阅读说明：本技术 柔性神经探针以及基于液态金属的输入/输出（i/o）连接器 (Flexible neural probe and liquid metal-based input/output (I/O) connector ) 是由 邢怡铭 李玥 阿斯米特·维罗妮卡 于 2020-03-02 设计创作，主要内容包括：本公开提供一种柔性神经探针,其包括：位于所述柔性神经探针中心的感测区域,所述感测区域包括多个柔性同心环和多个蛇形连接结构,所述多个柔性同心环中的内侧的至少一个柔性同心环中集成有用于测量神经信号的至少一个有机电化学晶体管,所述多个柔性同心环由所述多个蛇形连接结构连接以形成柔性网状结构。本公开还提供一种柔性输入/输出连接器,用于与上述柔性神经探针的接合垫连接,并且包括柔性有机模具,所述柔性有机模具的一侧设置有多个微流体通道,用于填充液态金属。(The present disclosure provides a flexible nerve probe, comprising: a sensing region centered on the flexible nerve probe, the sensing region comprising a plurality of flexible concentric rings and a plurality of serpentine connections, at least one organic electrochemical transistor integrated in an inner one of the plurality of flexible concentric rings for measuring a neural signal, the plurality of flexible concentric rings connected by the plurality of serpentine connections to form a flexible mesh. The present disclosure also provides a flexible input/output connector for connecting with the bonding pad of the above flexible nerve probe, and including a flexible organic mold having a side provided with a plurality of microfluidic channels for filling with a liquid metal.)

1. A flexible neural probe, comprising:

a sensing region centered on the flexible nerve probe, the sensing region comprising a plurality of flexible concentric rings and a plurality of serpentine connections, at least one organic electrochemical transistor integrated in an inner one of the plurality of flexible concentric rings for measuring a neural signal, the plurality of flexible concentric rings connected by the plurality of serpentine connections to form a flexible mesh.

2. The flexible neural probe of claim 1, further comprising bond pads on both sides of the sensing region, the bond pads being electrically connected to the sensing region.

3. The flexible neuroprobe of claim 1, wherein the serpentine connection structure and the flexible concentric rings each comprise a substrate formed of at least one of polyimide, SU-8, parylene C, and PDMS, and a wire formed on the substrate.

4. The flexible nerve probe of claim 3, wherein the wire is wrapped with an insulating polymer and the insulating polymer is the same material as the substrate.

5. The flexible nerve probe of claim 1, wherein the serpentine connection structure comprises a serpentine bend at the center of the sensing region and a straight portion at the edge of the sensing region.

6. The flexible neuroprobe of claim 4, wherein the organic electrochemical transistor comprises a source electrode and a drain electrode, and a conductive polymer between the source electrode and the drain electrode, and wherein the conductive polymer is made from PEDOT: PSS.

7. The flexible neural probe of claim 6, wherein the source and drain electrodes are each comprised of a wire,

wherein a wire constituting a drain electrode extends outwardly from the sensing region to be electrically connected to a corresponding one of the connection plates of the bonding pad; and is

Each of the one or more wires constituting a source electrode extends outwardly from the sensing region to be electrically connected to the respective two connection plates.

8. The flexible nerve probe of claim 7, wherein each of the one or more wires comprising the source electrode extends outwardly from the sensing region to an outermost concentric ring of the plurality of concentric rings and continues outwardly at the outermost concentric ring to be electrically connected to the respective two connection plates, respectively.

9. The flexible nerve probe of claim 2, wherein a bond pad comprises a substrate and a plurality of connection plates formed on the substrate, each connection plate electrically connected to the sensing region.

10. A flexible input/output connector for connection with the bonding pad of the flexible neural probe of claim 9, and comprising a flexible organic mold having a side provided with a plurality of microfluidic channels for filling with liquid metal.

11. The flexible input/output connector according to claim 10, wherein a side of the flexible organic mold provided with the plurality of microfluidic channels is bonded to the substrate of the bonding pad such that the liquid metal filled in each microfluidic channel is electrically connected to the corresponding connection plate of the bonding pad and each microfluidic channel is not communicated with each other,

wherein each microfluidic channel corresponds to one connection plate of a bond pad of the flexible probe.

12. The flexible input/output connector of claim 10, wherein the length of each microfluidic channel is half the length of the connection plate of the bonding pad of the flexible probe.

13. The flexible input/output connector of claim 10, wherein the flexible organic mold is made of polydimethylsiloxane.

14. The flexible input/output connector as recited in claim 10, wherein the liquid metal comprises eutectic gallium-indium (EGaIn) comprising 75% gallium and 25% indium by weight.

Technical Field

The present disclosure relates to the field of neural interfaces, and more particularly to a uniquely designed implantable high compliance flexible neural probe and liquid metal based surface mount flexible input/output (I/O) connector.

