TAPE STARTS – [00:00]


Dr. Robert Frykberg: They used to call healing wounds wound healing. Now, it's regenerative medicine. Has anybody else noticed that change in the last 10 years or so? And in the last decade also, there's been a plethora of new and exciting different types of advanced modalities and products. So our next speaker is well-experienced with this area. Ryan Fitzgerald was a writer. I don't think you're still writing for residency insight anymore, are you? Or you're still, but he had written a number of articles where it presents online and residency insight. He is a Clinical Assistant Professor of Surgery at University of South Carolina, and comes to us from Greenville, South Carolina. So let's welcome Dr. Ryan Fitzgerald.

Dr. Ryan Fitzgerald: Well, it's great to be back. I had the opportunity, probably five or six years ago, to do some of these talks, and so it's nice to get to interact with the team again. So we're getting the band back together as it were. But Dr. Frykberg made an excellent point that the transition from wound care to wound healing, and then ultimately regenerative medicine to just a paradigm shift that is occurring, and we have the opportunity to sort of be on the front of this as it occurs.

And so one of the things that we're going to be talking about for a little bit briefly today is the sense of this continuum of care and kind of where do the various products that are now available to us fit into those places. Because all too often, particularly in ancillary centers where you're getting, you know, sort of secondary and third referrals, folks have been progressed through a series of other modalities up until now and they haven't had great success, and the question is, why not? And it's not so much that these products don't work, but if you use the wrong product in the wrong time, you're not going to get a positive outcome.

[02:01]

So that's kind of the broad strokes. We could sort of end with that and then have just a dialogue about specifics but this is sort of the point. The idea of knowing what to use, when, and where, and to identify the roles and the things that will come into keeping wounds from healing, because we have to remember that the wound wants to heal. The natural state is for wound to heal. When we have these patients that we become accustomed to them having wounds and they become accustomed to having wounds, the sense of the urgency of healing goes away. Many of our neuropathic patients can't feel their wounds, and so there's no impetus for moving forward, but we have to remember that the normal stage is healing.

There just is an aside and this is kind of an oversimplification, but it really, really highlights the point, the idea of the continuum. Because we could superimpose sort of various products into these spaces in terms of wound healing. We all know that the initiating event is some sort of trauma to the tissue, which relates to an inflammatory process, which is essentially the body's attempt to clean up the broken pieces. After that, the body needs to lay down a new tissue and that's the proliferative process. That's where the body is making new things to fill the gap on whatever was damaged before, and then ultimately remodeling that tissue that was made in the proliferative phase to progress on to healing. That is the normal state of affairs, those three stages.

So when we think about wounds that are not healing, chronic non-healing wounds, they're stuck somewhere in these first two. And there are unique component pieces of each of the stages of wound healing where a wound that is stuck in inflammatory is going to be – is quintessentially different than one that is stuck in a proliferative phase. So this is what we have to think about. We have to think about the perfect product would be able to assess the wound and kind of provide what is necessary. I did some work with Dr. Armstrong many, many years ago and he always talked about, you know, if you could just put a litmus paper down onto a wound and it would just tell you what you needed, then you know how to do exactly that. And honestly, the technology is evolving, leaps and bounce in that direction certainly, but we're not there yet.

[03:59]

So you have to have a sense of what do the products do, first of all? Like what is their function? How do they work? And then, how do we incorporate them in our practice to help our patient? So in the concept, the tissue graphs, you have to think of the different types of graphs that exist. Globally speaking, you can think of them as sort of scaffolds or cytokine delivery vehicles, coverings, or things that are designed to create a biologic process. Kind of new in the market that in the sense of it is applying the ideas of wound healing and biologic wound healing to biologic bone healing, to osteogenesis. And that's kind of becoming one of the forerunners of the technology in the space.

So as you are thinking about your chronic difficult to heal wounds, you have to consider where do you think they are. What is happening to these patients that is limiting their capacity to heal? Now, I will tell you that the entire rest of this talk presupposes that we have already checked the vascular status. They're adequately offloaded at all specific, you know, infection, and things like that have been addressed. Because that's the standard of care and it's important to understand that advanced modalities are not used in lieu of standard of care, or rather in addition to standard. So having performed good standard of care and these wounds are not healing, then what?

