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Repair / Healing / Regeneration
Regeneration : growth of cells & tissue replacing the lost structure.
Seen in superficial wound which damages only the epithelium It requires an intact connective tissue frame work

Healing : tissue response to a wound/ to an inflammatory process/ to cell necrosis - varying proportions of regeneration and scar formation. Occurs in organ which is incapable of regeneration Damage to the dermis cause fibrosis

Results when the connective tissue frame work is damaged.

3 groups of cells depending on the proliferate activity

Labile cells: Continuously dividing cells epithelia of skin, GIT.. Quiescent/Stable cells:Low levels of replication liver, kidney.. Permanent cells: cannot divide neurons, cardiac muscle

Adult stem cells
Reservoir of stem cells in adults Lineage specific – restricted differentiation capacity Bone marrow stem cells : Hematopoietic stem cells Trans differentiation- stem cell differentiating from one cell type to another Developmental plasticity – Multiplicity of stem cells differentiation Tissue stem cells : Liver, Brain ( Neural precursor cells),Skeletal muscle ( satellite cells), cardiac muscle.

Repair by healing, scar formation & Fibrosis
Healing : is a fibroproliferative response which patches up the damaged tissue It involves : Inflammatory response, with removal of dead tissue Proliferation & migration of parenchymal & connective tissue cells Angiogenesis & formation of granulation tissue ECM synthesis & collagen deposition Tissue remodeling & wound contraction Acquisition of wound strength

Factor influencing repair process

- Tissue environment & extent of tissue damage - Intensity & duration of stimulus - Factors retard healing : foreign body, poor blood supply - Disease states : DM, steroid intake

Goal of the repair : restore tissue to the original state Regeneration Fibrosis : chronic inflammation; connective tissue deposition Granulation tissue : pink soft granular appearance seen on the surface of the wounds. Proliferation of new blood vessels & fibroblasts with the deposition of collagen

Angiogenesis/ neovascularisation
Critical for : chronic inflammation & fibrosis; tumor growth & vascularisation of ischemic tissue Mechanism 1. From endothelial precursor cells ( EPC) 2. From preexisting blood vessels

Angiogenesis by modulation of EPCs from the bone marrow

Angiogenesis by modulation of EPCs from the bone marrow
Hemangioblasts : give rise to the generate hematopoietic stem cells Angioblasts : Proliferate, migrate and differentiate into endothelial cells. EPCs replace lost endothelial cells, reendothelisation of vascular implants & neovascularisation of ischemic organs, cutaneous wounds & tumors

Angiogenesis from preexisting blood vessels

Steps in the angiogenesis from preexisting blood vessels
Vasodilatation: NO; VEGF ( > vascular permeability) Proteolytic degradation of BM: metaloproteinases Disruption of cell- cell contact of endothelial cells: plasminogen activator Migration of endothelial cell towards angiogenic stimulus

Proliferation of the endothelial cells behind the leading front of migrating cells Maturation of endothelial cells; remodeling into capillary tubes Recruitment of periendothelial cells (pericytes & smooth muscle cells) for support & form mature vessel

Growth factors involved in angiogenesis
Most important : VEGF, Angiopoietins 1 & 2 VEGF – VEGF A, VEGF B, VEGF C, VEGF D Secreted by mesenchymal cells & stromal cells Inducing agents : hypoxia , TGF-, PDGF, TGF-  Receptors : VEGFR -1, VEGFR –2( endothelial cells) , VEGFR –3 ( lymphatic endothelial cells) Function : mobilization of EPC from bone marrow Proliferation & differentiation at the site of angiogenesis

Also stimulate proliferation and motility of endothelial cells – sprouting of new capillaries

FGF-2 can enhance these functions of VEGF-2
Angiopoietins 1 – binds with Tie2 – recruit periendothelial cells Angiopoietins 2 : Tie2 – has opposite effect PDGF – recruitment of smooth muscle cells, & TGF - - enhances the production of ECM proteins

Cutaneous wound healing
Divided into 3 phases :
1. Inflammation 2. Granulation tissue formation &

3. Wound contraction, ECM deposition &


Growth factors in wound healing
Monocyte chemotaxis : PDGF, FGF, TGF -  Fibroblast migration : PDGF, EGF,FGF, TGF- , IL-5

Fibroblast proliferation : PDGF, EGF,FGF, TNF
Angiogenesis : VEGF, Ang , FGF Collagen synthesis : TGF - , PDGF Collagen secretion : PDGF, FGF, EGF,TNF,
TGF-  inhibits

Healing by first intention/ primary union
Healing of a clean, uninfected, surgical wound approximated by sutures Incisional space filled with clotted blood with fibrin blood cells Dehydration of surface clot - scab

Within 24 hours Neutrophils at the margins move along the cut margins of the dermis Deposition of BM Fuse in the midline beneath the scab Continuous thin epithelial layer that close the wound

Day 3 : Neutrophils replaced by macrophages Granulation tissue fills incision space Vertical orientation of collagen fibers Thickening of epidermal layer

Day 5 :

Complete filling of the incision space by granulation tissue Max neovascularisation Abundant collagen; horizontal orientation Epidermal maturation

2nd week Proliferation of fibroblasts Continuous accumulation of collagen Disappearance of inflammation & oedema By 4 weeks scar is made of cellular connective tissue covered by intact epidermis

Fibrous union

Healing by second intention
when the loss of cells and tissue is extensive Regeneration of parenchyma cells is not complete Differences from the primary healing Large tissue defect; intense inflammatory reaction Large amount of granulation tissue Wound contraction which occurs in the surface wounds : Net work of actin containing fibroblasts at the wound edge ; permanent contraction by myofibroblasts Substantial scar formation & thinning of epidermis

Wound strength
1st week : 10 % of unwounded skin 4th week : increases rapidly 3 months : reaches a plateau ( 7-80 5 of strength

Factors adversely affecting healing
Systemic factors Nutrition : protein & Vit C deficiency inhibit collagen synthesis Metabolic status : DM : microangiopathy Circulatory status : Inadequate blood supply – AS; varicose veins Hormones : Glucocorticoids : inhibit collagen synthesis Anemia, uremia, trace metal – Zn, Cu deficiency, systemic infections..

Local factors:
Infection : persistent tissue injury & inflammation Mechanical factors : early motion of the wound: separate wound edge & compress blood vessels Foreign body suture, glass, bone .. Retard healing Site, location & type of wound : site with rich vascular supply heal faster ; Small incision wound heal faster than large wounds caused by blunt trauma Denervation, hematoma, necrotic tissue ….

Complications in cutaneous healing
Deficient granulation tissue /scar formation : wound dehiscence & ulceration – pressure / inadequate blood supply; neuropathic ulcers Excessive formation of repair components : hypertrophic scars; keloid; exuberant granulation tissue ( blocks re epithelisation); aggressive fibromatosis( desmoids ) Formation of contractures : wound deformities - in burns impaired wound contraction : Stromelysin 1 deficiency

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