Integrated Giant Magnetoresistance Technology for Approachable Weak Biomagnetic Signal Detections

sensors

Review Integrated Giant Magnetoresistance Technology for Approachable Weak Biomagnetic Signal Detections

Hui-Min Shen 1, Liang Hu 2,* and Xin Fu 2

1 School of Mechanical Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China; [email protected] 2 State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou 310028, China; [email protected] * Correspondence: [email protected]; Tel.: +86-571-8795-3395

Received: 26 November 2017; Accepted: 5 January 2018; Published: 7 January 2018

Abstract: With the extensive applications of biomagnetic signals derived from active biological tissue in both clinical diagnoses and human-computer-interaction, there is an increasing need for approachable weak biomagnetic sensing technology. The inherent merits of giant magnetoresistance (GMR) and its high integration with multiple technologies makes it possible to detect weak biomagnetic signals with micron-sized, non-cooled and low-cost sensors, considering that the magnetic field intensity attenuates rapidly with distance. This paper focuses on the state-of-art in integrated GMR technology for approachable biomagnetic sensing from the perspective of discipline fusion between them. The progress in integrated GMR to overcome the challenges in weak biomagnetic signal detection towards high resolution portable applications is addressed. The various strategies for 1/f noise reduction and sensitivity enhancement in integrated GMR technology for sub-pT biomagnetic signal recording are discussed. In this paper, we review the developments of integrated GMR technology for in vivo/vitro biomagnetic source imaging and demonstrate how integrated GMR can be utilized for biomagnetic field detection. Since the field sensitivity of integrated GMR technology is being pushed to fT/Hz0.5 with the focused efforts, it is believed that the potential of integrated GMR technology will make it preferred choice in weak biomagnetic signal detection in the future.

Keywords: giant magnetoresistance; biomagnetic signal; integration; 1/f noise; CMOS

1. Introduction Non-invasive detection of biomagnetic signals derived from active biological tissue, including magnetocardiograms (MCGs) [1–3], magnetoencephalograms (MEGs) [4–6], magnetospinograms (MSGs) [7,8], and magnetomyograms (MMGs) [9,10], has been a promising study method for biological phenomena with respect to high fidelity, temporal and spatial resolution. However, the weak biomagnetic signals can be easily polluted by environmental noise. Biomagnetic signals are normally sampled by strict detection systems in magnetically shielded rooms (MSRs). Since the biomagnetic fields attenuate rapidly by the distance to the neural sources, miniaturized sensors placed at closer range will provide stronger signals. With the extensive applications of biomagnetic source imaging (BMSI), approachable biomagnetic signal detection systems for point-of-use and point-of-care applications are attractive for both medical diagnostics and academic research [3,6,10]. During the past decades, there has been an increasing need of extensive biomagnetic signal applications in micro-dimensional detection for higher spatial resolution and system integration for real-time and robust processes. Traditional BMSI systems face challenges in further progress and enhancement. As a rapidly expanding field of medical research, the biomagnetism community has stressed that the development of alternative, miniaturized, and approachable biomagnetic

Sensors 2018, 18, 148; doi:10.3390/s18010148 www.mdpi.com/journal/sensors Sensors 2018, 18, 148 2 of 20 detectors would constitute an important step towards the wider distribution of biomagnetism [11,12], e.g., clinical diagnoses, human-computer interaction (HCI), and education. Giant magnetoresistive (GMR) sensors can realize reliable size-independent magnetic signal detection in the sub-nT range at room temperature using micron-sized structures. The large-scale fabrication process of GMR provides high capacity of integration with low power consumption and cost. These make GMR sensors good candidates for enhanced BMSI [13–15]. The GMR effect is a basic phenomenon that occurs in magnetic materials ranging from nanoparticles over multilayered thin ﬁlms to permanent magnets. The discoverers of this phenomenon, Grünberg [16] and Fert [17], were awarded with the Nobel Prize in Physics in 2007. During the early stage, applications of GMR sensors were focused on industry [18–20] for information storage, which is now a well-established technology. High quality integrated GMR systems combined with multiple technologies have been proposed [21–23]. In recent years, an extensive research activity has been triggered to exploit the potentials of integrated GMR in ultra-low biomagnetic signal detection [21–29]. Without involving increased cost and complicated structure, integrated GMR brings aggregative performance improvements [23,28,29] in the fabrication process, structure size, anti-noise ability and sensitivity, taking advantages of multiple technologies and the inherent properties of GMR. In this contribution, we intend to provide a review of integrated GMR for biomagnetic signal detection and demonstrate the feasibility of integrated GMR for approachable biomagnetic ﬁeld applications. Firstly, heuristic models for GMR and biomagnetic signals are provided, and challenges in BMSI are highlighted. Then, we focus on the current developments in 1/f noise reduction and sensitivity enhancement of the integrated GMR technologies for comparable intensity to biomagnetic signals (sub-pT), to provide guidance for future development of the integrated GMR technology in BMSI. Finally, frontier research of integrated GMR systems in in vivo/vitro BMSI applications is presented, illustrating the application feasibility. It is expected that this review will be a valuable reference for GMR research in weak biomagnetic signal detections.

2. Integrated GMR Sensors towards BMSI

2.1. Physical Principles of GMR Multilayers The GMR effect is a quantum mechanical magnetoresistance effect. The physical origin is related to spin-dependent scattering in magnetic multilayers, which introduced scientists to a new discipline termed spintronics [30]. Nowadays the underlying physics of GMR and the inter-layer exchange coupling are broadly understood [31,32]. GMR sensors with greater resistance variation are now available, among them the spin valve (SV) sensor is an advanced type of GMR sensor. A good review of the SV mechanism is given in [33]. Based on the two current models proposed by Mott [34], the GMR effect can be understood by the simple resistor model (Figure1a). In a multilayer structure including a pair of ferromagnetic thin ﬁlm layers separated by a non-magnetic conducting layer (Figure1b), the resistance change arises when the externally applied magnetic ﬁeld aligns the magnetic moments of the successive magnetic layers. The conduction electrons in ferromagnetic layers transport via channels of spin-up and spin-down electrons. The spin-up and spin-down electrons with the spin direction parallel and antiparallel to the magnetization direction are termed ‘majority’ and ‘minority’ electrons, respectively. Based on the assumption that the electron mean free path for both spin channels are longer than the layer thickness, electrons with spin parallel to the layer magnetization are scattered in a different way to electrons with spin in the opposite direction to the layer magnetization. The spin-dependent scattering can be further explained with the density of state function for transition [35,36] (Figure1c). As illustrated in Figure1, stronger scattering of electrons with spin antiparallel to the magnetization direction produces a large resistance (represented by RH), while weaker scattering produces a small resistance (represented by Sensors 2018, 18, 148 3 of 20

RL) for the other spin direction. Consequently, the magnetoresistance ratio (MR) can be modeled by the simpleSensors resistor 2018, 18, model148 expressed as: 3 of 20

2 2 ∆R RRAP −RRRP (RRRL− RH) =  AP= P = LH, ,(1) (1) R RRRP PLH4 RRRLRH

Magnetization direction Spin up Spin down Cr Fe scattering

E E E RL RH F

RL RH

N(E) N(E) RP=2RLRH/(RL+RH)

E E EF RH RL

RL RH

N(E) N(E) RAP=(RL+RH)/2

(a) (b) (c)

Figure 1. (a) Schematic of the resistor model; (b) Schematic of spin‐dependent scattering at the Figure 1.interfaces(a) Schematic between ferromagnetic of the resistor and non model;‐ferromagnetic (b) Schematic layers with of parallel spin-dependent magnetization scattering (PM) and at the interfacesanti between‐parallel magnetization ferromagnetic (APM); and non-ferromagnetic(c) Schematic of density layers of electronic with parallel states with magnetization PM and APM. (PM)E, and anti-parallelthe electron magnetization energy; EF, (APM);the Fermi ( clevel;) Schematic N(E), density of density of states. of electronic states with PM and APM. E, the electron energy; EF, the Fermi level; N(E), density of states. 2.2. Progress in GMR with High Integration

2.2. ProgressThe in GMR simplicity with of High the IntegrationGMR mechanism mentioned above is a great adventure for ultra‐low biomagnetic signal detection. It has been proved that GMR sensors alone can realize pT (10−12T) (DC) Themagnetic simplicity field of sensing the GMR at room mechanism temperature mentioned [37]. By above the accurate is a great control adventure of the thin for ultra-low‐film materials, biomagnetic signal detection.interfaces Itand has electrical been proved characteristics, that GMR presently sensors manufacture alone can realize of GMR pT sensors (10−12 withT) (DC) micro/nano magnetic field sensingdimensions at room temperature is a mature technology [37]. By with the a accuratesolid footprint control in a wide of the range thin-film of applications materials, [13,15,18,38]. interfaces and GMR based technology is the preferred choice for low magnetic fields detection with high spatial electrical characteristics, presently manufacture of GMR sensors with micro/nano dimensions is a mature resolution. The maturity of GMR sensor fabrication relies on large‐scale methods, and offers technologymany with advantages: a solid footprint in a wide range of applications [13,15,18,38]. GMR based technology is the preferred choice for low magnetic fields detection with high spatial resolution. The maturity of GMR  Smart system integration with multiple components of Si‐based integrated circuits in small sensor fabricationplatforms relies with on decreased large-scale operation methods, difficulty and offers and power many consumption, advantages: such as lab‐on‐a‐chip devices [39,40], signal post‐process modules and communication modules; • Smart systemMiniaturized integration structures with without multiple sensitivity components loss providing of increased Si-based spatial integrated resolution circuits in weak in small platformsbiomagnetic with decreased fields sensing; operation difficulty and power consumption, such as lab-on-a-chip devices Room [39,40‐temperature], signal post-process operation without modules bulky andcooling communication systems and the modules;associated expensive costs; • Miniaturized Array applications structures with without robust sensitivity spatial measurements loss providing and compact increased systems spatial [2,41]; resolution in weak  biomagneticReal‐time fields and sensing;multi‐mode process based on high compatibility with standard CMOS processes, such as simultaneous electronic and magnetic readout [28,42]. • Room-temperature operation without bulky cooling systems and the associated expensive costs; Typical applications of integrated GMR systems are illustrated in Figure 2. In Figure 2a [39], • Array applications with robust spatial measurements and compact systems [2,41]; high sensitive detection of influenza virus using 8 × 8 GMR biosensor array (each GMR sensor has a • Real-timesize of 120 and μm multi-mode × 120 μm) was process realized based in real on time high without compatibility operator intervention. with standard As presented CMOS processes, in suchFigure as simultaneous 2b, an integrated electronic system based and on magnetic GMR sensor readout array was [28, 42reported]. in [40] for the detection of cell‐free DNA fragments (ALU115 and ALU247), taking advantages of integration and high Typicalsensitivity. applications In Figure 2c, of a integrated needle‐shaped GMR micromachined systems are silicon illustrated probe with in integrated Figure2. GMR In Figure sensing2 a [ 39], high sensitiveelements detection and a thin of film influenza electrode virus was fabricated using 8 ×and8 successfully GMR biosensor recorded array simultaneous (each GMR magnetic sensor has a size of 120 µm × 120 µm) was realized in real time without operator intervention. As presented in Figure2 b, an integrated system based on GMR sensor array was reported in [ 40] for the detection of cell-free DNA fragments (ALU115 and ALU247), taking advantages of integration and high sensitivity. In Figure2c, a needle-shaped micromachined silicon probe with integrated GMR sensing elements Sensors 2018, 18, 148 4 of 20

and a thinSensors film 2018 electrode, 18, 148 was fabricated and successfully recorded simultaneous magnetic4 and of 20 electric neural signals. As an emerging field, applications of GMR sensors for BMSI have benefited from the merits ofand high electric sensitivity neural signals. and high As integrationan emerging with field, multi-technologies. applications of GMR sensors for BMSI have benefited from the merits of high sensitivity and high integration with multi‐technologies.

