Wound healing Flashcards

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1
Q

Recap

A

Normal homeostasis

  • gets bombarded - you end up with an injury
  • which leads to acute inflammation
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2
Q

What happens from the outcome of acute inflammation ?

A

2 process of outcome:

  • outcome of that is that either you go through a process of repair which leads to perfect regeneration
  • your body is able to restore the are exactly how that is before- ideally but rare that occurs
  • Some tissues then regenerate but then go through a process of compensatory growth- e.g when you give a part of your liver to someone - you have a smaller liver but start to grow back slowly . - form of regeneration-
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3
Q

What happens after an injury ?

A

left with a wound site- left with lost tissue, lost cells and damaged extraellualr matrix that you need to fill and recover
-try to restore that area back

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4
Q

What is chronic inflammation ?

A
  • sometimes you can get wound closure- return back to a stable environment but can’t get rid of initial inflammatory cause- if you are repairing the site but still have the bacterial inflammation that you r body can’t get rid of- it will seal the bacterial infection in - it will still continue to cause inflammation and will continue to degrade some of the wound healing that you have started already and body is triggered to do more wound healing - cycle of healing, destruction from what’s causing inflammation, then healing again etc.- which is chronic inflammation
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5
Q

What can chronic inflammation cause ?

A

scarring reffered to as fibrosis

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6
Q

What is wound repair ?

A

ability to restore normal function and structure

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7
Q

What is regeneration ?

A

perfect restoration with no scar formation

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8
Q

what are the cell proliferation properties ?

A

3 types

-type of wound healing dependant on the particular cell type in that area

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9
Q

What are the 3 types ?

A
  1. Labile-
  2. Stable
  3. Permanant
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10
Q

What is cell proliferation ?

A

ability to divide and make new cells from their cells

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11
Q

What are labile cells?

A

constantly replicating
-tend to be epithelial cells
-divide and proliferate continuously throughout life
-derived from adult stem cells - cells that have capability to differentiate into different types of cell - they are most of those stem cells become adult cells during development
-But end up with some as pockets around the body such as in the bone marrow for producing blood cells - where you canc continuously get anew source of cells form
-

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12
Q

What are stable cells?

A
  • sitting performing normal homeostasis function
  • but if they are exposed to right chemical signals they can be induced to undergo mitosis, proliferate and start to increase in number to fill the space
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13
Q

What are permanant cells ?

A
  • cells that cannot replicate - once they become the cell type they are- if they damage - the cell is lost permanently
  • e.g certain neurones in brain and eye /retina .
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14
Q

Why do you continue to produce labile cells ?

A

because cells that you produce have a very limited lifespan
-for example gut epithelium
,corneal epithelium and blood cells

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15
Q

What is the corneal epithelium labile cells produced ?

A
  • transparent region of the front of the eye - cornea
  • around the edge where sclera meets the cornea - this region is the limbus
  • Have pockets of adult stem cells all around your eye, limbus- which continually produce epithelial cells which migrate over you cornea
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16
Q

Why do you have a continous production of epithelial cells down near your limbus?

A

Because the replacement of those corneal epithelium cells - due to being exposed to the tear film - have the ability to dry out pretty rapidly If you can’t produce enough tear film - leave your eyes open for too long - epithelial cells start to go through stress and die
-continues to produce epithelial cells near your limbus - they migrate to cornea

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17
Q

What happens to the dead cells in the central cornea ?

A

they are squeezed out and removed in the tear film every time you blink - stop dry eyes

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18
Q

What are the stable cells like ?

A
  • These cells normally divide at a slow rate.
  • However when stimulated by the right growth factors/ chemical signals (for e.g cytokines) they can significantly increase their replication/ proliferation rate and divide more rapidly: Hyperplasia
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19
Q

What are the different cells that they reproduce for when the right chemical signal is stimulated ?

A
Hepatocytes
Fibroblasts-
Vascular Endothelial Cells
Smooth Muscle cells
Osteoblasts- make bone
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20
Q

What are the permanent cells like ?

A

-These cells cannot divide, they cannot go through mitosis.
-However they may be capable of some cellular repair if necrosis is not initiated.
Examples
Neurons
For example rods, cones, ganglion cells of the retina
Cardiac Myocytes

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21
Q

What is proliferation ?

A

is cell division by means of mitosis.

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22
Q

How can mitosis be induced/triggered?

A

by exposure to cytokines- mediators of information

-Intergrin signalling

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23
Q

What is intergrin signalling ?

A

proteins expressing in cell surface which can signal to initiate that cell to undergo mitosis

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24
Q

How is extracellular matrix damaged in this injury ?

