A probe device for docking with cells, such as neurons, and associated devices, methods and uses

Abstract

A probe device for interfacing with cells (e.g. Neurons, preferably individual neurons) in brain tissue comprises a support structure having a longitudinal axis and a set of neuron interfacing electrodes arranged on the support structure, wherein the neuron docking electrode set is arranged and adapted to be movable between a first inserted configuration and a second extended configuration, the first configuration being different from the second configuration wherein the first configuration is adapted to reach a predetermined target area in the brain while causing minimal injury to the brain, wherein the second configuration corresponds to a predetermined regular three-dimensional grid configuration corresponding to a cubic, face-centered cubic (fcc), body-centered cubic (bcc) or hexagonal grid configuration.

Description

Technical Field

[0001] The present disclosure relates to the field of medical probes, such as neural probes.

[0002] Background Field

[0003] A thorough understanding of brain function is a global scientific challenge. Neuroelectrophysiological knowledge is extended by increasing the ability to record large-scale isolated single unit activity. To this end, 3D electrode arrays appear to give the best unit yield because of their relatively large monitoring volume and relatively increased monitoring volume. The increased monitoring volume can improve neuronal localization and increase the number of neurons detected, which leads to robust spike sorting.

[0004] Most of the existing state-of-the-art neural probes, including a single shaft or several shafts containing one or several electrodes, sample only in one-dimensional (1D) or two-dimensional (2D) space. They are limited to measurements along a small cylindrical volume around the probe shaft, which is insufficient to measure all neurons within the cortical column. Although three-dimensional (3D) rigid silicon neural probes (by stacking several 2D silicon probes) have been commercialized, they cause significant tissue damage and are difficult to insert into the brain. The high density of penetrating probe shafts leads to large tissue indentations during implantation, resulting in cell loss. In addition, these 3D probe arrays are limited in depth and cannot reach deep brain regions beyond a depth of 10 mm.

[0005] There is a need for neural probes with reduced tissue damage using a limited number of electrodes, better neuronal localization and increased neuronal identification and / or localization, which may lead to new therapeutic insights in addressing brain-related diseases and disorders.

[0006] Public Overview

[0007] The object of the present disclosure is to provide a probe device according to claim 1 for docking with preferably individual cells or small cell collections (for example, 2, 3, 4, 5 cells) (preferably neuronal cells); a related composite probe device; the use of the probe device or the probe composite device; a method for determining the location of individual neurons in brain tissue; a method for measuring neuronal activity in brain tissue; a method for stimulating neurons in brain tissue; and a method for manufacturing a probe device for docking with neurons in the brain.

[0008] In a first aspect of the present disclosure, a probe device (such as a neural probe) for docking with cells (preferably neuronal cells, preferably individual cells or neurons, alternatively with multiple cells or neurons in brain tissue) has been disclosed, comprising a support structure having a longitudinal axis and a collection of cell or neuron docking devices arranged on the support structure. The collection of cell or neuron docking devices is arranged and adapted to be movable between a first insertion configuration and a second extension configuration, the first configuration being different from the second configuration. The first configuration is preferably adapted to reach a predetermined target area in the brain while causing minimal damage to the brain. The second configuration preferably corresponds to a predetermined regular three-dimensional grid configuration, which is one of a cubic, face-centered cubic (fcc), body-centered cubic (bcc) or hexagonal grid configuration. Alternatively, the second configuration preferably corresponds to a predetermined regular three-dimensional grid configuration of a tetrahedral type.

[0009] The advantage is that for the same amount of cell / neuron docking devices per volume, a neural probe comprising cell / neuron docking devices employing any of these configurations allows for better identification and / or localization of individual cells / neurons when compared, for example, to cell / neuron docking devices employing random configurations.

[0010] According to a preferred embodiment, the probe device is configured such that, for example, in brain tissue, the electrode sensing radius (defining the sensing sphere) is in the range of 75 microns to 150 microns, and such that the electrode pitch (or minimum electrode distance or electrode spacing) is in the range of 45 microns to 150 microns. Typically, and as known in the art, the electrode pitch is measured from electrode center to electrode center.

[0011] Here, the electrode pitch is the minimum electrode distance of a corresponding predetermined regular 3D grid configuration. The predetermined type of three-dimensional grid configuration (one of cubic, face-centered cubic (fcc), body-centered cubic (bcc), tetrahedral or hexagonal grid) is further fully defined by the pitch value.

[0012] The electrode sensing radius is also typically determined by the electrode impedance.

[0013] According to a preferred embodiment, the electrode pitch is less than 150 microns, or less than 125 microns, or less than 100 microns, or less than 75 microns.

[0014] Preferably, the overlapping sensing spheres of at least four adjacent electrodes form an active volume within a predetermined regular three-dimensional grid configuration (cubic, face-centered cubic (fcc), body-centered cubic (bcc), hexagonal or tetrahedral shape).

[0015] This effective volume is required for cell / neuron identification (eg, by using known location determination techniques, such as triangulation techniques) so that more than three electrodes can simultaneously sense neural spike signals generated by the same cell / neuron.

[0016] According to a preferred embodiment, the electrode pitch is less than 150 microns, thereby obtaining a higher effective volume for achieving much better individual cell / neuron identification (e.g., using triangulation). Preferably, the electrode sensing radius is 150 microns or less, or about 150 microns or less. In some embodiments, this combination of ranges is applicable to a predetermined regular three-dimensional grid configuration corresponding to a cubic, fcc, or bcc configuration.

