Healing (Regeneration & Repair) PDF

HEALING ( Regeneration & Repair) HEALING ( Regeneration & Repair) Performance Objectives At the end of the instruction, the student should be able to : Describe Healing and its distinct processes: Regeneration & Repair Describe wound healing and fracture healing (Primary and Secondary) Describe th...

HEALING ( Regeneration & Repair) HEALING ( Regeneration & Repair) Performance Objectives At the end of the instruction, the student should be able to : Describe Healing and its distinct processes: Regeneration & Repair Describe wound healing and fracture healing (Primary and Secondary) Describe the complications of wound healing and fracture healing. Describe healing of the following specialized tissues : Nervous Tissue, Muscles, Mucosal surfaces and Organs.  Healing of Tissues Healing, means a body response to injury in an attempt to restore normal structure and function. It involves 2 processes: a) Regeneration: when healing takes place by proliferation of parenchymal cells and usually results in complete restoration of the original tissues. Eg: epithelium, liver ,etc.  b) Repair: when healing takes place by proliferation of connective tissue resulting in fibrosis and scarring. Occurs in tissues that are incapable of proliferation of parenchymal cells or if there is severe damage to the parenchymal tissue with destruction of connective tissue framework in tissues with proliferative capacity Chronic inflammation stimulates scar formation because of production of growth factors and cytokines that promotes fibroblasts proliferation and collagen synthesis- Fibrosis  RELATIONSHIP OF PARENCHYMAL CELLS WITH CELL CYCLE 1. Labile cells which are continuously dividing cells remain in the cell cycle from one mitosis to the next. e.g. haematopoietic cells of bone marrow, epithelium Regeneration possible in these tissues after injury 2. Stable cells are in the resting phase (G0) but can be stimulated to enter the cell cycle. e.g. parenchymal cells of liver, kidney, pancreas & thyroid. Regeneration possible in these tissues after injury 3. Permanent cells are non-dividing cells which have left the cell cycle and die after injury. Regeneration not possible in these tissues after injury, only repair (healing by fibrosis) possible after injury e.g. nervous system and cardiac muscle cells. Parenchymal cells in relation to cell cycle  Repair Repair is the replacement of injured tissue by fibrous tissue. Occurs when: there is severe injury so that parenchymal tissues( with labile and stable cells ) as well as connective tissue framework of the organ are destroyed Two processes are involved in repair: 1.Granulation tissue formation 2.Contraction of wounds  1.Granulation tissue formation (derived its name from granular & pink appearance of tissue, histologically seen as proliferation of new small blood vessels & young collagen). 3 phases are observed : 1. PHASE OF INFLAMMATION Following trauma, blood clots at the site of injury. There is acute inflammatory response with exudation of plasma, neutrophils and some monocytes within 24 hours. 2. PHASE OF CLEARANCE Combination of proteolytic enzymes liberated from neutrophils, autolytic enzymes from dead tissues cells, and phagocytic activity of macrophages clear off the necrotic tissue, debris and red blood cells.  Repair : 1.Granulation tissue formation(Contd.) 3. PHASE OF INGROWTH OF GRANULATION TISSUE This phase consists of 2 main processes: I. Angiogenesis or neovascularisation 2. Fibrogenesis 1.Angiogenesis (neovascularisation) : Formation of new blood vessels at the site of injury from pre-existing blood vessels. Steps involved are : Formation of solid buds of endothelial cells from the margins of the injured/cut blood vessels Lumen form within the buds soon after and start carrying blood. The newly formed blood vessels are leaky, giving rise to the oedematous appearance of new granulation tissue  1. Angiogenesis (neovascularisation) Mechanisms Growth factors for angiogenesis: a) Vascular endothelial growth factor (VEGF) elaborated by mesenchymal cells while its receptors are present in endothelial cells only. b) Platelet-derived growth factor (PDGF), transforming growth factor- (TGF)  Granulation tissue formation 2.Fibrogenesis Migration and proliferation of fibroblasts: fibroblasts migrate into the wound site and proliferate, in order to reconstitute the various connective tissue components collagen fibrils begin to appear by about 6th day. Growth factor for fibrogenesis FGF- promote migration of macrophages and fibroblasts to the damaged area.  