Healing & Repair

Question 1

Processes involved in healing and repair

Answer 1

Angiogenesis, granulation tissue, epithelial cell regeneration, extracellular matrix collagen synthesis, tissue repair, myofibroblast, wound contraction

Question 2

Regeneration involves?

Answer 2

Complete restitution of lost/damaged tissue type and structure
Depends on proliferative ability of cells and integrity of ECM
Involves tissue specific stem cells

Question 3

Organisation involves?

Answer 3

Deposition of collagen to fill gap, with end point being a fibrous scar with no original tissue function
Involves fibroblasts and growth (fibrogenic) factor secretion

Question 4

Role of macrophages

Answer 4

Clear site of inflammation of dead neutrophils and cell debris
Secrete cytokines and growth factors to promote ECM synthesis
(e.g. collagen proteoglycans, hyaluronic acid, elastin)

Question 5

Processes of healing & repair

Answer 5

1. Granulation tissue formation
2. Organisation and fibrous repair
3. Wound contraction
4. Scar maturation and healing

Question 6

What is involved in granulation tissue formation?

Answer 6

1. Cell regeneration
   - Formation of fibrous scar
   - Involves myofibroblasts, fibroblasts, stromal stem cells, endothelial cells
2. Cell migration
   - Re-epithelialisation
   - Cell-ECM interaction: cadherins, secretins, integrins

Question 7

What is involved in organisation and fibrous repair?

Answer 7

1. Angiogenesis
   - So that neutrophils can clear cellular debris
   - Induced by vascular endothelial growth factor
   - Endothelial cells divide to form solid sprouts, intracytoplasmic vacuoles fuse to form lumen, forming vessels, and vessels join to form an arborising network
   - This forms the temporary vascular network that will later be reabsorbed and replaced with fibrous tissue
2. ECM synthesis and modelling
   - Fibroblast and myofibroblast proliferation
   - Deposition of collagen and cross-linking of collagen fibres
   - Stimulated by growth factors e.g. PDGF, FGF

Question 8

What is involved in scar maturation and healing?

Answer 8

Stimulate matrix metalloproteinases to degrade collagen to balance formation
Promoted by PDGF, FGF, IL-1, TNF

Question 9

**ONLY tissues with pluripotent stem cells can regenerate
Proliferative capacity of cells in tissue

Answer 9

Labile tissues - continuously dividing (e.g. skin, GIT, haematopoietic cells)
Quiescent (stable) tissues - usually in G0 but can be stimulated to enter cell cycle (e.g. liver, fibroblasts, endothelium, smooth muscle)
Permanent tissues - permanently in G0 (e.g. cardiac, neurons)

Question 10

Since chemotherapy targets rapidly dividing cells, what are some potential side effects?

Answer 10

Skin - hair loss
GIT - vomiting + diarrhea
Bone marrow - immunosuppression (decreased WBC)
anemia (decreased RBC)
thrombocytopenia (decreased platelet count)

Question 11

Activation of fibrous repair

Answer 11

Persistent stimulus activates macrophages and lymphocytes
Macrophages and lymphocytes secrete growth factors, cytokines and decrease metalloproteinase activity
Growth factors stimulate proliferation of fibroblasts, endothelial cells, specialised fibrogenic cells, increasing collagen synthesis
Cytokines stimulate collagen synthesis
Decreased metalloproteinase activity results in decreased collagen degradation
Hence fibrosis

Question 12

Stem cell therapy

Answer 12

Ectoderm - neurons in Alzheimer’s disease, multiple sclerosis
Mesoderm - cartilage for osteoarthritis, stenosed arteries
Endoderm - liver

Question 13

Myofibroblasts

Answer 13

Derived from fibroblasts, epithelial cells, endothelial cells
Help secrete ECM (collagen)
Important for wound contraction - expresses smooth muscle actin and myosin
Undergoes apoptosis after wound healing is complete

Question 14

Scar maturation

Answer 14

Collagen synthesis - vitamin C required, initially type III is produced and later replaced by type I
Procollagen cleaved into collagen - increased tensile strength through cross-linkages

Question 15

Systemic factors affecting wound healing

Answer 15

Nutrition - vit C and zinc needed to synthesise collagen
Metabolic status - diabetes and hypothyroidism slows healing
Circulatory status - need good blood supply
Hormones - glucocorticoids inhibit collagen synthesis

Question 16

Local factors affecting wound healing

Answer 16

Infection - persistent tissue damage slows healing
Vascular - varicose veins and diabetes slow healing
Size, location and type of wound
Radiation

Question 17

Pathologic aspects of repair

Answer 17

Defective scar formation - dehiscence/rupture, incisional hernias
Excessive scar formation - hypertrophic scar, keloids
Excessive wound contraction - contracture (elastic tissue replaced by inelastic)

Question 18

Tissue healing examples

Answer 18

Fibrosis of valves > aortic and mitral stenosis > infective endocarditis > sepsis
Constructive pericarditis > HF
Myocardial infarction > fibrosis (permanent tissue)
Lungs - as long as basement membrane remains intact, can regenerate e.g. in pneumococcal pneumonia
Liver - fibrosis replaces sinusoids
Kidneys - glomerular damage is permanent but cortical tubules can regenerate

Question 19

Pure epidermal lesions

Answer 19

Regenerated by epithelial proliferation, no fibrous scarring

Question 20

Ulcers

Answer 20

Involves subserosa in stomach
Implies injury to both epidermis and dermis
Fibrous scarring occurs once dermis and deeper tissues are involved

Question 21

Cutaneous wounds - healing by primary intention (surgical procedures)

