Define resolution following tissue injury
Damaged tissue returns to normal and normal function is regained.
Occurs where there has been minimal damage to tissue architectureand support structures, allowing damaged cells to regenerate from residual stem cells.
Define regeneration of damaged tissue
Growth of cells and tissues to replace lost structures.
Requires intact tissue architecture and support structures or the ability to reproduce them.
Limited to certain cell types. Liver and kidney do not normally divide but can rapidly proliferate in reponse to damage. Surface epithelia are continually dividing and can regenerate following damage. Nerves and cardiac muscles cells cannot divide, loss is permanent.
When does fibrous repair occur?
In response to Wound e.g. skin and Inflammatory process in internal organs
Cell necrosis in organs, which are unable to regenerate
The extracellular matrix is damaged
Granulation tissue is formed, followed by collagen deposition
What are labile cells?
Continuously dividing cells.
Proliferate throughout life from stem cells
e.g. GI tract, skin
What are stable/quiescent cells?
Cells have a low level of replication under normal circumstances (G0) but undergo rapid division in response to stimuli
e.g. liver and kidney when damaged, osteocytes
What are permanent cells?
Terminally differentiated cells that cannot divide in postnatal life
e.g. cardiac muscle, nerve cells, skeletal muscle
What are the five steps of healing and repair?
Angiogenesis from existing vessels
Mitogenesis - local cells divide producing fibroblasts
Chemotaxis: Cells migrate towards damage
Fibrogenesis – collagen produced
Remodelling – collagen degrading enzymes produced
Give an example of a resolution of inflammatory exudate and describe the process that occurs
Type of acute inflammation of the lung that results from damaged caused by pathogenic bacteria within the alveolar air sacs.
Body produces an acute inflammatory exudate (neutrophils, macrophages, protein, fibrin, fluid) which enters the alveolar lumen. This spreads rapidly through the alveoli in a particular lobe of the lung and reduces the capacity for gaseous exchange.
Cells lining the alveoli die, but the stroma and vascular structure remains intact. If the patient is treated with antibiotics the neutophils in the exudate destroy the bacteria and remve dead cells. Exudate is removed and epithelial cells are regenerated, gaseous exhange can begin.
What is granulation tissue?
Specialised organ of tissue repair
What are the components of granulation tissue?
Macrophages and myofibroblasts
Other inflammatory cells
Growth factors and antibodies
Describe the role of angiogenesis in tissue repair
Pre-existing capillaries in the undamaged tissue form new capillaries by budding into the damaged area. Influenced by mainly by VEGF
Endothelial precursors from the bone marrow also migrate to areas of damage and being to rpoliferate and differentiate into new capillaries.
This forms the vascular granulation tissue, which is a fragile complex of interconnecting capillaries, macrophages and supporting cells. Replaces the area of tissue damage
How is fibrovascular granulation tissue formed?
Formed from chemotaxis and migration of fibroblasts and myofibroblasts.
Macrophages secrete TGF-beta and other cytokines (PDGF, FGF) which promote fibroblast growth and migration to the damaged tissue.
Activated fibroblasts beigin to synthesise and secrete collagen
Epidermal tissue slowly begins to grow over the layer of granulation tissue
Describe the role of fibrogenesis in healing and repair
Fibroblasts are activated by TGF-beta and cytokines released by macrophages, and being to synthesise and secrete collagen.
[some newly formed capillaries regress and a small number of vascular channels remain]
Fibroblasts align, so collagen is deposited in a uniform pattern running in the direction of greatest stress, which increases tensile strength (fibrous granulation tissue).
Contraction of the area of granulation tissue occurs through the action of myofibroblasts. The size of the damaged area is reduced.
Production of dense collagen by the fibroblasts forms a collagenous scar
How is the strength of a wound increased following scar formation?
Maturation and remodelling of the collagen. This involves degradation and cross linking of collagen.
MMPs (zinc dependent) degrades the collagen produced in granulation tissue (type III) which is replaced by dense type I collagen.
Define healing by primary and secondary intention
Healing by primary intention is when healing occurs between closely apposed surfaces, with a minimal amount of dead tissue limited to the edges of the wound. Re-epithelialization occurs close to the wound and a small scar forms.
Healing by secondary intention is healing of larger open wounds where there has been extensive loss of cells. The epidermis regenerates at the base and is filled in by granulation tissue. The healing process takes longer and there is more contraction, producing a collagenous scar.
Name 4 local factors which affect tissue healing and repair
Foreign material (dead tissue, sutures)
Apposition of the tissue (larger wounds take longer to heal)
Name 4 systemic factors which affect tissue healing and repair
Inadequate nutrition (zinc - MMPs, Vitmain C - collagen)
What is a keloid scar?
Smooth hard nodules that form due to excessive collagen production. They may occur spontaneously or follow skin trauma/surgery and they are often itchy.
Unlike hypertrophic scars (which fade within 12 months) keloids are persistent and may continue to enlarge.
Treated with steroid injections
Describe the process that occurs in the two weeks following a skin injury.
Day 1: Acute inflammatory cells response, epithelial cells start to divide and migrate
Day 2: Macrophages infiltrate wound and epithelial cells continue proliferating
Day 3-5: Vascular granulation tissue progressively deposited, epithelial layer thickens
Day 7: Wound has 10% tensile strength of normal skin
Day 10: Further fibroblast proliferation and collagen deposition increases the strength of the wound
Day 15: Collagen depositon follows stress lines, granulation tissue loses some vascularity
After 30 days wound has 50% tensile strength, in 3 months, 80% tensile strength
Regeneration and scar formation by the deposition of collagen.
Fibroproliferative response that 'patches' the damage. Tissue is not restored.
Describe the process of healing and repair
1. Angiogenesis: pre-existing capillaries sprout into the damaged area (stimulated by VEGF). Endothelial precursors from BM migrate to damaged area. Forms vascular granulation tissue
2. Mitogenesis and chemotaxis: fibroblasts migrate to site and start to proliferate (stimulated by TGF-beta). Collagen actively synthesised.
3. Fibrogenesis: fibroblasts continue to produce collagen and allign in areas of greatest stress. Collagen is uniform, increasing tensile strength. Forms fibrous granulation tissue
4. Remodelling: MMPs stimulated by PDGF cleave collagen and remodel the scar. Type III collagen replaced with type I (stronger)
Myofibroblasts around the edge of the wound contract and secrete ECM components.
Occurs in large surface wounds to decrease the gap between wound edges.
Briefly describe the stages of healing and repair of a fracture
Organisation: formation of a haematoma. Blood clots and dead cells induce inflammation. Macrophages and osteoclasts remove dead bone from the fracture site
Granulation tissue (callus) formation: Ingrowth of capillaries forms vascular granulation tissue.
Fibroblast growth: Fibroblasts from the periosteum invade the procallus and begin to synthesise collagen.
Proliferation of osteoblasts: Platelets and inflammatory cells release PDGF, TGF-beta and ILs which activate osteoprogenitor cells. Osteoblases deposit osteoid, which is mineralised, forming woven bone.
Remodelling: Woven bone is remodelled along lines of stress by osteoclasts and osteoblasts into lamellar bone.
Briefly describe the stages of healing and repair of a peripheral nerve
Proximal stumps of degenerated axons sprout and elongate to develop growth cones.
Growth cones are guided to the tissue by schwann cells which release chemotactic factors.
Growth rate is ~2mm/day