0.4 Wound Healing Flashcards
What are the definitions of regernation, repair, and healing?
Regeneration = replacement of injured tissue by parenchymal cells of the same type
Repair = replacement of injured tissue by fibrous tissue
Healing = regeneration, repair, or some comibination of the two
Woung healing can be achieved through regeneration or through repair (scar formation). What makes these processes different?
Regeneration = proliferation of residual + injured cells and maturing of tissue stem cells
Repair = connective tissue deposition / laying down fibrous tissue to enable structural integrity (NOT FIBROSIS)
Regeneration can occur in 3 types of cells, what are they?
- Labile cells
- Stable cells
- Permanent cells
What is the proliferative capacity of labile cells and where are they most commonly found?
Normally proliferate to replace cells that are being continually lost
Found: gut epithelium and bone marrow stem cells
What is the proliferative capacity of stable cells and where are they found?
Do not normally proliferate, but capable when required
Examples: fibroblasts, endothelial cells, and hepatocytes
What is the proliferative capacity of permanent cells and what are some examples?
Rarely proliferate
Examples: CNS neurons and cardiac myocytes
Many signals drive cellular proliferation, but what are the two main sources?
- From cells via growth factors
- From the ECM from integrins
What are possible sources for cell derived proliferation signals?
Macrophages
Endothelial cells
Epithelial cells
Stromal cells
How do cell derived proliferation signals work?
- Bind to ECM proteins
- Accumulate at site of tissue injury
- Ultimately signal gene expression that drives cell division
What are integrins and what so they do?
Integrins = Cell adhesion molecules
Roles:
1. Signal cell proliferation (mitosis leading)
- Signal quiescent stem cell activation + maturation
The intestinal epithelia is a good example of tissue regeneration as it is constantly dividing and regenerating. How does this process work?
- Toxins destroy the top surface, encouraging proliferation response
- If underlying base membrane is intact, proliferation of residual cells + differentiation of cells occurs
- Newly generated cells migrate to fill the defect = cells are pushed from the basement membrane to the surface
- Tissue integrity is restored
Parenchymal organs have some regenerative capacity but this is usually a limited process (liver excepted). What are the 4 other parenchymal organs?
- Pancreas
- Adrenal
- Thyroid
- Lung
The liver can regenerate in two ways. What are they?
- From hepatocytes
- From progenitor cells
What drives liver regeneration from hpetocytes and what amount can be corrected via proliferation?
Partial hepatectomy of up to 51-71% of liver can be corrected via residual hepatocytes
Kupffer cells drive this process via IL-6 + hepatocyte growth factor (HGF)
When would liver regeneration from progenitor cells occur and where do these progenitor cells come from?
Occurs when proliferative capacity of hepatocytes is impaired (ie chronic liver injury or inflammation)
Some of these cells reside in specialised niches call Canals of Hering (where bile canaliculi connect with larger bile ducts)
What are the major differences between first intention and second intention healing?
- First intention = surgeon involved, closed aseptic wounds
Characterised by: sutured margins promiting re-attachment and no infection
- Second intention = normal injury
Characterised by: torn + devitalised margins making attachment impossible and infection
What are the 4 stages of healing?
- Haemostasis = stop bleeding
- Inflammation = stop bacteria
- Proliferation = granulation tissue (soft callus) + scar / fibrosis (hard callus)
- Remodelling = contraction + scar maturation
What is the first stage/priority of the healing process and how is it achieved?
Haemostasis
Stop the bleeding via arteriole vasoconstriction and wound coagulum
What is wound coagulum?
Blood clot
A three-dimensional meshwork of fibrin filaments + platelets
What is the second stage/priority of the healing process and how is it achieved?
Inflamamtion
Warding off bacteria via recruitment of cells
WBC migrate form capillaries in response to cytokine signals within 6 - 48 hours after injury
What 2 things are responsible for recruiting neutrophils, and then monocytes?
