The Vision for Multi-organ Human-on-a-Chip Models

Many factors are considered when designing the appropriate human-on-a-chip model including the compound of interest, previous literature & observations, and the target tissue of the compound. For these reasons, we have found that we are most effective for our clients by operating as a service-based company, allowing pharmaceutical partners to design customized human-on-a-chip studies.  

MW: Can you tell us about the serum-free blood surrogate solution? 

JH: The use of serum has many drawbacks, including batch-to batch-variability and its undefined contents. This is because serum is collected from calf fetuses in a slaughterhouse, in most cases with no quality control. These drawbacks make reproducibility and transferability of data collected by its use difficult.

We have created a serum-free medium formulation that enables the in vitro culturing of a wide range of cell types up through several weeks. This formulation supports cardiomyocytes, multiple cancer lines, hippocampal neurons, motoneurons (MNs), sensory neurons, skeletal muscle, NMJ (neuromuscular junction) formation, hepatocytes, endothelial and epithelial cells, among others. For obvious reasons, we hold the detailed formulation close to our chest.

MW: While animal models have their limitations, in vitro models do too – do you think that human-on-a-chip models can remove the need for animal research in some settings?

JH: As pharmaceutical companies aim to tackle more complex diseases, the companies are faced with higher failure rates and larger investments lost. The net result is that only 1 in 1,000 new compounds will make it to approval, most of which will fail during animal testing. Even for the ones that make it through animal models, 9 in 10 will fail during human clinical trials. One reason for high failure rates is the continued reliance on animal models, which can be poor predictors of clinical results, especially when testing therapeutics for more complex diseases. For example, because humans have different genes than animals, when testing therapeutics for genetic diseases, animal models often give inaccurate predictions. Billions of dollars are wasted annually on drugs that could have been pre-screened and accurately predicted to fail. There are still many benefits to using animal models, but pharmaceutical companies are actively seeking ways to gain more information about their compounds before clinical trials.

We believe that in vitro body-on-a-chip systems are capable of producing more accurate predictions for drug action in the human body than animal experiments. Animal metabolism can differ substantially from human metabolism. This becomes evident when looking at the drug development process. For every 50 drugs that are safe for use in animals, typically only one drug proves safe for use in humans. This is an ethical dilemma, not only in terms of use of animals, but also for the patients involved in clinical trials. Using PBPK (physiologically based pharmacokinetic) models of the body-on-a-chip system and of humans, we can then convert the data obtained with the in vitro systems to make predictions for human beings.

While we do believe these human MPS models will eventually replace animal testing, there are quite a few hurdles to overcome before this can happen. Some of those hurdles are scientific, including the further development of certain organ models or, in some cases, increasing the complexity or architecture of current models.  Others include changing the regulatory mindset towards acceptance and reliance on the data generated. In the short term, we believe these systems are meant to supplement animal models and eventually to replace them or limit them to early rodent toxicology studies.

MW: There is significant physiological heterogeneity between people – how do you account for this in organ-on-a-chip models?

JH: We agree that there is significant heterogeneity between groups of people and this should be accounted for in the validation of these models. One of the beauties of these systems is that we can use human iPSCs (induced pluripotent stem cells) to derive certain phenotypes, or even samples from individual patients, and test molecules based on those groupings. For example, currently some drug compounds such as warfarin come with a black box warning that requires a genetic phenotyping to determine whether you are a high, low, or intermediate metabolizer of the compound based on point mutations in the CYP2C9 gene, which unfortunately was discovered after the fact. It is possible to test variants such as those within these MPS models and identify potential populations at risk, as well as tailor the therapeutic index per population.

MW: What has been the biggest challenge in the development process, and how did you overcome it?

JH: There have been two major hurdles to the development of these systems. The first was taking the prototype systems from a small laboratory scale to large production with increased automation. Thankfully, we received NCATS SBIR (National Center for Advancing Translational Science Small Business Innovation Research) Phase II and Phase IIb grants to help in this endeavour.

The second is getting the industry and the FDA to fully realize the usefulness of these systems and change the dogma surrounding drug development approaches; there is steady progress towards the acceptance of human-on-a-chip models in drug discovery.