KR102277536B1 - Anti-biofouling implantable medical device and method of forming anti-biofouling film on surface of implantable medical device - Google Patents

Abstract

The present invention relates to a composition for coating an implantable medical device for preventing biofouling, comprising biocompatible nanoparticles and a water-soluble polymer having a degree of freedom in shape, and an implantable medical device coated with the composition for biofouling and having an anti-biofouling function It relates to a device and a method for manufacturing the same. According to the present invention, the biofouling function can be introduced only by the arrangement of nanoparticles, there is no potential toxicity concern as a physical biofouling prevention function rather than a chemical biofouling prevention function, and a specific compound that goes through complicated steps is not used for synthesis. Since the coating step is simple, it can be usefully used for mass production at low cost.

Description

TECHNICAL FIELD Anti-biofouling implantable medical device and method of forming anti-biofouling film on surface of implantable medical device

The present invention relates to an implantable medical device for preventing biofouling and a method for forming a biofouling film on the surface of an implantable medical device, and more particularly, the present invention relates to biocompatible nanoparticles and a biocompatible polymer having a chain structure It relates to an implantable medical device for preventing biofouling, and a method for forming a biofouling prevention film on the surface of the implantable medical device, comprising:

A tracheostomy tube is a device that creates a bypass passage for breathing in critically ill patients, when self-respiration is impossible due to respiratory infection or tracheal obstruction.

However, the tracheostomy tube often occurs when the tube is occluded by the patient's mucus within a short time, and if the tube replacement or blockage is not resolved immediately, serious brain damage or death may result in the patient. In addition, when replacing the tube due to occlusion, it causes pain to patients or requires an economic burden. Therefore, it is necessary to reduce the pain and economic burden of patients due to frequent replacement by introducing a biofouling prevention function inside the tracheostomy tube.

However, the existing method for removing biofouling has limitations in that it requires complex technology or is expensive to manufacture.

As a conventional technique for removing biofouling, Korean Patent Laid-Open No. 10-2014-0024221 discloses that a butenolide-based compound having an antibacterial, anticancer, or biofouling prevention function is synthesized, and the synthesized compound is used for biofouling prevention function. A method for cleaning a contact lens, a medical device, and the like is disclosed. However, the method has a problem in that it has to go through a complex process of several steps in order to synthesize a compound having an anti-biofouling function.

In addition, Korean Patent Laid-Open No. 10-2011-0074868 discloses a peptide and a composition for preventing cell adhesion and a method of using the same. Specifically, an antibacterial peptide is obtained by fractionation from anemones by liquid chromatography, and the substance It is a technology that introduces a function of preventing biofouling by attaching to a non-living surface, and there is a limit to obtaining an amount for large-area application in that fractionation by liquid chromatography is required to obtain a specific component.

As such, the method for preventing chemical biofouling using a specific compound must go through complicated steps for the synthesis of a specific compound, and there is a possibility that the compound may be toxic in vivo, so it is limited to use in a composition for coating a medical device There is this.

Accordingly, there is a need for a new method capable of safely preventing biofouling of a medical device without exhibiting biotoxicity with a simple method and low cost.

1. Republic of Korea Patent Publication No. 10-2014-0024221 2. Republic of Korea Patent Publication No. 10-2011-0074868

A first object of the present invention is to provide a composition for coating an implantable medical device for preventing biofouling. Another object of the present invention is to provide an implantable medical device having an anti-biofouling function coated with the composition for coating the implantable medical device.

delete

A second object of the present invention is to provide a method for forming an anti-biofouling film on the surface of an implantable medical device.

In order to achieve the first object, the present invention provides an implantable medical device. The implantable medical device includes a tubular medical device; a first coating layer formed by coating at least an inner surface of the tubular medical device with a composition for coating nanoparticles comprising biocompatible nanoparticles and a water-soluble medical binder; A polymer coating composition comprising a chain-structured biocompatible polymer comprises a secondary coating layer formed by being coated on the primary coating layer, wherein some of the biocompatible nanoparticles in the primary coating layer are the medical water-soluble binder The biocompatible polymer of the chain structure of the second coating layer has a degree of freedom of shape by rotation of the CC bond, and the first coating layer forms a random nanopattern with increasing roughness by protruding out of the layer by And by forming the second coating layer together, it has a smaller surface energy compared to the case where the first coating layer and the second coating layer are formed alone, respectively, and freedom of shape by rotation of the roughness and the CC bond Also, due to the anti-biofouling synergistic action of the smaller surface energy, the biofouling prevention rate is greater than the thickness of the layer by the medical water-soluble binder, compared to the case where the second coating layer is formed alone. The size of the biocompatible nanoparticles is larger, the biocompatible nanoparticles are TiO ₂ or bentonite, the biocompatible nanoparticles have a thickness of 100 nm to 10 μm, and the biocompatible polymer of the chain structure is It is characterized in that it is bound to the biocompatible nanoparticles by electrostatic attraction using those charged with the opposite charge to the charge of the nanoparticles.

delete

delete

delete

Also preferably, the biocompatible nanoparticles may be included in an amount of 0.001 to 50 parts by weight based on 100 parts by weight of the total coating composition.

