WO2013152680A1 - 一种集成微透镜阵列装置 - Google Patents

一种集成微透镜阵列装置 Download PDF

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Publication number
WO2013152680A1
WO2013152680A1 PCT/CN2013/073525 CN2013073525W WO2013152680A1 WO 2013152680 A1 WO2013152680 A1 WO 2013152680A1 CN 2013073525 W CN2013073525 W CN 2013073525W WO 2013152680 A1 WO2013152680 A1 WO 2013152680A1
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WIPO (PCT)
Prior art keywords
microlens array
chip body
array device
integrated
chip
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PCT/CN2013/073525
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English (en)
French (fr)
Inventor
王振宇
魏显东
梁银针
戴良
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无锡国盛精密模具有限公司
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Publication of WO2013152680A1 publication Critical patent/WO2013152680A1/zh

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G01N21/6452—Individual samples arranged in a regular 2D-array, e.g. multiwell plates
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G01N21/6456—Spatial resolved fluorescence measurements; Imaging

Definitions

  • the invention relates to the field of biotechnology detection, and constructs a microanalysis system by fixing target molecules on the surface of the microlens, in particular to an integrated microlens array device.
  • the microarray technology is a planar carrier on which a gene or a protein molecule is regularly and specifically adsorbed, and a plurality of cells are arranged neatly in rows and columns on the microarray; an analysis device is called micro Arrays must meet the following criteria: regular, microscale, and planar requirements; microscales allow reactions to occur rapidly in reaction kinetics, enabling the detection of a large number of indicators.
  • microarray chips usually use standard glass slides (1 inch * 3 inches), and the glass slides have the following problems:
  • a peripheral device is required to control the evaporation of the sample during the reaction.
  • An integrated microlens array device comprising: at least one chip body and a cover body, wherein the cover body is adapted to an upper end surface of the chip body and closely cooperates with the chip to form a closed reaction cavity,
  • the chip body has at least one upper opening portion, and the upper opening portion extends downward along a central axis of the chip body to form a groove having a surface, and the outer surface of the groove is equally spaced with a plurality of protrusions.
  • the microlens is formed by a microlens array extending longitudinally from the outer surface of the groove through the bottom surface of the groove.
  • the chip body further includes a lower opening portion, and the lower opening portion is a tapered shape having a reduced diameter along the central axis of the chip body toward the upper opening portion Space, the male space is inclined at least 20 degrees with respect to the central axis of the chip body.
  • the integrated microlens array device wherein the chip body is made of a polymer material and is integrally molded.
  • the integrated microlens array device wherein the cover is a sealing cover, and the sealing cover is made of a metal material, and includes a cover body and a sealing ring solidified on an inner edge of the cover body.
  • the integrated microlens array device wherein the sealing cover is one of polypropylene, low density polyethylene, and high density polyethylene, and includes a cover body, a metal piece embedded inside the cover body, and cured a sealing ring at the edge of the metal sheet.
  • the integrated microlens array device wherein the chip body groove is surrounded by a wall or The outer peripheral wall of the chip is a matte surface.
  • microlens is a light conversion structure, or a light conversion structure and a light collection structure are assembled.
  • the integrated microlens array device wherein the light-converting structure is one of a truncated cone structure, a cylindrical structure, a square pillar structure, a hexahedral column structure, an octahedral column structure, or a three-dimensional geometric structure.
  • the integrated microlens array device wherein the outer surface of the light-converting structure is plated with a reflective film, and the reflective film is one of a metal reflective film, a dielectric reflective film, and a metal dielectric reflective film, and the light-converting structure is The surface is flat or shallow.
  • the integrated microlens array device wherein the concentrating structure is one of a convex lens and a Fresnel lens, and the concentrating structure is placed at the bottom of the light conversion structure to form an integrated structure.
  • the beneficial effects of the invention are as follows: after adopting the above technical solution, the fluorescence collection efficiency is nearly 10-20 times higher than that of the prior art lensless structure, and the detection sensitivity is high, the cover body and the integrated microlens The array of chips forms a completely closed reaction chamber, which effectively solves the problem of evaporation of samples during biomedical detection.
  • FIG. 1 is a schematic cross-sectional view of an integrated microlens array device of the present invention
  • FIG. 2 is a schematic cross-sectional view showing the structure of the sealing cover of the present invention.
  • Figure 3 is a schematic cross-sectional view showing another structure of the sealing cover of the present invention.
  • 4A-4D are schematic views showing the structure of a microlens of the present invention.
