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  1. NTU Theses and Dissertations Repository
  2. 電機資訊學院
  3. 電子工程學研究所
請用此 Handle URI 來引用此文件: http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/97037
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dc.contributor.advisor簡俊超zh_TW
dc.contributor.advisorJun-Chau Chienen
dc.contributor.author蕭晏葶zh_TW
dc.contributor.authorYan-Ting Hsiaoen
dc.date.accessioned2025-02-26T16:09:58Z-
dc.date.available2025-02-27-
dc.date.copyright2025-02-26-
dc.date.issued2025-
dc.date.submitted2025-02-11-
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[9] P. Dauphin-Ducharme et al., “Electrochemical Aptamer-Based Sensors for Improved Therapeutic Drug Monitoring and High-Precision, Feedback-Controlled Drug Delivery,” ACS Sensors, 4(10), pp. 2832-2837, 2019.
[10] B. S. Ferguson et al., “Real-time, aptamer-based tracking of circulating therapeutic agents in living animals,” Sci. Transl. Med., vol. 5, no. 213, Nov. 2013.
[11] Y. Dai et al., “Exploring the trans-cleavage activity of CRISPR-Cas12a (cpf1) for the development of a universal electrochemical biosensor,” Angew. Chem. Int. Ed., 58(48), 2019.
[12] J.-C. Chien and A. M. Niknejad, “Oscillator-Based Reactance Sensors with Injection Locking for High-Throughput Flow Cytometry Using Microwave Dielectric Spectroscopy,” IEEE J. Solid-State Circuits, vol. 51, no. 2, pp. 457–472, Feb. 2016.
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[15] Liu J, Wagan S, Dávila Morris M, Taylor J, White RJ, “Achieving reproducible performance of electrochemical, folding aptamer-based sensors on microelectrodes: challenges and prospects,” Anal Chem., vol. 86, no. 22, pp.11417-11424, Nov. 2014.
[16] P. Dauphin-Ducharme and K. W. Plaxco, “Maximizing the signal gain of electrochemical-DNA sensors,” Anal. Chem., vol. 88, no. 23, pp. 11654–11662, Dec. 2016.
[17] J.-C. Chien, S. W. Baker, H. T. Soh, and A. Arbabian, “Design and analysis of a sample-and-hold CMOS electrochemical sensor for aptamer based therapeutic drug monitoring,” IEEE J. Solid-State Circuits, vol. 55, no. 11, pp. 2914–2929, Nov. 2020.
[18] Jennifer A. Doudna and Emmanuelle Charpentier, “The new frontier of genome engineering with CRISPR-Cas9,” Science, vol. 346, no. 6213, Nov. 2014.
[19] Marianna Rossetti et al., “Enhancement of CRISPR/Cas12a trans-cleavage activity using hairpin DNA reporters,” Nucleic Acids Research, vol. 50, no. 14, pp. 8377–8391, Aug. 2022.
[20] L. R. Schoukroun-Barnes, F. C. Macazo, B. Gutierrez, J. Lottermoser, J. Liu, and R. J. White, “Reagentless, structure-switching, electrochemical aptamer-based sensors,” Annu. Rev. Anal. Chem., vol. 9, no. 1, pp. 163–181, Jun. 2016.
[21] J.-C. Chien, P. L. Mage, H. T. Soh, and A. Arbabian, “An aptamer-based electrochemical-sensing implant for continuous therapeutic-drug monitoring in vivo,” IEEE Symposium on VLSI Circuits (VLSI-C), Jun. 2019.
[22] J. J. Su, K. S. Demirci, and O. Brand, “A low-leakage body-guarded analog switch in 0.35-μm BiCMOS and its applications in low-speed switched-capacitor circuits,” IEEE Trans. Circuits Syst. II, Exp. Briefs, vol. 62, no. 10, pp. 947–951, Oct. 2015.
