Managing Challenging DFUs and Atypical Wounds

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Episode supported by Convatec.

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Welcome back to Podiatry Today Podcasts, where we bring you the latest in foot and ankle medicine and surgery from leaders in the field. I'm Dr. Jennifer Spector, the Assistant Editorial Director for Podiatry Today, and we're thrilled to bring you this special episode with Dr. Andrew Rader on managing challenging diabetic foot ulcers and atypical wounds. Today's episode is supported by Convatec, so stay tuned after the podcast for a message from our sponsor. Dr. Rader is a fellow of multiple podiatric and wound care organizations, including the American College of Podiatric Medicine, the American Professional Wound Care Association, the Association of Extremity Nerve Surgeons, the American Society of Podiatric Surgeons, the Academy of Physicians in Wound Healing, and the American College of Clinical Wound Specialists. He is the founder of Indiana Foot and Ankle located in Jasper, Indiana, and the medical director of Memorial Hospital Wound Care in Huntingburg, Indiana. Dr. Rader, thank you so much for being with us today to talk about this important topic. Thank you for inviting me. Well, let's get started today talking specifically about these challenging diabetic foot ulcers and atypical wounds under the umbrella of ECMs.

Can you tell us a little bit about these extracellular matrices, what their benefits are, and associated considerations?

Well, the extracellular matrices are particularly useful in wounds that are not progressing through healing like they're supposed to.¹ So wounds, were wonderfully created so that wounds are supposed to heal. And in the course of three or four weeks, we should see significant improvement in wounds, especially if we're doing the right things.² Those wounds are supposed to heal at a predictable rate. And we've got that literature provided to us from the likes of Peter Sheehan, who's no longer with us.³ But we know wounds are supposed to heal about half in four why is there just not going to heal? Extracellular matrices really become beneficial when wounds are not progressing through the normal healing process after the elimination of all other controllable causes like vascularity and offloading and getting rid of shear forces and compression and all the things that are listeners so I'm sure are very familiar with.⁴

Getting into a little bit more detail, could you share some of the benefits in your experience from placental extracellular matrices? Extracellular matrices can come in a variety of different shape sizes and origins. And some of the things that we've learned over time is that, and these are in vitro studies. But if you put elderly tissue, elderly extracellular matrices on young tissue, the young tissue will start to behave as though it's elderly.

We also know that the reverse is true. If you put young tissue on elderly tissue, then the elderly tissue will start to, for a period of time at least, behave as though it's young again. I don't know about you, but if I were trying to heal a wound, I would prefer to have my youth back and heal a wound in my youth as opposed to now in my 60s.⁵

So that's one benefit of placental ECMs and depends on the source, but human placenta is obviously probably not going to be no more than 40 weeks old.⁶ And if you get into other, like a porcine placenta, that's gonna be maybe the oldest it could be, would be three months, three weeks and three days old.⁷ So you're dealing with relatively young tissue.

One benefit of placental ECMs is its relative youth. All sorts of placental ECMs also are going to contain some unique products that aren't necessarily found in, in say, skin, for example. And that includes a lot of signaling molecules or growth factors we hear about cytokines, chemokines, ways to draw in what's necessary for the developing fetus to respond to any sort of problems in its environment.

Now, you can have too much of a good thing. So if, in some cases, there is a tumor developing and the placenta wants to quash the development of that tumor, it might produce a signal that says, "Hey, don't develop new tissue," or if there is an assault, it might produce a signal saying, "Oh, we need inflammation in this case." So it's a mixed bag of signals that you can get from a placenta.⁸ That being said, generally they're going to be a very positive influence on wound healing in our case.

That's so interesting putting it under the lens of the youthfulness of the tissue. Yes. That's definitely a novel way of looking at it.

There's been a lot of innovations in advanced products and wound care over the last several years like extracellular matrices. Can you tell us a little more about some of these?

Well, some of the things that I'm excited about, frankly, in the in these last years. And I think it requires maybe a historical perspective.

So we have to understand that back in the early 1900s, a guy named Henry Dakin, he developed Dakin's solution.⁹ We didn't call it that at the time, but he developed Dakin's solution. And in World War I, they saw good heavens, this saves a bunch of people and cleans up wounds. And they had the miracle. And along comes Fleming and he goes on vacation and comes back from his vacation.

