State of the Art in Topical Wound-Healing Products

Abstract

Chronic wounds represent a significant medical burden. Such wounds fail to normally progress through the stages of healing, often complicated by a proinflammatory milieu caused by increased proteinases, hypoxia, and bacterial burden. As a result, several modalities, such as dressings, antimicrobials, growth factors, and human skin substitutes, have been devised in an attempt to correct the chronic wound environment. This review addresses these modalities with a focus on evidence and randomized controlled trials.

Full text

WOUND HEALING
State of the Art in Topical Wound-Healing Products
Kenneth Fan, B.S.
Jennifer Tang, B.S.
Julia Escandon, M.D.
Robert S. Kirsner, M.D.,
Ph.D.
Miami, Fla.
Summary: Chronic wounds represent a significant medical burden. Such
wounds fail to normally progress through the stages of healing, often compli-
cated by a proinflammatory milieu caused by increased proteinases, hypoxia,
and bacterial burden. As a result, several modalities, such as dressings, antimi-
crobials, growth factors, and human skin substitutes, have been devised in an
attempt to correct the chronic wound environment. This review addresses these
modalities with a focus on evidence and randomized controlled trials. (Plast.
Reconstr. Surg. 127 (Suppl.): 44S, 2011.)
RATIONALE FOR
TOPICAL TREATMENT
Chronic wounds are a medical challenge, cost-
ing the U.S. health system over $25 billion
dollars per year.1Leg ulcers alone affect up-
ward of 2.5 million Americans, with 2 million work-
days lost per year.2Two-thirds of patients report neg-
ative emotional impact directly attributable to their
ulcer, illustrating the necessity for proper wound
care.3Although the causes of chronic wounds are
numerous, diabetic, arterial, venous, and pressure
ulcers constitute the majority of chronic wounds.
Despite unique pathophysiology, factors contribut-
ing to chronicity of nonhealing wounds become sim-
ilar with time4(Fig. 1).
BIOLOGY OF CHRONIC WOUNDS
Wound healing is a dynamic process of three
overlapping phases: inflammation, proliferative
phase with granulation tissue formation and epi-
thelialization, and tissue remodeling.5,6 Inflamma-
tion lasts several days in the acute healing wound
but persists in the chronic wound.7Driven by
proinflammatory cytokines,8–10 the prolonged and
overactive neutrophil response leads to increased
protease activity, mainly matrix metalloproteinases.11,12
In some cases, protease activity has been found to be
over 100 times higher in chronic compared with
acute wounds.13 Increased metalloproteinases lead
to degradation of growth factors, their receptors,11
and adhesion proteins, such as fibronectin and
vitronectin,14 preventing cell adhesion for normal
wound closure.11,13,15 As a result, topical treatments
aimed at inflammation and excess proteases have
been developed.
Wounding damages the blood supply, leading
to hypoxia,16 along with subsequent decreased ox-
idative bursts and microbicidal activity by poly-
morphonuclear leukocytes.17,18 The uncontrolled
polymorphonuclear leukocytes respond to low ox-
ygen tension by releasing proteinases and toxic
oxygen metabolites, which damages endothelial
cells, leading to cellular destruction, deposition of
fibrin, and further decreased delivery of nutrients
and oxygen, propagating a vicious cycle.16 Sys-
temic disorders, such as decreased cardiac output,
smoking, peripheral vascular disease, past irradi-
ation, and chronic infection, all contribute to hyp-
oxia in the local environment.15 Reperfusion in-
jury plays a role. During ischemia, substances such
as hypoxanthine and xanthine oxidase are made.
Reperfusion causes oxygen to react with these sub-
stances, producing superoxide bursts that further
damage the endothelium.19
The inflammatory state is also prolonged by the
presence of bacteria,20 leading to increased meta-
bolic demand and protease levels in the wound.21
The mere presence of bacteria in chronic wounds
does not affect healing.22 Definitions used for overt,
clinical infection include microorganism density
greater than 105to 106colony-forming units/g, as
these levels are used as a threshold for delayed
wound healing and disease.23–25 Symptoms such as
From the University of Miami, Miller School of Medicine,
and the Department of Dermatology and Cutaneous Surgery,
University of Miami.
Received for publication April 7, 2010; accepted July 12,
2010.
Copyright ©2010 by the American Society of Plastic Surgeons
DOI: 10.1097/PRS.0b013e3181fbe275
Disclosures: Dr. Kirsner has received honoraria as
an advisor to Organogenesis and Molnlycke and as
a speaker for Advanced Biohealing and Organogen-
esis, and research grants from Healthpoint and
Advanced Biohealing. There are no other financial
disclosures to report.
www.PRSJournal.com44S

exudate, odor, pain, change in color and texture
of tissue, wound deterioration, and rapid onset of
slough tissue herald increasing bacterial burden.21
However, infection should be considered if the
wound simply fails to heal, as symptoms are not
always reliable.20
Corticosteroids, immunosuppression, diabetes,
liver cirrhosis, and undernourishment may serve to
suppress the immune system, increasing the risk of
infection.26 Malnourishment also deprives the pa-
tient of essential vitamins and proteins necessary
for proper healing.27 Insufficient blood flow, se-
roma, necrosis, hematoma, and other local factors
further increase the risk of infection.26 The pres-
ence of foreign materials and necrotic tissue
greatly decreases the amount of bacteria necessary
for wound infection.15,28 Dressings and surgical
techniques for de´bridement of these foreign ma-
terials are available to the surgeon.
