CONOR: Dodi in our last episode, we talked about organ on a chip.
DODI: That's right and how it is well suited to be used in preclinical trials for newly discovered drugs or therapies. And we talked about how that's more beneficial than animal test models.
CONOR: Exactly, we laid the groundwork of what organ on a chip technology is. And since we talked about that, with our former colleague, Jan, we've done a lot more reading on science.org about organ on a chip technology. The reading is in the show notes. We've made some more calls, and there's just so much to talk about.
DODI:Well, let's get started then with today's episode of Discovery Matters.
CONOR: The story of today's discovery starts with some scientists who wanted to make biomimetic three-dimensional environments to study cardiomyocyte cells. That's a lot of big words, but it's essentially a simulated heart to experiment how a real heart might react to certain treatments or therapies. So first...
CHRISTOS MICHAS: I'm Christos Michas, I am a research and development scientist and engineer at Curi Bio, that's an organ and chip technology organization. My background is in electrical engineering and biomedical engineering. I work on integrating different technologies to facilitate the interface between the technologies and tissues for various applications, namely organ and chip technologies at the moment.
CONOR: And we were joined by...
ALICE WHITE: I'm Alice White. I'm a professor of mechanical engineering at Boston University. I spent the bulk of my career at Bell Laboratories, the R&D arm originally of AT&T and my background is in nanotechnology and nanofabrication. My laboratory uses two-photon direct laser writing to create structures of interest to advance the field of tissue engineering.
CONOR: So, Dodi, maybe our listeners don't know, and why would they, but the name Cytiva was a product many, many years ago, owned by our former company. It was the product name for an embryonic stem cell derived cardiomyocyte drug toxicity testing platform. So, it's just a real joy to see the science behind that idea and behind that name live on. This chip is known as the miniPUMP. It's a scaffold created through a very special kind of 3D printing direct laser writing, which is an additive process. It has a beam of photons crossing at exactly the right place inside the resin to make it go hard.
ALICE WHITE: It's actually one beam, but the intensity in the focus point of that beam in the resin – the coincidence of two photons – is what exposes the resin. So, the resin is transparent to the single photon, but solidifies at the focal point. And that focal point is determined by the two-photon cross section, if you will, so it's sub-micron and can be a few 100 nanometers.
DODI: So, in terms of creating their cardiomyocytes, how different was the process? Did they have to modify the cell culture media they used?
CHRISTOS MICHAS: The development of the miniPUMP was in a sense oblivious to these details. If you have cardiomyocytes, the challenge and the innovation of the miniPUMP is to assemble them in the proper 3D structure so they can produce the functional output that we want. So, we use one of the protocols that was already established in scientific literature, any other protocol could be used, and additional cells could be added. So, I think we are providing more of the context in which the cells can function as opposed to the cells in this study.
CONOR: You can read more about the methods and processes on the science.org article in the show notes, as we said, but conversationally Christos described for us how they had to convince the cells – I love this idea of convincing, coaxing cells – how they had to make them adhere and stick to the resin.
CHRISTOS MICHAS: I think we were also very fortunate in the sense that the material that we're using, should have some specific mechanical properties, because we care about the mechanics, and it should also be biocompatible. These are the requirements for this system. Otherwise, beyond that, for the cells we do provide a hydrogel that they can reside in, but they are also in contact with the resin and with the 3D-printed material. As long as the material doesn't impact the viability and function of the cells, then this is good enough for a system. One could imagine that as we further develop the material science behind this project, we will have more complex materials that actually encourage the cells to organize in a specific manner, or they encourage specific cell types to organize in specific manners to give cell type-specific structures within the tissues. So, you can see how we could work further into that. But the first aspect which is the mechanical component, that's the one that we mostly addressed in the study that had not been done before, at such a small scale.
ALICE WHITE: There was a lot of engineering involved, Christos's original idea was to use a cylindrical scaffold, which had auxetic properties. So negative Poisson's ratio, meaning that the structure when it was compressed in one direction is also compressed in the other direction, that was to amplify the function of the cardiomyocytes beating. But that structure just did not have enough strength to withstand the compaction of these cells. You have to understand at this scale materials behave very differently than they do in bulk scales. So, he had to engineer a structure, and he used modeling to inform what would only compress in the axial direction and not collapse in the radial direction.
