Basic Molecular of Wound

Healing of The Skin

Basic Surgery Tutorial

Tutor:
Dr. dr. Theddeus O. H. Prasetyono, SpBP-RE(K)
Wound
• Any violation in tissue integrity
• Wound in integument system = violation of
integrity of the skin.
• Three overlapping phases of wound
healing:
• Inflammatory phase
• Proliferative phase
• Remodeling phase
Molecular Biology of Wound Healing
• A cascade governed by various feedback and feedforward regulatory
cycle driven by signals coming from:
• Wounded tissue, wound microenvironment, and intervention.
• In other words: cellular communication.
Hemostasis
• A protective
physiological response
to vascular injury that
results in exposure of
blood components to
the subendothelial
layers of the vessel
wall.
Inflammation
• A response that is meant to
prepare the wound site for
subsequent wound closure.
• Resulting from: interaction
between sensors and
receptors.
• Affecting: transcription and
translation of genes.
Proliferation Phase
• Consists of:
• ECM formation in
granulation tissue
• Angiogenesis
• Wound contraction
• Re-epithelization
• For the proliferative
phase to start  active
inflammation needs to
end
• ECM formation in granulation
tissue
• Degradation of fibrin-platelet
provisional matrix by the
protease.
• Stimulation of fibroblast
proliferation and activity by
macrophage, mast cells, and
growth factors.
• Fibroblast synthesizes ECM
products:
• Fibronectin (early)
• Glycosaminoglycan hyaluronic
acid (early)
• Sulfated glycosaminoglycans (late)
• Collagen (late), type I  type III
• Angiogenesis
• Formation of new blood vessels
by the division and migration of
endothelial cell from existing
vessels.
Steps in angiogenesis
• Vasodilation: VEGF, NO
• Pericyte separation
• Basement membrane
breakdown
• Proliferation and migration of
endothelial cells behind the
leading tip: VEGF, FGF
• Periendothelial cells
recruitment: PDGF
• Suppression: TGF-β
• Re-epithelization
• Starts within hours after injury.
• Intercellular junction: dissolved, esp. the marginal basal cells.
• Wound margin keratinocyte works as migratory cells:
• Changes in genetic expression, such as:
• Expression of actin filament,
• Promigratory integrin, and
• Several MMP subtypes
• Collagen IV secretion to re-form the basement membrane
 Extracellular Matrix

• The scaffold that supports cells in both the unwounded and wounded
states
• The ECM is dynamic and is constantly undergoing remodeling during
repair, which can be conceptualized as the balance between synthesis,
deposition, and degradation
Remodelling phase
• Wound tensile strength increases rapidly from 1 to 8 weeks
after wounding and correlates with collagen cross-linking by
lysyl oxidase
• However, the tensile strength of wounded skin at best
reaches only approximately 80% that of unwounded skin
Collagen Remodelling
• in scars, the collagen forms cross-links to align in a single
direction parallel to the skin
• there is greater collagen density and larger fiber size in scars
compared to normal tissue
• The two dominant types of collagen in wound repair are
collagen I and III
• In normal skin, collagen fibrils are composed of both
collagen I and III with collagen III comprising 20% of the total
The histological differences in collagen
Myofibroblast
• The main function of fibroblasts is to maintain the physical integrity of
connective tissue by producing and remodelling the ECM
• Myofibroblasts are a specialized form of fibroblast responsible for the
deposition of a dense, fibrotic collagen matrix
• These cells express Ɑ -smooth muscle actin (SMA) and play a major
role in wound contraction
• Their most prominent ECM products are collagens I, III, IV, and V
Myofibroblast
• During the remodeling phase, myofibroblasts produce decorin, which
regulates collagen fibrillogenesis by presenting as a ‘‘C’’-shaped
structure that locates itself between collagen fibrils assuring uniform
spatial fibril arrangement
• Decorin also binds and neutralizes TGF-b, thereby minimizing the
stimulatory effects of this cytokine on collagen, fibronectin, and GAG
production
Excessive Healing

• Normal wounds have “stop” signals that halt the repair process when
the dermal defect is closed and epithelialization is complete
• A lack of programmed cell death, apoptosis, at the conclusion of
repair with the continued presence of activated fibroblasts secreting
ECM components
Excessive Healing
• Hypertrophic scars are defined as scars that have not overgrown the
original wound boundaries but are instead raised
• Keloids are scars that overgrow the original wound edges
References
• Sen CK, Roy S. Wound Healing. In: Gurtner GC, ed, Neligan Principles
of Plastic Surgery Vol 1. 2013.
• Kumar, Abbas, Aster. Robbins and Cotran Pathologic Basis of Disease.
9th ed, 2015.
• Landen NX, Li D, Stahle M. Transition from inflammation to
proliferation: A critical step during wound healing. Cell Mol Life Sci,
2016;73:3861-5.
• Xue M, Jackson CJ. Extracellular matrix reorganization during wound
healing and its impact on abnormal scarring. Adv Wound Care,
2015;4(3):119-36.