臺灣博碩士論文加值系統

Surface plasmon resonance (SPR) is a promising technology for real-time, label-free monitoring of biomolecules in biomedical applications. We have developed portable SPR sensor platform based on Kretschmann prism configuration to the rapid detection of different viruses in real-time. Our proposed multi-metallic (Al-Au-Ag-Au) sensor chip performed well with detection and quantification of VP1 protein of EV71 virus, Zika NS1 protein, and EV 71 virus species. We have compared the simulation result of the different thin metal structure, and Al-Au-Ag-Au layer sensor chip has the better quality factor than all other thin metal structure. Our multi-metallic sensor chip gives optimum resonance wavelength around 610 nm, which is same as our light source peak wavelength. At first, we successfully quantified the EV 71 virus species with a limit of detection (LOD) around 43 VP/mL. Further, we have detected the VP1 protein of EV 71 virus with our multi-metallic sensor chip successfully. We achieved the limit of detection (LOD) around 46 pg/mL. We also detected Zika NS1 protein successfully with a limit of detection around 35 pg/mL.

Recommendation Letter from the Thesis Advisor……………………………
Thesis Oral Defense Committee Certification………………………………..
Preface and Acknowledgement……………………………………………iii
Abstract…………………………………………………………..................v
Table of Contents…………………………………………………………..vi
List of Figures…………………………………………………....................x
List of Tables……………………………………………………………...xiv
Chapter (I) Introduction…………………………………………..................1
1.1) Overview of the SPR sensor Development……………………1
1.2) Motivation of the Research…………………………………….2
1.3) Research objective……………………………………………..3
1.4) Thesis Organization…………………………………................4
Chapter (II) Surface Plasmon Resonance Biosensor Theory………………..5
2.1) Introduction……………………………………………………...5
2.2) Surface plasmon dispersion relation……………………………..6
2.2.1) Derivation of dispersion equation for SPR .....................6
2.2.2) Surface Plasmon on Metal–Dielectric
Medium………………………………………………………12

2.3) Resonance condition of SPR sensor……………………………13
2.4) SPR system requirements………………………………………15
2.4.1) Sensor Chip Surface details…………………...............15
2.4.2) Contribution of light source in SPR sensor…...............16

2.4.3) PDMS flow cell details………………………………..17

2.5) Different configuration of SPR sensor…………………………18

2.5.1) Prism coupled total reflection configuration………….19

2.5.2) Optical fibers…………………………………………..20

2.5.3) Grating coupled configuration………………...............21

2.6) Different methodology of Surface Plasmon resonance sensor………………………………………………………………..22

2.6.1) SPR Sensors Based on Wavelength Interrogation Method……………………………….....................................23

2.6.2) SPR Sensors Based on Angular Interrogation Method………………………………………………………..24

2.6.3) SPR Sensors Based on Intensity Interrogation Method………………………………………………………..25

2.7) SPR sensor surface Modification process for biomolecules detection…………………………………………………………….26

2.7.1) Sensor surface modification by Self-Assembled Monolayer……………………………………………………26

2.7.2) Different types of surface immobilization process......................................................................................27

2.7.3) Amine coupling immobilization……………................28

2.8) SPR sensor performance……………………………................29

2.9) Introduction to enteroviruses and Zika viruses…………………31
2.9.1) Genomic structure of EV71…………………................33

2.9.2) Quantification………………………............................34

2.9.3) Biomarker detection…………………………………...35
2.9.4) VP1 Protein of EV 71 Virus………………..................36
2.9.5) NS1 protein of Zika virus……………………………...37
Chapter (III) Experimental design and Methodology...................................38

