Fabrication of Liquid-Crystal-Based Optical Sensing Platform for

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Fabrication of liquid crystal-based optical sensing platform for detection of hydrogen peroxide and blood glucose Lubin Qi, Qiongzheng Hu, Qi Kang, and Li Yu Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.8b03062 • Publication Date (Web): 05 Sep 2018 Downloaded from http://pubs.acs.org on September 6, 2018

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Analytical Chemistry

Fabrication of liquid crystal-based optical sensing platform for detection of hydrogen peroxide and blood glucose Lubin Qi,a,1 Qiongzheng Hu,b,1 Qi Kang,c and Li Yu a* a

Key Laboratory of Colloid and Interface Chemistry, Shandong University, Ministry of Education, Jinan 250100, PR China.

b

Salk Institute for Biological Studies, 10010 N Torrey Pines Rd, La Jolla, CA 92037, United States.

c

College of Chemistry, Chemical Engineering and Materials Science, Shandong Normal University, Jinan 250014, PR China.

*

Corresponding author: Prof. Li Yu

Phone number: +86-531-88364807 Fax number: +86-531-88564750 Email address: [email protected] 1

These authors contributed equally

1

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Analytical Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

1

Abstract

2

Rapid and accurate determination of H2O2 is of great importance in practical

3

applications. In this study, we demonstrate construction of liquid crystal (LC)-based

4

sensing platforms for sensitive and real-time detection of H2O2 with high accuracy for

5

the first time. Single-stranded DNA (ssDNA) adsorbed onto the surface of nanoceria

6

is released to the aqueous solution in the presence of H2O2, which disrupts

7

arrangement of the self-assembled cationic surfactant monolayer decorated at the

8

aqueous/LC interface. Thus, the orientation of LCs changes from homeotropic to

9

planar state, leading to change in the optical response from dark to bright appearance.

10

As H2O2 can be produced during oxidation of glucose by glucose oxidase (GOx),

11

detection of glucose is also fulfilled by employing the H2O2 sensing platform. Our

12

system can detect H2O2 and glucose with a concentration as low as 28.9 nM and 0.52

13

µM, respectively. It shows high promise of using LC-based sensors for the detection

14

of H2O2 and its relevant biomarkers in practical applications.

15

Keywords: liquid crystal, sensing platform, single-stranded DNA, H2O2, blood

16

glucose

2


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1

Introduction

2

Rapid and sensitive detection of bio-markers is significantly important in clinic

3

diagnosis.1-6 H2O2, as an important bio-marker, plays a crucial role in various

4

biological processes, environmental sensing, clinical analysis, food safety, and etc.7-9

5

Excess production of H2O2 results in oxidative stress that is highly associated with

6

many pathological events such as parkinson's diseases, alzheimer's diseases, diabetes,

7

and

8

chromatography,14-15

9

luminescence,23-24 and electrochemistry.25-28 However, most of these techniques

10

require intensive labor and complex instrumentation. It is essential to develop a simple,

11

convenient, and label-free assay to detect H2O2 with high accuracy and sensitivity,

12

which can meet the requirement of various practical applications.

myocardial

infarction.10-13 fluorescence

Currently,

H2O2

analysis,16-19

is

mainly

detected

colorimetry,20-22

by

chemical

13

Liquid crystalline materials have been widely used in biosensing applications

14

during the past decades.29-30 In liquid crystal (LC)-based sensors, LCs work as

15

amplifiers and transducers to report biomolecular events coupled to orientational

16

transitions of LCs at the functional LC interface.31 The optical responses of LCs are

17

visible by the naked eye.32-33 Thanks to significant advances of the LC-based sensors in

18

the recent years, they have been extensively applied in simple, convenient, real-time,

19

and label-free detection of various biomolecules such as enzyme,34-38 proteins,39-43

20

DNA,44-48 and small molecules.49-51 Although H2O2 is closely related to many critical

21

biological processes, due to its unique properties, development of a LC-based H2O2

22

sensing system is very challenging and has not been achieved yet, which greatly

23

impedes applications of the LC-based sensors.