[23] A. C. Sun, E. Alvarez-Fontecilla, A. G. Venkatesh, E. Aronoff-Spencer, and D. A. Hall, “High-density redox amplified coulostatic discharge based biosensor array,” IEEE J. Solid-State Circuits, vol. 53, no. 7, pp. 2054–2064, Jul. 2018.
[24] J. Yoo, L. Yan, D. El-Damak, M. A. B. Altaf, A. H. Shoeb, and A. P. Chandrakasan, “An 8-channel scalable EEG acquisition SoC with patient-specific seizure classification and recording processor,” IEEE J. Solid-State Circuits, vol. 48, no. 1, pp. 214–228, Jan. 2013.
[25] J. Gonzalez, J.-A. Sequí, “Square Wave Voltcoulommetry Analysis of the Influence of the Electrostatic Environment on the Electrochemical Functionality of Redox Monolayers,” ChemElectroChem., 6, pp. 2290–2301, 2019.
[26] J. Gonzalez, A. Molina, N. Abenza, C. Serna, M. M. Moreno, “Square wave voltcoulometry: a tool for the study of strongly adsorbed redox molecules,” Anal. Chem., 79, pp7580–7587, 2007.
[27] Y. -T. Hsiao et al., “A CMOS/Microfluidics Point-of-Care SoC employing Square-Wave Voltcoulometry for Biosensing with Aptamers and CRISPR-Cas12a Enzymes,” IEEE Symposium on VLSI Technology and Circuits (VLSI Technology and Circuits), pp. 1-2, June 2023.
[28] M. Crescentini, M. Bennati, M. Carminati, and M. Tartagni, “Noise limits of CMOS current interfaces for biosensors: A review,” IEEE Trans. Biomed. Circuits Syst., vol. 8, no. 2, pp. 278–292, Apr. 2014.
[29] D. Kim, B. Goldstein, W. Tang, F. J. Sigworth and E. Culurciello, “Noise Analysis and Performance Comparison of Low Current Measurement Systems for Biomedical Applications,” IEEE Transactions on Biomedical Circuits and Systems, vol. 7, no. 1, pp. 52-62, Feb. 2013.
[30] Alexander Shaver et al., “Optimization of Vancomycin Aptamer Sequence Length Increases the Sensitivity of Electrochemical, Aptamer-Based Sensors In Vivo,” ACS Sensors, 7(12), pp. 3895-3905, 2022.
[31] S. Pellerano, J. Alvarado, and Y. Palaskas, “A mm-Wave Power-Harvesting RFID Tag in 90 nm CMOS,” IEEE J. Solid-State Circuits, vol. 45, no. 8, pp. 1627–1637, Aug. 2010.
[32] B. Zhao, N.-C. Kuo, B. Liu, Y.-A. Li, L. Iotti, and A. M. Niknejad, “A 5.8GHz power-harvesting 116μmx116μm ‘dielet’ near-field radio with on-chip coil antenna,” IEEE International Solid-State Circuits Conference (ISSCC), pp. 456–458, Feb. 2018.
[33] H. Jiang, X. Zhou, S. Kulkarni, M. Uranian, R. Seenivasan, and D. A. Hall, “A Sub-1 μW multiparameter injectable BioMote for continuous alcohol monitoring,” IEEE Custom Integrated Circuits Conference (CICC), pp. 1–4, Apr. 2018.
[34] C. Yang et al., “31.4 A 128-Channel 2mm×2mm Battery-Free Neural Dielet Merging Simultaneous Multi-Channel Transmission Through Multi-Carrier Orthogonal Backscatter,” IEEE International Solid-State Circuits Conference (ISSCC), pp. 30–32, Feb. 2023.
[35] M. H. Nazari, M. Mujeeb-U-Rahman, and A. Scherer, “An implantable continuous glucose monitoring microsystem in 0.18μm CMOS,” IEEE Symposium on VLSI Circuits Digest of Technical Papers, pp. 1–2, Jun. 2014.
