Reduced order modelling of bone resorption and formation.
The bone remodelling process, performed by the Bone Multicellular Unit (BMU) is a key multi-hierarchically regulated process, which provides and supports various functionality of bone tissue. It is also plays a critical role in bone disorders, as well as bone tissue healing following damage. Improved modelling of bone turnover processes could play a significant role in helping to understand the underlying cause of bone disorders and thus develop more effective treatment methods. Moreover, despite extensive research in the field of bone tissue engineering, bonescaffold development is still very empirical. The development of improved methods of modelling the bone remodelling process should help to develop new implant designs which encourage rapid osteointegration. There are a number of limitations with respect to previous research in the field of mathematical modelling of the bone remodelling process, including the absence of an osteocyte loop of regulation. It is within this context that this research presented in this thesis utilises a range of modelling methods to develop a framework for bone remodelling which can be used to improve treatment methods for bone disorders. The study concentrated on dynamic and steady state variables that in perspective can be used as constraints for optimisation problem considering bone remodelling or tissue remodelling with the help of the grafts/scaffolds.The cellular and combined allosteric-regulation approaches to modelling of bone turnover, based on the osteocyte loop of regulation, have been studied. Both approaches have been studied different within wide range of rate parameters. The approach to the model validation has been considered, including a statistical approach and parameter reduction approach. From a validation perspective the cellular class of modes is preferable since it has fewer parameters to validate. The optimal control framework for regulation of remodelling has been studied. Future work in to improve the models and their application to bone scaffold design applications have been considered. The study illustrates the complexity of formalisation of the metabolic processes and the relations between hierarchical subsystems in hard tissue where a relatively small number of cells are active. Different types/modes of behaviour have been found in the study: relaxational, periodical and chaotic modes. All of these types of behaviour can be found, in bone tissue. However, a chaotic or periodic modes are ones of the hardest to verify although a number of periodical phenomena have been observed empirically in bone and skeletal development. Implementation of the allosteric loop into cellular model damps other types of behaviour/modes. In this sense it improves the robustness, predictability and control of the system. The developed models represent a first step in a hierarchical model of bone tissue (system versus local effects). The limited autonomy of any organ or tissue implies differentiation on a regulatory level as well as physiological functions and metabolic differences. Implementation into the cellular phenomenological model of allosteric-like loop of regulation has been performed. The results show that the robustness of regulation can be inherited from the phenomenological model. An attempt to correlate the main bone disorders with different modes of behaviour has been undertaken using Paget’s disorder in bone, osteoporosis and some more general skeleton disorders which lead to periodical changes in bone mass, reported by some authors. However, additional studies are needed to make this hypothesis significant. The study has revealed a few interesting techniques. When studying a multidimensional phenomenon, as a bone tissue is, the visualisation and data reduction is important for analysis and interpretation of results. In the study two novel technical methods have been proposed. The first is the graphical matrix method to visualise/project the multidimensional phase space of variables into diagonal matrix of regular combination of two-dimensional graphs. This significantly simplifies the analysis and, in principle, makes it possible to visualise the phase space higher than three-dimensional. The second important technical development is the application of the Monte-Carlo method in combination with the regression method to study the character and stability of the equilibrium points of a dynamic system. The advantage of this method is that it enables the most influential parameters that affect the character and stability of the equilibrium point to be identified from a large number of the rate parameters/constants of the dynamic system. This makes the interpretation of parameters and conceptual verification of the model much easier.
- PhD