Developing Microfluidics for Screening Drugs, Validating Compounds and Understanding Immune Response

Ann Nguyen:
Greetings, this is Ann Nguyen, Senior Associate Conference Producer with Cambridge Healthtech Institute. We are here for a podcast for the 3D Cellular Models conference at World Preclinical Congress 2017, taking place this June 12-16 in Boston, Massachussets. Today, we're talking with one of our speakers, also a chairperson and breakout discussion moderator, Dr. Mohammad Kiani, Professor of Mechanical Engineering, Bioengineering, and Radiation Oncology at Temple University.

Mohammad, thanks so much for joining us.

Mohammad Kiani:
You are welcome.

Ann Nguyen:
Can you describe your current projects at Temple University and how the resources there are contributing to your research goals and to the field of drug discovery and validation?

Mohammad Kiani:
Just to get started, I want to thank you for the opportunity to talk to you, but to also tell you a little bit about my background. I have a very interdisciplinary background, that includes two, three areas of engineering and radiation oncology and biological sciences and more recently, more immunology and things like that. So, I have a very interdisciplinary background and the type of work that I do spans several different disciplines. So I have a number of collaborations with people from both engineering, sciences, and medical school. So, my work kind of spans several different fields and I think that's the way good work is being done these days, interdisciplinary work is the way good and productive work is being done these days. So, more specifically, my work, my general expertise is in areas of microcirculation, blood flow, and particle-particle interaction, leukocyte-endothelium interaction, and how the immune response functions at the microcirculatory level.

A couple of areas that we're specifically involved in is ... one is this area of microfluidics. We are developing, using microfluidic devices for a better understanding of the immune response and the vasculature in various tissue, including normal and diseased tissue. And then we also have another kind of related area, which is targeted drug delivery – we are developing various particulate nanoparticle-type drug delivery system for targeting tumor tissue and also to … areas like cardiac tissue and things like that and also trying to deal with the aftereffects of inflammation. And then we also do some work in terms of understanding how ionizing radiation impacts the tissue and, to be more specific, how it impacts small vessels and the inflammatory response.

In doing this kind of work, we are collaborating with a number of people, both locally and other institutions, as I said, in engineering, in biomedical sciences, and in medical school, and clinical areas. So, for example, in the microfluidic work, we are developing a new generation of microfluidic devices that ... I can talk in more detail if you want. And that is in collaboration with a couple of companies here in Philadelphia and to be more specific, the company in Huntsville, Alabama, SynVivo. But then, also we have people from engineering involved, who help us with understanding some of the fluid mechanics aspects of the work, and then also some people from computer science, who help us develop some of the imaging techniques for these systems. And then we also collaborate with Dr. Kilpatrick, for example, in the medical school, who is an immunologist, to develop a new generation of anti-inflammatory compounds for treating inflammatory disease. And then we also collaborate with people from other schools who provide us with some of their reagents and some of the expertise that we need to use in devices to develop and screen for various applications.

Ann Nguyen:
What are the most persistent or significant challenges you've encountered when developing microfluidic systems with human representative architecture for drug screening? And how has your work addressed them?

Mohammad Kiani:
Microfluidics, as you may know, has been around for a while now and I think that some of the early work was done by our group and other groups to develop this and they're in the process of becoming one of the standard tools we use for screening and developing and validating various therapeutics. I think in our work from very early on we have had several principles that we have tried to stick to. One of the main issues that we've always looked at is how complex do these systems need to be versus what you see in vivo and compared to human tissue. And then do we have enough complexity, do we have too much complexity, and more importantly, do we have the right type of complexity?

So, for example, one of the things that we've been very conscious of is that since the vasculature of the core of almost every tissue in the body -- and that's essentially where a lot of the interesting and important processes, biological and biomedical processes occur -- we have to put that at the center of our work. Almost all the microfluidic devices that we have worked with and we have helped develop or we have used have the microvascular system at the core of the system that we have developed. So, every system that we have has a microvascular system and a tissue compartment, for example, various tissue compartments that are built around that microvasculature. That's the type of complexity that needs to be in these types of devices.

Just simply putting some parenchymal cells, we don't think is enough for example, to call it a liver-on-a-chip. Without the vasculature, the system would really not be realistic, especially if you're talking about developing therapeutics and validating therapeutics. And in that sense, we have developed systems, for example, that have been used now for mimicking the immune response at the microvascular level and we've had a lot of success with those. We've developed, for example, a blood-brain barrier system, again built around the vasculature that has been successful. We have also developed some tumor models that we've used for these kinds of purposes and so on. And several different types of tissue-on-a-chip.

One of the issues that we've been very careful is that you can build all kinds of, for the lack of a better word, cute microfluidic devices that look very nice and have all kinds of features and things like that. But the central question is how does this relate to the immune system, can you use and can you validate these systems in vivo? And more importantly how would you validate them against human tissue, which is the more important issue at the end?

So, every system that we have developed has been validated against some kind of animal model, and we think that’s critical to show at least your system can reproduce what you see in an animal model. Because otherwise the system might be technically interesting and challenging, but in terms of its application, it probably won't be well received in the community. And then, the bigger question, of course, is how do you validate this for human application and human use? Our view has always been that if we at least can show that it corresponds well to what we see in vivo in an animal model, let's say, then there is a chance, there is a better chance, let's say, that this would also work where you put human cells in there and human tissues in there. And so, we think this would have a much better chance.

The other … to our research has been that, as I said there have been a lot of different, by now there have been a lot of different types of microfluidic devices that have been developed, but the question is, have any of them been really used for real-world applications? And I think the answer is kind of a yes for it, if you're talking about drug toxicity; that is a very popular application of these kinds of things. You know, testing drugs to see if they're toxic to tissue or to cells or things like that.

However, the types of systems that we have developed can do both screening and toxicity of various compounds that may be of interest for treating diseases. So, for example, one of the things that we have developed is, as you may know, is that there is a lot of interest in developing therapeutics for treating immune disease and so we have been using our microfluidic system to screen and assess significance and work of novel therapeutics that we are developing a PKC-delta TAT peptide inhibitor that we think can go a long way in addressing some of the issues that we have in inflammatory disease.

The other aspect of this whole thing is, as you get closer and closer to using these microfluidic devices for let's say, testing drugs and for validating drugs and things like that using, let's say human cells and human tissue, and hopefully getting the FDA to agree to this as kind of a standard for testing these drugs and for validating these drugs. The question of reproducibility becomes very critical and if specifically the system you are using currently, let's say to validate a drug, does the system work in other people's hands as well? Or is it just something that you are doing in your lab and some specific system that you have in your lab that may be of interest?

That's important and that's the reason we have from very early on, we have collaborated with this company SynVivo in Alabama and they're using commercial products rather than an in-house development of these systems, because if you are to get to a point, as I said, for example, the FDA would approve these things, we would have a better chance of getting the FDA to approve these as a standard platform for testing and validating drugs. If these systems are standard and if these systems are such that everybody is using kind of similar systems, or the same system hopefully so the results are comparable between different groups. Very much similar to when we use an animal model, let’s say a mouse model such as the C57-Black that everybody uses and the data from different laboratories can be compared and corroborated from different experiments.

Ann Nguyen:
You'll discuss “A Biomimetic Microfluid Assay for Rapid Screening of Anti-Inflammatory Drugs” during the conference on June 15. What's the main theme you would like to convey to your peers in the audience and the research community?

Mohammad Kiani:
So, as I briefly mentioned before, inflammatory disease is a big concern and I think it's attracting more and more attention in clinical situations. These days there are very few diseases out there that don't have at least some kind of an inflammatory component to them and so this a big problem and of course there are diseases such as sepsis, for example, that kill hundreds of thousands of people a year. And these are essentially, you know, inflammatory diseases and there are many other ones like that. And so understanding the inflammatory response is very important and developing therapeutics to treat them is also very important.

