There are a growing number of globally approved products and clinical trials utilizing autologous and allogeneic therapeutic cells for applications in regenerative medicine and immunotherapies. However, there is a need to develop rapid and cost-effective methods for manufacturing therapeutically effective cells. Furthermore, the resulting manufactured cells may exhibit heterogeneities that result in mixed therapeutic outcomes. Engineering approaches that can provide distinct microenvironmental cues to these cells may be able to enhance the growth and characterization of these cell products. This mini-review describes strategies to potentially enhance the expansion of therapeutic cells with biomaterials and bioreactors, as well as to characterize the cell products with microphysiological systems. These systems can provide distinct cues to maintain the quality attributes of the cells and evaluate their function in physiologically relevant conditions.
RohK-HNeremRMRoyK.Biomanufacturing of therapeutic cells: state of the art, current challenges, and future perspectives. Annu Rev Chem Biomol Eng2016;
7:455–78
6.
GolchinAFarahanyTZ.Biological products: cellular therapy and FDA approved products. Stem Cell Rev Rep2019;
15:166–75
7.
FiorenzaSRitchieDSRamseySDTurtleCJRothJA.Value and affordability of CAR T-cell therapy in the United States. Bone Marrow Transplant2020;
55:1706–15
8.
PhinneyDG.Functional heterogeneity of mesenchymal stem cells: implications for cell therapy. J Cell Biochem2012;
113:2806–12
9.
HoAWagnerWFrankeW.Heterogeneity of mesenchymal stromal cell preparations. Cytotherapy2008;
10:320–30
ZhaoLCaoYJ.Engineered T cell therapy for cancer in the clinic. Front Immunol2019;
10:2250
12.
XieGDongHLiangYHamJDRizwanRChenJ.CAR-NK cells: a promising cellular immunotherapy for cancer. EBioMedicine2020;
59:102975
13.
SuenWC-WLeeWY-WLeungK-TPanX-HLiG.Natural killer cell-based cancer immunotherapy: a review on 10 years completed clinical trials. Cancer Invest2018;
36:431–57
14.
ConstantinoJGomesCFalcãoANevesBMCruzMT.Dendritic cell-based immunotherapy: a basic review and recent advances. Immunol Res2017;
65:798–810
15.
LesterhuisWJde VriesIJMSchreibeltGLambeckAJAarntzenEHJacobsJFScharenborgNMvan de RaktMWde BoerAJCroockewitS.Route of administration modulates the induction of dendritic cell vaccine-induced antigen-specific T cells in advanced melanoma patients. Clin Cancer Res2011;
17:5725–35
16.
ChabannonCKuballJBondanzaADazziFPedrazzoliPToubertARuggeriAFleischhauerKBoniniC.Hematopoietic stem cell transplantation in its 60s: a platform for cellular therapies. Sci Transl Med2018;
10: eaap9630
17.
DominiciMLe BlancKMuellerISlaper-CortenbachIMariniFKrauseDDeansRKeatingAProckopDHorwitzE.Minimal criteria for defining multipotent mesenchymal stromal cells. The international society for cellular therapy position statement. Cytotherapy2006;
8:315–7
18.
SquillaroTPelusoGGalderisiU.Clinical trials with mesenchymal stem cells: an update. Cell Transplant2016;
25:829–48
19.
LambertLHGoebrechtGKDe LeoSEO’ConnorRSNunez-CruzSLiT-DYuanJMiloneMCKamLC.Improving T cell expansion with a soft touch. Nano Lett2017;
17:821–6
20.
HickeyJWDongYChungJWSalatheSFPruittHCLiXChangCFraserAKBessellCAEwaldAJ.Engineering an artificial T‐cell stimulating matrix for immunotherapy. Adv Mater2019;
31:1807359
21.
DelalatBHardingFGundsambuuBDe-Juan-PardoEMWunnerFMWilleM-LJasieniakMMalatestaKAGriesserHJSimulaA.3D printed lattices as an activation and expansion platform for T cell therapy. Biomaterials2017;
140:58–68
22.
CheungASZhangDKKoshySTMooneyDJ.Scaffolds that mimic antigen-presenting cells enable ex vivo expansion of primary T cells. Nat Biotechnol2018;
36:160
23.
