CN112086474A - Image sensor for fluorescence detection - Google Patents
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Abstract
The embodiment of the invention discloses an image sensing device for fluorescence detection, which comprises a micro-fluidic chip, an image sensing chip and an optical fiber panel, wherein the micro-fluidic chip is arranged on the micro-fluidic chip; the microfluidic chip is provided with a micro-well; the image sensing chip is provided with a photosensitive pixel array; the photosensitive pixel array is provided with a micro lens; the optical fiber panel is provided with optical fibers; the optical fiber has an inner ring conductive structure; the inner ring conduction structures of the optical fibers correspond to the photosensitive pixel arrays of the image sensing chip one by one; one end of the optical fiber is directly connected with the micro lens; the other end of the optical fiber is matched with the micro-trap. Embodiments of the present invention may reduce optical crosstalk.
Description
Technical Field
The invention relates to the technical field of micro-fluidic chip manufacturing and chip processes, in particular to an image sensing device for fluorescence detection.
Background
The DNA fluorescence sequencing technology has wide application in medicine and biology, and can be applied to pregnant woman detection, cancer judgment and even future disease probability estimation. Meanwhile, the method can also be applied to biological analysis, such as determination of unknown sequences, positioning and identification of mutations, and the like. However, the currently used instruments and devices for reading and detecting fluorescence signals are bulky, expensive, and have low detection throughput. Therefore, the detection requirements of more people are difficult to meet due to more difficulties in the process of popularizing the system in small and medium-sized hospitals and research institutes.
In order to solve the above problems, a method of DNA fluorescence sequencing using fluorescence sensing with an image sensor is proposed. The method has the advantages of small equipment volume, high detection speed, high detection flux, low manufacturing cost and the like, and is favorable for popularizing to small and medium-sized hospitals and increasing audiences.
In the aspect of related research progress, experts and scholars such as b.jang et al, h.eltoukhy et al and a.manickam et al propose various structures for DNA fluorescence sequencing using image sensors, all of which are integrated structures of a sensor array, a molecular capture probe, a fluorescence excitation filter film, a readout circuit and an ADC circuit in pixel, and are distinguished by respectively using a fiber panel to connect and reduce crosstalk, using a related coupling sampling technology to eliminate background light, and using a resistive heater to realize an on-chip PCR amplification function.
The above background disclosure is only for the purpose of assisting understanding of the inventive concept and technical solutions of the present invention, and it is not necessarily prior art to the present invention, and should not be used for evaluating the novelty and inventive step of the present invention in the case that there is no clear evidence that the above disclosure has been made before the filing date of the present application.
Disclosure of Invention
The invention provides an image sensing device for fluorescence detection, which realizes effective connection between an image sensing chip and a micro-fluidic chip, and increases a metal barrier layer to enhance the inhibition effect of the metal barrier layer on optical crosstalk by changing the surface structure of the image sensing chip; meanwhile, in the image sensing chip, the photodiode area of part of the pixels is completely shielded, and the pixels are divided into effective photosensitive pixels, non-illumination pixels and non-response pixels, so that the influence of optical crosstalk and dark current in the pixels can be reduced, and the detection accuracy can be improved.
An image sensing device for fluorescence detection comprises a microfluidic chip, an image sensing chip and an optical fiber panel; the microfluidic chip is provided with a micro-well; the image sensing chip is provided with a photosensitive pixel array; the photosensitive pixel array is provided with a micro lens; the optical fiber panel is provided with optical fibers; the optical fiber has an inner ring conductive structure; the inner ring conduction structures of the optical fibers correspond to the photosensitive pixel arrays of the image sensing chip one by one; one end of the optical fiber is directly connected with the micro lens; the other end of the optical fiber is matched with the micro-trap.
In some preferred embodiments, the thickness of the bottom surface of the microfluidic chip is such that the position in the microwell where the fluorescence signal is generated is as close as possible to the fiber optic faceplate.
In some preferred embodiments, further comprising a support structure; the image sensing chip is provided with a non-photosensitive area; the supporting structure is arranged on the periphery of the optical fiber panel and connected to a non-photosensitive area of the image sensing chip.