3



1

Nano CeO2, one of the most active catalysts, has been commonly applied to detect

2

H2O2 due to its high peroxidase-like activity.52-54 Recently, Nano CeO2-based hybrid

3

materials have been prepared to improve detection limit of H2O2.20, 55-57 For example, it

4

was demonstrated that the strong affinity between Nano CeO2 and H2O2 could be used

5

as an alternative strategy to achieve detection of H2O2 with high sensitivity and

6

selectivity.21, 58

7

In this study, we report construction of a LC-based sensing platforms for detection

8

of H2O2 for the first time. The experimental system is shown in Figure 1a and 1b. LCs

9

are confined in the holes of the TEM grids supported on the octadecyltrichlorosilane

10

(OTS)-treated surface. In the presence of H2O2, single-stranded DNA (ss-DNA)

11

adsorbed on the surface of nano CeO2 is released to the aqueous solution, which

12

disrupts arrangement of the octadecytrimethylammonium bromide (OTAB) monolayer

13

at the aqueous/LC interface. Thus, the orientation of LCs changes from perpendicular

14

(Figure 1c) to planar state (Figure 1d), thereby inducing change of the optical response

15

from dark (Figure 1e) to bright appearance (Figure 1f). In addition, the developed H2O2

16

sensing platforms can be used to detect clinically significant biomarkers such as

17

glucose, cholesterol, uric acid, and lactic acid, which are related to many critical

18

biological processes. Detection of glucose is demonstrated as an example. Using this

19

strategy, we could detect H2O2 and glucose with a concentration as low as 28.9 nM and

20

0.52 µM, respectively. The LC-based H2O2 sensing platform is very promising and can

21

meet requirement of many practical applications.

4


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1 2

Figure 1 (a) Photograph viewed on top of the LC cell fabricated on the glass. (b)

3

Schematic illustration of the sideview of the LC cell. Schematic illustration of the

4

orientational transition of LCs from (c) homeotropic state to (d) planar state in the

5

presence of H2O2, corresponding to the (e) dark and (f) bright LC images,

6

respectively.

7

Experiment

8

Materials

9

16-mer single stranded DNA (5' to 3' AGAAAAAACTTCGTGC) and FAM

10

(carboxyfluorescein)-labeled ssDNA (5' to 3' FAM-AGAAAAAACTTCGTGC) were

11

purchased form Sangon Biotech Co., Ltd., China. Glucose oxidase (GOx) and

5



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1

4-(2-hydroxyethyl)-piperazine-1-ethanesulfonic acid (HEPES) were bought from

2

Sigma-Aldrich. Sodium carbonate, sodium bicarbonate, magnesium chloride, calcium

3

chloride, ferric chloride, sodium chloride, potassium chloride, glutathione and Sodium

4

dodecyl sulfate (SDS) were obtained by Sinopharm Chemical Reagent Co., Ltd., China.

5

20% CeO2 nanoparticle suspension (particle size is about 50 nm), nematic liquid crystal

6

4-cyano-4'-pentylbiphenyl

7

octadecytrimethylammonium bromide (OTAB), nucleosides, amino acid, uric acid,

8

fructose, galactose, and sucrose were purchased from J&K Scientific Co., Ltd., China.

9

Copper specimen grids (G75 with hole pitch of 340 µm, bar width of 55 µm, hole width

10

of 285 µm) were supplied by GILDER. Commercial glucose meter was purchased by

11

Bayer HealthCare LLC.

12

Preparation of OTS-treated glasses

(5CB),

octadecyltrichlorosilane

(OTS),

13

The glasses were prepared according to the previous publication.59-60 Briefly, at

14

first, the glass slides were cleaned by “piranha solution” (70% H2SO4/30% H2O2.

15

Caution: “piranha solution” reacts violently with organic substance and should be

16

handled with extreme caution; do not store the solution in closed containers.) for 30

17

min at 80 °C. The slides were rinsed with ultrapure water, ethanol, and methanol and

18

dried by nitrogen. Before used, the cleaned glasses were stored under vacuum at

19

110 °C for 12 h. Following, the “piranha-cleaned” glass slides were submerged in 80

20

mL n-heptane solution of OTS for 30 min (0.1 g OTS was used), rinsed with plentiful

21

amounts of methylene chloride and then dried under nitrogen.

