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Research Article
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Acupuncture Needle-Based Transistor Neuroprobe for In

Vivo Monitoring of Neurotransmitter
Ying Zhou, Binzhu Liu, Yongmin Lei, Lina Tang, Tingxian Li, Shanshan Yu,
Guo-Jun Zhang,* and Yu-Tao Li*
analysis of dynamic neurochemicals in

Chemical communication via neurotransmitters is central to brain functions. the living brain. These methods have their
Nevertheless, in vivo real-time monitoring of neurotransmitters released advantages, but they also have some disad-
in the brain, especially the electrochemically inactive molecules, remains vantages. For instance, microdialysis pre-
a great challenge. In this work, a novel needle field-effect transistor (FET) processes the samples in vitro by external
instruments, capable of simultaneous
microsensor based on an acupuncture needle is proposed, which is demon-
analysis of a variety of neurochemicals;
strated to be capable of real-time monitoring dopamine molecules as well isotopic trace has high sensitivity, and can
as neuropeptide Y in vivo. The FET microstructure is fabricated by succes- accurately locate and quantify the research
sively wrapping an insulating layer and a gold layer on the top of the needle, subjects under physiological conditions.
where the needle and the Au served as the source and drain, respectively. However, neither of them can perform
the real-time measurement. In recent
After assembling reduced graphene oxide (RGO) between the source and
decades, great progress has been made
drain electrodes, the specific aptamer is immobilized on the RGO, making in electrochemical sensors regarding real-
this needle-FET biosensor highly selective and sensitive to real-time monitor time monitoring of the dynamic changes
neurotransmitters released from rat brain, even in a Parkinson’s diseases of neuron signal molecules in vivo,[4] espe-
model. Furthermore, the needle-FET biosensor is applied to detect a variety cially the emerging implantable electrode
of targets including hormones, proteins, and nucleic acid. By constructing a arrays such as SU-8 multi-electrode arrays,
helical fiber bundles and so on, play an
FET sensing interface on an acupuncture needle and implanting the sensor
important role in brain activity moni-
in a rat’s brain for in vivo detection, this work provides a new sight in the FET toring,[5] from electrophysiological to neu-
domain and further expands the species of real-time in vivo detection. rochemical signals recording. However,
for a variety of electrochemically inactive
signaling molecules (such as amino acids,
1. Introduction neuropeptides, and proteins), the development of new methods
for real-time monitoring in vivo is desirable.
The processing of information via neurotransmitters in the Field-effect transistor (FET) biosensor allowing highly sensi-
brain is the heart of neuroscience. Deciphering neurotrans- tive and label-free detection of biomolecules by measuring their
mitter transmission, however, requires advanced techniques intrinsic charges change, has been regarded as one of the most
that approach multipath measurements of chemical neuro- promising biosensors in recent years.[6] In addition, the bias
transmission dynamics at both spatial and temporal scales. voltage of the FET biosensors is small (usually < 0.3 V), thus
Thus, real-time monitoring of signaling molecules in living causing little damage to the organisms. However, conventional
brain tissue is not only perspective but also challenging. A silicon-based FET chips are too large to be directly implanted
variety of techniques including microdialysis,[1] isotopic trace,[2] into living tissue for in vivo measurements. Recently, there
and electrochemistry[3] have been developed for quantitative have been some reports regarding small-sized FET devices. For
example, Lieber’s group reported a 3D kinked nanoscale FET
capable of being inserted into single cells for recording the
Y. Zhou, B. Liu, Y. Lei, L. Tang, T. Li, S. Yu, G.-J. Zhang, Y.-T. Li changes in intracellular pH and potential.[7] The FET biosensor
School of Laboratory Medicine based on glass nanopipette has also been reported, in which the
Hubei University of Chinese Medicine
16 Huangjia Lake West Road, Wuhan 430065, China device could flexibly detect signals in cells.[8] However, these FET
E-mail: zhanggj@hbtcm.edu.cn; lyt2015@hbtcm.edu.cn devices require high preparation technology, and the glass at the
Y. Zhou nanoscale is fragile, so these FET devices are limited by the appli-
Center for Clinical Laboratory cations at the cell level. Very recently, Kita et al. developed a “ver-
General Hospital of the Yangtze River Shipping tical” needle-topped electrode with a MOSFET amplifier for in
Wuhan Brain Hospital
Huiji Road, Wuhan 430030, China
vivo electrophysiology recording.[9] The high impedance charac-
teristics of the needle electrode enabled the recording of the local
The ORCID identification number(s) for the author(s) of this article
can be found under https://doi.org/10.1002/smll.202204142. field potential and action potential in vivo. However, despite these
advantages, none of a single needle FET device has been so far
DOI: 10.1002/smll.202204142 reported for real-time monitoring of signaling molecules in vivo.
