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Unidentified Male Speaker: Next up, it is my pleasure to bring to the podium, Dr. Windy Cole. She's an Adjunct Professor and Director of Wound Care Research at Kent State. I have the honor of seeing her there next week, we'll be in scenic Cleveland. Dr. Cole is an Adjunct Professor and has completed her undergraduate degree in biology from the University of Cincinnati. Her podiatry degree with honors from the Ohio College of Podiatric Medicine, my alma mater, go CPM. Then completed her surgical residency training at University Hospitals Health System in Cleveland.

Dr. Cole is board-certified by the American Board of Podiatric Surgery and a Fellow of the American College of Foot and Ankle Surgeons. She is an active member of the APMA, OPMA and AAWC. Dr. Cole has been in practice in Northeast Ohio for 17 years. Her interests are limb salvage and wound care, and currently serves as a Director of Wound Care Services of the Cleveland Residency Hospital and Medical Director at university hospital's Wound Care Center. Dr. Cole will be speaking to us today on Cellular Tissue Products, which is obviously a very current and very interesting topic to us all, please give a warm round of applause for Dr. Cole.

Dr. Windy Cole: Good afternoon. So today, we're going to talk about cellular tissue products, otherwise known as skin graft substitutes. I was in private practice for 15 years, but the past five or six year, I've really just been doing wound care, in both research and then as an outpatient Wound Care Center Director. So, I get to wear both hats. I get to play with the new products that are entering into the market, and then I get to put them to good use by applying them to my patients in the outpatient wound care setting. Here's my disclosure, I am on a speaker's bureau of Organogenesis, [indecipherable] [00:01:56] and MolecuLight. Today, we're going to talk about wound healing and reasons why wounds tend to stall.

[00:02:04]

Again, my love is for wound care. All patients are different, all wounds are different, wounds change from week to week. Oftentimes, I consider myself a wound care whisperer. I have to look at the wound and determine what do you need this week, and it changes all the time. So, it's good to have an idea of what products are out there on the market and commercially available. Cellular tissue products are kind of like a growing subset of wound care products. And so, it's quite daunting sometimes to know which products to use in which patients, and at what time to employ these particular products.

So hopefully, after my talk today, you'll have a better insight as to how to do that. So, as was mentioned in the previous lecture by [Matt] [00:02:50], wound care is complex, wound healing is complex. There's a lot of intercellular, extracellular mechanisms that are at play. Wounds tend to stall, they're not following this pre-planned path, they're not moving through at an accelerated rate, like an acute wound would. They're stuck inflammatory phase. They didn't get the memo. It must have went in their spam folder. We need to do something to get them out of that inflammatory phase, back on to the proliferative phase, and on to the road to healing.

And cellular and tissue products are available to help do that. Biologic matrices have entered into the wound care market, and there's quite a few out there. There are those with living cells and those without living cells, they give us that therapeutic option to help wounds to heal. As Podiatrist, where are surgically trained, oftentimes we went to cut-to-cure. We want to fix things. But in wound care, it's actually giving the wound the environment in which it wants to heal. The body wants to heal itself, we just have to give it the proper mechanisms in which to do so.

[00:03:56]

So, as mentioned, CTPs were formally described as skin graft substitutes, but cellular and tissue products are the most common and current nomenclature for this subset of wound care products. They do improve heal rates, and they decrease the risk on infection for our patients. One of the slides that Mat had used previously shows that, patients with diabetic foot ulcerations and those with amputations actually have a higher mortality than breast cancer, or a prostate cancer. But we don't see anybody having 5K erases to prevent chronic diabetic wounds. Unfortunately, it just isn't out there as one of the most common reasons that our elderly patients are passing away.

We need to get the word out. Hallmark of chronic wounds is increased in inflammatory processes, and then also that increased proteose activity. Proteoses are good in acute wounds, they actually can degrade devitalized tissues. But in chronic wounds, the proteose activity is elevated. It starts to breakdown the extracellular matrix, the good skin and soft tissue. And it causes wounds to become kind of like a caustic vat of acid. So, anything you put on the wound, and products that you apply to the wound can get degraded by these proteoses.

