阅读说明：本技术 高灵敏度光学检测系统 (High-sensitivity optical detection system ) 是由 陈敬红 于 2018-06-14 设计创作，主要内容包括：本发明公开了一种用于检测化学和生物分析物的高灵敏度光学系统,其包括容器、光导、分析物、激发光源、检测器、激发和发射滤光片以及导光组件。新颖的光学系统被固定在外壳中,并以外部连接或内部连接方式连接到设备,以进行数据输入、处理、显示、存储和通信。该光学系统可以以廉价的移动即时医疗方式对多种疾病进行临床水平的诊断。它可以是具有单个或一组光学结构的独立单元,也可以与其他检测系统例如移动显微镜结合使用成为定性和定量检测设备。它也可以在某些商业仪器中实施以提高灵敏度。此外,光学系统的尺寸可以大大减小,以形成高度集成的芯片实验室解决方案。(A high sensitivity optical system for detecting chemical and biological analytes includes a container, a light guide, an analyte, an excitation light source, a detector, excitation and emission filters, and a light guide assembly. The novel optical system is secured within the housing and is connected to the device either externally or internally for data entry, processing, display, storage and communication. The optical system can be used for diagnosing various diseases at a clinical level in an inexpensive mobile instant medical mode. It can be a stand-alone unit with a single or a set of optical structures, or it can be used in combination with other detection systems, such as a mobile microscope, as a qualitative and quantitative detection device. It can also be implemented in some commercial instruments to increase sensitivity. Furthermore, the size of the optical system can be reduced considerably to form a highly integrated lab-on-a-chip solution.)

1. An optical system for detecting chemical and biological analytes includes a container, a light guide separate from the container, an excitation light source at the proximal end of the container and/or at the side of the container, a detector at the distal end of the container, excitation and emission filters, lenses and other optical components along the excitation and emission light paths.

2. The optical system according to claim 1, wherein the light source is a mercury or xenon arc lamp, a laser, an LED, an OLED or the like, in the form of a single light source or a plurality of light sources.

3. The optical system of claim 1, wherein the light guide and receptacle:

made of glass, quartz, other inorganic materials, polymeric materials, metals, or combinations thereof; and is

Is transparent, or partially opaque, or is partially covered by an opaque material; and is

Is cylindrical, rectangular or other shape; and is

Solid or hollow, or other structures in whole or in part.

4. The optical system of claim 1, wherein the analyte:

is an absorbing or emitting material between the receptacle and the light guide and/or on the surfaces of the receptacle and the light guide; and is

Is self-absorbing or emissive, or has a marker of an absorbing or emissive material.

5. The optical system of claim 1, wherein the filter:

is an absorption filter, an interference filter or a diffraction filter, or a combination thereof; and is

Be it in single, series or in multiple forms.

6. The optical system according to claim 1, wherein the detector is a photodiode, CMOS, CCD, PMT or the like.

7. The optical system of claim 1, wherein the optical system comprises discrete, partially integrated, or highly integrated optical components, the optical components being present singly, in arrays, or in multiple forms.

8. The optical system of claim 1, wherein the optical system:

externally connected to a device, such as a (mobile) phone, tablet, computer, etc., for data input, processing, display, storage and communication, by a connector or wireless communication; or

Internal sensors connected to the device, such as (mobile) phone cameras, Ambient Light Sensors (ALS), proximity sensors, etc.

9. The optical system according to claim 8, wherein the optical system is used as a basic low-cost mobile point-of-care medical device for quantitative detection of very low concentrations of chemical and biological analytes or, if rapid visual imaging and quantitative detection of analyte concentrations are required at the same time, is used in combination with other detection systems such as mobile microscopes as detection means.

10. The optical system according to claim 9, wherein the mobile microscope is a stand-alone unit connected to a common structure of the apparatus, or is connected to an internal sensor of a device, such as a mobile phone camera or the like.

11. The optical system of claim 9, wherein the detection device is fixed within a mechanical housing, isolated from environmental interference, and protected from mechanical impact.

