Gamma-treated placental amniotic membrane ... - iKnow

(1)

ContentslistsavailableatScienceDirect

International Journal of Surgery Case Reports

j o u r n al ho m e p a g e :w w w . c a s e r e p o r t s . c o m

Case Series

Gamma-treated placental amniotic membrane allograft as the adjuvant treatment of unresponsive diabetic ulcer of the foot

Ihsan Oesman

^a

, Witantra Dhamar Hutami

^b,∗

aOrthopaedicSurgeon,ConsultantofFootandAnkle,DepartmentofOrthopaedic&Traumatology,CiptoMangunkusumoNationalCentralHospitaland FacultyofMedicineofUniversitasIndonesia,JalanDiponegoroNo.71,JakartaPusat,Jakarta10430,Indonesia

bDepartmentofOrthopaedic&Traumatology,CiptoMangunkusumoNationalCentralHospitalandFacultyofMedicineofUniversitasIndonesia,Jalan DiponegoroNo.71,JakartaPusat,Jakarta10430,Indonesia

a r t i c l e i n f o

Articlehistory:

Received31July2019 Receivedinrevisedform 10December2019 Accepted16December2019 Availableonline28December2019

Keywords:

Diabeticulcerofthefoot Placentalamnioticmembrane Allograft

Caseseries

a b s t r a c t

INTRODUCTION:Diabeticulcerofthefootisamajorcauseofmorbidityandisaleadingcauseofhospi- talizationinpatientswithdiabetes,andcausesproductivityandﬁnanciallossesthatlowerthequality oflifeofthepatient.Thewoundiscategorizedasresponsiveandunresponsivewound,whichoccursin debilitatedpatientsasseenindiabetesmellitus.Thedelayinwoundrepaircanbecausedbysenescent cells,absenceofgrowthfactors,andothercellularabnormalities.

METHOD:Thisisaretrospective,single-centrecaseserieswithnon-consecutivecases.Patientswithdia- beticulcerofthefootmanagedusinggamma-treatedplacentalamnioticmembrane,withtheminimum followupof1monthinacademicpracticesettingwererecruited.

RESULT:Threepatientswith4weeksperiodofoozingulcersandsignsofinﬂammationwereincluded inthiscaseseries.Twolayersofamnioticmembranedressingwasappliedweeklyaftercleaningand debridementfor3weeks.Woundsizeandsecretionweredocumentedbytakingphotographsevery week.Attheendofthethirdweek,thewoundhealed.

DISCUSSION:Placentalamnioticmembranesarecomposedofcells,extra-cellularmatrix(ECM),anda complexofregulatorycytokineswhichpromotecellproliferation,cellmodulation,andcytokinesecretion byvarietyofcelltypesinvolvedinwoundhealing.Ourstudyshowedthatthetreatmentofdiabeticulcer woundusingamnioticmembranewassuccessfulinachievingwoundhealinginunresponsive,chronic woundofdiabeticulcerofthefoot.

CONCLUSION:Ourresultsclearlyindicatedtheusefulnessoftheapplicationofamnioticmembranes intreatmentofdiabeticulcerofthefoot.Amnioticmembranefavouredhealingofunresponsiveand non-healingulcers.

1. Introduction

Diabeticulcerofthefootisamajorcauseofmorbidityandis aleadingcauseofhospitalizationinpatientswithdiabetes.Dia- beticulcerofthefootcancauseinfection,gangrene,amputation, andevendeathifessentialcareisnotprovided.Therateoflower limbamputation in patientswithdiabetesmellitus is15 times higherthanpatientswithoutdiabetes,moreoverit isestimated thatapproximately50%–70%ofalllowerlimbamputationsare duetodiabeticulcerofthefoot.Moreover,diabeticulcerofthe

∗Correspondingauthor.Present/permanentaddress:DepartmentofOrthopaedic

&Traumatology,CiptoMangunkusumoNationalCentralHospital,JalanDiponegoro No.71,CentralJakarta,Jakarta10430,Indonesia.

