Organ-on-a-chip - alternative to animal testing?

Constant search for the alternatives to animal testing keep pushing biotechnological research forward. Scientist is currently developing new mock organs that can fit in a palm of a hand.

Organ-on-a-chip is a multi-channel 3-D microfluidic cell culture chip that simulates the activities, mechanics and physiological responses of entire organs and organ systems. The convergence of labs-on-chips (LOCs) and cell biology has permitted the study of human physiology in an organ-specific context, introducing a novel model of in vitro multicellular human organisms. 

A lab-on-a-chip is a device that integrates one or several laboratory functions on a single chip that deals with handling particles in hollow microfluidic channels. Advantages in handling particles at such a small scale include lowering fluid volume consumption (lower reagents costs, less waste), increasing portability of the devices, increasing process control (due to quicker thermo-chemical reactions) and decreasing fabrication costs. Additionally, microfluidic flow is entirely laminar (i.e., no turbulence). Consequently, there is virtually no mixing between neighboring streams in one hollow channel. In cellular biology convergence, this rare property in fluids has been leveraged to better study complex cell behaviors, such as cell motility in response to chemotactic stimuli, stem cell differentiation, axon guidance, subcellular propagation of biochemical signaling and embryonic development.

3D cell-culture exceeds 2D models by promoting higher level of cell differentiation and tissue organization. In 3D cell-culture models flexible extracellular matrix accommodates shape changes and cell-cell connections making it more favorable comparing to 2D rigid substrates. However 3D cell-culture models still fail to mimic organ’s cellular properties lacking tissue-to-tissue interfaces, spatiotermal gradients of chemicals and mechanically active microenvironments. The application of microfluidics in organs-on-chips enables the efficient transport and distribution of nutrients and other soluble cues throughout the viable 3D tissue constructs.

One of the examples of organ-on-a-chip is a lung-on-a-chip. 

The chip contains two chambers separated by a flexible, porous membrane. One chamber contains human lung cells (alveoli), which are tiny air sacs with thin walls – this chamber allows researchers to introduce foreign particles, just as breathing would do in an organism. Across the membrane, the second chamber contains capillary blood cells (endothelium) which normally take up particles into the blood stream, as well as interface the immune system with potential toxins and pathogens. The computer chip is transparent, which allows real-time observation of how the cells respond to introduced particles. The chip is flexible, fluctuating the air pressure within a network of channels along its surface can replicate the mechanics of breathing – stretching and expanding the cells inside the chambers, roughly as they would in real life. This capacity for the chip to mimic breathing is an important step forward, because cell culture techniques are unable to replicate how mechanical factors influence cell behavior. Filling this gap brings laboratory models closer to the real-world organs they try to represent. 

The researchers have already studied the processes of pulmonary inflammation and pulmonary infection in this model

• Pulmonary inflammation

Pulmonary inflammatory responses entail a multistep strategy, but alongside an increased production of epithelial cells and an early response release of cytokines, the interface should undergo an increased number of leukocyte adhesion molecules. For example the pulmonary inflammation can be simulated by introducing medium containing a potent proinflammatory mediator. Only hours after the injury was caused, the cells in the microfluidic device subjected to a cyclic strain reacted in accordance with the previously mentioned biological response.

• Pulmonary infection

Living E-coli bacteria was used to demonstrate how the system can even mimic the innate cellular response to a bacterial pulmonary infection. The bacteria were introduced onto the apical surface of the alveolar epithelium. Within hours, neutrophils were detected in the alveolar compartment, meaning they had transmigrated from the vascular microchannel where the porous membrane had phagocytized the bacteria.

Additionally, researchers believe the potential value of this lung-on-a-chip system will aid in toxicology applications. By investigating the pulmonary response to nanoparticles, researchers hope to learn more about health risks in certain environments, and correct previously oversimplified in vitro models. Nevertheless, published studies admit that responses of a lung-on-a-chip don’t yet fully reproduce the responses of native alveolar epithelial cells.

Currently the organs that have been simulated by microfluidic devices include heart, kidney, cartilage, skin, bone, artery, lung, gut and several others. Researchers are also quite excited about creating a brain-on-a-chip. Scientists from John Hopkins School of medicine hope that in the future the fabrication of such devices can be commercialized and each organ-on-a-chip can be built from the cells of an individual person. 

Researchers are also working towards building a multi-channel 3D microfluidic cell culture system that compartmentalizes microenvironments in which 3D cellular aggregates are cultured to mimic multiple organs in the body (human-on-a-chip). Most organ-on-a-chip models today only culture one cell type, so even though they may be valid models for studying whole organ functions, the systemic effect of a drug on the human body is not verified. A human-on-a-chip can allow the researchers to study the systematic response of several organs together to particular drugs, inflammatory reactions and toxicology tests.

Though the current advances in the area of designing organs-on-a-chip look promising, there are still many limitations and we are far from completely replacing animal testing by these models, that still require a lot of validation and optimisation.  So far we are very limited by the number of experiments that we can perform in such models, making them more attractive for pharmaceutical companies in the assessment of pharmacokinetics.

Credits:
http://www.npr.org/blogs/health/2015/01/02/371945110/researchers-create-artificial-organs-on-microchips
http://en.wikipedia.org/wiki/Organ-on-a-chip
http://wyss.harvard.edu/viewpage/293/
http://singularityhub.com/2010/07/10/biological-microchip-mimics-a-real-lung-it-even-breathes/