Pathological Heterodoxies in Wound Care

Episode 11 • 18th September 2024 • Open Wound Research • Zweli Tunyiswa

[00:00:06] Zweli: Hi, my name is Zwelithini Tunyiswa, CEO of Open Wound Research and host of the Open Wound Research podcast.

[00:00:13] Zweli: I'm very excited to welcome Dr. Miles Yu to the podcast this week. How are you today, Dr. Yu?

[00:00:19] Myles: Oh, thank you very much for having me here. Hello there, everyone.

[00:00:22] Zweli: I'm going to do a quick introduction to the audience of Dr. Yu with these credentials, and then we'll get started on what I, uh, expect to be a very interesting podcast about pathology, its role in wound care, and some of the interesting findings and theories that Dr.

[00:00:38] Zweli: Yu has around wounds in general and pressure ulcers in particular. So, Dr. Yu received his, Medical degree from the Capital Medical University in Beijing, China. In 1986, he then, completed his PhD at Rutgers University in the great state of New Jersey, or as Jersey people call it, New Joisey. He then completed his residency and fellowship.

[00:01:07] Zweli: At the University of Florida in Jacksonville, and he also did a pathology residency at the University of Massachusetts Medical Center in Worcester, Massachusetts. I believe there was also some research, fellowship as well, particularly at the Whitehead Institute for Biomedical Research at MIT.

[00:01:28] Zweli: Dr. Yu was also a postdoctoral fellow at John Hopkins University. So it would suffice to say that Dr. Yu's academic credentials, are of the highest order, and he, also has served as the, a partner pathologist at his, in New Mexico, staff pathologist, and I believe currently you run your own lab, Dr.

[00:01:51] Zweli: Yu, is that correct? Yes, that's

[00:01:53] Myles: correct.

[00:01:54] Zweli: And that's in the great state of Washington,

[00:01:58] Myles: Seattle. Well, Zweli. You're really padding on me.

[00:02:02] Zweli: Well, just, you know, I prefer every interview. And, Many people, very smart people attend the podcast. I was just very impressed by, the work that you did as a student, both, the practical and the nonpractical.

[00:02:18] Zweli: So I just want to share that with everyone. Cause I think as we continue, in the podcast, A lot of that experience didn't come to the fore, so I just wanted to contextualize it. Dr. Yu, let's, let's talk a little bit about your origin story in wound care. obviously you didn't start, I don't believe, dealing with wounds and pathology until later on in your career.

[00:02:38] Zweli: So, how did you, how did wound care find you, or you find wound care?

[00:02:44] Myles: Very interesting. I've been practicing a pathology, uh, for 20 years before coming to, to work on the, uh, with the wound care, um, in pathology, actually, uh, the wound is neglected to the, uh, basically nobody pays particular attention to it. It is a debridement and there's nothing to it. As a matter of fact, a well known pathologist, a metapathologist, who was reading a wound care for a well known wound care physician, after a while he said, well, there's nothing to it.

[00:03:17] Myles: We're all very non specific. Anyway, so, um, in my lab in Seattle, uh, we are doing some, uh, testing for, uh, for the, um, uh, uh, nursing home community. And we attended the annual conferences in that community. And that's where I met, uh, Ryan, Ryan Dirks, uh, who runs the, um, runs a multiple, uh, wound care clinics, uh, in several states.

[00:03:45] Myles: And so we hit off. He said that the, uh, his providers, cause they're scattered all over the places, each send, uh, biopsies to their own local pathologists that becomes a little chaotic, you know, every, every practitioner has their own location. And yeah. So, we decided to centralize the pathology service for his, uh, wound care clinic, clinics.

[00:04:09] Myles: And that's how we, uh, we got together and started. And really, it's, uh, best of my, my time in my pathology career. Um, Ryan is, uh, very research oriented. He has some great ideas. I'm very, I'm very impressed as a, uh, practitioner. He's very, um, academic. So, um, we've been working together for a little over a year and over this one year we've made some discoveries, some observations that are highly satisfactory to me as a pathologist.

[00:04:44] Zweli: Well, that's brilliant.

[00:04:45] Zweli: And, as you know, Open Research, I co founded it with Ryan. Because we both had, you know, many questions about, the science of wound care and we had what some people might consider crazy theories, that might not be as crazy as we initially thought. And I think that, there's so much, there's so much known about wound care, but there's so much still unknown or misunderstood.

[00:05:10] Zweli: You're doing a lot of, the, uh, biopsy, patho work for, , the group up in Seattle. What, uh, initially, what were some of the challenges as a pathologist at the start and how did you deal with those in terms of sort of the mechanics of getting the samples, uh, and, and ensuring that when they arrive at your location, they're viable?

[00:05:32] Myles: Yeah, the mechanical part is actually easy. You take the biopsy, take a piece of tissue or from the wound and immediately placed in a formalin bottle. And once it's in there, it's safe for forever. And then just, uh, um, ship to us through FedEx. So the logistics is quite easy, um, works out, uh, smoothly. The, um, the challenge in it, when I started it, um, to read, uh, wound biopsies.

[00:05:59] Myles: After I practiced, I had to start, uh, from zero. Because as I mentioned earlier, uh, no pathologies, um, actually, uh, takes the, the wound biopsy seriously. It's just some dead tissue or some ulcer or something. Nothing going on here. That's the, that's the, uh, the, the common, uh, misconception after reading it, uh, I think for a half a year or so.

