Turk J Med Sci

34 (2004) 147-160
TBTAK

PERSPECTIVES IN MEDICAL SCIENCES

What is New in Wound Healing?

Senthil KUMAR, Peng Foo WONG, David John LEAPER

The Professorial Unit of Surgery, University Hospital of North Tees, Stockton-on-Tees United Kingdom TS19 8PE

Received: March 08, 2004

Abstract: Wound biology is complex. Wounds which were until recently seen only as defects in tissues are now increasingly
interpreted in cellular and molecular terms. Growth factors, cytokines, proteases and adhesion molecules which participate in wound
healing are discussed in this article. From a clinical perspective, conceptual shifts of importance, including moist wound healing,
wound bed preparation and wound assessment, are presented. The frontiers of therapeutics employed in wound healing continue to
advance with an increasing array of modalities joining the ranks at a regular pace. A range of currently available as well as evolving
therapies physical (topical negative pressure therapy, warming, electrical stimulation), biological (larva therapy, skin substitutes,
stem cell therapy, growth factors, gene therapy) and of a miscellaneous variety (hyperbaric oxygen, dressings) are appraised.

Key Words: Wound healing, Growth factors, Physical therapy, Biological therapy

Introduction The conceptual advances pertaining to wound healing

A healing wound is an extremely complex and dynamic will be outlined first, followed by a discussion on advances
tissue which in some ways could be regarded as an organ, in wound assessment. Finally the therapeutic advances
albeit a temporary one. Scientific enquiry into the many will be considered.
facets of wound healing is far from complete and Conceptual advances in wound healing
consequently the knowledge base is continually being
Advances from a molecular perspective
enriched by input, as much from the clinician at the
bedside, as the researchers bench. Normal wound healing occurs in recognisable, usually
progressive, though overlapping, phases: the
Increasing clarity in definitions, a systematic approach
haemostatic/inflammatory phase, the proliferative/cellular
to research, an organised and multi-professional
phase and the remodelling phase. Giant strides have been
approach to management, and a willingness to consider
the patients perspective are some of the important made in the understanding of wound healing at the
changes that have paralleled technological advances and molecular level by the discovery of many families of
expertise, which, as ever, have been the prime drivers of molecules which have provided insights into the
progress. multitude of steps and interactions involved in each of
these phases.
This article provides an overview which reflects on
some of the developments in cutaneous wound healing Wound healing is a collaborative process involving a
over the last couple of decades that have either changed variety of cells and matrix components which need to
or are likely to change the way wounds are understood, interact continually towards a common goal. Growth
evaluated and treated. In keeping with the generalist factors, cytokines, proteases and adhesion molecules,
theme of the article, discussion on specialised areas of which are discussed here, are but a few examples of
wound healing like scar management and issues relating substances by which cells conduct a molecular talk and
to specific problems like pressure ulcers have not been engage in interactive cascades. In addition, it is
addressed. increasingly becoming clear that important regulatory

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What is New in Wound Healing?

roles are played by systems as diverse as the plasmin primarily trophic effects on cells. However, they may
cascade and nitric oxide. indirectly influence inflammatory processes. Platelet
Growth factors and cytokines derived growth factor (PDGF), vascular endothelial growth
factor (VEGF), epidermal growth factor (EGF), fibroblast
Growth factors and cytokines are 2 distinct categories growth factor (FGF), connective tissue growth factor
of signalling proteins that modulate wound healing at a (CTGF), and transforming growth factor (TGF), along
molecular and cellular level. However, in certain instances with insulin-like growth factor (IGF) and colony stimulating
the distinction may be blurred and some mediators like factors (granulocyte-G-CSF; granulocyte/ macrophage- GM-
PDGF, TGF and TNF straddle the divide. CSF; macrophage-M-CSF) are amongst the key growth
Growth factors are constitutively present, usually factors in wound healing. A summary of the profiles of a
released by a few selected subsets of cells and have a few selected growth factors is given in Table 1.

Table1. Profile of selected growth factors of importance in wound healing.

Growth factor Physiological effects Clinical and experimental correlates

TGF Chemotactic to fibroblasts, monocytes, macrophages, Chronic wound fluid contains lower TGF
Transforming growth factor lymphocytes when compared to acute wounds
[1, 2, 3 isoforms] Proliferation of epithelial cells, macrophages, lymphocytes,
fibroblasts While higher concentrations of TGF1 and
Stimulates keratinocyte migration TGF2 are associated with hyperfibrotic
Induces expression of Pro- MMP-9 in keratinocytes disorders
Induces fibroblasts to secrete TIMPs TGF3 has been found to reduce scarring
Augments cell adhesion to matrix proteins by modulating
integrin receptor Scarless healing in the embryo has been
Stimulates fibroblasts to contract collagen matrix attributed to an absence of TGF

