CA2131902C - Controlled porosity expanded polytetrafluoroethylene products and fabrication - Google Patents

Abstract

A method of forming porous articles with a varying pore distribution by extrusion from a billet with varying lubricant distribution. A single-polymer polytetrafluoroethylene is extruded and then stretched and sintered to provide a differential porous PTFE structure composed of fibers and nodes connected to one another by these fibers. The microfibrous structure has a portion within the cross section that possesses a different pore size, accompanied by a different node and fiber geometry, than adjacent areas within the cross section. A
tube (10), having elongate nodes (12), fibrils (14), an inner surface (16) and an outer surface (18), of an expanded, porous fluoropolymer material, which is useful as a vascular graft, is formed. In a vascular graft, the pores taper inwardly, providing a fluid-tight lumen wall structure that prevents leakage, yet promotes cellular growth and natural tissue generation. A
node structure of radially-oriented plates provides flexibility, suture strength, and enhanced protection against collapse.

Description

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CONTROLLED POROSITY E~PARIDED
POLYTETRAFLUOROETgIYLENE PRODUCTS AND FABRICATION
~..~kc~ or and of the invention ,.
Many fluoropolymer materials, such as polytetrafluoroethylene (PTFE), are thermoplastic polymers. Tk~at is. they have the property of softening ~rhen heated and of hardening again when cooled. PTFE is generally produced in the form of white powdex referred to as resin. It has a higher crystalline melting point (S27°C) and higher viscosity than other thermoplastic polymers, which makes at difficult to fabricate in the same manner as OtiBer plae~tZ.~rt?o p~F~ is a long chain p4lymer composed of CF2 g~~ups. The chain length determines molecular weight; while Chain orientation dictates cry~tal~inity. The molecular weight and Gryst~llinity ~f a given res~.n prior to sintering are controlled ~y the polymerization prodess.
Currently; three different types of PTFE
resins are available Which are formed from two d,ifgerent p~lymerization processes. The three resins are g~~,nular polymer, a9fueous dispersions, and Coagulated dispersion products.
In the coagulated dispersion of PTFE resin, small diame.~er (0.1 - 0.2 midrometer) particles are coagulated under controlled conditions to yield :.n..y../: , d'':l at... ...r ..u . .'e s -~F i A . ,.
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-2- , agglomerates ranging in size from 400 to 500' micrometers in diameter. The morphological structure of these agglomerates can be considered as long chains of PTFE that are intermingled in a tangled network.
A known method of forming articles from fluoropolymer resins such as PTFE, is to blend a resin with an organic lubricant and compress it under relatively low pressure into a preformed billet.
Using a ram type extruder, the billet is then extruded through a die in a desired cross-section.
Next. the lubricant is removed from the extruded _ billet by drying or other extraction method. The dried extruded material (~extrudate), is then rapidly stretched and/or expanded 'at eleva~.ed temper2tures.
In the cage of PTFE. thisresults in the material taking on a microstructure characterized by elongated nodes interconnected by fibrils. Typically, the nodes are oriented with their elongated axis .
perpendicular to the direction of stretch.
After stretching. the porous extrudate is sintered by 'hewing i t to a temperature above its .
crystalline'melting point while it is maintained in its stretched condition. This can be considered as an amorphous'.locking process for permanently "loeking-in" the m3erostructure in its expanded or stretched configuration.
It has been foundthat the effect caused by stretching PTFE is dependent on extrudate strength, stretch temperature, and stretch rate. According to .~ z..."~~,~~'' ,'~ :' ,.'~:'~ "; .': '.v..t . . := ~"..'':' ..
VfO 93/ D 82 D 4 PLT/US93/0237 D
D3.S. patent 3,953,566 of W.L. Gore, products expanded at high rates of stretch have a more homogenous structure and possess much greater strength.
Eatrudate strength is more generally a function of the molecular weight and degree of crystallinity of the starting resin and extrusion conditions such as extrusion pressure, lubricant level, and reduction ratio. These parameters also control the degree of alignment that results from extrusion. The degree of alignment, in turn, affects one's ability to homogeneously stretch the extrudate.
Molecular weight and crystallinity affect the stretch characteristics, sinter profile and ultimately the final properties of the processed material. For the initial stages of fabrication, most PTFDr fine powders used for ram extrusion and ezpansion processing are highly crystalline (>90~5).
as determined by IR spectroscopy, but their molecular weights may differ.
Low molecular weight materials tend to crlsstaZlize qui~clcly and become highly crystalline and ~, very brittle. In addition; the intermolecular forces between difl~oromethylene groups are very low. Thus, in order to achieve'adequate strength, one needs either very high-molecular weigh , highly crystalline materiel or one needs some ~aay to disrupt the crystalline order. With a homopolymer, the best way to inhibit crystallization is to increase the viscosity of the molten mater~,al to very high values by selecting a polymer with very high molecular weight: In fact. PTFE coagulated dispersion resins that have very high molecular weights with VVO'93018214 PCT/US~3/02371 2131.90 ..
-4_ molecular weight distributions have been developed .
for expanded PTFE processes.
In line with these considerations. the c primary function of the "sintering" step is to heat .

the polymer above its crystalline melt point so that it can be reformed upon cooling to a low enough i crystalline content to achieve the sort of mechanical properties required for the current application. To maintain a 1~w crys alline content in the final product, the melt viscosity corresponding to the molecular weight of the polymer, must be very high.

Most known methods for processing PTFE

describe unilateral stretching techniques and stress the importance of stretching the luoropolyaner at rapid rates. For example, United States patent numbers 3,53,566 and 9y,187.390 issued to Gore state that while there is a ma:imum xate of expansion beyond which fracture of the material occurs the mia:imum ra a of eapasion is of-much more practical significance. andeed. the patents state that at high temperatures within the preferred range fear stretching (35C-327C) only the lower limit of expansion rate'has been detected: The patents estimate t~.is rate to be ten percent of the initia-I

length of the s arcing material per second. The patents go on to note that the lower limit of expansion rates interact with temperature in a roughly logarithmic. fashion so that at higher temperatures within the preferred stretching range, higher z~irdimum expansion rates are required.

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WQ 93/X$24 PCT/US93/02371 U.S. Patent No. 4,973,609 to Hrowne describes another method for producing porous PTFE
products by stretching at a rate of 10~ per second.
The patent also states that a differential structure is obtained by using an alloy of two different fluoropolymer resins which are characterized by significant~,y different stretch characteristics. The resins have different molecular weights andlorr crystallinities. Accordingly, the final physical properties; such as strength, of PTFE articles formed in such a way are affected by the different molecular weights anddor crystallinities of the starting resins.
U.S. Patent Nos. 4,208,745 and 4,?13,0?0 also describe methods for producing porous PTFE
products having a vaxiable s~ruc ere. The processes utilize a sintering step having a differential sintering jprofile. That i.s, one surface of an eapandled PTF~ article is'sintered at a temperature which is h~,gher han the sintering temperature of another surface. This results in fibrils teeing broken and grovii3es an inherently weak material.
~~~ary~of_~he Inver~ti~rn It is an objet of the invention to provide a process for producing a shaped poraus article which is more truly semi-permeable than known articles f~rmed of fluoropolymer materials. It is another object o~ the invention to provide such a process in which a fluoropolymer eatrudate can be homogeneously stretched 3r~dlependent,ly of rate. Still another object'is to provide a porous ar icle. Yet another object of the in~rention is to provide a porous n~:..n 'A:~: .;ry .
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~~.a ' 1~V~ 93/8214 ~ PCT/U~93/023~1 2~~~9~~ -6-article having a porosity which is variable in the direction of the article°s cross-section.
a 3'hese and other objects are achieved by the present invention which in one aspect features a process for producing a porous article. The process includes the steps of providing an eztrudate of a r fluoropolymer material which is capable of being stretched and bil~terally stretching the eztrudate al~ng its longitudinal azis. Conditions are maintained during stretching sufficient to~yield an article which is substantially uniformly stretched over a major portion of its length. These conditions include stretch rateo ratio. and temperature.
The stretched eztrudate has a microstructure which is characterised by el~nga~e nodes which are connected'by fibrils. This microstructure is locked in by sgntering the stretched eztrudate while maintaining it in its stretched state. .
p,~ important feature of the invention is that the fluoropol~mer eztrudate is bilaterally .
stretched. That is: in accordance with the invention both ends ~f the eztrud~te are displaced along the eztrudate°s 1~ngitud3nal azi~ away from a central portion of the ~ztrudate. It has been found that this stretching ~ethbd provides significant advantages over known stzetching methods wherein one end of ~n e~trud~te is held stationary while only the other end is displaced.
Tn various embodiments of this aspect of the invention the bilateral stretching is carried out at ! . .'.' 4, . .' ' ~,. . , ~ ~~~ ~" , ,.~4~ . ' ; ~ ~. ' ~ .. .
WO 93!182H4 P'CT/US93l02371 ,,."., ~~
rates not greater than. ten percent per second.
Indeed, it has been found that stretching at rates slower than even one percent per second provides a material having an extremely desirable microstructure of nodes and fibrils, the nodes being significantly larger than nodes resulting from known processes of rapidly stretching single~resin eatrudates unilaterally.
