CN117258044A

CN117258044A - Hydrogel coating with underwater stability and resistance reduction for implantation/intervention medical instrument and preparation method and application thereof

Info

Publication number: CN117258044A
Application number: CN202311291804.7A
Authority: CN
Inventors: 张笑来; 关永霞; 邱晓勇; 李蔚群; 黄�俊; 魏鲁星; 王满之; 孙韬
Original assignee: Shandong University
Current assignee: Shandong University
Priority date: 2023-09-28
Filing date: 2023-10-08
Publication date: 2023-12-22

Abstract

The invention provides a hydrogel coating with underwater stability and resistance reduction for an implantation/intervention medical instrument, a preparation method and application thereof. The hydrogel coating is prepared from water-soluble methacryloylated gelatin (GelMA), polyethylene glycol diacrylate (PEGDA), methacryloyloxyethyl trimethyl ammonium chloride (METAC) and a photoinitiator through a cross-linking polymerization reaction. A bonding layer is further arranged between the hydrogel coating and the substrate, and the bonding strength of the interface between the substrate and the hydrogel coating is improved through codeposition of PDA, PEI and grafting KH570. The hydrogel coating can be prepared on the surfaces of artificial hip joints, trachea cannula, urinary catheterization and titanium alloy, has excellent underwater stability and resistance reduction performance, can release medicines controllably, and can well meet the application requirement on the surfaces of implantation/intervention instruments.

Description

Hydrogel coating with underwater stability and resistance reduction for implantation/intervention medical instrument and preparation method and application thereof

Technical Field

The invention relates to a hydrogel coating for implantation/intervention medical equipment with the functions of drug release, underwater stabilization and drag reduction, a preparation method and application thereof, and belongs to the technical field of hydrogel coating application.

Background

An implant/interventional medical device is a device, such as a stent, implant, etc., that is used to treat a disease or restore bodily function. In the use process, the implantation devices are often required to be remained in the human body for a long time, so that the surfaces of the implantation devices are easy to be polluted and attached by organisms, and the effect and the safety of the implantation devices are influenced. At the same time there is friction and wear of the implant with the surrounding tissue, thereby reducing the useful life of the implant. There are some coatings on the surface of implanted/interventional medical devices for antifouling and biological attachment, but these coatings lack drug controlled release and drag reduction effects, limiting their application in the medical field. It is therefore of great interest to develop a hydrogel coating for implant/interventional medical devices with drug release, underwater stabilization and drag reduction.

The traditional hydrogel coating has poor stability in a liquid environment, single function, poor drag reduction performance and no drug release performance, and is difficult to meet the application requirement on the surface of an implantation/intervention instrument. For example, chinese patent document CN114209891A discloses a wet-state adhered super-lubricating hydrogel coating and a preparation method thereof. The method comprises the following steps: (1) Adding hydrogel monomer, sodium alginate powder, cross-linking agent N, N' -methylene bisacrylamide, ammonium persulfate and ionic cross-linking agent calcium sulfate dihydrate into deionized water to be completely dissolved; (2) Immersing the substrate in the pre-gel solution, taking out, and then placing the substrate under illumination at room temperature to obtain the wet-state adhered super-lubrication hydrogel coating. The invention effectively solves the problems of breakage and deformation of the coating caused by bending; but has no drug release capability, single function, no investigation on stability in liquid, poor drag reduction effect and difficult application on the surface of implantation/intervention instruments.

Accordingly, there is a need to develop a hydrogel coating for implant/interventional medical device surfaces with underwater stability, drug release and drag reduction.

Disclosure of Invention

In order to solve the problems that the traditional hydrogel coating has poor stability in a liquid environment, single function and poor resistance reduction performance and cannot meet the requirement of application on the surface of an implantation/intervention device, the invention provides a hydrogel coating with underwater stability and resistance reduction for an implantation/intervention medical device, and a preparation method and application thereof. The hydrogel coating is prepared from water-soluble methacryloylated gelatin (GelMA), polyethylene glycol diacrylate (PEGDA), methacryloyloxyethyl trimethyl ammonium chloride (METAC) and a photoinitiator through a cross-linking polymerization reaction. An adhesive layer is further arranged between the hydrogel coating and the substrate, and the adhesive layer improves the adhesive strength of the interface between the substrate and the hydrogel coating through codeposition of PDA (polydopamine), PEI (polyethylenimine) and grafting KH570 (gamma-methacryloxypropyl trimethoxysilane). The hydrogel coating can be prepared on the surfaces of artificial hip joints, trachea cannula, urinary catheterization and titanium alloy, has excellent underwater stability and resistance reduction performance, can release medicines controllably, and can well meet the application requirement on the surfaces of implantation/intervention instruments.

