LECTURE 10: Wound Healing
Dr. Philip Michael Vilches | 26 October 2019
OUTLINE:
I. HISTORY
II. ROLE OF GROWTH FACTORS IN NORMAL
HEALING
III. WOUND CONTRACTION
IV. HERITABLE DISEASES OF CONNECTIVE TISSUE
V. HEALING IN SPECIFIC TISSUES
VI. CLASSIFICATION OF WOUNDS
VII. CLASSIFICATION OF WOUND HEALING
VIII. FACTORS AFFECTING WOUND INFECTION
IX. CHRONIC WOUNDS
X. EXCESS HEALING
XI. TREATMENT OF WOUNDS
XII. References
HISTORY
 Sumerians in 2000 B.C
o 2 modes of treatment:
 Spiritual method (incantations)
 physical method (application of poultice like
materials to the wound)
 The Greeks, went even further and classified
wounds as acute or chronic in nature
o Galen of Pergamum (120-121 AD) emphasized
the importance of maintaining a moist
environment to ensure adequate healing
 Ignas Philipp Semmelweiss on handwashing with
soap and hypochlorite.
 Louis Pasteur on “Germ Theory”
 Joseph Lister on “Anti Sepsis” via rinsing of hands
and instruments and use of carbolic acid
 Currently, the practice of wound healing
encompasses manipulation and/or use of among
others, inflammatory cytokines, growth factors, and
bioengineered tissue.
PHASES OF WOUND HEALING
Hemostasis and Inflammation
 Division of blood vessels and direct exposure of
extracellular matrix to platelets
o Platelet aggregation--- Degranulation--
Activation of Coagulation cascade
Opleda
o Platelet  granules release a number of wound
activated substances (PDGF, TGF-β, PAF,
Fibronectin, Serotonin)
o Fibrin clots serves as scaffolding for the
migration into the wound of inflammatory cells
 PMNs are the first infiltrating cells to enter the wound
site and its migration is stimulated by
o Increased vascular permeability
o Local prostaglandin release
o Presence of chemotactic substances (i.e., IL-1,
TNF-)
 Primary Role of Neutrophils
o Phagocytosis of bacteria and Tissue Debris
 Macrophages are the second population of
inflammatory cells that invade the wound
o Activation and recruitment of other cells via
mediators (i.e. cytokines) or directly (cell-cell
interaction and intercellular adhesion molecules)
o Regulation of Angiogenesis and Matrix
Deposition and Remodelling
o Phagocytosis and Oxygen Radical and NO
synthesis (microbial stasis)
Proliferation
 Fibroblasts isolated from wounds synthesize more
collagen than non wound fibroblasts, proliferate
less and actively carry out matrix contraction
o Endothelial Cell Proliferation
o Formation of new capillaries
o Migration from intact venules close to the wound
Matrix Synthesis
 Collagen plays a critical role in the successful
completion of adult wound healing.
 Functional integrity of the wound
 Type I is the major component of ECM in skin
 Type III becomes more prominent and important
during the repair process
 Its synthesis is dependent on systemic factors
 Glycosaminoglycans comprise a large portion of
the “ground substance” that makes up granulation
tissue.
 Dermatan and Chondroitin Sulfate- major
glycosaminoglycans in wound
 Synthesized by fibroblasts and are in increased
concentration during the first 3 weeks of healing
 As scar collagen is deposited, the proteoglycans are
incorporated into the collagen scaffolding
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 LECTURE 10: Wound Healing
Dr. Philip Michael Vilches | 26 October 2019
 With scar maturation and collagen remodelling,
content of proteoglycans gradually diminishes
Maturation and Remodelling
 Begins during the fibroplastic phase and is
characterized by a reorganization of previously
synthesized collagen
 Wound strength and mechanical integrity in the fresh
wound are determined by both the quantity and
quality of the newly deposited collagen
o Fribronectin & Collagen Type III- early matrix
scaffolding
o Glycosaminoglycans & Proteoglycans
o Collagen Type Type I- final matrix
 Scar remodeling contunies for many (6-12) months
post injury resulting in a mature, avascular and
acellular scar.
 There is a constant turnover of collagen in the ECM
both in healing wound as well as during normal
tissue homeostasis.
 The balance between collagen deposition and
degradation is the ultimate determinant of wound
strength and integrity
Epithelialization
 Restoration of external barrier
 Characterized primarily by proliferation and
migration of epithelial cells adjacent to the wound
 Begins within 1 day of injury and is seen as
thickening of the epidermis at the wound edge
 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
 Fixed basal cells in a zone near the cut edge
undergo a series of rapid mitotic division
 Migrating epithelial cells become more columnar in
shape and increase in mitotic activity.
 Re-epithelialization is complete in less than 48
hours but may be longer in cases of larger wounds.
Opleda
 Epithelial + Superficial dermis damage= re-
epithelialization with minimal or no fibroplasia and
granulation tissue formation
 The whole process is mediated by a combination of
a loss of contact inhibition, exposure to constituents
of the ECM (fibronectin) and cytokines.
ROLE OF GROWTH FACTORS IN NORMAL HEALING
 Autocrine manner- GF acts on the cell producing it
 Paracrine manner- release into the extracellular
environment where it acts on the immediately
neighboring cells.
 Endocrine manner- effect of substance is distant to
the site of release and the substance is carried to
the effector site through the blood stream
WOUND CONTRACTION
 For wounds that do not have surgically
approximated edges, the area of the wound will be
decreased by contraction.
 Myofibroblast- the major cell responsible for
contraction
 Movement of cells with concomitant reorganization
of the cytoskeletons- postulated to be responsible
for contraction
HERITABLE DISEASES OF CONNECTIVE TISSUE
Ehler’s Danlos Syndrome
 Defect in collagen formation
 Thin, friable skin with prominent veins, easy bruising,
poor wound healing, atrophic scar formation,
recurrent hernias and hyperextensible
 GIT: Bleeding, hiatal hernia, intestinal diverticulate
&rectal prolapse
 Large vessels: aneurysms, varicosities or
arteriovenous fistulas or may spontaneously rupture
Marfan’s Syndrome
 Mutation in the FBN1 gene which encodes for fibrillin
 Tall stature, arachnodactyly, lax ligaments, myopia,
scoliosis, pectus excavatum and aneurysm of the
ascending aorta
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 LECTURE 10: Wound Healing
Dr. Philip Michael Vilches | 26 October 2019

