Instrument for use in blood vessel, and coating agent

Abstract

Provided are an instrument and a coating agent for use in blood vessels, which can be stably supplied, have excellent suppression of thrombus formation, and are unlikely to inhibit vascular endothelialization.　The instrument according to the present invention comprises a base material and a coating layer that covers at least a part of the surface of the base material, and is intended to be used in a blood vessel. The coating layer has a monomolecular layer formed by treating the surface of the base material with a low-molecular-weight compound having a functional group such as an albumin-binding functional group, and satisfies at least one of predetermined requirements.

Description

Intravascular devices and coating agents

[0001] The present invention relates to an instrument for use in a blood vessel and a coating agent.

[0002] The substrates constituting medical devices used in blood vessels, such as stents, are generally made of metal, which poses the problem of inducing thrombus formation when the device is left in the blood vessel for a long period of time. In response to this problem, an intravascular stent has been disclosed that aims to suppress thrombus formation by coating the substrate with a biocompatible polymer (for example, Patent Document 1).

[0003] Furthermore, in order to promote healing after placement, it is important that the medical device is quickly covered with vascular endothelial cells (vascular endothelialization).

[0004] Patent No. 5463513

[0005] There are also stents whose substrates are coated with polymers containing structural units derived from 2-methacryloyloxyethyl phosphorylcholine (MPC), which are biocompatible polymers that suppress thrombus formation, but these have the problem of being difficult to induce vascular endothelialization.

[0006] There are also medical devices in which the substrate is surface treated with a silane coupling agent as a primer and then coated with heparin molecules. This medical device has a high ability to suppress thrombus formation and is not likely to inhibit vascular endothelialization, but because it uses naturally derived heparin (such as porcine heparin) as a raw material, there has been the problem of supply being limited due to social conditions.

[0007] The present invention has been made in consideration of the above-mentioned problems, and aims to provide an instrument and a coating agent for use in blood vessels that are easy to supply stably, have excellent thrombus formation suppression ability, and are not likely to inhibit vascular endothelialization.

[0008] As a result of extensive research into solving the above problems, the present inventors have found that the above problems can be solved simply by treating the surface of a substrate with a low molecular weight compound having a functional group such as an albumin-binding functional group to form a monomolecular layer, thereby completing the present invention. Specifically, the present invention provides the following.

[0009] A first aspect of the present invention is an intravascular device comprising a substrate and a coating layer covering at least a portion of the surface of the substrate, wherein the coating layer has a monolayer formed by surface treating the substrate with a low-molecular-weight compound having an albumin-binding functional group, and the device satisfies at least one of the following (1) to (3): (1) the coating layer has the monolayer as the outermost surface and does not have a polymer layer on the surface side of the monolayer; (2) the average thickness of the coating layer is 30 nm or less; and (3) at least one of the Si element ratio and the P element ratio of the coating layer surface measured by X-ray photoelectron spectroscopy is 0.5 atm% or more.

[0010] A second aspect of the present invention is an intravascular device comprising a substrate and a coating layer covering at least a portion of the surface of the substrate, wherein the coating layer has a monomolecular layer formed by surface treating the substrate with a low-molecular compound having at least one functional group selected from the group consisting of an amino group, a halogen group, a carboxy group, and an alkyl group, and the device satisfies at least one of the following (1) to (3): (1) the coating layer has the monomolecular layer on the outermost surface, and does not have a polymer layer on the surface side of the monomolecular layer; (2) the average thickness of the coating layer is 30 nm or less; and (3) at least one of the Si element ratio and the P element ratio of the coating layer surface measured by X-ray photoelectron spectroscopy is 0.5 atm% or more.

[0011] A third aspect of the present invention is a coating agent containing a low molecular weight compound having an albumin-binding functional group, which is used in the production of the device of the first aspect.

[0012] A fourth aspect of the present invention is a coating agent containing a low molecular weight compound having at least one functional group selected from the group consisting of an amino group, a halogen group, a carboxy group, and an alkyl group, the coating agent being used in the production of the device of the second aspect.

