5

Acute and Chronic Wound Healing

Samantha Holloway, MSc, PGCE, FHEA, RN
Sophia Tate, MB, ChB
Joyce K. Stechmiller, PhD, ACNP-BC, FAAN
Gregory Schultz, PhD
We gratefully acknowledge the contributions of Keith Harding MB, ChB, FRCGP, FRCP,
FRCS for his work on previous editions of this chapter.

Objectives
After completing this chapter, you will be able to:
describe the physiology of normal and pathophysiology of abnormal wound
healing
discuss the cascade of wound healing events
compare and contrast acute and chronic wound healing
appraise terminology used in clinical practice to refer to a chronic wound
identify host factors that affect wound healing
discuss the effects of biofilms on wound healing
evaluate the key consensus statements for the assessment and treatment of
biofilms
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explain the principles of wound bed preparation and TIME in the management of
patients with wounds
describe symptoms and symptom clusters associated with chronic wounds.

Acute Wound Healing Events

When a patient experiences tissue injury, it’s essential that hemostasis is rapidly achieved and
tissue is repaired to prevent invasion by pathogens and restore tissue function. The process of
wound healing is a complex sequence of events that starts when the injury occurs and ends

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 with complete wound closure and successful, functional scar tissue organization. Although
tissue repair is commonly described as a series of stages, in reality it’s a continuous process
during which cells undergo a number of complicated biological changes to facilitate
hemostasis, combat infection, migrate into the wound space, deposit a matrix, form new
blood vessels, and contract to close the defect.
However, wound closure isn’t a marker of healing completion; the wound continues to
change, in a process called remodeling, for up to 18 months post closure. During this
prolonged phase of remodeling and maturation, the closed wound is still quite vulnerable.

Patient Teaching
Remind your patient that the process of wound healing can take up to 18 months. Although
the wound may appear to be closed, changes are occurring in the underlying tissue. This
means that the wound is still vulnerable to damage. Tell the patient to seek professional
advice if he or she has any concerns about the wound.

Acute Wound Healing Cascade

The process of healing is usually divided into four phases—hemostasis, inflammation,
proliferation/repair, and maturation/remodeling—each of which overlaps the others while
remaining distinct in terms of time after injury (Fig. 5-1).
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 Figure 5-1. Sequence of molecular and cellular events in skin wound healing.

Patient Teaching
Inform your patient that the process of healing is often separated into four different phases.
When a wound is being assessed, the clinician is looking for signs of progress as well as
deterioration.

Hemostasis
The disruption of tissue following injury causes hemorrhage, which initially fills the wound
and exposes the blood to various components of the extracellular matrix (ECM).1 Platelets
aggregate and degranulate, which activates factor XII (Hageman factor), resulting in clot
formation and hemostasis. Hemostasis stops hemorrhage at the site of blood vessel damage.
This is essential as it preserves the integrity of the closed and high-pressure circulatory
system to limit blood loss. A fibrinous clot forms during coagulation, acting as a preliminary
matrix within the wound space into which cells can migrate.
After the fibrin clot forms, another mechanism is activated as part of the body’s defense
system—fibrinolysis—in which the fibrin clot starts to break down. This process prevents
clot extension and dissolves the fibrin clot to allow ease of further cell migration into the
wound space,2 allowing the next stage of healing to proceed.

Inflammatory Phase
As the fibrin clot is degraded, the capillaries dilate and become permeable, allowing fluid
into the injury site and activating the complement system. The complement system is
composed of a series of interacting, soluble proteins found in serum and extracellular fluid
that induce lysis and the destruction of target cells. C3b, a complement molecule, helps bind
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(opsonize) neutrophils to bacteria, facilitating phagocytosis and subsequent bacterial

destruction.
Cytokines and some proteolytic fragments that are hemoattractive are also found in the
wound space.2 Their abundance and accumulation at the site of injury initiate a massive
influx of other cells. The two main inflammatory cells—neutrophils and macrophages—are
attracted to the wound space to mount an acute inflammatory response.3
Neutrophils appear in a wound shortly after injury and reach their peak number within 24
to 48 hours; their main function is to destroy bacteria by the process of phagocytosis.

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 Neutrophils have a very short life span: after 3 days without infection, their numbers reduce
rapidly.
Tissue macrophages are derived from blood monocytes and arrive approximately 2 to 3
days after injury, followed by lymphocytes. Like neutrophils, macrophages also destroy
bacteria and debris through phagocytosis; however, macrophages are also a rich source of
biological regulators, including cytokines and growth factors, bioactive lipid products, and
proteolytic enzymes, which are also essential for the normal healing process.2,4

Cytokines, Growth Factors, and Chemotaxis

Cytokine is a broad term that includes such molecules as growth factors, interleukins, tumor
necrosis factors, and interferons. These molecules act on a variety of cells by exerting a wide
range of biological functions by means of their specific receptors on target cells or proteins.
Pathogens, endotoxins, tissue degradation products, and hypoxia are all factors that stimulate
cells to produce cytokines following injury. The main cellular sources for these cytokines are
platelets, fibroblasts, monocytes and macrophages, and endothelial cells. These cells are
involved in physiological as well as pathological conditions (e.g., tumors), although in
wound healing, they play an important role as mediators. Cytokines regulate cell
proliferation, migration, matrix synthesis, deposition and degradation, and inflammatory
responses in the repair process (Table 5-1).

Table 5-1 Major Cytokines Involved in Wound Healing

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 Immediately after injury, platelet degranulation releases numerous cytokines, including
platelet-derived growth factor (PDGF), transforming growth factor (TGF), and epidermal
growth factor (EGF). These cytokines, together with other chemotactic agents, such as tissue
debris and pathogenic materials, attract neutrophils and, later, macrophages. In time, these
cells contribute to a larger number and variety of cytokines, which participate in the healing
process.3 (See Patient Teaching: Normal and abnormal signs of the inflammatory process.)
Cytokines have diverse effects on the healing process, interacting in additive, synergistic,
or inhibitory ways (Table 5-2). For example, keratinocyte growth factor enhances the
stimulation of collagenase synthesis exerted by insulin-like growth factor. TGF is inhibitory
to fibroblast growth in the presence of EGF but stimulates cell division when PDGF is
present.

