Full Text:   <124>

Summary:  <165>

CLC number: 

On-line Access: 2023-06-26

Received: 2023-03-16

Revision Accepted: 2023-05-08

Crosschecked: 2023-09-26

Cited: 0

Clicked: 147

Citations:  Bibtex RefMan EndNote GB/T7714




-   Go to

Article info.
Open peer comments

Journal of Zhejiang University SCIENCE B 2023 Vol.24 No.10 P.922-934


Cellulose nanofibril matrix drives the dynamic formation of spheroids

Author(s):  Yi LU, Guo LI, Yeqiu LI, Yuan YAO

Affiliation(s):  College of Chemical and Biological Engineering, Zhejiang University,Hangzhou310027,China; more

Corresponding email(s):   yyao1@zju.edu.cn

Key Words:  Cellulose, Nanofibril, Matrix, Self-assembly, Spheroid

Yi LU, Guo LI, Yeqiu LI, Yuan YAO. Cellulose nanofibril matrix drives the dynamic formation of spheroids[J]. Journal of Zhejiang University Science B, 2023, 24(10): 922-934.

@article{title="Cellulose nanofibril matrix drives the dynamic formation of spheroids",
author="Yi LU, Guo LI, Yeqiu LI, Yuan YAO",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

%0 Journal Article
%T Cellulose nanofibril matrix drives the dynamic formation of spheroids
%A Yi LU
%A Guo LI
%A Yeqiu LI
%A Yuan YAO
%J Journal of Zhejiang University SCIENCE B
%V 24
%N 10
%P 922-934
%@ 1673-1581
%D 2023
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B23d0003

T1 - Cellulose nanofibril matrix drives the dynamic formation of spheroids
A1 - Yi LU
A1 - Guo LI
A1 - Yeqiu LI
A1 - Yuan YAO
J0 - Journal of Zhejiang University Science B
VL - 24
IS - 10
SP - 922
EP - 934
%@ 1673-1581
Y1 - 2023
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B23d0003

Multicellular spheroids, which mimic the natural organ counterparts, allow the prospect of drug screening and regenerative medicine. However, their application is hampered by low processing efficiency or limited scale. This study introduces an efficient method to drive rapid multicellular spheroid formation by a cellulose nanofibril matrix. This matrix enables the facilitated growth of spheroids (within 48 h) through multiple cell assembly into size-controllable aggregates with well-organized physiological microstructure. The efficiency, dimension, and conformation of the as-formed spheroids depend on the concentration of extracellular nanofibrils, the number of assembled cells, and the heterogeneity of cell types. The above strategy allows the robust formation mechanism of compacted tumoroids and hepatocyte spheroids.


卢轶1,2,3, 李果1,2, 李叶秋2, 姚远1,2,3
1浙江大学化学工程与生物工程学院, 中国杭州市, 310027
2浙江大学杭州国际科创中心, 中国杭州市, 311215
3上海科技大学物质科学与技术学院, 中国上海市, 201210


Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article


[1]Abdul KhalilHPS,DavoudpourY,IslamMN,et al.,2014.Production and modification of nanofibrillated cellulose using various mechanical processes: a review.Carbohydr Polym,99:649-665.

[2]AbouzeidRE,KhiariR,BeneventiD,et al.,2018.Biomimetic mineralization of three-dimensional printed alginate/TEMPO-oxidized cellulose nanofibril scaffolds for bone tissue engineering.Biomacromolecules,19(11):4442-4452.

[3]AlegretN,Dominguez-AlfaroA,MecerreyesD,2019.3D scaffolds based on conductive polymers for biomedical applications.Biomacromolecules,20(1):73-89.

[4]Al-QararahAM,EkmanA,HjeltT,et al.,2015.A unique microstructure of the fiber networks deposited from foam-fiber suspensions.Colloids Surf A Physicochem Eng Aspects,482:544-553.

[5]AmaralAJR,PasparakisG,2016.Rapid formation of cell aggregates and spheroids induced by a “smart” boronic acid copolymer.ACS Appl Mater Interfaces,8(35):22930-22941.

[6]AumailleyM,2013.The laminin family.Cell Adh Migr,7(1):48-55.

