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Release Date: 03/16/2018 Expiration Date: 12/31/2018
Suhad Hadi, DPM
Louis Stokes Veterans Administration
Akron Community Based Outpatient Clinic
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Male Speaker: So I’d asked Dr. Suhad Hadi who now is at the Seattle VA where much of this seminal research commenced in the early ‘90s with Roderick Pecoraro [phonetic], Ed Boyko [phonetic] and Gail Ryber [phonetic]. And I'm very thrilled that Dr. Hadi is in such a good center and hope that she can carry on with all the work. I forgot to mention Ben Lipsky [phonetic], too, who is the IDSA chair for diabetic foot infections. So with that, I'd asked that Dr. Hadi to speak to you on the biology of wound healing. You have to understand the basic science behind all these things that we're saying. Otherwise, you're not going to know how to properly intervene or why it's important to intervene. So learn the science. Become doctors first before you become the super podiatric surgeons. You must become the doctor first. So with that, let's welcome Dr. Suhad Hadi to the podium.
Dr. Suhad Hadi: Alright. A lot of good information so far. Again, thank you to the committee and PRESENT for having me. So I want to touch on the biology of wound healing. I think we all have been exposed to the phases of wound healing. I think we need to start running to take things to the next level. It's definitely important to understand the science behind everything that we're putting on wounds in terms of the products, the dressings, what they're achieving for you also. And we'll touch on that briefly as well. Dr. Frankfurt gave a good summary -- an excellent summary in regards to the socioeconomic impact of diabetes. We're going to see how these factors into the wound aspect of diabetes. We're going to review the normal wound healing biochemistry and go through the phases. We're going to define the chronic wound and some principles for promoting active wound healing.
So there's about 6.5 million patients. And wounds compromise about $25 billion in estimated cost. And if you look at the way the wounds are divided, chronic wounds are definitely in there. It doesn't mean that any of the other wounds don't progress into the chronic wound stage. They kind of feed into that. It's a $15-billion wound care industry. So there's a lot of stuff out there that you could be using on wounds. And I think, again, this is the first step to understanding what you're putting on the wounds and why. Immense socioeconomic and social impact and compound and burden of care. It really requires a collaborative effort these days. No one person can do it alone, I don't believe.
So let's review the normal wound healing. First, I think you need to know that there are two signaling molecules that are important in wound healing. One is the cytokine and one is growth factors. Cytokines are your actual cell to cell signaling molecules. Their main source is macrophages and platelets. So in the initial phases of wound healing, they're going to see these signaling molecules increase in presence and they're going to trigger the events that need to happen in order to progress through the normal stages of wound healing. There are small proteins or glycoproteins and, again, they're secreted for the purpose of altering function target cells. And they control gene activation for cell migration.
The growth factors, they're polypeptides producing normal tissues and wounds. There is a whole array of growth factors and we'll have a list in the next slide. But they stimulate transcription and they actually regulate how the cells progress through each phase of the wound healing process. So you'll see them throughout the entire wound healing process. Platelet-derived growth factor, keratinocyte growth factor, vascular-endothelial growth factor. There are many involved in the wound process. And there are products out there that are made to enhance their presence in the wound healing process that we’re using. Things like Regranex, for example. So you definitely want to know where these play in the whole role.
The phases, I don't think they're foreign to anybody. We have the coagulation phase, inflammation, proliferation, and the remodeling phases. This is a well-orchestrated cascade of events. And so in the normal acute wound, they'll progress through these stages in a normal rapid fashion. It's what's happening that create these chronic wounds that we need to understand and what we need to do to stimulate the healing process.