Answer 21

Wound with closely apposed edges (e.g. surgical scalpel incision)
Minimal hematoma (collection of blood outside blood vessels)

2 days: Re-epithelialisation of epidermis
6 days: Well-formed granulation tissue (angiogenesis) with beginnings of dermal collagenisation
4 weeks: Mature collagenisation with good tensile strength in wound, with minimal wound contraction
12 weeks: Complete wound healing and repair with minimal/small scar formation

Question 22

Cutaneous wounds - healing by secondary intention

Answer 22

Large gaping wound with skin edges not apposed (e.g. laceration, skin ulcer)
Big hematoma
Large area of inflammation and granulation (angiogenesis) formation
Much longer time taken to form epidermal cover. Much more tissue fibrosis and wound contraction.
Larger deforming scar formed

Question 23

Complications of peptic ulcer in stomach

Answer 23

Rebleeding - if ulcer goes to one of major gastric vessels
Fistula
Decreased contractility - replacement of smooth muscle with fibrous tissue, causing obstruction and vomiting
Perforation - peritonitis (gastric acid digests peritoneum, causing septic shock)
Pyloric stenosis

Question 24

Complications post myocardial infarction/healing

Answer 24

Decreased contractility - cardiac muscle replaced by non-contractile fibrous tissue
Ventricular aneurysm - thromboembolism can go to any part of systemic circulation (formed from turbulent blood flow or stasis of blood)
e.g. Cerebral arteries > stroke > brain infarct
Renal arteries > renal artery stenosis > renal infarct
Cardiac tamponade - accumulation of blood in the pericardium squeezes and constricts heart from pumping blood properly
Ventricular tachycardia/ventricular fibrillation/arrhythmia - replacement of conduction system (SA node, AV node, Purkinje fibres) with fibrous tissue

Question 25

Lung healing post infection/pneumonia

Answer 25

If basement membrane is intact (minor injury, ECM matrix intact), type 2 pneumocytes are able to re-epithelialise the denuded and damaged areas and proliferate to form mature pneumocytes. Complete resolution with minimal lung scarring is possible.

If basement membrane is not intact (pneumonia, infectious trauma, ECM matrix not intact), there will be intra-alveolar as well as interstitial organisation and fibrosis (scarring).

Question 26

Liver healing and repair

Answer 26

Hepatocytes have huge (but not infinite) regenerative capacity. Outcome depends on severity and chronicity of disease. Hepatic stem cells are located near the bile ducts, where the sinusoids are.

Acute injury: Usually complete regeneration and restoration of structure and function is possible if connective tissue stroma, vasculature and bile ducts are intact. e.g. Acute chemical injury, acute fulminant viral hepatitis

Chronic persistent liver injury (if bile ducts in sinusoids are affected, stem cells die): Combination of fibrosis and regeneration. End point is liver cirrhosis and its inherent complications (e.g. hypoalbuminemia, portal hypertension, immunosuppression, inability to detoxify drugs) Most common causes are chronic viral hepatitis and alcohol abuse.

Question 27

Kidney healing and repair

Answer 27

Glomerular injury is irreversible. No regeneration. Healing is through fibrosis.
Cortical tubules can be regenerated completely if basement membrane is intact and injury is not prolonged.
Medullary tubules damage are usually associated with damage to interstitium and blood vessels. Healing is usually by fibrosis.

Question 28

Central and Peripheral Nervous System

Answer 28

Mature neurons are permanent cells. Lost neurons cannot be regenerated. Axons can be regenerated if cell body is undamaged.

Gliosis (proliferation of glial cells) is the equivalent of fibrous scarring in the CNS.

Spinal cord injury: Regeneration of axons is still possible up to 2 weeks after injury.

Question 29

Fracture Healing

Answer 29

Fracture/break is initially bridged by a hematoma (blood clot) and later granulation tissue and collagenous fibrous tissue (fibrosis).

Cytokines and growth factors stimulate proliferation of osteoblasts from endosteum and periosteum to form/deposit new immature woven bone (callus) to bridge the gap. Callus has no strength and tears easily. Need to immobilise with cast.

Bone remodelling (osteoclasts) occurs with formation of mature lamellar bone which has good tensile strength. (Takes time for woven bone to be replaced with lamellar bone + lamellar bone is weaker and more prone to re-fracture) Metal screws and plates are added to align such that mature lamellar bone can be deposited in the right direction.

Question 30

Complications of fracture healing

Answer 30

Non-union of bone
Fibrous union of bone - pseudoarthrosis (false joint), unstable, worse in weight-bearing joints/bones
Malunion of bone - union with angulation, mildly unstable
Infection/osteomyelitis - especially when bone is exposed - need to drain abscess because antibiotics do not reach the bone

Question 31

Factors that affect one’s healing process

Answer 31

Wound infection (wound debridement, surgically debrided?)
Age
Nutritional status - e.g. Vit. C deficiency
Medical history - connective tissue disorders e.g. Marfan Ehlers Danlos syndrome
Drug history - e.g. steroids for asthma

Question 32

Liver cirrhosis histology

Answer 32

Regenerating hepatocyte nodules surrounded by dense bands of collagenised fibrous tissue. Permanent, irreversible liver injury

Question 33

Role of HIF-VEGF-PIGF Pathway in fracture

Answer 33

As a consequence of fracture, blood vessels in the bone rupture and cause fracture site to become hypoxic. VEGF and PIGF expression stimulates the angiogenic response. Together with other cytokines, PIGF recruits inflammatory cells to clear cellular debris, and induces the proliferation of periosteal cells (a source of osteogenic cells). In the subsequent phases, PIGF contributes to the turnover of the cartilage matrix and remodelling of the newly formed woven bone by controlling osteoclast formation.