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Instrumented cardiac microphysiological devices via multimaterial three-dimensional printing

Nature Materials volume 16, pages 303–308 (2017)Cite this article

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Abstract

Biomedical research has relied on animal studies and conventional cell cultures for decades. Recently, microphysiological systems (MPS), also known as organs-on-chips, that recapitulate the structure and function of native tissues in vitro, have emerged as a promising alternative1. However, current MPS typically lack integrated sensors and their fabrication requires multi-step lithographic processes2. Here, we introduce a facile route for fabricating a new class of instrumented cardiac microphysiological devices via multimaterial three-dimensional (3D) printing. Specifically, we designed six functional inks, based on piezo-resistive, high-conductance, and biocompatible soft materials that enable integration of soft strain gauge sensors within micro-architectures that guide the self-assembly of physio-mimetic laminar cardiac tissues. We validated that these embedded sensors provide non-invasive, electronic readouts of tissue contractile stresses inside cell incubator environments. We further applied these devices to study drug responses, as well as the contractile development of human stem cell-derived laminar cardiac tissues over four weeks.

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Figure 1: Device principle and microscale 3D-printing procedure.
Figure 2: Micro-grooves guide cardiomyocyte self-assembly into anisotropic engineered tissues.
Figure 3: CB:TPU gauge factor, sensor readout and example drug-dose studies.
Figure 4: Long-term hips-CM contractile development and thicker laminar NRVM tissue devices.

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References

  1. Bhatia, S. N. & Ingber, D. E. Microfluidic organs-on-chips. Nat. Biotechnol. 32, 760–772 (2014).

    Article  CAS  Google Scholar 

  2. Mammoto, A. et al. Control of lung vascular permeability and endotoxin-induced pulmonary oedema by changes in extracellular matrix mechanics. Nat. Commun. 4, 1759 (2013).

    Article  Google Scholar 

  3. Feinberg, A. W. et al. Muscular thin films for building actuators and powering devices. Science 317, 1366–1370 (2007).

    Article  CAS  Google Scholar 

  4. Boudou, T. et al. A microfabricated platform to measure and manipulate the mechanics of engineered cardiac microtissues. Tissue Eng. A 18, 910–919 (2011).

    Article  Google Scholar 

  5. Wang, G. et al. Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies. Nat. Med. 20, 616–623 (2014).

    Article  CAS  Google Scholar 

  6. Hinson, J. T. et al. Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy. Science 349, 982–986 (2015).

    Article  CAS  Google Scholar 

  7. Agarwal, A. et al. Micropatterning alginate substrates for in vitro cardiovascular muscle on a chip. Adv. Funct. Mater. 23, 3738–3746 (2013).

    Article  CAS  Google Scholar 

  8. Grosberg, A., Alford, P. W., McCain, M. L. & Parker, K. K. Ensembles of engineered cardiac tissues for physiological and pharmacological study: heart on a chip. Lab Chip 11, 4165–4173 (2011).

    Article  CAS  Google Scholar 

  9. Park, S.-J. et al. Phototactic guidance of a tissue-engineered soft-robotic ray. Science 353, 158–162 (2016).

    Article  CAS  Google Scholar 

  10. Lewis, J. A. Direct ink writing of 3D functional materials. Adv. Funct. Mater. 16, 2193–2204 (2006).

    Article  CAS  Google Scholar 

  11. Hardin, J. O., Ober, T. J., Valentine, A. D. & Lewis, J. A. Microfluidic printheads for multimaterial 3D printing of viscoelastic inks. Adv. Mater. 27, 3279–3284 (2015).

    Article  CAS  Google Scholar 

  12. Sun, K. et al. 3D printing of interdigitated Li-Ion microbattery architectures. Adv. Mater. 25, 4539–4543 (2013).

    Article  CAS  Google Scholar 

  13. Miller, J. S. et al. Rapid casting of patterned vascular networks for perfusable engineered three-dimensional tissues. Nat. Mater. 11, 768–774 (2012).

    Article  CAS  Google Scholar 

  14. Kolesky, D. B., Homan, K. A., Skylar-Scott, M. A. & Lewis, J. A. Three-dimensional bioprinting of thick vascularized tissues. Proc. Natl Acad. Sci. USA 113, 3179–3184 (2016).

    Article  CAS  Google Scholar 

  15. Matsuhisa, N. et al. Printable elastic conductors with a high conductivity for electronic textile applications. Nat. Commun. 6, 7461 (2015).

    Article  CAS  Google Scholar 

  16. Lipomi, D. J. et al. Skin-like pressure and strain sensors based on transparent elastic films of carbon nanotubes. Nat. Nanotech. 6, 788–792 (2011).

    Article  CAS  Google Scholar 

  17. Berthier, E., Young, E. W. & Beebe, D. Engineers are from PDMS-land, biologists are from polystyrenia. Lab Chip 12, 1224–1237 (2012).

    Article  CAS  Google Scholar 

  18. Kléber, A. G. & Rudy, Y. Basic mechanisms of cardiac impulse propagation and associated arrhythmias. Physiol. Rev. 84, 431–488 (2004).

    Article  Google Scholar 

  19. Pasqualini, F. S., Sheehy, S. P., Agarwal, A., Aratyn-Schaus, Y. & Parker, K. K. Structural phenotyping of stem cell-derived cardiomyocytes. Stem Cell Rep. 4, 340–347 (2015).

    Article  CAS  Google Scholar 

  20. Feinberg, A. W. et al. Controlling the contractile strength of engineered cardiac muscle by hierarchal tissue architecture. Biomaterials 33, 5732–5741 (2012).

    Article  CAS  Google Scholar 

  21. Sheehy, S. P. et al. Quality metrics for stem cell-derived cardiac myocytes. Stem Cell Rep. 2, 282–294 (2014).

    Article  CAS  Google Scholar 

  22. OštIádalová, I. et al. Early postnatal development of contractile performance and responsiveness to Ca2+, verapamil and ryanodine in the isolated rat heart. J. Mol. Cell. Cardiol. 25, 733–740 (1993).

    Article  Google Scholar 

  23. Zhang, D. et al. Tissue-engineered cardiac patch for advanced functional maturation of human ESC-derived cardiomyocytes. Biomaterials 34, 5813–5820 (2013).

    Article  CAS  Google Scholar 

  24. Zimmermann, W. H. et al. Three-dimensional engineered heart tissue from neonatal rat cardiac myocytes. Biotechnol. Bioeng. 68, 106–114 (2000).

    Article  CAS  Google Scholar 

  25. Reiser, P. J., Portman, M. A., Ning, X.-H. & Moravec, C. S. Human cardiac myosin heavy chain isoforms in fetal and failing adult atria and ventricles. Am. J. Physiol. 280, H1814–H1820 (2001).

    CAS  Google Scholar 

  26. Lundy, S. D., Zhu, W-Z., Regnier, M. & Laflamme, M. A. Structural and functional maturation of cardiomyocytes derived from human pluripotent stem cells. Stem Cells Dev. 22, 1991–2002 (2013).

    Article  CAS  Google Scholar 

  27. Nunes, S. S. et al. Biowire: a platform for maturation of human pluripotent stem cell-derived cardiomyocytes. Nat. Methods 10, 781–787 (2013).

    Article  CAS  Google Scholar 

  28. Xiao, Y. et al. Microfabricated perfusable cardiac biowire: a platform that mimics native cardiac bundle. Lab Chip 14, 869–882 (2014).

    Article  CAS  Google Scholar 

  29. Zimmermann, W.-H. et al. Tissue engineering of a differentiated cardiac muscle construct. Circ. Res. 90, 223–230 (2002).

    Article  CAS  Google Scholar 

  30. LeGrice, I. J. et al. Laminar structure of the heart: ventricular myocyte arrangement and connective tissue architecture in the dog. Am. J. Physiol. 269, H571–H582 (1995).

    CAS  Google Scholar 

Download references

Acknowledgements

The authors thank L. K. Sanders for her work on photography and time-lapse movies, J. A. Goss for his assistance with fabrication of the device holder and J. Minardi for his development of Mecode, and his help with machine automation. This work was performed in part at the Center for Nanoscale Systems (CNS), a member of the National Nanotechnology Infrastructure Network (NNIN), which is supported by the National Science Foundation under NSF award no. ECS-0335765. CNS is part of Harvard University. This work was also supported by the National Center For Advancing Translational Sciences of the National Institutes of Health under Award Number UH3TR000522, the US Army Research Laboratory and the US Army Research Office under Contract No. W911NF-12-2-0036, the Air Force Research Laboratory under Contract No. FA8650-09-D-5037-0004, and the Harvard University Materials Research Science and Engineering Center (MRSEC) award no. DMR-1420570. J.U.L. gratefully acknowledges support from the Villum Foundation. J.A.L. gratefully acknowledges support from the Office of Naval Research, Vannevar Bush National Security Science and Engineering Faculty Fellowship (Award No. N00014-16-1-2823).

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Author notes

  1. Hongyan Yuan

    Present address: Present address: Department of Mechanical, Industrial and Systems Engineering, University of Rhode Island, Kingston, Rhode Island 02881, USA.,

  2. Johan U. Lind and Travis A. Busbee: These authors contributed equally to this work.

Authors and Affiliations

  1. Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02115, USA

    Johan U. Lind, Travis A. Busbee, Alexander D. Valentine, Francesco S. Pasqualini, Hongyan Yuan, Moran Yadid, Sung-Jin Park, Arda Kotikian, Alexander P. Nesmith, Patrick H. Campbell, Jennifer A. Lewis & Kevin K. Parker

  2. John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 02138, USA

    Johan U. Lind, Travis A. Busbee, Alexander D. Valentine, Francesco S. Pasqualini, Hongyan Yuan, Moran Yadid, Sung-Jin Park, Arda Kotikian, Alexander P. Nesmith, Patrick H. Campbell, Joost J. Vlassak, Jennifer A. Lewis & Kevin K. Parker

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Contributions

J.U.L., T.A.B., J.A.L. and K.K.P. designed the study. J.U.L. and T.A.B. designed the device. T.A.B. coded the 3D-print procedure and automation. J.U.L., T.A.B., A.K. and A.D.V. developed and characterized the printable materials. J.U.L., A.D.V. and T.A.B., optimized and printed devices. P.H.C. performed NRVM harvesting and prepared culturing media. J.U.L., M.Y. and A.P.N. performed NRVM culture, drug-dose experiments, and data analysis. M.Y. and J.U.L. conducted hiPS-CM culture, experiments and data analysis. F.S.P. and J.U.L. performed tissue staining, confocal imaging, and OOP analysis. S.-J.P. and J.U.L. conducted optical mapping experiments and analysis. H.Y. and J.J.V. developed the mechanical model of the device. J.U.L., T.A.B., J.A.L. and K.K.P. prepared illustrations and wrote the manuscript. F.S.P. and A.D.V. contributed to writing the manuscript.

Corresponding authors

Correspondence to Jennifer A. Lewis or Kevin K. Parker.

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The authors declare no competing financial interests.

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Lind, J., Busbee, T., Valentine, A. et al. Instrumented cardiac microphysiological devices via multimaterial three-dimensional printing. Nature Mater 16, 303–308 (2017). https://doi.org/10.1038/nmat4782

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