[0017] According to a preferred embodiment, the electrode pitch is less than 100 microns, thereby obtaining a higher effective volume for achieving much better individual cell / neuron identification (e.g., using triangulation). Preferably, the electrode sensing radius is 100 microns or less, or about 100 microns or less. In some embodiments, this combination of ranges is applicable to a predetermined regular three-dimensional grid configuration corresponding to a cubic, fcc, or bcc configuration.

[0018] According to a preferred embodiment, the predetermined regular three-dimensional grid configuration corresponds to a cubic, fcc or bcc configuration, and the electrode pitch is between 60 microns and 85 microns, and if the electrode sensing radius is 75 microns or about 75 microns (such as, for example, 75±12.5 microns), the highest effective volume is obtained for achieving much better individual cell / neuron identification.

[0019] According to a preferred embodiment, the predetermined regular three-dimensional grid configuration corresponds to a cubic, fcc or bcc configuration, and the electrode pitch is between 85 microns and 100 microns, and the highest effective volume is obtained for achieving much better individual cell / neuron identification if the electrode sensing radius is 100 microns or approximately 100 microns (such as, for example, 100±12.5 microns).

[0020] According to a preferred embodiment, the predetermined regular three-dimensional grid configuration corresponds to a cubic, fcc or bcc configuration, and the electrode pitch is between 100 microns and 125 microns, and the highest effective volume is obtained for achieving much better individual cell / neuron identification if the electrode sensing radius is 125 microns or approximately 125 microns (such as, for example, 125±12.5 microns).

[0021] According to a preferred embodiment, the predetermined regular three-dimensional grid configuration corresponds to a cubic, fcc or bcc configuration, and the electrode pitch is between 125 microns and 150 microns, and the highest effective volume is obtained for achieving much better individual cell / neuron identification if the electrode sensing radius is 150 microns or approximately 150 microns (such as, for example, 150±12.5 microns).

[0022] Preferably, the neuron docking device is an electrode. Alternatively, the neuron docking device is an optical interaction device, which includes a light source (such as, for example, an LED) and / or an optical sensor. According to a preferred embodiment, the neuron docking device is an electrode, and a corresponding optical interaction device may be provided adjacent to some or all of the electrodes. The optical interaction device allows not only to identify individual neurons and provide electrical stimulation or a readout thereof, but also to stimulate the identified neurons by a light beam or signal. For example, different types of neurons may be marked so that each type of neuron becomes sensitive to a specific type of light wave (such as, for example, a specific wavelength) and thereby to a specific type of LED, i.e. active and silent.

[0023] According to a preferred embodiment, the support structure comprises a flexible material, such as a flexible biocompatible polymer. The support structure is rigid enough to penetrate the tissue during insertion configuration. The support structure is suitable for positioning the electrode in the tissue. Preferably, the flexible biocompatible polymer comprises polyimide, polyparaxylene, epoxy, polyetheretherketone (PEEK), polyetherimide (Ultem), SU-8, polydimethylsiloxane (PDMS), silicone. Alternatively, a dissolvable material can be used that is rigid during implantation and dissolves over time once implanted, for example, in a brain tissue environment.

[0024] According to a preferred embodiment, the support structure generally defines a longitudinal probe shape, which defines a circumferential wall, which includes a cylindrical cover portion describing an angular section of the cylindrical surface, and when in the first configuration, the neuron docking device is adjacent to the cylindrical cover portion and / or positioned on the cylindrical cover portion.

[0025] The support structure may preferably include a circular cross-section in a direction perpendicular to its longitudinal axis. Such a circular cross-section support structure provides an advantage over conventional rectangular cross-section silicon-based probes in that significantly less tissue damage is produced during insertion of the probe into brain tissue. Tissue damage results in scar tissue formation, further compromising the recording and stimulation functions of the neural probe.

[0026] According to a preferred embodiment, the support structure comprises a longitudinal central portion and a plurality of at least 1 (e.g. 1) (or at least 2 (e.g. 2), or at least 3 (e.g. 3), or at least 4 (e.g. 4)) flexible arm sets, each arm extending approximately from a corresponding first end at the central portion of the support structure to a second end as an independent distal end, for example, thereby forming a 3D grid. Preferably, each arm comprises at least one neuron docking device, wherein when in a second configuration (corresponding to the second configuration of these arms), these arms are adapted and arranged to position the neuron docking device in a predetermined regular grid configuration by bending radially outward according to a predetermined range. Preferably, each flexible arm has a tip suitable for insertion into brain tissue.

[0027] According to an alternative preferred embodiment, the support structure comprises a longitudinal central portion and a plurality of flexible arms, each arm extending substantially from a respective first end at the central portion of the support structure to a second end as an independent distal end. Preferably, each arm comprises at least one neuronal docking device (such as an electrode), and the central portion comprises one or more neuronal docking devices (such as electrodes), and the central portion and the flexible arms are adapted and arranged to position the neuronal docking devices in a predetermined regular grid configuration by bending the flexible arms radially outward according to a predetermined range when in the second configuration.

[0028] According to a preferred embodiment, the predetermined range is determined by a predetermined internal stress in the arm causing the distal end to be biased radially outward relative to the first end of the arm and by a predetermined movement of the device in brain tissue along a direction corresponding to its longitudinal axis.

[0029] According to a preferred embodiment, a probe device for docking with neurons in brain tissue comprises a flexible 2D substrate that is at least partially or completely rolled up, preferably processed and patterned. As is known in the art, the term processing is used to perform microfabrication or microelectronic processing steps. For example, the microfabrication processing step may include forming one or more layers (such as connecting layers and dielectric layers) on the 2D substrate, and patterning these layers, and providing microelectronic structures or components on the substrate. The step of patterning the flexible 2D substrate after the (microfabrication) processing step includes patterning the substrate itself, for example, in order to provide a 2D template that provides corresponding arms when rolled up.

