Modeling and Simulation of Diffusion Process in Tissue Spheroids Encaged into Microscaffolds (Lockyballs)

Abstract

Abstract Nutrition, organization, growth and signal transduction in cells are largely determined by diffusion mechanisms. The complex three-dimensional shapes of cellular environment complicate the experimental analysis and computational simulation of diffusion in live cells. Three-dimensional cell aggregates are called tissue spheroids and they are widely used in the field of tissue engineering because emulate in vivo microenvironments more accurately than conventional monolayer cultures. The greater contact of the cells with the culture medium is directly related to oxygen diffusion and thereafter with the cell viability and the increase of proliferation rate. Due to the characteristics of a 3D environment, at some zones within the tissue spheroids the cells are not equally exposed to the culture medium, and the result of an insufficient supply of oxygen to the cell impact in the formation of microenvironments with decreased oxygen, nutrients and soluble factors produced by cellular metabolism leading to the formation of low proliferation areas and consequently hypoxia and necrosis (cell death). The fusion of cells also changes the catabolites flow, generating a very heterogeneous diffusion. The idea of this work is to develop and improve microscaffolds based on the concept of lockyballs that have cell support function for tissue engineering. These microscaffolds are composed by hooks (which attach to other hooks or loops of neighbor lockyballs), loops (elevated pentagons, which allows hooks attaching) and tubes (that preventing entry of cells). It is presented one original type of lockyball (control) which has no internal structure (it is a hollow structure) further other three types of lockyballs. The first model has a spherical outer structure and inner hollow microsphere constituted by pores with diameters smaller than the cell ones, whose function would be to prevent cell entry. The second model has tubes constituted by pores and the third model has a spiral tube constituted by pores too. These inner structures provide an environment suitable to the diffusion gradient necessary for the cell viability of the spheroid avoiding necrosis. The first stage of the work consisted on the generation of different three-dimensional models by Computer Aided Design (CAD) software Rhinoceros 5.0. At the second stage, the CAD model was imported into volume element method (VEM) software (Star-CCM +/CD-Adapco) to perform computational fluid simulation (CFD). The CFD simulations were essential to predict the diffusion phenomenon inside the whole 3D structure. The development of new microscaffolds models can enhance the regenerative capacity and 3D tissues construction.