Elastic electrode matrix for subdural intraoperative monitoring and its manufacturing method

Abstract

FIELD: medical equipment.SUBSTANCE: elastic electrode matrix for subdural intraoperative monitoring, obtained by sequentially performing vacuum deposition, laser engraving, galvanization and photolithography, and a method for its manufacture. The matrix includes an elastic base made of polydimethylsiloxane, an adhesive sublayer located on the surface of the elastic base, a conductive layer located on the adhesive sublayer, and a dielectric layer. The conductive layer includes recording electrode pads, configured to record electrical signals from the brain, conductive tracks and contact pads, configured to transmit electrical signals from the brain to a communication interface with a recording device, a detachable technical pad connected to the contact pads and configured to be cut off from the elastic base, navigation contours of the internal holes and a navigation contour of the external boundaries of the matrix. The recording electrode pads are connected to the contact pads via conductive tracks, the navigation contours of the internal holes are designed to provide perfusion of liquids through the elastic electrode matrix, and the dielectric layer is located on the elastic base and the conductive layer with a coating of the conductive tracks. The manufacturing method initially involves creating a blank in the form of a glass substrate with a layer of polymer structure and a layer of elastic base made of polydimethylsiloxane with a sprayed adhesive sublayer and a conductive layer. A layer of polymer structure is placed between an elastic base and a glass substrate. Then the recording electrode pads, conductive tracks and contact pads are engraved. Next, the recording electrode pads, conductive tracks and contact pads are galvanized. Then a photopattern is made. Next, a dielectric layer is formed and the recording electrode pads and contact pads are exposed. Next, the elastic matrix is separated from the glass substrate by dissolving the polymer structure layer.EFFECT: development of an elastic electrode matrix for subdural intraoperative monitoring and a method for its manufacture.2 cl, 4 dwg

Description

[0001] The invention relates to the field of medicine and veterinary science, in particular to medical equipment, namely to devices for recording the electrical activity of the brain in vivo, and can be used for research and medical purposes for analyzing and visualizing the electrical activity of the brain.

[0002] Further in the text, the applicant provides terms that are necessary to facilitate a clear understanding of the essence of the declared materials and to eliminate contradictions and / or controversial interpretations when performing an examination on the merits.

[0003] In vivo is a scientific term that refers to research being conducted in a living being [https: / / www.vocabulary.com / dictionary / in vivo].

[0004] Electroencephalogram (EEG) is a recording of the brain's electrical activity using electrodes placed on the surface of the scalp, unless otherwise noted. [https: / / www.asclin.ru / upload / iblock / bf8 / bf8141a968a421178a5b8e435e4dfa40.pdf].

[0005] NFC (near field communication) is a short-range wireless data transmission technology that enables data exchange between devices located at a distance of about 10 centimeters. [https: / / ru.wikipedia.org / wiki / NFC].

[0006] Action potential (AP) is an excitation wave moving along the membrane of a living cell in the form of a short-term change in membrane potential in a small area of ​​an excitable cell (neuron or cardiomyocyte), as a result of which the outer surface of this area becomes negatively charged relative to the inner surface of the membrane, while at rest it is charged positively [https: / / ru.wikipedia.org / wiki / Потенциал_активия].

[0007] Adhesion (from Latin adhaesio - sticking, adhesion, attraction) is the connection between dissimilar condensed bodies during their molecular contact [https: / / bigenc.ru / c / adgeziia-d16db4].

[0008] Dielectric is a substance (material) that conducts electric current relatively poorly [https: / / ru.wikipedia.org / wiki / Диэлектрик].

[0009] Polydimethylsiloxane (PDMS) is a linear polymer of dimethylsiloxane [https: / / ru.wikipedia.org / wiki / Полидиметсилоксан].

[0010] Cerebrospinal fluid (CSF) is a fluid that constantly circulates within the ventricles of the brain, the space between its membranes. It is one of the elements of the brain's nutritional environment (it contains glucose and other substances) and serves as an intermediate link for the removal of waste products. It fills the central canal of the spinal cord, as well as the ventricles and subarachnoid space of the brain, protecting and acting as a shock absorber during sudden human movements. [https: / / medportal.ru / terms / 11159].

[0011] The functionality of our brain is a product of the activity of neural networks consisting of many neurons. Neural activity is determined by the generation of action potentials (AP) on the neuron membrane, each of which is triggered by the spatiotemporal summation of synaptic inputs to the neuron [Polikov, VS et al. / Response of brain tissue to chronically implanted neural electrodes / / J. Neurosci. Methods 2005, 148, 1-18, DOI: 10.1016 / j.jneumeth.2005.08.015]. To study neural activity, researchers have developed various types of electrophysiological recording methods, divided into extracellular and intracellular methods. Extracellular recordings allow us to obtain data on the total activity of an ensemble of neurons surrounding the recording electrodes. An array of extracellular recording electrodes of different configurations represents an electrode matrix and is the communication interface between neurons and the recording system.Data obtained using such electrode arrays can be used to analyze recorded neural signals to visualize brain activity or implement algorithms for controlling robotic limbs. However, this is only achievable with high signal-to-noise ratio (SNR) signals and relative biocompatibility of the electrode array materials with brain tissue. Electrode array parameters are a fundamental factor determining their effectiveness in key areas of applied medicine.

