Venturi-Electrosonic Spray Ionization Cataluminescence Sensor Array

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A Venturi-Electrosonic Spray Ionization Cataluminescence Sensor Array for Saccharides Detection Jiaying Han, Feifei Han, Jin Ouyang, Quanmin Li, and Na Na Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/ac400948k • Publication Date (Web): 16 Jul 2013 Downloaded from http://pubs.acs.org on July 21, 2013

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Analytical Chemistry

A Venturi-Electrosonic Spray Ionization Cataluminescence Sensor Array for Saccharides Detection Jiaying Hana, Feifei Hana, Jin Ouyanga, Quanmin Lib, and Na Naa∗∗

a

College of Chemistry, Beijing Normal University, Beijing 100875, China

b

Department of Endocrinology, General Hospital of The Second Artillery, Beijing 100088, China

∗

Corresponding author: Dr. Na Na, College of Chemistry, Beijing Normal University,

Beijing 100875, P.R. China E-mail: [email protected] ; Fax: +86-10-58802075 1

ACS Paragon Plus Environment


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Abstract In this article, a Venturi electrosonic spray ionization (V-ESSI) cataluminescence (CTL) sensor array was reported for discriminating saccharides in solution. Integrating electrosonic spray ionization (ESSI), a liquid system of Venturi self-pumping injection for CTL reaction was fabricated for enhancing CTL reactivity of aqueous samples. Comparing with simple Venturi injection by air and Venturi easy ambient sonic-spray ionization without electric assistance (V-EASI), the remarkable enhancement of CTL signals were resulted by V-ESSI. This system showed higher cross-reactive CTL responses catalyzed by alkaline earth metal-nanomaterials than other catalysts, giving different signals for a given saccharide on different catalysts, and different responses for different saccharides on a same catalyst. Then, a 4 × 2 CTL sensor array was used for obtaining “fingerprints” of distinct CTL response patterns. Analyzed by linear discriminant analysis (LDA), this V-ESSI CTL sensor array not only achieved the well discrimination of different saccharides (99.9% of total variation), but also discriminated four groups of urine sugar-level for urine samples from diabetic patients (98.1% of discrimination accuracy). It had good reproducibility and gave a linear range of 22.5-67558 µg/mL (R > 0.99) for xylose with a detection limit of 7.4 µg/mL on MgO. As a new artificial tongue, this system provided a simple, rapid, low cost, low energy consumption and environment friendly pathway for aqueous sample discrimination. It has dramatically expanded applications of CTL-based senor array and will be applicable to clinical diagnoses, environment monitoring, industrial controls, food industry and various marine monitoring.

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Introduction Sensor arrays (also known as artificial noses or artificial tongue) are devices composed arrays of sensors for identifying samples, which rely on characteristic spectra of small perturbation arising from multiple sensing elements.

1, 2

Numerous

sensor-transduction mechanisms have been employed to make sensor arrays,

3-7

among which optics analysis is a powerful technique to gather rich optical information such as wavelength, signal intensity, lifetime, and response time. The multiple information of every sensor element could also be simply obtained by an imaging, which has driven much development of sensing techniques for applications. 8-10

In recent years, a sensor array based on cataluminescence (CTL)11-13 was used for fast identification of analytes according to CTL signals, which provided stable responses by simple and low-cost devices.

14, 15

However, this sensor array still has

some limitations to fabricate “artificial tongue” for detecting aqueous samples, due to the relative high working temperature (200-500 °C) and high volume of injection. The adoption of high working temperature was generated from the consumption of energy during the vaporization of liquid sample. Therefore, to catch up on the lost energy for maintaining the reactivity of this thermo reaction, the working temperature should be further increased. In addition, because of the low sensitivity, large volume of samples were injected leading to sample waste and effluent pollution.16-18 Additionally, it showed low performance for analytes with lower CTL reactivity, and even no responses for some samples. Hence, finding a new strategy to fabricate CTL-based

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artificial tongue is imperative, which was supposed to provide high responses, well sensitivity and selectivity, as well as green-energy-saving properties. Electrosonic spray ionization (ESSI) is a soft ionization technique to produce ions from large and complex species in solution, which combines a supersonic gas jet with electrospray ionization (ESI).

19, 20

During the process, the produced small

droplets have relative high density of charges, which endows them relative high reactivity in reactions such as electrochemical reactions or redox ones. 21, 22 Based on Venturi effect, Venturi easy ambient sonic-spray ionization (V-EASI) was recently reported for liquid samples ionization, which utilized the high linear velocity of nebulizing gas to provide efficient pneumatic spraying of charged liquid samples.23, 24 Furthermore, in high-alternating voltage field, a low temperature plasma ionization 25, 26

and plasma-assisted CTL sensor array

27, 28

demonstrated the high CTL reactive

ability for analytes. Accordingly, if integrating V-EASI with ESSI in the high-voltage electric field, the charged analytes and radical ions would be easily generated from liquid samples. This may result the improved performance of CTL sensor array for liquid samples and to extend the application of this technique. In this article, a Venturi electrosonic spray ionization (V-ESSI) CTL sensor array was reported for discriminating saccharides in solution. By integrating Venturi self-pumping procedure into ESSI technique, the analytes could be released and activated from the aqueous media. The produced ions were further used for the generation of dramatically increased distinct CTL patterns for the discrimination. Then, the analysis of urine samples from diabetic patients demonstrated the potentials

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of V-ESSI CTL sensor array in clinical diagnosis.

EXPERIMENTAL SECTION Chemicals and Reagents. All reagents were of analytical-reagent grades. AgNO3 was purchased from Alfa Aesar Company. MgO, CaCl2, SrCl2·6H2O, BaCl2, Ba(OH)2·8H2O, Na2CO3, Na2SO4, NaOH, and NH3·H2O were obtained from Beijing Chemical Co., Ltd. Glucose, sucrose, D-(+)-maltose, L-ascorbic acid, β-hydroxybutyrate, uric acid, D-fructose, L-arabinose, D-xylose, D-galactose and α-lactose were purchased from Sinopharm Chemical Reagent Beijing Co., Ltd. The concentration of samples was 45 mM unless otherwise specified. The nitrogen gas (99.99%) was supplied by Beijing Haipu-Gas Co., Ltd. Water was deionized and further purified using a Milli-Q water purification system (Millipore, Bedford, MA). Alkaline-earth nanomaterials were synthesized by sol-gel methods, and then spotted orderly onto the surface of a ceramic chip to form a 4 × 2 array (~100 µm in thickness and 1 mm in diameter for each one). CTL properties were examined by the procedures described previously. 15, 17

Human Subjects and Collection of Urine. Overnight urine samples were collected from healthy (from Beijing Normal University) and diabetic volunteers (from The Chinese People's Liberation Army Second Artillery General Hospital and Peking University Third Hospital). In addition,

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all individuals gave informed consent to participate in the study. Urine samples were centrifuged at 10000 rpm for 20 min, and at last filtered through the 0.2 µm filter membrane.

Apparatus and Softwares. Similar to our previous work,27 CTL signals were detected by a BPCL ultraweak chemiluminescence analyzer (Bio-physics Institute of the Chinese Academy of Science in China) equipped with a CR-105 photomultiplier tube (PMT) (Hamamatsu, Tokyo, Japan). A continuous air was provided by a XWK-III oil-free air pump (Huasheng Analysis Instrument Co., Ltd., Tianjin, PRC), and the flow rate was controlled by a flow meter (Beijing Keyi Laboratory Instrument Co., Ltd., Beijing, PRC). The temperature of the sensor array was controlled by a digital temperature controller. The produced ions were analyzed by a Thermo LTQ linear ion trap mass spectrometer (Thermo Fisher Scientific, San José, CA). The data matrix was processed utilizing classical linear discriminant analysis (LDA) in SPSS (version 16.0). Noting that, we applied “all groups equal” mode to all variables during the analysis. The CTL pattern signals were transformed to canonical patterns and visualized in the canonical score plots. Thereupon, we calculated Mahalanobis distances of each individual pattern to the centroid of each group in a multidimensional space. The assignment of the case was based on the shortest Mahalanobis distance.

