Philip Scumpia, MD, PhD, assistant professor of dermatology, David Geffen School of Medicine, UCLA, talks about a new hydrogel material that can heal scars better than aver before.
What is it that you and your colleagues are working on in terms of this wound healing gel?
SCUMPIA: Hydrogels have been around for decades and there hasn’t been much innovation in them until recently. There are two common uses for hydrogels. One is in wounds and another is as a dermal filler. So Juvederm, Restylane, all these fillers that are used for cosmetic purposes. A lot of people are familiar with hydrogels from that but don’t know that they’re actually hydrogels.
What exactly is a hydrogel and is there a simple way of describing what it is that you’re using it for?
SCUMPIA: Hydrogels are basically a way to deliver water or fluid. It’s gooey and typically could be flowable or a little bit stiffer depending on the amount of water or amounts of other constituents in the hydrogel. Usually, the water is held together by something. It could even be something like JELL-O if you think about it.
Can you tell me where your research is at this point? Do you have something you think will work for wound healing?
SCUMPIA: This particular hydrogel we developed in 2014. In 2015 we had our first publication on it. Then, we just recently had two publications to follow them up. One where we put cells in the hydrogel and delivered it to the skin. That was in 2019 and was with the same collaborators that we originally invented the hydrogel with, Dino Di Carlo at UCLA Bioengineering, and Tatiana Segura who was at UCLA and now Duke. Then, in 2020 we recently had another publication where we activated an immune response from the hydrogel and were able to get skin regeneration. So, that is an exciting application.
Can you walk me through how this would work when you put it on someone’s skin?
SCUMPIA: It’s actually cool because it could be applied to any tissue. It’s a flowable solution almost like a slurry. So, it’s soft and a bit thicker than water. What happens is when it sets in the skin, we can make it what we call a neo or stick together. We usually do that with proteins or with light. We could do it with an enzyme that makes the proteins stick together or add something called ESMy which generates a small free radical that allows the hydrogel to cross-link in the presence of visible light. So, you could shine your iPhone light on it and that’ll make it stick together. The original hydrogel we made is basically microscopic beads that you can flow onto any surface or into any tissue. Then when it sticks together, it can also stick to the surrounding tissue and is stable in that tissue. When it sets, it’s a lot firmer than when it’s hot. However, because it’s a bunch of small beads, there’s spaces in between where cells can grow into. What we found is those spaces kind of mimic the natural extracellular matrix or the framework of the skin or whatever tissue. It’s basically made of strands of connective tissue that are linked together. That’s what our hydrogel is mimicking synthetically right now. You can also make it out of more natural materials as well because the body is 70 percent water and our hydrogen is about 80 to 90 percent water.
Does this encourage the skin or the cells to regenerate around the hydrogel? Is that how it works?
SCUMPIA: Typically, what happens when you put on a wound-healing hydrogel is your body treats it like a foreign body response, or a splinter. Your immune cells that don’t like it try to push it out. We initially found, back in 2015, when those cells go in, it prevents them from lining up at the outside and that allows blood vessels to grow into it. We start to see secondary structures. But the way we engineered the hydrogel is we wanted to make it so that it can degrade. We put sequences in the peptides that link it together that tell the body to break it down. What we were noticing is when we put it in the tissue, it wasn’t lasting as long as we wanted. We wanted it to degrade as the body fills it in. In this new project, we tried to change how those peptides process the hydrogel and change them so it would slow down the degradation so the body can fill in more. What happened was we changed the peptide to its mirror image. So, enzymes in the body break down proteins gobble them up. We took the mirror image of the peptide and the body couldn’t degrade it anymore. We thought that was the goal. When we did it in cell culture and in vitro, we found that the body’s enzymes that would degrade the hydrogels weren’t degrading anymore. But when we put it in the wounds, it degraded faster, so the exact opposite of what we thought. I am a dermatologist and a skin pathologist. So, I look under the microscope at a biopsy of skin and noticed the wounds weren’t just scarred. They had hair follicles and sebaceous glands, which are structures that should not appear in scar. If you ever burned yourself on your skin or ever had a scar, you’ll notice that you don’t have any hairs in those areas where you had the wound. It heals basically a flat thin piece of skin. What we noticed is there was no hydrogel there, but the skin that was there had regenerated. We tested the tensile strength of the skin and although it was weaker than normal skin, it was about double the strength of the healed skin without the hydrogels.
Does it look like nothing ever happened as opposed to when you would have a scar and the hair is not there?
