A multichannel thermal bubble-actuated impedance flow cytometer with on-chip TIA based on CMOS-MEMS

Shengxun Cai; Jianqing Nie; Kun Wang; Yimin Guan; Demeng Liu

doi:10.1088/1674-4926/45/5/052201

J. Semicond. > 2024, Volume 45 > Issue 5 > 052201

ARTICLES

A multichannel thermal bubble-actuated impedance flow cytometer with on-chip TIA based on CMOS-MEMS

Shengxun Cai¹, Jianqing Nie¹, Kun Wang², Yimin Guan^{1, 2} and Demeng Liu^{1, 2,}

+ Author Affiliations

1. School of Microelectronics, Shanghai University, Shanghai 201800, China
2. Shanghai AURE Technology Limited Company, Shanghai 201800, China

Author Bio:

Shengxun Cai received his B.Eng. degree from Qingdao University, he is currently a postgraduate student at the School of Microelectronics, Shanghai University. His research interests are intelligent microfluidic and analog integrated circuit design.

Jianqing Nie received his B.Eng. degree from Xi'an Jiaotong University, he is now a postgraduate student at the School of Microelectronics, Shanghai University. His research focuses on the integration of analog front-end integrated circuit design with MEMS arrays.

Kun Wang received his Ph.D. degree from Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences in 2019. He is now a microfluidic engineer at Shanghai AURE Technology Co., LTD. He is working on integration of inkjet printing and biomedicine.

Yimin Guan received his Ph.D. degree from Auburn University in1998. He is currently the co-tutor of the School of Microelectronics at Shanghai University and the CEO of Shanghai AURE Technology Co., LTD. His research focuses on intelligent microfluidic chips based on special application integrated circuit (ASIC) and micromotor system (MEMS) technologies.

Demeng Liu received his Ph.D. degree from Shanghai Institute of Advanced Study, Chinese Academy of Sciences in 2014. He is now a joint tutor at the School of Microelectronics of Shanghai University and an integrated circuit design engineer at Shanghai AURE Technology Co., LTD, for development of intelligent microfluidic chip based on CMOS-MEMS process.

Corresponding author: Demeng Liu, demeng_liu@shu.edu.cn

DOI: 10.1088/1674-4926/45/5/052201

Abstract: Electrochemical impedance spectroscopy (EIS) flow cytometry offers the advantages of speed, affordability, and portability in cell analysis and cytometry applications. However, the integration challenges of microfluidic and EIS read-out circuits hinder the downsizing of cytometry devices. To address this, we developed a thermal-bubble-driven impedance flow cytometric application-specific integrated circuit (ASIC). The thermal-bubble micropump avoids external piping and equipment, enabling high-throughput designs. With a total of 36 cell counting channels, each measuring 884 × 220 μm², the chip significantly enhances the throughput of flow cytometers. Each cell counting channel incorporates a differential trans-impedance amplifier (TIA) to amplify weak biosensing signals. By eliminating the parasitic parameters created at the complementary metal-oxide-semiconductor transistor (CMOS)-micro-electromechanical systems (MEMS) interface, the counting accuracy can be increased. The on-chip TIA can adjust feedback resistance from 5 to 60 kΩ to accommodate solutions with different impedances. The chip effectively classifies particles of varying sizes, demonstrated by the average peak voltages of 0.0529 and 0.4510 mV for 7 and 14 μm polystyrene beads, respectively. Moreover, the counting accuracies of the chip for polystyrene beads and MSTO-211H cells are both greater than 97.6%. The chip exhibits potential for impedance flow cytometer at low cost, high-throughput, and miniaturization for the application of point-of-care diagnostics.

