Organ-on-Chip Technology: Current State and Future Developments.

In the early days of pharmacy, the development of new drugs was frequently achieved by restless chemists who worked solitarily, day by day for years [...].

In the early days of pharmacy, the development of new drugs was frequently achieved by restless chemists who worked solitarily, day by day for years. As an example, it took two intensive years of work for Friedrich Sertürner to isolate and purify the pain medicine morphine, a drug derived from a mixture of substances known as opium in the year 1804 [1]. In those days, chemists tested the newly isolated or synthesized formulations by giving these to animals found in the vicinity of their laboratory, whether these were frogs, mice, or dogs. The dosing was adjusted just to be “sure” not to cause severe toxicity or death when scientists applied these newly synthesized chemicals on themselves or volunteers. Over the last two hundred years, science progressed enormously. Classical pharmacology can now utilize cells in culture for the screening of various small molecules (potential drugs) so that their therapeutic value can be identified. New drugs are now also searched or assessed computationally (in silico). Further, the human genome has been sequenced and is thus known in depth, a prerequisite for computational approaches that aim to recreate human physiology; the objective is to find possible candidates with therapeutic potential, and for that, large libraries of compounds are screened. In this in silico search, some important parameters are included to ensure better drug affinity, bioavailability, metabolic stability, and fewer side effects (selectivity). After the identification of a suitable compound, the new chemical formulation undergoes rigid pre-clinical research on microorganisms, eukaryotic cells in culture and living animals. The new chemical entity will be tested for its toxicity, safety, pharmacokinetics, and metabolism. Only then, after successful demonstration of the required effect without causing toxicity, can the regulatory approval be given to move into clinical trials (Phase I, II, III, and IV in humans). Two centuries ago, it took two years alone for the isolation of an active substance by one chemist. Nowadays, pharmaceutical companies seek to accelerate drug discovery. However, the development of new drugs still takes a minimum of two years and is now performed by groups of scientists and associated with costs of hundreds of millions of dollars, and in extreme cases over a billion of dollars [2]. Yet, the discovery of new pharmacologic active compounds is not performed by screening one substance after the other but in parallel and with the help of advanced in silico and in vitro methods (i.e., alternative methods) that were far from being available 200 years ago and, most notably, without risking lives.

These alternative methods have the potential not only to precede animal testing and add information but also to replace animal experiments completely. The many established cell lines derived from cancer tissue or by directed genetic modification contribute to straightforward screening approaches. Furthermore, due to advances in cell culture techniques and close collaboration with clinicians, more and more work has been done on primary cells obtained from patients or healthy donors. While conventional cell cultures use homogeneous cell populations cultivated in monolayer under static conditions, the development of Organs-on-a-Chip (OoCs) will enable more sophisticated systems that mimic organs, tissues, or whole organisms.

To reproduce physiological conditions, a whole battery of parameters needs to be considered when maintaining cells in culture. Temperature, acidity, air composition (O2, CO2), and even mechanical forces—these are all parameters that can be controlled in smart wells or microchips. The development of silicone, plastic, and glass chips and related microfluidic control systems push the boundaries of science and open up unseen potentials. The on-chip control of environmental parameters, the precise application of drug molecules, and precise readouts are now possible and help to cultivate and analyze cells and tissues in a more physiological environment. OoC technology is being employed by a growing number of laboratories worldwide. A variety of chip designs allows for the simulation of virtually every tissue in the human body, including the heart, lung, kidney, bone, and gut, among many others. The combination of various organ models on-chip facilitates a better understanding of a drugs’ action in a precisely controlled physiological environment. Further, multi-organ systems also take intermediate steps such as metabolism or barrier-transfer into account. The on-chip comparison of animal and human tissues will also help to understand species-specific differences and thus improve estimates on drug action in humans. Ultimately, a human-like system on a chip may be created, in which drug metabolism and effects on other organs can be determined. With the development of personalized medicine, tissues and cells from heterogenic origins can be used on OoCs; we can thus expect the rising need for ethical clarification and for laying down the regulations to use these cells and tissues.

In this special issue of Genes, we gathered research and review articles that cover new technological developments in the OoC field. These include novel engineering approaches in OoC manufacturing, new developments in sensor technology, and the use of OoC systems in the discovery of new drugs and their efficient delivery. Using primary cells facilitates the physiologic modeling of healthy and diseased tissue while taking the heterogeneity in genetic backgrounds of humans into account. Yet, utilizing this material is connected to ethical and legal issues that will also be addressed. Furthermore, this special issue includes reviews that focus on specific OoC systems such as lung and bone.

We can foresee a great future and a variety of applications for OoC. Drug testing, toxicity studies, pharmacology, cosmetics industry, cancer research, and material testing for implants are just a few of the fields that could benefit from this technology. Of course, there is a long way to go before reaching these objectives. Microelectronics and microfluidic control systems are being constantly improved and developed further. Major challenges for the coming years include a better understanding of cell–material interactions and the exact recreation of physiological parameters of the tissue of interest. Sharing the advances in this special issue will help to develop the OoC field. We thank the authors, reviewers, and editors for their commitment and for sharing their knowledge in the form of reviews and original data articles.