JPS6099259A - Plasma gas jet treatment for improving bilogical adaptability of bio-material - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION TECHNICAL FIELD This invention relates to methods for improving the biocompatibility of biomedical articles and blood contacting devices for diagnostic or therapeutic use, including dental and orthopedic implants, vascular grafts, heart valves, etc. Concerning articles used as such.

BACKGROUND ART The present invention has been approved by the National Institute of Health, Inc. /ls3 was carried out with government support.

Biomedical articles, especially those that come into contact with blood, require certain properties to ensure acceptance by the body and body tissues for prolonged incorporation into the body.

Artificial artery replacement in humans to correct damaged arterial flow is well accepted.

Although grafts of I-lyester, nato-9 fluoroethylene, and other synthetic materials are commonly used when the diameter of the arterial replacement is generally greater than or equal to 6 millimeters,
However, synthetic vascular grafts having diameters less than 6 millimeters have generally not been used because of the increased potential for thrombosis and occlusion occurrence due to thinning of the vessel wall.

Research into the ideal artificial artery graft began about 25 years ago, with research and development concentrating on smooth-walled, non-thrombotic, "inert" grafts.The idea was to remove blood during surgery. Focus has been placed on Teflon and Dacron low porosity tissues which do not require pre-coagulation as there is no leakage.Over the past decade, more "reactive" or early thrombogenic grafts have been increasingly used in surgical applications.

Knitted, outer and final, inner velors appeared, all of which were porous and woven surfaces increasingly required pre-coagulation. These are thought to be better integrated throughout the body on a long-term basis by external tissue fixation by fibroblast ingrowth through the pores, and perhaps also by endoluminal fixation of non-thrombogenic biomedical passivating surfaces. I was disappointed.

The real challenge to current vascular substitutes is the small diameter (≠ dwarf and/or) low blood flow conditions encountered in the femoral-popliteal region or more importantly in the coronary arteries.

Although patency rates remain as high as 5% for aortic grafts at 5 years, femoral-axillary grafts have a patency rate of 5% at 5 years.
It exhibits a patency of 0 to 70 inches. Coronary artery replacement with prosthetic materials has rarely been attempted.

Porous polytetrafluoroethylene tubing for use in vascular grafts is described in U.S. Patent No. 3. ri1y2, /! ; No. 3 and No. 3. the law of nature! 3. ! ; described in No. 66. US Patent No.≠
, 3θ≠, 010 describes the application of porous elastomer coatings on the external surface of strained porous polytetrafluoroethylene tubing for use in vascular grafts.

U.S. Patent No. ≠, 3.2. /, No. 2// is the incorporation of anticoagulant substances in strained porous polytetrafluoroethylene materials and PTFE containing substances that neutralize the anticoagulant.
The incorporation of an outer porous elastomeric coating around the material is described. US Patent No. 20g, 7 Hiroj describes a tensioned PTFE polymer in which the fibrous structure on the inner surface is made of thinner fibers than the fibrous structure on the outer surface. U.S. Patent No. ≠, / 3. /31@ describes the production and use of strained porous PTFE materials whose pores are filled with water-insolubilized water-soluble polymers, such as polyvinyl alcohol. U.S. Patent No. 'l-, 3/2. No. 20 describes the surface modification of polyurethane with silicone rubber alloys, the materials being useful in the manufacture of biomedical storage products. US Patent No. 4T, 2E, IGO describes the production of a hesolin-receptive surface on a mixture of particulate resin and graphite. U.S. Patent No. 11. ．． 2 and 27 describe the addition of heparin to charged surfaces of biomedical articles by means of complex compounds of heparin and particulate, colloidal aqueous solutions of cationic surfactants. US Patent No. ≠, /ib,! No. 9r describes the coating of polymeric substrates with specific compounds mixed with hegulin-like substances. U.S. Patent No. ≠, /7, 7! No. 1, No. 1, No. 1, No. 1, No. 1, No. 2003-2010, discloses the use of poly(alpha-olefin-sulfone) membranes made from C3-C, alpha-olefins and sulfur dioxide for use in biomedical articles. U.S. Patent No. xi-, o11. ．．
r, No. 77g begins manufacturing prosthetic plastics made from repeating units with the structure -CH2-, -0-. U.S. Patent No. 3. gJ3. No. 040 is a braided linear 4? treated with a densification solution used as a pulse graft. Discloses the use of lyester fabric. U.S. Patent No. 3. 39.7u3
The number refers to the surface that comes into contact with blood using the formula C1F21'l + l.
The preparation of antithrombotic articles made by coating with an organic polymeric OI having a CmH2n'+ − nitrogen side chain is described. Komebatsu Patent No. G, 167.
No. 0413 describes the use of surface-modified refined Dac1con materials to make them antithrombotic. US% 1:4th t
, /7f, No. 32 is a biomedical month F used in biomedicine.
) Particular types of graft copolymers used in the production of all 9
Post yourself. United States Rigoday≠, 04t7δ is. 2@• describes a bi-velor synthetic vascular graft made of Dacron.

