Wound Healing
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How does foetal repair differ to adult?
foetal repair == regeneration, scarless healing
Outline the stages of mesengenesis
• Mesenchymal stem celles • Commitment • Lineage progression (becoming an osteoblast, tenoblast, pre-vSMC, pre-fribroblast etc. • Differentiation and maturation (becoming an osteocyte, tenocyte, vSMC, fibroblast etc.) • Tissue formation (bone, tendon, vessel, skin etc.)
What regulates the migration, proliferation and differentiation of cells; synthesis and degradation of ECM protein?
soluble factors
How are the ECM and cells linked?
Dynamic relationship - collagen and elastin affected by ECM, ECM in turn affected by resident cells
Which cells organise new tissue?
• resident mesenchymal derived stromal cells - deposit and cross link matrix
Outline 6 stages of wound healing
• coagulation and initial acute inflammatory response • parenchymal regeneration (resident functional/not stromal) • re-epithelialisation and cell migration • proliferation of parenchyma and stromal cells • Synthesis of ECM proteins • Remodelling
What are the 3 “classic” stages of wound healing? How long roughly do these persist for?
• inflammation ~48hours (hypoxic, fibrin clot, abundant bacteria, platelets then neutrophils) • New tissue formation [granulation and re-epitheliasation, angiogenesis] ~2-10days (surface scab, most inflame cells moved away, new blood vessels predominate, epithelial cells migrate under scab) • remodelling/maturation ~1year+ (disorganised collagen laid down by fibroblasts, wound contracted near surface but deep bit still wide, re-epithelialized wound raised.
Which other tissue fixes itself in a similar way to skin?
Bone - woven bone forms at Fx site as bone laid down quickly rather than neatly
Which cells predominate in the coagulation phase?
platelets
Which cells predominate in the inflammatory phase?
neutrophils (also platelets and macrophages)
Which cells predominate in the new tissue formation (proliferation) phase?
macrophages and fibroblasts (also lymphocytes, epithelial and endothelial cells)
Which cells predominate in the matrix remodelling phase?
fibroblasts and lymphocytes
What events happen initially after injury to epithelium and underlying dermis?
• death of epithelial and dermal cells • damage of collagenous fibres in tissue • small vessel rupture -> vasodilation and permeability • release of blood into wound and surrounding tissue • coagulation • platelet deposition and aggregation • de-granulation releasing PDGF, TGFb, fibronectin • formation of fibrin clot
What happens during the inflammatory phase?
• attraction and activation of infiltrating cells (leucocyte influx) • neutrophils phagocytose matrix and release free radicals • monocyte/macrophages debride wound and encourage matrix turnover, provide stimulatory signals • lymphocytes recruited later, important in early remodelling
outline 5 main roles of macrophages in wound healing
• removal of wound debris (phagocytosis and matrix degredation using collagenases, elastase) • cell recruitment and activation via cyto and chemokines, growth factors • phagocytosis (antimicrobial function ROS) • angiogenesis using VEGF -matrix synthesis regulation via > growth factors (PDGF, TGFb) > cytokines (TNFa, IL1, IFNg) > degradive enzymes • eicosanoids (PGs)
What occours during the first half of the migration/proliferation stage?
• single keratinocyte layer migrates under fibrin clot, from wound edges • during/after migration, differentiation and stratification of neo-dermis occours
outline 5 main roles of keratinocytes in skin healing?
• migration/proliferation via integrins and adhesion molecules • ECM production inc basement membrane • growth factor/cytokine production via VEGF, TNFa, PDGF • angiogenesis via chemoattractants and VEGF • release of proteases to dissolve non-viable teissue and penetrate fibrin barrier
What occours during the second half of migration/proliferatioin stage?
• re-epithliasation and angiogenesis • fibrin clot - platelets and inflammatory cells secrete factors to promote re-epithelialisation • endothelial cell migration into wound • angiogenesis begins as endothelial cell buds, move along ) graidents and VEGF • macrophages andkeratinocytes (epithelial cells) provide angiogenic stimuli
What cells, factors etc. does vascular development require?
Arterial and venous endothelial cells producing VEGF Pericytes and smooth mm. cells producing PDGF to coordinate development
How else may angiogenesis occour?
• sprouting of new capillaries from parent vessels • initiated by GFs (bGF, VEGF) from nearby cells or inflame/hypoxia • endothelial cells produce proteases (MMP) to digest surrounding BL • cells migrate towards GFs, proliferate and divide • cells form tubes, leaky at first hence granulation tissue is usually oedematous, become less leaky as tubes acquire surrounding cells
What occours in the 3rd stage of migration/proliferation?
• fibroplasia • fibronblasts migrate into wound, synthesis and deposit ECM (collagen and proteoglycans) • fibroblasts turn into myofibroblasts and express contractile proteins (-> itching)
What is the role of fibroblasts in connective tissue formationand remodelling?
> ECM production (bond intracellular actin and ECM) - acts as scaffold for tensile strength > GF and cytokine production - EGF, FGF, CTGF, PDGF, Activin > Protease release - ECM remodelling, degrading non viable tissue and ECM > migration/proliferation - recruited from nearby tissues
When is granulation tissue established?
3-5d post injury
What does granulation tissue look like? What is it composed of?
• pink, soft, granular tissue below scab - fibroblasts, thin walled capillaries and loose ECM