Repair of injury 1 Pathology department China Three Gorges University YiLing Huang

Teaching plan: 2

repair begins very early in the process of inflammatory and involves two dichotomous process:  regeneration of injuried tissue by parenchymal cells of the same type  replacement by connective tissue (fibrosis), resulting in a scar Repair : the process of the body to return to its normal structure and function 3

 Physiological regeneration: cell and tissue Maintain Its normal structure and function in physiological process. eg. the epithelial of the mucous membrane (mucosa) of digestive tract blood cell the endometrium of the uterus  Pathological regeneration: take place after the cell and tissue was injured. 4

G1 = preparing for synthesis, S = DNA synthesis, G2 = preparing for mitosis, M = mitotic, G0= Quiescent cell Cell Cycle : a certain period of time which Proliferating cells progress through a series of Checkpionts and defined phases. 5

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Proliferative Potential of Cells  labile cells: Continuously dividing  hematopoietic cells  Majority of surface epithelia: Stratified epithelia of skin, oral cavity, vagina, cervix; cuboidal epithelia of exocrine ducts; columnar epithelium of GI tract, uterus; transitional epithelium of bladder; Based on their regenerative capacity 8

 stable cells: Quiescent in normal state but are capable of undergoing division in response to injury parenchymal cells of liver, kidney, pancreas; endothelial cells, smooth muscle cells, fibroblasts  permanent cells : Nondividing in postnatal life Neuron, cardiac myocytes, skeletal muscle cell 9

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 Entry and progression of cells through the cell cycle are controlled by changes in the levels and activities of a family of proteins called cyclins  Cyclins accomplish their regulatory functions by complexing with constitutively synthesized proteins called cyclin-dependent kinase (CDKs)  In addition to synthesis and degradation of cyclins, the cyclin-CDK complex are regulated by binding with CDK inhibitors Further information 11

Stem cells Hot topocs in biomedical investigation Regenerative medicine Prolonged self –renewal capacity Asymmetric replication:in every cell division, one of the cells retains its self-renewing capacity, the other enters a differentiation pathway and is converted to a mature nondividing population.

Regeneration of tissue Glandular epithelium Epithelium Covering epithelium Connective tissue Blood vessel Bone tissue (see fracture healing) 12

Covering epithelium Injury---- basal cell near it proliferate--- simple cuboidal or Columnar epithelialum --- Simple squamous epithelium 13

Gland epithelium When the basement membrane is complete, repair will be accomplished by the residual cells 14

When partially resected ---liver cells proliferation--- form new liver lobules--- structure and function normal when meshwork is complete--- liver cell proliferate along With the connective tissue---function normal When the meshwork is collapsed --- liver cell proliferate ---pseudo lobules liver Necrosis 15

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Connective tissue 17

Blood vessel Basement membrane and extracellular matrix degradation Endothelial migration Endothelial proliferation Lumen formation,maturation and inhibition of growth Increased permeability through Gaps and transcytosis 18

Control of cell regeneration 1. Extracellular matrix( ECM): 1) collagen 2) elastin 3) adhesive glycoproteins LN--- angiogenesis FN--- cell adhesion and migration 20

2. Growth factors: mainly accelerate repair process 1) PDGF:fibroblast, monocyte, smooth muscle cell 2) FGF : endothelial 3)EGF : epithelial, fibroblast, smooth muscle cell 4)TGF: fibroblast, smooth muscle cell 5)VEGF:endothelial 6)IL-1, TNF 21

3. Cell and cell interaction and chalons contact inhibition: The cessation of cellular growth and division due to physical contact with other cells tumor cells are exception chalons: are tissue specificity 22

When damage to both parenchymal cells and the stromal framework, repair occurs by replacement of the nonregenerated parenchymal Cells with connective tissue:  Formation of the new blood vessel  Migration and proliferation of fibroblasts  Disposition of ECM  Maturation and reorganization 23

Granulation tissue: New connective tissue and tiny Blood vessels that form on the surfaces of a wound during the healing process.  the best sign of wound healing  must be carefully supported while the wound heals  was so called by early clinicians because under examination by magnifying glass it has a granular appearance 24

Macroscopic  light red or dark pink in color  soft to the touch  "bumpy" in appearance  bleed easily Microscopic  new capillaries  fibroblast  Inflammatory cells 25

Granulation Tissue 26

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Granulation Tissue 28

effect of granulation tissue  Protect the wound and anti inflammatory  Supply the gap of the tissue  Organization or encapsulation the foreign body 29

Granulation tissue: 2-3days after injury Sequence: below top peripheral---central Become scar tissue 30

Scar tissue: old stage of granulation tissue Macroscopic : white or gray in color half transparent hard In texture poor elasticity Microscopic: mainly composed by fibre few cells and capillaries hyaline degeneration 31

Beneficial : keep the integrality of the tissue increase wound strength Harmful: wound contraction conglutination of the tissue keloid Effect of scar tissue 32

a complex series of events that begins at the moment of injury and can continue for months to years orderly phase of wound healing 33