In carrying out the stretching step in accordance with the grocess of the invention, the ends of the eatruc3ate can be displaced either simultaneously or sequentially. For example, in one embodiment of he invention, a first end of the eatruda~e is displaced to a.stretch ratio of not greater tha~n'two ~o one. That first end is then held stationary while the second end of the extrudate is displaced in the opposite direction to again result in a stretch ratio of not greater than two to one.
Restricting he individual stretches to stretch ratios of not greater than two to one ensures a substantially homogeneous microstructure along a major portion of the length of the extrudate.
In'another aspect, the invention features a process for producing a porous ube of polytetrafluoroethylene including the step of providing a preformed billet of a mixture of a polytetrafluoroethylene resin and a lubricant. As with the above~described aspect of the invention, the billet is extruded. the eatrudate is then dried, and bilaterally stretched along its longitudinal axis under conditions sufficient to yield a tube having a substantially homogenous microstructure over a major VliO 93/1821a . PCT/US93/02371 213~.Jf~~
-g_ portion of its length. The stretched tube is then sintered while being maintained in its stretched state to produce the porous tube.
In one embodiment of this aspect of the invention, the preformed billet is formed to have a lubricant level which selectively varies in the direction of'the billet's cross-section. That is, fnr ezample, the billet might have a lubricant level of fifteen percent by weight at its inner and outer surfaces and a'lubrican~ level of approximately twenty percent at a radial position between its inner and outer surfaces. When eztruded and stretched, such a billet resin s in a,porous tube having a microstructure which varies in a controlled fashion in the direction of the tube's cross-section. ,This phenomenon and its advantages are described below in greater detail.
Accordingly, in the various embodiments of this'aspect of the invention, a porous article having a desired microstructure is-provided by controlling the'bil~et lubricant level, the billet ~ec3uction ratio, and bilateral stretching conditions such as stretch rate and,ratio. These steps avoid the problems such as weak material which are associated with known resin-blending and varied-profile sintering techniques:
In still another aspect, the invention futures a tube foamed 'of an' ezpanded porous fluorogolymer material. The material has a miexostructure characterized by'ring shaped nodes interconnected by f~.brils. An important feature of _g_ this aspect of the invention is that substantially all of the nodes each circumscribes, at least in part, the longitudinal axis of the tube and extends from the inner to the outer surface of the tube wall, thereby creating between the nodes continuous through-pores from one surface to the opposite surface.
In accordance with yet another aspect, the invention features a tube formed of porous fluoropolymer material characterized by a structure of nodes and fibrils wherein the nodes are radially oriented and the fibrils extend substantially parallel to the axis of the tube between successive nodes, the nodes and fibrils forming pores having radially tapering size distribution conductive to tissue through-growth.
In accordance with another aspect, the invention features a method of producing a shaped porous article, such method comprising the steps of:
forming a billet of a single fluoropolymer material and a lubricant in which a lubricant concentration gradient has been established along a dimension of the billet, extruding the billet to form an extruded article having a shape and a lubricant component concentration that is varied in level corresponding to the concentration gradient of the billet, removing lubricant from the article and stretching the extruded article to form a porous article with predetermined pore sizes in different regions thereof, wherein larger pores -9a-are formed in regions where the extruded article had higher levels of lubricant, and sintering the porous article in its stretched state to fix its dimensions thereby forming a sintered porous article of a single fluoropolymer material having different porosities in predetermined regions thereof.
In accordance with yet another aspect, the invention features a prosthesis comprising an extruded body having a wall extending in a thickness direction between an inner surface and an outer surface, extending along an axis and formed of a single expanded polytetrafluoroethylene (PTFE) material, said wall having a microstructure of nodes of solid material with flattened aspect and oriented transverse to said axis and said nodes being interconnected by fibers, said extruded body having been stretched differently through its thickness and having been heated at elevated temperature to uniformly fix the nodal structure of said single material, whereby spaces between said nodes define tapering channels extending along the wall thickness direction.
In accordance with yet another aspect, the invention features a method of producing a prosthesis, such method comprising the steps of:
forming a billet of fluoropolymer material having a lubricant property which varies across a dimension of the billet corresponding to a desired porosity structure, extruding the billet to form an extruded prosthesis blank, the extruded prosthesis blank having a lubricant -9b-property distribution that varies in correspondence with said desired porosity structure, removing lubricant from the extruded prosthesis blank and stretching the extruded prosthesis blank to form a porous prosthesis blank, and sintering the porous prosthesis blank in its stretched state to fix its dimensions thereby forming a prosthesis having the desired porosity structure.
In yet a further aspect, the invention provides a method of manufacturing a porous PTFE article having a sintered microporous structure, the improvement comprising forming the article of PTFE material mixed with lubricant, and varying a property of the lubricant through a cross section of the article to achieve a tapered pore structure before sintering the article.
In accordance with a further aspect, the invention features an implantable prosthesis comprising a tube of porous PTFE including a tube wall with a porous microstructure of nodes and fibrils, wherein channels are defined by spaces between adjacent nodes and said channels are tapered and extend substantially through the wall of the tube, and wherein said wall is uniformly sintered throughout.
In accordance with a further aspect, the invention provides a method of producing a shaped porous article, such method comprising the steps of:
forming a billet of a single fluoropolymer material and a lubricant in which a lubricant concentration gradient -9c-has been established which is a step function along a dimension of the billet, extruding the billet to form a single-material extruded article having a shape and a lubricant component concentration that differs in level in different regions of the article in accordance with the lubricant concentration gradient of material in the billet, removing lubricant from the extruded article to form a porous article, and sintering the porous article thereby forming a sintered porous article having different porosities in different regions thereof, wherein larger pores are formed in regions where the extruded article had higher levels of lubricant.
In accordance with a further aspect, the invention features an implantable prosthesis comprising a wall of porous extruded polytetrafluoroethylene comprised of a single resin and having a porous microstructure consisting of nodes interconnected by fibrils, wherein interstitial spaces are defined by adjacent nodes, the interstitial spaces between said nodes being tapered and extending substantially through Said wall, and wherein said wall is uniformly sintered throughout.
In accordance with a further aspect, the invention features a process for producing a shaped porous article, the process comprising the steps of:

-9d-providing an extrudate of a fluoropolymer material which is capable of being stretched, the extrudate having a longitudinal axis and a desired cross-section, bilaterally stretching the extrudate in two opposing directions along the longitudinal axis to yield an article which is substantially uniformly stretched over a major portion of its length and has a microstructure characterized by elongate nodes connected by fibrils, and sintering the stretched extrudate while maintaining it in its stretched state to produce the shaped porous article.
In accordance with a further aspect, the invention features a process for producing a shaped article of polytetra-fluoroethylene comprising the steps of:
extruding a preformed billet of a mixture of a poly-tetrafluoroethylene resin and a lubricant to produce an extrudate having a longitudinal axis and a desired cross-section, removing the lubricant from the extrudate, bilaterally stretching the extrudate along the longitudinal axis in two opposing directions to yield an article having a substantially homogeneous microstructure over a major portion of its length, the microstructure being characterized by elongate nodes connected by fibrils, and sintering the stretched article while maintaining it in its stretched state to produce the shaped article.
In accordance with a further aspect, the invention provides a process for producing a porous tube of polytetrafluoro-ethylene comprising the steps of:

-9e-providing a preformed billet of a mixture of a polytetra-fluoroethylene resin and a lubricant, extruding the billet to produce a tubular extrudate having a longitudinal axis and a radial thickness, removing the lubricant from the extrudate, stretching the extrudate along the longitudinal axis at a rate of not greater than approximately ten percent per second to yield an article having a substantially homogeneous microstructure over a major portion of its length, the microstructure being characterized by elongate nodes connected by fibrils, and sintering the stretched article while maintaining it in its stretched state to produce the porous tube.
In accordance with a further aspect, the invention provides a process for producing a shaped porous article having a desired length along an axis and microstructure adapted for supporting a biological material thereon, such process comprising the steps of:
forming an extruded article of fluoropolymer material having an end-to-end dimension related to the desired length, stretching the extruded article at elevated temperature to form a stretched article of the desired length by actively moving each end of the extruded article in opposite directions away from a central portion of the extruded article, and sintering the stretched article, while maintaining it in a stretched state to produce the shaped porous article having the desired length.

i 9f -In a further aspect, the invention features an implantable article comprising a body formed of a single fluoropolymer material and having an expanded PTFE wall structure with tapered microchannels extending along a thickness dimension thereof and being uniformly sintered at a sintering temperature of said single fluoropolymer material.
In a further aspect, the invention provides a process for forming an expanded PTFE prosthesis of enhanced uniformity arid surface characteristics, characterized in that during formation of the prosthesis, a preformed article is stretched bar actively moving each end of the article outwardly from a central portion thereof before sintering whereby uniform stretch characteristics are imparted throughcut r_he article.