DRESSINGS
Two general categories of wound dressing
exist.21 Passive wound dressings mainly control
wound moisture levels. The synthetic polymers
in dressings afford customization in terms of
absorbency, physical form, and gas permeability
(Table 1).29–37 Active dressings locally alter the
wound’s biochemical environment.21
Passive Dressings
The rationale for occlusive dressings is often
traced to 1962, when Winter observed that mois-
ture-retaining dressing speeds epithelization of
acute, superficial compared with air-exposed
wounds in pigs.38 The following year, Hinman
and Miabach published results in humans dem-
onstrating similar results.39
The benefits of occlusion in partial-thickness
wounds are numerous. Without the impediment
of the crust seen in dry wounds, the wet dermal
surface provides a superior medium for epidermal
cells to migrate.40 Eaglstein and Mertz demon-
strated that occlusion accelerates epithelialization
in the acute split-thickness wound by 40 percent.41
Acute wound fluid under the occlusive bandage
contains substances, such as growth factors, that
stimulate proliferation of fibroblasts and endothe-
lial cells,42,43 promoting granulation tissue formation.44
Fig. 1. Flowchart of the nonhealing, chronic wound. ECM, extracellular matrix.
Volume 127, Number 1S •Topical Wound Healing
45S

Table 1. Available Passive Dressing Types*
Type Description
Discharge
Amount Indications Advantage Disadvantage
Examples of Available
Products
Alginates Produced from brown
seaweed; either 100%
calcium alginate or 80:20
calcium alginate to sodium
alginate; fibrous gel is
formed when calcium in
the dressing exchanges with
sodium from the wound29;
absorbs 20 times of weight;
nonocclusive; requires
secondary dressing; loose
rope or pad forms30
Heavy Moderate to heavy
exudate in
superficial to deep
wounds31; autolytic
de´bridement32;
rope form to pack
deep or tunneling
wounds; infected
wounds
Conformable; allows gas
exchange along with
protection from
contamination30; draws
out contaminates and
excess exudate in
heavily draining
wounds33
May dehydrate wounds
with minimal
exudate;
contraindicated in
third-degree burns31;
not recommended
for dry eschar or light
exudate,34 as it may
adhere and cause
pain on removal;
need to be changed
daily
Algicell Calcium Alginate
(Dermasciences,
Princeton, N.J.);
AlgiDERM (Bard
Medical, Covington,
Ga.); CURASORB
(Kendall, Dublin,
Ireland); KALTOSTAT
(ConvaTec, Skillman,
N.J.); Melgisorb
(Mo¨ lnlycke, Go¨teborg,
Sweden); Tegagen (3M,
St. Paul, Minn.)
Foams Air bubbles in a matrix of
polyurethane or silicone
capable of holding or
releasing fluids; highly
absorbent while
maintaining moisture;
provides thermal insulation;
dressings can be applied as
sheets or liquid30; some
require secondary dressings
Moderate Moderate to heavy
exudate in
superficial to deep
wounds31; autolytic
de´bridement;
padding and
protection in high
trauma areas31;
infected wounds;
under
compression
dressing
Silicone liquid form is
conformable to the
wound30; nonlinting
facilitates atraumatic
removal34; polyurethane
foam provides uniform
dispersion of exudate in
absorbant layer with
semipermeable backing
prevents strike-through,
which is when exudates
permeate dressings,
providing an entry point
for bacteria35
Does not conform well
to deep cavity or
sinus tracts; may
dehydrate wounds
with minimal
exudate; may
promote maceration
if saturated34
Allevyn Foam (Smith &
Nephew, London, United
Kingdom); Contreet
Foam (Coloplast,
Minneapolis, Minn.) ;
CURAFOAM (Kendall,
Dublin, Ireland);
Hydrocell Foam
(Dermasciences,
Princeton, N.J.); Invacare
Foam (Invacare Supply
Group, Elyria, Ohio);
LYOFOAM (Mo¨lnlycke,
Go¨teborg, Sweden);
Mepilex (Mo¨lnlycke,);
Versiva (ConvaTec,
Skillman, N.J.)
Transparent
film Thin sheet of polyurethane
film; semipermeable,
variable water vapor
transmission rate31;
impermeable to bacteria or
fluids
Scant Dry wounds to
maintain moisture;
IV site protection;
autolytic
de´bridement;
secondary dressing
Barrier against bacteria
and contaminants34;
binds tightly leading to
protection of high-
friction areas31,33;
flexible, can be placed
over joints
No absorbency; fluid
can accumulate,
break adhesive seal,
and cause infection
and maceration;
required border of
intact skin may be
torn by adhesives;
problematic with
fragile skin31;
adherent material can
come in contact with
wound and tear off
reepithelialized skin36
Comfeel Film (Coloplast,
Minneapolis, Minn.);
OpSite (Smith &
Nephew, London,
United Kingdom);
Polyskin (Kendall,
Dublin, Ireland);
ReliaMed Transparent
Film (ReliaMed, Fort
Worth, Texas);
Tegaderm (3M, St. Paul,
Minn.)
