CN113366653A - 用于测量电生理信号的石墨烯晶体管*** - Google Patents
用于测量电生理信号的石墨烯晶体管*** Download PDFInfo
- Publication number
- CN113366653A CN113366653A CN201980072941.7A CN201980072941A CN113366653A CN 113366653 A CN113366653 A CN 113366653A CN 201980072941 A CN201980072941 A CN 201980072941A CN 113366653 A CN113366653 A CN 113366653A
- Authority
- CN
- China
- Prior art keywords
- signal
- graphene
- transistor
- voltage
- frequency
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 title claims abstract description 47
- 229910021389 graphene Inorganic materials 0.000 title claims abstract description 44
- 239000000463 material Substances 0.000 claims abstract description 8
- 238000012545 processing Methods 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 18
- 238000012546 transfer Methods 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 230000007831 electrophysiology Effects 0.000 claims 2
- 238000002001 electrophysiology Methods 0.000 claims 2
- 230000005669 field effect Effects 0.000 abstract description 10
- 238000003491 array Methods 0.000 abstract description 8
- 235000012174 carbonated soft drink Nutrition 0.000 description 27
- 230000001054 cortical effect Effects 0.000 description 17
- 210000004556 brain Anatomy 0.000 description 10
- 230000000694 effects Effects 0.000 description 7
- 230000001629 suppression Effects 0.000 description 7
- 238000005516 engineering process Methods 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 108050002340 Annexin A13 Proteins 0.000 description 5
- 239000000523 sample Substances 0.000 description 4
- 229910021607 Silver chloride Inorganic materials 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 238000007428 craniotomy Methods 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 238000000537 electroencephalography Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 230000028161 membrane depolarization Effects 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 241000700159 Rattus Species 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 230000007177 brain activity Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 210000003792 cranial nerve Anatomy 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 230000010355 oscillation Effects 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 230000010287 polarization Effects 0.000 description 2
- 238000012805 post-processing Methods 0.000 description 2
- 230000001902 propagating effect Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 239000010703 silicon Substances 0.000 description 2
- 229910052709 silver Inorganic materials 0.000 description 2
- 239000004332 silver Substances 0.000 description 2
- 210000004092 somatosensory cortex Anatomy 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010010071 Coma Diseases 0.000 description 1
