1. What’s New and Innovative in Wound
Management: Problems and Solutions
Christine L. Theoret, DMV, PhD
You can positively influence repair by selecting appropriate wound-management techniques, but first,
you must understand the basic mechanisms underlying repair to better judge the validity of available
therapies. Author’s address: De´partement de Biome´decine Ve´te´rinaire, Faculte´ de Me´decine Ve´t-
e´rinaire, Universite´ de Montre´al, C.P. 5000 St-Hyacinthe, Que´bec J2S 7C6, Canada;
e-mail: christine.theoret@umontreal.ca. © 2006 AAEP.
1. Introduction
Traumatic wounds are challenging and often labor
intensive for both horse owners and equine practi-
tioners. A retrospective study of horses with trau-
matic wounds recently determined that primary
closure was successful in only 24% of horses in which
it was attempted.1
To compound the problem, repair
of wounds by second intention is subject to numerous
complications that compromise outcome in the horse,
including chronic inflammation, poor contraction, de-
velopment of exuberant granulation tissue (proud
flesh), and slow epithelialization.
Wound repair begins the moment a cellular bar-
rier is broken and follows a predictable pattern of
synchronized and interrelated phases including the
inflammatory phase, the proliferative phase, and
the remodeling phase (Fig. 1).2
The estimated market share of wound-care prod-
ucts for humans was over $3,000,000,000 in 2005.3
This reflects the number of available products, many
of which are exempted from stringent FDA testing
as a result of their topical (as opposed to systemic)
use. Although it is imperative that novel alterna-
tives in wound management be offered to equine
practitioners faced with this daily task, many com-
mercially available products have not been rigor-
ously evaluated and rely heavily on anecdotal
evidence. Furthermore, one must bear in mind
that because of the unique nature of wound repair in
the limbs of horses, therapies beneficial to other
species may not apply to the horse. The purpose of
this in-depth review is to reflect on the new concepts
and materials that have arisen from recent investi-
gations into the physiology of wound repair in this
species.
2. Therapy During the Inflammatory Phase
This is the phase during which the practitioner can
exert the greatest influence. Inflammation is es-
sential to protect against infection as well as to
initiate the repair process. Through release of mul-
tiple cytokines and growth factors, the macrophage
is attributed a key role in the transition between
inflammation and repair. Paradoxically, excessive
or prolonged inflammation may contribute to the
pathogenesis of a number of diseases characterized
by fibrosis and/or scarring (for example, the devel-
opment of exuberant granulation tissue on the distal
aspect of the limb of the horse). It has been shown
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IN-DEPTH: CURRENT CONCEPTS IN WOUND MANAGEMENT
NOTES

2. experimentally that inflammation in horses is weak
but protracted4
and that horse leukocytes produce
fewer reactive oxygen species essential to bacterial
killing.5
They also produce lower levels of other
mediators required to reinforce the inflammatory
response and to induce tissue formation and wound
contraction.5
In view of these facts, it may be wise
to facilitate a strong, early inflammatory response to
injury.
Debridement is an important step in the initial
treatment of a wound, particularly when necrosis,
exposed cortical bone, or frayed tendons are present;
it can be achieved through surgical, enzymatic,
wound dressing, laser, and biosurgical means. De-
bridement of non-viable tissue reduces the duration of
the inflammatory phase. After thorough debride-
ment, it is advisable to dress the wound briefly in an
effort to accelerate biological processes. Bandaging
can be combined with topical therapy to enhance the
inflammatory response.
Wilmink et al.6
recently investigated the use of a
protein-free dialysate of calf blooda
in deep wounds
of horses. In the first 4 wk after injury, Solcoseryl
stimulated repair by provoking greater inflammatory
response, faster contraction, and faster formation of
granulation tissue. Subsequently, it inhibited repair
by delaying epithelialization and prolonging inflam-
mation. The author recommends its use in the treat-
ment of deep wounds during the initial phase of repair
by second intention; treatment should cease when ep-
ithelialization predominates.
