Robert Frykberg, DPM, MPH presents the current knowledge behind wound bed preparation, wound healing and its relevance to the podiatric profession. Dr Frykberg reviews the phases of wound healing, the molecular involvement, and the principles of wound care treatment. Along with citing relevant literature, he discusses the usefulness of medical management for chronic wounds.
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Robert Frykberg, , DPM, MPH,
PRESENT Editor - Diabetic Limb Salvage
Carl T Hayden VA Medical Center
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Male Speaker: Our first topic is something we mentioned briefly this morning. Several of our speakers talked about wound bed preparation and Barry Rosenblum gave a very nice talk on the biology of wound healing. I’m going to reiterate some of what Barry had said. Recognize that the diabetic foot has compromised biology. This cartoon was first put forth by Frank LoGerfo who’s a retired vascular surgeon at the Beth Israel Deaconess Hospital in Boston. I thought it was very simple and elegant at the same time. If we think of the diabetic foot, we know it’s a foot that is compromised. We mentioned the role of sensory neuropathy as being the major predisposing factor for all of the problems or most all of the problems that we see in the diabetic foot. We have to also consider the important role of motor neuropathy or that causing that classic intrinsic minus foot, clawed toes, deformities and high plantar pressures, which lead to the repetitive stress that leads to foot ulcers. Along the same lines, we have to recognize the role of autonomic neuropathy, something that not everybody thinks about, but it’s always present when sensory neuropathy is present. Autonomic neuropathy leads to sympathetic failure or microneurovascular disturbances with vasomotor disturbances, endothelial dysfunction and hidrosis. All of these either help promote problems with the skin or help delay and impede wound healing. Autonomic neuropathy is a very, very important aspect of this as well. Then we talk about large vessel disease or vascular dysfunction and, of course, large vessels as we always think about for PAD, a major risk factor for amputation and a major risk factor also for ulceration and especially failures of ulcerations to heal. Let’s not also forget about the role of microvascular disease, which really plays part and parcel to autonomic neuropathy, and microvascular dysfunction is a close interplay between neuropathy and microvascular disease. Then finally, we recognize the role of immunopathy where diabetic patients have been shown to be more susceptible to infection than are their nondiabetic counterparts. All of these metabolic perturbations lead to that high risk foot that is setup for injury and setup for problems. We need to appreciate these underlying comorbidities that we’re able to effectively intervene, prevent and adequately treat these problems. As part of our talks on wound healing and diabetes, we need to recognize the difference between acute wounds and chronic wounds. Acute wounds were really defined mainly by Lazarus in 1994. Those wounds have healed in an orderly progression to complete closure. This is orderly, timely, sequence of events leading to healing at normal time intervals, three to perhaps four weeks. There’s a proper balance between cytokines, growth factors, and proteases that allow these wounds to heal on eventually. This is the normal circumstance. As opposed to chronic wounds or skin ulcers or dehiscent wounds or what have you, which were defined by Lazarus at the Wound Healing Society as those that do not heal on an orderly or timely sequence, and those that do not result in structural integrity at the proper time period, i.e., at the end of three weeks. These are wounds that have failed to heal generally within about 30 days or so. There’s an imbalance of biochemical signaling molecules. There’s a chronic inflammation. We all heard that these chronic wounds are stuck in an inflammatory phase due to the underlying biochemical imbalances and there’s excessive protease activity. I believe Barry Rosenblum had mentioned this earlier. We need to be aware of what’s going on in that hostile chronic wound environment if we are really going to be affective in making a difference. Barry also mentioned the wound healing cascade. Now, I don’t want to spend a lot of time going over this again, but recognize that the phases of wound healing, there used to be three in the old days, now we have four, where there’s hemostasis, inflammation, then you have the proliferative phase which includes cellular proliferation and migration. Also, including angiogenesis, protein synthesis, epithelialization, and finally wound contraction remodelling which would be in the final stage. We know it’s a very complex process, much different than what we thought of many, many years ago. We could see multiple components starting from inflammation, cytokines were mentioned earlier, the role of platelets coagulation, degranulation of platelets leading to the release of cytokines, and growth factors attracting the fibroblast and macrophages which also release more growth factor, and chemokines leading to angiogenesis, the collagen synthesis and then final repair.
