Brandon Hawkins, DPM, CWS discusses the various types of human placental based tissues available, their advantages, disadvantages and their application. Dr Hawkins cites specific studies and cases to support his statements.
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TAPE STARTS – [00:00]
Male Speaker 1: So our last speaker for the morning session, Brandon Hawkins, DPM. He is the CEO of the Stockdale Podiatry, medical director of the Bakersfield Heart Hospital, Wound Center and he is going to talk to us about placental grafts. So welcome to the stage.
Brandon Hawkins: Well, I've known Dr. Garofalis for a long time. He is a great lecturer and it's hard to follow his work, but I'll try to add to it and give you some stimulating things to talk about. So what we're going to talk about is the use of human placental tissue allografts in the treatment of lower extremity wounds. Why do we use placental tissue? Well, when I sat on the board of directors for the Association for Advancement in Wound Care, we would send global volunteers to these underdeveloped countries and instead of having advanced treatment modalities like we do here in major developed countries, they would use placental tissues. Placental tissue has been used in wound care since the early 1900s. So recently in the past 10 to 15 years, people have decided to look at placental tissue and look at why it has been used for so long. What placental tissue does show is that it has barrier property. It's going to modulate inflammation similar to what Dr. Garofalis had talked about. It's that inflammation that basically prevents wounds from healing. It's going to reduce scar tissue formation, so scar tissue can often cause ulcerations to re-occur. It has an immunological property to it. It also contains all of these growth factors that Dr. Garofalis had talked about and these growth factors are essential for wound healing. Without these, they would not go onto complete closure as well as it enhances wound healing whether in a diabetic patient or a non-diabetic patient. So in wound healing, we know that there are three stages to wound healing. There is the inflammatory phase, the promotional phase and then the prolonged phase where we get the scar modulation. When we look at both acute healing versus chronic healing. In acute healing, there are certain phases that occur. We noticed that there are scab formation occurs. We have inflammation going to that side, but it is a controlled type of inflammation. It's very minimal. And then through that, we get re-epithelialization. We get angiogenesis and then fibroblast formation and collagen. If we look at the chronic wound, what happens is this becomes a retarded effect. We get a promotional or prolonged formation of inflammation and what happens is we get hyper-inflammation or hyper-proliferation of the epidermis. And then through this, we get as noted a lot of inflammation. We get the immunological properties associated to the skin become compromised. And then we no longer have angiogenesis and through this, we get a retarded state where the wound will no longer heal. So let's look at some of the clinical efficacies of placental tissue based allografts and how they were used in clinical trials and what their data shows. So if we look at dHACM in the first DFU randomized comparative study, what they had shown is that they had taken nonhealing wounds for four weeks, put these into a trial and they had noticed that at six weeks, 92% of these wounds had gone onto complete wound closure, which was unheard of. Later in the crossover study, those patients who were put into the control in that first study were then added to the second study. So these wounds had already been nonhealing for about 10 weeks. And when they through these crossover patients in, they noticed again that 91% of the wounds had gone onto complete wound closure. When we look at the long-term follow-up and this was done by Dr. Zelen and Dr. Zorina [phonetics], they had noticed that almost 94% of these wounds that had healed had remained healed for 9 to 12 months, meaning they had no new ulcerations to that specific site. If we look at our randomized clinical trial, which was based on weekly applications versus biweekly applications, what they had noticed that if you apply the graft on a weekly basis, you had a 50% wound reduction in a better time period, so it became more efficacious to apply these grafts on a weekly basis. And then looking at a head-to-head study on diabetic foot ulcers, dHACM versus bio-engineered skin substitutes, what they had noticed is that 85% of those that had used the dHACM had healed in four weeks and 95 had healed in approximately six weeks in comparison to the bio-engineered skin substitute.