In a further aspect, the invention features a tube formed of a single expanded, porous fluoropolymer material -which =s ur_iiormly sintered and has a longitudinal axis arid a wail, t'.~.e tube having a microstructure characterized by ring-shaped nodes ir_terconnected by fibrils, a substantial plurality of the ring-shaped nodes each circumscribing the longitudinal a:c,s of the tube, the wall further having a microstructure c'.~.aracterized by a second group of nodes smaller than the ring-shaped r_odes and located along a radial region eatendi_~.g partway thrcugh the wall.

i -9g-In one embodiment, the invention provides the tubular article having a wall thickness of under about two millimeters.
In another embodiment, the invention provides the tubular article having a wall thickness of under about one millimeter.
In yet another embodiment, the invention provides the tubular article having a wall thickness of about 0.3 - 0.8 millimeters.
In a further aspect, the invention resides in a process for producing a porous tube of polytetrafluoroethylene comprising the steps of providing a preformed billet of a mixture of a polytetrafluoroethylene resin and a lubricant, extruding the billet to produce a tubular extrudate having a longitudinal axis and a radial thickness, removing the lubricant from the extrudate, stretching the extrudate along the longitudinal axis at a rate of not greater than approximately ten percent per second to yield an article having a substantially homogeneous microstructure over a major portion of its length, the microstructure being characterized by elongate nodes connected by fibrils, and sintering the stretched article while maintaining it in its stretched state to produce the porous tube.
In another embodiment, the invention provides that the lubricant is mixed in the billet at a level which is greater than approximately fifteen percent by weight.

-9h-These and other features of the invention will be more fully appreciated by reference to the following detailed WO 93!18214 PC.'T/US93/CD2371 2131 ~ ~ ~ -1~-Figure 3 is a scanning electron microscopic eiew of a raa~al cross-section of a porous article in accordance With the invention, Figure ~i is a schematic tlegictxow of a °
billet suitable fox extrusion in accordance with the invention;
Figure SA is a scanning electron microscope longitudinal cross-section view of another porous article in accordance with the invention, Figure 5B is a scanning electron microscope view of the inner surface of the porous article shown sn gigure ~A, Figure SC is a scanning electron microscope :view of the outer surface of-the porous article shown in Figure SA;
Figure 6fis a schematic longitudinal cross-section view of still anather porous article in accordance with the invention, Figure 7 is a sehemati~ representation of a tubular structure accore3ing to a presently preferred embodiment of the invention;
Figure ?A is a photomicrograph of a radial section through the structure of Figure 7, Figure 7B i~ a photomicrography of a tangent section-taken at the interir~r of the structure of Figure 7, V1'4D 9311821~d PCT/US93/02371 _1i_ 213~~0~
Figure 7C is a photomicrograph of a tangent section taken of the eaterior of the structure of Figure 9, Figure 8A schematically illustrates a tube - preform vaith layered material of radially decreasing Iube level, and .
Figures 88 and 8C are photomicrographs of tangential sections of a tube formed from the preform of Figure ~A, taken in the regions corresponding to ~ and C, respectively, of Figure T..
Detailed De,~~r~pt~gn As stated above: in one aspect the invention features a process fir producing a shaped porous article. p. significant feature of th.e process is that an az~ti~le having a homogeneous microstructure is formed ~:ndependently~ of the rate at which it is Stretched, 13y homogen~us microstructure, in this patent application; it is intended to convey first that the microstrucl'ure of the artiele9 including relatively I dense nodes separated bx relatively light connecting filbrill~: i~ ~eiatively uniform al~ng ~at least one dimension, e.g.; the length of the article, although as will be eiplained below, aspects of microstructure m~~ he; and,px~ferably are, intentionally varied in ~~oth~x direction, a:g., in cross~section of the article.

1W~ 93!18214 PC'T/tJS93/02371 Various fluoropolymer resins are suitable for use in the present invention. For example.
polytetrafluoroeth~lene or copolymers of tetrafluoroethylene with other monomers may be used.
&uch monomers may be ethylene, chlorotrifluoroethylene, perfluoroalkoxytetrafluoroethylene, or fluorinated ' propylenes such as hezafluoropropylene, In particular, however, polytetrafluoroethylene (PTFE) works well. Accordingly, while the inventive process can be utilized to produce porous articles formed of various fluoropolymer materials, the following description pertains specifically to the formation of an article from PTFE resin.
For purposes of the present invention, all fluoropolym~~s that require a lubricant/extrusion aid and are capable of being expanded can be used.
However, it is preferred to use highly crystalline, hagh molecular weight resins to achieve maximum strength: When PTFE is used: resin of a molecular weight between 5000;000 and 70.000.000 is suitable.
It should be noted; however, PTFE does nod dissolve iri any common solvent: herefore its molecular weight cannot be measured by the usual methods: According to the ~ncv~~~~'p'~; a Qf Polymer ~~"ience and EnQ'neer3n4 (Whey and Sons. 1989 ), though: the following relationship has been established between number-average molecular weight (Mn), fog molecular weights between 5.2 x 105 and 4.5 z 107. and the heat of crystallization (aHc) in Jouleslgram (calories/gram).

i f Mn=(2.1z 1010) z ~Iic'5.16 Accordingly, by determining the heat of crystallization of a given PTFE resin, a number average molecular weight of the resin is determined using this relationship.
As with known methods of processing PTFE, the invention utilizes a preformed billet which comprises a PTFE resin mired with an organic lubricant. Various lubricants are suitable such as naphtha, ISOPAR-'and ISOPAR-H~~available from Ezzon Corporation. Low odor paraffin solvents can be used as well. The blended resin is compressed at low pressure (less than 1000 PSI) into a tubular billet of approximately one third of the resin's original volume. Billet forming processes are generally known in the art.
As discussed above, extrusion conditions have a significant effect on the resulting eztrudate's reaction to being stretched. In particular, once a resin of a given molecular weight and crystallinity has been selected, eztrudate qualities are controlled by the level of lubricant mined with the resin to form the billet, the reduction ratio at Which the billet is extruded and the extrusion pressure. These are believed to influence the micromechanical properties of the extruded article because these parameters affect the degree to which the molecular chains of PTFE align themselves during extrusion.
" Trade Mark l~Yt3 93/18214 _ PCf/~JS93I02371 ". ..

The process of the invention is most effective when using preformed billets ranging in lubricant level from between 8 to 25 percent by Freight to produce an eztrudate well adapted for the inventive stretching process.
When PTFE eatrudate is subjected to an external tensile force, such as during stretching, the intermingled network of PTFE particles separate.

Accordingly, the force required to separate these particles, and hence stretch the eatrudate, is dependent upon the degree of intermingling of the PTFE particles. The longer the polymer chains (higher molecular weight), the greater the amount of intermingling that will occur and, therefore. the greater the force that will be required to separate the coagulated disp~rszon particles.

Two other ez ~cusivn parameters having an effect on a resulting eztrudate's reacta.on to stretching are reduction ratio and extrusion gressur~~ Tae range of suitable reduction~ratios is bounded ~t its lower end by the minimum reduction ' ratio permissible which provides an eatrudate of sufficient s rer~gth so as not' break during stretching. At its upper limit, the range of suitable reduction ratios is bou~n~ed by the mazimum ratio permissible wrhich provides an extrudate that is amenabae to being homogeneously s retched.

Accordingly. e=perimentation has shown that for purposes of the present'invention the preformed bullet should be eatruaed to;'a reduction ratio of between approximately 50:1 and 6Qa~l. A preferred WU X311$214 PCT/US93/02371 .. -15- y reduction ratio is between approximately 200:1 and 900x1.
Reduction ratio and stretch characteristics are interrelated since t?ne force required to deform a PTFE eatrudate and form fibrils from the nodes is related to how the material was aligned (packing densi.ty~ during eatrusion. Fibrils are not formed as easily from nodes With high reduction ratio e=trud;ates as they are with low reduction ratio eatrudates. This is believed to be because internal forces ire much higher in high reduction ratio eatrudates.
The third eutru ion parameter which has a significant effect on the resulting eatrudate's proper::ies upon being stretched is eatrusion pressure: While eatrusi'on-pressure is, to a certain eat~nt. ~'elated~to reduction ratio by warying lubricant level, extrusion pressure can be varied independently of reduction ratio.' While measured extrusion pressure will vary depending upon the type of extrusion equipment being used; the range of -uitable eatsusion pressures to practice the present invention will be apparent 'to those skilled in the art. For example: prossure~ between approximately 6000 P&I'and appraaimately 10;000 PSI have been used successfully for lrhe practice ~f the invention.
~nce an .eatrud'ate has 'been produced according to the above described parameters. in accordande with the inventive process it is stretched under conditions sufficient to yield an article that i~ uniform osier a major portion of its length.

WO 93/D~214 PC.'TlLJS93/02371 ..

Stretching processes are characterized in terms of stretch rate and stretch ratio. Stretch rate refers to the percentage change in length of the eztrudate per unit time. In the case of a fifty centimeter long extruded tube, for example, stretching five ' centimeters per second results in a stretch rate of ten percent per second. The percentage change is calculated with reference to the initial length of the eztrudate:
Stretch ratio, on the other hand. is nat time dependent but merely refers to the ratio of the final length of the stretched eztrudate to that of the anitial length of the unstretched eztrudate.
