Healing Physiology

Healing Physiology

so let's consider some of the physiological events that are happening during the process of wound healing and the stages in wound healing are the same whether a wound is healing by primary intention or secondary intention the stages are the same it's just a matter of the scale that's different and people classify the stages of wound healing in different ways but first of all let's try and run through and get a feel for their for the events that's happening so here we have er here we have a wound and any wound that penetrates into the dermis or below is going to cause hemorrhage so one of the first things you're going to get is bleeding into the wound so will get bleeding into the wound there will be coagulation the Bloods going to clot so the wound is initially going to fill with blood clot and that's the same whether it's a small wound that can heal by primary intention or a larger wound that's going to need to heal by secondary intention it just means you'll get a thinner layer of blood if its primary intention so here we have a wound filling with blood and this blood is going to clot fairly quickly and one of the first things that we're going to see is that the blood on top is going to dry and form a scab so we're going to get the blood on the top drying forming a scab so now we've got dry blood on top and we've got blood filling the wound cavity now when the tissue is injured that's going to release inflammatory cytokines from damaged tissue cells and as well as that in the blood there's going to be large cells called monocytes and these can also release inflammatory mediators and indeed there's going to be monocytes actually the not monocytes are they what do we call a monocyte when it's in the tissue spaces if we have this cell in the tissue spaces in it monocytes are in the tissue spaces they're called macrophages so around about the edge of the wound the macrophages become aware that there is an inflammatory insult going on and they too will release cytokines so we get the release of cytokines and inflammatory mediators and of course the inflammatory mediators bring about the process of inflammation is going to be inflammatory changes here and we've seen on the inflammation talk how essential this first stage is for healing inflammation is the first stage of the healing process and it's absolutely an essential stage of the healing process we can't skip it there has to be a phase of inflammation initiating the healing process so the cytokines and the inflammatory mediators one of the first things they're going to do is attract lots of neutrophils from the blood so we're going to get infiltration of the wound with neutrophils neutrophils are granule ascitic polymorphonuclear sites and they're going to be attracted into the area of inflammation and into the wound fairly quickly so within about an hour to two hours around about ninety minutes we're going to get quite large numbers of granular CITIC neutrophils in the wound this is good because in the wound that's probably going to be bacterial and of course the neutrophils are phagocytic they can eat and digest these bacteria reducing the risk of infection also because of the trauma there's going to be dead tissue cells and we don't want to leave dead necrotic tissue lying around in a wound because it forms an excellent bacterial habitat the bacteria can get in there they can live in there they can eat the dead tissue cells is their bacterial nutrient nutrient substrate and they can multiply causing infection so it's good that the neutrophils get in there really quite quickly these are the Emergency Response it's kind of a Quick Reaction Force isn't it the neutrophils of the the QRF of the body of the quick reaction force get in there start eating the bacteria start using the dead tissue cells excellent that's good and the neutrophils are also going to release some cytokines as well and one of the things that these cytokines do within 24-48 hours is into the wound it's going to attract a lot more of these large neutrophils so more neutrophils are going to be attracted so more macrophages are going to be attracted into the wound so the neutrophils are releasing the cytokines attracting lots of monocytes which become macrophages in the wound and in the tissues and the macrophages are absolutely vital not only are macrophages the ultimate phagocytosis they'll eat the damaged tissue in any residual bacteria but the macrophages also release growth factors now growth factors are a type of cytokine that are going to stimulate the release of regeneration of the wound by stimulating the mitosis in adjacent cells that can migrate in to facilitate wound healing and one of the first cells that are attracted into the wound as a result of the coordinating cytokine growth factor releasing activity of the macrophages are fibroblasts so in the tissues around about there's going to be fibroblasts these are going to be acted on by growth factors from the macrophages that's going to encourage the migration of fibroblasts into the wound it's going to encourage mitosis of fibroblasts and the migration of fibroblasts into the wound so now we've got fibroblasts in the wound as well so we've had the influx of inflammatory cells and we've had a destructive phase so sometimes this first stage can be called the destructive migratory phase of wound healing after the inflammatory phase because we're getting the migration in of useful cells and we're getting the destruction of the dead material and the back the bacterial meaning that we've got a kind of a physiological cleaning process going on here this is a physiological debridement getting the wound nice and clean and also during this stage the blood clot will start to be removed from the wound now in the blood there is a plasma protein called plasminogen plasminogen is a soluble protein in the blood so when we get a blood clot situation now the blood is escaped from the blood vessels they're still going to be plasminogen in that blood clot in a blood clot the plasminogen over time will be converted to plasmin and plasmon has enzymic activities and what plasma will do is plasma will digest and break up the fibrin strands that compose