Method of Producing a Multi-Layer Self-Sealing Graft

The present invention provides a method of forming a multi-layer self sealing vascular graft. The graft produced is suitable for dialysis access.

Vascular grafts formed from ePTFE (expanded polytetrafluoroethylene), elastomer materials and/or fabric materials are well known and have been used to replace and/or by-pass diseased arteries. One important application of vascular grafts is to facilitate dialysis access in patients with end stage renal disease. Dialysis is critical for such patients to remove toxic metabolites from their blood. Blood is removed from the patient via a needle accessing their vasculature, and then passed through a dialysis machine (also termed an artificial kidney) prior to being returned to the patient's circulature via a second access point It is preferable to insert the needles into natural blood vessels such as a vein, or more preferably into a vein surgically connected to an artery to improve the blood flow. However the patient will require dialysis treatment at least twice a week and over time the repeated puncture of the natural vessels leads to suitable natural access sites becoming exhausted. At this stage an artificial graft is usually inserted between an artery and a vein to allow dialysis access.

Commonly, such dialysis grafts are formed from expanded polytetrafluoroethylene (ePTFE), and the manufacture of ePTFE through paste extrusion, stretching and sintering to obtain a microporous node and fibre structure is well-known in the art (see, for example, US 3,955,566 of Gore).

However ePTFE is of a relatively inelastic nature and is consequently prone to leaking from puncture holes made by needle insertion. To

overcome this limitation, ePTFE grafts are not normally accessed until several weeks after implant to allow tissue to grow around and into the microporous structure of the graft. This ingrown tissue then assists in sealing the puncture holes created in the graft during dialysis treatment.

A self-sealing access graft would be desirable, and a number of suggested grafts, incorporating a self-sealing elastomeric layer, have been proposed.

Herweck (US 5,192,310) discloses a multi-layer graft having two ePTFE tubular structures concentrically arranged. Herweck refers to the space between the two layers being filled with self-sealing elastomer but does not indicate the method of introducing the elastomer.

Schanzer (US 4,619,641) refers to an inner ePTFE tube surrounded by a larger coaxial ePTFE tube, with the gap between the two ePTFE tubes being filled with silicone rubber. In the Schanzer process room temperature vulcanising silicone sealant is used. Firstly, the gap between the two tubes is sealed at one end with the silicone rubber. Secondly, after curing for 24 hours the coaxial cavity is filled with silicone rubber, diluted in solvent, using a syringe pump. After rolling by hand on a flat surface to distribute the silicone, the graft is cured for a further 24 hours. The process described is laborious and is clearly not practical for use of a mass- produced medical device. Apart from the excessive time taken, there is little control over the distribution of the elastomer and variations in thickness are likely.

Hood (WO 2005/092240) discloses a tubular conduit having an internal helical bead to decrease turbulence by imparting a helical flow to blood passing through the tube. The use of a mould and a moulding liquid is

described and the moulding liquid can then be sintered onto the tube. The moulding liquid can be polyurethane.

Lentz (US 6,428,571 ) refers to a variety of methods for producing a self- sealing graft having an elastomer layer. In one example a pre-formed elastomer tube is placed over the inner layer. In another example elastomer is spun directly onto the inner layer. Application of elastomer from solution is also envisaged. All these methods have the limitations of being slow and complex.

We have now found that forming a layer of thermoplastic elastomer onto a tubular graft can be achieved simply and speedily by means of injection moulding.

In one aspect the present invention provides a method of forming a multilayer vascular graft, said method comprising:

(i) providing a tubular structure having an external surface; (ii) locating the tubular structure within a cavity suitable for injection moulding, said cavity having an inner surface;

(iii) introducing a thermoplastic elastomer in liquid form into a gap located between the external surface of the tubular structure and the inner surface of the cavity, and allowing the thermoplastic elastomer to solidify; and (iv) locating an outer layer on top of the thermoplastic elastomer.

In one embodiment the tubular structure is located onto a mandrel prior to insertion into the cavity. Use of a mandrel may be useful where the tubular structure has a thin wall, or a wall which may otherwise deform on

introduction of the thermoplastic elastomer, ^, or to assist central location of the tubular structure within the cavity.

Suitable thermoplastic elastomers include silicone, polyurethanes and styrene block copolymers. Optionally plasticisers can be included.

In one embodiment the thermoplastic elastomer is styrene-ethylene- propylene-styrene block copolymer (SEPS). Optionally a plasticiser (for example squalane) can be added.

In one embodiment, the thermoplastic elastomer forms a continuous layer over substantially the whole of the outer surface of the tubular structure, and in particular forms a continuous outer layer over the whole outer surface of the tubular structure which will be exposed to repeated needle puncture. Preferably it forms a continuous layer over the whole of the outer surface of the tubular structure.

