Medical ultrasonic hydrogel and preparation method thereof

Abstract

The application belongs to the technical field of medical ultrasonic imaging agents, and particularly relates to a medical ultrasonic hydrogel and a preparation method thereof. The application enhances the liposolubility of tannic acid by alkylating modification, is conducive to penetrating the cell membranes of gram-positive bacteria and gram-negative bacteria in a short period and exerting a sterilization effect, and can achieve a sterilization rate of more than 95% on staphylococcus aureus and escherichia coli within 15 minutes. Meanwhile, the alkylated modified tannic acid is conducive to reducing the acoustic attenuation of the hydrogel and the adhesion strength to the surface of skin tissue, facilitating the peeling of the hydrogel from the surface of the skin and the smooth sliding of an ultrasonic probe, and avoiding the poor user experience caused by pulling the skin.

Description

Technical Field

[0001] This application belongs to the field of medical ultrasound imaging agents, specifically relating to a medical ultrasound hydrogel and its preparation method. Background Technology

[0002] Ultrasound examination is one of the mainstream medical imaging methods, using ultrasound waves to display the internal structure of the human body and provide a basis for disease diagnosis. B-mode ultrasound is the most common type of ultrasound examination, displaying real-time two-dimensional images of tissues and is widely used in soft tissue and organ examinations, as well as prenatal diagnosis. Based on B-mode ultrasound imaging, elastography technology has been further developed. Ultrasound elastography quantitatively analyzes and measures the elastic modulus of soft tissues, generating an elasticity distribution map of the tested tissue. It is now used in the examination of breasts, thyroid glands, liver, and prostate. In clinical medicine, many diseases, such as breast cancer and cirrhosis, are accompanied by hardening of corresponding organs or lesions. Traditional palpation is a subjective qualitative analysis, and the diagnostic results rely on the doctor's clinical experience. Therefore, ultrasound elastography is considered a reliable and objective tool for achieving accurate diagnosis.

[0003] To ensure the diagnostic efficacy of ultrasound imaging, coupling agents must be used clinically. Liquid coupling agents can fill the gap between the probe and the skin, promoting the transmission of ultrasound energy from the probe to the skin. However, in areas with high local curvature, such as skin tumors, fingers, and elbows, the geometric structure limits the probe's ability to adhere well to the skin surface when using liquid coupling agents. This can lead to air trapping between the probe and the skin, resulting in poor ultrasound imaging. Therefore, there is an urgent clinical need for a flexible material with acoustic impedance matching. This material must be able to withstand pressure to ensure the accuracy of elastic imaging, possess excellent flexibility to conform to skin surfaces with high local curvature, and simultaneously alleviate stress concentration in tissues.

[0004] Hydrogels, using water as a dispersion medium, possess physical and physiological properties similar to living tissue, and their acoustic impedance is similar to water, making them excellent sound propagation media. They are also non-cytotoxic and biocompatible. Furthermore, hydrogels are elastic with adjustable modulus, and compared to liquid coupling agents, they do not trap air bubbles, thus alleviating stress concentration. However, hydrogels have drawbacks, including lack of antibacterial properties, excessively high adhesion strength affecting user experience, and a relatively high acoustic attenuation rate. Further improvements are needed to enable their application in high-resolution, high-precision ultrasound detection in clinical diagnostics. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this application modifies tannic acid by alkylation and uses it in acrylamide composite hydrogels, thereby reducing the acoustic attenuation rate and adhesion strength of the hydrogel on pigskin surfaces, and improving its short-term bactericidal effect against Gram-positive and Gram-negative bacteria.

[0006] To achieve the above technical objectives, the technical solution adopted in this application is as follows: In the first aspect, a medical ultrasonic hydrogel, the raw materials of which include: alkyl-modified tannic acid, acrylamide, N,N-methylenebisacrylamide, initiator and accelerator; The initiator is selected from one or both of ammonium persulfate and potassium persulfate; The accelerator is selected from tertiary amine compounds; Preferably, the accelerator is selected from one or more of triethylamine, 2,4,6-tris(dimethylaminomethyl)phenol and N,N,N',N'-tetramethylethylenediamine; More preferably, the promoter is selected from N,N,N',N'-tetramethylethylenediamine.

