JPS6192672A - Drug compounded collagen coated synthetic blood vessel implant tissue - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION (a) Industrial Application Field This invention relates to synthetic vascular grafts, and more particularly to drug-delivery, blood-sealing, collagen-coated synthetic vascular grafts, which do not require pre-coagulation and are easy to implant. It later acts as a reservoir for sustained dissociation of Drug 1 material.

(b) Prior Art It is well accepted in the art to replace segments of human blood vessels with synthetic vascular grafts. Synthetic vascular grafts 5& vary widely in shape and are constructed from a variety of materials. Accepted and successful 1f11f implants are constructed from biochemically compatible materials that maintain an open cavity that allows blood to flow through the synthetic graft after implantation.

The graft tissue can be made from biochemically compatible fibers such as Dacron and Teflon, may be knitted or woven, and may be of single, multifilament, or staple yarn.

An important factor in selecting a particular graft tissue matrix is the porosity of the fibrous walls that make up the graft. Porosity is important because it controls the tendency for bleeding during or after implantation and also controls the growth of tissue into the wall of the implant. The vascular graft tissue matrix provides sufficient blood sealing to prevent blood loss during transplantation, and the structure is sufficiently porous to permit ingrowth of fibroblasts and to attach the graft to the host tissue. Smooth muscle thinning is desirable. U.S. Patents 3,805,301 and 4,047,25
A synthetic vascular graft of the type described in 2 is Dacron.
It is a long sinterable tubular body made of thread.

In the former patent, the implant is a warp-woven tube, and in both patents, it is a double velor synthetic implant sold under the trademark A41 crovel.

These types of implants have a sufficiently porous structure to allow ingrowth of host tissue.

Common procedures for transplantation vessels include a precoagulation step in which the transplanted tissue is immersed in the patient's blood and allowed to survive for a sufficient period of time to ensure coagulation. After precoagulation, no bleeding occurs even when implantation occurs and tissue growth is unimpeded. Transplant tissue infection is the most dangerous sequela, occurring in an average of 2 percent of graft placements following prosthesis placement. It is associated with a high risk of limb loss, with patient mortality rates as high as 75% depending on the location of the implant. Infection traditionally becomes apparent shortly after surgery, but the time for more dangerous outcomes can be delayed. i
It was proposed in I patent 3,272,204, in which collagen is obtained from the deep flexor auricularis of domestic animals. Other patented vascular prostheses include U.S. Patent No. 3.479,6
70, which comprises an open-mesh cylindrical tube wrapped with an outer 9111 helical wrapping material of fused polypropylene filaments, which prevents the prosthesis from becoming resistant to bacteria and It is filled with collagen fibrils required to make it impermeable to adults. The collagen fibrils used were identical to those described in U.S. Pat. No. 3,272,204, and it is believed that the synthetic vascular grafts suggested by the prior art would be suitable for many applications. There is. However, it is desirable to provide a flexible vascular graft with zero porosity, which is susceptible to host tissue ingrowth, and which is a reservoir of drug material that slowly dissociates from the surface of the graft following implantation. It serves as a reservoir.

(C) SUMMARY OF THE INVENTION A collagen-crushed synthetic vascular graft is provided which provides a reservoir for the slow loading of drug material after implantation. The collagen fibrils in the coating are combined with pharmaceutical materials such as antibacterial, antithrombin, and antiviral agents to insure against implant infection.

The porous graft matrix may be a tubular vascular graft constructed from Dacron material and may be woven or knitted.

The collagen source is a highly purified aqueous fibril dispersion containing machinar wood and is applied to the graft matrix by pine surge to cover at least the entire inner surface area and thoroughly oT.
Offering a memorial plant @ moth. After repeated coating and drying, the collagen is cross-linked by exposure to formaldehyde vapor.

td) Problems to be Solved by the Investigation It is an object of the present invention to provide an improved synthetic plate transfer 1111 structure.

It is also an object of the present invention to provide an improved collagen-sheathed synthetic vascular graft.