In some preferred embodiments, the array of photosensitive pixels further comprises a metal barrier layer and a plurality of photodiodes; the metal barrier layer is arranged at the position of a gap between the adjacent photodiodes.
In some preferred embodiments, the metal barrier layer has the structure: the metal layer of the next highest layer has the longest length, the length of the metal layer is gradually reduced along with the gradual reduction of the metal layers, and the length of the metal layer of the highest layer is smaller than that of the metal layer of the next highest layer.
In some preferred embodiments, the array of photosensitive pixels comprises active photosensitive pixels, non-illuminated pixels, and non-responsive pixels; the periphery of each effective photosensitive pixel corresponds to the non-illumination pixel and the non-response pixel.
In some preferred embodiments, two of the non-illuminated pixels and four of the non-responsive pixels are disposed around each of the effective photosensitive pixels.
Compared with the prior art, the embodiment of the invention has the beneficial effects that:
the optical fiber panel is used for connecting the image sensing chip and the micro-fluidic chip, so that tighter connection and coupling can be realized, and optical crosstalk can be reduced.
In the aspect of surface technology of an image sensing chip, the metal barrier layers arranged in special shapes are used at the positions adjacent to the pixels, so that the influence of adjacent pixel micro lenses on target pixel photodiodes can be effectively reduced, and the concentration light intensity of the target pixel micro lenses can be kept while optical crosstalk is reduced.
For the arrangement structure of the photosensitive pixel array, non-illumination pixels and non-response pixels are added around effective photosensitive pixels, so that the influence of dark current and the influence of test crosstalk can be effectively eliminated.
Drawings
FIG. 1 shows fluorescence excitation on a microfluidic chip according to an embodiment of the present invention;
FIG. 2 shows an embodiment of the present invention using a fiber optic faceplate to connect the microfluidic chip to the image sensing chip;
FIG. 3 illustrates the structure of an isolation light-blocking metal layer according to one embodiment of the present invention;
fig. 4 shows an arrangement (top-down) of a photosensitive pixel array according to one embodiment of the present invention;
fig. 5 shows an arrangement of the isolation light blocking metal according to an embodiment of the present invention.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the embodiments of the present invention more clearly apparent, the present invention is further described in detail below with reference to fig. 1 to 5 and the embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
It will be understood that when an element is referred to as being "secured to" or "disposed on" another element, it can be directly on the other element or be indirectly on the other element. When an element is referred to as being "connected" to another element, it can be directly connected to the other element or be indirectly connected to the other element. The connection may be for fixation or for circuit connection.
It is to be understood that the terms "length," "width," "upper," "lower," "front," "rear," "left," "right," "vertical," "horizontal," "top," "bottom," "inner," "outer," and the like are used in an orientation or positional relationship indicated in the drawings for convenience in describing the embodiments of the present invention and to simplify the description, and are not intended to indicate or imply that the referenced device or element must have a particular orientation, be constructed in a particular orientation, and be in any way limiting of the present invention.
In the description of the embodiments of the present invention, "a plurality" means two or more unless specifically limited otherwise.
The present embodiment relates to a technique for suppressing crosstalk and dark current influence of an image sensor for fluorescence detection. The fluorescence reaction is generated on a glass substrate or a microfluidic chip 2 for processing the DNA fragment, and the material of the fluorescence reaction is glass or transparent media such as PDMS, PMMA and the like. Referring to FIG. 1, a base with a fluorophore is attached to a DNA strand so that the fluorophore is released, when the excitation light source 1 is turned on. Under the irradiation of excitation light, the fluorescent group generates a fluorescent signal, and the photon energy of the fluorescent signal is lower than that of the excitation light due to the loss of the photon energy in the excitation transition, that is, the wavelength of the fluorescent signal is greater than the wavelength of the excitation light. Therefore, the filter film 3 can be used to filter out the excitation light, leaving only the fluorescence signal. Referring to fig. 1 and 2, the filter film 3 may be disposed on the bottom of the microfluidic chip 2 or on the top of the image sensing chip 4.