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Scheme 1. Schematic illustrations of the design and application of needle field-effect transistor (FET). a) Layer-by-layer design and modification method
of a needle FET. Inside to outside: stainless steel acupuncture needle (drain), parylene, Au (source), and parylene (insulation). b) Schematic diagram
of the functionalization process and in vitro and in vivo detection of the needle FET biosensor.
Stainless steel acupuncture needles are widely used in the insulating layer (parylene between stainless needle and gold)
field of acupuncture and moxibustion for thousands of years were successfully fabricated, and the outermost layer of par-
with characteristics including small-sized, tough, smooth, and ylene was used for passivation to prevent leakage. Enlarged
safe (non-toxic).[10] The ability of acupuncture needles used as images show that the needle FET had the same morphology as
sensing devices has been well demonstrated for in vivo electro- the conventional chip FET device (Figure 1c). The EDS mapping
chemical monitoring of various biomolecules.[11] Inspired by and XPS were further employed to characterize the morphology
this, for the first time, a medical acupuncture needle-based FET and elementary composition of the prepared needle. The three-
microsensor is fabricated in this work, which can be inserted layer sandwich structure, especially the middle circle of the thin
into the rat brain to monitor the release of the neurotransmitter. gold layer, was obviously observed (Figure 1d,e), which was fur-
To construct the FET sensor, the needle body is subsequently ther demonstrated by XPS spectra where Au 4f peaks became
coated with a parylene insulating, Au, and parylene insulating very remarkable (Figure 1f). Figure 1g shows the optical images
layers, respectively (Scheme 1a). A micropipette polisher is of the acupuncture needle, the fabricated needle FET, and the
employed to grind the sharp tip of the needle to get a smooth commercially used injection syringe needle. It is clear that the
cross-section of the tip, exposing the structure of the stainless- prepared needle FET is nearly the same size as the bare acu-
parylene-Au-parylene layer inside. Then reduced graphene oxide puncture needle (The diameter of the needle body and the tip
(RGO) is dropped on a cross-section of the tip to connect the is 0.25 and 0.01 mm, respectively), but is significantly smaller
stainless needle (drain) and Au film (source), which is further than the normally used smallest injection syringe needle (26
modified by synthetic aptamer to specifically detect target trans- Gauge, O.D 0.46 mm). These results indicate that the needle
mitters (Scheme 1b). The widely used target dopamine (DA) FET will be minimally invasive and be easily inserted into the
was first used to demonstrate the detection ability of the needle rat body for in vivo measurement.
sensor. The prepared needle FET microsensor shows high sen-
sitivity and selectivity, excellent mechanical toughness with
minimal damage to living organisms, and has been successfully 2.2. Electronic Characterization of Needle FET
used to real-time monitor DA in a normal rat brain as well as
investigate the DA variations in a rat model of Parkinson’s dis- To construct an RGO needle FET, RGO was dipped on the top
ease in vivo (Scheme 1b). Then the needle-FET biosensor was of the device and then thermally annealed (150 °C, 2 h) to fur-
applied to detect a variety of targets including hormones (neuro- ther enhance the contact between RGO and the sensing area
peptide Y), proteins, and nucleic acid, and further proved to be (Figure 2a). As shown in Figure 1h, the SEM image shows
capable of real-time monitoring of neuropeptide Y in vivo. that the folds of large-scale RGO sheets connecting the drain
and source are clearly seen. Then, Raman spectroscopic char-
acterization of RGO was conducted. The results show that the
2. Results and Discussion intensity ratio between the D band (1350 cm−1) and G band
(1600 cm−1) was increased after the reduction of GO (Figure 1i,
2.1. Fabrication and Morphology Characterization of Needle the intensity ratio of D/G was 0.987 and 1.235, respectively,
FET Device before and after reduction of GO.), suggesting that there is a
decrease in the average size of the sp2 domains upon reduction
The preparation process of the needle FET device is shown of GO.[12] This result is consistent with that reported for chemi-
in Scheme 1, in which parylene and gold layers were succes- cally converted graphene,[13] indicating the successful reduction
sively deposited on the acupuncture needle surface. From of GO on the top surface of the needle.
SEM images of Figure 1a–c, it can be clearly seen that the well- Then the electrical properties of the RGO needle FET were
defined source (stainless needle), drains (gold layer) and an investigated by the output characteristic curves (Ids–Vds) and

Figure 1. Characterization of a needle FET. a–c) Scanning electron microscopy (SEM) images of the sensing cross-section of the bare needle-shaped
FET at different magnifications. d) Energy-dispersive spectroscopy (EDS) mapping of the sensing cross-section of the bare needle FET shows all the
elements that make up the sensor. e) EDS point analysis characterizes the element content of the Au layer of the bare needle FET. Insert: EDS mapping
of the Au layer. f) X-ray photoelectron spectroscopic spectra (XPS) characterization of the Au layer. g) The figure on the left is the overall optical picture
of the acupuncture needle and needle FET. The figure on the right is the dimension comparison between needle FET, commercially used acupuncture
needle, and the syringe needle. h) SEM image of the FET device after modification with RGO, the folds induced by large-scale RGO connecting the
source and drain. i) Raman spectroscopic characterization of RGO and GO on the sensing cross-section.
