Engineered 3D tissue models for cell-laden microfluidic channels

Abstract

Delivery of nutrients and oxygen within three-dimensional (3D) tissue constructs is important to maintain cell viability. We built 3D cell-laden hydrogels to validate a new tissue perfusion model that takes into account nutrition consumption. The model system was analyzed by simulating theoretical nutrient diffusion into cell-laden hydrogels. We carried out a parametric study considering different microchannel sizes and inter-channel separation in the hydrogel. We hypothesized that nutrient consumption needs to be taken into account when optimizing the perfusion channel size and separation. We validated the hypothesis by experiments. We fabricated circular microchannels (r = 400 μm) in 3D cell-laden hydrogel constructs (R = 7.5 mm, volume = 5 ml). These channels were positioned either individually or in parallel within hydrogels to increase nutrient and oxygen transport as a way to improve cell viability. We quantified the spatial distribution of viable cells within 3D hydrogel scaffolds without channels and with single- and dual-perfusion microfluidic channels. We investigated quantitatively the cell viability as a function of radial distance from the channels using experimental data and mathematical modeling of diffusion profiles. Our simulations show that a large-channel radius as well as a large channel to channel distance diffuse nutrients farther through a 3D hydrogel. This is important since our results reveal that there is a close correlation between nutrient profiles and cell viability across the hydrogel.

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References

  1. 1.

    Khademhosseini A, Langer R, Borenstein J, Vacanti JP (2006) Proc Natl Acad Sci 103:2480–2487

    Article  CAS  Google Scholar 

  2. 2.

    Orive G, Hernández RM, Gascón AR, Calafiore R, Chang TMS, De Vos P, Hortelano G, Hunkeler D, Lacík I, James Shapiro AM, Pedraz JL (2003) Nat Med 9:104–107

    Article  CAS  Google Scholar 

  3. 3.

    Drury JL, Mooney DJ (2003) Biomaterials 24:4337–4351

    Article  CAS  Google Scholar 

  4. 4.

    Hollister SJ (2005) Nat Mater 4:518–525

    Article  CAS  Google Scholar 

  5. 5.

    Yang S, Leong K, Du Z, Chua C (2001) Tissue Eng 7:679–689

    Article  CAS  Google Scholar 

  6. 6.

    Choi NW, Cabodi M, Held B, Gleghorn JP, Bonassar LJ, Strook AD (2007) Nat Mater 6:908–915

    Article  CAS  Google Scholar 

  7. 7.

    Baksh D, Davies JE (2000) Design strategies for 3-dimensional in vitro bone growth in tissue-engineering scaffolds. University of Toronto Press, Toronto

    Google Scholar 

  8. 8.

    Kim J (2005) Semin Cancer Biol 15:365–377

    Article  Google Scholar 

  9. 9.

    Pickl M, Ries CH (2009) Oncogene 28:461–468

    Article  CAS  Google Scholar 

  10. 10.

    Abbott A (2003) Nature 424:870–872

    Article  CAS  Google Scholar 

  11. 11.

    Khademhosseini A, Eng G, Yeh J, Kucharczyk P, Langer R, Vunjak-Novakovic G, Radisic M (2007) Biomed Microdevices 9:149–157

    Article  Google Scholar 

  12. 12.

    Ling Y, Rubin J, Deng Y, Huang C, Demirci U, Karp JM, Khademhosseini A (2007) Lab Chip 7:756–762

    Article  CAS  Google Scholar 

  13. 13.

    Khademhosseini A, Eng G, Yeh J, Fukuda J, Blumling J, Langer R, Burdick JA (2006) J Biomed Mater Res Part A 79:522–532

    Article  CAS  Google Scholar 

  14. 14.

    Nedović V, Willaert R(2003) Fundamentals of Cell Immobilisation Biotechnology, Kluwer, New York

  15. 15.

    Peter Lundberg PWK (1997) Magn Reson Med 37:44–52

    Article  Google Scholar 

  16. 16.

    Rotem A, Toner M, Bhatia S, Foy BD, Tompkins RG, Yarmush ML (2004) Biotechnol Bioeng 43:654–660

    Article  Google Scholar 

  17. 17.

    Augst AD, Kong HJ (2006) Mooney DJ 6:623–633

    CAS  Google Scholar 

  18. 18.

    Xu T, Gregory C, Molnar P, Cui C, Jalota S, Bhaduri SB, Boland T (2006) Biomaterials 27:3580–3588

    CAS  Google Scholar 

  19. 19.

