Monolithic 3D labs- and organs-on-chips obtained by lithography-based ceramic manufacture

  • Andrés Díaz Lantada
  • Adrián de Blas Romero
  • Martin Schwentenwein
  • Christopher Jellinek
  • Johannes Homa
  • Josefa Predestinación García-Ruíz
Open Access
ORIGINAL ARTICLE

Abstract

In this study, we present a novel approach for the design and development of three-dimensional monolithic ceramic microsystems with complex geometries and with potential applications in the biomedical field, mainly linked to labs-on-chips and organs-on-chips. The microsystem object of study stands out for its having a complex three-dimensional geometry, for being obtained as a single integrated element, hence reducing components, preventing leakage and avoiding post-processes, and for having a cantilever porous ceramic membrane aimed at separating cell culture chambers at different levels, which imitates the typical configuration of transwell assays. The design has been performed taking account of the special features of the manufacturing technology and includes ad hoc incorporated supporting elements, which do not affect overall performance, for avoiding collapse of the cantilever ceramic membrane during debinding and sintering. The manufacture of the complex three-dimensional microsystem has been accomplished by means of lithography-based ceramic manufacture, the additive manufacturing technology which currently provides the most appealing compromises between overall part size and precision when working with ceramic materials. The microsystem obtained provides one of the most remarkable examples of monolithic bio-microsystems and, to our knowledge, a step forward in the field of ceramic microsystems with complex geometries for lab-on-chip and organ-on-chip applications. Cell culture results help to highlight the potential of the proposed approach and the adequacy of using ceramic materials for biological applications and for interacting at a cellular level.

Keywords

Lithography-based ceramic manufacture Labs-on-chips Organs-on-chips Ceramic materials processing Biomedical microsystems MEMS Bio-MEMS 

References

  1. 1.
    Lanza R, Langer R, Vacanti J (2014) Principles of tissue engineering, 4th edn. ElsevierGoogle Scholar
  2. 2.
    Díaz Lantada A (2016) Handbook on microsystems for enhanced control of cell behaviour: fundamentals, design and manufacturing strategies, applications and challenges. SpringerGoogle Scholar
  3. 3.
    Jenkins G, Mansfield CD (2013) Microfluidic diagnostics: methods and protocols. SpringerGoogle Scholar
  4. 4.
    Preechaburana P, Filippini D (2011) Fabrication of monolithic 3D micro-systems. Lab Chip 11:288–295CrossRefGoogle Scholar
  5. 5.
    Gelber MK, Bhargava R (2015) Monolithic multilayer microfluidics via sacrificial molding of 3D-printed isomalt. Lab Chip 15(7):1736–1741CrossRefGoogle Scholar
  6. 6.
    Hengsbach S, Díaz Lantada A (2014) Rapid prototyping of multi-scale biomedical microdevices by combining additive manufacturing technologies. Biomed Microdevices 16(4):617–627CrossRefGoogle Scholar
  7. 7.
    Schmieder F, Ströbel J, Rösler M, Grünzner S, Hohenstein B, Klotzbach U, Sonntag F (2016) 3D printing—a key technology for tailored biomedical cell culture lab ware. Curr Dir Biomed Eng 2(1):105–108Google Scholar
  8. 8.
    Waheed S, Cabot JM, Macdonald NP, Lewis T, Guijt RM, Paull B, Breadmore MC (2016) 3D printed microfluidic devices: enablers and barriers. Lab Chip 16:1993–2013CrossRefGoogle Scholar
  9. 9.
    De Blas Romero A, Pfaffinger M, Mitteramskogler G, Schwentenwein M, Jellinek C, Homa J, Díaz Lantada A, Stampfl J (2016) Lithography-based additive manufacture of ceramic biodevices with design-controlled surface topographies. Int J Adv Manuf Technol, May (Online first) 1–9Google Scholar
  10. 10.
    Waldbaur A, Rapp H, Länge K, Rapp BE (2011) Let there be chip. Towards rapid prototyping of microfluidic devices: one-step manufacturing processes. Anal Methods 3(12):2681–2716CrossRefGoogle Scholar
  11. 11.
    Díaz Lantada A, De Blas Romero A, Chacón Tanarro E (2016) Micro-vascular shape-memory polymer actuators with complex geometries obtained by laser stereolithography. Smart Mater Struct 26:065018CrossRefGoogle Scholar
  12. 12.
    Hasan A, Paul A, Vrana NE, Zhao X, Memic A, Hwang YS, Dokmeci MR, Khademhosseini A (2014) Microfluidic techniques for development of 3D vascularized tissue. Biomaterials 35(26):7308–7325CrossRefGoogle Scholar
  13. 13.
    Gruber H et al (2006) Rapid-prototyping method and radiation-hardenable composition of application thereto. PCT/AT2006/000271, WO 2007002965 B1Google Scholar
  14. 14.
    Patzer JF (2011) Generative Fertigung von keramischen Bauteilen für dentale Anwendungen. Dissertation,TU WienGoogle Scholar
  15. 15.
    Felzmann R, Gruber S, Mitteramskogler G, Tesavibul P, Boccaccini AR, Liska R, Stampfl J (2012) Lithography-based additive manufacturing of cellular ceramic structures. Adv Eng Mater 14(12):1052–1058CrossRefGoogle Scholar
  16. 16.
    Schwentenwein M, Homa J (2015) Additive manufacture of dense alumina ceramics. Appl Ceram Technol 12(1):1–7CrossRefGoogle Scholar
  17. 17.
    Lennon DP, Haynesworth SE, Bruder SP, Jaiswal N, Caplan AI (2006) Human and animal mesenchymal progenitor cells from bone marrow: identification of serum for optimal selection and proliferation. In Vitro Cell Dev Biol 32:602CrossRefGoogle Scholar
  18. 18.
    Caplan AI, Dennis JE (2006) Mesenchymal stem cells as trophic mediators. J Cell Biochem 98(5):1076–1084CrossRefGoogle Scholar
  19. 19.
    Ogueta S, Muñoz J, Obregon E, Delgado-Baeza E, García-Ruiz JP (2002) Prolactin is a component of the human sinovial liquid and modulates the growth and chondrogenic differentiation of bone marrow-derived mesenchymal stem cells. Mol Cell Endocrinol 190(1–2):51CrossRefGoogle Scholar
  20. 20.
    Caplan AI (2013) Adult mesenchymal stem cells and the NO pathways. Proc Natl Acad Sci 110(8):2695–2696CrossRefGoogle Scholar
  21. 21.
    Alarcón H, Ynsa MD, Dang ZY, Torres-Costa V, Manso-Silván M, Wu JF, Breese MBH, García-Ruiz JP (2015) Conditioned bio-interfaces of silicon/porous silicon micro-patterns lead to the chondrogenesis of hMSCs. RSC Adv 5:92263–92269CrossRefGoogle Scholar
  22. 22.
    Díaz Lantada A, Alarcón Iniesta H, Pareja Sánchez B, García-Ruíz JP, (2014) Free-form rapid-prototyped PDMS scaffolds incorporating growth factors promote chondrogenesis. Adv Mater Sci Eng 612976Google Scholar
  23. 23.
    Díaz Lantada A, Alarcón Iniesta H, García-Ruíz JP (2015) Composite scaffolds for osteochondral repair obtained by combination of additive manufacturing, leaching processes and hMSC-CM functionalization. Mater Sci Eng C: Mater Biol Appl 59:218–227CrossRefGoogle Scholar
  24. 24.
    Romero-Prado M, Blázquez C, Rodríguez-Navas C, Muñoz J, Guerrero I, Delgado-Baeza E, García-Ruiz JP (2006) Functional characterization of human mesenchymal stem cells that maintain osteochondral fates. J Cell Biochem 98:1457CrossRefGoogle Scholar
  25. 25.
    Javed A, Guo B, Hiebert S, Choi JY, Green J, Zhao SC, Osborne MA, Stifani S, Stein JL, Lian JB, van Wijnen AJ, Stein GS (2000) Groucho/TLE/R-esp proteins associate with the nuclear matrix and repress RUNX (CBF (alpha)/AML/PEBP2(alpha)) dependent activation of tissue-specific gene transcription. J Cell Sci 113(Pt 12):2221Google Scholar
  26. 26.
    De Blas Romero A (2015) Optimization of photocurable zirconia slurries. Master’s Degree Thesis (J. Stampfl & A. Díaz Lantada (advisors)), TU Wien & Technical University of MadridGoogle Scholar
  27. 27.
    Eckel ZC, Zhou C, Martin JH, Jacobsen AJ, Carter WB, Schaedler TA (2016) Additive manufacturing of polymer-derived ceramics. Science 351(6268):58–62CrossRefGoogle Scholar
  28. 28.
    Li Z, Zhang DZ, Dong P, Kucukkoc I (2016) A lightweight and support-free design method for selective laser melting. Int J Adv Manuf Technol doi: 10.1007/s00170-016-9509-0
  29. 29.
    Soman P, Lee JW, Phadke A, Varghese S, Chen S (2012) Spatial tuning of negative and positive Poisson’s ratio in a multilayer scaffold. Acta Biomater 8(7):2587–2594CrossRefGoogle Scholar
  30. 30.
    Warkiani ME et al (2014) Slanted spiral microfluidics for the ultra-fast, label-free isolation of circulating tumor cells. Lab Chip 14:128–137CrossRefGoogle Scholar
  31. 31.
    Lee W, Kwon D, Choj W, Jung GY, Au AK, Folch A, Jeon S (2015) 3D-printed microfluidic device for the detection of pathogenic bacteria using size-based separation in helical channel with trapezoid cross-section. Sci Rep 5:7717CrossRefGoogle Scholar
  32. 32.
    Garcia-Ruiz JP, Matesanz Garcia AI, Perez Souza A, Souza Castelo P (2015) Thiosemicarbazone-Pt(II) complex causes a growth inhibitory effect on human mesenchymal stem cells. Med Chem 11(7):670–675CrossRefGoogle Scholar
  33. 33.
    Huh D, Hamilton GA, Ingber DE (2011) From 3D cell culture to organs on chips. Trends Cell Biol 21(12):745–754CrossRefGoogle Scholar
  34. 34.
    Wilhelm I, Fazakas C, Krizbai IA (2011) In vitro models of the blood-brain barrier. Acta Neurobiol Exp 71:113–128Google Scholar
  35. 35.
    Huh D, Kim HJ, Fraser JP, Shea DE, Khan M, Bahinski A, Hamilton GA, Ingber DE (2013) Microfabrication of human organs-on-chips. Nat Protoc 8:2135–2157CrossRefGoogle Scholar

Copyright information

© The Author(s) 2017

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  • Andrés Díaz Lantada
    • 1
  • Adrián de Blas Romero
    • 1
  • Martin Schwentenwein
    • 2
  • Christopher Jellinek
    • 2
  • Johannes Homa
    • 2
  • Josefa Predestinación García-Ruíz
    • 3
  1. 1.Product Development Laboratory, Department of Mechanical EngineeringUniversidad Politécnica de Madrid (UPM)MadridSpain
  2. 2.Lithoz GmbHViennaAustria
  3. 3.Departamento de Biología MolecularUniversidad Autónoma de MadridMadridSpain

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