The Science Beneath the Wound: Marjana Tomic-Canic on Debridement, Biomarkers, and Spaceflight
SAWC Difference Makers Podcast
Host: Robert Kirsner, MD, PhD
Guest: Marjana Tomic-Canic, PhD
Intro
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.
Welcome, everyone. I'm here today with Dr. Marjana Tomic-Canic, who is a professor in the Department of Dermatology at the University of Miami. She's the William H. Eaglstein Endowed Chair in Wound Healing and Director of Wound Healing and Regenerative Medicine at the Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery at the Miller School of Medicine at the University of Miami.
Marjana, it's great to have you here today.
Marjana Tomic-Canic, PhD:
It's great to be here with you.
Dr. Tomic-Canic’s path into wound healing
Dr. Kirsner:
Well, Marjana and I know each other very well because we work together, and it's been my honor and privilege to work with Marjana for years.
But for the people who don't know about your background and how you got into the wound healing space, maybe you can tell us a little bit about how you got to where you are.
Dr. Tomic-Canic:
I started my training in graduate school doing my thesis on skin biology, focusing primarily on how different hormones and vitamins regulate skin physiology and gene expression.
I kind of wandered into the wound healing space by asking questions: Why are keratinocytes not moving when you treat them with corticosteroids, and why is the glucocorticoid receptor inhibiting wound closure?
I did not know pretty much anything about wound healing at that point. I was on the tail end of my graduate studies when I was told that I should go to the Wound Healing Society meeting, or a wound care meeting, and get educated. And so I did.
At that time, I realized that not a whole lot was known about the process itself, about the biology of it, and about why patients don't heal. So I decided that would be a good field to explore and start a career in. The rest is history.
Dr. Kirsner:
Now, you picked up the story in the middle, though. Tell people that you started in a clinical field, right? Isn't that right?
Dr. Tomic-Canic:
That is true, yes. I actually started as a pediatric nurse in a burn unit, back when Silvadene did not exist and things like that. All we had was pretty much a high oxygen percentage to treat patients. I was very young at the time.
That was back in former Yugoslavia, where I originate from. And I kept asking too many questions, annoying everybody. They said, “Maybe you should consider research.”
Dr. Kirsner:
So that's what they do with annoying nurses. They make you go into science.
Dr. Tomic-Canic:
Exactly.
So I decided that this would be very interesting. I went back to school. I finished molecular biology and physiology, and then I came to the United States for graduate studies.
Understanding debridement biology
Dr. Kirsner:
You've made a number of seminal discoveries in wound healing. I wanted to touch upon a few of them before we get to your current work and interests.
Could you give a little background about how your work has transformed how we think about debridement and what we should debride, and what parts of the wound we should debride?
Dr. Tomic-Canic:
That was really, I would say, my first introduction to clinical wound healing. Back when I was in New York, I would go to the operating room and collect specimens to study them. It always puzzled me: How do they know how much of the tissue to cut out?
So I decided to figure that out. At the time, it was microarrays. That was the beginning of the genomics era, I would say. I decided to do the transcriptional profiles of before- and after-debridement specimens from chronic wounds and try to understand what happens with their biology.
Just by looking at the profiling, you could see the difference in biology, and how many genes would go up or down depending on whether the wound was debrided to the appropriate extent.
But I didn't end only there. We decided to pursue this using these biopsies. We grew primary cells out of them. The skin is beautiful for many reasons, but that's one of them: it is accessible, and you can actually generate primary cells in culture.
So we cultured patient cells before and after debridement, and then tested their responses to growth factors in terms of how they respond, how they proliferate, and how they migrate. It was very clear that before and after debridement, the biology of cells coming from these tissue specimens from patients responds differently.
In other words, before debridement, they do not respond. They do not move well. They do not respond to growth factors, no matter how many of them you put in the dish. But the cells that came from the post-debridement biopsy, again depending on how well the excisional debridement was done, would actually show the difference in terms of how well the cells regain their normal biology and respond to the stimuli that would normally stimulate wound healing.
