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BIOMATERIALSFOR3DTUMOR MODELING BIOMATERIALS FOR3DTUMOR MODELING Editedby
SUBHAS C.KUNDU 3B’sResearchGroup,I3Bs ResearchInstituteonBiomaterials,BiodegradablesandBiomimetics,Universityof Minho,HeadquartersoftheEuropeanInstituteofExcellenceonTissueEngineeringandRegenerativeMedicine, Guimara ˜ es,Portugal
ICVS/3B’s PTGovernmentAssociateLaboratory,Braga/Guimara ˜ es,Portugal
RUI L.REIS 3B’sResearchGroup,I3Bs ResearchInstituteonBiomaterials,BiodegradablesandBiomimetics,Universityof Minho,HeadquartersoftheEuropeanInstituteofExcellenceonTissueEngineeringandRegenerativeMedicine, Guimaraes,Portugal
ICVS/3B’s PTGovernmentAssociateLaboratory,Braga/Guimaraes,Portugal
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Contents ListofContributorsxi Prefacexvii
I Engineeringbiomaterialsfor3D cancermodelling 1.Trendsinbiomaterialsforthreedimensionalcancermodeling3
DavidCaballero,RuiL.ReisandSubhasC.Kundu
Abbreviations3
1.1Ahistoricalintroduction4
1.2Thethree-dimensionaltumor microenvironment6
1.3Engineeringthenativetumor microenvironmentusingcustom-designed three-dimensionalbiomaterials15
1.4Advancedmodelsofthethree-dimensional tumormicroenvironment22
1.5Applicationsofthree-dimensionaltumor modelsincancertherapeutics30
1.6Limitationsofbiomaterials-basedthreedimensionaltumormodels33
1.7Futureofthree-dimensionalbiomaterialsfor cancerresearch34
1.8Finalremarksandconclusions35 Acknowledgments36 References36
2.Bioinspiredbiomaterialstodevelop cell-richsphericalmicrotissuesfor3D invitrotumormodeling43
MariaV.Monteiro,Vı´torM.GasparandJoaoF.Mano
2.1Introduction43
2.2HumanTumormicroenvironment—key hallmarkstomimicinvitro44
2.33DInvitrotumormodels—bridgingthegap from2Dflatculturestoinvivo45
2.4Classesof3Dmulticellulartumormodels47
2.5Conclusions61
References62
3.Biofabricationof3Dtumormodelsin cancerresearch67
M.A.Grimaudo,A.Herreros-Pomares,M.Alonso,S.CalabuigFarinas,E.Jantus-LewintreandMariadelaFuente
3.1Currentchallengesinoncology67
3.2Thetumormicroenvironment69
3.3Developmentofthecancertherapeutics field71
3.43Dtumormodelsincancerresearch73
3.5Evaluationofanticancertherapeuticsin3D tumormodels78
3.6Implementationof3Dtumormodelsina clinicalsetting82
3.7Finalremarks86 Acknowledgments86 References86
4.Biomatricesthatmimicthe cancerextracellularenvironment91 SaraAmorim,RuiL.ReisandRicardoA.Pires
4.1Introduction91
4.2Thethree-dimensionalinvitromodels92
4.3Conclusionsandfutureremarks102
References102
5.3Dneuroblastomainvitromodelsusing engineeredcell-derivedmatrices107 EnricoAlmici,DavidCaballero,JoanMonteroandJosepSamitier
5.1Introduction107
5.2Neuroblastoma108
5.3Cell-derivedmatricesintumormodeling112
5.4Engineeringcell-derivedmatrix deposition115
5.5Cell-derivedmatricesandcellmorphodynamic characterization123
5.6Cell-derivedmatrixcapturerelevantprocesses involvedinneuroblastomamalignancy125
5.7Conclusions126
Acknowledgments126 References126
6.3Dculturesystemsasmodelsforsolid tumorsandcancermetabolism131
So ´ niaPiresCeleiro,Fa ´ timaBaltazarandMartaViana-Pereira
Abbreviations131
6.1Introduction132
6.2Solidtumors:tumormicroenvironmentand tumorigenesis133
6.3Cancermetabolism:influenceintumor microenvironment135
6.4Solidtumorsinvitromodels139
6.53Dcellculturesystemsincancerresearch143
6.63Dcellculturesystemsforstudycancer metabolism146
6.7Conclusions148 Acknowledgments149 Conflictofinterest149 References149
7.BiomaterialsasECM-likematricesfor 3Dinvitrotumormodels157
LaraPierantoni,JoanaSilva-Correia,AntonellaMotta,RuiL.Reis andJoaquimM.Oliveira
Abbreviations157
7.1Introduction158
7.2BiomaterialsasECM-likematricesforcancer 3Dinvitromodels158
7.3Conclusionandfuturetrends170 Acknowledgments170 References170
8.Three-dimensionalinvitromodelsof angiogenesis175
LauradiBlasio,MarianelaVara-MesslerandLucaPrimo
8.1Vesselsformationandtumorangiogenesis175
8.2Vascularextracellularmatrix176
8.3Endothelialcells-based3Dangiogenesis models178
8.4Vascularexplant-based3Dangiogenesis models182
8.5Microvesselsonachip184
8.6Futureperspectives186 Acknowledgments186 References187
9.Metastasisinthree-dimensional biomaterials191
BananiKundu,RuiL.ReisandSubhasC.Kundu
9.1Whybiomaterialisneededincancer modeling?191
9.2BiomaterialsemployedintumorECM modeling193
9.3Propertiesofcellsurroundingmatrix/niche contributetotumorcellmigration197
9.4Biomaterial-basedstepwisemodelingofcancer metastasis invitro 199
9.5Biomaterial-based invitro modelsofcancer dormancyandreactivation208
9.6Concludingremarks209
Acknowledgments210 References210
10.3Dcancerspheroidsand microtissues217
VirginiaBrancato,RuiL.ReisandSubhasC.Kundu
Abbreviations217
10.1Introduction217
10.2Biomaterialsadvancestumorcellcultureto thethirddimension219
10.3Recapitulatingthetumor stromacrosstalkin spheroidandmicrotissuemodels223
10.4Vascularizedmicrotumormodels224
10.5Thecontributionofimmunesystemcellsin microtumors226
10.6Spheroidsasscreeningplatformfordrug testing228
10.7Conclusionandfuturetrends230 Acknowledgments231 References231
11.Biomaterial-basedinvitromodelsfor pancreaticcancer235
EiriniVelliou,PriyankaGupta,ClaudioRicciandSerenaDanti
11.1Introduction235
11.2Invitro3Dmodelsforpancreatic cancer237
11.3Using3Dmodelsfordisease understanding241
11.4Using3Dmodelsfortherapeutic screening246
11.5Conclusionsandfuturetrends247 References247
12.Invitrothree-dimensionalmodeling forprostatecancer251
EleonoraDondossolaandClaudiaPaindelli
12.1Introduction251
12.2Modelingprimarytumors254
12.3Modelingearlystagesofprostatecancer progression267
12.4Modelingadvancedstagesofprostatecancer progression273
12.5Conclusion280 References281
13.3Dinvitrocutaneousmelanoma models287
AnaI.Soares,RuiL.ReisandAlexandraP.Marques
Abbreviations287
13.1Introduction288
13.2Typesofmelanoma289
13.3Riskfactorsformelanoma291
13.4Cutaneousmelanomadevelopment293
13.5Cutaneousmelanomatreatment293
13.6Invitromodels296 References300
14.3Dscaffoldmaterialsforskincancer modeling305
AmirZarebkohan,RoghayehSheervalilou,RoyaGhods,SubhasC. KunduandMazaherGholipourmalekabadi
14.1Introduction305
14.2Effectivefactorsincellculture;2Dand3D models308
14.3Skincancers313
14.4Modelingofskincancer315
14.5Conclusionandfutureprospective321 Acknowledgment322
Conflictofinterest322 References322
II Advancedmodelsforcancer research 15.Microfluidicsystemsincancer research331
DavidCaballero,MariaAnge ´ licaLuque-Gonza ´ lez,RuiL.Reisand SubhasC.Kundu
15.1Introduction331
15.2Fundamentalsofmicrofluidics:fluidmechanics inminiaturizeddevices336
15.3Fabricationprinciplesofmicrofluidic devices339
