Construction of a Flexible Optogenetic Device for Multisite and Multiregional Optical Stimulation Through Flexible µ-LED Displays on the Cerebral Cortex
Xue Shang
Department of Biomedical Engineering, Tianjin University, 92 Weijin Road, Tianjin, 300072 China
Search for more papers by this authorWei Ling
Department of Biomedical Engineering, Tianjin University, 92 Weijin Road, Tianjin, 300072 China
Research Center for Augmented Intelligence, Research Institute of Artificial Intelligence, Zhejiang Laboratory, Hangzhou, 311100 China
Search for more papers by this authorYing Chen
Institute of Flexible Electronic Technology of Tsinghua, Jiaxing, 314006 China
Jiaxing Key Laboratory of Flexible Electronics based Intelligent Sensing and Advanced Manufacturing Technology, Jiaxing, 314000 China
Search for more papers by this authorChenxi Li
State Key Laboratory of Precision Measuring Technology and Instruments, Tianjin University, 92 Weijin Road, Tianjin, 300072 China
Search for more papers by this authorCorresponding Author
Xian Huang
Department of Biomedical Engineering, Tianjin University, 92 Weijin Road, Tianjin, 300072 China
Institute of Wearable Technology and Bioelectronics, Qiantang Science and Technology Innovation Center, 1002 23rd Street, Hangzhou, 310018 China
E-mail: [email protected]
Search for more papers by this authorXue Shang
Department of Biomedical Engineering, Tianjin University, 92 Weijin Road, Tianjin, 300072 China
Search for more papers by this authorWei Ling
Department of Biomedical Engineering, Tianjin University, 92 Weijin Road, Tianjin, 300072 China
Research Center for Augmented Intelligence, Research Institute of Artificial Intelligence, Zhejiang Laboratory, Hangzhou, 311100 China
Search for more papers by this authorYing Chen
Institute of Flexible Electronic Technology of Tsinghua, Jiaxing, 314006 China
Jiaxing Key Laboratory of Flexible Electronics based Intelligent Sensing and Advanced Manufacturing Technology, Jiaxing, 314000 China
Search for more papers by this authorChenxi Li
State Key Laboratory of Precision Measuring Technology and Instruments, Tianjin University, 92 Weijin Road, Tianjin, 300072 China
Search for more papers by this authorCorresponding Author
Xian Huang
Department of Biomedical Engineering, Tianjin University, 92 Weijin Road, Tianjin, 300072 China
Institute of Wearable Technology and Bioelectronics, Qiantang Science and Technology Innovation Center, 1002 23rd Street, Hangzhou, 310018 China
E-mail: [email protected]
Search for more papers by this authorAbstract
Precisely delivering light to multiple locations in biological tissue is crucial for advancing multiregional optogenetics in neuroscience research. However, conventional implantable devices typically have rigid geometries and limited light sources, allowing only single or dual probe placement with fixed spacing. Here, a fully flexible optogenetic device with multiple thin-film microscale light-emitting diode (µ-LED) displays scattering from a central controller is presented. Each display is heterogeneously integrated with thin-film 5 × 10 µ-LEDs and five optical fibers 125 µm in diameter to achieve cellular-scale spatial resolution. Meanwhile, the device boasts a compact, flexible circuit capable of multichannel configuration and wireless transmission, with an overall weight of 1.31 g, enabling wireless, real-time neuromodulation of freely moving rats. Characterization results and finite element analysis have demonstrated excellent optical properties and mechanical stability, while cytotoxicity tests further ensure the biocompatibility of the device for implantable applications. Behavior studies under optogenetic modulation indicate great promise for wirelessly modulating neural functions in freely moving animals. The device with multisite and multiregional optogenetic modulation capability offers a comprehensive platform to advance both fundamental neuroscience studies and potential applications in brain-computer interfaces.
Conflict of Interest
The authors declare no conflict of interest.
