Preparation of hydrogel ultrasonic coupling patch for long-term stable continuous monitoring

Abstract

The invention belongs to the technical field of biomedical materials, and particularly relates to preparation of a hydrogel ultrasonic coupling patch for long-term stable continuous monitoring. According to the patch, an interpenetrating double-network structure system is formed by an alginate component and a polyacrylic acid component through intermolecular interaction, and the patch has excellent adhesion performance and mechanical performance. Compared with the prior art, by optimizing the components and the preparation process, the obtained hydrogel patch has the following advantages that the excellent acoustic impedance matching characteristic is achieved, and high-fidelity transmission of ultrasonic signals is ensured; the tissue adhesion is strong, and long-term stable attachment can be realized; good mechanical stability and durability are achieved, and the method is suitable for continuous monitoring application. The product effectively solves the technical problems that the traditional liquid coupling agent is easy to lose, the solid coupling patch is insufficient in adhesion and the like, and has important application value in the fields of medical ultrasonic diagnosis and long-term monitoring.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedical materials, and more specifically, relates to the preparation of a hydrogel ultrasound coupling patch for long-term stable continuous monitoring. Background Art

[0002] In the medical field, ultrasound testing, with its advantages of low cost, minimal trauma, and ease of clinical application, has been widely used in clinical diagnosis, such as organ testing, assessment of cardiovascular disease, tumors, and other pathologies, as well as in obstetrics, gynecology, and urology. In ultrasound diagnosis, high-resolution, rapid imaging and mapping are crucial for accurate diagnosis and prompt treatment. To improve the resolution of ultrasound imaging, various liquid or solid ultrasound coupling agents have been developed to eliminate air between the ultrasound probe and the human skin. This reduces the attenuation of ultrasound energy at the skin-probe interface, thereby enhancing ultrasound imaging.

[0003] However, traditional medical ultrasound coupling agents are gradually failing to meet the practical needs of doctors and patients. For example, commonly used liquid ultrasound coupling agents can rapidly flow and evaporate when squeezed by the probe, requiring constant replenishment. Furthermore, the low friction between the ultrasound probe and the skin can easily lead to slippage, distracting doctors from their diagnosis. Consequently, currently available liquid ultrasound coupling agents are unsuitable for long-term, continuous monitoring. Furthermore, the surfaces of commonly used ultrasound solid-state coupling patches in clinical practice lack the ability to adhere to the skin or ultrasound probe (even if adhesion exists, it is weak). These patches are prone to relative slippage when squeezed by the probe, making it difficult to achieve long-term, stable, and continuous monitoring of a specific area. For example, RTV (room temperature vulcanized silicone rubber) specifically used for ultrasound probes is limited by the requirements of ultrasound testing, which require excellent anti-fouling properties to prevent dust adhesion and interference with ultrasound imaging. The inert surface of the ultrasound probe makes it difficult for traditional ultrasound solid-state coupling agents to adhere to the probe. In order to solve the problem that the currently common liquid and solid ultrasonic coupling patches on the market are not suitable for long-term continuous monitoring, it is necessary to develop a new ultrasonic coupling patch that can adhere to the skin and ultrasonic probe materials. During long-term continuous monitoring (especially more than 24 hours), it is required to be able to maintain the stability of its own physical and chemical properties and have a stable adhesion effect on the skin and ultrasonic probe materials under the condition of 37°C, so as to achieve long-term and stable continuous monitoring of specific biological tissue areas. Summary of the Invention

[0004] In response to the aforementioned deficiencies or improvements in the prior art, the present invention aims to provide a hydrogel ultrasound coupling patch for long-term, stable, and continuous monitoring. By improving the composition and preparation method of the hydrogel ultrasound coupling patch, a two-component system consisting of alginate and polyacrylic acid components is employed to form an interpenetrating double network structure. The resulting hydrogel ultrasound coupling patch exhibits excellent acoustic properties, strong adhesion, and excellent stability. This hydrogel ultrasound coupling patch, used for medical ultrasound testing, addresses the challenges of physicians requiring handheld ultrasound probes and frequently using commercial liquid ultrasound coupling agents, which hinders their ability to focus on treatment, and the relative displacement of commercial solid-state coupling patches due to their lack of adhesion. The present invention particularly addresses the difficulty in achieving long-term, continuous monitoring due to the lack of adhesion between solid-state ultrasound coupling patches and the skin and ultrasound probe.

[0005] To achieve the above objectives, according to one aspect of the present invention, a hydrogel ultrasound coupling patch for continuous monitoring is provided, characterized in that it includes an alginate component and a polyacrylic acid component. The hydrogel ultrasound coupling patch for continuous monitoring is a transparent hydrogel patch formed by forming an interpenetrating double network system by the alginate component and the polyacrylic acid component.

[0006] As a further preferred embodiment of the present invention, the alginate component is selected from alginate and its derivatives, preferably selected from alginate, oxidized alginate, methacryloyl alginate, and oxidized methacryloyl alginate.

[0007] As a further preferred embodiment of the present invention, the polyacrylic acid component is selected from polyacrylic acid and its derivatives, preferably selected from polyacrylic acid, polymethacrylic acid, polymethyl acrylate, polyacrylamide, N-acryloyloxysuccinimidated polyacrylic acid, N-acryloyloxysuccinimidated polyacrylic acid salt, polyacrylic anhydride gelatin, cyanoacrylic acid, acrylic acid acylated polyvinyl alcohol, acrylated polyethylene glycol, acrylated four-arm polyethylene glycol; more preferably, it is at least one of polyacrylic acid, N-acryloyloxysuccinimidated polyacrylic acid and N-acryloyloxysuccinimidated polyacrylic acid salt.

