A Multiscale approach to Bone Remodelling

A Joint Project of

Modelling and Simulation Laboratory , University of Camerino

Istituti Ortopedici Rizzoli, Sheffield University

Computer Laboratory, University of Cambridge

Main investigators:

Emanuela Merelli, University of Camerino

Marco Viceconti, Istituti Ortopedici Rizzoli, Sheffield University

Pietro Lio', University of Cambridge

Bone Remodelling Team is exploring a new formal approach for modelling, analysis and prediction of the bone remodelling.
The aim of the project is to define a new computational model that supports, in a uniform way, the multiscale modelling and the behavioural analysis, from tissue mechanics to molecular interaction and back. The multiscale complexity of Bone Remodelling turns to be well-suited to exercise different existing modelling approaches, some of them considered natively multiscale, whereas some others simply adapted so as the one under study.

Coupling different levels of description (micro - meso - macro)is a great challenge, as it is likewise highlighted by the Virtual Physiological Human (VPH) FP7 project, whose main objective is the development of a computational framework and software tools for the multilevel modelling and simulation of the human anatomyand physiology.
A similar interest is perceived within the academic field of FormalMethods, where a growing attention for hierarchical and multiscale models is recently registered.

As well as multiscale, a biological system gives evidence that its behaviour, observable at a certain scale of abstraction, is the result of a well organized scenario at a lower level scale, where an adaptive system, consisting of many components interacting for a common goal, makes an effort to maintain the system environment at higher level, in a certain equilibrium. Thus the modelling must to take into account explicit factors like space, shape, motion and relations as perception and affinity to create faithfull models of biological reality and to allow meaningful analysis of the system properties.

Currently, the spectrum of the approaches used in multiscale modelling range over by PDE- ODE coupled systems and Complex Automata (CxA), more recently by Spatial P systems (SP) and BioShape.
Except from ODE/PDE models, the selected approaches aim at putting in evidence two complementary characteristics, which lack in the continuum-based approach: the ability to model the topological space of the components interactions and their motion, respectively supported in CxA, in SPs and both in BioShape.

Even if none of the above approaches fully support all the features that characterized a multiscale biological model, BioShape natively designed for this purpose seams to be promising.

In particular, we propose:
  1. to investigate on the appropriate computational approach suitable to zooming-in and zooming-out a multiscale model moving through different time and space scales.

  2. to describe, from the behavioural and topological point of view, BMU machine at cellular level - e.g. by automata, statecharts, adaptive agents, BioShape etc.

  3. to define an appropriate modal logic for specifying the qualitative and quantitative properties of the BR model we are interested to analyse. Qualitivative analysis, in terms of correct behavior = reachability; free of unwanted behaviors = safety; warrantee of correct behavior for any input = liveness. And quantitative analysis during the model simulation in terms of,
    1. "how much mineralized bone is destroyed by an Osteoclast (i.e. the cell responsible for bone resorption) and in how much time?"
    2. "how many cells are created by an Osteoblast (i.e. the cell responsible for bone regeneration) and in how much time?"
    3. "what is the maximal size an Osteoclast can reach before starting to erode the mineralized bone?"
    4. "how orientation of involved actors (Osteoblasts & Osteclast) affect resorption/regeneration activities in term of time and energy loss?"
    5. and
    6. "what is the expected number of BMUs actived in a certain time period?"
    7. "what is the expected number of Osteoclasts, Osteoblast, Ostocytes etc. present in a BMU at the Resorption, Reversal, Formation and Resting phases?"
    8. "how much the genetic expression changes respect to the tension of the bone structure?"
    9. "how much the bone strength depends on the optimization of the topological space at cellular level?"
  4. to predict the (behavioural) dynamics of a bone tissue

  5. to analyse the molecules and cells interactions at different scale levels as a basis to study the drugs interferences

  6. to represent into the model the personalise genetic information (...) towards a personalized model.

  7. to apply the new knowledge coming from biological methods and techniques back to the theory of formal methods.

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Nicola Paoletti received the HPC fellowship in 2011 for visiting Edinburgh, and Cambridge

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