Key words: EIS, flow cytometry, CMOS-MEMS, thermal bubble, lab-on-chip

References

[1]	Adan A, Alizada G, Kiraz Y, et al. Flow cytometry: Basic principles and applications. Crit Rev Biotechnol, 2017, 37(2), 163 doi: 10.3109/07388551.2015.1128876
[2]	Lu N, Tay H M, Petchakup C, et al. Label-free microfluidic cell sorting and detection for rapid blood analysis. Lab Chip, 2023, 23(5), 1226 doi: 10.1039/D2LC00904H
[3]	McKinnon K M. Flow Cytometry: An Overview, Curr Protoc Immunol, 2018, 120(1), 5 doi: 10.1002/cpim.40
[4]	Hurley J. Sizing particles with a coulter counter. Biophys J, 1970, 10(1), 74 doi: 10.1016/S0006-3495(70)86286-5
[5]	Don M. The coulter principle: Foundation of an industry. JALA J Assoc Lab Autom, 2003, 8(6), 72 doi: 10.1016/S1535-5535-03-00023-6
[6]	Rodriguez-Trujillo R, Mills C A, Samitier J, et al. Low cost micro-Coulter counter with hydrodynamic focusing. Microfluid Nanofluid, 2007, 3(2), 171 doi: 10.1007/s10404-006-0113-8
[7]	He Z, Mansfeld F. Exploring the use of electrochemical impedance spectroscopy (EIS) in microbial fuel cell studies. Energy Environ Sci, 2009, 2(2), 215 doi: 10.1039/B814914C
[8]	Pastor-Fernández C, Dhammika W W, Marco J, et al. Identification and quantification of ageing mechanisms in lithium-ion batteries using the EIS technique. 2016 IEEE Transportation Electrification Conference and Expo (ITEC), 2016, 1 doi: 10.1109/ITEC.2016.7520198
[9]	Giagkoulovits C, Cheah B C, Al-Rawhani M A, et al. A 16 x 16 CMOS amperometric microelectrode array for simultaneous electrochemical measurements. IEEE Trans Circuits Syst I Regul Pap, 2018, 65(9), 2821 doi: 10.1109/TCSI.2018.2794502
[10]	Xu J W, Hong Z L. Low power bio-impedance sensor interfaces: Review and electronics design methodology. IEEE Rev Biomed Eng, 2022, 15, 23 doi: 10.1109/RBME.2020.3041053
[11]	Bounik R, Cardes F, Ulusan H, et al. Impedance imaging of cells and tissues: Design and applications. BME Front, 2022, 2022, 1 doi: 10.34133/2022/9857485
[12]	Park J Y, Park S M. DNA hybridization sensors based on electrochemical impedance spectroscopy as a detection tool. Sensors, 2009, 9(12), 9513 doi: 10.3390/s91209513
[13]	Bernabini C, Holmes D, Morgan H. Micro-impedance cytometry for detection and analysis of micron-sized particles and bacteria. Lab Chip, 2011, 11(3), 407 doi: 10.1039/C0LC00099J
[14]	Cheung K, Gawad S, Renaud P. Impedance spectroscopy flow cytometry: On-chip label-free cell differentiation. Cytometry Pt A, 2005, 65A(2), 124 doi: 10.1002/cyto.a.20141
[15]	Honrado C, Bisegna P, Swami N S, et al. Single-cell microfluidic impedance cytometry: From raw signals to cell phenotypes using data analytics. Lab Chip, 2021, 21(1), 22 doi: 10.1039/D0LC00840K
[16]	Haandbæk N, With O, Bürgel S C, et al. Resonance-enhanced microfluidic impedance cytometer for detection of single bacteria. Lab Chip, 2014, 14(17), 3313 doi: 10.1039/C4LC00576G
