To optimize the mechanical properties and integrity of tissue-engineered aortic heart valves, it is necessary to gain insight into the effects of mechanical stimuli on the mechanical behavior of the tissue using mathematical models. In this study, a finite-element (FE) model is presented to relate changes in collagen fiber content and orientation to the mechanical loading condition within the engineered construct. We hypothesized that collagen fibers aligned with principal strain directions and that collagen content increased with the fiber stretch. The results indicate that the computed preferred fiber directions run from commissure to commissure and show a strong resemblance to experimental data from native aortic heart valves.

Mechanical loading is a powerful regulator of tissue properties in engineered cardiovascular tissues. To ultimately regulate the biochemical processes, it is essential to quantify the effect of mechanical loading on the properties of engineered cardiovascular constructs. In this study the Flexercell FX-4000T (Flexcell Int. Corp., USA) straining system was modified to simultaneously apply various strain magnitudes to individual samples during one experiment. In addition, porous polyglycolic acid (PGA) scaffolds, coated with poly-4-hydroxybutyrate (P4HB), were partially embedded in a silicone layer to allow long-term uniaxial cyclic mechanical straining of cardiovascular engineered constructs. The constructs were subjected to two different strain magnitudes and showed differences in biochemical properties, mechanical properties and organization of the microstructure compared to the unstrained constructs. The results suggest that when the tissues are exposed to prolonged mechanical stimulation, the production of collagen with a higher fraction of crosslinks is induced. However, straining with a large strain magnitude resulted in a negative effect on the mechanical properties of the tissue. In addition, dynamic straining induced a different alignment of cells and collagen in the superficial layers compared to the deeper layers of the construct. The presented model system can be used to systematically optimize culture protocols for engineered cardiovascular tissues.

Abstract-Load-bearing soft tissues predominantly consist of collagen and exhibit anisotropic, non-linear visco-elastic behavior, coupled to the organization of the collagen fibers. Mimicking native mechanical behavior forms a major goal in cardiovascular tissue engineering. Engineered tissues often lack properly organized collagen and consequently do not meet in vivo mechanical demands. To improve collagen architecture and mechanical properties, mechanical stimulation of the tissue during in vitro tissue growth is crucial. This study describes the evolution of collagen fiber orientation with culture time in engineered tissue constructs in response to mechanical loading. To achieve this, a novel technique for the quantification of collagen fiber orientation is used, based on 3D vital imaging using multiphoton microscopy combined with image analysis. The engineered tissue constructs consisted of cell-seeded biodegradable rectangular scaffolds, which were either constrained or intermittently strained in longitudinal direction. Collagen fiber orientation analyses revealed that mechanical loading induced collagen alignment. The alignment shifted from oblique at the surface of the construct towards parallel to the straining direction in deeper tissue layers. Most importantly, intermittent straining improved and accelerated the alignment of the collagen fibers, as compared to constraining the constructs. Both the method and the results are relevant to create and monitor loadbearing tissues with an organized anisotropic collagen network.

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Abstract-Tissue-engineered trileaflet aortic valves are a promising alternative to current valve replacements. However, the mechanical properties of these valves are insufficient for implantation at the aortic position. To simulate the effect of collagen remodeling on the mechanical properties of the aortic valve, a finite element model is presented. In this study collagen remodeling is assumed to be the net result of collagen synthesis and degradation. A limited number of fibers with low initial fiber volume fraction is defined, and depending on the loading condition, the fibers are either synthesized or degraded. The synthesis and degradation of collagen fibers are both assumed to be functions of individual fiber stretch and fiber volume fraction. Simulations are performed for closed aortic valve configurations and the open aortic valve configuration. The predicted fiber directions for the closed configurations are close to the fiber directions as measured in the native aortic valve. The model predicts the evolution in collagen fiber content and the effect of remodeling on the mechanical properties.