Organ-on-chip: a new paradigm for clinical trials – correspondence

Dear Editor,

It takes over a decade and billions of dollars to bring a new drug to market. These extensive financial and time commitments contribute significantly to the current soaring healthcare costs and pose substantial barriers to the delivery of innovative medicines to patients. These difficulties may be traced back in large part to the laboratory models used to create new medications. It is common practice to perform preclinical experiments on cell cultures and animals before moving on to human clinical trials. Both have trouble accurately simulating the inside circumstances of the human body. Tissue function, including cell–cell interactions and the dynamic nature of real organs, cannot be fully recapitulated by cell cultures in a Petri dish. Furthermore, animals are not human beings; even minute genetic variations across species may have profound physiological consequences.

In the case of cancer treatments, only around 8% of those that show promise in animal research really make it to human clinical trials. These costly and often dangerous late-stage failures occur because animal models seldom predict therapeutic effects in human clinical trials. Researchers have been working on a potential model, organ-on-a-chip, that may more precisely imitate the human body in an effort to solve this translation challenge¹. For the better part of a century, serum or extracellular matrix molecules have been used to coat two-dimensional (2D) substrates in order to maximize cell proliferation when live human cells have been cultivated in nutritional solution under static circumstances. Many experts in the area doubt the physiological significance of findings from in-vitro experiments since stimulating cell proliferation is frequently accompanied by the loss of tissue-specific functions. As a result, the discipline of microphysiological systems has developed to focus on the creation of culture methods that can better maintain tissue functioning for longer intervals in vitro.

The fields of microsystems engineering, tissue engineering and stem cell biology have all contributed to the creation of microphysiological systems. This has led to the development of several microscale culture system designs that can restore previously unachievable levels of tissue and organ function. To achieve better biological mimicry, researchers have taken one of two broad approaches to developing microphysiological systems: (1) developing more structurally complex static 3D culture systems, or ‘organ chips’ or (2) engineering microfluidic 3D culture devices that also incorporate dynamic fluid flow.

These biomimetic microfluidic devices have become more complicated despite their little size. Adapting a bioengineered skin equivalent that is constantly perfused via a microvascular channel has been a primary focus of organ-on-a-chip applications for skin-centred models. Human skin equivalents, human ex-vivo skin and hair follicle cultures all lived far longer in the organ-on-chip than they did in static 3D cultures, according to research by Ataç et al. ². Moreover, the chip cultures showed less tissue disintegration. While there is still a way to go before this technology can be fully used for wound-healing investigations, the power of a multi-level, organ-on-a-chip skin analogue has already been shown. The remaining challenge is to replicate the original skin’s three-layered architecture on a single organ-on-a-chip, complete with sensory organs, appendages like hair follicles and sebaceous and sweat glands, and a comprehensive vascular network. When completed, this will allow for more effective therapy screening approaches for wound-healing problems by being incorporated onto multiorgan chips that replicate the original environment of an entire organism.

One major benefit of these chips is that they are inexpensive to produce, which means that the effectiveness of a therapy in a variety of concentrations may be tested. As a result, scientific progress will be accelerated greatly thanks to organs-on-chip technology. The initial set of testing for a new medicine may be repeated several times without jeopardizing funding. There also would not be any of the ethical problems associated with animal experimentation³, which are becoming more pressing in modern culture. Growing controversy surrounds the intentional breeding of test animals for use in medical research; organs-on-chips might resolve this controversy once and for all.

Since the micro-environment of human cells (oxygen levels, temperature, pH) is crucial to the validity of the experiments, it is typically more accurately duplicated within a chip than in a Petri dish^4,5. Organs-on-chips are more intriguing than traditional 3D cell cultures because they can subject cells to chemical time gradients, which is not possible with traditional 3D cell cultures⁶. The utilization of microfluidics makes organs-on-chips an attractive and novel alternative for study more so than their 3D nature.

Microfluidic chips, which are used in organs-on-chips, are designed to be user-friendly, portable, small (about the size of a euro coin) and mass-producible. As a result of its miniaturization, numerous microfluidic systems may be combined onto a single chip, which reduces the need for extra space, materials and resources¹. When compared to competing technology, microfluidic chips provide several benefits. However, there are still some problems.

Microfluidic devices are on the order of a tenth of a micrometre in size, hence surface effects greatly outweigh volume effects. The phenomenon has a few benefits (such as trapping molecules of interest), but it also has some downsides, such as the adsorption of products of interest on the inner linings, which might compromise the quality of the analysis.

Furthermore, the Reynolds number will always be very low, below 1, for the relevant fluids in microfluidic dimensions. As a result, there will not be any turbulence in the flow when it enters the chips. This flow does not favour mixing, but it does allow for exact control of experimental conditions.

Finally, the buzz about portable microfluidics seems likely to level down. Reliable analysis requires the use of often cumbersome equipment, such as in the processing of pluripotent-induced stem cells, a cornerstone of personalized medicine. However, this final issue might be addressed by building on-chip measurement capabilities.

Using organs-on-chips systematically would help the pharmaceutical business save time and money, and it would also reduce the need to produce animals for clinical testing, as shown by this review. The chips have the potential to become powerful research accelerators if they enable researchers to run many early-stage experiments much more quickly. Despite the repeated successes of organs-on-chip technology, and the fact that some of these applications are now in use, we are still quite a ways off from creating a fully functional human on chip. It is now too difficult to link the organs, and research in this area must wait for advances in biology. Those chips are still useful for prioritizing drugs to test in the meanwhile. If we can iron out the kinks, this technology might pave the way towards universal access to personalized medication. Depending on a patient’s stem cell profile, the optimal dose of therapy might be administered.

Ethical approval

No ethical approval is required for correspondence.

Consent

Not applicable.

Sources of funding

No funding was received.

Author contribution

H.C. and S. C.: writing original draft and conceptualization; S.A., C.C., and K.D.: review and editing.

Conflicts of interest disclosure

The authors declare no conflicts of interest.

Research registration unique identifying number (UIN)

Not applicable.

Guarantor

Shopnil Akash.

Data availability statement

No new data sets were generated during the study.

Provenance and peer review

Not commissioned, externally peer-reviewed.