Referring to fig. 2, after the fluorescence signal is generated, the fluorescence signal needs to pass through the transparent bottom of the microfluidic chip 2 and enter the image sensing chip 4 to be converted into an electrical signal in the photodiode in the pixel. And a gap is necessarily formed between the two interfaces of the microfluidic chip 2 and the image sensing chip 4. In order to reduce the voids, the first method is to grow the microfluidic structure directly above the surface of the image sensing chip 4, which results in a more complex chip manufacturing process, which increases the cost; the second method is to bond the microfluidic chip 2 and the image sensing chip 4, which can separately manufacture the microfluidic chip and the image sensing chip, but if the bonding process is too tight, the chip structure may be damaged, and if the bonding process is not tight, the crosstalk problem still exists. The image sensor device for fluorescence detection provided in this embodiment adopts a third method: the microfluidic chip 2 and the image sensing chip 4 are connected by using the optical fiber panel 5, as follows.
Referring to fig. 2, the image sensing device for fluorescence detection of the present embodiment includes a microfluidic chip 2, an image sensing chip 4, and an optical fiber panel 5.
The microfluidic chip 2 has a micro well 21.
The image sensing chip 4 is provided with a photosensitive pixel array 41; wherein the photosensitive pixel array 41 is provided with a plurality of microlenses 42.
Referring to fig. 2, the fiber optic faceplate 5 is provided with optical fibers 51; wherein the optical fiber 51 has an inner turn conductive structure 510.
A fiber optic faceplate (e.g., 6um in diameter) 5 with a small inner diameter is used to connect the microfluidic chip 2 with the image sensing chip 4; the inner circle conducting structure 510 of the optical fiber 51 of the optical fiber panel 5 is matched with the specially designed photosensitive pixel array 41 to realize one-to-one correspondence; meanwhile, the other end of the optical fiber 51 is matched with the micro-well 21 in the micro-fluidic chip 2, so that the one-to-one correspondence between fluorescence generation and fluorescence sensing is realized. Meanwhile, when bonding connection is performed, the package on the surface of the image sensor chip 4 is opened, and one end of the optical fiber 51 is directly connected to the microlens 42; the supporting structure 6 is added around the optical fiber panel 5 and is adhered to the non-photosensitive area 43 of the image sensing chip 4, so as to reduce the distance from the optical fiber 51 to the micro lens 42 to the limit. On the other side, the thickness of the bottom surface of the microfluidic chip 2 is reduced, so that the position of the micro-wells 21 where the fluorescence signal is generated is as close as possible to the optical fiber panel 5, and the influence of the fluorescence signal in the adjacent micro-wells 21 is reduced by limiting the incident angle at which the total reflection of the incident light can occur by the optical fiber 51.
The image sensing device for fluorescence detection of the present embodiment enables the transmission signal in each micro well 21 to be correspondingly transmitted to a specific pixel on the image sensing chip 4, and can realize point-to-point conversion of the fluorescence signal and the pixel electrical signal. By utilizing the total reflection characteristic of the fibers in the optical fiber panel 5, the influence of fluorescent signals on the non-corresponding sensing pixels is reduced under the condition of ensuring that the transmission light intensity has no great loss. Referring to fig. 2, in addition, when the optical fiber panel 5 is used, a certain degree of connection damage may be allowed to exist on the connection surface thereof, so that the bottom of the microfluidic chip 2 and the optical fiber panel 5, and the image sensing chip 4 and the optical fiber panel 5 may be more closely connected, and the optical crosstalk phenomenon may be greatly suppressed.
