Healing: Regeneration and Repair

Question 1

Whatever the wound, what is the aim of the body?

Answer 1

To close the gap and repair it with a scar - the smaller the better.

Question 2

Processes in wound healing:

1. _____________ as all vessels are open.
2. _____________ as the tissue is injured.
3. _____________ (resolution and restitution) and/or repair (organisation), as structures have been injured or destroyed.

Answer 2

Haemostasis
Inflammation
Regeneration

Question 3

What is regeneration?

Answer 3

Restitution with no, or minimal evidence of previous injury - healing by primary intention of a superficial abrasion.

Question 4

What’s the difference between an abrasion and an ulcer?

Answer 4

In an abrasion, the top few layers of cells are lost (superficial scrape), but an ulcer is deeper - the injury goes into the submucosa.

Question 5

In regeneration, new differentiated cells are mainly derived from what?

Answer 5

Stem cells (many terminally differentiated cells can’t divide).

Question 6

Stem cells have prolonged ____________ activity and show asymmetric ___________ - they are part of the internal repair system to replace any lost/___________ cells in a tissue. The location of stem cells varies between tissues e.g. In the epidermis they are in the _______ layer adjacent to the ______ membrane, in the internal mucosa they’re at the bottom of the ________ and in the liver between the hepatocytes and the ______ ________.

Answer 6

Proliferative
Replication
Damaged
Basal - basal
Crypts
Bile ducts

Question 7

Describe the difference between unipotent, multipotent and totipotent stem cells.

Answer 7

Most adult stem cells are unipotent and only produce one type of differentiated cell (e.g. Epithelia). Multipotent SCs can produce several types of different cells e.g. Haematopoietic stem cells. Embryonic SCs are totipotent, which can produce any type of cell and so tissue in the body.

Question 8

Not all tissues can regenerate, it depends on which of 3 types they are, name them.

Answer 8

Permanent tissues, labile tissues and stable tissues.

Question 9

What are permanent tissues? Give examples.

Answer 9

Permanent tissues e.g. Neural tissue, skeletal and cardiac muscle, have mature cells that can’t undergo mitosis and few/no present stem cells.

Question 10

What are labile tissues? Give examples.

Answer 10

Labile tissues e.g. Surface epithelia, haematopoietic tissue, contain short lived cells replaced by cells derived from stem cells.

Question 11

What are stable tissues? Give examples.

Answer 11

Stable tissues e.g. Liver parenchyma, bone, fibrous tissue and endothelium, normally have a low level of replication, it can undergo rapid proliferation if necessary - both stem cells and mature cells proliferate.

Question 12

Tissues are based into groups based on their proliferative activity, where are the different types of tissue in the cell cycle?

Answer 12

Labile cells are continually cycling, stable cells are in G0 and can reenter when necessary and permanent cells can’t reenter the cell cycle.

Question 13

When is regeneration possible?

Answer 13

If damage occurs in labile/stable tissues and the tissue damage is not extensive - requires an intact connective tissue scaffold.

Question 14

What is fibrous repair/organisation?

Answer 14

Healing with the formation of fibrous connective tissue/a scar. Specialised tissue lost and healing by secondary intention.

Question 15

When does repair/organisation occur (instead of regeneration)?

Answer 15

When there is significant tissue loss/if permanent or significant tissue is injured.

Question 16

What is the progression of scar formation over time?

Answer 16

Seconds-minutes: haemostasis, minutes to hours: acute inflammation, 1-2 days: chronic inflammation, 3 days: granulation tissue forms, 7-10 days: early scar, weeks-2 years: scar maturation.

Question 17

Granulation tissue has a granular appearance and texture, what does it consist of and what is its function?

Answer 17

Consists of: developing capillaries, fibroblasts (and myofibroblasts) and chronic inflammatory cells.
Function: fills the gap, capillaries supply oxygen, nutrients and cells, it contracts and closes the hole.

Question 18

What cells can be expected to be seen in a forming scar/granulation tissue?

Answer 18

Inflammatory neutrophils and macrophages for phagocytosis of debris and macrophages and lymphocytes for the production of chemical mediators, endothelial cells - the proliferation of which drives angiogenesis, fibroblasts and myofibroblasts to produce extracellular matrix proteins and responsible for wound contraction - fibrils within myofibroblasts.

Question 19

Explain the colour and appearance of scars.

Answer 19

At first they are red, when there are a lot of blood vessels, then they eventually go white as melanocytes don’t regenerate. They also can’t lay down elastin, so the skin could be stretched - can’t replace deep, complex structures of sweat glands and hair follicles.

Question 20

Collagen is the most ________ protein, it provides the ____________ framework and is composed of ________ helices of various polypeptide alpha chains. Fibrillation collagens ___, ___ and ____ are responsible for tissue strength. Amorphous collagens ___, ___ and ___ are integral in the basement membrane.

Answer 20

Abundant
Extracellular
Triple
I, II and III
IV, V and VI

Question 21

Which type of collagen is the most common in hard and soft tissues (e.g. Bones and sclera) and which type in the basement membranes, secreted by epithelial cells?

Answer 21

Type I and Type IV.

Question 22

Fibrillar collagen production takes ___ hours: polypeptide alpha chains are made in the __ of fibroblasts, enzymatic modification steps, including vitamin __ dependent hydroxylation take place. Alpha chains align and _____ ______ into procollagen triple helix, which is soluble and ________. Procollagen is cleaved to ________, which polymerises to form a myofibril then fibril, bundles of fibrils form _____. Cross linking between fibres produces ______ strength and there is slow _________ by collagenases.

Answer 22

1-2
ER
C
Cross link
Secreted
Tropocollagen
Fibres
Tensile
Remodelling

Question 23

Diseases from defective collagen are either inherited or acquired, describe an acquired defective collagen disease.

Answer 23

Scurvy is vitamin C deficiency, with inadequate hydroxylation of procollagen alpha chains, meaning reduced cross linking and so defective healing, as there is a lack of strength and the molecule is vulnerable to degradation. It particularly affects the collagen supporting blood vessels. Unable to heal wounds, tendency to bleed, tooth loss (periodontal ligament collagen has a short T1/2, so normal collagen’s replaced by defective), old scars reopen as fresh wounds (collagen turnover remains high).

Question 24

Ehler’s-Danlos syndrome:
Heterogenous group of 11 __________ disorders involving defective cleaving of ___________ to tropocollagen. Collagen fibres lack adequate ________ _________, leading to poor would healing, hyperextensible _______, that is also thin, fragile and susceptible to ________ (can still ______ as the elastic fibres are normal). Joints are hypermobile and have a predisposition to ___________. In some forms there may be spontaneous rupture of the ______, large arteries or cornea, maybe with retinal ____________.

Answer 24

Inherited
Procollagen
Tensile strength
Skin
Injury
Recoil
Dislocate
Colon
Detachment

Question 25

Osteogenesis imperfecta aka ______ ______ disease, is where there is too little bone tissue and so extreme skeletal ____________. Sufferers must avoid __________ stress and some have severe, progressive _____________ of the long bones. Too little collagen means that the sclera are ___________ and so appear blue, often accompanied by __________ impairment or _________ abnormalities.

Answer 25

Brittle bone
Fragility
Mechanical
Deformation
Transparent
Hearing 
Dental

Question 26

Alport syndrome is usually x-linked as so appears more commonly in _______. It is abnormal type ___ collagen, resulting in a dysfunction of the glomerular _____________ membrane, cochlear of the ear and _____ of the eye. It presents with haematuria in _________\adolescents, which may point to _______ failure. There may also be neural deafness and _____ disorders.

Answer 26

Males
IV
Basement
Lens
Children
Renal
Eye

Question 27

Triggering and control of regeneration and repair is not fully understood, what is speculated/roughly known?

