Ultrasonic-based in-needle mixing method and system

Abstract

The invention relates to the technical field of in-needle mixing, in particular to an in-needle mixing method and system based on ultrasound, and the method comprises the steps: providing an in-needle mixing device; obtaining a first ultrasonic feature and a second ultrasonic feature of the sample, wherein the first ultrasonic feature comprises a test uniform mixing degree obtained by uniformly mixing the first-class sample and the second-class sample for a target time length under a plurality of ultrasonic frequencies; the second ultrasonic feature comprises a test damage degree obtained by uniformly mixing a class of samples for a target duration under a plurality of ultrasonic frequencies; selecting a reference ultrasonic frequency corresponding to the current sample from the first ultrasonic feature and the second ultrasonic feature according to the type of the to-be-tested item; and controlling the in-needle mixing process according to the reference ultrasonic frequency. According to the in-needle ultrasonic mixing technology, the sample mixing operation can be simplified, and the damage degree of special samples such as cells in the ultrasonic process can be relieved or avoided.

Description

Technical Field

[0001] The present invention relates to the field of detection technologies, and particularly relates to a method and system for in-needle mixing based on ultrasound. Background Art

[0002] In some biomedical detection projects, the mixing detection of two liquid samples is usually involved. At present, when an instrument mixes two liquid samples, it generally aspirates the liquid (or referred to as a sample or reagent) into a fixed consumable container and then mixes it. However, this mixing method has very low mixing efficiency and has many defects such as wasting consumables, wasting time, wasting samples and reagents.

[0003] In response to this, a mixing method of in-needle mixing has been proposed in the prior art.

[0004] For example, patent application CN108854650A discloses a mixing device and its mixing method. Specifically, it adopts an eccentric motion method, so that the power mechanism can drive the eccentric mechanism and the sampler to perform eccentric motion synchronously, thereby realizing the stirring function of the mixing device and promoting the uniform mixing of the mixed liquid.

[0005] For another example, patent application CN114624090A discloses a needle mixing structure and an automatic detection device. Specifically, it makes the tail of the reagent needle move at a high frequency within a certain circumferential range to promote the rotation and mixing of the liquid in the reagent needle. Among them, the mixing structure includes a movable mechanism, and the movable mechanism drives the reagent needle to vibrate when the power device is started, and the movable mechanism drives the reagent needle to return to its original position when the power device is turned off.

[0006] That is to say, the applicant noticed that even in the in-needle mixing technology, the adopted mixing concept is still a relatively traditional rotation mixing route, that is, rotating and mixing the liquid. However, the applicant found that this mixing method based on rotation mixing will have the following defects in the application process: The system of the mixing device is complex and the volume is relatively large. For example, due to the need for rotation mixing, a movable mechanism is correspondingly configured in the mixing device to allow the needle tube to rotate. And this movable mechanism will increase the complexity of the mechanical mechanism of the mixing device on the one hand and is likely to lead to a larger floor space for the device. In addition, during frequent mixing, the movement of the needle tube will also pose higher requirements on the mechanical stability of the device.

[0007] From another perspective, traditional in-needle mixing devices have relatively high configuration costs and maintenance costs.

[0008] Therefore, there is an urgent need for an in-needle mixing technology with smaller size, lower cost and higher stability at present. Summary of the invention

[0009] The object of the present invention is to provide a mixing device and an in-needle mixing method to partially solve or alleviate the above-mentioned deficiencies in the prior art, that is, to provide an in-needle mixing method and equipment that can achieve miniaturization, low cost and high stability.

[0010] In order to solve the above-mentioned technical problems, the present invention specifically adopts the following technical solutions: The first aspect of the present invention is to provide an ultrasound-based in-needle mixing method, comprising the steps of: S001, providing an in-needle mixing device, the in-needle mixing device comprising a needle tube, the needle tube being connected to an ultrasonic vibration device, and the needle tube being further connected to a connecting pipeline, wherein a negative pressure device is arranged in the connecting pipeline, and the negative pressure device is used to form a negative pressure or positive pressure environment in the connecting pipeline to guide the corresponding sample to enter or exit the needle tube; S002, obtaining a first ultrasonic feature and a second ultrasonic feature of the sample, wherein the sample includes: a first type of sample and a second type of sample, the first ultrasonic feature includes: a test mixing degree obtained by mixing the first type of sample and the second type of sample at multiple ultrasonic frequencies for a target time; the second ultrasonic feature includes: a test damage degree obtained by mixing the first type of sample at multiple ultrasonic frequencies for a target time; S003, selecting at least one reference ultrasonic frequency corresponding to the current sample from the first ultrasonic feature and the second ultrasonic feature according to the type of the item to be tested; S004, inputting at least one of the reference ultrasonic frequencies into the ultrasonic vibration device to promote mixing of the current sample under ultrasonic vibration.

[0011] In some embodiments, S003 includes: S0031, obtaining a guiding mixing degree and a guiding damage degree according to the type of the item to be tested; S0032: Select at least one first ultrasonic frequency from the first ultrasonic feature according to the guiding mixing degree, wherein the first ultrasonic frequency satisfies a first rule: Test the mixing degree - guide the mixing degree ≥ the first threshold; S0033, determining whether at least one second ultrasonic frequency can be further selected from at least one of the first ultrasonic frequencies according to the second ultrasonic feature, wherein the second ultrasonic frequency satisfies a second rule: Test damage degree - guide damage degree ≤ second threshold; Wherein, the first threshold value and the second threshold value are preset judgment values; if so, execute step S0034; S0034. Determine the reference ultrasonic frequency according to at least one second ultrasonic frequency.

[0012] In some embodiments, when the result of S0033 is no, S003 further includes the steps of: S0035. Select at least one third ultrasonic frequency and at least one fourth ultrasonic frequency from the first ultrasonic feature and the second ultrasonic feature; Wherein, the third ultrasonic frequency satisfies the third rule: Second threshold < Test breakage degree - Guidance breakage degree ≤ Third threshold; Test mixing degree - Guidance mixing degree ≥ First threshold; Wherein, the fourth ultrasonic frequency satisfies the second rule: Test breakage degree - Guidance breakage degree ≤ Second threshold; Fourth threshold < Test mixing degree - Guidance mixing degree < First threshold; S0036. Determine at least one first reference ultrasonic frequency and at least one second reference ultrasonic frequency according to at least one third ultrasonic frequency and at least one fourth ultrasonic frequency respectively.

