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Board Review Wound Care

The Role of Tissue Substitutes in Wound Care-The VA Experience

Robert Frykberg, DPM, MPH,

Robert Frykberg, DPM, MPH reviews the role of tissue substitutes by using the VA model. Dr Frykberg describes the different categories of tissue substitutes, distinguishing between wound management and wound healing products. He provides evidence from the literature and cost analysis from the VA system as well as specific data from the Phoenix VA. He also urges providers to use aggressive wound care with appropriate products for overall cost savings and improvement of patient care.

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Goals and Objectives
  1. Recognize the role of tissue substitutes in wound care.
  2. Describe the difference between acute and chronic wounds.
  3. List the risk factors for lower extremity amputations.
  4. Identify advanced wound care products.
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  • CPME (Credits: 0.75)

    PRESENT eLearning Systems, LLC is approved by the Council on Podiatric Medical Education as a provider of continuing education in podiatric medicine.

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    Release Date: 03/16/2018 Expiration Date: 12/31/2018

  • Author
  • Robert Frykberg, DPM, MPH,

    PRESENT Editor - Diabetic Limb Salvage
    Phoenix, AZ

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  • Lecture Transcript
  • �today, and I�m going to be discussing the role of tissue substitutes now in wound care. We talked about the role of ECM and how important that is as a basis for wound healing, but we also mentioned that there are many, many advanced modalities on the market, and many of these I�ve had personal experience with, and now we want to talk about the role of actual tissue engineered products in our wound care protocols. Again, my disclosures, this talk is also provided to you on behalf of Advanced Biohealing, but we�re going to try and make this as evidence based as possible, as always.

    We know, as we�ve heard from Dr Tamler and Dr Clutterjee, that diabetes is a very complicated disease, and especially in the lower extremity, diabetes has multiple complications that we need to be aware of, because many of our diabetic foot syndrome patients do have many of these metabolic perturbations at work when we�re treating them for a foot ulcer, a foot infection or a Charcot foot. And of course, one of the primary lower extremity complications in diabetes is always neuropathy, but we can�t just say neuropathy. We recognise that peripheral neuropathy is a many-splendored thing. We often will first think of our classic sensory glove and stocking neuropathy or loss of protective sensation, which is indeed a critical aspect in this regard, but also remember the very important role that motor neuropathy has in development of structural deformities, as well as autonomic neuropathy, which has direct role in sympathetic failure and microneurovascular dysfunction.

    Similarly, when we consider the role of vascular disease in these complicated diabetic patients, we don�t just consider the macrovascular disease that Dr Clutterjee has been speaking about this morning, and its impact on atherosclerosis and critical limb ischemia. We also need to think about the role of microvascular disease, and as he�s already mentioned, the role of small vessel disease was inappropriately attributed to microvascular occlusive disease years ago by Goldenberg in 1959. But now we know that microvascular disease is composed of basic structural abnormalities, thickening of basement membrane, but more importantly than not, it�s microneurovascular dysfunction in terms of disturbed blood flow through the smaller arterials and capillaries. This is promoted by autonomic neuropathy and loss of tone in the arteriovenous shunting system.

    So we have a high risk foot with all these underlying metabolic problems consequent to diabetes. We apply trauma to that high risk system, and with an impaired response to infection, we know that we often can develop these terrible wound that become chronic, that become infected, lead to gangrene, and in the presence certainly of PAD, result in amputation. While all of these underlying problems are not always existing in patients with diabetic foot disease, most or many of these problems will be at risk. So we need to be aware of these problems if we�re to properly intervene, and when you�re assessing your patients consider all of the complications that could be present in that patient, because by knowing the underlying pathophysiology you can better treat these patients and address the factors that are causing the problems themselves.

    Very important to recognize, based on Pecoraro�s classic study in 1990, that foot ulcers are major risk factors for subsequent amputations. And in fact, about 85% of all diabetes related lower limb amputations are preceded by a non healing ulceration. It�s critically important to appreciate this fact. This does not mean that 85% of ulcers go on to amputation � in fact it�s only about 15 to 20% - but if you look at all diabetes related LEAs, there was a non healing wound in the pathway leading to that amputation.