Figure 2. (a) Fabricated GMR chip for virus detection [39]; (b) GMR chips bonded on a printed circuit Figure 2.board(a) Fabricatedfor microfluidic GMR platform chip for (Adapted virus detection from [40] [39 with]; (b )permission GMR chips of bondedThe Royal on Society a printed of circuit board forChemistry); microﬂuidic (c) Integration platform (Adapted of GMR sensors from [ 40in] withneedle permission shape micromachined of The Royal silicon Society probes of Chemistry); for (c) Integrationneuronal of magnetic GMR sensors field recording in needle [28]. shape micromachined silicon probes for neuronal magnetic ﬁeld recording [28]. 3. BMSI towards High Resolution Portable Applications

3. BMSI3.1. towards Electrophysiological High Resolution Basis of Biomagnetic Portable Signals Applications

3.1. ElectrophysiologicalThe physiological Basis origin of Biomagnetic of biomagnetic Signals signals is the electrochemical activity of body cells [43–45]. As illustrated in Figure 3, when nerve cells (related to MEG and MSG) or muscle cells (related to TheMCG physiological and MMG) are origin excited, of biomagnetic their cell membrane signals can is produce the electrochemical electrochemical activity impulses of and body conduct cells [43–45]. As illustratedthem along in Figure the membrane.3, when The nerve ionic cells channels (related constitute to MEG an important and MSG) part or of muscle the cell cells membrane. (related The to MCG and MMG)flow areof these excited, ions in their neurons cell or membrane muscular fibers can forms produce the basis electrochemical of bioelectric phenomena, impulses and and conductexhibit them as biomagnetic signals at macro level. along the membrane. The ionic channels constitute an important part of the cell membrane. The ﬂow Typical biomagnetic signals derived from the electrochemical activity of nerve cells or muscle of thesecells, ions termed in neurons MEG, orMSG, muscular or MCG, ﬁbers are presented forms the in basisFigure of4. bioelectricSince the magnetic phenomena, permeability and exhibitof as biomagneticbiological signals tissue at is macro nearly level. homogeneous and almost identical to the vacuum, no distortion is Typicalintroduced biomagnetic to the biomagnetic signals derived signals of from the body the electrochemical surface by internal activity anatomical of nerve structures. cells orBesides, muscle cells, termedthe MEG, magnetic MSG, measurement or MCG, are is presentednot only non in‐invasive Figure 4but. Since also contact the magnetic‐less. Consequently, permeability BMSI of has biological tissue isbeen nearly a promising homogeneous method for and biological almost phenomena identical detection to the vacuum, of biological no distortiontissue and provides is introduced results to the with high temporal and spatial resolution. biomagnetic signals of the body surface by internal anatomical structures. Besides, the magnetic measurement is not only non-invasive but also contact-less. Consequently, BMSI has been a promising method for biological phenomena detection of biological tissue and provides results with high temporal and spatial resolution. Sensors 2018, 18, 148 5 of 20 Sensors 2018, 18, 148 5 of 20

Sensors 2018, 18, 148 5 of 20 Na+ K+ ++++Na+ ‒‒‒++++K+ ‒‒‒‒+++‒‒‒‒ ++++‒‒‒++++ ‒‒‒‒Excitation+++ area‒‒‒‒Axon ‒‒‒‒Excitation+++ area‒‒‒‒Axon ++++‒‒‒‒+++‒‒‒‒‒‒‒++++ ++++Depolarization‒‒‒++++ ConductionDepolarizationRepolarization Conduction Repolarization

FigureFigure 3. 3.Transmission Transmission ofof action potential. potential. Figure 3. Transmission of action potential.

Figure 4. (a) Typical MEG response evoked by a 50‐ms tone [44]; (b) Waveforms of the z‐component FigureFigure 4. (a) 4. Typical (a) Typical MEG MEG response response evoked evoked by by a 50-msa 50‐ms tone tone [ 44[44];]; ((bb)) Waveforms of of the the z‐zcomponent-component of of the MSG signals [46]; (c) Raw MCG signal measured by a SQUID at the chest center [47]. the MSGof the signals MSG signals [46]; (c [46];) Raw (c) MCGRaw MCG signal signal measured measured by by a SQUID a SQUID at at the the chest chest centercenter [47]. [47]. 3.2. Challenges for Approachable BMSI 3.2. Challenges for Approachable BMSI 3.2. ChallengesAs a for promising Approachable and effective BMSI medical diagnostic method, nowadays BMSI has achieved wide As a promising and effective medical diagnostic method, nowadays BMSI has achieved wide recognition and can be found in most regular hospitals, although there are still challenges in further As a promising and effective medical diagnostic method, nowadays BMSI has achieved wide recognitionprogress and and promotion can be found of BMSI in most for extensive regular hospitals,applications. although there are still challenges in further recognitionprogress and and can promotion be found of inBMSI most for regular extensive hospitals, applications. although there are still challenges in further (1). Extremely low magnitude order and signal‐to‐noise ratio progress(1). andExtremely promotion low magnitude of BMSI for order extensive and signal applications.‐to‐noise ratio The quality of detected biomagnetic signals directly decides the performance of BMSI. However, (1). ExtremelytheThe intensity quality low of magnitude of the detected biomagnetic biomagnetic order signals and signal-to-noise aresignals extremely directly low decides ratio (about the 100 performance fT (10−15T) for of MEG BMSI. [44] However, and theMSG intensity [8], and of severalthe biomagnetic tens of pT signals for MCG are [48] extremely and MMG low [9]) (about and several100 fT orders(10−15T) smaller for MEG than [44] the and TheMSGexternal quality [8], andinterface. of several detected The tens measurements biomagnetic of pT for MCG can signals be [48] easily directlyand disturbed, MMG decides [9]) for and instance, the several performance the orders signal ‐smallerto of‐noise BMSI. thanratio However, the the intensityexternal(SNR) in ofinterface. MEG the biomagnetic equaling The measurements 1 is common signals [49], can are inbe extremely spite easily of disturbed,the low expensive (about for and instance, 100 sophisticated fT (10 the− 15signal T)instruments. for‐to‐ MEGnoise Itratio [ 44] and MSG [(SNR)8],should and in several MEGhighlight equaling tens that of the1 pT is sensor forcommon MCG interference [49], [48] in and spite (1/ MMGf ofnoise) the [9 ])expensive largely and several degrades and orderssophisticated response smaller linearity instruments. than theand external It low‐frequency detection ability in GMR sensors [50], which is more difficult to suppress [51–53]. interface.should The highlight measurements that the cansensor be interference easily disturbed, (1/f noise) for instance,largely degrades the signal-to-noise response linearity ratio (SNR)and in lowVarious‐frequency technologies detection have ability been in studiesGMR sensorsto boost [50], the whichSNR, includingis more difficultelectromagnetic to suppress shielding [51–53]. MEG equaling 1 is common [49], in spite of the expensive and sophisticated instruments. It should Varioustechniques, technologies reference channels,have been and studies signal processingto boost the [8,54–56]. SNR, including electromagnetic shielding highlight that the sensor interference (1/f noise) largely degrades response linearity and low-frequency techniques,(2). Low‐ cost,reference flexible channels, and miniaturized and signal detectors processing [8,54–56]. detection ability in GMR sensors [50], which is more difficult to suppress [51–53]. Various technologies have been(2). Low studiesThe‐cost, wide to flexible diffusion boost theand of SNR, miniaturizedBMSI includingrelies greatly detectors electromagnetic on development shieldingof low‐cost, techniques, flexible and miniaturized reference channels, detectors. During the past decades, measurements of the extremely low biomagnetic signal are largely and signalThe processing wide diffusion [8,54 –of56 BMSI]. relies greatly on development of low‐cost, flexible and miniaturized dominated by superconducting quantum interference device (SQUID) with detection limit of 3fT/Hz0.5 detectors. During the past decades, measurements of the extremely low biomagnetic signal are largely at 4 K [6,52,53,57]. However, due to the hash cryogenic temperatures operating requirements, the 0.5 (2). Low-cost,dominatedSQUID is flexiblebulkyby superconducting and and costly miniaturized (a several quantum million detectors interference dollars device device costing (SQUID) over 100,000 with detection dollars in limitrunning of 3fT/Hz costs at per4 K year). [6,52,53,57]. In addition, However, flexible anddue miniaturizedto the hash sensorcryogenic arrangement temperatures shows operatinggreat potential requirements, to improve the TheSQUIDtemporal wide is bulky diffusion and spatial and costly of resolutions, BMSI (a several relies since million greatly the signal dollars on magnitude development device costing will be of over greater low-cost, 100,000 with dollarsthe flexible reduced in and running distance miniaturized costs detectors.per year). During In addition, the past flexible decades, and miniaturized measurements sensor ofarrangement the extremely shows lowgreat biomagnetic potential to improve signal are largelytemporal dominated and spatial by superconducting resolutions, since quantum the signal magnitude interference will device be greater (SQUID) with the with reduced detection distance limit of 3 fT/Hz 0.5 at 4 K [6,52,53,57]. However, due to the hash cryogenic temperatures operating requirements, the SQUID is bulky and costly (a several million dollars device costing over 100,000 dollars in running costs per year). In addition, flexible and miniaturized sensor arrangement shows great potential to Sensors 2018, 18, 148 6 of 20 improve temporal and spatial resolutions, since the signal magnitude will be greater with the reduced distance between sensor and tissues [58,59]. Besides, microscopic recording of a small region is needed in studySensors the 2018 asynchronous, 18, 148 biomagnetic signals, where multiple time scales are involved during6 of 20 the electrochemical process of biomagnetic signal generation [60]. between sensor and tissues [58,59]. Besides, microscopic recording of a small region is needed in 4. Integratedstudy the GMR asynchronous Technologies biomagnetic with Enhancedsignals, where Performance multiple time scales are involved during the electrochemical process of biomagnetic signal generation [60]. Benefitting from the maturity of GMR technology in the performance (large-scale fabrication, reliability,4. Integrated micron GMR size, Technologies room working with temperature Enhanced Performance and low costs) and high integration with multiple technologies,Benefitting integrated from the GMR maturity systems of GMR for technology BMSI began in the to drawperformance more (large attention‐scale infabrication, the past few decades.reliability, Although micron a size, GMR room sensor working in principle temperature can and reach low really costs) high and high sensitivity, integration taking with advantage multiple of size-independenttechnologies, resolution,integrated GMR the applications systems for of BMSI integrated began GMRto draw systems more areattention restricted, in the considering past few the harshdecades. condition Although of signal a GMR measurements sensor in principle and challenges can reach mentioned really high above sensitivity, in BMSI. taking New advantage approaches of for integratedsize‐independent GMR performance resolution, improvement the applications focuses of integrated on noise GMR reduction systems and are sensitivity restricted, considering enhancement in orderthe to realizeharsh condition comparable of signal intensity measurements detection to and biomagnetic challenges signals mentioned (sub-pT). above in BMSI. New approaches for integrated GMR performance improvement focuses on noise reduction and 4.1. Eliminationsensitivity enhancement of 1/f Magnetic in Noiseorder into Low-Frequencyrealize comparable Magnetic intensity Sensing detection to biomagnetic signals (sub‐pT). In principle, GMR sensors could compete with SQUID if the field gain or magneto-resistance can be increased4.1. Elimination largely of [ 611/f], Magnetic but in the Noise low-frequency in Low‐Frequency biomagnetic Magnetic Sensing fields sensing, the detectable minimum field is greatlyIn principle, limited GMR by thesensors 1/f couldmagnetic compete noise with [62 SQUID]. Figure if the5[ 63field] shows gain or recorded magneto‐ 1/resistancef noise in a yoke-typecan be GMR increased sensor largely at room [61], temperature but in the low with‐frequency different biomagnetic external appliedfields sensing, field, illustratingthe detectable that (a) the 1/minimumf noise increases field is greatly rapidly limited with by the the decrease 1/f magnetic of frequency noise [62]. Figure and (b) 5 there[63] shows is no recorded extra magnetic 1/f noise noise at lowin frequency.a yoke‐type GMR This sensor noise at originates room temperature from the with fluctuations different external of energy applied around field, equilibriumillustrating that due to the presence(a) the 1/f of noise magnetic increases domains rapidly [with64,65 the], anddecrease it can of be frequency dependent and (b) on there the shape, is no extra size magnetic and material propertiesnoise at of low the frequency. device. Therefore, This noise originates the maximum from the density fluctuations of 1/f ofmagnetic energy around noise equilibrium occurs in the due linear transitionto the ofpresence the sensor, of magnetic where domains the magnetization [64,65], and it of can the be sensing dependent layer on the is switching shape, size betweenand material the two properties of the device. Therefore, the maximum density of 1/f magnetic noise occurs in the linear saturation states. The power spectral density S (f ) of 1/f noise in GMR sensor is proportion to 1/f transition of the sensor, where the magnetizationV of the sensing layer is switching between the two and usually given by the Hooge relation [66,67]: saturation states. The power spectral density SV(f) of 1/f noise in GMR sensor is proportion to 1/f and