E-mailaddress:witantra.dhamar.h@gmail.com(W.DhamarHutami).

footcancausesigniﬁcantemotionalandphysicaldistressaswell asproductivityandﬁnanciallossesthatlowerthequalityoflifeof thepatient[1].

Thecauseofdiabeticulcerofthefootismultifactorial,however, the main contributing factors are peripheral neuropathy and peripheral vascular disease. The neuropathy is caused by hyperglycemia-inducedmetabolicabnormalities.Theconditionof hyperglycemiacausesanincreaseintheactionofanzymealdose reductaseandsorbitoldehydrogenase,causingtheconversionof intracellular glucoseto sorbitoland fructose. Theaccumulation of sorbitol and fructose will cause a decrease in the synthesis ofnervecellmyoinositolrequiredfor normalnerveconduction.

Moreover,the conversionof glucose willresult in depletionof storeof nicotinamideadeninedinucleotidephosphate, whichis essentialfor thedetoxiﬁcationofreactiveoxygenspecies(ROS) andforthesynthesisofthevasodilatornitricoxide.Theneuropa-

https://doi.org/10.1016/j.ijscr.2019.12.033

org/licenses/by/4.0/).

(2)

repairinchronicwounddoesnotfollowthenormalsequenceof healing.Thewoundiscategorizedasresponsiveandunresponsive wound,whichoccursindebilitatedpatientsasseenindiabetes mellitus.Thisunresponsivewoundmustbetreatedbasedontriad ofcareconsistingofintrinsic,extrinsic,andwoundenvironment factors.Unresponsivediabeticulcerofthefootisdeﬁnedasulcer thatdoesnot showareduction in sizeinone-monthperiod of adequatetreatment. The delay in wound repair can be caused bysenescent cells,absenceofgrowthfactors,and othercellular abnormalities.Senescentcellsaredeﬁnedasviablecells,buthave losttheirabilitytoproliferate.Thiscausethesecellstobeunre- sponsivetoendogenousandexogenousgrowthfactorbinwound milieu.Thewoundenvironmentfactorincludeswoundbedsta- tus,cellularactivityofthewound,anddevicesanddressingused for the treatment. About 15–20 % of chronic wound does not respondtoconventionaltherapyandrequiresadvancedtechnolo- giestostimulatethetissuerepair.Debridementofsenescentcells andnonviabletissue willincreasetheavailabilityofviablecells toproduce and respondto growthfactors and othercytokines [3].

Tomaximizethehealingofwound,skinsubstitutecanbeused topreventinfectionanddessication.Thistemporaryskincoverage canbeprovidedbysyntheticorbiologicaldressings.Thebiologi- caldressingincludesplacentalamnioticmembrane,allograftskin, orxenograftskin.Comparedtootherbiologicaldressing,placen- talamnioticmembranehasadvantagesasidealdressing.Placental amnioticmembranecanactasaneffectivebarrier,reduceslossof heat,ﬂuid,andprotein,andhasagoodadherencetothewound.It alsohasbacteriostaticproperty,thereforereducestheincidenceof infection.Moreover,ithassomeanalgesiceffect,andimportantly hasnoimmunologicalreaction[4].Histologically,amnioticmem- braneissimilartotheskin.Itsinnerlayeriscomposedoncuboidal cells,whereastheouterlayeriscomposedofmesenchymalcon- nectivetissue.Ithasnobloodvesselorlymphaticchannel.Theaim ofradiationinthepreparationofamnioticmembraneistoprolong itsshelf-life[4].

InIndonesia,preparationofplacentalamnioticmembranehas beenavailablecommercially,providedbyBATAN(NationalNuclear EnergyAgency)ResearchTissueBankinJakarta.Startedon1986, BATANResearchTissueBankhasdeveloped thepreservation of freshamnioticmembrane bylyophilization and sterilizationby gammaradiation.Thefreshplacentalamnioticmembranescontain collagen,hormones,andenzymesandisobtainedfromfetalpla- centadeliveredfromhealthymotherswhoarefreeformdiseases includinghumanimmunodeﬁciency(HIV)infection,andhepatitis BandC[5].

