CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority from Taiwan Patent Application No. 108124548, filed on Jul. 11, 2019, in the Taiwan Intellectual Property Office, the content of which is hereby incorporated by reference in its entirety for all purposes.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a biosensing system and method thereof, more particularly to an optical nano-biosensing system and method thereof.

2. Description of the Related Art

Biological sensing analysis is a new analytical technique, and the detection principle thereof is to detect the interaction between immobilized biomolecules and analyte molecules by using the immobilized biomolecules combined with signal transduction elements. The current structure of conventional nano-plasmonic biosensing platforms typically involves the immobilization of recognition molecules on the surface of noble metal nanoparticles, so that the recognition molecules on the surface of the noble metal nanoparticles can interact with an analyte selectively. As the recognition molecules on the noble metal nanoparticles bind with the analyte, the local refractive index at the surface of the noble metal nanoparticles changes, and hence the optical properties of the noble metal nanoparticles such as absorption and scattering cross-sections change correspondingly, thus being able to construct a nano-plasmonic biosensing platform with selectivity by this feature.

For some conventional optical biosensors that utilize noble metal nanostructures, an optical signal variation due to nano-plasmonic resonance signal is amplified by a current amplifier, and the nano-plasmonic resonance variation signal is then converted into a digital signal by an analog-to-digital converter. The nano-plasmonic resonance signal is further analyzed by a computer device. However, a processor that can effectively lower noise is not configured therein; hence, the measurement results may be affected due to too much noise in the process of the signal being amplified or converted. Furthermore, some conventional nano-plasmonic biosensing methods to observe the change of extinction or scattering of light by a noble metal nanostructure are usually performed by directly projecting an incident light from a light source to a sensing area. However, the lack of stable light-source control may result in an unstable incident wave of light which further affects the sensing results.

Accordingly, the inventor of the present invention has designed an optical nano-biosensing system in an effort to overcome deficiencies in terms of current techniques so as to enhance the implementation and application in industries.

SUMMARY OF THE INVENTION

In view of the aforementioned problems, the present invention provides an optical nano-biosensing system, including a nano-plasmonic sensing device, a high-resolution analog-to-digital converter, a signal acquisition and processing device, and an intelligent electronic device; wherein the nano-plasmonic sensing device further includes a light-source control circuit, a sample receiver, a light detector, and a signal-amplifying circuit. The sample receiver is connected to the light-source control circuit and receives a sample, and the light-source control circuit generates an incident light from the light source to be projected to the sample receiver. The incident light is frequency modulated at a specific modulation rate. Preferably, the light source emits a monochromatic light at a specific wavelength or a narrow-band light at a specific wavelength range. The light detector detects an emergent light from the sample receiver to generate a detection signal. The emergent light may be a transmitted light, a reflected light, or a diffracted light. The signal-amplifying circuit is connected to the light detector and converts a specific modulation frequency range of the detection signal to generate an amplified signal. The high-resolution analog-to-digital converter is connected to the signal-amplifying circuit and digitizes the amplified signal to generate a digital signal. The signal acquisition and processing device is connected to the high-resolution analog-to-digital converter and includes a signal calculator, and the signal calculator operates the digital signal to generate calculated information. The intelligent electronic device is connected to the signal acquisition and processing device and receives the calculated information, the intelligent electronic device converts the calculated information to generate sensing output information, and the sensing output information is presented on the intelligent electronic device in words, patterns, or a combination thereof.

Preferably, the light-source control circuit further includes a control circuit and a light-source projector, the control circuit correspondingly generates a light-source driving signal which is then transmitted to the light-source projector according to a feature of the light-source projector, and the light-source projector projects the incident light from the light source having a corresponding wavelength range to the sample receiver according to the light-source driving signal.

In case the signal acquisition and processing device may only process signals with non-negative voltages, a voltage-boosting circuit following the signal-amplifying circuit may further boost the amplified signal to above 0V, and the amplified signal after voltage-boosting is a non-negative value.

