CA1300022C - Heparin-containing adhesion prevention barrier and process - Google Patents
Heparin-containing adhesion prevention barrier and processInfo
- Publication number
- CA1300022C CA1300022C CA000548034A CA548034A CA1300022C CA 1300022 C CA1300022 C CA 1300022C CA 000548034 A CA000548034 A CA 000548034A CA 548034 A CA548034 A CA 548034A CA 1300022 C CA1300022 C CA 1300022C
- Authority
- CA
- Canada
- Prior art keywords
- heparin
- fabric
- absorbed
- adhesion
- regenerated cellulose
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
-
- 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
- A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
- A61L33/0005—Use of materials characterised by their function or physical properties
- A61L33/0011—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate
-
- 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
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/042—Polysaccharides
-
- 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
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/16—Biologically active materials, e.g. therapeutic substances
-
- 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
- A61L2300/23—Carbohydrates
- A61L2300/236—Glycosaminoglycans, e.g. heparin, hyaluronic acid, chondroitin
-
- 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
- A61L2300/424—Anti-adhesion agents
Abstract
Abstract An improved adhesion-preventative barrier fabric comprising an oxidized regenerated cellulose (ORC) fabric (or matrix having equivalent properties) which is drapable, conformable, adherent to body organs, and substantially absorbable within thirty (30) days in the body, which fabric has heparin absorbed thereon, said heparin being present in a non-toxic, adhesion-preventative, effective amount and potency and, the process of using said improved barrier fabric or matrix to administer heparin to prevent surgical adhesions.
J&J 1198
J&J 1198
Description
13~(1 22 HEPARIN-CONTAINING ADHESION PREVENTION BARRIER AND P~OCESS
Field of ~he Invention This invention relates to adhesion barrier materials useful in su~gery for preventing post operative adhesionz; and is more particul~rly concerned with a ma~rix which i8 drapable, conformable, adherent to body organs" substantially ahsorbable within thirty (3Q) days in the body, said matrix having an lo adhesion-preventa~ive amount of herparin incorporated therein, and is s~ill more particularly concerned, a~ a preferred version, with an absorbable matrix, such as a f~bric of oxidized regenerated cellulose (ORC) which i6 impregnated with an adhesion-preventative amount and potency of heparin, and to the process of ad~inistering heparin topically to an internal body organ by absorbing it on an ORC f~bric which i6 applied to the body organ during surgery.
Backqround of Invention Po~t operative adhe~ions represent a majo~ problem in patients recovering from surgery. When organs and tissues are subject to surgical and related trauma, there is a tendency for adhesions to form between the affected areas and neighboring tissue.
In the case of intestinal 6urgery, the lncidence of adhesions causing intestinal obstructions has been reported as app~oximately four times that due to 6trangulated hernia. The post operative formation or reformation of pelvir adhesions is reported to be a major factor contributing to the relatively poor results obtained in infertility surgery.
Various ~ethods h~ve been suggested for reduc;ng the incidence 3S of peritoneal adhesions following ~urgical inter~ention, but ~k J~J 1198 ~3~ 22 results have not been entirely favorable. One me~hod involves t~e application o~ chemical treating agents to the site of the ~urgical incision or abrasion in an effort to inhibit the physiological response responsible ~OL the for~ation of the S fibrous tissue which compri~e~ the adhesion mass. In this category are enzyme~ such as fibrinoly~in and papa~e, polyphloretinphosphate, oxyphenbutazone, a mixture of phenylbutazone and prednisolone, polyvinylpyrrolidone and dextran.
A second approach to preventing the formation of adhesions i~
to install a physical barrier material between the site of the surgical activ ty a~d the neighboring tissue where adhesions are most expected to occur. In thi~ category are ~ilicone sheets such as Silastic~, a medical grade 6ilicone elastomer available from Dow Corning, Gel~ilm*, an absorbable gelatin film available from Upjohn, and Surgicel~, a knit fabric of oxidized regenerated cellulose (ORC) available from Johnson &
Johnson Products, Inc.
The result obtained with the prior art materials and methods ~ave ~aried according to different investig~tors. In the case of oxidized cellulose, for example, very good results were reported by Lar~sen, Acta Chir Scand 144: pp. 37~-378 (1978) 2S and Raftery, Br. J. Surg. Vol. 67 pp. 57-58 ~19BO); negative results were obtained by Schroder, Acta Chir Scand 148 pp.
595-596 ~1982), Yemini, Int. J. Fertil 29 pp. 194-196 (1984) and Soule6,~ Am. J. Obstet & Gyn, Vol. 143 pp. 829-83~ (1982):
and mixed results were obtained by ~ishimura, Jpn. J. Surg.
~0 vol. 13 pp. 159-163 (1983~
In the copending Canadian patent application o~ Linsky and Cunningham, Serial No. 516,383-8, filed August 20, 1986, entitled "Me-~had and Material for Prevention o~ Surgical Adhesions", * Trade-mark J~J 1198 ~L30~22 a particular ~abric construction was disclosed resul~ing in an improv~d ad~e~ion barrier ~abric. Tha~
materia~ wa6 a ~abria of oxidiz~d regen~r~ted cellulo6e (ORC) charac~erized by having a poro6ity as defined by open area of 12 to 20 percent and a den~ity of ~ronl about ~ to 15 mg/cm2.
A typical abric i~ prepared from 60 clenier, lB ~ilament bright rayon yarn knitted on a 32 gauge 2 bar warp knitting machine.
The knit fabric is oxidized uaing conven~ional procedure6 a~
described for example in USP 3,364.200.
ORC Pabric6 construat2d in accordance wîth the invention of the a~ore~aid copendlng patent application have demonstrated 6uporior per~o~mance ~n reducing th~ incidence o~ pos~operati~e adhe~ion formation when compared to fabric6 of ORC previously a~a1lable.
The aboYe ~abric wa~ eSPective in reducing the incidence of postoperative adhes~ons wh~n positio~ed as a phy~ical barri~r between the site of the sury~cal acti~ity and neighboring ti~ue, but Purther improvement i~ ~till possible. Test re~ult~ using a preferred v~rsion of the above fabric, called TC-7, in adhesion reduction in a rabbit ut~rine ~orn model, established its ease of handling. It proved simple to apply, conformed well to the structure, adhered in place, and 6ubstantially absorbed within two weeks after ~urgery.
5ummar~ of ~he Invention We have now found unexpectedly that even greater improved resul~6 in reduci~g po6toperative adhesions are obtained when a drapable, conformable adhesion barrier Pabric constructed of a biore60rbable material~ such as the ORC kn;tted fabric di6clo6ed i~ the afore6aid copending~Canadian Patent ~pplication Serial No. 516,383-8 ~hereinaft~r ~led TC-7), or other matrix having similar propertie6, is impregnated with heparin. We J~J llg8 ~3(~ 2 have further found that such improved results occur when heparin is used to impregnate even the less effective ORC
barrier fabrics, such as Surgicel*. This is especially surprising since heparin alone, e.g., in lavage solution, is not effective to prevent adhesions. Heparin acts as an adhesion-preventing medicament when it i6 incorporaeed into the matrix of the present invention. A preferred embodiment of the matrix is ORC fabric. The haparin may be added to the matrix, e.g. ORC fabric. either before or during the surgery.
One advanta~e of adding the heparin to the barrier fabric is that the fabric absorbs and holds small quantities of heparin,so no excess amount of heparin is used which the body would have to absorb or eliminate. This allows much smaller amounts to be used, and is important when dealing with a potentially toxic substance. It ensures minimal heparin is spilled into or onto other organs or body cavities. By using the matrix or barrier fabric to deliver the heparin to the specific place in the body where the heparin is needed and especially intraperitoneally, the following important benefits are realized: localized delivery, smaller doses, maximum efficacy, minimum side effect, and reduction of lag time to build drug concentration.
The present in~ention includes both product and related process aspects. ID its product aspect, it involves: A matrix (as defined below) having an adhesion-preventative amount and potency of heparin incorporated therein; and also, an improved adhesion-preventative barrier Eabric comprising an oxidized regenerated cellulose fabric which is drapable, conformable, adherent to body organs, and substantially absorbable within thirty (30) days in the body, which fabric has heparin absorbed thereon, said heparin being present in a non-toxic, adhesion-preventative, effective amount and potency. Other matrices which could be used should ~ave properties equivalent to the * Trade-mark J~J 1198 , ,", j ~300022 oxidized eegenerated cellulo~e fabric. Among these are included, for illustrative and not exclu~ionary purpose6, material~ 6uch a6 hyaluronic acid, cros~-linked and uncross-linked collagen w~b6, ynthe~ic resorbable polymers, 5 gelatin films~ absorbable gel films, oxidized c~llulose fabri~s and the like, when fabricated into a form which i~ drapab}e, conformable, adherent to body organs, ~ubstan~ially absorbable within thirty (30) days in the body, capable of ab~orbing heparin, and 6afe for use in 6urgery.
