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Dr. Sean House: Our next speaker is Dr. Ron Guberman. He is co–chief for Podiatry Division, Department of Surgery, Wyckoff Heights Medical Center in Ridgewood, New Jersey. And his topic is, Cyclical Topical Wound Oxygen Therapy for the Management of Chronic Wounds. So please welcome Dr. Ronald Guberman.

Dr. Ronald Guberman: Thank you, Dr. Sean House [phonetic]. And hello and good afternoon, everyone.

So yes, I'm here to talk to you about topical oxygen therapy for your wound patients. I've had a lot of experience with topical oxygen for quite a number of years in our wound center, with my wound patients. And I found it to be an excellent therapy and device. But more exciting is that there are many new developments that have occurred in this field, and some very interesting applications and advances in the technology that I think provide even a better treatment for your patients and certainly better outcomes. There's also significant research and scientific and clinical data that support this. So, these are the things I'd like to review with you today.

So, as far as disclosure, I have nothing to disclose. So, what are the learning objectives? Well, what is topical wounds oxygen multimodality therapy? That's what we will be describing out – talk to you about some of my experiences with it as well. I want you to understand of course the role of oxygen in wound healing and the importance of oxygen in wound healing. We're going to review some of the really important research that has occurred in this area, and we'll present some of that today. And then, of course, talking about when can this therapy be utilized. So, we know oxygen is necessary. Oxygen is necessary for life, right?

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You can't stop breathing. You can't stop taking in oxygen. You won't survive very many minutes without oxygen. We also know from our study in biochemistry, the Krebs cycle, that oxygen is necessary for the production of ATP, right? An ATP provides cellular energy and function for your cells. So, we know oxygen, elemental oxygen is very, very important for all cellular activity and of course for wound healing.

So, what happens if you don't have enough oxygen? Well, these things happen. You'll have a stalled inflammatory process. How can you go through this process without oxygen? You won't have either proper or you won't have wound healing at all, and you'd be stuck with chronic wounds. You'll have a diminished or absent immune response. Things like infection, colonization, debris that's in the wound, nonviable tissue, will be present. You won't be able to get rid of those things. You'll have inhibition of angiogenesis. And we know without blood supply, without proper blood supply, you can't heal wounds. And you'll have impairment of collagen synthesis. The oxygen level and the oxygen tension in a wound is very, very important to prepare the cell and also help the cells heal, and promote, and allow for the laying down of proper collagen with proper crosslinking and strong and viable skin and tissue.

So, this is what's occurring when you breathe in oxygen. Oxygen is approximately 21% of the air we breathe. So, in millimeters of mercury, the partial pressure of oxygen is approximately 160 millimeters of mercury. By the time that gets to your arterial system, that's down to about 100 millimeters of mercury. And then, through the processes, whatever is occurring in your body and the use of oxygen, by the time it gets to your venous system, then it's 40 millimeters of mercury.

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So, this oxygen will flow through your body through areas of higher tension to lower tension according to Boyle's law. What's happening in the wound? Well, in the wound, in a chronic wound especially, you have very, very low oxygen tension, 10 millimeters of mercury or less at the center of these wounds. That is highly inadequate for wound healing to occur. So, without oxygen supplementation, without the presence of oxygen, you're going to stall your wound healing. You're not going to get proper wound healing. So, a question that always comes to mind, how do we know that supplying this topical oxygen is actually helping your wound? How do we know it's actually getting to your wound? Is it staying there?

So, this particular study, which was published in 2015 in Wounds International, utilize a device, provide the topical oxygen, and found that there was between three- and tenth-fold increase in the level of oxygen in wounds treated with the topical oxygen therapy. That might not sound very impressive, except this was measured one day following the therapy, 24 hours later. So, not only is the oxygen getting to the wound but it's staying in the wound. And you'll see in some future studies, it's even been measured 15 days later where the oxygen has been present in the wound. So, the functions that are necessary to occur with oxygen are actually occurring and taking place due to the supplementation.

Now, what happens in a normal wound? Okay, you have these three enzymes that we chose to highlight. One is for cell metabolism, one for collagen production, and one for fighting infections. So, these three enzymes at normal oxygen levels, are functional at the percentages as you can see listed. One at 50%, 55%, one at 75% and one at 95%.

