JP2003048840A - Antithrombogenic composition imparted with antibacterial effect and medical equipment coated with the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an antithrombogenic composition retaining its high antithrombogenicity for a long period and exhibiting antibacterial effect as well. SOLUTION: This antithrombogenic composition is imparted with antibacterial effect which is characterized in that at least part of the counteractions of at least one mucopolysaccharide is silver ion and organocation. The mucopolysaccharide is preferably a heparin salt, and the countercation is preferably a quaternary ammonium cation. The conjugate is imparted to at least part of the blood contact surface of medical equipment in contact with the blood.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an antithrombotic composite having antibacterial properties, which is useful as a material used in a medical device used in contact with blood. Further, by applying the antithrombotic complex having the antibacterial property to a conventional medical device, it can be used in contact with blood having excellent antithrombotic and antibacterial properties without impairing the original function of the medical device. The present invention relates to a medical device that does.

[0002]

2. Description of the Related Art Conventionally, central venous indwelling catheter, arterial indwelling catheter, blood circuit tube, sampling monitor tube, intra-aortic balloon pump, artificial heart blood pump, angiographic catheter, artificial lung, venous reservoir, artificial A technique for imparting antithrombogenicity to the surface of blood contact medical devices such as kidneys and arterial filters to prevent blood from coagulating has been developed and put into practical use. Mucopolysaccharides have been studied as the center of improving the antithrombogenicity of medical devices,
Among them, heparin or its derivative having a high anticoagulant effect is immobilized on the surface of a medical device by some method to obtain antithrombotic property. Mucopolysaccharide is a polysaccharide that exists in the living body and has a functional group having a negative charge such as a carboxyl group or a sulfonic acid group, and sodium or potassium is usually present as the counter cation. In addition, the heparin derivative (heparins) herein refers to those obtained by partially chemically treating heparin such as low molecular weight heparin and epoxidized heparin.

As a method for introducing and imparting heparin to the blood contact surface of a medical instrument used in contact with blood, various functional groups are introduced into heparin and immobilized on the substrate by covalent bonding. There is. As this method, Japanese Patent Laid-Open No. 4-19
7264 discloses a covalent bonding method in which an amino group of heparin and an amino group introduced on the above-mentioned medical device (hereinafter referred to as a substrate) are coupled with polyethylene glycol diglycidyl ether. Further, in JP-A-58-147404, after utilizing a terminal aldehyde group generated when heparin is made into a low molecular weight compound, the amino group introduced into the substrate is reacted with this aldehyde group to form a covalent bond. , A method of stabilizing a covalent bond generated by a reduction reaction is disclosed. In these covalent bonding methods, it is necessary to introduce a reactive group with heparin into a base material, that is, a medical device in some way, or heparin is too strongly bonded to the base material, and the degree of freedom is lost. There was a problem that the activity could not be fully exhibited. Furthermore, such a method requires a multi-step process, the cost becomes very high, and it becomes a big problem in the present situation that the medical cost is rising.

As another method, an organic cation compound such as ammonium salt or phosphonium is bound to the negative charge (sulfonic acid group or aminosulfonic acid group) of heparin to make it insoluble in water or solubilized in an organic solvent. A method of coating this on a medical device has been proposed. Japanese Patent Publication 48
-13341 is treated with heparin and a cationic surfactant to prepare a heparin complex that is insoluble in water and soluble in an organic solvent, and is dissolved alone or in an organic solvent together with plastic, which is then applied to the plastic surface. A method for obtaining an anticoagulant surface by applying the composition to a substrate and drying it is disclosed. These ion-binding methods have a high antithrombotic property in the initial stage, but have a drawback that they are lost to the blood early and the effect is lost.

On the other hand, materials having antibacterial properties have been reported in a wide range, not limited to medical applications. Japanese Patent Fair 6-5
5892 discloses an antibacterial material containing protein silver as an antibacterial active ingredient. Japanese Unexamined Patent Publication No. 9-67231 discloses an antibacterial material containing a small amount of fatty acid silver as an antibacterial active ingredient. Japanese Unexamined Patent Publication No. 9-100205 discloses an antibacterial material obtained by adding and mixing silver zeolite and sepiolite of hydrous magnesium silicate or smectite. Further, Japanese Patent Laid-Open No. 07-194687 discloses an antibacterial collagen matrix in which collagen contains protein silver. Although these techniques have been studied for their excellent antibacterial properties, they are not preferred as medical devices that come into contact with blood because they do not have antithrombotic properties. That is, even if these are applied to blood contact medical devices, thrombus will be formed on the surface of the device at an early stage, and the antibacterial property will be ineffective or significantly reduced.