the blood clot so what you actually have in a blood clot is fibrin strands with red cells sticking to it that's what a blood clot is in over time in the tissues the fibrin strands will be broken down by the plasmid meaning that the blood clot is basically going to dissolve the process will be called fibrinolysis fibrinolysis the fibrin part relates to the fibrin strands and the lysis part means to break up now also in this initial stage if it's a very small wound and the well if the gap between the wound edges is small anyway then in this initial migratory stage you can get the migration of new epithelial cells over the surface over it's a small wound we could have the wound here like in a surgical wound for example here we have the wound and the growth factors released by the macrophages will stimulate the epithelium to grow over and seal the top of the wound re a thelia lies ation and if a wound is well closed for example a surgical wound the epithelium is going to grow over the surface of the wound healing by primary intention in less than 48 hours so 48 hours postoperatively if the wound is healthy not infected and healing nicely it's reasonable to assume that the surface of the wound has realized that's why we can normally put surgical patients in the shower 48 hours after their surgery knowing that the react with utilization will have closed the surface of the wound so we have an inflammatory phase and we have a destructive migratory phase getting the wound nice and clean and the blood clot is gradually being dissolved so here we have the wound now little later on and what's happened now is that the fibroblasts the fibroblasts blast a blast cell is a cell which produces something isn't it so we have fibroblasts in here and the fibroblasts produce collagen and collagen is a high tensile strength protein and it's formed in strands so we're going to get strands of collagen forming in the wound this is good because the collagen strands start holding the edges of the wound together now in any fuel stages while we're still in the inflammatory stage the wound does stick together because the fibrin strands in the blood clot do hold it together to some extent but is a very weak fixation whereas later on when the fibroblasts have been attracted into the wound the fibroblasts start producing collagen and the collins collagen is good holding the wound together so over the next few days we're going to get increasing tensile strength of the wound and the fibroblasts as well as producing collagen also produce something else called the matrix or the ground substance matrix and ground substance mean the same thing and this is a glycoprotein it's a combination of carbohydrates and proteins and it's a sort of a gel and it fills up the gaps between the cells and the collagen strands the ground substance so now because of the activity of the fibroblasts the wounds getting filled with ground substance and also it's being held together by the collagen strands which is good now we've also what we've previously said that in the wound is going to be macrophages derived from the monocytes and the macrophages release growth factors they've released growth factors that have attracted macro sorry the macrophages have released growth factors that have already attracted the fibroblasts into the wound which is good so the first job for the growth factors produced by the macrophages was to attract in the fibroblasts but then the macrophages are amazing cells the release another type of growth factor and this growth factor goes into the surrounding blood vessels so here we have a adjacent blood vessel it's maybe been damaged as a result of the trauma and of course the blood vessels especially the small blood vessels are composed of vascular endothelium in fact all blood vessels are lined by vascular endothelium so these cytokine based growth factors produced by the macrophages are going to affect the adjacent capillaries and they're going to cause the adjacent capillaries to grow into the wound so new capillaries will start growing into the wound this is vital to bring oxygen and nutrients into the wound and the process whereby we get the growth of new blood vessels is called angio neo Genesis angio means to do with blood vessels neo means new Genesis means beginning so it's the growth or the beginning of new blood vessels some books just call it angiogenesis they leave the neo part out so angio neo Genesis or angiogenesis is the same thing it means the growth of new blood vessels into the wound so now we've got the collagen strands the fibroblasts the ground substance the macrophages and now we've got new capillaries growing into the wound as well and also another type of white cell is attracted into the wound the lymphocytes and the lymphocytes when they are proliferated when you get a proliferation of b-lymphocytes that forms the type of cell called a plasma cell so we get the infiltration of plasma cells into the wound and what the plasma cells do is the plasma cells secrete antibodies y-shaped antibodies immunoglobulin molecules providing a lot of immunity so we've got good immunity ready because the macrophages are phagocytic but we get even more immunity in the granulation tissue because the plasma cells produce antibodies this is why granulation tissue is usually very infection resistant and it's the body's healing tissue it's the body's healing tissue now we've noted that the macrophages are going to release growth factors stimulating the fibroblasts stimulating the mitosis of adjacent capillary endothelial cells facilitating the growth of new blood vessels into the wound but the macrophages also release growth factors that stimulate the regrowth of the epidermis so we're going to get regrowth of the epidermis now to be consistent with this previous diagram over the top of this wound we have a blood clot we've got a blood clot there that's essential to keep the cells underneath moist because if the healing cells the inflammatory cells or the young epithelial cells dry out they're going to die so the scab is good because it keeps it moist now in some larger wounds for example wounds healing by secondary intention where there's maybe a large ulceration we still need to keep