Bioreactors and Microfluidics for Osteochondral Interface Maturation

  • Raphaël F. Canadas
  • Alexandra P. Marques
  • Rui L. ReisEmail author
  • J. Miguel Oliveira
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1059)


The cell culture techniques are in the base of any biology-based science. The standard techniques are commonly static platforms as Petri dishes, tissue culture well plates, T-flasks, or well plates designed for spheroids formation. These systems faced a paradigm change from 2D to 3D over the current decade driven by the tissue engineering (TE) field. However, 3D static culture approaches usually suffer from several issues as poor homogenization of the formed tissues and development of a necrotic center which limits the size of in vitro tissues to hundreds of micrometers. Furthermore, for complex tissues as osteochondral (OC), more than recovering a 3D environment, an interface needs to be replicated. Although 3D cell culture is already the reality adopted by a newborn market, a technological revolution on cell culture devices needs a further step from static to dynamic already considering 3D interfaces with dramatic importance for broad fields such as biomedical, TE, and drug development. In this book chapter, we revised the existing approaches for dynamic 3D cell culture, focusing on bioreactors and microfluidic systems, and the future directions and challenges to be faced were discussed. Basic principles, advantages, and challenges of each technology were described. The reported systems for OC 3D TE were focused herein.


Bioreactors Microfluidics Dynamic systems Osteochondral tissue engineering 



This work is a result of the project FROnTHERA (NORTE-01-0145- FEDER-000023), supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). Thanks are also due to the Portuguese Foundation for Science and Technology (FCT) for the project PEst-C/SAU/LA0026/201 and for the distinction attributed to J.M. Oliveira under the Investigator FCT program (IF/00423/2012 and IF/01285/2015). The authors also thank FCT for the Ph.D. scholarship provided to R. F. Canadas (SFRH/BD/92565/2013).


  1. 1.
    van Duinen V, Trietsch SJ, Joore J, Vulto P, Hankemeier T (2015) Microfluidic 3D cell culture: from tools to tissue models. Curr Opin Biotechnol [Internet] 35(Supplement C):118–126. Available from: CrossRefGoogle Scholar
  2. 2.
    Griffith LG, Swartz MA (2006) Capturing complex 3D tissue physiology in vitro. Nat Rev Mol Cell Biol 7(3):211–224CrossRefGoogle Scholar
  3. 3.
    Martin I, Miot S, Barbero A, Jakob M, Wendt D (2007) Osteochondral tissue engineering. J Biomech [Internet] 40(4):750–765. Available from: CrossRefGoogle Scholar
  4. 4.
    Lories RJ, Luyten FP (2011) The bone-cartilage unit in osteoarthritis. Nat Rev Rheumatol 7(1):43–49CrossRefGoogle Scholar
  5. 5.
    Goldman SM, Barabino GA (2016) Spatial engineering of osteochondral tissue constructs through Microfluidically directed differentiation of Mesenchymal stem cells. Biores Open Access [Internet] 5(1):109–117. Available from: CrossRefGoogle Scholar
  6. 6.
    Liu X, Jiang H (2013) Preparation of an osteochondral composite with mesenchymal stem cells as the single-cell source in a double-chamber bioreactor. Biotechnol Lett [Internet] 35(10):1645–1653. Available from: CrossRefGoogle Scholar
  7. 7.
    Khademhosseini A, Langer R, Borenstein J, Vacanti JP (2006) Microscale technologies for tissue engineering and biology. Proc Natl Acad Sci U S A [Internet]. 103(8):2480–2487. Available from: CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Bhatia SN, Ingber DE (2014) Microfluidic organs-on-chips. Nat Biotech [Internet] 32(8):760–772. Available from: CrossRefGoogle Scholar
  9. 9.
    Barron V, Lyons E, Stenson-Cox C, McHugh PE, Pandit A (2003) Bioreactors for cardiovascular cell and tissue growth: a review. Ann Biomed Eng [Internet] 31(9):1017–1030. Available from: CrossRefGoogle Scholar
  10. 10.
    Costa PF, Vaquette C, Baldwin J, Chhaya M, Gomes ME, Reis RL et al (2014) Biofabrication of customized bone grafts by combination of additive manufacturing and bioreactor knowhow. Biofabrication [Internet] 6(3):35006. Available from: CrossRefGoogle Scholar
  11. 11.