Also preferably, the water-soluble medical binder may be medical polyurethane.

Also preferably, the biocompatible polymer of the chain structure having the degree of freedom in the form is polyethylene glycol (Polyethylene glycol, PEG), cetrimonium bromide (CTAB), (HS(CH ₃ ) ₁₁ (OCH ₂ CH) ₂ ) _n ) _m OH (n is an integer of 1 to 100, m is an integer of 1 to 100) and HS(CH ₃ ) ₁₀ CH ₃ It may be selected from the group consisting of.

Also preferably, the biocompatible polymer of the chain structure having the degree of freedom of the form may be included in an amount of 0.001 to 50 parts by weight based on 100 parts by weight of the total coating composition.

delete

delete

delete

Also preferably, the implantable medical device may be a tracheostomy tube.

In addition, in order to achieve the second object, the present invention provides a method of forming a biofouling prevention film on the surface of an implantable medical device. The method for forming an anti-biofouling film on the surface of an implantable medical device includes immersing the implantable medical device in a composition for coating nanoparticles containing biocompatible nanoparticles and a medical water-soluble binder, or applying the composition for coating nanoparticles into the body. A primary coating step of spraying or coating the device; and immersing the primary coated implantable medical device in a polymer coating composition comprising a biocompatible polymer of a chain structure, or spraying or coating the polymer coating composition on the primary coated implantable medical device 2 Including a primary coating step, in the first coating layer formed by the first coating step, some of the biocompatible nanoparticles protrude out of the layer by the medical water-soluble binder to increase the roughness, and a random nanopattern The biocompatible polymer of the chain structure of the secondary coating layer formed by the secondary coating step has a degree of freedom of shape by rotation of the CC bond, and biofouling having the first coating layer and the second coating layer By forming an anti-fouling film, the biofouling film has a smaller surface energy compared to the case where the first coating layer and the second coating layer are each formed alone, and the roughness and freedom of shape by rotation of the CC bond Also, due to the anti-biofouling synergistic action of the smaller surface energy, compared to the case in which the second coating layer is formed alone, the biofouling prevention rate of the biofouling prevention film is greater.

In addition, preferably, the size of the biocompatible nanoparticles is larger than the thickness of the layer by the medical water-soluble binder, and the biocompatible nanoparticles are TiO ₂ or bentonite.

According to the present invention, the biofouling function can be introduced only by the arrangement of nanoparticles, there is no potential toxicity concern as a physical biofouling prevention function rather than a chemical biofouling prevention function, and a specific compound that goes through complicated steps is not used for synthesis. Since the coating step is simple, it can be usefully used for mass production at low cost.

1 is a schematic diagram of an implantable medical device having a biofouling prevention function according to an embodiment of the present invention.
2 is a schematic diagram of an implantable medical device having a biofouling prevention function according to another embodiment of the present invention.
3 is a flowchart illustrating a method of manufacturing an implantable medical device having a biofouling prevention function according to an embodiment of the present invention.
4 is a schematic diagram showing a step of first coating nanoparticles in a method for manufacturing an implantable medical device having a biofouling prevention function according to an embodiment of the present invention.
5 is a schematic diagram showing the step of secondarily coating a biocompatible polymer of a chain structure in the method for manufacturing an implantable medical device having a biofouling prevention function according to an embodiment of the present invention.
6 is a photograph of the inner surface of an implantable medical device (medical tube) coated with _{TiO 2} nanoparticles according to an embodiment of the present invention observed with a scanning electron microscope.
7 is a photograph showing the coating layer thickness of the inner surface of the implantable medical device (medical tube) coated with _{TiO 2} nanoparticles according to an embodiment of the present invention _{((a) TiO 2} nanoparticles + PU binder coating layer, ( b) PU binder coating layer).
8 is a photograph and graph showing the roughness of the inner surface of an implantable medical device (medical tube) coated with _{TiO 2} nanoparticles according to an embodiment of the present invention ((a) PU medical tube, (b) PU binder Coating layer, (c) TiO ₂ nanoparticles + PU binder coating layer).
Figure 9 is showing the biological fouling prevention rate in the case where in the body implantable medical device having a bio fouling prevention according to one embodiment of the invention, the double coated with TiO ₂ nanoparticles alone coating and TiO ₂ nanoparticles with PEG polymer It is a graph.
10 is a graph showing the biofouling prevention rate in the case of a single coating of bentonite nanoparticles and a double coating of bentonite nanoparticles and a PEG polymer in an implantable medical device having a biofouling prevention function according to an embodiment of the present invention; to be.
11 is an implantable medical device (medical tube) according to an embodiment of the present invention, showing the results of evaluating the anti-biofouling effect in the tube according to the presence or absence of a coating composition for preventing biofouling by the impregnation method and the circulation method; It is a graph ((a) impregnation method, (b) circulation method).

