Wound Healing: Mechanism, Types, Primary, Secondary & Tertiary intention of healing & Complications

wound healing is the process where the body repairs damaged tissue following in any type of injury like skin abrasions ulcers cut injuries etc acute wounds usually heal up rapidly whereas chronic wounds take a longer time to heal and sometimes even months according to the regenerative capability tissues in our body can be divided into three categories labile tissues stable tissues and permanent tissues labile tissues contain stem cells these undifferentiated cells can proliferate rapidly and replace the damaged tissue these include epithelia like epidermis of the skin mucosal lining of the gi tract and the epithelium of the geneto urinary tract and hemopoietic tissues like bone marrow stable tissues normally have a very low proliferative activity however they can be stimulated to undergo cell division and replace the damaged tissue following an injury these include parenchymal tissues like liver kidney and pancreas mesenchymal cells like fibroblasts smooth muscle cells and vascular endothelial cells permanent tissues have left the cell cycle and cannot proliferate to produce new cells so if these tissues are damaged healing occurs by fibrosis also known as scar tissue formation and this will lead to loss of function of the affected area these type of tissues includes nervous tissue and skeletal and cardiac muscle tissue so in summary both labile and stable tissues are capable of regeneration while permanent tissues are not some tissues gain their original structure after healing this is called resolution and resolution is the ideal outcome of healing however for resolution to occur the tissue must contain cells which are capable of regeneration such as labile and stable cells and the extracellular matrix framework of the tissue should be intact after the injury if the extracellular matrix framework is damaged the tissue cannot regain its normal structure even when it is capable of regeneration and in resolution there is no associated fibrosis instances where tissues heal by resolution include the following mild to moderate liver injury skin abrasions where only the epidermal layer of skin is damaged acute tubular necrosis in the kidney and gastric erosions keep in mind that erosions are different from ulcers an ulcer extends beyond the epithelial surface including the extracellular matrix it is much deeper compared to an erosion which involves only the surface epithelium the other way of healing is repair it occurs when resolution is not possible in other words when the tissue is not capable of regeneration or when the extracellular matrix framework of the tissue is damaged repairing process involves scar tissue formation also known as fibrosis wounds and tissues which are capable of regeneration will heal by both regeneration and fibrosis for example in massive liver injury the extracellular matrix framework will be damaged so during the healing process both regeneration and scar tissue formation will occur and in gastric ulcers basement membrane of the gastric mucosa and the underlying extracellular matrix will be damaged therefore healing will occur by repair also in deep skin wounds that penetrate both the epidermis and dermis healing occurs by both regeneration and fibrosis permanent tissues that are unable to regenerate except brain will heal by fibrosis only for example following a myocardial infarction the necrotic tissue will be replaced by a scar even though brain contains permanent cells there will be no fibrosis in brain this is because the brain lacks a fibrous connective tissue framework therefore wounds in brain tissue will result in formation of cavitatory lesions these cavities later get filled with cerebrospinal fluid smaller defects will be repaired by a process called gliosis in which the glial cells proliferate and get deposited in the damaged areas they also produce small amounts of fibrillar proteins to fill the gaps in addition to above discussed instances chronic inflammation associated wounds also heal by repair this is due to the extensive tissue damage caused by chronic inflammation itself complex structures like glomeruli skin appendages like sweat glands and sebaceous glands and other structures may not be able to be restored and they undergo fibrosis ultimately so the process of healing depends on three main factors involved tissue whether it is capable of regeneration or not extent of tissue injury whether the extracellular matrix framework is intact and the nature of the injury whether it is persistent and associated with chronic inflammation or whether it is an acute one now let's discuss about the mechanism of wound healing let's take a cut injury to the skin as an example there are three steps in the process of healing hemostasis inflammation and the proliferative phase during this phase some tissues will undergo regeneration only some tissues will undergo both regeneration and fibrosis and some tissues will undergo fibrosis only hemostasis is the initial step to appear following an injury it will prevent further bleeding from the site of injury at first there will be vasospasm to reduce the blood flow to the area then the platelets get activated and they clump together to form a platelet plug finally due to the activation of clotting factors fibrin get deposited on the platelet plug to form a blood clot formation of a blood clot will temporarily stabilize wound edges and prevent further bleeding inflammation is an early non-specific response to tissue injury there are two main goals of the inflammatory response following an injury degradation and removal of necrotic tissue by inflammatory cells mainly the neutrals in macrophages and secretion of chemical mediators and growth factors by macrophages these growth factors are essential for cell division during the proliferative phase proliferative phase have two components cell regeneration and organization or scar tissue formation as we have discussed earlier some tissues may have both of these components and some may have only regeneration or only scar tissue formation as we have discussed about regeneration earlier now let's focus on the organization part there are three main steps in organization granulation tissue formation collagen synthesis and lay down and remodeling of the scar granulation tissue is composed of proliferating capillaries fibroblasts and residual inflammatory cells like macrophages it is metabolically active with formation of new blood vessels and proliferation of fibroblasts therefore granulation tissue needs a good blood supply to meet with the demand conditions where the blood supply is impaired like in diabetes mellitus formation of granulation tissue is defective so as a result there will be a delay in the healing process the process of new blood vessel formation