Qiao Lin

Columbia University, New York, New York, United States

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Publications (140)195.11 Total impact

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    ABSTRACT: This paper presents an aptameric graphene nanosensor for detection of small-molecule biomarkers. To address difficulties in direct detection of small molecules associated with their low molecular weight and electrical charge, we incorporate an aptamer-based competitive affinity assay in a graphene field effect transistor (FET), and demonstrate the utility of the nanosensor with dehydroepiandrosterone sulfate (DHEA-S), a small-molecule steroid hormone, as the target analyte. In the competitive affinity assay, DHEA-S specifically binds to aptamer molecules pre-hybridized to their complementary DNA anchor molecules immobilized on the graphene surface. This results in the competitive release of the strongly charged aptamer from the DNA anchor and hence a change in electrical properties of the graphene, which can be measured to achieve the detection of DHEA-S. We present experimental data on the label-free, specific and quantitative detection of DHEA-S at clinically appropriate concentrations with an estimated detection limit of 44.7nM, and analyze the trend observed in the experiments using molecular binding kinetics theory. These results demonstrate the potential of our nanosensor in the detection of DHEA-S and other small molecules in biomedical applications. Copyright © 2015 Elsevier B.V. All rights reserved.
    Biosensors & Bioelectronics 09/2015; 71:222-229. DOI:10.1016/j.bios.2015.04.025 · 6.45 Impact Factor
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    ABSTRACT: This letter presents a graphene field effect transistor (GFET) nanosensor that, with a solid gate provided by a high-κ dielectric, allows analyte detection in liquid media at low gate voltages. The gate is embedded within the sensor and thus is isolated from a sample solution, offering a high level of integration and miniaturization and eliminating errors caused by the liquid disturbance, desirable for both in vitro and in vivo applications. We demonstrate that the GFET nanosensor can be used to measure pH changes in a range of 5.3–9.3. Based on the experimental observations and quantitative analysis, the charging of an electrical double layer capacitor is found to be the major mechanism of pH sensing.
    Applied Physics Letters 03/2015; 106(12):123503. DOI:10.1063/1.4916341 · 3.52 Impact Factor
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    ABSTRACT: We here present a microfluidic aptasensor that integrates aptamer-based selective analyte enrichment, isocratic elution and conductance-based graphene nanosensing, achieving sensitive and label-free detection of small biomolecules. An aptamer specific to a target analyte is immobilized on microbeads for selective enrichment and isocratic elution of the analyte. A conductance-based graphene nanosensor using a competitive assay format achieves label-free detection, with a high sensitivity due to surface binding-induced changes in carrier concentration in the bulk of graphene. Experimental results show that our integrated device is capable of detecting arginine vasopressin (AVP), a small peptide, at clinically relevant low concentrations (1–500 pM).
    Micro Electro Mechanical Systems (MEMS), 2015 IEEE 28th International Conference on, Estoril, Portugal; 01/2015
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    ABSTRACT: We here present a microfluidic aptasensor that integrates aptamer-based selective analyte enrichment, isocratic elution and conductance-based graphene nanosensing, achieving sensitive and label-free detection of small biomolecules. An aptamer specific to a target analyte is immobilized on microbeads for selective enrichment and isocratic elution of the analyte. A conductance-based graphene nanosensor using a competitive assay format achieves label-free detection, with a high sensitivity due to surface binding-induced changes in carrier concentration in the bulk of graphene. Experimental results show that our integrated device is capable of detecting arginine vasopressin (AVP), a small peptide, at clinically relevant low concentrations (1–500 pM).
    Micro Electro Mechanical Systems (MEMS), 2015 IEEE 28th International Conference on, Estoril, Portugal; 01/2015
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    ABSTRACT: This paper presents a graphene field effect transistor (GFET) nanosensor that, with a solid gate provided by a high-κ dielectric, allows analyte detection in liquid media at low gate voltages. The gate is embedded within the sensor and thus is isolated from a sample solution, offering a high level of integration and miniaturization and eliminating errors caused by the liquid disturbance, desirable for both in vitro and in vivo applications. We demonstrate that the GFET nanosensor can be used to measure pH changes in a range of 5.3–9.3. Based on the experimental observations and quantitative analysis, the charging of an electrical double layer capacitor is found to be the major mechanism of pH sensing.
