Male Speaker: Our lead of speaker is here and ready to roll. I like, if possible, you like to have a certain flow to the meeting. And believe it or not, that's the hardest thing to do, have a flow where you're developing your thought processes and science as you go along. So I like to start out with basics first. And our first talk is going to be on Biology of Wound Healing, Principles and Practice. Because without understanding the biology and the basic tenets of care and the proper wound care practice, we don't have a chance. And we can't do anything with the advance process you'll be hearing unless you pay attention to the basics of good wound healing based on the biology of tissue repair. So I couldn't think of anyone better than my friend, Suhad Hadi, who's a great speaker, a very popular speaker for several of our events to come and deliver this leading talk.
Suhad trained at the University of Texas in San Antonio where I first met her years ago. She was in Sacramento. Back to San Antonio. Now, she comes to us from the Seattle VA where she's an attending podiatrist with her and her husband Johnny. And they're becoming actively involved in the wound care program there as well as in residency training. So with that said, let's welcome Dr. Suhad Hadi to the podium.
Dr. Suhad Hadi: Thank you. I want to thank, first of all, Dr. Fryeburg [phonetic] and the Desert Foot Committee. It's definitely been a privilege to take part in their events. I do want to talk about biology of wound healing. I couldn't agree more that if we don't understand what's happening at the cellular level, how do we implement all of these wonderful wound products that we have at our disposal now. So I have no financial relationships to disclose.
My goals are, first, to kind of impart a little bit about the socioeconomic impact of wounds. We all always ask how much does this cost? How much does that cost? But the burden financially and economically has been tremendous. And then going through reviewing the normal wound healing biochemistry, define the chronic wound and what makes our wounds chronic, what's happening when we're dealing with a chronic wound, and then discuss the principles that we can implement for promoting a more active wound healing environment to get these patients ultimately healed.
So 6.5 million patients in the U.S. today are dealing with the chronic wound. There's a $25-billion estimated cost that's involved with this. The wound care industry alone is estimated to be at about $15.3 billion. And there are now over a thousand wound care centers in the United States alone. So we can see the social and economic impact that chronic wounds have taken. And the burden of care that has come hand in hand with this.
So to understand the wound care process, wound healing process, I think it's important to understand what the primary mediators of wound healing are. And that's the cytokines and the growth factors. When we look at cytokines, they're released primarily by the platelets and the macrophages. So once we go through the wound phases, we'll see how this mediators are present throughout the entire phase of wound healing. The cytokines function is cell to cell signaling molecules. They're pleiotropic. And they ultimately alter the function of target cells. And they're responsible for both cellular migration and proliferation within the wound itself.
Growth factors, they're polypeptides producing normal tissue in wounds. And they stimulate cellular migration. They have multiple functions and they are many in number. And they are extremely potent with significant and rapid effects. So again, like I said, growth factors are numerous and we've heard them all. And they've all had their place in the wound products as well as the wound healing cascade.
So I think we're all familiar with the familiar with the phases of wound healing in general. I think we all understand that there's that initial coagulation in the inflammatory phase, proliferative phase, and then the remodeling or maturation phase. Understanding what's happening in each phase at the cellular level especially in today's wound care arena will help us better facilitate what we use, what we put on the wound, what we take away from the wound, and how we progress with the wound as it evolves. So the wounds have a well-defined time period. So when a wound heals through the normal healing cascade, there's a time period that we look for to see the ultimate healing from day one to day 21. [0:05:00] But what's important is to keep in mind the cellular events that are actually happening throughout these phases, how they overlap, and how they are individualized and defined in each particular phase. So we definitely want to understand what's happening when we coagulate the wound, the inflammation, formation of the extra cellular matrix and fibrous tissue, epithelialization, wound contraction, and remodeling.