In a surrogate marker for VLU study, they had noticed, and this was their first VLU study, that 62% of these patients had achieved 40% closure in four weeks, which was remarkable. And then a large VLU study or randomized clinical trial showed that 60% of those patients had complete wound closure in 12 weeks and 71 in 16 weeks and this is the only current VLU study noted. So the significance of clinical trials in placental tissues, if we look at each one because there are various types of placental tissues out there, there is what's called dHACM, there is cryopreserved as well as dehydrated amniotic grafts. If we look at each of these, they have their own things that kind of differentiate them. So if we look at the dHACM, we can see that it has both amnion and chorion. It does not have actual living cells. It is a dehydrated process. It is stored at room temperature and it has a safety sterility associated with this. And then when we look at the studies associated both with the DFU and with the VLU, we can see that in four weeks, they had 85% wound closure in comparison to the control. At six weeks, 95% and then at 12 weeks, they have 97% and this was a pretty large study if you look at the numbers. If we look at the cryopreserved, the difference is that yes there is amnion, there is no chorion. There are living cells. The problem with these is that now you are dealing with cryopreservation, so you have to store this at -80 degree Celsius. There is no safety sterilization associated with this and the only study that they show is that 62% of these diabetic foot ulcers go onto wound healing at 12 weeks. If we look at both the dehydrated amniotic grafts, there is one that has amnion and chorion and one that just has amnion. They're both dehydrated and both stored at room temperature. One does have a safety sterilization, the other no, and both of these have shown that at six weeks about 70% go onto wound closure and 46%. Now, when we look at the venous leg ulcers, only the dHACM currently has a VLU study. You can see that there are about 109 patients. Again, amnion, chorion but if we look, 60% of these patients went onto wound closure at 12 weeks and 71% at 16 weeks. So there are a range of placental tissues out there. So like my mother used to say the proof is in the pudding, we can see that there are single layer amnion and chorionic grafts. There are amnion and chorionic grafts. There are umbilical cord grafts as well as placental tissue grafts. And so you kind of have to be conscientious of what you are going to decide to use for what type of patient. So this is a patient that I had. This was a non-diabetic patient who was admitted to a skilled nursing facility for a problem not associated with this. She had a small skin tear and the nurses in the skilled nursing facility had wrapped this too tight basically causing a tourniquet effect. And you can see this is the tibialis anterior tendon exposed and necrotic with no more paratenon. She had two other consults prior to seeing me. The first consultation was with an orthopedic surgeon who opted to do a BKA. The second was with the plastic surgeon who opted to cut the tendon out and do a split-thickness skin graft. She didn't like either of those ideas because that’s not why she went into the skilled nursing facility. She was referred to me and what we opted to do is debride the paratenon off and debride the tendon. And at that time, we began applying the dHACM and you can see right here. You can see that dHACM graft right there. On week one, when she came back, you can see there is a granular bridge actually extending over the tendon. And by week three, we had complete granulation over the entire tendon, and by day 28, she was completely healed. Now, this was a healthy patient who had no comorbidities associated with this. So you can see the power of the graft is pretty substantial. Now, like Dr. Garofalis had talked about this type of graft has multiple platforms in which you can use this. So you can use it not only in wound care but when you want to control and modulate inflammation.
