Authorbios
Dr.MojtabaAghajaniDelavarisaResearchFellowatAthabascaUniversity.Hereceived hisB.Sc.inMechanicalEngineeringfromAmirkabirUniversityofTechnologyin2001, M.Sc.,andPh.D.inMechanicalEngineeringfromMazandaranUniversityin2003and 2010,respectively.HeworkedattheBabolNoshirvaniUniversityofTechnologyinIranas anassociateprofessorfrom2010until2019.ThenhejoinedprofessorWang’sresearch groupatAthabascaUniversity.Dr.Delavarhasover20yearsofexperienceinmodeling variousindustrialandbiologicalsystemsusingdifferentmodelingschemesincludingmathematicalandnumericalanalysisandsimulation.Hehasauthored/coauthoredover100papersincludingmorethan60peer-reviewedjournalpapers.
Dr.JunyeWangisaProfessorandtheCampusAlbertaInnovationProgram(CAIP) ResearchChairatAthabascaUniversity,Canada.HereceivedhisM.Sc.inThermo-physics fromHarbinShipbuildingEngineeringInstituteandPh.D.inChemicalandMechanicalEngineeringfromEastChinaUniversityofScienceandTechnologyin1989and1996, respectively.ThenhejoinedShanghaiJiaotongUniversityasanassociateprofessorin 1996.From1999till2013,heworkedattheUniversitiesofSheffield,Greenwich,and Loughborough,andScottishCropResearchInstitute,andRothamstedResearch,UK,asa researchassociate,researchscientist,andprincipalresearchscientist,respectively.Dr. Wanghasover30years’experienceinmultiscaleandmultidisciplinarymodelingandisan internationallyrecognizedleaderinmicrobiology,bioenergy,andenvironment.Hehas authored/coauthoredover160papers,includingover120refereedjournalpapers,and servesasassociateeditorandeditorialboardmemberonseveralinternationaljournals.He isalsoareviewerofpapersforover130internationaljournals.
Introduction
1.1Background
Microorganismsareoneofthemostextensivelyspreadandsuccessfulformsoflifeon earth,livinginnaturalhabitats,industrialequipment,andclinicaldevices(Stoodleyetal., 2002).Innaturalhabitats,mostmicroorganismsthriveincommunitiesratherthan planktoniccells.Microorganismstendtogrownotonlyasasinglespeciescommunityof pathogensandnonpathogensbutalsoasmultispeciescommunities(Donlan,2002; Kragh etal.,2016; Melaughetal.,2016).Biofilmscanadheretovarioussolid liquid, air liquid,orliquid liquidinterfaces,suchasimplantedmedicaldevices,livingtissues, industrialorpotablewaterpipes,anddevices,ornaturalaquaticsurfaces.Itiswidely acceptedthatbiofilmsaretheprimarylifestyleofbacteria,withauniquephenotypein termsofgenetranscriptionandgrowthrate.Itwasdiscoveredthat99.9%ofallbacteria adheredtoanaqueoussurfaceandproliferatedtogetherastheircrucialsurvivalstrategy (Geeseyetal.,1977; DonlanandCosterton,2002).Insomesituations,biofilmscanform asswimmingclustersinactivatedslimesinanaquaticenvironmentwheretheyarenot adherenttoasolidsubstratum.Theratioofepilithictoplanktonicmicroorganismsis greaterthan1000 10,000:1(https://www.cs.montana.edu/webworks/projects/stevesbook/ contents/chapters/chapter001/section003/green/page002.html).
Thecharacteristicsofbiofilmsinnaturalhabitatscandiffersubstantially,asevidencedby scanningelectronmicrographsofbiofilmsfromanindustrialwaterdeviceandariver stream(Fig.1.1)(Donlan,2002; Suarezetal.,2019).Asmulticellularcommunitiesof microbialcells,biofilmsareimmersedinaself-producedmatrixofextracellularpolymeric molecules(EPS).Fluorescenceinsituhybridization(FISH)analysesofbiofilm cryosectionsshowedthattheZ400biofilmwaslikelystratified,where Nitrospira was moreabundantinthemiddleofthebiofilmandtheanaerobicanammoxbacteriapresented inthedeeperlayerswhile Nitrosomonas biovolumewasthesamealongthedepthgradient (Fig.1.1AandB)(Suarezetal.,2019).InthethinZ50biofilms,nostratificationwas observedastheammoniaoxidizingbacteria(AOB)andtheoxygenatedwaterandnitrite oxidizingbacteria(NOB)populationswerelocatedsidebyside.Manymicrobial communitieshavecelldensitiesrangingfrom108 to1011 cellspergramofwetmass, comprising1millionto100billioncells(ByrneandDrasdo,2009; Gebreyohannesetal., 2019).Inhoneycombconfigurations,streambiofilmscancohabitwithalgae,EPS,and
Figure1.1
Physicalstructureand“buildingblocks”ofbiofilms:(A)Fluorescenceinsituhybridization(FISH) imagesofaZ400biofilmcryosectionwiththewater biofilminterfaceonthetop(Green:
diatomcells(Battinetal.,2003).Althoughthechemistryandphysiologyofbiofilms mightdifferduetodifferentbacteriaandtheirsurroundingenvironment,thebiomassof biofilmscontainsaround90%EPS,whichaddstotheresemblanceofthemushroom-like structure(Jamaletal.,2018; StewartandFranklin,2008).
Biofilmsinpopulationsaretypicallymadeupofnumerouscoloniesofvariousbacterial species(Vidakovicetal.,2018).Wastewatertreatmentsystemsconsistofthousandsof operatingtaxonomicgroupsatthespecieslevel(Lawetal.,2016; Saundersetal.,2016). Inthenaturalenvironment,biofilmscontainover750distinctspecies(Leyetal.,2006), andoralbiofilmscontainavarietyofthousandsofmicroorganismsasanembraceof bacteriaandeukaryotes.