And that's when we have to think about, what are we trying to do? Are we filling in a gap with the scaffold or do we need something that's biologic? Or are we just trying to provide coverage? And that's where we have to tease into the idea of these various graphs. Now, it is a challenge particularly these days. If you look at the literature, there are so many graph products available, particularly in the amniotic space. And there's a lot of options and some literature comes better than others, but we are literally flooded every day.

Our offices are flooded with a new product, a new graph, a new injectable version of something that you could get in a sheet prior the week before, or even. So you really have to think through and critically evaluate the efficacy of these graphs because one of the factors that as a resident I know and certainly my training experience, I never really considered sort of the healthcare economics, you know, the cost of things and the game on that side of it. But it becomes increasingly important once you get out to understand the cost of things and how they are reimbursed.

[06:09]

In South Carolina and in Georgia where I am now and actually in Atlanta, we're with Palmetto for Medicare. Palmetto will allow us to do 10 graphs per wound for the lifetime of the wound no matter what. And that's the wound, not the doctor. So if somebody has been seeing a patient and does five graphs that don't work and then they get referred to me, I only have five more to do. But you have to use the graph that's going to work. If you burn all your bridges using up your slots with something that is less effective, then that's just a bad care and it's expensive, particularly if the wound doesn't heal for the end of those 10.

So you really have to think through the economics and sort of beyond just the efficacy of does it work or does it work well and efficient? So that's the challenge, trying to get a sense of what is the right graph, how do you know? How do you look at the literature? And do we actually look at the literature? Here, and the reason I didn't say, when somebody came in, they give them product, you're handed the, you know, the requisite whitepaper. Have you ever looked at it again ever? I got three or four walking around the vendor hall and I've already probably thrown them away. That's not what the rest want to hear but that's the reality of things. We know that. It is the nature of the – but that's the challenge.

We are the doctors. We have to be better. We have to look at this information. We have to decide what the right answer is and then act on it. So one of the things when we start talking about the continuum of care and the idea of this wound healing space, we talked about the inflammatory component. What we are starting to understand is the role of biofilm plays in the context of wound chronicity. Biofilm as you know is the sense of bacteria in a space on a surface, you know, the diet coke, the tabletop and bio – and that's the potential for bacterial contamination that progresses on.

[08:00]

Now, not all bacteria creates biofilm, but those that do can significantly impair would healing. Current studies as the technology evolves to test for this have shown that up to 90% of chronic wounds contain biofilm. So think about that, nine out of 10 more likely than not, so for your chronic wounds, very likely that they have biofilm and the literature is increasingly demonstrating that the nature in which biofilm wound healing. Interestingly, approximately 17 million new biofilm infections occur in the United States every year. And when you think about biofilm, the presence of this contamination is not really an infection, but infection is the next step. If the wound is contaminated enough to be making biofilm, then the next thing is going to be wound infection.

And we know that those patients who get infected are going to ultimately end up in the hospital. They're going to have surgery. They're going to have amputation. So this is an opportunity to intervene to reduce these numbers. Interestingly, acute wounds only have about 6% of biofilm and there's a variety of reasons for that, but it also highlights the idea of debridement. The sense of going in and cleaning up the wound to convert – we've all heard the idea of converting a chronic wound to an acute wound, one of the reasons that that is useful is that it does change the position of how the biofilm is in the wound and how the wound is responding to that biofilm. And biofilm can be in a great many places and not just the wound bed. It can be in the dressing, it can be on the pin sites.

We had an excellent lecture about external fixation that I was sitting in the back on. Talking about pin site infections in the sense that the movement of the skin over the wire can ultimately lead to irritation and infection, but prior to being infected, it almost certainly coated in biofilm. So there's an opportunity to intervene. So how does biofilm impair wound healing? It's pretty interesting because it happens in a variety of ways. Not only is the biofilm itself irritating to the tissue because, you know, caustic, it creates an inflammatory response. Under the biofilm is a very low oxygen tension environment.

[10:03]

It is almost in oxy – so you can have floral blooms of anaerobic bacteria that are contaminants that can survive under the biofilm. You have competitive limits of oxygen in the context of this irritating inflammation, which allows continued inflammatory response. And if you remember the first slide, inflammation, proliferation and remodeling. If you're stuck in inflammation, you can't get to proliferation. You have to address the inflammation component and this just kind of highlights sort of how that happens, how the immune response causes tissue damage. Effectively think about a low boiling pot, it's continuing to boil over and over and over again, anything that you put in there will eventually be damaged even if it started water, same idea.

