Wound managment

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Wound managment

  1. 1. What’s New and Innovative in WoundManagement: Problems and SolutionsChristine L. Theoret, DMV, PhDYou 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 availabletherapies. 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. IntroductionTraumatic wounds are challenging and often laborintensive for both horse owners and equine practi-tioners. A retrospective study of horses with trau-matic wounds recently determined that primaryclosure was successful in only 24% of horses in whichit was attempted.1To compound the problem, repairof wounds by second intention is subject to numerouscomplications that compromise outcome in the horse,including chronic inflammation, poor contraction, de-velopment of exuberant granulation tissue (proudflesh), and slow epithelialization.Wound repair begins the moment a cellular bar-rier is broken and follows a predictable pattern ofsynchronized and interrelated phases including theinflammatory phase, the proliferative phase, andthe remodeling phase (Fig. 1).2The estimated market share of wound-care prod-ucts for humans was over $3,000,000,000 in 2005.3This reflects the number of available products, manyof which are exempted from stringent FDA testingas a result of their topical (as opposed to systemic)use. Although it is imperative that novel alterna-tives in wound management be offered to equinepractitioners faced with this daily task, many com-mercially available products have not been rigor-ously evaluated and rely heavily on anecdotalevidence. Furthermore, one must bear in mindthat because of the unique nature of wound repair inthe limbs of horses, therapies beneficial to otherspecies may not apply to the horse. The purpose ofthis in-depth review is to reflect on the new conceptsand materials that have arisen from recent investi-gations into the physiology of wound repair in thisspecies.2. Therapy During the Inflammatory PhaseThis is the phase during which the practitioner canexert the greatest influence. Inflammation is es-sential to protect against infection as well as toinitiate the repair process. Through release of mul-tiple cytokines and growth factors, the macrophageis attributed a key role in the transition betweeninflammation and repair. Paradoxically, excessiveor prolonged inflammation may contribute to thepathogenesis of a number of diseases characterizedby fibrosis and/or scarring (for example, the devel-opment of exuberant granulation tissue on the distalaspect of the limb of the horse). It has been shownAAEP PROCEEDINGS ր Vol. 52 ր 2006 265IN-DEPTH: CURRENT CONCEPTS IN WOUND MANAGEMENTNOTES
  2. 2. experimentally that inflammation in horses is weakbut protracted4and that horse leukocytes producefewer reactive oxygen species essential to bacterialkilling.5They also produce lower levels of othermediators required to reinforce the inflammatoryresponse and to induce tissue formation and woundcontraction.5In view of these facts, it may be wiseto facilitate a strong, early inflammatory response toinjury.Debridement is an important step in the initialtreatment 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 ofthe inflammatory phase. After thorough debride-ment, it is advisable to dress the wound briefly in aneffort to accelerate biological processes. Bandagingcan be combined with topical therapy to enhance theinflammatory response.Wilmink et al.6recently investigated the use of aprotein-free dialysate of calf bloodain deep woundsof horses. In the first 4 wk after injury, Solcoserylstimulated repair by provoking greater inflammatoryresponse, faster contraction, and faster formation ofgranulation tissue. Subsequently, it inhibited repairby delaying epithelialization and prolonging inflam-mation. The author recommends its use in the treat-ment of deep wounds during the initial phase of repairby second intention; treatment should cease when ep-ithelialization predominates.Dart et al.7examined the efficacy of a hydrogelbonsecond intention wound healing in horses. Hydro-gels are made from materials such as gelatin orpolysaccharide that are cross-linked with a polymerto form a sheet or gel. By enhancing the moisturecontent of necrotic tissue and increasing collagenaseproduction within the wound, hydrogels facilitateautolytic 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,1–4acetylated mannan,ccommercially available as a hy-drogel, is likewise touted to enhance macrophageactivity; it seems beneficial in the management ofdog foot-pad wounds8but has not been investigatedin the horse.A general strategy for improving wound repairmay be through any molecule that can recruit oractivate macrophages during the acute inflamma-tory phase. The trend of applying sugar or honey toopen wounds dates back a long time and has recentlyacquired some scientific merit.9Both products arechemoattractant