Classifications

• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
  • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
  • C12N5/0068—General culture methods using substrates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/14—Macromolecular materials
  • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
  • A61L27/507—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials for artificial blood vessels
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
  • C12N2533/00—Supports or coatings for cell culture, characterised by material
  • C12N2533/30—Synthetic polymers

Definitions

• the present invention relates to elastomeric polymeric surfaces that provide for the attachment, growth and adhesion of mammalian cells without pretreating the surfaces, as well as processes for the preparation of these surfaces. More particularly, the present invention relates to polymeric substrates of select copolymers useful as vascular grafts, and methods for preparing the fibers used therein. BACKGROUND OF THE INVENTION
• U.S. 4,546,083 is directed to a cell culture device for the cultivation of animal, plant, microbiological or artificial cells.
• the device involves an arrangement of fibers within a housing which provides for a continuous flow of nutrient fluid through the housing.
• the fibers are coated by covalent or noncovalent adsorptive attachment with any desired cells to be grown in culture.
• any . fiber-forming material which is capable by itself or through further treatment of adsorbing viable cells on its surface can be utilized.
• One category of fibers is identified as heterochain synthetic polymers and includes polyesters.
• the reference further indicates that the fibers may be used as such or pretreated by physical or chemical methods. However, the reference concentrates on the attachment of cells to fibers by introducing certain growth media or pretreating agents. It only generalizes to the study of cell growth on fibers without pret eatment.
• U.S. 4,804,381 concerns an artificial vessel made of a icroporous membrane having .pores which are filled with a permeable gel or which are closed over by a thin porous layer.
• a monolayer of endothelial cells is provided on the internal surface and smooth muscle cells are layered on the outer surface.
• the membrane pores are large enough to disrupt the growth of endothelial cells over them, and thus the gel or the thin porous layer smooths the surface of the membrane on the inside.
• the endothelial cells grow to form a closed continuous monolayer.
• the artificial vessel according to the reference requires the gel or the thin porous layer together with the membrane.
• PCT/AU88/00368 relates to the use of a copolymer of perfluoro-3,6- dioxa-4-methyl-7-octene sulfonyl fluoride and a monomer, as a surface for the attachment and growth of adherent animal cells.
• the copolymer is cited as having particular application to the manufacture and use of prosthetic vascular grafts, connective tissue replacements and soft tissue replacements that incorporate such a copolymer.
• the copolymeric surface is provided for the attachment and growth of adhesive serum proteins, forming a copolymer-protein complex. These surfaces are further exposed to cells, whereupon the cells adhere to the surface.
• NAFION® a trademark of E. I. du Pont de Nemours and Company, Inc.
• NAFION® a copolymer of tetrafluoroethylene and adhesive proteins
• Greisler et al. entitled “Hemodynamic Effects on Endothelial Cell Monolayer Detachment from Vascular Protheses” (Arch Surg., Vol. 124, April, 1989) evaluates the adherence of endothelial cells that were cultured on fibronectin-treated prosthetic materials that were perfused in vitro under different pulsatile hemodynamic conditions.
• a feature of the present invention is the ability of the polymeric substrate to retain cells securedly even at relatively high flow rates and pulsatile pressures encountered in vivo with vascular grafts, and further that the cells are functional.
• a further advantage of the presently disclosed polymeric substrates is that the substrate surface may be formed in a variety of textures and porosities.
• the present invention is directed to a polymeric substrate having cells attached thereto, said substrate comprising a copolymer of repeating units of a soft segment having carbon and oxygen in a ratio of from 2.6 to 4.5 and of repeating units of a crystallizable hard segment.
• the soft segment is poly(tetramethylene ether glycol) .
• the crystallizable hard segment is pol (butylene terephthalate) .
• the copolymer contains from about 18 to about 77 weight percent (most preferred from about 65 to about 77 weight percent) of repeating units of the soft segment, and from about 23 to about 82 weight percent (most preferred from about 23 to about 35 weight percent) of repeating units of the crystallizable hard segment.
• the crystallizable hard segment is the reaction product of ethylene diamine with methylene bis(4,4'-diphenylisocyanate) .