Granulation tissue formation 2.Fibrogenesis (Contd..) Main function of ECM: Provide support and anchorage for cells & regulate intercellular communication and segregates tissues from one another. Sequestrates water to provide turgor to soft tissues. Sequestrates minerals to provide rigidity to bone. Sequestrates growth factors like FGF & HGF for regeneration. Forms of ECM: oInterstitial matrix: synthesized by mesenchymal cells and fills the space between cells and supporting vascular and smooth muscle structure. oBasement membrane: interstitial matrix organizes itself around epithelium, endothelium and smooth muscle cells to form a meshwork, which anchors down the above cells to the loose connective tissue underneath. This meshwork is called “basement membrane” and consists of mainly collagen type IV and laminin Forms of ECM & Composition  ECM Composition : Macromolecules Composition of ECM - Macromolecules : A. COLLAGEN: Family of 18 types of fibrillar and non-fibrillar proteins which provide structural supports to fibrous tissue, bone, cartilage, valves of heart, cornea, basement membrane etc.. The collagen synthesis is stimulated by various growth factors and is degraded by collagenase. collagen turnover is well regulated so that the collagen content of normal organs remains constant. Defective regulation of collagen synthesis leads to hypertrophied scar, fibrosis, and organ dysfunction.  Type I collagen is normally present in the skin (80% of the collagen in normal skin ), bone and tendons and accounts for 90% of collagen in the body Type I, III and V are true fibrillar collagen which form the main portion of the connective tissue during healing of wounds in scars.  ECM Composition : Macromolecules B. ADHESIVE GLYCOPROTEINS. glue for the components of the ECM. i) Fibronectin (nectere = to bind) is the best characterised glycoprotein in ECM and has binding properties to other cells and ECM. ii) Tenascin or cytotactin is the glycoprotein associated with fibroblasts and appears in wound about 48 hours after injury. It disappears from mature scar tissue. iii) Thrombospondin is mainly synthesised by granules of platelets. It functions as adhesive protein for keratinocytes and platelets but is inhibitory to attachment of fibroblasts and endothelial cells.  Composition of ECM : Macromolecules C. ELASTIC FIBRES Provides the ability to recoil. Elastic fibers consist of 2 components—elastin glycoprotein and elastic microfibril. Elastases degrade the elastic tissue e.g. in inflammation, emphysema etc D. PROTEOGLYCANS.(molecules having 2 components :Carbohydrate & protein ). In wound healing, the deposition of proteoglycans (amorphous gel like substance ) precedes collagen laying.Various proteoglycans are distributed in different tissues : i) Chondroitin sulphate—abundant in cartilage, dermis ii) Heparan sulphate—in basement membranes iii) Dermatan sulphate—in dermis iv) Keratan sulphate—in cartilage v) Hyaluronic acid—in cartilage, dermis.  Repair: 2.Contraction of wounds. Contraction of wounds :The process by which wound is reduced by approximately 80% of its original size. This results in rapid healing since lesser surface area of the injured tissue has to be replaced Wound starts contracting after 2-3 days and the process is completed by the 14th day. Myofibroblasts cause active contraction & decreases the size of the wound defect.  The wound strength : site of injury, depth of incision and area of wound. After removal of stitches on around 7th day, the wound strength is approximately 10% which reaches 80% in about 3 months ( maximal strength of the wound)  HEALING OF SKIN WOUNDS Healing of skin wounds provides a classical example of combination of regeneration and repair. Wound healing can be accomplished in one of the following two ways: 1. Healing by first intention (primary union) 2. Healing by second intention (secondary union). 1.Healing by first intention (primary union): This is defined as healing of a wound which has the following characteristics: i) clean and uninfected; ii) surgically incised; iii) without much loss of cells and tissue; and iv) edges of wound are approximated by surgical sutures HEALING OF SKIN WOUNDS: By FIRST INTENTION/ Primary union 1. Initial haemorrhage Soon after injury the space between the wound is filled with blood which then clots & seal the wound against dehydration and infection. 