WO2011133019A2

WO2011133019A2 - Expanded ptfe medical devices with spiraled ridges and process of manufacture thereof

Info

Publication number: WO2011133019A2
Application number: PCT/MY2011/000038
Authority: WO
Inventors: John Edwin Tarun
Original assignee: Biovic Sdn Bhd
Priority date: 2010-04-22
Filing date: 2011-04-22
Publication date: 2011-10-27
Also published as: MY169594A; WO2011133019A3

Abstract

There is provided a unique process for the manufacture of a tubular PTFE or PTFE-tissue hybrid medical device is described having at least one luminal surface that is slightly ridged in a spiral configuration designed to rotate, or propagate the rotational flow of blood that is transitioning from an artery or vein into the implanted medical device. The process for the production of PTFE includes specially designed extrusion equipment depicted herein and/or specially designed tissue molding processes to be used in conjunction with the inventions of Pathak et al. and Edwin.

Description

Expanded PTFE Medical Devices with Spiraled Ridges and Process

Manufacture Thereof

FIELD OF THE INVENTION

The present invention generally relates to methods for the production of medical devices comprised of expanded (or stretched) polytetrafluoroethylene (PTFE) , and more particularly to a method for use in producing expanded polytetrafluoroethylene (ePTFE) based artificial blood vessels or grafts, and stent grafts or covered stents . BACKGROUND OF THE INVENTION

Biomaterials for medical devices have been dominated over the past 30 years by materials such as polyester or PET (Poly-Ethylene- Terephthalate) and /PTFE (Poly-Tetra-Fluoro- Ethylene) . These are still the materials choice when it comes to products like artificial blood vessels (vascular grafts such as AV access and bypass grafts) , vascular patches, hernia patches,^■ and covers for stent grafts.

Current Vascular Grafts (artificial blood vessels) that are on the market are tubular, sometimes with tapered or stepped ends. Their design inherently is that of a smooth internal surface produced and implanted in such a way as to not impinge the flow of blood. However, there are new thoughts now on the biological design of arteries and veins especially regarding flow characteristics. The new school of thought suggests that all flow within mammalian vasculature is actually rotational. The inventive products described herein incorporate features complimentary to this new finding.

Currently there are several companies that manufacture ePTFE materials for use in medical products, specifically vascular grafts and patches. Examples of these are C.R. Bard, .L. Gore, Atrium, and Boston Scientific. Manufacturing processes for these products are for the most part kept as trade secrets although over the years there are been many process patents filed. As the manufacture and use of ePTFE increases, there are fewer of these filed as the patented technology expires and lapses into the public domain. The dominant companies in this field as mentioned above have had products on the market for over 30 years. The users of these products and the regulatory bodies that govern and monitor their manufacture, sale and use are familiar with the current products on the market and their associated manufacturing processes. Typically they avoid making any changes to these, in fact it is bothersome for these companies to make any changes either to their product features or their production parameters as these would require notification to the regulatory bodies in question (e.g. the FDA in the USA) and may also entail re-validations and re-submission for approval. This is not the case for a new "start-up" company or a new entrant into the field. Such an entity often has carte blanche to modify/re-invent the production processes involved in order to make an improved product. The current invention falls into this category. Biovic Sdn Bhd has no ties or obligations to pre-existing manufacturing processes and thus can re-invent this in order to manufacture a superior product.

PTFE processing has been around since the 1960's. Invented by Sumitomo in 1968, the process of making expanded PTFE in order to create a porous structure that is conducive to tissue/cellular in-growth and therefore an ideal biomaterial is now commonplace and is documented in the public domain in several forms, e.g. process manuals that are provided when one purchases the raw material (e.g. Dupont Manual on PTFE Processing entitled "Fine Powder Processing Guide".) and expired process patents. Examples of these are US patent No. 3,953,566 "Process for Producing Porous Products" to Gore (issued in 1976) ; US patent No. 4,550,447 "Vascular Graft Prostheses" to Seiler et. al. (issued in 1985) and US patent No. 4,671,754 "Apparatus for Manufacturing Porous Polytetrafluoroethylene Material" to Okita et.al, issued in 1987. One of the earliest clinical uses of PTFE as a vascular graft is documented in US patent No. 6,436,135 to Goldfarb, filed in 1974 but only issued in 2002. Goldfarb also discloses the basic manufacturing process, similar in fashion to that described by raw material suppliers.

In another disclosure, particularly the Dupont manual as mentioned above describes the essential steps for the process of manufacturing ePTFE:

(a) Select the correct resin for the end-product (also important are handling and storage, preparation, and screening of the resin) .

(b) Blend or mix this resin with an extrusion aid or lubricant, examples of this include a mineral oil such as Isopar H or M, Naptha or Shellsol. The correct proportion for this varies from 15 to 20% by weight. Mixing devices can include rollers or V-shell blenders.

(c) Age or incubate and warm the mixture for at least 16 hours at a temperature optimal for the infiltration of the lubricant into the particles of resin. Typically this should be above 25 degrees C.

(d) Pre-form this resin-lubricant mixture into a candle-like cylinder by pressing it into this shape in a hydraulic or pneumatic press, this removes air and allows for handling.

(e) Insert the resin-lubricant cylinder into a ram or paste extruder such as that manufactured and sold by the Jennings Corporation of America.

(f) Extrude the cylinder into tubes or rods of the required dimension, ensuring the temperature is above 19 degrees C (transition temperature of the resin) .

(g) Dry the extruded tubes in an oven set at a temperature appropriate for the lubricant used, the size of extrudate and line speed. Often this is just below the flash point of the lubricant. For Isopar H this is approximately 49 degrees C.

(h) If the desired product is to be porous, then stretching must occur, as in the case of PTFE tape. In the case of extruded tubes, these are placed into a rack for the stretching or expansion process, then this is placed into an oven. The stretching process must be done at a temperature sufficient to allow plastic deformation of the material without necking or thinning of the material.

(i) Stretch the tubes/rods to the desired expansion ratio, corresponding to the desired level of porosity.