ZhangDKCheungASMooneyDJ.Activation and expansion of human T cells using artificial antigen-presenting cell scaffolds. Nat Protoc2020;
15:773–98
24.
CostariolERotondiMCAminiAHewittCJNienowAWHeathmanTRRafiqQA.Demonstrating the manufacture of human CAR‐T cells in an automated stirred‐tank bioreactor. Biotechnol J2020;
15:2000177
25.
CastellaMCaballero-BañosMOrtiz-MaldonadoVGonzález-NavarroEASuñéGAntoñana-VidósolaABoronatAMarzalBMillánLMartín-AntonioB.Point-Of-Care CAR T-cell production (ARI-0001) using a closed semi-automatic bioreactor: experience from an academic phase I clinical trial. Front Immunol2020;
11:482
26.
DaiXMeiYCaiDHanW.Standardizing CAR-T therapy: getting it scaled up. Biotechnol Adv2019;
37:239–45
27.
SutluTStellanBGilljamMQuezadaHCNahiHGahrtonGAliciE.Clinical-grade, large-scale, feeder-free expansion of highly active human natural killer cells for adoptive immunotherapy using an automated bioreactor. Cytotherapy2010;
12:1044–55
28.
MengYSunJHuTMaYDuTKongCZhangGYuTPiaoH.Rapid expansion in the WAVE bioreactor of clinical scale cells for tumor immunotherapy. Hum Vaccin Immunother2018;
14:2516–26
29.
AhnYHRenLKimSMSeoS-HJungC-RNohJ-YLeeSYLeeHChoMYJungH.A three-dimensional hyaluronic acid-based niche enhances the therapeutic efficacy of human natural killer cell-based cancer immunotherapy. Biomaterials2020;
247:119960
30.
EyrichMSchreiberSCRachorJKraussJPauwelsFHainJWölflMLutzMBde VleeschouwerSSchlegelPG.Development and validation of a fully GMP-compliant production process of autologous, tumor-lysate-pulsed dendritic cells. Cytotherapy2014;
16:946–64
31.
NavaSDossenaMPoglianiSPellegattaSAntozziCBaggiFGelleraCPolloBParatiEAFinocchiaroG.An optimized method for manufacturing a clinical scale dendritic cell-based vaccine for the treatment of glioblastoma. PLoS One2012;
7:e52301
32.
FeketeNBélandAVCampbellKClarkSLHoesliCA.Bags versus flasks: a comparison of cell culture systems for the production of dendritic cell-based immunotherapies. Transfusion2018;
58:1800–13
33.
UsluUErdmannMWiesingerMSchulerGSchuler-ThurnerB.Automated good manufacturing practice–compliant generation of human monocyte-derived dendritic cells from a complete apheresis product using a hollow-fiber bioreactor system overcomes a major hurdle in the manufacture of dendritic cells for cancer vaccines. Cytotherapy2019;
21:1166–78
34.
BallenKKGluckmanEBroxmeyerHE.Umbilical cord blood transplantation: the first 25 years and beyond. Blood2013;
122:491–8
35.
BaiTLiJSinclairAImrenSMerriamFSunFO’KellyMBNourigatCJainPDelrowJJ.Expansion of primitive human hematopoietic stem cells by culture in a zwitterionic hydrogel. Nat Med2019;
25:1566–75
36.
FerreiraMSVJahnen-DechentWLabudeNBoviMHieronymusTZenkeMSchneiderRKNeursS.Cord blood-hematopoietic stem cell expansion in 3D fibrin scaffolds with stromal support. Biomaterials2012;
33:6987–97
37.
MousaviSHAbrounSSoleimaniMMowlaSJ.3-Dimensional nano-fibre scaffold for ex vivo expansion of cord blood haematopoietic stem cells. Artif Cells Nanomed Biotechnol2018;
46:740–8
38.
GvaramiaDMüllerEMüllerKAtallahPTsurkanMFreudenbergUBornhäuserMWernerC.Combined influence of biophysical and biochemical cues on maintenance and proliferation of hematopoietic stem cells. Biomaterials2017;
138:108–17
39.
CsaszarEKirouacDCYuMWangWQiaoWCookeMPBoitanoAEItoCZandstraPW.Rapid expansion of human hematopoietic stem cells by automated control of inhibitory feedback signaling. Cell Stem Cell2012;
10:218–29
40.
