Female Speaker: Okay. And this is [indecipherable] [00:01] which I just found that out, I did not realize that. Itâs about growth factor therapies but with the focus on platelet drive growth factor, because it really does set the stage not only in terms of data that have these submitted to get it approved but also with out on the streets talking about good wound care, which Iâm also going to spend a good bit of time on. But before I start he said, we had to say wound care thing for a while. Well, let me put it into some sort of a timeframe for you. I have been a nurse for 37 years and I have been doing wound care for 33 of those years. So in 1980, I wander and gone off to my WCN training and at that point in time we did a lot of awesome care but we are just first having moist wound healing products came on the market. And so we started using these things and not really understanding why we were seeing what we are seeing, but for example we are seeing autolytic debridement. Who ever knew what that was in 1979 and 1980? We didnât. We didnât have a name for it. So we had films which went on to hydrocolloid and so, what we became very good at was doing wound care. And now, jump ahead 30 years weâre talking about wound healing, weâre talking about regenerative medicine, thatâs quite a leap. So the conceptional framework that I -- anyway, theyâre we go. Around the early â90s I got first laptop and I was in the age in high school where we have those cards, the punch cards that they used for the early computers. So I look at wound care as learning how to work on the computer, and everybody still does this part. If something goes wrong with the computer what are your three favorite keys? Control-alt-delete, right? But when weâre talking about wounds we canât control-alt-delete them. You know, we have to figure out which -- why is it working for you? Hey, go back, go back, go back. Donât give away my stuff, okay [Laughs]. So to me now that weâve learned wound healing --
Female Speaker: Okay, Iâll push the button. Now that weâre talking about wound healing, thatâs kind of like having to understand how that motherboard works. So, control-alt-delete doesnât do it. We've had to learn about wound healing. That took much longer to say that than I needed to. But again, but now with the conceptional framework again 30 years later or wound care to wound healing, now wound care and wound management and how we treat them are still critically important. Weâve gone from thinking about just the wound environment to thinking about the cellular activity thatâs happening at the wound environment. Weâve gone from passive to active wound bed preparation, as well as wound bed management. We have focused on the time to healing which in this economic environment is going to get even more important and especially we donât know whatâs going to happen to us in wound centers in terms how weâre going to get paid. Everybody else is on a perspective payment program, ours is yet to come. But the good thing is still, weâre focusing on the patient with diabetes and weâre focusing on their feet, and so many of the products that we have at a meeting like Desert Foot of course is going to do that. Okay, it does work when you push the button. In our basic training and we have a good lecture this morning, a lot of good information in a very short period of time on wound healing and the phases of wound healing. And we know that itâs an overlapping and a dynamic process that encompasses three or four phases depending on how you look at it that are overlapping, but itâs what we expect out of people who are going to heal. Another thing I found is, all these years of only being exposed to nonhealers is that I just donât expect people to heal, because thatâs my world. When my parents or somebody has a boo-boo or something that happens I just sit around and wait for them not to heal because I havenât been in a world of healing, but certainly this is how things are supposed to go in someone who heals. So when we talk about growth factors, they are the chemical mediators that pretty much orchestrate cytokines in general, certainly, but certainly, growth factors as a protein certainly orchestrate predominantly pretty much all of the activities that go on with wound healing creating chemotaxis, getting cells to migrate into the site, angiogenesis, all of the things that you can see on these bubble slide, all of those things are the end result of the activities of growth factors. So when we look at again that dynamic process and the fact that these phases of healing happen, one of the key chemical signalers, one of the key growth factors is the topic that we have been given today and that is platelet-derived growth factor or PDGF. When you look at the lack of singular growth factors on the market, a lot of them thereâs been so much things that had been taken to clinical trials, FGF, TGF. Thereâs been some good trials that have been done but they just couldnât meet the endpoints. It doesnât mean they didnât have value. But PDGF is one that was able to meet the endpoints of their trials, and part of it is just because itâs one of the key growth factors responsible for wound repair.
