CN111471583A - Gene detection substrate, gene detection chip, gene detection system and detection method - Google Patents
Gene detection substrate, gene detection chip, gene detection system and detection method Download PDFInfo
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- CN111471583A CN111471583A CN202010295999.2A CN202010295999A CN111471583A CN 111471583 A CN111471583 A CN 111471583A CN 202010295999 A CN202010295999 A CN 202010295999A CN 111471583 A CN111471583 A CN 111471583A
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Abstract
The invention discloses a gene detection substrate, a gene detection chip, a gene detection system and a gene detection method. The gene detection substrate comprises a substrate and at least one detection unit arranged on one side of the substrate, wherein the detection unit comprises an induction unit and a heating unit which are arranged on one side of the substrate, the heating unit is configured to heat the gene detection substrate, and the induction unit is configured to set a probe gene and perform induction measurement on an electric signal generated by gene hybridization induction. The gene detection substrate realizes unmarked electrical detection, has high detection sensitivity, and realizes the purposes of low cost, miniaturization and portability of gene chips.
Description
Technical Field
The invention relates to the technical field of gene detection, in particular to a gene detection substrate and chip, a gene detection system and a detection method.
Background
As a technical means for rapidly, accurately and high-flux detecting nucleic acid, the gene chip detection technology is widely applied to the fields of rapid diagnosis and treatment of diseases, screening of new drugs, pharmacogenomics, gene mutation detection, optimal breeding of crops, judicial identification, environmental monitoring, national defense and the like. Currently, the most mature and widely applied detection technology in gene chips is fluorescence labeling, which represents enterprises such as Affymetrix, Illumina, Agilent and the like. However, the detection technology has some defects, such as the need of fluorescence labeling of a target sample to be detected, complex process and high cost, the possibility of fluorescence quenching, expensive price and large volume size of a chip scanner, difficulty in realizing portability and miniaturization, and no accordance with the development trend of equipment in the current in vitro diagnosis industry.
Disclosure of Invention
The embodiment of the invention aims to provide a gene detection substrate, a gene detection chip, a gene detection system and a gene detection method so as to realize unmarked electrical detection of genes.
In order to solve the above technical problems, an embodiment of the present invention provides a gene detection substrate, including a substrate and at least one detection unit disposed on one side of the substrate, where the detection unit includes an induction unit and a heating unit disposed on one side of the substrate, the heating unit is configured to heat the gene detection substrate, and the induction unit is configured to set a probe gene and perform induction measurement on an electric signal generated by gene hybridization induction.
Optionally, the gene detection substrate further includes a temperature measurement unit, the temperature measurement unit is configured to detect the temperature of the gene detection substrate and feed back a temperature signal, and the heating unit is further configured to heat the gene detection substrate according to the temperature signal fed back by the temperature measurement unit.
Optionally, the sensing unit includes a first thin film transistor disposed on one side of the substrate, a passivation layer disposed on one side of the first thin film transistor facing away from the substrate, and a sensing electrode disposed on one side of the passivation layer facing away from the substrate, the sensing electrode is electrically connected to a gate electrode of the first thin film transistor, and a surface of the sensing electrode facing away from the substrate is configured to be provided with a probe gene.
Optionally, the material of the sensing electrode includes gold.
Optionally, the sensing unit further includes a control capacitor, the control capacitor includes a first plate located at the same layer as the gate electrode of the first thin film transistor and a second plate located at the same layer as the drain electrode of the first thin film transistor, and the first plate is electrically connected to the gate electrode of the first thin film transistor.
Optionally, the heating unit includes a heating layer, the passivation layer includes a first sub-passivation layer and a second sub-passivation layer stacked in sequence, the heating layer is located between the first sub-passivation layer and the second sub-passivation layer, and an orthographic projection of the heating layer on the substrate overlaps with an orthographic projection of the sensing electrode on the substrate.
Optionally, the thermometric unit comprises a second thin film transistor, the second thin film transistor is located between the substrate and the passivation layer, and an orthographic projection of the second thin film transistor on the substrate is located within an orthographic projection range of the heating layer on the substrate.
Alternatively, the gate electrode of the second thin film transistor is electrically connected to the gate electrode of the first thin film transistor.
In order to solve the above technical problem, an embodiment of the present invention further provides a gene detection chip, including the above gene detection substrate, where the number of the detection units is multiple, the gene detection chip further includes a cover plate disposed opposite to the gene detection substrate, and a wall disposed between the gene detection substrate and the cover plate, the wall is located at the periphery of the multiple detection units, the gene detection substrate, the cover plate, and the wall form a reaction chamber, and the cover plate is provided with a liquid inlet and a liquid outlet communicated with the reaction chamber.
In order to solve the above technical problem, an embodiment of the present invention further provides a gene detection system, including the gene detection chip described above, and further including a control unit electrically connected to the gene detection chip, where the control unit is configured to control the heating unit to heat the gene detection substrate, and the control unit is further configured to collect induced electrical signals of the induction unit, and obtain a gene detection result according to the induced electrical signals.
Optionally, the control unit is further configured to receive a temperature signal fed back by the temperature measurement unit, and control the heating unit to heat the gene detection substrate according to the temperature signal.
Optionally, the gene detection system further comprises a reset unit,
the sensing unit comprises a first thin film transistor, a sensing electrode electrically connected with a gate electrode of the first thin film transistor and a control capacitor electrically connected with the gate electrode of the first thin film transistor, a probe gene is arranged on the surface of the sensing electrode, the resetting unit is electrically connected with the gate electrode of the first thin film transistor, and the resetting unit is configured to reset the sensing unit.