usually given by the Hooge relation [66,67]: 2 SV ( f ) = γHV /NC f , (2) 2 SfVHC VNf, (2) where V is the applied voltage and NC is the number of charge carrier in the active volume. The parameter where V is the applied voltage and NC is the number of charge carrier in the active volume. The γH is called Hooge constant and it is used as comparison reference for 1/f noise. parameter γH is called Hooge constant and it is used as comparison reference for 1/f noise.

Figure 5. 1/f noise in a yoke‐type GMR with sensitivity of 0.4 nT/Hz0.5 for different external applied Figure 5. 1/f noise in a yoke-type GMR with sensitivity of 0.4 nT/Hz0.5 for different external applied fields [63]. fields [63]. The performance of GMR sensors in low‐frequency biomagnetic field detection is severely Thelimited performance by 1/f noise. of To GMR extend sensors the lower in low-frequency detectable limit, biomagnetic many efforts ﬁeld have detection been contributed is severely limitedto by 1/eliminatingf noise. To the extend 1/f noise. the lowerTwo kinds detectable of 1/f noise limit, elimination many efforts methods have are been reviewed contributed below, toincluding eliminating integrated GMR/microelectromechanical systems (MEMS) and optimized structure design.

Sensors 2018, 18, 148 7 of 20 the 1/f noise. Two kinds of 1/f noise elimination methods are reviewed below, including integrated GMR/microelectromechanical systems (MEMS) and optimized structure design. Approach I: Integrated GMR/MEMS Systems Sensors 2018, 18, 148 7 of 20 In recent years, the method by integrating GMR sensors with MEMS magnetic flux modulation Approach I: Integrated GMR/MEMS Systems (MFM) showsSensors 2018 great, 18, 148 potential in 1/f noise reduction [50,68–75]. The introduction of MEMS7 of MFM 20 can mechanicallyIn recent modulate years, the the quasi-staticmethod by integrating signal into GMR a sensors frequency with aboveMEMS magnetic the 1/f knee,flux modulation overcoming the higher noise(MFM)Approach spectrum shows I: Integrated great density potential GMR/MEMS present in 1/f Systemsnoise at the reduction low-frequency [50,68–75]. region The introduction [68–71]. Two of MEMS kinds MFM of MEMS can MFM mechanically modulate the quasi‐static signal into a frequency above the 1/f knee, overcoming the have been approached,In recent years, including the method electrostatic by integrating MEMS GMR sensors and piezoelectric with MEMS magnetic MEMS. flux modulation higher noise spectrum density present at the low‐frequency region [68–71]. Two kinds of MEMS (MFM) shows great potential in 1/f noise reduction [50,68–75]. The introduction of MEMS MFM can InMFM the work have presentedbeen approached, by Edeltein including [69 electrostatic–71], the employed MEMS and electrostatic piezoelectric MEMSMEMS. structure can realize mechanically modulate the quasi‐static signal into a frequency above the 1/f knee, overcoming the one to threeIn orders the work of 1/presentedf noise by magnitude Edeltein [69–71], reduction. the employed As presented electrostatic in Figure MEMS6 a,structure this system can was higher noise spectrum density present at the low‐frequency region [68–71]. Two kinds of MEMS fabricatedrealize on one silicon-on-insulator to three orders of 1/ wafers,f noise magnitude and consisted reduction. of a As pair presented of MFMs in Figure deposited 6a, this on system MEMS flaps MFM have been approached, including electrostatic MEMS and piezoelectric MEMS. was fabricated on silicon‐on‐insulator wafers, and consisted of a pair of MFMs deposited on MEMS driven by electrostaticIn the work combpresented drives by Edeltein and a SV [69–71], sensor the placed employed between electrostatic them. MEMS The motion structure of thecan MFMs flaps driven by electrostatic comb drives and a SV sensor placed between them. The motion of the modulatesrealize the one field to atthree the orders position of 1/ off noise the sensor magnitude and reduction. thus shifts As the presented operating in Figure frequency. 6a, this The system prototype MFMs modulates the field at the position of the sensor and thus shifts the operating frequency. The sensor waswas fabricated validated on by silicon shifting‐on‐insulator magnetic wafers, signals and consisted of 1.3 µ ofT a at pair 25 of Hz MFMs to the deposited high frequency on MEMS range prototype sensor was validated by shifting magnetic signals of 1.3 μT at 25 Hz to the high frequency flaps driven by electrostatic comb drives and a SV sensor placed between them. The motion of the (aroundrange 48 kHz), (around and 48 the kHz), results and the showed results thatshowed the that SNR the was SNR increased was increased by a by factor a factor of 2of using 2 using an an estimate MFMs modulates the field at the position of the sensor and thus shifts the operating frequency. The of the noiseestimate at 1 of Hz the [ noise71]. at 1 Hz [71]. prototype sensor was validated by shifting magnetic signals of 1.3 μT at 25 Hz to the high frequency range (around 48 kHz), and the results showed that the SNR was increased by a factor of 2 using an estimate of the noise at 1 Hz [71].

Figure 6. (a) Illustration of the concept of the MEMS MFM; (b) Scanning electron microscopy (SEM) Figure 6. (a) Illustration of the concept of the MEMS MFM; (b) Scanning electron microscopy (SEM) picture of the MEMS MFM [71]. picture of the MEMS MFM [71]. SimilarFigure 6. research (a) Illustration was implemented of the concept byof the Guedes MEMS et MFM; al. [68]. (b) ScanningAs shown electron in Figure microscopy 7a, a modulated (SEM) picture of the MEMS MFM [71]. SimilarAC field research at the SV was sensor implemented was created by by Guedes cantilever et al.with [68 flux]. As guide shown oscillation in Figure with7 thea, a operating modulated AC frequency shifted from DC to high frequencies. The feasibility of this integrated system was validated field at the SVSimilar sensor research was created was implemented by cantilever by Guedes with flux et al. guide [68]. As oscillation shown in with Figure the 7a, operating a modulated frequency by applying an AC signal of 10 Vp.p at 200 kHz to the cantilever gate electrode causing the AC field at the SV sensor was created by cantilever with flux guide oscillation with the operating shifted frommicrocantilever DC to high to oscillate frequencies. at 400 ThekHz. feasibility The results ofin thisFigure integrated 7b show that system the magnetic was validated output of by the applying frequency shifted from DC to high frequencies. The feasibility of this integrated system was validated an AC signalSV sensor of is 10 3.4 V μp.pV/Hzat 2000.5 with kHz modulation to the cantilever efficiency gateecant = electrode 0.11%, and causing a minimum the 540 microcantilever nT/ Hz0.5 to by applying an AC signal of 10 Vp.p at 200 kHz to the cantilever gate electrode causing the detectable static magnetic field is reported. oscillatemicrocantilever at 400 kHz. to The oscillate results at 400 in kHz. Figure The7 resultsb show in Figure that the 7b show magnetic that the output magnetic of output the SV of the sensor is 0.5 0.5 3.4 µV/HzSV sensorwith is modulation3.4 μV/Hz0.5 with efficiency modulationecant =efficiency 0.11%, and ecant a= minimum0.11%, and 540a minimum nT/ Hz 540 detectablenT/ Hz0.5 static magneticdetectable field is static reported. magnetic field is reported.

