臺灣博碩士論文加值系統

本論文之目的為開發ㄧ植入式無線葡萄糖感測系統，並植入於老鼠體內探討其功能性。本系統包含外部控制系統之人機介面及植入式電化學葡萄糖感測器，藉由無線射頻技術使得控制系統與植入端達到雙向傳輸之目的。外部系統以無線射頻耦合方式提供內部植入端所需的電能，藉射頻載波編碼方式命令植入端進行電化學感測，並將感測得之訊號傳送至外部顯示。植入端系統之微小化及封裝是為了便於將之植入老鼠體內，除了自製的微小化電極外，以聚二甲基矽氧烷封裝植入端系統，此微小化電極組乃是將工作電極、參考電極及輔助電極沉積於一矽晶上。本研究另一主軸為降低蛋白質吸附於工作電極，在此是以熱塑性聚氨酯(thermoplastic polyurethane, TPU)當作外層薄膜，將葡萄糖氧化酶(glucose oxidase, GOx)固定於TPU與微小電極之間，並於模擬組織間質液之環境中(組織間質替代液)以AUTOLAB PGSTAT 10測量葡萄糖濃度，藉此評估蛋白質吸附之程度，評估結果顯示，濃度為30 mg/ml之TPU具有降低蛋白質吸附之特性，以該TPU濃度製作之電極於模擬環境中測量亦有21天的穩定性，值得重視的是，該電極中之酵素活行仍維持在100%左右。此外，植入式感測系統之特性探討亦相當重要，本研究以所開發之系統與AUTOLAB進行探討，以相同之感測電極分別偵測不同濃度之過氧化氫，藉此評估植入式感測系統之解析度，由結果顯示，本系統及AUTOLAB之解析度分別為114及< 9.7 nA，有鑑於此，TPU薄膜應用於植入式葡萄糖感測系統之最佳濃度需得進一步評估，這項評估的結果顯示，以20 mg/ml TPU為固定酵素之薄膜，於組織間質替代液中檢測不同濃度之葡萄糖，本研究完成的系統其所擷取之電流訊號具有可分辨性。吾人乃將此感測器埋植於正常與糖尿病老鼠之體內進行實驗，當靜脈血糖濃度產生變化時，系統亦能測量出組織間質液之葡萄糖濃度有顯著差異，靜脈血糖濃度變化之時間點與本系統在組織間質液所偵測得葡萄糖濃度變化之對應時間點有30至170分鐘的遲滯。

This thesis developed an implantable wireless glucose sensing system and studied its functionality in rats. The system includes an external controller for serving as a human-system interaction interface and an implant unit for electrochemically sensing glucose. The communications between the controller and the implant are through a pair of antenna (or coils) based on peer-to-peer radio frequency (RF) technology. The electric power of the implant is supplied by the controller by means of RF coupling. The commands issued from the controller to the implant and the glucose signals sent back from the electrochemical analyzer of the implant to the controller all rely on the wireless RF technology. To be able to utilize the implant in rats, the implant unit requires not only miniaturization but also hermetically packaging. The whole part of the implant unit was sealed with poly-dimethylsiloxane except for a mini-electrode set. It is self-developed and is a piece of silicon containing working, reference and counter electrodes. This work also focuses on reducing protein absorption on surface of the electrode set when it is implanted within the rats. The working electrode modified with various TPU concentrations for GOx immobilization was used to evaluate the impact of the protein absorption. The evaluation study was carried out in simulated interstitial fluid (interstitial fluid surrogate, ISF surrogate) by an AUTOLAB PGSTAT10. Results indicate that 30 mg/ml of TPU reduced protein absorption most effectively. The modified electrode exhibited excellent stability as well because the TPU retained approximately 100% of GOx activity for more than 21 days. How the performance of the entire implantable glucose sensing system is even important in this work. Hydrogen peroxide signal measurements by the developed system and AUTOLAB were performed to evaluate the signal detection resolution. Results indicate the resolutions of the developed system and AUTOLAB were 114 and < 9.7 nA, respectively. This implied the TPU membrane to be used with the developed glucose sensing system requires modifications. The experimental results indicate that the developed system can detect a distinguishable glucose current response from ISF surrogate by using a 20 mg/ml TPU membrane. This implantable glucose biosensor with a TPU membrane was subsequently implanted in normal and diabetic rats. The signal responses obtained from the study rats’ ISF exhibited a significant difference when the blood glucose level changed. A comparison of intravenous and ISF glucose levels revealed a 30 to 170 minutes delay.

