PATHOLOGY OF WOUND HEALING MECHANISM, MORPHOLOGY, PATTERNS

2. REPAIR AND REGENERATION
Prof Dr. Ahsan Kazmi
Prof. Chemical Pathology
Sahara Medical College, Narowal.

3. LEARNING OBJECTIVES
• Classify and describe the tissues with different proliferative
capacities
• Describe role of cell proliferation, growth factors and extracellular
matrix in regeneration and repair
• Describe the process of scar formation
• Describe the factors that influence tissue repair
• Enlist types of wound healing and describe the mechanisms
involved in each type of wound healing
• Tabulate differences between healing with primary intention and
healing with second intention

4. DEFINITION OF REPAIR
Repair (Healing):
• Restoration of tissue architecture and function
after an injury.

5. DEFINITION REGENERATION
Regeneration:
• Replacement of the damaged cells
• by proliferation of tissue stem cells or the
residual (uninjured) cells
• that retain the capacity to divide,
• resulting in normal anatomical and
functional state

8. FOUR STAGES OF WOUND HEALING
Understanding the four stages of wound healing can
help us appreciate the complexity of the body’s natural
healing mechanisms.

10. 1. Hemostasis
• Immediate response to an injury,
• Primary objective is to stop bleeding.
• When a wound occurs, blood vessels constrict
to reduce blood flow.
• Platelets form a clot to plug the damaged
vessel, effectively sealing the wound.
• This active process prevents excessive blood
loss and lays the groundwork for the healing
process to begin.
FOUR STAGES OF WOUND HEALING

11. 2. Inflammation
• Typically begins within a few hours of the injury and can
last for a few days.
• White blood cells actively work to combat infection.
• Inflammation is marked by redness, heat, swelling, and
pain, as the body’s immune system fights off potential
threats.
• Essential for clearing away debris and initiating the
repair process.
FOUR STAGES OF WOUND HEALING

12. 3. Proliferation:
• The active reconstruction of damaged tissue takes
place.
• Duration: Starts within a few days after the injury and
can last for several weeks.
• Fibroblasts play a crucial role by actively generating
collagen and other extracellular matrix components.
• These proteins are the building blocks of new tissue.
• Neovascularization: Blood vessels also form, bringing
oxygen and nutrients to the wound site, while
keratinocytes multiply to create a new surface layer.
FOUR STAGES OF WOUND HEALING

13. 4. Remodeling:
is the final stage of wound healing and involves the active
refinement and strengthening of the newly formed tissue.
Collagen that was initially deposited is reorganized and
strengthened, improving the wound’s tensile strength. This
stage can last for months or even years, with the tissue
gradually regaining more of its original structure and
function. In the end, the scar tissue may not be identical to
the surrounding tissue, but it’s a testament to the body’s
remarkable regenerative abilities.
FOUR STAGES OF WOUND HEALING

14. WOUND HEALING OR REPAIR
• Two types of reactions:
– Regeneration
– Scar formation

15. REGENERATION MECHANISM
• Ability of the tissue to replace the damaged cells
and return to normal state.
• Occurs by proliferation of the uninjured cells.
– Replacement from tissue stem cells
– Mostly in labile tissues e.g mucosal ulcer

16. SCAR FORMATION
• If the injured tissues are incapable of
regeneration, repair occurs by formation of
fibrous tissue (connective tissue) resulting in
scar formation.
• This is seen mostly in permanent and stable
tissue e.g. in heart after myocardial infarction

18. TISSUES WITH DIFFERENT
PROLIFERATIVE CAPACITIES

19. CELL CYCLE
• G0
– Quiescent (not a very long or dominant phase)
• 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:, Cytokinesis)

21. 1. Labile tissues
– Continuously dividing tissues
– Continuously being lost and replaced by maturation
from stem cells and proliferation of mature cells.
– These tissues include surface epithelia, such as:

22. • stratified squamous epithelia of the skin, oral cavity,
vagina, and cervix
• the lining mucosa of all the excretory ducts of the
glands of the body (e.g., salivary glands, pancreas,
biliary tract)
• the columnar epithelium of the GI tract and uterus
• the transitional epithelium of the urinary tract
• cells of the bone marrow and hematopoietic tissues