So, if you just look at this list. This is just listing all the cells that weâre quite familiar with in terms of wound repair. But also these are the cells that produce PDGF. Starting of course with the platelet at the time of injury, and weâre going to have a slide on that. And then the cells that then that PDGF can act upon, again, cells that are critical and required for wound repair, and then the cellular response, the chemotaxis, the production of other growth factors as a result of that stimulation. And you can just read on. But the majority of the things are the fact that it is stimulating the cells to produce extracellular matrix. Itâs stimulating the cells to produce collagen, other macromolecules, proteoglycan, things of that nature. So, this is just a different way of looking at that. But when you look at the role of PDGF and we look at what it does in all of the phases of wound healing, as I mentioned, at the time of injury when the platelet interacts with injured collagen and releases the contents of alpha granule, a good number of mediators, cytokines, inflammatory cytokines and growth factors are released at that time to begin to recruit the cells to begin the healing process, and to start the inflammatory phase. PDGF is also chemotaxic for the neutrophils for that initial influx of neutrophils so that they can begin to come in and do the cleanup as well as the macrophage. Itâs a little but later in inflammation to continue to clean up and then, of course the macrophage stay over until the proliferative phase to begin to recruit cells so that granulation and repair can begin. Certainly, PDGF is very active in the proliferative process in terms of just helping to form granulation tissue but the key one is the stimulation of the extracellular matrix, especially collagen. And then once the wound is all closed of course healing hasnât occurred, weâre going to go through all the remodeling that youâre all familiar with. But PDGF also then helps to convert the fibroblast and that helps to remodel. So when we look at just PDGF and we call it, we think about it and talk about it more because thereâs an actual drug, Regranex of course. That is a platelet-derived growth factor, but itâs a specific isoform, a PGF. So, PGF is a family of growth factors, but itâs also a singular growth factor thatâs a protein, and itâs a dimeric protein that is available in, well, I used to say three, I feel like Iâm ringing up here, three different forms because Iâve always heard of AA, AB and BB. But actually when I started reading, and Iâm not going to talk it because I canât, I just found this. Thereâs actually been identified a PDGF-CC and a DD which are supposedly spinal cord-derived growth factor, so that there you have the full amount of what I know about them. But again now weâre seeing five listed in the literature. But the PDGF is a dimeric protein that has the five different forms. But most commonly youâll see PDGF-AA, which has two alpha chains, PDGF-AB which has an alpha and a beta chain, and then of course BB which has two beta chains, which has to do with the interaction with the receptor sites on the cells. So when you look at these isoforms, there are differences between the alpha and the beta receptors and their ability to bind to the cellular receptors. And then induce the signals that they do. The PDGF-AA will only bind to a alpha-alpha receptors, thatâs a heterodimer. The AB only will attach to a alpha and beta as a heterodimer. And then BB can attach to all three. Again thatâs probably why the BB was able to meet the endpoints in clinical trials because it has the ability to attach and to stimulate it, stimulatory to cells as they produce all of those different receptor sites. I tried to look for some information on AA and AB and thereâs really not a lot out there. There has been in vitro work in terms of what they might do. AA for example is a chemoattractant during embryonic development, and then later in wound healing. And then AB, and you can just see on the slide, there was an in vitro study that found that it may promote wound healing by stimulating extracellular matrix, and then play some sort of a role in collagen synthesis. But again, most of the information that you will find thatâs usable and current is going to be on the BB, because it was found to be the most potent isoform that will accelerate granulation tissue, both in vivo and in vitro, and of course has the clinical trial as a result.
PDGF-BB is involved as Iâve already shown on the slide, involved in all of the different phases in wound healing and initiates and modulates pretty much all of the repair processes. So these are the original becaplermin Regranex trials. Some of the early work that was been and I think at this time, I should let you know this. This is where I cut my teeth on this drug. I didnât know I was going to do this talk when we turned in our disclosures. But I was actually a part of Ortho-McNeil Pharmaceutical when they launched the drug Regranex. I learned from Danny Cooper and sort of grew up on this stuff. Not that Iâm a total expert in it, but it is kind of near and dear to my heart. These were the studies that were done. Dr. David Steed studied early on 118 patients. And actually thereâs some really good data that Iâm sure youâve seen but Iâm going to show you in a moment that came out of that trial. The pivotal trial, which is Dr. Wieman study, 382 patients, the outcome is like 35 versus 50% in the 100 microgram dosing. The third study was another dosing and the fourth study was an economic study. But the end result is that they had data that they could take to the FDA and it merited] approval for use on humans. And it was launched, thus the drug Regranex in 1997 officially with the FDA, and then really out on the streets in February of 1998. Thereâs been some other studies, and this is kind of interesting, and there was a really fascinating presentation that was done at SUWC. I think it was fall of last year. And it was looking at some of the trials and things that have been done but couldnât come to market just because of the endpoints required by the FDA are complete wound healing. And this was one of the ones that Marty Robson presented. It was a Riley Rees study on using PDGF with pressure ulcers. But, Marty Robson was in the study. They were just looking at using becaplermin