[17]	Nguyen T H, Nguyen H A, Tran Thi Y V, et al. Concepts, electrode configuration, characterization, and data analytics of electric and electrochemical microfluidic platforms: A review. Analyst, 2023, 148(9), 1912 doi: 10.1039/D2AN02027K
[18]	van Berkel C, Gwyer J D, Deane S, et al. Integrated systems for rapid point of care (PoC) blood cell analysis. Lab Chip, 2011, 11(7), 1249 doi: 10.1039/c0lc00587h
[19]	Sun D P, Lu J, Chen Z G. Microfluidic contactless conductivity cytometer for electrical cell sensing and counting. RSC Adv, 2015, 5(73), 59306 doi: 10.1039/C5RA08371K
[20]	Yang X P, Wang K, Huang P, et al. Thermal bubble-driven impedance-based high-throughput cell counting chip design. AIP Adv, 2023, 13(6), 065308. doi: 10.1063/5.0153846
[21]	Hassan U, Reddy B Jr, Damhorst G, et al. A microfluidic biochip for complete blood cell counts at the point-of-care. TECHNOLOGY, 2015, 3(4), 201 doi: 10.1142/S2339547815500090
[22]	Zhong J W, Liang M H, Ai Y. Submicron-precision particle characterization in microfluidic impedance cytometry with double differential electrodes. Lab Chip, 2021, 21(15), 2869 doi: 10.1039/D1LC00481F
[23]	Shen B Y, Dawes J, Johnston M L. A 10 MΩ, 50 kHz-40 MHz impedance measurement architecture for source-differential flow cytometry. IEEE Trans Biomed Circuits Syst, 2022, 16(5), 766 doi: 10.1109/TBCAS.2022.3182905
[24]	Iyer V, Issadore D A, Aflatouni F. The next generation of hybrid microfluidic/integrated circuit chips: Recent and upcoming advances in high-speed, high-throughput, and multifunctional lab-on-IC systems. Lab Chip, 2023, 23(11), 2553 doi: 10.1039/D2LC01163H
[25]	Carminati M, Gervasoni G, Sampietro M, et al. Note: Differential configurations for the mitigation of slow fluctuations limiting the resolution of digital lock-in amplifiers. Rev Sci Instrum, 2016, 87(2), 026102 doi: 10.1063/1.4941721
[26]	Sharma N, Kumar M, Kumari N, et al. Tantalum oxide thin films for electrochemical pH sensor. Mater Res Express, 2020, 7(3), 036405 doi: 10.1088/2053-1591/ab7ced
[27]	Carminati M, Ferrari G, Vahey M D, et al. Miniaturized impedance flow cytometer: Design rules and integrated readout. IEEE Trans Biomed Circuits Syst, 2017, 11, 1438 doi: 10.1109/TBCAS.2017.2748158
[28]	Lee K H, Nam J, Choi S, et al. A CMOS impedance cytometer for 3D flowing single-cell real-time analysis with ΔΣ error correction. 2012 IEEE International Solid-State Circuits Conference, 2012, 304 doi: 10.1109/ISSCC.2012.6177024
[29]	Fu Y S, Yuan Q B, Guo J H. Lab-on-PCB-based micro-cytometer for circulating tumor cells detection and enumeration. Microfluid Nanofluid, 2017, 21(2), 20 doi: 10.1007/s10404-017-1854-2
[30]	Chien J C, Ameri A, Yeh E C, et al. A high-throughput flow cytometry-on-a-CMOS platform for single-cell dielectric spectroscopy at microwave frequencies. Lab Chip, 2018, 18(14), 2065 doi: 10.1039/C8LC00299A
[31]	Feng Y X, Zhu J W, Chai H C, et al. Impedance-based multimodal electrical-mechanical intrinsic flow cytometry. Small, 2023, 19(45), 2370379 doi: 10.1002/smll.202370379

