Generic placeholder image

Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

The Application of Microfluidic Techniques on Tissue Engineering in Orthopaedics

Author(s): Lingtian Wang, Dajun Jiang, Qiyang Wang, Qing Wang, Haoran Hu and Weitao Jia*

Volume 24 , Issue 45 , 2018

Page: [5397 - 5406] Pages: 10

DOI: 10.2174/1381612825666190301142833

Price: $65


Background: Tissue engineering (TE) is a promising solution for orthopaedic diseases such as bone or cartilage defects and bone metastasis. Cell culture in vitro and scaffold fabrication are two main parts of TE, but these two methods both have their own limitations. The static cell culture medium is unable to achieve multiple cell incubation or offer an optimal microenvironment for cells, while regularly arranged structures are unavailable in traditional cell-laden scaffolds, which results in low biocompatibility. To solve these problems, microfluidic techniques are combined with TE. By providing 3-D networks and interstitial fluid flows, microfluidic platforms manage to maintain phenotype and viability of osteocytic or chondrocytic cells, and the precise manipulation of liquid, gel and air flows in microfluidic devices leads to the highly organized construction of scaffolds.

Methods: In this review, we focus on the recent advances of microfluidic techniques applied in the field of tissue engineering, especially in orthropaedics. An extensive literature search was done using PubMed. The introduction describes the properties of microfluidics and how it exploits the advantages to the full in the aspects of TE. Then we discuss the application of microfluidics on the cultivation of osteocytic cells and chondrocytes, and other extended researches carried out on this platform. The following section focuses on the fabrication of highly organized scaffolds and other biomaterials produced by microfluidic devices. Finally, the incubation and studying of bone metastasis models in microfluidic platforms are discussed.

Conclusion: The combination of microfluidics and tissue engineering shows great potentials in the osteocytic cell culture and scaffold fabrication. Though there are several problems that still require further exploration, the future of microfluidics in TE is promising.

Keywords: Microfluidics, tissue engineering, dynamic culture, scaffold, bone metastasis, orthopaedic diseases.