Microorganismsthrivinginacommunallifestylehavesomebenefitsoverplanktoniccells: (1)increasedrigiditytoerosionbystreamflowstress;(2)enhancedresistanceto antimicrobials;(3)higherbiomassdensityforthetreatmentofvariousinorganicand inorganicsubstratesinbioengineering;(4)improvedcell-to-cellinteraction,genedelivery, andmetabolicworkloadsharing;and(5)providedheterogeneousstructuresfordiffusion andconsumptionofnutrientsbenefits(WangandZhang,2010).
Fig.1.1AandB depictstheheterogeneityoftheEPSmatrixdevelopment(Suarezetal., 2019).Deterministicassemblyinbiofilmsdependsonspecificmechanisms.Forexample, structuredmicroenvironmentsmaylimitthediffusionofelectrondonorsandacceptorsin biofilms,resultinginformsteepgradients.Thethicknessoftheliquidboundarylayerthat limitsdiffusionofsolublesubstrates,includingdissolvedoxygen(DO),fromthebulk liquidtothebiofilmwasdeterminedbycomparingtheammoniumoxidationrates calculatedbythemodeltothosemeasuredduringthenitrogentransformationactivitytests (Suarezetal.,2019).Microorganismsthatliveinsoilaggregatesorhabitatscanadapt theiractivityandcompositioninresponsetothechangesinnutrientandenvironmental circumstances(YoungandCrawford,2004).Thepersistentgradientswerecreatedto enabledistinctlocalhabitatsonafinescale.Microorganismsinanaerobiccopiotrophic biofilmstratifyintermsofoxygenavailability.Becauseoxygenisextractedbyaerobic organismsinthehigherlayersofthebiofilm,alayerofanaerobesdevelopsinthelower layersofthebiofilmduetooxygendepletion.Thiscanbeattributedtothefactthatthe rateofoxygenconsumptionexceedstherateofdiffusion.
Nitrosomonas,Red: Nitrospira.Yellow: Nitrotoga.Blue: Brocadia.Gray:SYTO),(B)FISHimagesofa Z50biofilmcryosectionwiththewater biofilminterfaceonthetop(Green: Nitrosomonas,Red: Nitrospira.Yellow: Nitrotoga.Blue: Brocadia.Gray:SYTO)(Suarezetal.,2019),and(C)SEM (scanningelectronmicrograph)imageofanativebiofilmformedonlowcarbonsteelintersurface inanindustrialwatersystemoveran8-weekperiod,scalebar,20 mm(Donlan,2002).
Flemmingetal.(2016) showedthatbacteriaintheupperlayersofaerobicoligotrophic biofilmsarelikelytoconsumethemajorityofthenutrients,causingstarving microorganismsinthebottomlayers(Fig.1.2).Thesemicrobesadapttosluggishgrowth states,suchasinactivecells,orevencelldeath.Othergradientsinbiofilmsproducedby heterotrophicmetabolismincludepHgradientsandgradientsofsignalingchemicalsthat varywithdistancefromgeneratingcells.
Mostelementsinwater,soil,sediment,andsubsurfaceenvironmentsarecycled biogeochemicallybymicroorganisms(Battinetal.,2008; EhrlichandNewman,2008; Bhanjaetal.,2019; BhanjaandWang,2020, 2021; Meckenstocketal.,2015).The metabolismofterrestrialorganiccarboninfreshwaterenvironmentscontributes significantlytotheemissionofcarbondioxideintotheatmosphere(Battinetal.,2008).
Biofilmsthroughwell-definedinteractionsforspeciallydesignedpurposeshavebeenused inarangeofbioindustries,suchasimprovedsafetyoffoods(Stiles,1996),biosynthesis andbioremediation(Tsoietal.,2019),andinhibitionofpathogenicgrowthin nonfermented,refrigeratedfoods(Gombas,1989).
Biofilmsarefoundnumerouslyinawiderangeofinfectiousdiseasesinbothclinicaland publichealthsettings(Donlan,2002).Theycanpersistentlygrowonbothbioticand abioticsurfaces,suchasahumantoothorlung,acow’sintestine,orrockimmersedina fast-movingstream.Biofilmscancolonizeonvariousmedicaldevices,including
Figure1.2
Biofilmheterogeneitycharacteristics,andsocialcompetitionandcooperation(Flemmingetal., 2016).
intrauterinecontraceptivedevices,prostheticmedicaldevices,catheters,heartvalves, implantdevices,dentalmaterials,andcontactlenses,resultinginavarietyofdeviceassociatedillnesses.Clinicalinvestigationshaveemphasizedthesignificanceofbiofilmsin producinghumanillnesses,accountingforupto60%ofallinfections(ChenandWen, 2011).Biofilmshaveasubstantialinfluenceontheindustrialenvironment,including biofouling,biocorrosion,oilfieldsouring,andeffluent(KlapperandDockery2002).
1.2Historyofbiofilmsstudies
1.2.1Biofilmandbioaggregates
Mostofthehistoryofmicrobiologyhasclassifiedmicrobesasplanktonic,freelyswinging cellsinanutritionallyabundantaquaticenvironmentdependingontheirgrowth environment.However,themajorityofmicrobesinaquaticenvironmentsarenotfreesuspendedmicroorganismsbutinsteaddwellonimmergedsurfaces,wheretheyform organizedcoloniesknownasbiofilms.Untilthe17thcentury,biofilmswerefirst characterizedbyVanLeeuwenhoekfromDelft(1632 1723),whoobservedmicrobial coloniesonshavingsofplaquefromhisteethwithhiscrudemicroscope(Dobell,1932). Thegenestranscribedbybiofilmbacteriadifferfromthosedonebyplanktonic counterparts(Henrici1933).Asearlyas1933,theword“biofilm”wastermedintechnical andenvironmentalmicrobiology(Henrici,1933; ZobellandAllen,1935).