    Antoni D, Burckel H, Josset E, Noel G (2015) Three-dimensional cell culture: a breakthrough in vivo. Rahaman MN, editor. Int J Mol Sci [Internet] 16(3):5517–5527. Available from: CrossRefGoogle Scholar
  12. 12.
    Grayson WL, Bhumiratana S, Cannizzaro C, Chao PH, Lennon DP, Caplan AI et al (2008) Effects of initial seeding density and fluid perfusion rate on formation of tissue-engineered bone. Tissue Eng Part A [Internet] 14(11):1809–1820. Available from: CrossRefGoogle Scholar
  13. 13.
    Kleinhans C, Mohan RR, Vacun G, Schwarz T, Haller B, Sun Y et al (2015) A perfusion bioreactor system efficiently generates cell-loaded bone substitute materials for addressing critical size bone defects. Biotechnol J 10(11):1727–1738CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Gardel LS, Serra LA, Reis RL, Gomes ME (2013) Use of perfusion bioreactors and large animal models for long bone tissue engineering. Tissue Eng Part B Rev [Internet] 20(2):126–146. Available from: CrossRefGoogle Scholar
  15. 15.
    Massai D, Isu G, Madeddu D, Cerino G, Falco A, Frati C et al (2016) A versatile bioreactor for dynamic suspension cell culture. Application to the culture of cancer cell spheroids. Pesce M, editor. PLoS One [Internet] 11(5):e0154610. Available from: CrossRefGoogle Scholar
  16. 16.
    Goldstein AS, Juarez TM, Helmke CD, Gustin MC, Mikos AG (2001) Effect of convection on osteoblastic cell growth and function in biodegradable polymer foam scaffolds. Biomaterials [Internet] 22(11):1279–1288. Available from: CrossRefGoogle Scholar
  17. 17.
    Andersson H, van den Berg A (2004) Microfabrication and microfluidics for tissue engineering: state of the art and future opportunities. Lab Chip [Internet] 4(2):98–103. Available from: CrossRefGoogle Scholar
  18. 18.
    Cartmell SH, Porter BD, Garcia AJ, Guldberg RE (2003) Effects of medium perfusion rate on cell-seeded three-dimensional bone constructs in vitro. Tissue Eng 9(6):1197–1203CrossRefGoogle Scholar
  19. 19.
    Ishaug SL, Crane GM, Miller MJ, Yasko AW, Yaszemski MJ, Mikos AG (1997) Bone formation by three-dimensional stromal osteoblast culture in biodegradable polymer scaffolds. J Biomed Mater Res 36(1):17–28CrossRefPubMedGoogle Scholar
  20. 20.
    Polacheck WJ, German AE, Mammoto A, Ingber DE, Kamm RD (2014) Mechanotransduction of fluid stresses governs 3D cell migration. Proc Natl Acad Sci [Internet] 111(7):2447–2452. Available from: CrossRefGoogle Scholar
  21. 21.
    Tarbell JM, Shi Z-D, Dunn J, Jo H (2014) Fluid mechanics, arterial disease, and gene expression. Annu Rev Fluid Mech [Internet] 46:591–614. Available from: CrossRefGoogle Scholar
  22. 22.
    Li X (James), Valadez AV, Zuo P, Nie Z (2012) Microfluidic 3D cell culture: potential application for tissue-based bioassays. Bioanalysis [Internet] 4(12):1509–1525. Available from: CrossRefGoogle Scholar
  23. 23.
    Song L, Zhou Q, Duan P, Guo P, Li D, Xu Y et al (2012) Successful development of small diameter tissue-engineering vascular vessels by our novel integrally designed pulsatile perfusion-based bioreactor. PLoS One [Internet] 7(8):e42569. Available from: CrossRefGoogle Scholar
  24. 24.
    Wang B, Wang G, To F, Butler JR, Claude A, McLaughlin RM et al (2013) Myocardial scaffold-based cardiac tissue engineering: application of coordinated mechanical and electrical stimulations. Langmuir [Internet] 29(35):11109–11117. Available from: CrossRefGoogle Scholar
  25. 25.
    Grodzinsky AJ, Levenston ME, Jin M, Frank EH (2000) Cartilage tissue remodeling in response to mechanical forces. Annu Rev Biomed Eng [Internet] 2(1):691–713. Available from: CrossRefGoogle Scholar
  26. 26.