[00:06:24] Myles: And then I began to see things that I didn't realize. I didn't know, uh, was there before. So that, that's, uh, from there, then things become more and more interesting. We can go into the, uh, details a little later on.

[00:06:38] Zweli: Sure.

[00:06:39] Myles: Um,

[00:06:39] Zweli: so some of your previous, work, came from the cancer field. And you published and did research in, in cancer. I think one of the, cool ideas that Ryan oftentimes thinks about and we talk about is the, how cancer has developed as, as a specialty and the research and understanding around wounds. I mean, around, cancer and, initially, you know, cancer was cancer of this, cancer of that. And now the etiologies have become.

[00:07:07] Zweli: Much, vague is the wrong word, but, much more well understood that the blockation of the cancer is not equal to the type of the cancer. So I guess my question is, given, you know, your patho pathology background and some of your cancer work, what learnings or understandings did you take to wound care, and what models did you kind of apply when trying to understand what was going on?

[00:07:30] Myles: Very interesting. Um, cancer is at the forefront, the most important thing for pathologists and every pathologist deals with that every day. And that's the main thing. But my interest, my interest in, uh, in my 20 years of pathology career was actually the non cancer, uh, biopsies. Inflammations, say pneumonia, uh, uh, hepatitis, dermatitis, these things that, that cancer to me is kind of a straightforward, it is there, I mean, it's there, there's nothing to it.

[00:08:07] Myles: You, you characterize the cancer, say what it is, how extensive it has spread, and it's a standard. But, uh, Inflammatory conditions, non neoplastic, non cancerous inflammatory conditions are far more intriguing. There are a lot of subtleties, and that's what I really dwell on, and, um, and that I can apply all that knowledge to wound care.

[00:08:30] Myles: Wound care basically is a non cancerous inflammatory condition. So I found that much more useful, um, borrowing from my prior, um, interest and experience and knowledge of the inflammatory conditions, apply that to, to wound that that's where I think benefit the most

[00:08:49] Zweli: Okay. And, um, so you start reading these, these wound, biopsies, in the initial, let's say six months to a year, what was some of the initial observations you had, understandings or misunderstandings, and challenges?

[00:09:07] Myles: Yeah. You, you look at a wound or, um, actually the ulcers, I mean, basically it's an ulcer, the skin defect, uh, some, uh, tissue, uh, uh, dies off and slough off. And so you get a defect on the skin. It is 2D uninitiated like I was, and everyone looks similar. It's the same thing. Really, there wasn't much you can tell.

[00:09:34] Myles: This is an ulcer. What more can you say about it? An ulcer consists of, say, some dead tissue on the surface, and then there are some inflammation, and maybe there's some scarring underneath it. And some cases may have bacteria. Some don't. And that, that, that's all there was to it. And, um, I think the breakthrough, um, after about a half a year or so, then it occurs to me, um, the terminology in the field is, is wrong because we call it a wound care, uh, or, uh, say, uh, wound healing, the textbooks, the literature, or the, you know, the organizations, wound care society, or, you know, everything is wound.

[00:10:18] Myles: But actually, strictly speaking, if you talk to a surgeon, a wound is an acute event. Let's say, um, you fall and hit your, uh, say, um, your knee, for example, and then you get, you get a wound or you see a traffic accident, got hit by a car. That's a, uh, acute event. Um, there's a skin defect. Um, the skin was perfectly normal until, until the accident or surgery, surgeon cut you open.

[00:10:48] Myles: There's a surgical wound. So these, in these cases, these are the true wounds. The skin was perfectly normal and the cause of damage is external. Now, ulcer, that is what we're dealing with, um, in the wound care, uh, uh, field. We're dealing with every day, say, uh, venous ulcer, um, diabetic foot ulcer, all these things, uh, pressure ulcer.

[00:11:12] Myles: These are ulcers. Now, the cause of damage is internal. I think in particular, um, vascular lesions. You get a circulation problem. Say, arterial ulcer, you don't have, uh, enough oxygen, uh, blood delivered to the area. Um, so, uh, the skin, uh, was compromised long before it breaks up. Um, say there was a stasis ulcer, for example, you can have that with, you can have a stasis, uh, uh, uh, dermatitis for a decade or two, and then one day it breaks into an ulcer.

[00:11:49] Myles: So the skin was far more from healthy. It was compromised. For, for a long time before it finally becomes an ulcer. And we call it a wound chronic wound. So you see it's very different from the, uh, the acute wound, say a surgery or an accident. That's an, the skin was perfectly normal until the, the surgery or uh, accident.

[00:12:10] Myles: But what we are dealing here is really a, say, a pressure ulcer you press on it for, for a long time before the skin gives up and ulcerate. So that's, this is the, the confusing thing. Um. The, the, the wound and ulcer are different and the clinical importance of the, uh, of the difference between a wound and ulcer is wound, always heal, wound in any wound.

[00:12:37] Myles: They always, it's a powerfully, uh, genetically programmed, uh, programmed event, say a hundred years ago, say the two from. From the beginning of the mankind, we, we need, we have to deal with a trauma or wound and say, until a hundred years ago, people apply everything, including some, uh, fecal material to the wound, hope, thinking that will, whatever the belief was, it will facilitate wound healing.

[00:13:05] Myles: But no matter what we do in the last 2000 years, nothing we do can facilitate healing. The healing always happens at its own pace. So therefore there was a, um, uh, uh, a theory called a maximum rate of heating. That means, whatever you do, it doesn't matter, it has its own pace of healing. But anyway, it always heals.