He sees that this mold has now killed off a bunch of staff in his lab. He produces something that they call mold juice at the time.¹⁰ And obviously he needed a better PR person, because that didn't go over very well, but, the medical community kind of looked at it and thought, well, why would we need that? We already have Dakin's solution.

And so they didn't implement that until World War II came around. So this was the 1920s. It was later on during World War II, where they thought, well, let's give this stuff a try. And then we saw ads in World War II, thanks to penicillin, he will come home. And it became adapted. And that was kind of the origins of modern antibiotics near that time.¹¹

We've faced that same sort of battle and we still face the battle. In 1962 we had a winter who showed that moist wounds heal faster than then scabbed over or dry wounds.¹² Paul Brand came to the United States and brought his total contact casting to the United States.¹³ In 1965, Marty Robson showed us the bacterial concentrations greater than 10 to the fifth CFU in pair wound healing or in pair healing with grafts.¹⁴

And these are all things that we've discovered prior to wood stock, and yet we still are battling. The advent of using extracellular matrices in a particularly placental extracellular matrices really harkens back to around 1910.¹⁵ So around the same time that all these other discoveries are being made.

And they were looking in the burn unit, I believe, at Hopkins and they decided, well, we're gonna try some of this amniotic tissue, this placental membrane and see how it did. And sure enough, there was a positive response to that.¹⁶ Well, later on in the 1950s, it came into the eye care world and, and it did a lot of wonderful things in the eye world and much of what we do right now, we, we were able to take out of that eye care world.¹⁷

But developments continue to progress and during my time of training we started to see, oh, there's a lot of diseases that we need to screen for processes when in place for that. And we ended up with more of this modern plus central ECM products that are screened for diseases and are now found to be very safe to use. We've seen some, oh, we actually, we have a lot of literature that points to the fact that these modern products that we're able to use in wounds really do change the trajectory of wound healing and they are financially beneficial in that they decrease hospitalizations, ER visits, amputations, and there's an overall cost savings in spite of their relative expensive of profile, there's a relative cost savings to our US health care system.¹⁸

We have ways now of monitoring that better. So we've got all these different cameras which can image things and see what's happening in the microenvironment. We have a much more thorough understanding of what's impairing wound healing so we can add things to the extracellular matrices and we have antimicrobials for example added to an extracellular matrix to try to address more of that inflammatory or that cleanup phase of wound healing and and then in 2012 we then had had some really unique insight published which looked at, okay, there's a lot of extracellular matrices that we're putting in, are some better than others.¹⁹

What's the body's response to these extracellular matrices that we're putting in, and why does the body respond positively or negatively to these things. And so that I think was, it was a study that was published in Biomaterials back in 2012.²⁰ I doubt anybody else in the readership, including myself was reading Biomaterials in 2012. So it went under the radar, I didn't see it. But now, we're starting to pay more attention, because there's so many of these extracellular matrices out there.

How do we differentiate is the question. How do we know what's good, what's not good, what's marginally okay to stick inside of a wound?

Well, let's dive into a couple of those details. Specifically, can you talk a little bit about the importance of decellularization in extracellular matrices?

And that really does come from that article I mentioned back in 2012. They wrote an article about decellularization and the effect that that has on the wound micro environment. And really what the overarching theme that came out of that is they tested a bunch of different products is that the host's response to what you put into a wound is the key to the success of your intervention. So if you put something into a wound that the host is not particularly fond of, there's going to be a response. It's not going to be a great response to it.²¹

If you put something into a wound that the host, that the, you know, that the wound environment is very fond of there's going to be a positive response and they looked particularly at the immune response. And so what they found is that if there was cellular debris, a significant amount of cellular debris, and whether that cell membrane component intact cells or long strand DNA that the body looks at that and Um, you're not familiar to me and it creates an immune response. It's going to go ahead and try to decellularize that tissue first and that immune response is inflammatory, which is why so many of us anecdotally when we were putting things around tendon that still had, and that's what we were doing more of back in 2012, that still had a lot of cellular debris inside of it, then we would get seromas and sometimes we'd get that tissue spitting out and the body rejected it.²²

It didn't like that. They also found that if it was effectively decellularized, and that definition is still debated in these PhD circles. But if it's effectively decellularized, that that blunts any sort of an immune response to what you're putting inside the wound. And instead of the body working on decellularizing it, what it does is it takes the local wound environment and these proteolytic enzymes that are supposed to be present in that environment, the MMPs, and it starts to break down that extracellular matrix. When it breaks down the extracellular matrix, it creates a signal to the body, telling the body what to do next. And it does that through the creation of what's called cryptic peptides.²³