is called angiogenesis and it occurs via two mechanisms one is sprouting out from already damaged vessels and the other one is formation of new capillary network from endothelial precursor cells of bone marrow vgf or vascular endothelial growth factor is the principal mediator responsible for the process of angiogenesis it is secreted by the mesenchymal and stromal cells in the granulation tissue it enhances the proliferation of endothelial cells induces mobilization of endothelial precursor cells from bone marrow and induces maturation of proliferating endothelial cells in addition to vgf there is another mediator called angiopoietin the main function of angiopoietin is stabilization of the newly formed vessels the next step after granulation tissue formation is collagen synthesis and laid down by five problems in the granulation tissue it starts within three to five days following injury and continues for weeks depending on the size of the wound with increasing collagen mass the vascularity and cellularity of the area will be reduced as you can see in this picture in addition to collagen fibroblasts also secrete other extracellular matrix proteins including glycosaminoglycans and proteoglycans scar tissue formation is mediated by several cytokines secreted by macrophages platelets and activated endothelial cells the main one is transforming growth factor beta it induces the proliferation and migration of fibroblasts and increases collagen synthesis it also reduces the breakdown of extracellular matrix proteins by matrix metalloproteinases in addition to tgf beta they secrete other chemicals like platelet-derived growth factor fibroblast growth factor interleukin-1 and tumor necrosis factor alpha all of which increase the synthesis of collagen after formed scar tissue tends to contract therefore size of the scar is usually smaller than the area of injury scar contraction is mainly due to the presence of myo5 problems which have contractile properties formation of the correct amount of collagen and extracellular matrix proteins is called remodeling of the scar during remodeling synthesis and degradation of these proteins occur as parallel processes degradation is mainly due to the activity of matrix metalloproteinases in the early days of scar the predominant type of collagen is type 3 and towards the end it is replaced by type 1 collagen here is an image from robin's textbook of pathology showing the steps in healing okay now i will give you a small activity to see whether you have understood the basis of healing pause the video and write down the way of healing in following conditions take the first one as an example i will post the answers at the end of this video now let's discuss a bit about healing of deep skin wounds depending on the nature of the skin wound healing can be categorized as healing by primary intention healing by secondary intention and healing by tertiary intention healing by primary intention occurs in ideal wounds such as surgical incisions these type of wounds have smooth and closely approximated edges they are properly cleaned and no infection foreign material or necrotic debris present now let's discuss about the steps in healing by primary intention at first the narrow gap between the wound edges is sealed by a blood clot the superficial part of this clot will later become dehydrated which is then called the scab epidermis starts to grow under the scab as indicated by arrows in the picture and establishes the continuity within 48 hours as you can see in the second picture this process occurs via basal cell proliferation and epithelial cell migration from the free edges and it is stimulated by chemicals like epidermal growth factor transforming growth factor alpha and keratinocyte growth factor towards the end of the first week the epidermis grows more and the scab gets separated from the skin in the dermis healing occurs by repair within 24 hours after injury acute inflammation sets in and neutrophils infiltrate to the site neutrophils will then remove the small debris present if there is associated bleeding there will be a clot formation as well towards the later hours of inflammation macrophages will also recruit to the site within 48 hours formation of granulation tissue starts and within 72 hours collagen synthesis starts then the granulation tissue will be gradually replaced by collagen because the wound edges were closely approximated healing will leave a minimal scar at the site of injury here is another image which shows the steps in healing by primary intention healing by secondary intention occurs in open wounds with significant tissue loss such as tooth extraction sockets and severe burn injuries unlike ideal wounds the edges of these wounds are not closely approximated and sometimes the wound can be complicated by the presence of infection foreign material and necrotic debris the mechanism of healing of these wounds however more or less similar to the primary intention but it takes a longer time and there is more scar tissue formation due to the extensive tissue loss skin grafting controlling of the infection and removal of necrotic material may speed up the healing process of these wounds this image shows the steps in healing by secondary intention in healing by tertiary intention or delayed closure the wound is cleaned and purposefully left open due to the high likelihood of being contaminated by bacteria such as dog bite wounds if these wounds are closed early by primary intention it may trap bacteria inside and may lead to abscess formation or even bacteremia and sepsis therefore these wounds are regularly cleaned and closely observed for infection before they are being closed by primary intention now let's see what are the factors that delay the healing of wounds they can be local causes or systemic causes local causes include infection presence of foreign material and necrotic debris poor perfusion and ischemia and tissue irradiation systemic causes include malnutritional status diabetes mellitus which causes defects in microcirculation and long-term administration of glucocorticoids factors that enhance wound healing include treatment with antibiotics to control infection removal of foreign body and necrotic material suturing and skin grafting finally let's see some complications of defective wound healing one is deficient scar formation due to reduced or defective collagen synthesis or defective granulation tissue formation or both deficient scar formation may cause rupturing of sutured wounds due to the increased pressure inside the body such as in conditions like burst abdomen another complication is excessive scar tissue formation like hypertrophic scars and keloids and sometimes healing may result in contracture formation like in healed extensive burn injuries here are the answers for the questions i have given you you