Wound Healing: Physiology

Speaker A: 00:00:10

Okay, so in previous classes, we've talked about the anatomy and physiology of healthy skin. We've talked about things we can do to keep the skin healthy.

We've talked about common causes of skin breakdown and pressure injury formation in particular. And we've talked a lot about what we can do as clinicians to prevent pressure injuries from developing.

So now we're moving to a different area of the course, and we're going to talk about the process by which wounds heal. Now, one of the things you want to remember is that regardless of the etiologic factors, the pathway for healing is the same.

So this is really important content for you, because if you understand the process by which wounds heal, you'll be able to assess any given wound in terms of where is it to in the repair process, and you'll also have a good understanding of what you as a clinician need to do to help move that wound along. So our objectives for this section are to define the following terms. You want to know the current terminology.

So you want to know the difference between a partial thickness wound and a full thickness wound. You want to be able to define primary, secondary and tertiary and tension wound healing.

You want to be able to describe the partial thickness repair process and guidelines for management. You want to describe the repair process for acute and chronic full thickness wounds and guidelines for management of these wounds.

And finally, you want to be able to explain the role of each of the following in regulation of the repair process. So what is it that growth factors and cytokines do? What is it that extracellular matrix proteins do?

And then what role does the extracellular matrix itself play in wound repair? So you're going to watch the video.

Very helpful to read chapters to two and six for background information, but the critical required activities are to watch the video and complete the learning exercises. So we're going to start out with general concepts, in general terms related to wound healing.

Important to realize that for us as humans, there are two ways in which we can repair a wound. Ideally, we repair a wound with regeneration, which means I, we replace any lost tissue with essentially more of the same.

That is the mechanism of healing for wounds that are limited to the skin layers themselves.

So throughout your life, think how many times you have scraped your knees, scraped your elbow, maybe you had a superficial burn, but you are not a mass of scar tissue because all of those superficial wounds healed by replacing lost skin with new skin. They healed with no change in function and no change in appearance. It's very different for wounds that involve deep tissue layers.

So if a wound extends to the deep dermis and damages or destroys the sweat glands, the sebaceous glands, the hair follicles, if a wound involves the subcutaneous tissue or the muscle or the bone, those are structures that cannot regenerate. We talked about this. You can't make more hair follicles, you can't make more sweat glands, you can't make more fat, you can't make more muscle.

So if you have an extensive wound, a deep wound that involves those deeper tissue layers, you're going to have to heal that wound through a process of scarring, scar formation, also known as connective tissue repair. So you're not going to be able to fill that defect with new muscle, new fat, new hair follicles, new dermis, new epidermis.

Instead, what you're going to do is you're going to make a batch of scar tissue that fills the defect, and then you're going to cover over the scar tissue with skin, and that's known as connective tissue repair. Other terms you need to be familiar with and concepts.

So you are going to deal as a wound care clinician both with acute wounds and with chronic wounds. Acute wounds in general are much easier to manage. So, acute wounds are wounds that occur suddenly. They occur as a result of surgery or trauma.

They almost always involves significant bleeding, and they typically heal in a very predictable manner because healing of those wounds is controlled by growth factors. We'll talk about that. In contrast, when you're managing a chronic wound, it's very much an uphill course in getting that wound to heal.

So chronic wounds are wounds that are caused by chronic conditions. So it might be recurrent pressure, it might be venous insufficiency, it might be neuropathy in a diabetic patient.

It might be some other chronic condition that has caused this wound. It could also be an acute wound that failed to heal normally and now has fallen into the chronic wound category.

The problem with chronic wounds is most of the time there are no growth factors or very low levels of growth factors in the wound bed. So essentially no control of the repair process.

And these wounds tend to become indolent and just sit there until somebody who knows what they're doing, hopefully that's going to be you, arrives on the scene to get them back on track. You'll also hear the terms primary, secondary and tertiary, and tension wound healing.

We won't ask you a lot about this, but we do want you to get the concepts, and we want you to know these terms because sometimes they're on the certification exam. Primary and secondary intention wound healing is what you're typically dealing with.

So primary intention wound healing refers to a wound that is closed surgically or with steri strips or butterflies or whatever.

This is a surgical incision or a traumatic wound where the edges are brought together and secured by staples, by sutures, by surgical glue, fibrin glue, whatever. As a result, you can see there's minimal tissue defect, minimal defect in the skin surface. So there's not a lot of repair to be done.

You basically just have to knit the edges together.

So healing occurs fairly quickly and predictably in most cases, and you have minimal risk of infection because there's minimal gaps in that barrier provided by the skin. Secondary intention wound healing is wounds you're going to deal with every day. So these are pressure injuries. These are dehist incisions.

These are venous ulcers, neuropathic ulcers. These are wounds that are open.

So either the decision was made to leave the wound open, like sometimes patients come back from surgery and the surgeon says, we left the wound open to fascia level because there was extensive contamination and very high risk of infection. So you have an open surgical wound.

Other times it's something like a pressure injury, or it's an incision that was initially closed and now has opened up and the decisions made, leave it open, let it close from the inside out. So you've probably heard that terminology, let it close from the inside out.

That means this wound is going to close through the processes of granulation, tissue formation to fill the defect and epithelial resurfacing. These sometimes are large wounds. Sometimes they develop in patients with multiple comorbid conditions.

That's what interfered with healing in the first place. So healing is frequently delayed and prolonged because they're open wounds, there's much greater risk of infection.

So we're always monitoring these wounds for infection. We're always ready to intervene if infection occurs, and there will be variable amounts of scar tissue.

So patients frequently ask you, how much of a scar am I going to have? Well, it depends on how big the wound is.

So if I have a wound from here to here and here to here, I'm going to have a significant scar when this wound heals. Now, tertiary wound healing, that is delayed closure.

So occasionally you'll have a patient, they'll come back from surgery and they'll say, we left the wound open to fascia level because of heavy contamination, major risk for infection.

As soon as we get bacterial loads under control, we're going to take the patient back to surgery, and we're going to do delete delayed primary closure.

So you might be dealing with this wound on a temporary basis when it's open, managing that open wound, helping to eradicate bacterial loads and prepare the wound for tertiary intention closure. For delayed primary closure, these wounds are halfway in between primary and secondary intention wounds in terms of risk of infection.

While they're open, of course, they're much higher risk for infection. Once you close them, hopefully the risk goes down.

The amount of scar tissue that forms is usually greater than that in a primary intention wound, but much less than one healing by secondary intention. As a wound care clinician, your primary work is going to be in wounds healing by secondary intentions.

We're going to speak spend most of our time talking about that.

Now, just to reiterate, the mechanism by which any wound heals is dictated and determined by the tissue layers involved and the ability of those layers and structures to regenerate.

So if you have a wound that involves epidermal loss and partial dermal loss, it's going to heal by regeneration because epidermal structures regenerate. Most dermal structures regenerate.

The only dermal structures that cannot regenerate are your epidermal appendages, the hair follicles, sebaceous glands and sweat glands.

So if the wound is confined to loss of the epidermis and partial dermal loss, it's going to heal by regeneration, it's going to heal quickly, and everything's going to go back to normal. It will look the same and it will function the same.

If you have a wound that extends to the deep dermal structures and you do lose hair follicles, sweat glands, sebaceous glands, that wound is going to heal by scar formation, because now you have a wound that has extended to a level that is no longer able to regenerate, structures that cannot replace themselves. And obviously, if you have a wound that involves subcutaneous tissue, muscle or bone, it heals by scar formation. So surface wounds regenerate.

Deep wounds heal by scar formation.

So if you look at the two pictures on the bottom, you see obviously a wound with depth that extends past the skin layers into the fat and the muscle, and you see athlete. Once that wound is healed, there's evidence that there's scar tissue that's been covered over by skin.

