Healing and Repair PDF

HEALING AND REPAIR  OBJECTIVES Introduction Proliferative Potential of different cell types Growth factors Extracellular Matrix Wound healing process Wound closure intensions Features affecting wound healing Complication Summary Reference ...

HEALING AND REPAIR  OBJECTIVES Introduction Proliferative Potential of different cell types Growth factors Extracellular Matrix Wound healing process Wound closure intensions Features affecting wound healing Complication Summary Reference  INTRODUCTION Healing is the body response to injury for restoration of normal structure (architecture) and function Complete restoration of injured tissue requires the removal or destruction of the harmful agent. The healing process can be divided into regeneration and repair.  REGENERATION Some tissues are able to replace the damaged components and essentially return to a normal state; this process is called regeneration. Regeneration occurs by proliferation of cells  REPAIR Is when healing takes place by proliferation of connective tissue elements results in fibrosis and scarring. Repair of damaged tissues occurs by two types of reactions ;regeneration by proliferation of residual( uninjured) cells and maturation of tissue stem cells deposition of connective to form scar. At times both processes take place simultaneously  PROLIFERATION OF CELL Classification of cells by their proliferative potential On the basis of this criterion, the tissues of the body are divided into three groups:- Labile (continuously dividing)cells Continue to multiply throughout life under normal physiologic conditions. Cells are continuously proliferating Can easily regenerate after injury Contain a pool of stem cells  Stable cells These cells decrease or lose their ability to proliferate after adolescence but retain the capacity to multiply in response to stimuli throughout adult life. Cells have limited ability to proliferate Limited ability to regenerate ( except liver ) E.g. Parenchymal cells of organs like liver, pancreas, kidneys, bone and cartilage cells.  Permanent cells These cells lose their ability to proliferate around the time of birth. Cells can’t proliferate Can’t regenerate ( so injury always leads to scar ) Eg ; neurons of nervous system skeletal muscle and cardiac muscle cells.  GROWTH FACTORS These are very important in tissue repair. Are proteins that stimulate the survival and proliferation of particular cells and may also promote migrations differentiation and other cellular response Actions ;- Stimulate cell division and proliferation - Promote cell survival Are important for regulating a variety of cellular processes: Act as signaling molecules between cells. They promote entry of cell into the cell cycle. They enhance the synthesis of cellular proteins in preparation for mitosis  Growth Factors cont.. Signaling may occur : Autocrine signaling – cell responds to substances which it releases and thus changes take place in the cell itself. Paracrine signaling – signaling between adjacent cells Endocrine signaling- signaling over long distance. Signal molecules (hormones) are carried by bloodstream to the distant target cells.  EXTRACELLULAR MATRIX The ECM is a complex of several proteins that assembles into a network that surrounds cells and constitutes a significant proportion of any tissue. Tissue repair depends not only on growth factor activity but also on interactions between cells and ECM components.  Components of the Extracellular Matrix Fibrous structural proteins such as collagens and elastin's, provide tensile strength and recoil. Water-hydrated gels such as proteoglycans and hyaluronan, provide hydration and swelling pressure to the tissue enabling it to withstand compressional forces. Adhesive glycoproteins that connect the matrix elements to one another and to cells. i.e. Integrins to Fibronectin and Laminin.  ECM CONT… These macromolecules are present in intercellular junctions and cell surfaces and form two general organizations; Interstitial matrix The interstitial matrix is present in spaces between epithelial , endothelial and smooth muscle cells and in connective tissue.  It consists of fibrillar and nonfibrillar collagen elastin fibronectin proteoglycans hyaluronate and other components.  Basement membrane Produced by epithelial and mesenchymal cells and are closely associated with the cell surface.  They consist of network of amorphous nonfibrillar collagen (mostly type iv) laminin heparan sulfate proteoglycan and other glycoproteins.  FUNCTION ECM Mechanical support Determination of cell polarity Control of cell growth Maintenance of cell proliferation Establishment of tissue micro- environments Storage of regulatory molecules  WOUND HEALING PROCESS Wound healing is a dynamic processes consisting of four continuous overlapping precisely programmed phases. Interruptions or prolongation in the process can lead to delayed wound healing or a non-healing chronic wound.  STAGES OF WOUND HEALING These include: 1. Hemostasis 2. Inflammation 3. Proliferation and migration 4. Remodeling and maturation  HEMOSTASIS It begins immediately after injury, with vascular constriction and fibrin clot formation. Hemostasis mechanisms include: 1. Vascular constriction 2. Formation of a platelet plug  Hemostasis cont… 3. Formation of a blood clot as a result of blood coagulation. 