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WO1983003536A1 - A multilayer bioreplaceable blood vessel prosthesis - Google Patents

A multilayer bioreplaceable blood vessel prosthesis

Info

Publication number
WO1983003536A1
WO1983003536A1 PCT/US1983/000574 US8300574W WO1983003536A1 WO 1983003536 A1 WO1983003536 A1 WO 1983003536A1 US 8300574 W US8300574 W US 8300574W WO 1983003536 A1 WO1983003536 A1 WO 1983003536A1
Authority
WO
Grant status
Application
Patent type
Prior art keywords
blood
vessel
collagen
prosthesis
cross
Prior art date
Application number
PCT/US1983/000574
Other languages
French (fr)
Inventor
Institute Of Technology Massachusetts
Ioannis V. Yannas
Original Assignee
Massachusetts Inst Technology
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14Macromolecular materials
    • A61L27/26Mixtures of macromolecular compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, E.G. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/04Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
    • A61F2/06Blood vessels
    • A61F2/062Apparatus for the production of blood vessels made from natural tissue or with layers of living cells
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28Materials for coating prostheses
    • A61L27/34Macromolecular materials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/507Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials for artificial blood vessels
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B29WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE, IN GENERAL
    • B29CSHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C47/00Extrusion moulding, i.e. expressing the moulding material through a die or nozzle which imparts the desired form; Apparatus therefor
    • B29C47/0009Extrusion moulding, i.e. expressing the moulding material through a die or nozzle which imparts the desired form; Apparatus therefor characterised by the shape of the articles
    • B29C47/0023Hollow rigid articles having only one tubular passage
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B29WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE, IN GENERAL
    • B29CSHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C47/00Extrusion moulding, i.e. expressing the moulding material through a die or nozzle which imparts the desired form; Apparatus therefor
    • B29C47/0009Extrusion moulding, i.e. expressing the moulding material through a die or nozzle which imparts the desired form; Apparatus therefor characterised by the shape of the articles
    • B29C47/003Articles having cross-sectional irregularities, i.e. being non-flat or having cylindrical cross-sections perpendicular to the extrusion direction
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B29WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE, IN GENERAL
    • B29CSHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C47/00Extrusion moulding, i.e. expressing the moulding material through a die or nozzle which imparts the desired form; Apparatus therefor
    • B29C47/08Component parts, details or accessories; Auxiliary operations
    • B29C47/78Heating or cooling the material to be extruded or the stream of extruded material or of a preformed part
    • B29C47/88Heating or cooling the stream of extruded material
    • B29C47/8895Heating or cooling the stream of extruded material using a bath, e.g. extruding into an open bath to coagulate or cool the material

Abstract

Process for forming a multilayer blood vessel prosthesis (10). Each layer is formed from bioreplaceable materials which include those produced by contacting collagen with an aminopoly-saccharide and subsequently covalently crosslinking the resulting polymer, polymers of hydroxyacetic acid and the like. Cross flow filtration molding and wet extrusion molding are two processes which are particulary useful for forming the inner layer (12) of the blood vessel prosthesis (10) the outer layer (14) of the blood vessel prosthesis (10) is preferably formed by freeze drying a dispersion of the bioreplaceable material onto the inner layer(s). The disclosed blood vessel prosthesis (10) is a multilayer structure with each layer having a porosity and other physicochemical and mechanical characteristics selected to maximize the effectiveness of the blood vessel. The prosthesis (10) functions initially as a thromboresistant conduit with mechanical properties which match those of the adjacent natural blood vessel. Eventually, the prosthesis (10) functions are a regeneration template which is replaced by new connective tissue that forms during the healing process following attachment of the prothesis.

Description

A MULTILAYER BIOREPLACEABLE BLOOD VESSEL PROSTHESIS

Government Sponsorship

Work relating to this invention was partially 'supported by a contract from the National Institutes of Health, Contract/Grant No. 5 R01 HL24 036-02.

Background of the Invention

It is widely acknowledged that the use of autologous vascular tissue in repair or replacement surgical procedures involving blood vessels, especially small blood vessels (i.e., 5mm or less) provides long-term patency superior to that of commercially available prostheses. However, the use of autologous vascular grafts (e.g., autologous vein grafts used in coronary bypass surgery) is associated with several problems. For example, harvesting of an autologous vascular .graft constitutes a serious surgical invasion which occa¬ sionally leads to complications. Furthermore, the autolo¬ gous vascular graft may frequently be unavailable due to specific morphological or pathophysiological characteristics of the individual patient. For example, a patient may lack a length of vein of the appropriate caliber or an existing disease (e.g., varicose veins) may result in veins of un¬ suitable mechanical compliance. In addition to the fore¬ going, the use of autologous vein grafts for coronary bypass or femoropopliteal bypass or for interposed grafting of ar¬ teries frequently leads to development of intimal prolifera¬ tion which eventually leads to loss of patency.

The experience with autologous vein grafts suggests the need for a suturable tubular product available without invading the patient. This product should be readily avail¬ able in sterile form and in a large variety of calibers, de¬ grees of taper of internal diameter and degrees of bifurca-

OMPI tion (branching). In addition to ready availability and long-term patentcy, the graft should also remain free of aneurysms, infection and calcification and should not cause formation of emboli nor injure the components of blood over the duration of anticipated use.

The present invention is a blood vessel prosthesis which meets all of the foregoing criteria.

Summary of the Invention

A blood vessel prosthesis in accordance with the present invention is a multilayer tubular structure with each layer being formed from a bioreplaceable material that is capable of being prepared in the form of a strong, sutur- able tubular conduit of complex geometry. This bioreplace¬ able material can be either a natural or a synthetic poly¬ mer. The preferred natural material is collage -aminopoly- saccharide . The preferred synthetic material is a polymer of hydroxyacetic acid. Adjacent layers can be prepared by use of different polymers giving a multilayered composite tubular structure.

The material of the blood vessel prosthesis is capable of undergoing biodegradation in a controlled fahion and re¬ placement, without incidence of cellular proliferative pro¬ cesses, synthesis of fibrotic tissue or calcification. The use of the prosthesis of the present invention enables a regeneration of the transected vascular wall of the host, thereby obviating long-term complications due to the pre- sence of an artificial prosthesis. Of course, the material of the blood vessel is compatible with blood and does not cause platelet aggregation or activation of critical steps of the intrinsic and extrinsic coagulation cascades.