Earlierstudiesofbiofilmsweremainlyinwastewaterfiltering,industrialequipment biofouling,anddentalplaque.LouisPasteur(1822 95)discoveredandsketchedbacterial aggregationastheoriginofaceticwine(Hoiby,2014, 2017).Forbiofilmdescription,much ofthebiofilmstudiesdependonthedevelopmentofinstruments,suchasscanningelectron microscopy(SEM)ortraditionalmicrobialculturetechniques.Twokeyadvancesinbiofilm researchoccurredinthepastfewdecades:thefirstonewastheuseoftheconfocallaser scanningmicroscopetoanalyzebiofilmultrastructure,andthesecondwasthestudyofthe genesrelatedtocelladhesionandbiofilmdevelopment(Battinetal.,2007).
RobertKoch(1843 1910)wasapioneeringmicrobiologistwhoattemptedtoisolateand characterizemicrobesfromtheirnaturalhabitats.Thepureculturetechniqueallowsthe highlevelofreplicationandhandlingtobetterunderstandhowmicroorganismsculture respondtodifferentsituations.Inmicrobiology,thisledtothe“GoldenAge”sinceit providedanopportunitytostudyorganismsinthelabinconsiderabledetailundertightly controlledsettings(suchasgrowthconditions)orwithgeneticmodifications.Because mostbacteriaexistasmultispeciescommunities,pureculturecannotdescribemultispecies communityphenomena.Becauseofthis,biofilmresearchincreasinglyemploysmethods previouslyreservedforstudyingpopulations,suchasmeta-omics-basedmethodologies andhigh-resolutionscanning(Battinetal.,2007).
Thebiofilmresearchwasrevivedinthe1970and1980s.Microorganismsthatgrewona surfacewereconsideredasflatanduniformfilmsofcellsencasedinslime.Thenatureof biofilmsinthehumanhostcanbesignificantlydifferentfromthatatthesurfacesexposedto theenvironment.Inthemid-20thcentury,scientistsdiscoveredthatbiofilmsareprimarily composedofdiversepopulationsofbacteria(Kraghetal.,2016; Melaughetal.,2016).
Environmentalchangesorthemetabolismandmigrationofothercommunitiescause dynamicchangesinnutritionalgradientsforeachpopulation.Thereforeacertainbiofilm community’ssuccessrateishighlydependentontheothermembers’performanceaswell asregulationandcontrolofquorumsensing(QS).Inmedicalmicrobiology, Nickeletal. (1985) introducedtheconceptof“biofilm”growthintheirpioneerresearchintothe physiologicalandbiochemicalfeaturesofbacteria.Theyfoundthatbiofilm-growing bacteriaexhibitedgreaterresistancethanplanktonicallydevelopingbacteria.
Theterm“film”isinsufficienttodescribebacteriallife;hencethename“biofilm”is somehowmisleading.Biofilmcellsdonotjustpileupontopofeachother;instead,they createcomplex,self-organizedstructuresfromthebottomup.Thereareawiderangeof biofilmsthatdifferfromonemicroorganismpopulationtoanother,dependingonthetype ofbacterialcommunityandenvironmentalconditions,suchas“streamers,”“columns,” “mushrooms,”“bioclusters,”“microbialmats,”“microcolonies,”and“bioaggregates” (Atkinsonetal.,1967).Apparently,becausethesetermsarealreadywidelyusedintheir respectivefields,whetherthetermofbiofilmsneedstobereplacedoriscontroversial (Baveye,2020; Flemmingetal.,2021).Asaresult,theword“biofilm”herereferstothe extensivebacterialattachmentonsurfacestodifferentiateaggregatedbacteriafromfree suspended“planktonic”bacteria.Biofilmsrepresentmulticellularmicrobialaggregatesthat arenotlimitedtomicrobialfilmsonsurfaces.
1.2.2Biofilmmodeling
Modelingofbiofilmsdatesbacktothe1970s.Biofilmsweredescribedashomogeneous biomassofasinglemicrobialspecies(AtkinsonandDavies,1974; Williamsonand McCarty1976; Harremoes,1976; RittmannandMcCarty,1980).Thefirst-generation approacheswerequickandeasytoimplement,sometimesusingasimplespreadsheet. However,theydescribeonlyuniformgrowthandcannotcaptureallnonevengrowth. Followingthat,stratifieddynamicmodelsweredevelopedassecond-generationmodels (WannerandGujer,1986).Theselayeredmodelsweredevelopedtorepresentinteractions betweenmultiplesubstratesandspeciesinsidethebiofilm.Theywere,however,unableto accountforthetypicalstructuraldiversity.Therefore,thethird-generationmodelsare developedtorepresentthecharacteristicstructuralheterogeneityinsideabiofilm.
Inthethird-generationmodels,thecoupledmodelofbiomassgrowthsubmodels(e.g., detachment,decay,biomassdivision,andspreading),andtransportsubmodels(e.g.,flow,
substratetransport,andreactions)aresolvedusingthefinitedifferencemethod(FDM)or thefinitevolumemethod(FVM)(Picioreanuetal.,2004).TheNavier Stokesequations, andreactivetransportequationshavebeendevelopedtosimulatebiofilmgrowths (Picioreanuetal.,1998a,b,2001, 2004; Eberletal.,2001; Pizarroetal.,2001; Laspidou andRittmann,2004; Xavieretal.,2005).Bothcontinuummodelsanddiscretemodelsfor biofilmgrowthstartedtobedevelopedtodescribetheformationofmultidimensional biofilmmorphologyinthe1990sandcarrytotodayasthethird-generationmathematical models.Inthecontinuummodels,biofilmgrowthisdescribedusingatransportequation (Eberletal.,2001)andcoupleswithhydrodynamicsandsubstratetransportprocesses.The term“discrete”denotesthatthesystem’sspace,time,andcharacteristicscanonlyhavea finitenumberofstates.Intheearlystage,adomainspaceisdiscretizedintoregulargrid elements,establishingalattice.Thelarge-scaledynamicsofmasstransportand hydrodynamicsaresolvedusingtheFDMortheFVMwhilethebiofilmstructuresaredone usingcellularautomata(CA)orindividual-basedmodel(IbM).