[0030] This provides a very elegant and low-cost production of neural probes.

[0031] According to a preferred embodiment, the arms are patterned in the 2D substrate such that they are arranged in a direction substantially parallel to the longitudinal axis.

[0032] According to a preferred embodiment, the neuronal docking devices have a tip portion for inserting the device into brain tissue and in a first configuration of the neuronal docking devices (corresponding to a first configuration of the arms), the arms point away from the tip portion.

[0033] According to an alternative preferred embodiment, the neuron docking devices have a tip portion for inserting the device into brain tissue and in a first configuration of the neuron docking devices (corresponding to the first configuration of the arms), the arms point towards the tip portion.

[0034] According to a preferred embodiment, the arms are patterned in the 2D substrate such that they are arranged in a direction substantially perpendicular to a longitudinal axis, and wherein the arms are wrapped or rolled around the longitudinal axis.

[0035] In a second aspect of the present disclosure, a composite probe device for docking with neurons in brain tissue is disclosed, comprising a tubular guide structure for inserting into brain tissue and comprising a longitudinal inner hole for accommodating and guiding a device according to any embodiment of the first aspect, the tubular structure comprising a set of openings having a predetermined configuration, the set of openings being arranged and adapted to guide the set of neuron docking devices toward a predetermined regular grid configuration.

[0036] This offers the advantage that neural probes can be inserted into the brain in a more controlled manner, also reducing potential damage to brain tissue.

[0037] According to a preferred embodiment, the composite device is adapted to guide a neuron docking device, which includes a support structure comprising a longitudinal central portion and at least 1 (e.g. 1) (or at least 2 (e.g. 2), or at least 3 (e.g. 3), or at least 4 (e.g. 4)) flexible arm set, each arm extending roughly from a corresponding first end at the central portion of the support structure to a second end as an independent distal end, and each arm including at least one neuron docking device, the arms being adapted and arranged to position the neuron docking devices in a predetermined regular grid configuration by bending radially outward according to a predetermined range when in the second configuration, and the openings being arranged and adapted to allow the corresponding arms to penetrate the corresponding openings in the opening set when the device moves along the inner hole (or in the direction of the axis of the inner hole).

[0038] According to a preferred embodiment, the arms are patterned in the 2D substrate so that they are arranged in a direction substantially perpendicular to the longitudinal axis, and wherein the arms are rolled or rolled around the longitudinal axis, and the openings are arranged and adapted to allow corresponding arms to penetrate corresponding openings in the set of openings when the device is rotated about its axis in the hole.

[0039] According to a preferred embodiment, each arm comprises at least one neuron docking device, such as an electrode. According to a further preferred embodiment, a light source / LED is provided adjacent to or below some electrodes, adjacent to or below a plurality of electrodes, or adjacent to or below each electrode. The distance between the light source or LED and the respective electrode is preferably less than 500 microns. When a light source is provided below an electrode, the electrode is preferably implemented as a transparent electrode.

[0040] According to a preferred embodiment, the neuronal docking devices of at least one arm are arranged on opposite sides of the arm, such as, for example, on opposite sides of a planar substrate forming the neuronal docking device. According to a preferred embodiment, wherein the arm is patterned as a flexible substrate, one or more neuronal docking electrodes or neuronal docking devices are provided on one side of the substrate, and one or more neuronal docking electrodes or neuronal docking devices are provided on the other side of the substrate.

[0041] In a third aspect of the present disclosure, a use of the probe device according to any embodiment of the first aspect or the second aspect has been disclosed, wherein the neuron interfacing device is an electrode for identifying individual neurons in brain tissue.

[0042] In the fourth aspect of the present disclosure, a method for determining the location of individual neurons in brain tissue has been disclosed, the method comprising: implanting a probe device according to any embodiment of the first or second aspect into the brain tissue, the probe device comprising electrodes serving as a neuron docking device, and reading signals from the electrode set.

[0043] According to a preferred embodiment, the method further includes performing a localization determination technique, such as a triangulation method for determining the localization of a specific neuron based on reading out a neural signal (e.g., a spike or spike signal) from a set of electrodes. An example of this method is disclosed in Boussard et al. (DOI: 10.1101 / 2021.11.05.467503).

[0044] In the fifth aspect of the present disclosure, a method for measuring neuronal activity in brain tissue is disclosed, comprising: implanting a probe device according to any embodiment of the first or second aspect into brain tissue, the probe device comprising electrodes serving as a neuronal docking device, and reading out signals from the neuronal docking device set.

[0045] In the sixth aspect of the present disclosure, a method for stimulating neurons in brain tissue is disclosed, comprising: implanting a probe device according to any embodiment of the first aspect or a composite device or a device set according to any embodiment of the second aspect into brain tissue, the probe device or the composite device or the device set comprising an electrode as a neuron docking device, and providing an electrical stimulation signal to the electrode set. Preferably, the electrical stimulation signal is provided based on a measurement signal obtained by the method according to the fifth aspect. According to a preferred embodiment, the stimulation signal for a predetermined neuron may be provided by a pair or more adjacent electrodes for the neuron. Preferably, but not necessarily, the adjacent electrodes used to stimulate the neuron are the same, or are selected from electrodes used for positioning determination techniques, such as the triangulation method used in the fourth aspect.