Open Research
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
Filename | Description |
---|---|
smll202302241-sup-0001-SuppMat.pdf1 MB | Supporting Information |
smll202302241-sup-0002-VideoS1.mp410.7 MB | Supplemental Video 1 |
smll202302241-sup-0003-VideoS2.mp421.9 MB | Supplemental Video 2 |
smll202302241-sup-0004-VideoS3.mp419.1 MB | Supplemental Video 3 |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1G. Vardi, J. Merrick, J. Policy Pract. Intellect. Disabil. 2007, 4, 215.
10.1111/j.1741-1130.2007.00122.x Google Scholar
- 2C. A. Lane, J. Hardy, J. M. Schott, Eur. J. Neurol. 2018, 25, 59.
- 3W. Dauer, S. Przedborski, Neuron 2003, 39, 889.
- 4E. H. Lo, T. Dalkara, M. A. Moskowitz, Nat. Rev. Neurosci. 2003, 4, 399.
- 5K. Blennow, D. L. Brody, P. M. Kochanek, H. Levin, A. McKee, G. M. Ribbers, K. Yaffe, H. Zetterberg, Nat. Rev. Dis. Primers 2016, 2, 16084.
- 6O. Lindvall, Z. Kokaia, Nature 2006, 441, 1094.
- 7C. J. Stam, Nat. Rev. Neurosci. 2014, 15, 683.
- 8K. Deisseroth, Nat. Methods 2011, 8, 26.
- 9L. Fenno, O. Yizhar, K. Deisseroth, Annu. Rev. Neurosci. 2011, 34, 389.
- 10V. Emiliani, E. Entcheva, R. Hedrich, P. Hegemann, K. R. Konrad, C. Luscher, M. Mahn, Z. H. Pan, R. R. Sims, J. Vierock, O. Yizhar, Nat Rev Methods Primers 2022, 2, 55.
- 11A. Bansal, S. Shikha, Y. Zhang, Nat. Biomed. Eng. 2022, 7, 349.
- 12H. Shin, Y. Son, U. Chae, J. Kim, N. Choi, H. J. Lee, J. Woo, Y. Cho, S. H. Yang, C. J. Lee, I.-J. Cho, Nat. Commun. 2019, 10, 3777.
- 13P. Jendritza, F. J. Klein, P. Fries, Nat. Commun. 2023, 14, 577.
- 14F. Pisanello, L. Sileo, L. A. Oldenburg, M. Pisanello, L. Martiradonna, J. A. Assad, B. L. Sabatini, M. D. Vittorio, Neuron 2014, 82, 1245.
- 15D. L. Hunt, C. Lai, R. D. Smith, A. K. Lee, T. D. Harris, M. Barbic, Nat. Biomed. Eng. 2019, 3, 741.
- 16M. Niall, C. Yunzhou, S. Robert, X. Enyuan, G. Erdan, F. R. Christopher, S. Rohit, T. Prashant, T. Prashant, R. Loren, B. Steve, M. Keith, Neurophotonics 2019, 6, 035010.
- 17M. Schwaerzle, P. Elmlinger, O. Paul, P. Ruther, Presented in 2015 28th IEEE Int. Conf. on Micro Electro Mechanical Systems (MEMS) IEEE, Estoril, Portugal 2015.
- 18S. D. Wang, Y. G. Huang, J. A. Rogers, IEEE Trans. Compon. Packaging Manuf. Technol. 2015, 5, 1201.
- 19H. G. Li, H. Z. Liu, M. Z. Sun, Y. G. Huang, L. Z. Xu, Adv. Mater. 2021, 33, 2004425.
- 20Y. L. Liu, W. H. Huang, Angew. Chem., Int. Ed. 2021, 60, 2757.
- 21J. M. Lee, D. Lin, H.-R. Kim, Y.-W. Pyo, G. Hong, C. M. Lieber, H.-G. Park, Nano Lett. 2021, 21, 3184.
- 22Y. Qiang, P. Artoni, K. J. Seo, S. Culaclii, V. Hogan, X. Zhao, Y. Zhong, X. Han, P.-M. Wang, Y.-K. Lo, Y. Li, H. A. Patel, Y. Huang, A. Sambangi, J. S. V. Chu, W. Liu, M. Fagiolini, H. Fang, Sci. Adv. 4, eaat0626.