Interestingly enough, the presence of biofilm also kicks up the MMPs in a wound. We've all heard the sense of the MMP's imbalance being a source of consternation in wound chronicity because the MMP's function in normal healing wound is to breakdown the bad stuff that's already broken collagens and then go away to allow for a new tissue to be developed. The problem is when you have too many MMPs that are staying in the wound, every time your body tries to lay down, new collagen, new MMPs absorb it. And what you can see is in various kinds of wounds, the amount of MMPs that exist relatively little in acute wounds because they haven't had the time to proliferate. But the longer the wound goes the more likely they are to have the different MMP.

Interestingly, in this study that was done in panel B, this was done in the wound repair and regeneration. You could see as a chronic VLU wound is healing, the level of MMPs drop. Which makes sense, but it's important to consider that's part of the process. So not only to address the potential for bioburden, but also the MMPs that are all consequence of bioburden to progress a wound from chronicity to healing. Get it back to the sense of an acute wound.

[12:00]

This is a study that was done in Gibson and some others that demonstrate just MMP-9 activity correlating with wound healing. So they basically had a wound that was doing okay, it was healing and the MMPs were dropping, as the MMPs drop, the wound area had dropped. As the MMP started uptick again, the wound area increased and there was this sort of overflow. Even as the MMPs stayed sort of stable, there was this huge overshoot of wound area. Really suggesting the idea, the role that MMPs play in wound chronicity and ultimately as the MMPs dropped again, the wound area dropped. All of this highlights the problem, the idea of what is happening with this patient? And then the question is, what do we do for them?

So how does this fit into our treatment paradigms? One of things that is becoming increasingly vogue in the literature and in conferences is this idea of biofilm-based wound management in the sense of a systematic approach to address that first component of non-healing in a wound, the inflammatory side of things. The biofilm and the potential for MMP imbalance in sort of one fell swoop. The question is how do you do it? And so there are variety of ways. Frequent debridement is certainly very effective. In fact, you can reduce a biofilm number in a wound very significantly by debridement. The challenge becomes how quickly the biofilm return. And that suggest in the literature about within anywhere between 12 to 24 to 48 hours to get a fully redeveloped colony.

If you think about the patient's that come in your wounds center, where your residency is based, your clinics, you debride them, they leave out. They come back maybe in a week. So they've only had a day or two biofilm-free before the biofilm comes back. So the idea is we have to do something that we can put on them that they will stay with them between office visits because it is not effective for us to debride them every day. So that's one of the challenges. We want something that's going to be antimicrobial because there're many bacteria that make biofilms. Some gram positive and some gram negative. You don't want to get pigeonholed into only being able to treat one side or type of bacteria.

[13:58]

And then you want to be able to address the sense of a step-down step-forward treatment, which is somewhat difficult to get in reading. And I've got a picture that kind of explains it more, but the idea is that it's meant to address the presence of biofilm while also addressing the produce MMP imbalance at the same time and that's kind of this idea. And it's a busy slide and it will be available for you guys, but in the sense of how you're going through the steps from the first few days to sort of the first week or two into the first couple of weeks and then ultimately on the healing. And that's what's important in the sense of aggression down the pathway because different wounds are different places in the pathway and at different places in the pathway, they need different things.

We have to be able to kind of get a sense of where they are and how to progress through them. So one of the things that is available to us is a crosslink collagen product that has PHMB. PHMB is polyhexamethylene biguanide and it's an antimicrobial component system that is very good at killing bacteria and we'll talk about why, but the idea of it is it's a two-layer – this product is a two-layer collagen with this PHMB that's sort of seated amongst the collagen. And the idea is that it allows for intact collagen to be there, which is good for binding MMPs and we'll talk about that in a minute, but also puts that PHMB into the space where the bacteria that would otherwise cause biofilm [indecipherable] [00:15:22].

PHMB has been quite commonly used in a variety of historically more industrial application as a sterilizing agent, but it is increasingly becoming useful in US in terms of the medical market. For example, who here wears contact lenses? Anybody? Contact lenses? Do you ever wonder why you can open up a bottle of contact lens solution, put it on the shelf and put it in the drops in your eyes for months at a time and it never goes bad, put in your eye all the time it's open? The stuff that's in contact lens solution that keeps it sterilized is PHMB. It's been around forever, but that, plus this collagen allows for a product that does indeed do that thing.

