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THE PHYSIOLOGY OF HEALING OF THE
CHRONIC WOUND
Section 2 of 10

• Authors and Editors
• The Physiology Of Healing Of The Chronic Wound
• Inflammatory Phase
• Proliferative Phase
• Maturation Phase
• Deterrents Of Wound Healing
• Common Chronic Wounds
• Conclusion
• Multimedia
• References

Nonhealing chronic wounds are a challenge to the patient, the health care
professional, and the health care system. They significantly impair the quality of
life for millions of people in the United States. Intensive treatment is required and
imparts an enormous burden on society in terms of lost productivity and health
care dollars. Therefore, the study of healing chronic wounds is vitally important.

Wound healing is a dynamic pathway that optimally leads to restoration of tissue
integrity and function. A chronic wound results when the normal reparative
process is interrupted. By understanding the biology of wound healing, the
physician can optimize the tissue environment in which the wound is present.
This article describes these mechanisms, a physiologic basis for wound
management based on these processes, and the application of management
strategies of common chronic wounds.

Healing pathways are set into motion at the moment of wounding. Wound healing
is the result of the accumulation of processes, including coagulation,
inflammation, ground substance and matrix synthesis, angiogenesis, fibroplasia,
epithelialization, wound contraction, and remodeling (see Image 1). These
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complex, overlapping processes are best organized into 3 phases of healing: the
inflammatory phase, the proliferative phase, and the maturation phase.

INFLAMMATORY PHASE
Section 3 of 10

• Authors and Editors
• The Physiology Of Healing Of The Chronic Wound
• Inflammatory Phase
• Proliferative Phase
• Maturation Phase
• Deterrents Of Wound Healing
• Common Chronic Wounds
• Conclusion
• Multimedia
• References

The inflammatory phase of wound healing is clinically characterized by the
cardinal signs of redness (rubor), heat (calor), swelling (tumor), pain (dolor), and
loss of function (functio laesa). The physiologic processes underlying this
inflammation begin immediately upon tissue injury. Simultaneously, the
coagulation cascade, the arachidonic acid pathways, and the creation of growth
factors and cytokines work together to initiate and maintain the inflammatory
phase and the sequence of cells involved in the process.

At the moment of wounding with vascular injury, tissue factor and intracellular
calcium are released, activating factor VII and initiating the extrinsic coagulation
cascade. Concomitant reflex vasoconstriction occurs to aid in hemostasis.
Hemostasis is ultimately secured by the end product of the coagulation cascade,
the fibrin plug. These fibrin fibers become a provisional wound matrix and are the
lattice on which platelets aggregate. Activated platelets are the most abundant
cells in the wound in the early postinjury period. They are sources of
proinflammatory substances, such as tissue growth factor-beta (TGF-beta) and
platelet-derived growth factor (PDGF).

Growth factors are peptides that act on inflammatory cells, fibroblasts, and
endothelial cells to direct the processes involved in wound healing. They are
noted in the earliest period postinjury because PDGF and basic fibroblast growth
factor (bFGF) are produced by the injured cell at the time of wounding.
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Subsequently, activated platelets release TGF-beta and PDGF to mediate
chemotaxis of neutrophils, monocytes, and fibroblasts into the wound.

Additionally, the injured tissue locally releases eicosanoids, which amplify the
early response to injury. Eicosanoids are arachidonic acid metabolites that are
derived from cell membrane fatty acids. Activated phospholipase A catalyzes the
production of prostaglandins and thromboxane from the arachidonic acid. These
substances play central roles in the regulation of vasomotor and platelet activity
after injury. Thromboxane A2 helps with hemostasis by its effects of
vasoconstriction and platelet aggregation.

After the initial insult and resultant vasoconstriction, vascular permeability is then
increased. The classic signs of inflammation are generated by these metabolites.
For example, the redness caused by vasodilation is primarily a result of
prostacyclin (PGI2). Others include prostaglandin A, prostaglandin D, and
prostaglandin E (PGE). Swelling is caused by the leakage of plasma proteins
through gaps in the vascular endothelium. This edema is potentiated by PGE2
and prostaglandin F2-alpha (PGF2-alpha). PGI2 and PGE2 promote local blood
flow, causing the localized warmth in the area of inflammation, but also allow for
entry of inflammatory cells into the wound, which is due to increased vascular
permeability.

