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Instrumented cardiac microphysiological devices via multimaterial three-dimensional printing

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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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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Authors

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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