Hereinafter, embodiments according to the present invention will be described in detail with reference to the accompanying drawings.

While the present invention is susceptible to various modifications and variations, specific embodiments thereof are illustrated and shown in the drawings and will be described in detail hereinafter. However, it is not intended to limit the invention to the particular form disclosed, but rather the invention includes all modifications, equivalents and substitutions consistent with the spirit of the invention as defined by the claims.

The present invention provides a composition for coating an implantable medical device for preventing biofouling.

The present inventors have been studying a method for safely preventing biofouling without exhibiting biotoxicity at low cost and in a simple method and at low cost in an implantable medical device, such as a medical tube, and biocompatible nanoparticles such as _{titanium dioxide (TiO 2 )} When dip-coating with a coating solution containing a polyurethane binder and a polyurethane binder, it has the effect of patterning due to the random arrangement of nanoparticles, and it has been found that the adhesion of biofouling substances is reduced due to the reduction of surface energy by patterning of these nanoparticles, and , the present invention was completed.

Accordingly, it is a feature of the present invention to provide a composition for coating an implantable medical device for preventing biofouling, comprising biocompatible nanoparticles and a medical water-soluble binder.

The biocompatible nanoparticles can be used as long as they are nanoparticles that do not show toxicity in vivo, for example, TiO ₂ or bentonite.

The size of the biocompatible nanoparticles is preferably greater than the thickness of the binder layer in order to exhibit the effect of nanopatterning, and for this purpose, the thickness of the biocompatible nanoparticles is preferably 100 nm to 10 μm, but limited thereto it's not going to be

The biocompatible nanoparticles may be included in an amount of 0.001 to 50 parts by weight based on 100 parts by weight of the total coating composition, so it is preferable to maximize the effect of nanopatterning when included within this range, and if the nanoparticles are 50 parts by weight When the amount is exceeded, nanoscale surface patterning may not be generated due to agglomerate of nanoparticles, and uniform mixing with a medical water-soluble binder becomes difficult, so that nanoparticles may be easily detached.

The water-soluble medical binder should have strong resistance to water after curing and should have biocompatibility. In addition, it should be suitable for the surface of the tube to be coated so that the biocompatible nanoparticles can be well attached to the curved surface. The water-soluble binder may include, but is not limited to, medical grade polyurethane.

In addition, the composition for coating according to the present invention may further include a biocompatible polymer having a chain structure having a degree of freedom in shape.

Since the biocompatible polymer of the chain structure has a degree of freedom in shape due to rotation of the C-C bond, it may not be easily attached even if a biofouling material approaches, or the attached biofouling material may be easily removed. Accordingly, it is possible to obtain a synergistic effect by increasing the functional effect of preventing biofouling when combined with the surface patterning of nanoparticles.

The biocompatible polymer of such a chain structure is polyethylene glycol (PEG), cetrimonium bromide (CTAB), (HS(CH ₃ ) ₁₁ (OCH ₂ CH ₂ ) _n ) _m OH (n is 1 An integer of ~100, m is an integer of 1-100) and HS(CH ₃ ) ₁₀ CH ₃ It may be selected from the group consisting of.

In addition, since the biocompatible polymer of the chain structure is coupled to the nanoparticles by electrostatic attraction, it is preferable to use a charge opposite to the charge of the nanoparticles. For example, when the nanoparticles _{are used as TiO 2} and the biocompatible polymer is _{used as PEG, since TiO 2} has a negative charge, the PEG used has an amine group bonded to the terminal so as to have a positive charge as a whole. It is preferable to use

Also preferably, the biocompatible polymer of the chain structure may be included in an amount of 0.001 to 50 parts by weight based on 100 parts by weight of the total coating composition. If the biocompatible polymer of the chain structure is used in excess outside of this range, unnecessary material cost increases, and the biocompatible polymer of the chain structure is attached too tightly, thereby limiting the degree of freedom in the form of the chain structure. Therefore, there may be a problem that the effect of preventing biofouling is lowered.

In addition, the present invention provides an implantable medical device having an anti-biofouling function, coated on the surface with the coating composition for preventing biofouling.

1 and 2 are schematic diagrams of an implantable medical device having a biofouling prevention function according to an embodiment of the present invention.

