技术领域Technical Field
本发明涉及神经监测技术领域，具体涉及一种神经鞘瘤术中载瘤神经走形绘制阵列微电极装置及其制作方法。The present invention relates to the technical field of nerve monitoring, and in particular to an array microelectrode device for drawing the shape of a tumor-bearing nerve during neurilemmoma surgery and a manufacturing method thereof.
背景技术Background technique
听神经瘤又称前庭神经鞘瘤，占所有颅内肿瘤的8％，是成人最常见的桥小脑角区肿瘤，这些肿瘤常来自于前庭耳蜗神经(第八对颅神经)前庭支的髓鞘雪旺细胞，以听力下降、耳鸣、面瘫等为主要症状。目前，手术治疗仍是较大听神经瘤的首选治疗方式。然而术后遗留的面瘫和听力下降问题是困扰着听神经瘤患者和神经外科大夫的两大难题。当前，随着各种诊断和治疗方式的进步，包括放射成像、神经监测和显微外科技术等，已经使得前庭神经鞘瘤的治疗目标成为实现最佳肿瘤控制的同时保留面部活动及听力功能。术者丰富的手术经验和术中电生理监测在保面和保听方面发挥了重要作用。随着神经外科医生手术经验的积累，在术中面神经自由肌电监测及面神经诱发肌电监测的帮助下，听神经瘤术后面瘫发生率已经大大降低。然而，一方面不同水平的神经外科医生对于术中面神经解剖轨迹的判断有较大的差异；另一方面有时面神经会被听神经瘤挤压变形失去正常的解剖结构甚至肉眼难以分辨，而当前的电生理监测方法要么是通过主动刺激采集诱发电位实现对面神经的粗略定位，要么是在危险操作已经发生时才进行预警，故仍有部分患者出现术后面瘫的情况，对于肿瘤直径大于2.5厘米的患者，术后永久性部分或完全性面瘫的风险高达50％，即便是直径小于1.5厘米的患者，其术后面瘫的风险也接近10％。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 originate from the myelinated Schwann cells of the vestibular branch of the vestibulocochlear nerve (eighth cranial nerve), with hearing loss, tinnitus, and facial paralysis as the main symptoms. At present, surgical treatment is still the preferred treatment for larger acoustic neuromas. However, the facial paralysis and hearing loss left after surgery are two major problems that plague acoustic neuroma patients and neurosurgeons. At present, with the advancement of various diagnostic and treatment methods, including radiographic imaging, neuromonitoring, and microsurgical techniques, the treatment goal of vestibular schwannoma has become to achieve optimal tumor control while preserving facial movement and hearing function. The rich surgical experience of the surgeon and intraoperative electrophysiological monitoring play an important role in preserving the face and hearing. With the accumulation of surgical experience of neurosurgeons, with the help of intraoperative facial nerve free electromyography monitoring and facial nerve evoked electromyography monitoring, the incidence of facial paralysis after acoustic neuroma surgery has been greatly reduced. However, on the one hand, neurosurgeons of different levels have great differences in their judgment of the anatomical trajectory of the facial nerve during surgery; on the other hand, sometimes the facial nerve will be squeezed and deformed by the acoustic neuroma and lose its normal anatomical structure and even be difficult to distinguish with the naked eye. The current electrophysiological monitoring methods either achieve a rough positioning of the facial nerve through active stimulation and acquisition of evoked potentials, or issue an early warning only when dangerous operations have already occurred. Therefore, some patients still experience postoperative facial paralysis. For patients with tumors larger than 2.5 cm in diameter, the risk of permanent partial or complete facial paralysis after surgery is as high as 50%. Even for patients with tumors smaller than 1.5 cm in diameter, the risk of postoperative facial paralysis is close to 10%.
