MXPA97004971A - Biabsorbible medical devices from polyacaridos oxida - Google Patents

Abstract

Bioabsorbable medical devices are prepared by oxidizing cellulose derivatives, including methylcellulose, carboxymethylcellulose and cellulose acetate. The resulting material is formed into films, sponges and, in the case of oxidized methylcellulose, gels, due to its unique property of being water-soluble. The resulting devices are particularly useful for limiting surgical adhesions, and for hemostasis. Other uses include wound dressing and as a replacement for more expensive bioabsorbable gels such as hyaluronic acid

Description

BIOABSORBABLE MEDICAL DEVICES FROM OXIDIZED POLYSACCHARIDES BACKGROUND FIELD OF THE INVENTION The present invention relates generally to oxidized polysaccharides, especially cellulose derivatives, and methods for their production and u =, o.

STATE OF THE PREVIOUS TECHNIQUE Surgeons face numerous problems even during routine surgery; One of the most frustrating is the formation of adhesions after a surgical procedure. An adhesion is a connection that occurs between two internal surfaces of the body that are not normally connected. Adhesions can occur for a number of reasons that are not related to surgery. However, since the formation of adhesions can be considered as analogous to the formation of a scar, it is not surprising that adhesions occur after surgery. It has been estimated that adhesion formation occurs in almost 90% of all surgical procedures, and that about 10% of these cause post-surgical problems (Ellis H. The causes and prevention of intestinal adhesions. Br D Surg 69: 241- 243; 1982; Weibei MA, Majno G. Peptoneal adhesions and t.heir relation < or abdo inal surgery, Am. D. Surg. 125: 345-353, 1973). Depending on the anatomic site of adhesion formation, different problems may arise. For example, adhesions involving the fallopian tubes can cause infertility. Adhesions involving the intestine can cause intestinal obstruction. In the thorax after a cardiac procedure, the formation of adhesions can seriously complicate a redoesternot orma. The typical procedure to reduce the formation of adhesions is to limit the trauma to the areas where the adhesions are formed. However, even the most experienced surgeons induce sufficient trauma during many procedures that induce some degree of surgical adhesions. This is especially true during more invasive procedures such as open-heart surgery. Also, some patients are more likely to form adhesions. At present, there are no drugs or appropriate devices which effectively reduce the formation of adhesions after cardiac surgery. However, a regenerated oxidized cellulose canvas (TNTFRCFED available from .lohnson &Johnson Medical, Inc.,) has been approved by the United States Food and Drug Administration to reduce surgical adhesions in certain pelvic procedures, and has been demonstrated which has a general effect limiting adherence in other surgical procedures. It has also been suggested that certain water-soluble gels obtained from hyaluronic acid or carboxymethylcellulose may be useful in limiting the formation of surgical adhesions. However, these substances have certain disadvantages. Hyaluronic acid is difficult to produce. It is purified from crests do rooster, or it is produced by fermentation. The carboxymethyl cellulose (CMC) is very economical to produce it, but it does not degrade in the body. As with other cellulose derivatives such as nitrocellulose and hydroxyethylcellulose, their metabolic fate is uncertain and can be sequestered by cells of the reticuloendothelial system (Hueper, UC Macrornolecular substances as pathogenic agents, Arch. Pathol. 33: 267- 290, 1942; Hueper UC, Experimental studies, cardiovascular pathology, XI, Thesaurosis and atheromatosis, produced by the intravenous injections of sodium cellulose glycollate, Am. D. Pathol, 21: 1021-1029, 1945, Hueper UC. Experimental st? Dies in cardiovascular pathology XII Athero atosis in dogs following repeated intravenous injections of hydroxyethylcellulose solutions, Arch. Pathol 41: 130-138, I94ñ). The carboxycellulose (CMC) is a member of a class of cellulose derivatives that form water-soluble gels. Cellulose by itself can become bioabsorbable by exposing it to oxidants. This was first discovered in 1936 by U. Kenyon, of the Eastman Kodak Research Laboratories, who was carrying out fundamental studies on the oxidation of cellulose. Kenyon found that a new type of product can be obtained through the use of nitrogen dioxide or oxidizing agent. The material was soluble in alkali and in contrast to the usual friable materials resulting from other cellulose oxidation methods, this material maintained its original shape and much of its original tensile strength. The product was shown to be a copolymer of anhydroglucose and anhydrous hydrochloric acid. This oxidized cellulose material was developed in a bioabsorbable fabric hernostat by Parke Davis and Johnson ft Johnson. A good discussion of the procedure can be found in the article and the following patents, all of which are incorporated herein by reference: "Oxidation of Oellulosa", by Richard Kenyon, Industrial and Engineepng Chernistry, vol 41 (1) 2-8 , 1949; US patents No. 2,232,990 issued in 1941; 2,298,387 issued in 1943; 3,364,2000 issued in 1968; the Patent of E.U.A. No. 3,364,200, by Ashton et al. Issued January 16, 1968, and the US Patent. No. 5,180,398, by Boardman and others issued on January 19, 1993 and their equivalents from abroad, EP 0,492,990, Japanese Application No. 361083/91. The oxidative action of numerous oxidants on cellulose has been studied under widely varying conditions of temperature, pH, reaction time and concentration. The main problem in studying oxidized celluloses is the difficulty in producing materials which are homogeneous in physical and chemical properties. Several of the oxidants used are apparently non-selective as to the particular hydroxyl groups of the anhydroglucose unit on the cellulose molecules which are attacked. Many oxidation methods are topochemical. When the oxidation is moderate, the products often consist of an oxidized portion and an unmodified residue of unreacted or slightly modified cellulose. The most drastic oxidation produces a greater proportion of oxidized material accompanied by increased degradation. The physical degradation that accompanies oxidation separates the cellulose fibers and often the material is friable and easily pulverized. Although the first works on the preparation of oxidized cellulose with nitrogen dioxide date back to the late 30s and 40s, chemistry recently expanded, so it is possible to prepare other bioabsorbable polymers from cellulose derivatives and other carbohydrates. . It has recently been discovered that cellulose derivatives such as carboxymethylcellulose, water-soluble cellulose monoacetate and rilethylcellulose, among others, can also be oxidized with nitrogen dioxide to bioabsorbable materials. (Czechoslovak patent No. 118,765 dated June 15, 1966, by Jozef Tarnchyna and Frantisek Skoda, describes the oxidation of starch with nitrogen tetroxide, but there is no mention of bioabsorbability of oxidized starch). It has also been found that carbohydrates of the formula (C-H-OHOSIN such as guar, konjac, starch and dextrin) can also be oxidized with nitrogen dioxide to bioabsorbent polymers, and have also been oxidized to dextran, postulate and cyclodextrin in bioabsorbent polymers. Oxidated Alginates The eticel of cellulose and carboxymethyl cellulose (CMC) are two of the most widely used water soluble cellulose derivatives and have applications in the food, cosmetics and pharmaceutical industries, obtained by the reaction of alkali cellulose. With methyl chloride or chloroacetic acid, respectively, the reaction conditions are often chosen so that only partial substitution of the three hydroxyl groups in each monomer cellulose are substituted, thus the cellulose derivatives such as inetiicellulose and carboxymethylcellulose. they are partially substituted cellulose derivatives, they dissolve in water p To form dense aqueous solutions, the viscosity of which depends on the concentration of the polymer and its molecular weight. Ethylcellulose has been marketed by a number of companies, one of which is Dow Chemical Company, which sells the product under the name of METHOCEL A commercial products. The carboxy ethyl cellulose is sold among others by Aqualon under the generic name of carboxyethylcellulose. sodium. Neither methiicellulose, carboxymethylene cellulose nor cellulose acetate are bioabsorbable polymers. If a film, powder, sponge, solution or any device made of these polymers is placed inside the body cavity, it would be dissolved as a water-soluble polymer of high molecular weight. Although some excretion is possible, part of the polymer would eventually find its way into the walls of the blood vessels, renal glomeruli, and the cells of the retjuloendotelal system., possibly initiating damage in the same ones (Uiseman, D.M. Polymers for the Prevention of Surgical Adhesions in: Poly er Site μocific Ph rnacotherap, Dornb, A. (ed.) John Uiley, Chichester, 1994 pp 3B5). For a polymer to be bioabsorbable, it must be degraded in some way in fragments of ba or molecular weight that can be metabolized by the liver or excreted through the kidneys. For example, medical devices made from collagen and gelatin, when placed inside the body, are enzymatically degraded into peptides and low molecular weight amino acid fragments which are nebolized by the liver into new proteins or excreted by the liver. kidneys Polymers such as poly licolide for absorbable sutures and polyanhydrides for controlled drug release, are sensitive to moisture and are degraded by body fluids to hydrosoluble fragments of ba or molecular weight that leave the body in the urine or are metabolized by the liver. Oxidized cellulose is stable at pH 7, but as the pH approaches and exceeds that of the body fluid, the polymer chain is degraded into oligosacchards and water-soluble sugar-like portions of ba or molecular weight, which are passed through the kidneys and eliminated in the urine. A good discussion of the sensitivity of oxidized cellulose to pH is presented by Alexander Meller in "Holzforschung" Vol. 14, pg. 78-89, 129-139 (1960).