DODI: Oh, my goodness! You've got to put this into everyday language for me, Conor.
CONOR: Yeah. So first off, look at the interdisciplinary work again. We keep coming back to this in these current episodes, with so many disciplines working together. But really a large part of this has to do with what the heart actually does. It just pumps blood. It draws blood from one side of the vasculature of the body, and it pushes it to the other side. So, to do that, it has some structural elements. It's the muscle, and it has this cavity-shaped ventricle, and it’s that cavity that contracts and propels the blood. It also has valves that regulate the direction of the blood flow.
CHRISTOS MICHAS: If we are to model on a chip the pressure patterns that the heart experiences – the flow of the blood – we need those structural elements. And because we're talking about such miniaturized models, we're talking about something a device that will be smaller than a coin. You have to be able to build mechanical components that replicate the function of the structural elements of the heart with such fine resolution. So that's where the technology comes in. We are able to make a 3D heart cylinder on a chip that can actually contract and can also store blood and its volume to propel it. We can also make valves that control the flow that the tissue generates on a very small scale, thanks to the fine resolution of the 3D printing technique that we're using. So, I think the difference in our system is that we are proposing a way where this technology, which has been validated in other applications, can also be used in organ and chip technology and can improve the scope of features that organ on a chip models can include.
DODI: Hey, I'm starting to see it now. Where do Alice and Christos go from here? What are the challenges that they need to overcome?
CONOR: One of the challenges as with any system in this field is standardization; building a system that is designed to do exactly what you wanted to do. It needs a lot of work in a repeatable manner. And of course, people need to know that the organ on the chip is doing exactly the same thing in every environment and that standardization can help it get taken up by the industry.
DODI: We love to talk about scaling up and scaling out. The repeatability is really basic scientific method kind of stuff that we're coming back to. But Christos, like you were saying about the interdisciplinary activity here, that is what Christos believes is going to be the kicker here.
CONOR: It's going to be the magic sauce!
DODI: Yes, you're right.
CONOR: This is really helped by the fact that this was such an integral interdisciplinary approach. Again, we've talked about the disciplines within science, they're just artificial walls in our minds, right?
CHRISTOS MICHAS: So, the cell materials need to be standardized, the fabrication methods to make the system needs to be standardized, and the systems that monitor the tissue and extract data from it need to be standardized. This is a challenge not necessarily for Alice and I, this is for the entire community. We need to come together and build the infrastructure so the entire field can have a stronger commercial aspect. For our system specifically, I think something that we would look into would be the fabrication scalability, so being able to make many copies that are in theory identical in a fast and efficient manner.
CONOR: So, this is really about having diversity in our researchers doing the work.
ALICE WHITE: Back to my background at Bell Labs, which was a place that actually flourished because of the diversity of backgrounds of the people coming to the institution. In fact, I joke that no one ever asked me what my degree was in, they only wanted to know what I could do. Because of that diversity, I think we had very innovative solutions to very challenging problems. It was interesting coming to a university, because I think of universities as being hotbeds of innovation. But there are some very institutional structures, which can be barriers. In fact, the College of Engineering here at BU has a relatively low barrier between departments. So, it was an opportunity for this kind of work to flourish.
DODI: In our previous episode, Conor, talked about organs on a chip, we looked at these organs on a chip and this technology, and we compared it to testing drugs on an animal model. So, let's do the same thing with this miniPUMP technology. How do we compare those?
CHRISTOS MICHAS: You will be able to have more than typical animal experiments. I think organ and chip is somewhere between the initial cell culture experiments in the animal, in the sense that it will give you more information, but with fewer replications. I would imagine someone having 48 or 96 wells. Then it's up to the standardization that I was referring to, to what extent how many of those 96 wells would one have. This is the challenge that the field needs to address. So being able to scale up so we can test more candidates. In an ideal world, the systems will be so accurate that we could eventually phase out animal models or as part of the clinical trials, but we're still not there yet. This is what we're still working on as a field.
DODI: And as Christos see this as a technical challenge?