The multilayer tubular structure in accordance with the present invention possesses mechanical strength suffi- cient for convenient suturing and for withstanding without rupture the cyclical load pattern imposed on it by the car¬ diovascular system of which it forms a part. Its mechanical compliance matches the compliance of the blood vessel to which the graft is sutured, thereby minimizing thrombus for- mation caused by a geometric discontinuity (expansion or contraction of conduit) . The prosthesis has sufficiently low porosity at the bloodgraft interface to prevent sub¬ stantial leaking of whole blood or blood components. The blood compatibility is sufficient to prevent thrombosis or injury to blood components or generation of emboli over the period of time during which the graft is being replaced by regenerating vascular tissue.

The prosthesis has the property of replacing the vital functions of the blood vessel both over a short-term period, up to about 4 weeks, in its intact or quasi-intact form; as well as the property of replacing the functions of a blood vessel over a long-term period, in excess of about 4 weeks, in its regenerated form, following a process of biological self-disposal and replacement by regenerating vascular tis¬ sue of the host. The long-term function of the prosthesis is related to its ability to act as a tissue regeneration template, a biological mold which guides adjacent tissue of the blood vessel wall to regrow the segment which was re¬ moved by surgery. The term bioreplaceable refers to this process of biological" self-disposal and replacement by re¬ generation.

Accordingly, an object of the invention is to provide a blood vessel prosthesis which possesses many of the advan¬ tages of autologous vascular tissue and which can be used in place of autologous vascular grafts to eliminate many of the problems associated with their use.

A further object of the invention is to provide a pro¬ cess .for making such a blood vessel prosthesis.

Brief Description of the Drawing

Fig. 1 is a cross-sectional view of a blood vessel prosthesis in accordance with the present invention;

Fig. 2 is a diagrammatic illustration of the process of the present invention. Description of the Preferred Embodiments"

At the outset, the invention is described in its broadest overall aspects with a more detailed description following. As is shown in Fig. 1, the blood vessel pro¬ sthesis 10 of the present invention is, in one important embodiment, a multilayer tubular structure consisting of an inner tubular layer 12 comprising a relatively smooth and non-porous bioreplaceable polymeric lining, optionally seeded with endothelial, smooth muscle or fibroblast cells prior to grafting, and which serves as a scaffold for neo- intimal and neomedial tissue generation; and, an outer tubu¬ lar layer 14 comprising a rough and highly porous biore¬ placeable polymeric layer optionally seeded with smooth muscle or fibroblast cells prior to grafting and which serves as a scaffold for neoadventitial and neomedial tissue generation and mechanical attachment of the graft to the host's perivascular tissues.

Following the complete disposal of the graft by bio- degradation and its replacement by neovascular tissue with¬ out incidence of cellular proliferative processes, the newly formed blood vessel possesses the histological structure of the physiological blood vessel wall.

The preferred materials for the prosthesis of the present invention are cross-linked collagen-aminopoly- saccharide composite materials disclosed in U.S. Patent 4,280,954 by Yannas et al, the teachings of which are incor¬ porated herein by reference.

These composite materials have a balance of mechanical, chemical and physiological properties which make them useful in surgical sutures and prostheses of controlled biodegradability (resorption ) and controlled ability to prevent development of a foreign body reaction, and many are also useful in applications in which blood compatibility is required. Such materials are formed by intimately contact¬ ing collagen with an aminopolysaccharide under conditions at which they form a reaction product and subsequently cova- lently cross-linking the reaction product.

The products of such syntheses are collagen molecules or collagen fibrils with long aminopolysaccharide chains attached to them. Covalent cross-linking anchors the amino¬ polysaccharide chains to the collagen so that a significant residual quantity of aminopolysaccharide remains permanently bound to collagen even after washing in strong aminopoly¬ saccharide solvents for several weeks.

Collagen can be reacted with an aminopolysaccharide in aqueous acidic solutions. Suitable collagen can be derived from a number of animal sources, either in the form of solid powder or in the form of a dispersion, and suitable amino- polysaccharides include, but are not limited to, chondroitin 4-sulfate, chondroitin 6-sulfate, heparan sulfate, dermatan sulfate, keratan sulfate, heparin, hyaluronic acid or chito- san. These reactions can be carried out at room tempera¬ ture. Typically, small amounts of collagen, such as 0.3% by weight, are dispersed in a dilute acetic acid solution and thoroughly agitated. The polysaccharide is then slowly added, for example dropwise, into the aqueous collagen dis¬ persion, which causes the coprecipitation of collagen and aminopolysaccharide. The coprecipitate is a tangled mass of collagen fibrils coated with aminopolysaccharide which some¬ what resembles a tangled ball of yarn. This tangled mass of fibers can be homogenized to form a homogeneous dispersion of fine fibers and then filtered or extruded and dried.

The conditions for maximu attachment of aminopoly¬ saccharide without significant partial denaturation (gela- tinization) has been found to be a pH of about 3 and a temperature of about 37 C. Although these conditions are preferred, other reaction conditions which result in a sig¬ nificant reaction between collagen and aminopolysaccharide are also suitable.

Collagen and aminopolysaccharides can be reacted in many ways. The essential requirement is that the two mater¬ ials be intimately contacted under conditions which allow the aminopolysaccharides to attach to the collagen chains. The collagen-aminopolysaccharide product prepared as des¬ cribed above can be formed into sheets, films, tubes and other shapes or articles for its ultimate application. In accordance with the present invention the collagen-amino- polysaccharide product is formed into tubes and thereafter is cross-linked.

Although the natural collagen-aminopolysaccharide polymer is the preferred material of the invention, other biodegradable and bioreplaceable materials, both natural and synthetic can be used. An example of a synthetic material useful in the invention is a polymer of hydroxyacetic acid. Polyhydroxyacetic ester eventually undergoes complete biode- gradation when implanted, its short term strength makes it quite useful as a prosthetic device material.

One method for forming the inner conduit 12 is the cross flow filtration molding process disclosed in U. S. Pa¬ tent 4,252,759 entitled "Cross Flow Filtration Molding Method", by Yannas et al, the teachings of which are incor¬ porated herein by reference. The molding apparatus includes a mold with porous walls having the predetermined shape. The porous walls contain pores having a size sufficient to retain dispersed particles on the wall surface as liquid medium passes through the walls. Means for' introducing dis¬ persion to the mold are also present, and typically comprise a pump for pumping dispersion through the mold. Means for applying hydrostatic pressure to dispersion in the porous mold are also part of the apparatus. Typically, such means for applying pressure might be a source of compressed gas attached to a reservoir for the dispersion. The reservoir and a flow development module to eliminate hydrodynamic end effects in the mold are optionally employed.