for tissue macrophages and when ap-plied to contaminated or infected wounds, may haveantibacterial properties. Indeed, the stimulatory ef-fect of honey may be imparted through up-regulationof various inflammatory cytokines within mono-cytes.10Both sugar and honey have been shown toenhance fibroplasia as well as epithelialization. Asynthetic form of sugar, Maltodextrin N.F.,dis com-mercially available. On application, Intracell worksby mixing with wound exudate to form a semi-perme-able barrier, and thus, it maintains moisture whileprotecting the wound from environmental contami-nants. Furthermore, it attracts endothelial cells, fi-broblasts, and epithelial cells to minimize scarring andreduce the incidence of proud flesh. Although anec-dotal evidence is encouraging, no scientific studieshave been conducted to evaluate the efficacy of naturalor synthetic sugar in the management of horsewounds.Ketanserin,ea serotonin receptor, is the activeingredient in Vulketan gel. Macrophage activationmay be suppressed by serotonin present in the earlyinflammatory phase; ketanserin antagonizes this se-rotonin-induced suppression and thus, allows astrong and effective inflammatory response to occurwithin wounds. This should translate into a supe-rior control of infection and a better orchestration ofFig. 1. Phases of wound repair.266 2006 ր Vol. 52 ր AAEP PROCEEDINGSIN-DEPTH: CURRENT CONCEPTS IN WOUND MANAGEMENT
  3. 3. the later phases of repair when growth factors re-leased by the activated macrophage play an impor-tant role. Vulketan gel was clinically testedagainst an antiseptic and a desloughing agent inequine limb wounds. Vulketan gel was 2–5 timesmore likely to result in successful closure, because itreduced infection and the development of exuberantgranulation tissue.11Many wounds located on the distal limb of horsesexhibit signs of chronic inflammation, regardless ofwhether or not they are infected. Chronic woundsseem to be “stuck” at some critical stage of repair,probably during inflammation or cell proliferation.Current emphasis of chronic wound managementfocuses on three main issues: (1) identification ofthe obstruction to healing, (2) removal of the ob-struction by debridement, (3) creation of a favorableenvironment at the wound site. Suggested therapyfor 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)/collagendressingfhas been developed for wounds that havenot 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 studyin diabetic rats found faster epithelialization ofwounds treated with ORC/collagen than with hydro-colloid dressing alone; this was accompanied by higherlevels of various growth factors.12Promogran con-sists of a sterile, freeze-dried matrix composed of col-lagen and ORC that is formed into a sheet. In thepresence of wound exudate, the matrix absorbs liquidand forms a soft, conformable, biodegradable gel thatphysically binds and inactivates MMPs. The gel alsobinds naturally occurring growth factors within thewound; this protects them from degradation by pro-teinases by releasing them back into the wound in anactive form as the gel is slowly broken down. To thebest of my knowledge, the use of this product has notbeen described in veterinary literature.3. Therapy During the Proliferative PhaseThe proliferative phase of repair involves epithelial-ization, fibroplasia, and angiogenesis. The thera-peutic goal during this phase is to enhance cellmigration and proliferation and limit the activity ofsynthetic fibroblasts to avoid excessive deposition ofextracellular-matrix (ECM) components. Assum-ing that inflammation is now resolved, one mightwish to continue with chemoattractant agents (spe-cific to endothelial and epithelial cells as well asfibroblasts) and provide a scaffold for migrationshould the natural one be lacking.The horse activates wound-collagen formation to agreater extent and earlier during repair than doother species,13pre-disposing it to the formation ofexuberant granulation tissue with subsequent re-tardation of contraction and epithelial migration.In most species, fibroplasia and epithelialization arefavored by the moist wound environment providedby certain bandages, whereas in the horse, fullyocclusive dressings significantly prolong healingtimes and favor the production of excess wound ex-udate and granulation tissue.14,15A notable excep-tion is achieved with the use of amnion, a biologicalocclusive wound dressing.16,17Proud flesh has been the topic of many new stud-ies; some focus on its pathophysiology, and othersdiscuss the prevention of its development. It hasrecently been documented in horses that cytokinesand growth factors are key players in the repairprocess. In particular, members of the transform-ing growth factor-beta (TGF-␤) family have beenincriminated in the fibrotic response to traumanoted in horse limb wounds.18–20Because problematic wound repair, includingchronicity and