(636e) Effects of Scaffold Degradation and Geometrical Structure On Vascularization: A Multi-Agent Systems Approach

Abstract

Modeling and simulation are used to gain a better understanding of the underlying mechanisms of biomedical systems, resulting in improved theoretical knowledge and facilitating the design of experiments. In this work, degradation of biomaterial scaffolds and its effects on scaffold vascularization have been investigated using a multi-layer agent-based model (ABM). Tissue engineering scaffolds are used as a physical support structure and regulator of cellular activities in a wide range of biomedical applications, including production of functional implants for regenerative medicine. Scaffold vascularization is of essential importance for providing the growing tissue cells within the scaffold structure with sufficient oxygen and nutrients.

The computational models investigating the effect of biomaterial scaffold architecture on vascularization assume that the scaffold structure remains constant over time and do not account for the effects of scaffold degradation on vascularization. The degradation behavior of the scaffold is important for predicting the lifetime of biomaterials. When designing a scaffold for tissue engineering, it is important that the scaffold degrades at a balanced rate to provide mechanical support so that scaffold integrity is preserved during tissue development until enough tissue has formed. As a result, the microstructure of biomedical scaffolds is characterized by parameters such as porosity, average pore size, interconnectivity, and pore shape as well as mechanical properties such as Young’s modulus, which change dynamically with the degradation of scaffold. Predicting the degradation behavior of biomaterials allows optimization of the tissue engineering scaffolds.

We have included a structural-kinetic model describing the bulk degradation of PEG hydrogels in our models for vascularization of scaffolds to predict the degradation of the porous hydrogel scaffolds and study the effects of scaffold degradation on angiogenesis and tissue growth. Since the degradation model is based on fundamental parameters that are taken directly from the physical system, it would be possible to use the model for different types of hydrogels that are degraded via similar bulk erosion mechanism.

The developed framework is implemented in Java, using Repast (Recursive Porous Agent Simulation Toolkit), which is an open-source agent-based modeling and simulation platform. Software agents are developed as independent computational entities to represent endothelial cells (ECs). EC agents interact with their neighbors and with their microenvironment, leading to formation of new capillaries and invasion into deeper parts of scaffolds. As the scaffold degrades, more space becomes available for EC invasion, facilitating capillary ingrowth.

An embedded rule base governs the behavior of individual EC agents. EC agents are capable of sensing their microenvironment to perceive the location of neighboring agents as well as the geometry of surrounding scaffold and concentrations and gradients of the soluble and insoluble factors. They perform migration, elongation, proliferation, and sprouting, leading to capillary extension and branching. In each capillary branch, only the leading EC, referred to as tip cell, is active and capable of performing EC actions. Other ECs in each branch are referred to as stalk cells, and are only activated randomly during simulation to perform sprouting, if other conditions in their environment allow them to do so.

Three-dimensional scaffold models with heterogeneous spherical pores, designed previously in our group, have been utilized to investigate the combined effects of scaffold architecture and degradation on rate of capillary growth and invasion. Simulation results illustrate that various scaffold degradation dynamics affect scaffold vascularization in a complex manner. These results are used to identify the optimal combination of scaffold porous structure and degradation dynamics, yielding improved scaffold vascularization. It is observed that the effect of scaffold degradation becomes more significant at lower porosities and pore sizes.  Experimental studies are being undertaken to investigate these findings. Controlling scaffold vascularization through modulating EC behavior with changes in the characteristics of the extracellular environment enables development of improved functional replacement tissues. The model results help us better understand the complex interactions between the growing blood vessel network and a degrading scaffold structure and identify optimal combinations of geometric and degradation characteristics of tissue engineering scaffolds.