In order to achieve the above purpose, the invention is realized by the following technical scheme:

a hydrogel coating for use in an implant/interventional medical device having underwater stability and drag reduction, said hydrogel coating consisting of a hydrogel of a polymer cross-linked network structure; the hydrogel with the polymer cross-linked network structure is prepared from methacryloylated gelatin (GelMA), polyethylene glycol diacrylate (PEGDA) and methacryloyloxyethyl trimethyl ammonium chloride through cross-linking polymerization reaction in the presence of water and a photoinitiator.

Preferably, according to the invention, the hydrogel coating further comprises a drug; the medicine is uniformly dispersed in the hydrogel with the polymer crosslinked network structure.

According to the invention, the thickness of the hydrogel coating can be adjusted in the range of 60 μm to 280. Mu.m.

The preparation method of the hydrogel coating for the implantation/intervention medical appliance with the functions of drug release, underwater stabilization and drag reduction comprises the following steps:

(1) Fully dispersing methacryloylated gelatin (GelMA), polyethylene glycol diacrylate (PEGDA), methacryloyloxyethyl trimethyl ammonium chloride (METAC) and a photoinitiator in deionized water to obtain a prepolymer;

(2) Soaking a substrate in a solution containing dopamine hydrochloride and Polyethyleneimine (PEI), and washing the substrate by deionized water to obtain a substrate loaded with a polydopamine and polyethyleneimine coating; then soaking the substrate in a mixed solution containing ethanol, KH570 and deionized water, and washing the substrate with deionized water to obtain a substrate loaded with a bonding layer;

(3) Coating the prepolymer on the surface of the bonding layer of the substrate loaded with the bonding layer, and performing ultraviolet curing to obtain the hydrogel coating on the surface of the substrate.

According to a preferred embodiment of the invention, in step (1), the polyethylene glycol diacrylate (PEGDA) has a number average molecular weight of 300 to 500, preferably 400.

According to a preferred embodiment of the invention, in step (1), the mass ratio of methacryloylated gelatin (GelMA) to polyethylene glycol diacrylate (PEGDA) is 0.5-5:0.5-5, preferably 1:1.

According to a preferred embodiment of the present invention, in step (1), the mass ratio of methacryloylated gelatin (GelMA) to methacryloyloxyethyl trimethylammonium chloride (METAC) is 1:1.

Preferably, according to the present invention, in step (1), the photoinitiator is phenyl-2, 4, 6-trimethylbenzoyl lithium phosphite (LAP); the mass of the photoinitiator is 5-15% of that of the methacryloylated gelatin.

According to a preferred embodiment of the present invention, the prepolymer in step (1) further comprises a drug; preferably, the medicine is rhodamine B, doxycycline hydrochloride, baicalin, leech freeze-dried powder, isosorbide mononitrate or orlistat; the mass of the medicine is 1-2% of that of the methacryloylated gelatin.

According to the invention, in the step (1), the mass ratio of the methacryloylated gelatin (GelMA) to the deionized water is 1:10-20.

According to a preferred embodiment of the invention, in step (2), the substrate is selected from the group consisting of artificial hip joints, endotracheal tubes, catheters, titanium alloys, bone-implant magnesium-aluminum alloys, dental molds and glass.

According to a preferred embodiment of the invention, in step (2), the number average molecular weight of the Polyethyleneimine (PEI) is 400-800, preferably 600.

According to a preferred embodiment of the present invention, in step (2), the solution comprising dopamine hydrochloride and Polyethylenimine (PEI) is a Tris buffer (Tris-buffer) having a concentration of 50mM and a ph=8.5, wherein the concentration of dopamine hydrochloride is 0.1-0.3mg/mL.

According to a preferred embodiment of the present invention, in step (2), the mass ratio of dopamine hydrochloride to Polyethylenimine (PEI) is 1:1.

According to the invention, in step (2), the substrate is immersed in a solution containing dopamine hydrochloride and Polyethylenimine (PEI).

According to the present invention, preferably, in the step (2), the soaking time in the solution containing dopamine hydrochloride and Polyethylenimine (PEI) is 6-10 hours, the soaking temperature is room temperature, and the soaking is performed under stirring. During the soaking process, dopamine hydrochloride is oxidized to form Polydopamine (PDA) on the surface of the substrate.

According to the invention, in the step (2), the mixed solution containing ethanol, KH570 and deionized water has the mass concentration of KH570 of 2-4% wt, and the volume ratio of ethanol to deionized water of 0.5-2:0.5-2, preferably 1:1.

According to the invention, in the step (2), the substrate is immersed in a mixed solution containing ethanol, KH570 and deionized water.

According to the preferred embodiment of the present invention, in the step (2), the soaking temperature in the mixed solution containing ethanol, KH570, deionized water is room temperature, and the soaking time is 2-4 hours.