[16:02]

The importance of collagen cannot be downplayed particularly in the context of MMPs. We know that collagen upregulates the activity of fibroblast to make more collagen and secrete growth factor, so there is this positive upregulatory effect in the context of putting collagen into a wound space. But in addition, intact collagen fibers function as a sacrificial substrate for the MMPs, which is to say in those times when you have MMP imbalance, too many MMPs putting collagen, intact collagen particularly into that space is of value. The native structure is particularly important because it's a bit like a child's block puzzle. Collagens and MMPs are enzymes and they're looking for a specific site.

Think of a star or a rectangle or a circle. Intact collagen has the intact requisite star or circle or whatever. Morselized collagens, things that where they take the collagen, they chop it up and they put it back down on a cellulous paper sort of thing, these little pieces of it. So you might not get the full star. You might just get two pointy corners, which is not what the enzyme is looking for. It doesn't bind as well. So that's why the native collagen and the native biofilm materials is more effective in binding those. And there's been a variety of studies that have demonstrated this and you can kind of get a sense of reconstituted collaged.

This would be something like a Prisma or Promogran where its collagen is chopped up and then it has a cellulous component versus native collagen, so it's got that intact structure and how the produce levels are affected in the presence of MMPs. So basically, what this suggested in the context of intact collagen, the produce levels are lower, which makes sense. Because if you think about the purpose of the MMP in the first place is the idea of breaking down collagens, so it's going to look for intact collagen. The less the collagen looks like collagen the less effective it's going to be in terms of binding – so that's the value for that in terms of intact collagen. It is been well demonstrated that VLUs close faster in the presence of intact collagen for that reason and some others and it just kind of shows it in that as well.

[18:03]

So PHMB, polyhexamethylene biguanide, we talked about this and effectively, what it does is it pops off – it is positively charged and pops off a phospholipid negatively charged ion on the outside of bacteria. So it effectively goes in and it binds to the bacteria and pops a little hole in it and if you look at the electron microscopes about it, you can actually see the little dimples where the holes have been. The cells will then lice and die. Now, what is interesting about that is that because these bacteria have this phospholipid on their membranes, they can't evolve away from it because it's part of being a bacteria in the abstract and some fungus. Human cells done have that same phospholipid so the PHMB is safe, not going to put holes in the human cells.

But also, the bacteria cannot evolve against it. They can't adapt because if they did, they wouldn't be bacteria, because they wouldn't have the specific [indecipherable] [00:18:52]. So it shows no resistance in that regard. So it's a broad spectrum because bacteria both gram positive and gram negative have this phospholipid including MRSA and pseudomonas, which as we think about the nature of the pathologies and the pathogens associated with many of our diabetic foot infection, particularly polymicrobial, particularly these offending bacteria. So it's important to think about, so now, this is something that you have in your toolkit. You have this capacity for this product that has collagen to address the MMPs and the PHMB to address the bacterial component.

And it is broad spectrum against MRSA, equalized pseudomonas, aspergillus and candida. Again, the idea of being that you want something that's going to be most effective against most likely all comers. And so that's very, very effective in that regard. This is just a pre-clinical model and this was interestingly done. This is a study at the University of Miami, which showed they basically seeded a series of wound with a certain amount of MRSA, 4.24. So they knew how much MRSA they put into the wound and then they treated it with a variety of different dressings and graphs and stuff. And then came back at the course of a couple of days, they did a 72-hour and then a – a 24-hour and 72-hour timeline.

[20:07]

And what they ultimately found was that in the context of nanosilver, two-layer nanosilver or –bio-occlusive any of the silver products, there was more MRSA in the wounds at the end than when it started. Which if you think about, it means that MRSA grew in the presence of silver in this condition, which is bad. If we're treating MRSA and there's more MRSA at the end, then that's not an effective treatment. Conversely, in the Polyhexamethylene Biguanide group, there was less, 4.2 to 3.1. Not only did it hold the level of MRSA steady, it declined it, so it was bactericidal. It killed the bacteria. So that is effective and it's important in the context of our management of these kinds of wounds.

So it is useful in three ways, the idea that purified type 1 collagen to address the MMPs, the barrier just as a functional barrier and then ultimately the PHMB as an antimicrobial. So that's one of the things that we have in our toolkit now to address this sense of biofilm-based wound management. In addition to surgical debridement, now, we have this potential graph that we can put down onto a wound that will hold the line so they can come back. Try to reduce the reformation of biofilm. Now, it's really important to get this concept, the idea is the graph or the product, you're not looking for that to kill biofilm. You're good debridement, what's doing that.