Dart et al.7
examined the efficacy of a hydrogelb
on
second intention wound healing in horses. Hydro-
gels are made from materials such as gelatin or
polysaccharide that are cross-linked with a polymer
to form a sheet or gel. By enhancing the moisture
content of necrotic tissue and increasing collagenase
production within the wound, hydrogels facilitate
autolytic debridement. Contrary to expectations,
the hydrogel investigated in this study did not pro-
duce beneficial effects on healing of small full-thick-
ness skin wounds on the limb of horses. A b,1–4
acetylated mannan,c
commercially available as a hy-
drogel, is likewise touted to enhance macrophage
activity; it seems beneficial in the management of
dog foot-pad wounds8
but has not been investigated
in the horse.
A general strategy for improving wound repair
may be through any molecule that can recruit or
activate macrophages during the acute inflamma-
tory phase. The trend of applying sugar or honey to
open wounds dates back a long time and has recently
acquired some scientific merit.9
Both products are
chemoattractant for tissue macrophages and when ap-
plied to contaminated or infected wounds, may have
antibacterial properties. Indeed, the stimulatory ef-
fect of honey may be imparted through up-regulation
of various inflammatory cytokines within mono-
cytes.10
Both sugar and honey have been shown to
enhance fibroplasia as well as epithelialization. A
synthetic form of sugar, Maltodextrin N.F.,d
is com-
mercially available. On application, Intracell works
by mixing with wound exudate to form a semi-perme-
able barrier, and thus, it maintains moisture while
protecting the wound from environmental contami-
nants. Furthermore, it attracts endothelial cells, fi-
broblasts, and epithelial cells to minimize scarring and
reduce the incidence of proud flesh. Although anec-
dotal evidence is encouraging, no scientific studies
have been conducted to evaluate the efficacy of natural
or synthetic sugar in the management of horse
wounds.
Ketanserin,e
a serotonin receptor, is the active
ingredient in Vulketan gel. Macrophage activation
may be suppressed by serotonin present in the early
inflammatory phase; ketanserin antagonizes this se-
rotonin-induced suppression and thus, allows a
strong and effective inflammatory response to occur
within wounds. This should translate into a supe-
rior control of infection and a better orchestration of
Fig. 1. Phases of wound repair.
266 2006 ր Vol. 52 ր AAEP PROCEEDINGS
IN-DEPTH: CURRENT CONCEPTS IN WOUND MANAGEMENT

3. the later phases of repair when growth factors re-
leased by the activated macrophage play an impor-
tant role. Vulketan gel was clinically tested
against an antiseptic and a desloughing agent in
equine limb wounds. Vulketan gel was 2–5 times
more likely to result in successful closure, because it
reduced infection and the development of exuberant
granulation tissue.11
Many wounds located on the distal limb of horses
exhibit signs of chronic inflammation, regardless of
whether or not they are infected. Chronic wounds
seem to be “stuck” at some critical stage of repair,
probably during inflammation or cell proliferation.
Current emphasis of chronic wound management
focuses on three main issues: (1) identification of
the obstruction to healing, (2) removal of the ob-
struction by debridement, (3) creation of a favorable
environment at the wound site. Suggested therapy
for chronic wounds includes a combination of pro-
teinase inhibitors and anti-inflammatory agents fol-
lowed by the application of growth factors.
An oxidized regenerated-cellulose (ORC)/collagen
dressingf
has been developed for wounds that have
not progressed beyond the inflammatory phase.
It is designed to modify the chronic wound environ-
ment by decreasing the activity of key matrix met-
alloproteinases (MMPs) in the wound fluid. A study
in diabetic rats found faster epithelialization of
wounds treated with ORC/collagen than with hydro-
colloid dressing alone; this was accompanied by higher
levels of various growth factors.12
Promogran con-
sists of a sterile, freeze-dried matrix composed of col-
lagen and ORC that is formed into a sheet. In the
presence of wound exudate, the matrix absorbs liquid
and forms a soft, conformable, biodegradable gel that
physically binds and inactivates MMPs. The gel also
binds naturally occurring growth factors within the
wound; this protects them from degradation by pro-
teinases by releasing them back into the wound in an
active form as the gel is slowly broken down. To the
best of my knowledge, the use of this product has not
been described in veterinary literature.
3. Therapy During the Proliferative Phase
The proliferative phase of repair involves epithelial-
ization, fibroplasia, and angiogenesis. The thera-
peutic goal during this phase is to enhance cell
migration and proliferation and limit the activity of
synthetic fibroblasts to avoid excessive deposition of
extracellular-matrix (ECM) components. Assum-
ing that inflammation is now resolved, one might
wish to continue with chemoattractant agents (spe-
cific to endothelial and epithelial cells as well as
fibroblasts) and provide a scaffold for migration
should the natural one be lacking.
