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

Periodic Reporting for period 1 - G-Valve (Unraveling the mechanobiology of tissue growth in native and tissue-engineered heart valves)

Reporting period: 2016-05-01 to 2017-04-30

The incidence and prevalence of valvular heart disease are increasing worldwide, and present a major economic burden to the European healthcare system. Current valve replacements are life-saving devices, but are associated with serious drawbacks due to the fact that they cannot grow, remodel, or repair. Tissue engineering has been anticipated to revolutionize current valve replacement therapies, as the creation of living valve replacements presents these engineered valves with the intrinsic ability to grow and adapt in response to their hemodynamic environment. A deep mechanistic understanding of this growth potential is essential to ensure the long-term functionality and adequate adaptation potential of these tissue-engineered valves. The current project aims for developing 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 and optimizing the growth potential of tissue-engineered valves. As mechanical factors are known to be important drivers of cardiovascular growth, the first objective of this project is to identify the most important mechanical trigger for valve growth in native human valves. The second objective consists of developing computational models that incorporate the responsible biological mechanisms for growth by integrating the fields of mechanics and biology, in order to understand the responsible biological mechanisms involved in mechanically-induced valve growth.
It is generally hypothesized that biological tissues adapt to maintain a certain mechanical homeostatic state, although the identification of the preserved mechanical parameters is difficult and the responsible parameters may vary across different tissues. To address the first objective of the project, an extensive set of human aortic and pulmonary valves was quantitatively analyzed in terms of changes in geometry, structure, and material properties with age. 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.

As a next step, computational algorithms were developed to understand and predict the relative importance of growth (i.e. changes in volume) and remodeling (i.e. changes in material properties) for preserving this stretch homeostasis in human valves. Again, quantitative information from the experimental data set was used as input for the computational simulations. Systematic variations of the processes included in simulating valve adaptation 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 that are responsible for growth and homeostasis. Here, the communication between individual cells was modeled in relation to the stabilization of cardiovascular tissues. Specifically, the effects of mechanical factors on cell-cell communication were modeled via incorporating experimental data into a theoretical framework. Remarkably, the first predictions with these computational models revealed that establishment of homeostasis can arise suddenly upon certain changes in tissue geometry. This study therefore provides a biological motivation for the presence or absence 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.
Regenerative medicine in general, and cardiovascular tissue engineering specifically, rely on the intrinsic capacity of the human body to regenerate tissues. Consequently, a fundamental understanding of the responsible processes is critical for guiding regeneration to ensure long-term functionality and preventing adverse outcomes. Although mechanical factors are widely known to affect cardiovascular growth and remodeling, the underlying mechanisms are still only partly understood due to the complex and dynamic 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 so far 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 where mechanical factors were incorporated in a theoretical framework describing cell-cell communication represent a first and essential step towards understanding the molecular pathways that are ultimately responsible for establishing tissue homeostasis.

Together, the results of this project so far contribute to understanding how native cardiovascular tissues adapt throughout life in response to changes in hemodynamic conditions. This knowledge is essential for defining rational designs of tissue-engineered constructs in general and heart valves in particular, that will guide towards long-term functionality and tissue homeostasis.
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