ARTICLE
Auteur(s) : K Welt, R Hinrichs, JM Weiss, W Burgdorf, Th
Krieg, K Scharffetter-Kochanek
Introduction
Chronic “wounds” such as leg ulcers and pressure sores are an
expensive problem for society. Because they are chronic and not in
any way glamorous, they have not in the past been subjected to much
study. Today research and technical developments in many areas have
enhanced our understanding of the process of wound healing and now
enable us to offer new hope to many patients. Dermatology has been
in the forefront of such efforts.
Physiological wound healing comprises a finely-tuned, carefully
coordinated sequence of events such as inflammation, formation of
granulation tissue, extracellular matrix synthesis and tissue
remodeling. Evolution has optimized wound healing, which is usually
amazingly effective. Nonetheless there are several disorders where
wounds simply do not close. Wound healing of the skin has
fascinated researchers and clinicians from various clinical and
basic research disciplines. The skin is an accessible organ and the
underlying mechanisms of skin repair processes are highly relevant
for tissue repair of other organs.
A chronic wound is defined as a secondary healing wound that
does not heal in a period of 12 weeks or does not show tendency to
heal after 8 weeks of adequate therapy. In the industrialized
countries about two percent of the population suffer from
non-healing wounds. Chronic wounds severely reduce the patient’s
quality of life and are of major medical economic impact.
Calculations that include medical costs and the lost productivity
in professional lives suggest that chronic wounds cost several
million Euros annually.
The prevalence of chronic venous insufficiency in the population
increases with age. In Europe, 5 to 15% of adults between the ages
of 30 and 70 present this disease, being that 1% present a varicose
ulcer. Type II diabetes mellitus has a prevalence of 2%; in this
group, 15% of patients develop difficult-to-treat diabetic foot
ulcers, which often lead to amputation. Leg amputation in such
patients increases the mortality rate [5]. Furthermore, demographic
studies show that the percentage of the elderly will significantly
increase during the next twenty years. Therefore, apart from the
resulting increased numbers of patients suffering from chronic
venous leg ulcers and diabetic foot ulcers, growing numbers of
patients with mechanically-induced pressure ulcers are expected.
The development of novel, cost-effective strategies for clinical
management of wound patients leading to more rapid healing and
fewer recurrences is thus a necessity, not a luxury. This ultimate
goal can only be achieved if politicians and health care
authorities support cost-effective and therapeutically effective
concepts for clinical management. A prerequisite for this goal
is to further explore and detect the underlying causes and
molecular mechanisms responsible for wound healing
disturbances.
Impaired wound healing
Some causes of impaired wound healing are summarized in table 1. The most common non-healing wounds are
venous leg ulcers, diabetic foot ulcers and pressure ulcers; we
will concentrate our comments on these lesions. Chronic wounds
among others fail to progress through the normal pattern of wound
repair but remain in a chronic inflammatory state with little signs
of healing [6]. There is increasing evidence that the persisting
infiltration of neutrophils and macrophages in conjunction with
elevated iron deposition in the ulcer tissue play a major role in
the generation of the prooxidant, hostile microenvironment in
chronic ulcers which tilts the balance towards proteolysis and a
non-healing state.
Table 1 Causes of non-healing wounds
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Metabolic disorders
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– Diabetes mellitus
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– Gout with hyperuricemia
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Mechanical strain
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– Pressure ulcers
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Vascular disorders
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– Vasculitis
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– Occlusive vasculopathy
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– Chronic venous insufficiency
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– Obstructive arteriosclerosis
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Genetic diseases
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– Leukocyte adhesion deficiency syndromes I and II
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– Werner syndrome
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– Syndromes with collagen defects (Ehlers-Danlos syndrome, Marfan
syndrome)
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– Epidermolysis bullosa (many variants)
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– Coagulopathies
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Autoimmune disorders
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– Lichen planus
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– Lupus erythematosus
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– Systemic sclerosis
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– Acquired blistering diseases
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Miscellaneous
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– Ulcerated skin tumors
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Treatment of chronic wounds
The management of the underlying disease should be optimized. In
the case of chronic venous insufficiency and arteriosclerosis,
reconstructive surgery should be considered. In the case of
pressure ulcers, prophylaxis is paramount, with frequent
repositioning and the use of specialized mattresses or pillows.
Cutaneous infections should be promptly treated and wound ointments
and creams containing likely allergens or irritants should be
avoided, as both infections and contact dermatitis delay wound
healing. Some of the specialized approaches to wound healing are
considered below in greater detail.