尽管术中神经监测(IONM)曾显示改善手术结果，但现有形式只能间接评估神经结构和功能。在前庭神经鞘瘤的IONM中，面神经诱发电位和脑干听觉诱发电位(BAEPs)分别通过面部肌肉和头皮获取。由于头皮、颅骨和硬膜的绝缘作用，BAEPs的幅度较低。因此，需要大量刺激序列提高信噪比(SNR)并提取生理电信号。这些刺激序列也无法实现实时监测，可能导致神经损伤长时间未被发现。最后，由于肿瘤压迫，面-耳神经复合体变得消瘦，失去典型结构，难以与肿瘤区分。头皮上记录电极与神经手术部位的物理分离，使得无法记录时空、解剖和生理反应特征。无法直接识别神经通路使得在肿瘤切除过程中保护神经组织免受损伤成为一项无法实现的目标。Although intraoperative neuromonitoring (IONM) has been shown to improve surgical outcomes, current modalities can only indirectly assess neural structure and function. In IONM for vestibular schwannomas, facial nerve evoked potentials and brainstem auditory evoked potentials (BAEPs) are obtained through facial muscles and scalp, respectively. The amplitude of BAEPs is low due to the insulating effects of the scalp, skull, and dura mater. Therefore, a large number of stimulation sequences are required to improve the signal-to-noise ratio (SNR) and extract physiological electrical signals. These stimulation sequences also fail to achieve real-time monitoring, which may cause nerve damage to remain undetected for a long time. Finally, due to tumor compression, the facial-otic nerve complex becomes emaciated and loses its typical structure, making it difficult to distinguish from the tumor. The physical separation of the recording electrodes on the scalp from the surgical site of the nerve makes it impossible to record the spatiotemporal, anatomical, and physiological response characteristics. The inability to directly identify the neural pathway makes protecting neural tissue from damage during tumor resection an unattainable goal.
发明内容Summary of the invention
本发明旨在提供一种神经鞘瘤术中载瘤神经走形绘制阵列微电极装置及其制作方法，所要解决的技术问题至少包括如何适应并稳定地贴合于神经与肿瘤的复杂界面，从而灵敏捕捉神经信号的复杂时空模式，并在整个神经鞘瘤手术过程中能够精确绘制出二维神经轨迹图。The present invention aims to provide an array microelectrode device for mapping the trajectory of tumor-bearing nerves during neurofibroma surgery and a method for manufacturing the same. The technical problems to be solved include at least how to adapt to and stably fit the complex interface between nerves and tumors, so as to sensitively capture the complex spatiotemporal patterns of nerve signals and accurately map a two-dimensional nerve trajectory during the entire neurofibroma surgery.
为了实现上述目的，本发明提供一种神经鞘瘤术中载瘤神经走形绘制阵列微电极装置，包括顶部绝缘层、接触垫、柔性基底层、微型电极点和导电线路；所述的接触垫、微型电极点和导电线路设置在所述的顶部绝缘层和柔性基底层之间；所述的接触垫和微型电极点之间通过所述的导电线路电连接；所述的顶部绝缘层上设置有窗口部，所述的窗口部的位置与所述接触垫的位置对应；所述的接触垫透过所述的窗口部暴露在所述的顶部绝缘层之外；所述的柔性基底层使所述的神经鞘瘤术中载瘤神经走形绘制阵列微电极装置能够适应并稳定地贴合于神经与肿瘤的复杂界面。In order to achieve the above-mentioned purpose, the present invention provides an array microelectrode device for mapping the path of a tumor-bearing nerve during neurofibroma surgery, comprising a top insulating layer, a contact pad, a flexible base layer, microelectrode points and a conductive circuit; the contact pad, microelectrode points and conductive circuit are arranged between the top insulating layer and the flexible base layer; the contact pad and the microelectrode points are electrically connected through the conductive circuit; a window portion is arranged on the top insulating layer, and the position of the window portion corresponds to the position of the contact pad; the contact pad is exposed outside the top insulating layer through the window portion; the flexible base layer enables the array microelectrode device for mapping the path of a tumor-bearing nerve during neurofibroma surgery to adapt to and stably fit the complex interface between nerves and tumors.
