Self-adapting hydrogel coupling agent, preparation method and application thereof

Abstract

The application discloses a self-adapting hydrogel coupling agent and a preparation method and application thereof, and belongs to the field of medical devices, and particularly relates to a preparation method of a self-adapting hydrogel coupling agent; the preparation method comprises the following steps: under the conditions of light avoidance and sterility, main monomers, functional monomers, a molecular weight regulator and reinforcing fillers are dissolved in sterilized deionized water, and then free radical polymerization is carried out under the action of a persulfate solution and tetramethylethylenediamine, and after dialysis and sterilization treatment, the self-adapting hydrogel coupling agent is obtained. The self-adapting hydrogel coupling agent prepared by the application eliminates tissue deformation caused by probe pressurization, significantly improves the measurement accuracy of an actual distance of a target in an operation by ultrasonic waves, and is good in biocompatibility, can be sterilized, is convenient to operate, and is suitable for open or endoscopic operation wounds.

Description

Technical Field

[0001] This invention relates to the field of medical device technology, specifically to a self-adaptive hydrogel coupling agent, its preparation method, and its application. Background Technology

[0002] Intraoperative ultrasound is an important auxiliary tool in surgery, especially for tumor resection. It can provide real-time visualization of deep tissue structures, helping surgeons to accurately locate tumor boundaries, deep blood vessels and important nerves, assess the extent of resection, and improve surgical precision and safety.

[0003] To obtain clear ultrasound images, an air gap must be eliminated between the ultrasound probe and the human tissue. This is because air strongly reflects ultrasound waves, severely affecting image quality. In the surgical setting, the most commonly used method is the "drip coupling method," which involves continuously dripping sterile saline solution into the area where the probe contacts the tissue.

[0004] However, the existing technology has the following core problems: (1) The distance measurement is significantly shortened. When using the dripping method, in order to ensure the continuous existence of the acoustic window, the operator usually needs to apply a certain pressure to the probe to maintain the stability of the water film. This pressure will cause local deformation and depression of the tissue, especially soft tissue. This deformation directly causes the distance from the actual acoustic window surface of the probe to the target tumor to be "shortened", resulting in the measured distance value being less than the true distance. In surgical procedures that pursue precise resection margins, this systematic deviation may cause the risk of excessive or insufficient resection. Excessive resection will increase tissue damage, while insufficient resection may lead to residual lesions. (2) Unstable coupling. Water is fluid and it is difficult to form a stable and uniform coupling layer on uneven tissue surfaces such as the gyri and liver surface. Probe movement or slight tilting can easily lead to coupling failure, requiring frequent water replenishment and adjustment, which affects the smoothness of the operation. (3) Inconvenient operation. Continuous dripping requires the cooperation of an assistant or additional irrigation device, which increases the complexity of the operation. Liquid may also accumulate in the surgical area, affecting the field of vision. (4) Insufficiency of existing alternatives. Commercial medical ultrasound coupling agents are mostly viscous polymer gels. While they provide stable coupling, their composition is often complex, potentially containing mineral oil, carbomer, preservatives, etc. They are strictly prohibited from use inside open surgical wounds to prevent risks such as foreign body reactions, inflammation, or even tumor implantation. Furthermore, standard coupling agents are mostly non-sterile, and their viscosity makes it difficult to precisely adapt to the complex tissue morphology during surgery.

[0005] Therefore, there is a need in the field for a novel coupling solution that is suitable for open surgical environments, can eliminate the influence of probe pressure, accurately adapt to tissue morphology, is safe and sterile, and can significantly improve the accuracy of intraoperative ultrasound distance measurement. Summary of the Invention

[0006] The purpose of this invention is to provide a self-adaptive hydrogel coupling agent, its preparation method, and its application. Compared with the sterile water used in traditional intraoperative ultrasound, it not only effectively eliminates the air gap between the probe and the tissue and avoids tissue deformation caused by applied pressure, thereby improving the accuracy of intraoperative ultrasound in measuring the distance to the lesion; but also, by improving biocompatibility and tissue adhesion, its adaptive viscoelasticity and shear thinning properties enable it to perfectly fill and conform to various complex tissue morphologies during surgery, ensuring the consistency of acoustic coupling and effectively reducing image artifacts.

[0007] The technical solution adopted by the present invention to achieve the above objectives is as follows:

[0008] A method for preparing a self-adaptive hydrogel coupling agent, comprising,

[0009] Under light-protected and sterile conditions, the main monomer, reversible dynamic cross-linking functional monomer, molecular weight regulator and reinforcing filler are dissolved in sterile deionized water and then undergo free radical polymerization under the action of initiator and accelerator. After dialysis and sterilization, a self-adaptive hydrogel coupling agent is obtained.

[0010] The main monomer is at least one of acrylamide, N,N-dimethylacrylamide, N-hydroxyethylacrylamide, hydroxyethyl methacrylate, poly(ethylene glycol) methacrylate, and polyethylene glycol methyl ether methacrylate.

