Method for producing a neural interface

Abstract

A method for producing a neural interface is implemented by preparing a three-dimensional supporting frame (2) on which aa plurality of microelectrodes are applied. Said microelectrodes are connected with a control unit configured to exchange signals therewith. Neuronal cells are then applied on the frame and their growth is promoted until the supporting frame (2) is completely covered.

Description

[0001] DESCRIPTION METHOD FOR PRODUCING A NEURAL INTERFACE

[0002] Technical field

[0003] The present invention relates to the technical field of neurotechnological devices.

[0004] In particular, the present invention relates to a method for producing neural interfaces and the resulting interface.

[0005] State of the art

[0006] Reference is made in particular to brain-computer interface (BCI) technology, which relates to human-machine interfaces that allow neural signals of the human brain to interact directly with a computer or another electronic device, without the use of movements or other physical actions. The objective of BCI is to translate the neural signals into commands that can be used to control an external device, such as a robotic arm or a cursor on a computer screen.

[0007] In the field of neurotechnology, BCI can be used in various applications, such as helping patients with paralysis or other motor disorders to control their environment, communicate with others and improve their quality of life.

[0008] BCIs can also be used for neuroscientific research, as it provides a non- invasive method for monitoring brain activity and developing models of brain activity or else in work and play environments to improve efficiency and the user experience.

[0009] To date, there have been two main approaches to BCI technology: the non-invasive approach and the invasive approach.

[0010] In the non-invasive approach, the sensors placed on the surface of the scalp (EEG) or soft tissues close to the brain (fNIRS) detect electrical activities or changes in blood flow correlated to brain activity and these signals are then processed and used to control an external device. Although the non-invasive approach is relatively easy to use and less costly, the spatial and temporal resolution of the brain signals collected is very low, limiting the number of commands that can be detected.

[0011] In the invasive approach, the BCI interface provides for the implantation of a set of electrodes directly in the patient’s brain. These electrodes detect the neural signals with greater spatial and temporal resolution compared to an EEG or fNIRS. Even though the invasive approach is more precise and sensitive than the non-invasive approach, it requires a surgical intervention for the implantation of the electrodes and thus entails greater risks for the patient and a significant increase in the complication of the installation procedure.

[0012] A practical example of the invasive BCI approach is the use of a neural recording implant to control a robotic arm or a prothesis for amputees. In this case, an electrode or an array of electrodes is implanted inside the patient’s brain in order to record the neuronal activity associated with the movement of the limbs. These neural signals are then processed by a signal processing system, which translates the brain activity into motor commands to control the robotic arm or the prothesis.

[0013] For example, the patient could imagine moving his or her right arm, and this thought would activate a specific area of the brain, which is recorded by the implanted electrodes. These neural signals are then processed by the signal processing system and translated into commands for controlling the robotic arm or the prothesis, which would perform the desired movement. In this manner, the patient could use his or her brain activity to control the artificial limb replacement and carry out movements that would otherwise not be possible.

[0014] However, invasive BCI still remains a technology at the stage of development and experimentation, with several limitations and risks associated with the implantation of electrodes inside the brain.

[0015] In particular, the implantation of invasive electrodes directly into the brain requires complex surgical procedures that entail risks for the patient, such as bleeding, infections, and damage to brain tissue. These risks limit the number of patients who can benefit from the invasive BCI interface.

[0016] Furthermore, the neural signals detected by the invasive electrodes can change over time due to factors such as scarring, movement of the electrodes and inflammation. This can influence the quality of the signals detected and reduce the effectiveness of the invasive BCI interface over time.

[0017] Finally, the invasive BCI interface is at present a costly technology and requires a surgical intervention which further increases the cost of the treatment. This can limit access to the technology for patients who need it. In this context, the technical task at the basis of the present invention is to propose a method for producing neural interfaces which overcomes at least some of the abovementioned drawbacks of the prior art.

[0018] In particular, it is an object of the present invention to provide a method for producing neural interfaces which is capable of providing interfaces that are more easily implantable and more compatible and resistant compared to the currently available ones.

[0019] The stated technical task and the specified objects are substantially achieved by a method for producing neural interfaces, comprising the technical features disclosed in one or more of the appended claims.