[0013] According to the present invention, it is possible to provide an instrument and a coating agent for use in blood vessels that can be easily supplied stably, have excellent thrombus formation suppression ability, and are less likely to inhibit vascular endothelialization.

[0014] Graph showing the results of a thrombosis test in an example. Graph showing the results of a thrombosis test in an example. Graph showing the results of a thrombosis test in an example. Graph showing the results of a thrombosis test in an example. Graph showing the results of a thrombosis test in an example. Graph showing the results of a thrombosis test in an example. Graph showing the results of a thrombosis test in an example. Graph showing the results of a thrombosis test in an example. Graph showing the results of a thrombosis test in an example. Graph showing the results of a thrombosis test in an example. Graph showing the results of a thrombosis test in an example. Graph showing the results of a thrombosis test in an example. Graph showing the results of a thrombosis test in an example. Graph showing the results of a thrombosis test in an example. Graph showing the results of a thrombosis test in an example. Graph showing the results of a thrombosis test in an animal body in an example.

[0015] Hereinafter, embodiments of the present invention will be described in detail, but the present invention is not limited to the following embodiments and can be implemented with appropriate modifications within the scope of the object of the present invention.

[0016] <<Device>> The device according to the present invention comprises a substrate and a coating layer covering at least a portion of the surface of the substrate. The coating layer has a monomolecular layer formed by surface treating the substrate with a low-molecular compound having an albumin-binding functional group. The device satisfies at least one of the following (1) to (3): (1) the coating layer has a monomolecular layer on the outermost surface, and does not have a polymer layer on the surface side of the monomolecular layer; (2) the average thickness of the coating layer is 30 nm or less; and (3) at least one of the Si element ratio and the P element ratio of the coating layer surface measured by X-ray photoelectron spectroscopy is 0.5 atm% or more.

[0017] As described above, the present inventors have discovered that by simply treating the surface of a substrate with a low-molecular-weight compound having an albumin-binding functional group to form a monolayer, even without providing a polymer layer on the surface side of the monolayer, an instrument can be obtained that exhibits excellent thrombus formation inhibitory ability and is less likely to inhibit vascular endothelialization. The above conditions (1) to (3) represent the characteristics of the present invention. While the reason for this effect is not entirely clear, it is presumed that the albumin-binding functional group exposed on the outermost surface of the coating layer adsorbs albumin in the blood, and the surface of the instrument is first coated with albumin, making it difficult for coagulation proteins to adsorb to the surface of the instrument, thereby inhibiting thrombus formation and making it less likely to inhibit vascular endothelialization.

[0018] In condition (2), the average thickness of the coating layer is 30 nm or less, preferably 20 nm or less, more preferably 10 nm or less, and even more preferably 5 nm or less. Being within the above range means that the coating layer does not have a polymer layer or has a polymer layer only partially. The lower limit of the average thickness of the coating layer is not particularly limited, but is, for example, 0.1 nm or more. In this specification, the average thickness of the coating layer refers to the arithmetic average of the thicknesses of the coating layer at three arbitrary locations on the coating layer, measured in water using an atomic force microscope (AFM) by scraping the coating layer with a cantilever, and measuring the thickness of the coating layer from the step between the exposed substrate surface and the coating layer.

[0019] In condition (3), at least one of the Si element ratio and the P element ratio measured by X-ray photoelectron spectroscopy on the coating layer surface is 0.5 atm% or more, preferably 0.8 atm% or more. Being within the above range means that the majority of the monomolecular layer formed by the low-molecular-weight compound containing Si element or P element is located on the surface side of the coating layer. The upper limits of the Si element ratio and the P element ratio are not particularly limited, but are, for example, 15 atm% or less, 10 atm% or less, or 5 atm% or less, respectively. In this specification, the Si element ratio and the P element ratio are values ​​obtained by measuring the surface of the coating layer by X-ray photoelectron spectroscopy, determining the peak area of ​​each element, and calculating the mass ratio of each element.

[0020] <Substrate> The substrate is not particularly limited, and any substrate conventionally known for devices used in blood vessels can be used.

