Wound Healing Flashcards
1
Q
Define parenchyma
A
Parenchyma =
Organ specific cells related to the function
e.g. renal parenchyma = renal tubular epithelium
E.g. heart parenchyma = cardiac muscle cells
2
Q
Define stroma
A
Stroma = background tissue that provides structure, mechanical and nutritional support to the organ
3
Q
What are the 4 types of tissue and their functions?
A
- Epithelial –> characterised by close cell apposition, found at free surfaces.
- function of protection
- containment of body fluids
- absorption and secretion
- Connective tissue –> several types of cell and EC products
- mechanical reinforcement
- Immune surveillance
- diffusion of nutrients and waste
- Muscle
- gross movement by cellular contraction
- Nervous tissue:
- responsible for rapid long distance signalling
4
Q
Describe connective tissue:
Function
cell arrangement
make up
A
- Connective tissue function:
- mechanical reinforcement
- immune surviellance
- diffusion of nutrients and waste
- Cells not in close contact, embedded in ECM and can be vascularised (not in all cases e.g. cornea where collagen is arranged for transparency).
- Made up of:
- Fibrous components: Collagen and elastin
- GAG’s –> support collagen
- Proteoglycans –> GAG attached to core protein
5
Q
What are the two main types of connective tissue?
A
- Variation in the composition of ECM determines the properties of connective tissue
-
Two main types:
- Loose connective tissue
- Dense irregular connective tissue
Loose connective tissue:
- numerous cells
- loose fibre arrangement in viscous matrix
- e.g. haematopoetic and lymph connective tissue, found between many organs acts to both shock absorb, bind together and allow diffusion of nutrients
Dense irregular connective tissue:
- Dense woven network of collagen fibres in viscous matrix (more collagen than loose connective)
- Irregular means collagen arranged in random directions gives greater strength overall
- E.g. tendon/ joint capsule/ ligaments
*
6
Q
List the specialised forms of connective tissue
What are their definitive features?
A
- Loose connective tissue under the skin:
- formed of dermal cells, collagen, elastin and fibroblasts
- Adipose tissue:
- formed of adipocytes, specialised cells that store lipid within their cytoplasm
- adipose tissue found surrounding certain organs e.g. liver/ kidneys and for thermoregulation
- adipocytes sat on reticular fibre structure
- Reticular tissue:
- formed of reticulocytes that secrete a mesh supportive network on which other cells sit
- cartilage:
- formed of chondrocytes that occupy spaces called lacunae
- coil fibres and semi solid ECM
- Bone:
- dense, formed of osteoblasts, osteocytes,
- collagen fibres
- calcified ECM
- Blood:
- Formed of erythrocytes, leukocytes, thrombocytes –> proteins that are soluble for clotting
- ECM –> plasma
7
Q
Define wound
A
Wound = injury/ trauma to tissues that disrupts the function and structure of the tissue
8
Q
Define healing
A
Healing = process of returning to health. Restoration of structure and function of diseased tissues
9
Q
Describe the stages of wound healing
A
- Haemostasis –> 24 hrs
- wound closed by clotting/ coagulation cascade
- platelets/ fibrin adhere to site
- formation of a thrombus
- Inflammatory process –> 0-4 days
- platelets control bleeding
- macrophages to prevent infection
- neutrophils and inflammation
- Proliferative process –> 1-14 days
- angiogenesis
- epithelialisation
- contraction
- fibrous tissue formation
- Remodelling process –> day 21 (years)
- maturation phase
- collagen is remodelled and becomes realigned
- injured sites tend to be weaker than norm (80% tensile strength).
10
Q
Define tissue repair
What are the two types of tissue repair?
A
- Tissue repair = the restoration of structure and function of damaged tissue
- Two types:
- Regeneration -> complete restoration of tissue to normal state, with right cytokines and GF’s it will grow into idea cell type for that tissue
- Scar formation
11
Q
What is regeneration?
What growth factors are involved?
A
- Regeneration = new growth completely restores portions of damaged tissue to their normal state
- Driven by GF’s:
- PDGF’s
- VEGF
- TGF-B --> activated by macrophages, main role to close wound by laying down collagen. Coverts fibroblasts into myofibroblasts which lay down excess collagen
- ECM plays major function in regeneration
12
Q
What are three types of tissue that have different regenerative capacity?
A
- Labile tissues:
- continuously proliferating in order to replace the dead or sloughed off cells e.g. Skin/GI tract/ Salivary gland tissue
- Stable tissues:
- cells that normally exist in non dividing state
- may enter cell cycle in response to certain stimuli e.g. injury
- e.g. liver/ kidney/ pancreas
- Permanent tissue:
- non dividing cells leads to scar formation
- e.g. cardiac and skeletal
13
Q
What are Growth factors?