PDGF Neutrophil, monocyte, lymphocyte chemotaxis First growth factor to be licensed for
Platelet derived growth factor Monocyte maturation topical therapy
Potentiates VEGF production
Stimulates MMP production by fibroblasts
Stimulates myofibroblasts to contract matrix collagen

KGF Potent mediator of keratinocyte proliferation which under the Trials of topical application underway
Keratinocyte growth factor influence of KGF 2, upregulates the expression of many genes
[KGF-1, KGF-2] Stimulates keratinocyte and fibroblast motility

VEGF Potent angiogenic factor VEGF administration improves granulation-

Vascular endothelial growth tissue formation
factor Potential being explored in salvage of
ischaemic flaps and in tissue expansion

EGF Directs epithelialisation in an autocrine fashion Aged dermal fibroblasts have a decreased
Epidermal growth factor Stimulates fibroblast collagenase secretion EGF-receptor expression
Inhibits foetal wound contraction EGF may contribute to the scarless repair
seen in utero

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Cytokines are small molecular weight mediators which gelatinases, 2 matrilysins, 3 stromelysins, 6 membrane
primarily have a variable effect on inflammatory type MMPs and a miscellaneous group of 7 enzymes.
processes by their influence on the cells of the immune Remodelling of the extracellular matrix, which is an
system. They may be released by practically all nucleated important step in a number of stages in wound healing
cells, are expressed transiently and locally and elicit like cell migration, angiogenesis and wound contraction,
varying responses in different cells. A summary of the is dependant on the MMPs. The alteration of the matrix
profiles of a few selected cytokines is given in Table 2. architecture may have profound secondary effects on
Proteases and their inhibitors cellular proliferation, morphology and migration. In
addition, the MMPs may modulate the wound milieu by
Matrix metalloproteinases (MMPs) are a large family their effect on the rate of degradation of growth factors,
of about 24 mammalian endopeptidases that play a cytokines and their receptors (1).
crucial role in wound healing. There are 4 collagenases, 2

Table 2. Profile of selected cytokines in wound healing.

Cytokine Physiological effects Clinical and experimental correlates

TNF Leucocyte chemotaxis Elevated levels linked to insufficient

Tumour necrosis factor Monocyte maturation collagen deposition and poor healing
Macrophage activation
Inhibits fibroplasia Levels high in chronic nonhealing wounds
Stimulates IL-6 by fibroblasts
Increases activity of MMP-2 and MMP-9
Potentiates VEGF production

Interleukin-1 Leucocyte and fibroblast chemotaxis High levels associated with delayed healing
Macrophage activation
Angiogenic
Stimulates fibroblast MMP production
Stimulates keratinocyte migration

Interleukin-6 Inhibits extracellular matrix breakdown High levels associated with poor healing
Stimulates fibroblasts to secrete TIMP Peaks at 24 h

Interleukin-8 Leukocyte chemotaxis Parallels IL-6, peaking at 24 h

Enhances epithelialisation
Keratinocyte migration
Upregulates plasminogen activator in keratinocytes
Inhibits fibroblast induced contraction of collagen

Interleukin-4 and Interleukin-10 Inhibit leucocyte chemotaxis IL-10 exhibits bimodal wound levels
(The anti-inflammatory interleukins) Downregulate expression of many pro-inflammatory peaking at 3 h and 72 h
cytokines

Interferons Inhibitory to fibroblasts IFN reduces keloid size when

(The antifibrogenic cytokines) Inhibit post-translational changes to collagen administered intradermally
Increase collagenase activity

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The activity of the MMPs is counterbalanced by tissue Advances from a clinical perspective
inhibitors of MMPs (TIMPs) which bind to the MMPs, Moist wound healing
inactivating them (2). TIMPs may also independently
Ever since Winters studies (5-7) highlighted the
stimulate or inhibit cellular proliferation and act to inhibit
importance of a moist wound environment, there has
angiogenesis (2,3). Other inhibitors include 2
been a growing body of evidence lending it support. The
macroglobulin, which serves as the predominant
concept of maintaining a moist wound environment has
antiprotease immediately after wounding.
sparked the so-called dressing revolution with a wide
Realisation of the importance of this protease- spectrum of moisture-retaining and semi-occlusive
antiprotease balance has opened new avenues amenable dressings flooding the market.
to intervention in an effort to improve wound outcomes.
A moist wound environment is claimed to have the
Examples include Promogran , a dressing consisting of
following advantages:
collagen and oxidised regenerated celulose that seeks to
mop up and inactivate the MMPs in the wound, and the 1. It prevents tissue dehydration, which helps to
possibility of manipulating the protease content in a preserve the viability and proliferative potential of the
wound by gene therapy. cells. This is associated with earlier epithelialisation.