Answer 27

Cells communicate with each other to produce a proliferative response. The signalling may be via hormones (auto/para/endocrine), local mediators or direct cell-to-cell/cell-to-stroma contact.

Question 28

Growth factors (such as TNF, epidermal growth factor - misleading names) are important in wound healing. Polypeptides act on cell surface receptors, coded by proto-oncogenes, bind and stimulate the transcription of genes that regulate cell cycle entry (and passage through the cycle). What are some of the possible effects?

Answer 28

Proliferation/inhibition of division, locomotion, contractility, differentiation, viable, activation, angiogenesis.

Question 29

What type of cell might produce growth factors, important in regeneration and repair?

Answer 29

Platelets, macrophages and endothelial cells.

Question 30

What is contact inhibition?

Answer 30

Signalling through adhesion molecules (cadherins bind cells together, integrins bind cells to ECM), which inhibits proliferation in intact tissues and promotes it where damaged. This is altered in malignant cells.

Question 31

Descriptions of wound healing relate to the size of the wound and the amount of tissue lost, what are the 2 types?

Answer 31

Healing by primary and by secondary intention.

Question 32

What are the criteria for a wound to heal by primary intention?

Answer 32

Incised, closed, non-infected and sutured wounds - disruption of the basement membrane continuity, but death of only a small number of epithelial and connective tissue cells - minimal clot and granulation tissue.

Question 33

When a wound is healing by primary intention, what happens?

Answer 33

The epidermis regenerates (basal epidermal cells creep over denuded cells at approximately 0.5mm/day, deposit the basement membrane and fuse in the midline to undermine the scab, which falls off), the dermis undergoes fibrous repair, sutures come out at ~10 days when there is 10% normal strength. With minimal contraction and scaring, there is good strength.

Question 34

What type of would may heal by secondary intention?

Answer 34

An excisional wound with tissue loss and separated edges, maybe infectious e.g. An infarct, an abscess, or an ulcer. The open wound is filled by abundant granulation tissue, which grows in from the wound margins.

Question 35

What is the process of healing by secondary intent like?

Answer 35

Similar to that by primary intent, but more so. Considerable wound contraction is necessary (initially occurs as a scab contracts, then rise and shrinks, after 1 week, myofibroblasts appear and contract), margins are drawn into the centre, so the shape of the scar depends on that of the wound. There is substantial scar formation, the new epidermis is often thinner than usual and it can take some time.

Question 36

Why do skin grafts heal successfully?

Answer 36

The donor site is fine because the wound is very superficial - the skin is meshed and ends up like a net.

Question 37

Briefly, what are the stages of bone healing?

Answer 37

A haematoma, granulation tissue forms, a soft callus then a hard callus, lamellar bone replaces woven bone and there is remodelling.

Question 38

Bone healing:
The purpose of the haematoma is …
Cytokines in the granulation tissue activate …
The soft callus forms when containing what?
When does the hard callus form and how does it improve?
What stimulates remodelling?

Answer 38

The haematoma fills the gap and surrounds the injury. Osteoprogenitor cells.
Soft callus forms at 1 week - fibrous tissue and cartilage.
Hard callus after several weeks, initially weaker and less organised woven bone (but forms quickly).
Remodelled to the direction of mechanical stress - bone not stressed is reabsorbed and the outline is reestablished.

Question 39

What are the local factors that influence wound healing?

Answer 39

Type, size and location of the wound, mechanical stress, blood supply, local infection - foreign bodies.

Question 40

What are the general factors that influence wound healing?

Answer 40

Age, anaemia, hypoxia, hypovolaemia, obesity, diabetes, genetic disorders, drugs, vitamin deficiency, malnutrition.

Question 41

List some possible complications of fibrous repair.

Answer 41

Insufficient fibrosis (maybe from steroids), formation of adhesions - compromise organ function/block tubes, loss of function - replacement of specialised functional parenchymal cells by scar tissue
 (E.g.after MI),disruption of complex tissue relationships with an organ, overproduction of fibrous scar tissue (Keloid), excessive scar contraction - fixed flexures.