Textbook Reading : Schwartz’s Principle of Surgery

WOUND HEALING

Preseptor:
dr. Deddy Saputra, Sp. BP-RE (K)

dr. Fecky Fihayatul Ichsan

PPDS Ilmu Bedah FK UNAND
2023
HISTORY OF WOUND HEALING
• 2000 b.c  the Sumerians  Incantations + applying poultice-like
materials to the wound
• Egyptians  1st Differentiate  Wound = Infected / Non Infected
• 1650 b.c.  Edwin Smith Surgical Papyrus  Describes at least
48 different types of wounds
• 1550 b.c  Ebers Papyrus  Honey (Antimicrobial) + Lint
(Absorbent) + Grease (Grease) for wound treatment
• 120–201 a.d  Galen of Pergamum (Greek) a doctor to the Roman
gladiators  Moist environment to ensure adequate healing
• 1818–1865  Ignaz Philipp Semmelweis (Hungarian
obstetrician)  Hand washing with soap & hypochlorite 
Lower pueperial fever incidence
• 1822–1895  Louis Pasteur  theory of spontaneous generation
of germs and proving that germs existed in and were always
introduced from the environment
• 1865  Joseph Lister  soaking surgical instrument + Spraying
operating rooms with PHENOL  Reducing PostOp Mortality
from 50% to 15%
• 1876  Robert Wood Johnson  cotton gauze impregnated with
iodoform
• 1960s and 1970s  Customized polymeric dressings 
permeability to gases (occlusive vs. semi-occlusive) + varying
degrees of absorbency, and different physical forms
• Currently, the practice of wound healing encompasses
manipulation and/or use of among others, inflammatory
cytokines, growth factors, and bioengineered tissue. The role of
organism in the perpetuation of nonhealing of chronic wounds
has been better understood
• The future of wound healing is in “precision medicine” in
which treatment strategies will be based on the host, the
underlying mechanism, and the organisms in the wound bed
and tissue.
PHASES OF WOUND HEALING

• Wound healing = Complex Process + overlapping phases  initiated by an

injury/wound
• Normal wound healing phases  characteristic cellular populations and
biochemical activities:
(a) hemostasis and inflammation
(b) proliferation, and
(c) maturation and remodeling
• Successful wound healing  Need progress through all phases
HEMOSTASIS AND INFLAMMATION
division of
HEMOSTASIS blood vessels

Disrupts
WOUNDING Tissue
Integrity direct
exposure of
extracellular
matrix to
platelets
Hemostasis
SUBENDOTHELIAL COLLAGEN vs PLATELET

• Platelet aggregation
• Degranulation
• Activation of coagulation cascade

FIBRIN CLOT
Inflammation
Fibrin clot  Migration of inflammatory cells to wound
- Polymorphonuclear leukocytes (PMN, Neutrophil)
- Monocytes
1st  PMN enter wound site (24-48hr)
- Increased vascular permeability
- Local prostaglandin release
Stimulate neutrophil migration
- Presence of chemotactic substances
- Bacterial products
neutrophils Phagocytosis of bacteria
Phagocytosis tissue debris
TNF-α angiogenesis
collagen synthesis
Inflammation
• 2nd  Macrophages (48 to 96 hours post injury and remain present
until wound healing is complete)
• Derived from circulating monocytes

Macrophages Wound debridement Phagocytosis

Microbial stasis Oxygen radical & nitric oxide synthesis

Macrophages Regulate Cell proliferation

Matrix synthesis
Angiogenesis

T-lymphocyte numbers peak at about 1 week post injury and truly bridge the
transition from the inflammatory to the proliferative phase of healing
Proliferation
• The proliferative phase is the second phase of wound healing and
roughly spans days 4 through 12.
• phase that tissue continuity is reestablished
• Fibroblasts and endothelial cells infiltrate the healing wound
• The strongest chemotactic factor for fibroblasts is PDGF (platelet-
derived growth Factor)