优选地，所述的神经鞘瘤术中载瘤神经走形绘制阵列微电极装置包括32个微型电极点。Preferably, the array microelectrode device for mapping the course of the tumor-bearing nerve during schwannoma surgery comprises 32 microelectrode points.
优选地，所述柔性基底层的材质为光敏聚酰亚胺。Preferably, the flexible base layer is made of photosensitive polyimide.
优选地，所述顶部绝缘层的材质为聚酰亚胺。Preferably, the top insulating layer is made of polyimide.
优选地，所述微型电极点的面积为120×120μm2。Preferably, the area of the micro-electrode point is 120×120 μm2 .
优选地，当所述的神经鞘瘤术中载瘤神经走形绘制阵列微电极装置完全制备并暴露于磷酸盐缓冲液中时，其在1kHz的电化学阻抗将稳定地保持在100至400千欧的范围内。Preferably, when the schwannoma intraoperative tumor-bearing nerve mapping array microelectrode device 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 kilo-ohms.
优选地，所述神经鞘瘤术中载瘤神经走形绘制阵列微电极装置的长度为66mm，宽度为7mm。Preferably, the array microelectrode device for mapping the course of the tumor-bearing nerve during schwannoma surgery has a length of 66 mm and a width of 7 mm.
优选地，所述接触垫的尺寸为0.7×0.7mm2。Preferably, the contact pad has a size of 0.7×0.7 mm2 .
优选地，相邻的所述接触垫之间的横向间距为1.6mm，纵向间距为1.3mm。Preferably, the lateral spacing between adjacent contact pads is 1.6 mm, and the longitudinal spacing between adjacent contact pads is 1.3 mm.
优选地，所述的接触垫通过导电银浆或各向异性导电胶与外部电路连接。Preferably, the contact pad is connected to an external circuit via conductive silver paste or anisotropic conductive adhesive.
本发明提供一种神经鞘瘤术中载瘤神经走形绘制阵列微电极装置的制作方法，包括以下步骤：The present invention provides a method for manufacturing an array microelectrode device for mapping the path of a tumor-bearing nerve during a neurilemmoma operation, comprising the following steps:
S1、在一个四英寸的氧化硅晶片上旋涂一层光敏聚酰亚胺形成柔性基底，随后经过光刻技术图案化电极外形；S1, a layer of photosensitive polyimide is spin-coated on a four-inch silicon oxide wafer to form a flexible substrate, and then the electrode shape is patterned by photolithography technology;
S2、在电极旋涂双层光刻胶，紫外光刻图案化金属引线，利用磁控溅射技术从下到上依次溅射5纳米厚的铬、100纳米厚的金和5纳米厚的铬组成的金属层，最终利用剥离工艺(lift-off)形成金属导线；S2, spin-coating a double layer of photoresist on the electrode, patterning the metal lead by ultraviolet lithography, using magnetron sputtering technology to sputter a metal layer consisting of 5 nanometers thick chromium, 100 nanometers thick gold and 5 nanometers thick chromium from bottom to top, and finally using a lift-off process to form a metal wire;
S3、在电极上覆盖约4微米厚的第二层聚酰亚胺，作为顶部的绝缘层；S3, covering the electrode with a second layer of polyimide about 4 microns thick as an insulating layer on the top;
S4、进一步通过光刻技术图案化，以确定微型电极点4的精确位置并暴露微型电极点4；S4, further patterning by photolithography technology to determine the precise position of the micro-electrode point 4 and expose the micro-electrode point 4;
S5、制作过程中会在微型电极点的表面形成氧化层，使用40％的氢氟酸来去除氧化层，然后使所述的神经鞘瘤术中载瘤神经走形绘制阵列微电极装置从所述的氧化硅晶片上分离。S5. During the manufacturing process, an oxide layer is formed on the surface of the micro-electrode point. 40% hydrofluoric acid is used to remove the oxide layer, and then the array micro-electrode device for mapping the path of the tumor-bearing nerve during schwannoma surgery is separated from the oxide silicon wafer.