[0011] Reversible dynamic crosslinking functional monomers include at least one of the following categories: borate ester bond dynamic crosslinking, host-guest interaction, multiple hydrogen bond, and ionic crosslinking.

[0012] The self-adaptive hydrogel coupling agent disclosed in this invention is formed by free radical polymerization of monomers such as acrylamide under the action of an initiator. Through reversible dynamic cross-linking, the material acquires properties such as adaptability to complex surface shapes, self-healing, and high hydrophilicity. The dynamic cross-linking of the hydrogel coupling agent can be achieved through one or more of the following mechanisms: dynamic cross-linking of borate ester bonds, host-guest interactions, multiple hydrogen bonding, and metal ion coordination. The self-adaptive hydrogel coupling agent prepared by this invention can significantly improve the accuracy of ultrasound measurements, adhere to tissue surfaces without external pressure, effectively eliminate deformation errors caused by probe pressure, and possesses excellent biocompatibility, sterilizability, and acoustic properties. It is easy to operate and its physicochemical properties are adjustable, making it suitable for various intraoperative ultrasound scenarios.

[0013] Preferably, the main monomer is acrylamide, and the reversible dynamic crosslinking functional monomers are 3-acrylamidophenylboronic acid and N-acryloyl(tris(hydroxymethyl)aminomethane.

[0014] Preferably, the dynamic cross-linking of borate ester bonds includes phenylboronic acid derivatives and polyhydroxy comonomers. The phenylboronic acid derivatives include at least one of 3-acrylamidophenylboronic acid, 2-acrylamidophenylboronic acid, 4-vinylphenylboronic acid, and 3-vinylphenylboronic acid. The polyhydroxy comonomers are N-acryloyl(tris(hydroxymethyl))aminomethane and / or methacryloyldextrin.

[0015] Preferably, the host-guest interaction class includes 6-acrylamido-β-cyclodextrin and N-(1-adamantyl)acrylamide.

[0016] Preferably, the multiple hydrogen bond type is ureidopyrimidinone methacrylate.

[0017] Preferably, the ionic crosslinking class includes at least one of acrylic acid, 3-methacrylamide dopamine, and 4-vinylpyridine.

[0018] Preferably, the initiator is at least one of ammonium persulfate aqueous solution, potassium persulfate aqueous solution, and sodium persulfate aqueous solution; the promoter is tetramethylethylenediamine; the molecular weight regulator is at least one of cysteine, N-acetylcysteine, cysteamine, and 3-mercaptopropionic acid; and the reinforcing filler is cellulose nanocrystals and / or cellulose nanofibers.

[0019] Preferably, a method for preparing a self-adaptive hydrogel coupling agent specifically includes,

[0020] Under light-protected and sterile conditions, the main monomer, reversible dynamic crosslinking functional monomer, molecular weight regulator, and reinforcing filler are dissolved in sterile deionized water. Initiator and accelerator are added and quickly mixed evenly. The mixed solution is then rapidly transferred to a sterile polytetrafluoroethylene mold and reacted at 0-10℃ for 12-48 hours. After the reaction, an elastic hydrogel is formed. The hydrogel is removed from the mold and placed in a dialysis bag. It is then immersed in sterile deionized water at 0-10℃ for dialysis for 12-48 hours, with the deionized water being replaced every 1-4 hours. After dialysis, the hydrogel is removed, the surface liquid is blotted dry, and terminal sterilization is performed using gamma rays at a dose of 20-30 kGy. After sterilization, the hydrogel is packaged in a sterile aluminum foil bag to obtain a self-adaptive hydrogel coupling agent.

[0021] More preferably, the main monomer is at least one selected from acrylamide, N,N-dimethylacrylamide, N-hydroxyethylacrylamide, hydroxyethyl methacrylate, poly(ethylene glycol) methacrylate, and polyethylene glycol methyl ether methacrylate. This invention uses at least one selected from acrylamide, N,N-dimethylacrylamide, N-hydroxyethylacrylamide, hydroxyethyl methacrylate, poly(ethylene glycol) methacrylate, and polyethylene glycol methyl ether methacrylate as the main monomer to form the hydrogel network framework structure, providing basic hydrogel forming ability and mechanical properties.

[0022] More preferably, the molecular weight of poly(ethylene glycol) methacrylate is 300-1000.

[0023] More preferably, the molecular weight of polyethylene glycol methyl ether methacrylate is 360-500.

[0024] More preferably, the reversible dynamic crosslinking functional monomer includes at least one of the following categories: borate ester bond dynamic crosslinking, host-guest interaction, multiple hydrogen bonding, and ionic crosslinking. The reversible dynamic crosslinking functional monomer used in this invention can achieve reversible dynamic crosslinking through borate ester bond dynamic crosslinking, host-guest interaction, multiple hydrogen bonding, metal ion coordination, etc.