Now, we mentioned briefly in a previous class that repair is different for the fetus during the second trimester.

So if you have an infant who requires intrauterine surgery, and if that intrauterine surgery is done during the second trimester, that baby is going to heal with no scar formation.

We think that's due to increased levels of hyaluronic acid that allows cells to migrate readily and to carry out repair processes quickly, and also to the fact that there's essentially no inflammatory response. And we know that inflammation is linked to scar formation.

So ongoing research to gain more understanding into how is it that those little ones heal so quickly and without scar? What can we learn from that in managing wounds and everyone else?

Now, when we talk about wound healing, we're going to divide it into partial thickness repair. Those are the wounds that heal by regeneration.

Because, remember, partial thickness wounds, by definition, are wounds that involve partial loss of the skin layers.

So loss of the epidermis may be partial loss of the dermis, but preservation of the deep dermal structures, preservation of the hair follicles and sweat glands and sebaceous glands. These wounds are characteristically very superficial.

So many times they have very irregular edges and there's no measurable depth because you've just lost the epidermis or maybe a little bit of the dermis. So very shallow, very superficial. They typically have a pink red wound base.

If the wound extends into the dermis, remember, the dermis is heavily collagen. Collagen is white. So if it extends into the dermis, instead of being pink red, it will probably be pink white.

You might see distinct red dots that represent the basement membrane of the epidermis. So you might have kind of a pale wound bed with distinct red epithelial eyelids across the board.

If the patient has intact sensation, they will report these wounds as being painful, because when you take off this outer skin, you expose all those nerve endings. And these wounds are very sensitive, so they typically feel much better once you dress them.

So we're going to go through the repair process for these wounds, and then we're going to talk about the things that you as a clinician can do to promote the repair process. So first thing you should know is that these wounds usually heal pretty quickly, and they usually heal even if they're not managed optimally.

But if you do manage them appropriately, they will heal faster. So what happens first is that there's a brief inflammatory phase in response to skin loss, and that results in crust formation.

So you think about when you've scraped your knee, scraped your elbow, what ends up happening? You get a thin layer of serous fluid on the surface of the wound that dries to form a crustace and then dries further to form a scab.

If you leave it open to air. So you've got that brief inflammatory phase that is complete within hours. Then the first major phase is epithelial resurfacing.

So you have a defect in the skin. You need to resurface that defect. How does that happen?

So all of the keratinocytes in the wound bed, the epidermal cells in the wound bed and in the surrounding tissue undergo a proliferative burst. So they reproduce at a faster rate and they begin to migrate across the wound surface. So all the epidermal cells, they get an alert look.

We have this major defect. We've got to get this covered. They start to reproduce at a faster rate.

They actually develop little pseudopods, which is like cell feet, that allow them to migrate, and they begin to migrate laterally across the wound surface. As they begin to migrate across the wound surface, they attach to the open wound bed, to the extracellular matrix in the wound bed.

Once that cell attaches, attaches to the wound bed, and in response to growth factors within the wound bed, that cell moves out of the resting phase and into the active reproductive phase of the cell cycle. So the cell has broken its attachments to surrounding skin.

Cells developed, little feet migrated onto the wound surface, attached to the wound surface. Then it moves out of the resting phase and produces another cell.

So now that cell does the same thing, develops little feet, migrates, attaches, reproduces, and you gradually resurface the wound and the cell. I mean, the wound goes from red and wet, which is what you see on top, to pink and dry, which you see on bottom.

And new epithelium for all of us is that pepto bismol, pink and dry, it never matches anybody's skin color. Now, what are the factors that affect the rate at which that wound is going to resurface?

The rate at which the skin cells migrate, attach, reproduce, migrate, attach, reproduce. First of all, keeping the surface moist. And what we have found is that if you keep the wound surface moist, the cells start to migrate.

You start to get this resurfacing as early as 8 hours post injury.

Now, I want to go back just a little bit to how we learned about the importance of a moist wound surface, because a lot of you grew up during the years when our thinking was that we should leave wounds open to the air, we should allow scabs to form. And so you probably remember growing up with scabs.

And if you remember, the scabs would first start to lift at the periphery, and of course, they would itch and annoy us. And so then what did we do? We picked in our scabs. We all did.

And we picked the scab off, and then we got a new wound, but it was smaller than the old wound, and our new scab was smaller than the old scab. And the process repeated until finally we had just a little tiny central scab. It fell off and the wound was healed.

Now, what we have learned is that when a scab forms, it blocks migration of the skin cells, because you've got this scab adherent to the wound bed.

So what the cells have to do is burrow down to a moist layer, produce an enzyme, start to lift the scabs so they can migrate a little bit, stop, make enzymes, lift the scab, migrate. And that's why the wounds always healed from the outside in. If you think about wounds covered with scabs, they always healed from the outside in.

Well, that was standard of care for many, many years.

And then back in the sixties, scientists named Winter started thinking, and he said, you know, I think wounds would heal faster if we kept them moist. People were like, well, why would you say that? No, that's not right. Why would you say that? And he said, well, think about it.

Every cell in our body that is living lives in a fluid environment. How do cells live? They live through exchange with the fluid outside the cell. So they're all used to a fluid environment.

And they were like, no, no, no. The skin, those cells are dry. He's like, yes, but those surface cells, they're dead.

So the living cells, they're still surrounded by a moist environment. His fellow scientists are like, no, no, no.

If you let those wounds get wet, they're going to get infected because a moist surface is going to promote bacterial growth. It's like, but think about wounds inside the mouth. They're wet. Think how many times you take a hunk out of the inside of your mouth.

No place with higher bacterial counts, and yet those wounds heal readily. But they dismissed him.

So what he did was he took domestic pigs, he created two wounds on the back of each pig, anesthetized them, created two wounds. One wound he left open to air. The other wound he covered with essentially plastic wrap, saran wrap, to keep it moist.

And he was able to demonstrate that the covered wounds healed, on average, 40% faster than the dry wounds. So then people are like, well, those are pigs. What do you expect? Those are pigs. He's like, pigs.

And humans have a lot in common, especially when it comes to skin. This was at a very different time.

So researchers were actually able to recruit humans who were willing to have surface wounds created and to have wounds managed either in a dry or a wet environment, and they were able to reproduce his results. That ushered in the era of what we call moist wound healing, and that is now the standard of care.

So we know that if we want to promote rapid healing of a surface wound, one of the critical things to do is to keep that wound surface moist. We also know it's important to maintain low bacterial loads across the wound surface because high bacterial counts interfere with cell migration.

Epidermal cells are apparently very picky, and if there's a lot of bacteria on the surface, they're like, no, no, no, I don't want to go there. It's dirty, clean it up. So you want to keep the surface moist, you want to keep bacterial loads low, you want to maintain normal glucose levels.

Hyperglycemia interferes with cell migration and reproduction. And it's important to have normal levels of growth factors and what we call matrix metalloproteases. We'll talk more about those enzymes.

We're still learning about how we go about controlling levels of growth factors and levels of mmps. We know how to create a moist wound surface, maintain a moist wound surface. We have strategies for keeping bacterial counts low.

We definitely can control glucose levels. We're learning about how to control things at the microscopic level.

Now, once you get through phase one, that resurfacing phase, you're going to have a wound that's covered by new skin. It's going to be pink, dry, just a few cell layers thick and fragile. So what happens next?

The next thing that happens is that area reestablishes normal skin thickness and normal skin function. Now, think about what's been happening.

You've had these little cells that were migrating laterally, so they broke their attachments, developed, feet migrated, attached to the wound bed, reproduced, created another cell that then repeated that same process until the entire area was resurfaced. Once the entire area is resurfaced, a process or a phenomenon known as contact inhibition kicks in. And this is how contact inhibition works.