(j) Sinter or "cook" the stretched tubes at a temperature above the second melt point of the resin, for extrusion grade PTFE this is typically at a temperature above 327 degrees C. This heat cycle will lock in the molecular structure as the energy from this heat cycle is absorbed into the molecular bonds of the repeating Carbon-Fluorine structure .

The above steps are the general ones suggested by the manufacturer of the raw material or resin used for this process. Examples of these companies are DuPont Inc., Asahi Glass, and 3M. Modifications to these general guidelines are practiced by almost all companies using this raw material for the manufacture of medical devices, as evidenced by filed or issued process patents. Examples of these are the "Radially Expandable Tubular Polytetrafluoroethylene Grafts and Method of Making the Same" by Edwin et. al. (US Patent No. 6,039,755) and "Reinforced Vascular Graft and Method of Making Same" by Kalis, (US Patent No. 5, 609, 624).

In spite of continuing advancements in the processing of vascular grafts , current drawbacks for ePTFE products on the market today still exist. This is exhibited by the fact that the gold standard for vessel reconstruction is still the autologous saphenous vein, harvested from the patient's own body. ePTFE is typically only used in situations when vein is not available or is being conserved for potential future operations such as coronary bypass, for which the ePTFE graft is a relatively poor candidate. The reasons for this are many, but the biggest failure mode for ePTFE vascular grafts being used for vessel reconstruction is distal occlusion secondary to intimal hyperplasia, which is typically comprised of smooth muscle cell hyper- proliferation. The current thoughts on why ePTFE grafts occlude seem to be focused on flow dynamics, and it is now felt that the blood flow characteristics of a graft will be a predictor of its performance. Thus Dr. Hans Scholz and Mr. Peter Harris, both renowned surgeons of European descent modified their implanted vascular grafts with distal "cuffs" or radially enlarged ends that are designed to control the flow and optimize performance. Scholz et. al. added an ePTFE cuff, previously sutured to the distal end but now available in a one-piece graft ("Venaflo" graft sold by C.R. Bard and patented in US patent No. 6,273,912 assigned to IMPRA) to greatly enhance the clinical performance of Arterio-Venous access grafts used for dialysis by reducing the flow disruption that is created by shunting high flow arterial blood into the low flow venous system. Harris et. al . previously utilized autogenous harvested vein to create a "chamber" at the end of an ePTFE graft, inside which a vortex of flow is created which controls shear, thus preventing or reducing the formation of distal intimal hyperplasia; and again enhancing the clinical performance of end to side grafts used in above and below knee bypasses. This likewise is patented in US Patent No. 5,861,026 to Peter Harris and Thien How. Once again a one piece graft is now available from C.R. Bard, called "Distaflo".

In the science of fluid mechanics, fluid flow in tubes is depicted in terms of turbulent or non-turbulent flow, fully or partially developed. Flow rate however is more critical for a synthetic graft. Any vascular surgeon or nephrologist will attest to the fact that low blood flow rates in a synthetic graft will rapidly contribute to graft occlusion. In fact in an ePTFE arterio-venous shunt, flow rates of less than 400 ml/min will often be referred back to the surgeon or to an interventional radiologist for repair as this will most certainly result in an occluded shunt, especially if the shunt comprises ePTFE. In addition it is said that the long term performance of a peripheral bypass graft is wholly dependent on the resistance to flow of the outflow arteries, whereby the higher the resistance, the more the propensity of back-pressure or flow stagnation at the distal anastomotic site, and the higher the occlusion rate.

Further, recent research into the physiological flow of blood in homogenous arteries and veins suggest that there is a rotational flow component to all blood vessels that cannot be reproduced in current synthetic arteries and veins as these are typically "passive" devices, simply connected to the artery/vein in the form of an end-to-side or end-to-end anastomosis. In this case, blood transitions from the native blood vessel which is inherently pulsatile and rotational; into a lifeless synthetic tube. The flow profile that was generated by the native vessels thus cannot be propagated anymore, increasing the propensity to turbulence, or disordered flow. The natural flow characteristics are gradually lost and the longer the synthetic vessel, the more difficult for the blood to maintain its rotational form and velocity. This theory has been studied in atherosclerotic blood vessels and is documented by several authors including Peter Stonebridge, e.g. "Spiral Laminar Flow in Arteries?" in the Lancet, Nov. 1991 and "Non spiral and spiral (helical) flow patterns in stenoses: In vitro observations using spin and gradient echo magnetic resonance imaging (MRI) and computational fluid dynamic modeling" In International Journal of Angiology, Sept. 2004.

Due to the shortcomings of clinically used ePTFE vascular grafts as discussed above, it is a primary purpose of the present invention to provide the manufacturing process for a unique ePTFE vascular graft that exhibits superior flow, performance, feel and handling characteristics .

The current invention therefore provides solutions to the problem as discussed in the preceding paragraphs. To one skilled in the art of ePTFE processing there are several notable process modifications, however two in particular really create a superior artificial blood vessel out of ePTFE. The re-invented process is listed below step by step.

It is an aspect of the invention to use the appropriately produced vascular grafts instead of those currently on the market to create a vascular graft that is superior in performance and handling to standard or existing products. Existing products do not have any features that enhance flow characteristics and typically damage these flow profiles in such a way that the long term performance of the graft is affected. Existing ePTFE vascular grafts also do not have the handling and feel of native homogenous vein, the gold standard of vascular reconstruction. The novel graft of the current invention enhances the flow profile by maintaining the natural rotational component of blood flow and when produced in conjunction with adequately prepared mammalian tissue (as taught by Edwin in WO/2007/137211 "Tissue Synthetic-Biomaterial Hybrid Medical Devices") will provide the handling and feel of vein, thereby improving clinical performance and outcome. Other techniques for creating or maintaining rotational flow will be readily apparent to those skilled in the art in light of the teachings of the present invention.