Accordingly: tretching a fifty centimeter long extruded tube to one hundxed centimeters, results in a stretch ratio of 2:1 regardless of the duration of the stretch:
With this in mind, it is an important feature of the invention that extruded materials are stretehed to fozm porous articles independently of stretch rate: In certain instances the process is' dependent on stretch ratio. As stated above, known methods for processing fluoropolymer materials teach that stretching must be carries out at a rate generally exceeding approximately ten percent ger second. In accordance with the inventiono however.
homogeneous articles are produced at stretch rates not gxeater than apProzimately ten percent per sec~nd. Indeed; the preferred rxte of stretching ~ang,~s from approaamat~2ly 0.5 percent per second to approximately 10 percent per second.
.

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WO 93/a~2~14 PCT/~JS93/02371 To stretch an eztrudate, the eztrudate must be placed in tension. This is done by applying r opposed forces to the ends of the eztrudate. The level of force applied to the eztrudate, and hence the rate at which the eztrudate stretches, determines a ,.
how the above-described intermingled network of PTFE
particles unravels: Tn known methods for ~stretchxng PTFE, force is applied to place the eatrudate in tension by displacing one end of the eztrudate with w respect to the other end. At stretch rates lower ,.
than ten percent per second, this method of stretching cannot uniformly stretch the eztrudate to greater than a 2:1 ratio. To the contrary, at greater ratios the material stretches preferentially at its moving'end: The fined end of the material, on the other hand; ez~eriences significantly less stretching.
In accordance with the invention, on the other hand, bilateral stretching results in more even force distri;buta:on along the length of the eztrudate and pr~duces a more homogeneously stretched material: T~ has been found that stretching bilaterally, that is: displacing both ends of the eztrudate ~w,ay from the middle of the estrudate~
provides a m~rterial that is homogeneously stretched ~ver the maj~rity of its length independent of the stretch rate;
After the eztrudate has been bilaterally stretched it is sintered by heating it above its cr~stallan~ melting point under tension. As discussed shove, this locks in the microstructure of p ,: .
,, .,..i 9- , i . .y . a-..
a : ,. r .
,.,: ;. ,. ::. ,. ,:.. , :. .. , ;. , :' , ' ! ..:'.
..,,.~..." ,~...,.. ...i..;::....:.,......a, .~..~..,:3.~.~ , ....:......~~...~,:............ ...,....t.,,.;....."...::..,...:~,..
,.,.,".::.. .. .-:::...:.-. :. ,... ....,~,::...:...,....
w~ 9~i~8z~a ~cr~u~93ooz~m .. .
-le-the material and completes the process of producing the porous article.
Figure 1 is a schematic representation of a porous tube 10 foamed by the above described bilateral stretching process. For purposes of description, the microstructure of the tube 10 has been ezaggerated: Accear8ingly, while the dimensions of the microstructure are enlargedo the general character of the illustrated microstructure.is representative of that microstructure prevailing in an article formed by the inventive process.
The tube 10-includes a microstructure chatact~erized by,elongate nodes 12 interconnected by fibrils 19. A significant feature of the tube 10 is that the nods I,2 are ring-shaped to form, in effect a-series of washer-type, or phate-like solid bodies circumscribing the tube',s longitudinal axis L. .The nodes I2 are oriented generally radially, i.e., perpendicularly to the azis of stretching.
represented by arrows T which is coincident with the longitudinal azis L.
Another significant feature of the tube's microstructure is that substantially all of the nodes 12 eztend along a transverse azis t f som an inner surface 16 of:the tube to an outer surface l~ of the tube. This dimensi~n of the nods 12 along the inside-to-outside direc~,ion is significantly larger than the corresponding ~limen~ion of nodes formed by a~nventional single--resin fluoropolymer processing methods. Such nodes are randomly arranged and may be characterized by a transverse axis which is generally . . ~:.e 4 , n ~,i.,~.,.. .,:,:~.:... ., ,....;:., .:'~.=.~r'~'.!~,1 ,.. ~,~., ',:..' ,. ...
;,.
W~ 93118214 PCTlLJ~93102371 oriented perpendicularly to the a~~is of stretch.
Notably, however, the nodes of these known structures are considerably shorter and smaller than nodes produced in accordance with the present invention.
Indeed, the above-referenced U.S. patents to Gore note that nodes formed by that known technique generally range in sire from smaller than one micron to approximately 400 microns.
Unlike the short. randomly stacked nodes and microfibrillax spaces formed by conventional single-resin fluoropolymer stretch or expansion processing, the method of the present invention provides a microporous structure having miero~ibrillar spaces which define through-pores or channels extending entirely from the inner to the outer wall of the egpanded eztrudate. These t3arough-pores ase perpendicularly oriented internodal spaces which traverse from one surface to another.
As discussed below in-greater detail, by varying Iubricant levels such internadal through-pores are preferentially altered in accordance with the.presen~ invention such that the 'surface pore on one surface is made to be larger or smaller than the surface pore on the opposing surface.
A longitudinal cross-section view of a tubular article formed by the process of the invention is sh~wn in Figure,2. There, it can be seen that the present invention produces an article having a microstructure characterized by elongate nodes which are substantially larger than the nodes of materials produced by known single-xesin forming i methods. Indeed. the nodes shown in Figure 2 consistently range in size from approximately 500 microns to approximately 900 microns. Substantially all of the nodes of the article shown in Figure 2 extend from the inner surface of the tubular article to the outer surface of the tubular article. thereby creating through-pores substantially all of which traverse from one surface of the article to the other.
Figure 3 is a radial cross-section view of the tubular article shown in Figure 2. There it can be seen that while the nodes are generally oriented perpendicularly to the axis of stretch, as represented in Figure 1, they are not perfectly flat and, therefore, a radial cross-section cuts through many nodes. Accordingly, while the schematic representation in Figure 1 is useful for purposes of explanation, the scanning electron microscope photographs in Figures 2 and 3 are more accurate depictions of the microstructure of a product produced by the inventive process.
Products provided by the invention are suitable for a wide range of biological applications such as for vessel implants or organ wall grafts. In particular, as described below, vascular grafts formed by the process of the invention enjoy various advantages. Indeed. the processes of the invention are well suited for the formation of the various biological devices described in the following commonly assigned and co-pending U.S. Patent No.
5,411,550 for "IMPLANTABLE PROSTHETIC DEVICE FOR THE
DELIVERY OF A BIOACTIVE MATERIAL"; U.S. Patent No.

i r 5,197,976 for "MANUALLY SEPARABLE MULTI-LUMEN VASCULAR
GRAFT"; U.S. Patent No. 5,320,100 for "IMPLANTABLE

INDICIA"; U.S. Patent No. 5,370,681 for "POLYLUMENAL
IMPLANTABLE ORGAN"; and U.S. Patent No. 5,192,310 for "SELF-SEALING IMPLANTABLE VASCULAR GRAFT" all of which were filed I6 September 1991.
As stated, several structural, clinical and biological advantages accrue from the microstructure engendered by the inventive process. For example, as discussed below in greater detail with regard to the various examples. larger node size provides a structure having a significantly improved radial tensile strength. Also. tubes formed by the inventive process have improved burst pressure and suture strength characteristics. The flat ring-like node structure imparts significantly more flexibility. without kinking, than conventional fluoropolymer processes, in addition to providing superior resistance to radial twist compression (colloquially known as "torque twist"). The tubular article formed by the process of the invention allows a significant degree of bending or radial twist, before experiencing lumen collapse or kinkinq, unlike conventional fluoropolymer articles which exhibit significantly less resistance to "torque twist" or "bending." Conventional articles, therefore, kink under smaller stress loads than do the articles of the current invention.
Additionally, the method of the current inve:rtion produces articles which exhibit VY4 93118214 PCTlLIS93/02371 2~3~.~~2 _22_ r significantly more resistant to compression than conventionally processed articles. This provides i more resistance to luminal collapse under equivalent stress loads. The articles provided by the invention also exhibit increased flexibility for enhanced a drapability, or ability to bend more readily, without restricting lumanal cross-sectional area. thereby improving ease of handling during surgery. while not increasing stress on the points of attachment and fi~.ation. The ring like.nodal architecture of the invention also produces tubular structures with significantly more resistance to tearing or splitting in the horizontal direction, as compared to conventional non-reinforced fluoropolymer tubular articles, For experimentation, an eatrudate was prepared by blendxnq PTFE resin (Fluon CD-123 obtained from ICI Americas) with "ISOPAR-H" odorless solvent (produced by Eaaon Corporation) used as an extrusion azd at a level of 150 cc of solvent per pound of resin: The bleradl was compressed into a tubular billet; heated to 300°C. and extruded into a 6 mm I.D. by ? mm O.D::!tube in a ram extruder having a reduction ratio of about 149:1 in cross-sectional area from billet to the extruded tube. The volatile extrusion aid'was removed by drying in a heated oven prior to stretching.
Tb demonstrate the advantages of bilateral stretching in accordance with the invention, samples of the tubular eztrudate were then stretched various ways as discussed below.

W~ 93/1214 PCTIL1S93l42371 2~.3~.~02 An apparatus was developed that allowed samples of the tubular extrudate to be stretched at controlled rates and temperatures. The apparatus Consisted Of two Clamps for holding the tubes One clamp held fined within the oven and another clamp attached to a chain drive coupled to a~ variable~speed motor. The tube was stretched an amount equal to 50%
of its original length at a rate of approximately 10%
per second. The fired and moveable ends were then inverted and the stretching step repeated. The stretch and inversion steps were repeated until the extrudate sample had been stretched to ~ final stretch ratio of three to one. The oven temperature ~~s then raised to 370~C for ten minutes while the samples were held elamped.

. An ~pp~r~tus'was developed that allowed both ends of the eztrud~te to be displaced simultaneously, at a controlled temperature arid rate. The apparata~s includes two,clamps independently mounted to two stile drive sys~ems~ Followring mounting to the stretch apparatus, both sides v~ the sample were displaced simultane~usly at equal speeds in opposite directions for'a selected distance: The applied stretch rate using the combined displacements rates from eaeh side way caleulated to be approximately 10%
per' second: The final stretch ratio was a~proa~imately three to one:

WO 93/18214 ' PCf/US93/02371 The apparatus described in Method~2 was used to displace each end of the eatrudate sequentially.
That is. first one end ~f the eatrudate Was held fiaed while-the other was displaced a given distance at a constant speed. then, without inverting the sample, the previouslx displaced end was held stationary while the formerly sl:ationary end was displaced the semen distance at the same speed.
Again, the sample,was stretched at a rate of approximately 14% per second to a final ratio of approximately three to one.
Samples produced by the above described methods were then tested al~ng with commercially available PTFE tubes produced by conventional.
unilateral stretch techniques, the results appearing be l ow .
~, Conventional 3060 ' 640 '7.9 55 2.2 800 Method 1 2660 803 2.9 90 0.5 1462 Method 2 2720 833 2.8 ~5 0.5 1382 Method 3 2400 895 2.8 95 0.5 1861 Where A is'longitudinal tensile strength Cpounds per square inch);

'WO 93/18214 PC1'/US93/02371 r _~5- 2I3~~Q2 where E is radial tensile strength (pounds per square inch);
where C is water entry level (pounds per square inch);
where D is radial laurst pressure (pounds per square inch):
where E is ethanol bubble point (pounds per square inch); and ~rhere F is suture strength (in grams) for a ~ mm bato.
Further, tubular eatrudate samples as produced above were bilafatally stretched, displacing both ends simultaneously, at other stretch rates.
d~gain, the st~~tc~ xates were calculated by combining the-dzspl~cement saes ~f both ends e~f the eatruda~te. Tests performed on samples produced in this manner yielded the results detailed below.
~ $
10%ls~~ 2232 ?80 2.8 95 1838 5~ae'sec 2144 933 2.4 9p 1657 0:5~5/sec 23?2 953' 2:1 105 1612 The data clearly indicate that enhanced radial strength and suture strength along with a corresponding decrease in hater Entry Pressure and Ethanol Bubble Point; result fr~m the inventive bilateral stretching process:

PCT/fJS931~2371 WO X3/18214 ~ ~ ~ ~ ~ ~ ~ , ,~ T~
-a 5- -:,..
For purposes of evaluating homogeneity. ' additional tubular eztrudate samples were marked at 1!2" spaced intervals using a permanent marker. The samples were mounted and stretched either unilaterally with one end held fized throughout the I stretching process or bilaterally in which both ends were displaced simultaneously. After stretching at rates eelual to or lower than 10% per second the samples were sint~rea and analyzed by measuring the distance between the marks along the sample lengths.
This distance, divided by the original half-inch spacing yields a local measure of the expansion ratio. The results'detailed below indicate that at low rates of stretch bilateral stretching produces a structure Which is more uniform than unilaterally stretched products. That is, with the bilaterally stretched samples, each half inch segment stretched an amount comparable to all segments through the length of the sample. Each unilaterally stretched samples on the other handy stretched preferentially at its moving end, often by a factor three to five times greater than that of its restrained end.

...'. ... ..,... ......... .., . ,::..' ....L....: , ... .....~. . .. ..~~~~~~
~. .~et.:~~~ .,': . ;::'~ . , '..:.5 ~:,. . .' ~ ~<~~~
W~ 93/18214 P~.'I'/US~310237a -2?-BILATERAL STRETCHING
FINAL STRETCH LENGTH IN INCHES
OF EACH SEGP~IE~IT
~o~ssEC S~~sEc ORIGINAL
DISTAI3cE 3:1 4:1 3:1 4:1 FROM RATIO RATIO RATIO RATIO
g~II DOLE .
,~II3CHES ~
2.0 1.375 1.75 1.~5 1.75 1.5 1:375 1.875 1.5 2.0 1:0 1.375 1:875 1.375 2.0 0 ~ 5 1 ~ 5 1.. 875 1. 5 I o 875 0.5 1:5 1.?5 1.5 1.875 . 2 f0 1 a 5 ~ a 0 m . . 1 a 375 .

0Ø .... , a 1 . ~5.. 1 s 5 .

I~ can be seen that ~t a rate of 10~a ger seeon~; bi~;at~rally str~tchir~g an eatrudat~ to a ra~~;o of 3:1 in aecardanee ~ invention lipids pith ~h aaa achi eved e~cpansi~n faetor that vazaes by under 10s along the length of e~trudate.
the stretehed Bilater ally str~tGhing to a 4:1 ra tio at this rate yields a variation of less than B~S .

Hi~:at~r~lly stretehing at 5% lair sacond yields similar unif~rmities in aGh ieeed ez~ansion faetor. Moreover, such variations as there are, V6~0 93118214 PCTIUS93/02371 ~131JU~ -2~-appear to be distributed in a more spatially uniform way.
UNILATERAL STRETCHING
FINAL STRETCH
LENGTH
IN
INCHES

OF
EACH
SEGMENT

10%/SEC 5%/SEC 0.5%/SEC

ORIGINAL

DISTANCE 3s1 4.1 3:1 9:~. 3:1 9:1 FROM ktATIO RATIORATIO RATIO RATIO RATIO

FIXEp END
~s ~~i~~

0.5 1:25 l.3?51:0 0.5 0.875 0.75 1:0 1:125 15 1.0 0:5 0.875 0.75 1,5, 1:0 1.75 1.0- 0.875 0.875 0.75 .0 1;225 1:8751.125 1.5 1:0 1.0 2.5 1:375 2:25 1.25 1:875 1.3?5 1.75

3 ~. lfi25 2,3T51.5 3:5 1,875 3.5 r 3.5 2.125 2.75 2.125 9.0 2.25 4.0 2.875 2:75 2.375 4.0 2.625 4.25 These show that wi h ilateral results un stretchin g ~t the above-noted rates and ratios. a far greatei v ariation in hieved expansion results. In ac particula r, the show that at the se rates and results ratios, a unilaterally stretched sample stretche s preferent ially its at mo~ing,end 'WO 93/182D4 PCT/US93/02371 In another embodiment of the invention, a porous article is formed utilizing a preformed billet such as billet 50 shown in Figure 4. Billet 50 includes radial inner portion 52 and radial outer portion 54. A significant feature of billet 50 is that while radial portions 52 and 54 comprise the same resin, different lubricant properties, prevail in the portions. ~'or a:ample, different types of , lubricant, different molecular weight lubricants of the same type. lubricants of different viscosity. or a single lubricant but at different relative proportions may be used.
The f~rmation of layered preform billets is generally known in the art. For euample, various known techni~iues have been used to produce.eatrudates having a conductive layer in electronic applications or a colored'~layer in general tubing applications.
U.S. Patent No.'4.973.609 assigned to Browne describes a layering technigue using different resins.
Tn accordance with this aspect of the present invention, the microstructure of an extruded end a:ganded'FTF~ article is controlled using a single resin'with a varying Tube characteristic, preferably tk~e tube level, through the preform billet. For~insfiance."the sample shown in Figures 5A
through'5C was produced using a single DaTFE resin that was preformpd in a layered fashion at two different lube levels acr~ss its cross-section and pr~cessed according to the above described bilateral stretching process.

4 ~ ~ ~ ~ 9 0 ~ ' ~ PCTlUS93l02371 Figure 5A is a longitudinal cross-section view of a wall 60 of a tubular artiele formed utilizing the billet 50 in accordance with~the above-described inventive process. ~As can be seen in the Figure, the material forming the wall 60 is characterized b~ a microstructure of large nodes 62A
and small nodes 62B interconnected by fibrils 64.
This results due to the inner radial portion 52 of billet 50 having a lower lubricant level than the outer radial portion 54. That is, lower lubricant levels result in smaller, more closely spaced nodes.
Several advantages accrue from the structure of wall 60. For example, by forming a tube having porosity at an inner surface 66 (FIGURE 58) which is smaller than the porosity at an outer surface 68 (FIGURE SCE. a vascular graft is provided which defines an -efficient flow channel at its inner surface while fastexing improved cellular ingrowth at its outer suxface:
It should be understood that in addition to the illustrated embodiment, billets can be formed in accordance with the present invention having lubricant properties-which vary in a selected pattern thxcaugh the cross-section to achieve desired pore or channel distribution: For eaampl;e. by forming a tubular billet which has a lubricant level which is different at a radial position of the cross-section from the lubricant level at another position, e.g..
the inner or outer surfaces of the cross-section, and by carefully extruding a preform'from the billet. a unique product is formed. For example. a tubular article having a wall 70, such as shown in Figure 6, ... ..... ..r. , ~.. . ...' . . . . ,, ,.. .. S ., WO ~3/18~14 PCTIUS93l02371 can be formed by this method. Plote that the wall 70 has relatively Large pores at its inner and outer surfaces 76 and 78 but includes a barrier region 80 of smaller pores between the inner and outer surfaces. Such a structure used as an implant or vascular graft is expected to promote cellular ingrowth from both sides of the wall ?0 while greventing cellular growth completely through the wall.
From the fact that stretching of the eztrudate yields an article with pore structure corresponding to the lobe distribution of the preform, it appears that flow in the long tapered extrusion head is highly laminar. Sueh flow can result in a uniformity of PTFE,molecular orientation. Applicant expects this property to result in an eztrudate that: after sintering (but even without any stretching), will have high tensile strength, as compared to conventionally extruded materials. Accordingly, it is also comprehended within the scope of the present invention to extrude an eatrudate fr~am a billet of varying lube Level or other characteristic; and; without stretching the eatrudate. sinter it to fix its dimensions.
For- biological applications, the unique through-gore orientation created by the individual nodal spaces is-exploited: for example, to either increase or decrease the migration of certain cellular and or biological materials directly into or onto the inventive tubu3ar structure. This results in improved biocompetibility. For example. it is well 8ocument~d that specific cell types penetrate, .,w. ~

grow into, or onto porous fluoropolymer structures.
By providing a matriz of large. oriented nodes to present non-tortuous pathways, full cellular penetration is possible, without "dead ended"
channels. This offers a significantly improved cellular environment, for ezample, to promote the growth of morphologically complete capillaries. The provision of large-entry channels with a taper offers similar advantages. with the added feature of precisely limiting the depth of tissue penetration.
Hence the hybrid nodal structure design of this invention offers many structural, physical and biological characteristics not found with other, well documented pure fluoropolymer, composite or coated tubular articles.
In accordance with the invention, therefore, methods and materials are provided for the formation of biological implants having enhanced structures and tissue support features. Hoth organ wall grafts and vessel implants can be formed by practice of the invention. Representative methods of fabricating tube structures with taper nodal geometry will now be briefly described.

PTFE resin identified as Fluoz~ CD-123 obtained from ICI Americas was blended in two separate containers with 98 cc and 150 cc, respectively, per pound of resin, of an odorless mineral solvent, identified as Isopar-H produced by Ezaon Corporation. The solvent serves as a lubricanr_ for extrusion of the resin, in a manner well known in the art. The two resin/lube mixes were then * Trade Meric WU 9311821a PC.'f/US93/OZ371 _33_ separately poured into a,preforming cylinder in concentric layers to form a billet or preform 50 as shown in Figure 4. Inner layer 5Z of extrusion preform 50 contained the lower Iube level (98 cc i Iube/lb) resin. Outer layer 54 of preform 50 contained the higher Iube level (150 ccllb) resin. A
core-rod cylinder was fitted over the core rod of the preforming cylinder to separate the layers during pouring. The cylinder was removed after pouring was completed. and the extrusion preform, or billet. was formed by compacting the layered mass under a .
compaction pressure of 600 psi, to produce a dense preform billet having a concentric stepped concentration of Lube level.
The preform billet was then inserted into a ram extruder and extruded into a 4 mm I.D./5.3 mm O.D:tube, the ram ~atruder having a reduction ratio of 350:1 in cross-sectional area from preform to extruded tube. Fifteen inch samples were cut from the tubular ex~rudate anc3 allowed to bake at 300°C
fog five minutes prior to stretching in order to remove the lubricant; which was a volatile extrusion aid. The samples were hen stretched at 300°C at a rate of 0.5% per second to a length of 45 inches.
Sintering gas effec ed by clamping the tube ends and heating the'restrained samples to a tempez'ature of 370°C for four minutes.
Figure 7 indicates in schema a tube structure 150 formed in this fashion having interior surface 152 and exterior surface 154, with the section lines A, H, and C identifying radial and W~ 93/18214 ~ ~ ~ ~ ~ ~ PCT/US93/0237~"~e.
.t inside and outside sections far which electron rnicragraphs of a prototype tube are discussed below.
Indicated sample sections of the ezpanded .
tube were then prepared and subjected to electron micrography, as shown in Figures ?A-?~.
As best seen in the radial section, Figure ?A, the inner surface 152 of a tube prepared in this manner had a mere frequent node structure than the outer surface. with nodes spaced almost twice as frequently along the tube axis as at the outer surface 154. Fibril length is therefore necessarily shorter, but both: inner and outer regions have full, densely-arrayed fibrils with none of the coalescence that characterizes the differential-heating approach to node tailoring of the prior art. Moreover, the diameter of the fibrils is essentially the same at the inside and outside regions.
As seen in Figure ?C~ the node-fibzil structure in the radially outer por ion of the tube is characterised by large intact node bodies, spaced 40-80 micrometers apart, whereas that of the radially inner portion his a node spaying in the range of 25-50 micrometers (Figure 78~. The a~rerall farm of the nods is that of flat plates oriented perpendicular to the tubs axis, and extending in g~artial or complete annuli ab~ut the central lumen of the tube. The inside edges of the nodes may be seen to be omewhat fragmented or frayed in appearanee, while still preserving he overall plate-like form and radial orientation of the outer portion, despite $heir closer spacing:

1: "~
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~.
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...,.
,. . .:~ 7.
,:'7 .
r I :a5, .. r.". ~..
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. n, u. ~'~ . . . r .. . .. . . .. .. .
... .. .,. ..,:.a,., ." ,. .. ..~.1.''.,.. . ... . .. ... .. .,,.. .. , . ,;~~
W~ 93118214 : ~ PCT/US93/02371 ,...,<..
-g5-The resulting structure therefore has through-pores extending substantially continuously from the inside to the outside. In addition, applicant has found this material to have a strength comparable to conventional stretched PTFE products fabricated using much higher stretch rates.
PTFE-re5in as used in Method 4 was blended in two separate containers with 104 cc and I50 cc, respectively, of Isopar-H per pound' of resin. The two resin/lube mixes were then separately poured into a preforming cylinder in concentric layexs as shown in Figure 8A with the inner 3ayer 52' of eatrusion preform 50' comprised of higher tube level (150 cc lubellb) resin and the outer layer 54' of preform 50' comprised of loner lube level (104 cc/.lb) resin. As before; a core-rod cylindex was fftted aver the core rod a~ the p~cefoxming cylinder to separate the layers during pouring and w'a removes after pouring was completed. An extrusion preform was then formed by compacting the layers'under a pressure of 6Ua psi.' The preformwas hen e= ruled into a 4. mm I.D:/5.5 mm 4:D. tube ire a ram extruder having a rediuction ratio of 220:1 in cross-sectional area from preform to extruded tube. Fifteen inch-samples were cut from the tubular eztrudate and allowed to bake at 300°C for five minutes prior to stretching in order to remove the extrusion lubricant: The samples were then stretched at a rate of 2:5% ger second to a length of .45 inches, followed by sintering by heating WO g3/, 8214 ~ ~ ~ ~ ~ ~ ~, PCT/US9~102371 _36_ the restrained.samples to a temperature of 370°G fox four minutes.
As shown in Figure ~H, a tangential section at the inner region of a tube so formed has a nodal structure of relatively large, ring-like sheets oriented perpendicular to the tube azis. As indicated in k'igure 8C, the nodal structure at the outer region retains the same orientation, but becomes more closely spaced. Thus, the relative porosity varies. from the inside to the outside, in a sense opposite to that of the tube structure produced by Method 4:
It wild be appreciated by those skilled in the art that in each of the foregoing embodimeni;s the structure of nodes and fibrils results in a pore structure wherein interstitial paces of tapering aspect extend entirely, or substantially entirely through the'wall of the tube.
As described above, extrusion from a billet fo~cmed with varying levels of lubricant produces a pr~forr~; and after stretching results in an article.
having a pore structure that varies. Applicant ezpects a similar effect to result fr~m use o~ a 'billet wherein,,ra>rher thanvarying the level.of lubricant. one position (e:g., inside, or outside) is Formed using a lubricant of different density or a different camposition than'is used in the other portion: For the example, the preform may be made using a layer of PTFE material mined with an Isopar-like lubricant, e.g..' a simple hydrocarbon solvent of density approzimately .6, and a layer of i WO 93/18214 . PCT/US93/02371 the same PTFE material mixed with a heavy oil, such as a more viscous hydraulic pump oil or a glycerin-containing fluid. Following eztrusion, both lubricants are baked out, and the final stretched or unstretched article is sintered to fix its microporous structure.