Fig. 1. (Color online) Schematic of EIS flow cytometry and equivalent circuit model of animal cells.

DownLoad: Full-Size Img PowerPoint

Fig. 2. (Color online) Microfluidics and circuits design of the chip. (a) 3D diagram of the microchannel, coplanar three electrodes, and thermal bubble micropump. (b) Schematic of two-stage operational amplifier of TIA. (c) Bode plot of two-stage operational amplifier. (d) Overall schematic of the EIS flow cytometry chip.

DownLoad: Full-Size Img PowerPoint

Fig. 3. (Color online) Chip manufacturing process profile based on CMOS-MEMS technology.

DownLoad: Full-Size Img PowerPoint

Fig. 4. (Color online) Images of EIS flow cytometry after encapsulation, welding, and dispensing. (a) The front view of the complete EIS flow cytometry device. (b) The back view of the complete EIS flow cytometry device. (c) Microscopic view of a single channel consisting of a microchannel, coplanar three electrodes, a thermal bubble micropump, and two TIAs for reading the induced current signal. (d) Micrograph of the fabricated 0.35 μm CMOS TIA IC.

DownLoad: Full-Size Img PowerPoint

Fig. 5. (Color online) Test principle and equipment of EIS flow cytometry chip. (a) Illustration of the test bed for EIS flow cytometry. (b) Block diagram for TIA and lock-in amplifier circuit. (c) The experimental test setup for evaluating the EIS flow cytometry with on-chip TIA, including electrical, optical, and fluidic interfaces.

DownLoad: Full-Size Img PowerPoint

Fig. 6. (Color online) (a) TIA output voltage waveform measured by an oscilloscope. (b) Linearity of TIA magnification, the resistance of R_F is 5, 10, 20, 30, 40, 50 and 60 kΩ respectively.

DownLoad: Full-Size Img PowerPoint

Fig. 7. (Color online) (a) Measured voltage amplitude versus the size of polystyrene beads. (b) The output voltage amplitude histogram of each single-particle event, 300 for each particle, demonstrates clear separation by particle size.

DownLoad: Full-Size Img PowerPoint

Fig. 8. (Color online) (a) Measured voltage transient signal real component (I-channel) shown above real-time inverted microscope images taken when a 7 μm single bead is transiting across the electrodes. (b−d) The linear fit between the number of 7 and 14 μm polystyrene beads, and 211H cells observed by inverted microscope and the number of signals detected by EIS flow cytometry.

DownLoad: Full-Size Img PowerPoint

Table 1. Accuracy of detection of different types of particles.

Particle types	Number of inverted microscope observation particles (pcs)	Number of signals measured by EIS analyzer (pcs)	Detection accuracy (%)
7 μm polystyrene beads	300	293	97.66
14 μm polystyrene beads	300	296	98.66
211H cells	300	294	98.0

DownLoad: CSV

Table 2. Performance comparison of impedance flow cytometers.

First author (year)	Signal readout method	Drive type	Number of detection channels	Device size	Cell measurement	Coefficient of determination (R²)	Throughput	Ref
This work	On-chip TIA + lock-in amplifier	Thermal bubble micropump	36	24 mm²	MSTO-211H	0.999	16 200 cells/s	−
Liu et al. (2023)	Lock-in amplifier	Thermal bubble micropump	100	38 mm²	MSTO-211H	0.999	45 000 cells/s	[20]
Sun et al. (2015)	Lock-in amplifier	Syringe pump	1	21 cm²	MCF-7, HCM	0.984	60 cells/min	[19]
Carminati et al. (2017)	Lock-in amplifier	Syringe pump	2	46 cm²	Yeast cells	−	2000 cells/s	[27]
Lee et al. (2012)	Discrete IC	Syringe pump	1	−	RBC	−	267 cells/s	[28]
Fu et al. (2017)	Lock-in amplifier	Syringe pump	1	−	RBC, WBC, CTC	0.992	−	[29]
Johnston et al. (2022)	Discrete IC	Syringe pump	1	0.28 mm²	−	−	1 cells/s	[23]
Niknejad et al. (2018)	Discrete IC	Syringe pump	1	−	THP-1, MDA-MB-231	−	1000 cells/s	[30]
Wang et al. (2023)	Lock-in amplifier	Syringe pump	1	−	MDA-MB-468	−	500 cells/min	[31]

