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ACell

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ACell

  1. 1. ACell’s CytalTM Wound Matrix Tzvi Najman ACell,acompanythat producesregenerativemedical products,hasanew line of wound matricesthat theybelieve “facilitatethe body’sabilitytorepairandremodel tissue[1] ”.They describe theirproductas follows: “Cytal Wound Matrix is intended forthemanagementof woundsincluding:partialand full- thicknesswounds,pressureulcers,venousulcers,diabeticulcers,chronic vascularulcers, tunneled/undermined wounds,surgicalwounds(donorsites/grafts, post-Mohssurgery,post-laser surgery,podiatric,wound dehiscence),trauma wounds(abrasions,lacerations,second-degreeburns, skin tears) and draining wounds.[1] “ There isevidence inthe currentliterature tosupportthisclaim. ForexampleRupertconducteda case studyinthree diabeticfootulcersintwopatientsthatwere treatedwithHADWM (HumanAcellular Dermal WoundMatrix), FSTS (Flowable SoftTissue Scaffold),andNPWT(Negative Pressure Wound Therapy) where there wasan observedcomplete epithelialisationof the ulcers [2] . Similarly,inthe William’scase study, three diabeticpatientssufferingfromcomplex ulcersexperiencedcomplete closure of theirwoundsafterHADWMand FSTSapplicationandtreatmen [3] .Otherrelatedstudieswith analoguesresultsbyStacyet.al.and Reyzelmanet.al.serve togive ECMbasedwoundhealingproducts credence aspotential therapeuticstotreat chroniculcers[4],[5] . Furthermore,itshouldalsobe notedthatthe Rupertcase dealtwithpatientssufferingfrom underlyingcomorbidities(osteomyelitis) thatwere surgicallydealt withpriortothe HADWT therapy [2] . ThisindicatesthatHADWT (andpossiblyotherECMtherapies)maybe useful inkeepingcleanedulcers frombecomingre infected. These scaffoldsnotonlyprovide astructural networkwhere newepithelial cellsandblood vesselscangrow,butalsorelease growthfactors,cytokines,metalloproteases, andimmuno-regulatory glycol- proteinsasthe therapeuticmembrane decaysatthe site of the ulcer.These key wound-healing elements replenishthe ulcerof the depletedimmunological agentsthatare necessaryforthe ulcer’s auto debridement,angiogenesis,andultimate healing. Thisissupportedin currentliteraturethat relatestoothertreatmentsfornon-healingwounds.Forexample,Zuloff-Shani et.al.treatedhardto heal advanced pressure ulcers (stages3-4) withanActivatedMacrophage Suspension(AMS).When comparedto the standardof care,woundstreatedwithAMS were 50.1% more likelytofullyclose comparedto the standardof care [6] .Thismost likelyhastodowiththe fact that the activated macrophagesstimulate manyimmunological woundhealingpathwaysthatare unable tooccur due to the immune-depletionof the ulcer.Furthermore,Stronget.al.showsinhismouse model thatpro- inflammatoryagentssuchasTGF-beta, PDGF-betaand angiogenic geneswere all upregulatedin pressure ulcerstreatedwithAdipose Stromal Cellsinmice,andresultedintheirwounds completely healing[7] . WhilethisdatadoesnotdirectlytestHADWTor similar ECMbased products(like thatof ACell),itdoessupportACell’saforementionedclaim.
  2. 2. The Wound Matrix that ACell sellsismade fromporcine urinarytractECM. It containsan epithelial layeranda laminapropinalayer.The laminapropinalayerisrichinimmune regulatory proteins,enzymesandmolecules.The epithelial layer isrichin collagens thatprovide the structural matrix and scaffold,givingthe newfunctional tissueafootholdatthe site of the ulcer. While acellularmatriceshave beenstudied,there isneedforlarge randomizedclinical studiesto evaluate itseffectiveness: “While several studies have reported outcomes in chronic wounds, most are not randomized controlled studies specifically evaluating AM therapy use in diabetic foot ulcers[5]” An experimental designsimilartothatof Reyzekmanet.al.wouldbe ideal,however,withone critical difference.We wouldbe includingpatientswithdeep,advancedstage PU’swithanunderlying osteomyelitiscomorbidity(theyonlyincludedpatientswithanabsence of infectiousbasedcriteria). A sample size close ton=100 wouldbe ideal inordertomaximize statistical significance. The study wouldneedto be randomized,andpatientsthatmetthe followingcriteriawouldbe randomlyassignedtoreceive ACelltreatmentorstandardof care treatment(control). The randomlyselecteddiabeticpatients withsufferingfromatleastone pressure ulcer osteomyelitiswouldthenbe screenedtoidentifythemascontrolledoruncontrolleddiabetics.The controlleddiabeticswouldexhibitthe followingqualifications: Transcutaneous oxygen at the foot dorsum greater than or equal to 30 mmHg Ankle Brachial Index from 0.7-1.2 HgA1c level from 6%-12% Serum creatine levels below 3.0 mg/dL *These qualifications were taken from the Reyzelman et. al. study [5]. Anypatientsexhibitinghigherlevelsof the aforementionedbiomarkerswill be classifiedas uncontrolleddiabeticsforthe purposesof thisstudy (exceptforthe ABIwhichwouldbe lowerfor uncontrolleddiabetics).We willtrytohave a relativelyevensplit(50uncontrolledand50 controlled) of the subjectsinthe study.Thiswill allowustodetermine the reachof ACell’sproductanditsability(or lack thereof) toheal ulcersonuncontrolleddiabetics(UCD) ascomparedto controlleddiabetics(CD). 