- 101000959674 Homo sapiens Annexin A13 Proteins 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 239000004642 Polyimide Substances 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 210000001130 astrocyte Anatomy 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 239000013060 biological fluid Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000005684 electric field Effects 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000005153 frontal cortex Anatomy 0.000 description 1
- 238000002599 functional magnetic resonance imaging Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 230000002102 hyperpolarization Effects 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000000879 optical micrograph Methods 0.000 description 1
- 238000002161 passivation Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001721 polyimide Polymers 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Images
Classifications
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01L—SEMICONDUCTOR DEVICES NOT COVERED BY CLASS H10
- H01L29/00—Semiconductor devices specially adapted for rectifying, amplifying, oscillating or switching and having potential barriers; Capacitors or resistors having potential barriers, e.g. a PN-junction depletion layer or carrier concentration layer; Details of semiconductor bodies or of electrodes thereof ; Multistep manufacturing processes therefor
- H01L29/66—Types of semiconductor device ; Multistep manufacturing processes therefor
- H01L29/68—Types of semiconductor device ; Multistep manufacturing processes therefor controllable by only the electric current supplied, or only the electric potential applied, to an electrode which does not carry the current to be rectified, amplified or switched
- H01L29/76—Unipolar devices, e.g. field effect transistors
- H01L29/772—Field effect transistors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
- A61B5/30—Input circuits therefor
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
- A61B5/25—Bioelectric electrodes therefor
- A61B5/263—Bioelectric electrodes therefor characterised by the electrode materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
- A61B5/25—Bioelectric electrodes therefor
- A61B5/279—Bioelectric electrodes therefor specially adapted for particular uses
- A61B5/291—Bioelectric electrodes therefor specially adapted for particular uses for electroencephalography [EEG]
- A61B5/293—Invasive
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
- A61B5/316—Modalities, i.e. specific diagnostic methods
- A61B5/318—Heart-related electrical modalities, e.g. electrocardiography [ECG]
- A61B5/367—Electrophysiological study [EPS], e.g. electrical activation mapping or electro-anatomical mapping
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