A
  • if damage cells , extracellular matrix around the damaged cell (secreted proteins and sugars by the cells forming whir scaffolding) is untouched
    -any residual damaged cells can proliferate , migrate and fill the pre-exisiting scaffold which is perfect for regeneration
    -
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25
Q

What can you do If you extracellular matrix is not damaged ?>

A

repair through regeneration

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26
Q

What happens if the cell is damaged and extracellular matrix (scaffolding) ?

A

you can’t regenerate because you also need to degrade and regenerate extracellular matrix so you go through wound repair - would healing

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27
Q

What is your extracellular matrix ?

A
  • not purely there just for scaffold - not purely mechanical
  • it is also there because it controls cell growth- through inter-grin cellular receptors (proteins expressed on cells surface and interact directly with extracellular matrix-
  • Maintain cell differentiation – Again Integrin Receptors
  • Scaffold for Tissue Renewal- Requires Basement Membrane – IF the basement membrane is damaged then you will get scar formation.
  • Storage & Regulation of Cytokines for rapid deployment (ie Epidermal Growth Factor; EGF, fibroblast growth factor; FGF)
Components: 
Collagen
Type I – bone, tendon, scars
Type III – tissue scaffold/ interstitial matrix
Type IV – basement membranes

Elastin
Glycoproteins, i.e fibronectin
Proteoglycans i.e. Heparin sulphate proteoglycan

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28
Q

What are the main components of the extracellular matrix ?

A
  • Components:

- Collagen- protein secreted by cells

29
Q

What are the type of collagen that produce extracellular matrix ?

A
  • Type I – bone, tendon, scars= main- produces process of wound healing (scars)
  • Type III – tissue scaffold/ interstitial matrix- majority of collagen in the body -found in your intersistial matrix
  • Type IV – basement membranes -

Elastin

  • Glycoproteins, i.e fibronectin
  • Proteoglycans i.e. Heparin sulphate proteoglycan
30
Q

What does the extracellular matrix made up of?

A

below epithelium you have extracellular matrix containing collagen type 4

  • blood vessels - (endothelial cells) secrete basement membrane- composed of collagen type 4
  • fibroblast and intersistial matirx- containing collagen type 3- apart from when It goes through wound repair - has type 1
31
Q

What is ECM?

A

important for signalling- -Extracellular matrix (ECM) components can initiate intracellular signalling.

  • maintains its relationship with the cells its secreted form
  • anhnored to proteins on the membrane of cells.
  • Integrins binds ECM components.
  • These integrins interact with the cellular cytoskeleton. This can produce intracellular signals.
32
Q

What would damage to the ECM do ?

A

can induce a cellular response in wound repair
-tension and mechanical changes in this protein in the plasma membrane which will induce intracellular signalling in a cell to induce another cell to undergo mitosis - as there is damage to ECM

33
Q

What else can happen if you damage your ECM ?

A
  • release cytokines and bound within the ECM
  • such as basic fibroblast growth factor (bFGF) or known as FGF2 ( Fibroblast growth factor 2)
  • They are bound in interstitial matrix - if you get damage to the ECM - its released and flow down and bind to receptors on plasma membrane of cells in that environment and induce them to go through mitosis and and start proliferating in response - get proliferation phase of wound repair
34
Q

What are the 2 ways the ECM can induce cells to undergo mitosis without having g to use cytokine signalling from another cell - when damage occurs to a cell?

A

z

35
Q

What are the 2 main types of damage ?

A
  • primary intention
    -secondary intention
    and get healing
36
Q

What is the difference between them ?

A

separated by the type of injury

37
Q

How do you heal primary intention ? for e.g get a paper cut with a fine blade ?

A

you dont lose tissue you just lose the cells immediately adjacent to the wound site.

  • get haemostats and blood clot formation
  • epidermis starst to proliferatie aan fill the gap as it already has tissue below it to grow - because its healing up and a few cells need to grow.
38
Q

How do you heal secondary intention ?

e.g when you fall over and graze your knee and take a chunk out of it

A
  • lots of tissue that needs to be replaced
  • filled with a blood clot formed by heamostasis
  • as you lost a lot of tissue- need to replace it before you have something for the epithelial cells to migrate acorss to seal the wound
39
Q

What happens with acute inflammation ?

A
  • start with edema - due to vascular responses.permeability opening up and allow
  • neutrophils to come in- they are the main. players in a cute inflammation and do most the work to get rid of it but they also recruit
  • monocytes form peripheral circulation- come in and if find nothing to phagocytosis or kill they turn into
  • macrophages - as soon getting into tissue- and they start to secrete the cytokines which induce wound repair
40
Q

What are the phases of wound healing ?