[0006]

DISCLOSURE OF THE INVENTION The present invention solves the above-mentioned drawbacks of the prior art, simply holds a high antithrombotic property for a long period of time, and also exhibits antibacterial properties and imparts an antibacterial property. Intended to provide the body.

[0007]

Means for Solving the Problems In view of the above problems, the present inventors have made extensive studies and found that a complex of silver ion or an organic cation and mucopolysaccharide is useful, and arrived at the present invention. That is, the present invention is an antibacterial imparting antithrombotic complex, characterized in that at least a part of the counter cation of at least one mucopolysaccharide is a silver ion and an organic cation.

It is preferable that at least heparin salt or heparin salt is contained as the mucopolysaccharide. Further, among the counter cations of the mucopolysaccharide, it is preferable that at least a part of the organic cations contains an organic cation derived from a quaternary ammonium salt. Further, it is preferable that at least a part of the organic cations among the counter cations of the mucopolysaccharide contains an organic cation derived from a quaternary ammonium salt, and the quaternary ammonium salt is insoluble in water.

At least a part of the counter cation of the mucopolysaccharide contains an organic cation derived from a quaternary ammonium salt, and the quaternary ammonium salt is a water-soluble quaternary ammonium salt. It is preferred to select from a combination with water-insoluble quaternary ammonium salts. Here, "insoluble in water" means that the ammonium salt is weighed so as to have a concentration of 1% by weight in pure water at 40 ° C., which is close to the body temperature, and when stirred in water, it does not become a transparent homogeneous solution but becomes oily. Is either separated from water or dispersed in a cloudy state. Soluble in water here is close to the body temperature 4
That is, the ammonium salt is weighed so as to have a concentration of 1% by weight in pure water at 0 ° C., and it becomes a transparent homogeneous solution when stirred in water.

In the present invention, a mucopolysaccharide, preferably heparin, is combined with a silver ion and an organic cation derived from a quaternary ammonium salt so that the silver ion is liberated upon contact with blood. The antithrombotic property can be obtained, and the antithrombotic property can be obtained by using heparin or an ionic complex of heparin and an organic cation. As the organic cation of the present invention, quaternary ammonium and quaternary phosphonium are preferably used.

The other organic cation compound which forms a complex with the heparin salt or heparin salt in the present invention is mainly an ammonium salt compound. Among them, the water-insoluble ammonium salt is preferably 2 out of 4 aliphatic alkyl groups. One is an ammonium salt which is a long-chain alkyl group having 12 or more carbon atoms, and is a didodecyldimethylammonium salt or a ditetradecyldimethylammonium salt,
Dihexadecyldimethylammonium salt, dioctadecyldimethylammonium salt, dieicosanyldimethylammonium salt, didocosanyldimethylammonium salt,
There are ditetraeicosanyldimethylammonium salts and the like, but dihexadecyldimethylammonium salt and dioctadecyldimethylammonium salt are particularly preferable. Also,
Among water-insoluble ammonium salts, organic ammonium salts in which three of four aliphatic alkyl groups are long-chain alkyl groups having 10 or more carbon atoms include tridecylmethylammonium salt, tridodecylmethylammonium salt and tritetradecyl. There are methylammonium salt, trihexadecylmethylammonium salt, trioctadecylammonium salt, trieicosanylmethylammonium salt and the like, but tridodecylmethylammonium salt and trihexadecylmethylammonium salt are particularly preferable.