Background

The bidirectional interface can realize the bidirectional communication between the outside and the nervous system so as to effectively monitor the brain state and influence each area in the brain to treat neurological diseases or recover consciousness and motor functions. Both brain-machine interface (BMI) and neural interface are devices that enable such two-way communication. Communication between neurons is a combination of electrochemical signals and electrical signals that constitute the primary source of information for the BMI. This field has now attracted considerable attention from the research community, where studies have developed various new types of electrodes based on electrode control. The main research has been directed to creating new techniques for treatment protocols, such as neural signals obtained from the motor cortex of paralyzed patients have been used to operate auxiliary devices such as robotic prostheses.

Neural technology is crucial for understanding the complex functions of the brain and neuronal networks. In recent years, research on a nerve probe applied to diagnosis of neurodegenerative diseases such as alzheimer disease, epilepsy, and dementia in a clinical environment has been advanced, and this has been attracting growing attention in an aging society. Implantable nerve probes are an important component of brain-computer interfaces for recording or stimulating specific areas or regions of the brain. Electrical signals in the form of spikes are considered critical for extracting meaningful information (e.g., motion-related activities, etc.). The implantable probe can be brought closer to the neuron to record extracellular activity or local field potentials. Monofilament electrodes and glass microtubular electrodes are commonly used electrodes in electrophysiological studies. However, advances in micro-electro-mechanical systems (MEMS) have made possible the development of implantable nerve probes in recent years.

Currently, micromechanical probes, such as Michigan style probes (Michigan style multi-site probes) and Utah style electrode arrays (Utah style electrode array), have become commercial neural recording and stimulation tools and are widely used. These probes have had great success in the field of neuroscience research, but they have had certain limitations in the field of practical applications. Implantation of these rigid probes causes undesirable neuroinflammatory responses relative to the flexibility of brain tissue, and thus mechanical property mismatch is a key technical challenge facing rigid probes. The characteristics of this inflammatory or foreign body response include an acute response followed by a chronic response upon insertion of the probe, which encapsulates the probe with glia. Micro-motion caused by vibration of a probe attached to the skull bone or pulsatile motion associated with heart rhythm or respiration can also cause reactive tissue reactions. Compliant probes can mitigate micro-damage to surrounding tissue, thereby reducing the incidence of immune responses. One solution is to design a rigid material by adjusting the size, structure and geometry to achieve a lower effective stiffness. To reduce mechanical property mismatch, conventional silicon-based brain probes are designed on the micrometer scale. Although these probes show the potential to record high signal-to-noise ratio signals due to their miniaturized size and low impedance nature of silicon. However, the rigid probe is severely incompatible with brain tissue and produces a foreign body response, which results in the probe being encapsulated by glia and neuronal death, and thus its functionality as a long-term implant is extremely limited.

Based on the cognition of the limitation of planar electronics in the aspect of connecting a three-dimensional biological system, a three-dimensional flexible brain probe with a macroporous structure is designed. The neural probe is designed as a mesh-like macroporous structure because it has high porosity similar to brain tissue to allow the integration and interpenetration of neuronal cells. It is believed that a two-dimensional structure of about 80% open area and submicron features would result in a mesh design with high flexibility and sufficient bending stiffness well below that of conventional planar polymer structure devices. The probe is designed with strain elements, so that the probe can be self-organized into a three-dimensional reticular macroporous structure. Furthermore, the actual volume probed by the mesh device is close to the other probes present (except for the utah array) taking into account the number of recording sites. Therefore, the three-dimensional reticulated macroporous structure is by far the most suitable for constructing a novel neuroprobe and providing it with a structure of minimal device size and good sensing capability. However, these probes generally require a special insertion and, due to the inherent stresses that determine their position, the implantation of the sensor requires precise control and is more limited.

Disclosure of Invention

Embodiments of the present disclosure provide a flexible nerve probe, including: a sensing region centered on the flexible nerve probe, the sensing region comprising a plurality of flexible concentric rings and a plurality of serpentine connections, at least one organic electrochemical transistor integrated in an inner one of the plurality of flexible concentric rings for measuring a neural signal, the plurality of flexible concentric rings connected by the plurality of serpentine connections to form a flexible mesh.

In some embodiments, the flexible neural probe further comprises bonding pads on both sides of the sensing region, the bonding pads being electrically connected to the sensing region.

In some embodiments, the serpentine connection structure and the flexible concentric rings each include a substrate formed of at least one of polyimide, SU-8, parylene c (parylene c), and PDMS, and a wire formed on the substrate.

In some embodiments, the wire is surrounded by an insulating polymer, and the insulating polymer is the same material as the substrate.

In some embodiments, the serpentine connection structure includes a serpentine bend portion at the center of the sensing region and a straight portion at the edge of the sensing region.

In some embodiments, an organic electrochemical transistor comprises a source electrode and a drain electrode, and a conductive polymer between the source electrode and the drain electrode, and wherein the conductive polymer is made from PEDOT: PSS.