US Patent No. 3.5P≠0. No. 0 is available for MJ, 39
Polyvinyl chloride and thermoplastic polyester type pa? A blood sac made from urethane is described. American 1rF No. t, 3/
No. 363 is glutaral 7-hydro tanned.
) describes a tube of colloidal tissue that provides cross-linked colloidal fibrils for use as graft material;

A review of the safety and performance of currently available vascular grafts by American, Society, Huo, Artificial, Internal, Organs, Vol.
D. MortenSen's "Safety, And,"
4.Formance,Otsu,Calendar,Available,
It can be found in ``Vascular, Gu2xies''.

This paper also cites a comprehensive literature review conducted by Lid, Biomedical, Testing, Uga2 Tree, 7Edral, Food, And, Dog, Adonistration on vascular grafts and their safety. .

DISCLOSURE OF THE INVENTION It is an object of the present invention to improve the biocompatibility of matrix materials by
It is an object of the present invention to provide a method for treating a substrate material by exposing it to a plasma gas jet in the presence of at least one gas capable of forming a biocompatible surface on the substrate exposed to the plasma gas jet.

It is further an object of the present invention to provide surface-modified biomedical articles and methods of making such articles that are antithrombotic and/or blood biocompatible for a substantial period of time.

Another object of the invention is to provide an article that improves the biocompatibility of the surface of the article being treated by treating the surface in plasma gas projection in the presence of one or more selected gases.

It is a further object of the present invention to provide vascular grafts and vascular graft materials with substantially anti-embolism properties that reduce embolization over a substantial period of time. It is an object of the present invention to provide a method for producing 762 Zuma gas in the presence of 7 gases.

It is further an object of the grafting invention to expose the blood-exposed internal surfaces to a plasma gas jet in the presence of one or more selected gases to substantially improve the blood-contacting surfaces of the graft material, e.g. The object of the present invention is to provide a vascular graft that is substantially antithrombotic for a substantial period of time without affecting its properties, histology, surface contact area, and mechanical properties.

These and other objectives are to prepare a substrate material and to cover the surface of the substrate material with a uniform, co-M bonded, mechanically strong, extremely thin layer of ff1-formation capable of forming at least a biocompatible surface on the substrate. This is accomplished by exposure to plasma gas projection in the presence of one gas.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Implants, diagnostic or therapeutic blood-contacting devices, artificial vascular grafts, which can be used for a substantial period of time, especially when in contact with blood, and which are substantially non-thrombogenic. There is a need for original synthetic materials that are suitable for other articles of manufacture.Also, the small diameter replacements required are difficult to use in the human body organs currently used due to their tendency to be quickly blocked by blood clots. The thigh that produces females -
There is a need for vascular graft materials that can be used as axillary or axillary-tibial artery replacements and possibly in cardiac biopsy surgery.It is known to provide organic surface coatings on substrates by plasma polymerization. .

H, Yasuda's paper J, Macromol,
ScL-chem,.

A10C3), 3g3-1/120 pages (176), entitled "Grazma for modification of polymers"
The effects of IJ mer-formed Buzolazmas and polymer-forming Goodsmas on plasma-sensitive polymeric substrates are described.

The "f, F Zuma" used is the "f, F Zuma" generated by glow discharge.
It is used to mean "low temperature f2z i" or "cold glazma." The glasma produced by an electrical glow discharge contains various species that are chemically active or of sufficient energy to cause a chemical reaction, ie, covalent bonding to a suitable substrate material. For example, electrons, ions of both charges, excited molecules of various excitation levels, free radicals, and photons of various energies can be
is generated by

This includes tissue grafts and other orthopedic implants, diagnostic and/or therapeutic blood contact devices, catheters, vascular graft materials such as porous knitted or woven Dacron materials. , the deposition of certain gases as biocompatible polymers on the clean surfaces of substrate materials used as biologically suitable fillers in ponds. By "deposition" is meant the formation of a covalent bond between the substrate and the coating deposited on the substrate surface.

