Puncture needle based on pH-triggered ultrasonic development and preparation method thereof

Abstract

The invention discloses a puncture needle based on pH-triggered ultrasonic development and a preparation method thereof, and belongs to the technical field of medical instruments. A needle body of the puncture needle is coated with a hemostatic first functional coating containing amino polysaccharide substances, and a needle tip is coated with a developing second functional coating containing pH-responsive acid source microspheres, carbonate substances and a film-forming matrix. The preparation method comprises the steps of microsphere preparation, needle body pretreatment, coating liquid preparation, partitioned coating and cross-linking post-treatment. The hemostasis and active development functions are integrated, development is accurate and targeted, the material process is mature, the cost and the operation difficulty are effectively reduced, and the operation safety and precision are improved.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medical devices, and particularly relates to a puncture needle based on pH-triggered ultrasonic imaging and a preparation method thereof. BACKGROUND

[0002] Percutaneous biopsy and interventional therapy are the core technologies of modern tumor diagnosis and treatment, and the key to the successful implementation thereof is to accurately deliver the puncture needle to the target lesion. Ultrasonic imaging has become the mainstream imaging technology for clinical puncture guidance due to its strong real-time performance, no radiation, convenient operation and other outstanding advantages. However, the traditional puncture needle faces two key technical bottlenecks in actual application: first, the ultrasonic imaging effect of the needle tip is poor, especially in deep tissues or complex echo characteristic tumor regions, and the accurate position of the needle tip is difficult to identify clearly, which easily leads to lesion sampling deviation, incomplete treatment range coverage and other problems; second, the puncture operation can cause tissue damage and bleeding along the needle path, which not only increases the risk of complications for patients, but also further interferes with the quality of the ultrasonic image, exacerbates the visual field blur and affects the accuracy of the operation.

[0003] At present, the technical optimization of the puncture needle is mainly focused on the improvement of a single function, and the synergistic integration of imaging and hemostasis cannot be achieved. In terms of imaging optimization, the physical structure of the needle body is mainly modified to enhance ultrasonic scattering, or the signal of the target region is strengthened by injecting exogenous contrast agents into blood vessels; the improvement of the hemostatic function mainly adopts a single biological material coating strategy, which utilizes the coagulation-promoting properties of the material to reduce bleeding along the needle path. These technologies have significant limitations: the single function cannot meet the clinical multifunctional requirements, the imaging accuracy is insufficient and the mechanism is passive, which depends on external conditions such as the circulatory system, and the use of special structure processing and contrast agents also increases the technical cost and operation complexity, which is difficult to adapt to the actual needs of the clinical puncture needle intelligentization and high efficiency. SUMMARY

[0004] The puncture needle provided by the application has the functions of "hemostasis" and "active imaging" through the surface integrated double-function coating, reduces tissue bleeding and plasma exudation through the coating of the needle body, realizes effective needle channel hemostasis, and provides accurate needle tip active imaging. The specific technical solutions are as follows: the puncture needle based on pH-triggered ultrasonic imaging includes a puncture needle body, the needle body surface of the puncture needle body is coated with a first functional coating, the needle body surface of the puncture needle body is coated with a first functional coating, the first functional coating contains amino polysaccharide substances, specifically chitosan or its derivatives, the bioactivity of chitosan is used to realize the effects of promoting coagulation and antibiosis, and the needle channel bleeding can be continuously reduced during the puncture process; the needle tip surface of the puncture needle body is coated with a second functional coating, the second functional coating is an environment-responsive imaging coating, which contains acid source substances, carbonate substances and film-forming matrix, wherein the acid source substances are solid organic acids, the carbonate substances are anhydrous sodium carbonate, and the film-forming matrix is chitosan, wherein the acid source substances are wrapped by pH-responsive polymer microspheres, the wall material of the pH-responsive polymer microspheres is a polymer that dissolves at pH<7.0 and does not dissolve or swells at pH>7.0, and the molar mass of the carbonate substances is much greater than the releasable H⁺ molar mass of the acid source substances. When the needle tip reaches the weakly acidic microenvironment of the tumor with pH≈6.5, the pH-responsive acid source microsphere wall material relaxes, the internal acid source substances dissolve and diffuse, neutralization reaction occurs with excess sodium carbonate to generate CO2 microbubbles, the reaction formula is: 2H⁺+CO3²⁻→CO2↑+H2O, the CO2 microbubbles are strong ultrasonic scattering sources, form high echo signals of the needle tip position on the ultrasonic image, and realize accurate positioning.