(Continued)
Plastic and Reconstructive Surgery •January Supplement 2011
46S

Table 1. Continued
Type Description
Discharge
Amount Indications Advantage Disadvantage
Examples of Available
Products
Hydrocolloids Mixture of materials such as
gelatin, pectin,
polycarboxymethylcellulose,
elastomers bonded to a
semipermeable film or a
foam sheet; highly
occlusive; brown, self-
adherent surface; usually
waterproof; absorbs
moisture slowly; available in
sheet form or
paste/granules to fill deep
wounds37
Minimal Light to moderate
exudate in shallow
full-thickness
defects31; wounds
requiring
moisture, such as
granulation tissue;
used under
compression
dressing; autolytic
de´bridement,
especially with
necrotic, dry
eschar
Available in ultrathin
conformable form;
reduce pain; highly
occlusive property allows
patient to continue daily
activity; molds well to
wound; some
transparent forms allow
visualization of wound;
barrier versus bacteria
and contaminants23, 31;
can be left for 7 days30
May leave residue or
adhere to wound
surfaces34;not
recommended with
heavy exudate, active
infection, or sinus
tracts34;contraindicated
in third-degree burns31;
injury of periwound
skin; highly occlusive
property can promote
anaerobic infection in
certain patients31;may
promote hypertrophic
granulation tissue; may
leave residue and odor
that can be mistaken
for infection
Allevyn (Smith & Nephew,
London, United
Kingdom); DuoDERM
(ConvaTec, Skillman,
N.J.); Hydrocol (Bertek,
Rockford, Ill.); Invacare
Hydrocolloid (Invacare
Supply Group, Elyria,
Ohio); Tegasorb (3M,
St. Paul, Minn.)
Hydrogels Glycerin- or water-based cross-
linked polymer gels or
sheet; up to 96%
water-based30;
semipermeable, transmits
vapor and water;
amorphous gels, sheet
dressings, or beads;
secondary dressing can
provide enhanced
absorption and
compression33; bead type
dressing can absorb
microorganisms, exudate,
or wound debris30
Minimal/
scant Minimal to
moderate exudate
in superficial to
deep wounds31;
rehydration of
wound bed; gel
form can pack
deep wounds and
conform to wound
defects; autolytic
de´bridement,
especially with
necrotic, dry
eschar; change
daily to 7 days
Cooling effect of sheet
hydrogels may provide
relief in burned or
excoriated wounds31;
can be used with
infection34
Minimal absorption;
desiccates quickly
without covering;
excess use can cause
wound maceration;
may promote yeast31;
sheet dressing
requires secondary
securement
Amorphous types include
Comfeel Triad (Coloplast,
Minneapolis, Minn.),
DuoDERM (ConvaTec,
Skillman, N.J.), and
Restore Hydrogel
(Hollister, Libertyville, Ill.);
Sheet types include
AQUAFLO (Kendall,
Dublin, Ireland), Aquasite
(Dermasciences,
Princeton, N.J.),
AQUASORB (DeRoyal,
Powell, Tenn.), and
CarraDres (Carrington
Laboratories, Irving,
Texas)
Contact
layers/low
adherent
Provides layer between
dressing and wound bed to
protect fragile healing
tissue34; single layer; reduces
adherence of wound to
dressing; woven or
nonwoven
Scant Granulation tissue
requiring some
moisture; apply
directly over the
wound or over
topical medication
Cheap; widely available Exudates will soak
through to above
dressing, not to be
used in viscous
exudates or third-
degree burns
Dermanet Wound Contact
Layer (DeRoyal, Powell,
Tenn.); Mepitel Soft
Silicone Wound Contact
Layer (Mo¨ lnlycke
Health Care, Go¨ teborg,
Sweden); Profore WCL
(Smith & Nephew);
ProGuide WCL (Smith
& Nephew); 3M
Tegapore (3M, St. Paul,
Minn.) (Continued)
Volume 127, Number 1S •Topical Wound Healing
47S

Depending on the type, occlusive dressings can also
manage exudates (Table 1).45,46 Randomized trials
have demonstrated increased speed and less painful
healing in acute, superficial wounds compared with
nonocclusive modalities.47,48 An increased rate of
healing has been observed when dressings are
placed within 2 hours of injury and kept on for at
least 24 hours.49
Theoretically, a moist environment provides a
good environment for bacterial colonization and
possibly infection, which can be an impedance to
applying occlusion. This has not been shown to be
true: occlusion actually provides a barrier against
infection and reduces infection rates.23,34,36,50
Although partial-thickness healing is faster un-
der occlusion, it is less clear whether occlusive dress-
ings speed acute, full-thickness wound healing.48 In
the absence of wound site disease, full-thickness
wounds will eventually heal by means of secondary
intention.51 Although some experimental data in
pigs suggest complete healing is faster with occlusive
dressings in full-thickness wounds versus nonocclu-
sive therapy,52,53 the speed at which epithelialization
occurs and concomitant contractures are often not
optimal or desirable in patients. Most clinicians will
opt for grafts or flaps instead.
Similarly, the effect of occlusion on chronic
wounds has not been fully elucidated, as evidence
is mixed. It has been demonstrated that chronic
wound fluid under occlusive dressings actually in-
hibit cell proliferation in vitro54 by restricting entry
into the S phase and DNA production,55 and deg-
radation of adhesion proteins.14
Despite this, there are many reasons to justify the
use of occlusion in chronic wounds. It has been
shown to facilitate painless and effective autolytic
de´bridement,56 which is the use of enzymes within
the wound fluid to remove necrotic debris.36 Occlu-
sion reduces cost because of less frequent dressing
changes compared with standard gauze.57,58 Further-
more, the same principles of pain reduction,40,58 ex-
udate management, and safety59 with the use of oc-
clusive dressings apply in the chronic wound.
