An array microelectrode device for intraoperative tracing of tumor-bearing nerve in schwannoma

Abstract

The present application relates to a kind of schwannoma intraoperative tumor-bearing nerve tracing drawing array microelectrode device, which comprises top insulating layer, contact pad, flexible substrate layer, microelectrode point and conductive circuit;The contact pad, microelectrode point and conductive circuit are arranged between the top insulating layer and flexible substrate layer;The contact pad and microelectrode point are electrically connected by the conductive circuit;The top insulating layer is provided with window part, and the position of the window part corresponds to the position of the contact pad;The contact pad is exposed outside the top insulating layer through the window part;The flexible substrate layer enables the schwannoma intraoperative tumor-bearing nerve tracing drawing array microelectrode device to adapt and stably adhere to the complex interface of nerve and tumor.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of nerve monitoring, in particular to a tumor-bearing nerve tracing array microelectrode device for acoustic neuroma surgery and a manufacturing method thereof. BACKGROUND

[0002] Acoustic neuroma, also known as vestibular schwannoma, accounts for 8% of all intracranial tumors and is the most common tumor in the cerebellopontine angle region in adults. These tumors often come from the myelin Schwann cells of the vestibular branch of the vestibulocochlear nerve (the eighth cranial nerve), and the main symptoms are hearing loss, tinnitus, facial paralysis, etc. At present, surgical treatment is still the preferred treatment for large acoustic neuromas. However, the problems of postoperative facial paralysis and hearing loss are two major difficulties that trouble acoustic neuroma patients and neurosurgeons. At present, with the progress of various diagnostic and treatment methods, including radiological imaging, nerve monitoring and microsurgical techniques, the treatment goal of vestibular schwannoma has become to achieve optimal tumor control while preserving facial activity and hearing function. The rich surgical experience of the operator and intraoperative electrophysiological monitoring play an important role in preserving the face and hearing. With the accumulation of surgical experience of neurosurgeons, the incidence of facial paralysis after acoustic neuroma surgery has been greatly reduced with the help of intraoperative facial nerve free electromyography and facial nerve evoked electromyography. However, on the one hand, neurosurgeons of different levels have great differences in the judgment of the anatomical trajectory of the facial nerve; on the other hand, sometimes the facial nerve will be squeezed and deformed by the acoustic neuroma, losing the normal anatomical structure and even being difficult to distinguish with the naked eye, and the current electrophysiological monitoring method either achieves rough positioning of the facial nerve through active stimulation to collect evoked potentials or only provides early warning when dangerous operation has occurred, so some patients still have postoperative facial paralysis. For patients with tumor diameter greater than 2.5 cm, the risk of postoperative partial or complete facial paralysis is as high as 50%, and even for patients with tumor diameter less than 1.5 cm, the risk of postoperative facial paralysis is close to 10%.

[0003] Although intraoperative neuromonitoring (IONM) has shown to improve surgical outcomes, the current form can only indirectly assess neural structures and function. In IONM for vestibular schwannoma, facial nerve evoked potentials and brainstem auditory evoked potentials (BAEPs) are acquired through facial muscles and scalp, respectively. Due to the insulating effect of the scalp, skull, and dura, the amplitude of BAEPs is low. Therefore, a large number of stimulation sequences are needed to improve the signal-to-noise ratio (SNR) and extract physiological electrical signals. These stimulation sequences also cannot achieve real-time monitoring, which may lead to a long time without finding nerve damage. Finally, due to tumor compression, the facial-auricular nerve complex becomes atrophic, loses the typical structure, and is difficult to distinguish from the tumor. The physical separation of the recording electrodes on the scalp from the neural surgical site makes it impossible to record the spatiotemporal, anatomical, and physiological response characteristics. The inability to directly identify the neural pathway makes it impossible to protect the neural tissue from damage during tumor resection. Summary of the Invention

[0004] The present invention aims to provide an array microelectrode device for mapping the course of the tumor-bearing nerve during schwannoma surgery and its manufacturing method. The technical problems to be solved include at least how to adapt to and stably fit the complex interface between the nerve and the tumor, thereby sensitively capturing the complex spatiotemporal patterns of nerve signals, and accurately mapping the two-dimensional nerve trajectory map throughout the schwannoma surgery.