So, we have to do something to maintain it, and to decrease the proteose activity in these wounds. Unfortunately, that will lead to decrease growth factors, also disfunction of proteins, and all of these normal processes that the body has in order to heal wounds will kind of go haywire. So, using cellular tissue products have collagen matrices are very important. Collagen is very helpful to the extra cellular matrix. It actually also acts as a sacrificial substrate to proteose activity. Proteoses love collagen, so they'll degrade the collagen in the Cellular Tissue Products as opposed to the natural collagen in the extra cellular matrix. So then, it will help to support skin growth and wound healing.

[00:06:05]

CTPs over the past 20 years have emerged in vast numbers. I mean, we have bovine, porcine, ovine the other day. A couple of months ago, I was told about a liver-derived cellular tissue product. We have human-derived cellular tissue products, those with active cellular components, those without. So, it can almost make your head spin as to the amount of products that are out there on the market. The ideal skin substitute though would be nontoxic, would be non-immunogenic, so it wouldn't cause a reaction in our patients. It would also be a compatible to our patient population.

Of course, we would not want to transmit any diseases to our patients. So, CTPs have many functions. You can see in this wound, there's a lot devitalized tissue, there's nooks and crannies where active bacterial contamination can occur. So, we want to minimize the open areas and decrease bacterial content. We also want to prevent water loss and electrolyte loss. We want to maintain function. You can see in this particular patient, her Achilles tendon is exposed, so we want to cover those deep structures, so that desiccation doesn't occur in order to retain function and promote mobility in a patient such as this.

So, CTPs can help to do a lot of these functions. In broad categories, there are autologous grafts, there are scaffold grafts, there are active cellular grafts, and then the amniotic products. There's an overlap among these broad categories as well. And again, some of these have the active cellular components, and some are Acellular. When you look at the Acellular CTPs out there, cadaveric skin, some of the porcine, bovine and fish skin grafts, they act as a scaffold. Just like when your building a building and you have to have that scaffold in order to place the building blocks, the same thing occurs in wound care.

[00:08:04]

These Acellular scaffolds are important to maintain the structure, the extra cellular matrix, they allow for cellular ingrowth into wounds, and increase angiogenesis. Something for that, whose new blood vessels to latch on to and allows for the wounds to go on from that inflammatory phase into the proliferation and remodeling phase. There are cellular-containing products as well, they contain keratinocytes, which are the pre-cursors to epithelial cells. Fibroblast, which can lay down collagen, which is very important building block to skin regeneration.

And then of course, mesenchymal stem cells, these are pluripotent cells that can differentiate into any type of tissue that the wound would need to heal. They can be autologous, allergenic, or xerogenic that for any species out there and available. So, we're going to first discuss autologous grafts, and these are kind of like the granddaddy of skin graft substitute or cellular tissue products. They're autografts, they could be full thickness skin grafts, split thickness skin grafts and then also epidermal autografts are available. So, split thickness skin grafts, we take the dermatome, and we remove the patient's own skin.

We remove the epidermis and part of the dermis, we can mesh this, so it does cover a lot of real estate. It's fairly inexpensive, because we're using the skin that's already available on the patient. The promise, there are complications, one of which is a seroma and sometimes a hematoma. And then the major con is that we're creating a wound to heal a wound. Here's a patient that I had seen about two years ago. She is a 72-year-old lady who does a lot of gardening. She was outside gardening, and she had a scratch in her leg, and within hours, her leg became red-hot painful.

[00:10:06]

She went into the ER, there was gas in her tissue. Unfortunately, she was diagnosed with necrotizing fasciitis. She had to be taken to the OR, and she had a very thorough debridement of the lower extremity, as you can see. So, we needed to cover this wound quickly, and we needed to get healing for this patient as quickly as possible. So, in this case, a split thickness skin graft as you can see was our best course action for her. Epidermal autografts historically, have been very difficult. Pinch grafts or blister grafts were used by plastic surgeons with limited successes.

