Transcript
Robert Kirsner, MD, PhD:
Welcome to the SAWC Difference Makers Podcast. We share stories that inspire, mentorship that equips, and the evidence behind innovations improving wound care.
I'm Robert Kirsner, and this is the SAWC Difference Makers Podcast.
Today we have a fantastic guest: Rivka Stone, MD, PhD, associate professor in the Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery at the University of Miami Miller School of Medicine. She's also vice chair of translational research and innovation in the department. We're thrilled to have you here, Rivka.
Rivka Stone, MD, PhD:
Thank you so much for the invitation. Happy to be here.
Kirsner:
Rivka, to give the audience a little background, what was your journey? How did you get involved in science and then wound healing? How did that all transpire?
Stone:
We're going back a few years.
I did my training in New Jersey. At the time, I did an MD-PhD program there at New Jersey Medical School, and I was not studying wound healing. But I acquired a lot of skills in big data analysis.
When I came to the University of Miami to be part of the research residency program, which is a combination of dermatology training and postdoctoral research, I quickly discovered that the departmental strength was in wound healing research. It was evident that I was there at just the right time because there was a need to use the techniques and approaches that I had developed as a graduate student and apply them to wound healing science.
It ended up being a really fortuitous confluence of skill sets and needs at the time. That's what introduced me to the field.
One of the wonderful things about dermatology in general is having the skin as such an accessible model, which was what brought me to the specialty. Looking particularly at wound healing as a process became of great interest to me and formed the basis for all my future work.
Kirsner:
Fantastic. You discussed the idea that the skin is so accessible. I know that you're a very important member of the NIH-supported Diabetic Foot Consortium. You're funded by the NIH and funded by the Diabetic Foot Consortium as well.
You're a dermatologist, a physician-scientist. You love the skin. But you're also thinking about ways that people who aren't as conversant with the skin can understand how a patient might do—predict whether they're going to heal or not heal, and so forth.
Tell us about your work in that area using other biomaterials and how you got to that point.
Stone:
Absolutely. I think what you're referring to is a lot of the biomarker research and work that I've been doing. Maybe we didn't call it that at the very beginning.
The idea is that, rather than approaching patients as a group where you try the same treatment for everybody, from the moment they come into the clinic, you measure something about them or know something about them and their biology that allows you to predict how they might do on a particular therapy or whether they'll have a more severe or less severe phenotype.
Rather than following every diabetic foot ulcer the same way, we'd like to be able to know up front which ones are going to do well with standard of care and which ones may not, and to use that same approach for a lot of dermatologic diseases.
Whereas other specialties perhaps are a little more restricted to looking at blood, urine, or other biospecimens, dermatology has the benefit of the skin being very accessible. We can really make use of the information we get from a very simple skin biopsy, particularly in the context of wounds, where debridement is often part of standard care.
We are obtaining tissue. Rather than discarding that tissue, we can look at it to see whether it tells us something specific about an individual patient's biology that can guide therapies and also monitor response to therapy.
That's a really unique opportunity to help patients in a very personalized, precision medicine way.
Kirsner:
But you haven't given up on blood and urine. Tell us about that.
Stone:
Absolutely not.
Whereas the skin is accessible, blood and urine are more easily accessible, particularly at the point of care. A lot of the work that we've done with the Diabetic Foot Consortium has specifically looked at the primary outcomes of the consortium: the likelihood of a diabetic foot ulcer to heal and the likelihood of a diabetic foot ulcer to progress and develop infection, which can then progress to amputation and potentially lead to that mortality statistic that's so severe.
We want to see whether we can take urine from the patient. Specifically, we are interested in looking at something called microRNAs, which circulate in the urine and blood and are very, very stable. In other applications, they potentially can be measured at the point of care.
You can imagine a scenario where the patient comes in, you get a specimen from them in the clinic, you measure levels of these microRNAs, and based on that result, you can tell what's likely to happen with the patient and guide management of their wound from that perspective.
Skin is great, but being able to do it as noninvasively as possible is ideal.