    Micro Electro Mechanical Systems (MEMS), 2015 IEEE 28th International Conference on, Estoril, Portugal; 01/2015
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    ABSTRACT: Gene expression analysis at the single-cell level is critical to understanding variations among cells in heterogeneous populations. Microfluidic reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) is well suited to gene expression assays of single cells. We present a microfluidic approach that integrates all functional steps for RT-qPCR of a single cell, including isolation and lysis of the cell, as well as purification, reverse transcription and quantitative real-time PCR of messenger RNA in the cell lysate. In this approach, all reactions in the multi-step assay of a single lysed cell can be completed on microbeads, thereby simplifying the design, fabrication and operation of the microfluidic device, as well as facilitating the minimization of sample loss or contamination. In the microfluidic device, a single cell is isolated and lysed; mRNA in the cell lysate is then analyzed by RT-qPCR using primers immobilized on microbeads in a single microchamber whose temperature is controlled in closed loop via an integrated heater and temperature sensor. The utility of the approach was demonstrated by the analysis of the effects of the drug (methyl methanesulfonate, MMS) on the induction of the cyclin-dependent kinase inhibitor 1a (CDKN1A) in single human cancer cells (MCF-7), demonstrating the potential of our approach for efficient, integrated single-cell RT-qPCR for gene expression analysis.
    RSC Advances 01/2015; 5(7):4886-4893. DOI:10.1039/C4RA13356K · 3.71 Impact Factor
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    ABSTRACT: In this work, we present for the first time a centrifugal microfluidic system for the detection of analytes in blood using a low cost (< 10$) blu-ray pickup head for detection. The microfluidic operations are carried out on a disk, while the detection method is based on optical measurements of the rotation dynamics of functionalized magnetic nanobeads (MNBs) in an oscillating uniaxial magnetic field. INTRODUCTION There is a need for low-cost and fast methods at the point of care level (POC) to quantify the pres-ence of multiple analytes directly from a patient sample. Several technologies have been proposed in re-cent years, but, in many cases the need for state of the art readout methods, complex microfludics and high-end sensors or optics inevitably limits their real commercialization potential. Here we present a novel diagnostic technology based on the integration of a homogeneus immuno-assay based on the use of magnetic nanoparticles (MNPs) with centrifugal microfluidics. The sensing technique, based on the previously presented magneto-optical method[1] is sensitive to the presence of clustered particles in the sample which is related to the target concentration. A Blu-ray optical pickup unit (OPU) is used as a single excitation and sensing element. The technology holds great commercial potential as the basic technological elements – Blu-ray OPU and microfluidic disks – are already mass-produced. In addition, different types of assay can be implemented over multiple chambers using the same magneto-optical readout method[1]. EXPERIMENTAL Figure 1 shows the set-up configuration, where a Sony Blu-ray pickup head (the same as in the Playstation 3) is used as a laser source (=405nm) and as a detector, as the light beam is reflected back by a mirror. The blood (15L) is inserted in the disk, as shown in panel (a) and is separated into plasma, which is mixed with MNPs (30 L, 0.2 mg/mL) functionalized with antibodies specific for the target an-tigen. The disks were manufactured in Poly(methyl methacrylate) (PMMA) and bonded using pressure sensitive adhesive (PSA). The magneto-optical signal is measured in the final reservoir after a magnetic incubation step. This reservoir is placed between two electromagnets (see panel (b)), which are used to generate a sinusoidal uniaxial magnetic field parallel to the laser beam direction. The magnetic field has a fixed amplitude B 0 = 2 mT at a frequency f up to 10 kHz. For the magneto-optical measurements[1] the beam is reflected on an adjustable mirror and directed back through the reservoir to the four quadrant photo detector after passing the beam splitter of the OPU. A customized circuit is used to extract and pre-amplify the signal sum of the four quadrants. Under magnetic actuation, the collective behavior of the particles modulates the light transmission measured by the photodetector. By extracting with a software the intensity of the 2 nd harmonic signal from the photo detector and its phase lag with respect to the mag-netic field excitation at different frequencies the dynamic rotation of the MNPs is characterized. 978-0-9798064-7-6/µTAS 2014/$20©14CBMS-0001 2044 18th International Conference on Miniaturized
