(717b) An Agent Based Model of Angiogenesis and Tissue Growth Within Porous Scaffolds

Repair and replacement of large tissue defects involve the combination of many complex interacting factors and provide challenges to tissue engineers. Experiments alone are not sufficient to study the effects and interactions of various components involved in tissue formation such as biodegradable scaffolds, signaling molecules and different types of cells. A computational model that can realistically simulate the behavior of such systems over time would be beneficial for many different theoretical and practical purposes. These purposes include rapid testing of alternative hypotheses, better understanding the mechanisms involved, estimation of the important variables of the system and prediction of their effects on system level behaviors. A simulation based on the computational model will provide a tool for rapidly screening alternatives, determining the most promising experimental search space and investigating ways of intervening in such systems for functional tissue formation.

Researchers in computational biology and biomedical engineering have started using multi-agent modeling techniques to study complex systems with many interacting elements. The central idea in agent-based models (ABM) is to define agents that represent the building blocks of a system and to develop rules that regulate their interactions. The rules originate from the vast qualitative and quantitative knowledge gained through many years of studying the individual components of these biological systems. Agent-based systems are naturally suitable for modeling biological systems as they are comprised of individual constituents like cells that interact with each other to form macro-scale bodies like tissue.

In this study, a multi-layer ABM is presented to simulate tissue growth and vascular network formation within porous biodegradable scaffold. For cells to survive and form functional tissue, they should receive necessary nutrition and oxygen from blood vessels and this requires the scaffold to be well vascularized. Consequently, development of blood vessels should be considered simultaneously with tissue formation. In our model, one layer describes the event occurring within the scaffold, the second layer describes the angiogenesis, focusing the individual behavior of endothelial cells, and finally the third layer simulates the behavior of tissue cells.

Endothelial cells, the cells lining the blood vessel wall, and tissue cells are represented by different agents. These agents are capable of migration, growth (or elongation), proliferation and differentiation into desired tissue. Cells go through the cell cycle during their life time, and depending on their stage in cell cycle, they can perform different actions. Tissue cells are homogenously seeded in the pores scaffold and they undergo severe hypoxia until anatomized blood vessels reach their vicinity. On the other hand, the cells under hypoxia secrete the growth factor which stimulates the endothelial cell proliferation.

This computational framework couples two different cell types interacting each other and with their environment. Using this simulation framework, we can quantify the dynamic impact of cellular level events and actions on a complex multi-cellular system. This framework can be used to predict in vivo and in vitro tissue formation from individual seeded cells and host blood vessels and find the optimal environmental conditions for functional tissue.