MAthematical TISSues: an in vitro-in silico approach for engineering design and production of a new generation of vascularized organoid-based tissues – MATISSe

Within the context of tissue engineering and regenerative medicine, organoids, which are simplified miniature organs, can be considered as building blocks for the fabrication of macroscopic tissues (~mm-cm). The main obstacle to this scaling process is the integration of a perfusable vascular network to avoid cell necrosis due to lack of oxygen and nutrients.
Experimentally, we will rely on P#2's expertise in the customized production of organoids using a patented microfluidic technique, and on P#3's expertise in the production of artificial blood vessels (vesseloids).
Unlike most of existing techniques that rely on empirical guidelines, MATISSe methodology combines i) an experimental approach guided by self-organization and multicellular positioning and ii) in silico modeling, which will feed on experimental data before guiding the optimization of the different steps towards the production of the final tissue prototype.
The mathematical model for tissue growth and self-organization will be developed within the framework of the Thermodynamically Constrained Averaging Theory, a modern theory for multiphase porous systems already validated by P#1 in the field of physical oncology. The vascularized tissue will be modeled as a deformable, reactive and multiphase porous medium with two porous compartments: the first one, called extravascular porosity, is saturated by cell populations and interstitial fluid (mixture of water and nutritive species); the second one, called vascular porosity, represents the volume occupied by the vessels where an oxygenated medium circulates. The extracellular matrix constitutes the solid scaffold of the multiphase continuum.
Building on this in vitro-in silico synergy, the overall goal of MATISSe is to provide a computer-assisted methodology for the optimized, multi-scale design of a new generation of vascularized organoid-based artificial tissues.
Even though experimental and mathematical modeling grounds on universal biophysical features, tissue specificity will be addressed by aiming for a liver tissue as a proof of concept. The methodology of MATISSe is structured in three steps:
1) The generation of pre-vascularized organoids that will facilitate and accelerate the connections with the larger-scale tissue vasculature.
2) The study of the behavior of a pre-vascularized organoid in proximity to an artificial blood vessel. A process of angiogenesis, i.e. the creation of new micro-vessels growing from the vesseloid, and their connection with the micro-vessels of the organoid (anastomosis) will be studied experimentally by optical imaging in real time and modeled numerically.
3) The assembly of several pre-vascularized organoids around at least two vesseloids playing the role of vein and artery to generate a larger scale vascularized tissue. Indeed, after a phase of merging of the pre-vascularized organoids (coalescence) and of interconnection between the micro- and macro-vascular systems, a perfusable tissue of millimetric size will be obtained.
Our consortium led by an applied mathematician expert in porous materials, is completed with i) a physicist expert in tissue engineering and biophotonics, and ii) a biologist expert in angiogenesis and 3D cell models.
Our combination aims to propose optimized and robust design rules. Thanks to the support of mathematical modeling, the expected experimental results will constitute a major advance in the field of tissue engineering. Reciprocally, thanks to the support of controlled experiments, the developed mathematical model will constitute an important and versatile tool for digital twinning of biological tissues.