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Fabrication of V-ESSI CTL Sensor Array. V-EAESSI ion source was fabricated by integrating Venturi unit into ESSI technique. As shown in Figure 1, V-ESSI consists of three parts: high voltage section, V-ESSI unit, and CTL sensor array. A tunable electrical potential was employed in maintaining the electric field. Venturi unit is composed of a simple Swagelok tee tube with a polytetrafluoroethylene (PTFE) tube passed through: a 14.5 mm long PTFE tube for the gas flow (i.d. = 750 µm and o.d. = 1.59 mm), and a fused-silica capillary (i.d. = 250 µm and o.d. = 530 µm) in the PTFE tube as the sonic-spray exit for the liquid flow. Hereupon, a high-velocity of gas flowed through the PTFE tube, and resulted in a reduced pressure to generate a self-pumping effect for maintaining efficient pneumatic spraying of the charged liquid sample (namely Venturi effect). In the high-voltage electric field, the solvent evaporated from the offspring droplets, and therefore the charge density increased dramatically and resulted in the Coulomb repulsion for the generation of gaseous ions as well as radical ions.29 Then, the small, charged droplets were generated by this V-ESSI system. Subsequently, the activated charged microdroplets were sprayed onto a 4 × 2 CTL sensor array for the generation of CTL signals, whose sensing elements were alkaline-earth nanomaterials.

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PMT hv hv hv hv

Electrical potential KV

Gas jet Temperature Sample

Catalyst array

PTFE PTEEtube tube

Spray capillary

Electrospray

Nebulizing gas

Figure 1. Schematic diagram of V-ESSI CTL sensor array.

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RESULTS AND DISCUSSION Effect of V-ESSI for CTL Enhancement To examine the effect of V-ESSI system for CTL enhancement, CTL signals were compared with the data from the other two setups: (A) The reported system with the simple Venturi injection by air through a double wall tube

18, 30, 31

(a i.d. 750 µm-

polyethylene tube for the inner liquid flow, and a i.d. 4.0 mm- polyethylene tube for the outer gas flow), without any electro-assisted device; (B) The V-EASI system

[23]

injected by nitrogen through a double wall tube (a i.d. 750 µm- polyethylene tube for outer gas flow and a i.d. 250 µm capillary for the inner liquid flow), without electric assistance. In fact, the difference between V-ESSI and V-EASI is whether to turn on the DC power. Then, the responses to three saccharides (glucose, maltose and sucrose) were recorded by three systems, in which MgO nanomaterials acted as the catalysts. As demonstrated, the remarkable enhancement of CTL signals were resulted by our V-ESSI system, which showed the much higher CTL intensity than the other two systems. As shown in Figure 2A, we obtained the quite weak CTL signals by the reported system of simple Venturi injection by air (about 2000 a.u. CTL for glucose, while no remarkable signal for maltose and sucrose). In addition, to obtain these CTL signals, relative high volume of samples were injected, which led to quite a lot liquid waste. By V-EASI (Figure 2B), although we obtained the remarkable CTL signals of glucose (about 23000 a.u.), the signals of maltose and sucrose were still quite low. However, by V-ESSI, the extremely high responses were recorded (Figure 2C),

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presenting CTL responses of 65000 a.u. for glucose, 22000 a.u. for maltose, and 30000 a.u. for sucrose. Furthermore, the additional examinations on eight saccharides catalyzed by a given nanomaterials as well as a given sample catalyzed by different catalysts were employed. They were respectively carried out through V-ESSI system and the simple Venturi injection by air, which also demonstrated the cross-reactive enhanced responses for different samples catalyzed by different catalysts (see Figure S1, Supporting Information). These different signals were generated from different activated energy on different catalysts.14 Moreover, it should be noted that the present detection system worked at a relative lower temperature (147°C) than the previous studies (200-500 °C).18, 30

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Figure 2. CTL signals for glucose, maltose and sucrose. (A) Simple Venturi injection by air; (B) V-EASI; (C) V-ESSI. DC: 7 kV. Catalyst: MgO. Temperature: 147 °C.