3.1) SPR sensor platform configuration…………………................38
3.1.1) Experimental set up…………………………………..38
3.1.2) Trapezoid prism……………………………................39
3.1.3) OLED light source…………………………................40
3.1.4.) Microstructure of BEF and DBEF…………………….41
3.1.5) Sensor Chips………………………………..................43
3.1.5.1) Conventional Au Monolayer………................43
3.1.5.2) Novel Multilayer (Al-Au-Ag-Au) sensor chip fabrication for our experiment…………………………44
3.2) Measurement Objective………………………………………......46
3.3) EV 71 virus Culture procedure…………………………………….46
3.4) Enterovirus Antigen VP1 Plasmid, Protein expression and purification process………………………………………………………...47
Chapter (IV) Result and Discussion ………………………………………48
4.1) Further improvement…………………………………………..48
4.1.1) Experiment with conventional sensor chip…................48
4.1.2) Simulation result of single layer, bi-layer and multilayer sensor chip……………………………………………………53
4.1.3) Alcohol solution measurement with multilayer (Al-Au-Ag-Au) sensor chip………………………..............................57
4.2) EV 71 virus series dilution by viral plaque assay….………….59
4.3) EV 71 virus measurement with Al-Au-Ag-Au layer sensor chip…………...……………………………………………………..60
4.3.1) EV 71 virus quantification experiment………………..60
4.4) Attachment of EV 71 virus in sensor surface observed by SEM……...……………………………………………….................64
4.4.1. SEM image……………..……………………………...64

4.5) Enterovirus Antibody VP1 and Enterovirus Antigen VP1 Experiment by surface immobilization process………64

4.5.1) Biochemical materials and Preparation process………………………………………………………..65

4.5.2) Sensor surface modification by amine coupling
process………………………………………………………..65

4.5.3) Enterovirus VP1 experiment details………………….68

4.6) Detection of NS1 protein of Zika virus by Al-Au-Ag-Au sensor chip......................................................................................................70

Chapter (V) Conclusion & Future work……………………………………73
5.1) Conclusion …………………………..........................................73
5.2) Future work……………………………………………………73
Bibliography……………………………………………………………….75



List of Figures
Figure 2.1: SPR Reflectivity curve (Line A and Line B) of two different refractive indices of analyte flow on the metal sensor chip……………………………………………………………………………………6
Figure 2.2: SPP propagation geometry at the interface between metal (Medium2) and a dielectric medium (Medium1)…………..............................7
Figure2.3. (a): Dispersion relation of surface plasmon where surface plasmon wave vector is not equal to the light wave vector………………………………………………………………………………..14

Figure2.3. (b): Dispersion relation of surface plasmon where surface plasmon wave vector is equal to the light wave vector………………………………………………………………………………..15

Figure 2.4: Schematic view of PDMS flow cell……………………………….17

Figure 2.5: Schematic image of Prism coupling configuration. (a) Otto configuration. (b) Kretschmann configuration………………………………..19

Figure 2.6: Schematic design and characteristics of fiber optic sensor……………………………………………………………………………….20

Figure2.7: Schematic view of grating coupled SPR configuration……………………………………………………………………….21

Figure 2.8: The concept of surface plasmon resonance sensors with different methods…………………………………………………………………..22

Figure 2.9(a): Schematic of SPR sensor based on wavelength interrogation method………………………………………………………………………………23

Figure 2.9 (b): The design of the SPR sensor based on angular interrogation method………………………………………………………………………………24

Figure 2.9 (c): The design of SPR sensor based on Intensity interrogation method………………………………………………………………………………25

Figure 2.10: Different surface immobilization techniques with the carboxylic modified sensor surface………………………………………………………….28

Figure 2.11: Sensorgram from an amine coupling in Biacore 3000, which is described the amounts of ligand bound and the amount immobilized during the immobilization process………………………………………………………29

Figure 2.12: Direct and indirect process of SPR sensors to find out the characteristics……………………………………………………………………..29