The cells recognize each other, epidermal cells recognize each other, and they're like, oh, you're one of me. We must have this wound resurfaced. We can go back to standard operating procedure. So what is standard operating procedure?

Vertical migration, contact. I mean, lateral migration to resurface, recognition of another epidermal cell. No further lateral migration. Resumption of vertical migration.

And as the cells migrate vertically, they reestablish the cell layers. All functions go back to normal. You begin to produce melanin. That's one of the normal functions of skin.

The melanocytes become functional again, and gradually the new skin repigments to match the existing skin. Now, if the wound extends into the dermis at the same time that this resurfacing is going on, dermal repair is going on.

And what you see there is by about five days post injury, you get separation between the epidermal and the dermal layers, and you get a layer of fluid accumulating. Then you get collagen synthesis.

And then the last thing that happens, once the collagen repair is complete, you reestablish the epidermal, the REIT ridges, Reet pegs that dip down into the dermis, and you reestablish the dermal papillae. All of that is going on underneath the surface. If the wound extends into the dermis, but you see at the end of it, what do you have?

The collagen has been repaired, so the dermal layer has been repaired.

You have reestablished that interlocking configuration between the epidermis and dermis, and the surface has been reestablished with newly migrating epidermal cells, and then vertical migration to reestablish normal skin thickness. So at the end of the repair process, everything looks the same, everything works the same as before the injury.

So when you have a surface wound, putting it all together, what do you want to do? You want to keep the surface moist and protected. You want to maintain normal glucose levels.

If you're concerned about bacterial loads, you would use antimicrobial dressings to keep bacteria under control.

And then when you have a fragile, newly epithelialized wound, you keep that area protected until you have reestablishment of normal skin thickness and normal skin color. Those are the easy wounds. So now let's move into full thickness wounds. So full thickness wounds, by definition, involve total loss of the skin layer.

So epidermis is gone, dermis is gone, epidermal appendages are gone. The wound extends into the fat, the subcutaneous tissue, possibly the muscle, possibly to the bone.

These are the wounds that have to heal by connective tissue repair, also known as scar formation. And there are three major phases to the full thickness repair process. There's the inflammatory phase, also known as the cleanup phase.

There's the proliferative phase, also known as the rebuilding phase, and then the maturation, or strengthening and remodeling phase.

So we're going to talk about each of those, but one thing to think about is when you're talking about full thickness wounds, they could be either acute or chronic. Your acute wounds are going to be your incisional wounds or your wounds caused by trauma, like lacerations.

We actually know a fair amount about the process for acute wound healing because we can reproduce this in the lab.

We can take laboratory animals, anesthetize them, create an incision, create a traumatic wound, and then monitor that wound, re anesthetize the animal, excise the wound at different points, and study it under the microscope. We can manage it under different conditions, study it under the microscope so that we have a good idea as to the timeline for acute wound repair.

And we have very good information about what are the conditions that promote repair and what conditions inhibit repair. But what about chronic wounds? We've already said that they're different.

They're frequently caused by comorbid conditions, or they're caused by an acute wound that failed to heal. So obviously, something's going on systemically, and chronic wounds are a lot harder to study. You can't create a chronic wound.

And if you post an advertisement for, you know, a diabetic pig who smokes and who has a chronic wound to show up in the lab, they do not respond.

So what we've had to do is take what we know about acute wound healing and what we observe to be different in chronic wounds and kind of put those together to figure out what's different about chronic wounds and what are the implications for management.

So we tried to think about what's the best way to present this, and we decided what we would do is we would first walk through full thickness wound healing, and acute wounds go through what we know very well, and then we'll talk about how it differs for chronic wounds. So here's what we know about full thickness repair and acute wounds.

So you're thinking surgical incision, thinking a traumatically induced wound, like a deep laceration. The first phase of wound healing is going to be the cleanup phase, the inflammatory phase. And in an acute wound, it's a pretty short phase.

It's usually one to four days. Why is it so short? Because what's the goal of the cleanup phase? It's to control bleeding, to establish bacterial control.

Acute wounds typically have pretty low bacterial count, so it doesn't take very long to meet these guidelines and to meet the goals for this phase of repair and move the wound up.

So when you think about phase one, the cleanup phase, you've got to stop the bleeding, you've got to control bacterial loads, establish a clean wound bed, and the two key events are hemostasis and inflammation, and we're going to talk about each of those. So, obviously, goal number one is stop the bleeding. If we don't do a good job with that, there will be no step two.

So we have to do a good job with hemostasis.

And for a patient undergoing surgery, of course, they're going to tie off bleeders, they're going to use the Bovi, they're going to do all of these things to control bleeding. The body has its own set of mechanisms for hemostasis, and hemostasis, from the body's perspective, is initiated by blood in contact with collagen.

So you think about what happens when you make an incision or when you cut your foot or cut your hand. Well, as soon as you disrupt a blood vessel, that blood comes in contact with collagen and that activates the clotting pathways.

In addition, injury causes a brief period of vasoconstriction, which narrows the vessel and supports hemostasis. So you've created an incision or you've sustained a traumatic laceration.

Now, you have blood in contact with collagen and you have narrowed blood vessels.

So while the surgeon's tying off bleeders, or while you're holding pressure on your lacerated hand or foot or whatever, the body's like, okay, I'm on board, here's what I'm doing. So, blood in contact with collagen activates platelet aggregation. So the platelets start to clump together and you get a fibrin clot that forms.

Now, that fibrin clot helps to seal the hole in the vessel, and it also provides a temporary scaffolding that lets cells begin to migrate into the area of injury and begin the repair process. So injury, blood, contacts, collagen, activates clotting pathways, causes platelets to aggregate, causes fibrin clot formation, seals the vessel.

We're doing everything we can to help by pressure that reduces blood flow through the vessel and allows that clot to form, or by tying off bleeders, which is what the surgeon does or using the bovie.

Now, here's a very important aspect of wound repair that we didn't even learn about until the eighties, I think is when we learned about the seventies or eighties, when the platelets degranulate. When the platelets begin to clump together and platelet walls break down, it causes release of growth factors.

And growth factors are substances that attract the cells needed for repair and essentially control the wound repair process. So I think of growth factors as the first guy on the scene of a major accident. And what does the first person on the scene of a major accident do?

They get out their cell phone, they call 911, they get the police headed to the site.

They determine whether or not, or they tell the police whether or not an ambulance is needed, whether or not it looks like there's a fuel leak and fire department might be needed. So they mobilize all the resources. What do the growth factors do?

As soon as the platelets break down and release the growth factors, the growth factors start to attract the cells needed for repair. That's critically important.

If you have growth factors on site, they're going to keep the wound on track, and they play a critical role in assuring normal process and wound healing.

We found that if you have a patient with impaired clotting, the platelets don't clump, they don't degranulate, they don't release growth factors, and you get delayed healing. Goal number one, stop the bleeding, release the growth factors, start sending out signals to the cells needed for the repair process.

Goal number two, establish a clean wound bed. So get bacterial loads under control, break down any necrotic tissue, and get it out of there.

Now, the timeframe for this inflammatory phase, this cleanup phase, is normally about three days. And the processes that support the cleanup phase, first of all, you get vasodilation in response to trauma.

So in response to trauma, you release histamine. Histamine causes the vessels to dilate.

After that brief constrictive phase, when the vessels dilate, it takes more blood, more oxygen to the wound bed. The bloodstream provides transport for the white blood cells that are needed for wound cleanup.

And the growth factors send out chemical signals actively attracting the white blood cells.

So you've got increased blood flow, more blood, more oxygen, more white blood cells, and you've got a chemical signal attracting the white blood cells into the wound bed. Now, the first white blood cell to arrive is the neutrophil, the polymorphonuclear leukocyte.

They can be detected in the wound bed within two minutes of injury, which is pretty amazing. That is pretty darn quick.