The horse activates wound-collagen formation to a
greater extent and earlier during repair than do
other species,13
pre-disposing it to the formation of
exuberant granulation tissue with subsequent re-
tardation of contraction and epithelial migration.
In most species, fibroplasia and epithelialization are
favored by the moist wound environment provided
by certain bandages, whereas in the horse, fully
occlusive dressings significantly prolong healing
times and favor the production of excess wound ex-
udate and granulation tissue.14,15
A notable excep-
tion is achieved with the use of amnion, a biological
occlusive wound dressing.16,17
Proud flesh has been the topic of many new stud-
ies; some focus on its pathophysiology, and others
discuss the prevention of its development. It has
recently been documented in horses that cytokines
and growth factors are key players in the repair
process. In particular, members of the transform-
ing growth factor-beta (TGF-␤) family have been
incriminated in the fibrotic response to trauma
noted in horse limb wounds.18–20
Because problematic wound repair, including
chronicity and fibrosis, may result from excessive
inflammation and an abnormal cytokine profile, in-
vestigators have attempted to alter this balance to
ameliorate the quality of wound repair in the horse.
Topical application of TGF-␤ improves wound repair
in a variety of species, especially in models of
chronic, impaired wound healing. A study by Steel
et al.21
tested the recombinant growth factor, found
to be effective in laboratory animals, on full-thick-
ness wounds located on the limb of horses. There
were no beneficial effects on total amount of granu-
lation tissue and epithelialization area or on clinical
assessments of wound biopsies. Conversely, Ohne-
mus et al.22
achieved promising results by topically
applying the anti-fibrotic isoform TGF-␤3 to wounds
on the limbs of horses. Granulation tissue had a
healthier appearance and did not become exuberant
in treated wounds, despite the use of bandages.
Numerous companies now promote products
based on their bioactive molecule (cytokine/growth
factor) content. For example, an all-natural,
equine-specific wound healantg
is currently mar-
keted in the United States. The company claims
that a gel containing activated platelets and their
released growth factors induces wound repair in in-
juries previously deemed untreatable.23
Because
application of a single growth factor does not mimic
natural processes and should not improve healing
unless impairment was caused by the relative lack
of that single protein, a cocktail approach, such as
motivating the use of platelet-rich plasma, might
indeed impart benefit.
Along those same lines, we recently accelerated
wound repair in diabetic rats with topical applica-
tion of elk velvet-antler extracts.24
Velvet antler
contains various growth factors and a soluble ex-
tract that stimulates dermal fibroblast growth in
vitro. According to the premise that slow growth of
dermal fibroblasts from equine limbs may contribute
to the poor healing characteristics of wounds of the
distal aspect of the limbs of horses,25
we suggest
that this extract may be an economical adjunct to
the treatment of full-thickness wounds in this loca-
tion on horses.
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IN-DEPTH: CURRENT CONCEPTS IN WOUND MANAGEMENT

4. Therapy During the Remodeling Phase
We recently investigated the efficacy of a silicone-gel
dressingh
in the treatment of proud flesh in limb
wounds of horses. This therapy is successful in
reversing hypertrophic scarring in human burn pa-
tients, apparently by exerting pressure on the mi-
crovasculature of the scar and altering levels of
various growth factors, notably pro-fibrotic TGF-␤.
The anoxic fibroblasts undergo apoptosis rather
than proliferating and secreting ECM. In our
study, the silicone-gel dressing surpassed a conven-
tional dressing in preventing formation of exuberant
granulation tissue and improving tissue quality in
horse wounds. Microvessels were occluded signifi-
cantly more often in wounds dressed with the sili-
cone gel.26
Thus, we recommend integrating the
silicone dressing into a management strategy de-
signed to improve the repair of limb wounds in
horses.