[0021] The substrate material is preferably one that is highly rigid and biocompatible. Examples of such materials include titanium, nickel, stainless steel, platinum, gold, silver, copper, iron, chromium, cobalt, aluminum, molybdenum, manganese, tantalum, tungsten, niobium, magnesium, calcium, and alloys containing these metals. Synthetic resin materials such as polyolefins (e.g., polyethylene (PE) and polypropylene (PP)), polyamides, polyvinyl chloride, polyphenylene sulfide, polycarbonate, polyethers, and polymethyl methacrylate can also be used. Furthermore, biodegradable resins (biodegradable polymers) such as polylactic acid (PLA), polyhydroxybutyrate (PHB), polyglycolic acid (PGA), and polyε-caprolactone can also be used. Among these, titanium, nickel, stainless steel, platinum, gold, silver, copper, magnesium, and alloys containing these metals are preferred. Examples of alloys include Ni-Ti alloys, Cu-Mn alloys, Cu-Cd alloys, Co-Cr alloys, Cu-Al-Mn alloys, Au-Cd-Ag alloys, Ti-Al-V alloys, and alloys of magnesium with Zr, Y, Ti, Ta, Nd, Nb, Zn, Ca, Al, Li, Mn, etc. In addition to the above, non-biodegradable resins can also be used as the substrate material. As such, the substrate may be formed from any material as long as it is biocompatible.

[0022] The shape of the substrate is not particularly limited and can be appropriately selected depending on the type of device. For example, if the device is a stent, it may be a general stent structure having a skeletal shape that can expand and contract in diameter. The substrate preferably has a linear portion. When the substrate has a linear portion, the surface area is increased and thrombus formation is more likely to be induced, thereby making it easier to achieve the effects of the present invention.

[0023] <Coating Layer> The coating layer is a layer that covers at least a part of the surface of the substrate and has a monomolecular layer. The coating layer may cover the entire surface of the substrate.

[0024] (Monomolecular Layer) In this specification, the term "monomolecular layer" refers to a layer composed of organic molecules, having a thickness approximately equal to the length of one constituent molecule, and consisting of molecules that are physically or chemically bound to a substrate. Examples of monomolecular layers include self-assembled monolayers (SAMs). For each molecule of the monomolecular layer that is physically or chemically bound to the substrate, 1 to 10 (preferably 1 to 5, more preferably 1 to 3) identical molecules may be bound in a beaded or mesh-like pattern. The monomolecular layer is formed by surface treating the substrate with a low molecular weight compound having an albumin-binding functional group.

[0025] The thickness of the monolayer is, for example, 0.1 to 5 nm, or 0.1 to 3 nm. In this specification, the thickness of the monolayer is measured by optical ellipsometry.

[0026] [Low molecular weight compound having an albumin-binding functional group] The albumin-binding functional group refers to a functional group that adsorbs and physically or chemically bonds with albumin in blood. Examples of low molecular weight compounds having an albumin-binding functional group include low molecular weight compounds having at least one functional group selected from the group consisting of an amino group, a halogen group, a carboxy group, and an alkyl group (hereinafter simply referred to as "low molecular weight compound"). Among these, low molecular weight compounds having an amino group are preferred from the viewpoints of coagulation activity and antibacterial properties (including, but not limited to, antibacterial properties against gram-negative bacteria).

[0027] The alkyl group is preferably a linear or branched alkyl group having 1 to 20 carbon atoms, more preferably a linear alkyl group having 1 to 5 carbon atoms.

[0028] The low molecular weight compound having an albumin-binding functional group preferably further has a functional group that is covalently bonded to the substrate surface, i.e., in the monolayer, the constitutional unit derived from the low molecular weight compound having the albumin-binding functional group is preferably covalently bonded to the substrate surface.

[0029] The functional group that is covalently bonded to the surface of the substrate is not particularly limited and can be appropriately selected depending on the substrate. For example, an alkoxy group, a thiol group, a phosphonic acid group (-PO ３ H ２) are listed.

[0030] As the low molecular weight compound having an albumin-binding functional group, silane coupling agents, thiol compounds, and phosphonic acid compounds are preferred, with silane coupling agents being more preferred because they are more likely to bond stably to the surface of the substrate.