BRIEF DESCRIPTION OF THE INVENTION It has been found that not only can cellulose be converted to a bioabsorbable material by oxidation, but also other polysaccharides, and especially cellulose derivatives, can be oxidized with nitrogen dioxide in bioabsorbable polymers. The starting material and the oxidation process are relatively inexpensive when compared to bioabsorbent polymers of naturally occurring animal origin, such as hyaluronic acid and dexamethasone. In addition, they are used to limit surgical adhesions, and also for ostasis, for the controlled release of drugs and materials for bandaging wounds in many medical uses. A bioabsorbable material according to the present invention comprises an oxidized polysaccharide, preferably comprising a cellulose derivative. Preferably, the cellulose derivative is selected from the group consisting of: ethylcellulose, carboxymethyl cellulose or cellulose acetate. Pre fepb 1 ernment, ol rnat rial is estep1 and irradiation is used as the preferred sterilization method. The material can be provided in the form of a film, gel, powder, fibrous mat or sponge, among others. In the case of oxidized cellulose, it is bioabsorbable and water-soluble and can be mixed with a sufficient amount of water or physiologically acceptable pH regulator to form a gel. The gel can be impregnated in a bioabsorbable substrate, such as a canvas formed of oxidized regenerated cellulose. The mixed body material can also be produced by coating a solution of cellulose on a rayon or cellulose sheet and drying to produce a film on the surface of the fabric, or allowing the solution of methyl cellulose to impregnate the interstices of the fabric. Being dry, the mixed body can be oxidized with nitrogen dioxide gas to produce a completely bioabsorbable fabric with a bioabsorbable gel that forms polymer incorporated within its structure. A method according to the invention for inhibiting adhesions comprises the step of applying a bioabsorbable material comprising an oxidized removing poly comprising a cellulose derivative to a site in the body susceptible to adhesions. A preferred method comprises placing the material, more preferably an oxidized etiicel gel, in the thoracic cavity to inhibit cardiac adhesions. The gel can also be placed in the abdominal cavity, to prevent abdominal adhesions. Fl gel can also be applied to the body through a lumen in an endoscope.

DETAILED DESCRIPTION OF THE INVENTION Of the cellulose derivatives, the rilethylcellulose is perhaps most exciting because it becomes a water-soluble bioabsorbable polymer when reacted with nitrogen dioxide, while the other oxidized cellulose derivatives that have been examined are soluble in water. The oxidized rnet cellulose polymer forms viscous aqueous gels at concentrations > 3%, which are stable under pH 7 but disintegrate above pH 7 to low-density aqueous solutions. Oxidation of methylcellulose can be carried out in a number of ways, one of which involves exposing a suspension of methylcellulose powder to a solution of nitrogen dioxide in an inert solvent such as carbon tetrachloride. The rneti1 cellulose suspension is exposed to the nitrogen dioxide solution by 2-48, preferably 4-16 hours. At the end of the period, the oxidized methylcellulose powder is filtered from the solvent and washed in 90% isopropyl alcohol, 10% water or 90% acetone, and 10% water to remove excess dioxide gas. of nitrogen. The oxidized iron oxide powder is dried with 100% acetone or isopropyl alcohol at 100% to produce a white powder which is then water-soluble. The solutions can be filtered to remove all more soluble material. Solutions of oxidized rnetilcellaa of concentrations between 0.5 and 5% can be emptied onto glass with a casting knife and left to dry on films, or the aqueous solution can be dehydrated by freezing in sponges. The oxidized polymer can also be precipitated from aqueous solutions by pouring the solution into acetone or isopropyl alcohol which are non-solvent for L polinero. It is speculated that the oxidation chemistry of rnetiicellulose is similar to that for the oxidation of cellulose. A typical structure of the netilcel ulosa is shown below. The substitution of methyl ether groups in the hydroxyl groups of the cellulose can occur in the primary hydroxyl group or the two secondary hydroxyl groups. The figure below shows an ideal structure with the methyl substitution only in the primary group but, in reality, METHOCEL A has a substitution degree of 1.6-1.9, which means that more than one methyl group is substituted in each structure of ring. The distribution of the methyl groups has been reported by Y. Tezuka, K. Irnai, M. Oshirna and T. Chiba, Macromolecules Vol. 20, pg. 2413-2418, 1987. When nitrogen dioxide comes into contact with the methylcellulose polymer, the oxidation of some of the secondary alcohol groups to ketones occurs together with the oxidation of some of the unsubstituted primary alcohol groups to carboxylic acid. . The polymer (ie, the oxidized cellulose) can be characterized by its carboxylic acid content, which can vary from about 3-8%.