gel in the treatment of pressure ulcers. And the end result of the trial they were looking at complete healing, certainly. They also wanted to look at greater than or equal to 90% healing and then they also wanted to look at the overall volume reduction. And the end result was that there definitely was an increase overall in the incidence of complete healing, but a larger increase, greater than or equal to 90% closure. But because they didnât meet the complete healing endpoint, it didnât come on as an indication. My point really is that these wounds donât know that they arenât diabetic, but unfortunately the FDA has these stringent rules in terms of getting things to market so this is not something that we would be able to get it paid for in terms of using it on patients. That was just the rest of it. So in summary on the PDGF side, and then thereâs still a lot more very important information to talk about when using growth factors, itâs an important singular growth factor for singular in each phase of the healing process. You can see the different isoforms that BB definitely was found to be the most potent in terms of accelerating the formulation of granulation tissue and igniting the healing process through all four of those phases. Now there are some other options in terms of getting platelets and I wanted to just bring this up because what really was on the market first, many of you, maybe, will remember the curative wound healing centers and they had a platelet-derived wound healing formula. But they again did not have the data to really get to the point where they would have any kind of reimbursement. So that was taken off the market. But there are the platelet gels that people still do and can create using a device at the bedside where Iâm sure thereâs other ways to do it. This is just one that we were involved in the clinical trial where you draw the blood, you spin out the platelets, thatâs mixed with thrombin and it releases the contents of the alpha granule. And thatâs just showing the actual gel being put on to the surface of a wound. And then thereâs Regranex, becaplermin, 0.1%. It is a PDGF-BB. It is a prescription drug that was off the market for a while. And you donât really know that youâre going to miss something until itâs gone. Since itâs been back on the market weâve actually gone through three tubes. This is a little dab at a time in our clinic. So it is refrigerated, 15-gram tube. The indication as you see here is for the treatment of lower extremity diabetic neuropathic foot ulcers or ulcers that extend into subcutaneous tissue or beyond, and have an adequate blood supply, which was brought up this morning. None of the things I havenât talked about this morning are for use on ischemic ones.
I mean, they might help, but we want to know if they have least an adequate blood supply to heal. But I think the bigger message is that Regranex, these products have to be used in the context of good wound care. And Iâll make some very important points about that, which include sharp debridement, includes anti-bacterial control, offloading and of course in the diabetic foot, we cannot expect something to heal if weâre not going to offer the patient and then pressure greatly for them, infection control. We did have the clinical data that supported the fact that they can make the claim of increasing the incidents of complete healing of diabetic foot ulcers. So I want to spend some time on this. And the message is definitely for Regranex because I was very proud in the mid to late â90s, in early 2000s about how we were changing wound care in terms of trying to get the message out of the importance of good wound care, including infection control and all the things that you see on here, and weâll talk more about them. One is of course we have to make sure we have the bacteria under control. Iâm not going to spend any time except for this one slide talking about that, but it can fool us. It can fool us. If weâre not seeing at least some change in the wound then, certainly bacteria is a place that we want to go looking to see if thatâs the culprit. It may certainly have an abundance of both topical anti-microbial dressings to address this, I donât know if Tom Serena is in the room but he and I have gone back and forth about this critically colonized concept. But when the wound is building up to the point where that bacteria level is critical enough to impact the host, we need to do something about it. So before then, if we can reduce obviously the bacteria, weâre going to turn that around before it invades into the tissues, in the deeper spaces and becomes an infection. So assessing infection at the bedside and you would look at that and say, âWell I wouldnât put an advanced product on that.â But people do, people do. We have to assess the infection, and actually thatâs not the first picture that should be there. Thereâs another picture before, that the toe really looked threatened, somehow they got reversed. And thatâs after it was debrided. So it looks dicey but itâs not he lives in the hospital, versus the one on the right, of course, which is a surgical emergency. And we certainly donât want the wounds to get to that point. And so debridement is key. And you think in this day and age with all the companies that are talking about good wound bed preparation and good debridement that everybody would agree, and most people do, itâs in every single guideline for chronic wound care for treating wounds. And it has definitely demonstrated, especially with the Steve data that Iâm going to show you, an improvement in wound healing in clinical trials. And thereâs a variety of ways that we can accomplish this, certainly sharp excisional is what most of us turned to before weâre going to use an advanced product. But weâre in a world where not everybody can get into a wound center or canât come into a wound center every single week or canât have all their debridement accomplished in one sitting. And so we might say a combined surgical and excisional with enzymatic or autolytic in order to get the process done as quickly as we possibly can so that we can move on. The sooner we get it done, we can start healing. Weâre not going to start healing obviously. Iâm speaking to the choir here until we get it done. We need to get it accomplished, and youâre maybe sitting there thinking, âWhy is she telling us this?