• Cytokines
Wound fibroblasts  proliferate  activated
Macrophages
• Growth factors
Proliferation
• The proliferative phase is the second phase of wound healing and
roughly spans days 4 through 12.
• phase that tissue continuity is reestablished
• Fibroblasts and endothelial cells infiltrate the healing wound
• The strongest chemotactic factor for fibroblasts is PDGF (platelet-
derived growth Factor)
• Fibroblasts synthesize collagen
• Additionally, lactate
adenosine diphosphate
(ADP)-ribosylation
Regulate collagen synthesis
Proliferation
- CYTOKINES
- GROWTH FACTORS Endothelial cells migrate
from intact venules to the wound

ANGIOGENESI
S
Matrix Synthesis
Biochemistry of Collagen
• Deposition
Functional integrity WOUND
COLLAGE • Maturation of the wound HEALING
N
• Remodeling

Type I collagen (Skin Extracellular Matrix)

18 types of collagen
Type III

WOUND REPAIR PROCESS

 INTRACELLULAREXTRACELLULAR
PROTOCOLLAGEN
Prolyl hydroxylase requires:
• Oxygen
• iron
• α-ketoglutarate
• ascorbic acid (vitamin C)

PROCOLLAGEN

further polymerization and cross-linking

Proteoglycan Synthesis

• Glycosaminoglycans comprise a large portion of the “ground substance”

that makes up granulation tissue

• The polysaccharide chain Iduronic acid

Repeating
Glucuronic acid
Disaccharide
Hexosamine

FIBROBLAST 3 weeks
Major glycosaminoglycans in wounds = Dermatan sulfate
= Chondroitin sulfate
Proteoglycan Synthesis
• As scar collagen is deposited, the proteoglycans are incorporated into
the collagen scaffolding

• However, with scar maturation and collagen remodeling, the content

of proteoglycans gradually diminishes
Maturation and Remodeling
• The maturation & remodeling of the scar begins during the
fibroplastic phase and is characterized by a reorganization of
previously synthesized collagen
• Collagen is broken down by matrix metalloproteinases (MMPs)
• Net wound collagen content is the result of a balance between
collagenolysis and collagen synthesis
• Wound strength & Mechanical integrity in the fresh
wound are determined by both the quantity and quality of
the newly deposited collagen
 EARLY NEX FINAL
MATRIX T MATRIX

FIBRONECTIN + GLYCOSAMINOGLYCANS COLLAGEN TYPE I

COLLAGEN TYPE III + PROTEOGLYCANS

By several weeks post injury, the amount of collagen in the wound

reaches a plateau, but the tensile strength continues to increase for
several more months
 Fibril formation Decreased collagen solubility
Fibril cross-linking Increased strength

Increased resistance to enzymatic

degradation of the collagen matrix

FIBROBLASTS Fibrillin Formation of elastic fibers found in connective tissue

Scar remodeling continues for many (6 to 12) months post injury, gradually resulting in a
mature, avascular, and acellular scar.

The mechanical strength of the scar never achieves that of the uninjured tissue.
Epithelialization
• Epithelialization is the final step in establishing tissue
integrity
• Characterized primarily by proliferation and migration of
epithelial cells adjacent to the wound
• Begins within 1 day of injury
• Seen as thickening of the epidermis at the wound edge
 Layering of the epithelium is reestablished, and the
surface layer eventually keratinizes
Once the defect is bridged, the migrating epithelial cells lose
their flattened appearance, become more columnar in shape, and
increase their mitotic activity
Fixed basal cells in a zone near the cut edge undergo a series of rapid
mitotic divisions, and these cells appear to migrate by moving over
one another in a leapfrog fashion until the defect is covered

Marginal basal cells at the edge of the wound lose their firm
attachment to the underlying dermis, enlarge, and begin to migrate
across the surface of the provisional matrix
• Reepithelialization is complete in less than 48
hours in the case of approximated incised
wounds but may take substantially longer in
the case of larger wounds

• If only the epithelium and superficial dermis

are damaged, such as occurs in split-thickness
skin graft donor sites or in superficial second-
degree burns, then repair consists primarily
of reepithelialization with minimal or no
fibroplasia and granulation tissue formation
Role of Growth Factors in Normal Healing