RaicARödlingLKalbacherHLee-ThedieckC.Biomimetic macroporous PEG hydrogels as 3D scaffolds for the multiplication of human hematopoietic stem and progenitor cells. Biomaterials2014;
35:929–40
41.
XueCKwekKYChanJKChenQLimM.The hollow fiber bioreactor as a stroma‐supported, serum‐free ex vivo expansion platform for human umbilical cord blood cells. Biotechnol J2014;
9:980–9
42.
KlinkerMWMarkleinRASurdoJLLWeiC-HBauerSR.Morphological features of IFN-γ–stimulated mesenchymal stromal cells predict overall immunosuppressive capacity. Proc Natl Acad Sci U S A2017;
114:E2598–E607
43.
MarkleinRALo SurdoJLBellayrIHGodilSAPuriRKBauerSR.High content imaging of early morphological signatures predicts long term mineralization capacity of human mesenchymal stem cells upon osteogenic induction. Stem Cells2016;
34:935–47
44.
LamJBellayrIHMarkleinRABauerSRPuriRKSungKE.Functional profiling of chondrogenically induced multipotent stromal cell aggregates reveals transcriptomic and emergent morphological phenotypes predictive of differentiation capacity. Stem Cells Transl Med2018;
7:664–75
45.
LamAT-LLiJTohJP-WSimEJ-HChenAK-LChanJK-YChoolaniMReuvenySBirchWROhSK-W.Biodegradable poly-ε-caprolactone microcarriers for efficient production of human mesenchymal stromal cells and secreted cytokines in batch and fed-batch bioreactors. Cytotherapy2017;
19:419–32
46.
YuanYKallosMSHunterCSenA.Improved expansion of human bone marrow‐derived mesenchymal stem cells in microcarrier‐based suspension culture. J Tissue Eng Regen Med2014;
8:210–25
47.
da SilvaJSSeverinoPWodewotzkyTICovasDTSwiechKMartiLCSuazoCAT.Mesenchymal stromal cells maintain the major quality attributes when expanded in different bioreactor systems. Biochem Eng J2020;
161:107693
48.
de Sousa PintoDBandeirasCde Almeida FuzetaMRodriguesCAJungSHashimuraYTsengRJMilliganWLeeBFerreiraFC.Scalable manufacturing of human mesenchymal stromal cells in the vertical‐wheel bioreactor system: an experimental and economic approach. Biotechnol J2019;
14:1800716
49.
MizukamiAChilimaTDPOrellanaMDNetoMACovasDTFaridSSSwiechK.Technologies for large-scale umbilical cord-derived MSC expansion: experimental performance and cost of goods analysis. Biochem Eng J2018;
135:36–48
50.
RaoVVVuMKMaHKillaarsARAnsethKS.Rescuing mesenchymal stem cell regenerative properties on hydrogel substrates post serial expansion. Bioeng Transl Med2019;
4:51–60
51.
LiCXTaleleNPBooSKoehlerAKnee-WaldenEBalestriniJLSpeightPKapusAHinzB.MicroRNA-21 preserves the fibrotic mechanical memory of mesenchymal stem cells. Nat Mater2017;
16:379–89
52.
WongSWLenziniSCooperMHMooneyDJShinJ-W.Soft extracellular matrix enhances inflammatory activation of mesenchymal stromal cells to induce monocyte production and trafficking. Sci Adv2020;
6:eaaw0158
53.
NewickKO'BrienSMoonEAlbeldaSM.CAR T cell therapy for solid tumors. Annu Rev Med2017;
68:139–52
54.
SzöőrÁTóthGZsebikBSzabóVEshharZAbkenHVerebG.Trastuzumab derived HER2-specific CARs for the treatment of trastuzumab-resistant breast cancer: CAR T cells penetrate and eradicate tumors that are not accessible to antibodies. Cancer Lett2020;
484:1–8
55.
DillardPKöksalHInderbergE-MWälchliS.A spheroid killing assay by CAR T cells. J Vis Exp2018;
10:58785
56.
PavesiATanATKohSChiaAColomboMAntonecchiaEMiccolisCCeccarelloEAdrianiGRaimondiMT.A 3D microfluidic model for preclinical evaluation of TCR-engineered T cells against solid tumors. JCI Insight2017;
2:e89762
57.