Referring to FIG. 1 , the implantable medical device having a biofouling prevention function according to the present invention includes biocompatible nanoparticles 10 and medical water solubility on the inner surface of the implantable medical device, for example, a medical tube 30 . The coating composition including the binder 20 may be in a coated form.

The implantable medical device having an anti-biofouling function according to the present invention has the effect of patterning due to the random arrangement of the biocompatible nanoparticles, and the adhesion of the biofouling material due to the reduction of surface energy due to the patterning of the nanoparticles Biofouling can be prevented by reducing

Descriptions of the biocompatible nanoparticles 10 and the water-soluble medical binder 20 are the same as those described in the coating composition, and thus are omitted to avoid overlapping descriptions.

In this case, the implantable medical device 30 may be a tube used for medical purposes, preferably a tracheostomy tube.

In addition, in the implantable medical device having an anti-biofouling function according to the present invention, a coating composition comprising biocompatible nanoparticles and a medical water-soluble binder is applied to the inner surface of the implantable medical device in order to increase the functional effect of preventing biofouling. It may be prepared in a form in which a coating composition is first coated on the first coating, and a coating composition comprising a biocompatible polymer having a chain structure having a degree of freedom in shape is secondarily coated on the first coating.

If the biocompatible nanoparticles, medical water-soluble binder, and the biocompatible polymer of a chain structure are mixed and coated at once, the biocompatible polymer of the chain structure reacts with the binder first and is coated in a state trapped inside the binder or , since there is a problem in that it cannot be evenly distributed on the surface, it is preferable to proceed with coating of the biocompatible polymer of the chain structure after the coating of the nanoparticles firstly.

In this case, as shown in FIG. 2, the biocompatible polymer 40 of the chain structure is attached to the nanoparticles through electrostatic bonding with the nanoparticles 10, and the biocompatible polymer of the attached chain structure is attached. Since the C-C bond has a degree of freedom in shape, it cannot be easily attached even when a biofouling material approaches, or the attached biofouling material is easily peeled off, so it is possible to increase the functional effect of preventing biofouling.

Since the description of the biocompatible polymer 40 of the chain structure is the same as that described in the coating composition, it is omitted to avoid overlapping description.

In addition, the present invention provides a method for manufacturing an implantable medical device having a biofouling prevention function.

3 is a flowchart illustrating a method of manufacturing an implantable medical device having a biofouling prevention function according to an embodiment of the present invention.

4 is a schematic diagram showing the step of first coating nanoparticles in the method for manufacturing an implantable medical device having a biofouling prevention function according to an embodiment of the present invention.

3 and 4, the method for manufacturing an implantable medical device having an anti-biofouling function according to the present invention is a composition for coating nanoparticles comprising biocompatible nanoparticles and a medical water-soluble binder. and coating (S10).

At this time, the composition for coating nanoparticles is as described above, and the coating method is performed by immersing the implantable medical device in the composition for coating nanoparticles, or spraying or coating the composition for coating nanoparticles on the implantable medical device. can do.

In addition, in order to increase the anti-biofouling functional effect, the secondary coating step (S20) is further performed with a polymer coating composition comprising a chain structure biocompatible polymer in addition to the first coated body implantable medical device. can

5 is a schematic diagram showing the step of secondarily coating a biocompatible polymer of a chain structure in the method for manufacturing an implantable medical device having a biofouling prevention function according to an embodiment of the present invention.

At this time, the composition for coating the biocompatible polymer of the chain structure is the same as described above, and the coating method is to immerse the first coated body implantable medical device in the composition for coating the biocompatible polymer of the chain structure, or the chain structure It can be carried out by spraying or coating the composition for coating the biocompatible polymer of the first coated body implantable medical device.

Hereinafter, a preferred preparation example (example) is presented to help the understanding of the present invention. However, the following preparation examples are only for helping understanding of the present invention, and the present invention is not limited by the following preparation examples.

< manufacturing example 1> Manufacture of implantable medical device (medical tube) with biofouling prevention function

(One) TiO ₂ Preparation of nanoparticle coating solution

50 g of TiO ₂ nanoparticles were dispersed in 125 mL of distilled water in TiO ₂ suspension, and 375 mL of a water-soluble polyurethane binder containing 35% polyurethane was mixed and then mixed at 3000 rpm for 30 minutes using a homogenizer. Thus, a coating solution for patterning nanoparticles was prepared.

(2) Coating the inner surface of the medical tube with a nanoparticle coating solution

As a medical tube, a polyurethane tube, which is typically used for medical purposes, was used, and in order to pattern the surface of only the inside of the medical tube with nanoparticles, the outside of the tube was wrapped with Teflon tape that is easy to remove later.

