{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:17:35Z","timestamp":1760059055065,"version":"build-2065373602"},"reference-count":35,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T00:00:00Z","timestamp":1747267200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"AMED","doi-asserted-by":"publisher","award":["JP22gm1510010","JP23H05450","JP24K23054"],"award-info":[{"award-number":["JP22gm1510010","JP23H05450","JP24K23054"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"name":"MEXT KAKENHI","award":["JP22gm1510010","JP23H05450","JP24K23054"],"award-info":[{"award-number":["JP22gm1510010","JP23H05450","JP24K23054"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Micromachines"],"abstract":"<jats:p>Artificial retinal devices require a high-density electrode array and mechanical flexibility to effectively stimulate retinal cells. However, designing such devices presents significant challenges, including the need to conform to the curvature of the eyeball and cover a large area using a single platform. To address these issues, we developed a parylene-based multi-module retinal device (MMRD) integrating a complementary metal-oxide semiconductor (CMOS) system. The proposed device is designed for suprachoroidal transretinal stimulation, with each module comprising a parylene-C thin-film substrate, a CMOS chip, and a ceramic substrate housing seven platinum electrodes. The smart CMOS system significantly reduces wiring complexity, enhancing the device\u2019s practicality. To improve fabrication reliability, we optimized the encapsulation process, introduced multiple silane coupling modifications, and utilized polyvinyl alcohol (PVA) for easier detachment in flip-chip bonding. This study demonstrates the fabrication and evaluation of the MMRD through in vitro and in vivo experiments. The device successfully generated the expected current stimulation waveforms in both settings, highlighting its potential as a promising candidate for future artificial vision applications.<\/jats:p>","DOI":"10.3390\/mi16050580","type":"journal-article","created":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T06:59:16Z","timestamp":1747292356000},"page":"580","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Development and Evaluation of Multi-Module Retinal Devices for Artificial Vision Applications"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1939-6127","authenticated-orcid":false,"given":"Kuang-Chih","family":"Tso","sequence":"first","affiliation":[{"name":"Institute for Research Initiatives, Nara Institute of Science and Technology, Ikoma 6300192, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshinori","family":"Sunaga","sequence":"additional","affiliation":[{"name":"Institute for Research Initiatives, Nara Institute of Science and Technology, Ikoma 6300192, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuki","family":"Nakanishi","sequence":"additional","affiliation":[{"name":"Division of Materials Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Ikoma 6300192, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuo","family":"Terasawa","sequence":"additional","affiliation":[{"name":"Institute for Research Initiatives, Nara Institute of Science and Technology, Ikoma 6300192, Japan"},{"name":"NIDEK Co., Ltd., Gamagori 4430036, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Makito","family":"Haruta","sequence":"additional","affiliation":[{"name":"Institute for Research Initiatives, Nara Institute of Science and Technology, Ikoma 6300192, Japan"},{"name":"Department of Opto-Electronic System Engineering, Faculty of Science and Engineering, Chitose Institute of Science and Technology, Chitose 0668655, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5718-3958","authenticated-orcid":false,"given":"Kiyotaka","family":"Sasagawa","sequence":"additional","affiliation":[{"name":"Division of Materials Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Ikoma 6300192, Japan"},{"name":"Medilux Research Center, Graduate School of Science and Technology, Nara Institute of Science and Technology, Ikoma 6300192, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8194-9020","authenticated-orcid":false,"given":"Jun","family":"Ohta","sequence":"additional","affiliation":[{"name":"Institute for Research Initiatives, Nara Institute of Science and Technology, Ikoma 6300192, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e106","DOI":"10.1016\/S2214-109X(13)70145-1","article-title":"Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: A systematic review and meta-analysis","volume":"2","author":"Wong","year":"2014","journal-title":"Lancet Glob. Health"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1001\/archopht.122.4.564","article-title":"Prevalence of age-related macular degeneration in the United States","volume":"122","author":"Friedman","year":"2004","journal-title":"Arch. Ophthalmol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1016\/j.ophtha.2017.09.019","article-title":"Assessment of the electronic retinal implant Alpha AMS in restoring vision to blind patients with end-stage retinitis pigmentosa","volume":"125","author":"Edwards","year":"2018","journal-title":"Ophthalmology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.visres.2015.03.001","article-title":"Artificial vision with wirelessly powered subretinal electronic implant Alpha-IMS: Implantation and functional outcomes in humans","volume":"111","author":"Stingl","year":"2015","journal-title":"Vision Res."