[0013] In some embodiments, in S004, the strong - weak alternating mixing method is used for mixing. Correspondingly, S004 includes the steps of: S0041. Mix for the first duration using the first reference ultrasonic frequency; S0042. Mix for the second duration using the second reference ultrasonic frequency, wherein the second duration is greater than the first duration; the first reference ultrasonic frequency is greater than the second reference ultrasonic frequency; S0043. Mix for the third duration using the first reference ultrasonic frequency; wherein, the first duration and the second duration are less than the corresponding target duration.

[0014] In some embodiments, S004 further includes the steps of: Repeat S0041 - S0043 at least once.

[0015] In some embodiments, it includes the steps of: S005. Record the actual mixing degree and actual breakage degree of the current sample; S006. Determine whether the actual mixing degree and the actual breakage degree meet the requirements of the guidance mixing degree and the guidance breakage degree; if so, execute the steps of: S007. Record the current ultrasonic working data and correspondingly update the first ultrasonic feature or the second ultrasonic feature.

[0016] In some embodiments, the inner diameter of the syringe 12 is 0.4 - 0.9 mm.

[0017] The present invention also provides an in-needle mixing system based on ultrasound, comprising: A syringe, which includes a first syringe and a second syringe. Among them, the inner diameter of the first syringe gradually decreases along the direction from its first end to its second end, and an anti-drip part is provided at the second end of the first syringe; wherein, the anti-drip part includes: at least two extending wall surfaces formed by extending outward from the second end of the first syringe, and a vacancy surface is formed by spacing between adjacent two extending wall surfaces; A connecting pipeline, the first end of which is communicated with the second syringe; An ultrasonic vibration device, which is connected to the second syringe; A negative pressure device, which is arranged on the connecting pipeline, and the negative pressure device is used to form a negative pressure or positive pressure environment in the connecting pipeline to guide the corresponding sample to enter or exit the syringe.

[0018] In some embodiments, the duty area of one or more of the vacancy surfaces is 1 / 3 to 1 / 2, and the duty area = the total area of all the vacancy surfaces / (the total area of all the vacancy surfaces + the total area of all the extending wall surfaces); and / or, the inner diameter of the second syringe is 0.4 - 0.9 mm.

[0019] In some embodiments, the edge of the corner of the extending wall surface is a first arc edge, and a second arc edge is transitionally arranged between adjacent extending wall surfaces; wherein, the corresponding vacancy surface is formed by connecting the first arc edge, the second arc edge, and the first arc edge in sequence.

[0020] Beneficial technical effects: Generally, in some biological detection projects, it is necessary to mix and detect biological samples. The traditional manual mixing method is usually rather cumbersome. Therefore, the in-needle mixing technology has been proposed in the prior art to improve the mixing efficiency and reduce the waste of samples during the mixing process.

[0021] The applicant has noticed that in order to mix liquid samples in a narrow syringe, traditional in-needle mixing all needs to adopt the method of rotating the syringe to guide the liquid sample to move greatly in the tube, so as to achieve the purpose of mixing.

[0022] However, this method of rotating the syringe makes it necessary to configure a complex moving mechanism on the in-needle mixing device, which in turn leads to a relatively high cost and large size of the in-needle mixing device. Moreover, this complex moving mechanism is very likely to become unstable after long-term operation.

[0023] Contrary to the traditional method of rotating the syringe, the present invention proposes a method for ultrasonic mixing based on a fixed position (or an in-situ ultrasonic mixing method). Specifically, in order to fully mix a small amount of sample in a fixed and limited syringe, the present invention provides a frequency screening method for alternately screening ultrasonic frequencies based on three major factors: sample type, mixing index, and breakage index. This screening method can provide relatively reliable ultrasonic conditions for mixing various types of samples, and thus, on the basis of meeting the requirement of sufficient mixing, it can avoid the breakage of the core detection object (such as cells) and affect the detection results.

[0024] It should be noted that especially when the object to be detected is a patient. For example, when the immune function of a patient is abnormal, the stability of the red blood cell membrane decreases, and the fragility of red blood cells increases. Therefore, during the mixing process in the syringe, the problem of rupture is more likely to occur. In addition, during the mixing process, the liquid in the needle is also likely to spill and contaminate the operating platform.

[0025] In response to this special mixing requirement, the present application proposes a mixing scheme with less restriction on the operating environment and sample type. Specifically, an in-situ ultrasonic mixing scheme with an anti-drip function is adopted. Among them, the extended wall surface of the anti-drip area cooperates with the vacant surface, which can reduce the adhesion ability of the liquid droplet at the head of the syringe, and prompt the formed liquid droplet to quickly drip at the head of the syringe to avoid excessive liquid residue at the head. Furthermore, when the syringe is moved, it is not easy for the liquid to spill at its head. In addition, during the ultrasonic vibration process, the situation of liquid splashing can also be avoided. On the other hand, in the in-situ ultrasonic mixing method, the syringe and the ultrasonic vibration device can be connected in a relatively fixed manner. Therefore, to a large extent, the mechanical structure design is simplified, and at the same time, the size of the mixing device is reduced.

[0026] Furthermore, for the anti-drip part on the fine structure of the needle head in the present invention, the adoption of a multi-segment arc-shaped edge setting can not only play the role of anti-drip, but also reduce the processing difficulty and improve the strength of the head.

[0027] Furthermore, when it involves mixing of multiple types of samples, especially mixing of cell samples and the mechanical strength of the cells is low, strong and weak vibration parameters (i.e., reference ultrasonic frequencies) are obtained by alternating selection and screening based on the first and second ultrasonic characteristics, and short-term strong vibrations and long-term weak vibrations are performed alternately based on the alternating screening parameters, thereby ensuring sufficient mixing of multiple types of samples while ensuring cell integrity as much as possible. Furthermore, for multiple types of trace samples, especially mixing scenarios involving cell samples, the present invention also provides a double-layer screening step to select ultrasonic frequencies. The double-layer screening step includes: 1) initial screening of the database, that is, for mixing scenarios involving three or more types of samples, the present invention can select ultrasonic features in a targeted manner based on the primary and secondary relationships of the samples; 2) fine screening of the reference characteristic frequency, and secondary alternating screening of the first and second ultrasonic features based on comprehensive mixing and damage indicators, thereby quickly screening out ultrasonic frequencies suitable for alternating ultrasonic vibrations.