So they get there and they immediately establish a perimeter to keep bacteria out, to start breaking down bacteria within the wound bed. So we consider them the first responders in terms of the inflammatory response, in terms of the immune system.

Within two to three days, the macrophages start to arrive.

Remember, they are derived from monocytes, so they don't get there as fast, but they start to show up about day two to three, and they kind of take over from the neutrophils. They can phagocytize the bacteria. They can also break down the necrotic tissue, and they can produce growth factors to keep the wound on track.

You also get t lymphocytes in higher numbers in the wound bed, and they help to control viral loads within the wound bed. So the whole immune system is on board doing cleanup. So putting it all together, phase one, the inflammatory phase, is all about hemostasis.

So stop the bleeding through platelet aggregation and clot formation. Platelet aggregation causes release of growth factors. Growth factors attract the white blood cells to the wound bed.

The white blood cells are responsible for breaking down necrotic tissue, controlling bacterial loads, and establishing a clean wound bed. The critical cells, the polymorphonuclear leukocytes, are critical for early defense, but the most critical cells are the macrophages.

And what we know is if you have a patient who is neutropenic and has very low levels of monocytes and therefore very low levels of macrophages, they do not heal their wounds normally. Now, what do we see clinically?

Because we're looking at a wound clinically, and we're trying to relate this to what's going on internally at the wound bed.

So during that inflammatory phase, that brief cleanup phase, it's normal in the early days after surgery or after you have undergone closure of a maceration, of a laceration, or even if the laceration is left open, it's normal to find Mildred erythema around the incisional border or around the wound edges. But typically, it resolves pretty quickly, because, remember, the inflammatory phase in an acute wound lasts about one to four days.

So by day three, that erythema should be subsiding, the tenderness should be starting to get better, the amount of edema should be starting to diminish.

But what if day four, you see persistent, worsening, extending erythema, increasing in duration, increasing tenderness, increasing edema, that tells you that you've got a developing infection. So normally, you see all the inflammatory signs subsiding.

By day three to four, if you see persistent erythema, then you know you have a wound that is developing an infection and is high risk for dehiscence. Now, what are the factors that impact on the duration and the severity of the inflammatory response?

What are the things that could cause delayed healing? Well, anytime you have high bacterial loads.

So if you do sustain a laceration when you get to urgent care or to the emergency room, one of the first things they're going to do is they're going to do high volume irrigation to try to flush everything out of the wound bed. If there's any dead devitalized tissue in the wound bed, they're going to debride that away.

If there's any foreign bodies, they're going to eliminate them in order to control the inflammatory phase. So high bacterial loads, if it's a contaminated wound, it's much higher risk for a prolonged inflammatory phase.

If there's dead tissue in the wound, that prolongs the inflammatory phase. If there's ischemia, because what's the whole mechanism by which you get white blood cells to the wound bed? Vasodilation. So normal blood flow.

In addition, what do the white blood cells use to kill bacteria? Oxygen. So you think about white blood cells marching around with their little machine guns?

Well, if they don't have any oxygen, they don't have any ammunition. So you need white blood cells, which means you need blood flow and normal levels of white blood cells being produced by the bone marrow.

You also need oxygen in order for the white blood cells to engulf and destroy bacteria. So ischemia is going to delay healing. It's going to prolong the inflammatory face. What about hyperglycemia?

What impact does that have if you have a poorly controlled diabetic? Well, it turns out that when your glucose levels are high, especially if they're over 180, your white blood cells are dysfunctional.

They're very sluggish. It's like they're in a post dinner coma. And so they see the bacteria, but they're not actively engulfing the bacteria.

So you have white blood cells on site, but they're not doing a good job of controlling bacterial loads. The continued presence of bacteria promotes ongoing inflammation.

So you get a wound that is stuck in the inflammatory cycle but not making much progress in establishing a clean wound bed.

So high bacterial loads of dead tissue, poor blood flow, low oxygen levels, high glucose levels, all contribute to prolonged inflammation, as does high levels of pro inflammatory cytokines. And we're going to talk more about that as we talk about factors that influence wound repair at a regulatory level.

What's the impact, what's the impact of a prolonged inflammatory phase? So does it matter if it takes two weeks to get through the inflammatory phase instead of four days? Yes. First of all, the wound does not move forward.

You do not start to form granulation tissue. You don't start to heal the wound until a clean wound bed is established.

So if you have a prolonged inflammatory phase, it means you have a delay in wound healing, and that places the wound at very high risk for dehiscence. So when we see infected incisions, those are wounds that are very likely to fall apart to dehis.

In addition, we know that the intensity and the duration of the inflammatory phase is directly linked to the amount of scar tissue. So the longer the wound is stuck in the inflammatory phase, the higher risk that patient is for excessive scar tissue formation.

Okay, well, let's say this wound is healing normally. So let's say this is an incision. So you went to surgery, you had the incision, you came back. Hemostasis, no problem.

By the end of the surgical procedure, there was no active bleeding. Hemostasis was complete. So you know that what's happening during those next few days is that you're getting increased blood flow to the wound.

You're delivering white blood cells to the wound. In response to the growth factors, the white blood cells are breaking down bacteria, eliminating any little bits of unhealthy avascular tissue.

And the macrophages are also producing growth factors that attract the fibroblast to begin phase two of the repair process, which is the proliferative or rebuilding phase.

So the key events in this phase are epithelial resurfacing, granulation tissue formation, and if it's an open wound, contraction that occurs only in open wounds, we'll cover that. So let's talk about epithelial resurfacing. And we're going to start with incisional wounds that are closed.

So if you have a wound that is closed at the surface, it's closed with sutures, it's closed with staples or with fibrin glue, you have this minimal epidermal defect. So goal number one is to reestablish an intact barrier that keeps bacteria out.

And so you want the keratinocytes or the epidermal cells on either side of the incision to start to reproduce and feel that little defect between this side of the incision and this side of the incision that actually happens, typically within two to three days postoperatively, is that defect gets filled with new epidermis from the migrating keratinocytes. So you think what's happening, you've got trauma that activates epithelial proliferation. The little skin cells do just what we said.

They grow feet, they crawl across, they attach, they make a new skin cell.

The same thing happens until you've got skin cell meeting skin cell, and then they go back to standard operating procedure, vertical migration, minimal defect, very little time required to resurface that minimal defect, usually complete within two to three days. Most agencies have protocols for keeping new incisions covered with a dry, sterile dressing for the first two to three days. Some surgeons will.

Instead, they'll use fibrin glue or they'll use some kind of plasticizing agent to cover that incision for the first few days until epithelial resurfacing is complete, because they want to maintain that bacterial barrier.

Now, what if, instead of a closed incision, what if you have an open laceration, and when you got to the emergency room, they're like, wow, this is a very contaminated laceration. We don't feel comfortable closing it. There's too much risk of infection. We're going to leave it open. We're going to let it close from the inside out.

You cannot get epithelial resurfacing in that case, until the wound fills with granulation tissue. So if you had an open wound, epithelial resurfacing would be delayed until granulation formation was complete.

Okay, so let's assume we're talking about our surgical incision. So now we have epithelial resurface, and what's the next thing that has to happen?

Well, you have to knit the defect in the deeper tissue layers, so the keratinocytes are going to mend the defect at the skin surface. But, of course, your incision extends through the fat, through the muscle.

And so you have to make enough granulation tissue, enough new connective tissue to mend that defect all the way down across the entire incisional line. What's the timeframe again?

You don't have to make a lot of granulation tissue to mend the defect because the surgeons already pulled the muscle layers together, pull the fat together, pull the dermis together. So requires just a small amount of connective tissue, glue or granulation tissue formation to knit those layers together.

It usually starts about day five. Postoperatively, it's usually complete by day 21. Usually peaks between day nine and day 15. How do you know what's going on?

