Hi, I'm Robert Kersner and I'm going to talk about advanced therapies in wound healing. I'm currently Chairman and Harvey Blank Professor at the Dr. Philip Frost Department of Dermatology and Cutaneous Surgery at the University of Miami Miller School of Medicine. And I have these disclosures for this presentation. Now the two chronic wounds I'm going to focus on today are the diabetic foot ulcer and the venous leg ulcer. I'm choosing these chronic wounds because those are the chronic wounds that are most commonly likely to be seen in outpatient practices. The diabetic foot ulcer is the most common foot ulcer and the venous leg ulcer is the most common leg ulcer. Both are prevalent, expensive, and serious. As an example, diabetic foot ulcers are associated with a 33% five-year mortality. And venous leg ulcers, as an example, cost the health care system up to $15 billion annually. Now when we present it with these wounds, what we do is generally start with standard of care after we do a full evaluation to determine the diagnosis. For venous leg ulcer, that's compression therapy. For diabetic foot ulcers, it's offloading or getting pressure off of the wound. And then what typically happens is we give them a period of time, about four weeks, to see whether or not they are improving. That is, is the wound getting smaller? If it is, that means they're on the right wound healing trajectory and we continue therapy. But if there isn't, meaning their wounds are not getting smaller by a significant amount, then we move on to adjunctive care. This presentation is really going to be focusing on some of that adjunctive care. You still continue with standard of care, compression and offloading, but now you want to do something additional because the wound is not responding to standard of care. This is a more complex diagram that we published in the New England Journal of Medicine 20 years ago. And essentially what it is, is it's looking at diabetic foot ulcers, plantar diabetic foot ulcers, and asking several questions about diagnosis and management. The first question that's asked is, is there pulses? And if there is, great, and you continue down the left side of the algorithm. If there's not, then there should be a vascular evaluation to be carried out and maybe referral to a vascular surgeon or vascular medicine specialist. Then what happens is we make sure that there's no infection, either soft tissue infection or bone infection. If there is one, we treat it. If there's not, then we continue down the algorithm and we put them in an offloading device for diabetic foot ulcers. Then what happens is we look at how that patient does over that first four weeks of period of time, which I've mentioned before. And some very elegant studies that have been replicated a number of times have suggested that if a diabetic foot ulcer is getting smaller by at least 50% over a four week period of time, that suggests it has probably an 85% chance of going on to healing. If it's not getting smaller by about 50% for diabetic plantar foot ulcers, then you might go on to either see what you've missed. Did you miss a soft tissue or bone infection? Or going on to standard adjunctive care in addition to standard of care. Now when we talk about some of the things we want to think about in that initial management of a wound as part of standard of care, we often think of it as a pyramid. That there are things that we do at the bottom of the pyramid, kind of the base of the pyramid, that are going to be critical to the success of the healing of the wound, whatever you do higher up on the pyramid. So for example, at the base of the pyramid, you may do things like maximize perfusion. So we evaluate for perfusion. Things as simple as taking pulses, doing non-invasive arterial studies such as pulse volume recordings or ankle brachial index, and then moving on to more invasive studies of perfusion if needed. The second is to address tissue mechanics. For diabetic foot ulcers, we're talking about offloading the foot so it's not under repetitive or constant pressure. And for compression, we might want to use compression to assure the adequate venous return to the heart. And then we look for infection, whether there's surrounding cellulitis and soft tissue infection where you might need to use systemic antibiotics, or whether there's things like biofilm or bacterial contamination of the wound that you may want to get rid of with debridement. Of course, the goal is to take this chronic ulcer that you start with and eventually get it to a healed ulcer. After you do that, if the wound is responding, you continue because it's on the right trajectory. But if it's not responding, then you want to go on to some of these adjunctive therapies I'm going to share with you. And I'm going to use the diabetic foot ulcer as a model of some of these adjunctive therapies because of some of the things that have been learned through the diabetic foot ulcer, some of which you might be able to apply to venous leg ulcers, and others may not be quite as applicable. I was fortunate enough to be part of this publication by the American Diabetes Association that looked at the management of diabetic foot ulcers with a group of other experts. I created this chart for this publication looking at evidence-based advanced therapies at the time. There were over 80 plus products available and we looked at the indication for diabetic foot ulcers. We looked at a variety of different therapies listed up top. Some of those therapies were growth factors such as recombinant platelet-derived growth factor and platelet release aid. Others were cellular constructs such as the bilayered living cellular construct or human skin equivalent, Apligraft. And