient vascularization of tissues for improved nutrient delivery, scale-up, long-term maintenance, and modeling of physiological cell–cell cross-talk mechanisms. c, Addressing problems of reproducibility and variability across cell lines and across batches of the same line. d, Engineering an ECM that mimics the compositional diversity, structural alignment and mechanical robustness of native cardiac ECM. e, Optimization of universal multi-cell-type culture media. f, Improving scalability for both industrial and clinical applications. g, Enhancing electromechanical integration of transplanted tissue to the host myocardium. h, Development of improved 3D imaging technologies and real-time functional assays. i, Integration with multiple organ chips for systems-level modeling of diseases and drug responses.