alternative wound management: translating science into

Clinical Management Extra

Alternative Wound Management TranslatingScience into PracticePushkar Satish Sathe MPharm Student Department of Pharmaceutics Dr Bhanuben Nanavati College of Pharmacy Mumbai Maharashtra IndiaDivyashree V Prabhu MPharm Research Associate Dr Bhanuben Nanavati College of Pharmacy Mumbai Maharashtra IndiaPadmini Ravikumar PhD Assistant Professor Department of Pharmaceutics Dr Bhanuben Nanavati College of Pharmacy Mumbai Maharashtra IndiaLaura L Bolton PhD Adjunct Associate Professor of Surgery Robert Wood Johnson University Medical School New Brunswick New Jersey

C M E1 AMA PRA

Category 1 CreditTM

ANCC25 Contact Hours

The authors faculty staff ainterests in any commercialTo earn CME credit you muexpire for physicians on SewwwNursingCentercomC

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GENERAL PURPOSE To present a scoping review of preclinical and clinical trial evidence supporting the efficacy andor safety ofmajor alternative wound care agents to summarize their effects on validated elements of wound bed preparation and woundmanagement paradigmsTARGET AUDIENCE This continuing education activity is intended for physicians physician assistants nurse practitioners and nurseswith an interest in skin and wound careLEARNING OBJECTIVESOUTCOMES After participating in this educational activity the participant will1 Differentiate the effectiveness of the topical wound care agents included in this review2 Compare the preventive efficacy of intravenous agents administered to trauma and surgical patients3 Select the effectiveness of products in this review that are left in place after surgical procedures4 Identify an oral agent that can be helpful in mitigating the effects of COVID-19

ABSTRACTEffective wound healing is achieved by well-timed host celland environment interactions involving hemostasisinflammation formation of repaired dermal structures andepithelialization followed by months to years of scarremodeling Globally various natural or synthetic agents ordressings are used to optimizewound environments prolongdrug release aid in fluid absorption provide favorablehealing environments and act as amechanical barrier againstwound trauma In this scoping review of evidence from thePubMed and clinicaltrialsgov databases authors examinedclinical study evidence supporting the efficacy and safety ofselected phytochemicals vehicles polymers and animalproducts considered ldquonaturally derivedrdquo or ldquoalternativerdquowound interventions to provide a summary of preclinicalevidence Agents with the most clinical evidence werehoney alginates polyurethane gelatin and dextran Practiceimplications are described in the context of the TIMERSclinical paradigmKEYWORDS alginates alternative dextran gelatin honeyhydrogels natural phytochemicals polymers polyurethanewound care

ADV SKIN WOUND CARE 202134517ndash24

DOI 10109701ASW000077287203584ae

nd planners in any position to control the content of this CMENcompanies relevant to this educational activityst read the CME article and complete the quiz online answeringptember 30 2023 and for nurses September 6 2024 All testsEASWC for nurses Complete NCPDCME information is on th

517

Copyright copy 2021 Wolters Kluwer

INTRODUCTIONTheWorld Health Organization has estimated that 3129million surgical procedures were performed in 20161

and that millions of children and adults suffer the phys-ical and emotional trauma of burns conferring morethan $300 million of economic burden on patients andsystems2 In 2014 in the US alone 82 million Medicarebeneficiaries had at least one chronic or acute woundor related infection (an estimated cost of US$286 to US$968 billion)3 Although the true clinical economicand patient-centered burden of wounds remains to beclarified wound care is clearly a global concern affectinghundreds of millions of people annuallyWounds may be classified based on their locations

depth nature or cause of injury45 and whether theyare acute or chronic6 Acutewound healing requires goodcirculation immune function and a moist environmentfree of dead tissue or foreign matter supporting func-tion of the many cells and molecules that participate inrepair7ndash9 Chronic wounds are often resistant to treat-ment and need prolonged time to heal Repair can behindered by environmental factors such as trauma des-iccation and infection or host factors such as immunedeficiency compromised circulation or respiratory

CPD activity have disclosed that they have no financial relationships with or financial

at least 7 of the 10 questions correctly This continuing educational activity willare now online only take the test at httpcmelwwcom for physicians ande last page of this article

ADVANCES IN SKIN amp WOUND CARE bull OCTOBER 2021

Health Inc All rights reserved

function which delay the normal progression throughthese healing phases6

The rich global heritage of naturally derived woundhealing products sometimes loosely described as ldquoalter-nativerdquo agents have received increased attention recentlyand many researchers have explored their safety and

Table PRECLINICAL EVIDENCE SUPPORTING THE USE OF PHPhytoconstituent Preclinical Evidence

Curcumin (Curcuma longa)

Curcumin makes up between 2-9 ofantioxidant anti-inflammatory and antibupregulate prostaglandin synthesis and irepair Curcumin acts as a potent woundfacilitates fibrinolysis and cellular migratio

Gotu kola (Centella asiatica)

Centella asiatica contains triterpenes ascollagen synthesis and increase local vasextract increases remodeling of collagenprotein synthesis1213

Aloe veraThere is considerable historic evidence tpossesses antimicrobial and anti-inflammkeratinocytes crucial in cutaneous repair

Marigold (Calendula officinalis)

Thermal injury generates abundant freeofficinalis inhibits inflammation by supprCalendula officinalis contains free radicalycopene lutein quercitin lupeol and behealing as demonstrated by substantial i

Female ginseng (Angelica sinensis)Angelica sinensis extracts contain ferulicproliferation It promotes collagen secretiacts as a scavenger of reactive oxygen s

Neem (Azadirachta indica)Azadirachta indica promotes wound healincollagen synthesis and maintaining skin eanti-inflammatory activity As a humecta

Rosemary (Rosmarinus officinalis)

Two principal components of R officinalisvia various mechanisms as a local antioproliferation and decreasing microbial adependent activity of 15 10 and 5

Green tea (Camellia sinensis)

Flavonoid-rich green tea exhibits antioxidits potency in wound healing In one studapplied topically for 10 d reduced expresneovascularization in granulation tissue oreduction in 14 d for second-degree burnsilver sulfadiazine 1 cream19

