healing and repair

1. Inflammation & Repair
Lecture 10

2. Healing by Regeneration

3. OBJECTIVES AND KEY PRINCIPLES TO BE
TAUGHT:
• Categorize cell types according to their regenerative ability
• Identify the conditions that favours healing by regeneration
• Enumerate molecular events involved in cell growth
• Enumerate the components of repair by connective tissue
• Identify the factors which favours healing by connective tissue.
• Define granulation tissue and describe how it is formed
• Describe the process of angiogenesis and enumerate its mediators
• Describe the process of fibrosis, identify the cells involved and
enumerate the mediators of this process
• Enumerate the enzymes involved in scar remodelling and identify
their function, and their inhibitors.

4. Tissue Renewal
• The healing process of tissue damage caused by any cause
e.g. surgical resection, wounds, and diverse types of chronic
injury can be broadly separated into two processes,
regeneration and repair
Regeneration
refers to growth of cells and tissues to replace lost structures
requires an intact connective tissue framework. Regeneration
results in restitution of lost tissues.
Repair
- occurs if the extracellular matrix (ECM) framework is
damaged, causing alterations of the tissue architecture.
- may restore original structures but involves collagen
deposition and scar formation.

5. Cell types
• Labile cells: continue to proliferate throughout life :
squamous, columnar, transitional epithelia;
hematopoitic and lymphoid tissues
• Stable cells: retain the capacity of proliferation but
they don’t replicate normally: parenchymal cells of
all glandular organs & mesenchymal cells e.g. liver
and kidney
• Permanent cells: cannot reproduce themselves
after birth: neurons and the skeletal and cardiac
muscle cells.

6. CELL CYCLE
• G0
– Quiescent (not a very long)
• G1
– PRE-synthetic, but cell GROWTH taking place
• S
– Cells which have continuous “turnover” have longer, or
larger S-phases, i.e., DNA synthesis
– S-phase of TUMOR CELLS can be prognostic
• G2
– PRE-mitotic
• M (Mitotic:, P,M,A,T, Cytokinesis)

7. Cell Cycling is
controlled by ---
CYCLIN
S

8. Slide 4.2

10. Polypeptide growth factors
• Most Important Mediators affecting Cell
Growth
• Present in serum or produced locally
• Exert pleiotropic effects; proliferation, cell
migration, differentiation, tissue remodeling
• Regulate growth of cells by controlling
expression of genes that regulate cell
proliferation

11. Growth Factors (GFs)
• Epidermal
• Transforming (alpha, beta)
• Hepatocyte
• Vascular Endothelial
• Platelet Derived
• Fibroblast
• Keratinocyte
• Cytokines (TNF, IL-1, Interferons)

12. Growth Factor-mediated Proliferation
• Platelet Derived Growth Factor (PDGF)
– promotes the chemotactic migration of fibroblasts and smooth muscles
– chemotactic for monocytes
– competence factor that promotes the proliferative response of fibroblasts and smooth
muscles upon concurrent stimulation with progression factors
• Epidermal Growth Factor (EGF)
– promotes growth for fibroblasts, endothelial and epithelial cells
– is a progession factor - promotes cell-cycle progression.
• Fibroblast Growth Factor (FGF)
– promote synthesis of fibronectin and other extracellular matrix proteins
– chemotactic for fibroblast and endothelial cells
– promotes angiogenesis
– links extracellular matrix components (collagen, proteoglycans) and macromulocules
(fibrin, heparin) to cell-surface integrins.
• Transforming Growth Factors (TGFs)
– TGF-α - similar to EGF
– TGF-β - mitosis inhibitor that aids in modulating the repair process. May be responsible
for hypertrophy by preventing cell division. Chemotactic for macropahges and fibroblasts
• Macrophage-derived cytokines (IL-1 and TNF)
– promote proliferation of fibroblasts, smooth muscle and endothelial cells

13. VE(Vascular Endothelial) GF
• Made in mesenchymal cells
• Increases vascular permeability
• Mitogenic for endothelial cells
• KEY substance in promoting
“granulation” tissue

14. SIGNALING
• Autocrine (same cell)
• Paracrine (next door neighbor) (many
GFs)
• Endocrine (far away, delivered by
blood, steroid hormones)

16. ExtraCellular Matrix (ECM)
• Collagen(s) I-XVIII
• Elastin
• Fibrillin
• CAMs (Cell Adhesion Molecules)
– Immunoglobulins, cadherins, integrins, selectins
• Proteoglycans
• Hyaluronic Acid

17. Extracellular matrix (ECM) regulates
cell behavior
• It is not just a scaffold for cells to grow on
• Regulates cell growth, motility and
differentiation
• Insoluble elements of the ECM include
collagens, laminin and fibronectin
• Soluble elements include polypeptide growth
factors

18. Continuous assessment
• Cell cycling is controlled by :
A) Integrins
B) PECAM-1
C) Cyclins
D) Selectin

19. Inflammation & Repair
Lecture 11

20. Healing by Repair
( Connective Tissue
Replacement/scarring )

21. Repair by Connective Tissue Replacement
• FOLLOWS INFLAMMATION
• PROLIFERATION and MIGRATION of connective
tissue cells
• ANGIOGENESIS (Neovascularization)
• Collagen, other ECM protein synthesis
• Tissue Remodeling
• Wound contraction
• Increase in wound strength (scar = fibrosis)

