Anthony R. Iorio, DPM discusses acute and chronic diabetic and venous leg and foot ulcers, and their dramatic response to the application of dehydrated human amnion chorion membrane in conjunction with compression therapy and excellent wound care. Dr Iorio cites multiple studies and statistics that support these applications for treating these as well as other types of wounds.
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Release Date: 03/16/2018 Expiration Date: 12/31/2018
Anthony Iorio, DPM, MPH
Assistant Dean for Continuing Education
Chairman, Department of Community Health and Medicine
New York College of Podiatric Medicine
New York, NY
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TAPE STARTS – [00:00]
Male Speaker: I'm happy to introduce Dr. Anthony Iorio from the New York College of Podiatric Medicine who’s the assistant dean for continuing education, and chairman of department of community medicine. Dr. Iorio is well-traveled in the diabetic foot and wound care circles.
And he is going to give us his insights on the current state of affairs for advanced therapies, for chronic wounds. So let’s welcome Dr. Anthony Iorio. Okay.
Antony Iorio: Thank you, sir. Okay. As we’re all trickling in, I did want to first thank the chairperson and the committee for inviting me today.
And I will be sharing with you as Dr. Farberick said some of the things in which we have employed in the clinics particularly one of the city hospitals, Lincoln Medical Center in the Bronx, for which we have put together our own wound center from scratch. So it’s a mom and pop operation for which we proudly say that we have employed and used a lot of different types of technologies, and have made up some of our own protocols, which could be a very help... hopefully we can share that with you this morning and some take up points for you and your hospital to consider.
So with that, this is my disclosures. I just have a... I speak for companies which is Smith & Nephew, Bio Medics, Valiant and CSI, and at times it can be a medical consultant to the advisory board as well.
So this morning and in the 30 minutes that we have, I’d like to review with you, most of you already heard this from Dr. Farberick this morning, but a lecturer of this type can echo on without going through some of the quick epidemiology and prevalence of diabetes and associated diabetic foot ulcerations.
We also are going to differentiate between the acute and the chronic wound because there is a difference when we speak about a wound that’s fresh or under a certain amount of time, and then when does a wound change from being an acute to being chronic?
We’re also going to discuss some of the standards of care initiation of advance wound therapy and what types and what is out there from a generic point of view.
And that’s going to be led by level 1 evidence which is going to be the number of scientific and clinical studies for which are out there that I'll share with you some of those results.
And of course lastly some world real cases that we see on a regular basis.
So with that, and as you know Dr. Farberick mentioned this, but when I started too, 35 years ago, diabetes was just hitting the country. But in the next 15 years, we’re going to actually see about seven million people are going to have diabetic lower extremity ulcerations in the United States. And as we get older and as we populate more, we’re going to see that prevalence to those newer cases to be such.
So let’s take a look of what the epidemic of a diabetic foot disease looks like in the United States.
And here we see that every 30 seconds somewhere in the world, we are seeing that a leg is lost to diabetes and that can be extrapolated more by saying that any 85% of the diabetic related to lower extremity amps are usually preceded by a foot ulceration, and that’s something that we see all the time.
And it’s estimated that up to 85% of all amputations are due to diabetes, can be prevented. So here, we’re looking into prevention and how we can look, and looking out to see how we can prevent diabetic ulceration.
So taking a look of one day in the United States, we see the following; a long statistics from our colleagues where 5,000 new diagnosed patients of diabetes are accounted each day of which millions of the healthcare dollars are spent on treating that. Not to mention the number of... hundreds of costly lives that are lost and also unnecessary limbs that are amputated.
Talking about the economic cost and everyday changing healthcare environment, we’re looking at these... of the types of amputations which actually of a low extremity, are a detriment to our economy.
Not to mention that on the patient side, we all know that 50% of diabetic patients who have had or will have within the next... and one amputation, we’ll have in the next five years, an additional one, not to mention the mortality rate which is approaching the average of 50% and these are the things in which we need to get a point across not to neglect, but in this side of the river of venous leg ulcers in the state of New Jersey for those that are treated similarly but not to a great event, major event, I thought I would throw in the venous leg ulcers as well because venous leg ulcers also have a high recurrent rate and also does cause and does take the toll on healthcare dollars.
And we’re going to go through with you with some... one study that shows that this can be cut down.
So when we look at it and we see that there’s the stage of healing, we look at 49% of our ulcers may fail to heal despite good wound care.
So let’s define what good wound care is because we all do it and perhaps we need to just freshly remind ourselves of what we do.