[0005] To achieve the above objectives, the present invention provides a microelectrode device for mapping the course of the tumor-bearing nerve during schwannoma surgery, comprising a top insulating layer, a contact pad, a flexible base layer, microelectrode points, and conductive lines; the contact pad, microelectrode points, and conductive lines are disposed between the top insulating layer and the flexible base layer; the contact pad and the microelectrode points are electrically connected through the conductive lines; a window is provided on the top insulating layer, the position of which corresponds to the position of the contact pad; the contact pad is exposed outside the top insulating layer through the window; the flexible base layer enables the microelectrode device for mapping the course of the tumor-bearing nerve during schwannoma surgery to adapt to and stably conform to the complex interface between the nerve and the tumor.

[0006] Preferably, the microelectrode device for mapping the course of the tumor-bearing nerve during schwannoma surgery includes 32 microelectrode points.

[0007] Preferably, the flexible substrate layer is made of photosensitive polyimide.

[0008] Preferably, the top insulating layer is made of polyimide.

[0009] Preferably, the area of ​​the microelectrode points is 120 × 120 μm. 2 .

[0010] Preferably, when the microelectrode device for mapping the course of the tumor-bearing nerve during schwannoma surgery is fully prepared and exposed to phosphate buffer, its electrochemical impedance at 1 kHz will be stably maintained in the range of 100 to 400 kilohms.

[0011] Preferably, the length of the microelectrode device for mapping the course of the tumor-bearing nerve during schwannoma surgery is 66 mm and the width is 7 mm.

[0012] Preferably, the contact pad has a size of 0.7 × 0.7 mm. 2 .

[0013] Preferably, the lateral spacing between adjacent contact pads is 1.6 mm and the longitudinal spacing is 1.3 mm.

[0014] Preferably, the contact pad is connected to the external circuit via conductive silver paste or anisotropic conductive adhesive.

[0015] This invention provides a method for fabricating an array microelectrode device for mapping the course of the tumor-bearing nerve during schwannoma surgery, comprising the following steps:

[0016] S1. A layer of photosensitive polyimide is spin-coated onto a four-inch silicon oxide wafer to form a flexible substrate, and then the electrode shape is patterned using photolithography.

[0017] S2. Spin-coat a double layer of photoresist onto the electrode, pattern the metal leads with ultraviolet light, and use magnetron sputtering technology to sequentially sputter a metal layer composed of 5 nm thick chromium, 100 nm thick gold and 5 nm thick chromium from bottom to top. Finally, use a lift-off process to form the metal wire.

[0018] S3. A second layer of polyimide, approximately 4 micrometers thick, is applied to the electrode as a top insulating layer.

[0019] S4. Further patterning is performed using photolithography to determine the precise location of the microelectrode point 4 and expose the microelectrode point 4;

[0020] S5. During the fabrication process, an oxide layer is formed on the surface of the microelectrode points. The oxide layer is removed using 40% hydrofluoric acid, and then the microelectrode device for mapping the course of the tumor-bearing nerve during schwannoma surgery is separated from the silicon oxide wafer.

[0021] Compared with the prior art, the beneficial effects of the present invention are:

[0022] The microelectrode array device for intraoperative mapping of nerve pathways during schwannoma surgery described in this invention is a highly flexible and high-density microelectrode array. Compared to traditional intraoperative neuromonitoring (IONM), it exhibits superior performance in schwannoma surgery, sensitively capturing complex spatiotemporal patterns of nerve signals, enabling precise mapping of two-dimensional nerve trajectories throughout the surgical procedure. The application of this grid in high-resolution mapping, along with its excellent flexibility and stable adhesion to irregular tumor surfaces, suggests its potential to enhance neurosurgical interventions and neuromodulation therapies, expanding from vestibular schwannoma cases to a wider range of clinical scenarios. Attached Figure Description

[0023] The accompanying drawings are provided to further understand the technical solutions of the present invention and constitute a part of the specification. They are used together with the specific embodiments of this application to explain the technical solutions of the present invention and do not constitute a limitation on the technical solutions of the present invention.

[0024] Figure 1This is a schematic diagram of the array microelectrode device for mapping the course of the tumor-bearing nerve during surgery for schwannomas, as described in this invention.

[0025] Figure 2 This is the electrode design diagram of the array microelectrode device for drawing the course of the tumor-bearing nerve during the surgery of the aforementioned schwannoma.

[0026] Figure 3 This is a partially enlarged schematic diagram of the microelectrode points.

[0027] Figure 4 This is a schematic diagram showing the dimensions of the microelectrode points.

[0028] Figure 5 This is a partial dimensional schematic diagram of the microelectrode points and conductive circuits.