- A61B5/316—Modalities, i.e. specific diagnostic methods
- A61B5/369—Electroencephalography [EEG]
- A61B5/37—Intracranial electroencephalography [IC-EEG], e.g. electrocorticography [ECoG]
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/403—Cells and electrode assemblies
- G01N27/414—Ion-sensitive or chemical field-effect transistors, i.e. ISFETS or CHEMFETS
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
- A61B2562/02—Details of sensors specially adapted for in-vivo measurements
- A61B2562/0209—Special features of electrodes classified in A61B5/24, A61B5/25, A61B5/283, A61B5/291, A61B5/296, A61B5/053
- A61B2562/0217—Electrolyte containing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
- A61B2562/04—Arrangements of multiple sensors of the same type
- A61B2562/046—Arrangements of multiple sensors of the same type in a matrix array
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
- A61B5/242—Detecting biomagnetic fields, e.g. magnetic fields produced by bioelectric currents
- A61B5/245—Detecting biomagnetic fields, e.g. magnetic fields produced by bioelectric currents specially adapted for magnetoencephalographic [MEG] signals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
- A61B5/316—Modalities, i.e. specific diagnostic methods
- A61B5/369—Electroencephalography [EEG]
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Physics & Mathematics (AREA)
- Molecular Biology (AREA)
- Pathology (AREA)
- General Health & Medical Sciences (AREA)
- Biomedical Technology (AREA)
- Biophysics (AREA)
- Heart & Thoracic Surgery (AREA)
- Surgery (AREA)
- Animal Behavior & Ethology (AREA)
- Medical Informatics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Microelectronics & Electronic Packaging (AREA)
- Chemical & Material Sciences (AREA)
- General Physics & Mathematics (AREA)
- Power Engineering (AREA)
- Immunology (AREA)
- Biochemistry (AREA)
- Analytical Chemistry (AREA)
- Electrochemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Condensed Matter Physics & Semiconductors (AREA)
- Cardiology (AREA)
- Physiology (AREA)
- Psychology (AREA)
- Psychiatry (AREA)
- Neurosurgery (AREA)
- Computer Hardware Design (AREA)
- Ceramic Engineering (AREA)
- Investigating Or Analyzing Materials By The Use Of Electric Means (AREA)
- Measurement And Recording Of Electrical Phenomena And Electrical Characteristics Of The Living Body (AREA)
Abstract
本发明的目的基于石墨烯溶液门控型场效应晶体管(gSGFET)的柔性表皮层和皮层内阵列,其能够记录超慢信号以及典型的局部场电势带宽中的信号。本发明的目的基于用于测量电生理信号的石墨烯晶体管***,其包括处理单元和至少一个石墨烯晶体管(gSGFET),该石墨烯晶体管包括石墨烯作为通过两个端子接触的沟道材料,在晶体管(gSGFET)的漏极和源极端子上的可调谐电压源称为栅极电压,并且至少一个滤波器被配置为从晶体管获取信号并将信号分成至少两个频带,低频带和高频带,其中第一信号和第二信号分别以增益值放大。
Description
技术领域
本发明的目的属于物理技术领域,更确切地说,属于测量电信号。
本发明的目的在于用于测量和记录某些电生理信号的装置和使用所述装置的方法。
背景技术