Substrate materials from which the biomedical articles of the present invention can be made include a wide range of materials. Generally, synthetic resins are conveniently used in the manufacture of articles. Such substrate materials are often polyethylene, polyacrylic, ? Lipropylene, polyvinyl chloride, polyamide, polystyrene, polyfluorocarbine, polyester, silicone rubber, hydrocarbon rubber, polycarbonate, and other such synthetic toilet materials. The substrate can be rigid or flexible, woven or non-woven, molded or shaped, porous or non-porous. Depending on the application to which the substrate is placed, e.g. valves,
bottles, catheters, sleeves.

Vascular grafts, surgical tubing, etc., are formed into the desired shape or configuration. The surface of the substrate to be treated is then coated with at least 7
Exposure to a plasma gas jet in the presence of a seed gas forms a uniform, tightly bonded, mechanically strong, extremely thin polymer layer on the surface of the substrate.

Preferably, norosma gas polymerization is carried out by placing the substrate in a vacuum chamber and applying radio frequency energy to the substrate in the vacuum chamber by means of a suitable transmitter. When exposed to glow discharge energy, the gas molecules present in the vapor have a high enough energy (approximately 4 teV) to break carbon-hydrogen bonds.
This leads to the formation of free radicals and pond species.

From this point on, polymerization begins gi4 and a thin, uniform polymer film is deposited on a substrate placed in a vacuum chamber. In the vapor state, organic gases 4, like other gases, are ionized by bombardment by electrons under discharge conditions, and such ions have excess energy which, when neutralized, leads to rapid polymerization.

Solid films can be produced from organic gases at a rate of several ounces per KWH. The thickness can be controlled by the IOA and depends on the concentration of the gas and the time the substrate is exposed to the 762 beam.

Exposing the substrate to glow discharge energy also affects the surface of the organic polymeric substrate that is in contact with the cold plasma gas. Energy species from the organic polymeric substrate surface break organic bonds, possibly releasing gaseous products such as hydrogen and forming carbon radicals. These groups can cause cross-linking of the substrate surface and surface modification of the substrate. The free radical sites formed on the substrate can also be used to directly initiate polymerization so that the polymer can be firmly attached to the substrate by carbon-carbon bonds.

Gases that can be used to form coatings or films on substrate materials include those capable of forming a biocompatible coating bonded to the substrate material in the presence of plasma gas projection;
For example, hydrocarbons, halohydrocarbons, halocarbons and 7
U/ is included. In particular, tetrafluoroethylene, chlorofluoroethylene, and chlorofluoroethylene can be used.

Parameters that define the thread that projects the plasma include the gas itself, the gas flow rate, the initial system pressure, the reactor geometry, and the frequency or projection power of the glow discharge device. f2 Zuma projection interface or capacitance method or um.

Any suitable method can be used. Electric energy is transferred to a neutral species, in this case a gas, and converts it into an active species. f-Zamma projection also results in surface active species of the substrate material when using organic polymeric resin substrates. The active gas species is covalently bonded to the substrate.

In the treatment of vascular graft materials to render them biocompatible, particularly hemocompatible, the vascular graft material is first washed with a suitable solvent and then dried under vacuum before being exposed to plasma gas projection. It is preferable. The graft material is then preferably subjected to surface etching and activation of the matrix.
t in the presence of an atmosphere of inert gas, e.g. argon.
-io.

'77) +7) Add energy to plasma gas projection.

This is then coated in the presence of an atmosphere of gas to deposit a biocompatible coating bonded to the substrate material.
Plasma gas projection treatment with watt energy. The pressure used can vary, but is generally within 0.10 to 10 torr. The treatment time during which the substrate is exposed to the glow discharge can be between 59 and 7 hours. The resulting surface coating is uniform, non-leaching, and repeatable over the entire surface of the substrate.

The following examples are illustrative of, but should not be considered limiting, the claimed methods and articles.

FIG. 1 is a schematic representation of the equipment used to process vascular graft material. Vascular graft material 1 was suspended in a glass reactor 2 such that the gas used for surface modification flowed at 3 into the reactor vessel and through the inside of the graft material 1. The reactor vessel was surrounded by a series of induction coils connected to a glow discharge generator. The gas outlet 5 in the reactor vessel is connected to an outflow solenoid valve 6 by a flexible stainless steel tube.
It was connected to a liquid nitrogen drag 7, a backflow filter 8 and a vacuum ponder 9. Gas containing container 1 used for surface modification of vascular graft material in a reactor container
0 was connected to the reactor vessel by a gas distribution line 11, and gas flow was controlled by an in-70 solenoid valve 12 and a micrometer low pulp 13. A pressure sensor 14 connected to sense the gas pressure within the reactor vessel was connected to a pressure gauge 15.

