WOUND HEALING,

TISSUE REPAIR, AND

FIBROSIS
DR. RIBKA THEODORA
D R . R E Y H A N FA R A N D I
DR. GOESTI YUDISTIRA
D R . N U R N AT H A N I A
DRG. DINA NOVIANTI
 Wound Healing
• Wound : a break in the epithelial integrity of the skin + disruption of the
structure & function of underlying normal tissue
• Healed Wound :
◦ Connective tissues have been repaired + re-epithelialized
◦ Returned to its normal anatomical structure and function
• Type :
1. Acute wounds :
- Occur within the past 3-4 w
2. Chronic wounds :
- Persist trough 4-6 w
- Chronic wounds = non healing wounds, recalcitrant, delayed healing
Wound Assessment
Paper-made ruler, transparent
gridlines
 Phases of wound healing:
Inflammatory Phase (day 1-3)
Purpose: attain homeostasis, remove devitalized tissue
and prevent invasive infection

1. Attainment of homeostasis
• Fibrillar collagen and tissue factor  act to
activate the clotting cascade  prevent
hemorrhage
• Platelets degranulates and releases .. Fibrin
polymerization into a gelatin

2. Removal of devitalized tissue & prevent infection

• Recruitment of inflammatory cells (neutrophils)
attracted by TGF-β & lipopolysaccharide followed
by monocytes  macrophages phagocytosis
• Lymphocyte enters at day 5-7
 Proliferative Phase: day 4-21
Purpose: to achieve wound closure by granulation,
angiogenesis, and epithelization

1. Tissue proliferation
• Macrophages as a conductor of cell interaction
and mediators  VEGF, FGF, TGF-α& β
• Fibroblast  FGF-2  regeneration of
endothelial cells
• Endothelial cells  IGF  proliferation of
keratinocytes and fibroblast
• Keratinocytes  TGF-α& β 1,2,3 
keratinocytosis (centripetal)

Granulation tissue is largely composed of

fibroblasts, macrophages, and endothelial cells.
2. Angiogenesis
• Macrophage  VEGF, FGF, angiopoietin 1,
thrombospondin
• Upregulated by hypoxia inducible factor
Formation of blood vessels and subsequent
granulation tissue  to provide the newly
formed tissue matrix  important for survival
3. Matrix formation (dermis-skeletal
structures)
• Fibroblast  collagen III increases
 Remodelling Phase: day 21-1
year
Purpose: obtaining matrix equilibrium, reorganizing the
collagen matrix into a well-organizing one to provide a
softer and flatter scar
1. Wound contraction
• Myofibroblast  scar contraction via specific
integrin-mediated cell-matrix interactions
with the dermal environment tighten
wound edges
2. Collagen remodeling
• Over the next few weeks to months col III will
be replaced by col type I (1:4), which are
more in regular alignment.
3. Matrix remodeling
• Matrix metalloproteinases degrade ECM 
along with resorption of fluid  flatter scar
 The role of macrophages in
wound healing
1. Efferocytosis: removal of apoptosis cells (neutrophils) by phagocytosis.
Failure in removal of inflammatory cells  non-healing wounds
2. Source of growth factor: VEGF (promotion of angiogenesis), FGF (fibroblast
proliferation), and ECM synthesis
The roles of neutrophils in
wound healing
Effective decontamination  destroying normal tissue.
Produce free oxygen radicals  superoxide and hydrogen peroxide  delaying
repair process and modifying healing outcome
 Serine proteases
• Include cathepsin-G, elastase, and protease-3  have the same proteolytic
activities  cleave a variety of extracellular matrix proteins (elastin,
fibronectin, laminin, vitronectin, collagen IV.
• Unfortunately, they could potentially interfere with re-epithelization.
(Gramerin, an elastase inhibitor accelerates re-epithelization. Elastase levels
have been observed in chronic wounds)
 MMP vs TIMP
Matrix metalloproteinase: degrade protein molecule on the wound bed. Secreted by neutrophils.
Among 23 types, there are 4 types that play important roles in wound healing: MMP-1 (kolagenase-1),
MMP-2, MMP-8 (kolagenase neutrophil), MMP-9
• Inflammatory phase:

MMP degrades damage ECM at wound edge  wound cells to synthesize new ECM to cover raw
surface area
• Proliferative phase:

MMP degrades capillaries membrane  neovascularization, also collagen  new epithelial and
endothel could move across matrix.
• Maturation phase:

Plasmin was activated and subsequently activates prokolagenase to kolagenase. Decrease over
synthesized matrix.

TIMP: inhibit MMP activities to allow normal healing process, low TIMP  chronic wound.
Resolved inflammation
So how do these processes turn off? Apoptotic Efferocytosis Proteases
neutrophils & apoptotic neutrophils are inhibitor
These events are programmed  fibroblast eventually engulfed by a1-antitrypsin, a1-
gradual self-destruction of cellular macrophages antichymotrypsin, and
apoptosis. secretory leukocyte
protease inhibitor
Afterwards, the proteases activity is (SLPI)
being countered by circulating
proteases inhibitor.
Resolved inflammation
relatively acellular scar. Less erythematous, less itch flatter scar

Lower apoptotic rates/ failure in apoptotic cell removal  persistent inflammation.