The hemostasis and coagulation is the initial immediate response whenever there's a wound present. And then after that, we go into the inflammatory phase. So when we look at this flow chart, initially, you're going to get the clot. And the clot is composed of the collagen platelets, the thrombin, and the fibronectin. Remembering that some of these components are responsible for the release of cytokines and growth factors within the wound. Once these cytokines and growth factors are released into the wound, they initiate the presence of neutrophils within the wound. The neutrophils are the scavenger cells that are going to help debride some of the necrotic tissue, the bacterial burden within the wound. Once these neutrophils are initiated into the wound environment, this is what initiates the inflammatory response. The neutrophils, their role will ultimately be taken over by the macrophages which, again, monocytes progress to macrophages and take over that role. That puts us into the immediate inflammatory phase. And we'll see three cell players that are involved during this time period. The PMNs, the macrophages, and the T lymphocytes.
So again, the polymorphonuclear cells, they're the first cells. They take 24 to 48 hours. They're responsible for the neutrophil migration. They are a major source of cytokines within the wound. These triggering molecules. They release the proteases and collagenases. They are activated neutrophils. They scavenge the necrotic debris and bacteria. And again, their role will be taken over by the macrophages which are the second cell to enter into the inflammatory phase. The macrophages will be present after about day four. They actually persist through the entire process of wound healing through each phase. Therefore, they are truly central to wound healing. They orchestrate the release of cytokines also. And increase within 48 to 96 hours. They induce PMN apoptosis which is important because you eventually want apoptosis of the neutrophils. Otherwise, this will also result in complications of the wound. And a wound that stalls or lingers within the inflammatory phase. And we'll discuss that a little bit further as we go along. It also helps reduce nitric oxide.
So this slide, as scary as it seems, definitely demonstrates the role that macrophages play in angiogenesis, cell recruitment, and activation, matrix synthesis and regulation, overall wound debridement, and phagocytosis or antimicrobial function. And again, they are present throughout the entire phases of wound healing. The T lymphocytes, though they are less in number than macrophages, peak at about one week post-injury or post-wound. They are actually the cells that are going to bridge the transition from the inflammatory into the proliferative phase. And then when we see a depletion or a decrease of these cells, this is when we start to see a decline in the wound strength and the collagen within the wound bed itself.
Once all these happens and we get through the inflammatory phase, again, this is talking normal progression of wound healing, we'll go into the proliferative phase. And the proliferative phase is defined on average from days three to day 21. This is when you're going to see your granular bed laid down. You're going to see a bed of collagen. You're going to see new capillaries, angiogenesis that promote the wound healing, contraction of wound edges. And again, it goes from days on average three to 21. Four major steps to keep in mind during this process, again, the angiogenesis which provide the nutrients supplied to the wound. Granulation tissue formation in which the fibroblast is the main cell type for production, and is dependent on multiple growth factors and cytokines. Epithelialization, tissue formation, and collagen formation. This is the important phase because this is the phase where we want to see that healthy granular wound bed that's going to prompt epithelialization, healing, and contraction of the wound. This phase is dependent on the fibroblast. And it's very important that we're critical in this phase. Because when you see compromising your granulation tissue or the bed of the wound, this is when your suspicion needs to be raised whether or not the wound is stalled, lingering, whether there is a bacterial bioburden or some component that's inhibiting your healing from this point on.
So healthy granulation tissues, usually gritty in appearance. You scrape it. It's difficult to get it to start bleeding. It will eventually bleed. But itâs more gritty. But when the tissue is more spongy or in a more compromised area or if the granulation tissue is compromised in colors, maybe more brown or tan in color, then you definitely know there's a component that needs to be addressed [0:10:00 ] further in the wound healing process. Again, this is the stage where fibroblast will proliferate and deposit the extracellular matrix. PTGF is the strongest chemotactic factor from fibroblast. And we've seen its role in some of the wound products that are out there today. And then, they are present after stimulation by the macrophages. They become the predominant cell by day three to five within the wound bed. And then, again, produce the components of the extracellular matrix. Once we move out of the proliferative phase, we're moving into the remodeling phase. And this can last anywhere up to two years. This is the point when new collagen forms to increase the overall tensile strength of wounds. And then again, remembering that even once healed and fully remodeled, the scar tissue is only 80 percent as strong as the original tissue.
