Under the Microscope with...Cherie Stabler, Ph.D.
Dr. Cherie Stabler is excited.
For years, she has focused on engineering a platform that can house and help protect transplanted islet cells – a major step toward the DRI’s goal of building a “mini organ” that mimics the native pancreas. Now, with the development of a “scaffold” – a sponge-like substance, slightly larger than a quarter – her research is moving us closer to that goal. The DRI expects to begin testing of the scaffold in clinical trials next year.
But that’s not all she’s excited about. As you’ll read below, there are many other promising developments in the research pipeline that will help create an optimal environment for the new islet cells.
Throughout this interview, Dr. Stabler, director of tissue engineering, emphasized how the ability to work with researchers from a variety of disciplines – a unique aspect of the DRI - is critical for reaching a biological cure for diabetes.
“It really is unparalleled,” she said of her ability to collaborate with a multidisciplinary team. “I go other places and they say, ‘I cannot believe you have this kind of access.’” And that access allows progress at a faster rate. “I’m excited to see all of the things we have in the pipeline, to see all these pieces that will fit very well together, that will be highly complementary and will truly improve what we have now in terms of current clinical islet transplantation.”
Q. Can you update us on your research using scaffolds?
A. We’ve done extensive studies in several preclinical models and have obtained encouraging results with them. We’ve achieved promising insulin function in all of the recipients, and we’ve achieved insulin independence in many of them.
Q. What’s the next step?
A. So far, we’ve achieved these promising results using scaffolds made by hand. Now we’re working on fabricating the scaffolds in a reproducible manner, so we can scale up. When we have this perfected manufacturing protocol, which is what we’re in the midst of right now, we will perform definitive pre-clinical model studies.
Along with this are many the requirements from the FDA – all of the regulatory paperwork, quality assurance, and other issues required for clinical trials – for use in people with diabetes that we have to complete and finalize.
Q. How close are you to using these scaffolds in clinical trials?
A. We anticipate about a three month process for the manufacturing and regulatory issues, three-to-six months for pre-clinical trials, and then we’ll work with the FDA for approval. So, our plan is to be able to transplant these by 2013.
Q. What material is used to make up the scaffold?
A. We’ve been focusing on PDMS, also known as silicone. It’s been used for medical implants for decades. It’s has a great clinical profile already. It’s highly biocompatible and stable. So, we knew in terms of trying to translate these to the clinic that we had an easier regulatory pathway.
We have procured clinical-grade silicone that’s an appropriate source for long-term use. We feel like this is the best material for us to move forward with, in the strategy of having a retrievable device long term, so it’s something we can go in and take out if we need to, as well as the safety associated with that.
In the selection of the material, we really wanted a platform that could incorporate all of the additional components needed to create an even more optimal implant, such as the ability to deliver drugs and oxygen generating materials, and this is very amenable to those kinds of things.
Q. Where will the scaffolds be placed in the body?
A. We will continue to focus on the omental pouch (in the abdomen) as the site of transplant. In our studies, led by Dr. Norma Kenyon (DRI senior scientist and Martin Kleiman Professor of Surgery, Medicine, Microbiology and Immunology), we’ve looked at several different sites. I think we’ve seen the most promise and most flexibility with the omental pouch. We can transplant the size implant that we want. There’s wonderful vascularization and healthy remodeling. We’ve seen positive responses to implants at this site. So, I think we’ll continue to use this as our site moving forward.
Q. So far, islets have been transplanted into the liver. Why the new site?
A. There are many challenges with the liver. One is that you’re putting islets in direct contact with the bloodstream, and the bloodstream is contains inflammatory cells and inflammatory reactions. So, you are exposing islets to a lot of inflammation when you transplant into the bloodstream.
Also, many drugs are processed in the liver and the byproducts of the drug metabolism can be toxic to the islets.
Another challenge is that we lack control over being able to define where the islet cells go because they get scattered throughout the liver.
When we are able to place islets into a defined, confined site, we will have control of that local micro-environment. And that really opens up many doors of being able to incorporate novel strategies to promote islet cell viability, islet function and protection, among others.
So, while there’s been very promising results in islet transplantation in the liver -- illustrating the great promise of islet transplantation -- we believe we can make a safer and better islet cell transplant by taking it out of the liver and implanting it in a definable, retrievable site.
Q. If the scaffold serves as kind of a “base platform” to house the islet cells, then what else is needed to create an optimal environment for the insulin-producing cells?
A. The big thing for islets is oxygen. Because islets are kind of “super athletes” in the cell world, and their oxygen consumption rates are so much higher, we really need to meet their oxygen demands. Blood vessels deliver that oxygen, so we can put agents into the scaffold that will promote the growth of blood vessels, or vascularization, as quickly as possible in a very organized structure.
But it’s still going to take time for all those structures to develop. So we have developed an oxygen-generating material that has the capacity to supplement oxygen during that interim time period. We’ve demonstrated that this oxygen-generating material has tremendous benefits for islets in preventing hypoxia-induced necrosis, which is cell death induced by low oxygen. Our vision for this oxygen-generating material is really to serve as a bridge between when we implant the cells to when the islets are fully vascularized.