New devices have emerged onto the market that can help make these tissue grafts a little bit more viable. The good things is you need a very little tissue, just a bit of epidermis for these types of grafts. And they have been shown to be effective in certain types of wounds. Here's an example of a patient that I used epidermal autograft on. You can see the way we removed the skin, and we used a device, it kind of looks like an Easy-Bake Oven to me. It applies a little bit of heat and a little bit of suction pressure to make those epidermal autografts kind of rise.

Once you see the microdomes are ready, you remove the lid off of the construct, you put a bit of oocyte on there and then, you pull a lever that cuts off the epidermal autografts. Then they're applied to the wound, they definitely look like little skin cells. You could see the area where the epidermal autografts were removed, kind of only looks like a sunburn. So, if you don't have that big deficit that you would in a split thickness skin graft, and this is the patient several weeks down the road, and he has regrown his epidermis and has very good success.

[00:12:04]

This particular type of device and this type cellular tissue product I think works best for very superficial wounds, you can't have much depth to these wounds because this are friable skin tissues that we're placing on the area. So, you can see the underlying wound in this patient, it's nice beefy red and granular. All I needed was that top layer of skin to grow. And by putting the epidermal autografts on the area, I was able to do just that. There are a couple of new products that have entered into the wound care world, one of which would be considered spray on skin. What is done? This is typically done in the OR.

You remove a split thickness skin graft, quite a bit smaller piece of split thickness skin graft than you would if you were doing a true coverage of the large deficit or wound. It's treated with enzymes at the bedside table in about 30 minutes, then you are able to isolate the keratinocytes and the fibroblast. And you can actually spray the skin back on the deficit at the table. This particular company, it has randomized clinical trials that they are undergoing for the burn patient population in the United States. In Europe, this particular product is used for burns and that it's also used in chronic wounds. They have not studied chronic wounds in the US as of yet, but hopefully they will soon. The burn information that they have thus far is very interesting.

So, I can't wait to see exactly how this all plays out. There's another new, autologous graft company out there, and with this particular product, you take a full thickness skin graft from a patient and you send it to their laboratory. They actually extrapolate the mesenchymal stem cells from the hair follicles, and they do a 3D kind of printing, and extrapolation of those mesenchymal stem cells, and they send you back the product to apply onto your patients. So, it actually has the patient's own mesenchymal stem cells.

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Here's a particular patient. This was his original wound. Here is where I took the full thickness skin graft, so it made me a little uncomfortable taking a full thickness skin graft on the contralateral leg of a patient who already has a wound that hasn't healed in quite some time, I think. Actually, this wound had been open for seven years, and I was probably like the 10th person that he had seen for treatment. This is what came back. It almost like cottage cheese or Caesar dressing if you will. This is actually an ostomy ring, it's basically like a very thick DuoDERM. So, you kind of make a well around it, so that the tissue graft doesn't get run off or displaced, and then you apply a non-stick layer. And you keep that intact for about three weeks. So, he's currently in process right now.

We're seeing him, and he has several areas of new skin growth to that region. Like I've said, it's been open seven years. So, it's quite interesting. I'll follow him on and see how he does. The subset of CTPs or another subset I should say is dermal scaffolds, and these products help you regenerate and revascularize tissue. Usually, they're Acellular in nature, Acellular dermal matrices, or cadaveric skin. I've used quite a bit in my practice, also xenografts, porcine, fish skin grafts, they can help with re-epithelialization, and they act as sort of like a biologic bandage. So, they help with maintaining moisture control in these patients and then also, preventing ingrowth of any bacterial infection. This particular patient, she was a young lady. She was 47, 48 when she came into my office.

[00:16:00]

Sorry, the picture is very blurry, but it's the best one I can find. Of course, her history was, this had been present for about two or three days like they all tell, but there was a lot of odor, there was, you can see the tissues had split, there was blistering. This was boggy, I knew she had to go directly into the hospital. So admitted her, did an MRI, and luckily, the MRI showed very little involvement of the calcaneus. There was some increase in edema of the calcaneal cortex, but that was it. The cortex was intact. So, I took her to surgery. I actually had a conversation with the infectious disease physician, who happen to be the Medical Staff Director at the time.