According to a preferred embodiment of the invention, in step (3), the coating method is selected from one of dip coating, spray coating, spin coating or brush coating.

According to the invention, in the step (3), the ultraviolet wavelength of ultraviolet curing is 365nm, the power is 10-30W, and the ultraviolet curing time is 10-30s.

The application of the hydrogel coating with underwater stability and resistance reduction for the implantation/intervention medical instrument is applied to the surface of the implantation/intervention medical instrument as a coating.

The invention has the technical characteristics and beneficial effects that:

1. the hydrogel coating provided by the invention adopts GelMA, PEGDA and METAC as grid structures, wherein GelMA is a main hydrogel network, gelMA hydrogel is modified gelatin, has excellent biological performance, can form a covalent network through ultraviolet crosslinking, and can adjust the mechanical performance of the coating. The METAC hydrogel has higher hydrophilicity, can increase the water content in the coating, improve the lubricating performance of the hydrogel coating and reduce the friction coefficient of the hydrogel coating. PEGDA is a much smaller molecule than GelMA, which can form an interpenetrating crosslinked network with GelMA, so that the hydrogel coating has sufficient hardness, the mechanical properties, durability and wear resistance of the hydrogel coating are improved, the size of the grid can be regulated, and the release of the drug in the hydrogel coating is controlled. In the cross-linked grid structure, all the structural units do not act independently, but are taken as a whole, and complex interactions exist among the structural units, so that the hydrogel layer has excellent underwater stability, drag reduction performance, mechanical performance, durability and wear resistance, and meanwhile has the controllable drug release capability.

2. The preparation of the prepolymer liquid adopts a one-pot method, wherein the proportion of the methacryloylated gelatin (GelMA) and the polyethylene glycol diacrylate (PEGDA) needs to be proper, if not proper, the mechanical property, the durability and the wear resistance of the coating are greatly reduced. In addition, the ratio of methacryloylated gelatin (GelMA) to polyethylene glycol diacrylate (PEGDA) has a certain influence on the release rate of the drug.

3. The invention is also provided with a bonding layer between the hydrogel coating and the substrate; the bonding layer forms physical and chemical double links between the coating and the substrate material by codeposition of PDA+PEI and grafting KH570, so that the bonding strength of the interface between the substrate and the hydrogel coating is improved, and the stability in underwater and complex environments can be realized. Any one or more of PDA, PEI or KH570 is/are missing, so that the hydrophilicity and stability of the hydrogel coating are greatly reduced.

4. The hydrogel coating can be applied to the surfaces of various implantation/intervention instruments, such as artificial hip joints, trachea cannulas, urinary cannulas, titanium alloys and the like, has good biocompatibility, excellent underwater stability, resistance reduction performance, mechanical properties, durability and wear resistance, can release drugs controllably, can well meet the application requirements on the surfaces of implantation/intervention instruments, and has good clinical application prospects.

Drawings

FIG. 1 is a schematic diagram (b) of the preparation flow (a) and structure of the hydrogel coating according to the invention;

FIG. 2 is a photograph of hydrogel coating prepared on the surface of different implant/interventional instruments (a) artificial hip joint model, (b) tracheal tube, (c) urinary catheter, (d) titanium alloy in example 1;

FIG. 3 is a graph showing the drug release rate test of the hydrogel coating prepared in example 2;

FIG. 4 is a graph showing the underwater stability test of the hydrogel coating of test example 1;

FIG. 5 is a graph showing the mechanical properties of the hydrogel coating of test example 3;

FIG. 6 is a graph of the surface root mean square roughness test before and after the coating friction test in test example 4.

Detailed Description

The invention will now be described in further detail with reference to the drawings and specific examples, which should not be construed as limiting the invention. The experimental procedures and reagents not shown in the formulation of the examples were all in accordance with the conventional conditions in the art.

Example 1

The hydrogel coating preparation process is schematically shown in fig. 1 (a):

in step one, 0.2g of dopamine hydrochloride and 0.2g of polyethyleneimine having a number average molecular weight of 600 were dissolved in 100mL of buffer solution (Tris-buffer 50mM, pH=8.5) and stirred to dissolve completely. Then soaking the cleaned substrate (artificial hip joint model, trachea cannula, catheter or titanium alloy) in the solution, stirring for 8 hours at room temperature, and cleaning with deionized water after stirring to obtain the substrate loaded with PDA/PEI. Next, a mixed solution containing 50mL of ethanol and 50mL of deionized water was prepared, and 3wt% KH570 was added to the above solution. The PDA/PEI loaded substrate was immersed in the mixed solution for 3 hours at room temperature. Finally, the substrate is rinsed with deionized water and immersed in deionized water for further use.

Step two, 0.5g of GelMA, 0.5g of PEGDA (with a number average molecular weight of 400), 0.5g of METAC, 0.05g of photoinitiator (phenyl-2, 4, 6-trimethylbenzoyl lithium phosphite) and 0.005g of rhodamine B are dissolved in 8.45g of deionized water, magnetically stirred for 30 minutes, and ultrasonically stirred for 5 minutes to obtain a hydrogel coating prepolymer.

Step three, taking part of the hydrogel coating prepolymer, coating the prepolymer on the surface of the bonding layer of the substrate loaded with the bonding layer in a spin coating mode, and curing for 20s by ultraviolet light (ultraviolet wavelength is 365nm and 30W), so as to prepare the hydrogel coating with the thickness of about 70 mu m on the surface of the substrate, as shown in figure 2. The schematic structure is shown in fig. 1 (b).

Example 2

Preparation process of hydrogel coating loaded with rhodamine B and drug release process

In step one, 0.2g of dopamine hydrochloride and 0.2g of polyethyleneimine having a number average molecular weight of 600 were dissolved in 100mL of buffer solution (Tris-buffer 50mM, pH=8.5) and stirred to dissolve completely. And then soaking the cleaned substrate (glass substrate) in the solution, stirring for 8 hours at room temperature, and cleaning with deionized water after stirring is finished to obtain the substrate loaded with PDA/PEI. Next, a mixed solution containing 50mL of ethanol and 50mL of deionized water was prepared, and 3wt% KH570 was added to the above solution. The PDA/PEI loaded substrate was immersed in the mixed solution for 3 hours at room temperature. Finally, the substrate is rinsed with deionized water and immersed in deionized water for further use.

Step two, 0.5g GelMA, 0.5g PEGDA (with a number average molecular weight of 400), 0.5g METAC, 0.05g photoinitiator (phenyl-2, 4, 6-trimethylbenzoyl lithium phosphite) and 0.0075g rhodamine B are dissolved in 8.45g deionized water, magnetically stirred for 30 minutes, and ultrasonically stirred for 5 minutes to obtain a hydrogel coating prepolymer.

Step three, taking part of the hydrogel coating prepolymer, coating the prepolymer on the surface of the bonding layer of the substrate loaded with the bonding layer in a spin coating mode, curing for 20s by ultraviolet light (the wavelength of ultraviolet light is 365nm and the power is 30W), and preparing the rhodamine B-containing hydrogel coating with the thickness of about 70 mu m on the surface of the substrate.

The prepared hydrogel coating was immersed in a 100ml pbs buffer solution (ph=7.4) at room temperature, and the drug release rate of the coating was monitored using an ultraviolet spectrophotometer. As shown in fig. 3, the rhodamine B release rate was relatively fast, and almost half of rhodamine B was released in the first 4 hours. The release rate was then slowed, but the entire process continued for about 12 hours, with approximately 72% of rhodamine B released from the coating into PBS (ph=7.4).

Example 3

Preparation process of doxycycline hydrochloride-loaded hydrogel coating

In step one, 0.2g of dopamine hydrochloride and 0.2g (number average molecular weight 600) of polyethylenimine were dissolved in 100mL of buffer solution (Tris-buffer 50mM, pH=8.5) and stirred to dissolve completely. And then soaking the cleaned substrate (glass substrate) in the solution, stirring for 8 hours at room temperature, and cleaning with deionized water after stirring is finished to obtain the substrate loaded with PDA/PEI. Next, a mixed solution containing 50mL of ethanol and 50mL of deionized water was prepared, and 3wt% KH570 was added to the above solution. The PDA/PEI loaded substrate was immersed in the mixed solution for 3 hours at room temperature. Finally, the substrate is rinsed with deionized water and immersed in deionized water for further use.

Step two, 0.5g GelMA, 0.5g PEGDA (with a number average molecular weight of 400), 0.5g METAC, 0.05g photoinitiator (phenyl-2, 4, 6-trimethylbenzoyl lithium phosphite) and 0.0075g doxycycline hydrochloride are dissolved in 8.45g deionized water, magnetically stirred for 30 minutes, and ultrasonically stirred for 5 minutes to obtain a hydrogel coating prepolymer.

Step three, taking part of the hydrogel coating prepolymer, coating the prepolymer on the surface of the bonding layer of the substrate loaded with the bonding layer in a spin coating mode, curing for 20s by ultraviolet light (the wavelength of ultraviolet light is 365nm and the power is 30W), and preparing the doxycycline hydrochloride-containing hydrogel coating with the thickness of about 70 mu m on the surface of the substrate.

Example 4

Preparation process of hydrogel coating loaded with baicalin

Step two, 0.5g of baicalin is subjected to surface hydrophilic treatment, dissolved in dopamine hydrochloride solution (2 mg/mL,10mM, PBS with pH=8.5), and reacted for 12 hours at room temperature. The reaction solution was centrifuged (at 8000 rpm) by a centrifuge for 5 minutes, and the precipitate was collected and washed 3 times to obtain hydrophilically treated baicalin for further use.

Step three, 0.5g GelMA, 0.5g PEGDA (with a number average molecular weight of 400), 0.5g METAC, 0.05g photoinitiator (phenyl-2, 4, 6-trimethylbenzoyl lithium phosphite) and 0.0075g hydrophilically treated baicalin were dissolved in 8.45g deionized water, magnetically stirred for 30 minutes, and ultrasonically stirred for 5 minutes to obtain a hydrogel coating prepolymer solution.

And step four, taking part of the pre-polymerized liquid of the hydrogel coating, coating the pre-polymerized liquid on the surface of the bonding layer of the substrate loaded with the bonding layer in a spin coating mode, and curing for 20s by ultraviolet light (the wavelength of ultraviolet light is 365nm and the power is 30W) to prepare the baicalin hydrogel coating with the thickness of about 70 mu m on the surface of the substrate.

Example 5

Preparation process of hydrogel coating loaded with leech freeze-dried powder

In step one, 0.2g of dopamine hydrochloride and 0.2g (number average molecular weight 600) of polyethylenimine were dissolved in 100mL of buffer solution (Tris-buffer 50mM, pH=8.5) and stirred to dissolve completely. And then soaking the cleaned substrate (catheter) in the solution, stirring for 8 hours at room temperature, and cleaning with deionized water after stirring is finished to obtain the substrate loaded with PDA/PEI. Next, a mixed solution containing 50mL of ethanol and 50mL of deionized water was prepared, and 3wt% KH570 was added to the above solution. The PDA/PEI loaded substrate was immersed in the mixed solution for 3 hours at room temperature. Finally, the substrate is rinsed with deionized water and immersed in deionized water for further use.

Step two, 0.5g of leech freeze-dried powder is subjected to surface hydrophilic treatment and dissolved in dopamine hydrochloride solution (2 mg/mL,10mM, PBS with pH=8.5) to react for 12 hours at room temperature. The reaction solution was centrifuged (rotational speed 8000 rpm) by a centrifuge for 5 minutes, and the precipitate was collected and washed 3 times to obtain hydrophilically treated leech lyophilized powder for further use.

Step three, 0.5g GelMA, 0.5g PEGDA (with a number average molecular weight of 400), 0.5g METAC, 0.05g photoinitiator (phenyl-2, 4, 6-trimethylbenzoyl lithium phosphite) and 0.0075g hydrophilically treated leech lyophilized powder are dissolved in 8.45g deionized water, magnetically stirred for 30 minutes, and ultrasonically stirred for 5 minutes, thus obtaining a hydrogel coating prepolymer.

And step four, taking part of the hydrogel coating prepolymer, coating the prepolymer on the surface of the bonding layer of the substrate loaded with the bonding layer in a spin coating mode, and curing for 20s by ultraviolet light (the wavelength of ultraviolet light is 365nm and the power is 30W), thereby preparing the leech freeze-dried powder hydrogel coating with the thickness of about 70 mu m on the surface of the substrate.

Example 6

Hydrogel coating preparation process

In step one, 0.2g of dopamine hydrochloride and 0.2g (number average molecular weight 600) of polyethylenimine were dissolved in 100mL of buffer solution (Tris-buffer 50mM, pH=8.5) and stirred to dissolve completely. And then soaking the cleaned substrate (titanium alloy) in the solution, stirring for 8 hours at room temperature, and cleaning with deionized water after stirring is finished to obtain the substrate loaded with PDA/PEI. Next, a mixed solution containing 50mL of ethanol and 50mL of deionized water was prepared, and 3wt% KH570 was added to the above solution. The PDA/PEI loaded substrate was immersed in the mixed solution for 3 hours at room temperature. Finally, the substrate is rinsed with deionized water and immersed in deionized water for further use.

Step two, 0.5g of GelMA, 0.5g of PEGDA (with the number average molecular weight of 400), 0.5g of METAC and 0.05g of photoinitiator (phenyl-2, 4, 6-trimethylbenzoyl lithium phosphite) are dissolved in 8.45g of deionized water, magnetically stirred for 30 minutes and ultrasonically stirred for 5 minutes, so as to obtain a hydrogel coating prepolymer.

Step three, taking part of the hydrogel coating prepolymer, coating the prepolymer on the surface of the adhesive layer of the substrate loaded with the adhesive layer in a spin coating mode, curing for 20s by ultraviolet light (the wavelength of ultraviolet light is 365nm and the power is 30W), and preparing the hydrogel coating which is about 70 mu m and is not added with medicine on the surface of the substrate.