Thereafter, using a dip coater, the coating solution for patterning the nanoparticles is dip-coated inside the medical tube at a coating speed of 1.0 mm/s, and then dried in an oven at 100° C. for 30 minutes for curing of the polyurethane binder for biofouling. A medical tube (T@PU) with an preventive function was prepared.

< manufacturing example 2> Manufacture of medical tube with anti-biofouling function

(1) Preparation of nanoparticle coating solution

50 g of TiO ₂ nanoparticles were dispersed in 125 mL of distilled water in TiO ₂ suspension, and 375 mL of a water-soluble polyurethane binder containing 35% polyurethane was mixed and then mixed at 3000 rpm for 30 minutes using a homogenizer. Thus, a coating solution for patterning nanoparticles was prepared.

(2) Primary coating with nanoparticle coating solution in medical tube

As a medical tube, a polyurethane tube, which is typically used for medical purposes, was used, and in order to pattern the surface of only the inside of the medical tube with nanoparticles, the outside of the tube was wrapped with Teflon tape that is easy to remove later.

Thereafter, the coating solution for patterning the nanoparticles was dip-coated inside the medical tube at a coating speed of 1.0 mm/s using a dip coater, and then dried in an oven at 100° C. for 30 minutes for curing of the polyurethane binder.

(3) Preparation of PEG coating solution

PEG-Amine (MW5000) was dissolved in distilled water to a concentration of 0.1 mg/mL to prepare a PEG coating solution.

(4) Secondary coating with PEG coating solution in medical tube

In a dip coater containing the prepared PEG coating solution, put the nanoparticle patterned tube inside the tube and dip coating at a speed of 0.05 mm / s to coat the PEG coating solution a second time, then 30 in an oven at 100 ° C. It was dried for a minute to prepare a medical tube having a biofouling prevention function.

< manufacturing example 3-4> Manufacture of medical tube with anti-biofouling function

A medical tube having a biofouling prevention function was prepared in the same manner as in Preparation Examples 1 and 2, except that 1% bentonite was used instead of TiO _{2 as nanoparticles.}

< comparative example 1>

An uncoated medical tube (bare PU) was used.

< comparative example 2>

A medical tube (PU@PU) coated with medical polyurethane alone was prepared.

< Experimental example 1> Surface morphology and coating layer thickness measurement

After cutting the medical tube prepared in Preparation Example 1, Comparative Example 1 and Comparative Example 2 to a length of 1 cm using a scalpel, one is attached to the sample holder so that the cross-section of the cut tube is visible, and the other is the surface was attached to the sample holder so that it was visible.

Next, Pt/Pd was coated on the sample surface for 60 seconds, and then surface and cross-sectional images were measured using a scanning electron microscope (FEG Quanta 250, FEI) and shown in FIGS. 6 and 7, respectively, and an atomic force microscope ( The surface roughness was measured using AFM; NX-10) and is shown in FIG. 8 .

6 is a photograph of the inner surface of a medical tube coated with _{TiO 2} nanoparticles according to an embodiment of the present invention observed with a scanning electron microscope.

As shown in FIG. 6 , _{it can be seen that spherical TiO 2} nanoparticles are relatively uniformly distributed on the surface.

Figure 7 is a photograph showing the coating layer thickness of the inner surface of the medical tube coated with _{TiO 2} nanoparticles according to an embodiment of the present invention _{, in this case (a) is TiO 2} nanoparticles + PU binder coating layer of Preparation Example 1 , (b) represents the PU binder coating layer of Comparative Example 2.

_{7, the thickness of the coating layer coated with TiO 2} nanoparticles according to the present invention was 4.49 μm, and a thicker coating film was formed due to the nanoparticles compared to the PU binder coating layer (2.3 μm). It is thought that the thickening of the coating film makes a relatively thick layer by the presence of inorganic particles improving the viscosity during dip coating. However, since _{the thickness of the TiO 2} coating film was formed to be less than 10 μm, this coating film is mechanically flexible, and thus can be applied in various fields.

Meanwhile, despite the presence of inorganic nanoparticles _{, the coating layer coated with TiO 2} nanoparticles according to the present invention was formed to a uniform thickness by dip coating. It is considered that since TiO ₂ nanoparticles have a spherical shape, small particle size, and uniform dispersion, they were uniformly dispersed in the coating solution and well dispersed throughout the coating layer.

This indicates that the coating method of the present invention has the potential to be usefully applied to mass production.

_{8 is a photograph and graph showing the roughness of the inner surface of a medical tube coated with TiO 2} nanoparticles according to an embodiment of the present invention, wherein (a) is a PU medical tube of Comparative Example 1, (b) is It shows the PU binder coating layer of Comparative Example 2, (c) shows the TiO ₂ nanoparticles + PU binder coating layer of Preparation Example 1.