Table 5-2 Major Growth Factor Families

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Proliferation Phase
The proliferation phase usually begins 3 days after an injury and lasts for a few weeks. This
phase is characterized by the formation of granulation tissue in the wound space. The new

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 tissue consists of a matrix of fibrin, fibronectin, collagens, proteoglycans,
glycosaminoglycans (GAGs), and other glycoproteins.5 Fibroblasts move into the wound
space and proliferate. Because the type III collagen in the wound has decreased tensile
strength, the patient is at risk for such abnormalities as wound dehiscence or opening of
wound edges in a previously closed wound that healed by primary intention. If organs are
protruding from the now opened wound, it’s called evisceration, which is a medical
emergency that requires immediate surgery.

Patient Teaching Normal Signs of the Inflammatory

Process
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Copyright © 2020. Wolters Kluwer Health. All rights reserved.

Practice Point
Keep in mind that the induration, heat, discomfort, redness, and swelling experienced
during the inflammatory phase are part of the normal wound healing processes and aren’t,
at this stage, likely to be due to wound infection. Remember to share this information with
your patients.

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 Practice Point
During the first 3 weeks after surgery, the patient is at high risk for wound dehiscence and
evisceration. Advise the patient that he or she should follow any postsurgical advice very
carefully as the repaired tissue will not regain its full strength. The wound is at risk of
breakdown if undue pressure is exerted on the area. For instance, patients who have
undergone an abdominal procedure should support their abdomen with a soft pillow if they
need to cough. They should also avoid any heavy lifting or exertion as designated by their
physician.

Role of Fibroblasts
Fibroblasts play a key role during the proliferation phase, appearing in large numbers within
3 days of injury and reaching peak levels on the 7th day. During this period, they undergo
intense proliferative and synthetic activity. Fibroblasts synthesize and deposit extracellular
proteins during wound healing, producing growth factors and angiogenic factors that regulate
cell proliferation and angiogenesis.6
Granulation tissue is composed of many mesenchymal and nonmesenchymal cells with
distinct phenotypes, inflammatory cells, and new capillaries embedded in a loose ECM
composed of collagens, fibronectin, and proteoglycans.

Role of ECM Proteins

ECM consists of proteins and polysaccharides and their complexes produced by cells in the
wound space. The two main classes of matrix proteins are fibrous proteins (collagens and
elastin) and adhesive proteins (laminin and fibronectin). In addition, the ECM contains
polysaccharides called proteoglycans and GAGs.
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Collagen is the most abundant protein in animal tissue and accounts for 70% to 80% of
the dry weight of the dermis.7 The collagen molecule consists of three identical polypeptide
chains bound together in a triple helix. Made mainly by fibroblasts, at least 19 genetically
distinct collagens have been identified. Collagen synthesis and degradation are finely
balanced.2
Elastin is a protein that provides elasticity and resilience.8 It is composed of fibrous coils
that stretch and return to their former shape, much like metallic coils. Because of these
properties, elastin helps maintain tissue shape. Elastin represents only 2% to 4% of the
human skin’s dry weight; it’s also in the lungs and blood vessels. It’s secreted into the

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 extracellular space as a soluble precursor, tropoelastin, which binds with a microfibrillar
protein to form an elastic fiber network.
Laminin and fibronectin are two fiber-forming molecules. Their function is to provide
structural and metabolic support to other cells. Fibronectin is found in plasma and contains
specific binding sites on its molecular wall for cells, collagens, fibrinogens, and
proteoglycans. It plays a central role in tissue remodeling, acting as a mediator for physical
interactions between cells and collagens involved in ECM deposition, thereby providing a
preliminary matrix.
Proteoglycans consist of a central core protein combined with a number of GAG chains
that may be one or several types. GAGs consist of long, unbranched chains of disaccharide
units that can range in number.2 A highly complex group of molecules, proteoglycans, are
characterized by their many diverse structural and organizational functions in tissue. Forming
a highly hydrated gel-like “ground substance,” they can contain up to 95% (w/w)
carbohydrates. Originally, however, they were thought to contribute to tissue resilience due to
their capacity to fill much of the extracellular space.

Angiogenesis
Angiogenesis is the formation of new vessels in the wound space and is an integral and
essential part of wound healing.9 The vascular endothelial cell (VEC) plays a key role in
angiogenesis and arises from the damaged end of vessels and capillaries. New vessels
originate as capillaries, which sprout from existing small vessels at the wound edge. The
endothelial cells from these vessels detach from the vascular wall, degrade and penetrate
(invade) the provisional matrix in the wound, and form a knob-like or cone-shaped vascular
bud or sprout. These sprouts extend in length until they encounter another capillary, to which
they connect to form vascular loops and networks, allowing blood to circulate. This pattern
of vascular growth is similar in skin, muscle, and intestinal wounds.

Epithelialization
Epithelial healing, or epithelialization, which begins a few hours after injury, is another
important feature of healing. Marginal basal cells, which are normally firmly attached to the
underlying dermis, change their cell adhesion property and start to lose their firm adhesion,
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migrating in a leapfrog or train fashion across the provisional matrix. Horizontal movement
is stopped when cells meet. This is known as contact inhibition.

Wound Contraction
The final feature of the proliferation phase is wound contraction, which normally starts 5
days after injury. Wound contraction appears to be a dynamic process in which cells organize
their surrounding connective tissue matrix, acting to reduce the healing time by reducing the
amount of ECM that needs to be produced. The contractile activity of fibroblasts and
myofibroblasts provides the force for this contraction. These cells may use integrins and

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 other adhesion mechanisms to bind to the collagen network and alter its motility, bringing the
fibrils and, subsequently, the wound edges closer.2 Such contraction may not be important in
a sharply incised, small, and noninfected wound; however, it’s critical for wounds with large
tissue loss.10
The myofibroblast theory suggests that the contraction force occurs when the movement
of microfilament (actin) bundles (also termed stress fibers) contracts the myofibroblast in a
muscle-like fashion. Because the myofibroblast displays many cell–cell and cell–matrix
(fibronexus) contacts, the cellular contraction pulls collagen fibrils toward the body of the
myofibroblast and holds them until they’re stabilized into position. This gathering of
collagen fibers toward the myofibroblast cell “body” leads to the shrinkage of granulation
tissue. The ECM of the wound is continuous with the undamaged wound margin, enabling
the granulation tissue shrinkage to pull on the wound margin, leading to wound contraction.
The myofibroblast theory further proposes that the coordinated contraction (cellular
shortening) of many myofibroblasts, synchronized with the help of gap junctions, generates
the force necessary for wound contraction.6
The traction theory proposes that fibroblasts bring about a closer approximation of matrix
fibrils by exerting “traction forces” (analogous to the traction of wheels on tarmac) on ECM
fibers to which they’re attached. This theory proposes that fibroblasts neither shorten in
length nor act in a coordinated multicellular manner (as proposed by the myofibroblast
theory); rather, a composite force, made up of traction forces of many individual fibroblasts,
is responsible for matrix contraction. Such traction forces act as shearing forces tangential to
the cell surface generated during cell elongation and spreading. According to the traction
theory, the composite effect of many fibroblasts gathering collagen fibrils within the wound
is thought to bring about wound contraction.11