Maturation is the final phase. This is when the wound is closed and collagen has converted from type 3 to type 1 and then cellular activity reduces. And there's a decline in the angiogenesis process since the wound is fully epithelialized.
So when we look at wounds, there are multiple ways to define them. One is by the depth. So superficial wounds is loss of epidermis only. Partial thickness wounds involve the epidermis and the dermis. And then full thickness wounds involve the dermis, subcutaneous, fat, and sometimes occasionally will go down to the bone level. When we look at acute wounds, these are wounds that progress through that normal cascade of wound healing that we just defined. It goes through the typical stages of wound healing, through the phases in a timely fashion without compromise. When we look at chronic wounds, this is when there is a compromise in that cascade. And wounds can be stalled in a particular phase. Or they can actually be in limbo between two phases based on what can be predicted is happening at the cellular level or by the appearance of the wound itself. And there's deficiencies in the stage of healing. Ultimately, when you have a chronic wound, changes occur within the molecular environment of a chronic wound that are not conducive to healing. And so you will have high levels of inflammatory cytokines, proteases and low levels of growth factors that prompt the progression through the wound healing process.
So let's look at some of the factors. Sustained inflammation. This is probably one of the biggest ones where wounds are stuck in the inflammatory phase. We know that if neutrophils linger into the wound, that will actually prompt some of the mediators for chronic inflammation. Certain disease processes as was mentioned earlier, diabetes, or chronic inflammatory components, and can cause the wound to linger in this stage. I will elaborate a little bit more.
Bacterial bioburden, it was a great conversation earlier because it hit on some of these key points. But I think everyone has a level of contamination. And I think it's up to us to decide or to be critical as to when that level of contamination has now become a burden to the wound or when it has become an active infectious process. And this is when our wound dressings might change or our oral therapies may change. Or it may implement an antibiotic or implement a wound dressing that has more of an antiseptic or antibacterial effect to help lessen this bacterial bioburden and help wounds to get past this. Because this burden will also sustain a wound into an inflamed response as well as an infection that could compromise overall healing and lead to something more detrimental or more big for the patient.
Profusion for vascular disease, I think, we've all become more adept at recognizing vascular compromise in our wounds and getting them referred in a timely fashion and appropriately to the vascular surgeon so that they can decide whether an intervention is necessary to help augment the healing ultimately by increasing profusion to the area. Metabolic disorder such as diabetes and other systemic diseases, again, some of these diseases have a chronic inflammatory component to them. Diabetes has also been shown to reduce the appropriate apoptotic events of certain cellular structures. So certain cells that are meant to move out of phase to allow progression into another phase and may linger within a wound. And that can become a problem. Senescent cells, so you may progress to a healthy granular wound bed. But the appropriate cells may be present but not functioning to capacity. And this is when we need to be alerted to whether or not we need to implement a treatment that will help jumpstart the wound, help bring the cellular components to the wound that will be necessary to help it move forward in the healing process. Or possibly a skin graft or scaffold that will help implement the progression of the wound.
Deficient growth factors, again, there's some wound products out there that are claiming to bring certain growth factors to the wound bed that are necessary to initiate the process. Nutritional deficiency, I think, this is one component that sometimes is not neglected but usually forgotten. I think it's important for us to realize the role that a lot of the nutritional factors [0:15:00] play. A lot of the components of collagen synthesis are reliant or dependent upon a healthy nutritious diet or status of the patient. So I think it's important for us to refer appropriately to a nutritionist and work with the primary care doctors to implement an appropriate supplementation program that will help these patients get past that point. And then age, also, we know with increased age, we have a decline in ability to heal and respond appropriately at the cellular level to move forward with the healing.