These cells then release cytokines responsible for fever production. Pain is
elicited by the effects of PGI2, PGE, and PGE2 on peripheral sensory nerve
endings. Eicosanoids thus exert mediatory actions on the injured tissue's platelet
plug formation, vascular permeability, and cellular chemotaxis to influence wound
healing.

Another class of mediators involved in this stage of wound healing is the
cytokines. After hemostasis has been obtained, polymorphonuclear (PMN)
leukocytes enter the area of injury, drawn by chemotactic substances such as
those released with the degranulation of platelets. These are then the
predominant cells for the first 3 days after wounding, with the number peaking at
approximately 48 hours (see Image 2). They are the first to begin bactericidal
activities using inflammatory mediators and oxygen free radical metabolites.
However, PMN leukocytes have been shown to not be crucial to the wound
healing process, with normal healing progression occurring experimentally in
their absence.

Other leukocytes, specifically helper T cells, are the source of the cytokine
interleukin (IL)–2. IL-2 promotes the proliferation of further T cells to aid in the
immunogenic response to injury. IL-1 is a cytokine produced by macrophages.
Circulating monocytes enter the wound after the PMN leukocytes and reach their
maximum numbers 24-36 hours later (see Image 2). They mature into tissue
macrophages, which carry the major load of wound debridement. Macrophages
secrete substances such as bFGF, a chemotactic and mitogenic factor for
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fibroblasts and endothelial cells, and IL-1. IL-1 stimulates the proliferation of
multiple cells of inflammation and induces the replication of endothelial cells,
promoting angiogenesis. The depletion of macrophages causes a severe
alteration in wound healing, with poor debridement and inadequate fibroblast
proliferation and angiogenesis.

As eicosanoids accumulate in the wound during the progression of the
inflammatory phase, they begin to interact with the cells present. For example, a
rise in the ratio of PGF2-alpha to PGE2 during late inflammation is a stimulus for
fibroblasts to begin to synthesize collagen and ground substance. Additionally,
the macrophage-derived growth factors are now at optimal levels, strongly
influencing the influx of fibroblasts, then keratinocytes and endothelial cells, into
the wound. The cellular population of the wound becomes predominantly
mononuclear, with a declining number of neutrophils and macrophages, signaling
the end of the inflammatory phase and the initiation of the proliferative phase.

PROLIFERATIVE PHASE
Section 4 of 10

• Authors and Editors
• The Physiology Of Healing Of The Chronic Wound
• Inflammatory Phase
• Proliferative Phase
• Maturation Phase
• Deterrents Of Wound Healing
• Common Chronic Wounds
• Conclusion
• Multimedia
• References

The proliferative phase of wound healing begins approximately 2-3 days after
wounding and is signaled by the arrival of fibroblasts into the wound. Fibroblasts
migrate from the wound margins using the fibrin-based provisional matrix
established during the inflammatory phase. Within the first week after wounding,
fibroblasts are driven by macrophage-derived bFGF, TGF-beta, and PDGF to
proliferate and synthesize glycosaminoglycans and proteoglycans, the building
blocks of the new extracellular matrix of granulation tissue, and collagen.

Because macrophage numbers have begun to diminish in the acute wound by
this time, fibroblasts start to produce bFGF, TGF-beta, and PDGF. They also
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begin producing keratinocyte growth factor and insulinlike growth factor-1.
Fibroblasts become the dominant cell type, reaching their peak numbers at 7-14
days. After secretion of collagen molecules, fibroblasts then assemble them
extracellularly into collagen fibers. These fibers are then cross-linked and
organized into bundles. Collagen is the major component of acute wound
connective tissue, with net production continuing for the next 6 weeks. The
increasing content of wound collagen correlates with increasing tensile strength.

During fibroblast proliferation, keratinocyte and endothelial cell populations are
also stimulated to increase their numbers. In turn, keratinocytes and endothelial
cells produce their own growth factors stimulatory for their respective cell
proliferation. Simultaneously with cellular proliferation, angiogenesis in the
developing granulation tissue occurs through budding from intact vessels at
wound margins and requires endothelial cell production from factors described
previously.

This neovascularization accompanies the advancing line of fibroblasts into the
wound to provide them with nutrients and to produce plasminogen activator and
collagenase. This begins the degradation of the fibrin clot and provisional matrix
once the new granulation tissue (ie, extracellular matrix, collagen, capillaries) is
laid down. Granulation tissue production continues until the defect is covered.
Finally, as the hyaluronic acid–containing provisional matrix is broken down, the
decreasing hyaluronic acid concentration and rising chondroitin sulfate levels
signal the slowing of fibroblast migration and proliferation. This shift in the ratio of
these glycosaminoglycans acts to inhibit fibroblast activity, inducing them to
differentiate, and thus initiating the maturation phase of wound healing.