Figure 7. (a) Cross sectional view of the integrated sensor with all relevant features. (b) SV voltage output induced by the microcantilever at 200 kHz [68]. Figure 7. (a) Cross sectional view of the integrated sensor with all relevant features. (b) SV voltage Figure 7.Compared(a) Cross to sectional electrostatic view ofMEMS the integrated hybrid systems, sensor withhybrid all relevantsystem integrates features. (bGMR) SV voltageand output induced by the microcantilever at 200 kHz [68]. outputpiezoelectric induced MEMS by the can microcantilever provide more at advantages. 200 kHz [68 Since]. no air‐gap capacitor is required compared with capacitive MEMS, piezoelectric MEMS devices are more area‐efficient with simpler geometry. Compared to electrostatic MEMS hybrid systems, hybrid system integrates GMR and Comparedpiezoelectric to electrostatic MEMS can provide MEMS more hybrid advantages. systems, Since hybrid no air system‐gap capacitor integrates is required GMR and compared piezoelectric MEMScan with provide capacitive more MEMS, advantages. piezoelectric Since MEMS no devices air-gap are capacitor more area is‐efficient required with compared simpler geometry. with capacitive

Sensors 2018, 18, 148 8 of 20

MEMS, piezoelectric MEMS devices are more area-efficient with simpler geometry. Besides, lower driving voltage is required [76], and piezoelectric materials are reversible helping for cost reduction. Sensors 2018, 18, 148 8 of 20 All of these advantages make piezoelectric MEMS more attractive. A verticalBesides, lower motion driving flux voltage modulation is required scheme [76], wasand piezoelectric developed materials by Hu et are al. reversible [50,73–75 helping]. As illustratedfor cost reduction. All of these advantages make piezoelectric MEMS more attractive. in FigureSensors8a, 2018 the, proposed18, 148 structure is composed of a silicon cantilever with a piezoelectric8 of 20 ceramic and a soft magneticA vertical film,motion which flux modulation is simpler scheme compared was developed with the aforementionedby Hu et al. [50,73–75]. structure. As illustrated The magnetic in Figure 8a, the proposed structure is composed of a silicon cantilever with a piezoelectric ceramic field measuredBesides, lower by GMR driving elements voltage inis required the air gap [76], is and partly piezoelectric transferred materials to a are higher reversible frequency helping domain for as a and a soft magnetic film, which is simpler compared with the aforementioned structure. The cost reduction. All of these advantages make piezoelectric MEMS more attractive. result ofmagnetic the flux field modulation measured by film GMR vibration. elements in Thus, the air high-frequency gap is partly transferred magnetic to a fieldhigher with frequency much lower A vertical motion flux modulation scheme was developed by Hu et al. [50,73–75]. As illustrated 1/f noisedomain can beas a detected, result of the providing flux modulation improved film vibration. SNR. The Thus, power high‐frequency spectrum magnetic presented field in with Figure 8b in Figure 8a, the proposed structure is composed of a silicon cantilever with a piezoelectric ceramic much lower 1/f noise can be detected, providing improved SNR. The power spectrum presented 0.5in shows thatand thea soft noise magnetic level offilm, the which modulated is simpler magnetic compared field with can bethe reduced aforementioned from 2000 structure. nV/Hz The at 1 Hz Figure 0.58b shows that the noise level of the modulated magnetic field can be reduced from 2000 nV/Hz0.5 to 10 nV/Hzmagnetic fieldaround measured 7 kHz. by GMR The low-frequencyelements in the air detection gap is partly ability transferred of the to prototype a higher frequency sensor can be at 1 Hz to 10 nV/Hz0.5 around 7 kHz. The low‐frequency detection ability of the prototype sensor can improveddomain to 120 as a pT/Hz result of0.5 theat flux 1 Hz, modulation which is film about vibration. 83 times Thus, higher high‐frequency than the magnetic detection field ability with of used be improved to 120 pT/Hz0.5 at 1 Hz, which is about 83 times higher than the detection ability of used much lower 1/f noise can0.5 be detected, providing improved SNR. The power spectrum presented in GMR elementsGMR elements (10 nT/Hz (10 nT/Hzat0.5 at 1 Hz)1 Hz) [ 50[50].]. AtAt a frequency frequency of of7 kHz, 7 kHz, the themodulation modulation efficiency efficiency of this of this Figure 8b shows that the noise level of the modulated magnetic field can be reduced from 2000 nV/Hz0.5 structurestructure can achieve can achieve 18.8%. 18.8%. at 1 Hz to 10 nV/Hz0.5 around 7 kHz. The low‐frequency detection ability of the prototype sensor can be improved to 120 pT/Hz0.5 at 1 Hz, which is about 83 times higher than the detection ability of used GMR elements (10 nT/Hz0.5 at 1 Hz) [50]. At a frequency of 7 kHz, the modulation efficiency of this structure can achieve 18.8%.

Figure 8.Figure(a) Solid 8. (a) Solid model model of the of the vertical vertical motion motion fluxflux modulation modulation structure structure [73]; [(73b) ];Noise (b) Noiseand signal and signal spectrum of the vertical motion flux modulation sensor without external magnetic field [75]. spectrum of the vertical motion flux modulation sensor without external magnetic field [75].

A parallel approach that combines a SV sensor, MFM, and A1N‐based MEMS piezoelectric Figure 8. (a) Solid model of the vertical motion flux modulation structure [73]; (b) Noise and signal cantilevers was proposed in [72]. The schematic and SEM picture of the proposed device are A parallelspectrum approach of the vertical that motion combines flux modulation a SV sensor, sensor without MFM, external and A1N-basedmagnetic field [75]. MEMS piezoelectric cantileverspresented was proposed in Figure 9a. in If [72 the]. measured The schematic low‐frequency and SEM field picture at frequency of the f proposed1 flows through device the are MFM presented on the MEMS cantilevers with a motion frequency f0, an oscillatory (AC) magnetic field at frequencies in Figure9a.A If parallel the measured approach low-frequency that combines fielda SV atsensor, frequency MFM, andf 1 flows A1N‐ throughbased MEMS the MFM piezoelectric on the MEMS 2f0 ± f1 will be induced and detected by the SV sensor. MFM made by multilayers of antiferromagnetic cantilevers was proposed in [72]. The schematic and SEM picture of the proposed device are cantileverscoupled with CoFeB a motion layers frequency (([CoFeB 38f 0Å/Ru, an oscillatory18 Å] × 32/CoFeB (AC) 38 magnetic Å) is placed field on at the frequencies surface of MEMS 2f 0 ± f 1 will presented in Figure 9a. If the measured low‐frequency field at frequency f1 flows through the MFM be inducedcantilevers, and detected and modulate by the the SV low sensor.‐frequency MFM magnetic made bysignals multilayers above 20 ofkHz. antiferromagnetic Based on the noise coupled on the MEMS cantilevers with a motion frequency f0, an oscillatory (AC) magnetic field at frequencies CoFeB layersspectrum ([CoFeB curve in 38 Figure Å/Ru 9b 18we Å] can× get32/CoFeB that the sensitivity 38 Å) is of placed this integrated on the surface device was of MEMS301 nT/Hz cantilevers,0.5 2f0 ± f1 will be induced and detected by the SV sensor. MFM made by multilayers of antiferromagnetic for static field detection, and 602 nT/Hz0.5 for low‐frequency fields if the loss from the amplitude and modulatecoupled theCoFeB low-frequency layers (([CoFeB magnetic 38 Å/Ru 18 signals Å] × 32/CoFeB above 20 38 kHz. Å) is placed Based on on the the surface noise of spectrum MEMS curve modulated sidebands equals one half. The modulation efficiency with a 1 mT applied static field is in Figurecantilevers,9b we can and get modulate that the the sensitivitylow‐frequency of magnetic this integrated signals above device 20 waskHz. 301Based nT/Hz on the 0.5noisefor static about 1.59%, which can achieve 50% through finite element model simulations. field detection,spectrum andcurve 602 in Figure nT/Hz 9b0.5 wefor can low-frequency get that the sensitivity fields of if this the integrated loss from device the amplitudewas 301 nT/Hz modulated0.5 0.5 sidebandsfor static equals field one detection, half. The and modulation 602 nT/Hz efficiency for low‐frequency with a 1fields mT if applied the loss static from the field amplitude is about 1.59%, modulated sidebands equals one half. The modulation efficiency with a 1 mT applied static field is which can achieve 50% through finite element model simulations. about 1.59%, which can achieve 50% through finite element model simulations.

Figure 9. (a) The schematic and SEM picture of the integrated device; (b) Noise spectrum in magnetic units in the 1–100 kHz range for different biasing currents in the proposed sensor [72].

Figure 9.Figure(a) The 9. (a) schematic The schematic and and SEM SEM picture picture of of thethe integrated integrated device; device; (b) Noise (b) Noise spectrum spectrum in magnetic in magnetic units in the 1–100 kHz range for different biasing currents in the proposed sensor [72]. units in the 1–100 kHz range for different biasing currents in the proposed sensor [72].