    Santoro M, Lamhamedi-Cherradi S-E, Menegaz BA, Ludwig JA, Mikos AG (2015) Flow perfusion effects on three-dimensional culture and drug sensitivity of Ewing sarcoma. Proc Natl Acad Sci U S A [Internet] 112(33):10304–10309. Available from: CrossRefPubMedCentralGoogle Scholar
  27. 27.
    Kou S, Pan L, van Noort D, Meng G, Wu X, Sun H et al (2011) A multishear microfluidic device for quantitative analysis of calcium dynamics in osteoblasts. Biochem Biophys Res Commun [Internet] 408(2):350–355. Available from: CrossRefGoogle Scholar
  28. 28.
    Porter B, Zauel R, Stockman H, Guldberg R, Fyhrie D (2005) 3-D computational modeling of media flow through scaffolds in a perfusion bioreactor. J Biomech [Internet] 38(3):543–549. Available from: CrossRefGoogle Scholar
  29. 29.
    Godara P, McFarland CD, Nordon RE (2008) Design of bioreactors for mesenchymal stem cell tissue engineering. J Chem Technol Biotechnol [Internet] 83(4):408–420. Available from: CrossRefGoogle Scholar
  30. 30.
    Mao AS, Mooney DJ (2015) Regenerative medicine: current therapies and future directions. Proc Natl Acad Sci U S A [Internet] 112(47):14452–14459. Available from: CrossRefGoogle Scholar
  31. 31.
    Gharravi AM, Orazizadeh M, Ansari-Asl K, Banoni S, Izadi S, Hashemitabar M (2012) Design and fabrication of anatomical bioreactor systems containing alginate scaffolds for cartilage tissue engineering. Avicenna J Med Biotechnol [Internet] 4(2):65–74. Available from: Google Scholar
  32. 32.
    Powers MJ, Domansky K, Kaazempur-Mofrad MR, Kalezi A, Capitano A, Upadhyaya A et al (2002) A microfabricated array bioreactor for perfused 3D liver culture. Biotechnol Bioeng 78(3):257–269CrossRefPubMedGoogle Scholar
  33. 33.
    Naciri M, Kuystermans D, Al-Rubeai M (2008) Monitoring pH and dissolved oxygen in mammalian cell culture using optical sensors. Cytotechnology [Internet] 57(3):245–250. Available from: CrossRefGoogle Scholar
  34. 34.
    da Costa PF, Martins AMP, Gomes MME, das Neves NJMA, dos Reis RLG (2011) Multichamber bioreactor with bidirectional perfusion integrated in a culture system for tissue engineering strategies [Internet]. Google Patents. Available from:
  35. 35.
    Sucosky P, Osorio DF, Brown JB, Neitzel GP (2004) Fluid mechanics of a spinner-flask bioreactor. Biotechnol Bioeng [Internet] 85(1):34–46. Available from: CrossRefGoogle Scholar
  36. 36.
    Altman GH, Horan RL, Martin I, Farhadi J, Stark PRH, Volloch V et al (2002) Cell differentiation by mechanical stress. FASEB J [Internet] 16(2):270–272. Available from: CrossRefGoogle Scholar
  37. 37.
    van der DWJ S, van ACC S, Boonen KJM, Langelaan MLP, Bouten CVC, Baaijens FPT (2013) Engineering skeletal muscle tissues from murine myoblast progenitor cells and application of electrical stimulation. J Vis Exp 73:e4267Google Scholar
  38. 38.
    Tsimbouri PM, Childs PG, Pemberton GD, Yang J, Jayawarna V, Orapiriyakul W et al (2017) Stimulation of 3D osteogenesis by mesenchymal stem cells using a nanovibrational bioreactor. Nat Biomed Eng [Internet] 1(9):758–770. Available from: CrossRefGoogle Scholar
  39. 39.
    Canadas RF, Marques AP, Oliveira JM, Reis RL (2014) Rotational dual chamber bioreactor: methods and uses thereof [Internet]. WO2014141136 A1. Available from:
  40. 40.
    Canadas RF, Oliveira JM, Marques AP, Reis RL (2016) Multi-chambers bioreactor, methods and uses [Internet]. Association for the Advancement of Tissue Engineering and Cell Based Technologies and Therapies - A4Tec; WO 2016042533 A1. Available from:
  41. 41.