Dr. Kirsner:
What you found was that not only should you debride the wound bed, which everybody kind of envisioned, but you realized that the wound edge was diseased. Only by getting far enough away from the wound did it become more normal and behave like normal skin, or like an acute wound should behave.
Dr. Tomic-Canic:
Not only that, but we studied that tissue on many different levels.
As I said, one of them is really looking for where the growth factor receptors are. We know that they failed in many clinical trials, except for one. It was puzzling to me, given how powerful they are in general for skin cells.
It turns out that in the before-debridement specimens, if you look at where the receptors are for the growth factor—in other words, when growth factors come, that receptor on the membrane of the cell needs to be out there to receive that stimulus—the growth factor receptors actually are sequestered where they should not be in pre-debridement specimens.
But in post-debridement, they actually are reconstituted back, so the tissue can receive the signals that are being offered. This is also an explanation for why the therapy did not succeed, among other things: these growth factor receptors in the patients are not ready. They're not biologically able to transmit the signal.
Obviously, one of the reasons for the clinical success of PDGF at the time was because debridement was part of the trial protocol. That was a seminal paper that proved debridement is really important. Excisional debridement is important.
Dr. Kirsner:
You're saying that you can have a pitcher, and you could put in a pitcher, but if you don't have a catcher, you're not going to have a successful pitch or game.
Dr. Tomic-Canic:
Exactly. Yes.
Biomarkers and predicting healing
Dr. Kirsner:
You therefore got a sense of good and evil in wound healing—that is, bad things that were happening in the wound, and that you could, in some cases by debridement, get to a place where good things might happen.
Taking a lot of work and making a big jump, eventually you moved into an area of predicting healing, biomarkers, and whether a wound would or would not heal based on things that could be found in the biology of the wound. Could you tell us a little bit about that?
Dr. Tomic-Canic:
Again, I approached the tissue—this excised tissue from debridement—as a goldmine.
In studying this, it became very apparent that there are certain proteins and certain markers that are always present. We keep seeing them in non-healing wounds. We started looking into whether we can use this tissue, because it's normally discarded post-debridement, and whether we can capture that tissue and use it for predictive purposes.
That was one of the aspects of clinical trials that we have worked together on: testing whether these specific markers that we selected can predict healing of patients better than what we currently have, which is the duration, the size of the wound, and maybe some surrogate endpoints of four-week closure.
But I think this is an area of rapid development, because using tissue is not the only approach that can be used. We have developed multiple different ones because it stems from the concept that the presence of the wound has systemic manifestations to the body. If that's the case, then you would be able to capture these biological elements in either blood or, for example, urine.
So we use that approach, and we are currently working, again as work in progress, as part of the Diabetic Foot Ulcer Consortium that was funded by NIDDK and the National Institutes of Health. We are looking into whether we can use small RNAs from urine specimens of patients to predict whether they're going to heal by week 12.
We are also trying to use serum microRNAs from both humans and bacteria to predict infection and detect infection prior to clinical onset. These are clinical trials that are currently ongoing and have shown quite significant promise, I would say. But again, we have identified markers, and we are now in a phase where we are validating prospectively and in a blinded fashion.
Dr. Kirsner:
Your original work with debridement and understanding the value of tissue really led to this idea that you could determine good from bad and predict outcomes. The NIH got excited about this as part of a whole initiative, and now you're going from tissue that's in the wound to tissue that may be, for many people, more accessible. Not everyone takes tissue or debrides as well as other people, but drawing blood or giving urine seems to be more homogeneous.
Wound healing in space
Dr. Kirsner:
You were talking about growth factors and receptors, and that kind of reminds me of a spaceship docking on a spaceport in outer space. I know that you've done some work in healing in outer space settings. Tell us a little bit about that, and what implications space healing may have for a person who's in the clinic someday.
Dr. Tomic-Canic:
This is the part where I think we all need to be reminded how exciting science is. This was a very exciting experiment. It's been a while since I was so excited to participate in an experiment.
