Microfluidic 3D Cell Cultures and Organ Models for Drug Testing

Ann Nguyen:
Hi there. This is Ann Nguyen, Senior Associate Conference Producer with Cambridge Healthtech Institute. Welcome to this podcast interview for the 3D Cellular Models meeting taking place in Boston, Massachusetts as part of the World Preclinical Congress this June 14-17. With us today is one of our speakers, Dr. Jeffrey Borenstein, Laboratory Technical Staff in Biomedical Microsystems at Draper Laboratory.

Jeff Borenstein:
Oh, thank you. Glad to be here, Ann.

Ann Nguyen:
Can you describe your path from physics doctorate to North American Phillips Corporation and Mobil Corporation to Draper? What resources do you have at Draper for your work on microsystems-based approaches for organ assist devices and organ models for drug efficacy and safety testing, and what about that area do you find so fruitful?

Jeff Borenstein:
My path from the physics doctorate through the different organizations that you described, I really started as a solid-state physicist working in the semiconductor industry and working on problems associated with the development of new commercial products based on semiconductor device development in areas like, first in electronic devices and then more specifically at Mobil Corporation in solar energy and photovoltaics.

When I moved to Draper in the early 1990s, I was interested in moving into this emerging field called MEMS or microelectromechanical systems, and the focus there would be to leverage my capabilities in fabrication and wafer processing, which I had originally used for these electronic devices in solar energy arrays, and to use those for applications such as fabrication of devices, microsensors, and also microfluidic devices. The path eventually led to the development of novel microfluidic fabrication technologies, and the goal was to really look for applications of those technologies in new areas. The focus at that point in the late 1990s shifted towards biomedical engineering applications, and in collaboration with groups here in Boston at the Massachusetts General Hospital and at MIT, we started working on the development of microfluidic fabrication technologies toward tissue engineering, laboratory-grown organs, and organ assist devices, which was a very exciting journey because it was very early, but also full of promise for having an impact on patient care in areas like transplant medicine.

I think that I and my colleagues quickly realized that the timeline for a lot of those technologies was going to be quite lengthy, and so we were looking for ways to take these microfluidic fabrication technologies that are used to develop organ systems and to use them with nearer-term applications and impact on patient care. From that emerged the efforts in organ models, and the organ models that we're developing would essentially be similar to the tissue-engineered structures of the laboratory-grown organs, but they would be smaller scale. They would be small-scale elements of these organ systems, and they'd used for testing drug efficacy and safety testing.

What we find so fruitful about this area is that it provides us with the ability to do a couple of key things that make this highly relevant for pharmaceuticals development. One of them is to use human cells in these systems, either human primary cells or stem cells, iPS cells, to obtain data that's directly relevant to what we believe will be seen in human clinical testing.

The other aspect that we find so fruitful is that we can recreate the organ microenvironment and do very controlled experiments that are difficult to do in animals and in animal studies. By doing this, we can essentially create either healthy organ models or disease models for particular disease areas and study things like drug efficacy against a particular disease target or the safety of a drug that is designed to treat a particular disease, and do this in a very controlled and precise manner, so we believe this will be a very important advance for the pharmaceuticals industry.

Ann Nguyen:
What do you consider the most promising tools for recapitulating the in vivo microenvironment in 3D cell culture models?

Jeff Borenstein:
Yes, so in talking about the ability to recapitulate the microenvironment, we think that in general the microfluidic tools are very important, most specifically that there are aspects of these tools that mimic what we see in physiological tissues and structures. One of the most promising tools we believe is the ability to form topographic features and structures, because it turns out in looking at the basement membrane of many tissues in the eye and the kidney and in other organs, we see that the basement membrane is not smooth, but it has specific features and geometries, particular patterns, and these patterns may be grooves or various types of structures, and these are at the microscale or the nanoscale. The tools that we are developing are capable of recapitulating those topographic features, and we see in the case of the kidney – and this has been published by my colleagues here – we see very important signaling occurring between these topographic features and the cells that are representative of what happens in vivo.

I think a second important and very promising tool is the ability to create flow in these microstructures, so in a normal 96-well plate for instance, the culture is done statically and we don't have the opportunity to recapitulate the dynamics associated with flow that is imparted and sheer stress that is imparted onto the cells that are being cultured. In the tools that we and others are developing, we're able to generate and precisely control flow that is representative of what's happening in blood vessels, vascular flow, lymphatic flow, perhaps the flow that's occurring in interstitial fluids in various tissues and organs in the body, and with these changes in flow, we see very important responses in the tissue constructs that again are representative of what happens in vivo.

Ann Nguyen:
You will discuss “Microfluidic Technologies for Multiplex and Interacting Organ Models” during the conference on June 17. What's the primary message you would like to convey to your peers related to your development progress, challenges for the field, or beyond?

Jeff Borenstein:
Thank you. I think it's an important question to think about what are the primary messages that we're conveying to the attendees at the conference. I think that these primary messages relate to the relevance of these tools and technologies toward current needs in the pharmaceuticals industry. It's always interesting and important to make scientific and technical advances that bring us closer to understanding what's occurring in terms of the development of tissue constructs and organ models.

I think that what's going to be very important is to develop these technologies in a way that they have near-term utility in the pharmaceuticals industry. To do that, they have to meet certain requirements, so I think that the primary message I will be conveying is what do we perceive as some of the key requirements in these organ models in order for them to have an impact on drug development and to be useful to the pharmaceuticals industry. We think that those are aspects like ease of use and compatibility with the existing infrastructure in the pharmaceuticals industry.

We believe that many microfluidic tools, while they're very interesting when they're developed in the research lab, are very complex and maybe involve aspects that make them difficult to use outside of the lab that has developed them. We also believe that the concept of being able to multiplex these models in a convenient and economic way is going to be very important as well, that if these are single-use, single constructs that require a high level of operator intervention or management that they will be difficult to scale for pharmaceuticals’ use, and that the ideas of multiplexing them to a 24-, 96-, or 384-well plate will be very important so that they can be used economically, and also to generate the kind of statistics and meaningful data and correlations, in vivo, in vitro correlations that are required in order to use them for drug development.

Ann Nguyen:
It sounds like a very applicable and of course a very exciting area of research to be in. Thank you again, Jeff, for sharing a bit about your work. We're looking forward to finding out even more about it at the conference this summer.

Jeff Borenstein:
Thank you very much, Ann. It's been a pleasure talking with you.

Ann Nguyen:
That was Jeff Borenstein of Draper. He'll be speaking at the 3D Cellular Models meeting in Boston during the World Preclinical Congress this June 14-17. To learn more from him meanwhile, visit www.WorldPreclinicalCongress.com/3D-Cellular-Models for registration info, and enter the keycode “Podcast”. I'm Ann Nguyen. Thanks for listening.