[0028] The ultrasonic frequency selection result obtained based on the double-layer screening step can ensure the effective mixing of multiple types of samples, and at the same time ensure that the core detection objects (such as the first cell) in the mixed samples can maintain a relatively complete morphology, thereby avoiding damage to the detection objects during the mixing process and causing detection failure. BRIEF DESCRIPTION OF THE DRAWINGS In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings required for use in the embodiments or the prior art descriptions are briefly introduced below. In all the drawings, similar elements or parts are generally identified by similar reference numerals. In the drawings, each element or part is not necessarily drawn according to the actual scale. Obviously, the drawings described below are some embodiments of the present invention. For those of ordinary skill in the art, other drawings can also be obtained based on these drawings without paying creative labor.

[0029] Figure 1 A mixing device in an exemplary embodiment of the present invention; Figure 2 is a schematic diagram of a partial structure of a first needle tube in an exemplary embodiment of the present invention; Figure 3 is a side view of a first needle tube in an exemplary embodiment of the present invention; Figure 4 is a first schematic diagram of a needle tube in an exemplary embodiment of the present invention; Figure 5 is a second schematic diagram of a needle tube in an exemplary embodiment of the present invention; Figure 6 It is a schematic flow chart of the steps of an ultrasonic mixing method in an exemplary embodiment of the present invention; Figure 7Schematic diagram of the selection process of the ultrasonic frequency in an exemplary embodiment of the present invention.

[0030] Reference numerals: syringe 1, first syringe 11, anti-drip part 111, extending wall surface 1111, vacant surface 1112, second syringe 12, connecting pipeline 2, negative pressure device 3, type I medium 4, type II medium 5, ultrasonic vibration device 6, fixed pipe sleeve 7. Detailed implementation manners

[0031] To make the objectives, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention. Apparently, the described embodiments are some but not all of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0032] In this article, suffixes such as "module", "component" or "unit" used to represent elements are only for the convenience of describing the present invention, and have no specific meaning in themselves. Therefore, "module", "component" or "unit" can be used interchangeably.

[0033] In this article, terms such as "upper", "lower", "inner", "outer", "front", "rear", "one end", "the other end", etc. indicate the orientation or positional relationship based on the orientation or positional relationship shown in the drawings. They are only for the convenience of describing the present invention and simplifying the description, rather than indicating or implying that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation, and thus cannot be construed as a limitation of the present invention. In addition, the terms "first" and "second" are only used for descriptive purposes and cannot be construed as indicating or implying relative importance.

[0034] In this article, unless otherwise clearly defined and limited, terms such as "installation", "provided with", "connection", etc. shall be understood in a broad sense. For example, "connection" can be a fixed connection, a detachable connection, or an integral connection; it can be a mechanical connection, a direct connection, or an indirect connection through an intermediate medium, and can be the communication inside two elements. For those of ordinary skill in the art, the specific meanings of the above terms in the present invention can be understood according to specific situations.

[0035] In this article, "and / or" includes any and all combinations of one or more of the listed related items.

[0036] In this article, "a plurality of" means two or more, that is, it includes two, three, four, five, etc.

[0037] As used in this specification, the term "about" typically means + / - 5% of the stated value, more typically + / - 4% of the stated value, more typically + / - 3% of the stated value, more typically + / - 2% of the stated value, even more typically + / - 1% of the stated value, and even more typically + / - 0.5% of the stated value.

[0038] In this specification, certain embodiments may be disclosed in a format that is within a certain range. It should be understood that this description of "within a certain range" is merely for convenience and brevity and should not be construed as a rigid limitation on the disclosed range. Therefore, the description of the range should be considered to have specifically disclosed all possible sub-ranges and the individual numerical values within that range. For example, the description of the range 1-6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., as well as the individual numbers within that range, such as 1, 2, 3, 4, 5, and 6. The above rules apply regardless of the breadth of the range.

[0039] The applicant notes that in traditional in-needle mixing technical solutions of a rotary type, there are the following difficulties: the system of the mixing device is complex and the volume is relatively large. For example, due to the need for rotary mixing, a movable mechanism is correspondingly configured in the mixing device to allow the syringe to rotate. And this movable mechanism will, on the one hand, increase the complexity of the mechanical mechanism of the mixing device and also easily lead to a wider floor space for the device. In addition, during frequent mixing processes, the movement of the syringe will also pose higher requirements for the mechanical stability of the device.

[0040] In contrast to the traditional in-needle mixing technology of a rotary type, the present invention provides a fixed in-needle mixing technology, as Figure 1 shown, the second syringe 12 is connected to the ultrasonic vibration device 6. When the ultrasonic vibration device 6 is started, it directly changes the physical state of an object (such as a syringe) based on the interaction between ultrasonic waves and the object through high-frequency vibration, so as to cause the sample liquid in the syringe to be fully mixed under high-frequency vibration. In particular, the present invention does not require an additional movable mechanism to enable the syringe to perform circular or eccentric rotation, and the syringe can be directly fixedly connected to the ultrasonic vibration device 6, so it can also have high stability under high-frequency vibration.

[0041] However, during the application process, the applicant found that it is extremely demanding for the ultrasonic frequency to mix samples inside a narrow syringe while keeping the syringe in a fixed position. However, the selection of the ultrasonic frequency will also affect the quality of some special samples. For example, especially for some detection items involving cell samples, the high-frequency vibration process relied on for mixing in the limited syringe space at a fixed position is very likely to increase the risk of cell sample breakage, thereby reducing the reliability of the detection results.

[0042] Specifically, taking the blood sample detection item as an example, it is necessary to mix red blood cells and plasma. However, when the detected object is a patient, their red blood cells may be in an unhealthy state due to diseases or other reasons. Therefore, under high-frequency vibration, they are very likely to break. And the breakage of red blood cells will seriously affect the reliability of the detection results of the mixed samples.

[0043] In addition, the in-needle mixing technology is also prone to polluting the detection environment. During the sampling process, some liquid residues may be generated at the head of the syringe, and during the movement of the syringe, these liquids may drip and pollute the detection operation table. Especially during the rotation or vibration of the syringe, it may lead to a large pollution area.

[0044] In contrast to the traditional rotary mixing technology route, the present invention provides an in-needle mixing method for inputting high-frequency vibration energy into the limited space inside the needle at a fixed position. This in-needle mixing method is more conducive to meeting the design requirements such as miniaturization, high stability, and low application cost of in-needle mixing devices.

