The future of wound healing

0:00This is Stanford Engineering's The Future of Everything, and I'm your host Russ Altman. I thought it would be good to revisit the original intent of this show. In 2017, when we started, we wanted to create a forum to dive into and discuss the motivations and the research that my colleagues do across the campus in science, technology, engineering, medicine, and other topics. Stanford University and all universities, for the most part, have a long history of doing important work that impacts the world. and it's a joy to share with you how this work is motivated by humans who are working hard to create a better future for everybody.

0:37In that spirit, I hope you will walk away from every episode with a deeper understanding of the work that's in progress here and that you'll share it with your friends, family, neighbors, co-workers as well. And that whole area of research led to the discovery of some molecules that we think are very efficient at stimulating bone building signals. And so those are now in phase three clinical trials and soon to be commercialized. It's not pie in the sky, you know, maybe someday. No, it's today.

1:17This is Stanford Engineering's The Future of Everything, and I'm your host, Russ Altman. If you're enjoying the show or if it's helped you in any way, please consider rating and reviewing it. Again, you've heard me say this before. Give us a five if we deserve it. Otherwise, give us what we deserve. Your input is extremely valuable and helps other people learn about the show and its quality. Today, Jill Helms will tell us that healing deteriorates starting when you're about 30 years old. And the healing just doesn't go as well. But we are learning about the physical and biological signals that we may be able to manipulate to improve healing for people of all ages.

1:54It's the future of wound healing. Today, we're continuing our new feature called Future in a Minute. At the end of my interview with Jill Helms, we'll ask her a few questions in rapid-fire style, and we'll ask her to give us answers in rapid-fire style. Before we get started, another reminder to rate and review the Future of Everything podcast so that we can know how we're doing and other people can find out about it.

2:22we all know about wounds you cut yourself you burn yourself and the skin starts healing it's kind of a miracle the cells slowly creep in and form some kind of new barrier sometimes it looks almost perfect sometimes there's a scar but it happens reliably in addition there are deeper wounds that can happen like a broken bone where you have to remodel the bone and have it get exactly the same shape and structure as it had before the break. And especially in young people, this works out great and little kids can break their bones and heal with very little long-term effects. However, as we get older, like 30 years or older, our wound healing gets less good.

3:04And scientists have been studying all of the cells that respond to wounds to understand how they do their thing, how they realize that there's been a wound, how they mobilize, and how they start releasing the cells and the chemicals that are needed to rebuild whatever has been wounded. Well, Jill Helms is a professor of surgery and plastic and reconstructive surgery at Stanford University, and she's an expert at wound healing. She's going to tell us that we're starting to really understand these physical and biological signals, and they begin to give us a future where we're able to have all of us get wound healing as if we were little kids.

3:42Jill, why did you decide to focus on wound healing as a major focus in your research? It started from an interest in embryonic development, how tissues form. And once you get an idea of how tissues form, it seems pretty obvious that the next thing you'd want to ask is, well, when they're injured, do the repair using the same mechanisms. So it was sort of a natural offshoot. And you may know that I'm in the Department of Surgery. And if there's one thing surgeons are interested in, it's how do we make that healing as effortless and as efficient as possible. So I know it's an incredibly complicated process.

4:26But for people who don't think about wound healing every day, can you give a little tutorial about like what are the stages or what happens? I nicked myself shaving this morning and I thought, perfect. but we can use that as our test case of wound healing. So yeah, what do we need to know about wound healing to appreciate the rest of our conversation? Well, the first is that the body senses it has been wounded likely through disruption of physical integrity. So it's a physical signal that stimulates the body to jump into action to repair a wound. And I'll talk about two kinds of wounds. One is sort of a superficial wound or a wound that is part of the natural turnover of tissues.

5:16And then I'll talk about more extensive wounds that activate different stem cell niches. So the first thing is the body jumps into action to stop the bleeding, keep the outsides out and the insides in. And that means close over the wound. And invariably, that means to stimulate the division of cells around the edge of a wound to cover it over. And that involves stem cells that reside within the tissue. Once the wound is closed over... going to stop you there because a stem cell is one of these kind of very magical cells that has the ability to turn into lots of different things. Sometimes they can turn into everything, but sometimes they have a more limited range.

6:03I just want to make sure we get that right. That's perfectly well explained. And in this case, it's the latter where cells at the edge of a wound just produce daughter cells to cover over the wound. Once the outside is on the out and the inside is on the in, then the body undergoes a much more laborious process of removing all of the bacteria and microbes that have penetrated. So that involves immune system. And then the truly hardest work is remodeling the scar tissue that forms. So that's a lot of, that's an extended process. And now I'll just tell you briefly that when you have a deeper wound, a more extensive wound, let's say a burn, where you destroy a lot of the stem cells that exist around the edge of the wound, then you activate, the body activates a set of stem cells that are called quiescent stem cells.

7:07You can think of them as sort of sleepers and they exist within tissues. And if the local stem cells aren't sufficient to heal a wound, then these sleeper stem cells jump into action to contribute to the repair. Do they do a more approximate, are they the kind that would lead to scars or a more approximate healing versus kind of the perfect healing that we sometimes see? Or can they do a perfectly good job as well? You know, the whole idea of perfect wound healing, I would say that's, you know, as we get older, Russ, our wound healing really declines in its level of perfection. And here's the bad news is that older means like in your 30s.

7:55Oh, my goodness. Yeah. Yes. So I'll give you an example from my orthopedic colleagues. When a child, say 10 or 12, breaks a bone, a pediatric orthopedic surgeon colleague of mine said, you can put the two bones in the same room and they'll heal. Wow. But if you have the same injury and you're 30, the process takes much, much longer. And if you have the same injury and you're in your 60s, well, yeah. Okay. All right. I hear you. So let me just ask about one thing, which is you said that both the quiescent cells and kind of the normal stem cells can both do a reasonable job, especially if you're young.

8:38But for those young people, it's sometimes just – and even for older people, sometimes healing is just amazing because it captures – like it recaptures the skin like almost perfectly or the bone, as you said. And I know this is a big question. I hope it's not too hard. But, you know, here on The Future of Everything, we like to ask the hard questions. Yes. Like how the heck does the body know how to replace all of those tissues so that they almost either look perfect or nearly perfect? Even the shapes, the, you know, the shapes, the textures, everything comes back a lot. And how the heck does that happen?

9:15Oh, man. Now you see, you've already tapped my knowledge out. You know, the idea of how does the structure and the function, not just the structure, but the function return. Here's where when you talk about skin healing as being nearly perfect, you know, sadly, it's not. For example, you can probably look somewhere on your body and find the scar that you got when you were 15 years old. Yes. That tells you something. That's because the hair follicles and the sweat glands, what we call epithelial appendages, those don't reform. And so what you have is a scar. If the scar is small enough, no problem.

10:02But if it's larger, say after a burn and you don't have hair follicles, sweat glands, then you can no longer thermoregulate. You can't, a lot of the plasticity of the skin is gone. And so the repair is far from perfect. There are some tissues that do a great job of repairing, but very slowly, like bone. But even here's one that doesn't repair, articular cartilage. Oh, yeah. Oh, my gosh. So the repair is hardly what I would call perfect. So I don't have to answer your question. I like it. Bad question, Russ. It's not even true. I reject the premise. It doesn't have been that perfectly. Okay. Okay.

10:49Fair enough. Now, you said something really interesting, and I know you've written about this as well. So I wanted to ask you about, you kind of distinguished in your first description about healing between a physical signal, and in your writing, you've also talked about biological signals. And I find that distinction to be very interesting. So could you tell me, what's the difference between a biological signal and a physical signal to you in the context of wound healing? Yeah. Well, you know, as a biology trained person, I tend to think about biological signals as predominating. But I work with a number of engineering colleagues, especially a longtime colleague, John Brunsky, who is a mechanical engineer.

11:31And he talks about physical signals as being the drivers. And I'll give you an example. We know that tissues are shaped by physical forces. Just think about an astronaut in space where there's no gravity and the bone atrophies, right? We also know that if patients are on bed rest, their muscles atrophied. So there's a role for physical forces in shaping tissues. And the way we think about that is that physical forces, say stretch or compression, create strains within tissues and cells sense those strains. And so the act of injury at a very fundamental level, we think, disrupts the physical integrity of a tissue and cells sense that.

12:27And now what do they do in response? You know, there's a Nobel prize that was given out recently for understanding and pinpointing some of these mechanosensitive proteins. And then what we try to do is understand how those physical signals connect with biological signals, because clearly the biological signals are being... And when you say biological signals, you mean things like I release a molecule and this molecule is sensed by other cells and they do something in response to that molecule. There you go. And then there's some hand-waving about how those physical signals and those biological signals overlap.

13:07And that's where we like to find ourselves, right in that niche where we're trying to understand how the two forces, physical forces and biological signals, work together to modulate tissue healing. Great. Okay. So you gave us a great tutorial. We're all pretty comfortable now with wound healing and the vocab. One of the things I know you're very passionate about is this field called regenerative medicine, where we don't just passively let the body do whatever it's going to do. But I think part of the goal is to use our knowledge of these physical and biological signals to make wound healing better, faster, stronger.

13:45How is that field going? Like, where are we? Well, I mean, if you would have asked me 10 years ago, I would have said we're, you know, just at the beginning, but now we have multiple kinds of clinical trials, testing theories that were formulated about regenerative medicine, the idea that we can understand how the body normally forms tissues, how it normally repairs, and think of ways to accelerate those processes, especially as we get older and things tend to slow down. Um, so I would say that the field has really expanded to now. I don't think of it as so much as the edge of the unknown, but rather, uh, you know, part of personalized medicine.

14:36So it sounds like one of the, I'm sure it's a lot, a big agenda with lots to do. Like, let's just acknowledge that. But it sounds like from your last comments that one of the agenda items is bringing back the healing ability after 30 years old, if you want. And so I'm sure there's a lot of discovery that has to happen about what are the molecules or what are the physical. And are we trying to do clinical trials or have things already reached the clinic? Absolutely. I'll give you one example. So I talked about bone before. And one of the things that happens as we age is we lose bone mass. And there's two names for it, osteopenia.

15:21That's when it's at the beginning, osteoporosis, when the bone loss is significant enough that we see porosity in the bone. And you can imagine that makes the bone structurally weaker, more prone to fracture. In the past, the drugs that we've used to treat osteoporosis are those that try to block the resorption process of bone that we think predominates as we get older, instead of there being a balance between formation and resorption. But those drugs had side effects. And a whole new class of bone anabolic agents, that is bone building agents were investigated. And a lot of that early work was predicated on understanding how does a skeletal stem cell decide to become an osteoblast and why does that process slow as we age?

16:24And that whole area of research led to the discovery of some molecules that we think are very efficient at stimulating bone building signals. And so those are now in phase three clinical trials and soon to be commercialized. Okay. So this is great because this is real stuff that's going to be hitting the... It is. It's not pie in the sky, you know, maybe someday. No, it's today. Amazing. So just one example. Another thing you've discussed and I know you've worked on is, and you said this in your tutorial, that one of the things that has to happen is getting, I think you said, get rid of all those bacteria.

17:05And I know that that's a major focus of your work. So what is the challenge there? Because I think we all know about infections, and we all know that our skin is not the most sterile place in the world. And when you get a cut, you're very worried that there's going to be a big infection. How is our regenerative medicine approaches towards kind of fighting infection doing? Yeah. Well, you know, there's two ways to look at this. One, you can look at the wound healing part, closing off the outside out, the inside in, and then clear up the bacteria using your immune system. But then, you know, as well, I have a clinical background, so I'm interested in clinically unmet needs.

17:45And one of them that sort of centers on this infection area is that we have a lot of medical devices that penetrate the skin. So they go from the outside to the inside. And I'll give you an example, catheters, ports, dental implants, even the bone anchored limb prostheses for people who have undergone amputation. Auditory cochlear implants, these penetrate the external skin or mucosa and they go into the body and they they are marvels of engineering and i'm speaking to an engineer so you you love to hear this they are marvels of engineering these limb prostheses but they fail because of infection at the site where the device exits the skin and so the question is the skin has formed around the device, but it doesn't heal.

18:59It's not the same as the wound healing. And there is a conduit for bacteria. Now, you mentioned the skin is not a sterile environment. Well, that's an understatement, eh? The oral cavity. There are only a few places in the human body that are more filled with bacteria. So how do you protect the inside? And so, you know, you might think, okay, if let's just say with a limb anchored prosthesis, a bone anchored prosthesis for the limb, you might say, well, why don't we just put antibiotics on that area? But I think we all know that that's no long-term solution, right? There's antibiotic resistance?

19:47How often are you going to put this on for the lifetime of the... So that doesn't... That doesn't... Just gross superbugs. Right. Okay. So then another strategy you might think as an engineer, you might say some kind of glue. But that... A sealant. That's what we use around the edge of our tub. Maybe we can do that around the edge of Why not do that? So here's where you have to understand the biology of skin. The reason skin is such an effective barrier is because it's constantly turning over and it turns over because of those stem cell niches. So a glue, a sealant that you put on one day will be lost because of So now you don't have a way to protect that because it never really healed.

20:43And so this is where we turn to nature's evolved solutions to just this kind of problem. And I want to get to that in our next segment. Excellent. This is The Future of Everything with Russ Altman. We'll have more with Jill Helms next.

21:17Welcome back to the Future of Everything. I'm Russ Altman. I'm speaking with Jill Helms from Stanford University. In the last segment, Jill gave us a great tutorial on how cells work together to heal wounds. And she told us about the biological and physical signals that the body is aware of as it's doing this wound healing. In this segment, we're going to talk about nature as a source of new solutions for wound healing challenges. Jill will tell us some great stories that may even involve sharks. Don't forget, at the end of this episode, we're going to do our new feature, The Future in a Minute, where I'm going to ask Jill a few questions rapidly, and she's going to answer them rapidly.

21:54At the end of the last segment, Jill, you made a very interesting kind of pivot, and you talked about nature kind of as an inspiration. So talk to me about why we're talking about nature in the context of high-tech wound healing technologies. Well, because nature through evolution over billions of years has come up with solutions for some of these human challenges that we face. And I'm particularly interested in this idea of how with medical devices that go from the outside of the body to the inside of the body, how do we make these robust? How do we make the interface, the healing around those devices as robust as possible?

22:39And nature has evolved solutions. Oh, my goodness. And so the first thing you might wonder is, well, where in the body do we have something, what we call a transmucosal device, something that extends from the outside where the bacteria are abundant to the inside and that nature has evolved a mechanism for maintaining the health of that transmucosal entity. So where do you think that is, Russ? Well, I mean, I thought about like the mouth, but I don't know if that counts because you can think about it as a big tube and which is still on the outside kind of. So I'm going to reject that. And then I was thinking about if there was anything going on in the ear, but I don't I'm not an ENT and I don't really know.

23:28So so I'm drawing a blank here. You were close. I needed to get you to say, I don't know. That's good. Good. I'm glad I would say that. So in the mouth, the teeth. Ah, darn it. So I know. So it turns out that the tissue that we study to understand how to make a great seal is the gum tissue around a tooth. And now there should be no surprise that that can become diseased and there are plenty of diseases. But in health, it has the ability to maintain itself for the lifetime of an organism. And it does so because of a stem cell niche that is constantly generating new cells that form around the neck.

24:20Oh, that is such a cool analogy. It's so obvious that my tooth is like an implant. Yes. In fact, they have dental, as you know very well, they have dental implants. Absolutely. And so it's a bone-anchored kind of implant, just like a bone-anchored limb prosthesis. And so nature has evolved this attachment mechanism. And we think that by studying the mechanisms by which this attachment is maintained through a very high rate of cell turnover, through a stem cell niche, through an elaborate formation of attachment proteins that are constantly being renewed, if we can mimic that around a man-made device, we will have a better kind of, I don't want to use the word lightly, seal that extends the lifetime of these medical devices that are really engineering marvels.

25:24And I can see why you didn't want to use the word seal, because you gave us a nice speech before about sealant is not the right analogy because this, I'm sure the interface between the tooth and the inside of the body is turning over all the time. It must be a very dynamic interface. And so seal doesn't connote the kind of activity that you would expect that is successful. I would say this is where nature serves as a blueprint because nature's solution is sustainable. It's a closed loop system. It effectively controls the amount of bacteria that come in. The tissue itself has multiple immune cells that attack bacteria as soon as they come in.

26:08So it has multiple functions, which are exactly what we want to mimic around medical devices like implants of any kind. So is the program now to understand, is it mostly a scientific discovery program at this point? Like we need to understand how it works or have we gotten to the point where there are already kind of prototypes of how we could make this kind of niche exist in other implants? I think we're getting close to that. Through NIH funding, we've been able to come up with a lot of the basic principles that underlie nature's solution. And now we're testing the extent to which we can replicate those around medical devices, say dental implants or so.

26:59And here's where, if you just looked at all of the features that nature has evolved to maintain this biological interface, you might not know which ones are most important. Right, right. So here's where, again, we think about, you know, nature never comes up with one solution to a problem. Multiple mechanisms have evolved. And you only have to think about, well, animals have evolved multiple ways to replace teeth. Yeah, you have me thinking about sharks. There's alligators, crocodiles, extinct marine reptiles. These are also informing us how did nature evolve mechanisms to protect the teeth of those animals.

27:58And by comparing, I mean, you might think it's so far afield. Why do we care about how a gecko replaces the teeth? But if you see the mechanisms that were used in lizards and marine animals and you compare them to mammals, you start finding what are the essential foundational building blocks. Because you see it across many different species. Exactly. They all have their own little. And what you're saying is so important because at first I was thinking, oh, this means we have to really study human teeth. And of course that's true. But now you and people don't always understand this. This is why we do research on these organisms that seem to be irrelevant.

28:42Exactly. Exactly. Because nature builds over time a better and better seal. You know, maybe crocodiles and alligators use a completely different mechanism. And instead of building a good soft tissue interface, they just replace teeth. But you can understand much more about the foundational elemental components of such a soft tissue barrier if you look over time. So just to be mischievous a little bit, are there animals whose teeth you're finding particularly intriguing? Yes. if when when i saw this my colleague um julian peterson in leipzig um he showed me a picture of i think they're called sheep's head fish oh that have teeth and russ when he showed it to me i said photoshop photoshop no way and wow look like human teeth coming out of a fish mouth which is already sort of the ick factor is pretty high.

29:54But I look at something like that and say, how did nature do this? And if we can understand some foundational difference and similarities, I think we'll be in a position to build better soft tissue barriers. You know, this is a little bit random, but just by your story just now reminded me that I think it was in science magazine in the last few months, I saw a paper about some organism that has super hard enamel and they were doing all kinds of work on it. And it was like ridiculously hard teeth, which who knows if that's going to give us ideas about ways to improve. Absolutely. It will. There's, there's no doubt about it.

30:35It's a hard tissue we can't replace. We cannot replace it because the cells that make it are gone after the teeth erupt. But if we understood how to make it harder. Don't you think that might be the end of dental decay? Oh my goodness. And therefore my biggest phobia in my life. Well, there you have it. Thank you so much to Jill Helms. We're now going to move to this new segment that we're calling The Future in a Minute. I'm going to ask you a few rapid fire questions and I'm hoping you'll give me some rapid fire answers. Does that sound okay? Absolutely. Okay, so here we go. First question. What is one thing that gives you the most hope about the future?