A two-dimensional (2D) systems biology-based discrete liver tissue model: A simulation study with implications for ultrasound elastography of liver fibrosis

Abstract

Continuum tissue models that were often used to simulate or analyze the mechanical properties of tissues being imaged may not be biologically realistic. Our primary objective was to establish the feasibility of using systems biology to construct biologically relevant tissue models linking tissue structure, composition and architecture to the ultrasound measurements directly. The first application was designated to model fibrotic liver tissues. The proposed liver tissue model leveraged established histopathology knowledge of fibrotic liver tissues. Particularly, rules of systems biology derived from molecular histopathology were first implemented into an agent-based software platform SPARK to reflect progressions of liver fibrosis with/without steatosis. Then, microscopic compositions of tissues (e.g. cellular components) were converted to computing grids (at the 50-100 micrometer scale) for wave simulations using an open-source K-Wave. To verify the physical soundness of the proposed model, virtual wave speed measurements (i.e. shear wave speed [SWS] and the speed of sound [SOS]) were performed. Our initial results demonstrated that the simulated SWS values increased with the progression of liver fibrosis (from 1.5 m/s [Fibrosis stage 1] to 4 m/s [Fibrosis stage 4]). Similarly, the simulated SOS values were within the range of clinical data (from 1575 m/s [Fibrosis stage 0-3] to 1594 m/s [Fibrosis stage 4]). In summary, we found that those systems biology simulated fibrotic liver tissues with and without steatosis can reflect spatial characteristics of relevant histology. Also, their mechanical characteristics (i.e. shear/compressional wave speed) were in good agreement with data reported in the clinical literature.

A rule-based multiscale model of hepatic stellate cell plasticity: critical role of the inactivation loop in fibrosis progression

“…However, modelling HSC dynamics does not capture the full complexity of the microenvironment that governs these dynamics such as the multitude of events regulated by immune cells. Other multiscale models include the role of Kupffer cells in HSC activation via TNF- α [13, 15] or antagonistic regulation by M1 and M2 macrophages [16]. Similarly, it is difficult to include all the components involved in extracellular matrix remodeling.…”

“…This model was then modified by preventing the migration of collagen-producing cells, thus providing a more accurate dynamic of collagen deposition [14]. The Dutta-Moscato model has also been extended and modified by Wand and Jiang [15] to include information about lipid accumulation induced by CCl4 treatment, making it possible to study the progression of liver fibrosis in presence or absence of steatosis. In addition to these agent-based models, Friedman and Hao recently published a partial differential equation (PDE) model for liver fibrosis that includes information on inflammation regulation and ECM remodeling, enabling exploration of anti-fibrotic drugs [16].…”

On the soft tissue ultrasound elastography using FEM based inversion approach

“…micromechanics-based, hyper elastic, viscoelastic and anisotropic) have been used to formulate elastography problems, the linear elastic homogeneous model is still highly common in the research community. 31,32 In a different study, Lawson 33 also developed a FE based direct inversion method for elastic modulus reconstruction, which has similarity to the presented method. In order to evaluate their method, they used a heterogeneous model under compression in-silico.…”

“…micromechanics-based, hyper elastic, viscoelastic and anisotropic) have been used to formulate elastography problems, the linear elastic homogeneous model is still highly common in the research community. 31,32…”

Computational simulation of liver fibrosis dynamics

“…Compared with in vivo and in vitro methods, they have substantial advantages in generating and validating hypotheses. For liver fibrosis, to recapitulate overall cellular population dynamics based on local interactions, agent-based models (ABMs) have been used [30][31][32][33][34] . Dutta-Moscato et al developed an ABM model that simulates the progression of drug-induced liver fibrosis, represented by tetrachloromethane (CCl 4 ) exposure 31 .…”