And he was aggressive in thinking that we needed to do a bone culture on her to determine what IV antibiotics to put her on. And I'm very conservative when it comes to calcaneal bone, because I've seen it liquify so readily when bacteria enters into it. And I had an intact cortex, although there were some evidence of edema, but I thought, if we could just put her on an IV antibiotic, we could probably decrease the fact that she'll have less aggressive or more aggressive osteomyelitis. So anyway, he agreed to tailor her antibiotics with just a deep tissue culture.

I took her to surgery, resected all of the bad necrotic tissue, did a very good irrigation to that area, felt very satisfied with her vascular status, and the health of the tissue that remained. So, I used an Acellular dermal matrix, or cadaveric graft to kind of act as a scaffold or a bridge, and then I put a wound [indecipherable] [00:17:46] on her. You can see several weeks later how well that Acellular dermal matrix is incorporating. So, we can remove these staples that were present, and we can see how it's filled in very nicely. There's no signs of infection present. Another nice granulation tissue peeking through, and she went on to complete healing.

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I got a call from that infectious disease doctor a couple of weeks later, and he basically said, that he agreed with my course of action, he's glad that we went that way. And after that conversation, I was consulted on every single one of his patients, so we made good friends after that, which is good. But I use dermal scaffolds to kind of fill in large deficits. When we have a thicker wound, or something that needs a lot more structure, I think the dermal scaffolds really fit the bill. Here is a product made of a fish skin, it's also considered a dermal scaffold. The fish skin amazingly enough, is very thick, and it's [pore] [00:18:47] content is very similar to that human tissues.

So, the collagen matrix is very similar. It's Icelandic cod, so it has a very thick skin. This particular patient had a fall. I'm from Ohio, so we have really bad winters. He was on, I think Xarelto anticoagulant. He fell and had a huge hematoma on his calf. Evacuated the hematoma, put him on negative pressure therapy, and this is what we had, it was a large wound. But it was very healthy and very granular. He had a lot of pain though, because this was a trauma wound, of course. Surprisingly enough, the patient that I did the split thickness skin graft in couple of slides back in the beginning, that was his wife. She had had that issue two years prior to this.

And so, he knew what a split thickness skin graft was, he knew they had to go back to surgery, and he knew what the healing was with the split thickness skin graft. So, he wasn't really all that interested in going back to the OR, he didn't want to have a split thickness skin graft taken from him, so I started using the dermal scaffold, the fish skin dermal scaffold on him. And you can see this is, when it's moistened, you could see the cells, or the scales of the fish skin.

[00:20:08]

After I want to say 11, 13 weeks, I can't remember off the top, but it was a couple of months, less than three months, he went on to complete healing with that dermal scaffold. Here's another case of using a different type of dermal scaffold. This particular patient, she was an 87-year-old patient. She peripheral vascular disease, and she was actually wearing her compression stocking. She was very compliant with her compression therapy. But unfortunately, her aide, when putting the compression therapy on her, scratched her with her ring, and she developed this ulceration. It was heavily exudating, it was fairly clean to the naked eye, it didn't look like it had a lot of debris in it.

But we are using multi-layer compression, and some advanced wound care dressings, and it really wasn't budging. So, I have at my center a fancy camera, it's a violet image camera, and that violet light can reflect the florescence of bacterial contamination on a wound. So, when we looked at this wound, and this was after debridement. When we looked at this wound after debridement, we can see kind of some pink or red fluorescing in the periphery. And then there's an area here that almost looks like a blueish green.

Those are indicative that there's bacterial infection in and around the wound. These red florescence areas are perforin-producing bacteria. And then this area here that shows like a bright white or a greenish white is actually pseudomonas. The perforin-producing bacteria could be a number of different bacteria. Most commonly, it's staph aureus, or MRSA. We're not sure. We can't differentiate between the two. So, started using a dermal scaffold that actually had – is coated with antibiotic, PHMB.