[0029] Figure 6 This is a schematic diagram showing the dimensions of the contact pad.

[0030] Figure 7 This is a schematic diagram of the detection results data from the array microelectrode device used to map the course of the tumor-bearing nerve during the surgery for the aforementioned schwannoma. Detailed Implementation

[0031] The invention is described in more detail below to aid in understanding it.

[0032] Neurosurgical tumor surgery often involves deep, delicate, and highly sensitive anatomical structures within the brain, making the procedure extremely challenging, especially when the tumor is adjacent to important nerves or blood vessels. Sometimes, the boundary between the tumor and normal neural tissue is difficult to distinguish, further complicating the surgery. Neurological dysfunction is one of the major postoperative complications, potentially leading to long-term functional impairment. This risk becomes particularly pronounced when it is impossible to accurately distinguish between tumor and normal brain tissue. For example, in vestibular schwannoma (VS) surgery, although most of these tumors are benign, their complex intracranial location can lead to a range of complications such as hearing loss, facial nerve damage, and balance disorders. To mitigate these risks, intraoperative neurophysiological monitoring (IONM) has become standard practice in modern neurosurgery. IONM provides surgeons with intraoperative neuromonitoring, enabling them to assess and protect neurological function in real time, ensuring complete tumor resection while preserving neurological function to the greatest extent possible.

[0033] While current literature clearly demonstrates the importance of IONM in improving surgical outcomes, traditional IONM techniques primarily rely on far-field potential monitoring, which only provides surgeons with indirect assessments of neural structure and function. For example, in vestibular schwannoma (VS) surgery, conventional rigid electrode stimulation of the intracranial facial nerve induces facial nerve evoked potentials (VEPs) of the facial muscles, while brainstem auditory evoked potentials (BAEPs) are electrical responses recorded from the scalp based on auditory stimulation. Due to the electrical insulation of the scalp, skull, and dura mater, frequent stimulation is often required to achieve a high signal-to-noise ratio (SNR). This method has significant limitations in real-time detection of nerve damage and may lead to delays in identifying nerve injuries. Tumor compression can cause degeneration or thinning of the facial and auditory nerves, blurring their interface with the tumor and further increasing the difficulty of identifying the tumor's neural boundaries. Furthermore, the physical distance between the scalp recording electrodes and the surgical area significantly limits the precise monitoring of the spatiotemporal, anatomical, and physiological properties of neural pathways, thus increasing the potential risk of damage to neural structures during tumor resection.

[0034] To overcome these challenges, this application employs a revolutionary technology: a flexible microelectrode array. With its superior spatial resolution, robust conductivity, and sustained electrophysiological response, the flexible microelectrode array enables precise neural visualization of irregular tumor surfaces in IONM. The microelectrode array device for intraoperative mapping of tumor-bearing nerves in schwannomas described in this application can display the entire course of the corresponding nerve in real time, setting a new benchmark for high-fidelity neural visualization during surgery and far surpassing traditional electrophysiological monitoring methods. In summary, this application provides a real-time, precise neural visualization platform for vestibular schwannomas surgery, thereby significantly improving the success rate of preserving key nerve functions postoperatively.

[0035] like Figures 1 to 6 As shown, the intraoperative nerve pathway mapping array microelectrode device for schwannomas described in this application includes a top insulating layer 1, a contact pad 2, a flexible base layer 3, microelectrode points 4, and conductive lines 5. The contact pad 2, microelectrode points 4, and conductive lines 5 are disposed between the top insulating layer 1 and the flexible base layer 3. The contact pad 2 and the microelectrode points 4 are electrically connected through the conductive lines 5. A window portion 11 is provided on the top insulating layer 1, and the position of the window portion 11 corresponds to the position of the contact pad 2. The contact pad 2 is exposed outside the top insulating layer 1 through the window portion 11. The flexible base layer 3 enables the intraoperative nerve pathway mapping array microelectrode device for schwannomas to adapt to and stably conform to the complex interface between the nerve and the tumor.

[0036] In this embodiment, the exposure of the micro electrode points 4 is achieved by photolithographic patterning, without setting a corresponding window portion 11.

[0037] Preferably, the microelectrode device for mapping the course of the tumor-bearing nerve during schwannoma surgery includes 32 microelectrode points 4, and the number of microelectrode points 4 is the same as that of the contact pads and they correspond one-to-one.

[0038] Preferably, the flexible substrate layer 3 is made of photosensitive polyimide.