Preferably, the sample receiver includes a nano-plasmonic sensor and a sample vessel; the nano-plasmonic sensor is disposed in the sample vessel; the sample vessel receives and holds the sample for subsequent detection, it may be part of a microfluidic chip; the nano-plasmonic sensor includes a substrate, a plurality of noble metal nanoparticles, and a plurality of recognition molecules; the plurality of noble metal nanoparticles are disposed on the substrate; one end of each of the recognition molecules is correspondingly disposed on each of the noble metal nanoparticles; the sample vessel accommodates the sample so that the sample is in contact with the nano-plasmonic sensor; a plurality of analyte molecules in the sample bind correspondingly with the other end of each of the recognition molecules; when the nano-plasmonic sensor receives the incident light from the light source, the incident light is absorbed or scattered by the nano-plasmonic sensor; the light detector detects the emergent light of the nano-plasmonic sensor to generate the detection signal. It should be noted that the plurality of noble metal nanoparticles can be disposed on the substrate before or after the sample is introduced into the sample holder. In case the plurality of noble metal nanoparticles are to be disposed on the substrate after the sample is introduced, the same type or a second type of recognition molecules should be disposed on the substrate before the sample is introduced. The substrate may be a slide, an optical waveguide, or a grating. Preferably, the substrate is an optical waveguide. The optical waveguide may be selected from the group consisting of a cylindrical optical waveguide such as optical fiber, a planar optical waveguide such as slab waveguide and channel waveguide, and a tubular optical waveguide. In case the substrate is a slide or the like, the incident light approaches the surface of the slide perpendicularly or at a small angle of incidence (<45°), the emergent light may be a transmitted light or a reflected light. In case the substrate is an optical waveguide, the incident light may be coupled into the optical waveguide by direct focusing, prism coupling, or grating coupling at one end of the optical waveguide, and the emergent light is a transmitted light which may be coupled out at the other end of the optical waveguide by direct transmission, prism coupling, or grating coupling, respectively. In case the substrate is a grating or a grating waveguide, the incident light approaches the surface of the slide perpendicularly or at an angle, the emergent light is a diffracted light from the same side or opposite side of the grating.

Preferably, the nano-plasmonic sensor is an optical waveguide-based nano-plasmonic sensor, and most preferably, the nano-plasmonic sensor is an optical fiber-based nano-plasmonic sensor.

Preferably, the signal calculator includes a root-mean-square processor, and the root-mean-square processor operates the digital signal to generate the calculated information according to a root-mean-square algorithm.

Preferably, the signal calculator includes an absolute-mean processor, and the absolute-mean processor operates the digital signal to generate the calculated information according to an absolute-mean algorithm.

Preferably, the optical nano-biosensing system further includes a comb filter, wherein the comb filter is connected to the high-resolution analog-to-digital converter, and the comb filter operates to modify the digital signal.

Preferably, the intelligent electronic device includes an indicator acquisition processor, the indicator acquisition processor operates the calculated information to generate a plurality of indicator messages, and the intelligent electronic device is embedded with a plurality of preset threshold values; when each of the indicator messages correspondingly is in compliance with each of the preset threshold values, the intelligent electronic device determines that the calculated information as a typical molecular binding kinetic curve.

Preferably, the indicator acquisition processor includes a descent-rate indicator-acquisition unit, a surge-component indicator-acquisition unit, and a tail-signal indicator-acquisition unit; the plurality of indicator messages include a descent-rate indicator message, a surge-component indicator message, and a tail-signal indicator message; the plurality of preset threshold values include a descent-rate preset threshold value, a surge-component preset threshold value, and a tail-signal preset threshold value; the descent-rate indicator-acquisition unit operates the calculated information to generate the descent-rate indicator message; the surge-component indicator-acquisition unit operates the calculated information to generate the surge-component indicator message; the tail-signal indicator-acquisition unit operates the calculated information to generate the tail-signal indicator message; the intelligent electronic device determines that the calculated information as the typical molecular binding kinetic curve when the descent-rate indicator message is in compliance with the descent-rate preset threshold value, the surge-component indicator message is in compliance with the surge-component preset threshold value, and the tail-signal indicator message is in compliance with tail-signal preset threshold value.

Preferably, the intelligent electronic device operates the plurality of indicator messages to generate a baseline calibration message according to a baseline algorithm, and the intelligent electronic device calibrates the sensing output information according to the baseline calibration message.