then others were dermal skin substitutes such as the dermal equivalent, Dermagraft. Some were acellular constructs either listed here. Others were placental membranes listed here. And then there were two others that had at least evidence from at least one randomized control trial, negative pressure wound therapy and hyperbaric oxygen therapy. In this publication, we looked at the number of patients that were evaluated, the healing rate, the time to closure, whether that indication was FDA approved or not, how good was the study quality in each of these studies, whether there's just one or multiple randomized control trials, and whether or not there was not only efficacy data, meaning a randomized control trial, but was there's real world data, effectiveness data. And this table summarized all this. Another presentation in this series is going to be talking about what we now describe as CAMPs, cellular and acellular matrix products. That means the cell constructs, the acellular constructs, and the placental membranes will be discussed elsewhere. But what I plan to focus on in the remainder of the talk are the technologies that are not CAMPs, not cellular and acellular matrix products or not skin substitutes, and things like negative pressure wound therapy, hyperbaric oxygen, and growth factor therapy that has been shown to be effective in diabetic foot ulcers. So let's start with negative pressure wound therapy, which over the past 30 years, since its inception, has really been the gold standard for many acute and chronic wounds. There are really several different types of negative pressure wound therapy. The basic type, or traditional negative pressure wound therapy, I'll show you in a moment, consists of a foam or gauze attached to tubing that applies a pressure to the wound, somewhere between 75 and 120 millimeters of mercury that applies suction. But there's also portable or single-use negative pressure therapy, which I'll briefly discuss, and installation negative pressure wound therapy, where not only do you apply suction that allows the cells to stretch and become more proliferative and productive, but also instill something like antibiotic fluid or saline. And these technologies have been generally used to treat wounds. There's also another technology called incisional negative pressure wound therapy, which is used on enclosed wounds. And the idea here is to prevent wound dehiscence and perhaps lead to better quality of scarring in the final defect after wound closure. But we're going to focus primarily on wound treatment during this presentation. So this is a typical wound on the dorsum and maybe plantar aspect of the foot, where a dressing is applied. It may be a foam, it could be a black foam or a white foam, it may be gauze. And then on top of it, suction is placed in. It's sealed to create a system in a pressurized environment. And then it's hooked to a device that applies negative pressure. That negative pressure causes the wound bed to attach very tightly and herely to the dressing and create an environment that is supposedly and proven to be beneficial for healing. This is the device to which typically traditional negative pressure is attached to. There's a large canister where the fluid will drain and can be periodically removed. And then it's hooked up to a fairly large device traditionally that the patient has to carry with them. It is kind of cumbersome, but can be quite effective. And typically the primary dressing is left on for approximately three days. Now this is an example of someone who had a surgical wound in the abdomen. And acute surgical wounds, this technology does very, very well. Here you can see the original wound and here's the eventual closed wound with the negative pressure wound therapy. So what happens is that negative pressure removes fluid and exudate, removes the associated bacteria, stretches the cells which cause them to proliferate, and physically brings the wound edges together to get a faster healed, completely healed wound. Here's another example of a diabetic foot. Also again, a surgical incision that is used, negative pressure was used with beneficial effects. There have been a number of studies that have looked at the benefit of negative pressure wound therapy. Back in 2016, an analysis was done that revealed 1,300 plus studies in this analysis. But if you go down and look at the number of ones that were human studies, the ones that were retrospective, prospective, or systematic reviews, of those 1,300 initial results from this analysis, 23 were randomized controlled trials. One was on incisional at the time, some were on these variations, and then there was a handful that was compared negative pressure in some way, shape, or form to dressings. As I mentioned, there are a lot of publications. This is a technology that's 30 years old. In the beginning, it was slow to accumulate data, but actually with each one of these new interventions in negative pressure wound therapy, the evidence began to increase more and more. And you can see the number of publications that have grown over the last 30 years. Now, the probably two studies that showed the benefit of negative pressure wound therapy in chronic wounds, in diabetic foot ulcers, were these. The first was by Armstrong and Lavery, published in The Lancet, and then other details were published in Diabetes Care. This was a study of 165 patients who had a chronic diabetic foot ulcer, and then had an amputation, and they were randomized to negative pressure versus standard of care for 16 weeks. There was a statistically significant improvement in complete wound closure, 56% versus 34%. There was increased granulation tissue during the period of the 16-week study