迫切需要具有宽的电生理记录带宽的柔性,大规模和高密度的阵列。灵活,大规模和高密度的电极阵列是最新技术。但是,这些阵列不能在电生理信号的整个频率带宽中提供高保真记录。
电生理信号的频率和振幅范围很广:从分钟长的高振幅信号(如皮层扩展抑制)到毫秒长的微伏尖峰。以高时空分辨率记录完整范围的电生理信号将有助于揭示其关系和相互作用,并确保不会丢失任何有意义的信息。
大多数微电极阵列遭受电压漂移和振荡的影响,该电压漂移和振荡会影响其超慢信号的记录性能,该超慢信号的频率低于0.1Hz。众所周知,大多数记录***都包括高通滤波器,以解决由于基线漂移而引起的饱和问题,其代价是不能记录潜在的生理和病理学信息。
在过去的几年中,人们对脑活动在频率低于0.1Hz时的波动特别感兴趣,这种频率通常被称为非常慢、极慢或超慢活动(ISA)。建议它们指示脑部状态(例如睡眠,麻醉,昏迷,清醒),并在功能性磁共振成像中与静息状态网络相关。它们还可能极大地促进了在生理信号的时间过程中观察到的高可变性。
有一些报道的超慢信号,例如仅以非常低的频率记录的称为“皮质扩展抑制(CSD)”的皮质传播波,因此由于电流电极的阻碍,很难以习惯的方式研究它们。CSD被定义为神经元和星形胶质细胞的去极化缓慢传播波,随后一段时期的大脑活动受到抑制,并且通常在发生脑部发作时触发,例如在患有血管性或外伤性脑中风以及偏头痛和其他脑部疾病的患者中。监视或检测它们可以改善诊断,但最重要的是会影响疗法变化。
传统上已使用非侵入性技术(例如脑电图(EEG)和磁脑电图(MEG))来执行包括亚低频在内的全频带记录。但是,它们有限的空间分辨率和平均信号带来了严重的局限性;例如单凭EEG仍不足以进行非侵入性CSD检测。由于这些原因,侵入性电生理技术是最常用的记录超慢脑电波的技术。
正确记录ISA需要使用直接耦合放大器和极其稳定且低阻抗的侵入电极。传统上,使用液体填充的玻璃微量移液器,仅允许进行一点或几点测量。为了获得更高的空间分辨率和映射,可以使用不可极化的银/氯化银(Ag/AgCl)电极,这样可以防止界面处的电荷积聚,从而防止电压漂移。然而,由于银的毒性,将这种电极用于人或慢性动物体内监测不是一种选择。尽管尚未发现能够提供与Ag/AgCl电极相当的性能的替代微电极材料,但它促进了对低阻抗和漂移的替代微电极材料的研究。因此,目前人类的ISA记录是使用铂电极进行的,由于伪像和瞬变,这对CSD检测提出了挑战。重要的是,以亚低频率出现的基线振荡形式的基线漂移会妨碍其“真实”特性(例如幅度或波形)的确定,因为用于消除这种影响的任何高通滤波器都会改变信号的形状。
微电极技术的另一个固有局限性是基于微电极阻抗与记录设备的输入阻抗(分别为Z′e和Z′a)之间的关系。
记录的信号(Vin)由两个阻抗形成的分压器确定:
等式(1)暗示当Z′a实质上不大于Z′c时,相对于Vsig,记录的信号将被衰减和延迟。即使使用高输入阻抗放大器,对于直径为50μm的金微电极,其衰减也有望超过50%。重要的是要强调指出,由于电极阻抗与其面积成反比关系而导致对记录信号的高通滤波,当电极面积按比例缩小时,达到等于1的电压增益的Z′a>>Z′e要求受到了损害。
因此,由于相关的电极阻抗增加,电极尺寸的小型化以实现更高的空间分辨率会导致对ISA进行固有的高通滤波。
侵入性光学技术(例如钙成像)也用于监视ISA,但如今仍面临着解决大量神经元24,25高频活动的严峻挑战,其固有的指标需求限制了向临床的转化。因此,仍缺少在潜在的完全可植入,无毒,临床规模的***中允许测量包括超慢频率在内的大规模,高时空分辨率记录的技术。
除了常用的微电极技术外,用场效应晶体管(FET)记录电生理信号还具有许多优点,包括由于其固有的电压至电流放大功能而对环境噪声较不敏感,并且可以轻松进行多路复用26。尽管如此,将高栅极电容和载流子迁移率硅FET与柔性材料结合在一起的困难历来阻碍了其在体内记录中的使用。已经提出了石墨烯溶液门控型场效应晶体管(gSGFET)以潜在地克服大多数先前的缺点。石墨烯的柔韧性使gSGFET可以嵌入超柔软和柔性的基材中,而不会损失性能,而其宽的电化学窗口和生物相容性则使其可以直接与生物体液和组织接触,并确保在体内条件下的安全操作。此外,石墨烯的二维性质可提供最高的表面积与体积之比,从而使石墨烯对其表面的电荷非常敏感。重要的是,gSGFET跨导的频率响应在包括亚低频率在内的宽带宽内是平坦的。
另一方面,基于石墨烯的溶液门控型场效应晶体管(G-SgFET)已作为各种分析物的潜在生物传感器得到了广泛研究,例如在WO2011004136A1中公开了一种用于检测至少一个生物分子的存在的传感器和用于生产这种传感器的方法,该传感器包括图案化的石墨烯结构,布置成与图案化的石墨烯结构接触以确定电导率的至少两个电触点;以及至少一个连接至所述图案化的石墨烯结构的至少部分的接头,其中所述至少一个接头对所述至少一个生物分子具有结合亲和力。
发明概述
本发明解决了对具有宽的电生理记录带宽的柔性,大规模和高密度阵列的需求。本发明的目的是基于石墨烯溶液门控型场效应晶体管(gSGFET),优选地是石墨烯溶液门控型场效应晶体管(gSGFET)的阵列,其能够记录超慢信号以及典型局部场电势带宽中的信号。优选将石墨烯溶液门控型场效应晶体管(gSGFET)放置在表皮位置和皮层内位置。
本发明通过提供由石墨烯的电化学惰性产生的大大增加的基线稳定性,同时克服了现有技术中仍然存在的挑战,因为通过使用晶体管作为记录元件,其还超过了由于电极记录***中存在的阻抗除数而引起的信号衰减。
本发明的石墨烯溶液门控型场效应晶体管(gSGFET)是使用挠性基板制造的,以克服适应不同生物结构的几何形状的困难,因此优选石墨烯溶液门控型场效应晶体管(gSGFET)是挠性的。同样,当以阵列布置时,所述阵列以可扩展的方式设计,使得可以针对不同种类的电触点(例如位于组织表面(与穿透组织相反)上的那些),根据需要将晶体管从微型级放大到宏观级。
因此,本发明的用于测量电生理信号的石墨烯晶体管***包括处理单元,以及至少一个包含石墨烯作为沟道材料的石墨烯晶体管(gSGFET),该沟道材料通过两个端子接触,在晶体管(gSGFET)的漏极端子和源极端子上的可调电压源指的是栅极电压,并且
与至少一个滤波器(104[V/A]的低通滤波器(LPF),被配置为产生频率设置为0Hz至0.16Hz的低通滤波带,或者增益为106[V/A]的带通滤波器(BPF),被配置为产生具有在0.16Hz和10kHz之间的频率的频带滤波的频带),被配置为获取来自晶体管的信号并将来自晶体管的信号分成至少两个频带,低频带和高频带,连接;并且是分别以增益值放大的第一信号和第二信号。