[0025] More preferably, the dynamic crosslinking of borate ester bonds includes phenylboronic acid derivatives and polyhydroxy comonomers. The phenylboronic acid derivatives include at least one of 3-acrylamidophenylboronic acid, 2-acrylamidophenylboronic acid, 4-vinylphenylboronic acid, and 3-vinylphenylboronic acid. The polyhydroxy comonomers are N-acryloyl(tris(hydroxymethyl))aminomethane and / or methacrylamide dextran. The ratio of phenylboronic acid derivatives to polyhydroxy comonomers is 1:0.5-2. This invention introduces phenylboronic acid derivatives and polyhydroxy comonomers into a self-adaptive hydrogel coupling agent. On one hand, the phenylboronic acid groups in the phenylboronic acid derivatives can form dynamic phenylboronic ester bonds with the ortho-hydroxyl groups in the polyhydroxy comonomers, providing dynamic crosslinking points for the gel construction. Furthermore, the ester bonds in the phenylboronic acid derivatives can undergo rapid exchange reactions at room temperature, endowing the gel with self-healing ability and shear-thinning properties, making it easy to coat and able to recover structural stability after standing. It may also enhance weak interactions with glycoproteins on tissue surfaces, thereby improving interfacial adhesion. On the other hand, polyhydroxy comonomers, with their polyhydroxy structure, significantly enhance the hydrophilicity, water absorption and biocompatibility of hydrogels. While introducing hydrogen bonding sites into the system, they also help maintain the gel in a physiologically friendly environment.

[0026] More preferably, the host-guest interaction class includes 6-acrylamido-β-cyclodextrin and N-(1-adamantyl)acrylamide, and the mass ratio of 6-acrylamido-β-cyclodextrin to N-(1-adamantyl)acrylamide is 1:0.5-2.

[0027] More preferably, the multiple hydrogen bond type is ureidopyrimidinone methacrylate.

[0028] More preferably, the ionic crosslinking class includes at least one of acrylic acid, 3-methacrylamide dopamine, and 4-vinylpyridine.

[0029] More preferably, the molecular weight regulator is at least one selected from cysteine, N-acetylcysteine, cysteamine, and 3-mercaptopropionic acid. This invention uses at least one of cysteine, N-acetylcysteine, cysteamine, and 3-mercaptopropionic acid as a molecular weight regulator, whose thiol group can be stripped of a hydrogen atom by carbon free radicals during free radical polymerization, initiating a chain transfer reaction and thus terminating carbon chain growth. Through this mechanism, the molecular weight of the self-adaptive hydrogel coupling agent can be effectively controlled.

[0030] More preferably, the reinforcing filler is cellulose nanocrystals and / or cellulose nanofibers.

[0031] More preferably, the initiator is at least one selected from ammonium persulfate aqueous solution, potassium persulfate aqueous solution, and sodium persulfate aqueous solution. This invention uses tetramethylethylenediamine and persulfate solution to form a redox initiator pair, which significantly improves the free radical generation efficiency through electron transfer reaction, enabling the polymerization reaction to proceed at low temperatures.

[0032] More preferably, the mass concentration of the ammonium persulfate aqueous solution is 2-10%.

[0033] More preferably, the mass concentration of the potassium persulfate aqueous solution is 2-10%.

[0034] More preferably, the mass concentration of the sodium persulfate aqueous solution is 2-10%.

[0035] More preferably, the accelerator is tetramethylethylenediamine.

[0036] More preferably, the ratio of the main monomer to sterile deionized water is 1g:5-30mL.

[0037] More preferably, the mass ratio of the main monomer to the dynamically crosslinkable functional monomer is 1:0.02-0.2.

[0038] More preferably, the mass ratio of the main monomer to the molecular weight regulator is 1:0.01-0.5.

[0039] More preferably, the mass ratio of the main monomer to the reinforcing filler is 1:0.02-0.2.

[0040] More preferably, the volume ratio of the initiator to sterile deionized water is 1:15-60.

[0041] More preferably, the volume ratio of the accelerator to the initiator is 1:2-10.

[0042] The present invention also discloses the self-adaptive hydrogel coupling agent prepared by the above preparation method.

[0043] This invention also discloses the application of a self-adaptive hydrogel coupling agent in intraoperative ultrasound-assisted measurement of target distance.

[0044] This invention utilizes a host monomer and a dynamically crosslinkable functional monomer to form a self-adaptive hydrogel coupling agent through free radical polymerization. The host unit is at least one of acrylamide, N,N-dimethylacrylamide, N-hydroxyethylacrylamide, hydroxyethyl methacrylate, poly(ethylene glycol) methacrylate, and polyethylene glycol methyl ether methacrylate. The reversible dynamically crosslinkable functional monomer includes at least one of the following categories: borate ester bond dynamic crosslinking, host-guest interaction, multiple hydrogen bonding, and ionic crosslinking. Reversible dynamic crosslinking is achieved through borate ester bond dynamic crosslinking, host-guest interaction, multiple hydrogen bonding, and metal ion coordination, thus providing the following beneficial effects: First, the self-adaptive hydrogel coupling agent prepared by this invention can effectively eliminate tissue deformation caused by probe pressure, avoiding the resulting distance measurement shortening error. By providing a seamless and stable acoustic coupling interface, the measurement results are closer to the actual anatomical distance. Simultaneously, because it can maintain a stable coupling state, no additional pressure is required during clinical use, thus completely solving the problem of pressure deformation. Secondly, the self-adaptive hydrogel coupling agent prepared in this invention also exhibits excellent tissue adhesion. With its adaptive viscoelasticity and shear-thinning properties, it can perfectly fill and conform to various complex tissue morphologies during surgery, such as protrusions and depressions, ensuring consistent acoustic coupling and effectively reducing image artifacts. Regarding biosafety, the self-adaptive hydrogel coupling agent prepared in this invention is synthesized using biocompatible monomers with well-defined components and can be strictly sterilized, meeting the requirements for direct contact with open wounds and avoiding risks such as foreign body reactions, infection, and measurement errors that may arise from traditional coupling agents or drip methods. It is easy to use, readily available, and applied, requiring no continuous dripping by an assistant or additional equipment, significantly simplifying the surgical procedure and saving surgical time. Furthermore, the performance of the self-adaptive hydrogel coupling agent can be precisely controlled over a wide range by adjusting parameters such as monomer ratio, concentration, and crosslinking density, including its physical and mechanical properties (such as viscoelastic modulus and strength) and rheological behavior (such as shear-thinning and self-healing), to adapt to different tissue types, such as soft brain tissue or relatively firm liver tissue, while maintaining appropriate adhesion and achieving residue-free removal. Finally, the high water content makes its acoustic impedance similar to that of human tissue and water, giving it excellent ultrasonic transmittance and low echo characteristics, which will not interfere with image quality. Attached Figure Description

[0045] Figure 1 This is a rheological test diagram of a self-adaptive hydrogel coupling agent.

[0046] Figure 2 The graph shows the sound velocity and attenuation test results for the self-adaptive hydrogel coupling agent.

[0047] Figure 3 For 3D printing soft models.

[0048] Figure 4 Ultrasonic imaging of a 3D-printed soft model using a self-adaptive hydrogel coupling agent.

[0049] Figure 5 This is an image of an isolated pig liver model.

[0050] Figure 6 Ultrasound imaging of an ex vivo porcine liver model using a self-adaptive hydrogel coupling agent.

[0051] Figure 7 A graph showing the applied force values ​​for ultrasonic measurement of a self-adaptive hydrogel coupling agent. Detailed Implementation

[0052] The present invention will now be described in further detail with reference to specific embodiments. The given embodiments are merely illustrative of the invention and not intended to limit its scope. The embodiments provided below can serve as a guide for further improvements by those skilled in the art and do not constitute a limitation on the invention in any way.

[0053] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the materials and reagents used in the following examples are commercially available.

[0054] Example 1:

[0055] The preparation method of the self-adaptive hydrogel coupling agent includes,

[0056] Under light-protected and sterile conditions, the main monomer, reversible dynamic crosslinking functional monomer, molecular weight regulator, and reinforcing filler were dissolved in sterile deionized water. Initiator and accelerator were added and quickly mixed evenly. The mixed solution was then rapidly transferred to a sterile polytetrafluoroethylene mold and reacted at 4°C for 24 hours. After the reaction, an elastic hydrogel was formed. The hydrogel was removed from the mold and placed in a dialysis bag. It was then immersed in sterile deionized water at 4°C for dialysis for 24 hours, with the deionized water being replaced every 2 hours. After dialysis, the hydrogel was removed, the surface liquid was blotted dry, and terminal sterilization was performed using a 25 kGy dose of gamma rays. After sterilization, the hydrogel was packaged in a sterile aluminum foil bag to obtain a self-adaptive hydrogel coupling agent. The main monomer is acrylamide; the reversible dynamic crosslinking functional monomers include 3-acrylamidophenylboronic acid and N-acryloyl(tris(hydroxymethyl)aminomethane), wherein the mass ratio of 3-acrylamidophenylboronic acid to N-acryloyl(tris(hydroxymethyl)aminomethane) is 1:1; the molecular weight regulator is cysteine; the reinforcing filler is cellulose nanofibers; the initiator is a 4% (w / w) ammonium persulfate aqueous solution; and the accelerator is tetramethylethylenediamine. The volume ratio of the main monomer to sterile deionized water is 1 g:15 mL, the mass ratio of the main monomer to the reversible dynamic crosslinking functional monomer is 1:0.1, the mass ratio of the main monomer to the molecular weight regulator is 1:0.05, the mass ratio of the main monomer to the reinforcing filler is 1:0.1, the volume ratio of the initiator to sterile deionized water is 1:30, and the volume ratio of the accelerator to the initiator is 1:5.

[0057] Example 2:

[0058] The preparation method of the self-adaptive hydrogel coupling agent is the same as that in Example 1, except that the main monomer component is changed to N,N-dimethylacrylamide.