I. Inflammatory Phase A) Immediate to 2-5 days B) Hemostasis Vasoconstriction Platelet aggregation Thromboplastin makes clot C) Inflammation Vasodilation Phagocytosis 34

II. Proliferative Phase A) 2 days to 3 weeks B) Granulation Fibroblasts lay bed of collagen Fills defect and produces new capillaries C) Contraction Wound edges pull together to reduce defect D) Epithelialization Crosses moist surface Cell travel about 3 cm from point of origin in all directions 35

III. Remodeling Phase A) 3 weeks to 2 years B) New collagen forms which increases tensile strength to wounds C) Scar tissue is only 80 percent as strong as original tissue 36

Healing by first intension Definition:The relatively simple, rapid process of healing in a clean skin wound which has been closed promptly and where tissue damage is minimal and no infection.(e.g. a surgical incision). Also called healing by primary intention 37

General process: Within 24hours : neutrophils migrate toward the fibrin clot. basal cells at the cut edge begin to exhibit increased miotic activity Within 24hours to 48hours: epithelial cells from both edges begin to migrate and proliferate along the dermits Day 3: neutrophil replaced by macrophages Granulation tissue progressively invades the incision space 38

Day 5: neovascularization reaches its peak Collagen fibrils abundant and bridge the incision During the second week: continued collagen accumulation and fibroblast proliferation By the end of the first month: scar comprises cellular connective tissue and covered by an essential normal epithelial 39

Healing by second intention: Definition: healing of an open wound where there is significant tissue loss, or where there is ongoing tissue damage from infection differs from primary healing in several respects:  Large tissue defects intrinsically have a greater volume of necrotic debris,exudate and fibrin that must be removed  Much larger amounts of granulation tissue are formed  Wound contract significantly 40

Carefully sutured wounds:70% of the strength of the unwounded skin when sutures removed at 1 week:wound strength is 10% of normal, reaches 70%-80% of normal by 3 month Wound strength 41

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Factors influencing healing Systemic: Age: the healing process becomes slower and less effective with increasing age. Nutritional deficiencies, e.g. vitamin C, zinc, protein Metabolic diseases, e.g. renal failure, diabetes mellitus Catabolic state associated with malignancies Systemic drugs, e.g. corticosteroids temperature 44

Local: Persisting infection, foreign material or other stimulus to inflammation Inadequate blood supply Excessive movement Irradiation Locally applied drugs, e.g. corticosteroids 45

Poor wound healing in a patient being treated with corticosteroids. 46

Keloid 47

Keloid 48

Hyalinized collagen in a keloid 49

Complication of wound healing  Infection of wound  Wound dehiscence  Pigmentation  Keloid formation  Incisional hernia  Neoplasitc formation 50

a process of restoring the structural and biological properties of injured bone 51

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Stage I : Inflammatory Phase a. Stage of haematoma formation. b. Stage of granulation tissue.Stage of haematoma formation.Stage of granulation tissue 53

 When a bone breaks, the gap is filled with blood from the ruptured periosteal and endosteal vessels.  This blood distends the soft tissues and clots to form a haematoma.  This process takes about 1-2 daysdays 54

 The soft tissues in the region undergo the usual changes of acute aseptic inflammation with vasodilatation and exudation of plasma and leucocytes.  The clotted blood is invaded by fine capillaries and young connective tissue cells and converted into granulation tissue in about 2 weeks.  The cellular element in this mass consists of multipotent mesenchymal cells which are capable of differentiating into fibroblasts, chondroblasts and osteoblasts. 55

Stage II: Reparative Phase a. Stage of fibrocartilaginous callus. b. Stage of bony callus.Stage of fibrocartilaginous callusStage of bony callus. 56

 granulation tissue next matures into a fibrocartilaginous mass which holds the fragments together  The new bone cannot be seen on x-rays  usually lasts until 4 to 8 weeks after the injuryinjury 57

 The fibrocartilaginous mass is converted first into spongy immature bone and later into mature lamellar bone, producing bony union between the fragments in about 8-12 weeks.  This conversion takes place in some areas by membranous ossification and in other areas by endochondral ossification.  By this time clinical union of the fracture is complete. 58

Stage III: The Remodelling Stage  the newly formed bone adapts to its new function  remodel the fracture callus down to a normal sized bone cell density increases the collagen reorient along the lines of stress, the bone material itself increases in strength  continues for many months to a few years in adults and is seen better in children 59

The bone will eventually calcify and complete its healing process. 60

What is a nonunion? A nonunion is defined as a bone that does not heal after a certain period of time.  If left untreated, a nonunion will persist and may lead to more serious complications.  A nonunion is typically treated by revising fixation (plate and screws, or rods) and placing a graft material between the ends of the unhealed bone. 61

Dead bone and fibrous tissue in a nonunion fracture prevent new bone formation from occurring. 62