REVIEW
Chronic Wound Healing: A Review of Current
Management and Treatments
George Han
.
Roger Ceilley
Received: October 20, 2016 / Published online: January 21, 2017
Ó The Author(s) 2017. This article is published with open access at Springerlink.com
ABSTRACT
Wound healing is a complex, highly regulated
process that is critical in maintaining the barrier
function of skin. With numerous disease
processes, the cascade of events involved in
wound healing can be affected, res ulting in
chronic, non-healing wounds that subject the
patient to significant discomfort and distress
while draining the medical system of an
enormous amount of resources. The healing of
a superficial wound requires many factors to
work in concert, and wound dressings and
treatments have evolved considerably to
address possible barriers to wound healing,
ranging from infection to hypoxia. Even
optimally, wound tissue never reaches its
pre-injured strength and multiple aberrant
healing states can result in chronic
non-healing wounds. This article will review
wound healing physiology and discuss current
approaches for treating a wound.
Keywords: Biofilms; Chronic wounds; Growth
factors; Hyperbaric oxygen; Negative pressure
wound therapy; Skin infection; Skin substitutes;
Wound dressings; Wound healing
INTRODUCTION
The process of cutaneous wound healing is
incredibly complex, dependent on an intricate
interplay between a number of highly regulated
factors workin g in concert to restore injured
skin towards repaired barrier function. This
sequence of events plays out normally in the
vast majority of superficial wounds; however, it
can go awry at numerous steps along the
pathway, especially with underlying disease
states such as diabetes. When wound healing
does not progress normally, a chronic wound
may result and this is at significant burden to
both the patien t and the medical system. It has
been estimated that a single diabetic ulcer
carries a cost of nearly US$50,000 [1] and
chronic wounds as a whole cost the medical
system over US$25 billion per year, with the
number of patients affected growing yearly
from 6.5 million, given the increasing
prevalence of diabetes and other chronic
diseases that may affect wound healing [2].
Aside from the burden of a chronic wound,
even simple wounds created after minor
procedures such as outpatient surgeries require
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A287F06016A19FA2.
G. Han (&)
Icahn School of Medicine at Mount Sinai, New York,
NY, USA
e-mail: george.han@mountsinai.org
R. Ceilley
University of Iowa, Iowa City, IA, USA
Adv Ther (2017) 34:599–610
DOI 10.1007/s12325-017-0478-y
proper attention and care, and understandably,
patients may be concerned about possible
resultant scarring. It is no surprise, then, that
wound healing has receiv ed a great deal of
attention, both from a basic science standpoint
and a business perspective. The basic science of
how a wound heals is fascinating, with new
discoveries elucidating mechanisms of
physiologic wound repair constantly being
reported. Meanwhile, wound healing is also a
huge commercial enterpris e, with the market
for wound care products exceeding US$15
billion and treating wound scarring another
US$12 billion [3]. In this review, basic concepts
of wound healing will be discussed, with a focus
on current practice in treatment of wounds and
future directions in wound care. This article is
based on previously conducted studies and does
not involve any new studies of human or
animal subjects performed by any of the
authors.
PHYSIOLOGIC WOUND HEALING
After a superficial wound, a myriad of systems
are activated at the site in order to clear foreign
material, as the primary barrier function of the
skin is lost, and to eventually restore the normal
structure of the skin. While this may only be
successful to a limited degree—a wound will
never reach the maximum tensile strength of
unwounded skin, and at best reaches about 70%
[4]—most of the essential functions of the skin
will be returned to a wound. This does,
however, require the delivery of various
inflammatory cells, chemokines, cytokines,
matrix molecules, and nutrients to the wound
site with a concordant increase in metabolic
demand. These processes occur simultaneously
and are generally divided into three main
phases of wound healing: inflammatory,
proliferative, and remodeling.