In addition to the water-insoluble ammonium salt, it is effective in terms of antibacterial properties to combine and mix water-soluble ammonium salt. This is because the ammonium salt itself has antibacterial properties, and the ammonium salt forming the complex liberates a simple ammonium salt upon contact with body fluid, and the fact that this ammonium salt is water-soluble contributes to the antibacterial property. . A high antibacterial property can be maintained by dissolving a water-soluble ammonium salt in the blood in addition to silver ions. Examples of the water-soluble ammonium salt in the present invention include decylbenzyldimethylammonium salt, dodecylbenzyldimethylammonium salt, tetradecylbenzyldimethylammonium salt, hexadecylbenzyldimethylammonium salt, octadecylbenzyldimethylammonium salt, eicosanylbenzyldimethylammonium salt. Further, there are benzethonium, etc., such as an aqueous solution for disinfecting a mixture of alkylbenzyldimethylammonium having 8 to 18 carbon atoms, which is sold under the trade name of Osvan.

Examples of the mucopolysaccharides include heparins, hyaluronic acid, chondroitin sulfate and ketalan sulfate, and heparins are particularly preferred from the viewpoint of antithrombotic property. Examples of heparins include heparin sodium, heparin potassium, heparin lithium, heparin calcium, heparin zinc, heparin low molecular weight heparin, and epoxidized heparin.

A method of applying the composite of the present invention to the blood contact surface of a medical device used in contact with blood will be described with heparin as an example. First, the organic cation compound and heparin are mixed in a solvent and stirred to obtain a precipitate (complex). Then, the complex is recovered and washed to wash out the unreacted heparin and the organic cation compound. Next, this complex is subjected to stirring treatment in an aqueous solution of a water-soluble silver compound for a certain period of time to replace a part of the counter cation with silver ion. Next, this silver compound-treated complex is washed with water to remove excess silver compound. By dissolving this in an appropriate organic solvent and coating it on the surface of a medical device, the medical device of the present invention used in contact with blood having antibacterial and antithrombotic properties can be obtained. The treatment of the silver compound is preferably 50% or less because the solvent solubility of the complex is impaired if the ratio of substitution with silver ions in the counter cation is too large.

As another method for applying the complex to the blood contact surface of another blood contact medical device, an organic cation compound and heparin are mixed in a solvent and stirred to form a precipitate (complex).
To get Then, the complex is recovered and washed to remove the unreacted heparin and the organic cation compound by washing. The obtained heparin-organic cation complex is dissolved in an organic solvent. The solution is brought into contact with the surface of the medical device, and then the solvent is removed to form a film of a complex of mucopolysaccharide, that is, heparin and an organic cation compound, on the blood contact surface of the medical device. Next, the medical device is immersed in an aqueous solution of a water-soluble silver compound. By this treatment, a part of the counter cation is replaced with silver ion. Finally, it is thoroughly washed with pure water to obtain the medical device of the present invention having antibacterial and antithrombotic properties.

The organic solvent used in the coating of the present invention is selected so that it does not damage the surface of the medical device as the base material as much as possible, but it is generally methanol, ethanol, isopropyl alcohol or normal propyl. Alcohol, normal hexane, cyclohexane, tetrahydrofuran (hereinafter THF), 1,4-dioxane, cyclohexanone, N, N-dimethylformamide,
N, N-dimethylacetamide, N-methylpyrrolidone and the like and mixtures thereof are used.

As a method for applying the antibacterial property-imparting antithrombotic composite of the present invention to the blood contact surface of a medical device, a dipping method, a spraying method, a coating method using a brush or the like is used. It is not limited. Here, as the material for the base material of the medical device, all materials that are usually used are included. That is, polyvinyl chloride, polycarbonate, polyethylene terephthalate, polyethylene, polypropylene, polymethylpentene, thermoplastic polyether polyurethane, thermosetting polyurethane, silicone rubber such as polydimethylsiloxane having a crosslinked portion, polymethylmethacrylate, polyvinylidene fluoride, Examples thereof include tetrafluorinated polyethylene, polysulfone, polyether sulfone, polyacetal, polystyrene, ABS resins and mixtures of these resins, metals such as stainless steel, titanium and aluminum.

