A Novel Flex-Stretch-Flow Bioreactor for the Study of Engineered Heart Valve Tissue Mechanobiology |
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Authors: | Jr" target="_blank">George C EngelmayrJr Lorenzo Soletti Sarah C Vigmostad Stephanus G Budilarto William J Federspiel Krishnan B Chandran David A Vorp Michael S Sacks |
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Institution: | (1) Department of Bioengineering, McGowan Institute for Regenerative Medicine, University of Pittsburgh, 100 Technology Drive, Suite 200, Pittsburgh, PA 15219, USA;(2) Department of Biomedical Engineering, College of Engineering, The University of Iowa, Iowa City, IA 52242, USA |
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Abstract: | Tissue engineered heart valves (TEHV) have been observed to respond to mechanical conditioning in vitro by expression of activated myofibroblast phenotypes followed by improvements in tissue maturation. In separate studies, cyclic
flexure, stretch, and flow (FSF) have been demonstrated to exhibit both independent and coupled stimulatory effects. Synthesis
of these observations into a rational framework for TEHV mechanical conditioning has been limited, however, due to the functional
complexity of tri-leaflet valves and the inherent differences of separate bioreactor systems. Toward quantifying the effects
of individual mechanical stimuli similar to those that occur during normal valve function, a novel bioreactor was developed
in which FSF mechanical stimuli can be applied to engineered heart valve tissues independently or in combination. The FSF
bioreactor consists of two identically equipped chambers, each having the capacity to hold up to 12 rectangular tissue specimens
(25 × 7.5 × 1 mm) via a novel “spiral-bound” technique. Specimens can be subjected to changes-in-curvature up to 50 mm−1 and uniaxial tensile strains up to 75%. Steady laminar flow can be applied by a magnetically coupled paddlewheel system.
Computational fluid dynamic (CFD) simulations were conducted and experimentally validated by particle image velocimetry (PIV).
Tissue specimen wall shear stress profiles were predicted as a function of paddlewheel speed, culture medium viscosity, and
the quasi-static state of specimen deformation (i.e., either undeformed or completely flexed). Velocity profiles predicted
by 2D CFD simulations of the paddlewheel mechanism compared well with PIV measurements, and were used to determine boundary
conditions in localized 3D simulations. For undeformed specimens, predicted inter-specimen variations in wall shear stress
were on average ±7%, with an average wall shear stress of 1.145 dyne/cm2 predicted at a paddlewheel speed of 2000 rpm and standard culture conditions. In contrast, while the average wall shear stress
predicted for specimens in the quasi-static flexed state was ∼59% higher (1.821 dyne/cm2), flexed specimens exhibited a broad intra-specimen wall shear stress distribution between the convex and concave sides that
correlated with specimen curvature, with peak wall shear stresses of ∼10 dyne/cm2. This result suggests that by utilizing simple flexed geometric configurations, the present system can also be used to study
the effects of spatially varying shear stresses. We conclude that the present design provides a robust tool for the study
of mechanical stimuli on in vitro engineered heart valve tissue formation.
George C. Engelmayr, Jr. and Lorenzo Soletti are contributed equally. |
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Keywords: | Tissue engineering Bioreactor Heart valve Flexure Tension Flow Fluid shear stress |
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