LECTURE NOTES – WOUND HEALING
What is a wound?
- Any breach in the surface of the body
- Any tissue disruption deep to the skin produced by
application of energy
- Injury to the body that typically involves laceration or
breaking of a membrane and damage to underlying
tissues
Wound healing
- Complex cellular and biochemical cascade that leads to
restitution to integrity and function
Phases of Wound healing
- Hemostasis and inflammation
- Proliferation
- Maturation and remodeling
HEMOSTASIS AND INFLAMMATION
- Starts with disruption of blood vessels  bleeding
o Subendothelial collage is exposed  platelet
aggregation
- Hemostasis – 1st goal achieved in healing process
- Exposure to subendothelial collagen to platelets results
in platelet aggregation, degranulation, and activation of
the coagulation cascade
- Platelet α granules – release number of wound-active
substances
o PDGF, TGF-β, PAF, fibronectin, and serotonin
- Fibrin clot
o Serves as scaffolding for the migration into the
wound of inflammatory cells (PMNs, neutrophils)
and monocytes
- Cellular infiltration after injury follows a characteristic,
predetermined sequence
- PMNs are the first infiltrating cells to enter wound site –
peaks at 24 to 48 hours
- Increased vascular permeability, local PG release, and
presence of chemotactic substances (complement
factors, IL-1, TNF- α, TGF-β, PF4, bacterial products)
o All stimulate neutrophil migration
- Primary role of neutrophils is phagocytosis of bacteria
and tissue debris
- Also a major source of cytokines early during
inflammation, especially TNF-a3 which may have
significant influence on subsequent angiogenesis
- PMNs also release protease such as collagenases, which
participate in matrix and ground substance degradation
in the early phase of wound healing
- No role in collagen deposition or acquisition of
mechanical wound strength
- The second of population of inflammatory cells that
invades the wound consists of macrophages, which are
recognized as being essential to successful healing
- Derived from circulating monocytes, macrophages
achieve significant numbers in wound by 48-96 hours
post-injury and remain present until wound healing is
complete
Macrophages
- Wound debridement via phagocytosis and contribute to
microbial stasis via oxygen radical and nitric oxide
synthesis
- Most pivotal function is activation and recruitment of
other cells via mediators such as cytokines and growth
factors
- Lay a significant role in regulating angiogenesis and
matrix deposition and remodeling
T-Lymphocytes
- Comprise another population of inflammatory/immune
cells that routinely invades the wound
- Less numerous than macrophages
- Numbers peak at about 1 week postinjury
- Bridge the transition from inflammatory to the
proliferative phase of healing
PROLIFERATIVE PHASE
- Aka reparative phase
- The proliferative phase is the second phase of wound
healing and roughly spans days 4 through 12
- It is during this phase that tissue continuity is re-
established
- Fibroblasts and endothelial cells are the last cell
populations to infiltrate the healing wound, and the
strongest chemotactic factor for fibroblasts is PDGF
Endothelial cells
- Also proliferate extensively during this phase of healing
- Participate in the formation of new capillaries
(angiogenesis)
- Migrate from intact venules close to the wound
o Their migration, replication and new capillary tubule
formation is under influence of such cytokines and
growth factors as TNF-α, TGF-β and VEGF
Matrix synthesis
- Collagen
o The most abundant protein in the body, plays a
critical role in the successful completion of adult
wound healing
- Its deposition, maturation, and subsequent remodeling
are essential to the functional integrity of the wound
- 18 types of collagen described, the main ones of interest
to wound repair are types I and III
- Type 1 collagen – major component of extracellular
matrix in skin
Proteoglycan synthesis
- Major glycosaminoglycans present in wounds are
Dermatan and Chondroitin Sulfate
- Fibroblasts synthesis there compounds, increasing their
concentration greatly during the first 3 weeks of healing
MATURATION AND REMODELING
- Beings during the fibroblastic phase
- And is characterized by reorganization of previously