[36] Q. Liu et al., “Droplet Microfluidics Co-Designed with Real-Time CMOS Luminescence Sensing and Impedance Spectroscopy of 4nL Droplets at a 67mm/s Velocity,” IEEE International Solid-State Circuits Conference (ISSCC), pp. 326–328, Feb. 2024.
[37] C. Zhu et al., “CMOS-Driven Pneumatic-Free Scalable Microfluidics and Fluid Processing with Label-Free Cellular and Bio-Molecular Sensing Capability for an End to-End Point-of-Care System,” IEEE International Solid-State Circuits Conference (ISSCC), pp. 278-279, 2021.
[38] D. Lee, K.-S. Choi, F. Jiang, H. Liu, D. Jung, Y. Kong, M. Saif, Z. Huang, J. Wang, and H. Wang, “Fully Integrated CMOS Ferrofluidic Biomolecular Processing Platform with On-Chip Droplet-Based Manipulation, Multiplexing and Sensing,” IEEE International Solid-State Circuits Conference (ISSCC), vol. 67, pp. 324–326, 2024.
[39] E.-C. Yeh, C.-C. Fu, L. Hu, R. Thakur, J. Feng, and L. P. Lee, “Self-powered integrated microfluidic point-of-care low-cost enabling (SIMPLE) chip,” Sci. Adv., vol. 3, no. 3, Mar. 2017.
[40] I. K. Dimov, L. Basabe-Desmonts, J. L. Garcia-Cordero, B. M. Ross, A. J. Ricco, and L. P. Lee, “Stand-alone self-powered integrated microfluidic blood analysis system (SIMBAS),” Lab Chip, vol. 11, no. 5, pp. 845–850, 2011.
[41] Y. -T. Hsiao et al., “An RFID-inspired One-step Packaged Multi-mode Bio analyzer with Vacuum Microfluidics for Point-of-Care Diagnostics,” IEEE International Solid-State Circuits Conference (ISSCC), Feb. 2025.
[42] M. Schormans, V. Valente, and A. Demosthenous, “Practical inductive link design for biomedical wireless power transfer: A tutorial,” IEEE Trans. Biomed. Circuits Syst., vol. 12, no. 5, pp. 1112–1130, Oct. 2018.
[43] J. Charthad et al., “A mm-Sized Wireless Implantable Device for Electrical Stimulation of Peripheral Nerves,” in IEEE Transactions on Biomedical Circuits and Systems, vol. 12, no. 2, pp. 257-270, Apr. 2018.
[44] Y. Su, J. Holleman, and B. P. Otis, “A digital 1.6 pJ/bit chip identification circuit using process variations,” IEEE J. Solid-State Circuits, vol. 43, no. 1, pp. 69–77, Jan. 2008.
[45] T. Minamiki, T. Sekine, M. Aiko, S. Su, and T. Minami, “An Organic FET with an Aluminum Oxide Extended Gate for pH Sensing,” Sensors and Materials, vol. 31, no. 1, p. 99, Jan. 2019.
[46] Bettazzi F, Romero Natale A, Torres E, Palchetti I, “Glyphosate Determination by Coupling an Immuno-Magnetic Assay with Electrochemical Sensors,” Sensors, 18(9):2965, Sep. 2018.
[47] Yang C-M, Chang J-Y, Chen M-Y, Lai C-S, “A Systematic Study and Potential Limitations of Proton-ELISA Platform for α-Synuclein Antigen Detection,” Chemosensors, 10(1):5, Dec. 2022.
[48] D. A. Hall et al., “A CMOS Molecular Electronics Chip for Single-Molecule Biosensing,” IEEE International Solid-State Circuits Conference (ISSCC), pp. 1-3, 2022.
[49] S. -Y. Lee et al., “A Wireless Urine Detection System and Platform with Power-Efficient Electrochemical Readout ASIC and ABTS-CNT Biosensor,” IEEE Symposium on VLSI Technology and Circuits, pp. 246-247, 2022.
