Anti-adhesion coating for implantable device and implantable device

Abstract

The invention discloses an anti-adhesion coating for an implantable device and the implantable device, and belongs to the technical field of implantable device coatings. The preparation method of the anti-adhesion coating comprises the following steps: blending carboxymethyl chitosan and hyaluronic acid, adding a cross-linking agent to enable the carboxymethyl chitosan to be subjected to a cross-linking reaction to generate cross-linked carboxymethyl chitosan, and after the cross-linking reaction, obtaining hydrogel in which the hyaluronic acid is distributed in pores of the cross-linked carboxymethyl chitosan; and stirring the hydrogel, shearing and thinning, coating the surface of the implanted device with the hydrogel, and drying to obtain the anti-adhesion coating. According to the implantable device with the anti-adhesion coating attached to the surface, the adhesion effect between the implantable device and biological tissue can be reduced, the biocompatibility and the performance of the device are improved, complications caused by adhesion are reduced, and the service life of the implantable device is prolonged.

Description

Technical Field

[0001] The invention relates to the technical field of implantable device coatings, and in particular to an anti-adhesion coating for implantable devices and the implantable device. Background Art

[0002] In modern medicine, various medical implants (such as pacemakers, vascular stents, artificial joints, etc.) are widely used to treat a variety of diseases and injuries. When these devices come into contact with human tissue, adhesion between the tissue and the device surface may occur. This adhesion may lead to a variety of complications, such as inflammatory response, infection, scar formation, device dysfunction, etc. In some cases, due to tissue adhesion, a secondary operation may be required to remove or replace the implanted device, which not only increases the patient's pain, but also brings additional risks and costs. Anti-tissue adhesion coatings can effectively reduce the adhesion between tissue and implanted devices. Current coating preparation technologies such as chemical vapor deposition (CVD) and layer-by-layer self-assembly are cumbersome; or through surface modification technologies such as plasma treatment and chemical modification, the properties of the device surface can be changed to make it less likely to adhere to tissue, but may cause local inflammatory reactions. Summary of the invention

[0003] In view of the above-mentioned deficiencies in the prior art, the object of the present invention is to provide an anti-adhesion coating for implantable devices and an implantable device. A polymer hydrogel is prepared by using natural products, and the polymer hydrogel is further processed to form a coating on the surface of the implantable device. The coating has a simple structure, is inexpensive, can reduce tissue adhesion and wrapping at the implantation site, and is degradable.

[0004] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0005] An anti-adhesion coating for an implantable device, wherein the preparation method of the anti-adhesion coating comprises the following steps:

[0006] (1) uniformly blending carboxymethyl chitosan and hyaluronic acid to obtain a mixed material;

[0007] (2) adding a cross-linking agent, genipin, to the mixed material obtained in step (1) to cause a cross-linking reaction of the carboxymethyl chitosan to generate cross-linked carboxymethyl chitosan, and after the cross-linking reaction, obtaining a hydrogel in which hyaluronic acid is distributed in the pores of the cross-linked carboxymethyl chitosan;

[0008] (3) the hydrogel obtained in step (2) is subjected to shear thinning after stirring;

[0009] (4) Wrapping the thinned hydrogel obtained in step (3) on the surface of the implantable device, and obtaining the anti-adhesion coating after drying.

[0010] Furthermore, in step (1), the weight ratio of the carboxymethyl chitosan to the hyaluronic acid is (1-6):1.

[0011] Furthermore, in step (2), the weight ratio of carboxymethyl chitosan to cross-linking agent genipin in the mixture is (100-1000):1.

[0012] Furthermore, the cross-linking reaction in step (2) is carried out under heating and stirring conditions, with a stirring speed of 400-600 rpm, a reaction temperature of 60-70° C., a reaction time of 18-24 h, and a pH value greater than 7.

[0013] Furthermore, the cross-linked carboxymethyl chitosan obtained in step (2) has a porous structure; in the obtained hydrogel, hyaluronic acid is filled in the pores of the cross-linked carboxymethyl chitosan.

[0014] Furthermore, the stirring treatment in step (3) is carried out at room temperature, with a stirring speed of more than 800 rpm and a stirring time of 2-10 minutes.

[0015] Furthermore, in step (4), the thinned hydrogel is wrapped on the surface of the implantable device by dipping, spin coating or scraping; during the drying process, the drying temperature is 50 to 80° C. and the drying time is 1.5 to 4.5 hours.

[0016] The implantable device prepared as above with an anti-adhesion coating attached to its surface has excellent biocompatibility and anti-inflammatory properties; when implanted, macrophages, fibroblasts and other cells that easily form fibrous capsules at the device location cannot adhere to the surface of the coating, that is, it has an excellent physical barrier effect and can inhibit the adhesion of platelets.

[0017] The implantable devices include in-body sensors, cardiac pacemakers, artificial joints, vascular stents or urinary catheters, etc.