Woven or knitted small diameter vascular graft material (44j and j mm I D ) consisting of adaklon (polyethylene terephthalate) was prepared in 20% ethylene solution.
It was subjected to sonication for a minute and then a similar sonication wash in methanol and deionized water. /4420. for specific graft materials. /ri/7 and 2♂67 cc/
ctrt, 1A3-mmI with an average porosity of min
D Sauvage filamentous velor graft and/or
6 mm with a porosity of 7 J' cc/cIL·min
A USCI De Bakery tissue graft was included.

The cleaned grafts were fixed in a reactor vessel, supported along the central longitudinal axis of a cylindrically designed Goo discharge glass reactor as described above, and dried under vacuum to less than 0,000 torr. The reactor was flushed with argon gas for 5 minutes at 0.5 Torr. 0. ．． The samples were reacted for 5 minutes during a glow discharge of approximately /j watts with argon pressure adjusted to 20 torr. The glow discharge was discontinued and argon was allowed to flow through the sample for 5 minutes at o. 7' plasma gas projection resulted in surface etching and activation of the Dacron vascular graft material with argon gas. Argon gas was then replaced from the reactor vessel by tetrafluoroethylene gas. The samples were equilibrated in a tetrafluoroethylene atmosphere for 5 minutes at o, so tor and then subjected to glow discharge treatment for 30 minutes at o-io torr of tetrafluoroethylene at lj quat energy. After the glow discharge treatment, the graft material was placed in the reactor. The container was kept in an atmosphere of tetrafluoroethylene gas for about an hour. The resulting treated graft is ESCA
(electron spectroscopy chemical analysis) studies showed that it had a highly fluorinated internal surface with uniform reproducibility.

FIG. 2 shows the ESCA spectra of glow discharge treated graft material furnace treated according to the method described above in comparison to untreated graft material. Figure 3 shows the ESCA spectrum of glow discharge treated graft material treated by the above method in comparison to Teflon. The properties of the matrix material remained otherwise unchanged. The surface texture of the treated material was unchanged as shown by scanning microscopy examination and mechanical properties of the vascular graft material. The surface was modified by activation and etching, followed by oxidation of the etched material surface by exposure to atmosphere, by treatment with a plasma gas blast at 5'θ Watt energy for 5 minutes.

Glow discharge treated and control untreated grafts were treated with 5Nas
tic Connecting the cannulated femoral artery of the baboon to the cannulated femoral vein by the method of shunting eX, v
This ex vivo model of arterio-venous shunt injury has human-like platelet, f-purin lysis and clot formation functions. The graft material was evaluated by measuring patency, flow rate, platelet consumption, platelet survival, and graft platelet precipitation during three periods post-graft placement: /) Acute response (O-2 hours) 2) Steady state Conditional response (>7 days) 3) Discontinuation response (<7 weeks) Figure 27 shows the blood flow versus vascular time (tetrafluoroethylene treated □, untreated and treated with argon only). Significantly improved patency and correspondingly improved flow was observed in the tetrafluoroethylene treated vascular grafts versus untreated control Dacron grafts.

Argon etched only vascular grafts showed inferior patency and flow when compared to untreated control vascular grafts.
ID vascular grafts showed improved patency when compared to vascular grafts treated 1 week later.

In Figure 6, jmmlD treated vascular grafts showed improved patency when compared to untreated vascular grafts after 1 week.

It was determined by laser scattering detection that untreated vascular grafts generated approximately three times as many emboli as did tetrafluoroethylene treated vascular grafts.

[Brief explanation of drawings]

Figure 1 is a schematic diagram of the equipment used for article processing; Figures 2 and 3 are graphical evaluations of treated and untreated artificial artery grafts using the ESCAC chemical analysis electronic spectrometer; is treated according to the present invention and 7'c44jmml
D Graph of patency vs. time in the ex vivo baboon femoral shunt study model of highly porous Dacron/Veroanite and comparative untreated highly porous Dacron veloranit, again in the same cracked femoral shunt test model. Figure 6 is a graph of the average relative surface liquid flow versus time for similarly treated and untreated velorite for /1 treated according to the present invention;
2. No treatment, 3. Graph of patency vs. time for the baboon femoral shunt test model of 5 mm 10 da 207 tissue treated with argon only, Figure 7 is also the same as Figure 6 for the same cracked femoral shunt test model.
1 is a graph of average relative surface liquid flow versus time for a Dacron structure. DESCRIPTION OF SYMBOLS 1... Graft material, 2... Reactor, 7... Liquid nitrogen drug, 9... Vacuum pump, 10... Gas storage container. Continued from Page 1 of 7 (Continued) Inventor Andrew Engerwinkle Inventor Stephen Arnoson 1512 North 85th Street, Seattle, Washington 98103 United States Encinitas Met-Vista, California 92024 Way 201 Procedural Correction Correction Power Formula) % Formula % ■, Incident Display Patent Application No. 1, 1982. 62753
No. 3. Relationship with the person making the amendment Applicant's name: Washington Research Foundation 4, Agent □