  • FIG. 5 is a cross-sectional view showing another embodiment of the integrated microlens array device of the present invention. detailed description
  • the present invention provides an integrated microlens array device.
  • the present invention will be further described in detail below with reference to the accompanying drawings and embodiments.
  • the present invention provides a chip integrated with a microlens array, which is innovative in that it has an edge along the upper end of the chip body.
  • a recessed area extending downward from the central axis ie, forming a groove having a flat surface
  • a plurality of microlenses capable of improving fluorescence collection efficiency are uniformly disposed on the upper surface of the recessed area, each microlens being distributed outside the recessed area
  • the surface and the inner cavity layer of the chip body ie, the bottom surface of the groove
  • the microlens is designed to have a light-converting and/or concentrating structure, when the excitation light from the lower portion of the chip body is irradiated to have the probe In the microlens of the molecule, the microlens changes the direction of the diverging fluorescence, and the fluorescence is diverted to the fluorescent detector on the lower part of the chip body by the reflection of the light-converting structure to detect and display in the form of an image; the invention realizes the zero of the detection sample. Evaporating, also having a cover that fits and closely fits the upper end of the chip body, Cover and the micro
  • the integrated microlens array device of the present invention comprises: a chip body 100, a cover 200, and a cover 200 (ie, a sealing cover) is overlaid on the chip body 100 and matched with the outer peripheral wall of the chip body 100. Closely forming a closed reaction chamber; wherein: the upper end of the chip body 100 has an opening portion, and the opening portion is a depression extending downward along the central axis a region 110 (that is, a circular recessed platform 110 having an upward opening with a concave cross section and a circular cross section); the upper surface of the circular recessed table 110 is equally spaced with a plurality of protrusions.
  • the structure of the microlens is designed to have a light-converting structure and/or a concentrating structure, so that the fluorescence collection efficiency is higher than that of the prior art lensless structure.
  • the number of the microlenses 120 and the pitch thereof can be adjusted as needed, and the lower end portion of the chip body 100 further has a lower opening portion, and the lower opening portion is a frustum space 1 30 which is reduced in diameter toward the upper opening direction along the central axis ( The tapered space formed by the bottom opening is 1 30, the opening is downward, the axial section is trapezoidal, and the radial section is circular.)
  • the downward opening of the chip body is designed to have a certain male structure in order to reduce the distribution.
  • the microlens fluorescence loss at the edge of the circular recess 110, the angle of the angle A should be at least 20 degrees, the tilt angle A is based on the central axis of the chip body;
  • the chip body is made of high molecular polymer material, It is one of materials such as polystyrene, polyvinyl chloride, and cycloolefin polymer.
  • the microlens array formed by the chip body having upper and lower openings and several equal intervals is integrally molded; however, the upper end of the chip body 100 is open. It is not limited to a circular groove. It can also be designed as a square, rectangular or other structural groove.
  • the corresponding lower opening should also be designed as a square or Frustum shape, that is: the longitudinal opening of trapezoidal section, square or rectangular transverse cross-section.
  • a recessed bottom surface 140 is formed between the circular recess 110 formed by the upper end opening of the chip body 100 and the tapered space 1 30 formed by the lower opening, and the microlens 120 is arranged from the top to the bottom of the circular recess 110.
  • the longitudinal surface of the circular recessed table 110 is distributed with a plurality of microlenses. For example, 60 microlenses can be designed for each chip, and a target molecule (for example, a gene, a protein molecule, etc.) can be fixed on the surface of each microlens 120. ), so that multiple indicators can be detected. If there are 60 microlenses, 60 indicators can be detected.
  • the outer peripheral surface of the chip is made into a frosted surface 150, and the frosted surface is processed by an electric discharge machining process to form a fine fire pattern on the inner wall of the chip mold, so that the molded chip is made.
  • the outer surface has a matte finish.
  • FIG. 2 and FIG. 3 is a schematic view of a sealing cover adapted to the chip body according to the present invention.
  • the sealing cover 200 includes a cover body 210 and a sealing ring 220 disposed on an inner wall of the cover body 210.
  • the cover body 210 can be made of a metal material. For example, aluminum, stainless steel and the like have high reflectivity metal, as shown in FIG. 2; the cover body 210 is manufactured by a stamping process.
  • the sealing cover 200 is prepared by an injection molding process, such as polypropylene, low density polyethylene, high density polyethylene, etc., and the sealing cover includes a cover body 210, a sealant 220, and a metal piece 230 embedded in the groove of the cover body 210.