So I don't know how far you want to go into that, but I do think it's important. These cryptic peptides are tremendously important. It can only do that after it's done with the immune response. So if you put in a tissue or an extracellular matrix into a wound that has a lot of cell components and long -strand DNA, the first thing the body's gonna do is decelerize it. And then after the several day process that it takes to decellularize it, then it's going to start to break down that collagen into signaling molecules to the body that tells the body what to do next. I would add maybe one thing to that and that was discovered by Hesketh.²⁴

And this is something that we're just talking about in the wound care world right now, although it's now six years old, almost seven years old, and that's the discussion about macrophages. So we know that in these non-healing wounds, or wounds that are being very slow to heal, that they all have a type of macrophage that's called an M1 type of macrophage. That's a phenotype that is pro -inflammatory and it's all about cleaning up.²⁵

And when I was trained in the 1980s, if we saw macrophages in an environment, we went, "Oh, well, there must be inflammation "because they're the cleanup cells "and they eat up all the cellular debris, and that's what they're all about. We've learned since then that there are many different phenotypes of macrophages, and the M2 types, four that I'm familiar with of macrophages, that phenotype is after the M1s are done, there's a signal back to the bone marrow that says that's producing monocytes. It says, "Hey, we don't need to clean up the wound anymore.²⁶

Now what we need to do is, is we need an anti-inflammatory type of macrophage that's pro -proliferative. And so these M2 types of macrophages are now being produced by the bone marrow and that's what really makes wound healing start to take off. It also, And we did learn between Keen and Haspeth, so between 2012 and 2017, that a thoroughly decellularized matrix will lead to an M2 macrophage polarized response.²⁷

Haspeth showed us in 2017 then that an M2 polarized response that that macrophage type has everything to do with the scar tissue formation that we get afterwards. And so we want wounds to heal in a way that are more durable with less scarring and increased tensile strength. And we want that M2 polarized response and that again gets tied back to the thoroughly decellularize matrix.

Wow, that was a big ferris wheel we jumped on and I'm glad we got back on the ground again. This definitely lends itself to what you mentioned previously about so many features to think about among this huge grab bag of skin substitute options that are out there.

In your experience, what factors do you believe are the most important when choosing from all of these options?

Well, I think the effect that it has on the body is of utmost importance, so that's the host response is absolutely everything. I also have to think about how does the processing affect what we're putting in so it might start off as a wonderful product but if the processing is aggressive, and it adds what's called cross-linking to the product because of too much gamma radiation, for example, or mechanical manipulation, then the body is, again, gonna look at it and think, "Well, I don't recognize you, you're foreign, "and so I need to have a foreign body reaction to you." I also need to note, as it produce any sort of an response? Is it the is the processing to meet consistent? And is it reproducible? And then finally, because there are synthetic products that you can stick inside a wound, I would ask, does it actually provide anything to the wound? And that again, gets back to as our body breaks down these extra seven matrices, does it create a signal back to the rest of the body telling it what to do next. Those are some great points for sure.

Another feature that's often discussed when it comes to skin substitute products is that of live cells. What has your experience been with this feature and what's what does the evidence show?

So, live cells I love, especially if they come from the host. That's called, you're right. That's the perfect situation. There's a beautiful extracellular matrix that you can take at 15 1000th of an inch off the lower leg called a split-thickness graft and you can apply it to a wound bed that is adequately prepared and low the old skin will grow and it's just a wonderful thing.²⁸ So live cells can be wonderful. Live cells that the body doesn't recognize can be an issue.

Those live cells immediately, if they are perinatal or placental types of cells, can can offer some benefit. There is absolutely an anti -inflammatory benefit immediately. And there is also a release of growth factors immediately, but they don't become our cells.

So if I put somebody else's live cells into my wound, they're not going to become my skin. They're going to die. And during that process of dying or apoptosis, that's going to send a negative signal to the body.

And we're going to see an increase in apoptosis with that. We're also going to see the body work on getting rid of those cells. There is recognition.

And I've heard from several different circles that, you know, "Dr. Rader, what you don't understand is there's immune privilege in a lot of this." And I think that it may be worthwhile just to touch on immune privilege.