â Of course we debride. Well I travel a lot and I do all these talks and I have people tell me that, âOh, I canât get my [indecipherable] [18:39], I canât get my doctor handle it whenever to do the debridements.â Or Iâll have a representative from a company say, âYou know what, I canât get them to debride on that.â We have to make sure weâre not only getting the wound down to good healthy tissue, whether youâre using Regranex or anything else, and also get the edge which Iâll talk about. So excisional and sharp debridement of course is a faster way to do it, or some combination. And then making sure that weâre getting the edge. I have somebody call me the other day and described this wound, but they were using a negative pressure device and itâs just not working and theyâre describing this shelf of callus thatâs on the bottom of this foot. And then like, well they need to cut that away and theyâre not. So we have to always go back and say, âAm I doing enough debridement?â Now this is hallmark data. This is from the 1996, well Dr. Steve published it in â96 but this was from the initial Regranex trial, 118 patients. There were 10 centers and when they analyzed it retrospectively they found that, there were 10 centers, and four of them were combined here for statistical significance. But in every case whether they were in the placebo or the active group, where there was more debridement there was more healing, whether they have an active product or not. So again, it just really drives some of the fact that weâve got to get these patients debrided.
So thatâs what weâve learned. We need a balance of debridement, a balance of the bacteria load and moisture and then we have to balance patient. Thatâs where we have to get them offloaded. So as we talk a little bit more about this, I want to address some of the things that have come up in these years, in terms of using becaplermin, in terms of using Regranex. Cost comes up. Now itâs being relaunched. Itâs being put back out. The drug itself is the same. Itâs the drug that weâve come to count on and that we know will work when used in the context of very good wound care. And it works consistently. But there are a couple of things that I think may come up as you think about using it, as you get to start using it again. So one is the cost, and when you look at the other, cost is some of the things that we have in our disposal now, they are expensive. They all have had extensive clinical trials done. Those cost a lot. The processing of many of these things, the making of this drug takes money, if theyâre going to carry a cost with the cost of the product. This was launched in a pre-Part D era. We didnât have Medicare Part D when it was first launched into the market. We had some pretty coverage and the state Medicaid would cover someone. Even to this day, itâs still covered by the majority of Part D Medicaid and commercial payers. But the cost of the patient is going to depend upon the copay. It could be up to 6 to $25 or it can be up to $100. So itâs a kind of thing we want to have a conversation with the patient and this is about this product or anything else. John Lantis from New York did a retrospective analysis in 2008 and he looked at 12 months of his patientâs use. He had 121 patients that have used Regranex in that 12-month period. The average use was 1.54 tubes. Weâll bring that up again. The average use was 1.54 tubes. But the average cost to the patient per tube was only about $28. This was post Part D so 25 for Medicare, $2 sometimes for Medicaid. There usually is covered, but the important thing, and actually we had a patient and I was telling him that Regranex was coming back on the market. This was maybe a year ago. He said, âOh, you know, I had this wound and I used it and it did very well.â But he says, âYou know what you guys need to do?â He looks at me very seriously and I said, âWhat?â And he says, âYou need to have a conversation with the patient before they leave with the prescription.â If they know thereâs going to be a cost involved, they can sort of be thinking about, can I put it on the credit card, can I talk to my children, whatever. So we you need to have that conversation with them. Thereâs reimbursement assistance, thereâs patient assistance, there is a copay program. But unfortunately what has to fall on this and only we can do it, is to fill up the forms when they get to our place of care. Like our pharmacists in the Orlando area, when a patient goes in with his prescription, be it linezolid, be it becaplermin, anything that carries a high price, theyâre going to automatically fax us a form that we have to fill out and sign and itâs easy to have those get stuck on a desk somewhere. So you want to talk to our providers and make sure that weâre filling out the forms. But I think the most important thing is to have the conversation with the patient, because again, it doesnât matter what weâre using, I tend to feel that sometimes we make financial decisions for patients. We decide that probably they wonât want to pay the copay for whatever we want to use. And so many times they will. They want to keep their leg. They want to keep their foot. And so I think we have to make sure, not only that we have a conversation with them because they deserve to get it if they can. But also from a legal standpoint, you want to know that you offered them everything that was possible. The other thing is on the package insert, it says, twice daily, dressing changes. In the original clinical trials, remember, this was in the early â90s. So the moist gauze was always the control and it was just the way things were done. The original trials where that we put the Regranex on the morning, covered it with a moist gauze. And then there was a second dressing change done at the end of the day. The interaction of the PDGF-BB with the receptor sites is within nanoseconds. I mean, itâs quick. By the end of the day, whatâs happened has happened. The second dressing change was to clean the wound and reapply a moist gauze. It wasnât to remove the product. My reason for this picture is if you try to call a home care agency and say, âWould you do twice daily visits because this package insert says that thatâs the way it should be?â They arenât going to be happy and they wonât do it. They cannot do it. They canât afford to do it.
