Modeling fluid flow through irregular scaffolds for perfusion bioreactors

Direct perfusion of 3D tissue engineered constructs is known to enhance osteogenesis, which can be partly attributed to enhanced nutrient and waste transport. In addition flow mediated shear stresses are known to upregulate osteogenic differentiation and mineralization. A quantification of the hydrodynamic environment is therefore crucial to interpret and compare results of in vitro bioreactor experiments. This study aims to deal with the pitfalls of numerical model preparation of highly complex 3D bone scaffold structures and aims to provide more accurate wall shear stress (WSS) estimates. µCT imaging techniques were used to reconstruct the geometry of both a titanium (Ti) and a hydroxyapatite scaffold, starting from 430 images with a resolution of 8 µm. To tackle the tradeoff between model size and mesh resolution we selected two concentric regions of interest (cubes with a volume of 1 and 3.375 mm3, respectively) for both scaffolds. A flow guidance in front of the real inlet surface of the scaffold was designed to mimic realistic inlet conditions. With a flow rate of 0.04 mL/min perfused through a 5 mm diameter scaffold at an inlet velocity of 33.95 µm/s we obtained average WSSs of 1.10 and 1.46 mPa for the 1 mm3 and the 3.375 mm3 model of the hydroxyapatite scaffold compared to 1.40 and 1.95 mPa for the 1 mm3 model and the 3.375 mm3 model of the Ti scaffold, showing the important influence of the scaffold micro‐architecture heterogeneity and the proximity of boundaries. To assess that influence we selected cubic portions, of which the WSS data were analyzed, with the same size and the same location within both 1 and 3.375 mm3 cubic models. Varying the size of the inner portions simultaneously in both model selections gives a quantification of the sensitivity to boundary neighborhood. This methodology allows to get more insight in the complex concept of tissue engineering and will likely help to understand and eventually improve the fluid‐mechanical aspects. Biotechnol. Bioeng. 2009;103: 621–630. © 2009 Wiley Periodicals, Inc.

[1]  J. Glowacki,et al.  Perfusion Enhances Functions of Bone Marrow Stromal Cells in Three-Dimensional Culture , 1998 .

[2]  T. Einhorn.  Clinically applied models of bone regeneration in tissue engineering research. , 1999, Clinical orthopaedics and related research.

[3]  E H Burger,et al.  The production of nitric oxide and prostaglandin E(2) by primary bone cells is shear stress dependent. , 2001, Journal of biomechanics.

[4]  G. B. Fiore,et al.  Mechanobiology of engineered cartilage cultured under a quantified fluid-dynamic environment , 2002, Biomechanics and modeling in mechanobiology.

[5]  Antonios G. Mikos,et al.  Fluid flow increases mineralized matrix deposition in 3D perfusion culture of marrow stromal osteoblasts in a dose-dependent manner , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[6]  Cato T Laurencin,et al.  Human osteoblast-like cells in three-dimensional culture with fluid flow. , 2003, Biorheology.

[7]  Robert E Guldberg,et al.  Effects of medium perfusion rate on cell-seeded three-dimensional bone constructs in vitro. , 2003, Tissue engineering.

[8]  D. Carter,et al.  Pressure and Shear Differentially Alter Human Articular Chondrocyte Metabolism: A Review , 2004, Clinical orthopaedics and related research.

[9]  Noo Li Jeon,et al.  Diffusion limits of an in vitro thick prevascularized tissue. , 2005, Tissue engineering.

[10]  M G Mullender,et al.  Mechanobiology of bone tissue. , 2005, Pathologie-biologie.

[11]  Jenneke Klein-Nulend,et al.  A comparison of strain and fluid shear stress in stimulating bone cell responses—a computational and experimental study , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[12]  Roger Zauel,et al.  3-D computational modeling of media flow through scaffolds in a perfusion bioreactor. , 2005, Journal of biomechanics.

[13]  Margherita Cioffi,et al.  The effect of hydrodynamic shear on 3D engineered chondrocyte systems subject to direct perfusion. , 2006, Biorheology.

[14]  F. Boschetti,et al.  Prediction of the micro-fluid dynamic environment imposed to three-dimensional engineered cell systems in bioreactors. , 2006, Journal of biomechanics.

[15]  Gabriele Dubini,et al.  Modeling evaluation of the fluid-dynamic microenvironment in tissue-engineered constructs: a micro-CT based model. , 2006, Biotechnology and bioengineering.

[16]  Nicola Elvassore,et al.  Mathematical Modeling of Three-Dimensional Cell Cultures in Perfusion Bioreactors , 2006 .

[17]  M. Mullender,et al.  Mechanotransduction of bone cellsin vitro: Mechanobiology of bone tissue , 2006, Medical and Biological Engineering and Computing.

[18]  C P Chen,et al.  Enhancement of cell growth in tissue‐engineering constructs under direct perfusion: Modeling and simulation , 2007, Biotechnology and bioengineering.

[19]  Harmeet Singh,et al.  Flow modeling in a novel non‐perfusion conical bioreactor , 2007, Biotechnology and bioengineering.

[20]  Robert E Guldberg,et al.  Noninvasive image analysis of 3D construct mineralization in a perfusion bioreactor. , 2007, Biomaterials.

[21]  Helen M. Byrne,et al.  MODELLING SCAFFOLD OCCUPATION BY A GROWING, NUTRIENT-RICH TISSUE , 2007 .

[22]  M. Mastrogiacomo,et al.  Regeneration of large bone defects in sheep using bone marrow stromal cells , 2008, Journal of tissue engineering and regenerative medicine.