CN116983473A - Implantable medical device and preparation method thereof - Google Patents

Abstract

The invention relates to an implanted medical device and a preparation method thereof, which includes a device base and an antibacterial coating. Antibacterial coating is provided on the device base. Antimicrobial coatings contain antimicrobial agents. In the direction from the device base to the surface of the antibacterial coating away from the device base, the concentration of the antibacterial agent in the antibacterial coating first increases and then decreases. The antibacterial agent in the antibacterial coating forms a two-way concentration gradient toward the inner and outer sides. On the one hand, the above-mentioned implanted medical device can avoid the presence of a high concentration of antibacterial agents on the surface of the implanted medical device and avoid the explosive release of antibacterial agents. On the other hand, the antibacterial coating with a two-way concentration gradient forms a slow-release antibacterial agent reservoir. Therefore, compared with forming a pure antibacterial agent coating directly on the surface of the device, it greatly improves the biocompatibility problems caused by the explosive release of antibacterial agents. It also prolongs the effective duration of the antibacterial agent and helps improve the utilization rate of the antibacterial agent. , which can improve the anti-infection ability of implanted medical devices and reduce the incidence of PJI.

Description

Implantable medical device and preparation method thereof

Technical field

The present invention relates to the technical field of medical devices, and in particular to an implanted medical device and a preparation method thereof.

Background technique

Implanted medical devices refer to any device that is fully or partially inserted into the human body or natural orifice through surgical procedures, or is left in the body for a long time after the surgical procedure is completed, or is partially left in the body for at least 30 days. Among them, medical devices used to replace a certain limb, organ or tissue of the human body are also called prostheses. Periprosthetic joint infect (PJI) often causes an inflammatory reaction around the implant, leading to dissolution of surrounding bone tissue and loosening and failure of the prosthesis. It is considered a catastrophic complication after implanted medical device replacement.

Therefore, how to improve the anti-infection ability of implanted medical devices to reduce the incidence of periprosthetic infection (PJI) has become extremely important.

Contents of the invention

Based on this, it is necessary to provide an implantable medical device and a preparation method thereof that can improve the anti-infection ability.

The present invention is achieved through the following technical solutions.

One aspect of the present invention provides an implantable medical device, including:

device base; and

An antibacterial coating is provided on the device base body, and the antibacterial coating contains an antibacterial agent; in the direction from the device base body to the surface of the antibacterial coating away from the device base body, the antibacterial coating layer The concentration of the antimicrobial agent first increased and then decreased.

In one embodiment, the antibacterial coating further includes at least one of a biocompatible material and a matrix material.

In one embodiment, the combination form of the antibacterial agent in the antibacterial coating and the base material and/or the biocompatible material is physical mixing or chemical bonding.

In one embodiment, the antibacterial coating includes a first sub-antibacterial layer and a second sub-antibacterial layer sequentially provided on the surface of the instrument base;

In the direction from the instrument base to the surface of the antibacterial coating away from the instrument base, the concentration of the antibacterial agent in the first sub-antibacterial layer gradually increases, and the concentration of the antibacterial agent in the second sub-antibacterial layer increases gradually. The concentration of the antimicrobial agent was gradually reduced.

In one embodiment, the first sub-antibacterial layer also contains a matrix material;

And/or, the second sub-antibacterial layer also contains biocompatible materials.

In one embodiment, the first sub-antibacterial layer is a diffusion coating formed by diffusion of an antibacterial agent to the surface of the device base;

And/or, the second sub-antibacterial layer is a diffusion coating formed by diffusion of an antibacterial agent in a direction away from the device base.

In one embodiment, the antibacterial coating further includes a third sub-antibacterial layer, the third sub-antibacterial layer is formed of undiffused antibacterial agent.

In one embodiment, the implanted medical device further includes a biocompatible coating disposed on a surface of the second sub-antibacterial layer away from the device base.

In one embodiment, the antibacterial coating is formed by coating the device substrate multiple times in sequence.

In one embodiment, the maximum antibacterial agent concentration P1 in the antibacterial coating is 5wt% to 100wt%;

And/or, the minimum antibacterial agent concentration P2 in the first sub-antibacterial layer is ≤ 40wt%;

And/or, the minimum antibacterial agent concentration P3 in the second sub-antibacterial layer is ≤ 40wt%.

In one embodiment, the biocompatible material and the material of the biocompatible coating are each independently selected from one of metals, metal oxides and medical non-metallic materials.

In one embodiment, the instrument base is made of metal material;

And/or, the antibacterial agent is at least one of a metal antibacterial agent, a metal-containing antibacterial agent, and an organic antibacterial agent.

In one embodiment, the thickness of the antibacterial coating is 0.01-500 μm.

Another aspect of the invention provides a method for preparing an implanted medical device, including the following steps:

An antibacterial coating containing an antibacterial agent is formed on the instrument base; in the direction from the instrument base to the surface of the antibacterial coating away from the instrument base, the concentration of the antibacterial agent in the antibacterial coating first increases After increasing, it decreases.

In one embodiment, the step of forming an antibacterial coating containing an antibacterial agent on the device base includes the following steps:

An antibacterial material layer and a biocompatibility material layer are formed on the surface of the device base body in sequence, and then annealing and diffusion processing is performed, so that the antibacterial agent material layer is respectively in contact with the surface of the device base body and the biocompatibility material layer. Material layers diffuse into each other.

In one embodiment, the temperature of the annealing and diffusion treatment is 200-1000°C, and the time is 0.5h-80h.

The concentration of the antibacterial agent in the antibacterial coating of the above-mentioned implanted medical device first increases and then decreases in the direction from the device base to the surface of the antibacterial coating away from the device base; that is: the antibacterial agent in the antibacterial coating moves toward the device A two-way concentration gradient is formed between the base body and the surface of the antibacterial coating away from the device base body, that is, the concentration of the antibacterial agent in the antibacterial coating gradually decreases both inward and outward. On the one hand, the above-mentioned implantable medical device can avoid the presence of a high concentration of antibacterial agents on the surface of the implanted medical device and avoid the explosive release of antibacterial agents. On the other hand, the antibacterial coating with a two-way concentration gradient forms a slow-release antibacterial agent reservoir. Therefore, compared with forming a pure antibacterial agent coating directly on the surface of the device, it greatly improves the biocompatibility problems caused by the explosive release of antibacterial agents. It also extends the effective duration of the antibacterial agent and helps improve the utilization rate of the antibacterial agent. , which can improve the anti-infection ability of implanted medical devices and reduce the incidence of PJI.

Description of drawings

Figure 1 is a schematic diagram of an implanted medical device according to an embodiment of the present invention;

Figure 2 is a schematic cross-sectional structural diagram of the implanted medical device shown in Figure 1 at position A;

Figure 3 is a schematic diagram of the state of the implanted medical device shown in Figure 2 during the preparation process;

Figure 4 is a schematic cross-sectional structural diagram of an implanted medical device at position A according to another embodiment;

Figure 5 is a schematic cross-sectional structural diagram of an implanted medical device at position A according to another embodiment;

Figure 6 is a schematic cross-sectional structural diagram of an implanted medical device at position A according to another embodiment.

Explanation of reference symbols:

100. Implanted medical device; 110. Device base; 120. Antibacterial coating; 121. First sub-antibacterial layer; 122. Second sub-antibacterial layer; 123. Third sub-antibacterial layer; 130. Biocompatibility coating ;

101. Antibacterial agent material layer; 102. Biocompatibility material layer.

Detailed ways

In order to facilitate understanding of the present invention, the present invention will be described more fully below with reference to the relevant drawings. Preferred embodiments of the invention are shown in the drawings. However, the invention may be embodied in many different forms and is not limited to the embodiments described herein. It should be understood that these embodiments are provided to provide a thorough and comprehensive understanding of the disclosure of the present invention.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the technical field to which the invention belongs. The terminology used herein in the description of the invention is for the purpose of describing specific embodiments only and is not intended to limit the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.

In the present invention, unless otherwise expressly stated and limited, a first feature being "on" or "below" a second feature may mean that the first and second features are in direct contact, or the first and second features are in indirect contact through an intermediate medium. touch. Furthermore, the terms "above", "above" and "above" the first feature is above the second feature may mean that the first feature is directly above or diagonally above the second feature, or simply means that the first feature is higher in level than the second feature. "Below", "below" and "beneath" the first feature to the second feature may mean that the first feature is directly below or diagonally below the second feature, or simply means that the first feature has a smaller horizontal height than the second feature.

In the description of the present invention, it should be understood that the terms "first" and "second" are only used for descriptive purposes and cannot be understood as indicating or implying relative importance or implicitly indicating the number of indicated technical features. Therefore, features defined as "first" and "second" may explicitly or implicitly include one or more of these features. In the description of the present invention, "plurality" means two or more than two, unless otherwise explicitly and specifically limited.

Referring to Figures 1 and 2, one embodiment of the present invention provides an implantable medical device 100, which includes a device base 110 and an antibacterial coating 120.

The antibacterial coating 120 is provided on the instrument base 110 . The antibacterial coating 120 contains antibacterial agents. In the direction from the instrument base 110 to the surface of the antibacterial coating 120 away from the instrument base 110 , the concentration of the antibacterial agent in the antibacterial coating 120 first increases and then decreases.

In other words, the antibacterial agent in the antibacterial coating 120 forms a bidirectional concentration gradient toward the instrument base 110 and toward the surface of the antibacterial coating 120 away from the instrument base 110 , that is, the concentration of the antibacterial agent in the antibacterial coating 120 gradually increases both inward and outward. reduce. The above-mentioned implanted medical device 100 can, on the one hand, avoid the presence of a high concentration of antibacterial agents on the surface of the implanted medical device 100 and avoid the explosive release of the antibacterial agents. On the other hand, the antibacterial coating 120 with a two-way concentration gradient forms a sustained-release Antibacterial agent reservoir, therefore compared to directly forming a pure antibacterial agent coating on the surface of the device, it greatly improves the biocompatibility problems caused by the explosive release of antibacterial agents, and also prolongs the effective duration of the antibacterial agent and is conducive to improving the effectiveness of the antibacterial agent. The utilization rate can thereby improve the anti-infection ability of the implanted medical device 100 and reduce the incidence of PJI.

In one embodiment, the antibacterial coating 120 further includes at least one of a biocompatible material and a matrix material.

In one embodiment, the antibacterial agent in the antibacterial coating 120 is combined with the base material and/or the biocompatible material in the form of physical mixing or chemical bonding.

Please continue to refer to FIG. 2 . In one embodiment, the antibacterial coating 120 includes a first sub-antibacterial layer 121 and a second sub-antibacterial layer 122 sequentially provided on the surface of the instrument base 110 . In the direction from the instrument base 110 to the surface of the antibacterial coating 120 away from the instrument base 110 , the concentration of the antibacterial agent in the first sub-antibacterial layer 121 gradually increases, and the concentration of the antibacterial agent in the second sub-antibacterial layer 122 gradually decreases.

In this way, as the action time of the implanted medical device 100 prolongs, the lower concentration of antibacterial agent on the surface of the second sub-antibacterial layer 122 in the antibacterial coating 120 is released first, and the higher concentration of antibacterial agent on the inside of the second sub-antibacterial layer 122 is released. The antibacterial agent is continuously released to the outside to provide supply. At the same time, the antibacterial agent with a higher concentration on the outer side of the first sub-antibacterial layer 121 is also continuously released to provide supply. Finally, the antibacterial agent inside the antibacterial coating 120 is balanced at a lower concentration and continues to provide supply. The low-concentration release greatly improves the effective duration of the antibacterial agent and the utilization rate of the antibacterial agent.

In one embodiment, the first sub-antibacterial layer 121 also includes a base material. In this way, the first sub-antibacterial layer 121 contains both the base material and the antibacterial agent, which can improve the adhesion performance between the instrument base 110 and the antibacterial coating 120 .

Further, the first sub-antibacterial layer 121 is a diffusion coating formed by diffusion of antibacterial agents to the surface of the instrument base 110 .

In one embodiment, the second sub-antibacterial layer 122 also includes biocompatible materials. In this way, the first sub-antibacterial layer 121 contains both biocompatible materials and antibacterial agents, which can improve the biocompatibility of the second sub-antibacterial layer 122 with living organisms.

Further, the second sub-antibacterial layer 122 is a diffusion coating formed by the antibacterial agent diffusing in a direction away from the instrument base 110 . Furthermore, the second sub-antibacterial layer 122 is a diffusion coating formed by the diffusion of antibacterial agents to the biocompatible material layer 102 .

Please refer to FIG. 3 . In one embodiment, the first sub-antibacterial layer 121 and the second sub-antibacterial layer 122 are formed by the antibacterial material layer 101 diffusing with the surface of the instrument base 110 and the biocompatible material layer 102 respectively. It can be understood that during the preparation process, the first sub-antibacterial layer 121 and the second sub-antibacterial layer 122 can be simultaneously diffused and formed in the same process.

It can be understood that the diffusion between the antibacterial material layer 101 and the surface of the instrument base 110 and the biocompatible material layer 102 is mutual, but there may be a relative speed difference. Particularly, when the antibacterial agent in the antibacterial agent material layer 101 is a metal material, the diffusion between it and the instrument base 110 which is also a metal material is very rapid.

It can be understood that the thickness of the instrument base 110 changes slightly before and after diffusion. Since the thickness of the instrument base 110 is relatively large, it can be ignored here.

It can be understood that the coating in the antibacterial coating 120 may not be limited to the first sub-antibacterial layer 121 and the second sub-antibacterial layer 122. For example, it may also include an antibacterial layer with no obvious gradient change in the concentration of the antibacterial agent.

Referring to FIG. 4 , in one embodiment, the antibacterial coating 120 further includes a third sub-antibacterial layer 123 , and the third sub-antibacterial layer 123 may be formed of the above-mentioned undiffused antibacterial agent. Further, the third sub-antibacterial layer 123 is the remaining undiffused coating in the antibacterial agent material layer 101 . In other words, the antibacterial agent in the third sub-antibacterial layer 123 has no concentration change in the above direction.

Furthermore, the concentration of the antibacterial agent in the third sub-antibacterial layer 123 is greater than the concentration of the antibacterial agent in the first sub-antibacterial layer 121 and is also greater than the concentration of the antibacterial agent in the second sub-antibacterial layer 122 . Furthermore, the third sub-antibacterial layer 123 is a pure antibacterial agent coating.

It can be understood that the above-mentioned antibacterial coating 120 can be formed in other ways, for example, by coating the device base 110 multiple times in sequence. Specifically, it suffices to control the antibacterial agent in each coating liquid used to form the antibacterial coating 120 according to the order of coating to show an overall trend that the concentration of the antibacterial agent first increases and then decreases.

Specifically, the first sub-antibacterial layer 121 and the second sub-antibacterial layer 122 are formed by coating on the instrument base 110 for multiple times in sequence. Specifically, the antibacterial agent in each coating liquid used to form the first sub-antibacterial layer 121 is controlled according to the coating sequence to show an overall trend of increasing antibacterial agent concentration; the antibacterial agent concentration is controlled to be used to form the second sub-layer 121 according to the coating sequence. The antibacterial agent concentration in each coating liquid of the antibacterial layer 122 shows a decreasing trend as a whole. That is to say, there may be two or more adjacent coatings with the same antibacterial agent concentration in the coating liquid, which is allowed as long as the above-mentioned concentration gradient trend is ensured as a whole. The third sub-antibacterial layer 123 can be produced by one-time coating.

Referring to FIG. 5 , in one embodiment, the implanted medical device 100 further includes a biocompatible coating 130 provided on the surface of the second sub-antibacterial layer 122 away from the device base 110 .

It should be noted that the material of the biocompatible coating 130 here is a biocompatible material that does not contain antibacterial agents. It can be formed separately on the second sub-antibacterial layer 122 or can be the antibacterial agent material layer 101 In the step of diffusing the antibacterial agent into the biocompatible material layer 102, the remaining biocompatible material layer 102 is not diffused with the antibacterial agent. This can further improve the biocompatibility of the implanted medical device 100 . Further, the thickness of the biocompatible coating 130 is ≤1500 μm, and the coating can be provided with a microscopic or macroscopic pore structure as needed.

Please refer to FIG. 6 , which is basically the same as the specific example shown in FIG. 4 , except that the surface of the second sub-antibacterial layer 122 away from the instrument base 110 is also provided with the above-mentioned biocompatible coating that does not contain antibacterial agents. 130.

In one embodiment, the instrument base 110 is made of metal material. Further, the material of the instrument base 110 is one of titanium, titanium alloy, tantalum, tantalum alloy, medical stainless steel, cobalt-chromium alloy, magnesium alloy, and iron alloy. The surface of the instrument base 110 can be provided with microscopic or macroscopic pore structures as needed.

Further, the instrument base 110 may be an artificial joint (or joint prosthesis), a bone plate, a screw, an intramedullary nail, a bone needle, a steel wire, a cable, a dental implant, a spinal implant, a bone defect implant, or an orthopedic implant. Medical devices such as positioners that replace or contact bone tissue.

Further, the artificial joint may be a hip joint, a knee joint, a condylar joint, an elbow joint, a wrist joint, a finger joint or a shoulder joint. It can be understood that joint prostheses include but are not limited to this.

In one embodiment, the antibacterial agent is an inorganic antibacterial agent or an organic antibacterial agent; further, the inorganic antibacterial agent is a metal antibacterial agent or a metal-containing antibacterial agent. Further, any of the above-mentioned antibacterial agents is independently selected from at least one metal antibacterial agent such as copper metal, silver metal, and zinc metal. Metal-containing antibacterial agents include alloys containing at least one of copper metal, silver metal, and zinc metal, and oxides formed from at least one of copper metal, silver metal, and zinc metal, such as copper oxide, silver oxide, and zinc oxide. .

Further, the organic antibacterial agent includes at least one of gentamicin and vancomycin.

In one embodiment, the biocompatible material, the biocompatible material layer 102 and the biocompatible coating 130 are each independently selected from metals, metal oxides and medical non-metallic materials. A sort of. Furthermore, the metal here can be tantalum or titanium with good biocompatibility, and the metal oxide can be tantalum oxide or titanium oxide. Medical non-metallic materials include but are not limited to at least one of hydroxyapatite, bioactive glass and calcium silicate materials.

For example, in a specific example, the antibacterial agent is copper metal, the biocompatible material layer 102 and/or the biocompatible coating 130 is a titanium metal coating, and the instrument base 110 is made of titanium metal. Through the above diffusion step, the first sub-antibacterial layer 121 and the second sub-antibacterial layer 122 formed are both copper-titanium alloy.

In one embodiment, the maximum antibacterial agent concentration P1 in the antibacterial coating 120 is 5wt%˜100wt%. The concentration of 100wt% represents a pure antibacterial agent coating.

In one embodiment, the minimum antibacterial agent concentration P2 in the first sub-antibacterial layer 121 is ≤ 40 wt%.

In one embodiment, the minimum antibacterial agent concentration P3 in the second sub-antibacterial layer 122 is ≤ 40 wt%.

Further, when the antibacterial agent is a metal antibacterial agent or an antibacterial agent containing metal, the maximum antibacterial agent concentration P1 in the antibacterial coating 120 is 30wt% to 100wt%; and/or the minimum antibacterial agent in the first sub-antibacterial layer 121 The concentration P2≤40wt%; and/or, the minimum antibacterial agent concentration P3 in the second sub-antibacterial layer 122≤40wt%.

Further, when the antibacterial agent is an organic antibacterial agent, the maximum antibacterial agent concentration P1 in the antibacterial coating 120 is 5wt% to 50wt%; and/or the minimum antibacterial agent concentration P2 in the first sub-antibacterial layer 121 is ≤ 20wt%; And/or, the minimum antibacterial agent concentration P3 in the second sub-antibacterial layer 122 is ≤ 20 wt%.

In one embodiment, the thickness of the antibacterial coating 120 is 0.01-500 μm, such as 0.1 μm, 0.2 μm, 0.3 μm, 0.5 m, 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, 10 μm. .

Further, the thickness of the first sub-antibacterial layer 121 is 0.005-250 μm. Further, the thickness of the second sub-antibacterial layer 122 is 0.005-250 μm.

Further, the thickness of the third sub-antibacterial layer 123 is no more than 450 μm.

It can be understood that the above-mentioned antibacterial coating 120 can be formed on part or all of the surface of the instrument base 110 .

Furthermore, the antibacterial coating 120 provided on the surface of the implanted medical device 100 is not limited to one layer, and may be a stack of multiple antibacterial coatings 120 . In other words, a plurality of the above-mentioned antibacterial coatings 120 with the above-mentioned bidirectional concentration gradient are provided on the device base 110 of the implanted medical device 100 .

When there are multiple antibacterial coatings 120 , each antibacterial agent and each biocompatible material in each antibacterial coating 120 can be independently selected from the above categories; in other words, each antibacterial agent and each biocompatible material in each antibacterial coating 120 Compatible materials can be the same or different.

Further, in some embodiments, the above-mentioned biocompatible coating 130 may be provided between two adjacent antibacterial coatings 120 . In the same implanted medical device 100, the above-mentioned biocompatible coating 130 can be disposed between at least two adjacent antibacterial coatings 120. It can be understood that the above-mentioned biocompatible coating 130 can also be provided between any two adjacent antibacterial coatings 120 . Further preferably, the above-mentioned biocompatible coating 130 is provided on the outermost surface of the implanted medical device 100 .

Please continue to refer to Figure 1. Another embodiment of the present invention also provides a method for preparing an implanted medical device 100, which includes the following steps:

An antibacterial coating 120 containing an antibacterial agent is formed on the device base 110; in the direction from the device base 110 to the surface of the antibacterial coating 120 away from the device base 110, the concentration of the antibacterial agent in the antibacterial coating 120 first increases and then decreases. .

Please continue to refer to Figure 3. In one embodiment, the step of forming an antibacterial coating 120 containing an antibacterial agent on the instrument base 110 includes the following steps S10 to S30:

Step S10: Form the antibacterial material layer 101 on the surface of the instrument base 110.

Step S20: Form a biocompatible material layer 102 on the surface of the antibacterial material layer 101 obtained in step S10 away from the device base 110.

Step S30: After step S20, an annealing and diffusion process is performed to diffuse the antibacterial agent material layer 101 with the surface of the device base 110 and the biocompatible material layer 102 respectively.

It can be understood that, depending on the thickness and degree of diffusion of the antibacterial agent material layer 101 and the biocompatible material layer 102, the antibacterial coating 120 formed may only contain the above-mentioned first sub-antibacterial layer 121 and second sub-antibacterial layer 122, or It contains a first sub-antibacterial layer 121, a second sub-antibacterial layer 122 and a third sub-antibacterial layer 123; further, the formed implanted medical device 100 may have residual antibacterial agent not diffused on the surface of the second sub-antibacterial layer 122. The biocompatible material layer 102 forms the above-mentioned biocompatible coating 130 or does not contain the biocompatible coating 130 .

Further, in steps S10 to S20, the method of forming the antibacterial material layer 101 and the biocompatibility material layer 102 on the surface of the instrument base 110 can be independently selected from one of the following common coating preparation methods: electrochemical deposition. , electrophoretic deposition, sputter deposition, chemical vapor deposition, spray coating method, sol-gel method, dip coating method, pull method, hydrothermal reaction method, sandblasting modification. The specific method to choose can be selected based on the specific material characteristics of the antibacterial agent material layer 101 and the biocompatible material layer 102 .

Taking the material of the antibacterial agent material layer 101 formed in step S10 as a copper metal coating as an example, it can be obtained by an electrochemical deposition method; specifically, copper sulfate (CuSO ₄ ), copper chloride (CuCl ₂ ), etc. can be used. A salt solution of Cu ²⁺ serves as the electrolyte.

Further, the antibacterial agent material layer 101 and/or the biocompatible material layer 102 may have a microscopic or macroscopic pore structure.

In one embodiment, the thickness of the antibacterial agent material layer 101 formed in step S10 is 0.1-10 μm, such as 0.1 μm, 0.2 μm, 0.3 μm, 0.5 m, 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8μm, 9μm, 10μm.

In one embodiment, the thickness of the biocompatible material layer 102 formed in step S20 is 1 to 50 μm, such as 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, 10 μm, 15 μm, 20 μm, 25μm, 30μm, 35μm, 40μm, 45μm, 50μm.

Further, in some examples, steps S10 to S20 may be repeated multiple times, and then step S30 may be used to form multiple antibacterial coatings 120 having the above-mentioned bidirectional concentration gradient. In other examples, multiple antibacterial coatings 120 with the above bidirectional concentration gradient can be formed by repeating multiple cycles of steps S10 to S30.

Further, when there are multiple antibacterial coatings 120, each antibacterial agent and each biocompatible material in each antibacterial coating 120 can be independently selected from the above categories; in other words, each antibacterial agent in each antibacterial coating 120 and each biocompatible material may be the same or different.

In one embodiment, the temperature of the annealing and diffusion treatment is 200-1000°C, and the time is 0.5h-80h. This temperature can be beneficial to the diffusion of metal antibacterial agents such as copper metal, silver metal and zinc metal.

Further, the temperatures of annealing and diffusion treatment are 200℃, 300℃, 400℃, 500℃, 600℃, 700℃, 800℃, 900℃, 1000℃; the time is 0.5h, 1h, 2h, 5h, 10h, 15h , 20h, 25h, 30h, 35h, 40h, 45h, 50h, 55h, 60h, 65h, 70h, 75h, 80h.

Further, the atmosphere of the annealing and diffusion treatment can be selected from an inert gas atmosphere or a vacuum atmosphere.

Preferably, the biocompatible material layer 102 is one of metal and metal oxide. This is because the diffusion speed of metal antibacterial agents in these materials is faster than the diffusion speed in medical non-metallic materials such as hydroxyapatite, bioactive glass and calcium silicate materials.

In one embodiment, the above-mentioned antibacterial coating 120 can be formed by coating the device substrate multiple times in sequence, which will not be described in detail here.

It can be understood that coating includes but is not limited to brushing, printing, spraying and other methods.

Specifically, the first sub-antibacterial layer 121 and the second sub-antibacterial layer 122 are formed by coating on the instrument base 110 for multiple times in sequence.

In a specific example, the steps of forming an antibacterial coating on the surface of a titanium metal substrate are as follows:

Step 1: Mix metallic copper powder and titanium powder according to the proportion to obtain the following mixed powders: 1) 70wt% Ti+30wt% Cu; 2) 30wt% Ti+70wt% Cu; 3) 100wt% Cu; 4) 30wt %Ti+70wt%Cu; 5) 70wt%Ti+30wt%Cu.

Step 2: Spray the above-mentioned powders from 1) to 5) on the surface of the titanium metal substrate sequentially using the spraying method to obtain a copper-titanium physical mixed coating with a bidirectional concentration gradient on the surface of the titanium metal substrate.

Further, on the basis of the above step 2), step 3 can be further performed: annealing the titanium metal substrate containing the above coating in step 2), so that copper and titanium locally diffuse each other to form a copper-titanium alloy.

In another specific example, gentamicin, an organic antibacterial agent, is used, and the biocompatible material is polymethylmethacrylate (PMMA) as an example. The steps to form an antimicrobial coating on the surface of a metal substrate are as follows:

Step 1: Mix the solid phase prepolymer PMMA with an organic antibacterial agent to obtain the following mixed powders: 1) PMMA; 2) PMMA containing 3wt% gentamicin; 3) PMMA containing 10wt% gentamicin ;4) PMMA containing 3wt% gentamicin;

Step 2: Mix the above powder with liquid phase MMA (methyl methacrylate) monomer containing polymerization initiator, and apply it on the surface of the metal substrate in sequence from 1) to 4). After the PMMA is cured, a bidirectional concentration gradient is obtained. Gentamicin-PMMA physical hybrid coating.

The technical features of the above-described embodiments can be combined in any way. To simplify the description, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, All should be considered to be within the scope of this manual.

The above-mentioned embodiments only express several implementation modes of the present invention, and their descriptions are relatively specific and detailed, but they should not be construed as limiting the scope of the invention. It should be noted that, for those of ordinary skill in the art, several modifications and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention should be determined by the appended claims, and the description and drawings can be used to interpret the content of the claims.

Claims (16)

1. An implantable medical device, characterized in that it includes: device base; and An antibacterial coating is provided on the device base body, and the antibacterial coating contains an antibacterial agent; in the direction from the device base body to the surface of the antibacterial coating away from the device base body, the antibacterial coating layer The concentration of the antimicrobial agent first increased and then decreased. 2. The implanted medical device according to claim 1, wherein the antibacterial coating further includes at least one of a biocompatible material and a matrix material. 3. The implanted medical device according to claim 2, wherein the combination of the antibacterial agent in the antibacterial coating and the base material and/or the biocompatible material is physically mixed or formed. Chemical bonding. 4. The implantable medical device according to claim 1, wherein the antibacterial coating includes a first sub-antibacterial layer and a second sub-antibacterial layer sequentially provided on the surface of the device base; In the direction from the instrument base to the surface of the antibacterial coating away from the instrument base, the concentration of the antibacterial agent in the first sub-antibacterial layer gradually increases, and the concentration of the antibacterial agent in the second sub-antibacterial layer increases gradually. The concentration of the antimicrobial agent was gradually reduced. 5. The implanted medical device according to claim 4, wherein the first sub-antibacterial layer further contains a matrix material; And/or, the second sub-antibacterial layer also contains biocompatible materials. 6. The implanted medical device according to claim 4, wherein the first sub-antibacterial layer is a diffusion coating formed by diffusion of an antibacterial agent to the surface of the device base; And/or, the second sub-antibacterial layer is a diffusion coating formed by diffusion of an antibacterial agent in a direction away from the device base. 7. The implanted medical device according to claim 6, wherein the antibacterial coating further includes a third sub-antibacterial layer, the third sub-antibacterial layer is formed of undiffused antibacterial agent. 8. The implanted medical device according to claim 4, wherein the implanted medical device further comprises a biocompatible coating disposed on the surface of the second sub-antibacterial layer away from the device base. . 9. The implanted medical device according to claim 1, wherein the antibacterial coating is formed by coating the device substrate multiple times in sequence. 10. The implanted medical device according to any one of claims 4 to 9, wherein the maximum antibacterial agent concentration P1 in the antibacterial coating is 5wt% to 100wt%; And/or, the minimum antibacterial agent concentration P2 in the first sub-antibacterial layer is ≤ 40wt%; And/or, the minimum antibacterial agent concentration P3 in the second sub-antibacterial layer is ≤ 40wt%. 11. The implantable medical device according to any one of claims 5 to 9, wherein the biocompatible material and the material of the biocompatible coating are each independently selected from the group consisting of metals, metal oxides and One of the medical non-metallic materials. 12. The implanted medical device according to any one of claims 1 to 9, characterized in that the material of the device base is a metal material; And/or, the antibacterial agent is at least one of a metal antibacterial agent, a metal-containing antibacterial agent, and an organic antibacterial agent. 13. The implanted medical device according to any one of claims 1 to 9, wherein the thickness of the antibacterial coating is 0.01-500 μm. 14. A method for preparing implantable medical devices, characterized in that it includes the following steps: An antibacterial coating containing an antibacterial agent is formed on the device base body; in the direction from the device base body to the surface of the antibacterial coating away from the device base body, the concentration of the antibacterial agent in the antibacterial coating first increases After increasing, it decreases. 15. The preparation method according to claim 14, wherein the step of forming an antibacterial coating containing an antibacterial agent on the instrument substrate includes the following steps: An antibacterial material layer and a biocompatible material layer are formed on the surface of the device base in sequence, and then annealed and diffused, so that the antibacterial material layer is respectively in contact with the surface of the device base and the biocompatibility. The layers of material diffuse into each other. 16. The preparation method according to claim 15, wherein the temperature of the annealing and diffusion treatment is 200-1000°C, and the time is 0.5h-80h.