[0020] Summary of the invention

[0021] According to the present invention, a method for producing neural interfaces is shown.

[0022] The method is implemented by preparing a supporting frame.

[0023] A plurality of microelectrodes are applied on the supporting frame.

[0024] The microelectrodes are connected with a control unit, which is in particular configured to receive and transmit signals from and to the microelectrodes.

[0025] Neuronal cells are then applied on the supporting frame.

[0026] Finally, a growth of the neuronal cells is promoted until the supporting frame is completely covered. Advantageously, the method proposed herein enables a highly compatible interface to be produced, since the inorganic components are completely enclosed within a highly biocompatible covering (organoid) before the implantation thereof.

[0027] The subject matter of the present invention also relates to a neural interface that comprises a three-dimensional supporting frame, a plurality of microelectrodes, a control unit, and an organoid.

[0028] The supporting frame has a three-dimensional structure suitable for replicating the conformation of a brain area.

[0029] The microelectrodes are applied on the supporting frame (superficially or integrated therewith).

[0030] The control unit is connected to the microelectrodes and is configured to receive and transmit signals from and to the microelectrodes;

[0031] The organoid is coupled to the supporting frame and configured to cover it completely.

[0032] In particular, the organoid comprises neuronal cells, preferably solely neuronal cells.

[0033] Advantageously, the neural interface has an optimal biocompatibility and a greater ease of application, since the mechanical-electronic components are completely enclosed in a biological organoid that can be more easily integrated within a brain area.

[0034] The dependent claims, incorporated herein by reference, correspond to different embodiments of the invention.

[0035] Brief description of the figures

[0036] Additional features and advantages of the present invention will emerge more clearly from the approximate and hence non-limiting description of a preferred but not exclusive embodiment of a neural interface and of the method for the production thereof, as illustrated in the appended drawings, in which:

[0037] - figure 1 shows one of the components of a neural interface according to the present invention;

[0038] - figure 2 shows a simulated representation of an organoid contributing to defining the neural interface and completely covering the component in figure 1.

[0039] Detailed description of the invention

[0040] In the appended figures, the reference number 1 generically denotes a neural interface, which will be referred to below simply as the interface 1 .

[0041] From a structural viewpoint, the interface essentially comprises a supporting frame 2, a plurality of microelectrodes, a control unit and an organoid 3.

[0042] The supporting frame 2 has a three-dimensional structure preferably produced by means of a three-dimensional printing process.

[0043] Alternatively, the supporting frame 2 can be produced by carrying out a two-photon lithography process.

[0044] In this context the supporting frame 2 comprises a vitreous material (for example glass) or is entirely produced with that material.

[0045] In general, irrespective of the method of production thereof, the supporting frame 2 can have a spongy structure.

[0046] The supporting frame 2 has, in general, a conformation adapted to replicate a corresponding structure of a brain area.

[0047] In other words, and as will be explained in greater depth below, the supporting frame 2 is produced in such a way as to have a shape and structure that reproduce as closely as possible the geometry of a brain area that will be used as a seat for the implantation of the interface 1 itself. This will promote and increase the overall compatibility of the interface 1 with the organ, the brain (from the viewpoint of both the central and peripheral nervous systems), in which it will be implanted in a configuration of use, since a supporting frame 2 is introduced which faithfully replicates the local conformation of the organ itself.

[0048] By way of non-limiting example, the supporting frame 2 can be produced using at least one biocompatible material, preferably selected from: Matrigel, natural hydrogel, Polyethylene Glycol (PEG) or synthetic hydrogel.

[0049] In particular, it is preferable to use a hydrophobic material.

[0050] The frame 2 thus performs, in general, the function of a skeleton of the interface 1 , and a plurality of microelectrodes, designed and configured for the reception and production of electrical stimuli from and to the neural structures (dendrites, axons...) of the organ in which the interface 1 will be implanted, are applied on the surface thereof.

[0051] The microelectrodes can be applied on the supporting frame 2 following its production, and thus installed on the surface thereof, or they can be applied during the production of the supporting frame 2, and thus completely integrated within it.

[0052] The microelectrodes are connected with the control unit, which is configured to exchange signals with them, electrical signals in particular.

[0053] In other words, the control unit can receive electrical signals from the microelectrodes, for example electrical stimuli generated and propagated by neural structures which the microelectrodes come to be in contact with or adjacent to, and / or it can generate electrical stimuli and send them to one or more microelectrodes so as to be able to make them reach the neural structures interfaced with them.

[0054] By way of example, a microelectrode can be composed of a small metal probe positioned directly inside the brain tissue.

[0055] Preferably, the microelectrodes are of the bidirectional type, i.e. they have the capacity to record electrical activity and to send electrical signals to the neurons.

[0056] These signals can be used to stimulate specific areas, thereby activating or inhibiting the activity of the neurons involved.

[0057] The bidirectional microelectrodes can be based on different technologies; one of them is based on flexible neural probes made of graphene, known as graphene-derived nanoplatelets (gDNP). In greater detail, the control unit comprises in particular a microprocessor, a power supply unit and an antenna.

[0058] The microprocessor is responsible for managing the overall operation of the interface 1 , being tasked with controlling and guiding the generation and acquisition of the signals.

[0059] The power supply unit provides the necessary electrical power to the various components of the interface 1 which require it for their operation, including, specifically, the microprocessor and the antenna.

[0060] Advantageously, the power supply unit can be a bioelectronic power supply unit, i.e. a power supply unit that can be charged / powered through biological processes, or it could alternatively comprise a battery enclosed in a hermetic container made of a biocompatible material (such as, for example, titanium) or else be of the rechargeable type, for example rechargeable through wireless processes such as an inductive process.

[0061] The antenna, by contrast, is directly connected to the microprocessor and is configured to exchange signals with at least one remote terminal using a wireless communication protocol, preferably operating at a high frequency, i.e. at frequencies in the order of GHz.

[0062] The antenna can be made of materials including copper, gold or aluminium and have any form selected, for example, from: a spiral, a patch, a dipole, or a loop.

[0063] From an operational viewpoint, the antenna is thus designed to act as a go-between for the connection and transfer of signals between the control unit (specifically the microprocessor thereof) and a remote external terminal.

[0064] Therefore, the antenna makes it possible to receive, from the remote terminal, command signals as a function of which the control unit generates electrical stimuli that are then sent to the microelectrodes and / or to receive signals identifying the electrical stimuli picked up by the microelectrodes in order to send them to the remote terminal.

[0065] In general, by means of the specific connections of the control unit, the microprocessor will thus be configured overall to:

[0066] 1. acquire signals from the microelectrodes originating from the neurons;

[0067] 2. stimulate / provide signals from the microelectrodes towards the neurons;

[0068] 3. process the signals exchanged in particular with the microelectrodes;

[0069] 4. encrypt the processed signals;

[0070] 5. remotely transmit signals via the antenna.

[0071] In order to favour and optimise the compatibility of the interface 2 with the biological structure in which it is to be implanted and simplify the insertion operations, the supporting frame 2 and the associated components described thus far are completely covered by the organoid 3.

[0072] In particular, the organoid 3 is grown over the supporting frame 2 and is configured to cover it completely.

[0073] The organoid thus completely envelops and permeates the structure of the supporting frame 2, filling and covering it and thus forming an interface that is interposed, in a configuration of use, between artificial elements of the interface 1 (supporting frame 2 and control unit) and the biological structure of the organ in which it is implanted.

[0074] In detail, the organoid is specifically an organoid comprising and composed of neuronal cells; preferably, the entire organoid is solely and exclusively composed of neuronal cells.

[0075] Therefore, the supporting frame 2 defines overall a structure that acts as a substrate for the growth of the organoid 3, in order to obtain a brain tissue which, by following the conformation of the supporting frame 2, can precisely replicate the structure and conformation of a specific brain area in which it is planned to introduce / implant the interface 1 .

[0076] In this manner and advantageously, it is possible to maximise the compatibility of the interface 1 with the seat in which it is to be implanted, since the electronic / mechanical components thereof are completely covered and enveloped by the biological interface defined by the organoid, which reproduces the characteristics of the brain area in which it will be implanted. Advantageously, the interface 1 can also comprise the remote terminal or a plurality of remote terminals connectible and interfaceable with the control unit.

