Hi everyone. My name is Hadar Levtov. I'm a board certified dermatologist and a fellow of the American Academy of Dermatology. I'm currently on the faculty of dermatology at the University of Miami. Today, I will discuss with you skin substitutes as part of our wound healing curriculum. And I'm really excited to share some of the data and experience with these class of treatments that has really transformed how we treat chronic wounds and more recently acute wounds when it comes to healing those really bad disease for our patients. This is me again. All right. So what are skin substitutes? I think one definition looks at it as a group of products and their goal is to recapitulate the advantages of autologous skin grafts, but not give the patient the associated morbidity and some of the limitations that we have with autologous skin grafts. As you look through the literature or some commercial materials, you may recognize this with other names such as tissue engineered skin equivalents, human cell tissue, cellular and tissue based products, the HCTP. And more recently, a consensus statement decided on the name cellular, acellular and matrix like product to really include everything that's on the market. So we've defined what these skin substitutes are, but what is really the rationale for using them? So let me take you through a case that was given to us by Dr. Kersner in our department. So here on the top left, you can see a chronic wound that's been there for a while and the surgeon is doing a pinch graft. They will harvest skin from the thigh of the patient and apply it on the distal extremity where the wound is. A small piece of skin multiplied by a few and you can see that that was on the day of treatment on the top right. Now the patient came back for follow-up a week later and this is what was seen. And the question I have for you when you compare the picture on the bottom left to the picture on the top left is this, did the graft fail? And this is a really critical question to consider because we don't see any take of the graft. In fact, one would say that everything disappeared and declare this a failure. But here's an interesting thing that happened without any change to the care, the patient returned a short time later and that was the picture. And then a couple of weeks after that, completely healed. And the question really became what happened here? And the answer is that probably these pinch grafts and so do skin substitutes, they all work like a medication rather than just a coverage. And this really spun off the idea that maybe we can leverage this, whatever stuff that these skin substitutes or grafts provide to the wound, be it cells, growth factors, and other chemokines to help the cell really recuperate, that really validated this idea. So what happened later is that with technological advances in cell culture, companies were able to take those cells, grow them as sheets and actually commercialize that and bring that to the clinic with a reasonable shelf life. And even though it's expensive, but still reasonable cost. And so this way, they were able to capitalize on these advantages of the graft, but they don't have to harvest it from a live person, which, you know, not only is a morbidity and cause, but sometimes with, for example, large burns, it's not even practical. Now the question remains, how do these skin substitutes work? And more recently, a few years ago, a group led by Dr. Tomic in our department shed some clue into this. It seems that skin substitutes work by reverting the chronic wound into an acute wound phenotype. And briefly, I'll go over some of their findings here because I really think it's fascinating. And so here the group did a real randomized clinical trial in which they gave some of the patients the bilayer skin construct that was applied on the wounds. And they harvested tissue in the first week and then at baseline and then the week after treatment. And then they looked at the expression phenotype of the tissue before and after. They also compared it to known phenotypes of acute and chronic wounds as well as intact skin. So I'll try to take you through this, but if you look at model A, part A of the figure, you can see that acute wounds are expressing this particular gene CasP14 at a low level when they're in an acute wound, but this is expressed at a very high level in a chronic wound. And then look at what happened in the wounds now in the second part of panel A. You can see here that at baseline, CasP14, which really is not important what the gene is, but just conceptually understand that the gene was highly expressed at week zero as expected for a chronic wound. But then using the bilayer skin construct, that led to reduction in this gene that is towards an acute wound phenotype. Now, this principle doesn't have to work in that direction alone. So if you look at panel B on the left with ITM2A, which again is not relevant what the gene product is, really what's important because they've seen this in a slew of these genes. But really, you see again that an acute wound is going to be expressed at a higher level this time of ITM2A, and then a chronic wound is lower. And so what would you expect? Well, when you apply the bilayer construct, you see exactly reversal of the phenotype. At week zero, it is low as you would expect in a chronic wound. And then the treatment makes that gene to be expressed at a higher level as as you would expect in an acute wound. Same goes here in this case again, and again, the treatment does the effect. And so looking at it and putting all the data together, a picture emerges that suggests that those skin substitutes work by reverting the chronic wound into an acute wound phenotype that then goes on to heal. So that was a little