[0008] As a further preferred embodiment of the present invention, the thickness of the hydrogel ultrasound coupling patch that can be used for continuous monitoring is 1.0 to 100 mm.

[0009] According to another aspect of the present invention, a method for preparing the hydrogel ultrasound coupling patch for continuous monitoring is provided, characterized in that the preparation method comprises using alginate or a derivative thereof as a first raw material and acrylic acid or a derivative thereof as a second raw material, dissolving the first raw material, the second raw material, an initiator, a cross-linking agent, and a polyol moisturizer in deionized water to obtain a pre-gel solution; then, pouring the pre-gel solution into a template and forming a hydrogel through cross-linking and polymerization reactions, and then demolding to obtain the hydrogel ultrasound coupling patch for continuous monitoring;

[0010] The initiator includes hydrogen peroxide, ammonium persulfate, sodium persulfate, potassium persulfate, 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone (IC-2959), α-ketoglutaric acid, phenyl (2,4,6-trimethylbenzoyl) lithium phosphate (LAP), hydrogen peroxide-Fe 2+ One of the systems;

[0011] The cross-linking agent is at least one of N,N-methylenebisacrylamide, methacrylic anhydride gelatin, polyethylene glycol diacrylate, polyethylene glycol, and polypropylene glycol;

[0012] The polyol moisturizing agent is at least one of glycerol, propylene glycol, butylene glycol and pentaerythritol.

[0013] As a further preferred embodiment of the present invention, the mixed solvent system of deionized water and glycerol is obtained by mixing deionized water and glycerol in a mass ratio of 1:1 to 1:4.

[0014] According to another aspect of the present invention, the present invention provides the use of the above-mentioned hydrogel ultrasound coupling patch that can be used for continuous monitoring in the preparation of an extracorporeal ultrasound coupling patch, wherein the extracorporeal ultrasound coupling patch is used to adhere to the skin surface or to adhere to an ultrasound probe; when the extracorporeal ultrasound coupling patch is adhered to the skin surface, it can be in conformal contact with the skin.

[0015] As a further preference of the present invention, the extracorporeal ultrasound coupling patch is capable of long-term continuous ultrasound coupling, the time being not shorter than 12 hours, preferably not shorter than 24 hours, and more preferably not shorter than 48 hours.

[0016] Through the above technical solutions conceived by the present invention, compared with the existing art, a hydrogel ultrasound coupling patch with both high stability and high adhesion is obtained. This two-component system composed of alginate and polyacrylic acid components presents a colorless and transparent solid hydrogel shape. It has excellent acoustic properties, strong adhesion, and high stability, enabling long-term, stable, and continuous monitoring of tissue ultrasound sites. It can be used to form an ultrasound gel product for in vitro tissues such as skin, and is used for ultrasound imaging of tissues including highly curved joints and uneven throats, for long-term, stable, and continuous in vitro monitoring. Taking skin and ultrasound probe adhesion as an example, the patch's immediate adhesion strength to skin and RTV rubber is approximately 76 N / m and 21 N / m, respectively, demonstrating excellent adhesion and minimizing the impact of air gaps at the interface on ultrasound imaging.

[0017] The hydrogel ultrasound coupling patch obtained by the present invention can remain almost dry for a long time in an environment of 37°C, thereby maintaining the stability of the physical and chemical properties of the hydrogel ultrasound coupling patch, such as shape, size, water content and flexibility; at the same time, it can stably adhere to the skin and the ultrasound probe, and can minimize the influence of air at the interface on ultrasound imaging, providing a new approach for long-term, stable and continuous ultrasound monitoring.

[0018] Specifically, the present invention can achieve the following beneficial effects:

[0019] 1. The hydrogel ultrasound coupling patch of the present invention is a dual-network hydrogel ultrasound coupling patch of alginate and its derivatives / polyacrylic acid and its derivatives, which is composed of two components, alginate and polyacrylic acid, to form an interpenetrating dual-network structure. The resulting adhesive hydrogel has excellent acoustic properties and good adhesion, and can stably adhere to biological skin and ultrasound probe materials. Compared with commercially available liquid coupling agents, the patch obtained by the present invention helps to reduce the relative slippage between the probe and the skin. Compared with commercially available solid gel coupling agents, it can effectively solve the problem of difficulty in forming conformal contact between the probe and the tissue. The hydrogel ultrasound coupling patch of the present invention can especially introduce polyacrylic acid (salt) modified with N-acryloyloxysuccinimide, which can form covalent bonds with chemical groups such as amino and hydroxyl groups on the skin, thereby enabling firm adhesion to tissues such as the skin. Taking the adhesion to skin and ultrasound probe as an example, the instantaneous adhesion strength of the patch to skin and RTV rubber is approximately 76N / m and 21N / m, respectively, which has excellent adhesion and can minimize the impact of air gaps at the interface on ultrasound imaging.

[0020] 2. The present invention introduces a moisturizer into the hydrogel ultrasound coupling patch. The introduced moisturizer enables the hydrogel patch to maintain its own physical and chemical properties for a long time under the condition of 37°C. Combined with N-acryloyloxysuccinimide-modified polyacrylic acid (salt), it can achieve better hydrogel self-stability and adhesion stability, thereby achieving better long-term stable and continuous monitoring effect.

[0021] 3. The hydrogel ultrasound coupling patch prepared in this invention is used in medical ultrasound monitoring, resolving the issues of current commercial liquid coupling agents, which are prone to volatility and are unsuitable for long-term continuous monitoring. It also addresses the general lack of adhesion and difficulty in conforming to tissue contact and the tendency for relative slippage in commercial solid-state ultrasound coupling patches, making them difficult to maintain continuous monitoring over time. This hydrogel ultrasound coupling patch provides a new means for long-term, stable, high-quality continuous imaging.