the transfer characteristic curves (Ids –Vg) of liquid-ion-gated PBS solution and tested for 10 cycles. As shown in Figure 2d,
needle transistors under various gate biases. As shown in the repeated transfer curves basically coincided, and the charge-
Figure 2b, the drain-source current was linearly relative to the neutrality point voltage (VCNP) of the transfer curve remained
drain-source voltage with different voltage values from −0.7 almost consistent during 10 cycles, and the relative standard
to 0 V. It is clear that the drain-source current increased with deviation (RSD) was calculated to be 1.9% (Figure 2d, inset).
the increase of the gate voltage. From the transfer character- In addition, the repeatability experiment was also conducted
istic curves, the typical ambipolar characteristic curve of the by measuring 10 different needle FET samples in the same
graphene could be observed under ambient conditions. The 0.1 × PBS buffer. As shown in Figure S1, Supporting Informa-
Dirac points of bipolar curves obtained by both the needle FET tion, the VCNP of the transfer curve from 10 different needle
and a conventional chip FET were almost at the same position FET remained almost consistent, and the relative standard devi-
(Figure 2c), revealing that the electronic performance of needle ation (RSD) was calculated to be 6.6%. These results indicate
FET is comparable to that of a conventional FET device. that the constructed needle FET devices have high repeatability.
Then, the stability of the RGO needle FET was evaluated by
storing the device in a vacuum oven for several days and meas-
2.3. Repeatability and Stability uring the transfer curve. As shown in Figure 2e, the transfer
curve of the device did not change significantly in 7 days. By
In order to study the repeatability of the fabricated RGO needle quantifying the shift of the Dirac voltage, it was found that the
FET sensor, the FET interface of the needle was immersed in Dirac voltage still maintained 82% of the original value after

Figure 2. Characterization of the electrical properties of needle FET. a) The figure on the left is a schematic diagram of a needle FET modified with RGO,
the figure on the right is a schematic diagram of sensor detection. b) Output characteristics of the RGO needle-shaped FET. c) Transfer characteristics
of RGO needle FET and RGO chip FET. Insert: normalized recording results of VCNP of RGO needle FET and RGO chip FET. Error bars indicate the
standard deviation (n = 3). d) Transfer curves of the RGO needle FET were measured 10 times. Insert: the corresponding VCNP changes for 10 times
measurement. e) Transfer curves characterize the one-week stability of the RGO needle FET. Insert: the corresponding VCNP changes for one-week
stability measurement. Error bars indicate the standard deviation (n = 3). f) Transfer curves of the needle FET after repeated grinding of the device
for 0, 20, 40, 60, 80, and 100 times. Insert: the corresponding VCNP changes for repeated grinding measurement. g) The transfer curves of the surface
functionalization process of the device including PASE modification, DA aptamer immobilization, and DA binding, respectively. h) The transfer curves
of DA aptamer-modified RGO needle FET in response to different concentrations (1, 10, and 100 nM, 1 and 10 µM) of DA. i) Calibration curve at a series
of target DA concentrations. Error bars indicate the standard deviation (n = 3). The dashed line refers to the three-fold noise level. (c–h, Vds = 0.1 V).
7 days (Figure 2e, inset, this shift is probably due to the nonspe- there was negligible change in the shape of the bipolar curve.
cific surface adsorptions[14]). The VCNP of the transfer curve varied by 2% and 14.6% after the
needle was ground 20 and 100 times, respectively (Figure 2f,
inset), demonstrating the excellent reusability of the needle-
2.4. Reusability shaped FET. After the sensor needle is polished, it can be used
for the re-functionalization process only by ultrasonic cleaning
The sensing interface can be reused by polishing the surface and with ethanol. In such a case, other residues, such as aptamer,
reassembling the conductive materials. To investigate the reus- are removed during the process of grinding. However, since the
ability of this needle transistor device, the electrical properties of tip of the needle is conical, the distance between the source and
the RGO needle FET with different polishing times were meas- the drain becomes larger and larger during the grinding pro-
ured. The tip is conical, and the surface area between the source cess, leading to the variation between batches to batches.
and drain may become larger and larger with the increasing
times of polishing. So it is understandable that a certain impact
on the shape and current of the graphene bipolar curve would 2.5. Response to Dopamine
occur. As shown in Figure 2f, after repeating the grinding of the
device for 0, 20, 40, 60, 80, and 100 times, despite some varia- In order to detect DA, a specific aptamer to DA was function-
tion in the current due to the change of tip size after grinding, alized on the RGO surface of the needle by 1-pyrenebutanoic

acid succinimidyl ester (PASE), a cross-linking molecule. Elec- 2.2 nm in 0.1 × PBS, respectively.[18c] It is obvious that 1 × PBS
trical measurements were performed to verify that the step-by- has a shorter Debye screening length, leading to a decrease in
step modification process on the RGO surface was successful sensitivity when switched to physiological solutions.