[50] H. M. Jafari, K. Abdelhalim, L. Soleymani, E. H. Sargent, S. O. Kelley and R. Genov, “Nanostructured CMOS Wireless Ultra-Wideband Label-Free PCR-Free DNA Analysis SoC,” IEEE Journal of Solid-State Circuits, vol. 49, no. 5, pp. 1223-1241, May 2014.
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dc.identifier.urihttp://tdr.lib.ntu.edu.tw/jspui/handle/123456789/97037-
dc.description.abstract本論文提出了一種CMOS/微流道生物分析儀,專為即時醫療(PoC)應用設計,其中包含了兩代感測晶片系統(Gen.1 和 Gen.2)。
在 Gen.1中,我們實現了方波伏特庫侖測量(SWVC)進行電化學讀取,有效利用氧化還原標記分子的電子轉移特性,達成超過100倍的訊號增強。該系統在輸入負載為3.3 nF時,展現了5.2 pArms的輸入參考雜訊電流,使訊噪比(SNR)優於先前的研究。此外,Gen.1成功實現了:(1)利用適體(Aptamer)檢測萬古黴素(Vancomycin)和(2)透過DNA適體與CRISPR蛋白檢測細胞激素 TGF-β1。
在Gen.2中,我們將無線供電與通訊整合至CMOS晶片,並透過晶片上的線圈在700 MHz近場運作,這減少了組合CMOS與微流道所需的繁複步驟。此外,Gen.2整合了Amperometric、pH 及溫度感測器。其中,Amperometric感測器 採用訊號折疊技術(Signal-Folding),在100 Hz頻寬下實現0.24 pArms的輸入參考雜訊電流,並具備129.8 dB的動態範圍。該系統利用真空下PDMS自然的滲透現象以驅動流體流動,並已透過質子(Proton-Based)與氧化還原(Redox-Based)免疫分析檢測進行驗證。
Gen.1和Gen.2晶片皆採用TSMC 180-nm CMOS製程,功耗分別為2.4 mW 和2.5 mW。
zh_TW
dc.description.abstractThis thesis presents a CMOS/microfluidics bio-analyzer designed for point-of-care (PoC) applications, including two generations of sensor SoCs (Gen.1 and Gen.2).
In Gen.1, we implemented square-wave voltcoulometry (SWVC) for electrochemical readout, effectively leveraging the redox reporters’ electron transfer properties to achieve a >100× signal enhancement. The system demonstrates an input-referred noise current of 5.2 pArms with an input loading of 3.3 nF, resulting in a superior SNR compared to previous works. Additionally, Gen.1 successfully enabled: (1) vancomycin detection using aptamers and (2) cytokine (TGF-β1) detection using DNA aptamers and CRISPR-associated proteins.
In Gen.2, we integrated fully wireless power and communication into the CMOS chip using an on-chip coil operating at 700 MHz in the near field. This design eliminates packaging complexity and the need for external fluidic actuation, while incorporating amperometric, pH, and temperature sensors. The amperometric front-end employs a signal-folding technique, achieving an input-referred noise current of 0.24 pArms at a 100 Hz bandwidth, along with a dynamic range of 129.8 dB. The system utilizes the natural permeability of PDMS under vacuum to drive fluid flow and has been validated using proton-based and redox-based immunoassay reagents.
Both Gen.1 and Gen.2 SoCs are fabricated in TSMC 180-nm CMOS, consuming 2.4 mW and 2.5 mW, respectively.