Q. How is the issue of rejection and immunosuppression being addressed?
A. We want to minimize, as much as possible, the need for systemic immunosuppression. One avenue we’re exploring is local drug delivery, and the scaffold is very amenable to local drug delivery. This material is already being used in the clinical to deliver drugs locally for other applications, so that proof of concept is already out there. We’ve been collaborating with Dr. Peter Buchwald (director of DRI Drug Discovery Program) and Dr. Antonello Pileggi (director of DRI Translational Models Program) on the release of various types of immunosuppressive or anti-inflammatory agents to dampen the immune response in the local micro-environment.
This local immunosuppression offers the opportunity of posing minimal side effects because you’re really only suppressing the site of transplantation, and it opens the door to a lot of novel drugs that may not need to be delivered systemically, and at substantially lower doses. The field of drug delivery through biomaterials has advanced significantly in the last five years. Many studies have shown that when you use local delivery, you have a more potent effect at a much lower dosage rate, and the DRI has been at the forefront of these studies.
Q. Of all the research you’re doing, what excites you the most?
A. I’m definitely excited about having the clinical trials coming soon, and seeing that move forward, but I’m also excited to see all of the things we have in the pipeline, to see all these pieces that will fit very well together, that will be very complementary and will really improve what we have now in terms of current clinical islet transplantation.
So, that to me is really exciting. We have all of these other strategies in different stages of research that will make things even better. So for me, it’s always about continually moving forward, to build the optimal implant.
Q. You mentioned that one of the challenges in transplanting islets is that the site of the transplant becomes inflamed. Can you explain the issue of inflammation further?
A. Whenever you have trauma, you have inflammation. So, even if you implant a basic piece of material with nothing living on it, you’re going to have an inflammatory response to that. There are certain subsets of cells, part of the immune system, which come to that site because of this trauma.
Those cells do interact with the standard immune system as you may know it. If you have a very large inflammatory response, it stimulates a more aggressive immune response.
So, inflammation is not something you want instigated. You want to minimize inflammation.
Q. You and your colleagues are studying how certain cells – Mesenchymal Stem Cells, or MSCs – can dampen inflammation. These cells would be placed in the scaffold. Can you explain how MSCs would help?
A. MSCs secrete things that definitely have the ability to dampen inflammation. But they also play another important role.
You actually need inflammation to have blood vessel development, and we need blood vessels to deliver nutrients to the islet cells. So, say you implant something and you want it to become vascularized, and you use a huge amount of anti-inflammatory drugs, it will not become vascularized. So you have to be really careful not to use too much anti-inflammatory therapy, because then you won’t have vascularization.
The great advantage of MSCs is that they are anti-inflammatory but at the same time they are pro-blood vessel development. So they actually help what we term as a more positive remodeling response.
These MSCs are termed “helper cells” because they really help facilitate blood vessel development, but they do in the absence of inflammation.
Q. Where does research stand in the use of MSCs in scaffolds?
A. We have performed pre-clinical model experiments using a scaffold coated with MSCs. We were able to use fewer islets and we had more efficient function when we used MSCs than when we did not.
Now this was only with one model, so we cannot make broad statements about what that means. But we did see encouraging results with that. So, we have seen how MSCs could be very beneficial to the transplant micro-environment. That’s something we will continue to explore -- to facilitate engraftment, to facilitate blood vessel development, and to facilitate immunomodulation.
Q. Another major focus of your research is “nano-encapsulation” – coating islet cells with very thin layers of “polymers” to physically protect the cells from immune attack. Can you update us on this?
A. We have been working on nanoscale encapsulation for a while, and the development of novel polymers that allow us to essentially “dip coat” islets for encapsulation. You take an islet and dip it into one polymer then another polymer to build these layers. My colleague, Dr. Kerim Gattas Asfura, is an amazing polymer chemist and he is the one who has created these polymers.
We have developed several coated strategies for islets and we’re now transplanting them into pre-clinical models to assess the level of protection.
We had early prototypes that were fairly promising, with a ~ 60% improvement in the survival of the coated islets long term. We’re now trying to improve that, to make more stable capsules and more uniform capsules. With these newer coatings, we believe we have made significant improvements in capsule stability and uniformity.
What’s really wonderful to see is that we have these fully encapsulated islets with these exceptionally thin nanoscale coatings. For example, if you took an encapsulated islet using our technology and looked at it under a microscope, and compared it to a cell that wasn’t encapsulated, you would see virtually no difference between the two. How we know it is there is because we fluorescently label that coating and you can see it under a fluorescent microscope.
The great thing is that when we expose the encapsulated cells to glucose and look at insulin secretion, we see absolutely no delay in insulin secretion. That’s really important, because traditional microencapsulation of islets causes these significant delays. So, we’re eliminating the delay, but we still have these very nice coatings. We just now need to assess if these bench-top results translate to long term protection from the immune system.
We also collaborate heavily with Drs. Alice Tomei and Jeffery Hubbell on our complementary encapsulation projects, as we have identical goals. We collaborate to ensure that all of the technology that we are developing are screening and tested in the more efficient way possible. This collaboration benefits both of our technologies and significantly strengthens our efforts in this area.
So, I’m very, excited about the work that we and our collaborators have done and I am highly optimistic about the future.