What do they stimulate?
where are they produced?
How do they act?
examples?
A
- Growth factors are proteins that stimulate:
- survival
- proliferation
- migration
- differentation
- Produced mainly by macrophages and lymphocytes at the site of injury as part of the inflammatory process
- other GF’s are produced by parenchymals cells or stromal cells in response to injury
- stimulates the entry of cells into the cell cycle
- GF’s produced transiently in response to external stimulus and act by binding cellular R’s
- examples: TGF=b, VEGF, EDGF, FGF
14
Q
What is the role of the ECM in wound healing?
A
- The ECM is the ever changing background for regeneration and wound healing
- Functions to:
- store and present growth factors
- act as a scaffold to which migrating cells can adhere
15
Q
Describe scar formation:
what is it?
when/ where does it occur?
A
- Scar formation = replacement of damaged parenchymal cells with connective tissue, incomplete restoration of architecture and function
- Occurs:
- severe and crhonic injuries that result in damage of parenchymal cells as well as connective tissue
- permanent non dividing tissues
- lymphocytes/ neutrophils/ macrophages activated in inflammatory process
- collagenous matrix laid down in irregular manner -> scar forms
16
Q
What is angiogenesis?
What does it involve?
What is it stimulated by?
When is it critical?
A
Angiogenesis= process of new blood vessel development, involves the sprouting of new vessels from existing ones
- Involves endothelial cell proliferation and migration.
- angiogenesis is stimulated by GF’s e.g. VEGF
Angiogenesis is critical in:
- healing at sites of injury
- development of collateral circulation at sites of ischaemia
17
Q
What is granualtion tissue?
How does granulation tissue form?
What is it derived by?
A
- Granulation tissue = new connective tissue and microscopic blood vessels that form on the surface of a wound during the healing process
- Granulation tissue is laid down in two steps:
- migration and proliferation of fibroblasts to the site of injury
- Deposition of ECM proteins produced by these cells
- Derived by GF e.g. TGF B, PDGF, FGF
- New connective tissue together w blood vessels has a PINK appearance = granulation tissue
18
Q
What is remodeling in healing?
What does the outcome of the repair process depend on?
What is the maximal wound strength that can be achieved and in what time frame?
A
- Remodelling is where the connective tissue in the scar continues to be modified and remodelled to improve the tensile strength of the wound
- outcome of the repair process is a balance between ECM protein synthesis and degradation
- Degradation of collagen is accomplished by fam of matrix metalloproteinases (MMP’s)
- Too little collagen produced –> lowered tensile strength and increased chance of the wound opening up again
- If too much collagen produced also issues
- wound strength never reaches full strength only 70-80% of normal by around 3 months and usually does not improve further.
19
Q
How does skin repair?
A
- Involves epithelial regeneration
- Formation of connective scar
Depending on the nature/ size of a wound healing skin wounds occurs by:
- First intention/ primary union
- Second intention/ second union
20
Q
When does skin healing by 1st intention / primary union occur?
what does the incision cause?
main mechanism of repair?
what forms eventually?
A
- Healing by 1st intention occurs in clean, uninfected surgical incisions approximated by surgical sutures
- Incision causes only focal disprution of epithelial cell BM with death of few epithelial connective tissue cells
- Epithelial regeneration is the main mechanism of repair
- small scar forms but there is minimal wound contraction
21
Q
Describe the mechanism of skin healing by 1st intention/ primary union?
A
- Narrow incision space filled with fibrin clotted blood
- within 24 hrs neutrophils seen at incision margin and migrate towards fibrin clot –> acute inflammation
- within 24-48 hrs basal cells of epidermis from both sides start proliferating and migrating towards the incisional space. Wound is covered by layer of epithelium in 48 hours.
- Epidermal cells separate underlying viable dermis from overlying necrotic material forming scab.
- by day 3-7 neutrophils largely replaced by macrophages
- angiogenesis reaches its peak
- Fibroblasts also invade wound area by day 3, start froming new collagen fibrils
- granulation tissue progressively invades the incision space
- 2nd week –> continued collagen accumulation and fibroblast proliferation –> scar maturation
- remodelling of scar continues for months aiming to increase wound tensile strength
22
Q
When does healing by second intention (secondary union) occur?
A
- Wound that is open and large, can be infected e.g. sites of abscess formation/ ulceration/ infarction
- has extensive loss of cells and tissues
- wound is not approximated by surgical suture but left open
23
Q
Describe the events in 2nd intention (secondary union) in skin wound repair?