Wepresenteda caseseriesof diabeticulcerpatientstreated with gamma-treated placental amniotic membrane allograft.

This case series had been presented in line with PROCESS guideline[6].

upof1month.Thedatawascollectedusingmedicalrecord.The inclusioncriteriaforstudyparticipantwasadultwithdiabeticulcer andtheexclusioncriteriawasotherimmunocompromisedcondi- tions.

Afterplacentalamnioticmembranesfromthescreeneddonor wereselected,themembrane werecollectedandprepared.The preparationofplacentawasstartedwithwashingthefreshamni- oticmembraneusingsterilesalinefollowedbywashingin0.05% sodiumhypochloritesolutionandthensteriledistilledwateruntil theywerecompletelyclearedofbloodparticles.Finallythemem- braneweresterilizedbygammairradiatin25kGy[4].Thisamniotic membranewaspreparedinBATANResearchTissueBank,Jakarta (Fig.1).

3. Result

Threepatientswereincludedinthiscaseseries.Thebaseline dataofthepatientisdescribedinTable1.Patientscamewithhis- toryoftrauma,andafter4weeksofnonoperativetreatment,the painhadnotsubsided.Clinicalexaminationshowedoozingulcerin allthreepatientswithsignsofinﬂammation.Noexposedbonewas foundonexamination.Beforeapplicationofamnioticmembrane, thewoundofeachpatientwasmeasuredandcleaned.Twolayers ofamnioticmembranedressingwasappliedweeklyaftercleaning anddebridementfor3weeks.Standarddressingwasthenapplied overthegraft.Thepatientwasadvisednottoremovethedressing andtokeepitdryuntilthenextvisit.Woundsizeandsecretion weredocumentedbytakingphotographseveryweek(Figs.2–4).

Thedebridementanddressingwasperformedbythesinglesurgeon (I.O).

Ineachweek,thesizeoftheulcerwasdecreasing,thepusdimin- ished,andreepithelialisationoccurred.Painalsodiminished.Atthe endofthethirdweek,thewoundhealedwithnoulcerappeared.

Thesignsofinﬂammationalsodisappeared.

4. Discussion

Placentalamnioticmembranes arecomposedof cells,extra- cellularmatrix(ECM),andacomplexofregulatorycytokineswhich function tosupport tissue growth and modulateinﬂammation.

Theyalsopromotecellproliferationandcellmodulation,andmod- ulatecytokinesecretionbyvarietyofcelltypesinvolvedinwound healing.Thereareabout226growthfactorsidentiﬁed inamni- oticmembrane,includinggrowthfactors,cytokines,chemokines, andregulatoryinhibitorsofmetalloproteinases(TIMPs),suchas PDGF-AA,PDGF-BB,TGF-␣,TGF-␤,bFGF,EGF,VEGF,IL-10,IL-4,pla- centalgrowthfactor(PlGF),TIMP-1,TIMP-2and TIMP-4,which possessimportantregulatoryrolesinregulatingfetaldevelopment andpregnancy.

(3)

Fig.1. AmnioticMembranePreparation.

Fig.2.ClinicalManifestationofPatientOne.

FetalplacentaltissuescontainlowlevelsofHLAantigensandhas noimmunerejection.Therefore,placentaltissuescanbecleansed toremovebloodandhazardousmaterials,whilepreservingthenat- uralbiologicalactivityofthetissuefortrans-plantationwithout completedecellularization.Toprovideaproductforpatientuse, allografttissuesrequirepreservationtechniquestoallowfortrans- portationandstorage.Themostcommonmethodtopreservetissue grafts and prevent degradation is through cryopreservation or freezing.Anincreasinglypopularalternativetocryopreservationis tissuedehydration.Tissuecanbedehydratedunderheat,openair, orfreezedrying(lyophilization).Byremovingresidualmoisture, tissuecanbepreservedbyreducing activityofsolublechemical reactionsandwater-dependentenzymaticactivityandinhibiting theviabilityofmicroorganismsina lowmoistureenvironment.

