This document summarizes research on ACell's Cytal Wound Matrix product for treating chronic wounds. It provides evidence from case studies that show ECM-based products like ACell's can help diabetic foot ulcers and pressure ulcers heal. The document proposes a randomized controlled clinical trial to further evaluate Cytal Wound Matrix's effectiveness on chronic ulcers with osteomyelitis in both controlled and uncontrolled diabetics. It hypothesizes the product will increase healing frequency and rate compared to standard care due to its structural support and immunoregulatory elements.

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. 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. 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. 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.