Avarietyofdiscreterulescanresultinfundamentallydiverseandratherrandomstructures forCA.Therulesemployedtosimulateinteractionsatthelocallevelcanbeinspiredonly bybiologicalprinciples,asopposedtoanalysisaccordingtoamathematicalandphysical framework(Alpkvistetal.,2006).IbMwasappliedtodescribebiofilmgrowth(Picioreanu etal.,2004; Yanetal.,2017).Asaresultoftheactionsaswellasinteractionsofthe biomassunitswithoneanotherandtheirsurroundings,thecomplexmorphologyofbiofilms evolves.ThoughCAissimpletobuild,theincreasingbiomasscanonlytravelinarestricted numberoflatticedirections.Additionally,biofilmsaresupposedtobelivingsystemsthat areintrinsicallystochastic.TheCAmodeldescribesstochasticity(Laspidouetal.,2010).
Thethird-generationbiofilmmodelsincludehydrodynamics,masstransfer,and transformations(Eberletal.,2001).Therefore,theyareabletorepresentthe2Dor3D microbialbiofilmmorphologies(Picioreanuetal.,1999; Nogueraetal.,1999a).EPSand QSprocesseshavebeenconsideredinthethird-generationmodels.Biofilmbiomassis madeupofbiologicalgelEPSandwater,accordingtothebiofilm’sconceptualmodelby CoganandKeener(2004).Followingtheconcept, Winstanleyetal.(2011, 2015) developedaconceptualmodeltostudybiofilmblockageinsingleporespace.Later, Kreft andWimpenny(2001) introducedtheIbMtoapproximateEPScreationandspread.The synthesisofEPSwasstoichiometricallyconnectedtothegrowthofbacteria.TheEPS functionedasthefirstlineofprotectionagainsterosionandinvasionofthebacterialcells. Togetherwiththebacterialcells,theexcretedagentEPSwillbeinvolvedintheshoving mechanism(KreftandWimpenny,2001).
QSisacell-to-cellcommunicationfunctionthatbacteriacoordinategeneexpressionand behaviorinthecommunities(Fredericketal.,2011).QSmodelingisrelativelyrecent. Ueckeetal.(2014) developedanIbMforQSsimulationconsideringfluidflow.Ordinary
differentialequationstorepresenttheQSmoleculardiffusionwerecoupledwiththe exteriorflowfieldtosimulatethetimeevolutionoftheinnercells. ZhaoandWang(2017) developedanumerical3DmodelforsimulationsofQSandantibacterialpersistencein heterogeneousmultispeciesbiofilms.
ThelatticeBoltzmannmodel(LBM)forbiofilmmodelinghasbeendevelopedinthepast fewdecades(DelavarandWang,2021a,b).LBMhasitsrootsinstatisticalphysicsand latticegascellularautomata(LGCA)(Frischetal.,1986).LBMusesdistributionfunctions torepresentparticleparceldynamicsandismoresuitableforcouplingwith nonequilibriuminterfaceswithCAorIbM.InLBM-basedframeworks,thebiomassis describedasdiscretequantitiesusingCAorIbM,assignedeithertonumericalgridblocks ortoparticles.Thisallowsthebiofilmmatrixtospreadinmorethanonedirection. Continuummodelsareusedforthetransportofsubstratesusingreactivetransport equationsorLBM. Eberletal.(2001) indicatedinherentdrawbacksinthediscrete approach,suchasthesmallsetofspreadingdirections,biofilmgrowinginauniform environment,adhoc,orsomewhatarbitraryrulesforpriority.However,becauseofthe fundamentalkineticnatureofLBM,itsinterfaceprocessescouldbecoupledeasily throughthedistributionfunctionsinthemesoscaleincomparisonwithtraditional computationalfluiddynamics(CFD)usingFDMorFVM.Therefore,theLBM-based modelshaveseveraladvantages:(1)nonequilibriumdynamics,suchasdiscontinuous interfaceprocesses,multiphaseflow,andflowinporousmediaorcomplexgeometries,(2) easyparallelization,and(3)norequirementofsolvingPoisson’sequationof pressure velocitycouplingthatiscomputationallyexpensive(DelavarandWang,2020).
Becauseofthesecharacteristics,LBMisagoodchoiceformodelingmicroscopic/ mesoscalebiofilmformationusingsimplifiedkineticmodels.Afewhybridtheoretical frameworksthatlinkedparticle-basedandcontinuum-basedmodelsseamlesslyhavebeen developed(DelavarandWang,2021a):(1)integratedLBMandIbM(LBM-IbM)(Graf vonderSchulenburgetal.,2009; TianandWang,2019)and(2)integratedLBMandCA (LBM-CA)(Picioreanuetal.,1999; Tangetal.,2013; Knutsonetal.,2005; Beniougetal., 2017,2019; DelavarandWang,2020, 2021b).Thesefourth-generationmodelsareusually effectiveinstrumentsformodelingbiofilmsindifferenttypesofsituations(Delavarand Wang,2021a).However,iflarge-scaleheterogeneoussystemsaresimulated,thelevelof detailinbiofilmdescriptioncanbealimitation.Mostnotably,LBM-IbMsneed substantiallygreatercomputerresourcesthanthebiomass-basedmodelsunderthesame spatialresolution.
1.3Problemsandobjectivesofbiofilmresearch
Biofilmsareanaturalphenomenonoftheearth’secology,justasbacteriaandfungiare. Manybiofilmsaredetrimentalbecausetheycausemetalcorrosionorwoundinfections.
Everyyear,biofilmscausethelossesoftheUnitedStatesliterallyhundredsofbillionsof dollarsduetoenergylosses,devicecorrosion,foodpoison,biofouling,andclinical infection.Largeseagoingships’fuelconsumptionisexpectedtoriseby30%asaresultof theviscousdragincreasescausedbybiofouling(deCarvalho,2018).Otherbiofilmsmay beusefulforresolvingmajorissues,particularlyinwastewaterpretreatmentsystemsand bioremediationofcontaminatedsoilswhilenaturalbiofilmscanbeharmfultohuman healthandtheenvironment.Forexample,industrialbiofilmsaremoreefficientandstable intermsofbioconversionsandpollutantdegradation.