12. The optical system of claim 1, wherein the optical system is used in a retrofit of existing instruments, such as ELISA plate readers, to further increase detection sensitivity by adding multiple light guides to a multi-well plate.

13. The optical system of claim 1, wherein the optical system is used for the retrofit of a microfluidic based detection instrument, such as GenXpert, to further improve detection sensitivity by adding excitation and/or emission light guides within the fluid chamber.

14. The optical system of claim 1, wherein the optical system is a lab-on-a-chip solution that:

including light sources, microfluidic cavities, analytes, light detectors, waveguide structures, filters, (photolithographic) lenses and other (micro) optical components; and is

In a discrete, partially integrated or highly integrated form; and is

Are single, serial or in multiple forms; and is

As various spectrometers, such as fluorescence, UV-Vis and IR spectrometers, etc., the associated optical components are tunable over a wide spectral range;

is assembled on a substrate of silicon, glass, ceramic, metal, polymer, or the like.

15. A device for detecting chemical and biological analytes, comprising:

an optical system comprising a light source, a receptacle, a light guide, an analyte, a filter, a detector, and a light guide assembly; and

a housing, the optical system being fixed to the housing; and

the equipment has the functions of data input, processing, display, storage and communication.

16. The detection device of claim 15, wherein the housing:

made of metals, alloys, ceramics, polymeric materials, combinations thereof, and the like; and is

Rigid, semi-rigid, or flexible, as required by the application; and is

Configured to prevent interference of the emission light source from reaching the detector, control the position and exposure area of the light source, and facilitate insertion and removal of the test vessel and light guide;

is opaque, isolating the optical system from environmental interference; or

Is translucent or transparent, especially in lab-on-a-chip solutions, the optical system is completely covered by an opaque coating.

17. The detection apparatus of claim 15, wherein the device:

mobile or fixed telephones, tablets, computers, and other widely used devices; and is

Externally connected to the optical system by a connector or wireless communication; or

Connected directly to the optical system by its internal sensors, such as cameras, video cameras, Ambient Light Sensors (ALS), proximity sensors, etc.

18. The detection device of claim 15, wherein the detection device is single, serial, or in multiple formats.

Technical Field

The present application relates to optical systems for chemical and biological analyte detection, and more particularly, to mobile optical detection systems for point-of-care (POC) applications that can obtain highly sensitive test results from trace and ultra-low concentration samples despite the use of small and low cost optical components.

Background

In recent years, the point-of-care (POC) test has steadily increased, primarily because it provides less costly preventive care to patient families in developed countries and more effective prevention of infections in developing countries. However, to date, the main successes have been only glucose biosensors, lateral flow test strips for cardiac markers, and pregnancy tests.

The widespread popularity of POC technology is limited by the testing capabilities of small handheld devices and the high cost of desktop devices, which are essentially laboratory instruments of reduced size and complexity. The key to widespread adoption of POC is still how to transfer the complex disease detection capabilities and sensitivity of microscopes and spectrometers from the laboratory to small mobile devices with low cost components, and performance is not affected. The increasing use of global mobile phones and the explosive development of mobile technology has fueled a desire and led to unprecedented research in recent years for mobile devices for medical diagnostics. POC devices can reduce costs by taking advantage of external and internal sensors and ubiquitous accessibility of communications, computing, display, and data storage. However, various internal sensors, selected only for mass consumer applications, have not been commercially successful in providing enhanced detection sensitivity.

Fluorescent labels are widely used in biochemical analysis and disease diagnosis. Standard devices for fluorescence detection are fluorometers, fluorescence spectrometers, and enzyme-linked immunosorbent assay (ELISA) plate readers for detecting the presence of substances in high-throughput biological assays. In the above instrument, both the excitation and emission of fluorescence in the liquid solution are greatly attenuated before reaching the detector. As a result, the light collection efficiency is reduced, and a high-power and expensive photomultiplier tube (PMT) is generally required to amplify a weak signal.