So hemostasis coagulation is immediate. Some people don't even count that as a phase. It's certain, the more [indecipherable] [0:04:43], the more it's getting content to the inflammatory phase. But it's a phase in itself and that this is where your platelets start to aggregate. This is where your fibrin clot forms. And this is important because the platelets, again, are the factors that are helping stimulate the cytokine response and these signaling molecules to [0:05:00] also allow progression into the next phases. The inflammatory phase is immediate, two to five days. This is where you're going to see hemostasis, basic constriction. Again, the platelet aggregation and inflammation. And this is where phagocytosis is going to happen. So if we look here, it’s immediate, two to five days. The bleeding stops and then inflammation starts. The inflammation is important because you get this vasodilatory effect. And this is how leukocytes are brought into the wound. And they are also important in stimulating the process.
But there are three main cell functions that you're going to want to understand in the inflammatory phase, the PMNs, the macrophages, and the T-lymphocytes. The PMNs are the first cells to peak in the wound healing process in the inflammatory phase. There are neutrophil migration. They, too, are major sources of cytokines. Again, those signaling molecules. They release the proteases and the collagenases which are also important for breaking down tissue to allow the buildup of the healthier tissue. And they activated neutrophils. They scavenge in the necrotic debris and the bacteria within the wound bend. And they are replaced by the macrophages which are the second population of inflammatory cells. And they're really the central cell to wound healing in this phase. They orchestrate the release of the cytokines and stimulate the processes of wound healing. They induce the PMN apoptosis and produce nitric oxide. Macrophages are present throughout the entire wound healing phase. They have a predominance here in this inflammatory phase. And they start to decrease as you get out more towards the end of the phases.
That's important also because they've actually shown that an increase in macrophages in the late stages where you're trying to get closure of the wound will actually further hinder the wound and allow it to sit in a chronic state. So you do want to see this natural progression where the macrophages decrease in presence within the wound. Again, this is really just to show you the importance of the macrophage and all the cellular events that take place that are triggered by the macrophage from release of growth factors to activation of cells to move in an appropriate way. Phagocytosis to remove debris from the wound.
The T-lymphocytes are present in less number than the macrophages. But they're important in terms of bridging that transition from the inflammatory phase to the proliferative phase. The proliferative phase is really where you want to get to with the wounds. This is where we're going to start seeing the extracellular matrix and the granulation tissue form. So if you don't have this bridging effect and any hindrance in any of the cell structures that we discussed will cause you to get stuck on that inflammatory phase. The proliferative phase starts anywhere from day two and last up to three weeks. Again, this is where you're going to see granulation, contraction of the wound, and epithelialization.
So the fibroplast -- you’re going to see fibroplasia, that's predominant cell in this phase. It's going to release platelet-derived growth factor after stimulation by macrophages. You get the cytokines again. They become the predominant cell. The fibroblast by day three to day five and clean, non-infected wounds. So again, the macrophages and all the cells we discussed earlier, the PMNs, the T-lymphocytes, those are important in cleaning up the wound so that this process can start. If that doesn't happen, you won't see this and you won't see the forming components -- sorry. Hold on. The production of the extra cellular matrix where you get collagen laid, the glycoproteins, and the basal lamina started.
After you move out of the proliferative phase, you're going to go into the remodeling phase. This can take anywhere up to two years. So this is where you're laying down then your healthier extra cellular matrix, you’re getting the epithelialization, the keratinocytes, the contraction of the wound, and the wound is closing. And then you're allowing this wound to mature in terms of the underlying soft tissue structures.
So when you look at wounds, we're going to look at their superficial wounds, partial thickness, and full thickness. And I think we probably all know that superficial is loss of the epidermis only. Partial thickness involves the epidermis and the dermis. And full thickness is when you're down the subcutaneous tissue and sometimes the bone. Any one of these wounds can find themselves stuck into a chronic state where you're delayed or hindered in the inflammatory phase. But acute wounds, again, they'll follow these linear progression and the chronic wound is asynchronous progression of the phases where you're stuck somewhere and not necessarily just in one phase. Some wounds have been shown to be stuck in two phases and they're in limbo, kind of, and you can't get past it. And this is when you have to start becoming [0:10:00] critical in assessing the wound and deciding what deficiencies are there present in the stage of healing that you're in, so that you can implement the appropriate wound healing products, techniques, wound care hygiene, all of that to get past it. Some of the factors that will cause you to get into this delayed phase to sustain the inflammation is probably the one you'll hear about the most where you get stuck in that inflammatory phase.