23. 2. Stable tissues
– Cells are quiescent and have the capacity to regenerate
after injury
the parenchymal cells of liver, kidneys, and
pancreas
mesenchymal cells such as fibroblasts and smooth
muscle
chondrocytes and osteocytes
vascular endothelial cells
lymphocytes and other leukocytes

24. 3. Permanent tissues
– Nondividing tissues
– Contain cells that have left the cell cycle and cannot undergo
mitotic division in postnatal life
– Terminally differentiated and not proliferative at all:
Neurons
Cardiac myocytes
Skeletal muscle cells (some regeneration through
satellite cells)

25. CONTROL OF CELL PROLIFERATION
• Several cell types proliferate during tissue repair
– Remnants of injured tissue
– Vascular endothelial cells
– Fibroblasts
• Proliferation of these cell types is driven by
proteins called growth factors and extra
cellular matrix

26. GROWTH FACTORS
• Most growth factors are polypeptides
• Stimulate survival and proliferation of the cells
• Promote migration and differentiation of the cells
• Stimulate angiogenesis and fibrogenesis

27. • These factors can have restricted or multiple
cell targets
• May also promote cell survival, locomotion, contractility,
differentiation, and angiogenesis, in addition to their
growth-promoting effects
• All growth factors function as ligands that bind to specific
receptors, which deliver signals to the target cells
• These signals stimulate the transcription of genes that
may be silent in resting cells, including genes that control
cell cycle entry and progression

28. GROWTH FACTORS INVOLVED IN
REGENRATION AND REPAIR

29. EXTRACELLULAR MATRIX (ECM)
• A proteinaceous complex assembled as network and
surrounds the cells
• Constitutes significant proportion of any tissue, provides
mechanical support to tissue
• Regulates proliferation, movement and differentiation of
the cells by supplying a substrate for cell adhesion and
migration
• Serves as a reservoir for growth factors

30. • The ECM is composed of three groups of
macromolecules:
1. fibrous structural proteins, such as collagens and
elastins that provide tensile strength and recoil
2. adhesive glycoproteins that connect the matrix
elements to one another and to cells
3. proteoglycans and hyaluronan that provide resilience
and lubrication

31. COMPONENTS OF ECM
• Basement membrane
– Collagen membrane which is present beneath the
epithelium.
– It consists of nonfibrillar collagen (mostly type IV),
laminin, heparin sulfate, and proteoglycans.
• Interstitial matrix
– Present in spaces between epithelial, endothelial, and
smooth muscle cells, as well as in connective tissue.
– It consists mostly of fibrillar and nonfibrillar collagen,
elastin, fibronectin, proteoglycans, and hyaluronan.

34. ROLE OF ECM IN REPAIR
An intact ECM is required for tissue regeneration and if
ECM is damaged, repair can be accomplished only by
scar formation, For Example: Liver

36. Healing by Scar Formation and Fibrosis
• If tissue injury is severe or chronic, and results in damage of both
parenchymal cells and the stromal framework of the tissue, healing can
not be accomplished by regeneration.
• Under these conditions, the main healing process is repair by deposition
of collagen and other ECM components, causing the formation of a scar.
• In contrast to regeneration which involves the restitution of tissue
components, repair by scar formation is a fibroproliferative response that
“patches” rather than restores the tissue.
• Deposition of collagen is part of normal wound healing. However, the
term fibrosis is used more broadly to denote the excessive deposition of
collagen and other ECM components in a tissue. Fibrosis most often
indicates the deposition of collagen in chronic diseases.

37. Repair by connective tissue deposition includes the
following basic features:
 Inflammation
 Angiogenesis
 Migration and proliferation of fibroblasts
 Scar formation
 Connective tissue Remodeling
– Maturation and reorganization of fibrous tissue to
produce stable fibrous scar

39. STEPS IN SCAR FORMATION

40. Direct observation of fibrous repair.
1) Exudate clots. 2) Neutrophils infiltrate
and digest clot
3) Macrophages and
lymphocytes are
recruited

41. Direct observation of fibrous repair.
4) Vessels sprout,
myofibroblasts make
glycoproteins
5) Vascular network;
collagen synthesised;
macrophages reduced
6) Maturity. Cells
much reduced; collagen
matures, contracts,
remodels

42. ANGIOGENESIS
Angiogenesis is the process of new blood vessel development.
 Angiogenesis from Preexisting Vessels
 Angiogenesis from Endothelial Precursor Cells (EPCs)
Several growth factors contribute to angiogenesis; the most
important are VEGF and basic fibroblast growth factor
(FGF-2).