[0012] In vivo electrode arrays have different geometric and electrophysical parameters and materials depending on their location relative to the brain during signal recording. When selecting a suitable electrode array, it is necessary to consider the trade-off between the quality of the recorded signal and the degree of invasiveness. For example, electrode arrays implanted in the brain have higher SNR values ​​than EEG electrode arrays located on the scalp. Currently, preference is given to electrode arrays based on polymers with a low Young's modulus. The material used to manufacture electrode arrays is a key aspect of their functionality, so the main goal of modern research has been to increase their flexibility and elasticity. Research in the field of flexible electronics began approximately 30 years ago [Garnier F. et al. / All-Polymer Field-Effect Transistor Realized by Printing Techniques / / Science 1994, 265, 1684-1686, DOI: 10.1126 / science.265.5179.1684, Bao Z. et al. / High-Performance Plastic Transistors Fabricated by Printing Techniques / / Chem. Mater. 1997, 9, 1299-1301, DOI: 10.1021 / cm9701163] в ответ на спрос на макроэлектронику [Reuss R.H. et al. / Macroelectronics: Perspectives on Technology and Applications / / Proc. IEEE 2005, 93, 1239-1256, DOI: 10.1109 / JPROC.2005.851237], такую как, например, гибкие светоизлучающие устройства [Rogers J.A. et al. / Paper-like electronic displays: Large-area rubber-stamped plastic sheets of electronics and microencapsulated electrophoretic inks / / Proc. Natl. Acad. Sci. USA 2001, 98, 4835-4840, DOI: 10.1073 / pnas.091588098; Gelinck G.H. et al. / / Flexible active-matrix displays and shift registers based on solution-processed organic transistors / / Nat. Mater. 2004, 3, 106-110, DOI: 10.1038 / nmat1061].Flexible and stretchable electronics revealed their potential applications in the late 2000s, when the concept of biologically integrated electronics was proposed [Rogers JA et al. / Materials and Mechanics for Stretchable Electronics / / Science 2010, 327, 1603-1607, DOI: 10.1126 / science.1182383]. This opened the way to the creation of stable and long-lasting, personalized bioelectronic interfaces, including epidermal devices for monitoring vital signs [Gelinck GH et al. / Flexible active-matrix displays and shift registers based on solution-processed organic transistors / / Nat. Mater. 2004, 3, 106-110., DOI: 10.1038 / nmat1061; Rogers JA et al. / Materials and Mechanics for Stretchable Electronics / / Science 2010, 327, 1603-1607, DOI: 10.1126 / science.1182383; Kim D.-H. et al. / Epidermal Electronics / / Science 2011, 333, 838-843, DOI: 10.1126 / science.1206157], brain-computer interfaces with devices for mapping electrocardiogram, electrocorticography, and electromyography [Kim D.-H. et al. / Dissolvable films of silk fibroin for ultrathin conformal bio-integrated electronics / / Nat. Mater. 2010, 9, 511-517, DOI: 10.1038 / nmat2745, Viventi J. et al. / Flexible, foldable, actively multiplexed, high-density electrode array for mapping brain activity in vivo / / Nat. Neurosci. 2011, 14, 1599-1605, DOI: 10.1038 / nn.2973; Xu B. et al. / An Epidermal Stimulation and Sensing Platform for Sensorimotor Prosthetic Control, Management of Lower Back Exertion and Electrical Muscle Activation / / Adv. Mater. 2016, 28, 4462-4471, DOI: 10.1002 / adma.201504155; Kim D.-H. et al. / Electronic sensor and actuator webs for large-area complex geometry cardiac mapping and therapy / / Proc. Natl. Acad. Sci. USA 2012, 109, 19910-19915, DOI: 10.1073 / pnas.1205923109; Viventi J. et al. / A Conformal, Bio-interfaced Class of Silicon Electronics for Mapping Cardiac Electrophysiology / / Sci. Transl. Med. 2010, 2, 24ra22., DOI: 10.1126 / scitranslmed.3000738], as well as minimally invasive surgical instruments [Kim D.-H. et al. / Materials for multifunctional balloon catheters with capabilities in cardiac electrophysiological mapping and ablation therapy / / Nat. Mater. 2011, 10, 316-323., 10.1038 / nmat2971; Kim D.-H. et al. / Thin, Flexible Sensors and Actuators as 'Instrumented' Surgical Sutures for Targeted Wound Monitoring and Therapy / / Small 2012, 8, 3263-3268, DOI: 10.1002 / smll.201200933]. When using such bioelectronic interfaces, it is crucial that they match the mechanical properties of the tissues of the biological system, ensuring biocompatibility.For example, for brain-computer interfaces, electrode arrays, firstly, should detect changes in electrical potential from several tens of microvolts; secondly, electrode arrays should have high spatial resolution; thirdly, the substrate on which the electrode array is located should be thin enough to ensure the absence of inelastic mechanical interaction with the brain; and, finally, the electrode array material should be biocompatible. It is shown that such bioelectronic interfaces can be additionally combined with wireless signal transmission systems, such as Bluetooth and NFC technologies [Lin CT et al. / Development of Wireless Brain Computer Interface With Embedded Multitask Scheduling and its Application on Real-Time Driver's Drowsiness Detection and Warning / / IEEE Trans. Biomed. Eng. 2008, 55, 1582-1591, DOI: 10.1109 / TBME.2008.918566; Lin CT et al. / Noninvasive Neural Prostheses Using Mobile and Wireless EEG / / Proc. IEEE 2008, 96, 1167-1183, DOI: 10.1109 / JPROC.2008.922561], and the ability to function in an aquatic environment has also been realized [Lee SM et al. / Self-adhesive epidermal carbon nanotube electronics for tether-free long-term continuous recording of biosignals / / Sci. Rep. 2014, 4, 6074, DOI: 10.1038 / srep06074]. Due to their high portability and adaptability, bioelectronic interfaces have also shown good results in systems for diagnosing the state of the body [Page NG and Gresty, MA / Motorist's vestibular disorientation syndrome / / J. Neurol. Neurosurg. Psychiatry 1985, 48, 729-735, DOI: 10.1136 / jnnp.48.8.729].

[0013] Advances in materials science have led to the development of high-density planar non-penetrating electrode arrays for electroencephalography and electrocorticography. However, measuring biological electrical signals using electrode arrays must not cause collateral harm to the human body. Therefore, it is recommended that the base and metal parts comprising the electrode be made of materials that do not induce chronic reactions, such as immune system responses. When developing flexible electrode arrays for implantation, special attention is paid to long-term biocompatibility and biostability under real-world recording conditions.