It is therefore a primary purpose of the present invention to provide a method for use in producing an implantable medical device based on ePTFE, said device is suitably designed in a manner such that it is able to rotate, or propagate the rotational flow of blood that is transitioning from an artery or vein into the implanted vascular graft, or in a stent graft used as a scaffold for a diseased or occluded vessel. It is a secondary purpose of this invention to provide a method for use in producing an implantable vascular graft that has superior handling and feel characteristics similar to that of native vein.

Further purposes of the present invention will become evident from review of the following specification. SUMMARY OF THE INVENTION

The present invention discloses an implantable expanded polytetrafluoroethylene (ePTFE) medical device comprising at least one luminal surface that is slightly ridged in a spiral configuration designed to rotate, or propagate the rotational flow of blood that is transitioning from an artery or vein into the said implanted medical device. The invention also discloses the use of a ePTFE-tissue hybrid device to provide the handling and feel of native vein. In another aspect of the present invention there is provided a method for producing an expanded PTFE based medical device comprising the steps of: providing high molecular weight resin; mixing said resin with lubricant or extrusion aid; incubating the mixture for a predetermined period and optimal temperature that results in effective infiltration of lubricant into resin; pre-shaping the mixture into a cylindrical form; subjecting the resin-lubricant cylinder to a paste extrusion stage using an extrusion mandrel with trench cut into it's surface; and wherein during this stage the cylinder is reduced to tube form with predetermined internal ridge (s); drying the extruded tubes in an oven set at a temperature just below the flash point of the lubricant;_placing these extruded tubes into a rack for the stretching or expansion process, then placing this rack into an oven subjecting the extruded tubes to an expansion stage, wherein the tubes/rods are accordingly stretched to the desired expansion ratio corresponding to the desired level of porosity; wherein during expansion said tube is stretched in a manner such that a spiral portion is formed along the internal length of tube; and sintering the stretched tubes at a temperature above the crystalline melt point of the resin.

In yet another aspect of the current invention, there is provided both a product and a process of manufacture by which the inventive ePTFE vascular graft or stent graft can be combined with mammalian tissue to create a product that flows, handles, and performs like native artery or vein. The mammalian tissue can be prepared preferably as described by Pathak and Thigle in WO/2006/026325 or by other means known to one skilled in the art of tissue processing, and can be combined with PTFE as taught by Edwin in WO/2007/137211 "Tissue Synthetic-Biomaterial Hybrid Medical Devices".

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention is best understood by reference to the detailed figures and description set forth herein. Nevertheless, the accompanying drawings are not to be understood as superseding the generality of the preceding description of the invention.

FIG 1 illustrates a spiraled tube with internal ridges in accordance with the present invention;

FIG 2 illustrates a bare stent to be incorporated with the tube forming a stent graft of the present invention;

FIG 3 illustrates a straight tube formed in accordance with the prior art;

FIG 4 illustrates a stent graft in the process of being formed in accordance with the present invention;

FIG 5 illustrates a completed laminated stent graft formed in accordance with the present invention; FIG 6 illustrates an extrusion mandrel used for the purpose of the present invention;

FIG 7 illustrates grooves cut into the taper and land of the mandrel to form the internal ridge (s) of the medical device according to the present invention;

FIG 8 illustrates a radial cross section of the tube in accordance with the present invention;

FIG 9 illustrates an extruded tube with internal ridges of the present invention;

FIG 10 illustrates a mandrel being positioned through the extruded tube in accordance with the present invention; and

FIG 11 illustrates the expansion and rotation of tube in accordance with the process of the present invention.

FIG 12 illustrates a grooved tubular mandrel and spiraled wire for the process of creating a spiraled-ridged tissue graft in accordance with the present invention.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Embodiments of the invention are discussed below with reference to the Figures. However, those skilled in the art will readily appreciate that the detailed description given herein with respect to these figures is for explanatory purposes as the invention extends beyond these limited embodiments.

In the first embodiment a stent graft for opening or maintaining patency of a lumen of a blood vessel is presented. The stent graft includes a stent support structure including struts, an internal surface and an external surface, and at least one spiraled vascular graft or lining is present on the luminal surface of the stent-graft. The abluminal stent graft surface may be metal, plastic, or organic material, or even plain PTFE: this surface is not critical to blood flow as it is removed from exposure. The stent graft is compressible for delivery into the blood vessel via a catheter. Minimally invasive medical technology is the current trend in vascular and interventional clinical medicine. The advantage of this stems from the avoidance of major surgery: instead of a large, traumatic incision and invasive operation to implant a medical device, catheters are used to place the device, using the vasculature as a "road" or tunnel to the desired site. Typically, stents and stent grafts are compressed into such a catheter and are delivered over guide wires.. Guide wires are the "rails" over which the delivery catheter is run. These springy and flexible rails can be seen with fluoroscopy or x-ray, as the physician guides it through the vasculature into the correct part of the blood vessel to be treated. Once the guide wire is in place, "over-the-wire" delivery catheters are run over the guide wire, over and through the blood vessel lumen until the stent graft is in position. Once in place, the delivery catheter is pulled back over the stent graft, allowing the spring steel of the stent, or temperature response of, for example, but not limited to, Nitinol to force the stent-graft to expand, thereby opening up into the blood vessel, but allowing blood to continue flowing through its lumen once the delivery catheter is withdrawn. Nitinol, or nickel-titanium alloy, is a metal with shape memory. That is, it remembers what shape it was formed into, and then under cold temperatures, can be formed into other shapes with ease. Once returned to its trained temperature, it reverts back to its pre-programmed shape, thus the name "shape memory". This material is ideal for a stent as it can be "trained" at the dilated or expanded shape, chilled (into its martensite phase) and compressed to be loaded into the delivery catheter. Then when it sees body temperature without the delivery catheter to constrain it, it will expand back to its pre-programmed shape (austenite phase) thereby supporting or propping open the blood vessel to be treated. One such patent that describes this material in stent form is US Patent No. 6,042,606 issued to Frantzen.