[0046] In a seventh aspect of the present disclosure, a method for manufacturing a probe device for docking with neurons in brain tissue according to any embodiment of the first or second aspect comprises:

[0047] -Provide flexible, biocompatible, planar (2D) substrates;

[0048] - patterning the planar substrate to define at least one (e.g. 1) (or at least two (e.g. 2), or at least three (e.g. 3), or at least four (e.g. 4)) sets of flexible arms;

[0049] - processing the planar substrate to provide each flexible arm with at least one electrically connected neuron docking device, preferably an electrode;

[0050] - At least partially rolling up the planar substrate into a tubular configuration.

[0051] In an eighth aspect of the present disclosure, a method is disclosed for exchanging signals with brain tissue or docking or interacting with brain tissue through an electrode set from a device according to any embodiment of the first aspect or a composite device or a device set according to any embodiment of the second aspect when the device or the composite device is implanted in the brain tissue.

[0052] In a preferred embodiment, exchanging signals with brain tissue includes determining the location of individual neurons in the brain tissue by reading out signals from a collection of electrodes.

[0053] In a preferred embodiment, exchanging signals with the brain tissue comprises measuring neuronal activity, preferably individual neuronal activity, in the brain tissue by reading out signals from a set of electrodes.

[0054] In a preferred embodiment, exchanging signals with the brain tissue comprises stimulating (preferably individual) neurons in the brain tissue by providing stimulation signals (preferably electrical stimulation signals) to the set of electrodes.

[0055] In a ninth aspect, a device for exchanging signals with brain tissue or docking or interacting with brain tissue via an electrode set is disclosed, the device comprising a device according to any embodiment of the first aspect, or a composite device or a device set according to any embodiment of the second aspect.

[0056] In a preferred embodiment, the device is adapted to determine the location of individual neurons in brain tissue by reading out signals from the set of electrodes.

[0057] In a preferred embodiment, the device is adapted to measure (preferably individual) neuronal activity in brain tissue by reading out signals from the set of electrodes.

[0058] In a preferred embodiment, the device is adapted to stimulate (preferably individual) neurons in brain tissue by providing a stimulation signal (preferably an electrical stimulation signal) to a set of electrodes.

[0059] As the skilled person will appreciate, features and advantages disclosed with respect to one of the above-described aspects of the present disclosure are thereby implicitly disclosed with respect to the other aspects as well, mutatis mutandis. BRIEF DESCRIPTION OF THE DRAWINGS

[0061] The present disclosure will be further clarified by the following description and accompanying drawings.

[0062] Figure 1 is a graph illustrating simulation results of overlapping monitoring volumes of 4 adjacent electrodes (located in 3D space) for different spatial configurations of neuron docking electrodes.

[0063] Figure 2 include Figure 1 Comparison with similar graphs for different electrode sensing radius values.

[0064] 3(a) to (e) illustrate the definition of electrode pitch for corresponding regular grid configurations.

[0065] Figures 3(f) and (g) illustrate the overlapping measurement fields of the electrodes.

[0066] 4(a)-(d) illustrate electrode configurations for a neural probe according to various embodiments of the present disclosure.

[0067] 5(a) and (b) illustrate a first preferred embodiment of the present disclosure, which is a composite device including a probe device and a tubular guide structure for the probe device.

[0068] FIG6 illustrates a second preferred embodiment of a probe device according to the present disclosure, which can preferably be combined with a guide structure as described for the first embodiment. Further details thereof are given in Figure 8 Chinese commentary.

[0069] FIG. 7 illustrates a third preferred embodiment of a probe device according to the present disclosure, which preferably can be combined with a guiding structure as described for the first embodiment.

[0070] FIG. 9 illustrates a fourth preferred embodiment of a probe device according to the present disclosure, which preferably can be combined with a guiding structure as described for the first embodiment.

[0071] Detailed Description of the Preferred Embodiments

[0072] The present disclosure will be described with respect to specific embodiments and with reference to certain drawings, but the disclosure is not limited thereto but only by the claims. The drawings described are schematic and non-limiting only. In the drawings, for illustrative purposes, the size of some of the elements may be exaggerated and not drawn to scale. The dimensions and relative dimensions do not necessarily correspond to actual reductions to the practice of the present disclosure.

[0073] Furthermore, the terms first, second, third and the like in the description and in the claims, are used for distinguishing between similar elements and not necessarily for describing a sequential or chronological order.

[0074] The various embodiments (although referred to as "preferred") are to be construed as examples in which the disclosure may be implemented, rather than limiting the scope of the disclosure.

[0075] Figure 1 is a graph illustrating simulation results for different spatial configurations of electrodes for neuron docking.

[0076] The effective volume (y-axis, in square micrometers (μm)) is plotted for different spatial configurations in the form of regular 3D grid structures and linear arrays of electrodes (1D). 3 )) is plotted as a function of the pitch (x-axis, in microns) between the electrodes that the neurons are docked to. For the corresponding regular grid configuration, the effective volume is the overlapping monitoring volume of 4 adjacent electrodes covering the 3D volume. It has been assumed that one electrode can sense activity within a radius of 75μm (microns). The graph shows which spatial electrode configuration (BCC, FCC, etc.) covers the largest volume (a total of 384 electrodes are used) for increasing electrode pitch. However, for increasing electrode pitch, it is important to note that this involves 4 adjacent electrodes that can sample the 3D volume. This means that only 2 of the 4 electrodes can be located on the same axis. A minimum of 4 electrodes have been used because at least 4 electrodes are needed to define the location of the neuron in the 3D volume. The graph shows a general trend that once the electrode pitch is too small, there will be too much overlap and redundant volume, so the total volume is limited. Once the electrode pitch becomes too large, the amount of overlap is too small, making it impossible to locate the neuron within a specific spatial configuration. It can be concluded that the linear configuration is the least efficient configuration for sampling the volume. Compared with Figure 2Together, the FCC and BCC configurations are able to sample the largest volume for a particular electrode pitch, considering that the electrodes can sense a radius of 75μm-150μm. At an electrode sensing radius of 75μm-150μm, simple cubic, tetrahedral, or hexagonal grids capture the 3rd-5th volume for a particular electrode spacing. Finally, at an electrode pitch of 45μm-15μm and an electrode sensing radius of 75μm-150μm, electrodes configured in 2D achieve a relatively smaller volume than any 3D grid configuration.