[0014] The structure of any electrode array can be roughly divided into a base (substrate) and an electrode part. If the base of the electrode array is too rigid, it can damage brain tissue, the Young's modulus of which is approximately 3 kPa. Therefore, it is extremely important to use a material with an appropriate Young's modulus that is close to that of brain tissue. For silicone used in microelectrodes, it is close to values ​​of approximately 130-185 GPa. The Young's modulus of polymeric materials is usually several GPa - much lower than that of silicone, but still higher than that of brain tissue. Such materials include, for example, the biocompatible photopolymer SU-8 [Cho SH et al. / Biocompatible SU-8-Based Microprobes for Recording Neural Spike Signals From Regenerated Peripheral Nerve Fibers / / IEEE Sens. J. 2008, 8, 1830-1836, DOI: 10.1109 / JSEN.2008.2006261; Altuna A. et al. / SU-8 based microprobes with integrated planar electrodes for enhanced neural depth recording / / Biosens.Bioelectron. 2012, 37, 1-5, DOI: 10.1016 / j.bios.2012.03.039], polydimethylsiloxane (PDMS) [Kim J.-M. et al. / Plateau-Shaped Flexible Polymer Microelectrode Array for Neural Recording / / Polymers 2017, 9, 690, DOI: 10.3390 / polym9120690], polyimide (PI) [Lee K.-K. et al. / Polyimide-based intracortical neural implant with improved structural stiffness / / J. Micromech. Microeng. 2004, 14, 32, DOI: 10.1088 / 0960-1317 / 14 / 1 / 305] and poly(chloro-p-xylylene) (parylene C) [Hsu J. et al. / Encapsulation of an Integrated Neural Interface Device with Parylene C / / IEEE Trans. Biomed. Eng. 2009, 56, 23-29., DOI: 10.1109 / TBME.2008.2002155; Shin JH et al / Carbon-Nanotube-Modified Electrodes for Highly Efficient Acute Neural Recording / / Adv. Healthc. Mater. 2014, 3, 245-252, DOI: 10.1002 / adhm.201300183]. The close Young's modulus of such materials makes them suitable for use as a basis for the manufacture of electrode matrices.Shape memory polymers such as (parylene-C + polyvinyl alcohol) (PVA) [Simon DM et al. / Design and demonstration of an intracortical probe technology with tunable modulus / / J. Biomed. Mater. Res. A 2017, 105, 159-168, DOI: 10.1002 / jbm.a.35896], liquid crystal polymers [Hwang G.-T. et al. In Vivo Silicon-Based Flexible Radio Frequency Integrated Circuits Monolithically Encapsulated with Biocompatible Liquid Crystal Polymers / / ACS Nano 2013, 7, 4545-4553, DOI: 10.1021 / nn401246y] and composites based on cellulose nanofibers and a polyvinyl acetate matrix [Hess AE et al. / Development of a stimuli-responsive polymer nanocomposite toward biologically optimized, MEMS-based neural probes / / J. Micromech. Microeng. 2011, 21, 054009, DOI: 10.1088 / 0960-1317 / 21 / 5 / 054009], the use of which will reduce invasiveness due to a greater match between the Young's modulus of brain tissue and the base material of the electrode matrix.Currently used electrode arrays are capable of stably measuring electrical signals of the brain in vivo for several days or weeks [Polikov, VS et al. / Response of brain tissue to chronically implanted neural electrodes / / J. Neurosci. Methods 2005, 148, 1-18, DOI: 10.1016 / j.jneumeth.2005.08.015; Jackson A. and Fetz EE / Compact Movable Microwire Array for Long-Term Chronic Unit Recording in Cerebral Cortex of Primates / / J. Neurophysiol. 2007, 98, 3109-3118, DOI: 10.1152 / jn.00569.2007; Aflalo T. et al. / Decoding motor imagery from the posterior parietal cortex of a tetraplegic human / / Science 2015, 348, 906-910, DOI: 10.1126 / science.aaa5417; Perge JA et al. / Intra-day signal instabilities affect decoding performance in an intracortical neural interface system / / J. Neural Eng. 2013, 10, 036004, DOI: 10.1088 / 1741-2560 / 10 / 3 / 036004; Bensmaia SJ and Miller LE / Restoring sensorimotor function through intracortical interfaces: Progress and looming challenges / / Nat. Rev. Neurosci. 2014, 15, 313-325, DOI: 10.1038 / nrn3724]. It was also shown that electrode arrays made using SU-8 as a base material successfully recorded single APs for 8 months [Fu T.-M. et al. / Stable long-term chronic brain mapping at the single-neuron level / / Nat. Methods 2016, 13, 875-882, DOI: 10.1038 / nmeth.3969].