The stent graft described above and shown in FIG 5 has an advantage over the bare stent shown in FIG 2 in that the struts or lattice of the stent are covered with a biocompatible material such as ePTFE which serves the purpose of preventing plaque or hyperplastic tissue from growing into it; or blood from flowing out of it if used to treat an aneurysm or traumatic fistula. It is a preferred embodiment of the current invention to have a covered stent or stent-graft with an ePTFE outer or abluminal surface and a spiraled-ridged ePTFE internal or luminal surface, with the stent in-between, or sandwiched between these two layers. Referring to FIG 1 the spiraled-ridged ePTFE layer 18 would propagate flow in such a way that the inherent rotational flow of blood is maintained or preserved. As depicted in FIG 4, the assembly of the stent graft of the current invention includes the steps of placing the bare stent 20 over the internal spiraled-ridged ePTFE tube 18. Then a straight tube as illustrated in FIG 3 is placed over this combination as in FIG 5 and the resultant stent-graft 24 is formed using either pressure and heat, or appropriately selected adhesive.

It is another embodiment of this invention to have appropriately processed mammalian tissue as the spiraled-ridged luminal layer, attached to the abluminal ePTFE layer via adhesive or another third material. The tissue luminal surface of the present invention would be spiral-ridged internally and would propagate flow in such a way that there will be little or no disruption to blood components passing through the lumen. If as described above, this ridged luminal surface were made from specially treated tissue laminated onto ePTFE through the stent, it would harness the ability to endothelialize, (grow endothelial cells which protect the surface) , and heal thus providing for an organic and living blood flow surface that would be 100% incorporated into the body. In addition, a drug-loaded polymer can be attached to the tissue and then dissolved or delivered into the blood stream over time in order to enhance/accelerate or complement the desired healing response. Applicable drugs are, for example but not limited to, anti-restenosis agents, anticoagulants, anti-infective compounds, growth factors, and other synthetic or biological compounds .

Other techniques to enhance/accelerate the healing response will be readily apparent to those skilled in the art in light of the teachings of the present invention.

As mentioned earlier, the smaller the diameter of the stent graft and subsequently the delivery catheter, the easier it is to perform the treatment and navigate the delivery catheter through a tortuous vasculature. Therefore if so desired, the processed mammalian tissue of this embodiment can be selected from intestinal mucosa/membrane or omentum, for example, or other tissues that are typically very thin, in order to maintain a low profile and the PTFE, for example, can be manufactured very thin and strong in order to complement the tissue in the area of strength.

Furthermore, in the case of the tissue-based stent graft, a selection of a tissue source with a high coefficient of radial expansion will allow the use of balloon-expandable stent (such as stainless steel) applications such as the use of an angioplasty balloon to force the stent structure to expand radially. The external PTFE can be designed to radially dilate along with the tissue and stent. For such a configuration, it will be necessary to have a deflated angioplasty balloon positioned in the lumen of the stent graft, and then for the physician to inflate the balloon once the delivery catheter has been pulled back. This will force the stent graft to expand in the radial direction, thus allowing the structure to become tubular, and sit with snug or close "apposition" within the blood vessel walls. Such stent technology was originally described in Patent No 4,733,665 to Palmaz . Although the biomaterial mentioned in this preferred embodiment is PTFE, other synthetic biomaterials may also be used in the same fashion.

The combination of synthetic biomaterial with the treated tissue component mitigates deficiencies found in current devices as taught by Edwin. In accordance with the present invention, such a combination may comprise of a bare stent 19 as seen in FIG 2 placed over the spiraled-ridge tissue tube 18 formed with the process of the present invention shown in FIG 12 (which will be described shortly) and attaching this to the straight ePTFE tube shown in FIG 3 through the struts of the bare stent thus forming a stent-graft with a luminal spiral ridged tissue based surface FIG 5.

It is another embodiment of the present invention to use three- dimensionally shaped- tissue as taught by Pathak et al. either alone or in conjunction with PTFE to create the vascular substitute or tube with spiral ridge (s) . An appropriately selected harvested tissue processed in accordance with Pathak et al. is taken and then placed over a dimensionally sized mandrel with one or more spiral grooves machined into it as depicted in 29 of FIG 12. Once the tissue is over the mandrel, then the spiraled wire 30 is placed into the outer surface of the tissue tube forcing the formation of a ridge by pushing the tissue into groove 29. The tissue is then treated and after removal of wire 30, will result in a tissue tube with one or more spiraled ridges, similar to FIG 1. It is noted that this tissue tube with inventive spiraled luminal ridge (s) can be configured to be biostable, or partially or completely degradable in accordance with known techniques. Note also that the size and number of ridges depicted in FIG 1 are for example only; it should be pointed out that the actual size and number of ridges will depend on tube diameter, flow conditions, and length of tube. In accordance with a preferred embodiment of the current invention, the steps as described in the earlier paragraphs can also be deployed to produce/manufacture an arterio-venous (AV) access graft. The AV access graft feature includes a luminal surface that is spiraled, or rotates about its center axis as a result of the rotated expansion process .

AV access shunts are typically connected between an artery and vein, "shunting" high flow oxygen rich arterial blood straight into the venous system, thereby providing the dialysis needle an ample source of blood to draw from. In a patient with kidney failure, the toxins in the blood need to be cleaned out externally as the kidneys normally provide this function. Passing the blood through a dialysis machine with a suitable filter that removes the toxins and then returning the cleaned blood to the body accomplishes this. A shunt allows the dialysis machine access to a blood flow in the region of 0.4 to 1 liter of blood per minute, thus keeping the dialysis session down to 2-3 hours several times per week. AV or arterio-venous shunts/grafts are surgically placed into the body under the skin typically between a vein and an artery to create a path of rapidly flowing blood. The shunt is placed by tunneling it under the skin, then creating a suture line or anastomosis between a source artery and outflow vein. The dialysis clinic will use this shunt to extract the blood to be cleaned by using two needles, one to withdraw the blood and another to return the cleaned blood to the shunt.

