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Unraveling the mechanobiology of tissue growth in native and tissue-engineered heart valves

Periodic Reporting for period 2 - G-Valve (Unraveling the mechanobiology of tissue growth in native and tissue-engineered heart valves)

Reporting period: 2017-05-01 to 2018-04-30

The prevalence of valvular heart disease is increasing worldwide, and presents a major economic burden to the European healthcare system. Current valve replacements are life-saving devices, but are associated with serious drawbacks as they cannot grow, remodel, or repair. Tissue engineering has been anticipated to revolutionize current valve replacement therapies, as the creation of living tissues presents these valves with the intrinsic ability to grow and adapt in response to their hemodynamic environment. A mechanistic understanding of this growth potential is essential to ensure their long-term functionality. The aim of this project was to develop computational models to understand and predict the growth of valves, with specific emphasis on understanding the natural growth profiles of native human valves and predicting the growth of tissue-engineered valves. As mechanical factors are known to drive cardiovascular growth, the first objective was to identify the most important mechanical trigger for valve growth in native human valves. The second objective was to develop computational models that incorporate the biological mechanisms responsible for growth.

An experimental data set of human aortic and pulmonary heart valves was obtained and computationally analyzed to investigate if certain mechanical parameters would be similar for both valves and constant with age. Mechanical stretch appeared to fulfil both criteria and is therefore hypothesized to determine mechanical homeostasis in human semilunar heart valves. To unravel the biological mechanisms responsible for growth, a computational model was developed that predicts how a critical cell-cell signaling pathway drives growth and homeostasis in cardiovascular tissues. Finally, a computational investigation of the growth potential of tissue-engineered heart valves revealed that material parameters, valve geometry, and boundary conditions all have a major impact on how these valves may grow.
For the first objective, an extensive set of human aortic and pulmonary valves was quantitatively analyzed in terms of geometry, structure, and material properties. Based on this information, subject-specific computational models were developed to estimate the mechanical state for both valves as a function of age. Although mechanical stress is often hypothesized to be preserved in cardiovascular tissues, this parameter was predicted to increase with age and have different magnitudes for the aortic and the pulmonary valve. Strikingly, the deformation (stretch) of the valve was fairly stable with age and remarkably similar for both the aortic and pulmonary valve. Accordingly, these data suggest that stretch serves as a homeostatic mechanical parameter in heart valves.

Next, computational algorithms were developed to understand the relative importance of growth (i.e. changes in volume) and remodeling (i.e. changes in material properties) for preserving stretch homeostasis. Systematic analyses revealed that growth is most important for preserving stretch early in life, whereas tissue remodeling, surprisingly, appeared to be unfavorable with regard to preserving stretch. In contrast, tissue remodeling was identified as being the crucial factor for maintaining stretch later in life, whereas changes in the valve geometry had a negative effect in terms of preserving stretch homeostasis.

For the second objective, computational models were developed to obtain a more fundamental understanding of the biological processes responsible for growth and homeostasis. Specifically, the effects of mechanical factors on cell-cell communication were modeled via incorporating experimental data into a theoretical framework. Predictions with these models revealed that establishment of homeostasis can arise suddenly upon certain changes in tissue geometry. This study therefore provides a biological motivation for the emergence of homeostasis depending on the mechanical state of the tissue, where the integration of mechanics and biology into computational models has been essential to understand the implications of mechanobiological mechanisms.

To predict the growth potential of tissue-engineered valves, a computational framework was developed where growth was predicted locally based on the local mechanical state. The prediction of native valve growth demonstrated that the assumption of growth in response to stretch enables the establishment of a homogeneous stretch state. Interestingly, although the amount of growth now varied locally within the valve, the total amount of growth was still in good agreement with the experimentally observed valve growth. Furthermore, it was noticed that the predicted heterogeneity in leaflet thickness matched very well with the observed geometry of native valves. Application of this framework to predicting growth of tissue-engineered heart valves demonstrated that growth does not necessarily lead to preservation of a physiological or functional valve geometry. It appears that there are many factors that contribute to valve growth, where material parameters, valve geometry, and boundary conditions have a major effect.

Dissemination of the research results was realized through 4 scientific publications (of which 1 in the prestigious PNAS journal) and 10 conference presentations. Additional publications are expected in the future. Furthermore, theory and results have been included in courses at TU/e, and formed the basis for student projects.
Regenerative medicine relies on the intrinsic capacity of the human body to regenerate tissues. A fundamental understanding of the responsible processes is critical for guiding regeneration to ensure long-term functionality. Although mechanical factors are widely known to affect cardiovascular growth and remodeling, the underlying mechanisms are only partly understood due to the complex interplay between mechanical factors and tissue adaptation, and the spatial heterogeneity and different time scales involved. Computational models are indispensable for analyzing and integrating experimental studies, testing and proposing hypotheses for mechanobiological mechanisms, and predicting the outcomes for complex in vivo conditions.

Unique aspects of the current project are that quantitative experimental data of human heart valves were used to inform computational simulations of heart valves, which allowed for (1) identifying the homeostatic state of heart valves, and (2) understanding the interplay of growth and remodeling in preserving this homeostatic state. Moreover, the simulations of cell-cell communication driven by mechanical cues represent a first and essential step towards understanding the molecular pathways that are ultimately responsible for establishing tissue homeostasis. The prediction of growth of tissue-engineered heart valves demonstrates that it is not trivial to obtain physiological growth patterns in these valves, implying that the valve design should be chosen carefully.

Together, the results of this project contribute to understanding how native cardiovascular tissues adapt throughout life in response to changes in hemodynamics, how tissue-engineered heart valves may grow with time, and how biological mechanisms contribute to establishing mechanical homeostasis. This knowledge is essential for defining rational designs of tissue-engineered constructs in general and heart valves in particular.