15.4Mimickingthetumormicroenvironmentusing microfluidics343
15.5Microfluidicmodelsofcancer354
15.6Futureperspectives366
15.7Conclusions370 Acknowledgments370 Conflictsofinterest370 References370
16.Perfusion-based3Dtumor-on-chip devicesforanticancerdrugtesting379 NandiniDhimanandSubhaNarayanRath
Abbreviations379
16.1Introduction379
16.2Disadvantagesof2Dinvitro,3Dinvitro,and animalmodels380
16.3Microfluidicdevicesfortumormodeling382
16.4Tumorcomponentsandtheirinclusionin tumor-on-chip383
16.5Typesofperfusionmethods387
16.6Benefitsofperfusionandspecific applications388
16.7Specificdesignsforenhancingperfusion393
16.8Conclusion394 Acknowledgments394 References394
17.Engineeringbreastcancermodels invitrowith3Dbioprinting399 BradA.KrajinaandDanielaF.DuarteCampos
17.1Breastcancermicroenvironmentinvivo399
17.2Biomaterial-basedbreastcancerinvitro models401
17.3Biomaterialsdesignforinvitrobreastcancer models407
17.43Dbioprintingmethodsandtheirsuitability forbreastcancerinvitroengineering413
17.5Discussionandoutlook417
References419
18.Apredictiveoncologyframework— modelingtumorproliferationusingaFEM platform427
GianpaoloRuocco,PaoloCaccavaleandMariaValeriaDeBonis
Chapterpoints427
18.1Introduction427
18.2Aperspectiveframeworkofpredictive oncology430
18.3Detailedmodelformulationusinglevel1 modeling436
18.4Asensitivityanalysisofhallmarkparameters: results439
18.5POEMasatooltoempowertheclinical decisions448
18.6Conclusions448
Acknowledgments449
Glossary449
References449
III Tumormodelsfordrugdiscovery andtherapeutics 19.Tissue-engineered3Dcancer microenvironmentforscreening therapeutics453
NancyT.Li,IleanaL.Co,NatalieLandon-Brace,SimonLatour andAlisonP.McGuigan
19.1Introduction453
19.2Tumormicroenvironment454
19.3Currentstrategiesforcreatingcellandmatrix organizationtomimic microenvironment458
19.4Modelingimportantaspectsofthetumor microenvironment462
19.5Futureoutlook472
References473
20.Three-dimensionaltumormodeland theirimplicationindrugscreeningfor tacklingchemoresistance481
ManashiPriyadarshini,SibasishMohanty,TanushreeMahapatra, PallaviMohapatraandRupeshDash
Abbreviations481
20.1Chemoresistanceincancer482
20.23Dtumorculture:anadvancedmodel preferredover2Dculture483
20.33Dcultureandchemoresistance486
20.4Methodsofgenerating3Dculture system487
20.53Dcultureandbiomaterials490
20.6Drugscreeningin3Dculture494
20.7Futureaspectsofthe3Dtumororganoid model:biobanksfortumortissues497
20.8Limitationsof3Dculturetechnology498
20.9Conclusion498
Acknowledgment498 References498
21.Co-cultureand3Dtumormodelsfor drug/genetherapytesting505
LaraS.Costard,HarumiRamanayakeandCarolineM.Curtin
21.1Introduction505
21.2Lungcancer506
21.3Breastcancer515
21.4Prostatecancer523
21.5Futureoutlook527
References527
22.Newlyemergedengineeringofinvitro 3Dtumormodelsusingbiomaterialsfor chemotherapy533
BoCai,QiyingLv,ZhengWangandLinWang
22.1Introduction533
22.2Constitutionofartificiallyengineeredtumor models534
22.3Newlyemergedengineeringofinvitro3D tumorsforchemotherapy536
22.4Summary545 References546
23.Marine-derivedbiomaterialsforcancer treatment551
CatarinaOliveira,AnaC.Carvalho,RuiL.Reis,NunoN.Neves, AlbinoMartinsandTiagoH.Silva
23.1Introduction551
23.2Marinebiopolymersasbioactiveagents553
23.3Drug-deliverysystems556
23.4Three-dimensional invitro modelsof cancer562
23.5Conclusions569
23.6Acknowledgments570 References570
24.Mesoporoussilicananoparticlesfor cancertheranosticapplications577 MohammadEltohamy
24.1Introduction577
24.2MSNschemistry579
24.3BiologicaleffectsofMSNs580
24.43DmodelingofMSNforcancertherapy583
24.5MedicalapplicationsofMSNs584
24.6DiagnosticapplicationofMSNs594
24.7TheranosticsapplicationofMSNs596
24.8Conclusionsandoutlook597 References597
IV Point-of-careapplications 25.Causesofcancer:physical,chemical, biologicalcarcinogens,andviruses607
SubhayanDas,MoumitaKundu,BikashChandraJenaand MahitoshMandal
Abbreviations607
25.1Introduction608
25.2Physicalcarcinogens611
25.3Chemicalcarcinogens617
25.4Biologicalcarcinogensandviruses621
25.5Conclusion629
Acknowledgments631 References631
26.Biodetectionandsensingforcancer diagnostics643
RitaRebelo,AnaI.Barbosa,SubhasC.Kundu,RuiL.Reisand VitorM.Correlo
26.1Introduction643
26.2Biomarkersforcancerdetection644
26.3Cancerbiosensors648
26.4Commercializationandclinicaltrialsofcancer biosensors654
26.5Conclusions656
Acknowledgments657
References657
27.Understandingtheimpactof controlledoxygendeliveryto3Dcancer cellculture661
DavidGrosh,WilliamJ.Wulftange,RobertW.Robey,ThomasJ. Pohida,NicoleY.MorganandMichaelM.Gottesman
27.1Introduction661
27.2Whatisknownaboutphysiologicaloxygen levels?662
27.3Importanceofoxygenlevelsinvariousstages ofcancerprogression664
27.4Techniquesformeasuringoxygenation668
27.5Traditional/currentstrategiesforcontrolling oxygenconcentrationinvitro674
27.6Characterizingtheeffectsofoxygenationon cellsandtissues684
27.7Conclusionsandfutureprospects688 Acknowledgments689 Disclaimer689 References689
28.Tissueengineeringstrategiesforthe treatmentofskeletalmaxillofacialdefects resultingfromneoplasmsresections697
J.P.Ribeiro,EstebanA.Astudillo-Ortiz,PedroS.Baboand ManuelaE.Gomes
28.1Background697
28.2Tissueengineeringforreconstructionof ablatedskeletalmaxillofacialtissues705
28.3Futureperspectivesandunmetchallenges720 References722
Index731
ListofContributors EnricoAlmici NanobioengineeringGroup, InstituteforBioengineeringofCatalonia (IBEC),TheBarcelonaInstituteofScienceand Technology(BIST),Barcelona,Spain; DepartmentofElectronicsandBiomedical Engineering,UniversityofBarcelona, Barcelona,Spain;NetworkingBiomedical InvestigationCenterforBioengineering, BiomaterialsandNanomedicine(CIBERBBN),Madrid,Spain
M.Alonso Nano-OncologyandTranslational TherapeuticsUnit,HealthResearchInstitute ofSantiagodeCompostela(IDIS),SERGAS, SantiagodeCompostela,Spain;Cancer ResearchNetwork(CIBERONC),Spain
SaraAmorim 3B’sResearchGroup,I3Bs ResearchInstituteonBiomaterials, BiodegradablesandBiomimetics,University ofMinho,HeadquartersoftheEuropean InstituteofExcellenceonTissueEngineering andRegenerativeMedicine,Guimara ˜ es, Portugal;ICVS/3B’s-PTGovernment AssociateLaboratory,Braga/Guimaraes, Portugal
EstebanA.Astudillo-Ortiz 3B’sResearch Group,I3Bs ResearchInstituteon Biomaterials,Biodegradablesand Biomimetics,UniversityofMinho, Guimaraes,Portugal;ICVS/3B’s PT GovernmentAssociateLaboratory,Braga/ Guimaraes,Portugal;GIROResearchGroup inOralRehabilitation,UniversityofCuenca, Cuenca,Ecuado