[0077] In particular, the interface 1 can comprise a remote terminal interfaced with the control unit in such a way as to exchange signals therewith (in particular by receiving and transmitting signals from and to the antenna of the control unit).

[0078] The remote terminal can for example comprise a prothesis, specifically a robotic prothesis, and a processor which is operatively connected or in any case connectable with the control unit.

[0079] The processor is configured to communicate with the control unit of the interface 1 in such a way as to receive therefrom the signals picked up by the microelectrodes, which are representative of the activation of specific brain areas with which said microelectrodes are interfaced following the implantation of the interface 1 .

[0080] As a function of these signals, the processor can then activate the prothesis, controlling the movement thereof and providing to the control unit a respective feedback signal, representative of the operation of movement carried out, which is then transmitted to the microelectrodes.

[0081] The microelectrodes then generate / propagate, consequently, a corresponding electrical stimulus that stimulates the neuronal structures of the brain area surrounding the microelectrodes themselves.

[0082] This process optimises the integration and the controllability of the prothesis by a user, since, during use, there is a linear chain of transmission of the stimuli / signals in both directions, from the brain to the prothesis and vice versa.

[0083] Advantageously, the present invention achieves the proposed objects by overcoming the drawbacks complained of in the prior art and providing the user with a neural interface 1 which, thanks to its specific structure, ensures optimal levels of compatibility and integrability with the brain structures in which it is to be implanted. The subject matter of the present invention also relates to a method for producing a neural interface 1 , in particular a neural interface 1 having any combination of the features disclosed above.

[0084] In detail, the method is implemented by preparing a three-dimensional supporting frame 2.

[0085] Specifically, this operation is carried out by mapping a brain area of interest, by identifying a plurality of neural structures.

[0086] On the basis of the information acquired it is possible to generate a faithful digital representation of the brain area of interest, which represents the entire structure / conformation thereof.

[0087] On the basis of the digital representation, the supporting frame 2 is produced in such a way as to faithfully replicate the acquired structure, that is, in such a way as to generate a supporting frame 2 structurally corresponding to the area of interest.

[0088] Preferably, the production of the supporting frame 2 is performed by means of a three-dimensional printing process carried out with biocompatible materials selected, for example, from the ones already indicated.

[0089] Alternatively, the supporting frame 2 is produced by means of a two- photon lithography process.

[0090] Once the frame is completed, one then proceeds to apply a plurality of microelectrodes on it.

[0091] The microelectrodes are in particular and preferably applied in such a way as to replicate the spatial positioning of neuronal cells and / or portions thereof.

[0092] Alternatively, the microelectrodes can be integrated (completely or partially) within the supporting frame 2, for example by being applied or comoulded during the process of production thereof.

[0093] The microelectrodes are then connected with the control unit, which is configured to receive and transmit signals (such as the already mentioned electrical stimuli) from and to the microelectrodes. Upstream of the connection, the control unit is prepared by integrating and connecting together the microprocessor (which will then effectively be the first connection interface with the microelectrodes), the power supply unit (produced according to the methods already described) and the antenna, which is connected to the microprocessor and by means of which the interface can be allowed to communicate with remote terminals.

[0094] The operations described thus far make it possible to produce the inorganic (mechanical-electronic) components of the interface 1 .

[0095] The organoid 3 is then applied over said components and this operation can be carried out in particular by collecting potential stem cells, in particular and preferably potential stem cells having a profile of compatibility with the individual in whom it is planned to implant the interface 1 .

[0096] In greater detail, the pluripotent stem cells are not collected from human embryos.

[0097] The potential stem cells are then processed in such a way as to induce a differentiation which transforms them by generating neuronal cells.

[0098] The neuronal cells thus obtained are then applied directly on the supporting frame 2 and are made to grow, thus generating the organoid, in particular until obtaining a complete covering / permeation of the supporting frame 2.

[0099] In this manner, the components of the interface 1 are enveloped with a high-compatibility biological covering that has the further advantage of faithfully replicating the structure and conformation of the brain area in which the interface 1 is to be implanted.

[0100] Advantageously, the method can further comprise one or more test steps / procedures for verifying the functionality of the interface 1 .