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So that's all well and good and that's a normal wound with normal oxygen. But what happens when you don't have enough oxygen? Okay. Now, you're talking about the function of these necessary enzymes for processes to occur for wound healing at somewhere between 0% and 30% to 35% function. And again, that's highly inadequate to heal a wound or to have proper wound healing. So, both pf those things are problematic. When you add supplemental oxygen, what happens? These enzymes are really at 100% function. So, there's some evidence, and I'll show you a little later on, that this level of oxygen actually supercharges these enzymes to the point where you're not only getting wound healing. You're accelerating the wound healing and you're getting superior wound healing. There's evidence to support this.

So, the wound healing you may be getting in the type of tissue and skin production, the type of collagen crosslinking you're getting on a three-dimensional basis, is actually superior to normal wound healing. So, it makes you think perhaps with wounds this should be considered as a more frontline device or therapy for wounds that are not healing because you're going to get superior healing, more durable wounds, and as you'll see, less recurrence of those wounds.

Okay. This particular slide highlights both in the pig and human models. What occurs when you're adding oxygen with respect to neovascularization, which we know is critical for wound healing, and also the maintenance of a healed wound and less recurrence of that healed wound. Providing proper oxygen and blood supply on a long-term and short-term basis is obviously critical and will prevent recurrence, and will help those wounds heal.

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So, regarding the human mode, VEGF and FGF2, which is the fibroblast growth factor and the vascular endothelial growth factor, there's a 20- and 70-fold increase in the activity of those particular necessary substances in order to heal your wounds. There's also, as I stated earlier, the treated wounds in the pig model showed a presence of elevated oxygen even 15 days after the last treatment. So, this oxygen is not only getting there, it's staying there, and the activity of it is still present.

Okay. This histological slide show skin in the untreated or controlled side on the left side of the screen. First is the oxygen-treated. So, what do you see? The epithelial level on the left side, the controlled, the untreated, is far too thick and abnormal. There's even bits of dermis within the epidermis. The dermal, epidermal junction, is quite abnormal. The collagen is not as thick and robust as far as the collagen formation. And a more specific analysis shows that the crosslinking again is, as I formerly mentioned, is less. So, the wound is less durable, less strong. The amount of disclamation that's occurring, which is critical, is decreased in the untreated wound. So, what does that mean? You'll likely get increased callus formation. You'll get more scarring. You'll get a less viable wound. You'll get a less successful final product.

So, we know, even on dorsal wounds, but especially on plantar wounds, when you have this callus formation as your final outcome of your wound healing, none of us are ever really satisfied with that and for good reason.

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Because those wounds are highly prone to breakdown and recurrence. They cause pressure locally, both underneath and on the sides of the area where this is occurring, and we know that often we get breakdown and inadequate longevity of these wounds.

Now, when we're speaking about infection, specifically I want to highlight here the strict anaerobic percentages in both the diabetic and pressure ulcers which you can see, are quite high. This was from a study done and published in 2008. So, not only does the oxygen have a direct bactericidal effect on these anaerobic bacteria which is of course critical to healing these wounds, but the immune response in general is upregulated by the presence of oxygen. And the oxygen itself is shown to potentiate the antibiotic activity of whatever therapy that you're utilizing.

Okay. So, what has just been clear to use? What types wounds can you use this for? Well, the FDA – this is a device and this is a therapy. So, the FDA clears this for use on acute and chronic wounds such as – the such as means that this is not limited to these types of wounds. This therapy, this device can be used on any wound. And it's within guidelines to do so, and it has been used on many other wounds. But this just highlights many of the most common wounds we see. Skin ulcers from diabetic ulcers, venous stasis, postsurgical gangrene, decubiti, amputations, skin grafts, burns, frostbite. Now, in addition, it's been used on things such as sickle cell ulcers. It's been used very successfully. It's been used on ulcers that are secondary to post radiation soft tissue treatment where there's radiation, necrosis, burns, and it's been used successfully there.

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It's been used on ulcers or wounds created because of calciphylaxis. So, those are just a few additional examples. But the usage is not limited to these things but to whatever your imagination can imagine. Okay. So, the device itself will go over.

Now, if you want to see this device up close and personal which I would highly suggest, there's going to be a workshop tomorrow. The workshop time is 10:30 to 1:30. Desby [phonetic] who's really an expert on this device, as well as a lot of the research and the physiological data, and the clinical data, she's going to be there instructing you and showing you how this works. You can really see it up close, and I think that it will be very much worth your while to stop by. I should be there as well. So, if you have any additional questions, I'd be happy to take questions at the end as well.