What we did is collect skin—again, healthy skin. We grew primary human cells out of the skin, keratinocytes and fibroblasts, and we wounded them. We used a very special system called lab-on-a-chip. It's a relatively very small and contained microfluidic station.
We loaded human skin cells that were wounded and unwounded. We also did a three-dimensional mix in Matrigel of keratinocytes and fibroblasts to have a three-dimensional structure. Then we packed that all up and sent it to the International Space Station to test how these cells would respond to microgravity, to spaceflight, and how the wound healing process would take place.
The whole experiment was for seven days. After the reaction was stopped, the whole box remained at the ISS for 30 days and then came back to Earth. We obviously did the parallel experiment in Cape Canaveral that stayed on as a control.
Then we did a lot of different analysis on omics profiling and discovered that there are interesting changes. When we did comparisons between chronic wounds and these results that we got from space, it turns out that there are some similar patterns that occur in space that dysregulate wound healing and tissue repair.
At least skin cells, in response to microgravity, heal poorly. They show elements of fibrosis. They resemble several aspects of what we actually find in chronic wound patients here on Earth.
Conceptually, what this means is that what's good for patients here on Earth is very good for astronauts in space to stimulate healing of their wounds.
Dr. Kirsner:
That's it. So you started off as a nurse, became a scientist, and now you're a space researcher.
The future of wound healing science
Dr. Kirsner:
But that's just part of who you are. Obviously, you're a leader. You've been president of the Wound Healing Society, and you're a mentor to many people who have succeeded in science, clinical medicine, and other areas.
If you took out your crystal ball, what do you see for the future of wound healing research and science? Are you optimistic? What are the challenges going to be?
Dr. Tomic-Canic:
From the perspective of science, I would say that this is probably the most exciting era of science ever. I don't only mean because of AI technology, but also because of advancements in technologies that allow us to analyze tissue from patients, for example, to such resolution that has never been done before.
The amount of information that we are gaining now feels like the speed of light when you compare it with the beginning of when I started. It's such excitement to see how, now, complex data sets can be analyzed and put together—not only from the omics side, but also from different kinds of elements and different types of analysis.
These technologies gave us such high resolution, and they're advancing knowledge in an unbelievable manner. Now, of course, with the help of AI, we go beyond our brains to analyze this.
So there are a lot of exciting developments in that area. I think the future in the science of wound healing is becoming very, very exciting, if it wasn't before.
Advice to future scientists
Dr. Kirsner:
I know that you have a professional progeny, and you also have a personal progeny. You have two wonderful children and a grandchild.
Let's say, fast forward, your grandchild decides to be a scientist 20 or 30 years down the road. What advice would you give to them about how to approach and think about science and discovery, what you went through, what people are going through now, and what you might predict they would go through if they became a scientist?
Dr. Tomic-Canic:
I think it all starts with a question that excites you. You need to be passionate about the question because science has its ups and downs, and it's not easy. But if you are driven by a question that's a driving force every day, I think you have to love and be passionate about the question you're asking.
The other part is also resilience and grit. Looking back from what I've learned and looking around at the younger generations of trainees, this is something that, whether you're looking at funding or looking to publish the paper, there has to be a certain stamina, I would say.
It's a long game. You need to be prepared for failures and embrace them, try to learn from them, and move forward. There is always an answer to a problem, and that can be solved.
Science is exciting. The moment you do your experiments, whether you're in a dark room or in the lab, you are the only person on the planet who actually has and captured the answer to a question that nobody else knows.
And what is more exciting than that?
Closing
Dr. Kirsner:
Marjana Tomic-Canic: nurse, scientist, space researcher, mentor, leader, and philosopher.
On behalf of the wound healing field, we're thrilled that you put your genius and your hard work and your grit and your stamina toward wound healing research. We're blessed to have you, blessed to have you in our department in Miami.
Thank you so much for joining us today on our podcast.
Dr. Tomic-Canic:
Thank you so much.
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.