Currently, dressing modalities are chosen
mostly based on opinion, as high-level evidence is
conflicting.60,61 Although some meta-analyses have
demonstrated benefits of occlusive dressings in
the treatment of pressure ulcers62 and chronic
wounds,32,63 other authors have found insufficient
evidence to recommend modern dressings for
pressure ulcers,64,65 arterial leg ulcers,29 chronic
leg ulcers,66 venous ulcers,30,67 or surgical wounds
healing by secondary intention.61,68 The lack of
effective animal models available for study69 and
Table 1. Continued
Type Description
Discharge
Amount Indications Advantage Disadvantage
Examples of Available
Products
Composites Two or more distinct
dressings combined to take
advantage of each different
property; usually has an
absorptive layer, adhesive
border, and nonadherent/
semiadherent layer for
wound covering
Aquacel Hydrofiber
(ConvaTec, Skillman,
N.J.); Comfeel Plus
(Coloplast, Minneapolis,
Minn.); CovaDerm
(DeRoyal, Powell,
Tenn.); Tegaderm
Alginate (3M, St. Paul,
Minn.); Tegaderm Foam
(3M); Tegaderm
Hydrocolloid (3M);
Tegaderm with
Absorbent Pad (3M)
IV, intravenous.
*Data from Ovington L. The art and science of wound dressings in the twenty-first century. In: Falabella AF, Kirsner RS, eds. Wound Healing. Boca Raton, Fla.: Taylor & Francis Group; 2005:1–7;
Cuzzell J. Choosing a wound dressing. Geriatr Nurs. 1997;18:260–265; Hess CT. Wound Care. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2005; and Jones V, Grey JE, Harding KG.
Wound dressings. BMJ. 2006;332:777–780.
Plastic and Reconstructive Surgery •January Supplement 2011
48S

level I evidence makes providing evidence-based
recommendations difficult.29,30,32,66
Awaiting better evidence, dressing choices should
be based on clinical experience.70,71 Ease of use, pa-
tient preference, amount of wound drainage, and
protection against bacteria should all be taken into
consideration (Table 1).30,64,72 Amoistyetabsorbent
environment needs to be maintained, avoiding
wound maceration or dehydration.30,70,71,73,74 Dress-
ings should minimize external forces such as friction
and sheer and should stay in place.70,71 Fear of mac-
eration and its potential complications in certain
wound types suggest completely occlusive and highly
adhesive dressings should be avoided in diabetic foot
ulcer,75 and hydrogels should be used instead.65
Active Dressings
Interest in development of active dressings stems
from the altered biology of the chronic wound (Ta-
ble 2).27,34,68,77 Potential targets include increased
bacterial load and excessive protease levels, which
lead to the development of antimicrobial, protease
inhibitor,76 and collagen dressings.21 The combina-
tion of antimicrobials with the dressings described
above affords bacterial reduction and maintains a
moist environment.
Collagen Dressings
Collagen has long been known to have a crit-
ical function in wound healing, providing platelet
aggregation; hemostasis; and chemotaxis of mac-
rophages, granulocytes, and fibroblasts.78 It was
rationalized that exogenous collagen matrices
might provide a scaffold for tissue ingrowth when
endogenous collagen is disrupted by the proteo-
lytic wound environment.21 In addition, dressings
containing oxidized regenerated cellulose bind
the high level of proteases seen in chronic wounds,
protecting growth factors from destruction and
neutralizing free radical damage.79,80
However, randomized controlled trials of 55
percent bovine collagen to 44 percent oxidized
regenerated cellulose dressing (Promogran wound
matrix; Systagenix, North Yorkshire, United
Kingdom) did not demonstrate significantly bet-
ter wound closure of Wagner grade I or II dia-
betic foot ulcers81 or venous leg ulcers,82 al-
though variability of loading (for the former
study) and dressing change procedure might
have negatively affected these results.
Another collagen dressing comprised of por-
cine-derived acellular small intestine submucosa
(Oasis Wound Matrix, Fort Worth, Texas) was found
to be equivalent to recombinant human platelet-
derived growth factor (rhPDGF)-BB in diabetic ul-
cers (see below) (becaplermin, Regranex; Systage-
nix, Commonwealth, Mass.).83 The dressing was
found to improve healing in full-thickness diabetic
ulcers84 and mixed vascular ulcers85 when compared
with standard-of-care treatment at 12 weeks and pe-
troleum gauze at 8 weeks, respectively.
TOPICAL ANTIMICROBIALS
The ideal antimicrobial exists in an equilib-
rium whereby bacteria bioburden is reduced with-
out interfering with cellular processes by means of
cytotoxicities.16,20,86 Although antibiotics have spe-
cific sites of activity, antimicrobials have a lower
incidence of resistance and multiple sites of ac-
tivity, and target a wide variety of bacteria, proto-
zoa, fungi, viruses, and prions.16,20,87 The most
commonly used products include chlorhexidine,
povidone-iodine, cadexomer iodine, alcohol, ac-
etate, hydrogen peroxide, boric acid, silver sulfa-
diazine (an antibiotic), silver nitrate, and sodium
hypochlorite (Table 3).26,45,88–106
Iodophors, a class of antiseptic including po-
vidone-iodine and cadexomer iodine, are slow-
release carriers designed to curb elemental iodine
toxicity.87 Most in vitro studies suggest that povi-
done-iodine is toxic to the cells that participate in
wound healing. In vivo studies have not found that
it promotes good wound healing.91,107 However,
evidence exists suggesting cadexomer iodine,
compared with standard-of-care regimens, results
in significantly higher complete venous ulcer heal-
ing rates.96 It is also more cost effective, results in
less infection, and has fewer adverse effects than
hydrocolloids or paraffin gauze.97
Silver compounds, particularly silver nitrate
and silver sulfadiazine, have been used widely in
burns. The reactivity of silver compounds with
negative substances such as DNA, RNA, proteins,
and components of the electron transport system
is the heart of its antimicrobial effect.87 Such re-
activity requires a carrier for consistent slow de-
livery to balance the cellular toxicity against the
microbicidal activity.