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Injection system for V-ESSI In order to find a suitable injection system for V-ESSI, two injection methods including simple self-pumping injection and micro-pump injection were compared. As shown in Figure 3A-a, a micro-syringe loaded with the sample solution was set in a micro-pump, and the DC power was connected with the liquid flow through the steel needle of the micro-syringe, which was similar to the liquid system of electrosonic spray ionization (ESSI)

[21]

or desorption electrospray ionization (DESI)

32

. Then, the remarkable CTL signals of glucose on MgO nanomaterials were

recorded (Figure 3A). However, although we obtained the increased CTL signals with DC power on comparing with the data with DC off (Figure 3A-b), the peaks broadened in a certain range and the enhancement was still not so ideal showing the increased factor of only 1.3 (IDC-on/IDC-off, in which IDC-on refers to CTL intensity with DC on, and IDC-off refers to signals with DC off). Therefore, this device is not an ideal one for the sample injection. As shown in Figure 3B-a, a simple self-pumping injection, inserting the capillary into the sample solution directly, was connected with the electrospray system. Then with N2 as the nebulizing gas, the sample was injected under the negative pressure. Interestingly, as shown in Figure 3B-b, we obtained extremely high responses when DC was set at 7 kV, whose intensity was about 3 times higher than the data obtained when DC was off. In addition, the self-pumping injection provided lower background and higher signal to noise ratio than the micro-pump one.

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Therefore, the self-pumping injection was much better than micro-pump injection, which seems promising for the fast and real-time monitoring of samples in solutions.

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DC On

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Figure 3. Injection systems of V-ESSI. (A) Micro-pumping injection. (B) Self-pumping injection. (a) The schematic diagram of setups; (b) CTL signals on MgO obtained with DC on and off. Temperature: 147 °C; N2: 0.15 MPa; air: 80 mL/min.

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Cross-reactivity of V-ESSI CTL sensor array To examine the cross-reactivity of V-ESSI CTL sensor array for discriminating saccharides, a 4 × 2 CTL sensor array made of alkaline-earth nanomaterials was fabricated for the examination. As shown in Figure 4A, the CTL signals on different catalysts were distinct for a given compound. For instance, glucose gave the strongest signal on MgO (about 64000 a.u.), but a weak signal on TiO2 (about 1000 a.u.). Similarly, the same catalyst showed different CTL properties upon exposure to different analytes. On Ag/MgO, we obtained the highest signal for glucose (about 9000 a.u.), a medium signal for sucrose (about 5000 a.u.), and the lowest response for maltose (about 2000 a.u.). In order to demonstrate the enhanced efficiency of V-ESSI, a V-ESSI assistance factor was defined as: V-ESSI assistance factor = Ion/ Ioff , where Ion is the V-ESSI-CTL intensity and Ioff is the CTL intensity obtained by V-EASI. Then, the increased factors of V-ESSI for different samples on different catalysts were further compared in Figure 4B. As demonstrated, different catalysts possess different increased factor for a given analyte, and the same catalyst shows different increased factor for different analytes. It should be noted that due to the quite weak responses by V-EASI, the increased factor on TiO2 is much higher than others, which further demonstrated the well assistance of high-voltage electric field for CTL enhancement. Consequently, the V-ESSI CTL system provides distinct CTL signals for different samples, which is important for fast discrimination.

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CaCO 3 CaO M gO SrO ZrO 2 TiO 2

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ZrO2 TiO2 SrO BaSO4 5%Ag CaCO3 CaO MgO /ZnO

V-ESSI Increased Factor

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Sam ples

Figure 4. (A)The cross-reactive CTL responses for glucose, sucrose, and maltose by V-ESSI. (B) V-ESSI assistance factors for eight saccharides. Working temperature: 147 °C. DC: 7kV.

