Nano Research 1 https://doi.org/10.1007/s12274Nano Res -018-2127-4 Nano functional neural interfaces 1,§ 2,§ 3,4,§ 5 2 2 Yongchen Wang , Hanlin Zhu , Huiran Yang , Aaron D. Argall , Lan Luan , Chong Xie (), and Liang Guo3,6 () Nano Res., Just Accepted Manuscript • https://doi.org/10.1007/s12274-018-2127-4 http://www.thenanoresearch.com on Jun. 12, 2018 © Tsinghua University Press 2018 Just Accepted This is a “Just Accepted” manuscript, which has been examined by the peer-review process and has been accepted for publication. A “Just Accepted” manuscript is published online shortly after its acceptance, which is prior to technical editing and formatting and author proofing. Tsinghua University Press (TUP) provides “Just Accepted” as an optional and free service which allows authors to make their results available to the research community as soon as possible after acceptance. After a manuscript has been technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Please note that technical editing may introduce minor changes to the manuscript text and/or graphics which may affect the content, and all legal disclaimers that apply to the journal pertain. In no event shall TUP be held responsible for errors or consequences arising from the use of any information contained in these “Just Accepted” manuscripts. To cite this manuscript please use its Digital Object Identifier (DOI®), which is identical for all formats of publication. Nano Res. Nano Res. 63 TABLE OF CONTENTS (TOC) Nano functional neural interfaces Yongchen Wang1†, Hanlin Zhu2†, Huiran Yang1,3†, Aaron D. Argall1, Lan Luan2, Chong Xie2*, and Liang Guo1* 1 The Ohio State University, U.S.A. 2 The University of Texas at Austin, U.S.A. 3 Nanjing Tech University, China † Equal contribution Engineered functional neural interfaces serve as essential abiotic-biotic transducers between an engineered system and the nervous system. This review covers the exciting developments and applications of functional neural interfaces that rely on nanoelectrodes, nanotransducers, or bionanotransducers to establish an interface with the nervous system. Guo Lab: http://guolab.engineering.osu.edu Xie Lab: http://faculty.engr.utexas.edu/xie Nano Research Nano Res. Nano Res. 1 DOI Review Article Nano functional neural interfaces 1† 2† 3,4† 5 2 2 Yongchen Wang , Hanlin Zhu , Huiran Yang , Aaron D. Argall , Lan Luan , Chong Xie (), and Liang 3,6 Guo () 1 Department of Biomedical Engineering, The Ohio State University, Columbus 43210, USA 2 Department of Biomedical Engineering, The University of Texas at Austin, Austin 78712, USA 3 Department of Electrical and Computer Engineering, The Ohio State University, Columbus 43210, USA 4 Key Laboratory of Flexible Electronics and Institute of Advanced Materials, Jiangsu National Synergetic Innovation Center for Advanced Materials, Nanjing Tech University, Nanjing 211816, China 5 Biomedical Sciences Graduate Program, The Ohio State University, Columbus 43210, USA 6 Department of Neuroscience, The Ohio State University, Columbus 43210, USA † Equal contribution Received: day month year ABSTRACT Revised: day month year Engineered functional neural interfaces (fNIs) serve as essential abiotic-biotic Accepted: day month year transducers between an engineered system and the nervous system. They (automatically inserted by convert external physical stimuli to cellular signals in stimulation mode, or read the publisher) out biological processes in recording mode. Information can be exchanged using electricity, light, magnetic fields, mechanical forces, heat, or chemical © Tsinghua University Press signals. fNIs have found applications for studying processes in neural circuits and Springer-Verlag Berlin from cell cultures to organs to whole organisms. fNI-facilitated signal Heidelberg 2014 transduction schemes, coupled with easily manipulable and observable external physical signals, have attracted considerable attentions in recent years. This KEYWORDS enticing field is rapidly evolving toward miniaturization and biomimicry to achieve long-term interface stability with great signal transduction efficiency. Neural interface, Not only a new generation of neuroelectrodes has been invented, but advanced neurotechnology, fNIs that explore other physical modalities of neuromodulation and recording nanoelectrode, have started to bloom. This review covers these exciting developments and nanomaterial, applications of fNIs that rely on nanoelectrodes, nanotransducers, or neural recording, bionanotransducers to establish an interface with the nervous system. These neural stimulation nano fNIs are promising in offering a high spatial resolution, high target specificity, and high communication bandwidth by allowing for a high density and