    18th Int. Conf. on Miniaturized Systems for Chemistry and Life Sciences (MicroTAS 2014), San Antonio, Texas, USA; 10/2014
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    ABSTRACT: Controlled manipulation, such as isolation, positioning and trapping of cells, is important in basic biological research and clinical diagnostics. Micro/nanotechnologies have been enabling more effective and efficient cell trapping than possible with conventional platforms. Currently available micro/nanoscale methods for cell trapping, however, still lack flexibility in precisely controlling the number of trapped cells. We exploited the large compliance of elastomers to create an array of cell-trapping microstructures, whose dimensions can be mechanically modulated by inducing uniformly distributed strain via application of external force on the chip. The device consists of two elastomer polydimethylsiloxane (PDMS) sheets, one of which bears dam-like, cup-shaped geometries to physically capture cells. The mechanical modulation is used to tune the characteristics of cell trapping to capture a predetermined number of cells, from single cells to multiple cells. Thus, enhanced utility and flexibility for practical applications can be attained, as demonstrated by tunable trapping of MCF-7 cells, a human breast cancer cell line.
    Sensors and Actuators A Physical 08/2014; 215:197-203. DOI:10.1016/j.sna.2013.10.016 · 1.94 Impact Factor
  • Yuan Jia, Bin Wang, Jing Zhu, Qiao Lin
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    ABSTRACT: We present a flexible, polymer based MEMS differential scanning calorimetric (DSC) device combining integrated microfluidic channels, highly sensitive thermoelectric sensing, and real-time temperature monitoring for thermodynamic characterization of biomolecular samples with minimized sample consumption. The device uses an inexpensive, commercially available polymer substrate and a novel fabrication approach to create a microstructure consisting of a pair of microchannels (containing the sample and reference buffer, respectively), which are integrated with resistive temperature sensors (for in-situ measurement of sample temperature) and an antimony-bismuth (Sb-Bi) thermopile (for measurement of the temperature difference between the sample and reference channels). We demonstrate the utility of this MEMS DSC device by measuring the unfolding of lysozyme in a small volume (1 μL), and at practically relevant protein concentrations (approaching 1 mg/mL). Thermodynamic properties including the total enthalpy change per mole of protein (ΔH) and melting temperature (Tm) at different protein concentrations during this conformational transition are determined and found to agree with published data.
    2014 IEEE 27th International Conference on Micro Electro Mechanical Systems (MEMS); 07/2014
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    ABSTRACT: This paper presents an integrated magnetic micropump that uses in-plane compliance-based check valves and a magnetically actuated membrane. The device, which allows for simple fabrication and system integration with other functional elements, consists of two functional layers both fabricated from poly(dimethylsiloxane) (PDMS). The upper PDMS layer provides a compliant membrane with an electroplated thin-film permalloy strip for actuation, while the lower PDMS layer incorporates microfluidic components including the microchannels, pump chamber, and a pair of check valves for flow regulation. The PDMS check valves, each having a compliant flap in contact with a stiff stopper to allow for unidirectional fluid flow with minimized leakage, are located at the inlet and outlet of the pump chamber, respectively. As such, the unidirectional flow at a controlled volumetric rate can be readily generated in accordance with the pumping actions. Systematic characterization of the micropump has been performed by studying the dependence of its pumping flow rate on the driving frequency of magnetic actuation, and the back pressure. Experimental results show that this micropump is capable of generating fluid flow of 0.15 μL/min at the frequency of 2 Hz, corresponding to a volume resolution of 1 nL per stroke, and working reliably against a maximum back-pressure of 550 Pa, demonstrating the potential application of this micropump for various integrated lab-on-a-chip systems.