Table of content
中文摘要 I
Abstract II
謝 誌 IV
Table of content V
List of figures VIII
List of tables XII
Chapter 1 Introduction 1
1.1 Diabetes mellitus 1
1.2 Glucose monitoring technologies 3
1.2.1 Self-monitoring blood glucose devices 3
1.2.2 Continuous glucose monitoring 5
1.3 Bidirectional wireless transmission 9
1.4 Overview of potentiostatic circuitries 10
1.5 Study motivation 11
1.6 Framework of dissertation 14
Chapter 2 Performance characteristic studies of glucose biosensors modified by MPTMS and polyaniline 16
2.1 Introduction 16
2.2 Methods and Materials 19
2.2.1 Fabrication of PA-GOx-PAn/Pt electrodes 19
2.2.2 Preparation of MPTMS Sol-gel 20
2.2.3 Fabrication of PA-GOx-MPTMS/Pt biosensors 20
2.3 Results and Discussion 21
2.3.1 Effect of overoxidation 21
2.3.2 Optimization of thickness of the PAn film 24
2.3.3 Optimization of MPTMS solution concentration 26
2.3.4 Current response comparisons of the PAn-and MPTMS-modified biosensors 27
2.3.5 Optimization of operating potential 29
2.3.6 Effects of temperature and pH value 31
2.3.7 Characteristics of PA-GOx-PAn(2-cycle)/Pt and PA-GOx-MPTMS(10%) /Pt biosensors 33
2.3.8 Stability performance 35
Chapter 3 Mini-electrode development and glucose sensing mini-electrode characteristic studies 37
3.1 Introduction 37
3.2 Methods and Materials 38
3.2.1 Fabrication of mini-electrode 38
3.2.2 Preparation of interstitial fluid surrogate 40
3.2.3 Fabrication of glucose mini-electrode 42
3.3 Results and Discussion 45
3.3.1 Characteristics of the mini-electrode 45
3.3.2 MPTMS-based mini-electrode test in vitro and in ISF surrogate 48
3.3.3 Optimization of TPU concentration 51
3.3.4 Optimization of operation potential of glucose sensing mini-electrode 55
3.3.5 Stability performance of glucose sensing mini-electrode 57
Chapter 4 Studies of telemetry-based implantable electrochemical biosensor 58
4.1 Introduction 58
4.2 Methods and Materials 60
4.2.1 External subsystem 60
4.2.2 Internal subsystem 62
4.2.3 Internal subsystem assembling and sealing 64
4.2.4 Functionality verification of implantable electrochemical biosensor 67
4.2.5 Misalignment study 69
4.3 Results and Discussion 71
4.3.1 Characteristics of implantable electrochemical biosensor 71
4.3.2 Vertical misalignment analysis 74
4.3.3 Lateral misalignment analysis 76
Chapter 5 System integration and animal studies 78
5.1 Introduction 78
5.2 Methods and Materials 80
5.2.1 Optimized TPU concentration to be used in implantable glucose sensing system 80
5.2.2 Monitoring glucose levels in normal and diabetic rats 81
5.3 Results and Discussion 84
5.3.1 Performance of the implantable glucose sensing system 84
5.3.2 Continuous monitoring of glucose levels 87
5.3.3 Stability of the implantable glucose sensing system 92
Chapter 6 Conclusion and suggestions for future work 94
6.1 Conclusion 94
6.2 Suggestions for future work 96
Reference 98
Appendix I The mini-electrode connection method 106
Appendix II The monitoring software and display 107
Appendix III Chemical reagents used in this work 108
Appendix IV Apparatus used in this work 110
Publication list 111
 
List of figures
Figure 1 1 Illustration of real-time continuous monitoring devices (A) CGMS Gold (Medtronic), (B) Seven Plus (DEXCOM), (C) MiniMed Paradigm® Revel™ Insulin Pump (D) Abbott Freestyle Navigator 7
Figure 1 2 Clarke error grid analysis 7
Figure 1 3 Schematic diagram of Class E power amplifier 9
Figure 1 4 Schematic diagram of (A) traditional three-electrode circuitry (B) parallel a capacitance 10
Figure 1 5 The implantable biosensor 12
Figure 1 6 Framework of this study 15
Figure 2 1 Schematic diagram of biosensor fabrication 18
Figure 2 2 Current response variation in measuring 1 mM glucose in the PBS by the glucose sensor PA-GOx/Pt without the over-oxidation procedure (operating voltage at 0.7 V, 25 oC, and pH=7.0) 23
Figure 2 3 Amperometric currents measuring 1 mM glucose in PBS by the glucose sensors (a) PA-GOx/Pt, (b) PA-GOx-PAn(2 cycles)/Pt, and (c) PA-GOx-MPTMS (10%)/Pt (operating voltage at 0.7 V, 25 oC, and pH=7.0) 28