Ideally these AV grafts will shunt blood from artery to vein without modifying the flow characteristics, but the normal pulsatile, parabolic and rotational laminar flow profile is converted to a non- laminar almost turbulent flow that is lacking in pulsatility as it passes into the synthetic and passive ePTFE graft of the prior art. The implanted graft is not capable of propagating the pulse that is inherent in the external elastic lamina of the artery, and the rotational flow aspect is also lost. However the graft of the current invention will maintain the rotational aspect of flow though the pulsatility is lost. When the flow arrives at the vein, the pulsatility component will return and the rotational component is continued.

Suitably, to form an AV graft, the ePTFE graft with spiral ridged luminal surface would be produced as described above and depicted in FIG 1, noting once again that the size and number of ridges would depend on the application. The AV graft may be used by itself, or once again it could be used in conjunction with a tissue luminal surface which can be attached to the abluminal, external, PTFE using PEO or polyethylene glycol (PEG) or other suitable material as the adhesive. The lubricious outer surface of the PTFE is low friction and allows for ease in tunneling the graft under the skin. If treated tissue is used to form the spiraled ridges, as described above and shown in FIG 12 the PTFE could also bolster the strength of the tissue, preventing any chance of dissection or blowout whilst the tissue would provide the handling and feel of native vein as well as the potential for healing once implanted. Furthermore, in alternative embodiments, the tissue can be configured to deliver drugs that dissolve into the blood stream to enhance/accelerate healing. Note that it is within the realm of this invention for the properly processed tissue to be used either alone or in conjunction with the PTFE or other biomaterial.

Another embodiment of the AV access graft features a cannulation region. As with most PTFE AV grafts, a two week maturation period is required after implant or creation of the shunt before it can be used. The needles used to remove and return the blood into the graft are fairly large, and leave behind gaping holes that often take a while to clot over and stop bleeding once the dialysis session is completed. Leaving the graft under the skin for two weeks before using it for dialysis allows some level of tissue ingrowth (cells growing into the graft surface) , thereby allowing the holes left behind by the needles to close over more rapidly. Creating a cannulation or needle entry region that is self-sealing can circumvent this two week maturation time making this an instant use graft, similar to a centrally placed catheter. Other techniques to circumvent this two week maturation time will be readily apparent to those skilled in the art in light of the teachings of the present invention. In one aspect of the present invention as mentioned above, a space between the tissue and PTFE or biomaterial surfaces may be used to create a cannulation region for the AV access shunt. A form of sealant, for example but not limited to silicon rubber, can be trapped within said space to serve as an early cannulation region for immediate dialysis access using a dialysis needle as described in WIPO patent application No. WO/2006/02672 to Edwin et. al . Once a needle is pulled out of the silicon cannulation region, the silicon will seal over the hole, just like a vaccine vial when the syringe needle is pulled out. In a further embodiment of the invention, the sealant can also be treated with a clot promoting drug or material for ease of use in dialysis access . This clot promoting drug would cause quick clotting of the blood that tried to exit through the needle hole. One example, but not limited to, of such a drug is thrombin. One example, without limitation, of a clot promoting material is polyester. In another embodiment, the PTFE portion can also be porous but with some or all pores filled with a material such as gelatin. Gelatin is known for its ability to attract cells and to encourage tissue incorporation external to the graft. This is another mode of assisting bleeding cessation after dialysis needle withdrawal. Other techniques to assisting bleeding cessation after dialysis needle withdrawal will be readily apparent to those skilled in the art in light of the teachings of the present invention. In a further embodiment, a flange of tissue can be added to the distal end of the graft as suggested in Edwin, WO/2007/137211. In yet another preferred embodiment the graft is either coated with or comprises an elastic type material that mimics and continues the pulsatility of natural artery. In other embodiments, the graft contains or comprises treated biological tissue.

In another embodiment of the present invention, a bypass graft (not shown, but similar to the graft shown in FIG 1) is formed. In patients with occluded or badly diseased blood vessels, often the only way to get blood flow past the blockage to the extremities would be to jump around it, or "bypass" the occlusion much as one would detour around a road construction site. This would send blood to areas that are not receiving it due to the blockage, thus relieving the "ischemia" or dearth of blood symptoms. It is well documented in the clinical literature that peripheral PTFE bypass grafts fail due to intimal hyperplasia or prolific cell growth at the ends, typically the distal end, of the graft. The PTFE material creates a slow rejection response that eventually occludes or shuts down the flow of blood either into or out of the graft. The inventive bypass graft would include the standard graft just described, but with a spiraled, ridged, luminal surface for bypassing blood from a larger artery down to an area that is ischemic and lacking in arterial blood. Again, the flow at the artery-graft transition is affected but the inventive graft will continue the rotational component of the flow profile. Another embodiment includes spiral or ringed beading on the abluminal surface of the vascular graft to provide kink and crush resistance. In yet another embodiment the graft is either coated with or comprises an elastic type material that mimics and continues the pulsatility of natural artery. In other embodiments, the graft contains or comprises treated biological tissue that provides the handling, feel and healing characteristics of autogenous vein. The spiraled ridges for this purpose will be evident and it can be imagined that these would result in the blood flow being propagated in a rotational fashion. Once again the inventive PTFE spiral graft can be used alone or in conjunction with a spiraled tissue luminal substrate the preparation of which is shown in FIG 12. A further preferred embodiment has the spiraled-ridged tissue line the entire inside surface and is laminated to the PTFE outer tube with the use of polymeric adhesives. The improved device of the present invention may be constructed with further addition of a tissue flange or cuff to the distal end of the graft. For instance, spiraled, ridged, PTFE is used as a bypass graft configured with the preferably treated tissue attached at the distal end via a suture line or other attachment means. In a further embodiment of the present invention, the same can be done at the proximal end as well by suturing a band of tissue via a suture line or other attachment means to the PTFE. The use of this technique distally simulates the Taylor patch or Miller cuff configurations utilized to enhance the patency of a peripherally placed PTFE graft used for infra-inguinal bypass, as described in published article "Reduced Elastic Mismatch Achieved by Interposing Vein Cuff in Expanded PTFE Femoral Bypass Decreases Intimal Hyperplasia" found in Artificial Organs, Volume 29, 2005 by Edmundo I., et. al . This particular embodiment could be used in several different configurations and shapes to construct Miller Cuffs, Taylor Patches, or St. Mary Boots used to enhance the patency of grafts sutured to a below knee outflow artery bypassing an occlusion.