[0007] The alkyl-modified tannic acid is obtained by ring-opening reaction of an epoxy compound containing C4-C16 alkyl side chains with the phenolic hydroxyl groups of tannic acid. Preferably, the alkyl side chain of the epoxy compound containing C4-C16 alkyl side chain is selected from C4-C16 straight-chain alkyl, branched alkyl, or cycloalkyl. Preferably, the epoxy compound containing C4-C16 alkyl side chains is selected from any one of lauryl glycidyl ether, isooctyl glycidyl ether, or cyclohexane epoxy. Further, the step of alkyl-modified tannic acid includes: reacting tannic acid with an epoxy compound containing C4-C16 alkyl side chains under the catalysis of tetraalkyl halides and at 80-120°C to obtain the product; Preferably, the tetraalkyl halide is selected from any one of: hexadecyltrimethylammonium chloride, hexadecyltrimethylammonium bromide, hexadecyltriethylammonium chloride, hexadecyltriethylammonium bromide, tetrabutylammonium chloride, or tetrabutylammonium bromide; Preferably, the molar ratio of tannic acid to an epoxy compound containing C4-C16 alkyl side chains is 1:(5-10); Preferably, the amount of tetraalkyl halide used is 0.5-3 wt% of the total mass of tannic acid and epoxy compound containing C4-C16 alkyl side chains.

[0008] Furthermore, the raw materials of the medical ultrasonic hydrogel, by weight, are: 45-55 parts acrylamide, 0.1-0.5 parts N,N-methylenebisacrylamide, 0.5-1 part initiator, 0.1-0.2 parts accelerator, and 2-6 parts alkyl-modified tannic acid.

[0009] Secondly, the preparation method of the above-mentioned medical ultrasonic hydrogel includes: S1. Acrylamide is dissolved in deionized water at room temperature to obtain an aqueous solution of acrylamide; S2. At 0°C to room temperature, N,N-methylenebisacrylamide, initiator, accelerator and alkyl-modified tannic acid are added to an aqueous solution of acrylamide and mixed and stirred to obtain a pregel solution. S3. Transfer the pregel solution into a mold and allow it to stand at 35-60℃ for 1-24 hours to polymerize and obtain a hydrogel. S4. After freezing the hydrogel at -20°C for 1-12 hours, freeze-dry it for 1-24 hours to obtain the dried hydrogel.

[0010] Preferably, the deionized water at least meets the technical standards for Grade III water in GB / T 6682-2008.

[0011] Thirdly, the above-mentioned medical ultrasound hydrogel is used as an ultrasound imaging agent.

[0012] The beneficial effects of the technical solution proposed in this application are as follows: By alkylating tannic acid, its lipid solubility is enhanced, which facilitates its penetration into the cell membranes of Gram-positive and Gram-negative bacteria in a short period of time and exerts a bactericidal effect, achieving a sterilization rate of more than 95% against Staphylococcus aureus and Escherichia coli within 15 minutes. Simultaneously, alkylated tannic acid helps reduce the acoustic attenuation of the hydrogel and its adhesion strength to the skin surface, facilitating the peeling of the hydrogel from the skin surface and the smooth sliding of the ultrasound probe, avoiding skin pulling and resulting in a poor user experience. Detailed Implementation

[0013] The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the protection scope of the present invention. It should be noted that the terminology used herein is only for describing specific implementation methods and is not intended to limit the exemplary implementation methods according to the present invention.

[0014] Unless otherwise specified, the experimental conditions used in the examples are generally in accordance with conventional conditions in the art or the conditions recommended by the reagent company. Unless otherwise specified, the materials and reagents used in the examples can be purchased commercially.

[0015] Unless otherwise stated or in case of contradiction, the terms or phrases used herein shall have the following meanings: The terms "and / or," "or / and," and "and / or" as used herein include any one of two or more of the related listed items, as well as any and all combinations of the related listed items. These arbitrary and all combinations include any two related listed items, any more related listed items, or a combination of all related listed items. It should be noted that when at least three items are connected by at least two conjunctions selected from "and / or," "or / and," and "and / or," it should be understood that in this application, the technical solution undoubtedly includes technical solutions connected by "logical AND," and also undoubtedly includes technical solutions connected by "logical OR." For example, "A and / or B" includes three parallel solutions: A, B, and A+B. For example, the technical solution of "A, and / or, B, and / or, C, and / or, D" includes any one of A, B, C, and D (that is, a technical solution that is connected by "logical OR"), as well as any and all combinations of A, B, C, and D, that is, combinations of any two or three of A, B, C, and D, and also combinations of all four of A, B, C, and D (that is, a technical solution that is connected by "logical AND").

[0016] In this application, the terms "multiple", "various", "multiple times", "multi-dimensional", etc., unless otherwise specified, refer to a quantity greater than or equal to 2. For example, "one or more" means one or more than or equal to two.