The discovery that a readily available low-cost starting material with methylcellulose can be converted into a water-soluble bioabsorbable polymer has important implications in the area of bioabsorbable medical devices. For example, recent teachings in the field of post-surgical adhesion prevention show that water-soluble gels obtained from hyaluronic acid (Gel for Prevent ing Ahdesion Between Body Tissues and Process for iteration Production, PCT / SER5 / 00282, Pharmacia Corp: : (U senan, DM, Johns, DB Anatomical synergy between sodium hyaluronate (HA) and INTFRCEFD barrier in rabbits with o types of adhesions. (Fertil Steril, Prog. Supp. S25, 1993) or viscous solutions of carotoximet i] cellulose (Viscoelast ic fluid for use in sphe and general surgery and other therapies and method of using same.) Pennell PE, Blackmore JM, Alien MD, US Patent No. 5,156,839 of October 20, 199 ?; Assessrnent of carboxyrnet hylcellulosa and 32% dextran 70 for prevenfion of adhesions in a rabbit uterine horn model Diamond, MP, DeCherney AH, linksy, CB, Cunningharn T, Constant me B. Int J Fertile 33, -278 -282, 1988), can be discharged in the body cavity for coat tissues and organs with a viscous solution of these polymers. The viscous coatings prevent adjacent tissues from coming in contact with each other for a period of 1 to 10 days, enough to allow the tissue to heal and prevent adhesions from forming between the juxtaposed tissues. Aqueous viscous gels of oxidized cellulose may function in the same way. The gel coats organs and tissues to prevent them from coming in contact with each other, and slowly disintegrates as body lipids regulate the pH of the solution above pH 7. In addition, solutions of oxidized methylcellulose can be used during surgery to reduce the minimum damage to tissues by abrasion, desiccation and other incidental handling, as described for other materials (Goldberg EP and Yaacobi Y, Method for preventing surgical adhesions using a dilute solution of polymer, US Patent No. 5,080,893, of January 14, 1992, incorporated herein by reference, Diamond, MP and the Sepracoat ™ Adhesion Study Group: Precoatmg with Sepracoat ™ (C ™) reduces postoperative de novo adhesion forrnation in a rnulticenter randonized, placebo-controlled gynecologic climcal tpal. J Soc Gynecol Tnvest 3, -2 Suppl 90A, 1996). Sponges or oxidized icelulose tnet films can be sterilized by gamma irradiation. When placed in the body, they slowly turn into a viscous gel and then gradually dissolve as the polymer is degraded and solubilized in water-soluble fragments. Sponges or oxidized methyelulose films can be used as devices for the controlled release of drugs by incorporating a medicament into the polymer solution and emptying a film, by dehydrating the solution in a sponge, or by using the viscous medicated solution as a solution. a gel. Oxidized methylcellulose can also function as a synovial fluid replacement for the lubrication of a joint, tendon sheath or bag. To prepare films of oxidized rnethylcellulose, rnetylcellulose such as METHOCEL A, polymer grades A15LV, A4C, A15C or A4M (available from Dow Chemical) with a degree of substitution of 1.65-L.92, it is dissolved in water at 60 °. C in accordance with the manufacturer's instructions, at concentrations of 0.5% weight / weight up to 15% weight / weight. The solution is poured on a flat surface at nominal densities of .0127 cm to .508 cm and allowed to dry. The crystalline and flexible films are oxidized in the gas phase with nitrogen dioxide gas or with a nitrogen dioxide solution in an inert solvent such as carbon tetrachloride or Freon 113. In the preferred gas phase oxidation, the films of netilcelulosa are placed in a resin kettle which is flushed with nitrogen gas to displace the air. Chilled nitrogen dioxide of 1-3 times by weight of the films is placed in a small flask fixed to the resin kettle through a side arm. The nitrogen dioxide gas is allowed to slowly evaporate in the resin kettle and wrap around the films. The resin boiler is equipped with a cold condenser de-flushed into the atmosphere which prevents the pressure from rising. The inet movies! cellulose are exposed to nitrogen dioxide gas for a period of 2-48 hours, preferably 4-16 hours. At the end of this period, the resin boiler is flushed with nitrogen to liberate it from excess nitrogen dioxide gas and the films are removed. The oxidized films are washed in 90% isopropanol solution several times to remove the adhered adhesive. It is found that the resulting crystalline flexible film material is dissolved in 0.5 N NaOH to give a thin aqueous solution, indicating that it is likely to be bioabsorbable. The oxidized film will also dissolve in water to produce a viscous acid solution. The oxidized met ilcel ulosa is characterized by its carboxylic acid content which fluctuates from 3-8%. This oxidized film material was then sterilized by gamma irradiation (2.8 MRad) and implanted subcutaneously in rats. The macroscopic observation of the implant site 10 and 20 days after the surgery did not reveal visible signs of the test material in any of the animals implanted with the oxidized rnethyl cell. The microscopic evaluation of the cellular response * concluded that the test material was rapidly purified from the subcutaneous implant. At 10 days after the operation, the test material had not caused unusual or unexpected cellular reaction. Oxidized methylene chloride films were also tested for their ability to prevent adherence to stomach or abdominal cysts. The oxidized cellulose films can also be impregnated on a fabric, for example a fabric composed of regenerated oxidized cellulose or an absorbable mesh made from a glycol lactic acid copolymer. Oxidized cellulose, methylcellulose powder such as METHOCEL A4C, A15, -LV or A4M available from Dow Chemical Cornpany, with a degree of substitution of 1.65-1.92 is evenly distributed in a box at a depth of 2-8 nm. The ca is placed inside a chamber which is flushed with nitrogen gas to displace the oxygen. Gas nitrogen tetroxide in quantities of one-half to three times the weight of the lenticle powder is introduced into the chamber, which is vented to a caustic trap to absorb nitrogen oxides. Exposure to nitrogen tetroxide can be carried out from 2 to 48 hours. After exposure, the vessel is purged with nitrogen, the oxidized powder is washed with 70-90% isopropyl alcohol and air-dried. Alternatively, the cellulose powder may be suspended in an inert liquid such as Freon 113 in which the nitrogen tetroxide has been dissolved, and this suspension is stirred for 2-48 hours. The oxidized powder is separated from the inert liquid by filtering the powder at the end of the reaction period and washing the powder in 70-90% isopropyl alcohol. In the case of methylcellulose, the oxidized powder is soluble in water, which can be purified from some particles by dissolving it in water at a concentration between 0.5 and 10% and filtering to remove the more soluble matter. The resulting solution can be used as this, or it can be lyophilized to produce a sponge for testing. The carboxyl irnetylcellulose and the cellulose monoacetate are two other water-soluble cellulose derivatives that have been converted into bioabsorbable polymers by the action of nitrogen dioxide. Cellulose acetate is water soluble when the degree of substitution of acetate is less than 1. This water-soluble polymer from Celanese Corporation should be distinguished from the most common non-water-soluble cellulose acetate used to make textile fabrics which has a degree of substitution of 2 or more. Carboxymethylcellulose is produced by Aqualon in vain degrees, with degrees of substitution between 0.38 and 1.45 and all grades are water-soluble. When the carboxy etiicellulose or cellulose acetate is oxidized with nitrogen dioxide, the resulting oxidized material is not water-soluble, but it will dissolve in aqueous solutions with a? H >7 to produce low density and low viscosity solutions, indicating degradation and alkaline sensitivity of the oxidized polymer. Carboxymethylcellulose and cellulose acetate can be produced in films and sponges from diluted solutions of the polymer in water. The draining of a dilute aqueous solution of carboxymethyl cellulose or cellulose monoacetate on glass or plastic plates with a 2-hand blade produces a film when dry. The dehydration by freezing of a diluted aqueous solution of between Q.5% -3% concentration, will produce a sponge of these polymers. The films and sponges can be oxidized with nitrogen dioxide gas over a period of 16 hours to produce the corresponding oxidized polymer, which are now insoluble in water and bioabsorbable. Films and sponges of oxidized carboxy ethylcellulose or oxidized cellulose acetate can be sterilized by gamma irradiation. These bioabsorbable devices can produce good drug delivery systems, medications, barriers to the prevention of adhesions, and absorbable hemostats that help to counteract bleeding during surgery. Other cellulose derivatives that can be oxidized include ethylene cellulose. The ethylcellulose polymer commercially available from Hercules has a degree of substitution of 2.46, which is too high to allow enough primary or secondary hydroxyl groups in the base structure of the cellulose to become oxidized, and become bioabsorbable, as demonstrated by dissolution in sodium hydroxide at 0.5N. However, if ethylcellulose with a degree of substitution of 0.3 1.0 is oxidized with nitrogen tetroxide, it will be transformed into a bioabsorbable derivative of oxidized cellulose.