Microbialsystembehaviorsresultfromintricateinteractionsbetweenalargenumberof cellsandtheirbioticandabioticsurroundings.However,biofilmsdevelopedonsubmerged sedimentareverydifferentfromthatonourteethorfromtheirplanktoniccousins.Itisa keytopichowbiofilmsservemultipleactivitiesofmicroorganismsandbestowthemwith specificfunctionalitiesfordiverseapplicationsthatareusefultocompaniesandthe environment(Vasudevan,2014).Understanding,controlling,andengineeringbiofilmsare allgoalsdrivenbyscientificandpracticalconsiderationssuchasbioremediation,corrosion andbiofoulingprevention,medicalhealthandpharmaceuticals,andecosystemrespiration.
Becausebiofilmsarepresentthroughoutareasofindustrialsystems,theenvironment,and humanhealth,biofilmresearchnowextendsfromthenotionofbiofilmdevelopmentto biofilmbasetechnologiesandtheirengineeringapplications.Biofilmformationiscriticalin boththeearlyphasesofbiofilmdevelopmentandthelatterstagesofthematuredbiofilm lifecycleviacelldispersalinavarietyofindustries.Anenhancedunderstandingofthe emergentpropertiesofbiofilmsandtheirlifestyleallowsanappreciationofbiofilms’ ecologicalandindustrialsuccess,aswellasthepotentialvalueinecologicalandindustrial applicationstodoenormousgoodforourworldasawholeortocontrolandremovebad biofilmsofindustrialandclinicalconcern(Coganetal.,2016).Itwillbefeasibleto manipulatethegrowthandformationofbiofilmsifthebiofilmfunctioncanmechanistically relatetobiotechnologies.Asaresult,scientistsandengineerscanreconsidertheir techniquesinhandlingbiofilmproblemsandsolutionsthatwerepreviouslyneglectedornot handledeffectivelyoncethepathwaystobiofilmgrowthareunderstood.Theycanmodify theirdevicesorbioprocessesinclinical,environmental,orindustrialapplicationstoblock toxicbiofilmsorstimulatefavorableones(Moonsetal.,2009).
Becausebiofilmactivityandbehaviorarecomplexinteractionsbetweenphysical, chemical,andbiologicalprocesses,theinherentlyinterdisciplinarynaturenecessitates researchcontributionsfromdisparatedisciplinessuchasbiochemistry,engineering, mathematics,andmicrobiology,withapplicationsrangingfrombiofoulingtosoil microbialecologytobioremediationtowastewatertreatmenttochronicbacterial infections(Flemmingetal.,2021).Biofilmsarenotviewedaseitherbeneficialorharmful inthiscontext,butratherasacrucialcomponentoftheecosystemsthatsurroundus.Asa
result,understandingbiofilmsrequiresresearchfrommultipleindustries,environments, anddisciplinesonhowbacteriainteractwiththeirsurroundingsandhowtheyimpactthe creationorbreakdownofawiderangeofchemicals. Fig.1.3 depictsthethreemajor domainsofbiofilmsinscienceandengineering.
Clinicalandhealth: Biofilmscanbeharmfultohumanhealthduetomicroorganism infectionsinpatients.Everyyear,millionsofpeoplesufferfromchronicdiseasessuchas cysticfibrosispneumonia,long-standingwounds,chronicinflammation,andimplant-and catheter-associatedinfections,andmanyofthemloseone’slifeasaresult(Bjarnsholt 2013; Sonderholmetal.,2017; TorrettaandPignataro,2018).Indeed,numeroushost environments,suchasblood,tears,saliva,intervascularfluid,andrespiratorysecretions, canbesuitableforbacteriagrowth.Microbialcorrosion,medicaldevice-relatedillnesses, andpersistentwoundsareallcausedbybiofilmsembeddedinhostmaterialastiny aggregates.Foodcontaminatedbybiofilmbacteriaisalsoaglobalpublichealthconcern (Sreyetal.,2013).Asaconsequence,biofilmsareregardedastheprimarycauseof infectioninpublichealth.
Microorganismsmaybenaturallyresistanttoantimicrobialsandantibiotics.Biofilmassociatedorganisms,inparticular,candevelopresistancedeterminantstowithstand antibiotics.Microorganismsinabiofilmare1000 1500timesmoreresistanttodrugsthan
Figure1.3
Problemsandobjectivesofthreemainareasofbiofilms.
theirplanktonicmicroorganisms(SocranskyandHaffajee,2002).Antibioticresistanceisa criticalconcernduetorisingmorbidity,mortality,andhealthcarecosts.Antimicrobial resistancecanalsosignificantlyinfluencehealthcaresettingsandhumanhealthbycauseof contaminationofindwellingmedicaldevicesandthesubsequentspreadofinfections relatedtothesedevices.Themechanismsofthisincreasedresistancedifferfromspeciesto species,antibioticstoantibioticsindifferenthabitats.Thisantibioticresistanceinbiofilms isconsiderablyinfluencedbytheirnutritionalconditions,species,temperature,pH,and exposuretimetoeffectiveconcentrationsofantimicrobialagents.Furthermore,bacterial speciesinabiofilmthatarelesssusceptivetoantibioticsleadtoslowergrowth.Biofilms canbeimpervioustothediffusionofantibioticsandchangethetranslationaland therapeuticpotentialduringinfection.Forexample,thebiofilmcanbeusedasanion exchangerinremovingsuchmoleculesfromthesolutionbecausestronglychargedor chemicallyhighlyreactiveagentsmayberesistedtoreachitsdeeperzones.Asaresult,it isstillunknownhowtoelucidatetheuniquegeneexpressionofbiofilm-associated organisms,evaluatevariousantimicrobialagentsandantimicrobiallocks,andanalyzethe efficiencyofnewhandlinginpreventingorremediatingbiofilmcolonizationofmedical devices.Biofilmsinmedicaldevicesareextremelydifficulttodealwithsincetheirgrowth involvesavarietyoffeatures,phases,andreducedantimicrobialsusceptibility.Hence,new tacticsforcontrollingbiofilmformationinmedicaldevicesarenecessary,suchasthe functionofbiofilmsinantimicrobialresistance,biofilmsasahostforpathogenic organisms,andbiofilmsasacauseofchronicdiseases.