    So it�s very important that we aggressively manage these wounds so that we can heal them quickly, so that they do not become infected. We also know from Larry Lavery�s work that the longer an ulcer is present, the more likely it is to become infected. Even to the point of if it�s present for over 30 days, there�s a several fold increased risk for infection. And when you develop infection then you�re at a higher risk for subsequent osteomyelitis and necessary amputation.

    So it�s important that we recognize the classic diabetic foot ulcer as a very, very important risk factor, not just for further ulceration but also for amputation.

    We know, as we mentioned somewhat in my prior discussion on the wound healing process, which starts immediately after injury and complete remodeling takes place in the course of months down the end that we start the hemostatis, platelet aggregation, neutrophil migration, monocyte migration, development of granulation tissue, and now we�re seeing as we go from the acute clotting, hemostasis stage to the inflammatory stage to the proliferative stage, subsequent wound closure, subsequent scar remodeling, the ECM remodeling that we talked about, which can go on for years. So it�s important that we just have a basic appreciation of what�s going on in these four stages of wound repair. Very active metabolically active stages with many roadblocks in place, as we�ve said, especially in the chronic wound, which is defined as that wound which does not follow the orderly temporal sequence leading to final repair in a four-week time period.

    As was discussed in the last talk also, we know that the chronic wound environment, especially in diabetes, there are many underlying disturbances, characterized by persistent inflammation, biochemical perturbations as we�ve mentioned, the imbalance between the proteases and the inhibitors of those proteases leading to multiple problems with growth factors and growth factor receptors, so excessive inflammation, excessive elevation of pro-inflammatory cytokines, MMPs, and proteases. This also results in cellular dysfunction, where chronic wounds are typified by cellular senescence, cells that are not proliferating properly, they�re not synthesizing properly, there�s a lack of normal apoptosis. They�re essentially living but yet non functioning cells. That is typified in a chronic wound.

    Disturbed apoptosis because these cells survive longer than they�re supposed to, but they�re not metabolically active, they�re not synthesizing, they�re not proliferating. We�ve also mentioned that bacterial burden is high in these chronic wounds, which also can lead to the persistent inflammation and the biochemical perturbations, just stalling these wounds and keeping them in that chronic inflammatory state. Also, typified by oxygen deficiency with impaired perfusion not only by peripheral arterial disease but by even neuropathic edema and a loss of normal capillary flow based on the edema, based on the other metabolic perturbations that we�ve already mentioned.

    So this is the typical chronic wound that we are dealing with, so we need to know what�s happening so that we can reverse that failed healing course, so that we can get these wounds to finally heal.

    This was from Ralph Lobin�s paper in Diabetes Care in 2005, where he really just typifies in a graphic sense the difference between the healing wounds and the chronic ulcers. Again, the chronic ulcer is typified by cells with low mitogenic activity, high levels of pro-inflammatory cytokines, high levels of proteases in senescent cells as we�ve said. Exactly


    the opposite is happening in normal acute healing wounds, typified by cells with high mitogenic and secretory activities, low levels of inflammatory cytokines, low levels of proteases, high levels of tissue inhibitors of matrix metalloproteases, and mitotically competent cells. That�s basically the underlying profile of these two types of wounds. And our job, when we�re addressing the wound with our wound bed preparation and proper wound care management, we�re trying to convert that chronic ulcer and tip the scale towards a healing wound, by providing cells with high mitogenic activity, low levels of pro-inflammatory cytokines. So we�re really trying to reverse a chronically stalled course and convert it into normal healing acute wounds typified by these factors.

    So we�re going to talk specifically now on our experience in the VA. Many of us are in the VA who are in this room, or at least several of us are. And the VA has been an experiment in multidisciplinary management for the last 15 years or so. We�ve been very aggressive in managing these chronic wounds because we have so many very, very sick people with so many chronic diseases, including diabetic foot ulcers and chronic venous leg ulcers. We know that there are a great number of diabetic foot ulcers in our system. We have a large number of amputations, but these are amputations of all levels, not major amputations. And it costs a lot of money to take care of these patients. We have too many patients in my estimation who are walking around with a leg missing, but part of this is due to not addressing peripheral arterial disease years ago as well as non compliance. So we have to do the best that we can with the patients that we�re dealing with, but this is a big problem in the VA. We have a large number of diabetic patients, at least 25% of our patient population in the VA is a diabetic population, and a large number of these patients have peripheral arterial disease. It was interesting to hear Dr Clatterjee mention the progression of ischemia over the course of years in his one paper. We are seeing exactly the same thing. We rarely see a purely neuropathic ulcer any more. It�s usually more typified by a neuroischemic ulcer.