synthesized collagen
- Collagen is broken down by MMPs
- The net wound collagen content is the result of a
balance between collagenolysis and collagen synthesis
LECTURE NOTES – WOUND HEALING
- Wound strength and mechanical integrity in the fresh o Results in fluid accumulation in the third
wound are determined by both quantity and quality of space, increased abdominal pressure, and
the newly deposited collagen tissue edema
- Scar remodeling continues for many months (6-12
months) post-injury, gradually resulting in a mature, BONE
avascular, and acellular scar - Hematoma formation – initial stage
- The mechanical strength of the scar never achieves that - Consists of accumulation of blood at the fracture site,
of the uninjured tissues which also contains devitalized soft tissue, dead bone,
Epithelialization and necrotic marrow
- While tissue integrity and strength are being re- - The next stage accomplishes the liquefaction and
established, the external barrier must also be restored degradation of nonviable products at the fracture site
- This process is cx primarily by proliferation and migration - The normal bone adjacent to the injury site can then
of epithelial cells adjacent to the wound undergo revascularization, with new blood vessels
- The process begins within 1 day of injury and is seen as growing into the fracture site
thickening of epidermis at the wound edge - 3-4 days following injury, soft tissue forms a bridge
- Marginal basal cells at the edge of the wound lose their between the fractured bone segments in the next stage
firm attachment to the underlying dermis, migrate - Soft callus stage
across the surface of the provisional matrix o Serves as an internal splint, preventing damage to
- Fixed basal cells in a zone near the cut edge undergo a the newly laid blood vessels and achieving a
series of rapid mitotic division, and these cells appear to fibrocartilaginous union
migrate by moving over one another in a leapfrog o The soft callus is formed externally along the bone
fashion until the defect is covered shaft and internally within the marrow cavity
- The next phase consists of mineralization of the soft
HEALING IN SPECIFIC TISSUES callus and conversion to bone
- GI tract - Hard callus stage
- Bone o This may take up to 2-3 months and leads to
- Cartilage complete bony union
- Tendon o This stage is followed by the remodeling phase, in
- Nerve which excessive callus is reabsorbed and the marrow
cavity is recanalized
GASTROINTESTINAL TRACT
Submucosa HERITABLE DISEASES OF CONNECTIVE TISSUE
- Lies radially and circumferentially outside the lamina Ehlers-Danlos Syndrome (EDS)
propria and muscularis mucosa - Group of 10 disorders that present as a defect in
- Comprised of abundant collagenous and elastic fibers, collagen formation
and supports neural and vascular structures - Over half of affected patients manifest genetic defects
- The layer that imparts the greatest tensile strength and encoding alpha chains of collagen type V
greatest suture-holding capacity - Causing it to be either quantitatively or structurally
Serosa defective
- Healing is essential for quickly achieving a watertight - These changes lead to “classic” EDS with phenotypic
seal from the luminal side of the bowel findings that include:
- The importance of serosa is underscored by the o Thin, friable skin with prominent veins
significantly higher rates of anastomotic failure observed o Easy bruising
clinically in segments of bowel that are extraperitoneal o Poor wound healing
and lack serosa (i.e., the esophagus and rectum) o Atrophic scar formation
Technical Considerations o Recurrent hernias
- In order for an anastomosis to heal without o Hyperextensible joints
complications it must be: - GI problems include:
1. Tension free o Bleeding
2. Have an adequate blood supply o Hiatal hernia
3. Receive adequate nutrition o Intestinal diverticula
4. Free of sepsis o Rectal prolapse
- Small blood vessels are fragile, making suturing difficult
- The amount of IV fluid administered perioperatively during surgery
affects many aspects of recovery from colonic surgery - Large vessels may develop:
- Experimental and clinical data show that anastomotic o Aneurysms