Dehydrationpreservestissuewithouttheneedforfreezers,dry

ice,orliquidnitrogenandcertainmethodsofdehydrationhave beenshowntoretainequivalentorsuperiorbiologicalactivitycom- paredtocryopreservation,withthebeneﬁtsofbeingshippedand storedatambientconditions.Dehydratedtissuesarealsotypically strongerandeasiertohandlethanwettissues.Thoughdehydra- tionmayalterthetissue’smicrostructurebycausingthematrix tobecome more compactin the absenceof water, bypreserv- ingthenativetissuematrixproteinsthedehydratedtissuecanbe rehydratedinthewoundenvironmenttoreturnthetissuetoits originalstate.Followingdehydration,humanamnioticmembrane tissueiseasytohandleandcanbestoredatambientconditions withashelf-lifeofupto5years,whilepreservingthestructural integrityandbiochemicalactivityofnativeamnioticmembrane.

Eventhoughdehydrationrendersamnioticcellsnonviable,these cellsremainstructurallyintact,includingthecellularandpericel-

(4)

Fig.3.ClinicalManifestationofPatientTwo.

lularcomponentsthatplayessentialrolesinregulatingbiological activity.Retentionofbioactivefactorsisthoughttobecriticalto theclinicalefficacyofamniotictissueallograftsinwoundrepair andtissueregeneration.Therefore,harshcleansingprocessesthat washbioactivematerialoutofthegraftsmaygreatlyreducethe cytokinecontentanddiminishtheclinicalefficacyofthenaturally derivedtissues.Anadditionalbenefitoftissuedehydrationisthat theallograftscanbeterminallysterilizedtoreducetheriskofinfec- tiousdiseasefromthedonortissue.Whileallallografttissuesare asepticallyprocessedtoreducetheriskofbacterialorviralcon- tamination,dehydratedtissuescanbeterminallysterilizedusing techniquessuchasgammarayorelectronbeamirradiationtofur- therreducetheriskofdiseasetransmission.Thoughhighlevels ofradiationmaypotentiallycrosslinkordenatureproteinswithin tissues,terminallysterilizedamnioticmembranesallograftshave beenproventoretainbiologicalactivitybothclinicallyandthrough

invitroexperiments.Thesedatasuggestthatsterilizationdoesnot signiﬁcantlydiminishthebioactivityofamnioticmembraneallo- graftsandisworthwhiletoensuremaximalsafetytopatients[4].

Ourstudyshowedthatthetreatmentofdiabeticulcerwound usingamnioticmembranewassuccessfulachievingwoundheal- ing.ThisissimilartostudybyBarskietal.andElHeneidyetal.who foundthattheapplicationofamnioticmembranehelpinwound healing[7,8].Inmeta-analysisofwoundcareindiabeticfootper- formedbyLoffelbeiletal.[9],theyfoundthatwoundcareusing amnioticmembraneresultedinlesshypertrophicscarringwhen comparedtowoundwithoutamnioticmembrane.Thisﬁndingsup- portedourﬁndingthatamnioticmembranegraftis effectivein acceleratinghealingofdiabeticfootulcer.InthestudybyLoffel- beiletal.[9]intheuseofamnioticmembraneforwoundcarein swineandhumanmodels,theyfoundthatintheswinemodel,the useofamnioticmembranepreventedcicatrisationandenhanced

(5)

Fig.4.ClinicalManifestationofPatientThree.

theformationofbasementmembrane.Theenhanced formation ofbasementmembranewillimprovedefensivecapacitiesofthe woundagainstmicrobialinfections,becausethebasementmem- braneformsalineofresistance,eveniftheoverlyingepitheliallayer isnotcomplete.Theadvantageofamnioticmembranedressingin humanmodelwasstatisticallysignificant,andcanbeusedascost effectivealternativeofwounddressingparticularlyindeveloping country[9].Thefindingsinthepreviousstudiessupportthefinding inourcaseseries,inwhichtheuseofplacentalamnioticmembrane improvedhealinginunresponsivediabeticulcerofthefootandthat ithasthepotencyofbeingcosteffectiveinthedevelopingcountry likeIndonesia.