- 23H. Ding, L. Lu, Z. Shi, D. Wang, L. Li, X. Li, Y. Ren, C. Liu, D. Cheng, H. Kim, N. C. Giebink, X. Wang, L. Yin, L. Zhao, M. Luo, X. Sheng, Proc. Natl. Acad. Sci. USA 2018, 115, 6632.
- 24C. Chu, P. Wu, J. Chen, N. Tsou, Y. Lin, Y. Lo, S. Li, C. Chang, B. Chen, C. Tsai, Y. Chen, T. Liu, S. Chen, Adv. Healthcare Mater. 2022, 11, 2101310.
- 25S. Park, Y. Guo, X. Jia, H. K. Choe, B. Grena, J. Kang, J. Park, C. Lu, A. Canales, R. Chen, Y. S. Yim, G. B. Choi, Y. Fink, P. Anikeeva, Nat. Neurosci. 2017, 20, 612.
- 26S. Park, H. Yuk, R. Zhao, Y. S. Yim, E. W. Woldeghebriel, J. Kang, A. Canales, Y. Fink, G. B. Choi, X. Zhao, P. Anikeeva, Nat. Commun. 2021, 12, 3435.
- 27Y. Zhang, A. D. Mickle, P. Gutruf, L. A. McIlvried, H. Guo, Y. Wu, J. P. Golden, Y. Xue, J. G. Grajales-Reyes, X. Wang, S. Krishnan, Y. Xie, D. Peng, C.-J. Su, F. Zhang, J. T. Reeder, S. K. Vogt, Y. Huang, J. A. Rogers, R. W. Gereau, Sci. Adv. 2019, 5, eaaw5296.
- 28K. N. Noh, S. I. Park, R. Qazi, Z. Zou, A. D. Mickle, J. G. Grajales-Reyes, K.-I. Jang, R. W. Gereau Iv, J. Xiao, J. A. Rogers, J.-W. Jeong, Small 2018, 14, 1702479.
- 29J. Yu, W. Ling, Y. Li, N. Ma, Z. Wu, R. Liang, H. Pan, W. Liu, B. Fu, K. Wang, C. Li, H. Wang, H. Peng, B. Ning, J. Yang, X. Huang, Small 2021, 17, 2005925.
- 30Y. Wu, M. Wu, A. Vázquez-Guardado, J. Kim, X. Zhang, R. Avila, J.-T. Kim, Y. Deng, Y. Yu, S. Melzer, Y. Bai, H. Yoon, L. Meng, Y. Zhang, H. Guo, L. Hong, E. E. Kanatzidis, C. R. Haney, E. A. Waters, A. R. Banks, Z. Hu, F. Lie, L. P. Chamorro, B. L. Sabatini, Y. Huang, Y. Kozorovitskiy, J. A. Rogers, Nat. Commun. 2022, 13, 5571.
- 31Y. Yang, M. Wu, A. Vázquez-Guardado, A. J. Wegener, J. G. Grajales-Reyes, Y. Deng, T. Wang, R. Avila, J. A. Moreno, S. Minkowicz, V. Dumrongprechachan, J. Lee, S. Zhang, A. A. Legaria, Y. Ma, S. Mehta, D. Franklin, L. Hartman, W. Bai, M. Han, H. Zhao, W. Lu, Y. Yu, X. Sheng, A. Banks, X. Yu, Z. R. Donaldson, R. W. Gereau, C. H. Good, Z. Xie, et al., Nat. Neurosci. 2021, 24, 1035.
- 32W. Ling, J. Yu, N. Ma, Y. Li, Z. Wu, R. Liang, Y. Hao, H. Pan, W. Liu, B. Fu, K. Wang, H. Wang, L. Li, X. Sheng, H. Peng, B. Ning, J. Yang, X. Huang, Adv. Funct. Mater. 2020, 30, 2002644.
