A method of preparing a hydrogel, a hydrogel, a composite material and a device

Abstract

The application discloses a preparation method of a hydrogel, the hydrogel, a composite material and a device, relates to the technical field of in-vivo medical sensing, and comprises the following steps: preparing a hydrogel precursor solution; insulating part of a flexible carbon nanotube fiber electrode; pasting the insulating flexible carbon nanotube fiber electrode on the surface of a catheter; performing hydrophilic treatment on the surface of the catheter; immersing the hydrophilic treated catheter in the hydrogel precursor solution, taking it out, and placing it under ultraviolet light to form a hydrogel coating on the surface of the catheter; and preparing a high polymer film encapsulation layer outside the hydrogel coating. The application can effectively ensure that the temperature sensor works normally in the body, avoid swelling and leakage of system ions, and realize close adhesion with the catheter, so that the performance is stable after complex deformation and long-term implantation, and the problems of poor in-vivo stability, easy swelling, substance exchange, easy separation and falling off from the catheter of the hydrogel sensor in the prior art are solved.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of in vivo medical sensing technology, and more particularly, to a preparation method of a hydrogel, the hydrogel, a composite material and a device. BACKGROUND

[0002] Catheters are widely used in clinical applications, including drainage tubes (brain, abdominal cavity, urethra), central venous catheters, etc. They not only facilitate the direct delivery of drugs to the intended site, but also can drain the pus from the surgical site to prevent the accumulation of harmful substances. However, the implantation of devices can easily cause infection at the implantation site, and if not detected in time, it can easily cause irreversible pathological damage or cognitive behavioral abnormalities, especially the infection existing in the ventricular drainage can directly lead to increased mortality. When infection occurs, the first and most obvious feature is the local temperature rise, and the body temperature or core temperature used in clinical diagnosis has a lag and an error of 2-4℃, which cannot accurately reflect the change of local temperature. Therefore, it is of great significance to improve the catheter-tissue interface and achieve in-situ monitoring at the implantation site through real-time temperature sensing.

[0003] In clinical practice, in order to monitor the temperature at the implantation site, an additional monitoring instrument is usually inserted at the same time as the catheter during the operation to collect information, but when the additional device is no longer needed, it needs to be removed again through surgery, which can cause secondary damage to the surgical site. In addition, the additional equipment also increases the medical cost of the healthcare system and the patient, resulting in a certain waste of medical resources. Recent scientific research has integrated temperature sensor arrays made of gold and platinum directly onto the surface of the catheter to achieve local temperature sensing, but due to the mismatch in mechanical properties, the temperature sensor array in contact with the tissue can cause physical irritation and damage at the implantation site.

[0004] Hydrogel sensors are a class of sensors with flexibility and biocompatibility, and when used as temperature sensors, they have the advantages of high sensitivity, short response time to temperature, and high precision. Although many works have tried to develop temperature sensing hydrogels as electronic skin to monitor the temperature changes of the epidermis, there are still challenges in the application of in vivo medical devices. On the one hand, hydrogels are an open system, and there will be ion, water and other material exchange in the body, and the hydrogel itself will swell, resulting in poor sensor stability; on the other hand, hydrogels need to be in-situ polymerized on the hydrophobic surface of the catheter, and it is not easy to form a tightly fitted and uniform thickness hydrogel coating, which can cause the sensor to fall off easily. These factors make it difficult to achieve a stable temperature sensing hydrogel coating on the surface of the catheter in-situ. SUMMARY

[0005] 1. Technical problems to be solved

[0006] In view of the problems in the prior art that the hydrogel sensor has poor in-vivo stability, is easy to swell, exchange substances and easily separate from the catheter, the application provides a preparation method of a hydrogel, a hydrogel, a composite material and a device, which can effectively ensure normal operation of the temperature sensor in the body, avoid swelling and leakage of system ions, and closely adhere to the catheter, and still maintain stable performance after complex deformation and long-term implantation.

[0007] 2. Technical solution

[0008] The object of the application is achieved by the following technical solutions.

[0009] One aspect of the embodiments of the present application provides a preparation method of a hydrogel for a temperature sensor hydrogel coating on a catheter, comprising: preparing a hydrogel precursor solution; insulating part of a flexible carbon nanotube fiber electrode; attaching the insulating flexible carbon nanotube fiber electrode to the surface of the catheter; performing hydrophilic treatment on the surface of the catheter; immersing the hydrophilic treated catheter in the hydrogel precursor solution, taking it out and placing it under ultraviolet light to form a hydrogel coating on the surface of the catheter; and preparing a high molecular film packaging layer outside the hydrogel coating.

[0010] Further, the step of preparing the hydrogel precursor solution is: dissolving 1wt% sodium chloride and 1mol / L to 3mol / L acrylamide in 20mL deionized water, stirring uniformly to generate A1 solution; adding 10wt% acrylic acid to the A1 solution, stirring uniformly to generate A2 solution; adding 2wt% chitosan to the A2 solution, stirring uniformly to generate A3 solution; adding 0.28wt% methylene bisacrylamide and 0.5wt% α-ketoglutaric acid to the A3 solution, stirring uniformly to obtain the hydrogel precursor solution; wherein the stirring is magnetic stirring.

[0011] Further, the step of insulating part of the flexible carbon nanotube fiber electrode is: mixing A liquid and B liquid of polydimethylsiloxane at a weight ratio of 10:1, coating on the carbon nanotube fiber electrode, and curing at 80℃ for 1h to 2h.

[0012] Further, the step of attaching the insulating flexible carbon nanotube fiber electrode to the surface of the catheter is: using biological glue to fix the carbon nanotube fiber electrode on the surface of the catheter.

[0013] Further, the step of performing hydrophilic treatment on the surface of the catheter is: cleaning the catheter with isopropyl alcohol, and then drying under nitrogen flow; and performing oxygen plasma treatment for 3min using a plasma cleaner.

[0014] Further, the step of preparing the hydrogel coating layer is: configuring 20 mL of an acetone solution containing 10 wt% of benzophenone; immersing the plasma-treated catheter into the benzophenone acetone solution for 3 min and drying under a nitrogen flow; inserting the catheter into the hydrogel precursor solution and then slowly pulling it out; and irradiating the catheter with 330 nm to 380 nm ultraviolet light for 30 min to 60 min.