MATURATION PHASE
Section 5 of 10

• Authors and Editors
• The Physiology Of Healing Of The Chronic Wound
• Inflammatory Phase
• Proliferative Phase
• Maturation Phase
• Deterrents Of Wound Healing
• Common Chronic Wounds
• Conclusion
• Multimedia
• References
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New collagen production remains the dominant process in wound healing from
the first week after wounding until approximately 6 weeks. Collagen is deposited
randomly in acute wound granulation tissue. Remodeling of the collagen into a
more organized structure occurs during wound maturation, increasing the
wound's tensile strength. During the formation of the scar, the type III collagen of
the granulation tissue is replaced by type I collagen until the normal skin ratio of
4:1 for type 1 collagen to type III collagen is present. With the remodeling
process, a dynamic turnover of collagen occurs but collagen synthesis equals
that of collagenolysis. This results in a tensile strength plateau achieved after
approximately 2 years postinjury of approximately 80% of normal strength,
beyond which wound strength cannot exceed.

The wound is eventually closed by the migration of epithelial cells from the
wound edge, filling the defect until they reach other epithelial cells and halt their
advance due to contact inhibition. This adds nothing to wound strength, and
remodeling continues beneath the epithelial cover.

When wound fibroblasts reach a concentration with which their density causes
contact inhibition, they differentiate into myofibroblasts containing alpha-smooth
muscle actin fibrils. These cells tightly bind to each other and to the wound
margins, drawing the wound edges closer together. The extent of importance of
the role of myofibroblasts in wound contraction is, at present, equivocal. Some
investigators believe the myofibroblast are the principal controller of wound
contraction, while others maintain they are only the precursors to cell apoptosis
and do not serve in contraction. By whatever means, as wound contraction
proceeds, the volume of injured tissue is reduced by replacement with uninjured
tissue.

DETERRENTS OF WOUND HEALING
Section 6 of 10

• Authors and Editors
• The Physiology Of Healing Of The Chronic Wound
• Inflammatory Phase
• Proliferative Phase
• Maturation Phase
• Deterrents Of Wound Healing
• Common Chronic Wounds
• Conclusion
• Multimedia
• References
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The wound healing process can be applied to both acute and chronic wounds.
However, in the latter, the sequential process has been disrupted. When a
wound proceeds through an orderly and timely reparative process and results in
a sustained restoration of anatomic and functional integrity, it is termed an acute
wound. Conversely, a chronic wound is one that has failed to proceed through
the usual stepwise fashion. As a result, the healing process is prolonged and
incomplete, with lack of restoration of integrity.

A chronic wound occurs when some factor causes the disruption of the normal,
controlled inflammatory phase or the cellular proliferative phase. Thus, each
wound should be evaluated to determine what factors are present and how to
correct the problem. Many factors can contribute to poor wound healing. The
most common include local causes such as wound infection; tissue hypoxia;
repeated trauma; the presence of debris and necrotic tissue; and systemic
causes such as diabetes mellitus, malnutrition, immunodeficiency, and the use of
certain medications.

Wound infection is likely the most common reason for poor wound healing. All
wounds are contaminated with bacteria. Whether a wound becomes infected is
determined by the host's immune competence and the size of the bacterial
inoculum. With normal host defenses and adequate debridement, a wound may
bear a level of 100,000 (105) microorganisms per gram of tissue and still heal
successfully. Beyond this number, a wound may become infected.

Soft tissue cellulitis prolongs the inflammatory phase by inducing tissue
proteases to degrade new granulation tissue and tissue growth factors and by
delaying collagen deposition. Exudative fluid drawn from chronic wounds, in
contrast to acute wounds, has elevated protease activity, diminished growth
factor activity, and elevated levels of proinflammatory cytokines. Therefore,
infection impedes healing by interfering with many steps in the normal
progression from inflammation to proliferation to maturation of the wound.