It’s not that simple. You need to be aware of this. We don’t have the time really to talk about this, but this should be part of your bread and butter, and you need to know these basic attributes in the wound healing cascade because it’s all important. Recognize that the chronic wounds are those that had the excessive protease activities are stuck in that inflammatory phase, which is why we have to convert these wounds as part of our wound bed preparation from that chronic hostile environment to the acute healing environment, which has that normal balance of proteases and actively proliferating cells. Again, cytokines and growth factors are small polypeptide signaling molecules. These are signals that make other target cells do certain things. Those certain things are protein synthesis, cellular proliferation, maturation, proliferation, et cetera. We know that the cytokines growth factors are secreted by multiple cell types, almost all cell types in the wound healing environment. They control cellular proliferation, differentiation, migration, metabolism, and especially protein synthesis. Part of that protein synthesis is also extracellular matrix synthesis, so keep that in mind as well. The essential components, these are essential components of the wound healing cascade because it’s the release and the timing of the release of cytokines and growth factors that really orchestrate the sequence of events that lead to a normally healed wound. When that orchestration becomes interrupted or disturbed, we have chronic wounds that are stuck in the inflammatory phase. How do growth factors work? Well, once again, we know that different cells secrete different growth factors and can express several different receptors. Cells, fibroblasts, neutrophils and especially macrophages will release growth factors and will also have receptors for other growth factors. We know that growth factors have target cells. When they bind with the receptors on those target cells, they’ll cause those target cells to produce something, i.e., mature or upregulate gene expression for protein synthesizes or proliferation, DNA synthesis, et cetera. We also have to keep in mind that those proteases degrade protein, not just collagen, not just growth factor, but also growth factor receptors. Excessive proteases can really interrupt this normal process. Think of chronic wounds as a very hostile environment for these very sensitive very key components of cellular or wound repair. We mentioned proteases. When we talk about proteases, we’re really talking about matrix metalloproteinases, which are a family of protein degrading enzymes that are calcium and especially zinc dependent. There are many types of proteases. As I said, they need calcium and zinc ions for a proper shape and proper activity as do many enzymes. They’re made by almost every cell in the wound especially macrophages and neutrophils. They can degrade cell components of the extracellular matrix. You have your last stages, you have collagenases, you have serine proteases or many different types of proteases, but these are normal for wound repair. When they become excessive in the wound, then we start seeing such high levels that they are actively degrading normal constituents or wound repair like growth factors or growth factor receptors as well as all the newly laid down collagen. With every action as a reaction and with every component, there’s a counterbalancing agent. In this regard, it’s TIMPs, tissue inhibitors of metalloproteinases. So the levels of proteases are normally counterbalanced by levels of tissue inhibitors of matrix metalloproteinesis. When this balance becomes imbalanced, then we know that the scales are tipped towards the protease side, leading to a stalled wound. It’s important to recognize that. Excessive MMPs in the chronic wounds are characteristic of these chronic wounds. Chronic wound fluid is noxious. It is noxious to wound healing and will degrade growth factors. As I said, MMPs will also degrade growth factor receptors, a elastin and collagen, which are all part of the newly laid down wound matrix.
We see that their hostile wound environment also includes diminished receptor sites and growth factor activity and these will delay healing. You really have to have an understanding for what’s going on in these chronic wounds that makes them so difficult to repair. This is from Ralph Lowe [phonetic] in his paper in 2005 in diabetes care. This is just a simplistic look at the difference between healing wounds and chronic ulcers. In a normal healing wound, or as we’ve defined, an acute wound, it is characterized by cells with high mitogenic activity, with low levels of inflammatory cytokines, low levels of proteases as we’ve said from several slides back, and mitotically competent cells. Now, that’s an acute normal wound that would go on to heal. Contrast that with chronic ulcers, i.e., diabetic foot ulcers, these are characterized by cells with low mitogenic activity, with high levels of inflammatory cytokines, including high levels of proteases which are noxious to the healing wound. Also, characterized by senescence cells, cells that aren’t behaving properly, that don’t die but yet are not metabolically active or they’re not secreting the proper amounts of proteins. What we have to do in our wound bed preparation is convert that scale that is tipped on the nonhealing side here to a healing milieu or a healing characteristic by doing active wound bed preparation. Our goal is always to convert that noxious, inflamed, nonhealing wound into more of an acute wound by removing these noxious substances and converting it over to normal balances of chemokines, cytokines, and growth factors and bring in new actively competent cells. Why don’t diabetic foot wounds heal? We know that what I was illustrating has been chronic wounds in general, but what makes diabetic foot wounds particularly difficult? Well, as I mentioned earlier this morning, it’s neuropathy. Neuropathy can lead to many problems, mainly due to insensitivity, unrecognized trauma and repeated trauma on a wound. When you have a wound, you have normal sensation, you protect that wound. As Paul Brand said, you lose the gift of pain if you have neuropathy, so you keep traumatizing that traumatized wound just making it worst. That’s critically important. Also with autonomic neuropathy in the concurrent sympathetic failure and hidrosis and microneurovascular dysfunction, there is an impairment in normal responses that allow these things to heal. Then also remember, your motor neuropathy which results in deformities which cause increased pressures, high pressures, and all of these combined lead to constant repetitive trauma or impairments in that diabetic patient to heal. This is regardless of diabetes status and glucose levels, which also are very important parameter that we need to consider when dealing with a nonhealing diabetic wound. Let’s also consider the important role of ischemia. I don’t think that’s a surprise for anyone here. The susceptibility of these patients to infection, increased bioburden on many of these chronic wounds, also can lead to an impairment of healing. Underlying osteomyelitis especially if you have these chronic wounds that are open for six months, probe to bone, you’ve got to consider perhaps that osteomyelitis, is that low level of inflammation and infection that’s preventing things from healing. We’ve mentioned adequately the biochemical perturbations that are very, very common in these wounds, cellular dysfunctions, senescence, inadequately secreting cells, and of course, inadequate offloading, which is critical because these people are not adequately offloaded. Especially if they come walking in to you in a shoe that might have caused the ulcer, these will not heal. That’s why foot ulcers need to be treated not in a shoe that cause them but in a particular offloading devices. We mentioned the chronic wound environment, persistent information, biochemical perturbations, cellular dysfunction. As I’ve mentioned several times, bacterial burden or that biofilm that’s chronically present on the surface of the wound, oxygen deficiency, either ischemia and/or edema and even microedema can cause problems in capillary perfusion in this regard, and of course, repetitive trauma due to their inadequate offloading. Again, I’ve reiterated the same problems that make diabetic foot wounds more difficult to heal and sometimes prevents these things from healing.