Henna (Lawsonia inermis)

Lawsonia inermis contains various alkaloimportant roles in wound healing exhibitper 100 mL of L inermis extracts in gelatand collagen formation and reduced the iby immunohistochemical staining20 Anoincreased hydroxyproline content and tenointment of L inermis compared with 02

Aromatic oils (tea tree oilchamomile oil)

Extensive clinical and preclinical researcof tree tea oil in burn wound healing FurtA chamomile oil-loaded topical formulathealing on days 8 and 16 compared with

ADVANCES IN SKIN amp WOUND CARE bull OCTOBER 2021 518

Copyright copy 2021 Wolters Kluwer H

efficacy in wound management7ndash9 Preclinical evidencepresented in the Table suggests many ways that variousagents obtained fromplant or animal sources aswell as cer-tain smart excipients may affect wound environments10ndash21

Supporting evidence for translating theory into practicefor alternative wound care agents has been described as

YTOCONSTITUENTS IN WOUND HEALING

turmeric It is extracted from the rhizomes of C longa and has importantacterial properties that make it useful for treating wounds Curcuminoidsnhibit leukotrienes stimulating collagen synthesis which leads to tissuehealing agent by altering urokinase plasminogen activator expression whichn necessary in the wound healing process1011

iaticoside madecassoside Asiatic acid and madecassic acid which triggercular endothelial growth factor to support wound healing Centella asiaticaand granulation tissue production as reflected by increasing DNA and

hat the multipurpose herbal extract of the leaves of the aloe vera plantatory properties and promotes proliferation and migration of fibroblasts and14

radicals that are associated with inflammation and infection Calendulaessing activities of proinflammatory cytokines and cyclooxygenase 2l scavengers including triterpenoids flavonoids and alkaloids such asta carotene These properties contribute to its effectiveness in burn woundn vivo evidenceacid which has analgesic and antimicrobial properties and stimulates cellon calcium ion regulation and cellular mobility In addition female ginsengpecies that reinforce wound healing activityg in rats by enhancing granulation tissue formation re-epithelialization andlasticity15 It exhibits recognized antimicrobial antifungal antioxidant andnt in wound formulations it helps promote moist wound healing16

extracts are carnosol and ursolic acid which contribute to wound healingxidant at the wound site stimulating revascularization fibroblastnd collagenase activity A 21-d in vivo study identified significant dose-of rosemary extract on reducing wound area17

ant antimicrobial anti-inflammatory and antiallergic effects contributing toy18 conducted on excision wounds in rats 400 mgmL of C sinensis extractsion of inflammatory cells and increased collagen deposition with densef healing wounds Another study reported significantly greater areas on rats treated topically with green tea compared with petroleum jelly or

ids tannins flavonoids steroids glycosides and saponins that playing antioxidant antimicrobial and collagen synthesis activity Thirty gramsin oxidized starch electrospun nanofiber mats increased re-epithelializationnflammatory macrophage zone surrounding burn sites on mice as measuredther study in rats reported significantly faster wound contraction withsile strength of full-thickness excisions treated topically with 5 or 10 nitrofurazone ointmenth has identified the antiseptic antibacterial and anti-inflammatory activityher chamomile oil has been assessed for its wound healing activity in ratsion (solid lipid nanoparticles and cream) showed better wound closurethe untreated group21

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ealth Inc All rights reserved

Figure 1 PRISMA FLOW DIAGRAM

Figure 2 NUMBER OF CLINICAL STUDIES SUPPORTINGEACH ALTERNATIVE AGENT

ldquopromisingrdquo22 but remains to be summarized in the con-text of clinical practice for wound bed preparation2324

and management paradigms2526

PurposeThe authors conducted a scoping review of preclinical andclinical trial evidence supporting the efficacy andor safetyofmajor alternativewound care agents to summarize theireffects on validated elements of wound bed preparationand wound management paradigms

METHODSThe PubMed reference database was searched fromJanuary 1 1970 throughNovember 20 2020 for originaland derivative clinical trial references addressing theMeSH (Medical Subject Headings) terms for ldquoclinicaltrialrdquo combined with those for each of the agents listedin the Table Randomized controlled trials (RCTs) ornonrandomized clinical trials were included if they re-ported a significant improvement (P lt 05) in one or moremeasured and valid wound outcomes27 Case studieswere included to support wound safety but in vivoand in vitro studies were excluded as were those unre-lated to cutaneous wound care or the alternative agentsin question Further studies combining an alternativeagentwith other agents preventing evaluation of its spe-cific effects were excluded from analysisAll authors evaluated the clinical literature search results

and a single investigator extracted from qualifying clinicalstudies the first authorrsquos last name year of publicationtype of clinical study (randomized nonrandomized orcase series) number of patients studied and wound eti-ology Data were used to populate a spreadsheet whichcalculated the number of studies supporting each agent

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The usefulness of each agent was then described basedon its reported outcomes related to elements of theTIMERS (Tissue management reducing Inflammationand Infection Moisture balance Edge and Epithelial ad-vancement Regeneration and Repair or Social issues)wound management mnemonic

RESULTSOf 1380 references screened 281 abstracts or full-text ar-ticles were reviewed and 274 studies on 28315 patientswere included in the analysis (Figure 1) Agents withmore than 10 RCTs supporting clinical wound outcomes(Figure 2) were honey alginate gels or fiber dressingspolyurethane gel or adhesive dressing aloe vera gel ordextran powder Results are discussed below indicatingeach agentrsquos potential roles in wound managementusing the TIMERS paradigm or meeting other aspectsof patient or wound clinical needsTwo case series involving 24 patients supported the

safety of agar hydrogel (TIMERS component E) inepithelializing skin graft donor sites (SGDSs)Thirty-two clinical trials involving 2147 patients in-

cluded alginate dressings (TIMERS components I M E)These dressings contain highly absorbent calcium alginateor calcium sodium alginate fibers or yarns that supporthemostasis or form a gel when in contact with a moistwound surface accordingly they can be lifted off orwashed



off at dressing removal They improved healing or reducedinfection rates of SGDSs compared with gauze dressingswith similar wound healing outcomes to hydrofiber filmor silicone dressings which all healed SGSD at least7 daysmore slowly than SGDSs dressed with a hydrocol-loid dressing28 The benefits of alginate dressings wereless clear for venous leg ulcers29 diabetic foot ulcers30

or pressure injuries31 because alginate dressings were of-ten used in combination with other dressings or agentsHealing and pain improvement were similar for chronicor acute wounds dressed with an alginate or a silverdressing32 In participants with chronic wounds and highbacterial burdens topical silver alginate powder reducedwound area and signs of infection over 4weeks comparedwith a foam dressing33 Studies of such combined inter-ventions or studieswhere ldquostandard carerdquo included algi-nates with other dressings were not included in Figure 2because it was not possible to discern the specific effectsof the alginate component of the dressingThis review included 18 clinical trials on aloe vera use

for 1113 patients (TIMERS components I E) Systematicreviews reported improved healing of patients withburns and burn wound infection managed with aloevera with effects comparable with those of topical anti-biotics or antiseptics34 Improved healing was reportedfor pressure injuries cleansed with a spray containingphysiologic saline aloe vera and decyl glucoside com-pared with isotonic saline but it was not clear that aloevera caused the healing effect35

Calendula officinalis (Marigold) or C flos extract wasexamined by 9 clinical studies involving 1086 patients(TIMERS components I E) Marigold was typicallydelivered as a 3 ointment or hydroglycolic spray withvarying effects36 Reduced pain and improved healingwere reported for gynecologic surgical wounds venousleg ulcers and diaper dermatitis but not diabetic leg ulcersor partial-thickness burns comparedwith standard of careThe extract improved radiation dermatitis symptomscompared with trolamine with similar healing bene-fits to topical aqueous gel36

Centella asiaticawas included in 9 clinical studies on atleast 426 patients (TIMERS components I E) withchronic or surgical wounds and second-degree burnsthis agent reportedly improved healing nerve injuryand scar tissue37

The search for chitin or chitosan returned 10 clinicalstudies on 681 patients (TIMERS component E) reveal-ing improved hemostasis and healing ofmilitary or civil-ian full- or partial-thickness acute or chronic woundsincluding SGDSs diabetic foot ulcers pressure injuriesvenous ulcers and oral surgery sites3839

Carrageenan searches returned no clinical studiesreporting any clinical benefit related to wound healingThis agent was mainly used in preclinical studies as a



pain- or inflammation-inducing agent in rodents or aprimer for liver or lung endotoxin shock studies in vivo40

Curcumin also called diferuloylmethane was sur-veyed in 11 clinical studies on 1227 patients (TIMERScomponent I) and reduced radiationmucositis dermati-tis or periodontal inflammation when delivered orallyor as a topical gel often encapsulated in liposomes4142

Considerable preclinical research has been conductedto develop a formulation with adequate solubility andsystemic absorption to optimize its safe delivery and ef-ficacy in wound management43

Dextran involved in 16 studies on 9519 patients (TIMERScomponents T I) was used as a topical dextranomerpowder to heal chronic wounds or burns4445 Adding6 dextran-70 (70000 molecular weight) administeredinfusion to lactated Ringerrsquos solution was more effectivethan lactated Ringerrsquos solution alone in preventing acuterespiratory distress syndrome and improving low BP as-sociated with shock in trauma patients en route to thehospital46 However later studies reported that hypertonicsaline (75) prevented posttraumatic hypotension aseffectively without adding dextran-7047 To prevent post-surgical deep vein thrombosis (DVT) 500 to 1000 mL ofdextran-40 or dextran-70 during the first 2 to 6 hours post-operatively followed by 500 mL per day for 1 week waseffective in preventing DVT compared with 0 dextranHowever researchers reported the possibility that dex-tran may worsen progressive hypercoagulation in thesetrauma patients48 Dextran infusions prevented morepostsurgical hematomas than low-molecular-weight hep-arin whereas heparin interventions limited more DVTsthan dextran did Topical treatment of chronic woundswith dextranomer paste was less effective in healingsloughy pressure injuries than similar treatment withan amorphous hydrogel49 In general dextran polymerformulations showed initial promise in emergency re-suscitation and preventing postsurgical DVT as wellas debriding chronic wounds but their efficacy andsafety were exceeded by other agents in at least 18subsequent RCTsGelatin was used in 20 studies on 1560 patients

(TIMERS component E) It was typically applied as afoam sponge drug delivery system or to aid in hemosta-sis or healing of ruptured tympanic membrane50 or as apacking agent following nasal51 sinus52 or other sur-gery It was often combined with collagen or fibrin glueto deliver growth factors or other agents in studies ex-cluded from this analysis because the effects of the gela-tin per se were unclear The efficacy of other agentsexceeded gelatin as a posttraumatic infusion in reducingcapillary leakage As a sealant for vascular prosthesesgelatin transiently increased circulating leukocytes for2 weeks after grafting without other notable adverse ef-fects53 Gelatin can be used as an acceptable absorbable

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hemostatic sponge54 but if left in place after the removalof thyroid cancer it may mimic residual or recurrentthyroid carcinoma during follow-up ultrasound sur-veillance55When injected into individuals with severebrain trauma gelatin solutions improved intracranialpressure Glasgow Coma Scale scores at 1 to 2 weeksand 3-month Glasgow Outcome Scale scores comparedwith traditional management56

Two studies on 139 patients involved ginseng (TIMERScomponent I) saponin glycosides administeredwith pe-ripheral bloodmonocytes improved circulationmeasuresand 6-minute walking distance of patients with criticallimb ischemia comparedwith peripheral bloodmonocytesadministered alone It was often included in complex Chi-nese traditional medicine formulations but its effects inthese were unclear It has been reported to protect againstmyocardial ischemia-reperfusion injury57 but anaboliceffects during or after exercise have not been confirmedin anRCT58 Researchers have raised concerns that patientstaking unreported botanic supplements such as ginsengginkgo biloba garlic ginger valerian kava St Johns wortephedra or echinacea may experience unforeseen seri-ous complications during surgery59

