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The anisotropic collagen architecture of an engineered cardiovascular tissue has a major impact on its in vivo mechanical performance. This evolving collagen architecture is determined by initial scaffold microstructure and mechanical loading. Here, we developed and validated a theoretical and computational microscale model to quantitatively understand the interplay between scaffold architecture and mechanical loading on collagen synthesis and degradation. Using input from experimental studies, we hypothesize that both the microstructure of the scaffold and the loading conditions influence collagen turnover. The evaluation of the mechanical and topological properties of in vitro engineered constructs reveals that the formation of extracellular matrix layers on top of the scaffold surface influences the mechanical anisotropy on the construct. Results show that the microscale model can successfully capture the collagen arrangement between the fibers of an electrospun scaffold under static and cyclic loading conditions. Contact guidance by the scaffold, and not applied load, dominates the collagen architecture. Therefore, when the collagen grows inside the pores of the scaffold, pronounced scaffold anisotropy guarantees the development of a construct that mimics the mechanical anisotropy of the native cardiovascular tissue.

Electrospinning is a promising technology to produce scaffolds for cardiovascular tissue engineering. Each electrospun scaffold is characterized by a complex micro-scale structure that is responsible for its macroscopic mechanical behavior. In this study, we focus on the development and the validation of a computational micro-scale model that takes into account the structural features of the electrospun material, and is suitable for studying the multi-scale scaffold mechanics. We show that the computational tool developed is able to describe and predict the mechanical behavior of electrospun scaffolds characterized by different microstructures. Moreover, we explore the global mechanical properties of valve-shaped scaffolds with different microstructural features, and compare the deformation of these scaffolds when submitted to diastolic pressures with a tissue engineered and a native valve. It is shown that a pronounced degree of anisotropy is necessary to reproduce the deformation patterns observed in the native heart valve.

Preclinical studies of tissue-engineered heart valves (TEHVs) showed retraction of the heart valve leaflets as major failure of function mechanism. This retraction is caused by both passive and active cell stress and passive matrix stress. Cell-mediated retraction induces leaflet shortening that may be counteracted by the hemodynamic loading of the leaflets during diastole. To get insight into this stress balance, the amount and duration of stress generation in engineered heart valve tissue and the stress imposed by physiological hemodynamic loading are quantified via an experimental and a computational approach, respectively. Stress generation by cells was measured using an earlier described in vitro model system, mimicking the culture process of TEHVs. The stress imposed by the blood pressure during diastole on a valve leaflet was determined using finite element modeling. Results show that for both pulmonary and systemic pressure, the stress imposed on the TEHV leaflets is comparable to the stress generated in the leaflets. As the stresses are of similar magnitude, it is likely that the imposed stress cannot counteract the generated stress, in particular when taking into account that hemodynamic loading is only imposed during diastole. This study provides a rational explanation for the retraction found in preclinical studies of TEHVs and represents an important step towards understanding the retraction process seen in TEHVs by a combined experimental and computational approach. Keywords : Heart valve tissue engineering; Stress generation; Retraction; Myofibroblast; Finite element method

Tissue engineering represents a promising technique to overcome the limitations of the current valve replacements, since it allows for creating living autologous heart valves that have the potential to grow and remodel. However, also this approach still faces a number of challenges. One particular problem is regurgitation, caused by cell-mediated tissue retraction or the mismatch in geometrical and material properties between tissue-engineered heart valves (TEHVs) and their native counterparts. The goal of the present study was to assess the influence of valve geometry and tissue anisotropy on the deformation profile and closed configuration of TEHVs. To achieve this aim, a range of finite element models incorporating different valve shapes was developed, and the constitutive behavior of the tissue was modeled using an established computational framework, where the degree of anisotropy was varied between values representative of TEHVs and native valves. The results of this study suggest that valve geometry and tissue anisotropy are both important to maximize the radial strains and thereby the coaptation area. Additionally, the minimum degree of anisotropy that is required to obtain positive radial strains was shown to depend on the valve shape and the pressure to which the valves are exposed. Exposure to pulmonary diastolic pressure only yielded positive radial strains if the anisotropy was comparable to the native situation, whereas considerably less anisotropy was required if the valves were exposed to aortic diastolic pressure.

Cardiovascular tissues have a prominent load-bearing function. Collagen fibers in the extracellular matrix provide strength to these tissues. In particular the content and organization of these fibers contribute to overall strength [1]. In case of changes in mechanical demand, collagen content and organization can be adapted; a process referred to as collagen remodeling. For the creation of engineered cardiovascular tissues knowledge about collagen remodeling is of utmost importance to produce tissues with load bearing function. In case of in situ tissue engineering (TE) collagen content and organization in the developing tissue can be influenced by local tissue strains as well as scaffold structure and degradation properties [2, 3].Copyright © 2013 by ASME

In the last decade electrospinning has shown its potential of being a feasible technique to manufacture scaffolds for tissue engineering [1]. Previous studies observed that, on a micrometer scale, the topology of the scaffold plays a fundamental role in the spreading and the differentiation of the cells [2], and in the growth of neo-extracellular matrix. On a tissue scale (in the order of cm) the stiffness of the construct enables the possibility of applying mechanical cues for the development of a functional engineered tissue [3]. Studies on scaffold mechanics based on volume-averaging theory succeeded in demonstrating that the arrangement of the micro-scale scaffold components influences the macro-scale mechanical behavior [4].Copyright © 2012 by ASME

Although existing valve prostheses generally have resulted in enhanced survival and quality of life, they have serious drawbacks that limit their long-term efficacy. These include thrombo-embolic complications requiring lifelong anticoagulation in case of mechanical valves, limited durability due to calcification and structural failure in case of bioprostheses and structural deterioration and shortage of donor material when using a homograft. In addition, the inability to grow restricts the application of currently available prostheses in pediatric patients. Heart valve tissue engineering (TE) is a promising alternative to create living valves that may have the capacity to grow and remodel. The traditional TE approach requires the growth of tissue on a scaffold in a bioreactor before implantation (1).Copyright © 2011 by ASME