Adhesion molecules 2. Accelerates angiogenesis.

3. Increases breakdown of dead tissue and fibrin
Adhesion, at a molecular level between cells and
contributing to autolytic debridement.
between cells and the matrix, is a vital physical process
which initiates and modulates many chemical and 4. Potentiates interaction of growth factors with their
biological effects. Adhesion is accomplished by a large target cells.
family of adhesion molecules which are transmembrane 5. Reduces the incidence of infection.
proteins that serve as lines of communication between
6. Is associated with less pain.
the internal processes of the cell and its exterior. There
are currently 6 recognised superfamilies of adhesion In the contrast, exposure of the wound to air causes
molecules the immunoglobulin-like superfamily, the wound dessication and scabbing, which delay
cadherins, the integrins, the receptor protein tyrosine epithelialisation. The healing time of superficial and deep
phosphatases, the selectins and the hyaluronate cutaneous wounds has been shown to be faster and less
receptors. The 3 illustrative examples which follow painful when treated with a moisture- retaining dressing
outline how indispensable these ubiquitous recognition as against a simple gauze dressing (8-10).
molecules are to the process of wound healing. Wound bed preparation
Platelet aggregation and leucocyte margination in the Wound bed preparation is a concept which attempts
capillaries, one of the earliest steps in the inflammatory to systematize the management of the chronic wound
phase of wound healing, is dependent on the expression with a view to accelerate endogenous healing and to
of selectins and integrins. facilitate the effectiveness of other therapeutic measures.
The 3 pillars of wound bed preparation are management
Keratinocyte migration is an important step in re-
of necrotic burden by debridement, managing bacterial
epithelialisation . Migrating keratinocytes overexpress a
burden and maintaining moisture balance. Additional and
set of integrins which engage molecules like fibronectin
related goals include correcting cellular dysfunction and
and vitronectin in the blood clot and matrix to provide
achieving biochemical balance.
them a foothold as they edge forward.
Debridement could be achieved by surgical,
Adhesion molecules may also be shed by endothelial
mechanical or enzymatic means.
cells at the direction of cytokines released by activated
leucocytes. Soluble E selectin and soluble VCAM-1 Mechanical debridement refers to a range of
(vascular cell adhesion molecule-1) shed in this manner techniques like wet-to-dry dressings, which cause
adhere to adjacent endothelial cells and exert a direct separation of eschar and its removal with the dressing;
wound irrigation, which ideally is irrigation of the wound
angiogenic effect (4).

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by saline using a 20 gauge catheter at 15 pounds per Some systems like those used for assessing pressure
square inch of pressure; and whirlpool or foot soaks in ulcers are useful in day to day practice. Others, like the
medicated saline to remove debris. Enzymatic ASEPSIS score (11) and the Southampton grading system
debridement refers to the topical use of bacterial (12) pertaining to postoperative wounds, are useful tools
collagenase, DNAse/fibrinolysin, papain/urea combination that are mainly employed in the research setting. Because
or trypsin to achieve clearance of debris. of the heterogeneity of the wounds, to date there is no
Bacterial burden may be reduced by a combination of single acceptable system that could be adopted universally
debridement; correcting underlying causes like ischaemia to assess all wounds.
and immunosuppression, and topical antiseptics delivered Infection: Wound infection has been and continues to
through dressings like cadexomer iodine and silver based be an elusive term to define and reach a consensus on.
dressings. One systematic review (13) addressing the quality of
Maintaining moisture balance involves the control of measurement of surgical wound infection identified 41
exudate while maintaining a moist wound environment different definitions of wound infection in the 90
that is conducive to healing. Exudate may be controlled prospective studies included in the analysis. This aside,
using specially designed absorbent dressings or attempts to correlate clinical signs and symptoms with
mechanical devices such as topical negative pressure wound infection have met with some success. Cutting and
therapy. Moisture-retaining dressings like hydrogels, Harding (14) identified friable bright red granulation,
hydrocolloids and foams aid in maintaining a balance and exuberant granulation, increased discharge and new areas
preventing dessication. of slough at the wound base as possible signs of infection.
Though the individual components mentioned above Gardner et al. (15) validated pain, increasing wound size,
are not entirely new, the concept of wound bed new areas of breakdown and odour as signs with a high
5
preparation has unified the different approaches, giving correlation with > 10 colony forming organisms per
clinicians a global perspective of the problem facing them gram of tissue. Grayson et al. (16) validated the exposure
at the wound bed while at the same time stressing the of or probing to bone in diabetic foot ulcers as a useful
importance of each of the components. bedside test for deep infection with a specificity of 85%
and positive predictive value of 89%.
Advances in the assessment and investigation of
wounds Quantitation of bacterial load in a wound by tissue
biopsy is expensive and time consuming. A
Wound assessment has several dimensions clinical,
semiquantitaive swab technique has been proposed as an
physical, physiological, biochemical, histological and
alternative. The wound is first swabbed after the bed is
genetic. While advanced techniques employed in wound
cleaned with saline. The swab is then used to streak 4
healing research like cytological, immunohistochemical
quadrants of a solid medium sequentially. A growth in the
and molecular methods have made significant
fourth quadrant of > 30 colony forming units has been
contributions to our understanding, only those of 5
correlated with a bacterial burden of > 10 organisms
immediate relevance to the practicing clinician are
per gram of tissue (17).
considered here.
Biochemical assessment: Advances in technology
Scoring and Grading: Wounds are heterogeneous not
have made measurement of cytokines, growth factors
only in terms of aetiology but also in quantitative (size,
and proteases possible. Wound fluid and biopsy
shape) and qualitative terms (wound bed, slough,
specimens of wounds have been the tools of investigation
discharge, effects produced etc). Over the years scoring
with respect to these factors.
and grading systems have been designed to objectively
assess the wound to minimise inter-observer variation. The pro-inflammatory cytokine content and protease
Scoring or grading wounds also helps in classifying content of chronic wounds has been observed to be
wounds and to an extent provides prognostic higher than in acute healing wounds. The levels of TNF
information. Uniformity in reporting allows for and IL-1 remain elevated in chronic wounds (18,19).
comparisons amongst and between various wounds as Chronic wounds also tend to have a lower growth factor
well as following the progress of a wound over time. content.

