{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:55:58Z","timestamp":1787028958857,"version":"build-2736575974"},"reference-count":52,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,5,12]],"date-time":"2021-05-12T00:00:00Z","timestamp":1620777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japan Society for the Promotion of Science","award":["16K14660; 17H02083"],"award-info":[{"award-number":["16K14660; 17H02083"]}]},{"name":"LiaoNing Revitalization Talents Program","award":["XLYC1902061"],"award-info":[{"award-number":["XLYC1902061"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Micromachines"],"abstract":"<jats:p>Microfluidic microphysiological systems (MPSs) or \u201corgans-on-a-chip\u201d are a promising alternative to animal models for drug screening and toxicology tests. However, most microfluidic devices employ polydimethylsiloxane (PDMS) as the structural material; and this has several drawbacks. Cyclo-olefin polymers (COPs) are more advantageous than PDMS and other thermoplastic materials because of their low drug absorption and autofluorescence. However, most COP-based microfluidic devices are fabricated by solvent bonding of the constituent parts. Notably, the remnant solvent can affect the cultured cells. This study employed a photobonding process with vacuum ultraviolet (VUV) light to fabricate microfluidic devices without using any solvent and compared their performance with that of solvent-bonded systems (using cyclohexane, dichloromethane, or toluene as the solvent) to investigate the effects of residual solvent on cell cultures. Quantitative immunofluorescence assays indicated that the coating efficiencies of extracellular matrix proteins (e.g., Matrigel and collagen I) were lower in solvent-bonded COP devices than those in VUV-bonded devices. Furthermore, the cytotoxicity of the systems was evaluated using SH-SY5Y neuroblastoma cells, and increased apoptosis was observed in the solvent-processed devices. These results provide insights into the effects of solvents used during the fabrication of microfluidic devices and can help prevent undesirable reactions and establish good manufacturing practices.<\/jats:p>","DOI":"10.3390\/mi12050550","type":"journal-article","created":{"date-parts":[[2021,5,12]],"date-time":"2021-05-12T22:46:14Z","timestamp":1620859574000},"page":"550","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Evaluation of the Effects of Solvents Used in the Fabrication of Microfluidic Devices on Cell Cultures"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9423-5171","authenticated-orcid":false,"given":"Xiaopeng","family":"Wen","sequence":"first","affiliation":[{"name":"Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Yoshida-Ushinomiya-cho, Sakyo-ku, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seiichiro","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Incubation Center Organs On Chip Project, Ushio INC, 1-6-5 Marunouchi, Chiyoda-ku, Tokyo 100-8150, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Hatakeyama","sequence":"additional","affiliation":[{"name":"Incubation Center Organs On Chip Project, Ushio INC, 1-6-5 Marunouchi, Chiyoda-ku, Tokyo 100-8150, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2948-3264","authenticated-orcid":false,"given":"Ken-ichiro","family":"Kamei","sequence":"additional","affiliation":[{"name":"Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Yoshida-Ushinomiya-cho, Sakyo-ku, Kyoto 606-8501, Japan"},{"name":"Wuya College of Innovation, Shenyang Pharmaceutical University, Liaoning 110016, China"},{"name":"Department of Pharmaceutics, Shenyang Pharmaceutical University, Liaoning 110016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Proserpio, V. (2019). Single Cell Methods: Sequencing and Proteomics, Springer.","DOI":"10.1007\/978-1-4939-9240-9"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nprot.2016.154","article-title":"Single-cell barcoding and sequencing using droplet microfluidics","volume":"12","author":"Zilionis","year":"2017","journal-title":"Nat. Protoc."