In some embodiments, the source and drain are each comprised of a wire, wherein the wire comprising the drain extends outwardly from the sensing region to electrically connect to a respective one of the connection plates of the bond pad; and each of the one or more wires constituting a source electrode extends outwardly from the sensing region to be electrically connected to the respective two connection plates.

In some embodiments, each of the one or more wires making up the source extends outwardly from the sensing region to an outermost concentric ring of the plurality of concentric rings and continues outwardly at the outermost concentric ring to be electrically connected to the respective two connection plates, respectively.

In some embodiments, a bond pad includes a substrate and a plurality of connection plates formed on the substrate, each connection plate electrically connected to the sensing region.

Embodiments of the present disclosure provide a flexible input/output connector for connecting with a bonding pad of the flexible neural probe, and include a flexible organic mold having one side provided with a plurality of microfluidic channels for filling with a liquid metal.

In some embodiments, a side of the flexible organic mold on which the plurality of microfluidic channels are disposed is bonded to the substrate of the bonding pad such that the liquid metal filled in each microfluidic channel is electrically connected to a corresponding connection plate of the bonding pad and each microfluidic channel is not in communication with each other, wherein each microfluidic channel corresponds to one connection plate of the bonding pad of the flexible probe.

In some embodiments, the length of each microfluidic channel is half the length of the web of bonding pads of the flexible probe.

In some embodiments, the flexible organic mold is made of polydimethylsiloxane.

In some embodiments, the liquid metal comprises eutectic gallium-indium (EGaIn), which comprises 75% gallium and 25% indium by weight.

Drawings

The accompanying drawings, which are included to provide a further understanding of the disclosure and are incorporated in and constitute a part of this specification, illustrate embodiments of the disclosure and together with the description serve to explain the disclosure without limiting the disclosure. In the drawings:

fig. 1 is an overall view of an implantable high compliance flexible nerve probe according to an embodiment of the present disclosure and schematically illustrating the wire width and base width of a serpentine connection structure;

FIG. 2A is a schematic view of a central portion sensing region of the nerve probe of FIG. 1, the sensing region comprising flexible concentric rings interconnected by stretchable serpentine links;

FIG. 2B is an enlarged view of a portion of the serpentine shaped connection;

FIG. 3A shows a view of the distribution of sensors on the concentric rings in FIG. 2A;

FIG. 3B is an enlarged view of one of the transistors of FIG. 3A;

fig. 4A and 4B are a cross-sectional view and a side view, respectively, of a flexible I/O connector with microfluidic channels according to an embodiment of the present disclosure; and

FIG. 5A is a schematic diagram showing the connection of the liquid metal-filled I/O connector of FIGS. 4A and 4B to the I/O pad of the flexible nerve probe of FIG. 1;

FIG. 5B is an enlarged view of the I/O connector portion.

Detailed Description

The present disclosure proposes an implantable high compliance flexible nerve probe inspired by the cobweb, having a sensing region formed as a highly flexible three-dimensional mesh macroporous structure at the center of the probe for implantation in the brain. The nerve probe comprises a flexible concentric ring at the center of the probe integrated with an organic electrochemical transistor OECT that can be used to measure nerve signals (recording nerve activity). These concentric rings are interconnected by serpentine connections to form a spider-web structure that allows for good stretchability, compliance, and ease of nerve integration following implantation. The serpentine connection structure comprises a wire wrapped in a flexible insulation (i.e., the wire is completely covered by the flexible insulation). The present disclosure also discloses a liquid metal based surface mount input/output (I/O) microfluidic connector. The connector comprises a thin and flexible organic mold comprising microfluidic channels filled with liquid metal, thereby providing a stable connection to the I/O pads of the flexible neural probe for obtaining reliable detection signals.

The technical characteristics of implantable nerve probes are critical to the practical application of neural interfaces. These properties include high spatial and temporal resolution, high signal-to-noise ratio, and good biocompatibility. Miniaturization has become increasingly popular, and therefore, implantable multi-array neuroprobes with these properties are being developed and used for research, diagnosis and therapy.

The rigid probe is severely incompatible with brain tissue and produces a foreign body response that results in encapsulation of the probe by glia and neuronal death, thus its functionality as a long-term implant is extremely limited. The key to optimizing the mechanical matching degree and the compliance of the probe to the brain tissue is to utilize a flexible material with an elastic modulus similar to that of the brain tissue and adjust the size and the structure of the probe. Polymers are inherently flexible and are ideal substrates for replacing silicon. Some polymers (e.g., polyimide, SU-8, parylene C, and PDMS) have elastic moduli on the GPa scale and even lower than silicon or other metals, and are of great interest for their potential applications in flexible nerve probes. These polymers have good flexibility, biocompatibility and long-term stability, and become ideal constituent materials for making flexible nerve probes. They can meet the requirements of spinal column and brain tissue for static and dynamic mechanical properties, and can implement three-dimensional integrated dense array.

