Board Review Wound Care

Cellular Tissue Substitutes: What the Literature Tells Us

Gary Rothenberg, CDE, DPM

Gary Rothenberg, CDE, DPM discusses cellular and acellular products and their impact on wound healing. Dr Rothenberg reviews various conclusions derived from trials and literature on wound healing and results using cellular tissue substitutes.

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Goals and Objectives
  1. Identify key differences between cellular and acellular products
  2. Analyze factors influencing successful wound healing
  3. Explain the role of wound bed preparation in the use of LSE (Living Skin Equivalent)
  4. Describe appropriate patient selection criteria for use of LSE
  5. Develop an appreciation for the RCT (random controlled trials) data associated with cellular based products
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  • CPME (Credits: 0.5)

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

  • Author
  • Gary Rothenberg, CDE, DPM

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  • Lecture Transcript
  • Male Speaker: Okay. Next for return engagement, I've asked Dr. Gary Rothenberg, who gave a nice presentation yesterday to talk about cellular tissue substitutes, what the literature tells us and we should always be relying on the literature. So let's welcome Dr. Gary Rothenberg.

    Gary Rothenberg: Thank you. Good morning. Thank you again for the opportunity. Some of these products have been discussed in these categories over the past day-and-a-half. And so I'm going to, hopefully, go through that fairly quickly and get to the more interesting literature based evidence as Dr. Freiberg [phonetic] just introduced. You can see my disclosures available for you there. And this morning, again, what I'd really like to talk about is the difference between cellular and acellular products and then what the literature tells us about when we should be utilizing these products and how we should be utilizing them. So for me, it's pretty easy to try and categorize things. And the difference between cellular and acellular products is, you can see in different siloes or buckets up on the screen for you. The easiest way for me to understand this is cellular based products either are going to be cryopreserved for us or they're going to have a short shelf life. Acellular products, as you know, do not contain living cells, so they potentially have a longer shelf life. So cellular based products, which we're going to focus on this morning, are in two categories, either bioengineered which you're familiar as to the two products, Apligraf and dermal graft or through donated tissues, we've heard about as well. They're through cadavers or placental tissue. The acellular products, there are usually of different origin, either porcine or bovine and they are largely collagen-based products. So we'll talk about the indications. And again, sticking to the literature, this is a slide which tells us about the dynamic interaction of wound healing prosthesis, which rely very heavily on cellular based products or cellular-based technologies. So we see here that cells are required, keratinocytes and fibroblast. And they only are responsive when you have appropriate signaling molecules, such as growth factors and cytokines. And you also have to have a strong matrix for that. So I was making analogy that healing a wound is kind of like building a house. And you need to do that from the ground up. You need structure. You need the foundation. You need the feel of the walls. And what most of us really appreciate is putting the roof on or a closure of that. The problem is the things can go wrong at each of these interaction sites. So the cells becomes senescent. We have cytokines and growth factors that are at abnormal levels and we don't get the response that we want. Oftentimes, the extracellular matrix or the structural support also becomes dysfunctional. So this is the dynamic interaction that's required for successful wound healing. So the living skin equivalents as cellular-based products are bioengineered tissue. They come from human fibroblast cells cultured from neonatal foreskins. And we hope that they accelerate wound healing by providing a moist wound environment, acting as that structural support and eliciting or soliciting, if you will, the growth factor response that's required. So how do they really work through their mechanism of action as I just said. A lot of people believe that there's a protective value to the coverage utilizing these cellular-based products. And in fact, donating that structural support and guiding the appropriate phases of wound healing to happen. So I'm always reminded of that quote that you see in the box there that says, the art of medicine consists of keeping the patient amused while nature heals the disease. That was by Voltaire many, many centuries ago. But that's essentially what we do every day, is through these products, hopefully, accelerate the normal processes that the body will go on to heal. So again, in the acute phase of wound healing, these processes happen in a normal, well-orchestrated cascade of events. But in the chronic wound model, most of our wounds become stuck in the inflammatory phase as we know because either, something is missing or something is there too much. And specifically, you can see where the cytokines and chemokines play a role most specifically in the inflammatory phase, and that's exactly what they do, is they have a check and balance system that cytokines do to actually pull those wounds out of the inflammatory phase and make sure that we don't get stuck there. And again, through the normal processes of wound healing stimulate that proliferation and migration. So from a historical perspective, living skin equivalents or cellular based products are not that new. They originated probably in the 1970s when we were looking for options for coverage. And through skin biopsies and different things of utilizing these products, we saw the keratinocytes were grown, in vitro.


    So they became popular in the burn acute and chronic wound arenas. So again, we think that these products provide a temporary coverage and elicit the immune response or the normal response of processes of wound healing to occur. So they come in different forms today, cadaveric allograft, cultured epidermal replacements, dermal replacements and composite replacements. So the concept of wound bed preparation I think is really important and you can't use these products without doing good wound bed preparation, which underscores everything. And what we've been hearing about over the past day, again, is doing the right thing at the onset. So wound bed preparation, though, is extremely important. And most people I think believe that wound bed prep is really debridement. It's much more of an active process than debridement alone. It certainly does include debridement, but it also talks about working on that bacterial burden of the biofilm that's oftentimes present on the chronic wound and management of exudate because that becomes a competitor for healing for a lot of our advanced biologic products as well. So we talk more about dressing selection in addition to debridement when Vince Falanga and others kind of popularized that concept of wound bed preparation. So this is a key take-home point for me, utilizing these products. And where I think some of the challenges when we look at these wounds on a daily basis, the truth is that not all wounds that appear ready for advanced biologics is that patient ready for an advanced biologic. So we can see even in this clinical photo a nice wound bed. Yes, there's some macerations at the periwound tissue, for sure. We have to deal with that. But the other thing that we have to remember is that that foot is, obviously, attached to a specific person. And I can tell you this patient story, you know, he is a elderly gentleman who's had this transmetatarsal amputation who has advanced dementia. His thing in the middle of the night is that he gets up and he walks. So he doesn't put on his removable cast boot. He's not a good candidate for a total contact cast. So again, I caution you that we have to comprehensively evaluate these patients because utilization of these cellular based products may not be successful if you don't do all those things at the frontend. So again, getting back to the literature, always, our goal in the skin coverage is going to be what do we choose to do it with. Do we use split-thickness skin grafts, do we use living skin equivalents. This article is published last year. It's kind of a comprehensive review and the summary points are there for you. You know, it's interesting that it still states in the literature that split-thickness skin grafts remain the gold standards for a reconstruction of a diabetic foot wounds. Ultimately, our goal is, of course, coverage. But orthobiologic substitutes oftentimes may have an opportunity to give us some flexibility for coverage and in my opinion, oftentimes, are very important go-to because not all of our patients are candidates for taking them to the operating room for a split-thickness skin graft. We know they're successful, but in my institution, for example, every patient that goes to the operating room has to be cleared by their primary care physician per hospital bylaws. So for me to get some of these patients with advanced comorbidities cleared for an operative-based procedure is very difficult. So the things that I can do in a clinic setting, oftentimes, are more advantageous for me and of course, for the patient. So speaking of each of these products briefly, fair skin is the cadaveric allograft that is, again, donated tissue providing temporary wound coverage. It came out of the burn arena and it does have some issues potentially. Though, it is aseptically processed with graft rejection and disease transmission. It's cryopreserved. It will come to you frozen. Graphics [phonetic] is the other donated tissue. Again, we heard about these products yesterday or this product specifically yesterday. It is placental tissue, which contains growth factors and proteins. It is donated cellular based tissue, fibroblast and epithelial cells with an ECM and what I thought to be multipotent mesenchymal stem cells. Dermal graft, we also heard presentation on yesterday, donated tissue as well, bioengineered from originally donated tissue and it comes cryopreserved as well. The initial pivotal trials was reviewed yesterday, so I'll just highlight the points. Thirty percent of patients had closure of 12 weeks compared to the control at 18 percent. So this was enough for the FDA to give PMA or approval for indication of diabetic foot ulcer healing. Apligraf is the bilayered construct and it does not come cryopreserved. It comes to us in a appropriate shipping box which has approximately a ten-day shelf life.


    This is the dynamic interaction between the keratinocyte and fibroblast of the bilayered construct. And you can see all of the growth factors that are elicited through that structural component. Their pivotal trial showed 56 percent improvement for wound healing compared to 38 percent in their multicenter trial. Again, it got the stamp of approval and the indication for diabetic foot ulcer healing. So this is an interesting study which I prefer to spend some time on as well. This was done across the street from my institution at the University of Miami with Dr. Krasner [phonetic]. This talks about advanced biologic therapies for diabetic foot ulcers. And this study actually wanted to see our practice pattern. So you and me as clinicians, when do we refer patients to centers that utilize advanced therapies and what are our practice patterns of how quickly we move to these advanced products. So that was really the purpose of this study, was to raise the question of when do we utilize these advanced biologic therapies. And actually, the fact that they studied this advanced biologic products, Apligraf, Regranex, and Procuren for me, is not necessarily even the point. The point is, what they found was that they were longer times to healing with larger wounds, more severe wound grades. These are intuitive things that we know. The deeper it is and the larger the wound, the more complicated it is. It didn't come overnight, so it's not going to heal overnight. The longer duration of the wound prior to the first visit was indicative of longer time to healing too as well as the prolonged time from that first visit to treatment with advanced biologic therapies. So essentially, we know, the earlier an advanced biologic therapy is initiated, the sooner the wound is likely to heal. And proper treatment is critical for the management of chronic diabetic foot ulcers. Again, you can't use these products on ischemic wounds or on patients that are not able or willing to comply and adhere with offloading or patients who have hemoglobin A1c of 14. These things are just not going to work. Those are not appropriate patients to select for this particular products. So ultimately, delaying appropriate treatment when needed lengthens the time to healing. This is an evidence based summary that we really should be using these products quickly and in the right place at the right time. This is probably one of the newest things that came out in the literature just two months ago, three months ago, talking about cellular-based products as well. This had the purpose. It is part of the Healthpoint 802, HP802, which is their spray keratinocyte fibroblast product that's in phase 3 trials. This was an offshoot of that study and this too is being done across the street at the University of Miami in our area. And what they wanted to look at was to see where their predictive values or predictive outcomes that we can see in influencing success when you, in fact, use the cellular-based products. So I think we know and there is solid evidence based medicine that cellular therapies are effective. But why is it that sometimes these wounds, even when we use these advanced cellular-based products, what roadblocks or what predictors of those roadblocks can we identify ahead of time. So there were two things that came out of this study which were very significant in success of cellular-based products. Now, this is a venous leg trial that they're using the spray keratinocyte and fibroblast product on. There were two things that came out very significant in the ability for the cellular-based product to be successful in wound closure. One was the wound duration. Again, the longer the wound is open or the longer the wound is present, the more difficult it's going to be to heal that wound. And the second thing which was even more interesting talked about the bacterial bioburden, which again, I think is a great area of research today. And what they found is part of the trial and of course, none of these patients were clinically infected. They wouldn't have been able to be enrolled in the trial if they were deemed infected. But as part of the protocol, they did deep tissue biopsies and they did quantitative biopsies on these. And what they came out with was a group of inhibitory and non-inhibitory bacteria that were present on the bioburden or the biofilm in the wound base. The interesting part that they found was that of the patients that they used cellular-based products on, 51 percent of those patients were remained open at the end of their end point, whereas 92 percent of the control. So they did not use the cellular based products on those. It remained open. So there's something about inhibitory and non-inhibitory bacteria that are present within the wound base that the cellular-based therapy was able to potentially overcome at a higher rate than those that did not use cellular-based therapies.


    So I don't know that we can extrapolate a whole lot from this, except in this patient population which was venous leg ulcers that's using cellular based product had some sort of effect on the bioburden and it made the product to be more successful. So the potential implications, again, for you and me is when we see these roadblocks to wound healing, should we be considering tissue biopsy. And the reality is that I'm not sure all of our hospitals are equipped to do quantitative tissue biopsies, but this may be an area which more research will identify and help us to predict when these patient outcomes are going to be better or when we're going to struggle even more. So I include this because this is a VA meeting. This is an evidence-based approached to treating DFUs in the VA population. And we can see that cellular based products are the end result of both of these arms of this algorithm, but the low risk diabetic foot ulcer patient and the high risk diabetic foot ulceration patient. So of course, the algorithm which was designed by Howard Kimmel at the Cleveland VA talks about a comprehensive patient assessment, vascular referral infection control and management. Doing the standard of care for four weeks as we're all kind of trained to do. And when we don't see that progression towards wound healing, the preferred way of dealing with these is through living skin equivalents or cellular-based products as a strong option for you. The right-hand side of the algorithm talks about that high risk DFU patient when we may even want to consider these cellular-based products even more quickly. So in conclusion, we see that there is a bridge, hopefully, to be met between what's happening at the cellular level and what you and I as clinicians see every day in our clinics in this patient population and really understanding the basic science and correlating that to the clinical applications will be our success. Living skin equivalents or cellular-based products should not be looked at as the last resort therapies. We heard lectures yesterday on hyperbarics and some of the controversies with HBO therapy are probably inherent in the patient selection of who we, as clinicians, choose to use hyperbaric oxygen therapy on. I think it's the same here. Sometimes we choose these products as last resort options and that doesn't necessarily need -- or is projected based on the literature of the way that we should be utilizing these. And I think the good wound bed preparation and understanding that bridge is really going to lead to successful outcomes. And we can see where in the phases of wound healing all of this correlates. These are my references for you. Thank you for your attention.