[0077] The representation of different spatial configurations is illustrated in FIG3 . It also shows the definition of the electrode pitch P per configuration as a function of the corresponding grid constant X (i.e., the minimum electrode distance for the corresponding predetermined regular 3D grid configuration). FIG3( a) illustrates a tetrahedral configuration with 4 electrodes. FIG3( b) illustrates a simple cubic configuration with 8 electrodes. FIG3( c) illustrates a body-centered cubic (BCC) configuration with 9 electrodes. FIG3( d) illustrates a face-centered cubic (FCC) configuration with 14 electrodes. FIG3( e) illustrates a hexagonal configuration with 12 electrodes.

[0078] 3(f) and (g) illustrate the overlapping fields of the electrodes when the sensing radius of the electrodes is assumed to be approximately 2 / 3 of the electrode pitch P for tetrahedral and simple cubic configurations.

[0079] 4(a) to (d) illustrate electrode configurations for a neural probe 100 according to various embodiments of the present disclosure. The neural probe 100 may include a support structure 1, or may be a composite device including a support structure 1 and a tubular guide structure 4 (not depicted in FIGS. 4(a) to (d)).

[0080] The probe 100 comprises a support structure 1, which is preferably made of a flexible biocompatible material, such as, for example, polyimide, polyparaxylene, epoxy, polyetheretherketone (PEEK), polyetherimide (Ultem), SU-8, polydimethylsiloxane (PDMS) or silicone. It is adapted to dock with neurons in brain tissue so that the material does not damage the cells, and the cells do not damage the structural material. It comprises a support structure 1 having a longitudinal axis and a set of neuron docking electrodes 3 arranged on the support structure 1.

[0081] The neuron docking electrode 3 set is arranged and adapted to be movable between a first insertion configuration and a second extended configuration. The first configuration is different from the second configuration. The first configuration (on the left side of each pair of associated figures (a), (b), (c), (d)) is adapted to reach a predetermined target area in the brain while causing minimal damage to the brain. The second configuration corresponds to a simple cubic (or cubic), face-centered cubic, body-centered cubic, hexagonal or tetrahedral grid configuration.

[0082] The support structure 1 defines a longitudinal probe shape defining a circumferential wall including a cylindrical hood portion describing an angular section of the surface of the cylinder, for example between 180° and 360°, and to which the neuron docking electrode 3 abuts when in a first configuration. The support structure 1 comprises a longitudinal central portion and a set of flexible arms 2, each arm 2 extending substantially from a respective first end at the central portion of the support structure 1 to a second end as an independent distal end, and each arm 2 comprising at least one electrode 3. The arms 2 are adapted and arranged to position the electrodes 3 in a predetermined regular grid configuration by bending radially outward according to a predetermined range when moving towards and ending in a second configuration of the electrodes 3 (corresponding to the second configuration of the arms; on the right side of each pair of associated figures). The arms have a sharp distal end for insertion into brain tissue.

[0083] In FIG. 4( a ), the second configuration of electrodes corresponds to a cubic configuration.

[0084] In FIG. 4( b ), the second configuration of electrodes corresponds to a body-centered configuration.

[0085] In FIG. 4( c ), the second configuration of electrodes corresponds to a face-centered configuration.

[0086] In FIG. 4( d ), the second configuration of electrodes corresponds to a hexagonal grid configuration.

[0087] Preferably, as illustrated in FIG. 5 , the support structure 1 is part of a composite device or probe 100 (1, 4) comprising a tubular guide structure 4 for insertion into brain tissue and comprising a longitudinal inner bore or cylindrical volume for accommodating and guiding the support structure 1. The tubular guide structure comprises a sharp insertion tip 44 at a first end for penetrating brain tissue. The support structure 1 may be positioned in the tubular guide structure 4 when the guide structure is inserted into the brain. Alternatively, the support structure 1 may be accommodated by the guide structure 4 after the guide structure has been inserted into the brain. The material of the tubular guide structure should be rigid enough to penetrate brain tissue and may be made of a biocompatible polymer material or a rigid material using microfabrication techniques. The tubular structure 4 comprises a set of openings 40 having a predetermined configuration, which are arranged and adapted to the set of guide arms 2 and thus the neuron docking electrodes 3 toward a predetermined regular grid configuration. When the support structure 1 moves relative to and within the inner bore of the guide structure 4, for example by sliding in the direction of the bore (or the axis of the cylindrical volume) toward or away from the insertion tip 44 of the tubular structure 4, or by rotating the support structure 1 about its axis within the bore or cylindrical volume, the openings 40 are arranged and adapted to allow the corresponding arm 2 to penetrate a corresponding opening in the set of openings 40.

[0088] The support structure 1 or probe 100 (in the absence of a tubular guide structure 4) is manufactured by partially or completely rolling up a processed and patterned flexible 2D substrate 10. Before the substrate 10 is rolled up, the arm 2 is patterned in a predetermined manner in the 2D substrate. In a first configuration of the electrodes (corresponding to a first configuration of the arm 2), the arm 2 extends in a direction substantially parallel to the longitudinal axis.

[0089] 4(a) to (d), in a first configuration of electrodes (and arms), the neural probe 100 (or support structure 1 in the absence of tubular guide structure 4) has a tip portion 14 for inserting the device into brain tissue, and the arms 2 point away from the tip portion 14. Slight withdrawal of the probe in a direction outward from the brain will open the arms and cause them to penetrate the brain tissue radially outward.

[0090] For example, the embodiments of Figures 4(a) to (d) may be used independently or in a configuration with a tubular guiding structure 4 as explained in conjunction with Figure 5, whereby in the latter case the arms point away from the tip portion 44 in their first configuration (corresponding to the first configuration of the electrode).

[0091] 9(a) to (d) illustrate an embodiment of a support structure 1 which is similar to that of FIGS. 4(a) to (d) and which may be used in conjunction with a tubular guide structure 4. The support structure of FIGS. 9(a) to (d) does not include a tip portion 14.

[0092] Alternatively, as illustrated in FIGS. 6( a ) to ( d ), the support structure 1 is used in combination with a tubular guide structure 4 having a tip portion 44 at its lower end (not depicted), towards which the arm 2 may be pointed.

[0093] When the support structure 1 is moved axially along the longitudinal axis of the hole (away from or towards the tip portion 44, depending on the embodiment), the arm 2 encounters a corresponding opening 40 in the tubular guide structure 4 and extends through the opening into the brain tissue, thereby exposing the electrode 3 to the brain tissue. Alternatively, or in combination therewith, the arm 2 can also be deployed due to a guide 45 arranged in the tubular guide structure 4, such as Figure 8 For example, the guide 45 may include an arcuate surface adapted to guide the arm towards a corresponding opening in the tubular guide structure 4.

[0094] In the embodiment depicted in Figures 7(a) to (d), the arms are patterned in the 2D substrate so that they are initially arranged in a direction generally perpendicular to the longitudinal axis of the probe or more preferably the composite probe, and the arms 2 are coiled along the longitudinal axis. When the arms 2 are deployed by rotating the support structure 1 about its longitudinal axis in the hole, the arms 2 encounter corresponding openings 40 in the tubular guide structure 4 and extend through the openings into the brain tissue, thereby exposing the electrodes 3 to the brain tissue.

[0095] For all the aforementioned embodiments, each arm comprises at least 1 electrode 3. According to a preferred embodiment, each arm comprises 1 or 2 electrodes 3.

[0096] In certain embodiments, wherein at least one arm 2 of the plurality of arms 2 comprises at least two electrodes 3 , the electrodes 3 may be provided on opposite sides of the arm 2 , corresponding to opposite sides of the substrate 10 .

[0097] For all embodiments, the electrodes 3 or other neuronal interfacing devices (such as optical interaction devices) are connected to readout or stimulation circuitry by suitable electrical connections, as is known in the art.

[0098] Those skilled in the art will understand that:

[0099] - the disclosed neural implant or probe 100 can be efficiently used to identify individual neurons in brain tissue to measure neuronal activity, especially predetermined neurons (e.g., identified neurons), and stimulate one or more predetermined neurons (e.g., identified neurons) in brain tissue;

[0100] - The neural probe 100 can be implanted in the brain tissue and the signal can be read out from the electrodes 3;

[0101] -Location determination techniques (e.g., triangulation methods) can be used to determine specific neuron locations based on signals read from the electrode set of the disclosed neural implant. Examples of triangulation methods that can be used are described in Boussard et al. (DOI: 10.1101 / 2021.11.05.467503). The use of triangulation methods is not possible for devices disclosed in, for example, US2013-0281811A1, US20060173263A1, US20150119673A1, US20170080210A1, US2020359965A1, US20070088417A1, US20100114272A1, and US20170105641A1, where the electrode pitch is too large.

[0102] The disclosed embodiments of a probe device for interfacing with neurons in brain tissue may be manufactured by a method comprising the steps of;

[0103] - Providing a flexible, biocompatible, planar (2D) substrate 10; for example, the material may be applied by spin coating or other MEMS deposition techniques on a carrier substrate. For patterning purposes, the substrate may be photosensitive or non-photosensitive.

[0104] - patterning the planar substrate 10 to define at least two sets of flexible arms 2 (e.g., 2, 3 or 4 flexible arms 2), for example by using micromachining techniques such as dry etching techniques or wet etching techniques or by photolithography of the material itself;

[0105] - processing the planar substrate 10 so as to provide each flexible arm 2 with at least one electrically connected neuron docking electrode 3 (for example by using a metal deposition technique such as PECVD or a sputter coating technique), wherein the metal may be patterned using a lift-off technique or using a dry or wet etching technique (or for example by electroplating). For very small feature sizes in the nanometer range, (e.g. less than, for example, 5 nm or less than 3 nm), for example, a focused ion beam technique may be used;

[0106] -Rolling up a planar substrate into a tubular configuration, for example by using a mold and a micromanipulator.

[0107] Some advantages of various embodiments and aspects of the present disclosure are as follows:

[0108] - The disclosed probe 100 can identify more neurons (by a factor of 10) than a probe having the same number of microelectrodes as used in a standard linear electrode array;

[0109] - reduced tissue damage in case of a composite device; this tissue damage is largely limited to that caused by the tubular guiding structure 4, while the recording will be performed by the electrodes on the thin flexible polymer arms 2 (substrate and polymer arms have a typical thickness between 1 and 30 micrometers);

[0110] - The configuration of the electrodes 3 is such that they capture most of the 3D spatial characteristics of the spike waveform, allowing better neuronal discrimination and localization compared to conventional linear electrode arrays;

[0111] - The disclosed probe 100 with the claimed electrode configuration can also reach deep brain regions located at depths greater than 10 mm from the brain surface. This is not possible using prior art stacked 2D probe arrays or 1D linear probe matrices.

[0112] Protection may be sought for the following:

[0113] 1. A probe device (100) for docking with cells (preferably neurons in brain tissue), comprising: a support structure (1) having a longitudinal axis and a set of cell or neuron docking electrodes (3) arranged on the support structure (1), wherein the cell or neuron docking electrode (3) set is arranged and adapted to be movable between a first insertion configuration and a second extension configuration, the first configuration being different from the second configuration, wherein the first configuration is adapted to reach a predetermined target area in the brain while causing minimal damage to the brain, and wherein the second configuration corresponds to a predetermined regular three-dimensional grid configuration, the predetermined regular three-dimensional grid configuration corresponding to a cubic, face-centered cubic (fcc), body-centered cubic (bcc), hexagonal or tetrahedral grid configuration.

[0114] 2. The probe device (100) according to item 1, wherein the neuron docking electrode comprises a sensing radius in the range of 75 microns to 150 microns, and wherein an electrode pitch of the neuron docking electrode is in the range of 45 microns to 150 microns.

[0115] 3. The probe device (100) according to item 1 or 2, wherein the predetermined regular three-dimensional grid configuration corresponds to a cubic, face-centered cubic (fcc), or body-centered cubic (bcc) configuration.

[0116] 4. A device according to any of the preceding items, wherein the support structure comprises a flexible material, such as a flexible biocompatible polymer.

[0117] 5. An apparatus according to any of the preceding items, wherein the support structure roughly defines a longitudinal probe shape, the longitudinal probe shape defines a circumferential wall, the circumferential wall includes a cylindrical cover portion describing an angular cross-section of the cylindrical surface, and wherein when in the first configuration, the neuron docking electrode is adjacent to the cylindrical cover portion.

[0118] 6. A device according to any of the preceding items, wherein the support structure comprises a longitudinal central portion and a collection of at least four flexible arms (2), each arm extending substantially from a respective first end located in the central portion of the support structure to a second end as an independent distal end, and each arm (2) comprising at least one electrode, wherein the arms are adapted and arranged to position the electrode in the predetermined regular grid configuration by bending radially outwardly according to a predetermined range when in the second configuration.

[0119] 7. A device according to item 6, wherein the predetermined range is determined by predetermined internal stresses in the arms and by predetermined movement of the device in the brain tissue along a direction corresponding to its longitudinal axis, the predetermined internal stress causing the distal ends of the arms to be radially biased outward relative to the first end.

[0120] 8. The device according to any of the preceding items 6 or 7, comprising an at least partially or completely rolled, processed and patterned flexible 2D substrate (10).

[0121] 9. The device according to item 8, wherein the arms are patterned in the 2D substrate (10) so that they are arranged in a direction substantially parallel to the longitudinal axis.

[0122] 10. A device according to item 9, wherein the device has a tip portion (14) for inserting the device into brain tissue, and wherein in the first configuration of the electrode (3), the arm (2) points away from the tip portion (14).

[0123] 11. A device according to item 9, wherein the device has a tip portion (14) for inserting the device into brain tissue, and wherein in the first configuration of the electrode, the arm (2) points towards the tip portion (14).

[0124] 12. A device according to item 8 or 9, wherein the arms (2) are patterned in the 2D substrate (10) so that they are arranged in a direction substantially perpendicular to the longitudinal axis, and wherein the arms (2) are coiled along the longitudinal axis.

[0125] 13. Device according to any of the preceding items 6 to 12, wherein the arm comprises at least 1 electrode (3).

[0126] 14. The device according to item 13, comprising at least one arm having at least two electrodes (3), and wherein the electrodes of the at least one arm (2) are arranged on opposite sides of the arm.

[0127] 15. A composite device or a collection of devices, comprising a tubular guide structure (4) for insertion into brain tissue and comprising a longitudinal inner hole for accommodating and guiding a device according to any of the preceding items, the tubular structure (4) comprising a collection of openings (40) having a predetermined configuration, the collection of openings (40) being arranged and adapted to guide a collection of neuron docking electrodes (3) toward the predetermined regular grid configuration.

[0128] 16. A composite device or a collection of devices according to item 15, for guiding a device according to any one of items 1 to 14, wherein the openings (40) are arranged and adapted to allow the corresponding arms (2) to penetrate the corresponding openings in the collection of openings (40) when the device moves along the inner hole.

[0129] 17. A composite device or a collection of devices according to item 15, for guiding a device according to any one of items 1 to 14, wherein the opening (40) is arranged and adapted to allow the corresponding arm (2) to penetrate the corresponding opening in the collection of openings when the device is rotated about its axis in the hole.

[0130] 18. Use of a device according to any one of items 1 to 14 or a composite device or a collection of devices according to any one of items 15 to 17 for identifying individual neurons in brain tissue.

[0131] 19. A method for determining the location of individual neurons in brain tissue, comprising implanting a device according to any one of items 1 to 14 or a composite device or a collection of devices according to any one of items 15 to 17 into the brain tissue, and reading out signals from a collection of electrodes (3).