与现有技术相比，本发明的有益效果是：Compared with the prior art, the present invention has the following beneficial effects:
本发明所述的神经鞘瘤术中载瘤神经走形绘制阵列微电极装置是一种极具柔性和高密度的微电极阵列，其在神经鞘瘤手术中相较于传统临床术中神经监测(IONM)具有更加卓越的性能，能够灵敏捕捉神经信号的复杂时空模式，使得在整个手术过程中能够精确绘制出二维神经轨迹图。这种网格在高分辨率映射中的应用，以及其在不规则肿瘤表面上的卓越柔性和稳定附着性，表明其有潜力在提高神经外科干预和神经调控疗法方面发挥作用，从前庭神经鞘瘤案例扩展到更广泛的临床场景。The array microelectrode device for mapping the path of the tumor-bearing nerve during neurothema surgery described in the present invention is an extremely flexible and high-density microelectrode array, which has more excellent performance in neurothema surgery than traditional clinical intraoperative neuromonitoring (IONM), and can sensitively capture the complex spatiotemporal patterns of nerve signals, so that a two-dimensional nerve trajectory map can be accurately drawn throughout the operation. The application of this grid in high-resolution mapping, as well as its excellent flexibility and stable adhesion on irregular tumor surfaces, indicate that it has the potential to play a role in improving neurosurgical interventions and neuromodulation therapies, expanding from vestibular neurotherapies to a wider range of clinical scenarios.
附图说明BRIEF DESCRIPTION OF THE DRAWINGS
附图用来提供对本发明技术方案的进一步理解，并且构成说明书的一部分，与本申请的具体实施方式一起用于解释本发明的技术方案，并不构成对本发明技术方案的限制。The accompanying drawings are used to provide a further understanding of the technical solution of the present invention and constitute a part of the specification. Together with the specific implementation methods of the present application, they are used to explain the technical solution of the present invention and do not constitute a limitation on the technical solution of the present invention.
图1是本发明所述的神经鞘瘤术中载瘤神经走形绘制阵列微电极装置的结构示意图。FIG1 is a schematic structural diagram of an array microelectrode device for mapping the path of a tumor-bearing nerve during schwannoma surgery according to the present invention.
图2是所述的神经鞘瘤术中载瘤神经走形绘制阵列微电极装置的电极设计图。FIG. 2 is an electrode design diagram of the array microelectrode device for mapping the path of the tumor-bearing nerve during schwannoma surgery.
图3是所述微型电极点的局部放大示意图。FIG. 3 is a partial enlarged schematic diagram of the micro-electrode point.
图4是所述微型电极点的尺寸示意图。FIG. 4 is a schematic diagram showing the dimensions of the micro-electrode points.
图5是所述微型电极点和导电线路的部分尺寸示意图。FIG. 5 is a partial schematic diagram of the dimensions of the micro-electrode points and the conductive circuits.
图6是所述接触垫的尺寸示意图。FIG. 6 is a schematic diagram showing the dimensions of the contact pad.
图7是所述神经鞘瘤术中载瘤神经走形绘制阵列微电极装置的检测结果数据示意图。FIG. 7 is a schematic diagram of the detection result data of the array microelectrode device for mapping the shape of the tumor-bearing nerve during the schwannoma surgery.
具体实施方式Detailed ways
在下文中更详细地描述了本发明以有助于对本发明的理解。The present invention is described in more detail hereinafter to facilitate understanding of the present invention.