4. Eventual growth of fibrous tissue into the blood clot to close the hole in the vessel permanently.  Hemostasis cont.. The clot and surrounding wound tissue release pro- inflammatory cytokines and growth factors such as transforming growth factor (TGF)-β platelet-derived growth factor (PDGF) fibroblast growth factor (FGF) epidermal growth factor(EGF). Once bleeding is controlled, inflammatory cells migrate into the wound (chemotaxis) and promote the inflammatory phase.  INFLAMMATION Platelet activation is followed by an influx of inflammatory cells within the first 1 to 2 days influenced by polymorphonuclear leukocytes (PMN). Neutrophils monocytes fibroblasts endothelial cells deposit on a fibrin scaffold formed by platelet activation.  Inflammation cont.. These PMNs are the major source of proinflammatory cytokines, such as IL-1α, IL-1β, IL-6, and TNF-α, and exert cascades of inflammatory reactions and prevent infection. Monocytes come to the wound bed after PMN and transform into macrophages, which are abundant during day 2 and 3 but remain there for weeks.  Inflammation cont.. PMNs are removed by macrophages through apoptosis, called PMN debridement via slough eschar. This inflammatory phase lasts for the first 4 days in normal wound healing process.  PROLIFERATION This is the phase when the wound is rebuilt with new tissue made up of collagen and extracellular matrix. The wound contracts as new tissues are built It involves re-epithelialization angiogenesis granulation tissue formation and collagen deposition.  Proliferation cont.. Re-epithelialization: is wound recovery with new epithelium and consists in both migration and proliferation of keratinocytes from the lesion periphery. These events are regulated by three main agents growth factors integrins and metalloproteases.  Proliferation cont.. Angiogenesis: involves a process in which new blood vessels are formed from preexisting vessels and these participate in the formation of temporary granulation tissue and supply nutrients and oxygen to the growing tissue.  Endothelial cell migration is initiated on day 2 of post- wounding and stimulated by VEGF FGF angiopoietin Transforming Growth Factor-β.  Proliferation cont.. Proteolytic degradation of the parent vessel basement membrane occurs, allowing formation of capillary sprout. Migration of endothelial cells from the original capillary toward an angiogenic stimulus. Proliferation of the endothelial cells behind the leading edge of stimulus Maturation, inhibition of growth and organization into capillary tubes  Proliferation cont.. The newly formed vessels are leaky, and this leak contributes to the edematous appearance of tissue undergoing repair. As healing is completed the nonfunctional vessels are degraded leaving few blood vessels in mature scar tissue.  Granulation This is the hallmark of healing. Granulation tissue progressively invades the site of injury. The term granulation tissue derives from its pink, soft, granular appearance seen in area of wound healing. Granulation tissue is ;  the proliferation of fibroblasts  new thin- walled , delicate capillaries (angiogenesis), in a loose extracellular matrix.  admixed inflammatory cells , mainly macrophages Histologically the main cellular components of granulation tissue are endothelial cells and the fibroblasts, although some inflammatory cells are also commonly present.  Collagen synthesis & ECM formation Fibroblasts first appear in the wound after 24 hours and require adequate oxygen supply for collagen production. Without oxygen to assist in the hydroxylation of proline and lysine residues chemical bonds will not form appropriately to create mature collagen.  Fibroblasts are also responsible for elastin production and organization of the extracellular matrix. The extracellular matrix is important for the growth and normal maintenance of vessels because in addition to acting as the support platform for cell migration it also acts as modulator of the release of growth factors such as FGF2 and TGF-β.  REMODELING Transition from granulation tissue to scar involves shift in the composition of the extracellular matrix. Even after its synthesis and deposition of scar, ECM continues to be modified and remodeled Can take years as the skin first produces collagen fibers, which are broken down and rearranged to withstand stress.  Remodeling cont.. The main cytokines involved in this phase are tumor necrosis factor (TNF-α), interleukin (IL-1), PDGF and TGF-β produced by fibroblasts, in addition to those produced by epithelial cells such as EGF and TGF-b  The wound also undergoes physical contraction throughout the entire wound-healing process, which is believed to be mediated by contractile fibroblasts (myofibroblasts) that appear in the wound.  