Kirsner:
Beautiful.
The audience may not know that some of your work has been, from a scientific thought standpoint, paradigm shifting. What I'm referring to is your work looking at how inflammation changed with the application of a tissue-engineered skin or cellular, acellular, and matrix-like product—what we now call CAMPs.
Can you tell the audience a little bit about what you found and how that has changed the way wound healers think about inflammation and chronic wounds?
Stone:
Absolutely. This is actually a study that I was fortunate to work on right when I came to Miami.
The study looked at the mechanism of action of a cellular construct that's used and has been proven to have efficacy in helping the healing of venous leg ulcers.
In terms of the study design, the group here in Miami recruited patients with venous leg ulcers who were really poor healers, meaning that they monitored them for a few weeks. Those that were not progressing toward healing by a significant percentage were enrolled to receive either standard care—which, for venous leg ulcers, as I'm sure many in the audience know, is compression therapy—or compression therapy plus the cellular construct.
The key question we were trying to ask with this study was: What is the construct doing to the wound that's affecting such a significant improvement in healing outcomes?
What made this really interesting is that if you look at the patient and the wound itself, you put the construct on the venous leg ulcer, but a week later it's gone. Yet you don't really see the difference in healing outcomes until 3 to 6 months later.
There must be something that the construct is doing very quickly and almost temporarily to the wound itself, to the venous ulcer, that's flipping the switch from off to on.
The study was nicely designed in that biopsies were collected before and after the application for both groups—the control group with compression and the group with the construct. My job was to come in, look at the data that were collected, and make sense of them.
What we found as a group was that this cellular matrix was reactivating an acute wound-healing phenotype, which is exactly what you might have thought was happening. But we were able to show in a very mechanistic way that all those signals we'd want to see—the ones we see in acute healing wounds that successfully progress to closure—were being turned back on by the application of this matrix and by the signals it was emitting.
It was affecting changes in the cells of the ulcer itself, and those would go on to show improved healing months later.
Even though the construct was gone, the signals that it was emitting and perpetuating in the patient's own tissue were sustained. That was a very interesting finding and, in the sense of being paradigm shifting, no treatment up until that point had been shown to affect that mechanism specifically.
Kirsner:
I also think that many wound healers felt or knew the idea that chronic wounds are stuck in the inflammatory phase.
The approach was to try to shut off the inflammation: All inflammation is bad, so let's shut it off and make it zero.
I think this work really highlighted that there's good inflammation and bad inflammation. Bad inflammation is chronic inflammation and chronic wound inflammation. Good inflammation is acute wound inflammation. Products have an opportunity to turn that switch, as you call it, from bad to good.
For many, I think that was novel and changed the way they thought about things.
You have a very active mind. Paradigm-changing research and predicting what's going to happen with diabetic foot ulcers aren't enough. You're also studying scarring and fibrosis, which has implications in wound healing but also well beyond that, across the spectrum of diseases.
Tell us how you migrated some of your work into that area and what's going on.
Stone:
That actually was an outgrowth of the same study we just spoke about.
In the process of collecting the skin biopsies from the ulcers that were treated with the construct, we took samples from the wound edge, which is really where we captured that significant effect of the shift from chronic to acute inflammation.
But we also took biopsies from the center of the venous leg ulcer. What had been known about that is that, in general, denser fibrosis present in the ulcers is predictive of poorer healing, which may not be a surprise, but that had at least been described clinically.
What we saw was that the construct in the center of the wound, or the wound bed, actually reversed some of those fibrotic or profibrotic signaling pathways. We were able to demonstrate that at the molecular mechanistic level as well.
That really caught my interest because I started to think about fibrosis and look into the literature about skin fibrosis—actually, fibrosis in general. It's a really conserved pathway.
Regardless of the tissue that you're looking at, the progression seems to be an injury signal leading to chronic inflammation that is perpetuated, which then drives the production of too much collagen and poor outcomes across the board.
Again, regardless of the organ or tissue you're looking at—liver fibrosis, cardiac fibrosis, kidney fibrosis—all of these have a lot of conserved pathways.