Immune privilege is actually something that happens in the body. There are five immune privilege sites in the body, the anterior chamber of the eye, the cornea, the brain perincoma, the pregnant uterus, and the testes.²⁹ And if you take something and like say an amniote and you put it in the eye, there's absolutely a blunted immune response to that because you're putting it into an immune privilege site.

But immune privilege is a one-way street. It has to do with receiving and not giving. So if I take the cornea out of an eyeball and I wanna stick it on a wound, that wound is gonna, and it's not on the same person, that wound is going to look at that thing.

Well, you're not me, I don't recognize you. And there will be a response to that. So there is some benefit to those live cells, but then the body has to get rid of that flag of, hey, I'm from somebody else before it can actually use the extracellular matrix it's left behind.³⁰

So there's going to be an initial benefit, an immune response, and then there's going to be a benefit again later. So it's a mixed bag of of pros and cons with that. Just hard to back to those live cell products going back to 1998 with the advent of graft skin and and then following from that with again, these are plus or perinatal products that they did affect the trajectory of wound healing.

Now, what we didn't understand when they were doing that research back then is the influence of bacteria, biofilm, wounds being stuck in the inflammatory phase.³¹ So we don't really, we don't have it in a modern day setting that sort of clinical evidence, but it did affect the trajectory wound healing. More wounds healed with products that offered cellular tissue technology than standard wound care, which was wet-to-dry saline dressings.³²

So you spoke before about some of the benefits of central extracellular matrices. Can you talk a little bit more about how these advantages might compare to typical xenograft extracellular matrices?

So I think xenograft as far as the collagen itself, which gets broken down, that the collagen is remarkably preserved across mammalian species.³³ So those building blocks, the amino acids, they're very much the same between me and a pig and a dog and a horse and going down the list across mammalian species.

And as we break down the collagen, it creates these signals, these cryptic peptides. And in that way, That's wonderful. We also know that there are now, we understand that there is embedded in the collagen these things called matrix bound nanovesicles, which look a whole lot like exosomes, although I think we're not allowed to call them exosomes.³⁴

And we might be familiar with exosomes from the whole stem cell world when we talked about all that stuff. And in the past 10 years, zones are little suitcases that the cells package up and they send a signal out to the body saying, "Hey, this is what we need to fix the problem." And so they send this signal out to the body and in the case of an extracellular matrix when there's an injury, the signal they send out is, "Hey, we need multi -potent, pluripotent stem cells to come in and help that out."³⁵ What they don't contain in say, oh, if you took a horse eyelid, I hope there's no product that's a horse eyelid, but if you take a horse eyelid, what they don't do in that case is they don't have a lot of the growth factors that are present in placental tissues or these signaling molecules, and it's really nice to have some of the interleukins and the VEGF and the, you know, TGF beta and some of those things that push along wound healing. And there's just so much research being done right now, especially in the whole IL-1R groups.

IL-3 is a part of the IL-1 And these interleukins and these signaling molecules have much to do with healing of the wounds and healing in a rapid and effective way.³⁶ And the research is being done and I cannot tell you where it's going to end up, but there's benefit to the placental tissues. Going back to those placental tissues, human placental grafts or H-CTPs have been used for quite some time.

From your experience, what are some of the risks with using these types of products and or how do they compare with xenograft products?

Sure, sure. So, if you asked a group of folks, what would you rather have placed if you had a wound, what would you rather have placed or if you had a heart valve or whatever, would you rather have a human tissue? Would you rather if it's a allograft or would you rather have a xenograft? And I've done this in rooms before. Most of the hands say, well, I'd rather have an allograft because at least it's more similar to me.

And so you're already thinking about, okay, immune responses. But an issue that we have, and we talked about age before, is that allograft frequently is not going to be from someone that was very young. So say we take skin from somebody. It's usually after they're deceased and they've lived their life. And because of that, we've got old tissue that we're trying to put on new tissue and to get new tissue to grow and it's not going to behave like new tissue. It's gonna behave like older tissue.

So that's one issue. As far as the placental products in the xenograft world, we're able to put up a barn and make for a beautiful environment if we chose to feed a perfectly healthy diet, make sure that they don't eat ultra-processed foods and smoked cigarettes, make sure that they're not doing those things that we know are harmful, and yet the products that come from an allograft. And they're not 18 year old moms who have eaten a vegan diet their entire life have never taken any medicines who have never smoked, who have done yoga and meditation, we're not able to control the environment like that, thankfully. So you're going to get a variety, and this has to do with the consistency of the product.³⁷

You can control everything about the environment of a xenograft. It's possible. It's not done for all xenographs, so not all xenografts are created equal.