Moyer et al. found that 0.5% silver nitrate
administered on gauze dressing achieved such
balance.102,108 However, silver nitrate darkens tis-
sue, causes hyponatremia and hypochloremia,
and has been shown to be systemically absorbed.103
The very frequent applications, up to 12 times per
day, results in a large excess of silver at the wound
site.109 Furthermore, nitrate is converted to nitrite,
an oxidant capable of cell damage.
The advent of silver sulfadiazine, created from
the combination of silver nitrate and sodium sulfa-
diazine, allowed for better delivery of silver, allowing
Volume 127, Number 1S •Topical Wound Healing
49S

Table 2. Available Active Dressing Types*
Type Indications Comment Commercial Available Products
Antimicrobial
dressings Moderate to heavy exudate
depending on the passive
dressing27; may be
primary or secondary
depending on the
dressing chosen34
Silver-releasing foam shown to
decrease ulcer area, odor,
leakages, and maceration77;
no significance in terms of
achieving complete wound
healing, greater reduction in
chronic, infected, ulcer size
with silver-containing foam
dressings compared with
standard foam or best local
practice after 4 wk68
Acticoat (Smith & Nephew, London, United
Kingdom); Algicell Ag (Dermasciences, Princeton,
N.J.); Aquacel Ag (ConvaTec, Skillman, N.J.);
Contreet Foam/Biatain–Ag (Coloplast, Minneapolis,
Minn.); Contreet Hydrocolloid/Comfeel Ag
(Coloplast); Invacare Silver Alginate (Invacare
Supply Group, Elyria, Ohio); Iodosorb Gel and
Iodoflex Pad (Healthpoint, Fort Worth, Texas);
Maxorb Extra (Medline, Mundelein, Ill.); ReliaMed
Silver Alginate (ReliaMed, Fort Worth, Texas);
Restore Foam with Silver (Hollister, Libertyville,
Ill.); Silvasorb (Medline, Mundelein, Ill.); Silvercel
(Johnson & Johnson, New Brunswick, N.J.); Silverlon
(Silverlon Consumer Products, Geneva, Ill.)
Collagen
dressings Moderate to heavy exudate
in superficial to deep
wounds 27; can be use in
infected wounds27; can be
used in skin grafts, donor
sites, red or yellow
wounds27
Provides a scaffold for growth
of tissue; hydrophilic nature
allows cell attachment;
collagen encourages
hemostasis; chemotactic to
fibroblasts, granulocytes,
macrophages; oxidized
regenerated cellulose
inactivates excess protease
and protects growth factors
55% bovine collagen and 45% oxidized regenerated
cellulose (Promogran wound matrix; Systagenix,
North Yorkshire, United Kingdom); 90% bovine
collagen and 10% alginate (Fibracol plus collagen
dressing with alginate; Systagenix); 100% bovine
collagen (Medifill; Human BioSciences,
Gaithersburg, Md.); 100% porcine collagen (Oasis,
Cook Biotech, Fort Worth, Texas); collagen with
sodium alginate (Colactive; Smith & Nephew,
London, United Kingdom); type 1 hydrolyzed
bovine collagen (CellerateRX; Wound Care
Innovations, Fort Lauderdale, Fla.)
*Data from Ovington L. The art and science of wound dressings in the twenty-first century. In: Falabella AF, Kirsner RS, eds. Wound Healing. Boca Raton, Fla.: Taylor & Francis Group; 2005:1–7;
Cuzzell J. Choosing a wound dressing. Geriatr Nurs. 1997;18:260–265; Hess CT. Wound Care, 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2005; and Jones V, Grey JE, Harding KG.
Wound dressings. BMJ. 2006;332:777–780.
Plastic and Reconstructive Surgery •January Supplement 2011
50S

Table 3. Commonly Used Antiseptics*
Type Composition Indications Comments
Povidone-iodine Iodophor; complex of
polyvinyl/pyrrolidone
and 1–10% iodine;
available as a solution,
cream, scrub, ointment
Approved for short-term
treatment of
superficial and acute
wounds89
FDA has concluded no evidence of improved or slowed
wound healing89; irrigation with povidone-iodine in 12-hr-
old wounds colonized by Staphylococcus aureus in guinea pigs
showed no significant decrease in bacterial count90; 1%
povidone-iodine decreased wound infection in surgical
wounds, whereas 5% povidone-iodine aerosol inhibited
leukocyte migration and resulted in increased infection26;
1% povidone-iodine was nonsignificant in decreasing
bacterial counts vs. normal saline in acute traumatic wounds
after 10-min soak91; 1% povidone-iodine no more effective
than saline in chronic pressure ulcers92; no effect on wound
healing in 1% formulations26; no resistance has been
demonstrated93
Cadexomer iodine Iodophor; microspheres
0.1–0.3 mm in diameter
in a cadexomer-starch
with iodine physically
fixed within the sphere;
iodine performs its
antimicrobial activity as
bacteria and exudates
are absorbed within the
sphere45; available as
ointment or cream
Short-term use in
healable, superficial
wounds with high
bacterial burden94;
silver dressings, silver
sulfadiazine, and
cadexomer effective
against MRSA95
Found to generate higher rates of complete healing at 4–6 wk
vs. control when all patients receive standard of care in
venous leg ulcers96; cadexomer iodine paste more cost
effective vs. hydrocolloid or paraffin dressings in venous
ulcers with compression therapy97; increased epidermal
regeneration in full-thickness wounds compared with
cadexomer-starch ointment or saline treatment,98 and
partial-thickness wounds88; avoid use in in patients with
thyroid abnormalities97; good absorptive properties; 1 g of
cadexomer can absorb 7 ml of liquid35
Hydrogen peroxide 3% hydrogen peroxide is
most common; 6% in
some medical
formulations
Effective debrider by
loosening necrotic
debris88
No statistical difference in wound infection rates in surgical
wounds in 3% hydrogen peroxide vs. control99; may cause