DownLoad: CSV

[1]	Adan A, Alizada G, Kiraz Y, et al. Flow cytometry: Basic principles and applications. Crit Rev Biotechnol, 2017, 37(2), 163 doi: 10.3109/07388551.2015.1128876
[2]	Lu N, Tay H M, Petchakup C, et al. Label-free microfluidic cell sorting and detection for rapid blood analysis. Lab Chip, 2023, 23(5), 1226 doi: 10.1039/D2LC00904H
[3]	McKinnon K M. Flow Cytometry: An Overview, Curr Protoc Immunol, 2018, 120(1), 5 doi: 10.1002/cpim.40
[4]	Hurley J. Sizing particles with a coulter counter. Biophys J, 1970, 10(1), 74 doi: 10.1016/S0006-3495(70)86286-5
[5]	Don M. The coulter principle: Foundation of an industry. JALA J Assoc Lab Autom, 2003, 8(6), 72 doi: 10.1016/S1535-5535-03-00023-6
[6]	Rodriguez-Trujillo R, Mills C A, Samitier J, et al. Low cost micro-Coulter counter with hydrodynamic focusing. Microfluid Nanofluid, 2007, 3(2), 171 doi: 10.1007/s10404-006-0113-8
[7]	He Z, Mansfeld F. Exploring the use of electrochemical impedance spectroscopy (EIS) in microbial fuel cell studies. Energy Environ Sci, 2009, 2(2), 215 doi: 10.1039/B814914C
[8]	Pastor-Fernández C, Dhammika W W, Marco J, et al. Identification and quantification of ageing mechanisms in lithium-ion batteries using the EIS technique. 2016 IEEE Transportation Electrification Conference and Expo (ITEC), 2016, 1 doi: 10.1109/ITEC.2016.7520198
[9]	Giagkoulovits C, Cheah B C, Al-Rawhani M A, et al. A 16 x 16 CMOS amperometric microelectrode array for simultaneous electrochemical measurements. IEEE Trans Circuits Syst I Regul Pap, 2018, 65(9), 2821 doi: 10.1109/TCSI.2018.2794502
[10]	Xu J W, Hong Z L. Low power bio-impedance sensor interfaces: Review and electronics design methodology. IEEE Rev Biomed Eng, 2022, 15, 23 doi: 10.1109/RBME.2020.3041053
[11]	Bounik R, Cardes F, Ulusan H, et al. Impedance imaging of cells and tissues: Design and applications. BME Front, 2022, 2022, 1 doi: 10.34133/2022/9857485
[12]	Park J Y, Park S M. DNA hybridization sensors based on electrochemical impedance spectroscopy as a detection tool. Sensors, 2009, 9(12), 9513 doi: 10.3390/s91209513
[13]	Bernabini C, Holmes D, Morgan H. Micro-impedance cytometry for detection and analysis of micron-sized particles and bacteria. Lab Chip, 2011, 11(3), 407 doi: 10.1039/C0LC00099J
[14]	Cheung K, Gawad S, Renaud P. Impedance spectroscopy flow cytometry: On-chip label-free cell differentiation. Cytometry Pt A, 2005, 65A(2), 124 doi: 10.1002/cyto.a.20141
[15]	Honrado C, Bisegna P, Swami N S, et al. Single-cell microfluidic impedance cytometry: From raw signals to cell phenotypes using data analytics. Lab Chip, 2021, 21(1), 22 doi: 10.1039/D0LC00840K
[16]	Haandbæk N, With O, Bürgel S C, et al. Resonance-enhanced microfluidic impedance cytometer for detection of single bacteria. Lab Chip, 2014, 14(17), 3313 doi: 10.1039/C4LC00576G