神经外科肿瘤手术所涉及的部位多为脑深部、精细且高度敏感的解剖结构，这使得手术变得极为棘手，特别是当肿瘤与重要神经或血管相邻时。有些时候，肿瘤与正常的神经组织的边界很难区分，进一步加剧了手术难度。神经功能障碍是术后的主要并发症之一，可能导致患者长期的功能障碍。在无法准确区分肿瘤和正常脑组织的情况下，这种风险变得尤为明显。例如，在前庭神经鞘瘤(VS)手术中，尽管这种肿瘤大多数是良性的，但由于其在颅内的复杂位置，其手术切除可能伴随着如听力下降、面神经功能损伤及平衡障碍等一系列的并发症。为了减少这种风险，术中神经电生理监测(IONM)已成为现代神经外科手术的标配。IONM为外科医生提供术中的神经监测，使其能够实时评估并保护神经功能，确保肿瘤得到彻底切除的同时最大程度地保留神经功能。Neurosurgery involves deep, delicate and highly sensitive anatomical structures in the brain, which makes the operation extremely difficult, especially when the tumor is adjacent to important nerves or blood vessels. Sometimes, the boundary between the tumor and normal nerve tissue is difficult to distinguish, which further increases the difficulty of the operation. Neurological dysfunction is one of the main complications after surgery and may cause long-term functional impairment in patients. This risk becomes particularly obvious when it is impossible to accurately distinguish between tumors and normal brain tissue. For example, in vestibular schwannoma (VS) surgery, although most of these tumors are benign, due to their complex location in the skull, their surgical resection may be accompanied by a series of complications such as hearing loss, facial nerve damage and balance disorders. In order to reduce this risk, intraoperative neurophysiological monitoring (IONM) has become a standard feature of modern neurosurgery. IONM provides surgeons with intraoperative neurological monitoring, enabling them to evaluate and protect neurological function in real time, ensuring that the tumor is completely removed while preserving neurological function to the greatest extent possible.
虽然目前的文献已经明确了IONM对提高手术疗效的重要性，但传统的IONM技术主要依赖于远场电位的监测，这仅仅能够为医生提供间接的神经结构和功能的评估。例如，在前庭神经鞘瘤(VS)的手术中，通过传统的硬电极刺激颅内面神经，医生可以诱导出面肌的面神经诱发电位，而脑干听觉诱发电位(BAEPs)则是基于听觉刺激而从头皮上记录下的电反应。由于头皮、颅骨及硬脑膜的电绝缘性，常常需要频繁的刺激以获得较高的信号噪声比(SNR)。此方法在实时检测神经损伤方面具有明显的局限性，并可能导致识别神经损伤的延迟。肿瘤的压迫可使面神经和听觉神经退变或变细，使其与肿瘤的界面变得更为模糊，进一步增加了鉴别肿瘤神经边界的难度。并且，由于头皮记录电极与手术区域有一定的物理距离，这大大限制了对神经通路时空、解剖和生理属性的精确监测，因此在肿瘤切除过程中对神经结构造成的潜在损伤风险增加。Although the current literature has clearly established the importance of IONM in improving surgical efficacy, traditional IONM technology mainly relies on monitoring of far-field potentials, which can only provide doctors with indirect assessment of neural structure and function. For example, in vestibular schwannoma (VS) surgery, doctors can induce facial nerve evoked potentials of facial muscles by stimulating the intracranial facial nerve with traditional hard electrodes, 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 obtain a high signal-to-noise ratio (SNR). This method has obvious limitations in real-time detection of neural injury and may lead to delays in identifying neural injury. Tumor compression can cause the facial nerve and auditory nerve to degenerate or become thinner, making their interface with the tumor more blurred, further increasing the difficulty of identifying the tumor nerve boundary. In addition, due to the physical distance between the scalp recording electrode and the surgical area, this greatly limits the precise monitoring of the spatiotemporal, anatomical, and physiological properties of the neural pathway, thereby increasing the risk of potential damage to neural structures during tumor resection.