[7]BadeaMA,BalasM,HermeneanA,et al.,2019.Influence of Matrigel on single-and multiple-spheroid cultures in breast cancer research.SLAS Discov,24(5):563-578.

[8]BagleyJA,ReumannD,BianS,et al.,2017.Fused cerebral organoids model interactions between brain regions.Nat Methods,14(7):743-751.

[9]BergmannS,LawlerSE,QuY,et al.,2018.Blood-brain-barrier organoids for investigating the permeability of CNS therapeutics.Nat Protoc,13(12):2827-2843.

[10]BroutierL,MastrogiovanniG,VerstegenMMA,et al.,2017.Human primary liver cancer-derived organoid cultures for disease modeling and drug screening.Nat Med,23(12):1424-1435.

[11]BryantKL,StalneckerCA,ZeitouniD,et al.,2019.Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer.Nat Med,25(4):628-640.

[12]BuchroithnerB,KlauseggerA,EbschnerU,et al.,2004.Analysis of theLAMB3 gene in a junctional epidermolysis bullosa patient reveals exonic splicing and allele-specific nonsense-mediated mRNA decay.Lab Invest,84(10):1279-1288.

[13]ChenJ,ZhangJT,YangL,et al.,2023.Facile suspension culture protocol of the liver biliary organoids.Bio-Des Manuf,6(1):74-81.

[14]ChenYW,HuangSX,deCarvalho ALRT,et al.,2017.A three-dimensional model of human lung development and disease from pluripotent stem cells.Nat Cell Biol,19(5):542-549.

[15]ChungH,JungH,LeeJH,et al.,2014.Keratinocyte-derived laminin-332 protein promotes melanin synthesis via regulation of tyrosine uptake.J Biol Chem,289(31):21751-21759.

[16]CruzNM,SongXW,CzernieckiSM,et al.,2017.Organoid cystogenesis reveals a critical role of microenvironment in human polycystic kidney disease.Nat Mater,16(11):1112-1119.

[17]CurvelloR,KerrG,MicatiDJ,et al.,2021.Engineered plant-based nanocellulose hydrogel for small intestinal organoid growth.Adv Sci,8(1):2002135.

[18]DaviesJA,2013.The power and limitations of self-assembly. In: Davies JA (Ed.),Mechanisms of Morphogenesis,2nd Ed.Academic Press, Waltham, p.17-30.

[19]di MartinoJS,NobreAR,MondalC,et al.,2022.A tumor-derived type III collagen-rich ECM niche regulates tumor cell dormancy.Nat Cancer,3(1):90-107.

[20]DrostJ,CleversH,2018.Organoids in cancer research.Nat Rev Cancer,18(7):407-418.

[21]EdelmanGM,1983.Cell adhesion molecules.Science,219(4584):450-457.

[22]EvdokimovaOL,AlvesCS,Krsmanović WhiffenRM,et al.,2021.Cytocompatible cellulose nanofibers from invasive plant speciesAgave americana L. andRicinus communis L.: a renewable green source of highly crystalline nanocellulose.J Zhejiang Univ-Sci B (Biomed & Biotechnol),22(6):450-461.

[23]FangM,GoldsteinEL,MatichEK,et al.,2013.Type I collagen self-assembly: the roles of substrate and concentration.Langmuir,29(7):2330-2338.

[24]FerreiraFV,OtoniCG,de FranceKJ,et al.,2020.Porous nanocellulose gels and foams: breakthrough status in the development of scaffolds for tissue engineering.Mater Today,37:126-141.

[25]FitsialosG,BourgetI,AugierS,et al.,2008.HIF1 transcription factor regulates laminin-332 expression and keratinocyte migration.J Cell Sci,121(Pt 18):2992-3001.

[26]FujiiM,ShimokawaM,DateS,et al.,2016.A colorectal tumor organoid library demonstrates progressive loss of niche factor requirements during tumorigenesis.Cell Stem Cell,18(6):827-838.

[27]GarretaE,PradoP,TarantinoC,et al.,2019.Fine tuning the extracellular environment accelerates the derivation of kidney organoids from human pluripotent stem cells.Nat Mater,18(4):397-405.

