Sampler and sampling method for collecting biological molecules on tissue surface

Abstract

The invention provides a sampler and a sampling method for collecting biological molecules on the surface of tissue, the sampler is provided with a sampling direction, the sampler comprises a main body, the main body is provided with an arc-shaped track, the center of the arc-shaped track corresponds to the center of the main body, and the sampling direction of the main body is equal to that of the arc-shaped track in one length direction of the track. And the radius of the arc-shaped track is gradually increased or decreased. According to the sampler for collecting the biological molecules on the surface of the tissue, a plurality of sampling needles are arranged, a sampling liquid drop corresponding to a sampling center can be formed and maintained among the output ends of the plurality of sampling needles, and a non-embedded sampling mode is realized through contact between the liquid drop and the surface of the biological tissue; the damage to the integrity of key biomolecules possibly caused by a traditional method is avoided, the acquisition of high-fidelity biomolecules is facilitated, and the sampler can reduce physical disturbance and mechanical damage to fragile tissues to the maximum extent.

Description

Technical Field

[0001] The present invention relates to the technical field of biomolecule sampling, and in particular to a sampler and a sampling method for collecting biomolecules on a tissue surface. Background Art

[0002] With the continuous advancement of modern medicine and life science research, especially in the fields of molecular biology, pathology, and precision medicine, which are moving towards a more microscopic scale, biomolecule sampling technology has become a crucial front-end link in understanding the mechanisms of life activities and conducting pathological diagnosis research. In particular, with the rapid development of minimally invasive diagnostic and treatment technologies, the demand for in-situ collection and real-time analysis of biomolecules on the surfaces of biological tissues is becoming increasingly urgent. These biological tissue surfaces may include the surface of the brain, mucous membranes, corneas, or wounds undergoing regeneration. The ability to accurately and non-destructively collect and analyze biomolecules at these sites is key to obtaining relevant biological signals and conducting in-depth research.

[0003] In the existing technology, for the conventional process from local biomolecular sample collection to analysis, local sampling facilitates high-resolution spatial profiling of biological tissue samples. Microdialysis in situ sampling technology enables the collection of biological tissue samples by implanting them at the sampling site. However, these embedded samplers carry the potential risk of inducing local tissue damage and additional inflammatory responses, masking primary biological responses and leading to misinterpretation of biological sample analysis, and also potentially compromising biomolecular integrity. In addition, non-embedded biomolecular samplers that utilize droplet microfluidics technology provide a non-invasive sampling procedure that potentially eliminates tissue interference and enables spatially resolved biomolecular sample collection. However, these samplers generally require hard contact with the biological tissue during sample collection, i.e., applying pressure along the sampling direction, which can also cause significant interference or mechanical damage to the local tissue surface.

[0004] It can be seen that the existing sampling technology has the following defects when dealing with fragile biological tissues:

[0005] The surface barrier and self-protection functions of fragile tissues (such as mucosa and wound surface) are relatively weak, and traditional sampling methods may cause unnecessary mechanical damage to the tissues;

[0006] Traditional methods may also damage the integrity of key biomolecules (such as low-concentration metabolites, proteins, cells, etc.), affecting the accuracy of subsequent analysis;

[0007] At the same time, the spatial resolution of traditional sampling technology is limited, which makes it difficult to meet the needs of accurate sampling of areas of different sizes.

[0008] Therefore, in order to solve the above problems, the present invention proposes a sampler for collecting biomolecules on the tissue surface, which can avoid mechanical damage to the tissue, avoid damage to the integrity of key biomolecules, and has adjustable spatial resolution. Summary of the Invention

[0009] In order to solve the above problems existing in the prior art, the present invention provides a sampler and a sampling method for collecting biomolecules on the surface of a tissue.