and the recognition was feasible. As shown in Figure 2g, the The selectivity of the aptamer-modified needle FET sensor
Dirac point shifted positively after the modification of PASE, towards DA was conducted by adding various interfering spe-
which was induced by p-doping from positive charges provided cies including other neurotransmitters such as glutamate (Glu),
by PASE.[15] After the DA aptamer was immobilized, the Dirac epinephrine (EP), ascorbic acid (AA), norepinephrine (NE), ace-
point shifted negatively, which was caused by the contribution tylcholine (Ach), and so on. As depicted in Figure 3e, negligible
of the negatively charged DNA aptamer. Once DA was cap- current fluctuations were observed when interferences were
tured by the aptamer, the negative shift of the Dirac point was introduced, while a dramatic decrease in current was observed
attributed to the n-doping induced by the configuration change when DA was introduced. The change rates of current are sum-
of the specific aptamer.[16] Specifically, upon binding with DA, marized in Figure 3f (current change rate ∆I/I0 = (I2−I1)/I1,
the aptamer switches to a stable and compact conformation[16,17] where I2 is the stable current after adding the substance, and
(Figure 3d). Thereby, the negatively charged DA-aptamer com- I1 is the steady-state current before adding the substance). The
plex approaches the RGO surface, increasing negative charges results demonstrate that the aptamer-modified needle FET
in the RGO channel, and hence generating a detectable negative sensor has excellent selectivity to DA.
shift. The shifts of transfer curves indicate that the DA aptamer
was successfully modified on the needle FET and could spe-
cifically recognize DA. Then, the aptamer-modified needle FET 2.7. Real-Time Monitoring of DA in PC12 Cell
sensor was applied to detect different concentrations of DA. As
displayed in Figure 2h, in the range from 1 nM to 10 mM, Dirac Based on the highly sensitive and specific response of the
points of transfer curves negatively shifted with increasing con- needle FET to DA in the buffer, we further used the sensor
centrations of DA. Figure 2i shows a linear relationship between to monitor the release of DA at the cellular level (Figure 3g).
DA concentrations and changes in ∆VCNP (∆VCNP = VCNP after PC12 cells are a type of catecholamine cells that synthesize,
incubating DA – VCNP of DA aptamer) with a correlation coef- store and release DA.[19] It has been reported that stimulation
ficient value (R2) of 0.9824. All the above results show the excel- of PC12 cells with a high K+ solution leads to the release of
lent response of the DA-aptamer FET biosensor to the DA. DA from large dense-core vesicles of the cells.[20] After PC12
cells were grown for 48 h under the action of neuronal growth
factor (NGF), the development of new neurites was observed
2.6. Real-Time Measurement of DA In Vitro (Figure 3h, inset) and used for electrical testing. As shown in
Figure 3h, when 10 mM high potassium was added to the PC12
We further investigated the performance of the needle FET cultured well, the current dropped immediately and slowly sta-
by real-time measuring electrical response to different con- bilized after a period of time (red line). In a control experiment,
centrations of DA from 1 nM to 10 µM in PBS (Figure 3a). when high potassium was added to 1 × PBS without PC12,
As displayed in Figure 3b, the current decreased along with the current signal slightly increased (black line). The above
the increasing concentration of DA, while the response of the results strongly indicate that the observed current response
needle FET without aptamer modification was negligible. The was derived from DA release in PC12 cells. The histogram in
linear relationship between the change rate of current and con- Figure 3i shows the electrical change of real-time measurement
centrations of DA is summarized in Figure 3c. The fitting equa- of the medium with the same cell density by the needle FET
tion is expressed as −∆I/I0 = 3.06 lgCDA + 29.19, R2 = 0.9905, sensor. Repeated experiments under the same conditions had
where ΔI = Ids−I0, Ids is drain-source current, and I0 is the ini- obviously similar electrical responses. Cell experiments show
tial current. On the basis of the signal that exceeds the baseline that the needle FET sensor responds well to DA in a physiolog-
by three-fold, the detection limit was calculated to be 370 pM ical environment, and the excellent sensing performance lays
according to the linear relationship of the working curve. To the foundation for subsequent in vivo experiments.
further ascertain that the RGO needle FET biosensor could To prove the biocompatibility of the aptamer-modified needle
work well in complex physiological solutions, a mock sample FET sensor, the toxicity test was conducted using a CCK-8
that contained 10% fetal bovine serum (FBS) was also con- assay.[21] After the tips of both the acupuncture and the aptamer-
ducted. As shown in Figure S6, Supporting Information, it was modified needle FET sensors were cut off and cultured with PC
clearly observed that the current reduced as the concentration 12 cells for 24 h, the results of the CCK-8 assay show that the
of DA increased, which is consistent with the above-mentioned normalized viabilities at the two conditions remained as high
experimental results. The linear relationship was represented as 96%, and 93%, respectively (Figure S2, Supporting Informa-
by −ΔI/I0 = 1.07 lgCDA + 10.22, R2 = 0.9852. The experiments tion), indicating the good biocompatibility of the as-prepared
demonstrate the sensor’s satisfactory performance in complex sensor.
physiological solutions. The ionic strength influences the sen-
sor’s performance greatly due to the Debye screening effect.