2. Acute inflammatory response. Occurs within 24 hours with the appearance of neutrophils followed by 3rd day, by macrophages. 3. Epithelial changes. Basal cells of epidermis from both the cut margins proliferate & migrate towards incisional space in the form of epithelial spurs, wound is re-epithelialized (48 hours) & separates the dermal layer from overlying clot & debris. By 5th day, a multilayered new epidermis is formed which is differentiated into superficial and deeper layers. 4. Organisation. Fibroblasts invade the wound area and matures forming collagen. In 4 weeks, the scar tissue with scanty cellular and vascular elements, a few inflammatory cells and epithelialised surface is formed.  HEALING OF SKIN WOUNDS By FIRST INTENTION/ Primary union 5. Suture tracks. Sutures are removed around 7th day, scar tissue is formed at the sites of incision and suture track. Scar is neat due to close apposition of the margins of wound. (18) Surgical wound healing - YouTube  HEALING BY SECOND INTENTION (SECONDARY UNION) This is defined as healing of a wound having the following characteristics: i) open with a large tissue defect, at times infected; ii) having extensive loss of cells and tissues; and iii) the wound is not approximated by surgical sutures but is left open. Inflammatory phase. The basic events in both types of healing are similar but secondary union differs in having a larger tissue defect which has to be bridged from base upward and also from the margins inwards. Healing by second intention is slow and results in a large, at times ugly, scar as compared to rapid healing and neat scar of primary union. The sequence of events : 1& 2 similar in both primary and secondary union  HEALING OF SKIN WOUNDS: SECONDARY UNION) 3.Epithelial changes. As in primary healing, basal cells of epidermis from both the margins of wound start to proliferate & migrate into the wound space but re- epithelialisation is incomplete as the wound is covered by the granulation tissue,. 4. Granulation tissue : forms the main bulk of secondary healing. fragile, deep red, granular Scar in secondary healing is quite large & ugly-looking 5.Wound contraction. Important feature of secondary healing, not seen in primary healing. Caused by the action of myofibroblasts present in granulation tissue. 6. Presence of infection Bacterial contamination of an open wound delays the process of healing Secondary union of skin wounds (18) Wound Healing – YouTube Steps in wound healing by first intention (left) and second intention (right). Secondary healing differs from primary healing: 1. inflammatory reaction is more intense. 2. Much larger amounts of granulation tissue are formed. 3. wound contraction, by myo-fibroblasts at the wound site decreases the gap between the dermal edges of the wound. 4. Substantial scar formation and thinning of the epidermis.  HEALING OF SKIN WOUNDS Differences between primary and secondary union of wounds  HEALING OF SKIN WOUNDS Differences between primary and secondary union of wounds  FACTORS INFLUENCING HEALING Two types of factors influence the wound healing: those acting locally, and those acting in general. A. LOCAL FACTORS: 1. Infection is the most important factor acting locally which delays the process of healing 2. Poor blood supply to wound slows healing e.g. injuries to face heal quickly due to rich blood supply while injury to leg with varicose ulcers having poor blood supply heals slowly. 3. Foreign bodies including sutures interfere with healing and cause intense inflammatory reaction and infection. 4. Movement delays wound healing. 5. Exposure to ionising radiation delays granulation tissue formation. 6. Exposure to ultraviolet light facilitates healing. 7. Type, size and location of injury determines whether healing takes place by resolution or organisation.  FACTORS INFLUENCING HEALING B. SYSTEMIC FACTORS: 1. Age. Wound healing is rapid in young and somewhat slow in aged and debilitated people due to poor blood supply to the injured area in the latter. 2. Nutrition. Deficiency of constituents like protein, vitamin C (scurvy), vitamin A and zinc delays the wound healing. 3. Systemic infection delays wound healing. 