[17]	Nguyen T H, Nguyen H A, Tran Thi Y V, et al. Concepts, electrode configuration, characterization, and data analytics of electric and electrochemical microfluidic platforms: A review. Analyst, 2023, 148(9), 1912 doi: 10.1039/D2AN02027K
[18]	van Berkel C, Gwyer J D, Deane S, et al. Integrated systems for rapid point of care (PoC) blood cell analysis. Lab Chip, 2011, 11(7), 1249 doi: 10.1039/c0lc00587h
[19]	Sun D P, Lu J, Chen Z G. Microfluidic contactless conductivity cytometer for electrical cell sensing and counting. RSC Adv, 2015, 5(73), 59306 doi: 10.1039/C5RA08371K
[20]	Yang X P, Wang K, Huang P, et al. Thermal bubble-driven impedance-based high-throughput cell counting chip design. AIP Adv, 2023, 13(6), 065308. doi: 10.1063/5.0153846
[21]	Hassan U, Reddy B Jr, Damhorst G, et al. A microfluidic biochip for complete blood cell counts at the point-of-care. TECHNOLOGY, 2015, 3(4), 201 doi: 10.1142/S2339547815500090
[22]	Zhong J W, Liang M H, Ai Y. Submicron-precision particle characterization in microfluidic impedance cytometry with double differential electrodes. Lab Chip, 2021, 21(15), 2869 doi: 10.1039/D1LC00481F
[23]	Shen B Y, Dawes J, Johnston M L. A 10 MΩ, 50 kHz-40 MHz impedance measurement architecture for source-differential flow cytometry. IEEE Trans Biomed Circuits Syst, 2022, 16(5), 766 doi: 10.1109/TBCAS.2022.3182905
[24]	Iyer V, Issadore D A, Aflatouni F. The next generation of hybrid microfluidic/integrated circuit chips: Recent and upcoming advances in high-speed, high-throughput, and multifunctional lab-on-IC systems. Lab Chip, 2023, 23(11), 2553 doi: 10.1039/D2LC01163H
[25]	Carminati M, Gervasoni G, Sampietro M, et al. Note: Differential configurations for the mitigation of slow fluctuations limiting the resolution of digital lock-in amplifiers. Rev Sci Instrum, 2016, 87(2), 026102 doi: 10.1063/1.4941721
[26]	Sharma N, Kumar M, Kumari N, et al. Tantalum oxide thin films for electrochemical pH sensor. Mater Res Express, 2020, 7(3), 036405 doi: 10.1088/2053-1591/ab7ced
[27]	Carminati M, Ferrari G, Vahey M D, et al. Miniaturized impedance flow cytometer: Design rules and integrated readout. IEEE Trans Biomed Circuits Syst, 2017, 11, 1438 doi: 10.1109/TBCAS.2017.2748158
[28]	Lee K H, Nam J, Choi S, et al. A CMOS impedance cytometer for 3D flowing single-cell real-time analysis with ΔΣ error correction. 2012 IEEE International Solid-State Circuits Conference, 2012, 304 doi: 10.1109/ISSCC.2012.6177024
[29]	Fu Y S, Yuan Q B, Guo J H. Lab-on-PCB-based micro-cytometer for circulating tumor cells detection and enumeration. Microfluid Nanofluid, 2017, 21(2), 20 doi: 10.1007/s10404-017-1854-2
[30]	Chien J C, Ameri A, Yeh E C, et al. A high-throughput flow cytometry-on-a-CMOS platform for single-cell dielectric spectroscopy at microwave frequencies. Lab Chip, 2018, 18(14), 2065 doi: 10.1039/C8LC00299A
[31]	Feng Y X, Zhu J W, Chai H C, et al. Impedance-based multimodal electrical-mechanical intrinsic flow cytometry. Small, 2023, 19(45), 2370379 doi: 10.1002/smll.202370379