healing may be adversely affected by overzealous fluid o Varicosities
administration o Arteriovenous fistulas
LECTURE NOTES – WOUND HEALING
o Or may spontaneously rupture b) Local causes (arterial insufficiency, local
- Skin Hyper-elasticity vasoconstriction, or excessive tension on
- Translucent skin tissues)
- Hyper-extensible joints
- Steroids and chemotherapeutic drugs
Marfan’s Syndrome o Large doses are chronic usage reduce collagen
- Patients with Marfan’s syndrome have: synthesis and wound strength
o Tall stature o The major effect of steroids is to inhibit the
o Arachnodactyly inflammatory phase of wound healing (angiogenesis,
- The genetic defect associated with Marfan’s syndrome is neutrophil and macrophage migration, and
a mutation in the FBN1 gene, which encodes for Fibrillin fibroblast proliferation) and the release of lysosomal
- Walkers sign enzymes
- Steinberg sign o Steroids also inhibit epithelialization and contraction
- Pectus excavatum some have carinatum and contribute to increased rates of wound infection
- Ectopia lentis o All chemotherapeutic drugs adversely affect wound
- Dislocation of lens healing by inhibiting cell proliferation and wound
- Aortic dissection DNA and protein synthesis, all of which are critical to
successful repair
Osteogenesis Imperfecta
- Patients with OI have: - Metabolic disorders
o Brittle bones o Diabetes mellitus is the best known of the metabolic
o Osteopenia disorders contributing to increased rates of wound
o Low muscle mass infection and failure.
o Hernias o Uncontrolled diabetes results in reduced
o Ligament and joint laxity inflammation, angiogenesis, and collagen synthesis
- OI is a result of a mutation in type I collagen o The large- and small-vessel disease that is the
- Type I – Type IV hallmark of advanced diabetes contributes to local
hypoxemia
Epidermolysis Bullosa o Defects in granulocyte function, capillary ingrowth,
- The disease manifestation include impairment in tissue and fibroblast
adhesion within the epidermis, basement membrane, or o Obesity, insulin resistance, hyperglycemia, and
dermis resulting in tissue separation and blistering with diabetic renal failure contribute significantly and
minimal trauma independently to the impaired wound healing
- Characteristic features of EB are blistering and ulceration observed in diabetics.
- Epidermolysis bullosa is classified into four major o Uremia also has been associated with disordered
subtypes wound healing
o Obesity is the largest growing public health problem
FACTORS AFFECTING WOUND HEALING in the United States and the world
- Advance age  Many studies indicate that obese patients have
o Aging produces intrinsic physiologic changes that high rates of perioperative complications, with
result in delayed or impaired wound healing estimates as high as 30% for wound dehiscence,
o Direct correlation between older age and poor 17% for surgical site infections, 30% for
wound healing outcomes incisional hernias, 19% for seromas, 13% for
o The increased incidence of: hematomas, and 10% for fat necrosis
a) Cardiovascular disease - Nutrition
b) Metabolic diseases (diabetes mellitus) o Poor nutritional intake or lack of individual nutrients
c) Malnutrition, and vitamin deficiencies significantly alters many aspects of wound healing
d) Cancer o The vitamins most closely involved with wound
e) Widespread use of drugs that impair wound healing are Vitamin C and Vitamin A
healing o Scurvy or Vitamin C Deficiency leads to a defect in
- Hypoxia, anemia, and hypoperfusion wound healing, particularly via a failure in collagen
o Low oxygen tension has a profoundly deleterious synthesis and cross-linking
effect on all aspects of wound healing o With zinc deficiency, there is decreased fibroblast
o Optimal collagen synthesis requires oxygen as a proliferation, decreased collagen synthesis, impaired
cofactor, particularly for the hydroxylation steps overall wound strength, and delayed
o Major factors affecting local oxygen delivery include: epithelialization
a) Hypoperfusion
LECTURE NOTES – WOUND HEALING
- Infections
o Many otherwise successful surgical operations fail
because of the development of wound infections
o The occurrence of infections is of major concern