PedroS.Babo 3B’sResearchGroup,I3Bs ResearchInstituteonBiomaterials, BiodegradablesandBiomimetics,Universityof Minho,HeadquartersoftheEuropeanInstitute ofExcellenceonTissueEngineeringand RegenerativeMedicine,Guimara ˜ es,Portugal; ICVS/3B’s PTGovernmentAssociate Laboratory,Braga/Guimara ˜ es,Portugal
Fa ´ timaBaltazar LifeandHealthScience ResearchInstitute(ICVS),Schoolof Medicine,UniversityofMinho,Braga, Portugal;ICVS/3B’s PTGovernment AssociateLaboratory,Braga/Guimaraes, Portugal
AnaI.Barbosa 3B’sResearchGroup,I3Bs ResearchInstituteonBiomaterials, BiodegradablesandBiomimetics,Universityof Minho,HeadquartersoftheEuropeanInstitute ofExcellenceonTissueEngineeringand RegenerativeMedicine,Guimaraes,Portugal; ICVS/3B’s PTGovernmentAssociate Laboratory,Braga/Guimaraes,Portugal
VirginiaBrancato 3B’sResearchGroup,I3Bs ResearchInstituteonBiomaterials, BiodegradablesandBiomimetics,Universityof Minho,HeadquartersoftheEuropeanInstitute ofExcellenceonTissueEngineeringand RegenerativeMedicine,Guimaraes,Portugal; ICVS/3B’s PTGovernmentAssociate Laboratory,Braga/Guimaraes,Portugal
DavidCaballero 3B’sResearchGroup,I3Bs ResearchInstituteonBiomaterials, BiodegradablesandBiomimetics,University ofMinho,HeadquartersoftheEuropean InstituteofExcellenceonTissueEngineering andRegenerativeMedicine,Guimara ˜ es, Portugal;ICVS/3B’s PTGovernment AssociateLaboratory,Braga/Guimara ˜ es, Portugal
PaoloCaccavale UniversityofBasilicata, CollegeofEngineering,Modelingand PrototypingLaboratory—ModProLab, Potenza,Italy
BoCai ResearchCenterforTissueEngineering andRegenerativeMedicine,UnionHospital, TongjiMedicalCollege,Huazhong UniversityofScienceandTechnology, Wuhan,P.R.China
S.Calabuig-Farin˜as MolecularOncology Laboratory,GeneralUniversityHospitalof ValenciaResearchFoundation,Valencia, Spain;CancerResearchNetwork (CIBERONC),Spain;Departmentof Pathology,UniversitatdeVale ` ncia,Valencia, Spain
AnaC.Carvalho 3B’sResearchGroup,I3Bs ResearchInstituteonBiomaterials, BiodegradablesandBiomimetics,University ofMinho,HeadquartersoftheEuropean InstituteofExcellenceonTissueEngineering andRegenerativeMedicine,Guimaraes, Portugal;ICVS/3B’s,PTGovernment AssociateLaboratory,Braga/Guimaraes, Portugal
So ´ niaPiresCeleiro LifeandHealthScience ResearchInstitute(ICVS),Schoolof Medicine,UniversityofMinho,Braga, Portugal;ICVS/3B’s PTGovernment AssociateLaboratory,Braga/Guimaraes, Portugal
IleanaL.Co DepartmentofChemical EngineeringandAppliedChemistry, InstituteforBiomaterialsandBiomedical Engineering,UniversityofToronto,Toronto, ON,Canada
VitorM.Correlo 3B’sResearchGroup,I3Bs ResearchInstituteonBiomaterials, BiodegradablesandBiomimetics,University ofMinho,HeadquartersoftheEuropean InstituteofExcellenceonTissueEngineering andRegenerativeMedicine,Guimaraes, Portugal;ICVS/3B’s PTGovernment AssociateLaboratory,Braga/Guimaraes, Portugal
LaraS.Costard TissueEngineeringResearch Group(TERG),DepartmentofAnatomyand RegenerativeMedicine,RoyalCollegeof SurgeonsinIreland(RCSI),Dublin,Ireland
CarolineM.Curtin TissueEngineering ResearchGroup(TERG),Departmentof AnatomyandRegenerativeMedicine,Royal CollegeofSurgeonsinIreland(RCSI), Dublin,Ireland;TrinityCentreof Bioengineering(TCBE),TrinityCollege Dublin(TCD),Dublin,Ireland;Advanced
MaterialsandBioengineeringResearch Centre(AMBER),RCSIandTCD,Dublin, Ireland.
SerenaDanti DepartmentofCiviland IndustrialEngineering,UniversityofPisa, Pisa,Italy
SubhayanDas SchoolofMedicalScienceand Technology,IndianInstituteofTechnology Kharagpur,Kharagpur,India
RupeshDash InstituteofLifeSciences, Bhubaneswar,India
MariaValeriaDeBonis Universityof Basilicata,CollegeofEngineering,Modeling andPrototypingLaboratory—ModProLab, Potenza,Italy
MariadelaFuente Nano-Oncologyand TranslationalTherapeuticsUnit,Health ResearchInstituteofSantiagodeCompostela (IDIS),SERGAS,SantiagodeCompostela, Spain;CancerResearchNetwork (CIBERONC),Spain
NandiniDhiman DepartmentofBiomedical Engineering,IndianInstituteofTechnology Hyderabad,Kandi,India;Departmentof ChemistryandBiotechnology,Facultyof Science,Engineering,andTechnology, SwinburneUniversityofTechnology, Hawthorn,VIC,Australia
LauradiBlasio DepartmentofOncology, UniversityofTorino,Turin,Italy;Candiolo CancerInstituteFPO-IRCCS,Candiolo,Italy
EleonoraDondossola DavidH.KochCenter forAppliedResearchofGenitourinary Cancers,TheUniversityofTexasMD AndersonCancerCenter,Houston,TX, UnitedStates
DanielaF.DuarteCampos Departmentof MaterialsScience&Engineering,Stanford University,CA,UnitedStates
MohammadEltohamy GlassResearch Department,NationalResearchCentre,Giza, Egypt
Vı´torM.Gaspar DepartmentofChemistry, CICECO—AveiroInstituteofMaterials, UniversityofAveiro,CampusUniversita ´ rio deSantiago,Aveiro,Portugal
RoyaGhods OncopathologyResearchCenter, IranUniversityofMedicalSciences,Tehran, Iran;DepartmentofMolecularMedicine, FacultyofAdvancedTechnologiesin Medicine,IranUniversityofMedicine Sciences,Tehran,Iran
MazaherGholipourmalekabadi Department ofMolecularMedicine,FacultyofAdvanced TechnologiesinMedicine,IranUniversityof MedicineSciences,Tehran,Iran;Cellularand MolecularResearchCenter,IranUniversity ofMedicalSciences,Tehran,Iran; DepartmentofTissueEngineering& RegenerativeMedicine,FacultyofAdvanced TechnologiesinMedicine,IranUniversityof MedicalSciences,Tehran,Iran
ManuelaE.Gomes 3B’sResearchGroup,I3Bs ResearchInstituteonBiomaterials, BiodegradablesandBiomimetics,University ofMinho,HeadquartersoftheEuropean InstituteofExcellenceonTissueEngineering andRegenerativeMedicine,Guimara ˜ es, Portugal;ICVS/3B’s PTGovernment AssociateLaboratory,Braga/Guimara ˜ es, Portugal
MichaelM.Gottesman LaboratoryofCell Biology(LCB),CenterforCancerResearch, NationalCancerInstitute(NCI),National InstitutesofHealth,Bethesda,MD,United States
M.A.Grimaudo Nano-Oncologyand TranslationalTherapeuticsUnit,Health ResearchInstituteofSantiagodeCompostela (IDIS),SERGAS,SantiagodeCompostela, Spain
DavidGrosh Trans-NIHSharedResourceon BiomedicalEngineeringandPhysicalScience (BEPS),NationalInstituteofBiomedical ImagingandBioengineering(NIBIB), NationalInstitutesofHealth,Bethesda,MD, UnitedStates
PriyankaGupta BioprocessandBiochemical EngineeringGroup(BioProChem), DepartmentofChemicalandProcess Engineering,UniversityofSurrey,Surrey, UnitedKingdom
A.Herreros-Pomares MolecularOncology Laboratory,GeneralUniversityHospitalof
ValenciaResearchFoundation,Valencia, Spain;CancerResearchNetwork (CIBERONC),Spain
E.Jantus-Lewintre MolecularOncology Laboratory,GeneralUniversityHospitalof ValenciaResearchFoundation,Valencia, Spain;CancerResearchNetwork (CIBERONC),Spain;Departmentof Biotechnology,UniversitatPolite ` cnicade Vale ` ncia,Valencia,Spain
BikashChandraJena SchoolofMedical ScienceandTechnology,IndianInstituteof TechnologyKharagpur,Kharagpur,India
BradA.Krajina DepartmentofMaterials Science&Engineering,StanfordUniversity, CA,UnitedStates
BananiKundu 3B’sResearchGroup,I3Bs— ResearchInstituteonBiomaterials, BiodegradablesandBiomimetics,University ofMinho,HeadquartersoftheEuropean InstituteofExcellenceonTissueEngineering andRegenerativeMedicine,Guimara ˜ es, Portugal;ICVS/3B’s—PTGovernment AssociateLaboratory,Braga/Guimara ˜ es, Portugal
MoumitaKundu SchoolofMedicalScience andTechnology,IndianInstituteof TechnologyKharagpur,Kharagpur,India
SubhasC.Kundu 3B’sResearchGroup, I3Bs—ResearchInstituteonBiomaterials, BiodegradablesandBiomimetics,University ofMinho,HeadquartersoftheEuropean InstituteofExcellenceonTissueEngineering andRegenerativeMedicine,Guimaraes, Portugal;ICVS/3B’s—PTGovernment AssociateLaboratory,Braga/Guimaraes, Portugal
NatalieLandon-Brace Departmentof ChemicalEngineeringandApplied Chemistry,InstituteforBiomaterialsand BiomedicalEngineering,Universityof Toronto,Toronto,ON,Canada
SimonLatour DepartmentofChemical EngineeringandAppliedChemistry, InstituteforBiomaterialsandBiomedical Engineering,UniversityofToronto,Toronto, ON,Canada
NancyT.Li DepartmentofChemical EngineeringandAppliedChemistry, InstituteforBiomaterialsandBiomedical Engineering,UniversityofToronto,Toronto, ON,Canada
MariaAnge ´ licaLuque-Gonza ´ lez 3B’s ResearchGroup,I3Bs ResearchInstituteon Biomaterials,Biodegradablesand Biomimetics,UniversityofMinho, HeadquartersoftheEuropeanInstituteof ExcellenceonTissueEngineeringand RegenerativeMedicine,Guimara ˜ es,Portugal; ICVS/3B’s PTGovernmentAssociate Laboratory,Braga/Guimara ˜ es,Portugal
QiyingLv ResearchCenterforTissue EngineeringandRegenerativeMedicine, UnionHospital,TongjiMedicalCollege, HuazhongUniversityofScienceand Technology,Wuhan,P.R.China
TanushreeMahapatra InstituteofLife Sciences,Bhubaneswar,India
MahitoshMandal SchoolofMedicalScience andTechnology,IndianInstituteof TechnologyKharagpur,Kharagpur,India
Joa˜oF.Mano DepartmentofChemistry, CICECO—AveiroInstituteofMaterials, UniversityofAveiro,CampusUniversita ´ rio deSantiago,Aveiro,Portugal
AlexandraP.Marques 3B’sResearchGroup, I3Bs—ResearchInstituteonBiomaterials, BiodegradablesandBiomimetics,University ofMinho,HeadquartersoftheEuropean InstituteofExcellenceonTissueEngineering andRegenerativeMedicine,Braga/ Guimara ˜ es,Portugal;ICVS/3B’s—PT GovernmentAssociateLaboratory,Braga/ Guimara ˜ es,Portugal
AlbinoMartins 3B’sResearchGroup,I3Bs ResearchInstituteonBiomaterials, BiodegradablesandBiomimetics,University ofMinho,HeadquartersoftheEuropean InstituteofExcellenceonTissueEngineering andRegenerativeMedicine,Guimara ˜ es, Portugal;ICVS/3B’s,PTGovernment AssociateLaboratory,Braga/Guimara ˜ es, Portugal
AlisonP.McGuigan DepartmentofChemical EngineeringandAppliedChemistry, InstituteforBiomaterialsandBiomedical Engineering,UniversityofToronto,Toronto, ON,Canada
SibasishMohanty InstituteofLifeSciences, Bhubaneswar,India;RegionalCenterfor Biotechnology,Faridabad,India
PallaviMohapatra InstituteofLifeSciences, Bhubaneswar,India;RegionalCenterfor Biotechnology,Faridabad,India
MariaV.Monteiro DepartmentofChemistry, CICECO—AveiroInstituteofMaterials, UniversityofAveiro,CampusUniversita ´ rio deSantiago,Aveiro,Portugal
JoanMontero NanobioengineeringGroup, InstituteforBioengineeringofCatalonia (IBEC),TheBarcelonaInstituteofScienceand Technology(BIST),Barcelona,Spain
NicoleY.Morgan Trans-NIHSharedResource onBiomedicalEngineeringandPhysical Science(BEPS),NationalInstituteof BiomedicalImagingandBioengineering (NIBIB),NationalInstitutesofHealth, Bethesda,MD,UnitedStates
AntonellaMotta BIOtechResearchCenter, DepartmentofIndustrialEngineeringand EuropeanInstituteofExcellenceonTissue EngineeringandRegenerativeMedicine, UniversityofTrento,Trento,Italy
NunoN.Neves 3B’sResearchGroup,I3Bs ResearchInstituteonBiomaterials, BiodegradablesandBiomimetics,Universityof Minho,HeadquartersoftheEuropeanInstitute ofExcellenceonTissueEngineeringand RegenerativeMedicine,Guimara ˜ es,Portugal; ICVS/3B’s,PTGovernmentAssociate Laboratory,Braga/Guimara ˜ es,Portugal
CatarinaOliveira 3B’sResearchGroup,I3Bs ResearchInstituteonBiomaterials, BiodegradablesandBiomimetics,University ofMinho,HeadquartersoftheEuropean InstituteofExcellenceonTissueEngineering andRegenerativeMedicine,Guimara ˜ es, Portugal;ICVS/3B’s,PTGovernment AssociateLaboratory,Braga/Guimara ˜ es, Portugal
JoaquimM.Oliveira 3B’sResearchGroup, I3Bs—ResearchInstituteonBiomaterials, BiodegradablesandBiomimetics,University ofMinho,HeadquartersoftheEuropean InstituteofExcellenceonTissueEngineering andRegenerativeMedicine,Guimara ˜ es, Portugal;ICVS/3B’s—PTGovernment AssociatedLaboratory,Braga/Guimara ˜ es, Portugal
ClaudiaPaindelli DavidH.KochCenterfor AppliedResearchofGenitourinaryCancers, TheUniversityofTexasMDAnderson CancerCenter,Houston,TX,UnitedStates; DepartmentofCellBiology,Radboud InstituteforMolecularLifeSciences, RadboudUniversityMedicalCenter, Nijmegen,TheNetherlands
LaraPierantoni 3B’sResearchGroup,I3Bs— ResearchInstituteonBiomaterials, BiodegradablesandBiomimetics,University ofMinho,HeadquartersoftheEuropean InstituteofExcellenceonTissueEngineering andRegenerativeMedicine,Guimaraes, Portugal;ICVS/3B’s—PTGovernment AssociatedLaboratory,Braga/Guimaraes, Portugal
RicardoA.Pires 3B’sResearchGroup,I3Bs ResearchInstituteonBiomaterials, BiodegradablesandBiomimetics,University ofMinho,HeadquartersoftheEuropean InstituteofExcellenceonTissueEngineering andRegenerativeMedicine,Guimara ˜ es, Portugal;ICVS/3B’s-PTGovernment AssociateLaboratory,Braga/Guimara ˜ es, Portugal
ThomasJ.Pohida SignalProcessingand InstrumentationSection(SPIS), ComputationalBioscienceandEngineering Laboratory,CenterforInformation Technology,NationalInstitutesofHealth, Bethesda,MD,UnitedStates
LucaPrimo DepartmentofOncology, UniversityofTorino,Turin,Italy;Candiolo CancerInstituteFPO-IRCCS,Candiolo,Italy
ManashiPriyadarshini InstituteofLife Sciences,Bhubaneswar,India;KIITSchoolof Biotechnology,KIITUniversity, Bhubaneswar,India
HarumiRamanayake TissueEngineering ResearchGroup(TERG),Departmentof AnatomyandRegenerativeMedicine,Royal CollegeofSurgeonsinIreland(RCSI), Dublin,Ireland
SubhaNarayanRath Departmentof BiomedicalEngineering,IndianInstituteof TechnologyHyderabad,Kandi,India
RitaRebelo 3B’sResearchGroup,I3Bs ResearchInstituteonBiomaterials, BiodegradablesandBiomimetics,University ofMinho,HeadquartersoftheEuropean InstituteofExcellenceonTissueEngineering andRegenerativeMedicine,Guimaraes, Portugal;ICVS/3B’s PTGovernment AssociateLaboratory,Braga/Guimaraes, Portugal
RuiL.Reis 3B’sResearchGroup,I3Bs— ResearchInstituteonBiomaterials, BiodegradablesandBiomimetics,University ofMinho,HeadquartersoftheEuropean InstituteofExcellenceonTissueEngineering andRegenerativeMedicine,Guimaraes, Portugal;ICVS/3B’s—PTGovernment AssociatedLaboratory,Braga/Guimaraes, Portugal
J.P.Ribeiro 3B’sResearchGroup,I3Bs ResearchInstituteonBiomaterials, BiodegradablesandBiomimetics,University ofMinho,HeadquartersoftheEuropean InstituteofExcellenceonTissueEngineering andRegenerativeMedicine,Guimaraes, Portugal;ICVS/3B’s PTGovernment AssociateLaboratory,Braga/Guimaraes, Portugal
ClaudioRicci NationalInteruniversity ConsortiumofMaterialsScienceand Technology(INSTM),Florence,Italy; DepartmentofCivilandIndustrial Engineering,UniversityofPisa,Pisa,Italy
RobertW.Robey LaboratoryofCellBiology (LCB),CenterforCancerResearch,National CancerInstitute(NCI),NationalInstitutesof Health,Bethesda,MD,UnitedStates
GianpaoloRuocco UniversityofBasilicata, CollegeofEngineering,Modelingand PrototypingLaboratory—ModProLab, Potenza,Italy
JosepSamitier NanobioengineeringGroup, InstituteforBioengineeringofCatalonia (IBEC),TheBarcelonaInstituteofScienceand Technology(BIST),Barcelona,Spain; DepartmentofElectronicsandBiomedical Engineering,UniversityofBarcelona, Barcelona,Spain;NetworkingBiomedical InvestigationCenterforBioengineering, BiomaterialsandNanomedicine(CIBERBBN),Madrid,Spain
RoghayehSheervalilou Cellularand MolecularResearchCenter,Resistant TuberculosisInstitute,ZahedanUniversityof MedicalSciences,Zahedan,Iran
TiagoH.Silva 3B’sResearchGroup,I3Bs ResearchInstituteonBiomaterials, BiodegradablesandBiomimetics,University ofMinho,HeadquartersoftheEuropean InstituteofExcellenceonTissueEngineering andRegenerativeMedicine,Guimaraes, Portugal;ICVS/3B’s,PTGovernment AssociateLaboratory,Braga/Guimara ˜ es, Portugal
JoanaSilva-Correia 3B’sResearchGroup, I3Bs—ResearchInstituteonBiomaterials, BiodegradablesandBiomimeticsof UniversityofMinho,Headquartersofthe EuropeanInstituteofExcellenceonTissue EngineeringandRegenerativeMedicine, Guimaraes,Portugal;ICVS/3B’s—PT GovernmentAssociatedLaboratory,Braga/ Guimara ˜ es,Portugal
AnaI.Soares 3B’sResearchGroup,I3Bs— ResearchInstituteonBiomaterials, BiodegradablesandBiomimetics,University ofMinho,HeadquartersoftheEuropean InstituteofExcellenceonTissueEngineering andRegenerativeMedicine,Braga/ Guimara ˜ es,Portugal;ICVS/3B’s—PT GovernmentAssociateLaboratory,Braga/ Guimaraes,Portugal
MarianelaVara-Messler Departmentof Oncology,UniversityofTorino,Turin,Italy; CandioloCancerInstituteFPO-IRCCS, Candiolo,Italy
EiriniVelliou BioprocessandBiochemical EngineeringGroup(BioProChem), DepartmentofChemicalandProcess Engineering,UniversityofSurrey,Surrey, UnitedKingdom
MartaViana-Pereira LifeandHealthScience ResearchInstitute(ICVS),SchoolofMedicine, UniversityofMinho,Braga,Portugal;ICVS/ 3B’s PTGovernmentAssociateLaboratory, Braga/Guimara ˜ es,Portugal
LinWang ResearchCenterforTissue EngineeringandRegenerativeMedicine, UnionHospital,TongjiMedicalCollege, HuazhongUniversityofScienceand Technology,Wuhan,P.R.China;Department ofClinicalLaboratory,UnionHospital, TongjiMedicalCollege,Huazhong UniversityofScienceandTechnology, Wuhan,P.R.China
ZhengWang ResearchCenterforTissue EngineeringandRegenerativeMedicine, UnionHospital,TongjiMedicalCollege, HuazhongUniversityofScienceand Technology,Wuhan,P.R.China;Department ofGastrointestinalSurgery,UnionHospital, TongjiMedicalCollege,Huazhong UniversityofScienceandTechnology, Wuhan,P.R.China.
WilliamJ.Wulftange Trans-NIHShared ResourceonBiomedicalEngineeringand PhysicalScience(BEPS),NationalInstituteof BiomedicalImagingandBioengineering (NIBIB),NationalInstitutesofHealth, Bethesda,MD,UnitedStates;Laboratoryof CellBiology(LCB),CenterforCancer Research,NationalCancerInstitute(NCI), NationalInstitutesofHealth,Bethesda,MD, UnitedStates
AmirZarebkohan DepartmentofMedical Nanotechnology,FacultyofAdvanced MedicalSciences,TabrizUniversityof MedicalSciences,Tabriz,Iran;DrugApplied ResearchCenter,TabrizUniversityof MedicalSciences,Tabriz,Iran
Preface Traditionally,invitroapproaches employedtomodeltumorprogression involvetheuseoftissuecultureflasksand asinglecellpopulation.Thisoversimplified scenarioisincontrastwiththedynamic tumormicroenvironmentthatisobserved invivo,whichisthree-dimensional(3D) andcontainsmultiplecelltypes.During therecentyears,anewgenerationofpredictivetumormodelshasbeenemerging. Thisnewparadigmintumormodelscombinestheadvantagesof3Dbiomaterials withthemostrecentadvancementsinthe fieldsoftissueengineering,nanotechnology,cellbiology,biochemistry,3Dbioprinting,andcomputersimulation.Asaresult, morerealisticandpredictiveplatform(s) havebeencreated,definingtheroadmap fortheirfutureuseaspreclinicaldrug/ therapyscreeningplatformsincancer research.
Theeditorsfeelveryproudtohavecollectedadiversevarietyofrelevantchapters fromrecognizedinternationalleaders, whichincludetheirpersonalandforwardlookingvisioninthefields.Thechapters reportfurtheronthelatesttrendsof
biomaterialsfor3Dcancermodeling,and inparticular,abouttheirusesasphysiologicallyrelevantplatformsfordrugdiscovery andscreeningaswellasformechanistic investigations.Theeditorsbelievethatthis bookwillbeanadditionalsupportandstimulifordesigningnewexperimentsindifferentresearchareas,suchasbiomaterials, tissueengineering,regenerativemedicine, biomedicaldevices,pharmacology,and preclinicalexperimentations.Furthermore, thisbookwillbeingeneralhelpfultothe materialscience,biology,andmedicalscientificcommunitiesworkinginthefieldof cancer-relatedresearch.Overall,thisnew paradigmin3Dinvitrotumormodeling willunivocallyimprovethefieldofcancer diagnosisandtreatment.
Finally,wearegratefultoalltheauthors andco-authorsfortheircontributionsin thisbook.Wearealsothankfultotheentire Elsevierteamfortheircontinuoussupport andhelpduringtheeditionofthisbook. Wesincerelyacknowledgethefinancial supportfromtheprojectForefront Researchin3Ddiseasecancermodelsas invitroscreeningtechnologies(FoReCaST),
whichissupportedbytheEuropeanUnion FrameworkProgramforResearchand InnovationHorizon2020undergrant agreementno.668983.ThisERA-Chairs wideningspreadingofexcellenceproject aimstodevelopanewgenerationof3D invitrotumormodelsfordrugscreening applicationsandhas,therefore,motivated ustoeditthisuniquebook.WealsosincerelythankalltheFoReCaSTcollaborators andteam-members,namelyDrs.Joaquim M.Oliveira,VitorM.Correlo,David Caballero,BananiKundu,Virginia Brancato,andRicardoPiresfortheir encouragementduringtheentirecourseof actionforeditingthisbook.