[0005] The application further provides a preparation method of the puncture needle based on pH-triggered ultrasonic imaging, and the specific steps are as follows: Step 1: preparing pH-responsive acid source microspheres: dissolving a pH-sensitive polymer in an organic solvent to form an oil phase, dispersing a solid organic acid powder in an aqueous solution containing an emulsifier to form a water phase; dropping the oil phase into the water phase and emulsifying at a high speed to form a water-in-oil emulsion, stirring in a water bath to volatilize the organic solvent, centrifuging to collect the microspheres, washing and drying; the pH-sensitive polymer is Eudragit E100, the organic solvent is dichloromethane, and the emulsifier is Span 80; the high-speed shearing speed is 8000-10000 rpm, and the emulsification time is 3-5 minutes; the water bath temperature is 30-40 DEG C, and the stirring time is 2-3 hours; Step 2: pretreatment of the puncture needle: sequentially ultrasonically cleaning the puncture needle body with acetone, anhydrous ethanol and deionized water, then immersing the puncture needle body in a 60-70 DEG C 1M NaOH solution for 30 minutes, rinsing with deionized water and blowing dry with nitrogen; Step 3: preparing a coating solution: dissolving chitosan or its derivative in an acidic aqueous solution to form a matrix solution; taking part of the matrix solution, adding the pH-responsive acid source microspheres prepared in Step 1 and a carbonate substance, and stirring to uniformly disperse to obtain a second functional coating solution; the remaining matrix solution is used as a first functional coating solution; the acidic aqueous solution is a 1% v / v acetic acid aqueous solution, and the concentration of the matrix solution is 1.0-2.0% w / v; the molar ratio of the carbonate substance to the solid organic acid is (3-5):1; Step 4: zoned coating: shielding the needle body part of the puncture needle body, exposing only the needle tip area, coating the second functional coating solution on the exposed needle tip area, and immediately immersing in a pre-cooled Na2CO3 solution for pre-gelation; after removing the shielding material, coating the first functional coating solution on the needle body; the coating mode of the second functional coating solution is microspotting or dip-coating (pulling speed <0.5 mm / s); the pre-cooled Na2CO3 solution has a concentration of 2% w / v and a temperature of 4 DEG C, and the immersion time is 5-15 seconds; Step 5: cross-linking, solidification and post-treatment: immersing the coated puncture needle body in an aqueous cross-linking agent solution, cross-linking at 37 DEG C, rinsing with deionized water to remove residual reagents, drying in a sterile environment, and then sterilizing to complete the preparation; the cross-linking agent is genipin, the concentration of the aqueous cross-linking agent solution is 0.1-0.3% w / v, the cross-linking time is 6 hours, the drying temperature is 35-40 DEG C, and the sterilization mode is ethylene oxide sterilization or low-temperature plasma sterilization.

[0006] Compared with the prior art, the application has the following beneficial effects: 1. Through the design of "partition coating", the "hemostasis" and "active ultrasonic imaging" dual core functions are realized on the same puncture needle, solving the problem that the imaging scheme and the hemostasis scheme are mutually separated in the prior art. The chitosan coating of the needle body can effectively reduce the needle path bleeding and reduce the risk of infection, and the pH-responsive composite coating of the needle tip can accurately feedback the position of the needle tip; 2. The imaging mechanism triggered by the weak acid microenvironment of the tumor is adopted, and only when the needle tip reaches the target lesion area, CO2 microbubbles are generated in situ. The high echo signal formed by the microbubbles is highly corresponding to the anatomical position of the needle tip, which fundamentally solves the clinical pain points of the traditional puncture needle, such as the blurred imaging of the needle tip and the inaccurate positioning, and significantly improves the sampling accuracy of the puncture biopsy and the targeting accuracy of the interventional therapy; 3. The materials such as chitosan and sodium carbonate used are mature and easy to obtain, and the coating and cross-linking processes have strong scalability, which can not only effectively control the manufacturing cost, but also match the production and sterilization process of the existing medical devices, and has high clinical transformation potential and market promotion value. BRIEF DESCRIPTION OF DRAWINGS

[0007] In order to more clearly illustrate the technical solutions of the embodiments of the application, the drawings used in the description of the embodiments will be briefly introduced.