    Microelectronic Engineering 04/2014; 117:35–40. DOI:10.1016/j.mee.2013.11.014 · 1.34 Impact Factor
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    ABSTRACT: Isolation of cells from heterogeneous biological samples is critical in both basic biological research and clinical diagnostics. Affinity-based methods, such as those that recognise cells by binding antibodies to cell membrane biomarkers, can be used to achieve specific cell isolation. Microfluidic techniques have been employed to achieve more efficient and effective cell isolation. By employing aptamers as surface-immobilised ligands, cells can be easily released and collected after specific capture. However, these methods still have limitations in cell release efficiency and spatial selectivity. This study presents an aptamer-based microfluidic device that not only achieves specific affinity cell capture, but also enables spatially selective temperature-mediated release and retrieval of cells without detectable damage. The specific cell capture is realised by using surface-patterned aptamers in a microchamber on a temperature-control chip. Spatially selective cell release is achieved by utilising a group of microheater and temperature sensor that restricts temperature changes, and therefore the disruption of cell-aptamer interactions, to a design-specified region. Experimental results with CCRF-CEM cells and sgc8c aptamers have demonstrated the specific cell capture and temperature-mediated release of selected groups of cells with negligible disruption to their viability.
    IET Nanobiotechnology 03/2014; 8(1):2-9. DOI:10.1049/iet-nbt.2013.0028 · 1.72 Impact Factor
  • Yao Zhou, Qiao Lin
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    ABSTRACT: This paper presents a class of novel microfluidic concentration gradient generation (CGG) devices that create temporally stable chemical concentration gradients with complex shapes in a flow-free environment. The devices feature a two-layer channel design and the incorporation of a semipermeable membrane, which effectively segregates the concentration gradient region in the lower layer from the flow of reagent sample (simply “sample” onward) and buffer in the upper layer. In the mean time, free diffusion across the membrane constantly replenishes sample and buffer to maintain a stable concentration. The shapes of the concentration gradients are controlled by the geometries of the micro-channels and chambers. Concentration gradients with complex shapes can be achieved by piecewise combining constituent gradients with elementary shapes. Capable of generating concentration gradients in a flow-free environment, our devices eliminate undesirable flow stimulation on biological cells under investigation, while maintaining a stable chemical environment for cell studies.
    Sensors and Actuators B Chemical 01/2014; 190:334-341. DOI:10.1016/j.snb.2013.08.073 · 3.84 Impact Factor
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    ABSTRACT: This paper presents an aptamer-based graphene nanosensor capable of detecting small molecules. To address difficulties in direct detection of small molecules associated with their low electric charges, we use a competitive sensing approach as demonstrated with dehydroepiandrosterone sulfate (DHEA-S) as a target analyte, which is a small molecular steroid hormone with important applications in clinical diagnostics. A DHEA-S aptamer is captured by a complementary short DNA probe immobilized on the graphene and released upon exposure to DHEA-S in solution due to the binding between DHEA-S and the aptamer. The aptamer release is detected by measuring the change in the conductivity of graphene. Experimental results show that the time rate of aptamer release from the graphene is inversely proportional to DHEA-S concentration in solution. Thus, the nanosensor can potentially enable label-free, specific and quantitative measurement of DHEA-S and other small molecules.
    Micro Electro Mechanical Systems (MEMS), 2014 IEEE 27th International Conference on, San Francisco, CA; 01/2014
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    ABSTRACT: This paper presents a microfluidic device for affinity selection and amplification of cell membrane protein-binding strands from a randomized single-strand DNA (ssDNA) oligomer library, thereby isolating specific cell-targeting aptamers. The device consists of the selection and amplification microchambers situated on a temperature control chip. Affinity selection, integrated with cell culturing, of cell-binding ssDNA is performed in the selection chamber; the selected strands are then amplified by bead-based polymerase chain reaction (PCR) in the amplification chamber. Transfer between the selection and amplification microchambers using pressure-driven flow realizes multi-round aptamer isolation on a single chip. Experimental results demonstrate the feasibility of using this device to develop aptamers that specifically bind to target cells.
