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levels of TGF-β1 are associated with pathologic and hypertrophic
scarring.
Scarless Wound Healing
In the early gestation fetus and in the oral mucosa of mammals,
wounds heal without scars; healed fetal skin is identical to uninjured
tissue, including for skin appendages (eg, hair follicles, sebaceous
glands, and sweat glands). “Scarless” healing and tissue
regeneration, including limb regrowth, are reported in several
animals (eg, axolotls and salamanders), and—in specific cases—in
adult mammals (eg, rodents’ digits). Humans seem to lose their
“scarless” ability at 24 weeks of gestation. Fetal healing has a less
robust inflammatory reaction (cell migration and cytokines such as
IL-6, IL-8, TGF-β1, and TGF-β2), a higher fibroblast activity (higher
ratio of type III to type I collagen and hyaluronic acid), and an
absence of myofibroblasts. Similar differences occur in the oral
mucosa of adult humans, because of intrinsic characteristics of
mucosal cells.
3
Impaired Healing and Risk Factors
Several patient-related or external factors can alter, delay, and halt
normal healing; these factors must be identified through a
comprehensive and holistic assessment of each patient and wound.
Factors to assess include:
genetic factors: hereditary healing disorders, disorders of
collagen and connective tissue, sickle cell disease, etc.;
patient-related factors: age, genetic sex, sex hormones,
stress and cortisol levels, obesity, possibility of self-harm
(including Munchausen syndrome), etc.;
local conditions: cutaneous diseases, skin infection and
biofilm presence, dysregulation of skin microbiome,
mechanical tension, tissue ischemia, peripheral vascular
disease, radiation, prolonged and excessive pressure,
presence of a foreign body or debris, prior long-standing
injury/scar (including risk for Marjolin ulcer), etc.;
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systemic conditions: cancer, immunodeficiency, diabetes,
chronic inflammatory status, rheumatologic conditions,
metabolic disease, etc.;
concurrent pharmacologic therapies: glucocorticoid steroids,
nonsteroidal anti-inflammatory drugs (NSAIDs),
chemotherapy, etc.;
metabolic status: malnutrition and/or nutritional deficiencies,
vitamin deficiencies, etc.;
substances: use of supplements, smoking, alcoholism,
addictive drugs, etc.
A detailed discussion of each of these and other factors goes
beyond the scope of this chapter.
Nonhealing “Chronic” Wounds
There is no absolute consensus on the correct definition of a CW;
these are commonly described as a failure to progress toward
gradual, timely, and functional closure. CW have a high rate of
recurrence (eg, 40% of diabetic wounds and 70% of venous wounds
within 12 months).
4,5
Although any wound, in the presence of risk factors, might become
chronic, four categories of CW are commonly identified by etiology:
vascular (arterial, venous, and mixed etiology), diabetic, pressure,
and cutaneous radiation CW. These CW share common pathologic
processes including exaggerated and persistent inflammation,
hyperproliferative and nonmigratory epidermis, limited proliferation
and migration of other cell types, microbial colonization or infection
and biofilm formation, dysregulated proteases, senescent fibroblasts,
poor tissue perfusion and oxygenation, and reduced stem cell
recruitment and activation. Below we provide an overview of the
characteristics of these CW (cutaneous radiation injuries and
pressure ulcers are discussed in Chapters 20: Radiation and
Radiation Injury and 113: Pressure Sore Management).
Vascular CW include venous (70% of cases), arterial (10%), or
mixed (15%) etiology, with the remaining cases caused by less
common diseases.
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Venous CW
These are the most common CW (after pressure ulcers). Estimated
prevalence is 1.5 to 3/1000 persons, and CW are more common in
women and the elderly. In individuals aged 65 years or older,
prevalence can reach 5% (yearly incidence of 1.2%). Valvular
incompetence of veins in lower extremities drives backflow of blood
and increased venous pressure, which leads to endothelial
inflammation and capillary leakage of plasma constituents (eg, fibrin,
hemosiderin). This causes lipodermatosclerotic alterations of soft
tissues and ultimately ulceration. Venous CW are typically located
above the medial malleolus, have irregular edges, and tend to be
superficial; clinical presentation is accompanied by visible varicose
veins and tissue edema. The wound bed is yellow/pale red (because
of the deposition of leaked fibrin) and exudate is common.
Surrounding skin is indurated and hyperpigmented because of
fibrosis. Pain is not always present.
Arterial CW
These are less common than venous CW, although peripheral
arterial disease (PAD) affects one-third of patients over 65 years
(>200 million people worldwide). Arterial CW are most often caused
by atherosclerotic narrowing or occlusion of arterial vessels,
especially in the lower extremities. Other less frequent causes
include embolism, vasculitis, pyoderma gangrenosum, and
hematological disorders (eg, sickle cell disease and thalassemia).