So it becomes the providerâs option to not have the patient do it twice a day, to do it as once a day dressing change as long as weâre just creating an environment that the dressing will last 24 hours and not dry out in between. Then the other thing is that since the time that the drug was launched is the box warning that is now on the package insert. Remember we launched in 1998 and it was added in 2008 after over a million prescriptions have been written for the drug. It was related to a post-market study that looked at cancer mortality and cancer deaths that was statistically significant in high exposure groups and these were people who had greater than three tubes. Actually in our hands and in our practice, I donât think weâve ever prescribed more than three tubes. If you look at 121 patients that John Lantis treated in 2008, they had an average of 1.54 tubes. If you really want some interesting reading, because I wish I could sit here and tell you all the ins and outs of the study, but itâs really confusing to read. The bottom line was they were looking at this massive United Healthcare set of patients. They were looking at patients who had had Regranex prescribed and then comparing them to people who have the same demographics, the same comorbidities and then looking after cancer risk overall. It was two years worth of data from 2003 to 2005. The end result was that they found that there was an increased risk of cancer, and death from cancer after three tubes. I mean, three tubes over time, I donât think if someone has a large wound that, you know, if you have to use three tubes in a week, but nonetheless itâs very rare that patients have three tubes. Then Ziyadeh and some others followed that up. They took the same data and this is the data. This is what they were looking at from this original study. There are 1,622 becaplermin indications with 28 confirmed cancers and nine deaths. And there were 2,800 plus match comparators with 43 confirmed deaths cancers and 16 cancer deaths. He did some additional work. They did some additional work. Extended the time out through 2006 another year. Their end results, their data showed there was no elevated cancer mortality risk overall, and also no statistically significant increase in the subgroup that use more than three tubes. The VA, which I know many of you work for this system, they had some concerns when the drug was launched just because of the drug. Then they were of course more concern when the post-market study came out. They decided to look at their own data within their own system, of course they have probably the largest database of patients that you could possibly find in the country, and did their own cohort study. They looked at 6,400 patients that had becaplermin ordered since the onset of the drug. They were reassured because they found that there were substantial evidence that there was no increase in the cancer risk for the patients with becaplermin. With that being said, still on the package insert, itâs still a box warning. I think again itâs in the package insert that is contraindicated in patient with no neoplasms at the site, and so we should in using it with caution in patients with a non-malignancy overall. But as clinicians and providers, we need to balance the risk and the benefit and again, have the conversation with the patients. If we feel like the benefit to having the drug and being able to use it for diabetic foot ulcer early on because you can use it from the day one after we get it cleaned is going to be the best benefit for the patient, then we have to feel confident and being able to prescribe it and have the patient not feel like they are being put at risk. When we look at clinical trial data thatâs submitted to the FDA, of course weâre looking at efficacy. This really lends itself towards the risk benefit concept. When we look at efficacy, itâs been proven to the FDA, theyâve submitted the right kind of data, they met the right kind of endpoints to have it come to the market. It was effective and safe in the treatment population and the clinical trials. But effectiveness of course is how does it work in our hands? I have a little bit of a different feeling about this. I always feel like the things that we use whether itâs Regranex or the bioengineered tissues or what we use, tends to work better in our hands.
