In silico bone tissue engineering - a multiscale and multiphysics approach
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Mechanical stimulation in terms of fluid flow and mechanical strain can enhance the osteogenesis. Biomaterial scaffolds used in bone tissue engineering experiments have extremely complex geometry, which will result in the complex multiphysics environment within scaffolds. However, due to the limitations of measurement techniques, computational approach is needed for characterising the resultant mechanical stimulation (i.e. fluid shear stress and mechanical strain) within scaffolds and imparting on cells. In addition, the mechanical responses (i.e. stiffness and contractility) of human adipose stem cells (hASCs) during osteogenic differentiation, which were affected by mechanical stimulation, are still unclear. Moreover, the influence of mechanical stimulation on cell migration within tissue engineering (TE) scaffold has not been fully investigated yet. Furthermore, most of previous mechano-regulation algorithms, which predicted the bone tissue formation within scaffolds were based on the compression loading. However, a more comprehensive in silico study, which investigates various loading regimes has not been carried out yet. Therefore, five studies in this thesis are carried out to address these emerging questions in bone tissue engineering and mechanobiology field. The first study of this thesis investigated the influence of scaffold geometry (i.e. architecture, pore size and porosity) and external loading on the mechanical stimulation within scaffolds using a computational approach. The study of geometric variation was conducted for both fluid perfusion and mechanical compression loading, which were modelled by computational fluid dynamics (CFD) and fluid-structure interaction (FSI) methods, respectively. It was found that the pore size had a greater influence on mechanical stimulation within the scaffold than the architecture and porosity. A combination of fluid perfusion and mechanical compression with different profiles was also investigated using an FSI approach. Mechanical stimulation was amplified within the scaffold under combined loading, which indicated a better suitability for cell stimulation within a bone TE scaffold. In the second study of this thesis, the author developed a novel multiscale CFD and FSI model to determine the mechanical stimulation of osteoblast cells in an idealised TE scaffold under fluid flow, and a finite element (FE) model to show the stimulation of osteoblast cells in the TE scaffold under mechanical compression. The WSS, fluid velocity and pressure in the global scaffold were characterised by the global CFD model, and the mechanical stimulation of osteoblasts was determined by implementing a sub-scaffold (cellular level) FSI model, with boundary conditions derived from CFD model. It was predicted that there was significant amplification of WSS on cell membranes in the sub-scaffold model, when compared to the wall shear stress (WSS) acting on the scaffold surface in similar locations (in some cases a five-fold increase). It was shown that bridged cells within the TE scaffold were highly stimulated, whereas attached cells received minimal levels of stimulation. Interestingly, for stimulation by mechanical compression, the FE model revealed that attached cells experienced higher stimulation than bridged cells. For stimulation by perfusion, cellular stimulation tended to be at a maximum within the central channel of the sub-scaffold model. In the third study of this thesis, the author developed a novel multiphysics model to predict cell migration, which is based on a coupled thermal-pore pressure approach. This model was applied to investigate the cell migration within an idealised hydrogel scaffold with different seeding conditions and under different loading regimes. It was found that the interface-seeded condition could result a more equally distributed cell density within scaffold than peripheral seeding. Importantly, fluid pressure loading (i.e. 100kPa) had distinct influence on the cell migration, moreover, more distinct influence was found in a peripherally-seeded scaffold than that in an interface-seeded one. Furthermore, mechanical compression with the compressive strain of 0.5% did not show a significant influence on cell migration, compared to that in static condition. In the fourth study of this thesis, in vitro bone tissue regeneration in a hydrogel scaffold was investigated by a mechano-regulation algorithm. Moreover, five typical loading regimes were applied to the model to predict the tissue differentiation. Finally, it was found that lower-level mechanical loadings, i.e. compression strain of 0.5%, fluid pressure of 10kPa and a combination of compression (0.5%) and fluid pressure (10kPa), could induce more osteogenic differentiation and form higher bone tissue fraction, while higher cartilage and fibrous tissue fractions were produced under higher-level mechanical loadings (i.e. compression strain of 5.0% and fluid pressure of 100kPa). In the final part of this thesis, the effect of equiaxial stretching and different culture substrates on the osteogenic differentiation and mechanical properties of hASCs was investigated by characterising the proliferation, ALP activity, cell morphology, focal adhesions and mechanical properties. It was shown that the osteogenic differentiation of hASCs on Polydimethylsiloxane (PDMS) substrates could be enhanced by mechanical stretching. However, cell proliferation was restrained under long-term mechanical stretching. In the mechanically stimulated samples, the cytoskeleton and focal adhesions were distinctively stronger leading to higher cellular Young’s modulus and contractility. Moreover, hASC stiffening was observed during osteogenic differentiation. These findings may provide important information for bone tissue engineering experiments and insight into the mechanobiology of hASCs osteogenic differentiation.
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