[0018]

EXAMPLES The present invention will be described below based on examples.
The present invention is not limited to the examples. (Example 1) 20 parts by weight of water-soluble dodecylbenzyldimethylammonium bromide (manufactured by Tokyo Kasei) and 60 parts by weight of water-insoluble ditetradecyldimethylammonium bromide (manufactured by Tokyo Kasei) were dissolved in 150 parts by weight of methyl alcohol. 70% by weight of water after confirming complete dissolution
Add to the concentration. At this time, a part of the ammonium salt is deposited, but after this, the temperature of the solution is raised to 50 ° C. to form a uniform solution (this is the above ammonium salt solution). Separately, 30 parts by weight of heparin are dissolved in 150 parts by weight of deionized water. Then 30% by weight of methanol
Add until the concentration is reached. Also at this time, a part of heparin is precipitated and becomes a suspension, but a uniform solution is obtained by raising the temperature to 70 ° C. While stirring this heparin solution, the entire amount of the ammonium salt solution is added dropwise. Since the reaction product is insoluble in the solution, it immediately forms a precipitate. The precipitate is collected and washed sufficiently to remove unreacted heparin and ammonium salt. Next, 150 ml of a 1 wt% silver nitrate aqueous solution was added, and the mixture was washed with excess water which was stirred for 4 hours and finally freeze-dried to obtain a complex of heparin of the present invention and the above ammonium salt. This complex was a complex in which about 2% of the anionic groups of heparin were bound to silver ions and the rest were bound to ammonium salts.

Example 2 15 parts by weight of water-soluble benzethonium chloride and 72 parts by weight of water-insoluble dioctadecyldimethylammonium bromide were added to 150 parts of methyl alcohol.
It dissolved in parts by weight. After confirming complete dissolution, water is added to a concentration of 70% by weight. At this time, a part of the ammonium salt is deposited, but after that, the temperature of the solution is raised to 50 ° C. to form a uniform solution (this is referred to as an ammonium salt solution). Separately, 30 parts by weight of heparin is dissolved in 150 parts by weight of ion-exchanged water. Then add methanol 3 times.
Add until 0 wt% concentration. Also at this time, a part of heparin is precipitated and becomes a suspension, but a uniform solution is obtained by raising the temperature to 70 ° C. While stirring this heparin solution, the ammonium salt solution is added dropwise. Since the reaction product is insoluble in the solution, it immediately forms a precipitate. The precipitate is collected and washed sufficiently to remove unreacted heparin and ammonium salt. Then, this precipitate (reaction product) was added with 150 ml of a 1% by weight silver nitrate aqueous solution, stirred for 4 hours, washed with excess water, and finally freeze-dried to obtain a complex of heparin and ammonium salt of the present invention. Got the body This complex contains about 1 of the anionic groups of heparin.
% Of the complex bound to silver ion and the rest bound to ammonium salt.

Example 3 20 parts by weight of water-soluble tetradecylbenzyldimethylammonium chloride (manufactured by Tokyo Kasei) and 40 parts by weight of water-insoluble dimethyldipalmitylammonium bromide were dissolved in 150 parts by weight of methyl alcohol. After confirming complete dissolution, water is added to a concentration of 70% by weight. At this time, a part of the ammonium salt is deposited, but after that, the temperature of the solution is raised to 50 ° C. to form a uniform solution (this is referred to as an ammonium salt solution). Next, 30 parts by weight of heparin is added to 150 parts of ion-exchanged water.
Dissolves in parts by weight. Subsequently, methanol is added until the concentration reaches 30% by weight. Also at this time, a part of heparin is precipitated and becomes a suspension, but a uniform solution is obtained by raising the temperature to 70 ° C. While stirring this heparin solution, the ammonium salt solution is added dropwise. Since the reaction product is insoluble in the solution, it immediately becomes a precipitate. The precipitate is collected and washed sufficiently to remove unreacted heparin and ammonium salt. Next, a 1 wt% aqueous solution of silver nitrate
After adding 200 ml and stirring for 4 hours, it was washed with excess water and finally freeze-dried to obtain a complex of heparin and ammonium salt of the present invention. This complex was a complex in which about 1% of the anionic group of heparin was bound to silver ion and the rest was bound to ammonium salt.