- Chemotactic agents from complement activation
- Chemokines (IL-8) from activated platelets
Macrophages play a central role in repair and are recruited after neutrophils. What are the roles of M1 and M2?
M1 = clear microbes, necrotic tissue, and promote inflammation in a positive feedback loop
M2 = produce growth factors that stimulate proliferation of many cell types
What is stage 3 of the healing process and how is it characterised?
Proliferation
Epithelial, endothelial, and fibroblasts proliferate and close the now clean wound (takes up to 10 days)
Result = granulation tissue which is highly vascular (leaky w/ oedema)
What 3 cell types are involved with proliferation and what are their individual roles?
- Epithelial cells = produce local growth factors + migrate over the wound creating a seal
- Endothelial cells = proliferate to form new blood cells (angiogenesis)
- Fibroblasts = proliferate + migrate to lay down collagen fibres and ECM components at injury site
What is angiogenesis?
The sprouting of new blood vessels
What factors mediate angiogenesis?
VEGF-A = stimulates migration + proliferation of endothelial cells
What is the role of matrix metalloproteinases (MMPs) in angiogenesis?
MMPs degrade ECM to permit remodelling and extension of vasculature
What is stage 4 of the healing process?
Remodelling = depsoited collagen fibres are reorganised to produce a stable fibrotic scar
Wound gains ~20% strength by 3 weeks. A scar is only about 70% of normal skin.
How is collagen synthesis and degradation in remodelling controlled?
Metalloproteinases (produced by macrophages, epidermal cells, endothelial cells, and fibroblasts)
How do scars mature?
- Progressive vascular regression (tranforming highly vascularised granulation tissue to pale, avascular scar)
- Wound contraction
How does wound contraction happen?
Fibroblast transformation into myofibroblasts via TGF-beta and PDGF
Scar tissue = firmer, less flexible and can cause permanent flexion of tissue
Eventually, conenctive tissue is degraded and the scar shrinks. How does this occur?
- Degradation of collagen and other ECM components via MMPs
- Activated collagenases can be rapidly inhibited by TIMPs (tissue inhibitors of metalloproteinases) produced by mesenchymal cells
- Balance of MMPs and TIMPs = regulation of size + nature of scar
Which MMPs are responsible for which roles in the degradation of collagen and other ECM components?
MMP 1, 2 & 3 = interstitial collagenases which cleave fibrillar collagen
MMP 2 & 9 = gelatinases which degrade amorphous collagen and fibroconectin
MMP 3, 10 & 11 = stromelysins which degrade a variety of ECM constituents such as proteoglycans, laminin, fibronectin, and amorphous collagen
In brief, what 3 aspects mark the maturation of a wound into scar tissue?
- Removal of vessels
- Removal of fibroblasts
- Accumulation of collagen
What are possible systemic factors affecting healing?
- Nutrition
- Vitamin deficiency
- Age
- Immune status
- Other diseases
What are the possible local factors affecting healing?
- Necrosis
- Infection
- Apposition
- Blood supply
- Mobility
- Foreign body
Intrinsic and Extrinsic factors can affect the quality of the reparative process. What are 6 factors that impair tissue repair?
- Infection
- Diabetes
- Nutritional status
- Glucocorticoids (steroids)
- Mechanical factors
- Poor perfusion
How does infection impair tissue repair?
Most important/common cause of delayed healing
Prolongs information and potentially increases the local tissue injury
How does diabetes impair tissue repair?
A metabolic disease that compromises tissue repair and is a systemic cause of abdominal wound healing
How does nutritional status impair tissue repair?
Protein malnutritionand vit C deficiency, for example, inhibit collagen synthesis and slow healing
How do glucocorticoids impair tissue repair?
Weakens scar tissue as they inhibit TGF-beta production and diminishes fibrosis
Sometimes a desirable anti-inflammatory effect though
How do mechanical factors impair tissue repair?
Increase local pressure may cause wounds to pull apart
What are the key differences in healing in nature and in human surgical practice?