6


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1

Fabrication of the optical cell

2

First, OTAB dissolved in chloroform was added to the nematic liquid crystal

3

4-cyano-4'-pentylbiphenyl (5CB), and then dried under gaseous nitrogen. The final

4

concentration of OTAB in the 5CB was 300 µM. Copper grid was placed onto the

5

OTS-treated glass. Then, about 1.5 µL 5CB containing 300 µM OTAB was dispensed

6

onto the grid. Subsequently, the excess 5CB was removed by using a 20 µL capillary

7

tube. For fabrication of SDS-laden LC interface, the optical cell was constructed by

8

pure 5CB as described above. Then, 1 mM aqueous solution of SDS was transferred

9

onto LC interface. At last, we exchanged the aqueous solution of SDS with HEPES

10

three times to remove free SDS.

11

Detection of H2O2 by the LC-based sensing platform

12

H2O2 solution was first mixed with nano CeO2 colloid solution. The final

13

concentration of nano CeO2 was 50 µg/mL. Then, single-stranded DNA (ssDNA) in

14

HEPES buffer (pH=7, 10 mM HEPES and 150 mM NaCl) was added into the

15

above-mentioned mixture. The final concentration of ssDNA was 1 µM. After that, 50

16

µL of the mixed solution was transferred into the fabricated optical cell. A polarized

17

light microscope (XPF-800C, Tianxing, Shanghai, China) attached with a 2.5х

18

objective lens and a digital camera (TK-9301EC, JVC, Japan) was used to capture the

19

optical images of 5CB at room temperature. Bright area coverage ratios (Br) of the

20

optical images were calculated using the Adobe Photoshop 6.

21

Detection of glucose

7



1

Detection of glucose was performed as follows. First, various concentrations of

2

glucose were incubated with glucose oxidase in the HEPES buffer at 37 °C for 40 min.

3

Then, those solutions were added into nano CeO2 colloid solution with a final

4

concentration of 50 µg/mL, respectively. Subsequently, ssDNA with a final

5

concentration of 1 µM was added into the above-mentioned mixture. To confirm

6

selectivity of the sensing platform, glucose were replaced by 0.1 mM fructose,

7

galactose, and sucrose, respectively. To detect blood glucose, blood sample from a

8

healthy donor was diluted 500 times and used as blank to detect blood glucose. The

9

standard addition method was used to minimize the matrix effect. Briefly, 10 µL

10

glucose solution with varying concentrations (0-40 µM) and 10 µL diluted blood was

11

added into 80 µL HEPES buffer (containing 150 mM NaCl and 1 mM MgCl2). Then,

12

the samples were measured as described before. The calculated value was multiplied by

13

5000 to obtain the blood glucose concentration A commercial glucose meter was

14

applied to measure the blood glucose following the recommended protocol.

15

UV-Visible Spectrometry

16

The mixed solutions of 50 µg/mL nano CeO2 nanoparticle suspension and

17

different concentrations H2O2 were examined by using a Hitachi U 4100 UV-Vis

18

spectrometer with a 10 mm path length quartz cell at the wavelength from 250 to 500

19

nm. The background signal was subtracted from the sample signal with water used as

20

reference.

21

Circular Dichroism (CD)

8


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1

CD spectra were recorded by using a JASCO J-810 spectropolarimeter ranging

2

from 220 to 320 nm at a controlled scanning speed of 100 nm/min. Complexes of 60

3

µM ssDNA and different concentrations of nano CeO2 were analyzed in a 10 mm path

4

length cell. Each sample was measured three times and the resulting values were then

5

averaged automatically.

6

Results and discussion

7

Effect of ssDNA and ssDNA/nano CeO2 complex on orientations of LCs

8 9

Figure 2 Polarized microscopy images of LCs upon addition of (a) 10 µM ssDNA, (b)

10

1 µM ssDNA, (c) 0.1 µM ssDNA (d) 0.01 µM ssDNA; Polarized microscopy images

11

of LCs upon addition of 1 µM ssDNA complexed with (e) 100 µg/mL nano CeO2, (f)

12

50 µg/mL nano CeO2, (g) 10 µg/mL nano CeO2, and (h) 1 µg/mL nano CeO2. The

13

concentrations indicated are the final concentrations.

