This document discusses pathophysiology of wound healing and factors affecting it. It begins with an introduction to wound classification and the normal phases of acute wound healing. It then discusses factors that can impair wound healing and cause chronic wounds, such as diabetes, peripheral artery disease, radiation therapy, malnutrition, and infection. Recent developments to expedite healing, such as negative pressure wound therapy, are also covered. NPWT applies subatmospheric pressure to a wound which increases blood flow and stimulates cellular processes to promote granulation tissue growth and accelerate wound closure.

1. +
Pathophysiology of wound
healing and factors
affecting it
Dr.H.Fadaak
Dr.Mariam Alqurashi
King Fahd Hospital of The University
16 Nov 2011

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Introduction
 A wound is a disruption of the normal structure and function of the skin
and underlying soft tissue.
 Acute wounds in normal, healthy individuals heal through an orderly
sequence of physiological events that include hemostasis,
inflammation, epithelialization, fibroplasia, and maturation.
 When this process is altered, a chronic wound may develop and is
more likely to occur in patients with underlying disorders such as
peripheral artery disease, diabetes, venous insufficiency, nutritional
deficiencies, and other disease states.

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Wound mechanism
 Wounds are generally classified as acute or chronic.
 chronic wounds are generally associated with physiological
impairments that slow or prevent wound healing.
 Wounds may be caused by a variety of mechanisms including acute
injury to the skin (abrasion, puncture, crush), surgery and other
etiologies that cause initially intact skin to break down (eg,
ischemia, pressure).

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Surgical wounds
 Surgical wounds are a controlled form of trauma created in the
operating room environment.
 Classified according to the degree of bacterial load or contamination
of the surgical wound.
 The categories, clean, clean-contaminated, contaminated, and dirty
are used to predict the risk of surgical wound infection which can
impact wound healing.
 The majority of clean and clean-contaminated wounds are closed
primarily at the completion of the surgery.
 Contaminated and dirty wounds (eg, fecal contamination,
debridement for wound infection) are typically packed open

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Phases of wound healing
 Wound healing occurs as a cellular response to tissue injury and
involves activation of keratinocytes, fibroblasts, endothelial cells,
macrophages, and platelets.
 The process involves organized cell migration and recruitment of
endothelial cells for angiogenesis.
 Many growth factors and cytokines released by these cell types
coordinate and maintain wound healing.

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 Acute wounds transition through the stages of wound healing as a
linear pathway, with clear start- and endpoints.
 Chronic wounds are arrested in one of these stages, usually the
inflammatory stage, and cannot progress further.

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Hemostasis
 Immediately after injury to the skin, small vessels within the wound
constrict to provide at least a measure of hemostasis for 5 to 10
minutes.
 Platelets aggregate in severed vessels and trigger the clotting
cascade and release essential growth factors and cytokines that are
important for the initiation and progression of wound healing (eg,
platelet-derived growth factor, transforming growth factor- ).β
 The fibrin matrix that results stabilizes the wound and provides a
provisional scaffold for the wound healing process.

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Hemostasis

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Inflammation
 the lag phase because wound strength does not begin to return
immediately.
 The inflammatory phase is completed within 3 days, except in the
presence of infection or other causes of wound chronicity.
 Key components of this phase are increased vascular permeability,
and cellular recruitment.
 The presence of necrotic tissue, foreign material and bacteria result
in the abnormal production of metalloproteases which alter the
balance of inflammation and impair the function of the cytokines

10. +

11. +The healing progression of chronic wounds usually
becomes arrested in this inflammatory stage

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Epithelialization
 also called migration refers to basal cell proliferation and epithelial
migration occurring in the fibrin bridgework inside a clot.
 it continues until individual cells are surrounded by cells of similar
type.
 In a clean surgical wound, the epithelial cells migrate downward to
meet deep in the dermis. Migration ceases when the layer is
rejuvenated; this is normally completed within 48 hours of surgery.
 The superficial layer of epithelium creates a barrier to bacteria and
other foreign bodies. However, it is very thin, easily traumatized, and
gives little tensile strength.

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Epithelialization

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Fibroplasia
 Fibroplasia consists of fibroblast proliferation, accumulation of
ground substance, and collagen production.
 Fibroblasts are transformed from local mesenchymal cells, are
usually present in the wound within 24 hours, and predominate by
the 10th
postoperative day.
 They attach to the fibrin matrix of the clot, multiply, and produce
glycoprotein and mucopolysaccharides, which make up ground
substance.