Glucan derived from yeast cell walls or certain mush-rooms was licensed as a drug in Japan in 1983 This re-view included 5 studies on 1363 patients using glucan(TIMERS components I E) Most of its clinical trialscombined a glucan with a monoclonal antibody to limitcancer metastases improve gastrointestinal disorderoutcomes lower cholesterol or address immune disor-ders all of which are beyond the scope of this review60

Further β-glucans have been reported to modulate in-flammation coagulation abnormalities and digestivedisorders associated with COVID-1961 In critically illpatients with trauma wounds high-protein parenteralsupplements with β-13-glucans reduced pneumoniasepsis organ failure and ventilator time6263 Further14 g daily doses of β-1316-glucan for 5 days precedingcoronary artery bypass graft surgery reduced ischemia-reperfusion injury64 Oral 05 mgkg of yeast-cell-wallPGG glucan (one dose preoperatively and three dosespostoperatively) reduced the incidence of serious post-operative infections or death following noncolorectalsurgery in high-risk patients but was associated withadverse events in colorectal surgery65 Finally topicaluse of water-insoluble β-13-glucan purified from bakerrsquosyeast (Saccharomyces cerevisiae) was associated with ve-nous ulcer healing in one case series66

Green tea is derived from the tea treeMelaleuca alternifoliaFive studies on 264 patients (TIMERS component I) re-ported on green tea Its catechins had antimicrobialproperties and anti-inflammatory effects on the cycloox-ygenase and lipoxygenase eicosanoid pathways butwhen taken orally (1080 mg of catechins in 1350 mg



of green tea extract with 50 mg of vitamin C per day)for 3months did not reduce skin erythema leukocyte re-sponse or eicosanoid responses to a UV light inflamma-tory challenge Pretreating skin with green tea polyphenolextracts protected volunteersrsquo skin from sun damage67 Ifapplied within 30 minutes after thermal burns a greentea extract spray reduced burn pain but water cooledthe burned skin more68 and was similarly effective intreating postpartum nipple pain69

Two studies on 100 patients (TIMERS components I E)discussed henna Henna derived from Lawsonia inermisimproved healing and pain when applied topically toepisiotomies compared with placebo70 In an ointmentformulation it improved healing pain pruritus anddischarge of radiation dermatitis sites when applied im-mediately after 45 to 50 Gy radiotherapy comparedwitha similar application of 1 hydrocortisone creamHoney was the most well-studied alternative agent in

this review investigators noted 32 clinical studies on2147 patients (TIMERS components T I M E) Honeyis a humectant made by honeybees Trials on a wide vari-ety of acute surgical trauma or burn wounds radiation-inducedmucositis71 and chronic pressure injuries venousleg ulcers or diabetic foot ulcers support the promotionof a moist wound healing environment improvedhealing and better debridement orwound infection out-comes with a variety of honey sources72 These resultshave been confirmed by independent systematic reviewson various etiologies of acute or chronic wounds73ndash75

Marigold (Tagetes) and Calendula (Calendula) are bothin the Asteracea family and not always distinguishedfrom one another in the literature These researchersnoted 9 clinical studies on 960 patients (TIMERS compo-nents I E) Calendula ointment shortened the inflam-mation phase of acute healing and improved radiationdermatitis76 similar to the effects of aqueous cream andhad mixed effects on chronic venous or diabetic ulcersor acute burn wounds36 In gynecologic surgery Calen-dula ointment improved episiotomy healing and painor cesarean section healing compared with standardof care7778

Neem (Azadirachta indica) returned no studies where itwas applied to wounds alone as a topical or systemic in-tervention It was often combinedwith other topicalwoundtreatments such as turmeric This reduced the clarity ofits effects in wound carePectin a hydrocolloid substance derived from fruit was

examined in 5 clinical studies on 167 patients (TIMERScomponents M E) It was often combined with otheragents or mixed with other biopolymers to add moist-adherent properties to skin or wound adhesives Pectinwas applied as a skin barrier to prevent or heal tape dam-age on peristomal areas or near tracheostomy sites79 or toprotect the delicate intact facial skin of premature infants80



Polycaprolactone was frequently studied as a ldquobio-inkrdquo for three-dimensional printing of tissue scaffoldsor as a delivery system for other agents or sensors81 Re-peated searches found no clinical studies of its effects onany human skin woundPolylactic acid (PLA 9 studies on 248 patients TIMERS

component E) may foster periodontal cleft palate ortendon healing The SGDSs dressed with a PLA copoly-mer dressing healed similarly to those dressed with acellulose nanofiber dressing with comparable pain butthe PLA dressed wounds had thicker less elastic scars1 month postoperatively82 When used to guide flexortendon repair PLA membranes reduced adhesions im-proving interphalangeal joint function compared withuntreated sites as did freeze-dried amniotic membranesbut PLA elicited more complications83 The use of bio-absorbable PLA screws instead of metallic screws provedreliable and effective for ankle fracture fixation avoidinga second surgery to remove metallic screws with similarresults for PLA rotator cuff anchors but using PLA kneejoint fixation screws was associated with complicationsincluding bone resorption84 Most studies on PLA-bonescrew interactions were excluded from this work unlessthey also pertained to skin woundsPolyethylene glycol (PEG) was included in 13 studies

involving 1171 patients (TIMERS components T I M)Certain PEG hydrogels have been reported to be effectivein preventing surgical adhesion as a topical debridingagent or as a dural sealant after spinal surgery85 Whenused before radiation therapy to expand space betweenprostate cancer and the bowel it has reduced adverse ef-fects of radiation Its use in presurgery bowel preparationreduced electrolyte disturbance for elective colorectal pro-cedures with mixed efficacy8687