Patient Teaching
Teach your patient who has a wound left open to heal (secondary intention) that clinicians
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will be looking for indications that wound healing is progressing normally:

Healthy pink tissue in the wound bed
Signs of new tissue growth at the wound edges
Decreasing wound size over time

Maturation Phase
The maturation phase normally starts 7 days after injury and may last for 1 year or more. The
initial component in the deposited ECM is fibronectin, which forms a provisional fiber
network. Other components include hyaluronic acid and proteoglycans. The network has two

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 main roles: as a substratum for the migration and growth of cells and as a template for
subsequent collagen deposition. Collagen deposition becomes the predominant constituent of
the matrix and soon forms fibrillar bundles and provides stiffness and tensile strength to the
wound.
Collagen deposition and remodeling contribute to the increased tensile strength of skin
wounds. Within 3 weeks of injury, the tensile strength is restored to approximately 20% of
normal, uninjured skin. As healing continues, the skin gradually reaches a maximum of 70%
to 80% tensile strength. Different organs regain tensile strengths to differing degrees. The
remodeling process involves the balance between the synthesis and degradation of collagen.
A range of collagenases regulates the latter. This process is also characterized by a gradual
reduction in cellularity and vascularity.3 Differentiation of fibroblasts into myofibroblasts
with resultant apoptosis (programmed cell death) are also features of tissue remodeling.12

Practice Point
A patient history should always include information about prior wounds. Healed wounds
never achieve the same tensile strength as uninjured skin, thereby increasing the potential
for reinjury.

Patient Teaching
Remind the patient that the wounded area is never as strong as uninjured tissue so it is
always vulnerable to damage. Simple measures such as keeping the scar tissue moisturized
will help to optimize the condition of the tissue. Advise the patient to seek help if the scar
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begins to break down.

The scar is the final product of wound healing and is a relatively avascular and acellular mass
of collagen that serves to restore tissue continuity and some degree of tensile strength and
function. However, the strength of the scar remains less than that of normal tissue, even many
years following injury, and it’s never fully restored (Box 5-1).

Box 5-1 Summary of Wound Healing

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Copyright © 2020. Wolters Kluwer Health. All rights reserved.

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 Practice Point
The width of the resultant scar of a wound healing by secondary intention is about 10% of
the original defect, primarily due to the process of wound contraction, working in
conjunction with proliferation.

Patient Teaching
Inform the patient of the changes that occur to scar tissue over time. Initially, the scar may
be red and raised but over time will become paler and flatten out. This process may take up
to 2 years. Occasionally, there may be signs of abnormal healing, such as a scar remaining
raised or swollen. If this occurs, the patient should seek further advice from a healthcare
practitioner as this may indicate hypertrophic or keloid scarring.

Role of Matrix Metalloproteinases in Wound Healing

Proteases, especially the matrix metalloproteinases (MMPs), play essential roles in all phases
of normal wound healing (Box 5-2). For example, during the inflammatory phase, damaged
ECM proteins (such as collagen) must be removed so that newly synthesized collagen
molecules can correctly align with collagen molecules in the wound matrix, permitting
migration of epidermal cells and fibroblasts into the wound bed (Box 5-3). To remove
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damaged collagen molecules, collagenases (Box 5-4), make a single cut in collagen
molecules, which permits the gelatinases to further degrade collagen molecules into small
fragments that are then removed from the injury area by neutrophils and macrophages.
MMPs also play a key role in angiogenesis by first degrading the basement membrane that
surrounds VECs. This causes new capillary buds to sprout and “channels” to erode the ECM,
through which the VECs migrate, eventually creating new capillary arcs. Furthermore,
MMPs are required for myofibroblasts to contract ECM during the maturation or remodeling
phase. The actions of MMPs are controlled by their natural inhibitors, the tissue inhibitors of
metalloproteinases (TIMPs).

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 Box 5-2 Role of MMPs in Wound Healing
Proteases (especially MMPs) play important, beneficial roles in normal wound healing.
They perform the following functions:
Contract wound matrix through use of myofibroblasts
Implement angiogenesis (breakdown of capillary basement membrane)
Migrate cells (epidermal cells, fibroblasts, VECs)
Remodel scar ECM
Remove damaged ECM (especially during the inflammatory phase of healing)

Box 5-3 ECM Proteins and MMPs: Critical Factors for Epithelial
Migration, Angiogenesis, and Contraction
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Box 5-4 Families of MMPs, TIMPs, and ADAMs

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 Acute Versus Chronic Wound Healing
Molecular and Cellular Abnormalities in Chronic Wounds
There would appear to be little consensus regarding the definition of acute and chronic
wound etiologies. Chronicity implies a prolonged or lengthy healing process, whereas acute
implies uncomplicated, orderly or organized, or rapid healing. Bates-Jensen and Woolfolk13
define an acute wound as “a disruption in the integrity of the skin and underlying tissues that
progresses through the healing process in a timely and uncomplicated manner.” Typically,
surgical and traumatic wounds, which heal by primary intention, are classified as acute.
On the other hand, Sussman14 defines a chronic wound as “one that deviates from
expected sequence of repair in terms of time, appearance, and response to aggressive and
appropriate treatment.” The Wound Healing Society uses the definition of chronic wound as
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proposed in 1994 by Lazarus and colleagues: chronic wounds are wounds that “fail to
progress through a normal, orderly, and timely sequence of repair or wounds that pass
through the repair process without restoring anatomic and functional results”.15 Chronicity is
being said to occur when a wound does not heal within a 4-week period or in an orderly and
timely manner with standard care.16 Such wounds usually heal by secondary intention and
are associated with pathology, for example, diabetes, vascular disease (venous leg ulcers)
ischemic disease, pressure damage, and inflammatory diseases. However, with appropriate
treatment, most venous leg ulcers should heal within 3 to 4 months,17 so there is somewhat of
a disconnect between the definition of a chronic wound in terms of duration versus how long
it might take to heal. There are a number of different terms used to refer to a chronic wound

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 (Box 5-5).