为了克服这些挑战，本申请采用了一种革命性的技术：柔性微电极阵列。柔性微电极阵列凭借其优越的空间分辨率、稳健的导电特性和持久的电生理响应，在IONM中能够实现精确的不规则肿瘤表面的神经可视化。本申请所述的神经鞘瘤术中载瘤神经走形绘制阵列微电极装置能够实时地显示相应的神经全程走行，为手术中的高保真神经可视化树立了新的标杆，远远超越了传统的电生理监测方法。总之，本申请在前庭神经鞘瘤手术中提供了一个实时、精确的神经实时可视化平台，从而显著提高了手术后保留关键神经功能的成功率。To overcome these challenges, the present application adopts a revolutionary technology: flexible microelectrode arrays. With its superior spatial resolution, robust conductive properties, and persistent electrophysiological response, flexible microelectrode arrays can achieve accurate nerve visualization on irregular tumor surfaces in IONM. The array microelectrode device for mapping the course of tumor-bearing nerves during schwannoma surgery described in the present application can display the entire course of the corresponding nerve in real time, setting a new benchmark for high-fidelity nerve visualization during surgery, far surpassing traditional electrophysiological monitoring methods. In short, the present application provides a real-time and accurate nerve real-time visualization platform in vestibular schwannoma surgery, thereby significantly improving the success rate of retaining key nerve functions after surgery.
如图1至图6所示，本申请所述的神经鞘瘤术中载瘤神经走形绘制阵列微电极装置包括顶部绝缘层1、接触垫2、柔性基底层3、微型电极点4和导电线路5；所述的接触垫2、微型电极点4和导电线路5设置在所述的顶部绝缘层1和柔性基底层3之间；所述的接触垫2和微型电极点4之间通过所述的导电线路5电连接；所述的顶部绝缘层1上设置有窗口部11，所述的窗口部11的位置与所述接触垫2的位置对应；所述的接触垫2透过所述的窗口部11暴露在所述的顶部绝缘层1之外；所述的柔性基底层3使所述的神经鞘瘤术中载瘤神经走形绘制阵列微电极装置能够适应并稳定地贴合于神经与肿瘤的复杂界面。As shown in Figures 1 to 6, the array microelectrode device for mapping the path of the tumor-bearing nerve during neurofibroma surgery described in the present application includes a top insulating layer 1, a contact pad 2, a flexible base layer 3, a microelectrode point 4 and a conductive circuit 5; the contact pad 2, the microelectrode point 4 and the conductive circuit 5 are arranged between the top insulating layer 1 and the flexible base layer 3; the contact pad 2 and the microelectrode point 4 are electrically connected through the conductive circuit 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 array microelectrode device for mapping the path of the tumor-bearing nerve during neurofibroma surgery to adapt to and stably fit the complex interface between nerves and tumors.
该实施例中，微型电极点4的暴露通过光刻图案化实现，不设置对应的窗口部11。In this embodiment, the exposure of the micro-electrode points 4 is achieved by photolithography patterning, and no corresponding window portion 11 is provided.
优选地，所述的神经鞘瘤术中载瘤神经走形绘制阵列微电极装置包括32个微型电极点4，微型电极点4与接触垫数量相同且一一对应。Preferably, the array microelectrode device for mapping the path of the tumor-bearing nerve during schwannoma surgery comprises 32 microelectrode points 4, and the number of the microelectrode points 4 is the same as that of the contact pads and they correspond one to one.
优选地，所述柔性基底层3的材质为光敏聚酰亚胺。Preferably, the flexible base layer 3 is made of photosensitive polyimide.
优选地，所述顶部绝缘层1的材质为聚酰亚胺。Preferably, the top insulating layer 1 is made of polyimide.
优选地，所述微型电极点4的面积为120×120μm2。Preferably, the area of the micro-electrode point 4 is 120×120 μm2 .
优选地，当所述的神经鞘瘤术中载瘤神经走形绘制阵列微电极装置完全制备并暴露于磷酸盐缓冲液中时，其在1kHz的电化学阻抗将稳定地保持在100至400千欧的范围内。Preferably, when the schwannoma intraoperative tumor-bearing nerve mapping array microelectrode device 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 kilo-ohms.