In addition, the signal quality, long-term stability and recording ability of the neural probe are strongly correlated with the electrode impedance. In addition to being invasive, which leads to foreign body reactions, the larger electrode size is also a major factor in causing tissue damage. Therefore, to improve spatial resolution and mitigate tissue damage, electrodes with smaller size and higher electrical sensitivity are required. While smaller electrode locations may provide better selectivity, and may distinguish between individual cells having higher signal amplitudes, they typically have higher impedance and thermal noise. Reducing the impedance by increasing the electrode surface area can effectively improve signal quality. The conflicting performance forces one to choose an electrode material that reduces resistance without increasing the size of the electrode. Therefore, conducting polymers, carbon nanotubes, graphene and organic nanotransistor elements are viable materials to constitute long-term stable, sensitive nerve probes.

Furthermore, the closer the amplification site of the signal is to the electrode site, the more desirable the signal processing will be and thus a higher quality signal will be. Small changes in the effective potential due to neural activity in a transistor can cause large current changes due to its inherent amplification or gain. In recent years, Field Effect Transistors (FETs) have been widely used in the field of neural network interfaces because of their minimal invasiveness while locally amplifying and transmitting signals. However, silicon-based planar fets have limited temporal and spatial resolution because the cells are not tightly connected, resulting in a large potential signal leakage, and the inability to detect the activity of individual neurons. Nanoscale field effect transistors have been used to replace planar field effect transistors because they are more easily integrated with neurons, and have controllable three-dimensional sensing feasibility and long-term stability. In recent years, OECTs have been widely used due to their excellent signal transmission and signal amplification functions. In contrast to field effect transistors with dielectric layers for connection or electrostatic gating, OECTs have no dielectric layer, but instead an active organic layer that can be directly connected to the cell, which allows efficient coupling of biological signals to electrical signals. Researchers have conducted in vivo studies of electrocorticogram (ECoG) of rat somatosensory cortex using highly conformal OECT array devices, and the results show that the signal-to-noise ratio (i.e. obtained by OECT) of this method is significantly superior to that of conventional recording electrodes. In addition, OECT is able to record low intensity and fast signals from inside the brain that conventional methods cannot record. Therefore, the development of flexible implantable probes and the long-term stable evaluation of in vivo and in vitro studies by using OECT devices are an emerging field of neuroscience, and provide a wide prospect for future studies.

Developing highly flexible neuroprobes to provide seamless binding to neurons is challenging, but a more interesting part is the interface of the I/O pads to obtain reliable signals. The main problem is due to the flexibility of the nerve probe, because of the rigid device that functions like a commercial connector, the use of wire connections/soldering can cause significant damage to the I/O pads, resulting in unstable connections or device failure.

In recent years, liquid metals have gained wide popularity as ideal materials for wearable electronics, biomedical devices, and soft robots. Liquid metal is a highly flexible material with unique composite properties such as high fluidity, high conductivity, shape change properties, and most importantly, it is almost non-toxic. Liquid metal eutectic gallium-indium (egain), wherein 75% Ga and 25% In by weight, is a conductive fluid metal that can be injected into a microchannel at room temperature to form a conductive path with self-healing properties. The liquid metal material (EGaIn) has unique advantages over welding: the steps of heating and cooling during soldering can create mechanical stresses that damage organic and soft materials. Therefore, the use of biocompatible polymers (e.g., PDMS) and injection of EGaIn into microfluidic channels to fabricate microfluidic devices may serve as a good alternative to directly attached I/O pads.

Accordingly, the present disclosure proposes a flexible neural probe having a web-like structure resembling a spider web and provided with spatially distributed organic electrochemical transistors. The present disclosure also relates to a liquid metal-based I/O connector connected to a bond pad of a flexible probe.

In one embodiment of the present disclosure, a uniquely designed, three-dimensionally inspired, biomimetic, minimally invasive neural probe with a three-dimensional, reticulated macroporous structure is provided that facilitates seamless binding of neurons to the entire probe. The porosity of the central network makes it suitably compliant, and when implanted in a given area of the brain, it forms a wide spatial distribution of networks. This function is designed to ensure easy insertion while achieving minimal size, and minimal damage. The smaller the size of a neuroprobe according to embodiments of the present disclosure, the closer it is to neurons, which may improve signal-to-noise ratio and enable higher specificity recordings. Incorporation of an OECT as a sensing device in a neural probe according to embodiments of the present disclosure to locally amplify and record a biological signal can significantly improve sensitivity and selectivity.