and the patients not only healed to a greater extent but healed faster. A second study, a larger study of 342 patients, was carried out on Wagner, which is a staging system for diabetic foot ulcers. Two or three, meaning a slightly deeper Wagner wound, deeper diabetic foot ulcer wounds, was carried out for 116 days. And again, better wound closure and shorter time to closure were observed in the patients who received the negative pressure wound therapy. Of note, that in this study some of the patients were able to receive adjunctive, other adjunctive therapies, which may further replicate what happens in the real world. The wound may start granulating and you might apply a cell or a cellular matrix product onto the wound. Importantly, not only do wounds heal better and heal faster, but in this study they showed fewer amputations, which is one of the dreaded complications of diabetic foot ulcers, osteomyelitis and amputation. We recently published an outpatient study of patients who received standard negative pressure wound therapy that I showed you before, compared to this more simple single-use device that you place on a wound for a week. The caveat here is that the wounds can't be heavily draining because there's no canister that absorbs the fluid, that collects the fluid. In fact, all the fluid is collected into that dressing and the negative pressure is driven by that little device that can be easily wrapped into a dressing or held by the patient. Interestingly, this started as a non-inferiority study and to demonstrate that there was no difference in healing between the two, but interestingly for these venous leg ulcers in this case and diabetic foot ulcers, there was better healing with this negative pressure dressing for these simple smaller wounds. Primarily because, which has been confirmed in animal studies, that the epithelialization part of the healing process is superior when you use this device. Primarily because this negative pressure actually extends not just to the wound bed, but beyond, onto the wound edges and allows for better epithelialization. So that represents negative pressure wound therapy. The second technology I want to discuss is hyperbaric oxygen therapy, which is the use of pressurized air, pressurized oxygen between 2 and 2.5 atmospheres, typically for 1 to 2 hours or 60 to 120 minutes daily. Patients typically will have a series of these over a month or two period of time, 20 to 40 treatments, and the patients sit in a chamber and receive this treatment. Hyperbaric oxygen seems to work, positive results in a number of different indications, but one caveat is that there hasn't been the definitive randomized control trial. Most of the trials have suffered from small patient size, patient selection of who's involved in the treatment or not, how well patients were randomized, importantly blinding has been an issue in some of these studies, the ulcer characteristics, how well they actually correspond to what's done in real life, the degree to which there's peripheral vascular disease in these patients, and what other treatments have been used. So there's positive indications, still some questions remain unanswered in this situation. Now the initial thought was that as you apply hyperbaric oxygen, you get better oxygen diffusion between blood vessels, the high pressure pushes the oxygen to now oxygenate previously ischemic zones in between capillaries and blood vessels, and you could see the degree of angiogenesis that occurs as you increase pressure in various models. But it turns out that it's probably much more complicated mechanisms by which hyperbaric oxygen works than purely oxygen diffusion. As an example, what's been learned is that when you give hyperbaric oxygen, you mobilize endothelial progenitor cells, EPCs, from the bone marrow into the circulation that hopefully will hone to the area of tissue injury. So on the graph on your left, you can see that when you give hyperbaric oxygen, the number of endothelial cells increases. But interestingly, this seems to be dependent on nitric oxide. So if you block nitric oxide, you no longer get the mobilization of endothelial progenitor cells. So these endothelial progenitor cells or EPC cells are mobilized in a nitric oxide dependent fashion. And with that nitric oxide and the mobilization of endothelial progenitor cells, you also get an increase in vascular endothelial growth factor and its receptors in the blood, which is a pro-healing or pro-vascular cytokine. So the mechanisms by which this works are multiple. Here is a number of prospective control trials, all of which individually suffer for some of the limitations I mentioned before. The limitations of sample size, limitations of patient selection, limitations of randomization, and blinding. But if you look at all of these studies and then look at the outcomes of healed versus in the hyperbaric versus the control group and amputations in the hyperbaric and control group, you can see that there seems to be a benefit when you combine all these results with 62% healing versus a much less healing 27% in the control group and a reduction in major amputations. That is not a minor foot amputation but a more major amputation in only 7% compared to 24% of the control. So this data suggests that hyperbaric oxygen for certain diabetic foot ulcers may be beneficial. Again, there's been a lot of studies in hyperbaric oxygen but none of them completely high quality. There have been systematic reviews, randomized control trials, no randomized control trials, cohort, and case series. But many of them suffer from small sample size apart from the cohort studies which obviously do not have necessarily a built-in control group. Probably the