[0018] The design mechanism of the present invention is as follows:

[0019] The present invention adopts carboxymethyl chitosan and hyaluronic acid, by forming Schiff base bond with genipin and carboxymethyl chitosan to construct coating skeleton, a specific amount of hyaluronic acid is used to fill the pores between the coating skeletons to obtain a hydrogel, forming a state in which hyaluronic acid and cross-linked carboxymethyl chitosan are mutually wrapped, and the ability of its shear thinning is used to change from solid hydrogel to liquid hydrogel after stirring treatment under certain conditions, and it is more convenient to use as an anti-adhesion coating material for implantable devices of different shapes, and a tight package can be formed on the device surface. The materials used by the coating material are all natural products, with excellent biocompatibility, and its own anti-inflammatory properties and smaller rejection reactions can greatly reduce the inflammatory reaction after device implantation. In addition, macrophages, fibroblasts, etc. are easy to form fibrous capsules in the device position. Cells cannot be attached to the coating surface, i.e., physical barrier effects, and platelet adhesion can be suppressed, and can be widely used in the anti-adhesion coating of implantable devices.

[0020] In the present invention, carboxymethyl chitosan is processed with natural polysaccharide (chitosan) as raw material, and the cross-linking agent genipin is obtained with plant extract (derived from gardenia) as raw material. Through a cross-linking reaction under specific conditions and utilizing the shear thinning property of the material, an injectable and coatable anti-adhesion coating for implantable devices is successfully synthesized, and the prepared coating also exhibits excellent biocompatibility and anti-inflammatory ability.

[0021] The advantages and beneficial effects of the present invention are as follows:

[0022] 1. The present invention provides an implantable device with an anti-adhesion coating attached to the surface, which can reduce the adhesion between the implantable device and biological tissue, improve the biocompatibility of the device, reduce complications caused by adhesion, and extend the service life of the implantable device.

[0023] 2. The preparation method of the anti-adhesion coating of the present invention is simple, the process conditions are mild, it is easy to mass produce, and the cost is low, which is conducive to clinical promotion and application.

[0024] 3. The anti-adhesion coating of the present invention has better retention, which is superior to the sodium hyaluronate gel used clinically, and can form a better physical barrier effect around the device.

[0025] 4. The anti-adhesion coating of the present invention applied to the surface of an implanted device can increase the service life of the implanted device and has degradable properties, which can perfectly match the degradable implantable device.

[0026] 5. The anti-adhesion coating of the present invention is suitable for various implantable devices, such as in vivo sensors, cardiac pacemakers, artificial joints, vascular stents, urinary catheters, metal electrodes or polymer packaging layers, and has broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1For infrared spectroscopy analysis.

[0028] Figure 2 The microscopic morphologies of the hydrogels prepared in Example 1 and Comparative Example 1; wherein: (a) Example 1; (b) Comparative Example 1.

[0029] Figure 3 The biocompatibility of the hydrogel prepared in the example; wherein: the left bar graph is the culture medium, and the right bar graph is the culture medium with cCMCS-HA hydrogel added.

[0030] Figure 4 For wrapping of neural electrodes.

[0031] Figure 5 Anti-fibroblast adhesion of cCMCS-HA-attached neural electrodes.

[0032] Figure 6 Anti-macrophage adhesion of neural electrodes attached with cCMCS-HA; wherein: (a) cell culture dish; (b) cCMCS-HA.

[0033] Figure 7 cCMCS-HA-attached neural electrodes promote M2 macrophage polarization.

[0034] Figure 8 Anti-platelet adhesion experiment of neural electrodes attached with cCMCS-HA; wherein: (a) device; (b) coating. DETAILED DESCRIPTION

[0035] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is described in detail below in conjunction with embodiments. The specific embodiments described herein are intended to explain the present invention, but are not intended to limit the present invention.

[0036] The present invention utilizes hyaluronic acid to replace medical sodium hyaluronate to improve the retention and physical barrier duration of the coating, and at the same time introduces carboxymethyl chitosan that can generate negative charges to form repulsive force with the negative charges on the surface of cells to enhance the ability to prevent cell adhesion, thereby reducing the adhesion of implantable devices to tissues and improving the working efficiency and stability of implantable devices.

[0037] The anti-adhesion coating of the present invention is mainly used to prevent the adhesion of implantable devices to surrounding tissues, which is specifically described below through examples.

[0038] Embodiment 1:

[0039] The process of preparing the anti-adhesion coating in this embodiment is as follows:

[0040] 1. Evenly mix carboxymethyl chitosan and hyaluronic acid in a weight ratio of 3:1 to obtain a mixed material;

[0041] 2. Add 0.5% of the weight of carboxymethyl chitosan as a crosslinking agent genipin to the mixed material to cause the carboxymethyl chitosan to undergo a crosslinking reaction and generate a porous crosslinked carboxymethyl chitosan. After the crosslinking reaction is carried out for 20 hours in a system with a pH greater than 7, a hydrogel is obtained; the crosslinking reaction is carried out at 65° C., and stirring is performed while heating at a stirring speed of 500 rpm.

[0042] The obtained hydrogel is called cCMCS-HA hydrogel ( Figure 1 ). In the hydrogel, hyaluronic acid fills the pores of cross-linked carboxymethyl chitosan, such as Figure 2 (a) As shown. The hydrogel has good biocompatibility. Figure 3 shown.