Figure 2 4 Amperometric currents versus operating potentials measuring (a) 1 mM glucose, (b) 0.5 mM AA, (c) 0.5 mM UA, and (d) 0.5 mM acetaminophen in PBS by the PA-GOx-PAn(2-cycle)/Pt glucose sensor (25 oC, pH=7.0) 30
Figure 2 5 Amperometric currents versus operating potentials measuring (a) 1 mM glucose, (b) 0.5 mM AA, (c) 0.5 mM UA, and (d) 0.5 mM acetaminophen in PBS by the PA-GOx-MPTMS(10%)/Pt glucose sensor (25 oC, pH=7.0) 30
Figure 2 6 Effect of temperature on the responses of (a) the PA-GOx-PAn(2-cycle)/Pt and (b) the PA-GOx-MPTMS(10%)/Pt glucose sensors studied by amperometric method for 1 mM glucose in PBS (operating voltage at 0.4 V, pH=7.0) 32
Figure 2 7 Effect of pH on the responses of (a) the PA-GOx-PAn(2-cycle)/Pt and (b) the PA-GOx-MPTMS(10%)/Pt glucose sensors studied by the amperometric method for 1 mM glucose in PBS (operating voltage at 0.4 V, 25 oC) 32
Figure 2 8 Typical calibration curves of (a) the PA-GOx-PAn(2-cycle)/Pt and (b) the PA-GOx-MPTMS(10%)/Pt glucose sensors in PBS (operating voltage at 0.4 V, 25 oC, pH=7.0) 34
Figure 2 9 Lineweaver-Burke reciprocal plots for the steady state response of (a) the PA-GOx-PAn(2-cycle)/Pt and (b) the PA-GOx-MPTMS(10%)/Pt glucose sensors according to data in Figure 2-8 34
Figure 2 10 Stability of (a) the PA-GOx-PAn(2-cycle)/Pt and (b) the PA-GOx-MPTMS(10%)/Pt glucose sensors stored in 0.1 M PBS (pH=7.0) at room temperature. Determined by 1 mM glucose in PBS; operating voltage at 0.4 V. 36
Figure 3 1 Schematic diagram of the mini-electrode design 39
Figure 3 2 Micro-machining processes of the fabricated mini-electrode 39
Figure 3 3 Fabrication of the Ag/AgCl reference electrode 39
Figure 3 4 Diagram of fabricated MPTMS-based glucose mini-electrode 44
Figure 3 5 TPU structure consists of diisocyanate(), chain extender(¡), and polyol(－) 44
Figure 3 6 Characteristics of CPE and mini-electrode upon the cyclic voltammetric background (pH 7 phosphate buffer, 0.1 M) responses (A) and the response for 5 mM ferri/ferro-cyanide (B). a and b represent the CPE and mini-electrode independently 46
Figure 3 7 Quasi-chronoamperometric curves recorded at the glucose mini-electrode measuring glucose in (A) pH 7.0 phosphate buffer (0.1 M), and (B) the ISF surrogate. The calibration curves include the measurement in PBS (a) and the ISF surrogate (b). Each ascent in PBS or ISF surrogate is 5 mM glucose (operation potential is 0.4 V). 50
Figure 3 8 Quasi-chronoamperometric curves recorded at 10(A), 15(B), 20(C), 25(D), and 30(E) mg/ml TPU-based glucose mini-electrode. The test solution was in PBS (-1) and the ISF surrogate (-2). The calibration curves represent -3, the blue line represents measurement in PBS and the red line represents the ISF surrogate. 53
Figure 3 9 Hydrodynamic voltammogram recorded at 30 mg/ml TPU-based glucose mini-electrode. The test solutions are (a) pH 7.0 phosphate buffer, (b) 5mM glucose, (c) 0.2 mM ascorbic acid, (d) 0.2 mM acetaminophen, and (e) 0.5 mM uric acid. 56
Figure 3 10 Hydrodynamic voltammogram recorded at 30 mg/ml TPU-based glucose electrode. The test solutions are (a) pH 7.0 phosphate buffer, (b) 5mM glucose, (c) 0.2 mM ascorbic acid, (d) 0.2 mM acetaminophen, and (e) 0.5 mM uric acid. 56
Figure 3 11 Stability of the 30 mg/ml TPU-based glucose mini-electrode stored in the ISF surrogate at 37 oC. Determined by 2 mM glucose in the ISF surrogate; operating voltage at 0.2 V. 57
Figure 4 1 Diagram of bi-directional wireless transmission electrochemical biosensors 59
Figure 4 2 Functional block of external subsystem 60
Figure 4 3 External subsystem 61
Figure 4 4 Functional block of internal subsystem 62
Figure 4 5 Circle assemble processes of the internal subsystem 66
Figure 4 6 Ellipse assemble processes of the internal subsystem 66
Figure 4 7 External coil and internal coil apart from 2 cm 68
Figure 4 8 Schematic diagram of the misalignment study includes lateral and vertical displacement 69
Figure 4 9 Amperometric curve recorded by (A) circle (B) ellipse type of bi-directional wireless transmission electrochemical biosensor system. Each injection concentration of hydrogen peroxide was 0.05 mM. 72