In order to solve the above technical problem, an embodiment of the present invention further provides a gene detection method, using the gene detection system described above, the method including:
obtaining I of the induction unit after setting a probe geneds-VgA curve as a standard curve;
adding a target gene into the gene detection chip;
obtaining the I of the sensing unit after the target gene and the probe gene are hybridizedds-VgA curve as a sensing curve;
and comparing the sensing curve with the standard curve to obtain a gene detection result.
Optionally, collecting I of the sensing unit after setting the probe geneds-VgThe curve, as a standard curve, includes:
setting a probe gene on the surface of the induction electrode;
resetting the induction unit through the resetting unit;
the control capacitor comprises a first polar plate and a second polar plate, the first polar plate is electrically connected with a gate electrode of the first thin film transistor, a voltage signal Vg is applied to the second polar plate, and a current I between a source electrode and a drain electrode of the first thin film transistor is collecteddsObtaining Ids-VgThe curve is taken as a standard curve.
According to the gene detection substrate provided by the embodiment of the invention, the sensing unit is configured to set the probe gene and perform sensing measurement on the electric signal generated by gene hybridization induction, and the sequence of the target gene can be obtained through the electric signal obtained by the sensing unit, so that the label-free electrical detection is realized, the detection sensitivity is high, and the purposes of low cost, miniaturization and portability of a gene chip are realized. The heating unit heats the substrate, which is beneficial to the deformation and cracking of the target gene on the substrate. In DNA heteroconjugate pairs, the binding force of mismatch or partial coordination is low, and the corresponding denaturation temperature is also low. The heating unit 40 heats the substrate to melt mismatched or partially coordinated molecules, thereby reducing the problem of mismatch or partial coordination between the target gene and the probe gene and reducing the probability of false positive.
Additional features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The objectives and other advantages of the invention may be realized and attained by the structure particularly pointed out in the written description and drawings.
Drawings
The accompanying drawings are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the example serve to explain the principles of the invention and not to limit the invention.
FIG. 1 is a schematic view of a gene assaying substrate according to an exemplary embodiment of the present invention;
FIG. 2 is a schematic top view of a gene assaying substrate according to an exemplary embodiment of the present invention;
FIG. 3 is a schematic view of the cross-sectional structure A-A of FIG. 2;
FIG. 4a is a schematic structural diagram of a flat layer formed during the process of forming the sensing electrode;
FIG. 4b is a schematic diagram of the structure after patterning the planarization layer during the formation of the sensing electrode;
FIG. 4c is a schematic structural diagram of a deposited sensing film during the formation of a sensing electrode;
FIG. 5 is a schematic view of a partial top view of a gene assaying substrate according to one exemplary embodiment;
FIG. 6 is a schematic sectional view showing the structure of a gene assaying chip according to an exemplary embodiment;
FIG. 7 is a schematic plane view of a gene assaying chip according to an exemplary embodiment;
FIG. 8 is a schematic illustration of a genetic testing system in an exemplary embodiment;
FIG. 9 is a circuit schematic of a sensing element in an exemplary embodiment.
Description of reference numerals:
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, embodiments of the present invention will be described in detail below with reference to the accompanying drawings. It should be noted that the embodiments and features of the embodiments in the present application may be arbitrarily combined with each other without conflict.
The ordinal numbers such as "first", "second", "third", and the like in the present specification are provided for avoiding confusion among the constituent elements, and are not limited in number.
In this specification, a transistor refers to an element including at least three terminals, i.e., a gate electrode, a drain electrode, and a source electrode. The transistor has a channel region between a drain electrode (drain electrode terminal, drain region, or drain electrode) and a source electrode (source electrode terminal, source region, or source electrode), and current can flow through the drain electrode, the channel region, and the source electrode. In this specification, the channel region refers to a region through which current mainly flows.
In this specification, the first electrode may be a drain electrode and the second electrode may be a source electrode, or the first electrode may be a source electrode and the second electrode may be a drain electrode. In the case of using transistors of opposite polarities, or in the case of changing the direction of current flow during circuit operation, the functions of the "source electrode" and the "drain electrode" may be interchanged. Therefore, in this specification, "source electrode" and "drain electrode" may be exchanged with each other.
In the present specification, "thickness" is a dimension of the film layer in a direction perpendicular to the substrate.
In the present specification, PBS buffer (phosphate buffered saline), Tris buffer, and HEPES buffer are commonly used in the field of biological detection.
The most mature and extensive detection technology applied in the gene chip is a fluorescence labeling method, but the detection method has some defects, is difficult to realize portability and miniaturization, and does not meet the development trend of equipment in the current in-vitro diagnosis industry. The electric detection mode can realize label-free detection, and the detection is realized by utilizing the electric signal change of the electric potential, the electric potential or the electric conductance of the surface of the biomolecule carrier material caused by DNA hybridization reaction. Compared with a fluorescence detection mode, the electric detection can realize label-free detection, the detection process is simple and quick, the detection sensitivity is high, complex detection equipment is not needed, and the purposes of low cost, miniaturization and portability of the gene chip can be really realized.
The signal generated by DNA hybridization needs to be transmitted by the surface of a biological carrier by adopting a gene chip of a label-free electrical detection technology. Therefore, it is required that the carrier material has excellent electrical properties and good chemical and physical stability, and the surface is easily functionalized by chemical modification, so that the probe molecules can be stably immobilized on the surface of the carrier. The carrier materials used for detection include carbon materials (carbon nanotubes or graphene), silicon nanowires, organic semiconductor materials, noble metals, and the like. Noble metal materials such as gold (Au) are suitable for large-area production in view of chemical stability, ease of modification and possibility of automating large-area processing. The gold electrode is used as an induction electrode, the probe is modified on the surface of the gold electrode, and the surface charge accumulation of the electrode is induced through DNA hybridization, so that an electric signal is generated for detection.
FIG. 1 is a schematic diagram of a gene assaying substrate according to an exemplary embodiment of the present invention, FIG. 2 is a schematic diagram of a top view of the gene assaying substrate according to an exemplary embodiment of the present invention, and FIG. 3 is a schematic diagram of a cross-sectional view A-A of FIG. 2. As shown in fig. 1, 2 and 3, the gene assaying substrate includes a base 10 and at least one assay unit 20. At least one detecting unit 20 is disposed at one side of the substrate 10, and the at least one detecting unit 20 is arranged in an array. The sensing unit 20 includes a sensing unit 30 and a heating unit 40 (not shown in fig. 1). The heating unit 40 is configured to heat the gene assaying substrate. The sensing unit is configured to set a probe gene and to perform sensing measurement on an electric signal generated by gene hybridization induction.
According to the gene detection substrate provided by the embodiment of the invention, the sensing unit is configured to set the probe gene and perform sensing measurement on the electric signal generated by gene hybridization induction, and the sequence of the target gene can be obtained through the electric signal obtained by the sensing unit, so that the label-free electrical detection is realized, the detection sensitivity is high, and the purposes of low cost, miniaturization and portability of a gene chip are realized. The heating unit 40 heats the substrate, which is beneficial to the deformation and cracking of the target gene on the substrate. In DNA heteroconjugate pairs, the binding force of mismatch or partial coordination is low, and the corresponding denaturation temperature is also low. The heating unit 40 heats the substrate to melt mismatched or partially coordinated molecules, thereby reducing the problem of mismatch or partial coordination between the target gene and the probe gene and reducing the probability of false positive.
In an exemplary embodiment, the gene assaying substrate may further include a temperature measuring unit. The temperature measuring unit is configured to detect the temperature of the gene detection substrate and feed back a temperature signal. The heating unit is also configured to heat the gene detection substrate according to the temperature signal fed back by the temperature measurement unit. In an exemplary embodiment, the temperature measuring unit 50 detects the temperature of the gene assaying substrate and feeds back a temperature signal to the external control unit, and the external control unit controls the heating unit 40 to heat the gene assaying substrate according to the temperature signal fed back by the temperature measuring unit 50. Therefore, the real-time temperature control of the gene detection substrate can be realized. By adopting the gene detection chip of the gene detection substrate, the upper and lower circular flows can be formed in the reaction chamber in the processes of cyclic heating and heat release, so that the problems of mismatching and partial coordination of target genes and probe genes are further reduced, and the probability of false positive is reduced.
In one exemplary embodiment, as shown in fig. 1, 2 and 3, the sensing unit 30 includes a first thin film transistor 31. The first thin film transistor 31 is disposed at one side of the substrate 10. The first thin film transistor 31 includes a gate electrode 312, a source electrode (not shown in fig. 3), and a drain electrode (not shown in fig. 3). The sensing unit 30 further comprises a passivation layer 33 disposed on a side of the first thin film transistor 31 facing away from the substrate 10, and a sensing electrode 32 disposed on a side of the passivation layer 33 facing away from the substrate 10. The sensing electrode 32 is electrically connected to the gate electrode 312 of the first thin film transistor 31. In an exemplary embodiment, the material of the sensing electrode 32 may include gold (Au), and the probe gene is disposed on the surface of the sensing electrode 32. The induction electrode made of the gold material has better chemical stability, easy modification and the possibility of automatic large-area processing, thereby facilitating the preparation of the induction electrode and providing a good incubation place for a probe gene.
Here, the sensing electrode 32 is electrically connected to the gate electrode 312, so that the hybridization of the target gene and the probe gene can induce the accumulation of charges on the surface of the sensing electrode 32, the accumulated charges can affect the voltage of the gate electrode 312, and thus the source-drain current of the first thin film transistor 31, and the hybridization of the target gene and the probe gene can be obtained through the source-drain current of the first thin film transistor 31, and thus the sequence of the target gene can be obtained.
In an exemplary embodiment, as shown in fig. 1, 2 and 3, the sensing cell 30 may further include a control capacitor 34, and the control capacitor 34 includes a first plate 341 and a second plate 342. The first plate 341 is electrically connected to the gate electrode 312 of the first thin film transistor 31. In one exemplary embodiment, the first plate 341 is electrically connected to the gate electrode 312 of the first thin film transistor 31. The first plate 341 is located at the same layer as the gate electrode 312 of the first thin film transistor 31, and the second plate 342 is located at the same layer as the source or drain electrode of the first thin film transistor 31. In an exemplary embodiment, the second plate 342 of the control capacitor 34 is configured to be electrically connected to an external voltage.
In one exemplary embodiment, as shown in fig. 1, 2, and 3, the heating unit 40 may include a heating layer 42. The heating layer 42 is positioned at a side of the sensing electrode 32 facing the substrate 10, and a second sub-passivation layer 332 is disposed between the heating layer 42 and the sensing electrode 32. Therefore, the target gene is located on the surface of the second sub-passivation layer 332 and does not directly contact the heating layer 42, so that the damage of the target gene PBS buffer solution to the heating layer 42 is avoided, and the service life of the gene detection substrate is prolonged.
In one exemplary embodiment, the heating unit 40 may further include a connection line 43, and the connection line 43 is located at the same layer as the drain electrode of the first thin film transistor 31. In one exemplary embodiment, the first sub-passivation layer 331 is disposed between the drain electrode of the first thin film transistor 31 and the heating layer 42, and the passivation layer 33 may include the first sub-passivation layer 331 and the second sub-passivation layer 332. The heating layer 42 is electrically connected to the connection line 43 through the first sub-passivation layer 331. The connection line 43 is configured to be electrically connected with an external control unit to realize control of the heating layer 42 by the external control unit. The external control unit can control the current of the heating layer 42 so that the gene detection substrate can be heated at different temperatures to reduce nucleic acid mismatches or partial coordination.
