CN109647556B - POCT (point of care testing) micro-fluidic chip integrated with self-aligned lens and preparation method thereof - Google Patents

POCT (point of care testing) micro-fluidic chip integrated with self-aligned lens and preparation method thereof Download PDF

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CN109647556B
CN109647556B CN201910064553.6A CN201910064553A CN109647556B CN 109647556 B CN109647556 B CN 109647556B CN 201910064553 A CN201910064553 A CN 201910064553A CN 109647556 B CN109647556 B CN 109647556B
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lens
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channel
self
integrated
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CN109647556A (en
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李经民
梁超
刘冲
牛爱英
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Dalian University of Technology
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502707—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the manufacture of the container or its components
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B13/00—Optical objectives specially designed for the purposes specified below
    • G02B13/001—Miniaturised objectives for electronic devices, e.g. portable telephones, webcams, PDAs, small digital cameras
    • G02B13/0015—Miniaturised objectives for electronic devices, e.g. portable telephones, webcams, PDAs, small digital cameras characterised by the lens design
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/02—Adapting objects or devices to another
    • B01L2200/026—Fluid interfacing between devices or objects, e.g. connectors, inlet details
    • B01L2200/027—Fluid interfacing between devices or objects, e.g. connectors, inlet details for microfluidic devices
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0689—Sealing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/10—Integrating sample preparation and analysis in single entity, e.g. lab-on-a-chip concept
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • B01L2300/0654—Lenses; Optical fibres
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/12—Specific details about materials

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  • Chemical & Material Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Dispersion Chemistry (AREA)
  • Analytical Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Clinical Laboratory Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)

Abstract

The invention belongs to the technical field of polymer micro-fluidic chip instant detection, and particularly relates to a POCT micro-fluidic chip integrated with a self-aligned lens and a preparation method thereof. The micro-fluidic chip comprises a cover plate layer, a micro-channel, a lens layer and a bottom plate layer; the micro-channel and the lens layer are provided with micro-channels and integrated self-aligned lenses at two sides of the micro-channels; the integrated auto-collimation lens is of a specific lens arc surface structure, the curvature radius and the focal length of the lens are determined according to a geometric optics theory, and the focal point of the lens is ensured to be in a micro-channel detection area; the thickness of the micro-channel and the lens layer of the micro-fluidic chip is 50-5000 μm; the shapes, sizes and relative positions of the micro-channel and the lens arc structure are designed in laser drawing software, and the micro-channel and the lens arc structure are processed and formed at one time by laser processing, so that the micro-channel and the lens arc structure have self-alignment characteristics, and a complex optical alignment process is avoided. The invention integrates the lens on the micro-fluidic chip, reduces the volume and the manufacturing cost of the detection equipment, and has important significance for realizing real instant detection.

