Organ-on-a-chip: recent breakthroughs and future prospects

Abstract

The organ-on-a-chip (OOAC) is in the list of top 10 emerging technologies and refers to a physiological organ biomimetic system built on a microfluidic chip. Through a combination of cell biology, engineering, and biomaterial technology, the microenvironment of the chip simulates that of the organ in terms of tissue interfaces and mechanical stimulation. This reflects the structural and functional characteristics of human tissue and can predict response to an array of stimuli including drug responses and environmental effects. OOAC has broad applications in precision medicine and biological defense strategies. Here, we introduce the concepts of OOAC and review its application to the construction of physiological models, drug development, and toxicology from the perspective of different organs. We further discuss existing challenges and provide future perspectives for its application.

Keywords: Human organs; Microfluidic chip; Organ-on-a-chip; Physiological model; Stem cell.

Fig. 1

Schematic of the DLM-based liver tumor-on-a-chip. a Preparation of the DLM solution from a natural liver; b 3D schematic representation of the various components of the equipment (top and bottom, top and bottom microchannels, PET membrane, air inlet, and outlet) and their respective dimensions (reprinted with permission from [52] Copyright © 2006, Royal Society of Chemistry)

Fig. 2

Lung-on-a-chip system. a An alveolar–capillary barrier was produced on porous flexible PDMS membranes coated with ECM using spaced PDMS microchannels. The device reproduced respiratory motion through a vacuum leading to mechanical stretching and the formation of an alveolar–capillary barrier; b following inhalation, the diaphragm contracts, reducing pleura pressure. The alveolar–capillary interface became stretched due to alveoli tension; c device development: a porous membrane between the upper and lower channels bound irreversibly following plasma exposure; d PDMS moved through the side of the channels and then was removed following vacuum pressure. e Actual images of the device (reprinted with permission from [64] Copyright © 2010, American Association for the Advancement of Science)

Fig. 3

a Kidney tubular chip. Sandwich assembly of the PDMS channel, porous membrane, and PDMS reservoir (reproduced from [74]); b the channel can replicate the urinary cavity and capillary lumen of the glomerulus. The porous flexible PDMS membrane can be used to functionalize the protein laminin to mimic the glomerular basement membrane. Cyclic mechanical pressure to the cell layer via vacuum stretching of the flexible PDMS film can be produced (reprinted with permission from [76] Copyright © 2018, Royal Society of Chemistry)

Fig. 4

3D heart-on-a-chip. a Two separate PDMS microchambers were employed. The CMs are positioned in the central channel to create a 3D construct, whilst the medium is replaced trough side-channels; b the lower end of the compartment is pressurized to deform the PDMS membrane and compress the 3D structure. Compression is converted to uniaxial strains applied to the 3D cell structure; c PDMS layers are aligned and irreversibly combined. Upper layers are present in the culture chamber and the drive chambers represent the lower layers; d 3D illustration; e real-life chip; f SEM of the chip cross section (reprinted with permission from [85] Copyright © 2016, Royal Society of Chemistry)

Fig. 5

a Illustration of the intestine-on-a-chip device; b images of the device composed of transparent PDMS elastomers; c cross-sectional view of the channels and square illustrations showing a top view of the porous film; d schematic of intestinal monolayers cultured on the chips (top) and phase contrast images (bottom) plus (left) or minus (right) mechanical strains (30%); arrows indicate the direction). e pressure quantitation (reprinted with permission from [91] Copyright © 2012, Royal Society of Chemistry)

Fig. 6

a Multi-throughput multi-organ-on-a-plate systems; b projection of a culture device containing a 4 × 4 culture chamber illustrated through a culture chamber of an X–X’ cross section; c design of microfluidic networks in the microfluidic plates for 8-throughput 2-organ systems and a 4-throughput 4-organ system. Design of the microfluidic networks in microfluidic plates for eight-channel dual-organ systems and four-flux four-organ systems. Closed circles indicate the location of the hole leading to the top surface of the microfluidic plate. Dark and light-shaded areas are deep and shallow microfluidic channels, respectively. Areas surrounded by green lines represent the circulation culture unit. Blue lines indicate the wall of the culture room. Thin red lines surrounding the exit indicate the Laplace valve. d Media circulation was performed using pneumatic pressure in the two-organ system. Red arrows indicate the direction of media flow (reprinted with permission from [112] Copyright © 2017, Royal Society of Chemistry)

Fig. 7

Tissue sources for the organ-on-a-chip (OOAC) devices. Embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and adult stem cells (ASCs) can be differentiated and integrated into microfluidic chips as for cell lines and primary cells. The figure illustrates the advantages (white) and limitations (black) of ESCs, ASCs, iPSCs, primordial and tissue biopsies, and cell lines in OOC devices. Cell lines and primary cells are more common in oocytes as they typically display good biological response characteristics. However, cell lines do not represent normal physiological conditions and primary cell culture time is limited, and the quality is unstable. In contrast, stem cells are readily available and are an infinite cell source. Even with current limitations on differentiation and maturation protocols, stem cells represent a promising technology that can be incorporated into OOC devices (reprinted with permission from [125] Copyright © 2019, Elsevier)

Fig. 8

Future trends in stem cell research. a Building blocks. b Organ-on-a-chip techniques can mimic real-life in vivo states (reprinted with permission from [133] Copyright © 2015, John Wiley and Sons)