Microfluidic generation of Buddha beads-like microcarriers for cell culture

微流控制备仿佛珠微载体用于细胞培养研究

Abstract

The fabrication of functional microcarriers capable of achieving in vivo-like three-dimensional cell culture is important for many tissue engineering applications. Here, inspired by the structure of Buddha beads, which are generally composed of moveable beads strung on a rope, we present novel cell microcarriers with controllable macropores and heterogeneous microstructures by using a capillary array microfluidic technology. Microfibers with a string of moveable and releasable microcarriers could be achieved by an immediate gelation reaction of sodium alginate spinning and subsequent polymerization of cell-dispersed gelatin methacrylate emulsification. The sizes of the microcarriers and their inner macropores could be well tailored by adjusting the flow rates of the microfluidic phases; this was of great importance in guaranteeing a sufficient supply of nutrients during cell culture. In addition, by infusing multiple cell-dispersed pregel solutions into the capillaries, the microcarriers with spatially heterogeneous cell encapsulations for mimicking physiological structures and functions could also be achieved.

摘要

构建可用于细胞三维培养的多功能微载体在组织工程的应用中至关重要. 本文受佛珠手串中佛珠可以在绳子上自由滑动这一特殊结构的启发, 利用毛细管阵列微流控技术制备了一种具有可控大孔微结构的新型异质细胞微载体, 用于细胞三维培养.仿佛珠微载体的构建首先需要通过海藻酸钠与钙离子的快速凝胶化形成海藻酸钙纤维, 随即在纤维上包覆可聚合的细胞预聚溶液, 通过流体的剪切实现溶液乳化并将其同化聚合, 从而获得串有可以自由滑动的微载体的纤维串.纤维上释放的微载体中间的大孔结构的尺寸高度可控, 这一特点在微载体用于细胞三维培养中具有重要意义, 因为微载体中间的大孔结构能够有效保证载体内部细胞氧气、 营养物质的充分交换, 减少细胞坏死.此外, 通过将多种细胞预聚溶液引入微流控通道中, 还可以获得具有多组分异质结构的细胞微载体, 从而有望实现体内复杂的组织器官结构与功能的模拟.

References

  1. 1

    Souza GR, Molina JR, Raphael RM, et al. Three-dimensional tissue culture based on magnetic cell levitation. Nat Nanotech, 2010, 5: 291–296

    Article  Google Scholar 

  2. 2

    Sun K, Liu M, Liu H, et al. Semi-egg-like heterogeneous compartmentalization of cells controlled by contact angle hysteresis. Adv Funct Mater, 2015, 25: 4506–4511

    Article  Google Scholar 

  3. 3

    Yuan B, Jin Y, Sun Y, et al. A strategy for depositing different types of cells in three dimensions to mimic tubular structures in tissues. Adv Mater, 2012, 24: 890–896

    Article  Google Scholar 

  4. 4

    Lee M, Yang K, Hwang YH, et al. Spheroform: therapeutic spheroid-forming nanotextured surfaces inspired by desert beetle Physosterna cribripes. Adv Healthcare Mater, 2015, 4: 511–515

    Article  Google Scholar 

  5. 5

    Cheng Y, Zheng F, Lu J, et al. Bioinspired multicompartmental microfibers from microfluidics. Adv Mater, 2014, 26: 5184–5190

    Article  Google Scholar 

  6. 6

    Yu Y, Fu F, Shang L, et al. Bioinspired helical microfibers from microfluidics. Adv Mater, 2017, 29: 1605765

    Article  Google Scholar 

  7. 7

    Frey O, Misun PM, Fluri DA, et al. Reconfigurable microfluidic hanging drop network for multi-tissue interaction and analysis. Nat Commun, 2014, 5: 4250

    Article  Google Scholar 

  8. 8

    Seo J, Lee JS, Lee K, et al. Switchable water-adhesive, superhydrophobic palladium-layered silicon nanowires potentiate the angiogenic efficacy of human stem cell spheroids. Adv Mater, 2014, 26: 7043–7050

    Article  Google Scholar 

  9. 9

    Chen Y, Shi J. Mesoporous carbon biomaterials. Sci China Mater, 2015, 58: 241–257

    Article  Google Scholar 

  10. 10

    Cheng Y, Yu Y, Fu F, et al. Controlled fabrication of bioactive microfibers for creating tissue constructs using microfluidic techniques. ACS Appl Mater Interfaces, 2016, 8: 1080–1086

    Article  Google Scholar 

  11. 11

    Zhang X, Xia LY, Chen X, et al. Hydrogel-based phototherapy for fighting cancer and bacterial infection. Sci China Mater, 2017, 60: 487–503

    Article  Google Scholar 

  12. 12

    Zhao Y, Cheng Y, Shang L, et al. Microfluidic synthesis of barcode particles for multiplex assays. Small, 2015, 11: 151–174

    Article  Google Scholar 

  13. 13

    Liu X, Jin X, Ma PX. Nanofibrous hollow microspheres self-assembled from star-shaped polymers as injectable cell carriers for knee repair. Nat Mater, 2011, 10: 398–406

    Article  Google Scholar 

  14. 14

    Wang J, Cheng Y, Yu Y, et al. Microfluidic generation of porous microcarriers for three-dimensional cell culture. ACS Appl Mater Interfaces, 2015, 7: 27035–27039

    Article  Google Scholar 

  15. 15

    Fu F, Shang L, Zheng F, et al. Cells cultured on core–shell photonic crystal barcodes for drug screening. ACS Appl Mater Interfaces, 2016, 8: 13840–13848