when implants are used, and their occurrence may
lead to the removal of the prosthetic material
o Most surgical wound infections become apparent
within 7 to 10 days postoperatively
CLASSIFICATION OF WOUNDS
I. ACUTE
- Heal in predictable manner and time frame
- The process occurs with few, if any, complication
- The end result is a well-healed wound
Different Clinical Approaches to the Closure and Healing of
Acute Wounds
1) Healing with Primary intention
- Close wound
2) Healing with Secondary Intention
- Heal underlying wound before closing the wound
3) Tertiary Intention or Delayed Primary Closure
- Heal by secondary intention
- And if wound is almost healed, close it
II. CHRONIC WOUNDS
- Wounds that have failed to proceed through the orderly
process that produces satisfactory anatomic and
functional integrity
- Wounds that have proceeded through the repair process
without producing an adequate anatomic and functional
result
- Majority of wounds that have not healed in 3 months are
considered chronic
Other causes:
- Repeated trauma
- Poor perfusion or oxygenation
- Excessive inflammation contributes to the causation and
the perpetuation of the chronicity of the wound
Venous Stasis Ulcers
- Venous stasis occurs due to the incompetence of either
the superficial or deep venous systems
- Chronic venous ulcers usually are due to the
incompetence of the deep venous system and are
commonly painless
- Stasis ulcers tend to occur at the sites of incompetent
perforators, the most common being above the medial
malleolus
- Painful – arterial occlusion
o Associated with claudication
- The products of this breakdown are irritating and cause
pruritus and skin damage
- The resulting brownish pigmentation of skin combined
with loss of subcutaneous fat produces cx changes called
Lipodermatosclerosis
- The clinically cx picture is that of an ulcer that fails to re-
epithelialize despite the presence of adequate
granulation tissue
Decubitus or Pressure Ulcers
- A pressure ulcer is localized area of tissue necrosis that
develops when 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
- Pressure ulcer formation is accelerated in the presence
of friction, shear forces, and moisture
- Other contributory factors:
o Immobility, altered activity levels, altered mental
status, chronic conditions, altered nutritional status
o Incidence: 2.7% to 9% in acute care setting; 2.4% to
23% in long-term care facilities
Staging for Pressure Ulcers
- Stage I – skin is unbroken but inflamed; non-blanching
erythema
- Stage II – Skin is broken to epidermis or dermis
- Stage III – Ulcer extends to subcutaneous layer
- Stage IV – Ulcer extends to muscle or bone; undermining
is likely
Diabetic Wounds
- The major contributors to the formation of diabetic
ulcers include:
- Neuropathy (60-70%)
o Neuropathy is both sensory and motor
 Secondary to the persistently
elevated glucose levels
o The loss of sensory function allows unrecognized
injury to occur from ill-fitting shoes, foreign-bodies,
or other trauma
- Foot deformity
- Ischemia (15-20%)
o 15-20% - combination
- The motor neuropathy or Charcot’s foot
- Leads to collapse or dislocation of the inter-phalangeal
or metatarsophalangeal joints, causing pressure on areas
with little protection
- There is also severe micro- and macrovascular
circulatory impairment
Marjolin’s ulcer
- Malignant transformation of chronic ulcers can occur in
any long-standing wound
- Any wound that does not heal for a prolonged period of
time is prone to malignant transformation
- Cancers arising de novo in chronic wounds include both
squamous and basal cell carcinomas
EXCESS HEALING
- Hypertrophic scar
o An over-abundance of fibroplasia in the dermal
healing process
LECTURE NOTES – WOUND HEALING
o HTSs rise above the skin level but stay within the
confines of the original wound
o Often regress over time
o HTSs usually develop within 4 weeks after trauma
- Keloid
o An over-abundance of fibroplasia in the dermal
healing process
o Keloids rise above the skin level as well, but extend
beyond the border of original wound
o Rarely regress spontaneously
o Keloids tend to occur 3 months to years after the
initial insult
o And even minor injuries can result in large lesions