Phase-adapted moist therapy
Moist wound healing facilitates healing by acceleration of
autolytic debridement, stimulation of the tissue granulation and
epithelialization. Modern wound dressings include film, hydrogel,
foam, alginate and hydrocolloid dressings. Choosing the correct
dressing for a given wound requires clinical experience, but is
essential for the effective use of this category of agents, as
reviewed by several groups [4, 8, 9].
Surgical procedures
One approach to resistant leg ulcers is shave therapy to eliminate
liposclerotic tissue adjacent to the ulcers [7]; the underlying
concept of shave therapy is to switch the pathophysiology of a
chronic wound to the normal healing sequence of an acute wound. The
prooxidative microenvironment is switched to a more favorable one
enhancing tissue repair. Shaving the callus around a tissue defect
is a cornerstone of treating diabetic foot ulcers.
Growth factors
The activity of several growth factors required for coordinated
tissue repair is significantly reduced in chronic wounds. Topical
application of human PDGF-BB to diabetic foot ulcers in combination
with extended surgical debridement and enhanced diabetic management
resulted in a significantly improved healing rate. PDGF-BB is the
first growth factor to be approved and introduced into the US and
European markets. Although still in phase II studies,
granulocyte/macrophage colony stimulating factor (GM-CSF) also
appears effective. When injected perilesionally around chronic
ulcers of the lower extremity, GM-CSF led to a significantly
improved and accelerated healing rate as shown by results of a
double blind, placebo controlled multicenter study. Both of these
growth factors are very expensive, so socioeconomic factors will
probably determine the exact role of these useful agents.
Vacuum-assisted closure (VAC) therapy
This effective therapeutic option is based on the generation of a
controlled vacuum thus constantly eliminating the interstitial
fluid from wounds. In this way the destructive enzymes oozing from
wounds are partially eliminated, allowing the growth factors to
work more effectively. VAC therapy also protects the wound edge
from maceration. It has been best tested in diabetic foot ulcers
but can also be employed in chronic venous leg ulcers and pressure
ulcers.
Skin substitutes
Using tissue engineering, researchers at academic institutes and
companies have developed several in-vitro skin substitutes
consisting of various combinations of epidermis and dermis. While
there is good evidence that patients with extensive burn wounds and
diabetic foot ulcers profit from these products, there is no double
blind, placebo controlled study that includes sufficient patient
numbers with chronic venous leg ulcers. However, skin substitutes
may be able to counteract the hostile microenvironment of chronic
wounds by the release of multiple growth factors. In addition they
enhance re-epithelialization or covering of the wound, which helps
protect against infections.
Modulation of protease activity
Many studies have shown that difficult-to-treat wounds are
characterized by a prolonged inflammatory phase, which leads to
enhanced protease levels and subsequent degradation of connective
tissue components as well as growth factors. There is accumulating
evidence that silver ions not only combat bacterial infections, but
also inhibit the activation of matrix metalloproteases; a number of
novel products attempt to take advantage of this function. In
addition, a bioresorbable, amorphous, open-pored matrix has been
developed, which appears to act as a scavenger of reactive oxygen
species to counteract the prooxidative hostile microenvironment,
reduce the activity of key proteases and protect growth factors
from being degraded. This product has been tested in diabetic foot
ulcers but deserves studying in venous and pressure ulcers.
Future developments
There are a number of exciting areas of intensive research which
are expected to pay clinical dividends in the not-too-distant
future. They are briefly discussed below.
Selective pick-up principle
The identification of factors delaying wound healing has been
crucial for the development of a novel therapeutic concept that
finally led to a new dressing concept called the selective pick-up
principle. Selectively acting biomolecules are bound to the surface
of traditional wound dressing materials to remove or eliminate
specific deleterious substances from wound exudates. Selective
pick-up dressings are able to adjust the composition of wound
fluids locally, in contrast to the systemic action of orally given
dugs. A prototype selective pick-up dressing to remove iron
ions based on the iron chelator deferoxamine (DFO) has been
designed; in in-vitro tests, it does complex iron and blocked the
iron-driven upregulation of proteases [10].
Molecular modeling of protease-resistant growth
factors
In chronic venous leg ulcers, levels of the angiogenic growth
factor, vascular endothelial growth factor (VEGF), are reduced,
because of plasmin cleavage of VEGF. Thus revascularization of the
ulcer is delayed. A recombinant VEGF has been created with a
mutation at the site of plasmin cleavage conferring resistance to
this formation of degradation; it also retains its in vitro
activity [2]. This approach appears to offer another elegant way to
modulate the protease activity so important in delaying wound
healing.