TheEditors, SubhasC.Kundu RuiL.Reis
August1st
3B’sResearchGroup,I3Bs-Research InstituteforBiomaterials,Biodegradables, andBiomimetics,UniversityofMinho, Guimara ˜ es,Portugal
Trendsinbiomaterialsfor three-dimensionalcancermodeling DavidCaballero1,2,RuiL.Reis1,2 andSubhasC.Kundu1,2
13B’sResearchGroup,I3Bs ResearchInstituteonBiomaterials,Biodegradablesand Biomimetics,UniversityofMinho,HeadquartersoftheEuropeanInstituteofExcellenceon TissueEngineeringandRegenerativeMedicine,Guimaraes,Portugal 2ICVS/3B’s PT GovernmentAssociateLaboratory,Braga/Guimara ˜ es,Portugal
Abbreviations 2D Two-dimensions
3D Three-dimensions
4D Four-dimensions
ADMET Adsorption,distribution,metabolism,excretion,andtoxicity
CAFs Cancer-associatedfibroblasts
CDMs Cell-derivedmatrices
CTCs Circulatingtumorcells
ECM Extracellularmatrix
EMEA EuropeanMedicinesAgency
EMT Epithelial-to-mesenchymaltransition
EPR Enhancedpermeabilityandretention
FDA Federaldrugagency
HA Hyaluronicacid
HUVEC Humanumbilicalveinendothelialcells
MMPs Matrixmetalloproteases
PDMS Polydimethylsiloxane
PEG Poly(ethyleneglycol)
TAMs Tumor-associatedmacrophages
TME Tumormicroenvironment
ToC Tumor-on-a-chip
VEGF Vascularendothelialgrowthfactor
Biomaterialsfor3DTumorModeling
DOI: https://doi.org/10.1016/B978-0-12-818128-7.00001-0
1.1.1Invitroandinvivomodels:anoverview Duringthelastdecade,thetypeofbiologicalassaysthatareusedforextractinginformationabouttheefficiencyofdrugs(includingcancer-relatedcompounds)havedramatically changed.Thereasonisthatalargeamountofthesedrugsfailwhentheyaretestedinpreclinicalassays.Thisisbecausemostpre-clinicaldrugevaluationsrelyonsimplifiedinvitro assaysbasedonflattwo-dimensional(2D)surfaces.Thistypeofassaypoorlycorrelateswith thehumandiseasestate.Therein,thecellsdisplayartificialphenotypesandperturbedgene expressions.Ingeneral,thedrugsresponddifferentlythaninvivo.Exvivo(e.g.,biopsies) andinvivo(e.g.,animal)modelsarealsoemployedfordrugevaluation.Incancerresearch, thesemodelsdisplaycertainadvantagesover2Dsurfaces,suchasagreaterbiologicalcomplexity.Thismakesthedrugstoproducenative-likeresponses.However,exvivomodels typicallylackperfusionandarenotrepresentativeoftheheterogeneityofthetumor.Incontrast,invivo(animal)modelsarehighlydynamicsystems,buttheyareverycostly,lackthe humanimmunesystem,andareethicallycontroversial.Inaddition,regardlessofthetypeof animalmodel,itisextremelydifficulttoinvestigatecellularandphysiologicalinteractionson thistypeofmodels.Moreadvancedtumormodelsarepatient-derivedxenografts,wherea surgicallyresectedtumorsampleofapatientisengraftedintoanimmunodeficientmice. However,thesemodelsareextremelyexpensiveandtime-consuming,theyareassociated withethicalconcerns,andindividualparameterscannotbeisolated [1]
1.1.2Aparadigmshift Toresolvetheabovementionedissues,aparadigmshifthasoccurredsincethelate 1990sabouthowthecellsarestudied [2,3].Indeed,thereisahugedifferencebetweencells culturedonflatsurfacesand/oronthree-dimensional(3D)environments.Indeed,seminal worksusing3Dinvitromodelshavedemonstratedtheimportantdifferencesinthe phenotypesandactivitiesbetweencellsgrownin2Dsurfacesand3Dcultures.Thelatter recapitulatetheimportantinteractionsbetween—healthyandmalignant—cellsandthe surrounding3Denvironment [4,5].Asaresult,thecancerresearchcommunity,including academicresearchers,pharma/biotechindustries,andclinicians,havestartedtomove towardthethirddimension.Inthisregard,2DassaysintheformoftraditionaltissuecultureflasksorPetridishes,arebeingreplacedbymoresophisticated3Dtissue-engineered cellculturemicroenvironments.Therein,thecellsdisplayseveralsimilaritieswiththe nativescenario,andtherefore,areconsideredasphysiologicallyrelevantenvironments thatbridgethegapbetweenobsoleteflatmaterialsandthenativescenario.Inparticular, theearlyeventsofcancerprogressioncancloselybereproducedin3Dcultureplatforms, wherethecellsdisplayphenotypes,morphodynamics,andgeneexpressionpatternsmuch closertotheinvivophysiologicalmicroenvironment.Inaddition,aspreviouslymentioned,thisisofupmostimportanceduringthedevelopmentofdrugs,wherethecells respondtocompoundsastheydoinvivo.
Finally,thecombinationofcutting-edgenanotechnologieswithadvancesinmaterialsscienceandtissueengineeringtools,havecreatedapowerfultoolboxinthefieldofbiomedical
andhealthsciencescapabletocreateanewgenerationof3Dbiomaterialswithunprecedentedpossibilitiesincancerresearch.Thesebiomaterialsarecapable(1)tocopycatthetremendouscomplexity(physical,biological,structural,biochemical,andrheological)ofthe naturaltumormicroenvironment(TME);(2)toinvestigateinaphysiologicallyrelevantenvironmentthepathogenesisoftumors;and(3)toscreentheefficiencyandpharmacokinetics/ pharmacodynamicsofdrugsinareliablemanner.Alltheseadvancedcapabilitiesmakethis newgenerationof3Dbiomaterialsidealcandidatesfor3Dtumormodeling.
1.1.3Three-dimensionalbiomaterialsforcancermodeling ThepioneeringworkbytheBisselllabinthisfieldchangedcompletelythevisionand paradigmofhowcancercellsneedtobeculturedinvitro [6].Thethirddimensionreproducesthephysiologicalbehaviorofcellsinthehumanbody.Asanexample,theinhibition of β1integrininhumanbreastcancercellsseededina3Dmodelreversedthemalignant phenotypeofcellsresultingintonormalmorphologiesandfunctionalphenotypes;cells losttheirabnormalshapesandpatternsofgrowth.Thisworkshowsclearlythatthecontext(i.e.,environment)wherecellsareculturedinfluencesthephenotypeandresponseof cells,andinparticular,cancerouscells.Similarly,thewayhowtumorsarecultured invitroalsoinfluencesthemigrationcapacityofcellsandtheirmotilitymechanism [7].In thisregard,newmigrationmodes,whicharenotobservedin2D,arerevealedwhen tumorcellsareseededin3D.Inthiscase,thecellsswitchtoanamoeba-likeformofmigration.Thisnewtypeofmigrationmechanismenhancesthecapacityofcancercellsto squeezetophysicalconstrictionsoftheextracellularmatrix(ECM)andinvadethetumor stroma.
Cancerresearchershavefocusedindevelopingbiomimetic3Dplatformswithcontrolled composition,bioactivefunctionalgroups,architecture,mechanicalproperties,anddegradationrates,capabletoreproducethemechanochemicalandhydrodynamicpropertiesofthe TME,overcomingthelimitationsofstandardbiomaterials.Thesebiomaterialsmayalsodisplay“smart”characteristicsandrespondtothepresenceofanexternalstimulus,suchas pHvariationsortemperature,ortoself-assemblefollowingspecificconfigurations [8].
Typicalbiomaterialsfor3Dcancermodelingincludetheuseofnatural-basedhydrogels orscaffoldsthatarerichinproteinsoftheECM,suchascollagen,gelatin,MatrigelTM,or blendsofthem.Thesebiomaterialsdisplayinterestingmechanochemicalproperties,which canbemodulatedtoreproducethoseofthenativescenario.Thisisofupmostimportance becausesolidevidenceshaveshownthatbothmechanicaland(bio)chemicalcuesregulate multiplecellularfunctionsandfateinaprocessknownas mechanotransduction.However, thesebiomaterialsalsodisplaycertaindrawbacks,suchasthebatch-to-batchvariationthat impedesthedirectcomparisonoftheresultsobtainedbydifferentlaboratories.Othertype ofbiomaterialswithmorecontrolledcompositionandmorereproducibleforcancer modelingincludesilkfibroin,gellangumhydrogels/scaffolds,orblendsofthem [9 12]. Finally,moreadvancedbiomaterialsalsoinclude3Dtopographicalsubstrates,3Dbioprintedscaffolds,ormicrofluidicplatforms.
1.1.4Fromthelabtotheclinic Three-dimensionalbiomaterial-basedcancermodelshaveattracttheinterestofpharmaceuticalandbiotechnologicalcompanieswhohaverealizedtheirpotentialindeveloping betterdrugsinacheaperway.PlentyofcompaniesaresellingthesetypesofFederalDrug Agency(FDA)-andEuropeanMedicinesAgency(EMEA)-approved3Dbiomaterialplatformsforcancerresearchapplications.However,anddespitethegenerousfundsthat havebeenprovidedbyseveralnationalfundingagenciestoboosttheirdevelopmentand theirinitialexpectations,mostofthecurrentresearchisstillbasedonflatsurfaces.This mayalsoexplainthedecreaseinthedevelopmentofinnovativeanticancerdrugsandtherapiesduringthelastdecade.Newapproachesandcharacteristicsareindeedneededto promotetheiradoptionbythemarket.Inparticular,theintegrationofmaterialsscience withnanotechnology,tissueengineering,andbiosensortechnologyisexpectedtoboost andsolidifythisemergingfieldofresearch.
Overall,3Dbiomaterialsprovideanimprovedinvitromodelforcancerresearch,which reproduceinabettermanner,whathappensinthelivingtissuesofthehumanbody. Theseadvancedmodelsprovidemultipleadvantageswhencomparedwithflat,laborintensive,andexpensiveanimalmodels.Therefore,theymaybridgethegapbetweenboth typeofmodels,eventhough3Dbiomaterialsandrelatedtechnologiesarenotexpectedto completelyreplaceanimalexperimentation.However,theywilldefinitelycontributeto improve(1)ourknowledgeintumorbiologybyprovidingnewinsightsabouttumorpathogenesis;(2)theefficacyofdrugdevelopmentandtesting,and(3)toreduceanimalexperimentation.Inthischapter,wedescribethecurrenttrendsinthefieldof3Dbiomaterials forcancermodeling,theirmainapplications,limitations,anddiscussabouttheirpresent andfuturechallenges.
