A review about organ on chip

Introduction

organs on a chip microfluidicsOrgans on chips are microengineered biomimetic systems that replicate key functions of living organs. These microdevices provide a more accurate model than conventional cell culture for simulating complex cell-cell and cell-matrix interactions. Thus, they potentially represent a very interesting tool for pharmaceutical and chemical applications. They also allow to study human physiology for a specific organ and thus enable the development of new in vitro disease models.

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FOR CELL CULTURE

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From 3D cell culture to organ on chip

3D cell culture and organs on chipIn 3D cell culture, cells are cultivated in an artificially created micro-environment that allows them to grow and interact with their surrounding in all three dimensions. They are several culturing tools that provide the advantages of 3D cell culture, such as extracellular matrices or scaffold, rotating bioreactors, microcarriers or hanging drop plates.

3D cell culture provides the cells a microenvironment more similar to the in vivo microenvironment than conventional 2D cell culture, enhances the expression of differentiated functions and improves tissue organization. 3D spheroids are thus improved models for cell migration, differentiation and growth. Moreover, a cell cultivated in 3D shows a better degree of polarization and exhibits gene expression levels different from those of cells cultivated in 2D.

For example, 3D cell culture can be used to mimic acinar structures (cluster of cells that resembles a many-lobed berry, such as a raspberry, acinus is Latin for “berry”) in healthy and cancerous breast tissue models. These spheroids are more suitable than conventional cell culture for long term drug screening.

However, 3D cell cultures fail to reproduce features of living organs that are crucial for their functions, such as tissue-tissue interfaces (between epithelium and vascular epithelium for example), chemicals or oxygen gradients or the mechanical action of the microenvironment.

Organs on chip take advantage of microfluidics and microfabrication benefits to overcome these limitations in order to better mimic the microstructure, the dynamic mechanical properties and the biochemical functionalities of living organs.

Microfabrication techniques for cell biology

Microfabrication organs on a chipOrgans on chip rely on two core techniques. The first one is microfluidics, which enables manipulating small amount of liquids, and allows to precisely controlling fluid flows or creating concentration gradients. With microfluidic techniques, nutrients and other chemical cues can be delivered in a very controlled way.

The second one is microfabrication (photolithography, replica molding, microcontact printing) that is well suited to create microstructures allowing to control cell shape and function.

Early microsystems used silicon microfabrication, leading to complex and expensive microfabrication processes. To overcome this limitation, researchers developed microfluidic systems made of polydimethylsiloxane (PDMS). PDMS has several properties that make it particularly suited for the fabrication of microdevices for cell or tissue culture. Firstly, PDMS has a rich gas permeability that ensures oxygen supply to the cells inside the microchannels. This eliminates the need of an external oxygenator, commonly required for cell culture in silicon, glass or plastic devices. Then, PDMS enables live cell imaging thanks to its optical transparency. Lastly, PDMS is very flexible, which allows using on chip valves or applying mechanical actions to the cells through PDMS local deformations.

However, PDMS has also drawbacks. The major drawback of PDMS for cell culture is that PDMS tends to adsorb small molecules on its surface. For more information, see our critical review about PDMS in biology.

Organ models on a chip

A wide range of tissue models has been developed by industry or academic labs. Here we provide a short overview of some organ on chip models.

Intestine on a chip

organs on chip intestineThis organ on chip is a very important model for drug screening. When orally administrated, drugs are mainly absorbed by the small intestine and then diffused though two barriers: a mucous layer and the epithelial cell layer of the intestinal wall. An intestine on a chip is a complex model and should take into account several features: cellular composition (mainly enterocytes and goblet cells), structural features (villi and mucus) and dynamic features (intestinal movements, called peristalsis).

Kimura et al [1] created an intestinal model with two independent channels separated by a semi permeable membrane on which cells are inoculated and cultivated.