[28]GoetzJG,MinguetS,Navarro-LéridaI,et al.,2011.Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis.Cell,146(1):148-163.

[29]Gonzalez-RodriguezD,GuevorkianK,DouezanS,et al.,2012.Soft matter models of developing tissues and tumors.Science,338(6109):910-917.

[30]GrassiL,AlfonsiR,FrancescangeliF,et al.,2019.Organoids as a new model for improving regenerative medicine and cancer personalized therapy in renal diseases.Cell Death Dis,10(3):201.

[31]HaleLJ,HowdenSE,PhipsonB,et al.,2018.3D organoid-derived human glomeruli for personalised podocyte disease modelling and drug screening.Nat Commun,9:5167.

[32]HegedüsB,MargaF,JakabK,et al.,2006.The interplay of cell-cell and cell-matrix interactions in the invasive properties of brain tumors.Biophys J,91(7):2708-2716.

[33]HolmesDF,LuYH,StarborgT,et al.,2018.Collagen fibril assembly and function.Curr Top Dev Biol,130:107-142.

[34]HomanKA,GuptaN,KrollKT,et al.,2019.Flow-enhanced vascularization and maturation of kidney organoids in vitro.Nat Methods,16(3):255-262.

[35]HuKS,KulkarniDD,ChoiI,et al.,2014.Graphene-polymer nanocomposites for structural and functional applications.Prog Polym Sci,39(11):1934-1972.

[36]HuangC,DaiJX,ZhangXA,2015.Environmental physical cues determine the lineage specification of mesenchymal stem cells.Biochim Biophys Acta (BBA)‍-Gen Subj,1850(6):1261-1266.

[37]JadinKD,WongBL,BaeWC,et al.,2005.Depth-varying density and organization of chondrocytes in immature and mature bovine articular cartilage assessed by 3D imaging and analysis.J Histochem Cytochem,53(9):‍1109-1119.

[38]JaeckelS,KallerM,JackstadtR,et al.,2018.Ap4 is rate limiting for intestinal tumor formation by controlling the homeostasis of intestinal stem cells.Nat Commun,9:3573.

[39]JagerM,BlokzijlF,SasselliV,et al.,2018.Measuring mutation accumulation in single human adult stem cells by whole-genome sequencing of organoid cultures.Nat Protoc,13(1):59-78.

[40]JungSN,LimHS,LiuLH,et al.,2018.LAMB3 mediates metastatic tumor behavior in papillary thyroid cancer by regulating c-MET/Akt signals.Sci Rep,8:2718.

[41]KarageorgiouV,KaplanD,2005.Porosity of 3D biomaterial scaffolds and osteogenesis.Biomaterials,26(27):5474-5491.

[42]KarzbrunE,KshirsagarA,CohenSR,et al.,2018.Human brain organoids on a chip reveal the physics of folding.Nat Phys,14(5):515-522.

[43]KatsudaT,KawamataM,HagiwaraK,et al.,2017.Conversion of terminally committed hepatocytes to culturable bipotent progenitor cells with regenerative capacity.Cell Stem Cell,20(1):41-55.

[44]KobayashiY,SaitoT,IsogaiA,2014.Aerogels with 3D ordered nanofiber skeletons of liquid-crystalline nanocellulose derivatives as tough and transparent insulators.Angew Chem Int Ed,53(39):10394-10397.

[45]KronenbergHM,2003.Developmental regulation of the growth plate.Nature,423(6937):332-336.

[46]KrügerM,OosterhoffLA,van WolferenME,et al.,2020.Cellulose nanofibril hydrogel promotes hepatic differentiation of human liver organoids.Adv Healthc Mater,9(6):1901658.

[47]LandryMJ,RolletFG,KennedyTE,et al.,2018.Layers and multilayers of self-assembled polymers: tunable engineered extracellular matrix coatings for neural cell growth.Langmuir,34(30):8709-8730.

[48]LawlorKT,VanslambrouckJM,HigginsJW,et al.,2021.Cellular extrusion bioprinting improves kidney organoid reproducibility and conformation.Nat Mater,20(2):‍260-271.