So a good wound care for which is the standard of care, is to be... is making sure that we debride the wound well and how do we do that? Well, we have a number of agents that we can do that. We have sharp debridement which our gold standard and similarly you can use entrematic and also autolytic types of debriding agents that will help and assist that, all of which work to a certain degree, but of course the sharp debridement is the gold standard.
Then we move on and we check the vascular status of our patients to make sure that we have enough blood going to the area. We have the aide of our interventional cardiologist, radiologist, and our vascular surgeons that can assess with that, that can help us, and assist with helping that diabetic patient.
Moving forward, we then look at what is the bioburden and what is the infection of the patients?
So if the patient has no infection, we obviously are going to treat prophylactically and/or conservatively to keep the biofilm free from that wound by cleansing the wound regularly and have the patient also do that.
But if it’s more systemic, then we deal with the osteomyelitis and/or these... the soft skin infection from a parental and also other types of treatment. And then lastly, we look at, for a good wound care, the total contact pass. Offloading is extremely important, and we definitely need to make sure that the patient is offloaded.
Offloaded property can be gold standard until a contact has... but any method that can work in your own material that we have out there for our patients, will help.
So still, besides having said all that, still about 51% of our patients still fail to heal and that’s what good traditional good ulcer care. So what do we need to do for the other 51%?
Well, we’re beginning to realize that if we adopt some certain types of advanced protocols and appropriate care in a cost effective manner, we can actually help decrease the incidences of the new diabetic extremity ulcerations and we can also speed up healing which will help the patient as well.
Now, the answer is given away here because we understand that between… as it approaches 100%, we know that the five-year mortality rate for neuropathic and ischemia ulcers are high. When we compare that to our other types of treatable cancer, preventable cancers as the prostate, breast, combined.
But yet the problem lies that there is not enough being set out there. I think our patients and ourselves as clinicians, need to get that point across to help our patients become compliant.
So let’s take a look at... now that we have accomplished doing good wound care, how can we do better wound care and let’s going to attend this... that’s going to take us into today’s topic of what is advanced therapies for chronic wounds?
Well, way back in the 1990s, we all started with grow factors and then we know that the number one FDA growth factor has been out there since late 1990s. Then we move on to [indecipherable] [00:08:00] which we considered to be a great help in helping form the structure of the status of having to have that wound heal correctly and we move on to a biological skin and that all had hit the literature in about 15 years ago.
And of course some of the external factors such as negative pressure wound therapy as an adjunct to the wound care or all part of the... of all the things in which we have and which we should use and continue to use in helping getting through that advanced stage.
Now, one of the things which I'm going to work on moving forward, is that we have a new dehydrated amniotic chorion membrane and that is an allograph that I'm going to spend some... give sharing with you some of the information because I think that this processed dehydrated human on chorion membrane allograph is probably gaining a lot of popularity. Why? Because there are a number of scientific and clinical literature out there that support its use not only from... in the diabetic foot but also in the venous leg ulcers as well as other parts of the body.
So taking a look and seeing what that is, we all know what amniotic membrane is. Actually, this is probably the first one that ever came about. This is over a 105 years old and this has been actually used in a number areas but the processes and the types of prioritized technology is what makes this product stand out from other products.
And in this product, we’re looking at the human amniotic membrane and looking at the literature in this, support of enhancing wound tissue and healing and how does it do that?
It does it by four ways and the most important thing that it does, is it modulates inflammation and as we know inflammation is a good thing but it’s also can be a bad thing. So when inflammation is a bad thing, this is where this comes in to play.
Additionally, research has shown that the amniotic membrane also reduces scar formation and this helps particularly at the end when the ulcer has healed and the scar goes through its remodeling phase and during that remodeling phase, and as it goes to that end phase, it has some scar tissue, but this can also help with that as well.
Immunologically, it’s privileged and it contains essential amounts of growth factors. So let’s take a look of the… of a… mark histological look and what the source of the amnion looks like. There are several layers to this and every layer it does not get thrown out.
As you can see in the centers the amniotic stack and then we look at the amnion. Now, the amnion is the thinnest layer of this diagram, and it is the part that’s closest to the child, the fetus.
The second layer is the chorion which is much thicker, several times thicker, and that’s toward the mother and that is a thicker layer. Now, we also use the chorion plate where we can use some of that type of material membrane for which we can use some type of technology to utilize it for injection and injections in areas be it in soft tissue and in the wounds.
And now, we’re begriming to see that there are just as many growth factors in the umbilical cord as there are in the chorion layer. So now, we are looking at the umbilical cord as being one of those high preference areas for which we’re beginning to look into the literature to find out the form of its type.