As shown in Figure 8, the PU medical tube (a) without coating does not show any special protrusions, so the surface roughness value (Ra) is 2.83 nm, which is a very low value, and when only the PU binder is coated (b) ), the Ra value was relatively low at 4.63 nm. However, according to an embodiment of the present invention, _{when coated with TiO 2} nanoparticles (c), it was clearly observed that the nanoparticles were randomly distributed on the surface, through which most of the particles were located in the PU binder matrix, It was found to partially protrude outward to form random nanopatterns. And the surface roughness value (Ra) was 14.07 nm, and it was confirmed that the surface roughness value was significantly increased compared to the PU medical tube without coating (a) and the PU medical tube coated with only the PU binder (b).

This increase in surface roughness suppresses adhesion of biofouling materials, thereby improving the anti-biofouling effect.

< Experimental example 2> Toxicity evaluation in cell lines

In order to find out whether the composition for medical coating according to the present invention is toxic to the body, the following experiment was performed.

Specifically, a human bronchial epithelial cell line was cultured so that the 50,000 cell / mL to (Human bronchical epitehlial cell, BEAS- 2B), into the cultured cells in each 100 μL 96 well plate incubated at 37 ℃ CO ₂ incubator for 24 hours did.

_{Next, the concentration of the coating composition containing the TiO 2} nanoparticles of Preparation Example 1 and the coating composition containing the PU binder of Comparative Example 2 in the cultured cell is 1,000, 500, 250, 100, 50, 25, 10 , 5, 1 and 0.1 μg/mL of the prepared suspensions were treated and cultured for 24 hours, and only cells not treated with nanoparticles were cultured as a control.

After 24 hours of incubation, remove the nanoparticle suspension and wash twice with Phosphate buffered saline (PBS) solution. After washing, put 200 μL of cell culture solution into each well, and add 20 μL of EZ-cytox reagent. incubated for hours.

For comparison, 200 µL of cell culture medium and 20 µL of EZ-cytox solution were put into a clean well where cells were not cultured and used as a blank.

After incubation, the cells were shaken for 5 minutes using a shaker, absorbance was measured at 450 nm using a microplate reader, and the cell viability (IC ₅₀ ) was calculated using Equation 1 below.

[Equation 1]

The results are shown in Table 1 below.

division IC ₅₀ (μg/mL) Preparation Example 1 161.5 Comparative Example 2 3,212

As shown in Table 1, the medical PU binder and TiO ₂ nanoparticles have IC ₅₀ of 3,212 μg/mL and 161.5 μg/mL, respectively, indicating that they do not exhibit biotoxicity, are safe, and have biocompatibility. , Accordingly, the coating composition according to the present invention can be usefully used in medical devices.

< Experimental example 3> Measure surface energy

Surface energy is one of the important factors affecting biofouling, and the low surface energy of the coating layer prevents adsorption of biofouling such as liquid.

Accordingly, the surface energy of the coating layer coated with the coating composition was measured in order to examine the biofouling prevention effect of the coating composition of the present invention.

Specifically, 3 μL of 3 different solvents (water, ethylene glycol, liquid diiodomethane) were dropped on the film surface, and then the contact angle was measured using a contact angle meter (SDS-TEZD, FEMTOFAB, Seongnam, Korea). did.

The surface energy of the coated film was calculated according to Equation 2 below based on the Lifshitz-van der Waals and Lewis acid-base method.

[Equation 2]

(In the above formula,

θ is the contact angle,

i is the solvent number,

γ is the surface energy,

LW is a Lifshitz-van der Waals interaction, including London dispersion, Keesom dipole-dipole and Debye induction,

AB is a Lewis acid-base interaction,

γ ⁺ is a Lewis acid (electron acceptor),

γ ^- is a Lewis base (electron donor).

The calculation results are shown in Table 2 below.

division Comparative Example 2 (PU@PU) Preparation Example 1 (T@PU) contact angle water (distilled water) 70.5° 76.1° ethylene glycol 49.0° 53.3° liquid diiodomethane 30.1° 33.6° surface energy γ ⁺ (mJ/m ² ) 6.83 7.80 γ ^- (mJ/m ² ) 0.67 0.81 γ ^AB (mJ/m ² ) 4.28 5.03 γ ^LW (mJ/m ² ) 69.2 63.8 γ ^sv (mJ/m ² ) 73.5 68.8

^{As shown in Table 2, the final surface energy (γ sv} ) of the coating layer coated with the composition for coating nanoparticles according to the present invention is 68.8 mJ/m ² , compared to the coating layer coated with the PU binder (73.5 mJ/m ^{2 )} It was found that the surface energy was reduced.

Therefore, the composition for coating according to the present invention can suppress the adhesion of biofouling materials by reducing surface energy by nanoparticle patterning, thereby exhibiting an effect of preventing biofouling.

