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Tinjauan Pustaka

The Physiologic Basis of Surgery


Chapter 6
Wound Healing: Normal and Abnormal
Mechanisms and Closure Techniques

Pembimbing
dr. Deddy Saputra, Sp. BP-RE

Chapter 6
Wound Healing: Normal and Abnormal
Mechanisms and Closure Techniques
Phases Of Wound Healing
Cytokines/Chemokines and Growth Factor
Disturbances Of Wound Healing
Chronic Wounds and Abnormal Scar
Formation
Wound Closure

Phases Of Wound Healing

Early Phases
Intermediate Phases
Late Phases
Terminal phases

Early Wound Healing Events


In all injuries that penetrate the epidermis,
blood vessels are disrupted, resulting in
hemorrhage. Hemostasis must be the first
event achieved in the healing process.
Cellular damage occurs with any injury,
and this initiates an inflammatory
response. The inflammatory response
triggers events that have implications for
the entire healing process.

Hemostasis is created primarily by aggregated


platelets and fibrin.
Endothelial lining is disrupted, platelet
aggregation exposure to collgen and other
intravascular and extravascular proteins.
Platelets adhere to collagen and release
adenosine diphosphate (ADP) in the presence of
calcium, and Thrombin produced by the
coagulation cascade and fatty acids released by
injured cells further platelet aggregation.

Platelet adhesion to other platelets and to


subendothelial proteins is mediated primarily by
fibrinogen and von Willebrand factor although
thrombospondin, fibronectin, vitronectin and
laminin may also be involved
Platelet aggregation release of cytokines
platelet-derived growth factor (PDGF),
transforming growth factor (TGF-a), TGF-B
fibroblast growth factor-2 (FGF-2) and platelet
derived epidermal growth factor (EGF).

The intrinsic and extrinsic coagulation cascades


are triggered by separate events. The alternative
extrinsic coagulation pathway tissue factor,
which binds factor VII or VIIa
production of thrombin, catalyzes the conversion
of fibrinogen fibrin. Thrombin contributes to
the increased vascular permeability seen after
injury, facilitates the extravascular migration of
inflammatory cells and may have a role in both
epithelialization and angiogenesis.

Fibrin, along with fibronectin that becomes bound to it,


forms a lattice migration of inflammatory, endothelial,
and mesenchymal cells, aids in cellular attachment and
modulates the migration of various cell types into the
wound.
The binding of cell surface integrins with fibronectin
allows cells to attach to the lattice pull themselves
through the lattice as they migrate to sites. The fibrinfibronectin lattice also binds cytokines released, serves
as a reservoir for these factors as healing progresses,
has direct effects on inflammatory cells, stimulus to
angiogenesis.

Hunter (1794) physical signs of inflammation


(erythema, edema, pain, and heat)
Vasodilation generates erythema and heat in the area of
injury, mediated by histamine, kinins,
prostaglandins,leukotrienes and endothelial cell
products.
The migration of cells and fluid into the injured area
generates edema.
Alterations in pH resulting from breakdown products of
tissue and bacteria, along with swelling and decreased
tissue oxygenation from damage to the blood supply
pain noted in areas of injury.

Neutrophils, macrophages, and lymphocytes are


leukocytes involved in the inflammatory
response to injury.
Neutrophils function as defensive units that engulf foreign
material and digest it through the action of hydrolytic
enzymes Phagocytosed by macrophages or die, releasing
oxygen radicals and destructive enzymes into the wound.
Macrophages phagocytose bacteria and dead tissue and also
secrete matrix metalloproteinases (MMPs) that break down
damaged matrix. Macrophages are a primary source of
cytokines that stimulate fibroblast proliferation, collagen
production, and other healing processes..
Lymphocytes produce factors essential for normal healing
(Heparin-binding EGF and a form of basic FGF)

Intermediate Wound Healing Events


include mesenchymal cell chemotaxis,
mesenchymal cell proliferation,
angiogenesis, and epithelialization.
These processes predominate 2 to 4 days
after wounding and are all mediated by
citokines.

