Claire C Beauchesne1,2, Morgan Chabanon3, Benjamin Smaniotto4, Benoît Ladoux5, Benoît Goyeau6, Bertrand David2. 1. Lab. EM2C, UPR CNRS 288, CentraleSupélec, Université Paris-Saclay, 3 rue Joliot-Curie, 91192, Gif-sur-Yvette Cedex, France. 2. Lab. MSSMat, UMR CNRS 8579, CentraleSupélec, Université Paris-Saclay, 3 rue Joliot-Curie, 91192, Gif-sur-Yvette Cedex, France. 3. Single Molecule Biophotonics Lab. ICFO, The Institute of Photonic Sciences, av. Carl Friedrich Gauss, 3, 08860, Castelldefels, Barcelona, Spain. 4. ENS Paris Saclay, LMT, CNRS, UMR 8535, 61 avenue du Président Wilson, 94230, Cachan, France. 5. Institut Jacques Monod (IJM), UMR CNRS 7592, Université Paris Diderot, 15 rue Hélène Brion, 75013, Paris, France. 6. Lab. EM2C, UPR CNRS 288, CentraleSupélec, Université Paris-Saclay, 3 rue Joliot-Curie, 91192, Gif-sur-Yvette Cedex, France. benoit.goyeau@centralesupelec.fr.
Abstract
BACKGROUND: Perfusion bioreactors for tissue engineering hold great promises. Indeed, the perfusion of culture medium enhances species transport and mechanically stimulates the cells, thereby increasing cell proliferation and tissue formation. Nonetheless, their development is still hampered by a lack of understanding of the relationship between mechanical cues and tissue growth. METHODS: Combining tissue engineering, three-dimensional visualization and numerical simulations, we analyze the morphological evolution of neo-tissue in a model bioreactor with respect to the local flow pattern. NIH-3T3 cells were grown under perfusion for one, two and three weeks on a stack of 2 mm polyacetal beads. The model bioreactor was then imaged by X-ray micro-tomography and local tissue morphology was analyzed. To relate experimental observations and mechanical stimulii, a computational fluid dynamics model of flow around spheres in a canal was developed and solved using the finite element method. RESULTS: We observe a preferential tissue formation at the bioreactor periphery, and relate it to a channeling effect leading to regions of higher flow intensity. Additionally, we find that circular crater-like tissue patterns form in narrow channel regions at early culture times. Using computational fluid dynamic simulations, we show that the location and morphology of these patterns match those of shear stress maxima. Finally, the morphology of the tissue is qualitatively described as the tissue grows and reorganizes itself. CONCLUSION: Altogether, our study points out the key role of local flow conditions on the tissue morphology developed on a stack of beads in perfusion bioreactors and provides new insights for effective design of hydrodynamic bioreactors for tissue engineering using bead packings.
BACKGROUND: Perfusion bioreactors for tissue engineering hold great promises. Indeed, the perfusion of culture medium enhances species transport and mechanically stimulates the cells, thereby increasing cell proliferation and tissue formation. Nonetheless, their development is still hampered by a lack of understanding of the relationship between mechanical cues and tissue growth. METHODS: Combining tissue engineering, three-dimensional visualization and numerical simulations, we analyze the morphological evolution of neo-tissue in a model bioreactor with respect to the local flow pattern. NIH-3T3 cells were grown under perfusion for one, two and three weeks on a stack of 2 mm polyacetal beads. The model bioreactor was then imaged by X-ray micro-tomography and local tissue morphology was analyzed. To relate experimental observations and mechanical stimulii, a computational fluid dynamics model of flow around spheres in a canal was developed and solved using the finite element method. RESULTS: We observe a preferential tissue formation at the bioreactor periphery, and relate it to a channeling effect leading to regions of higher flow intensity. Additionally, we find that circular crater-like tissue patterns form in narrow channel regions at early culture times. Using computational fluid dynamic simulations, we show that the location and morphology of these patterns match those of shear stress maxima. Finally, the morphology of the tissue is qualitatively described as the tissue grows and reorganizes itself. CONCLUSION: Altogether, our study points out the key role of local flow conditions on the tissue morphology developed on a stack of beads in perfusion bioreactors and provides new insights for effective design of hydrodynamic bioreactors for tissue engineering using bead packings.
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