SCUMPIA: When we first did this experiment, we used hairless mice because it makes it easier to splint the skin. The problem with mouse skin is mice have evolved so that their skin rips easily but then it contracts. Human skin, we have underneath it basically a fascia layer that prevents that from happening. Mice have the skeletal muscle layer, sort of like what we have here under our skin. It’s called the panniculus carnosus. In mice, that contracts and that’s how wound healing occurs. To prevent that from happening, we must split the skin. Basically, we sutured these little splints on and held the wound open to mimic how human skin heals. When we looked at the healed wounds in those hairless mice, we couldn’t actually find the scars until we flipped it over and saw the defect on the underside. The skin looked normal in the mice that healed with the hydrogel, whereas, in the mice that healed with the scar, you could tell where the scar was.
Have you tested this in humans? Is it moving into clinical trial?
SCUMPIA: We have not. We started a company back in 2015 called Temple Therapeutics. The goal was to commercialize the hydrogel and move it into clinical trials in people. Our first problem is wounds since that’s what we have the most experience with. Right now, we submitted to the FDA to use this hydrogel in people. We have done studies in mice, in guinea pigs, in rats, and in pig wounds to move it along into humans. We’ve done safety testing in humans where we put it in people to make sure it didn’t cause an allergic response. That was part of the approval process that the FDA wanted us to use. So, we received the response from the FDA and additional studies that they want us to do. But the goal would be to move it into humans within the next year or two and do clinical trials in difficult-to-heal wounds.
What could be the benefit in difficult-to-heal wounds? I immediately think of diabetics and our military. Could you list some of the benefits in humans to having this available?
SCUMPIA: I agree completely. It could benefit diabetic foot ulcers and complex wounds or basically any wounds that aren’t healing for a variety of reasons. These types of wounds we typically have to wait a month before we can use advanced therapies because the advanced therapies are so expensive. So, our hydrogel, which is basically synthetic materials that are less expensive, could potentially be used earlier in these wounds to prevent them from being chronic wounds. It could also be used in these chronic wounds because of the way it works. It anneals to the tissue and allows the tissue to regrow into it. The goal would be we’re changing the environment of those difficult-to-heal wounds into something that’s more an acute wound rather than this chronic state where it can’t repair itself.
How long would that process take, and would it be dependent upon the person and the wound?
SCUMPIA: In pig studies, it starts to occur immediately. We’ve done histology in the pig studies as early as five days and see cells starting to grow into the hydrogel. We compared it to other advanced materials that are out there including a hydrogel that’s commercially available and a cell-based therapy that’s commercially available. We see differences in how our product works compared to how those products work. Later on, we’re finding based on the histology and what we’re seeing is the immune system changing. Instead of having these type 1 immune responses which lead to foreign body responses, we’re seeing a different type of immune response. It’s the type 2 immune response where individual macrophages are able to gobble up the hydrogel. They turn into these foamy cells that are degrading the material rather than turning into these giant cells that degrade tissue and destroy the tissue.
Is that the difference between what you are developing and the hydrogels that are already available for medical use? Do some of them spark that immune response but the body wants to reject it, whereas this product won’t?
SCUMPIA: That’s what we’re finding with one of the commercially available hydrogels that we compared it to. That hydrogel induced a very robust immune response right away whereas ours took time to develop an immune response and was different. The immune response was much gentler. That’s why we think we’re able to regenerate the tissue better with our product. So, we’re excited about the possibilities.
As the skin grows back in and fills out, does the hydrogel get absorbed into the body, or is it like a coating that just stays there as part of the body?
SCUMPIA: What happens is the skin heals over the hydrogel. It uses it as a scaffold and then the dermis grows into it. Then the immune cells, the macrophages which are the main cells that degrade things in the skin, degrade the individual particles. Those macrophages die and the hydrogel material gets reabsorbed by the body. Because it’s 90 percent water and a lot of peptides, there’s a little bit of polyethylene glycol in it, but it could be changed to any other kind of material including hyaluronic acid which is what other fillers are made out of. So, it’s basically a platform that’s completely tunable depending on the application you want.
Is there anything you would like to add that you want people to know?
SCUMPIA: There are a few different applications I foresee the research going in my lab. And, depending on how it works out, it could be translated to therapeutics. One of them is obviously the wound healing products. But another thing, being a dermatologist, the dermal filler products are another potential avenue of research and development of the hydrogel, especially tissue-regenerative hydrogel, rather than one that just sits in tissue like the current hydrogels that are there because they’re the bulk hydrogels. This one could potentially lead to regenerated tissue and your own body making tissue that can sit there after the fillers have been injected. Another application that we’re trying is could we change the platform to directly activate the immune system and use this for vaccines? As we know with the COVID situation, there is an urgent need for the development of new vaccine platforms. And, because the way the hydrogel works and how slowly it’s degraded, we’re possibly able to extend the immune response to whatever antigen or protein that you want to develop an immune response against. That may lead to longer lasting immune responses or a one-shot immune response, a one-shot vaccine rather than needing multiple boosters.
Interview conducted by Ivanhoe Broadcast News.
END OF INTERVIEW
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