Figure 4 10 Quasi-chronoamperometric curves recorded by (A) AUTOLAB and (C) bidirectional wireless transmission electrochemical biosensor system at the same bare mini-electrode. The test solutions were hydrogen peroxide from 0 to 0.5 mM. Each ascent was 0.1 mM in (A) and (C). The calibration curves (B) and (D) represented AUTOLAB and the system respectively. 73
Figure 4 11 Quasi-chronoamperometric curves recorded by (A) AUTOLAB and (B) implantable system at the same bare mini-electrode. The test solutions were hydrogen peroxide containing 0, 10, 20, 50, 70 and 100 M. Square (C) represented the AUTOLAB, and circle (D) represented the system in calibration curves. The resolution of AUTOLAB (E) and the system (F) were < 9.7 and 114 nA respectively. 73
Figure 4 12 (A) peak-to-peak voltage of the internal coil and (B) data complete rate versus vertical displacement under the various peak-to-peak voltages of the external subsystem transmitted including (a) 150, (b) 200, (c) 250, (d) 300, (e) 350 V. 75
Figure 4 13 (A) peak-to-peak voltage of the internal coil and (B) data complete rate versus lateral displacements under the various vertical displacements including (a) 10 , (b) 20, (c) 30, (d) 35, and (e) 40 mm. The external subsystem provided a 300 Vpp for internal subsystem use. 77
Figure 4 14 Available operation space of the internal subsystem 77
Figure 5 1 Animal study setup including a glucose meter, a cylinder shape animal holder, an external subsystem, and a computer for recording data. 83
Figure 5 2 Quasi-chronoamperometric curves recorded at 15(A), 20(B), 25(C), and 30(D) mg/ml TPU-based glucose mini-electrode. The test solution was in PBS (-1) and the ISF surrogate (-2). The calibration curves represent -3, the blue line represents measurement in PBS and the red line represents the ISF surrogate. 86
Figure 5 3 Glucose level variation study in normal rats recorded by a glucose meter (triangle) and the developed system (circle). The unit of blood glucose levels is mg/dl. The unit of the current response for ISF detected by the system is A. (A) represents the first normal rat. (B) the second normal rat 88
Figure 5 4 Glucose level variation study in diabetic rats recorded by a glucose meter (triangle) and the developed system (circle). The unit of blood glucose levels is mg/dl. The unit of the current response for ISF detected by the system is A. (A) represents the first diabetic rat. (B) the second diabetic rat. 89
Figure 5 5 The stability study by monitoring the time couse of the developed wireless implantable sensing system’s responses (upon injection of 5 mM glucose) 93
Figure 5 6 (A) The lift-off TPU membrane adhered to the dermis; (B) The internal subsystem damaged by the rat 93
 
List of tables
Table 1 1 Diagnostic criteria for diabetes (4) 2
Table 1 2 Characteristics of continuous glucose sensing systems (18) 8
Table 2 1 Current signal amplitude and steadiness comparisons between the electrodes of PA-GOx-w/Pt and and PA-GOx-wo/Pt in 10 measurements of 1 mM glucose (operating voltage at 0.7 V, 25 oC, and pH=7.0) 23
Table 2 2 Amperometric responses of glucose and ascorbic acid measured by PA-GOx/Pt-based biosensors modified by PAn with various polymerization cycling numbers (operating voltage at 0.7 V, 25 oC, and pH=7.0) 25
Table 2 3 Amperometric responses of glucose and ascorbic acid measured by PA-GOx/Pt-based biosensors modified by MPTMS sol-gel with various concentrations (operating voltage at 0.7 V, 25 oC, and pH=7.0) 25
Table 2 4 Comparison of electrode performance characteristics 34
Table 3 1 Characteristics of TPU-based glucose mini-electrode measured in PBS 54
Table 3 2 Characteristics of TPU-based glucose mini-electrode measured in the ISF surrogate 54
Table 5 1 Characteristics of the TPU-based glucose mini-electrode measured in PBS recorded by implantable glucose sensing system 85
Table 5 2 Characteristics of the TPU-based glucose mini-electrode measured in ISF surrogate recorded by implantable glucose sensing system 85

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