One idea that I didn't quite get to when I talked about the biotech trends I was most excited about for 2018 was organ chips. But that doesn't mean I'm not excited about them!

These microscale models that simulate human physiology are being used to personalize drug prescriptions and dosing, study the progression of disease, and even model the fundamental processes by which progenitor cells grow and develop into functional tissues.

Earlier this month, I attended a Keystone Symposium on Organs- and Tissues-on-Chips in Big Sky, Montana—possibly the most remote place I've visited for a scientific conference, but well worth the multiple plane flights and van rides. Here are a few of my takeaways from the biotech perspective.



Variability is a critical issue

And there are a lot of variables in organ chips.

First, each organ chip starts with some manner of progenitor cells, typically induced pluripotent stem cells (iPSCs), though practitioners will be quick to tell you that iPSCs are not always the best or most biologically suitable starting point, even if they're reasonably convenient and easy to work with.

Even though iPSCs have been reprogrammed with the ability to differentiate into many different kinds of cells, every iPSC was derived from a human at some point in its ancestry. While we've made a lot of progress in creating truly synthetic eukaryotic cells, the technology isn't available yet to mass produce synthetic pluripotent cells, so we need to find a way to account for the variable human background of each batch of cells. Thinking about it this way, it seems obvious that if you start with iPSCs from two different human sources, even if you treat them in the exact same way, you will not necessarily produce two identical tissues.

Another source of variability is the almost artisanal nature of creating organ chips. Right now, when a laboratory wants to make an organ chip, it creates one from scratch that happens to be perfectly tailored to the situation it wants to investigate. This method is great for creating reproducible data in the context of a single study but is hopelessly low-throughput for creating a scalable technology accessible to clinicians. Fortunately, some research groups are already beginning to work on automated manufacturing approaches to creating organ chips, so that at least dimensions and materials will be standardized.

Intra-lab variability, though, is arguably trivial when compared with inter-lab variability. Operating two identical chips under a given set of conditions in Boston and Houston is by no means a guarantee that they'll produce the same physiological responses.

When I spoke with Randy Rettberg of the iGEM Foundation last year, he opined that the reproducibility crisis in biology is a consequence of laboratory biology being a "craft industry": different scientists have different names for the same instrument, culture medium, or even cellular receptor, and everyone uses house-made reagents tweaked in a way that works for their own lab.

There's a similar sentiment in the organ chip field, which is why the NIH has funded research institutions across the country to perform massive inter-lab validation testing. Some in the field are skeptical that these efforts will actually solve any problems, but everyone seems to agree that it is critical for organ chips to be useful and practical outside of a developer's own lab.





Multi-organ chips come with unique challenges but nearly limitless possibilities

The human body is not, of course, a collection of single organs working in isolation. How organs are connected and how they interact with each other is obviously an important property to consider, but these questions can be easy to overlook when you're more immediately concerned with cell differentiation, fluid flow, imaging, and of course reproducibility. It would be trivializing a lot of hard work to say that those problems have been solved, but the technology has at least matured enough that they're no longer the most technically complex problems the field is facing.

Combining different organ chips into organ-systems-on-chips is a problem of exponential complexity, and depending on how you choose to define an organ, you quickly generate an absurd number of possible multi-organ chips. Of course, some of them make more sense than others—I don't think anyone is clamoring for a gallbladder-and-pharynx chip—but there are a lot of combinations that are physiologically meaningful. For instance, combining a heart with a lung on a chip might be an interesting way to model respiration and oxygen transfer to the blood, a liver-and-kidney chip makes sense to better understand how drug metabolites are excreted, and a blood-brain-barrier chip combined with a neuron chip could elucidate brain chemistry and function.

Before any of that is possible, it's important to consider the particular challenges that arise with combining tissue types in the same microsystem. There are biological factors: not every cell thrives in the same medium, responds to the same growth factors or differentiation cues, or adheres to the same matrix. But there are also more mundane physical concerns dealing with partitioning fluid flow correctly to interact with all of the cells at the same time, or deciding how to design connections and valves to avoid the problem of losing all of a metabolite of interest to simple dilution. Some organ chip developers fix that problem by using a robot, rather than microfluidic connections, for liquid transfer—which of course introduces its own concerns about physiological reality.



The great PDMS debate

Until a few weeks ago, I had no idea that a simple carbon/silicon polymer whose biological inertness is one of its greatest virtues would prompt such a heated debate. Poly(dimethylsiloxane), or PDMS, is a material with unusual elastic, viscous, and crosslinking properties: it can easily flow or be patterned into a desired shape with micron-scale "features" and then be treated to maintain that shape practically forever. These characteristics have for decades made it the material of choice for microfluidic devices; despite its potential shortcomings, most of the recent innovations and debates in this space have been on the biological applications side and not in materials chemistry.

It was only upon attending the meeting that I heard a coherent case in opposition: some organic molecules—like the cellular metabolites that many kidney and liver chips were built specifically to monitor—readily diffuse into PDMS devices. This nonspecific absorption has to be considered in mathematical modeling (a complication, but one that can be accounted for), but the PDMS critics contend that the more serious problem is the physiological absurdity of encasing your tissue model in semi-transparent, organic-absorbing rubber and expecting not to lose any molecular information. The counter-argument from the pro-PDMS crowd is that non-specific absorption happens all the time in the body, particularly for organs that have a lot of fat cells in their local environments.

This debate notwithstanding, there's a lot of optimism surrounding moving toward materials that are especially well suited to a given situation. For example, in certain cases, a device's mechanical properties might be more important than its optical properties, so a more opaque polymer might be equally suitable. Sometimes you want to be able to functionalize a device's surface with adhesion or growth factors, so you need a molecularly "sticky" surface; other times, the stiffness of the substrate is what counts, and not what you decorate it with. And if you need durability and transparency but not elasticity, why not just use glass?





What comes next?

I was pleasantly surprised at the diversity of backgrounds and opinions at this conference, which featured everyone from academics and clinicians to regulators and entrepreneurs. The organs-on-chips field has clearly given a lot of thought not only to its science but also to its applications and its relationship to external factors like markets and governance.

So maybe a diabetes patient can't yet go to her doctor, get a cheek swab, and come back a week later to an individualized insulin dose approximated from a fully personalized model of her pancreas. But I don't think that scenario will remain science fiction for long.