Tissue engineering is used to develop methods for
the repair and restoration of injured or missing body
parts. ECM is at the heart of most scaffold-based
therapies, because it represents a collection of mole-
cules organized in a three-dimensional ultrastructure,
unique for each tissue/organ. The components are
principally collagen, proteoglycans, glycoproteins, and
growth factors secreted by resident cells that provide,
in addition to the structural framework, a source of
information that contributes to cell phenotype and be-
havior.27
ECM does not cause perfect regeneration
but will accelerate wound closure and improve tissue
quality. The healed, remodeled tissue is associated
with differentiated cell and tissue types with minimal
scar tissue.
A natural biocompatible collagen matrix derived
from porcine small-intestinal submucosai
or uri-
nary-bladder submucosaj
and containing a plethora
of proteins and growth factors is available to veter-
inarians. A recent study determined that porcine
small intestinal submucosa offers no apparent ad-
vantage over a non-biological dressing for treatment
of small, granulating wounds of the distal limb of
horses.28
Indeed, no differences were detected in
bacterial proliferation, inflammatory reaction, vas-
cularization of the graft, and overall healing be-
tween the biological dressing and the non-biological,
non-adherent synthetic pad. This said, ECM scaf-
folds are not intended for applications in which nat-
ural healing results in normal or near-normal tissue
structure and function. Porcine urinary bladder
submucosa has been on the market for a shorter
period of time and has not been evaluated exten-
sively. The perceived best use for this product is in
large avulsion injuries of the distal extremity in
which ECM bioscaffolds provide not only a protec-
tive barrier against dehydration but also a first line
of antibacterial defense, a source of angiogenic and
mitogenic growth factors, and a favorable surface for
accelerated epithelial coverage. The Veterinary
Wound Management Society has planned a multi-
center trial for porcine urinary bladder submucosa
in traumatic wounds of both horses and small
animals.
4. Conclusions
In conclusion, acceleration and improvement of re-
pair may not prove as simple as applying a single
treatment to the wound. A more precise under-
standing of the mechanisms of dermal repair and
scarring in the horse is needed before reasoned ther-
apeutic approaches can be implemented. The abil-
ity to directly influence the repair process is a
powerful impetus to drive research into aspects of
impaired healing, such as that frequently occurring
in the horse.
References and Footnotes
1. Wilmink JM, van Herten J, van Weeren PR, et al. Retro-
spective study of primary intention healing and sequestrum
formation in horses compared to ponies under clinical circum-
stances. Equine Vet J 2002;34:270–273.
2. Theoret CL. Update on wound repair. Clin Tech Equine
Pract 2004;3:110–122.
3. Business Communications Company, Inc. Advanced Wound
Care Business to Cross $3 Billion by 2005. Available online
at http://bccresearch.com/editors/RC-077N.html. Accessed
on September 12, 2006.
4. Wilmink JM, van Weeren PR, Stolk PW, et al. Differences
in second-intention wound healing between horses and po-
nies: histological aspects. Equine Vet J 1999;31:61–67.
5. Wilmink JM, Veenman JN, van den Boom R, et al. Differ-
ences in polymorphonucleocyte function and local inflamma-
tory response between horses and ponies. Equine Vet J
2003;35:561–569.
6. Wilmink JM, Stolk PW, van Weeren PR, et al. The effec-
tiveness of the haemodialysate Solcoseryl for second-inten-
tion wound healing in horses and ponies. J Vet Med A
Physiol Pathol Clin Med 2000;47:311–320.
7. Dart AJ, Cries L, Jeffcott LB, et al. Effects of 25% propylene
glycol hydrogel (Solugel) on second intention wound healing
in horses. Vet Surg 2002;31:309–313.
8. Swaim SF, Vaughn DM, Kincaid SA, et al. Effect of locally
injected medications on healing of pad wounds in
dogs. Am J Vet Res 1996;57:394–399.
9. Molan PC. The role of honey in the management of wounds.
J Wound Care 1999;8:415–418.
10. Tonks AJ, Cooper RA, Jones KP, et al. Honey stimulates
inflammatory cytokine production from monocytes. Cyto-
kine 2003;21:242–247.
11. Engelen M, Besche B, Lefay MP, et al. Effects of ketanserin
on hypergranulation tissue formation, infection, and healing
of equine lower limb wounds. Can Vet J 2004;45:144–149.
12. Jeschke MG, Sandmann G, Schubert T, et al. Effect of oxi-
dized regenerated cellulose/collagen matrix on dermal and epi-
dermal healing and growth factors in an acute wound. Wound
Rep Regen 2005;13:324–331.