In one exemplary embodiment, as shown in fig. 2 and 3, an orthographic projection of the sensing electrode 32 on the substrate 10 partially overlaps an orthographic projection of the heating layer 42 on the substrate 10. Thus, the DNA hybridization above the sensing electrode 32 can be subjected to a heating cycle by the heating layer 42, reducing non-specific adsorption and mismatch hybridization, and reducing the instances of mismatch or partial coordination.
In an exemplary embodiment, as shown in fig. 2 and 3, the temperature measuring unit 50 may include a second thin film transistor 51. The second thin film transistor 51 is locatedBetween the substrate 10 and the heating layer 42. Source-drain current I of second thin film transistor 51dsThere is a corresponding relationship with the temperature of the heating layer 42. The second thin film transistor 51 is electrically connected to an external control unit. The second thin film transistor 51 applies a source-drain current IdsIs fed back to an external control unit, and the external control unit feeds back the signal to the external control unit according to the source-drain current IdsThe temperature of the heating layer 42 is obtained, and the heating state of the heating layer 42 is controlled in real time.
In one exemplary embodiment, an orthographic projection of the second thin film transistor 51 on the substrate 10 is located within an orthographic projection range of the heating layer 42 on the substrate 10. Thus, the temperature measurement accuracy of the second thin film transistor 51 can be improved.
In one exemplary embodiment, the second thin film transistor 51 includes an active layer 511 on a side of the substrate 10, a first insulating layer 61 on a side of the active layer 511 facing away from the substrate 10, a gate electrode 512 on a side of the first insulating layer 61 facing away from the substrate 10, a second insulating layer 62 on a side of the gate electrode 512 facing away from the substrate 10, a drain electrode 513 on a side of the second insulating layer 62 facing away from the substrate 10, and a source electrode 514. The drain electrode 513 and the source electrode 514 are electrically connected to the active layer 511 through the second insulating layer 62 and the first insulating layer 61. The first sub-passivation layer 313 is located on a side of the second thin film transistor 51 facing away from the substrate 10.
In one exemplary embodiment, each film layer of the first thin film transistor 31 and each film layer of the second thin film transistor 51 are located at the same layer, that is, the active layer, the gate electrode, the source electrode, and the drain electrode of the first thin film transistor 31 are located at the same layer as the active layer, the gate electrode, the source electrode, and the drain electrode of the second thin film transistor 51, respectively. Thus, the manufacturing process of the substrate can be reduced.
In an exemplary embodiment, the surface of the gene assaying substrate on the side away from the substrate 10 is provided with main flow channels and branch flow channels corresponding to the assay units one by one. The main flow channel is used for receiving PBS buffer solution of the target genes. One end of each branch flow channel is communicated with the main flow channel, and the other end of each branch flow channel is communicated with the corresponding detection unit. Therefore, the PBS buffer solution of the target gene in the main flow channel can enter the corresponding detection unit through the branch flow channel, and the hybridization reaction with the corresponding probe gene is realized.
Those skilled in the art can understand that micro pumps, micro valves and complex pipelines at the periphery of the gene detection substrate can be used for realizing the driving control of the liquid in the main flow channel and the branch flow channel, or the micro-fluidic technology can be used for realizing the driving control of the liquid in the main flow channel and the branch flow channel.
The following describes the technical scheme of the gene assaying substrate in detail by the method for preparing the gene assaying substrate. It is to be understood that "patterning" in this embodiment includes processes of coating photoresist, mask exposure, development, etching, stripping photoresist, etc. when the material to be patterned is an inorganic material or a metal, and includes processes of mask exposure, development, etc. when the material to be patterned is an organic material, and evaporation, deposition, coating, etc. in this embodiment are well-established preparation processes in the related art.
S1: a first thin film transistor 31, a control capacitor 34, and a second thin film transistor 51 are formed on one side of the substrate 10. This step may include:
an active layer (not shown) of the first thin film transistor 31 and an active layer 511 of the second thin film transistor 51 are formed on one side of the substrate 10. The active layer may be amorphous silicon, polycrystalline silicon, or microcrystalline silicon, or may be a metal Oxide material, and the metal Oxide material may be Indium Gallium Zinc Oxide (IGZO) or Indium Tin Zinc Oxide (ITZO).
A first insulating layer 61 is formed on the side of the active layer 511 facing away from the substrate 10. The first insulating layer 61 may be made of silicon nitride SiNx, silicon oxide SiOx, or a composite layer of SiNx/SiOx.
A first metal layer is formed on the side of the first insulating layer 61 facing away from the substrate 10, the first metal layer comprising the gate electrode 312 of the first thin-film transistor 31, the gate electrode 512 of the second thin-film transistor 51 and the first plate 341 of the control capacitor 34.
A second insulating layer 62 is formed on the side of the first metal layer facing away from the substrate 10. The second insulating layer 62 may be made of silicon nitride SiNx, silicon oxide SiOx, or a composite layer of SiNx/SiOx.
A second metal layer is formed on a side of the second insulating layer 62 facing away from the substrate 10, and includes a drain electrode (not shown) and a source electrode (not shown) of the first thin film transistor 31, a drain electrode 513 and a source electrode 514 of the second thin film transistor 51, the connection line 43, the second plate 342 of the control capacitor 34, and the sensing transfer line 313. The sensing patch 313 and the gate electrode 312 of the first thin film transistor 31 are electrically connected through a via hole passing through the second insulating layer 62. The sensing patch 313 is used to electrically connect a sensing electrode formed later with the gate electrode of the first thin film transistor. The drain electrode 513 and the source electrode 514 of the second thin film transistor 51 are electrically connected to the active layer 511 through the second insulating layer 62 and the first insulating layer 61, respectively. In an exemplary embodiment, the second metal layer may further include a power patch, one end of which is electrically connected to the second plate 342 of the control capacitor, and the other end of which is used to be electrically connected to the external voltage VDD.