Box 5-5 Terminology Used to Describe a Chronic Wound

Delayed healing16
Nonhealing16
Complex wound17
Recalcitrant18
Stalled19
Hard-to-heal20
Teaching patients the words used to describe the types of wound healing (acute, chronic,
primary, secondary) may help them appreciate the time it may take for their wound to heal.
Discuss the importance of moist wound healing to your patients, and inform them of
what factors have been taken into consideration when deciding the most appropriate
treatment for their wound.

Practice Point
Consider the terminology that is used in your own clinical practice, and reflect on how this
might affect your assessment, documentation, and subsequent management of a patient
with a wound.

The physiological differences between wounds that heal slowly and those that heal rapidly
have been studied in a variety of ways (Box 5-6). One experiment explored the effect of
chronic wound fluid on cell function.21 Researchers cultured fibroblasts from human
neonatal foreskin to use as a laboratory model of acute wounds. They then exposed the model
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to either chronic wound fluid or a control and found that chronic wound fluid dramatically
inhibited the growth of the fibroblasts. According to Phillips et al.,21 these results indicate
that the microenvironment of chronic wounds impairs wound healing.

Box 5-6 Imbalanced Molecular Environments of Healing and

Chronic Wounds

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 Box 5-7 Factors Suggested to Affect Wound Healing

Adapted from Guo, S., DiPietro, L.A. “Factors Affecting Wound Healing.” Journal Dental Research 89(3):219-29,
Copyright © 2020. Wolters Kluwer Health. All rights reserved.

2010.

Other researchers22,23 theorize that prolonged inflammation is the most significant factor in
delayed healing. Indeed, Hart22 proposes that the prolonged inflammatory phase is due to the
presence of inflammatory leukocytes, typically neutrophils and their production of
proinflammatory cytokines that perpetuate inflammation. He also argues that the release of
tissue-damaging proteinases, which degrade newly formed tissue, delays or prevents normal

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 wound healing processes. In addition to prolonged inflammation, Hart22 suggests several
other factors that may induce chronicity, including recurrent physical trauma, ischemic
reperfusion injury, subclinical bacterial contamination, and foreign bodies.
Because chronic wounds are typically characterized by full-thickness tissue loss,
reepithelialization is prolonged due to the loss of appendages.14 Normally, epithelial cells
require the smooth, moist surface of the basement membrane to move across the wound. In
chronic wounds, epithelial cells latch onto and pull themselves across the scaffolding of
macromolecules of the provisional matrix, such as laminin and fibronectin. Common types of
chronic wounds include venous ulcers, pressure injuries/pressure ulcers, diabetic foot ulcers,
arterial ulcers, infected open surgical incisions, and contaminated traumatic wounds.

Factors Affecting Wound Healing

Host Factors
Host factors (e.g., age, disease burden, sex, race/ethnicity, compromised immunity,
medications, BMI, nutritional status, lifestyle habits including smoking) affect wound
healing. Patient characteristics including age are related to the increased incidence and
prevalence of chronic wounds. Studies have also shown sex-related differences in wound
healing and outcomes.24
Aging. Older individuals experience an increased abundance of proinflammatory
cytokines and a lower level of growth factors. Unlike relatively healthy patients with acute
wounds in which growth factors and cytokines are increased, older individuals with chronic
wounds experience decreased levels of growth factors and increased levels of
proinflammatory cytokines.25 However, even in the presence of limited growth factors,
patients with chronic wounds experience delayed healing, because their fibroblasts are not as
reactive to growth factors’ stimuli as those of younger patients.26–28 Increased activity of
MMPs in older adults can also delay healing, degrading collagen and collagen fragments,
that are characteristic in older adults. Neutrophil elastase breaks proteins and peptide bonds
and tends to be increased in chronic wounds in older patients.29 Furthermore, degrading
proteins (e.g., fibronectin, vitronectin, tenascin) decrease the ECM’s reformation and further
delay healing.30
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Comorbidities. Comorbidities may contribute to inflammatory dysfunction in chronic

wounds and symptom burden.31 However, how different comorbidities and other factors
affect healing outcomes are virtually unknown in older individuals with chronic wounds.32
Research has shown that the immune system is affected by host comorbidities that may affect
the wound healing process. Some examples of comorbidities have been studied including
diabetes, venous insufficiency, congestive heart failure, abnormal white blood cell function,
and obesity.33 Patients who are obese experience low-grade inflammation, which include
many components of the traditional inflammatory response to pathogens, such as local
wounding and systemic increases in cytokines.