[00:13:31] Myles: The wound always heals. Because skin was normal and our body can fix it. And so there is so called first dimension healing and second dimension, uh, second intention healing. First intention healing meaning, um, you get a perfectly clean surgical wound and they suture it up and there is no bacteria involved.

[00:13:53] Myles: And that's a first intention healing. It heals quickly. Um, and then there's a second intention healing, and that is you have an open wound for whatever reason you can't suture it up and you have a trauma or too large an area of the skin defect, can't close it. And that's a second intention healing, but nonetheless, first or second, it always heals.

[00:14:16] Myles: Now for ulcer, here's a major difference. It took me six months to realize this. The wounds we're dealing with in our clinics. Our authors and also have no intention to heal. See, that's a major, uh, realization. So, ah, we're dealing with a different animal. The authors don't heal. We have to do something. To make it heal.

[00:14:42] Myles: So that's the first, uh, major realization, say, Oh, and by the way, see, um, most of the knowledge we learned about wound healing, for example, the four phases, a hemostatic and then the, uh, the inflammatory and, um, uh, the repair and the finally, uh, surgery. Scar reorganization, uh, all that it's, uh, we learned that from animal models and animal models are actually wound.

[00:15:07] Myles: They are not ulcers because we surgically cut off, remove a piece of skin from the, the mouse, um, say, uh, back. And that, that skin, uh, was normal. And we, we apply an external, uh, injury, a surgical, uh, procedure. So that's fundamentally different from what we're dealing with. the ulcers. And of course, the researchers tried very hard to mimic the, the human ulcers that we're treating.

[00:15:38] Myles: So they can, for example, cut off the arterial supply, And sort of create a, uh, animal, uh, ulcer or the, the, the knock lady, the wound with some bacteria, or they raise diabetic, uh, I mean, they try to mimic the human ulcers. Um, they, they can approximate to some extent, but they can never really truly create a human ulcer because most of these, uh, uh, patients with a chronic, uh, ulcers, they have a complex com, um, comorbidity, uh, morbidities.

[00:16:14] Myles: And immobility, a lot of bad reading, and this and that, malnutrition. So research, they know that. They can never create a perfect human cancer, ulcer like animal model. So that's, it's a long time. Basically, there's a difference between wound and ulcer. An ulcer has no intention to heal, and that's what we're dealing with every day in our clinic.

[00:16:39] Zweli: So when the implication of this is that there needs to be some intervention. Right. Yes. Right. And, and so I, to you, well, let's, let's take one step back before we go forward towards what possible interventions or how this event, what endpoints those interventions have to touch.

[00:17:03] Zweli: In the case of pressure ulcers, right, which I think are in some ways fundamentally different, when you peer through your microscope, and this is very interesting to me because as a stats, as a quant person, my N equals a thousand, two thousand, three thousand, your N is very small. It's one at a microscopic level.

[00:17:25] Zweli: And so when you peer through your microscope at let's say a pressure ulcer, What are you seeing? Like, what is the mechanism that's occurring on these, um, ulcerations that have no intent to heal?

[00:17:40] Myles: That's, that's the whole game. That's the key question, the most fundamental question. If anybody can answer that, um, I think that that's a, that's something that, that will, um, improve, um, tremendously what we do. Um, basically it's an ulcer. So as the names, um, implies, it says pressure ulcer. The, I think the, um, mechanisms for, uh, for this ulcer is that.

[00:18:08] Myles: Press on it, and then the microcirculation is compromised, the blood vessel network in the skin, in the subcutaneous fat, or maybe even deeper. So the blood vessel, the blood vessels are compressed by this pressure, external pressure. And this, uh, Um, so you actually some research can monitor the hydrostatic pressure in that the microcirculation is very much elevated and that was compromised the local circulation and gradually it says basically the tissue is malnourished without, um, sufficient oxygen and other nutrient supply.

[00:18:49] Myles: And they finally they ulcer it. That's the the ulcer. Basically, it's an ischemic event. lack of sufficient blood supply. So that that what makes it. And then say, um, the, the, the, the escape ischemic state or lack of a sufficient black blood supply estate persists. It's always there. So that also remains.

[00:19:15] Myles: So that's why are the way we deal with offload. We try to, Remove that compression on the local circulation so that blood can flow more freely and therefore remove the injury. The, the assault to the local skin, and that will help, help the ulcer heal. And the, um, very importantly, to the whole field of, wound care, whether it's a pressure ulcer or it's a venous ulcer or a diabetic, bacteria is considered the most important, factor in, in wound, healing failure.

[00:19:50] Myles: It's almost a synonym. When you talk about, whenever you talk about chronic wounds, the wound, they say biofilm bacteria. And the central tenet for that is that it is the bacteria infection that prolongs this perpetual inflammation, which keeps the wound open. They can't heal because there's always inflammation there.

[00:20:16] Myles: So that's a kind of a central dogma for the field. And as I just said, this is an ulcer resulting, resulted from insufficient blood supply, a compromised microcirculation. And so, in, in, in my experience in the last year and, uh, last year and a half, a little less than that, I found that actually, um, bacteria, Don't play that a significant role.

[00:20:45] Myles: I be right now. I believe it is still it's a Circulation blood circulation. That's the key thing. If we can improve that we're going to solve the problem.