Narrower calcified vessels decrease perfusion of tissues, ultimately
causing ulceration and necrosis. Arterial CW have a punched-out
appearance and are classically located on the lateral side of the
lower leg and/or distally and over bony prominences (eg, toes, heels,
and ankles). Poor proximal (femoral/popliteal) and distal (dorsalis
pedis/posterior tibial) pulses by palpation or Doppler examination are
present. Arterial CW usually have a smaller size compared to
venous CW but extend deeper (involving muscles, tendons, and
bones) and are more painful. The wound bed has necrotic eschars,
while the surrounding skin has signs of atrophy, with pale color and
loss of hair.
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Diabetic CW: These are extremely common in individuals with
diabetes, with a worldwide incidence among these individuals as
high as 41 cases/100 person-years. Among these patients, 3% will
develop a CW each year, and 15% during their lifetime. A diabetic
CW carries a >10-fold increased risk of LEA and a two/threefold
increased risk of death. Diabetic CW form because of abnormal
chronic inflammation (increased levels of proinflammatory cytokines,
such as IL-1, IL-6, and TNF-α), nonenzymatic binding of sugar
residues to proteins and advanced glycation end products, damage
to endothelia of capillaries and consequent inadequate perfusion and
tissue hypoxia, and higher levels of free radicals. Hyperglycemia
enhances expression of MMPs, leading to changes of the ECM that
exacerbate inflammation and impair angiogenesis, cell migration,
and proliferation. Depending on the predominant mechanism of
injury, diabetic CW can be categorized as neuropathic, ischemic, or
neuroischemic. Neuropathic CW occur in areas of high pressure on
the plantar surface of the foot (typically the metatarsal head) and
might follow initial distortion of the bony structure (Charcot foot) and
callus formation; peripheral neuropathy prevents individuals from
sensing excessive pressure (positional, shoes, etc.) that compresses
tissues, leading to a CW. Callus formation creates focal points of
heightened pressure leading to tissue injury that goes undetected
because of poor sensation. Ischemic CW are similar to arterial CW
and present with skin atrophy, a necrotic eschar, and reduced or
absent distal pulses. Undermining and infection are frequent, often
reaching bones and causing osteomyelitis.
Other Conditions
Numerous other conditions can lead to CW. Traumatic orthopedic
wounds with internal fixation might not heal when osteomyelitis or
biofilm on the orthopedic hardware is present: removal of infected
hardware, bone debridement, long-term antibiotics, and/or use of
antibiotic-impregnated cement will permit healing. Chronic and
subacute osteomyelitis requires prolonged antibiotic treatment (six or
more weeks) and an antibiotic-free period before bone cultures to
confirm eradication of infection. Aggressive malignancy (primary
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cutaneous, infiltrating, or metastatic) can cause ulcerated and
fungating CW; concerted discussion with patients, their families, and
all involved healthcare professionals will guide decision-making and
define whether palliative treatment/wound care or wound resection
and coverage are advised in the best interest of patients. Evidencebased guidelines and established protocols are lacking. Some
palliative oncologic treatments (eg, chemotherapy or radiation
therapy) can decrease tumor—and hence CW—size. Other
conditions not discussed in detail here include vasculitis,
hypertension (Martorell ulcer), self-harm (eg, Munchausen
syndrome), infections (eg, Buruli ulcer [Mycobacterium ulcerans
infection]), metabolic disease (eg, gout, prolidase deficiency),
pyoderma gangrenosum, calciphylaxis, hematologic disorders (eg,
cryofibrinogenemia, cryoglobulinemia, sickle cell disease),
necrobiosis lipoidica diabeticorum, neuropathic CW (eg,
syringomyelia), and hidradenitis suppurativa.
Infections and Microbiome in Wound Healing
Infection significantly determines healing rates of surgical wounds
(surgical site infections), traumatic wounds, and CW. Multiple
pathogens responsible for wound infections are now resistant to
standard antibiotics. Cost of care for wound infections has been
growing steadily.
Pathogens colonize wounds either migrating from the patients’
own microbic flora or through contamination by water or soil/dirt.
Gram-positive bacteria (eg, Staphylococcus aureus, Enterococcus
spp.) and gram-negative organisms (eg, Pseudomonas aeruginosa,
Acinetobacter spp.)—including fungi (eg, Candida spp. and
Aspergillus spp.)—can cause acute wound infections, impairing local
healing, and cause life-threatening systemic diseases. CW have
polymicrobial colonization organized in biofilms (a complex
consortium of multiple colonies of pathogens embedded in a matrix
of polymeric extracellular DNA, proteins, and polysaccharides, which
are adherent to poorly vascularized surfaces) that protect pathogens
from immune response and antimicrobial therapy. Fungi can
significantly contribute to biofilm formation.
