Wound Healing and Repair

Question 1

Define parenchyma

Answer 1

organ specific cells related to the function

E.g. Parenchyma of the Kidney – Epithelial tissue (renal tubes)

Parenchyma of the Heart – Muscle Tissue (Cardiac muscle cells)

Question 2

Define Stroma

Answer 2

‘Background’ tissue - provides the structure, mechanical and nutritional support to the organ

Question 3

Distinguish between the two types of connective tissue

Answer 3

Loose Connective tissue – contains numerous cells, loose fiber arrangement in a viscous matrix

E.g. Haemopoietic/lymphatic tissue

Dense irregular connective tissue – dense woven network of collagen and fibers in a viscous matrix

E.g. joint capsules, tendon and ligaments

Question 4

Define a wound

Answer 4

Injury/ trauma to tissues

Disruption of the function and structure of tissue

Question 5

Define healing

Answer 5

Process of returning to health

Restoration of structure and function of injured/diseased tissues

Question 6

Outline the stages of wound healing

Answer 6

1. Haemostasis process - wound closed by clotting (coagulation process), platelets and fibrin adhere, formation of a thrombus - <24h
2. Inflammatory process - platelets control bleeding, macrophages prevent infection, neutrophils (inflammation) - 0-4days
3. Proliferative process - Angiogenesis, epithelialisation, contraction, fibrous tissue formation - 1-14 days
4. Remodeling process - maturation phase, collgen is remodeled and becomes realigned, injured sites tend to be weaker than normal sites (80% tensile strength) - 21days - years

Question 7

what is meant by resolution?

Answer 7

• clearance of injurious stimuli
• clearance of mediators and acute inflammatory cells
• replacement of injured cells
• normal function

Question 8

Desctibe the possible outcomes after injury and inflammation

Answer 8

Question 9

What is meant by tissue repair?

Answer 9

The restoration of structure and function of damaged tissue

Question 10

What are the 2 types of reactions that occur in tissue repair (healing)?

Answer 10

Regeneration

Scar formation

Question 11

What is regeneration?

What is it driven by?

Answer 11

• Healing in which new growth completely restores portions of damaged tissue to their normal state
• Driven by growth factors such as PDGF, VEGF, and TGF-Beta
• ECM plays a major function in regeneration

Question 12

What is meant by a labile tissue?

Give examples

Answer 12

Continuously proliferating in order to replace dead or sloughed-off cells

E.g. skin, gastrointestinal, salivary gland tissue

Question 13

What is meant by a stable tissue?

Give examples

Answer 13

Cells that normally exist in a non-dividing state but may enter the cell cycle in response to certain stimuli, such as cell injury

E.g. Parenchymal cells of the liver, kidney and pancreas

Question 14

What is meant by permanent tissue?

Give examples

Answer 14

Non-dividing cells, leads to scar formation

E.g. Cardiac and skeletal

Question 15

What role do growth factors have in regeneration?

Answer 15

• Proteins that stimulate survival, proliferation of particular cells, may also promote migration and differentiation
• Produced mainly by macrophages and lymphocytes at the site of injury as part of the inflammatory process.
• Other growth factors are produced by parenchymal cells or stromal (connective tissue) cells in response to cell injury
• Stimulate entry of cells into cell cycle
• Produced transiently in response to an external stimulus and act by binding to cellular receptors
• E.g. EGF, TGF-alpha, VEGF anf FGF

Question 16

What is the role of ECM in regeneration?

Answer 16

• Stores and presents growth factors
• acts as a scaffold to which migrating cells can adhere

Question 17

What is scar formation and when does it occur?

Answer 17

• Replacement of damaged parenchymal cells with connective tissue
• Incomplete restoration of architechture and function
• Occurs in: Severe or chronic injuries that result in damage of parenchymal cells as well as connective tissue (scaffolding) and Permanent non-dividing tissues

Question 18

What are the stages of scar formation?

Answer 18

1. Tissue injury
2. Inflammation
3. Formation of granulation tissue
4. Scar formation

Question 19

What is angiogenesis?

Answer 19

• The process of new blood vessel development
• Involves sprouting of new vessels from existing ones - involved proliferation and migration of endothelial cells
• Derived by GF e.g VEGF
• Critical in healing at sites of injury and in the development of collateral circulations at sites of ischaemia

Question 20

How does granulation tissue form?

Answer 20

Occurs in two steps:

• Migration and proliferation of fibroblasts into the site of injury
• Deposition of ECM proteins produced by these cells

Derived by GF e.g. TGF-Beta, PDGF and FGF

New connective tissue together together with new blood vessels has pink granular appearance - Granulation tissue

Question 21

What is remodeling?