That might be skewed in my brain. But the people that we have in our practices are far from perfect patients or the measures are all A1c below whatever. I heard one talking about it, it can be below 10 or 12 this morning. But a lot of the earlier trials, they had to have an A1c below seven. Ours are like 9, 10, 17, something like that. Theyâre on steroids. Theyâre on chemotherapy. They have all these baggage that comes along with them that makes them an even worse healer, so if we can use something that changes that around that augments their healing process, it makes sense that theyâre going to work better. So, Dave Margolis did the study. It was published in Wound Repair Regeneration 2005 looking at effectiveness. Okay, it was proven in the clinical trial, but is it effective in the hands of the user? You want them to be equal. In the previous trial, it was 35% more ulcers healed at 20 weeks than those that didnât get the drug which equal relative risk of 1.35. That was again efficacy in very tightly controlled clinical trial situation. So he did this retrospective cohort study where he was able to control for the treatment bias. What he found was the relative risk was 1.32, which is right about the same. It was one population of patients with one group of wound centers but still nonetheless, it showed that again it equaled the efficacy and the effectiveness were equal in this group. I just feel like, with most of the advanced things that we use, we get better results than that. Working towards the end and the summary, with PDGF and diabetic foot ulcer, which is of course the indication, we know that so many things can go wrong with patients who have diabetic foot ulcers. A big majority of them donât show normal healing, and because of the nature of this needing Desert Foot, itâs kind of like how many jelly beans are in the jar, so I think, how many times over the next three days someone is going to show 65,000 diabetic amputations every single year. One every eight minutes, where you would rather have certain cancers than have an amputation because of the morbidity and mortality, five-year survival on that. We know what risks these people are at and of course this is meaning all about the foot. PDGF is certainly one thing in our toolbox that we can use to get people started earlier. Thereâs no waiting period. Thereâs no thing that says you have to wait four week or three weeks before you start it. If we get it well prepared, and we have to do that, and start something like this early, then we can get a nice healthy granular bed, and then it still could enable us to move on to other things that you might want to use. But itâs a great first line option. This is just a slide I use for nurses and I just used this a couple of weeks ago to a bunch of nursing home nurses. I put this up there and I asked them which one of these would you rather take care of? You know what they all said, âI want the little one.â Of course, I want the little one. But really this one is a venous ulcer. I should have given you that information first, albeit a bad on. But he was hypercoagulable and he didnât know, so once you figure all these stuff out and get them on anticoagulated, have some surgery and have skin grafting and everything was right. Everything was well with the world. This one however, you know, not treated well can scare you to death. Thatâs the person whoâs going to lose the limb. This again what the meeting is about and what so many of these products are about. Itâs a drug and itâs an optional toolbox to take in a very short period of time with good wound bed preparation, good bacterial control, and good offloading, have patients that have options or outcomes likes this. It doesnât really matter where it is on the foot. As long as we do those three things and get the wound bed prepared well, then using topical PDGF because of this interaction with being such actively interactive with the majority of the cells and wound repair and because weâve prepared the wound well, itâs going to be a very good combination. This is a gentle giant, I call him. Heâs a guy in our practice, had multiple foot and toe ulcers. This is just a story presented to the ER. They sent him over to us. We got him cleaned and we started the Regranex and he went on to heal just fine.
Of course, we can show you pictures after pictures. The proof is in the pudding, and the proof is getting the patients in, getting them prepared well and using something like this drug to get them closed early. This was interesting. This was a guy who was actually in our platelet gel study who was debrided. We started him on the platelet gel trial and diabetic of course. After the trial was completed, he didnât do well on the trial so you can see when he came back in, that was pre-debridement. Started some ORC collagen and then he was still open about a month later. We started him on the Regranex and he went on to heal, but he had not healed with his own platelets. Thatâs kind of my point. We were able to get him to heal. Again, he was this clinical trial patient so he was in a pretty good shape for someone who has a foot ulcer. So Iâm going to close with this. Those superhero bandage arenât so super and sheâs asking why not. Then they put it on a scrape an hour ago and it hasnât healed yet. The things that weâre talking about, they are sources of scientific cells, a growth factor that is known to induce healing. Theyâre not magic. Theyâre a tool in our toolbox and theyâre something certainly that used in the right patient at the right time with the right kind of preparation. May not heal in an hour but certainly will heal it faster than the patient might have healed otherwise. Weâre the advocates for our patients. We try to get them to prevent, we educate them, we do all the right stuff which is offloading all the things that weâve outlined. We have to continually look at the barriers to healing and figure out if theyâre not moving in the direction that we want and move on to an active agent as quickly as possible. To me thatâs where PDGF is in, something that we start from the moment we get them clean and getting them well prepared, getting them a granular base. Either stop there but certainly be able to move on to something else. But, in terms of the costs and the expense for everything thatâs been talked about today, the expense of wound as weâve all said in our lectures is the one thatâs not healing. With that, I think I did get done early, seven minutes for you. Thank you.