Analytical and Bioanalytical Chemistry

, Volume 395, Issue 1, pp 185–193 | Cite as

Engineered 3D tissue models for cell-laden microfluidic channels

  • Young S. Song
  • Richard L. Lin
  • Grace Montesano
  • Naside G. Durmus
  • Grace Lee
  • Seung-Schik Yoo
  • Emre Kayaalp
  • Edward Hæggström
  • Ali Khademhosseini
  • Utkan Demirci
Original Paper


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.


3D tissue engineering Tissue perfusion Microfluidic channel Scaffold 



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.


  1. 1.
    Khademhosseini A, Langer R, Borenstein J, Vacanti JP (2006) Proc Natl Acad Sci 103:2480–2487CrossRefGoogle 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 9:104–107CrossRefGoogle Scholar
  3. 3.
    Drury JL, Mooney DJ (2003) Biomaterials 24:4337–4351CrossRefGoogle Scholar
  4. 4.
    Hollister SJ (2005) Nat Mater 4:518–525CrossRefGoogle Scholar
  5. 5.
    Yang S, Leong K, Du Z, Chua C (2001) Tissue Eng 7:679–689CrossRefGoogle Scholar
  6. 6.
    Choi NW, Cabodi M, Held B, Gleghorn JP, Bonassar LJ, Strook AD (2007) Nat Mater 6:908–915CrossRefGoogle 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, TorontoGoogle Scholar
  8. 8.
    Kim J (2005) Semin Cancer Biol 15:365–377CrossRefGoogle Scholar
  9. 9.
    Pickl M, Ries CH (2009) Oncogene 28:461–468CrossRefGoogle Scholar
  10. 10.
    Abbott A (2003) Nature 424:870–872CrossRefGoogle Scholar
  11. 11.
    Khademhosseini A, Eng G, Yeh J, Kucharczyk P, Langer R, Vunjak-Novakovic G, Radisic M (2007) Biomed Microdevices 9:149–157CrossRefGoogle Scholar
  12. 12.
    Ling Y, Rubin J, Deng Y, Huang C, Demirci U, Karp JM, Khademhosseini A (2007) Lab Chip 7:756–762CrossRefGoogle Scholar
  13. 13.
    Khademhosseini A, Eng G, Yeh J, Fukuda J, Blumling J, Langer R, Burdick JA (2006) J Biomed Mater Res Part A 79:522–532CrossRefGoogle Scholar
  14. 14.
    Nedović V, Willaert R(2003) Fundamentals of Cell Immobilisation Biotechnology, Kluwer, New YorkGoogle Scholar
  15. 15.
    Peter Lundberg PWK (1997) Magn Reson Med 37:44–52CrossRefGoogle Scholar
  16. 16.
    Rotem A, Toner M, Bhatia S, Foy BD, Tompkins RG, Yarmush ML (2004) Biotechnol Bioeng 43:654–660CrossRefGoogle Scholar
  17. 17.
    Augst AD, Kong HJ (2006) Mooney DJ 6:623–633Google Scholar
  18. 18.
    Xu T, Gregory C, Molnar P, Cui C, Jalota S, Bhaduri SB, Boland T (2006) Biomaterials 27:3580–3588Google Scholar
  19. 19.
    Mittal SK, Aggarwal N, Sailaja G, van Olphen A, HogenEsch H, North A et al (2000) Vaccine 19:253–263CrossRefGoogle Scholar
  20. 20.
    Stevens MM, Qanadilo HF, Langer R (2004) Biomaterials 25:887–894CrossRefGoogle 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 16:491–501CrossRefGoogle Scholar
  22. 22.
    Weibel DB, Whitesides GM (2006) Curr Opin Chem Biol 10:584–591CrossRefGoogle Scholar
  23. 23.
    Nguyen KT, West JL (2002) Biomaterials 23:4307–4314CrossRefGoogle Scholar
  24. 24.
    Albrecht DR, Tsang VL, Sah RL, Bhatia SN (2005) Lab Chip 5:111–118CrossRefGoogle Scholar
  25. 25.
    Demirci U, Montesano G (2007) Lab Chip 7:1139–1145CrossRefGoogle Scholar
  26. 26.
    Khademhosseini A, May MH, Sefton MV (2005) Tissue Eng 11:1797–1806CrossRefGoogle Scholar
  27. 27.
    Chrobak KM, Potter DR, Tien J (2006) Microvasc Res 71:185–196CrossRefGoogle Scholar
  28. 28.
    Nahmias Y, Kramvis I, Barbe L, Casali M, Berthiaume F, Yarmush ML (2006) FASEB J 20:E1828–E1836CrossRefGoogle Scholar
  29. 29.
    Shin M, Matsuda K, Ishii O, Terai H, Kaazempur-Mofrad M, Borenstein J et al (2004) Biomed Microdevices 4:269–278CrossRefGoogle Scholar
  30. 30.
    Fatin-Rouge N, Starchev K, Buffle J (2004) Biophys J 86:2710–2719CrossRefGoogle Scholar
  31. 31.
    Nicholson C (2001) Rep Prog Phys 64:815–884CrossRefGoogle Scholar
  32. 32.
    Frykman S, Srienc F (1998) Biotechnol Bioeng 59:214–226CrossRefGoogle Scholar
  33. 33.
    Jones KS, Sefton MV, Gorczynski RM (2004) Transplantation 78:1454–1462CrossRefGoogle Scholar
  34. 34.
    Gehrke SH, Fisher JP, Palasis M, Lund ME (1997) Ann N Y Acad Sci 831:179–207CrossRefGoogle Scholar
  35. 35.
    Khademhosseini A, Yeh J, Jon SY, Eng G, Suh KY, Burdick J, Langer R (2004) Lab Chip 4:425–430CrossRefGoogle Scholar
  36. 36.
    Volokh KY (2006) Acta Biomater 2:493–504CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Young S. Song
    • 1
  • Richard L. Lin
    • 1
  • Grace Montesano
    • 1
  • Naside G. Durmus
    • 2
  • Grace Lee
    • 1
  • Seung-Schik Yoo
    • 3
  • Emre Kayaalp
    • 4
  • Edward Hæggström
    • 5
  • Ali Khademhosseini
    • 3
    • 6
  • Utkan Demirci
    • 1
    • 3
    • 6
  1. 1.Bio-Acoustic-MEMS in Medicine Lab, HST Center for BioengineeringBrigham and Women’s Hospital, Harvard Medical SchoolCambridgeUSA
  2. 2.Department of Biomedical EngineeringBoston UniversityBostonUSA
  3. 3.Brigham and Women’s HospitalHarvard Medical SchoolBostonUSA
  4. 4.Yeditepe University Faculty of MedicineKayisdagiTurkey
  5. 5.Electronics Research Laboratory, Department of PhysicsUniversity of HelsinkiPOB 64,Finland
  6. 6.Division of Health Sciences and TechnologyHarvard-MITCambridgeUSA

Personalised recommendations