Next-generation tissue-engineered heart valves with repair, remodelling and regeneration capacity

Valvular heart disease is a major cause of morbidity and mortality worldwide. Surgical valve repair or replacement has been the standard of care for patients with valvular heart disease for many decades, but transcatheter heart valve therapy has revolutionized the field in the past 15 years. However, despite the tremendous technical evolution of transcatheter heart valves, to date, the clinically available heart valve prostheses for surgical and transcatheter replacement have considerable limitations. The design of next-generation tissue-engineered heart valves (TEHVs) with repair, remodelling and regenerative capacity can address these limitations, and TEHVs could become a promising therapeutic alternative for patients with valvular disease. In this Review, we present a comprehensive overview of current clinically adopted heart valve replacement options, with a focus on transcatheter prostheses. We discuss the various concepts of heart valve tissue engineering underlying the design of next-generation TEHVs, focusing on off-the-shelf technologies. We also summarize the latest preclinical and clinical evidence for the use of these TEHVs and describe the current scientific, regulatory and clinical challenges associated with the safe and broad clinical translation of this technology.</p

Computational modeling for cardiovascular tissue engineering:the importance of including cell behavior in growth and remodeling algorithms

\u3cp\u3eUnderstanding cardiovascular growth and remodeling (G&amp;R) is fundamental for designing robust cardiovascular tissue engineering strategies, which enable synthetic or biological scaffolds to transform into healthy living tissues after implantation. Computational modeling, particularly when integrated with experimental research, is key for advancing our understanding, predicting the in vivo evolution of engineered tissues, and efficiently optimizing scaffold designs. As cells are ultimately the drivers of G&amp;R and known to change their behavior in response to mechanical cues, increasing efforts are currently undertaken to capture (mechano-mediated) cell behavior in computational models. In this selective review, we highlight some recent examples that are relevant in the context of cardiovascular tissue engineering and discuss the current and future biological and computational challenges for modeling cell-mediated G&amp;R.\u3c/p\u3

Predicting and understanding collagen remodeling in human native heart valves during early development

\u3cp\u3eThe hemodynamic functionality of heart valves strongly depends on the distribution of collagen fibers, which are their main load-bearing constituents. It is known that collagen networks remodel in response to mechanical stimuli. Yet, the complex interplay between external load and collagen remodeling is poorly understood. In this study, we adopted a computational approach to simulate collagen remodeling occurring in native fetal and pediatric heart valves. The computational model accounted for several biological phenomena: cellular (re)orientation in response to both mechanical stimuli and topographical cues provided by collagen fibers; collagen deposition and traction forces along the main cellular direction; collagen degradation decreasing with stretch; and cell-mediated collagen prestretch. Importantly, the computational results were well in agreement with previous experimental data for all simulated heart valves. Simulations performed by varying some of the computational parameters suggest that cellular forces and (re)orientation in response to mechanical stimuli may be fundamental mechanisms for the emergence of the circumferential collagen alignment usually observed in native heart valves. On the other hand, the tendency of cells to coalign with collagen fibers is essential to maintain and reinforce that circumferential alignment during development. Statement of Significance: The hemodynamic functionality of heart valves is strongly influenced by the alignment of load-bearing collagen fibers. Currently, the mechanisms that are responsible for the development of the circumferential collagen alignment in native heart valves are not fully understood. In the present study, cell-mediated remodeling of native human heart valves during early development was computationally simulated to understand the impact of individual mechanisms on collagen alignment. Our simulations successfully predicted the degree of collagen alignment observed in native fetal and pediatric semilunar valves. The computational results suggest that the circumferential collagen alignment arises from cell traction and cellular (re)orientation in response to mechanical stimuli, and with increasing age is reinforced by the tendency of cells to co-align with pre-existing collagen fibers.\u3c/p\u3

A computational model to predict cell traction-mediated prestretch in the mitral valve

\u3cp\u3ePrestretch is observed in many soft biological tissues, directly influencing the mechanical behavior of the tissue in question. The development of this prestretch occurs through complex growth and remodeling phenomena, which yet remain to be elucidated. In the present study it was investigated whether local cell-mediated traction forces can explain the development of global anisotropic tissue prestretch in the mitral valve. Towards this end, a model predicting actin stress fiber-generated traction forces was implemented in a finite element framework of the mitral valve. The overall predicted magnitude of prestretch induced valvular contraction after release of in vivo boundary constraints was in good agreement with data reported on valvular retraction after excision from the heart. Next, by using a systematic variation of model parameters and structural properties, a more anisotropic prestretch development in the valve could be obtained, which was also similar to physiological values. In conclusion, this study shows that cell-generated traction forces could explain prestretch magnitude and anisotropy in the mitral valve.\u3c/p\u3

Growth and remodeling play opposing roles during postnatal human heart valve development

\u3cp\u3eTissue growth and remodeling are known to govern mechanical homeostasis in biological tissue, but their relative contributions to homeostasis remain unclear. Here, we use mechanical models, fueled by experimental findings, to demonstrate that growth and remodeling have different effects on heart valve stretch homeostasis during physiological postnatal development. Two developmental stages were considered: early-stage (from infant to adolescent) and late-stage (from adolescent to adult) development. Our models indicated that growth and remodeling play opposing roles in preserving tissue stretch and with time. During early-stage development, excessive tissue stretch was decreased by tissue growth and increased by remodeling. In contrast, during late-stage development tissue stretch was decreased by remodeling and increased by growth. Our findings contribute to an improved understanding of native heart valve adaptation throughout life, and are highly relevant for the development of tissue-engineered heart valves.\u3c/p\u3

Lateral induction limits the impact of cell connectivity on Notch signaling in arterial walls

\u3cp\u3eIt is well known that arteries grow and remodel in response to mechanical stimuli. Vascular smooth muscle cells are the main mediators of this process, as they can switch phenotype from contractile to synthetic, and vice-versa, based on the surrounding bio-chemo-mechanical stimuli. A correct regulation of this phenotypic switch is fundamental to obtain and maintain arterial homeostasis. Notch, a mechanosensitive signaling pathway, is one of the main regulators of the vascular smooth muscle cell phenotype. Therefore, understanding Notch dynamics is key to elucidate arterial growth, remodeling, and mechanobiology. We have recently developed a one-dimensional agent-based model to investigate Notch signaling in arteries. However, due to its one-dimensional formulation, the model cannot be adopted to study complex nonsymmetrical geometries and, importantly, it cannot capture the realistic “cell connectivity” in arteries, here defined as the number of cell neighbors. Notch functions via direct cell-cell contact; thus, the number of cell neighbors could be an essential feature of Notch dynamics. Here, we extended the agent-based model to a two-dimensional formulation, to investigate the effects of cell connectivity on Notch dynamics and cell phenotypes in arteries. The computational results, supported by a sensitivity analysis, indicate that cell connectivity has marginal effects when Notch dynamics is dominated by the process of lateral induction, which induces all cells to have a uniform phenotype. When lateral induction is weaker, cells exhibit a nonuniform phenotype distribution and the percentage of synthetic cells within an artery depends on the number of neighbors.\u3c/p\u3

Controlling tissue engineered heart valve geometry by using predefined inserts during culture

Various inserts, called shapers and spacers, are provided for controlling tissue engineered heart valve (TEHV) leaflet geometry during culture. These inserts will prevent TEHV leaflet retraction during culture, be able to control the leaflet geometry during culture, enable culturing TEHV leaflets with a larger coaptation area, control the height of the coaptation area, maintain TEHV leaflet curvatures, and/or enable possibilities to culture TEHV leaflets in open configuration

Prediction of cell alignment on cyclically strained grooved substrates

Cells respond to both mechanical and topographical stimuli by reorienting and reorganizing their cytoskeleton. Under certain conditions, such as for cells on cyclically stretched grooved substrates, the effects of these stimuli can be antagonistic. The biophysical processes that lead to the cellular reorientation resulting from such a competition are not clear yet. In this study, we hypothesized that mechanical cues and the diffusion of the intracellular signal produced by focal adhesions are determinants of the final cellular alignment. This hypothesis was investigated by means of a computational model, with the aim to simulate the (re)orientation of cells cultured on cyclically stretched grooved substrates. The computational results qualitatively agree with previous experimental studies, thereby supporting our hypothesis. Furthermore, cellular behavior resulting from experimental conditions different from the ones reported in the literature was simulated, which can contribute to the development of new experimental designs