[0101] The test procedure can be performed, for example, by transmitting and receiving signals to and from said control unit and verifying an activation of the microelectrodes as a function of said signals.

[0102] Finally, the control unit can be connected with the remote terminal, specifically with the processor that controls the operation of activating a prothesis, in particular a robotic prothesis.

[0103] In this manner it is possible to verify, prior to the implantation thereof, the actual communication capacity and correct transfer and / or interpretation of the signals between the control unit and the processor.

Claims

CLAIMS1 . Method for producing a neural interface comprising the steps of:- preparing a three-dimensional supporting frame (2);- applying a plurality of microelectrodes on said supporting frame (2);- connecting said microelectrodes with a control unit configured to receive and transmit signals from and to the microelectrodes;- applying neuronal cells on said supporting frame (2);- promoting a growth of the neuronal cells until the supporting frame (2) is completely covered; wherein the step of preparing the supporting frame (2) comprises the substeps of:- mapping a brain area of interest, by identifying a plurality of neural structures and generating a digital representation of said brain area;- producing, as a function of said digital representation, a supporting frame (2) structurally corresponding to said brain area.

2. Method according to claim 1 , comprising, upstream of the application of the neuronal cells on the supporting frame (2), the steps of:- collecting pluripotent stem cells not from human embryos;- inducing a differentiation in said pluripotent stem cells, thereby generating neuronal cells.

3. Method according to claim 1 or 2, comprising, upstream of the step of connecting the microelectrodes with the control unit, a step of preparing a control unit comprising:- a microprocessor connectible with said microelectrodes;- a power supply unit, preferably a bioelectronic power supply unit, connected to the microprocessor and configured to supply electrical power to said microprocessor;- an antenna connected to the microprocessor and configured to exchange signals with at least one remote terminal by means of a wirelesscommunication protocol.

4. Method according to any one of the preceding claims, wherein the step of producing the supporting frame (2) is performed by means of a three- dimensional printing process.

5. Method according to any one of claims 1 to 3, wherein the step of producing the supporting frame (2) is performed by means of a two-photon lithography process.

6. Method according to any one of the preceding claims, comprising a test step performed by transmitting and receiving signals to and from said control unit and verifying an activation of the microelectrodes as a function of said signals.

7. Neural interface comprising:- a three-dimensional supporting frame (2) structurally corresponding to a brain area;- a plurality of microelectrodes applied on said supporting frame (2);- a control unit connected with said microelectrodes and configured to receive and transmit signals from and to the microelectrodes;- an organoid (3) coupled to the supporting frame (2) and configured to completely cover said supporting frame (2); said organoid (3) comprising neuronal cells, preferably solely neuronal cells.

8. Interface according to claim 7, wherein the control unit comprises:- a microprocessor connectible with said microelectrodes;- a power supply unit connected to the microprocessor and configured to supply electrical power to said microprocessor, said power supply unit preferably comprising a bioelectronic power supply unit and / or said power supply unit comprising a power supply unit that is rechargeable by meansof induction processes;- an antenna connected to the control unit and configured to exchange signals with at least one remote terminal.

9. Interface according to claim 7 or 8, wherein the supporting frame (2) is produced by means of a three-dimensional printing process.

10. Interface according to claim 7 or 8, wherein the supporting frame (2) is produced by means of a two-photon lithography process, preferably said supporting frame (2) comprising a glass material.

11. Interface according to any one of claims 7 to 10, wherein the supporting frame (2) has a sponge-like structure, preferably having a conformation adapted to replicate a corresponding structure of a brain area, and said organoid is configured to completely permeate said sponge-like structure.

12. Interface according to any one of claims 7 to 1 1 , wherein the supporting frame (2) comprises at least one biocompatible material, preferably a biocompatible material selected from: Matrigel, natural hydrogel, polyethylene glycol (PEG) or synthetic hydrogel.

13. Neural interface according to any one of claims 7 to 12, comprising a remote terminal interfaced with said control unit in order to receive and transmit signals from and to said control unit.

14. Interface according to claim 13, wherein said remote terminal comprises a prosthesis and a processor, associated with the prosthesis, connectable with the control unit, said prosthesis being movable as a function of one or more signals transmitted by said control unit and received by the processor.

Images