A
  1. Heamostasis
    Purpose – Form a clot, seal the wound. Prevent blood loss and prevent infection.

2.Inflammatory /reactive phase
Purpose – A clot is induced to seal wound. Inflammatory cells stimulate local tissues to respond at the site of injury.

1,2 - are acute inflammation- form blood clot- seal it , prevent infection and then eradicate what’s there and macrophages come in the end which secrete the cytokine and chemical messengers which will initiate those cells (fibroblast, epithelial cells etc) in that area to start to proliferate . Now lead to proflerative phase

  1. Proliferative phase
    Purpose – Surrounding healthy cells begin to proliferate. Formation of granulation tissue. Large production of collagen at injury site.
  2. Maturation phase (aka remodelling of tissue being produced)
    - Scar contraction, collagen cross-linking, shrinkage and loss of oedema
41
Q

What else do we get in the inflammatory reactive phase ?

A
  • dont just get inflammatory cells accumulating in the tissue around the area that is damaeg- they also migrate into the blood clot and start signalling there- as have to get to a point to start filling
42
Q

What are the main players ?

A

Macrophages

43
Q

What are the macrophages ?

A

-Essential for progression onto Proliferative Phase
- they release cytokines which help initiate the
proliferative phase of wound healing.

For example:
VEGF – vascular endothelial growth factor - inducing blood vessels in endothelial cells to proliferate and migrate
FGF – fibroblast growth factor inducing fibroblast cells , proliferate and migrate
TGF – transforming growth factor- important in inducing epithelial cells, in bones important in osteoblast etc

44
Q

What else do the macrophages do apart from releasing cytokines to induce cells for proliferation ?

A

-start to break down any damaged extracellular matrix in the area
-if you have damaged ECM - dont want it in the way if you want to create a new environment so
Macrophages secrete the enzyme Collagenase. Which catalyses the breakdown of collagen in the area to get rid of this

45
Q

What are the other cells which secrete cytokines that initiate proliferation apart from macrophages ?

A

–Platelets, Mast cells, T lymphocytes and vascular endothelial cells will all secrete cytokines at a wound site to initiate proliferation.

46
Q

What are the 3 stages of proliferative phase?

A
  1. Angiogenesis
  2. Granulation - fibroblast proliferation and migration
  3. Epithelisation
47
Q

What is important about the proliferative phase?

A

phase 1 and 2 occur at the same time

48
Q

What is the proliferative phase accompanied by ?

A

This is accompanied crucially by a Extracellular matrix
formation - collagen deposition-
lots of collagen laid down- as cells proliferate and migrate- there will be lots of collagen and ECM to start filling that space

49
Q

When does the process fo angiogenesis occur ?

A

-Process begins after 1-2 days of wounding.
- have blood vessel - to induce this sprout coming off the side of it - you have something secreting the VEGF
- VEGF induces vascular endothelial cells to proliferate.
These form capillary buds at the wound edges.
- also Macrophages also secrete collagenase which degrades the
basement membrane around surviving vessels and allows
capillary buds to form.

Buds then grow to form capillary network.

50
Q

When does the process fo angiogenesis occur ?

A

-Process begins after 1-2 days of wounding.
- have blood vessel - to induce this sprout coming off the side of it - you have something secreting the VEGF
- VEGF induces vascular endothelial cells to proliferate.
These form capillary buds at the wound edges.

  • also Macrophages also secrete collagenase which degrades the
    basement membrane around surviving vessels and allows
    capillary buds to form and proliferate out and migrate.
    -to allow new sport to come out a pre existing membrane you have to break down some of that collagen to allow space in bsasememnt membrane for new cells to grow through.

-Buds then grow to form capillary network.

51
Q

What do these blood vessel grow into ?

A
  • need blood vessels to grow into something and a the same time you have to have proliferation of other cells types n the area- primarily fibroblasts
52
Q

What is the process of growing blood vessels into something and proliferation of cells ?

A

-Via granulation
Cells and extracellular matrix are lost; either from cell necrosis or a tissue loss injury.

This space fills with granulation tissue.
Fibroblasts

-Fibroblasts divide by mitosis. Induced by PDGF, EGF-
They migrate in to fill the space at the same time blood vessels are growing fill the space
-as they are filling the space they are secreting collagen to make a new interstitial matrix- and endothelial cells are secreting collagen to make basement memrbane

Occurs in conjunction with ANGIOGENESIS

53
Q

What do connective tissue do ?