Stem cells
Recent evidence indicates that bone marrow contains stem cells with
the potential for differentiation into a variety of tissues
including the skin. Preliminary data show that bone marrow-derived
progenitor or stem cells improve healing when applied to chronic
wounds [1].
Gene therapy
Blisters may advance to extensive erosive wounds. Dystrophic
epidermolysis bullosa includes a number of severe inherited
blistering disorders which are difficult to treat. In the most
severe form, collagen VII, a major protein linking the dermis and
epidermis, is absent. In a first attempt to correct this disorder,
the entire human collagen VII locus was transferred to human
keratinocytes of patients suffering from dystrophic epidermolysis
bullosa by microinjection. Sustained biosynthesis and secretion of
procollagen VII with identical properties to the authentic
counterpart was found. These data demonstrate a “proof of
principle” for somatic gene therapy as a means of restoring
collagen VII production [3]. Such an approach should also be
possible to induce local production serine protease inhibitors or
antioxidant enzymes in an effort to correct the disturbance in
chronic wounds.
Clinical wound management
The clinical management of difficult-to-treat wounds is in a stage
of evolution. Financial restraints mean that patients can no longer
be hospitalized for long periods of time to await complete healing.
Many multidisciplinary outpatient wound clinics have been
established, often with internists, anesthesiologists (pain
control), reconstructive surgeons and neurologists. After the
patient has been evaluated to assess underlying causes and
predisposing factors, as well as to insure optimum management of
these problems, a short hospital stay may be needed for some form
of surgical wound management or coverage, or for intravenous
treatment of wound infections. Afterwards, they are followed as
outpatients in the chronic wound clinic. Dermatology often serves
as the home for such clinics, incorporating the established
subspecialties of phlebology and allergology into the program.
Furthermore, educational programs for patients and nurses have been
successfully developed. Also the concept of wound nurses, very well
trained in the topical treatment of wounds, has been successfully
implemented. In one model, nurses visit and treat patients in their
homes. In some instances this concept has been overstretched. As
the underlying causes of wound healing disturbances are manifold,
the initial diagnosis and coordination of actions need to be
supervised by a medical doctor with a specific training in wound
healing disturbances. Otherwise an ineffective inexpensive
treatment for a long period of time may be more costly than an
effective aggressive expensive approach.
Basic research – moving between bedside and bench
Dermatology has achieved recognition for combining effective
interdisciplinary wound management with clinical and basic
research. Clinical questions arising in the daily routine are
transferred to basic research laboratories with adequate molecular
and biochemical capacities. During the last couple of years this
bridge between bedside and the bench has been highly successful as
supported by high ranking publications in basic research related to
inflammation, cancer and wound healing coming from dermatologic
departments. As result, a number of industry ties have been
developed to both unravel pathogenic principles and develop new
products. Dermatologists are among the founding members of the
European Tissue Repair Society (ETRS), whose aim is to increase our
molecular and cellular understanding of tissue repair and its
disturbances and to develop new preventive, educational and
therapeutic approaches. The ETRS brings together different clinical
disciplines and researchers from basic science with
cross-fertilization of ideas, concepts and financial support. The
independent ETRS has strong bounds to the Wound Healing Society in
the United States of America, organizing combined meetings every
other year.
Perspectives
Dermatology in Europe in its collaborative effort with other
clinical and basic science oriented disciplines has a solid concept
to further develop and improve preventive and therapeutic
strategies to manage difficult-to-treat chronic wounds in a
cost-effective way. This valuable concept requires communication
with and support from health care authorities including health
insurance companies and politicians. Chronic wounds are a major
societal problem. We must not concentrate on short-term
money-saving measures but instead look to the future, with
adequately funded research to develop newer, more effective, more
rapidly acting therapies which will improve patients’ quality of
life, return individuals to productivity and in the long run, be
cost-effective.
References
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endothelial growth factor165 variant by a site-directed mutation at
the plasmin sensitive cleavage site. FEBS Lett 2002; 531:
309-13.
3 Mecklenbeck S, Compton SH, Meja JE, et al.
A microinjected COL7A1-PAC vector restores synthesis of intact
procollagen VII in a dystrophic epidermolysis bullosa keratinocyte
cell line. Hum Gene Ther 2002; 13: 1655-62.
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