 Prone to hernias

Osteogenesis Imperfecta

Epidermolysis Bullosa
 Impairment in tissue adhesion within the epidermis,
basement membrane or dermis
 4 major subtypes:
o EB simplex
o Junctional EB
o Dystrophic EB
o Kindler’s syndrome

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 LECTURE 10: Wound Healing
Dr. Philip Michael Vilches | 26 October 2019

o Soft tissue forms a bridge between the fractured

bone segments in the next stage
o Soft tissue is deposited where
neovascularization has taken place and serves
as an internal splint
 Hard Callus Stage
o Mineralization of the soft callus and conversion
to bone
o 2- 3 months
 Remodeling Phase

Cartilage
 Superficial Injury
o disruption of the proteoglycan matrix and injury
to the chondrocytes
o slow to heal and often result in persistent
structural defects
 Deep injury
Acrodermatitis Enteropathica o involves underlying bone and soft tissue
o hyaline cartilage is eventually formed which
restores the structural and functional integrity of
the injured site

Tendon
 Hematoma
 Organization
 Laying down (collagen types i and iii)
 Scar formation

Nerve Wound Healing

 Nerve Injury
o Neurapraxia (focal demyelination)
o Axonotomesis (disrupted axonal continuity with
maintenance of Schwann cell basal lamina)
o Neurotmesis (complete transection)