Description

POCT (point of care testing) micro-fluidic chip integrated with self-aligned lens and preparation method thereof
Technical Field
The invention belongs to the technical field of polymer micro-fluidic chip instant detection, and particularly relates to a POCT micro-fluidic chip integrated with a self-aligned lens and a preparation method thereof.
Background
POCT (Point-of-care testing), also known as Point-of-care testing or Point-of-care testing, has recently been defined by the national academy of clinical biochemistry as "clinical tests conducted by clinical personnel not receiving clinical practice in close proximity to the treatment of patients or by patients themselves" in their established "POCT evidence-based documents" draft. POCT is all rapid tests and clinical applications performed outside the traditional, core or central laboratory based on traditional laboratory medicine. Although laboratory medicine has high detection precision, large biochemical detection equipment is needed as a diagnosis tool, and the large biochemical detection equipment is expensive in cost and complex to operate. In contrast, current diagnostics are increasingly moving towards portable, rapid, and point-of-care testing. POCT can be directly completed around a hospital bed, during treatment or at home of a patient, and powerful guarantee is provided for rapid and long-time monitoring of some diseases. In view of the characteristics of POCT, the detection equipment of the POCT has the advantages of short detection time, high efficiency, miniaturization and easy operation.
The micro-fluidic chip is a device for controlling fluid at micrometer scale, and integrates a micro-channel network, a micro-pump, a micro-valve, a micro-mixing and micro-reaction functional unit on a chip with several square centimeters by adopting micro-processing technology, so as to realize operations of sample introduction, mixing, separation, reaction, detection and the like in biochemical reaction. The micron-scale channel of the microfluidic chip brings high heat conduction and conduction rate, improves the detection efficiency and reduces the consumption of precious reagents. Moreover, by adopting a micro-processing technology, a plurality of functional components can be integrated on the same micro-fluidic chip. The operations of reaction, separation, detection and the like can be completed in a piece at one time, and on the basis, portable equipment with complete functions can be manufactured, so that the microfluidic chip is very suitable for instant detection.
Although the micro-fluidic chip has small volume, high degree of function integration and simple and convenient operation, the detection equipment has large volume and difficult operation, and the comprehensive application of the micro-fluidic chip in the field of instant detection is limited. For example, in optical detection of a microfluidic chip, a fluorescence microscope is often used as a detection tool, and the fluorescence microscope is often composed of optical devices such as a laser light source, a collimator lens, a filter, a plurality of sets of lenses, a reflecting mirror, and a spectroscope. Moreover, the alignment coupling performance of these optical devices has a great influence on the detection result, which results in the need of precise debugging of the fluorescence microscope before each detection so as to avoid adverse effects on the detection result.
The invention provides an integrated self-aligning lens of a POCT (point of care testing) microfluidic chip, which integrates an optical lens on the microfluidic chip, has a self-aligning characteristic and does not need to carry out complicated optical path debugging operation. The invention has important significance for reducing the volume of detection equipment, simplifying the detection process and realizing real instant detection.
Disclosure of Invention
Aiming at the situation, the invention provides the POCT micro-fluidic chip integrated with the self-aligned lens to overcome the defects of the prior art, and solves the problems of complex alignment adjustment and low integration degree of optical devices in POCT optical detection equipment.
In order to achieve the purpose, the invention adopts the following technical scheme:
a POCT micro-fluidic chip integrated with a self-aligned lens comprises a cover plate layer, a micro-channel, a lens layer and a bottom plate layer;
the micro-channel and lens layer is provided with a micro-channel and integrated self-aligned lenses at two sides of the micro-channel; the integrated self-aligning lens is of a lens arc surface structure, the curvature radius and the focal length of the lens are determined according to the geometric optics theory, and the focal point of the lens is ensured to be in a micro-channel detection area; the thickness of the micro-channel and the lens layer of the micro-fluidic chip is 50-5000 μm;
the cover sheet layer, the micro-channel, the lens layer and the bottom sheet layer are sealed into a whole by a micro-fluidic chip sealing method.
The integrated self-aligning lens is in a structural form of one or a combination of more than two of a single-sided convex lens, a double-sided convex lens, a single-sided convex lens-single-sided convex lens group, a double-sided convex lens-double-sided convex lens group, a single-sided convex lens-double-sided convex lens group and a double-sided convex lens-single-sided convex lens group, so that the requirement of optical detection equipment on the characteristics of focusing light rays is met.
The POCT micro-fluidic chip integrated with the self-aligning lens is made of polymethyl methacrylate (PMMA), polyethylene terephthalate (PET), polytetrafluoroethylene (Teflon PTFE), Polycarbonate (PC), Polystyrene (PS), Polyethylene (PE), polypropylene (PP), polyvinyl chloride (PVC), nylon, Polyurethane (PU) or styrene-methyl dimethacrylate copolymer (SMMA).
A preparation method of a POCT micro-fluidic chip integrated with a self-aligned lens comprises the following steps:
first, the integrated design of micro-channel and lens based on traditional geometric optics
Lens arc surfaces of the integrated self-aligning lens are designed on two sides of the micro-channel of the micro-fluidic chip, the curvature radius and the focal length of the integrated self-aligning lens are designed according to the geometric optics theory, and the focus of the integrated self-aligning lens is ensured to be in a micro-channel detection area; second step, the micro-channel and lens integrated manufacture based on laser processing method
Based on a laser processing system, adjusting processing parameters, and processing a micro-channel and a lens structure, namely a micro-channel and a lens layer, on a transparent polymer material at one time; cutting the microchannel and the lens layer material completely by using laser to form the side wall of the microchannel and the light-gathering arc surface of the lens;
third, polishing treatment
After laser processing, polishing the surfaces of the micro-channel and the lens layer; firstly, sequentially using No. 800, No. 1000 and No. 2000 abrasive paper to polish the side wall of the micro-channel and the surface of the integrated self-alignment lens, and then using polishing paste to perform polishing treatment;
fourthly, sealing
Sealing the micro-channel and the lens layer with the cover sheet layer and the bottom sheet layer; the sealing method adopts a conventional micro-fluidic chip sealing method.