Fibroblasts are the primary mesenchymal cell


involved in wound healing healing, although
smooth muscle cells are also involved.
Additional fibroblasts migrate to the wounded
area under the influence of chemotactic factors
(PDGF, Fibronectin, EGF)
Fibroblasts have the capacity to secrete matrix
MMPs including collagenase or (MMP-l),
gelatinase (MMP-2) and stromelysin (MMP-3)

The mesenchymal cell population in a


wound proliferation of both resident and
newly arrived cells.
PDGF is a potent mitogenic stimulant for
both fibroblasts and smooth muscle cells.
(TGF-B, TNF, IL-1, lymphokines, insulin,
and insulin-like growth factor (IGF)

Angiogenesis reconstructs the vasculature in


areas where t has been damaged by wounding
and is stimulated by high lactate levels, acidic
pH, and decreased oxygen tension in the tissue

Small capillary sprouts develop on venules at


the periphery of the devascularized area grow
with endothelial cell proliferation the cells
develop a curvature that results in a lumen
they contact other sprouts growing from other
directionsinterconnect, forming a vascular
loop, and the sprouting process begins anew.
Cytokines (FGF-l, Heparin, TGF-a, TGFb,wound fluids, prostaglandins, adipocyte lipids)

the sequence of events that comprise


epithelialization include cellular detachment,
migration, proliferation, and differentiation

In first 24 hours after injury, thickening of the basal cell layer begins.
Marginal basal cells elongate, detach from the underlying basement
membrane, and migrate into the wound as a monolayer across the
denuded area. Migrating orient themselves along collagen fibers
and exhibit what is called contact guidance.
Basal cells at the edge of the denuded area begin to divide 48 to72
hours after injury. Epithelial cell proliferation contributes new cells to
the advancing epithelial monolayer. Cells migrate until they reach
cells migrating from a different direction( contact inhibition)
differentiate into more basal-like cells with hemidesmosomes.
Cellular proliferation continues in the new basal cells as a
multilayered epidermis is reestablished. Subsequently, new surface
cells begin to keratinize.

EGF stimulates the migration and proliferation of epithelial


cells. TGF-B stimulates epithelial migration, although it
slows epithelial proliferation. Keratinocyte growth factor
(KGF), also known as fibroblast growth factor-7 (FGF-7),
is another potent stimulant of epithelialization.

Regenerated epithelium does not retain all of the


functional advantages of normal epithelium. There are
fewer basal cells in regenerated epidermis, and the
interface between epidermis and dermis is abnormal .
The epithelium is thicker at the wound edge than in the
midportion of a re-epithelialized area.

Late Wound Healing Events


Collagen is synthesized by fibroblasts in a
complex process that begins 3 to 5 days after
injury, increases rapidly for 2 to 4 weeks in most
wounds.
It gradually replaces fibrin as the primary
structural matrix element in the wound. After 4
weeks, collagen synthesis rates decline,
eventually balancing the rate of collagen
destruction by collagenase.
Age, tension, pressure, and stress affect the
rate of collagen synthesis.
TGF-B stimulates collagen synthesis, whereas
glucocorticoids inhibitit

Type I collagen makes up 80% to 90 % of


collagen in skin
10% to 20 % being type III, are seen
embryonically and in early phases of wound
healing.
Type V predominates in smooth muscle.
Types II and XI are seen primarily in cartilage,
type IV is seen predominantly in basement
membranes.

After the collagen molecule is synthesized, it is


secreted into the extracellular space it
appears in the form of procollagenThis linear
extension, or registration peptide, interferes with
the subsequent aggregation of collagen
molecules into fibrils.
Successful cleavage of the registration peptide
by specific enzymes yields a collagen molecule,
which can aggregate into collagen fibrils. Fibril
formation is facilitated by proteoglycans in the
extracellular matrix.

Another critical component of collagen synthesis is the


hydroxylation of lysine and proline moieties within the
polypeptide chains.
Hydroxlproline is found almost exclusively in collagen
and serves as a marker of the quantity of collagen in
tissue. This hydroxylation process requires specific
enzlrnes for lysine and proline and, in addition, requires
as cofactors oxygen, vitamin C, a-ketoglutarate, and
ferrous iron

fibronectin, are critical components of the


mature matrix as well as the provisional matrix
that initially forms after wounding. As mentioned,
a variety of cell types synthesize it.
Elastin is a third component of the connective
tissue matrix; however, it is not synthesized in
response to injury. Normal skin has elastic
properties that scar lacks due to the lack of
elastin in scar.