Sensors 2018, 18, 148 9 of 20

Approach II: Optimized Structure Design Sensors 2018, 18, 148 9 of 20 The presence of magnetic domains in the active region is the dominant source of 1/f noise in Approach II: Optimized Structure Design low frequency for GMR sensors [63,64]. As illustrated in Figure 10, a yoke-type shape structure was reported inThe [63 ],presence where of no magnetic magnetic domains domains in the active exist region in the is activethe dominant region. source The of conﬁguration1/f noise in low of the frequency for GMR sensors [63,64]. As illustrated in Figure 10, a yoke‐type shape structure was proposed spin valve sensor includes a soft layer made of NiFe(3.5)/CoFe bilayer (thicknesses are given reported in [63], where no magnetic domains exist in the active region. The configuration of the in nm) andproposed a hard spin layer valve made sensor of includes CoFe/IrMn a soft or layer CoFe/PtMn. made of NiFe(3.5)/CoFe According to bilayer the general (thicknesses power are density formulagiven presented in nm) inand (2), a hard the 1/layerf noise made dependsof CoFe/IrMn mainly or CoFe/PtMn. on the parameter AccordingNc to thein small general structures power and then is inverselydensity formula proportional presented in to (2), the the volume 1/f noise (1/dependswl)0.5 mainly. Besides, on the it parameter has been Nc veriﬁed in small structures that to keep the yoke stableand then with is domains inversely formationproportional and to the a hystereticvolume (1/wl behavior,)0.5. Besides,w itshould has been be verified smaller that than to keep 12 µ them. In case of goodyoke contacts stable on with the domains GMR stacks,formation a power and a hysteretic of 5 mW behavior, with a sensingw should current be smaller of than 3 mA 12 was μm. usedIn and case of good contacts on the GMR stacks, a power of 5 mW with a sensing current of 3 mA was used the maximaland the resistance maximal resistance was chosen was chosen to provide to provide high high sensitivity. sensitivity. With With the the 1/f 1/ noisef noise as the as limitation, the limitation, l shouldl beshould then be maximized. then maximized.

Figure 10. The magnetic configuration of the yoke after saturation and decrease to zero external field Figure 10. The magnetic configuration of the yoke after saturation and decrease to zero external field as obtained from micro‐magnetic simulation [63]. as obtained from micro-magnetic simulation [63]. Based on these remarks, a yoke‐type sensor with l = 60 μm and w = 6 μm has been achieved, and 0.5 Basedthe sensitivity on these of remarks, the proposed a yoke-type yoke‐type sensor GMR sensor with atl =room 60 µtemperaturem and w = is 60.4µ mnT/Hz has been. The 1/ achieved,f noise in this yoke‐type GMR sensor presented in Figure 5 shows that there is no difference between 0.5 and thethe sensitivity 1/f noise in of the the saturated proposed state yoke-type (100 G) and GMR in the sensor sensitive at area room (10 temperature G and 20 G). The is 0.4 noise nT/Hz . The 1/fmeasurementsnoise in this in yoke-type two regimes GMR in Figure sensor 5 demonstrate presented that in Figure there is5 noshows extra thatmagnetic there noise is no at differencelow betweenfrequency the 1/f noisedue to in magnetic the saturated domain stateformation (100 in G) the and proposed in the yoke sensitive‐type GMR area (10sensor. G and 20 G). The noise measurements in two regimes in Figure5 demonstrate that there is no extra magnetic noise at low frequency4.2. due Sensitivity to magnetic Enhancement domain for High formation Spatial Resolution in the proposed yoke-type GMR sensor. The unique power of BMSI is the localization of active neural areas with reasonable spatial 4.2. Sensitivityresolution Enhancement and excellent for temporal High Spatial accuracy. Resolution The biomagnetic fields are very weak and require sub‐pT (MCG) or even fT (MEG) sensitivity level. Despite the 1/f noise, accurate measurements of Theraw unique ultra‐low power biomagnetic of BMSI signals is the depend localization on high of field active sensitivity. neural Magnetic areas with flux reasonableconcentrator spatial resolution(MFC) and can excellent concentrate temporal the external accuracy. field Thein the biomagnetic sensor region fields with an are appropriate very weak geometry. and require The sub-pT (MCG)employment or even fT (MEG)of MFCs sensitivity decreases the level. linear Despite operating the range 1/f noise,of GMR accurate sensor without measurements bringing of raw ultra-lowadditional biomagnetic noise [77]. signals The dependeffective gain on high G introduced field sensitivity. by the MFCs Magnetic is defined flux by concentrator the ratio between (MFC) can concentratethe magnetic the external field in field the gap in and the external sensor field, region which with can an reach appropriate hundreds [78]. geometry. The gain Thedepends employment on the geometrical parameters, including length, yoke/pole ratio, and intrinsic magnetic properties of of MFCsthe decreases material, theincluding linear operatingmagnetic permeability. range of GMR There sensor are two without types bringingof MFC, additionalincluding soft noise‐ [77]. The effectiveferromagnetic gain G materialintroduced‐based by MFC the and MFCs superconducting is defined by‐based the ratioMFC. between the magnetic field in the gap and external field, which can reach hundreds [78]. The gain depends on the geometrical parameters, Approach I: Integration of GMR and Soft‐Ferromagnetic Material‐based MFC Systems including length, yoke/pole ratio, and intrinsic magnetic properties of the material, including magnetic permeability.MFC There made are of soft two ferromagnetic types of MFC, materials including (e.g., NiFe soft-ferromagnetic or amorphous Co based material-based alloys) can realize MFC and significant sensitivity enhancement to pT level at room temperature [77‐81]. In the work presented superconducting-basedby Leitao et al. [81] MFC. (Figure 11), an ultra‐compact sensor consisting of nanometric SV sensor placed Approachwithin I: Integration the gap of of 6000 GMR Å–thick and Soft-Ferromagnetic thin‐film MFC element Material-based was designed. MFC As Systems shown in Figure 11b, a maximum gain of 20.7 was obtained for pole‐sensor distance of 400 nm with sensitivity increased MFCfrom made 0.18%/mT of soft to ferromagnetic 3.7%/mT. With materials the proposed (e.g., microfabrication NiFe or amorphous process, Co the based patterned alloys) MFCs can realize significantexhibited sensitivity a clean enhancement liftoff profile (down to pT to level 380 nm), at room leading temperature to an extremely [77 –small81]. active In the sensing work presentedarea. by Leitao et al. [81] (Figure 11), an ultra-compact sensor consisting of nanometric SV sensor placed within the gap of 6000 Å–thick thin-film MFC element was designed. As shown in Figure 11b, a maximum gain of 20.7 was obtained for pole-sensor distance of 400 nm with sensitivity increased from 0.18%/mT to 3.7%/mT. With the proposed microfabrication process, the patterned MFCs exhibited a clean liftoff profile (down to 380 nm), leading to an extremely small active sensing area. Sensors 2018, 18, 148 10 of 20

Sensors 2018, 18, 148 10 of 20

Figure 11.Figure(a) 11. Illustration (a) Illustration of an of integratedan integrated device device combing SV SV sensor sensor and and MFCs; MFCs; (b) Transfer (b) Transfer curves curves comparing the isolated SV sensor with the corresponding device including the MFC [81]. comparing the isolated SV sensor with the corresponding device including the MFC [81]. Approach II: Integration of GMR and Superconducting Technology Approach II:SuperconductingFigure Integration 11. (a) Illustration of GMR MFC and ofprovides an Superconducting integrated an extra device field combing Technology gain by SV transformingsensor and MFCs; the (weakb) Transfer field curveson a large surfacecomparing to a strong the fieldisolated on SVa small sensor surface with the based corresponding on the Meissner device effectincluding [25,26], the MFC and [81].makes it possible to Superconductingdetect fT signals at MFC low frequency provides (as an illustrated extra field in Figure gain 12a). by transforming In this kind of integrated the weak detector, field on a a large surfacesupercurrentApproach to a strong II: Integration is induced field on of by GMR a magnetic small and Superconducting surface signal and based generates Technology on locally the Meissner enhanced flux effect lines [ 25in a,26 constriction,], and makes it possiblewhich to detectSuperconducting can be fT detected signals byMFC at the low providesGMR frequency sensor an extraplaced (as field above illustrated gain or belowby transforming in the Figure constriction. 12 thea). weak InThe this gainfield kind of on this a of largekind integrated detector,ofsurface aintegrated supercurrent to a strong sensor field device is inducedon a can small reach surface by over a magnetic based 1000 on[27]. the signal In Meissner the YBCO and effect generates‐based [25,26], devices, and locally themakes GMR enhanced it possible can work fluxto lines with a higher current at 4.2 K. Figure 12b gives the noise spectral density for the niobium‐based device in a constriction,detect fT signals which at low can frequency be detected (as illustrated by the GMR in Figure sensor 12a). placed In this kind above of integrated or below detector, the constriction. a withsupercurrent a sensing is current induced of by respectively a magnetic 1signal and 15 and mA generates under noise locally level enhanced of 540 fT/Hz flux lines0.5. Figure in a constriction, 12c shows The gainthatwhich of the this can noise kind be detected level of integrated of by the the YBCO GMR sensor‐ basedsensor device device placed can withabove reach the or samebelow over sensing the 1000 constriction. [current27]. In isThe the about gain YBCO-based 32of thisfT/Hz kind0.5. devices, the GMRComparisonof integrated can work ofsensor withFigures device a 12b,c higher can demonstrates reach current over at1000 that 4.2 [27].the K. best In Figure the sensitivity YBCO 12b‐based gives achieved devices, the with noise the a SQUIDGMR spectral can is aboutwork density for the niobium-based1with fT/Hz a higher0.5 for acurrent device 1.5 cm at2 loop with 4.2 K. with aFigure sensing low 12b‐Tc SQUIDgives current the and noise of about respectively spectral 30 fT/Hz density0.5 1 with andfor the high 15 niobium mA‐Tc SQUID under‐based [82]. noise device The level of 540 fT/Hzfinalwith0.5 integrateda .sensing Figure current system12c shows of is respectively incorporated that the 1 noise andin a 15portable level mA under of Dewar. the noise YBCO-based level of 540 fT/Hz device0.5. Figure with the 12c sameshows sensing 0.5 currentthat is about the noise 32 fT/Hz level 0.5of .the Comparison YBCO‐based of device Figure with 12b,c the demonstrates same sensing current that the is best about sensitivity 32 fT/Hz achieved. Comparison of Figures 12b,c0.5 demonstrates that2 the best sensitivity achieved with a SQUID is about 0.5 with a SQUID is about 1 fT/Hz for a 1.5 cm loop with low-Tc SQUID and about 30 fT/Hz with 1 fT/Hz0.5 for a 1.5 cm2 loop with low‐Tc SQUID and about 30 fT/Hz0.5 with high‐Tc SQUID [82]. The high-TcfinalSQUID integrated [82]. Thesystem final is incorporated integrated in system a portable is incorporated Dewar. in a portable Dewar.