    This comes from the Carles paper published in 2011 in the Journal of the American Podiatric Medical Association. Just looking at the costs for our system of diabetic foot ulcers, comparing commercial carriers with Medicare, and those patients with DFUs requiring amputation versus those without amputation, and as one would expect, costs are doubled on the commercial side here when patients require amputation for obvious reasons. Patients that go on to heal a diabetic foot ulcer primarily without the need for hospitalization, without the need for amputation, are going to be treated as a much lower cost than those who require amputation. And similar numbers were found almost doubling the costs as well in the Medicare population. But these problems are very, very expensive problems. They not only affect the quality of life of our patients but they are very, very costly for our healthcare system.

    Within the VA itself, this is data extrapolated from Gail Riber�s 1994 data. We can see that the VA estimated costs of diabetic foot ulcers and amputations in the VA system itself is over half a billion dollars. Okay? So these are very, very expensive problems for us in the VA.

    Several years ago, our dear leader Jeff Robbins put forth this paper: �Calling to Action�. Those of us in the wound care field looking at mortality rates and diabetic foot ulcers and the need to recognize the severity of these problems and the mortality risk that has been evident by several papers. And so the message of this paper is that new ulcers, diabetic foot ulcers, need to be considered a marker for significantly increased mortality. We�ll talk more about that in my next talk this afternoon. But we need to be aggressively managing


    these problems earlier rather than later, as I mentioned I believe in my previous talk, the longer that an ulcer remains open, the more likely it is to become infected and require amputation.

    So we very aggressively employ various types of advanced wound healing modalities. As do many of you in your own practices. I�ve used most of these products, and I can use most of these products, despite my practicing in a closed environment such as the VA. We�re very aggressive in using advanced products as appropriate. We�ve already mentioned the use of the extracellular matrix scaffolds, but we remember that the granddaddy of modern wound care products was really Granex gel, the Calamine gel because that was the first one to undergo a randomized clinical trial prior to its coming on the market. But we use a variety of extracellular matrix scaffolds for all the reasons we discussed in the last talk. I very commonly use cell-based tissue technologies, because I believe these are able to deliver exogenous growth factors and exogenous living neonatal cells that really can jumpstart some of these chronically stalled wounds. And of course the products that we use now are both Apligraf and Dermagraft products, stem cell products are available. We don�t have them freely at our disposal now. You can get these commercially, or use autogenous stem cells for helping your wounds. And of course I think everybody in this room uses negative pressure wound therapy to some degree. These are all part of our protocols for managing chronic wounds. We don�t use them all for every patient of course, but many times we�ll use several of these products in sequence or concurrent with one another to get these chronically stalled wounds to heal.

    We like to make a distinction between wound management products and wound healing products, and only several products have really undergone pre-marketing approval indications for healing diabetic foot wounds. That means they�ve undergone clinical trials, randomized clinical trials, rigorous trials, prior to putting such products on the market. And those three products � this is data based on their published peer reviewed randomized clinical trial, and this is intent to treat data. Very rigorous. We have the three products, only three products with pre-marketing approval on the market � which are Regranex, Apligraf and Dermagraft.

    We already mentioned the Regranex. We�re all familiar with the role of Apligraf, which was really the first tissue substitute on the market, and then of course Dermagraft. I�ve used all of these products as well.

    But now let�s talk about bioengineered skin equivalence for replacements. I view them as drug delivery systems, or cell delivery and drug delivery. That drug meaning growth factor, new production of extracellular matrix, new production of growth factor receptors, cytokines, etc. Those two products now are, as I�ve mentioned, Apligraf and Dermagraft. These are producing cytokines, various growth factors, various matrix proteins and living neonatal cells that are primed for proliferation and synthesis. Okay? So they�re really delivery systems, which is why I like to use these very aggressively, and I use them early on for our chronically stalled wounds.