[0015] Further, the step of preparing the polymer film encapsulation layer outside the hydrogel coating layer is: adding 4 g of polyvinylidene fluoride

[0016] —CO— hexafluoropropylene into 16 mL of an N-methylpyrrolidone solution to obtain a C solution; inserting the catheter into the C solution and then quickly placing it in a 50°C blast drying oven for 10 min to 30 min to evaporate the solvent, thereby obtaining a catheter coated with a temperature-sensing hydrogel coating layer.

[0017] Another aspect of the embodiments of the present specification also provides a hydrogel prepared by the method for preparing a hydrogel.

[0018] Another aspect of the embodiments of the present specification also provides a composite material, comprising: carbon nanotubes and a hydrogel prepared by the method for preparing a hydrogel, the hydrogel being coated on the surface of the carbon nanotubes.

[0019] Another aspect of the embodiments of the present specification also provides a temperature-sensing device, comprising: a support body and a hydrogel prepared by the method for preparing a hydrogel; the hydrogel being coated on the surface of the support body; and an electrode embedded in the hydrogel for conducting changes in the physical properties of the hydrogel coating layer.

[0020] 3. Beneficial effects

[0021] Compared with the prior art, the present application has the following advantages:

[0022] (1) The polyacrylamide / acrylic acid-chitosan tri-network structure hydrogel is constructed, acrylamide provides hydrophilicity, acrylic acid provides negative charge, and chitosan brings biocompatibility, the copolymerization of the three monomers forms a stable three-dimensional network structure, enhances the mechanical strength of the hydrogel, and inhibits swelling;

[0023] (2) α-ketoglutaric acid and methylene bisacrylamide are used as crosslinking agents to introduce a large number of crosslinking points in the gel network, enhance the stability of the network structure, and improve the mechanical strength of the hydrogel;

[0024] (3) A polyvinylidene fluoride-hexafluoropropylene copolymer waterproof isolation layer is coated on the outer layer of the hydrogel to inhibit the exchange diffusion of water molecules and ions and ensure the long-term stability of the hydrogel. BRIEF DESCRIPTION OF DRAWINGS

[0025] Figure 1This is a schematic flowchart of a method for preparing a hydrogel coating according to an embodiment of the present invention;

[0026] Figure 2 This is a schematic diagram of a composite material structure in one embodiment of the present invention;

[0027] Figure 3 This is a comparison diagram of the AC impedance of the temperature-sensing hydrogel coating on the catheter at different temperatures in one embodiment of the present invention;

[0028] Figure 4 This is a diagram illustrating the in vitro temperature sensing performance of the temperature-sensing hydrogel coating on the catheter in one embodiment of the present invention.

[0029] Figure 5 This is a temperature monitoring diagram of the temperature-sensing hydrogel coating on the catheter in vivo after infection and intervention, according to an embodiment of the present invention.

[0030] Figure 6 This is a statistical chart showing the survival rate of rats under different monitoring and prognostic conditions after in vivo infection following infection, based on a temperature-sensing hydrogel coating on a catheter in one embodiment of the present invention.

[0031] Figure 7 This is a pathway diagram of the formation of temperature-sensing hydrogel coating on a catheter in rats under different monitoring and prognostic conditions after in vivo infection, according to one embodiment of the present invention.

[0032] Figure 8 This is a statistical graph showing the distance formed in rats under different monitoring and prognostic conditions after in vivo infection following infection, based on a temperature-sensing hydrogel coating on a catheter in one embodiment of the present invention. Detailed Implementation

[0033] The present invention will now be described in detail with reference to the accompanying drawings and specific embodiments.

[0034] A catheter is a medical catheter implanted in the body, such as an abdominal drainage tube or a central venous catheter. A catheter is a long, thin tube used to deliver medication directly to a specific site in the body or to drain fluids. Common medical catheters include drainage tubes and central venous catheters. Catheters can cause infection after implantation, necessitating monitoring of temperature changes at the catheter-tissue interface for early warning. Integrating sensors directly onto the catheter surface allows for in-situ monitoring of the implantation site. Hydrogel sensors can be used on catheter surfaces and have good biocompatibility. However, in-situ polymerization of hydrogel sensor coatings on catheter surfaces still presents technical challenges. Methods for forming stable and uniform hydrogel sensor coatings on catheter surfaces need to be developed.

[0035] An implantable hydrogel, the components of the hydrogel include acrylamide, acrylic acid, chitosan, methylene bisacrylamide and α-ketoglutaric acid, a three-dimensional network structure is formed through free radical polymerization and cross-linking reaction between components, good biocompatibility and long-term stability in vivo are achieved, and the specific embodiments are as follows:

[0036] Acrylamide, acrylic acid and methylene bisacrylamide, which can undergo free radical polymerization under ultraviolet light irradiation to form a main chain framework. Chitosan and α-ketoglutaric acid, which can undergo cross-linking reaction with the amino groups in acrylic acid and chitosan, introduce cross-linking points in the main chain framework to form a three-dimensional network. The concentration change of the carrier ions sodium ion and chloride ion can cause the change of the conductivity of the gel, realizing the sensing of temperature change.

[0037] Through the design of the above components and reaction mechanism, the hydrogel forms a stable three-dimensional network structure, which has temperature sensitivity, good biocompatibility and long-term stability in vivo. Compared with the prior art, the hydrogel in this scheme solves the problems of easy swelling, material exchange and shedding, and improves the in vivo stability of the sensor.

[0038] More specifically, acrylamide, acrylic acid and methylene bisacrylamide all contain carbon-carbon double bond structures, which will undergo homochiralization under ultraviolet light irradiation, destroying the stability of the double bond and producing free radicals; growth and termination reactions occur between free radicals, i.e. free radical addition reaction, a monomer free radical reacts with another monomer to form a dimer free radical, the dimer free radical reacts with a monomer to form a trimer, and the reaction continues, producing a high molecular polymer; finally, through this free radical polymerization reaction, covalent bonds are formed between acrylamide, acrylic acid and methylene bisacrylamide, which constitute the main chain framework. The three monomers each provide different properties, acrylamide provides hydrophilicity, acrylic acid provides negative charge, and methylene bisacrylamide provides cross-linking points, which together build the main chain framework. This free radical polymerization reaction is initiated and quickly completed under the action of ultraviolet light, and the required main chain framework structure can be effectively obtained.