[00:20:56] Zweli: So let me ask you a question. I was actually doing some, some reading last night and you know, if it's, if there are patients, there are patients, let's say a geriatric in a, in a nursing home, you observe a hundred patients and the patients have similar comorbidities, but some of those patients, if you're controlling for similar, let's say Brayden scores, they all have similar Brayden scores.

[00:21:20] Zweli: Okay. Some develop pressure ulcers, some don't, all things being relatively equal. So, you know, if these micro assaults are happening on the tissue, right. Um, in essence, if I'm understanding you correctly. Uh, this compromised circulation, the pressure over time, right? Time is sort of that other component.

[00:21:44] Zweli: There's an inflection point where the tissue fails and then it exponentially worsens, right? Like an accelerated failure model. Like, is that the right way to kind of think about that? And then the implication being what is the underlying or the latent, uh, protection some patients have that others don't?

[00:22:06] Myles: Great question. Yeah Obviously if you have a more a fatty pad, you probably have a you can handle the pressure a little better you have a cushion better cushion and of course the the Systemic factors, mobility, for example, I mean, if you're lying, you're bedridden, that's very bad for circulation. So you're compromised, you know, the systemic level to begin with.

[00:22:33] Myles: And of course, age, older age, you know, that's, that's a factor of some other comorbidities. Um, all these factor in, um, so that if a young kid, and that's a much less likely to develop a pressure ulcer. Well, if, if a bedridden for whatever reason, I mean, uh, over a period of time, I think even a kid can develop that too.

[00:22:57] Myles: I mean, it's just a balance, uh, your, how your defense and how the injury, if the injury, um, takes the upper hand and then you, you get a pressure ulcer and, uh, you know, let's say the, the kid have a, say better circulation there are hormonally, um, um, I mean, uh, compared to the, the, the, the older folks and older folks, definitely as a greater disadvantage.

[00:23:22] Myles: in such events. It's local factors and systemic factors.

[00:23:29] Zweli: Sure. Let me ask you a theoretical question, right? So let's say that. You could, you, in this sample of 100 patients, uh, high risk for pressure ulcer and you could travel across time and know which ones would develop the pressure ulcer.

[00:23:45] Zweli: If you were to biopsy the, let's assume it's a sacrum, right? Would you be able to observe? Um, they're that that latent state of failing tissue before they develop the first pressure ulcer ever. Would you actually be able to observe that under the microscope?

[00:24:06] Myles: Um, actually that is that observation that before the skin failure, um, is done clinically.

[00:24:12] Myles: That's why I think they prefer, they prefer the term, uh, pressure injury also is the last stage. I mean, the skin fails, but before that there are some local changes. You can see the color changes. In that area, that will probably forecast a future failure. They call it, um, that's a pre ulcer stage. Uh, so pressure injury, they call it.

[00:24:34] Myles: So that you, you don't biopsy that you're kind of a precipitate the problem if you, you know, poke it open,

[00:24:42] Zweli: but if you, I guess my question is, of course, we don't want to poke it open. But if you were to poke it open, you would observe that underlying tissue damage that was going on.

[00:24:53] Myles: Um, I am sure you are right.

[00:24:56] Myles: Uh, I am sure there are, uh, Well, uh, the tissue is suboptimal. Um, it's not as healthy as you would, you would expect from any other skin, um, without these, um, pressure injury. Definitely.

[00:25:12] Zweli: Okay. There's some interesting devices out there that, monitor moisture, for example. And these are used to, in essence, predict forward on, on compromised skin.

[00:25:21] Zweli: And it's, it's a very interesting area because I think, wound care, up until this point at least has been very much reactive. If we want to deal with the alterations. when they have occurred. I think there's an exciting thought around prevention, primary prevention on identifying those patients or cohorts and then getting ahead of the game.

[00:25:42] Zweli: Because we know once, especially with pressure ulcers, once they get to stage three or four, it, the, it becomes incredibly difficult, to assist them in healing, and incredibly expensive as well.

[00:25:55] Myles: Totally agree. Yeah, there's nothing more to be at. You are exactly right. But I think that requires a lot of, it's a demand for the, um, caring personnel who really have to be very, um, vigilant about these things.

[00:26:08] Zweli: So if we could, I would be very interested in, I know that you brought, some images. To be honest, I don't know what I'm looking at without you holding my hand and guiding me through like Virgil. Would it be possible to kind of. Walk the audience through, some cases visually and what and how you see it.

[00:26:28] Zweli: I, I think it's fascinating. Yeah, the vista that I've always had is at the patient level or at the wound level. It's super interesting to go micro, for a second.

[00:26:37] Myles: Yeah, thank you that I am waiting for this moment. Here's the, um, here's the, uh, little background, as I mentioned a little earlier, um, bacteria are believed to play a central role in, um, in the, the, the chronic wounds or actually strictly speaking ulcer.

[00:26:59] Myles: Anyway, I'll just use the. The conventional terminology a chronic wound. Um, so it is believed that, uh, uh, bacteria will cost will cause a inflammation and the inflammation is there do some damage. So that tissue cannot properly heal. This is an example of what you, um, Zweli. Do you see the photo? All right.

[00:27:27] Myles: They made. All right. Yes, we do. Okay, in the center, this is a bone biopsy for osteomyelitis. In the center, there is a column, a pink column, that's a, uh, bone. And on either side is a bone marrow space and osteomyelitis, um, is a bacteria getting get into the bone marrow space. And so you got a fulminant inflammation.