  • the sealing ring 220 is placed on the metal piece 230, as shown in FIG.
  • the shape and size of the sealing cover depend on the shape and size of the chip body.
  • the sample in the chip is heated by heating from the upper part of the sealing cover, thereby realizing the zero evaporation of the detection sample, effectively solving the biomedicine.
  • the evaporation of the sample during the test which is of great significance for expensive biological agents, and has been tested in biology and medicine.
  • the sealing cover can highly reflect the excitation light or the emitted light, and can effectively enhance the effect of the excitation light and the collection effect of the emitted light.
  • the sealing cover 200 Under the pressure of the upper heating plate of the sealing cover, the sealing cover 200 forms a completely closed reaction space with the chip 100 of the integrated microlens array.
  • the sample in the chip fills the entire reaction space, and the sealing structure can realize 5ul sample at 95. Zero evaporation is maintained for three hours, and the volume of the reaction space can be adjusted as needed.
  • the chip body and the sealing cover described above are all single bodies, and generally use a connection structure of a plurality of chips formed at one time, for example, eight, twelve, and ninety-six; the corresponding sealing cover is a multi-chip connection structure.
  • the integrally formed structure is fitted and not shown in the drawings.
  • the microlens 120 structure of the present invention can be designed as a light-conducting structure such as a truncated cone structure, a cylindrical structure, a square pillar structure, a hexahedral column structure or an octahedral column structure, by which the divergent fluorescence is changed.
  • the direction is such that it can be detected by a fluorescent detector placed under the chip body;
  • the microlens structure can also be formed by a combination of a light-converting structure and a concentrating structure, that is, a concentrating structure is integrated at the bottom of the light-converting structure, such as Convex lens structure, Fresnel lens, etc.; Since the light-converting structure mainly relies on reflection to deflect the fluorescence, the reflective film can be plated on the reflective surface (ie, the outer surface) of the microlens-converting structure to increase the fluorescence reflectivity and reduce the fluorescence transmission loss. For example, a metal reflective film, a dielectric reflective film, a metal dielectric reflective film, or the like.
  • the light-converting structure is a truncated cone structure, and integrated under the light-converting structure is a concentrating structure; in FIG. 4A, the microlens 120 is composed of a truncated cone structure 121 and a Fresnel lens 122, The Neel lens 122 is a concentrating structure, and the bottom surface and the side of the truncated cone structure 121
  • the angle of the face is designed to be a fixed value ⁇ (the angle is designed to be 45-70 degrees), and the angle depends on the material used; the round table interface I is!
  • the surface of the film i.e., the outer surface of the light-converting structure
  • the light within a certain angular range generated by the fluorescent molecular layer 121b distributed on the upper surface 121a of the round table is totally reflected at the interface I, and the reflected light is at the collecting interface II.
  • a reflection occurs, and then the light is refracted at the concentrating interface, and finally the light is reflected at the concentrating interface IV to be received by a detector located directly below the chip body.
  • 4B is composed of a truncated cone structure 121 and a convex lens 123. Light rays distributed within a certain angle range generated by the fluorescent molecular layer 121b of the upper surface 121a of the truncated cone are totally reflected at the interface of the truncated cone I, and finally the reflected light is at the concentrating interface V. A refraction occurs that is received by the detector directly below the body of the chip.
  • 4C is composed of a truncated truncated cone structure 121 and a convex lens 123, and the fluorescent light path pattern generated by the fluorescent molecular layer 121b distributed on the upper end recessed groove 121c of the truncated cone is the same as that of the fluorescent optical path of FIG. 4B, and is omitted here.
  • the fluorescent light path generated by the fluorescent molecular layer 121b on the upper end recessed groove 121c of the circular table is the same as that of the fluorescent light path of FIG. 4A, and is omitted here. .
  • the upper surface of the microlens 120 (ie, the truncated cone surface 121a of the light-converting structure) is designed as a planar structure mainly for a microlens having a small size.
  • the sampler can be passed through.
  • a solution of the target molecule is spotted on the upper surface 121a of the truncated cone.
  • the microlens surface structure in which the upper end surface of the round table is designed as the recessed groove 121c can be used for storing a small amount of liquid in a large-sized microlens, for example, when the surface of the upper end surface groove 121c of the round table is When the diameter is larger than the diameter of the head of the pipetting tip (about 0.8 mm), the solution of the target molecule can be dispensed on the groove surface 121c by using a micropipette without using an expensive spotting device.
  • This structure is suitable for inspection organizations that do not require a large number of indicators and lack spotting equipment.