• Growth factors and cytokines are polypeptides

produced in normal and wounded tissue that stimulate
cellular migration, proliferation, and function.
• Growth factors have divergent actions on different
cells; they can be chemoattractive to one cell type
while stimulating replication of a different cell type
Wound Contraction
The myofibroblast has been
postulated as the major cell
STRESS FIBERS

?
FIBROBLAST
responsible for contraction, and it
differs from the normal fibroblast
in that it possesses a cytoskeletal
structure
HEALING IN SPECIFIC TISSUES
Gastrointestinal Tract
Repair and healing of the gastrointestinal tract is essential

Absorptive, Barrier, Motor functions

HEALING OF FULL-THICKNESS GI = SURGICAL OR MECHANICAL REAPPOSITION

FAILURE = DEHISCENCE, LEAKS, AND FISTULAS

EXCESSIVE HEALING = STRICTURE FORMATION AND STENOSIS OF THE LUMEN

HEALING IN SPECIFIC TISSUES
Gastrointestinal Tract

• The submucosa  greatest tensile strength  greatest suture-holding

capacity  SURGICAL REPAIR
• Serosal healing  watertight seal
(i.e., the esophagus and rectum !)
early matrix
HEALING IN SPECIFIC TISSUES
Gastrointestinal Tract
Technical Considerations
Anastomosis  tension free
 adequate blood supply
 adequate nutrition
 free of sepsis
Debate exists concerning methods of creating an anastomosis (Suture?
Staple? Layer? Suturing material?)
HEALING IN SPECIFIC TISSUES
Bone

HEMATOMA FORMATION  liquefaction and degradation

ANGIOGENESIS + GRANULATION
4 days  (SOFT CALLUS STAGE)
 (HARD CALLUS STAGE)-mineralization
2 to 3 months  Complete union
 REMODELING
HEALING IN SPECIFIC TISSUES –
Cartilage
• Cartilage = (chondrocytes) surrounded by an extracellular matrix
• EXTRACELLULAR MATRIX  .proteoglycans +
.collagen fibers +
.water
• CARTILAGE  Avascular
• Injuries = permanent defects
• superficial injury = no inflammatory response (Slow healing)
• deep injuries = inflammatory response  mediator activation
HEALING IN SPECIFIC TISSUES –
Tendon
• Tendons and ligaments  consist of parallel bundles of collagen
interspersed with spindle cells
• Tendon and ligament healing progresses in a similar fashion as in
other areas of the body
HEALING IN SPECIFIC TISSUES –
Nerve
• Peripheral nerves are a complex arrangement of axons, nonneuronal
cells, and extracellular elements
• Phagocytes remove the degenerating axons and myelin sheath from
the distal stump (Wallerian degeneration)
• Functional units are formed when the regenerating axons connect with
the appropriate end targets
 THREE TYPES OF NERVE PREDICTABLE PATTERN OF
INJURIES: CHANGES

NEURAPRAXIA
 Focal demyelination Survival of axonal cell bodies

AXONOTMESIS Regeneration of axons that grow across

 Interruption of axonal continuity but
the transected nerve to reach the distal
preservation of Schwann cell basal
lamina stump

NEUROTMESIS Migration and connection of the regenerating

 complete transection nerve ends to the appropriate nerve ends or
organ targets
HEALING IN SPECIFIC TISSUES –
Fetal Wound Healing
• The main characteristic that distinguishes the healing of fetal wounds
from that of adult wounds is the lack of scar formation
• Characteristics differences between fetal and adult
wounds:
- wound environment
- inflammatory responses
- Differential growth factor profiles
- wound matrix
CLASSIFICATION OF WOUNDS
• Wounds are classified as either acute or chronic
• Chronic = healing > 4 weeks of treatment
• Acute Wound:
Factors Affecting Wound Healing
Infections

Degree of contamination that occurs during the

operation:
clean—class I
clean contaminated—class II
contaminated—class III
dirty—class IV
Classes II, III, and IV procedures treated with
appropriate prophylactic antibiotics have only one third
the wound infection rate of previously reported untreated
series

REPEAT DOSING OF ANTIBIOTICS:

• lengthy cases
• large-volume blood loss and fluid replacement
• Prosthetic implants
• unexpected contamination
• Anatomically, wound infections can be classified as superficial incisional,
deep incisional, and organ/space wound infections, involving fascia,
muscle, or the abdominal cavity
• Clinical diagnosis is easy when a postoperative wound looks edematous
and erythematous and is tender
• Inspection of the wound is most useful in detecting subtle edema around
the suture or staple line, manifested as a waxy appearance of the skin,
which characterizes the early phase of infection
• several stitches or staples around the most suspicious area should be
removed with insertion of a cotton-tipped applicator into the subcutaneous
area to open a small segment of the incision
• Presence of pus mandates further opening of the subcutaneous and skin
layers to the full extent of the infected pocket
• Samples should be taken for aerobic and anaerobic cultures, with very few
patients requiring antibiotic therapy
• Deep wound infections arise immediately adjacent to the fascia, either
above or below it, and often have an intraabdominal component
• Sometimes wound dehiscence will occur
• The most dangerous of the deep infections is necrotizing fasciitis. This is an
invasive process that involves the fascia and leads to secondary skin
necrosis.
Chronic Wounds-Ischemic Arterial Ulcers
lack of blood supply
Intermittent claudication, rest pain, and color or trophic changes
diminished or absent pulses with decreased ankle-brachial index
poor formation of granulation tissue dryness of skin, hair loss,
scaling, and pallor
wound itself usually is shallow with smooth margins, and a
pale base and surrounding skin

Th/: Revascularization + Wound care

1.0-1.4: Normal
Chronic Wounds-Venous Stasis Ulcers
Theory:
Distention of the dermal capillaries with leakage of fibrinogen into the
tissues
Neutrophils adhere to the capillary endothelium and cause plugging
with diminished dermal blood flow
Venous hypertension and capillary damage lead to extravasation of
hemoglobin
Lipodermatosclerosis

Th/: Compression therapy + Wound Care

1.0-1.4: Normal
Chronic Wounds-Diabetic Wounds
The major contributors to the formation of diabetic ulcers include
neuropathy, foot deformity, and ischemia

1.0-1.4: Normal
EXCESS HEALING
DRESSING
 • ABSORBENT
• NONADHERENT
• OCCLUSIVE & SEMIOCCLUSIE
TYPES • HYDROPHILIC & HYDROPHOBIC
• HYDROCOLLOID & HYDROGEL
• ALGINATES
• etc
SKIN REPLACEMENTS
The use of skin grafts or bioengineered skin substitutes
and other innovative treatments (e.g., topically applied
growth factors, systemic agents, and gene therapy)
cannot be effective unless the wound bed is adequately
prepared.

This may include debridement to remove necrotic or

fibrinous tissue, control of edema, revascularization of
the wound bed, reduction in the bacterial burden, with
minimal exudate.
Cellular and Tissue-Based Products in Chronic Wound and Ulcer Management

Act by altering the biology

of wounds and ulcers or by
CTPs are divided into two
preparing the wound/ulcer
categories :
bed for healing and other
potential procedures

1. Dermoinducive
• help provide cells and factors
that will activate healing
within the wound by inducing
tissue growth or inducing
granulation within the wound.

2. Democonductive
• provide scaffolding to a
wound ending in a neodermis
by allowing migration of
surrounding tissues across the
wound, and this helps healing.
 Growth
factor
therapy

Oxygen
therapy

Biofilm and
Gene or cell chronic
therapy wound
healing
HERITABLE DISEASES OF CONNECTIVE TISSUE

Five major types:

defect in collagen formation
tall stature, arachnodactyly, lax ligaments
• Ehlers-Danlos syndrome, myopia, scoliosis, pectus excavatum, and
aneurysm of the ascending aorta
• Marfan’s syndrome
• Osteogenesis imperfecta mutation in type I collagen

• Epidermolysis bullosa tissue separation and blistering with

minimal trauma
• Acrodermatitis enteropathica
inability to absorb sufficient
Zinc  inhibition of cell
proliferation
Terima Kasih