Related effects are also expected when forming a billet wherein one portion has its lubricant less uniformly dispersed in or mixed with the resin. In that case, the voids left upon baking out the lubricant may be expected to result in regions having different nodal size in the coarsely-mized eztrudate than in the well-mixed eztrudate. Thus. the invention is understood to include articles formed by extrusion of two different eztrusion materials, wherein the materials have the same resin, and differ only in type, quantity, uniformity or other property of the lubricant included in the material.
It will be further understood that while the invention has been described with reference to extrusion of a billet formed of different concentric cylinders to maka a tubular item, billets of other shape may advantageously be used to eztrude articles of other aspect or shape. such as multi-lumenal solid or perforated bodies as described in applicant's aforesaid United States patents.

WO 513/18214 , PCT/US93/02371 ,.

Furthermore. a tubular product as described above, may be slit longitudinally to provide a belt-like sheet, and one or more such sheets may be joined or assembled in a mufti-layer stack to form an article having through--wall porosities of two or more successive or opposed tapers. Tn other constructions; a tube as described abave may be pressed flat so that it forms a strip two layers thick, with a Larger (or smaller) pore structure at its center than at either outside surface.
Tn addition; as noted above, the invention contemplates the manufacture of articles which have been extruded with a varying lubricant distribution, but nat sulbjected ~o a stretching or expansion step.
These articles have a generally moxe rigid structure with lower porosity. and do not have the fibril structure characteristic of the ezpanded product, but may still benefit fxom the additional. control over porosity combined with enhanced microstructure ali'gnmer~t as provided by the present invention, to tailor their mechanical properties.
According to a,principal aspect of one presentl~r preferred embodiment of the invention, this /structure is employed in a vascular graft, formed of PTFE tube having a'lower inside than outside porosity, the variation being introduced by extrusion from a billet having higher outside Tube levels, followed by stretching and sintering. Advantageously, the node structure of plate-like sheets oriented perpendicular to the axis of the tube permits deep cellular ingrowth, and provide:: a flexible anti-kink WO 93/1 X214 PCT/US93/023? 1 -3~-and non-collapsing lumen structure, yet prevents blood leakage at the smaller -posed wall:
Tn a proof-of--principle experiment carried out with a tubular prosthesis made in accordance with Method 4 above, the tubes were implanted in the carotid artery of dogs and left in vivo for eztended periods to assess patency, cell growth and tissue compatibility.' In amplarrts that remained patent, tissue ingrowth had progressed by forty-five days such that morphologically complete normal capillaries h.aa grown through the entire thickness of the tube wall. This single-resin expanded fluoropolymer graft thus appeared to demonstrate, for the first time l~nown to the inventors; an artificial vesse l replacement structure essentially capable of supparting natural vessel-wall regrowth extending not only along the interior surface; Ibut between the inside end outside surfaces:
It is expected that'in other areas where it has historically been possible toachieve tissue growth only for limited times ox to limited depths, different forms of prosthesis made'in accordance with the above pore-tailoring ana uniformity-promoting processes will support enhanced natural or seeded growth of-other Gel3 tyges to f~rm replacement tissue for diverse'.organs, vessels and tissue structures.
For example, the invention contemplates that an organ prosthesis; partial organ, patch, graft, ox organlike structure be formed of material having the desirable permeability o fluids: on a macroscopic scale and porosity to receive cellular growth, i possibly in connection with one or more lumena defining flow paths therethrough for carrying blood and/or other biological fluids. For a discussion of a range of shaped porous articles intended for diverse such uses. reference is made to applicant's abov~-mentioned U.S. patents. Such shapes may be configured to constitute.grafts, intended to patch over and regenerate regions of tissue that have been lost to trauma, disease or surgery, or may constitute entire organs. Furthermore, such prostheses need not be patched into an existing organ, but may, for ezample. be seeded with culturable cells, cultured and implanted into a well-vascularized region capable of supporting tissue growth and of receiving the material ezpressed by the tissue for circulating it in the bloodstream. Thus, the inventive prosthesis provides a bioreactor for producing biological material, the walls and lumens serving to sustain the culture and allow exchange of cultured products in the body.
For this latter application, the tailored pore structure of articles of the present invention allows tissue growth and exchange of expressed bioactive materials, without allowing exogenous cells to circulate and without allowing immunity-mediating cells to reach the cultured tissue. The cellular containment thus diminishes the likelihood of inducing a whole body rejection or cell-mediated immune response. By way of ezample, an artificial pancreas for insulin replacement therapy may be formed by seeding a closed multiluminal article to grow islets of Langerhans, with the cell products and secretions entering bl~od circulating through one or ,... . . ,.. ,.. ... . ,.,s . ... ~.. ..F . .. .... , t. ~ . t. . . .. . .. .r ,.. ' VV~ 93J1821~4 PCTILJS93I0237~

more of the lumens. In this case, it is desirable to culture the cells and supporting material in vitro, and then implant the functioning culture body to initiate insulin or other replacement therapy. In other examples of this method of use of articles of the present invention, endothelial cells may be cultured to provide their cell products into the bloodstream. .
An~ther class of articles of the present invention having varying pore structure is the class of filters or filtration units. For this applicati.~ri, the presence of a tapering pore structure can be used, for example, in different orientations t~ prevent particles from reaching and clogging subsurface regions of a filter membrane, or to allow greater fluid pressure through the depth of a filts~ membrane, in each case having the effect of ent~aneing ~verall the filter's lifetime, capacity or filtration rate:' Still another class of articles directly pertaining to the present invention is that of s culture beds or bioculture reactors, wherein an eatxudate, e.g:; a poraus tubs ~x sheet made in accordaa~ce with the invention; serves as the anchoring structure for cellular material.-. tissue or macroorgani ms - that synthesize'an enzyme or other substance whibh is the end product of the process.
In this case, the porositg, possibly in a tubular or multi.lumenal structure may allow the transport of nutriea~ts to ons side of the article, and the WO 93/18214 ~ PC°TlUS93/02379 _~a_ harvesting of product at another or the same side, without having to break up the cell mat to affect such feeding or harvesting. .
Further alterations to the above described embodiments of the invention will be apparent to those skilled in the art and are intended. therefore, to be embraced within the spirit and scope of the inv~ntxon. That is, the preceding detailed description is intended as illustrative rather than limiting: Accordingly, the invention is to be defined not by the preceding detailed description but by the claims ttaat follow.
What is claimed is:

Claims (57)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A method of producing a shaped porous article, such method comprising the steps of:
forming a billet of a single fluoropolymer material and a lubricant in which a lubricant concentration gradient has been established along a dimension of the billet, extruding the billet to form an extruded article having a shape and a lubricant component concentration that is varied in level corresponding to the concentration gradient of the billet, removing lubricant from the article and stretching the extruded article to form a porous article with predetermined pore sizes in different regions thereof, wherein larger pores are formed in regions where the extruded article had higher levels of lubricant, and sintering the porous article in its stretched state to fix its dimensions thereby forming a sintered porous article of a single fluoropolymer material having different porosities in predetermined regions thereof.

2. The method of claim 1, wherein the step of forming the billet includes forming with a lubricant level that varies along a direction through the billet from a level no lower than about ten percent to a level no higher than about twenty-four percent.

3. The method of claim 1, wherein the fluoropolymer material is a single-resin fluoropolymer.

4. The method of claim 1, wherein the billet is formed with lubricant levels in different regions selected to provide an article having a pore size distribution that permits tissue growth on at least a portion of the article without permitting fluid leakage through the article.

5. The method of claim 3, wherein the step of sintering is performed to uniformly sinter the porous article at the sintering temperature of said single-resin fluoropolymer.

6. The method of claim 1, wherein the step of forming a billet includes forming a billet in plural layers, at least two layers having different levels of lubricant.

7. The method of claim 1, wherein the step of extruding includes extruding a tubular extruded article.

8. The method of claim 7, wherein the tubular article has a tube axis, and includes a plurality of nodes of flattened aspect oriented transverse to the axis and extending substantially through the tube wall.

9. The method of claim 8, wherein the tubular article has a wall thickness of under about two millimeters.

10. The method of claim 9, wherein the tubular article has a wall thickness of under about one millimeter.

11. The method of claim 10, wherein the tubular article has a wall thickness of about 0.3 - 0.8 millimeters.

12. The method of claim 11, wherein the step of stretching is performed by stretching at a rate below approximately two percent per second.

13. The method of claim 12, wherein the step of stretching is performed by stretching at a rate below approximately one percent per second.

14. The method of claim 13, wherein the step of stretching is performed by stretching at a rate below approximately one tenth of one percent per second.

15. The method of claim 1, wherein the step of extruding includes extruding a tubular extruded article having a lumen, and the step of stretching includes stretching so as to produce radially-oriented nodes extending about the lumen and interconnected by fibrils, spaces between the nodes defining through pores from said lumen to an outer surface of the article.

16. The method of claim 15, wherein the stretching produces nodes having regions of flattened aspect.

17. The method of claim 1, wherein the step of forming a billet includes forming a billet having different lubricants at different positions along its cross-section.

18. The method of claim 17, wherein the different lubricants are lubricants of different density.

19. The method of claim 17, wherein the different lubricants are lubricants of different viscosity.

20. A prosthesis comprising an extruded body having a wall extending in a thickness direction between an inner surface and an outer surface, extending along an axis and formed of a single expanded polytetrafluoroethylene (PTFE) material, said wall having a microstructure of nodes of solid material with flattened aspect and oriented transverse to said axis and said nodes being interconnected by fibers, said extruded body having been stretched differently through its thickness and having been heated at elevated temperature to uniformly fix the nodal structure of said single material, whereby spaces between said nodes define tapering channels extending along the wall thickness direction.

21. A prosthesis according to claim 20, wherein the spaces are inwardly tapering.

22. A prosthesis according to claim 20, wherein said extruded body is expanded with a local expansion ratio that varies by no more than about 10% along its length.

23. A method of producing a prosthesis, such method comprising the steps of:

forming a billet of fluoropolymer material having a lubricant property which varies across a dimension of the billet corresponding to a desired porosity structure, extruding the billet to form an extruded prosthesis blank, the extruded prosthesis blank having a lubricant property distribution that varies in correspondence with said desired porosity structure, removing lubricant from the extruded prosthesis blank and stretching the extruded prosthesis blank to form a porous prosthesis blank, and sintering the porous prosthesis blank in its stretched state to fix its dimensions thereby forming a prosthesis having the desired porosity structure.

24. The method of claim 23, wherein the lubricant property is one of the lubricant density, the lubricant viscosity, and the lubricant molecular weight.

25. The method of claim 24, wherein the prosthesis is a vascular prosthesis and the lubricant property is selected to provide a pore size for tissue growth.

26. The method of claim 25, wherein the porosity structure tapers between inside and outside of the vascular prosthesis.

27. In a method of manufacturing a porous PTFE article having a sintered microporous structure, the improvement comprising forming the article of PTFE material mixed with lubricant, and varying a property of the lubricant through a cross section of the article to achieve a tapered pore structure before sintering the article.

28. The method of manufacture of claim 27, wherein the porous PTFE article is a sheet article having a pore size on one surface to define a region of tissue ingrowth, and having a different pore size outside said region.

29. An implantable prosthesis comprising a tube of porous PTFE including a tube wall with a porous microstructure of nodes and fibrils, wherein channels are defined by spaces between adjacent nodes and said channels are tapered and extend substantially through the wall of the tube, and wherein said wall is uniformly sintered throughout.

30. A method of producing a shaped porous article, such method comprising the steps of:
forming a billet of a single fluoropolymer material and a lubricant in which a lubricant concentration gradient has been established which is a step function along a dimension of the billet, extruding the billet to form a single-material extruded article having a shape and a lubricant component concentration that differs in level in different regions of the article in accordance with the lubricant concentration gradient of material in the billet, removing lubricant from the extruded article to form a porous article, and sintering the porous article thereby forming a sintered porous article having different porosities in different regions thereof, wherein larger pores are formed in regions where the extruded article had higher levels of lubricant.

31. The method of claim 30, further comprising the step of stretching the extruded article prior to sintering.

32. An implantable prosthesis comprising a wall of porous extruded polytetrafluoroethylene comprised of a single resin and having a porous microstructure consisting of nodes interconnected by fibrils, wherein interstitial spaces are defined by adjacent nodes, the interstitial spaces between said nodes being tapered and extending substantially through Said wall, and wherein said wall is uniformly sintered throughout.

33. Process for producing a shaped porous article, the process comprising the steps of:
providing an extrudate of a fluoropolymer material which is capable of being stretched, the extrudate having a longitudinal axis and a desired cross-section, bilaterally stretching the extrudate in two opposing directions along the longitudinal axis to yield an article which is substantially uniformly stretched over a major portion of its length and has a microstructure characterized by elongate nodes connected by fibrils, and sintering the stretched extrudate while maintaining it in its stretched state to produce the shaped porous article.

34. Process for producing a shaped article of polytetra-fluoroethylene comprising the steps of:
extruding a preformed billet of a mixture of a poly-tetrafluoroethylene resin and a lubricant to produce an extrudate having a longitudinal axis and a desired cross-section, removing the lubricant from the extrudate, bilaterally stretching the extrudate along the longitudinal axis in two opposing directions to yield an article having a substantially homogeneous microstructure over a major portion of its length, the microstructure being characterized by elongate nodes connected by fibrils, and sintering the stretched article while maintaining it in its stretched state to produce the shaped article.

35. Process for producing a porous tube of polytetrafluoro-ethylene comprising the steps of:
providing a preformed billet of a mixture of a polytetra-fluoroethylene resin and a lubricant, excluding the billet to produce a tubular extrudate having a longitudinal axis and a radial thickness, removing the lubricant from the extrudate, stretching the extrudate along the longitudinal axis at a rate of less than ten percent per second to yield an article having a substantially homogeneous microstructure over a major portion of its length, the microstructure being characterized by elongate nodes connected by fibrils, and sintering the stretched article while maintaining it in its stretched state to produce the porous tube.

36. Process as set forth in any of claims 33-35, wherein said stretching step is carried out a rate not greater than approximately ten percent per second.

37. Process as set forth in claim 36, wherein said rate is not greater than approximately five percent per second.

38. Process as set forth in claim 36, wherein said rate is not greater than approximately two percent per second.

39. Process as set forth in claim 38, wherein said rate is not greater than approximately one percent per second.

40. Process as set forth in claim 33 or 34, wherein said bilaterally stretching step is carried out by displacing opposite ends simultaneously.

41. Process as set forth in claim 33 or 34, wherein said bilaterally stretching step is carried out by displacing opposite ends sequentially.

42. Process as set forth in claim 41, wherein each of the sequential displacements results in a stretch ratio not greater than two to one.

43. Process as set forth in claim 33 or 34, wherein said bilaterally stretching step is carried out while maintaining the extrudate at a temperature between approximately 35 degrees centigrade and approximately 327 degrees centigrade.

44. Process as set forth in claim 33 or 34, wherein said cross-section is circular and said shaped article is a tube.

45. Process as set forth in claim 34 or 35, wherein the lubricant is mixed in the billet at a level which is greater than approximately fifteen percent by weight.

46. Process as set forth in claim 45, wherein the lubricant is mixed in the billet at a level which is greater than approximately twenty percent by weight.

47. Process as set forth in claim 34 or 35, wherein the lubricant level is varied through the cross-section.

48. A process for producing a shaped porous article having a desired length along an axis and microstructure adapted for supporting a biological material thereon, such process comprising the steps of:
forming an extruded article of fluoropolymer material having an end-to-end dimension related to the desired length, stretching the extruded article at elevated temperature to form a stretched article of the desired length by actively moving each end of the extruded article in opposite directions away from a central portion of the extruded article, and sintering the stretched article, while maintaining it in a stretched state to produce the shaped porous article having the desired length.

49. The process of claim 48, wherein the step of forming includes forming a billet having a thickness dimension and a lubricant distribution which across the thickness dimension, and extruding the billet to form an extruded tubular article, whereby the step of stretching introduces corresponding radial variations of microstructure.

50. The process of claim 49, wherein the billet is formed with a lubricant distribution for introducing a radially tapering pore structure extending from a surface of the stretched article.

51. An implantable article comprising a body formed of a single fluoropolymer material and having an expanded PTFE
wall structure with tapered microchannels extending along a thickness dimension thereof and being uniformly sintered at a sintering temperature of said single fluoropolymer material.

52. An implantable article according to claim 51, wherein the article is shaped as a natural biological tissue structure, and the tapered microchannels taper outwardly to a wall on which tissue is to be grown.

53. A process for forming an expanded PTFE prosthesis of enhanced uniformity and surface characteristics, characterized in that during formation of the prosthesis, a preformed article is stretched by actively moving each end of the article outwardly from a central portion thereof before sintering whereby uniform stretch characteristics are imparted throughout the article.

54. Tube formed of a single expanded, porous fluoropolymer material which is uniformly sintered and has a longitudinal axis and a wall, the tube having a microstructure characterized by ring-shaped nodes interconnected by fibrils, a substantial plurality of the ring-shaped nodes each circumscribing the longitudinal axis of the tube, the wall further having a microstructure characterized by a second group of nodes smaller than the ring-shaped nodes and located along a radial region extending partway through the wall.

55. A tube as set forth in claim 54, wherein the nodes define internodal through-pores, the through-pores providing substantially straight passageways which traverse from one surface of the tube to another.

56. A tube as set forth in claim 54, wherein the ring shaped nodes and the second group of nodes define passageways having a size distribution for controlling the extend of tissue ingrowth.

57. Tube as set forth in claim 54, wherein the fluoropolymer material comprises a copolymer of tetrafluoroethylene and monomer selected from the group consisting of ethylene, chlorotrifluoroethylene, perfluoroalkoxytetrafluoroethylene, and fluorinated propylenes.