• the copolymer contains from about 85 to about 95 weight percent (most preferred from about 85 to about 90 weight percent) of repeating units of the soft segment, and from about 5 to about 15 weight percent (most preferred from about 10 to about 15 weight percent) of repeating units of the crystallizable hard segment.
• the cells are selected from the group consisting of fibroblasts, adipose cells, endothelial cells, epithelial cells, organ parenchymal cells, muscle cells, nerve cells, cartilage cells, bone cells and mixtures thereof.
• the present invention further encompasses shaped articles comprising the above described polymeric substrate and having cells attached thereto.
• a preferred article according to the invention is shaped as a vascular graft and connecting a vessel to another portion thereof or to another vessel.
• the article comprises a polymeric substrate having an interior surface and an exterior surface, the interior surface defining an aperture therethrough and having cells attached thereto.
• the substrate comprises a copolymer of repeating units of a soft segment having a carbon and oxygen ratio of from 2.6 to 4.5 and of repeating units of a crystallizable hard segment.
• the present invention also includes various methods for the preparation of shaped articles of the invention.
• One such method is for the preparation of shaped articles comprising a polymeric substrate having cells attached thereto, said substrate comprising a copolymer of repeating units of a soft segment having carbon and oxygen in a ratio of from 2.6 to 4.5 and of repeating units of a crystallizable hard segment.
• the method comprises: shaping said polymeric substrate into the desired shaped article; and attaching said cells to said polymeric substrate.
• Figure 1 is a plot of total cell response as a function of the carbon to oxygen ratio in polyester segments of polymeric substrates according to the invention.
• Figure 2 is an illustration of the ex vivo shunt apparatus used in examples herein.
• Figure 3 is a series of photomicrographs illustrating blood clot formation for various polymeric surfaces.
• the polymeric substrates of the present invention are adaptable to a wide variety of biological and physical applications. In general, these substrates find utility in any environment wherein natural or artificial vessels, tissues, organs and the like are to be joined together. Thus the present polymeric substrates are useful for the support and functioning of mammalian cells. Exemplary of such uses but without intending to limit the generality of the foregoing are vascular grafts, arterio-venus fistulae, artificial hearts, heart valves, aneurysm repair, ventricular assist devices, and cardiac patches, support for artificial organs such as pancreas and bone marrow and other cellular therapy devices and tissue cultures.
• the polymeric substrates may also be used to introduce artificial pancreas, artificial liver or other artificial organs into a biological system. These substrates may also serve as bone marrow cell growth, nerve cell growth, cells from other tissues, and the like.
• the polymeric substrates also find utility with respect to specific depletion therapy, transgenic cell approaches, cell-drug delivery systems, and in vitro cell culture devices.
• the polymeric substrates developed as vascular grafts are considered to be particularly useful in blood vessel bypass procedures, wherein the graft connects an artery to another portion thereof or to another artery. Another utility of these polymeric substrates is to enhance peripheral circulation and wherein the graft connects a blood vessel to another portion thereof or to another blood vessel.
• the crystallizable hard segment be an aromatic diacid.
• the preferred carbon to oxygen ratio of the soft segment is from 4.0 to 4.3.
• the surface characteristics of the polymeric substrate affect the attachment, growth and securedness of the various cells supported by the substrate. For example, if the substrate surface texture is rough (defined generally as having a variety of indentations and other features so that it is not topically uniplanar) the cells are not afforded a suitable base to promote desirable attachment to the surface. In particular, the texture with such features in the range of about 0.1 to 50 ⁇ m is detrimental to endothelial cell attachment and growth. However and preferably if the substrate surface is smooth in texture, the various cells generally attach to the surface; further the cells are capable of growth on a smooth surface and are secured to the surface sufficiently to withstand certain levels of flow rate and pressures of fluids that move relative to the cells in situ. These cells may function to prevent blood clotting.
• the porosity of the surface of the polymeric substrate is the porosity of the surface of the polymeric substrate.
• the surface may have no porosity; that is, the surface has no apertures of any type therein.