In another embodiment of the present disclosure, a biocompatible flexible I/O connector is provided in place of a commercial rigid connector. The flexible I/O connector includes a microfluidic channel filled with a liquid metal. Rigid connectors or the use of solder to make connections to external PCB boards can cause severe damage to the soft flexible probes, resulting in degraded signal quality. The liquid metal-based connector is well compatible with the flexible nerve probe according to embodiments of the present disclosure, can form a reliable and stable interface, and is not significantly damaged. In the near future, this part of the present disclosure applies extensions to the attachment of flexible biosensors.

The present disclosure relates to the field of neural interfacing, and in particular to a uniquely designed implantable high compliance flexible neural probe integrated with organic electrochemical transistors (OECTs) for efficient recording of neural activity; the present disclosure also relates to a liquid metal based surface mount flexible input/output (I/O) connector to achieve a reliable and stable connection with a nerve probe.

Fig. 1 is an overall view of a biomimetic spider-web structured flexible neural probe 1 according to an embodiment of the present disclosure. Not shown are I/O connectors that will be described in detail below. A polymer having an elastic modulus closer to brain tissue is used as a substrate on which a wire of a flexible nerve probe is fabricated. For example, the substrate may be formed of at least one of polyimide, SU-8, parylene C, and PDMS, which have an elastic modulus on the GPa scale or even lower, and good flexibility, biocompatibility, and long-term stability.

The nerve probe 1 includes a sensing region at a central portion of the nerve probe 1 and I/O pads 4 symmetrically positioned at both sides of the sensing region. Wherein the I/O pads 4 are connected to the sensing area.

The sensing region comprises a plurality of flexible concentric rings 2. These concentric rings 2 are interconnected by a plurality of serpentine connections 3 to form a three-dimensional reticulated macroporous structure that allows for good stretchability, conformability, and ease of nerve integration following implantation. When a certain or some of the serpentine connections 3 are deformed, the radius of a portion of the concentric rings 2 corresponding to the deformed portion of the serpentine connections 3 may also be varied. Thereby ensuring good stretchability and compliance of the entire mesh-like sensing region. In a net structure formed by interconnecting a plurality of flexible concentric rings 2 by a plurality of serpentine shaped connecting structures 3, the ratio of the area of the holes to the total area is greater than 80%. This network is thus referred to as a macroporous structure.

The serpentine shaped connecting structure 3 comprises a wire wrapped in a flexible insulating material, which is made of the same material as the substrate. Integrated on the plurality of flexible concentric rings 2 are organic electrochemical transistors (OECTs) that can be used to measure neural signals (record neural activity), as will be described in detail below with respect to fig. 3.

Also shown in FIG. 1 are I/O pads 4 for connection with I/O connectors. The I/O pad 4 is also connected to a flexible concentric ring 2 of the sensing area via an intermediate wire and further connected to a sensor (organic electrochemical transistor) arranged in the flexible concentric ring 2 by a wire of a serpentine connection structure 3. In one embodiment of the present disclosure, the intermediate wire is wrapped with the same material as the flexible insulating material. In one embodiment of the present disclosure, the I/O pad 4 comprises the same material as the flexible insulating material on which a plurality of I/O connection boards are disposed. In one embodiment of the present disclosure, the I/O connection plate is made of a metallic material. In one embodiment of the present disclosure, the insulating material of the I/O pad 4 is connected with the insulating material that wraps the middle wire, which in turn is connected with the flexible insulating material of the flexible concentric rings 2 and the serpentine connection structure 3; and the I/O connecting plate is connected with the corresponding middle metal wire and further connected with the flexible concentric ring 2 and the snake-shaped connecting structure 3.

As shown in fig. 1 to 3B, one end of each serpentine connection structure 3 is connected to the innermost concentric ring and, in turn, to the outermost concentric ring. The plurality of serpentine connections 3 space apart the concentric rings and the plurality of serpentine connections 3 do not coincide with each other.

As shown in fig. 1, key parameters of a flexible neural probe according to one embodiment of the present disclosure are as follows: the total width W of the probe was 20mm, and the length L was 44 mm. The maximum diameter D of the concentric rings is 6mm and the sensors are arranged in the innermost three of the flexible concentric rings 2, which have diameters (i.e. the part implanted in the brain) of 0.3mm, 0.6mm and 1mm (preferably in the range between 1mm and 1.2 mm), respectively. The width wm of the wire of the serpentine-shaped connection structure 3 and the width w1 of the substrate on which the wire is located can be set as desired, for example, wm is 10 μm; w1 is in the range of 16 μm to 20 μm, and such a size setting makes it more ensured that the metal connection is not affected by manufacturing defects and is less likely to fall off and break. The total number of channels (i.e., circuit channels in the flexible neural probe) is the number of sensors that can be used for measurement. As shown in fig. 3A, the total number N of channels is 12; the conductive polymer region shown in fig. 3B has a diameter of 16 μm, and the substrate region on which the conductive polymer is disposed has a diameter of 24 μm. In an embodiment of the present disclosure, each I/O pad 4 comprises 7I/O connection plates 8, each I/O connection plate 8 having a size of 2mm by 7mm, and the distance between the centers of two adjacent I/O connection plates is 2.54 mm. In other embodiments of the present disclosure, other numbers of I/O connection boards 8 may also be provided. Each I/O connection plate 8 is connected to a respective serpentine connection structure 3 at the outermost one of the concentric rings 2.

The sensing region of the central portion of the neural probe includes a plurality of flexible concentric rings. These concentric rings are interconnected by a serpentine connection structure as described below. When the probe is implanted into the human brain, the serpentine connection structure will be further extended into a planar strip to provide stretchability to the probe, so that the probe is distributed in a wide range of flexible networks within the brain. The nerve probe is embedded in the center with an OECT that serves as a sensor to sense and locally amplify and record biological signals, where a wire (metal trace) runs over a serpentine connection structure, eventually connected to an I/O pad designed on a larger flexible portion of the probe. The wires are all wrapped by a layer of insulating polymer. The flexible probe is integrally prepared by adopting a standard photoetching technology. Details will be described below.

Figure 2A is a schematic view of the central portion sensing region of the nerve probe of figure 1, comprising flexible concentric rings 2 interconnected by stretchable serpentine connections 3. Fig. 2B is an enlarged view of a portion of the serpentine connection structure 3. As shown in fig. 2A, the serpentine curved portion of the serpentine connection structure 3 is mainly concentrated in the central portion of the sensing region to ensure that the whole mesh structure is stretchable, and at the position of the concentric ring adjacent to the outer side of the plurality of flexible concentric rings 2 (the sensing region of this portion is not required to be implanted in the human brain), the requirement for stretchability of the mesh structure is reduced, and therefore, the serpentine connection structure 3 is designed to be straight, which can reduce the resistance of the whole sensor (electrode). The straight serpentine connection 3 extends further outwards to connect to the I/O pad 4, thereby enabling connection of the I/O pad 4 by a wire to a sensor arranged in a concentric ring.

As shown in fig. 2B, the serpentine-shaped bent portion of the serpentine connection structure 3 includes a plurality of partial circular ring-shaped strips and a plurality of straight strips, wherein one end of a first partial circular ring-shaped strip is connected to one end of a first straight strip, the other end of the first straight strip is connected to one end of a second partial circular ring-shaped strip, and the other end of the second partial circular ring-shaped strip is connected to a second straight strip, and wherein the other end of the second partial circular ring-shaped strip is not disposed opposite to the one end of the first partial circular ring-shaped strip. For one partially circular strip, its two ends are connected to one end of the other two partially circular strips by respective straight strips. The above connections are repeated to form a serpentine connection as shown in fig. 2A.

As shown in fig. 2B, the parameters of the size of each of the plurality of partially circular ring-shaped bands are: inner diameter R20 μm, α 15 °; each of the plurality of straight strips has a length L ═ 8 μm.

The nerve probe 1 is designed into a highly porous and flexible structure through the arrangement of the snake-shaped connecting structure 3, which can promote the growth and combination of neurons. The size of the snake-shaped connecting structure of the nerve probe is optimized, so that the nerve probe has high flexibility and compliance.

FIG. 3A is a view showing the distribution of OECTs disposed on the concentric rings in FIG. 2A; FIG. 3B is an enlarged view of one of the OECTs of FIG. 3A. How to form the plurality of flexible concentric rings 2 and the plurality of serpentine shaped connection structures 3, and how to construct the plurality of OECTs for measuring signals will be described below with reference to fig. 3A and 3B.

The plurality of flexible concentric rings 2 and the plurality of serpentine connections 3 can be made simultaneously using standard photolithographic techniques and using the same materials, i.e., each photolithography forms a layer of concentric rings and serpentine connections simultaneously. Each of the plurality of serpentine connections 3 is connected to each of the plurality of flexible concentric rings 2.

Specifically, the bases of the concentric rings 2 and the serpentine connections 3 are formed simultaneously using standard photolithographic techniques, with the gray portion of FIG. 3A being the base formed.

The wires of the concentric rings 2 and the serpentine-shaped connecting structures 3 are respectively arranged on the substrate to constitute the corresponding OECTs, and the black parts in fig. 3A are the formed wires. The wire is disposed on a base provided with the innermost three concentric rings of the OECT. No wires are provided on the base of the concentric rings where no OECT is provided.

A layer of insulating polymer is formed on the substrate of the same material as the substrate to seal the base of the concentric rings 2 and serpentine connections 3 and to encase the wires. In this way, concentric rings 2 and serpentine connections 3 are formed.