Detsch R, Stoor P, Grünewald A, Roether JA, Lindfors NC, Boccaccini AR. Increase in VEGF secretion from human fibroblast cells by bioactive glass S53P4 to stimulate angiogenesis in bone. J Biomed Mater Res A 2014; 102(11): 4055-61.
Carvalho MR, Reis RL, Oliveira JM. Mimicking the 3D biology of osteochondral tissue with microfluidic-based solutions: breakthroughs towards boosting drug testing and discovery. Drug Discov Today 2018; 23(3): 711-8.
Whitesides GM. The origins and the future of microfluidics. Nature 2006; 442(7101): 368-73.
Riehl BD, Lim JY. Macro and microfluidic flows for skeletal regenerative medicine. Cells 2012; 1(4): 1225-45.
Yu W, Qu H, Hu G, et al. A microfluidic-based multi-shear device for investigating the effects of low fluid-induced stresses on osteoblasts. PLoS One 2014; 9(2): e89966.
Gao X, et al. Regulation of cell migration and osteogenic differentiation in mesenchymal stem cells under extremely low fluidic shear stress. Biomicrofluidics 2014; 8(5): 052008.
Zhong W, et al. An integrated microfluidic device for characterizing chondrocyte metabolism in response to distinct levels of fluid flow stimulus. Microfluid Nanofluidics 2013; 15(6): 763-73.
Gu Y, Zhang W, Sun Q, Hao Y, Zilberberg J, Lee WY. Microbeads-Guided Reconstruction of 3D Osteocyte Network during Microfluidic Perfusion Culture. J Mater Chem B Mater Biol Med 2015; 3(17): 3625-33.
Lin YH, Yang YW, Chen YD, Wang SS, Chang YH, Wu MH. The application of an optically switched dielectrophoretic (ODEP) force for the manipulation and assembly of cell-encapsulating alginate microbeads in a microfluidic perfusion cell culture system for bottom-up tissue engineering. Lab Chip 2012; 12(6): 1164-73.
Wang CC, Yang KC, Lin KH, Liu HC, Lin FH. A highly organized three-dimensional alginate scaffold for cartilage tissue engineering prepared by microfluidic technology. Biomaterials 2011; 32(29): 7118-26.
Hsiao AY, Torisawa YS, Tung YC, et al. Microfluidic system for formation of PC-3 prostate cancer co-culture spheroids. Biomaterials 2009; 30(16): 3020-7.
Leclerc E, David B, Griscom L, et al. Study of osteoblastic cells in a microfluidic environment. Biomaterials 2006; 27(4): 586-95.
Middleton K, et al. Microfluidics approach to investigate the role of dynamic similitude in osteocyte mechanobiology. J Orthop Res 2017.
Chao PG, Tang Z, Angelini E, West AC, Costa KD, Hung CT. Dynamic osmotic loading of chondrocytes using a novel microfluidic device. J Biomech 2005; 38(6): 1273-81.
Kou S, Pan L, van Noort D, et al. A multishear microfluidic device for quantitative analysis of calcium dynamics in osteoblasts. Biochem Biophys Res Commun 2011; 408(2): 350-5.
Zhong W, Tian K, Zheng X, et al. Mesenchymal stem cell and chondrocyte fates in a multishear microdevice are regulated by Yes-associated protein. Stem Cells Dev 2013; 22(14): 2083-93.
Kim KM, Choi YJ, Hwang JH, et al. Shear stress induced by an interstitial level of slow flow increases the osteogenic differentiation of mesenchymal stem cells through TAZ activation. PLoS One 2014; 9(3): e92427.
Al-Dujaili S, You L, Guenther A. Microfluidic Fluid Shear Delivery System for in Vitro. Bone Mechanoregulation 2010; pp. 184-6.
Wu MH, Wang HY, Liu HL, et al. Development of high-throughput perfusion-based microbioreactor platform capable of providing tunable dynamic tensile loading to cells and its application for the study of bovine articular chondrocytes. Biomed Microdevices 2011; 13(4): 789-98.
Li S, Glynne-Jones P, Andriotis OG, et al. Application of an acoustofluidic perfusion bioreactor for cartilage tissue engineering. Lab Chip 2014; 14(23): 4475-85.
Jonnalagadda US, Hill M, Messaoudi W, et al. Acoustically modulated biomechanical stimulation for human cartilage tissue engineering. Lab Chip 2018; 18(3): 473-85.
Song SH, Choi J, Jung HI. A microfluidic magnetic bead impact generator for physical stimulation of osteoblast cell. Electrophoresis 2010; 31(16): 2762-70.