[0031] Examples of silane coupling agents include amino group-containing silane coupling agents such as (3-aminopropyl)triethoxysilane (APTES) and (3-aminopropyl)trimethoxysilane, and alkyl group-containing silane coupling agents such as trimethoxymethylsilane (TMMS) and triethoxymethylsilane. Among these, amino group-containing silane coupling agents are preferred from the viewpoints of coagulation activity and antibacterial properties (including, but not limited to, antibacterial properties against gram-negative bacteria).

[0032] The thiol compound is a compound having a thiol group, and examples thereof include carboxyl group-containing thiol compounds such as 3-mercaptopropionic acid (MPA), thioglycolic acid, 4-mercaptobutanoic acid, 5-mercaptopentanoic acid, 6-mercaptohexanoic acid, 7-mercaptoheptanoic acid, 8-mercaptooctanoic acid, 9-mercaptononanoic acid, 10-mercaptodecanoic acid, 11-mercaptoundecanoic acid, and 12-mercaptododecanoic acid.

[0033] The phosphonic acid compound is a compound having a phosphonic acid group, and examples thereof include alkyl group-containing phosphonic acid compounds such as octadecylphosphonic acid.

[0034] The molecular weight of the low molecular weight compound having an albumin-binding functional group is preferably 1,000 or less, more preferably 500 or less.

[0035] (Polymer Layer) The coating layer may have a polymer layer, but preferably does not have a polymer layer. This allows the albumin-binding functional groups of the monolayer to be exposed on the outermost surface of the coating layer, making it easier to achieve the effects of the present invention. In this specification, the polymer layer means a layer made of a polymer that is not a monolayer. The thickness of the polymer layer is, for example, 1 nm or more, 10 nm or more, or 10 nm to 10 μm.

[0036] The polymer constituting the polymer layer is not particularly limited, and examples thereof include polymers that have been used to impart thrombus formation inhibitory properties to medical devices, such as polymers containing structural units derived from 2-methacryloyloxyethylphosphorylcholine (MPC) and polymers composed of heparin molecules.

[0037] <Method for Producing the Device> The method for producing the device is not particularly limited, and for example, a monolayer is formed by treating the surface of a substrate with a low molecular weight compound having an albumin-binding functional group.

[0038] The method for forming a monolayer by surface treatment is not particularly limited, and any method conventionally known for forming a self-assembled monolayer can be used, such as a method of immersing a substrate in a solution containing a low molecular weight compound having an albumin-binding functional group, followed by drying.

[0039] <Use> The device is used in a blood vessel, and is preferably used so that part or all of it is placed in the blood vessel. The device is preferably a medical device, and more preferably an implant for endovascular treatment. Examples of implants for endovascular treatment include stents, coils, shunts, catheters, etc. Among these, stents are preferred. In addition to being used as a medical device for treatment, the device can also be used as a device that is placed in the body (in the blood vessels) of an animal such as a human and connected to an external network.

[0040] <Another embodiment of the device> In another embodiment of the device, the monolayer may be formed from a low molecular weight compound having at least one functional group selected from the group consisting of an amino group, a halogen group, a carboxy group, and an alkyl group. The low molecular weight compound having at least one functional group selected from the group consisting of an amino group, a halogen group, a carboxy group, and an alkyl group is the same as the low molecular weight compound described in [Low molecular weight compound having an albumin-binding functional group].

[0041] <Coating Agent> The coating agent is used in the production of the above-described device and contains a low molecular weight compound having an albumin-binding functional group. The low molecular weight compound having an albumin-binding functional group contained in the coating agent is the same as the low molecular weight compound having an albumin-binding functional group described in [Low molecular weight compound having an albumin-binding functional group].

[0042] The coating agent may contain other components (such as an organic solvent) in addition to the low molecular weight compound having an albumin-binding functional group. The amount of the low molecular weight compound having an albumin-binding functional group in the coating agent is not particularly limited.