    Now, Apligraf, as I said, was the first product that was put on the market. It�s indicated both for diabetic foot ulcers as well as venous leg ulcers that haven�t responded to good standard conventional wound care for four weeks. Same thing for the treatment of full thickness diabetic foot ulcers. We always use these products in conjunction with good



    standard wound care, and ulcers that have not responded to at least three weeks of conventional therapy was the entry criteria for the trial for the diabetic foot ulcers.

    So these products, again, are not substitutes for good basic wound care � they�re adjunctive to good basic wound care which we must follow in every single case.

    This is just a picture of the growth factor expression in the Apligraf which is a bilayered product consisting of both neonatal fibroblasts as well as keratinocytes, in a bovine collagen mesh. We can see we have the production of PDGF, the basic fibroblast growth factor, transforming growth factor beta, transforming growth factor alpha, as well as insulin like growth factor 2. And we can just see how these are producing increased levels of cytokines specifically growth factors. That�s what these products do, based on the neonatal fibroblasts and keratinocytes residing in these implants, these tissue implants, as we might call them.

    This is the data from Aris Levis�s published trial in 2001, where we saw in the graft skin, which was the original terminology for Apligraf, 56% healed in 12 weeks compared to 38% control. Maximum of five applications over a four week period of time. And we saw there was an increased odds ratio for healing in the active group. This is what we would expect, and also more rapid time to close. So this is what you would typically expect; if they didn�t reach these numbers or there was no significant difference, this product never would have made it to the market, because this was a PMA product. It had undergone clinical trials prior to getting it approved for market use.

    Now we talk about the other product as well, which is Dermagraft, which is a monolayer of neonatal fibroblasts grown on a mesh of bioabsorbable mesh. Your Vicryl mesh, polyglycolic acid. So these are the fibroblasts seated into the substrate, and they�re grown in a laboratory, and delivered frozen and sterile to the end user. Again, as in the previous product, these cells are synthesizing growth factors and cytokines, matrix proteins, glycosaminal glycines, which are part of the extracellular matrix, and these cells are actively multiplying and that�s the key. So again, growth factor delivery system.

    Again, we see the expression of various growth factors in these products. And also the development of an enhanced extracellular matrix production according to the time period to effect proper wound healing. These are the different stages of wound healing, and how this product interacts at these various stages to effect final wound closure.

    Here is the trial published by Bill Marston, Diabetes Care, 2003. I think there was a poorly executed trial, quite frankly, because we can see although there�s a significant difference between the active Dermagraft group and the control group, it was significant, but much lower than in other randomized trials. Now, when you look at studies like this, we always have to look at the control group for efficacy or for trial design, and we know that based on Margolis�s previous publications, that most control groups for, should be in the range of 30, 35% healing at 12 weeks. And these were all 12 week trials. Why was this lower? Well, I think it was inadequate offloading. I think that the design was such that they weren�t rigorous in their offloading, and now we know that any new clinical trials have very aggressive offloading as a very basic part of the care.

    But despite the design difficulties in this trial, it was a significant difference, and in fact it was a 67% improvement over the control, which is actually the highest marginal effect of any of the pre-marketing approval products, despite the difficulties in the execution of this


    trial, which was a random distribution of differences of effect across both groups. We see that this was a 67% improvement over the control. So it did receive pre-marketing approval for this product, which came out around 2003 or 2001, 2002, but this was the published trial.

    So what is the appropriate patient for tissue therapy? You always need to address the underlying vascular status. You always need to debride. You always need to assess for infection and control infection first, and we need to offload properly, because that is one of the basic tenets of wound repair, and we also must pay particular attention to medical optimization as well as nutritional optimization. Many of these patients are not well nourished, even though they might look very robust, they do have nutritional issues that need to be addressed, so we usually get a nutritional consult on every one of our inpatients to help manage these patients.

    So we see from published evidence, highlighted here, that we believe that utilization of the PMA approved wound healing therapy at four weeks makes a lot of sense. Based on prior studies that show that wounds that fail to achieve a 50% reduction at four weeks are more likely than not, not to heal. So very aggressively we will start using such products if we haven�t achieved that 50% healing level at four weeks� time. And this is evident in the data.