Various methods of increasing sensitivity have been explored, including amplifying diagnostic targets, such as culture or Polymerase Chain Reaction (PCR), using highly selective and high light intensity molecular labeled probes, using highly sensitive optical detection systems, and the like. The present invention focuses on improving the sensitivity of optical detection systems.

Disclosure of Invention

The present invention provides a design concept for a high sensitivity optical detection system that includes a vessel, an internal light guide, an excitation light source located at the proximal end of the vessel, and/or a vertical excitation light source located at the side of the vessel, a detector located at the distal end of the vessel, excitation and emission filters, and other light-guiding optical components. The optical system may be used to detect emitting or absorbing materials between the receptacle and the light guide and/or on the surfaces of the receptacle and the light guide. The optical system can realize a large signal and a high signal-to-noise ratio (S/N) quantitative analysis even with low-cost and small-sized components. High sensitivity results from efficient optical excitation of the material, efficient emission guided by the light guide and/or vessel sidewall to the detector, and interference isolation between the light source and the detector. This novel optical system and its variants enable clinical-level diagnosis in a cheap mobile point-of-care (POC) manner, which may be key to promote the widespread acceptance of POC for more disease detection.

In a preferred embodiment, the optical system has one end LED and two side LEDs in the emission and detection light paths, a glass light guide and container, a fluorescent analyte solution, a pair of filters, a photodiode detector, and a plurality of lenses. The optical system is fixed in an opaque mechanical structure that eliminates interference from ambient light and prevents light from the excitation light source from leaking, allowing only light to pass along a set optical path. The optical system is externally connected to a telephone, tablet or computer, etc. for data input, processing, display, storage and communication. The optical system can produce detection signals and sensitivity similar to commercial fluorometers and enzyme-linked immunosorbent assay (ELISA) plate readers.

In one example, the optical system, in addition to being a stand-alone unit having a single or series of the above-described optical structures, may be combined with other detection systems, such as a moving microscope, to form a qualitative and quantitative detection device.

For example, another example and variations thereof may be used in existing analytical instruments such as ELISA plate readers. The fixture with attached duplicate light guides can be inserted into the wells of the ELISA plate to achieve higher sensitivity.

For example, another example and variations thereof may be incorporated into existing microfluidic devices such as GenXpert, with the insertion of excitation and/or emission light guides to further improve detection sensitivity.

For example, another example, and variations thereof, may be used for lab-on-a-chip solutions that include highly integrated light sources, microfluidic chambers, analytes, light detectors, waveguide structures, filters, photolithographic lenses, and other micro-optical components. When the associated optical components are adjustable over a wide spectral range, the device can be used as a variety of spectrometers, such as fluorescence, UV-Vis and IR spectrometers, and the like.

While multiple examples are disclosed, still other examples of the invention will become apparent to those skilled in the art from the following detailed description. It will be appreciated that the examples can be modified in various respects, all without departing from the spirit and scope of the examples. Accordingly, the drawings and detailed description are to be regarded as illustrative in nature and not as restrictive.

Drawings

The invention is explained in further detail in connection with the following figures. These drawings are not intended to limit the scope of the present invention, but rather to demonstrate certain attributes of the invention.

FIG. 1 shows a 2D view of a representative high sensitivity optical detection system and associated optical components of a preferred embodiment.

Figure 2 shows a 2D view of a representative high sensitivity optical detection system of the preferred embodiment, fixed in a mechanical housing and attached to a mobile phone.

Fig. 3 is a 2D view of a representative mobile device including the optical system of fig. 1 and a microscope coupled to a telephone camera.

Fig. 4 is a 2D view of a representative ELISA plate with a light guide and side light source for better signal sensitivity.

FIG. 5 is a 2D view of a representative fixture having a light guide and end structures that can be attached to an ELISA plate.

Figure 6 is a 2D view of a modified design of the microfluidic chip in GenXpert with the addition of an emission light guide in the fluid chamber to improve detection sensitivity.

