An Investigation in the Cellular Mechanisms of Bone Remodeling using a Hybrid Cellular Automaton Approach

One of the most intriguing aspects of bone is its ability to grow, repair damage, adapt to mechanical loads, and maintain mineral homeostasis. It is generally accepted that bone adaptation occurs in response to the mechanical demands of our daily activities; moreover, strain and microdamage have been implicated as potential stimuli that regulate this sophisticated process. While researchers have made significant advances in our understanding of the bone adaptation process, there are many aspects that remain unknown. For instance, it is not fully understood how the mechanical stimulation experienced by bones influences the biochemical signaling that drives the cellular activity of remodeling. Due to the fact that evidence for bone metabolic diseases points toward the disruption of the cellular mechanisms of remodeling, such a relationship is crucial to understanding the key factors that result in pathological remodeling activity. Over the past several decades, various theoretical and computational models have been developed to study the bone adaptation process. These computational models have primarily focused on predicting net changes in organ and tissue level bone architecture. While these simulations are able to capture phenomena such as net increases or decreases in bone volume or reorientation of tissue level structures, they do not capture cellular level details. In an attempt to ameliorate this deficiency of previous models, more recent studies have focused on simulating the remodeling response at a single site in bone. However, few models attempt to combine models of cellular activity with the classical phenomenological remodeling paradigms. The primary focus of this dissertation is to present a new computational framework that mechanistically models the cellular behavior involved in the bone remodeling process. This framework uniquely combines established phenomenological remodeling paradigms with cellular mechanisms to predict remodeling activity for a damaged site in bone. Biological rules were implemented to control the recruitment, differentiation, and activation of osteoclasts and osteoblasts, based on observations from histological studies. The results of this work are the first of their kind to demonstrate spatially and temporally accurate remodeling behavior at the cellular level. Furthermore, these results provide unique insights regarding key parameters that influence cellular level remodeling activity.