4. Administration of glucocorticoids has anti-inflammatory effect. 5. Uncontrolled diabetics are more prone to develop infections and hence delay in healing. 6. Haematologic abnormalities like defect of neutrophil functions (chemotaxis and phagocytosis), and neutropenia and bleeding disorders slow the process of wound healing  COMPLICATIONS OF WOUND HEALING keloid keloid Contracture s Infected Post Operative Wound Wound dehiscence Contractures Contractures limitation of motion from burn scar and webbing on hand and wrist due to contractures  COMPLICATIONS OF WOUND HEALING Implantation (epidermal) cyst formation- due to persistence of epithelial cells in the wound after healing. Deficient scar formation - due to inadequate formation of granulation tissue. Hypertrophied scars and keloid formation. excessive, ugly and painful scars formed due to excessive amount of collagen ; may result in keloid (claw-like) formation, seen more commonly in Africans. Hypertrophied scars differ from keloid in that they are confined to the borders of the initial wound while keloids have tumour like projection of scar tissue. Neoplasia. Rare, scar may be the site for development of carcinoma later e.g. squamous cell carcinoma in Marjolin’s ulcer i.e. a scar following burns on the skin.  Healing In Specialized Tissue - Bone Healing of fracture by callus formation depends upon some clinical considerations like the type of the fracture. Types of bone fractures: Traumatic or pathological bone fracture Complete or incomplete like green-stick fracture; and Simple (closed) or compound (communicating to skin surface) Comminuted (splintering of bone),  Basic events in healing of any type of fracture are similar and resemble healing of skin wound to some extent Primary union- of fractures occurs in a few special situations when the ends of fracture are approximated as is done by application of compression clamps. In these cases, bony union takes place with formation of medullary callus without periosteal callus formation. Secondary union- is more common &described under the following 3 headings: i) Procallus formation ii) Osseous callus formation iii) Remodelling  Healing In Specialized Tissue - Bone i) Procallus formation: ia) Haematoma forms due to bleeding, filling the area surrounding the fracture. blood and fibrin clot forms a loose meshwork which acts as framework for subsequent granulation tissue formation. ib) Local inflammatory response, polymorphs and macrophages. The macrophages clear away the fibrin, red blood cells, inflammatory exudate and debris. Fragments of necrosed bone are scavenged by macrophages and osteoclasts.  Healing In Specialized Tissue - Bone ic) Ingrowth of granulation tissue, begins with neovascularization and proliferation of mesenchymal cells from periosteum and endosteum. A soft tissue callus is thus formed which joins the ends of fractured bone without much strength. id) Provisional callus or Procallus : Callus of woven bone and cartilage Formation starts within the first few days. The cells of inner layer of the periosteum lay down collagen as well as osteoid matrix in the granulation tissue. The osteoid undergoes calcification and is called woven bone callus. The cortex on either side of fractured ends is covered by spindle- shaped or fusiform shaped woven bone callus that bridge the gap between the fractured ends. Sometimes cartilage also forms in the Procallus. In poorly immobilised fractures (e.g. fracture ribs), the subperiosteal osteoblasts may form cartilage at the fracture site  Healing In Specialized Tissue - Bone ii)Osseous callus formation: The procallus acts as scaffolding on which osseous callus composed of lamellar bone forms. Osteoclasts clear away the woven bone and the calcified cartilage disintegrates. Newly-formed blood vessels and osteoblasts invade the area, laying down osteoid which is calcified and lamellar bone is formed by developing Haversian system concentrically around the blood vessels. iii)Remodeling: During the formation of lamellar bone, osteoblastic laying and osteoclastic removal are taking place remodeling the united bone ends, which after sometime, is indistinguishable from normal bone. Healing In Specialized Tissue - Bone Healing In Specialized Tissue – Bone summary  Healing In Specialized Tissue – Bone Complications 1. Fibrous union may result instead of osseous union if the immobilisation of fractured bone is not done. Occasionally, a false joint may develop at the fracture site (pseudo-arthrosis). 