Digital twinning of Cellular Capsule Technology: Emerging outcomes from the perspective of porous media mechanics.

Stéphane Urcun,Pierre Nassoy,Stéphane P A Bordas,Pierre-Yves Rohan,Giuseppe Sciumè,Wafa Skalli,Krishna Garikipati

doi:10.1371/journal.pone.0254512

Abstract

Spheroids encapsulated within alginate capsules are emerging as suitable in vitro tools to investigate the impact of mechanical forces on tumor growth since the internal tumor pressure can be retrieved from the deformation of the capsule. Here we focus on the particular case of Cellular Capsule Technology (CCT). We show in this contribution that a modeling approach accounting for the triphasic nature of the spheroid (extracellular matrix, tumor cells and interstitial fluid) offers a new perspective of analysis revealing that the pressure retrieved experimentally cannot be interpreted as a direct picture of the pressure sustained by the tumor cells and, as such, cannot therefore be used to quantify the critical pressure which induces stress-induced phenotype switch in tumor cells. The proposed multiphase reactive poro-mechanical model was cross-validated. Parameter sensitivity analyses on the digital twin revealed that the main parameters determining the encapsulated growth configuration are different from those driving growth in free condition, confirming that radically different phenomena are at play. Results reported in this contribution support the idea that multiphase reactive poro-mechanics is an exceptional theoretical framework to attain an in-depth understanding of CCT experiments, to confirm their hypotheses and to further improve their design.

Highlights

As a tumor grows, it deforms the surrounding living tissues which, in turn, produce pressure on the growing tumor and causes strains and associated stresses
This article focuses on the Cellular Capsule Technology (CCT), an experimental protocol developed by some of the authors in [7] where multi-cellular tumor spheroids (MCTS) were cultured within spherical porous alginate capsules
It is relevant to quantify the characteristic time of this process since one can infer that a relatively high pressure sustained by a cell during a relatively short time does not lead to phenotype modifications

Summary

Introduction

It deforms the surrounding living tissues which, in turn, produce pressure on the growing tumor and causes strains and associated stresses. This article focuses on the Cellular Capsule Technology (CCT), an experimental protocol developed by some of the authors in [7] where multi-cellular tumor spheroids (MCTS) were cultured within spherical porous alginate capsules The latter, after confluence (i.e. when the MCTS comes in contact with the inner wall), work as mechanosensors i.e., from their deformation, one can retrieve the stress state within the MCTS. As envisioned in [7], the interaction pressure between the MCTS and the capsule, coming from the basic action-reaction principle, is a capital information since it could enable the prediction of stress-induced phenotype alterations to characterize cell invasiveness. It is relevant to quantify the characteristic time of this process since one can infer that a relatively high pressure sustained by a cell during a relatively short time does not lead to phenotype modifications

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