• a nonporous surface promotes adhesion, growth and attachment of the cells, and it is a requirement for shaped articles that must insulate the flow of fluids (i.e., no exhange of materials across the polymeric substrate) .
• a surface with very large pores is not a suitable substrate for the attachment and support of cells.
• there is a range of pore size of the surface that is suitable for cell attachment while simultaneously providing a means for the exchange of fluids through the substrate.
• the useful range of porosity of this invention is from 0.01 to 10 ⁇ m.
• cells useful with the present invention classified as mammalian cells
• most preferred are endothelial cells.
• the substrate may further comprise an adsorption promoting layer of chemical compound interposed between the substrate and the cells.
• shaped articles contemplated according to the invention may be formed from the copolymeric soft and hard segments reviewed previously.
• the shaped article may be formed with a soft segment of poly(tetramethylene ether glycol) .
• crystallizable hard segment used to form the shaped article may be selected from either poly(butylene terephthalate) or alternatively the reaction product of ethylene diamine with bis (4,4 '-diphenylisocyanate) .
• These articles may further employ aliphatic diacids for the hard segment.
• the polymeric substrates can be fabricated in a variety of shapes, including flat, tubular, fiber and bead. Hence, the variety of shapes herein is expressed in general terms as planar, cylindrical and spherical. Generally the surface diameter should be at least about twice the diameter of the spread cell being deposited.
• a preferred shaped article is the aformentioned vascular graft. Particularly preferred in a vascular graft constructed of a soft segment of poly(tetra ⁇ methylene ether glycol) and a crystallizable hard segment of pol (butylene terephthalate) or alternatively the reaction product of ethylene diamine with methylene bis (4, 4'-diphenylisocyanate) .
• the vascular graft of the present invention is particularly attractive when the inner surface of the graft is lined with endothelial cells. In tests, these cells remained secured to the graft as fluid passes through the graft, at flow rates of up to 200 ml/min and pulsatile pressures of up to 150 over 80 mm Hg.
• a method considered particularly useful in preparing vascular grafts according to the invention comprises shaping the polymeric substrate into a shaped article (preferably a fiber) having an interior surface and an exterior surface, with the interior surface defining an aperture therethrough. Cells are introduced into the interior surface of the fiber. Unattached cells are removed from the interior surface thereof, and the article is placed in a suitable growth medium under conditions sufficient to allow the cells to grow to a desired density along the interior surface thereof.
• Central to the instantly claimed polymeric substrates is the ratio of carbon to oxygen in the copolymer soft segment. As revealed in Figure 1, the total cell response (considered as attachment and growth of the cells) increases as the ratio of carbon to oxygen is increased wherein the soft segment is polyester.
• thermoplastic copolyester elastomer consisting essentially of a multiplicity of recurring intralinear long chain and short chain ester units connected head- to-tail through ester linkages, said long chain ester units being represented by the following structure:
• G is a divalent radical remaining after removal of terminal hydroxyl groups from poly(alkylene oxide) glycols having a carbon to oxygen ratio of about 2.5-4.3, a molecular weight above about 400 and a melting point below about 60°C;
• R and R 1 are divalent radicals remaining after removal of carboxyl groups from dicarboxylic acids having molecular weights less than about 300;
• D is a divalent radical remaining after removal of hydroxyl groups from a low molecular weight diol having a molecular weight less than about 250; with the provisos that the short chain ester units constitute about 23-82% by weight of the copolyester, at least about 80% of the R groups must be 1, -phenylene radicals, at least about 80% of the D groups must be 1,4-butylene radicals, and the sum of the percentages of the R groups which are not 1,4-phenylene radicals and of the D groups which are not 1,4-butylene radicals cannot exceed about 20%.
• long chain ester units as applied to units in a polymer chain refers to the reaction product of a long chain glycol with a dicarboxylic acid. Such "long chain ester units", which are a repeating unit in the copolyesters of this invention, correspond to the Formula (a) above.
• the long chain glycols are polymeric glycols having terminal (or as nearly terminal as possible) hydroxy groups and a molecular weight above about 400 and preferably from about 400-40U0.
• the long chain glycols used to prepare the copolyesters of this invention are pol (alkylene oxide) glycols having a carbon to oxygen ratio of about 2.5-4.3.
• Representative long chain glycols are poly(1,2- and 1,3-propylene oxide) glycol, poly(tetramethylene oxide) glycol, random or block copolymers of ethylene oxide and 1,2-propylene oxide (used in proportions such that the carbon to oxygen mole ratio in the glycol exceeds 2.5) and random or block copolymers of tetrahydrofuran with minor amounts of a second monomer such as methyltetrahydro- furan (used in proportions such that the carbon to oxygen mole ratio on the glycol does not exceed about 4.3) .
• short chain ester units as applied to units in a polymer chain refers to low molecular weight compounds of polymer chain units having molecular weights less than about 550. They are made by reacting a low molecular weight diol (below about 250) with a dicarboxylic acid to form ester units represented by Formula (b) above.
• polymers having a poly(tetramethylene ether glycol) soft segment and a hard segment of poly(butylene terephthalate) are described in U.S. Patent 4,906,729 which is incorporated by reference herein. It is to be understood that in selecting a polymer according to the reference or otherwise according to the invention, the polymer must be substantially free of contaminants and impurities. For example, the polymers must be substantially free of silicon. This is not to say that additives cannot be incorporated into the polymer; depending on the desired properties certain additives may be appropriate for addition. Rather, and as is understood by those skilled in the art, these polymers must be biocompatible and accordingly types of additives and levels of impurities must be carefully controlled.
• At least about 80 mole percent of the dicarboxylic acid incorporated into the polymer be terephthalic acid and at least about 80 mole percent of the low molecular weight diol incorporated into the polymer be 1,4-butanediol.
• at least 80% of the R groups in Formulae a and b above are 1,4-phenylene radicals and at least about 80% and the D groups in Formula b above are 1,4-butylene radicals.
• a further requirement in making the polymers of this invention is that the sum of the percentages of the R groups which are not 1,4-phenylene radicals and the D groups which are not 1,4-butylene radicals cannot exceed about 20%.
• the copolyesters of this invention contain about 23-82% by weight of short chain ester units corresponding to Formula (b) above, the remainder being long chain ester units corresponding to Formula (a) above.
• the copolyesters contain less than about 48% by weight short chain units, the tear strength and solvent resistance of the copolyesters fall to undesirably low levels and when the copolyesters contain more than about 65% short chain units, the low temperature properties worsen and the copolyesters become less elastomeric.
• the opt.imum balance of properties is obtained when the short chain ester content is about 23-35%.
• the preferred copolyesters of this invention are those prepared from dimethylterephthalate, 1,4-butane ⁇ diol and poly(tetramethylene oxide) glycol having a molecular weight from about 600-2000.
• the polymers described herein can be made conveniently by a conventional ester interchange reaction.
• poly(tetramethylene ether glycol) soft segment together with the reaction product of ethylene diamine with methylene bis(4,4'-diphenyl ⁇ isocyanate) as the hard segment is one of a family of polymers considered useful for the present invention.
• segmented polyurethane There are long chain synthetic polymers that comprise at least 85% by weight segmented polyurethane.
• the terms "soft segment” and “hard segment” refer to specific portions of the polymer chains.
• the soft segments are the polyester portion ' s of the segmented polyurethane and polymer and the hard segments refer to the portions of the polymer chains that are derived from the reaction of an organic diisocyanate with a diamine chain extender.
• Glycol acidity refers to end groups, such as acid end groups, of the polyester glycol precursor which do not react with organic diisocyanates under conventional urethane-for ing conditions, such as those illustrated in the examples below.
• the isocyanate end group content of a polymer may be referred to as the NCO content.
• segmented polyurethanes contain the recurring linkage -0-CO-NH-.
• a substantial number of the urethane nitrogens may be joined to radicals, usually aromatic, which are further attached to a ureylene residue -NH-C0-NH-.
• these segmented polyurethanes are prepared from hydroxyl-terminated prepolymers such as hydroxyl-terminated polyethers of low molecular weight.
• the prepolymer Reaction of the prepolymer with a stoichiometric excess of organic diisocyanate, preferably an aromatic diisocyanate, produces an isocyanate-terminated polymeric intermediate, which may then be chain-extended with a difunctional, active hydrogen-containing compound, such as water, hydrazine, organic diamines, glycols, dihydrazides, amino-alcohols, etc.
• a difunctional, active hydrogen-containing compound such as water, hydrazine, organic diamines, glycols, dihydrazides, amino-alcohols, etc.
• the preferred hydroxyl-terminated prepolymers are the polyether glycols, and random or blocked copolymers of tetrahydrofuran with minor amounts of a second monomer such as methyl tetrahydrofuran.
• the preferred polyether glycols include polytetramethylene ether glycol and glycols of polytetramethylene ether having urethane
• the hydroxyl-terminated soft segment is generally . reacted with an organic diisocyanate which is preferably an aromatic diisocyanate, as indicated hereinabove.
• organic diisocyanate which is preferably an aromatic diisocyanate, as indicated hereinabove.
• aromatic diisocyanates include p-phenylene diisocyanate, 4,4'-biphenylene diisocyanate, p,p'-methylenediphenyl diisocyanate, and p,p'-isopropyl- idenediphenyl diisocyanate.
• Aliphatic and cycloaliphatic diisocyanates for example, 4,4'- methylenedicyclohexyl diisocyanate, are also suitable.
• the diisocyanates may contain other substituents, although those which are free from reactive groups other than the two isocyanate groups, are ordinarily preferred.
• the organic diisocyanate is not critical for this invention.
• the difunctional, active hydrogen-containing compounds suitable as chain-extenders include a wide variety of compounds, as indicated hereinabove.
• Organic diamines are preferred. Suitable diamaines include ethylenediamine, tetramethylenediamine, 1,2-propylene- diamine, m-xylylenediamine, p-xylylenediamine, cyclohexylenediamine, piperazine, and many others. Symmetrical aliphatic diamines are preferred, but aromatic diamines, e.g., p-phenylenediamine and p,p'-methylenedianiline, may be used.
• polyester soft segments into the polyurethane-based polymer.
• the soft segment is poly(tetramethylene ether glycol) and the hard segment is either poly(butylene terephthalate) or the reaction product of ethylene diamine with methylene bis(4,4'- diphenylisocyanate)
• these copolymers may be used as elastomeric matrices.
• Pure cultures of endothelial cells are obtained from excized canine jugular veins by either gently scraping the lumen of the vein with a scalpel, or by everting the blood vessel onto a glass rod and enzymatically treating the lumen of the vessel to remove the cells as commonly described in the literature.
• the cells Once removed from the lumen of the blood vessel, the cells are grown in culture media suitable for endothelial cells supplemented with 10% fetal calf serum and 2.5% endothelial cell growth supplement. Cells are maintained in culture for three to five passages before use.
• Polymer membranes of the examples are cut into discs (13 mm in diameter) , sterilized and placed into wells of a standard 24-well tissue culture dish. Samples are tightly secured to the bottom of the well by insertion of a thin, non-toxic gasket at the circumference of the well. All samples are run in triplicate and average attachment and growth results tabulated.
• endothelial cells are allowed to attach to polymer surfaces as described above. After one hour unattached cells are removed, growth medium is replaced and the cells are returned to the incubator for 48 hours to allow time for cell growth and replication. After 36 hours, cell growth medium is replaced with fresh medium containing 0.5 ⁇ Ci/ml 3 H-Thymidine. After 12 hours of cell growth in labeling medium, the cells are washed of free label, DNA is purified from each sample and counts incorporated into DNA are determined. D. Seeding and Growth of Cells on Polymers in Tubular Configuration
• Polymers in tubular configuration are plugged on one end.
• Cells in growth medium are then added to the lumen of the tube at a final concentration of 2 x 10 5 cells/cm 2 .