优选地，所述神经鞘瘤术中载瘤神经走形绘制阵列微电极装置的长度为66mm，宽度为7mm。Preferably, the array microelectrode device for mapping the course of the tumor-bearing nerve during schwannoma surgery has a length of 66 mm and a width of 7 mm.
优选地，所述接触垫的尺寸为0.7×0.7mm2。Preferably, the contact pad has a size of 0.7×0.7 mm2 .
优选地，相邻的所述接触垫之间的横向间距为1.6mm，纵向间距为1.3mm。Preferably, the lateral spacing between adjacent contact pads is 1.6 mm, and the longitudinal spacing between adjacent contact pads is 1.3 mm.
优选地，所述的接触垫通过导电银浆或各向异性导电胶与外部电路连接。Preferably, the contact pad is connected to an external circuit via conductive silver paste or anisotropic conductive adhesive.
本发明提供了一种神经鞘瘤术中载瘤神经走形绘制阵列微电极装置，包括32通道微阵列电极，通过配套软件能够实现实时可视化。微阵列电极配备了32个微型电极点，每个微型电极点的面积为120×120μm2。其特异的柔性基底设计使其可以适应并稳定地贴合于神经与肿瘤的复杂界面，这对于神经鞘瘤手术中的应用尤为关键。The present invention provides an array microelectrode device for mapping the path of the tumor-bearing nerve during neurothelia surgery, including a 32-channel microarray electrode, which can be visualized in real time through supporting software. The microarray electrode is equipped with 32 microelectrode points, each of which has an area of 120×120μm2 . Its unique flexible substrate design allows it to adapt to and stably fit the complex interface between nerves and tumors, which is particularly critical for its application in neurothelia surgery.
本申请还提供一种神经鞘瘤术中载瘤神经走形绘制阵列微电极装置的制作方法，包括以下步骤：The present application also provides a method for manufacturing an array microelectrode device for mapping the path of a tumor-bearing nerve during schwannoma surgery, comprising the following steps:
S1、在一个四英寸的氧化硅晶片上旋涂一层光敏聚酰亚胺形成柔性基底，随后经过光刻技术图案化电极外形；S1, a layer of photosensitive polyimide is spin-coated on a four-inch silicon oxide wafer to form a flexible substrate, and then the electrode shape is patterned by photolithography technology;
S2、在电极旋涂双层光刻胶，紫外光刻图案化金属引线，利用磁控溅射技术从下到上依次溅射5纳米厚的铬、100纳米厚的金和5纳米厚的铬组成的金属层，最终利用剥离工艺(lift-off)形成金属导线；S2, spin-coating a double layer of photoresist on the electrode, patterning the metal lead by ultraviolet lithography, using magnetron sputtering technology to sputter a metal layer consisting of 5 nanometers thick chromium, 100 nanometers thick gold and 5 nanometers thick chromium from bottom to top, and finally using a lift-off process to form a metal wire;
S3、在电极上覆盖约4微米厚的第二层聚酰亚胺，作为顶部的绝缘层；S3, covering the electrode with a second layer of polyimide about 4 microns thick as an insulating layer on the top;
S4、进一步通过光刻技术图案化，以确定微型电极点4的精确位置并暴露微型电极点4；S4, further patterning by photolithography technology to determine the precise position of the micro-electrode point 4 and expose the micro-electrode point 4;
S5、制作过程中会在微型电极点的表面形成氧化层，使用40％的氢氟酸来去除氧化层，然后使所述的神经鞘瘤术中载瘤神经走形绘制阵列微电极装置从所述的氧化硅晶片上分离。S5. During the manufacturing process, an oxide layer is formed on the surface of the micro-electrode point. 40% hydrofluoric acid is used to remove the oxide layer, and then the array micro-electrode device for mapping the path of the tumor-bearing nerve during schwannoma surgery is separated from the oxide silicon wafer.