    2014 IEEE 27th International Conference on Micro Electro Mechanical Systems (MEMS); 01/2014
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    ABSTRACT: Single-nucleotide polymorphisms (SNPs) are the most abundant type of genetic variations; they provide the genetic fingerprint of individuals and are essential for genetic biomarker discoveries. Accurate detection of SNPs is of great significance for disease prevention, diagnosis and prognosis, and for prediction of drug response and clinical outcomes in patients. Nevertheless, conventional SNP genotyping methods are still limited by insufficient accuracy or labor-, time-, and resource-intensive procedures. Microfluidics has been increasingly utilized to improve efficiency; however, the currently available microfluidic genotyping systems still have shortcomings in accuracy, sensitivity, throughput and multiplexing capability. To address these challenges, we developed a multi-step SNP genotyping microfluidic device, which performs single-base extension of SNP specific primers and solid-phase purification of the extension products on a temperature-controlled chip. The products are ready for immediate detection by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), providing identification of the alleles at the target loci. The integrated device enables efficient and automated operation, while maintaining the high accuracy and sensitivity provided by MS. The multiplex genotyping capability was validated by performing rapid, accurate and simultaneous detection of 4 loci on a synthetic template. The microfluidic device has the potential to perform automatic, accurate, quantitative and high-throughput assays covering a broad spectrum of applications in biological and clinical research, drug development and forensics.
    RSC Advances 01/2014; 4(9):4269. DOI:10.1039/c3ra44091e · 3.71 Impact Factor
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    ABSTRACT: A continuous glucose monitor with a differential dielectric sensor implanted within the subcutaneous tissue that determines the glucose concentration in the interstitial fluid is presented. The device, created using microelectromechanical systems (MEMS) technology, consists of sensing and reference modules that are identical in design and placed in close proximity. Each module contains a microchamber housing a pair of capacitive electrodes residing on the device substrate and embedded in a suspended, perforated polymer diaphragm. The microchambers, enclosed in semi-permeable membranes, are filled with either a polymer solution that has specific affinity to glucose or a glucose-insensitive reference solution. To accurately determine the glucose concentration, changes in the permittivity of the sensing and the reference solutions induced by changes in glucose concentration are measured differentially. In vitro characterization demonstrated the sensor was capable of measuring glucose concentrations from 0 to 500 mg dL(-1) with resolution and accuracy of ~1.7 μg dL(-1) and ~1.74 mg dL(-1), respectively. In addition, device drift was reduced to 1.4% (uncontrolled environment) and 11% (5 °C of temperature variation) of that from non-differential measurements, indicating significant stability improvements. Preliminary animal testing demonstrated that the differential sensor accurately tracks glucose concentration in blood. This sensor can potentially be used clinically as a subcutaneously implanted continuous monitoring device in diabetic patients.
    Lab on a Chip 11/2013; 14(2). DOI:10.1039/c3lc51026c · 5.75 Impact Factor
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    ABSTRACT: Continuous glucose monitoring (CGM) sensors based on affinity detection are desirable for long-term and stable glucose management. However, most affinity sensors contain mechanical moving structures and complex design in sensor actuation and signal readout, limiting their reliability in subcutaneously implantable glucose detection. We have previously demonstrated a proof-of-concept dielectric glucose sensor that measured pre-mixed glucose-sensitive polymer solutions at various glucose concentrations. This sensor features simplicity in sensor design, and possesses high specificity and accuracy in glucose detection. However, lack of glucose diffusion passage, this device is unable to fulfill real-time in-vivo monitoring. As a major improvement to this device, we present in this paper a fully implantable MEMS dielectric affinity glucose biosensor that contains a perforated electrode embedded in a suspended diaphragm. This capacitive-based sensor contains no moving parts, and enables glucose diffusion and real-time monitoring. The experimental results indicate that this sensor can detect glucose solutions at physiological concentrations and possesses good reversibility and reliability. This sensor has a time constant to glucose concentration change at approximately 3 min, which is comparable to commercial systems. The sensor has potential applications in fully implantable CGM that require excellent long-term stability and reliability.
