Robert Frykberg, DPM, MPH discusses the acute vs chronic wound healing pathways. Dr Frykberg introduces the idea of advanced wound care including the use of mesenchymal stem cells to heal diabetic foot ulcers.
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Robert Frykberg, DPM, MPH
PRESENT Editor - Diabetic Limb Salvage
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Male Speaker: Okay. Speaking about neuropathy and one of the major contributors to diabetic foot problems for sure. We’re going to talk about a new therapy for chronic wounds with stem cells. It’s viable human matrix tissue with stem cells. It has been shown to be quite effective for managing chronic diabetic foot ulcers. These are my disclosures. The learning objectives as published. So let’s talk about chronic non-healing wounds. We know that the definition of chronic wound, as defined by Lazarus and the Wound Healing Society in 1994, specifies that these are wounds with a failure to proceed through an orderly and timely sequence leading to complete wound care at within two to three weeks for sure. These would include your diabetic foot ulcers, your venous leg ulcers, partial ulcers, et cetera. On the other hand, wounds such as this are acute wounds. Acute wounds are those wounds that are defined by following the normal temporal sequence of events resulting in a healed wound at two weeks. Lacerations, incisions, punctures, abrasions, et cetera. We have to define what is an acute wound and what is a chronic wound and what typifies one from the other from a microbiological or I should say a cellular level, and the constituents of the cytokine profiles of each type of wound. Now, Ralph Lobmann in 2005 published this graphic where it’s defining healing wounds, on the left, as those with high cells with high mitogenic activity, low levels of inflammatory cytokines, low levels of proteases, and mitotically competent cells. However and in contrast, chronic ulcers, chronic wounds, are those typified by cells with low mitogenic activity, high levels of inflammatory cytokines as we know, high levels of proteases and senescent cells. So our job is to convert a chronic wound into an acute wound so that we can stimulate that reparative process of course. We’re aware of that very much so in our daily practices. Now it’s also helpful to get a summary of all the various interrelated underlying metabolic perturbations in that diabetic lower extremity. It can be daunting obviously because any diabetic patient can have all of these various problems and underlying metabolic perturbations at one time. It’s important that we are aware of all these underlying problems if we’re going to be effectively treating these patients. Of course as we’ve said, neuropathy is the key component leading to many diabetic lower extremity problems including ulcers, including Charcot foot of course, including infections, amputations, et cetera. As it’s been very nicely shown by [Dr. Bromley] [03:07], autonomic neuropathy is also an important part of this underlying abnormality in the diabetic host. Of course we also recognize the important role of vascular disease, both macrovascular and microvascular disease. So that sets up a high risk foot. You apply trauma to that high risk system. With the bodies, the diabetic person, the diabetic host impaired response to infection, you can see how you can easily develop a diabetic foot ulcer and an infected diabetic foot ulcer which leads to subsequent amputation if not treated aggressively and early. So it serves us well to really keep an eye on all of these underlying metabolic problems so that we can address them as we progress with our treatment of these patients. Now there’s really not much new in terms of how we approach treating diabetic foot ulcers. Certainly nothing new compared to what we knew 30, 35 years ago. But it’s been codified more or less by several recent or fairly recent clinical practice guidelines 2006, ACFAS and the Wound Healing Society. 2010, Bob Snyder, one of our often frequent lecturers here produced a wound care consensus document. Then in 2016, you have two new ones. The Wound Healing Society has just updated their diabetic foot ulcer guidelines, and the Society for Vascular Surgery in concert with the APMA has just produced a series of documents referring to diabetic foot ulcer guidelines. Nothing really is different, going back from 20, 30 years ago to now. But now we recognize that to properly manage any of these wounds we need to pay attention to the basics of wound care. That includes a diagnosis and management of underlying arterial disease. We need to address the wound environment as we’ve heard from very nice talks early this morning.
Infection control, diagnosis and control of infection, proper offloading without offloading where all bets are off you’re never going to be successful. The use of advance therapies. Very, very important especially over the last decade or 15 years but using advance therapies as necessary and intelligently, I think that’s the most important thing. Of course paying attention to the important role of surgery, whether it be curative, reconstructive, or other types of surgical offloading as we say. Amputations can become limb salvage procedures, especially partial foot amputation of course. As Dr. McCain will say, always remember the important role of biopsy to make sure you know you’re treating a venous leg ulcer or a diabetic foot ulcer or what have you. So it’s important to pay attention to all these basics all the time, all the time. This is a graph. Hopefully you can see it, but really just summarizes all the guidelines that we’ve talked about, all the review articles, and including the recent Journal of Vascular Surgery diabetic foot ulcer guideline. So we see a diabetic foot ulcer presents. We have to properly assess that to address each underlying problem. We need to do the vascular assessment. We need to assess for any underlying infection. We need to always do our imaging. This is standard part of our care. Once you’ve done your proper assessment, you can properly classify the ulcers. In my view, classification facilitates and guides your treatment. Then we can classify according to the University of Texas or the Pedo system or even the Wagner system as long as you pay attention to the vascular status. So once we classify, we facilitates and guides our treatment, which always consist of debridement, offloading as we’ve said, wound bed preparation with dressings, mesh or the pulsatile lavage that we heard earlier, surgery whether that includes reconstructive foot surgery, bone resections, local amputations, or vascular surgery, and of course medical management, concurrent with all the other therapies that we’re doing. So we work as a team always and we’re always working on behalf of that patient concurrently really, not sequentially. Then we’ve all know the four week, 50% rule. We reassess that wound at four weeks. Look for about 50 % reduction in the wound area. If we have noted that we’re healing satisfactorily, we continue the care, continue the offloading and the basic wound care. Once they’re completely healed, we put them into a surveillance and a prevention program. But we know all too painfully that many times this is not the case. And that after four weeks these wounds have stalled. Why? Because there were high levels of proteases that chronic inflammatory process that these wounds become stuck and because of perhaps excess bio burden or maybe there is some degree of ischemia, or you have inadequately offloaded these people. So then we need to reassess. If we reassessed the patient and found that yes, our basic wound care has been satisfactory, we’ve addressed all the basic tenants but we find that we need a push. We need some type of advance therapy that we have now. Then we start looking towards our advanced therapy. Over the last decade, 15 years has been an enormous increase in the number of possible advance therapies. We’re obviously not going to talk about all these but we can talk about isolated growth factors, various types of extracellular matrix scaffolds, whether they be collagen tissues or dermal tissues, acellular dermal tissues. Then we have our cellular-based tissues. We know we had two PNA products and now we have a viable human placental-derived matrix with stem cells, we will be talking more about. Then we also talk about negative pressure therapy. We know there are many, many different types of negative pressure therapy devices on the market. I should say that many times I’ll use these several combinations of these products which I call multimodal therapies, either sequentially or concurrently. Often time while using an advance tissue product in conjunction with negative pressure therapy to expedite my repair. So you have to base your decisions on the evidence, what’s available, what’s worked in your hands, what evidence lead you to believe that your product might be beneficial for the patient that you’re treating at the current time. So this brings us to one of my favorite advance tissues. That’s with mesenchymal stem cells. I think if you look at the medical literature, even [Bob Bartlet] [09:41] this morning had said that stem cells and stem cell therapies now are native through the host. It’s an exciting new development in therapies. I hope to show you why I think mesenchymal stem cells might be that optimum cellular approach for managing these chronic wounds.
We know that MSCs are widespread throughout multiple tissues in the body including the bone marrow as we’ve heard earlier. Blood, fat, placenta, amnion, and chorion, all richly containing mesenchymal stem cells. Placental membranes are not only a convenient source of MSCs but they are very, very rich source of MSCs, hence the reason why you’re seeing so many studies now on placental tissues. But most of the studies that you’ve seen are acellular placental tissues which really act as growth factors or reservoirs for those endogenously produced cytokines and growth factors that had been produced by the mesenchymal stem cells. So mesenchymal stem cells are pluripotential. But by the term mesenchymel, they lead to mesenchymel tissues, bone, cartilage, tendon. Not skin. So why would it work to place MSCs in a dermal situation? Well they secrete multiple growth factors and cytokines, they can orchestrate wound repair and tissue regeneration very, very well, and they’re responsive to the local environment. You put them in a hypoxic environment. They’ll up-regulate the production of VEGF. You put them into an inflammatory environment, they’ll up-regulate anti-inflammatory cytokines and growth factors. So very important. They’re really smart cells. Now when you mention stem cells, you can envision many different arguments and ethical dilemmas. But we’re not talking about embryonic stem cells. We’re talking adult stem cells. Neonatal-derived stem cells or I consider adult stem cells. They’re mature individual. We’re not talking about hemopoietic stem cells which can induce an immune response. We’re talking mesenchymal stem cells for a variety of reasons. These are connective tissue stem cells. As I said, they’re in the stromal, bone, muscle cartilage, ligaments, tendons and fat are all mesenchymal tissues. You can find mesenchymal stem cells in all of these tissues. Once again, the MSCs biology is characterized by these cells being immune privileged. They don’t engender an immune response when implanted from one host to another. They’re anti-inflammatory by their very, very nature. They’re tissue protective and they’re tissue regenerative. So very, very attractive type of implant to make for these chronic wounds. Remember, these are living stem cells that can synthesize. They can proliferate, and synthesize many different types of cytokines and growth factors. But I raise the question earlier. If we’re taking a mesenchymal cell and putting it into skin, how can that work because skin is not a mesenchymal or mesodermal tissue. It’s dermal, it’s ectodermal. Well, the rationale is that yes, direct differentiation, normal differentiation of mesenchymal stem cells or direct terminal differentiation would be to chondroblast, osteoblast, et cetera. However it’s that indirect or paracrine function of the MSCs key to us in this regard. Remember, these are potent synthesizers of angiogenic growth factors, like VEGF, like PDGF. They also can produce osteoinductive bone marrow protein – or BMPs. I’m sorry. It’s just escaping my mind. Right now, the bone morphogenic proteins. We implant them into ectodermal tissue into skin because they’re a growth factor, factory is I’d like to talk about them. It’s a paracrine function. You put them into a host wound and they’ll generate a very aggressive response by synthesizing these very important growth factors that will help to direct the normal repair that we’re looking for. Again, we’re taking chronic wounds that are characterized by cells with low mitogenic activity, high inflammatory milieu if you will. By implanting MSCs they can redirect or shift the profile of that wound into one that is characterized by healing wound environment as we can see here. So what about the clinical data? Again, in vitro studies are fine but we need to make sure that translates into proper clinical effect as well. So I’m just going to go over study. One recently published RCT that was pivotal in this regard. This is by Lavery. Lavery published it in International Wound Journal in 2014 that was a multicenter RCT, single blinded of 20 US sites. The most interesting part about this is they have – it was a typical RCT but looking at a crossover arm as well. For those patients who after 12 weeks did not achieve complete healing, they were allowed to crossover with the active group.
From the control group to the active group to assess effect at that point after 12 weeks of non-healing. It was an adaptive design meaning that a priority within the protocol they were allowed to reevaluate those patients in the interim to determine effect. In fact they did find that there was a positive effect here and they stopped the trial early. So the primary end point was complete wound closure of the index diabetic foot ulcer, secondary of course time to initial closure, a number of treatments, time to closure, [coughs] et cetera as you can see. This is just a brief summary of the results. You could see after 12 weeks the graphics groups, the MSC active group had a 62% complete closure group compared to 21% in the control group. I can’t address as to why the control group was 21% but it was. This was randomized. Everybody had the same offloading, the same standard of care with the exception of those in the active group who obviously received the MSC amniotic matrix tissue. The important point here was the 62% versus 21% significant result but it results in a 191% relative improvement. 191% relative improvement compared to the control group. [Coughs] This was the greatest margin of effect ever published by any study published to date. Here we can see the curve, the cap and [mayo] [16:36] curve between the two groups seeing that early separation between the active group, the graphics groups, and the control group. We mentioned the crossover design here. So at 12 weeks, those patients in the control arm who did not achieve the primary outcome of complete healing were able to crossover and receive the active agent. In this case, you can see 26 patients crossed over. [Coughs] Look at the growth curve, the curve here. We see a rapid takeoff in the incidence of healing and those patients had stalled wounds during the 12 weeks of controlled treatment. I think this is very powerful results. Now it’s being incorporated into many more designs in diabetic foot ulcer studies. So I think that’s a really powerful signal to show that the viable human placental matrix with MSCs can really stimulate repair in these chronic wounds by responding to that noxious environment of chronic wounds. Here’s just a simple example from my own clinic. A man with a TMA dehiscence, non-reconstructable vascular disease after failing his bypass. He had stalled wounds. We were afraid that he was going to lose his leg. We even had bone exposed. Bone was just debrided in our clinic. We started to apply the MSC viable matrix and we can start seeing a rapid steady progressive improvement in this chronic-failed TMA patient with underlying vascular disease. He remains healed to this day. We were very worried about this because he had no other treatment options and we were able to get this completely healed. But we’ve seen this over and over again with other very difficult complex patients. In fact we went on to do another study that I can’t really report on right now, using this product, this MSC containing viable human placental derived matrix on chronic wounds with exposed bone and exposed tendon to see if we can get these to heal. We found very, very nice results that will be reported at the SAWC meeting next month. That’s about as much as I’m allowed to tell you about that because the results really haven’t been released yet except that we had a very successful trial. So these materials really can stimulate endogenous wound healing by altering the wound milieu if you will, stimulating them by synthesizing growth factors and cytokines to promote a proper wound repair as we would expect. Here’s just a graph comparing percent wound improvement over control groups from published studies with 12 week outcomes – no. There are other studies out with six weeks outcomes but this is on 12 weeks outcomes. You can see on the left the 191% relative improvement compared to control group on published RCTs and peer-reviewed literature. Higher relative improvement compared to any other treatment on the market that has undergone similar types of rigorous studies. So I think that is a very important signal to me that this is something that needs to be taken care of because this was a very, very rigorous RCT.
I pay attention to data like this because I think it really helps justify why we would go ahead and use such advance tissue products. So in summary, you always must pay attention to standard basic wound care. The basic wound tenants can never be violated. There are many advance wound therapies available and you need to choose those with evidence when available. Most products do not have good evidence. There are a few comparative trials or a few RCTs and even fewer comparative trials that exist. I think mesenchymal stem cells offer a unique mechanism of action. As I hope I’ve shown you very, very briefly, that the most recent RCT involving mesenchymal stem cell with viable placental matrix tissue shows superior evidence of clinical efficacy in healing diabetic ulcers. As I said, we’ve also extended that to other types of chronic complex wounds and had found similar success rates. With that, thank you very much for your time.