Figure 12. (a) Schematic view of the integrated device, comprising a GMR sensor with a superconducting loop; (b) The noise spectrum of the voltage output of the GMR and the field sensitivities; (c) The noise spectrum of the YBaCuO mixed sensor at 4.2 K and 77 K [25].

5. Integrated GMR Systems for In Vivo/Vitro Biomagnetic Signal Detection Figure 12. (a) Schematic view of the integrated device, comprising a GMR sensor with a Figure 12. a Thesuperconducting brief( ) overview Schematic loop; on (integratedb view) The ofnoise GMR the spectrum integrated technologies of the device, voltage in Section output comprising 3 demonstrates of the GMR a GMR thatand itthe sensor is afield feasible with a superconductingstrategysensitivities; to employ loop;(c) The integrated (noiseb) The spectrum noiseGMR of spectrumsensors the YBaCuO for of ultramixed the‐low voltagesensor magnetic at 4.2 output K andfields of77 K the(nT/Hz [25]. GMR 0.5 to and fT/Hz the0.5 field) sensitivities;sensing. However, (c) The noise application spectrum of ofintegrated the YBaCuO GMR mixed technology sensor atin 4.2vivo/vitro K and 77 biomagnetic K [25]. signal detection5. Integrated still GMRfaces greatSystems challenges, for In Vivo/Vitro and has only Biomagnetic been validated Signal by Detection a few research groups. Table 1 5. IntegratedsummarizesThe GMR brief the overview Systems reported on for studiesintegrated In Vivo/Vitro successfully GMR technologies Biomagnetic utilized inintegrated Section Signal 3 GMRdemonstrates Detection system thatfor itin is vivo/vitro a feasible biomagneticstrategy to employsignal sensingintegrated in recentGMR yearssensors mainly for ultra by two‐low researchmagnetic groups. fields (nT/HzThe integrated0.5 to fT/Hz GMR0.5) Thesystemssensing. brief overview inHowever, Table 1 are onapplication mainly integrated subject of GMRintegrated to the technologies biomagnetic GMR technology signal in Section in inthe 3vivo/vitro low demonstrates‐frequency biomagnetic band. that There it signal is a is feasible 0.5 0.5 strategynodetection to need employ forstill specific faces integrated great shielding challenges, GMR in biomagnetic sensors and has foronly signal ultra-low been sensing validated magnetic with by higha few fields intensity,research (nT/Hz groups.such as Table actionto fT/Hz 1 ) sensing.potentialsummarizes However, from the the application reported skeletal studiesmuscle of integrated [83].successfully But in detection GMR utilized technology ofintegrated biomagnetic GMRin vivosignal system/vitro lower for than biomagnetic in vivo/vitro pT level, signal detectionsuchbiomagnetic still as MCG faces signal and great MEG, sensing challenges, shielding in recent will and years be has necessary mainly only been toby avoid two validated researchthe pollutions bygroups. a few from The research the integrated environmental groups. GMR Table1 summarizes systems the in Table reported 1 are mainly studies subject successfully to the biomagnetic utilized signal integrated in the low GMR‐frequency system band. for Therein vivo is /vitro no need for specific shielding in biomagnetic signal sensing with high intensity, such as action biomagneticpotential signal from sensingthe skeletal in muscle recent [83]. years But mainly in detection by twoof biomagnetic research signal groups. lower The than integrated pT level, GMR systemssuch in Table as MCG1 are and mainly MEG, shielding subject to will the be biomagnetic necessary to avoid signal the in pollutions the low-frequency from the environmental band. There is no need for specific shielding in biomagnetic signal sensing with high intensity, such as action potential from the skeletal muscle [83]. But in detection of biomagnetic signal lower than pT level, such as MCG Sensors 2018, 18, 148 11 of 20 and MEG, shielding will be necessary to avoid the pollutions from the environmental noise (nT level). In the work by Pannetier-Lecoeur et al., the noise level of the integrated GMR and superconducting loop system at 77 K can reach fT, comparable to low-Tc SQUID, and the final system is incorporated in Sensors 2018, 18, 148 11 of 20 a portable Dewar. All the SV sensors utilized in Table1 work at room temperature with µm dimension. The reportednoise (nT successful level). In the applications work by Pannetier of integrated‐Lecoeur GMRet al., the technology noise level inof the biomagnetic integrated GMR signal and detection are detailedsuperconducting in the following. loop system at 77 K can reach fT, comparable to low‐Tc SQUID, and the final system is incorporated in a portable Dewar. All the SV sensors utilized in Table 1 work at room temperature 5.1. GMR-Superconductingwith μm dimension. IntegratedThe reported Sensors successful for In Vivoapplications MCG Measurementsof integrated GMR technology in biomagnetic signal detection are detailed in the following. A GMR-superconducting integrated sensor (Figure 12) was developed by Pannetier et al. for the measurement5.1. GMR of‐Superconducting extremely low Integrated signals, Sensors such asfor MEG,In Vivo andMCG firstly Measurements reported in 2004 [26]. The stack of the GMR has theA GMR following‐superconducting composition integrated [Si/SiO sensor2/Ta(5)/Ni (Figure81 12)Fe was19(4)/Co developed90Fe 10by(1.2)/Cu(2.4)/Co Pannetier et al. for 90theFe 10(2.4)/ Ir20Mn80measurement(10)/Ta(10)] of (thicknesses extremely low are signals, given such in nm)as MEG, and and was firstly patterned reported in in a yoke-shape2004 [26]. The with stack a of MR ratio of 4% atthe room GMR temperature has the following and composition of 9% at 4.2 [Si/SiO K [262/Ta(5)/Ni]. The small81Fe19(4)/Co size90 prototypeFe10(1.2)/Cu(2.4)/Co can be used90Fe10(2.4)/ at 77 K and is capableIr20Mn of80 measuring(10)/Ta(10)] 30(thicknesses fT/Hz0.5 areor given 1 fT/Hz in nm)0.5 andat 4 was K. Sensitivity patterned in of a yoke the‐ sensorshape with is represented a MR ratio by the of 4% at room temperature and of 9% at 4.2 K [26]. The small size prototype can be used at 77 K and local field enhancement due to the supercurrent flowing through the loop. The integrated system is is capable of measuring 30 fT/Hz0.5 or 1 fT/Hz0.5 at 4 K. Sensitivity of the sensor is represented by the incorporatedlocal field in aenhancement portable Dewar due to to the realize supercurrent operation flowing of the through superconductor the loop. The flux-to-field integrated system transformer is at 0.5 low temperature.incorporated This in a systemportable suffers Dewar to from realize thermal operation noise of the with superconductor a noise level flux of few‐to‐field fT/Hz transformer. Based on the integratedat low system, temperature.in vivo ThisMCG system measurements suffers from thermal were presented noise with (as a noise shown level in of Figure few fT/Hz 13)0.5 correlated. Based with simultaneouson the integrated recording system, of the electrocardiographin vivo MCG measurements (ECG) laterwere inpresented shielded (as environment shown in Figure [27]. 13) Although small peakscorrelated corresponding with simultaneous to the heart recording signals of can the be electrocardiograph distinguished (Figure (ECG) 13 laterb), the in noiseshielded level of the environment [27]. Although small peaks corresponding to the heart signals can be distinguished measurements remains too high. (Figure 13b), the noise level of the measurements remains too high.

Figure 13. (a) MCG recorded on low‐TC SQUID (upper curve) and mixed sensor (lower curve), Figuresimultaneously 13. (a) MCG with recorded the ECG; on (b) low- DetailedTC SQUIDMCG response (upper (red) curve) and the and ECG mixed peak as sensor reference (lower [27]. curve), simultaneously with the ECG; (b) Detailed MCG response (red) and the ECG peak as reference [27]. An improved structure design was proposed later to overcome the interference brought by a high noise level [83,84]. The technique is proposed on a modulation of the supercurrent passing An improved structure design was proposed later to overcome the interference brought by a through two constrictions in parallel of the loop by a local Joule heating. Figure 14a illustrates the high noiseparallel level mixed [83‐,sensor84]. The design. technique MCG recordings is proposed were on successfully a modulation recorded of theby supercurrentthis device. As passing throughpresented two constrictions in Figure 14b, in the parallel waveform of thefeature loop fits by well a local with simultaneous Joule heating. ECG Figure recordings, 14a illustrateswhere the paralleltypical mixed-sensor components design. (the T MCG‐wave recordings and the QRS were‐complex) successfully of the cardiac recorded cycle by were this observed. device. As This presented in Figureintegrated 14b, the sensor waveform was fabricated feature either ﬁts with well a low with‐TC simultaneous(niobium) loop, or ECG with recordings, a high‐TC (YBaCuO) where typical componentsloop. All (the the T-wavefabrication and process the QRS-complex) can be realized by of standard the cardiac photolithography, cycle were ion observed. beam etching This and integrated sputtering techniques. Although this integrated GMR/superconducting integrated sensor applied for sensor was fabricated either with a low-TC (niobium) loop, or with a high-TC (YBaCuO) loop. All the fabrication process can be realized by standard photolithography, ion beam etching and sputtering Sensors 2018, 18, 148 12 of 20

Sensors 2018, 18, 148 12 of 20 techniques. Although this integrated GMR/superconducting integrated sensor applied for BMSI still is at the proof-of-conceptBMSI still is at the stage,proof‐of the‐concept measurements stage, the measurements of MCGs showed of MCGs promising showed promising results for results the for integrated the integrated GMR sensor as a sensitive technique for BMSI applications. It is reasonable to expect GMR sensor as a sensitive technique for BMSI applications. It is reasonable to expect that by reducing that by reducing the distance from the sensor to the surface of the Dewar, detection of MEG responses the distanceSensorscan be 2018 from realized., 18, the 148 sensor to the surface of the Dewar, detection of MEG responses can12 of be 20 realized.

BMSI still is at the proof‐of‐concept stage, the measurements of MCGs showed promising results for the integrated GMR sensor as a sensitive technique for BMSI applications. It is reasonable to expect that by reducing the distance from the sensor to the surface of the Dewar, detection of MEG responses can be realized.