Tissue perfusion may be impaired by arterial occlusion or vasoconstriction,
hypotension, hypothermia, and peripheral venous congestion. Reduced wound
oxygen tension can delay wound healing by slowing the production of collagen.
Collagen fibril cross-linking begins to fail as tissue oxygen pressure falls below
40 mm Hg because oxygen is required for the hydroxylation of proline and lysine
to synthesize mature collagen. Wound hypoxia also predisposes to bacterial
infection because the leukocyte's oxidative phosphorylation bactericidal activities
are severely impeded without normal tissue oxygen levels. These factors should
be corrected as much as possible.
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For example, hypoxia due to arterial occlusive disease can be improved by
angioplasty or bypass grafting. The patient should be urged to cease using
tobacco, which causes arterial vasoconstriction. A hypotensive or hypothermic
patient should be properly resuscitated to improve cardiac function and blood
volume as needed. Venous stasis is generally treated with compressive
garments to improve vascular return. Anemia is not detrimental to healing as long
as the hematocrit value is greater than 15% and the patient is euvolemic.
Because an adequate tissue oxygen tension directly correlates with the success
of wound healing, optimizing oxygen tension is essential in all patients with any
type of wound.

Devitalized tissue impairs healing because it provides a growth medium for
bacteria, increasing the probability of infection. Dead tissue also exudes
endotoxins that inhibit the migration of fibroblasts and keratinocytes into the
wound. Foreign bodies such as suture material also fall into the category of
debris when a wound is chronic in nature. The presence of a silk suture reduces
the number of bacteria required to incite infection by a factor of 10,000.
Therefore, debridement of all necrotic tissue and debris, whether performed by
surgical means or with the use of enzymatic agents or wound dressings, is
critical in achieving wound healing.

Underlying systemic disease in a patient with a wound can dramatically diminish
the probability that the wound will heal in a timely fashion. Diabetes mellitus is a
classic example. Wound healing is often delayed because of interruption of the
inflammatory and proliferative phases. Neutrophils and macrophages cannot
adequately keep the bacterial load of the wound controlled because their
glycosylation is inhibitory to phagocytic function. Infection thus prolongs the
inflammatory phase. When erythrocytes are affected by glycosylation (as
measured by hemoglobin A1c levels), they become less pliable, leading to
microvascular sludging and ischemia. Low tissue oxygen tension impairs cellular
proliferation and collagen synthesis as previously described.

Malnutrition causes a decreased rate of fibroblastic proliferation and
neovascularization and impairs both cellular and humoral immunity. A high rate
of metabolic activity is present at the wound site, especially within new
granulation tissue. If nutrients necessary for those activities are not provided, the
health of the tissue is tenuous. Proteins and their amino acid building blocks,
such as methionine, proline, glycine, and lysine, are essential for normal cell
function and the repair of cutaneous wounds. Linolenic and linoleic acid must be
supplied in the diet, which is why they are termed essential fatty acids.

Because they are critical constituents of the cell membrane and are the source of
prostaglandins that mediate inflammation, deficiency of essential fatty acids
causes impaired wound healing. Deficiency of vitamins C or K leads to scurvy
and coagulopathy, respectively. Minerals, including calcium, iron, copper, zinc,
and manganese, must be delivered to the wound milieu to act as cofactors for
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vital reactions in the synthesis of proteins needed in the healing process. If the
diagnosis is impaired wound healing resulting from malnutrition, ensure that the
patient receives adequate protein and energy (caloric) intake. Specific vitamin
and mineral supplements may be required for rapid recovery of the necessary
nutrients.

Finally, some medications prove to be detrimental to wound healing.
Corticosteroids suppress inflammation at all levels, thereby blunting this phase of
healing. Vitamin A reverses the negative effects of steroids and is indicated for
topical and systemic application for all patients with chronic wounds who cannot
discontinue corticosteroid therapy. Nonsteroidal anti-inflammatory agents such
as aspirin and indomethacin interfere with the arachidonic acid cascade,
impeding the elucidation of some of the healing scheme's primary mediators.
Additionally, these act to inhibit the actions of platelets and platelet aggregation,
thus disrupting the healing process from the first moment of wounding.

To provide the best chance for chronic wounds to heal, the surgeon should
attempt to identify any factors that may be acting to impede success, and then
correct the problem through optimization of the cellular and molecular wound
environment.

COMMON CHRONIC WOUNDS
Section 7 of 10

• Authors and Editors
• The Physiology Of Healing Of The Chronic Wound
• Inflammatory Phase
• Proliferative Phase
• Maturation Phase
• Deterrents Of Wound Healing
• Common Chronic Wounds
• Conclusion
• Multimedia
• References

Common chronic skin and soft tissue wounds include the diabetic foot ulcer, the
decubitus ulcer, and the venous stasis ulcer.