the wound moussed to facilitate the migration of healing cells but in some wounds you have to do that in larger wounds you might have to put a dressing on that keeps the wound moist we need to keep the wound moist or the healing cells will dry out the young cells will simply desiccate and they'll dry out also because the growth factors released by the macrophages particularly and indeed other cells fibroblasts will release on growth factors but because there's growth factors necessary to stimulate the healing of the blood vessels the regeneration of the epithelium these growth factors are going to be small proteins and they're going to have to be dissolved in the fluids of the wound so if the wound is too dry then the growth factors are not going to be able to diffuse around the tissue fluid of the wound to facilitate the effects on the healing cells that is going to be required in other words we need to allow the wound to heal in its own juice it's a bit crude but that's basically true the wound does to heal in his own juice now at the same time we don't want wounds to be too wet if a wound is too wet we say it's macerated and that can also reduce the efficiency of healing so we need just the right amount of moisture to facilitate moist wound-healing the combination of the macrophages the new capillary blood vessels the college in the ground substance the fibroblasts the plasma cells and the antibodies what do we call that what sort of tissue is this well of course this is granulation tissue granulation tissue is the essential intermediate tissue produced by the body to facilitate wound healing so wounds can heal in one of two ways they can heal by regeneration or fibrosis so we see if we've got a good wound healing environment we are going to get more regeneration there's going to be regeneration of the wound because there's going to be the increased mitosis and migration of the original cells which are going to replace the damaged cells so we're going to get healing by regeneration that's good and the other way that wounds can heal is by fibrosis and fibrosis is the accumulation of more collagen based fibrous tissue which becomes scar tissue so really what we want to do when we're thinking about wound healing is we want to encourage as much regeneration as possible regeneration meaning that the damaged cells are replaced on a like-for-like basis but we have to accept the fact that especially in bigger wounds as well as getting some regeneration there's going to be healing by fibrosis that's why we get scars so as time goes on yes the wound is going to get smaller because there's going to be Renick regeneration and in fact wood started talking about this process of realizations the epithelial cells from the surface of the skin need to migrate in a moist environment underneath the blood clot in this case or in some of the cases underneath the dressing that you provide and the epithelial cells can only migrate over the surface of healthy granulation tissue so we know all this is now granulation tissue that's necessary because living cells cannot migrate over necrotic tissue they must migrate over living granulation tissue and these cells can migrate over the surface three epithelial izing the wound which is good the process of realizations and the more reputable ization we can get the less scar tissue we're going to be left with but we do know in larger wounds we are going to be left with scar tissue so as time goes on we're going to get the formation of more scar tissue that's good because it's a patch it's going to increase the tensile strength of the wound significantly but it is going to leave some some scarring of course so this process is going to go on and this process is often called the proliferation granulation stage of wound healing for the proliferation of cells forming granulation tissue but as time goes on the granulation tissue is going to be converted more and more into scar tissue so the parts of the room which have not healed by regeneration are going to end up with fibrous scar tissue formation so in a sense we've gone from blood to granulation tissue to fibrous tissue so we've said wound healing starts with the inflammatory response goes on to the destructive migrator response goes on to the peripheral proliferation granulation response and then the final stage is often called the maturation or the remodeling stage of wound healing and this can go on for a long period of time this could go on for a year or more after a wound has initially been sustained so in the maturation phase we've still got this is where the wound was over time we can advise patients that your scars will get smaller and will fade now the reason that the scars fade is because the vascularity of the scar will reduce over time so young scars can still be quite red because they've got a lot of blood vessels there's a vascularity older scars the blood vessels are going to retract and the vascularity is going to reduce also within the wound we're going to get rearrangement of the collagen fibers so instead of being a bit higgledy-piggledy like they might have been at this stage where the kind of all over the place because there's constant formation and reabsorption of collagen the collagen is organized in a way which is going to increase the tensile strength of the wound so we're going to get decreased vascularity and reordering of the collagen now the fibroblasts in the wound what they do is they differentiate from being individual fibroblasts into being strips of fibroblasts altogether and when you get strips of eyebrows all together we call these myofibril busts and the reason we call them my Oh fibroblasts is because they look a bit like smooth muscle so we're going to get chains of fibroblasts in the wound called myofibril busts and these are going to be attached to the two edges of the wound and just like smooth muscle but happening much more slowly these myofibril asts will contract and as they contract they're going to reduce the size of the wound that's good because it means that a wound that starts off that size can end up with a scar that's that size a much smaller scar the scar will fade because of reduced vascularity and it will shrink in size because