tissue embolism in open wounds95; gas-producing property
may cause oxygen bubbles in newly formed skin100
Acetic acid 0.5–1% acetic acid (white
vinegar) Decreases pH to inhibit
Pseudomonas growth Possible cytotocitity,101 although other studies have shown no
effect on the wound healing environment in vitro100
Chlorhexidine Available in 0.5–4.0% Surgical irrigation,94
hand washing Persisting activity within the stratum corneum95; no definitive
evidence of cytotoxicity88; not enough evidence to draw
conclusion regarding chlorhexidine use in open wounds88
Silver compounds Silver nitrate; silver
sulfadiazine
(antibiotic); silver
charcoal;
nanocrystalline silver–
sustained silver-
releasing systems
(dressings); silver
calcium sodium
carboxymethylcellulose
dressing
Silver sulfadiazine is
commonly used as a
topical burn wound
treatment; silver
dressings, silver
sulfadiazine, and
cadexomer effective
against MRSA95
Silver nitrate stains objects on contact, causes hypochloremia
and hyponatremia, and is deposited within kidney, spleen,
liver, and muscles102,103; delay in healing of superficial and
partial-thickness burn wounds treated with silver
sulfadiazine for the full duration of treatment104,105; slow
emergence of silver-resistant bacteria with prolonged use106;
silver sulfadiazine rarely causes temporary leukopenia102
FDA, U.S. Food and Drug Administration; MRSA, methicillin-resistant Staphylococcus aureus.
*Data from Orsted H, Sibbald RG. Topical treatment of wound infection. In: Falabella AF, Kirsner RS, eds. Wound Healing. Boca Raton, Fla: Taylor & Francis Group; 2005:599– 615.
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51S

application two times per day. Fox demonstrated the
elimination of Pseudomonas in burn wounds, and
reduction in mortality and destruction in muscle
and skin compared with silver nitrate and mafenide
acetate.110,111 Since then, silver sulfadiazine gauze has
been used widely as an antibiotic in the topical treat-
ment of second- to third-degree burns. Nanocrystal-
line silver dressings represent further modification
in prolongation of silver delivery.109 With sustained
release of silver in a less rapidly deactivated form,
daily or weekly dressing change with steady silver
release can be achieved.
Despite large bodies of research on the ben-
efits of silver therapeutics, much less evidence re-
garding the effect of silver ion on the wound bed
exists.109 In vitro, silver has been shown to delay
wound healing when compared with tulle gras
dressing by means of toxicity to keratinocytes and
fibroblasts.112 In vivo, a similar delay in healing
exists with partial-thickness burns treated with sil-
ver sulfadiazine.113 Two recent Cochrane reports
found little evidence to support use of silver sul-
fadiazine in burn wounds or silver-containing
dressing in wounds because of a lack of clinical
proof of wound infection prevention or increased
rate of healing.104,105
As with occlusive dressings, a lack of high-quality
evidence exists.68,114,115 Recommendations are often
based on expert opinion or personal preference.94
Topical antiseptics should be reserved for signs of
bacterial burden detrimental to healing as evi-
denced by clinical signs (described above) or by
failure to heal to avoid possible cytotoxicity.20,21,109
GROWTH FACTORS
In a series of elegant experiments, Cohen no-
ticed that the purification of submaxillary gland
extracts led to earlier eyelid separation and erup-
tion of the incisor in mice, which eventually led to
the isolation of the first growth factor, epidermal
growth factor, and the 1986 Nobel Prize in
Medicine.116 Since Cohen’s discovery, knowledge
of growth factors has increased. In the acute
wound, growth factors function in a paracrine,
autocrine, intercrine, or endocrine manner, stim-
ulating healing.15 However, in the chronic wound,
the balance between stimulation and inhibition is
lost, as growth factors and their receptors are
destroyed,15,117 trapped,118 or maldistributed in the
chronic wound. Fibroblasts have also been re-
ported to be less responsive to growth hormone,
likely secondary to senescence.119
Platelet-Derived Growth Factor
Currently, rhPDGF-BB is the only growth fac-
tor approved by the U.S. Food and Drug Admin-
istration for use in chronic wounds (Table 4).121–123
Becaplermin is rhPDGF-BB produced by the yeast
Saccharomyces cerevisiae. The BB isoform is the only
one of the three (PDGF-AA, PDGF-AB, and PDGF-BB)
that has been shown to bind to both alpha and
beta receptors.120 Prepared as a topical gel, becapler-
min has been approved for the treatment of lower
extremity diabetic neuropathic ulcers that extend
into the subcutaneous tissue or beyond and have an
adequate blood supply (stage III or IV).
A meta-analysis of 922 patients among four
trials of rhPDGF-BB in full-thickness, nonhealing,
lower extremity diabetic ulcers found that becapler-
min with good wound care leads to a significant
increase in complete healing when compared with
placebo.121 Among the studies included in the meta-
analysis, Steed found that patients (n!118) treated
with rhPDGF-BB compared with placebo achieved
significantly higher complete wound healing rates
when evaluated at 20 weeks. Although not statisti-
cally significant, there was a greater recurrence rate
in placebo (46 percent) compared with rhPDGF-BB
(26 percent).124 This trial was the first to demon-
strate that topical application of a single growth fac-
tor could speed healing of a chronic wound. In a
pivotal trial, Wieman et al. found that patients (n!