Well, you know, because you've studied this class, and so you know what you expect to be going on, but also tipping typically between day five and 15. Not usually as early as day five. I would say more like by day nine to 15.

Usually, if you palpate along the incision, you can feel a hard edge, and they call that a healing edge. Sometimes the patient will say, feel my incision. It feels hard along there. Is that okay? It's better than okay. It's great.

It means that you're making that new tissue to that defect. So that's the healing ridge.

So, in a closed wound, like a stapled or sutured incision, granulation tissue formation occurs quickly between about day five and day 21, and then it's essentially complete.

But if you had an open wound, if you had a large laceration that was left open to closed from the inside out, it's going to take longer because you have to make more granulation tissue to fill the defect. So, very predictable in a closed wound, extremely variable in an open wound. Now, what are the key processes involved in making granulation tissue?

The primary ones are neo angiogenesis and then synthesis of new connective tissue proteins, also known as the extracellular matrix. So let's talk about what's involved there. So when you look at granulation tissue, it's going to be that bumpy, red granular tissue.

One component of granulation tissue is your new capillaries. Okay? And they form in loops. So that's neoangiogenesis. Break it down. Neo is new, angio is blood vessel. Genesis is formation.

So formation of new blood vessels. How does this happen?

Well, all the endothelial cells in the vessels adjacent to the open wound and in the wound bed start to migrate and to form hollow tubes. So they line up like this, and they form hollow tubes that eventually connect to existing capillaries. What causes that to happen?

Well, first of all, you have specific growth factors that target the endothelial cells and stimulate them to begin to reproduce and to line up in this fashion that forms the new vessels. Hypoxia that is typically present in the center of the wound is another stimulus to neoangiogenesis.

So the wound itself is a stimulus to neoangiogenesis. And the growth factors that are produced when the platelets break down and by the macrophages also contribute to and control that process.

What are the factors that interfere with neo angiogenesis and would interfere with healing? Well, if you have prolonged hypoxia, then that oxygen deficit interferes with the cell's ability to reproduce. So temporary hypoxia is a stimulus.

Prolonged hypoxia actually interferes with your ability to respond because you can't make new cells without oxygen. Oxygen fuels the repair process. What about diabetics with poorly controlled glucose levels? Yes.

Hyperglycemia interferes with your ability to establish new blood vessels. Do you know how we're always telling diabetic patients that if their glucose levels are poorly controlled, they're not going to heal normally?

You've already heard multiple ways in which hyperglycemia interferes, interferes with keratinocyte migration, interferes with white blood cells ability to engulf and destroy bacteria, interferes with the formation of new blood vessels. We have to control glucose levels.

And finally, of course, if your patient was on any kind of cytotoxic therapy, if they're getting radiation therapy or chemo, they're not going to do a good job of making any kind of new tissue because you're actually breaking down new cells and interfering with new tissue development. And unfortunately, advanced stage slows the rate at which you produce new blood vessels.

So when you have much older patients and you're managing their wounds, is it going to take them longer to heal? Yes, it's going to be a slower process. Now, fortunately, activity helps to overcome the negative impact of age.

So if you can just get these people up, moving around, they're going to do a better job of healing their wounds.

Okay, so granulation tissue is composed in part of new capillary loops, but the other component of granulation tissue is new connective tissue proteins, collagen, glycosaminoglycans, glycoproteins. Unfortunately, no elastin. So lots of connective tissue proteins, but no elastin. So explains why scar tissue is rigid. It's not very soft.

So what stimulates collagen synthesis and glycosaminoglycan synthesis? And proteoglycan synthesis? Well, remember those growth factors?

So, growth factors that are secreted by the macrophages actively attract fibroblasts to the wound bed. They upregulate binding sites on the cell membrane of the fibroblast. That encourages the fibroblast to migrate into the cell bed.

So first they recruit fibroblasts. Hey, we need you over here. Get over here. We have this big wound.

Once the fibroblasts arrive in the wound bed, the level of growth factors changes, and that changing level of growth factors converts the fibroblast, so that instead of becoming migratory fibroblasts, now they're stimulated to synthesize collagen. So first they're attracted, and then they're converted to fibroblast, focused on collagen synthesis.

So you can see again what an important role growth factors play, and you can see why wounds that have very low levels of growth factors or no growth factors, are very slow to heal. Now, let's talk a little bit more about collagen synthesis, this production of this extracellular matrix.

Fibroblasts are the only cell in the body that are able to synthesize connective tissue proteins. So you absolutely have to have functional fibroblasts to heal a wound.

And everything you do in wound management should be with the goal of creating a repair environment that is fibroblast friendly. So what do fibroblasts need? First of all, they cannot make collagen out of thin air.

They have to have adequate nutrients, they have to have adequate oxygen. So we've got to assure adequate perfusion.

We've got to control edema, we've got to provide adequate protein and adequate calories to supply the repair process and support the repair process. We also have to avoid anything that is toxic to fibroblasts.

So some of the antiseptics that have very commonly been used to prevent infection in open wounds have been determined to be toxic to fibroblasts. So high levels of iodine, betadine, toxic to fibroblast. High concentrations of daikin solution, toxic to fibroblast.

So if you're trying to get a wound to heal but you're dumping concentrated iodine or highly concentrated dacins into the wound, you're saying one thing, but you're killing off the fibroplast. And they're the only guys that can make the new tissue. So we have to be very careful and very selective when we're using antiseptics in open wounds.

Now, what about development of tensile strengthen?

So when collagen is initially synthesized, it's just like these little gel strands, collagen, proteoglycans, whatever, all of these little connective tissue proteins, they start out as little gel strands and then gradually they undergo a process of cross linking where the gel strands are linked to each other to provide tensile strength. But there's things that interfere, interfere with cross linking, interfere with tensile strength. And you're not going to be surprised.

Here are the things we've already talked about, high glucose levels. So again, we've got to manage our diabetics effectively. What if there are low oxygen levels?

You're not going to cross link normally, you're not going to develop tensile strength. What if you have a patient on high dose steroids that also interferes, and we know that those wounds do not heal?

And interestingly, deficiencies of a lot of your micronutrients, like vitamin C and iron and copper, interfere with cross linking. So what have we got to do? We've got to ensure adequate perfusion and oxygenation. We've got to control glucose levels.

We have to provide the critical nutrients if we're going to get those wounds to heal. Now, the type of collagen that is initially formed is type three collagen, which has very low tensile strength.

But as we've just said, it gradually undergoes modification, cross linking to become type one collagen, the type normally found in intact tissue.

There's one difference, though, in healthy tissue that's never been injured, type one collagen has an open basket weave design that is never reestablished. So yes, you get collagen formation. Yes, it's gradually converted to type one, but it's not quite the same. It lacks elastin.

It doesn't have the same elasticity, suppleness. It doesn't have exactly the same configuration. Now what about contraction?

Now contraction is a phenomenon that involves pulling the wound edges together. Now you're not going to get that in a sutured incision, a stapled incision, because the wound edges have already been pulled together.

But in an open wound, contraction can play an important role in speeding up the repair process by pulling the edges together. The mechanism by which contraction occurs is not clearly defined.

Some evidence that maybe the fibroblasts reorganize and they start to shrink the newly formed extracellular matrix. There's another thought that the modified fibroblasts can produce actin, which is a contractile protein.

And then you could have a strand attaching here and here, pulling here, here, pulling. That would gradually reduce the size of the wound.

We do know that contraction, the rate at which contraction occurs and the amount of contraction is affected by the mobility of the adjacent tissue. So in an abdominal wound and a sacral wound, contraction can play an important role.

But if it's a wound over a joint, then there's going to be limited mobility. And in fact, we don't really want contraction to occur over a joint because it could cause limited joint movement. It can cause a contracture.

If I have a facial wound, I don't want to get contraction because it can cause cosmetic defects and functional defects.

