Lecture notes for undergraduate veterinary students as they are introduce to the basic principles of pathology

1. PRINCIPLES OF VETERINARY PATHOLOGY (VMPA 302)
WOUND HEALING /REPAIR
BY
DR. F. S. UMAR
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2. REPAIR/ HEALING
– The process of restoring the structure & function of tissue/organ
following injury. It can also be a process by which lost or necrotic cells
are replaced by vital cells.
– Repair begins immediately after injury by inflammation.
The repair processes:
1) Regeneration: Replacement by cells of the same type, and/or
2) Replacement by c. t. (fibrosis)
 Fibrosis: Process resulting in an increase of collagen in tissue. Fibrosis
is often an important, & sometimes necessary component of the
repair process. Fibrosis usually results in increase in fibrous
connective tissues (i.e. fibroblasts & collagen).
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3. Regeneration: replacement of damaged tissue by proliferation of
parenchymatous cells of the affected tissue.
Based on their regenerative capacity, somatic cells are divided into three (3)
types:-
– Labile cells; Are able to multiply throughout life and replenish those lost
due to normal turnover e.g. epithelial cells of GIT, respiratory, epidermis,
endometrium, haemopoietic, lymphoid tissue. They can regenerate fully
after damage.
– Stable cells; Cells with latent capacity to regenerate. They stop multiplying
with cessation of growth but retain their mitotic ability after maturity &
could regenerate later in life. They have long life spans and do not turnover
quickly e.g. liver, renal tubular epithelium, fibroblast, glandular epithelia like
thyroid, pancreas, smooth muscle cells (also to a certain extent skeletal
muscle) etc. They can regenerate with appropriate stimulation.
– Permanent cells; They lose mitotic ability after birth. So they are incapable
of regenerating e.g. neurons and cardiac muscle cells. Neurons & cardiac
muscle cells can regenerate lost portions of cells e.g. axons can regenerate).
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4. Repair of skin wounds
Process: Starts with;
Phase of haemostasis:
– The process where by the wound is closed by blood clot.
– Haemostasis stage of wound healing happens rapidly in order to
arrest haemorrhage.
– Haemostasis starts after blood comes out of the injury, followed by
constriction of blood vessels to restrict the blood flow.
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5. … Phase of haemostasis contd.
– Platelets attach together, to seal the breakage in the vascular wall.
– Coagulation with fibrin formation which further binds & reinforces
the platelet plug.
Inflammatory phase
– Acute inflammation begins immediately resulting in hyperaemia &
inflammatory oedema.
– During the inflammatory stage, damaged cells & microbes like
bacteria are removed by neutrophils.
– Inflammation becomes fully achieved by 24 hrs & could last up to 4
days or more depending on cause of injury.
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6. …Inflammatory phase contd.
– Leucocytes (neutrophils & macrophages) commence the clearing
function & release enzymes, chemotactic & growth factors (cytokines).
– The cardinal signs of inflammation are usually observed at this stage.
– Inflammatory cellular response is an integral part of the wound
healing process and only becomes a problem if it gets prolonged &/or
excessive.
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7. Proliferative phase
– Occurs when new tissue made up of collagen and extracellular matrix
(ECM) are laid by fibroblasts & myofibroblasts (fibroplasia).
– Wound contraction begins as new granulation tissue is laid which
appear pinkish to reddish and uneven in texture.
– Myofibroblasts cause the wound to contract pulling the edges
together.
– Angiogenesis occurs when capillaries invade the fibrin/fibronectin-
rich wound clot and within a few days organize to form microvascular
network throughout the granulation tissue, for sufficient oxygen and
nutrients supply.
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8. …Proliferative phase contd.
– Epithelialization marks the final phase of the proliferative stage of wound
healing, by basal cell proliferation from wound edges until epithelial cells
resurface the injury.
– This can take 3 - 4 weeks or longer based on the size of wound.
Remodeling (maturation) phase
– This is when collagen become remodeled from type III to type I and the
wound fully closes.
–Unwanted cells used to repair the wound are removed by apoptosis.
–The collagen laid down during the proliferative phase is disorganized
making the wound is thick, it is aligned with the tension lines & water is
reabsorbed.
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9. …Remodeling phase contd.
–This brings collagen fibres closer together & enhance cross-
linkage.
–Cross linkaging reduces scar thickness and also strengthen the
wound.
–Remodelling begins about 21 days post injury & can continue for
a year or beyound.
–Healed wound are weaker than uninjured skin (has about 80% of
the tensile strength of skin before injury.
– Healed wounds lose the adnexa-hair follicles, sweat glands,
sebaceous glands.
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10. Types of Wound Healing
–Happen in 2 ways; healing by primary union or secondary union.
Healing by primary union (healing by first intention)
– Occurs in surgical & clean wounds which are uninfected, has
minimal tissue damage & apposed by sutures.
– Granulation tissue formation is minimal.
– Scar is thin & follows line of incision.
– Epithelialization occurs in 2-3 days.
– Heals by 7 days & by 14 days tensile strength is achieved.
Minimal scarring, good strength 10

11. Healing by secondary union (healing by second intention)
– Occurs in non-surgical, infected wounds.
– Edges rough & unapposed.
– Large scar.
– Prolonged healing time.
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12. 12

13. 13

14. 14
Granulation tissue, non-
healing ulcer, skin, distal
limb, horse. A, In the bed
of the ulcer, there is
extensive fibrosis and
granulation tissue.