The invention has the beneficial effects that: firstly, the integrated design process of the micro-channel and the micro-lens meets the geometrical optics theory, the theory is mature, and various simulation design software such as ZEMAX, LightTools, LensVIEW and the like can be used based on the theory, so that the design process is convenient and fast, and the result is reliable. Secondly, the side wall of the micro-channel and the arc surface of the lens are processed by laser at one time, on one hand, the laser processing efficiency is high, the cost is low, and the disposable micro-fluidic chip can be manufactured in a 'disposable and disposable' mode. On the other hand, the positional relationship between the lenses and the micro-channels is determined by the motion accuracy of the laser processing system. The laser processing system has high motion precision, so that a complicated optical device alignment coupling process is omitted. Finally, the lens is integrated on the microfluidic chip, so that the volume and the manufacturing cost of the detection equipment are reduced, the real instant detection is realized, and the optical detection device is widely applied to the optical detection of disease markers, water pollutants and the like.
Drawings
FIG. 1 is a schematic structural diagram of a POCT microfluidic chip integrated with a self-aligned lens;
fig. 2 is a schematic diagram of a microchannel and a lens layer of a POCT microfluidic chip integrated with self-aligned lenses, (a) - (f) are different forms of the microchannel and the lens layer;
FIG. 3 is a schematic diagram of a smartphone-based optical detection system built using a POCT microfluidic chip integrated with a self-aligning lens;
in the figure: 1 microfluidic chip cover plate; 2, a sample inlet; 3, exhausting holes; 4 micro-channels and a lens layer; 5, a sample introduction chamber; 6 time delay control chamber; 7 a detection chamber; 8 an integrated self-aligning lens; 9 a waste liquid collection chamber; 10 micro-fluidic chip micro-channel and lens layer thickness; 11 a microfluidic chip substrate; 801 single-sided convex lens; 802 lenticular lenses; 803 single-sided convex lens-single-sided convex lens group; 804 a biconvex lens-biconvex lens group; 805 single-sided convex lens-double-sided convex lens group; 806 biconvex lens-a biconvex lens group; 12 a smart phone; 13 a magnifying objective lens; 14 fluorescence emission; 15 a fluorescence emission light filter; 16LED excitation light; 17LED excitation light filter; 18LED excitation light sources.
Detailed Description
Reference will now be made in detail to the embodiments of the present invention, examples of which are illustrated in the accompanying drawings, wherein like reference numerals refer to the same or similar elements throughout, and wherein the same or similar elements have the same or similar functions. The embodiments described below with reference to the drawings are illustrative only and should not be construed as limiting the invention.
As shown in fig. 1, a POCT microfluidic chip integrated with a self-aligned lens is made of polymethyl methacrylate (PMMA) and is composed of three layers, i.e., a cover plate 1, a microchannel, a lens layer 4, and a substrate layer 11; the cover layer 1 is provided with a sample inlet 2 and an exhaust hole 3; the micro-channel and lens layer 4 is provided with a micro-channel and an integrated self-aligned lens 8, and the micro-channel is provided with a sample introduction chamber 5, a time delay control chamber 6, a detection chamber 7 and a waste liquid collection chamber 9; the integrated self-aligning lens 8 takes the form of a single convex lens-single convex lens group 803.
The preparation method of the integrated self-aligned lens POCT microfluidic chip comprises the following steps:
the method comprises the following steps that firstly, calculated by ZEMAX optical simulation optimization software, the curvature radius of a first single convex lens of a single-sided convex lens-single-sided convex lens group 803 is 12mm, the curvature radius of a second single convex lens is 4mm, the focal length is 16.5mm, and the thickness 10 of a micro-channel and a lens layer of a micro-fluidic chip is 0.5 mm;
secondly, processing the side wall of the micro-channel and the arc surface of the lens on the micro-channel of the micro-fluidic chip and the lens layer 4 by adopting a laser processing method, wherein the laser processing parameters are as follows: the laser power is 10w, and the laser scanning speed is 6 mm/s;
thirdly, polishing the surface of the laser processed product, wherein the processing method comprises the following steps: sequentially grinding the side wall of the micro-channel and the surface of the lens by using No. 800, No. 1000 and No. 2000 abrasive paper, and finally polishing the micro-channel and the surface of the lens by using PMMA special polishing paste (SONAX30500, Germany);
and fourthly, sealing the cover sheet layer 1, the micro-channel and lens layer 4 and the bottom sheet layer 11 by using an ultrasonic sealing method (with the authorization number: CN106622410B) based on the laser recast micro-energy-conducting bars.
As shown in fig. 3, immunofluorescence detection of cardiac injury marker troponin i (ctni) was performed using the POCT microfluidic chip integrated with self-aligned lenses of this example:
firstly, fixing a FITC labeled antibody in a sample injection chamber 5, and fixing a cTnI capture antibody in a detection chamber 7; adding 150 mu l of sample mixed with cTnI antigen into a sample inlet 2, enabling the sample to enter a sample injection chamber 5 to wash away FITC labeled antibody fixed at the sample injection chamber, and carrying out full mixing reaction on the sample and the FITC labeled antibody in a delay control chamber 6 to form a cTnI-FITC labeled antibody conjugate, and then enabling the conjugate to enter a detection chamber 7; in the detection chamber 7, the cTnI capture antibody captures the cTnI-FITC labeled antibody conjugate. The excessive sample enters a waste liquid collecting cavity 9;
the cTnI-FITC labeled antibody conjugate in the detection cavity 7 needs to be excited to emit fluorescence, and the fluorescence intensity and the concentration of the cTnI antigen are in a linear relation, so that the concentration of the cTnI antigen can be obtained through the fluorescence intensity;
therefore, the POCT microfluidic chip based on the integrated self-aligned lens builds an optical detection system of a smart phone platform, and is used for exciting the cTnI-FITC labeled antibody conjugate to emit fluorescence and acquiring corresponding fluorescence intensity; in the system, the LED excitation light 16 emitted by the LED excitation light source 18 enters the integrated self-aligned lens 8 after being filtered by the LED excitation light filter 17, and the lens plays a role in focusing the LED excitation light 16. The focused LED exciting light enters the detection chamber 7, and the cTnI-FITC labeled antibody conjugate in the detection chamber is excited to emit fluorescence; the LED excitation light 16 is orthogonal to the fluorescence emission light 14, so that the influence of the LED excitation light on the detection signal is reduced; the fluorescence emission light 14 enters the amplifying objective lens 13 through the fluorescence emission light filter 15, the fluorescence intensity information is acquired by a photosensitive element in the smart phone 12, the fluorescence information is processed by a smart phone processor, a corresponding fluorescence intensity value is output, and a corresponding cTnI concentration value can be obtained after calibration.
The detection system has the advantages of small volume, high integration level and simple and convenient operation, and meets the requirement of instant detection.