In one embodiment the thermoplastic elastomer is heated above its melting point to become liquid and is introduced into the gap between the external surface of the tubular structure and the inner surface of the cavity whilst molten. In this embodiment the thermoplastic elastomer solidifies as its temperature drops below its melting point.

In one embodiment the thermoplastic elastomer is introduced into the gap between the external surface of the tubular structure and the inner surface of the cavity in the form of a solution and removal of the solvent leads to solidification of the elastomer. Optionally the elastomer can be polymerised in situ.

The tubular structure can be formed of any suitable material, and mention may be made of polypropylene, polyurethane, polytetrafluoroethylene, expanded polytetrafluoroethylene and the like.

In one embodiment the tubular structure is formed from ePTFE. The ePTFE can be extruded in tubular form or can be formed into a tubular structure using one or more helically wound layers of ePTFE tape or sheet. Optionally the layers of ePTFE tape or sheet can be helically wound onto a suitably sized mandrel, heated above the crystalline melting point of ePTFE for 10 to 60 minutes (for example 20 to 40 minutes) in order to sinter the layers into a coherent tubular structure.

In one embodiment, the tubular structure is of ePTFE and is pre-treated with a plasma, such as an oxygen plasma, to improve bonding to the elastomer. The plasma treatment process used to treat ePTFE is a low pressure plasma technique. The grafts are placed in a vacuum vessel which is pumped down to a pressure of 100 mTorr. Gas such as oxygen is then introduced into the chamber at a constant flow rate, this gas is ionised in the chamber by applying a high frequency across two electrodes, to form a plasma. The ionised oxygen gas forms numerous high energy species, which react with the surface hydrophobic bonds on the ePTFE and modify them to hydrophilic species. Only the outermost portion (to a depth of approximately 10nm) of the ePTFE grafts are affected by this plasma, this means that the physical properties of the grafts will remain unchanged.

The outer layer located on top of the solidified thermoplastic elastomer can be formed of any suitable material, and mention may be made of polypropylene, polyurethane, polytetrafluoroethylene, expanded polytetrafluoroethylene and the like.

In one embodiment, the outer layer is in the form of a tube prior to location on top of the solidified thermoplastic elastomer.

In one embodiment the outer layer is formed from ePTFE. The ePTFE can be extruded in tubular form or can be formed using one, two or more layers of ePTFE tape or sheet. Use of a thinner tape structure can be advantageous where improved flexibility and handling is required.

The outer layer can be attached to the vascular graft by heating bonding, for example heating the whole assembly at a temperature of from 100°C to 160°C for 10 to 30 minutes. Optionally the heat bonding step can be conducted under pressure.

In one embodiment, the outer layer is of ePTFE and is pre-treated with a plasma, such as an oxygen plasma, to improve bonding to the elastomer in the same way as described above for the tubular structure.

Optionally, both the tubular structure and outer layer are formed from ePTFE and are pre-treated with a plasma as described above.

The cavity suitable for injection moulding can conveniently be the cavity of an injection moulding tool. Generally the cavity will be cylindrical and have an internal diameter, which is slightly larger than the outside diameter of the tubular structure. In one embodiment the coaxial annular gap formed around the graft will be 0.2mm to 0.8mm, preferably 0.3mm to 0.6mm.

In one embodiment, the cavity is designed and shaped so that the layer of solidified elastomer varies along the length of the graft.

In one embodiment the thickness of the elastomer layer is greater in the middle portion of the graft than at least one end, preferably both ends, of the graft. In one embodiment the thickness of the elastomer layer at one or both ends of the graft will be no greater than half of the elastomer layer thickness at the middle of the graft.

In one embodiment an ePTFE tube is placed onto a mandrel and introduced into the cavity of an injection moulding tool. The cavity of the injection moulding tool is essentially cylindrical with a diameter slightly larger than the outside diameter of the graft. The annular, coaxial gap so formed is filled with molten, thermoplastic elastomer in a conventional injection moulding machine. In one embodiment the thermoplastic elastomer is SEPS and is pre-compounded with 50% squalane.

Once the elastomer coated ePTFE graft is removed from the cavity it can have an external layer of ePTFE bonded to its outside. The outer layer may be a conventional extruded ePTFE tube or, advantageously, can be formed from thin ePTFE tape helically wrapped around the exterior of the solidified thermoplastic elastomer layer and preformed on a mandrel. The helically wrapped ePTFE tape will be sintered together into a coherent structure by heating above the crystalline melting point of ePTFE for 10 to 60 minutes, for example 20 to 40 minutes. The thinner tape structure is advantageous in that it improves the flexibility and handling of the graft.