The cross flow filtration molding process comprises pumping a dispersion of particles through a mold having porous walls which allow transport of a portion of the dis¬ persion medium therethrough. Hydrostatic pressure is ap¬ plied to drive dispersion medium through the porous mold walls thereby causing particles to deposit on the mold walls to form an article having the predetermined shape. After sufficient particles have deposited to provide the shaped article with the wall thicknesses desired, the flow of dis¬ persion through the mold is halted. If the dispersion used is the preferred collagen-arainopol saccharide, the shaped article is cross-linked to provide it with significantly im¬ proved structural integrity.

The amount of hydrostatic pressure necessary to drive the dispersion through the porous mold walls will vary with many factors, including the chemical composition, size, charge and concentration of particles; the chemical composi¬ tion of the liquid medium; the shape, size, wall thickness, etc., of the article to be molded; and the size of pores in the mold walls. In the case of a dispersion of coprecipi- tated collagen-aminopolysaccharide particles, for example, the pressure applied should be at least about ten p.s.i.g. to achieve a practical rate of medium transport through the mold walls. With larger particles, lower pressures can be used. Also, the desired pressure difference across the mold wall can be established by applying vacuum to the mold ex¬ terior.

The wall thickness of the tube produced in the mold can be varied. This is primarily done by adjusting the molding time, but other' factors such as the dispersion flow rate, the hydrostatic pressure applied, the dispersion con¬ centration, etc., also affect wall thickness. In accordance with the present invention, the wall thickness of inner tube 12 is between the range of 0.1 to 5.0 mm.

It is clear, of course, that a wide variety of mold shapes besides hollow tubing could be employed. In fact, it is believed that the mold could be virtually any closed shape which has at least two ports. Thus, the mold might have the shape of an elbow, T-joint, bifurcated tubes, tubes with tapering diameters, or other shape. The fact that the mold can be virtually any shape is particularly beneficial since a great variety of morphology is found in natural blood vessels.

The incorporation of a woven or knitted fabric, e.g., a polyester velour or mesh, within the prosthesis of the invention serves to mechanically reinforce the prosthesis. One way to incorporate such a fabric within the prosthesis is to line the cross flow filtration mold with the fabric before pumping the dispersion of bioreplaceable particles through the mold.

Another method for forming a collagen-a inopolysaccha- ride inner conduit 12 is the wet extrusion molding process. In this process, a collagen dispersion is extruded through a die over a mandrel into a precipitating aminopolysaccharide bath.

The preferred conditions for producing the collagen tubes by the wet extrusion process are a collagen concentra¬ tion of 2.5% and a pressure of 12 p.s.i.g. for extrusion. Thicker-walled tubes may be produced uniformly at slightly higher collagen concentrations and extrusion pressures.

The wet extrusion molding process is suitable for fast production of the inner conduit but currently appears limi¬ ted to fabrication of articles with axial symmetry, i.e., tubes, fibers or sheets. The cross flow filtration molding process, on the other hand, is relatively slow but is suit¬ able for molding of hollow articles of narrow shapes, inclu¬ ding bifurcated tubes and tubes with tapering diameters.

As seen in Fig. 2, after the initial formation of the preferred collagen-aminopolysaccharide inner conduit by either the wet extrusion method or the cross flow filtration method, it is cross-linked. If the inner conduit is formed from a synthetic bioreplaceable material, e.g., a polymer of hydroxyacetic acid, there is no cross-linking step, as the material degrades by hydrolyis. Covalent cross-linking can be achieved by many specific techniques with the general ca¬ tegories being chemical, radiation and dehydrotherraal meth¬ ods. An advantage to most cross-linking techniques contem¬ plated, including glutaraldehyde cross-linking and dehydro- thermal cross-linking, is that they also serve in removing bacterial growths from the materials. Thus, the composites are being sterilized at the same time that they are cross- linked.

One suitable chemical method for covalently cross- linking the collagen-aminopolysaccharide composites is known as aldehyde cross-linking. In this process, the inner tube 12 is contacted with aqueous solutions of aldehyde, which '"serve to~ cross-link the materials._ Suitable aldehydes include formaldehyde, glutaraldehyde and glyoxal. The pre¬ ferred aldehyde is glutaraldehyde because it yields the de¬ sired level of crosslink density more rapidly than other aldehydes and is also capable of increasing the cross-link density to a relatively high level. It has been noted that immersing the preferred collagen-aminopolysaccharide compo¬ sites in aldehyde solutions causes partial removal of the polysaccharide component by dissolution thereby lessening the amount of aminopolysaccharide in the final product.

Covalent cross-linking of the preferred collagen- aminopolysaccharide inner conduit serves to prevent dis¬ solution of aminopolysaccharide in aqueous solutions thereby making inner tube 12 useful for surgical prostheses. Cova¬ lent cross-linking also serves another important function by contributing to raising the resistance to enzymatic resorp- tion of these materials. The exact mechanism by which cross-linking increases the resistance to enzymatic degrada¬ tion is not entirely clear. It is possible that cross- linking anchors the aminopolysaccharide units to sites on the collagen chain which would normally be attacked by coll- agenase. Another possible explanation is that cross-linking tightens up the network of collagen fibers and physically restricts the diffusion of enzymes capable of degrading collagen.

The mechanical properties of collagen-aminopolysaccha¬ ride networks are generally improved by cross-linking. Ty¬ pically, the fracture stress and elongation to break are increased following a moderate cross-linking treatment. Maximal increases in fracture stress and elongation to break are attained if the molded tube is air dried to a moisture content of about 10%-wt. prior to immersion in an aqueous aldehyde cross-linking bath.

In accordance with the present invention, the cross- linked inner conduit 12 should have an M (number average molecular weight between cross-links) of between about 2,000 to 12,000. Materials with M values below about 2,000 or above about 12,000 suffer significant losses in their ech-

OMP fa >, V/IP anical properties while also undergoing bioreplacement at a rate which is either too slow (low M-.) or a rate which is too fast (high Mc) . Composites with an c of between about 5,000 and about 10,000 appear to have the best balance of mechanical properties and of bioreplacement rate, and so this is the preferred range of cross-linking for the inner conduit 12. Such properties must include low porosity (average pore diameter less than 10 microns) . Thus, the inner conduit should be permeable to low molecular weight constituents of blood, but should not allow leakage of whole blood.

If the inner conduit 12 is formed by cross flow fil¬ tration molding, a mandrel is inserted into the lumen of inner conduit 12 and is used to immerse conduit 12 into an aldehyde solution. The above described procedure of forming the inner tube by the cross flow filtration method and thereafter cross- linking the tube itself may be repeated to build up an inner tube having a wall thickness of 0.1 to 5.0 mm. If the inner conduit 12 is formed by wet extrusion molding, the mandrel which is already situated in the lumen of inner conduit 12 is used to immerse conduit 12 into an aldehyde solution.