43. Granulation Tissue
• Term derives from pink, soft, granular gross
appearance
• Combination of proliferating fibroblasts, loose
CT, new blood vessels, scattered chronic
inflammatory cells

44. CUTANEOUS WOUND HEALING
• Three phases:
1) Inflammation
2) Proliferation
3) Maturation
• The initial injury causes platelet adhesion and
aggregation and the formation of a clot in the surface of
the wound, leading to inflammation.
• In the proliferative phase there is formation of
granulation tissue, proliferation and migration of
connective tissue cells, and re-epithelialization of the
wound surface.
• Maturation involves ECM deposition, tissue remodeling,
and wound contraction.

46. HEALING OF SKIN WOUNDS
• Cutaneous wound healing involves both
– Regeneration
– Scar formation
• Depending on the nature and size of wound, the healing
can occur by
A. First intention or B. Second intention or
Primary union Secondary union

47. DIFFERENCE BETWEEN HEALING OF
SKIN WOUND
Primary intention
• Two edges are
approximated together
• Minimal tissue loss
• No sepsis
• Minimal amount of
granulation tissue, so the
scar is very thin
• Little contraction of the
scar
Secondary intention
• Wide gap
• Marked tissue loss and
necrosis
• Sepsis might be present
• Large amount of
granulation tissue so the
scar is large and wide.
• Much contraction of the
scar reaching 5-10 % of
the original one

48. HEALING OF SKIN WOUNDS

49. first intention healing second intention healing

52. Healing of skin ulcers.
A, Pressure ulcer of the skin, commonly found in diabetic patients. The
histologic slides show: B, a skin ulcer with a large gap between the edges
of the lesion; C, a thin layer of epidermal re-epithelialization and
extensive granulation tissue formation in the dermis; and D, continuing
re-epithelialization of the epidermis and wound contraction.

53. FACTORS THAT INFLUENCE TISSUE
REPAIR

54. Systemic factors
• Nutrition: Protein deficiency and vitamin C deficiency, inhibit
collagen synthesis and retard healing.
• Metabolic status: Diabetes mellitus, for example, is associated with
delayed healing, as a consequence of the microangiopathy that is a
frequent feature of this disease.
• Circulatory status: Inadequate blood supply, usually caused by
arteriosclerosis or venous abnormalities (e.g., varicose veins) that
retard venous drainage, also impairs healing.
• Hormones: such as glucocorticoids have well-documented anti-
inflammatory effects that influence various components of
inflammation. These agents also inhibit collagen synthesis.

55. Local factors
• Infection: it is the single most important cause of delay in healing,
because it results in persistent tissue injury and inflammation.
• Mechanical factors: such as early motion of wounds, can delay
healing, by compressing blood vessels and separating the edges of the
wound.
• Foreign bodies: such as unnecessary sutures or fragments of steel,
glass, or even bone, constitute impediments to healing.
• Location of wound: Wounds in richly vascularized areas, such as the
face, heal faster than those in poorly vascularized ones, such as the
foot.
• Size and type of wound: small incisional injuries heal faster and with
less scar formation than large excisional wounds or wounds caused by
blunt trauma.

56. PATHOLOGIC ASPECTS OF REPAIR
(1) deficient scar formation
 wound dehiscence
 ulceration
(2) excessive formation of the repair
components
 hypertrophic scars
 keloids
(3) formation of contractures

57. KELOID
– Excessive accumulation of collagen can give rise to
prominent raised scars known as keloid.
– It is formed by abundant broad irregular collagen
bundles with stretched overlying skin.
– This is an inherited condition and is more common in
blacks.

59. Wound contracture. Severe contracture of a
wound after deep burn injury

60. Summary