A graph-based framework for multi-scale modeling of physiological transport

Trillions of chemical reactions occur in the human body every second, where the generated products are not only consumed locally but also transported to various locations in a systematic manner to sustain homeostasis. Current solutions to model these biological phenomena are restricted in computability and scalability due to the use of continuum approaches where it is practically impossible to encapsulate the complexity of the physiological processes occurring at diverse scales. Here we present a discrete modeling framework defined on an interacting graph that offers the flexibility to model multiscale systems by translating the physical space into a metamodel. We discretize the graph-based metamodel into functional units composed of well-mixed volumes with vascular and cellular subdomains; the operators defined over these volumes define the transport dynamics. We predict glucose drift governed by advective-dispersive transport in the vascular subdomains of an islet vasculature and cross-validate the flow and concentration fields with finite-element based COMSOL simulations. Vascular and cellular subdomains are coupled to model the nutrient exchange occurring in response to the gradient arising out of reaction and perfusion dynamics. The application of our framework for modeling biologically relevant test systems shows how our approach can assimilate both multi-omics data from in vitro - in vivo studies and vascular topology from imaging studies for examining the structure-function relationship of complex vasculatures. The framework can advance simulation of whole-body networks at user-defined levels and is expected to find major use in personalized medicine and drug discovery. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/460337v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@16ff682org.highwire.dtl.DTLVardef@1a1101dorg.highwire.dtl.DTLVardef@1291b39org.highwire.dtl.DTLVardef@1ba65d6_HPS_FORMAT_FIGEXP M_FIG C_FIG SignificanceWithin a tissue, the short-range and long-range communications that sustain metabolism is mediated by the vessels perfusing through the cells. When blood flows through the vasculature, nutrient exchange occurs from cell-to-vessel in accordance with the concentration gradients arising out of cellular and vascular dynamics. Therefore, the topology of blood flow and the anatomical arrangement of cells act as primary determinants influencing the functional response of a tissue. We introduce a graph-based model for understanding the multi-scale connectivity observed across functional networks in a tissue. Our approach offers the flexibility to couple different scales by defining each component to the desired scale so as to balance the need for completeness without compromising on necessary details to answer the questions of interest.