  • the integrated microlens array device of the present invention can also be designed as the structure shown in FIG. 5, including: a chip body 100 and a cover body 200.
  • the cover body 200 covers the chip body 100 and is matched with the outer peripheral wall of the chip body 100.
  • the upper surface of the recessed area 110 is equally spaced with a plurality of protrusions.
  • the protrusion is a microlens 120.
  • the structure of the microlens is designed as any of the microlenses described above.
  • the structure of the chip body 100 can be designed as a circular table, a square table or a rectangular structure.
  • Each microlens is distributed on the outer surface of the planar groove 100 and penetrates the bottom surface 140 of the chip body to form a microlens array.
  • the peripheral side surface 1 30 of the groove 110 is a frosted surface, in order to avoid fluorescence interference between the chip and the chip; the cover 200 is sticky Sealing film, the adhesive sealing film sealing film may be a polymer material such as PET film, PP film, sealing film may be a metal such as an aluminum film, the adhesive sealing film should have sufficient adhesion.
  • the two structural chips of the present invention are sealed by a sealing film, and the advantage is that the chip is sealed after the sealing film, and no external action is required; the height of the chip body structure is low, so that the bottom does not need to be opened and the edge microlens fluorescent signal is not caused. Loss; and another chip sealed in the form of a sealing cap, which can highly reflect the excitation or emission light, The cover can be sealed, the height of the chip needs to be improved, and the package is favored.
  • the bottom of the chip has a certain tapered structure to reduce the fluorescence loss of the microlens distributed at the edge of the concave table.
  • the analytical method steps provided by the present invention are:
  • each target surface can be fixed with a target molecule, then multi-indicator detection of single sample can be realized in a single chip.
  • the number is proportional to the number of microlenses
  • a laser or a white light source is used as an excitation light source to vertically illuminate the microlens in the chip from below, and the fluorescence emitted by the fluorescent molecules is detected by using PMT, CCD or CMOS as a detector.

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  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Physics & Mathematics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
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  • Pathology (AREA)
  • Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
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Abstract

一种集成微透镜阵列装置，包括至少一芯片本体（100）和覆盖体（200），所述覆盖体（200）适配于所述芯片本体（100）上端面并与其紧密配合形成密闭反应腔，所述芯片本体（100）至少具有一个上开口部，所述上开口部沿芯片本体中心轴线向下延伸形成一表面为平面的凹槽（110），所述凹槽（110）外表面等间距分布有若干微透镜（120），微透镜（120）从所述凹槽（110）外表面纵向贯穿所述凹槽底面形成微透镜阵列，这种结构的微透镜阵列装置使荧光收集效率率高、而且检测灵敏度也较高，覆盖体与集成微透镜阵列的芯片所形成完全的密闭反应腔，有效地解决了生物医学检测过程中样本的蒸发问题。

Description

一种集成微透镜阵列装置
技术领域
本发明涉及生物技术检测领域，通过在微透镜表面固定靶标分子 构建微分析系统， 特别涉及一种集成微透镜阵列装置。
背景技术
现有技术中， 微阵列技术是一种平面载体， 它上面规则地、 特 异性地吸附着基因或蛋白质分子，微阵列上按照行和列整齐地排列着 许多单元； 一个分析装置被称为微阵列， 必须符合以下标准： 有规则 的、显微尺度的以及平面的要求； 显微尺度在反应动力学上使反应快 速发生， 实现大量指标的检测。
目前微阵列芯片通常使用标准玻璃载片 （1英寸 * 3英寸）， 玻璃 载片存在如下问题：
1) 玻璃载片易碎， 不利于操作；
2) 玻璃表面不易于做化学处理， 另外玻璃的背景信号高， 不利 于高灵敏度的检测；
3) 当玻璃载片上进行多样品反应时， 样品之间容易交叉污染；
4) 玻璃载片的平面结构导致荧光收集效率低， 不利于检测灵敏 度的提高；
5) 需要外围装置控制反应过程中样品的蒸发.