[0043] 3. Stirring the hydrogel obtained in step 2 at room temperature, with a stirring speed of 950 rpm and a stirring time of 5 minutes, so that the hydrogel is shear-thinned by stirring under such conditions;

[0044] 4. Immerse the implantable neural electrode in the diluted hydrogel so that it wraps around the electrode surface, and then dry it at 65° C. for 3 hours to obtain the anti-adhesion coating.

[0045] Figure 4 It is an implantable neural electrode with an anti-adhesion coating on the surface, which can inhibit the adhesion of fibroblasts and macrophages ( Figure 5 , Figure 6 ) and promote the transformation of macrophages into anti-inflammatory M2 macrophages, thereby reducing the inflammatory response ( Figure 7 In addition, the coating can reduce the adhesion of platelets ( Figure 8 ).

[0046] Comparative Example 1:

[0047] The difference from Example 1 is that:

[0048] In step 1, carboxymethyl chitosan and hyaluronic acid are uniformly mixed in a weight ratio of 3:0.3; the other processes are the same as in Example 1.

[0049] The morphology of the hydrogel prepared in this example is as follows Figure 2 As shown in (b), in the hydrogel, hyaluronic acid does not fill the pores of cross-linked carboxymethyl chitosan. After further stirring and wrapping on the surface of the neural electrode, the relatively rigid three-dimensional network structure of the cross-linked carboxymethyl chitosan makes it brittle and cannot form a uniform wrapping on the electrode surface.

[0050] Comparative Example 2:

[0051] The difference from Example 1 is that:

[0052] When the hydrogel obtained in step 2 of Example 1 is directly coated on the surface of the implanted device, or when the stirring parameters in step 3 are lower than 200 Hz, the shear rate or stress cannot reach the level at which the obtained hydrogel becomes thinner, so it is in a solid state and is not suitable for coating. It can only be adhered to the electrode surface after drying into a film, and cannot form a tight fit with the electrode, and cannot be adapted to devices of different shapes.

[0053] The above-described embodiments merely express the implementation methods of the present invention, but they cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that for those skilled in the art, any modifications, improvements, etc. made without departing from the concept of the present invention are all within the scope of protection of the present invention.

Claims

1. An anti-adhesion coating for an implantable device, characterized in that: The method for preparing the anti-adhesion coating comprises the following steps: (1) uniformly blending carboxymethyl chitosan and hyaluronic acid to obtain a mixed material; (2) adding a cross-linking agent, genipin, to the mixed material obtained in step (1) to cause a cross-linking reaction of the carboxymethyl chitosan to generate cross-linked carboxymethyl chitosan, and after the cross-linking reaction, obtaining a hydrogel in which hyaluronic acid is distributed in the pores of the cross-linked carboxymethyl chitosan; (3) the hydrogel obtained in step (2) is subjected to shear thinning after stirring; (4) Wrapping the thinned hydrogel obtained in step (3) on the surface of the implantable device, and obtaining the anti-adhesion coating after drying.

2. The anti-adhesion coating for implantable devices according to claim 1, characterized in that: In step (1), the weight ratio of carboxymethyl chitosan to hyaluronic acid is (1-6):

1.

3. The anti-adhesion coating for implantable devices according to claim 1, characterized in that: In step (2), the weight ratio of carboxymethyl chitosan to cross-linking agent genipin in the mixed material is (100-1000):

1.

4. The anti-adhesion coating for implantable devices according to claim 1, characterized in that: The cross-linking reaction in step (2) is carried out under heating and stirring conditions, with a stirring speed of 400-600 rpm, a reaction temperature of 60-70° C., a reaction time of 18-24 h, and a pH value greater than 7.

5. The anti-adhesion coating for implantable devices according to claim 1, characterized in that: The cross-linked carboxymethyl chitosan obtained in step (2) has a porous structure; in the obtained hydrogel, hyaluronic acid is filled in the pores of the cross-linked carboxymethyl chitosan.

6. The anti-adhesion coating for implantable devices according to claim 1, characterized in that: The stirring treatment in step (3) is carried out at room temperature, with a stirring speed of more than 800 rpm and a stirring time of 2-10 minutes.

7. The anti-adhesion coating for implantable devices according to claim 1, characterized in that: In step (4), the thinned hydrogel is wrapped on the surface of the implantable device by dipping, spin coating or scraping; during the drying process, the drying temperature is 50 to 80° C. and the drying time is 1.5 to 4.5 hours.

8. An implantable device based on the anti-adhesion coating according to any one of claims 1 to 7, characterized in that: The surface of the implantable device is attached with the anti-adhesion coating, which has excellent biocompatibility and anti-inflammatory properties; and cells such as macrophages and fibroblasts that easily form fibrous capsules at the device location cannot adhere to the surface of the coating, that is, it has an excellent physical barrier effect and can inhibit the adhesion of platelets.

9. The implantable device according to claim 8, characterized in that: The implantable devices include in vivo sensors, cardiac pacemakers, artificial joints, vascular stents or urinary catheters, metal electrodes or polymer packaging layers, etc.

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