Multi-layer Agent-based Modeling for Bone Tissue Engineerin

Bone tissue engineering (BTE) has emerged over the past few decades as a potential alternative to the field of conventional bone regenerative medicine due to the exceedingly high demand of adequate bone grafts. Regeneration of bone tissue in BTE requires synergistic combination of biomaterial scaffolds, growth factors, and osteogenic cells. Scaffolds with well-designed architectures and degradation characteristics, provided with appropriate angiogenic and osteogenic factors are essential for bone tissue regeneration. The formation of sufficient and adequate vascularized network in scaffolds is of critical importance for successful BTE and remains as a major limiting barrier in the development of clinically-applicable replacement tissues. Taking into account these factors that contribute to bone tissue regeneration process simultaneously and optimizing their characteristics presents a highly difficult task and cannot be addressed with experimentation alone.;Computational models combined with experimental methods provide better understanding of the underlying mechanisms of the complex process. This understanding is critical for identifying various parameters that can lead to optimized bone tissue regeneration and determining their most promising value ranges. The agent-based modeling (ABM) approach is used to develop three-dimensional models of vascularization and bone growth. ABM is a powerful modeling and simulation technique and is naturally suitable for complex biological system as it simulates actions and interactions of individual agents in an attempt to re-create and predict the appearance of complex phenomena.;In this work, a multi-layered, agent-based computational model has been proposed to simulate the vascularization and bone tissue regeneration in a porous, biodegradable biomaterial scaffold. This model aims to investigate the interactions between osteogenic cells, signaling molecules, and biomaterial scaffolds in order to hance scaffold vascularization and bone tissue formation. The model is constructed based on a previously developed angiogenesis model by Artel [7] and Mehdizadeh [8]. A tissue layer is implemented into the original model, with two new types of cells, mesenchymal stem cells (MSCs) and osteoblasts (OBs), to simulate the formation of bone tissue. Each agent represents an individual cell, interacting with each other and the surrounding micro-environment based on the implemented rule base, leading to the formation of vascular structure and bone tissue. Our previous works have already investigated the interactions between endothelial cells (ECs) and biodegradable scaffolds, and provided us significant insights into the combined effect of scaffold geometrical properties and degradation dynamics on scaffold vascularization. Furthermore, the controlled release of angiogenic growth factors has been studied to investigate their effects on vascularization process. This work will mainly focus on three aspects: 1) the improvement of scaffold degradation model. 2) the development of vascularized bone regeneration agent-based model in Repast High Performance Computing (Repast HPC). 3) the investigation of in vitro prevascularization strategy to enhance angiogenesis and overall bone regeneration in BTE applications. The developed model integrates all these factors and simulates the regeneration of bone tissue in biodegradable scaffolds over time. Simulation results can be used in combination with experimental data to design optimal scaffold constructs for bone tissue engineering.;A multi-layer scaffold model is implemented in the degradation ABM. Scaffold vascularization is enhanced by the multi-layer scaffold strategy without losing the necessary mechanical support of biomaterial scaffolds. A integrated vascularized bone tissue regeneration ABM was developed using Repast HPC platform. The model successfully simulated the scaffold vascularization and coupled osteogenic differentiation in a 3D porous scaffold. The study demonstrated that scaffolds with higher porosityand combined angiogenic and osteogenic GF factor resulted in optimal vascularized bone formation. A diffusion ABM is developed to simulate the growth factor release in the scaffold. Simulation results indicated a good agreement between the diffusion ABM and mathematical model. The prevascularization high performance ABM is developed to simulate the integrated process of in vitro prevascularization followed by in vivo vascularized bone formation and evaluate the potential of prevascularization strategy to enhance overall scaffold vascularization and bone formation. The results demonstrated that prevascularized scaffold increases overall defect vascularization and bone formation upon implantation.