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"6128","DOI":"10.1158\/0008-5472.CAN-10-0076","article-title":"A microfluidic platform for systems pathology: Multiparameter single-cell signaling measurements of clinical brain tumor specimens","volume":"70","author":"Sun","year":"2010","journal-title":"Cancer Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.copbio.2019.11.022","article-title":"Microfluidic systems for cancer diagnostics","volume":"65","author":"Maerkl","year":"2020","journal-title":"Curr. Opin. Biotechnol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.dmpk.2017.11.003","article-title":"Organ\/body-on-a-chip based on microfluidic technology for drug discovery","volume":"33","author":"Kimura","year":"2018","journal-title":"Drug Metab. Pharmacokinet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1146\/annurev-pathol-012414-040418","article-title":"Engineered In Vitro Disease Models","volume":"10","author":"Benam","year":"2015","journal-title":"Annu. Rev. Pathol. Mech. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1021\/acs.analchem.8b05293","article-title":"Recent Advances in Body-on-a-Chip Systems","volume":"91","author":"Sung","year":"2019","journal-title":"Anal. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1177\/1535370217707731","article-title":"Pre-clinical and clinical investigations of metabolic zonation in liver diseases: The potential of microphysiology systems","volume":"242","author":"Gough","year":"2017","journal-title":"Exp. Biol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"36777","DOI":"10.1039\/C7RA07716E","article-title":"Integrated heart\/cancer on a chip to reproduce the side effects of anti-cancer drugs in vitro","volume":"7","author":"Kamei","year":"2017","journal-title":"RSC Adv."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1089\/aivt.2016.0003","article-title":"Organs-on-Chips as Bridges for Predictive Toxicology","volume":"2","author":"Hutson","year":"2016","journal-title":"Appl. In Vitro Toxicol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.bbrc.2016.11.062","article-title":"Small molecule absorption by PDMS in the context of drug response bioassays","volume":"482","author":"Firth","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1039\/b612140c","article-title":"PDMS absorption of small molecules and consequences in microfluidic applications","volume":"6","author":"Toepke","year":"2006","journal-title":"Lab Chip"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.1039\/c2lc20982a","article-title":"Engineers are from PDMS-land, Biologists are from Polystyrenia","volume":"12","author":"Berthier","year":"2012","journal-title":"Lab Chip"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"100004","DOI":"10.1016\/j.ooc.2020.100004","article-title":"PDMS leaching and its implications for on-chip studies focusing on bone regeneration applications","volume":"2","author":"Carter","year":"2020","journal-title":"Organs Chip"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Campbell, S.B., Wu, Q., Yazbeck, J., Liu, C., Okhovatian, S., and Radisic, M. (2020). Beyond Polydimethylsiloxane: Alternative Materials for Fabrication of Organ-on-a-Chip Devices and Microphysiological Systems. ACS Biomater. Sci. Eng.","DOI":"10.1021\/acsbiomaterials.0c00640"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1039\/C8LC00796A","article-title":"Chemical-PDMS binding kinetics and implications for bioavailability in microfluidic devices","volume":"19","author":"Auner","year":"2019","journal-title":"Lab Chip"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Tsao, C.-W. (2016). Polymer Microfluidics: Simple, Low-Cost Fabrication Process Bridging Academic Lab Research to Commercialized Production. Micromachines, 7.","DOI":"10.3390\/mi7120225"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Wang, T., Chen, J., Zhou, T., and Song, L. (2018). Fabricating Microstructures on Glass for Microfluidic Chips by Glass Molding Process. Micromachines, 9.","DOI":"10.3390\/mi9060269"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3331","DOI":"10.1039\/C7LC00851A","article-title":"Configurable microfluidic platform for investigating therapeutic delivery from biomedical device coatings","volume":"17","author":"Li","year":"2017","journal-title":"Lab Chip"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1093\/nar\/24.2.375","article-title":"Chip PCR. I. Surface passivation of microfabricated silicon-glass chips for PCR","volume":"24","author":"Shoffner","year":"1996","journal-title":"Nucleic Acids Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1002\/adhm.201200283","article-title":"Phenotypic and Transcriptional Modulation of Human Pluripotent Stem Cells Induced by Nano\/Microfabrication Materials","volume":"2","author":"Kamei","year":"2013","journal-title":"Adv. Healthc. Mater."