Preferably, the optical nano-biosensing system further includes a Bluetooth device, wherein the Bluetooth device is connected to the signal acquisition and processing device and the intelligent electronic device, the signal acquisition and processing device transmits the calculated information to the Bluetooth device, and the Bluetooth device transmits the calculated information to the intelligent electronic device at a remote end.

On the basis of the aforementioned purpose, the present invention further provides an optical nano-biosensing method for an optical nano-biosensing system including a nano-plasmonic sensing device, a high-resolution analog-to-digital converter, a signal acquisition and processing device, and an intelligent electronic device, wherein the nano-plasmonic sensing device further includes a light-source control circuit, a sample receiver, a light detector, and a signal-amplifying circuit; the signal acquisition and processing device further includes a signal calculator; the optical nano-biosensing method includes the following steps: receiving a sample by the sample receiver; generating an incident light from the light source to be projected to the sample receiver by the light-source control circuit; detecting an emergent light from the sample receiver to generate a detection signal by the light detector; converting a specific modulation frequency range of the detection signal to generate an amplified signal by the signal-amplifying circuit; digitizing the amplified signal to generate a digital signal by the high-resolution analog-to-digital converter; operating the digital signal to generate calculated information by the signal calculator of the signal acquisition and processing device; and receiving the calculated information by the intelligent electronic device and converting the calculated information to generate sensing output information, wherein the sensing output information is presented on the intelligent electronic device in words, patterns, or a combination thereof.

In sum, the optical nano-biosensing system and method thereof of the present invention have the following advantages:

(1) The optical nano-biosensing system of the present invention provides a sample receiver, wherein the plurality of noble metal nanoparticles are disposed on the substrate, and each of the recognition molecules is correspondingly disposed on each of the noble metal nanoparticles. The sample may be introduced to the sample vessel and in contact with the nano-plasmonic sensor so that the analyte molecules in the sample bind with each of the recognition molecules. Moreover, the incident light from the light source may be properly projected onto the nano-plasmonic sensor by the light-source control circuit, and the incident light may perform multiple total internal reflections in the nano-plasmonic sensor such that the light detector may detect the emergent light from the sample receiver to generate a detection signal. With this structural configuration, each analyte molecule may be stably bound with each of the recognition molecules. In addition, since the noble metal nanoparticles may only absorb the incident light at a specific wavelength range and the substrate may effectively guide the incident light to perform multiple total internal reflections in the nano-plasmonic sensor, the light detector may thus exhibit an improved sensitivity in the detecting process.

(2) The optical nano-biosensing system of the present invention provides a signal acquisition and processing device to operate the digital signal, wherein the signal calculator of the signal acquisition and processing device includes a root-mean-square processor and an absolute-mean processor. The root-mean-square processor operates the digital signal to generate the calculated information according to a root-mean-square algorithm, whereas the absolute-mean processor operates the digital signal to generate the calculated information according to an absolute-mean algorithm. Since noise may be generated and direct current offset may occur during the process of waveforms being sensed, amplified, and voltage boosted, the signal calculator may thus be used to effectively decrease the noise to make the calculated information more accurate during the operating process.

(3) The indicator acquisition processor of the intelligent electronic device of the optical nano-biosensing system of the present invention may include a descent-rate indicator-acquisition unit, a surge-component indicator-acquisition unit, and a tail-signal indicator-acquisition unit. Each of the indicator-acquisition units operates the calculated information to respectively generate a corresponding indicator message, and the intelligent electronic device is embedded with a descent-rate preset threshold value, a surge-component preset threshold value, and a tail-signal preset threshold value. When each of the indicator messages correspondingly is in compliance with the preset threshold value, the intelligent electronic device determines that the calculated information as a typical molecular binding kinetic curve. With this system configuration, users may recognize the typical molecular binding kinetic curve by using the intelligent electronic device to further understand whether the current system condition or reaction condition functions normally.

To make the aforementioned purposes, technical features, and gains after actual implementation more obvious and understandable, the description hereinafter shall be described in more detail with reference to preferred embodiments together with related drawings.