Example 4 60 parts by weight of water-insoluble tridodecylmethylammonium bromide (manufactured by Tokyo Kasei) was dissolved in 150 parts by weight of methyl alcohol. After confirming complete dissolution, water is added to a concentration of 70% by weight. At this time, some ammonium salts are deposited, but after this, 50 ° C
Then, the temperature of the solution is raised to obtain a uniform solution (this is an ammonium salt solution). Separately, 30 parts by weight of heparin are dissolved in 150 parts by weight of deionized water. Subsequently, methanol is added until the concentration reaches 30% by weight. Also at this time, a part of heparin is precipitated and becomes a suspension, but a uniform solution is obtained by raising the temperature to 70 ° C. While stirring this heparin solution, the entire amount of the ammonium salt solution is added dropwise. Since the reaction product is insoluble in the solution, it immediately forms a precipitate. The precipitate is collected and washed sufficiently to remove unreacted heparin and ammonium salt. Then, the mixture was stirred for 4 hours in a 1% by weight aqueous solution of silver nitrate. Thereafter, this compound was washed with excess water and finally freeze-dried to obtain a complex of heparin and ammonium salt of the present invention. Tetrahydrofuran (hereinafter referred to as THF
To a concentration of 1.0% by weight, and an inner diameter of 3 m
m polyvinyl chloride, coated on the inner surface of a tube with a length of 1000 mm. After the coating was performed, it was dried in an oven at 50 ° C. for 12 hours under a nitrogen stream to remove THF.
Next, this tube was filled with a 0.05 wt% silver nitrate aqueous solution and shaken for 12 hours. Then, the water in the tube was discarded, the tube was washed with pure water, and then dried to obtain a tube coated with the composite of the present invention.

(Comparative Examples 1 and 2) In addition, as a comparative example, an aliphatic polyurethane tube (Tecoflex 80A) used as a blood contact medical device having high antithrombogenicity.
E., used as Comparative Example 1 by Thermedix Co., Ltd.) and a medical polyvinyl chloride resin tube (used as Comparative Example 2) containing 80 phr of diethylhexyl phthalate used as a material for blood circuits and the like.

(Evaluation Test 1: Evaluation of Antithrombotic Property) Example 1
Each of the complexes obtained in ~ 3 is dissolved in THF to a concentration of 1.0% by weight. Dissolved liquid has an inner diameter of 3 mm and a length of 1000 mm
Sample tubes 1 to 3 were obtained by passing through the inside of the polyvinyl chloride tube and coating. In Example 4, a tube coated with the composite as described above was directly subjected to the evaluation test. In Comparative Examples 1 and 2, a tube having an inner diameter of 3 mm was cut into the same length as the polyvinyl chloride tube, a physiological saline solution at 37 ° C. was circulated, and the antithrombotic property was evaluated by the same operation as described above. In order to observe the antithrombotic performance in an environment close to the actual usage condition, a physiological saline solution heated to 37 ° C is circulated inside the sample tube with a roller pump, and after one day, approximately 20 cm of the sample tube Was cut, one end was sealed with forceps, 504 μl of citric acid-added bovine blood adjusted to a citric acid concentration of 0.38% by weight was added to the sample tube, and the tube was sealed and incubated at 37 ° C. To coagulate blood, 56 μl of 1/40 normal calcium chloride solution was added to start coagulation of blood. After 3 minutes, 560 μl of trisodium citrate was added to the sample tube again to stop blood coagulation. The resulting thrombus was collected, lyophilized and weighed in 0.01 mg units. The results are shown in Table 1. The numerical values in Table 1 are the values obtained by calculating the relative weight ratio of the thrombus formed in the tube, with the amount of thrombus formed in the glass tube having the same diameter (blank test) set to 1.

[0024]

[Table 1]

(Evaluation Test 2: Evaluation of Antibacterial Property) The antibacterial property was evaluated by the following method. The series of operations were all performed aseptically. A Pseudomonas aeruginosa solution having a concentration of about 1 × 10 ⁷ cells / ml (hereinafter, this fungal solution is referred to as a stock solution) was prepared with a broth solution diluted 50 times with sterile physiological saline. The number of bacteria in this stock solution was measured as follows. 10 ^{4 of} stock solution
After doubling the dilution, 100 μl was spread on a regular agar plate, and the number of Pseudomonas aeruginosa colonies formed after 24 hours was counted. If the number of colonies is N ₁ , the concentration C of the stock solution is (1)
It is shown by the formula. C = 10 ⁴ × N ₁ /0.1=10 ⁵ × N ₁ (pieces / ml) (1)