[0022] The hydrogel ultrasound coupling patch obtained by the present invention has good adhesion and adhesion stability. It can achieve stable and firm adhesion to some tissue parts with high curvature, such as the skin, thereby achieving conformal contact with the surface of these uneven tissues. At the same time, it can achieve long-term adhesion to the rubber on the skin and the ultrasound probe (after 48 hours of adhesion to the materials of the skin and the ultrasound probe at 37°C, it still has a high adhesion effect). In addition, the ultrasound coupling patch can almost maintain the stability of physical and chemical properties such as shape, size, water content and flexibility when exposed to a 37°C usage environment for a long time. All of these can achieve long-term continuous and stable monitoring of ultrasound imaging parts such as human tissues and organs without the need for a handheld ultrasound probe.

[0023] 4. The raw materials of the hydrogel ultrasound coupling patch of the present invention are widely available, the preparation process is simple, the cost is low, and it has good biocompatibility.

[0024] The hydrogel ultrasound coupling patch of the present invention can be used for continuous in vitro monitoring. The alginate and its derivative system and the polyacrylic acid and its derivative system used in the preparation process can simultaneously improve flexibility and adhesion, so that it can better fit the skin and ultrasound probe, and at the same time achieve the purpose of adhesion to the ultrasound probe rubber, laying a good foundation for long-term stable and continuous ultrasound monitoring.

[0025] In summary, compared to existing technologies, this invention optimizes the components and preparation process to create a hydrogel patch with an interpenetrating double network structure formed by molecular interactions between alginate and polyacrylic acid components. The resulting hydrogel patch exhibits the following advantages: excellent acoustic impedance matching, ensuring high-fidelity transmission of ultrasound signals; strong tissue adhesion, enabling long-term stable attachment; and good mechanical stability and durability, making it suitable for continuous monitoring applications. This product combines excellent adhesion and mechanical properties, effectively addressing technical challenges such as the easy loss of traditional liquid coupling agents and the insufficient adhesion of solid-state coupling patches, and holds significant application value in the fields of medical ultrasound diagnosis and long-term monitoring. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 Schematic diagram of the structure of the hydrogel ultrasound coupling patch.

[0027] Figure 2 This is a physical picture of the hydrogel ultrasound coupling patch.

[0028] Figure 3 This is a comparison of the Young's modulus of the hydrogel ultrasound coupling patches SA / PAA-1, SA / PAA-2, and SA / PAA-3 prepared in Examples 1-3 and the hydrogel ultrasound coupling patch PAA prepared in Comparative Example 1.

[0029] Figure 4 This is the adhesion test of the hydrogel ultrasound coupling patch; Figure 4 (A) shows the test results of the commercially available medical ultrasound coupling patch and the hydrogel ultrasound coupling patch prepared in Example 1 for adhesion to pig skin; Figure 4 (B) is the test result of the commercially available medical ultrasound coupling patch and the hydrogel ultrasound coupling patch prepared in Example 2 adhering to the ultrasound probe material.

[0030] Figure 5 This is the adhesion stability test of the hydrogel ultrasound coupling patch; Figure 5 (A) shows the test results of the commercially available medical ultrasound coupling patch and the hydrogel ultrasound coupling patch prepared in Example 1 adhering to pig skin for 48 hours; Figure 5 (B) is the test result of the commercially available medical ultrasound coupling patch and the hydrogel ultrasound coupling patch prepared in Example 2 adhering to the ultrasound probe material for 48 hours.

[0031] Figure 6 The stability of commercially available medical ultrasound coupling patches and the hydrogel ultrasound coupling patches prepared in Examples 1-3 was tested in an environment of 37° C. and a relative humidity of 36.2% to 59.3%.

[0032] Figure 7This is a comparison of ultrasonic imaging of the human radial artery using a commercially available medical ultrasonic coupling patch and a hydrogel ultrasonic coupling patch prepared in Example 3; Figure 7 (A) corresponds to the use of commercially available ultrasonic coupling patches. Figure 7 (B) corresponds to the hydrogel ultrasound coupling patch prepared in Example 3.

[0033] Figure 8 The biocompatibility test of the hydrogel ultrasound coupling patch prepared in Implementation Case 1 and Implementation Case 3 on human keratinocytes (HaCaT) was conducted. DETAILED DESCRIPTION

[0034] In order to make the objectives, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely for the purpose of explaining the present invention and are not intended to limit the present invention. In addition, the technical features involved in the various embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.

[0035] The mass percentages of the components in the following examples and comparative examples refer to the mass percentages of the corresponding components in the precursor solution used to form the patch; the specific amounts of the raw materials used in the preparation process, except for the polyol moisturizer component and the solvent, are all converted based on these mass percentages. In addition, the light curing used in the following examples and comparative examples is carried out under a UV curing power of 200W / m 2 carried out under the conditions of.