14

In this study, the LC sensing platform was constructed on the cationic surfactant

15

OTAB-decorated LC interface, Based on previous studies, amphiphilic surfactants with 9



1

long hydrocarbon tails could form a self-assembled monolayer at the aqueous/LC

2

interface, inducing orientational transition of LCs from planar to homeotropic state31, 61.

3

Thus, the optical response of LCs changed from dark (Figure S1a) to bright (Figure S1b)

4

appearance in the presence of OTAB. The corresponding conoscopy image (Figure

5

S1c) confirmed the homeotropic orientation of LCs. First, we studied optical responses

6

of LCs after introducing different concentrations of ssDNA onto the OTAB-laden LC

7

interface. Figure 2a to Figure 2d showed that LCs gradually changed from bright to

8

dark appearance with reducing the concentrations of ssDNA from 10 µM to 0.01 µM.

9

These results suggest the organization of OTAB monolayer could be uniformly

10

disrupted by ssDNA with a concentration of above 1 µM.62-63 We also conducted

11

additional experiments to investigate the mechanism of this phenomenon. It was

12

found that the ssDNA could not disrupt the negatively charged SDS monolayer

13

(Figure S2a and S2b) at the aqueous/LC interface. In addition, we introduced FAM

14

(carboxyfluorescein)-labeled ssDNA onto the OTAB-laden and SDS-laden LC

15

interface, respectively. After removing free FAM-ssDNA, the bright image (Figure

16

S2c) of the OTAB-laden LC interface was observed under fluorescence microscope.

17

However, the image of the SDS-laden LC interface remained dark under fluorescence

18

microscope (Figure S2d). These results indicate electrostatic interactions between

19

ssDNA and OTAB play an important role in disruption of the OTAB monolayer.

20

Moreover, we also found when polyacrylic acid (PAA) or dsDNA were transferred

21

onto the OTAB-decorated LC interface, the appearance of LCs maintained dark

22

(Figure S2e and S2f), respectively. These results suggest the hydrophobic interactions

10


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1

of the nucletides of ssDNA also play an important role in disruption of the OTAB

2

monolayer. Based on these results and previous studies,46, 64 ssDNA could be adsorbed

3

onto the OTAB-laden LC interface and disrupt the orientation of LCs due to presence

4

of electrostatic interactions and hydrophobic interactions at the aqueous/LC interface.

5

Next, we investigated the effect of ssDNA/nano CeO2 complexes on the optical

6

responses of LCs. The complexes were formed by 1 µM ssDNA and nano CeO2 with

7

concentrations ranging from 100 to 1 µg/mL, respectively. Interestingly, we found that

8

the optical responses of LCs remained dark after transferring 1 µM ssDNA complexed

9

with 100 µg/mL nano CeO2 (Figure 2e) and 50 µg/mL nano CeO2 (Figure 2f) onto the

10

OTAB-decorated LC interface. The optical image of LCs exhibited partially bright

11

appearance and uniformly dark appearance with addition of 1 µM ssDNA complexed

12

with 10 µg/mL nano CeO2 (Figure 2g) and 1 µg/mL nano CeO2, respectively (Figure

13

2h). These results suggest disruption of the OTAB-decorated LC monolayer by ssDNA

14

could be counteracted with a sufficient amount of nano CeO2 as ssDNA was captured

15

onto the surface of nano CeO2 due to the coordination interaction between the ssDNA

16

backbone and nano CeO2.58 We also studied reponses of LCs to ssDNA and CeO2 with

17

increased concentrations. It was observed that higher concentrations of ssDNA could

18

be counteracted by higher concentrations of CeO2 (Figure S3). Thus, disruption of the

19

OTAB-decorated LC monolayer could be generated with appropriate concentration

20

ratio of ssDNA to CeO2. It has to pointed out that we focus on exploiting biosensing

21

applications of the experimental system by using a relatively low concentration (1 µM)

11



1

of ssDNA with a fixed concentration of CeO2, which can provide high sensitivity and

2

excellent reproducibility for quantification.