1.2Thethree-dimensionaltumormicroenvironment TheTMEisofextremebiochemical,structural(mechanicalandarchitectural),cellular, andrheologicalcomplexity.Asmentionedabove,itisrecognizedasakeyplayerinthe mechanochemicalmechanismoftumorprogressionandmetastasis.Duringthisprocess, thereisasynergisticinteractionbetweenthetumorcellsandthesurrounding3Dstroma thatguidestumorcellinvasion.Thismalignantinteractioncanbereproducedbyengineeringinvitrotumormodelsmadeofbiomimeticandbiodegradable3Dbiomaterials.Inthe following,webrieflydiscussaboutthissynergisticinteraction,aswellashow3DbiomaterialscanbeemployedasamodeltocopycatthecomplexityoftheTME.
1.2.1Thetumoranditsthree-dimensionalenvironment:asynergistic interaction
ThecompositionoftheTMEishighlycomplex [13].Itincludestheprimarytumormass madeofaheterogeneouspopulationofcancercells,stromacells[immunecells—Tlymphocytes,Blymphocytes,NK/NKTcells,tumor-associatedmacrophages(TAMs), myeloid-derivedsuppressorcellsdendriticcells,tumor-associatedneutrophils—,tumor
vasculatureandlymphaticcells,cancer-associatedfibroblasts(CAFs),pericytes,and/or stemcells],theECM,andadiversevarietyofsecretedfactors.Anexcellentsummaryof thefunctionofthesecellsintheTMEisprovidedinRef. [13].Thereisastronginterplay betweenthetumorandstromalcells,whichhaveadynamicandtumor-promotingfunctionduringallstagesoftumorigenesis.Indeed,thecontributionoftheTMEintumor progressioniswidelyrecognized [14 16].Thisisexemplifiedduringtheinitialstepsof tumorprogression,whencellsescapefromtheprimarytumorandmigratealongtheECM fibers(mainlymadeofcollagenandelastin)thathavebeenreorganizedandcross-linked intoparallelbundlesbyCAFs.Thesecellseventuallyintravasateintotheblood/lymphatic vessels,whichdisplayanenhancedpermeability.Afterintravasation,cancercellscirculate alongthevasculature.Thesecellsarecoinedas circulatingtumorcells (CTCs),whicheventuallyextravasateandinvadeatadistanttissueororgan.Finally,thesecellsproliferate andestablishasecondarytumorsite.
Asdescribedabove,theECMoftheTMEhasacriticalroleintumorprogression [17 19].Itnotonlyprovidesaphysicalenvironmentforthecellstoadherebutalsoisfundamentalforthedirectedmigrationofcancercells.Italsocontainskeycompoundsthat interactwithcellsandprovidesthetissuewithitsstiffness.TheTMEalsocontainsother typesofbiochemical,structural,andrheologicalcuesthatcontributetocarcinogenesis. Biochemicalcuesincludeadiversevarietyofcytokines,chemokines,growthfactors,and inflammatory/matrixremodelingenzymes.Thepresenceofmatrixmetalloproteases (MMPs)isofparticularinterest.Theyhavethefunctionofdegradingandremodelingthe ECM,andaresecretedbycancercells,TAMs,andCAFs.Becauseofthisdegradation,chemokines,growthfactors,andangiogenicfactors[e.g.,vascularendothelialgrowthfactor (VEGF)]arereleasedintotheTME.StructuralcuesincludetherigidityoftheECMaswell asitsarchitecture.Thetumoristypicallystifferthanthesurroundinghealthytissueasa consequenceofanincreasedECMdepositionbyCAFs,eventhoughcancercellsaresofter thantheirhealthycounterparts [20].Finally,rheologicalcuesincludethehydrodynamic propertiesoftheTME,suchasanenhancedinterstitialfluidflow,whichplaysafundamentalroleintriggeringtheinvasionofcellsintothevasculature.Overall,allthesecues synergizewiththecellsandregulatealltheeventsoccurringinthecascadeoftumor growthandmetastasis.
Finally,itisworthnotingthattheimportanceoftheTMEintumordisseminationisso highthattherapiestargetingthetumorECMhavebecomeverypopulartoimprovethe responseofthetumortochemotherapyandtheaccessofdrugs [21].Indeed,recentevidenceshaveshownthattheTMEcanmodulatethetherapeuticresponsesandresistance totherapies [22].ThisconfirmstheimportanceofmodelingtheTMEforthedesignof moreefficientanticancerdrugs.
1.2.2Biomaterialsasamodelofthetumorniche DespitetheacceptedimportanceoftheTMEinthegrowthandprogressionofatumor, itsexactroleisnotwellunderstoodyet.ThisismainlyaconsequenceofthehighcomplexityoftheTMEanditsconstituents,whichmakesdifficulttoidentifythemechanisticdeterminantsofdiseaseprogression.Forthisreason,largeeffortshavebeeninvestedin
FIGURE1.1 Schematicsofthedifferenttypeofmodelstypicallyemployedincancerresearchandother biomedical-relatedapplications.
modelingwithprecisionthehighcellular,biochemical,andstructuralheterogeneityofthe tumorniche.Standardtumormodelsbasedonflatsurfacescoatedwithpurifiedproteins oftheECMcannotreproducethishighheterogeneity,andinparticular,the3Darchitectureofthetumorniche(see Fig.1.1).Thisresultsinalimitedinformationabouttumoretiology,diseasemechanism,anddrugefficiency.Incontrast,engineered3Dbiomaterials canreproducebettertheintrinsicpropertiesofthenativeTME.Forthis,theintegrationof innovativeTEstrategies,nanotechnologytools,biosensingtechnologies,andmaterial sciences,haspermittedthedesignanddevelopmentofbiomimetic3Dbiomaterialsfor cancerresearchwithunprecedentedproperties.These3Dbiomaterialscanbeengineered toprovideprecisecontrolonthe(1)composition,(2)mechanicalproperties,(3)selfassemblingproperties,and(4)degradabilityofthebiomaterialthatcouldnotbeachieved withstandard2Dcultures.
Duringthelastdecade,3Dinvitrocancermodelshavewidelybeenemployedtounderstandbetterthetumorbiologyanddrugefficiency.Indeed,thereisalargebodyofliteraturedescribing3D-basedbiomaterialsasmodelsofthetumornichefordifferent applications.Typically,3Dbiomaterialsfortumormodelingcanbeclassifiedinto(1) scaffold-based or(2) scaffold-free.Theformersincludestiffbiomaterialsactingassupporting structuresandhydrogels,whereasthelatterincludemulticellulartumorspheroids [23] or organoids [24].Otherexisting3D-basedmethodstypicallyemployedincancerresearch includematrix-basedmodels,microcarriers,ortopographicallystructuredsurfaces [25] (see Fig.1.1).Allthesemethodshaveincommonthattheyprovidetocancerandstromal cellsabiomimetic3Dmulticellularmicroenvironmentimitatingthenativescenario. Overall,thesesystemsmaybridgethegapbetweentheconventional2Dinvitroandanimaltestingmodels [26]
1.2.2.1Scaffold-basedbiomaterials Invivo,tumorcellsaresupportedbyacomplex3DECM,whichinfluencestheir responsetoexternalstimuli.Thisnativephysicalmicroenvironmentcanbemimicked usingscaffold-basedbiomaterials,whichprovide3Darchitecturalsupporttotumorcells [10].Inthiscondition,tumorcellsdisplayphenotypesreminiscentofinvivocondition,
andtherefore,theseareidealplatformsfordrugdiscovery,screening,andtestingapplications [11,27 29].Asanexample,MCF7breastcancercellsseededinto3Dchitosanscaffoldsandexposedto tamoxifen,anantiestrogendrugtypicallyemployedinthetreatment ofthistypeoftumor [30],producedlactatelevelssimilartothoseobservedinvivo. Interestingly,theIC50 was10-foldhigherforthe3Dmodelthanthatoftheflatsurface.
Scaffold-basedbiomaterialsarealsoemployedasmodelstoinvestigatetheinteraction betweentumorcellsandothercelltypes(malignantandhealthy),suchasimmunecells, endothelialcells,stemcells,andothers [12].Typically,thematerialusedforthefabrication ofsuchscaffold-based3Dmodelsismadeofasinglecomponentorablendofdifferent materials [9].Indeed,theselectionofthismaterialiscrucialtocopycatthemechanochemicalpropertiesofthenativeECM.Aspecifictypeofscaffoldare hydrogels,whicharecrosslinkednetworksofpolymericchainscontaininghighamountofwater;thisfacilitatesthe exchangeofnutrientsandcellularmetabolites.Hydrogelshaveexcellentmechanicalproperties,whichcanbemodulatedtypicallybychangingpolymerconcentrationsorcrosslinkerdensitiestomatchthoseofthetargettissuesorECMs [31].Typically,themechanical propertiesofhydrogelsare,ingeneral,static;thatis,theydonotevolveovertime.Others displayreversiblepropertiesbyincorporatingreversiblechemistries,whichallowthemto reproducethedynamicpropertiesofthenativeECM [32].Oneexampleofsuchadynamic behavioristumorformation,wherethereisacontinuousstiffeningoftheECM [33] Importantly,specificbioactivemoietiescanbeincorporatedwithinthehydrogel,suchas adhesivesites,toinfluencethebehavioroftheencapsulated(cancer)cellsormatrixmetalloproteinases(MMPs).ThelattermakethebiomaterialsusceptibletodegradationbycellsecretedproteasesmimickingthenaturallyoccurringremodelingoftheECMbycancer cells.