现有技术实际应用中存在缺陷， 所以有待改进。
发明内容 本发明的目的是，针对上述现有技术存在的缺陷提供了一种集成 微透镜阵列装置，实现了无蒸发、免交叉污染和检测灵敏度高的目的。
本发明的技术方案如下： 一种集成微透镜阵列装置， 其特征在 于： 包括至少一芯片本体和覆盖体， 所述覆盖体适配于所述芯片本体 上端面并与其紧密配合形成密闭反应腔，所述芯片本体至少具有一个 上开口部，所述上开口部沿芯片本体中心轴线向下延伸形成一表面为 平面的凹槽， 所述凹槽外表面等间距分布有若干凸起， 所述凸起为微 透镜，所述微透镜从所述凹槽外表面纵向贯穿所述凹槽底面形成微透 镜阵列。
所述的集成微透镜阵列装置， 其中， 所述芯片本体还包括一下开 口部，所述下开口部为沿所述芯片本体中心轴线朝所述上开口部方向 缩径、截面呈梯形的锥形空间， 所述雄形空间倾斜角度相对于所述芯 片本体中心轴线至少为 20度。
所述的集成微透镜阵列装置， 其中， 所述芯片本体采用高分子聚 合物材料、 呈一体注塑成型件。
所述的集成微透镜阵列装置， 其中， 所述覆盖体为密封盖， 所述 密封盖为金属材料，其包括盖本体以及固化在所述盖本体内侧边缘的 密封圈。
所述的集成微透镜阵列装置， 其中， 所述密封盖为聚丙烯、 低密 度聚乙烯、 高密度聚乙烯其中之一材料， 其包括盖本体、 内嵌在盖本 体内侧的金属片以及固化在所述金属片边缘的密封圈。
所述的集成微透镜阵列装置， 其中， 所述芯片本体凹槽四周壁或 芯片本体外周壁为磨砂表面。
所述的集成微透镜阵列装置， 其中， 所述微透镜为转光结构， 或 转光结构和聚光结构集合而成。
所述的集成微透镜阵列装置， 其中， 所述转光结构为圆台结构、 圆柱结构、 方柱结构、 六面柱结构、 八面柱结构或具有立体几何形状 结构中的其中之一。
所述的集成微透镜阵列装置， 其中， 所述转光结构外表面镀有反 射膜，所述反射膜为金属反射膜，电介质反射膜，金属电介质反射膜其 中之一， 所述转光结构上表面呈平面或浅凹槽。
所述的集成微透镜阵列装置， 其中， 所述聚光结构为凸透镜、 菲 涅尔透镜其中之一，所述聚光结构置于转光结构的底部集合为一体成 型结构
本发明的有益效果为： 采用上述技术方案后， 使荧光收集效率与 现有技术中无透镜结构相比， 荧光收集率高近 10-20倍， 而且检测灵 敏度较高， 覆盖体与集成微透镜阵列的芯片所形成完全的密闭反应 腔， 有效地解决了生物医学检测过程中样本的蒸发问题。
附图说明
图 1 为本发明集成微透镜阵列装置剖面示意图；
图 2为本发明密封盖结构剖面示意图；
图 3为本发明密封盖另一结构剖面示意图；
图 4A-4D为本发明微透镜结构示意图；
图 5为本发明集成微透镜阵列装置另一实施例剖面示意图。 具体实施方式
本发明提供了一种集成微透镜阵列装置， 为使本发明的目的、技 术方案及优点更加清楚、 明确， 以下参照附图并举实施例对本发明进 一步详细说明。
为了解决现有技术在荧光免疫测定时所存在的微量样本蒸发、检 测灵敏度低等问题， 本发明提供了一种集成微透镜阵列的芯片， 其创 新点在于：通过在芯片本体上端部开有沿中心轴线向下延伸的凹陷区 域（即： 形成一表面为平面的凹槽）， 在凹陷区域的上表面均匀设置 有能够提高荧光收集效率的若干微透镜，每个微透镜分布在凹陷区域 的外表面并贯穿芯片本体的内腔层（即： 凹槽底面）形成微透镜阵列， 由于微透镜设计为具有转光和 /或聚光结构， 当来自于芯片本体下部 的激发光照射到具有探针分子的微透镜时，微透镜改变发散荧光方向， 通过转光结构的反射作用将荧光转向至芯片本体下部的荧光探测器 上进行探测并以图像形式显示出来；本发明为了实现了检测样本的零 蒸发， 还具有一和芯片本体上端部相适配并紧密配合的覆盖体， 覆盖 体与集成微透镜阵列的芯片形成完全密闭的反应腔空间，有效地解决 了生物医学检测过程中样本的蒸发问题。