[0015] The ultimate goal of creating electrode arrays is to safely record electrical signals from the brain over a long period of time. The material used in the conductive part of the electrode arrays should have high electrical conductivity properties to transmit an electrical signal, while not being toxic to a living organism. Copper (Cu) [Bickford RG et al. / Histologic changes in the cat's brain after introduction of metallic and plastic coated wire used in electro-encephalography / / Proc. Staff Meet. Mayo Clin. 1957, 32, 14-21, PMID: 13389553], gold (Au) [Kim R. et al. / Gold nanograin microelectrodes for neuroelectronic interfaces / / Biotechnol. J. 2013, 8, 206-214, DOI: 10.1002 / biot.201200219; Kim J.-H. et al. / Surface-modified microelectrode array with flake nanostructure for neural recording and stimulation / / Nanotechnology 2010, 21, 085303, DOI: 10.1088 / 0957-4484 / 21 / 8 / 085303; Seker E. et al. / The fabrication of low-impedance nanoporous gold multiple-electrode arrays for neural electrophysiology studies / / Nanotechnology, V. 21, 12, DOI: 10.1088 / 0957-4484 / 21 / 12 / 125504], платина (Pt) [Czeschik A. et al. / Fabrication of MEA-based nanocavity sensor arrays for extracellular recording of action potentials / / Phys. Status Solidi A 2014, 211, 1462-1466, DOI: 10.1002 / pssa.201330365; Xie C. et al. / Intracellular recording of action potentials by nanopillar electroporation / / Nat. Nanotechnol. 2012, 7, 185-190, DOI: 10.1038 / nnano.2012.8; Mathieson K. et al. / Large-area microelectrode arrays for recording of neural signals / / IEEE Trans. Nucl. Sci. 2004, 51, 2027-2031, DOI: 10.1109 / TNS.2004.835873; Jun S.B. et al. / Low-density neuronal networks cultured using patterned poly-l-lysine on microelectrode arrays / / J. Neurosci. Methods 2007, 160, 317-326, DOI: 10.1016 / j.jneumeth.2006.09.009; Park S. Et al. / Nanoporous Pt Microelectrode for Neural Stimulation and Recording: In Vitro Characterization. J. Phys. Chem. C 2010, 114, 8721-8726, DOI: 10.1021 / jp911256h; Takayama Y. et al. / Network-wide integration of stem cell-derived neurons and mouse cortical neurons using microfabricated co-culture devices / / Biosystems 2012, 107, 1-8, DOI: 10.1016 / j.biosystems.2011.08.001], серебро (Ag) [Dymond A.M. et al. / Brain tissue reaction to some chronically implanted metals / / J. Neurosurg. 1970, 33, 574-580, DOI: 10.3171 / jns.1970.33.5.0574], титан (Ti) [Beder O.E. and Eade G. / An investigation of tissue tolerance to titanium metal implants in dogs / / Surgery 1956, 39, 470-473], вольфрам (W) [Robinson F.R. and Johnson M.T / Histopathological studies of tissue reactions to various metals implanted in cat brains / / ASD Tech. Rep. 1961, 61, 13, PMID: 24546838], indium tin oxide [Zátonyi A. et al. / Functional brain mapping using optical imaging of intrinsic signals and simultaneous high-resolution cortical electrophysiology with a flexible, transparent microelectrode array / / Sens. Actuators B Chem. 2018, 273, 519-526, DOI: 10.1016 / j.snb.2018.06.092] and graphene [Park D.-W. et al. / Fabrication and utility of a transparent graphene neural electrode array for electrophysiology, in vivo imaging, and optogenetics / / Nat. Protoc. 2016, 11, 2201-2222, DOI: 10.1038 / nprot.2016.127], which exhibit high electrical conductivity at room temperature. However, copper and silver have a toxic effect on brain tissue when exposed to long-term radiation, making them unsuitable for use in chronic implantation.At the same time, platinum, gold, or a material such as highly doped polysilicon are considered safe for long-term exposure [Geddes LA and Roeder R. / Criteria for the Selection of Materials for Implanted Electrodes / / Ann. Biomed. Eng. 2003, 31, 879-890, DOI: 10.1114 / 1.1581292; Saha R. et al. / Highly Doped Polycrystalline Silicon Microelectrodes Reduce Noise in Neuronal Recordings In Vivo / / IEEE Trans. Neural Syst. Rehabil. Eng. 2010, 18, 489-497, DOI: 10.1109 / TNSRE.2010.2056389]. Recently, conductive polymers have been used as non-toxic materials, examples of which are poly-3,4-ethylenedioxythiophene (PEDOT) [Kim D.-H. Et al. / Conducting polymers on hydrogel-coated neural electrode provide sensitive neural recordings in auditory cortex / / Acta Biomater. 2010, 6, 57-62, DOI: 10.1016 / j.actbio.2009.07.034; Ludwig K. A. et al. / Chronic neural recordings using silicon microelectrode arrays electrochemically deposited with a poly(3,4-ethylenedioxythiophene) (PEDOT) film / / J. Neural Eng.2006, 3, 59-70, DOI: 10.1088 / 1741-2560 / 3 / 1 / 007], polypyrrole (PPy) [George PM et al. / Fabrication and biocompatibility of polypyrrole implants suitable for neural prosthetics / / Biomaterials 2005, 26, 3511-3519, DOI: 10.1016 / j.biomaterials.2004.09.037] and polyaniline (PANI) [Dimaki M. et al. / Fabrication and Characterization of 3D Micro- and Nanoelectrodes for Neuron Recordings / / Sensors 2010, 10, 10339-10355, DOI: 10.3390 / s101110339]. Therefore, a promising direction of development is the use of biocompatible neural devices based on polymers.

[0016] Based on the above, it can be concluded that when manufacturing electrode arrays, it is necessary to use materials with elasticity similar to that of brain tissue, which ensures their synchronous stretching and minimizes damage. Combined with complete biocompatibility, this reduces trauma and allows for acute or chronic recording of brain electrical activity.

[0017] From the prior art research, the applicant has identified an industrial design of an electrode array that is most similar in functionality to the claimed array [https: / / adtechmedical.com / epilepsy#subdural-electrodes]. The essence of the proposed device is an elastic electrode array for subdural intraoperative monitoring, consisting of the following structural elements: an elastic base, current-collecting elements, and conductive elements. This known technical solution is intended for intraoperative monitoring in humans.

[0018] The disadvantage of the known technical solution, in relation to the design compared to the declared technical solution, is:

[0019] - low elasticity, as a result of which there is loose contact of some matrix electrodes with the surface of the brain with complex curvature;

[0020] - low transparency of the material, complicating control of electrode positioning;

[0021] - high risk of brain damage during chronic implantation due to low elasticity of the elements.

[0022] From the studied prior art, the applicant has identified a method for manufacturing an electrode array that is closest in manufacturing methods to [Ochoa M. et al. / A Hybrid PDMS-Parylene Subdural Multi-Electrode Array / / Biomed Microdevices 2014, 15(3): 437-443, DOI: 10.1007 / s10544-013-9743-2]. The essence of the known method is the manufacture of an elastic electrode array for recording the electrical activity of the brain, consisting of the following steps. The known manufacturing method consists of the stages of vacuum deposition and photolithography. The technical solution obtained by the known manufacturing method is intended for work with laboratory animals.