bit about what those are, what is the rationale and some of the data to support how they work. How should we classify these skin substitutes? There are many of them on the market, and I'll show you some example. Well, it's good to understand what's in it, and maybe you can classify them as cellular and acellular. That may determine how good they are, but really what it really determines is the cost and how they need to be preserved, for example. You also want to ask yourself, what is the matrix? Is it human? Is it animal? Is it synthetic? Some people have certain allergies, so that's key to know as well, for example. So this information could be important. And then, of course, you want to know if those skin substitute products have cells, what kind of cells are being delivered to the skin. I've listed here a table of some of the commercially available example of these skin substitutes, and I classify them here as allergenic, xenogenic, or xenogenic and allergenic. And you can see that there is a variety of products on the market that include a variety of cells and different type of matrices. Usually, when we talk about human cells, these are neonatal foreskin cells, be it keratinocytes or fibroblasts. And then you have cells that are also sourced from placental material, amnionic membrane, and more recently we see from other animals as well. What is the clinical evidence to support use of these skin substitutes? Well, I'll show you some of the data and highlight some of the challenges, but hopefully I think the data has improved over the years. Now, these studies are really getting dated now. This is the first one from 2003 and then 2005. These were sort of landmark studies in which those products were used in a clinical trial looking at treatment of diabetic foot ulcers. And you can see here that on the left, we have a skin substitute with cells in it called Dermagraft. Now, you can see here that the success rate, first of all, is not that high. This is at 12 weeks and the healing proportion of patients that are healed is only 30%. Compare that to the control, it's not very impressive. And then not too long after, we also had another study in which they compared a product called Oasis, which is a matrix without cells. And sure, this was a better success, but look at the numbers. They're relatively low, the participants. And then interestingly, assuming that this is a similar population of diabetic foot ulcer patients, you can see that the control in the study on the right is almost as effective as the treatment, might I add, a very expensive treatment on the left. So certainly, we have some data to support it. It seems to work, but the data has some problems as well. More recent studies now learn from that. And you can see that here in a product called Graphix, for example, even though the numbers are small, there is a very strong delta supporting its efficacy. And on the other product, Integra, for example, even though the delta is a little lower, we still have better numbers in terms of the number of participants. So I wanted to highlight to you that there is randomized control trials to support their use, for sure, but some of the data, especially the high placebo rate, could be challenging in helping us to interpret exactly the data. Okay. So how do we use these things? Well, every product is unique, but common rules do apply. The most important thing I would say is whatever product you choose to include in your practice is to get trained. Call the company, have one of their trainers come, or maybe they have a training session in a large meeting that's around the corner. And so go get trained, get familiar, develop a relationship with the company so they can train you and explain to you how to use it. And so you become an expert. You should consider potential allergies as you would with any treatment. And then really, I think the key to success is to make sure that you apply it on the right wound. Namely, you want to prepare the wound bed, make sure there's no infection, make sure that you have a granulating bed. With rare exceptions, this should not be applied on an infected wound bed or a wound bed that's not granulating, meaning you should not apply those with some exception directly on bone or tendon, for example. Then you will apply the product. The key thing to know, and it's really not rocket science, you just put it on, but the key thing is to make sure that the product stays in contact with the wound bed throughout the days that follow. So the patient doesn't go home and it just falls or the common thing is that you get exudate that separates the product from the wound bed. Then you want to make sure that you ensure contact with the wound bed, as I said, and secure it. Traditionally, it used to be secured with sutures. Now, some adhesives should be enough, but really it is up to you. However you want to secure it is fine. And of course, like every treatment we do, we want to make sure that the patient is part of the picture. You want to educate them, make them understand what was done, what kind of wound care they need to provide, and then have the right expectations. For example, it is not uncommon that as we switch on the acute healing part on these wounds, that the wound becomes red and some exudate appears, and it almost seems like an infection when in reality we're just switched on the acute healing inflammatory pathways, which is an expected thing. So educating the patients to know what to expect is critical. And with that, I want to thank you for your time. I want to encourage you to get expertise in using these skin substitutes, as they can really make a difference in our patients' lives. Thank you.

skin substitutes

wound healing

dermatology

chronic wounds

patient care