Stages of wound healing
Hemorrhage
Inflammation
Granulation tissue (soft callus)
Scar – Fibrosis (hard callus)
Remodeling & Wound strength

Healing – replacement by connective tissue
Regeneration – Repair of injured tissue by parenchymal cells of the same type
Cell cycle
5 phases of cell cycle
G0( Quiescent phase)
G1( Pre synthetic phase)
S( phase of DNA synthesis)
G2( premitotic growth phase)
M( mitotic phase)
Transition between the phases regulated by cyclins and CDKs( cyclin dependent kinases)
The kinases on activation will phosphorylate proteins, form mitotic spindles, cause dissolution of nuclear membranes and chromosome condensation
CDK inhibitors like TP53 are important for buying time for DNA repair, or to induce apoptosis if the DNA cannot be repaired.

Proliferative Potential
Labile cells - continuously dividing
Epidermis, mucosal epithelium, GI tract epithelium etc
Stable cells - low level of replication
Hepatocytes, renal tubular epithelium, pancreatic acini
Permanent cells - never divide
Nerve cells, cardiac myocytes, skeletal mm
Polypeptide growth factors
Most Important Mediators affecting Cell Growth
Present in serum or produced locally
Exert pleiotropic effects; proliferation, cell migration, differentiation, tissue remodeling
Regulate growth of cells by controlling expression of genes that regulate cell proliferation
Angiogenesis: bFGF, VEGF
Scar formation: TGBβ, PDGF, FGF
Remodelling: metalloproteinases
Signaling
Types of signaling between cells:
Gap junctions
Autocrine signalling
Paracrine signalling
Endocrine signalling
Synapsis
Receptors of growth factors and cytokines:
Ion channels eg Ca++ channels
Receptors with intrinsic kinase activity, eg Ras, which activates the IP3/DAG pathway
G protein coupled receptors, which either increase or decrease the cGMP in the cell- Gs and Gi respectively

Repair by connective tissue
Occurs when repair by parenchymal regeneration alone cannot be accomplished
Involves production of Granulation Tissue
replacement of parenchymal cells with proliferating fibroblasts and vascular endothelial cells
Extracellular matrix
ECM, esp basement mb is very crucial to healing
ECM has collagen, elastin, proteoglycans and hyaluronan, which act as scaffolding for tissue repair
The collagen and laminin of basement mb, and the adhesive glycoprotein of the ECM like fibronectin and laminin hold the cells via integrins in the cell mb.
Note: proteoglycans are proteins linked to glycosaminoglycans( GAG) like dermatan sulphate and heparan sulphate while hyaluronan is not linked to any proteins.


Components of the process of fibrosis
Angiogenesis - New vessels budding from old
Fibrosis, consisting of emigration and proliferation of fibroblasts and deposition of ECM
Scar remodeling, tightly regulated by metalloproteinases like collagenase, elastase, etc and protease inhibitors

Epidermal Wound healing
Induction of acute inflammatory response by an initial injury
Parenchymal cell regeneration
Migration and proliferation of parenchymal and connective tissue cellsBasement membrane crucial to wound healing: collagen in the bm binds to cells via proteins like integrins, fibronectin and laminin.
Synthesis of ECM proteins
Remodeling of parenchymal elements to restore tissue function
Remodeling of connective tissue to achieve wound strength

Healing by First Intention
Focal Disruption of Basement Membrane and loss of only a few epithelial cells e.g. Surgical Incision

Chronological events in wound healing
24 hrs: neutrophils infiltrate, clot formation, increases mitosis in the basal cells which deposit new basement membrane and meet in the midline beneath the clot.
Day 3: macrophages replace neutrophils, granulation tissue formation, epithelial cell proliferation and collagen deposition
Day 5: neovascularisation and collagen deposition peaks, epithelium matures
2 weeks: the WBC and blood vessels decrease
1 month: tensile strength of the scar increased due to cross linking of collagen, wound contraction due to myofibroblasts dermal appendages like hair follicles and sweat glands are destroyed forever
Healing by Second Intention
Larger injury, abscess, infarction Process is similar but Results in much larger Scar and then CONTRACTION

Wound Strength
After sutures are removed at one week, wound strength is only 10% of unwounded skin (Walker’ Law)
By 3-4 months, wound strength is about 80% of unwounded skin (Walker’s Law)
Granulation tissue

Healing Skin wound




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