HEALING IN SPECIFIC TISSUES
Gastrointestinal Tract
 Collagenase is expressed post injury in all segments
of the GI tract, but it is much more marked in the
colon compared to the small bowel
 Anastomosis should be tension free, with good
blood supply, adequate nutritional status with no
sepsis
Bone
 Initial stage of hematoma formation
o accumulation of blood at the fracture site which
contains devitalized soft tissue, dead bone and
necrotic marrow
 Next stage
o accomplishes the liquefaction and degradation
of nonviable products at the fracture site
 Soft Callus Stage
o 3 to 4 days following injury
CLASSIFICATION OF WOUNDS
 Acute wounds
o Predictable manner and time frame
o The end result is a well-healed wound
 Chronic wounds
CLASSIFICATION OF WOUND HEALING
 Primary intention
o Occurs when
 The edges are clean and held together with
ligatures
 There is a little gap to bridge healing
o Healing properties(when uncomplicated)
 Occurs quickly
 Rapid ingrowth of wound healing cells
(macrophages, fibroblasts, etc.)
 Restoration of the gap by a small amount of
scar tissue
o Soundly united within 2 weeks
o Dense scar tissue is laid down within 1 month

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 LECTURE 10: Wound Healing
Dr. Philip Michael Vilches | 26 October 2019

o Indications
 Infected or unhealthy wounds with high
bacterial content
 Wounds with a long time lapse since injury,
or
 Wounds with a severe crush competent with
significant tissue devitalization
o Wound edges are approximated within 3-4 days
o Tensile strength develops as with primary
closure

 Secondary intention
o Occurs when
 The egdes are separated
 The gap can not be directly bridged
 Extensive epithelial loss
 Severe contamination
 Significant subepithelial tissue damage
o Healing properties
 Occurs slowly
 Granulation; healing from the bottom
towards thge surface
 Restoration of the gap by a small amount of
scar tissue
o Scarring
o Wound contracture

 Normal Healing - A constant and continual increase

that reaches a plateau at some point postinjury
 Delayed Healing - Decreased wound-breaking
strength in comparison to wounds that heal at a
normal rate
 Impaired Healing (Chronic) - A failure to achieve
mechanical strength

FACTORS AFFECTING WOUND INFECTION

Hypoxia, Anemia, and Hypoperfusion

 Tertiary intention
o Tertiary wound healing or delayed primary
closure
o Wounds that are too heavily contaminated for
primary closure but appear clean and well
vascularized after 4-5 days of open observation
o Inflammation  reduced bacterial concentration
(“debribe”)  allow safe closure
 Low oxygen tension has a profoundly deleterious
effect on all aspects of wound healing
 Optimal collagen synthesis requires oxygen as a
cofactor, particularly for the hydroxylation steps
 The level of vasoconstriction
o exquisitely responsive to fluid status,
temperature, and hyperactive sympathetic tone
as is often induced by postoperative pain