Claims (3)

1. A preparation method of a POCT micro-fluidic chip integrated with a self-aligned lens is characterized by comprising the following steps:
first, the integrated design of micro-channel and lens based on traditional geometric optics
Lens arc surfaces of the integrated self-aligning lens (8) are designed on two sides of the micro-channel of the micro-fluidic chip, the curvature radius and the focal length of the integrated self-aligning lens (8) are designed according to the geometric optics theory, and the focus of the integrated self-aligning lens (8) is ensured to be in the micro-channel detection area;
second step, the micro-channel and lens integrated manufacture based on laser processing method
Based on a laser processing system, adjusting processing parameters, and processing a micro-channel and a lens structure, namely a micro-channel and a lens layer (4), on a transparent polymer material at one time; cutting the materials of the micro-channel and the lens layer (4) completely by using laser to form the side wall of the micro-channel and the light-gathering arc surface of the lens;
third, polishing treatment
After laser processing, polishing the surfaces of the micro-channel and the lens layer (4); firstly, sequentially using No. 800, No. 1000 and No. 2000 abrasive paper to polish the side wall of the micro-channel and the surface of the integrated self-alignment lens (8), and then polishing by using polishing paste;
fourthly, sealing
Sealing the micro-channel and the lens layer (4) with the cover sheet layer (1) and the bottom sheet layer (11); the sealing method adopts a conventional micro-fluidic chip sealing method.
2. The POCT microfluidic chip integrated with the self-aligned lens, prepared by the preparation method according to claim 1, is characterized by comprising a cover plate layer (1), a microchannel, a lens layer (4) and a bottom plate layer (11);
the micro-channel and lens layer (4) is provided with a micro-channel and integrated self-aligned lenses (8) at two sides of the micro-channel; the integrated self-aligning lens (8) is of a lens arc surface structure, the curvature radius and the focal length of the lens are determined according to the geometric optics theory, and the focal point of the lens is ensured to be in a micro-channel detection area; the thickness of the micro-fluidic chip micro-channel and the lens layer (4) is 50-5000 μm; the integrated self-aligning lens (8) is in a structural form of one or a combination of more than two of a single-sided convex lens (801), a double-sided convex lens (802), a single-sided convex lens-single-sided convex lens group (803), a double-sided convex lens-double-sided convex lens group (804), a single-sided convex lens-double-sided convex lens group (805) and a double-sided convex lens-single-sided convex lens group (806), so that the requirement of optical detection equipment on the characteristics of focusing light rays is met;
the cover sheet layer (1), the micro-channel, the lens layer (4) and the bottom sheet layer (11) are sealed into a whole by a micro-fluidic chip sealing method.
3. The self-aligned lens integrated POCT microfluidic chip of claim 2, wherein the material of the self-aligned lens integrated POCT microfluidic chip is polymethyl methacrylate, polyethylene terephthalate, polytetrafluoroethylene, polycarbonate, polystyrene, polyethylene, polypropylene, polyvinyl chloride, nylon, polyurethane, or styrene-methyl dimethacrylate copolymer.
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