CA2186373A1 - Cell excluding sheath for vascular grafts - Google Patents
Cell excluding sheath for vascular graftsInfo
- Publication number
- CA2186373A1 CA2186373A1 CA002186373A CA2186373A CA2186373A1 CA 2186373 A1 CA2186373 A1 CA 2186373A1 CA 002186373 A CA002186373 A CA 002186373A CA 2186373 A CA2186373 A CA 2186373A CA 2186373 A1 CA2186373 A1 CA 2186373A1
- Authority
- CA
- Canada
- Prior art keywords
- sheath
- blood vessel
- polymeric material
- microporous polymeric
- vascular
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/16—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/28—Materials for coating prostheses
- A61L27/34—Macromolecular materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
- A61F2/06—Blood vessels
Abstract
The present invention is directed to a sheath for use with vascular prostheses derived from donor blood vessels, particularly mam-malian blood vessels. A vascular prosthesis of the present invention employs an external sheath around a donor blood vessel. The sheath pre-vents access to the donor vessel wall by host cells originating from perigraft tissue. While re-sistant to host cell ingrowth, the external sheath is permeable to the flux of macromolecules across its thickness. The exclusion of host cells by the external sheath and the bi-directional flow of macromolecules through the external sheath assists in maintaining the original function of the underlying donor vascular tissue of the prosthe-sis.
Description
~vo95/29711 2~ 8 6373 P~l/uv t'FT l . EXCLUDING SHl~ATH FOR VASCULAR GRAFTS
BACKGROUND OF THE INVENTION
S 1. Field of thelnvention The present invention relates to vascular prostbeses improved through the use of an external sheath that is resistant to cell ingrowth while being permeable to flux of fluid and macr molcc~ s across the thickness of the sheath. The sheath can also impart ~ 1 strength to the vascular tissue of the prostheses.
BACKGROUND OF THE INVENTION
S 1. Field of thelnvention The present invention relates to vascular prostbeses improved through the use of an external sheath that is resistant to cell ingrowth while being permeable to flux of fluid and macr molcc~ s across the thickness of the sheath. The sheath can also impart ~ 1 strength to the vascular tissue of the prostheses.
2. Description of Related Art Blood vessels taken from human or animal donors have been widely used to replace blocked, a.~ t,l.àl, or otherwise damaged arteries and veins. Both living and preserved human arterial allografts were extensively used as arterial substitutes in the 1950's and this initial use appeared C~l~c~7ccflll However, human allografts were largely ~h~n~ ' by 1960 due to a high incidence of ~uu~bo~i~, stenosis, andaneurysmal dilatation.
The practice of grafting with allogeneic arteries was ~h -~on,-d in favor of the", . k ~ lly superior ~It~,llla.i~e of using vascular grafts made of synthetic materials.
The synthetic materials principally used for this grafting are polyethylene terephthalate and expanded p~vlyt~ u~,lllylene (ePTFE). These materials offer C~ ;lity and provide sufficient ,.. ~ integrity to prevent a.l~
dilation. F~u~ll~.,li~,s made of these materials were shown to bt_ successful in the ,~ L,I 1. . . I l. .. It of large vessels such as the aorta or iliac alteries and are still ,ucc~ ~ 'ly used in these :lrpl~ tionc Although successful when used in large diameter 25 applications, the pâtency ~.ru.l,la,l~e of these materials in ~ ' '~ v small diameter ~rPli( ~ nc such as coronary artery bypass or peripheral arterial bypass distal to the popliteal artery, for example, has been s~lhct~ti~lly less than that of 1l l ' living autologous vessels.
Regardless of whether a prosthetic vascular graft is obtained from a donor or 30 is made of synthetic materials, it has been a common belief since the 1950's tbat ingrowth of host tissue into vascular grafts leads to improved function.
R~ s~":dliv~ of this belief is the following statement: "With existing p.."~ s, we believe that the best assurance of long term patency without ctlmrli~tion is ~l-;, "- ..l of complete healing of the prosthetic wall, which includes an 35 en-loth~ 1i7Pd flow surface. This final healed state is principally dependent upon I
WO 9~/29711 2 1 8 6 3 7 3 P~ .'C I' 7 ~
the ingrowth of areolar tissue from perigraft sources through the interstices of a pervious graft wall -' (Sauvage et al., "Future Directions in the Development ofArterial Prostheses for Small and Medium Caliber Arteries," Surgica~ C~inics of North America 54: 213-228 (1974)) With bio~o~i~Ally-derived ~u~lh~ ,s, host tissue ingrowth is observed to alter the donor graft material into one composed at least partially of recipient tissues. In addition, such ingrowth of autologous tissues usually generates a blood interface in the prosthetic T~plA~m~n~ composed in part of tissues of the host.
Ln the case of porous synthetic materials, ~Ou~ tissue ingrowth occurs through the interstices of the material. The apparent desirability of ingrowth of autologous tissue into grafts made of porous pol~t~,lldr~uoroethylene (ePTFE) isillustratedbytheresultsofastudyc~"",u~-;"gthepatencyp~,.rul...~..,~ofsmall caliber vascular ePTFE prosthetics having different porosities. The study showedthat high porosity ePTFE grafts with a fibril length of 100 ~Lm had lul. ~ ;~
15 irlgrowth of fibrous tissue into the interstices of the graft and remained 100% patent at six months pu~ot~ Li~,ly. Low porosity ePTFE grafts with a short fibril length (10 llm) had layers of tissue on either side of the graft wall, but no ingrowth of tissue into the interstices of the graft. These low porosity grafts were 67~o patent at six months pU~O~d~ Iy. (E~lorian et al., "Small Vessel R. ~ ". - With Gore-tex 20 (Expanded r~l~ t~ lluoroethylene)," Arch. Surg. 111:267-270 (1976)) The initial theory ~ ,lrUlll~ of vascular gfts was proposed by Wesolowski in 1963. This theory, based upon the c~",~ ", that ingrowth of host cells leads to better patency ~,lrulll~ C, remains the lul, ' theory today.
(See for example, Stanley et al., "Biologic and Synthetic Vascular Grafts," Vascular 25 Surgery A Comprehensive Review Fourth Edition, Chapoer 21, pp 370-389, ~) 1993, referring to Wesolowski, S.A., Dennis, C., 'T -1- "~ of Vascular Grafting," New York, McGraw-Hill, 1963) TII~ IIIA1 exclusion of host cells from the interstices and lumen of a vascular Bft in order to prevent the host cells from adversely affecting the patency 30 ~lru~ d~ of the vascular Bft has not been previously described. Moreover, application of an external porous synthetic sheathing material to a vascular graft that prevents disruption or lul--o~' ' g~ of the graft by host cells while being permeable to the flux of biological fluids and molecules across its thickness has heretofore not been described.
VO 95/29711 2 1 ~ ~ 3 ~ 3 ~ 7 SUMM~Y OF THE INVENTION
The present invention is directed to improved vascular prostheses derived from donor blood vessels. It is an object of the present invention to provide 5 improved ~Iru~ llce for vascular prostheses by preventing many of the failuresthat are a . of the invasion of an implant by host cells. It is a further object of the present invention to provide improved p~,lrullll~e for vascular prostheses by providing a cell excluding covering for the vascular tissue of a prosthesis that permits exchange of biological fluids and ,..~ c c across the 10 vascular tissue of the implant and the perigraft tissue of a recipient.
Contrary to the widely accepted theory that the ~lrullll~ulcc of vascular grafts is enhanced by host tissue ingrowth, the present invention achieves enhanced paoency l,.,.rollll~ul~,e of vascular grafts by employing an external sheath around a donor blood vessel that is resistant to host cell ingrowth ... ;yi -l;..~ from perigraft 15 tissue.
It has been diDc~ i that ingrowth of host cells into a vascular graft derived from donor blood vessels of oen causes disruption of the function of the graft. Such remodeling can have serious negative co , such as ,.... 1 , ~I failures in fhe form of al.~,ul~DIll~l dilatation, .~ f 1.;~. -- c, frank graft disruption, as 20 well as Illlulllbu~;~ relaoed to the alteration of the blood vessel wall c~mrocifi~n By blocking the access of host cells to the donor blood vessel with a cell excluding sheath of the present invention, the host cells l~,D,UU..D;blC for r~motlf lin~ the vessel walls cannot grow into the donor blood vessel and disrupt the al~;ll;L~UIt; of the vessel walls. As a result, many of the above- ' vascular graft failures can be 25 delayed or prevented.
It has also been I;D~U~ d that pl-rm~ ilify of the cell-excluding exoernal sheath of the present invention to ions, water, and 1ll~ ( c for example, is necessary for " ,~ the function of the donor blood vessel after; ~
Permeability of the external sheath is achieved by Culll,LIu ,~ g the sheath so that it is Illi~lU})UIUUD.
Accordingly, the present invention is a covering for a blood vessel which comprises a sheath ,ulluu-ldi..g the blood vessel, wherein the sheath comprises a UPUIUUD polymeric material and wherein the sheath serves as a barrier to external cellular contact to the blood vessel, while being permeable to macrom.~ s WO 95129711 2 18 6 3 7 3 r~ 7 ~
DF.CCRTPTION OF T~F. DRAWIN~S
The operation of the present invention should become apparent from the following t~f-5~rjr~i.m when considered in c~,..ju..~lio.~ with the d~,~,OIll~Jd--y g 5 drawings, in which:
Figure 1 is a cross-sectional view of a m ~m~l artery (2) having the ~xternal sheath (I) applied thereto;
Flgure 2 is another view of the ~, l,o-l;,, ,t of the present invention illustrated in Figure 1.
DET.An ~n DE~CRlPrlON OF THE INVENTION
The present invention is directed to a sheath for use in vascular prostheses derived from donor blood vessels, particularly ' blood vessels. A vascular 15 prosthesis may employ an external sheath of the present invention around a donor blood vessel. The sheath prevents access to the donor vessel wall by host cells c~ri~in~in~ from perigraft tissue. While resisting host cell ingrowth, the external sheath is permeable to the flux of -.~ across its thickness. The exclusion of host cells by the external sheath and the bi-directional flow of Ill.l~lUlllO' ' ~
20 through the external sheath assists in ~ e the original function of the u~J~Ily ~ donor vascular tissue of the prosthesis. The term ~ r l S~ is l~ od to include, but not be limited to, molecules having a molecular weight up to dnd including about 2,000,000 MW.
In the present invention, it has been found that the original ~uul.;t~ and 25 function of vessel derived vascular grafts can be ' if invasion of the donor vessel wall by host cells is prevented while the flux of macromol~r~ across the wall is permitted. If the original ~, ' ~i and function of the arterial wall of a vascular graft is so I, many of the failures ~-I,vh~ui~ly noted with ~r~n~r~ ~ vessels can be ~ , resulting in improved patency ~.fu...~ .,e of 30 these biologically derived grafts. The teachings of the present invention are thus directly opposite those of the prior art in this field regarding the d~si.~.l,;lily of host cell ingrowth into the donor tissue of a biological vascular graft.
Since host cellular invasion largely proceeds from the perigraft region radiallytoward the lumen, prevention of cellular invasion of the donor blood vessel wall used 35 as a vascular graft is achieved by dl,lJlic~Lio.. to the external surface of the vessel ~W095129711 21 ~637~ r_l~u~. ol~7 wall of a sheath that is resistant to cell ingrowth. A structure ~ ,G,..bli-.~ this c~. r;~ ;n~ is shown in Figures 1 and 2. The sheath (1) is applied to the external surface of a .. ~.. AI . - blood vessel (2) forming a tubular vascular graft (3). The flux of Illa ~ lllO~ 'llPQ across the thickness of the external sheath is achieved by5 co.,~L~u-,Li~,g the sheath of materials that are permeable to macrnmnlP~--lPs while being resistant to cell ingrowth. The preferred materials for Cull~l u~,i of theexternal sheath are synthetic materials that are llli~lUIuC~!uus. Suitable materials for co--~i~ u~liull of the external sheath of the present invention include, but are not limited to, the group of polymer materials with 1'~ iocnmr~ti~ y and 10 stability under implant c~n~litinn~ such as, pol~ u~,~.yl~"c (PTFE), polyethylene t~ llldt~, rh ' ethylene propylene (FEP), polyethylene, poly~u u~uyl~ " and siloxane, for example. The exterr~al sheath employed in the preferred l ..~ l of the present invention is rnade of expanded PTFE (ePTFE) as produced in U.S. Patent 3,953,566, issued to Gore, which is ill1Ul,U~ herein by 15 reference.
The pore size that is effective in resisting cell ingrowth across the thickness of the sheath is dependent upon the thickness of the wall itself and the tortuosity of the pores - ~ the outer surface with the inner surface of the sheath. In the case of regular uniform porGs in a thin sheath cu..~L. u~ (about 10-20 llm in thickness) 20 the pores should be selected to be less than about 3 ~m. This value is based upon Boyden chamber migration assays where the limit of fibroblast invasion of straight, uniform pores is about 5-8 llm and the limit of leukocyte invasion through straight, uniform pores is about 3-5 ~Lm. (A. Albini et al., "Fib:~oblast ('hPmnt~xic," Collagen Rel. Res. 5:283-296, (1985); W. Morzycki et al., "Tumor Necrosis Factor-alpha but 25 not T~ ill-l Induces Pol~w-, ~ ~'~ Leucocyte Migration Through Fibroblast Layers by a Fibroblast-Dependent M~ -, - "," Immunology, 74:107-113, (1991)) In the case of a thicker, more tortuous, or laminate structure, the individual pores can be somewhat larger and still serve as an effective barrier to the passage of cells across the layer.
For an ePTFE or similar fibrillated sheath, the pore size of the sheath is related to the fibril length of the sheath material and the thickness of the sheath material.
Thicker fibrillated sheath materials generally have more tortuous pathways c,.---,~ one end of a pore to the other end of the pore. As a result, a thicker fibrillated sheath may have pores that are larger than invading cells, but will remain resistant to cell ingrowth due to the increased tortuosity of the pathways of the W095/29?11 21 8 6 37 3 ~ c~
pores in thicker sheath material. Regardless of the thickness of the sheath, the fibril length should be chosen to form pores that resists cellular access through the sheath, while being permeable to macr~mnl~ c.~l~ c In defining the ability of the sheath to resist cell ingrowth, a Dnnr~ r assay 5 method has been developed. Based upon the published values that 3 ,um represents the lower limit of cell pPrm~hilify through straight pores, 3 ,um ~ uv~JllvlrvS can be used to - -r~ ;f ~lly determine whether a given sheath will exslude particles of this diameter. C~ C~l.. lly~ any sheath material that excludes 3 llm Illi, 1l . ' v~ should effectively prevent cellular movement across the sheath.
Fibril length is measured as described in U.S. Patent 4,482,516, issued to Bowman et al., which is ill~vullJulaLed herein by reference. The fibril length of porous ePTFE that has been expanded in a single direstion is defined herein as the average of ten ...v~vu.~ between nodes connected by fibrils in the direction of ~-Yr^nc;~)n Ten Illc~ are made in the following manner. First, a 15 ullolulll;-,lu~ is made of a l~ ,llL~Liv~; portion of the sample surfase, of adequate m~lenifir~tion to show at least five sequential fibrils within the length of the pll~ulll~ u~ l. Two parallel lines are drawn across the length of the pl~olullli~lugraph so as to divide the pl~ol()" ,' into three equal areas, with the lines being drawn in the direstion of expansion and parallel to the direstion of ~
20 of the fibrils. Measuring from left to right, five of fibril length are made along the top line in the ~hntner ~rh beginning with the first node to intersest the line near the left edge of the ,UII~IU~ and c, 7 with . sL v~ nodes ~ the line. Five mone Ill~,o.;~,lll~,llL~ are made along the other line from right to left beginning with the first node to intersect the line on the right hand side 25 of the ~ u~u~ The ten III~ UlUIll~ v obtained by this method are averaged to obtain the fibril length of the material.
For a porous, ePTFE material that has been expanded in more than one direstion, the fibril length is estimated by examining a l~ll,vv..lali~., pl~vlullli~lu~;l~l~ of the material surface and cnmr~rine fibril lengths as described 30 above in a manner that represents the various direstional uli~ liullv of the fibrils.
The sheath may be ~ UL t~ in a tubular configuration and applied to the external surface of a stabilized artery . An external sheath can also be applied as a film to the outside of a donor blood vessel, and the film layers vU~ Uvll~ly bonded together.
~W095n9711 21 8 6 3 73 ~ 7 Once a pore size and Coll~LI uuliull method are chosen for the sheath, the pPrmPohility cllala~L~,~iali~:, of the sheath can be evaluatecl by testing with markers of known size, such as dextrans and pol~,~yl~,.lc Illi~lU~l~ ,s. For example, dextran, with an average molecular weight of about 2,000,000 MW, labelled with the colored S compound fluorescein (Sigma Chemical Co., St. Louis, MO), can be used to test the ability of the sheath to pass macrnmol~ ' Cell; " ,l,. . " ,~ y of the sheath can be tested using polystyrene ll-~lu~h~,~s with a diameter of about 3 llm (Polysciences, Inc., Warrington, PA) at a cù . ,l, ,~ ;. .. of about 2.5~o solids in s crc nCi~n, for example.
When testing the sheath for pPrmPohili~y with colored markers, the markers are s~lcrPn~lccl as an aqueous solution or as an aqueous CllcrPncirm at co~
sufficient to provide a distinctly visible color. The preferred . ol.~ ;o~ of the Lluvl~,sc~... labeled dextran solution is alJlJII ' ' Iy 0.2 mg dextran/ml. The preferred CullC-,llLlaliOl~ of the a ~ 1 of the polystyrene IlliL,I~ . ' is a~ 'y 0.02 ml Illi~lua~ lml - - -r '~ , to yield about 4.5 x 107 beads/ml J ~ C~ The evaluation of the sheath pPrmPqhility occurs at about 23C. The sheath is prepared for permeability oesting by rendering it permeable to water, if necessary. For example, sheaths CulI:~Llu~,t~,.;i of ePTFE are wetted with 10091o ethyl alcohol and then flushed with water to remove the alcohol before pPrmPohility 20 testing.
To oest the pP.rmPqhility of the sheath to macr~lmolpclllpc~ the dextran test solution is instilled in the lumen of a sheath and ,UI~ UIi~ to about 20.7 kPa using a syringe. The contents of the syringe are forced through the sheath and the liquid that filters through the sheath wall is collected and visually inspecoed against a white 25 bd~,l~lu. 1 for evidence of the colored dextran.
In preparation for testing the pPrmPqhility of a sheatb to cells, the number of ua~ "L,. in the sllcpPnci~ n are cl~.~ .",; ~ by using an dlJ~Jlul counting device, such as a h~,~lla~tulll~t~ for example. The pPrmPqhility of the sheath is then oested by forcing the IlliLlU~ ,lc;-C-~ U~ siu.. through the sheath material 30 at about 20.7 kPa using a syringe. The syringe is refilled with water and the waoer also forced through the sheath at about 20.7 kPa. The liquid that filters through the sheath wall is collecoed and subjected to c~l.tli~u~a~ion at about 300 x g for about 5-10 minuoes. The ~u~u~ll-aL~u~L is decanted and discarded and the pellet of IlLi~-ua~ ;, is l~ d in a known volume of waoer. The number of WO95/29711 21 8 6 3 7 3 r~l~u. 5 ~ '' 7 ...,~,.u~,h~ in tl~e r~c~c~.n-l~d pellet are counted and compared with the original " The numbe} of I~ ualJllelcs that pass through the sheath are expressed as a percentage of the number illLlUdUC~,~;i into the lumen of the sheath. An alJ~JIU~ t~, sheath for use in the present invention will pass the about 2,000,000 5 MW dextran at pressures at or below about 20.7 kPa so that the colored solution that filters through the sheath is clearly visible when viewed against a white ba~,k~.uulld. Additionally, the sheath will not allow more than about 5% of the 3 ~Lm IIU~ , ' I,S to pass across its thiclcness at a pressure of about 20.7 kPa.
Some suitable methods for applying the sheath of the present invention to 10 vascular prostheses derived from naturally occurring tissue and vascular prostheses using synthetic materials are included in a U.S. patent application of Bruchman et al., entitled "Improved Blood Contact Surfaces Employing Natural ~lhPn~lotl~
Matrix And Method Of Malcing And Using Same," which is ' - .u~ly filed herewith and ill~,ol~)ulat~,~ herein by reference. It is u--d~ uod that the vascular 15 tissue ~ Jau~iùl~ processes described in this ~ ly filed orrliro~i~ln are only some of the suggested uses of the sheath of the present invention.
In addition to ~.c~. v ingrowth of host ce!ls into the prosthesis of the present invention, while being permeable to Illa~ ' ul~ 5, the sheath of the present invention can also function as a culll~ of a vascular prosthesis that supplies .. l ,: ~l ,","~.. ,~ "" for the prosthesis. While a biologic c~ of the graft, such as a donor blood vessel, supplies the allli~lu u~bulic properLies to the vascular prosthesis, the long term l ~' l stability is usually supplied by the sheath c~ Accu~di~ y, the sheath of the present invention is selected to provide ""~, l. .,;, ~l strength necessary for the particular diameter of the graft used in 25 order to resist the hoop stress induced by blood pressure, to provide sufficient - ' I strength for creating ~ s~ and to resist ~ ....ul; stresses.
The sheath is co--~ t~.d by wrapping a mandrel with multiple layers of ePTFE film, such as those described in U.S. Patent 3,953,566 and 4,187,390, bothissued to Gore, each of which is i--cul,ou-~.~,d herein by reference, and adhering the 30 film to itself by heating the film and mandrel in an oven at about 380C for about 10 to about 20 minutes. The film tube is removed from the mandrel arld prepared tissue graft installed in the lumen of the polymeric tube. Other materials, or c~...l.;.,-:;....~ of materials, may be applied to the tissue tube similarly, using t~ IalUIC~ and times a~JlU~I;aLv for the physical properties of the chosen material.
~Yo 951~97~ 8 6 3 7 3 P~ c 1-~7 Other methods of ,. ."r~ g the sheath malerial include placing a processed artery onto a mandrel and wrapping the artery with multiple layers of an ePTFE and FEP composite film, and heating the film layer very briefly from about310C to about 350C to adhere the film wrap to itself on the outer surface of the 5 vessel. The FEP-coated ePTFE film is made by a process which includes the steps of:
a) contacting a porous PTFE substrate, usually in the form of a membrane or film, with another layer which is rreferably a film of FEP or alternatively of another . " " ,~ polymer; b) heating the co~ uo tiliol~ obtained in step (a) to a above the melting point of the ~ l...u~ ic polymer; c) stretching the 10 heated C~n~ J~ of step (b) while l~ the b~lllAU~ UUCi above the melting point of the thermoplastic polymer; and d) cooling the product of step (c).
Another sheath construction method is the f~hrir~tir~n of a tubular form of ePTFE Cul~ u~t~ according to U.S. Patent 3,593,566 to Gore using a uniaxial ~Yr~nr;~-n The processed blood vessel is inserted into the ePTFE tube so 15 Cull~llu~,~d. As in the other forms of the sheath, the tubular form must be permeable to the passage of macr lm~ c~ s but exclude the passage of cells.
Str~ tllres of Sh~:lthc Made in Accor I ~n~ with thl~ Present Tnv~nfion Without intending to limit the score of the present invention, the following examples illustrate how the present invention can he made and used.
EXAMPLES
EXAMPLE I Film Sb~th C ~ iu., A sheath tube was CO~ Iu~ from a porous expanded polyt~ fluu-u~..ylene (ePTFE) film. The porous ePTFE film from which the sheath tube of the present invention was c~ u~ d, was made as taught by U.S. Patents 30 3,953,566 and 4,187,390, both issued to Gore, each of which is i.~cu-luu.,. ~,~ herein by reference.
This porous ePTFE film had a Ill;~lu~llu.,~ of nodes i~.t.,l~u~ c~ by fibrils. The film was made by expansion by stretching in a single dircction, which was the direction in which the resulting fibrils were prima~ily oriented. The film used 35 in the preparabon of this invention had a fibril length of about 50 ~m, a density of WO95/29711 21 8 6 37 3 P~ o 1~7 about 0.3 g/cm, a thickness of about 0.01 mm, and were 86% porous by bulk volume.
The fibril length of the porous ePTFE film referred to above was an estimated mean value obtained by examining a scanning electrop ~llulollu~,lu~la~ll of the film.To construct the sheath, the film was applied to a metal mandrel about 5 mm in S diameter by wrapping the mandrel with the film in a helical manner. The pitch of the helix was such that each wrap of film overlapped a,u,ulu~dlll..t~.ly two-thirds of the previous wrap. The mandrel was wrapped three times in this fashion, resulting in a film tube CUI.~uu.,t.,~ of about nine layers of film. The wrapped mandrel was then heated in a oven at about 378C for seven minutes to adbere the film layers togetber.
10 The mandrel was removed from the oven and allowed to cool. Once cool, the film sheath was removed from the mandrel.
The sheath was tested for ability to pass Illa~ r.~ uI~ .s as follows. A
solution of lluu-., ,~.,;..-labeled dextran with an average molecular weight of 2,000,000 MW was prepared in water at a cor- nn of about 0.2 mg/ml. A
15 portion of the sheath, about 10 cm in length, was mounted on a barbed Luer fitting and wetted with 100% ethyl alcohol. Tbe alcohol was removed by flushing the sheath with water using a syringe to force the water through the pores of the sheath.
Using a syringe, the dextran test solution was instilled in the lumen of the sheath and IUI~ ' J to about 20.7 kPa. The contents of the sylinge were forced through the 20 sheath and the liquid that filtered through the sheath wall was collected and visually inspected against a white background for evidence of the colored dextran. The solution was distinctly yellow colored, and the sheath, therefore, permeable to . . .n~ c The sheath was tested for ability to prevent cellular infiltration. A second 10 25 cm length of sheath was wetted with ethyl alcohol and the alcohol replaced with water as described above. ~ ,s about 311m in diameter (Poly~k,..c~,;"
Warrington, PA) were used to determine the ability of the sheath to prevent cellular infil~ inn A stock, ~l7- .~:ù ~ of ~u~,-u~lUII~ , . was prepared. The number of U~,UIIG.~,~ in the ~ was dc~nninPd to be about 4.7 x 107 spheres/ml 30 using a l.~,.lla~,ylulll~ . The ~lh,-u~ lG-containing ~ c: J~ was tested by forcing the contents of the syringe, 5 ml of stock :~Ui~U~ iVl~7 through the sheath rnaterial at 20.7 kPa. The syringe was refilled with water and the water also forced through the sheath at 20.7 kPa. The liquid that filtered through the sheath wall was collected and subjected to c~ irll~linn at about 300 x g for 5 minutes. The ~VO 95/29711 2 1 8 6 3 7 3 r.~ o ~ -~7 was decanted and discarded, and the pellet of ...;~.u~ c.cis was ;,. .,.l d in one ml ûf water. The number ûf ~ u~ s in the 1. ~ f d pellet was counted as for the original ~U~.Isiol. and Lhe count expressed as a ~1~ "f, of the number of l~ lu~ lf ~ used for the test. The ~I-~,lIL.l~ of 5 I.u~ , passing through the wall of the sheath was 0.17%. The sheath can be - ' ~,d resistant to cell ingrowth since less than 59~ of the --;c.~ pass through the sheath wall.
A sheath of porous ePTFE was c u~,t d. The sheath was permeable to lr, ~IP~ and resistant to cellular infi~ tio~ by the defining tests. The sheath 10 can be installed onto arterial ~ --- grafts comprised of tissue from allogeneic or YPnogf nPir sources by sliding the processed artery into the lumen of the sheath.
EXAMPLE 2 Fn7~me Millir~p Carotid arteries removed from a donor dog were placed in 15%
dimethylsulfoxide in Hanks' Balanced Salt Solution (DMSO/HBSS) and stored in liquid nitrogen. For treatment, the arteries were thawed, rinsed in HBSS, and the adventitia dissected from the arteries. Both arteries were mounted onto barhed Luer fittings.
Both arteries were filled with calcium and 1,~ free HBSS c- 1~
0.4 mM cLI.~ ..f tetraacetic acid (EDTA) to inhibit the action of cnll~.vP ~o that may penetrate to the lumen. The ends of the arteries were plugged and the arteries rinsed again in HBSS. Both arteries were immersed in separate i ~uh~tion tubes . g 0.2 M Tris-HCI, pH 7.5, containing 0.1 M -amino-n-caproiC acid, 5 25 mMN-ethyl~ I. 5mMI ' ~ andO.36mMCaCI22H2O(allfromSigma Chemical Co., St. Louis, MO). To one tube, 35 units of type 1 A c~-ll q ~ (Sigma) per ml of buffer was added. Both arteries were incubated at 37C for about 5.5 hours.
After inrllh~ion the arteries were rinsed thoroughly in BSS and were 30 sleeved with a 5 mm tube and pressure fixed in 0.25% glutaraldehyde in 0.020 M N-2-l~ydl~J~ytilllyl~ .,.,;,.~N'-2-ethane sulfonic acid (HEPES), pH 7.3, with 0.44%
NaCI and 0.26% MgCI2 6H2O, at about 27.6 kPa for about 2 hours. The arteries were then removed from their sleeves and left immersed in the fixing solution overnight. After fixing, the arteries were rinsed thoroughly in normal saline and WO95/29711 2 1 86373 ~ `7 ~
sleeved with the sheath from Example 1. The finished wall thickness of the sleeved digested artery was 0.14 mm while the finished wall thickness of the sleeved control artery was o.æ mm.
EXAMPLE 3 Sheath Applied Directly to Fixed Artery Distal limbs were obtained from cows at slaughter and stored frozen at about -20C until required for ~)lU~ illg. The legs were thawed by illllll~ illg them in warm (37C) water and the arteries dissected from the legs. After rinsing in Hanks' Balanced Salt Solution (HBSS), the adventitia was dissected free and the arteries 10 stored in HBSS until fixed.
Arteries of an ~ t~ size to provide a finished internal diameter of alJIJIU ly 4 mm were selected. The arteries were sleeved with 5 mm GORE-TEX~ Vascular Graft (W. L. Gore & Associates, Inc., Flagstaff, AZ), mounted on barbed Luer fittings and were pressure fixed at about 27.6 kPa for 2 hours in 2.59?o 15 ~ -o~al-l~hyde in 0.2 M Sorenson's phosphate buffer, pH 7Ø Fixation occurred at about 23C. After fixation, the arteries were rinsed in normal saline, and stored in normal saline at about 4C until required for use.
Arplirqtion of the sheath to the fixed arteries was performed as follows. The artery was plæed onto a 3 mm diameter mandrel and the ends of the artery secured20 with wire ties. Next, a helical wrap of 25.4 mm wide film was applied over the outer surface of the arteries. The film used for the helical wrapping was a porous ePTFE
film with an additional layer or coating of nu. ~ ethylene propylene (FEP) on one surface. The FEP-coated porous ePTFE film was made by a process which comprises the steps of:
a) contacting a porous ePTFE substrate, usually in the form of a ' ~
or film, with another layer which is preferably a film of FEP or al.~,.ll.lii~,ly of another th~,llllu~ ic polymer;
b) heating the composition obtained in step (a) to a t~-~.~iu-~ above the melting point of the thl-nnorl~c-ir polymer;
c) stretching the heated composition of step (b) while ~ l;l g the i above the melting point of the L~l~,.ll.u~lasLic polymer; and d) cooling the product of step (c).
The FEP coating of the porous ePTFE film for this example was .1;~ ."~
thereby resulting in a porous composite film. The porous FEP-coated ePTFE film ~O9Sl2971l 21 ~ 63 73 r~l"~ 7 used to make this example had a thickness of about 0.03 mm, a density of about 0.3 glcc, a fibril length of about 40 ~Lm, and a width of about 25.4 mm.
The Fl;P-coated side of the film was placed against the fixed arKrial tissue.
The pitch of the helical wrap was chosen such that each wrap of the film u~ la~d5 a~ y two-thirds of the priûr wrap. The arteries were wrapped three times in this fashion, resulting in a film layer C~ DL,u~.t~,~ from about nine layers of film. While still on the mandrel, the film-wrapped arteries were contacted very briefly by an aluminum fixture heated to about 350C to thermally bond the layers of film together while ~ the heating of the fixed artery. The fixture was an aluminum ring 10 with an inKmal diameter of about 0.8 cm, a wall thickness of about 1.5 cm and an overall length of about 5 cm. The process employed to bond the film layers was to place the wrapped artery through the hole in the fixture, contact the surface of the film to the heated fixture and rotate the graft assembly. One revolution of a graft with an outside diameter of about 5 mm was performed in 1.5 to 2.0 seconds. After 15 heating, the wire ties attaching the artery to the mandrel were removed and the fixed artery with the sheath applied removed from the mandrel.
The artery-sheath composite was stored in norrnal saline or water until y testing of the sheath could be performed. The sheath was removed from the artery and the artery discarded. The sheath was tested for ability to pass 20 macr~m~lPc~lPc and to prevent cellular ~ as described in Example 1. The sheath, when pretreaKd by wetKd with 100% ethyl alcohol, readily passed the 2,000,000 MW dextran, indicating that a sheath ~,.,t~,~ in this fashion was permeable to macrotnrlPc-llpc The same sheath allowed no Illr ~ lr quantity of the 3 llm lll;.,lUD~ ,D to pass through, indicating that this sheath ,.~Liul- is25 resistant to cellular infiltr:~til EXAMPLE 4 Burst TestinF of Sleeved and Unsleeved Fixed Arteri~ll Tissue Carotid arteries from a y,lc~' ' dog were placed into normal saline. The 30 adventitia was dissecKd away and the arteries were m~unted on barbed Luer fittings and sleeved with a 5 mm GORE-TEX~9 Vascular Graft (W. L. Gore & Associates, Inc., Flagstaff, AZ) to provide a fixed artery with about a 4 mm intemal diameter. Thearteries were pressure fixed at about 27.6 kPa for two l1ours at 23C in 2.5%
.hyde in 0.2 M Sorenson's phosphate buffer, pH 7Ø After fixation, tne 35 fixing sleeves were removed and the arteries rinsed in norrnal saline ovemight.
WO95/29711 '2~ 8 637 3 .~ 10~ 7 ~
One artery of the pair was sleeved with the sheath described in Example 1.
The other was unsleeved. Testing occurred at aboul 23CC. To test, each artery was slipped over a segment of latex tubing and one end of the tubing and graft assembly connected to a pressure source. The tubing was filled with water and the other end 5 of the assembly clamped with a hemostat. The water pressure inside the tubing was irlcreased at about 69 kPa/sec until the graft ruptured. The pressure at which rupture occurred was recorded.
The fixed artery segment with no sheath applied ruptured at about 579 kPa.
The fixed artery segment with the sheath material applied ruptured at about 135810 kPa, .i. ~ that the sheath material provides an i~ .. in strength to the fixed artery.
EXAMPLE S pPrmpsl~lp ~nri I~ Shp~th Co~ lu~
r~ y of the sheath of the present invention to l.l~l"~ , while being resistant to host cell ingrowth is a necessary element in providing improved patency p~,.~""~ i of donor blood vessels. In this example, permeable and ",. ~ p sheaths were co..~L,u~t~ from ePTFE tubing prepared as described in U.S. Patent 3,953,566, issued to Gore, which is - , ' herein by reference. The20 tubing had a mean fibril length of 5 llm, an internal diameter of about 5 mm, arld a wall thickness of about 0.48 mm.
The tubing was cut into segments about 10 cm in length. Half of the segments were rendered i~lh .. ".. ,.~,IP by wetting the tubing with 1,1,2 trichloro-1,2,2-~linLJ,~ SFreon TF, E.I. duPont de Nemours, Inc., Wilmington, DE) and 25 infiln~ v the pores of the tubing with a 50% (~ll ) (v:v) mixture of 1,1,2 trichloro-1,2,2-L illuv,.,~,tl.~.c, and Silastic Type A Medical Grade Adhesive (Dow Corning, Inc., Midland, Ml). The tubing was then placed on a 5 mm diameter mandrel and additional unthinned adhesive was applied to the outer surface of the tubing.
The tubing was placed in a forced air oven at about 100C for ~ ly two 30 hours to cure the adhesive. Both the ;"~ hl~ tubing and a section of untreated e~l~ tubing were cut to 5 cm and sterilized by autoclave.
The permeable and ;~ ",P~ . sheaths described above were tested for the capacity to pass macromolecules but block the passage of cells using the procedure described in Example 1. The ;~ r silicone-coated sheath blocked the 35 passage of the 2,000,000 MW dextrans and the 3 llm beads. The uncoated ~VO95/29711 2 ~ 8 6 3 73 r~ . .c~ 7 permeable sheath passed the dextran - ' ' but did not allow the 3 ~Lm beads to pass. Thus, the above constructions provided a sheath that is ;"~l~ "~ to Illd~ q5 and cells, and a sheath that is permeable according to the I~UiU~ of the present invention.
The arterial tissue to be sleeved with the sheaths prepared above was obtained from the femoral arteries of a greyhound dog. A 6 cm length of both femoral arteries was removed and the arterial branches ligated with silk ligatures.
Each artery was placed in 15% DMSO in HBSS and frozen in liquid nitrogen for 15 days.
The arteries were prepared for ;",l ~ ;r ~ into a recipient greyhound dog by first thawing the frozen arteries. The arteries were rapidly thawed by illl~ illg the freezing tubes co~f~inin~ the arteries in 37-C water. The arteries were rinsed in saline and the adventitia trimmed. One end of each artery was attached to a barbed Luer fitting and the arteries sleeved with a segment of 5 mm GORE-TEX~ Vascular Grdft (W. L. Gore & Associates, Inc., Flagstaff, AZ) so that when fixed in .hyde, the arteries would have a finished internal diameter of about 4 mm and an outer diameter of 5 mm. The arteries were pressure fixed in 2.5%
glutaraldehyde (v:v) in 0.2 M Sorenson's phosphate buffer, pH 7.0 at about 27.6 kPa for 2 hours.
Using sterile technique, the arteries were removed from the gl,-f~r~ hyde solution, cut free of the fittings, and the GORE-TEX~ ~ascular Graft sleeves removed. The arteries were immersed in 500 ml of sterile normal saline to remove the excess glutaraldehyde, and stirred at room t~ iUlC for 15 minutes, at which timethe saline was replaced with 500 ml of fresh sterile norfnal saline. The arteries were rinsed for an addifional 15 minutes in the fresh sterile saline. At the end of the second rinse, the arteries were stored in ftesh sterile normal saline until required for For imrl~nf:~tion each fixed artery segment was placed within the lumen of one of the sterile sheaths previously prepared. The ends of the fixed arteries were cut flush with the ends of the sheaths. The composite ~rafts so c~ .u.,t~,d wereabout 5 cm in length.
The femoral arteries of a recipient greyhound dog were surgically exposed and a segment of about 5 cm excised from both femoral arteries. Each graft was surgically interposed into one of the femoral arteries using end-to-end technique and a C~ suture. Both layers of the composite grafts were ,~ o~d to the WO 9~i/29711 ~ l 8 6 3 7 3 host femoral arteries with CV-6 GOr~E-TE~ Suture (W. L. Gore & Associates, Inc.,Flagstaff, AZ).
At 19 days following imrlAAntA~icm the femoral artery replaced with a processed artery covered with the ;"'l~ .. r ll,lr. sheath was found to be occluded by S duplex scanner UlL~A~O~C~ . Occlusion was confirmed at 20 days postoperation with contrast arteriography.
After 60 days implantation, the remaining femoral artery replaced with a processed artery covered with a permeable sheath of the present invention was visualized using ~t~,liO~ and was found to be patent.
10 Thus, the fixed graft with the ill.lh..... lll.. ~ll'. sheath was found occluded at 19 days after illl"l~ , while the graft with the selectively permeable sheath of the present invention remained patent for at least 60 days, at which time the grafts were explanted and the patent graft subjected to histological studies. Histological r~ ;C~ l of the patent graft showed the inner layers of the biologic ~ ~r of 15 the patent graft had . . . ~ d the O~ of the original donor artery.
These results ~ -- that the use of the sheath of the present invention with a preserved donor artery in a vascular prosthesis provides improved patency~-~lllldl,~,e compared to a preserved donor artery having an ;---l,. . ",~ , sheath.
While particular . L " of the present invention have been illustrated 20 and described herein, the present invention should not be limited to such ill -- -and d~ ,., ;l,l ;. .--c It should be apparent that changes and ,. .,~.l; l ;. A l;l~.l ~ may be d and embodied as part of the present invention within the scope of the following claims.
The practice of grafting with allogeneic arteries was ~h -~on,-d in favor of the", . k ~ lly superior ~It~,llla.i~e of using vascular grafts made of synthetic materials.
The synthetic materials principally used for this grafting are polyethylene terephthalate and expanded p~vlyt~ u~,lllylene (ePTFE). These materials offer C~ ;lity and provide sufficient ,.. ~ integrity to prevent a.l~
dilation. F~u~ll~.,li~,s made of these materials were shown to bt_ successful in the ,~ L,I 1. . . I l. .. It of large vessels such as the aorta or iliac alteries and are still ,ucc~ ~ 'ly used in these :lrpl~ tionc Although successful when used in large diameter 25 applications, the pâtency ~.ru.l,la,l~e of these materials in ~ ' '~ v small diameter ~rPli( ~ nc such as coronary artery bypass or peripheral arterial bypass distal to the popliteal artery, for example, has been s~lhct~ti~lly less than that of 1l l ' living autologous vessels.
Regardless of whether a prosthetic vascular graft is obtained from a donor or 30 is made of synthetic materials, it has been a common belief since the 1950's tbat ingrowth of host tissue into vascular grafts leads to improved function.
R~ s~":dliv~ of this belief is the following statement: "With existing p.."~ s, we believe that the best assurance of long term patency without ctlmrli~tion is ~l-;, "- ..l of complete healing of the prosthetic wall, which includes an 35 en-loth~ 1i7Pd flow surface. This final healed state is principally dependent upon I
WO 9~/29711 2 1 8 6 3 7 3 P~ .'C I' 7 ~
the ingrowth of areolar tissue from perigraft sources through the interstices of a pervious graft wall -' (Sauvage et al., "Future Directions in the Development ofArterial Prostheses for Small and Medium Caliber Arteries," Surgica~ C~inics of North America 54: 213-228 (1974)) With bio~o~i~Ally-derived ~u~lh~ ,s, host tissue ingrowth is observed to alter the donor graft material into one composed at least partially of recipient tissues. In addition, such ingrowth of autologous tissues usually generates a blood interface in the prosthetic T~plA~m~n~ composed in part of tissues of the host.
Ln the case of porous synthetic materials, ~Ou~ tissue ingrowth occurs through the interstices of the material. The apparent desirability of ingrowth of autologous tissue into grafts made of porous pol~t~,lldr~uoroethylene (ePTFE) isillustratedbytheresultsofastudyc~"",u~-;"gthepatencyp~,.rul...~..,~ofsmall caliber vascular ePTFE prosthetics having different porosities. The study showedthat high porosity ePTFE grafts with a fibril length of 100 ~Lm had lul. ~ ;~
15 irlgrowth of fibrous tissue into the interstices of the graft and remained 100% patent at six months pu~ot~ Li~,ly. Low porosity ePTFE grafts with a short fibril length (10 llm) had layers of tissue on either side of the graft wall, but no ingrowth of tissue into the interstices of the graft. These low porosity grafts were 67~o patent at six months pU~O~d~ Iy. (E~lorian et al., "Small Vessel R. ~ ". - With Gore-tex 20 (Expanded r~l~ t~ lluoroethylene)," Arch. Surg. 111:267-270 (1976)) The initial theory ~ ,lrUlll~ of vascular gfts was proposed by Wesolowski in 1963. This theory, based upon the c~",~ ", that ingrowth of host cells leads to better patency ~,lrulll~ C, remains the lul, ' theory today.
(See for example, Stanley et al., "Biologic and Synthetic Vascular Grafts," Vascular 25 Surgery A Comprehensive Review Fourth Edition, Chapoer 21, pp 370-389, ~) 1993, referring to Wesolowski, S.A., Dennis, C., 'T -1- "~ of Vascular Grafting," New York, McGraw-Hill, 1963) TII~ IIIA1 exclusion of host cells from the interstices and lumen of a vascular Bft in order to prevent the host cells from adversely affecting the patency 30 ~lru~ d~ of the vascular Bft has not been previously described. Moreover, application of an external porous synthetic sheathing material to a vascular graft that prevents disruption or lul--o~' ' g~ of the graft by host cells while being permeable to the flux of biological fluids and molecules across its thickness has heretofore not been described.
VO 95/29711 2 1 ~ ~ 3 ~ 3 ~ 7 SUMM~Y OF THE INVENTION
The present invention is directed to improved vascular prostheses derived from donor blood vessels. It is an object of the present invention to provide 5 improved ~Iru~ llce for vascular prostheses by preventing many of the failuresthat are a . of the invasion of an implant by host cells. It is a further object of the present invention to provide improved p~,lrullll~e for vascular prostheses by providing a cell excluding covering for the vascular tissue of a prosthesis that permits exchange of biological fluids and ,..~ c c across the 10 vascular tissue of the implant and the perigraft tissue of a recipient.
Contrary to the widely accepted theory that the ~lrullll~ulcc of vascular grafts is enhanced by host tissue ingrowth, the present invention achieves enhanced paoency l,.,.rollll~ul~,e of vascular grafts by employing an external sheath around a donor blood vessel that is resistant to host cell ingrowth ... ;yi -l;..~ from perigraft 15 tissue.
It has been diDc~ i that ingrowth of host cells into a vascular graft derived from donor blood vessels of oen causes disruption of the function of the graft. Such remodeling can have serious negative co , such as ,.... 1 , ~I failures in fhe form of al.~,ul~DIll~l dilatation, .~ f 1.;~. -- c, frank graft disruption, as 20 well as Illlulllbu~;~ relaoed to the alteration of the blood vessel wall c~mrocifi~n By blocking the access of host cells to the donor blood vessel with a cell excluding sheath of the present invention, the host cells l~,D,UU..D;blC for r~motlf lin~ the vessel walls cannot grow into the donor blood vessel and disrupt the al~;ll;L~UIt; of the vessel walls. As a result, many of the above- ' vascular graft failures can be 25 delayed or prevented.
It has also been I;D~U~ d that pl-rm~ ilify of the cell-excluding exoernal sheath of the present invention to ions, water, and 1ll~ ( c for example, is necessary for " ,~ the function of the donor blood vessel after; ~
Permeability of the external sheath is achieved by Culll,LIu ,~ g the sheath so that it is Illi~lU})UIUUD.
Accordingly, the present invention is a covering for a blood vessel which comprises a sheath ,ulluu-ldi..g the blood vessel, wherein the sheath comprises a UPUIUUD polymeric material and wherein the sheath serves as a barrier to external cellular contact to the blood vessel, while being permeable to macrom.~ s WO 95129711 2 18 6 3 7 3 r~ 7 ~
DF.CCRTPTION OF T~F. DRAWIN~S
The operation of the present invention should become apparent from the following t~f-5~rjr~i.m when considered in c~,..ju..~lio.~ with the d~,~,OIll~Jd--y g 5 drawings, in which:
Figure 1 is a cross-sectional view of a m ~m~l artery (2) having the ~xternal sheath (I) applied thereto;
Flgure 2 is another view of the ~, l,o-l;,, ,t of the present invention illustrated in Figure 1.
DET.An ~n DE~CRlPrlON OF THE INVENTION
The present invention is directed to a sheath for use in vascular prostheses derived from donor blood vessels, particularly ' blood vessels. A vascular 15 prosthesis may employ an external sheath of the present invention around a donor blood vessel. The sheath prevents access to the donor vessel wall by host cells c~ri~in~in~ from perigraft tissue. While resisting host cell ingrowth, the external sheath is permeable to the flux of -.~ across its thickness. The exclusion of host cells by the external sheath and the bi-directional flow of Ill.l~lUlllO' ' ~
20 through the external sheath assists in ~ e the original function of the u~J~Ily ~ donor vascular tissue of the prosthesis. The term ~ r l S~ is l~ od to include, but not be limited to, molecules having a molecular weight up to dnd including about 2,000,000 MW.
In the present invention, it has been found that the original ~uul.;t~ and 25 function of vessel derived vascular grafts can be ' if invasion of the donor vessel wall by host cells is prevented while the flux of macromol~r~ across the wall is permitted. If the original ~, ' ~i and function of the arterial wall of a vascular graft is so I, many of the failures ~-I,vh~ui~ly noted with ~r~n~r~ ~ vessels can be ~ , resulting in improved patency ~.fu...~ .,e of 30 these biologically derived grafts. The teachings of the present invention are thus directly opposite those of the prior art in this field regarding the d~si.~.l,;lily of host cell ingrowth into the donor tissue of a biological vascular graft.
Since host cellular invasion largely proceeds from the perigraft region radiallytoward the lumen, prevention of cellular invasion of the donor blood vessel wall used 35 as a vascular graft is achieved by dl,lJlic~Lio.. to the external surface of the vessel ~W095129711 21 ~637~ r_l~u~. ol~7 wall of a sheath that is resistant to cell ingrowth. A structure ~ ,G,..bli-.~ this c~. r;~ ;n~ is shown in Figures 1 and 2. The sheath (1) is applied to the external surface of a .. ~.. AI . - blood vessel (2) forming a tubular vascular graft (3). The flux of Illa ~ lllO~ 'llPQ across the thickness of the external sheath is achieved by5 co.,~L~u-,Li~,g the sheath of materials that are permeable to macrnmnlP~--lPs while being resistant to cell ingrowth. The preferred materials for Cull~l u~,i of theexternal sheath are synthetic materials that are llli~lUIuC~!uus. Suitable materials for co--~i~ u~liull of the external sheath of the present invention include, but are not limited to, the group of polymer materials with 1'~ iocnmr~ti~ y and 10 stability under implant c~n~litinn~ such as, pol~ u~,~.yl~"c (PTFE), polyethylene t~ llldt~, rh ' ethylene propylene (FEP), polyethylene, poly~u u~uyl~ " and siloxane, for example. The exterr~al sheath employed in the preferred l ..~ l of the present invention is rnade of expanded PTFE (ePTFE) as produced in U.S. Patent 3,953,566, issued to Gore, which is ill1Ul,U~ herein by 15 reference.
The pore size that is effective in resisting cell ingrowth across the thickness of the sheath is dependent upon the thickness of the wall itself and the tortuosity of the pores - ~ the outer surface with the inner surface of the sheath. In the case of regular uniform porGs in a thin sheath cu..~L. u~ (about 10-20 llm in thickness) 20 the pores should be selected to be less than about 3 ~m. This value is based upon Boyden chamber migration assays where the limit of fibroblast invasion of straight, uniform pores is about 5-8 llm and the limit of leukocyte invasion through straight, uniform pores is about 3-5 ~Lm. (A. Albini et al., "Fib:~oblast ('hPmnt~xic," Collagen Rel. Res. 5:283-296, (1985); W. Morzycki et al., "Tumor Necrosis Factor-alpha but 25 not T~ ill-l Induces Pol~w-, ~ ~'~ Leucocyte Migration Through Fibroblast Layers by a Fibroblast-Dependent M~ -, - "," Immunology, 74:107-113, (1991)) In the case of a thicker, more tortuous, or laminate structure, the individual pores can be somewhat larger and still serve as an effective barrier to the passage of cells across the layer.
For an ePTFE or similar fibrillated sheath, the pore size of the sheath is related to the fibril length of the sheath material and the thickness of the sheath material.
Thicker fibrillated sheath materials generally have more tortuous pathways c,.---,~ one end of a pore to the other end of the pore. As a result, a thicker fibrillated sheath may have pores that are larger than invading cells, but will remain resistant to cell ingrowth due to the increased tortuosity of the pathways of the W095/29?11 21 8 6 37 3 ~ c~
pores in thicker sheath material. Regardless of the thickness of the sheath, the fibril length should be chosen to form pores that resists cellular access through the sheath, while being permeable to macr~mnl~ c.~l~ c In defining the ability of the sheath to resist cell ingrowth, a Dnnr~ r assay 5 method has been developed. Based upon the published values that 3 ,um represents the lower limit of cell pPrm~hilify through straight pores, 3 ,um ~ uv~JllvlrvS can be used to - -r~ ;f ~lly determine whether a given sheath will exslude particles of this diameter. C~ C~l.. lly~ any sheath material that excludes 3 llm Illi, 1l . ' v~ should effectively prevent cellular movement across the sheath.
Fibril length is measured as described in U.S. Patent 4,482,516, issued to Bowman et al., which is ill~vullJulaLed herein by reference. The fibril length of porous ePTFE that has been expanded in a single direstion is defined herein as the average of ten ...v~vu.~ between nodes connected by fibrils in the direction of ~-Yr^nc;~)n Ten Illc~ are made in the following manner. First, a 15 ullolulll;-,lu~ is made of a l~ ,llL~Liv~; portion of the sample surfase, of adequate m~lenifir~tion to show at least five sequential fibrils within the length of the pll~ulll~ u~ l. Two parallel lines are drawn across the length of the pl~olullli~lugraph so as to divide the pl~ol()" ,' into three equal areas, with the lines being drawn in the direstion of expansion and parallel to the direstion of ~
20 of the fibrils. Measuring from left to right, five of fibril length are made along the top line in the ~hntner ~rh beginning with the first node to intersest the line near the left edge of the ,UII~IU~ and c, 7 with . sL v~ nodes ~ the line. Five mone Ill~,o.;~,lll~,llL~ are made along the other line from right to left beginning with the first node to intersect the line on the right hand side 25 of the ~ u~u~ The ten III~ UlUIll~ v obtained by this method are averaged to obtain the fibril length of the material.
For a porous, ePTFE material that has been expanded in more than one direstion, the fibril length is estimated by examining a l~ll,vv..lali~., pl~vlullli~lu~;l~l~ of the material surface and cnmr~rine fibril lengths as described 30 above in a manner that represents the various direstional uli~ liullv of the fibrils.
The sheath may be ~ UL t~ in a tubular configuration and applied to the external surface of a stabilized artery . An external sheath can also be applied as a film to the outside of a donor blood vessel, and the film layers vU~ Uvll~ly bonded together.
~W095n9711 21 8 6 3 73 ~ 7 Once a pore size and Coll~LI uuliull method are chosen for the sheath, the pPrmPohility cllala~L~,~iali~:, of the sheath can be evaluatecl by testing with markers of known size, such as dextrans and pol~,~yl~,.lc Illi~lU~l~ ,s. For example, dextran, with an average molecular weight of about 2,000,000 MW, labelled with the colored S compound fluorescein (Sigma Chemical Co., St. Louis, MO), can be used to test the ability of the sheath to pass macrnmol~ ' Cell; " ,l,. . " ,~ y of the sheath can be tested using polystyrene ll-~lu~h~,~s with a diameter of about 3 llm (Polysciences, Inc., Warrington, PA) at a cù . ,l, ,~ ;. .. of about 2.5~o solids in s crc nCi~n, for example.
When testing the sheath for pPrmPohili~y with colored markers, the markers are s~lcrPn~lccl as an aqueous solution or as an aqueous CllcrPncirm at co~
sufficient to provide a distinctly visible color. The preferred . ol.~ ;o~ of the Lluvl~,sc~... labeled dextran solution is alJlJII ' ' Iy 0.2 mg dextran/ml. The preferred CullC-,llLlaliOl~ of the a ~ 1 of the polystyrene IlliL,I~ . ' is a~ 'y 0.02 ml Illi~lua~ lml - - -r '~ , to yield about 4.5 x 107 beads/ml J ~ C~ The evaluation of the sheath pPrmPqhility occurs at about 23C. The sheath is prepared for permeability oesting by rendering it permeable to water, if necessary. For example, sheaths CulI:~Llu~,t~,.;i of ePTFE are wetted with 10091o ethyl alcohol and then flushed with water to remove the alcohol before pPrmPohility 20 testing.
To oest the pP.rmPqhility of the sheath to macr~lmolpclllpc~ the dextran test solution is instilled in the lumen of a sheath and ,UI~ UIi~ to about 20.7 kPa using a syringe. The contents of the syringe are forced through the sheath and the liquid that filters through the sheath wall is collected and visually inspecoed against a white 25 bd~,l~lu. 1 for evidence of the colored dextran.
In preparation for testing the pPrmPqhility of a sheatb to cells, the number of ua~ "L,. in the sllcpPnci~ n are cl~.~ .",; ~ by using an dlJ~Jlul counting device, such as a h~,~lla~tulll~t~ for example. The pPrmPqhility of the sheath is then oested by forcing the IlliLlU~ ,lc;-C-~ U~ siu.. through the sheath material 30 at about 20.7 kPa using a syringe. The syringe is refilled with water and the waoer also forced through the sheath at about 20.7 kPa. The liquid that filters through the sheath wall is collecoed and subjected to c~l.tli~u~a~ion at about 300 x g for about 5-10 minuoes. The ~u~u~ll-aL~u~L is decanted and discarded and the pellet of IlLi~-ua~ ;, is l~ d in a known volume of waoer. The number of WO95/29711 21 8 6 3 7 3 r~l~u. 5 ~ '' 7 ...,~,.u~,h~ in tl~e r~c~c~.n-l~d pellet are counted and compared with the original " The numbe} of I~ ualJllelcs that pass through the sheath are expressed as a percentage of the number illLlUdUC~,~;i into the lumen of the sheath. An alJ~JIU~ t~, sheath for use in the present invention will pass the about 2,000,000 5 MW dextran at pressures at or below about 20.7 kPa so that the colored solution that filters through the sheath is clearly visible when viewed against a white ba~,k~.uulld. Additionally, the sheath will not allow more than about 5% of the 3 ~Lm IIU~ , ' I,S to pass across its thiclcness at a pressure of about 20.7 kPa.
Some suitable methods for applying the sheath of the present invention to 10 vascular prostheses derived from naturally occurring tissue and vascular prostheses using synthetic materials are included in a U.S. patent application of Bruchman et al., entitled "Improved Blood Contact Surfaces Employing Natural ~lhPn~lotl~
Matrix And Method Of Malcing And Using Same," which is ' - .u~ly filed herewith and ill~,ol~)ulat~,~ herein by reference. It is u--d~ uod that the vascular 15 tissue ~ Jau~iùl~ processes described in this ~ ly filed orrliro~i~ln are only some of the suggested uses of the sheath of the present invention.
In addition to ~.c~. v ingrowth of host ce!ls into the prosthesis of the present invention, while being permeable to Illa~ ' ul~ 5, the sheath of the present invention can also function as a culll~ of a vascular prosthesis that supplies .. l ,: ~l ,","~.. ,~ "" for the prosthesis. While a biologic c~ of the graft, such as a donor blood vessel, supplies the allli~lu u~bulic properLies to the vascular prosthesis, the long term l ~' l stability is usually supplied by the sheath c~ Accu~di~ y, the sheath of the present invention is selected to provide ""~, l. .,;, ~l strength necessary for the particular diameter of the graft used in 25 order to resist the hoop stress induced by blood pressure, to provide sufficient - ' I strength for creating ~ s~ and to resist ~ ....ul; stresses.
The sheath is co--~ t~.d by wrapping a mandrel with multiple layers of ePTFE film, such as those described in U.S. Patent 3,953,566 and 4,187,390, bothissued to Gore, each of which is i--cul,ou-~.~,d herein by reference, and adhering the 30 film to itself by heating the film and mandrel in an oven at about 380C for about 10 to about 20 minutes. The film tube is removed from the mandrel arld prepared tissue graft installed in the lumen of the polymeric tube. Other materials, or c~...l.;.,-:;....~ of materials, may be applied to the tissue tube similarly, using t~ IalUIC~ and times a~JlU~I;aLv for the physical properties of the chosen material.
~Yo 951~97~ 8 6 3 7 3 P~ c 1-~7 Other methods of ,. ."r~ g the sheath malerial include placing a processed artery onto a mandrel and wrapping the artery with multiple layers of an ePTFE and FEP composite film, and heating the film layer very briefly from about310C to about 350C to adhere the film wrap to itself on the outer surface of the 5 vessel. The FEP-coated ePTFE film is made by a process which includes the steps of:
a) contacting a porous PTFE substrate, usually in the form of a membrane or film, with another layer which is rreferably a film of FEP or alternatively of another . " " ,~ polymer; b) heating the co~ uo tiliol~ obtained in step (a) to a above the melting point of the ~ l...u~ ic polymer; c) stretching the 10 heated C~n~ J~ of step (b) while l~ the b~lllAU~ UUCi above the melting point of the thermoplastic polymer; and d) cooling the product of step (c).
Another sheath construction method is the f~hrir~tir~n of a tubular form of ePTFE Cul~ u~t~ according to U.S. Patent 3,593,566 to Gore using a uniaxial ~Yr~nr;~-n The processed blood vessel is inserted into the ePTFE tube so 15 Cull~llu~,~d. As in the other forms of the sheath, the tubular form must be permeable to the passage of macr lm~ c~ s but exclude the passage of cells.
Str~ tllres of Sh~:lthc Made in Accor I ~n~ with thl~ Present Tnv~nfion Without intending to limit the score of the present invention, the following examples illustrate how the present invention can he made and used.
EXAMPLES
EXAMPLE I Film Sb~th C ~ iu., A sheath tube was CO~ Iu~ from a porous expanded polyt~ fluu-u~..ylene (ePTFE) film. The porous ePTFE film from which the sheath tube of the present invention was c~ u~ d, was made as taught by U.S. Patents 30 3,953,566 and 4,187,390, both issued to Gore, each of which is i.~cu-luu.,. ~,~ herein by reference.
This porous ePTFE film had a Ill;~lu~llu.,~ of nodes i~.t.,l~u~ c~ by fibrils. The film was made by expansion by stretching in a single dircction, which was the direction in which the resulting fibrils were prima~ily oriented. The film used 35 in the preparabon of this invention had a fibril length of about 50 ~m, a density of WO95/29711 21 8 6 37 3 P~ o 1~7 about 0.3 g/cm, a thickness of about 0.01 mm, and were 86% porous by bulk volume.
The fibril length of the porous ePTFE film referred to above was an estimated mean value obtained by examining a scanning electrop ~llulollu~,lu~la~ll of the film.To construct the sheath, the film was applied to a metal mandrel about 5 mm in S diameter by wrapping the mandrel with the film in a helical manner. The pitch of the helix was such that each wrap of film overlapped a,u,ulu~dlll..t~.ly two-thirds of the previous wrap. The mandrel was wrapped three times in this fashion, resulting in a film tube CUI.~uu.,t.,~ of about nine layers of film. The wrapped mandrel was then heated in a oven at about 378C for seven minutes to adbere the film layers togetber.
10 The mandrel was removed from the oven and allowed to cool. Once cool, the film sheath was removed from the mandrel.
The sheath was tested for ability to pass Illa~ r.~ uI~ .s as follows. A
solution of lluu-., ,~.,;..-labeled dextran with an average molecular weight of 2,000,000 MW was prepared in water at a cor- nn of about 0.2 mg/ml. A
15 portion of the sheath, about 10 cm in length, was mounted on a barbed Luer fitting and wetted with 100% ethyl alcohol. Tbe alcohol was removed by flushing the sheath with water using a syringe to force the water through the pores of the sheath.
Using a syringe, the dextran test solution was instilled in the lumen of the sheath and IUI~ ' J to about 20.7 kPa. The contents of the sylinge were forced through the 20 sheath and the liquid that filtered through the sheath wall was collected and visually inspected against a white background for evidence of the colored dextran. The solution was distinctly yellow colored, and the sheath, therefore, permeable to . . .n~ c The sheath was tested for ability to prevent cellular infiltration. A second 10 25 cm length of sheath was wetted with ethyl alcohol and the alcohol replaced with water as described above. ~ ,s about 311m in diameter (Poly~k,..c~,;"
Warrington, PA) were used to determine the ability of the sheath to prevent cellular infil~ inn A stock, ~l7- .~:ù ~ of ~u~,-u~lUII~ , . was prepared. The number of U~,UIIG.~,~ in the ~ was dc~nninPd to be about 4.7 x 107 spheres/ml 30 using a l.~,.lla~,ylulll~ . The ~lh,-u~ lG-containing ~ c: J~ was tested by forcing the contents of the syringe, 5 ml of stock :~Ui~U~ iVl~7 through the sheath rnaterial at 20.7 kPa. The syringe was refilled with water and the water also forced through the sheath at 20.7 kPa. The liquid that filtered through the sheath wall was collected and subjected to c~ irll~linn at about 300 x g for 5 minutes. The ~VO 95/29711 2 1 8 6 3 7 3 r.~ o ~ -~7 was decanted and discarded, and the pellet of ...;~.u~ c.cis was ;,. .,.l d in one ml ûf water. The number ûf ~ u~ s in the 1. ~ f d pellet was counted as for the original ~U~.Isiol. and Lhe count expressed as a ~1~ "f, of the number of l~ lu~ lf ~ used for the test. The ~I-~,lIL.l~ of 5 I.u~ , passing through the wall of the sheath was 0.17%. The sheath can be - ' ~,d resistant to cell ingrowth since less than 59~ of the --;c.~ pass through the sheath wall.
A sheath of porous ePTFE was c u~,t d. The sheath was permeable to lr, ~IP~ and resistant to cellular infi~ tio~ by the defining tests. The sheath 10 can be installed onto arterial ~ --- grafts comprised of tissue from allogeneic or YPnogf nPir sources by sliding the processed artery into the lumen of the sheath.
EXAMPLE 2 Fn7~me Millir~p Carotid arteries removed from a donor dog were placed in 15%
dimethylsulfoxide in Hanks' Balanced Salt Solution (DMSO/HBSS) and stored in liquid nitrogen. For treatment, the arteries were thawed, rinsed in HBSS, and the adventitia dissected from the arteries. Both arteries were mounted onto barhed Luer fittings.
Both arteries were filled with calcium and 1,~ free HBSS c- 1~
0.4 mM cLI.~ ..f tetraacetic acid (EDTA) to inhibit the action of cnll~.vP ~o that may penetrate to the lumen. The ends of the arteries were plugged and the arteries rinsed again in HBSS. Both arteries were immersed in separate i ~uh~tion tubes . g 0.2 M Tris-HCI, pH 7.5, containing 0.1 M -amino-n-caproiC acid, 5 25 mMN-ethyl~ I. 5mMI ' ~ andO.36mMCaCI22H2O(allfromSigma Chemical Co., St. Louis, MO). To one tube, 35 units of type 1 A c~-ll q ~ (Sigma) per ml of buffer was added. Both arteries were incubated at 37C for about 5.5 hours.
After inrllh~ion the arteries were rinsed thoroughly in BSS and were 30 sleeved with a 5 mm tube and pressure fixed in 0.25% glutaraldehyde in 0.020 M N-2-l~ydl~J~ytilllyl~ .,.,;,.~N'-2-ethane sulfonic acid (HEPES), pH 7.3, with 0.44%
NaCI and 0.26% MgCI2 6H2O, at about 27.6 kPa for about 2 hours. The arteries were then removed from their sleeves and left immersed in the fixing solution overnight. After fixing, the arteries were rinsed thoroughly in normal saline and WO95/29711 2 1 86373 ~ `7 ~
sleeved with the sheath from Example 1. The finished wall thickness of the sleeved digested artery was 0.14 mm while the finished wall thickness of the sleeved control artery was o.æ mm.
EXAMPLE 3 Sheath Applied Directly to Fixed Artery Distal limbs were obtained from cows at slaughter and stored frozen at about -20C until required for ~)lU~ illg. The legs were thawed by illllll~ illg them in warm (37C) water and the arteries dissected from the legs. After rinsing in Hanks' Balanced Salt Solution (HBSS), the adventitia was dissected free and the arteries 10 stored in HBSS until fixed.
Arteries of an ~ t~ size to provide a finished internal diameter of alJIJIU ly 4 mm were selected. The arteries were sleeved with 5 mm GORE-TEX~ Vascular Graft (W. L. Gore & Associates, Inc., Flagstaff, AZ), mounted on barbed Luer fittings and were pressure fixed at about 27.6 kPa for 2 hours in 2.59?o 15 ~ -o~al-l~hyde in 0.2 M Sorenson's phosphate buffer, pH 7Ø Fixation occurred at about 23C. After fixation, the arteries were rinsed in normal saline, and stored in normal saline at about 4C until required for use.
Arplirqtion of the sheath to the fixed arteries was performed as follows. The artery was plæed onto a 3 mm diameter mandrel and the ends of the artery secured20 with wire ties. Next, a helical wrap of 25.4 mm wide film was applied over the outer surface of the arteries. The film used for the helical wrapping was a porous ePTFE
film with an additional layer or coating of nu. ~ ethylene propylene (FEP) on one surface. The FEP-coated porous ePTFE film was made by a process which comprises the steps of:
a) contacting a porous ePTFE substrate, usually in the form of a ' ~
or film, with another layer which is preferably a film of FEP or al.~,.ll.lii~,ly of another th~,llllu~ ic polymer;
b) heating the composition obtained in step (a) to a t~-~.~iu-~ above the melting point of the thl-nnorl~c-ir polymer;
c) stretching the heated composition of step (b) while ~ l;l g the i above the melting point of the L~l~,.ll.u~lasLic polymer; and d) cooling the product of step (c).
The FEP coating of the porous ePTFE film for this example was .1;~ ."~
thereby resulting in a porous composite film. The porous FEP-coated ePTFE film ~O9Sl2971l 21 ~ 63 73 r~l"~ 7 used to make this example had a thickness of about 0.03 mm, a density of about 0.3 glcc, a fibril length of about 40 ~Lm, and a width of about 25.4 mm.
The Fl;P-coated side of the film was placed against the fixed arKrial tissue.
The pitch of the helical wrap was chosen such that each wrap of the film u~ la~d5 a~ y two-thirds of the priûr wrap. The arteries were wrapped three times in this fashion, resulting in a film layer C~ DL,u~.t~,~ from about nine layers of film. While still on the mandrel, the film-wrapped arteries were contacted very briefly by an aluminum fixture heated to about 350C to thermally bond the layers of film together while ~ the heating of the fixed artery. The fixture was an aluminum ring 10 with an inKmal diameter of about 0.8 cm, a wall thickness of about 1.5 cm and an overall length of about 5 cm. The process employed to bond the film layers was to place the wrapped artery through the hole in the fixture, contact the surface of the film to the heated fixture and rotate the graft assembly. One revolution of a graft with an outside diameter of about 5 mm was performed in 1.5 to 2.0 seconds. After 15 heating, the wire ties attaching the artery to the mandrel were removed and the fixed artery with the sheath applied removed from the mandrel.
The artery-sheath composite was stored in norrnal saline or water until y testing of the sheath could be performed. The sheath was removed from the artery and the artery discarded. The sheath was tested for ability to pass 20 macr~m~lPc~lPc and to prevent cellular ~ as described in Example 1. The sheath, when pretreaKd by wetKd with 100% ethyl alcohol, readily passed the 2,000,000 MW dextran, indicating that a sheath ~,.,t~,~ in this fashion was permeable to macrotnrlPc-llpc The same sheath allowed no Illr ~ lr quantity of the 3 llm lll;.,lUD~ ,D to pass through, indicating that this sheath ,.~Liul- is25 resistant to cellular infiltr:~til EXAMPLE 4 Burst TestinF of Sleeved and Unsleeved Fixed Arteri~ll Tissue Carotid arteries from a y,lc~' ' dog were placed into normal saline. The 30 adventitia was dissecKd away and the arteries were m~unted on barbed Luer fittings and sleeved with a 5 mm GORE-TEX~9 Vascular Graft (W. L. Gore & Associates, Inc., Flagstaff, AZ) to provide a fixed artery with about a 4 mm intemal diameter. Thearteries were pressure fixed at about 27.6 kPa for two l1ours at 23C in 2.5%
.hyde in 0.2 M Sorenson's phosphate buffer, pH 7Ø After fixation, tne 35 fixing sleeves were removed and the arteries rinsed in norrnal saline ovemight.
WO95/29711 '2~ 8 637 3 .~ 10~ 7 ~
One artery of the pair was sleeved with the sheath described in Example 1.
The other was unsleeved. Testing occurred at aboul 23CC. To test, each artery was slipped over a segment of latex tubing and one end of the tubing and graft assembly connected to a pressure source. The tubing was filled with water and the other end 5 of the assembly clamped with a hemostat. The water pressure inside the tubing was irlcreased at about 69 kPa/sec until the graft ruptured. The pressure at which rupture occurred was recorded.
The fixed artery segment with no sheath applied ruptured at about 579 kPa.
The fixed artery segment with the sheath material applied ruptured at about 135810 kPa, .i. ~ that the sheath material provides an i~ .. in strength to the fixed artery.
EXAMPLE S pPrmpsl~lp ~nri I~ Shp~th Co~ lu~
r~ y of the sheath of the present invention to l.l~l"~ , while being resistant to host cell ingrowth is a necessary element in providing improved patency p~,.~""~ i of donor blood vessels. In this example, permeable and ",. ~ p sheaths were co..~L,u~t~ from ePTFE tubing prepared as described in U.S. Patent 3,953,566, issued to Gore, which is - , ' herein by reference. The20 tubing had a mean fibril length of 5 llm, an internal diameter of about 5 mm, arld a wall thickness of about 0.48 mm.
The tubing was cut into segments about 10 cm in length. Half of the segments were rendered i~lh .. ".. ,.~,IP by wetting the tubing with 1,1,2 trichloro-1,2,2-~linLJ,~ SFreon TF, E.I. duPont de Nemours, Inc., Wilmington, DE) and 25 infiln~ v the pores of the tubing with a 50% (~ll ) (v:v) mixture of 1,1,2 trichloro-1,2,2-L illuv,.,~,tl.~.c, and Silastic Type A Medical Grade Adhesive (Dow Corning, Inc., Midland, Ml). The tubing was then placed on a 5 mm diameter mandrel and additional unthinned adhesive was applied to the outer surface of the tubing.
The tubing was placed in a forced air oven at about 100C for ~ ly two 30 hours to cure the adhesive. Both the ;"~ hl~ tubing and a section of untreated e~l~ tubing were cut to 5 cm and sterilized by autoclave.
The permeable and ;~ ",P~ . sheaths described above were tested for the capacity to pass macromolecules but block the passage of cells using the procedure described in Example 1. The ;~ r silicone-coated sheath blocked the 35 passage of the 2,000,000 MW dextrans and the 3 llm beads. The uncoated ~VO95/29711 2 ~ 8 6 3 73 r~ . .c~ 7 permeable sheath passed the dextran - ' ' but did not allow the 3 ~Lm beads to pass. Thus, the above constructions provided a sheath that is ;"~l~ "~ to Illd~ q5 and cells, and a sheath that is permeable according to the I~UiU~ of the present invention.
The arterial tissue to be sleeved with the sheaths prepared above was obtained from the femoral arteries of a greyhound dog. A 6 cm length of both femoral arteries was removed and the arterial branches ligated with silk ligatures.
Each artery was placed in 15% DMSO in HBSS and frozen in liquid nitrogen for 15 days.
The arteries were prepared for ;",l ~ ;r ~ into a recipient greyhound dog by first thawing the frozen arteries. The arteries were rapidly thawed by illl~ illg the freezing tubes co~f~inin~ the arteries in 37-C water. The arteries were rinsed in saline and the adventitia trimmed. One end of each artery was attached to a barbed Luer fitting and the arteries sleeved with a segment of 5 mm GORE-TEX~ Vascular Grdft (W. L. Gore & Associates, Inc., Flagstaff, AZ) so that when fixed in .hyde, the arteries would have a finished internal diameter of about 4 mm and an outer diameter of 5 mm. The arteries were pressure fixed in 2.5%
glutaraldehyde (v:v) in 0.2 M Sorenson's phosphate buffer, pH 7.0 at about 27.6 kPa for 2 hours.
Using sterile technique, the arteries were removed from the gl,-f~r~ hyde solution, cut free of the fittings, and the GORE-TEX~ ~ascular Graft sleeves removed. The arteries were immersed in 500 ml of sterile normal saline to remove the excess glutaraldehyde, and stirred at room t~ iUlC for 15 minutes, at which timethe saline was replaced with 500 ml of fresh sterile norfnal saline. The arteries were rinsed for an addifional 15 minutes in the fresh sterile saline. At the end of the second rinse, the arteries were stored in ftesh sterile normal saline until required for For imrl~nf:~tion each fixed artery segment was placed within the lumen of one of the sterile sheaths previously prepared. The ends of the fixed arteries were cut flush with the ends of the sheaths. The composite ~rafts so c~ .u.,t~,d wereabout 5 cm in length.
The femoral arteries of a recipient greyhound dog were surgically exposed and a segment of about 5 cm excised from both femoral arteries. Each graft was surgically interposed into one of the femoral arteries using end-to-end technique and a C~ suture. Both layers of the composite grafts were ,~ o~d to the WO 9~i/29711 ~ l 8 6 3 7 3 host femoral arteries with CV-6 GOr~E-TE~ Suture (W. L. Gore & Associates, Inc.,Flagstaff, AZ).
At 19 days following imrlAAntA~icm the femoral artery replaced with a processed artery covered with the ;"'l~ .. r ll,lr. sheath was found to be occluded by S duplex scanner UlL~A~O~C~ . Occlusion was confirmed at 20 days postoperation with contrast arteriography.
After 60 days implantation, the remaining femoral artery replaced with a processed artery covered with a permeable sheath of the present invention was visualized using ~t~,liO~ and was found to be patent.
10 Thus, the fixed graft with the ill.lh..... lll.. ~ll'. sheath was found occluded at 19 days after illl"l~ , while the graft with the selectively permeable sheath of the present invention remained patent for at least 60 days, at which time the grafts were explanted and the patent graft subjected to histological studies. Histological r~ ;C~ l of the patent graft showed the inner layers of the biologic ~ ~r of 15 the patent graft had . . . ~ d the O~ of the original donor artery.
These results ~ -- that the use of the sheath of the present invention with a preserved donor artery in a vascular prosthesis provides improved patency~-~lllldl,~,e compared to a preserved donor artery having an ;---l,. . ",~ , sheath.
While particular . L " of the present invention have been illustrated 20 and described herein, the present invention should not be limited to such ill -- -and d~ ,., ;l,l ;. .--c It should be apparent that changes and ,. .,~.l; l ;. A l;l~.l ~ may be d and embodied as part of the present invention within the scope of the following claims.
Claims (11)
1. A covering for a blood vessel which comprises:
a sheath surrounding the blood vessel;
wherein the sheath comprises a microporous polymeric material; and wherein the sheath serves as a barrier to external cellular contact to the blood vessel, while being permeable to macromolecules.
a sheath surrounding the blood vessel;
wherein the sheath comprises a microporous polymeric material; and wherein the sheath serves as a barrier to external cellular contact to the blood vessel, while being permeable to macromolecules.
2. The covering of claim 1 wherein the sheath permits the flow of macromolecules therethrough up to a molecular weight of approximately 2,000,000 MW.
3. The covering of claim 1 wherein the microporous polymeric material is selected from the group consisting of at least one of polytetrafluoroethylene, polyethylene terepthalate, fluorinated ethylene propylene, polyethylene, polypropylene, and siloxane.
4. The covering of claim 1 wherein the sheath comprises an expanded polytetrafluoroethylene.
5. A protective covering for a blood vessel which comprises:
a sheath of microporous polymeric material, the microporous polymeric material being resistant to cell ingrowth and cell passage therethrough:
wherein the sheath contains the blood vessel to protect the blood vessel along its length from ingrowth of host cells and to reinforce the blood vessel.
a sheath of microporous polymeric material, the microporous polymeric material being resistant to cell ingrowth and cell passage therethrough:
wherein the sheath contains the blood vessel to protect the blood vessel along its length from ingrowth of host cells and to reinforce the blood vessel.
6. The protective covering of claim 5 wherein the microporous polymeric material allows the passage of water therethrough.
7. The protective covering of claim 6 wherein the microporous polymeric material allows the flow of macromolecules therethrough up to a molecular weight of about 2,000,000 MW.
8. A method for protecting a blood vessel which comprises:
providing a sheath comprising a microporous polymeric material resistant to cell passage therethrough;
covering the blood vessel with the sheath so as to protect the blood vessel along its length from ingrowth of host cells and to reinforce the blood vessel.
providing a sheath comprising a microporous polymeric material resistant to cell passage therethrough;
covering the blood vessel with the sheath so as to protect the blood vessel along its length from ingrowth of host cells and to reinforce the blood vessel.
9. The method of claim 8 which further comprises:
providing as the microporous polymeric material a material which allows the flow of water therethrough: and covering the blood vessel with the microporous polymeric material so as to allow the flow of water through the sheath.
providing as the microporous polymeric material a material which allows the flow of water therethrough: and covering the blood vessel with the microporous polymeric material so as to allow the flow of water through the sheath.
10. The method of claim 8 which further comprises:
providing as the microporous polymeric material a material which allows the flow of macromolecules therethrough; and covering the blood vessel with the microporous polymeric material so as to allow the flow of macromolecules through the sheath.
providing as the microporous polymeric material a material which allows the flow of macromolecules therethrough; and covering the blood vessel with the microporous polymeric material so as to allow the flow of macromolecules through the sheath.
11. The method of claim 8 which further comprises:
providing as the microporous polymeric material expanded polytetrafluoroethylene which allows the flow of macromolecules through the sheath.
providing as the microporous polymeric material expanded polytetrafluoroethylene which allows the flow of macromolecules through the sheath.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/235,071 US5584876A (en) | 1994-04-29 | 1994-04-29 | Cell excluding sheath for vascular grafts |
| US08/235,071 | 1994-04-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2186373A1 true CA2186373A1 (en) | 1995-11-09 |
Family
ID=22883986
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002186373A Abandoned CA2186373A1 (en) | 1994-04-29 | 1995-04-17 | Cell excluding sheath for vascular grafts |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US5584876A (en) |
| EP (1) | EP0757561A1 (en) |
| JP (1) | JPH09512456A (en) |
| AU (1) | AU2292895A (en) |
| CA (1) | CA2186373A1 (en) |
| WO (1) | WO1995029711A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6428571B1 (en) | 1996-01-22 | 2002-08-06 | Scimed Life Systems, Inc. | Self-sealing PTFE vascular graft and manufacturing methods |
| US5941908A (en) * | 1997-04-23 | 1999-08-24 | Vascular Science, Inc. | Artificial medical graft with a releasable retainer |
| US6001067A (en) | 1997-03-04 | 1999-12-14 | Shults; Mark C. | Device and method for determining analyte levels |
| US20050033132A1 (en) | 1997-03-04 | 2005-02-10 | Shults Mark C. | Analyte measuring device |
| US8527026B2 (en) | 1997-03-04 | 2013-09-03 | Dexcom, Inc. | Device and method for determining analyte levels |
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-
1994
- 1994-04-29 US US08/235,071 patent/US5584876A/en not_active Expired - Fee Related
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1995
- 1995-04-17 CA CA002186373A patent/CA2186373A1/en not_active Abandoned
- 1995-04-17 JP JP7528270A patent/JPH09512456A/en active Pending
- 1995-04-17 AU AU22928/95A patent/AU2292895A/en not_active Abandoned
- 1995-04-17 EP EP95916422A patent/EP0757561A1/en not_active Withdrawn
- 1995-04-17 WO PCT/US1995/004687 patent/WO1995029711A1/en not_active Application Discontinuation
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| EP0757561A1 (en) | 1997-02-12 |
| US5584876A (en) | 1996-12-17 |
| WO1995029711A1 (en) | 1995-11-09 |
| JPH09512456A (en) | 1997-12-16 |
| AU2292895A (en) | 1995-11-29 |
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| Date | Code | Title | Description |
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| EEER | Examination request | ||
| FZDE | Discontinued |