Toward the Next Generation of Neural Iontronic Interfaces

Abstract

Neural interfaces are evolving at a rapid pace owing to advances in material science and fabrication, reduced cost of scalable complementary metal oxide semiconductor (CMOS) technologies, and highly interdisciplinary teams of researchers and engineers that span a large range from basic to applied and clinical sciences. This study outlines currently established technologies, defined as instruments and biological study systems that are routinely used in neuroscientific research. After identifying the shortcomings of current technologies, such as a lack of biocompatibility, topological optimization, low bandwidth, and lack of transparency, it maps out promising directions along which progress should be made to achieve the next generation of symbiotic and intelligent neural interfaces. Lastly, it proposes novel applications that can be achieved by these developments, ranging from the understanding and reproduction of synaptic learning to live-long multimodal measurements to monitor and treat various neuronal disorders.

Keywords: biomimetics; iontronics; neural interfaces; neuromorphic devices; seamless integration.

Figure 1

To harness the full potential of neural interfaces to interoperate with neural systems, they will have to integrate seamlessly into the biological tissue.

Figure 2

Overview of established neural interface technologies: A wide range of devices are available to fulfill various requirements of size, electrode density, conformability, depth, and transparency. These devices have to achieve locally tight coupling to their electrodes (or transistors) while the encapsulation interacts globally with the tissue and is tailored to specific needs such as transparency, deformability, stretchability, and biocompatibility. Devices can be planar (reproduced with permission.^{[ 20 ]} Copyright 2014, IEEE), penetrating (reproduced with permission.^{[ 23} , ²⁴ , ^{25 ]} Copyright 1997, 2021, 2022, Elsevier, American Association for the Advancement of Science [AAAS], Springer Nature), or conformally adapt to irregular shapes. Reproduced with permission.^{[ 26} , ²⁷ , ^{28 ]} Copyright 2018, 2009, 2015, Wiley‐VCH GmbH, IOP Publishing, AAAS. The devices can also have low footprint like meshes (reproduced with permission.^{[ 29} , ^{30 ]} Copyright 2020, 2019, Elsevier, Springer Nature), wrap around thinner structures (reproduced with permission.^{[ 31} , ^{32 ]} Copyright 2016, 2021, Wiley‐VCH GmbH, Springer Nature), or resemble sieves to adapt to nerves. Reproduced with permission.^{[ 33 ]} Copyright 2002, Wiley Periodicals LLC. The electrodes can be made of various materials (reproduced with permission.^{[ 34} , ³⁵ , ^{36 ]} Copyright 2015, 2021, 2012, Elsevier, Forschungszentrum Jülich, Frontiers), or nanotopograhpic shapes (reproduced with permission.^{[ 37} , ³⁸ , ³⁹ , ⁴⁰ , ^{41 ]} Copyright 2022, 2015, 2022, 2017, 2019, Springer Nature, Springer Nature, Wiley‐VCH GmbH, IOP Publishing, American Chemical Society) to improve cell‐adhesion. The insulation around the electrodes, which makes the bulk of the device, can be of various ceramics, elastomers, or even biomimetic materials. Reproduced with permission.^{[ 35} , ^{42 ]} Copyright 2021, 2012, Forschungszentrum Jülich, Springer Nature. The combination of the global geometry, the choice of electrodes, and the bulk material enable the study of a host of systems ranging from a few neurons in vitro (reproduced with permission.^{[ 43} , ^{44 ]} Copyright 2018, 2020, Elsevier, Springer Nature) to slices and organoids (reproduced with permission.^{[ 35} , ⁴⁵ , ^{46 ]} Copyright 2021, 2021, 2021, Forschungszentrum Jülich, Elsevier, AAAS) to even full brains. Reproduced with permission.^{[ 47 ]} Copyright 2015, Springer Nature.

Figure 3

Roadmap to achieve the next generation of neural iontronic devices: Increased bandwidth is necessary to record and stimulate as many neurons as possible. Biological compliance is important for cells to attach and interface the device seamlessly. In order to increase signal quality and stimulation capabilities, the surface of electrodes needs to be tailored to increase cell‐electrode couplings. Similarly to electrical stimulus and readout, devices need the capability to also operate in the chemical domain, for example by measuring and delivering neurotransmitters. In light of this, more understanding of what stimulus waveforms and concentrations should be used along their spatio‐temporal coherence to best impact the neural system under study. Finally, these technologies should enable to have artificial‐intelligence powered closed‐loop control over neural systems by enabling rich, varied input (stimuli) into the network with a high‐bandwidth, and a high‐quality readout of the network's response.

Figure 4

Applications to biological systems: The technological innovations that would lead to neural interfaces of higher‐bandwidth, intelligent closed‐loop capabilities, with biologically compliant shapes, increased cell‐electrode coupling, with multifunctional (electrical, chemical) stimulation and read‐out possibilities could greatly benefit several systems of interest. Among these, reconstructed in vitro assemblies could benefit from soft, 3D shapes and higher bandwidth. Reproduced with permission.^{[ 151} , ^{152 ]} Copyright 2014, 2020, The Company of Biologists, Frontiers. Small neural networks would benefit from high‐density, high‐bandwidth closed‐loop, and neuromorphic devices. Reproduced with permission.^{[ 153} , ¹⁵⁴ , ^{155 ]} Copyright 2022, 2005, 2009, The Royal Society of Chemistry, Elsevier, Springer Nature. Organoids and assembloids need higher‐banwidth and closed‐loop devices with perfusion capabilities of medium, oxygen and neurotransmitters. Reproduced with permission.^{[ 10} , ^{46 ]} Copyright 2022, 2021, Springer Nature, AAAS. Human brain circuits and in vivo animal models require in addition biologically highly compliant devices for long‐term interfacing of the neural tissue (images of brain‐circuit M.Hausser at University College London).