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Measurement and Control of Biomolecules Using Hybrid Nanostructure-based Devices

   Biomolecules such as proteins, cells, enzymes, and DNAs play important roles in living systems. They are involved in many important biological processes, and, thus, the measurement and control of the biomolecules is a key task in the research and application of biology. On the other hand, the progress in nanotechnologies has led to the development of nanostructure-based devices for versatile applications. One of our research interests is to measure and control biomolecules using hybrid nanostructure-based devices. Here, we have developed versatile bionano-devices and platforms based on hybrid nanostructures, and they could be utilized to monitor and control various types of biomolecules. Significantly, our bionano-devices were very sensitive, and, thus, even a ‘single’ biomolecule could be detected or controlled using our devices.

  Following are a few examples of our researches on the measurement and control of biomolecules using hybrid nanostructure-based devices.

 1) Interfacing Membrane Proteins with Carbon Nanotube Networks for Direct Monitoring of Cell Activities

Quantitative Electrophysiological Monitoring of Anti-histamine Drug Effects on Live Cells via Carbon Nanotube-based Reusable Sensor Platforms
(Biosens. Bioelectron. 94 707 2017)

  We developed nanostructure-based platforms for the direct monitoring of various live-cell activities, via the interfacing of cell membrane proteins with carbon canotube (CNT) networks. For example, we fabricated a reusable sensor platform (RSP) based on aligned semiconducting single-walled CNTs and floating electrodes. Then, we placed a single HeLa cell on the channel of the RSP via a microcapillary manipulation, interfacing membrane proteins in the cell with CNT networks. By analyzing electrical signals in the RSP, we could monitor the real–time electrophysiological responses of a single HeLa cell to histamine with different concentrations. The measured electrophysiological responses were attributed to the activity of histamine type 1 receptors on a HeLa cell membrane by histamine. Furthermore, the effects of anti–histamine drugs such as cetirizine or chlorphenamine on the electrophysiological activities of HeLa cells were also evaluated quantitatively. It is worth to mention that we utilized only a single device to monitor the responses of multiple HeLa cells to each drug. This allowed us to quantitatively analyze the antihistamine drug effects on live cells without errors from the device-to-device variation in nano-device characteristics. Such quantitative evaluation capability of our method would promise versatile applications such as drug screening and nanoscale biosensor researches.

 2) Hybrid Nanostructure-based Real-time Sensors
  Biosensors are widely used for various applications such as disease diagnosis, drug screening, environmental monitoring, and the prevention of bioterrorism. Taking an advantage of our large-scale manufacturing technologies for hybrid nanostructure-based devices, we are developing versatile nanostructure-based biosensor platforms capable of overcoming the limitations of conventional biosensors.

Biosensor System-on-a-Chip Including CMOS-based Signal Processing Circuits and 64 Carbon Nanotube-based Sensors for the Detection of Neurotransmitters
(Lab on a Chip 10 894 2010)

  For example, we developed a carbon nanotube (CNT)-based biosensor system-on-a-chip (SoC) for the detection of neurotransmitters. In this system, 64 CNT-based sensors were integrated with silicon-based signal processing circuits in a single chip. Here, the CNT-based sensors were composed of CNT network-based electronic channels and enzymes immobilized on the channels. The CNT channels could be fabricated via a surface-programmed assembly method combined with a conventional photolithography, and the enzymes could be immobilized via a substrate functionalization strategy. Electrical-currents in the integrated sensors could be efficiently analyzed via CMOS-based signal-processing circuits, enabling the highly-sensitive real-time monitoring of neurotransmitter-enzyme reactions. This result shows the benefits of integrating nanostructure-based sensors with conventional microelectronics. Further, our CNT-based biosensor SoC can be readily integrated with larger scale lab-on-a-chip (LoC) systems for various applications such as LoC systems for neural networks.

Nanoneedle Transistor-based Sensors for the Selective Detection of Intracellular Calcium Ions
(ACS Nano 5 3888 2011)

  In addition, we developed a nanoneedle transistor-based sensor (NTS) for the selective detection of calcium ions inside a living cell. In this work, a single-walled carbon nanotube-based field effect transistor (swCNT-FET) was first fabricated at the end of a glass nanopipette and functionalized with Fluo-4-AM probe dye. The selective binding of calcium ions onto the dye molecules altered the charge state of the dye molecules, resulting in the change of the source-drain current in the swCNT-FET as well as the fluorescence intensity from the dye. We demonstrated the electrical and fluorescence detection of the concentration change of intracellular calcium ions inside a HeLa cell using the NTS.

3) Magnetic Control of Biomolecules for Reusable Biosensor

Magnetically-Refreshable Receptor Platform Structures for Reusable Nano-Biosensor Chips
(Nanotechnology 27 45502 2015)

  One of the major hurdles holding back the practical applications of nano-biosensors can be their high fabrication cost. Thus, a strategy to reuse a single nano-biosensor chip for repeated sensing operations can be a key stepping stone to bring the high-performance, but expensive, nano-biosensors toward practical applications. We developed a magnetically-refreshable receptor platform structure (MRP) which can be integrated with quite versatile nano-biosensor structures to build reusable nano-biosensor chips. A nickel-based MRP structure was ferromagnetic and its hysteresis properties could be utilized to generate attractive (or repulsive) forces between receptor-functionalized magnetic nanobeads and the MRP structure under external magnetic fields. Thus, by applying magnetic fields, one can trap (or remove) receptors on a nano-biosensor based on the MRP structure. Importantly, we could remove used receptor molecules on the nano-biosensor surface and place new receptors, enabling repeated sensing operations with a single biosensor chip.

Operation of a Reusable Nano-Biosensor Chip
(Nanotechnology 27 45502 2015)

  As an application of the MRP, we developed an immunofluorescence biosensor chip based on the MRP structure. Using the chip, we could repeatedly detect IL-4 antigen molecules while maintaining the sensitivity and selectivity of the sensor.

Detection of Different Target Molecules Using a Single Reusable Carbon-Nanotube-based Biosensor Chip
(Nanotechnology 27 45502 2015)

  Further, we integrated the MRP structures with CNT transistor structures to build reusable biosensor chips. Here, the MRP structure based on nickel was integrated as part of the floating electrodes in a CNT-based transistor device. Then, we could trap receptor-functionalized nanobeads on the MRP, and detect the receptor’s target molecule using the device. Importantly, tacking the advantage of the MRP, we could remove used nanobeads and put different nanobeads functionalized with other kinds of receptors. Thus, using a single sensor chip, we could detect different target molecules, simply by replacing receptors.