[0039] Preferably, the top insulating layer 1 is made of polyimide.

[0040] Preferably, the area of ​​the microelectrode point 4 is 120×120μm. 2 .

[0041] Preferably, when the microelectrode device for mapping the course of the tumor-bearing nerve during schwannoma surgery is fully prepared and exposed to phosphate buffer, its electrochemical impedance at 1 kHz will be stably maintained in the range of 100 to 400 kilohms.

[0042] Preferably, the length of the microelectrode device for mapping the course of the tumor-bearing nerve during schwannoma surgery is 66 mm and the width is 7 mm.

[0043] Preferably, the contact pad has a size of 0.7 × 0.7 mm. 2 .

[0044] Preferably, the lateral spacing between adjacent contact pads is 1.6 mm and the longitudinal spacing is 1.3 mm.

[0045] Preferably, the contact pad is connected to the external circuit via conductive silver paste or anisotropic conductive adhesive.

[0046] This invention provides a microelectrode array for mapping the course of the tumor-bearing nerve during schwannoma surgery, comprising a 32-channel microelectrode array, which enables real-time visualization via accompanying software. The microelectrode array is equipped with 32 microelectrode points, each with an area of ​​120 × 120 μm. 2 Its unique flexible substrate design allows it to adapt to and stably conform to the complex interface between nerves and tumors, which is particularly crucial for its application in schwannoma surgery.

[0047] This application also provides a method for fabricating an array microelectrode device for mapping the course of the tumor-bearing nerve during schwannoma surgery, comprising the following steps:

[0048] S1. A layer of photosensitive polyimide is spin-coated onto a four-inch silicon oxide wafer to form a flexible substrate, and then the electrode shape is patterned using photolithography.

[0049] S2. Spin-coat a double layer of photoresist onto the electrode, pattern the metal leads with ultraviolet light, and use magnetron sputtering technology to sequentially sputter a metal layer composed of 5 nm thick chromium, 100 nm thick gold and 5 nm thick chromium from bottom to top. Finally, use a lift-off process to form the metal wire.

[0050] S3. A second layer of polyimide, approximately 4 micrometers thick, is applied to the electrode as a top insulating layer.

[0051] S4. Further patterning is performed using photolithography to determine the precise location of the microelectrode point 4 and expose the microelectrode point 4;

[0052] S5. During the fabrication process, an oxide layer is formed on the surface of the microelectrode points. The oxide layer is removed using 40% hydrofluoric acid, and then the microelectrode device for mapping the course of the tumor-bearing nerve during schwannoma surgery is separated from the silicon oxide wafer.

[0053] Due to the complexity of schwannoma surgery, multiple nerve electrical stimulations and electrophysiological signal detections are often required to achieve precise localization and visualization of nerve pathways. Against this backdrop, this application introduces a novel electrode design: a flexible microelectrode array. Compared to traditional electrodes, the flexible microelectrode array proposed in this application is equipped with 32 microelectrode points, each with an area of ​​120 × 120 μm. 2 Its unique flexible base design allows it to adapt to and stably conform to the complex interface between nerves and tumors, which is particularly crucial for its application in schwannoma surgery.

[0054] like Figure 7 As shown, the detection results of the microelectrode array used to map the course of the tumor-bearing nerve during surgery for schwannomas, as described in this application, show that the standardized signal at the nerve site is significantly different compared to other sites. Combined with software to generate a color temperature map, the nerve region can be clearly depicted based on the standardized signal intensity.

[0055] During the research and development process, the applicant discovered that by placing microelectrodes on the surface of vestibular schwannomas, the rapid collection of facial and auditory nerve data can improve the fidelity of these recordings and reduce the number of trials required, thereby achieving real-time spatiotemporal mapping. Furthermore, by using a high-channel-count microelectrode array for recording, a two-dimensional (2D) neural pathway diagram can be generated, which helps to more accurately identify the nerve trajectories at the resection site during vestibular schwannomas surgery.

[0056] To address the challenges of existing technologies, the applicant designed the aforementioned flexible microelectrode array with superior spatial resolution, reliable conductivity, and stable electrical properties, enabling it to better adapt to irregular tumor surfaces during intraoperative neural monitoring (IONM). This high-resolution neural boundary is unattainable by current electrophysiological monitoring techniques. To achieve real-time visualization of neural pathways, the applicant independently developed a complementary software program. This technology provides a near-instantaneous IONM approach when data analysis and plotting are integrated in real time. In conclusion, the flexible microelectrode mesh of this application can enhance IONM and may also have applications in other fields.