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 LECTURE 10: Wound Healing
Dr. Philip Michael Vilches | 26 October 2019
Steroids and Chemotherapeutic Drugs
 Large doses of glucocorticoids
o reduce collagen synthesis and wound strength
 Steroids
o inhibit the inflammatory phase of wound healing
and the release of lysosomal enzymes
o first 3 to 4 days postinjury do not affect wound
healing
o contribute to increased rates of wound infection
 Steroid-delayed healing of cutaneous wounds
o can be stimulated to epithelialize by topical
application of vitamin A
 Collagen synthesis of steroid-treated wounds also
can be stimulated by vitamin A.
Metabolic Disorders
o Diabetes Mellitus
o best known of the metabolic disorders
contributing to increased rates of wound
infection and failure
 Uncontrolled diabetes results in
 ↓ Inflammation
 ↓ Angiogenesis
 ↓ Collagen synthesis
 ↓Granulocyte function
 ↓ Capillary ingrowth
 ↓ Fibroblast proliferation
 Insulin
o restores collagen synthesis and granulation
tissue formation to normal levels if given during
the early phases of healing
 Type I diabetes mellitus
o noted to decrease wound collagen accumulation
in the wound, independent of the degree of
glycemic control.
 Type II diabetic patients
o showed no effect on collagen accretion when
compared to healthy, age-matched controls
 The diabetic wound
o appears to be lacking in sufficient growth factor
levels, which signal normal healing
 Improved wound healing
o Careful preoperative correction of blood sugar
levels
o Increasing the inspired oxygen tension
o judicious use of antibiotics
o correction of other coexisting metabolic
abnormalities all can result
Nutrition
o Poor nutritional intake
o significantly alters many aspects of wound
healing
Opleda
o impaired healing response as well as reduced
cell-mediated immunity
o Malnutrition
o correlates clinically with enhanced rates of
wound complications and increased wound
failure after diverse surgical procedures
o Vitamin C
o Deficiency leads to a defect in wound healing,
particularly via a failure in collagen synthesis
and cross-linking
o Deficiency associated with an increased
incidence of wound infection and it tends to be
more severe
o recommended dietary allowance is 60 mg daily
o may increase to as high as 2 g daily in severely
injured
o Vitamin A
o increases the inflammatory response in wound
healing,
o directly increases collagen production
o supplemental doses of vitamin A to severe
burned pt
o Doses ranging from 25,000 to 100,000 IU per
day
o Zinc
o is the most well-known element in wound
healing
o used empirically in dermatologic conditions
o In deficiency
o there is decreased fibroblast proliferation
o decreased collagen synthesis
o impaired overall wound strength and delayed
epithelialization
Infections
o Infections can weaken an abdominal closure or
hernia repair and result in wound dehiscence or
recurrence of the hernia
o Cosmetically, infections can lead to disfiguring,
unsightly, or delayed closures
o Antibiotic prophylaxis
o most effective when adequate concentrations of
antibiotic are present in the tissues at the time of
incision,
o assurance of adequate preoperative antibiotic
dosing and timing
o Antibiotics after operative contamination has
occurred is clearly ineffective
o Repeat dosing of antibiotics when
o Durations exceeding the biochemical half- life
(t1/2) of the antibiotic
o Large-volume blood loss and fluid replacement
o Additional doses of antibiotic may be administered
for 24 hours
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 LECTURE 10: Wound Healing
Dr. Philip Michael Vilches | 26 October 2019
o Prosthetic implants are used
o Unexpected contamination is encountered
o Patients with prosthetic heart valves or any
implanted vascular or orthopedic prostheses should
receive antibiotic prophylaxis before any procedure
in which significant bacteremia is anticipated
o If the wound is contaminated with >10^5
microorganisms, the risk of wound infection is
markedly increased
o Threshold may be much lower in the presence of
foreign materials
o The source of pathogens
o usually the endogenous flora of the patient's
skin, mucous membranes, or from hollow organs
o The incidence of wound infection bears a direct
relationship to the degree of contamination that
occurs during the operation from the disease
process itself
o Clean = Class I
o Clean contaminated = Class II
o Contaminated = Class III
o Dirty = Class IV
o Most surgical wound infections become apparent
within 7 to 10 days postoperatively
o With the hospital stay becoming shorter and shorter,
many infections are detected in the outpatient
setting
o Definition of wound infection
o Wounds that drain purulent material, with
bacteria identified on culture (Narrowest
definition)
o All wounds draining pus
o Wounds that are opened by the surgeon
o Wounds that the surgeon considers infected
o Superficial wound infections
o Involving skin and subcutaneous tissue
o Postoperative wound looks edematous and
erythematous and tender
o Development of postoperative fever (usually
low- grade)
o Development of a mild and unexplained
leukocytosis
o Presence of undue incisional pain should
direct attention to the wound
 Presence of pus mandates further opening of the
subcutaneous and skin layers to the full extent
o Systemic antibiotics treatment in
o Immunosuppressed patients
o Evidence of tissue penetration or systemic
toxicity
o Patients who had prosthetic devices inserted
o Deep wound infections
o Fever and leukocytosis
o The incision may drain pus spontaneously
Opleda
o The intra-abdominal extension may be
recognized after the drainage of what was
thought to be a superficial wound infection
o Necrotizing fasciitis is the most dangerous of the
deep infections
 The skin demonstrates hemorrhagic bullae
and subsequent frank necrosis
 The fascial necrosis is usually wider than the
skin involvement
 Toxic, has high fever, tachycardia, and
marked hypovolemia
 High-dose penicillin treatment stat(20 to 40
million U/d IV)
 Aim - thorough removal of all necrosed skin
and fascia
 Careful inspection every 12 to 24 hours
 reveal any new necrotic areas, and
these need further debridement and
excision
 Bacteria in a wound does not constitute an infection
 Contamination is the presence of bacteria without
multiplication
 Colonization is multiplication without host responsed
 Infection is the presence of host response in
reaction to deposition and multiplication of bacteria