WallstabeLGöttlichCNelkeLCKühnemundtJSchwarzTNerreterTEinseleHWallesHDandekarGNietzerSL.ROR1-CAR T cells are effective against lung and breast cancer in advanced microphysiologic 3D tumor models. JCI Insight2019;
4: e126345
58.
TemplesMNAdjeiIMNimocksPMDjeuJSharmaB.Engineered three-dimensional tumor models to study natural killer cell suppression. ACS Biomater Sci Eng2020;
6:4179–99
59.
AyusoJMRehmanSVirumbrales-MunozMMcMinnPHGeigerPFitzgeraldCHeasterTSkalaMCBeebeDJ.Microfluidic Tumor-on-a-chip model to evaluate the role of tumor environmental stress on NK cell exhaustion. Sci Adv2021;
7:eabc2331
60.
HaesslerUPisanoMWuMSwartzMA.Dendritic cell chemotaxis in 3D under defined chemokine gradients reveals differential response to ligands CCL21 and CCL19. Proc Natl Acad Sci U S A2011;
108:5614–9
61.
ChouDBFrismantasVMiltonYDavidRPop-DamkovPFergusonDMacDonaldABölükbaşıÖVJoyceCETeixeiraLSM.On-chip recapitulation of clinical bone marrow toxicities and patient-specific pathophysiology. Nat Biomed Eng2020;
4:394–406
62.
ZhengYChenJCravenMChoiNWTotoricaSDiaz-SantanaAKermaniPHempsteadBFischbach-TeschlCLópezJA.In vitro microvessels for the study of angiogenesis and thrombosis.Proc Natl Acad Sci U S A2012;
109:9342–47
63.
ZhangMWangPLuoRWangYLiZGuoYYaoYLiMTaoTChenW.Biomimetic human disease model of SARS‐CoV‐2‐induced lung injury and immune responses on organ chip system. Adv Sci2021;
8:2002928
64.
HaaseKOffedduGSGillrieMRKammRD.Endothelial regulation of drug transport in a 3D vascularized tumor model. Adv Funct Mater2020;
30:2002444
65.
NashimotoYOkadaRHanadaSArimaYNishiyamaKMiuraTYokokawaR.Vascularized cancer on a chip: the effect of perfusion on growth and drug delivery of tumor spheroid. Biomaterials2020;
229:119547
66.
BiYShirureVSLiuRCunninghamCDingLMeachamJMGoedegebuureSPGeorgeSCFieldsRC.Tumor-on-a-chip platform to interrogate the role of macrophages in tumor progression. Integr Biol2020;
12:221–32
67.
TruongDDKratzAParkJGBarrientosESSainiHNguyenTPockajBMouneimneGLaBaerJNikkhahM.A human organotypic microfluidic tumor model permits investigation of the interplay between patient-derived fibroblasts and breast cancer cells. Cancer Res2019;
79:3139–51
68.
SungKEYangNPehlkeCKeelyPJEliceiriKWFriedlABeebeDJ.Transition to invasion in breast cancer: a microfluidic in vitro model enables examination of spatial and temporal effects. Integr Biol2011;
3:439–50
69.
CougouleCLastrucciCGuietRMascarauRMeunierELugo-VillarinoGNeyrollesOPoinclouxR,
Maridonneau-Parini I. Podosomes, but not the maturation status, determine the protease-dependent 3D migration in human dendritic cells. Front Immunol2018;
9:846
70.
GunzerMSchäferABorgmannSGrabbeSZänkerKSBröckerE-BKämpgenEFriedlP.Antigen presentation in extracellular matrix: interactions of T cells with dendritic cells are dynamic, short lived, and sequential. Immunity2000;
13:323–32
71.
TomeiAASiegertSBritschgiMRLutherSASwartzMA.Fluid flow regulates stromal cell organization and CCL21 expression in a tissue-engineered lymph node microenvironment. J Immunol2009;
183:4273–83
ZhengYWatanabeNNagamura-InoueTIguraKNagayamaHTojoATanosakiRTakaueYOkamotoSTakahashiTA.Ex vivo manipulation of umbilical cord blood-derived hematopoietic stem/progenitor cells with recombinant human stem cell factor can up-regulate levels of homing-essential molecules to increase their transmigratory potential. Exp Hematol2003;
31:1237–46
KothaSSHayesBJPhongKTReddMABomsztykKRamakrishnanATorok-StorbBZhengY.Engineering a multicellular vascular niche to model hematopoietic cell trafficking. Stem Cell Res Ther2018;
9:1–14
76.
