Tumor tissue resection guiding device

Abstract

The invention discloses a tumor tissue excision guiding device which is provided with a sampling module, a detection module and a registration module which are matched with one another, and the three modules are matched with one another, so that the malignancy degree of tumor tissue in an operation can be detected in real time, a doctor can be helped to excide the tumor tissue more completely, the positive boundary rate is reduced, and the operation prognosis is improved.

Description

Technical Field

[0001] The present invention relates to the technical field of medical devices, and in particular to a tumor tissue excision guiding device. Background Art

[0002] As the tumor grows, the surrounding blood vessels are destroyed, the permeability increases, and the magnetic resonance contrast agent leaks from the blood vessels into the tissue, outlining the image boundary. Therefore, the contrast agent indicates the boundary of the destroyed vascular structure, not the actual tumor boundary.

[0003] Therefore, the disadvantages of using imaging methods such as magnetic resonance imaging in the existing technology are that it is not only expensive, the equipment costs tens of millions of yuan, but also requires professional operation, and it is difficult to fully indicate the tumor boundary. At present, when removing tumor tissue, it is difficult for doctors to completely and accurately remove tumor tissue. If cancer cells are still present in the resection margin tissue after surgery, a "positive surgical margin" (PSM) will appear, leading to rapid tumor recurrence and poor prognosis.

[0004] It can be seen that whether it is possible to provide an improved tumor tissue resection guidance device based on the deficiencies in the prior art has become a technical problem that needs to be urgently solved by those skilled in the art. Summary of the invention

[0005] The technical problem to be solved by the present invention is to provide a tumor tissue resection guidance device in order to overcome the defects in the prior art.

[0006] The present invention solves the above technical problems through the following technical solutions:

[0007] A tumor tissue resection guidance device, comprising:

[0008] A sampling module, including a sampler, which is used to extract tissue surface metabolites from surgical cut tissue. The sampling module divides the pure water column into tiny droplets and is used to dissolve tissue surface metabolites, and sequentially drips the sample droplets onto different positions of the Raman detection chip;

[0009] The detection module is used to automatically focus the laser through the objective lens onto the droplets on the Raman detection chip. The excited Raman signal is collected by the same objective lens and then enters the Raman detector. The Raman detector collects the droplet Raman signal and processes it through the Raman spectrum intelligent analysis system to automatically identify the target metabolites and determine the concentration of each metabolite through the change of Raman peak ratio;

[0010] The registration module includes a depth camera and a regional convolutional neural network deep learning module based on a mask image. The depth camera is used to capture the depth image of the position to be detected on the surgical section and generate a 3D topographic map of the tissue; the regional convolutional neural network deep learning module based on the mask image will track the color mark on the sampling pen tip of the sampler, record the three-dimensional spatial coordinate information and timing information of the sampling point, and fill the multi-metabolite data into the corresponding position in the 3D topographic map according to the timing information, thereby realizing the fusion matching of multiple metabolite distribution maps and the surgical section topographic map.

[0011] Preferably, the sampler comprises:

[0012] A multi-channel micro-droplet generation component comprises a sampling pen tip, wherein one end of the sampling pen tip in the length direction is a sampling end, and the other end is a connecting end. A liquid channel, a gas channel and a recovery channel are provided in the sampling pen tip, the outlet of the gas channel is connected to the liquid channel, and the outlet of the liquid channel and the inlet of the recovery channel intersect at the sampling end.

[0013] Preferably, the sampler further comprises:

[0014] A clamp, detachably mounted on the sampling pen tip;

[0015] A connecting sleeve, one end of which is detachably connected to the clamp;

[0016] A pen holder, detachably connected to the other end of the connecting sleeve;

[0017] Pipeline joints;

[0018] A liquid conduit is disposed in the pen barrel and communicated with the liquid channel through the pipe joint;

[0019] A gas conduit is disposed in the pen barrel and communicated with the gas channel through the pipe joint;

[0020] The recovery conduit is arranged in the pen barrel and communicated with the recovery channel through the pipe joint.

[0021] Preferably, the sampler further comprises:

[0022] A disc, one end of which is arranged at the connection end of the sampling pen tip and is provided with a through hole for the liquid conduit, the gas conduit and the recovery conduit to pass through;

[0023] A push rod is mounted on the other end of the disc;

[0024] The pressure sensor is arranged in the pen barrel and contacts the push rod.

[0025] Preferably, the sampler further comprises:

[0026] A pressure sensing assembly is installed at the connecting end, and the pressure sensing assembly includes an upper braking structure, a lower braking structure, an elastic member and a pressure sensor;

[0027] The upper brake structure comprises a first cross bar, a first vertical bar and a second cross bar connected in sequence;

[0028] The lower brake structure comprises a third crossbar, a second vertical bar and a fourth crossbar connected in sequence;

[0029] The elastic member connects the lower end of the first cross bar and the upper end of the third cross bar;

[0030] The lower end of the third crossbar and the upper end of the second crossbar are arranged opposite to each other and keep a gap;

[0031] The pressure sensor is disposed at the lower end of the third crossbar and is used to detect the distance between the second crossbar and the third crossbar.

[0032] Preferably, the sampler further comprises:

[0033] A connecting component is used to connect the sampling pen head and the pressure sensing component.

[0034] Preferably, the gas channel is located between the liquid channel and the recovery channel.

[0035] Preferably, the liquid channel comprises a first upper section and a first lower section;

[0036] The gas channel includes a second upper section and a second lower section;

[0037] The recovery channel includes a third upper section and a third lower section;

[0038] The first upper section, the second upper section and the third upper section are arranged in parallel along the length direction of the sampling pen tip;

[0039] The lower end of the first lower section and the lower end of the third lower section are close to each other and intersect;

[0040] The lower end of the second lower section is communicated with the first lower section.

[0041] Preferably, the diameter of the sampling end is smaller than the diameter of the connecting end.

[0042] Preferably, the sampling module also includes a microfluidic liquid control unit, which pushes pure water into the sampler in a controllable manner of flow rate and flow velocity. The pure water contacts the surgical section tissue at the sampling end of the sampling pen tip of the sampler and extracts metabolites from the tissue surface.

[0043] Preferably, the sampling module also includes a precise gas path control unit, which is integrated in the sampler and generates tiny droplets for extracting metabolites by cutting pure water through airflow.

[0044] Preferably, the detection module includes a sample loading head, an automatic displacement device, a Raman spectrometer, and a Raman detection chip. The automatic displacement device is used to automatically adjust the position of the Raman detection chip through a driving device and a transmission mechanism. The sample loading head is fixed in position and connected to a sampling channel. A microhole is provided at the bottom of the sample loading head to release droplets onto the surface of the Raman detection chip.

[0045] Preferably, the Raman detection chip comprises:

[0046] Silicon wafer;

[0047] A gold nanoarray, comprising a photocurable prepolymer layer, a chromium film layer and a gold film layer, wherein the photocurable prepolymer layer is coated on the upper end of the silicon wafer, a plurality of convex portions arranged in an aligned array are formed on the upper surface of the photocurable prepolymer layer, the chromium film layer is coated on the surface of the convex portions and the upper surface of the photocurable prepolymer layer; and the gold film layer is coated on the upper surface of the chromium film layer;

[0048] The reporter molecule layer is arranged on the upper surface of the gold film layer, and reporter molecules are distributed in the reporter molecule layer.

[0049] Preferably, the reporter molecules include but are not limited to: reporter molecules for MMP, HClO, pH, GSH, and ROS.

[0050] Preferably, the shape of the protrusion includes but is not limited to: cylindrical, triangular pyramidal, and square columnar.

[0051] Preferably, the registration module uses a global optimal iterative closest point algorithm to fill the multi-metabolite data into corresponding positions in the 3D topographic map according to the time series information.

[0052] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0053] The positive and progressive effect of the present invention is that the tumor tissue resection guidance device of the present invention is provided with a sampling module, a detection module and a registration module that cooperate with each other, which can realize real-time detection of tissue malignancy during surgery, can help doctors achieve more complete resection of tumor tissue, reduce the positive boundary rate, and improve surgical prognosis. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 Schematic diagram of the structure of a tumor tissue resection guidance device according to a preferred embodiment of the present invention.

[0055] Figure 2It is a schematic structural diagram of the sampling pen tip of the sampler according to the preferred embodiment of the present invention.

[0056] Figure 3 Schematic diagram of the structure of a sampler according to a preferred embodiment of the present invention.

[0057] Figure 4 It is a schematic structural diagram of a pressure sensing assembly of a sampler according to another embodiment of the present invention.

[0058] Figure 5 This is a cross-sectional view of a Raman detection chip according to a preferred embodiment of the present invention.

[0059] Description of reference numerals:

[0060] Sampling module 100

[0061] Sampling pen 1

[0062] Sampler 110

[0063] Sampling end 11

[0064] Connection terminal 12

[0065] Clamp 13

[0066] Connecting sleeve 14

[0067] Pen holder 15

[0068] Pipeline connector 16

[0069] Disc 17

[0070] Ejector 18

[0071] Pressure sensor 19

[0072] Liquid channel 2

[0073] Gas channel 3

[0074] Recycling channel 4

[0075] Tumor tissue 5

[0076] First crossbar 6

[0077] First vertical bar 7

[0078] Second crossbar 8

[0079] The third crossbar 9

[0080] The second vertical rod 10

[0081] Fourth Crossbar 101

[0082] Elastic member 102

[0083] Pressure sensor 103

[0084] Microfluidic liquid control unit 120

[0085] Precision gas path control unit 130

[0086] Detection module 200

[0087] Raman detection chip 210

[0088] Silicon Wafer 1000

[0089] Light-cured prepolymer layer 2000

[0090] Raised part 21000

[0091] Gold film layer 3000

[0092] Reporter 4000

[0093] Chrome film 5000

[0094] Registration module 300

[0095] Depth Camera 310

[0096] Mask image based regional convolutional neural network deep learning module 320 DETAILED DESCRIPTION

[0097] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments. The following description of at least one exemplary embodiment is actually only illustrative and is by no means intended to limit the present invention and its application or use. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0098] like Figure 1 As shown, this embodiment discloses a tumor tissue resection guidance device, which includes a sampling module 100, a detection module 200 and a registration module 300.

[0099] The sampling module 100 includes a sampler 110, a microfluidic liquid control unit 120 and a precise gas circuit control unit 130. The microfluidic liquid control unit 120 pushes pure water into the sampler 110 in a precise and controllable manner of flow rate and flow velocity. The pure water quickly contacts the surgical section tissue at the sampling end 11 of the sampling pen head 1 of the sampler 110 and extracts metabolites from the tissue surface. The precise gas circuit control unit 130 is integrated into the sampler 110, and uses airflow to cut pure water to generate tiny droplets for extracting metabolites, and pushes them to the automatic sampling system. The automatic displacement device and the transmission mechanism automatically adjust the position of the Raman detection chip 210, so that the droplet samples are automatically and sequentially dripped to different positions of the Raman detection chip 210.

[0100] like Figure 2 and Figure 3 As shown, the sampler 110 disclosed in this embodiment includes a multi-channel micro-droplet generation component, a pressure sensing component and a connection component.

[0101] The multi-channel micro-droplet generation component includes a sampling pen head 1, and the sampling pen head 1 has a sampling end 11 and a connecting end 12, and the sampling end 11 and the connecting end 12 are respectively located at the two ends of the length direction of the sampling pen head 1. Figure 1 In the figure, the sampling end 11 is the lower end of the sampling pen tip 1, and the connecting end 12 is the upper end of the sampling pen tip 1. The sampling pen tip 1 is provided with a liquid channel 2, a gas channel 3 and a recovery channel 4, the lower end of the gas channel 3 (the outlet of the gas channel 3) is connected to the side wall of the liquid channel 2, and the lower end of the liquid channel 2 (the outlet of the liquid channel 2) and the lower end of the recovery channel 4 (the inlet of the recovery channel 4) intersect at the sampling end 11. The upper end of the gas channel 3 (the inlet of the gas channel 3), the upper end of the liquid channel 2 (the inlet of the liquid channel 2) and the upper end of the recovery channel 4 (the outlet of the recovery channel 4) are all provided at the connecting end 12 of the sampling pen tip 1. The multi-channel micro-droplet generation component is composed of at least 3 micro-channels, namely at least 1 liquid channel 2, at least 1 gas channel 3, and at least 1 recovery channel 4.

[0102] In this embodiment, the diameter of the sampling end 11 is smaller than the diameter of the connecting end 12 to reduce interference and facilitate sampling.

[0103] Further, the gas channel 3 is located between the liquid channel 2 and the recovery channel 4. The liquid channel 2 includes a first upper section and a first lower section, the gas channel 3 includes a second upper section and a second lower section, and the recovery channel 4 includes a third upper section and a third lower section. The first upper section, the second upper section and the third upper section are arranged vertically and in parallel along the length direction of the sampling pen tip 1, the lower end of the first lower section (the outlet of the liquid channel 2) and the lower end of the third lower section (the inlet of the recovery channel 4) are close to each other and meet at the sampling end 11 of the sampling pen tip 1, and the lower end of the second lower section (the outlet of the gas channel 3) is connected to the first lower section.

[0104] Furthermore, the sampler also includes a clamp 13, a connecting sleeve 14, a pen holder 15, a pipe joint 16, a liquid conduit, a gas conduit and a recovery conduit.

[0105] The clamp 13 is detachably mounted on the sampling pen tip 1. Therefore, the detachable sampling pen tip can be replaced according to the sample tissue type and sampling accuracy. The clamp 13 is used to lock the liquid channel 2, gas channel 3 and recovery channel 4 reserved in the sampling pen tip 1 and the pipe joint at the connecting sleeve to ensure the sealing effect.

[0106] Both ends of the connecting sleeve 14 are provided with external threads, one end is detachably connected to the clamp 13 by means of threaded connection, and the pen holder 15 is detachably connected to the other end of the connecting sleeve 14 by means of threaded connection.

[0107] The liquid conduit is arranged in the pen barrel 15 and communicated with the liquid channel 2 through a pipe joint. The gas conduit is arranged in the pen barrel and communicated with the gas channel 3 through a pipe joint. The recovery conduit is arranged in the pen barrel and communicated with the recovery channel 4 through a pipe joint. The sealing can be ensured by setting the pipe joint.

[0108] In this embodiment, the sampler further includes a disc 17, a push rod 18 and a pressure sensor 19. The pressure sensor 19 is arranged in the pen barrel and contacts the push rod. One end of the disc 17 is arranged at the connection end of the sampling pen tip, and a through hole is provided for the liquid conduit, the gas conduit and the recovery conduit to pass through. The push rod 18 is fixedly installed on the other end of the disc by screws, that is, the push rod is connected to the sampling pen tip through the bottom disc on one side and contacts the pressure sensor on the other side for pressure transmission and feedback.

[0109] like Figure 4 As shown, in another embodiment, the pressure sensing component is installed at the connecting end 12 of the sampling pen head 1, as shown in FIG. Figure 3 As shown, the pressure sensing assembly includes an upper braking structure, a lower braking structure, an elastic member 102 and a pressure sensor 103 .

[0110] The upper braking structure comprises a first cross bar 6, a first vertical bar 7 and a second cross bar 8 which are connected in sequence.

[0111] The lower braking structure comprises a third cross bar 9, a second vertical bar 10 and a fourth cross bar 101 which are connected in sequence.

[0112] The elastic member 102 connects the lower end of the first crossbar 6 and the upper end of the third crossbar 9 . In this embodiment, the elastic member 102 is a spring, but is not limited thereto.

[0113] The lower end of the third cross bar 9 and the upper end of the second cross bar 8 are arranged opposite to each other, and a gap is maintained between them.

[0114] The pressure sensor 103 is disposed in the gap between the lower end of the third crossbar 9 and the upper end of the second crossbar 8 , and is used to detect the distance of the second crossbar 8 relative to the third crossbar 9 .

[0115] The fourth crossbar 101 is fixed on the structural member. When pressure is applied, the first crossbar 6 is displaced under the pressure, and the second crossbar 8 will be away from the pressure sensor 103. The smaller the pressure applied, the closer the second crossbar 8 is to the pressure sensor 103; the greater the pressure applied, the further the second crossbar 8 is away from the pressure sensor 103.

[0116] Pressure sensors or pressure sensing components can detect and feedback pressure. By setting the normal working pressure value / pressure range and providing indicator lights to indicate normal / abnormal working conditions, the normal sampling of the sampler and the corresponding sampling accuracy can be ensured between different operators, different sampling tissue surfaces, and different sampling points. (The sampling volume accuracy and sampling concentration accuracy are closely related to the sealing of the sampler-tissue surface, which is determined by the pressure applied when the sampler contacts the tissue surface.)

[0117] The pressure feedback indicates the operator's working status and adjusts the normal working pressure range of the sampler to avoid the sampling accuracy being affected by uneven pressure caused by different operators' usage habits, which helps to improve sampling accuracy and sampling repeatability.

[0118] The connecting component includes a connecting rod, a rivet, a knob cover, etc. The connecting component is used to connect the sampling pen head 1 and the pressure sensor component.

[0119] The sampling module of this embodiment also includes a connecting conduit. The connecting conduit is a flexible conduit used to connect the sampler with the microfluidic liquid control unit 120 and the precision gas path control unit 130.

[0120] This embodiment also discloses a method for sampling the surface of a tumor tissue 5. The method for sampling the surface of a tumor tissue 5 comprises the following steps:

[0121] Preparation step: pass the metabolite dilution solution into liquid channel 2, and stop when the liquid level reaches the intersection. At this time, the sampler is in the preparation completion stage.

[0122] Sampling steps: the sampling end 11 of the sampling pen head 1 is brought into contact with the surface of the tumor tissue 5 to be sampled, the metabolite diluent continues to be introduced into the liquid channel 2, and the gas (air) is introduced into the gas channel 3. By controlling the flow rate ratio of the diluent / gas, the quantitative segmentation of the trace droplets is achieved at the intersection of the lower ends of the liquid channel 2 and the gas channel 3; after the droplets are segmented, the liquid channel 2 is kept stable (the pressure can be stable, the pump can be stopped, etc.), and the gas is continued to be introduced into the gas channel 3, and the segmented droplets are pushed to the sampling end 11 where the lower end of the liquid channel 2 (the outlet of the liquid channel 2) contacts the surface of the tumor tissue 5, thereby, the metabolites on the surface of the tumor tissue 5 are dissolved and diffused into the droplets; during the dissolution and diffusion process, the gas channel 3 and the liquid channel 2 remain stationary to ensure that the contact process between the droplets and the surface of the tumor tissue 5 is stationary and stable, and the substances are fully dissolved and diffused into the droplets.

[0123] Collection step: After the dissolution and diffusion are completed, the sampling stage is completed. Continue to introduce gas into the gas channel 3, keep the liquid level in the liquid channel 2 stable, and the sampled droplets enter the recovery channel 4 from the lower end of the recovery channel 4 (the entrance of the recovery channel 4) under the action of the gas pressure. A detection module / equipment can be further added downstream of the recovery channel 4 to perform relevant detection on the metabolites inside the sampled droplets.

[0124] After the sampling process is completed, if it is necessary to clean the inside of the sampler (such as removing the residual liquid inside the channel during the previous sampling process to avoid affecting the metabolite detection of the next sampling point), a cleaning process is required.

[0125] S1: The sampling end 11 of the sampling pen tip 1 contacts a clean surface (sealing surface) (without the influence of the corresponding interfering molecules of metabolites), the metabolite diluent / cleaning liquid is introduced into the liquid channel 2, and the gas is introduced into the gas channel 3 at the same time. By adjusting the liquid flow rate of the liquid channel 2 and the gas flow rate of the gas channel 3, the liquid cannot enter the gas channel 3 at the intersection of the gas / liquid channel, and only enters the recovery channel 4 after contacting the clean surface from below. The downstream of the recovery channel 4 can be connected to a liquid storage tank, etc. to collect the cleaning liquid.

[0126] S2: After cleaning, stop the liquid injection of liquid channel 2, adjust the gas flow rate of gas channel 3, so that the liquid is divided at the intersection of gas / liquid channels, and the liquid below the intersection is pushed by the gas into the recovery channel 4 and finally completely discharged from the sampler. The sampler state returns to the preparation completion stage of the sampling process.

[0127] The sampler and sampling system of this embodiment can realize non-destructive extraction of metabolites and high spatiotemporal resolution extraction of metabolites. Non-destructive extraction of metabolites refers to the contact between the tiny droplets formed by the micro-droplet generation component and the sampling area of ​​the tumor tissue 5. The target metabolites on the surface of the tumor tissue 5 (such as hydrogen protons, glutamate, ammonia, ROS, proteases, etc.) have good water solubility, so the droplets can directly extract the above-mentioned metabolites from the surface of the tumor tissue 5 through diffusion and transport them to the detection system. During the whole process, only the tiny droplets generated by the sampling pen head 1 non-destructively contact the tumor tissue 5 area, and will not cause damage to the tumor tissue 5 to be detected. In this way, rapid online extraction of metabolites on the surface of the tumor tissue 5 is achieved, which can be applied to the next step of the metabolite detection process. High spatiotemporal resolution extraction of metabolites refers to the formation of microliter-level droplets with controllable volume through the micro-droplet generation component. On the one hand, the droplet volume control reduces the contact area between the droplet and the tumor tissue 5 and improves the spatial resolution of the sampling point. On the other hand, it also increases the material transfer performance between the droplet and the metabolites on the surface of the tumor tissue 5, that is, it reduces the mixing time of the droplet and the metabolites (within milliseconds to seconds), achieving high sampling time resolution.

[0128] The sampler and sampling module of this embodiment optimize the sampling droplet segmentation logic by changing the multi-channel gas / liquid structure inside the sampler to ensure that the volume of the micro-droplets formed at each sampling point is not affected by the sampling process and mechanical structure; at the same time, for the application scenario of the real tumor tissue 5, the sampler is equipped with a pressure sensor 103, and the normal working pressure range of the sampler is regulated through pressure feedback to ensure that the working pressure of each sampling point is consistent, thereby ensuring that the diffusion behavior of metabolites on the surface of each tumor tissue 5 is consistent, and finally the metabolite distribution characteristics of the sampling point on the surface of the corresponding tumor tissue 5 are obtained by detecting the metabolite concentration of the sampling droplet.

[0129] The detection module 2 includes a sample loading head, an automatic displacement device, a Raman spectrometer, and a Raman detection chip. The automatic displacement device is used to automatically adjust the position of the Raman detection chip 210 through a driving device and a transmission mechanism. The position of the sample loading head is fixed and connected to the injection channel. A microhole is opened at the bottom of the sample loading head to release the droplets to the surface of the Raman detection chip 210. According to the order of droplets, the detection module 200 automatically focuses the laser through the objective lens to the droplets on the Raman detection chip 210. The excited Raman signal is collected by the same objective lens and then enters the Raman detector. The Raman detector collects the Raman signal of the droplets and processes it through the Raman spectrum intelligent analysis system, automatically identifies the target metabolites, and determines the concentration of each metabolite through the change of the Raman peak ratio.

[0130] like Figure 5As shown, this embodiment discloses a Raman detection chip 210, which includes a Raman substrate and a reporter molecule layer disposed on the upper surface of the gold nanoarray of the Raman substrate, and reporter molecules 4000 are distributed in the reporter molecule layer.

[0131] In this embodiment, the reporter molecules 4000 include, but are not limited to: reporter molecules 4000 for MMP, HClO, pH, GSH, and ROS.

[0132] The Raman substrate includes a silicon wafer 1000 and a gold nanoarray. The Raman substrate with an array structure is the key to improving detection sensitivity, stability and repeatability. The gold nanoarray includes a photocurable prepolymer layer 2000, a chromium film layer 5000 and a gold film layer 3000. The photocurable prepolymer layer 2000 is covered on the upper end of the silicon wafer 1000. The upper surface of the photocurable prepolymer layer 2000 is formed with a plurality of aligned and arrayed protrusions 21000. The protrusions 21000 and the photocurable prepolymer layer 2000 are integrally formed.

[0133] The thickness of the chromium film layer 5000 is 5 nm, and it covers the entire surface of the protrusion 21000 and the portion of the upper surface of the photocurable prepolymer layer 2000 where there is no protrusion 21000. That is, the chromium film layer 5000 is a whole, completely covering the upper surface of the protrusion 21000 and the photocurable prepolymer layer 2000.

[0134] The thickness of the gold film layer 3000 is 10-50 nm, and it covers the upper surface of the chromium film layer 5000 .

[0135] Further, in this embodiment, the size of the silicon wafer 1 is 5 cm×5 cm. The shape of the protrusion 21000 includes but is not limited to: cylindrical, triangular pyramid, and square column. When the protrusion 21000 is cylindrical, the diameter of the cylinder is 50-300 nm and the height is 70-200 nm. When the protrusion 21000 is a triangular pyramid, the side length of the triangular pyramid is 60-300 nm and the height is 100-200 nm. When the protrusion 21000 is a square column, the side length of the square column is 50-300 nm and the height is 100-200 nm.

[0136] Raman detection chip 210 is the core of the target metabolite detection, while reporter molecule 4000 is the key to the rapid and quantitative detection of target metabolites in samples by Raman detection chip. The design of reporter molecule 4000 needs to meet the following conditions: (1) It can be covalently labeled to the surface of gold nanoarray to improve the detection stability and repeatability; (2) The characteristic peaks of different reporter molecules 4 are intertwined and can be accurately identified in the spectrum of complex biological systems; (3) Reporter molecule 4 binds / reacts quickly with the target metabolite, and the characteristic peak of reporter molecule 4 has a ratiometric response characteristic during the binding process; (4) Reporter molecule 4 is highly specific to the target metabolite and will not be interfered by other compounds in the sample and microenvironmental factors.

[0137] The reporter molecule 4000 modified on the surface of the Raman detection chip will specifically identify the target metabolite in the droplet sample, and the binding / reaction between the reporter molecule 4000 and the metabolite will promote the ratio-type change of the characteristic Raman signal of the reporter molecule 4000. The principle of signal change is: the metabolite response reporter molecule 4000 specifically recognizes and binds to the target detection object, causing the charge redistribution within the reporter molecule 4000. The chemical bond charge on the non-conjugated system changes (is affected) less, and its corresponding Raman peak intensity remains unchanged, while the chemical bond charge inside the conjugated system changes significantly (affected to varying degrees), and its Raman peak intensity is also enhanced to varying degrees, and the quantitative detection of metabolites is achieved according to the intensity ratio between the spectral peaks. Therefore, the Raman substrate of this embodiment can achieve high sensitivity and high repeatability detection of target metabolites. The Raman detection chip of this embodiment can achieve rapid and quantitative detection of target metabolites.

[0138] The registration module 300 includes a depth camera 310 and a mask image-based regional convolutional neural network deep learning module 320. The depth camera 310 is used to capture the depth image of the position to be detected on the surgical section and generate a 3D topographic map of the tissue. The mask image-based regional convolutional neural network (Mask R-CNN) deep learning module will track the color mark on the sampling pen head 1 of the sampler 110, record the three-dimensional spatial coordinate information and timing information of the sampling point, and then use the global optimal iterative closest point (Go-ICP) algorithm to fill the multi-metabolite data into the corresponding position in the 3D topographic map according to the timing information, so as to achieve the fusion matching of multiple metabolite distribution maps and the surgical section topographic map.

[0139] The tumor tissue resection guidance device of this embodiment is provided with a sampling module 100, a detection module 200 and a registration module 300 which cooperate with each other, and can realize near real-time detection of intraoperative tissue malignancy, and can help doctors realize more complete resection of tumor tissue, reduce the positive boundary rate, and improve surgical prognosis.

[0140] It should be noted that in the claims and description of this patent, the terms "include", "comprises" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device. In the absence of further restrictions, the elements defined by the sentence "comprises a" do not exclude the existence of other identical elements in the process, method, article or device including the elements.

Claims

1. A tumor tissue resection guidance device, It is characterized in that include: A sampling module, including a sampler, which is used to extract tissue surface metabolites from surgical cut tissue. The sampling module divides the pure water column into tiny droplets and is used to dissolve tissue surface metabolites, and sequentially drips the sample droplets onto different positions of the Raman detection chip; The detection module is used to automatically focus the laser through the objective lens onto the droplets on the Raman detection chip. The excited Raman signal is collected by the same objective lens and then enters the Raman detector. The Raman detector collects the droplet Raman signal and processes it through the Raman spectrum intelligent analysis system to automatically identify the target metabolites and determine the concentration of each metabolite through the change of Raman peak ratio; The registration module includes a depth camera and a regional convolutional neural network deep learning module based on a mask image. The depth camera is used to capture the depth image of the surgical section to be detected and generate a 3D topographic map of the tissue; the regional convolutional neural network deep learning module based on the mask image will track the color mark on the sampling pen tip of the sampler, record the three-dimensional spatial coordinate information and timing information of the sampling point, and fill the multi-metabolite data into the corresponding position in the 3D topographic map according to the timing information, thereby realizing the fusion matching of multiple metabolite distribution maps and the surgical section topographic map.

2. The tumor tissue resection guidance device according to claim 1, It is characterized in that The sampler comprises: A multi-channel micro-droplet generation component comprises a sampling pen tip, wherein one end of the sampling pen tip in the length direction is a sampling end, and the other end is a connecting end. A liquid channel, a gas channel and a recovery channel are provided in the sampling pen tip, the outlet of the gas channel is connected to the liquid channel, and the outlet of the liquid channel and the inlet of the recovery channel intersect at the sampling end.

3. The tumor tissue resection guidance device according to claim 2, It is characterized in that The sampler also includes: A clamp, detachably mounted on the sampling pen tip; A connecting sleeve, one end of which is detachably connected to the clamp; A pen holder, detachably connected to the other end of the connecting sleeve; Pipeline joints; A liquid conduit is disposed in the pen barrel and communicated with the liquid channel through the pipe joint; A gas conduit is disposed in the pen barrel and communicated with the gas channel through the pipe joint; The recovery conduit is arranged in the pen barrel and communicated with the recovery channel through the pipe joint.

4. The tumor tissue resection guidance device according to claim 3, It is characterized in that The sampler also includes: A disc, one end of which is arranged at the connection end of the sampling pen tip and is provided with a through hole for the liquid conduit, the gas conduit and the recovery conduit to pass through; A push rod is mounted on the other end of the disc; The pressure sensor is arranged in the pen barrel and contacts the push rod.

5. The tumor tissue resection guidance device according to claim 3, It is characterized in that The sampler also includes: A pressure sensing assembly is installed at the connecting end, and the pressure sensing assembly includes an upper braking structure, a lower braking structure, an elastic member and a pressure sensor; The upper brake structure comprises a first cross bar, a first vertical bar and a second cross bar connected in sequence; The lower brake structure comprises a third crossbar, a second vertical bar and a fourth crossbar connected in sequence; The elastic member connects the lower end of the first cross bar and the upper end of the third cross bar; The lower end of the third crossbar and the upper end of the second crossbar are arranged opposite to each other and keep a gap; The pressure sensor is disposed at the lower end of the third crossbar and is used to detect the distance between the second crossbar and the third crossbar.

6. The tumor tissue resection guidance device according to claim 5, It is characterized in that The sampler also includes: A connecting component is used to connect the sampling pen head and the pressure sensing component.

7. The tumor tissue resection guidance device according to claim 2, It is characterized in that The gas channel is located between the liquid channel and the recovery channel.

8. The tumor tissue resection guidance device according to claim 2, It is characterized in that The liquid channel comprises a first upper section and a first lower section; The gas channel includes a second upper section and a second lower section; The recovery channel includes a third upper section and a third lower section; The first upper section, the second upper section and the third upper section are arranged in parallel along the length direction of the sampling pen tip; The lower end of the first lower section and the lower end of the third lower section are close to each other and intersect; The lower end of the second lower section is communicated with the first lower section.

9. The tumor tissue resection guidance device according to claim 2, It is characterized in that The diameter of the sampling end is smaller than the diameter of the connecting end.

10. The tumor tissue resection guiding device according to claim 2, It is characterized in that The sampling module also includes a microfluidic liquid control unit, which pushes pure water into the sampler in a controllable manner of flow rate and flow velocity. The pure water contacts the surgical section tissue at the sampling end of the sampling pen tip of the sampler and extracts metabolites from the tissue surface.

11. The tumor tissue resection guiding device according to claim 10, It is characterized in that The sampling module also includes a precise gas path control unit, which is integrated in the sampler and generates tiny droplets for extracting metabolites by cutting pure water through airflow.

12. The tumor tissue resection guiding device according to claim 1, It is characterized in that The detection module includes a sample loading head, an automatic displacement device, a Raman spectrometer, and a Raman detection chip. The automatic displacement device is used to automatically adjust the position of the Raman detection chip through a driving device and a transmission mechanism. The sample loading head is fixed and connected to a sampling channel. A microhole is opened at the bottom of the sample loading head to release droplets onto the surface of the Raman detection chip.

13. The tumor tissue resection guiding device according to claim 12, It is characterized in that The Raman detection chip comprises: Silicon wafer; A gold nanoarray, comprising a photocurable prepolymer layer, a chromium film layer and a gold film layer, wherein the photocurable prepolymer layer is coated on the upper end of the silicon wafer, a plurality of convex portions arranged in an aligned array are formed on the upper surface of the photocurable prepolymer layer, the chromium film layer is coated on the surface of the convex portions and the upper surface of the photocurable prepolymer layer; and the gold film layer is coated on the upper surface of the chromium film layer; The reporter molecule layer is arranged on the upper surface of the gold film layer, and reporter molecules are distributed in the reporter molecule layer.

14. The tumor tissue resection guiding device according to claim 13, It is characterized in that The reporter molecules include, but are not limited to, reporter molecules for MMP, HClO, pH, GSH, and ROS.

15. The tumor tissue resection guiding device according to claim 13, It is characterized in that The shape of the protrusion includes but is not limited to: cylindrical, triangular pyramid, and square column.

16. The tumor tissue resection guiding device according to claim 1, It is characterized in that The registration module uses a global optimal iterative closest point algorithm to fill the multi-metabolite data into the corresponding positions in the 3D topographic map according to the time series information.

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