I started to think a little more broadly about fibrosis in the skin and to look beyond classic wounds to other sources of signals that injure the skin or promote an injury response in the skin. That's what led me to radiation, and that is the second major focus of my research program.
The idea is that many cancer patients receive radiotherapy as part of their protocol to treat their internal tumors or cancers, but the skin is affected. What I had not realized and came to learn was that many of these patients, after they survive their cancer, suffer from skin fibrosis from that radiation injury.
Again, it's not necessarily a surgical wound or a chronic wound per se, but it is a chronic wound signal that's perpetuated and similarly causes a lot of fibrosis down the line that can go on for months to years.
That really caught my attention. What also struck me was that this was relatively underexplored in dermatology and in survivorship. That's been a major focus of my research as well.
Kirsner:
You're caring for patients, some of them very complicated patients. You're doing high-level science and publishing in great journals and doing paradigm-shifting work.
The audience may also not know that you have a big family and are raising certainly a basketball team's worth of children.
You're managing a lot of things. Do you have any advice for everybody—not just physician-scientists or physicians, but in general—about how you balance all these activities and can laugh and stay sane?
Stone:
That's an excellent question.
The first thing I will say is no one said I do it particularly well or perfectly, but here I am.
I think one of the key things that has helped me along the way is recognizing that there is no such thing as a perfect balance, and that is OK.
At any given point in time, things will shift in favor of more attention or effort toward one or the other. It doesn't mean neglecting something entirely, but just accepting that part of the joy, the inspiration, and the wonderful part of having so many facets to life is knowing that you can't have them all exist at the same time. Being not only comfortable with but leaning into that reality has been helpful.
Also, learning how to pick and choose among opportunities. One of the dangers—maybe not dangers, per se—of being a scientist, researcher, or clinician-scientist is getting very interested in a lot of different things. Learning how to prioritize, even among opportunities at the personal level, has been helpful.
And then really leaning into the idea of support and network. No one person can do everything.
That extends from having a wonderful environment of colleagues to, on a personal level, a great husband, very helpful children, and a great supportive community.
Knowing that asking for help and building a community are strengths and benefits, not weaknesses—I would say those are the things that have helped me along the way.
Kirsner:
The wound-healing community has truly benefited from your ability to manage these various facets exquisitely. Our department has certainly benefited. The patients you treat and our scientific community have truly benefited immensely.
What people not looking at you right now don't realize is that you're relatively youthful—and they probably inferred that by having children running around the house—so you have many, many more contributions to make.
People hearing this and getting to know you for the first time will be able to follow your great work, scientific and clinical. And, as I think is clear from how well you communicate the messages of your science, you're a great educator as well.
We're truly blessed.
Any final things you would like to tell the audience before we bid them adieu?
Stone:
First of all, thank you for the opportunity and for the really kind words.
Looking at my journey in the wound-healing space as a whole, I just wish more people knew how important and how critical this domain and this patient population are and how great the needs are.
Outside of the wound-healing community, I think it's an area that's relatively less known, despite how common chronic wounds and wound-healing issues, including fibrosis, are.
The better we can do as a community not only to come together, collaborate, and work to advance the science and patient care but also to engage other stakeholders—whether they're other scientists, pharma, industry, etc—the better. Making that part of the mission is so critical.
Here I am talking a little bit about my world of science. But if we can translate that pitch or message and really convey to others how critical this is—to get more people on board across domains—I think we can really impact patients' lives.
Kirsner:
Rivka Stone, you truly are a difference maker.
Thank you so much for doing the scientific work, translating it to patients and other clinicians, and sending the message out to broaden who hears about this important population and the great work you're doing.
It's a pleasure to have you here today. Thank you so much.
Stone:
Thank you for having me.
Outro:
The SAWC Difference Makers Podcast is brought to you by the Symposium on Advanced Wound Care, one of the leading forums for advancing wound care education, research, and collaboration, and by Wounds, the official journal of SAWC.