Polyurethane film or foam was mentioned in 25 stud-ies on 1565 patients (TIMERS components I M E) Itwas reported to prevent pressure injury developmentin older adults recovering from hip fractures Resorbablepolyurethane used as postoperative nasal packing im-proved endoscopic sinus surgery outcomes Postsurgicalpolyurethane wound drains reduced thrombus forma-tion and pain on removal comparedwith polyvinyl chlo-ride drains88 further polyurethane adhesive removedand reapplied every 48 hours did not damage periwoundskin around venous leg ulcers as much as hydrocolloidadhesivewound dressings did89 Adhesive wound dress-ings with a polyurethane film or foam backing reducedhealing time pain and infection rates in surgical sitesacute wounds or chronic wounds compared with gauzedressings90ndash92 Evidence on dressings where a polyure-thane foam or adhesive was used at the wound interfaceis summarized in Figure 2Rosemary (Rosmarinus officinalis) is an evergreen shrub

from South America and the Mediterranean coast with



preclinical evidence of antioxidant anti-inflammatoryanticancer and antihyperglycemic properties93 No stud-ies were found supporting its effects on patients withwounds Ursolic acid extracted from rosemary (150 mgonce daily for 12weeks) lowered bodymass indexweightwaist circumference and fasting glucose and increasedinsulin sensitivity in 12 patients with diabetes mellituscompared with a placebo94 but effects on wounds werenot studied

DISCUSSIONThis scoping review suggests that many naturally de-rived agents previously categorized as ldquoalternative prac-ticerdquo merit consideration given their potential to improvewound outcomes Those backed by evidence from at least10 RCTs include honey alginate gel or fiber dressingspolyurethane gel or adhesive dressings aloe vera geland dextran powder Some of these have already en-tered the ranks of agents or delivery systems used inclinical practice been cleared by regulatory authoritiesfor mainstream clinical use and drawn the attention ofCochrane or other reviewers Opportunities abound forimprovements in managing hemostasis scarring or ad-hesions These agents may support recognized aspectsof healing such as fibroplasia angiogenesis and epithe-lialization improvewound inflammation infection andpain or maintainmoisture balance tominimize the needfor frequent dressing changes Further clinical researchis needed to determine if these alternative agents im-prove outcomes compared with current standard ofpractice either combined with current products or asadjunct interventionsThis review limited itself to the agents with which the

authors were familiar Other alternative agents in useelsewhere in the world may merit similar reviews andorclinical studies

CONCLUSIONSThe preclinical evidence and clinical literature reviewedsuggest that honey alginate gels or fiber dressings poly-urethane gel or adhesive dressings aloe vera gel anddextran powder have clinical evidence of potential effi-cacy in wound management Many other alternativeagents are supported by sufficient clinical research tosuggest their potential as smart excipients or novel ac-tive agents within future multifaceted wound manage-ment delivery systems

PRACTICE PEARLSbull Ten or more RCTs support continued research andpractice using honey alginate gel or fiber dressingspolyurethane gel or adhesive dressings aloe vera gelor dextran powder on various clinical wounds

WWWASWCJOURNALCOM


bull Several agents previously considered ldquoalternativerdquoare now cleared by regulatory authorities and have be-come mainstream wound care treatments These agentsmay improvewoundhemostasis inflammation infectionpain angiogenesis fibroplasia and epithelializationbull Substantial research suggests that alternative prod-ucts have potential as smart excipients or novel activeagents within future multifaceted wound manage-ment delivery systemsbull Exploring these and other alternative wound man-agement agents may have the potential to improveoutcomes for patients with woundsbull

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Bull World Health Organ 201694(3)201-9F2 World Health Organization Fact sheet on Burns 2018 wwwwhointnews-roomfact-sheetsdetail

burns Last accessed July 27 20213 Nussbaum SR Carter MJ Fife CE et al An economic evaluation of the impact cost and Medicare

policy implications of chronic nonhealing wounds Value Health 201821(1)27-324 Young A McNaught C-E The physiology of wound healing Surg 201129(10)475-95 Gantwerker EA Hom DB Skin histology and physiology of wound healing Facial Plast Surg Clin

North Am 201119(3)441-536 Lazarus GS Cooper DM Knighton DR et al Definitions and guidelines for assessment of wounds and

evaluation of healing Arch Dermatol 1994130(4)489-937 Hosseinkhani A Falahatzadeh M Raoofi E Zarshenas MM An evidence-based review on wound

healing herbal remedies from reports of traditional Persian medicine J Evid Based Complement AlternMed 201722(2)334-43

8 Kumar B Vijayakumar M Govindarajan R Pushpangadan P Ethnopharmacological approaches towound healingmdashexploring medicinal plants of India J Ethnopharmacol 2007114(2)103-13

9 Saini S Dhiman A Nanda S Traditional Indian medicinal plants with potential wound healing activitya review Int J Pharm Sci Res 20161809-19

10 Dai X Liu J Zheng H et al Nano-formulated curcumin accelerates acute wound healing throughDkk-1-mediated fibroblast mobilization and MCP-1-mediated anti-inflammation NPG Asia Mater20179(3)e368

11 El-Refaie WM Elnaggar YSR El-Massik MA Abdallah OY Novel curcumin-loaded gel-corehyaluosomes with promising burn-wound healing potential development in-vitro appraisal and in-vivostudies Int J Pharm 2015486(1-2)88-98

12 Kosalwatna S Shaipanich C Bhanganada K The effect of one percent Centella asiatica cream onchronic ulcers Siriraj Med J 198840(6)455-61

13 Shukla A Rasik AM Dhawan BN Asiaticoside-induced elevation of antioxidant levels in healingwounds Phyther Res 199913(1)50-4

14 Hekmatpou D Mehrabi F Rahzani K et al The effect of aloe vera clinical trials on prevention andhealing of skin wound a systematic review Iran J Med Sci 201944(1)1-9

15 Ilango K Maharajan G Narasimhan S Anti-nociceptive and anti-inflammatory activities ofAzadirachta indica fruit skin extract and its isolated constituent azadiradione Nat Prod Res 201327(16)1463-7

16 Maver T Maver U Stana Kleinschek K Smrke DM Kreft S A review of herbal medicines in woundhealing Int J Dermatol 201554(7)740-51

17 Alizargar J Kuchaki E Shaabani A Namazi M Properties of wound healing activities of rosemaryextract J Biol Act Prod Nat 20122(4)218-24

18 Hajiaghaalipour F Kanthimathi MS Abdulla MA Sanusi J The effect of Camellia sinensis on woundhealing potential in an animal model Evid Based Complement Altern Med 20132013386734