[0045] Furthermore, the present invention provides a fixed in-needle mixing solution with an anti-drip function. The setting of the anti-drip function can reduce the risk of liquid dripping onto the detection operation table. That is to say, the present invention actually provides a mixing solution with less restriction on the operation environment and sample types (i.e., applicable to different types of cells). The preferred mixing device of the present invention is shown in Figures 1 - 5 as follows.

[0046] The present invention provides an in-needle mixing device (or mixing equipment) capable of realizing fixed mixing, including: A syringe 1, the syringe includes a first syringe 11 and a second syringe 12. Among them, the syringe preferably adopts a segmented design with an anti-drip function. For example, the inner diameter of the first syringe 11 gradually decreases along the direction from its first end to the second end, and the first syringe 11 further includes: an anti-drip part 111 provided at its second end; among them, as shown in Figure 3 as follows, the anti-drip part 111 includes: at least two extending wall surfaces 1111 formed by extending outward from the second end of the first syringe 11 (for example, along the direction close to the axis of the syringe).Figure 3 As shown, the cross-section of the first syringe 11 is trapezoidal), and a vacancy surface 1112 is formed at intervals between adjacent extending wall surfaces 1111; wherein, the second end of the first syringe is also referred to as the head of the syringe. Connecting pipeline 2, the first end of the connecting pipeline 2 is communicated with the second syringe 12. Ultrasonic vibration device 6, the ultrasonic vibration device 6 is connected to the second syringe 12. Negative pressure device 3 (which can also be called a power device), the negative pressure device 3 is arranged on the connecting pipeline, and the negative pressure device 3 is used to form a negative pressure or positive pressure environment in the connecting pipeline to guide the corresponding sample to enter or exit the syringe.

[0047] For example, in some embodiments, refer to Figure 1 As shown, the mixing device includes: a fixed tube sleeve 7. One end of the fixed tube sleeve 7 is sleeved on the second syringe, and the other end is fixedly arranged on the ultrasonic vibration device. Therefore, the syringe can maintain a relatively fixed position during vibration and only vibrate rapidly under the action of high-frequency ultrasound.

[0048] For example, in some embodiments, the fixed tube sleeve 7 can be used to indirectly connect the ultrasonic vibration device and the second syringe. For example, a tubular connecting part can be arranged on the ultrasonic vibration device, and the fixed tube sleeve 7 can be directly fixed on the tubular connecting part to indirectly connect the second syringe and the ultrasonic vibration device.

[0049] Or, in some embodiments, the syringe can be directly arranged on the ultrasonic vibration device, and the fixed tube sleeve 7 is mainly used to strengthen and fix the connection part of the syringe and the ultrasonic vibration device. For example, in some embodiments, the fixed tube sleeve can be provided with internal threads for fixedly connecting with the second syringe 12 by means of thread fitting.

[0050] For example, in some embodiments, a micro ultrasonic vibrator can be used as the ultrasonic vibration device to reduce the size of the mixing device.

[0051] For example, in some embodiments, a channel can be arranged in the middle of the ultrasonic vibration device to facilitate the second syringe (or the extension part of the second syringe, or the connecting pipeline 2) to pass through the channel, so that the rear end of the second syringe can be connected to the negative pressure device to achieve the purpose of liquid suction and liquid discharge with the assistance of the negative pressure device. For example, a tubular connecting part is formed at the channel, and the tubular connecting part can be sleeved on the second syringe (or the extension part of the second syringe, or the connecting pipeline 2).

[0052] For example, in some embodiments, the negative pressure device 3 is connected to the second end of the connecting pipeline 2, and a plunger is arranged in the negative pressure device 3. The plunger can reciprocate along a set direction to promote the syringe to inhale and discharge the secondary medium 5 through the second end of the first syringe 11 under the action of the plunger; Wherein, when the plunger moves in the first direction, a part of the primary medium 4 in the syringe 1 is discharged from the first end of the second syringe 12 under the action of the plunger, and the secondary medium 5 can be inhaled from the external space to complete the replacement of the primary medium by the secondary medium; when the plunger moves in the second direction, the secondary medium 5 in the syringe 1 is discharged from the second end of the first syringe.

[0053] In some embodiments, the primary medium 4 refers to the air in the syringe, and the secondary medium 5 refers to the liquid sample to be mixed (or simply referred to as liquid).

[0054] In this embodiment, the extended wall surface is matched with the vacant surface to reduce the adhesion ability of the liquid droplets at the head of the syringe, so that the formed liquid droplets will quickly drip at the head of the syringe to avoid excessive liquid residue at the head. Furthermore, when the syringe moves, it is not easy for liquid to spill at its head.

[0055] In some embodiments, the occupation area of one or more of the vacant surfaces is 1 / 3 to 1 / 2, and the occupation area = the total area of all vacant surfaces / the total area of all vacant surfaces + the total area of all extended wall surfaces.

[0056] In this embodiment, by restricting the occupation area, it is possible to avoid the liquid droplets from hanging at the narrowest end of the extended wall surface.

[0057] In some embodiments, refer to Figure 3 As shown, the edge of the corner of the extended wall surface 1111 is the first arc edge l1, and the second arc edge l2 is transitionally arranged between adjacent extended wall surfaces 1111; wherein, the corresponding vacant surface is formed by connecting the first arc edge, the second arc edge, and the first arc edge in sequence.

[0058] In some embodiments, the radius of curvature of the first arc edge l1 is smaller than the radius of curvature of the second arc edge l2. Or rather, the smoothness of the second arc edge is higher than that of the second arc edge.

[0059] Preferably, refer to Figure 3As shown, the vacant surface is formed by connecting multiple arc-shaped edges of two adjacent extended wall surfaces. Among them, the arc-shaped edge at the head is set to make the corners of the protruding extended wall surface more rounded. This rounding treatment can play a certain protective role for the anti-drip part, such as avoiding defects such as breakage caused by improper contact during the use of the head. On the other hand, the second arc-shaped edge is set with a slightly larger radius of curvature, which can also reduce the processing difficulty of fine structures to a certain extent, while avoiding excessive stress concentration in local areas and ensuring the strength of the fine structures.