Weseektofindawayhowtoeffectivelyinhibitorregulatebiofilmgrowth,whichissafe andsimpletobeimplementedinclinical,food,water,andenvironmentalmicrobiology. Thekeytosuccessinbiofilmpreventionandcontrolmaybeabetterunderstandingof whatdistinguishesthebiofilmphenotypefromtheplanktonicphenotype(Donlan,2002). Hence,themostpromisingtechniquesaretounderstandhowtopreventbiofilmgrowthas wellashowtodealwiththeseverediseasesrelatedtobiofilminfections(Nogueraetal., 1999b).Forexample,incomplexenvironments,theminimumeffectiveinhibitory concentrationofanymedicineshouldbeidentifiedineliminating,preventing,or destroyingbiofilmswhilebeingresistanttomicrobialresistance(Vasudevan,2014).New treatments,suchastheuseofantiadhesionchemicalsortheutilizationofbacterially createdsignalstopromotebacterialdispersal,shouldbeinvestigatedforexcitingfastacting,effective,andbioavailablemethods(Kostakiotietal.,2013).Bacteriacanalsobe inhibitedbyenvironmentalfactors(OfekandDoyle,1994).Understandingthesignificance ofbiofilmsininfectionshouldimproveclinicaldecision-making(Donlan,2001).Thebest clinicalpracticeswillbeincludedinregulatoryscienceandchoicesbecauseofthe comprehensivescientificexpertconsultprocess,educationaltraining,andstandardization. Thisreducesthelikelihoodofinfectionandencouragestheformationofbiofilm-inhibiting products.
Environmentalprotection: Industrialandagriculturalproductionraisessevereworries aboutcontaminatedsoilandwater.Livestockproductionisthemainsourceof eutrophicationduetophosphorusrunoffanddepletionoftheoxygenintheaquatic systems.Biofilmsareimportantinself-purificationprocessesinsoil,water,andsediments, aswellasinthenaturalattenuationoforganicmatterandpollutants,suchas contaminants,phenols,andspilledoils(LofflerandEdwards,2006).Thetechnologiesof biofilmshaveilluminatedtheirutilityintheremovalofnutrients,pollutants,andheavy metalsfromwastewater,waterdetoxification,andspilledoildegradationbypromoting naturallyoccurringorimportedmicrobiomes.Sincetheendofthe18thcentury,biofilms havebeenusedforbioremediationincontaminatedsitesbybreakingdownundesired materialcreatedbydeadfishandplantresiduals,andbyabsorbingheavyionsfromthe wastewaterwithoutreducingtheoxygenlevel(Nicolellaetal.,2000).Asaresult,biofilms haveenormouspotentialforcleaninguphazardouswastesites,filteringmunicipaland industrialwaterandwastewater,buildingbiobarrierstoavoidpollutionofsoiland groundwater,andmaintainingecologicalbalance.Furthermore,soilmicrobiomesin biofilmsalsoplayacriticalroleinecosystemrespirationandsoilcarbonsequestrationin climatechange(Bhanjaetal.,2019; BhanjaandWang,2020, 2021).Microorganismscan contributefavorablytotheecologicalbalancetoconferthedetrimentalconsequencesof theecosystemandclimatechange.
Microbiologyhastraditionallyconcentratedonsinglespeciescommunities,whichhas tremendouslyaidedourunderstandingofmicrobialgrowth,adaptability,andbiofilm formation.However,inthenaturalenvironment,mostbiofilmsaremultispecies communitiesratherthansinglespeciescommunities.Biofilmsystemsarenotrandomly distributed,butrathertailoredtocertainniches(EliasandBanin,2012).Interspeciescan collaborateandcompetewithoneanother.Interspeciescooperationhasbeendemonstrated toincreasetolerancetohazardouscompoundssuchasantibiotics,antimicrobials,chlorine, anddetergents(Costertonetal.,1994).Multispeciescommunitiesinbioremediationare recognizedtobemoreadaptivetomorecomplexconditionsindecontaminatingpolluted environments.Indeed,bioremediationofcontaminatedwaterandsoilhasbecomean appealingmethod,asorganicpollutants,suchasphenols,areconvertedtoinnocuous compoundsandsecondarymineralwastesbytheprocess.Theeffectivenessof bioremediation,ontheotherhand,isdependentonthesurvivalandpersistenceof microorganismswithinamultispeciesbiofilm.Cooperationandcompetitionamongthese complexcommunitiesarecriticalforincreasingtheresilienceandsurvivalofthevarious species(Moonsetal.,2009).Althoughresearchonmultispeciesbiofilmsisstillinitsearly stages,ithasbeendiscoveredthattheadditionofawell-selectednutritionsupplyor additionalspeciesmicroorganismscansteerthecommunitiestowardmoreefficient bioremediation.Forexample, Juangetal.(2008) showedthatphenolmaybedegraded moreeffectivelyinthepresenceoftetrasodiumpyrophosphatebyutilizingbiofilmsof
Pseudomonasputida BCRC14365.Furthermore,thepresenceofironpromotesthe degradationoftheisothiazolinonebiocide(5-chloro-2-methyl-4-isothiazolin-3-one).Asa result,biofilmtechnologyhasenormouspotentialinremediatinghazardoussites,filtering municipalandindustrialwastewater,buildingbiobarrierstoavoidpollutionofsoiland water,andmaintainingecologicalconservation.