6
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Differently from external pathogens, the normal cutaneous
microbiome has an important role in promoting healing and their
dysregulation contributes to the formation of a CW; additional
research is needed to better elucidate how cutaneous microbiota
cross talks with host cells in CW.
PRINCIPLES OF MANAGEMENT OF ACUTE
WOUNDS
Management of acute wounds must take care of all patient-related,
wound-related, and external factors that impair the normal course of
healing. Modifiable factors should be included in the therapeutic plan
(eg, nutritional and vitamin supplementation, smoking cessation,
relief of patient’s stress). Risk of infection should be contemplated
and prophylactic antibiotic coverage prescribed when needed. Pain
must be controlled, for patients’ well-being and to support healing
both directly (biological mechanism) and indirectly (patient
adherence to prescribed care).
Dressings should maximize patients’ comfort and their ability to
return rapidly to routine activities. For example, cyanoacrylate-based
adhesives help wound closure while providing wound sealing for
better comfort and easier wound management at home. When there
is a risk for tension, advanced dressing and devices that release
mechanical stress from wound edges are recommended (taping also
has benefits); consistently, wound offloading is essential. Reversely,
the biological effects of mechanical forces on tissues can be
leveraged to support and facilitate healing in wounds at higher risk
for dehiscence (closed incision negative pressure therapy).
MANAGEMENT OF CW
Primary Prevention
Primary prevention is the pillar of modern CW care and the most
cost-effective approach for individuals and healthcare systems. For
general recommendations, adherence to a healthy lifestyle (eg,
healthy body weight, moderate-to-vigorous physical activity, high-
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quality diet, no alcohol drinking or smoking) before and after a
diagnosis of diabetes is associated with a lower risk of CW, and
similar findings are reported for CW of other etiologies. Other
general recommendations include avoid trauma to tissues, minimize
prolonged sitting/standing, elevate legs often, use comfortable
footwear (eg, avoid high heels), and apply emollients to keep skin
moist. Control of stress, emotional health, and sleep quality are also
important.
7
Etiology-specific recommendations also exist (pressure ulcers, for
which frequent repositioning and use of specialized pressurereducing surfaces/mattresses is critical, are discussed in Chapter
113: Pressure Sore Management). For patients with venous
insufficiency, compression therapy (graduated compression
stockings or compression bandages) to support venous return and
mitigate venous pooling is a cornerstone of both prevention and
therapy. Multicomponent devices with an elastic are superior to
inelastic wraps, and compression should be at up to the knee or
thigh, and at about 20 to 30 mm Hg. For patients with PAD, exercise
rehabilitation therapy is the most effective preventive measure, also
improving glucose metabolism, cholesterol levels, and
cardiovascular fitness. For patients with diabetes, offloading and
pressure relief with custom footwear, orthotics, and contact casting is
essential; removal of calluses also reduces focal plantar pressure.
8
In high-risk cases, prophylactic surgical intervention is
recommended. In patients with venous insufficiency, prophylactic
superficial venous surgery (open or endovenous ablation) has been
suggested, but there is no definitive evidence that it can reduce
incidence of CW (instead, therapeutic surgery has a positive effect
on healing and recurrence). In patients with diabetes, prophylactic
lengthening of contracted tendons can decrease points of focal
pressure; removal of osseous prominences of the foot or ankle has
also been suggested in patients with Charcot arthropathy. Lower
extremity revascularization (eg, bypass grafts to pedal arteries or
endovascular angioplasty) improves distal perfusion in patients with
PAD or diabetes; robust studies on the preventive effects of
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prophylactic treatment are missing, but initial evidence suggests a
beneficial role.
Prevention should include patient education, multidisciplinary
screening, and regular evaluations, which significantly reduce rates
of CW formation and CW severity or complications. In high-risk
individuals, compliance with a screening/education program can
reduce risk of developing a CW by up to 54 times and risk of a future
LEA by up to 20 times. Patient education can discuss behavioral
changes and the need for a healthy lifestyle, foot care, or knowledge
on CW and their complications, using various formats (lectures,
workshops, exercises, behavioral programs, etc.). Screening
emphasizes the need for routine interaction, education, and
collaboration with primary care clinicians. Annual foot exams are
recommended for patients with diabetes and PAD. Screening for
peripheral neuropathy is essential: Semmes-Weinstein monofilament
testing on four plantar sites on the forefoot identifies 90% of patients
with sensation loss, but a biothesiometer or a simple tuning fork can
also be used. Plantar pressure distribution can be screened using
load-measuring mats or shoe insoles. PAD is usually screened using
an ankle-brachial index (ABI), with a value of 0.90 or less strongly
association with risk of CW; transcutaneous oximetry is also
reported.