[0036] Taking sodium alginate as the first component and N-acryloyloxysuccinimidized polyacrylic acid as the second component as an example, based on the present invention, the precursor solution (also called prepolymer solution) of the ultrasonic coupling patch contains sodium alginate (mass fraction can be 0.1-3%), acrylic acid (mass fraction can be 1-30%), N-acryloyloxysuccinimide (mass fraction can be less than or equal to 30%), crosslinker (mass fraction can be 0.01%-0.50%), initiator (when the initiator is a photoinitiator α-ketoglutaric acid, the mass fraction can be 0.01%-0.50%; when the initiator is a thermal initiator potassium persulfate, the mass fraction can be 0.1%-1%); it also contains water and glycerol. After the prepolymer solution is polymerized, an ultrasonic coupling patch can be obtained. The preparation method of the ultrasonic coupling patch may include the following steps:

[0037] (1) Preparation of prepolymer solution: A certain amount of glycerol, sodium alginate, acrylic acid monomer, N-acryloyloxysuccinimide, crosslinker, and initiator were dissolved in deoxygenated deionized water, stirred magnetically to form a uniform solution, and dissolved in a low-temperature environment with ice cubes.

[0038] The magnetic stirring time for dissolving sodium alginate can be 0.5 to 24 hours, and the magnetic stirring rate can be 50 to 2000 r / min. The magnetic stirring time for dissolving acrylic acid monomer can be 0.01 to 24 hours, and the magnetic stirring rate can be 50 to 2000 r / min. The magnetic stirring time for dissolving N-acryloyloxysuccinimide can be 0.1 to 5 hours, and the magnetic stirring rate can be 50 to 2000 r / min. The magnetic stirring time for dissolving N,N-methylenebisacrylamide can be 0.01 to 1 hour, and the magnetic stirring rate can be 50 to 2000 r / min. The magnetic stirring time for dissolving a photoinitiator or thermal initiator can be 0.01 to 1 hour, and the magnetic stirring rate can be 50 to 1500 r / min.

[0039] (2) Curing of the prepolymer: The mixed solution is deaerated in a planetary mixer. After the deaeration process is completed, the deoxygenated prepolymer solution is poured into a glass mold of a preset size and cured by UV light at 2-8°C or thermally polymerized at 37°C. After the curing process is completed, the prepolymer is removed from the mold to obtain a hydrogel ultrasound coupling patch (which can be sealed and stored at 2-8°C).

[0040] During the light curing process, the UV curing power can be 200W / m 2 , the curing time can be 40 minutes; during the thermal curing process, the polymerization temperature can be other temperatures greater than 30°C, and the curing time can be 24 hours.

[0041] The following are specific embodiments:

[0042] Implementation Case 1

[0043] The prepolymer solution of the hydrogel ultrasound coupling patch in this embodiment includes: N,N-methylenebisacrylamide (mass fraction 0.050%), sodium alginate (mass fraction 1.5%), acrylic acid (mass fraction 20%), N-acryloyloxysuccinimide (mass fraction 1.0%), α-ketoglutaric acid (mass fraction 0.20%); it also includes glycerol and water.

[0044] The method for preparing the hydrogel ultrasound coupling patch using the photocuring method in this embodiment is as follows:

[0045] (1) A crosslinking agent is dissolved in a mixed solvent of glycerol and water, and the solution is dissolved by magnetic stirring. The dissolution temperature is room temperature, the magnetic stirring rate is 500 r / min, and the stirring time is 30 min. The crosslinking agent is N,N-methylenebisacrylamide, and the mass ratio of the solvent glycerol to water is 1:1.

[0046] (2) Sodium alginate was added to the homogeneous solution obtained in step (1) and dissolved by magnetic stirring. The dissolution temperature was room temperature, the magnetic stirring rate was 500 r / min, and the stirring time was 12 h.

[0047] (3) Acrylic acid was added to the homogeneous solution obtained in step (2), and the mixture was uniformly stirred by magnetic stirring at room temperature at a rate of 1200 r / min for 1 h.

[0048] (4) Add N-acryloyloxysuccinimide to the mixed solution obtained in step (3) and dissolve it by magnetic stirring. The dissolution temperature is 2-8° C., the magnetic stirring rate is 1200 r / min, and the stirring time is 1 h.

[0049] (5) Under light-proof conditions, α-ketoglutaric acid was added to the mixed solution obtained in step (4), and dissolved by magnetic stirring at a dissolution temperature of 2 to 8° C., a stirring time of 10 min, and a rotation speed of 1200 r / min.

[0050] (6) The mixed solution obtained in step (5) is debubbled in a planetary mixer. After the debubbling process is completed, the mixed solution is carefully injected into the mold and light-cured at 2-8°C for 40 minutes. After the curing process is completed, the hydrogel ultrasound coupling patch is removed from the mold and sealed and stored at 2-8°C.

[0051] The hydrogel ultrasound coupling patch obtained in Example 1 is denoted as SA / PAA-1.

[0052] Figure 2 This is a physical picture of the hydrogel ultrasound coupling patch for implementation case 1.

[0053] The acoustic properties of Example 1 were tested with reference to the test methods reported in the prior art. (For details, see: Yi J, Nguyen KT, Wang W, et al. Polyacrylamide / Alginate double-network tough hydrogels for intraoral ultrasound imaging. J Colloid Interface Sci. 2020; 578: 598-607.; or, Yi J, Nguyen KT, Wang W, et al. Mussel-Inspired Adhesive Double-Network Hydrogel for Intraoral Ultrasound Imaging. ACS Appl Bio Mater. 2020; 3(12): 8943-8952.) The hydrogel ultrasound coupling patch SA / PAA-1 obtained in Example 1 was tested for its acoustic properties. The results are shown in Table 1.

[0054] Table 1 Acoustic properties test results of the hydrogel ultrasound coupling patch in Example 1

[0055]

[0056] Implementation Case 2

[0057] The prepolymer solution of the hydrogel ultrasound coupling patch in this embodiment includes: N,N-methylenebisacrylamide (mass fraction 0.025%), sodium alginate (mass fraction 1.5%), acrylic acid (mass fraction 20%), N-acryloyloxysuccinimide (mass fraction 1.0%), α-ketoglutaric acid (mass fraction 0.20%); it also includes glycerol and water.