So if you go to the emergency room and you have a laceration on your arm and it's contaminated, they might decide to just let that heal on its own, fill in, contract, resurface.

But if you have a comparable wound on your face, they will always close it in order to prevent excessive scarring, loss of normal function, cosmetic defects. So you never want contraction over a facial wound. The last phase of full thickness wound healing is the maturation phase.

And during this phase, your scar tissue gains tensile, strengthen strength and it gradually undergoes conversion from that type three collagen to the type one collagen. Now, your goal is to establish a strong, mature scar. You hope that it's going to be strong, but thin.

Is that scar ever going to be as strong as the original tissue? And the answer is no. At best, that scar tissue will be 80% as strong as the original tissue, so it's never as strong as the original tissue.

Formation of maximum tensile strength can take up to a year, but most tensile strength is gained within the first three months. So you see that you get 20% of normal strength in about three weeks. You get 80% of normal tensile strength in about three months, and that's maximum.

So hopefully you heal normally and you end up with a fine, thin, strong scar. But there can be complications, and the two most common complications are hypertrophic scars and keloids.

Now, hypertrophic scars are what you see on the top slide. So those scars are raised very obviously, frequently itchy, but they're confined to the original boundaries. They don't extend beyond.

So if your incision started out being 6 cm long and 3 cm wide, you can get a raised scar involving that area, but it doesn't become 9 cm by 6 cm. Hypertrophic scars are common over joints, and that can be problematic because they can form contractors. Keloids are different.

So keloids are like scar tissue tumors. They're like granulation tissue tumors. They extend beyond the original boundaries.

So you can see people who had a piercing, and they end up with this huge keloid that extends way beyond the original boundaries. And what happens is the body just gets locked into granulation tissue formation and never moves out of that and just makes more and more and more.

Keloids are much more common on the trunk and the ear lobes. You don't see them as much on the extremities. The good thing is you don't have any myofibroblasts, so you don't get contractors.

They're typically nothing itchy, but they're very obvious, and they create deformities, essentially. So who's at risk for hypertrophic scarring? Keloid formation, and what can we do about it?

Well, we know that skin pigmentation plays a role because people with lightly pigmented skin have much lower incidence of hypertrophic and keloidan scars. Not like it doesn't occur, but not nearly as often.

The more darkly pigmented the skin, the higher the risk for hypertrophic and keloid scars, for reasons we don't really understand at this point? Definitely heredity plays a role.

So if other people in your family have had surgery and have developed hypertrophic or keloid scars, you're much more likely to do so than if no one else in your family has that other things are easier to control. So how much mechanical stress was there on the wound? So let's say I have an abdominal wound, I'm morbidly obese, and I have chronic lung disease.

So there's a lot of mechanical tension on my wound, and I'm coughing, coughing, coughing, a lot of mechanical tension. It's going to take more scar tissue to heal that wound.

And so I'm higher risk for hypertrophic scarring if there was a lot of mechanical stress that the wound was exposed to. And remember we said that if you have a prolonged or very intense inflammatory phase, it's linked to increased scar formation.

do? We know more than we did: 2030

We don't have all the answers yet.

One thing that you'll see used a fair amount is silicone sheet dressings, and they affect water consumption, concentration, and in turn affect the help to flatten hypertrophic scars. Much more effective with hypertrophic scars than with keloids. Steroid injections.

Now, steroid injections make good sense because what do steroids do to wound healing? They slow the repair process. They interfere with repair. Right. Well, what are keloids and hypertrophic scars?

They're an overabundance of granulation tissue formation. So steroids can damp that down and help prevent recurrence.

So sometimes you'll see a patient, they take them in, they excise the hypertrophic or the keloid scar, and then they inject the area with steroids to keep it from happening again. Pressure dressings also can help flatten out that tissue. And as we've already said, sometimes it comes down to surgical excision.

They have sometimes used radiation therapy, but that's not that common.

So what you're likely to see is on the prevention side, silicone sheet dressings that can be used for months to help flatten hypertension, trophic scars. If you have a scar that does not respond to that or if you have a keloid, it's probably going to be surgical excision and steroid injections.

So we're going to summarize what we've covered so far, and then we're going to move in the next class into talking about chronic wounds and regulation of the repair process. So what have we talked about so far? We've said humans have two ways to repair. They can either replace the lost tissue with more of the same.

That's known as regeneration, or if the wound involves tissues that are not capable of regeneration, you heal by scar formation, fill the defect with granulation tissue with new connective tissue proteins, cover with skin partial thickness wounds. Those are the ones confined to skin layers. Those are the ones that heal by regeneration. They usually heal quickly if managed correctly.

The major components of the repair process, epithelial resurfacing, then reestablishment of the normal thickness to promote healing. You want to maintain a clean, moist wound surface, manage your bacterial loads, control glucose levels. Full thickness wounds.

Those are wounds that extend through the deep dermis, into the fat, into the muscle, into the bone. Those are wounds that cannot regenerate. They're forced to heal by scar formation, so they'll fill with granulation and cover with new skin.

So you can have either acute or chronic full thickness wounds. The best example of an acute full thickness wound is a surgical incision or a laceration. Three major phases of healing.

Phase one is hemostasis, establish control of bleeding and inflammation to establish a clean wound bed. Phase two is proliferation, which is filling the defect with granulation tissue and covering with scar tissue.

And phase three is maturation, which is production of scar tissue with maximum tensile strength. Maximum tensile strength is no more than 80% of the original. Okay, so that's it for this part of wound healing physiology.

In the next class, we'll go on to chronic wounds. Okay, so now we're going to talk about the repair process for chronic full thickness wounds. We're going to talk about regulation of wound healing.

And then in another class, we're going to talk about factors that impact on wound healing from a systemic level. So we're going to talk about how chronic wounds differ in the repair process as compared to acute wounds.

So when we're talking about chronic wounds, remember you're talking about pressure injuries, diabetic foot ulcers. So your neuropathic wounds, your venous ulcers, or your dehist wounds, your acute wound that fell apart.

So in phase one, the cleanup phase, your goals are the same. You want to establish a clean wound. Bede, you no longer need to worry about hemostasis because these wounds aren't bleeding.

Now, there's a lot of significance to the fact that these wounds aren't bleeding. Remember, with an acute wound, the process of clot formation involves platelet breakdown.

And when platelets break down, they release those growth factors that control the repair process. It's the growth factors that attract the white blood cells, that attract the fibroblasts, that promote establishment of new blood vessels.

So when you have a chronic wound like this, a wound that's just sitting there, it might have looked like this for months. Many times you hear people say, yeah, she's had that for months. So no bleeding, obviously, no growth factors, and no progress in wound till.

So you, as the wound clinician, have to work really hard to get this wound back on track because the growth factors are missing in action. How long does it take to establish a clean wound bed? In an acute wound, it just takes a few days.

Typically, in a chronic wound, it can take weeks to establish a clean wound bede. So it's frequently prolonged. It's going to last until all of the dead tissue is eliminated and until bacterial loads are controlled.

And then hopefully, we can get the wound to move forward into the proliferative phase. Now, notice it's very common for chronic wounds to get stuck in this inflammatory phase.

And our challenge as clinicians is to implement therapies that will move the wound out of the inflammatory phase into the proliferative phase.

One thing that is frequently recommended is to surgically debride this wound, to have the surgeon take the patient to the operating room or to use sharp instruments at the bedside to remove the necrotic tissue, knowing that what you want to do is make the wound bleed so that you will get clot formation, you will get platelet breakdown, and you'll get growth factor release to get the wound back on track. We don't have good data about that, but it makes really good sense from a science perspective. So during the inflammatory phase, what is our focus?

What are we trying to do? We're trying to get rid of all the necrotic tissue. We're trying to reduce back to loads, and we have to manage.