count of signal channels with minimum material volume and area to dramatically improve the chronic integration of the fNI to the target neural tissue. Such demanding advances in nano fNIs will greatly facilitate new opportunities not only for studying basic neuroscience, but also for diagnosing and treating various neurological diseases. Address correspondence to Prof. Liang Guo, [email protected]; and Prof. Chong Xie, [email protected] Nano Res. Nano Res. 2 fNIs are of a major focus. Such demanding advances in fNIs will greatly facilitate new opportunities not 1. Introduction only for studying basic neuroscience, but also for diagnosing and treating various neurological 1.1 What are functional neural interfaces? diseases. Engineered functional neural interfaces (fNIs) serve as essential abiotic-biotic transducers between 1.3 Why nano? an engineered system and the nervous system. They Conventional electrode-based neurotechnologies convert external physical stimuli to cellular signals in are facing two major hurdles: (1) susceptibility of the stimulation mode, or read out biological processes in abiotic-biotic interface to immune responses and (2) recording mode. Information can be exchanged using communication inefficiency through the electricity, light, magnetic fields, mechanical forces, abiotic-biotic interface [2]. Nano fNIs are compelling heat, or chemical signals. fNIs have found in offering more effective solutions to both of these applications for studying processes in neural circuits two aspects. from cell cultures to organs to whole organisms. fNI-facilitated signal transduction schemes, coupled 1.3.1 Chronic stability with easily manipulable and observable external Even though many electrode-based physical signals, have attracted considerable neurotechnologies have made great strides during attentions in recent years. This enticing field is the preceding few decades in proving their feasibility rapidly evolving toward miniaturization and in treating and restoring impaired neural functions, biomimicry to achieve long-term interface stability their clinical potential is severely restricted by issues with great signal transduction efficiency. This review in integration of the neural interface within the covers the developments and applications of fNIs complex tissue environment. Not only do these that rely on nanoelectrodes, nanotransducers, or mechanically and chemically distinct neural bionanotransducers to establish an interface with the interfaces cause significant infection, but the nervous system. communication at the electrode-tissue interface is significantly diminished as the implant is isolated by 1.2 Why are fNIs important? fibrosis over time as a consequence of the In the past decade, the field of fNIs has foreign-body reactions [3]. This discovery of fibrotic experienced a dramatic revolution. The once encapsulation developing around the implanted electrical-engineering concentrated field has evolved neuroelectrodes over a short time window of a few to a new stage that has absorbed an ever-large months [4-7], which physically screens the electrical research population and ever-diverse sensors from accessing to the target neurons, has multidisciplinary approaches. Not only a new largely shaped the thinking and practice in the field generation of neuroelectrodes has been invented, but in the past decade. The resulting new concepts in advanced fNIs that explore other physical modalities neural interfacing have motived both the of neuromodulation and recording have started to development of a new generation of miniaturized bloom, partially stimulated by the great success of neuroelectrodes [2, 8-10] and the exploration of optogenetics [1]. This new stage is facilitated by alternative approaches that feature minimum or even advocations and funding supports on brain-related none invasiveness. Reduction of the footprint of the research across the globe. Specifically, in the USA, the neural implant down to the nanoscale to make it Brain Research through Advancing Innovative less “sensible” to the host tissue environment has Neurotechnologies (BRAIN) and Stimulating proven to dramatically improve the chronic stability Peripheral Activity to Relieve Conditions (SPARC) of the neural interface [8-10]. Alternatively, to Initiatives aim to significantly promote brain and mitigate the problems associated with the bioelectric medicine research by accelerating the conventional electrode-based approaches, such as the development and application of novel and requirement for implantation of the bulky interface paradigm-shifting neurotechnologies, among which into the immediate target neural tissue [11], Nano Res. 3 nonspecific and variable activation, bio-fouling, potentials (spikes)