本发明的方法和相关设备通过提供信号的放大以及在记录位置处测量晶体管传递曲线的能力来满足本领域中的上述需求。这样既可以选择晶体管的最佳工作点,又可以应用校准方法(已记录信号的电流到电压转换),以确保在宽的带宽中进行高保真记录。
本发明目的的主要应用是在研究或临床实施中,例如在神经病学中,监视全频带脑信号。这些相同的优势适用于脑外其他生物***,例如心脏、肾脏、胃、颅神经和其他区域。石墨烯晶体管阵列的灵活性和多功能性允许多种应用和部署,范围从硬膜下,硬膜外和皮质内装置到脑、外周和颅神经、心脏、血管、脊髓和其他生物结构或类似于脑电图的非侵入性的其他位置放置。
附图说明
为了补充进行的描述并且为了帮助更好地理解本发明的特征,根据本发明的实际实施方案的优选实施例,附有一组附图作为所述描述的组成部分,其中,已如下表示说明书和非限制性的字符:
图1a-1g示出了:柔性石墨烯溶液门控型场效应晶体管阵列技术及其表征的表示。1a:以共栅模式极化的石墨烯晶体管的示意图。1b:4×4gSGFET阵列和15通道皮层内阵列的有效区域的光学显微镜图像。1c:神经探针的照片。1d:在10mM磷酸盐缓冲盐水(PBS)中,漏源电压偏置(Vds)为50mV的情况下,100x50-μm2gSGFET阵列的稳态特性。1d:该曲线图示出了gSGFET传递曲线,漏极-源极电流(Ids)与栅极-源极电压(Vgs)以及均值(深色曲线)和标准偏差(较亮的曲线)。箱线图插图显示了电荷中性点分散度(中线,中位数;箱形极限,上下四分位数)。1e:阵列中所有gSGFET的泄漏电流(Igs)的曲线图。1f:gSGFET的传递曲线(蓝色正方形和直线)及其一阶导数(跨导(gm),黑色线)的曲线图形。1g:传递曲线的两个不同点处的跨导频率响应的曲线图;(e):Vgs低于CNP(绿色),其中gm为负,导致信号反转(相位为180°);Vgs高于CNP(橙色),其中gm为正,因此不会反转(相位为0°)。gm的模块与gSGFET极化的传递曲线的分支无关,gm的模块类似于宽带宽(≈0-1kHz)的稳态值。
图2a至图2d示出了本发明的示例性实施方案,其结合了gSGFET,定制电子电路和后处理方法,还作为所记录信号的实施例:神经信号的超低,局部场电势和宽带体内gSGFET记录。图2a是gSGFET记录设置和信号后处理方法的示意图。定制电子电路用于执行体内表征(传递曲线),并在低通滤波(LPF)频带和带通滤波(BPF)频带中记录晶体管电流。从这两个信号的组合并考虑电流到电压的转换,可以获得宽带信号((Vsig)。图2b,在诱导四个CSD事件期间用gSGFET表皮层阵列获得的电生理记录(蓝色阴影)。从上至下:当前的LPF信号,当前的BPF和电压转换的宽带信号。
图3示出了定制电子电路的示例性实施方案。a,用于控制gSGFETS极化(Vgs,Vds)并以不同方式放大上述两个频带的定制电子仪器的示意图:LPF(≈0-0.16Hz,增益=104)和BPF(0.16Hz-10kHz,增益=106)。我们使用定制的电子仪器来表征gSGFET的稳态行为以及石墨烯晶体管的AC调制。
图4显示了gSGFET电流记录以恢复栅极处的电压信号的校准过程。a,通过参考电极施加的10Hz,0.85mV峰值正弦门信号的gSGFET电流记录。石墨烯晶体管的偏置电压为Vds=50mV和Vgs=250mV。b,相同石墨烯晶体管在Vds=50mV时的传递曲线。虚线表示在a中使用的Vgs偏置电压。c,通过将每个晶体管的电流信号(a)内插到其相应的传递曲线并去除Vgs偏移获得的电压信号。
图5显示了用石墨烯晶体管绘制的皮层扩展抑制。a,在发生CSD事件期间,由4x4、400μm网格间距,gSGFET阵列(黑线)记录的亚低频率信号,如左上图所示。等高线图显示了CSD发作相对于平均时间的时延,说明了CSD的时空过程。b,内插空间电压图,显示了由gSGFET阵列测量的同一CSD事件的传播。a,b包括0.1Hz的高通滤波记录(a中的红线和b中的底部空间电压图),以说明常规微电极记录中信号信息的丢失。
图6a,6b描绘了由大鼠皮层中的皮层扩展抑制引起的亚低频电压变化的深度曲线。a,制作的15通道石墨烯皮质内探针的布局和有序的局部场电势记录。发生CSD事件期间的亚低频记录(黑线)。虚线是从附近的晶体管内插的。b,CSD事件期间,大鼠皮层深度处的超慢变化的时间过程的彩色图。a-b,包含以0.1Hz高通滤波的相同信号(红线)及其时空彩色图,以说明常规微电极记录中信息的丢失。
发明详述
本发明的第一方面旨在用于记录诸如皮质扩展抑制(CSD)信号之类的电生理学超慢信号的***,即频率值低于0.1Hz的那些信号;该装置包括与该装置相关联或嵌入在该装置中的处理单元,以及至少一个石墨烯晶体管(gSGFET),优选为石墨烯晶体管的阵列,该石墨烯晶体管包括石墨烯作为通过源极和漏极端子接触的沟道材料,并以参考作为栅极端子。所述石墨烯晶体管至少连接到诸如低通滤波器(LPF)的滤波器。使用记录到记录开始的晶体管传递曲线Ids-Vgs,将记录的电流信号转换成电压信号。
在本发明的替代实施方案中,至少一个带通滤波器(BPF)与低通滤波器(LPF)一起以顺序或级联布置的方式布置。但两个滤波器(LPF,BPF)的配置均应使各自的切割点具有相同的值。
gSGFETS是这样一种装置,其中石墨烯用作沟道材料,与两条金属引线(源极和漏极端子)接触,并浸入电解液中,其中参考电极用作栅极端子(图1a)。产生了包含皮层和皮层内设计的gSGFET的阵列的柔性探针。尤其是,设计了一个100μm宽×50μm长的4x4阵列用于皮层记录,而由15个石墨烯沟道(80μm宽,30μm长)的线性阵列组成的设计用于皮层内记录(图1b)。两种阵列设计均在涂覆在4英寸硅晶圆上的10μm厚的聚酰亚胺层上制作。柔性的gSGFET阵列放置在零***力连接器中,用于与记录电子设备接口(图1c)。使用固定的漏极-源极电压(V_ds)测量每个阵列中所有gSGFET的传递曲线、漏极电流(I_ds)与栅极-源极电压(V_gs)。电荷中性点的色散(CNP=243.6±6.1mV)是传递曲线的最小值,表明了晶体管的均匀性(图1d)。重要的是,由于V_gs和V_ds偏置是共享的,因此小CNP色散允许同一阵列中所有gSGFET的接近最佳记录性能。图1e显示了阵列中所有gSGFET的泄漏电流总和(I_gs),在整个电压扫描过程中,泄漏电流的总和处于nA范围内,这表明钝化层具有良好的绝缘性,并且石墨烯的反应性可忽略不计。此外,我们测量了gSGFET的跨导(gm)的频率响应,这表明了信号耦合的效率在包括亚低频在内的宽带宽中获得了恒定值(图1f-g)。如果Vgs值的负gm低于CNP,则在这种偏置下测得的信号会发生反相(180°相位)。对于高于CNP的Vgs值,将保留信号相位。