[0043] <Another embodiment of the coating agent> Another embodiment of the coating agent may be a coating agent containing a low molecular weight compound having at least one functional group selected from the group consisting of an amino group, a halogen group, a carboxy group, and an alkyl group. The low molecular weight compound having at least one functional group selected from the group consisting of an amino group, a halogen group, a carboxy group, and an alkyl group is the same as the low molecular weight compound described in [Low molecular weight compound having an albumin-binding functional group].

[0044] The present invention will be specifically explained below with reference to examples, but the present invention is not limited to these examples.

[0045] Example 1: A commercially available stent substrate (NiTi alloy) was irradiated with plasma to hydrophilize its surface. The treated stent was immersed in a 5% by mass solution of (3-aminopropyl)triethoxysilane (APTES) at 20°C for 120 minutes. The treated stent was removed from the solution and dried at 70°C. The resulting stent had a coating layer without a polymer layer, an average thickness of 3 nm or less, and a Si element ratio of 1 atm% on the coating layer surface as measured by X-ray photoelectron spectroscopy. A metal plate (NiTi alloy) was also prepared by similar treatment instead of the commercially available stent substrate. Metal plates were also prepared in the following Comparative Examples 1 to 4.

[0046] (Comparative Example 1) A commercially available stent substrate (NiTi alloy) was irradiated with plasma to hydrophilize the surface. The treated stent was immersed in a 2% by mass solution of 2-(methacryloyloxy)ethylphosphorylcholine (MPC) for 10 minutes. The treated stent was removed from the solution and dried at 70°C. The coating layer on the resulting stent did not have a monolayer.

[0047] (Comparative Example 2) A commercially available stent substrate (NiTi alloy) was irradiated with plasma to hydrophilize the surface. The treated stent was immersed in a 4 mass% solution of 2-(methacryloyloxy)ethylphosphorylcholine (MPC) for 10 minutes. The treated stent was removed from the solution and dried at 70°C. The coating layer on the resulting stent did not have a monolayer.

[0048] (Comparative Example 3) A commercially available stent substrate (NiTi alloy) was irradiated with plasma to hydrophilize its surface. The treated stent was immersed in a 5% by mass solution of 3-aminopropyltriethoxysilane (APTES) for 120 minutes. The treated stent was removed from the solution and vacuum dried at 70°C. The dried stent was then immersed overnight in a 0.1-1.0% by mass solution of heparin. The treated stent was removed from the solution and dried. The resulting stent had a coating layer with a polymer layer containing heparin molecules, an average thickness of 100 nm, and a Si element ratio of less than 0.5 atm% on the coating layer surface as measured by X-ray photoelectron spectroscopy.

[0049] Comparative Example 4 A commercially available stent substrate (NiTi alloy) was used as it was.

[0050] Example 2: A commercially available stent substrate (NiTi alloy) was irradiated with plasma to hydrophilize its surface. The treated stent was immersed in a 5% by mass solution of trimethoxymethylsilane (TMMS) at 20°C for 120 minutes. The treated stent was removed from the solution and vacuum dried at 70°C. The resulting stent had a coating layer without a polymer layer, an average thickness of 3 nm or less, and a Si element ratio of 1 atm% on the coating layer surface as measured by X-ray photoelectron spectroscopy.

[0051] Example 3: A commercially available stent substrate (NiTi alloy) was irradiated with plasma to hydrophilize its surface. The treated stent was immersed in a 10% by mass solution of 3-mercaptopropionic acid (MPA) at 20°C for 120 minutes. The treated stent was removed from the solution and vacuum dried at 70°C. The resulting stent had a coating layer without a polymer layer, and the average thickness of the coating layer was 3 nm or less.

[0052] (Comparative Example 5) A commercially available stent substrate (NiTi alloy) was irradiated with plasma to hydrophilize the surface. The treated stent was immersed for 120 minutes in a 10% by mass solution of 3-mercapto-1-propanol (MPOH), which does not have an albumin-binding functional group. The treated stent was removed from the solution and vacuum-dried at 70°C.