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What is New in Wound Healing?

The protease-antiprotease balance seems to be critical reconstructive surgery, the ability of TNP in reducing the
and a close correlation between the high ratios of size of a tissue defect, which has been termed the
TIMP/MMP-9 and healing of pressure ulcers has been reverse expansion effect, has been exploited to enable
noted (20). Wounds that are healing normally show a downgrading of the wound on the reconstructive ladder
peak MMP-9 level at 24 h which declines significantly by so that a simpler procedure (for example, secondary
48 h. Persistent elevation of MMP-9 in wound fluid has suture) may be used instead of a more complex one (such
been shown to be a useful marker of delayed healing. as a local flap).
Absence of a decline in MMP-9 between 24 and 48 h in Problems with TNP include pain, fluid loss especially
postoperative wounds has been correlated with infection
in large wounds and risk of bleeding. Large controlled
and chronicity of wounds (21).
trials which are underway will hopefully define its precise
Though currently wound fluid analysis remains largely role in the therapeutic armamentarium of the wound care
a research tool, in future it may evolve further as a source provider.
of vital prognostic wound information or may even be
Warming (therapeutic heat)
useful in directing therapy.
Although the application of warmth to wounds in the
Developments in therapy
form of compresses is a well known practice since time
Physical methods immemorial, the primary objective had been pain relief.
Topical negative pressure therapy (TNP) The science behind the beneficial effects of heat on tissues
has only been explored relatively recently. Although per-
Pioneered by Fleischmann et al. (22) and Morykwas
operative warming is now standard anaesthetic practice,
and Argenta (23) in the mid 90s, TNP involves the
the application of warming as a modality to reduce wound
application of an external sub-atmospheric pressure to
infection and to augment wound healing is a novel
exert a suction force across the wound. Vacuum assisted
approach which holds promise.
closure (VAC), sub-atmospheric pressure dressing (SPD),
vacuum sealing technique (VST), sealed surface wound The following facts are now established
suction (SSS), and negative pressure therapy (NPT) are Warming improves blood flow and oxygen tension
alternative terminologies. in tissues (24,25)
The wound is compartmentalised by an airtight seal Warming decreases the rate of wound infection in
around it and through a dressing interface (which is clean elective surgery (26)
usually a polyurethane or polyvinyl alcohol foam) the
Warming reduces the risk of developing pressure
compartment is connected to an external suction
ulcers (27)
apparatus. The application of pressure may be continuous
or intermittent. Pressures used range between -125 and Warming may eradicate established MRSA infection
-175 mmHg. Dressings are usually changed every 48-72 in pressure sores (28)
h. Warming may be applied systemically or locally.
TNP has been shown to increase dermal perfusion, Systemic warming is usually done using specially designed
stimulate granulation tissue, decrease interstitial fluid, warming blankets (Bair-Hugger, Arizant Health Care) or
control wound exudate and decrease bacterial load. mattresses (Pegasus-Inditherm mattresses). The
mechanisms used include circulating warm air/water or
These effects have clinically translated to better
healing rates of wounds in a variety of specialities electrically powered coils. Local warming is applied using
including plastic, cardiothoracic and orthopaedic surgery. specially designed pads which may use an external source
The clinical indications of TNP are ever expanding from of electricity (Warm up dressing, Augustine Medical Inc.)
ulcers and burns to wound dehiscences and fistulae. Other or an exothermic reaction triggered by exposure to
useful roles are as an adjunct in tissue salvage in oxygen.
reconstructive surgery, burns and trauma where the The ideal duration and intensity of heat needed for
application of TNP has had the effect of preserving the optimising the wound milieu is yet to be determined.
vitality of tissues and flaps of borderline viability. In Warming is attractive as an option for many reasons:

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1. It can be applied prophylactically as well as after liposuction (31). Large well powered, blinded,
therapeutically. randomised controlled trials are needed before the clinical
2. Is simple to apply (systemically or locally) and well role of these modalities can be judged.
tolerated. B. Biological Therapy
3. Is cheap and cost effective. 1. Larva therapy
4. May help to reduce the use of antibiotics. Although conceptually many centuries old, larva
5. May be useful in circumstances where antibiotics therapy in its current form was rediscovered in the late
fail. 1980s and was given a fresh breath of life by the work
of Sherman (32) in the US and popularised in the UK by
Electrical stimulation
the biological research unit at Bridgend in Wales.
Research into the effects of electricity on living tissues
Also termed maggot therapy and biosurgery, it
has unravelled the pivotal role of electrical charge in
involves the application onto the wound of necrophagous
interactions in biological systems both at cellular and
larvae of the green bottle fly Lucilia Sericata, reared in a
molecular level. Electricity-induced tissue hyperaemia and
controlled and sterile environment.
galvanotaxis, the purposeful predictable movement of
cells under the influence of electricity, are well Maggots augment wound healing by a number of
documented. However, only over the past couple of mechanisms:
decades has electrical stimulation made the slow Antimicrobial effect: Larvae ingest and kill bacteria
transition from the realms of research to the clinical and may secrete chemicals with antimicrobial
arena. action. The larval secretions increase the pH of the
The devices used to deliver the current are wound to 8-8.5, which has an inhibitory effect on
heterogeneous in terms of the type of current, voltage, certain bacteria.
intensity and waveforms used. Gardner et al. in a meta- Selective debridement: Several proteases capable of
analysis reviewed the effect of electrical stimulation in degrading many matrix components have been
healing chronic wounds (29). Of the 14 studies included, characterised in their secretions, which cause rapid
9 were randomised controlled trials. The primary and selective debridement of dead tissue (33,34).
outcome measure was the mean percentage area of the
Promotion of tissue interactions: Larval secretions
wound healed per week. There were 591 ulcers in the
favourably influence the fibroblast to extracellular
electrical stimulation group and 212 in the control group.
matrix interactions, which is critical in many
The mean percentage area of the wound healed per week
processes in wound healing. Secretions by
in the ES group was 22.5% compared to 9% in the
removing the fibrin cuff might kick- start the
control group. Pressure ulcers had the greatest response.
healing process in a static chronic wound (32-34).
Further research is needed to define the optimum
The larvae are 1-2 mm in size and do not multiply in
dose-response and the relative effectiveness of the
the wound. The recommended dose of larvae is 10 larvae
different modalities of electrical stimulation.
per square centimetre of wound. Usually 1-2 applications
4. Miscellaneous physical methods achieve adequate debridement. The dressing, which is left
Magnetism, laser phototherapy, cycloidal vibration in place for 2-3 days, needs to be oxygen-permeable and
therapy and ultrasound are some of the other physical provide a moist environment. Larva therapy is best suited
modalities which have been observed to have beneficial for wounds with slough and infection and has been shown
effects on various steps of the wound healing cascade, to be useful in diabetic ulcers, pressure sores and venous
both in the laboratory and in the clinic. However, most of ulcers. It can be a useful tool against drug resistant
the evidence to date has been in the form of observational strains of bacteria, for example Methicillin resistant
studies with very few controlled trials employing small Staphylococcus aureus (MRSA). Larva therapy is cost
numbers of patients. Magnetism in particular was more effective and tolerance is excellent. Apart from the
effective than control in healing plantar ulcers in leprosy presence of fistulas, and the proximity of the wound to
(30) and resulted in better wound outcomes in patients major blood vessels or vital organs, there appear to be no

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What is New in Wound Healing?