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 Additionally, chronic wound healing in older adults can be influenced by comorbidity
treatments, medications, antibiotic resistance, additional infected areas, proinflammatory
wound condition, systemic inflammation, compromised immunity, poor circulation, poor
hydration, and other nutritional deficiencies.34
Medications and Antibiotic Resistance. Chemotherapy medications such as
antineoplastic agents (e.g., Eloxatin for metastatic colon cancer) can interfere with wound
healing by disrupting cellular replication.35 Meanwhile, other medications, such as antibiotics
without cultures and sensitivities that are still prescribed by some practitioners for chronic
wounds, may simply be ineffective in treating chronic wounds, especially in patients with
antibiotic resistance.36
Additional Infections. When an individual has another infection (e.g., viral, bacterial,
fungal, protozoal), monocytes can travel to peripheral tissues, including the area of the
chronic wound. Monocytes’ presence and their eventual differentiation to macrophages can
further reinforce inflammation and delay healing.37
Proinflammatory Conditions. Proinflammatory conditions, such as vasculitis and
rheumatoid arthritis, result in the release of proinflammatory cytokines (e.g., IL-1, IL-6, and
TNF-α), which, in turn, promote and prolong the inflammatory process.38
C-reactive protein (CRP) is a clinically validated marker of inflammation, and measuring
its values can be useful in determining the degree of systemic inflammation, as well as the
progress and effectiveness of treatments. Measuring systemic cytokines can also provide
much needed understanding of the extent of specific inflammatory proteins in individuals
with chronic wounds.
Compromised Immunity. An individual’s body’s lack of response to wound infection
may be due to compromised immunity that may impact wound healing. For example, patients
who are HIV positive with AIDS experience compromised immunity, because they have low
(<100) CD4+ T-cell counts.39 Low count in these white blood cells means limited protection
from infection and, thus, prolonged wound healing.40
Inadequate Circulation. Patients with circulatory problems (such as in diabetes mellitus
and chronic venous ulcers) have impaired tissue repair, because reduced blood flow leads to
limited oxygen supply for the wound.41 Since oxygen is imperative for collagen synthesis by
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fibroblasts and tissue regeneration, limited blood supply can further delay wound healing.42
Poor Nutrition and Hydration. The effects of a patient’s nutritional status can be
critical to an individual’s wound healing. Patients who have frequent diarrhea from
medications for their comorbidities (e.g., omeprazole for heartburn or stomach ulcers,
NSAIDs for arthritis, metformin for diabetes) can experience nutrient and water deficiencies.
Limited water and nutrient supply to the wound can undermine and hinder many of the
processes of healing, including epithelialization and collagen synthesis.43
Factors suggested to affect wound healing have been summarized in Box 5-7.

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 Wound Biofilms
Bacterial biofilms are known to contribute to numerous chronic inflammatory diseases, and
recent evidence suggests that biofilms also play an important role in impairing healing in
chronic skin wounds.44–48 Wound bacteria that grow in clumps embedded in a thick, self-
made, protective, slimy barrier of sugars and proteins are called a wound biofilm. Biofilms
are defined as complex, dynamic microbial communities made up of microorganisms
(bacteria and fungi) that synthesize and secrete a protective matrix that attaches the biofilm
firmly to the surface of the wound bed and also buried deeper under the surface of the wound
bed.48–50 They consist of a single bacterial or fungal species or, more commonly, may be
polymicrobial, that is, they contain multiple diverse species that are continuously changing.54
Biofilms trigger a chronic inflammatory response that results in the accumulation of
neutrophils and macrophages surrounding biofilms. The neutrophils and macrophages secrete
high levels of ROS that affect the biofilm and the surrounding tissue. Inflammatory cells also
secrete high levels of proteases (MMPs and elastase) that can help to break down the
attachments between biofilms and the tissue, dislodging the biofilms from the tissue.58
However, chronically elevated levels of proteases and ROS can also damage normal
surrounding tissue, proteins, immune cells, and tissue cells, impairing healing, as is the case
in most chronic wound beds.

Predisposing Factors for Development of Wound Biofilms

In vulnerable tissue, biofilms arise from planktonic bacteria attaching and forming a
protective community before they are killed by the patient’s immune system, by antibiotics,
or by debridement. Thus, general conditions that impair the immune system or reduce the
effectiveness of antibiotic drugs favor the development of biofilms in wounds. These
conditions include ischemia or necrosis of tissue; poor patient nutrition; comorbidities that
impair immune function, such as HIV, diabetes, major trauma, and radiation treatment; or
treatment with immune-suppressing drugs.

Assessment of Biofilms
The consensus guidelines for identification and treatment of biofilms in chronic and
nonhealing wounds59 states that “biofilms are present in most chronic wounds and are likely
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to be located both on the surface and in deeper wound layers, but may not be present
uniformly across or within the wound” (p. 745).59 Key consensus statements also confer that
“wounds that contain biofilms may not be identified, resulting in ineffective treatment and
delayed healing” (p. 745).59 In chronic wounds, it can be difficult to distinguish biofilms
from slough. “Wound biofilms are difficult to visualize macroscopically and slough, debris,
and exudate may be visually mistaken for biofilm” (p. 745).59 Wound slough has been
described as a viscous, yellow, and relatively opaque layer on wound beds, while biofilm
found in wounds can appear more gel-like and shiny.60 There is an important link between
biofilms and slough. Biofilms stimulate inflammation, which increases vascular permeability

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 and the production of wound exudate and buildup of fibrin slough.33 Therefore, slough may
indicate that biofilm is present in the wound. Unfortunately, chronic skin wounds are
frequently assessed with standard clinical microbiology laboratory assays that are designed to
culture single, planktonic bacteria, and they do not adequately measure biofilm bacteria.
Currently, the most reliable method to confirm the presence of microbial biofilm is
specialized microscopy.61–65 An analysis using special cultivation techniques of biopsies
from chronic wounds found that 60% of the specimens contained biofilm structures in
comparison with only 6% of biopsies from acute wounds.47 A recent meta-analysis of
published papers that reported on various aspects of chronic wounds found that on average,
about 80% of chronic wounds had strong evidence of bacterial biofilms in samples collected
from the chronic wounds.66

Management of Biofilms
Antibiotics and antiseptics kill single bacteria very easily, but the biofilm matrix can reduce
penetration of most chemically reactive antiseptic molecules from reaching all the bacteria,
particularly in the center of the biofilm matrix by chemically reacting with and neutralizing
the antiseptic molecule, which has been called the “reaction–diffusion problem.” In addition,
some bacteria in mature biofilms become metabolically dormant, which is important because
antibiotics typically only kill metabolically active bacteria by interfering with essential
bacterial processes like cell wall synthesis, energy production, synthesis of proteins, DNA, or
RNA.67 Therefore, bacteria in biofilms become very tolerant to most antibodies, antibiotics,
disinfectants, and phagocytic inflammatory cells. Wound biofilms can be effectively treated
by a combination of debridement and/or cleansing to remove the biofilms, followed by
application of dressings that block new bacteria from reaching the wound and killing bacteria
left in the wound bed. This concept for treatment of chronic wounds that likely have biofilm
bacteria has been termed “biofilm-based wound care”.68,69 These treatments can heal
wounds, but patients must comply with the treatment plan because biofilms can reform
within a couple of days and the wound will not heal.70 The consensus guidelines for
identification and treatment of biofilms in chronic and nonhealing wounds states that
“important indicators that a wound is likely to contain a biofilm include recalcitrance to
treatment with antibiotics or antiseptics” (p. 745).59
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An ex vivo porcine skin explant biofilm model that preserves key properties of biofilm
attached to skin at different levels of maturity (0 to 3 days) was used to assess the efficacy of
commercially available antimicrobial dressings and topical treatments.71 Five types of
antimicrobial agents (iodine, silver, polyhexamethylene biguanide, honey, and ethanol) and
four types of moisture dressings (cotton gauze, sodium carboxymethylcellulose fiber, calcium
alginate fiber, and cadexomer beads) were assessed. Time-release silver gel and cadexomer
iodine dressings were the most effective in killing mature biofilm, reducing the level of
biofilm-protected bacteria between 105 and 107 colony-forming units (CFUs) for a total of
107 CFUs of biofilm bacterial. In contrast, all other dressing formulations reduced biofilm