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Received: 23 November 2023 Revised: 04 January 2024 Online: Accepted Manuscript: 22 January 2024Uncorrected proof: 01 February 2024Published: 10 May 2024

Article Navigation > Journal of Semiconductors > 2024 > 45(5): 052201

Shengxun Cai, Jianqing Nie, Kun Wang, Yimin Guan, Demeng Liu. A multichannel thermal bubble-actuated impedance flow cytometer with on-chip TIA based on CMOS-MEMS[J]. Journal of Semiconductors, 2024, 45(5): 052201. doi: 10.1088/1674-4926/45/5/052201 ****S X Cai, J Q Nie, K Wang, Y M Guan, and D M Liu, A multichannel thermal bubble-actuated impedance flow cytometer with on-chip TIA based on CMOS-MEMS[J]. J. Semicond., 2024, 45(5), 052201 doi: 10.1088/1674-4926/45/5/052201

Citation:

Shengxun Cai, Jianqing Nie, Kun Wang, Yimin Guan, Demeng Liu. A multichannel thermal bubble-actuated impedance flow cytometer with on-chip TIA based on CMOS-MEMS[J]. Journal of Semiconductors, 2024, 45(5): 052201. doi: 10.1088/1674-4926/45/5/052201 ****

S X Cai, J Q Nie, K Wang, Y M Guan, and D M Liu, A multichannel thermal bubble-actuated impedance flow cytometer with on-chip TIA based on CMOS-MEMS[J]. J. Semicond., 2024, 45(5), 052201 doi: 10.1088/1674-4926/45/5/052201

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A multichannel thermal bubble-actuated impedance flow cytometer with on-chip TIA based on CMOS-MEMS

DOI: 10.1088/1674-4926/45/5/052201

1.
School of Microelectronics, Shanghai University, Shanghai 201800, China
2.
Shanghai AURE Technology Limited Company, Shanghai 201800, China

More Information

Shengxun Cai received his B.Eng. degree from Qingdao University, he is currently a postgraduate student at the School of Microelectronics, Shanghai University. His research interests are intelligent microfluidic and analog integrated circuit design
Jianqing Nie received his B.Eng. degree from Xi'an Jiaotong University, he is now a postgraduate student at the School of Microelectronics, Shanghai University. His research focuses on the integration of analog front-end integrated circuit design with MEMS arrays
Kun Wang received his Ph.D. degree from Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences in 2019. He is now a microfluidic engineer at Shanghai AURE Technology Co., LTD. He is working on integration of inkjet printing and biomedicine
Yimin Guan received his Ph.D. degree from Auburn University in1998. He is currently the co-tutor of the School of Microelectronics at Shanghai University and the CEO of Shanghai AURE Technology Co., LTD. His research focuses on intelligent microfluidic chips based on special application integrated circuit (ASIC) and micromotor system (MEMS) technologies
Demeng Liu received his Ph.D. degree from Shanghai Institute of Advanced Study, Chinese Academy of Sciences in 2014. He is now a joint tutor at the School of Microelectronics of Shanghai University and an integrated circuit design engineer at Shanghai AURE Technology Co., LTD, for development of intelligent microfluidic chip based on CMOS-MEMS process
Corresponding author: demeng_liu@shu.edu.cn
Received Date: 2023-11-23
Revised Date: 2024-01-04

Available Online: 2024-01-22

Abstract

Abstract

Electrochemical impedance spectroscopy (EIS) flow cytometry offers the advantages of speed, affordability, and portability in cell analysis and cytometry applications. However, the integration challenges of microfluidic and EIS read-out circuits hinder the downsizing of cytometry devices. To address this, we developed a thermal-bubble-driven impedance flow cytometric application-specific integrated circuit (ASIC). The thermal-bubble micropump avoids external piping and equipment, enabling high-throughput designs. With a total of 36 cell counting channels, each measuring 884 × 220 μm², the chip significantly enhances the throughput of flow cytometers. Each cell counting channel incorporates a differential trans-impedance amplifier (TIA) to amplify weak biosensing signals. By eliminating the parasitic parameters created at the complementary metal-oxide-semiconductor transistor (CMOS)-micro-electromechanical systems (MEMS) interface, the counting accuracy can be increased. The on-chip TIA can adjust feedback resistance from 5 to 60 kΩ to accommodate solutions with different impedances. The chip effectively classifies particles of varying sizes, demonstrated by the average peak voltages of 0.0529 and 0.4510 mV for 7 and 14 μm polystyrene beads, respectively. Moreover, the counting accuracies of the chip for polystyrene beads and MSTO-211H cells are both greater than 97.6%. The chip exhibits potential for impedance flow cytometer at low cost, high-throughput, and miniaturization for the application of point-of-care diagnostics.
- EIS,
- flow cytometry,
- CMOS-MEMS,
- thermal bubble,
- lab-on-chip