The process of the present invention has the advantage that injection moulding is a rapid and precise process. Cycle times are well below one minute, in contrast to the extended times required for hand assembly of elastomer tubes, spinning or spraying. Furthermore, the thickness of the elastomer layer can be controlled and kept consistent. It is also possible to vary the thickness of the elastomer along the length of the graft. This is

useful in precisely adapting the properties of the graft to the function it is intended to fulfil. For example, the central portion of the graft will be punctured by the large needles used for dialysis. The elastomer layer is preferably thick in this central position to give it the required self-sealing properties and durability to resist repeated puncture. However, the ends of the graft will not be used for access and it is preferable to have the elastomer layer thinner at the end portions. This makes it easier to anastomose the graft to the patient's vessels, whilst the thin elastomer is sufficient to control suture hole bleeding.

The present invention will now be further described with reference to the following, non-limiting, examples:

Example 1

An ePTFE graft was made through the normal process of paste extrusion, stretching and sintering. The internal diameter was 6mm, the wall thickness 0.4mm and the length 400mm. The ePTFE graft was optionally pre-treated with an oxygen plasma using a Europlasma CD400 gas plasma system, a base pressure of 10OmTorr, RF power of 750 watts and oxygen flow rate of 250cm ³ /min for a process time of 400 seconds. This graft forms the tubular structure required in the invention. A 6mm stainless steel mandrel 450mm long was inserted into the graft lumen. The graft and mandrel were then inserted into the cavity of an injection mould tool. The dimensions of the cavity were such as to give a coaxial, annular gap around the graft 0.4mm wide in the central section and 0.2mm wide at the ends. The tool was designed so that the ends of the cavity sealed around the ends of the graft.

The tool containing the graft was placed in a 110 tonne Demag ET110 moulding machine and SEPS, pre-compounded with 50% squalane, was injected at a melt temperature of 21O ⁰ C. The cycle time was 36 seconds. The conventional process was used to make unsintered ePTFE tape with a thickness of 0.05mm and a width of 12mm. This tape was wound as a double layer onto a stainless steel mandrel with an outside diameter of 10mm. The mandrel was placed in an oven at 380° C for 10 to 20 minutes to sinter the tape together into a thin walled tube. After cooling, the tube was removed from the mandrel and optionally pre-treated with an oxygen plasma using a Europlasma CD400 gas plasma system, a base pressure of 100m Torr, RF power of 750 watts and oxygen flow rate of 250cm ³ /min for a process time of 400 seconds. The tube was then placed on top of the cooled SEPS coated ePTFE graft that had been taken out of the injection mould tool, but still had the mandrel in its lumen. Pulling the ends of the outer tube caused its diameter to decrease so that it was in intimate contact with the SEPS layer. PET heat shrink tubing was placed on the outside of the three layers, and the whole assembly placed in an oven at 13O ⁰ C for 15 minutes. The elevated temperature and pressure exerted by the heat shrink tubing caused the outer layer to bond to the SEPS. Once cool, the heat shrink tubing was removed.

Comparative Example

A 6mm internal diameter ePTFE graft was made as described in Example 1. Unsintered ePTFE tape was used to make a thin walled tube as described in Example 1.

SEPS pre-compounded with 50% squalane was extruded as a tube with an internal diameter of 5mm and a wall thickness of 0.2mm using a Davis Standard Jockey 2020 screw extrusion machine.

The ePTFE graft was placed on a 6mm. stainless steel mandrel. The 5mm SEPS tubing was expanded by placing inside a 10mm internal diameter acrylic tube and turning the ends of the SEPS around the ends of the acrylic tube to form a seal and then drawing a vacuum through a side port. This allowed the SEPS tubing to be placed on top of the ePTFE graft on its mandrel. A double layer was placed in the central section of the graft to give a wall thickness of 0.4mm. Once the vacuum tube was removed, the thin wall tube was applied and heat bonded, as described in Example 1.

The total time to manufacture this graft was around 36 minutes, in contrast to the 22 minutes taken to produce a graft using injection moulded SEPS.

Example 2

Grafts made according to the method of Example 1 and the comparative example were pressurised with water at 120mm Hg and punctured with 16g dialysis needles. The amount of leakage after removal of the needles was compared. The two grafts were equally effective at preventing leakage.

The test was repeated with anti-coagulated blood. Again, both grafts were effective at preventing leakage.

The bond strength of the two grafts was compared by gripping the inner and outer layers in the jaws of a tensile tester (Hounsfield H5KS) and pulling them apart at a speed of 100 mm/min. No difference in bond strength was observed.

It can be concluded that, in spite of the more rapid manufacturing method, injection moulding produces a graft that performs as well as the more laborious hand assembly method.