Magnetic assembly of microfluidic spun alginate microfibers for fabricating three-dimensional cell-laden hydrogel constructs


Microfluidic devices employed as “printing” head provide a mild condition to fabricate cell-laden hydrogel modules for three-dimensional (3D) assembly to create cellular constructs. However, because of the poor controllability of hydrogels and unstable microfluidic fabrication process, it remains a challenge to fabricate morphologically accurate structures to mimic in vivo tissues, which hinders the building of in vitro models of organs. In this paper, we combine a magnetic-driven strategy into a microfluidic “printing” method to handle this challenge. To enhance the controllability, we encapsulate magnetic nanoparticles (MNPs) into cell-laden alginate hydrogel microfibers and then magnetically assemble these microfibers on the surface of designed support models. To keep a continuous spinning process, we immerse the spinning orifice of microfluidic device into phosphate-buffered saline filled in a Petri dish to eliminate the influence of droplets generated during microfibers ejection. Meanwhile, a dextran flow impulse is employed to prevent the blockage of microchannels. Interestingly, this impulse can achieve to temporarily cease the spinning process. Moreover, an optimized magnetic assembly is achieved by considering both the assembling area on a ring magnet and the MNPs concentration in microfibers. After the test of cell survival, a high cell viability of 97.2 % can be confirmed in assembled structures, which indicates that our method allows a biocompatible assembly of cell-laden hydrogels to build macroscopic 3D cellular structures similar to tissues observed in vivo.

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  1. Agarwal P, Zhao ST, Bielecki P, Rao W, Choi JK, Zhao Y, Yu JH, Zhang WJ, He XM (2013) One-step microfluidic generation of pre-hatching embryo-like core-shell microcapsules for miniaturized 3D culture of pluripotent stem cells. Lab Chip 13:4525–4533. doi:10.1039/C3LC50678A

  2. Ahn SH, Lee HJ, Bonassar LJ, Kim GH (2012) Cells (MC3T3-E1)-laden alginate scaffolds fabricated by a modified solid-freeform fabrication process supplemented with an aerosol spraying. Biomacromolecules 13:2997–3003. doi:10.1021/bm3011352

  3. Chung SE, Dong XG, Sitti M (2015) Three-dimensional heterogeneous assembly of coded microgels using an untethered mobile microgripper. Lab Chip 15:1667–1676. doi:10.1039/c5lc00009b

  4. Cuadros TR, Skurtys O, Aguilera JM (2012) Mechanical properties of calcium alginate fibers produced with a microfluidic device. Carbohydr Polym 89:1198–1206. doi:10.1016/j.carbpol.2012.03.094

  5. Duan B, Hockaday LA, Kang KH, Butcher JT (2013) 3D bioprinting of heterogeneous aortic valve conduits with alginate/gelation hydrogels. J Biomed Mater Res Part A101:1255–1264. doi:10.1002/jbm.a.34420

  6. Ghorbanian S, Qasaimeh MA, Akbari M, Tamayol A, Juncker D (2014) Microfluidic direct writer with integrated declogging mechanism for fabricating cell-laden hydrogel constructs. Biomed Microdevices 16:387–395. doi:10.1007/s10544-014-9842-8

  7. Hu CZ, Nakajima M, Yue T, Takeuchi M, Seki M, Huang Q, Fukuda T (2014) On-chip fabrication of magnetic alginate hydrogel microfibers by multilayered pneumatic microvalves. Microfluid Nanofluid 17:457–468. doi:10.1007/s10404-013-1325-3

  8. Kang E, Jeong GS, Choi YY, Lee KH, Khademhosseini A, Lee SH (2011) Digitally tunable physicochemical coding of material composition and topography in continuous microfibres. Nat Mater 10:877–883. doi:10.1038/NMAT3108

  9. Kang E, Choi YY, Chae SK, Moon JH, Chang JY, Lee SH (2012) Microfluidic spinning of flat alginate fibers with grooves for cell-aligning scaffold. Adv Mater 24:4271–4277. doi:10.1002/adma.201201232

  10. Leng L, McAllister A, Zhang BY, Radisic M, Gunther A (2012) Mosaic hydrogels: one-step formation of multiscale soft materials. Adv Mater 24:3650–3658. doi:10.1002/adma.201201442

  11. Li YH, Huang GY, Zhang XH, Li BQ, Chen YM, Lu TL, Lu TJ, Xu F (2013) Magnetic hydrogels and their potential biomedical applications. Adv Funct Mater 23:660–672. doi:10.1002/adfm.201201708

  12. Lin YS, Huang KS, Yang CH, Wang CY, Yang YS, Hsu HC, Liao YJ, Tsai CW (2012) Microfluidic synthesis of microfibers for magnetic-responsive controlled drug release and cell culture. PLoS ONE. doi:10.1371/journal.pone.0033184

  13. Liu J, Shi J, Zhang F, Wang L, Yamamoto S, Takano M, Jiang Lianmei, Zhang Haoli (2012) Segmented magnetic nanofibers for single cell manipulation. Appl Surf Sci 258:7530–7535. doi:10.1016/j.apsusc.2012.04.077

  14. Marga FM, Jakab K, Khatiwala C, Shepherd B, Dorfman S, Hubbard B, Colbert S, Forgacs G (2012) Toward engineering functional organ modules by additive manufacturing. Biofabrication. doi:10.1088/1758-5082/4/2/022001