[0058] The method for preparing the hydrogel ultrasound coupling patch using the photocuring method in this embodiment is as follows:

[0059] (1) A crosslinking agent is dissolved in a mixed solvent of glycerol and water, and the mixture is dissolved by magnetic stirring at room temperature, a magnetic stirring rate of 500 r / min, and a stirring time of 30 min. The crosslinking agent is N,N-methylenebisacrylamide. The mass ratio of the solvent glycerol to water is 2:1.

[0060] (2) Sodium alginate was added to the homogeneous solution obtained in step (1) and dissolved by magnetic stirring. The dissolution temperature was room temperature, the magnetic stirring rate was 500 r / min, and the stirring time was 12 h.

[0061] (3) Acrylic acid was added to the homogeneous solution obtained in step (2), and the mixture was uniformly stirred by magnetic stirring at room temperature at a rate of 1200 r / min for 1 h.

[0062] (4) Add N-acryloyloxysuccinimide to the mixed solution obtained in step (3) and dissolve it by magnetic stirring. The dissolution temperature is 2-8° C., the magnetic stirring rate is 1200 r / min, and the stirring time is 1 h.

[0063] (5) Under light-proof conditions, α-ketoglutaric acid was added to the mixed solution obtained in step (4), and dissolved by magnetic stirring at a dissolution temperature of 2 to 8° C., a stirring time of 40 min, and a rotation speed of 1200 r / min.

[0064] (6) The mixed solution obtained in step (5) is debubbled in a planetary mixer. After the debubbling process is completed, the mixed solution is carefully injected into the mold and light-cured at 2-8°C for 40 minutes. After the curing process is completed, the hydrogel ultrasound coupling patch is removed from the mold and sealed and stored at 2-8°C.

[0065] The hydrogel ultrasound coupling patch obtained in Example 2 is denoted as SA / PAA-2.

[0066] Implementation Case 3

[0067] The prepolymer solution of the hydrogel ultrasound coupling patch in this embodiment includes: N,N-methylenebisacrylamide (mass fraction 0.025%), sodium alginate (mass fraction 1.0%), acrylic acid (mass fraction 20%), N-acryloyloxysuccinimide (mass fraction 1.0%), α-ketoglutaric acid (mass fraction 0.20%); it also includes glycerol and water.

[0068] The method for preparing the hydrogel ultrasound coupling patch using the photocuring method in this embodiment is as follows:

[0069] (1) A crosslinking agent is dissolved in a mixed solvent of glycerol and water, and the mixture is dissolved by magnetic stirring at room temperature, a magnetic stirring rate of 500 r / min, and a stirring time of 30 min. The crosslinking agent is N,N-methylenebisacrylamide. The mass ratio of the solvent glycerol to water is 4:1.

[0070] (2) Sodium alginate was added to the homogeneous solution obtained in step (1) and dissolved by magnetic stirring. The dissolution temperature was room temperature, the magnetic stirring rate was 500 r / min, and the stirring time was 12 h.

[0071] (3) Acrylic acid is added to the homogeneous solution obtained in step (2), and after being uniformly stirred by magnetic force at room temperature, the pH of the solution is adjusted to between 3.2 and 4.5. The magnetic stirring rate is 1200 r / min, and the stirring time is 1 h. The pH adjuster is sodium hydroxide solution or ammonia water.

[0072] (4) Add N-acryloyloxysuccinimide to the mixed solution obtained in step (3) and dissolve it by magnetic stirring. The dissolution temperature is 2-8° C., the magnetic stirring rate is 1200 r / min, and the stirring time is 1 h.

[0073] (5) Under light-proof conditions, α-ketoglutaric acid was added to the mixed solution obtained in step (4), and dissolved by magnetic stirring at a dissolution temperature of 2 to 8° C., a stirring time of 10 min, and a rotation speed of 1200 r / min.

[0074] (6) The mixed solution obtained in step (5) is debubbled in a planetary mixer. After the debubbling process is completed, the mixed solution is carefully injected into the mold and light-cured at 2-8°C for 40 minutes. After the curing process is completed, the hydrogel ultrasound coupling patch is removed from the mold and sealed and stored at 2-8°C.

[0075] The hydrogel ultrasound coupling patch obtained in Example 3 is denoted as SA / PAA-3.

[0076] Figure 7 The commercial coupling patch and the hydrogel ultrasound coupling patch in implementation case 3 were tested for monitoring the human radial artery.

[0077] Implementation Case 4

[0078] The prepolymer solution of the hydrogel ultrasound coupling patch in this embodiment includes: N,N-methylenebisacrylamide (mass fraction 0.050%), sodium alginate (mass fraction 1.0%), acrylic acid (mass fraction 20%), α-ketoglutaric acid (mass fraction 0.20%); glycerol; and water. N-acryloyloxysuccinimide is not present.

[0079] The preparation method is as follows:

[0080] (1) Dissolve a crosslinker and sodium alginate in a certain amount of deionized water and dissolve by magnetic stirring at room temperature, a magnetic stirring rate of 500 r / min, and a stirring time of 12 hours. Furthermore, in the method for preparing a hydrogel ultrasound coupling patch described in the present invention, the crosslinker is N,N-methylenebisacrylamide.

[0081] (2) Glycerol was added to the homogeneous solution and mixed uniformly by magnetic stirring. The dissolution temperature was room temperature, the magnetic stirring rate was 1200 r / min, and the stirring time was 1 hour. Furthermore, in the method for preparing a hydrogel ultrasound coupling patch described in the present invention, the mass ratio of the solvent glycerol to water was 1:1.