Scaffold-basedmaterialscanbeclassifiedas natural,synthetic,orhybrid:
• Natural-derived:Thistypeofbiomaterialsdisplaybetterbiocompatibility, biodegradability,andbioavailability.Theyalsohaveahighersimilaritytothenative ECM,andtherefore,cellsinteractbetterwiththistypeofbiomaterials.Inaddition,the mechanicalandphysicochemicalpropertiesofnatural-derivedhydrogelscanbe modulated,andtheirmorphologyadapted.TypicalexamplesincludenaturalECMderivedproteins,suchascollagen,laminin,hyaluronicacid(HA),fibrinogen,or reconstitutedbasementmembrane,suchasMatrigel TM (Table1.1).However,these biomaterialspresentcertainlimitations,suchasbatch-to-batchvariability,complex molecularcomposition,oruncontrolleddegradation.Inaddition,theyshowalimited abilitytoaltertheirstiffnessandthedensityofcelladhesionpeptides.Thismakes challengingtocontroltheinfluenceofspecificparametersoftheECMoncancercells. Othertypeofnatural-derivedbiomaterialsincludeothertypesofproteins,suchassilk fibroin [29],andpolysaccharides,suchaschitosan,gellangum,oralginate(Table1.1). Thesebiomaterialshaveabroaderrangeofchemicalandmechanicalproperties. However,theylackcelladhesionsitesandoftenrequirechemicalmodificationfor cross-linking.
• Synthetic-derived:Thistypeofmaterialstypicallydisplaybettermechanicalproperties comparedtonaturalones.Theyare,ingeneral,easiertosynthesizethantheirnatural counterpartsandprovidebetterexperimentalcontroloverbiochemicalandmechanical
TABLE1.1 Examplesofnaturalandsyntheticoriginbiomaterialsusedincancerresearch.
MaterialCharacteristicsandapplications
Naturalorigin
MatrigelTM
Derivedfrommousetumor;containsangiogenicandtumorpromotingfactors; cytocompatibility;celladhesionsites;tunablephysicalproperties;possiblepresenceof undefinedsubstances.
CollagenIMostprominentECMproteinoftheTME;multiplecross-linkingmethods;biocompatibility; biodegradability;angiogenesispotential.
FibrinogenBloodclotting;cellularandmatrixinteractions;neoplasia;architecturemimicsnativeECM;3D microenvironmentforcancergrowth.
HAGlycosaminoglycanfoundinextracellulartissueinmanypartsofbody;majorcomponentof nativebrainECM;usedforstudyingtumormigrationprocesses.
ChitosanAnalysisofinteractionofprostatecancertumorcellswithimmunecells;formationoftumor spheroids.
AlginatePropertiesforcelltransplantation,drugdelivery,andTE;suitableforhydrogelmicrospheres; promotesconversionofculturedcancercellstoamoremalignantinvivo-likephenotype; nonadhesivetocells.
Cell-derivedmatrices (CDMs) Distinctlydifferentcellmorphology,aggregationpattern,proliferationprofile,andinvasive potential;however,thesematricesdonotfullyrepresentthecompositionandstructureofthe TME.
SilkfibroinUniquemechanicalproperties;goodbiocompatibility;well-controlleddegradability;versatile processability.
AgaroseAmenablemechanicalandbiologicalproperties;morestablethantraditionalnaturalhydrogels.
Syntheticorigin
PolyethyleneglycolBiocompatibility;high-watercontent;multitunableproperties;specificbiologicalfunctionalities canbecovalentlyincorporated.
Poly(lactic -co-glycolic) acid Highlyporousscaffolds;convenienttohandle;amenabletolarge-scaleuse.
Poly ε-caprolactoneBiologicallyinertsyntheticpolymer;highporosity;largesurfacearea:volumeratioforcellular attachment;tunablefiberdiameter;lowcost.
SyntheticpeptidesControlledaminoacidcompositionforeasyincorporationofspecificbiologicalrelevant ligands.
AdaptedfromCarvalhoMR,etal.Evaluatingbiomaterial-andmicrofluidic-based3Dtumormodels.TrendsBiotechnol2015;33(11):667 78 [1] withpermissionofElsevier.
propertiesoftheTME.Theyalsodisplaylowbatch-to-batchvariabilityandaremore reproducible.Examplesofsynthetichydrogelsusedforbiomedicalapplicationsinclude poly(acrylamide),poly(ethyleneglycol)(PEG),poly(vinylalcohol),poly(methacrylic acid),orpoly(acrylicacid),andtheirderivatives(Table1.1).However,synthetic-derived biomaterialslacknaturalcelladhesionsitesand,ingeneral,arenotremodeledbycells. However,theycaneasilybefunctionalizedwithwell-controlleddensityofcelladhesion ligands,likeRGDorMMP-sensitivepeptides.
• Hybrid(bio)materials:Thistypeofmaterialincludesthecombinationoftwoormore biomaterialsfromnaturaland/orsyntheticorigin.Therefore,theresultingbiomaterial individuallyorsynergisticallydisplaysalltheadvantagesoftheconstituentpartsor provideanaddedvalue,suchasthepresenceofspecificmoieties.Insomecases,oneof thematerialsisusedasasacrificialtemplatetoengineermicrostructures,suchas channels,forcellstoadhereorforflowingafluid.HybridbiomaterialsincludePEGconjugatedproteins,biofunctionalizedalginate,orothertypeofblends,suchasgellan gumandsilkfibroin [9],whichhasrecentlyshownitsperformancetomodel osteosarcoma.Overall,hybridbiomaterialsprovidecombinatorialadvantagesofboth naturalandsyntheticmaterialsforthedevelopmentof3Dbioengineeredscaffoldsfor cancerresearchapplications.
Altogether,scaffold-basedbiomaterialscanbeengineeredmechanically,chemically, andstructurallytomodulatethemorphodynamicsofcellsaswellastomimicthe3D architectureofthenativeTME.
1.2.2.2Matrix-based
Matrix-basedbiomaterialstrytoreproducethefibrillarstructureandcompositionofthe nativeECMnetwork.Thiscategoryof3Dbiomaterialcanagainbeofnatural-orsynthetic originandincludeadiversesubsetoffabricationmethods.Themainmethodsthoughare basedon(1)cell-derivedmatrices(CDMs),(2)decellularizedtissues,and(3)electrospun meshwork.
• CDMs:ThesearenaturalECMsthataredepositedbycells,typicallyfibroblasts,on tissueculturedishes,whichcloselymimictherandomstromalfiberorganizationand molecularcontentofthenativeECMs [34].CDMsprovidearichmolecularcontent, whichissimilartotheinvivoscenario,withthicknessesthatareintheorderof 10 20 μm.Thesecuesstimulatesignalingpathwaysthatregulateadhesion,survival, proliferation,polarity,andcellmigration.Aderivationofthisapproachistheuseofa guidingtemplatetoguidethegrowthof3Dmatriceswithspecificmorphologies.Thisis ofspecialrelevancewhentryingtomimictheTME,wherethecollagenfibersare alignedintoparallelbundles.Thisapproachwasrecentlyfollowedbycombiningthe confluentcultureofNIH3T3fibroblastswithmicrofabricatedguidingtemplatesto directthe3Dgrowthofwell-definedextracellularnetworks [35].TheresultingECM modelrecapitulatedthestructuralandbiomolecularcomplexityoffeaturestypically foundinvivo.Overall,CDMscanbeemployedasa3Dmodeltoreproducethe architectureandmechanochemicalpropertiesoftheTME.Importantly,bymanipulating thecultureconditions(e.g.,culturemediacompositionandadditives,morphologyof theculturesubstrates,celltypes,cultureperiods,passagenumber,andothers),a significantcontroloverCDMcompositionandmicrostructurecanbeachieved.Forthis, CAFscanbeusedtoobtainaCDMwithtumor-likeproperties.
• Tissue/organ-deriveddecellularizedmatrices:Decellularizedtissuesandorgansare extensivelyusedintissueengineeringandregenerativemedicineapplications.This methodisbasedontheremovalofthecellularcontentofatissueororganresulting withonlythematrixcomponent.Thiscontainsasimilarcompositionand3D architectureofthenativeECM.Forthis,differentdecellularizationprotocolshavebeen