CHRONIC WOUNDS
 Defined as wounds that have failed to proceed
through the orderly process that produces
satisfactory anatomic and functional integrity or that
have proceeded through the repair process without
producing an adequate anatomic and functional
result
 The majority of wounds that have not healed in 3
months are considered chronic
 Skin ulcers
o occur in traumatized or vascularly compromised
soft tissue
o considered chronic in nature
o proportionately are the major component of
chronic wounds
 Repeated trauma, poor perfusion or oxygenation,
and/or excessive inflammation
o contribute to the causation and the perpetuation
of the chronicity of wounds
Ischemic arterial ulcers
 Non-healing of these wounds is the norm unless
successful revascularization is performed
 Adequate blood supply, most such wounds progress
to heal satisfactorily
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 LECTURE 10: Wound Healing
Dr. Philip Michael Vilches | 26 October 2019

 Treatment of diabetic wounds involves local and

systemic measures
o Adequate blood sugar levels
o Eradication of the infectious source
o Employ antibiotics that achieve adequate levels
both in soft tissue and bone

Decubitus/pressure ulcers
 A localized area of tissue necrosis that develops
when a soft tissue is compressed between a bony
prominence and an external surface
 Excessive pressure causes capillary collapse and
impedes the delivery of nutrients to body tissues
 The four stages of pressure ulcer formation are as
follows
o Stage I, nonblanchable erythema of intact skin
Venous stasis ulcers o Stage II, partial-thickness skin loss
 Treatment (epidermis/dermis)
o compression therapy o Stage III, full-thickness skin loss (Except fascia)
 Wound care o Stage IV, full-thickness skin loss (muscles &
o focuses on maintaining a moist wound bones)
environment, which can be achieved with  Treatment of pressure ulcers
hydrocolloids o Debridement of all necrotic tissue
 can be healed with perseverance and by addressing o Maintenance of a favorable moist wound
the venous hypertension environment
 Recurrences are frequent because of patients' lack o Relief of pressure
of compliance o Addressing host issues such as nutritional,
metabolic, and circulatory status

EXCESS HEALING

Diabetic ulcers
 60 to 70% are due to neuropathy
 15 to 20% are due to ischemia
 15 to 20% are due to a combination of both
Keloids
 15x more common in pts with darker skin
pigmentation
 Develop 3 months-years after trauma
 Collagen fibers are larger, random & not bundled
 Expand beyond wound edges, can become large
 Rarely regress
 Excision alone (45-100% recurrence)
 Excision + corticosteroid injections
 Topical silicone + external compression

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 LECTURE 10: Wound Healing
Dr. Philip Michael Vilches | 26 October 2019

 Radiation (10 to 100% recurrence when used alone)

 Topical retinoids
 IFN-γ,Chemotherapy (5-FU, bleomycin)
Skin Replacements
 Conventional Skin Grafts
o Autograft – Transplant from another site
o Allograft – Transplant from a living non- identical
donor or cadaver , may rejection and contain
pathogens
o Xenograft – From another species, may
rejection and contain pathogens
o Preparation of wound bed – Debridement of
necrotic/fibrinous tissue, control of edema,
minimizing exudate, revascularization of wound
bed, ↓ bacterial load

END OF TRANSCRIPTION

REFERENCES
 Dr. Vilches Lecture and PPT

TREATMENT OF WOUNDS

Local Care
 Antibiotics
 Dressings
 Skin Replacements
 Growth Factor Therapy

Antibiotics
 Use only when there is an obvious wound infection
 Signs of infection : erythema, cellulitis, swelling,
purulence
 Base on organisms suspected to be found within the
infected wound and the patient's overall immune
status

Dressings
 Mimics epithelial barrier, protection of site
 Compression provides hemostasis, decreases
edema
 Occlusion controls hydration and allows for
oxygenation/gaseous diffusion
 Occlusion stimulates collagen synthesis and
epithelial cell migration

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 LECTURE 10: Wound Healing
Dr. Philip Michael Vilches | 26 October 2019

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