[00:22:03]

And wrapped her back up in her multilayer compression, she comes back in the next week, and this is what it looks like. A dramatic change in size. And then we took another picture, with our fancy violet light camera, and we see, there's a little bit of florescence in through here, but most of the bacteria has disappeared by using this particular dermal scaffold. There are viable human cellular grafts as well, and they allow for the structural advantage of having the dermal substitutes, so the extra cellular matrix, but then they also have active cellular components available.

There are two-layered skin grafts that are out there. There's a dermal layer that has a bovine collagen 1, and the fibroblast. And then also, second layer of that has keratinocytes, so it really mimics human skin. This particular patient I saw on a LTAC facility, I didn't do this initial surgery, a colleague of mine did, but she also had necrotizing fasciitis and had to have a really aggressive debridement to the area. When I saw her, we started her on negative pressure therapy, so we had a nice granulation tissue base. She was on an LTAC hospital, and she didn't want to go back to the hospital or readmitted to the hospital.

Plus, she was actually on a vent, she was just a very sick lady. So, it was best to keep her on the LTAC hospital, so we started using a cellular tissue grafts with active cellular components, and you can see there's this line of increased epithelialization. And then also, centrally in the wound, we have this island epithelialization that's occurring. And she's even getting pigmentation back by using this particular graft material. There are single layer neonatal fibroblast grafts as well. That's what I used in this particular patient. Again, you see nice beefy red granulation tissue.

[00:23:59]

We are able to apply the single layer graft with fibroblast activity. The fibroblast allowed for collagen synthesis, and we're getting a nice thin layer of epithelial tissue on top of that. And so, with just one graft product, this patient went on to complete healing. I like to use the active cellular component grafts when I just need that thin layer of tissue on the top to form, when you have a nice healthy granulation tissue base. Very little depth to the wound, this can be a very good closer for your patients. Amniotic tissues are probably my favorite cellular tissue product. I use them quite a lot in my wound care practice.

They're very effective in reducing inflammation. If you remember, these chronic wounds are stuck in that inflammatory phase. The amniotic tissues have interleukins that can counteract that inflammation. They also reduce scar tissue. So, we're not only healing these patients faster, but we're healing them with better skin turgor and better skin quality. We all are excited when Mrs. Jones heals, but our hearts fall when Mrs. Jones calls back three months later with a reopening of that same injury. If we're able decrease scar tissue and contracture while healing, we can prevent these wounds from hopefully reopening in the future.

They also contain growth factor and cytokines. I often tell my patients that these are like a fertilizer, a Miracle-Gro for the wounds. They'll allow the wounds to heal rapidly, just like when you apply fertilizer or Miracle-Gro to your garden, it helps for your plants to grow. And they understand this sort of analogy, and then it also of course, can help speed healing. There are a lot of amniotic tissues out there in the market. What tissues are retained and how the tissues are processed is what sets them apart from one another. There are amniotic-only tissue grafts, there are chorion-only tissue grafts, or grafts with both amnion and chorion. Some are dehydrated, some are cryopreserved, and some are hypothermicly store or fresh.

[00:26:03]

So, when you look at the dehydrated amniotic products, there are no active cellular components once that tissue is dehydrated. But it does retain the cytokines and the growth factors, those Miracle-Gro products that help these wounds to heal. They also do have an extracellular matrix that is supportive to collagen regrowth and regeneration. I'm a big believer in using the dehydrated amniotic tissue products in patients with pyoderma. Pyoderma is a very difficult diagnosis sometimes to make, this particular patient of mine was in her 80s, she was healthy as a horse, she didn't have any other inflammatory processes going on with her.

She had no peripheral vascular disease. Her arterial flow is great. She had these two ulcerations on her leg, and they just weren't progressing with good aggressive wound care. I would do a debridement. We're using aggressive wound care products, and every week, they would look worse and worse. You start to see all – sorry, where are we? Okay, sorry. You see all this devitalized tissue, you see all of this inflammation around the area, and then you can kind of see these violaceous areas around the wound. And this is what gets to think that there's pyoderma involved. Unfortunately, there's no real diagnosis for a pyoderma, it's kind of a diagnosis of exclusion.