19 Fatemi MJ Nikoomaram B Rahimi AAK Talayi D Taghavi S Ghavami Y Effect of green tea on thesecond degree burn wounds in rats Indian J Plast Surg 201447(3)370-4

20 Hadisi Z Nourmohammadi J Nassiri SM The antibacterial and anti-inflammatory investigation ofLawsonia inermis-gelatin-starch nano-fibrous dressing in burn wound Int J Biol Macromol 2018107(pt B)2008-19

21 Gad HA Abd El-Rahman FAA Hamdy GM Chamomile oil loaded solid lipid nanoparticles a naturallyformulated remedy to enhance the wound healing J Drug Deliv Sci Technol 201950329-38

22 Dorai AA Wound care with traditional complementary and alternative medicine Indian J Plast Surg201245(2)418-24

23 Harries RL Bosanquet DC Harding KG Wound bed preparation TIME for an update Int Wound J201613(S3)8-14

24 Lim K Free B Sinha S Modified TIME-H a simplified scoring system for chronic wound managementJ Wound Care 201524(9)415-9

25 Beitz J Using wound care algorithms a content validation study J Wound Ostomy Continence Nurs199926(5)238-49

26 Bolton L McNees P van Rijswijk L et al Wound-healing outcomes using standardized assessmentand care in clinical practice J Wound Ostomy Continence Nurs 200431(2)65-71

27 Driver VR Gould LJ Dotson P et al Identification and content validation of wound therapy clinical



endpoints relevant to clinical practice and patient values for FDA approval Part 1 Survey of thewound care community Wound Repair Regen 201725(3)454-65

28 Broumllmann FE Eskes AM Goslings JC et al Randomized clinical trial of donor-site wound dressingsafter split-skin grafting Br J Surg 2013100(5)619-27

29 Norman G Westby MJ Rithalia AD Stubbs N Soares MO Dumville JC Dressings and topical agentsfor treating venous leg ulcers Cochrane Database Syst Rev 20186(6)CD012583

30 Dumville JC OrsquoMeara S Deshpande S Speak K Alginate dressings for healing diabetic foot ulcersCochrane Database Syst Rev 2013(6)CD009110

31 Westby MJ Dumville JC Soares MO Stubbs N Norman G Dressings and topical agents for treatingpressure ulcers Cochrane Database Syst Rev 20176(6)CD011947

32 Beam JW Topical silver for infected wounds J Athl Train 200944(5)531-333 Woo KY Coutts PM Sibbald RG A randomized controlled trial to evaluate an antimicrobial dressing

with silver alginate powder for the management of chronic wounds exhibiting signs of criticalcolonization Adv Skin Wound Care 201225(11)503-8

34 Norman G Christie J Liu Z et al Antiseptics for burns Cochrane Database Syst Rev 20177CD011821

35 Moore ZE Cowman S Wound cleansing for pressure ulcers Cochrane Database Syst Rev 20132013(3)CD004983

36 Givol O Kornhaber R Visentin D Cleary M Haik J Harats M A systematic review of Calendulaofficinalis extract for wound healing Wound Repair Regen 201927(5)548-61

37 Muangman P Praditsuktavorn B Chinaroonchai K Chuntrasakul C Clinical efficacy test of polyestercontaining herbal extract dressings in burn wound healing Int J Low Extrem Wounds 201615(3)203-12

38 Malmquist JP Clemens SC Oien HJ Wilson SL Hemostasis of oral surgery wounds with theHemCon dental dressing J Oral Maxillofac Surg 200866(6)1177-83

39 Kircik LH Comparative study of the efficacy and tolerability of a unique topical scar product vs whitepetrolatum following shave biopsies J Drugs Dermatol 201312(1)86-90

40 Cacircmara CC Ramos HF da Silva AP et al Oral gabapentin treatment accentuates nerve andperipheral inflammatory responses following experimental nerve constriction in Wistar rats NeurosciLett 201355693-8

41 Farhood B Mortezaee K Goradel NH et al Curcumin as an anti-inflammatory agent Implications toradiotherapy and chemotherapy J Cell Physiol 2019234(5)5728-40

42 Xu H Gong Z Zhou S et al Liposomal curcumin targeting endometrial cancer through the NF-κBpathway Cell Physiol Biochem 201848(2)569-82

43 Nguyen M-H Lee SE Tran T-T et al A simple strategy to enhance the in vivo wound-healing activityof curcumin in the form of self-assembled nanoparticle complex of curcumin and oligochitosan MaterSci Eng C 20199854-64

44 Ljungberg S Comparison of dextranomer paste and saline dressings for management of decubitalulcers Clin Ther 199820(4)737-43

45 Hulkko A Holopainen YV Orava S et al Comparison of dextranomer andstreptokinase-streptodornase in the treatment of venous leg ulcers and other infected woundsAnn Chir Gynaecol 198170(2)65-70

46 Vassar MJ 75 Sodium chloridedextran for resuscitation of trauma patients undergoing helicoptertransport Arch Surg 1991126(9)1065

47 Vassar MJ Perry CA Holcroft JW Prehospital resuscitation of hypotensive trauma patients with 75 NaCl versus 75 NaCl with added dextran a controlled trial J Trauma 199334(5)622-32

48 Delano MJ Rizoli SB Rhind SG et al Prehospital resuscitation of traumatic hemorrhagic shock withhypertonic solutions worsens hypocoagulation and hyperfibrinolysis Shock 201544(1)25-31

49 Colin D Kurring PA Quinlan D Yvon C Managing sloughy pressure sores J Wound Care 19965(10)444-6

50 Lou Z-C Wei H Lou Z-H Comparison of the medical costs and effects of large traumatic eardrumperforations treatment Am J Otolaryngol 201940(1)46-51

51 Kim S-D Hong S-L Kim M-J et al Effectiveness of hemostatic gelatin sponge as a packing materialafter septoplasty a prospective randomized multicenter study Auris Nasus Larynx 201845(2)286-90