3

Mechanism of H2O2 detection

4

5

Figure 3. CD spectra of indicated systems.

6

H2O2 was reported to bind to nano CeO2 more strongly than ssDNA.21, 58 Hence,

7

the captured ssDNA on the surface of nano CeO2 could be released into the aqueous

8

solution in the presence of H2O2, which might disrupt the OTAB-decorated monolayer

9

at the aqueous/LC interface, thereby inducing change of the optical response from dark

10

to bright appearance. To confirm this hypothesis, CD experiments were first conducted.

11

As shown in Figure 3, the CD spectrum of ssDNA shows bisignated CD peaks with a

12

negative signal at 242 nm and a positive signal at 275 nm, respectively. The CD

13

spectrum was slightly red-shifted and its intensity decreased when ssDNA was mixed

14

with 200 µg/mL nano CeO2. The CD signal disappeared when ssDNA was mixed with

15

500 µg/mL nano CeO2. These results reveal that ssDNA could be captured by nano

16

CeO2, inducing decrease of the ssDNA signals.65 However, the CD spectrum showed

12


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1

up again when ssDNA was mixed with nano CeO2/H2O2 complexes, suggesting ssDNA

2

could not be absorbed onto the surface of nano CeO2 in the presence of nano

3

CeO2/H2O2 complexes. The interactions between nano CeO2 and H2O2 were also

4

confirmed by the UV-vis spectra (Figure S4). The broad shoulder peak from 400 to 450

5

nm implies the adsorption of H2O2 on the surface of nano CeO2.

6

We then examined the LC responses upon transfer of nano CeO2/H2O2 complexes

7

formed by 50 µg/mL nano CeO2 and a series of concentrations of H2O2 onto the

8

OTAB-decorated LC interface. It was found that all the polarized microscopy images

9

of LCs were uniformly dark (Figure S5), indicating the nano CeO2/H2O2 complexes

10

could not induce change of the optical responses of LCs. However, in the presence of

11

the 50 µg/mL nano CeO2 and 1 µM H2O2, ssDNA induced reorganization of the

12

OTAB-decorated monolayer at the aqueous/LC interface (Figure 4a). These results

13

imply ssDNA could lead to change of the optical response from dark to bright

14

appearance in the mixture of nano CeO2 and H2O2. Ionic strength effect on H2O2

15

adsorption was also studied and shown in Figure S6. It is found that H2O2 adsorption is

16

not largely affected by ionic strength (Figure S6).

17

Detection limit and specificity of H2O2

18

After confirmation of feasibility, we investigated detection limit of the H2O2

19

sensing platform. The optical images of LCs gradually changed from uniformly bright

20

to dark appearance with decreasing the concentrations of H2O2 from 1 µM to 20 nM

21

(Figure 4a). Time-dependent bright area coverage (Br) for the LC images were shown

22

in Figure 4b. These results indicate that the brightness of LC images was associated

13



1

with concentrations of H2O2. The Br at 5 min is plotted as a function of the H2O2

2

concentration (Figure 4c). There is a good linear relationship from 20 to 150 nM. The

3

detection limit of H2O2 was determined to be 28.9 nM (3σ/slope). The H2O2 sensing

4

platform demonstrated in our study shows highest sensitivity among all nano

5

CeO2-based sensors.

6

7

Figure 4 (a) Optical images of LCs corresponding to different concentrations of H2O2

8

under the polarized microscope. (b) The time-dependent bright area coverage (Br) of

14


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1

LC images corresponding to different concentrations of H2O2. (c) Dose-response

2

curve for H2O2. The observation time of Br is 5 min.

3

4

Figure 5 Specificity test toward amino acids, nucleotides, sugars salts and other

5

metabolites. H2O2 concentration is 0.001 mM and the concentrations of others are 0.1

6

mM.

7

Specificity of the system was examined for detection of H2O2. 0.1 mM amino

8

acids, nucleotides, sugars, salts and common metabolites were tested. The LC optical

9

images are shown in Figure S7 and Br of these images at 5 min are demonstrated in

10

Figure 5. Those results indicate remarkable specificity of H2O2 detection.