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Fibroplasia
 Fibroblasts produce contractile proteins.These contractile cells,
which are designated myofibroblasts, are present in the wound
by the 5th
day and have characteristics of smooth muscle cells
with the ability to contract.
 Myofibroblastic cells are lost via apoptosis as repair resolves to
form scar.
 In pathological fibrosis, myofibroblasts persist and are
responsible for fibrosis via increased matrix synthesis and for
contraction.The exuberant scarring may impede normal organ
function or, in the case of skin, result in keloid.

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Fibroplasia
 Fibroblasts also synthesize collagen, the primary structural protein
of the body.
 Collagen production begins on the 2nd
postoperative day, when it is
secreted as an amorphous gel devoid of strength.
 Maximum collagen production does not begin until day 5 and
continues for at least 6 weeks.
 The developing collagen matrix stimulates angiogenesis.
 Granulation tissue is the result of the combined production of
collagen and growth of capillaries

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Maturation
 Key elements of maturation include collagen cross-linking, collagen
remodeling, and wound contraction.
 5 types of collagen have been identified; types I and III predominate in
the skin and aponeurotic layers.
 The tensile strength of the wound is directly proportional to the
amount of collagen. As disorganized collagen is degraded and
reformed, covalent cross-links are formed that enhance tensile
strength.

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Maturation

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Maturation
 Maximum strength depends upon the interconnection of collagen
subunits.
 Approximately 80% of the original strength of the tissue is
obtained by 6 weeks after surgery, but the diameter and
morphology of collagen fibers do not have the appearance of
normal skin until 180 days.
 Rest and immobility are important during the immediate
postoperative period for successful healing to occur.
 However, some physical activity is essential during the maturation
phase because light tension increases tensile strength by
remodeling, which may continue for many years.

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Tensile strength
 The tensile strength of a wound is a measurement of its load
capacity per unit area.
 The bursting strength of a wound is the force required to
break a wound regardless of its dimension. It varies with skin
thickness.
 Peak tensile strength of a wound occurs approximately 60
days after injury.
 A healed wound only reaches approximately 80% of the
tensile strength of unwounded skin.

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Impaired wound healing
 There is usually not a single primary factor that contributes to
impaired wound healing
 There are multiple, smaller contributing issues that can disrupt the
process.
As examples,
-local tissue ischemia and neuropathy can impair chemotaxis during
the hemostasis and inflammatory stages.
-Tissue necrosis and infection alter the balance of inflammation and
compete for oxygen.
-Uncontrolled periwound edema and wound instability disrupt
myofibroblast activity, and collagen deposition and cross-linking.

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Risk factors for non-healing
 Chronic wounds affect a substantial proportion of the population and
contribute to a significant burden in the hospital setting.
 Certain patients are at risk for development of a non-healing wound
such as:
 impaired arterial or venous circulation,
 immunocompromised states,
 the elderly,
 diabetes, and
 any patient with neuropathy or spinal cord injury

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 The most common nonhealing wounds affecting the lower
extremities are associated with peripheral artery disease,
diabetes and chronic venous insufficiency.
Lipscomb, GH, Ling, FG. Wound Healing, Suture Material, and Surgical Instrumentation. In:
TeLinde's Operative Gynecology, 9th edition, Rock, JA, Jones, HA, III (Eds), 2003. p.233.

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Peripheral artery disease
 Severe peripheral artery disease (PAD) with multilevel arterial
obstruction decreases arterial blood flow and diminishes the
delivery of oxygen and nutrients to the tissues, and impairs removal
of metabolic waste products.
 Critical limb ischemia develops when blood flow does not meet the
metabolic demands of tissue at rest, and manifests clinically with
extremity pain, non-healing wounds or tissue loss.

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DM
 Diabetes is a particularly important risk factor for the development of
chronic wounds because it is associated with vasculopathy,
neuropathy and immunopathy.
 It is frequently associated with severe PAD with atherosclerosis
developing at a younger age and affecting more distal arteries.
 PAD in combination with diabetic neuropathy contributes to higher
rates of non-healing ulcers and limb loss in diabetic patients
compared with nondiabetic patients .