由于神经鞘瘤手术的复杂性，为了实现神经走形的精确定位和可视化，经常需要进行多次神经电刺激和电生理信号的检测。在此背景下，本申请介绍了一种新型电极设计，即柔性微电极阵列。与传统电极相比较，本申请提出的柔性微电极阵列配备了32个微型电极点，每个微型电极点的面积为120×120μm2，其特异的柔性基底设计，使其可以适应并稳定地贴合于神经与肿瘤的复杂界面，这对于神经鞘瘤手术中的应用尤为关键。Due to the complexity of schwannoma surgery, multiple nerve electrical stimulations and electrophysiological signal detections are often required to achieve accurate positioning and visualization of the nerve path. In this context, this application introduces a new electrode design, namely a flexible microelectrode array. Compared with traditional electrodes, the flexible microelectrode array proposed in this application is equipped with 32 microelectrode points, each with an area of 120×120μm2 . Its specific flexible substrate design allows it to adapt to and stably fit the complex interface between nerves and tumors, which is particularly critical for its application in schwannoma surgery.
如图7所示，本申请所述的神经鞘瘤术中载瘤神经走形绘制阵列微电极装置的检测结果显示，相较于其他部位，神经处的标准化信号有显著差异。配合软件形成彩色温度图，依据标准化信号强度能够清晰地描绘神经区域。As shown in Figure 7, the detection results of the array microelectrode device for mapping the path of the tumor-bearing nerve during schwannoma surgery described in this application show that the standardized signal at the nerve is significantly different compared with other parts. The color temperature map is formed with the software, and the nerve area can be clearly depicted according to the standardized signal intensity.
申请人在研发过程中发现，通过在前庭神经鞘瘤表面放置微电极，快速收集面神经和耳神经数据，能够提高这些记录的保真度并减少所需试验次数，从而实现实时时空映射。此外，通过使用高通道计数的微电极阵列进行记录，将生成二维(2D)神经通路示意图，有助于在前庭神经鞘瘤手术过程中更精确地识别切除部位的神经轨迹。During the research and development process, the applicant found that by placing microelectrodes on the surface of the vestibular schwannoma and quickly collecting facial nerve and ear nerve data, the fidelity of these recordings can be improved and the number of required trials can be reduced, thereby achieving real-time spatiotemporal mapping. In addition, by recording with a high-channel count microelectrode array, a two-dimensional (2D) neural pathway diagram will be generated, which will help to more accurately identify the nerve trajectory of the resection site during vestibular schwannoma surgery.
为了应对现有技术中的挑战，申请人设计了以上所述的具有卓越空间分辨率、可靠导电性和稳定电特性的柔性微电极阵列，在术中神经监测(IONM)期间能够更好地适应不规则肿瘤表面。这种高分辨率神经边界是目前电生理监测技术无法达到的。为了实现神经通路的实时可视化，申请人独立开发了一款配套的软件程序。当数据分析和绘图实时整合时，这项技术可以提供几乎即时的IONM方法。总之，本申请的柔性微电极网格可以增强IONM，还可能应用于其他领域。In order to meet the challenges in the prior art, the applicant has designed the above-mentioned flexible microelectrode array with excellent spatial resolution, reliable conductivity and stable electrical properties, which can better adapt to the irregular tumor surface during intraoperative nerve monitoring (IONM). This high-resolution nerve boundary is not achievable by current electrophysiological monitoring technology. In order to achieve real-time visualization of neural pathways, the applicant independently developed a matching software program. When data analysis and drawing are integrated in real time, this technology can provide an almost instant IONM method. In short, the flexible microelectrode grid of the present application can enhance IONM and may also be applied to other fields.
以上描述了本发明优选实施方式，然其并非用以限定本发明。本领域技术人员对在此公开的实施方案可进行并不偏离本发明范畴和精神的改进和变化。The above describes the preferred embodiments of the present invention, but it is not intended to limit the present invention. Those skilled in the art may make improvements and changes to the embodiments disclosed herein without departing from the scope and spirit of the present invention.
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