Bioengineeringandtechnology: Theabilitytopromotethegrowthofgoodbiofilmsor inhibitthegrowthofbadbiofilmshasbeenwidelyrecognizedinthefieldsofclinic treatment,biologicalproduction,andenvironmentalprotection.Bioproducts,soluble organicmolecules,andEPSsubstancesconvertedbybacteriaareexamplesofmicrobial productsofinterest(Nogueraetal.,1999b; DelavarandWang,2021a).Many bioconversiontechnologies,includinganoxic/oxygenicphotosynthesisanddark/photo fermentation,havebeendevelopedforbiofuelandbiohydrogenproduction(Delavarand Wang,2021a,b),aswellaswastewatertreatment(DelavarandWang,2020).Theyallare dependentoninteractionsbetweenmicrobialmetabolismandphysical chemical processes.Theprimarygoalsofbioengineeringandbiotechnology,suchasbioconversion, biosynthesis,bioremediation,carbonsequestration,andwastetreatment,aretoincrease efficiency,optimizeresourceutilization,decreaseenvironmentalload,andlowerproduct costs.Variousbioreactors,suchasmovingbedbiofilmreactors(MBBRs),integratedfixedfilmactivatedsludge(IFAS)processes,andmembrane-supportedbiofilmreactors (MBfRs),aretheprimarymeansofconstructingmicrobiomesfortheuseofbiofilmsin recoveringvaluableresourcesfromwastewatertreatmentorsynthesizingbioproducts (Mccartyetal.,2011; Torresietal.,2016).Biofilmformationsinthebioreactorsarethe primarymechanismfororganicpollutantbioconversion(e.g.,organicmatter,nitrogen,and phosphorus).However,usingorganismsinbiofilmreactorsmustbemorecost-effective.To designabioreactororacompleteplant,inwhichbiofilmsconvertsubstrates,exact knowledgeofthebiofilmgrowthprocessesismandatorytoensurethegreatestefficiency andthelowesttotalcosts.Newmetabolicpathwaysorbioreactorstructureshavebeen exploredtoimprovetheefficiencyofbiofilmreactorsandtoincreasetheireconomic potential.Forexample, Roeselersetal.(2008) discoveredtheanaerobicammonium oxidation(anammox)processinapilot-scaledenitrifyingfluidizedbedbiofilmreactor.A significantlyenrichedmicrobialcommunitycollectedfromthisenvironmentwas dominatedbyasingledeep-branchingplanctomycete, CandidatusBrocadia anammoxidans (Roeselersetal.,2008).Weneedtoimprovemicrobialprocessesformore efficientbioconversion,biosynthesis,orbiodegradation,orweneedtofindstrategiesto combatbacteriatoproducecleanenergy.
Microorganismsofmultiplespeciescancontributetohighermetabolismthroughtwoto fourspeciesthansinglespecies,buttheyaresubstantiallymorecomplicatedsystems.A numberofemergentfeatureshavebeenobservedinbothdefinedandundefined populations,includingimprovedstresstolerance,greaterbiomassyield,QSsignaling,and
metaboliccooperation(Tsoietal.,2019).Thehighestprocessingcapacitiesaregenerally consideredasconversionratespertotalreactorvolume,andthespatialstructurehasa significantimpactonsubstratedistribution-relatednutrienttransferandavailabilityfor bacteriauptake(Battinetal.,2016).Naturalhabitatsorindustrialbiofilmshavespatial variabilityrangingfromnanoscalesignalstomicroscalenutritionalgradientstomillimeter structuralsurfacecharacteristicsthatdrivepopulation-levelactivities(HolandDekker, 2014).Thesinglespeciesandhomogenousevaluationsmayexploretimelynoveltraits connectedwithmultispeciescommunities.Furthermore,smartbioengineeringwillbe essentialforenhancingefficiency.Togetherwithspeciesselection,geneticengineeringcan increaseunderstandingofbiofilmformationbetweendiverseorganismsandimprove reactorperformance(Liuetal.,2008).Asaresult,thegenuinepotentialexistsinmixedspeciescommunitiestoachievehighefficiencyonawiderangeofsubstrates.Research datafrompilot-scaleplantsandmodelingcanbehighlybeneficialforassessingthe performanceofprojectedfull-scaleplantsfordesigningandtestingnewtypesofbiofilm processesorreactorstructures.Evenifthereisnofullunderstandingofbiofilmprocesses forsuchacomplexsystemofbioreactors,biofilmresearchmaybecriticalindetermining howabiofilmformsordevelopsinbioreactorsandwhetheranadequatedesignwould encouragethestudyofcertainbiofilmactivities.
1.3.1Objectivesofbiofilmmodeling
Thegoalsofbiofilmmodelingaretogainabetterknowledgeofbiofilmprocesses,reduce experimentaltesting,andscaleup.Amathematicalmodelisasystematictesttotransfera real-worldsystem’sconceptualknowledgeintoamathematicalformulaandlinkvarious processesandweightheirrelativecontributionstostructuralformationandgrowthof biofilms(Wanneretal.,2006).Amathematicalmodelcanbeusedtocombinemany mechanismsthatoperateatdistinctspatialandtemporalscales,suchastransport, metabolic,chemical,mechanical,andgeneticactivitieswithinbiofilms.Biofilmmodeling canhelpresearchersbetterunderstandbiofilmstructure,function,andpopulation dynamics,aswellasthetransition(structureandbehavior)ofbiofilmsgrowingunder variousenvironmentalconditions,potentiallyopeningupnewbiotechnologyapplications (Nogueraetal.,1999b).Innovativesolutionscanbedevelopedbycombiningscientific discoveryinscienceandengineeringforsustainablenaturalresourcemanagementand humanandanimalhealth.