[0008] Figure 1 is the overall structure schematic diagram of the embodiment 1 of the application.

[0009] Figure 2 is the in-vitro experimental verification diagram, wherein Figure 2 A is the state of microsphere bubble generation in the pH=6.5 phosphate buffer solution, Figure 2 B is the high echo imaging image of the bubbles around the needle tip under ultrasound.

[0010] The structure names represented by the numbers in the drawings are: 1-puncture needle body, 2-first functional coating, 3-second functional coating. DETAILED DESCRIPTION

[0011] The application will be described in detail below with reference to the drawings and specific embodiments. Obviously, the described embodiments are only part of the embodiments of the application, not all embodiments.

[0012] Embodiment: 1 refer to Figure 1As shown, the puncture needle based on pH-triggered ultrasonic imaging of the present embodiment comprises a puncture needle body 1 which adopts a medical stainless steel puncture needle of 18G specification. The needle body surface of the puncture needle body 1 is coated with a first functional coating 2 which takes chitosan as the core component and mainly plays the roles of hemostasis and antibiosis; the needle tip surface of the puncture needle body 1 is coated with a second functional coating 3 which is composed of citric acid, anhydrous sodium carbonate, chitosan and pH-responsive polymer microspheres (wall material is Eudragit E100), wherein the molar amount of anhydrous sodium carbonate is 4 times that of citric acid releasable H⁺ molar amount, ensuring that the reaction proceeds fully.

[0013] The use flow is as follows: the operator holds the puncture needle body 1 and punctures the target lesion area under the guidance of ultrasound. During the puncture process, the first functional coating 2 of the needle body contacts with the human body tissue, continuously reduces the bleeding of the needle path in the way of adsorbing red blood cells and promoting platelet aggregation, and avoids the interference of blood exudation with the ultrasonic field. When the needle tip reaches the weakly acidic microenvironment (pH≈6.5) of the tumor, the wall material of the pH-responsive polymer microspheres in the second functional coating 3 relaxes, the internally wrapped citric acid gradually dissolves and diffuses outward, and neutralization reaction occurs with the surrounding excess anhydrous sodium carbonate to generate a large amount of CO2 microbubbles in situ. The CO2 microbubbles serve as strong ultrasonic scattering sources and form clear high echo “comet tail” signals on the ultrasonic image. According to the signals, the position of the needle tip is accurately confirmed, and then the puncture angle and depth are adjusted to complete the biopsy sampling or interventional treatment operation.

[0014] The preparation flow of the puncture needle based on pH-triggered ultrasonic imaging is completed according to the following steps: 1. Preparation of pH-responsive acid source microspheres: weigh 500 mg of Eudragit E100 polymer, dissolve in 20 mL of dichloromethane, and stir for 30 minutes to form a uniform oil phase; weigh 200 mg of citric acid powder (screened through a 400-mesh sieve), disperse in 50 mL of 0.5% (w / v) Span 80 deionized water solution, and use a high-speed shear emulsifier to pre-emulsify at a speed of 8000 rpm for 1 minute to form an aqueous phase. Slowly drop the oil phase into the aqueous phase at a rate of 1 mL / min, while increasing the shear speed to 10000 rpm, and continue to emulsify for 5 minutes to form a stable water-in-oil emulsion. Transfer the emulsion to a 250 mL round-bottom flask, place it in a 35°C constant temperature water bath, and stir at a speed of 300 rpm with a magnetic stirrer for 2.5 hours to completely volatilize the dichloromethane. Then centrifuge the suspension at 5000 rpm for 5 minutes, discard the supernatant, and repeat the washing-centrifuging operation 3 times with deionized water to remove residual emulsifiers and uncoated citric acid. Collect the microspheres and dry them in a 30°C vacuum drying oven overnight to obtain pH-responsive acid source microspheres with a particle size of 8-15 μm.