[0060] It should be noted that the syringe used for sampling is usually very thin, especially when the size of the first syringe gradually decreases near its second end. Therefore, the processing difficulty of the structure on this fine structure is also very high. In this regard, the multi-segment arc-shaped edge setting in this embodiment can not only play the role of anti-drip, but also reduce the processing difficulty and improve the strength of the head.

[0061] In addition, it should be noted that in this embodiment, reciprocating movement is used to mix the liquid, so that the tip of the syringe can basically remain in place during the mixing process, thereby improving the structural stability of the syringe during the mixing process and also avoiding the splashing of the liquid.

[0062] And this fixed syringe type (that is, no circular motion or eccentric motion is required) can further simplify the mechanical design difficulty of the mixing device.

[0063] In some embodiments, the negative pressure device is a piston pump.

[0064] In some embodiments, the inner diameter of the second syringe 12 is 0.4 - 0.9 mm.

[0065] In some embodiments, the second syringe is preferably suitable for mixing 10 - 20 μL of type II medium (or called sample).

[0066] In some embodiments, the inner wall of the syringe is provided with a hydrophobic coating.

[0067] Preferably, the inner wall surface of the syringe in this embodiment has hydrophobic properties, thereby restricting the spreading ability of the liquid on the inner wall, reducing the contact area between the liquid and the surface, and further hindering the generation of bubbles.

[0068] In some embodiments, the inner wall of the syringe is treated by water grinding.

[0069] Preferably, the inner wall of the syringe in this embodiment adopts a smooth surface (that is, the smoothness can be improved by water grinding treatment). On the one hand, this can avoid the generation of bubbles, and on the other hand, it can also avoid the red blood cells from being broken due to external stimulation during the reciprocating movement.

[0070] In some embodiments, the syringe is a glass needle.

[0071] In some embodiments, the syringe is a steel needle.

[0072] As mentioned above, the present invention actually provides a fixed in-needle mixing method (or in-situ ultrasonic mixing method), which uses ultrasonic action at a relatively high frequency to mix the samples in a limited space inside the needle. And in order to coordinate the contradiction between mixing uniformity and the risk of sample breakage, the present invention provides an ultrasonic mixing method based on screening ultrasonic frequencies according to key features.

[0073] The present invention also provides an in-needle mixing method based on ultrasound, see Figure 6 shown, including the steps: S001, provide an in-needle mixing device, the in-needle mixing device includes a syringe, and the syringe is connected with an ultrasonic vibration device, and the syringe is also connected with a connecting pipeline, and a negative pressure device is arranged in the connecting pipeline, and the negative pressure device is used to form a negative pressure or positive pressure environment in the connecting pipeline to guide the corresponding sample to enter or exit the syringe; The in-needle mixing device can be the in-needle mixing device described in any one of the embodiments of the present invention.

[0074] S002, obtain the first ultrasonic feature and the second ultrasonic feature of the sample, wherein the sample includes: a first type of sample and a second type of sample, the first ultrasonic feature includes: the test mixing degree obtained by mixing the first type of sample and the second type of sample for a target duration at multiple ultrasonic frequencies; the second ultrasonic feature includes: the test breakage degree obtained by mixing the first type of sample for a target duration at multiple ultrasonic frequencies; Preferably, the first type of sample is usually a liquid sample containing cells. Further, the first type of sample is usually a liquid sample containing cells to be detected (such as red blood cells, white blood cells, etc.), and the cells to be detected can be the test objects of the items to be detected.

[0075] For example, in some embodiments, before the formal ultrasonic vibration mixing, multiple groups of preliminary experiments can be carried out to obtain multiple data records. A data record can include: vibration frequency, vibration time (equivalent to the target duration), test results - test mixing degree and / or test breakage degree. According to multiple data records, a corresponding feature database of the first ultrasonic feature and the second ultrasonic feature can be statistically generated. Of course, in other embodiments, the above data records can also be application records generated in real time during the application process (such as when the operator completes a real detection operation, that is, synchronously recording the ultrasonic parameters selected in the process and the final test results), that is, the feature database can also be gradually expanded as the actual detection data is generated.

[0076] For example, in some embodiments, the test results at different ultrasonic frequencies and different vibration durations can be recorded in the feature database.

[0077] For example, in some embodiments, the first ultrasonic feature can be a first fitting curve formed according to multiple data records. Among them, one data record includes: vibration time, vibration frequency, and the mixing result of the test (such as the degree of mixing). Correspondingly, according to multiple data records, a relationship curve between the vibration frequency and the degree of mixing can be fitted. Taking a rectangular coordinate system as an example, the vibration frequency can be represented by the X-axis, and the degree of mixing can be represented by the Y-axis.

[0078] Similarly, the second ultrasonic feature can also be a second fitting curve formed according to multiple data records. Among them, one data record includes: vibration time, vibration frequency, and the mixing result of the test (such as the degree of breakage). Correspondingly, according to multiple data records, a relationship curve between the vibration frequency and the degree of breakage can be fitted. Taking a rectangular coordinate system as an example, the vibration frequency can be represented by the X-axis, and the degree of breakage can be represented by the Y-axis.

[0079] S003. Select at least one reference ultrasonic frequency corresponding to the current sample from the first ultrasonic feature and the second ultrasonic feature according to the type of the item to be tested; Preferably, the sample to be mixed includes: sample A and sample B. Among them, sample A contains cells. Correspondingly, the first ultrasonic feature is selected or collected through sample A and sample B (equivalent to a type of sample and a second type of sample), that is, the first ultrasonic feature is preferably the mixing parameter of the actual samples A and B to be mixed, while the second ultrasonic feature is selected or collected through sample A (equivalent to the second type of sample).

[0080] S004. Input at least one of the reference ultrasonic frequencies into the ultrasonic vibration device to cause the current sample to be mixed under ultrasonic vibration.

[0081] For example, in some embodiments, as shown in Figure 7 S003 includes: S0031. Obtain the guiding mixing degree and the guiding breakage degree according to the type of the item to be tested; For example, in some embodiments, the types of items to be tested are divided into quantitative detection and qualitative detection. Different item types may put forward different requirements for the mixing quality (such as the degree of mixing, the degree of breakage).

[0082] For example, in some embodiments, the degree of mixing of a liquid sample can be evaluated by its appearance (such as color or turbidity). Alternatively, in some embodiments, the degree of mixing of a liquid sample can also be evaluated by quantitative testing means such as chromatography, mass spectrometry, and infrared spectroscopy. Specifically, scores can be set for different degrees of mixing, and the degree of mixing of the sample can be scored based on the above appearance observations or quantitative tests.