382) treated with 100
!
g/g of becaplermin gel ex-
perienced significantly increased complete diabetic
lower extremity ulcer closure compared with place-
bo-treated patients.125
Despite the impressive findings, becaplermin
has recently received a new black box warning
from the U.S. Food and Drug Administration. Al-
though no increase in incidence of cancer was
found, there was an increased mortality secondary
to malignancy in those using three or more
tubes.122 The U.S. Food and Drug Administration
does not recommend becaplermin for those with
known malignancies. However, longer follow-up
of those patients in the original report found that
the increase in mortality among the becaplermin-
treated group did not persist.126
Epidermal growth factor and macrophage col-
ony-stimulating factor are being examined for use
in wound healing.127,128 Although initial results
were promising, fibroblast growth factor-2 has had
its production discontinued.129
ENGINEERED LIVING SKIN
Despite use of standard of care and advanced
topical treatments, some wounds fail to improve.130
Plastic and Reconstructive Surgery •January Supplement 2011
52S

Another topical therapy, engineered skin, is an
option (Table 5). Engineered skin was initially
envisioned to treat burn wounds when autologous
grafts were unavailable.131 However, skin substi-
tutes have received wider applications in chronic
venous132 and diabetic133,134 wounds, stimulating
healing through a variety of potential mecha-
nisms. Two major classes of cellular engineered
skin are currently used in the United States: der-
mal and bilayered constructs.132–144
Cellular Dermal Constructs
As a living dermal substitute, human fibroblast–
derived dermal substitute is created by seeding
fibroblasts derived from neonatal foreskin onto
abioabsorbablepolyglactinmatrix(Dermagraft;Ad-
vanced BioHealing, Inc., La Jolla, Calif.).146 The fi-
broblasts secrete adhesion molecules and growth
factors as epithelialization occurs over the dermal
bed replacement.143,147,148 Dermagraft was found to
result in a faster and higher percentage of com-
plete healing in full-thickness, chronic ("6 weeks)
diabetic ulcers compared with conventional therapy.133
Bilayered Constructs
The bilayered construct is composed of living
keratinocytes for epidermis and fibroblasts de-
rived from neonatal foreskin, placed within a bo-
vine type 1 collagen matrix for dermis.149 Apligraf
(Organogenesis, Canton, Mass.) is designed to re-
semble skin, with cells producing a milieu of
growth factors, collagen, and extracellular matrix
proteins to promote reepithelialization, granula-
tion tissue formation, and angiogenesis, while pro-
viding protection against infection.132,145,150,151 In
randomized controlled trials, Apligraf achieved a
significantly faster and higher rate of complete
healing in venous ulcers132,152 and diabetic foot
ulcers,134 with lower incidences of osteomyelitis
and amputations in the latter disease compared
with the standard of care.
ENGINEERED ACELLULAR SKIN:
ACELLULAR DERMAL SUBSTITUTES
In addition to cellular constructs, acellular
constructs have been developed primarily for
burn wounds. One such product is AlloDerm
(LifeCell Corp., Branchburg, N.J.), a cadaveric
skin processed to remove cellular and antigenic
components, leaving an acellular dermal matrix
with an intact basement membrane complex.138
It has seen use in burns,139 abdominal wall
reconstruction,153 and breast reconstruction,154,155
to name a few.
Table 4. Available Growth Factors in Wound Healing*
Growth Factor Indication Advantages Disadvantages Comments
rhPDGF-BB/becaplermin
(Regranex; Systagenix,
Commonwealth,
Mass.)
Indicated for the treatment of
lower extremity diabetic
neuropathic ulcers that
extend into the
subcutaneous tissue or
beyond and have an
adequate blood supply
Adverse effects similar in
incidence across all
treatment groups,
including placebo121
New black box FDA warning: although
no increase in incidence of cancer
was found, there was an increased
mortality secondary to malignancy
in those using 3 or more tubes; the
FDA does not recommend
becaplermin for those with known
malignancies122; cost is $586 per 15-g
tube which, for a 2-cm2ulcer, will
last 4 wk; treatment typically takes at
least 10 wk, requiring 2–3 tubes123
rhPDGF-BB is produced by yeast;
moist saline changes every 12
hr121; daily application, thin
layer should be applied for 12
hr121; treatment should
continue for 10 wk or
complete ulcer healing
FDA, U.S. Food and Drug Administration.
*Data from Broughton G II, Janis JE, Attinger CE. Wound healing: An overview. Plast Reconstr Surg. 2006;117:1S–32S.
Volume 127, Number 1S •Topical Wound Healing
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Table 5. Available Skin Substitutes*
Type FDA Indications Advantages Disadvantages
Dermal replacement
Human cryopreserved
allograft skin Temporary coverage for burns until permanent
coverage; supplied by tissue banks Long use has provided much experience Limited supply; disease transmission;
sloughing/rejection by 2 wk135,136;
difficult to remove off of wound
bed136; loss of viability and
performance with
cryopresservation137
Bioabsorbable membrane
impregnated with
human dermal
fibroblasts from
neonatal foreskin
(Dermagraft, Advanced
BioHealing, Inc., La
Jolla, Calif.)