A
- Initail haemorrhage
- inflammatory phase
- epithelial proliferation
- granulation tissue formation : main bulk of secondary healing is by granulation
- Repair process more complex, develop abundant granulation tissue
- get the accumulation of ECM and formation of a large scar
- Scar formation followed by wound contraction mediated by the action of myofibroblasts
- myofibroblasts are FB’s that have been activated by GF TGF beta
- with time the scar becomes pale and white due to increase in collagen and decreased vascularity
- specialised structures of skin e.g. hair follicles/ sweat glands not replaced.
24
Q
How does second intention healing differ from first intention?
A
- 2nd intention occurs in larger wounds that can be infected
- involves a larger clot and scab formation
- inflammation is more intense as large tissue defects have a greater volume of necrotic debris, exudate and fibrin that must be removed
- Requires larger volume of granulation tissue to fill in the gaps - -> generally results in greater mass of scar tissue
- secondary healing involved contraction of wound
- -> w/in 6 wks large skin defects may be reduced to 5-10% of original size
25
How might the healing of cortical and trabecular bone differ?
Trabecular bone may heal slightly better than cortical bone as there is better blood supply and there is usually less necrosis in trabecular bone.
26
What are the stages of fracture healing?
1. Haematoma
2. Granulation tissue
3. Callus formation
4. Woven bone
5. Lamellar bone
6. Remodelling
Note there is some overlap in all these stages.
27
Describe the details of fracture healing stages
1. Haematoma:
* blood vessels rupture and bleeding forms haematoma
* inflammatory reaction and phagocytes move into the area
2. Granulation tissue:
* Capillary loops in loose connective tissue form and replace the haematoma = granulation tissue
* cell proliferation in response to growth factors / cytokines
3. Callus formation:
* Irregular swelling of fibrocellular material and cartilage that bridges the gap between then broken ends forming a callus (soft callus)
* eventually gets replaced by woven bone
4. Woven bone:
* Osteoprogenitor cells proliferate and move into the area and form woven bone strengthening the callus from around 3 weeks
5. Lamellar bone:
* initial woven bone callus is gradually replaced by mature lamellar bone
6. Remodelling
* Osteoclasts and osteoblasts remodel the lamellar bone into an appropriate form related to function in response to stresses
* excessive callus is resorbed and medullary cavity is reestablished
28
What does fibrosis refer to?
* Fibrosis used to denote the excessive deposition of collagen and other ECM components in a tissue
* Scar and fibrosis used interchangaebly but most often refers to depostion of collagen in chronic disease
* Basic mechanisms of fibrosis are same as those for scarring during tissue repair
* fibrosis in chronic disease often responsible for organ dysfunction/ failure
* e.g. RA and pannus formation, pulm. fibrosis
29
What factos can affect tissue repair?
* Local factors:
* Infection
* mechanical factors
* foreign body
* size and location of wound
* type of wound
* Systemic factors:
* nutritional status
* metabolic status
* circulatory status
* hormones
* age
* collagen disorders
30
How can infection affect tissue repair?
Infection = clinically most important delay in healing
prolongs inflammation
potentially increases local tissue injury
31
How can nutrition affect healing?
* Profound effects on repair
* protein deficiency and vitamin C deficiency inhibit collagen synthesis
* retards healing
32
How can poor perfusion affect healing?
* Limited blood supply therefore limited delivery of oxygen and nutrients required to fuel the cells required for tissue repair
* Due to arteriosclerosis/ diabetes/ obstructed venous system eg varicose
33
How can foreign body affect healing?
How can mechanical variables affect healing?
* Foreign body impedes healing
* Mechanical variables such as increased local pressure or torsion can cause wounds to pull apart or burst open (dehisce)
34
How can the type and extent of injury affect healing?
* Type and extent of injury maater as complete restoration can only occur in tissues composed of stable and labile cells
* injury to tissue composed of permanent cells results in scarring e.g. MI
35
What can complicate tissue repair?
1. Inadequate formation
2. Excessive formation
3. Formation of contracture
36
Inadequate formation examples
* **Dehiscence or rupture** --\> separation of layers of surgical wound
* **Evisceration** --\> extrusion of viscera outside the body through a surgical incision
* **Ulceration** --\> lesion through the skin or a mucous membrane resulting from loss of tissue usually with inflammation
37
Examples of excessive complication of tissue repair
* Keloid formation --\> accumulation of excess amount of collagen which gives rise to prominent raised scars
* Healing wound also can generate excessive granulation tissue which protrudes above the level of the surrounding skin and hinders re-epithelialisation "proud flesh"
38
How can contracture develop?
* Contracture develops when there is fibrosis of connective tissue in skin, fascia, muscle or joint capsule that prevents normal mobility of the related tissue or joint
* Myofibroblasts play a major role in their pathogenesis
* E.g. burns or neurological conditions such as stroke/ nerve damage