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Luo, Y.H.L., and da Cruz, L. (2016). A review and update on the current status of retinal prostheses (bionic eye). Prog. Retin. Eye Res., 50.","DOI":"10.1016\/j.preteyeres.2015.09.003"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1001\/2013.jamaophthalmol.221","article-title":"The detection of motion by blind subjects with the epiretinal 60-electrode (Argus II) retinal prosthesis","volume":"131","author":"Dorn","year":"2013","journal-title":"JAMA Ophthalmol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1007\/s00417-007-0563-z","article-title":"Evaluation of microfabricated retinal stimulating electrodes implanted in rabbit eyes","volume":"245","author":"Fujikado","year":"2007","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Ayton, L.N., Blamey, P.J., Guymer, R.H., Luu, C.D., Nayagam, D.A., Sinclair, N.C., Shivdasani, M.N., Yeoh, J., McCombe, M.F., and Briggs, R.J. (2014). First-in-human trial of a novel suprachoroidal retinal prosthesis. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0115239"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4726","DOI":"10.1167\/iovs.10-6836","article-title":"Testing of semichronic implantation of suprachoroidal-transretinal stimulation prosthesis in patients with advanced retinitis pigmentosa","volume":"52","author":"Fujikado","year":"2011","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Ho, E., Lei, X., Flores, T., Lorach, H., Huang, T., Galambos, L., Kamins, T., Harris, J., Mathieson, K., and Palanker, D. (2019). Photovoltaic retinal prosthesis for restoring sight to the blind. J. Neural Eng., 16.","DOI":"10.1088\/1741-2552\/ab34b3"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Stieglitz, T. (2009). Development of neural interfaces: Critical review and perspectives. J. Neural Eng., 6.","DOI":"10.1088\/1741-2560\/6\/6\/065005"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Tong, W., Stamp, M., Apollo, N.V., Ganesan, K., Meffin, H., Prawer, S., Garrett, D.J., and Ibbotson, M.R. (2019). Optimizing mechanical stimulation of retinal neurons with carbon fiber microelectrodes. J. Neural Eng., 17.","DOI":"10.1088\/1741-2552\/ab5299"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Bareket, L., Barriga-Rivera, A., Zapf, M.P., Lovell, N.H., and Suaning, G.J. (2017). Progress towards a high-density retinal implant: A review of the Alpha AMS, Argus II, and PRIMA Systems. J. Neural Eng., 14.","DOI":"10.1088\/1741-2552\/aa6cbb"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1016\/j.clinph.2019.11.029","article-title":"An update on retinal prostheses","volume":"6","author":"Ayton","year":"2020","journal-title":"Clin. Neurophysiol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Bloch, E., Luo, Y., and da Cruz, L. (2019). Advances in retinal prosthesis systems. Ther. Adv. Ophthalmol., 11.","DOI":"10.1177\/2515841418817501"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1038\/nm.3851","article-title":"Photovoltaic restoration of sight with high visual acuity","volume":"21","author":"Lorach","year":"2015","journal-title":"Nat. Med."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Chenais, N.A.L., Airaghi Leccardi, M.J.I., and Ghezzi, D. (2021). Photovoltaic retinal prosthesis restores high-resolution responses to single-pixel stimulation in blind retinas. Commun. Mater., 2.","DOI":"10.1038\/s43246-021-00133-2"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Schaffrath, K., Lohmann, T., Seifert, J., Ingensiep, C., Raffelberg, P., Waschkowski, F., Viga, R., Kokozinski, R., Mokwa, W., and Johnen, S. (2021). New epiretinal implant with integrated sensor chips for optical capturing shows a good biocompatibility profile in vitro and in vivo. Biomed. Eng. Online, 20.","DOI":"10.1186\/s12938-021-00938-9"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Wu, C.-Y., Sung, W.-J., Kuo, P.-H., Tzeng, C.-K., Chiao, C.-C., and Tsai, Y.-C. (2015, January 22\u201324). The design of CMOS self-powered 256-pixel implantable chip with on-chip photovoltaic cells and active pixel sensors for subretinal prostheses. Proceedings of the 2015 IEEE Biomed. Circuits Syst. Conf. (BioCAS), Atlanta, GA, USA.","DOI":"10.1109\/BioCAS.2015.7348318"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Allen, P.J., Kolic, M., Baglin, E.K., Titchener, S.A., Kvansakul, J., Nayagam, D.A.X., Yeoh, J., Briggs, R.J., Villalobos, J., and Williams, C.E. (Clin. Exp. Ophthalmol., 2025). Second-Generation (44-Channel) Suprachoroidal Retinal Prosthesis: Surgical Stability and Safety During a 2-Year Clinical Trial, Clin. Exp. Ophthalmol., early view.","DOI":"10.1111\/ceo.14502"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Petoe, M.A., Abbott, C.J., Titchener, S.A., Kolic, M., Kentler, W.G., Nayagam, D.A.X., Baglin, E.K., Kvansakul, J., Barnes, N., and Walker, J.G. (2025). A Second-Generation (44-Channel) Suprachoroidal Retinal Prosthesis: A Single-Arm Clinical Trial of Feasibility. Ophthalmol. Sci., 1.","DOI":"10.1016\/j.xops.2024.100525"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1167\/tvst.10.10.12","article-title":"A Second-Generation (44-Channel) Suprachoroidal Retinal Prosthesis: Interim Clinical Trial Results","volume":"10","author":"Petoe","year":"2021","journal-title":"Transl. Vis. Sci. Technol."