And so in this case, we took a micronized version of this graft applying it into the plantar fascial region to modulate the inflammation [Indecipherable] [0:10:10] plantar fasciitis. Now, this is one of my patients where we applied the umbilical cord graft with dHACM. And you can see this is a 60-year-old male who was insulin-dependent type 2 diabetic, had hypertension. He had a gangrene and went on to a transmetatarsal amputation. And he had had previous history of blood clots. At three weeks, you can see what we did. So this is him initially coming in status post amputation and he had this dehiscence site and this happens with a lot of TMAs because of the vascularity. So on week one, we debrided this. We applied the umbilical graft and you can see here is the umbilical graft. It's a little bit different than the previous dHACM grafts. And here it is, by week one, we had shrunk the wound substantially. On the second application, the wound was about 50% of what it was. And then by day 21, we had complete closure with a scab formation. Now, what makes placental tissue allografts unique. They are ideal for large wounds, wounds that we don't normally see but these very substantial wounds. The grafts do contain bioactive proteins both in the amnion and chorion and they have the umbilical cord component which adds component of the extracellular matrix. And what's nice is that you're dealing with human based tissue and not a xenograft material. So looking at the normal umbilical cord portion, we can see in the H&E stain that there are multiple nuclei. And in the process of denuclearizing or decellularizing the grafts so that there are no components associated with this from the maternal part, you can see in H&E stain there are no more nuclei. It is decellularized, but it still contains the extracellular matrix as well as both the type 1 collagen and also the extracellular matrix components. Looking at the proliferative studies and if we look at a controlled study associated with just a normal person, this being the control, we can see that the human fibroblast proliferation rate is about 60% associated with the wound. When we look at these other types of grafts including the human placental tissue graft, the porcine graft and human dermis, we can see that the human placental tissue allograft actually has a higher ratio of human dermal fibroblast proliferation and that will help configure the area. So I'm going to go over two cases associated with this dHACM graft and placental tissue allograft. I think the first one is actually out of order, let me see. Yeah, so the first one is out of order. So case one, this was a patient who was a diabetic patient, a 45-year-old male, history of smoking, had peripheral vascular disease, was actually admitted to a hospital and had an I&D and had previously had a wound VAC and this is what the residual ulceration looked like and it was about 6 cm x 4.5 cm. We began, when she came in, applying the graft and it was a micronized version. And you can see what this allows is that we can apply to a larger surface area. So instead of using multiple types of small grafts, we have a graft that we can lay over the whole area. This is week one. You can see that the wound had shrunk by almost 50% and had decrease in depth. By week 14, we again began to shrink but what was nice is there was no more depth associated to the wound and you can see the wound contracture margins. By day 21, again we had smaller size. We had contracture of the wound margins to the sides. By day 35, the wound was almost completely healed. And by day 42, we had 1.5 cm x 0.6 cm and by day 49, this was healed. Now, you are thinking that took 49 days, but again you're looking at a person who is severely vascular compromised, who had multiple problems associated with this and that he had a very, very large wound. So this is again another placental tissue allograft on a patient. The difference is this patient had both diabetes, lymphedema, peripheral vascular disease, venous insufficiency and was a smoker. When he initially came in, this was a 6 x 5 cm wound on the dorsum of the foot. We began applying the allograft and you can see that by day 10, it was smaller in size.
The difference with this individual is he was a lot more noncompliant. He would not show up to his appointments. So by day 15, we had a smaller size and decrease in depth. By day 20, we're 3.5 x 3.8. Day 44, again smaller. By day 50, again smaller. By day 64, we're on the complete wound closure. So here is his case overview and you can see that there are multiple visits that he didn't come into. But you can see if we had put this onto a linear curve that there was almost an exponential curve associated with this on the wound healing on how he was going. So this patient here, this is a 46-year-old male who had a history of diabetes both insulin and noninsulin dependent, noncompliant patient, history of smoking approximately one pack per day, had previous amputation associated with other foot as well as he had a history of gangrenes associated with the toe and that’s where the amputation that he came in and he had already been revascularized. So again we began applying the allograft, placental tissue in a micronized version. This is day 0 and you can see how easy it is to apply to the wound. By day 7, the wound had already started to contract. And then by day 14, it was much smaller, but the interesting thing with him is that he began missing more and more appointments and his sugars started acting more radically. He started going out to dinner a lot more. His sugars ended up -- I think his hemoglobin A1c was at 10 and we were getting anywhere between 250 and 300 was his average on a daily basis. But again even with those elevated sugars, we were still getting wound contracture. By day 33, you can see and by day 47, and by day 89, you can see that it is almost completely healed and then by day 119, he was completely healed. So in conclusion, these are very, very easy grafts to use, very simplified forms. And the nice thing is like I said there are multiple platforms in which you can use these. You can use them not only in diabetic foot ulcers but you can use them in venous ulcers and arterial ulcers as well as pressure ulcers.
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