en
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dc.description.provenanceMade available in DSpace on 2025-02-26T16:09:58Z (GMT). No. of bitstreams: 0en
dc.description.tableofcontents口試委員會審定書 i
誌謝 ii
中文摘要 iii
Abstract iv
Contents v
List of Figures viii
List of Tables xiii
Chapter 1 Introduction 1
1.1 Motivation & Review 1
1.2 Electrochemical Aptamer-Based Sensor 4
1.3 CRISPR/Cas Technology 7
1.4 Electroanalytical Methods 9
1.4.1 Cyclic Voltammetry (CV) 9
1.4.2 Square wave Voltammetry (SWV) 10
1.4.3 Chronoamperometry (CA) 12
Chapter 2 Electrochemical Sensor SoC Generation 1 14
2.1 System Architecture 14
2.2 R-2R DAC 16
2.2.1 DNL and INL 18
2.2.2 Design of a 11b R-2R DAC 20
2.2.3 Measurement Results of 11-bit R-2R DAC 24
2.3 Potentiostat Amplifier 26
2.3.1 Design of a Potentiostat Amplifier 27
2.4 Analog Front-End (AFE) 30
2.4.1 Design of an Integrator/TIA 31
2.4.2 Design of a Low-Noise Amplifier 36
2.4.2 4b R-String DAC 39
2.4.3 Low-Leakage Switch 40
2.5 Switched-Capacitor Filter 43
2.5.1 Operation Details 45
2.5.2 Core Amplifier Design and Measurement 45
2.6 Square-wave Voltcoulometry (SWVC) 48
Chapter 3 Experimental Results for Generation 1 51
3.1 Electrical Noise Measurements 54
3.2 Vancomycin Detection 56
3.3 CRISPR-Cas12a Detection 58
Chapter 4 Electrochemical Sensor SoC Generation 2 63
4.1 System Architecture 65
4.2 Wireless Powering 67
4.3 Digital Circuits for System 70
4.3.1 Power-on Reset (POR) & End-of-Power Pulse (EOP) 70
4.3.2 Downlink (DL) 72
4.3.3 Uplink (UL) 76
4.3.4 Random ID Generator 79
4.4 FSM - Chip Operation 83
4.4.1 Design Flow 86
4.3.2 Measurement Results of FSM 89
4.5 AFE with Auxiliary Reset 93
4.6 Memory Controller 96
Chapter 5 Experimental Results for Generation 2 102
5.1 Temperature & pH Measurements 105
5.2 HRP/TMB Measurements 107
5.3 Glucose/Avidin-GOx Measurements 109
Chapter 6 Conclusion and Future Work 111
References 114
-
dc.language.isoen-
dc.subject適體zh_TW
dc.subject電化學感測器zh_TW
dc.subject方波伏特庫侖法zh_TW
dc.subject微流道zh_TW
dc.subjectCRISPRzh_TW
dc.subject即時醫療系統晶片zh_TW
dc.subjectsquare-wave voltcoulometry (SWVC)en
dc.subjectmicrofluidicsen
dc.subjectCRISPRen
dc.subjectAptameren
dc.subjectPoint-of-Care SoCen
dc.subjectelectrochemical sensoren
dc.title應用於檢測核酸及 CRISPR-Cas12a 酶之電化學生物感測器zh_TW
dc.titleCMOS Electrochemical Sensor for Biosensing with Aptamers and CRISPR-Cas12a Enzymesen
dc.typeThesis-
dc.date.schoolyear113-1-
dc.description.degree碩士-
dc.contributor.coadvisor劉宗德zh_TW
dc.contributor.coadvisorTsung-Te Liuen
dc.contributor.oralexamcommittee廖育德;林宗賢zh_TW
dc.contributor.oralexamcommitteeYu-Te Liao;Tsung-Hsien Linen
dc.subject.keyword即時醫療系統晶片,適體,CRISPR,微流道,方波伏特庫侖法,電化學感測器,zh_TW
dc.subject.keywordPoint-of-Care SoC,Aptamer,CRISPR,microfluidics,square-wave voltcoulometry (SWVC),electrochemical sensor,en
dc.relation.page119-
dc.identifier.doi10.6342/NTU202500453-
dc.rights.note同意授權(限校園內公開)-
dc.date.accepted2025-02-12-
dc.contributor.author-college電機資訊學院-
dc.contributor.author-dept電子工程學研究所-
dc.date.embargo-lift2030-01-31-
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