[0023] The disadvantages of the known manufacturing method, compared to the declared technical solution, are:

[0024] - low coating thickness due to the absence of a galvanization process for conductive elements;

[0025] - lack of possibility of regulation and tuning of electrical parameters during the manufacturing process;

[0026] - using photolithography technology to form conductive elements;

[0027] - lack of navigation contours for positioning the electrode on the brain under conditions of close refractive indices of PDMS and cerebrospinal fluid.

[0028] Due to the fact that the analysis of the studied level of technology did not allow identifying analogs that are the closest in terms of the set of coinciding features in relation to the claimed elastic electrode matrix for subdural intraoperative monitoring, the independent claims of the invention are drawn up without a limiting part.

[0029] The purpose of the claimed invention is the development of an elastic electrode matrix for subdural intraoperative monitoring and a method for its manufacture.

[0030] The technical problem solved by the claimed invention and the technical result of the claimed invention is an elastic electrode matrix that provides:

[0031] - presence of navigation contours for positioning the electrode on the brain;

[0032] - the ability to create technical zones for cerebrospinal fluid perfusion;

[0033] - can be used to record electrical activity of the brain.

[0034] The technical problem solved by the claimed method of manufacturing the matrix is is the sequence of using the technologies of vacuum deposition, laser engraving, galvanization and photolithography, as well as the use of polydimethylsiloxane as the base material of the matrix, which ensures:

[0035] - biocompatibility of the electrode matrix;

[0036] - flexibility and stretchability of the matrix base while maintaining elasticity comparable to brain tissue, without deteriorating the electrical characteristics of the conductive elements;

[0037] - the ability to regulate electrical parameters during the manufacturing process.

[0038] The technical result is achieved by the fact thatThe matrix is ​​made of biocompatible materials, has visualization of technical areas and boundaries, and is provided with the ability to control and manage electrical properties after the manufacturing process.

[0039] The technical result is achieved by the fact that The sequence of technologies is as follows: vacuum deposition, laser engraving, galvanization and photolithography, while polydimethylsiloxane is used as the matrix base material, which is close in mechanical characteristics to the mechanical properties of the brain, which together ensures the elasticity and solidity of the electrode matrix, as well as the reproducibility of the electrode matrix parameters.

[0040] The claimed technical solution is illustrated in Fig. 1, Fig. 2.

[0041] Fig. 1 shows a schematic representation of a possible embodiment of the claimed elastic electrode matrix for subdural intraoperative monitoring.

[0042] Fig. 2 shows a diagram of the technological processes for manufacturing the claimed elastic electrode matrix for subdural intraoperative monitoring.

[0043] 2A - schematic structure of the electrode matrix after the stage of vacuum deposition of the conductive layer 8 (left), micrograph of the relief of PDMS coated with the conductive layer 8, obtained using a high-resolution optical microscope (center), schematic image of the result of laser engraving of the conductive layer 8 (right),

[0044] 2B - schematic view after laser engraving of conductive layer 8 (left), diagram of galvanization of sections of conductive layer 8 (in the center), diagram of coating the structure with a dielectric layer 10 made of PDMS (right),

[0045] 2B - diagram of applying a photoresist mask (black rectangles) to a dielectric layer 10 (left), chemical etching of areas of the dielectric layer 10 not covered by the photoresist mask (in the center), dissolving the photoresist mask and the sacrificial layer 11 and separating the elastic electrode matrix from the glass substrate 12 (right).

[0046] Fig. 3 shows the electrical parameters of the conductive tracks 5 of the claimed elastic electrode matrix for subdural intraoperative monitoring.

[0047] 3A - example of the current-voltage characteristic of conductive track 5,

[0048] 3B - an example of the change in conductivity of the conductive track 5 under 50 bending cycles of the declared matrix.

[0049] Fig. 4 shows an example of the implementation and use of the claimed elastic electrode matrix for subdural intraoperative monitoring.

[0050] 4A - an example of manufacturing the declared elastic electrode matrix for subdural intraoperative monitoring using the declared technology,

[0051] 4B - an example of a prepared preparation in the form of an open surface of the rat brain for testing the functionality of the declared elastic electrode matrix for subdural intraoperative monitoring,

[0052] 4B - an example of the placement of the declared elastic electrode matrix for subdural intraoperative monitoring on a preparation of the open surface of the rat brain,

[0053] 4G - An example of recorded rat brain activity on two recording electrode pads 3 of the proposed elastic electrode array for subdural intraoperative monitoring. The red curve represents the recorded electrical activity in the left hemisphere, and the blue curve represents the right hemisphere of the anesthetized rat.

[0054] The positions on the figures indicate:

[0055] 1 - elastic base,

[0056] 2 - contours of internal holes,

[0057] 3 - electrode pads,

[0058] 4 - contour of the outer boundaries of the matrix,

[0059] 5 - conductive tracks,

[0060] 6 - contact pads,

[0061] 7 - detachable technical platform,

[0062] 8 - conductive layer,

[0063] 9 - adhesive sublayer,

[0064] 10 - dielectric layer,

[0065] 11 - sacrificial layer,

[0066] 12 - glass substrate.

[0067] Table 1 shows the purpose of the elements of the declared elastic electrode matrix for subdural intraoperative monitoring.