2. Non-union may result if some soft tissue is interposed between the fractured ends. 3. Delayed union may occur from causes of delayed wound healing in general such as infection, inadequate blood supply, poor nutrition, movement and old age.  Healing in Specialized tissues – Nervous Tissue ▪ CENTRAL NERVOUS SYSTEM The nerve cells of the brain, spinal cord and ganglia once destroyed are not replaced. Axons of CNS also do not show any significant regeneration. The damaged neuroglial cells may show proliferation of astrocytes called gliosis. PERIPHERAL NERVOUS SYSTEM The peripheral nerves show regeneration, mainly from proliferation of Schwann cells and fibrils from distal end. The pathologic reactions of the PNS in response to injury may be in the form of degenerations causing peripheral neuropathy or formation of a traumatic neuroma.  Healing in Specialized tissues – Nervous Tissue PNS 3 main types of degenerative processes occur in the PNS: 1.Wallerian degeneration : Follows transection of the axon by knife wounds, compression, traction and ischaemia. Axon and myelin sheath distal to the transection site undergo disintegration up to the next node of Ranvier, followed by phagocytosis. The process of regeneration occurs by sprouting of axons and proliferation of Schwann cells from the proximal end. 2.Axonal degeneration Degeneration of the axon begins at the peripheral terminal and proceeds backward towards the nerve cell body. The cell body undergoes chromatolysis, loss of axonal integrity occurs  Healing in Specialized tissues – Nervous Tissue PNS 3.Segmental demyelination : Loss of myelin of the segment between two consecutive nodes of Ranvier, denuding the axon segment. Schwann cell proliferation results in remyelination of the affected axon. Traumatic neuroma Normally, the injured axon of a peripheral nerve regenerates at the rate of approximately 1 mm per day. If the process of regeneration is obstructed due to an interposed haematoma or fibrous scar, the axonal sprouts ,Schwann cells and fibroblasts form a peripheral mass called as traumatic or stump neuroma. Healing in Specialized tissues – Nervous Tissue PNS: Pathologic reaction of peripheral nerve to injury  Healing in Specialized tissues- Muscles SKELETAL MUSCLE. On injury, the cut ends of muscle fibres retract but are held together by stromal connective tissue. 1.If the muscle sheath is intact, sarcolemmal tubes containing histiocytes appear along the endomysial tube which, in about 3 months time, restores properly oriented muscle fibres e.g. in Zenker’s degeneration of muscle in typhoid fever. 2. If the muscle sheath is damaged, it forms a disorganised multinucleate mass and scar composed of fibrovascular tissue e.g. in Volkmann’s ischaemic contracture.  Healing in Specialized tissues- Muscles SMOOTH MUSCLE Non-striated muscle has limited regenerative capacity e.g. appearance of smooth muscle in the arterioles in granulation tissue. However, in large destructive lesions, the smooth muscle is replaced by permanent scar tissue. CARDIAC MUSCLE Destruction of heart muscle is replaced by fibrous tissue. However, in situations where the endomysium of individual cardiac fibre is intact (e.g. in diphtheria and coxsackie virus infections), regeneration of cardiac fibres may occur in young patients.  Healing in Specialized tissues Healing of Mucosal Surfaces The mucosal cells are labile cells and are normally being lost and replaced continuously e.g. mucosa of alimentary tract, respiratory tract, urinary tract, uterine endometrium etc. Regeneration occurs by proliferation from margins, migration, multilayering and differentiation of epithelial cells in the same way as in the epidermal cells in healing of skin wounds. Healing of Solid Epithelial Organs like kidney, liver and thyroid Following gross tissue damage to organs , the replacement is by fibrous scar e.g. in chronic pyelonephritis and cirrhosis of liver. In Parenchymal cell damage with intact basement membrane or intact supporting stromal tissue, regeneration may occur; eg. Regeneration in acute tubular necrosis in kidneys, liver in viral hepatitis Reference Harsh Mohan and Sugandha Mohan. (2017) Essential Pathology for Dental Students. 5th ed. Jaypee Brothers T h a nk Yo u