The effective electrical field of FET biosensors could only be 2.8. Real-Time Monitoring of DA In Vivo
controlled within a distance called the Debye length (λD), and
λD is inversely proportional to the ionic strength of the solu- The ability of the sensor for in vivo measurement was then
tion.[18] As reported, the value of λD is 0.7 nm in 1 × PBS, and evaluated. After anesthesia and stereotaxic procedures, the rats

Figure 3. In vitro dopamine monitoring using an aptamer/RGO needle FET. a) Schematic illustrations showing an in vitro experiment in PBS buffer
containing dopamine. b) Real-time current measured by aptamer/RGO needle FET sensor, responding to different concentrations (1, 10, and 100 nM
and 1 and 10 µM) of DA in 0.1 × PBS with Vds = 0.07 V and Vg = −0.1 V. Signal is defined by ΔI/I0, where ΔI is the current change (drain current [Ids]
− initial drain current [I0]) and I0 is the initial drain current. Insert: Real-time current of non-aptamer-modified RGO needle FET, responding to the
addition of DA. c) Calibration curve of aptamer/RGO needle FET to a series of DA concentrations in PBS. Error bars indicate the standard deviation
(n = 3). The dashed line refers to a three-fold noise level. d) Schematic illustrations showing the surface functionalization of the RGO sensing channel
of needle FET. e) Real-time current curve of aptamer/RGO needle FET, responding to various interferents and 100 nM DA. Vds = 0.07 V and Vg = −0.1 V.
f) Histogram of the current change rates versus various interferents and DA, where the concentration of interferents was higher than the concentration
of DA. g) Schematic illustrations showing an in vitro experiment in PBS buffer containing PC12 cells. h) Real-time current responses of the aptamer/
RGO needle FET stimulated by 10 mM K+ with PC12 (red) and without PC12 (black). Vds = 0.07 V and Vg = −0.1 V. Insert: optical photo of PC12 cells.
i) Normalized results of the aptamer/RGO needle FET to the response of PC12 cells. Error bars indicate the standard deviation (n = 3).
were fixed on a stereotaxic frame, and the aptamer-modified same location did not cause any significant electrical response
needle FET sensor was implanted into the DA-rich dorsal stri- (Figure 4c), demonstrating that the needle sensor can respond
atum (DS) for recording[22] (Figure 4a,b). After implantation, to DA in vivo. Then, the needle FET was implanted into the
the electronic properties of the needle FET were further con- dorsal striatum (DS) tissue. Upon the addition of high K+ stim-
firmed by collecting the transfer curves from the needle FET. ulation, the current of the sensor declined significantly, which
As shown in Figure S3, Supporting Information, the transfer is ascribed to the rapid DA release. As a comparison, the cur-
curve showed typical FET characteristics. The real-time meas- rent response of the sensor without aptamer was negligible
urement model was then used to record the DA concentration under similar experimental conditions (Figure S4, Supporting
change during high K+ stimulation. Firstly, 100 µL of 1 nM Information). Subsequently, the sensor was located within the
DA solution was injected directly into the rats’ brains near the non-DA-rich forelimb region of the primary somatosensory
sensor’s implantation site to evaluate the performance of the cortex[22b] (S1FL, Figure 4a, green arrow). Compared to the
needle FET sensor. The results show that the current response obvious response from DA-rich DS, no noteworthy response
was sensitive to DA, while the injection of the saline at the was found from non-DA-rich S1FL and the current change rate

Figure 4. In vivo dopamine monitoring using an aptamer/RGO needle FET. a) Schematic diagram of in vivo experiment. b) Photographs of in vivo
experiments. c) Real-time measurement of pumped saline and 1 nM DA in rat brain using aptamer/RGO needle FET. Vds = 0.07 V and Vg = −0.1 V.
d) Real-time measurement of DA release from DA-rich DS and non-DA-rich S1FL, respectively. Vds = 0.07 V and Vg = −0.1 V. Insert: the histogram of
the average current change rates induced by two different detection regions. Error bars indicate the standard deviation (n = 3). e) Real-time measure-
ment of aptamer/RGO needle FET responding to DA from DS under high K+ stimulant. The yellow curve is the response after the administration of
pimozide. The blue curve is the control without drug injection. The red curve is the response after the administration of nomifensine. Vds = 0.07 V and
Vg = −0.1 V. Insert: the histogram of the average current change rates induced by the two different drugs. Error bars indicate the standard deviation
(n = 3). f) Real-time measurements of aptamer/RGO needle FET responding to DA released by high K+ stimulant in parkinsonian rats (purple) and
the normal rats (blue), respectively. Vds = 0.07 V and Vg = −0.1 V. Insert: the histogram of the average current change rates responded to DA released
in rat models and the normal rats. Error bars indicate the standard deviation (n = 3).