[0132] 20. The method according to item 19 further comprises: performing a location determination technique, for example, a triangulation method for determining the location of a specific neuron based on the readout signals from the set of electrodes (3).

[0133] 21. A method for measuring neuronal activity in brain tissue, comprising implanting a device according to any one of items 1 to 14 or a composite device or a collection of devices according to any one of items 15 to 17 into the brain tissue, and reading out signals from a collection of electrodes (3).

[0134] 22. A method for stimulating neurons in brain tissue, comprising implanting a device according to any one of items 1 to 14 or a composite device or a collection of devices according to any one of items 15 to 17 into the brain tissue, and providing a stimulation signal (preferably an electrical stimulation signal) to a collection of electrodes (3).

[0135] 23. A method for manufacturing a probe device 100 for interfacing with neurons in brain tissue, comprising:

[0136] - Providing a flexible, biocompatible, planar (2D) substrate (10);

[0137] - patterning the planar substrate (10) to define at least one (e.g. 1) (or at least two (e.g. 2), or at least three (e.g. 3), or at least four (e.g. 4)) set of flexible arms (2);

[0138] - processing the planar substrate to provide each flexible arm (2) with at least one electrically connected neuron docking electrode (3);

[0139] - Rolling up the planar substrate into a tubular configuration.

Claims

1. A probe (100) device for docking with cells (preferably neurons in brain tissue), comprising: A support structure (1) having a longitudinal axis and a collection of cell or neuron docking electrodes (3) arranged on the support structure (1), wherein the cell or neuron docking electrode (3) collection is arranged and adapted to be movable between a first insertion configuration and a second extension configuration, the first configuration being different from the second configuration, wherein the first configuration is preferably adapted to reach a predetermined target area in the brain while causing minimal damage to the brain, and wherein the second configuration corresponds to a predetermined regular three-dimensional grid configuration, the predetermined regular three-dimensional grid configuration corresponding to a cubic, face-centered cubic (fcc), body-centered cubic (bcc), or hexagonal grid configuration, Wherein the neuron docking electrode comprises a sensing radius in brain tissue in the range of 75 microns to 150 microns, and wherein the electrode pitch of the neuron docking electrode (3) is in the range of 45 microns to 150 microns.

2. The device according to any of the preceding claims, wherein the support structure (1) comprises a flexible material, such as a flexible biocompatible polymer.

3. A device according to any one of the preceding claims, wherein the support structure (1) roughly defines a longitudinal probe shape, the longitudinal probe shape defines a circumferential wall, the circumferential wall includes a cylindrical cover portion describing an angular section of the cylindrical surface, and wherein when in the first configuration, the neuron docking electrode is adjacent to the cylindrical cover portion.

4. A device according to any one of the preceding claims, wherein the support structure (1) comprises a longitudinal central portion and a collection of at least one flexible arm (2), each arm extending approximately from a corresponding first end located in the central portion of the support structure to a second end as an independent distal end, and each arm (2) comprises at least one electrode (3), wherein the arm is adapted and arranged to position the electrode (3) in the predetermined regular grid configuration by bending radially outward according to a predetermined range when in the second configuration.

5. The device according to claim 4, comprising an at least partially or completely rolled, processed and patterned flexible 2D substrate (10).

6. Apparatus according to claim 4 or 5, wherein the arms (2) are patterned in the 2D substrate (10) such that they are arranged in a direction substantially parallel to the longitudinal axis.

7. The device according to claim 6, wherein the arms (2) are patterned in the 2D substrate (10) so that they are arranged in a direction substantially perpendicular to the longitudinal axis, and wherein the arms (2) are rolled along the longitudinal axis.

8. A composite device or a collection of devices, comprising a tubular guide structure (4) for being inserted into brain tissue and comprising a longitudinal inner hole for accommodating and guiding a device according to any one of the preceding claims, wherein the tubular guide structure (4) comprises a collection of openings (40) having a predetermined configuration, and the collection of openings (40) is arranged and adapted to guide the collection of neuron docking electrodes (3) toward the predetermined regular grid configuration.

9. A composite device or a collection of devices according to claim 8, for guiding a device according to any one of claims 1 to 8, wherein the openings (40) are arranged and adapted to allow the corresponding arms (2) to penetrate the corresponding openings in the collection of openings (40) when the device moves along the inner hole.

10. A composite device or a collection of devices according to claim 8, for guiding a device according to any one of claims 1 to 8, wherein the openings (40) are arranged and adapted to allow the corresponding arms (2) to penetrate the corresponding openings in the collection of openings (40) when the device is rotated about its axis in the hole.

11. A method for exchanging signals with brain tissue by means of the electrode set from the device according to any one of claims 1 to 7 or the composite device or device set according to any one of claims 8 to 10 when the device or the composite device is implanted in brain tissue.

12. The method of claim 11, wherein exchanging signals with the brain tissue comprises determining neuronal locations (preferably individual neuronal locations) in the brain tissue by reading out signals from the set of electrodes.

13. The method of claim 11, wherein exchanging signals with the brain tissue comprises measuring neuronal activity (preferably individual neuronal activity) in the brain tissue by reading out signals from the set of electrodes.

14. The method of claim 11, wherein exchanging signals with the brain tissue comprises stimulating neurons (preferably individual neurons) in the brain tissue by providing stimulation signals (preferably electrical stimulation signals) to the electrode set.

15. A device for exchanging signals with brain tissue via an electrode set, the device comprising a device according to any one of claims 1 to 7 or a composite device or a set of devices according to any one of claims 8 to 10.

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