将本发明的装置与常规的高通滤波记录进行比较,为此,对使用4×4表皮gSGFET阵列的皮质扩散抑制(CSD)事件的传播进行映射,然后与在常规的高通滤波记录中观察到的进行比较(图5a-b)。用gSGFET阵列记录整个CSD事件表明,尽管所有gSGFET的负移发作都相似,但随后的恢复变化更多,某些晶体管的第二负移幅度比第一负移幅度高。在恢复的和仍然受抑制的大脑区域共存的gSGFET记录的空间图(图5b)的最后一帧(分别对应于80s和90s)中也可以观察到这种效果。重要的是,该信息在常规的微电极记录中会丢失,在传统的微电极记录中,由于记录电子设备中的高通滤波器,仅会观察到CSD发作。以下结果涉及从体感皮层的两个不同受试者收集的10个CSD的样本:我们发现CSD事件的平均持续时间为47.24±7.65s,传播速度为7.68±1.35mm/min,与将CSD定义为超慢脑波的文献一致。
为了进一步说明本发明的装置的潜力并利用该技术提供的设计多功能性,设置了跨越整个皮质深度的15gSGFET的线性阵列(图6a)。从有序记录或时空电压图(图6b),可以看出CSD是如何在整个皮质深度发生的。这些结果凸显了本发明的装置揭示皮质中超慢信号的丰富模式的能力。在这种特殊情况下,可以清楚地观察到从表层长的去极化到较短的去极化的过渡,在之前和之后在较深的层中发生了超极化。这种与深度有关的效应的起因尚未得到很好的理解,将成为利用gSGFET技术已证明的能力以高空间分辨率监测ISA的进一步研究的目标。
在本发明的第二方面中,提供了用于记录超慢大脑信号的方法,该超慢信号是那些频率值低于0.1Hz的超慢信号,选择了皮层扩展抑制(CSD)来说明本发明的目的在以宽带宽进行记录的能力。实验上,在异氟烷麻醉的Wistar大鼠的左半球进行了两次颅骨切开术:在主要的体感皮层进行了较大的开颅手术,在该处放置了皮层探头,在额叶皮层中进行了较小的开颅,在局部施用了5mM KCl来诱导CSD(图2b)。定制的电子电路使我们可以同时记录两个频带:具有不同增益的低通滤波频带(LPF,≈0-0.16Hz)和带通滤波频带(BPF,0.16Hz-10kHz)(分别为104和106),避免分别由于高振幅CSD信号造成的放大器饱和。在第一组实验中,我们在诱发CSD事件的过程中用皮层gSGFET阵列记录了LPF和BPF电流信号(图2c)。石墨烯晶体管在空穴传导状态下被极化,即Vgs<CNP(负gm);因此,记录的LPF和BPF电流信号相对于在栅极处出现的电压信号反相。LPF信号显示非常缓慢的CSD事件,而BPF信号对应于局部电场电势,揭示了皮质扩散抑制所特有的活动静默。在对LPF和BPF信号求和后,将电流转换为电压信号(使用在开始记录之前在体内记录的晶体管传递曲线Ids-Vgs),可以获得宽带电生理信号(请参见图2a,c)。在每次CSD事件中,通常会在抑制之前出现1-2mV的小正移,此后立即观察到急剧的负变化(≈-20mV),此变化在接下来的一分钟左右会缓慢恢复。CSD相关的高频活动静默及其逐步恢复如图2d的电压波和频谱图所示。
Claims (7)
1.用于测量电生理信号的石墨烯晶体管***,包括:
a.处理单元,以及
b.至少一个石墨烯晶体管(gSGFET),其包含石墨烯作为通过两个端子接触的沟道材料,
其特征在于所述装置包括连接至石墨烯晶体管(gSGFET)的以下部件:
a.晶体管(gSGFET)的漏极端子和源极端子上的可调电压源,称为栅极电压,以及
b.至少一个滤波器,其配置为从晶体管获取信号并将所述信号分成至少两个频带,即低频带和高频带,其中,第一信号和第二信号分别以增益值放大。
2.根据权利要求1所述的用于测量电生理学的石墨烯晶体管***,其中,所述滤波器配置为生成以下之一:
a.低通滤波频带,其频率设置在0Hz到0.16Hz之间,以及
b.频率介于0.16Hz到10kHz之间的经过频带滤波的频带。
3.根据权利要求2所述的用于测量全频带电生理学的石墨烯晶体管***,其中,所述低通滤波器(LPF)和所述带通滤波器(BPF)具有不同的增益;分别为104[V/A]和106[V/A]。
4.使用权利要求1-3中任一项所述的石墨烯晶体管***测量电生理信号的方法,其特征在于包括:
a.通过所述滤波器将输入信号分为频率信号和高频信号,
b.合并由相应增益加权的低频信号和高频信号,以及
c.根据晶体管的固有增益将信号转换为电压。
5.根据权利要求4所述的方法,其中,对于每个信号,所述放大的增益值是不同的。
6.根据权利要求4所述的方法,其中,通过使用石墨烯晶体管传递曲线Ids-Vgs的插值,执行向电压信号的转换。
7.根据权利要求6所述的方法,其中,以固定的漏极-源极电压(V_ds)产生所述晶体管传递曲线Ids-Vgs。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ESP201831068 | 2018-11-06 | ||
ES201831068A ES2759053B2 (es) | 2018-11-06 | 2018-11-06 | Sistema de transistores de grafeno para medir señales electrofisiológicas. |
PCT/ES2019/070728 WO2020094898A1 (es) | 2018-11-06 | 2019-10-28 | Sistema de transistores de grafeno para medir señales electrofisiológicas |
Publications (1)
Publication Number | Publication Date |
---|---|
CN113366653A true CN113366653A (zh) | 2021-09-07 |
Family
ID=70483270
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201980072941.7A Pending CN113366653A (zh) | 2018-11-06 | 2019-10-28 | 用于测量电生理信号的石墨烯晶体管*** |
