On-chip in vitro cell-network pre-clinical cardiac toxicity using spatiotemporal human cardiomyocyte measurement on a chip

Kaneko, Tomoyuki; Nomura, Fumimasa; Hamada, Tomoyo; Abe, Yasuyuki; Takamori, Hideo; Sakakura, Tomoko; Takasuna, Kiyoshi; Sanbuissho, Atsushi; Hyllner, Johan; Sartipy, Peter; Yasuda, Kenji

doi:10.1038/srep04670

Cited by 45 publications

(47 citation statements)

References 28 publications

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“…Unlike other pre-existing models where only individual cell types were typically included [3,7,75–77], doxorubicin elicited dose-dependent responses towards both cardiomyocytes and endothelial cells in our model. The beating rate of the cardiomyocytes decreased to 70.5% and 1.62% (close to 0 bpm) at Day 6 post exposure to 10 µM and 100 µM drugs, respectively, while the control endothelialized myocardial organoids largely maintained a high relative beating rate at approximately 88.3% (Fig.…”

Section: Resultsmentioning

confidence: 99%

Bioprinting 3D microfibrous scaffolds for engineering endothelialized myocardium and heart-on-a-chip

et al. 2016

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Engineering cardiac tissues and organ models remains a great challenge due to the hierarchical structure of the native myocardium. The need of integrating blood vessels brings additional complexity, limiting the available approaches that are suitable to produce integrated cardiovascular organoids. In this work we propose a novel hybrid strategy based on 3D bioprinting, to fabricate endothelialized myocardium. Enabled by the use of our composite bioink, endothelial cells directly bioprinted within microfibrous hydrogel scaffolds gradually migrated towards the peripheries of the microfibers to form a layer of confluent endothelium. Together with controlled anisotropy, this 3D endothelial bed was then seeded with cardiomyocytes to generate aligned myocardium capable of spontaneous and synchronous contraction. We further embedded the organoids into a specially designed microfluidic perfusion bioreactor to complete the endothelialized-myocardium-on-a-chip platform for cardiovascular toxicity evaluation. Finally, we demonstrated that such a technique could be translated to human cardiomyocytes derived from induced pluripotent stem cells to construct endothelialized human myocardium. We believe that our method for generation of endothelialized organoids fabricated through an innovative 3D bioprinting technology may find widespread applications in regenerative medicine, drug screening, and potentially disease modeling.

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Section: Resultsmentioning

confidence: 99%

Bioprinting 3D microfibrous scaffolds for engineering endothelialized myocardium and heart-on-a-chip

et al. 2016

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“…Despite most of studies use single cells, the CMs syncytium seems to be a critical parameter in biosensor assembly as unstable signals are obtained in case of individual or small cluster of cells (Kaneko et al, 2007(Kaneko et al, , 2014. These methods follow mostly action potential, cell to cell conductivity or electrical cell-substrate impedance (Giaever and Keese, 1984).…”

Section: Introductionmentioning

confidence: 98%

Atomic force microscopy combined with human pluripotent stem cell derived cardiomyocytes for biomechanical sensing

Pešl

Přibyl

Aćimović

et al. 2016

Biosensors and Bioelectronics

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Cardiomyocyte contraction and relaxation are important parameters of cardiac function altered in many heart pathologies. Biosensing of these parameters represents an important tool in drug development and disease modeling. Human embryonic stem cells and especially patient specific induced pluripotent stem cell-derived cardiomyocytes are well established as cardiac disease model.. Here, a live stem cell derived embryoid body (EB) based cardiac cell syncytium served as a biorecognition element coupled to the microcantilever probe from atomic force microscope thus providing reliable micromechanical cellular biosensor suitable for whole-day testing. The biosensor was optimized regarding the type of cantilever, temperature and exchange of media; in combination with standardized protocol, it allowed testing of compounds and conditions affecting the biomechanical properties of EB. The studied effectors included calcium , drugs modulating the catecholaminergic fight-or-flight stress response such as the beta-adrenergic blocker metoprolol and the beta-adrenergic agonist isoproterenol. Arrhythmogenic effects were studied using caffeine. Furthermore, with EBs originating from patient's stem cells, this biosensor can help to characterize heart diseases such as dystrophies.

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“…3,4 By enabling measurements of viability and function after compound exposure, these technologies can provide mechanistic information about the proposed therapeutic compounds and provide valuable insight into their potential safety, efficacy, pharmacokinetics and pharmacodynamics concerns prior to testing the chemical in higher organisms. 3,4 By enabling measurements of viability and function after compound exposure, these technologies can provide mechanistic information about the proposed therapeutic compounds and provide valuable insight into their potential safety, efficacy, pharmacokinetics and pharmacodynamics concerns prior to testing the chemical in higher organisms.…”

Section: Introductionmentioning

confidence: 99%

Long-term non-invasive interrogation of human dorsal root ganglion neuronal cultures on an integrated microfluidic multielectrode array platform

Enright

Felix

Fischer

et al. 2016

Analyst

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Scientific studies in drug development and toxicology rely heavily on animal models, which often inaccurately predict the true response for human exposure. This may lead to unanticipated adverse effects or misidentified risks that result in, for example, drug candidate elimination. The utilization of human cells and tissues for in vitro physiological platforms has become a growing area of interest to bridge this gap and to more accurately predict human responses to drugs and toxins. The effects of new drugs and toxins on the peripheral nervous system are often investigated with neurons isolated from dorsal root ganglia (DRG), typically with one-time measurement techniques such as patch clamping. Here, we report the use of our multi-electrode array (MEA) platform for long-term noninvasive assessment of human DRG cell health and function. In this study, we acquired simultaneous optical and electrophysiological measurements from primary human DRG neurons upon chemical stimulation repeatedly through day in vitro (DIV) 23. Distinct chemical signatures were noted for the cellular responses evoked by each chemical stimulus. Additionally, the cell viability and function of the human DRG neurons were consistent through DIV 23. To the best of our knowledge, this is the first report on long-term measurements of the cell health and function of human DRG neurons on a MEA platform. Future generations will include higher electrode numbers in customized arrangements as well as integration with different tissue types on a single device. This platform will provide a valuable testing tool for both rodent and human cells, enabling a more comprehensive risk assessment for drug candidates and toxicants.

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On-chip in vitro cell-network pre-clinical cardiac toxicity using spatiotemporal human cardiomyocyte measurement on a chip

Cited by 45 publications

References 28 publications

Bioprinting 3D microfibrous scaffolds for engineering endothelialized myocardium and heart-on-a-chip

Bioprinting 3D microfibrous scaffolds for engineering endothelialized myocardium and heart-on-a-chip

Atomic force microscopy combined with human pluripotent stem cell derived cardiomyocytes for biomechanical sensing

Long-term non-invasive interrogation of human dorsal root ganglion neuronal cultures on an integrated microfluidic multielectrode array platform

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