Those skilled in the art will appreciate that various layers of the thin film transistor can be formed using techniques conventional in the art and will not be described in detail herein.
S2: a first sub-passivation layer 331 is formed at a side of the first and second thin film transistors facing away from the substrate 10. The first sub-passivation layer 331 is formed with a first via hole for exposing the connection line 43 and a second via hole for exposing the sensing patch line 313.
S3: a heating layer 42 is formed on a side of the first sub-passivation layer 331 facing away from the substrate 10, and the heating layer 42 is electrically connected to the connection line 43 through a first via hole. The orthographic projection of the heating layer 42 on the substrate 10 includes the orthographic projection of the second thin film transistor on the substrate 10. The material of the heating layer 42 may include Indium Tin Oxide (ITO) or Indium Zinc Oxide (IZO).
S4: a second sub-passivation layer 332 is formed on a side of the heating layer 42 away from the substrate 10, the second sub-passivation layer 332 is provided with a third via hole at the second via hole, and the sensing patch cord 313 is exposed through the third via hole.
S5: the sensing electrode 32 is formed on a side of the second sub-passivation layer 332 facing away from the substrate 10, and the sensing electrode 32 is electrically connected to the sensing patch 313 through the third via hole. This step may include:
a planarization layer 91 is formed on a side of the second sub-passivation layer 332 away from the substrate 10, as shown in fig. 4a, and fig. 4a is a schematic structural diagram after a planarization layer is formed in a process of forming the sensing electrode. This step may include: pre-cleaning the formed substrate; spin-coating a planarization glue layer on the side of the second sub-passivation layer 332 facing away from the substrate 10 at a speed of 1500 rpm, wherein the spin-coating time is about 45 s; the glue layer is cured at about 230 c for about 30 minutes to form a planar layer 91, as shown in fig. 4 a.
The planarization layer 91 is patterned to remove the planarization layer at the sensing electrode position and retain the planarization layer at other positions, as shown in fig. 4b, where fig. 4b is a schematic structural diagram of the planarization layer after patterning in the process of forming the sensing electrode. This step may include: coating photoresist on the side of the flat layer 91, which is far away from the substrate 10, wherein the photoresist can be coated by adopting a spin coating method, and the spin coating speed is about 3000 r/min; curing the photoresist, wherein the photoresist can be baked at 110 ℃ for about 90 s; carrying out mask exposure on the photoresist by adopting a mask, wherein the exposure intensity is about 100 mJ; developing the photoresist and the flat layer by using a developing solution such as TMAH for about 60s, removing the photoresist and the flat layer at the position of the sensing electrode, and reserving the photoresist 92 and the flat layer 91 at other positions; the remaining photoresist and planarization layer were baked at 110 c for about 90 seconds.
Depositing an induction film 32' on the side of the photoresist 92 away from the substrate 10, depositing the induction film by a sputtering method, as shown in fig. 4c, which is a schematic structural diagram after depositing the induction film in the process of forming the induction electrode in fig. 4 c; soaking the substrate with N-methylpyrrolidone (NMP) at 25 deg.C for about 30 min; the planarization layer 91 is separated from the surface of the second sub-passivation layer 332, the photoresist and the sensing thin film on the surface of the planarization layer 91 are separated from the substrate along with the planarization layer 91, and the sensing electrode position is formed by the sensing thin film at the sensing electrode position remaining due to the absence of the planarization layer, as shown in fig. 3. In one exemplary embodiment, the material of the sensing electrode may include gold. The thickness of the induction electrode is 40 nm to 60 nm. In one exemplary embodiment, the sensing electrode has a thickness of 50 nanometers.
S6: a main flow passage and a branch flow passage are formed on the surface of one side of the gene detection substrate facing the induction electrode. The main flow channel is used for receiving PBS buffer solution of the target genes. One end of each branch flow channel is communicated with the main flow channel, and the other end of each branch flow channel is communicated with the corresponding detection unit. It will be appreciated by those skilled in the art that the main flow channels and the trunk flow channels can be prepared using conventional techniques and will not be described in detail herein.
FIG. 5 is a schematic view of a partial top view of a gene assaying substrate according to an exemplary embodiment. In an exemplary embodiment, as shown in fig. 5, the gene assaying substrate includes a base 10 and a plurality of assay units 20 located at one side of the base 10, wherein the plurality of assay units 20 are arranged in an array.
In one embodiment, the number of array elements of the detecting unit 20 may be 10 to 1000000, and the sensing electrode of each detecting unit 20 may be provided with a different probe gene (nucleic acid probe).
On the other hand, the invention also provides a gene detection chip. FIG. 6 is a schematic sectional view of the gene assaying chip according to an exemplary embodiment. FIG. 7 is a schematic plane view of the gene assaying chip according to an exemplary embodiment. As shown in FIGS. 6 and 7, the gene assaying chip includes the gene assaying substrate 100 as described above. The gene assaying chip may further include a cover plate 200, and the cover plate 200 is disposed opposite to the gene assaying substrate 100. The gene assaying chip may further include a fence 70 disposed between the cover plate 200 and the gene assaying substrate 100, the fence 70 being located at the periphery of the plurality of assaying units 20. The enclosing wall 70, the gene assaying substrate 100 and the cover plate 200 form a reaction chamber 80.
According to the gene detection chip provided by the embodiment of the invention, the temperature measuring unit 50 measures the temperature of the gene detection substrate and feeds the temperature back to the external control unit, and the external control unit controls the heating unit 40 to heat the target gene according to the feedback of the temperature measuring unit 50, so that the real-time temperature control of the detection substrate can be realized, and the deformation and cracking of the target gene on the substrate are facilitated. In DNA heteroconjugate pairs, the binding force of mismatch or partial coordination is low, and the corresponding denaturation temperature is also low. The real-time temperature control of the detection substrate can enable the interior of the reaction chamber to form an upper circulation flow and a lower circulation flow in the processes of cyclic heating and heat release, can melt mismatched or partially coordinated molecules, reduces the problems of mismatched and partially coordinated target genes and probe genes, and reduces the probability of false positive.
In an exemplary embodiment, as shown in fig. 6 and 7, the cover plate 200 defines a liquid inlet 201 and a liquid outlet 202, and the liquid inlet 201 and the liquid outlet 202 are only schematically shown in fig. 6. The liquid inlet 201 may correspond to a main channel on the gene detection substrate, the PBS buffer solution of the target gene is injected into the reaction chamber from the liquid inlet 201, and then enters the detection unit along the main channel and the branch channels, and the waste liquid after the test is discharged from the liquid outlet 202.
In an exemplary embodiment, as shown in fig. 6, the enclosing wall 70 includes a support layer 71 on a side of the gene detection substrate 100 facing the cover plate 200, and the material of the support layer 71 may include an organic material, such as polyimide, photoresist, and the like. The enclosure wall 70 may further include a protective layer 72 covering the outer surface of the support layer 71, and the protective layer 72 may increase the structural strength of the enclosure wall 70 and may prevent moisture from entering the reaction chamber. In one exemplary embodiment, the material of the protective layer may include at least one of silicon nitride, silicon oxide, and silicon oxynitride.
The preparation process of the gene detection chip can comprise the following steps:
s7: a wall 70 is formed on the side of the gene detection substrate 100 facing the sensing electrode 42, and the wall 70 is located at the periphery of the plurality of detection units 20. This step may include:
s71: a support layer 71 is formed on the side of the gene assaying substrate 100 facing the sensing electrode 42, and the support layer 71 is located at the periphery of the plurality of detecting units 20. This step may include: applying (e.g., spin-coating) a solution of a support material on the side of the gene assaying substrate 100 facing the sensing electrode 42 at a rate of about 200 rpm; baking the support material solution at 110 ℃ for about 2 minutes to form a support film; patterning the supporting film by adopting a mask exposure process, wherein the exposure intensity is about 999mJ, the distance between an exposure light source and a mask is about 100 micrometers, and the exposure time is about 15 seconds; after developing for about 45 seconds by adopting a developing solution, retaining the supporting film at the position of the supporting layer, and developing and removing the supporting films at other positions; the remaining support film was cured at about 230 ℃ for about 30 minutes, and the support film formed a support layer 71, the thickness of the support layer 71 in the direction perpendicular to the gene assaying substrate 100 being about 52 μm.
S72: a protective layer 72 covering the surface of the support layer 71 is formed on the surface of the support layer 71. This step may include: depositing a protective film on one side of the supporting layer 71, which is far away from the gene detection substrate 100, wherein the thickness of the protective film is about 300 nm; the protective film is subjected to patterning treatment, the protective layer formed by leaving the protective film on the surface of the position supporting layer 71 is removed, and the protective film at the other position is removed.
S8: and curing and packaging the cover plate and the enclosing wall of the chip obtained through the steps through the alignment adhesive to form the gene detection chip. In one exemplary embodiment, spacers (spacers) are mixed in the curing glue. A liquid inlet and a liquid outlet are formed in the cover plate, and the liquid inlet and the liquid outlet can be formed in the cover plate in a laser array punching mode.
In an exemplary embodiment, before S8, the process of preparing the gene assaying chip may further include: shaking the chip obtained in step S72 with 10 times of PBS buffer solution for 15 minutes; shaking the mixture for 15 minutes by using 1 time of PBS buffer solution; shaking twice with ultrapure water for 15 min; blowing the chip dry by nitrogen; connecting different probe genes on a plurality of sensing electrodes through a sample applicator, and incubating overnight at 4 ℃; and eluting the chip with Tris buffer solution, HEPES buffer solution and pure water respectively, and drying the chip by using nitrogen.
In another aspect, the invention also provides a gene detection system. FIG. 8 is a schematic diagram of a genetic testing system in an exemplary embodiment. In an exemplary embodiment, the genetic testing system includes the genetic testing chip as described above, and further includes a control unit 500 electrically connected to the genetic testing chip. The control unit 500 is configured to receive the temperature signal fed back from the temperature measuring unit 50, and control the heating unit 40 to heat the target gene according to the temperature signal. The control unit 500 is further configured to receive the induced electrical signal of the sensing unit 30 and compare the induced electrical signal with a reference electrical signal to obtain a gene detection result.
In an exemplary embodiment, the gene testing system may further include a reset unit 600. The reset unit 600 is electrically connected to the sensing unit 30 in each sensing unit 20. In one exemplary embodiment, as shown in fig. 1, the reset unit 600 is electrically connected to both the gate electrode of the first thin film transistor 31 and the first plate 341 of the control capacitor 34. The reset unit 600 is configured to reset the sensing unit 30. In an exemplary embodiment, the reset unit 600 is configured to reset the sensing unit 30, that is, the reset unit 600 is configured to ground both the gate electrode of the first thin film transistor 31 and the first plate 341 of the control capacitor 34, so as to eliminate the residual charge of the sensing unit 30, which is beneficial to improving the measurement accuracy of the sensing unit 30.
In an exemplary embodiment, the control unit 500 is further configured to detect an induced electrical signal of the sensing unit 30, and obtain a gene detection result according to the induced electrical signal. That is, the control unit 500 is further configured to obtain I by applying a voltage to the second plate 342 of the control capacitance to apply a gate voltage to the gate electrode of the first thin film transistor 31 and detecting a source-drain current of the first thin film transistor 31ds-VgRelation of (1), IdsIs the current between the source electrode and the drain electrode of the first thin film transistor, VgIs a voltage applied to the second plate 342.
In another aspect, the present invention also provides a gene assaying method using the gene assaying system as described above. The method can comprise the following steps:
collecting I of the induction unit after setting the probe geneds-VgA curve as a standard curve;
adding a target gene into the gene detection chip;
collecting I of the induction unit after the hybridization of the target gene and the probe geneds-VgA curve as a sensing curve;
and comparing the sensing curve with the standard curve to obtain a gene detection result.
In an exemplary embodiment, the I of the sensing unit after setting the probe gene is collectedds-VgCurve, as a standardQuasi-curves, may include:
setting a probe gene on the surface of the induction electrode;
resetting the induction unit through the resetting unit;
the control capacitor comprises a first polar plate and a second polar plate, the first polar plate is electrically connected with a gate electrode of the first thin film transistor, a voltage signal Vg is applied to the second polar plate, and a source-drain current I of the first thin film transistor is acquireddsObtaining Ids-VgThe curve is taken as a standard curve.
The gene assaying method will be described in detail below with reference to a circuit diagram (shown in fig. 9) of a sensing unit, and fig. 9 is a schematic circuit diagram of the sensing unit in an exemplary embodiment. As will be understood by those skilled in the art, IdsIs a current between the source electrode and the drain electrode of the first thin film transistor, i.e., a current between S1 and D1.
Applying a voltage V to terminal C (i.e., the second plate of control capacitor 34)gFurther, a voltage is applied to the gate electrode G1 of the first thin film transistor 31 to detect I in the first state of the first thin film transistor 31ds-VgCurve line.
The sensing electrode 32 is connected with a probe gene, and in an exemplary embodiment, the probe gene may be disposed on the sensing electrode by a soaking and adsorbing manner.
Resetting the sensing unit by a reset unit, comprising: the gate electrode of the first thin film transistor 31 is grounded through the reset unit so that Vc＝VFG0, wherein VcFor controlling the voltage between the two plates of the capacitor 34, VFGIs the gate electrode voltage of the first thin film transistor 31.
The reset cell is suspended and a voltage V is applied to terminal C (i.e., the second plate of control capacitor 34)gFurther, a voltage is applied to the gate electrode G1 of the first thin film transistor 31, and I in the second state of the first thin film transistor 31 is obtainedds-VgCurve, as a standard curve, at this time, Vc＝VFGWherein V iscFor controlling the voltage between the two plates of the capacitor 34, VFGIs a first thin film transistor 3A gate voltage of 1.
Adding PBS buffer solution of target gene into gene detection chip, performing hybridization reaction between target gene and probe gene, inducing surface charge accumulation of induction electrode 42 (gold electrode), and inducing QFG＝QSENSWherein Q isFGFor gate electrode charge variation, QSENSIs the amount of charge change of the sensing electrode 42. This step may include the following processes: injecting PBS buffer solution of the target gene into the liquid inlet of the gene detection chip, heating the heating layer 42 to a target temperature (for example, 90 ℃ to 100 ℃, or 95 ℃) by the heating unit under the control of the control unit, and performing denaturation and lysis on the target gene at the target temperature; the control unit controls the heating unit to stop heating, and the temperature in the reaction chamber 80 is cooled back to the room temperature; in the reaction chamber 80, the denatured lysate of the target gene and the probe gene on the sensing electrode are subjected to hybridization reaction for about 30 minutes; hybridization of the target gene with the probe gene induces charge accumulation on the surface of the sensing electrode 42, QFG＝QSENSThat is, the gate electrode charge variation amount is equal to the sense electrode charge variation amount; the chip was eluted with Tris buffer, HEPES buffer and purified water, respectively.
Obtaining the I of the sensing unit after the target gene and the probe gene are hybridizedds-VgThe curve, as a sensing curve, may include: applying a voltage V to terminal C (i.e., the second plate of control capacitor 34)gObtaining I of the first thin film transistor 31 after the hybridization of the target gene and the probe geneds-VgCurve as a sensing curve, when VFG＝Vc+QSENS/CcWherein V isFGIs the gate voltage, V, of the first thin film transistor 31cFor controlling the voltage between the two plates of the capacitor 34, QSENSTo sense the amount of charge change of the electrode 42, CcTo control the capacitance value of capacitor 34.
Comparing the sensing curve with the standard curve to obtain a gene detection result, that is, comparing the sensing curve with the standard curve to know which probe genes are hybridized and matched with the target genes, so that the nucleic acid sequence of the gene to be detected can be obtained through the nucleic acid sequence of the probe genes hybridized and matched with the target genes.
When the gene detection system and the gene detection method provided by the embodiment of the invention are used for detecting the gene, the real-time temperature control of the detection substrate can be realized, and the deformation and the cracking of the target gene on the substrate are facilitated. In DNA heteroconjugate pairs, the binding force of mismatch or partial coordination is low, and the corresponding denaturation temperature is also low. The real-time temperature control of the detection substrate can enable the interior of the reaction chamber to form an upper circulation flow and a lower circulation flow in the processes of cyclic heating and heat release, can melt mismatched or partially coordinated molecules, reduces the problems of mismatched and partially coordinated target genes and probe genes, and reduces the probability of false positive. The gene detection chip, the gene detection system and the gene detection method realize unmarked electrical detection, have high detection sensitivity and realize the purposes of low cost, miniaturization and portability of the gene chip.
In the description of the embodiments of the present invention, it should be understood that the terms "middle", "upper", "lower", "front", "rear", "vertical", "horizontal", "top", "bottom", "inner", "outer", etc., indicate orientations or positional relationships based on those shown in the drawings, and are only for convenience in describing the present invention and simplifying the description, but do not indicate or imply that the referred device or element must have a specific orientation, be constructed in a specific orientation, and be operated, and thus, should not be construed as limiting the present invention.
In the description of the embodiments of the present invention, it should be noted that, unless explicitly stated or limited otherwise, the terms "mounted," "connected," and "connected" are to be construed broadly, and may be, for example, fixedly connected, detachably connected, or integrally connected; can be mechanically or electrically connected; they may be connected directly or indirectly through intervening media, or they may be interconnected between two elements. The specific meanings of the above terms in the present invention can be understood in specific cases to those skilled in the art.
Although the embodiments of the present invention have been described above, the above description is only for the convenience of understanding the present invention, and is not intended to limit the present invention. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (14)
1. A gene detection substrate is characterized by comprising a base and at least one detection unit arranged on one side of the base, wherein the detection unit comprises an induction unit and a heating unit which are arranged on one side of the base, the heating unit is configured to heat the gene detection substrate, and the induction unit is configured to arrange probe genes and carry out induction measurement on electric signals generated by gene hybridization induction.
2. The substrate of claim 1, further comprising a temperature measuring unit configured to measure a temperature of the substrate and feed back a temperature signal, wherein the heating unit is further configured to heat the substrate according to the temperature signal fed back by the temperature measuring unit.
3. The gene detection substrate according to claim 2, wherein the sensing unit comprises a first thin film transistor disposed on one side of the substrate, a passivation layer disposed on one side of the first thin film transistor facing away from the substrate, and a sensing electrode disposed on one side of the passivation layer facing away from the substrate, wherein the sensing electrode is electrically connected to the gate electrode of the first thin film transistor, and a surface of the sensing electrode facing away from the substrate is configured to be provided with a probe gene.
4. The gene detection substrate according to claim 3, wherein the material of the sensing electrode comprises gold.
5. The gene detection substrate according to claim 3, wherein the sensing unit further comprises a control capacitor, the control capacitor comprises a first plate located at the same layer as the gate electrode of the first thin film transistor and a second plate located at the same layer as the drain electrode of the first thin film transistor, and the first plate is electrically connected to the gate electrode of the first thin film transistor.
6. A gene detecting substrate according to any one of claims 3 to 5, wherein the heating unit comprises a heating layer, the passivation layer comprises a first sub-passivation layer and a second sub-passivation layer which are sequentially stacked, the heating layer is located between the first sub-passivation layer and the second sub-passivation layer, and an orthographic projection of the heating layer on the substrate partially overlaps with an orthographic projection of the sensing electrode on the substrate.
7. The gene detection substrate according to claim 6, wherein the thermometric unit comprises a second thin film transistor, the second thin film transistor is located between the substrate and the passivation layer, and an orthographic projection of the second thin film transistor on the substrate is located within an orthographic projection range of the heating layer on the substrate.
8. The gene detection substrate according to claim 6, wherein a gate electrode of the second thin film transistor is electrically connected to a gate electrode of the first thin film transistor.
9. A gene detection chip, comprising the gene detection substrate of any one of claims 1 to 8, wherein the number of the detection units is multiple, the gene detection chip further comprises a cover plate arranged opposite to the gene detection substrate and a wall arranged between the gene detection substrate and the cover plate, the wall is arranged at the periphery of the detection units, the gene detection substrate, the cover plate and the wall form a reaction chamber, and the cover plate is provided with a liquid inlet and a liquid outlet communicated with the reaction chamber.
10. A gene detection system, comprising the gene detection chip of claim 9, and further comprising a control unit electrically connected to the gene detection chip, wherein the control unit is configured to control the heating unit to heat a gene detection substrate, and the control unit is further configured to collect an induced electrical signal of the induction unit and obtain a gene detection result according to the induced electrical signal.
11. The gene detecting system according to claim 10, wherein the control unit is further configured to receive a temperature signal fed back by the temperature measuring unit, and control the heating unit to heat the gene detecting substrate according to the temperature signal.
12. The gene assaying system according to claim 10, further comprising a reset unit,
the sensing unit comprises a first thin film transistor, a sensing electrode electrically connected with a gate electrode of the first thin film transistor and a control capacitor electrically connected with the gate electrode of the first thin film transistor, a probe gene is arranged on the surface of the sensing electrode, the resetting unit is electrically connected with the gate electrode of the first thin film transistor, and the resetting unit is configured to reset the sensing unit.
13. A gene assaying method using the gene assaying system according to any one of claims 10 to 12, the method comprising:
obtaining I of the induction unit after setting a probe geneds-VgA curve as a standard curve;
adding a target gene into the gene detection chip;
obtaining the I of the sensing unit after the target gene and the probe gene are hybridizedds-VgA curve as a sensing curve;
and comparing the sensing curve with the standard curve to obtain a gene detection result.
14. The method of claim 13, wherein the detection of I in the sensing unit after the probe gene is set is performedds-VgThe curve, as a standard curve, includes:
setting a probe gene on the surface of the induction electrode;
resetting the induction unit through the resetting unit;
the control capacitor comprises a first polar plate and a second polar plate, the first polar plate is electrically connected with a gate electrode of the first thin film transistor, a voltage signal Vg is applied to the second polar plate, and a current I between a source electrode and a drain electrode of the first thin film transistor is collecteddsObtaining Ids-VgThe curve is taken as a standard curve.
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