of different brain regions is summarized in Figure 4d. This the location was found to be almost the same as that reported in
negligible response in the non-DA-rich area provided clear sup- the literature,[24b] proving the localization of the DS is accurate,
port that the change of current recorded in the dorsal striatum and the experimental results we obtained are reliable.
was caused by DA release in origin. The above experimental
results indicate the excellent performance of the aptamer-modi-
fied needle FET sensor, which can be used to real-time monitor 2.9. Comparison of Signal Response to DA in Parkinsonian Rats
the dynamic change of DA in a complex living environment. and Normal Rats
Numerous studies have shown that the ameliorative action
of dopaminergic antagonists and agonists can alter cognitive Parkinson’s disease is a central nervous system degenerative
functions. To study the effect of DA antagonists and agonists disease, which is characterized by a significant decrease in DA
on DA release levels in DS tissue, an administration involving in the striatum. Therefore, real-time monitoring of the dynamic
two drugs was observed by the needle sensor. Pimozide is a level of DA is of great significance in disease diagnosis and pro-
kind of DA receptor antagonist, which inhibits the production gression. Here, the stimulated DA release level in Parkinson’s
of DA and the transportation of DA vesicles, thus reducing DA disease model rats and normal rats was investigated. 6-Hydroxy-
release.[23] Nomifensine is a competitive DA transporter inhib- dopamine was injected into the substantia nigra pars compacta
itor that can inhibit the transport of DA and increase the cumu- and ventro tegmental area of the rat brain to establish a parkinso-
lative concentration of DA in the tissue fluid.[24] Under injection nian rat model.[25] Firstly, the Morris water maze experiment was
of pimozide, the change of current (yellow) was significantly conducted to verify the PD model rat (Figure S6a, Supporting
lower than that of the control group (blue), while the change Information). As shown in Figure S6b,c, Supporting Informa-
of current (red) was higher than that of the control when tion, the total swimming length and swimming time for the PD
nomifensine was applied (Figure 4e). To further distinguish the model group were higher than those in the control and sham-
response, the average (n = 3) current change rates are summa- operated groups, demonstrating the successful establishment of
rized. As shown in Figure 4e, inset, the changes in DA release the PD rat model. Then the tyrosine hydroxylase (TH) staining
induced by drugs are in agreement with previous literature further confirms that the brown TH-positive cell density of the
reports.[22a,23b] The results indicate that the developed needle parkinsonian rat model brain section was lower than that of the
FET sensor can monitor the dynamic changes of DA concentra- normal rat brain section, meaning that the number of dopa-
tion in vivo after the administration of different drugs. minergic neurons in the parkinsonian rat model was reduced
In order to demonstrate the needle sensor was accurately (Figure S6d, Supporting Information). Both experimental results
located in the DS area, the brain tissue was dissected after in prove that the PD model rat has successfully been prepared.
vivo experiment, and sections were taken out for verification. As Then the electrical measurements were performed using
shown in Figure S5, Supporting Information, obvious signs were the needle FET sensor, and the corresponding results are dis-
observed in the DS tissue in the frozen section of the brain, and played in Figure 4f. Under a high K+ stimulant, the response of

the FET sensor to DA released from Parkinson’s rat models in electrochemically inactive substances, such as hormones,
three times experiments (purple) was significantly lower than proteins, and nucleic acid. Three representative substances
that of normal rats (blue). The reduced DA signal is ascribed including neuropeptides Y (NPY), transmembrane glycoprotein
to the destruction of dopaminergic neurons, so the synthesis Mucin 1 (MUC1), and miRNA21 were used for proof-of-concept
and release of DA are reduced in the Parkinson’s rat model. validation. To detect NPY, NPY aptamer was modified on the
According to the calibration curve in a mock sample (Figure S7, tip of the needle surface through PASE. After NPY was cap-
Supporting Information), the measured dopamine concentra- tured by the specific aptamer, the Dirac point negatively shifted,
tion of normal and PD rats are 20.79 ± 4.35 and 1.75 ± 0.36 nM, which was attributed to the n-doping induced by the configura-
respectively, compared to other in vivo sensors, the detected DA tion change of the NPY aptamer. The response mechanism is
concentration is the lowest (Table S1, Supporting Information), similar to that of DA-aptamer binding. As shown in Figure S9a,
indicating that the developed needle FET sensor is highly sen- Supporting Information, the transfer curves indicate that the
sitive and able to distinguish the Parkinson’s rat model from NPY aptamer was successfully modified on the needle FET
the normal rats by detecting the level of DA release, which has and could specifically recognize NPY. Then, the aptamer-mod-
great potential for clinical application in the future. Further- ified needle FET sensor was further applied to detect different
more, LC-MS analysis of dopamine in rat brain tissues further concentrations of NPY. As shown in Figure 5a, Dirac points
confirms that the electrical signal detected from rat brain tissue negatively shifted with increasing concentrations of NPY from
is dopamine (Figure S8, Supporting Information). 100 pM to 1 µM. Figure 5a inset shows a linear relationship
between NPY concentrations and the VCNP changes.