[0083] For example, in some embodiments, the degree of damage to a cell sample can be characterized by a damage rate as follows: Damage rate = (number of damaged cells / total number of cells) × 100%. For example, in some embodiments, the direct counting method (microscopic observation method, such as by trypan blue staining method, fluorescence staining method) can be used for statistics. Or, the optical density measurement method (indirect method) can be used for statistics.

[0084] ‌S0032, select at least one first ultrasonic frequency from the first ultrasonic features according to the guided mixing degree, where the first ultrasonic frequency satisfies the first rule: ; Preferably, in some embodiments, the first rule is: ; that is, select at least one ultrasonic frequency from the first ultrasonic features that can achieve sufficient mixing.

[0085] For example, when the first ultrasonic feature is the first fitting curve obtained by fitting multiple data records, at least one first line segment with Y≥guided mixing degree can be selected from the first fitting curve, and at least two ultrasonic frequencies corresponding to the first line segment can be recorded accordingly. For example, the ultrasonic frequencies corresponding to its two endpoints can be obtained.

[0086] S0033, determine whether at least one second ultrasonic frequency can be further selected from at least one of the first ultrasonic frequencies according to the second ultrasonic feature, where the second ultrasonic frequency satisfies the second rule: ; Wherein, the first threshold and the second threshold are preset determination values; preferably, the first threshold and the second threshold can be preset by the user.

[0087] For example, in some embodiments, suitable second ultrasonic frequencies can be further screened from the first line segment. Specifically, the test damage degrees corresponding to at least two ultrasonic frequencies in the first line segment can be queried respectively, and the following rule can be selected: select of the ultrasonic frequencies as the second ultrasonic frequency.

[0088] If so, execute step S0034; S0034. Determine the reference ultrasonic frequency according to at least one second ultrasonic frequency.

[0089] For example, in some embodiments, one second ultrasonic frequency can be selected from multiple second ultrasonic frequencies as the reference ultrasonic frequency.

[0090] Again, for example, in some embodiments, at least two second ultrasonic frequencies can be selected from multiple second ultrasonic frequencies as the reference ultrasonic frequencies, and the vibration process can use multiple reference ultrasonic frequencies for alternating vibration.

[0091] Again, for example, in some embodiments, the mean value of multiple second ultrasonic frequencies can be calculated as the reference ultrasonic frequency.

[0092] It should be noted that for different types of detection items, the types of samples and the number of samples to be mixed are different, so the mixing indexes and breakage requirements involved also vary greatly.

[0093] Especially when facing the mixing of multiple types of samples, and special types of cells are involved in the samples. For example, the red blood cells of anemia patients are relatively fragile and are prone to breakage during the ultrasonic process. Therefore, when it comes to the mixing process of red blood cells or other cells with lower mechanical strength, it will be difficult to balance the requirements of the mixing index and the breakage index. In this regard, the present invention provides a method for alternately screening ultrasonic frequencies based on the sample type, mixing index, and breakage index for the in-situ mixing method to meet the mixing requirements of cells with lower mechanical strength.

[0094] Furthermore, in some embodiments, when the result of S0033 is negative, S003 further includes the steps of: S0035. Select at least one third ultrasonic frequency and at least one fourth ultrasonic frequency from the first ultrasonic feature and the second ultrasonic feature; Among them, the third ultrasonic frequency satisfies the third rule: ; ; Among them, the fourth ultrasonic frequency satisfies the second rule: ; ; S0036. Determine at least one first reference ultrasonic frequency and at least one second reference ultrasonic frequency according to at least one third ultrasonic frequency and at least one fourth ultrasonic frequency respectively.

[0095] For example, one first reference ultrasonic frequency can be selected from at least one third ultrasonic frequency, or the mean value of at least one third ultrasonic frequency can be calculated as the first reference ultrasonic frequency.

[0096] For example, a second reference ultrasonic frequency may be selected from at least one fourth ultrasonic frequency, or the mean value of at least one fourth ultrasonic frequency may be calculated as the second reference ultrasonic frequency.

[0097] It can be understood that one or more of the above thresholds can be preset by the user.

[0098] In this embodiment, at the selected third ultrasonic frequency, the mixing degree of the sample is relatively high, but the risk of cell breakage may also be relatively high. In this regard, the vibration at the third ultrasonic frequency can also be called strong vibration. At the selected fourth ultrasonic frequency, the mixing uniformity of the sample is relatively low, but the risk of cell breakage also decreases accordingly. In this regard, the vibration at the fourth ultrasonic frequency can also be called weak vibration.

[0099] In some embodiments, in S004, the strong and weak alternating mixing method is used for mixing. Correspondingly, S004 includes the steps of: S0041, mixing for a first duration using the first reference ultrasonic frequency; S0042, mixing for a second duration using the second reference ultrasonic frequency, where the second duration is greater than the first duration, and the first reference ultrasonic frequency is greater than the second reference ultrasonic frequency; S0043, mixing for a third duration using the first reference ultrasonic frequency; where the first duration and the second duration are less than the corresponding target duration.

[0100] Preferably, the second duration is greater than the first duration and greater than the third duration.

[0101] In this embodiment, based on the strong and weak vibration data obtained by the above alternating screening, alternating strong and weak vibrations are performed, thereby ensuring the sufficient mixing of multiple types of samples on the basis of ensuring the integrity of cells as much as possible.

[0102] In some embodiments, S004 further includes the steps of: Performing at least one repetition of S0041 - S0043.

[0103] It should be noted that the alternating vibration scheme based on alternating screening proposed by the present invention can further limit the degree of breakage of cell samples on the basis of ensuring the mixing uniformity of the samples, and avoid damaging the samples.

[0104] Furthermore, for the mixing scenario of multiple types of samples, the samples may contain multiple types of cells. For example, at least two samples are cells or liquid samples containing at least one type of cell. The S002 step includes: (1)Determine the first cell and the second cell according to the type of the detection item, wherein the first cell can directly or indirectly reflect the required detection index; on the contrary, the second cell can be the cell attached in the liquid sample, which usually does not have an adverse effect or interference on the final detection result under normal conditions.