One example is that in the recent year, for example, there have been about 150 drugs, anti-inflammatory drugs, that have been developed in animal models to treat sepsis. But all of these drugs have failed in clinical trials. So, just let me repeat this, I think that this is important: About 150 different types of drugs in the past 10-15 years have been developed using animal models and none of them, zero have worked in a clinical situation.

This has created a situation where people are now making all kinds of comments about them even the viability of animal models. Of course, a lot of it is exaggerated. I mean it's gotten to a point 2-3 years ago where New York Times had this big headline article that said much money and time has been wasted developing an animal model for treating sepsis. And, in the article, they kind of implied that animal models are of no use and things like that, which of course is an exaggeration, of course animal models are important. But, I think the issue of, for example, going from animal models to human disease is an important issue and there are, of course, many components to it, from genetic variability from the type of cells that you get from the phenotypes that are different ... from one tissue to another. For example, the phenotype of endothelial cells in the liver are the different from the phenotype of endothelial cells in the brain. And so I think it's very important to be conscious of this fact that animal models have their use and are very important, but when you go from an animal model to a human application, it's very important to have models that can help us develop these things, specifically for humans.

So, that has been one of the core areas as I said before that we have been pursuing and developing the microfluidic systems. And the microfluidic systems that we have, have all been validated against in vivo data. And so we have now started using them for screening and validating different anti-inflammatory compounds to see how they could be used to at least predict the possible success of these models in humans and also in animals. One scenario, for example, that we have been pursuing is, even before we do expensive and time-consuming animal studies, can we get some animal cells, put it in our microfluidic system, test the system against novel anti-inflammatory therapeutics and see whether it has any response, whether it does anything. For example, can it downregulate the inflammatory response in these animal cells?

And if it does, then we at least have some idea that it may work in animal studies. And then let's say you do your animal studies and see, okay, there is some correspondence between what you find in the microfluidic system and in the animal model. Then, you could do the same thing with human cells. You could come back using your microfluidic system, put human cells in there, which these days is relatively straightforward, develop the microfluidic system using human cells, test your anti-inflammatory therapeutics again on human cells and see whether you are getting any kind of response.

And this is important for two reasons. One is that of course you get some mechanistic ideas as to how this drug might work, how this new therapeutic may work or not work, and what are the reasons behind it which will allow you to optimize it at a later time. But, maybe it will also give you at least some idea of if this drug is going to be successful if you start doing it in humans. Which is kind of what I was saying before in terms of marching towards hopefully a period where these kinds of microfluidic devices become a standard method for screening drugs while you are working with the FDA to get approval. And hopefully this will speed up the screening of drugs and shorten the amount of time that you spend working with animal models and reduce this 10, 11 years that it takes for a compound to get from early stage to the market, maybe reduce that by a significant amount of time.

So, that has been the direction we have been going and that's what I want to talk about when I come to the conference. A specific interest, for example, is a new compound that we are developing, an anti-inflammatory compound that we are developing in collaboration with Dr. Kilpatrick at the medical school here. A PKC-delta peptide inhibitor that has shown great promise, we think, in treating sepsis, and some of the early work that we have done, which was just published and featured on the cover of Journal of Leukocyte Biology at the end of 2016 shows that this drug has a lot of promise in treating sepsis and maybe other anti-inflammatory diseases.

But the way we approach this study was we started with the microfluidic system and we tested the system in the microfluidic system to show that it has some promise in both animal cells and human cells. Then, we validated this in animal models and now we are doing some more studies with human cells and also with animal cells to show that, to at least get a sense of, a predictive sense of what the promise of this drug may be if we're treating sepsis in humans. And that is the direction and that is the approach that we are taking and we are hoping that this will contribute to this idea of using this microfluidic system for rapid screening of drugs and validating various therapeutics.

Ann Nguyen:
That was Mohammad Kiani of Temple University. He'll be speaking during the 3D Cellular Models conference at World Preclinical Congress 2017, taking place this June 12-16 in Boston, Massachusetts.

To learn more from him, visit www.worldpreclinicalcongress.com/3d-cellular-models for registration info and enter the keycode "Podcast".

This is Ann Nguyen. Thank you for listening.