A

-Contiusly making new connective tissue as these cell types are growing through the process fo granulation and angionenesisi

54
Q

What is the connective tissue formation ?

A
  • from granulation - normally your interstitial matirx is predominantly made up of collagen type 3
    -but when we undergo granuatlion we produce a scar- so wants to be tough- so body secretes the collagen type 1 too.
  • As fibroblasts migrate in to form the granulation tissue, they
    secrete collagen. Re-building the damaged scaffold of the
    tissue.
55
Q

what are the types of collagen deposited in the wound ?

A

The types of Collagen deposited in a wound are

  • Collagen Type III
    • Collagen Type I
56
Q

What do the c.t also produce ?

A
  • They also produce the interstitial matrix, the mix of polysaccharides and fibrous proteins that fill the space between cells.
  • These affect the architecture of the collagen that is laid down
  • Formed of proteoglycans (glycosaminoglycans (GAGS) with a protein core)- secrets these in Extracellular space as they love water and trap water molecules in the new tissues being made- good as they help to fill space rapidly.
57
Q

What is epithelisation ?

A
  • after granulation and angiogenesis is done - you have now created a new platform , a new fill void over which you epithelial cells can migrate
  • The squamous stratified epithelium is in constant renewal (Labile cells)- they proliferate and migrate over the new granulation tissue that has been formed
  • they fill
  • Basal epithelial cells at the wound margin flatten, mobilise and migrate into the open wound. Across the granulation tissue.
  • Basal cells at margin multiply (mitosis) in horizontal direction
  • EGF derived from macrophages and platelets initiate the response.
58
Q

What is the first process of maturation ?

A

-Wound contraction

59
Q

What is wound contraction ?

A
  • when you have big tissue taken out , as your c .t is elastic - will spring more open than the tissue that was lost originally
  • body fill with clot and granulation tissue doesnt pull it back together completely - it just fills the space and seals it - once done- the fibroblast that have migrated in to form granulation tissues - some of those are myofibroblast- contractile properies- once the epithelial is closed- those my-fibroblast can contract and pull the edges of wound back together to restore the normal archeitecture of the wound

-The edges of the original wound are pulled together
(contracture)

-Myofibroblast: contractile properties
They contract and pull the tissue together.

-During contraction you have a re-modeling of the collagen in the extracellular matrix of the granulation tissue. Also deposition of further collagen and proteoglycans to maintain new architecture.

  • ECM shifts from a disorganised structure to organised.
  • Increase in Collagen type I content.
60
Q

What is the 2nd process of maturation phase ?

A

-Scar maturation

61
Q

What happens in scar maturation ?

A
  • Occurs after 3 weeks from acute inflammation.
  • Can take months to years to fully progress

-Increases the strength of the collagen through cross linking.
No further increase in Collagen content though

  • Maturation of capillary network
  • Decreased proteoglycan content in ECM- no longer need lots of water . This reduces water at the scar site and reduces residual oedema.
  • also mature blood vessels to grow and supply nutrients
62
Q

What are the Delayed healing - Local factors ?

A
  • Infection
    The single most common cause of delay in healing

-Mechanical Factors
Early motion of wounds  compressing blood vessels & separating the edges of the wound  Delayed healing

  • Foreign Bodies
    e. g. Bone fragments, Glass shards  keep causing cell damage

-Nutrition
Protein deficiency, Vit. C deficiency
inhibits collagen synthesis and cell replication
 delayed healing

-Metabolic Status
Diabetes microangiopathy  delayed healing

-Circulatory Status
Arteriosclerosis (inadequate blood supply) or varicose veins (retarded venous drainage)  delayed Healing

63
Q

What are the complication of wound healing ?

A

Three general categories:

1. Inadequate formation of granulation tissue or assembly of a scar
2. Excessive formation of the components of the repair process – hypertrophic and keloid scars
3. Formation of contractures and
64
Q

What does the healing with scar formation and contraction appear as ?

A

the white space /tissue represents increased collagen production and water being bound in. that tisseu- not as dense as should be - but sealed as quickly as possible to make sure sterile environment

65
Q

What is the inflammatory phase ?

A

acute inflammation- few days

-then towards the end the macrophages start migrating in triggering proliferative phase of wound healing

66
Q

What happens in the proliferative phase?

A

proper re- epithelisation to get tissue remodelling

67
Q

Excessive formation of the components of the repair process

A

Accumulation of excess collagen 

Hypertrophic Scars and Keloids

68
Q

Wound Contracture

A

Excessive wound contraction can cause permanent damage to mobility