The graph product is holding the space to limit the reformation of biofilm in your absence while you're waiting for the patient to do what else they're going to do before they come back for their next visit. But it does have the capacity to allow them to limit this by limiting the – by having the broad spectrum antimicrobial nature holds that line, keeps that biofilm from reforming. So in addition to the basic tenets of wound care that we talked about in the sense of standard care, now, we have all of these things, but now we have the capacity to address biofilm as well. So when I was coming through that was the sense of sort of the triad of disease offloading vascularity and infection. And if it was offloaded, it was profuse and not infected, then it would heal, except a lot of wounds did not heal.

[22:09]

We're now starting to see that biofilm is [indecipherable] [00:22:11] to that. But let's say we get past all of these things. We do all the good debridements and we're still not healing. This is just a lot of information for a relatively short amount of time but we've still have access to it later. The sense of the reason for debridement both and the idea of removing senescent cells, denatured collagen, all of this stuff much like the guy from before said – or a few stuff, this is the why of debridement. But effectively, to clean the wound up to make it that acute space, better progress it from that inflammatory space onto proliferation and then ultimately – for variety of different wounds.

And this is just a study of us talking about how to incorporate that into your practice model. So not just is it profuse, is it offloaded, is it infected, but is there biofilm and what am I doing about it? What is my plan to address the biofilm to progress? So in addition, what else do we have? We've got these barrier dressings, negative pressure therapies that are coming out, insulation vac. Who uses insulation, anybody? Yeah? Did you have a good success with it? Yeah. It's an interesting idea and we'll talk about a little bit the idea that you're basically providing wound chemotherapy in an infusion space to flush the wound repeatedly, which is effectively sort of a type of debridement.

It has the same idea and then synthetic graphs. So the challenge with barrier dressings, it is more of a passive antimicrobial defense and the question always becomes is it protecting the wound or the dressing? Antimicrobial dressing, the stuff that is antimicrobial is in the dressing. So whatever part of that is touching the wound is theoretically doing something, but the rest of it is just dressing. Now, that can be useful in terms of highly exudative wounds that could theoretically infectious getting trapped in that sort of containing it. But there's some question about how much actual effect it's having on the wound itself. Tissue compatibility becomes an issue particularly when you consider the types of things that can be.

[24:02]

Silver is usually one of the more common ones and then the questions becomes about efficacy. How effective is it actually? There's not a lot of great literature out there that describes the value of barrier dressing. There're a lot of them on the market. So you have to really kind of consider what you're trying to accomplish. Negative pressure, we talked about this a little bit. The idea of wound lavage, wound chemotherapy and this is a study that was done that demonstrated a variety of wounds with the difference in terms of negative pressure. But negative pressure with insulation in terms of the overall biofilm concentration. And as you can see, the biofilm group dropped more significantly in the context of the insulation vac, which makes sense.

It is both a mechanical agreement, just the actual flushing of the tissue is a value. But also, whatever the chemical might be, be it PHMB or an antimicrobial, an antibacterial or something, that has a role to play. Sailing even has been shown to be effective, just the mechanical nature of washing that lavage. There're other advance tissue products. We talked about the idea of a matrix. Collagen matrix is for dermal regenerative scaffolds. When you have a big hole, you want to fill it with something. The scaffold's function is a bit like building scaffolds. You know, think about the context of a wound that heals with a scar. I always use the metaphor it's like a building site. You just toss the bricks down into – toss the bricks willy-nilly until there's a stack of bricks, pile of bricks.

Now, if you squint that just right it kind of looks like a building and it could be tall enough theoretically to cast a shadow like a building, but it's just a pile of bricks. It's not functional. You can't come and go. There're not doors – take that same building site, put a scaffold around it and that allows you to put the bricks down in an organized fashion. At the end of the day, it may be just as tall as the stack of bricks and cast the same shadow, but because of the organized nature in which the bricks were laid down, it allows for function. You can come and go doors and windows and that's what a collagen matrix scaffold does. It provides a scaffold for the body to lay down organized tissue in a regular way, which is going to be tissue regeneration, not scar formation.