[0010] According to one object of the present invention, the present invention provides a sampler for collecting biomolecules on a tissue surface, wherein the sampler is provided with a sampling direction and comprises:

[0011] A main body, wherein the main body is provided with an arc-shaped track, the center of the arc-shaped track corresponds to the center of the main body, the radius of the arc-shaped track gradually increases or decreases in one length direction of the track, and the track is symmetrically arranged with respect to the center of the main body;

[0012] a plurality of sampling arms, each movably connected to a corresponding track, the sampling arms being arranged along the sampling direction, the distal end of the sampling arm being located on one side of the main body in the sampling direction, the sampling arm being provided with a fluid tube, the distal end of the fluid tube extending to the outside of the distal end of the sampling arm and connected to a sampling needle, the sampling needles on different sampling arms being capable of forming or recovering droplets;

[0013] A brake member is connected to the main body in a manner of rotating around the center of the main body, and the brake member synchronously drives and connects the plurality of sampling arms, wherein the output end of the sampling needle is always kept facing the sampling center.

[0014] Preferably, the track is arranged in a spiral shape, and the number of the track and the number of the sampling arms are both two.

[0015] Preferably, the two opposite sides of the main body in the sampling direction are an assembly side and a tissue side, respectively, the track connects the assembly side and the tissue side of the main body, the end of the sampling arm is located on the tissue side of the main body, and the head end of the sampling arm is located on the assembly side of the main body;

[0016] A guide groove is provided in the middle of the braking member along the sampling direction, and the braking member is sleeved on the outer side of the head end of the sampling arm through the guide groove.

[0017] Preferably, a central rotor is rotatably connected to the middle part of the main body, the axis of the central rotor is arranged along the sampling direction, the central rotor is provided with a first shaft through-hole in the radial direction, a second shaft through-hole is provided on the sampling arm, a rotating shaft is passed through the first shaft through-hole and the second shaft through-hole, and the rotating shaft is sequentially passed through the second shaft through-hole of one of the sampling arms, the central rotor and the second shaft through-hole of the other sampling arm.

[0018] Preferably, a central boss is provided on the assembly side of the main body, and the brake member is sleeved on the radially outer side of the central boss through the guide groove;

[0019] The brake member is arranged in close proximity to the main body, and a retaining member is formed on the radially outer side of the central boss and is engaged with a side of the brake member facing away from the main body. The retaining member is configured to pass through the guide groove when the brake member rotates to a preset position.

[0020] The main body is provided with an openable and closable guide opening on the radial outer side of the arc-shaped track, which is connected with the inside and outside of the track.

[0021] Preferably, the head end of the sampling arm is provided with a circular boss with an arc, the circular boss is movably arranged on the inner side of the guide groove, and the side of the circular boss close to the main body extends radially outward to form an outer limit boss, and the outer limit boss is close to the assembly side of the main body;

[0022] An inner limiting boss extending outward is provided in the middle of the sampling arm, a limiting groove is provided on the inner side of the track, the inner limiting boss and the limiting groove are slidably matched, and the inner limiting boss is provided with the second axis through-hole in the radial direction.

[0023] Preferably, the sampling arm is hollow, a tube outlet communicating with the inside and outside is provided at the end of the sampling arm, a tube inlet communicating with the inside and outside is provided at a position of the sampling arm close to the main tissue side, the fluid tube is embedded in the inner side of the sampling arm, and the fluid tube is configured to pass through the tube inlet and pass through the tube outlet;

[0024] A notch communicating the inside and the outside is provided on the radial outer side of the sampling arm, and the notch is connected between the tube inlet and the tube outlet.

[0025] Preferably, the sampling needle can be equipped with sampling needle tips of different shapes to provide different degrees of support for the formed droplets;

[0026] An angle is preset between the sampling needle tips arranged on the two sampling arms.

[0027] Preferably, the fluid tube, the sampling needle and the sampling needle tip are made of low-absorption materials.

[0028] The present invention also provides a collection method, comprising the above-mentioned sampler, the collection method comprising the following steps:

[0029] S1. Moving the sampler to a coordinate at a certain height from the tissue surface;

[0030] S2. Adjust the distance between the sampling needles by rotating the brake to adjust the subsequent droplets to a preset size;

[0031] S3. Buffer solution is injected into the sampling needle through the fluid tube, and the sampling needle tip of the sampling needle forms droplets of buffer solution on the tissue surface;

[0032] S4. Recover the droplets and complete the sampling.