    Bancroft GN, Sikavitsas VI, Mikos AG (2003) Technical note: design of a flow perfusion bioreactor system for bone tissue-engineering applications. Tissue Eng [Internet] 9(3):549–554. Available from: CrossRefGoogle Scholar
  42. 42.
    Kim JB (2005) Three-dimensional tissue culture models in cancer biology. Semin Cancer Biol [Internet] 15(5):365–377. Available from: CrossRefGoogle Scholar
  43. 43.
    Rodday B, Hirschhaeuser F, Walenta S, Mueller-Klieser W (2011) Semiautomatic growth analysis of multicellular tumor spheroids. J Biomol Screen [Internet] 16(9):1119–1124. Available from: CrossRefGoogle Scholar
  44. 44.
    Vunjak-Novakovic G, Obradovic B, Martin I, Bursac PM, Langer R, Freed LE (1998) Dynamic cell seeding of polymer scaffolds for cartilage tissue engineering. Biotechnol Prog [Internet] 14(2):193–202. Available from: CrossRefGoogle Scholar
  45. 45.
    Sikavitsas VI, Bancroft GN, Mikos AG (2002) Formation of three-dimensional cell/polymer constructs for bone tissue engineering in a spinner flask and a rotating wall vessel bioreactor. J Biomed Mater Res [Internet] 62(1):136–148. Available from: CrossRefGoogle Scholar
  46. 46.
    Vunjak-Novakovic G, Searby N, De Luis J, Freed LE (2002) Microgravity studies of cells and tissues. Ann N Y Acad Sci [Internet] 974(1):504–517. Available from: CrossRefGoogle Scholar
  47. 47.
    Vunjak-Novakovic G, Martin I, Obradovic B, Treppo S, Grodzinsky AJ, Langer R et al (1999) Bioreactor cultivation conditions modulate the composition and mechanical properties of tissue-engineered cartilage. J Orthop Res [Internet] 17(1):130–138. Available from: CrossRefGoogle Scholar
  48. 48.
    Goodwin TJ, Prewett TL, Wolf DA, Spaulding GF (1993) Reduced shear stress: a major component in the ability of mammalian tissues to form three-dimensional assemblies in simulated microgravity. J Cell Biochem [Internet] 51(3):301–311. Available from: CrossRefGoogle Scholar
  49. 49.
    Marlovits S, Tichy B, Truppe M, Gruber D, Vecsei V (2003) Chondrogenesis of aged human articular cartilage in a scaffold-free bioreactor. Tissue Eng 9(6):1215–1226CrossRefPubMedGoogle Scholar
  50. 50.
    Saini S, Wick TM (2003) Concentric cylinder bioreactor for production of tissue engineered cartilage: effect of seeding density and hydrodynamic loading on construct development. Biotechnol Prog [Internet] 19(2):510–521. Available from: CrossRefGoogle Scholar
  51. 51.
    Williams KA, Saini S, Wick TM (2002) Computational fluid dynamics modeling of steady-state momentum and mass transport in a bioreactor for cartilage tissue engineering. Biotechnol Prog [Internet] 18(5):951–963. Available from: CrossRefGoogle Scholar
  52. 52.
    Barrila J, Radtke AL, Crabbé A, Sarker SF, Herbst-Kralovetz MM, Ott CM et al (2010) Organotypic 3D cell culture models: using the rotating wall vessel to study host–pathogen interactions. Nat Rev Micro [Internet] 8(11):791–801. Available from: CrossRefGoogle Scholar
  53. 53.
    Wendt D, Marsano A, Jakob M, Heberer M, Martin I (2003) Oscillating perfusion of cell suspensions through three-dimensional scaffolds enhances cell seeding efficiency and uniformity. Biotechnol Bioeng [Internet] 84(2):205–214. Available from: CrossRefGoogle Scholar
  54. 54.
    Sikavitsas VI, Bancroft GN, Holtorf HL, Jansen JA, Mikos AG (2003) Mineralized matrix deposition by marrow stromal osteoblasts in 3D perfusion culture increases with increasing fluid shear forces. Proc Natl Acad Sci U S A [Internet] 100(25):14683–14688. Available from: CrossRefPubMedCentralGoogle Scholar
  55. 55.
    Gomes ME, Sikavitsas VI, Behravesh E, Reis RL, Mikos AG (2003) Effect of flow perfusion on the osteogenic differentiation of bone marrow stromal cells cultured on starch-based three-dimensional scaffolds. J Biomed Mater Res Part A [Internet] 67A(1):87–95. Available from: CrossRefGoogle Scholar
  56. 56.