[0068] Table 1. Purpose of the elements of the elastic electrode array for subdural intraoperative monitoring

[0069] Element Execution Purpose elastic base 1 planar polymer structure made of PDMS of complex geometric shape arrangement of the main elements of the electrode matrix contours of internal holes 2 parts of the conductive layer 8, located along the perimeter of possible openings in the matrix, not having electrical contact with the recording electrode pads 3, conductive tracks 5, contact pads 6 and detachable technical pad 7 visualization of the contours of the internal holes, which can be made, if necessary, to ensure the perfusion of fluids through the matrix, as well as ease of movement of the electrode matrix recording electrode pads 3 a part of the conductive layer 8 in the form of a circle, connected to the corresponding contact pad 6 by means of a conductive track 5, not covered by a dielectric layer 10 recording of electrical signals from the brain contour of the outer boundaries of the matrix 4 parts of the conductive layer 8, located along the perimeter of the matrix, not having electrical contact with the recording electrode pads 3, conductive tracks 5, contact pads 6 and detachable technical pad 7 and covered with a dielectric layer 10 visualization of the contours of the outer boundaries of the matrix, to determine the boundaries of the electrode matrix during use conductive tracks 5 part of the conductive layer 8 in the form of a strip connecting the corresponding recording electrode pads 3 with the contact pads 6, covered with a dielectric layer 10 transmission of registered electrical signals of the brain from recording electrode pads 3 to contact pads 6 contact pads 6 a part of the conductive layer 8 in the form of a circle, connected to the corresponding recording electrode pad 3 by means of a conductive track 5, not covered by a dielectric layer 10 transmission of recorded electrical signals from the brain to the communication interface with the recording device detachable technical platform 7 a rectangular part of the conductive layer 8, connected to all contact pads 6, not covered by the dielectric layer 10 the technical part of the electrode matrix, necessary for galvanizing the recording electrode pads 3, conductive tracks 5 and contact pads 6, as well as checking the electrical parameters of the conductive layer 8, separated after testing by cutting off from the elastic base 1 conductive layer 8 a set of metal planar structures made of gold, including recording electrode pads 3, conductive tracks 5, contact pads 6, a detachable technical pad 7, contours of internal holes 2 and a contour of the external boundaries of the matrix 4 recording and transmitting the recorded electrical signals to the communication interface with the recording device in the case of electrode pads 3, conductive tracks 5 and contact pads 6; a technological element for galvanizing and evaluating the electrical parameters of the electrode matrix in the case of a detachable technical pad 7; an element for visualizing the boundaries of areas in the case of contours of internal holes 2 and contours of the external boundaries of the matrix 4 adhesive sublayer 9 a metal planar structure made of chromium located between the elastic base 1 and the conductive layer 8 improving the strength of the connection between the elastic base 1 and the conductive layer 8 dielectric layer 10 a planar polymer structure made of PDMS located on an elastic base 1 and, partially, on a conductive layer 8 electrical insulation of conductive paths 5 from contact with conductive fluids and brain tissue sacrificial layer 11 a planar polymer structure located between the elastic base 1 and the glass substrate 12, not included in the final composition of the matrix, but necessary for the manufacturing process an intermediate technical layer for the safe separation of the elastic base 1 from the glass substrate 12, temporarily fixing the elastic base 1 on the glass substrate 12 and dissolving at the end of the technological processes glass substrate 12 a glass plate that is not part of the final matrix composition, but is necessary for the manufacturing process a plate for holding and positioning the elastic base 1 during the technological process of manufacturing the claimed electrode matrix

[0070] The claimed elastic electrode matrix for subdural intraoperative monitoring consists of the following structural elements (Fig. 1, 2): elastic base 1, adhesive sublayer 9, dielectric layer 10, conductive layer 8, represented by recording electrode pads 3, conductive tracks 5, contact pads 6, detachable technical pad 7, contours of internal openings 2 and contour of external boundaries of matrix 4, characterized in that it is made of biocompatible materials, having visualization of technical areas and boundaries, as well as the ability to control and manage electrical properties after the manufacturing process.

[0071] The elastic base 1 is a planar PDMS polymer structure with a complex geometric shape and is necessary for arranging the main elements of the claimed matrix. An adhesive sublayer 9, made, for example, of chromium, is located on the surface of the elastic base 1 and is necessary for improving the strength of the connection between the elastic base 1 and the conductive layer 8. A conductive layer 8 is located on the adhesive sublayer 9 and is a combination of metal planar structures made, for example, of gold, including recording electrode pads 3, conductive tracks 5, contact pads 6, a detachable technical pad 7, contours of internal openings 2, and the contour of the external boundaries of the matrix 4.The recording electrode pad 3 is presented in the form of a circle and is connected to the corresponding contact pad 6 in the form of a square by means of a conductive track 5 in the form of a strip, wherein the recording electrode pads 3 and the contact pads 6 are not covered by a dielectric layer 10, and the conductive tracks 5 are covered by a dielectric layer 10. The electrode pads 3 perform the function of recording electrical signals of the brain, and the conductive tracks 5 and the contact pads 6 perform the function of transmitting electrical signals to the communication interface with the recording device. In this case, the dielectric layer 10, which is a planar polymer structure made of PDMS, located on the elastic base 1 and on the conductive layer 8, provides electrical insulation of the conductive tracks 5 from contact with conductive fluids and brain tissue.In turn, the contours of the internal holes 2 do not have electrical contact with the recording electrode pads 3, conductive tracks 5, contact pads 6, and detachable technical pad 7. However, the contours of the internal holes 2 are capable of visualizing the contours of the internal holes, which, if necessary, can be created to ensure fluid perfusion through the matrix, as well as ease of movement of the electrode matrix. The contour of the external boundaries of the matrix 4 is designed to visualize the matrix boundaries and to determine the matrix boundaries during use on the brain under conditions of similar refractive indices of PDMS and cerebrospinal fluid. Detachable technical pad 7 is rectangular, connected to all contact pads 6, is not covered by the dielectric layer 10, and is separated after testing by cutting it from the elastic base 1.In this case, the detachable technical pad 7 is a technical part of the claimed matrix, necessary for galvanizing the recording electrode pads 3, conductive tracks 5 and contact pads 6, as well as checking the electrical parameters of the conductive layer 8. The sacrificial layer 11, which is a planar polymer structure located between the elastic base 1 and the glass substrate 12, is not included in the final composition of the matrix, but is necessary for the technological manufacturing processes. The glass substrate 12 is not included in the final composition of the matrix, but is necessary for the technological manufacturing processes, namely, for holding the elastic base 1 during the technological processes with the help of the intermediate sacrificial layer 11, which is dissolved at the end of the technological manufacturing processes for the safe separation of the elastic base 1 from the glass substrate 12.

