1. Mechanisms and Factors Affecting Healing and Repair
Dr. Mamlook Elmagraby

2. Objectives of the lecture
Upon completion of this lecture, students should be able to:
Understands the concept of healing and repair with wounds healing by first and second intention as an example
Knows the factors leading to poor healing and inadequate tissue repair

3. Tissue repair: restoration of tissue architecture and function after an injury
It occurs in two ways:
Regeneration of injured tissue
Replacement by connective tissue (scarring)
Usually, tissue repair involves both processes
Mechanisms of tissue repair:
regeneration and scar formation.
Following mild injury, which damages the epithelium but not the underlying tissue, resolution occurs by regeneration,
but after more severe injury with damage to the connective tissue, repair is by scar formation

4. Cellular Regeneration
Restoration of normal structure (Compensation for the cell loss by equivalent newly formed cells)
It requires that the surviving affected parenchymal cells have the capacity to proliferate or can be induced to proliferate
This occurs when the connective tissue infrastructure remains relatively intact
Regeneration occurs by:
Proliferation of cells that survive the injury and retain the capacity to proliferate
Replacement from stem cells
Restoration the action of returning something to a former condition

5. Mechanisms of tissue repair.
injury to the liver is repaired by regeneration if only the hepatocytes are damaged,
or by laying down of fibrous tissue if the matrix is also injured

6. Cellular Regeneration
Regeneration involves cell proliferation & interaction between cells and extracellular matrix
Cell proliferation is stimulated by:
Growth factors
Interactions of cells with the extracellular matrix
The contact of cell membrane with ECM can trigger growth stimuli and mimic the action of growth factors
Cell proliferation is controlled by the cell cycle
cell cycle
the series of events that take place in a cell leading to its division and duplication of its DNA (DNA replication) to produce two daughter cells

7. Intrinsic proliferative capacity
Tissues are divided into three groups according to their proliferative capacities :
Continuously dividing (labile) tissues
Stable tissues
Permanent tissues

8. Intrinsic proliferative capacity
Continuously dividing (labile) tissues
Cells are continuously proliferating
They can easily regenerate after injury
They contain a pool of stem cells
Examples: bone marrow, skin, GIT epithelium
Stable tissues
Normally in the G0 stage of the cell cycle and NOT proliferating
Capable of dividing in
response to injury or loss of tissue mass
Examples: liver, kidney, pancreas

9. Intrinsic proliferative capacity
Permanent tissues
Cells can’t proliferate
Cells Can’t regenerate (so injury always leads to scar)
Examples: neurons, cardiac muscle

10. Scarring
Repair occurs by the deposition of connective (fibrous) tissue
Although the fibrous scar is not normal, it provides enough structural stability that the injured tissue is usually able to function
Repair occurs by scar formation when:
Tissue injury is severe or chronic
There is damage to parenchymal cells as well as the connective tissue
Nondividing cells are injured

11. Scarring Steps in Scar Formation: Inflammation
Angiogenesis (new vessel formation)   
Migration and proliferation of fibroblasts   
Scar formation (synthesis of collagen)   
Connective tissue remodeling

12. Scarring Granulation tissue:
The red, granular tissue filling the nonhealing wounds
Granulation tissue occurs in all wounds during healing but that it may occur in chronic inflammation as well
It consists of
Fibroblasts
Surrounded by abundant ECM
Newly formed blood vessels
Scattered macrophages, and some other inflammatory cells

13. Granulation tissue

14. Granulation tissue

15. Scarring Scar The granulation tissue evolves into a scar composed of:
Inactive, spindle-shaped fibroblasts
Dense collagen
Fragments of elastic tissue
Other ECM components
As the scar matures, it become pale, largely avascular tissue

16. Scar

17. Scarring The role of macrophages in repair by connective tissue:
Cleanup of debris
Recruitment of other cells
Stimulation of matrix production
Remodeling of the scar

18. Scarring Myofibroblasts:
Myofibroblasts have hybrid properties of fibroblasts and smooth muscle cells
Myofibroblasts are found in the granulation tissue
Myofibroblasts are important for the contraction of wounds and the prevention of dehiscence

19. Skin Wound Healing

20. Cutaneous Wound Healing
Formation of Blood Clot
Formation of Granulation Tissue
Cell Proliferation and Collagen Deposition
Scar Formation
Wound Contraction
Connective Tissue Remodeling
Recovery of Tensile Strength
healed wound areas continue to be weaker than uninjured skin, generally only having 80% of the tensile strength of unwounded skin
tensile strength The resistance of a structure to stretching or tearing
tensile, having the ability to be extended or stretched
Remodeling Any process of reshaping or reorganizing structural modifications

21. SKIN WOUND HEALING First intention Second intention
Intention The process by which a wound heals

22. Healing by First Intention
Occurs in small wounds that close easily
Epithelial regeneration predominates over fibrosis
Healing is fast, with minimal scarring
Examples:
Well-approximated surgical incisions

23. Arm, healing surgical incision - Clinical presentation
This image demonstrates healing by first intention, which occurs in clean, uninfected wounds that have apposed edges

24. Healing by First Intention
Healing by First Intention: Timeline
–By 24 hours
Clot forms
Neutrophils come in
Epithelium begins to regenerate

25. Healing by First Intention
Healing by First Intention: Timeline
-By 3-7 days
Macrophages come in
Granulation tissue is formed
new blood vessels
Fibroblasts
Collagen begins to bridge incision
Epithelium increases in thickness

26. Skin, healing surgical incision, granulation tissue - High power
This higher power view illustrates the classic appearance of granulation tissue, newly formed reparative tissue that will eventually form collagen and contract to form a fibrous scar. Note
the loose, edematous ground substance,
prominent vessels, and
plump fibroblast nuclei

27. Healing by First Intention
Healing by First Intention: Timeline
- Weeks later
Granulation tissue has gone
Collagen is remodeled
Epidermis full, mature
(but without dermal appendages)
Eventually, scar forms

28. Healing by Second Intention
Occurs in larger wounds that have gaps between wound margins
Fibrosis predominates over epithelial regeneration
Healing is slower, with more inflammation and
granulation tissue formation, and more scarring
Examples:
Infarction
Large burns and ulcers

29. Hand, healing by secondary intention
Wounds with a large tissue defect heal by secondary intention
Note the red granular appearance of the granulation tissue
A whitish-greenish-yellow neutrophilic exudate represents an inflammatory response to bacterial invasion of the wound
Hand, wound healed by secondary intention, same case as previous image, eight months later - Clinical presentation
As the granulation tissue matures,
the myofibroblasts contract to close the wound.
They then become mature fibroblasts, which produce collagen, forming a fibrous scar.

30. The most common causes of delayed wound healing:
Infection
Foreign bodies in the wound
Mechanical factors
Poor perfusion
Nutritional deficiencies
Excess corticosteroids