As seen in Fig. 2, after the desired wall thickness is achieved, the inner tube 12 is treated to provide it with outer layer 14, having a thickness of at least 1.0 mm. As has been set forth above, the outer layer 14 is also formed from bioreplaceable materials, preferably collagen—amino¬ polysaccharides. The outer layer 14 is applied to the inner layer 12 by a freeze drying process. In its broadest overall aspects, this process is performed by immersing the cross-linked inner tube 12 in a pan 22 containing the appropriate bioreplaceable polymeric dispersion. As is shown in Fig. 2, the inner tube 12 is supported on a mandrel 38 and the inner tube 12 is covered with the dispersion 17 to form the outer layer of bioreplaceable material. The pan 22 itself is placed on the shelf of a freeze dryer which is maintained at -20 C or lower by mechanical refrigeration or other methods known to the art. Soon after making contact with the cold shelf surface," the bioreplaceable polymer dis¬ persion freezes and the ice crystals formed thereby are sub¬ limed in the vacuum provided by the freeze dryer. Eventual¬ ly, the dispersion is converted to a highly porous, spongy, solid mass which can be cut to almost any desired shape, i.e., elbow, bifurcated tubes, tapered cylinder, by use of an appropriate tool. By use of such a tool, the porous mass is fashioned to a cylinder which includes the inner layer and the mandrel.

If the outer layer of the conduit is made from colla- gen-a inopolysaccha ides, then after the freeze dried slab is cut to the desired shape and wall thickness, the mandrel with the freeze dried conduit is subjected to temperature and vacuum conditions which lightly cross-link the multi- layered structure, thereby preventing collapse of pores following immersion in aqueous media during subsequent pro¬ cessing or applications. This treatment also serves as a first sterilization step. Following such treatment, the conduit is further cross-linked, e.g., by immersing it in an aqueous glutaraldehyde bath. This process also serves as a second sterilization step. The conduit is then rinsed ex¬ haustively in physiological saline to remove traces of un- reacted glutaraldehyde.

The preferred collagen-aminopolysaccharide outer layer of the prothesis is biodegradable at a rate which can be controlled by adjusting the amount of aminopolysaccharide bonded to collagen and the density of cross-links. The M-, for this layer is between the range of 2,000 to 60,000 with 10,000-20,000 being the preferred range. Deviations from this range give nonoptimal biodegradation rates. The re¬ quired mean pore diameter is 50 microns or greater.

Optional treatments of the formed multilayered conduit include: (a) seeding of the inner or outer layers by inocu¬ lation with a suspension of endothelial cells, smooth muscle cells, or fibroblasts using a hypodermic syringe or other convenient seeding procedure; and (b) encasing the conduit in a tube fabricated from a woven or knitted fabric, e.g., a polyester velour or mesh. By seeding at certain loci, cell growth occurs rapidly in pla'ces where it"would be' elayed if allowed to occur naturally, thereby drastically reducing the amount of time necessary to regenerate the vascular tissue. Sheathing the conduit with fabric serves to provide a mecha¬ nical reinforcement for the conduit.

The mandrel, which the multilayered conduit is mounted on, is removed preferably following the above optional pro¬ cessing steps and prior to storage of the sterile conduit in a container. Just prior to use, the conduit is removed from its sterile environment and used surgically as a vascular bypass, as an interposed graft or as a patch graft for the blood vessel wall.

To be suitable for vascular prostheses, vessels 10 must have certain minimum mechanical properties. These are mechanical properties which would allow the suturing of can¬ didate vessels to sections of natural vessel, a process known as anastomosis. During suturing, such vascular (blood vessel) grafts must not tear as a result of the tensile forces applied to them by the suture nor should they tear when the suture is knotted. Suturability of vascular grafts, i.e., the ability of grafts to resist tearing while being sutured, is related to the intrinsic mechanical strength of the material, the thickness of the graft, the tension applied to the suture, and the rate at which the knot is pulled closed. Experimentation performed indicates that the minimum mechanical requirements for suturing a graft of at least 0.01 inches in thickness are: (1) an ulti¬ mate tensile strength of at least 50 p.s.i.? and (2) an elongation at break of at least 10%.

The best materials for vascular prostheses should duplicate as closely as possible the mechanical behavior of natural vessels. The most stringent physiological loading conditions occur in the elastic arteries, such as the aorta, where fatigue can occur as a result of blood pressure fluc¬ tuations associated with the systole-diastole cycle. The static mechanical properties of the thoracic aorta can be used as a mechanical model. The stress-strain curve of the thoracic aorta in the longitudinal direction of persons

OMP "20-29 years of age has been 'determined by Yamada." See. Ya ada, H., "Strength of Biological Materials," ed. F.G. Evans, Chapter 4, Williams & Wilkins (1970). From this plot, the mechanical properties were calculated and found to be: (1) an ultimate tensile strength of 360 p.s.i.; (2) elon¬ gation at break of 85%; (3) tangent modulus at 1% elongation of 50 p.s.i.; and (4) fracture work, i.e., the work to rup¬ ture (a measure of toughness), of 21,000 p.s.i.-%. These four mechanical properties serve as a quantitative standard for mechanical properties of vascular prostheses.

The process of the present invention is further illus¬ trated by the following non-limiting examples.

EXAMPLE 1 The raw material for molding was a bovine hide colla- gen/chondroitin 6-sulfate dispersion prepared as follows: Three grams of glacial acetic acid were diluted into a vo¬ lume of 1.0 liter with distilled, deionized water to give a 0.05 M solution of acetic acid. The fibrous, freeze-dried bovine hide collagen preparation was ground in a Wiley Mill, using a 20-mesh screen while cooling with liquid nitrogen. An Eberbach jacketed blender was precooled by circu¬ lating cold water. (0 -4C) through the jacket. Two hundred milliliters (ml) of 0.05 M acetic acid were transferred to the blender and 0.55 g of milled collagen was added to the blender contents. The collagen dispersion was stirred in the blender at .high speed over 1 hr.

A solution of chondroitin 6-sulfate was prepared by dissolving 0.044 g of the aminopolysaccharide in 20 ml of 0.05 M acetic acid to make a 8%-wt. solution (dry collagen basis). The solution of aminopolysaccharide was added dropwise over a period of 5 min to the collagen dispersion while the latter was being stirred at high speed in the blender. After 15 min of additional stirring the dispersion was stored in a refrigerator until ready for use.