Figure 14. (a) Schematic of an antiparallel mixed sensor; (b) Simultaneous recordings of MCG (top) Figure 14.and (ECGa) Schematic (bottom) averaged of an antiparallel during 30 s with mixed the mixed sensor; sensor (b) Simultaneousreported in [84]. recordings of MCG (top) and ECG (bottom) averaged during 30 s with the mixed sensor reported in [84]. 5.2. Integrated GMR‐Based Microprobes for Biomagnetic Response

5.2. IntegratedThe GMR-Based BMSI allow Microprobesreference‐free for and Biomagnetic coherent measurements, Response but the extremely low intensity Figure 14. (a) Schematic of an antiparallel mixed sensor; (b) Simultaneous recordings of MCG (top) requires the magnetic sensor to be placed as close as possible to the field sources. The merit that the The BMSIand ECG allow (bottom reference-free) averaged during and coherent 30 s with the measurements, mixed sensor reported but the in [84]. extremely low intensity requires GMR sensors can be fabricated at nanoscale size [21] makes it possible to realize measurements of the magnetic sensor to be placed as close as possible to the field sources. The merit that the GMR sensors 5.2.biomagnetic Integrated signalsGMR‐Based within Microprobes several tens for Biomagneticof micrometers Response distance from the signal source. This will can be fabricatedprovide micron at nanoscale‐size spatial size resolution [21] makes in neurophysiology it possible to realize studies. measurements As summarized of in biomagnetic Table 1, two signals within severalresearchThe tens groupsBMSI of allow micrometershave reportedreference distancesuccessful‐free and from coherentvalidations the measurements, signal of local source. recording but This theof will biomagnetic extremely provide low signals micron-size intensity using spatial resolutionrequiresintegrated in neurophysiology the GMR magnetic‐based sensor silicon studies. to probes be placed As [21–23,28,85,86]. summarized as close as possible in Table to the1, field two sources. research The groups merit that have the reported GMR sensors can be fabricated at nanoscale size [21] makes it possible to realize measurements of successful validationsIn the work by of Barbieri local recording et al. [85], ofa bio biomagnetic‐compatible sensor signals integrated using integrated SV sensor was GMR-based presented silicon biomagneticto record the signalsmagnetic within fields several derived tens from of action micrometers potentials distance of a mouse from skeletalthe signal muscle. source. As Thisshown will in probes [21–23,28,85,86]. provideFigure 15a, micron the proposed‐size spatial integrated resolution GMR in neurophysiologyprobe consists three studies. aligned As SV summarized sensor of 1.7 in mmTable × 4001, two μm Inresearchon the a worksilicon groups bysubstrate, Barbierihave reported and et a al.1 successfulcm [85‐long], a soleus bio-compatible validations muscle of was local sensorplaced recording on integrated the of topbiomagnetic of SVthe magnetic sensor signals was probe.using presented to recordintegratedThe the recorded magnetic GMR simultaneous‐based fields silicon derived magnetic probes from [21–23,28,85,86]. fields action by the potentials three segments of a mouse of the probe skeletal derived muscle. from active As shown in Figure 15potentiala, theIn the proposed after work electrical by integratedBarbieri stimulation et al. GMR [85], on probe a the bio nerve‐compatible consists are presented three sensor aligned integrated in Figure SV sensor 15b.SV sensor Magnetic of 1.7 was mm field presented× traces400 µ m on a to record the magnetic fields derived from action potentials of a mouse skeletal muscle. As shown in silicon substrate,are averages and over a 1 500 cm-long trials and soleus filtered muscle with was a low placed‐pass onfilter. the The top tendency of the magnetic and the probe.peak‐to‐ Thepeak recorded Figureamplitude 15a, (2.7the proposednT) of the detectedintegrated magnetic GMR probe fields consists agree well three with aligned the predictions. SV sensor of The 1.7 results mm × validate400 μm simultaneous magnetic fields by the three segments of the probe derived from active potential after onthe a suitability silicon substrate, of integrated and a GMR1 cm‐‐longbased soleus probe muscle for biomagnetic was placed signal on the sensing, top of andthe magneticconfirm that probe. the electricalThetransmembrane stimulation recorded simultaneous oncurrents the nerve contribute magnetic are presented little fields to bythe the innet Figure threebiomagnetic segments 15b. Magneticfields. of the This probe fieldwork derived tracesprovides from are essential averagesactive over 500 trialspotentialtool and to reveal filtered after the electrical with relationship a low-passstimulation between filter. on thethe The localnerve tendency sources are presented and and the the inmacroscopic peak-to-peak Figure 15b. MEG Magnetic amplitude signals. field (2.7traces nT) of the detectedare magnetic averages fieldsover 500 agree trials well and with filtered the with predictions. a low‐pass The filter. results The tendency validate and the the suitability peak‐to‐ ofpeak integrated GMR-basedamplitude probe (2.7 for nT) biomagnetic of the detected signal magnetic sensing, fields and agree confirm well with that the the predictions. transmembrane The results currents validate contribute the suitability of integrated GMR‐based probe for biomagnetic signal sensing, and confirm that the little to the net biomagnetic fields. This work provides essential tool to reveal the relationship between the transmembrane currents contribute little to the net biomagnetic fields. This work provides essential local sourcestool to andreveal the the macroscopic relationship between MEG signals. the local sources and the macroscopic MEG signals.

Figure 15. (a) Photography of the recording chamber and GMR sensor configuration; (b) Expected and recorded simultaneous magnetic signal on the three GMR‐sensor derived from active potential after electrical stimulation of the nerve [85].

Figure 15. (a) Photography of the recording chamber and GMR sensor configuration; (b) Expected Figureand 15. (recordeda) Photography simultaneous of the magnetic recording signal chamber on the three and GMR GMR‐sensor sensor derived conﬁguration; from active ( bpotential) Expected and recordedafter simultaneous electrical stimulation magnetic of the signal nerve on[85]. the three GMR-sensor derived from active potential after electrical stimulation of the nerve [85].

Sensors 2018, 18, 148 13 of 20

Table 1. Representative studies on integrated GMR system for biomagnetic signal detection.

Sensors Measured Noise Level & Sensitivity References Biomagnetic Signal Type Size Environment Distance & Recorded Level GMR integrated a SV sensor 2 µm width; 3 fT/Hz0.5 & 3 pT/Hz0.5 & [27,29] In-vivo MCG of human body 2 77 K & MSR 25~30 mm Pannetier- superconducting loop superconducting loop 25 × 25 mm few pT Lecoeur, M. et al. In-vitro action potential of a 3.5 nT/Hz0.5 & [85] 3 SV sensors 1.7 mm long NR mouse skeletal soleus muscle 0.5 nT/Hz0.5 & PPA 2.7 nT In-vivo neuronal activity in the NR & 7 nT/Hz0.5 at 10 Hz & Joint research [86] SV sensor array 30 × 4 µm2 Inside the neuropil visual cortex of cats PPA 2.5 nT Room temperature 2~3 µV & 30 nT/Hz0.5 at [21,22] 15 SV sensors 30 × 2 µm2 1 µm In-vitro synaptic/action potential 1 kHz & 2.5 µT Freitas, P.P. et al. current in a mouse brain slice Few nV/Hz0.5 & [28] 2 SV sensors 40 × 2 µm2 1 µm 54 nT/Hz0.5 at 5 Hz & 33 nT PPA is the abbreviation of Peak-to-peak amplitude. Sensors 2018, 18, 148 14 of 20

AnotherSensors 2018 group, 18, 148 focused on research in integrated GMR-based silicon probe applied for14 of low 20 order neuronal magnetic fields detection [13,21–23,28]. In their work, an integrated brain signal detector integrated withAnother GMR group sensors focused for on the research magnetic in integrated response GMR of‐ neuronsbased silicon from probe a mouse applied hippocampus for low order brain slice hasSensorsneuronal been 2018 proposed. , magnetic18, 148 fields The first detection generation [13,21–23,28]. of detector In their employs work, an a integrated planar array brain of signal 15 microfabricated detector14 of 20 integrated with GMR sensors for the magnetic response of neurons from a mouse hippocampus brain MR sensing elements according to the arrangements of 3 × 50 µm2 (width × distance between electrical sliceAnother has been group proposed. focused The on first research generation in integrated of detector GMR employs‐based a silicon planar probe array applied of 15 microfabricated for low order leads) [neuronal21MR,23 sensing]. Themagnetic elements top pinnedfields according detection SV to sensors the [13,21–23,28]. arrangements are structured In oftheir 3 × 50work, as μm followings:2 an(width integrated × distance Si/Al brain between 2signalO3 500/Ta electricaldetector 20/NiFe 25/CoFeintegratedleads) 20/Cu [21,23]. 20/CoFe with TheGMR top 22/MnIr sensors pinned for 60/Ta SVthe magneticsensors 20/TiW(N are response structured2) 150 of (thicknessesneurons as followings: from a are mouse Si/Al given hippocampus2O3 in 500/Ta Å) and 20/NiFe thebrain substrate is Si withslice25/CoFe Al has2O been320/Culayer. proposed. 20/CoFe The microfabricated 22/MnIrThe first 60/Tageneration 20/TiW(N wafer of detector2) is 150 diced (thicknessesemploys into a individual planar are given array in magnetoresistive of Å) 15 and microfabricated the substrate chip and wire-bondedMRis Si sensing with to aAl elements ribbon2O3 layer. flat according The cable microfabricated withto the siliconearrangements wafer gel is for ofdiced 3 protection. × 50 into μm individual2 (width The × distancemagnetoresistive fabricated between GMR electricalchip sensor and shows a sensitivityleads)wire‐bonded of[21,23]. 1.5%/mT. to The a ribbon top In pinned theflat cable extracellular SV with sensors silicone are measurements, gelstructured for protection. as followings: the The planar fabricated Si/Al GMR2 OGMR3 sensor 500/Ta sensor array20/NiFe shows is placed 25/CoFea sensitivity 20/Cu of 20/CoFe1.5%/mT. 22/MnIr In the extracellular60/Ta 20/TiW(N measurements,2) 150 (thicknesses the planar are given GMR in sensor Å) and array the substrate is placed under the excited brain slice (Figure 16), and the distance between them is about several micrometers. isunder Si with the Al excited2O3 layer. brain The slice microfabricated (Figure 16), and wafer the distance is diced between into individual them is magnetoresistiveabout several micrometers. chip and The magneticwireThe ‐magneticbonded field to created field a ribbon created in flat the in cable the SV SVwith sensor sensor silicone can can begel be estimatedforestimated protection. at at 6.5 6.5The nT. nT. fabricated GMR sensor shows a sensitivity of 1.5%/mT. In the extracellular measurements, the planar GMR sensor array is placed under the excited brain slice (Figure 16), and the distance between them is about several micrometers. The magnetic field created in the SV sensor can be estimated at 6.5 nT.

