Multi-scale computational modeling and characterization of bioprinted tissue scaffolds
Authors:   , Nair Kalyani , Sun Wei 
Published: July 2021

The 2007 Federal Multi-Agency Strategic Plan, initiated by NIH, NSF, DoD and other Federal agencies, has redefined tissue engineering as "the use of physical, chemical, biological and engineering processes to control and direct the aggregate behaviors of cells". In this new paradigm of tissue science and engineering, living cells are used as basic building blocks to "manufacture" cell-integrated constructs. This offers tremendous opportunities for designing in vitro physiological models to study disease pathogenesis, inventing molecular or cell-based therapeutics in clinical applications, and developing novel pharmaceutical methods for reducing the use of animals in drug testing. However, during and after the biomanufacturing process, cells are subjected to an array of mechanical forces which may cause injury. One major challenge in this field has been the lack of understanding regarding how external loads affect cells and how the mechanical signals are translated into the cascade of biochemical reactions that lead to cellular differentiation. While experimental studies have been conducted for specific bio-fabrication systems in order to understand the cell responses, an engineering model is also needed that can be used to predict the effect of mechanical forces to cells. The objective of this research is to develop a multi scale modeling approach for the analysis of cell damage in bioprinted tissue constructs. The approach includes analysis of the tissue constructs at three different scales: a macro scale model where the macro-scale tissue construct is characterized, a multi-cellular model where a sufficiently large multi-cellular representative element volume is selected to represent a microstructure of the tissue construct., and a single cell model wherein the microstructures of the cell like the nucleus and the cytoplasm have been incorporated. In the macro-scale model, we have developed a non-linear numerical model and used the hyperelastic Ogden material model to characterize the structural properties of the scaffold and to also provide the macro deformation and stresses. At the next scale, we have developed a model comprising of multiple cells modeled as single phase spherical inclusions to quantify the 3D stresses and deformations of the cells. In the third scale, a single cell model has been developed to determine the stresses and deformations within the substructures of the cell. Additionally, a strain energy based damage theory has been formulated to link the cellular responses to the applied mechanical forces at the macroscopic level. A stochastic approach is also developed to predict the resulting cell viability within the construct. Comparison between the predicted cell viability and the cell viability from the experimental data shows a fair agreement in capturing the trend of the damage observed from the experimental study. The major accomplishments reported in this thesis includea) The development of a three dimensional multi-scale computational modeling approach for the analysis of mechanical load induced cell damage in bioprinted tissue constructs. This methodology quantifies 3D stresses and deformations in the micro-scale level comprising of multiple cells, and studies cell damage at a cellular level wherein individual cell components like the nucleus and cytoplasm are modeled.