The strength of our study was that the intervention given between the patients was similar to each other and that this treatmentprovidednewinsightinthetreatmentofunhealedor unresponsivediabeticulcerofthefoot.However,ourstudysize wassmall.Alarger,betterstudyinthefutureisawaited.

5. Conclusion

Ourresultsclearlyindicatedtheusefulnessoftheapplication ofamnioticmembranesintreatmentofdiabeticulcerofthefoot.

Amnioticmembraneimprovedhealingofunresponsiveandnon- healingulcers.

Conﬂictofinterest

The authors certify that they have NO affiliations with or involvementinanyorganizationorentitywithanyfinancialinter- estor non-financial interest in the subject matter ormaterials discussedinthismanuscript.

Sourcesoffunding

The authors received no ﬁnancial support for the research, authorship,and/orpublicationofthisarticle.

Ethicalapproval

Theethicalapprovalwasprovided.

Consent

Informedconsenthadbeenobtainedfromthepatientbeforethe manuscriptwaswritten.

Authorcontribution

IhsanOesman:studyconcept,datacollection,datainterpretation,andwritingthepaper.

WitantraDhamarHutami:datacollection,datainterpretation andwritingthepaper.

Registrationofresearchstudies

ThiscaseseriesisregisteredinANZCTR(AustralianNewZealand ClinicalTrialsRegistry)withthetrialnumberof378871.

Guarantor IhsanOesman.

Provenanceandpeerreview

Notcommissioned,externallypeer-reviewed

Acknowledgement

AuthorswouldliketogivetheirbiggestgratitudetotheDepart- ment of Orthopaedic and Traumatology, Cipto Mangunkusumo NationalCentralHospitalandFacultyofMedicineofUniversitas Indonesiaformakingthiscaseseriesdeliverable.

References

[1]M.M.Kasiya,G.D.Mang’anda,S.Heyes,R.Kachapila,L.Kaduya,J.Chilamba, etal.,Thechallengeofdiabeticfootcare:reviewoftheliteratureand experienceatQueenElizabethCentralHospitalinBlantyre,Malawi,Malawi Med.J.29(2)(2017)218–223.

[2]R.L.Harries,K.G.Harding,Managementofdiabeticfootulcers,Curr.Geriatr.

Rep.4(3)(2015)265–276.

[3]G.D.Mulder,Diabeticfootulcers:oldproblems-Newtechnologies,Nephrol.

Dial.Transplant.16(4)(2001)695–698.

[4]R.Singh,U.S.Chouhan,S.Purohit,P.Gupta,P.Kumar,A.Kumar,etal.,Radiation processedamnioticmembranesinthetreatmentofnon-healingulcersof differentetiologies,CellTissueBank.(2004).

[5]M.R.Herson,M.B.Mathor,J.MoralesPedraza,TheimpactoftheInternational AtomicEnergyAgency(IAEA)programonradiationandtissuebankingin Brazil,CellTissueBank10(2)(2009)143–147.

[6]R.A.Agha,M.R.Borrelli,R.Farwana,K.Koshy,A.Fowler,D.P.Orgill,SCARE Group,ThePROCESS2018Statement:UpdatingConsensusPreferredReporting ofCaseSeriesinSurgery(PROCESS)guidelines,Int.J.Surg.60(2018) 279–282.

[7]D.Barski,H.Gerullis,T.Ecke,G.Varga,M.Boros,I.Pintelon,etal.,Human amnioticmembranedressingforthetreatmentofaninfectedwoundduetoan entero-cutaneousﬁstula:Casereport,Int.J.Surg.CaseRep.[Internet].Surgical

(6)

OpenAccess

ThisarticleispublishedOpenAccessatsciencedirect.com.ItisdistributedundertheIJSCRSupplementaltermsandconditions,which permitsunrestrictednoncommercialuse,distribution,andreproductioninanymedium,providedtheoriginalauthorsandsourceare credited.