But this part right here, this is the oxygen-concentrated. This plugs into the wall, and this creates the oxygen and sends it to this, which is the controller. Now, the controller, what that does is it sets the time for therapy. It manages the therapy. It allows for the different pressure created in this – the pressure in this device goes from 10 to 50 millibars, up and down on a regular basis, to create this positive pressure, which is important. And it has been shown to diminish local edema. Interstitial edema is decreased, so much of the inflammatory cells and nonviable products that are present in the interstitial fluid are pushed away with this pressure.

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In addition, this humidifier, the humidifier itself which is this here, the humidifier comes into this area, this port. And the humidifier itself provides for moist wound healing. So, you can add this moisturization to the wound as necessary, as you think is necessary. It's a sustained humidification that will occur during the entire treatment. And it also nourishes and humidifies, moisturizes the local tissue so that they don't dry out, and they're more supple and viable, which is obviously very, very important.

So, why is it called multimodal therapy? Well, there's three things that are occurring. We have the oxygen supplementation, right? The increased higher levels of oxygen that you're getting. You have the sickle compression which I described. That sickle compression is between the 10 and 50 millibars, and that creates a level oxygen that's equal to approximately 800 millimeters of mercury in general with this device. That could be dialed down a little bit if necessary, but that's the standard. And then of course, the humidification. So that's why it's multimodal therapy.

Now, there's quite a bit of really compelling research that is supportive of this. And the research that's been done, this particular study especially, this is a level one study. As you can see, it's a multinational, multicentered, randomized double blind placebo-controlled study. And this particular study tested specifically the efficacy of the cyclical topical oxygen therapy for chronic diabetic ulcers. It was presented as the late-breaking abstract 2018 at the ADA Scientific Sessions. It was also presented at DEF CON in 2018, and I was a Blue Ribbon Award recipient.

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So, what was the study? What do the study do? The study – the primary endpoint was healing, 100% healing in 12 weeks. Secondary endpoints, you can see wound recurrence up to 12 months, reduction of wound area, incisive amputation and quality of life, and economic assessment. Now, this is quite significant that at the first, a priority interim analysis, there was such a strong statistical significance between the treated arm and the untreated arm that there was no reason to go further. This is based on design of the project. And what it means is that when there's such a significant difference, either in a positive or negative light, that the study is over. Because either you're providing such an excellent and significant advance in that patient that it would be unethical to continue, because it would be unethical to not offer this to patients that are not receiving it, or it could work vice-versa.

That is, it's so terrible, the results, that you'd have to stop it. But in this case, it was so positive. This 41.7% to 13.5% healing was so statistically significant that that was it. Now, those numbers may not seemingly high, but because of the type of study that was done, there were four weeks of standard of care treatment given. At the enrollment period, there was an additional two weeks given in any wound that showed any potential for healing or increased healing, they were eliminated from the study. So, these only wanted wounds that were really nonhealing wounds. So, that is quite significant. And again, just to illustrate that it's a 3.7 times likelihood for the treated arm versus the untreated arm to heal, and that is quite significant.

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In addition, and again, these are really bad wounds. So, the untreated arm actually showed a 2% increase in wound size. That's how bad these wounds were. And the standard of care that was provided at all these sites was equal, all over, and determined to be adequate standard of care. And with the treated arm, you saw a 64% decrease after 12 weeks on average.

So, this is another study. Now, this one was published in 2010. This study had to do with severe diabetic foot ulcers. It was a perspective-controlled study, still a very good study. This particular study had 82.4% of the ulcers that were with the oxygen treatment that healed to 12 weeks. Very significantly, there was no ulcer recurrence during the 24–month follow up, which I think is pretty remarkable. And again, given credence to the idea that which we showed both from research and histologically that this is superior formation of collagen and of skin, and with less scaring. So that is really, really to me quite significant, and again makes me think about when I should this and how early I should use this if I want my patients to really have proper and really great wound healing that's going to be sustainable over the long hole. The increased vascularization, you see too that's present in these wounds, will sustain that patient, as that patients ages.

And that circulation may be diminished, that increased vascularization that you see, and I think that we'll get into this a little bit later, is more sustainable for this wound than without it, of course. So, the average time for wound closure was 94 days for the oxygen therapy compared with 340, 340 days for the untreated arm.

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Okay. Now, we've talked about diabetic ulcers. This is a study done on venous ulcers. And this particular study was published in 2013 in vascular and endovascular surgery. Now, these were really – they say refractory old ulcers, that have been present. Every one of them was over two years and the average was nine years. So, these ulcers were on average, present for nine years. So, they measured – this is what they measured, the endpoints, the amount of healing after 12 weeks, full healing, reduction in size, the time to healing, and the recurrence over three years which is a very significant period of time, a long period of time to watch something. And what did they find? So, the oxygen-treated ulcers had a 65% higher rate of complete healing compared with the conventional therapy that was used, which is compression therapy. In addition, as I mentioned earlier, with little or no scar formation noted in the oxygen-treated wounds. So, this is just one example, okay?