[0017] In this application, "optionally," "optionally," and "optional" mean that something is optional, that is, it means that it is selected from either "with" or "without." If there are multiple "optional" entries in a technical solution, unless otherwise specified, and there are no contradictions or mutual constraints, each "optional" entry shall be independent.

[0018] In this application, the technical features described in an open-ended manner include both closed technical solutions composed of the listed features and open technical solutions composed of the listed features.

[0019] Example 1 Preparation of straight-chain alkyl-modified tannic acid 85 g (0.05 mol) of tannic acid and 97 g (0.4 mol) of lauryl glycidyl ether were added to 180 mL of dioxane in a reaction vessel. The mixture was heated to 100 °C with stirring, and then 1.8 g of hexadecyltrimethylammonium bromide was added as a catalyst. The mixture was refluxed at this temperature for 5 hours. Infrared spectroscopy was performed at 920 cm⁻¹. -1 The disappearance of the nearby epoxy characteristic peak indicates that the epoxy group of lauryl glycidyl ether reacts completely with the phenolic hydroxyl group of tannic acid. The solvent is removed by vacuum distillation at 60°C to obtain alkyl-modified tannic acid.

[0020] Example 2 Preparation of branched alkyl modified tannic acid The lauryl glycidyl ether in Example 1 was replaced with 74.5 g (0.4 mol) of isooctyl glycidyl ether, and the other raw materials and steps were the same as in Example 1.

[0021] Example 3 Preparation of cycloalkyl-modified tannic acid The lauryl glycidyl ether in Example 1 was replaced with 49g (0.5mol) of cyclohexane oxide, and the remaining raw materials and steps were the same as in Example 1.

[0022] Example 4 Preparation of medical ultrasonic hydrogel: Acrylamide was used as the polymer monomer, N,N-methylenebisacrylamide as the bifunctional crosslinking agent, ammonium persulfate (APS) as the initiator, and N,N,N',N'-tetramethylethylenediamine as the accelerator for acrylamide crosslinking. 50g of acrylamide was dissolved in 250mL of deionized water at room temperature. Under ice bath cooling, 3g of alkyl-modified tannic acid prepared in Example 1, 0.25g of N,N-methylenebisacrylamide, 0.65g of APS initiator, and 0.15g of N,N,N',N'-tetramethylethylenediamine were added. After mixing and stirring for 20 minutes, a pregel solution was obtained. The pregel solution was transferred to a polytetrafluoroethylene mold (groove dimensions: 80×10×6mm). 3 The mixture was polymerized at 40°C for 8 hours to obtain a hydrogel, which was then frozen at -40°C for 8 hours and then freeze-dried for 24 hours to obtain the dried hydrogel.

[0023] Example 5 Based on Example 4, the amount of alkyl-modified tannic acid used in Example 1 was changed to 5g, and the remaining steps were the same as in Example 4.

[0024] Example 6 Preparation of medical ultrasonic hydrogel: Acrylamide was used as the polymer monomer, N,N-methylenebisacrylamide as the bifunctional crosslinking agent, ammonium persulfate (APS) as the initiator, and N,N,N',N'-tetramethylethylenediamine as the accelerator for acrylamide crosslinking. 50g of acrylamide was dissolved in 250mL of deionized water at room temperature. Under ice bath cooling, 3g of alkyl-modified tannic acid prepared in Example 2, 0.25g of N,N-methylenebisacrylamide, 0.65g of APS initiator, and 0.15g of N,N,N',N'-tetramethylethylenediamine were added. After mixing and stirring for 20 minutes, a pregel solution was obtained. The pregel solution was transferred to a polytetrafluoroethylene mold (groove dimensions: 80×10×6mm). 3 The mixture was polymerized at 40°C for 8 hours to obtain a hydrogel, which was then frozen at -40°C for 8 hours and then freeze-dried for 24 hours to obtain the dried hydrogel.

[0025] Example 7 Based on Example 6, the amount of alkyl-modified tannic acid used in Example 2 was changed to 5g, and the remaining steps were the same as in Example 6.

[0026] Example 8 Preparation of medical ultrasonic hydrogel: Acrylamide was used as the polymer monomer, N,N-methylenebisacrylamide as the bifunctional crosslinking agent, ammonium persulfate (APS) as the initiator, and N,N,N',N'-tetramethylethylenediamine as the accelerator for acrylamide crosslinking. 50g of acrylamide was dissolved in 250mL of deionized water at room temperature. Under ice bath cooling, 3g of alkyl-modified tannic acid (prepared in Example 3), 0.25g of N,N-methylenebisacrylamide, 0.65g of APS initiator, and 0.15g of N,N,N',N'-tetramethylethylenediamine were added. After mixing and stirring for 20 minutes, a pregel solution was obtained. The pregel solution was transferred to a polytetrafluoroethylene mold (groove dimensions: 80×10×6mm). 3 The mixture was polymerized at 40°C for 8 hours to obtain a hydrogel, which was then frozen at -40°C for 8 hours and then freeze-dried for 24 hours to obtain the dried hydrogel.