So biochemical characteristics of wound demonstrating delayed healing, again, an elevated inflammatory markers, high levels of proteases including MMPs which have been implicated in a majority of the delays in wound healing as they have a big role and we'll discuss those. Diminished growth factor activity and reduced cell numbers within the wound. So MMPs, these are enzymes which act on proteins. And they're responsible for protein breakdown to allow new tissue formation. They're produced by inflammatory cells. And the wound cells involved in the healing process in general. And they're classically inhibited by TIMP or Tissue Inhibitors of Metalloproteinases. So knowing this, there is clearly a role for the MMPs within wound healing. And they do have a positive effect. In the inflammatory phase, they're responsible for removal of damaged extracellular matrix and removal of bacteria from the wound. They're also in a proliferative phase relying for capillary basement membrane degradation so that continued angiogenesis can occur through the process in epidermal cell migration. And then in remodeling, they facilitate contraction and remodeling of the extracellular matrix and scarring.
It's when they're in excess that they really start to demonstrate a negative role within the wound. So growth factors, extracellular matrix, proteins, and receptors are reduced in the presence of excess MMPs. And the excess is usually due to a continuous neutrophil recruitment. And again, this would cause the wound to be stagnant or stalled within the inflammatory phase. MMP-8 specifically has been identified to affect extracellular matrix degradation. Another factor is, sometimes there is a decrease in the TIMPs in the wound, therefore, allowing an excess of the MMPs. And then an increase in the last days which results in fibronectin degradation. And this also will stimulate MMP production, therefore, allowing them in excess in the wounds. Overall, this results in impaired healing and then you get off-target destruction of cells. So where they had their positive role in regards to affecting the extracellular matrix, angiogenesis, cell migration, in excess, this can have a negative effect in the wound healing. And again, cause the wound to be stagnant or linger in a particular phase.
So ideally, understanding the biology or the chemistry behind wound healing, what the cellular biology is, and what's happening will allow us to be more critical, be more effective in selecting an appropriate wound care product. So when you get to a wound, this wound looks simple. It was granular but it stayed that way for about four weeks and it was in a non-weight bearing area. And we could not get this gentleman to heal his wound. So when you look at this, you know you're in the proliferative phase, you know the granulation bed has been laid, he had cellulites that has resolved, the infection component is gone. So this is when you pull your resources together and you use something to augment the wound healing. It seems like a simple wound that should have healed. But then two week later, healed with the facilitation of something that helped bridge that wound healing process. So again, factors affecting wound healing, it's a vicious cycle. You want to reduce the inflammatory response. You want to have the appropriate cells that produce the appropriate components and stimulators for wound healing and allow progression to stimulate the wound healing and get optimal wound management.
When we're looking at the factors, again, it's important that you recognize the cause of your wound to make sure that it will help you determine whether there's an underlying infectious component or more aggressive debridement necessary. What the drainage looks like, you need to be critical about it. Is it sanguineous? Is it serious? Is it more soupy in appearance which could be a predictor of an increased factor of bioburden or infection to the wound bed. The wound base appearance, again, we talked about the integrity of the granulation tissue and the wound bed that's been laid in the process of the healing. Periwound skin integrity, is it macerated, is it inflamed. So that could be addressed appropriately. And then to critically address your wound as it's moving through each phase. Because as it moves through each phase, you have to change the treatment that you're applying to that wound at that particular time.
And again, there's definitely not a paucity of wound products out there. And they all definitely have their place in the wound healing cascade. It's up to you [0:20:00] to look at the wound and critically evaluate it and see what is missing, what is lacking, where am I at in the process of the wound healing and what do I need to implement whether it's a dressing that's going to help with the wound, whether it's an antibacterial management, whether it's a skin substitute or scaffold that is going to help facilitate the progression of cells. Some of your absorbent dressings make the claim that they actually absorb the MMPs out of the wound therefore decreasing their presence and allowing progression for wound healing.
So I think, like, Dr. Fryeburg mentioned, it's important to speak to the vendors outside, the exhibitors, and really understand what is this product offering you so that you can more critically select what's appropriate for your wound at the given time and stage of its healing. Understand the wound history, be able to assess your wound, not just clinically in how it appears but really understand how to apply what level it's at in regards to cellular healing. And then the vascular status and nutrition to ultimately bring everything full circle and to healing. So I want to thank you all for your time. And this is probably the first time I finished on time. Thank you.