[26:00]

That's the value of this sort of thing. We talked about the idea of antimicrobial elements, silver, copper, PHMB and there're all manners that are coming out. Zinc is the one that it's being researched. There's a lot coming in that space from a biochemical standpoint. So be on the lookout for that. We talked about the sense of type 1 collagen from PHMB and acute and chronic wound. This was a lady that had a [sinus as sub five] [00:26:23], had an ulcer blue out on the top and just wouldn't heal, wouldn't heal, wouldn't heal. But ultimately, the reason for her not healing was the fact that I wasn't considering potential for biofilm, at least not at first. When we started to address the biofilm component, she healed within a week.

But then, the question becomes, when do you transition to living cell therapy? It seems particularly, folks get pigeonholed into I only use this graph or I only use this graph and they get successful and it's the kind of wound that that graph will be for, not kind of all comer. So when do you go to living cell therapy? Over a scaffold, and that's really in the space where you're trying to talk about that proliferative space when something is not happening because a living cell therapy graph is going to promote growth factor. I think it's almost a misnomer than to call the graphs frankly because a graph is a covering and we lose the activity of the graph. Think of it more like growth factor factory. You're putting a growth factor factory onto the wound as a growth factor to stimulate the wound to do something.

And that could be either time-driven to decide or patient-driven. What are the reasons that you transition over? When you have progressed through the inflammatory phase and now you feel that the wound is stalling because of proliferative issue, you want to stimulate it with something. That something is going to be a biologic active graph. And so there was a paper that came out in 2011, International Wound Journal, talking about the sense of time-driven versus patient-driven and ultimately it's as you'd expect. But it's a way to kind of quantify your thinking about the process. What makes you make that – what prompts the next step?

[28:00]

These are cytokine delivery vehicles. They are growth factor factories that go into space – growth factor, and they can go in a variety of ways and we talked about the sense of even now, augment is an example of using that idea in bone healing and osteogenesis. Providing growth factors to a space to do something, make the body do something more. The whole background idea of amniotic tissue and the potential for mesenchymal stem cells is the same idea. The same function in the sense of growth factor and stimulating the senescent cells in the chronic wound space that have progressed beyond inflammation. But are still stuck in proliferation because we want to get them out of proliferation into remodeling to get them on to healing and that's what these will do.

So when we think about the time to healing, the prognostic indicators, we've all heard the idea that 50% reduction as it pertains to diabetic foot, but you may not know that there's actually a similar study data for pressure ulcers and venous leg ulcers. And interestingly, it's a less – you don't need as much healing for venous leg ulcers to demonstrate that they're not going to heal and they're not – the question I challenge you, and I challenge myself on is, how of us actually do this? We all measure our work, right? We document it. It's important particularly in the context of building and coding of, you know, how much was wasted et cetera, et cetera. But have you ever done the math to really know? Do you have a sense of it? It's slightly bigger, slightly smaller, but realistically, is it 50% or not?

That is an opportunity for us to do better. We have the data. We know it's real. It's evidence-based, it's been proven time and time again. We have these tools. We just have to use them. And when you think about the benefits and it's kind of a no brainer. There was a consensus paper that came out about the use of advance wound healing modalities and they actually thought to put it in, which was always funny to me, the sense of a phrase, a line that said the expeditious – the goal of wound healing is expeditious healing or something like that. Like the goal of the healing is we want it to heal, which seems ridiculous in the title.

[30:07]

And these guys were not foolish guys, that they put it in there was important to remind all of us that we lose sight of the overall goal because we're so used to it all the time. You see a room full of people with chronic wounds and you just get used to the idea. They get used to the idea of it. We have to progress into the healing and there're a lot of reasons to do so. In addition to, you know, better patient care, there're less negative outcomes and there's plenty of data that demonstrates that. But adding these sorts of things, the fiberglass and stem cells and growth factors into the wound to stimulate on the healing is what is missing. It's that X-factor. Now, as our technology evolves, we'll be able to specify even with greater specificity – specifics of what is needed, but now sort of a kitchen sink for lack of a better word.

But we have tools available that we can use that we didn't have 10, 15 years ago. So that's, you know, the goal of wound closure is the goal. The wound wants to heal and if you can figure out the thing that it need, the thing that it is lacking, it will heal and it will heal like [Young's Bus] [00:31:11]. It's amazing. These wounds had been present for years and it will be healed in a month or so, because you finally landed on the right combination of what you needed. In addition to addressing this stuff, you know, the produce as we talked about, collagen we talked about, bioburden and all of these things are the things that we have to consider and address.