It is an object of the present invention to provide a synthetic vascular graft coated with improved collagen in which Kolaken serves as a reservoir for the late 1F14 of the drug after +'4 implantation.

Yet another object of the invention is to coat synthetic vascular grafts with collagen. It is an object of the present invention to provide an improved procedure that renders the transplanted tissue non-hemorrheic and that serves as a slow release reservoir of drug after transplantation.

Still other objects and advantages of the present invention will be apparent from, and in part may be taken from, the specification.

(e) Means for solving the problem The invention therefore includes a number of features, characteristics and relationships of elements and the relationship of one or more such means to each other. , which are illustrated in the following detailed disclosure, with the scope of the invention being indicated in the claims.

A synthetic vascular graft 10 constructed and arranged in accordance with the present invention is shown in FIG. Implant 10 includes a tubular matrix portion 12 constructed from a biochemically compatible fibrous synthetic material, preferably polyethylene terephthalate such as p-Dacron. Substrate 12 is made of porous Dacron warp knitted fabric and has internal and external velor surfaces as described in U.S. Pat. No. 4,047,252; Any biocompatible fibrous material can be used for the matrix if it can be made into a porous structure that allows ingrowth and maintains an open cavity for blood flow. can.

The inner surface of the g-shaped portion 12 is coated with a collagen coating shown as 16. Collagen coating 16 is comprised of a series of at least three applied collagen fibrils. FIG. 2 shows a bifurcated collagen graft 20. The graft 20 includes a main tubular portion 22 and two branches 24 . The main tubular section 22 and the bifurcated section 24 are cut from Dacron's cracked substrate 26. The inner surface of the matrix 26 is coated with a collagen coat 28, which is also composed of at least three j's of collagen fibrils.

According to the present invention, a porous graft tissue base suitable for one-story use can be used.
are preferably made from 1) acrone multifilament yarns by the knitting or knitting process commonly used in the construction of these products. Generally, the porosity of Dacron-based wood is about 2,0f) 0 to 3,000 ml/min.
-cyrL2 (purified water at 1207++xHp)
within the range of Inside a cross-linked Koraken? The treatment is applied by filling the tubular matrix with a slurry of collagen and machiji agent, masturbating it by hand, removing the ultra-A surname, and draining the deposited juice. .

After final application, the collagen coating is cross-linked by exposure to formaldehyde, air dried, and then vacuum dried to remove excess moisture and excess formaldehyde. The 'graft tissue coated according to the present invention has essentially zero porosity.

(f) EXAMPLE The following example is set forth to illustrate the method of preparing purified collagen from maggot skin and coated implants according to the present invention. The examples are given for illustrative purposes and are not intended to be in a limiting sense.

;Ke111 Mechanically remove fresh cowhide from young calves, fetuses or stillborn calves and rinse under cold running water in a rotating container until the water is clear of surface dirt, blood and/or tissue. . The subcutaneous tissue is mechanically cleaned to remove contaminated tissue such as fat and blood vessels. Next, cut the skin lengthwise by about 12C.
Cut into 11L long strips, cut into 11T strips, and cut into 11T strips of wood or plastic, such as those customarily used for necks.
1α inside.

Peel the skin using a flusher solution of IMCa(OH), 2
Hair is removed for 5 hours. Alternatively, the skin may be dehaired by mechanical means or by a combination of chemical and mechanical means. Following hair removal, the skin is cut into small pieces approximately 1' x 1' and washed in cold water.

Following washing, 120 Kf of cowhide, 260 L of water,
2L NaOH (50%) and 0.4L Ht Ut
(35 inches). Ingredients are 40 and 12
Mix slowly for ~15 hours, wash with excess running water for 30 minutes, and serve with partially clarified peels. Partially purified skin was mixed with 26 OL of water and 1.2 L of NaOH (
50% ) &pi 1.4 Kt in a solution of CaO for 5 minutes at slow mixing speed. This process is done twice a day25
It continued for days. Following this treatment, the layer solution was decanted and discarded, and the skins were washed with excess tap water for 90 minutes with constant stirring.