< Experimental example 4> Biofouling prevention rate evaluation test

The biofouling effect of the composition for coating a medical device according to the present invention was evaluated in the following way.

Specifically, mucin was used as a biofouling material, and 10 g of mucin was dissolved in 100 mL distilled water to prepare a 10% mucin solution.

After that, the medical tube prepared in Preparation Example 1, Preparation Example 2, Preparation Example 3, Preparation Example 4, and Comparative Example 1 as a control was cut to a length of 1 cm using a scalpel, and then the coated surface of the sample was coated with a 10% mucin solution. After immersing in the oven, it was put in an oven at 37° C. for 90 minutes and left to stand, and then, after staining the coated surface with Alcian Blue, a dyeing reagent, in order to dissolve the Alcian Blue dyed in the remaining mucin, 30% H ₂ O ₂ Samples were placed in 3 mL of the solution and sonicated for 30 minutes.

Thereafter, 200 μL of a solution from each sample was placed in a 96 well plate and absorbance was measured at UV wavelength 495 nm using a microplate reader to calculate the OD (Optical Density) value, and the results are shown in FIGS. 9 and 10 indicated.

Figure 9 is showing the biological fouling prevention rate in the case where in the body implantable medical device having a bio fouling prevention according to one embodiment of the invention, the double coated with TiO ₂ nanoparticles alone coated with TiO ₂ nanoparticles with PEG polymer It is a graph, and FIG. 10 is a graph showing the biofouling prevention rate in the case of single coating of bentonite nanoparticles and double coating of bentonide nanoparticles and PEG polymer.

9 and 10, when the coating composition comprising biocompatible nanoparticles and a medical water-soluble binder according to the present invention is first coated on the inner surface of an implantable medical device, 70 due to nanopatterning % of the biofouling prevention effect was shown, and in the case of double coating with nanoparticles and PEG polymer, the biofouling prevention effect was increased to about 96%.

Therefore, the coating composition according to the present invention can suppress the adhesion of biofouling substances by the nanoparticle patterning and the polymer of the chain structure, thereby exhibiting the biofouling prevention effect.

In addition, in order to find out the effect of preventing biofouling of the medical tube coated according to the present invention, an experiment was performed using the impregnation method and the circulation method.

(a) impregnation

50 g of mucin was dissolved in 450 mL of distilled water and 50 mL of alcian blue was mixed to prepare a mucin alcian blue mixed solution.

Next, the mucin alcian blue mixed solution was filled in the medical tubes prepared in Preparation Example 2 and Comparative Example 1 as a control, and both ends were sealed using Parafilm. Thereafter, the tubes filled with the mucin alcian blue mixed solution were placed in an oven at 37° C. for 90 minutes and left to stand, then the mucin alcian blue mixed solution was removed, and 2 mL of Phosphate Buffer Saline (PBS) was used. After washing, it was dried while standing at room temperature.

Next, in order to dissolve the residual mucin Alcian Blue in the tube, a tube cut to a length of 1 cm was placed in 3 mL of a _{30% H 2} O _{2 solution and sonicated for 30 minutes.}

Thereafter, 200 μL of a solution from each sample was placed in a 96 well plate and absorbance was measured at UV wavelength 495 nm using a microplate reader to calculate the OD (Optical Density) value, and the result is shown in FIG. 11(a). indicated.

(b) cycle method

Preparation Example 2, as a control, the mucin alcian blue mixed solution inside the medical tubes prepared in Comparative Example 1 was circulated at 37° C. for one week using a tube peristaltic pump. Thereafter, the mucin alcian blue mixed solution was removed, washed with 2 mL of phosphate buffer (PBS), and dried while standing at room temperature.

Next, in order to dissolve the residual mucin Alcian Blue in the tube, a tube cut to a length of 1 cm was placed in 3 mL of a _{30% H 2} O _{2 solution and sonicated for 30 minutes.}

Thereafter, 200 μL of a solution from each sample was placed in a 96 well plate and absorbance was measured at UV wavelength 495 nm using a microplate reader to calculate the OD (Optical Density) value, and the result is shown in FIG. 11(b). indicated.

11 is a diagram illustrating the effect of preventing biofouling in the tube according to the presence or absence of a coating composition for preventing biofouling in the implantable medical device (medical tube) according to an embodiment of the present invention (a) impregnation method and (b) circulation method It is a graph showing the evaluation result.

11, the coating composition comprising biocompatible nanoparticles and a medical water-soluble binder according to the present invention is primarily coated on the inner surface of the implantable medical device, and the degree of freedom of shape on the primary coating A medical tube coated with a coating composition containing a biocompatible polymer of a chain structure having a (a) impregnation method is 88.9%, ( b) When evaluated by the circulation method, it showed an effect of preventing biofouling of 82.0%.