[0039] More specifically, there are a large number of amino groups in chitosan, and carboxyl groups in α-ketoglutaric acid and acrylic acid can react with the amino groups in chitosan to form amide bonds; the carboxyl groups in α-ketoglutaric acid can also react with the amino groups in chitosan to form amide bonds. Both of these cross-linking reactions belong to the formation of amide bonds, and the chitosan molecules are connected to two small molecules through covalent bonds; thus, a large number of cross-linking points are introduced into the main chain framework, which connects the main chain to the chitosan molecules. The cross-linking reaction changes the linear main chain into a network structure, thereby forming a three-dimensional network framework. This network framework enhances the mechanical strength of the hydrogel and improves the stability. Chitosan also endows the hydrogel with biocompatibility, and α-ketoglutaric acid provides cross-linking points to jointly construct a three-dimensional network. This cross-linking reaction does not require external stimulation and can occur spontaneously, thereby simplifying the preparation process of the hydrogel.

[0040] More specifically, sodium ions and chloride ions exist as carriers in the hydrogel. When the temperature rises, the hydrogel matrix will shrink, resulting in an increase in the concentration of sodium ions and chloride ions, which means an increase in the number of carriers, thereby increasing the conductivity of the gel. Conversely, if the temperature decreases, the hydrogel matrix will expand, the concentration of sodium ions and chloride ions will decrease, the number of carriers will decrease, and the conductivity will decrease. Therefore, by detecting the change in the conductivity of the hydrogel, the change in the temperature of the solution can be reflected. The concentration gradient change of sodium ions and chloride ions is the reason for the change in conductivity, which enables the hydrogel to have temperature responsiveness without the need to introduce additional sensing elements, thereby simplifying the preparation process and reducing the cost. The use of carrier concentration changes to achieve temperature sensing is a simple and effective technical means.

[0041] In summary, the stable main chain framework is formed by radical polymerization, and the three-dimensional network is constructed by cross-linking reaction, thereby achieving good biocompatibility and long-term stability in vivo, which overcomes the poor in-vivo stability of the hydrogel in the prior art. Acrylamide, acrylic acid, chitosan, and other raw materials are used, and these monomers and polymers have good biological safety. However, the components in the prior art have poor biocompatibility, and the cross-linking reaction conditions are mild and can occur spontaneously without external stimulation, thereby simplifying the preparation process and reducing the manufacturing complexity. The change in the concentration of the carrier enables the hydrogel to be sensitive to temperature without the need to introduce additional sensing elements, thereby reducing the possible biological incompatibility. In the prior art, a sensing substance needs to be added. The hydrogel utilizes a variety of mechanisms such as radical polymerization, cross-linking reaction, and carrier concentration change to achieve functionality, and has excellent comprehensive performance. The mechanisms in the prior art are relatively single, and the performance is limited. The hydrogel has temperature sensitivity, biocompatibility, long-term stability in vivo, and other advantages, and can effectively solve the problems and deficiencies of the prior art.

[0042] The acrylamide is one of the components of the hydrogel precursor solution, and the acrylamide can occur radical polymerization reaction with the acrylic acid and the methylene bis-acrylamide under ultraviolet light irradiation. The three-dimensional network structure of the hydrogel can be formed by the acrylamide participating in the radical polymerization reaction. The acrylamide is an organic compound containing a double bond, and the acrylamide can be polymerized by radical polymerization to generate polyacrylamide, which is a good film material. The acrylamide as one of the components of the hydrogel precursor solution is conducive to forming a stable hydrogel network by radical polymerization, improving the stability of the hydrogel in the body, and the addition of the acrylamide helps to solve the technical problem of poor in-vivo stability of the existing hydrogel sensor.

[0043] The acrylic acid is also one of the components of the hydrogel precursor solution, and the acrylic acid can occur radical polymerization reaction with the acrylamide and the methylene bis-acrylamide. The acrylic acid can also occur cross-linking reaction with the chitosan. The three-dimensional network structure of the hydrogel can be formed by the radical polymerization of the acrylic acid and the cross-linking reaction with the chitosan. The acrylic acid is an unsaturated carboxylic acid containing a double bond, and the acrylic acid can be polymerized by radical polymerization to generate polyacrylic acid, which is an important industrial raw material. The acrylic acid has water solubility, which can promote the dissolution of the chitosan. The acrylic acid as a hydrogel precursor monomer can be used to generate a stable hydrogel network structure by radical polymerization and cross-linking reaction. The addition of the acrylic acid helps to improve the in-vivo stability of the hydrogel coating. The acrylic acid generates a stable hydrogel network by radical polymerization and cross-linking reaction, and the addition of the acrylic acid can enhance the mechanical strength and in-vivo stability of the hydrogel coating.

[0044] The chitosan is also one of the components of the hydrogel precursor solution, and the chitosan can occur cross-linking reaction with the acrylic acid. The chitosan can also occur cross-linking reaction with the α-ketoglutaric acid. The three-dimensional network structure of the hydrogel can be formed by the cross-linking reaction of the chitosan. The chitosan is a natural polysaccharide obtained by deacetylation of N-acetyl-D-glucosamine. The chitosan has biocompatibility and biodegradability. The chitosan has film-forming property and can form a hydrogel. The chitosan as a hydrogel precursor can be used to generate a stable hydrogel network by cross-linking reaction. The addition of the chitosan can improve the biocompatibility of the hydrogel coating. The cross-linking of the chitosan can enhance the mechanical strength and in-vivo stability of the hydrogel coating. In summary, the chitosan generates a hydrogel network by cross-linking reaction, and the addition of the chitosan can improve the biocompatibility and mechanical strength of the hydrogel coating.

[0045] The methylene bisacrylamide is also one of the components of the hydrogel precursor solution, and can be subjected to a free radical polymerization reaction with acrylamide and acrylic acid. Through the free radical polymerization reaction, the methylene bisacrylamide can form a three-dimensional network structure of the hydrogel. The methylene bisacrylamide is a compound containing two unsaturated double bonds, and can be a crosslinking agent to produce crosslinking. When the methylene bisacrylamide is used as a hydrogel precursor, the stable hydrogel network can be generated by using the free radical polymerization and crosslinking reaction. The addition of the methylene bisacrylamide can enhance the mechanical strength of the hydrogel coating. The crosslinking of the methylene bisacrylamide can improve the stability of the hydrogel in the body. In summary, the methylene bisacrylamide can enhance the hydrogel network by the free radical polymerization and crosslinking reaction, and the addition of the methylene bisacrylamide can improve the mechanical strength and the stability in the body of the hydrogel coating.

[0046] The a-ketoglutaric acid is also one of the components of the hydrogel precursor solution, and can be subjected to a crosslinking reaction with chitosan. Through the crosslinking reaction with chitosan, the a-ketoglutaric acid can form a three-dimensional network structure of the hydrogel. The a-ketoglutaric acid is an organic compound containing a ketone group and a carboxyl group, and can be used as a small molecule crosslinking agent. When the a-ketoglutaric acid is used as a hydrogel precursor, the stable hydrogel network can be generated by using the crosslinking reaction with chitosan. The addition of the a-ketoglutaric acid can enhance the mechanical strength of the hydrogel coating. The crosslinking of the a-ketoglutaric acid can improve the stability of the hydrogel in the body. The a-ketoglutaric acid can improve the hydration capacity of the hydrogel. In summary, the a-ketoglutaric acid can enhance the stability of the hydrogel network by the crosslinking with chitosan, and the addition of the a-ketoglutaric acid can improve the mechanical strength and the stability in the body of the hydrogel coating.

[0047] The acrylate, chitosan and a-ketoglutaric acid in the hydrogel precursor solution can be subjected to a crosslinking reaction. The crosslinking reaction is a chemical reaction that can connect atoms in two or more molecules through covalent bonds to generate a three-dimensional network of macromolecules. Through the crosslinking reaction, a three-dimensional network structure of the hydrogel can be formed. The crosslinking reaction of chitosan with acrylate and a-ketoglutaric acid generates a network structure that enhances the mechanical strength of the hydrogel. The crosslinking network improves the structural stability of the hydrogel coating in the body. The crosslinking reaction can be carried out at room temperature, and can generate a stable hydrogel network to improve the stability of the hydrogel coating in the body. The crosslinking reaction plays an important role in the regulation of the properties of the hydrogel. In summary, the crosslinking reaction generates a network structure to enhance the mechanical strength and the stability in the body of the hydrogel coating, and is crucial for obtaining a hydrogel with desired properties.

[0048] The hydrogel has a three-dimensional network structure formed by radical polymerization and cross-linking reaction of the hydrogel precursor, the three-dimensional network is a three-dimensional framework connected by cross-linking points, the three-dimensional network structure gives the hydrogel a certain shape and mechanical strength, the three-dimensional network enhances the structural integrity of the hydrogel coating, the stable three-dimensional network structure improves the stability of the hydrogel in the body, the three-dimensional network provides swelling space for the hydrogel, and appropriate three-dimensional network density is crucial to obtain the desired hydrogel performance, the three-dimensional network hydrogel prepared by radical polymerization and cross-linking reaction can improve the stability of the hydrogel coating in the body, and the three-dimensional network is the basis for the hydrogel to achieve the expected function. In summary, the three-dimensional network enhances the mechanical properties of the hydrogel and improves its stability in the body, which is the key to realizing the expected function of the hydrogel.

[0049] The hydrogel precursor solution contains sodium ions and chloride ions as carriers, the carriers are charged particles that can move in solution or gel, the sodium ions and chloride ions can move freely in the hydrogel, the movement of the carriers will cause the conductivity of the solution, when the temperature change causes the concentration gradient of the carriers to change, the conductivity of the hydrogel will change, the temperature change is detected by using the concentration gradient change of the carriers, which is the sensing mechanism of the hydrogel, the sodium ions and chloride ions as carriers increase the response sensitivity of the hydrogel to temperature, the presence of the carriers improves the performance of the hydrogel as a temperature sensor, and appropriate carriers help the hydrogel to achieve accurate temperature sensing. In summary, sodium ions and chloride ions as carriers are an important part of the hydrogel to realize temperature sensing function.

[0050] The sodium ions and chloride ions exist in the hydrogel network as carriers, when the temperature rises, the carriers gain energy and move faster, and move more randomly in the gel network, the carriers diffuse from the denser area to the sparser area as the temperature rises, the concentration gradient decreases, and the gel conductivity increases when the concentration gradient decreases because the gel conductivity is related to the concentration of the carriers, when the temperature decreases, the carrier movement slows down, the concentration gradient increases, and the gel conductivity decreases, by detecting the change of the gel conductivity, the temperature change can be reflected, the concentration gradient change of sodium ions and chloride ions is positively correlated with the temperature change, and the optimization of the type and concentration of the carriers can obtain good linear relationship of temperature response, and the gel conductivity and temperature change are determined by the movement rule of the carriers. In summary, this technology utilizes the movement rule and concentration distribution change of the carriers caused by temperature change to realize the response of the sol to temperature change.

[0051] Figure 1 The preparation method of the hydrogel coating in an embodiment of the application is shown in the flowchart as shown in Figure 1 The obtained coating prepared by the preparation method of the hydrogel coating is applied to the specific technical steps of the catheter as follows:

[0052] Preparation of the hydrogel precursor solution, first, 1 wt% sodium chloride and 1 mol / L acrylamide were dissolved in 20 mL of deionized water with continuous magnetic stirring for 1 hour. Then, 10 wt% acrylic acid was added to the above solution and stirred for 30 min until the solution became uniform. Subsequently, 2 wt% chitosan was added to the above solution and stirred for 1 h. Finally, after the solution was clear, 0.28 wt% (relative to acrylamide) methylene bisacrylamide as a crosslinking agent and 0.5 wt% of α-ketoglutaric acid as an initiator were added to the mixed solution and stirred for 30 min. The whole process was carried out in a dark environment.

[0053] In this embodiment, 1 mol / L acrylamide, but those skilled in the art can understand that other concentrations of acrylamide can also be selected as long as they do not affect the function of the prepared hydrogel precursor solution. Specifically, the molar concentration of acrylamide can be selected in the range of 1 mol / L to 3 mol / L.

[0054] Treatment of carbon nanotube electrode, mixing A and B of polydimethylsiloxane at a weight ratio of 10:1, coating on the carbon nanotube fiber after stirring uniformly, and curing at 80℃ for 1h.

[0055] In this embodiment, curing at 80℃ for 1h. But those skilled in the art can understand that the curing time can also be set according to the actual situation as long as it does not affect the treatment of the carbon nanotube electrode. Specifically, the curing time ranges from 1h to 2h.

[0056] Fixing of the electrode, it is fixed on the surface of the medical catheter using biological glue, leaving only the 3mm part exposed at the end to contact the hydrogel.

[0057] Surface treatment of the catheter, the catheter is cleaned with isopropyl alcohol solution and then dried under nitrogen flow. In order to improve its wettability, oxygen plasma treatment is carried out using a plasma cleaner for 3 min.

[0058] Formation of the hydrogel coating, 20 mL of acetone solution of 10 wt% benzophenone (hydrophobic photoinitiator) is prepared. Then the medical catheter after plasma treatment is immersed in the benzophenone acetone solution for 3 min and dried again under nitrogen flow. Next, the catheter is inserted into the hydrogel precursor solution and then pulled out slowly. Subsequently, the catheter is irradiated with 365 nm ultraviolet light for 30 min. Through the action of the two initiators of benzophenone and α-ketoglutaric acid, acrylamide and acrylic acid are crosslinked to form a polyacrylamide / acrylic acid hydrogel. This process allows the formation of a stable polyacrylamide / acrylic acid-chitosan tri-network hydrogel coating on the catheter. The unreacted monomers are thoroughly rinsed with deionized water.

[0059] In this embodiment, the catheter is irradiated with 365 nm ultraviolet light for 30 min. However, those skilled in the art can understand that, under other conditions, the wavelength of the ultraviolet light can also be selected in the range of 330 nm to 380 nm, and the irradiation time of the catheter can range from 30 min to 60 min.

[0060] The preparation of the encapsulation layer, 4 g of poly(vinylidene fluoride-co-hexafluoropropylene) is added to a 16 mL N-methylpyrrolidone solution, which is then quickly placed in a 50°C blast drying oven for 15 minutes to evaporate the solvent, thereby obtaining the final catheter coated with the temperature sensing hydrogel coating. The catheter product coated with the hydrogel and the polymer encapsulation layer is obtained.

[0061] In this embodiment, the catheter is irradiated with 365 nm ultraviolet light for 30 min. However, those skilled in the art can understand that, under other conditions, the wavelength of the ultraviolet light can also be selected in the range of 330 nm to 380 nm, and the irradiation time of the catheter can range from 30 min to 60 min.

[0062] Specifically, the hydrogel precursor solution, acrylamide provides a hydrophilic group, acrylic acid provides a negative charge, chitosan improves biocompatibility, and methylene bisacrylamide and α-ketoglutaric acid provide crosslinking points. These monomers undergo free radical polymerization under ultraviolet light to form a main chain and a network. Carbon nanotube electrode treatment: polydimethylsiloxane is used to insulate and coat the carbon nanotube to improve the heat insulation performance and serve as a flexible conductive electrode. Catheter surface treatment: improve the surface energy and increase the hydrophilic group, which is beneficial to the adhesion of the hydrogel coating. Hydrogel coating formation: ultraviolet light initiates the free radical polymerization of the monomers in the precursor solution to construct a crosslinked network on the catheter surface, realizing the temperature response function. Encapsulation layer preparation: coating the polymer protective coating to improve the mechanical strength and service life.

[0063] In summary, the present application constructs a polyacrylamide / acrylic acid-chitosan three-dimensional network structure, enhances the mechanical strength of the hydrogel, improves the stability in vivo, and reduces the swelling and shedding problems. The introduction of chitosan improves the biocompatibility of the hydrogel and reduces the adsorption of biological macromolecules. The surface treatment increases the groups, the photochemical crosslinking reaction conditions are mild, the interfacial bonding force between the hydrogel coating and the catheter is enhanced, the adhesion is improved, and the shedding problem is reduced. The setting of the encapsulation layer further enhances the mechanical strength of the hydrogel coating, avoids shedding, and prolongs the service life. The in vivo stability of the hydrogel coating is comprehensively enhanced, and the key technical problem of poor stability of the hydrogel sensor in the in vivo environment in the prior art is solved.

[0064] In the preparation of the hydrogel precursor solution, magnetic stirring is adopted, which is a method of stirring by mechanical force generated by magnetic field. The magnetic stirrer is usually put into the stirring container, and the solution is stirred under the action of an external magnetic field. Magnetic stirring can be used for homogeneous mixing and dispersion. Magnetic stirring is suitable for solution preparation without special requirements for the stirring process. Magnetic stirring operation is simple and can provide continuous and stable stirring force. In the preparation of the hydrogel precursor solution, magnetic stirring can obtain a uniformly mixed solution, which is beneficial to the formation of the subsequent gel network. Magnetic stirring helps to fully dissolve the components and obtain an ideal precursor solution. Therefore, in the preparation of the hydrogel precursor solution, magnetic stirring can obtain a solution with uniformly mixed components, ensuring the ideal formation of the hydrogel network.

[0065] In the preparation of the hydrogel precursor solution, the components are mixed by weight ratio. Weight ratio mixing refers to mixing according to the weight percentage or weight ratio of each component. The components are weighed according to the given weight ratio, and then mixed to prepare the solution. Weight ratio mixing can accurately control the content of each component. The weight ratio mixing method is simple to operate. The component ratio of the hydrogel directly affects the network structure and performance. Through weight ratio mixing, the ratio of the components of the hydrogel can be accurately controlled. Weight ratio mixing is beneficial to obtaining hydrogel products with consistent composition. The use of weight ratio mixing can ensure the consistency of the composition of each batch of hydrogel precursor solution. Therefore, by mixing the components of the hydrogel by weight ratio, the content of the components can be accurately controlled, the consistency of different batches of products can be ensured, and stable hydrogels with stable performance can be obtained.

