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Layer-by-Layer Cellulose Nanofibrils: A New Coating Strategy for Development and Characterization of Tumor Spheroids as a Model for In Vitro Anticancer Drug Screening
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Nano Biotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0003-1558-1154
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Fibre- and Polymer Technology, Fibre Technology.ORCID iD: 0000-0002-6544-9955
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Nano Biotechnology.ORCID iD: 0000-0003-0956-2002
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
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2022 (English)In: Macromolecular Bioscience, ISSN 1616-5187, E-ISSN 1616-5195, Vol. 22, no 10, article id 2200137Article in journal (Refereed) Published
Abstract [en]

Three-dimensional multicellular spheroids (MCSs) are complex structure of cellular aggregates and cell-to-matrix interaction that emulates the in-vivo microenvironment. This research field has grown to develop and improve spheroid generation techniques. Here, we present a new platform for spheroid generation using Layer-by-Layer (LbL) technology. Layer-by-Layer (LbL) containing cellulose nanofibrils (CNF) assemble on a standard 96 well plate. Various bi-layer numbers, multiple cell seeding concentration, and two tumor cell lines (HEK 293 T, HCT 116) are utilized to generate and characterize spheroids. The number and proliferation of generated spheroids, the viability, and the response to the anti-cancer drug are examined. The spheroids are formed and proliferated on the LbL-CNF coated wells with no significant difference in connection to the number of LbL-CNF bi-layers; however, the number of formed spheroids correlates positively with the cell seeding concentration (122 ± 17) and (42 ± 8) for HCT 116 and HEK 293T respectively at 700 cells ml−1. The spheroids proliferate progressively up to (309, 663) µm of HCT 116 and HEK 293T respectively on 5 bi-layers coated wells with maintaining viability. The (HCT 116) spheroids react to the anti-cancer drug. We demonstrate a new (LbL-CNF) coating strategy for spheroids generation, with high performance and efficiency to test anti-cancer drugs.

Place, publisher, year, edition, pages
Wiley , 2022. Vol. 22, no 10, article id 2200137
Keywords [en]
anti-cancer drug screening, cellulose nanofibrils, layer-by-layer, tumor spheroids, Cell culture, Cellulose, Diagnosis, Diseases, Nanofibers, Tumors, Anticancer drug, Bi-layer, Cell seeding, Drug-screening, In-vitro, Layer by layer, New coatings, Tumor spheroid, Cells, cellulose nanofiber, irinotecan, Article, atomic force microscopy, cell proliferation, cell viability, coating (procedure), drug screening, fluorescence intensity, human, human cell, in vitro study, Hardiness, Spheres, Wells
National Category
Medical Biotechnology
Identifiers
URN: urn:nbn:se:kth:diva-326459DOI: 10.1002/mabi.202200137ISI: 000835450100001PubMedID: 35899862Scopus ID: 2-s2.0-85135253200OAI: oai:DiVA.org:kth-326459DiVA, id: diva2:1758302
Note

QC 20230522

Available from: 2023-05-22 Created: 2023-05-22 Last updated: 2023-11-29Bibliographically approved
In thesis
1. Utilizing Biopolymers in 3D Tumor Modeling and Tumor Diagnosis
Open this publication in new window or tab >>Utilizing Biopolymers in 3D Tumor Modeling and Tumor Diagnosis
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cancer represents a significant global public health challenge and ranks as the second mostcommon cause of death in the United States. The onset of cancer entails an initial phasewhere cells lose their polarity and disconnect from the normal basement membrane, allowingthem to form distinct three-dimensional (3D) configurations that interact with adjacent cellsand the surrounding microenvironment. Cells grown in 2D monolayers demonstrate differentgene expression patterns and different activation of signaling pathways compared to cellscultivated within the natural structure of tumor tissue of the same cell type. Multicellulartumor spheroids (MCTS) are extensively investigated as a well-studied model of organotypiccancer. These spheroids are formed by tumor cells, either alone or in combination with othercell types, and they can be created with or without the application of supportive scaffolds.The MCTSs are also considered promising models for preclinical assessments of chemosensitivity.However, the creation of these tumor spheroids presents challenges, as not alltumor cell lines can consistently form regular spheroids.Cellulose nanofibrils (CNF) have become essential as a sustainable and environmentallyfriendly material. For example, thin films, with inherent mechanical properties, and flexibility,offer versatility across various applications. Also known for its biocompatibility and non-toxicnature, native CNF is a natural option to use. Its fibrous structure closely mimics the collagenmatrix in human tissue, showing potential as an effective scaffold for 3D cell culture. In thisregard, an innovative Layer-by-Layer (LbL) coating technique using CNF-polyelectrolytebilayers was investigated to generate spheroids. This method constructs bilayers of CNFand polyelectrolytes and can coat various surfaces. In this thesis, the first focus was ondemonstrating the spheroid formation capability using low molecular weight polyelectrolytesin LbL assembly. Secondly, an investigation was conducted involving embedding of LbLgrownspheroids in a decellularized extracellular matrix (ECM) aiming to determine howECM, possessing suitable mechanical characteristics, could influence the cancer stem celltraits in spheroids. Thirdly, the thesis demonstrated the utilization of LbL for capturing andreleasing of circulating tumor cells. Lastly, the shift from using low molecular weightpolyelectrolytes in the LbL assembly to high molecular weight counterparts and analyzingthe differences in spheroid formation abilities to assess the underlying differences inmolecular weights of the polyelectrolytes was explored. All-in-all, employing the CNF-basedLbL surface coating strategy explored in the thesis has proven to be promising for thedevelopment of spheroid models closely resembling in vivo conditions and holds significantpotential for applications in drug development.

