Scaffold‐Free Liver‐On‐A‐Chip with Multiscale Organotypic Cultures

Abstract

The considerable advances that have been made in the development of organotypic cultures have failed to overcome the challenges of expressing tissue-specific functions and complexities, especially for organs that require multitasking and complex biological processes, such as the liver. Primary liver cells are ideal biological building blocks for functional organotypic reconstruction, but are limited by their rapid loss of physiological integrity in vitro. Here the concept of lattice growth used in material science is applied to develop a tissue incubator, which provides physiological cues and controls the 3D assembly of primary cells. The cues include a biological growing template, spatial coculture, biomimetic radial flow, and circulation in a scaffold-free condition. The feasibility of recapitulating a multiscale physiological structural hierarchy, complex drug clearance, and zonal physiology from the cell to tissue level in long-term cultured liver-on-a-chip is demonstrated. These methods are promising for future applications in pharmacodynamics and personal medicine.

Liver‐on‐a‐Chip Models of Fatty Liver Disease

“…Another design recapitulates a multiscale structural hierarchy featuring drug clearance and zonal physiology for long‐term culture (Fig. B) . However, because of the absence of NPCs important for normal liver physiology, this model did not adequately reflect the physiological regulation of hepatocellular function and polarization.…”

“…(E) Perfused multiwell plate for 3D liver tissue engineering. Reprinted (A) with permission from Elsevier, (B) and (D) from John Wiley & Sons, respectively, (C) from IOP publishing, and (E) from Royal Society of Chemistry . Abbreviation: PLCs, primary liver cells.…”

“…2B). (17) However, because of the absence of NPCs important for normal liver physiology, this model did not adequately reflect the physiological regulation of hepatocellular function and polarization.…”

“…This model was then used to screen drugs such as pioglitazone and metformin, showing decreased TAG accumulation. Although hepatocytes responded to high concentrations of FFAs by reducing the activity of metabolic enzymes such as cytochrome P450 family 3 subfamily A member 4 and expressing several adipokines, they lacked many features of NAFLD/ (17,18) respectively, (C) from IOP publishing, (19) and (E) from Royal Society of Chemistry. (20) Abbreviation: PLCs, primary liver cells.…”

Necklace‐Like Microfibers with Variable Knots and Perfusable Channels Fabricated by an Oil‐Free Microfluidic Spinning Process

“…With lower nutrient supply, cells in Z2 and Z3 were found to be more sensitive to hepatic lesion. The nutrient supplying difference in the liver acinus contributed to metabolic, morphological, and functional heterogeneity of hepatocytes, which was associated with different drug‐induced liver injury . The hollow spindle‐knot has unique advantage for liver acinus mimicking as its consistent size, perfusability and unique permeability.…”