Xavier M, Oreffo ROC, Morgan H. Skeletal stem cell isolation: A review on the state-of-the-art microfluidic label-free sorting techniques. Biotechnol Adv 2016; 34(5): 908-23.
Yin L, Wu Y, Yang Z, et al. Microfluidic label-free selection of mesenchymal stem cell subpopulation during culture expansion extends the chondrogenic potential in vitro. Lab Chip 2018; 18(6): 878-89.
Thomas RS, Mitchell PD, Oreffo RO, Morgan H. Trapping single human osteoblast-like cells from a heterogeneous population using a dielectrophoretic microfluidic device. Biomicrofluidics 2010; 4(2): 022806.
Xavier M, et al. Skeletal stem cell sorting: characterisation of physical properties for microfluidic separation applications, in Tissue and Cell Engineering Society (TCES) meeting. 2015: Southampton, United Kingdom. p. 109.
Xavier M, et al. Label-free microfluidic sorting of primary human skeletal stem cells for bone regeneration: a bio-physical characterisation, in The 20th International Conference on Miniaturized Systems for Chemistry and Life Sciences. 2016: Dublin, Ireland. p. 242-243.
Nève N, Kohles SS, Winn SR, Tretheway DC. Manipulation of Suspended Single Cells by Microfluidics and Optical Tweezers. Cell Mol Bioeng 2010; 3(3): 213-28.
Stacey MW, Sabuncu AC, Beskok A. Dielectric characterization of costal cartilage chondrocytes. Biochim Biophys Acta 2014; 1840(1): 146-52.
Middleton K, You L. A microfluidic system to study the effects of mechanically loaded osteocytes on osteoclast recruitment and formation 18th International Conference on Miniaturized Systems for Chemistry and Life Sciences 2014; San Antonio, Texas, USA. 2014; pp. 627-29.
Wei CW, Cheng JY, Young TH. Elucidating in vitro cell-cell interaction using a microfluidic coculture system. Biomed Microdevices 2006; 8(1): 65-71.
Middleton K, Al-Dujaili S, Mei X, Günther A, You L. Microfluidic co-culture platform for investigating osteocyte-osteoclast signalling during fluid shear stress mechanostimulation. J Biomech 2017; 59: 35-42.
George EL, Truesdell SL, York SL, Saunders MM. Lab-on-a-chip platforms for quantification of multicellular interactions in bone remodeling. Exp Cell Res 2018; 365(1): 106-18.
Moraes C, Wang G, Sun Y, Simmons CA. A microfabricated platform for high-throughput unconfined compression of micropatterned biomaterial arrays. Biomaterials 2010; 31(3): 577-84.
Jang K, Sato K, Igawa K, Chung UI, Kitamori T. Development of an osteoblast-based 3D continuous-perfusion microfluidic system for drug screening. Anal Bioanal Chem 2008; 390(3): 825-32.
Kasten SM. Microfluidic PLGA Microcapsules for the Sustained Delivery of Recombinant Human Bone Morphogenetic Protein 2 in 3D Printed PCL/ β TCP Scaffolds 2016; 12.
Li Y, Qin J, Lin B, Zhang W. The effects of insulin-like growth factor-1 and basic fibroblast growth factor on the proliferation of chondrocytes embedded in the collagen gel using an integrated microfluidic device. Tissue Eng Part C Methods 2010; 16(6): 1267-75.
Rivera A, Baskaran H. The Effect of Biomolecular Gradients on Mesenchymal Stem Cell Chondrogenesis under Shear Stress. Micromachines (Basel) 2015; 6(3): 330-46.
Occhetta P, Centola M, Tonnarelli B, Redaelli A, Martin I, Rasponi M. High-Throughput Microfluidic Platform for 3D Cultures of Mesenchymal Stem Cells, Towards Engineering Developmental Processes. Sci Rep 2015; 5: 10288.
Tian K, Zhong W, Zhang Y, Yin B, Zhang W, Liu H. Microfluidics-based optimization of neuroleukin-mediated regulation of articular chondrocyte proliferation. Mol Med Rep 2016; 13(1): 67-74.
Nason F, et al. Design of microfluidic devices for drug screening on in-vitro cells for osteoporosis therapies. Microelectron Eng 2011; 88(8): 1801-6.
Ming L, Zhipeng Y, Fei Y, et al. Microfluidic-based screening of resveratrol and drug-loading PLA/Gelatine nano-scaffold for therepair of cartilage defect. Artif Cells Nanomed Biotechnol 2018; 46(sup1): 336-46.