fibrosis, may result from excessiveinflammation and an abnormal cytokine profile, in-vestigators have attempted to alter this balance toameliorate the quality of wound repair in the horse.Topical application of TGF-␤ improves wound repairin a variety of species, especially in models ofchronic, impaired wound healing. A study by Steelet al.21tested the recombinant growth factor, foundto be effective in laboratory animals, on full-thick-ness wounds located on the limb of horses. Therewere no beneficial effects on total amount of granu-lation tissue and epithelialization area or on clinicalassessments of wound biopsies. Conversely, Ohne-mus et al.22achieved promising results by topicallyapplying the anti-fibrotic isoform TGF-␤3 to woundson the limbs of horses. Granulation tissue had ahealthier appearance and did not become exuberantin treated wounds, despite the use of bandages.Numerous companies now promote productsbased on their bioactive molecule (cytokine/growthfactor) content. For example, an all-natural,equine-specific wound healantgis currently mar-keted in the United States. The company claimsthat a gel containing activated platelets and theirreleased growth factors induces wound repair in in-juries previously deemed untreatable.23Becauseapplication of a single growth factor does not mimicnatural processes and should not improve healingunless impairment was caused by the relative lackof that single protein, a cocktail approach, such asmotivating the use of platelet-rich plasma, mightindeed impart benefit.Along those same lines, we recently acceleratedwound repair in diabetic rats with topical applica-tion of elk velvet-antler extracts.24Velvet antlercontains various growth factors and a soluble ex-tract that stimulates dermal fibroblast growth invitro. According to the premise that slow growth ofdermal fibroblasts from equine limbs may contributeto the poor healing characteristics of wounds of thedistal aspect of the limbs of horses,25we suggestthat this extract may be an economical adjunct tothe treatment of full-thickness wounds in this loca-tion on horses.AAEP PROCEEDINGS ր Vol. 52 ր 2006 267IN-DEPTH: CURRENT CONCEPTS IN WOUND MANAGEMENT
  4. 4. Therapy During the Remodeling PhaseWe recently investigated the efficacy of a silicone-geldressinghin the treatment of proud flesh in limbwounds of horses. This therapy is successful inreversing hypertrophic scarring in human burn pa-tients, apparently by exerting pressure on the mi-crovasculature of the scar and altering levels ofvarious growth factors, notably pro-fibrotic TGF-␤.The anoxic fibroblasts undergo apoptosis ratherthan proliferating and secreting ECM. In ourstudy, the silicone-gel dressing surpassed a conven-tional dressing in preventing formation of exuberantgranulation tissue and improving tissue quality inhorse wounds. Microvessels were occluded signifi-cantly more often in wounds dressed with the sili-cone gel.26Thus, we recommend integrating thesilicone dressing into a management strategy de-signed to improve the repair of limb wounds inhorses.Tissue engineering is used to develop methods forthe repair and restoration of injured or missing bodyparts. ECM is at the heart of most scaffold-basedtherapies, because it represents a collection of mole-cules organized in a three-dimensional ultrastructure,unique for each tissue/organ. The components areprincipally collagen, proteoglycans, glycoproteins, andgrowth factors secreted by resident cells that provide,in addition to the structural framework, a source ofinformation that contributes to cell phenotype and be-havior.27ECM does not cause perfect regenerationbut will accelerate wound closure and improve tissuequality. The healed, remodeled tissue is associatedwith differentiated cell and tissue types with minimalscar tissue.A natural biocompatible collagen matrix derivedfrom porcine small-intestinal submucosaior uri-nary-bladder submucosajand containing a plethoraof proteins and growth factors is available to veter-inarians. A recent study determined that porcinesmall intestinal submucosa offers no apparent ad-vantage over a non-biological dressing for treatmentof small, granulating wounds of the distal limb ofhorses.28Indeed, no differences were detected inbacterial 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 tissuestructure and function. Porcine urinary bladdersubmucosa has been on the market for a shorterperiod of time and has not been evaluated exten-sively. The perceived best use for this product is inlarge avulsion injuries of the distal extremity inwhich ECM bioscaffolds provide not only a protec-tive barrier against dehydration but also a first lineof antibacterial defense, a source of angiogenic andmitogenic growth factors, and a favorable surface foraccelerated epithelial coverage. The VeterinaryWound Management Society has planned a multi-center trial for porcine urinary bladder submucosain