[0033] Compared with the prior art, the present invention has the following beneficial effects:

[0034] This sampler for collecting biomolecules from tissue surfaces is equipped with multiple sampling needles. A sampling droplet corresponding to a sampling center is formed and maintained between the output ends of the multiple sampling needles. The droplet contacts the biological tissue surface, achieving a non-embedded sampling method. This avoids damage to the integrity of key biomolecules that may be caused by traditional methods and helps to achieve high-fidelity biomolecule acquisition. Unlike traditional contact or invasive samplers, this non-embedded sampling method can minimize physical disturbance and mechanical damage to fragile tissues.

[0035] By setting the sampling needle on the sampling arm, the sampling arm is installed in the track of the main body and driven by the brake part, the relative distance between the sampling arm and the output end of the sampling needle on the sampling arm can be adjusted by controlling the rotational position of the brake part on the main body, thereby realizing controllable adjustment of the sampling radius, wherein the sampling radius is the spatial resolution, which further limits the shape of the track. Compared with linear adjustment, the fineness of the adjustment of the sampling needle is improved, and the sampling radius can be dynamically adjusted.

[0036] The present invention is further described below with reference to the accompanying drawings and embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 This is an overall schematic diagram of a sampler for collecting biomolecules on a tissue surface according to the present invention;

[0038] Figure 2 This is a schematic cross-sectional view of the entire sampler for collecting biomolecules on a tissue surface according to the present invention;

[0039] Figure 3This is a schematic diagram of the main body of a sampler for collecting biomolecules on a tissue surface according to the present invention;

[0040] Figure 4 A schematic diagram of a brake component in a sampler for collecting biomolecules from a tissue surface according to the present invention;

[0041] Figure 5 A schematic diagram of a sampling arm in a sampler for collecting biomolecules on a tissue surface according to the present invention;

[0042] Figure 6 A schematic diagram showing one perspective of an embodiment of a sampling needle in a sampler for collecting biomolecules on a tissue surface according to the present invention;

[0043] Figure 7 This is a schematic diagram from another perspective of one embodiment of a sampling needle in a sampler for collecting biomolecules on a tissue surface according to the present invention;

[0044] Figure 8 This is a schematic diagram from one perspective of a second embodiment of a sampling needle in a sampler for collecting biomolecules on a tissue surface according to the present invention;

[0045] Figure 9 This is a schematic diagram from another perspective of a second embodiment of a sampling needle in a sampler for collecting biomolecules on a tissue surface according to the present invention;

[0046] Figure 10 This is a schematic diagram showing one of three embodiments of a sampling needle in a sampler for collecting biomolecules on a tissue surface according to the present invention;

[0047] Figure 11 A schematic diagram showing another perspective of the third embodiment of the sampling needle in the sampler for collecting biomolecules on the tissue surface according to the present invention;

[0048] Figure 12 This is a schematic diagram of one embodiment of the sampling method of the present invention;

[0049] Figure 13 This is a schematic diagram of another embodiment of the sampling method of the present invention. DETAILED DESCRIPTION

[0050] The following description is intended to fully illustrate the present invention so that those skilled in the art can implement the present invention. The preferred embodiments described below are intended to be exemplary only, and those skilled in the art will readily appreciate other obvious variations. The basic principles of the present invention defined in the following description may be applied to other embodiments, variations, improvements, equivalents, and other technical solutions that do not depart from the spirit and scope of the present invention.

[0051] See also Figure 1-2 The present invention provides a technical solution: a sampler for collecting biomolecules on a tissue surface, wherein the sampler is provided with a sampling direction A and comprises:

[0052] A main body 100, wherein the main body 100 is provided with an arc-shaped track 101, wherein the center of the arc-shaped track 101 corresponds to the center of the main body 100, and the radius of the arc-shaped track 101 gradually increases or decreases along one length direction of the track 101, and multiple tracks 101 are symmetrically arranged about the center of the main body 100;

[0053] A plurality of sampling arms 200, each movably connected to a corresponding track 101, arranged along the sampling direction A, with a distal end of the sampling arm 200 located on one side of the main body 100 in the sampling direction A. A fluid tube 201 is mounted on the sampling arm 200, with the distal end of the fluid tube 201 extending to the outside of the distal end of the sampling arm 200 and connected to a sampling needle 202. The sampling needles 202 on different sampling arms 200 can respectively form or recover droplets;

[0054] The brake member 102 is connected to the main body 100 in a manner of rotating around the center of the main body 100. The brake member 102 synchronously drives the plurality of sampling arms 200, wherein the output end of the sampling needle 202 is always kept facing the sampling center.