The Harvard’s Wyss Institute also realized a “gut-on-a-chip” with the same principle that also stretches periodically to mimic the peristaltic motion of the intestine. In addition, the researchers were able to grow common intestinal microbes inside this organ on chip. [2]

Liver on a chip

Liver on chip is a key element for assessing drugs toxicity. Actually, half of drugs withdrawals occurs because of acute liver toxicity.

Midwoud et al [3] developed a microfluidic liver on chip that integrates liver and intestinal slices into compartments with sequential perfusion between the compartments in order to investigate interorgan interactions.

Lung on a chip

organs on chip lung harvardThe lung epithelium is subject to a wide range of environmental assaults, such as pathogens or pollution. A lung on chip would thus be an excellent model for environmental applications.

Huh et al. [4] cultured epithelial, alveolar epithelial and immune cells on a flexible membrane. Culture medium is pumped in the lower channel to mimic blood flow through lung microvasculature. Two side hollow channels are periodically inflated and deflated to mimic physiological breathing movements.

Tumor on a chip

One of the biggest challenge for cancer research is to develop drugs that will target cancerous cells but leave intact healthy cells.

Different strategies have been developed to create relevant models for tumors, including multicellular spheroids, hollow fibers and multicellular layer models. Perfusion systems are used to delivers therapeutic agents to these 3D models, mimicking blood supply to tumor cells.

Muscle on a chip

Skeletal muscles play a major role in diabete, because of their contribution in glucose homeostasis. On chip skeletal muscle models require structural features (myotubes alignement and assembly into sarcomers) and the presence of embedded electrodes to stimulate muscles contractions.

On chip myotubes alignment has been realized with substrate patterning or stiffness. Kaji et al [5] demonstrated the positive correlation between the contractibility of the myotubes and the glucose uptake by individually controlling myotubes with a microelectrode array.

Multiple organs on a chip

organs on chip humanAll these organs on chip could be used altogether to predict drugs toxicity on the whole body. In these animal-on-chip or human-on-chip systems, multiple chips representing different organs are connected with channels.

However, despite major breakthroughs in this field, several challenges remain, such as using human primary cells instead of cancerous cell lines, monitoring cells response to stimuli, or controlling the quality of the microenvironment (metabolites, O2 saturation, pH).

Other interesting reviews about organs-on-chip are references [6] and [7].

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For more tutorial about microfluidics, please visit our other tutorials here: «Microfluidics tutorials». The photos in this article come from the Elveflow® data bank, Wikipedia or elsewhere if precised. Article written by Emmanuelle Nadal and Timothée Houssin.

References

[1] Kimura, H. et al., An integrated microfluidic system for long-term perfusion culture and on-line monitoring of intestinal tissue models, Lab On Chip, 2008

[2] Kim HJ, Huh D, Hamilton G, Ingber DE. Human gut-on-a-chip inhabited by microbial flora that experiences intestinal peristalsis-like motions and flow. Lab Chip. 22 may 2012;12(12):2165‑74

[3] Paul M. van Midwoud, Marjolijn T. Merema, Elisabeth Verpoorte and Geny M.M. Groothuis, A Microfluidic Approach for In Vitro Assessment of Interorgan Interactions in Drug Metabolism Using Intestinal and Liver Slices, Lab On Chip, 2010

[4] Huh, D. et al., Reconstituting organ-level lung functions on a chip, Science, 2010

[5] Kaji H, Ishibashi T, Nagamine K, Kanzaki M, Nishizawa M. Electrically induced contraction of C2C12 myotubes cultured on a porous membrane-based substrate with muscle tissue-like stiffness. Biomaterials. sept 2010;31(27):6981‑6

[6] Amir M. Ghaemmaghami, Matthew J. Hancock, Helen Harrington, Hirokazu Kaji and Ali Khademhosseini, Biomimetic Tissues on a Chip for Drug Discovery, Drug discovery today, 2012

[7] Dongeun Huh, Geraldine A. Hamilton and Donald E. Ingber, From 3D cell culture to organs-on-chips, Trends in Cell Biology, 2011