Specifically, as shown in fig. 3A, among the wires of the included 12 serpentine-shaped connection structures 3, the wires 01 and 02 extend in the serpentine-shaped connection structures 3 and extend to intersect each of the three concentric rings 2 provided with the OECTs, respectively being connected to the corresponding wire serving as the source of the OECTs provided in the corresponding concentric ring; the wires 31, 32, 33 and 34 extend in the serpentine connection structure 3 and extend to intersect with the outermost concentric ring of the three concentric rings 2 provided with the OECTs to serve as the drain of the OECTs, wherein the wires 31, 32 extend along the concentric rings toward both ends of the wire 301 provided in the concentric rings to serve as the source of the OECTs, respectively, and a conductive polymer is provided between the wires 31, 32 and the respective ends of the wire 301, respectively, to constitute two OECTs, wherein the wires 31, 32 serve as the drains of the two OECTs constituted, respectively, and the wires 301 in the concentric rings serve as the sources of the OECTs, respectively.

Specifically, as shown in fig. 3A, in the outermost concentric ring of the three concentric rings 2 provided with the OECTs, the wire 301 to which the wire 01 is connected is between the wires 31 and 32, and a conductive polymer is provided between the wire 301 and the respective wires 31 and 32 to constitute two OECTs, respectively.

Similarly, wires 33 and 34 and wire 302 and the conductive polymer therebetween form two OECTs, respectively.

Similarly, in the middle one of the three concentric rings 2 provided with the OECTs, the wires 21 and 22 and the wire 201 and the conductive polymer therebetween constitute two OECTs, respectively; and the wires 23 and 24 and the wire 202 and the conductive polymer therebetween constitute two OECTs, respectively.

In the innermost concentric ring of the three concentric rings 2 provided with the OECTs, the wires 11 constitute two OECTs with the wire 101 in the innermost concentric ring to which the wire 01 is connected and the wire 102 in the innermost concentric ring to which the wire 02 is connected, and the conductive polymer therebetween, respectively; and the wire 12 forms two OECTs with the wires 101 and 102, respectively, and the conductive polymer therebetween. That is, in the innermost concentric ring, both the wire 11 and the wire 12 function as the drains of the two OECTs, respectively.

Therefore, in the above manner, 4 OECTs are provided in each concentric ring, so that 12 OECTs are formed, and the total number of channels N of the formed nerve probe is 12. In other embodiments of the present disclosure, other numbers of OECTs may be provided depending on the number of sensors required.

For each of the wires 01 and 02 used as the source of the OECT, a ground is required when performing signal measurement, so both wires 01 and 02 are connected to two I/O pads to ensure that they can be grounded. Specifically, as shown in fig. 1, each of the wires 01 and 02 serving as a source is divided into two wires at the outermost concentric ring among the plurality of concentric rings 2, respectively extending to the two I/O pads to be connected thereto. Also, as shown in FIG. 1, each of the 12 wires that would serve as drains extends from the concentric rings to the I/O pads for connection thereto. More specifically, each of these wires is connected to a respective I/O connection board 8.

In the embodiment of the present disclosure, in the sensing region, a total of 7 flexible concentric rings 2 are disposed, wherein the OECTs are disposed in the innermost 3 flexible concentric rings 2, the OECTs are not disposed in the outer 4 flexible concentric rings 2, and the outer 4 flexible concentric rings 2 serve as a support to facilitate implantation and secure a mesh structure before implantation.

In other embodiments of the present disclosure, other numbers of flexible concentric rings 2 may be provided, including several flexible concentric rings 2 with OECTs disposed and several flexible concentric rings 2 without OECTs disposed as supports, depending on the number of sensors required. Other numbers of serpentine connections 3 may be provided depending on the number of sensors required. In the plurality of flexible concentric rings 2, the spacing between adjacent concentric rings is different, and from inside to outside, as the diameter of the concentric rings increases, the spacing between adjacent concentric rings also increases.

In one embodiment of the present disclosure, the conductive polymer disposed between the source and drain electrodes may be made of a suitable material, such as PEDOT: PSS. It should be noted that the OECT portions shown in FIGS. 3A and 3B are not encased in a polymer substrate that forms concentric rings and serpentines, but are covered by the conductive polymer PEDOT: PSS.

In the embodiments of the present disclosure, the polymer substrate and the metal wires constituting the concentric rings and the serpentine structures have good flexibility and stretchability, so that when the probe is implanted into the brain of a human, the mesh structure is implanted from the center of the concentric rings, and then the mesh structure forms a three-dimensional structure similar to a closed umbrella.

As described above, the outermost concentric ring among the several flexible concentric rings 2 provided with the OECTs has a radius of 0.5 to 0.6mm due to stretchability of the concentric rings and the serpentine structure. Specifically, for example, if the outermost concentric ring provided with the OECTs has a radius of 0.5mm, the depth of the OECTs distribution may be slightly greater than 0.5mm after implantation of the probe into the human brain due to the stretchability of the concentric ring and the serpentine structure. Depending on the desire of this probe to measure cortical signals, the electrodes of the sensor will typically only be implanted to a depth of 1 to 2mm, and to ensure that all sensors can detect signals, probes according to the present disclosure are designed with a probe depth of about 0.5 mm. Whereas the concentric ring without the OECT and the I/O pad 4 are not implanted in the human brain.