[0066] In the present application, biological glue is used as one of the raw materials of the hydrogel. Biological glue is a kind of natural polymer material, such as gelatin, guar gum, chitosan, etc. Biological glue has biocompatibility and biodegradability. Chitosan is used as biological glue in the present application. Chitosan has film-forming property and can be used as a hydrogel gelling agent. Chitosan can form a hydrogel network through cross-linking. The use of biological glue chitosan can improve the biocompatibility of the hydrogel. Chitosan cross-linking can improve the structural stability of the hydrogel in the body. Biological glue is beneficial to the degradation of the hydrogel after use, reducing the biological safety risk. The use of biological glue to prepare the hydrogel solves the problem of poor biocompatibility of the existing hydrogel. Therefore, chitosan as biological glue used in the preparation of the hydrogel can improve the biocompatibility and form a stable hydrogel network, solving the technical problem of the biocompatibility of the current hydrogel.

[0067] The sensor surface is subjected to hydrophilization treatment, the hydrophilization treatment is a treatment process for making the surface of the material hydrophilic, the hydrophilization can increase the hydrophilic group on the surface, form a hydrophilic film layer, after the hydrophilization treatment, the surface contact angle will be reduced, the hydrophilicity is enhanced, the hydrophilization of the sensor surface can enhance the adhesion of the hydrogel coating, the hydrophilization is beneficial to the formation of the hydrogel coating, improves the bonding force of the hydrogel coating and the sensor, can enhance the stability of the sensing performance, the bonding force of the hydrogel coating and the sensor is weak in the prior art, and there is a problem of falling off, the hydrophilization treatment can solve the problem of poor bonding force of the hydrogel coating in the existing hydrogel sensor, the hydrophilization enhances the adhesion of the hydrogel coating, and improves the stability of the sensor.

[0068] The polyvinylidene fluoride-CO-hexafluoropropylene is used as the coating material of the electric sensor, which is a fluorine-containing copolymer, has good solvent resistance, and has the heat resistance of polyvinylidene fluoride and the chemical resistance of hexafluoropropylene, the coating material has strong hydrophobicity on the surface and needs to be subjected to hydrophilization treatment, the material can form a smooth and dense coating to protect the sensor, the solvent resistance and heat resistance of the coating material can improve the stability of the sensor, the chemical resistance of the sensor coating is poor in the prior art, and the stability is reduced, the coating material can solve the problems of poor solvent resistance and heat resistance of the coating in the prior art, improve the heat resistance and chemical resistance of the coating, and enhance the stability of the sensor. In summary, the coating material has excellent performance, can improve the chemical stability and service life of the radio temperature sensor.

[0069] The N-methyl pyrrolidone solution is used as a hydrophilization treatment reagent, the N-methyl pyrrolidone is a nitrogen-containing heterocyclic ether compound, the N-methyl pyrrolidone molecule contains a hydrophilic carbon-oxygen double bond part, the N-methyl pyrrolidone can introduce a hydrophilic group on the surface by chemical reaction with the surface, and the N-methyl pyrrolidone solution can form a hydrophilic film layer on the surface. The N-methyl pyrrolidone hydrophilization treatment condition is mild and does not damage the sensor coating, the N-methyl pyrrolidone hydrophilization can improve the adhesion of the hydrogel coating on the sensor surface, the sensor surface is improperly handled in the prior art, resulting in poor bonding force of the hydrogel coating, the N-methyl pyrrolidone hydrophilization can effectively solve the problem of poor bonding force, the N-methyl pyrrolidone hydrophilization enhances the adhesion of the hydrogel, and improves the stability of the sensor. In summary, the N-methyl pyrrolidone hydrophilization can enhance the adhesion of the hydrogel coating on the sensor, improve the stability and reliability of the sensor.

[0070] Figure 2 A composite material structure schematic diagram in an embodiment of the application is shown in FIG. 1. Figure 2The composite material is used for preparing a hydrogel coating and is composed of carbon nanotubes and polydimethylsiloxane. The carbon nanotubes have good conductivity and can be used as a conductive substrate of a sensor. The polydimethylsiloxane has electrical insulation and can form an insulation layer on the surface of the carbon nanotubes, thereby improving the in-vivo stability of the sensor.

[0071] Specifically, the carbon nanotubes are a kind of conductive material with a six-membered ring network structure, which can ensure the conductivity of the sensor. The polydimethylsiloxane is an inorganic siloxane polymer, and methyl side groups exist in the molecular chain of the polydimethylsiloxane. The methyl side groups can be connected to the surface of the carbon nanotubes through hydrophobic interaction.

[0072] More specifically, the surface of the carbon nanotubes is hydrophobic, and the methyl groups on the side chains of the polydimethylsiloxane are also hydrophobic. According to the "similar solution" principle, similar hydrophobic groups will interact with each other through hydrophobic interaction. The methyl groups on the side chains of the polydimethylsiloxane interact with the hydrophobic surface of the carbon nanotubes through hydrophobic attraction. This interaction is a relatively weak intermolecular force, but it can promote the adsorption and adhesion of the polydimethylsiloxane side chains to the surface of the carbon nanotubes. Through this hydrophobic attraction, the polydimethylsiloxane is connected to the carbon nanotubes. This interaction is mild and does not require additional chemical reactions, which is simple and easy to implement. Hydrophobic interaction provides a simple and effective non-covalent connection method, which is conducive to building a coating layer on the surface of the carbon nanotubes. The function is achieved by utilizing the component properties of the two materials themselves, avoiding the introduction of additional linking groups, and reducing the complexity of the material.

[0073] The preparation method of the composite material is to immerse the carbon nanotubes in a polydimethylsiloxane solution, then take them out and drag them, and form a polydimethylsiloxane coating layer on the surface of the carbon nanotubes. The formation of the coating layer realizes the insulation and electrical isolation of the carbon nanotubes, which can effectively prevent the swelling and material exchange of the sensor in the body and improve its stability.

[0074] Therefore, the composite material retains the conductivity of the carbon nanotubes and utilizes the insulation layer formed by the polydimethylsiloxane, which can prepare a sensor with better in-vivo stability and help solve the problems in the prior art.

[0075] The composite material can be used to prepare a hydrogel coating of a medical catheter, a wire and a patch sensor. These sensors need to work stably in the body for a long time. The carbon nanotubes in the composite material play the role of an electrically conductive base material responsible for signal transmission. The polydimethylsiloxane plays the role of an insulator, and the insulating coating formed by the polydimethylsiloxane can prevent the sensor from swelling and exchanging substances in the body, thereby improving the long-term stability of the sensor in the body. The sensors in the prior art, especially the sensors implanted in the body, have poor in-vivo stability. The composite material can effectively improve the long-term stability of the sensor in the body. Among them, the good electrical conductivity of the carbon nanotubes is retained to ensure the signal transmission effect, and the insulating coating formed by the polydimethylsiloxane prevents swelling and substance exchange in the body, thereby significantly improving the long-term stability of the sensor in the body.

[0076] Figure 3 The temperature sensing hydrogel coating on the catheter in an embodiment of the present application is shown in FIG. 1. The temperature sensing hydrogel coating on the catheter in an embodiment of the present application is shown in FIG. 1. Figure 3 The temperature sensing hydrogel coating on the catheter in an embodiment of the present application is shown in FIG. 1. The temperature sensing hydrogel coating on the catheter in an embodiment of the present application is shown in FIG. 1. Figure 3

[0077] Under the condition of 100 kHz, with the increase of temperature, the impedance of the hydrogel coating shows a significant downward trend, and the temperature and the impedance show a good corresponding relationship. Compared with other frequency conditions, the impedance of the hydrogel coating is most sensitive to temperature changes at 100 kHz, and the temperature sensing effect is best. This is consistent with the design principle of the hydrogel, that is, the carrier mobility is affected by temperature, and the carrier migration speed increases when the temperature rises, resulting in a decrease in the impedance of the hydrogel.

[0078] It can be seen from the above that the hydrogel coating realizes sensitive response to temperature changes, and overcomes the problems of poor in-vivo stability and insufficient sensitivity of the hydrogel in the prior art. Under the condition of 100 kHz, the hydrogel coating shows excellent linear response to temperature changes, which is beneficial to accurate monitoring of body temperature. The results verify that the technical scheme can obtain a stable and sensitive temperature sensing hydrogel coating, and realize real-time monitoring of body temperature.

[0079] Figure 4 The temperature sensing performance of the temperature sensing hydrogel coating on the catheter in an embodiment of the present application is shown in FIG. 2. The temperature sensing performance of the temperature sensing hydrogel coating on the catheter in an embodiment of the present application is shown in FIG. 2. Figure 4 The temperature sensing performance of the temperature sensing hydrogel coating on the catheter in an embodiment of the present application is shown in FIG. 2. The temperature sensing performance of the temperature sensing hydrogel coating on the catheter in an embodiment of the present application is shown in FIG. 2. Figure 4

[0080] ​​The temperature and resistance show good linear relationship, the correlation coefficient reaches 0.998, which indicates that the linear response is excellent, the temperature resistance response coefficient is as high as 2.90% ℃-1, which shows high temperature sensitivity, and the test temperature range covers the main range of body temperature change, and has good applicability. The results show that the hydrogel coating successfully realizes the sensitive monitoring of temperature change, and overcomes the problem of external environment interference in the prior art. Compared with the in-vivo environment, the in-vitro test condition has less effect on the hydrogel coating, and can better reflect the temperature-sensitive performance of the material itself.

[0081] The temperature resistance response coefficient reflects the response sensitivity of the sensor resistance value to temperature change, that is, the relative change amount of the resistance value to temperature change, and the greater the response coefficient, the more sensitive the sensor is to temperature change. The present application improves the response coefficient by optimizing the hydrogel components. In the prior art, the hydrogel sensor is not sensitive to temperature change, and improving the response coefficient can enhance the temperature detection accuracy of the sensor. Optimizing the proportion of hydrogel components and regulating the network structure can improve the response coefficient and obtain a hydrogel with high response coefficient, which is conducive to improving the sensitivity of the sensor. High response coefficient is helpful for the hydrogel sensor to realize accurate temperature monitoring. In summary, improving the temperature resistance response coefficient can enhance the response sensitivity of the sensor to temperature change and improve the detection accuracy of the hydrogel sensor.

[0082] In summary, the excellent in-vitro test results verify the effect of the technical scheme, and lay a foundation for subsequent in-vivo tests. Combined with the protection of the packaging layer, the present application can be used stably for a long time in a complex physiological environment and can monitor the in-vivo temperature change in real time. The present application can solve the problems of poor stability and insufficient sensitivity of the existing in-vivo sensing material, and realize accurate body temperature monitoring.

[0083] Figure 5 The in-vivo infection and temperature monitoring after intervention of the temperature sensing hydrogel coating on the catheter in an embodiment of the present application is shown in FIG. 1, and the temperature sensing hydrogel coating on the catheter can monitor the temperature in real time during the whole process of infection and treatment in a rat brain infection model. Figure 5 As can be seen from FIG. 1, Figure 5 As can be seen from FIG. 1,

[0084] In the test of the rat brain infection model, the coating successfully realized the monitoring of the body temperature change before and after the infection. In the early stage of infection, the body temperature of the rat showed a significant upward trend, and the coating detection result could respond sensitively to this. After drug intervention, the body temperature of the rat gradually decreased, and the coating output result accurately reflected this trend. The results show that the present application can adapt to the complex in-vivo environment, monitor the body temperature change in real time, and overcome the in-vivo instability problem in the prior art. During the whole detection process, the coating works stably and does not have problems such as breakage and falling, which verifies the protection effect of the packaging layer.

[0085] In summary, the in vivo application of this application demonstrates good biocompatibility, laying the foundation for future practical clinical applications. This application achieves long-term stable in vivo monitoring.

[0086] Figure 6 This is a statistical chart showing the survival rate of rats under different monitoring and prognostic conditions after in vivo infection following infection, based on a temperature-sensing hydrogel coating on a catheter in one embodiment of the present invention. Figure 6 As shown, the survival rates of rats in the healthy control group, hydrogel-coated catheter group, ordinary catheter group, and disease control group were as follows: the survival rate of rats monitored and treated promptly using hydrogel-coated catheters was 90%, significantly higher than the 60% survival rate of rats monitored by body temperature. Figure 6 It can be seen from this:

[0087] In the group monitored and treated promptly using the hydrogel-coated catheter, the survival rate of rats reached as high as 90%. In contrast, the survival rate of rats monitored solely by a thermometer was only 60%. This clearly demonstrates that the in vivo monitoring effect of this coating is superior to that of traditional thermometers. The hydrogel coating enables early detection and continuous monitoring of infection, thereby guiding timely intervention and significantly reducing mortality. Intermittent monitoring, on the other hand, struggles to detect temperature changes in the initial stages of infection, leading to delayed treatment and decreased survival rates.

[0088] In summary, the application of the hydrogel coating in this application can significantly improve disease prognosis and survival rate. The use of this monitoring method will improve clinical treatment effectiveness and reduce mortality.

[0089] Figure 7 This is a pathway diagram of rat formation under different monitoring and prognostic conditions after in vivo infection following infection, as shown in one embodiment of the present invention, for the temperature-sensing hydrogel coating on the catheter. Figure 8 This is a distance statistical graph of rats formed under different monitoring and prognostic conditions after in vivo infection following infection, as shown in one embodiment of the present invention, with temperature-sensing hydrogel coating on the catheter. Figure 7 and Figure 8 As shown, statistical analysis of the movement distances of rats in the healthy control group, hydrogel-coated catheter group, ordinary catheter group, and disease control group revealed that the movement distance of rats monitored and treated promptly via hydrogel-coated catheters was similar to that of the healthy control group. However, the movement distance of the ordinary catheter group, monitored by body temperature, was only similar to that of the disease control group, demonstrating that the behavioral cognition of rats monitored and treated promptly via hydrogel-coated catheters was relatively normal. Figure 7 It can be seen from this:

[0090] The activity distance of the rats monitored by the hydrogel coated catheter and treated in time was basically the same as that of the healthy control group, while the activity distance of the rats monitored by the thermometer was only the same as that of the disease group, which showed that the application of the hydrogel coating could make the behavior and cognition of the infected rats basically return to normal. Through the continuous and real-time monitoring provided by the hydrogel coating, the disease could be found and treated in time, so as to avoid the further deterioration of the disease and the behavior damage to the rats. The intermittent monitoring was easy to cause the delay of treatment, and the movement ability of the rats was seriously decreased, which fully verified the advantages of the hydrogel coating in improving the pathological state. The sequelae after the infection of the central nervous system were effectively prevented. This provided the behavior evidence for the clinical popularization and application of the coating in the application.

[0091] The above has described the application and its embodiments in a schematic manner, which is not limited, and the application can be realized in other specific forms without departing from the spirit or essential characteristics of the application. The embodiments shown in the drawings are only one of the embodiments of the application, and the actual structure is not limited thereto, and any reference signs in the claims should not limit the claims. Therefore, if a person skilled in the art is inspired by the application, without departing from the spirit of the application, the similar structure and embodiments can be designed without creativity, which should belong to the protection scope of the patent. In addition, the word "comprising" does not exclude other elements or steps, and the word "one" before the element does not exclude "multiple" elements. The multiple elements stated in the product claim can also be realized by one element through software or hardware. The words "first", "second" and the like are used to represent the names, and do not represent any specific order.

Claims

1. A method for preparing a temperature sensor hydrogel coating on a catheter, comprising: preparing a hydrogel precursor solution; insulating a portion of a flexible carbon nanotube fiber electrode; attaching the insulated flexible carbon nanotube fiber electrode to a surface of the catheter; hydrophilizing the surface of the catheter; immersing the hydrophilized catheter in the hydrogel precursor solution, pulling it out, and placing it under ultraviolet light to form a hydrogel coating on the surface of the catheter; preparing a polymer film encapsulation layer on the outside of the hydrogel coating; the step of preparing the hydrogel precursor solution is: dissolving 1 wt% sodium chloride and 1 mol / L to 3 mol / L acrylamide in 20 mL of deionized water, stirring until uniform, to obtain A1 solution; adding 10 wt% acrylic acid to the A1 solution, stirring until uniform, to obtain A2 solution; adding 2 wt% chitosan to the A2 solution, stirring until uniform, to obtain A3 solution; adding 0.28 wt% methylene bisacrylamide and 0.5 wt% a-ketoglutaric acid to the A3 solution, stirring until uniform, to obtain the hydrogel precursor solution; wherein the stirring is magnetic stirring; the step of insulating a portion of the flexible carbon nanotube fiber electrode is: mixing A and B solutions of polydimethylsiloxane at a weight ratio of 10:1, coating onto the carbon nanotube fiber electrode, and curing at 80°C for 1 h to 2 h; the step of attaching the insulated flexible carbon nanotube fiber electrode to the surface of the catheter is: using biological glue to fix the carbon nanotube fiber electrode to the surface of the catheter; the step of hydrophilizing the surface of the catheter is: cleaning the catheter with isopropyl alcohol and then drying under a nitrogen stream; performing oxygen plasma treatment for 3 min using a plasma cleaner; the step of preparing the hydrogel coating is: preparing 20 mL of an acetone solution containing 10 wt% benzophenone; immersing the plasma-treated catheter in the benzophenone acetone solution for 3 min and drying under a nitrogen stream; inserting the catheter into the hydrogel precursor solution and then slowly pulling it out; irradiating the catheter with 330 nm to 380 nm ultraviolet light for 30 min to 60 min; the step of preparing a polymer film encapsulation layer on the outside of the hydrogel coating is: adding 4 g of polyvinylidene fluoride-CO-hexafluoropropylene to 16 mL of N-methylpyrrolidone solution to obtain C solution; inserting the catheter into the C solution and then quickly placing it in a 50°C forced air drying oven for 10 min to 30 min to evaporate the solvent, obtaining a catheter coated with a temperature sensing hydrogel coating; the electrode is fixed using biological glue to fix it to the surface of the medical catheter, leaving only a 3 mm portion of the end exposed to contact the hydrogel.

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