[00:27:52] Myles: These are all inflammatory cells. Let's say, uh, the, um, everybody in the, in the field says, okay, bacteria cause inflammation, as you see here. And you would expect to find a lot of, uh, bacteria, you would expect, um, these are actually inflammatory cells, all these pink balls. These are inflammatory cells. You would expect, um, this is where you find bacteria, where the inflammation is. But on, as you can see, this is a tissue gram stain, which is a tissue bacteria stain.

[00:28:27] Myles: And I don't see any bacteria in the marrow space. This is very counterintuitive. You think bacteria cause inflammation. So you, you look for, uh, bacteria in the middle of inflammation, you don't find them. And, uh, here is a, um, uh, peros or soft tissue outside the bone. And this is, uh, you can see this well for pathologist, very easy to tell.

[00:28:54] Myles: This is a piece of, uh, a dead tissue, infarcted tissue. And in here, do you see all these little rods, little, um, purplish, uh, rods. Yes, all these are bacteria and notice there's not a single inflammatory cells in here And what are the inflammatory cells look like? Okay Let's go back again. Here's the you see these big balls Say this is one inflammatory cell.

[00:29:36] Myles: This is a nucleus of the inflammatory cell. It's kind of a lobe Several lobes attached to each other. So they twist it. This is another Inflammatory cell neutral field This is another. See, these are pretty big, and the bacteria are very small.

[00:29:52] Zweli: Got it.

[00:29:53] Myles: So, okay. You see here, there are tons of bacteria, all these little rods here.

[00:30:02] Myles: This tissue is permeated with bacteria, but you don't see a single, um, you don't see a single, uh, uh, inflammatory cells. So what does that mean? Say, um, people say, well, bacteria cause inflammation. And here it tells you exactly the opposite. Bacteria do not cause inflammation. You see here? What kind

[00:30:24] Zweli: of ulceration is this?

[00:30:26] Zweli: And, uh, again, pardon me if I ask questions that are very ignorant, but what kind of, uh, ulceration was this taken from? Oh, okay. Um,

[00:30:37] Myles: I think this is, uh, this particular case is an, uh, um, pressure ulcer. Um, by the way, osteomyelitis, um, um, Mostly are seen in pressure ulcers because pressure ulcer goes very deep, it gets to the, uh, the bone and then so the bacteria can see the, uh, the bone marrow and another, um, a little less, uh, less than the, uh, pressure ulcer is a diabetic food ulcer when they, they can cause, uh, osteomyelitis anyway.

[00:31:03] Myles: So this is, uh, uh, osteomyelitis now, the, the central dogma says bacteria cause inflammation and inflammation delays the healing. In here, we have tons of bacteria, but no inflammation. And, uh, contrary to this, where you have a lot of inflammation, you don't see bacteria. So this is, this is, um, this finding doesn't support the, uh, the, the central dogma where, uh, bacteria cause inflammation.

[00:31:39] Myles: I see the opposite. Where I see inflammation, no bacteria. Where no inflammation, there are tons of bacteria. So that's, that makes me think, all right, um. I think we, we believe the wrong thing in wound care. Um, it, see, It is advertised that we do a weekly debridement to remove the biofilm and this and that so the wound can heal. And the reason for that is to remove bacteria, to remove the biofilms, hoping that, um, after eliminating, uh, bacteria, the wound will heal. Think that's, um, that's not what I see, uh, in my experience.

[00:32:21] Myles: I see the opposite. So that's the, I think that's what I learned in the, uh, in the last year and a half about this, wound healing. So back to the, uh, we talked, before this, I believe. Oh, by the way, let me just backtrack. So you see the, um, the necrosis that harbors the, uh, the bacteria, you can see here the necrosis.

[00:32:47] Myles: So what causes necrosis? I think that's the, uh, the central question here. Also, it's nothing but necrosis of the skin. That's why you have a skin defect.

[00:32:58] Myles: The thing's sloughed off. The skin undergoes necrosis or death, and then it's sloughed off. You have a defect, a hole in the skin. Now, it's not a bacteria that causes all these, um, skin defects or necrosis or sloughing. So if it's not bacteria, what is, what causes this sloughing? So just as we mentioned earlier, it's the lack of sufficient blood supply.

[00:33:29] Myles: That was the, um, to me, this is, I don't have a direct microscopic proof of that, but this is what I'm thinking, because infarct is caused by lack of blood supply. When you have a myocardial, , infarct or heart attack, it's because the, uh, the artery is blocked. So lack of, blood supply causes, tissue death.

[00:33:51] Myles: So, that's what, I'm, this is my hypothesis. No matter what, is it, whether it's an ulcer, a pressure ulcer, is a diabetic, not diabetic, it's a little different. It's a venous ulcer or arterial ulcer. I think the, the underlying, the uniform underlying, injury is, a compromised blood supply, not bacteria, bacteria is secondary.

[00:34:14] Myles: See, bacteria comes in colonized in dead tissue. It's just like you leave a piece of steak, um, out in the open in the summer. and it spoils because it's a piece of a steak that's a dead meat and bacteria find a rich nutrient source there. So that's what happened in the wound. So bacteria is secondary, it's passive.

[00:34:38] Myles: It's not, it's not the cause of everything. I think cause of the root cause of all these ulcers is compromised blood supply.

[00:34:48] Zweli: That's interesting. So let me, let me translate this because, you know, when I, when I hear clinicians talk, I like to kind of create a model in my head of the mechanism they're describing statistically. And so let me just take a stab at it just to make sure that I may be getting close. I know I'm going to be inaccurate, but I'm getting close.