Referring to fig. 2 and 3, the image sensing chip 4 has a photodiode region 400; the photodiode region 400 has a plurality of photodiodes 43. After the fluorescent signal is transmitted to the surface of the image sensor chip 4 through the optical fiber 51, the fluorescent signal is converged on the photodiode area 400 through the microlens structure at the topmost layer of the pixel. In this process, since some of the fluorescent signals transmitted through the optical fiber panel 5 are reflected multiple times inside the optical fiber 51 and then obliquely incident on the chip surface, the fluorescent signals are converged by the microlens 42 and then still maintain a certain deviation from the center, which may cause the signals to be sensed by the adjacent pixels during the transmission process from the microlens 42 to the photodiode region 400, that is, optical crosstalk occurs in the chip surface structure. To address this problem, the image sensor device for fluorescence detection of this embodiment employs a special isolation structure, and adds and optimizes the metal barrier layer arrangement at the intervals of photosensitive pixels, that is, adds an isolation light-blocking metal layer (i.e., metal barrier layer 44) having a specific arrangement shape array above the interval position (non-photodiode region) of the adjacent pixels; referring to fig. 3, the metal barrier layer 44 is composed of a metal as a signal line and a dummy metal for filling an area; therefore, false alarm caused by false reception of fluorescence signals by adjacent pixels can be reduced on the premise of not additionally increasing the occupied area of the pixels.
Referring to fig. 3, a metal barrier layer 44 is disposed at a position of a gap between adjacent photodiodes (i.e., at a space between adjacent pixels). The metal barrier layer 44 is implemented by a metal layer added in the back-end process, and the arrangement structure is an arrangement structure with an overall inverse step length arrangement and a reduced top layer length, that is: the metal barrier layer 44 has a plurality of metal layers, the metal layer of the next highest layer has the longest length, the length of the metal layer is gradually reduced as the metal layer is gradually reduced, and the length of the metal layer of the highest layer is smaller than that of the metal layer of the next highest layer. Referring to fig. 5, this structure can reflect the crosstalk light obliquely incident from other adjacent microlenses 42 well, and has less influence on the incident light converged by the correct microlenses 42. By this structure, the fluorescence signal obliquely incident to the corresponding pixel of the image sensor is reflected back to the corresponding pixel or reflected out of the image sensor chip 4, and the influence of the fluorescence signal on the adjacent pixel is reduced, so that the influence of optical crosstalk can be reduced, and the accuracy of detection can be improved.
When the fluorescence signal is transmitted to the photodiode region 400 within the pixel, the energy of the photon is absorbed by the pn junction of the photodiode and generates electron-hole pairs, in which electrons are bound in the space charge region of the pn junction under the action of an electric field. The part of electrons can be led out to enable the floating node to generate voltage change, namely, an electrical signal processed by a back-end circuit, and accordingly, conversion from an optical signal to an electrical signal is completed. At the time of accumulating the fluorescence signal (electrons are accumulated in the photodiode), electrons are generated and accumulated in the pn junction at a time other than the electrons excited in the pn junction by the fluorescence signal, and are also called dark current electrons. Dark current electrons are composed of diffusion of the substrate around the pn junction, electron-hole pairs generated by thermal motion within the pn junction, and electrons generated by surface defects, at a reduced but not eliminated level. This may have a great influence on the detection result when the fluorescence signal intensity is low, resulting in an increase in the detection error rate. In response to such a problem, the present embodiment proposes a novel photosensitive pixel array arrangement structure (photosensitive pixel array 41), that is: referring to fig. 4, a special non-illuminated and non-responsive pixel structure is added around the active photosensitive pixels 411 (also referred to as "chambered" pixels, the chambers being micro-chambers); wherein a non-illuminated pixel 412 (also referred to as a "chamber-less" pixel) is a pixel that is unobstructed above the photodiode region 400 but does not match a microwell 21 in the microfluidic core 2; the non-responsive pixel 413 is a pixel above the photodiode region 400 that is completely blocked by metal without generating a photocurrent signal. Wherein the spacing between adjacent effective photosensitive pixels 411 is about 0.9 pixel size; referring to fig. 4, a micro-channel is provided between two rows of active photosensitive pixels 411. Surrounding the non-illuminated pixels 412 around the active photosensitive pixels 411 for comparison to eliminate cross-talk effects; a non-responsive pixel 413 is surrounded around the active photosensitive pixel 411 to eliminate the dark current effect. Although the effective resolution ratio can be reduced, the pixel array structure can effectively improve the detection accuracy, and can be better matched with a liquid inlet channel and a liquid outlet channel which are arranged above and below the micro-well in the micro-fluidic chip 2, so that the pixel array structure has better engineering practicability.