[0105] It can be understood that the detection items referred to in the present invention can be conventional medical detection and biological detection items. Therefore, the selection of the first cell and the second cell can be specified according to the detection item, or the detection item can pre-record the type information of the first cell and the second cell; (2)Select at least one main sample from at least two samples, wherein the main sample is a sample with a sample content ratio greater than a preset ratio; (3)Select the corresponding first ultrasonic feature according to at least one main sample; For example, in some embodiments, the selected first ultrasonic feature is the first fitting curve.

[0106] Preferably, in some embodiments, two main samples can be selected, and the first ultrasonic features corresponding to a type of sample and the second sample corresponding to the two main samples can be selected.

[0107] Preferably, in some embodiments, the types of the two main samples are exactly the same as those of a type of sample and a second type of sample.

[0108] Alternatively, in some embodiments, the so-called a type of sample or a second type of sample can be a sample with the same or similar sample attributes (such as the viscosity, density, particle size of the liquid, such as the cell size) as the main sample. If they are similar, it means that the difference degree between the sample attributes of the two is within a preset difference ratio, such as within 10%, or even within 20%.

[0109] (4)Select the corresponding second ultrasonic feature according to the first cell; Generally, the first cell is the cell contained in the selected a type of sample or a second type of sample, or the first cell is the first type of sample or the second type of sample.

[0110] For example, in some embodiments, the actual process in step (4) is: select the second ultrasonic feature corresponding to a type of sample or a second type of sample containing the first cell.

[0111] For example, in some embodiments, the second fitting curve corresponding to the first cell (or the sample containing the first cell) can be selected.

[0112] In this embodiment, for the mixing scenario of multiple types of samples, a method for screening ultrasonic frequencies based on the main sample is proposed.

[0113] In some embodiments, the mixing of two or more types of cells is involved, such as the co - mixing of cell A, cell B, and cell C. However, if cell C is the main detection object, and cell C and cell A are the two types of cells with the highest content, then cell C (or, the liquid containing cell C) and cell A (or, the liquid containing cell A) can be used as the main samples, and the first ultrasonic feature can be selected according to cell C and cell A (for example, in the early stage of application, cell C and cell A can be pre - mixed and tested first, and the corresponding mixing results, such as the first fitting curve, can be recorded); further, the second ultrasonic feature of cell C is obtained (this part of the data can also be obtained through pre - mixing tests); finally, the reference ultrasonic feature is comprehensively selected through the first ultrasonic feature and the second ultrasonic feature.

[0114] It should be noted that for the mixing scenarios of multiple types of samples, the present invention provides a two - layer screening step to select the ultrasonic frequency. The two - layer screening step includes: 1) primary screening in the database, that is, for the mixing scenarios involving three or more types of samples, the present invention can selectively and specifically select ultrasonic features in combination with the primary and secondary relationships of the samples; 2) fine screening of the reference feature frequency, alternately screening the first and second ultrasonic features by comprehensively considering the mixing and breakage indexes, so as to quickly screen out the ultrasonic frequency suitable for alternating ultrasonic vibration.

[0115] And the ultrasonic frequency selection result obtained based on this two - layer screening step can, on the one hand, ensure the effective mixing of multiple types of samples, and at the same time ensure that the core detection object (such as the first cell) in the mixed sample can maintain a relatively complete morphology, avoiding damage to the detection object during the mixing process and resulting in detection failure.

[0116] In some embodiments, it includes the steps: S005, record the actual mixing degree and actual breakage degree of the current sample; S006, determine whether the actual mixing degree and the actual breakage degree meet the requirements of the guided mixing degree and the guided breakage degree (for example, the actual mixing degree and the actual breakage degree respectively meet the first and second rules); if so, execute the steps: S007, record the current ultrasonic working data, and correspondingly update the first ultrasonic feature or the second ultrasonic feature.

[0117] In some embodiments, the inner diameter of the syringe 12 is 0.4 - 0.9 mm.

[0118] Taking the mixing process of samples such as plasma and red blood cells as an example, the mixing method is exemplarily described as follows: First, a sampling container can be set on the equipment operating table, which holds the centrifuged blood sample, and the sample from top to bottom is the plasma layer, the platelet and white blood cell layer, and the red blood cell layer respectively.

[0119] Then, an appropriate amount of red blood cells (which is equivalent to the second sample in some embodiments) can be aspirated using a syringe.

[0120] Subsequently, the syringe is lifted to aspirate an appropriate amount of plasma (which is equivalent to the first sample in some embodiments).

[0121] Lift the syringe and raise the liquid level of the preliminarily mixed sample of red blood cells and plasma to be above or maintained at a first height H1, where the first height H1 is higher than or located at the demarcation line between the first syringe and the second syringe; ensure that no liquid droplets are hanging on the anti - dripping part 111; For example, in some embodiments, it can be visually observed by an operator that there are no hanging liquid droplets at the anti - dripping part 111.

[0122] Preferably, to prevent liquid splashing, the height of the upper and lower liquid levels can be maintained between a second height H2 and a third height H3. For example, the second height H2 is preferably above the demarcation line between the first syringe and the second syringe. Of course, in some embodiments, according to different liquid contents, the specific positions of the second height and the third height can be adaptively set by the operator.

[0123] For the in - syringe mixing requirements of a large number of types of samples, the present invention provides an in - situ mixing solution that performs intensity - interactive high - frequency vibration on the samples based on partial pre - test data. This in - situ mixing solution can simplify the mechanical design difficulty of the mixing device and reduce the application cost.

[0124] It can be understood that in actual detection applications, different detection items have different requirements for factors such as the type, content, and even the mixing degree of the samples. In addition, for different types of samples, such as different types of cells, or different cell samples collected from objects with different health conditions, there are also likely to be significant differences in their mechanical strengths.

[0125] In this regard, the alternating ultrasonic frequency screening technology provided by the present invention based on partial pre - test data can reduce the difficulty of selecting ultrasonic conditions and reduce the workload of pre - experiments before ultrasonic treatment.

[0126] It should be noted that in this article, the term "comprise", "include" or any other variant thereof is intended to cover non - exclusive inclusion, so that a process, method, article or device including a series of elements not only includes those elements but also includes other elements not expressly listed, or further includes elements inherent to such process, method, article or device. Without further limitations, an element defined by the statement "including one..." does not exclude the existence of additional identical elements in the process, method, article or device including that element.

