Liver Bioreactor Design Issues of Fluid Flow and Zonation, Fibrosis, and Mechanics: A Computational Perspective

Abstract

Tissue engineering, with the goal of repairing or replacing damaged tissue and organs, has continued to make dramatic science-based advances since its origins in the late 1980’s and early 1990’s. Such advances are always multi-disciplinary in nature, from basic biology and chemistry through physics and mathematics to various engineering and computer fields. This review will focus its attention on two topics critical for tissue engineering liver development: (a) fluid flow, zonation, and drug screening, and (b) biomechanics, tissue stiffness, and fibrosis, all within the context of 3D structures. First, a general overview of various bioreactor designs developed to investigate fluid transport and tissue biomechanics is given. This includes a mention of computational fluid dynamic methods used to optimize and validate these designs. Thereafter, the perspective provided by computer simulations of flow, reactive transport, and biomechanics responses at the scale of the liver lobule and liver tissue is outlined, in addition to how bioreactor-measured properties can be utilized in these models. Here, the fundamental issues of tortuosity and upscaling are highlighted, as well as the role of disease and fibrosis in these issues. Some idealized simulations of the effects of fibrosis on lobule drug transport and mechanics responses are provided to further illustrate these concepts. This review concludes with an outline of some practical applications of tissue engineering advances and how efficient computational upscaling techniques, such as dual continuum modeling, might be used to quantify the transition of bioreactor results to the full liver scale.

Fluids Alter Elasticity Measurements: Porous Wave Propagation Accounts for Shear Wave Dispersion in Elastography

“…Liver diseases do not only alter the elasticity of the cellular matrix of the liver but are known to affect the porous parameters, notably porosity and permeability, as well. These insights led different groups to numerically model the liver as a poro-elastic or poro-visco-elastic material in the last decade [1,9,[13][14][15][16][17][18][19]. However, albeit early realization of interstitial fluid flow as an dissipative mechanism for acoustic waves [20], few attempts to link the shear wave dispersion in the liver to its porous and fluid properties have been made to our knowledge.…”

“…The tortuosity takes into account the pore shape. It is generally assumed for cylindrical pores and is evaluated as the total length of the pore divided by the shortest path connecting its ends or in other words: "the ratio of the arc length of a curve relative to its end-to-end distance" [16]. It also accounts for the inertial coupling of the solid and fluid phase, where inertial coupling signifies that an accelerating solid drags parts of the surrounding fluid with it [33].…”

Dual continuum upscaling of liver lobule flow and metabolism to the full organ scale

“…We began with a simple idealized-lattice model for the lobule (Rezania et al, 2013a;Rezania et al, 2013b), which is the smallest structural unit that can independently serve all of the organ's functions. This idealized model was extended to consider structural and spatial variability of the lobule in two and three dimensions (Rezania et al, 2016;Rezania et al, 2020). Here, a hexagonal-based model with supplying and draining structures to represent a typical liver lobule was developed.…”

“…Frontiers in Systems Biology frontiersin.org Rezania et al, 2020) to calculate these zonal distributions.…”

Microtechnology-based in vitro models: Mimicking liver function and pathophysiology

“…Hepatic tissue can be divided into zones based on several factors, such as oxygen, and nutrients, and hepatocytes show different morphologies and functions depending on the zone. 33 This is one of the specific characteristics of the liver known as the liver zonation. Among these factors, the oxygen gradient is one of the key factors affecting the metabolic functions of hepatocytes.…”