[0015] 2. The puncture needle pretreatment: the puncture needle body 1 is sequentially placed in acetone, anhydrous ethanol, and deionized water for ultrasonic cleaning for 15 minutes each, so as to thoroughly remove surface oil stains and impurities. The cleaned puncture needle is immersed in a 65℃ 1M NaOH solution for 30 minutes, and after being taken out, it is repeatedly washed with deionized water until the washing liquid is neutral, and finally it is dried with nitrogen for standby use.

[0016] 3. Preparation of coating liquid: 1.5g of chitosan is slowly added into 100mL of 1% (v / v) acetic acid aqueous solution, and is magnetically stirred for 12 hours until completely dissolved, and is left standing for 4 hours to degas, so as to obtain a 1.5% (w / v) chitosan matrix solution. 10mL of the matrix solution is taken, 50mg of the pH-responsive acid source microspheres prepared above and 200mg of anhydrous sodium carbonate powder are added, and are first treated by a vortex oscillator for 1 minute, and then are magnetically stirred at a low speed of 100rpm for 30 minutes, so as to ensure that the microspheres and sodium carbonate are uniformly dispersed, so as to prepare a second functional coating 3 liquid; the remaining matrix solution is directly used as a first functional coating 2 liquid.

[0017] 4. Zonal coating: the needle body part of the puncture needle is completely shielded with high-precision photoresist, and only the area of the needle tip forward 2mm is exposed. The second functional coating 3 liquid is taken by a micro-sampling device, and is uniformly coated on the exposed surface of the needle tip, and immediately the needle tip is immersed in a 4℃ pre-cooled 2% (w / v) Na2CO3 solution for 10 seconds, so as to make the coating preliminarily gel. Then the photoresist is carefully peeled off, and the first functional coating 2 liquid is coated on the surface of the needle body by an immersion pulling method (the pulling speed is controlled at 0.3mm / s).

[0018] 5. Cross-linking and curing and post-treatment: the coated puncture needle is immersed in a 0.2% (w / v) genipin aqueous solution, and is placed in a 37℃ constant temperature incubator for cross-linking for 6 hours. After being taken out, it is washed with a large amount of deionized water to remove the residual genipin reagent on the surface, and is dried at 37℃ in a sterile environment for 8 hours. Finally, the puncture needle is sterilized by an ethylene oxide sterilization method, and the preparation is completed.

[0019] Performance verification experiment: 1. Microsphere performance verification: 10mg of pH-responsive acid source microspheres is taken and added into 5mL of PBS buffer with pH=6.5, and is vortexed for 30 seconds to ensure that the microspheres are uniformly dispersed without obvious aggregation. Bubbles as shown in Figure 2 A should be observed after a few minutes.

[0020] 2. Coating firmness verification: the adhesion of the coating is tested according to the grid method standard of ASTM D3359, and the coating should not have large area peeling.

[0021] 3. Needle tip coating verification: The coated needle tip is immersed in a preheated phosphate buffer solution at 37°C, pH = 6.8, and observed in real time under a clinical ultrasound diagnostic instrument (such as one equipped with a linear probe). Within 30-60 seconds after the needle tip enters the water, a continuous, dense, high-echo "snowstorm" or comet tail-like sonogram should appear, such as Figure 2 B, and the signal source is strictly limited to the needle tip.

[0022] The above examples are only used to illustrate the technical solutions of the present application, but not to limit the protection scope of the present application. For those skilled in the art, various modifications and changes can be made to the above examples without departing from the principles of the present application, and these modifications and changes shall fall within the protection scope of the present application.

Claims

1. A pH-triggered ultrasound-visualized puncture needle comprising a puncture needle body (1), characterized in that: The needle body (1) is coated with a first functional coating (2) containing an aminopolysaccharide substance, which can continuously reduce the bleeding along the needle path during the puncture process; the needle tip surface of the puncture needle body (1) is coated with a second functional coating (3), which is an environmentally responsive developing coating containing an acid source substance, a carbonate substance and a film-forming matrix, wherein the acid source substance is wrapped by pH-responsive polymer microspheres, and carbon dioxide microbubbles are generated by the reaction of the second functional coating (3) with the weakly acidic environment of the tumor, which can form a high echo signal of the needle tip position on the ultrasound image.