9
Diagnosis, Assessment and Staging, and
Longitudinal Monitoring
Diagnosis: Clinical evaluation is critical for diagnosis of wound
etiology and diagnostic suspicion of wound infection. This includes
patient history, characteristics of the CW (eg, location, appearance,
changes to surrounding tissues, pain, edema, odor, other associated
symptoms), and a vascular assessment (eg, peripheral pulses). The
sensitivity of a nondetectable pulse for PAD is 32%, whereas the
specificity is close to 99%; additional vascular tests include
time/delay in capillary refill response and the Buerger test. Patient
evaluation is particularly important in cases of atypical CW to timely
guide specific testing and assessments aimed at identifying the
underlying primary etiology and establishing appropriate primary
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treatment. In some CW, it is also critical to have a high suspicion for
malignancy (either as a direct cause of the CW or because of a CW)
so that proper diagnostic cancer workup and treatment are started.
Marjolin ulcers are aggressive malignancies (most commonly
squamous cell carcinomas) that arise after 30+ years in previously
injured skin, long-standing scars, and CW; early recognition and
treatment by excision are pivotal as prognosis is poor and
recurrence is high.
Imaging supports diagnosis and staging. Duplex ultrasonography
can identify incompetent perforators in venous insufficiency. Arterial
insufficiency can be studied with standard digital camera, thermal
cameras, continuous wave Doppler ultrasonography (monophasic or
absent sounds in PAD), ankle-brachial pressure index (ABI) (a ratio
of ≤0.8 indicates poor perfusion but endothelial calcification can
make ABI unreliable in most severe cases), and transcutaneous
oximetry (TcPO2) (time-consuming and most helpful in diabetic CW;
<40 mm Hg indicates poor perfusion). Less common techniques
include hyperspectral imaging, optical coherence tomography, laser
Doppler imaging, fluorescence imaging, and near-infrared
spectroscopy spectroscopy.
Invasive imaging includes CT angiography with intravenous
contrast timed for arterial enhancement or digital subtraction
angiography (allows simultaneous endovascular intervention).
Single-photon emission computed tomography/CT can also assess
peripheral perfusion. Magnetic resonance angiography is an
alternative to study tissue perfusion without the risk of radiation, but
its resolution is limited. Standard CT can study involvement of bone
and joints, but MRI is the preferred method to assess involvement of
both soft-tissue and bone pathology, given its higher sensitivity for
detection of infection (eg, osteomyelitis). Specifically for diabetic CW,
weight-bearing x-rays of the foot/ankle can identify foreign bodies,
bone deformities, Charcot arthropathy, or even chronic osteomyelitis
(non–weight-bearing radiographs do not topographically correlate
the wound with the bony issue).
10
Bacterial swab with quantitative processing can diagnose
infection, although their role in guiding antibiotic selection is debated
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because of the high rates of wound colonization and biofilm
presence.
Sensory evaluation for neuropathy (eg, Semmes-Weinstein
monofilament testing) is warranted for CW in diabetic patients.
Wound biopsies are usually not needed for initial diagnosis, but
can be considered for recurrent and recalcitrant CW or for CW of
uncertain etiology/atypical wounds (eg, rheumatologic, pyoderma
gangrenosum, calciphylaxis) or possibly because of a malignancy.
Cultures and histology of bone biopsies are the standard to confirm a
diagnosis of osteomyelitis; genetic sequencing is a new technique
that can further improve diagnostic accuracy in these cases.
Standard biochemical tests that can guide diagnosis and initial
patient assessment include blood glucose and hemoglobin A1c
(diabetes), hemoglobin (hematological disorders), urea and
electrolytes, serum prealbumin/albumin and transferrin (nutritional
deficiencies), lipids, rheumatoid factor, autoantibodies, white blood
cell count, erythrocyte sedimentation rate (osteomyelitis), C-reactive
protein, and renal (renal failure is a risk factor for LEAs) and liver
function tests. In complex cases or for research, biomarkers from the
serum or from the wound fluid can be measured to diagnose, stage,
or monitor the progression of specific wounds. Among studied
biomarkers, there are TNF (venous ulcers and pyoderma
gangrenosum), osteopontin (calciphylaxis), MMP13 (venous ulcers),
and others.
Assessment and staging: Numerous classification, staging, and
scoring systems for CW exist. These systems aim to guide clinical
decision-making, objectively monitor response to treatment and
clinical outcomes, and provide reliable data for research and quality
improvement.
11,12
The Society for Vascular Surgery (SVS) WIfI system is based on
three factors (wound, ischemia, and foot infection) with a 4-grade
scale to each factor: the combined score estimates risk of LEA at
1 year and/or the need for/benefit of revascularization. This
classification is associated with rates of limb salvage, amputation
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