Organs-on-Chips

Hardin Young: Welcome to Short Talks from the Hill, a research podcast from the University of Arkansas. I’m Hardin Young, and I’m a writer here at the university. Today I’d like to welcome Kartik Balachandran, associate professor of biomedical engineering. Balachandran’s research focuses on the development of microphysiological systems, also known as organs-on-chips. Balachandran has been with the university since 2012 and he’s busy working on several grants, including three from the Department of Defense, two from the National Institutes of Health and one from the National Science Foundation. Kartik Balachandran, welcome to Short Talks.

Kartik Balachandran: Thank you for having me.

HY: So, let’s just start with the basics. What are organs-on-chips and what makes them useful for research?

KB: Right, so organ-on-chip systems are basically what I would call an upgrade from your regular two-dimensional cell culture systems that are quite commonly used all across biomedical research. And what it does is it tries to recapitulate the three-dimensionality, the different cell types, all the different matrix proteins and other components that exist in organs to try and create a more complex model that one can use on the laboratory bench. And so this would, you know, include things like having multiple cell types interacting and talking to each other in a an experimental model, incorporation of things like blood flow or mechanical stimulation if that organ in question is, you know, dynamically moving, like the heart.

HY: So why are you guys using this as a research model? What makes it useful?

KB: Yeah, so I think the main motivation for using these kinds of models is that it is a much better mimic of what goes on inside the body. Short of using animal models, or you know, other sort of living models, organ-on-chip systems include and incorporate multiple different things that make an organ system more dynamic and it makes it more realistic. And so it’s for those reasons that we like that – at least in my research lab – we like to use these organ-on-chip systems because we think it’s a better mimic of what happens inside the body. Secondly, we can engineer these organ-on-chip systems using human cells and so that already gives it what we can consider an upgrade from small animals like mice or rabbit models. For these two reasons, I think organ-on-chips systems are advantageous in the laboratory compared to other models that are out there.

HY: So not only does it mimic human biology but it also eliminates… you could say it’s more humane… it eliminates animal testing.

KB: That is true. That is correct.

HY: How did you get into this?

KB: That’s a good question. So, I did my PhD at Georgia Tech, and we were using mostly animal-based cell and tissue models. And when I went on to my postdoctoral fellowship at Harvard University, that’s where I got introduced to this field of organ-on-chip systems. And there was a group there that was working on a lung-on-chip system, and I came in there with the view of creating a heart valve-on-chip type of system. And what I saw very quickly was the advantages of these organ on chip type of systems, like I was mentioning just before, and the possibility of learning some of the skills that these other research groups are using and trying to build these three-dimensional systems to incorporate different cell types, blood flow, and so on and so forth. Also, in that ecosystem, in and around Harvard, we had the opportunity to talk with folks from the pharma industry, with folks from other research groups, and I did see that there was a keen interest in these types of organ chip models, and how they could become more applicable for drug testing, understanding disease mechanisms. And so all these various factors motivated me to really dive into this line of research, you know, once I came here to the University of Arkansas.

HY: Okay, so let me ask you this. What organs are you specifically focusing on in your lab?

KB: Okay, so we’re mostly trying to understand organs which are dynamically moving around, because my background is in mechanical engineering, and I’m always interested in what the intersection of mechanical motion and forces are with disease. And so keeping that in mind, we’re looking at organs in the cardiovascular system, specifically the heart valve, and so we have a heart-on-chip and a heart valve-on-chip that I have, you know, one student each working on those systems. Another system that we’re working on is the blood brain barrier. So we have a blood brain barrier that is the interface between the blood and the brain and then we’ve developed a blood brain barrier-on-chip to look at the effects of traumatic brain injury and how that might affect the blood brain barrier short- and long-term. And most recently we’ve started working on a nasal airway-on-chip model. That is a project where we’re looking at the effects of particulate matter pollution and how that might affect nasal epithelia and any downstream effects that might have on the nasal biology.

HY: Okay, let’s just take an example of… we’ll use the blood brain barrier chip. Can you talk a little bit about how do you, in broad terms, how do you build a working model of the blood brain barrier? What are some of the broad steps you would take?