 BARRIERS OF WOUND HEALING PROCESS

NECROTIC BACTERIAL
EXUDATE
TISSUE LOAD

WOUND HEALING

IMPAIRED WOUND HEALING

 Factors influencing wound healing:
Local factors
• Infection: colonization and infection  bacterial bio-burden
• Foreign bodies: energy is consumed to remove debris and prolong
process of healing
• Hypoxia/Ischemia: no ATP  will lead to endothelial cells apoptosis &
necrosis
• Venous Insufficiency: metabolic waste being pooled in situ 
progressive blocking of blood flow
• Local toxin: from bacterial/ metabolic
• Radiation damage: due to heat penetration  radiation affects cell
proliferation
 Systemic Factors
Malnutrition:

o Glucose, the main fuel for collage synthesis

o Arginine and methionine for matrix deposition, cell proliferation, and angiogenesis
o Glutamine enhances the actions of PMN cells
o Mg, Mn, Cu, Ca, and Fe  co-factors in collagen production
o Vit C  collagen modification
o Glycine, arginine, methionine  control inflammation
o Zn  influences re-epithelization and collagen desposition
o L-arginine influences endothelial and metabolic function as well as NO synthesis
o Albumin  oncotic pressure to prevent edema
• Diabetes Mellitus: sorbitol  key byproduct of ineffective and inefficient glucose metabolism 
accumulates  toxic (impairs O2 delivery and nutrients) angiopathy.

• Systemic Corticosteroids: impairs immune system

• Alcoholism

• Cancer/malignancy: poor nutrition/receive chemotherapy, cytotoxic.

• Uremia

• Jaundice

• Obesity: increase cell-cell distance  decreased O2 perfusion. Difficulties in keeping his/her personal
hygiene of body fold & distant part

• Geriatric age: decreasing tissue regenerative ability

• Smoking: vasoconstriction agents: nicotine, hydrogen cyanide, CO2  increase platelet aggregation,
decrease collagen deposition

• Metabolic/ endocrine disease: hypothyroid: low hydroxyproline  collagen instability

 Tissue Repair
• The repair or reconstitution of a deficit in an organ or tissue, commonly the
skin.
• As an organism's global response to injury to re-establish homeostasis of
tissue/organ

• Every organisms and organ systems respond to injuries differently. Obviously,

most processes involve both, but usually one predominates and may be the
source of undesirable side effects that we would like to prevent or modify.
For cutaneous wounds, scar formation usually predominates.

• Occur in two ways : Regeneration and Reparation (Scar Formation)

Tissue types
Permanent
◦ nonproliferative in postnatal life
◦ neurons, cardiomyocytes, skeletal

Stable
◦ regeneration as response to injury
◦ parenchyma – liver, pancreas, renal tubules
◦ mesenchymal cells, endothelium

Continously
◦ continuous regeneration from stem cells (self-renewal)
◦ hematopoietic cells in bone marrow
◦ surface epithelia – skin, oral cavity, vagina, cervix
◦ duct epithelia – salivary glands, pancreas, biliary tract
◦ mucosas – GIT, uterus, fallopian tubes, urinary bladder
Tissue Types
 Occur in two ways :

Scar Formation
Substitution of cellular matrix  a patch 
to re-establish continuity physically and
physiologically
(replacement by connective tissue (fibrosis))
and
Tissue Regeneration
Re-creation of pre-existing tissue
(by parenchymal cells of the same type)
 Abnormal response to injury &
abnormal wound healing
Inadequate regeneration
• CNS injuries following traumatic injury or
tumor ablation
• Induce neural regeneration  implanted
neural stem/progenitor cells
• Bone nonunions & corneal ulcers
Inadequate scar formation
• Diabetic foot ulcers , sacral decubiti,
venous statis ulcers
• Abnormality in restoring cutaneous
integrity and collagen cross-linking
• Vit C deficiency
Excessive regeneration
• Hyperkeratosis in cutaneous psoriasis,
granuloma formation in healing wounds
• Loss of growth control & possible
transformation to overt cancer
Excessive scar formation
• Skin : hypertrophic scarring or keloid
formation.
• Pulmonary : fibrosis or cirrhosis.
Keloid vs Hypertrophic Scar
The ideal scar should be

• Similar to a fine line scar

• Pigmentation related to the

neighboring healthy tissue,

• Without any irregularities in

texture or contractures distorting
the adjacent skin
 Fibrosis
• Fibrois the formation of excess fibrous connective tissue in an organ or tissue.
• If injury is severe. regeneration can't happen. So, fibrosis (tissue scar) replaces
the injured tissue.
• Four components to this process :
1. New vessel formation
2. Fibroblast proliferation
3. Synthesis of collagen (scar formation)
4. Remodelling scar

• The prolonged secretion of inflammatory cytokines has been shown to induce

fibrosis in numerous in vitro and animal models. (Grabb and Smith)
Thank You