[0072] The identified technical problem is solved and the stated technical result is achieved through the use of a combination of methods, such as: vacuum deposition technology, laser engraving, galvanization and photolithography, as well as the use of polydimethylsiloxane as a base, which is close in mechanical characteristics to the mechanical properties of the brain, which together creates conditions for elasticity, solidity and reproducibility of the device parameters.The technology for manufacturing matrices for electrocorticography consists of six stages: (1) creating a blank in the form of a glass substrate 12 with a first layer of elastic base 1 made of PDMS with a sprayed adhesive sublayer 9 and a conductive layer 8, (2) engraving recording electrode pads 3, conductive tracks 5 and contact pads 6, (3) galvanizing electrode pads 3, conductive tracks 5 and contact pads 6, (4) manufacturing a photomask, (5) forming a dielectric layer 10 and opening electrode pads 3 and contact pads 6 and (6) separating the claimed matrix from the glass substrate 12 by dissolving the sacrificial layer 11.

[0073] The general scheme for creating a multilayer structure consists of the following steps: 1) preliminary cleaning of glass substrate 12, for example, in a soda solution and rinsing, for example, in deionized water; 2) final cleaning of glass in oxygen plasma in a plasma cleaning unit. 3) applying a sacrificial layer 11, for example, a photoresist, by spin coating and drying the photoresist on a hotplate; 4) mixing the PDMS base component with a thickener on a platinum catalyst; 5) applying liquid PDMS by spin coating and subsequent removal of excess PDMS from the edges of the workpiece; 6) polymerization of PDMS in a dry-heat oven; 7) thermal deposition in a vacuum of the adhesive sublayer 9 and the conductive layer 8 in a vacuum deposition unit.

[0074] Temperature polymerization of PDMS was chosen as optimal so that the compression of the PDMS film after polymerization and cooling to room temperature would lead to the formation of a relief on the surface of the workpiece, which, in combination with the deformation of the PDMS surface upon heating in the process of thermal deposition of metals, leads to an improvement in the mechanical properties of the claimed matrix (Fig. 2A).

[0075] The second stage in the manufacturing process of the claimed matrix was the formation of conductive tracks 5, electrode pads 3 and contact pads 6. In order to avoid the need to create an additional photomask for different configurations of the geometry of the claimed matrix, a laser engraving method was used, which allows removing sections of the conductive layer 8 in several passes with a resolution of up to 10 μm (Fig. 2A).

[0076] The galvanic deposition process was performed after rinsing the sample in deionized water under pressure. Next, a clamp was attached to the detachable technical platform 7, and the matrix was immersed in a galvanic bath containing a citric acid gold electrolyte, where gold was electrochemically deposited onto the conductive elements (Fig. 2B). This approach avoided excessive gold consumption in the previous deposition step and improved the mechanical properties of the conductive layer.

[0077] To insulate the tracks, a continuous dielectric layer 10 was applied to the surface of the conductive layer (Fig. 2B). The same material as the substrate (PDMS) was chosen for the dielectric layer 10 to ensure the matrix was resistant to bending and stretching.

[0078] To provide access to the electrode pads 3 and contact pads 6, the dielectric layer 10 was removed from these areas by plasma-chemical etching. The etching of the dielectric layer 10 of the claimed matrix in the area of ​​the electrode pads 3 and contact pads 6 was carried out by applying a protective photoresist mask and a subsequent lithography procedure using a photomask (Fig. 2B). The photomask was created using a laser engraving method, which is characterized by low cost and high productivity. After local etching of the dielectric layer 10 and removal of the protective photoresist mask, the claimed matrix was separated from the glass substrate 12 by selectively dissolving the sacrificial layer 11 (Fig. 2B).

[0079] Below are some implementation examples.

[0080] Example 1. Evaluation of the electrical properties of the conductive tracks of the claimed electrode array for subdural intraoperative monitoring

[0081] To evaluate the conductivity of the electrodes of the formed electrode matrices, the volt-ampere characteristics (VAC) were measured using, for example, a Keithley 2400 source-measure instrument, which served as a current source and a voltage meter. To calculate the surface resistance of the formed electrodes, a 2-probe measurement method was used. The VAC of the conductive tracks 5 made on a flexible substrate has a linear dependence (Fig. 3A). When bending the claimed electrode matrix for subdural intraoperative monitoring, deformations of the conductive tracks 5 and possible changes in their electrical characteristics are possible. However, the change in the conductivity of the conductive tracks 5 of the flexible electrode matrices after 50 cycles of bending and relaxation of mechanical stresses relative to the initial conductivity of the track before bending amounted to ((I изогн -I исх ) / I исх) no more than 10% of the initial value (Fig. 3B). In this case, upon bending, the conductivity predominantly decreased and returned to a value close to the initial one after relaxation.

[0082] Thus, the elastic properties of the claimed electrode matrix for subdural intraoperative monitoring were demonstrated, and it was also established that the claimed matrix does not cause significant changes in the electrical characteristics of the conductive elements under the influence of mechanical loads.

[0083] Example 2. Evaluation of the functionality of the claimed elastic electrode array for subdural intraoperative monitoring when recording brain activity in rats in vivo

[0084] To conduct experiments to test the functionality of the claimed elastic electrode matrix for subdural intraoperative monitoring, the matrix design variant shown in Fig. 4A was used; 3-month-old rats, for example, of the SHR line, were used.