The inflammatory phase of wound healing
starts shortly after hemostasis is achieved, and
the primary goal of this phase is to clear
pathogens as well as foreign material from the
wound and to contain the damage to a localized
area. Vascular permeability increases with
vasodilation, allowing neutrophils and
monocytes to localize to the wound site. A
complex interplay of cytokines also helps to
regulate this phase, culminating in monocyte
conversion to macrophages, often thought of as
the master regulator of this inflammatory phase
of wound healing [5]. The macrophages not
only phagocytose and digest tissue debris and
remaining neutrophils but also secrete growth
factors and cytokines that promote tissue
proliferation and cell migration. After about
3 days from the initial wound, the proliferative
phase centers around fibroblasts and
production of both collagen and ground
substance that will form the basis for the
tissue scaffold of the previous wound area.
Meanwhile, endothelial cells enter a rapid
growth phase and angiogenesis occurs within
the granulation tissue, creating a rich vascular
network supplying this very active area of
healing. After about 2–3 weeks, the wound
transitions to a remodeling, or maturation,
phase where the collagen type is restored to
usual (type I, rather than type III seen in a new
wound) [6] and the wound tissue matures,
resulting in full cross-linking and restoration
of a somewhat normal structure. The vascula r
network rapidly regresses as well [7]. As
previously discussed, the wound strength
never reaches its normal, pre-injury state.
An important consideration in physiologic
wound healing is oxygen supply and oxygen
tension in the wound bed. Wound healing
requires oxygen to interact with numerous
cytokines, supply the actively proliferating
cells, as well as provide an effector for the
neutrophil respiratory burst. It has been
estimated that a wound requires at least a
tissue oxygen tension of 20 mmHg to heal [8]
and non-healing wounds have been measured
to have oxygen tensions as low as 5 mmHg [9].
These effects seem to compound one another—
in situations of low oxygen tension, not only
will there be more necrotic debris to facil itate
bacterial growth but the primary mechanism of
the immune system in combating these
microbes is compromised. Thus, special care
must be taken with wounds resulting from
peripheral vascular disease and also in cases
where vascular compromise may play a role,
such as a diabetic ulcer. Additionally, the
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systemic optimization of nutritional status
should be evaluated in wound healing.
Numerous nutrients have proven to be
important in wound healing, especially
protein intake [10]. This was illustrated in a
study of elderly patients with pressure ulcers
where change in ulcer area was significantly
correlated with protein intake [11]; however,
other factors are also important, such as
vitamins A and C, and zinc [12]. The fine
balance of these nutrients has to be taken into
account, though. For example, with vitamin E,
an important lipophilic antioxidant, conflicting
studies have both shown reduced tensile
strength and colla gen content of experimental
wounds [13, 14] and, conversely, increased
wound strength and collagen [15]. As with all
aspects of wound repair, a fine balance is
necessary to ultimately achieve proper healing.
Given the tight regulation of a multitude of
factors required for proper wound healing, it is
not surprising that chronic wounds are rather
common. After an acute wound such as trauma,
surgery, or even a bug bite, the above
well-coordinated series of ev ents come into
play. The ultimate time course and outcome
will depend on the nature of the acute wound—
its location, size, depth, and type. However,
when other pathologic factors come into play,
such as an underlying disease state, a chronic
wound can form (see Fig. 1). This refers to a
wound that has somehow deviated from the
previously described natural physiologic course
of events and has stalled at some point. The
underlying mechanism varies greatly, but
includes factors influencing blood supply
(peripheral vascular disease), immune function
(such as immunosuppression or acquired
immunodeficiency), metabolic diseases (such
as diabetes), medications, or previous loca l
tissue injury (such as radiation therapy).
External factors, such as sustained pressure,
temperature, and moisture, also play an
important role in allowing a wound to heal.
As the pathophysiology of normal acute wound
healing has been well described, this review will
mainly focus on chronic wounds and their
treatment.
Aberrant wound healing can be seen rarely in
normal healthy subjects, but is usually
associated with an underlying process, ranging
from diabetes to cancer to malnutrition. Of the
major conce rns for chronic wounds, perhaps
none is as menacing or as important as diabetes.
In the USA, the number of people with diabetes
already reaches 20 million and is expected to
double by the year 2030 [16]. Diabetic foot
ulcers affect 15% of these patients and precede
the vast majority of amputations in this patient
population [17]. A wide variety of factors is
thought to contribute to this problem, affecting
all phases of wound healing and seem ingly
nearly every mo lecule involved in this process
[18], and evidence is emerging that proper
glycemic control can have a significant impact
on the rate of wound healing in a diabetic
patient [19]. This effect was mainly seen in
patients with markedly elevated
hemoglobin A1c levels, but it underscores
emerging evidence that diabetes plays a
Fig. 1 Chronic ulcers of peripheral vascular disease
Adv Ther (2017) 34:599–610
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multifactorial role in wound healing. It has
been well described that the neuropathy
experienced by diabetics can lead to a loss of
protective sensation, producing wounds that
eventuate into ulcers; however, there is an
emerging role of advanced glycation end
products in contributing to not only this
neuropathy but also the wound healing
cascade and small vessel disease [20]. While
achieving good glycemic control can certainly
be challenging, it also serves to reinforce the
need to address lifestyle choices and integration
of the primary care provider into treating a
chronic wound.
WOUND INFECTIONS
The most common preventable challenge to
wound healing is possible infection, and topical
antimicrobials have long been used empirically
to attempt to prevent wound infection. While
bacteria are a normal part of the skin flora and
thus woun ds, a critical threshold of 10
5
bacteria
has been proposed as the delineation between
colonization and a clinically relevant infection
that may impede wound healing [21]. It is also
necessary to distinguish between an incidental
positive culture and a true pathogen affecting a
wound. Repeat surface cultures in a wound are
of limited use, neither confirming nor ruling
out a continued infection; rather, clinical
diagnosis of an infected wound remains of
primary importance [22]. Deep tissue cultures
are somewhat more controversial. While they
have better sensitivity and specificity in
isolating a causative organism in an infected
wound, it is still not perfect; isolates from
different parts of the same wound have even
been shown to have different organisms [23].
Additionally, the practitioner is, in essence,
exacerbating the initial wound with an even
deeper wound, but this may still be a
worthwhile trade-off if it guarantees
appropriate antimicrobial coverage.
There are many approaches towards both
treatment and prevention of wound infections.
Silver has been used as adjunct in wound care
for over 2000 years [24] and remains a popular
wound care ingredient today. It has a broad
spectrum of activity and is availa ble in
numerous forms. Newer advances in using
silver for wound healing have focused on
allowing for sustained release of silver in high
enough concentrations to allow for retained
efficacy. Nanocrystalline silver dressings were
developed with this in mind and help to address
the shortcoming that silver nitrate has—to work
properly, it would have to be administered 12
times a day [25]. Furthermore, a recent review
found no convincing evidence that silver
sulfadiazine has any effect on wound healing
overall, despite its common use among
practitioners [26 ]. Similarly, iodine-containing
compounds have long been used in wound
healing but there have been some concerns
with toxicity of iodine-containing compounds,
especially over large wound areas. For limited
wounds, though, cadexomer iodine (iodine
within a starch lattice formed into
microbeads) has a good deal of data
supporting its use as a cost-effective adjuvant
for wound healing [27, 28].
Numerous topical formulations of
antibiotics have also been developed to apply
to wound sites. They remain popular, even
though emerging evidence has shown that the
benefit of this wholesale application of
antibiotic ointments may not be necessary and
the only real indicat ion for topical antibiotics is
a clinically infected wound, such as purulent
drainage, erythema, warmth, pain, tenderness,
or induration [29 ]. Numerous recent studies
have echoed this sentiment, with routine
administration of antibiotic ointment leading
to no better outcomes but often resulting in
patient discomfort, along with the possibility of
antibiotic resistance and contact dermatitis
[30, 31 ]. This is in conflict with a few earlier
studies where children with minor scratches
and insect bites had reduced rates of infection
with topical antibiotic ointment [32, 33],
although this cannot be clearly generalized to
all patients. Even after Mohs micrographic
surgery, a prospective study found the rate of
infection after clean surgical technique to be
less than 1%, with the highest rate of infections
in flap closures [34]. Overall, the consensus
seems to be that in dermatology, use of topical
antibiotics should be reserved for conditions
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such as impetigo or a clearly infected wound
and not for general prophylaxis [35].