Whatever is holding them back is what's going to keep us from healing forever or if we can address it is going to make you heal quickly. In addition to that, their overall cost. There's a great deal of data that's come out recently, the healthcare economics, the cost of graphs, the idea that healing wound quickly is cost effective. And that makes sense and we always believed it to be true, but there's now study that it actually supports that, which is useful when you're taking a run at the insurance companies about trying to get a graph to prove, things like that because there is actual objective data that just that.

[32:01]

And so you think about it, like we have increased patient satisfaction, better outcomes and overall cost. It should be a slam dunk and yet, we struggle with somehow. We can do better. And now as you are in your, you know, the cusp of your residency training and you're getting ready to go out in the world, this is your opportunity, your moment to be part of that advancing line of doing better, being better. You know, the old sense of working smarter and not harder, this is that. We have to be smarter and we have the tools to do so. And we've talked about the sense of when do we move?

Certainly after we've done all the basic stuff and when wounds have not evolved or responded to initial conservative care options beyond the basics, when we have progressed through the inflammatory phase and while addressing the proliferative phase. The wound will then heal, going to heal, wants to heal. We just have to land on the right combination of – in terms of diabetic foot obviously, all of this stuff and I bring it in to be redundant on purpose. Not in lieu of standard care, in addition to standard. All of these things. Any advance modality is extra. Standard care is still standard care. VLU, the same thing, but we add now bioburden managing that. We've got some cases.

These are some interesting cases that kind of came from my clinic just to tie it up because then we're running out of time here. These are wounds that have been present for years, initial visit. Significant reduction after a week, one week with the graph and compression. Healed at four weeks or healed it – the final visit is 11 weeks rather and then we get them into compression, we get them into something that's going to last. Now, it's important to talk about with our patients the sense of wound remission. I think wound healing is a good word. Wound remission is important as well in the sense that whatever compliments of symptoms and things that occurred for these patients to allow wound to be there in the first place could theoretically happen again.

[34:06]

So it's not just yehey, we did it or high fiving each other, all right, go away. It is okay, now having done this, getting it healed is the easy part. Keeping it healed is the battle and there's a whole lot of tech. We could spend a day talking about that technology, just the time, not today. But keeping it healed is key. Bilateral leg ulcerations, similar. Present for two years, two years. Think about that. Think about where you were two years ago. Can you imagine having a wound every day from then until now? Amazing. Look at what we can do when we get – we land on the right combination of treatments? Better in there and this patient ultimately went on to heal. I moved practices so I didn't get the last of the picture, but they did go on the healing [indecipherable] [00:34:59] burns.

Even with different pathologies that can cause them, you know, diabetic foot, VLU, things like that, the tenets remain the same of the sense of what should be happening is the same. Inflammation, proliferation, remodeling. So if your wounds, when you go back to your clinic on Monday and you're seeing a chronic wound patient and its being chronic, think about that. Inflammation or proliferation? One of those two is off and realistically probably both. But what are you doing to address each part of that? Because that's what's going to get these wounds – compression, kind of the combination of things. It's not just one thing that's going to work but the use of all of them at the same time progressing in the right direction. Fourteen months – kind of see that. This is the one we did with alpha graph.

[35:57]

This was somebody that we decided was had been through an inflammatory component. We treated him initially with the PHMB product and then transitioned over to a living cell therapy to provide a biologic stimuli, kind of poke it with a stick, if you will, to get it going. So you see six weeks in four applications, about done after 14 months. The Charcot patient, anybody in the Charcot knows that they're like quicksand, you know. Any Charcot you – down the rabbit hole with that, really hard to be particularly lateral one. Had failed out with a little contact, casting, had been open for 18 weeks, and got them to – pressure ulcer for heals, even as ulcer – same idea.

So in summary because I know I'm over my time here, things to take home. Basically, all of your wounds are going to have some element of biofilm. That is in the literature. It is proven and it is a thing. So it is incumbent upon us to do something about it. So in addition to offloading, vascularity, and the absences of infection, it's not just the absence of infection anymore. It is now absence of infection and addressing the biofilm. So that's our paradigm. We have to change and think differently. We don't have to work any harder, we just have to think smarter about what we're doing, and early and appropriate intervention when it is – are there any questions?


TAPE ENDS - [37:26]