contraindications. Limitations are the lack of aesthetic C. Cadaver derived processed dermis (Alloderm,
appeal and the short shelf-life of maggots. Life Cell Corporation)
2. Skin Substitutes Cadaveric skin is processed to remove all dermal and
That skin is the best dressing is a well known epidermal cells, resulting in an acellular dermal collagen
surgical aphorism. The normal structural and cellular matrix. Following application the graft revascularises
components of skin not only have a barrier function on from the wound bed and is repopulated by recipient cells.
the wound but also exert a complex, benign and active Bilayered Products
influence on the wound environment which has been
D. Bilayered skin equivalent (Apligraf ,
termed the biological effect of a skin dressing.
Organogenesis Inc.)
Tissue engineering has provided us with a number of
Bioengineered bilayered skin substitutes contain a
clinically viable alternatives to autograft skin that may be
used in a broad spectrum of clinical scenarios from dermal and epidermal layer closely resembling the
covering raw areas as in burns to stimulating the healing architecture of skin. They contain matrix proteins and
processes in a static chronic wound. The products may be expresses cytokines. They do not, however, contain
classified into single layered products (containing the melanocytes, Langerhans cells, macrophages,
equivalent of either the epidermis or the dermis) or lymphocytes, blood vessels or appendages. Apligraf is
bilayered products (containing layers which mimic both one such substitute which contains neonatal foreskin
the dermis and epidermis). A brief discussion on a few of fibroblasts and keratinocytes on a dermal matrix made of
the currently available products follows. bovine type I collagen. It has been proven to be effective
in achieving faster healing in diabetic and venous and
Single layered products
pressure ulcers when compared to conventional
A. Cultured keratinocytes (Epicel , Genzyme treatment (36-39). An infected wound and allergy to
biosurgery) bovine products are contraindications.
Keratinocytes harvested from the host can be grown E. TransCyte (Smith and Nephew Inc.)
to produce stratified sheets of keratinocytes in vitro. The
major advantage of this technique is that only a 2-8 cm2 This biological dressing contains human neonatal
area of the host skin is needed to generate sheets of fibroblasts cultured on the silicone membrane bonded
autologous keratinocytes which can cover 60-90% of the nylon mesh. This has been successfully used in treating
patients surface area. Expansion of the order of 100- partial thickness burn wounds (40).
1000 -fold is possible in 2-4 weeks. The main use of F. Integra (Integra Life Sciences)
keratinocyte sheets has been as a method of achieving
The dermal equivalent of this bilayered substitute is
early wound closure in extensive burns. It has also been
made of cross linked bovine collagen and chondroitin
applied over allogenic cryopreserved graft skin in this
sulphate. The epidermal equivalent is made of silicone. As
situation. Long term survival of keratinocytes has not
healing progresses, the dermal layer is replaced by an
been proven, but at least it functions as a moist occlusive
dressing and stimulates endogenous healing by endogenous matrix. The silicone layer may then be
generating cytokines and growth factors (35). removed and an epidermal autograft applied.

B. Human dermal replacement (Dermagraft, 3. Stem cell therapy

Smith and Nephew Inc.) Bone marrow derived stem cells are pleuripotent,
New- born foreskin derived fibroblasts when cultured being capable of differentiating into a variety of cells. This
on a 3-dimensional polymer scaffold remain metabolically property is being exploited in the wound healing
active, producing growth factors that support wound environment. Early reports from case series on the
healing. Dermagraft is single layered and cryopreserved. application of bone marrow derived cells on the chronic
The polymer scaffold is absorbable. It has been used in wound are promising (41). However, large controlled
burns and diabetic foot ulcers. trials are needed to clarify their role in therapeutics.

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 S. KUMAR, P. F. WONG, D. J. LEAPER