EXAMPLES Examples 1-5 show methods of oxidation of cellulose derivatives by exposure to nitrogen dioxide in the gas phase. This oxidation can also be achieved by exposure to nitrogen dioxide which is dissolved or carried in an appropriate solvent such as PF5050 as taught by Boardman and others (U.S. Patent No. 5,180,398). To ensure that the product does not dissolve during the washing phase, the amount of water in the wash solvent must be reduced to less than 50%, the rest of the solvent being comprised of an alcohol such as isopropyl alcohol.

EXAMPLE 1 Preparation of a solution of oxidized methylcellulose grams of METHOCEL A4M from Dow Chemical Co. were dissolved in 808 grams of distilled water to obtain a 3% solution. The solution was poured into trays and dehydrated by freezing to obtain sponges. The sponges were cut into small pieces and placed on a resin kettle, the boiler was flushed with nitrogen gas to move the air for 5 minutes. 15 grams of cooled nitrogen dioxide were placed in a fixed flask to the resin kettle by a side arm and the gas was allowed to diffuse into the sponges for a period of 24 hours. At the end of this period, the sponges were removed from the resin kettle and allowed to degas. Then, they were washed 3 times, each with a solution of 1 liter of 90% isopropyl alcohol and 10% water. The sponges were dried in 100% isopropyl alcohol. The dried, oxidized sponges, 25 grams, were dissolved in 2475 grams of distilled water and filtered to remove all more soluble matter. The pH of this solution was 2.3. The crystalline solution was poured into trays and dehydrated by freezing. A 0.5 gram piece of dry sponge was dissolved in 10 rnl of NaOH at .5N and titrated for the percentage of carboxylic acid. It was found that this sample had 7% by weight of carboxylic acid content. 10 grams of this sponge were dissolved in 115 grams of water to obtain an 8% solution. This viscous solution can be used to prevent abdominal and pelvic adhesions.

EXAMPLE 2 Preparation of oxidized methylcellulose films A 3% aqueous solution of METHOCEl. A4M from the Dow Chemical Company was poured on a glass plate and felled with a set of 2-knife blades at 635 microns. The film was allowed to dry overnight and was removed the next day from the glass plate to produce a 76.2u film. 3 grams of the film were placed in a boiler to which it was flushed with nitrogen gas to displace the air. A small flask containing 2 grams of cooled liquid nitrogen dioxide was adhered to the lid of the ream boiler with a side arm adapter. The nitrogen dioxide was allowed to diffuse into the ream kettle to oxidize the film over a period of 16 hours. At the end of this period, the film was removed from the ream bin and washed with a solution of 90% isopropyl alcohol and 0% water to remove all residual gas from the film. This film can be sterilized by gamma irradiation and used as a barrier to prevent adhesions. A piece of 0.5 g of the film dissolved in 10 ml of a sodium hydroxide solution at 0.5 N gives a crystalline solution with low viscosity, indicating its probable bioabsorbability. Another piece of 0.5 g of film dissolved in 10 ml of water gives a solution with moderately high viscosity. This film can be sterilized by gamma irradiation and used as a barrier to prevent adhesions.

EXAMPLE 3 Preparation of oxidized carboxymethylcellulose sponges grams of carboxymethyl cellulose grade 7HF with a degree of substitution of 0.65-0.90 from Aqualon were loosened in 490 grams of water to obtain a 2% solution. The solution was poured into trays of 7.62 cm x 10.16 crn approximately 0.635 cm deep. The solutions were frozen on the shelf of a deehydrator by freezing and when they were totally frozen, The vacuum pump was turned on to produce a vacuum of 100 rnilitorr. The temperature of the shelf was adjusted to 15 ° C and lyophilization was carried out for 20 hours. At the end of this period, the trays were removed from the dehydrator by freezing and sponges of carboxycellulose were obtained from each tray. These sponges were soft, but still hydrosoluble. The sponges, of almost 10 grams in total, were placed in a resin boiler to which a lateral arm was connected to a small flask. The beef boiler was flushed with nitrogen gas for a few minutes, then 10 grams of cooled nitrogen dioxide were added to the small mat and slowly diffused into the resin kettle containing the carboxymethyl cellulose sponges. After 20 hours of exposure to nitrogen dioxide gas, the sponges were removed from the resin boiler and washed with one liter of a 50:50 solution of isopropyl alcohol and water. This washing was carried out 2 times. The sponges were then placed in a tray under a source of fresh water and washed with fresh water for 5 minutes. The sponges were air dried after washing them in one liter of 100% isopropyl alcohol, or they could be dehydrated by freezing after washing them in water. In freeze dehydration to obtain sponges, complete dehydration is desirable since, otherwise, the sponge once formed can reabsorb moisture from the atmosphere. Oxidized carboxylated carboxy sponges are no longer water soluble. However, one gram is dissolved in 10 nl of sodium hydroxide at 0.5N to give a crystalline solution with a very low viscosity, showing that the oxidized carboxymethylcellulose sponge degrades at the high pH of this sodium hydroxide solution. The titration of the sponge in terms of carboxylic acid groups showed that there were more acid groups present after the oxidation than before. The increase in carboxylic acid content due solely to ring oxidation is 6%. Sponges are soft, have fine pores and will absorb 15 times - or weight in water. These sponges can be sterilized with gamma irradiation and after sterilization, the sponges implanted subcutaneously in rats abaorben within 10 days without visible reaction in the tissues. Carboxy and oxidized cellulose sponges produce good henostats. When tested in a model of splenic incision in pigs, these sponges will stop the hemorrhage in an average of 2.5 minutes, compared to oxidized cellulose fabrics (SURGTCEL), which stop the bleeding in 6.5 minutes. Sponges of oxidized carboxymethyl cellulose can also be used to fill tumorous beds, to cover wounds, as diaphragms for contraceptive control and as drug delivery systems. This method is preferred for the production of oxidized rnetylcellulose sponges.

EXAMPLE 4 Preparation of oxidized carboxymethylcellulose films Carboxymethyl cellulose solutions can be emptied onto a glass plate with a 2-hand blade and allowed to dry to give films which can also be oxidized by exposure to nitrogen dioxide gas, carboxy films and cellulose oxidized barriers can be used as absorbent barriers to prevent adhesions. A 3% aqueous solution of carboxymethyl cellulose grade 7MF with a degree of substitution of 0.90 from Aqualon was prepared and emptied onto a glass plate with a set of 2 handles to 762u openings. The film was left to be airborne throughout the night. The dried films (3 grams) were placed in a resin kettle which was flushed with nitrogen for 5 minutes to remove the air. A lateral arm was attached to the rec. Boiler. na, which communicated with a small flask containing 3 grams of cooled nitrogen dioxide. The liquid nitrogen dioxide was allowed to vaporize and diffuse into the body comprising the carboxymethyl cellulose films. The films were exposed to gas for a period of 20 hours. At this point, they were removed from the ream kettle and washed with water until the pH of the washings was above 3. The films were dried with isopropyl alcohol or acetone. Some were planted with 10% glycerol, which imparted flexibility to dry films. The films are more soluble in water but they dissolve in sodium hydroxide. When titrated as to their carboxylic acid content, they are found to have 26% by weight of acid content. The increase in the carboxyl content from ring oxidation is 7%. The films also absorb within 10 days when they are implanted subcutaneously in rats. These absorbable films are good barriers for the prevention of adhesions.

EXAMPLE 5 Preparation of oxidized cellulose acetate devices A 2% aqueous solution of water-soluble cellulose monoacetate available from Celanese Corporation was prepared and poured into trays. The solutions were dehydrated by freezing in a lyophilizer for 24 hours. By this procedure, soft white sponges were prepared. The sponges (3 grams) were placed in a resin boiler to which a lateral arm was connected to a flask. The resin kettle was flushed with nitrogen for 5 minutes. The flask was then filled with 3 grams of cooled nitrogen dioxide and the liquid was allowed to vaporize and diffuse into the cellulose acetate sponges. After 20 hours of exposure to the gas, the sponges were removed and washed with water until the pH of the wash water was greater than 3.0. The sponges were dried twice by washing with one liter of isopropyl alcohol. The sponges are white, soft and not water-soluble. They will dissolve in sodium hydroxide, and the titration of the sponge in terms of the carboxylic acid groups showed a carboxylic acid content of 13.3%. The sponges were tested for hemostatic efficacy and were found to stop the hemorrhage in a splendid incision model in pigs in 3 minutes when they averaged more than 5 tests comparatively with the oxidized cellulose a (SURGTCEL), which stopped the bleeding in 6 minutes in this same test. Cellulose acetate films can also be prepared by pouring an aqueous solution of the polymer onto a glass plate and allowing the solution to dry. The gaseous oxidation of the cellulose acetate films will produce oxidized cellulose acetate films, which are not water-soluble. Oxidized cellulose acetate is a bioabsorbable material and can function as a hemostat, wound dressing, adhesion barrier, controlled release device and in other medical functions where a bioabsorbable device is required.

EXAMPLE 6 Preparation of a mixed body of oxidized cellulose fabric and oxidized methylcellulose A dilute aqueous solution of 1.0% concentration of METHOCEL A15LV was prepared from Dow 20.

Chemical Company with a degree of substitution of 1.65, dispersing 1.0 grams of rneti-cellulose powder in 30 grams of water heated to 95 ° C. The mixture was continued until all the particles were completely soaked. To this dispersion 69 grams of cold water were added and the stirring was continued until all the powder was dissolved and the viscosity increased. A piece of 5 grams of knitted rayon fabric was immersed in a METHOCEL A15-LV solution for 20 seconds, and then it was removed and allowed to dry. The impregnated dry cloth weighed 5-25 grams, indicating a 5% uptake of methyl cellulose. The dry cloth impregnated with cellulose was placed in a resin kettle, which was flushed with nitrogen gas to displace the air and then exposed to 15 grams of nitrogen dioxide gas for a period of 16 hours. At the end of this period, the ream boiler was purged of the excess nitrogen dioxide by a nitrogen purge, which moved the oxidant to a caustic trap to neutralize the nitrogen dioxide. The cloth was removed and washed in 300 ml of isopropyl alcohol several times to remove the adhering oxidant. The tissue was then allowed to air dry. The titration of a sample of the fabric in terms of its carboxylic acid content indicated a carboxylic acid content of 18% and complete solubility in sodium hydroxide at 0.5N. The oxidized mixed body of the oxidized cellulose fabric impregnated with oxidized rnethylcellulose can be used to prevent post-surgical adhesions.

EXAMPLE 7 Preparation of a mixed body of oxidized cellulose cloth and oxidized carboxymethylcellulose An aqueous solution at 2.5% carboxymethyl cellulose grade 9M8 from Aqualon with a degree of substitution of 0.8-0.95, was drained on a woven rayon fabric and folded down with a 2-man blade, and it was dried. dried on the surface of the woven fabric, so that many of the pores of the fabric were covered by a thin film of carboxy ethylcellulose. The dry woven rayon fabric, with its thin film of carboxy-cellulose L-cellulose on the surface (weighing a total of 10 grams), was placed in a boiler equipped with a magnetic stirring bar and a condenser-dewatered towards a caustic bath to prevent the pressure from increasing. A lateral arm was attached to the cap of the resin kettle, which led to a small flask in which 15 grams of cold nitrogen dioxide were placed. The nitrogen dioxide was allowed to slowly evaporate in the ream kettle and cover the mixed body of woven rayon and carboxymethylcellulose film. After 20 hours of exposure, the excess gas was degassed with nitrogen gas and the cloth was removed and washed in 500 rnl of isopropyl alcohol several times. The cloth was allowed to air dry and a small sample was titrated as to its acid content, which was found to be 20% carboxylic acid. The oxidized sample was completely soluble in 0.5 N sodium hydroxide. The oxidized carboxy-ethylcellulose film on the surface of the oxidized woven rayon fabric was difficult to delaminate. When it was implanted subcutaneously in rats, the material was absorbed within? R days with minimal reaction in the tissues. The immediate body can be used to prevent post-surgical adhesions.

EXAMPLE 8 Preparation of oxidized carboxymethylcellulose powders and oxidized methylcellulose A suspension of ethylcellulose powder or carboxymethylcellulose is obtained in an inert solvent such as carbon tetrachloride. The suspension is exposed to a nitrogen dioxide solution in the inert solvent for 2-48, preferably 4-16 hours. At the end of the period, oxidized carboxymethylcellulose powder or oxidized methylcellulose is filtered from the solvent and washed in 90% isopropyl alcohol, 10% water or 90% acetone, and 10% water to remove excess dioxide gas. nitrogen. Oxidized carboxymethylcellulose powder or oxidized methylcellulose powder is dried with 100% acetone or 100% isopropyl alcohol to produce a white powder. The oxidized methyl cellulose powder will form an aqueous solution which can be filtered to remove all more soluble material. Solutions of met 11 oxidized cellulose of concentration between 0.5 and 5% can be drained on glass with a casting knife and allowed to dry on films, or the aqueous solution can be dehydrated by freezing in sponges. The oxidized methyl cell polymer can also be precipitated from aqueous solutions by viewing the solution in acetone or isopropyl alcohol, which are non-solvent for the polymer. By this method, bioabsorbable lubricants for gloves, lubricants for instruments and modi? Ed release agents can be obtained.

EXPERIMENTAL METHODS All animals are blindly and randomly assigned to a treatment group, which is revealed to the surgeon only after the abrasion has ended. All evaluations are done on a blind basis.

Model of pericardial adhesions in rabbits Under anesthesia, the thorax of white rabbits of New Zeeland is penetrated through a sternal incision in the midline. The pericardium is opened similarly, and the antepor surface of the heart is cut 40 times using a piece of gauze wrapped around the index finger. If an absorbable fabric or barrier such as the present invention is to be used, then an elliptical piece with shafts of about 5.08 cm x 7.52 cm is placed on the anterior surface of the heart, and may be saturated to the pericardium if desired. The thorax closes in layers. Twenty-three to thirty days later, the animals are sacrificed and the adhesions between the anterior surface of the heart and the lower surface of the sternum are evaluated. The percentage of adhesion formation of a strip 1 crn in width and extending from the apex to the base of the antecardiac surface is estimated. This strip represents the surface of the heart that is in intimate contact with the sternum and where adhesions are more likely to form and cause problems for the surgeon who is trying to regain access to the chest.

Model of the uterine horn in rabbits The pattern of adhesions of the uterine horn in rabbits was executed as described by Lins and others. Lmsky CB, Diamond MP, Cunningharn T, Constantme B, DeCherney AH, diZerega G. Adhesion reduction in the rabbit uterine horn model using an absorbable barrier- - TC7. J. Repro. Med. 32: 17-20,1987). Under appropriate aseptic anesthesia and technique, and using New Zealand female white rabbits (2-2.6 kg), the abdomen was penetrated through an incision in the ventral midline. Using a scalpel blade of LO number, lengths of 5 crn on both sides of each uterine shaft, starting approximately 1 cm from the uterine bifurcation, were scraped 20 times. Hemostasis was achieved by tamponade. The wound was closed in layers. Two weeks later, the animals were euthanized and the adhesions evaluated "blind" according to the following standard system. The extension of the adhesions was quantified by measuring the length of the uterine horn that had adhesions. The following scores were assigned: 0 = No adhesions 1 - 25% of traumatized area with adhesions 2 - 50% of traumatized area with adhesions 3 - 100% of traumatized area, that is, length of 5 crn wrapped with adhesions. The tenacity of the adhesions was classified as follows: 0.0 = No resistance to separation 0.5 = Abridious dissection required to achieve separation 1.0 - Severe dissection required to achieve separation The tenacity and extension scores were added to give a possible maximum score of 4, representing both the extent and severity of the inheritance.

EXPERIMENTAL RESULTS Model of cardiac adhesions A film of rnet ilcel ulosa (grade A15C from Dow Chemical) was oxidized in the gas phase by exposure to nitrogen tetroxide gas. After washing and irradiation, it was tested in the pattern of cardiac adhesions in rabbits by immersion in saline and then pressing on an absorbable adhesion barrier sheet INTERCEED "(TC7) An elliptical piece of this mixed body (5.08 crn) x 2.54 cm approximately) was placed on the anterior surface of the heart, and four weeks later, the adhesions were evaluated and an important reduction in adhesion formation was observed.

Animal number Percentage of adhesions Cont rol (without treatment) 217.03 100 218.33 100 218.49 80 218.04 90 Average 92.5 D.E. 9.57 N 4 I put 1 oxidized cellulose on barrier INTERCEEDR 217.04 50 217.02 100 219.53 80 218.32 15 218.03 10 Average 51 D.E. 39.4 N 5 Using the Student's t-test, there was a statistically significant decrease in adhesion formation when the mixed body of methylcellulose 3 b was used Oxidized / INTERCEED barrier (P <0.05). Historical results from a number of experiments, give an average score of adhesions of approximately 80%.

Oxidized methylcellulose tel (OMC) in the model of the uterine horn in rabbits Inethylcellulose powder (MFTHOCE Grade A4M from Dow Chemical) was oxidized in the gas phase and sterilized by irradiation (1.8 MRad) on dry ice. To 7.5 g of this sterile material, 115 rnl of sterile water and 3 rnl of sodium glycine (5% w / v) were added as regulator of μl-l. Unlike the non-oxidized material which dissolves slowly, the oxidized rnet-cellulose powder dissolves rapidly and easily by stirring for 1 minute to form a viscous solution. For comparative purposes, a 2% w / w solution of sodium carboxy ethylcellulose (CMC) (Hercules, 7H4F) was obtained using a mixer. This is a non-degradable material that forms a solution only after vigorous agitation. The carboxy etiicellulose was used as a positive control, since it has been previously demonstrated that it reduces the formation of adhesions (Viscoelastic fluid for use in spine and general surgery and other surgery and therapies and method of using same.) Pennell PE, Blackrnore JM, Alien U.S. Patent No. 5,156,839 of October 20, 1992; Diamond, MP., DeCherney, AH, Lmsky, CB, Cunningha, T., Constant e, B., Assesment of carboxymet hylcellulose and 32% dextran 70 for prevent ion of adhesions ma rabbit uterine horn model, Tnt Fert 33, 278-28 ?, 1980). The carboxymethylcellulose and the oxidizedcellulose solutions were of comparable viscosity. The patron model of the uterine horn was developed in rabbits. Shortly before closure, 20 ml of the solutions of carboxyinet icelulose or rnet ilcelulose oxidized were instilled into the abdominal cavity. Two weeks later, the adhesions were blindly evaluated.

Percentage without adhesions N P Control 17 12 Carboxymethylcellulose 42 12 0.0331 (not degradable) Methylcellulose 50 20 0.0055 oxi ada (degradable) N = Number of antlers evaluated P = probability of a tail using the Ch? ~ Square test, comparing the treatment with the control This result shows that a degradable gel of oxidized rnetylcellulose is able to reduce the adhesions to a degree comparable to the effect found for the carboxunet celu1 os. The present invention provides many advantages over the prior art. For example, previous teachings regarding cellulose derivatives appear to be limited to those which are not degradable by hydrolysis, but are perhaps eliminated from the intact body, or are sequestered by the endothelial system. The materials of the present invention provide similar physical or chemical properties, but can be degraded into small excretable fragments by simple hydrolysis. In the form of a film or sheet, these materials can be useful for the prevention of adhesions or as hernostats. Matepals can also be formed into sponges, mainly for use as hernostics. However, an oxidized rnetiicellulose sponge placed in a specific location within the body would quickly dissolve in a protective gel. These sponges can also be used to absorb fluids from the exudation of wounds, since they absorb at least a few times their weight of saline solution. Films or sponges can be used as a primary wound dressing to protect the wound and provide a moist environment for healing. All these materials have acid groups which can make them bactericidal. This is a particular advantage in the reduction of infections. Acid sites can also make these materials suitable for binding with certain drugs, providing a matrix pair-to its controlled release. For example, growth factors can be bound to the acid groups and subsequently released into the body cavity by ion exchange or as the polymer degrades. The viscoelastic nature of these materials makes them useful for a number of applications apart from the prevention of adhesions or release of drugs by acid binding. The viscous nature of the solutions or films of these materials alone may be useful for the release of drugs. The materials can also be useful as a degradable surgical lubricant for instruments and gloves. The use of these degradable materials as mold release agent for medical devices or as dust for glove lubrication, is a distinct advantage over the use of talc or starch which some glove users prefer to avoid. Oxidized carboxymethylcellulose or rnetylcellulose powders can be prepared by the suspension method described in Example 8. These materials provide similar characteristics to other materials which are more expensive or difficult to characterize because they are derived from natural sources or from fermentation. Such materials include hyaluronic acid, hepapna, chondroitme sulfate and dextran. Thus, the relatively inexpensive and easy to standardize materials of the present invention can be used as blood exsanosols, and as viscoelastic aids in ocular and orthopedic surgery and tissue expander materials. The materials produced can be sterilized by irradiation. Interleaving and derivatization methods known in the art can be used to refine the characteristics of the materials described by this invention, or to bind, covalently or otherwise, certain drugs to the patient. materials. The use of entanglement agents, such as di-ethiolurea (b? S (N- (hydrox? Met? I urea)), sulfur divirulica, etc., with the derivatives of oxidized cellulose, will retard their bioabsorption and will allow them to last in In some cases, this attribute can improve its performance.A lightly interlaced gel of oxidized etiicellulose will have greater gel strength and will be a little firmer than gels that do not enter the oxidized materials. drug release vehicles, and may also have pharmacological effects on themselves In the following experiment, the effects of regenerated oxidized cellulose alone and impregnated with hepapna were examined with respect to control of restenosis after trauma to a blood vessel. get similar results for other oxidized cellulose materials.The endothelium is removed from a length of 4L The common carotid artery in anesthetized rats. The portion of the blood vessel which was damaged is then wrapped with a piece of INTERCEED regenerated oxidized cellulose or with INTFRCEED, which is impregnated in situ with 400 U of USP injection of sodium hepapna. A third group does not receive treatment after the injury. A fourth group has 400 U of hepapna injected around the site of injury. Each group contained 5 animals. Measurements are made of areas of lumen, intima and media on cross sections of arteries recovered 20 days after surgery. Below are results, in which the numerical values represent the average cross-sectional area in square micrometers: Media Intima Lumen Hemorra ia Control 194,517 268,672 380,241 Absent INTERCEED alone 225,146 161,011 549,935 Absent INTERCEED and 218,260 107,529 630,026 Hematoma moderate heparin Heparma alone Death due to hemorrhage Two animals which were treated only with hepapna died of hemorrhage. Thus, this control group was not complete. However, only moderate hematomas in some of the animals treated with the same dose of INTERCEED heparma indicate that the hepapna was sequestered at the implantation site in the presence of INTERCEED. The loose endothelium associated with vascular surgery can produce thrombosis and restenosis at the site. Fsta is an important complication of all vascular surgery. The systolic release of drugs such as heparma to treat these conditions is not satisfactory due to the high dose levels that are required. Thus, local liberation is the preferred way. The results show that a matrix of regenerated oxidized cellulose impregnated with hepapna provides controlled local release of hepanna and a significant reduction in the damaging effects of trauma to the artery. Significantly, oxidized regenerated cellulose alone produced substantial results on the control group, indicating that regenerated oxidized cellulose has pharmacological activity on it as well. Although the invention has been described particularly in relation to specific embodiments thereof, it should be understood that this is by way of illustration and not limitation, and that the scope of the appended claims should be constructed as broadly as the prior art allows. . The oxidation of cellulose derivatives to produce bioabsorbable polymers is not limited to the examples herein, but may be extended to other derivatives such as those containing aliphatic groups attached to the cell ring.

Claims (44)

NOVELTY OF THE INVENTION CLAIMS

1. - A bioabsorbable material comprising oxidized inetcellulose with a replacement grit before oxidation of 0.50 to 1.9? and wherein the oxidized L-cellulose is bioabsorbable and hi-rosol a carboxylic acid content from ring oxidation between 1 and 10%.

2.- A material in accordance with the claim 1, further comprising a sufficient amount of water or pH regulator physiologically acceptable to form a gel.

3. A material according to claim 1, formed by the oxidation of rnet i icelulose in the presence of an oxidant selected from the group consisting of? of nitrogen dioxide or nitrogen tetroxide.

4. A material according to claim 1, wherein the carboxylic acid content of the oxidized cellulose is about 3-10%.

5.- A material in accordance with the reiviication 1, which is sterile.

6.- A material in accordance with the rei indication 1, further comprising a sufficient amount of water to form a gel and wherein the water gel and the oxidized cellulose ether is impregnated in a sheet formed of a second bioabsorbable material. 4+ | ': -.

7 - A material according to claim h, wherein the second bioabsorbable material is cellulose ex i given.

8.- A bioabsorbable material comprising an oxidized extruded poly ..

9 ..- A material in accordance with the claim 8, wherein the polysaccharide is selected from the group consisting of: et 11 ulosa cell, inet il cel ulosa, carbox metiicel ulosa or cellulose acetate.

10. A material in accordance with the claim 9, where the polysaccharide comprises carboxy etii cellulose with a degree of substitution between 0.38 and 1.45.

11.-A material in accordance with the claim 10, wherein the carboxylic acid content due to the oxidation of the primary alcohol of the cellulose structure is 3 to 12% by weight.

12. A material according to claim 8 in the form of a film, wherein the oxidized film material is plasticized with polyhydroxyalcohols such as glycerol or propylene glycol to impart flexibility.

13. A material according to claim 8, wherein the polysaccharide comprises ullage.

14. A material according to claim 8, wherein the polysaccharide comprises cellulose acetate.

15. A material according to the claim. 8, wherein the polysacchar or is selected from the group consisting of: starch, algmate, guar, konjac, dextrin, dextr-, pustula and cicLodext p na.

16. A material according to claim 8, which is sterile.

17. A material in accordance with the rei indication. 8, in the form of a movie.

18. A material according to claim 8, in the form of a gel.

19. A material according to claim 9, in the form of a sponge dehydrated by freezing.

20. The use of a bioabsorbable material obtained by oxidation of a polysaccharide comprising a cellulose derivative in the preparation of a composition to inhibit adhesions in a body in the susceptible to adhesions.

21. The use according to claim 20 and wherein the bioabsorbable material is a sterilized material.

22. The use according to claim 20, wherein the oxidant is selected from the group of nitrogen dioxide and nitrogen tetroxide.

23. The use according to claim 20, wherein the cellulose derivative is selected from the group consisting of the cellulose, methyl cellulose, carboxy etiicellulose or cellulose acetate.

24. The use according to claim 20, wherein the carboxylic acid content in the oxidized bioabsorbable material due to the oxidation of the primary alcohol of the cellulose derivative, it is 1 to 12% by weight.

25. Use FL according to claim 21, wherein the cellulose derivative compresses carboxy and l-cellulose with a degree of substitution between 0.38 and 1.45.

26.- The use of consistency with claim 3, wherein the cellulose derivative compresses ethyl cell with a degree of substitution between 0.3 and 1.0.

27.- The use of conformity with claim 3, wherein the reiulose derivative comprises cellulose acetate with a degree of substitution between 0.3 and 1.0.

28. Use in accordance with claim 23, wherein the cellulose derivative compresses the cellulose with a degree of substitution between 0.5 and 1.92.

29. The use according to claim 8, wherein the bioabsorbable material includes a sufficient amount of water or a physiologically acceptable pH regulator to form a g.

30. The use according to claim 27, wherein the gel is a gel impregnated on a bioabsorbable substrate.

31. The use according to claim 30, wherein the cellulose derivative is a cellulose derivative impregnated on a cellulose precursor of the fabric of the same time.

32. The use according to claim 30, wherein the substrate comprises a fabric composed of a bioabsorbable material.

33. The use according to claim 32, wherein the bioabsorbable material of the fabric comprises: oxidized cellulose, polyacid-glycolic acid, polyoxanone, polyacaprolactone, pol lanhi dp do, polyac One way, polyglucose, gelatin, collagen, elastma, pol i fospazeno, hyaluronic acid, poliort oester, or a combination of the same.

34. The use according to claim 32, wherein the substrate comprises oxidized cellulose.

35. The use according to claim 14, wherein the gel and the substrate are used by placing them in the thoracic cavity to inhibit cardiac adhesions.

36. The use according to claim 9, wherein the gel or article is used by placing them in the pelvic, peritoneal, cranial cavity or other body cavity, or around tendons, ligaments or eyes to inhibit adhesions. .

37. The use according to claim 29, wherein the gel is applied to the site of the body through a lumen in an endoscope, 38.- The use according to claim 37, wherein the methy] cellulose It is in the shape of a sponge. 39. The use according to claim 38, wherein the oxidized methylcellulose is further washed in a solvent for the oxidizing agent, but not in a non-solvent for the oxidized methylcellulose. 40. The use according to claim 39, wherein the solvent is selected from the group comprising: Lsopropyl alcohol and water. 41. The use according to claim 39, wherein the oxidized cellulose is in the form of a solution containing 1-10% oxidized methyl cellulose. 42.- The use of conformity with claim 39, wherein the oxidized ulcerous cell is in the form of a pei i cill. 43.- The use of consistency with reagent 39, where the oxidized methylcellulose is in the form of a spool. 44. The use according to claim 0, wherein the cellulose derivative is a cellulose derivative impregnated on the surface of a cellulose fabric.