[0053] <Thrombosis Test> The thrombus formation inhibitory ability of each stent in Example 1 and Comparative Examples 1 to 4 was evaluated using a Chandler loop model. Each stent was tested three times, and the average value was used for evaluation. Specifically, the test was performed as follows. A stent was placed in a tube with an inner diameter of 4.0 mm and a length of 600 mm. 7 mL of blood drawn from a healthy donor was collected in a blood collection tube, and 70 μL of heparin solution (a solution of heparin added to saline to make 100 IU / mL) was added. The blood collection tube was gently stirred up and down. 1 mL was dispensed, and immediately blood cells were counted. 2 mL of the remaining blood was added to the tube containing the stent, and the loop was closed. The tube was fixed to a rotator and rotated at 37°C and 10 rpm for 3 hours. The thrombus formation inhibitory ability of each stent in Examples 2 and 3 and Comparative Example 5 was also evaluated in the same manner, except that blood drawn from a different healthy donor was used.

[0054] (Blood cell count) EDTA was added to each blood sample collected from the tube, and then the blood cells were counted. The control was the number of platelets in the blood immediately after collection. The ratios (%) of the number of platelets in Example 1 and Comparative Examples 1 to 4 to the control are shown in Figure 1, and the ratios (%) of the number of platelets in Example 2 and Comparative Example 5 to another control are shown in Figure 2. A higher number of platelets indicates less likely coagulation reaction to occur and more excellent thrombus formation inhibitory ability.

[0055] (Appearance Evaluation) The state of thrombus formation in each stent recovered from the tube was observed with an SEM and evaluated according to the following criteria. The results for Examples 1 to 3 and Comparative Examples 1 to 5 are shown in Figure 3. SEM images of Example 1 and Comparative Examples 1 to 4 are shown in Figures 4 to 8, and SEM images of Examples 2, 3, and Comparative Example 5 are shown in Figures 9 to 11, respectively. 1: Almost no blood cells adhered. 2: Some platelets adhered, with their shape intact. 3: Platelets adhered, with their shape intact, over the entire area. 4: Some blood clots and platelets adhered. 5: Some blood clots and platelets adhered over the entire area. 6: A certain amount of blood clots and platelets adhered over the entire area. 7: Blood clots and platelets adhered over the entire area. 8: Some struts completely covered with blood cells. 9: Multiple struts completely covered with blood cells. 10: All struts completely covered with blood cells.

[0056] (Evaluation of Coagulation Activity) Each blood sample collected from the tube was separated at 4°C and 2500 rpm, and the supernatant plasma was collected. The TAT (thrombin-antithrombin complex) (ng / mL) in the collected plasma was measured. The results of Example 1 and Comparative Examples 2, 4, and 5 are shown in Figure 12. "Control" indicates the amount of TAT before the experiment. A smaller amount of TAT indicates lower coagulation activity and superior thrombus formation inhibitory ability.

[0057] <Vascular Endothelialization Test> The degree of promotion of vascular endothelialization was evaluated for each metal plate. Specifically, the test was carried out as follows. The metal plates of Example 1 and Comparative Examples 2 to 4 were placed in cell culture dishes, and vascular endothelial cells were seeded on the surface of the metal plate. 24 hours after seeding, the cells were observed under a fluorescence microscope, images were taken, and the area of ​​the fluorescent portion was measured to calculate the total area of ​​cell adhesion. The results are shown in Figure 13. Images of Example 1 and Comparative Examples 2 to 4 are also shown in Figure 14. Note that for Examples 2 and 3, results similar to those of Example 1 were obtained.

[0058] <In vivo vascular endothelialization test in animals> The stent of Example 1 was placed in the right internal thoracic artery of two miniature pigs (Gottingen, male, approximately 27 kg) and the stent of Comparative Example 1 was placed in the left internal thoracic artery for 7 days, and then the extent of vascular endothelialization of the stents was evaluated. Specifically, the test was performed as follows.