    Shahin K, Doran PM (2015) Shear and compression bioreactor for cartilage synthesis BT – cartilage tissue engineering: methods and protocols. In: Doran PM, editor. New York, NY: Springer New York. Methods Mol Biol 1340:221–233. Available from: CrossRefPubMedGoogle Scholar
  57. 57.
    Correia C, Pereira AL, Duarte ARC, Frias AM, Pedro AJ, Oliveira JT et al (2012) Dynamic culturing of cartilage tissue: the significance of hydrostatic pressure. Tissue Eng Part A [Internet] 18(19–20):1979–1991. Available from: CrossRefGoogle Scholar
  58. 58.
    Cochis A, Grad S, Stoddart MJ, Farè S, Altomare L, Azzimonti B et al (2017) Bioreactor mechanically guided 3D mesenchymal stem cell chondrogenesis using a biocompatible novel thermo-reversible methylcellulose-based hydrogel. Sci Rep [Internet] 7:45018. Available from: CrossRefPubMedCentralGoogle Scholar
  59. 59.
    Holt GE, Halpern JL, Dovan TT, Hamming D, Schwartz HS (2005) Evolution of an in vivo bioreactor. J Orthop Res [Internet] 23(4):916–923. Available from: CrossRefGoogle Scholar
  60. 60.
    Stevens MM, Marini RP, Schaefer D, Aronson J, Langer R, Shastri VP (2005) In vivo engineering of organs: the bone bioreactor. Proc Natl Acad Sci U S A [Internet] 102(32):11450–11455. Available from: CrossRefGoogle Scholar
  61. 61.
    Gupta N, Liu JR, Patel B, Solomon DE, Vaidya B, Gupta V (2016) Microfluidics-based 3D cell culture models: utility in novel drug discovery and delivery research. Bioeng Transl Med [Internet] 1(1):63–81. Available from: Google Scholar
  62. 62.
    Inamdar NK, Borenstein JT (2011) Microfluidic cell culture models for tissue engineering. Curr Opin Biotechnol [Internet] 22(5):681–689. Available from: CrossRefGoogle Scholar
  63. 63.
    Novotný J, Foret F (2017) Fluid manipulation on the micro-scale: basics of fluid behavior in microfluidics. J Sep Sci [Internet] 40(1):383–394. Available from: CrossRefGoogle Scholar
  64. 64.
    Gu H, Duits MHG, Mugele F (2011) Droplets formation and merging in two-phase flow microfluidics. Int J Mol Sci [Internet] 12(4):2572–2597. Available from: CrossRefGoogle Scholar
  65. 65.
    Lin L, Chu Y-S, Thiery JP, Lim CT, Rodriguez I (2013) Microfluidic cell trap array for controlled positioning of single cells on adhesive micropatterns. Lab Chip [Internet] 13(4):714–721. Available from: CrossRefGoogle Scholar
  66. 66.
    Geng T, Bredeweg EL, Szymanski CJ, Liu B, Baker SE, Orr G et al (2015) Compartmentalized microchannel array for high-throughput analysis of single cell polarized growth and dynamics. Sci Rep [Internet] 5:16111. Available from: CrossRefGoogle Scholar
  67. 67.
    Horayama M, Shinha K, Kabayama K, Fujii T, Kimura H (2016) Spatial chemical stimulation control in microenvironment by microfluidic probe integrated device for cell-based assay. PLoS One [Internet] 11(12):e0168158. Available from: CrossRefGoogle Scholar
  68. 68.
    Jivani RR, Lakhtaria GJ, Patadiya DD, Patel LD, Jivani NP, Jhala BP (2016) Biomedical microelectromechanical systems (BioMEMS): revolution in drug delivery and analytical techniques. Saudi Pharm J [Internet] 24(1):1–20. Available from: CrossRefGoogle Scholar
  69. 69.
    Lin J-L, Wang S-S, Wu M-H, Oh-Yang C-C (2011) Development of an integrated microfluidic perfusion cell culture system for real-time microscopic observation of biological cells. Sensors 11(9):8395–8411CrossRefPubMedGoogle Scholar
  70. 70.
    Mauleon G, Fall CP, Eddington DT (2012) Precise spatial and temporal control of oxygen within in vitro brain slices via microfluidic gas channels. PLoS One [Internet] 7(8):e43309. Available from: CrossRefGoogle Scholar
  71. 71.