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DM..
 Approximately 15% of patients with diabetes in the United States
will develop a foot ulcer. Peripheral artery obstruction is present
in about 20% of these patients, and diabetic neuropathy in about
50% with about 30% having both.
# Kurd SK, Hoffstad OJ, Bilker WB, Margolis DJ. Evaluation of the use of prognostic
information for the care of individuals with venous leg ulcers or diabetic neuropathic foot
ulcers. Wound Repair Regen 2009; 17:318.

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DM
 Neuropathy alone can be responsible for the development of
diabetic foot ulcers.
 Neuropathy associated with diabetes affects sensory, motor, and
autonomic nerves.
 Sensory neuropathy diminishes the perception of pain that is
protective when tissue injury has occurred.
 The motor nerves to the intrinsic muscles of the foot are affected in
approximately 50% of patients with diabetes resulting in claw
deformities that transfer pressure to the plantar metatarsal heads.
 The autonomic neuropathy causes the skin to become dry and
susceptible to skin fissures, tearing and infection due to a loss of
sweat and oil gland function.

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DM
 Over 100 known cytologic factors contribute to impaired wound
healing in patients with diabetes
 These include decreased or impaired:
 growth factor production,
 angiogenic response,
 macrophage function,
 collagen accumulation,
 epidermal barrier function,
 quantity of granulation tissue, etc

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Aging
 Skin is not excluded from the complex processes of aging.
 The supply of cutaneous nerves and blood vessels decreases with
age, and a general thinning of tissue including dermis and
basement membrane.
 There is a loss of collagen and ability to produce more collagen.
These physiologic changes associated with aging contribute to
slowed or impaired wound healing in the elderly

32. +
Sickle cell disease
 Sickle cell disease represents another form of local tissue
ischemia at the specific location of the wound.
 It is also obstructive in nature, similar to chronic peripheral artery
disease, but is caused by dysmorphic RBCs physically occluding
small vessels, usually of the lower extremities.
 The location and appearance of sickle cell wounds may be
similar to ischemic and venous ulcerations.
 sickle cell wounds are known to progress much slower through
wound healing and carry an increased risk of reoccurrence

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Chemotherapy
 The administration of chemotherapy may have a detrimental effect
on wound healing, specifically through its effects on vascular
endothelial growth factor (VEGF).
 VEGF is an important factor contributing to angiogenesis during the
early stages of wound healing, but may also be an important
regulator in malignancy, and thus, is a target of cancer therapy.
 Similar to these effects, any patient on immunosuppressive therapy is
at an increased risk for the development of chronic wounds and
wound infection

34. +
Radiation therapy
 Radiation therapy has evolved as a powerful tool for tumor control as a sole
therapy or administered perioperatively.
 More than 50% of cancer patients receive some form of radiation treatment
and, despite improvements in radiation technique, radiation-induced
injury still contributes to poor wound healing.
 The term “radiation injury” refers to the morphologic and functional
changes that can occur in noncancerous tissue as a direct result of ionizing
radiation and may include apoptosis with low doses of radiation, or
outright tissue necrosis with higher doses of radiation.

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Radiation therapy
 Irradiated skin in the chronic stage is thin, hypovascular, extremely
painful, and easily injured by slight trauma or infection
 Skin ulcers due to radiation injury are more commonly delayed in
presentation and are due to ischemic tissue changes.
 Characteristic features of delayed radiation injury include
telangiectasia and eccentric myointimal proliferation in the small
arteries and arterioles.
 These ulcers heal very slowly and may persist for several years.

36. +
Spinal cord disease &
immobilization
 Patients undergoing periods of prolonged immobilization,
particularly those with spinal cord disease, are at an increased risk
for the development of chronic wounds.
 These are typically pressure wounds, similar in pathogenesis and
appearance to neuropathic wounds occurring in areas of bony
prominence such as the sacrum, knees, ankle malleoli and heels.

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Malnutrition
 Nutrition is an important component of wound healing.
 Several studies have indicated that nutrient deficiencies are more
prevalent and cause delayed healing in patients with wounds.
 The exact role for nutrition and nutritional supplementation in the
management of wounds remains uncertain

38. +
Malnutrition
 Vitamin C is a cofactor for the collagen cross-linking
Lack of available vitamin C or scurvy impedes the
hydroxylation and, consequently, the collagen fails to
aggregate into fibers.
 Vitamin A potentiates epithelial repair and collagen
synthesis by enhancing inflammatory reactions, particularly
macrophage availability.
 Minerals also may affect healing; zinc deficiency reduces
the rate of epithelialization and retards cellular proliferation
and collagen synthesis.