[0057] The preferred embodiments of the present invention have been described above, but are not intended to limit the invention. Those skilled in the art can make modifications and variations to the embodiments disclosed herein without departing from the scope and spirit of the invention.

Claims

1. A method for making a microelectrode array device for intraoperative mapping of a tumor-bearing nerve in a schwannoma, the method comprising: providing a substrate; providing a plurality of microelectrodes; and coupling the plurality of microelectrodes to the substrate. The method comprises the following steps: S1. A flexible substrate is formed by spin-coating a photosensitive polyimide on a four-inch silicon wafer, and then patterning the electrode shape by photolithography; S2. A double-layer photoresist is spin-coated on the electrode, and the metal lead is patterned by UV lithography. A metal layer composed of 5 nm thick chromium, 100 nm thick gold and 5 nm thick chromium is successively sputtered from bottom to top by magnetron sputtering technology. Finally, the metal lead is formed by a stripping process; S3. A second layer of polyimide with a thickness of 4 microns is coated on the electrode as a top insulating layer; S4. The precise position of the micro electrode point is determined and the micro electrode point is exposed by further patterning by photolithography. The exposure of the micro electrode point is achieved by photolithography patterning without setting a corresponding window part; S5. An oxide layer is formed on the surface of the micro electrode point during the manufacturing process. The oxide layer is removed using 40% hydrofluoric acid, and then the schwannoma intraoperative tumor-bearing nerve tracing array microelectrode device is separated from the silicon wafer; The schwannoma intraoperative tumor-bearing nerve tracing array microelectrode device can display the corresponding nerve running in real time, and accurately draw a two-dimensional nerve trajectory graph during the entire neurosurgical tumor operation process; The schwannoma intraoperative tumor-bearing nerve tracing array microelectrode device comprises a top insulating layer, a contact pad, a flexible substrate layer, a micro electrode point and a conductive circuit; The top insulating layer is provided with a window part, and the position of the window part corresponds to the position of the contact pad. The material of the top insulating layer is polyimide; The flexible substrate layer enables the schwannoma intraoperative tumor-bearing nerve tracing array microelectrode device to adapt to and stably fit the complex interface of the nerve and tumor. The material of the flexible substrate layer is photosensitive polyimide; The contact pad, micro electrode point and conductive circuit are arranged between the top insulating layer and the flexible substrate layer; The contact pad and the micro electrode point are electrically connected through the conductive circuit; The contact pad is connected to the external circuit through conductive silver paste or anisotropic conductive adhesive; The contact pad is exposed outside the top insulating layer through the window part; The lateral spacing between adjacent contact pads is 1.6 mm, and the longitudinal spacing is 1.3 mm; The schwannoma intraoperative tumor-bearing nerve tracing array microelectrode device comprises 32 micro electrode points; Among the 32 micro electrode points, 30 are arranged in a 10×3 array, with 10 rows of micro electrode points distributed longitudinally, and the spacing between adjacent two rows of micro electrode points is 0.6 mm. There are 3 columns of micro electrode points distributed laterally, and the spacing between adjacent two columns of micro electrode points is 2.5 mm. The remaining 2 micro electrode points are located above the 10×3 micro electrode point array in the longitudinal direction, and the longitudinal spacing between the first row of electrode points in the 10×3 micro electrode point array and the 2 micro electrode points is 0.6 mm. The lateral spacing of the 2 micro electrode points is 2.5 mm; When the schwannoma intraoperative tumor-bearing nerve tracing array microelectrode device is completely prepared and exposed to a phosphate buffer solution, its electrochemical impedance at 1 kHz will stably remain in the range of 100 to 400 kilo-ohms.

2. The method for fabricating the array microelectrode device for mapping the course of the tumor-bearing nerve during surgery for schwannomas according to claim 1, characterized in that, The microelectrode point has an area of 120 x 120 pm 2 .

3. The method for fabricating the array microelectrode device for mapping the course of the tumor-bearing nerve during surgery for schwannomas according to claim 1, characterized in that, The length of the array microelectrode device drawn along the tumor-bearing nerve in the operation of the schwannoma is 66 mm, and the width is 7 mm.

4. The method for fabricating the array microelectrode device for mapping the course of the tumor-bearing nerve during surgery for schwannomas according to claim 1, characterized in that, The contact pad has a size of 0.7 x 0.7 mm 2 .

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