附图 1 所示， 本发明集成微透镜阵列装置包括： 芯片本体 100、 覆盖体 200 , 覆盖体 200 (即密封盖）盖合在芯片本体 1 00上面、 并 与芯片本体 100外周壁相适配， 紧密配合形成密闭反应腔； 其中： 芯 片本体 100上端部具有开口部、开口部为沿中心轴线向下延伸的凹陷 区域 110 (也就是圆形凹台 110 , 开口向上， 其轴向截面呈凹形， 径 向截面为圆形） ； 圆形凹台 110的上表面等间距地分布有若干凸起， 该凸起为微透镜 120 , 微透镜的结构设计为具有转光结构和 /或聚光 结构，这样使荧光收集效率比现有技术中无透镜结构的荧光收集率高
10-20倍，微透镜 120的数量及其间距根据需要可调整，芯片本体 100 的下端部还具有一下开口部、下开口部为沿中心轴线朝上开口方向缩 径的锥台空间 1 30 (底部开口所形成的锥形空间 1 30 , 开口向下， 其 轴向截面呈梯形， 径向截面为圆形）， 在芯片本体向下的开口设计为 具有一定雄形结构目的就是为了减少分布在圆形凹台 110 边沿位置 的微透镜荧光损失， 夹角 A的角度应至少为 20度， 该倾斜角度 A是 相对于芯片本体中心轴线为基准；所述芯片本体采用高分子聚合物材 料， 可以是聚苯乙烯， 聚氯乙烯， 环烯烃聚合物等材料之一， 芯片本 体所形成的具有上下开口、若干等间距地分布的微透镜阵列为一体注 塑成型件； 当然芯片本体 100的上端部开口并不局限于圆形凹槽， 也 可以设计为方形、 矩形等结构凹槽， 相对应的下开口也需设计为方形 或矩形锥台， 即： 下开口纵向截面呈梯形， 横向截面为方形或矩形。
芯片本体 100上端开口所形成的圆形凹台 11 0和下端开口所形 成的锥形空间 1 30之间形成凹槽底面 140 ,微透镜 120从圆形凹台 110 的外表面从上往下布置纵向贯穿凹槽底面 140; 圆形凹台 110的外表 面分布若干微透镜， 例如每个芯片可设计 60个微透镜， 每个微透镜 120表面可固定一种靶标分子（例如基因， 蛋白分子等） ， 这样便可 实现多指标检测， 如有 60个微透镜即可做 60个指标检测； 根据对荧 光斑入射界面能量分析， 本发明设计的具有荧光收集效果的微透镜， 理论上其荧光收集效率可达到 63. 4%, 而无透镜结构的荧光收集率为 1. 8%0
为了避免检测时芯片与芯片之间荧光信号的干扰，在芯片本体外 周表面制作为磨砂表面 150, 该磨砂表面使用电火花加工工艺在芯片 模具的内壁加工出细密的火花纹，使注塑出的芯片外表面具有磨砂效 果。
结合图 2 和图 3所示为本发明适配于芯片本体上的密封盖示意 图，密封盖 200包括盖本体 210和置于盖本体 210内壁的密封圈 220, 盖本体 210可采用金属材料制造， 例如铝、 不锈钢等具有高反射率的 金属， 见图 2所示； 盖本体 210通过沖压工艺制造， 沖压成形后， 将 一定量的特殊硅胶加入盖本体 210内侧， 静置数分钟， 由于盖的结构 及金属表面的性质， 硅胶将分布在盖本体 210的边缘， 然后在一定温 度下对其加热一段时间后固化在盖本体 210上即形成了密封圈 220； 密封盖也可以使用高分子材料、 由注塑工艺制造， 例如聚丙烯、 低密 度聚乙烯、 高密度聚乙烯等材料制备密封盖 200, 该密封盖包括盖本 体 210、 密封胶 220以及内嵌在盖本体 210凹槽内的金属片 230, 密 封圈 220置于金属片 230上， 见图 3所示。
密封盖形状和大小根据芯片本体的形状和大小而定， 在检测过 程中， 采用从密封盖上部加热的方式对芯片内的样本进行加热， 实现 了检测样本的零蒸发，有效地解决了生物医学检测过程中样本的蒸发 问题， 这对于昂贵的生物试剂具有重大意义， 且在生物、 医学检测过 程中， 该密封盖能对激发光或发射光起到高反射作用， 能有效地增强 激发光的作用效果和发射光的收集效果。在密封盖上部加热板的压力 下，密封盖 200与集成微透镜阵列的芯片 1 00形成完全密闭的反应空 间，反应过程中芯片内的样本充满整个反应空间， 此密封结构能够实 现 5ul样本在 95度下维持三个小时的零蒸发， 且反应空间的体积可 根据需要调整。