These were all points for you to intervene upon and consider and correct these underlying perturbations and causes for nonhealing wounds so that you can reverse the course, convert them to a chronic wound and get them to start healing, but you have to know what’s going on before you can do that. The principles of wound care are basically simple and Barry had mentioned them this morning. Obviously, medical management is key. That’s surrounding everything here with good nutrition, good metabolic control to diabetes and other comorbidities, but always look for and treat any vascular issues. Ischemia is there far more commonly than you think. When present, you need to diagnose it and revascularize them. We know the role of hyperbaric oxygen in certain cases in which we’ll hear on the next talk. A topical oxygen has a role in correcting these vascular or oxygen deficiency. Infection may not be acutely present, but may be indolent like underlying on osteomyelitis or excessive bioburden. You need to recognize that. Debride it and treat it as appropriately. Then finally, we get to wound care. The basics of wound care are always the same, debridement, wound bed preparation, and management through debridement and dressings and moisture and exudate control, offloading or compression if you have a chronic venous ulcer. Then after we do the proper wound bed preparation, then we consider our topical therapeutic agents where our normal advanced agents or whatever agent you want to use, but you have to pay attention to the basics first. That’s wound bed preparation. Then, it doesn’t really matter what you put on a wound, in most cases, at least in the initial parts of your treatment. Turn that off Allen. Wound bed preparation includes debridement, bacterial balance, exudate management, because remember, that exudate for the chronic wound fluid is noxious. Remember, chronic wound fluid is noxious to cytokines growth factors and growth factor receptors. Again, we need to convert it from the chronic to the acute wound environment. That’s absolutely critical. Debridement is an essential part of our care. Sharp debridement is always optimal. We know we have ultrasonic debridement, hydro jet debridement. Enzymes are useful, well, usually as maintenance debridement. Even biotherapeutic agents, biodebridement with maggot therapy, not tested by trials, but in certain cases, in certain patients, it’s certainly an effective way to convert these wounds from chronic toward the active state at least to remove a lot of excessive necrotic tissue in patients, perhaps, that can’t get to the operating room, there’s no acuity but you need to work on them. The typical example being, let’s say, nursing home patients might be very effective in that regard. As my friend, Larry Hart, which have said many years ago as far as offloading goes, it’s not what you put on the wound that counts. It’s what you take off. You need to pay close attention to offloading modality. This isn’t just a mantra we say, it’s absolutely essential. You never let that patient go out of the office or clinic in the same shoe that they walked in with, with that ulcer. No ulcer should be treated with a shoe. It should be treated with a particular offloading device. The best way, the very best is the total contact cast. It beats everything else ever studied, total contact cast. Second to that would be your removable CAM walker. Everything after that is trying to meet the same levels of success. Finally, in summary, getting wounds to heal requires a working knowledge of a normal wound healing cascade which you should all be fairly comfortable with and have a working knowledge of. Recognize the role of the biochemical and cellular constituents in a chronic wound because you need to know the disturbances and what’s normal and what’s abnormal. You need to know the pathophysiology of chronic wounds as we’ve already mentioned. You need to know the basics of wound care, which several of us have spoken about. It never changes. You always pay attention to the basics. You convert the chronic wound to the active wound. Offload and pay attention to infection. Pay attention to ischemia. In most cases, you’re going to be successful. It’s not rocket science. It’s wound care. It’s not always that simple, but you always pay attention to those basics. Okay. Thank you. I’m sorry, I went a couple of minutes but we’re still on time. Okay. Thank you.