    Journal of Microelectromechanical Systems 06/2013; 23(1):14-20. DOI:10.1109/JMEMS.2013.2262603 · 1.92 Impact Factor
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    ABSTRACT: Genotyping of single nucleotide polymorphisms (SNPs) allows diagnosis of human genetic disorders associated with single base mutations. Conventional SNP genotyping methods are capable of providing either accurate or high-throughput detection, but are still labor-, time-, and resource-intensive. Microfluidics has been applied to SNP detection to provide fast, low-cost, and automated alternatives, although these applications are still limited by either accuracy or throughput issues. To address this challenge, we present a MEMS-based SNP genotyping approach that uses solid-phase-based reactions in a single microchamber on a temperature control chip. Polymerase chain reaction (PCR), allele specific single base extension (SBE), and desalting on microbeads are performed in the microchamber, which is coupled with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) to analyze the SBE product. Experimental results from genotyping of the SNP on exon 1 of the HBB gene, which causes sickle cell anemia, demonstrate the potential of the device for rapid, accurate, multiplexed and high-throughput detection of SNPs.
    Sensors and Actuators A Physical 06/2013; 195:175–182. DOI:10.1016/j.sna.2012.07.025 · 1.94 Impact Factor
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    ABSTRACT: Surface enhanced Raman spectroscopy (SERS) has been used in a variety of biological applications due to its high sensitivity and specificity. Here, we report a SERS-based biosensing approach for quantitative detection of biomolecules. A SERS substrate bearing gold-decorated silicon nanopillars is functionalized with aptamers for sensitive and specific detection of target molecules. In this study, TAMRA-labeled vasopressin molecules in the picomolar regime (1 pM to 1 nM) are specifically captured by aptamers on the nanostructured SERS substrate and monitored by using an automated SERS signal mapping technique. From the experimental results, we show concentration-dependent SERS responses in the picomolar range by integrating SERS signal intensities over a scanning area. It is also noted that our signal mapping approach significantly improves statistical reproducibility and accounts for spot-to-spot variation in conventional SERS quantification. Furthermore, we have developed an analytical model capable of predicting experimental intensity distributions on the substrates for reliable quantification of biomolecules. Lastly, we have calculated the minimum needed area of Raman mapping for efficient and reliable analysis of each measurement. Combining our SERS mapping analysis with an aptamer functionalized nanopillars substrate is found to be extremely efficient for detection of low-abundance biomolecules.
    ACS Nano 05/2013; 7(6). DOI:10.1021/nn401199k · 12.03 Impact Factor
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    ABSTRACT: Micromachined viscometric affinity glucose sensors have been previously demonstrated using vibrational cantilever and diaphragm. These devices featured a single glucose detection module that determines glucose concentrations through viscosity changes of glucose-sensitive polymer solutions. However, fluctuations in temperature and other environmental parameters might potentially affect the stability and reliability of these devices, creating complexity in their applications in subcutaneously implanted continuous glucose monitoring (CGM). To address these issues, we present a MEMS differential sensor that can effectively reject environmental disturbances while allowing accurate glucose detection. The sensor consists of two magnetically driven vibrating diaphragms situated inside microchambers filled with a boronic-acid based glucose-sensing solution and a reference solution insensitive to glucose. Glucose concentrations can be accurately determined by characteristics of the diaphragm vibration through differential capacitive detection. Our in-vitro and preliminary in-vivo experimental data demonstrate the potential of this sensor for highly stable subcutaneous CGM applications.
    Journal of Micromechanics and Microengineering 05/2013; 23(5):55020. DOI:10.1088/0960-1317/23/5/055020 · 1.73 Impact Factor

Publication Stats

1k Citations
195.11 Total Impact Points

Institutions

  • 2006–2015
    • Columbia University
      • Department of Mechanical Engineering
      New York, New York, United States
  • 2002–2008
    • Carnegie Mellon University
      • Department of Mechanical Engineering
      Pittsburgh, Pennsylvania, United States
  • 2005
    • Wayne State University
      • Department of Electrical and Computer Engineering
      Detroit, MI, United States
  • 1998–2001
    • California Institute of Technology
      • • Division of Engineering and Applied Science
      • • Department of Electrical Engineering
      • • Department of Mechanical & Civil Engineering
      Pasadena, California, United States