Wound contraction, lsuch as collagen synthesis, begins


approximately 4 to 5 days after wounding.
Wound contraction, centripetal movement of the wound
edge toward the center of the wound.
Maximal wound contraction continues for 12 to 15 days,
although it will continue or longer periods if the wound
remains open.
A wound where the tissue is loose, will contract much
more than a wound where the skin is tighter. Wounds
with square edges contract more rapidly than circular
wounds.Wound contraction occurs to a greater extent in
relatively immobile areas

Large numbers of myofibroblasts are


found in wounds during wound contraction
Experimental work in contracting collagen
matrices has suggested that fibroblasts
within the wound are primary contributors
to wound contraction through interactions
with surrounding matrixmyo
Fibroblasts at the wound perimeter are
merely fibroblasts with stress fibers in their
cytoplasm.

Terminal Wound Healing Event


Approximately 21days after injury. Although collagen
content is maximal at this point, bursting strength of the
wound is only l5% of that of normal skin.
The process of scarre modeling dramatically increases
wound-bursting strength. The greatest rate of increase
occurs between 3 and 6 weeks after wounding. By 6
weeks after wounding, the wound has reached 80 % to
90 %of its eventual strength
The bursting strength of scar never reaches that of
unwounded skin, however, and it reaches a maximum of
approximately 80% to 90% of skin breaking strength at 6
months.

A continual turnover of collagen molecules


occurs as old collagen is broken down by
some of the matrix MMPs and new
collagen is synthesized in a denser, more
organized manner along stress lines
During this period of scar remodeling, the
number of intra- and intermolecular crosslinks between collagenfibers increases
dramatically.

DISTURBANCES OF WOUND HEALING

Local Factor
Infection
Hypoxia and Smoking
Delivery of oxygen to healing tissues is critical for
prompt wound repair. Oxygen is necessary for
cellular respiration and for hydroxylation of proline
and lysine residues.
Smoking can impair tissue oxygenation as it
acutelystimulates vasoconstriction

Radiation
Fibroblasts that migrate into irradiated tissue
are often abnormal, Collagen is sinthesized
to an abnormal degree in irradiated tissue,
causing a characteristic fibrosis.
The decreased vascularity and increased
fibrosis limits the ability of platelets and
inflammatory cells to gain access to
wounds in the area. The quantity of
cytokines released is therefore limited.

Systemic Factors
Malnutrition
Collagen synthesis essentially stops in the absence of protein
intake resulting in impaired healing
Wound healing slows when carbohydrate or fat stores are
limited.
Vitamin C is a necessary cofactor for hydroxylation of
lysine and proline during collagen synthesis
Vitamin A is essential for normal epithelialization,
proteoglycan synthesis, and normal immune function
Vitamin D is required required for bone healing.
Exogenous vitamin E impairs wound healing in rats, most
likely by influencing theinflammatory response in a
corticosteroid-like manner
Zinc deficiency can therefore result in an inhibition of cellular
proliferation and deficient granulation tissue formation and
healing

Cancer
Cancer-induced cachexia, which manifests itself as weight
loss, anorexia, and asthenia, significantly limits healing.
glucose turnover may be increased,leading to glucose
intolerance, protein catabolism may be accelerated, unable to
alter their metabolism to conserve energy by relying on fat for
most of their energy needs. Vitamin C may be preferentially
taken up by some tumors
Macrophages do not migrate or function normally in cancer
patients. Inflammatory cell dysfunction may limit the
availability of cltokines required for healing and may also
predispose to
infection.

Advanced Age
The elderly have been shown to heal less
efflciently than younger individuals.

Diabetes
Diabetes is associated with impaired
neutrophil chemotaxis and phagocytic
function

Steroids and Immunosuppression


Adrenocortical steroids inhibit all aspects of
the healing process.

Chemotherapeutic Agents
Chemotherapeutic agents impair healing
primarily through inhibitidn of cellular
proliferation

CHRONIC WOUNDS
Any wound that is affected by compromising
factors may become a chronic wound. Chronic
wounds do not respond to standard care and
remain substantially unhealed beyond the 6week period typically required for normal wound
healing. They are also characteized by slow
progression of either re-epithelialization or
contraction.

specific pathologies related to chronic


wounds include pressure ulcers, diabetic
foot ulcers, venous insufficiency
ulcers,hematologic uicers from sickle cell
disease and polycythemia, infected
wounds, neoplastic wounds, radiation
ulcers, neoplastic,wounds including
Marjolin ulcers, Kaposi sarcoma, and
metastatic lesions, and factitious ulcers.
progressive healing can be expected once
treatable comorbidities have been treated.

ABNORMAL SCAR FORMATION


Excessive healing can result in a raised,
thickened scar with both functional and
cosmetic complications. If the scar is
confined to the margins ofthe original
wound, it is called a hypertrophic scar

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