CONOR: Well, it's partly technical, but it's also about the limitations that we place on them in this conservative industry and it’s for the right reasons. Patient safety is at the heart of all we do. So, we've got to be careful.
CHRISTOS MICHAS: I think it's both. I think one of the challenges is that we don't understand the biology that we're modelling as well. So, we need to have a better comparison. What is the anticipated output of the system? We know that we see it in humans, but we can't run control experiments in humans to see exactly this is the factor that's most critical for this drug, and animals are not humans, right. And as the science behind the organ on a chip, not the technology, also develops then we would be able to resolve issues.
ALICE WHITE: Yeah, and I see a wonderful sort of circular thing happening where this development of this little miniPUMP could actually impact the science in the sense that if you could change the afterload, and the preload, and watch the effect of that. If your stem cells came from someone that had a genetic disease, you could model that disease in this pump. As we try to understand exactly what are the cues that impact the formation of organized heart tissue and what actually causes the disruption of the heart function, that will feed back into the technology as well.
DODI: So how does this miniPUMP differ in comparison to other organs on a chip?
CONOR: Well, this was the question I put to Alice and Christos. Why is this one going to really make a difference in a way that perhaps you know other flavors of organs on chips are less impressive, and there really is one important reason that Christos and Alice are focused on.
CHRISTOS MICHAS: So, on one hand, cardiac disease is one of the leading causes of death in the industrialized world. So, there is a lot of interest in understanding how this disease emerges, or how we can develop therapeutics. Heart on a chip, so an organ on a chip that's focused on the heart, is a research tool to enable these therapeutics and this research to happen. On the other hand, something that is also a little bit special about the heart is that if we can ignore this disease and we have a healthy heart, but we have a disease in some other organ, when we introduce drugs for other organs, it's possible that they will interact with the heart in a negative and harmful manner. So, we need to be able to predict what the side effects of drugs on the heart are.
CONOR: And that is a major concern for everyone in the biopharmaceutical industry.
DODI: Okay, so this chip could apply to any newly discovered drug or drug that is undergoing development. This miniPUMP, this heart on a chip, is more versatile in where it would be used, and in what type of research it would be used.
CONOR: Exactly. This means researchers can study things such as high blood pressure and how it affects heart tissue, for example.
DODI: I'm having flashbacks to our episode about the Framingham Heart Study.
CONOR: Exactly.
DODI: What does this mean for the future? Let's ask Alice.
ALICE WHITE: The main objective of CELL-MET, our engineering research center, is to develop a patch of cardiac tissue from a patient's own stem cells that would be used to repair a heart damaged by a heart attack. So, it is in fact to implant and replace those cells. The challenges there are vasculature, and the electrophysiology. So, this work is a step in that direction, and that is the main goal. It's a 10-year program, so not to minimize the challenge of it.
DODI: Sounds like there is a lot more to come from this team.
CONOR: And yes, I'm following this really closely. It's super exciting.
DODI: And it's a great story on collaboration right there at the forefront of an emerging field. Super cool.
CONOR: Definitely. And you know, it's on their shoulders that the future researchers within their field will stand. It's the beginnings of something, they're laying the groundwork for amazing things.
ALICE WHITE: I say all the time that this opportunity for me – that sort of came in the last decade in my career – has been such a gift. The chance to work on something that could be so impactful. I get excited every time I see a video of cardiomyocytes beating it's just unbelievable.
CHRISTOS MICHAS: I think the most interesting part is that this is also an emerging field and so there is no way to anticipate what you're going to see next. It's an adventure you know!
DODI: The only thing I'm wondering is when are they going to bring machine learning into this picture.
CONOR: Okay, and maybe the microbiome, and a mushroom or two, it would be great interdisciplinary adventure with it.
Our executive producer is Andrea Kilin. And this podcast is produced with the help of Bethany Grace Armitt-Brewster. Editing, mixing and music by the marvelous Tom Henley and Banda Produktions. My name is Conor McKechnie.
DODI:And I'm Dodi Axelson. Please rate us on Spotify or wherever you're listening to us. We do have a poll on Spotify and that would help us make every episode better. You can find it under the episode description. Looking forward to hearing from you. And we'll see you next time when we come back with another episode of Discovery Matters.
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