[0059] (Stent placement) A guiding catheter was delivered to the right internal thoracic artery from the femoral artery of a miniature pig via a sheath introducer. The vascular diameter of the right internal thoracic artery was measured and confirmed to be within an appropriate range for the stent. A microcatheter was delivered to the right internal thoracic artery via the guiding catheter. The stent of Example 1 was delivered to the right internal thoracic artery via the microcatheter and left indwelling for 7 days. At the same time, the stent of Comparative Example 1 was placed in the left internal thoracic artery of the same miniature pig for 7 days in the same manner as the stent of Example 1. Similarly, the stent of Example 1 was placed in the right internal thoracic artery of another miniature pig for 7 days, and the stent of Comparative Example 1 was placed in the left internal thoracic artery for 7 days.

[0060] (Extraction and Examination) A guiding catheter was delivered to the internal thoracic artery of the miniature pig through a sheath introducer from the femoral artery. An angiographic contrast agent was administered through the guiding catheter, and an angiographic examination confirmed that the blood flow and blood vessels were normal. After euthanizing the miniature pig, the internal thoracic artery was extracted. The extracted internal thoracic artery was immersed in formalin and fixed. The fixed internal thoracic artery was embedded in resin, and then sections were prepared by hematoxylin-eosin staining (HE staining) of the cross section of the internal thoracic artery where the stent was placed. Eight sections were prepared per internal thoracic artery (a total of 16 sections for each case).

[0061] The tissue coverage rate of each section was calculated using the following formula, and the average and standard deviation of the tissue coverage rate for each example were calculated. The results are shown in Figure 15. Tissue coverage rate (%) = (number of struts covered by endothelial-like cells or neointimal tissue / total number of struts) x 100

[0062] As shown by the results of the thrombus formation test and the vascular endothelialization test, vascular endothelialization was inhibited in Comparative Examples 1 and 2, which did not have a monolayer formed from a low molecular weight compound having functional groups such as albumin-binding functional groups, and in which the substrate was coated with a polymer containing structural units derived from MPC. Furthermore, Comparative Example 5, which had a monolayer formed from a low molecular weight compound without albumin-binding functional groups, was found to have poor thrombus formation inhibitory ability. On the other hand, Examples 1 to 3, which had a monolayer formed from a low molecular weight compound having functional groups such as albumin-binding functional groups, did not use naturally occurring heparin or the like as a raw material, and therefore were inexpensive and less likely to cause supply issues. Therefore, they were found to have excellent thrombus formation inhibitory ability and less likely to inhibit vascular endothelialization, comparable to Comparative Example 3, which was coated with heparin molecules.

Claims

1. An instrument for use within a blood vessel, comprising a substrate and a coating layer covering at least a portion of the surface of the substrate, wherein the coating layer has a monolayer formed by surface treating the substrate with a low molecular weight compound having an albumin-binding functional group, and wherein at least one of the following (1) to (3) is satisfied: (1) the coating layer has the monolayer as the outermost surface, and has no polymer layer on the surface side of the monolayer; (2) the average thickness of the coating layer is 30 nm or less; and (3) at least one of the Si element ratio and the P element ratio of the coating layer surface measured by X-ray photoelectron spectroscopy is 0.5 atm % or more.

2. An instrument for use within a blood vessel, comprising a substrate and a coating layer covering at least a portion of the surface of the substrate, the coating layer having a monolayer formed by surface treating the substrate with a low molecular weight compound having at least one functional group selected from the group consisting of an amino group, a halogen group, a carboxy group, and an alkyl group, and satisfying at least one of the following (1) to (3): (1) the coating layer has the monolayer as the outermost surface, and has no polymer layer on the surface side of the monolayer; (2) the average thickness of the coating layer is 30 nm or less; and (3) at least one of the Si element ratio and the P element ratio of the coating layer surface measured by X-ray photoelectron spectroscopy is 0.5 atm% or more.

3. A device as claimed in claim 1 or 2, for placement within a blood vessel.

4. The device according to claim 1 or 2, wherein the substrate has linear portions.

5. A coating agent containing a low molecular weight compound having an albumin-binding functional group, the coating agent being used in the manufacture of the device according to claim 1.

6. A coating agent used in the manufacture of the device according to claim 2, comprising a low molecular weight compound having at least one functional group selected from the group consisting of an amino group, a halogen group, a carboxy group, and an alkyl group.

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