In another embodiment the PTFE or other synthetic biomaterial could be used as the reinforcing abluminal surface for ease in tunneling, due to its low coefficient of friction, and if reinforced with external spiral or ringed beading, can also offer kink and crush resistance to the graft as is typical of several brands of PTFE grafts. This will 0038

20 bolster the artificial vessel strength, preventing dissection or disruption. Alternatively in yet another embodiment, the spiraled- ridged tissue can incorporate the cuff or distal flange and can be used as the luminal surface throughout, obviating the need for a suture line or attachment to the PTFE, to form the bypass graft with flange .

A further embodiment of the bypass graft described in the preceding paragraphs is a continuous spiral-ridged luminal tissue layer attached to an outer reinforcing layer, as depicted in the AV graft configuration, but a graft that would serve as a coronary bypass graft, obviating the need for harvesting saphenous vein or usage of the internal mammary artery as is typically done now for multiple vessel bypasses.

Other embodiments of the present invention include synthetic- biomaterial degradable-tissue composites, as taught by Pathak et al. A tissue surface is placed inside the luminal surface of the inventive spiral-ridged PTFE graft, but in this case the tissue is configured to partially or completely degrade over time leaving behind a PTFE surface either indigenous or with a pharmaceutical or growth factor such as Endothelial Cell Progenitor (ECP) compound or a Vascular Endothelial Growth Factor (VEGF) attached to force endothelialization or healing/incorporation of this surface.

Another embodiment uses a highly porous but longitudinally compressed PTFE in conjunction with crimped tissue for enhanced kink-resistance. The graft material is formed into an accordion-like tube to allow for enhanced bend radii.

Another embodiment of the present invention uses the spiraled-ridged ePTFE for an abdominal aortic aneurysm (AAA) or bifurcated graft. An AAA graft is used primarily to exclude or repair an aneurysm, which is the weakening and subsequent dilation or abnormal stretching of a blood vessel such as the abdominal aortic artery. In patients that have such aneurysms, the mortality rate is more than 90% if the aneurysm ruptures, therefore if diagnosed, immediate treatment is imperative. Often standard surgical repair is possible by implanting the AAA graft described above to replace the aneurysm. By using the inventive spiral-ridged PTFE graft in this application, the rotational flow component of aortic blood can be preserved. This device would encourage rotational spiral flow which has been observed in the aorta, as documented in "Spiral laminar flow in the abdominal aorta: a predictor of renal impairment deterioration in patients with renal artery stenosis?" by Houston et. al. printed in Nephrology, Dialysis and Transplant, July 2004.

It should be noted however that this type of abdominal aortic surgery is extensive and many are not candidates for such major surgery, even if time permits. Thus patients and physicians may prefer the minimally invasive approach or the use of a stent graft as mentioned previously, but constructed to match the bifurcated anatomy of an abdominal aortic aneurysm or in some cases, a thoracic aneurysm. Construction of such a stent graft can be wholly ePTFE but with the inventive spiral-ridged luminal surface, or may have the spiral-ridged treated tissue as the luminal blood contact surface and PTFE as the external or catheter contact surface, and a solid stent structure in between. The purpose of the stent structure in this stent graft is as pointed out previously, to maintain luminal patency or to buttress or scaffold the aorta since the PTFE and tissue in this case will be very thin for ease in placement within the delivery catheter. An additional interface of tissue glue at the proximal and distal necks of the stent graft would reduce or eliminate the current problem with endo-leaks which often occur due to a poor seal at the stent-graft to artery transition. This is usually due to the lack of good sealing or apposition between the host artery and the stent-graft. Tissue glues such as, but not limited to, Focalseal marketed by Genzyme Biosurgery or Duraseal marketed by Confluent surgical or simple methacrylates are candidates . Other embodiments of the present invention include all the embodiments mentioned above, but with the addition of radiopaque compounds incorporated into the treated tissue along with the processing polymer as mentioned in Pathak et al. This assists the physician in identifying the implant fluoroscopically, or under x-ray.

It should be recognized that although expanded PTFE has been cited as the synthetic biomaterial of choice, this invention does not limit itself to this polymer. Other examples of synthetic biomaterials include, but are not limited to, polyurethane, polyethylene, silicone rubbers, polyesters, nylon etc. Innovative processing methods may be developed in order to mimic the ridged spirals on the luminal surface of the inventive ePTFE.

Nor should only synthetic biomaterials be candidates for attachment to the tissue. Biological biomaterials such as, but not limited to, seaweed and chitin extracts are examples of other potential candidates .

It should also be recognized that although mammalian animal tissue of bovine, ovine, and porcine origin have been mentioned, all biological tissues including that of human origin can also be used and treated accordingly.

It should furthermore be recognized that although the technology of Pathak and Thigle has been cited as the preferred method of forming tissue into three (3) dimensional configurations, this in no way limits the invention to tissue processed in this way.

It should also be recognized that although technology for creation of rotational flow is being investigated by companies such as Tayside Flow Technologies, the inventive manufacturing process for creation of internally ridges in ePTFE grafts has not been cited elsewhere. Although US patent No. 5,609,624 to Kalis discusses external rib or ridges on a PTFE tube to create kink or crush resistance, the inverse or internal ridges are not addressed and neither is it obvious as previously the intent was not to obstruct blood flow in any way.

Method of ePTFE processing

In another aspect of the present invention and to achieve the forgoing and other objects and in accordance with the purpose of the invention, a novel method of ePTFE processing is presented. It shall be apparent to one skilled in the art that the steps involved may be slightly modified however not to depart from the intended outcome subject to the scope of claims. The method of processing ePTFE medical device in accordance with the present invention comprises the steps of:

(a) Selecting the correct resin for the end-product. One must select a high molecular weight resin, and in particular one that meets the reduction ratio (RR) requirements of the extrusion. Note that RR is the ratio of the PTFE in the preformed state, to the extruded PTFE tube state. Alternatively this can be calculated from the ratio of preform tube cross sectional area to extrusion die cross sectional area.