The total amount of collagen-chondroitin 6-sulfate dispersion used was first treated in a blender and then fed into an air-pressurized Plexiglas tank. A magnetic stirrer bar served:- to minimize particle concentration gradients in¬ side the vessel. Dispersion exited from the bottom of the pressure vessel and flowed into a flow development module and perforated aluminum tube split lengthwise which acted as a mold for tubes. Filter paper was carefully glued to each of the two halves of the aluminum tubes using alpha cyano- acrylate adhesive. The flow development module and mold had an inside diameter of 0.25 inches and the flow development module was 17 in. long whereas the mold was 10.5 in. long. Additionally, the perforated aluminum tubing had a series of 0.03" pores extending linearly every 45" of circumference and positioned every 0.01". upon entry into the tubular mold, a fraction of the water of the dispersion was forced through the filter paper and subsequently through the perforation in the tube wall where it evaporated into the atmosphere giving the outside of the mold a "sweating" appearance.

While transport of a fraction of water and particles proceeded radially inside the tube mold, the decanted bulk of the dispersion inside the mold flowed uneventfully in the axial direction and was pumped back to the pressure vessel through a dispersion return line where it was stirred and recycled back into the mold.

At an applied pressure of 30 p.s.i.g., and a flow rate of approximately 2.5 ml/min, a gel layer of about 0.004 inches thick had formed after a period of about 6 hours of operation which, when air dried after decanting the non- gelled fluid, was sufficiently concentrated to be handled without loss of shape.

Tubes fabricated in this manner were removed from the tubu¬ lar mold without being detached from the filter paper and were subjected to an Insolubilization (cross-linking) treat¬ ment by immersion in 250 ml. of 0.5% w/w glutaraldehyde sol¬ ution for 8 hours. The 10-inch tube obtained has a thick¬ ness of 0.0028, 0.0030, 0.0034, 0.0034 and 0.0034 inches at distances of 2, 4, 6, 8 and 10 inches, respectively, from the upstream end of the tube.

The tube was mounted on a cylindrical Plexiglas man- " drel, 0.0030 inches diameter, and was immersed in the.pan of a freeze dryer containing a volume of collagen-aminopoly¬ saccharide dispersion which was sufficient to cover the tube completely. The ends of the mandrel rested on supports mounted on the pan. In this manner, the side of the tube closest to the bottom of the pan was prevented from con¬ tacting the latter.

The pan was placed on the shelf of a Virtis freeze dryer. The shelf had ben precooled at -40°C or lower by mechanical refrigeration. The chamber of the freeze dryer was closed tightly and a vacuum of 120 mTorr was established in the chamber. Several minutes after contact with the shelf, the dispersion solidified into a frozen slab which was marked by the characteristic pattern of ice crystals. The temperature of the shelf was increased to 0 C. Several hours later, the temperature of the shelf was slowly raised to 22°C and the contents of the pan were removed in the form of a spongy, white solid slab. A specimen cut from the slab was examined in a scanning electron microscope revealing a mean pore diameter of about 80 m.

By use of a sharp tool, sufficient solid material was removed from the porous slab to expose the cylinder enclosed in the mass. A layer, approximately 1 mm thick, of porous material was left attached on the inner nonporous cylinder. The mandrel with the multilayered conduit was then placed in a vacuum oven where it was treated at 105 C and 50 mTorr pressure over 24 hours. Following removal from the oven, the mandrel was placed in 250 ml of 0.58% w/w glutaraldehyde solution over 8 hours where it was additionally crosslinked and sterilized before being rinsed in sterile physiological saline over 24 hours to remove traces of unreacted glutar¬ aldehyde. After removing the mandrel, the multilayered con¬ duit was stored either in 70/30 isopropanol water in a ster¬ ile container or was stored in the freeze-dried state inside a sterile container.

EXAMPLE 2 Example 1 was repeated except that 20%-wt. (dry colla- gen basis) of elastin was added to_ the collagen dispersion just before adding the mucopolysaccharide solution. Elastin was added to improve the mechanical behavior of the pros¬ thesis by increasing the elongation to break. Elastin pow¬ der from bovine neck ligament (Sigma Chemical Co.) or Crolastin, Hydrolysed Elastin, MW 4,000 (Croda, Inc., New York) were used.

EXAMPLE 3 Example 1 was repeated except that the mold used during cross flow filtration was much smaller in internal diameter, resulting in tubes with internal diameter of 2.6 mm and thickness 0.1 mm. The pressure level used to fabri¬ cate this tube was 100 p.s.i.g. rather than 30 p.s.i.g. used in Example 1, and the total molding time was 2 hours or less under these conditions. The tubes formed thereby had a fracture stress of 20 p.s.i. and an elongation to break of 15%.

EXAMPLE 4 Example 4 was repeated except that a dispersion of endothelial cells from a canine vein was prepared according to the method of Ford, et al (J. W. Ford, W. E. Burkel and R. H. Kahn, Isolation of Adult Canine Venous Endothelium for Tissue Culture, In Vitro 17, 44, 1981). The cell dispersion was then inoculated into the inner layer of a multilayer conduit by use of a sterile hypodermic syringe. During ino¬ culation the conduit was immersed in physiological saline maintained at 37 C.

Claims

1. A multilayer blood vessel prosthesis comprising: a first inner layer defining a relatively smooth walled lumen, said inner layer formed from bioreplaceable polymeric material and having a mean pore diameter below 10 microns and a wall thickness between 0.1 to 5.0 mm; and a second outer layer on said first layer, said outer layer formed from bioreplaceable polymeric material and having a mean pore diameter of 50 microns or greater and a thickness of at least 1.0 mm.
2. The blood vessel prosthesis as set forth in Claim 1 wherein the inner layer is formed from natural bioreplaceable polymeric material.
3; The blood vessel prosthesis as set forth in Claim 2 wherein the natural bioreplaceable polymeric material is co- valently cross-linked.
4. The blood vessel prosthesis as set forth in Claim 3 wherein the natural bioreplaceable polymeric material comprises collagen-aminopolysaccharide.
5. The blood vessel prosthesis as set forth in Claim 4 wherein the inner layer has been cross-linked to an average molecular weight between cross-links of between 2,000 to 12,000.
6. The blood vessel prosthesis as set forth in Claim 4 wherein the collagen-aminopolysaccharide comprises from 1 to 15% aminopolysaccharide.
7. The blood vessel prosthesis as set forth in Claim 4 wherein the aminopolysaccharide is selected from a member of the group consisting of chondroitin-4-sulfate, chondroitin the group consisting of" chohdroitin-4-sdlfate, chondroitin 6-sulfate, heparan sulfate, dermatan sulfate, keratan sulfate, heparin, hyauluronic acid and chitosan.
8. The blood vessel prosthesis as set forth in Claim 1 wherein the inner layer is formed from synthetic bioreplaceable polymeric material.
9. The blood vessel prosthesis as set forth in Claim 8 wherein the synthetic bioreplaceable material comprises a polymer of hydroxyacetic acid.
10. The blood vessel prosthesis as set forth in Claim 1 wherein the outer layer is formed from natural bioreplaceable polymeric material.
11. The blood vessel prosthesis as set forth in Claim 10 wherein the natural bioreplaceable polymeric material is covalently cross-linked.
12. The blood vessel prosthesis as set forth in Claim 11 wherein the natural bioreplaceable polymeric material comprises collagen-aminopolysaccharide.
13. The blood vessel prosthesis as set forth in Claim 12 wherein the outer layer has been cross-linked to an average molecular weight between cross-links of between 2,000 to 60,000.
14. The blood vessel prosthesis as set forth in Claim 12 wherein the collagen-aminopolysaccharide comprises from 1 to 15% aminopolysaccharide.
15. The blood vessel prosthesis as set forth in Claim 12 wherein the aminopolysaccharide is selected from a member of the group consisting of chondroitin 4-sulfate, chondroitin 6-sulfate, heparan sulfate, dermatan sulfate, keratan sulfate, heparin, hyaluronic acid, and chitosan.
16. The blood vessel prosthesis as" set forth in Claim 1 wherein the prosthesis has a tubular shape.
17. The blood vessel prosthesis as set forth in Claim 1 wherein the prosthesis has a bifurcated tubular shape.
18. The blood vessel prosthesis as set forth in Claim 1 wherein the prosthesis has a tapered cylinder shape.
19. The blood vessel prosthesis as set forth in Claim 1 wherein said inner layer is seeded with cells.
20. The blood vessel prosthesis as set forth in Claim 19 wherein said inner layer is seeded with endothelial cells.
21. The blood vessel prosthesis as set forth in Claim 19 wherein said inner layer is seeded with smooth muscle cells.
22. The blood vessel prosthesis a set forth in Claim 19 wherein said inner layer is seeded with fibroblasts.
23. The blood vessel prosthesis as set forth in Claim 1 wherein said outer layer is seeded with cells.
24. The blood vessel prosthesis as set forth in Claim 23 wherein said outer layer is seeded with smooth muscle cells.
25. The blood vessel prosthesis as set forth in Claim 23 wherein said outer layer is seeded with fibroblasts.
26. The blood vessel prosthesis as set forth in Claim 1 wherein the prostheis is sheathed with a woven or knitted fabric.
27. The blood vessel prosthesis as set forth in Claim 1 wherein the prosthesis has incorporated within it a woven or knitted fabric.
OMPI
28. A process for forming a _blood vessel prosthesis comprising:
A. forming a generally tubular inner layer of a covalently cross-linked reaction product of collagen and an aminopolysaccharide by:
1) cross flow filtration molding the reactants collagen and an aminopolysaccharide, and
2) after a tubular structure has formed, cross- linking the collagen-polysaccharide;
B. thereafter forming an outer layer on said inner layer by freeze drying a dispersion of collagen- aminopolysaccharide polymer on the outside surface of the tubular structure produced in step A and cross- linking the coating.
29. The process as set forth in Claim 28 wherein step A is repeated to produce an inner layer with a thickness between the range of 0.1 to 5.0 mm.
30. The process as set forth in Claim 29 including the step of seeding the inner layer by inoculation with a suspension of cells.
31. The process as set forth in Claim 28 including the step of seeding the outer layer by inoculation with a sus¬ pension of cells.
32. A process for forming a blood vessel prosthesis comprising:
A. forming a generally tubular inner layer of a covalently cross-linked reaction product of collagen ' and an aminopolysaccharide by:
1) extruding a collagen dispersion through a die over a mandrel into a precipitating aminopolysaccharide bath, and
2) cross-linking the collagen-aminopolysaccha¬ ride.
OMP
33-. The process as- set forth in Claim 32 wherein step A is repeated to produce an inner layer with a thickness between the range of .1 to 5.0 mm.
34. The process as set forth in Claim 33 including the step of seeding the inner layer by inoculation with a sus¬ pension of cells.
35. The process as set forth in Claim 33 including the step of seeding the outer layer by inoculation with a sus¬ pension of cells.
PCT/US1983/000574 1982-04-19 1983-04-18 A multilayer bioreplaceable blood vessel prosthesis WO1983003536A1 (en)

Priority Applications (2)

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US369,614820419 1982-04-19

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Cited By (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2558719A1 (en) * 1984-01-30 1985-08-02 Meadox Medicals Inc synthetic vascular graft, method of preparing such graft coated with collagen and sealed to blood and collagen fibril slurry for its preparation
GB2153235A (en) * 1984-01-30 1985-08-21 Meadox Medicals Inc Drug delivery collagen-coated synthetic vascular graft
FR2559666A1 (en) * 1984-02-21 1985-08-23 Tech Cuir Centre Process for manufacturing collagen tubes, in particular tubes of small diameters, and application of the tubes obtained in the field of vascular prostheses and nerve sutures
EP0206025A2 (en) * 1985-06-06 1986-12-30 Thomas Jefferson University Coating for prosthetic devices
EP0246638A2 (en) * 1986-05-23 1987-11-25 Cordis Corporation Biologically modified synthetic grafts
DE3639561A1 (en) * 1986-11-20 1988-06-01 Baumann Hanno A process for the preparation of non-thrombogenic substrates
US4820626A (en) * 1985-06-06 1989-04-11 Thomas Jefferson University Method of treating a synthetic or naturally occuring surface with microvascular endothelial cells, and the treated surface itself
EP0323144A2 (en) * 1987-12-28 1989-07-05 Vyzkumny Ustav Potravinarskeho Prumyslu Method of manufacturing at least single-layer tubular blood vessel endoprosthesis, especially of a small internal diameter, and extruding nozzle for carrying out this method
US4880429A (en) * 1987-07-20 1989-11-14 Stone Kevin R Prosthetic meniscus
WO1989010728A1 (en) * 1988-05-09 1989-11-16 Massachusetts Institute Of Technology Prosthesis for promotion of nerve regeneration
US5007934A (en) * 1987-07-20 1991-04-16 Regen Corporation Prosthetic meniscus
EP0457430A2 (en) * 1990-04-06 1991-11-21 Organogenesis Inc. Collagen constructs
US5131907A (en) * 1986-04-04 1992-07-21 Thomas Jefferson University Method of treating a synthetic naturally occurring surface with a collagen laminate to support microvascular endothelial cell growth, and the surface itself
WO1992014419A1 (en) * 1991-02-14 1992-09-03 Baxter International Inc. Pliable biological graft materials and their methods of manufacture
EP0504262A1 (en) * 1989-12-07 1992-09-23 Biosynthesis, Inc. Hollow viscus prosthesis and method of implantation
US5158574A (en) * 1987-07-20 1992-10-27 Regen Corporation Prosthetic meniscus
US5230693A (en) * 1985-06-06 1993-07-27 Thomas Jefferson University Implantable prosthetic device for implantation into a human patient having a surface treated with microvascular endothelial cells
US5263984A (en) * 1987-07-20 1993-11-23 Regen Biologics, Inc. Prosthetic ligaments
US5306311A (en) * 1987-07-20 1994-04-26 Regen Corporation Prosthetic articular cartilage
US5312380A (en) * 1985-06-06 1994-05-17 Thomas Jefferson University Endothelial cell procurement and deposition kit
US5314471A (en) * 1991-07-24 1994-05-24 Baxter International Inc. Tissue inplant systems and methods for sustaining viable high cell densities within a host
US5344454A (en) * 1991-07-24 1994-09-06 Baxter International Inc. Closed porous chambers for implanting tissue in a host
US5372945A (en) * 1985-06-06 1994-12-13 Alchas; Paul G. Device and method for collecting and processing fat tissue and procuring microvessel endothelial cells to produce endothelial cell product
EP0698396A1 (en) * 1994-08-12 1996-02-28 Meadox Medicals, Inc. Vascular graft impregnated with a heparin-containing collagen sealant
US5545223A (en) * 1990-10-31 1996-08-13 Baxter International, Inc. Ported tissue implant systems and methods of using same
US5569462A (en) * 1993-09-24 1996-10-29 Baxter International Inc. Methods for enhancing vascularization of implant devices
US5681353A (en) * 1987-07-20 1997-10-28 Regen Biologics, Inc. Meniscal augmentation device
US5713888A (en) * 1990-10-31 1998-02-03 Baxter International, Inc. Tissue implant systems
US5716660A (en) * 1994-08-12 1998-02-10 Meadox Medicals, Inc. Tubular polytetrafluoroethylene implantable prostheses
US5735902A (en) * 1987-07-20 1998-04-07 Regen Biologics, Inc. Hand implant device
US5741330A (en) * 1990-10-31 1998-04-21 Baxter International, Inc. Close vascularization implant material
US6060640A (en) * 1995-05-19 2000-05-09 Baxter International Inc. Multiple-layer, formed-in-place immunoisolation membrane structures for implantation of cells in host tissue
WO2000053121A1 (en) * 1999-03-09 2000-09-14 Froelich Juergen C Improved autologous vein graft
US6177609B1 (en) * 1997-03-10 2001-01-23 Meadox Medicals, Inc. Self-aggregating protein compositions and use as sealants
US6773458B1 (en) 1991-07-24 2004-08-10 Baxter International Inc. Angiogenic tissue implant systems and methods
US7241309B2 (en) 1999-04-15 2007-07-10 Scimed Life Systems, Inc. Self-aggregating protein compositions and use as sealants

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3272204A (en) * 1965-09-22 1966-09-13 Ethicon Inc Absorbable collagen prosthetic implant with non-absorbable reinforcing strands
US3883393A (en) * 1972-05-18 1975-05-13 Us Health Education & Welfare Cell culture on semi-permeable tubular membranes
US3949073A (en) * 1974-11-18 1976-04-06 The Board Of Trustees Of Leland Stanford Junior University Process for augmenting connective mammalian tissue with in situ polymerizable native collagen solution
US4060081A (en) * 1975-07-15 1977-11-29 Massachusetts Institute Of Technology Multilayer membrane useful as synthetic skin
US4252759A (en) * 1979-04-11 1981-02-24 Massachusetts Institute Of Technology Cross flow filtration molding method
US4280954A (en) * 1975-07-15 1981-07-28 Massachusetts Institute Of Technology Crosslinked collagen-mucopolysaccharide composite materials

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4286341A (en) * 1979-04-16 1981-09-01 Iowa State University Research Foundation, Inc. Vascular prosthesis and method of making the same

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3272204A (en) * 1965-09-22 1966-09-13 Ethicon Inc Absorbable collagen prosthetic implant with non-absorbable reinforcing strands
US3883393A (en) * 1972-05-18 1975-05-13 Us Health Education & Welfare Cell culture on semi-permeable tubular membranes
US3949073A (en) * 1974-11-18 1976-04-06 The Board Of Trustees Of Leland Stanford Junior University Process for augmenting connective mammalian tissue with in situ polymerizable native collagen solution
US4060081A (en) * 1975-07-15 1977-11-29 Massachusetts Institute Of Technology Multilayer membrane useful as synthetic skin
US4280954A (en) * 1975-07-15 1981-07-28 Massachusetts Institute Of Technology Crosslinked collagen-mucopolysaccharide composite materials
US4252759A (en) * 1979-04-11 1981-02-24 Massachusetts Institute Of Technology Cross flow filtration molding method

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Experimental Cell Research 94; issued 1975, MICHALOPOULOS, et al, Primary Culture of Parenchymal Liver Cells on Collagen Membranes, (pp 70-78) *
See also references of EP0107711A1 *