上面描述的芯片本体和密封盖均为单个体，通常使用的是一次成 型的多个芯片的连接结构，例如 八个，十二个，九十六个；相应的密封 盖为与多芯片连接结构相适配安装的一体成型结构，图中未示出省 略。
为了能够提高荧光收集效率， 本发明微透镜 120 结构可设计为圆 台结构、 圆柱结构、方柱结构、六面柱结构或八面柱结构等转光结构， 通过该转光结构来改变发散荧光的方向，使其能够被置于芯片本体下 方的荧光探测器探测到； 另外，微透镜结构也可以由转光结构和聚光 结构集合而成，即在转光结构的底部集成聚光结构， 如凸透镜结构、 菲涅尔透镜等； 由于转光结构主要依靠反射作用将荧光转向，因此可 在微透镜转光结构的反射面（即外表面）上镀反射膜增加荧光反射率， 减少荧光透射损失，例如金属反射膜，电介质反射膜，金属电介质反射 膜等。
如图 4A-4D所示，所述的转光结构为圆台结构，而集成在转光结构 下方为聚光结构； 图 4A中， 微透镜 120由圆台结构 121与菲涅尔透 镜 122组成， 菲涅尔透镜 122为聚光结构， 圆台结构 121的底面与侧 面的夹角设计为一固定值 Θ (该角度设计为 45-70度）， 此夹角根据 其采用的材料而定； 其中圆台界面 I为！^射膜表面（即转光结构的 外表面），分布在圆台上表面 121a的荧光分子层 121b所产生的一定 角度范围内的光线在界面 I发生全反射，反射出的光线在聚光界面 II 发生反射， 然后光线在聚光界面 ΠΙ发生折射， 最后光线在聚光界面 IV 发生反射至位于芯片本体正下方的探测器接收。
图 4B由圆台结构 121与凸透镜 123结构组成，分布在圆台上表面 121a的荧光分子层 121b所产生的一定角度范围内的光线在圆台界面 I发生全反射，最后反射出的光线在聚光界面 V发生折射位于芯片本 体正下方的探测器接收。
图 4C由带有凹槽的圆台结构 121与凸透镜 123组成，分布在圆台 上端面内陷凹槽 121c上的荧光分子层 121b所产生的荧光光路图与图 4B的荧光光路相同， 此处省略。
图 4D由带有凹槽的圆台结构 121与菲涅尔透镜 122组成，分布圆 台上端面内陷凹槽 121c上荧光分子层 121b所产生的荧光光路图与图 4A的荧光光路相同， 此处省略。
其中微透镜 120上表面 （即： 转光结构的圆台表面 121a )设计为 平面结构主要用于尺寸较小的微透镜，例如圆台上表面 121a 直径为 100画-500画 时，可通过点样仪将靶标分子的溶液点样于圆台上表面 121a上。
但将圆台上端面设计为内陷凹槽 121c的微透镜表面结构则可用于 尺寸较大的微透镜储存微量液体， 例如当圆台上端面凹槽 121c表面 直径大于移液吸头头部直径时（约为 0. 8mm)时，可不使用价格昂贵的 点样仪点样，而可以通过微量移液枪将靶标分子的溶液分配在凹槽表 面 121 c上， 这种结构适用于对指标数量要求不高， 且缺乏点样设备 的检测机构。
本发明集成微透镜阵列装置还可以设计为图 5所示结构， 包括： 芯片本体 100、 覆盖体 200 , 覆盖体 200覆盖在芯片本体 1 00上面、 并与芯片本体 100外周壁相适配， 紧密配合形成密闭反应腔； 其中： 芯片本体 100上端部开口向下延伸一凹陷区域 110 (该凹陷区域 110 可以是圆形凹台， 方形凹台、 矩形凹台等结构， 并不受该实施例的限 制， 其开口向上、 横截面呈凹形槽）， 凹陷区域 110上表面等间距地 分布有若干凸起， 该凸起为微透镜 120 , 微透镜的结构设计为上面描 述的微透镜任一种结构， 此处不做详述； 芯片本体 100可以设计为圆 台、 方形台或长方形等结构， 每个微透镜分布在平面凹槽 100的外表 面并贯穿芯片本体凹槽底面 140形成微透镜阵列，而凹槽 110的四周 侧壁表面 1 30为磨砂表面， 为了避免芯片与芯片之间的荧光干扰； 覆 盖体 200为粘性封膜，粘性封膜可以是高分子材料封膜，例如 PET膜、 PP膜等， 也可以是金属封膜， 例如铝膜， 粘性封膜要有足够的粘合 力。