},{"key":"ref_23","first-page":"235","article-title":"Safety and efficacy of semichronic suprachoroidal transretinal stimulation with femtosecond laser-induced porosity and smooth-surface electrodes","volume":"30","author":"Terasawa","year":"2018","journal-title":"Sens. Mater."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Noda, T., Nakano, Y., Terasawa, Y., Haruta, M., Sasagawa, K., Tokuda, T., and Ohta, J. (2018). Performance improvement and in vivo demonstration of a sophisticated retinal stimulator using smart electrodes with built-in CMOS microchips. Jpn. J. Appl. Phys., 57.","DOI":"10.7567\/JJAP.57.1002B3"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Tso, K.C., Fukunari, Y., Hagita, M., Haruta, M., Takehara, H., Tashiro, H., Sasagawa, K., Wu, P.W., and Ohta, J. (2021). Honeycomb-type retinal device using chemically derived iridium oxide biointerfaces. AIP Adv., 11.","DOI":"10.1063\/5.0058457"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Pan, K., Hagiwara, T., Tso, K.C., Siwadamrongpong, R., Akbar, L., Nakano, Y., Kono, T., Terasawa, Y., Haruta, M., and Takehara, H. (2023). A flexible retinal device with CMOS smart electrodes fabricated on parylene C thin-film and bioceramic substrate. Jpn. J. Appl. Phys., 62.","DOI":"10.35848\/1347-4065\/acaca5"},{"key":"ref_27","first-page":"315","article-title":"Effects of an asymmetric electrical pulse on retinal excitement for retinal prostheses","volume":"30","author":"Nakano","year":"2018","journal-title":"Sens. Mater."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Ortigoza-Diaz, J., Scholten, K., Larson, C., Cobo, A., Hudson, T., Yoo, J., Baldwin, A., Weltman Hirschberg, A., and Meng, E. (2018). Techniques and Considerations in the Microfabrication of Parylene C Microelectromechanical Systems. Micromachines, 9.","DOI":"10.3390\/mi9090422"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Nanbakhsh, K., Van Gompel, M., Ritasalo, R., Gollhardt, A., Horv\u00e1th, D., T\u00f3th, K., Mesz\u00e9na, D., Ulbert, I., Serdijn, W., and Giagka, V. (2025). An In Vivo Biostability Evaluation of ALD and Parylene-ALD Multilayers as Micro-Packaging Solutions for Small Single-Chip Implants. Small, 21.","DOI":"10.1002\/smll.202410141"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1016\/j.visres.2009.02.018","article-title":"Focal activation of the feline retina via a suprachoroidal electrode array","volume":"49","author":"Wong","year":"2009","journal-title":"Vision Res."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Villalobos, J., Fallon, J.B., Nayagam, D.A.X., Shivdasani, M.N., Luu, C.D., Allen, P.J., Shepherd, R.K., and Williams, C.E. (2014). Cortical activation following chronic passive implantation of a wide-field suprachoroidal retinal prosthesis. J. Neural Eng., 11.","DOI":"10.1088\/1741-2560\/11\/4\/046017"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1159\/000317034","article-title":"Threshold suprachoroidal-transretinal stimulation current required by different-size electrodes in rabbit eyes","volume":"45","author":"Liang","year":"2011","journal-title":"Ophthal. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1109\/TNSRE.2021.3090904","article-title":"Monitoring cortical response and electrode-retina impedance under epiretinal stimulation in rats","volume":"29","author":"Xie","year":"2021","journal-title":"IEEE Trans. Neural Syst. Rehabil. Eng."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1007\/s00417-015-3027-x","article-title":"Spatial characteristics of evoked potentials elicited by a MEMS microelectrode array for suprachoroidal-transretinal stimulation in a rabbit","volume":"253","author":"Yan","year":"2015","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1111\/j.1445-2197.2005.03498.x","article-title":"Stimulation of the retina with a multielectrode extraocular visual prosthesis","volume":"75","author":"Chowdhury","year":"2005","journal-title":"ANZ J. Surg."}],"container-title":["Micromachines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-666X\/16\/5\/580\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:33:13Z","timestamp":1760031193000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-666X\/16\/5\/580"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,15]]},"references-count":35,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["mi16050580"],"URL":"https:\/\/doi.org\/10.3390\/mi16050580","relation":{},"ISSN":["2072-666X"],"issn-type":[{"type":"electronic","value":"2072-666X"}],"subject":[],"published":{"date-parts":[[2025,5,15]]}}}