Figure 16. (a) Hippocampus slice with relative position of the sensor array with respect to the Figure 16.hippocampus(a) Hippocampus structure [13]; slice (b) Schematic with relative of the integrated position GMR of the probe sensor for neuronal array measurement. with respect to the hippocampus structure [13]; (b) Schematic of the integrated GMR probe for neuronal measurement. FigureAn improved 16. (a) Hippocampus detector combining slice with Si relative needles position and GMR of the sensors sensor arrayfor neuronal with respect magnetic to the field Andetection improvedhippocampus was developed detector structure based combining [13]; (onb) Schematicthe first Si generation needles of the integrated andto suit GMR GMRin vitro probe sensors experiments for neuronal for on neuronal measurement.brain tissue magnetic [22,28]. ﬁeld As shown in Figure 2c, the GMR sensors in [28] are incorporated in the tip of micro‐machined Si detectionneedles wasAn developed whichimproved could detector based allow the on combining detector the ﬁrst to generationSi be needles inserted and towithin suit GMR thein sensors vitrobrain experimentsslice for and neuronal get closer on magnetic brain to the tissue signalfield [22,28]. As showndetectionsource in Figurewith was minimum developed2c, the damage GMR based on sensors to the the first brain ingeneration [slice.28] Figure are to suit incorporated 17a in vitrogives experiments the schematic in the on tip viewbrain of micro-machined oftissue the [22,28].needle. Si needlesAsThe which shown bottom could in pinnedFigure allow 2c,SV the thesensors detector GMR are sensors tostructured be in inserted [28] as are following: withinincorporated the Si/SiO brain in 2 the(100)/Ta slice tip of and (2.0)/micro get ‐Nimachined closer80Fe20 to(6.0)/ theSi signal source withneedlesIr76Mn minimum24 which (7.0)/ couldCo80 damageFe allow20 (3.3)/ the toCu detector the (2.5)/ brain Coto be80Fe slice. inserted20 (2.3)/ Figure withinNi80Fe 17 20the a(2.8)/ givesbrain Ta slice the(6.0) and schematic (thicknesses get closer view toare the given of signal the in needle. sourcenm and with alloy minimum compositions damage in at.%). to the brain slice. Figure 17a gives the schematic view of the needle. The bottom pinned SV sensors are structured as following: Si/SiO2 (100)/Ta (2.0)/Ni80Fe20 (6.0)/ The bottom pinned SV sensors are structured as following: Si/SiO2 (100)/Ta (2.0)/ Ni80Fe20 (6.0)/ Ir76Mn24 (7.0)/Co80Fe20 (3.3)/Cu (2.5)/Co80Fe20 (2.3)/Ni80Fe20 (2.8)/Ta (6.0) (thicknesses are given in Ir76Mn24 (7.0)/ Co80Fe20 (3.3)/ Cu (2.5)/ Co80Fe20 (2.3)/ Ni80Fe20 (2.8)/ Ta (6.0) (thicknesses are given in nm andnm alloy and compositions alloy compositions in at.%). in at.%).

Figure 17. (a) Schematic view of the integrated GMR‐based Si needle cross section; (b) Recording of SV sensor generated by the action potential currents resulting from the activation of multiple neurons in the CA1 region [28]. Figure 17. (a) Schematic view of the integrated GMR‐based Si needle cross section; (b) Recording of Figure 17. (a) Schematic view of the integrated GMR-based Si needle cross section; (b) Recording of SV SVIn sensorthe in generatedvitro experiments by the action performed potential currentson mice resulting brain slices, from thethe activation SV sensor of multipledetects theneurons magnetic sensorfield generatedin arising the CA1 from region by the the [28]. neuronal action potential stimulation currents at a distance resulting of from 400 nm the from activation the field of multiplesource. As neurons shown in the CA1 region [28]. In the in vitro experiments performed on mice brain slices, the SV sensor detects the magnetic field arising from the neuronal stimulation at a distance of 400 nm from the field source. As shown In the in vitro experiments performed on mice brain slices, the SV sensor detects the magnetic

ﬁeld arising from the neuronal stimulation at a distance of 400 nm from the ﬁeld source. As shown in Sensors 2018, 18, 148 15 of 20

Figure 17b, the recorded biomagnetic signal derived from stimulation is 33 nT based on the assumption of pureSensors magnetic 2018, 18, 148 signal and the SV sensor sensitivity. The development of this integrated15 of 20 GMR platform will improve the electrophysiological researches. This work provides possible method to in Figure 17b, the recorded biomagnetic signal derived from stimulation is 33 nT based on the solve the problem that the intensity of biomagnetic field decreases greatly with increasing distance assumption of pure magnetic signal and the SV sensor sensitivity. The development of this integrated betweenGMR the platform neuronal will source improve and the the electrophysiological detector. researches. This work provides possible method Recently,to solve the a joint problem research that the by intensity the aforementioned of biomagnetic field two decreases groups greatly was carriedwith increasing out to distance record in vivo neuronalbetween magnetic the neuronal activity source in and the the visual detector. cortex of cats, and the results were reported in [86]. The developedRecently, needle-shaped a joint research magnetrode by the aforementioned consists two micron-sized groups was (4carried× 30 outµ mto 2record), non-cooled in vivo GMR neuronal magnetic activity in the visual cortex of cats, and the results were reported in [86]. The sensors and an electrode arranged in a meandering configuration on silicon substrate (200 µm thick) developed needle‐shaped magnetrode consists micron‐sized (4 × 30 μm2), non‐cooled GMR sensors insultedand by an Si electrode3N4/Al2 arrangedO3 (Figure in a 18 meanderinga). From the configuration noise spectrum on silicon presented substrate in(200 Figure μm thick) 18b insulted we can see that, 0.5 the probeby Si sensitivity3N4/Al2O3 (Figure at a typical 18a). From peak-to-peak the noise inputspectrum AC presented voltage ofin 500Figure mV 18b achieves we can 7see nT/Hz that, the (10 Hz). In the inprobe vivo sensitivityexperiment, at a typical the magnetrode peak‐to‐peak was input directly AC voltage inserted of 500 into mV theachieves tissue 7 nT/Hz to record0.5 (10 the Hz). neuronal magneticIn the and in vivo electric experiment, response the magnetrode after stimulation was directly (100 inserted ms duration) into the tissue simultaneously. to record the neuronal The recorded neuronalmagnetic magnetic and fieldelectric in Figureresponse 18 afterc shows stimulation that a (100 magnetic ms duration) response simultaneously. arises after stimulusThe recorded onset, but a neuronal magnetic field in Figure 18c shows that a magnetic response arises after stimulus onset, but 20 ms delay exits compared with magnification signals in Figure 18d. The peak-to-peak amplitude a 20 ms delay exits compared with magnification signals in Figure 18d. The peak‐to‐peak amplitude of neuronalof neuronal magnetic magnetic field field achieves achieves 2.5 2.5 nT. nT. The results results in inFigures Figure 18c,d 18 c,dvalidate validate the conduction the conduction delay delay betweenbetween the retina the retina and and the the related related primary primary cortex.cortex. The The work work of recording of recording inside inside magnetic magnetic fields fields providesprovides possibility possibility to better to better understand understand the the extracranialextracranial MEG MEG signals. signals.

FigureFigure 18. (a )18. Scanning (a) Scanning electron electron microscopy microscopy picturepicture of of a amagnetrode magnetrode with with GMR GMR elements elements deposited deposited on a silicon substrate; (b) Equivalent‐field noise spectral density SB from 1 Hz to 10 kHz of the on a silicon substrate; (b) Equivalent-field noise spectral density SB from 1 Hz to 10 kHz of the proposed probe; (c) In Vivo neuronal magnetic signals on the magnetrode; (d) Magnification of the proposed probe; (c) In Vivo neuronal magnetic signals on the magnetrode; (d) Magnification of the event‐related‐field around stimulus onset [86]. event-related-field around stimulus onset [86]. 6. Conclusions 6. Conclusions The inherent merits of GMR, which combines enhanced properties from multiple technologies, Themake inherent integrated merits GMR of systems GMR, good which candidates combines for enhanced weak biomagnetic properties signal from detection. multiple Enormous technologies, interest has been focused on applications of integrated GMR in BMSI (ranging from pT/Hz0.5 to make integrated GMR systems good candidates for weak biomagnetic signal detection. Enormous fT/Hz0.5 with the intensity decreasing with increasing distance). In this paper, the physical principles interest has been focused on applications of integrated GMR in BMSI (ranging from pT/Hz0.5 to fT/Hz0.5 with the intensity decreasing with increasing distance). In this paper, the physical principles of GMR multilayers and electrophysiological origin of biomagnetic signals have been presented. Progress in GMR and challenges in point-of-use and point-of-care BMSI are highlighted, and the Sensors 2018, 18, 148 16 of 20 meeting point between them is presented accordingly. Strategies of integrated GMR technologies focused on 1/f noise reduction and sensitivity enhancement are discussed with relevant literature references, to provide guidance for future development of the integrated GMR technology in sub-pT biomagnetic signal detection. The state-of-art progress of integrated GMR technology for in vivo/vitro BMSI applications is reviewed as well. As demonstrated in this review, with the increasing demands for portable BMSI devices in point-of-care and point-of-use applications, e.g., clinical diagnoses, HCI, education, and even entertainment, highly sensitive integrated GMR sensors are of enormous interest for high spatial and temporal biomagnetic signal detection, taking advantages of the high compatibility with standard CMOS process and size-independent sensitivity at room temperature, microminiature and low cost. With the various efforts focused on the integration of GMR and multiple technologies, its field sensitivity is being pushed to fT/Hz0.5. Although the integrated GMR technologies applied for BMSI are still at the proof-of-concept level and attempts were made to detect predictable and simple biomagnetic signals with nT to pT magnitude, the results show great potential for integrated GMR sensors as a sensitive technique for weak biomagnetic signal sensing. In addition to that, the local recording inside the tissues based on the integrated micro-sized GMR sensors offers an essential tool to further investigate and interpret external macroscopic biomagnetic signals, such as MEG. Nevertheless, there are still challenges for GMR applied in BMSI. Further work may need to address the further integration with CMOS for real-time readouts, non-uniformity issues in the microfabrication process, size effect in the superconducting flux-transformer, and biocompatibility for quasi-static BMSI. The potential of integrated GMR technology in detection of low-frequency ultra-low biomagnetic signal seems to be far from being fully exploited.

Acknowledgments: This work was supported by the National Natural Science Foundation of China (Nos. 51605291 and 51575476). Conﬂicts of Interest: The authors declare no conﬂict of interest.

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