[0055] By providing multiple sampling needles 202, a sampling droplet corresponding to the sampling center can be formed and maintained between the output ends of the multiple sampling needles 202. The droplet contacts the surface of the biological tissue, thereby realizing a non-embedded sampling method, avoiding damage to the integrity of key biological molecules such as low-concentration metabolites, proteins, and cells that may be caused by traditional methods, and facilitating high-fidelity acquisition of biological molecules. The non-embedded sampling method is different from traditional contact or invasive samplers, and this sampler can minimize physical disturbance and mechanical damage to fragile tissues.

[0056] By setting the sampling needle 202 on the sampling arm 200, the sampling arm 200 is installed in the track 101 of the main body 100 and driven by the brake part 102, the relative distance between the sampling arm 200 and the output end of the sampling needle 202 on the sampling arm 200 can be adjusted by controlling the rotation position of the brake part 102 on the main body 100, thereby realizing controllable adjustment of the sampling radius, wherein the sampling radius is the spatial resolution, which further limits the shape of the track 101. Compared with the linear adjustment, the fineness of the adjustment of the sampling needle 202 is improved, and the sampling radius can be dynamically adjusted to achieve accurate sampling of a specific micro area, showing the in-situ analysis capability with high temporal and spatial resolution.

[0057] In this embodiment, see Figure 1 and 3 The track 101 is arranged in a spiral shape, and the number of the track 101 and the sampling arms 200 are both 2, that is, the track 101 is a double-helix track 101. By loading the brake part 102, the sampling arm 200 can be moved according to the length of the track 101, thereby completing the synchronous and symmetrical radius transformation of the sampling needle 202. The number of double-helix turns of the track 101 and the radius of each spiral can be adjusted. If more precise radius control and adjustment are required, the number of turns can be increased, and vice versa. In addition, the two sampling arms 200 can be used for injecting the sampling liquid and extracting the liquid containing the sample to be sampled, respectively.

[0058] Regarding the driving connection structure of the brake member 102 and the sampling arm 200, see Figure 1 and 2 The main body 100 has an assembly side and a tissue side on opposite sides in the sampling direction A, respectively. The track 101 connects the assembly side and the tissue side of the main body 100. The distal end of the sampling arm 200 is located on the tissue side of the main body 100, and the head end of the sampling arm 200 is located on the assembly side of the main body 100.

[0059] A guide groove 1021 is formed in the middle of the brake member 102 along the sampling direction A. The brake member 102 is sleeved on the outer side of the head end of the sampling arm 200 through the guide groove 1021.

[0060] The middle part of the main body 100 is rotatably connected to a central rotor 103, and the axis of the central rotor 103 is arranged along the sampling direction A. The central rotor 103 is radially provided with a first axis through-hole 1031, and the sampling arm 200 is provided with a second axis through-hole 203. The first axis through-hole 1031 and the second axis through-hole 203 are penetrated by a rotating shaft 104. Specifically, the interior of the main body 100 is provided with a chamber for the movement of the rotating shaft 104, and the chamber is connected to the guide rail. The central rotor 103 and the rotating shaft 104 are arranged in the center of the sampler main body 100 and rotate together with the sampling arm 200. At the same time, because the central rotor 103 and the rotating shaft 104 are introduced, the central rotor 103 and the rotating shaft 104 form a centripetal maintaining structure, which ensures that the sampling arm 200 is always centripetal during the movement, thereby stabilizing the state of the needle tip, which is an important guarantee for achieving stable sampling and precise adjustment of the droplet radius.

[0061] Regarding the mounting structure between the main body 100 and the brake member 102, see Figure 1-3, a center boss 105 is provided on the assembly side of the main body 100, and a guide groove 1021 is provided in the middle of the brake member 102 along the sampling direction A. The brake member 102 is sleeved on the radial outer side of the center boss 105 through the guide groove 1021, and the brake member 102 is arranged in a manner close to the main body 100, and the radial outer side of the center boss 105 extends outward to form a locking member 1051, which is snap-fitted to the side of the brake member 102 away from the main body 100, and the locking member 1051 is configured to pass through the brake member 102 when the brake member 102 is rotated to a preset position. The guide groove 1021 is used to disassemble and assemble the brake member 102. Preferably, the clamping member 1051 is in a prism shape, and the number of the clamping members 1051 is 2. The clamping members 1051 are arranged at intervals in the circumferential direction of the boss. When in use, the clamping member 1051 is used to clamp the brake member 102. When in the correct position, the brake member 102 can be taken out and installed from the top of the main body 100. After installation, the brake member 102 moves against the side of the sampler assembly side, continuously exerting force in the arc tangent direction of the track 101, thereby pushing the sampling arm 200 to achieve switching of the droplet radius between the output ends of the sampling needle 202;

[0062] The main body 100 is provided with an openable and closable guide opening 106 on the radial outer side of the arc-shaped track 101, which connects the inside and outside of the track 101. Specifically, a slot structure is provided in the guide opening 106. When the slot structure is opened, the sampling arm 200 can be assembled. When the slot structure is closed, the sampling arm 200 can be prevented from escaping from the track 101.

[0063] Furthermore, the main body 100 can be equipped with a stepper motor to complete rotation and XYZ three-axis movement. Specifically, there is a groove in the middle of the central boss 105, and the groove is used to couple with the rotating motor. The rotating motor can drive the main body 100 to complete the overall rotation. Furthermore, the rotating motor can be connected to a horizontal displacement motor to complete the movement of the main body 100 in the XYZ three-axis space direction, providing a basis for automated and programmed control of the sampling process.

[0064] See also Figure 1 、 2 5 further illustrates the connection structure between the sampling arm 200 and the main body 100. The head end of the sampling arm 200 is provided with a circular boss 204 with a curvature. The circular boss 204 is movably arranged on the inner side of the guide groove 1021. The circular boss 204 is used to cooperate with the brake member 102 and the sampler main body 100. The curvature of the circular boss 204 is conducive to loading the brake member 102.

[0065] The circular boss 204 extends radially outward on a side close to the main body 100 to form an outer limiting boss 2041. The outer limiting boss 2041 is close to the assembly side of the main body 100. The brake member 102 is provided with a groove matching the outer limiting boss 2041 on the side facing the main body 100. The circular boss 204 can cooperate with the outer limiting boss 2041 to be stuck on the assembly side of the main body 100, thereby preventing the sampling arm 200 from moving along the sampling direction A on the main body 100.

[0066] The sampling arm 200 is provided with an inner limiting boss 205 extending outward at the middle part, and a limiting groove is provided on the inner side of the track 101. The inner limiting boss 205 and the limiting groove are slidably matched, and the sampling arm 200 can cooperate with the inner limiting boss 205 to move on the inner side of the track 101. The inner limiting boss 205 and the limiting groove form a match between the train wheel and the train track 101, which plays a limiting role. The inner limiting boss 205 is provided with a second axis through-hole 203 in the radial direction, and the rotating shaft 104 can sequentially penetrate one of the sampling arms 200, the central rotor 103 and the other sampling arm 200, thereby ensuring that the sampling arm 200 always maintains centripetal movement during the rotation process, further ensuring that the sampling needle 202 connected to the sampling arm 200 is centripetal, which is conducive to ensuring the stability of the suspended droplets;

[0067] Continue to see Figure 2 and 5 , showing the connection structure between the sampling arm 200 and the fluid tube 201. The sampling arm 200 is hollow, and a tube outlet 206 is provided at the end of the sampling arm 200 to connect the inside and the outside. A rectangular tube inlet 207 is provided at the position of the sampling arm 200 close to the tissue side of the main body 100 to connect the inside and the outside. The fluid tube 201 is embedded in the inner side of the sampling arm 200, wherein the fluid tube 201 is suitable for passing through the tube inlet 207 into the sampling arm 200 and passing through the tube outlet 206.

[0068] Furthermore, a notch 208 connecting the inside and the outside is provided on the radial outer side of the sampling arm 200, and the notch 208 is connected between the tube inlet 207 and the tube outlet 206. The long strip notch 208 on the side of the sampler, on the one hand, when the fluid tube 201 is made of a material with greater friction, the notch 208 can reduce the friction during loading, thereby providing a certain tolerance for the material selection of the fluid tube 201, and on the other hand, allowing the sampling arm 200 to be compatible with fluid tubes 201 of different thicknesses.

[0069] The sampling needle 202 can be equipped with sampling needle tips 2021 of different shapes to provide different degrees of support for the formed droplets, so as to cope with the occasions of sampling droplets with different spatial resolutions required for different biological tissues, such as Figure 6-11As shown, three designs of sampling needle tip 2021 are provided, wherein the lower surface of the sampling needle tip 2021, the sampling needle 202 and the sampling tissue jointly maintain the formation of a droplet;

[0070] An angle is set between the ends of the sampling arms 200, so that after the sampling needle tips 2021 are loaded, the needle tips of the two sampling arms 200 are at a specific angle relative to each other, a typical angle of 90° is used here, and surface tension and continuous fluid conditions are used to form stable sampling droplets, which is conducive to the formation and collection of suspended droplets;

[0071] Furthermore, the fluid tube 201, the sampling needle 202 and the sampling needle tip 2021 are made of low-adsorption materials, such as Teflon, to reduce the loss of biological molecules during transmission and reduce damage to biological molecules. Combined with the use of low-adsorption materials, the integrity of the products to be tested, such as low-concentration metabolites, proteins, etc., and the accuracy of the analysis are ensured.

[0072] Based on the above-mentioned sampler for collecting biomolecules on the tissue surface, the present invention also provides a collection method, comprising the following steps:

[0073] S1. Move the sampler to a coordinate at a certain height from the tissue surface;

[0074] S2. By means of the brake member 102, the distance between the sampling needle 202 heads is adjusted to adjust the subsequent droplets to a preset size;

[0075] S3. Buffer solution is injected into the sampling needle 202 through the fluid tube 201, and the sampling needle tip 2021 of the sampling needle 202 forms a buffer droplet;

[0076] S4. Recover the droplets and complete the sampling.

[0077] See also Figure 12 and 13 ,The present invention provides the following two embodiments, corresponding to the two modes usually used in actual use, continuous sampling and unified recovery after multi-point distribution, which can adapt to different experimental needs;

[0078] In one embodiment, the first mode is adopted, and steps S3 and S4 are performed simultaneously. The sampler first moves to coordinate 1, a certain height from the tissue surface, and then adjusts the radius by means of the brake 102 to form a droplet of appropriate size. Buffer is then continuously injected to form a droplet with a constant flow inside at the sampling point for a certain period of time (≥1 minute). During this process, the droplet is continuously recovered. Finally, sampling at point 1 is completed, and the sampler is then moved by the motor to coordinate 2, and subsequent sampling is completed in sequence.

[0079] In another embodiment, using the second mode, steps S3 and S4 are performed step by step. The sampler first moves to coordinate 1, a predetermined height above the tissue surface. The radius is then adjusted using brake 102 to form droplets of appropriate size. A predetermined amount of buffer is then injected, leaving droplets of constant diameter at the sampling site. The motor then moves the entire sampler to coordinate 2, where droplets are sequentially placed at each sampling site. After all droplets are placed, they are collected sequentially in the order in which they were placed, ultimately completing the entire sampling process.

[0080] Working method:

[0081] Here, we use the example of collecting inflammatory factors from the surface of a mouse brain after craniotomy and neural electrode implantation during brain-computer interface (BCI) implantation surgery. The collected biomolecular samples are used to dynamically assess local neuroinflammation during BCI surgery and ultimately provide high-spatial-resolution analysis of the inflammatory response. The droplet sampler, with its autonomous levitation and soft-contact properties, provides a feasible solution for characterizing local inflammation while minimizing disturbance to brain tissue.

[0082] Specifically, taking sampling mode 1 as an example, after waiting for the test mouse to complete the craniotomy and microelectrode implantation surgery, the coordinates of the XYZ axis are adjusted by the motor so that the sampler is located 300um at the top of the implantation site, the brake 102 is twisted to adjust the distance of the sampling arm 200, and the state of the sampling needle 202 is adjusted, which is 90 degrees perpendicular to each other. The fluid tube 201 is connected to the fluid pump, which can be a peristaltic pump. A constant flow rate of typically 20ul / min is set, which is used for buffer injection and extraction of samples containing inflammatory markers, respectively. With the help of surface tension and continuous fluid conditions, a stable sampling droplet with an average diameter of 0.52mm is formed between the sampling needles 202. After the droplet is maintained for one minute, the fluid pump that controls the inflow of the sample is turned off, and the droplets remaining on the brain surface are completely removed, and the sample is lifted. The sampler height is adjusted, and after being displaced a constant distance in a fixed direction, the sampler is adjusted to 300um at the top of the test point 2 to sample the second site. Similarly, the characterization of the whole brain inflammatory factor map is completed. Through the soft contact between the droplet and the brain surface, typical inflammatory markers such as cytokines in the local tissue diffuse into the droplet. The programmed fluid pump maintains the stable flow of the buffer solution in the droplet. The droplet samples at each sampling point are collected independently for subsequent analysis. This method of collecting cerebrospinal fluid (CSF) cytokines through soft contact between the droplet and the brain surface minimizes the impact of brain tissue and improves measurement accuracy and spatial resolution, and greatly improves the intraoperative spatiotemporal resolution detection capability of biomolecules, providing an innovative solution for rapid feedback and closed-loop biosafety management of invasive BCI surgery.

[0083] In summary, in order to solve the problems of damage, impaired sample integrity and limited spatial resolution that may be caused by the existing technology when sampling biological molecules on the surface of fragile biological tissues, the present invention proposes a sampler for collecting biological molecules on the tissue surface. The core of the sampler is the design of a position-adjustable sampling arm 200 to form a stable and controllable sampling droplet between the sampling needles 202 on the sampling arm 200. The droplet is in a "self-suspended" state and "softly contacts" the fragile biological tissue surface. This non-embedded sampling method and the method of soft contact between the droplet as a sampling medium and the tissue surface are the key to distinguishing it from traditional contact or invasive samplers, and can minimize physical disturbance and mechanical damage to fragile tissues such as the brain surface and mucous membranes.

[0084] The embodiments described above are only used to illustrate the technical ideas and features of the present invention. Their purpose is to enable those skilled in the art to understand the contents of the present invention and implement them accordingly. The scope of the patent application of the present invention cannot be limited by these embodiments alone. That is, any equivalent changes or modifications made according to the spirit disclosed by the present invention still fall within the patent scope of the present invention.

Claims

1. A sampler for collecting biomolecules on a tissue surface, wherein the sampler is provided with a sampling direction (A), characterized in that: The sampler comprises: A main body (100), wherein an arc-shaped track (101) is provided on the main body (100), wherein the center of the arc-shaped track (101) corresponds to the center of the main body (100), and in one length direction of the track (101), the radius of the arc-shaped track (101) gradually increases or decreases, and a plurality of the tracks (101) are symmetrically arranged about the center of the main body (100); A plurality of sampling arms (200), wherein the sampling arms (200) are movably connected to the corresponding tracks (101), the sampling arms (200) are arranged along the sampling direction (A), the ends of the sampling arms (200) are located on one side of the main body (100) in the sampling direction (A), a fluid tube (201) is installed on the sampling arm (200), the ends of the fluid tube (201) extend to the outside of the ends of the sampling arms (200) and are connected to sampling needles (202), and the sampling needles (202) on different sampling arms (200) can respectively form or recover droplets; A brake member (102) is connected to the main body (100) in a manner of rotating around the center of the main body (100), and the brake member (102) synchronously drives and connects multiple sampling arms (200), wherein the output end of the sampling needle (202) is always kept facing the sampling center.

2. A sampler for collecting biomolecules from tissue surface according to claim 1, characterized in that: The track (101) is arranged in a spiral shape, and the number of the track (101) and the number of the sampling arms (200) are both two.

3. A sampler for collecting biomolecules from tissue surface according to claim 2, characterized in that: The two opposite sides of the main body (100) in the sampling direction (A) are respectively an assembly side and a tissue side, the track (101) connects the assembly side and the tissue side of the main body (100), the end of the sampling arm (200) is located on the tissue side of the main body (100), and the head end of the sampling arm (200) is located on the assembly side of the main body (100); A guide groove (1021) is provided in the middle of the braking member (102) along the sampling direction (A), and the braking member (102) is sleeved on the outer side of the head end of the sampling arm (200) through the guide groove (1021).

4. A sampler for collecting biomolecules from tissue surface according to claim 3, characterized in that: The middle part of the main body (100) is rotatably connected to a central rotor (103), the axis of the central rotor (103) is arranged along the sampling direction (A), the central rotor (103) is radially provided with a first shaft through-hole (1031), the sampling arm (200) is provided with a second shaft through-hole (203), a rotating shaft (104) is passed through the first shaft through-hole (1031) and the second shaft through-hole (203), and the rotating shaft (104) is sequentially passed through the second shaft through-hole (203) of one of the sampling arms (200), the central rotor (103), and the second shaft through-hole (203) of the other sampling arm (200).

5. A sampler for collecting biomolecules from tissue surface according to claim 3, characterized in that: A central boss (105) is provided on the assembly side of the main body (100), and the braking member (102) is sleeved on the radially outer side of the central boss (105) through the guide groove (1021); The brake member (102) is arranged in close proximity to the main body (100); a locking member (1051) is formed by extending radially outward from the central boss (105); the locking member (1051) is engaged with a side of the brake member (102) facing away from the main body (100); and the locking member (1051) is adapted to pass through the guide groove (1021) when the brake member (102) rotates to a preset position; The main body (100) is provided with an openable and closable guide opening (106) on the radially outer side of the arc-shaped track (101) for connecting the inside and outside of the track (101).

6. A sampler for collecting biomolecules from tissue surface according to claim 4, characterized in that: The head end of the sampling arm (200) is provided with a circular boss (204) with an arc, and the circular boss (204) is movably arranged on the inner side of the guide groove (1021). The side of the circular boss (204) close to the main body (100) extends radially outward to form an outer limiting boss (2041), and the outer limiting boss (2041) is close to the assembly side of the main body (100); An inner limiting boss (205) extending outward is provided in the middle of the sampling arm (200), a limiting groove is provided on the inner side of the track (101), the inner limiting boss (205) and the limiting groove are slidably engaged, and the inner limiting boss (205) is provided with the second shaft through-hole (203) in the radial direction.

7. A sampler for collecting biomolecules from tissue surface according to claim 3, characterized in that: The sampling arm (200) is hollow, and a tube outlet (206) for communicating with the inside and outside is provided at the end of the sampling arm (200). A tube inlet (207) for communicating with the inside and outside is provided at a position of the sampling arm (200) close to the tissue side of the main body (100). The fluid tube (201) is embedded in the inner side of the sampling arm (200), wherein the fluid tube (201) is configured to pass through the tube inlet (207) and pass through the tube outlet (206); A notch (208) communicating the inside and the outside is provided on the radial outer side of the sampling arm (200), and the notch (208) is connected between the tube inlet (207) and the tube outlet (206).

8. A sampler for collecting biomolecules from tissue surface according to claim 2, characterized in that: The sampling needle (202) can be optionally equipped with sampling needle tips (2021) of different shapes and designs to provide different degrees of support for the formed droplets; An included angle is preset between the sampling needle tips (2021) provided on the two sampling arms (200).

9. A sampler for collecting biomolecules from tissue surface according to claim 1, characterized in that: The fluid tube (201), the sampling needle (202) and the sampling needle tip (2021) are made of low-absorption materials.

10. A collection method, characterized in that: A sampler for collecting biomolecules from a tissue surface according to any one of claims 1 to 9, wherein the collection method comprises the following steps: S1. Moving the sampler to a coordinate at a certain height from the tissue surface; S2. By rotating the brake member (102), the distance between the sampling needle (202) heads is adjusted to adjust the subsequent droplets to a preset size; S3. injecting a buffer solution into the sampling needle (202) through the fluid tube (201), and the sampling needle tip (2021) of the sampling needle (202) causes the buffer solution to form droplets on the tissue surface; S4. Recover the droplets and complete the sampling.

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