Figure 7 is a 2D view of a cross section of the emission light guide inside the GenXpert microfluidic chamber in figure 6. The bottom of the light guide attachment attached to the bottom wall of the microfluidic chamber may be continuous or have a plurality of pillars to reduce light leakage through the bottom wall.

Figure 8 is a 2D view of another modified design of a GenXpert microfluidic chip that adds excitation and emission light guides in the fluidic chamber to further improve detection sensitivity.

Fig. 9 shows a 2D view of a representative lab-on-a-chip solution that includes integrated light sources, microfluidic chambers, analytes, light detectors, waveguide structures, filters, photolithographic lenses, and other micro-optical components.

Detailed Description

In the following description of examples, reference is made to the accompanying drawings which form a part hereof, and in which is shown by way of illustration specific examples that may be practiced. It is to be understood that other examples may be used and structural changes may be made without departing from the scope of the disclosed examples.

The present invention provides a low cost mobile device for high sensitivity optical detection of chemical and biological analytes, and more particularly a POC apparatus for broad disease diagnosis. The novel optical device is structured to maximize excitation, efficiently collect and direct fluorescence signals to the detector, and isolate interference from the detector light source.

Fig. 1 shows a 2D view of a high sensitivity optical detection system 13. The system 13 comprises a vessel 4, an internal light guide 5, an excitation light source 1 located at the proximal end of the vessel, and/or excitation light sources 2-3 located at the sides of the vessel, a light detector 11 located at the distal end of the vessel, and excitation filters 7-9 located behind the excitation light sources 1-3 and an emission filter 10 located in front of the light detector 11. The optical system 13 is used for detecting the analyte 6 in liquid or solid phase between the receptacle 4 and the light guide 5 and/or on the surface of the receptacle 4 and the light guide 5. If desired, a lens 12 and/or other optical components may be selected to be interposed between the light sources 1-3 and the receptacle 4, and/or between the light guide 5/receptacle 4 and the light detector 11. The optical system 13 can achieve a large signal and high sensitivity of quantitative analysis even with the use of low cost LED light sources 1-3 and silicon photodetector 11.

The light sources 1-3 may be mercury or xenon arc lamps, lasers, Light Emitting Diodes (LEDs) and Organic Light Emitting Diodes (OLEDs); there may be one or more end light sources 1 and side light sources 2-3, which may be used alone or in various combinations. The vessel 4 and the light guide 5 may be made of materials such as glass, quartz, other inorganic materials, polymeric materials or metals; the receptacle 4 and the light guide 5 may be transparent, or partially opaque, or partially covered by an opaque material; the receptacle 4 and the light guide 5 may be cylindrical, rectangular or other shapes; the light guide 5 may be solid or hollow, or other structures; the height of the light guide 5 may be the same as or different from the height of the walls of the receptacle 4. The filters 7-10 may be absorption filters, interference filters and diffraction filters. The detector 11 may be a photodiode, a CMOS, a CCD or a PMT. The lens 12 may be a single lens or a compound lens made of glass or a polymer material. The analyte 6 may be a biological sample stock solution or a solution or dispersion of a processed biological sample, such as sputum, urine, blood, etc. The analyte 6 may be self-absorbing or emissive, or may be labelled with an absorbing or emissive material.

Fig. 2 shows an optical device with elements 13, the elements 13 being located in a small, opaque removable housing 50 into and out of which the test receptacles 4 and light guides 5 can be easily inserted and removed. The movable housing 50 eliminates interference from ambient light and prevents light leakage from the excitation light source, allowing light to pass through only the designated light path and in selected areas.

Fig. 2 also shows that the optical device may be linked to the outside of a mobile phone, tablet or computer 52 via a connector 51 for data input, processing, display, storage and communication. The optical system 13 may also be connected as an accessory to an internal sensor of a mobile device, such as a camera, an Ambient Light Sensor (ALS), a proximity sensor. In this case, the photodetector 11 is replaced with a camera CMOS, an Ambient Light Sensor (ALS), or a proximity sensor. The high sensitivity optical detection system 13 narrows the gap between the complex disease detection capabilities and the high sensitivity of laboratory spectrometers and small mobile devices with low cost components, which may be key to the promotion of widespread POC use for the detection of many diseases, including large-scale epidemics such as HIV and tuberculosis, etc., as well as chronic diseases such as diabetes, cardiac and vascular diseases, hormonal imbalances, etc. It can also be used for food safety inspection.