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Discrimination of urine samples from diabetic patients To demonstrate the potential of the V-ESSI CTL sensor array for discrimination, six saccharides (glucose, D-fructose, L-arabinose, D-galactose, sucrose, α-lactose) and two organic acids (L-ascorbic and beta-hydroxybutyrate) were tested. The V-ESSI CTL patterns of the training matrix (8 nanomaterials × 8 analytes × 3 replicates) were subjected to classical linear discriminant analysis (LDA). As shown in Figure 5A, the canonical patterns were clustered into eight different groups to achieve good discrimination. The first three canonical factors contain 92.4%, 6.3% and 1.2% of the variation, occupying 99.9% of total variation. Furthermore, vitamin C, β-hydroxybutyrate and uric acid, three kinds of main distracters in urine sugar test, can also be discriminated from other saccharides. This demonstrates the potentials of the present method in real sample detection. Urine analysis supplied a diagnostic technique without risk for patients. Thus, we tested the urine samples from diabetic patients by V-ESSI CTL sensor array, and tried to discriminate the diabetic samples from the healthy ones. According to the glucose content in serum, urine sugar content is generally divided into four levels for diabetics: "+" (0.25-0.50 g/dL), "++" (0.50-1 g/dL), "+++" (1-2 g/dL) and "++++" (> 2 g/dL). To establish models of urine samples, four levels of glucose were added into four aliquots urines from the same healthy human. There were three samples for each level. Then, 21 urine samples, including 12 model samples and 9 diabetic patients’ samples, were subjected to blind tests by the V-ESSI CTL sensor array. Their CTL patterns were processed using LDA, whose size of training matrix was 8 alkaline-earth

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nanomaterials × 21 samples × 3 replicates. The 3D classification score plot with the first three canonical factors (containing 88.9%, 6.4% and 2.8% of the variation, respectively) is shown in Figure 5B. Obviously, the canonical patterns are clustered into four groups of different urine sugar-level, which results the discrimination accuracy of 98.1%. Excitingly, this result is in accordance with the clinical diagnostic data. This has demonstrated the feasibility of using the V-ESSI CTL sensor array into the real sample detection.

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glucose D-fructose L-arabinose D-galactose sucrose a -lactose L-ascorbic acid ß -hydroxybutyrate

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Function (1) 88. 9%

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Figure 5. Canonical score plots of response patterns by LDA. (A) Discrimination of 45 mM of samples. (B) Discrimination of urine sugar-level for diabetic patients’ urine samples and four levels of glucose models (+: 0.28g/dL, 0.32g/dL, 0.37g/dL; ++: 0.60g/dL, 0.76g/dL, 0.85g/dL; +++: 1.21g/dL, 1.48g/dL, 1.69g/dL; ++++: 2.8g/dL, 4g/dL, 4.2g/dL).

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Preliminary mechanism studies on V-ESSI system The mechanism of V-ESSI CTL system was preliminarily studied. Based on Venturi process, a useful siphon effect, this Venturi self-pumping injection for CTL system has generated a high-velocity fluid, which could be used to concomitantly perform two important tasks for CTL reaction: (a) Venturi self-pumping of either analytes or solvent solutions and (b) ESSI. The sonic spray of an ionic solution forms very minute droplets with limited capacity of accommodating ions, and generates a statistically imbalanced distribution of charges. Then, under the high electric field, the V-ESSI forms and results the ionic environment, a dense bipolar cloud of droplets with either positive or negative charges.23 The bipolar V-ESSI also deposits very little energy into the gaseous ions,33 whereas the minute charged droplets would be beneficial for CTL reaction. It should be noted that although the charges could be generated without high electric assistance, the enhancement is still not obvious enough. This has been proven in Figure 2 and Figure 3. To better illustrate the mechanism of V-ESSI device for CTL reaction, glucose and arabinose were selected as samples for the ions generation. Then the produced ions were subjected into mass spectrometry detector for analysis (the schematic diagram of the set up is shown in the inset of Figure 6). As demonstrated, the corresponding ions of the both samples have been well detected, which has preliminary confirmed the mechanism. However, the mechanism is not clear enough, and the more studies are still needed in further works.

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KV

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Figure 6. Mass spectrometry detection for ions of glucose (A) and arabinose (B) after V-ESSI. The concentration of sample was 0.45 mM.