11

Glucose detection

12

H2O2 could be generated from oxidation of glucose by GOx. Therefore, our H2O2

13

sensing platform could be used to detect glucose. The time-dependent Br of LC images

14

corresponding to different glucose concentrations is demonstrated in Figure 6a. the

15

surface of nano CeO2 surface was occupied by the generated H2O2. Hence, free ssDNA

16

disrupted arrangement of the OTAB-decorated monolayer at the aqueous/LC interface,

15



1

resulting in an orientational transition of LCs from perpendicular to planar orientation.

2

Correspondingly, the optical responses of LCs changed from dark to appearance

3

accordingly. When the glucose concentrations were varied, Br of the LC images at 5

4

min were depicted in a dose-response curve for glucose detection (Figure 6b), which

5

shows a linear response with a detection limit of 0.52 µM glucose (3σ/slope). For

6

specificity test, only glucose exhibited distinct bright appearance among all examined

7

sugars (Figure 6c), suggesting the high specificity of our sensing platform.

8

9

Figure 6 (a) The time-dependent bright area coverage (Br) of LC images

10

corresponding to different glucose concentrations: (Ι) 50 µM, (ΙΙ) 30 µM, (ΙΙΙ) 15 µM,

11

(IV) 10 µM, (V) 5 µM, (VI) 0.7 µM and (VII) 0.1 µM, respectively. (b) Dose-response

16


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1

curve for glucose detection. The observation time of Br is 5 min. (c) Specificity test

2

toward other sugars. Glucose concentration is 0.05 mM and the concentrations of

3

other sugars are fixed on 0.5 mM.

4

In the end, we demonstrated measurement of blood glucose by using our H2O2

5

sensing platform. A commercial glucose meter was employed to determine the

6

concentrations of glucose in blood and a value of 5.2 ± 0.12 mM was obtained as a

7

reference. Diluted blood was precisely measured by our sensing platform based on the

8

oxidation reaction in the present of GOx due to highly sensitivity of our sensing

9

platform. The standard addition method was adopted to calibrate dose-response curve

10

and minimize the matrix effect (Figure S8). A value of 5.5 ± 0.29 mM was obtained

11

with a relative standard deviation (RSD) of 5.27% for blood glucose detection. In

12

comparision to the commercial glucose meter, our glucose sensing platform works well

13

in complex and physiological samples. It is highly competitive among existing glucose

14

sensors.

15

Conclusions

16

In summary, we demonstrated construction of LC-based sensing platforms for

17

sensitive, selective, and label-free detection of H2O2 with high accuracy for the first

18

time. ssDNA could disrupt the organization of the OTAB monolayer at the aqueous/LC

19

interface, thereby inducing change of the LC responses from dark to bright appearance.

20

In the mixture of complexed ssDNA and nano CeO2, the optical response of LCs

21

remained dark appearance due to absorption of ssDNA onto the surface of nano CeO2.

22

However, in the presence of H2O2, the ssDNA did not form the complexes with nano

23

CeO2 because H2O2 displaced ssDNA from nano CeO2. Thus the dark-to-bright shift in 17



1

the optical responses was observed. As H2O2 could be generated from oxidation of

2

glucose by GOx, detection of blood glucose was also demonstrated. The detection limit

3

of H2O2 and glucose reached as low as 28.9 nM and 0.52 µM, respectively. The

4

constructed LC-based sensing platforms are simple, convenient and inexpensive,

5

showing high sensitivity and selectivity in detection of H2O2 and glucose among

6

existing sensors. They are also very promising in sensitive, selective and label-free

7

detection of other clinically significant H2O2-related biomarkers such as cholesterol,

8

uric acid, and lactic acid.

9

Corresponding Author

10

*

11

Present Addresses

12

Phone number: +86-531-88364807

13

Fax number: +86-531-88564750

14

mail address: [email protected]

15

Author Contributions

16

1

17

Funding Sources

18

This work was supported by the National Natural Science Foundation of China (No.

19

21373128) and Scientific and Technological Projects of Shandong Province of China

20

(No. 2018GSF121024).

21

Corresponding author: Prof. Li Yu

These authors contributed equally.

18


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1

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Fabrication of Liquid-Crystal-Based Optical Sensing Platform for

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