52 Cho K-S Park C-H Hong S-L et al Comparative analysis of Cutanplast and Spongostan nasalpacking after endoscopic sinus surgery a prospective randomized multicenter study Eur ArchOtorhinolaryngol 2015272(7)1699-1705

53 Utoh J Goto H Hirata T Hara M Kitamura N Postoperative inflammatory reactions to sealedDracon prostheses a comparison of Gelseal and Hemashield J Cardiovasc Surg (Torino) 199738(3)287-90

54 Rossmann JA Rees TD A comparative evaluation of hemostatic agents in the management of softtissue graft donor site bleeding J Periodontol 199970(11)1369-75

55 Tublin ME Alexander JM Ogilvie JB Appearance of absorbable gelatin compressed sponge on earlypost-thyroidectomy neck sonography J Ultrasound Med 201029(1)117-20

56 Ai W Chen Y Yang Q [Clinical observation on effect of xuesaitong injection as auxiliary treatment ofsevere craniocerebral injury] Chinese J Integr Tradit West Med 200424(3)213-5

57 Zhan Y Xu XH Jiang YP [Protective effects of ginsenoside on myocardiac ischemic and reperfusioninjuries] Zhonghua Yi Xue Za Zhi 199474(10)626-8

58 Youl Kang H Hwan Kim S Jun Lee W Byrne HK Effects of ginseng ingestion on growth hormonetestosterone cortisol and insulin-like growth factor 1 responses to acute resistance exerciseJ Strength Cond Res 200216(2)179-83

59 Ciocon JO Ciocon DG Galindo DJ Dietary supplements in primary care Botanicals can affectsurgical outcomes and follow-up Geriatrics 200459(9)20-4

60 Vetvicka V Vannucci L Sima P Richter J Beta glucan supplement or drug From laboratory toclinical trials Molecules 201924(7)

61 Jawhara S How to boost the immune defence prior to respiratory virus infections with the specialfocus on coronavirus infections Gut Pathog 202012(1)47



62 de Felippe Juacutenior J da Rocha e Silva Juacutenior M Maciel FM Soares A de M Mendes NF Infectionprevention in patients with severe multiple trauma with the immunomodulator beta 1-3 polyglucose(glucan) Surg Gynecol Obstet 1993177(4)383-8

63 Fazilaty Z Chenari H Shariatpanahi ZV Effect of szlig-glucan on serum levels of IL-12 hs-CRP andclinical outcomes in multiple-trauma patients a prospective randomized study Ulus Travma AcilCerrahi Derg 201824(4)287-93

64 Aarsaeligther E Rydningen M Einar Engstad R Busund R Cardioprotective effect of pretreatment withβ-glucan in coronary artery bypass grafting Scand Cardiovasc J 200640(5)298-304

65 Dellinger EP Babineau TJ Bleicher P et al Effect of PGG-glucan on the rate of serious postoperativeinfection or death observed after high-risk gastrointestinal operations Betafectin GastrointestinalStudy Group Arch Surg 1999134(9)977-83

66 Medeiros SDV Cordeiro SL Cavalcanti JEC et al Effects of purified Saccharomyces cerevisiae(1rarr 3)-β-glucan on venous ulcer healing Int J Mol Sci 201213(7)8142-58

67 Elmets CA Singh D Tubesing K Matsui M Katiyar S Mukhtar H Cutaneous photoprotection fromultraviolet injury by green tea polyphenols J Am Acad Dermatol 200144(3)425-32

68 Cho YS Choi YH Comparison of three cooling methods for burn patients a randomized clinical trialBurns 201743(3)502-8

69 National Library of Medicine Drugs and Lactation Database (LactMed) Green Tea Bethesda MDNational Library of Medicine 2018

70 Zibanejad S Miraj S Rafieian Kopaei M Healing effect of Quercus persica and Lawsonia inermisointment on episiotomy wounds in primiparous women J Res Med Sci 20202511

71 Song JJ Twumasi-Ankrah P Salcido R Systematic review and meta-analysis on the use of honey toprotect from the effects of radiation-induced oral mucositis Adv Skin Wound Care 201225(1)23-8

72 Yilmaz AC Aygin D Honey dressing in wound treatment a systematic review Complement Ther Med202051102388

73 Wang C Guo M Zhang N Wang G Effectiveness of honey dressing in the treatment of diabetic footulcers a systematic review and meta-analysis Complement Ther Clin Pract 201934123-31

74 Broumllmann FE Ubbink DT Nelson EA Munte K van der Horst CMAM Vermeulen H Evidence-baseddecisions for local and systemic wound care Br J Surg 201299(9)1172-83

75 Norman G Christie J Liu Z et al Antiseptics for burns Cochrane Database Syst Rev 20177(7)CD011821

76 Kassab S Cummings M Berkovitz S van Haselen R Fisher P Homeopathic medicines for adverseeffects of cancer treatments Cochrane Database Syst Rev 2009(2)CD004845

77 De Angelis C Di Stadio A Vitale S et al Use of calendula ointment after episiotomy a randomizedclinical trial J Matern Fetal Neonatal Med 20201-5

78 Jahdi F Khabbaz AH Kashian M Taghizadeh M Haghani H The impact of calendula ointment oncesarean wound healing a randomized controlled clinical trial J Fam Med Prim Care 7(5)893-7

79 Chuang W-L Huang W-P Chen M-H Liu I-P Yu W-L Chin C-C Gauze versus solid skin barrier for



tracheostomy care a crossover randomized clinical trial J Wound Ostomy Continence Nurs 201340(6)573-9

80 Dollison EJ Beckstrand J Adhesive tape vs pectin-based barrier use in preterm infants NeonatalNetw 199514(4)35-9

81 Farzanfar S Kouzekonan GS Mirjani R Shekarchi B Vitamin B12-loaded polycaprolactongelatinnanofibrous scaffold as potential wound care material Biomed Eng Lett 202010(4)547-54

82 Koivuniemi R Hakkarainen T Kiiskinen J et al Clinical study of nanofibrillar cellulose hydrogeldressing for skin graft donor site treatment Adv Wound Care 20209(4)199-210

83 Liu C Bai J Yu K Liu G Tian S Tian D Biological amnion prevents flexor tendon adhesion in zone IIa controlled multicentre clinical trial Biomed Res Int 201920191-9

