GB2187192A - Graft forming material - Google Patents
Graft forming material Download PDFInfo
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- GB2187192A GB2187192A GB08708756A GB8708756A GB2187192A GB 2187192 A GB2187192 A GB 2187192A GB 08708756 A GB08708756 A GB 08708756A GB 8708756 A GB8708756 A GB 8708756A GB 2187192 A GB2187192 A GB 2187192A
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- collagen
- graft
- drug
- coated
- complexed
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- 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
-
- 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
- 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
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/507—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials for artificial blood vessels
-
- 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
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
-
- 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
- A61F2002/065—Y-shaped blood vessels
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/412—Tissue-regenerating or healing or proliferative agents
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/42—Anti-thrombotic agents, anticoagulants, anti-platelet agents
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/606—Coatings
- A61L2300/608—Coatings having two or more layers
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Transplantation (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Biomedical Technology (AREA)
- Engineering & Computer Science (AREA)
- Vascular Medicine (AREA)
- Molecular Biology (AREA)
- Gastroenterology & Hepatology (AREA)
- Pulmonology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Materials For Medical Uses (AREA)
- Prostheses (AREA)
Abstract
A collagen-coated/impregnated vascular graft including drug materials complexed with the collagen to be released slowly from the graft following implant is made by treating a porous synthetic vascular graft substrate with a collagen fibril suspension and cross-linking the collagen in situ (e.g. with formaldehyde) to render the porous substrate blood-tight. The drug materials complexed with the collagen fibrils may include antithrombic agents, antibacterial, antimicrobial agents and antifungal agents. Treatment is by an aqueous suspension containing 5-5 &cirf& 9% collagen fibrils complexed with an active amount of drug and 4-12% of plasticiser.
Description
GB 2 187 192 A 1
SPECIFICATION
Drug delivery collagen-coated synthetic vascular graft Background of the invention 5
This invention relates to a synthetic vascular graft, and more particularly to ad rug delivery blood-tig ht collagen-coated synthetic vascular graft which does not need to be pre- clotted and which acts as a reservoir for sustained release of a drug material after implant.
The replacement of segments of human blood vessels with synthetic vascular grafts is well accepted in the art. Synthetic vascular grafts have taken a wide variety of configurations and are formed of a wide variety of 10 materials. Among the accepted and successful vascular graft implants are those which are formed from a biologically compatible material which retains an open lumen to permit blood to flow through the synthetic graft after implant. The grafts maybe made from biologically compatible fibers, such as Dacron and Teflon, maybe knitted or woven and maybe of a mono-filiment yarn, mu Iti-fil i ment yarn or staple yarn.
An important factor in the selection of a particular graft substrate is the porosity of the fabric wall of which 15 the graft is formed. Porosity is significant because it controls the tendency to hemorrhage during and after implantation and controls the ingrowth of tissue into the wall of the graft. It is desirable thatthe vascular graft su bstrate be sufficiently blood-tight to prevent the loss of blood during implant, yet the structure must be sufficiently porous to permit ingrowth of fibroblast and smooth muscle cells in orderto attach the graft to the host tissue. Synthetic vascular grafts of the type described in United States Patents No. 3,805,301 andNo. 20 4,047,252, assigned to the assignee of the subject application, are elongated flexible tubular bodies formed of a yarn such as Dacron. In the earlier patent, the graft is a warp knitted tube and in the latter issued patent it is a double-velou r synthetic graft marketed under the trademark Microvel. These types of grafts have sufficiently porous structures to permit ingrowth of hosttissue.
The general procedure for implantation includes the step of pre-clotting, wherein the graft is immersed in 25 the blood of the patient and a] lowed to stand fora period of time sufficient for clotting to insue. After pre-clotting, hemorrhag ing does not occur when the graft is implanted and growth of tissue is not impeded.
Graft infection is a most serious complication and occurs in an average of two percent of prostheticgraft placements. It is associated with a high risk of limb loss and patient mortality is as high as 75% depending on the location of the graft. While infection usually becomes evident soon after surgery, the time maybe 30 extended which leads to more serious consequences.