    Khan DH, Roberts SA, Cressman JR, Agrawal N (2017) Rapid generation and detection of biomimetic oxygen concentration gradients in vitro. Sci Rep [Internet] 7(1):13487. Available from: CrossRefGoogle Scholar
  72. 72.
    Folch A, Ayon A, Hurtado O, Schmidt MA, Toner M (1999) Molding of deep polydimethylsiloxane microstructures for microfluidics and biological applications. J Biomech Eng [Internet] 121(1):28–34. Available from: CrossRefGoogle Scholar
  73. 73.
    Folch A, Toner M (1998) Cellular micropatterns on biocompatible materials. Biotechnol Prog 14(3):388–392CrossRefPubMedGoogle Scholar
  74. 74.
    Ling Y, Rubin J, Deng Y, Huang C, Demirci U, Karp JM et al (2007) A cell-laden microfluidic hydrogel. Lab Chip [Internet] 7(6):756–762. Available from: CrossRefGoogle Scholar
  75. 75.
    Martinez AW, Phillips ST, Whitesides GM (2008) Three-dimensional microfluidic devices fabricated in layered paper and tape. Proc Natl Acad Sci [Internet] 105(50):19606–19611. Available from: CrossRefGoogle Scholar
  76. 76.
    Derda R, Laromaine A, Mammoto A, Tang SKY, Mammoto T, Ingber DE et al (2009) Paper-supported 3D cell culture for tissue-based bioassays. Proc Natl Acad Sci [Internet] 106(44):18457–18462. Available from: CrossRefGoogle Scholar
  77. 77.
    Chen CS, Mrksich M, Huang S, Whitesides GM, Ingber DE (1997) Geometric control of cell life and death. Science [Internet] 276(5317):1425–1428. Available from: Google Scholar
  78. 78.
    Koh W-G, Pishko MV (2006) Fabrication of cell-containing hydrogel microstructures inside microfluidic devices that can be used as cell-based biosensors. Anal Bioanal Chem [Internet] 385(8):1389–1397. Available from: CrossRefGoogle Scholar
  79. 79.
    Tan W, Desai TA (2005) Microscale multilayer cocultures for biomimetic blood vessels. J Biomed Mater Res Part A [Internet] 72A(2):146–160. Available from: CrossRefGoogle Scholar
  80. 80.
    Boyden S (1962) The chemotactic effect of mixtures of antibody and antigen on polymorphonuclear leucocytes. J Exp Med [Internet] 115(3):453–466. Available from: CrossRefGoogle Scholar
  81. 81.
    Chung S, Sudo R, Mack PJ, Wan C-R, Vickerman V, Kamm RD (2009) Cell migration into scaffolds under co-culture conditions in a microfluidic platform. Lab Chip [Internet] 9(2):269–275. Available from: CrossRefGoogle Scholar
  82. 82.
    Kuo C-T, Liu H-K, Huang G-S, Chang C-H, Chen C-L, Chen K-C et al (2014) A spatiotemporally defined in vitro microenvironment for controllable signal delivery and drug screening. Analyst [Internet] 139(19):4846–4854. Available from: CrossRefGoogle Scholar
  83. 83.
    Takayama S, Ostuni E, LeDuc P, Naruse K, Ingber DE, Whitesides GM (2001) Laminar flows: subcellular positioning of small molecules. Nature [Internet] 411(6841):1016. Available from: CrossRefGoogle Scholar
  84. 84.
    Baker BM, Trappmann B, Stapleton SC, Toro E, Chen CS (2013) Microfluidics embedded within extracellular matrix to define vascular architectures and pattern diffusive gradients. Lab Chip [Internet] 13(16):3246–3252. Available from: CrossRefGoogle Scholar
  85. 85.
    Trietsch SJ, Israels GD, Joore J, Hankemeier T, Vulto P (2013) Microfluidic titer plate for stratified 3D cell culture. Lab Chip [Internet] 13(18):3548–3554. Available from: CrossRefGoogle Scholar
  86. 86.
    Nève N, Kohles SS, Winn SR, Tretheway DC (2010) Manipulation of suspended single cells by microfluidics and optical tweezers. Cell Mol Bioeng [Internet] 3(3):213–228. Available from: CrossRefGoogle Scholar
  87. 87.