WOUND CARE AND DRESSINGS
Wound care has become increasingly important
given the rise of chronic wounds and the
morbidity associated with them. An important
concept in wound care is the role of
debridement, or the removal of non-viable
tissue material. This can be achieved through
surgical or autolytic/enzymatic mechanisms—in
either case, the goal is to expose healthy,
well-perfused tissue that is able to proliferate
and populate the wound bed via epithelial cell
migration, rather than keeping necrotic debris
which only serves as fuel for infection and
impedes wound healing. The optimal timing
and frequency of surgical debridement are still
unclear, as they are likely to vary greatly
depending on the type of wound being treated,
but there is general agreement that surgical
debridement is an important component of
wound care. Autolytic debridement refers to
the self-activation of endogenous enzymes
involved in fibrin degradation generated in a
moist wound environment and seen with some
types of wound dressings [36]. While this can
have some utility in wound healing, it is
certainly not capable of removing devitalized
tissue as well as surgical debridement and, as
such, cannot serve as adequate replacement for
surgical debridement. Recently, there has been
some renewed interest in the use of so-called
biosurgical debridement, or the application of
larvae/maggots to a wound. This is intriguing in
that it achieves both a mechanical/surgical
debridement and an enzymatic debridement at
the same time, whilst having the capability to
eliminate pathogenic organisms and stimulate
fibroblast proliferation [37, 38]. Further studies
are needed, but it is certainly an intriguing
concept.
Manywound dressingshave beendeveloped to
try to both protect the healing wound from
infection and also to help promote the wound
healing process itself (Table 1). A moist occlusive
dressing helps support the inflammatory phase by
creating an environment with low oxygen
tension (thereby activating such factors as
hypoxia-inducible factor-1) [39]andalso
increases the rate of re-epithelialization [40].
Additionally, a limited amount of exudate
retained on the wound allows for autolytic
debridement, which serves to further promote
successful wound healing. However, traditional
dry gauze wound dressings may degrade this
process while also causing further injury when
removed. Low adherent dressings and
semipermeable films (i.e., Tegaderm) represent
the basic types of wound dressings commonly in
use, with the goal of restricting liquid and
microbial penetration but allowing air and water
vapor through. Hydrocolloids and hydrogels take
advantage of a hydrophilic material that absorbs a
certain amount of exudate but keep a moist
environment; hydrocolloids are furthermore
impermeable to air and are somewhat more
long-lasting, but should not be used on
exudative wounds because of its impermeable
nature. Hydrogels may additionally be used to
help promote moisture in an otherwise dry
wound. Another option is alginate dressings,
seaweed-derived non-woven fibers that are
generally reserved for highly exudative wounds
because of their ability to absorb large amounts of
fluid. As such, adverse effects can be seen in dry
wounds dressed with alginate [41]. Similarly,
foams have some absorptive capacity and can be
used on moderately exudative wounds, especially
helpful because they minimize trauma during
dressing changes. Lastly, collagen products have
been used on recalcitrant wounds and chronic
ulcers. While this collagen is not intended to be a
direct replacementfor new production of collagen
in wounded tissue (as it can be derived from
multiple sources, including bovine and porcine
collagen), it is thought to help facilitate an
environment attracting cell types critical to
wound healing while depleting negative
effectors such as free radicals and proteases [42].
Several more recent developments in wound
dressings have focused on integrating
antimicrobial compounds into the wound
dressing itself. These materials combine
traditional wound dressings such as foams or
hydrogels with antimicrobial compounds such
as silver, betaine, chitin, or polyhexamethylene
biguanide (Kendall AMD). These materials, as
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