In it6 proce~s a6pect6, the pre6ent invention involve6: The proce6s of preventing 6urgical adhesions which comprise6 positioning a6 a physical barrier, between the site of the surgical activity and neighboring ti66ue, a heparin-containing lS matrix, (as defined above) preferably in the form of an oxidized regenerated cellulose adhesion-peeventative barrier fabric; and the proces6 of admini~tering heparin topically to an internal body organ during 6urgery for the purpose of preventing surgical adhe~ions which compri6e~: applying an ~0 oxidized eegenerated cellulo~e fabric (or other matrix as defined above) containing heparin ab60rbed on it to the outer 6urface of an internal body organ, said fabric (or other matrix) being drapable, conformable, adberent to body organs, `~ and ~ub6tantially absorbable within thirty (30) days in the : 25 body. It al~o involves the proces~ of deliveeing heparin topically to a particular organ in the body by absorbing that drug on an ORC bareier fabric or ~imilar type of absorbable ~atrix, which is then applied to the outer surface of ~aid , oegan.
: 30 . Other Prior Art ' Heparin i~ normally administered i~travenously or subcu~aneou61y, not topically.
J&J 1198 ~300~2:2 In an article entitled ~Heparin Releasing Antiadhesive Membrane6~ by Y. Noi6hiki and T. ~iyata published in Jinko Zoki, 14~2), p. 7B8-791 (19~5), a collagen membrane (special treated human amnion) having protami~e cross-linked into the collagen network was immer~ed in ~% heparin ~olution 60 the heparin wa~ ionically bound to the protamine which had been cross-linked in the collagen. The resultant heparinized collagen membrane was stitched iDto place coveeing a wound on the sero~al membrane of the large inte~tines of dogs. The animal~ were examined a~ter 3 days, 60 days, 173 days and 687 days. No 6igns of adhesions were found. The collagen membrane wa6 not biodegradable, since much of it remained even after 6~7 days. The heparin was released slowly and steadily, 60 that 76% of the heparin originally pre6ent in the membrane was relea~ed over a period of three months.
Applicants' inYention differ6 from the above ar~icle in u~ing a biodegradable matrix or fabric a6 a carrier for heparin, the ORC fabric or other matrix being macroscopically broken down within thiety S30) days, (in the case of TC-7, most of it within 4 days); differs in not affixing the carrier ma~rix or ORC fabric with 6utures, but rather in u6ing a pliable, confor~able matrix or fabric which remains in place without need for sutures: differs in no~ exerting a systemic e~fec~ but only a local effect provided by the heparin ~oaked matrix or fabric of the present invention wherein all the heparin i6 relea~ed during the first we~k rather than 610wly and s~eadily over many months: and differs in that ~be heparin is not ionically bound to the carrier, but i6 only absorbed on the matrix or fabric.
Detailed De~cri~tion_of the Invencion The matrix useful in the present invention may be an ORC fabric or be made of any non-ORC material having the characteri~tic6 ., ~J 119~
, ~31~00Z2 described in connection with th~ ORC fabric below. Various useful matrices have been mentioned above, and cthers will be apparent to persons skilled in the art. The preferred matrix useful in the present invention is an oxidized regenerated cellulose (ORC) fabric which is drapable, conformable, adherent to body organs, and substantially absorbable within thirty (30) days in the body. The term "substantially absorbable within 30 days", means that macroscopically by gross observation ~here is no residual material remaining when the area of ~he body where the barrier fabric was placed is inspected at the time specified. Such a fabric is easy to apply and will stay in place on the organ without the use of sutures. It is biocompatible and resorbable.
The ORC fabric preferably is knit but could be fabricated in other forms, e.g., nonwoven, or woven, if desired.
Commercially available forms of ORC fabric include the following: Surgicel* and Surgicel Nu-Knit~ Adsorbable Hemostat which are described in the PDR (Physicians' Desk Reference), 1~86 edition. The TC-7 fabric previously identified aboYe is also knitted. It is currently being clinically tested.
For con~enience, the description of the present invention will ~ mainly refer to the most preferred embodi~ent, it being ; 25 understood that the other matrix materials, which are regarded as less preferred embodiments, would be used in a similar manner.
, Heparin (which term is intended to include salt forms, such as the calcium or sodium salt) is commercially available in different potencies, referred to as USP Heparin Units. The heparin potencies tested in the present in~ention range from 100 to 10,000 USP Heparin Units . We have found potencies of ; 100 to 2,000 units per six (6) square inches of fabric to be useful, with 500 to 1,500 being preferred. The TC-7 fabric J~J 1198 * Trade-mark ~3~13Z;2 soaked in a 601ution of lOO Heparin Units was better at preventing adhesions than the TC-7 fsbric alone, but the use of 500 USP Heparin Units or more i~ pre~Eerred with the fabric. No statistical difference wa6 een between TC-7 with 500 Heparin Units or lOOO USP Heparin Units. But lO,OOO USP Heparin Units was too poten~, since it'~ u6e on TC-7 fabric resulted in ~y~temic toxicity in the te~t animal~.
Heparin is preferably used in the same liquid form as would be u6ed for admini6tration by injection, e.g., as Heparin Sodium Injection. Use in this form easily provides the desired number of USP Heparin Units in sufficient liquid to be absorbed on the fabric. Typically l ml of Heparin Sodium Injection will wet and saturate or almost saturate a 2'ix3" piece of OCR fabric without running off or being vicible in the knitted fabric interstices.
~he heparin which i5 absorbed on the ORC fabric (or other matrix material) may be applied to the fabric in liquid form at the time of actual use on a body organ during surgery, i.e., the fabric is cut to the de6ired size and draped on and conformed to the body organ, and heparin is then applied, in a non-toxic, adhesion-preventative amount and potency, via syri~ge or pipette or the like to said fabric. The amount of heparin utilized normally should be ~ufficient to saturate the fabric but not 80 great that any heparin drips off or is spilled into or onto o~her organs or body cavities.
The heparin may al~ernatively be absorbed on the ORC fabric (or other matrix materials) and ~hen dried. The dried heparin-impregnated ~abric may then be applied to the body organ during ~urgery. Moi~ure from t~e body organ, or a solution (e.g. Ringer's, s~line cr wate~) can be applied to quickly rehydrate and return the heparin to a liquid form.
Using this alternative, the ORC fabric with heparin absorbed on J&J 1190 ~IL3~22 it, would be dried in any desired manner, e.g., air-dried, freeze-dried, oven-dried. vacuum-dried etc., after which it would be sealed in any desired type of sealable pouch or container customarily used to contain sterile surgical products S such as dressings, sutures, etc., and then sterilized. Mylar*
foil laminates may be used as the pouch material and radiation sterilization may be used to carry out this alternative. The heparin-impregnated barrier fabric (or matrix) can thus be made easily available for use in surgery in a variety of sizes.
Test Procedures Used The efficacy of various heparin-impregnated barrier fabrics of the present invention, as compared to otherwise identical lS non-heparin impregnated fabrics, was determined by the uterine horn scrape procedure as follows:
~ew Zealand Female White rabbits weighing between 2.0 and 3.5 kg are utilized. All animals are acclimated in the vivarium for at least two weeks prior to use. Rabbits are individually housed in stainless steel cages. They are fed Purina~ Lab rabbit chow (Ralston Purina Co., St. ~ouis) and given water ad libitum.
Animals are fasted overnight prior to surgery. Anesthesia is induced by an intramuscular injection of 1 ml of a Ketamine (Ketaset~)/Xylazine ~Rompun~) solution tl ml xylazine (20 mg/ml), 2 ml Ketamine ~100 mg/ml) and 1 ml sterile water~.
Additional anesthesia is administered via the marginal ear vein to maintain the animal on a surgical plane.
All animal surgery is done under aseptic conditions: this includes an iodine scrub, draping, and use of sterile technique. Laparotomy is made through a lower midline incision and the uterine horns are exposed.
J~J 1198 * Trad~-mark ~J
~301D022 --10-- , Five cm lengths of uterine horn starting 1 cm from the bifurcation are scraped using a #10 scalpel blade. The sc~ape, controlled in nature, fully removes the serosa and is characterized by engorgement of blood vessels and a small amount of punctate bleeding. Normally 20 strokes with the scalpel are sufficient to induce the described injury. In this model, hemostasis is achieved, when necessary, by tamponade.
The animals are treated by covering each horn with enough fabric so as to completely cover the in~ured area, i.e., the fabric is cut to a piece 2 inches by 3 inches in size. The appropriate dosage of heparin is then applied to the area by syringing and moistening the fabric with one ml of a heparin solution. The control animals have their horns left untreated, i.e., no fabric or heparin is used.
The musculo-peritoneal layer is closed with 4-0 Vicryl*suture (Ethicon, Somerville, NJ), the cutaneous layer with skin staples. Animals are then evaluated for adhesions two weeks after surgery. The evaluation is done via scoring which considers both the extent and severity of the adhesions.
The scoring system relies on the fact that an extensive length of uterine horn is traumatized: thus extent of adhesions can be quantified by measuring the length of the horn to give the following grading:
:` .
0 = ~o adhesions 1 = 25~ of traumatized area 2 = 50% of traumatized area 3 = Total involvement Fractional scores are given for extent of adhesions intermediate between the above grades. The severity (tenacity~
of the adhesions are measured as follows * Trade-mark J~J 1198 , .. .
~30~022 0 = No resistance to separation 0.5 = Some resistance (moderate force reguired) 1 = Sharp dissection needed The total ~rade thus is additive giving a range of adhesion scores of 0 - 4 wbich represents both extent and severity.
In the following examples, all the adhesion results listed were obtained by the above procedure, or by the above procedure iO without any heparin.
ExamPle 1: TC-7, With HeParin In Dried Form TC 7 fabric in 3x4 inch pieces was impregnated with Heparin Sodium Injection, USP. The heparin used was from Elkins Sinn (lot 065096-Exp. date 6/88) in a 10 ml vial at a concentration of 1000 USP units/ml. This solution was diluted ~:1 with sterile water for injection to give a concentration of 500 units~ml.
Two mls of the solution were pipetted on a 3x4 inch piece of fabric (TC 7) which sat in an XT polymer tray. These two mls completely saturated the fabric thus assuring uniform distribution. The wetted fabric was then allowed to sit overnight, during which time the solution flashed off leaving a dry, heparin impregnated fabric.
The dried heparin impregnated TC 7 fabric was then taken out of the tray and placed inside a Tyvek envelope (Grade 1013-B).
This was in turn placed inside a foil laminate envelope (Maraflex -0.5 gauge Mylar, 0.00135 foil) which was itself sealed. The packages were then sterilized via use of 2.5 Mrads Cobalt irradiation.
* Trade-mark J~J 1198 ~1~
~3~0ZZ
These dried impregnated fabrics were then tested in the rabbit uterine horn model. Each ~x4 inch piece was cu~ in half into two 2x~ inch pieces each piece was then applied ~o a scraped uterine horn of the rabbi~ T~erefore. each uterine horn was actually treated with 500 units of heparin. After applying each fabric so it was draped over and conformed to the uterine horn, ~he fabric wa~ wetted wieh a small amount o saline ~o enhance its tack to the u~erine horn tissue. When the rabbit was sa~rificed and the adhesion6 were evaluated two weeks later, the results were:
Untreated Controls HeParin I~Preqnated Fabric Right 4 2 Left 4 3 Right 4 o Lef~ 4 0 Right 4 0.5 Left 4 o o , 4 X = 0.67 3 animals 6 animals 6 horns 12 horns A~ can be ~een, the untreated controls all hava ~evere adhe6ion6 while mo6t of the animals with ~he above heparin-impregnated TC-7 fabri~ had no adhe6ion~, and a 6mall ~5 proportion had moderate adhesions.
J~ 119~
~3~002~
Examples 2-4: TC-7, With He~arin Added In Situ In Example6 2-4, the procedure of Example l was changed, 60 the heparin was added directly to the TC-7 fabric. In these Exa~ples, the TC-7 fabric (cut in a 2" x 3" size piece) was draped o~er and conformed to the ~terine horn. Then one millilitee (l ml) of the appropriate concentra~ion of heparin was pipetted onto the TC-7 fabric in situ~ ~hich saturated the fabric and made it adhere to the uterine horn. The concentration of heparin used wa~ 1000 USP units/ml starting concentration (lO00 USP unit6 actually applied to each uterine horn) foe Example 2; 500 U5P units/ml starting concentration (500 units actually applied) for Example 3; and lO0 USP
unit~/ml starting concentration (100 units actually applied) for Example 4.
The re6ults ob~ained are ~hown in the following table:
J~J 1}98 ~IL3~ 2 Example NosO 2 3 4 UntreatedHeparin ~ TC 7 Heparin ~ TC 7 Heparin ~ TC 7 Control 1000 Units son Units 100 Units g o 0 0 1 1.5 4 0.6 0 4 0 4 0 0 0.75 4 o 4 o 0~6 0 4 0 0 2 0 Z.5 4 0 0 0 0 0.5 4 0 0 0 0.2 0 4 1 1 1 3.5 0.5 ; 15 4 1 0.5 0 Z.5 o 3.5 0 0 0 2.5 1 0 1.5 20 _ _ _ _ X = 3.64 X = .48 X = .38 X = .76 7 animals 13 animals 6 animals 10 animal~
14 horns 26 horns 12 horns 20 horn~
U6ing the test re6ults obtained in the various examples, and also in other ~udie~, the ef~ect of varying the pote~cy of heparin tUSP units o~ Heparin units) used to impregnate the TC
7 fabric may be generally ~ummarized, ~or purpo~e~ of compari60n, as:
Control 3.3 TC 7 alone 1. a TC 7 ~ 100 Units ~parin 0.8 TC 7 ~ 500 Units Heparin 0.4 TC 7 ~ 1000 Unit6 Hep~Lin 0.4 TC 7 ~ 10,000 Unitfi Heparin Toxic J~J ll9B
~L30~
Example 5: Surqicel, With Heparin ~ddad In Situ Following the procedure of Example 2, but using Surgicel fabric in place of the TC-7 ~abric, i.e. a 2 inch by 3 inch piece of Surgicel fabric was draped on each uterine hsrn, ~and where : ~eparin was added, one ml. was applLed in a 1000 USP Heparin units/ml concentration). The Surgicel with heparin was compared to Surgicel used alone without heparin, and also ~o an untreated control uterine horn. The adhesion results (when the adhesions were evaluated two weeks later) are shown in the following table.
Surqicel ~1000 Units/Horn Heparin ~ Surgicel . Untreated Surgicel Alone 1000 Uni~s Control_ Control 1 4 3.0 ~0 0 4 3.0 0 4 4.0 0 4 ~.0 : . O ~.0 0 4.0 251.5 3.0 : 3.0 ~ .25 2.0 .~ 0 1.5 2.5 3.0 ; X 3 .2B X , 4 X . 3.1 5 Animals Z Animal~ 6 Animals ; 10 Horn~ ~ Borns 12 Horns : 35 J~J 1198
Field of ~he Invention This invention relates to adhesion barrier materials useful in su~gery for preventing post operative adhesionz; and is more particul~rly concerned with a ma~rix which i8 drapable, conformable, adherent to body organs" substantially ahsorbable within thirty (3Q) days in the body, said matrix having an lo adhesion-preventa~ive amount of herparin incorporated therein, and is s~ill more particularly concerned, a~ a preferred version, with an absorbable matrix, such as a f~bric of oxidized regenerated cellulose (ORC) which i6 impregnated with an adhesion-preventative amount and potency of heparin, and to the process of ad~inistering heparin topically to an internal body organ by absorbing it on an ORC f~bric which i6 applied to the body organ during surgery.
Backqround of Invention Po~t operative adhe~ions represent a majo~ problem in patients recovering from surgery. When organs and tissues are subject to surgical and related trauma, there is a tendency for adhesions to form between the affected areas and neighboring tissue.
In the case of intestinal 6urgery, the lncidence of adhesions causing intestinal obstructions has been reported as app~oximately four times that due to 6trangulated hernia. The post operative formation or reformation of pelvir adhesions is reported to be a major factor contributing to the relatively poor results obtained in infertility surgery.
Various ~ethods h~ve been suggested for reduc;ng the incidence 3S of peritoneal adhesions following ~urgical inter~ention, but ~k J~J 1198 ~3~ 22 results have not been entirely favorable. One me~hod involves t~e application o~ chemical treating agents to the site of the ~urgical incision or abrasion in an effort to inhibit the physiological response responsible ~OL the for~ation of the S fibrous tissue which compri~e~ the adhesion mass. In this category are enzyme~ such as fibrinoly~in and papa~e, polyphloretinphosphate, oxyphenbutazone, a mixture of phenylbutazone and prednisolone, polyvinylpyrrolidone and dextran.
A second approach to preventing the formation of adhesions i~
to install a physical barrier material between the site of the surgical activ ty a~d the neighboring tissue where adhesions are most expected to occur. In thi~ category are ~ilicone sheets such as Silastic~, a medical grade 6ilicone elastomer available from Dow Corning, Gel~ilm*, an absorbable gelatin film available from Upjohn, and Surgicel~, a knit fabric of oxidized regenerated cellulose (ORC) available from Johnson &
Johnson Products, Inc.
The result obtained with the prior art materials and methods ~ave ~aried according to different investig~tors. In the case of oxidized cellulose, for example, very good results were reported by Lar~sen, Acta Chir Scand 144: pp. 37~-378 (1978) 2S and Raftery, Br. J. Surg. Vol. 67 pp. 57-58 ~19BO); negative results were obtained by Schroder, Acta Chir Scand 148 pp.
595-596 ~1982), Yemini, Int. J. Fertil 29 pp. 194-196 (1984) and Soule6,~ Am. J. Obstet & Gyn, Vol. 143 pp. 829-83~ (1982):
and mixed results were obtained by ~ishimura, Jpn. J. Surg.
~0 vol. 13 pp. 159-163 (1983~
In the copending Canadian patent application o~ Linsky and Cunningham, Serial No. 516,383-8, filed August 20, 1986, entitled "Me-~had and Material for Prevention o~ Surgical Adhesions", * Trade-mark J~J 1198 ~L30~22 a particular ~abric construction was disclosed resul~ing in an improv~d ad~e~ion barrier ~abric. Tha~
materia~ wa6 a ~abria of oxidiz~d regen~r~ted cellulo6e (ORC) charac~erized by having a poro6ity as defined by open area of 12 to 20 percent and a den~ity of ~ronl about ~ to 15 mg/cm2.
A typical abric i~ prepared from 60 clenier, lB ~ilament bright rayon yarn knitted on a 32 gauge 2 bar warp knitting machine.
The knit fabric is oxidized uaing conven~ional procedure6 a~
described for example in USP 3,364.200.
ORC Pabric6 construat2d in accordance wîth the invention of the a~ore~aid copendlng patent application have demonstrated 6uporior per~o~mance ~n reducing th~ incidence o~ pos~operati~e adhe~ion formation when compared to fabric6 of ORC previously a~a1lable.
The aboYe ~abric wa~ eSPective in reducing the incidence of postoperative adhes~ons wh~n positio~ed as a phy~ical barri~r between the site of the sury~cal acti~ity and neighboring ti~ue, but Purther improvement i~ ~till possible. Test re~ult~ using a preferred v~rsion of the above fabric, called TC-7, in adhesion reduction in a rabbit ut~rine ~orn model, established its ease of handling. It proved simple to apply, conformed well to the structure, adhered in place, and 6ubstantially absorbed within two weeks after ~urgery.
5ummar~ of ~he Invention We have now found unexpectedly that even greater improved resul~6 in reduci~g po6toperative adhesions are obtained when a drapable, conformable adhesion barrier Pabric constructed of a biore60rbable material~ such as the ORC kn;tted fabric di6clo6ed i~ the afore6aid copending~Canadian Patent ~pplication Serial No. 516,383-8 ~hereinaft~r ~led TC-7), or other matrix having similar propertie6, is impregnated with heparin. We J~J llg8 ~3(~ 2 have further found that such improved results occur when heparin is used to impregnate even the less effective ORC
barrier fabrics, such as Surgicel*. This is especially surprising since heparin alone, e.g., in lavage solution, is not effective to prevent adhesions. Heparin acts as an adhesion-preventing medicament when it i6 incorporaeed into the matrix of the present invention. A preferred embodiment of the matrix is ORC fabric. The haparin may be added to the matrix, e.g. ORC fabric. either before or during the surgery.
One advanta~e of adding the heparin to the barrier fabric is that the fabric absorbs and holds small quantities of heparin,so no excess amount of heparin is used which the body would have to absorb or eliminate. This allows much smaller amounts to be used, and is important when dealing with a potentially toxic substance. It ensures minimal heparin is spilled into or onto other organs or body cavities. By using the matrix or barrier fabric to deliver the heparin to the specific place in the body where the heparin is needed and especially intraperitoneally, the following important benefits are realized: localized delivery, smaller doses, maximum efficacy, minimum side effect, and reduction of lag time to build drug concentration.
The present in~ention includes both product and related process aspects. ID its product aspect, it involves: A matrix (as defined below) having an adhesion-preventative amount and potency of heparin incorporated therein; and also, an improved adhesion-preventative barrier Eabric comprising an oxidized regenerated cellulose fabric which is drapable, conformable, adherent to body organs, and substantially absorbable within thirty (30) days in the body, which fabric has heparin absorbed thereon, said heparin being present in a non-toxic, adhesion-preventative, effective amount and potency. Other matrices which could be used should ~ave properties equivalent to the * Trade-mark J~J 1198 , ,", j ~300022 oxidized eegenerated cellulo~e fabric. Among these are included, for illustrative and not exclu~ionary purpose6, material~ 6uch a6 hyaluronic acid, cros~-linked and uncross-linked collagen w~b6, ynthe~ic resorbable polymers, 5 gelatin films~ absorbable gel films, oxidized c~llulose fabri~s and the like, when fabricated into a form which i~ drapab}e, conformable, adherent to body organs, ~ubstan~ially absorbable within thirty (30) days in the body, capable of ab~orbing heparin, and 6afe for use in 6urgery.
In it6 proce~s a6pect6, the pre6ent invention involve6: The proce6s of preventing 6urgical adhesions which comprise6 positioning a6 a physical barrier, between the site of the surgical activity and neighboring ti66ue, a heparin-containing lS matrix, (as defined above) preferably in the form of an oxidized regenerated cellulose adhesion-peeventative barrier fabric; and the proces6 of admini~tering heparin topically to an internal body organ during 6urgery for the purpose of preventing surgical adhe~ions which compri6e~: applying an ~0 oxidized eegenerated cellulo~e fabric (or other matrix as defined above) containing heparin ab60rbed on it to the outer 6urface of an internal body organ, said fabric (or other matrix) being drapable, conformable, adberent to body organs, `~ and ~ub6tantially absorbable within thirty (30) days in the : 25 body. It al~o involves the proces~ of deliveeing heparin topically to a particular organ in the body by absorbing that drug on an ORC bareier fabric or ~imilar type of absorbable ~atrix, which is then applied to the outer surface of ~aid , oegan.
: 30 . Other Prior Art ' Heparin i~ normally administered i~travenously or subcu~aneou61y, not topically.
J&J 1198 ~300~2:2 In an article entitled ~Heparin Releasing Antiadhesive Membrane6~ by Y. Noi6hiki and T. ~iyata published in Jinko Zoki, 14~2), p. 7B8-791 (19~5), a collagen membrane (special treated human amnion) having protami~e cross-linked into the collagen network was immer~ed in ~% heparin ~olution 60 the heparin wa~ ionically bound to the protamine which had been cross-linked in the collagen. The resultant heparinized collagen membrane was stitched iDto place coveeing a wound on the sero~al membrane of the large inte~tines of dogs. The animal~ were examined a~ter 3 days, 60 days, 173 days and 687 days. No 6igns of adhesions were found. The collagen membrane wa6 not biodegradable, since much of it remained even after 6~7 days. The heparin was released slowly and steadily, 60 that 76% of the heparin originally pre6ent in the membrane was relea~ed over a period of three months.
Applicants' inYention differ6 from the above ar~icle in u~ing a biodegradable matrix or fabric a6 a carrier for heparin, the ORC fabric or other matrix being macroscopically broken down within thiety S30) days, (in the case of TC-7, most of it within 4 days); differs in not affixing the carrier ma~rix or ORC fabric with 6utures, but rather in u6ing a pliable, confor~able matrix or fabric which remains in place without need for sutures: differs in no~ exerting a systemic e~fec~ but only a local effect provided by the heparin ~oaked matrix or fabric of the present invention wherein all the heparin i6 relea~ed during the first we~k rather than 610wly and s~eadily over many months: and differs in that ~be heparin is not ionically bound to the carrier, but i6 only absorbed on the matrix or fabric.
Detailed De~cri~tion_of the Invencion The matrix useful in the present invention may be an ORC fabric or be made of any non-ORC material having the characteri~tic6 ., ~J 119~
, ~31~00Z2 described in connection with th~ ORC fabric below. Various useful matrices have been mentioned above, and cthers will be apparent to persons skilled in the art. The preferred matrix useful in the present invention is an oxidized regenerated cellulose (ORC) fabric which is drapable, conformable, adherent to body organs, and substantially absorbable within thirty (30) days in the body. The term "substantially absorbable within 30 days", means that macroscopically by gross observation ~here is no residual material remaining when the area of ~he body where the barrier fabric was placed is inspected at the time specified. Such a fabric is easy to apply and will stay in place on the organ without the use of sutures. It is biocompatible and resorbable.
The ORC fabric preferably is knit but could be fabricated in other forms, e.g., nonwoven, or woven, if desired.
Commercially available forms of ORC fabric include the following: Surgicel* and Surgicel Nu-Knit~ Adsorbable Hemostat which are described in the PDR (Physicians' Desk Reference), 1~86 edition. The TC-7 fabric previously identified aboYe is also knitted. It is currently being clinically tested.
For con~enience, the description of the present invention will ~ mainly refer to the most preferred embodi~ent, it being ; 25 understood that the other matrix materials, which are regarded as less preferred embodiments, would be used in a similar manner.
, Heparin (which term is intended to include salt forms, such as the calcium or sodium salt) is commercially available in different potencies, referred to as USP Heparin Units. The heparin potencies tested in the present in~ention range from 100 to 10,000 USP Heparin Units . We have found potencies of ; 100 to 2,000 units per six (6) square inches of fabric to be useful, with 500 to 1,500 being preferred. The TC-7 fabric J~J 1198 * Trade-mark ~3~13Z;2 soaked in a 601ution of lOO Heparin Units was better at preventing adhesions than the TC-7 fsbric alone, but the use of 500 USP Heparin Units or more i~ pre~Eerred with the fabric. No statistical difference wa6 een between TC-7 with 500 Heparin Units or lOOO USP Heparin Units. But lO,OOO USP Heparin Units was too poten~, since it'~ u6e on TC-7 fabric resulted in ~y~temic toxicity in the te~t animal~.
Heparin is preferably used in the same liquid form as would be u6ed for admini6tration by injection, e.g., as Heparin Sodium Injection. Use in this form easily provides the desired number of USP Heparin Units in sufficient liquid to be absorbed on the fabric. Typically l ml of Heparin Sodium Injection will wet and saturate or almost saturate a 2'ix3" piece of OCR fabric without running off or being vicible in the knitted fabric interstices.
~he heparin which i5 absorbed on the ORC fabric (or other matrix material) may be applied to the fabric in liquid form at the time of actual use on a body organ during surgery, i.e., the fabric is cut to the de6ired size and draped on and conformed to the body organ, and heparin is then applied, in a non-toxic, adhesion-preventative amount and potency, via syri~ge or pipette or the like to said fabric. The amount of heparin utilized normally should be ~ufficient to saturate the fabric but not 80 great that any heparin drips off or is spilled into or onto o~her organs or body cavities.
The heparin may al~ernatively be absorbed on the ORC fabric (or other matrix materials) and ~hen dried. The dried heparin-impregnated ~abric may then be applied to the body organ during ~urgery. Moi~ure from t~e body organ, or a solution (e.g. Ringer's, s~line cr wate~) can be applied to quickly rehydrate and return the heparin to a liquid form.
Using this alternative, the ORC fabric with heparin absorbed on J&J 1190 ~IL3~22 it, would be dried in any desired manner, e.g., air-dried, freeze-dried, oven-dried. vacuum-dried etc., after which it would be sealed in any desired type of sealable pouch or container customarily used to contain sterile surgical products S such as dressings, sutures, etc., and then sterilized. Mylar*
foil laminates may be used as the pouch material and radiation sterilization may be used to carry out this alternative. The heparin-impregnated barrier fabric (or matrix) can thus be made easily available for use in surgery in a variety of sizes.
Test Procedures Used The efficacy of various heparin-impregnated barrier fabrics of the present invention, as compared to otherwise identical lS non-heparin impregnated fabrics, was determined by the uterine horn scrape procedure as follows:
~ew Zealand Female White rabbits weighing between 2.0 and 3.5 kg are utilized. All animals are acclimated in the vivarium for at least two weeks prior to use. Rabbits are individually housed in stainless steel cages. They are fed Purina~ Lab rabbit chow (Ralston Purina Co., St. ~ouis) and given water ad libitum.
Animals are fasted overnight prior to surgery. Anesthesia is induced by an intramuscular injection of 1 ml of a Ketamine (Ketaset~)/Xylazine ~Rompun~) solution tl ml xylazine (20 mg/ml), 2 ml Ketamine ~100 mg/ml) and 1 ml sterile water~.
Additional anesthesia is administered via the marginal ear vein to maintain the animal on a surgical plane.
All animal surgery is done under aseptic conditions: this includes an iodine scrub, draping, and use of sterile technique. Laparotomy is made through a lower midline incision and the uterine horns are exposed.
J~J 1198 * Trad~-mark ~J
~301D022 --10-- , Five cm lengths of uterine horn starting 1 cm from the bifurcation are scraped using a #10 scalpel blade. The sc~ape, controlled in nature, fully removes the serosa and is characterized by engorgement of blood vessels and a small amount of punctate bleeding. Normally 20 strokes with the scalpel are sufficient to induce the described injury. In this model, hemostasis is achieved, when necessary, by tamponade.
The animals are treated by covering each horn with enough fabric so as to completely cover the in~ured area, i.e., the fabric is cut to a piece 2 inches by 3 inches in size. The appropriate dosage of heparin is then applied to the area by syringing and moistening the fabric with one ml of a heparin solution. The control animals have their horns left untreated, i.e., no fabric or heparin is used.
The musculo-peritoneal layer is closed with 4-0 Vicryl*suture (Ethicon, Somerville, NJ), the cutaneous layer with skin staples. Animals are then evaluated for adhesions two weeks after surgery. The evaluation is done via scoring which considers both the extent and severity of the adhesions.
The scoring system relies on the fact that an extensive length of uterine horn is traumatized: thus extent of adhesions can be quantified by measuring the length of the horn to give the following grading:
:` .
0 = ~o adhesions 1 = 25~ of traumatized area 2 = 50% of traumatized area 3 = Total involvement Fractional scores are given for extent of adhesions intermediate between the above grades. The severity (tenacity~
of the adhesions are measured as follows * Trade-mark J~J 1198 , .. .
~30~022 0 = No resistance to separation 0.5 = Some resistance (moderate force reguired) 1 = Sharp dissection needed The total ~rade thus is additive giving a range of adhesion scores of 0 - 4 wbich represents both extent and severity.
In the following examples, all the adhesion results listed were obtained by the above procedure, or by the above procedure iO without any heparin.
ExamPle 1: TC-7, With HeParin In Dried Form TC 7 fabric in 3x4 inch pieces was impregnated with Heparin Sodium Injection, USP. The heparin used was from Elkins Sinn (lot 065096-Exp. date 6/88) in a 10 ml vial at a concentration of 1000 USP units/ml. This solution was diluted ~:1 with sterile water for injection to give a concentration of 500 units~ml.
Two mls of the solution were pipetted on a 3x4 inch piece of fabric (TC 7) which sat in an XT polymer tray. These two mls completely saturated the fabric thus assuring uniform distribution. The wetted fabric was then allowed to sit overnight, during which time the solution flashed off leaving a dry, heparin impregnated fabric.
The dried heparin impregnated TC 7 fabric was then taken out of the tray and placed inside a Tyvek envelope (Grade 1013-B).
This was in turn placed inside a foil laminate envelope (Maraflex -0.5 gauge Mylar, 0.00135 foil) which was itself sealed. The packages were then sterilized via use of 2.5 Mrads Cobalt irradiation.
* Trade-mark J~J 1198 ~1~
~3~0ZZ
These dried impregnated fabrics were then tested in the rabbit uterine horn model. Each ~x4 inch piece was cu~ in half into two 2x~ inch pieces each piece was then applied ~o a scraped uterine horn of the rabbi~ T~erefore. each uterine horn was actually treated with 500 units of heparin. After applying each fabric so it was draped over and conformed to the uterine horn, ~he fabric wa~ wetted wieh a small amount o saline ~o enhance its tack to the u~erine horn tissue. When the rabbit was sa~rificed and the adhesion6 were evaluated two weeks later, the results were:
Untreated Controls HeParin I~Preqnated Fabric Right 4 2 Left 4 3 Right 4 o Lef~ 4 0 Right 4 0.5 Left 4 o o , 4 X = 0.67 3 animals 6 animals 6 horns 12 horns A~ can be ~een, the untreated controls all hava ~evere adhe6ion6 while mo6t of the animals with ~he above heparin-impregnated TC-7 fabri~ had no adhe6ion~, and a 6mall ~5 proportion had moderate adhesions.
J~ 119~
~3~002~
Examples 2-4: TC-7, With He~arin Added In Situ In Example6 2-4, the procedure of Example l was changed, 60 the heparin was added directly to the TC-7 fabric. In these Exa~ples, the TC-7 fabric (cut in a 2" x 3" size piece) was draped o~er and conformed to the ~terine horn. Then one millilitee (l ml) of the appropriate concentra~ion of heparin was pipetted onto the TC-7 fabric in situ~ ~hich saturated the fabric and made it adhere to the uterine horn. The concentration of heparin used wa~ 1000 USP units/ml starting concentration (lO00 USP unit6 actually applied to each uterine horn) foe Example 2; 500 U5P units/ml starting concentration (500 units actually applied) for Example 3; and lO0 USP
unit~/ml starting concentration (100 units actually applied) for Example 4.
The re6ults ob~ained are ~hown in the following table:
J~J 1}98 ~IL3~ 2 Example NosO 2 3 4 UntreatedHeparin ~ TC 7 Heparin ~ TC 7 Heparin ~ TC 7 Control 1000 Units son Units 100 Units g o 0 0 1 1.5 4 0.6 0 4 0 4 0 0 0.75 4 o 4 o 0~6 0 4 0 0 2 0 Z.5 4 0 0 0 0 0.5 4 0 0 0 0.2 0 4 1 1 1 3.5 0.5 ; 15 4 1 0.5 0 Z.5 o 3.5 0 0 0 2.5 1 0 1.5 20 _ _ _ _ X = 3.64 X = .48 X = .38 X = .76 7 animals 13 animals 6 animals 10 animal~
14 horns 26 horns 12 horns 20 horn~
U6ing the test re6ults obtained in the various examples, and also in other ~udie~, the ef~ect of varying the pote~cy of heparin tUSP units o~ Heparin units) used to impregnate the TC
7 fabric may be generally ~ummarized, ~or purpo~e~ of compari60n, as:
Control 3.3 TC 7 alone 1. a TC 7 ~ 100 Units ~parin 0.8 TC 7 ~ 500 Units Heparin 0.4 TC 7 ~ 1000 Unit6 Hep~Lin 0.4 TC 7 ~ 10,000 Unitfi Heparin Toxic J~J ll9B
~L30~
Example 5: Surqicel, With Heparin ~ddad In Situ Following the procedure of Example 2, but using Surgicel fabric in place of the TC-7 ~abric, i.e. a 2 inch by 3 inch piece of Surgicel fabric was draped on each uterine hsrn, ~and where : ~eparin was added, one ml. was applLed in a 1000 USP Heparin units/ml concentration). The Surgicel with heparin was compared to Surgicel used alone without heparin, and also ~o an untreated control uterine horn. The adhesion results (when the adhesions were evaluated two weeks later) are shown in the following table.
Surqicel ~1000 Units/Horn Heparin ~ Surgicel . Untreated Surgicel Alone 1000 Uni~s Control_ Control 1 4 3.0 ~0 0 4 3.0 0 4 4.0 0 4 ~.0 : . O ~.0 0 4.0 251.5 3.0 : 3.0 ~ .25 2.0 .~ 0 1.5 2.5 3.0 ; X 3 .2B X , 4 X . 3.1 5 Animals Z Animal~ 6 Animals ; 10 Horn~ ~ Borns 12 Horns : 35 J~J 1198
Claims (14)
1. An improved adhesion-preventative barrier fabric comprising an oxidized regenerated cellulose fabric which is drapable, conformable, adherent to body organs, and substantially absorbable within thirty (30) days in the body, which fabric has heparin absorbed thereon, said heparin being present in a non-toxic, adhesion-preventative effective amount and potency.
2. The product of Claim 1 wherein the heparin absorbed on the fabric is applied to the fabric in liquid form at the time of actual use on a body organ during surgery.
3. The product of Claim 1 wherein the heparin is absorbed on said fabric and subsequently dried.
4. The product of Claim 1 wherein the heparin is absorbed on the fabric, and the heparin-containing fabric is then dried and sealed in sterile form.
5. The product of Claim 1 wherein the amount of heparin utilized is sufficient to saturate the fabric but not so great that any heparin drips off.
6. The product of Claim 1 wherein the heparin utilized is in the form of Heparin Sodium Injectible having a potency of 100-2000 USP Heparin Units.
7. The product of Claim 1 wherein the oxidized regenerated cellulose fabric is a knit fabric.
J&J 1198
J&J 1198
8. Use of a physical barrier consisting of the heparin-containing oxidized regenerated cellulose adhesion preventative barrier fabric of any one of Claims 1-7, for preventing surgical adhesions.
9. Use of an oxidized regenerated cellulose fabric containing heparin absorbed on it, said fabric being drapable, conformable, adherent to body organs, and substantially absorbable within thirty (30) days in the body, for preventing surgical adhesions.
10. Use of Claim 9 wherein the heparin is absorbed on the oxidized regenerated cellulose fabric after the fabric has been applied to said body organ.
11. Use of Claim 9 wherein the heparin is absorbed on the oxidized regenerated cellulose fabric before the fabric is applied to the body organ.
12. Use of Claims 9, 10 or 11 wherein the amount of heparin on the oxidized regenerated cellulose fabric is such that all the heparin remains on or in the fabric so no excess amount of heparin is present which could be spilled into or onto other organs or body cavities and is sufficient to contribute to improving the prevention of adhesions beyong that which would occur without the heparin but is not more than the amount which saturates the fabric and the potency of the heparin is 100-2000 USP Heparin Units.
13. An improved adhesion-preventative barrier material comprising a matric which is safe for use in surgery and is drapable, conformable, adherent to body organs, and substantially absorbable within thirty (30) days in the body, which matrix has heparin absorbed thereon, said heparin being present in a non-toxic, adhesion-preventative effective amount and potency.
14. Use of a physical barrier consisting of the heparin-containing adhesion-preventative barrier material of Claim 13, for preventing surgical adhesions.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US912,450 | 1986-09-29 | ||
| US06/912,450 US4840626A (en) | 1986-09-29 | 1986-09-29 | Heparin-containing adhesion prevention barrier and process |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1300022C true CA1300022C (en) | 1992-05-05 |
Family
ID=25431943
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000548034A Expired - Lifetime CA1300022C (en) | 1986-09-29 | 1987-09-28 | Heparin-containing adhesion prevention barrier and process |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US4840626A (en) |
| EP (1) | EP0262890B1 (en) |
| JP (1) | JP2563110B2 (en) |
| KR (1) | KR950013460B1 (en) |
| AT (1) | ATE98132T1 (en) |
| AU (1) | AU602726B2 (en) |
| CA (1) | CA1300022C (en) |
| DE (1) | DE3788404T2 (en) |
| DK (1) | DK510687A (en) |
| ES (1) | ES2047493T3 (en) |
| GR (1) | GR871484B (en) |
| IE (1) | IE63282B1 (en) |
| MX (1) | MX165863B (en) |
| MY (1) | MY100808A (en) |
| NZ (1) | NZ221806A (en) |
| PH (1) | PH24128A (en) |
| ZA (1) | ZA877284B (en) |
Families Citing this family (94)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5080893A (en) * | 1988-05-31 | 1992-01-14 | University Of Florida | Method for preventing surgical adhesions using a dilute solution of polymer |
| US5140016A (en) * | 1988-05-31 | 1992-08-18 | University Of Florida | Method and composition for preventing surgical adhesions using a dilute solution of polymer |
| US6010692A (en) * | 1988-05-31 | 2000-01-04 | University Of Florida Research Foundation, Inc. | Method and composition for preventing surgical adhesions and tissue damage |
| CA2004740A1 (en) * | 1988-12-07 | 1990-06-07 | Cary Linsky | Low molecular weight heparin, heparinoid and hexuronyl hexosaminoglycan sulfate containing adhesion prevention barrier and process |
| SE8900586L (en) * | 1989-02-21 | 1990-08-22 | Pharmacia Ab | COMPOSITION AND PROCEDURES TO PREVENT ADHESION BETWEEN BODY TISSUE |
| US4994277A (en) * | 1989-10-31 | 1991-02-19 | Pfizer Hospital Products Group, Inc. | Use of xanthan gum for preventing adhesions |
| CA2033046C (en) * | 1990-01-12 | 1999-08-03 | Lowell Saferstein | Process for preparing a neutralized oxidized cellulose product and its method of use |
| US5282829A (en) * | 1991-08-15 | 1994-02-01 | United States Surgical Corporation | Hollow body implants |
| SG81873A1 (en) * | 1991-08-16 | 2001-07-24 | Miles A Galin | Medicament coated refractive anterior chamber ocular implant |
| US5468505A (en) * | 1992-02-28 | 1995-11-21 | Board Of Regents, The University Of Texas System | Local delivery of fibrinolysis enhancing agents |
| US7117868B1 (en) | 1992-05-29 | 2006-10-10 | 3M Innovative Properties Company | Fibrous filtration face mask having a new unidirectional fluid valve |
| US5263629A (en) * | 1992-06-29 | 1993-11-23 | Ethicon, Inc. | Method and apparatus for achieving hemostasis along a staple line |
| US5279539A (en) * | 1992-08-17 | 1994-01-18 | Ethicon, Inc. | Drawstring surgical pouch and method of use for preventing ovarian adhesions |
| CA2114290C (en) * | 1993-01-27 | 2006-01-10 | Nagabushanam Totakura | Post-surgical anti-adhesion device |
| US5542594A (en) * | 1993-10-06 | 1996-08-06 | United States Surgical Corporation | Surgical stapling apparatus with biocompatible surgical fabric |
| US5505952A (en) * | 1994-04-19 | 1996-04-09 | United States Surgical Corporation | Modified synthetic cross-linked amino acid polymers and medical devices formed therefrom |
| US5601579A (en) * | 1994-12-29 | 1997-02-11 | Medex, Inc. | Method for the treatment of bowel adhesions |
| WO1996022115A1 (en) * | 1995-01-16 | 1996-07-25 | Baxter International Inc. | Self-supporting sheet-like material of cross-linked fibrin for preventing post operative adhesions |
| US6150581A (en) * | 1995-06-07 | 2000-11-21 | United States Surgical Corporation | Chitosan/alginate anti-adhesion barrier |
| US6461640B1 (en) | 1995-12-08 | 2002-10-08 | Board Of Regents, The University Of Texas System | Local delivery of fibrinolysis enhancing agents |
| US5668119A (en) * | 1996-02-22 | 1997-09-16 | Medenica; Rajko D. | Topical pharmaceutical containing heparin and method of treatment |
| US5696101A (en) * | 1996-04-16 | 1997-12-09 | Eastman Chemical Company | Oxidized cellulose and vitamin E blend for topical hemostatic applications |
| EP0917444A1 (en) | 1996-07-12 | 1999-05-26 | Baxter Travenol Laboratories, Inc. | A fibrin delivery device and method for forming fibrin on a surface |
| FR2778081B1 (en) * | 1998-04-29 | 2000-08-25 | Fabrice Thevenet | REINFORCEMENT IMPLANTS FOR TISSUE SUTURES |
| BE1012536A3 (en) | 1998-11-04 | 2000-12-05 | Baxter Int | Element with a layer fibrin its preparation and use. |
| ATE376433T1 (en) | 1999-03-25 | 2007-11-15 | Metabolix Inc | MEDICAL DEVICES AND USES OF POLYHYDROXYALKANOATE POLYMERS |
| US6325810B1 (en) | 1999-06-30 | 2001-12-04 | Ethicon, Inc. | Foam buttress for stapling apparatus |
| WO2001008594A1 (en) * | 1999-07-28 | 2001-02-08 | C.R. Bard, Inc. | Hernia prosthesis |
| US6702732B1 (en) | 1999-12-22 | 2004-03-09 | Paracor Surgical, Inc. | Expandable cardiac harness for treating congestive heart failure |
| US6273897B1 (en) | 2000-02-29 | 2001-08-14 | Ethicon, Inc. | Surgical bettress and surgical stapling apparatus |
| AU2001238383A1 (en) | 2000-03-10 | 2001-09-24 | Paracor Surgical, Inc. | Expandable cardiac harness for treating congestive heart failure |
| US6425856B1 (en) * | 2000-05-10 | 2002-07-30 | Acorn Cardiovascular, Inc. | Cardiac disease treatment and device |
| US7404819B1 (en) | 2000-09-14 | 2008-07-29 | C.R. Bard, Inc. | Implantable prosthesis |
| US6685956B2 (en) * | 2001-05-16 | 2004-02-03 | The Research Foundation At State University Of New York | Biodegradable and/or bioabsorbable fibrous articles and methods for using the articles for medical applications |
| ES2310609T3 (en) | 2001-09-07 | 2009-01-16 | Mardil, Inc. | METHOD AND APPARATUS FOR THE EXTERNAL STABILIZATION OF THE HEART. |
| US6723041B2 (en) * | 2001-09-10 | 2004-04-20 | Lilip Lau | Device for treating heart failure |
| CA2460307A1 (en) * | 2001-10-31 | 2003-05-08 | Paracor Medical, Inc. | Heart failure treatment device |
| US7022063B2 (en) | 2002-01-07 | 2006-04-04 | Paracor Medical, Inc. | Cardiac harness |
| US7174896B1 (en) | 2002-01-07 | 2007-02-13 | Paracor Medical, Inc. | Method and apparatus for supporting a heart |
| US6790213B2 (en) | 2002-01-07 | 2004-09-14 | C.R. Bard, Inc. | Implantable prosthesis |
| US20040101548A1 (en) * | 2002-11-26 | 2004-05-27 | Pendharkar Sanyog Manohar | Hemostatic wound dressing containing aldehyde-modified polysaccharide |
| US7252837B2 (en) * | 2002-06-28 | 2007-08-07 | Ethicon, Inc. | Hemostatic wound dressing and method of making same |
| US20040101546A1 (en) * | 2002-11-26 | 2004-05-27 | Gorman Anne Jessica | Hemostatic wound dressing containing aldehyde-modified polysaccharide and hemostatic agents |
| US7279177B2 (en) * | 2002-06-28 | 2007-10-09 | Ethicon, Inc. | Hemostatic wound dressings and methods of making same |
| US20040106344A1 (en) * | 2002-06-28 | 2004-06-03 | Looney Dwayne Lee | Hemostatic wound dressings containing proteinaceous polymers |
| NZ537735A (en) * | 2002-07-03 | 2006-08-31 | Pericor Science Inc | Compositions of hyaluronic acid and methods of use |
| CA2495818A1 (en) * | 2002-08-20 | 2004-03-04 | John N. Semertzides | Compositions comprising epithelial cells for the treatment and prevention of tissue adhesions |
| AU2003268549A1 (en) | 2002-09-05 | 2004-03-29 | Paracor Medical, Inc. | Cardiac harness |
| US7135027B2 (en) | 2002-10-04 | 2006-11-14 | Baxter International, Inc. | Devices and methods for mixing and extruding medically useful compositions |
| US7229405B2 (en) | 2002-11-15 | 2007-06-12 | Paracor Medical, Inc. | Cardiac harness delivery device and method of use |
| US7736299B2 (en) | 2002-11-15 | 2010-06-15 | Paracor Medical, Inc. | Introducer for a cardiac harness delivery |
| CA2504555C (en) * | 2002-11-15 | 2012-09-04 | Paracor Medical, Inc. | Cardiac harness delivery device |
| US7019191B2 (en) * | 2003-03-25 | 2006-03-28 | Ethicon, Inc. | Hemostatic wound dressings and methods of making same |
| US20040249242A1 (en) * | 2003-03-28 | 2004-12-09 | Lilip Lau | Multi-panel cardiac harness |
| US20040241212A1 (en) * | 2003-05-30 | 2004-12-02 | Pendharkar Sanyog Manohar | Biodegradable hemostatic wound dressings |
| US20040265371A1 (en) * | 2003-06-25 | 2004-12-30 | Looney Dwayne Lee | Hemostatic devices and methods of making same |
| JP2007528749A (en) * | 2003-07-10 | 2007-10-18 | パラコー メディカル インコーポレイテッド | Self-fixing cardiac harness |
| US20050137673A1 (en) * | 2003-11-07 | 2005-06-23 | Lilip Lau | Cardiac harness having electrodes and epicardial leads |
| US7158839B2 (en) * | 2003-11-07 | 2007-01-02 | Paracor Medical, Inc. | Cardiac harness for treating heart disease |
| US7155295B2 (en) | 2003-11-07 | 2006-12-26 | Paracor Medical, Inc. | Cardiac harness for treating congestive heart failure and for defibrillating and/or pacing/sensing |
| US20050171589A1 (en) * | 2003-11-07 | 2005-08-04 | Lilip Lau | Cardiac harness and method of delivery by minimally invasive access |
| WO2005055958A2 (en) * | 2003-12-09 | 2005-06-23 | Promethean Surgical Devices Llc | Improved surgical adhesive and uses therefor |
| JP2007518490A (en) * | 2004-01-12 | 2007-07-12 | パラコー メディカル インコーポレイテッド | Cardiac harness with interconnecting strands |
| US8298290B2 (en) * | 2004-09-20 | 2012-10-30 | Davol, Inc. | Implantable prosthesis for soft tissue repair |
| US20060257457A1 (en) * | 2004-10-20 | 2006-11-16 | Gorman Anne J | Method for making a reinforced absorbable multilayered hemostatic wound dressing |
| CN101137402B (en) * | 2004-10-20 | 2012-01-11 | 伊西康公司 | Reinforced absorbable multilayered fabric for use in medical devices and its preparation thereof |
| US20060258995A1 (en) * | 2004-10-20 | 2006-11-16 | Pendharkar Sanyog M | Method for making a reinforced absorbable multilayered fabric for use in medical devices |
| BRPI0516764B8 (en) * | 2004-10-20 | 2021-05-25 | Ethicon Inc | hemostat |
| US9358318B2 (en) * | 2004-10-20 | 2016-06-07 | Ethicon, Inc. | Method of making a reinforced absorbable multilayered hemostatic wound dressing |
| US9119901B2 (en) * | 2005-04-28 | 2015-09-01 | Warsaw Orthopedic, Inc. | Surface treatments for promoting selective tissue attachment to medical impants |
| US8414907B2 (en) | 2005-04-28 | 2013-04-09 | Warsaw Orthopedic, Inc. | Coatings on medical implants to guide soft tissue healing |
| US7587247B2 (en) * | 2005-08-01 | 2009-09-08 | Paracor Medical, Inc. | Cardiac harness having an optimal impedance range |
| US20070208217A1 (en) * | 2006-03-03 | 2007-09-06 | Acorn Cardiovascular, Inc. | Self-adjusting attachment structure for a cardiac support device |
| US20070270882A1 (en) * | 2006-05-19 | 2007-11-22 | Acorn Cardiovascular, Inc. | Pericardium management method for intra-pericardial surgical procedures |
| US20080097146A1 (en) * | 2006-06-29 | 2008-04-24 | Acorn Cardiovascular, Inc. | Cardiac support device with low friction delivery structures |
| US7651462B2 (en) | 2006-07-17 | 2010-01-26 | Acorn Cardiovascular, Inc. | Cardiac support device delivery tool with release mechanism |
| US7641608B1 (en) | 2006-09-26 | 2010-01-05 | Acorn Cardiovascular, Inc. | Sectional cardiac support device and method of delivery |
| US9289279B2 (en) | 2006-10-06 | 2016-03-22 | Promethean Surgical Devices, Llc | Apparatus and method for limiting surgical adhesions |
| US9693841B2 (en) | 2007-04-02 | 2017-07-04 | Ension, Inc. | Surface treated staples, sutures and dental floss and methods of manufacturing the same |
| US8192351B2 (en) | 2007-08-13 | 2012-06-05 | Paracor Medical, Inc. | Medical device delivery system having integrated introducer |
| US8299316B2 (en) * | 2007-12-18 | 2012-10-30 | Ethicon, Inc. | Hemostatic device |
| US20110165578A1 (en) * | 2008-09-09 | 2011-07-07 | Daniela Verthelyi | Methods for detecting and quantifying oversulfated glycosaminoglycans |
| US9072586B2 (en) | 2008-10-03 | 2015-07-07 | C.R. Bard, Inc. | Implantable prosthesis |
| US20110152924A1 (en) * | 2009-12-22 | 2011-06-23 | Michel Gensini | Oxidized regenerated cellulose adhesive tape |
| US9192385B2 (en) | 2010-10-12 | 2015-11-24 | Evan Richard Geller | Device and method to facilitate safe, adhesion-free surgical closures |
| US20130084324A1 (en) | 2011-09-30 | 2013-04-04 | Michel Gensini | Adhesion prevention fabric |
| US10744039B2 (en) | 2012-09-28 | 2020-08-18 | Ension Inc. | Methods of making bioactive collagen wound care dressings |
| US9796769B2 (en) | 2012-09-28 | 2017-10-24 | Ension Inc. | Methods of making bioactive collagen medical scaffolds such as for wound care dressings, hernia repair prosthetics, and surgical incision closure members |
| US9370425B2 (en) | 2012-10-12 | 2016-06-21 | Mardil, Inc. | Cardiac treatment system and method |
| US20140120057A1 (en) | 2012-10-25 | 2014-05-01 | Rutgers, The State University Of New Jersey | Polymers and methods thereof for wound healing |
| US9655621B2 (en) * | 2013-03-15 | 2017-05-23 | Covidien Lp | Surgical instrument for dispensing tacks and solution |
| USD717954S1 (en) | 2013-10-14 | 2014-11-18 | Mardil, Inc. | Heart treatment device |
| KR101878774B1 (en) * | 2015-04-15 | 2018-07-17 | 주식회사 삼양바이오팜 | Multifunctional hemostatic material and method for preparing the same |
| CN109789249B (en) | 2016-06-15 | 2022-01-25 | 土耳其科学技术研究理事会 | Multifunctional hernia paster |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3122479A (en) * | 1957-11-14 | 1964-02-25 | David F Smith | Hemostatic surgical dressings |
| US3364200A (en) * | 1960-03-28 | 1968-01-16 | Johnson & Johnson | Oxidized cellulose product and method for preparing the same |
| US3902497A (en) * | 1974-03-25 | 1975-09-02 | American Cyanamid Co | Body absorbable sponge and method of making |
| JPS5941656B2 (en) * | 1981-03-31 | 1984-10-08 | 工業技術院長 | Method for imparting anticoagulant properties to regenerated cellulose |
| JPS5941647B2 (en) * | 1981-03-31 | 1984-10-08 | 工業技術院長 | Method for producing anticoagulant regenerated cellulose |
| JPS58180162A (en) * | 1982-04-19 | 1983-10-21 | 株式会社高研 | Anti-thrombosis medical material |
| JPS59160465A (en) * | 1983-03-04 | 1984-09-11 | 株式会社 バイオ・エンジニアリング・ラボラトリ−ズ | Fusion inhibiting medical material and production thereof |
| JPS59225064A (en) * | 1983-06-03 | 1984-12-18 | ユニチカ株式会社 | Carrier for immobilizing physiologically active substance |
| JPS6014861A (en) * | 1983-07-05 | 1985-01-25 | 株式会社日本メデイカル・サプライ | Adhesion preventing material |
| US4668224A (en) * | 1983-10-24 | 1987-05-26 | Warner-Lambert Company | Oxidized cellulose as a medical lubricant |
| US4745098A (en) * | 1984-02-24 | 1988-05-17 | The Regents Of The University Of California | Compositions and method for improving wound healing |
| US5002551A (en) * | 1985-08-22 | 1991-03-26 | Johnson & Johnson Medical, Inc. | Method and material for prevention of surgical adhesions |
-
1986
- 1986-09-29 US US06/912,450 patent/US4840626A/en not_active Expired - Lifetime
-
1987
- 1987-09-14 NZ NZ221806A patent/NZ221806A/en unknown
- 1987-09-25 GR GR871484A patent/GR871484B/en unknown
- 1987-09-27 MX MX008583A patent/MX165863B/en unknown
- 1987-09-28 EP EP87308548A patent/EP0262890B1/en not_active Expired - Lifetime
- 1987-09-28 ES ES87308548T patent/ES2047493T3/en not_active Expired - Lifetime
- 1987-09-28 DK DK510687A patent/DK510687A/en not_active Application Discontinuation
- 1987-09-28 CA CA000548034A patent/CA1300022C/en not_active Expired - Lifetime
- 1987-09-28 MY MYPI87002075A patent/MY100808A/en unknown
- 1987-09-28 DE DE87308548T patent/DE3788404T2/en not_active Expired - Lifetime
- 1987-09-28 JP JP62241014A patent/JP2563110B2/en not_active Expired - Lifetime
- 1987-09-28 AU AU79026/87A patent/AU602726B2/en not_active Expired
- 1987-09-28 ZA ZA877284A patent/ZA877284B/en unknown
- 1987-09-28 IE IE260487A patent/IE63282B1/en not_active IP Right Cessation
- 1987-09-28 AT AT87308548T patent/ATE98132T1/en not_active IP Right Cessation
- 1987-09-29 PH PH35863A patent/PH24128A/en unknown
- 1987-09-29 KR KR1019870010809A patent/KR950013460B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| JPS63102752A (en) | 1988-05-07 |
| MY100808A (en) | 1991-02-28 |
| DE3788404T2 (en) | 1994-05-05 |
| PH24128A (en) | 1990-03-05 |
| NZ221806A (en) | 1989-07-27 |
| DE3788404D1 (en) | 1994-01-20 |
| KR880003605A (en) | 1988-05-28 |
| EP0262890A2 (en) | 1988-04-06 |
| EP0262890A3 (en) | 1989-08-16 |
| MX165863B (en) | 1992-12-08 |
| ZA877284B (en) | 1989-04-26 |
| ATE98132T1 (en) | 1993-12-15 |
| DK510687D0 (en) | 1987-09-28 |
| GR871484B (en) | 1988-02-03 |
| JP2563110B2 (en) | 1996-12-11 |
| AU7902687A (en) | 1988-03-31 |
| DK510687A (en) | 1988-03-30 |
| EP0262890B1 (en) | 1993-12-08 |
| AU602726B2 (en) | 1990-10-25 |
| ES2047493T3 (en) | 1994-03-01 |
| US4840626A (en) | 1989-06-20 |
| KR950013460B1 (en) | 1995-11-08 |
| IE63282B1 (en) | 1995-04-05 |
| IE872604L (en) | 1988-03-29 |
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