[0059] Example 3:

[0060] The preparation method of the self-adaptive hydrogel coupling agent is the same as that in Example 1, except that the main monomer component is changed to N-hydroxyethylacrylamide.

[0061] Example 4:

[0062] The preparation method of the self-adaptive hydrogel coupling agent is the same as that in Example 1, except that the main monomer component is changed to poly(ethylene glycol) methacrylate with a molecular weight of 500.

[0063] Example 5:

[0064] The preparation method of the self-adaptive hydrogel coupling agent is the same as that in Example 1, except that the main monomer component is changed to polyethylene glycol methyl ether methacrylate with a molecular weight of 400.

[0065] Example 6:

[0066] The preparation method of the self-adaptive hydrogel coupling agent, compared with Example 1, is the same as that in Example 1 except that the components of the reversible dynamic crosslinking functional monomer are changed to include 2-acrylamidophenylboronic acid and N-acryloyl(tris(hydroxymethyl)aminomethane, wherein the mass ratio of 2-acrylamidophenylboronic acid and N-acryloyl(tris(hydroxymethyl)aminomethane) is 1:1.

[0067] Example 7:

[0068] The preparation method of the self-adaptive hydrogel coupling agent, compared with Example 1, is the same as that in Example 1 except that the components of the reversible dynamic crosslinking functional monomer are changed to: the reversible dynamic crosslinking functional monomer includes 4-vinylphenylboronic acid and N-acryloyl(tris(hydroxymethyl)aminomethane, wherein the mass ratio of 4-vinylphenylboronic acid and N-acryloyl(tris(hydroxymethyl)aminomethane) is 1:1, and other conditions are the same as in Example 1.

[0069] Example 8:

[0070] The preparation method of the self-adaptive hydrogel coupling agent, compared with Example 1, is the same as that in Example 1 except that the components of the reversible dynamic crosslinking functional monomer are changed to: the reversible dynamic crosslinking functional monomer includes 3-vinylphenylboronic acid and N-acryloyl(tris(hydroxymethyl)aminomethane, wherein the mass ratio of 3-vinylphenylboronic acid and N-acryloyl(tris(hydroxymethyl)aminomethane) is 1:1, and other conditions are the same as in Example 1.

[0071] Example 9:

[0072] The preparation method of the self-adaptive hydrogel coupling agent, compared with Example 1, is the same as that in Example 1 except that the components of the reversible dynamic crosslinking functional monomer are changed: the reversible dynamic crosslinking functional monomer includes 3-acrylamidophenylboronic acid and methacrylamide dextran, wherein the mass ratio of 3-acrylamidophenylboronic acid and methacrylamide dextran is 1:1.

[0073] Example 10:

[0074] The preparation method of the self-adaptive hydrogel coupling agent, compared with Example 1, is the same as that in Example 1 except that the components of the reversible dynamic crosslinking functional monomer are changed: the reversible dynamic crosslinking functional monomer includes 2-acrylamidophenylboronic acid and methacrylamide dextran, wherein the mass ratio of 2-acrylamidophenylboronic acid and methacrylamide dextran is 1:1.

[0075] Example 11:

[0076] The preparation method of the self-adaptive hydrogel coupling agent, compared with Example 1, is the same as that in Example 1 except that the components of the reversible dynamic crosslinking functional monomer are changed: the reversible dynamic crosslinking functional monomer includes 4-vinylphenylboronic acid and methacrylamide dextran, wherein the mass ratio of 4-vinylphenylboronic acid and methacrylamide dextran is 1:1, and other conditions are the same as in Example 1.

[0077] Example 12:

[0078] The preparation method of the self-adaptive hydrogel coupling agent, compared with Example 1, is the same as that in Example 1 except that the components of the reversible dynamic crosslinking functional monomer are changed: the reversible dynamic crosslinking functional monomer includes 3-vinylphenylboronic acid and methacrylamide dextran, wherein the mass ratio of 3-vinylphenylboronic acid and methacrylamide dextran is 1:1, and other conditions are the same as in Example 1.

[0079] Example 13:

[0080] The preparation method of the self-adaptive hydrogel coupling agent is the same as that in Example 1, except that the components of the reversible dynamic crosslinking functional monomer are changed to include 6-acrylamido-β-cyclodextrin and N-(1-adamantyl)acrylamide, wherein the mass ratio of 6-acrylamido-β-cyclodextrin and N-(1-adamantyl)acrylamide is 1:1, and other conditions are the same as in Example 1.

[0081] Example 14:

[0082] The preparation method of the self-adaptive hydrogel coupling agent is the same as that in Example 1, except that the component of the reversible dynamic crosslinking functional monomer is changed to ureidopyrimidinone methacrylate.

[0083] Example 15:

[0084] The preparation method of the self-adaptive hydrogel coupling agent is the same as that in Example 1, except that the component of the reversible dynamic crosslinking functional monomer is changed to acrylic acid.