25 randomlyselectedUDsand25 randomlyselectedCDswillserve asthe experimental subjects, and the remainingvolunteerswillserve asthe control.Tominimize bias,the experimentwill be double blind. The subjectswillbe regularlyexaminedtomonitorwoundsize.Atthe endof the trial, percentage of woundclosure andrate of woundclosure will be calculatedandstatisticallyanalyzed.Tomake the studylongitudinalinnature,the trial will keepintouchwiththe subjectsandcalculate pressurewound recurrence forthree additional yearspostwoundclosure.
  3. 3. The objective of thisexperimentistocompare the woundhealingabilityandwoundhealing rate of ACell’sproductonchronicdiabeticulcerswithosteomyelitiscomorbiditytothe standardof care. It wouldalsoaccountfor ACell’sproduct’sabilityrange inpatientswithvaryingseveritiesof diabetes.To our knowledge,thiswouldbe the firstmajorclinical trial examiningthe effectsof ECMtreatmentin chroniculcerswithan underlyingbone infection. We expecttosee a higherfrequencyandfasterrate of ulcerclosinginthe experimental group relative tothatof the control group.If these expectationsare met,furtherexperimentationwouldneed to be done to establish,mechanisticallyspeaking,how ECMtechnologyhealschronicwounds.Basedon otherresearchby Stronget.al.,it isevidentthatgrowthfactors,transcriptionfactors,inflammatory cytokines,chemo-attractants,andmetalloproteasesare all up-regulatedinmouse model pressure ulcers at the onsetof woundhealing [8] .Thisindicatesthatthese factorsare importantforwoundhealing.The laminapropinalayerof the CytalTM Matrix by ACell isrichinmanyof these elements.A trial thattests the abilityof chronicpressure wounds toclose withadermal matrix comprisedentirelyof the epithelial layer(onlycollagenandnoimmunoregulatory elementsshouldbe tested against),asuspensionof the immunoregulatory agentswiththe original CytalTM Matrix asa control to see if the observedwound healingisdue tothe structural supportgivenbythe collagen,if the healingis due tothe elementsfound inthe laminapropinalayer,orif bothstructural and elementalpartsare necessary formaximumwound closure.
  4. 4. References: 1) ChronicWounds – ACell."ACellICal.N.p.,n.d.Web.09 June 2016. 2) Rupert,P."Human AcellularDermal WoundMatrix forComplex DiabeticWounds." Journal of Wound Care25.Sup4 (2016): n. pag.Web. 3) Williams,M.L.,Holewinski,J.“Experience UsingaFlowable SoftTissue Scaffoldin ConjunctionWithaHuman Dermal Matrix in LowerExtremityWounds.” Journalof Diabetic FootComplications.2013; 5: 3, 55–61 4) Stacy, D. H. “Use of an AcellularRegenerative Tissue Matrix OverChronicWounds.” Eplasty. 2013; 13: e61. 5) Reyzelman,Alexander,RyanT.Crews,JohnC.Moore, LilyMoore,JagpreetS.Mukker, StephenOffutt,ArthurTallis,WilliamB.Turner,DeanVayser,ChristopherWinters,and DavidG. Armstrong."Clinical Effectivenessof anAcellularDermal Regenerative Tissue Matrix ComparedtoStandardWound ManagementinHealingDiabeticFootUlcers:A Prospective,Randomised,MulticentreStudy." InternationalWound Journal6.3 (2009): 196- 208. Web. 6) Zuloff-Shani,Adi.Adunsky,Abraham.Even-Zahav,Aviva.Semo,Haim.Orenstein,Arie. Tamir,Jeremy.Regev,Eli.Shinar,Eilat.Danon,David. "Hardtoheal pressure ulcers(stage III- IV):efficacyof injectedactivatedmacrophage suspension(AMS) ascomparedwithstandard of care (SOC) treatmentcontrolledtrial.". Archivesof Gerontology and Geriatrics(11/2010): (0167-4943), 51 (3), p. 268. 7) Strong,AL. Bowles,AC,MacCrimmon, CP,Frazier,TP,Lee,SJ, Wu,X, Katz,AJ,Gawronska- Kozak,B, Bunnell,BA,Gimble,JM."Adipose stromal cellsrepairpressure ulcersinboth youngand elderlymice:potential role of adipogenesisinskinrepair.". Stemcells translationalmedicine(06/2015): (2157-6564), 4 (6), p. 632. 8) StrongAL, BowlesAC,MacCrimmonCP,et al.Characterizationof aMurine Pressure Ulcer Model to AssessEfficacyof Adipose-derivedStromal Cells. Plasticand Reconstructive Surgery Global Open.2015;3(3):e334.

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