• the open end of the tubing is then plugged and the tubing is rotated at 1 rpm for two hours while cells are attaching. After two hours, tubing samples are unplugged, rinsed free of unattached cells and placed in growth medium for 48 hours. In order to visualize, cells are stained with Hematoxylin.
• a catalyst is prepared by dissolving 111.05 ml of tetrabutyl titanate in 900 ml of dry butanol-1 to form a solv.tion.
• a second solution is prepared by dissolving 3 g of anhydrous magnesium acetate in 100 ml of dry meth nol. Two parts by volume of the first solution is mixed with 1 part by volume of the secoi ⁇ d solution, resulting in catalyst.
• a stainless steel stirrer with a paddle cut to conform with the internal radius of the flask is positioned about 1/8" from the bottom of the flask and agitation is started.
• the flask is placed in an oil bath at 160°C, agitated for five minutes and then 7.1 ml of the catalyst is added.
• Methanol distills from the reaction mixture as the temperature is slowly raised to 250°C over a period of one hour.
• the pressure is gradually reduced to 0.3 mm, Hg within 20 minutes.
• the polymerization mass is agitated at 250°C/0.3 mm, Hg for 90 minutes.
• the resulting viscous molten product is scraped from the flask in a nitrogen (water and oxygen free) atmosphere and allowed to cool.
• the inherent viscosity of the product at a concentration of 0.1 g/dl. in m-cresol at
• Samples of polytetrafluoroethylene manufactured by the Du Pont Company were obtained. The samples were formed into disks according to the procedure recited previously. The disks were not pretreated.
• Canine endothelial cells at passage number four were used with the polytetrafluoroethylene disks in conjunction with the attachment and growth assays.
• Attacliment results cpm 51 chromium
• Growth results cpm 3 H-Thymidine
• EXftMPlE 1 Disks of polyester elastomer prepared under (E) of the procedures discussion were used with the canine endothelial cells at passage number four in conjunction with the attachment and growth assays. The disks were not pretreated. Attachment results (cpm 51 chromium) were determined as 14,810 ( ⁇ 1,774) and 90 percent of the total cells attached. Growth results (cpm 3 H-Thymidine) were determined as 41,125 (+ 1,578) and 75 percent of the total cells exhibited growth.
• polymeric substrates according to the invention compare favorably to pretreated polystyrene and further are superior to unpretreated polytetrafluoroethylene. COMPARATIVE EXAMPLE 3
• Tubes of experimental material 12 are connected to catheters 14 and a silastic tubing 16 by polytetrafluoroethylene connectors 18 and silastic connectors 20 as shown.
• the canine subject is injected with 100 IU Heparin/kg, and the femoral artery and vein are catheterized and circulating blood is diverted from the artery into the shunt tubing and back into the femoral vein. Blood is shunted through the tubing for two hours at unrestricted flow rates and normal blood pressures .
• the tubes 12 of polyester elastomer not containing cells were introduced into the above system under the specified conditions.
• polyester elastomer tubing is run in the shunt without cells, the tubing surfaces 12 pick up both red clot and white blood cells.
• Figure 3C cross section of tube viewed under low magnification (X 30.4)
• Figure 3D cross section of the tube viewed under high magnification (X 1000)
• nearly the entire surface has picked up elements from the blood and clot has begun to be deposited.
• Tubes 12 of polyester elastomer including endothelial cells were used in the ⁇ vivo shunt system described in the preceding Comparative Example.
• segmented polyurethane contained approximately 36% solids and had a viscosity of about 2100 poises at 40°C. This polymer had an intrinsic viscosity of 0.95, measured at 25°C in N,N-dimethylacetamide at a concentration of 0.5 gram per 100 ml of solution.

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Cited By (7)

• 1991
  • 1991-06-07 WO PCT/US1991/003905 patent/WO1991019783A1/en not_active Application Discontinuation
  • 1991-06-07 EP EP91910702A patent/EP0535026A1/de not_active Withdrawn
  • 1991-06-07 JP JP91510493A patent/JPH05507847A/ja active Pending
  • 1991-06-07 CA CA002084645A patent/CA2084645A1/en not_active Abandoned

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