FDA approval for Dermagraft in full-thickness
diabetic foot ulcers that have been present
for longer than 6 wk and ulcers that extend
deeper into the skin where the blood vessels
are, but do not involve tendon, muscle, joint
capsule, or bone (PMA/2001); FDA approval
for Dermagraft for ulcers secondary to
epidermolysis bullosa (HDE/2004)
Dermagraft allows the patient’s own
epithelial cells to close the wound:
biodegradable matrix allows absorption in
3–4 wk138; lower number of wound
infections, osteomyelitis, and cellulitis and
fewer surgical procedures involving the
diabetic foot ulcer133
Short shelf life unless cryopreserved;
contraindicated in ulcers with
infections, sinus tracts, or in
patients with bovine product
hypersensitivity
Human allograft skin
chemically treated for
decellularization, freeze-
dried for moisture
removal, and
stabilization of dermal
matrix (AlloDerm,
LifeCell Corp.,
Branchburg, N.J.)
Burns, abdominal wall repairs, breast
reconstruction, nasal septum reconstruction,
tympanic membrane grafting
Immediate wound coverage; acellular,
immunologically inert; allows host cell
repopulation and ultrathin split-thickness
grafts; case series reports reduction in
scarring139
Low risk of disease transmission;
contraindicated in infected or
nonvascular wounds; cost
Polymer of bovine
collagen type 1 collagen
and shark chondroitin-6-
sulfate with an overlying
silastic sheet140 (Integra;
Integra LifeSciences
Corp., Plainsboro, N.J.)
Postexcisional treatment of life-threatening full-
thickness or deep partial-thickness thermal
injury where sufficient autograft is not
available (PMA/1996)135; patients undergoing
reconstructive surgery for burn scar
contracture where there is a limited amount
of their own skin to use for autografts or
they are too ill to have more wound sites
created (2002)
Immediate wound coverage; allows ultrathin
split-thickness autograft; better cosmetic
outcome versus split-thickness autograft135;
histologic analysis shows good wound
healing with minimal scarring141;
immunologically well tolerated142; silicone
is transparent, allowing visualization
Complete wound excision before
grafting; study performed within 7
days135; learning curve of 10
procedures135; contraindications
include known hypersensitivity to
ingredients and patients with
hemochromatosis, hemosiderosis,
hemolytic anemias, and pernicious
anemia; cost
Bilayered substitute
Live epidermal
keratinocyte and dermal
fibroblast impregnated
into a type 1 bovine
collagen lattice
(Apligraf;
Organogenesis, Canton,
Mass.; formerly
Graftskin or Living Skin
Equivalent)
Noninfected partial- and full-thickness skin
ulcers secondary to venous insufficiency "1
mo duration that have not responded to
conventional treatment132 (PMA/2000); full-
thickness neuropathic diabetic foot ulcers
that have extended into the dermis but not
with tendon, muscle, capsule, or bone
exposure, of greater than 3-wk duration, that
have not adequately responded to
conventional ulcer therapy (PMA/1998)
Immediate availability; self-heal when
injured143; no clinical evidence of
rejection, sensitization, or
immunogenicity132,134,138,144; does not
contain blood vessels, sweat glands, hair
follicles, macrophages, Langerhans cells,
lymphocytes, melanocytes; no difference in
wound infection, cellulitis, or pain in
venous ulcer treatment132; contains stratum
corneum to prevent desiccation145; benefit
in large, deep, and chronic venous
ulcers132
10-day shelf life; studies performed
an average of 3.9 applications for
diabetic ulcers134 and 3.34
applications for venous ulcers132;
learning curve correlates with
outcome134; contraindications
include patients with known bovine
collagen allergies or who have
infected wounds
FDA, U.S. Food and Drug Administration; PMA, premarket approval; HDE, Humanitarian Device Exemption; 510K, device provides similar efficacy and safety to the device it replaces.
*Data from Eisenbud D, Huang NF, Luke S, Silberklang M. Skin substitutes and wound healing: Current status and challenges. Wounds 2004;16:2–17; Bello YM, Phillips TJ. Recent advances
in wound healing. JAMA. 2000;283:716–718; and Phillips TJ. New skin for old: Developments in biological skin substitutes. Arch Dermatol. 1998;134:344 –349.
Plastic and Reconstructive Surgery •January Supplement 2011
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Another approach is to use acellular bovine
collagen matrices with shark-derived chondroitin
sulfate matrices bonded to a temporary Silastic
epidermis (Integra; Integra LifeSciences Corp.,
Plainsboro, N.J.).140 Along with serving as a con-
duit for growth factors and angiogenesis, these
acellular matrices serve as a transient biodegrad-
able scaffold as a new dermis is regenerated.143
Integra provides temporary covering when immedi-
ate grafting is not possible. Studies have shown that
Integra has similar graft take compared with non-
autograft controls in wounds with a large body sur-
face area, but with better patient satisfaction, less
hypertrophic scarring,135 and shorter hospital stays.156
Moiemen et al. demonstrated Integra’s use in recon-
structive surgery, especially in contracture and scar
repair, with patients reporting improvement in
range of motion, softness, and appearance.157
CONCLUSIONS
Wound healing has evolved much over the
past 40 years. Many therapies have been devised to
interrupt the vicious cycle of nonhealing wounds.
Exciting developments in the field of wound heal-
ing include the use of growth factors and skin
substitutes. Despite trials demonstrating the ben-
efits of the aforementioned treatments, many of
the modalities used in practice today, such as
dressings and antimicrobials, are based more on
clinical experience than evidence. High-quality
studies are lacking to evaluate such therapies.
Proof of patient benefit will provide the necessary
justification for use in clinical practice.
Robert S. Kirsner, M.D., Ph.D.
Department of Dermatology and Cutaneous Surgery
University of Miami Miller School of Medicine
1600 N.W. 10th Avenue
Rosenstiel Medical Science Building, Room 2023-A
Miami, Fla. 33136
rkirsner@med.miami.edu
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