But you should always get a biopsy, as which I did. We see some neutrophilic infiltrate, we see lymphocytes, all hallmarks of inflammatory processes. We see some vasculitis, it was negative for any bacteria or fungal elements, and of course in our differential is pyoderma. So, I started to use dehydrated amniotic tissue on her, we can see after two treatments of the dehydrated amniotic tissue, the Perry wound area is a lot happier, it's a lot less angry, we're having some bridging of epithelial tissue, and all of this devitalized tissue that we had seen previously is starting to go away, and she completely healed with the use of dehydrated amniotic tissue.

[00:28:05]

There's also cryopreserved amniotic tissue out there, frozen, it does retain the growth factors in the cytokines, there's limited damage to the matrix with freezing, and some viable cellular components can be maintained after thawing the frozen product. There's fresh amniotic tissue that's very recently entered into the market, exclusive to the native amniotic tissue. It has the most cellular viability, it has those mesenchymal stem cells, those pluripotent cells that can really differentiate into any type of tissues we might need.

And there is that much more of the cytokines and growth factors present in this particular product. Here's a patient, 47-year-old diabetic had a high level of Chopart's amputation, but still had an open wound on his plantar surface. You can see from the measurement that he has an area that tracks 1.6 centimeters. So, that's an area where infection can get right in there, bacteria can have a little party. And then this poor guy has to go on to a baloney amputation. He was referred to me by the colleague who did the amputation.

That colleague had tried negative pressure, collagen dressings, a lot of good wound care therapies. But he wasn't getting anywhere with getting this wound to heal. So, we were able to use the fresh amniotic tissue graft on him. This was after one application of the fresh amniotic tissue. That tunnel completely was gone after one application. After three applications, the wound was getting a whole lot smaller. And in five applications, the initial wound was close to healing. He did have a subsequent adjacent wound that opened up. But that also went on to complete healing with the use of the fresh amniotic tissue.

[00:30:00]

This patient had also a high-level amputation and we were able to use the amniotic tissue with her to get full resolution of her open ulcer as well. I would put a video in here, there's a YouTube video and if you want to google it, it's fresh amniotic tissue. You can google, and you'll see my face come up. But it was a news story that was done in Cleveland a couple of years ago, and it was on that particular patient, and embedded videos for me, don't play at all. So, I'll let you go. Look that up if you're interested. Stay tuned because there is going to be a publication. It will be in advances in wound care within the next month or two, and it is a randomized clinical trial showing that the effects of the fresh amniotic tissue is very helpful in the diabetic ulcerative population.

There's a lot of CTPs out there on the market. This is an old slide. It shows 63 currently available for Anthem. So, how do you really choose? I hope you don't choose by who brought pizza, or who brought lunch to your clinic. I hope you really kind of see what these products do, and how they work, and what types of wounds they work best in. Of course, they're not a substitute of good wound care. You have to make certain that infections controlled, necrotic tissues are removed. We have appropriate blood flow to the area, and systemic conditions are maintained too. There is my additional references, there is my contact information if anyone, gets a hold of me. And most importantly, there is my son eating pizza. Any questions for me? Yes?

Unidentified Male Speaker: [Indecipherable] [00:31:40]?

Dr. Windy Cole: Oh, it's a long-term acute care hospital. So, there's acute care hospitals, and there's skilled nursing facilities, and it's kind of somewhere in between. Patient isn't sick enough to be in acute care hospital, but they're not well enough to be in skilled nursing facilities, so they're in a LTAC hospital. Usually, patients are on dialysis, or on vents, or they have wounds, and they're getting IV antibiotics and such. Sure, yeah.

Unidentified Male Speaker: Which was the violent [indecipherable] [00:32:12]?

Dr. Windy Cole: Oh, the violet light camera is MolecuLight, yeah.

Unidentified Male Speaker: It's really nice, yeah.

Dr. Windy Cole: Oh, it's really cool. I could talk to you for hours on that too, maybe next year. Yeah. Any other questions? No? Okay. Thank you so much.


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