4. Growth factors 5. Gene therapy

Normal wound healing is heavily dependent on a Gene therapy, put simply, aims to help the cell to help
plethora of growth factors and cytokines which variably itself by providing it with specific genes. Genes once
interact with cells and the matrix at different stages. Use incorporated in the cell affect the cell and its milieu
of growth factors topically to augment wound healing, through their products of expression. These in the
although a very intuitive prospect, is fraught with context of wound healing are growth factors, their
difficulties for the following reasons: receptors, adhesion molecules and inhibitors of
The multitude of factors involved proteases. Gene therapy has the potential to circumvent
most of the shortcomings of topical growth factor
Problems in matching the spatial and temporal
therapy mentioned above.
profile found in wounds
Classical gene therapy involves incorporating the gene
Rapid degradation in the wound by proteases
to directly influence the wound by its product of
Lack of a vehicle for sustained release expression. Epigenetic therapy is a variation wherein a
Cost nucleotide sequence is used to modulate the expression of
Although animal studies have evaluated a number of the endogenous genes.
growth factors, only the following have shown promise in Genes can be delivered by biological (viral vectors),
clinical studies. physical (e.g., microinjection, microseeding), and chemical
Platelet derived growth factor (PDGF) (e.g., cationic liposomes) methods. A new method of
PDGF is currently the only growth factor licensed for sustained delivery of genes to the wound milieu called
topical use. The efficacy of recombinant PDGF-BB matrixenabled gene transfer or gene activated matrix
(becaplermin gel) in diabetic foot ulcers has been proven (GAM) therapy is evolving. This involves embedding genes
in a number of randomised trials (42,43). In a meta- onto a scaffold matrix which remains in the wound
analysis of 4 randomised controlled trials, patients with a increasing the length of exposure of target cells to the
2
median ulcer area of 1.5 cm treated with becaplermin genes (56).
gel at a concentration of 100 g/g, achieved a 39% Transfer could be established in vivo (the gene being
higher healing rate when compared to placebo gel (44). delivered to the cells in the wound directly) or ex vivo
Efficacy of PDGF in healing pressure ulcers has been (gene transfection is achieved outside the wound
demonstrated in phase I and II human studies (45,46). environment in a selected population of cells which are
then transplanted into the wound).
Keratinocyte growth factor 2 (KGF 2)
Once in the wound environment, the genes may also
A multicentric double blind controlled study using
be controlled by externally applied substances by specific
recombinant KGF-2 (Repifermin) on venous ulcers
mechanisms termed genetic switches.
showed that it healed twice the number of ulcers and at
twice the rate of controls in 12 weeks (47). The scope of gene therapy is expanding:
EGF and FGF Genes may be employed to augment an effect (e.g.,
EGF and basic FGF have been used topically to promote healing)
augment epithelialisation of skin donor sites. - Genes for growth factors and their receptors
Improvements in healing have, however, been negligible - Genes for tissue inhibitors of metalloproteinases
to modest (48-50).
Alternatively they may be used to inhibit an effect
While some studies found EGF to be effective in non- (e.g., suppress overhealing or excessive scarring)
healing chronic wounds (51), diabetic foot ulcers (52) and
in corneal wounds (53), Falanga did not detect any - Genes for antibodies against specific growth factors
significant improvement in venous ulcers (54). - Genes for soluble receptors of growth factors
FGF has proved useful when applied to pressure sores Gene therapy as applied to wound healing is
(55). understandably in its infancy. Currently trials are

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What is New in Wound Healing?

underway exploring the use of PDGF, VEGF and FGF 2. Dressings

genes in diabetic foot and venous ulcers. The sheer variety of dressings available today is
Future directions include using multiple genes probably matched only by the diversity in the wounds
concurrently (e.g., genes for growth factors and their they are employed to treat. Practices steeped in tradition
receptors), and fine tuning the gene expression as like the simple gauze soaked in antiseptics applied directly
required using genetic switches. to the open wound have given way to more evidence-
6. Other biological therapies based approaches aimed at maintaining a moist
environment that supports the healing wound. Another
Fibrin sealant, primarily used for its adhesive and
conceptual shift is targeted therapy. The appreciation that
haemostatic properties, has been claimed to accelerate
wounds have different barriers to healing at different
revascularisation, decrease wound contraction and
points in time has guided the evolution of the various
produce less inflammatory response when compared to
groups of dressings addressing specific problems. The
sutures. It has also been used as a vehicle for delivery of
choice of dressing is dictated by the needs of the wound
growth factors. However, its use in chronic non-healing
and this is reflected in the classification system shown in
wounds is limited.
Table 3.
Platelet gel prepared from autologous blood contains
However, this classification is not a rigid one as, in
supraphysiological doses of platelets which provide growth
practice, there are many hybrid or composite dressings
factors and proteins like fibronectin. In the field of
which combine aspects of members of different groups to
maxillofacial surgery they have been found to reduce
achieve an optimum effect. A brief discussion on some of
oedema and ecchymosis in the early postoperative phase
the types of dressings follows.
and to accelerate the ingrowth of autogenous bone grafts.
However, a randomised trial of its effect on venous ulcers Films are usually polyurethane based, transparent
did not find any significant effect on healing (57). allowing inspection, retain moisture, provide
C. Miscellaneous Therapies occlusion, prevent contamination but provide no
absorption. Typical use includes the postoperative
1. Hyperbaric oxygen
wound.
Oxygen is more than a nutrient. Most vital cellular and
Soft silicone mesh (Mepitel*) is a non-adherent,
molecular mechanisms are influenced either directly or
porous, semi-transparent dressing with a wound
indirectly by the available tissue levels of oxygen. Well
contact layer consisting of a flexible polyamide net
known impediments to healing like ischaemia act so
coated with soft silicone. Although it is non-
because of the tissue hypoxia they impose, whereas the
absorbant, the porous nature allows fluid to pass
beneficial effects of modalities like warming are at least
through to the secondary dressing. Primarily used
in part attributable to enhancement of tissue
in skin donor areas.
oxygenation. Hyperbaric oxygen therapy is one method of
increasing oxygen delivery to tissues and involves Hydrocolloids are composed of a mixture of
breathing 100% oxygen in pressurised chambers (2-2.5 adhesive, absorptive (carboxymethyl cellulose) and
atmospheres). The PO2 may reach 1500 mmHg. elastomeric ingredients. They are waterproof,
impermeable to bacteria, promote autolytic
A recent systematic review (58) on the use of
debridement and can be changed once every 3-7
hyperbaric oxygen in wounds identified 6 controlled trials
days. However, absorption is limited. Useful in
(2 of which were randomised) involving diabetic ulcers
granulating and epithelialising wounds with
and 1 non-randomised trial involving chronic non-healing
minimal exudates.
wounds. All of these studies reported statistically
Hydrogels are composed of a polymer
significant positive clinical outcomes in favour of
(carboxymethyl cellulose or modified starch),
hyperbaric oxygen therapy.
propylene glycol and up to 80% water. Their main
Hyperbaric oxygen therapy needs special equipment use is as hydrating agents in drying wounds. They
and expertise and is not without complications. This promote autolytic debridement but absorption is
restricts its use as an adjunct in recalcitrant ulcers. limited.

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 S. KUMAR, P. F. WONG, D. J. LEAPER

Table 3. Types of Dressings.

Broad category Primary goal Group Examples /Comments

General
purpose dressings 1. Cover with varying occlusion Augmented Fabrics Films Mepitel*, Vaseline gauze, tulle
Aerosols/Sprays Opsite*, Tegaderm*, Opsite*

2. Occlusion, Absorption, Foams Allevyn*, Lyofoam*

Hydration
Hydrogels Intrasite*, Tegagel*

Hydrocolloids Duoderm*,Comfeel*, Tegasorb*

Alginates Sorbsan*, Kaltostat*

Specialised dressings 3. Delivery Medicated dressings Iodine, silver, zinc and antibiotics can be delivered
by a variety of vehicles-ointments/creams/
impregnated beads

Nitric oxide releasing dressings Experimental

Cell platforms Experimental. Being developed to enable cell based

therapy

Gene activated matrix Experimental. Being developed to deliver genes

effectively

4. Tissue substitution Skin substitutes Epicel*, Demagraft*

5. Deodorisation Adsorbant and antibiotic Charcoal based dressings, Inadine* , Polysaccharide

impregnated types beads

6. Protease sequestration Promogran*

Modified dialdehyde cotton gauze

7. Compression Three and four layered bandages Tensopress*, Coban*

Alginates are derived from seaweed and are Promogran* is a protease modulating matrix
available as ropes, sheets or wafers. Are highly dressing made of collagen and oxidised
absorbent and convert to a gel on absorption. regenerated cellulose. Promogran binds proteases
However, if the wound is not producing enough which, when present in excess, are a major barrier
fluid, they may cause drying of the wound. Useful to healing. This also results in the increased
availability of growth factors in the wound.
in packing cavities, but usually require a secondary
Promogran has been found to be useful in venous
dressing.
and diabetic ulcers.
Foams are polyurethane based, non-adherent,
Modified dialdehyde cotton gauze is ordinary
heavily absorbent dressings which conform to
cotton gauze modified by oxidation,
wound contours and can be left in place for up to phosphorylation and sulphonation; it has been
4 days. However, they do not protect from shown in in vitro studies to have a 4-fold affinity
external contamination and usually need a to sequestrate neutrophil elastase (59). The
secondary dressing. Useful in wounds with large technology although promising needs to be tested
volume exudates. in the clinical setting.

157
What is New in Wound Healing?

Cell platform is an evolving method of delivering multidisciplinary, may evolve into a specialty in its own
cell based therapy to the wound. Keratinocytes right. However, wounds, as ubiquitous as they are, will
and fibroblasts grown on bioreactive microporous continue to be seen and treated by different strata of
beads enclosed in a polyethylene bag have shown health care providers. This means that while technologies
potential when applied to wounds in mice (60). like tissue engineering and gene therapy hold great
potential it is the appreciation of the pathophysiology of
wounds along with the awareness of the different
Conclusion modalities of treatment from which to choose which will
The healing wound has been recognised for millennia have the greatest impact on the average patient. This
as a minefield of activity an activity which we now know article seeks to address that need for dissemination.
is orchestrated by native and infiltrating cells interacting
with the matrix. The language of this complex machinery
is only beginning to be uncovered by the discovery of Corresponding autor:
Senthil KUMAR
many superfamilies of molecules. Defining the
9, Middlefield road
interactions precisely in space and time are the challenges
Hardwick
for the future. Developments in therapy would be
Stockton-on-Tees
expected to follow naturally.
United Kingdom
From a clinical standpoint it is tempting to speculate TS19 8PF
that wound management, which is increasingly becoming e-mail: sanskrity@hotmail.com

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