15. 15
B, Gross photograph of the surface of the granulation tissue. Note the fine nodules or “granulations” on
the surface that gave rise to the term granulation tissue. These are a mixture of newly formed blood
vessels, extracellular matrix (ECM), and fibroblasts, with minimal or no collagen deposition. It provides the
support for wound repair and remodeling via fibroplasia and reepithelialization.

16. 16
C, Photomicrograph of granulation tissue. Note how the new
fibroblasts are arranged perpendicularly to the newly formed
blood vessels in a rich bed of ECM

17. Role of cells in Wound Healing
Clearance of injured site
– End products of inflammation should be cleared for healing to progress.
– Phagocytes; neutrophils & macrophages perform this role through
phagocytosis & subsequent lysosomal degradation of materials like:
– Degenerating & necrotic cells including parenchymal cell, fibroblasts,
endothelial cells, cell infiltrates (neutrophils, macrophages, lymphocytes,
platelets & mast cells).
– Inflammatory mediators: cytokines, chemokines & eicosanoids.
– Serum proteins : albumin, complement, acute-phase proteins like
ceruloplasmin, ferritin, mannose-binding lectin etc.
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18. – Fibrin in blood clots.
– Extracellular matrix (ECM) proteins like chondroitin sulphate,
collagen, elastin, laminin, fibronectin etc.
– ECM enzymatic degradation is performed by macrophages &
fibroblasts release of metalloproteinases.
Synthesis of new extracellular matrix
– ECM proteins like collagens (several types), elastins & adhesive
proteins (fibronectin, vitronectin, laminin etc.) are produced to fill
the gaps created by injury.
– Collagen is synthesized by fibroblast & forms the framework of
ECM
– Collagen type I occurs in bones, skin & tendons (most abundant)
– Collagen type II – cartilage & vitreous humour 18

19. – Collagen type III – skin, perivascular area & healing wounds
– Collagen type IV – basal lamina of epithelial cells
– Collagen types V & VI – interstitial tissue
– Collagen type VII – anchor fibrils at dermoepidermal junction
– Collagen type VIII – endothelial cells
– Collagen types IX, X, XI - cartilage
– Proteoglycans component of ECM is produced by fibroblasts.
– Proteoglycans retains water that moisturizes the ECM.
– Moisture is particularly essential for epithelialization.
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20. Angiogenesis
– Formation of new blood vessels from exiting ones is essential in healing
process.
– Starts from migration & proliferation of endothelial cells to form endothelial
tubes which mature to form capillaries.
Hypertrophic scars (fibroproliferative disorders)
– They result from excessive proliferation of fibroblasts & collagen
(connective tissue) due to improper wound healing resulting in raised scars.
– Horses are prone to occurrence of exuberant granulation tissue causing
severe scar formation & referred to as ‘proud flesh’.
– Keloids: occur as excessive formation of granulation tissue & scar formation
that grows beyond margin of the wound. Appear firm, shiny & rubbery. Seen
more in blacks, Asians c.f. Europeans.
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21. 21
Exuberant granulation tissue (proud flesh), chronic ulcer,
skin, distal hindlimb, horse. Note the large proliferating
mass of fibrous tissue on the lower portion of the left
hindlimb. It often lacks superficial epithelium.
Keloid

22. Factors that affect Wound Healing
– Nutrition: Inadequate nutrition associated with protein deficiency, vit. C in
primates, (fibroblast function & collagen synthesis), vit. A (macrophage chemotaxis
and epithelialization), zinc (tissue proliferation)
_Inadequate blood supply
–Contamination by bacteria, fungus, Foreign bodies &tissue debris: Presence delay
wound healing.
– Health status: Diseases occurring concurrently, Systemic hormonal deficit: diabetes
mellitus; hyperadrenocorticism, anaemia etc. delay WH.
– Mobility of site delay WH by disrupting granulation tissue deposits.
– Medication like steroids are anti inflammatory & delay WH.
– Excessive dryness facilitate excess scab, reduces cell proliferation, wound
contraction, epithelialization.
– Ageing (old age) affects WH as with other body functions.
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