[0082] (3) Acrylic acid was added to the above solution and stirred evenly by magnetic stirring at a rate of 200 r / min for 1 h (at room temperature).

[0083] (4) Add α-ketoglutaric acid to the mixture under light-shielding conditions and dissolve it by magnetic stirring at a temperature of 2 to 8° C., a magnetic stirring rate of 500 r / min, and a stirring time of 1 hour. Furthermore, in the method for preparing a hydrogel ultrasound coupling patch described in the present invention, the stirring time is 1 hour and the rotation speed is 500 r / min.

[0084] (5) The mixed solution is removed from the mold in a planetary mixer to remove bubbles. After the bubble removal process is completed, the mixed solution is carefully injected into the mold and light-cured at 2-8°C for 40 minutes. After the curing process is completed, the hydrogel ultrasound coupling patch is removed from the mold and stored in a sealed environment at 2-8°C for later use.

[0085] The product is a patch without added N-acryloyloxysuccinimide. When adhered to the probe, the immediate adhesion and adhesion stability are the same as those of the product in Example 1; when adhered to the skin, the immediate adhesion is the same as those of the product in Example 1, and the adhesion stability is slightly reduced.

[0086] Comparative Example 1

[0087] The patch to be obtained in this comparative example has a prepolymer solution comprising: N,N-methylenebisacrylamide (mass fraction 0.05%), acrylic acid (mass fraction 20%), N-acryloyloxysuccinimide (mass fraction 1.0%), α-ketoglutaric acid (mass fraction 0.20%); glycerol; and water. It does not contain alginate components.

[0088] This comparative example does not use alginate components. Specifically, the method for preparing the hydrogel ultrasound coupling patch using the photocuring method is as follows:

[0089] (1) A crosslinking agent is dissolved in a mixed solvent of glycerol and water, and the mixture is dissolved by magnetic stirring at room temperature, a magnetic stirring rate of 500 r / min, and a stirring time of 30 min. The crosslinking agent is N,N-methylenebisacrylamide. The mass ratio of the solvent glycerol to water is 1:1.

[0090] (2) Acrylic acid was added to the homogeneous solution obtained in step (1), and the mixture was uniformly stirred by magnetic stirring at room temperature at a rate of 1200 r / min for 1 h.

[0091] (3) Add N-acryloyloxysuccinimide to the mixed solution obtained in step (2) and dissolve it by magnetic stirring. The dissolution temperature is 2-8°C, the magnetic stirring rate is 1200 r / min, and the stirring time is 1 h.

[0092] (4) Under light-proof conditions, α-ketoglutaric acid was added to the mixed solution obtained in step (3), and dissolved by magnetic stirring at a dissolution temperature of 2 to 8° C., a stirring time of 10 min, and a rotation speed of 1200 r / min.

[0093] (5) The mixed solution obtained in step (4) is debubbled in a planetary mixer. After the debubbling process is completed, the mixed solution is carefully injected into a mold and light-cured at 2-8°C for 40 minutes. After the curing process is completed, the hydrogel ultrasound coupling patch is removed from the mold and sealed and stored at 2-8°C.

[0094] The hydrogel ultrasound coupling patch obtained in Comparative Example 1 is denoted as PAA.

[0095] In addition, a commercially available medical solid-state coupling patch was used as a control sample. The commercially available medical solid-state coupling patch was purchased from Zhengzhou Kangyijian Medical Equipment Co., Ltd., with a circular specification of 45 mm in diameter and 3 mm in thickness, and an error of + / - 10% (product registration number: Yu Zheng Xie Bei 20160052; production registration certificate number: Yu Zheng Food and Drug Administration Machinery Production Bei 20150009). The commercially available medical solid-state coupling patch and the products obtained from various implementation cases and comparative proportions were tested.

[0096] The material used to encapsulate the ultrasound probe is room temperature vulcanized silicone rubber (RTV rubber, model 704). This rubber is used to test its adhesion to the hydrogel ultrasound coupling patch.

[0097] Adhesion and adhesion stability testing:

[0098] A 180° peel test was used to quantitatively characterize the adhesion of the hydrogel ultrasound coupling patch to pig skin and RTV rubber on the ultrasound probe material. The specific implementation scheme was as follows: a hydrogel ultrasound coupling patch measuring 70 mm × 20 mm × 2 mm was prepared using the aforementioned examples and comparative examples. This patch was then tightly attached to a 70 mm × 20 mm cut piece of clean pig skin and RTV rubber, with an overlap of 20 mm × 50 mm between the patch and the hydrogel. The patch was pressed to eliminate any air bubbles in the overlapped area. After sterilization, the following steps were performed:

[0099] i. Immediately test and record the maximum peeling force data of the hydrogel ultrasound coupling patch and pig skin and RTV rubber using a universal testing machine. The test peeling rate is 50mm / min. Then calculate and compare the peeling strength of each group and draw a picture using Origin drawing software. Figure 4 Histogram of data;

[0100] ii. Seal and store at 37°C for 1 hour and 48 hours respectively. Use a universal testing machine to test and record the maximum peeling force data of the hydrogel ultrasound coupling patch and pig skin and RTV rubber at 1 hour and 48 hours, with a test peeling rate of 50mm / min. Then calculate and compare the peeling strength of each group, and draw a picture using Origin drawing software. Figure 5 Column chart of data.

[0101] Figure 4 (A) is the test result of the adhesion performance of the hydrogel ultrasound coupling patch to the skin in Example 1. Figure 5 (A) is the adhesion stability test result of the hydrogel ultrasound coupling patch adhering to the skin in implementation case 1.

[0102] Figure 4 (B) Adhesion test results of hydrogel ultrasound coupling patch adhered to ultrasound probe material in implementation case 2. Figure 5 (B) Implementation Case 2: Adhesion stability test results of hydrogel ultrasound coupling patch adhered to ultrasound probe material.

[0103] pass Figure 4From the adhesion test results, it can be seen that the hydrogel ultrasound coupling patch obtained in the present invention has a good adhesion effect on pig skin (>70N / m), which is much greater than the calcium-modified silk protein ultrasound coupling patch reported in academic research (for details, see Lee SM, Lee T, Kim H, et al. Calcium-Modified Silk Patch as a Next-Generation Ultrasound Coupling Medium. ACS Appl Mater Interfaces. 2021; 13(47): 55827-55839., with a maximum adhesion strength of about 20N / m), and is also much greater than the fibrin glue commonly used in hospitals (for details, see Yu L, Liu Z, Tong Z, et al. Sequential-Crosslinking Fibrin Glue for Rapid and Reinforced Hemostasis. Adv Sci (Weinh). 2024; 11 (7): e2308171., wherein a common medical adhesive was tested, and the adhesion strength was less than 20N / m), while most common medical ultrasonic coupling patches currently available on the market have no adhesion properties or low adhesion properties. The adhesion strength after 48 hours of adhesion to pig skin decreased slightly. This may be due to the loss of water in the hydrogel ultrasonic coupling patch at 37°C in Example 1, which caused a decrease in adhesion properties. However, even with a slight decrease in adhesion strength, it can still form a good adhesion effect with pig skin, meeting the needs of long-term use in this field. RTV rubber itself is a common anti-fouling material. The surface itself is resistant to adhesion to various materials. As a result, when the hydrogel ultrasonic coupling patch obtained by the present invention comes into contact with it, the hydrogel ultrasonic coupling patch prepared by the present invention can form a chemical covalent bond with the skin due to the presence of some chemical groups such as amino and hydroxyl groups on the skin surface, resulting in its adhesion effect with RTV rubber not being as good as that with skin. The hydrogel ultrasound coupling patch with strong adhesion prepared by the present invention can form good conformal contact with the skin and the RTV rubber on the ultrasound probe material, minimizing the loss of ultrasound energy due to air gaps at the interface between the ultrasound coupling patch and the two. At the same time, due to the stable adhesion to the skin effect, stable and continuous ultrasound monitoring becomes feasible.

[0104] Water loss rate test:

[0105] The weighing method was used to quantitatively characterize the water loss of the hydrogel ultrasound coupling patch from 0 to 48 hours. The commercially available ultrasound coupling patch and hydrogel were cut into cylindrical shapes with a diameter of 10 mm and a height of 2 mm, and placed in a vacuum oven at 37°C. The mass and humidity of the hydrogel ultrasound coupling patch were recorded at different time points. After the experiment, the water loss rate was calculated and the Origin drawing software was used to draw the water loss rate. Figure 6 The water loss rate-time line graph. From the analysis results in the figure, it can be seen that in the same period of time, the commercially available ultrasonic coupling patch has a more serious water loss than the hydrogel ultrasonic coupling patch group. After 24 hours, the commercially available ultrasonic coupling patch has a water loss rate of more than 90%. At the same time, it also becomes very hard and has almost no flexibility. Therefore, the commercially available ultrasonic coupling patch is not suitable for long-term continuous monitoring. The present invention can control the water loss rate by regulating the composition of the hydrogel, so that the SA / PAA-3 hydrogel in Implementation Case 3 only loses water slightly after 24 hours, of which the water loss rate is about 3% at 32 hours and the water loss rate is controlled at about 5% at 48 hours, which can be considered to be almost no water loss. Therefore, it can be considered that the hydrogel ultrasonic coupling patch prepared by the present invention can maintain the stability of physical and chemical properties such as shape, size, water content and flexibility within 48 hours, which enables the present invention to achieve long-term stable and continuous ultrasonic monitoring. Comparison of ultrasonic imaging performance:

[0106] A hydrogel ultrasound coupling patch with a diameter of 45 mm and a thickness of 3 mm was prepared. The hydrogel ultrasound coupling patch and a commercially available ultrasound coupling patch were attached to the left radial artery of a volunteer. A 5 MHz ultrasound probe was used to compare the ultrasound imaging effects of the two on the radial artery within 10 minutes. The hydrogel ultrasound coupling patch had the following imaging effect on the radial artery: Figure 7 As shown in (A), the commercially available solid ultrasound coupling patch has the following effect on radial artery imaging: Figure 7 As shown in (B) in the figure, it can be seen that both can clearly perform ultrasonic imaging of the radial artery. From the comparison of the effects in the figure, it can be seen that the effect of the hydrogel ultrasonic coupling patch obtained by the present invention on vascular imaging is comparable to that of the commonly available solid ultrasonic coupling patch on the market.

[0107] Biocompatibility testing:

[0108] The CCK-8 method was used to detect the toxic effects of human immortalized epidermal cells (HaCaT) co-cultured with samples for 24 hours and 72 hours. The solidified hydrogel was placed in deionized water for full immersion to remove unreacted residual substances. After the immersion process was completed, a small sample of the hydrogel ultrasound coupling patch was taken and placed in the cell culture medium to form a 0.2g / mL leaching solution. HaCaT cells in the logarithmic growth phase were inoculated in a 96-well plate, with 5,000 cells inoculated in each well. After the cells adhered to the wall, the above-mentioned corresponding leaching solutions were cultured with the cells in the 96-well plate for 24 hours and 72 hours respectively. After the culture was completed, the culture medium was removed, each well was washed twice with PBS, 10μl CCK-8 working solution was added, and the well was placed in a 5% CO2, 37°C constant temperature incubator for 4 hours. After culturing for 4 hours, the absorbance value (OD value) at 450nm was detected with an enzyme marker, and the same number of HaCaT inoculated in the well plate was used as the control group. The Origin drawing software was used to make Figure 8 A bar chart of data from Figure 8 Analysis shows that the hydrogel has good biocompatibility.