(b) Mixing or compounding this resin with an extrusion aid or lubricant, examples of this include a mineral oil such as Isopar H or Isopar G. The correct proportion for this varies from 15 to 20% by weight. For the current inventive process a ratio of 500:95 is ideal, but this can also be dependent on the type of resin used. In addition, a V-blender such as that manufactured and sold by Perkin Elmer, is preferred for this mixing process. The gradual addition of lubricant into the spinning resin allows for a more even distribution of lubricant into the resin. Rolling blenders may also be used, at least 20 minutes of mixing time should be allowed.

(c) Incubating the mixture for at least 16 hours at a temperature optimal for the infiltration of the lubricant into the particles of resin. Typically this is above 25 degrees C or just below the flash point of the lubricant in order to optimize the penetration of the lubricant into the particles of resin. For Isopar H, an Isopariffinic Hydrocarbon (manufactured by Exxon-Mobil), the flash point is 49 degrees C, so the incubation temperature should be at least 10 degrees below this . (d) Pre-forming this resin-lubricant mixture into a candle-like cylinder by pressing it into this shape in a hydraulic or pneumatic press. Ensure that the press is exerting pressures in the range of 0.7 - 2.0 MPa or and that this pressure is held for at least 60 seconds, but may be held for up to 10 minutes. Preferably, a dual cylinder press that presses the candle-like pre-form into a pre-selected stainless steel tube from both directions should be used. Such a press will ensure a more even compaction of resin if pressed in opposing directions. The formation of this pre-form is for ease of introduction into the extruder.

(e) Inserting the resin-lubricant cylinder into a paste extruder such as that manufactured and sold by the Jennings Corporation of America. Preferably the extruder will be custom built to have features such as constant extrusion speed, plate speed and internal pressure read outs, and the ability to heat the pre-form during the extrusion process. The latter will allow for a better flow of material during the compaction and molecular alignment of the material. Note that the extrusion speed of the extrudate (extruded tubes) is the product of plate speed and RR MY2011/000038

25

(reduction ratio.) The reduction ratio is the ratio of starting cross sectional area (of the pre-formed resin) to the ending cross sectional area (of the tubular extrudate) . Also, the preferred extrusion mandrel should have numerous small (at least one, approximately l-5mm in depth), trenche(s) cut into its abluminal surface. This will give the extrudate small ridges that protrude from the inside surface. A preferred design of the extrusion mandrel with taper region 1 and end of land region 2 is shown in FIG 6. A groove cut 3, is formed along the mandrel taper region as seen in FIG 7 with close up view 4, so as to form the internal ridges on the inner surface of the extruded tube. The resulting extruded tube 5 in this case with grooves cut with four (4) 90 degrees apart thereby forming a four (4) internal ridge design 6 within the tube is as shown in FIG 8 (radial cross section) and FIG 9 (3 dimensional view) .

(f) Extruding the cylinder into tubes or rods of the required dimension. Ensure that the extrusion speed is about 3000 mm/min for optimal results . Speed must also be selected for ease of cutting the extrudate as very high speeds may not be practical . The extrudate must be cut into lengths that are preferably between 10 and 30 cm. depending on the final length of the tubes in the oven. These cut tubes must then be trimmed to length and then placed in a special expansion rack. The tubes will have mandrels placed in their internal diameter, and should be clamped into place over the mandrel on either end, one end tightly, but the moving end lightly (or over a sliding bearing) so that rotation and sliding can occur. Although the ridges created in the extrusion process will be flattened at the ends where the spacers are placed, this is of no consequence as the ends are cut off or otherwise removed post processing.

(g) Drying the extruded tubes in an oven set at a temperature just below the flash point of the lubricant. For Isopar H this is approximately 49 degrees C, so the drying cycle should be at about 40 2011/000038

26 degrees C. The drying cycle should be at least 3-4 hours for optimal results. The tubes will turn completely white which is a good indicator of the drying cycle being complete.

(h) If the desired product is to be porous, then place these extruded tubes into a rack for the stretching or expansion process, then place this into an oven. The stretching process must be done at a temperature sufficient to allow plastic deformation of the material without necking or thinning of the material. The inventive step involves ah elaborate expansion/stretching mechanism. This is depicted in FIG 10 on positioning of the tube 9 over mandrel 10 and in FIG 11 with the expansion at a direction shown as 13 and stretching mechanism of the tube 9. Retaining straps 11 (tight) , and 12 (loose) are suitably provided on each end of the tube so as to sustain or hold the tube in place in relation to the mandrel 10. The notable difference in accordance with the present invention is the rotation of the tubes during the expansion step. Rotational speed in the direction indicated by belt or drive 15 shown in FIG 11 can vary between 1 degree to 500 degrees per second, and rotational percentage for the entire process can vary between 100 to 10,000 % per cycle. It should be noted that the rotational effect from belt 15 in FIG 11 results in the formation of spiraled internal ridges 17 from rotation in direction 16.

A further inventive step is the step-wise extrusion process whereby one end is pulled, paused, then the other end pulled, paused, and so on and so forth; stretching and rotating the tube from alternate ends until the desired final length is reached. This process can give the product a pre-designed variation in porosity and density in certain sections that will complement the handling, kink and crush resistance of the graft.

(i) Stretch the tubes/rods to the desired expansion ratio, corresponding to the desired level of porosity, and to the final 0038

27 length of the oven. Remove the tubes from the stretching rack and then place them in the Sintering or curing rack.