[0027] Example 9 Based on Example 8, the amount of alkyl-modified tannic acid used in Example 3 was changed to 5g, and the remaining steps were the same as in Example 8.

[0028] Comparative Example 1 Preparation of medical ultrasonic hydrogel: Acrylamide was used as the polymer monomer, N,N-methylenebisacrylamide as the bifunctional crosslinking agent, ammonium persulfate (APS) as the initiator, and N,N,N',N'-tetramethylethylenediamine as the accelerator for acrylamide crosslinking. At room temperature, 50g of acrylamide was dissolved in 250mL of deionized water. Under ice bath cooling, 3g of tannic acid, 0.25g of N,N-methylenebisacrylamide, 0.65g of APS initiator, and 0.15g of N,N,N',N'-tetramethylethylenediamine were added. After mixing and stirring for 20 minutes, a pregel solution was obtained. The pregel solution was transferred to a polytetrafluoroethylene mold (groove dimensions: 80×10×6mm). 3 The mixture was polymerized at 40°C for 8 hours to obtain a hydrogel, which was then frozen at -40°C for 8 hours and then freeze-dried for 24 hours to obtain the dried hydrogel.

[0029] Comparative Example 2 Based on Comparative Example 1, the amount of tannic acid was changed to 5g, and the remaining steps were the same as those in Comparative Example 1.

[0030] Test section Sound velocity and sound attenuation performance test: Refer to the standard YY / T 0299-2022, and test the sound velocity, acoustic characteristic impedance and sound attenuation rate at 35℃ and 4.0MHz.

[0031] Adhesion performance test To evaluate the adhesion properties of hydrogels to moist tissue surfaces, a tensile testing machine was used to test the adhesion strength of hydrogels on pigskin. Pigskin is anatomically and physiologically very similar to human skin, making it an ideal model for evaluating the adhesion effect of hydrogels on skin tissue surfaces. The adhesion area of ​​the hydrogel on the pigskin surface was 50 mm × 50 mm, or 25 cm². 2 The hydrogel itself is 1 mm thick.

[0032] Antibacterial performance test The colony counting method was used to test the antibacterial rate of two common pathogenic bacteria, Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli, after 15 minutes of contact between the bacterial dilution and the hydrogel.

[0033] Specific testing method: Different types of bacteria were inoculated onto tryptone soybean agar medium and incubated at 37°C for 24 hours. The culture was then diluted to a concentration of 1×10⁻⁶. 5 CFU·mL -1 Take 20 mL of diluted bacterial culture medium and place it together with the hydrogel sample in a test tube. Calculate the antibacterial rate of the culture medium after 15 minutes of contact with the hydrogel using the following formula: a = (Na - Nb) / Na × 100%; Where a represents the antibacterial rate, Na represents the number of colonies before contact, and Nb represents the number of colonies after contact.

[0034] The test results are listed in Table 1.

[0035] Table 1 Analysis of the data in Table 1 shows that the sound velocity and acoustic characteristic impedance of Examples 4-9 and Comparative Examples 1-2 are not significantly different, and all meet the basic requirements of medical ultrasound coupling agents, approaching the sound velocity of human soft tissue of 1540 m / s. However, the acoustic attenuation rate of Comparative Example 1-2 is higher than that of Examples 4-9, indicating that the alkylation modification of tannic acid can reduce the acoustic attenuation of the hydrogel.

[0036] Regarding adhesion properties, the hydrogels in Comparative Examples 1-2 with added tannic acid showed significantly higher adhesion strength on pigskin surfaces than the hydrogels in Examples 4-9 with added alkylated modified tannic acid. The unmodified tannic acid had a higher content of phenolic hydroxyl groups, which formed strong hydrogen bonds with polar groups such as -OH and -NH2 on the pigskin surface, resulting in strong adhesion. The alkylation process consumed some of the phenolic hydroxyl groups in the tannic acid, introducing hydrophobic segments and significantly reducing the adhesion strength of the hydrogel on the skin surface. For the application scenario, excessively high adhesion strength leads to skin pulling and a poor user experience. Therefore, it is advisable to moderately reduce the adhesion strength of the hydrogel to 33-42 kPa (adhesion area 25 cm²). 2 This translates to approximately 9-10 kgf, making it easier for the hydrogel to peel off from the skin surface and also facilitating the smooth sliding of the ultrasound probe.