NelsonMRGhoshalDMejíasJCRubioDFKeithERoyK.A multi-niche microvascularized human bone marrow (hBM) on-a-chip elucidates key roles of the endosteal niche in hBM physiology. Biomaterials2021;
270:120683
77.
MohanrajBHuangAHYeger‐McKeeverMJSchmidtMJDodgeGRMauckRL.Chondrocyte and mesenchymal stem cell derived engineered cartilage exhibits differential sensitivity to pro‐inflammatory cytokines. J Orthop Res2018;
36:2901–10
78.
OcchettaPMainardiAVottaEVallmajo-MartinQEhrbarMMartinIBarberoARasponiM.Hyperphysiological compression of articular cartilage induces an osteoarthritic phenotype in a cartilage-on-a-chip model. Nat Biomed Eng2019;
3:545–57
79.
NguyenD-HTStapletonSCYangMTChaSSChoiCKGaliePAChenCS.Biomimetic model to reconstitute angiogenic sprouting morphogenesis in vitro. Proc Natl Acad Sci U S A2013;
110:6712–7
80.
BischelLLYoungEWMaderBRBeebeDJ.Tubeless microfluidic angiogenesis assay with three-dimensional endothelial-lined microvessels. Biomaterials2013;
34:1471–7
81.
KimSLeeHChungMJeonNL.Engineering of functional, perfusable 3D microvascular networks on a chip. Lab Chip2013;
13:1489–500
82.
TrkovSEngGDi LiddoRParnigottoPPVunjak‐NovakovicG.Micropatterned three‐dimensional hydrogel system to study human endothelial–mesenchymal stem cell interactions. J Tissue Eng Regen Med2010;
4:205–15
83.
ZhaoYRafatianNFericNTCoxBJAschar-SobbiRWangEYAggarwalPZhangBConantGRonaldson-BouchardK.A platform for generation of chamber-specific cardiac tissues and disease modeling. Cell2019;
176:913–27.e18
84.
Ronaldson-BouchardKMaSPYeagerKChenTSongLSirabellaDMorikawaKTelesDYazawaMVunjak-NovakovicG.Advanced maturation of human cardiac tissue grown from pluripotent stem cells. Nature2018;
556:239–43
85.
OsakiTUzelSGKammRD.Microphysiological 3D model of amyotrophic lateral sclerosis (ALS) from human iPS-derived muscle cells and optogenetic motor neurons. Sci Adv2018;
4:eaat5847
86.
ParkJWetzelIMarriottIDréauDD’AvanzoCKimDYTanziREChoH.A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer’s disease. Nat Neurosci2018;
21:941–51
87.
ShinYChoiSHKimEBylykbashiEKimJAChungSKimDYKammRDTanziRE.Blood–brain barrier dysfunction in a 3D in vitro model of Alzheimer's disease. Adv Sci2019;
6:1900962
88.
BenamKHVillenaveRLucchesiCVaroneAHubeauCLeeH-HAlvesSESalmonMFerranteTCWeaverJC.Small airway-on-a-chip enables analysis of human lung inflammation and drug responses in vitro. Nat Methods2016;
13:151–7
89.
SiLBaiHRodasMCaoWOhCYJiangANuraniAZhuDYGoyalGGilpinSE.Human organs-on-chips as tools for repurposing approved drugs as potential influenza and COVID19 therapeutics in viral pandemics. bioRxiv2020. https://doi.org/10.1101/2020.04.13.039917
90.
HanYDuanXYangLNilsson-PayantBEWangPDuanFTangXYaronTMZhangTUhlS.Identification of SARS-CoV-2 inhibitors using lung and colonic organoids. Nature2021;
589:270–5
91.
YangLHanYNilsson-PayantBEGuptaVWangPDuanXTangXZhuJZhaoZJaffréF.A human pluripotent stem cell-based platform to study SARS-CoV-2 tropism and model virus infection in human cells and organoids. Cell Stem Cell2020;
27:125–36. e7