Abstract [sv]

Cancer utgör en betydande global utmaning inom folkhälsan och rankas som den nästvanligaste dödsorsaken i USA. Cancer börjar med en initial fas där celler förlorar sin polaritetoch lossnar från basalmembranet, vilket tillåter dem att bilda distinkta tredimensionella (3D)kluster som interagerar med intilliggande celler och den omgivande mikromiljön. Celler somodlas i 2D-monolager visar olika genuttryck och olika signalvägar jämfört med celler somodlas som mer naturlig 3D struktur likt tumörvävnad. Multicellulära tumörsfärer (MCTS) ärväl studerade som modell för organotypisk cancer, dessa sfärer bildas av tumörceller,antingen av samma typ eller i kombination med andra celltyper, och de kan skapas medeller utan användning av underliggande stödjande strukturer. MCTS betraktas även somlovande modell för preklinisk bedömning av cellernas kemokänslighet. Dock är skapandetav dessa tumörsfärer utmanande, eftersom alla tumörcellinjer inte verkar kunna bildaregelbundna sfärer.Cellulosananofibriller (CNF) är ett alternativ som hållbart och miljövänligt material. Sombland annat kan forma till tunna filmer, med inbyggda mekaniska egenskaper, flexibilitet ,erbjuder mångsidighet över olika tillämpningsområden, till följd av dess flexibilitet och dessinbyggda mekaniska egenskaper. Känd för sin biokompatibilitet och ofarliga natur fungerarCNF som ett bra alternativ för användning även inom biomedicinska tillämpningar. CNFstrukturen liknar kollagenmatrisen i mänsklig vävnad och visar potential som ett effektivtunderlag för 3D-cellodling. Inom detta område undersöktes en innovativ lager-på-lager (LbL)beläggningsmetod innehållande CNF och polyelektrolyt bilager för att skapa sfärer. Metodbygger bilager av CNF och polyelektrolyter som kan belägga ytor av olika material. Dennaavhandling fokuseradar först på att demonstrera sfärformationsförmågan vid användning avpolyelektrolyter med lågmolekylvikt i de tillverkade LbL-modifieringarna. Däreftergenomfördes en undersökning som innefattar inbäddning av sfärerna som bildades pådessa LbL-ytor i extracellulärmatris (ECM) dels i form av collagen samt decellulariseradextracellulärmatris. För att undersöka om ECMs mekaniska egenskaper kan påverkacancercellernas egenskaper i sfärerna samt om EMC med liknande mekaniska egenskaperlikt naturlig vävnad är lämplig. Därefter demonstrerar avhandlingen användningen av LbLför att fånga cirkulerande tumörceller som sedan kunde släppas i en liten volym. Till sistutforskades övergången från användning av polyelektrolyter med låg molekylvikt vid LbLuppbyggnadentill samma typ av polyelektrolyter men med högre molekylvikt, samtanalysera skillnaderna i möjligheten att bilda sfärer. Sammantaget har användningen avCNF-baserad LbL-ytbeläggningsstrategi som utforskats i avhandlingen visat sig varalovande för utvecklingen av multicellulära sfäroidmodeller och som kan ha en betydandepotential för tillämpningar inom läkemedelsutveckling.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2023. p. 64
Series
TRITA-CBH-FOU ; 2023:57
Keywords
3D tumor modeling, Spheroids, Cellulose Nano Fibrils, Layer by Layer, Extracellular matrix, Circulating Tumor Capturing, Pancreatic ductal adenocarcinoma (PDAC), 3D-tumörmodellering, Sfärer, Cellulosa, Lager-på-lager, Extracellulärmatris, Infångning av cirkulerande tumörceller, Mänskliga Duktala Adenocarcinom-Hepatocyter
National Category
Biomaterials Science
Research subject
Fibre and Polymer Science
Identifiers
urn:nbn:se:kth:diva-339964 (URN)978-91-8040-788-5 (ISBN)
Public defence
2023-12-15, F3 (Flodis), Lindstedtsvägen 26, Stockholm, 13:00 (English)
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Note

QC 20231124

Available from: 2023-11-24 Created: 2023-11-23 Last updated: 2024-01-08Bibliographically approved

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Aljadi, ZenibAbbasi Aval, NegarKumar, TharaganRamachandraiah, HarishaPettersson, TorbjörnRussom, Aman

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