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Organ-on-Chip: Efficient Translational Platform
Posted on December 12th, 2016 by Jeffrey Paul, PhD in Pharma R&D
Several years ago, cellular and subcellular platforms aimed to replace in vivo animal testing. Cellular and molecular scientists, armed with their pipettes, shouted the battle hymn of the translational scientist: “From bench to bedside.” However, we now know simple cellular translations predict patient outcomes for only a few inheritable diseases. So, this is where organ-on-chip enters drug discovery. The organ chip is an appealing translational model that could provide the biological complexity of in vivo testing while providing the efficiency of cell-based platforms.
Organ-on-chips are microengineered systems that attempt to mimic the dynamic physical forces and 3D architecture of our organs. Organs such as lungs, kidneys, and heart, whose function is influenced by the rhythmic pulsatile pressures of blood flow, are good candidates. Liver-on-chip can also be good for evaluating drug clearance. The chips, made of a thin transparent polymeric material lined with living cells, attempt to mimic the architecture and various interfaces of the real organ. Organ chips do an especially good job with evaluating barrier functions, like blood brain barrier, or endothelium lining of capillaries, and solid tumor barriers.
One of the best examples of success is with the lung chip. Harvard scientist Dongeun Huh from Wyss Institute of Harvard fabricated a lung-on-chip. The cool-looking chip even won a design of the year award in 2015 (ref 1) and would look pretty on my living room coffee table. The chip mimics the biological complexity and dynamics of the lung air sac/blood capillary interface. With such a model, disease processes like edema, infection, and inflammation, as well as environmental toxins, can be studied.
Brain chips are another area of cutting edge basic research. Using a brain-on-chip approach and micro-fluid technologies, scientists can study the communication between different brain regions, and between local circuits in the same brain region (ref 2). This may turn out to be an important translational model for future neuroscientists and CNS drug discovery.
Developing an organ-on-chip requires a number of engineering advances (ref 3). Microfabrication, using space-age materials, attempts to mimic the internal 3-D architecture and microenvironment of biologic tissue. Lithography techniques are used to layer thin sheets of dimethylsiloxane to form a transparent polymer structure. Micro channels are lined with specialized cells mimicking physiological barriers. The chip uses a micro-pump to control flow, mimicking the sheer stress of pulsatile blood flow. Finally, the chip needs biosensors and automation control to maintain temperature, pH, oxygen, and micronutrients. Some of the state-of-the-art micro sensors have come from the mobile phone and automobile industries.
There are several organ-on-chips companies who have commercially available products, including the Organovo, Sphero, and Emulate (ref 4) product lines, which are growing quickly.
Several uses of organ-on-chip for drug development includes (ref 5):
Drug screening: The models fit well into a drug screening process because one can test clinically relevant responses with the level of complexity that cell monolayers can’t provide. The chips are especially helpful for studying drug delivery across biologic barriers. Also, the chips are particularly useful for phenotypic screening of drug candidates.
Drug Toxicity: Although organ-on-chip will probably never replace in-vivo toxicology studies, they can be used answer mechanism questions and for toxicity screening.
Pharmacokinetics: Chip systems can provide important information regarding drug absorption and clearance which would then be used with physiological-based PK models. The purpose would be to provide a good prediction of the human PK profile of new compounds, prior to conducting the first human PK study.
Patient enrichment: Organ-on-chip approach can help find patients who would have a high drug response. This is called a patient enrichment strategy if one recruits highly sensitive patients into drug trials. Cells that have specific phenotype and genotype profiles are added to the chip to mimic patient characteristics. The results can be used to seek certain patients who would benefit from the drug, rather than first conducting large clinical trials.
Although it is doubtful that organ-on-chip technologies will completely replace animal testing in drug development, it can be a pretty good mimic of complexity of in vivo experiments. The promise is that the discovery scientist would have a predictive, cost-efficient, translational tool. If one places in tandem all of the vital organs on chips, then it would be called human-on-chip: the future is waiting.
- Building and manipulating neural pathways with microfluidics; Berdichevsky Y1, Staley KJ, Yarmush ML; Lab Chip. 2010 Apr 21;10(8):999-1004.
- Organs-on-chips at the frontiers of drug discovery; Esch, EW, Bahinski, A, Huh, D; Nature Reviews Drug Discovery. 2015, 14, 248–260.
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Jeffrey Paul, PhD
Principal at JPharm Consulting
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