- 33K. Y. Kwon, H. Lee, M. Ghovanloo, A. Weber, W. Li, Front Syst Neurosci 2015, 9, 69.
- 34K. Y. Kwon, H. M. Lee, M. Ghovanloo, A. Weber, W. Li , 2014 IEEE 27th Int. Conf. on Micro Electro Mechanical Systems (MEMS), San Francisco, USA, January 2014.
- 35J. Lee, I. Ozden, Y.-K. Song, A. V. Nurmikko, Nat. Methods 2015, 12, 1157.
- 36K. Kampasi, D. F. English, J. Seymour, E. Stark, S. McKenzie, M. Voroslakos, G. Buzsaki, K. D. Wise, E. Yoon, Microsyst. Nanoeng. 2018, 4, 10.
- 37M. H. Doan, S. Kim, J. J. Lee, H. Lim, F. Rotermund, K. Kim, AIP Adv. 2012, 2, 022122.
- 38E. Pastrana, Nat. Methods 2011, 8, 24.
- 39J. Duebel, K. Marazova, J.-A. Sahel, Curr. Opin. Ophthalmol. 2015, 26, 226.
- 40J. Y. Shi, L. P. Yu, Y. Z. Wang, G. Y. Zhang, H. Zhang, Appl. Phys. Lett. 2002, 80, 2293.
- 41J. Ausra, M. Wu, X. Zhang, A. Vázquez-Guardado, P. Skelton, R. Peralta, R. Avila, T. Murickan, C. R. Haney, Y. Huang, J. A. Rogers, Y. Kozorovitskiy, P. Gutruf, Proc. Natl. Acad. Sci. USA 2021, 118, e2025775118.
- 42X. Cai, L. Li, W. Liu, N. Du, Y. Zhao, Y. Han, C. Liu, Y. Yin, X. Fu, D. Sheng, L. Yin, L. Wang, P. Wei, X. Sheng, iScience 2022, 25, 103681.
- 43C. Liu, Y. Zhao, X. Cai, Y. Xie, T. Wang, D. Cheng, L. Li, R. Li, Y. Deng, H. Ding, G. Lv, G. Zhao, L. Liu, G. Zou, M. Feng, Q. Sun, L. Yin, X. Sheng, Microsyst. Nanoeng. 2020, 6, 64.
- 44J. W. Reddy, I. Kimukin, L. T. Stewart, Z. Ahmed, A. L. Barth, E. Towe, M. Chamanzar, Front. Neurosci. 2019, 13.
10.3389/fnins.2019.00745 Google Scholar
- 45J. W. Reddy, I. Kimukin, E. Towe, M. Chamanzar Presented at 9th Int. IEEE/EMBS Conf. on Neural Engineering (NER), San Francisco, CA, March 2019.
- 46F. Wu, E. Stark, P.-C. Ku, K. D. Wise, G. Buzsáki, E. Yoon, Neuron 2015, 88, 1136.
- 47Y. Zhang, S. Wang, X. Li, J. A. Fan, S. Xu, Y. M. Song, K.-J. Choi, W.-H. Yeo, W. Lee, S. N. Nazaar, B. Lu, L. Yin, K.-C. Hwang, J. A. Rogers, Y. Huang, Adv. Funct. Mater. 2014, 24, 2028.
- 48A. Leibinger, A. E. Forte, Z. Tan, M. J. Oldfield, F. Beyrau, D. Dini, F. Rodriguez y Baena, Ann. Biomed. Eng. 2016, 44, 2442.
- 49S. Zhang, C. Wang, H. Gao, C. Yu, Q. Yan, Y. Lu, Z. Tao, C. Linghu, Z. Chen, K. Xu, J. Song, Adv. Mater. Interfaces 2020, 7, 1901775.
- 50J. H. Kim, G. H. Lee, S. Kim, H. W. Chung, J. H. Lee, S. M. Lee, C. Y. Kang, S.-H. Lee, Biosens. Bioelectron. 2018, 117, 436.
- 51J. M. Stujenske, T. Spellman, J. A. Gordon, Cell Rep. 2015, 12, 525.