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 between 100.3 and 102 log CFUs in 24 or 72 hours with a single exposure. Similar results
were found after 24-hour exposure to silver-release dressings using an in vivo pig burn
wound model, demonstrating correlation between the ex vivo and in vivo models. These
results indicate that commonly used microbicidal wound dressings vary widely in their
ability to kill mature biofilm, and the efficacy is influenced by time of exposure, number of
applications, moisture level, and the formulation of the microbicide, which sustained release
formulations providing improved killing.71 Consensus guidelines for identification and
treatment of biofilms in chronic and nonhealing wounds states that “debridement is one of
the most important treatment strategies against biofilms, but does not remove all biofilm, and
therefore cannot be used alone—this is one of the critical principles of wound bed
preparation (tissue, infection/inflammation, moisture balance, and edge of wound) (p. 745).59
Biofilms can reform rapidly; repeated debridement alone is unlikely to prevent biofilm
regrowth, however, effective topical antiseptic application within the time-dependent window
can suppress biofilm reformation” (p. 745).59 These factors have led to an expansion of the
original principles of biofilm-based wound care to now include the concept of “step-down
then step-up” treatment strategy for chronic wounds.59 Basically, this strategy emphasizes to
initiate treatment of chronic wounds that are suspected to have biofilm with the treatments
that are most effective at removing biofilms—especially sharp debridement—combined with
the topical and systemic treatments that are most effective at killing and removing biofilm
bacteria. As the biofilm bioburden becomes reduced, the level of inflammation will reduce,
which will lead to reduction on ROS and proteases in the wound bed. Treatment of the
wound bed can then “step-down” to less frequent debridement and to dressings that can
effectively kill and reduce planktonic bacteria. As the wound begins to heal, the decision can
be made to “step-up” the treatment strategy and use advanced wound treatments such as
growth factors, biologically active cell and tissue products, or skin grafts that can
dramatically stimulate healing because the wound bed has been properly prepared and these
protein-based/cell-based advanced treatments will work well because the levels of ROS and
proteases in the wound bed are too low to degrade the advanced treatment products.59

Wound Bed Preparation

The TIME acronym (Tissue, Infection/Inflammation, Moisture balance, and Edge of
wound) was first developed more than 15 years ago, by an international group of wound
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healing experts, to provide a framework for a structured approach to wound bed preparation,
a basis for optimizing the management of open chronic wounds healing by secondary
intention.72 The framework was therefore termed “wound bed preparation” and was
subsequently published in 2003 by Schultz and colleagues.73 Since then, the TIME acronym
has been widely used as a practical guide for the assessment and management of chronic
wounds. The clinical observations and interventions relating to wound bed preparation are
grouped into four areas, all of which need to be addressed at each wound assessment:
Tissue: assessment and debridement of nonviable or foreign material (including
host necrotic tissue, adherent dressing material, multiple organism–related biofilm

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 or slough, exudate, and debris) on the surface of the wound
Infection/Inflammation: assessment of the etiology of each wound, need for topical
antiseptic and/or systemic antibiotic use to control infection, and management of
inappropriate inflammation unrelated to infection
Moisture imbalance: assessment of the etiology and management of wound
exudate
Edge of wound: assessment of nonadvancing or undermined wound edges (and
state of the surrounding skin)
However, it should be recognized that the TIME principles are only a part of the systematic
and holistic evaluation of each patient at every wound assessment. An article by Leaper et
al.72 examines how new data and evidence generated in the intervening decade impact on the
original concepts of TIME and how they are translated into current best practice (Table 5-3).

Table 5-3 Summary Table of Developments Within the TIME Concept

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Copyright © 2020. Wolters Kluwer Health. All rights reserved.

Baranoski, Sharon, and Elizabeth A. Ayello. Wound Care Essentials, Wolters Kluwer Health, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/mcgill/detail.action?docID=6676900.
Created from mcgill on 2023-09-19 21:55:34.
 From Gould, L., Abadir, P., Brem, H., et al. “Chronic Wound Repair and Healing in Older Adults: Current Status and
Future Research.” Wound Repair and Regeneration 23(1):1-13, 2015. doi: 10.1111/wrr.12245.

Practice Point
The TIME framework can be used to provide a basis for discussion of wound assessment
and treatment goals with the patient.
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A summary of their findings for each element of the TIME principles is as follows72:
1. Tissue: A major advance has been the recognition of the value of repetitive and
maintenance debridement and wound cleansing, both in time-honored and novel
methods (notably using negative pressure wound therapy [NPWT] and hydrosurgery).
2. Infection/Inflammation: Clinical recognition of infection (and noninfective causes of
persisting inflammation) is critical. The concept of a bacterial continuum through
contamination, colonization, and infection is now widely accepted, together with the
understanding of biofilm presence. There has been a return to topical antiseptics to

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 control bioburden in wounds, emphasized by the awareness of increasing antibiotic
resistance. Recognition of the importance of biofilms (and the need for a simple
diagnostic), use of NPWT, evolution of topical antiseptic therapy as dressings and for
wound lavage (notably, silver and polyhexamethylene biguanide), and expanded
insight of the role of molecular biological processes in chronic wounds (with emerging
diagnostics and theranostics).
3. Moisture: The relevance of excessive or insufficient wound exudate and its molecular
components has led to the development and use of a wide range of dressings to
regulate moisture balance, to protect periwound skin, and to optimize healing.
4. Edge of wound: Several treatment modalities are being investigated and introduced to
improve epithelial advancement, which can be regarded as the clearest sign of wound
healing.