13. Chvapil M, Pfister T, Escalada S, et al. Dynamics of the
healing of skin wounds in the horse as compared with the rat.
Exp Mol Pathol 1979;30:349–359.
14. Howard RD, Stashak TS, Baxter GM. Evaluation of occlu-
sive dressings for management of full-thickness excisional
wounds on the distal portion of the limbs of horses. Am J
Vet Res 1993;54:2150–2154.
15. Berry DB, Sullins KE. Effects of topical application of anti-
microbials and bandaging on healing and granulation tissue
formation in wounds of the distal aspect of the limbs in
horses. Am J Vet Res 2003;64:88–92.
16. Bigbie RB, Schumacher J, Swaim SF, et al. Effects of am-
nion and live yeast cell derivative on second-intention healing
of horses. Am J Vet Res 1991;52:1376–1382.
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5. 17. Goodrich LR, Moll DH, Crisman MV, et al. Comparison of
equine amnion and a nonadherent wound dressing material
for bandaging pinch-grafted wounds in ponies. Am J Vet
Res 2000;61:326–329.
18. Theoret CL, Barber SM, Moyana TN, et al. Expression of
transforming growth factor b1, b3, and basic fibroblast
growth factor in full-thickness skin wounds of equine limbs
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19. Theoret CL, Barber SM, Moyana TN, et al. Preliminary
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266–273.
20. van den Boom R, Wilmink JM, O’Kane S, et al. Transform-
ing growth factor-beta levels during second- intention healing
are related to the different course of wound contraction in
horses and ponies. Wound Repair Regen 2002;10:188–194.
21. Steel CM, Robertson ID, Thomas J, et al. Effect of topical
rh-TGF-b1 on second intention wound healing in horses. Aust
Vet J 1999;77:734–737.
22. Ohnemus P, von Rechenberg BV, Arvinte T, et al: Applica-
tion of TGF-b3 on experimentally created circular wounds in
horses. Vet Surg 1999;28:216.
23. Carter CA, Jolly DG, Worden CE, et al. Platelet-rich plasma
gel promotes differentiation and regeneration during equine
wound healing. Exp Mol Pathol 2003;74:244–255.
24. Mikler J, Theoret CL, Haigh J. Effect of topical elk antler
velvet administration on cutaneous wound healing in an an-
imal model of streptozotocin-induced diabetes mellitus. J
Altern Complement Med 2004;10:835–840.
25. Bacon Miller C, Wilson DA, Keegan KG, et al. Growth char-
acteristics of fibroblasts isolated from the trunk and distal
aspect of the limb of horses and ponies. Vet Surg 2000;29:
1–7.
26. Ducharme-Desjarlais M, Lepault E´ , Ce´leste C, et al. Deter-
mination of the effect of a silicone dressing (CicaCare®) on
second intention healing of full-thickness wounds of the dis-
tal limb of horses. Am J Vet Res 2005;66:1133–1139.
27. Badylak SF. Extracellular matrix as a scaffold for tissue
engineering in veterinary medicine: applications to soft tis-
sue healing. Clin Tech Equine Pract 2004;3:172–181.
28. Gomez J, Schumacher J, Lauten SD, et al. Effects of three
biologic dressings on healing of cutaneous wounds on the
limbs of horses. Can J Vet Res 2004;68:49–55.
a
Solcoseryl Solco Basle Ltd, Birsfelden, Switzerland.
b
Solugel, Johnson & Johnson Medical Products, Markham,
Canada L3R 0T5.
c
Carravet Veterinary Products Laboratories, Phoenix, AZ
85067.
d
Intracell Macleod Pharmaceutical, Fort Collins, CO 80525.
e
Vulketan gel, Janssen Animal Health, Beerse, Belgium.
f
Promogran, Johnson & Johnson Medical Products, Markham,
Canada L3R 0T5.
g
Lacerum BeluMedX, Little Rock, AK 72212.
h
Cicacare, Smith Nephew, Hull, UK HU3 2BN.
i
Vet BioSISt, Cook Veterinary Products, Bloomington, IN
47404.
j
ACell Vet, Jessup, MD 20794.
k
Carrasorb, Carrington Laboratories, Irving, TX 75038.
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