    Mittal SK, Aggarwal N, Sailaja G, van Olphen A, HogenEsch H, North A et al (2000) Vaccine 19:253–263

    Article  CAS  Google Scholar 

  20. 20.

    Stevens MM, Qanadilo HF, Langer R (2004) Biomaterials 25:887–894

    Article  CAS  Google Scholar 

  21. 21.

    Zimmermann H, Reuss R, Feilen PJ, Manz B, Katsen A, Weber M, Ihmig FR, Gessner P, Behringer M, Steinbach A, Wegner LH, Sukhorukov VL, Schneider S, Weber MM, Volke F, Wolf R, Zimmermann U (2005) J Mater Sci Mater Med 16:491–501

    Article  CAS  Google Scholar 

  22. 22.

    Weibel DB, Whitesides GM (2006) Curr Opin Chem Biol 10:584–591

    Article  CAS  Google Scholar 

  23. 23.

    Nguyen KT, West JL (2002) Biomaterials 23:4307–4314

    Article  CAS  Google Scholar 

  24. 24.

    Albrecht DR, Tsang VL, Sah RL, Bhatia SN (2005) Lab Chip 5:111–118

    Article  CAS  Google Scholar 

  25. 25.

    Demirci U, Montesano G (2007) Lab Chip 7:1139–1145

    Article  CAS  Google Scholar 

  26. 26.

    Khademhosseini A, May MH, Sefton MV (2005) Tissue Eng 11:1797–1806

    Article  CAS  Google Scholar 

  27. 27.

    Chrobak KM, Potter DR, Tien J (2006) Microvasc Res 71:185–196

    Article  CAS  Google Scholar 

  28. 28.

    Nahmias Y, Kramvis I, Barbe L, Casali M, Berthiaume F, Yarmush ML (2006) FASEB J 20:E1828–E1836

    Article  CAS  Google Scholar 

  29. 29.

    Shin M, Matsuda K, Ishii O, Terai H, Kaazempur-Mofrad M, Borenstein J et al (2004) Biomed Microdevices 4:269–278

    Article  Google Scholar 

  30. 30.

    Fatin-Rouge N, Starchev K, Buffle J (2004) Biophys J 86:2710–2719

    Article  CAS  Google Scholar 

  31. 31.

    Nicholson C (2001) Rep Prog Phys 64:815–884

    Article  CAS  Google Scholar 

  32. 32.

    Frykman S, Srienc F (1998) Biotechnol Bioeng 59:214–226

    Article  CAS  Google Scholar 

  33. 33.

    Jones KS, Sefton MV, Gorczynski RM (2004) Transplantation 78:1454–1462

    Article  Google Scholar 

  34. 34.

    Gehrke SH, Fisher JP, Palasis M, Lund ME (1997) Ann N Y Acad Sci 831:179–207

    Article  CAS  Google Scholar 

  35. 35.

    Khademhosseini A, Yeh J, Jon SY, Eng G, Suh KY, Burdick J, Langer R (2004) Lab Chip 4:425–430

    Article  CAS  Google Scholar 

  36. 36.

    Volokh KY (2006) Acta Biomater 2:493–504

    Article  CAS  Google Scholar 

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Acknowledgment

We would like to thank the Randolph Hearst Foundation and Department of Medicine, Brigham and Women’s Hospital for the Young Investigators in Medicine Award. This research is performed at the Bio-Acoustic-MEMS in Medicine (BAMM) Labs, HST Center for Bioengineering, Brigham and Women’s Hospital, Harvard Medical School.

Author contributions

YSS, RLL, UD, and EH wrote the paper. YSS carried out the simulation. GM and GL performed the experiments and collected data. YSS created the model and the theoretical analysis. RLL, YSS, GM, EH, and UD conducted the data analyses. GD, SSY, EK, AK, and EH read and gave feedback on the paper.

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Correspondence to Utkan Demirci.

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Author contributions

RLL, YSS, GD, and EH wrote the paper. GM and GL performed the experiments and collected data. RLL, YSS, and EH worked on the theoretical analysis. RLL, YSS, GM, EH, and UD conducted the data analyses. GD, SSY, EK, AK, and EH read and gave feedback on the paper. UD oversaw the project, designed the experiments, and wrote the paper.

Young Seok Song and Richard L. Lin have contributed equally to this contribution

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Song, Y.S., Lin, R.L., Montesano, G. et al. Engineered 3D tissue models for cell-laden microfluidic channels. Anal Bioanal Chem 395, 185–193 (2009). https://doi.org/10.1007/s00216-009-2935-1

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Keywords

  • 3D tissue engineering
  • Tissue perfusion
  • Microfluidic channel
  • Scaffold