Claims (1)

[Scope of Claims] (1) A method of manufacturing an artificial vascular vessel by treating surfaces exposed to blood to render it long-term antithrombotic and/or blood compatible, the method comprising: cleaning and drying the material; , the vascular graft material is placed in a reactor vessel and the surface of the material exposed to blood is exposed to f2 plasma gas projection in the presence of an inert gas to generate surface etching and active species on the surface of the material exposed to blood. The surface of the substrate to be treated is exposed to a plasma gas jet in the presence of an organic gas selected from the group consisting of halohydrocarbons and nolocarzans, which can be precipitated in the presence of a 7"2 plasma gas jet, and A method comprising forming a thin covalently bonded coating on the surface of a material without changing the mechanical properties of the material or its surface texture. (2) an organic gas at a pressure ranging from 0.10 to 0.0 Torr. The material is exposed to an atmosphere of j~, and the substrate and gas atmosphere are
Glow discharge energy in the range of 100 watts /
A method according to claim 1, comprising exposing for a period of time. (3) The method according to claim (1), wherein the inert gas is argon and the organic gas is tetrafluoroethylene. (4) A method of manufacturing a vascular graft by treating the surface to render it long-term antithrombotic and/or hemocompatible, the method comprising: placing clean, dry graft material in a reactor vessel; Expose the material to a plasma gas jet in the presence of an atmosphere of argon, replace the argon with a halocargin gas, expose the material to a plasma gas jet in the presence of an atmosphere of argon, discontinue the plasma gas jet, and remove the material from the halocargin gas. placing the device in an atmosphere of ging gas for a predetermined period of time. (5) The method according to claim (4), wherein the artificial vascular material is woven polyethylene terephthalate. (6) the artificial vascular material is a porous fluorocarbon hydrocarbon, and the halocarbon gas is tetrafluoroethylene;
A method according to claim M(4). (7) The method according to claim (6), wherein the halocarbon gas is tetrafluoroethylene. (8) A surface-modified vascular-plant material whose treated surface is antithrombotic and/or hemocompatible for extended periods of time when exposed to blood, wherein the treated surface has a thin covalent bond on the surface. Weaving plants with coatings resulting from electrolytic discharge polymerization processes carried out primarily in a fluorocarbon atmosphere, 7000 yen! (9) A method for producing a surface-modified article whose modified surface is antithrombotic and/or blood-compatible for extended periods of time when exposed to blood, fluids, the method comprising: a substrate material; exposing the surface of a substrate material to a plasma gas projection in the presence of at least seven gases selected from the group consisting of halohydrocarbons and nolocarpines capable of forming a thin covalently bonded coating thereon; method including. (to) A biomedical article manufactured by the method according to claim (9). α or a method for producing a surface-modified matrix material, the modified surface of which is antithrombotic and/or hemocompatible for extended periods of time when exposed to blood, the method comprising: placing the matrix material in a reactor vessel; exposed to a plasma gas jet in the presence of an inert gas atmosphere for a time sufficient to etch and activate the surface of the substrate exposed to the inert gas atmosphere; The substrate material is exposed to a plasma gas jet in the presence of an organic gas selected from the group consisting of hydrocarbons and gases that can be deposited on the substrate as a thin covalently bonded coating, and the plasma gas The ionization of gas molecules, the partial reaction of the ionized molecules to yield polymer molecules, and the condensation of polymer molecules on the substrate to form covalently bonded sheeting on the substrate, as well as the mechanical properties of the substrate material and the 4. The method includes: 4) producing the surface set a and not producing the surface set a. . (6) Cleaning and drying the substrate material under vacuum prior to exposure to plasma gas projection, especially 1f! f request t
The method described in subsection (b). (2) The method of claim #M, wherein the plasma gas projection is generated by applying a high frequency wave generator to a substrate contained in a reactor vessel. α4 The applied pre-energy is j−60 watts and the presence of gas in the reactor vessel is 0, / 0−
Claim No. 7 (
2) Method described in section 2). . (g) A biocompatible article manufactured by the method described in claim 09.