    Courson DS, Rock RS (2009) Fast benchtop fabrication of laminar flow chambers for advanced microscopy techniques. PLoS One [Internet] 4(8):e6479. Available from: CrossRefGoogle Scholar
  88. 88.
    Sart S, Tomasi RF-X, Amselem G, Baroud CN (2017) Multiscale cytometry and regulation of 3D cell cultures on a chip. Nat Commun [Internet] 8(1):469. Available from: CrossRefGoogle Scholar
  89. 89.
    Wang X, Phan DTT, George SC, Hughes CCW, Lee AP (2016) Engineering anastomosis between living capillary networks and endothelial cell-lined microfluidic channels. Lab Chip [Internet] 16(2):282–290. Available from: CrossRefGoogle Scholar
  90. 90.
    Responte DJ, Lee JK, Hu JC, Athanasiou KA (2012) Biomechanics-driven chondrogenesis: from embryo to adult. FASEB J [Internet] 26(9):3614–3624. Available from: CrossRefGoogle Scholar
  91. 91.
    Alexander PG, Song Y, Taboas JM, Chen FH, Melvin GM, Manner PA et al (2013) Development of a spring-loaded impact device to deliver injurious mechanical impacts to the articular cartilage surface. Cartilage [Internet] 4(1):52–62. Available from: CrossRefGoogle Scholar
  92. 92.
    Buckwalter JA (2002) Articular cartilage injuries. Clin Orthop Relat Res (402):21–37CrossRefGoogle Scholar
  93. 93.
    Repo RU, Finlay JB (1977) Survival of articular cartilage after controlled impact. J Bone Joint Surg Am 59(8):1068–1076CrossRefPubMedGoogle Scholar
  94. 94.
    Haut RC, Ide TM, De Camp CE (1995) Mechanical responses of the rabbit patello-femoral joint to blunt impact. J Biomech Eng [Internet] 117(4):402–408. Available from: CrossRefGoogle Scholar
  95. 95.
    Kuiper NJ, Wang QG, Cartmell SH (2014) A perfusion co-culture bioreactor for osteochondral tissue engineered plugs. J Biomater Tissue Eng [Internet] 4(2):162–171. Available from: CrossRefGoogle Scholar
  96. 96.
    Chang C-H, Lin F-H, Lin C-C, Chou C-H, Liu H-C (2004) Cartilage tissue engineering on the surface of a novel gelatin–calcium-phosphate biphasic scaffold in a double-chamber bioreactor. J Biomed Mater Res Part B Appl Biomater [Internet] 71B(2):313–321. Available from: CrossRefGoogle Scholar
  97. 97.
    Mahmoudifar N, Doran PM (2013) Osteogenic differentiation and osteochondral tissue engineering using human adipose-derived stem cells. Biotechnol Prog [Internet] 29(1):176–185. Available from: CrossRefGoogle Scholar
  98. 98.
    Goldman SM, Barabino GA (2017) Cultivation of agarose-based microfluidic hydrogel promotes the development of large, full-thickness, tissue-engineered articular cartilage constructs. J Tissue Eng Regen Med [Internet] 11(2):572–581. Available from: CrossRefGoogle Scholar
  99. 99.
    Shi X, Zhou J, Zhao Y, Li L, Wu H (2013) Gradient-regulated hydrogel for interface tissue engineering: steering simultaneous osteo/chondrogenesis of stem cells on a chip. Adv Healthc Mater [Internet] 2(6):846–853. Available from: CrossRefGoogle Scholar
  100. 100.
    Lin H, Lozito TP, Alexander PG, Gottardi R, Tuan RS (2014) Stem cell-based microphysiological osteochondral system to model tissue response to interleukin-1β. Mol Pharm [Internet] 11(7):2203–2212. Available from: CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Raphaël F. Canadas
    • 1
    • 2
  • Alexandra P. Marques
    • 1
    • 2
    • 3
  • Rui L. Reis
    • 1
    • 2
    • 3
    Email author
  • J. Miguel Oliveira
    • 1
    • 2
    • 3
  1. 1.3B’s Research Group – Biomaterials, Biodegradables and BiomimeticsUniversity of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative MedicineBarco, GuimarãesPortugal
  2. 2.ICVS/3B’s – PT Government Associate LaboratoryBraga/GuimarãesPortugal
  3. 3.The Discoveries Centre for Regenerative and Precision MedicineHeadquarters at University of MinhoGuimarãesPortugal

Personalised recommendations