Some of them just frankly come from a slaughterhouse, and you're going to get what you get there. But you have the ability with a xenograft to control that environment. And then if you choose, there are different pathways you can go through with the FDA to get this approved to use in humans.

If you choose to go through a 510 process, and then you're allowed to thoroughly decellularize this, it's not subject to minimal manipulation, you're allowed to make it into something that could be truly useful to the wound, whereas the H-CTPs, those are those 361 products from the FDA, those are subject to minimal manipulation and we're limited with how much we can do with those which makes effective desilirization just impossible.³⁸ And so we picked on, I guess, xenografts the millions. I think the same thing goes for the fishes swimming in the river and the sea or anything else that you can make a xenograft out of.

Can you control the environment? Can you control the age? Can you control everything to make it an entirely consistent product. So every time you open up this product to use on a patient, you know exactly what you're getting. - Well, these are extremely vital components to think about when you're looking at these diabetic foot ulcers and atypical wounds that pose so many challenges for clinicians. 

For just a moment, we're going to ask you to bring out your crystal ball and think a little bit about the future. There were some proposed changes to the Medicare local coverage determinations that did not go into effect in 2023, but there does still seem to be some discussion about the future of billing and coding for skin substitutes. So looking into that crystal ball from your point of view, what do you think the future looks like for hard to heal wounds like these in a private office setting and hospital outpatient departments, what do you think this is going to look say in 2025 or even beyond? So as a disclaimer, if I had this information, I would open up one of those websites where you pay by the minute and I would talk very slowly and I would give you the information and I don't have the information.

I can tell you though what I observe and I am part of a group called the Alliance of Wound Care Stakeholders. Those of you who are in private practice, you need to know that there is access to that available now where there didn't used to be. And a lot of the information that I get comes through that alliance.

So all those disclaimers aside, I know that several recommendations were made and they received really overwhelming approval that for the HOPDs that HOPDs are being handcuffed a bit. If they have wounds that are larger than 25 square centimeters, they're left with this bundled price. And they are being penalized for using the, we'll call them skin substitutes for ease, but that's not what we're allowed to call them through CMS right now.

But these skin substitutes, they're being penalized. So there's increased cost, but the same bundled reimbursement. And so we saw Medicare take a hard look at that supposedly and come back and say, no, we're not going to change anything.

There's one big signal. Apparently, what I would decipher from that is that they're not hating the idea that a lot of wound care has moved from HOPD into the private office setting. They also told us in the past that private offices be where we're going to bundle your payments to.

And they thought about that and they backtracked on that and said, okay, we're going to need a little bit more information the longer the clock ticks on it. And this could come out absolutely any day.³⁹ It could still happen and it could show up and we could get bundled payments in the private office.

But I think some of the literature that has been coming out, and we saw with just to mention the first couple names, Armstrong, Tettlebach, Jeff Niezgoda. it's a long list of real leaders in the wound care world, you know, they looked at the cost effectiveness of these wound care, these wound or skin substitutes, and they found that they really were beneficial.⁴⁰ We've also looked and seen that even though a large portion of the cost is now shifting over to the private offices, we've seen a big uptick in that that overall there has been a savings to the, to all of CMS. And so the latest that I hear is that they're finding this to be a terribly complicated subject. 

And they're not sure still what to do with the private offices. I am, I would not be surprised if the private offices were allowed to continue to bill per unit and all products that came out immediately had a published ASP, a published price, and no more of this interim period where products can be immediately put into a high bundle category. I think that if they don't give a published price immediately, that they'll probably get put into a low bundle category, so they'll be reimbursed low and penalized for not giving a price immediately.

And that as long as it continues to save CMS money ultimately the decision is based on we've got a this much of a bucket full of money and if we can make it it go around and work uh that we're not going to probably change things too much so you know uh hurry up and wait is is the order of the day And the more things change, the more they stay the same. I don't see things changing tremendously other than a little bit of the onus being put on companies to have sizes available and to publish their prices immediately.

Well, all the more important, Dr. Rader, that you brought us back to the science behind these clinical decisions. Thank you so much for being here with us today and for sharing your insights on some of these options for hard to heal wounds.

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