Frederic Zenhausern, PhD, MBA, Professor and Director, Center for Applied Nanobioscience and Medicine at the University of Arizona talks about using a plant leaf scaffold for tumor engineering as an alternative to animal models.
Interview conducted by Ivanhoe Broadcast News in August 2018.
Tell me about how you came across the leaf as your scaffold.
Dr. Zenhausern: I have to go back almost two years ago. I was attending a conference of The National Academy of Inventors and I met a student there who was from Boston University and they started to look at new ways of making implants for regenerating heart tissue. They were looking at different scaffolds and they started also to look in plants. When I came back from that meeting I realized that also in cancer research we really had a challenge to look at the tumor, typically a solid tumor because right now we use mostly 2D- two dimensional cell culture. These are definitely not representative of a real tumor because they lack of heterogeneity in different cell types and more importantly they don’t have the rich vasculature network supplying blood to the tumor. Of course nowadays it’s a trend to go in three dimensions. Typically, we can create a partial model using a small microfluidic device allowing to suspend small droplets where you can grow a few cell types small organoids spheroids. But again it’s only a partial model with limited use as tissue are not getting representative nutrients. So one of the key issues is you need to bring in more type of cells growing together into a network with vasculature. That means there is a lot of blood vessels in a tumor. So the concept was can we make a scaffold to create an environment where we will have multiple types of cells, including blood vessels to bring nutrient and so on. The concept of course was wow, take the plant! Because the scaffold of the plant can be used to grow the cells but also now, all the vein and the stem of the leaf could be used as a vascular network system. That’s how we really started the program; we had a summer student last year and we started to grow those kinds of cells and those scaffolds. A particular interest is also to understand the effects of exposure of a tumor to radiations similarly to conventional radiotherapy treatment to better understand the mechanisms of interactions and potential toxicities.
I guess 3D is the biggest advantage of doing this, the biggest evolution of this study. If you would talk a little bit about that?
Dr. Zenhausern: Yeah, it’s the 3D structure that is definitely a key element. But it is also to find that now we can bring some of the nutrients in those kind of level of perfusion that are more dynamic and so realistic. You need to have a leaf that is not too thick because you really want to have all those different component interacting together in space and time mimicking human tissue systems. It’s more complicated than just thinking oh I need just to maintain the cells they will be happy. It’s really creating the environment where the physiology and all of the physical and mechanical properties as well are quite similar. So we can choose now all these elements by using particularly that alternative model prior to go to animals and human, ultimately.
How did you settle upon spinach?
Dr. Zenhausern: Spinach because it was the first model that was published in the literature as well but also it’s because the spinach has a vasculature network geometry that is quite well representative of some of the tumors we are interested to study in prostate cancer, for example. Now in the tumor model we can think about now tuning the geometry of the veins network, and that’s what we are looking at now is building a database of all the different phenotypes of leaves because they have different vasculature system. Some of them are reticulated and some of them are connected. And we hope to try to map indeed the phenotype of the leafs with the different organ tumors that we’ll be studying. Furthermore, genetic engineering may provide us with a rapid method to design specific vein network to understand better how during the angiogenesis of a tumor – meaning during the growth of the blood vessels during the tumor growth – cells are communicating and responding to environmental changes through drug or radiation treatments.
You were talking a minute ago about how you decided spinach was going to be one. How did you get there?
Dr. Zenhausern: Because that was the first model that was well demonstrated with heart tissue. Its physical and materials properties also fit very well for cell growth in terms of the different cancer cell lines that we have been studying. Breast, prostate, now we do of course lung with this project.
But you did a lot of different things that didn’t work so well?
Dr. Zenhausern: Yes we tried different things. The challenge here is how do you do the de- cellularization, that means you need to remove the cells from the plant, be sure that there is no residue coming out of the component of the plant (for example residual DNA and proteins) and then be able to bring back all the human components into those scaffolds. It’s just a lot of work, ongoing work to try to better understand, better control those parameters so we can really also build instrumentation to do that process in a more automated and controlled way.
How do you get the lung on the leaf?
Dr. Zenhausern: The fact that we are here within the College of Medicine in Phoenix where we have a unique opportunity to be working with clinicians and colleagues from the different fields. That’s really when I met with Ken our collaborator when he came with the concept of, if you can do that with that model can we look at the lung disease and that model and see if we can provide something that is a little bit more mimicking the human system more closely than artificial invitro system.
So you’re taking all the cells from the plant out and putting human cells in?
Dr. Zenhausern: Yes, that’s where there are a lot of different processes to do that. The first thing is we don’t want the plant cells themselves, we want them for their cellulosic fiber three-dimensional scaffold. Then what you want is to bring the cells, the human cells, and you want to be sure that they grow well, that you can co-culture those different cells and ultimately you can bring them the nutrients to the vasculature of the plant. Ultimately we can also now bring different type of cells, endothelial cells and others to now focus on blood vessels and reconstructing the blood vessels within the plant.
What are we building to? Once you perfect recreating the scaffold, recreating the lung cells on the leaf then where do you go from there?
Dr. Zenhausern: First of all, it’s really a model, a model to study for better understanding about the different type of tumors and their development into disease stages but also to look at potential drug targets. All different therapies and treatment that can be ultimately pre-validated in that model so we can try to bridge a little bit from that very fundamental work on cell lines that are not completely representative of the end point to the animal model that is ultimately required. I think having this in vitro system that’s more sophisticated and more representative of the overall tissue system will allow us to speed up that process and optimize the validation of promising therapies which might reduce the number of animals required and accelerate transition to human clinical trials. This may reduce cost of development while bringing new drugs faster to the clinicians and patients.
So ultimately are you looking to recreate this model to test therapies for lung disease, tumors?
Dr. Zenhausern: Yes. The program is working on different types of lung diseases that this approach will possibly better explain and also of course in application for lung cancer which is also a key issue that we want to study. So we are looking into that as well in collaboration with our clinical partners.
What haven’t I asked you about this project that you think I should include in the story?
Dr. Zenhausern: I think it’s a very interdisciplinary project, it’s adding that kind of approach to medicine. Exploiting technology that is done in a different field of science and technology, I think is very interesting. And the fact that we are really developing all these technologies in biology and engineering that are converging will open up huge opportunities to equip scientists and clinicians with new tools for better understanding the complexity of human health and guide disease interventions more precisely and more effectively. So the biology and the technology are really getting to the point now that they are really converging and providing a new type of information which will generate a huge amount of data driving the future of medicine.
It’s all collaborative isn’t it?
Dr. Zenhausern: Yes. We cannot do this alone and we need all kind of different profiles and training of the next generation of scientists, engineers and clinicians.
END OF INTERVIEW
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