[0085] Example 16:

[0086] The preparation method of the self-adaptive hydrogel coupling agent is the same as that in Example 1, except that the component of the reversible dynamic crosslinking functional monomer is changed to 3-methacryloyldopamine.

[0087] Example 17:

[0088] The preparation method of the self-adaptive hydrogel coupling agent is the same as that in Example 1, except that the component of the reversible dynamic crosslinking functional monomer is changed to 3-methacryloyldopamine.

[0089] Example 18:

[0090] The preparation method of the self-adaptive hydrogel coupling agent is the same as that in Example 1, except that the component of the reversible dynamic crosslinking functional monomer is changed to 4-vinylpyridine.

[0091] Example 19:

[0092] The preparation method of the self-adaptive hydrogel coupling agent is the same as that in Example 1, except that the molecular regulator component is changed to N-acetylcysteine.

[0093] Example 20:

[0094] The preparation method of the self-adaptive hydrogel coupling agent is the same as that in Example 1, except that the molecular regulator component is changed to cysteine.

[0095] Example 21:

[0096] The preparation method of the self-adaptive hydrogel coupling agent is the same as that in Example 1, except that the molecular regulator component is changed to 3-mercaptopropionic acid.

[0097] Example 22:

[0098] The preparation method of the self-adaptive hydrogel coupling agent is the same as that in Example 1, except that the composition of the reinforcing filler is changed to cellulose nanocrystals.

[0099] Example 23:

[0100] The preparation method of the self-adaptive hydrogel coupling agent is the same as that in Example 1, except that the composition of the initiator is changed to: the initiator is a 4% potassium persulfate aqueous solution, and the other conditions are the same as those in Example 1.

[0101] Example 24:

[0102] The preparation method of the self-adaptive hydrogel coupling agent is the same as that in Example 1, except that the initiator component is changed to a 4% sodium persulfate aqueous solution.

[0103] Comparative Example 1:

[0104] The preparation method of the self-adaptive hydrogel coupling agent is the same as that of Example 1, except that no reinforcing filler is added.

[0105] Experimental example:

[0106] 1. Rheological testing

[0107] The rheological properties of the self-adaptive hydrogel coupling agent prepared in Example 1 were tested using a Hacker rotational rheometer, and the frequency changes of storage modulus and loss modulus were obtained.

[0108] Figure 1 The rheological plots for the self-adaptive hydrogel coupling agent are shown, where G′ represents the storage modulus and G″ represents the loss modulus. The results are as follows: Figure 1 As shown, the viscoelasticity of the self-adaptive hydrogel coupling agent prepared in Example 1 of this invention exhibits a significant frequency dependence: at higher shear frequencies, its elastic response dominates, specifically manifested as a storage modulus (G′) greater than the loss modulus (G″). The self-adaptive hydrogel coupling agent prepared in Example 1 maintains a predominantly elastic characteristic in the high-frequency region, which helps stabilize acoustic impedance, thereby reducing sound wave reflection and scattering, and ultimately improving the signal-to-noise ratio of the image. Compared with Example 1, the preparation mechanism of the self-adaptive hydrogel coupling agents in Examples 2-24 is similar to that in Example 1, and the self-adaptive hydrogel coupling agents prepared therefrom have similar properties. The rheological test results of the self-adaptive hydrogel coupling agents prepared in Examples 2-24 of this invention are basically consistent with those of Example 1.

[0109] 2. Sound speed and attenuation test

[0110] The sound velocity and attenuation of the self-adaptive hydrogel coupling agents prepared in Example 1 and Comparative Example 1 were tested to obtain the sound velocity and sound attenuation coefficient.

[0111] Figure 2 The results are shown in the sound velocity and attenuation test graphs for the self-adaptive hydrogel coupling agent. Figure 2 As shown, compared with Comparative Example 1, the sound velocity and sound attenuation coefficient of the self-adaptive hydrogel coupling agent in Example 1 show similar trends. The sound velocity at frequencies of 1-10 MHz is approximately 1550 ± 10 m / s, and the sound attenuation coefficient is less than 0.4 dB / mm / MHz. This indicates that regardless of whether reinforcing fillers are added, the self-adaptive hydrogel coupling agent prepared in this invention meets the performance requirements of a high-quality ultrasonic coupling agent. Compared with Example 1, the preparation mechanism of the self-adaptive hydrogel coupling agents in Examples 2-24 is similar to that in Example 1, and the self-adaptive hydrogel coupling agents prepared therefrom have similar properties. The sound velocity and attenuation test results of the self-adaptive hydrogel coupling agents prepared in Examples 2-24 of this invention are basically consistent with those of Example 1.

[0112] 3. Organize simulation tests

[0113] A 3D-printed soft model was prepared using a soft silicone material with a Young's modulus of approximately 30 kPa. This model simulates the biomechanical properties of soft tissues such as the human liver. The model surface was structured to form irregular serrated feature areas. This design aims to simulate the irregular morphology of surgical sections, pathological tissues, or complex organ surfaces. The self-adaptive hydrogel coupling agent prepared in Example 1 of this invention was applied to the surface of the silicone model. Observations showed that the self-adaptive hydrogel coupling agent, due to its excellent rheological properties (such as shear thinning and low yield stress) and interfacial wettability, rapidly exhibited excellent surface self-adaptation capabilities after application. Subsequently, a high-frequency ultrasonic probe was used to scan and image the air interface of the hydrogel-coated silicone model.