For MUC1 and miRNA21 detection, the FET surface was
2.10. Proof-of-Concept Validation of Electrochemically Inactive modified with MUC1 aptamer and phosphorodiamidate mor-
Molecules pholino oligos (PMO) probe, respectively. Similar Dirac point
change trends regarding the modification and detection of
In order to further extend the application of this method, the MUC1 and miRNA21 process were obtained (Figure S9b,c, Sup-
needle device was functionalized and applied to detect other porting Information). As shown in Figure 5b,c, the prepared
Figure 5. Application of needle FET for the detection of electrochemically inactive molecules. a) The transfer curves of NPY aptamer-modified RGO
needle FET in response to different concentrations (100 pM, 1, 10, and 100 nM and 1 µM) of NPY. Vds = 0.1 V. Insert: calibration curve at a series of
target NPY concentrations. Error bars indicate the standard deviation (n = 3). The dashed line refers to the three-fold noise level. b) The transfer curves
of MUC1 aptamer-modified RGO needle FET in response to different concentrations (100 fg mL−1, 1, 10, and 100 pg mL−1 and 1 ng mL−1) of MUC1.
Vds = 0.1 V. Insert: calibration curve at a series of target MUC1 concentrations. c) The transfer curves of PMO-modified RGO needle FET in response
to different concentrations (100 fM, 1, 10, and 100 pM and 1 nM) of miRNA21. Vds = 0.1 V. Insert: calibration curve at a series of target miRNA21 con-
centrations. d) Real-time current measured by aptamer/RGO needle FET sensor, responding to different concentrations (100 pM, 1, 10, and 100 nM, 1
and 10 µM) of NPY in 0.1 × PBS with Vds = 0.07 V and Vg = −0.1 V. inset: the real-time response of the needle sensor without modification of the NPY
aptamer to PBS and 100 nM NPY, respectively. e) Real-time measurement of pumped saline and high K+ stimulant in rat brain using aptamer/RGO
needle FET. Vds = 0.07 V and Vg = −0.1 V. f) The histogram of the average current change rates induced by two different injection solutions. Error bars
indicate the standard deviation (n = 3).

needle FETs were sensitive to MUC1 and miRNA21 and small enough to be inserted into the body as minimally inva-
responded well at very low concentrations. For MUC1, in the sive as possible. Acupuncture needle, which has been used to
range from 100 fg mL−1 to 1 ng mL−1, the Dirac point negatively treat diseases for thousands of years, just meets the require-
shifted with increasing concentrations and the linear response ments. The needle-shaped FET microsensor has some merits:
was obtained. Similarly, for miRNA21 detection, the Dirac point 1) Diversity: the sensor can be used to detect a variety of targets
negatively shifted with increasing concentration and the results including small molecules, proteins, and nucleic acid. 2) Port-
show good linearity in the range from 100 fM to 1 nM. All the ability: the single-needle FET device is movable and portable,
above results indicate that the shift of the Dirac point depends and can be easily moved or inserted into cells or any part of
on the change in protein and nucleic acid concentration. These the living body for detection. 3) Toughness: The needle is tough
proof-of-concept validation experiments demonstrate that the enough so that in vivo detection can be realized and damage is
prepared needle FET sensor can be used to detect a variety of minimized. 4) Re-generation: due to its simple structure and
targets including hormones, proteins, and nucleic acid. easy-to-fabrication, it can be re-generated by grinding it hun-
NPYs, as a representative of electrochemical inactive neuro- dreds of times, which is economical and affordable. However,
transmitters, was further used for in vivo validation. The specific the demerits of the sensor also exist: due to the small needle
stereotaxic location of the brain is shown in the experimental tip and the functional process is not easy; moreover, there are
section based on the references that have been reported.[26] variations between batches to batches in the preparation of
Prior to in vivo detection, the real-time detection capability of biosensors.