100 μl of the above-mentioned stock solution of broth (sterilized raw solution)
Dilute with saline solution 40 times) to adjust the total volume to 40 ml.
(Hereinafter, this solution is referred to as an immersion stock solution). In the dipping stock solution,
Immerse the cut film sample into 5 cm x 5 cm,
It was cultured at 37 ° C for 24 hours. After culturing, immerse the undiluted solution in sterile physiological food.
10 times in series with salt waterⁿDiluted twice (hereinafter 10 ⁿ
Abbreviated as double dilution). Add 100 μl of diluted solution to normal agar medium
Pseudomonas aeruginosa formed on ordinary agar plate after 24 hours
Of 30 to 300 colonies
It was If the number of colonies obtained by measurement is Nn,
Product 25 cm²The number of bacteria after contact with film A of Na is (2)
Given by the formula. Na = 40 × 10ⁿ × Nn / 0.1 piece / 100μl (2) On the other hand, the number Nb of bacteria before contacting film A
The bacterial concentration of the bacterial stock solution before touching was C above,
Since the liquid volume is 100 μl, it is represented by the formula (3). Nb = 0.1 × C = 10^Four × N₁      Pieces / 100μl (3) 25 cm in 40 ml of dipping stock solution²With the size of film
The change in the number of bacteria (Nb → Na) due to contact is shown in Table 2.
The fact that contact reduces the number of bacteria means that the
It shows that the fungus is exhibited. Incidentally, the film
1-3 is 1% by weight of the composites obtained in Examples 1-3, respectively.
EOG sterilization (ethylene oxide
Polyvinyl chloride resin film sterilized by id gas)
And the film 4 is the polyvinyl chloride resin film described above.
Was treated by a method similar to the tube treatment shown in Example 4.
The film 5 is an untreated polyvinyl chloride film.
It is a nil resin film.

[0027]

[Table 2]

None of the tubes of the comparative examples, which were molded from resin widely used for tubes and catheters for medical purposes, had both high antithrombotic property maintenance and antibacterial property. On the other hand, the examples had both antithrombotic properties and high antibacterial properties for a long period of time. This is because the mucopolysaccharides (heparins) exert antithrombotic properties when they come into contact with liquid, and silver and / or the fourth cation which is a counter cation.
It is considered that the quaternary ammonium is eluted by the dissociation of the ionic bond with the mucopolysaccharide and exerts a bactericidal effect on the bacterium.

[0029]

The antibacterial imparting antithrombotic composite of the present invention comprises:
It is a material capable of imparting important functions, that is, antibacterial property and antithrombotic property, to medical devices.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61L 29/00 A61L 29/00 T 31/00 31/00 T 33/00 A61P 7/02 33/10 31 / 04 A61P 7/02 A61L 2/16 A 31/04 Z // A61L 2/16 33/00 T AF term (reference) 4C058 AA12 AA14 AA15 AA16 AA17 BB07 CC02 JJ03 JJ05 JJ06 JJ07 JJ08 JJ23 4C081 AB31 AC08 BA05 CD06 CE01 CE03 CG07 EA06 4C086 AA01 EA27 HA01 MA03 MA04 NA05 ZA54 ZB35 ZC75 4C206 AA01 FA41 JB01 MA03 MA04 MA28 NA05 ZA54 ZB35 ZC75

Claims (6)

[Claims] 1. An antibacterial imparting antithrombotic complex, wherein at least a part of counter cations of at least one mucopolysaccharide is silver ions and organic cations. 2. The antibacterial imparting antithrombotic complex according to claim 1, wherein the mucopolysaccharide is at least a heparin salt or a heparin-salt. 3. The antibacterial imparting antithrombotic complex according to claim 1, wherein at least a part of the organic cation which is a counter cation of the mucopolysaccharide is quaternary ammonium. 4. The antibacterial property imparting antithrombotic complex according to claim 1, wherein at least a part of the organic cation which is a counter cation of the mucopolysaccharide is a water-insoluble quaternary ammonium salt compound. 5. The quaternary ammonium salt compound which is soluble in water and the quaternary ammonium salt compound which is insoluble in water, at least a part of the organic cation which is a counter cation of the mucopolysaccharide. Antithrombogenic complex with antibacterial properties. 6. Contact with blood, characterized in that the antibacterial property imparting antithrombotic complex according to any one of claims 1 to 5 is applied to at least a part of the blood contact surface of a medical device that contacts blood. Medical equipment to use.