[49]LiJW,WuMX,ChenWH,et al.,2021.3D printing of bioinspired compartmentalized capsular structure for controlled drug release.J Zhejiang Univ-Sci B (Biomed & Biotechnol),22(12):1022-1033.

[50]LouisF,PannetierP,SouguirZ,et al.,2017.A biomimetic hydrogel functionalized with adipose ECM components as a microenvironment for the 3D culture of human and murine adipocytes.Biotechnol Bioeng,114(8):1813-1824.

[51]MalafayaPB,SilvaGA,ReisRL,2007.Natural-origin polymers as carriers and scaffolds for biomolecules and cell delivery in tissue engineering applications.Adv Drug Deliv Rev,59(4-5):207-233.

[52]Martinez-VidalL,MurdicaV,VenegoniC,et al.,2021.Causal contributors to tissue stiffness and clinical relevance in urology.Commun Biol,4:1011.

[53]MartoïaF,CochereauT,DumontPJJ,et al.,2016.Cellulose nanofibril foams: links between ice-templating conditions, microstructures and mechanical properties.Mater Des,104:376-391.

[54]MillerAJ,DyeBR,Ferrer-TorresD,et al.,2019.Generation of lung organoids from human pluripotent stem cells in vitro.Nat Protoc,14(2):518-540.

[55]MinerJH,YurchencoPD,2004.Laminin functions in tissue morphogenesis.Annu Rev Cell Dev Biol,20:255-284.

[56]MittalN,AnsariF,GowdaVK,et al.,2018.Multiscale control of nanocellulose assembly: transferring remarkable nanoscale fibril mechanics to macroscale fibers.ACS Nano,12(7):6378-6388.

[57]MohanN,GuptaV,SridharanB,et al.,2014.The potential of encapsulating “raw materials” in 3D osteochondral gradient scaffolds.Biotechnol Bioeng,111(4):829-841.

[58]MouwJK,OuGQ,WeaverVM,2014.Extracellular matrix assembly: a multiscale deconstruction.Nat Rev Mol Cell Biol,15(12):771-785.

[59]MuellerM,RasoulinejadS,GargS,et al.,2020.The importance of cell-cell interaction dynamics in bottom-up tissue engineering: concepts of colloidal self-assembly in the fabrication of multicellular architectures.Nano Lett,20(4):2257-2263.

[60]NechyporchukO,BelgacemMN,PignonF,2016a.Current progress in rheology of cellulose nanofibril suspensions.Biomacromolecules,17(7):2311-2320.

[61]NechyporchukO,BelgacemMN,BrasJ,2016b.Production of cellulose nanofibrils: a review of recent advances.Ind Crops Prod,93:2-25.

[62]NguyenNM,SeniorRM,2006.Laminin isoforms and lung development: all isoforms are not equal.Dev Biol,294(2):271-279.

[63]Ortega-PrietoAM,SkeltonJK,WaiSN,et al.,2018.3D microfluidic liver cultures as a physiological preclinical tool for hepatitis B virus infection.Nat Commun,9:682.

[64]ParkD,WershofE,BoeingS,et al.,2020.Extracellular matrix anisotropy is determined by TFAP2C-dependent regulation of cell collisions.Nat Mater,19(2):227-238.

[65]ParkM,LeeD,ShinS,et al.,2015.Effect of negatively charged cellulose nanofibers on the dispersion of hydroxyapatite nanoparticles for scaffolds in bone tissue engineering.Colloids Surf B Biointerfaces,130:222-228.

[66]PhipsonB,ErPX,CombesAN,et al.,2019.Evaluation of variability in human kidney organoids.Nat Methods,16(1):79-87.

[67]QianXY,JacobF,SongMM,et al.,2018.Generation of human brain region-specific organoids using a miniaturized spinning bioreactor.Nat Protoc,13(3):565-580.

[68]RasoulinejadS,MuellerM,Nzigou MomboB,et al.,2020.Orthogonal blue and red light controlled cell‍‒‍cell adhesions enable sorting-out in multicellular structures.ACS Synth Biol,9(8):2076-2086.

[69]ReidMS,VillalobosM,CranstonED,2017.Benchmarking cellulose nanocrystals: from the laboratory to industrial production.Langmuir,33(7):1583-1598.