[0114] Figure 3 For 3D printing soft models, Figure 4 Ultrasonic imaging of a 3D-printed soft model using a self-adaptive hydrogel coupling agent. Results are as follows: Figure 4 As shown, the serrated shape of the self-adaptive hydrogel coupling agent-air interface is clearly reflected in the ultrasound image, and the imaging quality is good with no obvious artifacts caused by poor interface coupling. This result confirms that the self-adaptive hydrogel coupling agent prepared in this invention has good conformal effect. Compared with Example 1, the preparation mechanism of the self-adaptive hydrogel coupling agent in Examples 2-24 is similar to that in Example 1, and the self-adaptive hydrogel coupling agents prepared therefrom have similar properties. The ultrasound imaging results of the self-adaptive hydrogel coupling agents prepared in Examples 2-24 of this invention are basically consistent with those in Example 1.

[0115] A local resection was performed on the surface of the isolated porcine liver tissue using a high-frequency ultrasonic scalpel, creating an "intraoperative resection depression" with a diameter of 30 mm and a depth of 10 mm. A simulated tumor, shaped like a peanut (5 mm × 7 mm), was implanted 20 mm below the intraoperative resection depression to simulate a small lesion hidden during liver resection, thus obtaining an isolated porcine liver model. The self-adaptive hydrogel coupling agent prepared in Example 1 of this invention was applied to the resection wound and surrounding tissue surface of the isolated porcine liver model, and scanning was performed using an ultrasonic probe at a frequency of 6~10 MHz.

[0116] Figure 5 This is an image of an isolated pig liver model. Figure 6 Ultrasound imaging of an ex vivo porcine liver model using a self-adaptive hydrogel coupling agent. Results are as follows. Figure 6 As shown, the simulated tumor appears as a hypoechoic region in the ultrasound image, with clearly distinguishable boundaries, forming a significant contrast with the surrounding liver tissue. Compared with Example 1, the preparation mechanism of the self-adaptive hydrogel coupling agent in Examples 2-24 is similar to that in Example 1, and the self-adaptive hydrogel coupling agents prepared therefrom have similar properties. The ultrasound imaging results of the self-adaptive hydrogel coupling agents prepared in Examples 2-24 of this invention are basically consistent with those in Example 1.

[0117] 4. External force value test

[0118] Control and experimental groups were set up, and external force values ​​were tested using an isolated pig liver model. The experimental treatment method for the control group was as follows: physiological saline was continuously dripped onto the surface of the isolated pig liver model until it covered the high-frequency linear array probe; to maintain an effective acoustic window, external pressure was applied to the high-frequency linear array probe, and the external pressure value was monitored in real time using a force sensor. The experimental treatment method for the experimental group was as follows: the self-adaptive hydrogel coupling agent prepared in Example 1 of this invention was taken, and its size was adjusted to match the contact surface of the high-frequency linear array probe; the self-adaptive hydrogel coupling agent was gently spread to completely fill the grooves on the surface of the isolated pig liver model, and then a high-frequency linear array probe of the same model was placed on the surface of the self-adaptive hydrogel coupling agent, relying solely on the weight of the high-frequency linear array probe to achieve contact, thus constructing a near-zero pressure state, and the contact force was recorded using a force sensor.

[0119] Figure 7 The image shows the force values ​​applied during ultrasonic measurement of the self-adaptive hydrogel coupling agent. The results are as follows: Figure 7 As shown, when the ultrasound image achieves equivalent clarity, defined as a clearly distinguishable tumor boundary without reverberation artifacts, the control group requires a vertical pressure of 19.3 ± 0.8 N, while the experimental group only requires a vertical pressure of 6.5 ± 0.3 N. This indicates that the self-adaptive hydrogel coupling agent prepared in this invention can significantly reduce the pressure required to maintain an effective acoustic window, decreasing by 66.3% compared to saline perfusion, proving that the self-adaptive hydrogel coupling agent prepared in Example 1 of this invention can achieve stable ultrasound coupling under near-zero pressure conditions. Compared to Example 1, the preparation mechanism of the self-adaptive hydrogel coupling agents in Examples 2-24 is similar to that in Example 1, and the self-adaptive hydrogel coupling agents prepared therefrom have similar properties. The external force test results of the self-adaptive hydrogel coupling agents prepared in Examples 2-24 of this invention are basically consistent with those of Example 1.