    This data comes from VA, partially due to Sang�s recent paper published in 2011, talking about the PACT system in the VA. PACT stands for Preservation, Amputation, Care and Treatment. A funny mnemonic, but that�s what it is. And we�ve seen a steady reduction over the last decade based on multidisciplinary aggressive approach towards these problems.

    Our own specific data � this is a little bit difficult to read, but here are a number of ulcers. This is our ulcer rate. And as we see, our actual numbers of ulcers have gone up. Our ulcer encounters have gone up over the last several years, but our rates of amputation, or ulcer rate, have gone down.

    Now, here we�re looking specifically at amputations. This is based on our PACT data, difficult to see, but as of 2008, or since 2008, we had a pretty significant reduction � 23% reduction � in major amputations, from 2008 to 2010. In concert with increasing numbers of ulcer patients. Here we can see our data, 3300 ulcer encounters with 3% amputation rate in 2008; 2009, increasing number of ulcer encounters, lower amputation rate, and even lower in 2010 with more ulcer encounter patients. We adopted an aggressive therapy of using tissue substitutes, the monolayered tissue substitute, Dermagraft, into our wound care protocols at that time, and thereby we noticed a 33% reduction in our amputation rates from 2008 to 2010. We had 21 relative fewer amputations in 2009 and 41 fewer relative amputations in 2010. This was relative to the number of ulcer encounters. Okay? And this was crude numbers reduction.

    Thereby extrapolating this data, we had a $4.6 million saved in 18 months. So the bottom line here is that your costs are loaded up front, but your reductions are accrued in the long run by reducing the number of amputations and hospitalizations necessary from non healing chronic wounds. And there have been several papers that have exemplified this in the literature. We�ve got one pending publication. Now there is a publication in the, there was a lake breaking abstract last year in the ADA that showed exactly that, that your costs are loaded up front, but your savings are accrued after six months, based on earlier wound


    healing and a lack or a reduced number of required amputations, bone resections and hospitalizations.

    So again, we have to look at wound management strategies versus wound healing strategies. Everything that�s been on the market that has a 510(k) approval, which is most of your products that are on the market because they�re similar to something else, are considered wound management strategies, including the ECM, which we use, sometimes in conjunction with the tissue therapies.

    But in this regard we�re talking about products that are indicated for wound healing, and these are the TMA products, like Regranex, like Apligraf and like Dermagraft. Again, these are cellular delivery systems and cytokine delivery systems. That�s the way that I look at them, to help jumpstart these chronically stalled wounds. And we�ll use these very aggressively because they�re readily available for very, very complex patients. Our patients have many underlying comorbidities, they often have failed revascularization, they often have renal insufficiency or are on chronic hemodialysis. So we have patients that are at great risk for amputation from the get go, so we tend to use these products earlier and very, very aggressively to get these wounds closed. Why? Because we know from the published data that I�ve already mentioned, the longer these wounds remain open, the more likely they are to develop infection and osteomyelitis, gangrene, and require subsequent amputation.

    So in conclusion, we know that living tissue substitutes have an important role in our wound care algorithm � certainly in our algorithms � and we�ve seen the effect of using these things very aggressively in our reduction of amputations, as I hope I�ve shown you. But despite that, the basic tenets of wound care are always followed. The nutritional support, the medical support, offloading, debridement, infection control, management of underlying peripheral arterial disease.

    The additional costs of these tissues are offset by the savings from accelerated wound healing and reduced complications. I think that�s the message really to take home. Yes, these can be expensive products, but there are actually cost savings when you consider in the long run the reduction in amputations and hospitalizations due to infection.

    But as in many of these products, there�ve been no direct comparisons between them, and I don�t expect that there will be, because they�re very expensive and you�re not going to get a company to sponsor such products unless you had a grant to compare the two. I don�t think it�s going to happen. So we view all of these products as being pretty much equivalent in terms of their ability to deliver growth factors and neonatal cells to the wounds. So, I think and hopefully you�ll see in the future, there will be some type of direct comparison, but right now we can consider them pretty much equivalent. It�s really a matter of your own personal choice and preference.

    So with that, I want to thank you for that. I think we�ve ended up right on � for the