But this particular amnion chorion layer which has purion process technology, is both the amnion and the chorion combined. Having said that, you’re going to ask, well, are all amniotic membranes equal? And obviously the histological slide show otherwise that it is... they are not equal.
We can see that the... in the amnion, we see about 20 plus or minus five, about 20%, of the growth factors allocated in just the amnion. Now, if you have using just the chorion, chorion is about 80%. But if you have mixed together both the amnion and the chorion, you can see that it contains at least 20 times more growth factors than any of the competitive single layer amniotic products.
That type of technology in science which has been quoted by Dr. Hoob who is this main... one of the main scientists, has shown that the chorion layer in addition to the amnion layer is privileged in having the most abundant amount of growth factors with cytokines and the like for wounds to mature to healing.
So let’s look at some of the scientific data that backs this up.
When we look and of course, we all go back to the wound pathophysiology and I give this credit to Dr. Sholtz. Dr. Sholtz, head of the university I believe of Gainesville in Florida, is one of the masters who actually speaks about the wound... the wound pathophysiology. And it starts when the wound... when there’s an injury that occurs.
And how does a wound become a... how does an acute wound become a chronic wound? Well, we look at the wound and the wound has repetitive ischemia and trauma to the area and bioburden and then that actually prolongs the amount of inflammation.
When you have a prolonged amount of inflammation, you’re going to increase your neutrophils, your macrophages and your mass cells just to name a few. And to simplify this more if there’s not an... that becomes an imbalance in the proteases and the inhibitors.
Remember, some things are good at certain times, so if you’re looking at your collagenases and your elastases, you’re looking at some of that are good, but too many may not be a good thing. You need to have the right things at the right time in the right place in order for this to prevent self-destruction because when these all happens, we have the [indecipherable] [00:13:58] we have the cell migration and the cell proliferation decreasing.
So what we need to do in this circle of events is to break the chain. We need to break the chain in one of those areas. It could be with a biologic, it could be an extra cellular matrix, it can be with a dressing, it can be with a growth factor.
Each of these advanced products that we have out there that we’re learning from, and learning about, will help get that wound to treat the chronic wound, should the chronic wound become one of the most... one of the things which is problematic to us.
So let’s take a look at some of the cascade of the wound healing and how it looks, and this is normal. And there is one phase that actually is missing and that’s the hemostatic phase. That’s the phase that happens immediately, that there is a wound and that’s the first time that the initial skin is traumatized. We move into the inflammatory phase which lasts for a couple of days in this activity with hemostasis, inflammation and cell signaling occurring during those days.
Now, when the wound is stalled or when the wound cannot go into the proliferative stage, that’s when the acute wound becomes a chronic wound. So in the proliferative stage, we’re looking for all types of angiogenesis, epithelialization and wound contracture.
And finally, when we go into the remodeling stage, that can go on for the latter part of healing the wound, we look at some of the new collagen synthesis and connected tissue forming. And this is where scar tissue may occur as well. Hence, the reason why when we use advanced therapy with amnion chorion, we can reduce the amount of scar formation when we get to that remodeling phase.
So taking a look at Shultz’s work, we have the term of dynamic reciprocity. In dynamic reciprocity, we rely on the extracellular matrix, which is something, which is the lattice and the building blocks. And that has a direct correlation with cellular signaling, which makes the cytokines and the growth factors activated. Similarly, the cytokines and the growth factors will work and help build the extracellular matrix to make that wound heal when we speak about tissue regeneration. And all are obviously relying on tissue regeneration by building new cells that’s going to help heal the area.
Do we all know what the four week rule is? And I believe everyone does here. This is by Dr. Peter Sheehan. And Dr. Peter Sheehan says that, you know, usually we look at the percent rate of reduction of a wound. And his theory is that, you know, if the wound closes by week 4, by going to the 50%, that wound has a great chance of healing. However, if that wound does not reduce in size by 50% or greater, then we’re looking at a wound that’s going from an acute state to a chronic state. And at that time, only about 9% of the wound, if left untreated by advanced therapy, is going to heal.
So the message here is to make sure early detection, making sure that it heals, and then of course, follow it up. And in four weeks, if the wound has not reduced in size by 50%, this is where your advanced therapy modalities become in place that will help close that wound. So begin advanced therapy when the diabetic foot wound has not reduced by 50% in that four weeks.