The optical system 13 and its variants can be used in combination with other detection systems, such as a mobile microscope, to form a mobile diagnostic device, which is preferred in certain circumstances if optical images etc. are also needed at the same time. Fig. 3 shows a 2D view of a mobile device with the optical system 13 of fig. 1 and a microscope 16 fixed on the camera 15 of the mobile phone 14. The light source 17 is placed in a small housing 21. The excitation filter 18 is placed on top of the housing 21 and the test sample 19 is positioned above the excitation filter 18. An emission light filter 20 is fixed at the end of the microscope 16. The entire assembly can be placed in a mechanical enclosure 53 to eliminate interference from the environment.

The optical system 13 and its variants can also be used as a component in existing devices like ELISA plate readers. Fig. 4 shows a 2D view of an ELISA plate 24, the ELISA plate 24 having a light guide 25 and side light sources 27 and 29 for better signal sensitivity. Light source 22 and filter 23 represent the original light source and filter in the ELISA plate reader. The light sources 27, 29 and the filters 28, 30 represent additional light sources and filters for improving the detection sensitivity. 26 is a stock solution of a biological sample, such as sputum, urine, blood, etc., or a solution or dispersion of an analyte of a processed biological sample. Fig. 5 shows a 2D view of a representative clamp 31, the clamp 31 having a light guide 25 and ends 32-33 attached to an ELISA plate 24. The holder 31 with the duplicate light guide 25 can be inserted inside the existing ELISA plate 24 to obtain a higher sensitivity. The ends 32-33 at both ends of the holder 31 are used to control the insertion depth of the light guide 25 and to fix the holder 31 to the ELISA plate 24. The ELISA surface treatment can be either on the microplate or on the waveguide holder, or both. If the ELISA surface treatment is on a microplate, the waveguide clamp can be reused.

The optical system 13 and its variants can also be applied in microfluidic chip design to further improve detection sensitivity. Figure 6 shows a 2D top view of a GenXpert microfluidic chip 39 located on the side of reaction cartridge 38. 46 and 47 represent microfluidic inlets and outlets, respectively. 48 is a fluid chamber, in which chamber 48 the PCR amplified material is excited and the resulting fluorescence is detected laterally at a 90 degree angle. 36 is the excitation light source in light box 34 and 37 is the emission light detector in detection box 35. 41-44 are excitation light paths. An emission light guide 40 is added to the fluid chamber 48 to increase detection sensitivity.

Fig. 7 shows a 2D view of a cross section of the emission light guide 40 inside the GenXpert microfluidic chamber 48, cut along section line 45 in fig. 6. The bottom of the light guide attachment 40 may be continuous to the bottom wall of the microfluidic chamber 48 or two or more posts may be used to reduce light leakage through the bottom wall.

In another configuration, fig. 8 shows a 2D view of a GenXpert microfluidic chip 39 located on the side of reaction cartridge 38. Fig. 8 is identical to fig. 6, except that an excitation light guide 49 is added to the fluid chamber to further improve detection sensitivity.

Fig. 9 shows a 2D view of an exemplary lab-on-a-chip solution including integrated light sources, microfluidic chambers, analytes, light detectors, waveguide structures, filters, photolithographic lenses, and other micro-optical components. The optical system of the lab-on-a-chip solution may be in single or array form. When the associated optical components are adjustable over a wide spectral range, the device can be used as a variety of spectrometers, such as fluorescence, UV-Vis and IR spectrometers, and the like. As the degree of integration increases and the size of each component shrinks, the amount of sample required to be analyzed per test decreases.

The foregoing description illustrates specific examples of the invention, but is not intended to limit the specific implementations thereof. The claims of this application, including all equivalents, are intended to be included to define the scope of the invention.