OECT has no dielectric layer, an active organic layer that can be directly connected to the cell, which allows efficient coupling of biological signals to electrical signals.

By disposing a plurality of flexible concentric rings 2 at the central portion of the nerve probe 1 and connecting each concentric ring by a serpentine connection structure 3, the nerve probe is designed into a three-dimensional net-like macroporous structure such that it has high porosity similar to brain tissue to allow the integration and interpenetration of neuronal cells.

The signal-to-noise ratio of the signal obtained by OECT is significantly better than that of conventional recording electrodes. The use of OECT allows the nerve probe to have long-term stability and sensitivity, thereby allowing long-term stability assessment of in vivo and in vitro studies.

Fig. 4A and 4B are a cross-sectional view and a side view, respectively, of a flexible I/O connector 5 with a microfluidic channel 6 according to an embodiment of the present disclosure. FIG. 4B is a schematic diagram showing the connection of I/O connector 5 with I/O pad 4. The I/O pad 4 is shown schematically in fig. 4B.

A plurality of microfluidic channels 6, each filled with liquid metal, are provided in the I/O connector 5 for I/O connection plates 8 on respective I/O pads 4 of the neural probe 1.

The depth d, width w and length l of each microfluidic channel are respectively 200 μm,1.5mm and 3.5mm, and the central distance l' between two adjacent microfluidic channels is the same as the central distance between two adjacent I/O connection plates, and is 2.54 mm. The cylindrical dots 7 on both ends of the microfluidic channel 6 represent the liquid metal injection and outflow openings, with a diameter D of 700 μm and a height H of 200 μm. As shown in fig. 4A and 4B, 7 microfluidic channels 6 are shown, the number of which is the same as the number of I/O connection plates 8 on the corresponding I/O pads 4 of the neural probe 1.

In embodiments of the present disclosure, the length of each microfluidic channel 6 (e.g., 3.5mm) is half the length of the I/O connection plate (e.g., 7mm) to ensure that the contact area of each microfluidic channel is the same and is the bottom area of the channel. And the liquid metal is only used for connecting the I/O pads and external circuits, and does not need much.

The I/O connector 5 comprises a mold made of Polydimethylsiloxane (PDMS) material (shown as a transparent portion in fig. 4A and 4B), which makes the I/O connector 5 highly flexible and highly biocompatible with the nerve probe 1. The microfluidic channel 6 with inlet and outlet points is sized specifically for the I/O pads 4 on the probe 1 and standard connector pins (not shown). The channels are filled with liquid metal to form conductive paths, and connector pins can be inserted from the other end for data acquisition. The PDMS mold may be bonded to the polymer of the I/O pad by a method such as plasma bombardment, so that the liquid metal filled in its microfluidic channel 6 is sealed, and thus, the lower end of the liquid metal is in direct contact with the I/O pad. In the embodiment of the disclosure, the contact area of the liquid metal filled in each microfluidic channel and the I/O pad is the same, and the microfluidic channels are not communicated with each other. The width of each microfluidic channel is designed to be narrower and the center distance between two adjacent microfluidic channels is wider to ensure that the PDMS mold is bonded to the polymer of the I/O pad 4 on the probe 1.

Liquid metal is a highly flexible material with unique composite properties such as high fluidity, high conductivity, shape change properties, and most importantly, it is almost non-toxic. In an embodiment of the present disclosure, EGaIn (75% Ga and 25% In by weight) is selected as the liquid metal injected into the microchannel, thereby forming a conductive path having self-healing properties.

FIG. 5A is a schematic diagram schematically illustrating the connection of the liquid metal-filled I/O connector of FIGS. 4A and 4B to the I/O pad of the flexible nerve probe of FIG. 1; FIG. 5B is an enlarged view of the I/O connector portion.

A flexible I/O connector 5 according to an embodiment of the present disclosure may be placed on the I/O pad 4 of the nerve probe 1 as shown in fig. 5. The liquid metal filled micro-channel can form a direct and reliable connection with the I/O pad of the flexible probe without causing any damage.

One embodiment of the present disclosure provides an implantable high compliance flexible nerve probe integrated with an OECT for efficient recording of nerve activity. Another embodiment of the present disclosure provides a liquid metal-based surface mount flexible input/output (I/O) connector to achieve a reliable and stable connection with a nerve probe.

It is to be understood that the above embodiments are merely exemplary embodiments that are employed to illustrate the principles of the present application, and that the present application is not limited thereto. It will be apparent to those skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope of the application, and these changes and modifications are to be considered as the scope of the application.