[0085] For the induction of anesthesia and maintenance during surgery, a gaseous anesthetic was used, such as isoflurane, for the initial induction and subsequent maintenance of anesthesia at concentrations of, for example, 5% and 1.5%, respectively. During surgery and the experiment, the animal was placed on a heat mat maintaining a constant temperature of, for example, 35-37°C. During the surgery, the scalp was removed from the dorsal surface of the rat's skull. The dorsal part of the animal's skull was also cleared of periosteum, and a portion of the skull surface over both hemispheres of the brain was removed (Fig. 4B). To ensure subsequent anesthesia, the animal was intraperitoneally injected with, for example, urethane (1.5 g / kg, Sigma-Aldrich, USA). During the experiment, the surface of the cortex was kept moist by applying, for example, a solution of artificial cerebrospinal fluid (NaCl 126 mM, KCl 3.5 mM, NaH2PO4 1.2 mM, CaCl2 2 mM, MgCl2 1.3 mM, NaHCO3 2.1 g / l, D-Glucose 1.98 g / l).

[0086] The claimed matrix was located on the surface in such a way that the electrodes were located on each of the cerebral hemispheres. Electrode pads 3 were in direct contact with the brain surface (Fig. 4B). Amplification, digitalization and recording of the electrical activity of the brain registered using the claimed matrix was carried out using, for example, an Open Ephys Acquisition Board amplifier (Open Ephys, USA) with a frequency of 30 kHz. Activity analysis was performed using the wEEGit software package [Suchkov D. et al. / WEEGit - software for visualization and annotation of the electrophysiological activity registration data / / ZHURNAL VYSSHEI NERVNOI DEYATELNOSTI IMENI IP PAVLOVA, 2023, V.73, 6, 857-872, DOI: 10.31857 / S0044467723060102].

[0087] The obtained electrical signal data in both hemispheres showed the presence of synchronous activity in both hemispheres of the brain (Fig. 4D), characteristic of the sleep state in which the animal was under anesthesia. Comparison of the experimental data with previously obtained results of brain activity at different levels of anesthesia [Torao-Angosto M. et al. / Up and Down States During Slow Oscillations in Slow-Wave Sleep and Different Levels of Anesthesia / / Front Syst Neurosci., 2021, 9:15:609645, DOI: 10.3389 / fnsys.2021.609645] confirmed this assumption.

[0088] Thus, the claimed elastic electrode matrix for subdural intraoperative monitoring is a functional invention and makes it possible to implement the recording of electrical activity of the brain in vivo in experimental animal models.

[0089] From the above, it can be concluded that the applicant has solved the identified problems and achieved the stated technical result, namely, an elastic electrode matrix for subdural intraoperative monitoring and a method for its manufacture have been developed.

[0090] A design and method for manufacturing an elastic electrode matrix for subdural intraoperative monitoring have been developed, containing elements that ensure:

[0091] - biocompatibility with the biological object under study;

[0092] - flexibility and stretchability of the matrix base with a Young's modulus close to brain tissue without deteriorating the electrical characteristics of the conductive elements;

[0093] - can be used to record brain activity.

[0094] The claimed technical solution was demonstrated using the example of manufacturing using vacuum deposition, laser engraving, galvanization and photolithography technologies.

[0095] The claimed technical solution ensures tight contact of recording electrodes on the surface of the brain with variable curvature and recording of its electrical activity.

[0096] The claimed technical solution meets the “novelty” criterion required for inventions, since the applicant has not identified any technical solutions from the studied prior art that possess the claimed set of essential features.

[0097] The claimed technical solution meets the “inventive step” criterion required for inventions, since no technical solutions have been identified that have features that coincide with the distinctive features of the claimed invention, and the influence of the distinctive features on the claimed technical result has not been established.

[0098] The claimed technical solution meets the “industrial applicability” criterion imposed on inventions, since it can be manufactured on standard equipment using known materials and production methods.

Claims

1. An elastic electrode matrix for subdural intraoperative monitoring obtained by sequentially performing vacuum deposition, laser engraving, galvanization and photolithography, including an elastic base made of polydimethylsiloxane, an adhesive sublayer located on the surface of the elastic base, a conductive layer located on the adhesive sublayer, and a dielectric layer; wherein the conductive layer includes recording electrode pads configured to record electrical signals from the brain, conductive tracks and contact pads configured to transmit electrical signals from the brain to a communication interface with a recording device, a detachable technical pad connected to the contact pads and configured to be cut off from the elastic base, navigation contours of the internal openings and a navigation contour of the outer boundaries of the matrix;wherein the recording electrode pads are connected to the contact pads using conductive tracks, the navigation contours of the internal openings are designed to provide perfusion of liquids through the elastic electrode matrix, and the dielectric layer is located on the elastic base and the conductive layer with a coating of the conductive tracks.

2. A method for manufacturing an elastic matrix for subdural intraoperative monitoring according to claim 1, comprising an elastic base made of polydimethylsiloxane, an adhesive sublayer located on the surface of the elastic base, a conductive layer located on the adhesive sublayer, and a dielectric layer; wherein the conductive layer includes recording electrode pads configured to record electrical signals from the brain, conductive tracks and contact pads configured to transmit electrical signals from the brain to a communication interface with a recording device, a detachable technical pad connected to the contact pads and configured to be cut off from the elastic base, navigation contours of the internal openings and a navigation contour of the outer boundaries of the matrix; wherein the recording electrode pads are connected to the contact pads using conductive tracks,the navigation contours of the internal holes are designed to provide perfusion of liquids through the elastic electrode matrix, and the dielectric layer is located on the elastic base and the conductive layer with a coating of conductive tracks, characterized in that first a blank is created in the form of a glass substrate with a layer of a polymer structure and a layer of an elastic base made of polydimethylsiloxane with a sprayed adhesive sublayer and a conductive layer, wherein the layer of the polymer structure is placed between the elastic base and the glass substrate, then recording electrode pads, conductive tracks and contact pads are engraved, then the recording electrode pads, conductive tracks and contact pads are galvanized, then a photomask is made, then a dielectric layer is formed and the recording electrode pads and contact pads are opened,then the elastic matrix is ​​separated from the glass substrate by dissolving the polymer structure layer.

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