Therefore, the implantable medical device coated with the coating composition according to the present invention exhibits an excellent anti-biofouling effect, has a simple manufacturing method, and can be mass-produced, so it can be usefully used instead of conventionally used medical devices .

Although the present invention has been described above with reference to preferred embodiments, it should be understood that the present invention is not limited to these embodiments. The present invention can variously change and modify the above embodiments within the scope of the claims described below, all of which fall within the scope of the present invention. Accordingly, the invention is limited only by the claims and their equivalents.

10: nanoparticles
20: water-soluble binder
30: implantable medical device (tube)
40: biocompatible polymer of chain structure

Claims (14)

tubular medical devices;
a first coating layer formed by coating at least an inner surface of the tubular medical device with a composition for coating nanoparticles comprising biocompatible nanoparticles and a water-soluble medical binder;
A polymer coating composition comprising a biocompatible polymer of a chain structure is coated on the first coating layer to include a secondary coating layer,
Some of the biocompatible nanoparticles in the first coating layer protrude out of the layer by the medical water-soluble binder to increase the roughness and form a random nanopattern,
The biocompatible polymer of the chain structure of the secondary coating layer has a degree of freedom of shape by rotation of the CC bond,
By forming the first coating layer and the second coating layer together, it has a smaller surface energy compared to the case where the first coating layer and the second coating layer are formed alone, respectively,
Due to the roughness, the degree of freedom of shape by rotation of the CC bond, and the anti-biofouling synergistic action of the smaller surface energy, compared to the case where the secondary coating layer is formed alone, the biofouling prevention rate is increased bigger,
The size of the biocompatible nanoparticles is larger than the thickness of the layer by the medical water-soluble binder, the biocompatible nanoparticles are TiO ₂ or bentonite, and the biocompatible nanoparticles have a thickness of 100 nm to 10 μm, and ,
The biocompatible polymer of the chain structure is an insertable type for preventing biofouling, characterized in that it is bound to the biocompatible nanoparticles by electrostatic attraction using a charge opposite to the charge of the nanoparticles. Medical Equipment.
delete delete delete According to claim 1,
The biocompatible nanoparticle is an implantable medical device for preventing biofouling, characterized in that it is contained in an amount of 0.001 to 50 parts by weight based on 100 parts by weight of the coating composition.
According to claim 1,
The medical water-soluble binder is an implantable medical device for preventing biofouling, characterized in that the medical polyurethane.
The method of claim 1,
The biocompatible polymer of the chain structure having the degree of freedom of the form is polyethylene glycol (PEG), cetrimonium bromide (CTAB), (HS(CH ₃ ) ₁₁ (OCH ₂ CH ₂ ) _n ) _m OH (n is an integer from 1 to 100, m is an integer from 1 to 100) and HS (CH ₃ ) ₁₀ CH _{3 An} implantable medical device for preventing biofouling, characterized in that it is selected from the group consisting of.
The method of claim 1,
The biocompatible polymer of the chain structure having the degree of freedom of the form is an implantable medical device for preventing biofouling, characterized in that it is contained in an amount of 0.001 to 50 parts by weight based on 100 parts by weight of the coating composition.
delete delete delete The method of claim 1,
The implantable medical device is an implantable medical device for preventing biofouling, characterized in that it is a tracheostomy tube.
A first coating step of immersing an implantable medical device in a composition for coating nanoparticles containing biocompatible nanoparticles and a medical water-soluble binder, or spraying or coating the composition for coating nanoparticles on an implantable medical device; and
A secondary method of immersing the first-coated implantable medical device in a polymer coating composition containing a biocompatible polymer of a chain structure, or spraying or coating the polymer coating composition on the primary coated implantable medical device coating step;
In the first coating layer formed by the first coating step, some of the biocompatible nanoparticles protrude out of the layer by the medical water-soluble binder to increase the roughness and form a random nanopattern,
The biocompatible polymer of the chain structure of the secondary coating layer formed by the secondary coating step has a degree of freedom of shape by rotation of the CC bond,
By forming an anti-biofouling film having the primary coating layer and the secondary coating layer, the biofouling film has a smaller surface energy, compared to the case where the primary coating layer and the secondary coating layer are each formed alone,
Due to the roughness, the degree of freedom of shape by rotation of the CC bond, and the anti-biofouling synergistic action of the smaller surface energy, in contrast to the case where the secondary coating layer is formed alone, the A method of forming an anti-biofouling film on the surface of an implantable medical device, characterized in that the biofouling prevention rate is higher.
14. The method of claim 13,
The size of the biocompatible nanoparticles is larger than the thickness of the layer by the medical water-soluble binder,
The biocompatible nanoparticles are TiO ₂ or a method of forming an anti-biofouling film on the surface of an implantable medical device, characterized in that the bentonite.

Images