So the wound on the far left, covered with necrotic tissue, you can see that there's evidence of infection. So obviously, high bacterial loads. Now, look at the wound right next to it. It's the same wound a week later. So we've made progress.

We've eradicated the high bacterial loads, at least to some extent, because we no longer have the periwound erythema in duration. We're starting to break down the necrotic tissue.

The third slide, a different wound so you can see that this wound is complicated both by infection and by necrotic tissue throughout the wound bed. A long way to go in getting that wound cleaned up. And then the wound on the far right is at the end of the inflammatory phase.

So now all the necrotic tissue is gone. Looks like bacterial loads are controlled, and hopefully we are ready to move this wound into the proliferative phase.

So how does the proliferative phase differ?

In a chronic wound, you've still got to fill the defect with granulation tissue, you've still got to cover it with epithelium, and you might need contraction to shrink the size of the wound. So, yes, your goals are the same. Fill the wound bed with new connective tissue, cover it with new skin.

But there's a difference in the order of these processes. So with a closed incision, what was the first thing that happened?

You got epithelial resurfacing and reestablishment of that barrier, and then granulation tissue occurred following that to knit the underlying layers together.

But notice that in an open wound, healing by secondary intention, granulation tissue formation occurs first because you have to fill the defect with healthy granulation tissue before the new skin cells can migrate across. So the time frame for granulation tissue formation is going to be extremely variable. In an acute wound, it's five to 21 days.

Well, you can't say that about an open wound because it depends on how deep is the wound, how large is the wound, what's the patient's nutritional status, how well are their glucose levels controlled, how well is the wound bed perfused, what other comorbid conditions are interfering? So you know how families and patients will frequently ask you how long do you think it's going to take to heal this wound?

And usually you go, uh, uh, uh, and then blah, blah, blah. And the bottom line is, we don't know exactly. It depends on all of these other factors, all of which is true.

So critical factors, size and depth of the wound, perfusion, nutritional status, overall health of the patient and their comorbid conditions. But you can see that both of those wounds are going to take a while because they're fairly extensive.

What can go wrong during the proliferative phase? A lot can go wrong.

And this is actually a common challenge in managing chronic wounds, is you may have a wound that fails to transition from clean but non granulating to actively granulating. So yes, you can get a wound cleaned up because you can use antibiotics to control bacterial levels loads.

You can use instrumental debridement, enzymatic debridement, chemical debridement to get rid of dead tissue. So you can create that clean wound bed, but you cannot provide that wound with granulation tissue.

You can't provide it with new blood vessels, new connective tissue proteins, new skin. That has to be done by the body. So using external therapies, I can establish a clean wound bed.

But getting the wound to progress from clean to actively granulating is totally dependent on engaging the body's own repair processes. What about contractions?

So your chronic wounds are almost always open wounds, and contraction can play contributing role in getting that wound to close, pulling those wound edges together. Contraction occurs simultaneously with granulation. So you're laying down connective tissue proteins at the same time.

You're either pulling the edges together with contractile proteins or you're compressing the newly formed extracellular matrix so it's more compact, which in turn pulls the wound edges together. So it can be helpful in open abdominal wounds. It can be helpful in sacral wounds.

Again, we really don't want to see contraction in wounds over joints. Epithelial resurfacing in a chronic wound is going to be delayed until the wound has filled with granulation tissue.

You need a healthy bed of granulation tissue for the skin cells to migrate. Remember, they have to attach to the wound bed, so you need a healthy wound surface. You also need what we call open wound edges.

And we'll talk about this more in some later classes. But sometimes what happens with a chronic wound and you've got delayed healing is that the wound edges close prematurely.

And you can see in this slide on the bottom that the wound edges along the, the top edge of the wound have curled in on themselves. So it's very much like a piercing. A lot of you have head piercings. So if you have a piercing, what happens?

You create a hole, and then what you want to have happen. So imagine that this is my piercing hole. Of course, I hope it's not this big, but you want the skin all the way around the hole to heal, right?

So you should have a hole, and then you should have closed wound surfaces all the way around. Well, that's good with a piercing. But what if that same phenomenon happens around an open wound?

Then you have an open wound that doesn't close because the wound edges have already turned under on themselves, created a closed wound edge, and then you have to take action to create an I open wound edge because remember, to get epithelial resurfacing, the keratinocytes. Keratinocytes have to be able to migrate. And if you have a healed wound edge, they're trapped, they can't migrate. So two approaches.

One is to take a cutting curette or a scalpel and pair the wound edges to create open wound edges. The other approach is to take silver nitrate sticks and burn the wound edges to burn off the occluding epidermal cells.

Again, we'll talk more about that.

The other thing you should be aware of is if you have a very large wound and it's now filled with granulation tissue and you're ready for epithelial resurfacing, that wound might require a graft. So it's not hard to get epithelial resurfacing for relative relatively small wounds.

But there seem to be limits on how far epithelial cells will go before they kind of stop migrating and you end up with a non healing wound. So if you have a very large wound or if you have a wound that fails to complete resurfacing, grafting is one option for management.

What about the maturation phase? Much of that is the same.

So once you get the wound to granulate in and to resurface, then over the next few months, what's going to happen is that that granulation tissue will undergo modification. Type three collagen will be converted to type one collagen. You get that cross linking to provide increased tensile strength.

But remember, we're talking much larger wounds. When you're talking chronic wounds, usually you have much larger surface area.

And remember, the final score is never as strong as the original tissue. So that has implications for us.

If I have a wheelchair bound patient who has ischial wounds, if I allow those wounds to granulate in resurface and cross link, when the wounds healed, it's only 80% as strong as the original tissue, which means my patient's higher risk for recurrent wounds. So I might want to read to consider a plastics referral to see is this patient a candidate for a flap? We'll talk about that in a later class.

What if I have a newly healed pressure injury over the sacrum?

What if I have a newly healed plantar surface ulcer in a diabetic patient who's ambulatory as soon as it's resurfaced, do I want them to resume two hour positioning on the sacrum? Do I want that ambulatory patient walking normal distances in this newly healed wound? No, I want to remember.

It's going to take three months to acquire 80% tensile strengthen.

So I very gradually increase weight bearing time, very gradually increase walking time, because I have to remember that even though it looks healed at the surface, that underlying tissue is, baby tissue has minimal tensile strength. It's going to take at least three months to get maximum tensile strength. Now, we're going to cover just a few more concepts here.

We're going to talk a little bit more in terms of acute versus chronic wounds, and then we're going to talk about the factors that control the repair process and impact on the repair process. So just to summarize, acute versus chronic wounds. Acute wounds occurred as a result of trauma or surgery. They heal rapidly.

They almost always involve bleeding, clot formation, growth factor release, so they heal and predictable manner, and typically with durable closures. So once they're healed, they're usually healed.

Chronic wounds include acute wounds that somehow fell off track at some point and failed to heal normally or durably, or wounds that result from some kind of chronic process like ischemia, venous insufficiency, whatever.

A number of factors contribute to chronicity to this wound that tends to be indolent, that tends to be very slow to heal and very difficult to manage. So first of all, the failure to bleed and the absence of growth factors, we've mentioned that several times. Secondly, systemic factors.

So what if I have a diabetic with poorly controlled glucose levels? Hyperglycemia interferes with every phase of repair.

It interferes with your ability to establish a clean wound bed and control bacterial loads, interferes with your ability to produce granulation tissue and to cross link interferes with epithelial resurfacings. We have to get glucose levels under control.

What if I have a patient with either perfusion issues or severe anemia or severe lung disease so that they're unable to provide the wound bed with adequate levels of oxygen? That's going to have significant impact on the repair process.

Malnutrition will prevent wound repair because how can you make new tissue if you lack the building block? You can't. If you're currently losing weight, getting in inadequate levels of proteins, no way you can build new tissue.