Yes, it healed. Okay. So, after three months – now, we know conventional therapy is going to help some people, and it did, 46% healed but 76% of the treated, the oxygen-treated healed. That's quite higher. After 36 months, look at the recurrence rates, 6% versus 47%. And MERS [phonetic] elimination, 46% versus 0. And lastly, the pain decreased significantly with the oxygen treatment. Okay. So, when can this therapy be used? Well, we went through this before but I'd like to get a little more detail on it. This, we already discussed, these types of ulcers.

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That's all well and good. Now, also, this therapy can be used, and I think this is pretty critical when it comes to practical treatment that this can be used with nearly old, primary and secondary dressings. This is a guess. It will permeate through most primary and secondary dressings. There are exceptions and those things you can discuss with your representatives, and make sure you're not using those particular things. They're all alternatives and that's fine.

Now, I found this to be the case as well, in my practice, that these things not only work with or don't disturb other things that you're doing for the wounds like AmnioMatrix grafts, biologics, and advanced wound care dressings or skin grafts. They actually help these things. You're providing additional oxygen to the wound. What is that going to do? It's going to decrease your bacterial count. It's going to add oxygen to the wound to allow for better wound healing, for stronger wound healing and faster wound healing. So, that's going to assist, and these things work synergistically. And clinically, I found that for sure to be the case, and we'd been doing that quite often.

Now, importantly, this thing is very easy to use. It's comfortable. The patients are very satisfied. I found this to be the case. My patients come in, they're very happy. As a result, they're very compliant. It's relatively painless. I could say it's completely painless. It's a noncontact application. It doesn't touch the wound, and that is very satisfying. In addition, you can have this patient use this at home. Let's say as we often do in the wound center, we may have a bandage or dressing we use that we only change in a weekly basis. Well, that's all well and good. This patient is now receiving additional therapy at home that's helping their wound heal, and you don't have to take the bandage off for a week, and they're still able to get the therapy. There's not many other things you can say that would do that kind of thing for your patients.

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So again, I highlight that with all this that we should maybe consider this more frequently as a frontline treatment for nonhealing wounds, along with other therapies. Now, I should mention that of course, those without saying, that you still need to provide for your patients all the other things that you would normally provide for wound healing such as diabetic control, revascularization where indicated. Offloading, antibiotic or infection management, proper nutritional analysis, proper nutritional care. All the other things are of course of primary appoint. This is not a standalone treatment. This is something that goes along with all that normal and effective wound care practice that you would incorporate into your therapy.

So, what are some of the other advantages? Well, again, the low recurrence rates, and the fact that's it's – I mean, the research is really pretty strong and supportive, and it's been very good research. From a physiological standpoint and scientific standpoint, it's logical as well. So, you can see that's true. You're going to receive edema reduction and that's been also shown. You're going to have faster healing. And another thing that I didn't mention before is that the pressure gradient created through this device is very effective on tunneling wounds. You're going to get that oxygen into those deep tunneling wounds. And the fistulas that it created inside those tunneling wounds will be prevented from collapsing during therapy due to that pressure gradient that's created. So, that's a significant advantage and will lower your bacterial count and especially your anaerobic bacteria. Again, it's supported by data. And the other thing to mention, pragmatically, I found – and this is another thing that makes it tolerable or palatable for me, is that the company that provides this device will handle things like insurance coverage.

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Pretty seemly, there's not a lot of extra work for me, which I appreciate it. And I know whoever is involved with practice is, the last thing you need is extra work. They deliver the device and all the materials to the patients, and they're available to answer questions. I don't have to answer the questions. They answer the questions. And they instruct the patients and family, and they're available to questions for the patient and family. So, that's really been a big positive for me as well.

So, with that in mind, I say thank you very much for having me. And if there's any questions, I'd be happy to answer them. And again, I just want to remind you about the workshop tomorrow which I'll be there and Desby will be there between 10:30 and 1:30. And please come and see me and ask whatever the questions, but any other questions now? Yes Dr. Mins [phonetic]?

Yes. The sham arm is the one that didn't receive the oxygen. Yeah. So, the question is, what's the sham arm? The sham arm is the oxygen-treated arm in the sham arm. The sham arm is the one that didn't receive the oxygen therapy. Anything else? All right. Well, thank you very much.


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