[70]RenJ,WangY,YaoY,et al.,2019.Biological material interfaces as inspiration for mechanical and optical material designs.Chem Rev,119(24):12279-12336.

[71]RenX,WangFY,ChenC,et al.,2016.Engineering zonal cartilage through bioprinting collagen type II hydrogel constructs with biomimetic chondrocyte density gradient.BMC Musculoskelet Disord,17:301.

[72]RobinsSP,2006.Fibrillogenesis and maturation of collagens. In: Seibel MJ, Robins SP, Bilezikian JP (Eds.),Dynamics of Bone and Cartilage Metabolism,2nd Ed.Academic Press,San Diego, p.41-53.

[73]RoerinkSF,SasakiN,Lee-SixH,et al.,2018.Intra-tumour diversification in colorectal cancer at the single-cell level.Nature,556(7702):457-462.

[74]RohnF,KordesC,CastoldiM,et al.,2018.Laminin-521 promotes quiescence in isolated stellate cells from rat liver.Biomaterials,180:36-51.

[75]RoiA,ArdeleanLC,RoiCI,et al.,2019.Oral bone tissue engineering: advanced biomaterials for cell adhesion, proliferation and differentiation.Materials (Basel),12(14):2296.

[76]RossiG,ManfrinA,LutolfMP,2018.Progress and potential in organoid research.Nat Rev Genet,19(11):671-687.

[77]SaitoY,MuramatsuT,KanaiY,et al.,2019.Establishment of patient-derived organoids and drug screening for biliary tract carcinoma.Cell Rep,27(4):1265-1276.e4.

[78]SteinbergMS,1962.On the mechanism of tissue reconstruction by dissociated cells, III. Free energy relations and the reorganization of fused, heteronomic tissue fragments.Proc Natl Acad Sci USA,48(10):1769-1776.

[79]SunT,NortonD,McKeanRJ,et al.,2007.Development of a 3D cell culture system for investigating cell interactions with electrospun fibers.Biotechnol Bioeng,97(5):‍1318-1328.

[80]TevisKM,ColsonYL,GrinstaffMW,2017.Embedded spheroids as models of the cancer microenvironment.Adv Biosyst,1(10):1700083.

[81]ThunbergJ,KalogeropoulosT,KuzmenkoV,et al.,2015.In situ synthesis of conductive polypyrrole on electrospun cellulose nanofibers: scaffold for neural tissue engineering.Cellulose,22(3):1459-1467.

[82]TuvesonD,CleversH,2019.Cancer modeling meets human organoid technology.Science,364(6444):952-955.

[83]WinklerS,KaplanDL,2001.Biosynthesized materials: properties and processing. In: Buschow KHJ, Cahn RW, Flemings MC, et al. (Eds.),Encyclopedia of Materials: Science and Technology,2nd Ed.Elsevier,Amsterdam, p.609-615.

[84]XiaoRR,JinL,XieN,et al.,2022.Establishment and large-scale validation of a three-dimensional tumor model on an array chip for anticancer drug evaluation.Front Pharmacol,13:1032975.

[85]YangX,ReidMS,OlsénP,et al.,2020.Eco-friendly cellulose nanofibrils designed by nature: effects from preserving native state.ACS Nano,14(1):724-735.

[86]YeattsAB,ChoquetteDT,FisherJP,2013.Bioreactors to influence stem cell fate: augmentation of mesenchymal stem cell signaling pathways via dynamic culture systems.Biochim Biophys Acta (BBA)‍-Gen Subj,1830(2):‍2470-2480.

[87]ZhangXF,XiongR,KangS,et al.,2020.Alternating stacking of nanocrystals and nanofibers into ultrastrong chiral biocomposite laminates.ACS Nano,14(11):14675-14685.

[88]ZhuZH,SongJL,GuoYG,et al.,2020.LAMB3 promotes tumour progression through the AKT-FOXO3/4 axis and is transcriptionally regulated by the BRD2/acetylated ELK4 complex in colorectal cancer.Oncogene,39(24):‍4666-4680.

Open peer comments: Debate/Discuss/Question/Opinion


Please provide your name, email address and a comment

Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - 2024 Journal of Zhejiang University-SCIENCE