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1007\/s10544-017-0182-3","article-title":"Fabrication of cyclo olefin polymer microfluidic devices for trapping and culturing of yeast cells","volume":"19","author":"Puza","year":"2017","journal-title":"Biomed. Microdevices"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.jmatprotec.2007.12.146","article-title":"Microfluidic chip made of COP (cyclo-olefin polymer) and comparion to PMMA (polymethylmethacrylate) microfluidic chip","volume":"208","author":"Yi","year":"2008","journal-title":"J. Mater. Process. Technol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/s10404-010-0605-4","article-title":"Cyclic olefin polymers: Emerging materials for lab-on-a-chip applications","volume":"9","author":"Nunes","year":"2010","journal-title":"Microfluid. Nanofluidics"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2915","DOI":"10.1039\/C9LC00502A","article-title":"Reliable and reusable whole polypropylene plastic microfluidic devices for a rapid, low-cost antimicrobial susceptibility test","volume":"19","author":"Sun","year":"2019","journal-title":"Lab Chip"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1007\/s00542-002-0106-9","article-title":"Polymer microfabrication technologies","volume":"8","author":"Becker","year":"2002","journal-title":"Microsyst. Technol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10404-008-0361-x","article-title":"Bonding of thermoplastic polymer microfluidics","volume":"6","author":"Tsao","year":"2009","journal-title":"Microfluid. Nanofluidics"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"035009","DOI":"10.1088\/1748-605X\/abe660","article-title":"Cyclo olefin polymer-based solvent-free mass-productive microphysiological systems","volume":"16","author":"Yamanaka","year":"2021","journal-title":"Biomed. Mater."},{"key":"ref_29","first-page":"306","article-title":"Recommendation on test readiness criteria for new approach methods in toxicology: Exemplified for developmental neurotoxicity","volume":"35","author":"Hogberg","year":"2018","journal-title":"ALTEX"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.neuro.2016.05.013","article-title":"Organic solvent-induced changes in membrane geometry in human SH-SY5Y neuroblastoma cells\u2014A common narcotic effect?","volume":"55","author":"Meulenberg","year":"2016","journal-title":"Neurotoxicology"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"McQuin, C., Goodman, A., Chernyshev, V., Kamentsky, L., Cimini, B.A., Karhohs, K.W., Doan, M., Ding, L., Rafelski, S.M., and Thirstrup, D. (2018). CellProfiler 3.0: Next-generation image processing for biology. PLoS Biol., 16.","DOI":"10.1371\/journal.pbio.2005970"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1814","DOI":"10.1016\/j.wasman.2009.01.001","article-title":"Study of the solubility and stability of polystyrene wastes in a dissolution recycling process","volume":"29","author":"Gracia","year":"2009","journal-title":"Waste Manag."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"025013","DOI":"10.1088\/0960-1317\/18\/2\/025013","article-title":"Droplet formation from hydrodynamically coupled capillaries for parallel microfluidic contact spotting","volume":"18","author":"Tsao","year":"2008","journal-title":"J. Micromech. Microeng."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5097","DOI":"10.1021\/ac070220w","article-title":"Room-Temperature Bonding for Plastic High-Pressure Microfluidic Chips","volume":"79","author":"Mair","year":"2007","journal-title":"Anal. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3785","DOI":"10.1039\/C5LC00729A","article-title":"Liquid phase solvent bonding of plastic microfluidic devices assisted by retention grooves","volume":"15","author":"Wan","year":"2015","journal-title":"Lab Chip"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"R207","DOI":"10.1016\/j.cub.2017.02.006","article-title":"Basement membranes","volume":"27","author":"Jayadev","year":"2017","journal-title":"Curr. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/978-1-4939-9133-4_18","article-title":"Matrigel Plug Assay for In Vivo Evaluation of Angiogenesis","volume":"Volume 1952","author":"Kastana","year":"2019","journal-title":"Methods in Molecular Biology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/S0143-4004(05)80240-1","article-title":"Laser scanning confocal examination and comparison of nidogen (entactin) with laminin in term human amniochorion","volume":"15","author":"Smith","year":"1994","journal-title":"Placenta"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.matbio.2016.12.009","article-title":"The nature and biology of basement membranes","volume":"57\u201358","author":"Pozzi","year":"2017","journal-title":"Matrix Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4096","DOI":"10.1039\/D0AN00614A","article-title":"Microfluidic device fabrication mediated by surface chemical bonding","volume":"145","author":"Sivakumar","year":"2020","journal-title":"Analyst"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2520","DOI":"10.1016\/j.bbagen.2014.01.017","article-title":"Matrix regulators in neural stem cell functions","volume":"1840","author":"Wade","year":"2014","journal-title":"Biochim. Biophys. Acta Gen. Subj."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.stem.2009.06.016","article-title":"Control of Stem Cell Fate by Physical Interactions with the Extracellular Matrix","volume":"5","author":"Guilak","year":"2009","journal-title":"Cell Stem Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1603104","DOI":"10.1002\/smll.201603104","article-title":"Microfluidic-Nanofiber Hybrid Array for Screening of Cellular Microenvironments","volume":"13","author":"Kamei","year":"2017","journal-title":"Small"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1038\/s41563-019-0460-y","article-title":"Integrin nanoclusters can bridge thin matrix fibres to form cell\u2013matrix adhesions","volume":"18","author":"Changede","year":"2019","journal-title":"Nat. Mater."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1126\/science.282.5391.1145","article-title":"Embryonic stem cell lines derived from human blastocysts","volume":"282","author":"Thomson","year":"1998","journal-title":"Science"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1126\/science.1151526","article-title":"Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells","volume":"318","author":"Yu","year":"2007","journal-title":"Science"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.cell.2007.11.019","article-title":"Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors","volume":"131","author":"Takahashi","year":"2007","journal-title":"Cell"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"6078","DOI":"10.1364\/OL.402815","article-title":"Driving Intracellular Metal Ions of Human Induced Pluripotent Stem Cells with Intense Terahertz Pulses","volume":"45","author":"Tachizaki","year":"2020","journal-title":"Opt. Lett."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.5966\/sctm.2015-0095","article-title":"Concise Review: Stem Cell Microenvironment on a Chip: Current Technologies for Tissue Engineering and Stem Cell Biology","volume":"4","author":"Park","year":"2015","journal-title":"Stem Cells Transl. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"S14","DOI":"10.1016\/j.yrtph.2017.09.020","article-title":"The challenge of the application of \u2019omics technologies in chemicals risk assessment: Background and outlook","volume":"91","author":"Sauer","year":"2017","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Trujillo-de Santiago, G., Flores-Garza, B.G., Tavares-Negrete, J.A., Lara-Mayorga, I.M., Gonz\u00e1lez-Gamboa, I., Zhang, Y.S., Rojas-Mart\u00ednez, A., Ortiz-L\u00f3pez, R., and \u00c1lvarez, M.M. (2019). The Tumor-on-Chip: Recent Advances in the Development of Microfluidic Systems to Recapitulate the Physiology of Solid Tumors. Materials, 12.","DOI":"10.3390\/ma12182945"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3129","DOI":"10.1039\/C8LC00322J","article-title":"3D microfluidic ex vivo culture of organotypic tumor spheroids to model immune checkpoint blockade","volume":"18","author":"Aref","year":"2018","journal-title":"Lab Chip"}],"container-title":["Micromachines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-666X\/12\/5\/550\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:59:53Z","timestamp":1760162393000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-666X\/12\/5\/550"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,12]]},"references-count":52,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["mi12050550"],"URL":"https:\/\/doi.org\/10.3390\/mi12050550","relation":{},"ISSN":["2072-666X"],"issn-type":[{"value":"2072-666X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,12]]}}}