Example 7

The hydrogel coating preparation process was the same as in example 6, except that: in the second step, the adding amount of GelMA is 0.9g, and the adding amount of PEGDA is 0.1g (namely, the mass ratio of GelMA to PEGDA is 9:1); the other steps are the same as in example 6.

Example 8

The hydrogel coating preparation process was the same as in example 6, except that: in the second step, the adding amount of GelMA is 0.7g, and the adding amount of PEGDA is 0.3g (namely, the mass ratio of GelMA to PEGDA is 7:3); the other steps are the same as in example 6.

Comparative example 1

Hydrogel coating preparation process

Step two, 0.5g of GelMA, 0.5g of PEGDA (with the number average molecular weight of 400) and 0.05g of photoinitiator (phenyl-2, 4, 6-trimethylbenzoyl lithium phosphite) are dissolved in 8.95g of deionized water, magnetically stirred for 30 minutes and ultrasonically stirred for 5 minutes, so as to obtain a hydrogel coating prepolymer.

Step three, taking part of the hydrogel coating prepolymer, coating the prepolymer on the surface of the bonding layer of the substrate loaded with the bonding layer in a spin coating mode, curing for 20s by ultraviolet light (the wavelength of ultraviolet light is 365nm and the power is 30W), and preparing the non-METAC hydrogel coating with the thickness of about 70 mu m on the surface of the substrate.

Comparative example 2

Doxycycline hydrochloride-loaded hydrogel coating was prepared as described in example 3, except that: the adhesive layer is omitted. The method comprises the following specific steps:

step one, 0.5g GelMA, 0.5g PEGDA (number average molecular weight 400), 0.5g METAC, 0.05g photoinitiator (phenyl-2, 4, 6-trimethylbenzoyl lithium phosphite) and 0.0075g doxycycline hydrochloride were dissolved in 8.45g deionized water, magnetically stirred for 30 minutes, and ultrasonically stirred for 5 minutes to obtain a hydrogel coating prepolymer solution.

Step two, taking part of the hydrogel coating prepolymer, coating the prepolymer on the surface of a glass substrate in a spin coating mode, and curing for 20s by ultraviolet light (the wavelength of ultraviolet light is 365nm and the power is 30W), so as to prepare the doxycycline hydrochloride-containing hydrogel coating with the thickness of about 70 mu m on the surface of a substrate.

Comparative example 3

Doxycycline hydrochloride-loaded hydrogel coating was prepared as described in example 3, except that: in step one, 0.2g of dopamine hydrochloride and 0.2g (number average molecular weight 600) of polyethylenimine were dissolved in 100mL of buffer solution (Tris-buffer 50mM, ph=8.5) and stirred to dissolve completely. Then, the cleaned substrate (glass substrate) is soaked in the solution and stirred for 8 hours at room temperature, after the stirring is finished, the substrate loaded with PDA/PEI is obtained by cleaning with deionized water, and the substrate is soaked in the deionized water for further use. Other steps and conditions were the same as in example 3.

Comparative example 4

The hydrogel coating preparation process was the same as in example 6, except that: in the second step, the adding amount of GelMA is 1g, and the adding amount of PEGDA is 0g (namely, the mass ratio of GelMA to PEGDA is 10:0); the other steps are the same as in example 6.

Test example 1

Hydrogel coating underwater stability test

1. The hydrogel coatings prepared by the methods of example 3 (pda+pei+kh570), comparative example 2 (untreated), comparative example 3 (pda+pei) were immersed in PBS buffer at ph7.4 and incubated at room temperature for 20min, and then subjected to underwater ultrasonic cleaning (power 200W) in the above solutions. The photograph before cleaning is shown in the left diagram of fig. 4 (a). As shown in fig. 4 (a), the surface of the untreated substrate was damaged by the ultrasonic cleaning for 10 minutes, because the substrate failed to bond due to the surface hydration layer. For the substrate treated by PDA+PEI, partial shedding of the coating on the surface already occurs during 30min of ultrasonic cleaning, and large-area shedding of the coating already occurs during 60min of ultrasonic cleaning. It can be seen that pda+pei treatment, while improving the hydrophilicity of the substrate surface, the force between the hydrogel coating and the substrate is insufficient to resist external damage. The substrate surface treated by PDA+PEI+KH570 is still complete after the coating is cleaned by underwater ultrasonic for 60min, because the introduction of PDA+PEI and KH570 leads the hydrogel coating and the substrate surface to form covalent bonds and physical bonds, and the stability of the hydrogel coating is improved. Therefore, the hydrogel coating prepared by the method has good interface stability.

2. In order to test the underwater stability of the coating, long-term experiments were performed underwater on the hydrogel coating.

The hydrogel coating prepared by the method of example 3 (PDA+PEI+KH570) was fixed in a beaker and immersed in 500mL PBS buffer pH7.4 for 20min at room temperature, then immersed and sheared for 14 days at room temperature under stirring at 400rpm in the above solution. As shown in fig. 4 (b), the hydrogel coating had no significant change in shape and transparency. These results indicate that the adhesion strength between the hydrogel coating and the substrate increases after treatment with pda+pei+kh570. Therefore, the preparation of the hydrogel coating on the surface of the substrate treated by PDA+PEI+KH570 has good stability, and the method provides a simple thought for preparing the hydrogel coating.

Test example 2

Drag reduction performance of hydrogel coating

The hydrogel coatings prepared in example 6 (hydrogel coating 1) and comparative example 1 (hydrogel coating 2) were subjected to drag reduction testing, the hydrogel coating without METAC had a coefficient of friction of 0.005, the hydrogel coating with METAC had a coefficient of friction of 0.0015, and the inclusion of METAC improved the drag reduction performance of the coating.

Test example 3

Mechanical property test

First, hydrogel blocks were prepared by the same methods as in examples 6 to 8 and comparative example 4, respectively, except that: no substrate is used in step (three); namely: and (3) taking part of the hydrogel coating prepolymer, and curing for 20s by ultraviolet light (the wavelength of the ultraviolet light is 365nm and the power is 30W) to prepare the hydrogel block.

The influence of different PEGDA contents on the mechanical properties of the hydrogels was studied by compression experiments. As shown in fig. 5 (a), the compression sensor is in contact with the hydrogel sample from the beginning until it compression breaks. As shown in fig. 5 (b) - (c), hydrogel samples with mass ratios GelMA: pegda=10:0 (G-M-P-0%), 9:1 (G-M-P-1%), 7:3 (G-M-P-3%) and 5:5 (G-M-P-5%) were subjected to compression test. It is evident that the G-M-P-0% of the samples break under small compressive stress (62 kPa) and strain (38.3%). G-M-P-1% of the samples broke under compressive stress (94 kPa) and strain (49.5%). The G-M-P-3% samples failed under compressive stress (149.1 kPa) and strain (48.9%) and the G-M-P-5% samples failed under compressive stress (286 kPa) and strain (45%). Compression tests show that when the mass ratio of GelMA to PEGDA is increased from 10:0 to 5:5, the compression stress is improved by 4 times. Thus by increasing the PEGDA content, the hydrogel coating can increase its mechanical properties by increasing the network crosslink density.

Test example 4

Durability test

1. To investigate the durability of the various mass ratios GelMA: PEGDA hydrogel coatings (GelMA: PEGDA=10:0 (G-M-P-0%), 9:1 (G-M-P-1%), 7:3 (G-M-P-3%) and 5:5 (G-M-P-5%), long term friction experiments, constant normal force and angular velocity were performed using a rheometer on the hydrogel coatings prepared in examples 6-8, comparative example 4.

The friction test was performed on four hydrogel coatings of different compositions, the coefficient of friction of the G-M-P-0% coating being 0.005, probably due to the low mechanical strength of the coating, resulting in abrasion of the coating. As the PEGDA content increases, the friction coefficient of the coating decreases, the friction coefficient of G-M-P-1% is 0.004, the friction coefficient of G-M-P-3% is 0.003, the friction coefficient of G-M-P-5% coating is the lowest, and the friction coefficient of the coating is 0.0015, because the mechanical strength of the coating is improved, and the abrasion loss of the coating is reduced. In addition, all hydrogel coated samples initially reached a stable coefficient of friction due to rapid formation of a hydrated layer lubricant film on their surface.

2. To demonstrate that varying PEGDA content (GelMA: pegda=10:0 (G-M-P-0%), 9:1 (G-M-P-1%), 7:3 (G-M-P-3%) and 5:5 (G-M-P-5%) can adjust the coating abrasion resistance, the surface root mean square roughness of hydrogel coating samples prepared by the methods of examples 6-8, comparative example 4 were measured using laser microscopy before coating abrasion.

As shown in FIG. 6, the surface root mean square roughness before the G-M-P-0% coating friction test was 1.02 μm; the surface root mean square roughness of the G-M-P-1% coating before friction test is 1.94 μm; the surface root mean square roughness of the G-M-P-3% coating before friction test is 1.51 μm; the surface root mean square roughness before the G-M-P-5% coating friction test was 1.23. Mu.m. The test results show that the hydrogel coating prepared by the brushing and ultraviolet curing method has good surface integrity, and provides an application basis for the subsequent engineering application.

After the G-M-P-0% coating friction test, the surface root mean square roughness change is 25.4 mu M; after the G-M-P-1% coating friction test, the surface root mean square roughness change is 16.2 μm; after the G-M-P-3% coating friction test, the surface root mean square roughness was changed to 6.7 μm; after the G-M-P-5% coating friction test, the surface root mean square roughness was changed to 1.9. Mu.m. It was verified that the abrasion loss of the coating layer after long-term abrasion was reduced as the PEGDA content was increased. Therefore, increasing the PEGDA content, through rheology experiments, shows that the coating crosslink density is increased, the mechanical strength of the hydrogel coating can be improved, and the durability of the coating can be improved.

Claims

1. A hydrogel coating for use in an implant/interventional medical device having underwater stability and drag reduction, wherein the hydrogel coating is comprised of a hydrogel of a polymer cross-linked network structure; the hydrogel with the polymer cross-linked network structure is prepared from methacryloylated gelatin (GelMA), polyethylene glycol diacrylate (PEGDA) and methacryloyloxyethyl trimethyl ammonium chloride through cross-linking polymerization reaction in the presence of water and a photoinitiator.

2. The hydrogel coating for use in an implantable/interventional medical device according to claim 1, wherein the hydrogel coating further comprises a drug; the medicine is uniformly dispersed in the hydrogel with the polymer crosslinked network structure.

3. The hydrogel coating for use in an implantable/interventional medical device according to claim 1, wherein the hydrogel coating has a thickness adjustable in the range of 60 μm to 280 μm.

4. A method of preparing a hydrogel coating for use in an implantable/interventional medical device having underwater stability and drag reduction as claimed in any one of claims 1-3, comprising the steps of:

5. The method of preparing a hydrogel coating for use in an implantable/interventional medical device having underwater stabilization and drag reduction according to claim 4, wherein in step (1) one or more of the following conditions are included:

i. polyethylene glycol diacrylate (PEGDA) has a number average molecular weight of 300 to 500, preferably 400;

ii. The photoinitiator is phenyl-2, 4, 6-trimethyl benzoyl lithium phosphite (LAP); the mass of the photoinitiator is 5-15% of that of the methacryloylated gelatin.

iii, the mass ratio of the methacryloylated gelatin (GelMA) to the deionized water is 1:10-20.

6. The method of preparing a hydrogel coating for use in an implantable/interventional medical device having underwater stabilization and drag reduction according to claim 4, wherein in step (1) one or more of the following conditions are included:

i. the mass ratio of the methacryloylated gelatin (GelMA) to the polyethylene glycol diacrylate (PEGDA) is 0.5-5:0.5-5, preferably 1:1;

ii. The mass ratio of the methacryloyl gelatin (GelMA) to the methacryloyloxyethyl trimethyl ammonium chloride (METAC) is 1:1;

iii, the prepolymerization liquid also contains a drug; preferably, the medicine is rhodamine B, doxycycline hydrochloride, baicalin, leech freeze-dried powder, isosorbide mononitrate or orlistat; the mass of the medicine is 1-2% of that of the methacryloylated gelatin.

7. The method of preparing a hydrogel coating for use in an implantable/interventional medical device having underwater stabilization and drag reduction according to claim 4, wherein in step (2) one or more of the following conditions are included:

i. the substrate is selected from artificial hip joint, trachea cannula, catheter, titanium alloy, bone implantation magnesium-aluminum alloy or dental model;

ii. The number average molecular weight of Polyethylenimine (PEI) is 400-800, preferably 600;

in a solution containing dopamine hydrochloride and Polyethyleneimine (PEI), the solvent is Tris buffer (Tris-buffer) with the concentration of 50mM and the pH=8.5, wherein the concentration of the dopamine hydrochloride is 0.1-0.3mg/mL;

iv, dopamine hydrochloride and Polyethyleneimine (PEI) in a mass ratio of 1:1.

v, soaking in a solution containing dopamine hydrochloride and Polyethyleneimine (PEI) for 6-10h at room temperature under stirring.

8. The method of preparing a hydrogel coating for use in an implantable/interventional medical device having underwater stabilization and drag reduction according to claim 4, wherein in step (2) one or more of the following conditions are included:

i. in the mixed solution containing ethanol, KH570 and deionized water, the mass concentration of KH570 is 2-4%wt, and the volume ratio of ethanol to deionized water is 0.5-2:0.5-2, preferably 1:1;

ii. Soaking in mixed solution containing ethanol, KH570 and deionized water at room temperature for 2-4 hr.

9. The method of preparing a hydrogel coating for use in an implantable/interventional medical device having underwater stabilization and drag reduction according to claim 4, wherein in step (3) one or more of the following conditions are included:

i. the coating method is selected from one of dip coating, spray coating, spin coating or brush coating;

ii. The ultraviolet wavelength of ultraviolet curing is 365nm, the power is 10-30W, and the ultraviolet curing time is 10-30s.

10. Use of a hydrogel coating for implant/interventional medical devices with underwater stabilization and drag reduction as claimed in any of claims 1-3 as a coating applied to the surface of the implant/interventional medical device.