[0109] At the same time, the hydrogel ultrasound coupling patches SA / PAA-1, SA / PAA-2, SA / PAA-3 prepared in Examples 1-3 and the hydrogel ultrasound coupling patch PAA prepared in Comparative Example 1 were tested for Young's modulus. The results are as follows: Figure 3 As shown in the figure, it is clear that the mechanical properties of SA / PAA-1, SA / PAA-2, and SA / PAA-3 samples all outperform PAA, with SA / PAA-2 exhibiting the best mechanical strength (flexibility). Furthermore, as shown in Comparative Example 1, the polyacrylic acid system has poor mechanical properties. Once the hydrogel adheres to other objects, it is easily damaged during the debonding process, rendering it unusable. However, the present invention, by forming an interpenetrating double network system between alginate and polyacrylic acid components, improves the mechanical properties of the resulting hydrogel.

[0110] The above embodiments are merely illustrative. For example, the thickness of the hydrogel ultrasound coupling patch obtained based on the present invention can be flexibly adjusted based on actual needs (e.g., other thicknesses within the range of 1.0 to 100 mm can be used). The size and shape can also be flexibly adjusted based on actual needs. For another example, the curing parameters can be adjusted based on actual needs. For example, the UV curing power density and curing time can be flexibly adjusted (of course, the higher the power density, the shorter the required curing time). Furthermore, the thermal curing temperature can also be adjusted to other temperatures greater than 30°C.

[0111] It will be easily understood by those skilled in the art that the above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A hydrogel ultrasound coupling patch for continuous monitoring, characterized in that: The hydrogel ultrasound coupling patch, which can be used for continuous monitoring, comprises an alginate component and a polyacrylic acid component. The alginate component and the polyacrylic acid component form an interpenetrating double network system, thereby forming a transparent hydrogel patch.

2. The hydrogel ultrasound coupling patch for continuous monitoring according to claim 1, characterized in that: The alginate component is selected from alginate and its derivatives, preferably selected from alginate, oxidized alginate, methacrylated alginate, and oxidized methacrylated alginate.

3. The hydrogel ultrasound coupling patch for continuous monitoring according to claim 1, wherein: The polyacrylic acid component is selected from polyacrylic acid and its derivatives, preferably selected from polyacrylic acid, polymethacrylic acid, polymethyl acrylate, polyacrylamide, N-acryloyloxysuccinimidated polyacrylic acid, N-acryloyloxysuccinimidated polyacrylic acid salt, polyacrylic anhydride gelatin, cyanoacrylic acid, acrylic acid acylated polyvinyl alcohol, acrylated polyethylene glycol, acrylated four-arm polyethylene glycol; more preferably, it is at least one of polyacrylic acid, N-acryloyloxysuccinimidated polyacrylic acid and N-acryloyloxysuccinimidated polyacrylic acid salt.

4. The hydrogel ultrasound coupling patch for continuous monitoring according to claim 1, wherein: The thickness of the hydrogel ultrasound coupling patch that can be used for continuous monitoring is 1.0 to 100 mm.

5. The method for preparing the hydrogel ultrasound coupling patch for continuous monitoring according to any one of claims 1 to 4, characterized in that: The preparation method uses alginate or its derivatives as a first raw material and acrylic acid or its derivatives as a second raw material. The first raw material, the second raw material, an initiator, a cross-linking agent, and a polyol moisturizer are dissolved in deionized water to obtain a pre-gel solution. Then, the pre-gel solution is poured into a template and a hydrogel is formed through cross-linking and polymerization reactions. After demoulding, the hydrogel ultrasound coupling patch that can be used for continuous monitoring is obtained. The initiator includes hydrogen peroxide, ammonium persulfate, sodium persulfate, potassium persulfate, 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone (IC-2959), α-ketoglutaric acid, phenyl (2,4,6-trimethylbenzoyl) lithium phosphate (LAP), hydrogen peroxide-Fe 2+ One of the systems; The cross-linking agent is at least one of N,N-methylenebisacrylamide, methacrylic anhydride gelatin, polyethylene glycol diacrylate, polyethylene glycol, and polypropylene glycol; The polyol moisturizing agent is at least one of glycerol, propylene glycol, butylene glycol and pentaerythritol.

6. The preparation method according to claim 5, characterized in that: The mixed solvent system of deionized water and glycerol is obtained by mixing deionized water and glycerol in a mass ratio of 1:1 to 1:

4.

7. Use of the hydrogel ultrasound coupling patch for continuous monitoring as described in any one of claims 1 to 4 in the preparation of an extracorporeal ultrasound coupling patch, wherein the extracorporeal ultrasound coupling patch is used to adhere to the skin surface or to adhere to an ultrasound probe; when the extracorporeal ultrasound coupling patch is adhered to the skin surface, it can be in conformal contact with the skin.

8. The use according to claim 7, characterized in that The in vitro ultrasound coupling patch is capable of long-term continuous ultrasound coupling, which lasts for no less than 12 hours, preferably no less than 24 hours, and more preferably no less than 48 hours.

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