本发明两种结构芯片一个采用封膜密封，其优点在于芯片在封膜 以后便实现了密封，无需外部作用； 芯片本体结构的高度较低， 这样 底部不用开口也不会使边缘微透镜荧光信号损失；而另一个采用密封 盖形式密封的芯片， 密封盖能对激发光或发射光起到高反射作用， 为 了能采用盖密封， 芯片的高度就需要提高，利于封装， 该结构的芯片 底部开有一定锥形结构目的就是为了减少分布在凹台边沿位置的微 透镜荧光损失。
本发明所提供的分析方法步骤为：
1 ) 在微透镜的圆台上表面上固定靶标分子， 例如 DNA片段，抗原， 抗体等， 每个圆台表面可固定一种靶标分子， 那么在单个芯片 内便可实现单样品的多指标检测， 指标的数目与微透镜的数目 成正比；
2 ) 使圆台表面靶标分子与待检测样品中的分析物在合适的条件下 反应结合；
3 ) 通过标记物与靶标分子-分析物的复合物的反应对所述待检测 样品中的分析物与靶标分子的反应状况作定性或定量检测。
4 ) 检测过程中，使用激光器或者白色光源作为激发光源从下方垂 直照射芯片中的微透镜，荧光分子所发射的荧光用 PMT、 CCD或 者 CMOS等作为探测器来检测。
应说明的是， 以上实施例仅用以说明本发明的技术方案而非限 制， 尽管参照较佳实施例对本发明进行了详细说明， 本领域的普通技 术人员应当理解， 可以对本发明的技术方案进行修改或者等同替换， 而不脱离本发明技术方案的精神和范围，其均应涵盖在本发明的权利 要求范围当中。

Claims

权 利 要 求 书
1、 一种集成微透镜阵列装置， 其特征在于： 包括至少一芯片本体和 覆盖体， 所述覆盖体适配于所述芯片本体上端面并与其紧密配合形成密闭 反应腔， 所述芯片本体至少具有一个上开口部， 所述上开口部沿芯片本体 中心轴线向下延伸形成一表面为平面的凹槽， 所述凹槽外表面等间距分布 有若干凸起， 所述凸起为微透镜， 所述微透镜从所述凹槽外表面纵向贯穿 所述凹槽底面形成微透镜阵列。
2、 根据权利要求 1所述的集成微透镜阵列装置， 其特征在于， 所述 芯片本体还包括一下开口部， 所述下开口部为沿所述芯片本体中心轴线朝 所述上开口部方向缩径、 截面呈梯形的锥形空间， 所述锥形空间倾斜角度 相对于所述芯片本体中心轴线至少为 20度。
3、 根据权利要求 1或 2所述的集成微透镜阵列装置， 其特征在于， 所述芯片本体采用高分子聚合物材料、 呈一体注塑成型件。
4、 根据权利要求 1所述的集成微透镜阵列装置， 其特征在于， 所述 覆盖体为密封盖， 所述密封盖为金属材料， 其包括盖本体以及固化在所述 盖本体内侧边缘的密封圈。
5、 根据权利要求 1所述的集成微透镜阵列装置， 其特征在于， 所述 覆盖体为密封盖， 所述密封盖为聚丙烯、 低密度聚乙烯、 高密度聚乙烯其 中之一材料， 其包括盖本体、 内嵌在盖本体内侧的金属片以及固化在所述 金属片边缘的密封圈。
6、 根据权利要求 1所述的集成微透镜阵列装置， 其特征在于， 所述 芯片本体凹槽四周壁或芯片本体外周壁为磨砂表面。
7、 根据权利要求 1所述的集成微透镜阵列装置， 其特征在于， 所述 微透镜为转光结构， 或转光结构和聚光结构集合而成。
8、 根据权利要求 7所述的集成微透镜阵列装置， 其特征在于， 所述 转光结构为圆台结构、 圆柱结构、 方柱结构、 六面柱结构、 八面柱结构或 具有立体几何形状结构中的其中之一。
9、 根据权利要求 8所述的集成微透镜阵列装置， 其特征在于， 所述 转光结构外表面镀有反射膜， 所述反射膜为金属反射膜，电介质反射膜，金 属电介质反射膜其中之一， 所述转光结构上表面呈平面或浅凹槽。
10、 根据权利要求 7所述的集成微透镜阵列装置， 其特征在于， 所述 聚光结构为凸透镜、 菲涅尔透镜其中之一， 所述聚光结构置于转光结构的 底部集合为一体成型结构。
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