Persistent injury, you can't heal a wound if it's constantly being re injured.

And finally, there are some very interesting differences in the wound fluid associated with chronic wounds and the wound fluid associated with acute wounds. So they did an interesting study where they analyzed the fluid from an acute surgical wound. In this case, it was a mastectomy patient.

She had a drain to one of the bulb devices, and so they literally took the fluid out of the bulb and analyzed it.

And they found that in that acute wound, that surgical wound, there were very high levels of growth factors and very low levels of inflammatory agents. So that wound was programmed to heal. They did a similar thing. They took a pressure injury.

They covered the pressure injury with a transparent adhesive dressing, allowed fluid to accumulate, aspirated the fluid, analyzed it, they found the opposite. Low levels of growth factors, high levels of inflammatory substances.

So you see what an uphill battle you're facing when you're managing a chronic wound. Everything's kind of stacked against you.

So you have to control causative factors, you have to pay a lot of attention to systemic issues like perfusion, glucose control, nutrition, all of those things. You may very well need to do surgical debridement to try to activate bleeding and clotting and growth factor release.

So what do we know about the processes that regulate wound healing? Well, we're learning more every day. For a long time, wounds either healed or they didn't.

One of the ancient surgeons said, I make the wound, God heals them. Well, he was at least giving God the credit when the wound healed.

But I guess God got the blame if the wound failed to heal, which not a bad deal, I guess, for the surgeon.

But with electron microscopy and with our increased level of understanding about the repair process, we're beginning to create a profile that explains what happens in the wound bed, what the critical functions are and what the critical control mechanisms are.

What we've known for a long time is that it's the cells in the wound bed that control bacterial loads, break down necrotic tissue, create new tissues.

So, macrophages, fibroblasts, we know how critically important they are, and we know how critically important it is to avoid therapies that are cytotoxic. We should be working with the white blood cells, with the fibroblasts, not against them.

As we have discussed, we know a lot more about growth factors in cytokines.

So, growth factors in cytokines are substances that either attract cells to the wound bed, repel cells, stimulate cells to reproduce, to carry out specific functions. In general, growth factors are most active during the proliferative phase. Cytokines are inflammatory agents that are active during the cleanup phase.

But what growth factors and cytokines do is they control the cells. So what is it that attracts cells? What is it that stimulates cellular activities? Growth factor levels, cytokine levels. Then we have proteins.

Within the wound bed, there's two major categories. Matrix metalloproteases, known as mmps, and tissue inhibitors of matrix metalloproteases is known as timps.

And what those proteins do is affect the levels of growth factors in cytokines. So you see how this is all working together.

So the proteins control the levels of growth factors and cytokines, which in turn provide direction to the macrophages, the fibroblasts and the other cells involved in repair. So, obviously, this is a pretty complicated process.

Now, we also know that the wound bed itself, the extracellular matrix, those newly produced connective tissue proteins, impact on repair by either supporting cell migration and attachment or interfering with it. And we've talked a lot already about systemic factors and comorbidities, which will be the focus of our next class.

So let's talk about each of the regulatory functions just very briefly by themselves.

So when you look at the cells that contribute to wound repairs, the macrophages, which break down necrotic tissue, control bacterial loads, produce growth factors to attract other cells that control the proliferative phase.

During the proliferative phases, the fibroblasts that make new collagen and other connective tissue proteins, endothelial cells that make new blood vessels, keratinocytes that provide resurfacing. So the cells do the things that we can see with our eyes. They establish a clean wound bed, they produce new tissue, they resurface.

So we obviously need adequate numbers of those cells. We need to avoid cytotoxic therapies, and we have to be sensitive to the potential impact of cellular senescence in our much older patients.

What about growth factors and cytokines? Well, we've already said, we've talked a lot about what they do. They direct cell migration. They stimulate cells to proliferate.

They stimulate cells to carry out specific repair processes. Growth factors and cytokines are produced by the cells in the wound bed.

The platelets, the macrophages, the fibroblasts, all produce growth factors and cytokines. So again, if you have low levels of growth factors, that's one reason for failure to heal.

You actually have to have a threshold level of growth factors to move cells into the reproductive phase of the cell cycle. So these are critical. So you have to have functional cells. The cells are controlled by growth factors.

So you have to have adequate levels of growth factors and cytokines. And the levels of growth factors and cytokines are in turn controlled by mmps and timps.

So most of your mmps, those are enzymatic agents produced by the body itself. They have a number of actions. They create pathways in the tissue that promotes cell migration that can be very helpful.

They can increase or decrease the levels of growth factors and cytokines because they either cause release of growth factors and cytokines or they break down growth factors and cytokines. So if you're in the proliferative phase, you want growth factors to be released, you don't want them to be broken down.

Now, the, the problem is you can take all of the mmps, the matrix metalloproteases.

Some of them are anti inflammatory, but most of them are pro inflammatory, very helpful during the cleanup phase because they create pathways, they attract white blood cells. They help break down necrotic tissue.

If you look at a wound that's healing normally and you track levels of mmphemen, you find high levels of mmps during the cleanup phase. And then as a clean wound bed is established, the MMP levels start to come down.

But if you look at a wound that fails to heal normally, that gets stuck in that inflammatory phase, what you find is MMP levels rise.

And even after the necrotic tissue is removed and bacterial levels are controlled, mmp levels stay high and perpetuate an inflammatory environment that interferes with repair. Lots of implications for management. And we now have some products that can help down regulate MLP's. We'll talk about that in a later class.

What about timps? Well, timps are supposed to control mmps, so their tissue inhibitors of matrix metalloproteases.

So we've said normal to have high levels during the inflammatory phase. As a clean wound bed is established, you want the mmps to move off the field, sit on the bench, allow the proliferative phase to take over.

Timps help make that happen. They bind to the mmps and escort them off the field.

But if you have low levels of timps, it can allow excessive levels of mmps to delay healing a lot. We don't expect you to know details. We want you to get big picture about how complex the repair process is.

We definitely want you to know the term mmps because there are therapies available to you as a wound clinician to down regulate mmps. A couple of last things and then you're going to see that summary slide you're waiting for.

So the wound bed, the extracellular matrix itself, impacts on the repair process. Because remember that cells have to migrate into the wound bed.

They have to attach to the wound bed before they can carry out processes that are critical to repair. So if I'm just floating around in wound filtering fluid, I'm not making collagen, I'm not making you endothelial cells.

To do that, I have to attach to the wound bed, set up my workstation, and now I can start to synthesize collagen. Now I can start to reproduce. So if you have a healthy wound bed, it's going to support the repair process.

But if you have an unhealthy wound bede bed with not many attachment sites, that's going to interfere with repair.

Now, again, as we've learned more about this, innovative researchers have developed matrix dressings that we can actually put into the base of the wound to serve as a temporary scaffolding to promote cell migration, attachment and production of new connective tissue proteins. So something that we'll come back to. There's that slide. So, in summary, chronic wound healing is an uphill battle for you and for the wound.

It differs from acute wound healing in that you have a prolonged inflammatory phase.

There's a prolonged and frequently impaired proliferative phase, and epithelialization is delayed until a healthy bed of granulation tissue is established that is close to the wound surface.

We know that when you're managing a chronic wound, it's very common to have impaired healing, delayed healing or total failure of the healing process. Your goal as a wound clinician is to understand repair, recognize when a wound's in trouble, intervene appropriately.

What are the factors that regulate the repair process? It's the cells in the wound bed that carry out the critical repair processes that make the new tissue.

But it's the growth factors and cytokines in the wound bed that control cellular activity. It's the mmps and timps in the wound bed that control the levels of growth factors and cytokines.

Finally, we have to look at the wound bed itself and its systemic factors. And in the next class, we'll talk about systemic factors in detail. So you're through with this phase. Thank you.