Tumor tissue resection-guiding device

Abstract

Provided is a tumor tissue resection-guiding device, comprising a sampling assembly (100) configured for collecting a sample from a tissue surface, a detecting assembly (200) configured for detecting a biomarker in the sample, and a mapping assembly (300) configured for integrating a detection result of the biomarker to an image of the tissue surface.

Description

Tumor tissue resection guidance device

[0001] Cross-reference to related applications

[0002] This application claims priority and rights to the Chinese patent application filed with the China Patent Office on November 22, 2023, with application number 202311560872.9, and invention name “Tumor Tissue Resection Guidance Device”, all contents of which are incorporated herein by reference. Technical Field

[0003] The present invention relates to the technical field of medical devices, and in particular to a tumor tissue resection guidance device. Background Art

[0004] Solid tumors are defined as tangible tumors—masses that can be detected visually, palpably, or through clinical imaging. Surgical resection is the preferred treatment option for solid tumors, with the goal of achieving complete excision of the cancerous tissue. However, due to the invasive growth of cancer cells, accurate intraoperative identification of tumor boundaries can be difficult, making complete resection challenging.

[0005] Imaging techniques such as magnetic resonance imaging (MRI), computed tomography (CT), and ultrasound (US) are the primary means of clinically localizing solid tumors. These techniques pinpoint tumors based on structural abnormalities such as sclerosis, edema, and calcification. Compared to the tumor parenchyma, areas of cancer cell infiltration often lack significant structural changes, making them difficult to accurately locate using structural imaging techniques like MRI.

[0006] Metabolic reprogramming is a common hallmark of all tumors. It refers to the readjustment of the direction and flow of nutrients in the metabolic network. Its purpose is to meet the energy and material needs of cancer cells and support their proliferation, invasion and metastasis. The study of Faubert et al. (Faubert, B., A. Solmonson and RJ DeBerardinis, Metabolic reprogramming and cancer progression. Science, 2020. 368 (6487): p. eaaw5473) shows that metabolic phenotype changes occur in the lesion area during precancerous lesions, cancer infiltration and metastasis. The study of Reinfeld et al. (Reinfeld, BI, et al., Cell-programmed nutrient partitioning in the tumour microenvironment. Nature, 2021. 593 (7858): p. 282-288) shows that in the process of invasion of various tumors, the main way for cancer cells to obtain energy is transferred from glucose metabolism to glutamine metabolism. Glutamine metabolism can help cancer cells maintain their proliferation and acquire drug resistance in nutrient-deficient microenvironments. Tumor-associated protease activity can also increase or decrease. This metabolic reprogramming leads to significant changes in the types, concentrations, and spatial distribution of biomarkers during cancer cell invasion. Summary of the Invention

[0007] The present disclosure provides a tumor tissue resection guidance device, comprising:

[0008] A sampling assembly comprising a gas-liquid control unit, a transmission conduit, and a sampling pen fluidically connected to the gas-liquid control unit via the transmission conduit, wherein the gas-liquid control unit is configured to eject a liquid flow and / or an air flow through a pen tip of the sampling pen, wherein the sampling pen is provided with a recovery channel for extracting a sample, and the sampling pen is also provided with a positioning mark;

[0009] a detection assembly comprising a sample injector, a surface enhanced Raman scattering (SERS) array chip, a Raman probe, a laser, and a spectrometer, wherein the sample injector is fluidically connected to a recovery channel of the sampling pen to receive a sample, the SERS array chip comprises a plurality of detection sites arranged in an array, and the sample injector is configured to titrate the sample onto the detection sites, the Raman probe is configured to irradiate the sample on the detection sites with laser light from the laser and acquire the generated Raman scattered light, and the spectrometer is configured to detect the Raman scattered light and generate a detection result of a biomarker; and

[0010] The positioning component includes a depth camera and a processing unit, wherein the depth camera is configured to capture an RGB image, a depth image, and timing information of the positioning mark of the surgical section, and the processing unit is configured to fuse the detection results of the biomarkers of the sample into the RGB image and the depth image based on the timing information.

[0011] In some embodiments, the sampling pen is further provided with a liquid channel and a gas channel;

[0012] wherein the end opening of the gas channel terminates at the end section of the liquid channel, so that the gas flowing through the gas channel enters the end section of the liquid channel, and

[0013] Wherein, the end opening of the liquid channel and the end opening of the recovery channel at least partially intersect in the end surface of the pen tip.

[0014] In some embodiments, a liquid reservoir and a microchannel located downstream of the liquid reservoir are provided in the liquid channel.

[0015] In some embodiments, the gas-liquid control unit comprises:

[0016] Pressure controller;

[0017] a fluid reservoir fluidly connected to the pressure controller; and

[0018] a flow monitoring unit fluidly connected to the liquid storage tank;

[0019] The flow monitoring unit is connected to the liquid channel fluid of the sampling pen via the transmission conduit, and the pressure controller is connected to the gas channel fluid of the sampling pen via the transmission conduit.

[0020] In some embodiments, the pressure controller comprises:

[0021] control unit;

[0022] a pressure source in communication with the control unit; and

[0023] a pressure monitoring unit in communication with the control unit and in fluid connection with the pressure source;

[0024] Wherein, the liquid storage tank is fluidically connected to the pressure monitoring unit.

[0025] In some embodiments, the detection assembly further comprises a stage on which the SERS array chip is disposed, wherein the stage is configured to be movable in three dimensions.

[0026] In some embodiments, the SERS array chip comprises:

[0027] silicon wafers;

[0028] 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 surface of the silicon wafer, the photocurable prepolymer layer is formed with a plurality of protrusions arranged in an array, the chromium film layer is coated on the upper surface of the photocurable prepolymer layer, and the gold film layer is coated on the upper surface of the chromium film layer; and

[0029] a reporter molecule layer, disposed on the upper surface of the gold film layer, wherein reporter molecules are distributed in the reporter molecule layer;

[0030] Wherein, the detection site is formed on the protrusion.

[0031] In some embodiments, the shape of the protrusion includes but is not limited to: cylinder, triangular pyramid, and square column.

[0032] In some embodiments, the processing unit of the positioning component is configured to generate a 3D topographic map of the surgical section based on the depth image, and use a global optimal iterative closest point algorithm to fill the detection results of the biomarkers into the corresponding positions in the 3D topographic map based on the timing information.

[0033] In some embodiments, the detection result of the biomarker includes the concentration information of the biomarker.

[0034] In some embodiments, the biomarker is selected from the group consisting of pH, 2-hydroxyglutarate, arginine, reactive oxygen species level, matrix metalloproteinase activity, prostate specific antigen enzyme activity, and the like. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] The features, embodiments, and advantages of the present disclosure will be better understood when the following detailed description is read with reference to the accompanying drawings.

[0036] FIG1 is a schematic structural block diagram of a tumor tissue resection guidance device according to an exemplary embodiment;

[0037] FIG2 is a schematic structural block diagram of a sampling assembly according to an exemplary embodiment;

[0038] FIG3 is a schematic structural diagram of a sampling pen according to an exemplary embodiment;

[0039] FIG4 is a schematic cross-sectional view of a sampling pen according to an exemplary embodiment;

[0040] FIG5 is a schematic structural block diagram of a detection component according to an exemplary embodiment;

[0041] FIG6 is a schematic perspective view of a Raman detection chip according to an exemplary embodiment;

[0042] FIG7 is a schematic cross-sectional view of a Raman detection chip according to an exemplary embodiment;

[0043] FIG8 is a schematic structural block diagram of a positioning component according to an exemplary embodiment. DETAILED DESCRIPTION

[0044] The following will be combined with the accompanying 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 embodiments described 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 in no way 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 making creative efforts are within the scope of protection of the present invention.

[0045] As shown in FIG1 , this embodiment discloses a tumor tissue resection guidance device, which includes a sampling component 100, a detection component 200, and a positioning component 300. The sampling component 100 is configured to obtain a sample from the surface of tumor tissue, such as an aqueous solution containing dissolved biomarkers, and transmit the sample to the detection component 200. The detection component 200 is configured to perform Raman detection on the sample, identify and measure the biomarker detection results in the sample, such as biomarker concentration information. The positioning component 300 is configured to fuse the detection result information into the image of the surgical section, thereby indicating the tumor boundary to the operator, such as the surgeon.

[0046] 2 , which shows the gas / liquid passage of the sampling assembly 100 , which includes a gas / liquid control unit 110 , a transmission conduit 120 , and a sampling pen 130 fluidly connected to the gas / liquid control unit 110 via the transmission conduit 120 .

[0047] The gas-liquid control unit 110 is configured to generate a continuous liquid flow required for sampling, such as a pure water flow and an air flow required for cutting sampling droplets, and is connected to the sampling pen 130 via the transmission conduit 120 .

[0048] The gas-liquid control unit 110 may include a pressure controller 111 , a liquid storage tank 112 fluidically connected to the pressure controller 111 , and a flow monitoring unit 113 fluidly connected to the liquid storage tank 112 .

[0049] The pressure controller 111 may include a control unit 1113, a pressure source 1111 in communication with the control unit 1113, and a pressure monitoring unit 1112 in communication with the control unit 1113 and in fluid connection with the pressure source 1111. The pressure controller 111 is configured to supply pressurized air. For example, the pressure controller 111 may be configured to supply pressurized air to the liquid reservoir 112 and may directly supply pressurized air to the sampling pen 130.

[0050] The pressure source 1111 is configured to provide pressurized air, and may be implemented as any suitable type of pressure pump, or as a connector or valve connected to an external pressure gas source.

[0051] The liquid reservoir 112 can be implemented as any suitable sealed container that can store a liquid, such as pure water. The liquid reservoir 112 is fluidically connected to the pressure monitoring unit 1112 and receives compressed air from the pressure monitoring unit 1112. The liquid stored in the liquid reservoir 112 is pressurized by the pressurized air and supplied to the sampling pen 130 via the transmission conduit 120 under the control of the flow monitoring unit 113.

[0052] The pressure monitoring unit 1112 measures the pressure value of the pressurized air supplied by the pressure source 1111 and transmits the pressure value to the control unit 1113 .

[0053] The flow monitoring unit 113 may be implemented as a suitable flow meter, which monitors the pressure value of the pressurized liquid flow supplied by the gas-liquid control unit 110 and transmits the pressure value to the control unit 1113 .

[0054] The control unit 1113 includes electronic devices, such as one or more microprocessors, memory (e.g., RAM, ROM, etc.) that stores computer-readable instructions (i.e., software programs) executed by the microprocessors, and other suitable components. The microprocessor may include a general-purpose microprocessor, such as a The microprocessor provided by Freescale Semiconductor and others operates under the control of software stored in the associated memory. The software executed by the control unit 1113 can be parameterized according to experimental requirements.

[0055] Control unit 1113 controls pressure source 1111 to generate gas pressure, which then enters liquid storage tank 112 through pressure monitoring unit 1112, forcing pure water from liquid storage tank 112 to flow monitoring unit 113. The pure water then enters sampling pen 130 through transmission conduit 120. At the tip 132 of sampling pen 130, the pure water forms droplets containing dissolved biomarkers on the surface of tumor tissue. Simultaneously, control unit 1113 controls pressure source 1111 to generate the airflow required to cut sample droplets and enter sampling pen 130. The flow monitoring unit 113 and pressure monitoring unit 1112 provide input to control unit 1113 via a feedback path for precise feedback regulation.

[0056] 3 , which shows a schematic structural diagram of the sampling pen 130 .

[0057] The sampling pen 130 may include a pen body 131 and a pen tip 132 that is optionally detachably connected to the pen body 131. The pen body 131 may be designed in a cylindrical shape. The pen tip 132 may be designed in a conical shape that tapers to a pointed end. The overall shape of the sampling pen 130 may be similar to a ballpoint pen for easy grip. A positioning mark may be provided on the sampling pen 130. The positioning mark may be configured, for example, to be provided on the uppermost portion of the sampling pen 130, or to be provided on the pen tip 132, or a color mark 1321 or an infrared reflective ball, such as a color band formed on the circumference of the pen tip 132.

[0058] 4 , the sampling pen 130 may be provided with a liquid channel 130a for delivering liquid (e.g., pure water) to the pen tip 132 , a gas channel 130b for delivering gas to cut a sample (e.g., in the form of droplets) containing dissolved biomarkers, and a recovery channel 130c for extracting the sample and removing the droplets from the pen body 131 .

[0059] The liquid channel 130a is fluidically connected to the flow monitoring unit 113 to receive pressurized liquid; the gas channel 130b is fluidically connected to the pressure monitoring unit 1112 to receive pressurized air.

[0060] The liquid channel 130a is provided with a liquid reservoir 133 and a microchannel 134 located downstream of the liquid reservoir 133. As shown in Figure 4, the microchannel 134 can be arranged in an S shape. The liquid reservoir 133 is used to store liquid, and the microchannel 134 is used to accurately control the flow rate and flow rate of the liquid in the liquid channel 130a. The microchannel 134 can have a characteristic size ranging from tens of microns to hundreds of microns. By adjusting the pressure of the pressure source 1111 by the control unit 1113, the flow rate in each branch (including the liquid channel 130a and the gas channel 130b) can be controlled.

[0061] As shown in Figure 4, the end opening of the gas channel 130b terminates at the end section of the liquid channel 130a, allowing the gas flowing through the gas channel 130b to enter the end section of the liquid channel 130a to cut the droplet 500. After being cut, the droplet 500 contacts the tissue surface 400 again, preventing dissolved biomarkers from flowing back and contaminating the upstream liquid during contact, thereby making the detection results more accurate. On the other hand, the cutting of the droplet is completed in the channel, rather than when it contacts the tissue surface 400. This allows for more thorough cutting of the droplet 500, more precise control of the droplet 500 volume, and less interference with the detection.

[0062] The end opening of the liquid channel 130a and the end opening of the recovery channel 130c at least partially intersect at the end surface of the pen tip 132, so that the liquid channel 130a, the gas channel 130b, and the recovery channel 130c intersect at the pen tip 132 to form a micro-liquid reservoir. This reservoir can accommodate a droplet 500. The droplet 500 contacts the surface of the tissue to be detected 400. Because many biomarkers on the surface of tumor tissue (hydrogen protons, amino acids, ROS, proteases, etc.) have good water solubility, they can be incorporated into the droplet. The contact time of the droplet 500 with the infiltrated tissue surface 400 can be controlled by adjusting the air intake time.

[0063] During operation, after opening the gas channel 130b, gas enters the liquid reservoir and cuts the droplet 500, thereby forming a micro-droplet 500 containing dissolved tissue biomarkers. Simultaneously, the recovery channel 130c is opened, and the droplet 500 is transported by airflow to the subsequent detection assembly 200 for analysis. The sampling pen 130 can then be removed from the tissue surface 400 to perform the airflow cleaning step.

[0064] In particular, the transmission conduit 120 is implemented as a flexible conduit and may accordingly include a plurality of channels to be respectively connected to respective channels in the sampling pen 130 .

[0065] The sampling pen and sampling assembly according to the exemplary embodiments of the present disclosure can achieve non-destructive and high-temporal-resolution extraction of biomarkers. Non-destructive biomarker extraction refers to the contact of tiny droplets formed by the microdroplet generation assembly with the sampling area on the tumor tissue surface 400. Many biomarkers on the tumor tissue surface 400 (such as pH, 2-hydroxyglutaric acid, arginine, reactive oxygen species, matrix metalloproteinases, prostate-specific antigen enzymes, etc.) have good water solubility. Therefore, the droplets can directly extract these biomarkers from the tumor tissue surface 400 through diffusion and transport them to the detection assembly. Throughout the entire process, only the tiny droplets generated by the pen tip 132 non-destructively contact the tumor tissue surface 400 area, causing no damage to the tumor tissue surface 400 to be tested. In this way, rapid online extraction of biomarkers from the tumor tissue surface 400 is achieved, which can be applied to the next step of the biomarker detection process. High-temporal-resolution biomarker extraction refers to the formation of microliter-scale droplets with controllable volume by the microdroplet generation assembly. On the one hand, droplet volume control reduces the contact area between the droplet 500 and the tumor tissue surface 400, thereby improving the spatial resolution of the sampling point. On the other hand, it also increases the material transfer performance between the droplet and the biomarker on the tumor tissue surface 400, that is, it reduces the mixing time of the droplet and the biomarker (within the millisecond to second level), thereby achieving high sampling time resolution.

[0066] 5 , which shows a schematic structural block diagram of the detection component 200 .

[0067] The detection assembly 200 includes a sample injector 210 , a surface enhanced Raman scattering (SERS) array chip 220 , a Raman probe 230 , a laser 240 , a spectrometer 250 and a stage 260 .

[0068] The sample injector 210 can be configured to be fixedly arranged in the monitoring assembly 200. The sample injector 210 is fluidically connected to the recovery channel 130c of the sampling pen 130 to receive the sample. The bottom of the sample injector 210 can be provided with a microwell through which the sample droplets can be released onto the surface of the SERS array chip 220.

[0069] The SERS array chip 220 includes a plurality of detection sites 221 arranged in an array, and the sample injector 210 is configured to drop the sample onto the detection sites 221 , referring to FIG. 6 and FIG. 7 .

[0070] The Raman probe 230 is configured to irradiate the sample on the detection site 221 with laser light from the laser 240 and acquire the generated Raman scattered light.

[0071] The spectrometer 250 is configured to detect the Raman scattered light and generate a detection result of the biomarker.

[0072] The stage 260 is configured to carry the SERS array chip 22 and move in three dimensions. Specifically, the stage 260 may include an automatic displacement device, which includes a driving device and a transmission mechanism, for automatically adjusting the position of the SERS array chip 220 .

[0073] The SERS array chip 220 is described in detail with reference to FIG6 and FIG7 . The SERS array chip 220 may include a Raman substrate 222 and a reporter molecule layer 225 disposed on the upper surface of a gold nanoarray 223 of the Raman substrate 222 . Reporter molecules are distributed in the reporter molecule layer 225 .

[0074] Examples of reporter molecules may include, but are not limited to, those for pH (see Jin Z, Yue Q, Duan W, et al. Intelligent SERS navigation system guiding brain tumor surgery by intraoperatively delineating the metabolic acidosis [J]. Advanced Science, 2022, 9(7): 2104935.), 2-hydroxyglutarate, arginine (see Wang X, Yu J, Shi Y, et al. A new fluorescent probe with large Stokes shift for selective and sensitive detection of arginine [J]. Journal of Photochemistry and Photobiology A: Chemistry, 2025, 458: 115942; and Adam KM, Huang TT, Guan WL, et al. Novel synergistic effect-based fluorescent sensor for highly selective and sensitive detection of l-Arg [J]. Journal of Molecular Liquids, 2024: 125283.), reactive oxygen species levels (see Cui K, Fan C, Chen G, et al. al.para-Aminothiophenol radical reaction-functionalized gold nanoprobe for one-to-all detection of five reactive oxygen species in vivo[J].Analytical chemistry, 2018,90(20):12137-12144.), matrix metalloproteinase activity (see Liu X, Gu J, Wang J, et al. Cell Membrane-Anchored SERS Biosensor for the Monitoring of Cell-Secreted MMP-9 during Cell–Cell Communication[J].ACS sensors,2023,8(11):4307-4314.), reporter molecules for prostate-specific antigen enzyme activity, etc.

[0075] The Raman substrate 222 includes a silicon wafer 224 and a gold nanoparticle array 223. The arrayed Raman substrate 222 is key to improving detection sensitivity, stability, and repeatability. The gold nanoparticle array 223 comprises a photocurable prepolymer layer 2231, a chromium film layer 2232, and a gold film layer 2233. The photocurable prepolymer layer 2231 is overlaid on the top of the silicon wafer 224 and is formed with a plurality of aligned and arrayed protrusions 226. The protrusions 226 and the photocurable prepolymer layer 2231 are integrally formed.

[0076] The thickness of the chromium film layer 2232 is 5 nm, and it covers the entire surface of the protrusion 226 and the part of the upper surface of the photocurable prepolymer layer 2231 without the protrusion 226, that is, the chromium film layer 2232 is a whole, completely covering the protrusion 226 and the upper surface of the photocurable prepolymer layer 2231.

[0077] The thickness of the gold film layer 2233 may be 10 to 50 nm, and it covers the upper surface of the chromium film layer 2232 .

[0078] The upper surface of the gold nanoarray 223 forms the detection site 221 .

[0079] As an example, the dimensions of silicon wafer 224 may be 5 cm x 5 cm. The shapes of protrusions 226 may include, but are not limited to, cylindrical, triangular pyramidal, and square pillar-shaped. When protrusions 226 are cylindrical, the diameter of the cylinder is 50 to 300 nm and the height is 70 to 200 nm. When protrusions 226 are triangular pyramidal, the side length of the triangular pyramid is 60 to 300 nm and the height is 100 to 200 nm. When protrusions 226 are square pillar-shaped, the side length of the square pillar is 50 to 300 nm and the height is 100 to 200 nm.

[0080] The SERS array chip 220 is the core of the target biomarker detection, while the reporter molecule 4000 is the key to the rapid and quantitative detection of target biomarkers in samples by the Raman detection chip. The design of the reporter molecule 4000 needs to meet the following conditions: (1) It can be labeled on the surface of the gold nanoarray in the form of covalent bonds or near-covalent bond energies to improve detection stability and repeatability; (2) The characteristic peaks of different reporter molecules intersect with each other and can be accurately identified in the spectrum of complex biological systems; (3) The reporter molecules bind / react quickly with the target biomarker, and the characteristic peaks of the reporter molecules during the binding process have a ratiometric response characteristic; (4) The reporter molecules are highly specific to the target biomarker and will not be interfered with by other compounds in the sample or microenvironmental factors.

[0081] The reporter molecules modified on the surface of the Raman detection chip will specifically identify the target biomarkers in the droplet sample, and the binding / reaction between the reporter molecules and the biomarkers will promote the ratiometric change of the characteristic Raman signal of the reporter molecule 4000. The principle of the signal change is: the biomarker response reporter molecule specifically recognizes and binds to the target detection object, causing various chemical changes such as changes in the electronic energy levels of the chemical bonds in the reporter molecule, the addition or breakage of chemical bonds, or changes in the distance of the signal group relative to the enhancement substrate, which are then reflected as changes in the ratio of different peak intensities on the Raman spectrum. Quantitative detection of biomarkers is achieved based on the intensity ratio between the spectral peaks. Therefore, the Raman substrate according to the present disclosure can achieve high-sensitivity and high-repeatability detection of target biomarkers. The Raman detection chip according to the present disclosure can achieve rapid and quantitative detection of target biomarkers.

[0082] Specifically, during operation, the detection assembly 200 automatically focuses the laser through the objective lens onto the droplets on the SERS array chip 220 in the order of droplets. The excited Raman signals are collected by the same objective lens and then enter the Raman probe 230. The Raman probe 230 collects the droplet Raman signals and processes them through the Raman spectrometer 250, automatically identifying the target biomarkers and measuring the concentration of each biomarker through the change in the Raman peak ratio.

[0083] 8 , the positioning component 300 may include a depth camera 310 and a processing unit 320 .

[0084] The depth camera 310 is configured to capture an RGB image of the surgical section, a depth image, and timing information of the positioning marker 1321. The depth camera 310 can generate a 3D topographic map of the surgical section using the depth image.

[0085] The processing unit 320 is configured to fuse the detection results of the sample biomarkers into the RGB image and the depth image according to the time series information.

[0086] The processing unit 320 includes electronic devices, such as one or more microprocessors, memory (e.g., RAM, ROM, etc.) that stores computer-readable instructions (i.e., software programs) executed by the microprocessors, and other suitable components. The microprocessor may include a general-purpose microprocessor, such as a A microprocessor provided by Freescale Semiconductor and others that operates under the control of software stored in associated memory.

[0087] For example, the processing unit 320 may include a Mask R-CNN deep learning module, which tracks the positioning markers on the pen tip 132 and records the three-dimensional spatial coordinate information and timing information of the sampling points. The processing unit 320 may then employ a global optimal iterative closest point (Go-ICP) algorithm to populate the multi-biomarker data into the corresponding locations in the 3D topographic map based on the timing information, ultimately achieving a fusion match between the multiple biomarker distribution maps and the surgical section topography map.

[0088] According to the tumor tissue resection guidance device disclosed in the present invention, the sampling component 100, the detection component 200 and the positioning component 300 are provided to cooperate with each other, which can realize near real-time detection of tissue malignancy during surgery, and can help doctors achieve more complete resection of tumor tissue, reduce the positive boundary rate, and improve surgical prognosis.

[0089] The sampling pen 130 of the tumor tissue resection guidance device according to the present disclosure can be operated according to the following steps:

[0090] Preparation step: The biomarker diluent (such as pure water) is passed into the liquid channel 130a, and the flow stops when the liquid level reaches the intersection. At this time, the sampling pen 130 is in the preparation completion stage.

[0091] Sampling step: The sampling end of the pen tip 132 is brought into contact with the surface 400 of the tumor tissue to be sampled, the biomarker diluent continues to flow into the liquid channel 130a, and the gas (air) is simultaneously flowed into the gas channel 130b. By controlling the flow rate ratio of the diluent / gas, the micro-droplets are quantitatively segmented at the intersection of the lower ends of the liquid channel 130a and the gas channel 130b. After the droplets are segmented, the liquid channel 130a is kept stable (the pressure can be stable, the pump can be stopped, etc.), and the sample is continued. Gas is introduced into the gas channel 130b to push the divided droplets to the sampling end where the lower end of the liquid channel 130a (the outlet of the liquid channel 130a) contacts the tumor tissue surface 400. As a result, the biomarkers on the tumor tissue surface 400 are dissolved and diffused into the droplets. During the dissolution and diffusion process, the gas channel 130b and the liquid channel 130a remain stationary, ensuring that the contact process between the droplets and the tumor tissue surface 400 is stationary and stable, and the substances are fully dissolved and diffused into the droplets.

[0092] Collection Step: After dissolution and diffusion are complete, the sampling phase is complete. Gas continues to flow through gas channel 130b, while the liquid level in liquid channel 130a remains stable. Under the influence of gas pressure, sample droplets flow from the lower end of recovery channel 130c (the inlet of recovery channel 130c) into recovery channel 130c. Recovery channel 130c is connected to a monitoring component to detect biomarkers within the sample droplets.

[0093] After the sampling process is completed, if the inside of the sampling pen needs to be cleaned (such as removing the residual liquid inside the channel during the previous sampling process to avoid affecting the biomarker detection of the next sampling point), a cleaning process is required.

[0094] S1: The sampling end of the pen tip 132 contacts a clean surface (sealing surface) (without the influence of interfering molecules corresponding to the biomarker), and the biomarker diluent / cleaning liquid is introduced into the liquid channel 130a, while the gas channel 130b is introduced into the gas channel 130b. By adjusting the liquid flow rate in the liquid channel 130a and the gas flow rate in the gas channel 130b, the liquid cannot enter the gas channel 130b at the intersection of the gas / liquid channels, but only enters the recovery channel 130c after contacting the clean surface below. The downstream of the recovery channel 130c can be connected to a liquid storage tank, etc. to collect the cleaning liquid.

[0095] S2: After cleaning is completed, stop the liquid injection of the liquid channel 130a, adjust the gas flow rate of the gas channel 130b, so that the liquid is divided at the intersection of the gas / liquid channels, and the liquid below the intersection is pushed by the gas into the recovery channel 130c, and is finally completely removed from the sampling pen. The state of the sampling pen 130 returns to the preparation completion stage of the sampling process.

[0096] It should be noted that in the claims and description of this patent, the terms "comprises," "includes," or any other variations thereof are intended to cover non-exclusive inclusion, so that a process, method, article, or apparatus comprising a series of elements includes not only those elements, but also other elements not explicitly listed, or elements inherent to such process, method, article, or apparatus. In the absence of further limitations, an element defined by the phrase "comprising a" does not exclude the presence of other identical elements in the process, method, article, or apparatus comprising the element.

Claims

1. A tumor tissue resection guidance device, characterized in that: include: A sampling assembly, comprising a gas-liquid control unit, a transmission conduit, and a sampling pen connected to the gas-liquid control unit via the transmission conduit, wherein the gas-liquid control unit is configured to eject a liquid flow and / or an air flow via a pen tip of the sampling pen, wherein the sampling pen is provided with a recovery channel for extracting a sample, and the sampling pen is also provided with a positioning mark; A detection component, comprising an injector, a surface enhanced Raman scattering (SERS) array chip, a Raman probe, a laser and a spectrometer, wherein the injector is fluidically connected to a recovery channel of the sampling pen to receive a sample, the SERS array chip comprises a plurality of detection sites arranged in an array, and the injector is configured to titrate the sample on the detection site, the Raman probe is configured to irradiate the sample on the detection site with laser light from the laser and acquire the generated Raman scattered light, and the spectrometer is configured to detect the Raman scattered light and generate a detection result of a biomarker; and A positioning component includes a depth camera and a processing unit, wherein the depth camera is configured to capture an RGB image of a surgical section, a depth image, and timing information of the positioning mark, and the processing unit is configured to fuse the detection results of the biomarkers of the sample into the RGB image and the depth image based on the timing information.

2. The tumor tissue resection guidance device according to claim 1, characterized in that: The sampling pen is also provided with a liquid channel and a gas channel; wherein the end opening of the gas channel terminates at the end section of the liquid channel, so that the gas flowing through the gas channel enters the end section of the liquid channel, and Wherein, the end opening of the liquid channel and the end opening of the recovery channel at least partially intersect in the end surface of the pen tip.

3. The tumor tissue resection guidance device according to claim 2, characterized in that: The liquid channel is provided with a liquid storage tank and a microchannel located downstream of the liquid storage tank.

4. The tumor tissue resection guidance device according to any one of claims 2 to 3, characterized in that: The gas-liquid control unit comprises: Pressure controller; a fluid reservoir fluidly connected to the pressure controller; and a flow monitoring unit connected to the fluid storage tank; Wherein, the flow monitoring unit is connected to the liquid channel fluid of the sampling pen via the transmission conduit, and the pressure controller is connected to the gas channel fluid of the sampling pen via the transmission conduit.

5. The tumor tissue resection guidance device according to claim 4, characterized in that: The pressure controller comprises: Control unit; a pressure source in communication with the control unit; and a pressure monitoring unit in communication with the control unit and in fluid connection with the pressure source; Wherein, the liquid storage tank is fluidically connected to the pressure monitoring unit.

6. The tumor tissue resection guidance device according to any one of claims 1 to 5, characterized in that: The detection component also includes a stage on which the SERS array chip is arranged, wherein the stage is configured to be movable in three dimensions.

7. The tumor tissue resection guidance device according to any one of claims 1 to 6, characterized in that: The SERS array 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 surface of the silicon wafer, the photocurable prepolymer layer is formed with a plurality of protrusions arranged in an array, the chromium film layer is coated on the upper surface of the photocurable prepolymer layer, and the gold film layer is coated on the upper surface of the chromium film layer; and A reporter molecule layer is disposed on the upper surface of the gold film layer, and reporter molecules are distributed in the reporter molecule layer; Wherein, the detection site is formed on the protrusion.

8. The tumor tissue resection guidance device according to claim 7, characterized in that: The shape of the protrusion includes but is not limited to: cylindrical, triangular pyramid, and square column.

9. The tumor tissue resection guidance device according to any one of claims 1 to 8, characterized in that: The processing unit of the positioning component is configured to generate a 3D topographic map of the surgical section based on the depth image, and use a global optimal iterative closest point algorithm to fill the detection results of the biomarkers into corresponding positions in the 3D topographic map based on the timing information.

10. The tumor tissue resection guidance device according to any one of claims 1 to 9, characterized in that: The detection result of the biomarker includes the concentration information of the biomarker.

11. The tumor tissue resection guiding device according to any one of claims 1 to 10, characterized in that: The biomarker is selected from the group consisting of pH, 2-hydroxyglutarate, arginine, reactive oxygen species level, matrix metalloproteinase activity, prostate specific antigen enzyme activity, and the like.

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