- 52K. Podgorski, G. Ranganathan, J. Neurophysiol. 2016, 116, 1012.
- 53H. Wang, M. Kim, K. P. Normoyle, D. Llano, Front. Neurosci. 2016, 9, 00528.
- 54R. Chen, F. Gore, Q.-A. Nguyen, C. Ramakrishnan, S. Patel, S. H. Kim, M. Raffiee, Y. S. Kim, B. Hsueh, E. Krook-Magnusson, I. Soltesz, K. Deisseroth, Nat. Biotechnol. 2021, 39, 161.
- 55J. Y. Lin, Exp. Physiol. 2011, 96, 19.
- 56A. Soltan, B. McGovern, E. Drakakis, M. Neil, P. Maaskant, M. Akhter, J. S. Lee, P. Degenaar, IEEE Trans. Biomed. Circuits Syst. 2017, 11, 347.
- 57S. H. Lee, J. Kim, J. H. Shin, H. E. Lee, I.-S. Kang, K. Gwak, D.-S. Kim, D. Kim, K. J. Lee, Nano Energy 2018, 44, 447.
- 58H. Sekiguchi, H. Yasunaga, K. Tsuchiyama, R. Nitta, Electron. Lett. 2019, 55, 619.
- 59M. C. T. Bahaa, E. A. Saleh, Fundamentals of Photonics, Wiley, New York 1991
- 60A. Brahme, Comprehensive Biomedical Physics, Elsevier, New York 2014.
10.1016/B978-0-444-53632-7.00923-0 Google Scholar
- 61H. Shin, S. Jeong, J.-H. Lee, W. Sun, N. Choi, I.-J. Cho, Nat. Commun. 2021, 12, 492.
- 62M. Schwaerzle, P. Elmlinger, O. Paul, P. Ruther, Presented at 36th Annual Int. Conf. of the IEEE Engineering in Medicine and Biology Society, Chicago, Illinois, USA, August 2014.
- 63M. Schwaerzle, P. Elmlinger, O. Paul, P. Ruther, Presented at 28th IEEE Int. Conf. on Micro Electro Mechanical Systems (MEMS), Estoril, Portugal, January 2015.
- 64H. Park, H. J. Shin, I. J. Cho, E. s. Yoon, J. K. F. Suh, M. Im, E. Yoon, Y. J. Kim, J. Kim In, Annual Int. Conf. of the IEEE Engineering in Medicine and Biology Society, Boston, Massachusetts, USA, August 2011.
- 65M. Schwaerzle, O. Paul, P. Ruther, J. Micromech. Microeng. 2017, 27, 065004.
- 66K. Kampasi, D. F. English, J. Seymour, E. Stark, S. McKenzie, M. Vöröslakos, G. Buzsáki, K. D. Wise, E. Yoon, Microsyst. Nanoeng. 2018, 4, 10.
- 67A. M. Sharifi, S. H. Mousavi, M. Bakhshayesh, F. K. Tehrani, M. Mahmoudian, S. Oryan, Toxicol. Lett. 2005, 160, 43.
- 68Y. Kang, J. Liu, J. Wu, Q. Yin, H. Liang, A. Chen, L. Shao, Int. J. Nanomed. 2017, 12, 5501.
- 69U. Kim, T. Lee, Eur. J. Neurosci. 2012, 35, 1253.
- 70M. Matsumoto, O. Hikosaka, Nat. Neurosci. 2009, 12, 77.
- 71L. Pan, K. Huang, G. Min, X. Li, J. Shao, F. Ma, L. Kong, M. Zou, G. Meng, W. Chen, L. Yang, X.-Y. Liu, N. Lin, Sens. Actuators, B 2022, 358, 131474.
- 72L. Zou, H. Tian, S. Guan, J. Ding, L. Gao, J. Wang, Y. Fang, Nat. Commun. 2021, 12, 5871.
- 73A. A. Leino, A. Pulkkinen, T. Tarvainen, OSA Continuum 2019, 2, 957.