    Article  Google Scholar 

  16. 16

    Maeda K, Onoe H, Takinoue M, et al. Controlled synthesis of 3D multi-compartmental particles with centrifuge-based microdroplet formation from a multi-barrelled capillary. Adv Mater, 2012, 24: 1340–1346

    Article  Google Scholar 

  17. 17

    Liu Z, Shum HC. Fabrication of uniform multi-compartment particles using microfludic electrospray technology for cell coculture studies. Biomicrofluidics, 2013, 7: 044117

    Article  Google Scholar 

  18. 18

    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: 2809–2819

    Article  Google Scholar 

  19. 19

    Naqvi SM, Vedicherla S, Gansau J, et al. Living cell factories—electrosprayed microcapsules and microcarriers for minimally invasive delivery. Adv Mater, 2016, 28: 5662–5671

    Article  Google Scholar 

  20. 20

    Chen Q, Utech S, Chen D, et al. Controlled assembly of heterotypic cells in a core–shell scaffold: organ in a droplet. Lab Chip, 2016, 16: 1346–1349

    Article  Google Scholar 

  21. 21

    Tumarkin E, Kumacheva E. Microfluidic generation of microgels from synthetic and natural polymers. Chem Soc Rev, 2009, 38: 2161–2168

    Article  Google Scholar 

  22. 22

    Li Y, Yan D, Fu F, et al. Composite core-shell microparticles from microfluidics for synergistic drug delivery. Sci China Mater, 2017, 60: 543–553

    Article  Google Scholar 

  23. 23

    Griffin DR, Weaver WM, Scumpia PO, et al. Accelerated wound healing by injectable microporous gel scaffolds assembled from annealed building blocks. Nat Mater, 2015, 14: 737–744

    Article  Google Scholar 

  24. 24

    Headen DM, Aubry G, Lu H, et al. Microfluidic-based generation of size-controlled, biofunctionalized synthetic polymer microgels for cell encapsulation. Adv Mater, 2014, 26: 3003–3008

    Article  Google Scholar 

  25. 25

    Shang L, Fu F, Cheng Y, et al. Photonic crystal microbubbles as suspension barcodes. J Am Chem Soc, 2015, 137: 15533–15539

    Article  Google Scholar 

  26. 26

    Shang L, Fu F, Cheng Y, et al. Bioinspired multifunctional spindleknotted microfibers from microfluidics. Small, 2017, 13: 1600286

    Article  Google Scholar 

  27. 27

    Lee TY, Praveenkumar R, Oh YK, et al. Alginate microgels created by selective coalescence between core drops paired with an ultrathin shell. J Mater Chem B, 2016, 4: 3232–3238

    Article  Google Scholar 

  28. 28

    Sun J, Zhang L, Wang J, et al. Tunable rigidity of (polymeric core)-(lipid shell) nanoparticles for regulated cellular uptake. Adv Mater, 2015, 27: 1402–1407

    Article  Google Scholar 

  29. 29

    Utech S, Prodanovic R, Mao AS, et al. Microfluidic generation of monodisperse, structurally homogeneous alginate microgels for cell encapsulation and 3D cell culture. Adv Healthcare Mater, 2015, 4: 1628–1633

    Article  Google Scholar 

  30. 30

    Velasco D, Tumarkin E, Kumacheva E. Microfluidic encapsulation of cells in polymer microgels. Small, 2012, 8: 1633–1642

    Article  Google Scholar 

  31. 31

    Sakai S, Ito S, Inagaki H, et al. Cell-enclosing gelatin-based microcapsule production for tissue engineering using a microfluidic flow-focusing system. Biomicrofluidics, 2011, 5: 013402

    Article  Google Scholar 

  32. 32

    Matsunaga YT, Morimoto Y, Takeuchi S. Molding cell beads for rapid construction of macroscopic 3D tissue architecture. Adv Mater, 2011, 23: H90–H94

    Article  Google Scholar 

  33. 33

    Lu YC, Song W, An D, et al. Designing compartmentalized hydrogel microparticles for cell encapsulation and scalable 3D cell culture. J Mater Chem B, 2015, 3: 353–360

    Article  Google Scholar 

  34. 34

    Khetani SR, Bhatia SN. Microscale culture of human liver cells for drug development. Nat Biotechnol, 2007, 26: 120–126

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (21473029 and 51522302), the NSAF Foundation of China (U1530260), the Natural Science Foundation of Jiangsu (BK20140028), the Program for New Century Excellent Talents in University, the Scientific Research Foundation of Southeast University, and the Scientific Research Foundation of Graduate School of Southeast University.

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Correspondence to Yuanjin Zhao 赵远锦.

Additional information

Jie Wang received her BSc degree from Southeast University in 2014. She is now a PhD candidate under the supervision of Prof. Yuanjin Zhao at Southeast University. Her research interest is in the fabrication of functional materials based on microfluidics.

Yuanjin Zhao received his PhD degree in 2011 from Southeast University. In 2009–2010, he worked as a research scholar at Prof. David A. Weitz’s group in the School of Engineering and Applied Sciences, Harvard University. Since 2015, he was promoted to be a full professor of Southeast University. His current scientific interests include microfluidic-based materials fabrication, biosensors, and bio-inspired photonic nanomaterials.

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Microfluidic Generation of Buddha Beads-like Microcarriers for Cell Culture

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Wang, J., Zou, M., Sun, L. et al. Microfluidic generation of Buddha beads-like microcarriers for cell culture. Sci. China Mater. 60, 857–865 (2017). https://doi.org/10.1007/s40843-017-9081-5

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Keywords

  • microfluidics
  • microcarrier
  • cell culture
  • microfiber
  • emulsion