[0127] Through the description of the above embodiments, those skilled in the art can clearly understand that the above-described example methods can be implemented by means of software plus a necessary general hardware platform. Of course, they can also be implemented by hardware, but in many cases the former is a better implementation. Based on such an understanding, the technical solution of the present invention, in essence, or the part that contributes to the prior art can be embodied in the form of a software product. This computer software product is stored in a storage medium (such as ROM / RAM, magnetic disk, optical disk) and includes several instructions for causing a computer terminal (which can be a mobile phone, computer, server, or network device, etc.) to execute the methods described in various embodiments of the present invention.

[0128] The embodiments of the present invention have been described above in conjunction with the accompanying drawings. However, the present invention is not limited to the above specific embodiments. The above specific embodiments are merely illustrative and not restrictive. Under the inspiration of the present invention, those of ordinary skill in the art can also make many forms without departing from the purpose of the present invention and the scope protected by the claims. All of these are within the protection scope of the present invention.

Claims

1. An ultrasound-based in-needle mixing method, characterized in that: Includes steps: S001, providing an in-needle mixing device, the in-needle mixing device comprising a needle tube, the needle tube being connected to an ultrasonic vibration device, and the needle tube being further connected to a connecting pipeline, wherein a negative pressure device is arranged in the connecting pipeline, and the negative pressure device is used to form a negative pressure or positive pressure environment in the connecting pipeline to guide the corresponding sample to enter or exit the needle tube; S002, obtaining a first ultrasonic feature and a second ultrasonic feature of the sample, wherein the sample includes: a first type of sample and a second type of sample, the first ultrasonic feature includes: a test mixing degree obtained by mixing the first type of sample and the second type of sample at multiple ultrasonic frequencies for a target time; the second ultrasonic feature includes: a test damage degree obtained by mixing the first type of sample at multiple ultrasonic frequencies for a target time; S003, selecting at least one reference ultrasonic frequency corresponding to the current sample from the first ultrasonic feature and the second ultrasonic feature according to the type of the item to be tested; S004, inputting at least one of the reference ultrasonic frequencies into the ultrasonic vibration device to promote mixing of the current sample under ultrasonic vibration.

2. The ultrasound-based in-needle mixing method according to claim 1, characterized in that: S003 includes: S0031, obtaining a guiding mixing degree and a guiding damage degree according to the type of the item to be tested; S0032: Select at least one first ultrasonic frequency from the first ultrasonic feature according to the guiding mixing degree, wherein the first ultrasonic frequency satisfies a first rule: ； S0033, determining whether at least one second ultrasonic frequency can be further selected from at least one of the first ultrasonic frequencies according to the second ultrasonic feature, wherein the second ultrasonic frequency satisfies a second rule: ； Wherein, the first threshold value and the second threshold value are preset judgment values; if so, execute step S0034; S0034, determining the reference ultrasonic frequency according to at least one second ultrasonic frequency.

3. The ultrasound-based in-needle mixing method according to claim 2, characterized in that: When the result of S0033 is no, S003 further includes the steps of: S0035, selecting at least one third ultrasonic frequency and at least one fourth ultrasonic frequency from the first ultrasonic feature and the second ultrasonic feature; Wherein, the third ultrasonic frequency satisfies the third rule: ； ； Wherein, the fourth ultrasonic frequency satisfies the second rule: ； ； S0036: Determine at least one first reference ultrasonic frequency and at least one second reference ultrasonic frequency according to at least one third ultrasonic frequency and at least one fourth ultrasonic frequency, respectively.

4. The ultrasound-based in-needle mixing method according to claim 3, characterized in that: In S004, a strong and weak alternating mixing method is used for mixing. Correspondingly, S004 includes the steps of: S0041, using the first reference ultrasonic frequency to mix for a first time length; S0042, using the second reference ultrasonic frequency to mix for a second duration, wherein the second duration is greater than the first duration, and the first reference ultrasonic frequency is greater than the second reference ultrasonic frequency; S0043, using the first reference ultrasonic frequency to mix a third time length; wherein the first time length and the second time length are less than the corresponding target time lengths.

5. The ultrasound-based in-needle mixing method according to claim 4, characterized in that: S004 also includes the steps of: S0041-S0043 were repeated at least once.

6. The ultrasound-based in-needle mixing method according to claim 5, characterized in that: Includes steps: S005, recording the actual mixing degree and actual damage degree of the current sample; S006, judging whether the actual mixing degree and the actual damage degree meet the requirements of the guiding mixing degree and the guiding damage degree; if so, executing the steps: S007, record the current ultrasonic working data, and update the first ultrasonic feature or the second ultrasonic feature accordingly.

7. The ultrasound-based in-needle mixing method according to any one of claims 1 to 6, characterized in that: The inner diameter of the needle tube is 0.4-0.9 mm.

8. An ultrasound-based in-needle mixing system, characterized in that: include: A needle tube (1), the needle tube comprising a first needle tube (11) and a second needle tube (12), wherein the inner diameter of the first needle tube (11) gradually decreases along the direction from the first end to the second end thereof, and the second end of the first needle tube (11) is provided with an anti-drip portion (111); wherein the anti-drip portion (111) comprises: at least two extended wall surfaces (1111) formed by extending outwards from the second end of the first needle tube (11), and a vacant surface (1112) is formed between two adjacent extended wall surfaces (1111); A connecting pipeline (2), wherein a first end of the connecting pipeline (2) is connected to the second needle tube (12); an ultrasonic vibration device (6), the ultrasonic vibration device (6) being connected to the second needle tube (12); A negative pressure device is provided on the connecting pipeline and is used to form a negative pressure or positive pressure environment in the connecting pipeline to guide the corresponding sample to enter or be discharged from the needle tube.

9. The in-needle mixing system according to claim 8, characterized in that: The occupied area of ​​one or more of the vacant surfaces is 1 / 3 to 1 / 2, and the occupied area = the total area of ​​all the vacant surfaces / (the total area of ​​all the vacant surfaces + the total area of ​​all the extended wall surfaces); and / or the inner diameter of the second needle tube (12) is 0.4-0.9 mm.

10. The in-needle mixing system according to claim 9, characterized in that: The edge of the corner of the extended wall surface (1111) is a first arc-shaped edge, and a second arc-shaped edge is provided transitionally between adjacent extended wall surfaces (1111); wherein the first arc-shaped edge, the second arc-shaped edge, and the first arc-shaped edge are sequentially connected to form the corresponding vacant surface.

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