Lawrence Lavery, DPM, MPH takes a look at the numerous new amniotic tissue products currently on the market and presents clinical trials to evaluate cryopreserved vs freeze dried products.
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Release Date: 03/16/2018 Expiration Date: 12/31/2018
Lawrence Lavery, DPM, MPH
Professor and Director of Clinical Research
Department of Plastic Surgery
University of Texas
Southwestern Medical Center - Dallas, TX
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Male Speaker: I am going to talk about amniotic tissue for wound healing in this presentation. These are a list of my conflicts of interest; most of them I think are research-related although I am on the speakers’ bureau for several companies that have kind of products in the cellular or acellular tissue product space. Really, I have three objectives for this presentation. I want to discuss the deficits in diabetic foot ulcer healing, some of which had had been discussed. I think I’ll present some data that other people haven’t really addressed. I want to discuss the source and rationale for amniotic tissue products, and really the spaces is kind of divided into cryopreserved products and dehydrated products, and there are a lots and lots and lots of them as many of you know. I really want to spend hopefully most of the time talking about the clinical evidence because people can tell you all kinds of stories about my products as crosslinked through to theirs as they use formaldehyde. At the end of the day, you need to look at the clinical evidence because everything else is just nice background. So as many people have discussed today, wound healing and people with diabetes is complex. There is a bunch of different parts. It’s kind of like the blind man and the elephant at times, and people want to just grab one piece of that and say this is the truth, and it’s really much more complex than that. I think variations of this theme talking about the imbalance and the microenvironment in wound healing had been discussed today. What’s interesting is the imbalances identified in diabetic foot ulcers are also the same problems in many instances in people who had burns that failed to heal and pressure ulcers and venous stasis ulcers. In much of the literature, there are senescent cells in those wounds. There is an increase of inflammatory cytokines. There are increases in the proteases of the wound bed. There are deficits in growth factors, and there are deficits in stem cells, particularly in people with diabetes. They have a reduced number, not unlike what we see in neutrophil of a phagocyte killing in diabetics. There is a reduced number, and there is a change in morphology, and there is a reduced effectiveness in stem cells when the host has diabetes. I think the question is always, what can we do to change this imbalance. We are always looking for another tool that will help us understand how to fix this process. This was discussed earlier kind of the basic tenets of wound care and how even when people get a good standard of care, a hyper portion of people continue to fail healing. So I want to talk a little bit about the host. In people with diabetes, this is a host that is seriously flawed. If you look at the normal phases of wound healing, there is an exaggerated increase in the inflammatory phase that is also prolonged [Crosstalk], and there is a blunting of the regenerative phase because the inflammatory phase is prolonged, and there is some evidence that there is more fibrosis in the reparative and remodelling phase, so it is a faulty wound in almost every level of response. As far as stem cells go, there is a tremendous reduction in the number of stem cells that we have available in the normal aging process. There is only a few studies that look at stem cells in animal models, none that look at stem cells in people with diabetes versus non-diabetes in the human model, but this is a streptozotocin rodent model that looks at littermates that have diabetes-induced compared to normal littermates, and they show a dramatic reduction in the number of stem cells and a dramatic reduction in growth factors. There is a lot of literature that talks about deficiencies in growth factors in diabetic animals, a few studies that identify changes in growth factors in humans. Probably the best work, if you're interested in this area, is from [Indecipherable] [04:45] group from the Deaconess. I mean Aries has done a nice body of work that has been published in I think mostly in diabetes care. So mostly, that is available free online. You can download those articles. He has been a Deaconess, gosh, I think almost 25 or 30 years now, probably 25 years and has a beautiful body of work in this area.
So this is the population that has deficits in stem cells and growth factors, and if you look at the characteristics of mesenchymal stem cells and people with diabetes, they have altered morphology, they have decrease in growth, they have decrease in differentiation, and they have more senescent inactive cells. So you have a fewer number of troops, and they are not equipped very well. So again, what to do we do to change this imbalance. The first thing we do is we provide a higher level of care. I think a lot of senescent cells and chronic inflammatory cells are because of repetitive trauma, repetitive injury, and dead tissue in the wounds. So we debrided the wounds and we offload them aggressively. There is a really nice piece that is now a decade old from [Indecipherable] [05:58] that talks about the changes in the wound bed in the histology of diabetic foot wounds when you offload them in the cast compared to not offloading them, and I chose that they look more like an acute wound than a chronic inflamed when you take the pressure off the wound. In many ways, it's not magic. It is what we now I think understand as the gold standard for diabetic foot ulcers. This is obviously a slice of popular press about regenerative medicine. There has been a lot of anticipation about having stem cells in regenerative medicine, and you're going to get an injection, and stem cells can identify the area that's injured. They can provide whatever the deficit is, and you're going to have healing of your heart disease and peripheral vascular disease, and you know you're cavities will go away and you'll get taller, you'll lose weight, and it is going to be fabulous. Right now, where stem cells have been efficacious, has been in cardiovascular disease. I think they failed peripheral vascular disease trials, and they failed some human clinical trials. This is data from a clinical trial for cardiovascular disease, and it shows a significant improvement in almost every level, revascularization, myocardial infarction, death from MI, or MI rehospitalization. So, you know, that looks very attractive but you are not hearing, there is not a digger, come in to our cardiovascular clinic, and we are going to inject you with bone mesenchymal stem cells although I think a lot of the orthopedic surgeons are doing that for soft tissue injuries. So this is a Kaplan Meier survival analysis. This shows death, probably the ultimate endpoint for peripheral vascular disease was much lower. So we have really anticipated this. I think the peripheral vascular studies have failed. I think one of the areas that we looked at, there is an NIH funded stem cells study at the University of Miami that wasn't successful that I believe they used stem cells from bone marrow. Bone marrow and fat are the two kind of easiest sources, and I think the third source is from placental tissue. As you know from this meeting and probably from reps coming to your office, there has been an explosion of dehydrated and cryopreserved tissue products from every source you can imagine. Pick something on the cutting room floor and someone picked it up and got rid of the bacteria and want to present it to you, and if you ask them, "why did you pick goat heart?" and you know whatever and that uninformed rep will say, "well it was cheap." The 510k process is a very low inexpensive barrier to the market place, so there are lots and lots of companies that are trying to sell product. Very, very few have evidence that their product is effective and you have ask them, they will start making little hand puppets from your office lamp on the wall. I spent like 10 minutes pulling out list of acellular dehydrated tissue products. There is a ton of them. Go to the internet and find your favorite search word and you'll get pages of products you've never heard of, so also this for amniotic placental tissue products. These are divided into cryopreserved products and dehydrated products on this list.
I spent 15 minutes and this was probably 2 months ago. There are more products because it is an easy space to get into. People realize that there is a huge margin to be made, and so there are lots of companies in this space. It is kind of like when negative pressure when KCL lost a law suit about negative pressure. Every time I went to a wound meeting, there were little inexpensive foods with someone that had a new negative pressure wound therapy product that you would never hear of again. So the same thing, I mean there are lots of competition in this space, lots of disinformation, and very, very little data, but there is more and more data and probably in the last five years, there has been more successful and more started post marking site is phase 4 clinical trials trying to get evidence because I think payers are going to raise the bar. This is placental tissue, so it was first described in 1910 in a large case series. People used to just try down the labor and delivery I think and say, "I will take a pound of placental tissue." It contains a combination of growth factors, a very rich extra cellular matrix, and viable cells. There is neonatal fibroblast kind of like what we are used to getting from neonatal foreskin. There is neonatal fibroblast, epithelial cells, and there are stem cells available. Most of these companies get these from planned C-sections. There is a lot of debate, so what is the advantage of having a cryopreserved product or an acellular or dehydrated product. For dehydrated products, you're going to get a scaffold. If you're going to provide an extracellular matrix for cell migration, it's going to support the ingrowth of granulation tissue, and it is going to stimulate some production of growth factors. I will show you some data that actually says there are no growth factors. They will show you some data that shows the production of growth factors compared to cryopreserved products, and so there is a rationale why this works, and there is approximate – there’ve been on the market for a longtime from intestines of a pig submucosa to things that have just hit the market that we have never really heard of. This is a piece of literature from the ophthalmology literature. This isn't about wounds, but it looks at fresh [Crosstalk] tissue dried or dehydrated and then cryopreserved tissues. First if you look at the extracellular matrix, there is a significant difference in the tissue thickness, in the tissue degeneration, and in the basement membrane of the extracellular matrix and cryopreserved compared to dehydrated products, and the cryopreserved looks much more like the intact normal tissue, dramatic reduction in dehydrated tissue. If you look at growth factors, in this study, there are no growth factors detected with a dehydrated acellular product, and the production of the growth factors was sustained according to this article when you had a cryopreserved product. If you look at the epithelial cell outgrowth again, there was a dramatic reduction when there was a dehydrated product. I think a lot of this is probably what you'd expect. A cryopreserved product with viable cells is going to look more like the cellular tissue before it was cryopreserved or before it was dehydrated. So probably, you know, what you get with dehydrated or acellular products, you get an extracellular matrix that is going to provide some production of growth factors. If you look at the cellular products, the cellular products that had been on the market for a longtime now are Dermagraft and Apligraf. You're going to get an extracellular matrix with viable cells, and it's going to increase the level of growth factors and the duration of production of growth factors. There is an old now Apligraf study that shows an increase and a relatively sustained increase in growth factors with Apligraf for two weeks. So you know, it is a production that stays around for a long time, so maybe some of those products, instead of putting weekly, we did look at how long growth factors are still there and of course if the patient still keeps it on their wound for longer than a weekly application, and then if you get the amniotic tissue that's cryopreserved, you'd probably get the release of mesenchymal stem cells as well as growth factors and extracellular matrix production.
This is a paper that compares a cryopreserved amniotic tissue product with a dehydrate amniotic tissue product, and it shows that the change in platelet-derived growth factor and HGF overtime comparing these two products. Unlike the ophthalmology paper, it shows there is some release of growth factor when you have a dehydrated product, but it is substantially lower than compared to a cryopreserved product. This was presented at SAWC a couple of years ago. It was recently published, and I need to update the reference for this but it's sitting at home on my desk and not here. Next, I want to talk about evidence and I think a lot of evidence is this level of evidence. A rep is going to come into your office and say, "Trust me. This is great." and you say, "well how does it work." "It works. It's great." You wouldn't support this guy's research probably. You probably shouldn't support theirs. I want to talk about these 2 amniotic products that have RCT level data. The first is a cryopreserved product, and I am going to show you the data from a face re-clinical trial, and it's a classic FDA level clinical trial where people were offloaded. They are debrided every visit. They had to have ABIs of at least 0.7 to participate in the study. Their A1c had to be I think less than 12% to be on the study. So this was what the product looked like. It was a 12-week clinical trial. It was a study that we were one of the higher learning centers. I end up working on the clinical results. In this cryopreserved product that is part of their quality improvement, they had to have at least 70% viable cells in their final lot to be release to the public. This was the first clinical trial in this space that I know of where they had a planned interim analysis, so they originally had I think 200 to 300 people planned to be enrolled in the study. At 97 patients, they stopped enrolment did interim analysis, and they had a successful primary and all other secondary objectives were successful. So they stopped the clinical trial. If you look at the data, in 12 weeks, 62% of the patients healed in the active treatment group, 18% healed in the control arm. The median time to healing was 42 days compared to 70 days, and the infection rate was 50% less in people that had acellular tissue product. This is the survival analysis. As you can see, there is an early separation of the 2 treatment groups, and this study also had a crossover arm. So if you got standard of care, after you receive standard of care for 12 weeks, you could receive treatment every week for an additional 12 weeks or until you heal, and so this shows that those people that failed crossover 80% of those people eventually healed. Next, I want to talk about a dehydrated tissue product. There are 2 small clinical trials in this group. So the first was 13 people in that active treatment, 12 people in the control arm, 92% of people healed in active treatment arm in this study, 8% in the control arm. In the treatment group, the highest proportion wounds healed reported in literature, and the control arm, the lowest proportion of wounds had healed. No infections in the treatment group, 17% in the control arm, then they did a second study where they compared also a small study with 20 people in each treatment arm where they had standard of care. They compared cryopreserved neonatal foreskin Apligraf compared to their dehydrated tissue product, and they reported 85% to 90% of patients healed in the amniotic tissue product, 35% to 45% in the cryopreserved neonatal foreskin product and 30% to 35% in the control arm. Again, both small studies, I think studies, for me, are proof of concept, and this is the survival analysis for those studies. You can see the two control arms essentially overlap, but again, small studies I think proof of concept. Obvious they need a sample size, justification is going to warrant acceptance as a high quality study. In the cellular tissue products, there are only a few studies.
In the acellular tissue products, there is now an OASIS study that was recently published that's successful, a graft I could study that is 7 or 8 years old that Al Stresemann who was the PI hat was successful, an Integra study that was just published in wound repair and regeneration that was successful, so more recent clinical trials. So if you look at the cellular tissue products, and this is a comparison of the proportion of wounds that healed, the time to healing, and the adverse events, there is some difference, and I think as was discussed earlier, you can't really compare these products because they have different inclusion and excision criteria. Maybe from 50,000 feet, it is our nature to compare them. If you look at the relative risk or the likelihood that people are going to heal if they are treated in active treatment group. In the placental tissue products, there is about a 6 fold increase likelihood that you'll heal. If you get to active treatment group, about a 2 fold increase in the Dermagraft and Apligraf group in this study. So to me, that is an easier way to kind of get my head around that comparison. So to summarize, this is a really dynamic market place. The barriers had been blown down, so there are lots and lots of people that have products in this space, most have no evidence, some have poor evidence. I like evidence rather than trial and error, so some of you may like trial and error, but I think these are still at the best are expensive products, and I think it's hard to tell your patient, "You're going to have a 20% co-pay on a $1500 product," and there is no evidence to support its effectiveness. So with that I will finish and thank you for your attention.