Carotenuto, Angelo Rosario (2016) COUPLING CELLS COMPETITION, GROWTH AND REMODELLING IN MECHANICS OF BIOLOGICAL SYSTEMS. [Tesi di dottorato]

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Item Type: Tesi di dottorato
Lingua: English
Title: COUPLING CELLS COMPETITION, GROWTH AND REMODELLING IN MECHANICS OF BIOLOGICAL SYSTEMS
Creators:
CreatorsEmail
Carotenuto, Angelo Rosarioangelorosario.carotenuto@unina.it
Date: 30 March 2016
Number of Pages: 259
Institution: Università degli Studi di Napoli Federico II
Department: Ingegneria Chimica, dei Materiali e della Produzione Industriale
Scuola di dottorato: Ingegneria industriale
Dottorato: Ingegneria dei materiali e delle strutture
Ciclo di dottorato: 28
Coordinatore del Corso di dottorato:
nomeemail
Mensitieri, Giuseppemensitie@unina.it
Tutor:
nomeemail
Fraldi, MassimilianoUNSPECIFIED
Date: 30 March 2016
Number of Pages: 259
Uncontrolled Keywords: Biomechanics; Volterra-Lotka; Growth; Remodelling;
Settori scientifico-disciplinari del MIUR: Area 08 - Ingegneria civile e Architettura > ICAR/08 - Scienza delle costruzioni
Area 09 - Ingegneria industriale e dell'informazione > ING-IND/22 - Scienza e tecnologia dei materiali
Area 09 - Ingegneria industriale e dell'informazione > ING-INF/06 - Bioingegneria elettronica e informatica
Date Deposited: 12 Apr 2016 23:39
Last Modified: 27 Apr 2017 01:00
URI: http://www.fedoa.unina.it/id/eprint/10850

Abstract

The biomechanical behavior and the mechanobiology of cells, tissues and organs have been intensively investigated in the last decades, with the aim of discovering the key feedback mechanisms governing the ways in which cascades of chemical signals are transmitted within the hierarchically organized living structures and interplay with physical events at different scale levels. Continuum Mechanics has deeply contributed to develop this research area and to meet related challenges, by creating the physically and mathematically consistent ground on which large deformation, stresses, evolving constitutive laws, growth, remodeling and morphogenesis do interact. The needed multiphysics vision in analysing the complex behavior of the living matter has in particular consolidated Tissue Mechanics theoretical approaches and related modeling strategies which are currently recognized as indispensable tools for explaining experimental evidences, for predicting dynamics of living systems as well as for supporting the design of prostheses for both soft and hard tissues. Further impulse to these studies is then given by the rapidly growing advances of the research in tissue engineering which continuously redraw new scenarios for applications in medicine and lead to envisage innovative drug delivery systems and biomaterials. Within this vivid multidisciplinary debate, an increasing interest has been recently registered in the Literature for the mechanical properties of living cells -and for the understanding of the dynamics to which they obey at different scale levels- also motivated by some recent discoveries which seem to allow to envisage new horizons for therapy and diagnosis of human diseases like cancer, by for example exploiting the different in-frequency response of single healthy and tumor cells stimulated by Utrasound. However, at the macroscopic scale -say at the tissue level- the feedback mechanisms and the cascade of bio-chemical and physical signals characterizing the complex interaction of dynamics occuring at different scales significantly complicates the biomechanical response of living matter and growing tumor masses, thus requiring enriched models which encorporate the mechanobiology at the micro- and meso-scale levels. Cancer diseases in fact occur when in a healthy tissue the cell-cell and cells-ECM (the Extra-Cellular Matrix) interactions are altered, and hyperplasia is generated as effect of sudden and often unforeseeable genetic modifications followed by a cascade of biochemical events leading to abnormal cell growth, lost of apoptosis, back-differentiation and metastasis. As a consequence, the determination of models capable to macroscopically describe how tumor masses behave and evolve in living tissues by embodying tumor invasion dynamics determined by cell-cell and cells-environment to date still remains an open issue. Growth of biological tissues has been recently treated within the framework of Continuum Mechanics, by adopting heterogeneous poroelastic models where the interaction between soft matrix and interstitial fluid flow is additionally coupled with inelastic effects ad hoc introduced to simulate the macroscopic volumetric growth determined by cells division, cells growth and extracellular matrix changes occurring at the micro-scale level. These continuum models seem to overcome some limitations intrinsically associated to other alternative approaches based on mass balances in multiphase systems, because the crucial role played by residual stresses accompanying growth and nutrients walkway is preserved. Nevertheless, when these strategies are applied to analyse solid tumors, mass growth is usually assigned in a prescribed form that essentially copies the in vitro measured intrinsic growth rates of the cell species. As a consequence, some important cell-cell dynamics governing mass evolution and invasion rates of cancer cells, as well as their coupling and feedback mechanisms associated to in situ stresses, are inevitably lost and hence the spatial distribution and the evolution with time of the growth inside the tumor --which would be results rather than input-- are forced to simply be data. In order to solve this sort of paradox, the present Thesis work, within a consistent thermodynamic framework, builds up an enhanced multi-scale poroelastic model undergoing large deformation and embodying inelastic growth, where the net growth terms directly result from the "interspecific" predator-prey (Volterra/Lotka-like) competition occurring at the micro-scale level between healthy and abnormal cell species. In this way, a system of fully-coupled non-linear PDEs is derived to describe how the fight among cell species to grab the available common resources, stress field, pressure gradients, interstitial fluid flows driving nutrients and inhomogeneous growth do all simultaneously interact to decide the tumor fate. The stability of the predator-prey dynamics and some original theoretical results for the non-linear mechanics of growing media are also developed and discussed in detail. The general approach -that is the coupling of growth, large deformation and competitive cell dynamics- is therefore applied to actual biomechanical problems (in particular analyzing growth and stress in tumor spheroids and arterial walls) and the theoretical outcomes are finally compared with in vivo experiments and animal models to validate the effectiveness and the robustness of the proposed strategy.

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