Answer 21

Connective tissue in the scar continues to be modified and remodeled to improve the tensile strength of the wound

The outcome of the repair process is a balance between synthesis and degradation of ECM proteins

The degradation of collagens and other ECM components is accomplished by a family of matrix metalloproteinases

Wound strength reaches approx. 70-80% of normal by 3 months and usually does not improve substantially beyond that

Question 22

Give 3 examples of tissue repair

Answer 22

Healing of skin wound

Healing of bone fractures

Fibrosis in internal organs

Question 23

What does skin wound healing usually involve and how does it occur?

Answer 23

Skin wound healing involves both epithelial regenration and the formation of connective tissue scar

Depending on nature and size of the wound, healing occurs by

First intention (Primary union)

Second Intention (Secondary union)

Question 24

Give an example of healing by first intention

Answer 24

Healing of a clean, uninfected surgical incision approximated by surgical sutures

Question 25

What is the principal mechanism of repair in first intention?

Answer 25

Epithelial regeneration

Question 26

Describe how healing by first intention occurs

Answer 26

1. Narrow incisional space fills with **fibrin-clotted blood (**Scab) 2. **Neutrophils** are seen at the incision margin, **migrating towards fibrin clot** within 24 hours (acute inflammation) 3. **Epithelial cells** from both edges begin to **migrate and proliferate** along the dermis within 24-48 hours 4. Day 3-7 : **Neutrophils largely replaced by macrophages**, **angiogenesis** reaches its peak. **Granulation tissue progressively invades the incision space** 5. During second week, there is continued **collagen accumulation** and **fibroblast proliferation (scar maturation)** 6. **Remodeling** of the scar continues for months aiming to increase wound tensile strength

Question 27

Give examples of healing by second intention

Answer 27

* Large wounds at sites of abscess formation * ulceration * infarction

Question 28

Outline healing by second intention

Answer 28

The repair process is more complex and involves development of abundant granulation tissue, with accumulation of ECM and formation of a large scar Scar formation is followed by wound contraction mediated by the action of **myfibroblasts.**

Question 29

How is secondary healing different from primary healing?

Answer 29

* A larger clot or scab * Inflammation is more intense because large tissue defects have a greater volume of necrotic debris, exudate, and fibrin that must be removed * Larger defects require a greater volume of granulation tissue to fill in the gaps - greater mass of scar tissue * Secondary healing involved wound contraction - within 6 weeks large skin defects may be reduced to 5-10% of their original size

Question 30

Name the stages of fracture healing

Answer 30

1. Haematoma 2. Granulation tissue 3. Callus 4. Woven bone 5. Lamellar bone 6. Remodelling

Question 31

What is fibrosis?

Answer 31

Excessive deposition of collagen and other ECM components in a tissue Basic mechanisms are the same as those of scar formation during tissue repair Fibrosis seen in chronic diseases is often responsible for organ dysfunction and even organ failure E.g. RA pannus formation & ankylosis, pulmonary fibrosis

Question 32

Name some local factors affecting tissue repair

Answer 32

* Infection * Mechanical factors - increase local pressure/torsion may cause wound to pull apart * Foreign bodies * Size of wound * Location of wound * Type of wound - complete restoration can only occur in tissues composes of stable and labile cells - injuries to tissues composed of permanent cells must result in scarring e.g. MI

Question 33

Name some systemic factors affecting tissue repair

Answer 33

* Nutritional status - protein deficiency, vitamin C deficiency inhbit collagen synthesis and delay healing * Metabolic status * Circulatory status - poor perfusion due to ateriosclerosis/diabetes or obstructed venous drainage (varicose veins) impairs healing * Hormones * Age * Collagen disorders

Question 34

What is the most important cause of delay in healing and why?

Answer 34

INFECTION It prolongs inflammation and potentially increases the local tissue injury

Question 35

Name the 3 main complications of tissue repair

Answer 35

1. Inadequate formation 2. Excessive formation 3. Formation of contracture

Question 36

What is inadequate formation in tissue repair?

Answer 36

Rupture or dehiscence - separation of the layers of the surgical wound Evisceration - extrusion of viscera outside the body through a surgical incision Ulceration - A lesion through the skin or a mucous membrane resulting from loss of tissue, usually with inflammation

Question 37

What is excessive formation in tissue repair?

Answer 37

Keloid formation - accumulation of excess amounts of collagen , giving rise to raised scars May also generate exuberant granulation tissue that protrudes above the level of the surrounding skin and hinders epithelialistion ("proud flesh")

Question 38

What are contractures in tissue repair?

Answer 38

* Contractures - fibrosis of connective tissue in skin, fascia, muscle or a joint capsule that prevents normal mobility of the related tissue or joint * Myofibroblasts play a major role in their pathogenesis E.g. Severe burns, neurologic conditions -stroke/nerve damage