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

Abstract

Mechanics is of primordial importance to understand cancer; hence, experimental 14 and mathematical models providing quantitative information from the bio-chemo-mechanical 15 perspective play a pivotal role on the development of new therapies. Within this context, 16 encapsulated spheroids are emerging as exceptional in vitro tools to investigate the impact of 17 mechanical forces on tumor growth, since from the deformation of the alginate capsule the 18 internal pressure of the spheroid can be retrieved. 19 We show that multi-phase bio-chemo-poro-mechanics is a suitable theoretical framework to 20 understand, explain and design these in vitro tumor growth experiments. Such mechanistic 21 models are based on a set of coupled partial differential equations which are discretized in time 22 and space and solved within an open-source framework (FEniCS). Through sensitivity analyses, 23 our mathematical model suggests that the main parameters determining the encapsulated and 24 free growth configurations are independent. This observation indicates that radically different 25 phenomena are at play during free growth and constrained growth. Our mathematical model, 26 including its open-source implementation and associated sensitivity analysis can help 27 understand important mechanisms in oncophysics through reactive porous media mechanics 28 and serves as a basis for further clinical applications to supplement in vivo clinical data. 29 30 34 Alessandri et al. (2013)). Mathematical models complement experiments and help understand, 35 explain and build on these experimental findings Jain et al. (2014)(pp.5-6).36 Experimental approach 37 Multi-cellular tumor spheroid (MCTS) cultures have been primarily developed to investigate the 38 complex interactions between cells and the extra-cellular matrix (ECM), such as reactions involving 39 1 of 24 Manuscript submitted to eLife integrine or the differentiation of epithelial cells, which 2D cultures cannot describe Cukierman 40 et al. (2001). Moreover, the limitation of tissue properties in 2D culture does not allow the evalua-41 tion of the efficiency of therapeutic agents on tumor cells Alessandri et al. (2013). 42 The experiment reproduced here in silico is a confined MCTS culture obtained by the adaptation of 43 a patent process of liquid core hydrogel capsules Bibette et al. (2012). Alessandri et al Alessandri 44 et al. (2013) developed a microfluidic method based on the encapsulation and growth of cells in-45 side permeable, elastic, hollow microspheres for the production of size-controlled MCTS. Alginate 46 is used as a biomaterial for the encapsulation. Alginates are commonly used for the preservation 47of transplanted organs and their properties were investigated in Lee and Mooney (2012). Alginate 48 capsules ensure favorable conditions for cellular growth, because its permeability permits the free 49 flow of nutrients and oxygen without requiring additional molecules that could be potentially toxic 50 for the MCTS. By surrounding a growing tumor by an a...

Mechanistic modeling of vascular tumor growth: an extension of Biot’s theory to hierarchical bi-compartment porous medium system

“…Hence, results of the full VGA model have today only a qualitative value because are not validated with a suitable in vitro or in vivo experiment. Taking advantage from a previous in vitro-in silico study (20) where we have exhaustively validated the AG model, an improvement of the presented experimental methodology (confined co-culture of endothelial and tumor cells based on Cellular Capsule Technology, (21)) is under development to validate VG and VGA models. Despite the model is here specialized and applied for numerical simulation of vascular tumor growth, this general framework can be also used to simulate drugs delivery, physiological behavior of healthy tissues and further extended to account for the lymphatic system.…”