[0120] 5. Ultrasonic distance value test

[0121] In a simulated liver tumor resection scenario, a superficial tumor simulant was constructed on the surface of isolated porcine liver tissue to expose the surgical area. A control group and an experimental group were established. The experimental treatment method for the experimental group was as follows: The self-adaptive hydrogel coupling agent prepared in Example 1 was uniformly coated onto the surface of the isolated porcine liver tissue, ensuring complete coverage of the tumor simulant and its surrounding area. A sterile intraoperative convex array probe was gently placed on the self-adaptive hydrogel coupling agent layer prepared in Example 1, relying solely on the probe's own weight for contact force. After the ultrasound image clearly showed the tumor boundary, the distance from the upper surface of the tumor simulant to the surface of the liver tissue was accurately measured, repeated three times, and recorded as d_gel. The experimental treatment method for the control group was as follows: Physiological saline was continuously dripped to cover the target area, and a probe of the same model was placed on the liquid layer. After the image stabilized, the distance from the upper surface of the tumor simulant to the surface of the liver tissue was measured three times using the same method, recorded as d_saline. The baseline measurement used a precision vernier caliper to directly measure the actual anatomical distance from the tissue surface to the upper surface of the tumor simulant, recorded as d_actual.

[0122] Table 1. Ultrasonic measurement distance values ​​of self-adaptive hydrogel coupling agent

[0123] Measurement Group Measured values ​​(cm, Mean ± SD) absolute error relative error Actual anatomical distance (d_actual) 2.50±0.05 - - Experimental group (d_gel) 2.380±0.040 -0.120 -4.80 Control group (d_saline) 1.977±0.082 -0.523 -20.92

[0124] Table 1 shows the ultrasonic distance values ​​measured by the self-adaptive hydrogel coupling agent. As shown in Table 1, the actual anatomical distance from the tissue surface to the upper surface of the tumor simulator was 2.50 cm. The average measurement value of the experimental group was 2.380 cm, which is closer to the actual anatomical value, with a relative error of only 4.80%. In contrast, the average measurement value of the control group was 1.977 cm, systematically underestimating the actual depth, with a relative error of 20.92%, approximately 4.4 times that of the experimental group. This indicates that the self-adaptive hydrogel coupling agent prepared in this invention can effectively avoid pressure deformation of the probe on soft liver tissue under near-zero pressure conditions, while providing a stable acoustic interface and significantly improving the spatial fidelity of ultrasonic ranging. Compared with Example 1, the preparation mechanism of the self-adaptive hydrogel coupling agent in Examples 2-24 is similar to that in Example 1, and the self-adaptive hydrogel coupling agents prepared in these examples have similar properties. The ultrasonic distance test results of the self-adaptive hydrogel coupling agents prepared in Examples 2-24 of this invention are basically consistent with those in Example 1.

[0125] The conventional operations in the operation steps of this invention are well known to those skilled in the art and will not be described in detail here.

[0126] The embodiments described above provide a detailed explanation of the technical solutions of the present invention. It should be understood that the above descriptions are merely specific embodiments of the present invention and are not intended to limit the present invention. Any changes and modifications made within the scope of the principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing a self-adaptive hydrogel coupling agent, characterized in that, include: Under light-protected and sterile conditions, the main monomer, reversible dynamic cross-linking functional monomer, molecular weight regulator and reinforcing filler are dissolved in sterile deionized water and then undergo free radical polymerization under the action of initiator and accelerator. After dialysis and sterilization, a self-adaptive hydrogel coupling agent is obtained. The main monomer is acrylamide; the reversible dynamic crosslinking functional monomer is 3-acrylamidophenylboronic acid and N-acryloyl(tris(hydroxymethyl)aminomethane; The mass ratio of the main monomer to the dynamically crosslinkable functional monomer is 1:0.02-0.2; the mass ratio of the main monomer to the molecular weight regulator is 1:0.01-0.5; and the mass ratio of the main monomer to the reinforcing filler is 1:0.02-0.

2.

2. The method for preparing a self-adaptive hydrogel coupling agent according to claim 1, characterized in that, The ratio of the main monomer to sterile deionized water is 1g:5-30mL.

3. The method for preparing a self-adaptive hydrogel coupling agent according to claim 1, characterized in that, The volume ratio of the initiator to sterile deionized water is 1:15-60.

4. The method for preparing a self-adaptive hydrogel coupling agent according to claim 1, characterized in that, The volume ratio of the promoter to the initiator is 1:2-10.

5. The method for preparing a self-adaptive hydrogel coupling agent according to claim 1, characterized in that, The free radical polymerization reaction temperature is 0-10℃.

6. The method for preparing a self-adaptive hydrogel coupling agent according to claim 1, characterized in that, The initiator is at least one of ammonium persulfate aqueous solution, potassium persulfate aqueous solution, and sodium persulfate aqueous solution; the promoter is tetramethylethylenediamine; the molecular weight regulator is at least one of cysteine, N-acetylcysteine, cysteamine, and 3-mercaptopropionic acid; and the reinforcing filler is cellulose nanocrystals and / or cellulose nanofibers.

7. The self-adaptive hydrogel coupling agent prepared by any of the preparation methods described in claims 1-6.

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