So let’s take a look at some of the science, what science says about other things, and this is one of the things in which I’m going to point out is the myth of living cells. This is something that has recently hit the literature and it is out there and there are several articles that back this, that when the integration of applied stem cells and in the challenges that are faced when we look at living cells of living stem cells, we look at two challenges. The first one is the incorporation of the applied stem cells itself. The second one is the survival rate of when those stem cells get to the wound.
So we’re looking at the survival rate of the stem cells at the site. And this is where when we have a solution, we look at something such as amnion and chorion because the amnion/chorion membrane, the dehydrated type, usually facilitates the incorporation and the survival of the stem cells. So this is probably something which is important fact, not to mention the 57 growth factor cytokines and chemokines that are in the area, and also to mention over 225 undocumented ones as well.
So here we looked at the chorion and the amount of the PURION Process amnion and chorion. We looked at the relative growth factors between the two. And again, with the number of growth factors located on the bottom of the screen, you can see that the amnion has a certain amount, but most importantly, it’s the chorion. But of course, the added effect of the amnion and chorion together in one membrane is what is used here because it acts like a magnet. And how it acts is it contains these extracellular matrices that we spoke about. It also has the growth factors and the cytokines, which, by applying that membrane, will act as a magnet, so to speak, which will help stimulate and proliferate and upregulate some of the growth factors.
And it actually acts as a stem magnet because what it does is it goes through the adult mesenchymal stem cells and it draws it to the side of attention. As the literature points out and as Dr. Cobb had mentioned, he mentions that your own bone marrow, when you look at regenerative tissue and stem cell magnet, it acts as a stem cell magnet so the stem cells or the mesenchymal stem cells inside the bone marrow, the body recruits its own stem cells. And there’s really no need for living therapy because it will actually cause… it will recruit stem cells. And most importantly, it will become invaginated and implanted and it will then contain angiogenesis, which will then move on to healing the tissue. And in this article, it mentions that it is an inductor to epithelial cell migration, which helps in the epithelial cells and upregulates the biosynthesis of angiogenesis.
So with this type of human amnion/chorion membrane, dehydrated, the regenerative therapy through amniotic properties are all valid.
So let’s, in the next 10 minutes, go through some of the applications, some of the case studies where we find this to be somewhat helpful. Now, amnion and chorion, really, there are a few areas in which it cannot be used. It is definitely used for acute wounds. It can be used in chronic wounds, as I particularly use it for, and for full and partial thickness as well. It can be used in any specialty from head to toe. And now, we are finding that it’s very helpful in sports medicine and also in orthopedic medicine because of that additional reduction in scar formation that enhances some of these nice soft tissue for primary closure.
So let’s take a look on average, because size is very important to all of us, because in a conscious healthcare environment, we’re looking at how much is this going to cost. When we look at a diabetic foot ulcer, the average minimum area for that in the United States is about 1.35 centimeters, and a venous leg ulcer is about 2.32 millimeters. So when we look for and we look very consciously toward the cost of what things are, we look at the size and we pair it to who makes these sizes because we certainly don’t want to have waste. Because waste costs money, and city hospitals, they don’t put up for anything but making sure that every nickel and dime is accounted for. So here we’re looking for the appropriate size for the appropriate wound. And that’s one of the highlighted things I like to just mention to you about. So that’s one of the reasons why this is so popular.
But the most important reason by this article states that this randomized clinical trial in this outcome shows that the PURION processed human amnion/chorion membrane with the standard of care versus the standard of care had shown to heal 92% of the ulcers in six weeks. 92% of the ulcers had been healed in six weeks compared to 8% for the control with an average of 2.5 graphs to closure. And this is one of the most important scientific evidence that we have, and this is a good study to read by Dr. Cobb.
Not to mention that the wound has now healed, what about the wound staying healed? Because we always have that problem. We can get the wound to heal, but what about the follow-up studies that show that this wound has to be healed, and will it remain to healed? Well, in this study for nine months to a year out, we see that 18 out of the 22 eligible patients who returned for follow-up that were healed. One of the 18 had a recurrent diabetic foot ulcer but the other 17 had a 94.4% heal rate.
So one patient remained unhealed, so therefore, not only did it heal initially, it stayed healed for an additional of 9 to 12 months. And that study shows a follow-up of 94.4%. Even though they had 18 patients, it was still appropriate to state that it had significance when it comes to having the wound stay healed after healing.
And when you say, “How many should I use?” Well, it’s better to put it on weekly than it is to put it on every other week. It’s less cost, but most importantly, there is really no significant change to show that if it was put on weekly as opposed to put on every other week. So I like to put it on weekly and that’s where we get those good results.