Scale-upisabottleneckinbioprocessdesignanddevelopment.Optimalbiofilmcontrolis achallengeincomplexclinicaltherapy.Thebiomass,structures,andthicknessinbiofilms interactwithhydrodynamics.Ifonepartischanged,itispossiblethattheotherpartswill bechanged.Theinteractionofhydrodynamicsandbiofilmchangecanresultinerratic performance,whenachievingapseudo-steadystate,ataspecifiedtimeandspatialscales.
Theabilitytomonitor,modify,andsimulatebiofilmsfromfirstprinciples,frommolecules toindividualstopopulations,communities,andecosystems,maygomuchbeyondthe explanationoftheecologyandevolutionarytheory.Fromsamplesinshakeflaskstothe finalproductandclinicaltreatment,screeningtrialsinearly-stagedevelopmentof microbialprocessestakealongtime.Nevertheless,itischallengingtoconnectthe naturallyestablishedmultispeciescommunitieswiththefinalproduct.Modelingisto analyzequalitativelyandquantitativelytheeffectsofvariousfactorsonbiofilmformation andgrowth.
Whenexploringavarietyofbiofilm-relatedphenomena,biofilmmodelscanbeappliedfor qualitativeandquantitativeassessmentofexperimentaldataonhowpopulationsfunctionin theirnaturalconstructedconditions(Nogueraetal.,1999b).Athoroughanalysisof experimentalresultsprovidesaninsightintoreal-timecontrolofbiofilmactivitiesandthe potentialtomodifybiofilmformandfunction(Chevalieretal.,2018).Thisusually decreasesthenumberofexperimentaldesignsandteststhatallowtheunderlyinghypothesis tobetested,aswellasextractconceptualandinnovativeknowledgethatpromotes microbiomeresearch,leadingtonovelbiologicalprocessdesigns.Themodelingapproach, inparticular,allowsonetodefinetherelationshipsunderinvestigationandquantifiesthe relativequantitiesofspeciesinthepopulation,individualversusgeneralactivity,andsoon. Themodelingapproachalsoexaminesifbiofilmfunctionsaddresspracticalconcernsthat areintractablethroughfieldobservationsofcommunitiesoflargerspecies.Indeed,studies ofsocialbehaviorssuchascooperationandcompetitionareshiftingfromsingle-species systemstoincreasinglycomplexmultispeciessystems,suchasthoseinvolving host microbeinteractionsandmicrobialconsortia(DelavarandWang,2020).
Finally,despitetheuncertainties,theuseofmechanisticbiofilmmodelsinbiofilmreactor designandmanufacturingisubiquitousinconsultation,anditiscurrentlyhighlybeneficial inbioengineering.Forcomplexsystemswithnumerousinteractingphenomena,modelingis oneofthemostsuccessfulapproachesinacceleratingbothscientificadvancementand translationintonovelsolutions.Modelingcanbeappliedtoexplorenovelprocessdesigns without/atlowexpense,effort,orriskofimplementingallthestrategiestofindoptimal ones,comparedtoexperimentaltesting.Therefore,modelingallowsresearchersand practitionerstoefficientlyscreenalargenumberofdesignoptionstodiscardthosethatfail toachieveperformanceobjectives,suchasdesignedoperatingconditionsandnovel therapeutictechniques.Inbioengineeringandbiotechnology,aniterative design build test learn(DBTL)cyclecanbeusedformicrobiomedevelopment(Lawson etal.,2019).ThisDBTLcoversthelifecycledevelopmentofamicrobiome,fromaninitial microbiomedesigntoengineeringgoals,modelsystems,andexpectedoutcomes.The microbiomeiscreatedsothatitsfunctioncanbetestedagainstasetofmetricstoexamine ifthedesign buildoutcome(s)meetsthedesigngoal(thatis,establishcausation).Thiswill allowexaminingwhatworkedandwhatdidnot(andwhy).Thisisutilizedtoassist decision-makinginsubsequentDBTLdesigncycles.Thismethodcouldacceleratethe
developmentofproductsfromdesignconceptsforharnessingmicrobiomestorealproducts bygivingnovelsolutionsandexpandingscientificunderstandingthroughmodeling.
Biofilmmodelsarealsousedintheeducationandtrainingofprospectivescientistsand engineers(Nogueraetal.,1999b).Modelingapproachesallowstudents,researchers,and scientiststounderstandthemechanismofbiofilmdevelopmentanditsfunctionality,andto examinetheimpactofbiofilmformation,inducedcorrosion,andfoulingonsurfacesof devices.Understandinghowbiofilmsformandfunctionthroughsimulationisoneofthe mostefficientlearningsandtrainingwaysforachievingtheintendedresults.A combinationoffundamental(mechanistic)anddata-oriented(empirical)biofilmreactor designmodelsisrequiredforlearningandtrainingalthoughpredictingtheinteraction amongrelevantscalesisstilladifficulty.Environmentalcharacteristicssuchaslocalized gradientsinpH,dissolvedoxygen,redoxpotential,nutrient,andmetabolicproduct concentrationscanallbeinvestigatedtoexaminetheireffectsonbiofilmformationand development,whetherthebiofilmisalreadybuiltorstillintheconceptualstage(Noguera etal.,1999a; Flemmingetal.,2021).
Thereareseveralprioritiesthatrequiretobeconsideredwhileemployingmodeling approaches:(1)microorganismactivitywithinabiofilm,(2)elucidationofbiofilm deposition,formation,anddetachmentmechanisms,(3)assessmentofthemechanical propertiesofEPSandpreservationofextracellularenzymes,(4)identificationofkeydrivers andparameters,andecologicalinteraction(s)amongdifferentmicroorganisms,(5)increased resistancetoantibioticsandbiocides,(6)geneticexchange,recombination,thereunionof nucleicacidsinintercellularcommunication,andcollectivebehaviorsuchascooperation andcompetitioninresponsetothestressfulandchangingenvironment,(7)waterretention andpreventiontodehydration,and(8)real-timecontrolofbiofilmsystemsforthemost effectivebiologicaltreatmentmethods(Nogueraetal.,1999a; Flemmingetal.,2021).
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Furtherreading
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