84 Drogset JO Straume LG Bjoslashrkmo I Myhr G A prospective randomized study of ACL-reconstructionsusing bone-patellar tendon-bone grafts fixed with bioabsorbable or metal interference screws KneeSurg Sports Traumatol Arthrosc 201119(5)753-9

85 Wright NM Park J Tew JM et al Spinal sealant system provides better intraoperative watertightclosure than standard of care during spinal surgery a prospective multicenter randomized controlledstudy Spine (Phila Pa 1976) 201540(8)505-13

86 Fa-Si-Oen P Roumen R Buitenweg J et al Mechanical bowel preparation or not Outcome of amulticenter randomized trial in elective open colon surgery Dis Colon Rectum 200548(8)1509-16

87 Ancha HR Spungen AM Bauman WA et al Clinical trial the efficacy and safety of routinebowel cleansing agents for elective colonoscopy in persons with spinal cordinjurymdasha randomized prospective single-blind study Aliment Pharmacol Ther 200930(11-12)1110-7

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function which delay the normal progression throughthese healing phases6

The rich global heritage of naturally derived woundhealing products sometimes loosely described as ldquoalter-nativerdquo agents have received increased attention recentlyand many researchers have explored their safety and

Table PRECLINICAL EVIDENCE SUPPORTING THE USE OF PHPhytoconstituent Preclinical Evidence

Curcumin (Curcuma longa)

Curcumin makes up between 2-9 ofantioxidant anti-inflammatory and antibupregulate prostaglandin synthesis and irepair Curcumin acts as a potent woundfacilitates fibrinolysis and cellular migratio

Gotu kola (Centella asiatica)

Centella asiatica contains triterpenes ascollagen synthesis and increase local vasextract increases remodeling of collagenprotein synthesis1213

Aloe veraThere is considerable historic evidence tpossesses antimicrobial and anti-inflammkeratinocytes crucial in cutaneous repair

Marigold (Calendula officinalis)

Thermal injury generates abundant freeofficinalis inhibits inflammation by supprCalendula officinalis contains free radicalycopene lutein quercitin lupeol and behealing as demonstrated by substantial i

Female ginseng (Angelica sinensis)Angelica sinensis extracts contain ferulicproliferation It promotes collagen secretiacts as a scavenger of reactive oxygen s

Neem (Azadirachta indica)Azadirachta indica promotes wound healincollagen synthesis and maintaining skin eanti-inflammatory activity As a humecta

Rosemary (Rosmarinus officinalis)

Two principal components of R officinalisvia various mechanisms as a local antioproliferation and decreasing microbial adependent activity of 15 10 and 5

Green tea (Camellia sinensis)

Flavonoid-rich green tea exhibits antioxidits potency in wound healing In one studapplied topically for 10 d reduced expresneovascularization in granulation tissue oreduction in 14 d for second-degree burnsilver sulfadiazine 1 cream19

Henna (Lawsonia inermis)

Lawsonia inermis contains various alkaloimportant roles in wound healing exhibitper 100 mL of L inermis extracts in gelatand collagen formation and reduced the iby immunohistochemical staining20 Anoincreased hydroxyproline content and tenointment of L inermis compared with 02

Aromatic oils (tea tree oilchamomile oil)

Extensive clinical and preclinical researcof tree tea oil in burn wound healing FurtA chamomile oil-loaded topical formulathealing on days 8 and 16 compared with



efficacy in wound management7ndash9 Preclinical evidencepresented in the Table suggests many ways that variousagents obtained fromplant or animal sources aswell as cer-tain smart excipients may affect wound environments10ndash21

Supporting evidence for translating theory into practicefor alternative wound care agents has been described as

YTOCONSTITUENTS IN WOUND HEALING

turmeric It is extracted from the rhizomes of C longa and has importantacterial properties that make it useful for treating wounds Curcuminoidsnhibit leukotrienes stimulating collagen synthesis which leads to tissuehealing agent by altering urokinase plasminogen activator expression whichn necessary in the wound healing process1011

iaticoside madecassoside Asiatic acid and madecassic acid which triggercular endothelial growth factor to support wound healing Centella asiaticaand granulation tissue production as reflected by increasing DNA and

hat the multipurpose herbal extract of the leaves of the aloe vera plantatory properties and promotes proliferation and migration of fibroblasts and14

radicals that are associated with inflammation and infection Calendulaessing activities of proinflammatory cytokines and cyclooxygenase 2l scavengers including triterpenoids flavonoids and alkaloids such asta carotene These properties contribute to its effectiveness in burn woundn vivo evidenceacid which has analgesic and antimicrobial properties and stimulates cellon calcium ion regulation and cellular mobility In addition female ginsengpecies that reinforce wound healing activityg in rats by enhancing granulation tissue formation re-epithelialization andlasticity15 It exhibits recognized antimicrobial antifungal antioxidant andnt in wound formulations it helps promote moist wound healing16

extracts are carnosol and ursolic acid which contribute to wound healingxidant at the wound site stimulating revascularization fibroblastnd collagenase activity A 21-d in vivo study identified significant dose-of rosemary extract on reducing wound area17

ant antimicrobial anti-inflammatory and antiallergic effects contributing toy18 conducted on excision wounds in rats 400 mgmL of C sinensis extractsion of inflammatory cells and increased collagen deposition with densef healing wounds Another study reported significantly greater areas on rats treated topically with green tea compared with petroleum jelly or

ids tannins flavonoids steroids glycosides and saponins that playing antioxidant antimicrobial and collagen synthesis activity Thirty gramsin oxidized starch electrospun nanofiber mats increased re-epithelializationnflammatory macrophage zone surrounding burn sites on mice as measuredther study in rats reported significantly faster wound contraction withsile strength of full-thickness excisions treated topically with 5 or 10 nitrofurazone ointmenth has identified the antiseptic antibacterial and anti-inflammatory activityher chamomile oil has been assessed for its wound healing activity in ratsion (solid lipid nanoparticles and cream) showed better wound closurethe untreated group21

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alternative wound management: translating science into

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