Figure 2.13: Schematic of the genome structure of EV71……………………34

Figure3.1: Schematic design of our portable SPR sensor system……………………………………………………………………………….39
Figure 3.2: BK7 Trapezoidal Prism………………………………………39
Figure 3.3: Image of OLED light source………………………………………40
Figure 3.4: Integration of BEF and DBEF with OLED light source……………………………………………………………………………….41
Figure 3.5(a):Mechanism of brightness enhancement film (BEF)………………………………………………………………………………..42
Figure 3.5(b): Mechanism of dual brightness enhancement film (DBEF)……………………………………………………………………………...43
Figure 3.6: Schematic of (a) Conventional Au monolayer and (b) proposed Multilayer sensor chip……………………………………………………………43
Figure 4.1: OLED light source spectra. Peak wavelength is 610 nm……………………………………………………………………………………49

Figure 4.2: Simulation result of Cr-Au layer sensor chip with different thickness (47 nm, 45 nm, 40 nm). Light source spectra peak wavelength not matched with the resonance wavelength………………………………………..50

Figure 4.3: Intensity signal curve with the flow of 0 wt% to 5 wt% alcohol solution for Cr = 3nm, Au = 47nm sensor chip……………………………….51

Figure 4.4: Real time intensity curve observed from normalizing A-B value for Cr = 3nm, Au = 47 nm sensor chip…………………………………………51

Figure 4.5: Calibration curve for alcohol solution measurement with Cr = 3 nm, Au = 47 nm sensor chip……………………………………………………..52

Figure 4.6: Simulation result of Cr-Au sensor chip (Cr=3nm,Au= 47)………………………………………………………………............................53
Figure 4.7: Simulation result of Al-Au sensor chip (Al = 3nm, Au = 47)……………………………………………………………………………………54
Figure 4.8: Simulation result of Al-Ag-Au sensor chip (Al = 3nm, Ag = 20 nm, Au = 20 nm)………………………………………......................................55
Figure 4.9: Simulation result of Al-Au-Ag-Au sensor chip(Al = 3nm, Au = 10 nm, Ag =20 nm, Au = 20 nm).................................................................56
Figure 4.10: Experimental SPR dip with alcohol solution for multilayer sensor chip………………………………………………………………………….57
Figure 4.11: Intensity signal curve with the flow of 0 wt% to 5 wt% alcohol solution for Al-Au-Ag-Au layer sensor chip……………………………………58

Figure 4.12: Real-time intensity signal curve from A-B for Al-Au-Ag-Au layer sensor chip………………………………………………………………….58

Figure 4.13: Calibration curve for alcohol solution measurement with Al-Au-Ag-Au layer sensor chip……………………………………………………..59

Figure 4.14: SPR signal for ‘A’ and ‘B’ integration area from EV 71 quantification experiment………………………………………………………...61

Figure 4.15: SPR signal from normalized A and B value (A-B)…………………………………………………………………………………….62

Figure 4.16: Calibration curve for EV 71 quantification experiment with Al-Au-Ag-Au layer sensor chip………………….................................................63

Figure 4.17: SEM result for (a) bare sensor surface without virus particle, (b) incubated sensor surface with virus particle………………………………64
Figure 4.18: Real-time signal, chemical treatment of sensor surface activation and enterovirus VP1 antibody immobilization……………………66

Figure 4.19: Schematic of enterovirus VP1 detection process with chemical treatment and antigen-antibody binding………………………………………..67

Figure 4.20: Experimental result of series concentration of enterovirus VP1 detection…………………………………………………………………………….69

Figure 4.21: Curve fitting calibration of the SPR signal for VP1 protein of EV 71 virus detection……………………………………………………………..70

Figure 4.22: Real-time signal, chemical treatment of sensor surface activation and Zika NS1 antibody immobilization result…………………….71

Figure 4.23: The experimental result of the series concentration of Antigen Zika NS1 detection…………………………………………...............................71

Figure 4.24: Curve fitting calibration of the SPR signal for NS1 protein of Zika virus detection……………………………………………………………….72

List of Tables
Table 1.1: Clinical diseases of enterovirus serotypes…………....................33

Table 1.2: Preparation of different concentration of EV 71 virus solution for our experiment……………………………………………………………………..60
Table1.3: Detection process and experiment steps……………………………68

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