KB: So that’s a great question. We always start with, you know, what’s already available in nature. So that is the actual blood brain barrier. We typically begin first with a very deep dive into how the blood brain barrier is – you know, I’m going to use the word engineered – but how it’s made, from a perspective of what are the cell types? How are the cell types arranged? A very important question is “what are the length scales involved?” You know, how far apart are the cells from each other or how close are they to each other? Are there any barriers and how thick are the barriers between these various cell types? So once we have – and all this can be obtained from either from our clinical partners or histological, histopathological collaborators that we work with – and then once we get that information, then we ask ourselves in our research group how can we boil that down to a simple model that is feasible for engineering in the laboratory but at the same time incorporating some of the different complexities that exist that can give us some useful information. And so based on that we narrow it down to two or more cell types, a couple of different proteins that make up the overall matrix that these cells are growing in. We know the blood brain barrier involves blood flow and so we have to analyze what are the flow rates, what are the shear stresses, how big are the blood vessels in the blood brain barrier and you know can we build those kinds of structures in the lab. And so once we have a good understanding of the so-called “technical requirements,” we can then translate that into things that we can actually build on the bench. Once we’ve built it, then of course it’s an iterative validation step. So we examine its performance based on different engineering biological markers and then we see whether that mimics the actual real blood brain barrier. And then if it doesn’t, you know, we do a version two and so on and so forth until we feel we have achieved something that reasonably mimics what’s seen in the body.

HY: What kind of timeline does that typically – I mean, it may not be easy to generalize – a but how long would it typically take you to get like a solid working model?

KB: So, you know it’s a good question. You know, as researchers we’re always trying to get the perfect model, right? But sometimes we have to accept that you can’t get that 100% perfect model. And so typically this process would take a couple of versions of iteration and, you know, may take anywhere from six months to 1 ½-two years to get a model that’s working. And then once we have a working model while we’re using that model to ask questions – ask research questions – the iterations don’t stop. So we keep trying to improve on it, and at some point in the future we can get a version two or version three that is you know working better. And so all these things are working in parallel all the time. But to answer your first question, you know, it typically takes 6 to 24 months.

HY: So that’s to get a working model and then you can get increasingly more specific in what you study after that?

KB: Exactly, yeah, so we can study the effect of you know the communication between the different cell types, effects of traumatic brain injury. We can model transport of molecules across the blood brain barrier before and after injury. So we can do a wide variety of things with these models.

HY: I think that probably set up my next question, which is you’ve got a couple of grants with the blood brain barrier. One of which is to study traumatic brain injuries but there’s another one that’s got a commercial aspect. Can you talk a little bit about how this technology might be commercialized for broader use?

KB: Right, exactly. So, to refer to what you were talking about the grants, so we have a couple of SBIR and STTR grants together with a local start up here, Nanomatronix, with the ultimate end user being the Department of Defense and the Air Force. What they are interested in is being able to use this as a model to test various military-relevant insults that might happen to – in the case of the Air Force pilots or soldiers in the case of the army – following traumatic brain injury. So what we’re doing is we’re trying to create this model to be of relevance to them by using human cells, being able to inject any sort of chemical insults, and also using traumatic brain injuries that are of relevance to these different target populations. So essentially it’s not very different from a research oriented project but just some of these stimuli that we’re looking at that we can impose on the blood brain barrier chip model is slightly more relevant to the military context.

HY: So you’d have like a base model that they can adapt to their special needs?

KB: Exactly so. The idea here is we can build a model and we can ship it off to them and then they can either put their cells of interest and, do whatever experiments they want. Or we would have the cells and we would do the testing for them. And then, you know, we would ship it off and they would do their biological analysis. And that’s sort of the broad commercialization aspect of this whole thing.

HY: So one last question and it’s something we were kind of talking about offline. You said that you think that you’re really seeing this field accelerating. Could you chart out where you think it’s… where it’s going? Or even if you want to be more specific about what’s going to happen here on campus in your department?

KB: Okay, yeah, so I think you know like I said I mentioned this field is really expanding, it’s an exciting time to be in this particular field. And in terms of where I think this field might be going it really is A, to use more human relevant cells in these various models, whether it be the lung, the kidney, liver and so on and so forth. So what is really helping that is the increased prevalence of what are called induced pluripotent stem cells. These are stem cells that can be obtained from skin biopsies and so it at least goes around some of the ethical concerns that stem cells typically have. They’re taken from consenting patients from skin biopsies and then they are reverted back to a stem-cell like state and then can be made into different organ and cell types. Now there are many groups that are working to try and differentiate these induced stem cells into different cells of different organs. So we can take those and put them in these organs-on-chips. And B, the second place where organ-on-chips or the field is going is, I would say, in the combination of different organs, you know, putting them together. So this would be combining the lung or nasal chip with a heart chip, combining the heart with the gut or the liver, and putting all these things together and seeing if you can create, essentially, an overall sort of a human organ system on a chip and to try and interact those things together. And so towards that end some of the things that we hope to do in the future is maybe combine one or more of our organ systems together – mainly the nasal airway lung with the heart, for example, and to see if we can create a model of a breathing human oxygenating the blood and back and forth and try to see if we can look at diseases that affect those overall mechanisms.

HY: So like examining increasingly complex relationships?

KB:  Exactly, between these different organs and tissues in the body.

HY: Kartik Balachandran, thank you for coming in.

KB: Thank you for having me. This was great.