So what are some of those results in those clinical presentations? Again, we used them on heel ulcers and there’s a figure 1 going to figure 3. And this is a patient that I used enough for pyoderma gangrenosum, which was going to be undiagnosed but only in three, and we’re currently on three. And this is the latest picture on the right and three applications in the right.
This patient who had had the problems since this past summer is beginning to positively heal on the right as you can see. This is a diabetic foot ulceration that when using the human amnion/chorion layer, again, 30% reduction in seven days, and an additional 15% had reduced at day 14. So what we’re looking for here is that the wound is closed, the wound remains closed and then we will see that the wound will continue to close with the patient working in custom-molded shoes and moving forward.
Just a word on venous leg ulcers. I want to share with you that we also have done studies in venous leg ulcers, and this is by Dr. Serena who actually showed 84 patients the multicenter randomized control of venous leg ulcerations. And he has wanted to prove and just show, which he did, that the dehydrated human amnion/chorion membrane with the use of multilayer compression therapy, 62% of the patients had a greater than 40% closure than with just multilayer compression alone. So what we’re seeing here is that not only is it great for venous leg ulcers, it’s also creating a great scenario for closing to wound greater by 40% when you use the dehydrated human amnion/chorion membrane in conjunction with multilayer compression therapy.
Now that study was done in three arms. As you can see in the green of lower level, it shows just by compression alone, which is minimal. But what’s the significance, we can see that either with the one with the compression and the second one shows that it’s with the compression as well as with the dehydrated amnion, the combination of the two is more significant than it was for just the one alone. And there is use for other wounds, too.
So these are some of the wounds in addition to chronic wounds that we showed, that regeneration is helpful when we use it. This is a diabetic patient, 61 years old, full thickness, burned, bottom of the foot and the wound was treated with dehydrated human amnion/chorion membrane. And this wound had been maintained. And after which the burn had been treated, it was then used with a dry sterile dressing and hydrogel to maintain it.
Additionally, we have thermal burns that come in. We used PURION processed human amnion/chorion. We finished create human graphs, and actually it continuous to move. Our colleagues use it for radiation dermatitis, radiation dermatitis on the head. We showed that this, from our derm consults and our patients, we showed that it also works on the head as well.
It can and does work, as the literature says, on exposed bone and tendon as long as the primary infection is kept at bay. So we did a study and we then we showed that our four consecutive diabetic patients, we showed that with the wounds and exposed bone, which was appropriately treated with antibiotics in taking care of the bone, we showed that the ulceration had healed in a number of times, keeping in mind that we only lost patient for below-the-knee amputation from other causes.
But here we see that this is the wound that we see in 14 days. We used the human amnion membrane. We used split-thickness graph to augment it to help, so in 14 days we have a reasonable closure. Similarly, in our second case, we have debridement of all the fibrotic and necrotic tissue. And we applied the dehydrated membrane and skin graph in the 16 days. You can see an appreciable closure on the lower right.
And case number three, where we did a tendon transfer. We see that the wound had dehisced. Put on the thickness of skin graph and within three weeks with the aid of amnion/chorion membrane, the wound had begun or to close. But most importantly, when we look at the TMA, which all of us or most of us do, we see that the TMA site may be open. But with the adjunct of skin thickness graph and amnion/chorion layer, we have an augmentation in helping that wound to close heal earlier. Keeping in mind that in addition to good wound healing and advanced wound therapy, we can have this marriage between the two because it’s important to us and the application is quite easy.
You prepare the wound bed like I mentioned earlier, a good, clean wound bed, free of all infectious tissue. You have a graph selection because the sizes matter, because it does from 14 millimeters, because you want you want to make sure you just have no loss. You want to put a nice primary dressing, put over none in here, a contact layer. A secondary dressing can be of your choice and, of course, to put therapies.
The graph is usually compatible with offloading total contact casts, can be used with compression, negative pressure therapies, all of which help to heal the wound quicker and faster. And of course, the graph can be used with hyperbaric oxygen just to mention other external types of healing.
Why we do all these is because we look for the best treatment for our patients. We want to make sure that the patients are getting the best care in the most cost effective manner. We also want to look at some of the challenges that we face globally. And we want to make sure that we can get this paid for in hospitals because hospitals will look at us I think differently if we definitely get this better and get it down. But most importantly, the incentive to get our patients heal quickly and prevent re-wounding is probably one of the gifts that we, podiatric physicians and surgeons do when it comes to wound care.
With that, I will be around the rest of the afternoon. I want to thank you for your attention and thank you for inviting me to the conference. Thanks.
TAPE ENDS – [29:24]