Referring to fig. 4, in the present embodiment, there are 2 non-illuminated pixels 412 and 4 non-responsive pixels 413 around each effective photosensitive pixel 411, and the effective fluorescence signal intensity corresponding to each micro-well is calculated as follows:
let the output of the active photosensitive pixel 411 be a, the outputs of the corresponding non-illuminated pixel 412 be B1 and B2, and the outputs of the corresponding non-responsive pixel 413 be C1, C2, C3, and C4. The output (denoted as a') corresponding to the valid fluorescence signal is:
the crosstalk signal strength (denoted as B') is:
when B '/a ' is less than a threshold T, it can be considered that the influence of the effective pixel on the surroundings is small, and the effective pixel 411 is not influenced by the surrounding crosstalk, at this time, the obtained a ' subtracts the dark current signal intensity of the adjacent non-responsive pixel 413 by using the output of the effective pixel, and since the non-responsive pixel 413 is adjacent to the effective pixel 411, the dark current level is very close, that is, the value of the fluorescent signal intensity can be correctly reflected, and the accuracy is high; when B '/a' is greater than the threshold T, it is considered that the effective pixel 411 is affected by surrounding pixels, so that the result may be inaccurate. The reliability of the value is not high. Therefore, the detection accuracy can be improved. The threshold T may be modified according to an actual detection result.
The image sensing device for fluorescence detection of the embodiment can effectively reduce crosstalk phenomenon in a fluorescence transmission process and influence of dark current of image sensing pixels, can improve accuracy of fluorescence signal detection, and can provide technical support for a DNA fluorescence sequencing method based on an image sensing chip.
The foregoing is a more detailed description of the invention in connection with specific/preferred embodiments and is not intended to limit the practice of the invention to those descriptions. It will be apparent to those skilled in the art that various substitutions and modifications can be made to the described embodiments without departing from the spirit of the invention, and these substitutions and modifications should be considered to fall within the scope of the invention.
Claims (7)
1. An image sensor device for fluorescence detection, characterized in that: the micro-fluidic chip comprises a micro-fluidic chip, an image sensing chip and an optical fiber panel;
the microfluidic chip is provided with a micro-well;
the image sensing chip is provided with a photosensitive pixel array; the photosensitive pixel array is provided with a micro lens;
the optical fiber panel is provided with optical fibers; the optical fiber has an inner ring conductive structure;
the inner ring conduction structures of the optical fibers correspond to the photosensitive pixel arrays of the image sensing chip one by one;
one end of the optical fiber is directly connected with the micro lens;
the other end of the optical fiber is matched with the micro-trap.
2. The image sensor device for fluorescence detection according to claim 1, characterized in that: the thickness of the bottom surface of the microfluidic chip enables the position of the micro-trap generating the fluorescence signal to be as close to the optical fiber panel as possible.
3. The image sensor device for fluorescence detection according to claim 2, characterized in that: also includes a support structure; the image sensing chip is provided with a non-photosensitive area; the supporting structure is arranged on the periphery of the optical fiber panel and connected to a non-photosensitive area of the image sensing chip.
4. The image sensor device for fluorescence detection according to claim 1, characterized in that: the photosensitive pixel array further comprises a metal barrier layer and a plurality of photodiodes; the metal barrier layer is arranged at the position of a gap between the adjacent photodiodes.
5. The image sensor device for fluorescence detection according to claim 4, wherein the metal barrier layer has a structure of: the metal layer of the next highest layer has the longest length, the length of the metal layer is gradually reduced along with the gradual reduction of the metal layers, and the length of the metal layer of the highest layer is smaller than that of the metal layer of the next highest layer.
6. The image sensor device for fluorescence detection according to claim 1, characterized in that: the photosensitive pixel array comprises effective photosensitive pixels, non-illumination pixels and non-response pixels; the periphery of each effective photosensitive pixel corresponds to the non-illumination pixel and the non-response pixel.
7. The image sensor device for fluorescence detection according to claim 6, characterized in that: two non-illumination pixels and four non-response pixels are corresponding to the periphery of each effective photosensitive pixel.
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