the needle FET to NPY was verified. As shown in Figure 5d, the In conclusion, we have developed a novel needle FET sensor
current signal decreased as the concentration of NPY increased, based on a traditional acupuncture needle that perfectly meets
which is consistent with literature reports.[27] In addition, the the requirements for real-time monitoring of signal molecules
anti-interference experiments of NPY were performed by in vivo. The microsensor hopefully provides an effective tech-
selecting some potential interferents such as nitric oxide (NO), nique for neuroscience research. Efforts to employ other nano-
dihydroxy-phenyl acetic acid (DOPAC), hydrogen peroxide materials exhibiting semiconducting properties as sensing
(H2O2), 5-hydroxytryptamine (5-HT), and K+. The results are channels, and detect other electrochemically inactive molecules,
shown in Figure S10, Supporting Information, negligible cur- are currently being made in our laboratories. In the future, we
rent fluctuations were observed when interferences were intro- expect that the small dimensions of the electrode combined
duced, while a dramatic decrease in current was observed when with high sensitivity and selectivity will allow the needle FET to
100 nM NPY was added. The change rates of current are sum- become a powerful tool for the analysis of the signal molecules
marized in Figure S10b, Supporting Information. The results in vivo. This will possibly facilitate the development of inter-
demonstrate that the aptamer-modified needle FET sensor has disciplinary research areas across analytical chemistry and life
excellent selectivity to NPY. Then the needle sensor was further science.
used for in vivo detection. As exhibited in Figure 5e, after high
K+ stimulation, the current of the needle sensor declined signif-
icantly, which was caused by the rapid NPY release. As a com- 4. Experimental Section
parison, the current response of the sensor without aptamer
was negligible under similar experimental conditions. The Fabrication of Needle Field-Effect Transistor: The specific preparation
process of the needle field-effect transistor (FET) was as follows. Firstly,
average (n = 3) current change rates are summarized to further 7-µm-thick parylene layer was deposited on the surface of a clean
distinguish the response (Figure 5f). The above results demon- acupuncture needle using vacuum gas phase deposition. Subsequently,
strate that the prepared needle FET sensor can be successfully electroplating a gold film about 1 µm thick was coated on the parylene
used for real-time monitoring of electrochemical inactive signal layer. Thus, a simple FET device consisting of a metal acupuncture
molecules in vivo, greatly expanding the range of detection of needle, insulation layer, and gold layers sandwich structure was formed.
signal molecules in vivo. To prevent leakage of current during detection in the solution, a parylene
layer of insulation on the surface of the gold layer by vacuum gas phase
deposition was then deposited. After the needle FET was prepared, a
micropipette polisher was employed to grind the needle tip to get a
3. Conclusion and Future Perspective smooth cross-section FET surface. The prepared needle FET was stored
in a vacuum-drying oven. In order to ensure the quality of the needle
Compared to the amperometric method, the needle FET micro- FET from batch to batch, the professional company helped complete the
sensor allows real-time monitoring of physiological informa- fabrication process (Shanghai Parylene Biotechnology Co., Ltd).
Fabrication of RGO Needle FET: 1 mg mL−1 RGO suspension was
tion with higher sensitivity due to its intrinsic amplification
prepared as previously reported, and it could be stocked stably in the
capabilities and high signal-to-noise ratio. Furthermore, for refrigerator for months without aggregation.[12a] 0.2 mg mL−1 RGO
some non-electroactive signal molecules, the FET method is diluted from 1 mg mL−1 RGO was dropped on the tip of the needle to
more feasible (without enzyme catalysis and the lower detection connect stainless steel and Au film, and then the needle was thermally
voltage). Although many bio-FET sensors have been reported annealed at 150 °C in a vacuum oven for 2 h to further enhance the
for the detection of nucleic acid, proteins, and other biomol- contact between RGO and sensing area of the needle. Finally, the tip of
ecules using plasma samples or at the cellular level, the FET the needle was washed thoroughly with ultrapure water and dried under
nitrogen for subsequent experiments.
sensors for real-time and in vivo detection are seldom reported. Functionalization of Needle FET: In order to immobilize the probe
The main challenge of fabrication of in vivo FET devices lies such as aptamer or PMO on the sensing channel, 5 mM PASE (chemical
in two aspects: one is the good performance (sensitivity, speci- cross-linker molecule) in dimethyl-sulfoxide was incubated with
ficity, stability) and the other is that the device’s size must be RGO needle-shaped FET for 1.5 h. PASE was able to react with RGO

through π–π stacking between the pyrene group of PASE and the RGO. Keywords
Afterward, aptamer or PMO was incubated with PASE-modified RGO
FET for 2 h, where the succinimidyl ester group provided by the other acupuncture needles, field effect transistors, in vivo, neurotransmitters,
end of the PASE molecule was bound to the amino group provided by real-time
the capture probe through the formation of an amide bond. After the
DA aptamer was fixed on the RGO surface, 1 mg mL−1 bovine serum Received: July 6, 2022
albumin (B solution was used for blocking and preventing nonspecific Revised: October 27, 2022
adsorption during detection. Published online: November 7, 2022
Electrical Measurements: A Keithley 4200 semiconductor system
combined with an EverBeingBD-6 probe station was applied for the whole
electrical measurements. The two wires with an iron clip were used to
connect the probe station. For target measurements, the corresponding
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Acupuncture Needle-Based Transistor Neuroprobe for In

analysis of dynamic neurochemicals in

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