Bacterial bioburden, you know, we heard Dr. Joseph speak earlier or yesterday about don't give antibiotics to wounds that are not infected. I don't know that 100 percent. I don't want to say that I buy into that. I have found that antibiotics, if there is a bacterial bioburden to just kind of help clear some of that along with good wound care hygiene, helps kind of push the wound to that next phase that you need to get it into. Acute infection, you definitely want to address with antibiotics debridement IND. Profusion and vascular disease, I think is a whole different outlet that needs to be addressed if there is vascular disease involved. Metabolic disorders, senescent cells, just chronic wound fluid has been shown to put fibroblast into senescent state. So they're not functioning though they're present in the wound. So again, that's where wound hygiene products that are helping with that wound fluid out will help you continue progress, deficient growth factors, nutrition and age. Again, with age, we know there's an increase risk of senescent cells forming in that elderly population.
So factors that affect wound healing. Again, biochemical characteristics of wounds, elevated inflammatory markers, high levels of proteases and MMPs. Again, MMPs have their place in the wound. It's when these things are in excess that we're seeing failure of wounds. Diminished growth factor activity and reduced cell numbers in the wound. So when we talk about MMPs, these are enzymes which act on proteins. And again, they're important in the wound. They're responsible for helping to break down tissue so that there is buildup of tissue. They're produced by the inflammatory cells. So we're going to see them increase in presence in that inflammatory phase. And then they're inhibited by tissue inhibitors of MMPs.
What happens is MMPs and TIMP should be in a one-to-one ratio. And oftentimes, what we'll see in a chronic wound is that the MMPs are increasing and the TIMPs are decreasing. So we're not getting this relationship where they're inhibited as they need to be. So then they end up being more destructive to the wound as opposed to productive to the wound. So again, they are positive roles. They remove the damage extracellular matrix. They help remove bacteria. In the proliferative phase, they help with that capillary basement membrane. Epidermal cell migration and then in remodeling their -- they also aid in contraction and again remodeling of the extracellular matrix. But again, in excess, they will break down non-substrate proteins. So there is a continuous negative effect in the breakdown of the healthy tissue that's forming as well. And then impaired healing on the off-target destruction of cells. There are wound products that claim that they are effective in this respect in regards to wicking out the MMPs out of the wound. Again, I'm not speaking on behalf of any single product. But Prisma and Promogran are two of the ones that make this claim. And so you have to take that into account.
So again, it's a vicious cycle of delayed wound healing. You have the three phases and if tissues are healthy and they progress through that phase, they're going to heal uneventfully. But any delays within these phases will cause continued damage to tissue. Your granulation tissue won't be as healthy, red, and gritty as it should be. It will be more spongy, change in color more towards the brownish colors. To optimize this, you want to maintain wound healing environments. You want to reduce the microbial burden and you want to lower the protease activity within the wound bed itself. And optimizing these environments through the phases wound healing will also optimize your long term healing potential in the wounds.
Again, just to show you the distribution of the wound market these days, there are a lot of products out there. I think if you understand the underlying chemistry, the phases where you're at in the wound, and if you can critically look at it and evaluate it, you'll be able to choose products more appropriately in regards to how you're using among the wounds to progress your healing.
I think, that’s it. It's important history, wound assessment at the cellular and clinical level. What you're seeing vascular statuses is always important. And it's going to probably be a redundant theme. But you always want to make sure the vascular status is intact and nutrition becomes important in all of these factors as well. So if that was fast enough for Dr. Franklin. If anybody has any questions, please don't hesitate.