[0037] Regarding antibacterial properties, the hydrogels of Examples 4-9 all exhibited antibacterial rates exceeding 95%. However, the antibacterial properties of Comparative Examples 1-2 were significantly lower than those of Examples 4-9, particularly against Gram-negative *Escherichia coli* (antibacterial rate not reaching 90%). This is because Gram-negative bacteria have an additional outer membrane composed of lipopolysaccharides and phospholipids on their cell walls compared to Gram-positive bacteria. Unalkylated tannins have low lipid solubility and are difficult to penetrate the outer membrane of Gram-negative bacteria within a short time (15 minutes). Alkylated tannins have stronger hydrophobicity, enabling them to insert into the cell membranes of both Gram-positive and Gram-negative bacteria in a shorter time. Therefore, alkylation modification of tannins simultaneously enhances the bactericidal effect against different types of bacteria.

[0038] Finally, it should be noted that the above-described embodiments are merely illustrative of several implementation methods of this application, intended to facilitate a detailed understanding of the technical solutions of this application, but should not be construed as limiting the scope of protection of the patent application. It should be pointed out that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the scope of protection of this application. Furthermore, it should be understood that after reading the above teachings of this application, those skilled in the art can make various alterations or modifications to this application, and the equivalent forms obtained also fall within the scope of protection of this application. It should also be understood that technical solutions obtained by those skilled in the art based on the technical solutions provided in this application through logical analysis, reasoning, or limited experimentation are all within the scope of protection of the appended claims. Therefore, the scope of protection of this patent application should be determined by the content of the appended claims, and the specification can be used to interpret the content of the claims.

Claims

1. A medical ultrasonic hydrogel, the raw materials of which include: Alkyl-modified tannic acid, acrylamide, N,N-methylenebisacrylamide, initiator and accelerator; The initiator is selected from one or both of ammonium persulfate and potassium persulfate; The accelerator is selected from one or more of triethylamine, 2,4,6-tris(dimethylaminomethyl)phenol and N,N,N',N'-tetramethylethylenediamine; The alkyl-modified tannic acid is obtained by ring-opening reaction of an epoxy compound containing C4-C16 alkyl side chains with the phenolic hydroxyl groups of tannic acid. The epoxy compound containing C4-C16 alkyl side chains is selected from any one of lauryl glycidyl ether, isooctyl glycidyl ether, or cyclohexane oxide. The preparation method of the medical ultrasonic hydrogel includes: S1. Acrylamide is dissolved in deionized water at room temperature to obtain an aqueous solution of acrylamide; S2. At 0°C to room temperature, N,N-methylenebisacrylamide, initiator, accelerator and alkyl-modified tannic acid are added to an aqueous solution of acrylamide and mixed and stirred to obtain a pregel solution. S3. Transfer the pregel solution into a mold and allow it to stand at 35-60℃ for 1-24 hours to polymerize and obtain a hydrogel. S4. After freezing the hydrogel at -20°C for 1-12 hours, freeze-dry it for 1-24 hours to obtain the dried hydrogel. The step of modifying tannic acid with alkyl comprises reacting tannic acid with an epoxy compound containing C4-C16 alkyl side chains under the catalysis of a tetraalkyl halide and at 80-120°C; wherein the tetraalkyl halide is selected from any one of hexadecyltrimethylammonium chloride, hexadecyltrimethylammonium bromide, hexadecyltriethylammonium chloride, hexadecyltriethylammonium bromide, tetrabutylammonium chloride, or tetrabutylammonium bromide.

2. The medical ultrasonic hydrogel according to claim 1, characterized in that, The molar ratio of the tannic acid to the epoxy compound containing C4-C16 alkyl side chains is 1:(5-10).

3. The medical ultrasonic hydrogel according to claim 1, characterized in that, The amount of tetraalkyl halide used is 0.5-3 wt% of the total mass of tannic acid and epoxy compounds containing C4-C16 alkyl side chains.

4. The medical ultrasonic hydrogel according to claim 1, characterized in that, The raw materials, by weight, are: 45-55 parts acrylamide, 0.1-0.5 parts N,N-methylenebisacrylamide, 0.5-1 parts initiator, 0.1-0.2 parts accelerator, and 2-6 parts alkyl-modified tannic acid.

5. The use of a medical ultrasound hydrogel as described in any one of claims 1-4 in the preparation of an ultrasound imaging agent.

Images