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Lawrence Lavery, DPM, MPH discusses the rationale for using stem cell therapy in all phases of wound healing. Dr Lavery also reviews possibilities for the future of wound repair using stem cell therapy.
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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: Here’s my conflict of interest things again. So the objective of the lecture this morning is to discuss deficits in diabetic foot ulcer healing to discuss the source and rationale for mesenchymal stem cells from a variety of sources and to discuss the rationale specifically in DFU therapy. So I know that you all probably have had an overdose of stem cells this morning. I mean Bob and I were talking about this. This isn’t necessarily where all of us were raised or where we live but I think it’s the technology that is probably the most exciting thing that’s happened to our field in a long time. So I’m going to talk a little bit about that. I think there will be probably some redundancy with pieces other people have talked about. But I think everyone has a little bit different take and insight into this. So first I want to talk about the cost of diabetes. So I’ll give you my 68,000 people a year talk but it’s really about the money. So this is a really nice paper that was published in Diabetes Care in 2013 about the cost of Diabetes in the United States in 2012. They really have very limited specific data about lower extremity cost. The one piece that they have in this article, they don’t talk about anyone else specifically except dietary. So it’s an interesting little side item. I’m not going to give you that data but it’s kind of I thought bizarre that they pulled it out. So the prevalence of diabetes in the United States is about 22.3 million people diagnosed with diabetes or 7% of the population. In the last five years, there’s been a 27% increase in the prevalence of diabetes. But the cost has outpaced the prevalence. The total cost is about 245 billion dollars, a 41% increase in the last five years. I mean we can’t build enough dialysis centers. We can’t build enough wound centers. So this represents 20% of the US healthcare expenditures for 7% of the US population. This is an article you need to have a cup of espresso before you start because it’s not necessarily easy data to get through but it really—if you have an administrator and you need something for your patients with diabetes, I mean this is the article to read and put in front of them. It’s a really nice package about what’s happening to us in the United States. So here we go. I’ll give you my favorite Dave Margolis article. So this is a meta-analysis of the control groups for the standard of care arms in randomized clinical studies that either had a 12 weekend point or 20 weekend point. The proportion of wounds expected to heal in those time periods is horrible. 24% in the control arm in 12 weeks studies, 31% in studies with 20 weekend points. I mean that’s horrible. Although if you look at the control arm data that I presented on my talk and other people have presented in their talk, it’s not far off of what’s reported in the control arm for standard of care in randomized clinical studies. The randomized clinical study that I presented earlier was 21 percent. So the data isn’t very compelling. I mean we need to do more and have more tools in this space. So the wound healing and especially in people with diabetes is a complex problem. There’s a bunch of pieces and we’re still trying to figure out how they all fit in together. I mean we kind of live and die based on our education in biomechanics and vascular disease and neuropathy. Not so much in the basic science. We don’t live in a world of inflammatory cytokines or we weren’t brought up in that world. I think we’re living in it. And we’re trying to put this all together and I can tell you, especially as a young faculty person, I really kind of pooh-poohed all these studies because I thought if you debrided wounds, you offload them aggressively and you could revascularize people, you had this beat. I think there’s more to add to this and I think some of the signs presented today helps us understand that. So part of the regenerative medicine, looking at stem cells I think, is the promise of changing clinical outcomes and healing people that we couldn’t heal before and taking patients who have florid heart failure and giving them a new heart muscle.
That all sounds fabulous and everyone who is on the stem cell lag and we’re going to use—we’re going to take bone marrow from your tibia and inject it into your heart and life is going to be great. There’s a lot of anticipation built around—this is it. I mean we’re going to have some—it’s going to change clinical outcomes. We’re going to cure Alzheimer’s and take care of traumatic brain injuries for NFL football players. Now life is going to be good. But that really hasn’t come to fruition so far. So Suhad presented some of this data. So I’m going to go through this. The normal cascade of wound healing, inflammatory process, proliferary phase and remodeling phase, theoretically we should go through that in a nice timely manner. And if you were that little boy with his band aid on from Doc’s previous slide, you would expect that maybe you might even be anxious after a day or two. But in our world, our patients don’t look like that five-year-old boy. We have this chronic and prolonged inflammatory response. I mean this tails out way past where you would expect it to be. We have a blunted regenerative phase. And then when we finally heal, it’s not great tissue. It’s tissue that’s pliable and easily reinjured. It’s one of the reasons why I think the reulceration data is so compelling, this maybe the best part of some of the stem cell applications, is if we can have better healing tissue we stop that domino effect or the recidivism that cost us so much money. But this is really where we’re living. These people, obese people and obesity is just a generator for chronic inflammation. Okay. I should have used all those areas. So this is perhaps a simplistic way of looking at the data clip. I was brought up over here. I was brought up thinking we need to revascularize people. We need to make sure that their wounds aren’t infected. I really wasn’t kind of raised in the—there’s a lot of bacteria there that you don’t see. We should treat it and offloading pressure in people’s foot. But another side is that our patients are living in a milieu that is full of proteases that their cells are senescent and not really very dynamic or active and that it’s an inflammatory soup and our patients are amino compromised. So even when we do our best, we have an uphill battle to try to figure these people out and facilitate wound healing. So this is data that is now a little bit old. There are several studies that talk about the chronic inflammatory cells and NMPs and non-healing wounds. So say with the slide before, there are senescent cells that aren’t functioning properly. There’s a lot of inflammatory cytokines. There’s NMPs in the wound bed. If you look at this literature, to me it’s like when I’m on review panels and I’m surrounded by PhDs, they look at our clinic patients like they’re spread dolly rats and they’re looking at litter mates. So there’s very little information in studies like this that talk about the treatment as if the treatment doesn’t make any difference. So they don’t talk about the frequency of wound debridement which Doc just talked about. The type of offloading that was used, if infection was present or was treated. I don’t know if it was Lobeman study. I think it was. But 70% of people were treated with antibiotics during the study even though they said people weren’t infected. Well, why are you treating with oral antibiotics then? So there’s a bunch of confounding variables that don’t make sense to me like would you still have this picture the same if you were sure that they weren’t infected if you debride their wound aggressively and if you offloaded them optimally? I mean there are some nice Italian literature that says if you put someone in total contact cast, their wound looks like it’s an acute wound and not a chronic fibrotic wound. So I mean it’s not just what’s happening on the cellular level. It’s the stuff we do in clinic as well. I think we need to look at both of those and their effect.
I mean that being said, there are a number of papers. So this is a relatively recent publication from Aristidis’s group from Deaconess. A really nice body of work. If you pull up Aristidis and look at wound biomarkers, this group has a very nice, long history of external funding an very interesting work. So this is a perspective cohort study. They enrolled 118 patients, 36 healthy controls. The study participants were to contact the study coordinator if they developed the foot ulceration and they provided treatment at the Deaconess and followed standard guidelines. But this is what everyone says about their treatment. We just did standard of care. Trust us. We debrided the wound. We offloaded them. They were well perfused but they don’t tell us what it is. So I never believed them. I think I need more data. I need to know that they really did debride their wound. It’s not just self-reported. They really offloaded their wound. It’s just not we did our best. But if you look at these, there are—actually let me show the other data that is a little bit better. So these are the growth factors and inflammatory cytokines that they looked at. If you look at what the positive results are, there are some of the things we expect. There’s a deficit in PDGF beta or TGF-beta I’m sorry. PDGF is abnormal. FGF is abnormal. The TGF-beta and bIGF aren’t. There’s not a difference. I mean there’s a difference in some of the—the garden variety, everyday inflammatory markers that you would have hung your hat on should have been abnormal. They’re not. So sure there is a deficit in growth factors probably. There’s an increase in inflammatory cytokines. But this isn’t exactly consistent with what other people have reported. It’s part of the soup but I think there is more for us to understand. So the hope for using stem cell therapy is that these are cells that can mediate and modulate the wound and differentiate based on what’s happening at the study level and what your needs are. It’s being able to deliver something to the wound that you don’t even as a clinician know exactly what the deficit is. The stem cells can do that themselves. So the major properties of stem cells are that they’re unspecialized, that they have the ability to self-renew and they can change into mature cell types. So there’s a difference in your stem cells as you age. Bad news for our World War 2 dwindling and Korea War veteran population. But it’s highest in infants and obviously in placental tissue. But there’s a difference based on stem cells, based on where you procure your stem cells. So it’s interesting a lot of where people harvest cells is based on their specialty. So in the past, I belong to Department of Orthopedics, now in plastic surgery. So orthopedics likes bone marrow. So if you’re going to harvest bone marrow, your stem cells are going to be one per hundred thousand or million. If you harvest your tissue from fat, it’s going to be one per 20,000. If you harvest your tissue from placental tissue, it’s going to be one to one or one to four. So a much—if you’re looking for a dose response, this is probably the strongest drug delivery system that we have. That being said, these tissues have been used in animal studies and in human studies for a variety of disease professes. Some with very interesting outcomes especially for us. So what do you get when you are able to apply stem cells? Well, you downregulate that chronic inflammatory phase with our chronic people with diabetes. You’re able to promote tissue regeneration. You’re able to decrease scarring and perhaps better underlying tissue so people don’t reinjure or tear their wounds. So this is some data that was presented at the SAWC last year.
So this is a study that looks at cryopreserved amniotic tissue and an acellular matrix product without any active cells. So if you look at the study, you can see that there’s prolonged release of growth factors. Even with the acellular product, you get some increase in PDGF. But there’s a higher level of growth factors in both of these products and it’s delivered for a prolonged period of time. I think the other thing that’s exciting is that stem cells are able to change based on the wound environment. So this is a study that looks at again stem cells alone and stem cells, when they are included in the wound environment with TNF-alpha. Then they want to look at the response of keratinocyte growth factor. So TGF is a cell proliferative epithelialization and growth factor that prevents scar formation. In the presence of inflammation, like when you load it with TNF-alpha, it upregulates. So it recognizes this inflammatory process and it upregulates KGF. Same thing if you put that same product in a hypoxic wound environment. So you have a control wound. You put it in a hypoxic wound environment and then bIGF which is associated with angiogenesis increases in response to the wound environment. So stem cells can mediate modulate their wound environment. So in patients like this that we talked about that have this exaggerated and prolonged inflammatory response and a blunted cycle of growth factors, it can change that environment. So in the inflammatory phase, you get down regulation of inflammation. You get a restoration of your NMPs and your temps. Okay. That one. In the proliferative phase, you get increase in the cell-to-cell interaction activity and the building blocks of wound healing are increased. Then in the remodeling phase you get reduction in fibrosis. So you get that nice healing scar that isn’t going to be prone to reinjury. Several people have talked about the tissue source for stem cells and placenta. Some of the cryopreserved products, this is a slide that shows that there’s florescent microscopy so the dead cells are red. The active cells are green. Let’s just demonstrate it so you can deliver a cryopreserved product that has active cells. For those of you that remember when in 1998 when Dermagraft wasn’t approved. I think it was at the American Diabetes Association in Chicago. I think one of the problems was the quality control from the initial study and if there were actually active cells delivered. So active cells rather than an acellular dead matrix to deliver stem cells are going to change the environment. I think everyone is interested in the comparison of acellular products, bioengineered tissue products and products that can deliver stem cells. There’s been a huge volume of companies that have acellular matrix products from a variety of sources. From horse pericardium to intestinal pig mucosa. I mean everyone has some way that they make their product acellular that is better than another product. So what you get with these products is you get an increase in growth factors. You have this rich collagen matrix. When you have bioengineered tissue that either are fibroblast or fibroblast keratinocyte products, you get the same thing, growth factors and collagen rich matrix. But you also get epithelial cells and fibroblast that are active and alive in the wound bed. So those are class that we’ve been familiar with for ten years. And then when you add a cryopreserved product that has live mesenchymal stem cells, you get a product that can mediate the wound environment and deliver bIGF when there’s hypoxia or downregulate inflammation as well as well as these other building blocks.
So I think it’s a dynamic process that I don’t think we had available and it’s really kind of the dream of what makes a front page of Business Week and JAMA, the Saturday evening news. So a lot of the focus has been in cardiovascular disease. I mean if you look at some of the clinical trials, they look really compelling. So here’s a paper from—it was published in 2010 that was a double-blinded, super controlled, multicenter study. Looked at 204 patients with heart disease. So if you look at the patients that were treated, there’s a significant difference in a lot of the endpoints that you want for cardiovascular disease. Does this translate into what happens in the diabetic foot and the wounds? Perhaps not but it’s kind of the flavor of what we have. Similar survival analysis is significant and just what you’d expect. Does this translate into peripheral vascular disease? It hasn’t yet. There’s been several negative studies and the positive studies reported minor improvement like a 20 second increase in treadmill activity. So I think the next generation – I think there’s a lot of evidence. I think it’s exciting because there’s evidence. There is not—I’m not standing up here and other people have been saying I’m here making hand puppets. There are animal studies. There are maybe even human clinical studies. There’s an NIH funded study that’s taken place in the University of Miami and there’s data that you’ve seen today. So I think the promise, the expectations I think are finally translating into a clinical approved product. So I think there’s a disease process as stem cells are still a work in progress. I think what’s exciting is the dynamic response that we can have. I think there’s drilling evidence in our space and I think now there’s evidence with commercialized clinical products. So with that I’ll finish and thank you, Bob.