22. ANGIOGENESIS
(NEOVASCULARIZATION)
• From endothelial precursor cells
• From PRE-existing vessels
• Stimulated/Regulated by GF’s, especially
VEGF
• Also regulated by ECM proteins

23. 2nd Yr Pathology 2010
Critical steps in angiogenesis

24. The repair process
Three main phases of cutaneous wound
healing:
(1) Inflammation (Removal of debris, by tissue
macrophages).
(2) formation of granulation tissue
(3) ECM deposition (scar formation) and
remodeling

25. Slide 4.19

26. Granulation tissue
• As early as 24 hr. after injury, fibroblasts and
vascular endothelial cells begin proliferating to
form (by 3-5 days) granulation tissue :pink
soft granular appearance on the surface of
the wound.
• histologically : granulation tissue is composed
of :
• proliferation of new small blood vessels
• proliferation of fibroblasts

28. • Scaring: as the amount of collagen in
granulation tissue progressively increase, the
tissue become gradually less vascular and less
cellular

30. Factors that Impede Repair
• Retention of debris or foreign body
• Impaired circulation
• Persistent infection
• Metabolic disorders
– diabetes
• Dietary deficiency
– ascorbic acid
– protein

31. Continuous assessment
All the following are correct regarding
granulation tissue EXCEPT:
A) Formed mainly of fibroblasts and capillary buds.
B) It is a specialized type of tissue that is a
characteristic of healing by fibrosis.
C) It indicates tuberculosis infection. (T.B.)
D) Gradually it accumulates connective tissue
matrix and form scar.

32. Inflammation
Lecture 12

33. Wound Healing& Factors impair
healing

34. OBJECTIVES AND KEY PRINCIPLES TO BE
TAUGHT:
Upon completion of this lecture, the student should:
1- Compare and contrast the difference between healing by
primary intention and healing by secondary intention.
2- Define tensile strength and identify the timing and strength of
the scar.
2- List factors which are associated with delayed wound healing.
3- List complication of wound healing.

35. Wound healing
1. Primary union (healing by 1st intention)
clean surgical incision
no significant bacterial contamination
minimal loss of tissue
clot formation
scab formation

36. Wound healing
Primary union (healing by 1st intention)
Events:
24 hr.: neutrophils,mitotic activity
of basal layer, thin epithelial
layer
day 3: macrophages, granulation
tissue
day 5: collagen bridges the
incision, epidermis thickens
2nd week: continued collagen
and fibroblasts, blanching
End of 1st month: scar(cellular
connective tissue, intact
epidermis, lost appendages).

37. Wound healing
2. Secondary union (healing by 2nd intention)
Occurs when there is :
more extensive necrosis and laceration
with inability to achieve apposition of wound
margins and in the presence of foreign body and
infection .

38. Wound healing
Secondary union (healing by
2nd intention)
Differs from primary healing:
1. inflammatory reaction is
more intense
2. larger amounts of
granulation tissue are
formed
3. wound contraction reaching
5-10%of the original
one,achieved by
myofibroblasts
4.re-epithelialization may take
several weeks and may need
skin grafting

39. DIFFERENCES BETWEEN PRIMARY AND
SECONDARY UNION OF WOUNDS
Feature Primary Union Secondary Union
Cleanliness of wound Clean Unclean
Infection Generally uninfected May be infected
Margins Surgical clean Irregular
Sutures Used Not used
Healing Scanty granulation Exuberant
tissue at the incised granulation tissue
gap and along suture to fill the gap
Outcome Neat linear scar Contracted irregular
wound

40. Scar Formation and remodeling
• In both types of healing, the wound contracts in the
later stages due to the presence of the
myofibroblast, a contractile cell that has properties
of both fibroblasts and smooth muscle cells.
• Tensile strength of the wound in both kinds of
healing gradually increases with more fibroblast
activity and the laying down of collagen.

41. Tensile Wound Strength
• After sutures are removed at one week,
wound strength is only 10% of unwounded
skin
• By the third month, wound strength is about
80% of unwounded skin
• Result from the excess of collagen synthesis
during the first 2 months , and later from
structural modifications as cross linking and
increase collagen fiber size .

42. Causes of delayed wound healing
(LOCAL)
• Local Infection
• Decreased blood supply
• Foreign bodies and necrotic tissue
• Mechanical stress
• Irradiation

43. (SYSTEMIC)
• Advanced age
• Diabetes mellitus
• Decreased Blood supply
• Anemia
• Malignancy
• Malnutrition

44. Complications of wound healing
• 1.Retarded wound healing and deficient scar formation
may cause wound separation at wound margin: a wound
dehiscence.
• 2.If a large wound cannot be totally covered by epithelium,
the resulting ulcer may require a skin graft.
• 3. The laying down of excessive collagen results in keloid
which is prominent raised scar covered by thin epithelium
• 4. Exuberant granulation tissue “ Proud Flesh”: excessive
granulation tissue growth Protrudes above skin not covered
by epithelium
• 5. Wound contractures is related to the action of
myofibroblasts. This is seen especially following burns.

45. Wound dehiscence
Wound ulceration
Keloid
Contracture
Proud Flesh

46. Continuous assessment
Following laparotomy with a midline abdominal
incision, the maximum tensile strength to be
obtained in wound healing in skin is achieved
within:
A) One week
B) Two weeks.
C) Three months
D) One year