of the contraction of the wound under the influence of the Myo fibroblasts but this can be a problem as well because you get contractures in a scar for example in a burn to the hand the contractions can tighten and cause claw formation or you could get contractures over an elbow which means you lose the mobility of the joint and sometimes we need to surgically intervene to relieve contractures and a great deal of wound care management in burns patients for example is focused on preventing the formation of this scar tissue because we know that that is going to result in my own fibroblasts formation and contractures which could reduce the functional results of the final scar that's produced so this was going to get smaller and reduced in vascularity overtime which is good once the epithelium has closed over the wound once we have Rijeka theorization then this scar sorry this scab the scab over the top will simply slough off so it's best not to pick scabs off when it's time for the scab to fall off when there's been realisations underneath the scar it'll just come off on itself by itself and you'll see this nice new pink epithelial tissue underneath and these principles are exactly the same whether a wound is healing by primary intention or secondary intention you're still going to get the inflammatory phase the destructive migratory phase the proliferation granulation phase and the maturation remodeling phase but our management can be slightly different so we think of a wound here maybe an ulcer healing by secondary intention well yes we're still going to get it filled with granulation tissue which is good the wound will fill with granulation tissue and there will still be re epithelial ization over the surface of the wound here we see some epithelial cells which are dividing moving over the surface of the root increased mitosis in adjacent epithelial cells under the influence of cytokine growth factors from macrophages but I think you can see at this stage here we've got granulation tissue and some repa theory as epithelial ization which is good we want repartee legalization but the granulation tissue and the refr thelia lysing cells are going to dry out unless they're kept moist because we know we need a moist wound healing environment for cellular migration and for the diffusion of the growth factors throughout the wound so in this case we might need to use some sort of dressing that's going to keep the wound nice and moist while this process takes place and of course when we change the dressings we want to make very sure we don't damage the delicate granulation tissue or the delicate Rijeka thelia lized tissue but the stages are the same whether it's a more primary based healing or whether it's a secondary based healing process now this diagram shows the macrophages here in the wound and the macrophages release growth factors the growth factors can only diffuse through the wound if the wound is moist so here we see growth factors migrating towards the capillary endothelial cells it's going to cause the capillary endothelial cells to grow new capillaries into the wound which is essential for the formation of granulation tissue and healing and here we see growth factors also from the macrophages migrating towards these adjacent fibroblasts the growth factors from the macrophages are going to stimulate mitosis in the adjacent fibroblasts and stimulate the fibroblasts to migrate into the wound into the granulation tissue which is essential because the fibroblasts will produce the collagen and the ground substance which is essential we also see here that growth factors from the macrophages are migrating towards the adjacent epithelial cells the cells that form the epidermis and again the arrival of growth factors at these epithelial cells are going to start the process of mitosis in these cells stimulating mitosis and these cells are going to grow to cover the surface of the wound the process of really lies ation and when the cells from this side of the wound come into contact with the cells from that side of the wound is very clever because they inhibit their own further cell division a process called contact inhibition if that doesn't work you can get hypertrophic such as keloid scar formation but physiologically the meeting of the endothelial cells inhibits further endothelial cell mitosis so here we see the growth factors from the macrophages stimulating fibroblasts migration angiogenesis and re epithelial ization this diagram shows the components of granulation tissue so

24 thoughts on “Healing Physiology”

  1. Exellent teaching video for medical students during their surgical rotation! Any MD should have some understanding of wound types and factors that impair healing. Good medicine is based on basic anatomy and physiology. This video is now compulsory exam material for all medical students doing their 12 week surgical rotation with me. Thank you for this content.

  2. Thank you for your very clear explanations Dr J….I recognise a number of your terminologies …sound very military???? do …did you have some connection (QRF) etc mmmm.

  3. @Dr. John Campbell – We are trying to heal some cats that have ended up in our backyard with head wounds. We have washed them, disinfected them and bandaged them by applying paw-paw ointment on the bandages to stop them from sticking to the wounds, but every morning when we removed the bandages to wash the wounds the the granulated tissues that has formed overnight immediately comes off when the cats shake their heads or after we wash their wounds. So, every day is the same problem because the wounds have to start their healing process again without any solution. We have tried not to apply bandages to the wounds to try and speed up the healing process but this is not working either. On the other hand if we try not to wash their wounds every day they start to smell really bad. So, can you give us your urgent advice please? We do not want to put the cats down and would like to give them a chance at healing themselves. .

  4. This is a great explanation! . A step by step , it fills my gaps of understanding to the general wound healing process.
    Thank you dr.

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