2. The pH-triggered ultrasound-visualization based puncture needle according to claim 1, wherein: The aminopolysaccharide substance is chitosan or its derivative.

3. The pH-triggered ultrasound-contrast-based puncture needle according to claim 1, wherein: The acid source substance is a solid organic acid; the carbonate substance is anhydrous sodium carbonate; the film-forming matrix is chitosan; the molar mass of the carbonate substance is much greater than the releasable H⁺ molar mass of the acid source substance.

4. The pH-triggered ultrasound-visualization based puncture needle according to claim 1, wherein: The wall material of the pH-responsive polymer microspheres uses a polymer that dissolves at pH<7.0 and does not dissolve or swells at pH>7.

0.

5. The method for preparing the pH-triggered ultrasound-echo-based puncture needle according to any one of claims 1-4, comprising the following steps: S1: preparing pH-responsive acid source microspheres: dissolving a pH-sensitive polymer in an organic solvent to form an oil phase, dispersing a solid organic acid powder in an aqueous solution containing an emulsifier to form an aqueous phase; drop the oil phase into the aqueous phase and emulsify at high speed to form a water-in-oil emulsion, stir in a water bath to volatilize the organic solvent, collect the microspheres by centrifugation, wash and dry; S2: pretreatment of the puncture needle: sequentially ultrasonically clean the puncture needle body (1) with acetone, anhydrous ethanol and deionized water, then immerse it in a 60-70°C 1M NaOH solution for 30 minutes, rinse with deionized water and dry with nitrogen; S3: preparing a coating solution: dissolve chitosan or its derivative in an acidic aqueous solution to form a matrix solution; take part of the matrix solution, add the pH-responsive acid source microspheres prepared in S1 and a carbonate substance, and stir to disperse uniformly to obtain a second functional coating (3) solution; The remaining matrix solution is used as the first functional coating (2) liquid; S4: Zoning coating: shielding the needle body part of the puncture needle body (1), exposing only the needle tip area, coating the second functional coating (3) liquid on the exposed needle tip area, and immediately immersing it in a pre-cooled Na2CO3 solution for pre-gelation; after removing the shielding material, the first functional coating (2) liquid is coated on the needle body; S5: cross-linking and curing and post-processing: immerse the coated puncture needle body (1) in a cross-linking agent aqueous solution, cross-link at 37°C; rinse with deionized water to remove residual reagents, dry in a sterile environment, and then sterilize to complete the preparation.

6. The method for preparing a puncture needle based on pH-triggered ultrasound imaging according to claim 5, characterized in that: The pH-sensitive polymer in S1 is Eudragit E100, the organic solvent is dichloromethane; the emulsifier is Span 80; the high-speed shearing rotation speed is 8000-10000 rpm, and the emulsification time is 3-5 minutes; the water bath temperature is 30-40°C, and the stirring time is 2-3 hours.

7. The method for preparing a puncture needle based on pH-triggered ultrasound imaging according to claim 5, characterized in that: The acid aqueous solution in S3 is 1% v / v acetic acid aqueous solution, and the concentration of the matrix solution is 1.0-2.0% w / v; the molar ratio of the carbonate substance to the solid organic acid is (3-5):

1.

8. The method for preparing a puncture needle based on pH-triggered ultrasound imaging according to claim 5, characterized in that: In S4, the coating method of the second functional coating (3) liquid is micro-dots or immersion and pulling; the pre-cooled Na2CO3 solution has a concentration of 2% w / v and a temperature of 4°C, and the immersion time is 5-15 seconds.

9. The method for preparing a puncture needle based on pH-triggered ultrasound imaging according to claim 5, characterized in that: In S5, the cross-linking agent is genipin, the concentration of the cross-linking agent aqueous solution is 0.1-0.3% w / v, the cross-linking time is 6 hours; the drying temperature is 35-40°C, and the sterilization method is ethylene oxide sterilization or low-temperature plasma sterilization.

10. The puncture needle based on pH-triggered ultrasonic imaging in medical diagnosis or treatment devices according to any one of claims 1-4.

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