best study was published by Marcus Longdahl about 10 or 15 years ago where this study had a benefit of having a sham control. They included patients with diabetes and diabetic foot ulcers who had present more than three months and failed standard of care in a specialized clinic for two months and excluded patients who had some significant comorbid conditions. These patients received either hyperbaric oxygen or normobaric oxygen but a hundred percent. So it was a blinded treatment where they received five days a week for 90 minutes a day for eight weeks. And what they found was better healing. Interestingly, the statistical significance, there was improvement early on but it reached statistical significance in complete healing at 9 and 12 months. So you don't get necessarily the results in all the patients right in the beginning but it does take some time to sometimes realize the results. Now for the things that we're showing, we're talking about selected wounds and patients with diabetic foot ulcers, there are a number of indications, some of which have excellent data. Obviously air or gas embolism is certainly one of them. But for wound healing people, radiation seems to be another area where hyperbaric oxygen can be quite beneficial. I'm not going to go into the details of the studies and all the rationale for this beyond showing you this patient who had a radiation for a ward on the toe as a child and then 60 years later or so presented with this necrotic ulcer on the base of the second toe that was quite deep. And it was decided to treat this patient with hyperbaric oxygen. Sick treatments led to improvements but still a substantial wound. 30 treatments have improved the granulation, reduced the size of the wound, improved the quality of the tissue. But really you see the benefit here at six months after therapy that you get complete healing. Now in the last few minutes I want to talk about some growth factors that are approved for diabetic foot ulcer. The one growth factor, the first drug to be approved for wound healing, is a recombinant form of platelet-derived growth factor. The generic name is Bacaplamin. The brand name is GranX. It's gone through several different companies that have owned it over the years. It's basically a recombinant form of platelet-derived growth factor which stimulates granulation tissue and to a degree blood vessel growth locally in the wound. It's the only drug that's FDA approved by both the US FDA and European authorities. And an indication is for diabetic neuropathic foot ulcers that are full thickness that have adequate arterial perfusion that have been present longer than six weeks duration. Because this is a drug, when the studies were carried out in the late 1990s, a series of studies had to be carried out to show its efficacy. The data was strong enough to allow the 0.01% concentration to use once daily on these wounds to be approved for use. But the results are moderate, not spectacular. And the concern is that chronic diabetic foot ulcers are a very unforgiving environment filled with proteases that could break down proteins like a growth factor. So exquisite wound care, especially the combination of the growth factor with debridement, seems to facilitate the benefit of the debridement. And studies have shown that there is a synergy between surgical debridement and the use of recombinant platelet-derived growth factor in clinical practice. Now people have said well maybe we could use the patient's own blood because there are growth factors, not even just platelet-derived growth factors, but other growth factors in patient's blood. And in dermatology we have a fair bit of experience for a variety of indications, some of which are hair growth, some of which are cosmetic purposes, for the use of platelet-rich plasma or PRP, which is a portion of plasma fraction from autologous blood having a platelet concentration above baseline. There are a lot of different companies that have made systems to extract the platelet release and deliver it to skin or wound in some way, shape, or form. But in wound care, studies have suggested that this is of benefit for a patient's wound. Typically these studies have been again relatively small in selected populations, but databases have also suggested there's a benefit over standard of care. One such study that was carried out was not an intent-to-treat analysis, but a protocol analysis, that is the patients who actually received the platelet-rich plasma in the way it was supposed to be received. This was in a randomized controlled trial of 72 diabetic foot ulcers who were treated with the PRP gel compared to a controlled gel and had significantly better healing of their diabetic foot ulcers and a shorter healing time compared to the placebo. So what I've tried to do over the last 30 minutes or so is look at when to use advanced therapies and which ones, using diabetic foot ulcers as an example, have evidence to support its benefit. CAMPS will review cellular and acellular matrix products, will be reviewed elsewhere, but I covered negative pressure wound therapy, hyperbaric oxygen, platelet-derived growth factors, and a plate release aid. And what I would like to remind you as these are wound, these therapies are used for wounds that are not healing with standard of care and there is data for it, but the data for some of these products are limited and imperfect and therefore the evidence gap still exists for these patients. So I want to thank you very much for your attention and I wish you all the best taking care of these very challenging wounds. Thank you.

wound healing

diabetic foot ulcers

venous leg ulcers

advanced therapies

negative pressure wound therapy

platelet-rich plasma