Remodeling cont.. As a result of maturation and remodeling processes, most vessels, fibroblasts and inflammatory cells disappear from the wound site through a process of migration, apoptosis or other unknown death cell mechanisms, which means a scar with fewer cells. Conversely, if there is persistent cellularity at the site, there will be formation of hypertrophic scars or keloids  WOUND CLOSURE INTENSIONS Healing of skin wound is a process that involves both epithelial regeneration and formation of connective scar. Based on nature and the size of wound, the healing of skin wound occurs by ; 1. Healing by first (Primary) intention 2. Healing by second (secondary) intention  Healing by First Intention One of the simplest examples of wound repair, wound has the following characteristics:- Clean/uninfected wound with limited tissue loss. Surgically incised. Wound edges are easily approximated. Classic surgical wound closure using suture or adhesive tape.  Stages of Healing by First Intention 1. Initial haemorrhage. Immediately after injury, the space between the approximated surfaces of incised wound is filled with blood which then clots and seals the wound. 2. Acute inflammatory response. This occurs within 24 hours with appearance of polymorphs from the margins of incision. By 3rd day, polymorphs are replaced by macrophages. 3. Epithelial changes. Migration and proliferation of basal epidermal cells from cut margins towards incisional space. Well approximated wound is covered by a layer of epithelium in 48 hours. Scar formation to separate the underlying viable dermis from necrotic tissue. The basal cells from the margins continue to divide. A multilayered new epidermis is formed which is differentiated into superficial and deeper layers. 4. Organisation. By 3rd day, fibroblasts also invade the wound area. By 5th day, new collagen fibrils start forming which dominate till healing is completed. In 4 weeks, the scar tissue with scanty cellular and vascular elements, a few inflammatory cells and epithelialised surface is formed.  Healing by Second Intention This is defined as healing of a wound having the following characteristics: Large tissue loss. Heavy contamination. The wound is cleaned and left open to granulate (daily wound care promotes granulation) Surgeon may pack and place drain.  Stages of Healing by Second Intention 1. Initial haemorrhage. As a result of injury, the wound space is filled with blood and fibrin clot which dries. 2. Inflammatory phase. There is an initial acute inflammatory response followed by appearance of macrophages which engulf off clear the debris as in primary union. 3. Epithelial changes. -As in primary healing, the epidermal cells from both the margins of wound proliferate and migrate. 4. Granulation tissue. -Granulation tissue is formed by proliferation of fibroblasts and neovascularization from the adjoining viable elements. The newly-formed granulation tissue is deep red, granular and very fragile. The scar on maturation becomes pale and white due to increase in collagen and decrease in vascularity. Specialized structures of the skin like hair follicles and sweat glands are not replaced unless their viable residues remain which may regenerate. 5. Wound contraction. Contraction of wound is an important feature of secondary healing, not seen in primary healing. Due to the action of myofibroblasts present in granulation tissue, the wound contracts to one-third of its original size. Wound contraction occurs at a time when active granulation tissue is being formed. FACTORS AFFECTING WOUND HEALING Local Factors Local infection Blood supply (perfusion & oxygenation) Foreign bodies (including sutures) Mechanical stress Type of tissue, size and location of injury Ionizing radiation - delays granulation tissue formation UV light exposure - facilitates healing Systemic Factors Age (poor blood supply in aged and debilitated) Nutrition ( Protein, vitamin C, zinc, magnesium) Systemic infections Diabetes Smoking (nicotine, CO, hydrogen cyanide) Drugs (steroids, cytotoxic medications, intensive antibiotic therapy) COMPLICATION OF WOUND HEALING Can arise from abnormalities in any of the basic components of the repair process. These can be grouped into three general categories: 1. Deficient scar formation 2. Excessive formation of the repair 3. Formation of contractures. Defects in healing cont... 1. Dehiscence (wound rupture) Most frequently after abdominal surgery A result of increased abdominal pressure Excessive formation of the repair components Hypertrophic scar : Accumulation of excessive amounts of collagen which gives rise to a raised scar. This grows within the wound boundaries. Excessive formation of repair components……. Keloid : If the scar tissue grows beyond the boundaries of the original wound and does not regress.  Exuberant granulation/ proud flesh Formation of excessive granulation tissue which protrudes above the level of the surrounding skin and blocks re-epithelialization. Complications of wound healing cont... 3. Osteomyelitis Infection in chronic wounds can spread to surrounding tissues and to underlying bone. E.g. Diabetic foot ulcer, can develop osteomyelitis, thus increasing the risk of lower limb amputation. 4. Neoplasia Scar may be the site of development of carcinoma (rare) E.g Marjolin’s ulcer - Squamous cell carcinoma arising from burn wound. It can take 15-20 years to develop at the site of injury.  REFERENCE Robbins Basic Pathology,9th edition. Fundamentals of Pathology, 1st edition. Harsh Mohan Pathology Text Book 6th Edition Slade share net THANK YOU