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Optimizations of parameters To obtain the high CTL signals by V-ESSI system, several parameters including nebulizing gas, working temperature and electric power were optimized. Air and nitrogen were adopted for examining the effect of nebulizing gas for V-ESSI. As shown in Figure 7A, we obtained relatively high CTL intensity with nitrogen as nebulizing gas than the signals obtained with air as the nebulizing gas. In addition, we recorded more obvious different signals for different analytes using N2, which will be significant in the sample discrimination. As demonstrated in Figure 7B, the optimized gas pressure was 0.15 MPa. In addition, Figure 8A demonstrated changes of CTL intensity as a function of working temperature for saccharides detection, which results much lower optimized temperature of 147 °C than temperature for simple Venturi injection by air (200-500 °C). As shown in Figure 8B, to obtain the high signal to noise ratio (S/N), 7 kV was selected as the optimized power for the test. In addition, the high catalytic ability of alkaline earth nanomaterials for saccharides sensing by V-ESSI CTL system was demonstrated (Please see more details in Supporting Information).

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A

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Galactose Arabinose Xylose Fructose Glucose Relative CTL Intensity (a.u.)

Relative CL Intensity (a.u.)

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a MP a 0.1 MP 5 a N 0.1 .2MP a 2 P re 0 .25MP Pa ss 0 M u 0.3

Glucose Arabinose Lactose Maltose

re

Figure 7．(A) Different CTL signals of saccharides with air and N2 (0.15MPa) as nebulizing gases for V-ESSI. (B) CTL signals obtained at different N2 pressure for V-ESSI. Temperature: 147 °C; Air: 80 mL/min.

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120

135

147150 Temperature ( C)

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Baseline Glucose Arabinose

Relative CTL Intensity (a.u.)

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

Relative CTL Intensity (a.u.)


0

2

o

4 6 7 8 DC Power (kV)

10

Figure 8．Parameter optimizations. (A) Changes of CTL intensity as a function of working temperature for glucose and maltose. (B) CTL signals of glucose and arabinose at different DC power (Temperature: 147 °C). Sample concentration: 45 mM; Catalyst: MgO.

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Analytical Characteristics of V-ESSI CTL system As demonstrated, the quantification of saccharides can be employed based on the CTL signals. With the detection of xylose as an example, the linear range was 22.5-67558 µg/mL (R > 0.99) with a detection limit of 7.4 µg/mL on MgO (Figure S5). This linear range is much wider than the reported CTL method (30-2000 µg/mL)16 as well as the electrochemical method.34, 35 In addition, this V-ESSI CTL system also showed the quite stable and reproducible signals for the detection (Figure S6), which is important for the applications.

Conclusions In conclusion, integrating Venturi effect into ESSI technique, V-ESSI CTL sensor array has been well used for the discriminate of saccharides in solution. The CTL signals were dramatically increased through V-ESSI system, and also showed the cross-reactive characteristic for discriminating saccharides. This system acts as a new artificial tongue providing a simple, rapid, low cost, low energy consumption and environment friendly pathway for aqueous sample detection. The analysis of urine samples from diabetic patients demonstrated the potentials of V-ESSI CTL sensor array in clinical diagnosis. The V-ESSI technique has dramatically expanded the applications of CTL-based senor array and will be applicable to clinical diagnoses, environment monitoring, industrial controls, food industry and various marine monitoring.

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Supporting Information Available: This material is available free of charge via the Internet at http://pubs.acs.org.

Acknowledgment The authors gratefully acknowledge the support from the National Nature Science

Foundation

of

China

(21005007,

91027034,

21175014),

SRFDP

(20100003120014), and A Foundation for the Author of National Excellent Doctoral Dissertation of PR China (201221).

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For TOC only:

Electrical potential KV Gas jet

PMT

Ions

hv

Nebulizing gas

Temperature

Sample

Self-pumping Injection

hv

Electrospray

CTL sensor array

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Venturi-Electrosonic Spray Ionization Cataluminescence Sensor Array

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