[00:35:11] Zweli: So the theory is that there's micro trauma of the skin over time. And there's some inflection point, a latent barrier that gets crossed. Right. That damage then accelerates exponentially. Right. Once, once that damage accelerates exponentially, the bacteria that then makes its way into the body, um, does not actually impede the healing as, uh, impede the healing is that, am I, am I drawing the picture here?

[00:35:55] Myles: You're exactly right. It, um, they do not impede, uh, the wound healing process.

[00:36:01] Zweli: Okay. But everybody,

[00:36:02] Myles: everybody in the field believes that's, that's, they, they do impede that, that's their belief.

[00:36:08] Myles: I'm here to. Disprove that.

[00:36:13] Zweli: And so let's keep going down the causal pathway. Right. And again, I'm, I'm trying to translate this in, in, in real time. And then, so what is the impediment if not bacteria?

[00:36:28] Myles: So the root cause is, inadequate, blood supply and then the, the consequence of inadequate blood supply is, you get tissue, injury on death.

[00:36:39] Myles: So you get a piece of sloughing. Now, the sloughing itself invites inflammation. It's not a bacteria that causes inflammation as people believe. It's a dead tissue that attracts inflammation. And of course, when you have a, a flaming inflammation there, the repair is impeded.

[00:36:59] Zweli: Got it. So the slough, the necrotic tissue collects, it sits, and it attracts secondary detritus, which, which impedes everything else.

[00:37:12] Myles: Got it. You're right. You, you ideally hope the wound is quiet and clean so the repair can take place. But when you have a raging inflammation, everything is, the whole healing process is disrupted. And

[00:37:30] Zweli: you, so, you know, the standard of care is to debride, clean the wound, etc. Is, am I accurate in saying, and again, I think this is, you know, as understood, that creates the environment whereby the wound can then heal.

[00:37:48] Myles: Yes, they actually there. I mean, I probably I'm making a very outlandish statement. I think they're doing the right thing for the wrong reason. You hear the provider say, All right, it's a weekly debridement. To, uh, to, to clear the biofilms and sloughing. Oh, I think they are 50 percent right. The debridement is to remove the sloughing so that, uh, you can reduce inflammation.

[00:38:22] Myles: And at the same time, you remove the, uh, the colonizing bacteria, um, which, uh, To me, probably don't do much, don't do anything. They just, they find a rich nutrient. And they, they, they, they like to live there. Debridement is very important in removing the dead tissue.

[00:38:39] Myles: So that the, the, uh, the wound has a chance to heal.

[00:38:43] Zweli: So let me ask you this question. And when we look at distribution of wound healing times, right? Um, I think that sort of the empirical cumulative distribution supports your notion, you debride, you stabilize the wound, and then most wounds will heal, you know, relatively quickly.

[00:39:02] Zweli: Right. But then you have these wounds, um, you know, I'll say 20 percent of these wounds that can persist. For a very long time. So here's the question. You do everything you debris to create the correct environment, but the wound still persists. What what could possibly cause that at a micro level?

[00:39:25] Myles: You are addressing the, this is a root cause. The most important question to us is this. I believe it is the repetitive injury because the underlying etiology is still present. Let's say, poor circulation. It's still there. It causes the wound failure in the first place, and it continues to, to, uh, to injure the tissue as long as the wound is there, so that we have to re alleviate that.

[00:39:58] Myles: So remove the root cause of everything. If it's say, perfect blood supply, I, I think the wound will heal quickly and you clean it and there is an adequate blood supply. We don't have a problem. But you see people has a lot of, uh, have a lot of comorbidities. So they're, they're not moving, they're not ambulating, so they are, the blood kind of is stagnant.

[00:40:23] Myles: And, um, let's say they have diabetes and they have their own microcirculation issues, or if they say, not enough offloading, or in the case of a venous, um, you're not doing all these, proper things. So the injury remains and that is, ongoing injury. That's what keeps it open. If you remove all these, , injury, uh, remove the, the root cause that the wound will, that the ulcer will heal.

[00:40:54] Zweli: Okay. That makes sense. So basically, according to your causal graph, it's predicated on circulation, microcirculation. And Again, I'm trying to think of this statistically if I were to model it, right?

[00:41:09] Zweli: So there's a, there's a, a state of circulation. The ability for that person to, to, to, a continuous measure of, the strength of circulation. And patients can fall in different ways. Levels of that continuous variable, healthy people, um, are at the top level and then over time, people who experienced, for example, pressure ulcer, their level is, let's say towards a lower end, but they're not all at the same place.

[00:41:41] Zweli: So they're going to develop pressure ulcers at different rates because of this underlying difference in that latent variable. And then there's an implication obviously there for the injury to occur, but it's that very same mechanism, all things being equal when treatment has occurred, that also impedes closure.

[00:42:07] Myles: Mm hmm.

[00:42:08] Zweli: Yeah, absolutely. Yep. I totally agree with that. Okay. And so the implication, if I follow the graph correctly, is that for that subset of patients that don't heal. The focus should be on investigating, interrogating circulatory issues, whether it's, uh, you know, uh, revascularization, et cetera. Is that the implication at that point?

[00:42:36] Myles: Um, right. The root cause for pressure also is obviously there's a pressure there. Offloading is the primary thing to do. And, you know, I haven't. Say, I haven't, really, um, found out, say, identified an effective way of assessing the microcirculation in the ulcer, in the pressure ulcer. I think that's the next step I'm going to focus on, just to examine the microcirculation, see how I can really effectively evaluate the status of that.

[00:43:12] Myles: if there's a way to do so. And that will probably correlate with the clinical cause, whether it's going to heal or it's not going to heal, how the wound progress. That, that's my, yeah.

[00:43:26] Zweli: When I was in post acute, wound care with the team, we, and the, our team had these, devices that did, micro circulation on the, on the feet.

[00:43:37] Zweli: I believe they were called SPP machines and they were very useful for clinicians because for those non healing, foot ulcers where, every intervention had pretty much been exhausted and the patient simply was not healing, it provided great information for the clinician to say, okay, we, this is a fundamentally different patient in terms of micro, circulation and we have two options.

[00:44:03] Zweli: We can continue the standard of care turning repositioning, but we have to be comfortable with the fact that they're probably gonna heal very slowly or they're gonna get damaged again or we have to send them out for a revascularization. of some sort. Um, so that, that kind of comports with what I've seen, um, and seems to support your theory somewhat.

[00:44:28] Myles: Yeah. Looks like, we're actually going the same direction. Absolutely. Yeah, there are some, I think you did have some, devices, handheld devices, to assess the, the, the, the VAs, circulation, at the, at the side wound. Well, I, I hope I could, uh, develop a, analogous, thing, uh, microscopically.

[00:44:46] Myles: Because, I have a better look at the wounds I see at the cellular level. And when you magnify it 100 or 400 times, I see quite a bit more than when you just look at it closely. Yeah, that's my, that's my plan to do the next step. Assess and evaluate the microcirculation. In the ulcers.

[00:45:10] Zweli: One of the things you had mentioned, pre call was, the method by which you collect the biopsies.

[00:45:17] Zweli: So, it was my understanding early on that you would take one punch, in the middle of the wound. And recently you've modified that to take two punches, one in the middle and one at the periphery. What is kind of your thinking around that?

[00:45:35] Myles: Yeah. Um, say the, the, the wound base or the ulcer base usually is, uh, usually is covered with a, a sloughing Well, um, so if you just sample the, um, sloughing, it's a piece of dead tissue. There's nothing to see, just the only thing you can say. Okay. It's a dead tissue, probably with a lot of bacteria, colonizing bacteria in the, uh, in it.

[00:46:00] Myles: Uh, so there's, uh, doesn't give you a chance to evaluate, um, what's going on, see, uh, so that's why, um, there is a, a second biopsy on the edge where I see some viable tissue and you say, ah, I see a neoplasm or a non neoplasm, uh, let's see, I see some, um, something there I could assess. Let's see, uh, A well formed granulation tissue is there on the edge.

[00:46:28] Myles: That's a very good sign, uh, pretending that the, uh, boding well for future healing. But if on the, on the edge, I see an ulcer and with a very poor, um, ulcer bed, poorly formed granulation tissue, that wound will have a hard time healing. Because I think the wound, Granulation tissue is the scaffold, scaffold for, uh, for wound healing.

[00:46:55] Myles: I think I place importance on that. That's what I, and then of course, you can tell a lot of things, say, any vasculitis, for example. You see that on the viable, in the viable tissue. In the, in the wound base, in the center, it's all dead and you can't tell anything. Yeah, that's why we do. Preferably we do both.

[00:47:15] Myles: And actually, so you, uh, you want, you don't want to leave the, the dead tissue. Um, you, you want to look at that too, because they see, is it a colonized by bacteria or not? Some are, some are, some are not. Not always.

[00:47:31] Zweli: That's, that's very, very interesting. So you take that second sample at the periphery. Is it safe to say that, there's many different levels of that tissue, right?

[00:47:46] Zweli: Like you can go from very healthy to not healthy at all. And so you're, if I'm, if, if I'm understanding correctly, that provides you predictive. information because if that scaffolding is healthy and you remove the slough and you deal with the circulation issues, then that, that area should heal pretty efficiently.

[00:48:10] Zweli: If the scaffolding is not, then that person is going to not only heal slower, but could have future issues that repeat the whole cycle all over again. Is that correct? Yeah,

[00:48:23] Myles: Totally. Yes. Yes. Um, let's say, um, other than the scaffolding, you look at, is it very much inflamed or just mildly inflamed? All these things can give you something, but you see, I can only say vaguely about, I assess the granulation tissue, the scaffolding or the, uh, the level of, uh, extent of inflammation, but I, I don't think I have a perfect, um, algorithm to, uh, explain it.

[00:48:52] Myles: really well predict the future of this wound. That's what I'm working .

[00:48:58] Myles: on.

[00:48:59] Zweli: So would, so here's an interesting question. one of the things that we've worked on at OWR is thinking about, assessing for the, the first risk, the first, the probability of the first injury, right? But, as you observe the data, you see that the patients that are on the right side of the tail.

[00:49:22] Zweli: are the ones that have repeated reopenings, right? Secondary risks, tertiary risks, and so forth. And so what you've just said, would imply to me, if I'm looking at it sort of statistically thinking, okay, how do I bend the curve on that tail? If a patient presents with a, an initial pressure ulcer, it almost makes sense to me, at that point, That you take a biopsy at that stage and assess the scaffolding such that you could risk, you could basically re stratify that patient, not only for short term healing to first closure, but also attempt to predict to subsequent treatment.

[00:50:12] Zweli: injuries. Is that kind of making sense? Am I following the pathway? No,

[00:50:16] Myles: you're absolutely right.

[00:50:18] Myles: That's an ideal situation. Ideally, I have a good algorithm that can risk stratify these different lesions from different patients. And so we can act accordingly. Uh, I think, um, I am, uh, biased, uh, because the, the, the sample, the sampling, uh, the, the biopsy is biased as source.

[00:50:46] Myles: 'cause, uh, they only biopsy those, uh, uh, bad wounds. That that doesn't, uh, uh, show any improvement. So I'm not, I don't have the opportunity to, to see a spectrum from the, uh, the, with a wound that is progressing, uh, toward heating. I don't get to see that. I only see the, the bad ones that somehow they mean that the wound is worsening or is just refuse to improve.

[00:51:10] Myles: That, that's what I see. So I see one, uh, category of your risk, uh, strategy, uh, risk, uh, uh, uh, category. So that, that's what I see. Um, I don't have a benefit of evaluating the full spectrum of things, but I can imagine if it's improving, uh, pressure ulcer, I could imagine what I may see under the microscope of that wound, they will look a little prettier,

[00:51:39] Zweli: Yeah, we, we start guys call that, truncation, right? Truncation. Yeah, it's similar in idea to like censoring. Censoring talks more about time. So you observe something, uh, And then at this time point point .. ... you haven't observed it before, so you don't know what happened before.

[00:51:56] Zweli: So that's called left censoring. And then, let's say that patient disappears, that's right censoring. You don't know what happened to them. And then if you see a patient and you've observed them up to time point zero, And then they miss an appointment and then you see them at time point two, you have interval censoring and then you have truncation, which is what you just described where you, you can't observe the full, the full distribution.

[00:52:25] Zweli: Simply because you don't get an opportunity for it to be sent to you. So you have to infer, you know, so it's a, it's a classical, statistical, kind of machine learning problem. But I, I'm very excited by your work because I think the, I believe that wound care is a 20 percent problem.

[00:52:50] Zweli: That is to say that. 80 percent of wounds, once you get down to the root cause, or the first level of root cause, you get that slough out, you allow the opportunity for healing, they're going to heal, right? And it's just a case of creating the right environment. And dealing with any endogenic issues with the patient that are obvious.

[00:53:12] Zweli: But these 20 percent of wounds, these slow healers, repeat open, uh, repeat injury patients just persist for years and on end. And, we, during our meetings at OWR, we did that survival curve that we, we, we talked about. And what, what we observed was that, the stage three or four. The survival curve is, is literally a 40, uh, 35 degree angle.

[00:53:43] Zweli: What does that mean? It means that they just don't react, they don't heal, they just keep going on forever and ever. And for each marginal day, week, month, year, the costs just keep racking up. And so, I think the work you're doing, um, in being able to get a A biomarker, a sample of, of, of, of real data at, at a cellular level is just, would be huge because if we could take that data, and build a model, that can predict that, predict healing, but more importantly, predict reoccurrence or help to predict reoccurrence.

[00:54:24] Zweli: We could really bend that, that, that, that cost curve on these wounds. So, um, I admire the work you're doing for that.

[00:54:33] Myles: Fascinating what you do. Right. I never think of that macro level as you do.

[00:54:37] Zweli: know, it's, it's, What you see is just, it's got massive implications if you times it by a thousand, two thousand, a million, you know, um, and you know, we know that wound care is not a uniquely American problem.

[00:54:53] Zweli: It's an international problem. And so, uh, anything that we can do to kind of bend that curve has massive implications, not only obviously on the patient, but for the economic systems that support, uh, uh, the healthcare systems. Now that's brilliant. I, I think that's absolutely fascinating. I, Um, I'm constantly learning, talking to you and talking to people who do what you do.

[00:55:18] Zweli: And I, I have to say, you got very excited when you could show your cells.

[00:55:27] Zweli: Well, uh, we're, we're coming up on the hour here. And, there's a question that I ask, all of our guests, and I think I know your answer given what we've just talked about. But if you had infinite time, that's the clock. If you had infinite time and infinite resources and you could solve a single problem in wound care, what would that problem be?

[00:55:52] Myles: Gosh, back to the root cause. If we can figure out exactly what is the most critical factor that creates this wound and prolongs this wound, if we know what that thing is, we can act on it. I wish I know that. I have a rough idea, roughly, we're talking about circulation, but exactly how that happens, the critical event.

[00:56:19] Zweli: Would it be fair to call it the great unifying theory of wound injury.

[00:56:24] Myles: Yes, yes.

[00:56:27] Zweli: Well, I thank you for your time. I've I've learned a lot. And, the work you do is fascinating. I'm really excited by that new technique that you're trying out, and I'm really interested to to hear, what distribution of, of, of, of peripheral tissues you see?

[00:56:47] Zweli: 'cause I think that to me has just, just from a predictive, perspective, would be an, an amazing piece of data, to understand,

[00:56:56] Myles: Zweli I really appreciate that you, uh, you have me here to share, uh, my, um. my work with all the colleagues in the field. Um, thank you very much. Uh, I hope that we will keep talking and then exchange with, uh, uh, exchange notes and, um, discussing the, the very interesting, huge problem of a wound healing with, with colleagues.

[00:57:23] Zweli: That's brilliant. Thank you for your time, Dr. Yu. And I, uh, thank the audience for its time. And, folks, that's another episode of the Open Wound Research Podcast.

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