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References(31)

References

[1]	Adan A, Alizada G, Kiraz Y, et al. Flow cytometry: Basic principles and applications. Crit Rev Biotechnol, 2017, 37(2), 163 doi: 10.3109/07388551.2015.1128876
[2]	Lu N, Tay H M, Petchakup C, et al. Label-free microfluidic cell sorting and detection for rapid blood analysis. Lab Chip, 2023, 23(5), 1226 doi: 10.1039/D2LC00904H
[3]	McKinnon K M. Flow Cytometry: An Overview, Curr Protoc Immunol, 2018, 120(1), 5 doi: 10.1002/cpim.40
[4]	Hurley J. Sizing particles with a coulter counter. Biophys J, 1970, 10(1), 74 doi: 10.1016/S0006-3495(70)86286-5
[5]	Don M. The coulter principle: Foundation of an industry. JALA J Assoc Lab Autom, 2003, 8(6), 72 doi: 10.1016/S1535-5535-03-00023-6
[6]	Rodriguez-Trujillo R, Mills C A, Samitier J, et al. Low cost micro-Coulter counter with hydrodynamic focusing. Microfluid Nanofluid, 2007, 3(2), 171 doi: 10.1007/s10404-006-0113-8
[7]	He Z, Mansfeld F. Exploring the use of electrochemical impedance spectroscopy (EIS) in microbial fuel cell studies. Energy Environ Sci, 2009, 2(2), 215 doi: 10.1039/B814914C
[8]	Pastor-Fernández C, Dhammika W W, Marco J, et al. Identification and quantification of ageing mechanisms in lithium-ion batteries using the EIS technique. 2016 IEEE Transportation Electrification Conference and Expo (ITEC), 2016, 1 doi: 10.1109/ITEC.2016.7520198
[9]	Giagkoulovits C, Cheah B C, Al-Rawhani M A, et al. A 16 x 16 CMOS amperometric microelectrode array for simultaneous electrochemical measurements. IEEE Trans Circuits Syst I Regul Pap, 2018, 65(9), 2821 doi: 10.1109/TCSI.2018.2794502
[10]	Xu J W, Hong Z L. Low power bio-impedance sensor interfaces: Review and electronics design methodology. IEEE Rev Biomed Eng, 2022, 15, 23 doi: 10.1109/RBME.2020.3041053
[11]	Bounik R, Cardes F, Ulusan H, et al. Impedance imaging of cells and tissues: Design and applications. BME Front, 2022, 2022, 1 doi: 10.34133/2022/9857485
[12]	Park J Y, Park S M. DNA hybridization sensors based on electrochemical impedance spectroscopy as a detection tool. Sensors, 2009, 9(12), 9513 doi: 10.3390/s91209513
[13]	Bernabini C, Holmes D, Morgan H. Micro-impedance cytometry for detection and analysis of micron-sized particles and bacteria. Lab Chip, 2011, 11(3), 407 doi: 10.1039/C0LC00099J
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A multichannel thermal bubble-actuated impedance flow cytometer with on-chip TIA based on CMOS-MEMS

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A multichannel thermal bubble-actuated impedance flow cytometer with on-chip TIA based on CMOS-MEMS

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A multichannel thermal bubble-actuated impedance flow cytometer with on-chip TIA based on CMOS-MEMS

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A multichannel thermal bubble-actuated impedance flow cytometer with on-chip TIA based on CMOS-MEMS

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