(j) Sinter or "cure" the stretched tubes at a temperature above the crystalline melt point of the resin. For extrusion grade PTFE such as DuPont 601A this is typically a temperature above 327 degrees C, as depicted by the resin data sheet. This heat cycle will lock in the molecular structure as the energy from this heat cycle is absorbed into the molecular bonds of the repeating Carbon-Fluorine structure. Preferably the curing oven will be equipped with an automatic rotation device that will longitudinally (horizontal direction) rotate (reverse) the grafts 180 degrees during the cycle to ensure there is consistent flow of material and that there are no un-desired dense sections during this high temperature excursion. As disclosed in the preceding paragraphs, vascular grafts manufactured in the above way will have superior features. Notably, the texture will be soft (where this feature is desired) ; with a material microstructure that exhibits fairly large nodes and a good fibril density. If so desired, the grafts will also have pre-determined sections of enhanced density to complement handling and the anatomical placement within the body. The current invention will also embody the spiraled luminal surface that will propagate the rotational component of blood that exists naturally within mammalian vasculature. The inventive grafts may also have a tissue based luminal surface also with spiral ridges thereby significantly enhancing the handling, feel, healing and performance of the device likening it to autogenous vein, the gold standard for vascular reconstruction. The following describes the preferred embodiments with respect to the medical devices which may be produced based on the novel method provided herein.

In the current invention, a superior polytetrafluoroethylene (PTFE) vascular graft is presented, created by novel manufacturing methods. The device includes a luminal surface that is characterized by one or more spiraled ridges that rotate from end to end, as little as 360 degrees and as much as 360,000 degrees depending on the length of the graft and desired rotation. Further embodiments include a luminal tissue surface configured with spiraled ridge and means for providing pharmaceutical compounds that can be released over time into the blood stream. Still another embodiment includes means for providing radiopaque compounds so that the implanted vascular graft can be visualized using fluoroscopy.

Having fully described at least one embodiment of the present invention, other equivalent or alternatively configured ePTFE and PTFE-tissue hybrid compositions will be apparent to those skilled in the art. The invention has been described above by way of illustration, and the specific embodiments disclosed are not intended to limit the invention to the particular forms disclosed. The invention is thus to cover all modifications, equivalents, and alternatives falling with the spirit and scope of the following claims .

Claims

An implantable expanded polytetrafluoroethylene (ePTFE) tubular medical device comprising at least one luminal surface that is slightly ridged in a spiral configuration designed to rotate, or propagate the rotational flow of blood that is transitioning from an artery or vein into the said implanted medical device.

The implantable expanded PTFE medical device as claimed in Claim 1 wherein there is provided at least one (1) ridge along the inner surface of the medical device.

The implantable medical device as claimed in Claim 1 wherein the device comprises one or more biomaterials .

The implantable medical device as claimed in Claim 1 wherein the device comprises one or more proximal or distal cuffs.

The implantable medical device as claimed in Claim 1 wherein the device comprises pharmaceutical compounds designed to be released into the blood stream.

The implantable expanded PTFE medical device as claimed in Claim 1 wherein the spiraled ridges is formed in a manner such that it can rotate from end to end, as little as 360 degrees and as much as 360,000 degrees.

The implantable expanded PTFE medical device as claimed in Claim 1 wherein the device is formed in a manner such that it is able to maintain rotational aspect of liquid flow.

8. The implantable expanded PTFE medical device as claimed in Claim 1 wherein the device may further comprise of an elastic type material that mimics and continues the pulsatility of natural artery.

9. The implantable expanded PTFE medical device as claimed in Claim

1 wherein the device may further comprise of treated mammalian tissue .

10. The implantable expanded PTFE medical device as claimed in Claim 1 wherein the spiral ridges are formed in treated mammalian tissue .

1. The implantable expanded PTFE medical device as claimed in Claim 1 wherein the device is in the form of a stent graft.

2. The implantable expanded PTFE medical device as claimed in Claim 1 wherein the device is in the form of a vascular graft.

3. A method for producing an expanded PTFE based medical device comprising the steps of:

providing high molecular weight resin;

mixing said resin with lubricant or extrusion aid;

incubating the mixture for a predetermined period and optimal temperature that results in effective infiltration of lubricant into resin;

pre-shaping the mixture into a cylindrical form;

subjecting the resin-lubricant cylinder to a paste extrusion stage using an extrusion mandrel with trench cut into its surface; and wherein during this stage the cylinder is reduced to tube form with predetermined internal ridge (s);

drying the extruded tubes in an oven set at a temperature just below the flash point of the lubricant;

placing these extruded tubes into a rack for the stretching or expansion process, and then placing into an oven;

subjecting the extruded tubes to an expansion stage, wherein the tubes/rods is accordingly stretched to the desired expansion ratio, corresponding to the desired level of porosity; wherein during expansion said tube is stretched and rotated in a manner such that a spiral portion is formed along the length of tube; and

sintering the stretched tubes at a temperature above the crystalline melt point of the resin.

14. The method as claimed in Claim 13 wherein the paste extrusion stage includes the step of using a paste extruder comprising an extrusion mandrel which is formed with a groove cut along its taper and land regions so as to form internal ridges on the inner surface on extruded tubes.

15. The method as claimed in Claim 13 wherein at least one ridge is formed in the tube at the extrusion stage so as to form a spiral portion inside said tube during expansion stage.

16. The method as claimed in Claim 13 wherein the stretching or expansion process is performed in steps to create less and more dense regions that translate to soft and kink resistant regions.

17. An implantable medical device comprising mammalian tissue at least one portion of said device is formed with a spiral configuration in a manner such that it allows rotational blood flow transitioning into said device; wherein said spiral portion is formed such that it can maintain the rotational aspect of liquid flow.

18. An implantable medical device as claimed in Claim 17 wherein the spiral portion is formed in a manner such that it can rotate from end to end.

19. The method of claim 17 whereby at least one ridge is placed on the luminal surface of a tissue-PTFE hybrid graft.

20. The method of claim 17 whereby the ridge is spiraled at least 360 degrees.

21. The method of producing an internally ridged, spiraled tissue graft from properly treated mammalian tissue using a ridged mandrel and suitable spiraled wire.

22. The method of claim 17 wherein at least one spiraled ridge is formed in the treated mammalian tissue.