traumatic wounds of both horses and smallanimals.4. ConclusionsIn conclusion, acceleration and improvement of re-pair may not prove as simple as applying a singletreatment to the wound. A more precise under-standing of the mechanisms of dermal repair andscarring in the horse is needed before reasoned ther-apeutic approaches can be implemented. The abil-ity to directly influence the repair process is apowerful impetus to drive research into aspects ofimpaired healing, such as that frequently occurringin the horse.References and Footnotes1. Wilmink JM, van Herten J, van Weeren PR, et al. Retro-spective study of primary intention healing and sequestrumformation 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 EquinePract 2004;3:110–122.3. Business Communications Company, Inc. Advanced WoundCare Business to Cross $3 Billion by 2005. Available onlineat http://bccresearch.com/editors/RC-077N.html. Accessedon September 12, 2006.4. Wilmink JM, van Weeren PR, Stolk PW, et al. Differencesin 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 J2003;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 APhysiol Pathol Clin Med 2000;47:311–320.7. Dart AJ, Cries L, Jeffcott LB, et al. Effects of 25% propyleneglycol hydrogel (Solugel) on second intention wound healingin horses. Vet Surg 2002;31:309–313.8. Swaim SF, Vaughn DM, Kincaid SA, et al. Effect of locallyinjected medications on healing of pad wounds indogs. 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 stimulatesinflammatory cytokine production from monocytes. Cyto-kine 2003;21:242–247.11. Engelen M, Besche B, Lefay MP, et al. Effects of ketanserinon hypergranulation tissue formation, infection, and healingof 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. WoundRep Regen 2005;13:324–331.13. Chvapil M, Pfister T, Escalada S, et al. Dynamics of thehealing 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 excisionalwounds on the distal portion of the limbs of horses. Am JVet Res 1993;54:2150–2154.15. Berry DB, Sullins KE. Effects of topical application of anti-microbials and bandaging on healing and granulation tissueformation in wounds of the distal aspect of the limbs inhorses. 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 healingof horses. Am J Vet Res 1991;52:1376–1382.268 2006 ր Vol. 52 ր AAEP PROCEEDINGSIN-DEPTH: CURRENT CONCEPTS IN WOUND MANAGEMENT
  5. 5. 17. Goodrich LR, Moll DH, Crisman MV, et al. Comparison ofequine amnion and a nonadherent wound dressing materialfor bandaging pinch-grafted wounds in ponies. Am J VetRes 2000;61:326–329.18. Theoret CL, Barber SM, Moyana TN, et al. Expression oftransforming growth factor b1, b3, and basic fibroblastgrowth factor in full-thickness skin wounds of equine limbsand thorax. Vet Surg 2001;30:269–277.19. Theoret CL, Barber SM, Moyana TN, et al. Preliminaryobservations on expression of transforming growth factor b1,b3, and basic fibroblast growth factor in equine limb woundshealing normally or with proud flesh. Vet Surg 2002;31:266–273.20. van den Boom R, Wilmink JM, O’Kane S, et al. Transform-ing growth factor-beta levels during second- intention healingare related to the different course of wound contraction inhorses and ponies. Wound Repair Regen 2002;10:188–194.21. Steel CM, Robertson ID, Thomas J, et al. Effect of topicalrh-TGF-b1 on second intention wound healing in horses. AustVet 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 inhorses. Vet Surg 1999;28:216.23. Carter CA, Jolly DG, Worden CE, et al. Platelet-rich plasmagel promotes differentiation and regeneration during equinewound healing. Exp Mol Pathol 2003;74:244–255.24. Mikler J, Theoret CL, Haigh J. Effect of topical elk antlervelvet administration on cutaneous wound healing in an an-imal model of streptozotocin-induced diabetes mellitus. JAltern 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 distalaspect 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®) onsecond 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 tissueengineering 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 threebiologic dressings on healing of cutaneous wounds on thelimbs of horses. Can J Vet Res 2004;68:49–55.aSolcoseryl Solco Basle Ltd, Birsfelden, Switzerland.bSolugel, Johnson & Johnson Medical Products, Markham,Canada L3R 0T5.cCarravet Veterinary Products Laboratories, Phoenix, AZ85067.dIntracell Macleod Pharmaceutical, Fort Collins, CO 80525.eVulketan gel, Janssen Animal Health, Beerse, Belgium.fPromogran, Johnson & Johnson Medical Products, Markham,Canada L3R 0T5.gLacerum BeluMedX, Little Rock, AK 72212.hCicacare, Smith Nephew, Hull, UK HU3 2BN.iVet BioSISt, Cook Veterinary Products, Bloomington, IN47404.jACell Vet, Jessup, MD 20794.kCarrasorb, Carrington Laboratories, Irving, TX 75038.AAEP PROCEEDINGS ր Vol. 52 ր 2006 269IN-DEPTH: CURRENT CONCEPTS IN WOUND MANAGEMENT

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