Diabetic ulcers
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Diabetic ulcers are the most common cause of foot and leg amputation. In
patients with type I and type II diabetes, the incidence rate of developing foot
ulcers is approximately 2% per year. The average cost for 2 years of treatment is
$27,987 per patient (1999 data). The diabetic foot ulcer is mainly neuropathic in
origin, with secondary pathogenesis being a blunted leukocyte response to
bacteria and local ischemia due to vascular disease. These wounds usually
occur on weight-bearing areas of the foot.

The Wound Healing Society's standards of care include off-loading, attentive
debridement, and the maintenance of a moist wound environment. Because
diabetic ulcers are prone to infection, topical antimicrobials may be used if
infection is present; however, systemic antibiotics should be used if cellulitis
occurs. Systemic antibiotics should be discontinued once the wound has come
into bacterial balance because most agents inhibit fibroblast and keratinocyte
proliferation.

Because chronic wounds have been demonstrated to have markedly decreased
levels of several growth factors, these have been a focus to enhance the repair
of the wounds. Topically applied PDGF, TGF-beta, and platelet-derived wound
healing factor have been demonstrated to be effective agents to speed the
healing of diabetic ulcers. Because clinical trials have proven its efficacy and
safety, PDGF (Regranex) is the first recombinant growth factor to be approved by
the US Food and Drug Administration for use in the acceleration of wound
closure. In patients with diabetic ulcers and in persons with other types of chronic
wounds, pursue correction of the cause and institute measures to stimulate
healing.

Decubitus ulcers

The decubitus ulcer is a result of prolonged, unrelieved pressure over a bony
prominence that leads to ischemia. The wound tends to occur in patients who are
unable to reposition themselves to off-load weight, such as paralyzed,
unconscious, or severely debilitated persons. As defined by the US Department
of Health and Human Services, the major preventive measures include
identification of high-risk patients; frequent assessment; and prophylactic
measures such as scheduled repositioning, appropriate pressure-relief bedding,
moisture barriers, and adequate nutritional status.

Treatment consists of pressure relief, surgical and enzymatic debridement, moist
wound care, and control of the bacterial load. Topical applications of
antimicrobials and PDGF may be used. The Vacuum-Assisted Closure technique
(Kinetic Concepts, Inc) is successful in treating pressure ulcers. These
mechanisms of treatment strive to reestablish a normal healing trajectory by
correcting the source of the problem.

Venous stasis ulcers
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In the venous stasis ulcer, chronic passive venous congestion of the lower
extremities results in local hypoxia. One current hypothesis of the pathogenesis
of these wounds includes the impediment of oxygen diffusion into the tissue
across thick perivascular fibrin cuffs. Another belief is that macromolecules
leaking into the perivascular tissue trap growth factors needed for the
maintenance of skin integrity. Additionally, the flow of large white blood cells
slows due to venous congestion, occluding capillaries, becoming activated, and
damaging the vascular endothelium to predispose to ulcer formation.

The standard of care is compression garment therapy, debridement, and a moist
wound environment. Partial-thickness meshed skin grafts are effective for venous
leg ulcers. Bioengineered skin equivalent (Apligraf) is efficacious in these
wounds, acting as a moist dressing and providing a matrix, migration pathways,
growth factors, and living dermal and epidermal cells to the wound.

CONCLUSION
Section 8 of 10

• Authors and Editors
• The Physiology Of Healing Of The Chronic Wound
• Inflammatory Phase
• Proliferative Phase
• Maturation Phase
• Deterrents Of Wound Healing
• Common Chronic Wounds
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• Conclusion
• Multimedia
• References

These indolent wounds are similar in that each is marked by persistent
inflammatory stimuli, such as infection, ischemia, and repeated trauma, that
disrupt the normal healing process. The goal of wound management is to
reestablish the normal healing scheme. Chronic wounds affect millions of
patients and impose a great cost to society. Research into using growth factors
and new care techniques holds great promise, with the goal of lessening the
burden these wounds place on physicians, health care systems, and patients.

MULTIMEDIA
Section 9 of 10

• Authors and Editors
• The Physiology Of Healing Of The Chronic Wound
• Inflammatory Phase
• Proliferative Phase
• Maturation Phase
• Deterrents Of Wound Healing
• Common Chronic Wounds
• Conclusion
• Multimedia
• References

Media file 1: Schemes of the wound healing process.