Practice Point
In addition to the TIME assessment of the wound, there should be an evaluation of the
surrounding skin as this can provide valuable information to determine whether the wound
is progressing or deteriorating.

Symptoms and Symptom Clusters Associated with

Chronic Wounds
The communication between the brain and peripheral immunity is essential to regulating
stress and altering behaviors.51 Some examples demonstrate that immune molecules such as
cytokines induced by T cells directly affect pain,52 cognition,53 and sickness behaviors.
Sickness behaviors such as pain and fatigue, depression, and anxiety are common in people
who are undergoing illness.51,52 People with chronic wounds experience both psychological
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distress and sickness behaviors.54–57

Symptoms frequently accompany individuals with chronic wounds.74,75 Many patients
experience four or more concurrent symptoms, which frequently include pain, fatigue,
anxiety, depression, and sleep disturbances.

Pain
Pain commonly affects many individuals with chronic wounds and greatly complicates their
ability to care for their wound and perform self-care.76 Pain may result in delay of treatment

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 and reduce quality of life.74,75,77–80 Furthermore, pain associated with chronic wounds is
often not adequately identified or treated, which may result in delay in wound healing.74,81,82

Cognitive Changes, Fatigue, Depression, and Anxiety

Many individuals with chronic wounds also experience cognitive changes, fatigue,
depression, and anxiety that may also occur with pain.75 Chronic pain, anxiety, and
depressive symptoms may also impair cognitive abilities.81 There is increasing evidence that
individuals with chronic wounds experience both event-related pain and somatic pain.82
Depression has also been associated with delayed wound healing.83,84 Though pain and
cognitive/affective symptoms contribute to outcomes in chronic wounds, there is a paucity of
research that focuses on symptoms in individuals with chronic wounds, which requires future
study.

Summary
The molecular and cellular environment of chronic wounds differs substantially from that of
acute healing wounds. Specifically, nonhealing wounds have chronically elevated
proinflammatory cytokines, which lead to chronically elevated levels of proteases (MMPs
and neutrophil elastase) and ROS that degrade the components that are essential to healing,
such as ECM components, growth factors, and receptors. Wound bed preparation is an
overarching concept, applied in clinical practice using the TIME framework, which can help
clinicians to determine whether a wound is progressing or deteriorating.
A number of host factors including age, disease burden, sex, race/ethnicity, compromised
immunity, medications, BMI, nutritional status, and lifestyle habits including smoking have
been shown to affect wound healing. Bacterial biofilms also play an important role in
impairing healing in chronic skin wounds. There appear to be common symptoms/symptom
clusters associated with wounds, which frequently include pain, fatigue, anxiety, depression,
and sleep disturbances, which need to be addressed as part of the comprehensive
management of the patient.
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PATIENT SCENARIO
Clinical Data
Mrs. A is a 72-year-old woman who collapsed at home, catching her right shin on a coffee
table. She was taken to hospital for investigation of the cause of her fall. She had extensive
bruising and a hematoma on her right lower leg. On further investigation, she was found to
have a lower respiratory tract infection, and she was admitted for treatment of this. Mrs. A
is a smoker and has chronic obstructive pulmonary disease (COPD) and ischemic heart
disease. She is on dual antiplatelet therapy following a myocardial infarction and coronary
artery stents earlier in the year. She frequently takes oral steroids for infective exacerbations

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 of her COPD.

Case Discussion
Mrs. A’s leg was initially managed conservatively because of her chest infection; however,
5 days later, it became increasingly painful, and the skin around the hematoma was
erythematous and hot. She was referred to the trauma surgeons, who diagnosed infection of
the hematoma, and elected to evacuate it, creating an open wound on her leg (Fig. 5-2A). At
this stage, there is an acute surgical wound, but one that would be classified as Class IV
(dirty/infected) according to the Centers for Disease Control classification.85
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 Figure 5-2. (A) Hematoma post evacuation. (B) Post treatment with topical
antimicrobial dressings.

Following her procedure, negative pressure wound therapy was applied to her leg.
Microbiology samples sent from the operating room were used to guide antibiotic therapy,
but once the infected hematoma had been drained, the erythema settled quickly.
Multidisciplinary input was required to make a plan going forward for Mrs. A’s
management.86 In order to make a plan for her wound management, her other medical
problems, as well as the underlying causes of the wound, were considered.86 Split skin
grafting (SSG) was not carried out at her initial operation because of the infection present.
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While it was felt that a successful SSG would decrease the time taken for the wound to heal,
there were factors present that increased the risk of graft failure. Mrs. A did not feel she
would be able to stop smoking, and she did not want to have a second wound on her leg.
Mrs. A’s skin quality had been affected by the multiple courses of steroids she had taken for
her lung disease. Additionally, the risks of stopping Mrs. A’s anticoagulant medications
were thought to outweigh the benefits, and this increased the risk of bleeding at the donor
site. It was therefore decided that SSG would not be attempted and the tissue viability
nurses/WOC nurse took the lead in the care of Mrs. A’s leg.
The wound initially progressed well with the NPWT; however, there was evidence of

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 damage in the fragile periwound skin, despite the use of barrier creams. NPWT was
therefore discontinued, and a Hydrofiber primary dressing was applied to manage the
exudate. At each visit, the nurses measured the wound to assess progress. The wound
became static, with no reduction in size over 5 weeks. On examination at this time, the
wound bed was covered with a gelatinous slough. While there were no signs of spreading
infection (cellulitis, malaise), the wound edge appeared inflamed. By this point, the wound
would be classified as chronic, because of its duration, and the lack of progression through
the stages of wound healing as expected. The measurements also indicated it had become a
nonhealing wound. It was thought that the bioburden in the wound may be arresting the
normal healing process. Debridement of the wound bed was therefore undertaken. Topical
local anesthetic cream was used to enable sharp debridement with a ring curette. A
polyhexamethylene biguanide–containing wound cleanser was also used at dressing
changes between debridement procedures. An absorbent antimicrobial dressing (silver-
containing Hydrofiber) was applied. The wound began to make progress again, with
evidence of neoepithelialization at the wound edge and contraction (Fig. 5-2B). The
antimicrobial dressings were discontinued, and the wound continued to make progress.