The skin is soaked in 14 to 4 parts HCL (3 to 4 parts) while vigorously stirring.
5%) and 70 L of water. The acid was allowed to penetrate the skin for approximately 6 hours. The skin is acidified and then soaked in excess tap water for about 4 hours or -5.0
It was washed until The skins were reported to 3,3 to 3,4 using acetic acid containing 0.5% preservative.

The purified skins were then pressed through a grinder and through a series of filter sieves of constantly decreasing mesh size.

The final product was a white homogeneous smooth paste of collagen derived from pure cowhide.

A plasticizer is added to the collagen slurry prior to application in order to give the implant proper flexibility in the dry state. Suitable plasticizers are glycerin, sorbitol or 11!
! Contains biochemically acceptable plasticizers. Approximately 0.
In a collagen slurry containing 5 to 12 weight percent collagen, the plasticizer is present in an amount of about 4 and 12 weight percent.

Among the most important properties obtained when coating synthetic vascular grafts with collagen fibrils according to the present invention is the reduction of the porosity of the porous matrix to nearly zero. 20 randomly selected uncovered Microvel Dacs
The porosity of the ron synthetic vascular graft tissue is 120% with a standard deviation of 130%. 1796 ml/xmHr
m1n-an? The average porosity for purified water is determined. On the trowels with some collagen coatings applied, the porosity was reduced to zero. The following example illustrates a method of overturning a graft matrix.

Example 2 A 50 cc syringe is filled with an aqueous slurry of 2% purified calfskin collagen prepared according to Example 1. The collagen slurry contains 8 tiglycerol, 17% ethanol and balance water and has a viscosity of 30,000 cps. The syringe has a diameter of 8cm and a length of approximately 12c7rL.
eadox Medical MicrovellJa
It is placed into one end of the crotch graft. The slurry is injected into the cavity of ~1 iclobel of the graft and manually massaged to cover the entire inner surface area with the collagen slurry. Excess collagen coating 11- is removed through one of the open ends. The graft can be dried in a chamber width for about 1/2 hour. The coating and dry treatment were repeated three more times.

Following the fourth coating application, the collagen coating was cross-linked by exposure to formaldehyde vapor for 5 minutes. The photochromically bonded grafts were then air-dried for 15 minutes to remove moisture and excess formaldehyde, and then vacuum-dried for 24 hours.

The hemorrhea of the collagen-coated vascular graft prepared according to Example 2 was tested as follows.

Microvel graft 8mlX12cIIL was attached to the blood container at a pressure of 1zommHt due to the height of the container.

Heparin stabilized blood was passed through the graft and the blood collected through the graft was determined and expressed as rnl per m1n-12.

Porous FiO,04,0,0,0,more than 5runs
It was decided to use 0, 0, 04 and 0.03.

This showed an average porosity of 0.22 m7'/min-cm'', which was considered zero since mydriasis was within the actual and erect error of the study.

I will not resist this attack.
# To compare blood loss to 懺细熑, the experiment was repeated using uncovered grafts. The average porosity was 36 mi/min-ctrt''.

The bactericidal activity of collagen-coated knitted implants prepared according to the invention is explained as follows.

Side 14 The porosity of the collagen-coated knitted implant is reduced by 5 to about 1 percent less than the uncoated implant after three VL overlays. The standard water porosity test used to measure the water porosity of implants is as follows: A column of water equivalent to a pressure of 120 mu Hp is allowed to flow through the 1/2 orifice with a swatch of implant tissue past the orifice in 1 minute. The amount of water collected was measured. The total amount of water collected in one minute per α2 of the squared area is -
It was itchy. Separate readings were taken for each specimen. Porosity was reported as follows.

Pore 1'4 = mru/min/L: 1rL2
The water porosity of the Microvel graft knit is approximately 1,90
0mA! /min/crrt”.The porosity after coating was as follows.

Number of Coating Porosity Q 1,900 52.2 In each case the collagen coating was laid with a plastic slurry derived from cowhide prepared according to the composition mentioned in Example 2. Based on these results, it is desirable to provide a collagen coating of at least three or four layers of fibrils, most preferably with drying between each application and cross-linking to bond the coating to the substrate. It has 4 or 5 layers of collagen that stick together.

In accordance with the present invention, each layer of collagen coating applied to the porous matrix and at least the last two layers are chemically modified to prevent infection and to line the inner surface of the prosthesis.
Combined with drugs such as heparin or antithrombin agents to inhibit coagulation.

As noted, collagen can be complexed with various agents such as antiseptics, cocoonicidal agents, or antifungals to prevent infection of the implanted tissue. The anti-relaxation agents that can be used are oxanlin and gentami-7.

Including tetracyclines, cephalosporins, etc., which can be mixed with collagen fibrils or fibers prior to application to the graft matrix.

In addition to reduced porosity, implants coated with collagen according to the invention exhibit reduced thrombogenicity compared to uncoated implants.

? A homogeneous slurry derived from cowhide prepared according to 2.5.11 was prepared containing 1.5 hours of cowhide-derived collagen, 8.0 hours of glycerol, 17 hours of ethanol, and the balance water. ′@萄 1′ U1 AUN 7/(C5tap
hylococcus aureus) and aerogea suppressing infectious disease antibiotics (C
ephalosporin antibiotic)
Ceclor is 20 m9 per ml
(mixed into a slurry at a saturated level).

The collagen slurry containing Ceclor f was dried for 1/2 hour between crushing and then coated with double velor Dacro.
n coated with pine serge on both sides of the fabric.

The coating resulted in an addition of 3.1 m9/i.

As a control, a Dacron double velor fabric was also injected with the same collagen slurry except for the Ceclor antibiotic.

Both pieces of coated fabric were immersed for 1 minute in a solution of 40% formaldehyde, 10% glycerol, and
It was vacuum dried for an hour and sterilized using gamma radiation.

The bactericidal activity of Dacron vascular graft knits coated with Ceclor-infused collagen was determined using an agar diffusion assay.
) is determined within. A small piece of the IC1rL2 fabric was placed on an innocuous square surface to create a growth inhibition zone, which indicates that the antibiotic inhibits Staphylococcus aureus (34 H. inhibition zone). Vascular grafts coated with untreated control collagen showed no bactericidal effect. The results are shown in Table 1 and ■ below.

Table I S, aureus 36mm 31mm 35mm
34mlE, coli 33;xm 28mt
n 27mtn 29mm Table ■ S, aureus O000 14, coli OO00 Example 6 WJ prepared according to Example 1 containing 13.2% collagen protein (determined by hydroxyproline content)
Collagen gel 1j- was mixed with water in a ratio of 1:3 to make a 3.31 percent homogeneous collagen gel (G). Adjust the − of this collagen gel to 3.8,
Millimet 20 Da of Tetracycline (TC)
per er of gel. The collagen gel-tetracycline complex was mixed with gel taraldehyde (Q of gel taraldehyde, 3 ml per ml of gel) and injected into the subcutaneous tissue through an 18 gauge needle immediately before injection into two rabbits. did. Two rabbits as controls received tetracycline and water, 20 tnq TC/
A similar dose of ml water/Kf body weight was injected.

To study the percentage of tetracycline dissociated from the injected fetal position, blood was collected from the rabbit ear vein at various times. The content of TC in blood is Wilso
nOthers (Cl1n, Chem, Acta36;
260, 1972).

Post-injection within 2 hours to 7 days
The results of TC analysis of whole blood of four rabbits collected at post-injection are shown in FIG.

Figure 3 shows that after injection of TC in water, the drug reaches a maximum in the serum within 2 hours as shown by curve A. At 11 hours TC is no longer detectable. Tetracycline is geltaraldehyde (10G
+30W), serum TC levels remain stable for about 6 days as shown by curve B. Therefore, providing TC in a collagen gel prolonged the effective dissociation of the drug by 25 times compared to injection only in aqueous media.

The test described in column 1 7 1+lJ 5 was repeated using two different concentrations of collagen gel for the final injection.

Additionally, the content of the tetracycline is the Ir of the body Jx.
30m9 oxytetracycline at a dose of 9 to n1/:/
(OTC)/ml gel/Kf body weight or 50% more tetracycline per dose than Example 5.

The results shown in Figure 4 show that the collagen in the gel is 1,1
It has been shown that the degree of OTC dissociation from the collagenous RD stroma is influenced by the degree of OTC dissociation from the stroma. The thicker the collagen gel, the slower the drug will dissociate. In this example, the OTC
The kinetics of dissociation was studied for a total of 124 hours after injection of the tested compound into the subcutaneous tissue of six whole rabbits.

In Figure 4, curve A shows that OTC in water reaches a maximum in serum shortly after injection and is undetectable after 18 or 20 hours. Curve B shows OT complexed with collagen protein at a weight ratio of gel complex to water of 1:20.
Curve C is 3:2
0 is shown. The dissociation of OTC is faster with fewer gels in Curve B.

Example 8 A collagen gel containing 3% collagen measured on dry matter was mixed with tetracycline to produce (A) 50
'In9TC/d and (B) 100 mq TC/l
A concentration containing 1 of gel was made. rttl gel (G) 9
After mixing with 0.3 ml of 3% geltaraldehyde (Gl), compound A was injected at a dose of 2 Inl/Kf body weight and compound B'l! at a dose of 1 ml/-. : Injected. The plasma level concentration of TC in In9/ml is shown by curves A and B in FIG. Composite A
was also injected with a dose of 1 rat/Kg and is shown as curve C in Figure 5. The actual plasma levels during the period up to the 5th post-injection are shown in FIG.

The data in Figure 5 show that both the actual concentration of tetracycline as well as the external shape of the implant, shape, influence the level of magnitude of drug dissociation from the gel and the level of tetracycline in the plasma. There is.

It is therefore seen that the above-mentioned objects, among them those made clear from the foregoing description, are found to be effectively achieved, as set forth herein and without departing from the spirit and scope of the invention. All matter contained in the above description and shown in the accompanying drawings is to be interpreted as illustrative and not in a limiting sense, as changes may occur in the procedures described.

It goes without saying that the claims are intended to cover all general and specific features of the invention described herein and the full scope of the claimed invention contained therebetween as a matter of language. Nor.

In particular, references to components or compounds recited in the singular in the claims above are, of course, intended to include compatible mixtures of such components, wherever the meaning permits.

Examples of the present invention will be listed below for the sake of clarity.

(1) consisting of a tubular, flexible, porous graft matrix;
A synthetic vascular graft comprising a cross-linked coating of collagen fibrils at least on the inner wall of the tube.
l coating) d;, fp, surface camo The collagen fibrils are coated with a sufficient amount to render the implant non-bleeding and flexible and to cause sustained dissociation of the drug moieties in the composite after implantation. Compounding drugs and plasticizers (pla
Synthetic vascular graft tissue (2) characterized in that the drug portion in the composite is a mixture of a bactericidal agent (an
ti-microbial agents), antibacterial agents,
Anti-I! iI antifungal agents
), antithrombin agent (antithrombog-e
nic agents), cell proliferation promoters (cell
-proliferation promoting
agents) and mixtures of these drugs.
ical agent) (3) The inner and outer surfaces of the vascular graft tissue are collagen fibril A/
(4) The synthetic vascular graft tissue according to item 1 above, which is coated with a composite of collagen fibril-x lagen fibrils) and a drug. at least three layers formed by disposing an aqueous slurry of fibrils on the surface of the graft, the aqueous slurry being dried after each application to said surface and having a final (5) The synthetic vascular graft tissue according to item 1, wherein the porous graft tissue substrate is crosslinked after the coating layer is formed.
(6) The synthetic vascular graft tissue according to item 5, wherein the porous graft tissue substrate is woven (7) The porous graft tissue is a terephthalate. The synthetic vascular graft tissue (8) according to item 5, wherein the substrate is woven. The synthetic blood vessel according to item 1, wherein both the inner and outer surfaces of the graft tissue substrate are velor surfaces. Transplant tissue (9) Collagen fibrin (fibr)
(10) The synthetic vascular graft tissue according to item 1 above, wherein the synthetic vascular graft tissue (10) is formed by cross-linking by exposure to formaldehyde vapor. Compatible polyhydric
(11) The synthetic vascular graft tissue according to item 1, wherein the plasticizer is sorbitol (12) The synthetic vascular graft tissue according to item 1, wherein the plasticizer is glycerin. Synthetic vascular graft tissue (13) according to item 1 above: A method for producing a non-leakage, collagen-coated synthetic vascular graft tissue, the step of which is to prepare a porous, tubular, flexible synthetic vascular graft. providing a tissue substrate, having an aqueous slurry of collagen fibrils complexed with a drug on the surface of the transplant substrate, and disposing the collagen fibril complex within the porous tissue within the graft substrate; Massage the slurry to ensure a tight bond of the collagen, dry the collagen, and then cross-link the collagen coating by exposing it to formaldehyde vapor. 1 ink), and excess formaldehyde is removed by vacuum drying. After applying the slurry, repeat the process of rubbing the slurry in and then drying it at least three times on the edge 9.
(15) The method according to item 13, characterized in that the glaze is combined with at least a medicinally effective amount of collagen fibrils of about 0.5 to 5.9 t. , 4.0 to 12.0% plasticizer, and water for balance, a slurry for forming a non-leak synthetic vascular graft (16) tubular and flexible A synthetic vascular graft consisting of a porous terephthalate graft base, the inner tube surface of which is coated with at least five layers of cross-linked collagen fibrils compounded with a drug and mixed with a plasticizer. Yes, and at least 5 of the above
The two layers are made from an aqueous slurry containing about 1.5 to 40% by weight collagen fibrils and about 6 to 10% by weight plasticizer.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a partial cross-sectional view of a synthetic vascular graft coated with collagen in accordance with the present invention. FIG. 2 is a partial cross-sectional view of a bifurcated tubular implant of the type shown in FIG. FIG. 3 is a graph showing sustained dissociation of tetracycline from collagen slurry in rabbits. FIG. 4 is a graph showing sustained dissociation of tetracycline at different collagen gel concentrations/strengths. FIG. 5 is a graph showing sustained dissociation of tetracycline in collagen gels at different concentrations and doses. In the figure, 10... Synthetic vascular graft tissue 12... Tubular matrix portion 16... Collagen coating 20... Graft tissue 22... Main tubular portion 24... Bifurcated portion 26... Matrix 28 ...Collagen coating patent applicant: Medox Medicals F.
IG, / 2δ Flo, 2 Figure 3 U 1 Do j 4 0 Procedural amendment (voluntary) 1985 Ueba L51 Commissioner of the Japan Patent Office Manabu Shiga, Incident indication 1985 Patent summary No. 1qSq1 No. 2 , Name of the Invention: Synthetic Vascular Graft Tissue Made of Collagen-Coated Machine Medtux Medicals, Inc. 4, Full text of the agent's specification 7, Contents of the amendment The type-printed specification has been supplemented as shown in the attached sheet. Shine. (No R changes to the content) Procedural amendment (voluntary) Manabu Shiga, Commissioner of the Japan Patent Office, dated 2nd day of Alpha, 1985. Invention The name of the synthetic vascular graft tissue Medtux Medicals Inc., which has been formulated with collagen. and + for detailed description of the invention.
31.Claims: Tenip-shaped, 1" flexible porous graft matrix;
The synthetic vascular graft tissue is a synthetic vascular graft tissue, and there is a cross-linked cross-linked ridge of collagen fibrils on the wall surface of the tube P3, and the collagen fibrils do not leak through the transplanted tissue. Synthetic blood vessels made of a mixture of enough biological agents and plasticizers to make them blood-like and flexible, and to sustain and dissolve the part of the compound after transplantation. Transplant tissue Year 1985, month 15, number 1, type of procedural amendment written in clear #1, ill 'H#I@3 Ja@4' line ``Distribution M1mgtikJJt-``distribution non-bleeding''. (2) Same. Change “act” in line 7 to “it will act.” (3) Change “persistence” in line 13 to “maintain.” (4) Line S) I, third line, Line 12 and line @16 of “
"Prosthesis method" t - "Frothesis" (5) Section A) Line 1mj "Follow Jtr"Bridge" t81 1WI @ i The "non-blood leakage" in the i-da row is changed to "non-leakage". (9) "Element... has" and "relates to the element" in lines 3 to 3 of gJl. Ql The ``invention 2'' in the 9th true line ii is changed to ``crosslinking'' in the 1st wa line of development and @2/negative S line. σ3 In line 1o7a, i3, [water becomes J't-r water]. u41 "12" t-[12 in the 1st column is line
shall be. 1 wheel 17) l@, delete "ho" in the 7th line. [171! /ffJil, line 7, ltj, line 1J, and line 19 of r-listed materials. (IN!/ffTh! 9th line, 19th true 3rd line and λO 廄Je1 line's ``contrast'' is set as ``pair standard'') a!I '4iqg gth line and 73rd line 14111 fabric 2 r 翿alm thing". ■ The first/negative first line becomes "in the water Jt-r in the water." αυ The "extended" in the same 1st O line becomes "postponed." L27J 233+1 % in the row "Ryobanshi" is changed to "Both." T cover." Q4I In the 5th line, "Where permissible" is changed to "J when counting. CB @23 Negative number. From λ to line 73 “Tube...M
Correct "Kuru" as follows. 1. A tube-shaped, flexible, pore-dwelling graft tissue base.
A synthetic vascular graft, the graft comprising: At least 1. on the tube P3 side. There is a suspended body of collagen fibers, and the thigh collagen fibers make the transplanted tissue non-bleeding and flexible, and the drug part in the composite is continuously dissociated after transplantation. Synthetic blood vessel transplantation tissue area mother which has the advantage that it is a violet drug k (1 combined with plasticizer and all crystals combined) 26th negative 7th line, 8th line, near Sada line 7, @=g
The "collagen fibrils" in the qth row, the 7th row, the tlglzahakilwa row, the λq-th negative 3rd row, the 1st Q row, and the 16th row are referred to as "collagen fibrils." 0 Colo 75th line, H1, II line, first line of the 1st core page,
``Porous J'' of @ 2 Zaku @ 6th line and 29th 1% Wa line
tr porosity. Trouble: ``Porous'' in the first line of λg is changed to ``porous''. ■ Change "Arrangement" in line 7q to "Arrangement". C31J $, 2711m 12 lines 1/J r multivalent J
'k r Tasui ma J. Gll No. JJS! 5th line “Required in advance” t “
It is assumed that the process of pre-coagulation is necessary.Q tS negative @l1 line, 1g line and 20th line, ib
The "porosity" in the first and second rows of B is defined as "porosity". Figure 3 Procedural Amendment (Method) % Formula % 1. Indication of the case 1985 Metropolitan Police Permit II No. 1 Da, 1? / No. 2, Name of the invention: Synthetic vascular graft tissue using collagen transverse machine Medtux Medicals, Inc. 4, Agent 5, Date of amendment order: May 8, 1980

Claims (1)

[Claims] A tubular, flexible, porous graft matrix.
ft substituent), the graft tissue comprises a cross-linked coating of collagen fibrils, at least on the inner wall surface of the tube.
oating), and the collagen fibrils are complexed with a sufficient amount of the drug to render the implant non-bleedable and flexible and to sustain the dissociation of the drug moieties in the complex after implantation. Plasticizer
) A synthetic vascular graft tissue characterized by being a mixture of