Mitxelena-Iribarren O, Hisey CL, Errazquin-Irigoyen M, et al. Effectiveness of nanoencapsulated methotrexate against osteosarcoma cells: in vitro cytotoxicity under dynamic conditions. Biomed Microdevices 2017; 19(2): 35.
Mitxelena-Iribarren O, et al. Improved microfluidic platform for simultaneous multiple drug screening towards personalized treatment Biomed Microdevices 2018; S0956-5663(18): 30689-4.
You L, et al. 3D Microfluidic Approach to Mechanical Stimulation of Osteocyte Processes. Cell Mol Bioeng 2008; 1(1): 103-7.
Lee JH, Wang H, Kaplan JB, Lee WY. Microfluidic approach to create three-dimensional tissue models for biofilm-related infection of orthopaedic implants. Tissue Eng Part C Methods 2011; 17(1): 39-48.
Lee JH, Gu Y, Wang H, Lee WY. Microfluidic 3D bone tissue model for high-throughput evaluation of wound-healing and infection-preventing biomaterials. Biomaterials 2012; 33(4): 999-1006.
Sun Q, Gu Y, Zhang W, Dziopa L, Zilberberg J, Lee W. Ex vivo 3D osteocyte network construction with primary murine bone cells. Bone Res 2015; 3(3): 15026.
Sun Q, Choudhary S, Mannion C, Kissin Y, Zilberberg J, Lee WY. Ex vivo construction of human primary 3D-networked osteocytes. Bone 2017; 105: 245-52.
Sun Q, Choudhary S, Mannion C, Kissin Y, Zilberberg J, Lee WY. Ex vivo replication of phenotypic functions of osteocytes through biomimetic 3D bone tissue construction. Bone 2018; 106: 148-55.
Huang SB, Wu MH, Wang SS, Lee GB. Microfluidic cell culture chip with multiplexed medium delivery and efficient cell/scaffold loading mechanisms for high-throughput perfusion 3-dimensional cell culture-based assays. Biomed Microdevices 2011; 13(3): 415-30.
Lin YH, Yang YW, Chen YD, Wang SS, Chang YH, Wu MH. The application of an optically switched dielectrophoretic (ODEP) force for the manipulation and assembly of cell-encapsulating alginate microbeads in a microfluidic perfusion cell culture system for bottom-up tissue engineering. Lab Chip 2012; 12(6): 1164-73.
Goldman SM, Barabino GA. Cultivation of agarose-based microfluidic hydrogel promotes the development of large, full-thickness, tissue-engineered articular cartilage constructs. J Tissue Eng Regen Med 2017; 11(2): 572-81.
Goldman SM, Barabino GA. Spatial Engineering of Osteochondral Tissue Constructs Through Microfluidically Directed Differentiation of Mesenchymal Stem Cells Biores Open Access 2016; 5(1): 109-17
Shi X, Zhou J, Zhao Y, Li L, Wu H. Gradient-regulated hydrogel for interface tissue engineering: steering simultaneous osteo/chondrogenesis of stem cells on a chip. Adv Healthc Mater 2013; 2(6): 846-53.
Ugolini GS, Visone R, Redaelli A, Moretti M, Rasponi M. Generating Multicompartmental 3D Biological Constructs Interfaced through Sequential Injections in Microfluidic Devices. Adv Healthc Mater 2017; 6(10): 1601170.
Mondadori C, Visone R, Rasponi M, Redaelli A, Moretti M. Lopas. Development of an organotypic microfluidic model to reproduce monocyte extravasation process in the osteoarthritic joint. Osteoarthritis Cartilage 2018; 26: S122.
Movilla N, Borau C, Valero C, García-Aznar JM. Degradation of extracellular matrix regulates osteoblast migration: A microfluidic-based study. Bone 2018; 107: 10-7.
Bartnikowski M, Klein TJ, Melchels FP, Woodruff MA. Effects of scaffold architecture on mechanical characteristics and osteoblast response to static and perfusion bioreactor cultures. Biotechnol Bioeng 2014; 111(7): 1440-51.
Harink B, Gac SL, Blitterswijk CV, Habibovic P. Microfluidic Platform for the Simultaneous Generation of Four Independent Gradients: Towards the High Throughput Screening of Trace Elements for Bone Tissue Engineering 14th International Conference on Miniaturized Systems for Chemistry and Life Science 2010; Groningen, The Netherlands. 2010; pp. 638-40.
Espregueira-Mendes J, Pereira H, Sevivas N, et al. Osteochondral transplantation using autografts from the upper tibio-fibular joint for the treatment of knee cartilage lesions. Knee Surg Sports Traumatol Arthrosc 2012; 20(6): 1136-42.
Wang CC, Yang KC, Lin KH, Liu YL, Liu HC, Lin FH. Cartilage regeneration in SCID mice using a highly organized three-dimensional alginate scaffold. Biomaterials 2012; 33(1): 120-7.
Wang CC, Yang KC, Lin KH, et al. A biomimetic honeycomb-like scaffold prepared by flow-focusing technology for cartilage regeneration. Biotechnol Bioeng 2014; 111(11): 2338-48.
Wang CC, Yang KC, Lin KH, et al. Expandable Scaffold Improves Integration of Tissue-Engineered Cartilage: An In Vivo Study in a Rabbit Model. Tissue Eng Part A 2016; 22(11-12): 873-84.
Zhou Y, Gao HL, Shen LL, et al. Chitosan microspheres with an extracellular matrix-mimicking nanofibrous structure as cell-carrier building blocks for bottom-up cartilage tissue engineering. Nanoscale 2016; 8(1): 309-17.
Ding S, Li L, Liu X, Yang G, Zhou G, Zhou S. A nano-micro alternating multilayer scaffold loading with rBMSCs and BMP-2 for bone tissue engineering. Colloids Surf B Biointerfaces 2015; 133: 286-95.
Mendes AC, Baran ET, Lisboa P, Reis RL, Azevedo HS. Microfluidic fabrication of self-assembled peptide-polysaccharide microcapsules as 3D environments for cell culture. Biomacromolecules 2012; 13(12): 4039-48.
Li F, Truong VX, Thissen H, Frith JE, Forsythe JS. Microfluidic Encapsulation of Human Mesenchymal Stem Cells for Articular Cartilage Tissue Regeneration. ACS Appl Mater Interfaces 2017; 9(10): 8589-601.
Zhao X, Liu S, Yildirimer L, et al. Injectable Stem Cell-Laden Photocrosslinkable Microspheres Fabricated Using Microfluidics for Rapid Generation of Osteogenic Tissue Constructs. Adv Funct Mater 2016; 26(17): 2809-19.
Sayania B. Mesenchymal Stem Cell (MSC) Spheroid Constructs Containing Microfluidic BMP2-PLGA Microcapsules in Bone Tissue Engineering 2017; 26.
Hasani-Sadrabadi MM, Hajrezaei SP, Emami SH, et al. Enhanced osteogenic differentiation of stem cells via microfluidics synthesized nanoparticles. Nanomedicine (Lond) 2015; 11(7): 1809-19.
Kim B. Fabrication of Cell-Encapsulated Microfiber using Microfluidic Channel, in Solid-State Sensors Actuators and Microsystems Conference 2007; Lyon, France. 2007; pp. 1797-0.
Zuo Y, He X, Yang Y, et al. Microfluidic-based generation of functional microfibers for biomimetic complex tissue construction. Acta Biomater 2016; 38: 153-62.
Angelozzi M, Penolazzi L, Mazzitelli S, et al. Dedifferentiated Chondrocytes in Composite Microfibers As Tool for Cartilage Repair. Front Bioeng Biotechnol 2017; 5: 35.
Kirchhof K, Andar A, Yin HB, Gadegaard N, Riehle MO, Groth T. Polyelectrolyte multilayers generated in a microfluidic device with pH gradients direct adhesion and movement of cells. Lab Chip 2011; 11(19): 3326-35.
Zhang YN, et al. A Biological 3D Printer for the Preparation of Tissue Engineering Micro-Channel Scaffold. Key Eng Mater 2015; 645-646: 1290-7.
Ren G, Esposito M, Kang Y. Bone metastasis and the metastatic niche. J Mol Med (Berl) 2015; 93(11): 1203-12.
Rove KO, Crawford ED. Metastatic cancer in solid tumors and clinical outcome: skeletal-related events. Oncology (Williston Park) 2009; 23(14)(Suppl. 5): 21-7.
Bischel LL, Casavant BP, Young PA, Eliceiri KW, Basu HS, Beebe DJ. A microfluidic coculture and multiphoton FAD analysis assay provides insight into the influence of the bone microenvironment on prostate cancer cells. Integr Biol 2014; 6(6): 627-35.
Bersini S, Jeon JS, Dubini G, et al. A microfluidic 3D in vitro model for specificity of breast cancer metastasis to bone. Biomaterials 2014; 35(8): 2454-61.
Jeon JS, Bersini S, Gilardi M, et al. Human 3D vascularized organotypic microfluidic assays to study breast cancer cell extravasation. Proc Natl Acad Sci USA 2015; 112(1): 214-9.
Hasani-Sadrabadi MM, Dashtimoghadam E, Bahlakeh G, et al. On-chip synthesis of fine-tuned bone-seeking hybrid nanoparticles. Nanomedicine (Lond) 2015; 10(23): 3431-49.

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy