FR2759083A1 - Biodegradable collagen containing hydrophilic polymer - Google Patents

Abstract

A biocompatible collagenic material that is non-toxic, potentially adhesive, and biodegrades within a week comprises a crosslinked collagen, and a macromolecular hydrophilic additive, chemically inactive towards the collagen.

Description

 The present invention relates to a biocompatible, non-toxic, potentially adherent and rapidly biodegradable collagen material. It relates more particularly to a collagen material capable of inhibiting the formation of postoperative adhesions.

 The invention also relates to a process for obtaining such a material.

 Post-operative adhesions develop after surgery in a patient whose organs have suffered trauma caused by the surgical procedure itself.

Wounds created by dissection of organs and tissues, or any other intervention are characterized by two phenomena
these wounds are not watertight and spontaneously exude a plasma liquid containing fibrin, sometimes even blood if the hemostasis could not be completed in a perfect manner; certain organs allow other fluids to ooze, such as liver bile or cerebrospinal fluid in the nervous system.

 the injured surfaces no longer have an organized and stable tissue barrier and sometimes even are strewn with foreign bodies: suture threads, staples, clots, infectious agents, tissue burned by electrosurgical units or laser beams.

 These two characteristics cause the body to react, starting with inflammation and continuing with intense cell migration and proliferation, which are generally poorly organized. These most often create neoformed, fibrous, vascularized tissues, connecting the injured organs to neighboring organs.

 Many journals have been published on the subject (see in particular Dl ZEREGA (1994)).

 Various solutions have already been proposed, in particular on the pharmacological level, with more or less success.

 The most effective solution that we know to date is to put a physical barrier on the wound, isolating the organs from each other and allowing them to heal independently without developing interrelations.

 The physical barriers that lead to the best results are made of artificial, non-degradable tissue, on which the cells do not attach. Teflon g and silicone are among the most effective polymers.

 The major disadvantage is that these physical barriers must be removed several weeks later, with a second surgical operation which can, in addition, itself create other secondary adhesions at the level of laparotomy.

 It is therefore essential to develop biodegradable barriers which avoid a second intervention.

 For this purpose, many natural biodegradable polymers have already been proposed, starting from gelatin, collagen, polysaccharides, mucopolysaccharides, etc. but these have not led to satisfactory results.

According to the RODEHEAVER team (HARRIS et al., 1995)
The minimum objective is that the barrier remains present for at least 36 hours. This is due to the fact that a minimum time is necessary to allow the complex healing mechanisms.

 However, the absorption time should not be too long. If the material remains in contact with the wound for more than a week, it can cause persistent inflammatory reactions that promote an unorganized and larger fibrous reaction, and which can locally cause anatomical problems: thickness, rigidity, shrinkage, ischemia, granuloma or a persistent focus of infection especially in contact with the intestines and digestive organs.

 In addition, it appears that the material to serve as a physical barrier should adhere properly to injured tissue, especially for the protection of organs that are mobile or subject to variable distensions such as the intestine, or more simply to avoid migrating in response to movement. of the patient and the mechanical stresses which these entail.

 The difficulty of obtaining all these properties combined in the same biomaterial explains why the solutions and products offered to date still prove to be very insufficient.

 The biodegradable products marketed today for the prevention of adhesions are only partially active and give still insufficient results.

The cellulose derivatives marketed by Johnson & Johnson
Medical (Arlington, Texas, USA), such as products
SURGICELL or INTERCEED, cannot be used in the presence of blood and show, in certain animal models, disappointing results (HARRIS et al., 1995); on the other hand, they degrade in more than two weeks.

 The product SEPRAFILM OR, marketed by Genzyme, (Cambridge, Massachusetts, United States) is a film of hyaluronic acid and carboxymethylcellulose which appears only effective in half of the cases (BECKER et al., 1996). It degrades very quickly in a few days, but is difficult to handle. It is fragile, brittle and impossible to use through a laparoscopic trocar. Finally, it is not sufficiently adherent and can migrate at a distance, leaving the wound unprotected.

 Among the products recently described by researchers in the literature or published patent applications, it appears that many problems still remain unsolved.

 Among these, various collagen materials have been proposed.

KHOURY et al. (1994), for the company COLETICA (Lyon,
France), offer a collagen membrane consisting of two layers, one based on native collagen, forming a support and covered with a second layer of gelatin. The design of this membrane is inspired by a visceral surgery patch developed by
TAYOT et al. (1988). This material has a degradation time very much greater than 1 week and therefore does not have the essential property which is to disappear in less than 7 days. But above all it has the disadvantage of not being sufficiently adherent and consequently of requiring stitches for its application, which can cause undesirable complications.

 ORLY I. in 1994, for the company COLETICA, proposed a transparent collagen membrane, consisting of a single layer or two layers according to the examples, and most often associated with a non-degradable prosthesis, for the treatment of hernias or events. This membrane must be stapled or sutured; it is therefore not sufficiently adherent to be used without artifices.

To facilitate stapling, the transparency of the membrane is necessary to avoid injuring sensitive areas (nerves, vessels) as in inguinal hernias. The risks associated with stapling of hernial prostheses in particular are well known.

For this reason, surgeons would be more interested in bonding these prostheses, thus avoiding any sutures or staples.

ORLY I. specifies, surprisingly, that this membrane must not be adhesive, since the membrane developed by KHOURY et Coll.

in the same company COLETICA (cited above) cannot be used in this indication, due to its adhesive properties which do not facilitate introduction into laparoscopic surgery. The resorption time of this membrane is very much greater than 1 week since, at 5 weeks, the resorption is not complete and it is necessary to wait 3 months for the total elimination of the material. Despite these very long delays, the depositor paradoxically affirms the advantage of a relatively rapid absorption time.

YEUNG et al., For Collagen Corporation (Palo Alto,
California, United States) proposed, in 1995, to bind to a collagen substrate, an anti-adhesion agent derived from polyethylene glycol by covalent bonds. This product is very complex to produce and requires the use of polyethylene glycol derivatives which are difficult to manufacture, expensive and not without the toxic risks associated with their chemical reactivity. Finally, the resorption time of this material consisting of dense collagen is also much more than 1 week, since the minimum resorption time mentioned is 10 days and most often 30 to 50 days.

TARDY et al., In 1994 in a patent for the company
IMEDEX, now called SADUC, offer a liquid biological glue derived from collagen, which has anti-adhesive properties. The advantages of this product include its adhesion and rapid degradation in a few days. The adhesive properties come from the crosslinking of collagen molecules oxidized to periodic acid and kept liquid at acid pH. This crosslinking is triggered by the addition of an alkaline solution, or buffer, which neutralizes the pH and rapidly transforms the oxidized collagen solution into an adherent solid. The effectiveness of this product in the prevention of post-operative adhesions, demonstrated in several animal models, is however not easily exploitable in practice. Indeed, this product requires permanent storage in frozen form, difficult to achieve in current hospital circuits.

 Various collagenous biomaterials obtained by crosslinking of collagen after oxidation with periodic acid were also described in a patent by M. TARDY et al., In 1986. Films of crosslinked oxidized collagen were prepared by drying under a stream of sterile air. of oxidized collagen solutions with added glycerin. These films have properties which are a function of the amount of glycerin used. In order to obtain flexible, non-brittle films having an acceptable resistance, it is necessary to use a sufficient quantity of glycerin, approximately equal by weight to the quantity of collagen.

However, under these conditions, they stick to their support, gloves and surgeon's instruments, lack rigidity because of their finesse and are very difficult to use if they are not combined with another material.

 The invention described below overcomes the drawbacks mentioned above.

 It aims in particular to provide a biocompatible material, non-toxic and non-sticky to the touch in the dry state for ease of handling but which can develop adhesive properties in an aqueous medium, in particular in a physiological medium.

 The invention also aims to provide a rapidly biodegradable material, namely in less than a week.

 The invention also aims to provide a collagen material suitable for use as a post-operative anti-adhesion barrier.

 Another object of the invention is to provide a method for obtaining such a material.

 To this end, the invention relates to a biocompatible, non-toxic, potentially adhesive and biodegradable collagen material in less than a week, characterized in that it comprises collagen and at least one hydrophilic macromolecular additive, chemically non-reactive vis with respect to collagen, the collagen being crosslinked.

The invention also relates to a process for obtaining a biocompatible, non-toxic, potentially adherent and biodegradable collagen material in less than a week, characterized in that it comprises
a) the preparation of a modified collagen solution by oxidative cleavage
b) treatment by heating at a temperature above
37 "C, of said solution
c) mixing the resulting collagen solution with a
solution containing at least one hydrophilic additive
macromolecular, chemically non-reactive towards
collagen present;
d) neutralization of said mixture until neutral pH.

 The inventors have discovered, surprisingly, that a mixture of crosslinked collagen and a macromolecular hydrophilic additive, could constitute a biocompatible and non-toxic material which is non-sticky to the touch in the dry state, adherent in an aqueous medium ( physiological) and biodegradable in a few days.

 They demonstrated that such a material could be obtained by crosslinking collagen previously modified by oxidative cleavage and heating, in the presence of a macromolecular hydrophilic additive, chemically non-reactive with respect to collagen.

 They discovered in particular that the presence of the hydrophilic additive made it possible, unexpectedly, to increase the density and the mechanical resistance of the collagen, to allow a satisfactory adhesion, in particular in physiological medium, to organs and to favor its degradation , which can thus be reduced to a few days.

 The following describes the process for preparing a collagen material according to the present invention.

 The collagen used to obtain a collagen material as defined above, can be either of animal or human origin. Native collagen is preferably used, solubilized at acidic pH or after treatment by digestion with pepsin. It may in particular be bovine collagen type I or human collagens type I or III or alternatively mixtures of these latter in all proportions.

 Collagen is modified by oxidative cleavage. For this purpose, periodic acid or one of its salts can be used according to the technique described by M. TARDY et al. (1986).

 It is briefly recalled that this technique consists in subjecting an acidic solution of collagen to the action of the periodic acid or one of its salts by mixing with a solution of this acid or salt at a concentration of between 1 and 10-5 M, preferably between 5 10-3 M and 101 M, at a temperature close to room temperature, for a period which can range from 10 minutes to 72 hours.

 According to the invention, an acidic collagen solution is used, the concentration of which is between 5 and 50 g / l. The collagen concentration is preferably 30 g / l.

 This treatment causes cuts in certain constituents of collagen which are hydroxyproline and sugars, and thus creates reactive sites without causing crosslinking.

 The oxidized collagen thus prepared in solution is heated to a temperature above 37 "C, preferably to a temperature between 40 and 50 C.

 The cross-linking of the collagen is then carried out in the presence of at least one hydrophilic macromolecular additive, chemically non-reactive with respect to the collagen.

 The term “chemically non-reactive with respect to collagen” means a hydrophilic compound which is not capable of reacting with the collagen present, in particular which does not form a covalent bond with it during its crosslinking.

 The macromolecular hydrophilic additive according to the invention has a molecular weight advantageously greater than 3000 daltons.

They may be synthetic hydrophilic polymers, advantageously of molecular weight between 3,000 and 20,000
Daltons. Polyethylene glycol is particularly preferred.

 They can also be polysaccharides, among which mention may be made of starch, dextran and cellulose which are preferred.

 It is also possible to provide for the use of teis polysaccharides in oxidized form revealing carboxylic functions in these molecules.

 Mucopolysaccharides may also be suitable for the purposes of the invention but are not preferred since their particular animal origin makes them difficult to prepare by meeting regulatory standards for traceability.

 The hydrophilic additive is selected according to various parameters linked in particular to its application, such as its price, its safety, its biodegradability and / or its ease of elimination, in particular by the renal route, in the event of therapeutic application.

 Said crosslinking is carried out by mixing, at neutral pH, a solution of collagen modified by oxidative cleavage and heating as indicated above, with a solution containing at least one hydrophilic macromolecular additive.

 The concentration of hydrophilic additive (s) is 2 to 10 times lower than that of collagen.

 The crosslinking of the collagen in the presence of the hydrophilic additive is carried out at a temperature of between 4 and 30 ° C., preferably 18 to 25 ° C.

 According to an implementation variant, provision is made for crosslinking in the presence of glycerin which can be added to the collagen / hydrophilic additive mixture. In this case, the glycerin concentration is advantageously between 3 and 8 g / l, not exceeding one third of the concentration of collagen.

 The polymerization takes place during the drying of the material.

 According to the invention, it is believed, without this being considered as limiting, that the hydrophilic additive which is present during the crosslinking of collagen, is contained in the collagen network formed, although it does not react itself with collagen.

Depending on the applications envisaged, the crosslinked collagen material can be subjected to various conventional treatments such as drying, sterilization, etc.
The crosslinked collagen can be dried in particular in a sterile air flow, if necessary.

 Sterilization is advantageously carried out by irradiation with beta radiation (electronic irradiation) or gamma radiation (irradiation with radioactive cobalt).

 According to the invention, the collagen material can be prepared in the form of a film, gel or paste.

 Depending on the applications envisaged, the collagen material is advantageously provided in the form of a film.

 According to a particularly preferred embodiment, the solution containing the collagen, having been modified beforehand by oxidative cleavage and by heating, a hydrophilic macromolecular additive, and optionally glycerine, is distributed uniformly on a substantially flat inert support, to form a film reticle.

 The support is inert in that it does not react with the above-mentioned compounds and does not intervene in the crosslinking process. A hydrophobic support of PVC or polystyrene type can be used.

 In this case, a solution is applied to the support in which the concentrations of collagen, hydrophilic additive and glycerin, if present, are preferably between 2 and 6% respectively for collagen, 0.6 and 2 % for the hydrophilic additive, 0.3 and 0.8% for the glycerin.

 The applied thin layer advantageously has a density ranging from 0.05 to 0.3 g / cm2.

 After reaction, the film is separated from the support.

 The collagen material according to the invention contains collagen and at least one hydrophilic macromolecular additive in a collagen / hydrophilic additive (s) ratio from 1/1 to 9/1, preferably from 2/1 to 4/1 and more preferably still from 3/1.

 It is stable at room temperature, and remains stable for a sufficient time for its manipulation, in aqueous medium at temperatures up to 37 to 40 ° C.

 The collagen material according to the invention is useful for the prevention of post-operative adhesions.

 It can be prepared in ready-to-use form, for example by cutting to the dimensions appropriate for the intended application, a film as described above and packaging under sterile conditions.

 When it is prepared in the form of a film, it is particularly suitable for this application, in particular for simplifying and accelerating the surgical procedure.

 Indeed, the collagen film obtained is easy to handle because it does not stick to the touch in the dry state and it does not stick to instruments.

 It also has increased density and mechanical strength while being relatively flexible as necessary.

 Glycerin improves the flexibility of the final material obtained, and can thus facilitate its use.

 The collagen material according to the invention is capable of developing, in an aqueous medium, adhesion properties.

 After implantation in a patient, it can adhere sufficiently to the organ to be protected, which enables it to hold in place and is therefore suitable for use as a post-operative anti-adhesion barrier. Indeed, in contact with the tissues, a call of tissue water causes an immediate adhesion of the collagen film.

The call of water gradually inflates the collagen film, the crosslinking of which is not very dense to allow a certain mobility and flexibility of the chains constituting it.

 There is thus formed in a few minutes to a few hours, an oxidized collagen gel, crosslinked and very hydrated thanks to the hydrophilic additive trapped in the mesh of the gel.

 This gel acquires sufficient adhesive properties to establish a stable adhesion of the biomaterial to the wound to be protected.

 In addition, the macromolecular hydrophilic additive disappears by diffusion through the oxidized and crosslinked collagen material, in a few days, a material whose swelling promotes degradation in less than 7 days, most often in 2 to 3 days.

 The invention will be described in more detail using the examples given below by way of illustration and not limitation.

EXAMPLES
Example 1:
Preparation of a modified collagen acid precipitate by oxidative cleavage using periodic and non-crosslinked acid.

 This example is directly made from the previously cited patent of TARDY et al. (1994).

 The collagen used is bovine collagen type I, extracted from calf dermis by solubilization at acid pH or by digestion with pepsin and purified by saline precipitation according to techniques already described.

 The products marketed by COLLAGEN Corp., under the names of VITROGEN g or ZYDERM, may be suitable in this application.

 Dry collagen fibers are preferably used, obtained by precipitation of an acidic collagen solution by addition of NaCl, then washing and drying of the precipitate obtained with aqueous solutions of acetone of increasing concentration from 80% to 100%.

 One can, in the same way, use human collagens of type I or III or their mixture in all proportions.

 A 30 g / l collagen solution is prepared by dissolving in 0.01 N HCl. Its volume is 49 liters. It is added with periodic acid at a final concentration of 8 mM or 1.83 g / l.

 Oxidation is carried out at ambient temperature close to 22 "C, for 3 hours away from light.

Then, the solution is added with an equal volume of a sodium chloride solution to obtain a final concentration of 41 g / l
NaCI.

After waiting 30 minutes, the precipitate is collected by decantation through a sieve of fabric with a porosity close to 100 microns, then washed 4 times with a NaCl solution 41 g / l in HCl 0.01
N. 19 kg of acid saline precipitate are obtained. These washes allow the elimination of all traces of periodic acid or iodine derivatives formed during the oxidation of collagen.

 Then, several washes in 80% aqueous acetone solution allow the concentration of the collagen precipitate and the elimination of the salts present.

 A final washing in 100% acetone makes it possible to prepare 3.6 kg of a very dense acetone precipitate, of acid oxidized collagen, non-crosslinked, containing no other trace of undesirable chemical product.

Example 2:
Preparation of post-operative anti-adhesion collagen films according to the invention.

 The acetone paste prepared according to Example 1 is taken up in pyrogen-free distilled water at 40 "C, to obtain a collagen concentration of 3%.

 The 44 liter solution is heated for 30 minutes to 50 "C, then sterile filtered through a membrane with a porosity of 0.45 microns in an oven at 400 C.

 This solution is added at 30 ° C. to a concentrated sterile solution of PEG 6,000 (polyethylene glycol of molecular weight 6,000 Daltons) to reach a concentration of 1% in PEG, then of glycerin to reach a concentration of 0.6 % glycerin.

The pH of the solution is adjusted to 7.0 by adding a concentrated solution of NaOH sodium hydroxide.

The solution is then adjusted in volume with sterile water to reach a final concentration of 2.7% collagen, 0.9%
PEG and 0.54% glycerin, then distributed in a thin layer at a density of 0.133 g / cm2 on a hydrophobic flat support of PVC or polystyrene type. The surfaces are then subjected to a stream of sterile air at room temperature, which leads to evaporation in about 18 hours.

 The film obtained comes off very easily from the support. It can be easily cut to the dimensions desired for the experiment.

 Each film is individually packaged in a primary vapor-permeable sachet, then incubated for 12 hours in an oven at 37 ° C whose relative humidity is greater than 80%.

 Then, the previous sachet is included in a secondary packaging that is not breathable.

 The whole is sterilized by beta irradiation and receives a dose greater than or equal to 25 kilogreys.

 In general, the dried film still contains residual water up to a concentration of up to 20%.

 A typical composition in the example considered is 60% by weight of collagen, 20% by weight of PEG, 12% by weight of glycerin and 8% by weight of water.

 The film obtained is stable at room temperature. It remains stable and easy to handle after 2 hours of incubation in water at 37 "C.

 The presence of glycerin in the material is not essential; it improves the flexibility of the film and facilitates its use.

This example can be carried out by replacing PEG 6,000 with soluble starch (OSI France catalog, reference A2620) or with Dextran T40 (PHARMACIA Fine Chemicals catalog, Uppsala,
Sweden) or by carboxymethylcellulose. The concentrations used and the procedure are identical.

STUDY OF THE PROPERTIES OF THE COLLAGENIC FILM ACCORDING TO
INVENTION IN THE PREVENTION OF POST ADHESIONS
OPERATORIES.

Toxicolociy
The collagen-PEG film produced according to Example 2 (or a ground product of this film) gives satisfactory results in the standardized toxicological tests to which the biomaterials for implantation are subjected.
. absence of mutagenicity in the AMES test
. normal, moderate reaction in hypersensitivity test
delayed on guinea pig (class III reaction)
. absence of systemic toxicity intravenously or
intraperitoneal in mice and rats. degradation:
. in less than 7 days by subcutaneous route in rats
in 2 to 3 days intraperitoneally in rats.

Post-operative anti-adhesion properties
The post-operative anti-adhesion properties were analyzed according to the protocol described with reference by HARRIS et al.

(1995).

 The protocol described in this publication was carried out on groups of 10 rats.

 The tests consist in creating an abrasion and a dehydration on surfaces of 2 cm2 of peritoneal wall and cecum, in contact with each other.