Show What You Know

1. Which of the following would be considered abnormal in the inflammatory phase
of wound healing?
A. Redness
B. Bleeding
C. Pain
D. Swelling
E. Heat

2. Wound biofilm can be effectively treated by:

A. debridement.
B. cleansing.
C. dressings to block new bacteria and kill existing bacteria.
D. antibiotics.
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E. a combination of debridement, cleansing, and dressings.

3. Chronic wounds and comorbidities are associated with systemic inflammation, and
evidence indicates that the clinician should assess for:
A. sickness behaviors that may include pain, fatigue, depression, sleeping
difficulties, and cognitive changes.
B. symptom clusters that have been identified in individuals with chronic wounds.
C. pain that commonly affects many individuals with chronic wounds and ability to
care for their wound and perform self-care.

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 D. all of the above.

Answers to these questions are found on page 682.

References
1. Demidova-Rice, T.N., Hamblin, M.R., Herman, I.M. “Acute and Impaired Wound Healing: Pathophysiology and
Current Methods for Drug Delivery, Part 1: Normal and Chronic Wounds: Biology, Causes, and Approaches to
Care.” Advances in Skin and Wound Care 25(7):304-14, July 2012.
2. Baum, C.L., Arpey, C.J. “Normal Cutaneous Wound Healing: Clinical Correlation with Cellular and Molecular
Events.” Dermatologic Surgery 31:674-86, June 2005.
3. Schultz, G.S., Davidson, J.M., Kirsner, R.S., et al. “Dynamic Reciprocity in the Wound Microenvironment.” Wound
Repair and Regeneration 19:134-48, 2010.
4. Gill, G.E., Parks, W.C. “Metalloproteinases and Their Inhibitors: Regulators of Wound Healing.” The International
Journal of Biochemistry & Cell Biology 40:1334-47, 2008.
5. Midwood, K.S., Williams, L.V., Schwarzbauer, J.E. “Tissue Repair and the Dynamics of the Extracellular Matrix.”
The International Journal of Biochemistry & Cell Biology 36:1031-7, 2004.
6. McAnulty, R.J. “Fibroblasts and Myofibroblasts: Their source, Function and Role in Disease.” The International
Journal of Biochemistry & Cell Biology 39:666-71, 2007.
7. Li, J., Chen, J., Kirsner, R. “Pathophysiology of Acute Wound Healing.” Clinics in Dermatology 25:9-18, 2007.
8. Venus, M., Waterman, J., McNab, I. “Basic Physiology of the Skin,” Surgery 28(10):469-72, 2010.
9. Li, J., Zhang, Y.P., Kirsner, R.S. “Angiogenesis in Wound Repair: Angiogenic Growth Factors and the Extracellular
Matrix.” Microscopy Research and Technique 60:107-14, 2003.
10. Diegelmann, R.F., Evans, M.C. “Wound Healing: An Overview of Acute, Fibrotic and Delayed Healing.” Frontiers
in Bioscience 9:283-9, January 2004.
11. Stavrou, D., Haik, J., Weissman, O., et al. “From Traction and Contraction to Wound Closure.” Journal of Wound,
Ostomy & Continence Nursing 36(4):365-6, July/August 2009.
12. Desmoulière, A., Chaponnier, C., Gabbiana, G. “Tissue Repair, Contraction, and the Myofibroblast.” Wound Repair
and Regeneration 13:7-12, 2005.
13. Bates-Jensen, B.M., Woolfolk, N. “Acute Surgical Wound Management.” In C. Sussman, B.M. Bates-Jensen, eds.
Wound Care: A Collaborative Practice Manual for Health Professionals. Baltimore, MD: Lippincott Williams and
Wilkins, 2007:322-35.
14. Sussman, C., Bates-Jensen, B.M. “Wound Healing Physiology: Acute and Chronic.” In C. Sussman, B.M. Bates-
Jensen, eds. Wound Care: A Collaborative Practice Manual for Health Professionals. Baltimore, MD: Lippincott
Williams and Wilkins, 2007:21-51.
15. Lazarus, G.S., et al. “Definitions and Guidelines for Assessment for Wounds and Evaluation of Healing.” Archives
of Dermatology 130(4):489-93, April 1994.
16. Fletcher, J. “Differences between Acute and Chronic Wounds and the Role of Wound Bed Preparation.” Nursing
Standard 22(24):62-8, 2008. Available at: http://rcnpublishing.com/doi/abs/10.7748/ns2008. 02.22.24.62.c6412.
17. NHS. “Treatment: Venous Leg Ulcer.” 2019. Available at: https://www.nhs.uk/conditions/leg-ulcer/treatment/
18. Guo, S., DiPietro, L.A. “Factors Affecting Wound Healing.” Journal Dental Research 89(3):219-29, 2010.
Copyright © 2020. Wolters Kluwer Health. All rights reserved.

19. Doughty, D. “Why Won’t Some Wounds Heal.” Advances in Skin & Wound Care 17(7):342-4, September 2004.
20. Widgerow, A.D. “Deconstructing the Stalled Wound.” Wounds 24(3):58-66, March 2012.
21. Phillips, T.J., et al. “Effect of Chronic Wound Fluid on Fibroblasts.” Journal of Wound Care 7(10):527-32, November
1998.
29. Hart, J. “Inflammation 2: Its Role in the Healing of Chronic Wounds.” Journal of Wound Care 11:245-9, July 2002.
30. Yager, D.R., Nwomeh, B.C. “The Proteolytic Environment of Chronic Wounds.” Wound Repair and Regeneration
7(6):433-41, November-December 1999.
31. Ligi, D., Mosti, G., Croce, L., et al. “Chronic Venous Disease—Part I: Inflammatory Biomarkers in Wound Healing.”
Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease 1862(10):1964-74, 2016.
32. Barrientos, S., Stojadinovic, O., Golinko, M.S., et al. “Growth Factors and Cytokines in Wound Healing.” Wound
Repair and Regeneration 16(5):585-601, 2008.
33. Ågren, M.S., Steenfos, H.H., Dabelsteen, S., et al. “Proliferation and Mitogenic Response to PDGF-BB of

Baranoski, Sharon, and Elizabeth A. Ayello. Wound Care Essentials, Wolters Kluwer Health, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/mcgill/detail.action?docID=6676900.
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Baranoski, Sharon, and Elizabeth A. Ayello. Wound Care Essentials, Wolters Kluwer Health, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/mcgill/detail.action?docID=6676900.
Created from mcgill on 2023-09-19 21:55:34.