Cited By (56)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2153235A (en) * 1984-01-30 1985-08-21 Meadox Medicals Inc Drug delivery collagen-coated synthetic vascular graft
GB2153685A (en) * 1984-01-30 1985-08-29 Meadox Medicals Inc Collagen-coated synthetic vascular graft
FR2558719A1 (en) * 1984-01-30 1985-08-02 Meadox Medicals Inc synthetic vascular graft, method of preparing such graft coated with collagen and sealed to blood and collagen fibril slurry for its preparation
FR2559666A1 (en) * 1984-02-21 1985-08-23 Tech Cuir Centre Process for manufacturing collagen tubes, in particular tubes of small diameters, and application of the tubes obtained in the field of vascular prostheses and nerve sutures
EP0156740A1 (en) * 1984-02-21 1985-10-02 BIOETICA, Société Anonyme Method of manufacturing tubes from collagen, and its use in the field of vascular prostheses and nervous systems
US4820626A (en) * 1985-06-06 1989-04-11 Thomas Jefferson University Method of treating a synthetic or naturally occuring surface with microvascular endothelial cells, and the treated surface itself
EP0206025A2 (en) * 1985-06-06 1986-12-30 Thomas Jefferson University Coating for prosthetic devices
EP0206025A3 (en) * 1985-06-06 1988-03-02 Thomas Jefferson University Coating for prosthetic devices
US5372945A (en) * 1985-06-06 1994-12-13 Alchas; Paul G. Device and method for collecting and processing fat tissue and procuring microvessel endothelial cells to produce endothelial cell product
US5312380A (en) * 1985-06-06 1994-05-17 Thomas Jefferson University Endothelial cell procurement and deposition kit
US5230693A (en) * 1985-06-06 1993-07-27 Thomas Jefferson University Implantable prosthetic device for implantation into a human patient having a surface treated with microvascular endothelial cells
US5131907A (en) * 1986-04-04 1992-07-21 Thomas Jefferson University Method of treating a synthetic naturally occurring surface with a collagen laminate to support microvascular endothelial cell growth, and the surface itself
EP0246638A3 (en) * 1986-05-23 1989-03-15 Cordis Corporation Biologically modified synthetic grafts
EP0246638A2 (en) * 1986-05-23 1987-11-25 Cordis Corporation Biologically modified synthetic grafts
WO1988003813A1 (en) * 1986-11-20 1988-06-02 Ruprecht Keller Process for producing non-thrombogenic substrates
DE3639561A1 (en) * 1986-11-20 1988-06-01 Baumann Hanno A process for the preparation of non-thrombogenic substrates
US6042610A (en) * 1987-07-20 2000-03-28 Regen Biologics, Inc. Meniscal augmentation device
US5624463A (en) * 1987-07-20 1997-04-29 Regen Biologics, Inc. Prosthetic articular cartilage
US5007934A (en) * 1987-07-20 1991-04-16 Regen Corporation Prosthetic meniscus
US5681353A (en) * 1987-07-20 1997-10-28 Regen Biologics, Inc. Meniscal augmentation device
US5735903A (en) * 1987-07-20 1998-04-07 Li; Shu-Tung Meniscal augmentation device
US5158574A (en) * 1987-07-20 1992-10-27 Regen Corporation Prosthetic meniscus
US4880429A (en) * 1987-07-20 1989-11-14 Stone Kevin R Prosthetic meniscus
US5306311A (en) * 1987-07-20 1994-04-26 Regen Corporation Prosthetic articular cartilage
US5263984A (en) * 1987-07-20 1993-11-23 Regen Biologics, Inc. Prosthetic ligaments
US5735902A (en) * 1987-07-20 1998-04-07 Regen Biologics, Inc. Hand implant device
EP0323144A2 (en) * 1987-12-28 1989-07-05 Vyzkumny Ustav Potravinarskeho Prumyslu Method of manufacturing at least single-layer tubular blood vessel endoprosthesis, especially of a small internal diameter, and extruding nozzle for carrying out this method
EP0323144A3 (en) * 1987-12-28 1990-05-16 Vyzkumny Ustav Potravinarskeho Prumyslu Method of manufacturing at least single-layer tubular blood vessel endoprosthesis, especially of a small internal diameter, and extruding nozzle for carrying out this method
WO1989010728A1 (en) * 1988-05-09 1989-11-16 Massachusetts Institute Of Technology Prosthesis for promotion of nerve regeneration
EP0504262A1 (en) * 1989-12-07 1992-09-23 Biosynthesis, Inc. Hollow viscus prosthesis and method of implantation
EP0504262A4 (en) * 1989-12-07 1993-06-30 Biosynthesis, Inc. Hollow viscus prosthesis and method of implantation
EP0457430A3 (en) * 1990-04-06 1993-01-20 Organogenesis Inc. Collagen constructs
EP0457430A2 (en) * 1990-04-06 1991-11-21 Organogenesis Inc. Collagen constructs
US5545223A (en) * 1990-10-31 1996-08-13 Baxter International, Inc. Ported tissue implant systems and methods of using same
US5741330A (en) * 1990-10-31 1998-04-21 Baxter International, Inc. Close vascularization implant material
US5782912A (en) * 1990-10-31 1998-07-21 Baxter International, Inc. Close vascularization implant material
US5800529A (en) * 1990-10-31 1998-09-01 Baxter International, Inc. Close vascularization implant material
US5882354A (en) * 1990-10-31 1999-03-16 Baxter International Inc. Close vascularization implant material
US5713888A (en) * 1990-10-31 1998-02-03 Baxter International, Inc. Tissue implant systems
US5733336A (en) * 1990-10-31 1998-03-31 Baxter International, Inc. Ported tissue implant systems and methods of using same
US5593440A (en) * 1990-10-31 1997-01-14 Baxter International Inc. Tissue implant systems and methods for sustaining viable high cell densities within a host
WO1992014419A1 (en) * 1991-02-14 1992-09-03 Baxter International Inc. Pliable biological graft materials and their methods of manufacture
US5376110A (en) * 1991-02-14 1994-12-27 Baxter International Inc. Method of manufacturing pliable biological grafts materials
US5314471A (en) * 1991-07-24 1994-05-24 Baxter International Inc. Tissue inplant systems and methods for sustaining viable high cell densities within a host
US6773458B1 (en) 1991-07-24 2004-08-10 Baxter International Inc. Angiogenic tissue implant systems and methods
US5344454A (en) * 1991-07-24 1994-09-06 Baxter International Inc. Closed porous chambers for implanting tissue in a host
US5569462A (en) * 1993-09-24 1996-10-29 Baxter International Inc. Methods for enhancing vascularization of implant devices
EP0698396A1 (en) * 1994-08-12 1996-02-28 Meadox Medicals, Inc. Vascular graft impregnated with a heparin-containing collagen sealant
US5851230A (en) * 1994-08-12 1998-12-22 Meadox Medicals, Inc. Vascular graft with a heparin-containing collagen sealant
US6162247A (en) * 1994-08-12 2000-12-19 Meadox Medicals, Inc. Vascular graft impregnated with a heparin-containing collagen sealant
US5716660A (en) * 1994-08-12 1998-02-10 Meadox Medicals, Inc. Tubular polytetrafluoroethylene implantable prostheses
US6060640A (en) * 1995-05-19 2000-05-09 Baxter International Inc. Multiple-layer, formed-in-place immunoisolation membrane structures for implantation of cells in host tissue
US6177609B1 (en) * 1997-03-10 2001-01-23 Meadox Medicals, Inc. Self-aggregating protein compositions and use as sealants
US6299639B1 (en) 1997-03-10 2001-10-09 Meadox Medicals, Inc. Self-aggregating protein compositions and use as sealants
WO2000053121A1 (en) * 1999-03-09 2000-09-14 Froelich Juergen C Improved autologous vein graft
US7241309B2 (en) 1999-04-15 2007-07-10 Scimed Life Systems, Inc. Self-aggregating protein compositions and use as sealants

Also Published As

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EP0107711A4 (en) 1985-10-24 application

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