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Infection
 The presence of infection impairs several steps of the wound
healing process.
 Bacteria produce inflammatory mediators that inhibit the
inflammatory phase of wound healing and prevent
epithelialization.

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Recent developments that can
expedite healing of wounds

41. +
Negative Pressure Wound Therapy
 also called vacuum-assisted wound closure, refers to wound dressing
systems that continuously or intermittently apply subatmospheric
pressure to the surface of a wound
 NPWT has dramatically changed the surgical approach and time to
heal a wide variety of complex and difficult wounds.

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Negative Pressure Wound Therapy
 NPWT exerts its effect through direct and indirect effects of
subatmospheric pressure.
 These effects include
 stabilization of the wound environment,
 increased blood flow and deformation of the wound.
 Deformation is a powerful stimulus for cellular processes
that stimulate granulation tissue and accelerate wound
healing.

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Negative Pressure Wound Therapy
 Advantages:
 provides a close to ideal environment for temporizing coverage.
 provides a moist environment and promotes and accelerates the
growth of healthy granulation tissue while decreasing the
presence of infectious agents
 used effectively in a variety of wounds
 can be used as a longer-term dressing
 its use has decreased the need for secondary amputations
 remove excess fluid and promote wound contraction

44. +Technique of VAC fluid evacuation
Vacuum-assisted wound closure.The foam insert (sponge) within the
wound and covered by a clear, vapor permeable, plastic dressing.
Continuous subatmospheric pressure (suction) applied through the
tube causes fluid to flow out of the wound (arrows).

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Contraindications..
 Exposed vital structures
 Ongoing infection
 Devitalized tissue
 Malignant tissue
 Fragile skin
 Adhesive allergy
 Ischemic wounds

46. +Expedited Wound Healing with Noncontact, Low-Frequency
Ultrasound Therapy in Chronic Wounds: A Retrospective
Analysis
Kavros SJ, Liedl DA, Boon AJ, Miller JL, Hobbs JA, Andrews KL. Advances in Skin & Wound
Care.Vol. 21 no. 9. September 2008
Study Overview:
This was a retrospective observational study that assessed the
clinical role of MIST Therapy® in the treatment of chronic
lower-extremity wounds including venous leg ulcers, ischemic
lower extremity ulcers, neuropathic lower extremity ulcers and
multi-factorial ulcers.
 It included 210 patients: 163 whose treatment included MIST
Therapy plus standard of care and 47 who received only
standard of care.

47. +
Accelerating the Rate of Healing
 MIST Therapy uses low-frequency ultrasound to stimulate cells at
and below the wound surface to activate healing.
 A painless procedure
 The system creates low-frequency ultrasound waves that produce
and propel a gentle mist of sterile saline into the wound bed.The
saline mist improves the transfer of ultrasound from the device
without contact or pain to the patient.
 MIST Therapy promotes painless wound healing through:
• Active cell stimulation • Decreased bioburden
• Increased blood flow • Cleansing and gentle debridement

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MIST therapy..

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Key findings..
 WOUND REDUCTION was achieved in 72% of patient using
MIST therapy vs 46% of wounds treated using standard of
care alone. (P=.002)
 WOUND CLOSURE ws achieved in 70% of all wounds treated
with MIST therapy as compared to 20% of wounds treated
with SOC alone (P=.04)
 50% of wound treated with thrice weekly MIST therapy
healed over a mean of 147 days.
 Just 32% of wounds treated with SOC alone healed over a
mean 134 days. (P = .009)

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Summary
 A wound is a disruption of the normal structure and function of the
epidermis
 Wounds may be caused by a variety of mechanisms including
acute injury, surgery or other factors
 There is no specific time frame that distinguishes between acute
and chronic wounds.
 Chronic wounds are associated with physiologic derangements
that impair the wound healing process.

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Summary
 After hemostasis has been achieved, acute wounds normally heal in
an orderly and efficient manner characterized by four distinct, but
overlapping, phases: inflammation, epithelialization, fibroplasia,
and maturation.
 Many disease states alter the process of wound healing, the most
common of which are PAD, DM, and chronic venous disease.
 vacuum-assisted closure, is an adjunctive therapy used in the
management of open wounds that applies subatmospheric pressure
to the wound surface.

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