Country Status (6)
Country | Link |
---|---|
US (1) | US20210345930A1 (zh) |
EP (1) | EP3879582A4 (zh) |
JP (1) | JP2022511125A (zh) |
CN (1) | CN113366653A (zh) |
ES (1) | ES2759053B2 (zh) |
WO (1) | WO2020094898A1 (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP7048972B2 (ja) * | 2018-11-09 | 2022-04-06 | 国立研究開発法人理化学研究所 | 皮質脳波電極、脳活動処理システム、及び脳活動処理方法 |
EP3970614A1 (en) | 2020-09-17 | 2022-03-23 | Consejo Superior De Investigaciones Científicas (CSIC) | Acquisition device to limit leakage current in electrophysiological signal recording devices |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20140094674A1 (en) * | 2011-03-17 | 2014-04-03 | Brown University | Implantable wireless neural device |
CN103901089A (zh) * | 2014-04-16 | 2014-07-02 | 国家纳米科学中心 | 检测神经细胞电生理信号的传感器及制作方法和检测方法 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3826243A (en) * | 1972-07-10 | 1974-07-30 | W Anderson | Brainwave analysis and feedback method and apparatus |
US4417590A (en) * | 1978-06-09 | 1983-11-29 | Beckman Instruments, Inc. | Electroencephalograph |
WO2009090567A1 (en) * | 2008-01-11 | 2009-07-23 | Koninklijke Philips Electronics N.V. | Method and support system for presenting electrophysiological measurements |
GB2471672B (en) * | 2009-07-07 | 2015-12-09 | Swansea Innovations Ltd | Graphene biosensor |
WO2013123358A1 (en) * | 2012-02-17 | 2013-08-22 | Massachusetts Institute Of Technology | Multi-channel scalable eeg acquisition system on a chip with integrated patient specific seizure classification and recording processor |
US10206602B2 (en) * | 2017-04-05 | 2019-02-19 | LR Technologies, Inc. | Hybrid electromagnetic field signal detection system for human bioelectrical signal monitoring |
GB201801828D0 (en) * | 2018-02-05 | 2018-03-21 | Imperial Innovations Ltd | Analysis of spreading depolarization waves |
-
2018
- 2018-11-06 ES ES201831068A patent/ES2759053B2/es active Active
-
2019
- 2019-10-28 WO PCT/ES2019/070728 patent/WO2020094898A1/es unknown
- 2019-10-28 CN CN201980072941.7A patent/CN113366653A/zh active Pending
- 2019-10-28 EP EP19881753.8A patent/EP3879582A4/en active Pending
- 2019-10-28 JP JP2021549923A patent/JP2022511125A/ja active Pending
-
2021
- 2021-05-06 US US17/313,469 patent/US20210345930A1/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20140094674A1 (en) * | 2011-03-17 | 2014-04-03 | Brown University | Implantable wireless neural device |
CN103901089A (zh) * | 2014-04-16 | 2014-07-02 | 国家纳米科学中心 | 检测神经细胞电生理信号的传感器及制作方法和检测方法 |
Non-Patent Citations (1)
Title |
---|
BLASCHKE, B.M. ET AL.: "Mapping brain activity with flexible graphene micro-transistors", 2D MATERIALS, vol. 4, no. 2, pages 1 - 3 * |
Also Published As
Publication number | Publication date |
---|---|
ES2759053B2 (es) | 2020-10-08 |