  15. Matsunaga Y, Morimoto Y, Takeuchi S (2012) Molding cell beads for rapid construction of macroscopic 3D tissue architecture. Adv Healthc Mater 23:90–94. doi:10.1002/adma.201004375

  16. Murphy SV, Atala A (2014) 3D bioprinting of tissue and organs. Nat Biotechnol 32:773–785. doi:10.1038/nbt.2958

  17. Onoe H, Okitsu T, Itou A, Negishi MK, Gojo R, Kiriya D, Sato K, Miura S, Lwanaga S, Shigetomi KK, Matsunaga YT, Shimoyama Y, Takeuchi S (2013) Metre-long cell-laden microfibers exhibit tissue morphologies and functions. Nat Mater 12:584–590. doi:10.1038/NMAT3606

  18. Qin D, Xia Y, Whitesides GM (2010) Soft lithography for micro- and nanoscale patterning. Nat Protoc 5:491–502. doi:10.1038/nprot.2009.234

  19. Sun T, Hu CZ, Nakajima M, Takeuchi M, Seki M, Yue T, Shi Q, Fukuda T, Huang Q (2015) On-chip fabrication and magnetic force estimation of peapod-like hybrid microfibers using a microfluidic device. Microfluid Nanofluid 18:1177–1187. doi:10.1007/s10404-014-1511-y

  20. Tamayol A, Akbari M, Annabi N, Paul A, Khademhosseini A, Juncker D (2013) Fiber-based tissue engineering: progress, challenges, and opportunities. Biotechnol Adv 31:669–687. doi:10.1016/j.biotechadv.2012.11.007

  21. Tasoglu S, Diller E, Guven S, Sitti M, Demirci U (2014) Untethered micro-robotic coding of three-dimensional materials composition. Nat Commun. doi:10.1038/ncomms4124

  22. Thomas A, Gilson CD, Ahmed T (1995) Gelling of alginate fibres. J Chem Technol Biotechnol 64:73–79

  23. Wang HP, Huang Q, Shi Q, Yue T, Chen SQ, Nakajima M, Takeuchi M, Fukuda T (2015) Automated assembly of vascular-like microtube with repetitive single-step contact manipulation. IEEE Trans Biomed Eng. doi:10.1109/TBME.2015.2437952

  24. Xu F, Wu MCA, Rengarajan V, Finley TD, Keles HO, Sung Y, Li BQ, Gurkan UA, Demirci U (2011) Three-dimensional magnetic assembly of microscale hydrogels. Adv Mater 23:4254–4260. doi:10.1002/adma.201101962

  25. Xu CX, Chai WX, Huang Y, Markwald RR (2012) Scaffold-free inkjet printing of three-dimensional Zigzag cellular tubes. Biotechnol Bioeng 109:3152–3160. doi:10.1002/bit.24591

  26. Yamada KM, Cukierman E (2007) Modeling tissue morphogenesis and cancer in 3D. Cell 130:601–610. doi:10.1016/j.cell.2007.08.006

  27. Yamada M, Sugaya S, Naganuma Y, Seki M (2012a) Microfluidic synthesis of chemically and physically anisotropic hydrogel microfibers for guided cell growth and networking. Soft Matter 8:3122–3130. doi:10.1039/c2sm07263g

  28. Yamada M, Utoh R, Ohashi K, Tatsumi K, Yamato M, Okano T, Seki M (2012b) Controlled formation of heterotypic micro-organoids in anisotropic hydrogel microfibers for long-term preservation of liver-specific functions. Biomaterials 33:8304–8315. doi:10.1016/j.biomaterials.2012.07.068

  29. Yang K, Peng HB, Wen YH, Li N (2009) Re-examination of characteristic FTIR spectrum of secondary layer in bilayer oleic acid-coated Fe3O4 nanoparticles. Appl Surf Sci 256:3093–3097. doi:10.1016/j.apsusc.2009.11.079

  30. Yu Y, Wen H, Ma JY, Lykkemark S, Xu H, Qin JH (2014) Flexible fabrication of biomimetic bamboo-like hybrid microfibers. Adv Mater 26:2494–2499. doi:10.1002/adma.201304974

  31. Yue T, Nakajima M, Takeuchi M, Hu CZ, Huang Q, Fukuda T (2014) On-chip self-assembly of cell embedded microstructures to vascular-like microtubes. Lab Chip 14:1151–1161. doi:10.1039/c3lc51134k

  32. Zhao Y, Yao R, Ouyang LL, Ding HX, Zhang T, Zhang KT, Cheng SJ, Sun W (2014) Three-dimensional printing of hela cells for cervical tumor model in vitro. Biofabrication. doi:10.1088/1758-5082/6/3/035001

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We thank Hasegawa Laboratory at Nagoya University for the help of the design of microfluidic device and cell experiments. This research was supported by the National Nature Science Foundation of China under Grants 61375108 and 61520106011, and “111 project” under Grant B08043.

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Correspondence to Qing Shi.

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Sun, T., Huang, Q., Shi, Q. et al. Magnetic assembly of microfluidic spun alginate microfibers for fabricating three-dimensional cell-laden hydrogel constructs. Microfluid Nanofluid 19, 1169–1180 (2015).

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  • Magnetic assembly
  • 3D cellular structures
  • Microfluidic “printing” method
  • Alginate microfibers
  • Magnetic nanoparticles