An absorbable collagen reinforced graft is proposed in United States Patent No. 3,272,204 wherein the collagen is obtained from the deep flexortendon of cattle. Another reinforced vascular prosthesis is described in United States Patent No. 3,479,670 which includes an open mesh cylindrical tube wrapped by an outer helical wrapping of fused polypropylene mono-filiment filled with collagen fibrils which are claimed to 35 renderthe prosthesis impermeable to bacteria and fluids. The collagen fibrils utilized are the same as described in Patent No. 3,272,204.
The synthetic vascular grafts suggested bythe prior art are claimed to be suitablefor many applications.
However, it is desirable to provide a flexible vasculargraft having zero porosity, onewhich is receptiveto ingrowth of hosttissue and serves as a reservoirfor drug materialsto be released slowlyfrom the surface of 40 the graftfollowing implant.
Summaryof theinvention
Acollagen coated synthetic vascular graftwhich provides a reservoirforthe slow release of a drug material after implant is provided. The collagen fibrils in the coating are complexed with a drug material such as 45 antibacterial agents, antithrombic agents and antiviral agents to insure against graft infection.
The porous graftsubstrate may be a tubularvascular graftformed of a Dacron material and may bewoven or knit. The collagen source is an aqueousfibril dispersion of high purity including a plasticizer and is applied to the graftsubstrate by massageto cover at leastthe entire innersurface area to provide a flexible graftwith good hand. After repeated coating and drying applications, the collagen is cross-linked by exposureto 50 formaldehyde vapor.
Accordingly, it is an object of the invention to provide an improved synthetic vascular graft.
Anotherobject of the invention isto provide an improved collagen-coated synthetic vascular graft.
Afurtherobject of the invention isto provide an improved collagen-coated synthetic vascular graft wherein the collagen serves as a reservoirforthe slow release of a drug after implantation. 55 Still anotherobject of the invention isto provide an improved process for coating a synthetic vascular graft with collagen to renderthe graft blood-tight and serveas a reservoirforthe slow release of a drug after implantation.
Still other objects and advantages of the invention will in part be obvious and will in part be apparentfrom the specification. 60
The invention accordingly comprises the article possessing thefeatures, properties and the relation of elements and the several steps and the relation of one or more of such stepswith respectto each of the others,which are exemplified in thefollowing detailed disclosure, and the scope of the invention will be indicated in the claims.
2 2 Brief description of the drawing
For a fuller understanding of the invention, reference is had to the following description taken in connection with the accompanying drawing, in which:
Figure 1 is a partial cross-sectional view of a collagen-coated synthetic vascular graft in accordance with the invention; 5 Figure2 is a partial cross-sectional view of a branched tubular graft of the type illustrated in Figure 1; Figure 3 is a graph illustrating sustained release of tetracycline from a collagen slurry in rabbits; Figure 4 is a graph illustrating sustained release of tetracycline at different collagen gel concentrations; and Figure 5is a graph illustrating sustained release of tetracycline in a collagen gel at different concentrations 10 and dosage.
Description of the preferred embodiments
A synthetic vascular graft 10 constructed and arranged in accordancewith the invention isshown in Figure 1. Graft10 includes a tubular substrate portion 12which isformed of a biologically compatiblefilamentary 15 synthetic material, preferablya polyethyleneterephthalate, such as Dacron. Substrate 12 is a porous Dacron warp knitfabric having an innerand outer velour surface of thetype described in U.S. Patent 4,047,252. While tubular portion 12 isformed of Dacron, any biocompatiblefilimentary material may be used forthesubstrate provided itmay befabricated into a porous structure which will permittissue ingrowth and maintain an open lumen forflow of blood. 20 The innersurface of tubular portion 12 is coatedwith a collagen coating shown as 16. Collagen coating 16is formedfrom a series of at leastthree layers of applied collagen fibrils. Figure 2 shows a bifurcated collagen-coated graft20. Graft20 includes a maintubular portion 22 andtwo branches 24. Maintubular portion 22 and bifurcated portion - s 24 are formed from a Dacron knit substrate 26. The inner surface coating of substrate 26 is coated with a collagen coating 28 also formed of at leastthree layers of collagen fibrils. 25 Porous vascular graft substrates suitablefor use in accordance with the invention, preferably are produced from Dacron mu Iti-filiment yarns by knitting or weaving processes which are commonly used in manufacture of these products. Generally, the porosity of the Dacron substrate ranges from about 2,000 to 3,000 mi/min_CM2 (purified water at 120mm Hq). The inner coating of cross-linked collagen is applied by filling a tubularsubstrate with a slurry of collagen fibrils and plasticizer and massaging manually, removing the 30 excess and permitting the deposited dispersion to dry. Afterthe final application, the collagen coating is cross-linked by exposure to formaldehyde vapor, air dried and then vacuum dried to remove excess moisture and excess formaldehyde. The coated grafts in accordance with the invention have essentially zero porosity.
The following examples are setforth to illustrate the method of preparing purified collagen from bovine skin and coated grafts in accordance with the invention. The examples are setforth for purposes of 35 illustration and not intended in a limiting sense.
Example 1
Fresh calf skinswere mechanically stripped from young calves, fetuses or stillborns andwashed in a rotating vessel with cold running water until the waterwas observed to befreefrom surface dirt, blood 40 and/or tissues. The su bcutis was mechanically cleaned to remove contaminating tissues, such asfatand bloodvessels. Subsequently, the skins were cut in the longitudinal direction intostripsabout 12cmwideand were placed in awood orplasticvessel ascommonlyused inthe leather industry.
The skins were dehaired byusing aflusher solution of 1 M Ca(01-1)2for25 hours. Alternatively, the skin may bedehaired byrnechanical meansorbya combination of chemical and mechanical means. Followingthe 45 dehairing,the skins were cut into small size piecesabout 1 " x 1 " andwerewashed in coldwater.
Following washing, 120 Kg of the bovine skin was placed in a vessel having 260 Lwater, 2 L NaOH (50%) and 0.4 L H202 (35%). The componentswere mixed slowlyfor 12to 15 hours at4C and washed with an excess of tapwaterfor 30 minutesto provide partially purified skins. The partially purified skins were treated in a solution of 260 L water, 1.2 L NaOH (50%) and 1.4 Kg CaO for 5 minutes with slow mixing. This treatmentwas 50 continued twice dailyfor 25 days. Following this treatment, the solution was decanted and discarded and the skins were washed with an excess of tap waterfor 90 minutes under constant stirring.
The skins were acidified bytreatmentwith 14 kg HCI (35%) and 70 Lwaterwhile subjecting the skinsto vigorous stirring. The acid was allowed to penetrate the skins for about 6 hours. Following acidification, the skins were washed in an excess of tap waterfor about 4 hours or until a pH of 5.0 was reached. The pH of the 55 skins was readjusted to 13-3.4 using acetic acid with a 0.5% preservative. The purified skin was then passed through a meat grinder and extruded under pressure through a series of filter sieves of constantly decreasing mesh size. The final product was a white homogeneous smooth paste of pure bovine skin-derived collagen.
In orderto impart adequate pliability to the grafts in the dry state, plasticizers are added to the collagen slurry before application. Suitable plasticizers include glycerine, sorbitol or other biologically acceptable 60 plasticizers. In a collagen,s] u rry containing between about 0.5 to 5.0 percent collagen by weight,the plasticizer is present in an amount between about 4 and 12 weight percent.
Among the most important properties obtained when coating a synthetic vascular graft with collagen fibrils in accordance with the invention is reduction of porosity of the porous substrate to about zero.The porosity of twenty randomly selected uncoated Microvel Dacron synthetic vascular grafts have a mean 65 3 GB 2 187 192 A 3 porosityto purifiedwaterof 1796 mi/min_CM2 at 120 mm Hg with a standard deviation of 130. Afterapplying several collagen coatings, the porosity is reduced to zero. The following example illustratesthe method of coating the graftsubstrate.
Example2 5
A 50 ccsyringe is filled with an aqueousslurryof 2%purified bovine skin collagen prepared inaccordance with Example 1. The collagen slurry includes 8% glycerol, 17% ethanol and the remainder water and a viscosity of 30,000 cps. The syringe is placed intooneendof a MeadoxIVIedical Microvel Dacron graft8mm in diameter by approximately 12cm in length. The slurry is injected into the lumen of the Microvel graftandit ismassaged manuallyin order to cover the entire inner surface area with the collagen slurry. Any excess 10 collagen slurry is removed through oneoftheopen ends. The graft is permited to dry for about 1/2 hourat room temperature. The coating and drying steps were repeated three more times.
Following the fourth coating application, the collagen coating was crosslinked byexposureto formaldehyde vaporfor 5 minutes. The cross-linked graft was then air dried for 15 minutes and then vacuum dried for 24 hours to remove moistureand any excess formaldehyde. 15 Example 3
Theblood-tightnessof a collagen-coated vascular graft prepared in accordance with Example 2 was tested as follows. A Microvel graft8mm X 12cmwasattachedtoa blood reservoirata pressureof 120mm Hgclue to the height of the reservoir. Heprin stabilized blood was passed through the graft and bloodcoilected 20 through the grafts was determined andexpressedin mi permin_CM2 The porosity over 5 runs was determinedto be 0.04,0.0,0.0,0.04 and 0.03. This represents a mean porosityofO.022 mi/min_CM2 whichwas considered zero, as the value is within the experimental error of the study.
In order to compare this result with the blood lossforuncoated M icrovel graft, the experiment was repeated using an uncoated graft. The mean porosity was 36 mi/min_CM2. 25 The antimicrobial activity of a collagen coated fabric graft prepared in accordance with the invention is demonstrated as follows.
Example4
The porosity of a collagen coated fabric graft is reduced to less than about 1 percent of an uncoated graft 30 afterthree coatings. A standard water porositytest used to measure water porosity of a graft is as follows. A column of water equivalent to 120 mm Hg pressure is allowed to flow through a one-half CM2 ofifice having a sample of graft overthe orifice for one minute. The amount of water collected was measured. The milliliters of water collected per minute per CM2 squared area was calculated. Several readings are taken for each sample. The porosity is reported as follows: 35 porosity = mi/min/cM2 The water porosity of a Microvel graftfabricwas about 1,900 milmin/cM2. The porosity aftercoating wasas follows:
Number of coatings Porosity 40 0 1,900 1 266 2 146 3 14 45 4 5 2.2 6 0 In each case the collagen coating was a bovine skin derived-plasticized slurry prepared in accordance with 50 the composition described in Example 2. Based on these results, it is preferable to provide a collagen coating of at leastthree orfour layers of fibrils, and most preferablyfour orfive layers with drying between each application and cross-] inking to fix the coating to the su bstrate.
In accordance with the invention, each layer of the collagen coating and at least the last two layers applied to a porous substrate are chemically modified to incorporate a drug or an antithrombic agent, such as heprin, 55 in orderto prevent infection and to inhibit clotting along the inner surface of the prosthesis. As noted,the collagen maybe complexed with a variety of drugs, such as antibacterial agents, antimicrobial agents or antifungal agents in order to prevent graft infection. Typical anti bacterial agents which maybe utilized include oxacillin, gentamicin, tetracycline, cephalosporin and the like which maybe complexed with the 6() collagen fibrils priorto application to the graft substrate. 60 In addition to reduced porosity, collagen coated vascular grafts in accordance with the invention exhibit reduced thrombogenicity compared to uncoated grafts.
65 4 GB 2 187 192 A 4 Example 5
Ahomogeneous slurryof bovine skin derived collagen prepared in accordancewith Example 1 was prepared containing 1% bovine skin derived collagen, 8% glycerol, 17% ethanol withthe remainderwater.
Ceclor,a cephalosporin antibiotic of Eli Lilly and Companywhich inhibitsthe growth of Staphylococus aureus and Escherichia coli, was blended into the slurry at a concentratin of 20 mg per mi. The collagen slurry 5 including the Ceclor was massaged coated onto a double velour Dacron fabric on both sides with 1/2 hour drying periods between coats. The coating resulted in the addition of 3.1 mg collagen per CM2.
As a control, Dacron double velourfabricwas also impregnated with the same collagen slurry omitting the Ceclor antibiotic. This control had a coating of 4.1 mg of collagen per CM2.
Both pieces of coated fabric were immersed for 1 minute in 4% formaldehyde, 10% glycerol solution, 10 vacuum desiccated for 64 hours and sterilized using gamma radiation.
The antimicrobial activity of the collagen coated Dacron vascular graftfabric, impregnated with Ceclor, was determined in an agar diffusion assay. Fabric swatches of 1 CM2 were placed on innoculated agar surfaces resulting in growth inhibition zones which indicated thatthe antibioticwas active against S. aureus (34 mm zone of inhibition) and E. coli (29 mm zone of inhibition). The untreated control collagen coated 15 vascular graftfabric did not exhibit any antimicrobial effect. The results are tabulated in the following Tables 1 and 11.
Table 1
20 Treated collagen coated fabric PLA TE 1 PLA TE2 PLA TE 3 X3 S.aureus 36mm 31 mm 35mm 34mm 25 E. colf 33mm 28mrn 27mm 29mm Table 11
30 Untreated collagen coated fabric PLA TE 1 PLA TE2 PLA TE 3 X3 35 S.aureus 0 0 0 0 E. coli 0 0 0 0 Example 6 40
A col 1 ag en si u rry prepa red i n accorda nce with Exa m p 1 e 1 co nta i n i n g 13.2% co 11 ag en protei n (determ i ned by its hyd roxypro 1 i ne co ntent) was m ixed i n a 1: 3 ratio with water (W) to form a 3.3 weig ht percent homogeneous col 1 ag en gel (G). The pH of the co 11 a gen gel was adj usted to 3.8 a n d 20rng of tetracycl i ne (TC) was added per m i 11 imeter of gel. 1 m mediately before i njectio n into two ra bbits, the col lag en g el-tetracycl i n e corn plex was mixed with g 1 utaral dehyde (0.3 m 1 of 3% g 1 uta ral dehyde per m 1 of the gel) and i njected th rou 9 h 45 18 gag e need les i nto the su bcutis. Two ra bbits as co ntrol s were i njected with a si m i la r dose of tetracycl ine and water, 20 m g TC/m 1 water/kg body weig ht.
1 n order to study the rate of tetracycl i ne rel eased f rom th e i nj ected site, bl ood was co 11 ected at various ti me intervals from the rabbit's ear vein. The content of TC i n the blood was measu red according to the procedure of Wilson, et a]. (Cl in. Chem. Acta., 36; 260,1972). The resu Its of th e TC a n a lysis i n the b 1 ood of the tota 1 of fou r 50 rabbits col lected withi n 2 ho u rs to 7 days post-i nj ection a re set forth i n Fig u re 3.
Figu re 3 sh ows that after i njection of TC i n water th e d rug reaches its maxi m u m i n the seru m withi n two hoursas shown byCurveA. At 11 hours the TC is no longer detectable. When tetracycline was administered in a collagen gel cross-linked with glutaraldehyde (1 OG + 30W), the level of serum TC remained stable for about 6 days as shown by Curve B. Thus, administration of TC in collagen gel prolonged the effective release 55 of the drug 25 times compared with injection in an aqueous medium only.
Example 7
The test described in Example 5was repeated using collagen gel attwo different concentrations forthe final injection. Additionally, the tetracycline contentwas 30 mg oxytetracycline (OTC)/m] gel/kg bodyweight 60 ata dose of 1 mi/kg of bodyweight, or50% more tetracycline perdosethan Example5. The results illustrated in Figure 4 show thatthe cpricentration of collagen in the gel affectsthe rate of OTC releasefrom thecollagen matrix.The denserthe collagen gel,the slower isthe release of the drug. Inthis Example,the kinetics ofthe OTC release was studied foratotal of 124 hours after injection of thetested complex in the subcutis of atotal of six rabbits. 1 65 GB 2 187 192 A 5 In Figure 4 Curve A shows that the OTC in water reaches its maximum in the serum shortly afterinjection and is notcletectable after 18 or20 hours. Curve B shows OTCserum concentration for OTC complexed with a collagen matrixata weight ratio of gel complexto water of 1:20 and Curve C at3:20. Release of the OTCis more rapidforthe less concentrated gel of Curve B. ExampleB
Collagen gel containing 3%collagen, measured as a dry substance, was mixed with tetracycline to form two concentrations, containing (A) 50mg TC/mi and (B) 10Orng TC/m] gel. After mixing with 0.3 mi of 3% glutaraldehyde (G1) per mi gel (G), complexAwas injected ata dosage of 2 m]/kg bodyweightand complex13 was injected ata dosageof 1 ml/kg. Plasma level concentrations of TC in mg/mi are shown in CurvesAand B 10 of Figure 5. ComplexAwasalso injected ata dosage of 1 mi/kg and is shown byCurve C in Figure 5.The actual plasma levelsof tetracycline duringthe period upto 5 days post- injection are shown in Figure5.
The data of Figure 5showthat both the actual concentration of tetracycline aswell as the surface geometry of the implant affects the level of magnitude of drug releasefrom the gel andthe level of tetracycline inthe plasma. 15 Rwill thus be seenthatthe objects setforth above, among those made apparent from the preceding description, are efficiently attained and, since certain changes may be made inthe article and in carrying out theabove processsetforth without departing from the spirit and scope of the invention, it is intendedthatall mattercontained in the above description and shown inthe accompanying drawings shall be interpreted as illustrative and not in a limiting sense. 20 It is also to be understood thatthe following claims are intended to coverall of the generic and specific features of the invention herein described and all statements of the scope of the invention which, as a matter of language, might be said to fall therebetween.
Particularly it isto be understood that in said claims, ingredients or compounds recited in the singularare intended to include compatible mixtures of such ingredients whereverthe sense permits. 25
Claims (1)
1. A slurry for forming a drug delivery blood-tig ht synthetic vascular graft comprising about 0.5 to 5.9 percent collagent fibrils complexed with at least an effective amount of a drug material, 4.0 to 12.0 percent 30 plasticizer and the balance water.
Printed for Her Majesty's Stationery Office by Croydon Printing Company (UK) Ltd,7187, D8991685.
Published by The Patent Office, 25Southampton Buildings, London WC2A l AY, from which copies maybe obtained.
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Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US57509184A | 1984-01-30 | 1984-01-30 |
Publications (3)
Publication Number | Publication Date |
---|---|
GB8708756D0 GB8708756D0 (en) | 1987-05-20 |
GB2187192A true GB2187192A (en) | 1987-09-03 |
GB2187192B GB2187192B (en) | 1988-12-14 |
Family
ID=24298898
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB08502156A Expired GB2153235B (en) | 1984-01-30 | 1985-01-29 | Drug delivery collagen-impregnated synthetic vascular graft |
GB08708756A Expired GB2187192B (en) | 1984-01-30 | 1987-04-13 | Drug delivery collagen slurry for synthetic vascular graft |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB08502156A Expired GB2153235B (en) | 1984-01-30 | 1985-01-29 | Drug delivery collagen-impregnated synthetic vascular graft |
Country Status (11)
Country | Link |
---|---|
JP (1) | JPH0636817B2 (en) |
AU (1) | AU575617B2 (en) |
BE (1) | BE901611A (en) |
CA (1) | CA1250235A (en) |
CH (1) | CH670380A5 (en) |
DE (1) | DE3503126C2 (en) |
FR (1) | FR2558720B1 (en) |
GB (2) | GB2153235B (en) |
IL (1) | IL74180A (en) |
NL (1) | NL193263C (en) |
SE (1) | SE464009B (en) |
Families Citing this family (28)
Publication number | Priority date | Publication date | Assignee | Title |
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US4699141A (en) * | 1986-01-16 | 1987-10-13 | Rhode Island Hospital | Neovascularization |
DE3608158A1 (en) * | 1986-03-12 | 1987-09-17 | Braun Melsungen Ag | VESSELED PROSTHESIS IMPREGNATED WITH CROSSLINED GELATINE AND METHOD FOR THE PRODUCTION THEREOF |
FI83729C (en) * | 1987-11-26 | 1991-08-26 | Biocon Oy | SURGICAL IMPLANTS. |
US6004346A (en) * | 1990-02-28 | 1999-12-21 | Medtronic, Inc. | Intralumenal drug eluting prosthesis |
US5545208A (en) * | 1990-02-28 | 1996-08-13 | Medtronic, Inc. | Intralumenal drug eluting prosthesis |
CA2049973C (en) * | 1990-02-28 | 2002-12-24 | Rodney G. Wolff | Intralumenal drug eluting prosthesis |
CS277367B6 (en) * | 1990-12-29 | 1993-01-13 | Krajicek Milan | Three-layered vascular prosthesis |
CA2074924A1 (en) * | 1991-08-05 | 1993-02-06 | Matthew E. Hermes | Method and composition for treating bioabsorbable surgical articles |
DE4222380A1 (en) * | 1992-07-08 | 1994-01-13 | Ernst Peter Prof Dr M Strecker | Endoprosthesis implantable percutaneously in a patient's body |
US6334872B1 (en) | 1994-02-18 | 2002-01-01 | Organogenesis Inc. | Method for treating diseased or damaged organs |
EP1364627B1 (en) * | 1994-02-18 | 2007-09-12 | Organogenesis Inc. | Method for producing a bioremodelable collagen graft prosthesis |
FR2722678B1 (en) * | 1994-07-25 | 1996-12-27 | Braun Celsa Sa B | PLUG-IN MEDICAL PROSTHESIS FOR USE IN THE TREATMENT OF ANEVRISMS, DEVICE COMPRISING SUCH A PROSTHESIS |
US5665114A (en) * | 1994-08-12 | 1997-09-09 | Meadox Medicals, Inc. | Tubular expanded polytetrafluoroethylene implantable prostheses |
US20020095218A1 (en) | 1996-03-12 | 2002-07-18 | Carr Robert M. | Tissue repair fabric |
DE19521642C2 (en) * | 1995-06-14 | 2000-11-09 | Aesculap Ag & Co Kg | Implant, its use in surgery and process for its manufacture |
US6177609B1 (en) * | 1997-03-10 | 2001-01-23 | Meadox Medicals, Inc. | Self-aggregating protein compositions and use as sealants |
SE514944C2 (en) * | 1997-12-30 | 2001-05-21 | Lars Sunnanvaeder | Apparatus for the therapeutic treatment of a blood vessel |
US6129757A (en) * | 1998-05-18 | 2000-10-10 | Scimed Life Systems | Implantable members for receiving therapeutically useful compositions |
EP1083843A4 (en) | 1998-06-05 | 2005-06-08 | Organogenesis Inc | Bioengineered vascular graft support prostheses |
US6369039B1 (en) | 1998-06-30 | 2002-04-09 | Scimed Life Sytems, Inc. | High efficiency local drug delivery |
US6797743B2 (en) | 2000-09-27 | 2004-09-28 | Michigan Biotechnology Institute | Antimicrobial polymer |
US6939554B2 (en) * | 2002-02-05 | 2005-09-06 | Michigan Biotechnology Institute | Antimicrobial polymer |
WO2003080730A1 (en) | 2002-03-20 | 2003-10-02 | Michigan Biotechnology Institute | Conductive polymer-based material |
US6951902B2 (en) | 2002-08-16 | 2005-10-04 | Michigan Biotechnology Institute | Two dimensional polymer that generates nitric oxide |
US6923996B2 (en) | 2003-05-06 | 2005-08-02 | Scimed Life Systems, Inc. | Processes for producing polymer coatings for release of therapeutic agent |
US7329531B2 (en) * | 2003-12-12 | 2008-02-12 | Scimed Life Systems, Inc. | Blood-tight implantable textile material and method of making |
JP4719133B2 (en) * | 2006-11-21 | 2011-07-06 | 株式会社東京機械製作所 | Frustration device |
DE102009037134A1 (en) | 2009-07-31 | 2011-02-03 | Aesculap Ag | Tubular implant for replacement of natural blood vessels |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
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DE1185332B (en) * | 1961-03-01 | 1965-01-14 | Ethicon Inc | Surgical prosthesis |
DE1491218C3 (en) * | 1963-06-15 | 1973-01-04 | Spofa Sdruzheni Podniku Pro Zdravotnickou Vyrobu, Prag | Blood vessel prosthesis and method for making the same |
US3272204A (en) * | 1965-09-22 | 1966-09-13 | Ethicon Inc | Absorbable collagen prosthetic implant with non-absorbable reinforcing strands |
US3479670A (en) * | 1966-10-19 | 1969-11-25 | Ethicon Inc | Tubular prosthetic implant having helical thermoplastic wrapping therearound |
DE1566358B2 (en) * | 1967-03-09 | 1977-04-21 | Meadox Medicals, Inc., Haiedon, NJ. (V.StA.) | VESSEL PROSTHESIS FOR SURGICAL PURPOSES |
DE1766340A1 (en) * | 1967-05-19 | 1971-07-01 | Vyzk Ustav Pletarzsky | Textile collagen prosthesis |
FR2029155A5 (en) * | 1969-01-15 | 1970-10-16 | Mo Med I | Prosthetic vessels of high biological - permeability |
US3688317A (en) * | 1970-08-25 | 1972-09-05 | Sutures Inc | Vascular prosthetic |
US3928653A (en) * | 1975-02-05 | 1975-12-23 | Tee Pak Inc | Collagen slurry containing partial fatty acid esters of glycerin |
DE2601289C3 (en) * | 1976-01-15 | 1978-07-13 | B. Braun Melsungen Ag, 3508 Melsungen | Method for sealing synthetic velor vascular prostheses |
DE2843963A1 (en) * | 1978-10-09 | 1980-04-24 | Merck Patent Gmbh | BODY-RESORBABLE SHAPED MATERIAL BASED ON COLLAGEN AND THEIR USE IN MEDICINE |
SU904693A1 (en) * | 1980-05-12 | 1982-02-15 | Первый Московский Ордена Ленина И Ордена Трудового Красного Знамени Медицинский Институт Им. И.М.Сеченова | Vessel prosthesis |
US4416028A (en) * | 1981-01-22 | 1983-11-22 | Ingvar Eriksson | Blood vessel prosthesis |
US4546500A (en) * | 1981-05-08 | 1985-10-15 | Massachusetts Institute Of Technology | Fabrication of living blood vessels and glandular tissues |
WO1983003536A1 (en) * | 1982-04-19 | 1983-10-27 | Massachusetts Inst Technology | A multilayer bioreplaceable blood vessel prosthesis |
-
1985
- 1985-01-28 IL IL74180A patent/IL74180A/en not_active IP Right Cessation
- 1985-01-29 FR FR858501219A patent/FR2558720B1/en not_active Expired
- 1985-01-29 NL NL8500239A patent/NL193263C/en not_active IP Right Cessation
- 1985-01-29 CA CA000473090A patent/CA1250235A/en not_active Expired
- 1985-01-29 GB GB08502156A patent/GB2153235B/en not_active Expired
- 1985-01-30 JP JP60014591A patent/JPH0636817B2/en not_active Expired - Lifetime
- 1985-01-30 BE BE0/214420A patent/BE901611A/en not_active IP Right Cessation
- 1985-01-30 AU AU38196/85A patent/AU575617B2/en not_active Ceased
- 1985-01-30 CH CH411/85A patent/CH670380A5/de not_active IP Right Cessation
- 1985-01-30 DE DE3503126A patent/DE3503126C2/en not_active Expired - Lifetime
- 1985-01-30 SE SE8500422A patent/SE464009B/en not_active IP Right Cessation
-
1987
- 1987-04-13 GB GB08708756A patent/GB2187192B/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
IL74180A (en) | 1992-06-21 |
SE8500422D0 (en) | 1985-01-30 |
CA1250235A (en) | 1989-02-21 |
DE3503126C2 (en) | 1996-05-15 |
AU575617B2 (en) | 1988-08-04 |
FR2558720B1 (en) | 1989-10-20 |
FR2558720A1 (en) | 1985-08-02 |
JPH0636817B2 (en) | 1994-05-18 |
CH670380A5 (en) | 1989-06-15 |
AU3819685A (en) | 1985-08-08 |
NL193263C (en) | 1999-05-06 |
SE464009B (en) | 1991-02-25 |
SE8500422L (en) | 1985-09-02 |
NL8500239A (en) | 1985-08-16 |
BE901611A (en) | 1985-05-17 |
NL193263B (en) | 1999-01-04 |
JPS6192672A (en) | 1986-05-10 |
GB2153235B (en) | 1988-12-14 |
IL74180A0 (en) | 1985-04-30 |
GB2187192B (en) | 1988-12-14 |
GB2153235A (en) | 1985-08-21 |
GB8502156D0 (en) | 1985-02-27 |
GB8708756D0 (en) | 1987-05-20 |
DE3503126A1 (en) | 1985-08-01 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PE20 | Patent expired after termination of 20 years |
Effective date: 20050128 |