ES2759053A1 (es) | 2020-05-07 |
JP2022511125A (ja) | 2022-01-28 |
EP3879582A4 (en) | 2022-11-02 |
US20210345930A1 (en) | 2021-11-11 |
WO2020094898A1 (es) | 2020-05-14 |
EP3879582A1 (en) | 2021-09-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Masvidal-Codina et al. | High-resolution mapping of infraslow cortical brain activity enabled by graphene microtransistors | |
Li et al. | Novel passive ceramic based semi-dry electrodes for recording electroencephalography signals from the hairy scalp | |
US9675298B2 (en) | Apparatus and method for measuring bioelectric signals | |
Fiedler et al. | Novel multipin electrode cap system for dry electroencephalography | |
Gruetzmann et al. | Novel dry electrodes for ECG monitoring | |
Taheri et al. | A dry electrode for EEG recording | |
US8860504B2 (en) | Method and apparatus for measuring biological signal | |
KR101736978B1 (ko) | 생체 신호를 측정하는 장치 및 방법 | |
US8798707B2 (en) | Flexible, multi-channel microelectrode for recording laboratory animal EEG and method for recording laboratory animal EEG using the same | |
WO1999038437A1 (en) | System and method for enhancing and separating biopotential signals | |
EP1708615A1 (en) | Active dry sensor module for measurement of bioelectricity | |
US20210345930A1 (en) | Graphene transistor system for measuring electrophysiological signals | |
KR102083559B1 (ko) | 생체용 전극, 생체 신호 처리 장치 및 생체 신호 처리 방법 | |
Garcia-Casado et al. | Enhancement of non-invasive recording of electroenterogram by means of a flexible array of concentric ring electrodes | |
Pazzini et al. | An ultra-compact integrated system for brain activity recording and stimulation validated over cortical slow oscillations in vivo and in vitro | |
KR20150017931A (ko) | 유연한 용량성 결합 능동전극 및 생체 신호 측정 장치 | |
Svärd et al. | Design and evaluation of a capacitively coupled sensor readout circuit, toward contact-less ECG and EEG | |
Kuronen | Epic sensors in electrocardiogram measurement | |
Yang et al. | Optimal combination of electrodes and conductive gels for brain electrical impedance tomography | |
Akinin et al. | Biopotential measurements and electrodes | |
Li et al. | Development and application of a microfabricated multimodal neural catheter for neuroscience | |
WO2018088400A1 (ja) | 脳波スペクトル分析装置のためのセンサ接続装置 | |
Journée et al. | Extramuscular recording of spontaneous EMG activity and transcranial electrical elicited motor potentials in horses: characteristics of different subcutaneous and surface electrode types and practical guidelines | |
Barański et al. | Simply and low coast electromyography signal amplifier | |
Li et al. | Multifunctional lab-on-a-tube (LOT) probe for simultaneous neurochemical and electrophysiological activity measurements |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |