DE3503127A1 - COLLAGEN-COVERED SYNTHETIC VESSEL REPLACEMENT - Google Patents

Description

Patent attorneys Dipl.-Ing. H. Weickmann, "Dipl.-Phys. Dk.K '. Fincke

Dipl.-Ing. R A.Weickmann, Dipl.-Chem. B. Huber Dr.-Ing. H. Liska, Dipl.-Phys. Dr. J. Prechtel

8000 MUNICH 86 3503127 POSTBOX 860 820

MDHLSTRASSE 22

TELEPHONE (0 89) 98 03 52

TELEX 522 621

TELEGRAM PATF.NTWniCKMANN MUNICH

MEADOX MEDICALS, INC.
103 Bauer Drive
Oakland, New Jersey 07436
United States

Collagen-coated synthetic vascular substitute

The invention relates to a synthetic vascular substitute, and in particular to a synthetic vascular substitute a series of plasticized collagen fibril layers, which make the vascular substitute blood-tight without pre-clotting. 05

The replacement of parts of human blood vessels with a synthetic vascular substitute is widely used. Synthetic vascular grafts can have a variety of configurations and made from a variety of materials be constructed. Among the successfully used vascular grafts are those derived from a biological Compatible material can be formed that has an open lumen so that blood can be replaced by synthetic material can flow after implantation. The substitute can be made from biologically compatible fibers such as Dacron and Teflon, it can be knitted or woven and can be made from a single-fiber yarn,

- / - • (οι fibrous yarn or a staple yarn are formed.

An important factor in choosing a particular carrier for vascular replacement is the porosity of the tissue wall, from which the replacement is formed. The porosity is important because it has a tendency to bleed during and Post-implantation regulates and tissue ingrowth into the wall of the replacement. It is desirable that the wearer of the vascular graft is sufficiently blood-tight to prevent blood loss during implantation, but the structure must be sufficiently porous to allow fibroblast and smooth muscle cell ingrowth to allow the replacement to connect to the host tissue. Synthetic vascular grafts of the type shown in US patents No. 3,805,301 and 4,047,252 of the assignee of the present application, consists of elongated flexible tubular bodies formed from a yarn such as dacron. In the earlier one The patent is the replacement of a warp-knitted tube and in the later granted patent it is a synthetic double velor replacement, which is sold under the trademark Microvel. These types of vascular substitutes possess sufficient porous structures to allow host tissue ingrowth. The general procedure of im- plantation includes the stage of pre-clotting, with the replacement being immersed in the patient's blood and remains therein for a period of time sufficient for clotting. After the pre-clotting occurs no bleeding when the replacement is implanted and tissue growth is not hindered. But it is desirable Avoid pre-curdling because it takes up valuable time during the procedure.

In U.S. Patent No. 3,272,204 a blood-tight absorbable collagen fortified replacement is suggested. the The type of collagen described is obtained from the deep flexion

tendons obtained from cattle. Tendon-derived collagen is generally highly crosslinked and difficult processed by the enzyme degradation described in the patent. Another reinforced vascular prosthesis is shown in the US patent No. 3,479,670, which describes an open mesh cylindrical tube formed with a helical outer sheath is provided, which consists of fused polypropylene monofibers, which are covered with collagen fibrils can be filled to make the prosthesis impermeable to bacteria and fluids. The collagen f Eyeglasses are the same as those described in Patent No. 3,272,204.

The synthetic vascular graft proposed in the prior art is said to be suitable for many applications. However, it remains desirable to provide a flexible vascular graft that has essentially none Has porosity, and yet remains sufficiently susceptible to host tissue ingrowth, and which is lighter can be processed as is known from the prior art.

The invention relates to a synthetic vascular substitute coated with collagen and having a tubular, porous structure Structure made from a biocompatible fibrous A material comprising a crosslinked coating of at least three layers of mixed with a plasticizer Has collagen fibrils that make the replacement blood-tight without pre-clotting. The porous substitute carrier (substrate) may be a tubular vascular substitute formed from a dacron material, and may be woven or knitted.

The collagen source is preferably bovine hide which has been processed by acid digestion to form a fibril dispersion high purity. An aqueous purified collagen slurry that contains a plasticizer,

is applied to the synthetic vascular graft by rubbing it in to cover the entire surface to result in a manageable, flexible replacement. After at least three repeated coating and drying stages the collagen is crosslinked by exposure to formaldehyde vapor. The substitute porosity is reduced to less than about 1% of the porosity of the replacement prior to coating.

^ q The object of the invention is therefore to provide a improved synthetic vascular substitute.

Another object of the invention is to provide an improved blood-tight synthetic vascular graft.

Another object of the invention is to provide an improved collagen-coated synthetic vascular graft.

Another object of the invention is to provide an improved collagen coating made from cowhide.

Another object of the invention is to provide an improved method for making a collagen OC coated synthetic vascular substitute.

Another object of the invention is to provide an improved method of coating a synthetic vascular substitute with collagen to protect the blood vessels set to make blood-tight.

These objects are achieved with the objects and methods according to the patent claims.

ο, - Further tasks, subjects and advantages of Invention are in part obvious and obvious partly from the description.

The invention therefore includes the articles having the features, properties and association of elements, and the various stages and the ratio of one or more such stages with respect to each other, such as they are exemplified in the following detailed description; the scope of the invention will appear in the claims.

For a more complete understanding of the invention, reference is made to the following description in conjunction with the accompanying drawings Referred to drawings in which:

1 is a partial cross-section of a collagen-coated synthetic vascular graft according to FIG of the present invention;

FIG. 2 is a partial cross-sectional view of a branched tubular vasculature of the type illustrated in FIG. 1 Kind; and

Fig. 3 is a graph showing the reduction in porosity after a series of collagen coatings according to the invention.

Fig. 1 shows a constructed and arranged according to the invention synthetic vascular replacement 10. The vascular replacement 10 contains a tubular support part 12, which is made of a biologically compatible fibrous synthetic material is formed, preferably a polyethylene terephthalate, such as Dacron. Backing 12 is a porous warp knitted dacron fabric that has an inner and outer Has a velor surface of the type described in U.S. Patent 4,047,252. Although the tubular part 12 is made of Dacron any biocompatible fibrous material can be used for the carrier provided that that it can be processed into a porous structure

den that allows tissue ingrowth and maintains an open lumen for blood flow.

The tubular part 12 has on the inner surface a coating of collagen as shown in FIG. the Collagen coating 16 is made up of at least three layers of an aqueous dispersion of collagen fibrils and plasticizer formed, which were crosslinked by the action of formaldehyde vapor. Fig. 2 shows a bifurcated collagen coated vascular replacement 20. The replacement 20 includes a main tubular portion 22 and two branches 24. The main tubular portion 22 and the bifurcated portions 24 are formed from a Dacron knitting substrate 26 which has an inner surface coating of a collagen coating 28, which consists of at least three layers of collagen fibrils is formed.

Porous vascular replacement carriers which are suitable according to the invention are preferably produced from multifilament dacron yarns by knitting or weaving processes, as are generally used for the production of such products. In general, the porosity of the Dacron carrier ranges from approx. 2,000 to 3,000 ml / min-cm ² (purified water with 120 mm of mercury). The inner branched collagen coating is applied by filling a tubular support with a slurry of collagen and emollient and massaging in manually, removing the excess and allowing the settled dispersion to dry. After the final application, the collagen coating is crosslinked by exposure to formaldehyde vapor, air dried and then vacuum dried to remove excess moisture and excess formaldehyde. The coated vascular replacement of the present invention has essentially zero porosity.

The following examples illustrate the process for making purified collagen from bovine hide and coated vascular grafts according to the invention. The examples explain the invention in more detail without it but to limit it to that.

example 1

Fresh calf skins were obtained by mechanical skinning from IQ young calves, fetuses or stillborn babies and in a rotating vessel washed with cold running water until the water is free of surface dirt, blood and / or fabrics. The subcutaneous tissue (subcutis) was mechanically cleaned to remove contaminating tissue components, such as fat and blood vessels to remove. After that were the skins are cut longitudinally into strips approx. 12 cm wide and placed in a wooden or plastic container, as it is commonly used in the leather industry.

The skins were cleaned using a 1 M Ca (OH) n rinse solution Depilated for 25 hours. Alternatively, the skin can be by mechanical means or by a combination depilated by chemical and mechanical means.

After dehairing, the skins were cut into small pieces approximately 1 "1" (2.54 χ 2.54 cm) and cut into washed in cold water.

After washing, 120 kg of the bovine hide were placed in a vessel containing 260 liters of water, 2 liters of NaOH (50%) and 0.4 liters of H ₃ O ₂ (35%). The components were slowly mixed for 12 to 15 hours at 4 ^° C. and washed with an excess of tap water for 30 minutes to give partially cleaned skins. The partially Qc cleaned skins were treated in a solution of 260 liters of water, 1.2 liters of NaOH (50%) and 1.4 kg of CaO with slow mixing for 5 minutes. This treatment was twice a day

Continued for 25 days. After this treatment, the solution was decanted and discarded, and the skins in an excess of tap water for 90 minutes with constant stirring.

The skins were treated with 14 kg of HCl (35%) and 70 l of water treated, the skins being subjected to vigorous stirring * The acid was allowed to die Penetrate skins for about 6 hours. After acidification, the skins were placed in an excess of tap water Washed for about 4 hours until a pH of 5.0% was reached. The pH of the skins was restored adjusted to 3.3-3.4 using acetic acid containing 0.5% preservative. The cleaned Skin was then passed through a meat grinder and, under pressure, through a series of filter screens extruded with constantly decreasing mesh size. The end product was a white homogeneous uniform paste pure collagen from cowhide.

In order to impart adequate pliability to the vascular replacement when dry, a plasticizer such as e.g. Glycerin, sorbitol or other biologically acceptable plasticizers of an aqueous collagen slurry before it Application added. In a collagen slurry, which contains between about 0.5 to 5.0 wt .-% collagen, the plasticizer is in an amount between about 4 and 12 wt% present. Between approx. 10 and 25% ethanol can be present to accelerate the evaporation of the water.

The most important property obtained by using a synthetic vascular substitute with collagen coatings and plasticizer coated according to the invention, the reduction in porosity of the porous support is about zero. For comparison, the porosity has 20 randomly selected

uncoated synthetic Meadox Microvel vascular replacement materials have an average porosity to water of 1796 ml / min-cm ² at 120 mm mercury and a standard deviation of 130. After coating according to the invention, the porosity is reduced to zero. The following example shows the method of coating the vascular graft carrier according to the invention.

Example 2

A 50 ecm injection syringe is used with an aqueous Slurry of 2% purified bovine hide collagen, which was prepared according to Example 1, filled. The KoI sheet slurry contains 8% glycerine, 17% ethanol and the remainder water and a viscosity of 30,000 cps (30 Pa.s). The injection syringe is inserted into one end of a Meadox Medical Microvel Dacron vascular graft 8 mm in diameter and inserted approx. 12 cm in length. The slurry is poured into the Lumen of the Microvel replacement is injected and manually massaged to cover the entire inner surface with the collagen to cover slurry. Excess collagen slurry is removed through one of the open ends. The replacement is allowed to dry for approximately 1/2 hour at room temperature. The coating and drying stages are then repeated three times.

After the fourth application of the coating, the collagen layer became by bringing it into contact with formaldehyde gO for 5 minutes steam networked. The crosslinked vascular set was then air dried for 15 minutes, then for 24 hours dried in vacuo to remove moisture and excess formaldehyde.

-VX-
Y Example 3

The blood tightness of a collagen-coated vascular replacement produced according to Example 2 was tested as follows: A Microvel vascular replacement of 8 mm × 12 cm was connected to a blood reservoir and a pressure of 120 mm of mercury, which corresponded to the height of the reservoir. Blood stabilized with heparin was passed through the vascular substitute. The blood collected by the replacement, Q, was determined and expressed in ml / min-cm ² . The porosity of five passes was determined to be 0.04, 0.0, 0.0, 0.04, and 0.03. This corresponds to an average porosity of 0.022 ml / min-cm ² , which is regarded as zero because the value is within the experimental error limit.

In order to compare this result with the blood loss at uncoated Microvel, the experiment was repeated using an uncoated substitute material. The mean porosity was 36 ml / min-cm ² .

Example 4

As shown below, the porosity of a “p. collagen-coated replacement material reduced to less than approx. 1% after three coats. A standard water porosity test used to measure the water porosity of a vascular set is as follows. A water column, corresponding to a pressure of 120 ml _ ₀ mercury is, by a half cm ² large orifice having a sample of the replacement above the opening, one minute flowed through. The amount of water collected was measured. There were the ml of water ^{collected per minute per cm 2} _p. were calculated. Several readings were taken for each sample. The porosity is given as follows:

Porosity = ml / min / cm ²

The water porosity of a Microvel replacement material was approx. 1,900 ml / min / cm ² . The post-coating porosity was as follows.

Number of coatings porosity

0 1,900

1 . 266

2 146

3 14

4 5

5 2 6 0

In each case the collagen coating was made with a plasticized slurry obtained from bovine hide carried out according to the composition as described in Example 2 was prepared. These Results are given in the graph of FIG. 3. On this basis, it is preferred to have a collagen coating of at least three layers of fibril, and especially four or five layers, after each Application a drying takes place, and after the last layer a crosslinking to the coating on the substrate to fix.

In addition to decreased porosity, it shows collagen with coated vascular substitute according to the invention compared to uncoated replacement materials have a reduced tendency to thrombosis (thrombo-genicity). The following examples illustrate the significantly lower thrombogenicity of vascular grafts impregnated with collagen compared to Controls.

Example 5

The antithrombogenicity was determined in vitro according to the method by Imai and Nose (J. Biomed. Mater Res. j5, 165, 1972) determined. According to this procedure, a volume of 0.25 ml ACD blood (stabilized citric acid) with 25 μΐ 0.1 mixed in CaCl_ and into the inner surface of a Microvel vascular substitute, coated with collagen and produced according to Example 2, is given. The same volume

IQ was placed in an uncoated Microvel replacement as a control. The same geometry of the blood stain was observed after 5, 10 and 15 minutes. The clotting reaction was stopped by adding 5 ml of distilled water to the test samples. Striking differences were observed between the two tube replacements tested and the following semi-quantitative parameters were determined:

τβ- —r. uncoated

impregnated

Speed of penetration

the replacement matrix with blood fast slow

Thrombus formation in 5 min 0 ++

10 min + +++

15 _m in ++ ++++

A comparison of thrombus formation in the inner surface of the collagen-impregnated Microvel replacement and the Microvel replacement as a control was the following. In the replacement impregnated with collagen, after 5 min no fibrin clotting. At 15 minutes, clotting on the collagen-impregnated replacement was much less than that of the corresponding untreated substitute.

The surface of the Microvel replacement in contact with the blood drop was almost hydrophobic. It Took between approx. 10 and 15s before the blood penetrated the material of the Dacron-knitted substitute. It stands

in contrast to the substitute impregnated with collagen, in which the blood flows into the substitute matrix evenly and quickly penetrated.

No thrombosis residue was found on the collagen-coated replacement after 5 minutes. At the same time there was a thin but defined thrombus on the surface of the untreated Microvel control substitute. After 10 and 15 minutes the total volume was there Thrombus on the inner surface of the replacement is less in the collagen-coated replacement than in the Controls.

Based on the above observations under in vitro conditions, with no blood flow, the collagen-coated, knitted Microvel-Dacron replacement quickly soaked up with it Blood full without thrombus within 5 min. At that time, control showed substitute materials Thrombus formation. Thereafter, after 10 and 15 minutes, the amount of thrombus in the collagen-impregnated replacement was less than in the untreated Dacron control substitutes.

Example 6
25th

The tendency to thrombosis (thrombogenicity) of having collagen impregnated Microvel vascular graft was tested in vitro (dogs) as follows: A femoral artery bypass (AV) was applied to greyhounds under deep anesthesia. A 5 cm long prosthetic material was applied to both Provide ends with plastic conical tubes for better handling. This allowed an easier introduction of the test segments in the arterial bypass. After insertion, a clamp was slowly removed and that arterial end slowly released afterwards. The blood flow circulated through the implant for 10 minutes or 30 minutes.

Then both ends of the shunt were clamped off again and the inserted prosthesis removed. The excess on Blood was aspirated and the weight determined. The presence of adhering to the surface of the substitute Thrombus was observed macroscopically. The jar set was then washed with excess distilled water (three times) and weighed again.

A standard 6 mm diameter Microvel Dacron replacement was used as a control. This replacement was made before the Introduction to the shunt subjected to pre-clotting. This test therefore provided both a visual one as well as objective gravimetric detection of thrombogenicity on the tested surface. The weight of the Blood oozing through the wall of the vascular substitute was also determined to be the difference between the Specify the samples tested.

Collagen-coated replacements were not at all Bleeding noted.

After introduction of a pre-clotted control set In the AV shunt, an average of 30 ml of blood / 5 cm replacement was lost in the first 5 minutes.

Only 3 to 5 ml of blood was lost over the next 5 minutes. In one of the control substitute materials tested, the Was tested for 30 minutes, there was minimal bleeding of 1 ml / min / 5 cm through the with throughout the rest of the test a pre-clotting treated replacement.

The replacement impregnated with collagen, which lasts 10 or 30 min was implanted for a long time showed the same resistance behavior to a macroscopically observed thrombus formation. A thin smooth layer of shiny protein material covers the collagen layer. After repeated Washing in distilled water will work in most

A continuous film of protein (fibrin) is observed in the prosthesis. Typical clotting was seen in the prosthetic sample not observed.

Of the five pre-clotted uncoated Dacron replacement implants tested, three showed distinct multiple thromboses. These were transverse to the direction of blood flow over 1/3 to 1/2 of the circumference localized. In the other two prostheses, a similar layer of protein skin covered the inner surface. the The outer surface of each control substitute contained large thromboses due to continuous bleeding through the wall.

Based on these observations, the thrombogenicity of Dacron vascular sets impregnated with collagen was significant lower than in the case of the pre-coagulated controller sets. This could either be reduced by a Thrombosis may be caused due to the collagen coating, or due to the in the controller sets because of the Need for pre-coagulation formed thrombus. Since blood clotting is a process that occurs when there is excessive Cell reaction occurs with the fibrotic replacement, it is beneficial to prevent the thrombus formation within the matrix of the Dacron substitutes decrease, resulting in a lower one Risk of embolism.

By applying at least three according to the invention Layers of collagen fibrils and plasticizer on a synthetic porous vascular graft substrate are specified Desired improvements are obtained when the replacement is surgically used as a vascular replacement in a human patient is used. These expected benefits include the need for pre-clotting is not required, but is not limited to.

Conventional porous substitute materials, although proven for long-term patency, require

the replacement of a pre-clotting with the patient's blood to avoid excessive blood loss at the time to prevent implantation. Typically, the pre-clotting stage is a time consuming step requires some practice and skill. That is why it was a primary function of the collagen coating that Eliminate the need for pre-clotting in synthetic substitutes.

Place the porous synthetic vascular graft substrates provide an ideal matrix for tissue ingrowth and eliminate the need for pre-clotting. Additionally this also reduces the significantly lower thrombogenicity of synthetic vascular substitutes impregnated with collagen the risk of embolism. The coating according to the invention of a synthetic vascular graft containing a slurry of collagen and plasticizer in a series of coatings also provides a vascular replacement that remains flexible and easy to handle.

Where components or compounds in the description or claims are given in the singular, refer to Such statements also assume that they also include mixtures of such constituents, provided that they are with one another are compatible.

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Claims (17)

Patent attorneys Dipl.-Ing. H. Weickmann ", Dipl.-FhYs. Dk. K. Fincke Dipl.-Ing.FAWeickmann, Dipl.-Chem. B. Huber Dr.-Ing.H. Liska, Dipl.-Phys. Dr. J. Prechtel 8000 MUNICH 86 g Q Jan. 1985. ". ·, POST BOX 860 820 ■ ■ J j 'MOHLSTRASSE 22 - TELEPHONE (0 89) 98 03 52 TELEX 522621 TELEGRAM PATENTWF.ICKMANN MUNICH MEADOX MEDICALS, INC. Bauer Drive Oakland, New Jersey 07436 USA Collagen-Coated Synthetic Vascular Replacement Claims 1. Synthetic vascular substitute containing: a tubular flexible porous pad for replacement, this pad on at least the inner Surface has a cross-linked coating of at least three layers of collagen fibrils, mixed with an effective amount of a plasticizer to make the replacement blood-tight and flexible. 2. vessel replacement according to claim 1, characterized in that that the porous support is polyethylene terephthalate. v, 3. vascular replacement according to claim 2, characterized in that that the porous substrate is knitted. 15th 4. vessel replacement according to claim 2, characterized in that the porous substrate is woven. 5. vascular replacement according to claim 1, characterized in that the inner and the outer surface of the carrier have a velor surface. 6. vascular replacement according to claim 1 _f, characterized in that that the collagen fibrils by the action of formaldehyde vapor are networked. 7. vessel replacement according to claim 1, characterized in that that the plasticizer is a biocompatible material containing multiple hydroxyl groups. 8. vascular replacement according to claim 7, characterized in that the plasticizer is sorbitol. 9. vascular replacement according to claim 7, characterized in that the plasticizer is glycerol. 10. vascular replacement according to claim 1, characterized in that that the coating layers are formed by a deposited aqueous slurry that is between approx. Contains 0.5 and 5.0% by weight collagen fibrils and between about 4 and 12% by weight plasticizers. 11. Vascular replacement according to claim 1, characterized in that the collagen fibrils are derived from bovine skin. 12. A vessel replacement according to claim 1, characterized in that both inner and outer surfaces of the Replacement are coated. 13. Process for the production of a blood-tight, collagen-coated synthetic vascular substitute, identified characterized by: Providing a porous tubular flexible synthetic supports for vascular replacement; Applying an aqueous slurry of collagen fibrils and plasticizers on at least the inner surface of the support; Massaging the carrier to ensure intimate mixing of the collagen fibrils into the porous structure of the carrier;
Drying the collagen; Applying a second layer of collagen and plasticizer slurry to the first layer of the Carrier and drying; Applying a third layer of collagen and plasticizer slurry to the support and drying; Cross-linking of the collagen coating through the action of formaldehyde vapor; and Vacuum drying to remove excess formaldehyde. 14. Slurry of collagen fibrils to form a blood-tight synthetic vascular substitute containing approx. 0.5 to 5.0% by weight of fibrils, 4.0 to 12.0% by weight a biologically compatible plasticizer and the remainder water. 15. Slurry according to claim 14, characterized in that that the collagen fibrils by acid digestion of bovine hide can be obtained. 16 · Slurry according to claim 14, characterized in that that the plasticizer is selected from the group consisting of sorbitol and glycerin. 17. Synthetic vascular replacement containing: gg a tubular flexible porous polyethylene terephthalate carrier, the inner surface of which is a coating of at least five layers of soft- macher has intermingled cross-linked collagen fibrils, and the layers of an aqueous slurry containing between about 1.5 to 4.0 weight percent collagen fibrils and containing between 6 and 10% by weight plasticizer.