 The control rat group received no wound protection product thus created. It is compared to the group of rats which receives a collagen-PEG film according to Example 2, completely covering the wounds, extending 5 mm over the non-abraded external parts.

After 7 days of waiting, in accordance with the published protocol, the results are clear
No adhesion is observed between the two surfaces
injured, in the group of rats treated with the film of the invention
and the healing of each initial wound is complete.

 . All traces of the film have disappeared.

 The group of control rats, not treated with the film of the invention, shows adhesions for each of the 10 rats, the characteristics of which are identical to the results published in the document HARRIS et al. (1995) mentioned above.

REFERENCES 1. Dl ZEREGA GS (1994) - ((Contemporary adhesion prevention,
Fertility and Sterility. 61 (2), 219-235.

2. HARRIS ES - MORGAN RF - RODEHEAVER GT (1995)
Analysis of the kinetics of peritoneal adhesion formation in the
rat and evaluation of potential antiadhesive agents, Surgery,
117 (6), 663-669.

3. BECKER JM - DAYTON MT - FAZIO VW - BECK DE
STRYKER SJ - WEXNER SD - WOLFF BG - ROBERTS PL
SMITH LE - SWEENEY SA - MOORE M. (1996) - ((Prevention
of postoperative abdominal adhesions by a sodium hyaluronate
based bioresorbable membrane: A prospective, randomized,
double-blind multicenter study)>, The J. of Amer. College of
Surgeons, 183 (4), 297-306.

4. KHOURY W. - ABDUL-MALAK N. - HUC A. (1994) - ((Membrane
postoperative anti-adhesion collagen, Request for
patent in France N "94 06995 of 08.06.94 (published under N
2,720,945).

5. TAYOT JL - MARESCAUX J. - DUMAS H. - TARDY M. (1988)
Visceral surgery patch, Patent US-A-5,201,745 issued on 13
April 1993 (under priority of French patent application N 88
03321 of 15.03.88, issued on 13.07.90 sub / e N 2 628
634).

6. ORLY I. (1994) - es Use of collagen membranes as peritoneal
renewing prostheses, WO international patent application
96/082 77 (under priority of the French patent application
N 94 11 015 of 15.09.94).

7. YEUNG J.E. - CHU G.H. - DE LUSTRO F.A. - RHEE W.M.

(1995) - Anti adhesion films and compositions for medical
use, European patent application N 96 102 339. 7 (published
under N 0 732 110J (under priority of patent application
American Serial N 403 360 of 14.03.95).

8. TARDY M. - TIOLLIER J. - TAYOT JL (1994) - Composition
adhesive, for surgical use, based on collagen modified by
oxidative and uncrosslinked cleavage - French patent application
N 94 00715. of 24.01.94, issued 02.08.96 under N 2 715309.

9. TARDY M. - TAYOT JL (1986) - Process for the treatment of
collagen, notably for facilitating its cross-linking, and the
collagen obtained by the application of the said process, Patent US-A-4 931546 issued 05/06/1990 (under priority of the
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12.05.89 under N 2 601 371).

Claims (16)

 1. Biocompatible, non-toxic, potentially adhesive and biodegradable collagen material in less than a week, characterized in that it comprises collagen and at least one hydrophilic macromolecular additive, chemically non-reactive with respect to collagen, collagen being crosslinked.  2. Collagenic material according to claim 1, characterized in that it comprises collagen modified by oxidative cleavage and heating above 37 "C, crosslinked in the presence of at least one hydrophilic macromolecular additive chemically non-reactive with respect to screw of said collagen.  3. Collagenic material according to any one of the preceding claims, characterized in that the collagen is modified by oxidative cleavage using periodic acid or one of its salts.  4. Collagenic material according to any one of the preceding claims, characterized in that the hydrophilic macromolecular additive has a molecular weight greater than 3000 Daltons.  5. Collagenic material according to any one of the preceding claims, characterized in that the hydrophilic additive is a hydrophilic polymer of molecular weight between 3,000 and 20,000 Daltons.  6. Collagenic material according to any one of the preceding claims, characterized in that the hydrophilic additive is polyethylene glycol.  7. Collagenic material according to any one of claims 1 to 5, characterized in that the hydrophilic additive is a polysaccharide preferably chosen from starch, Dextran and cellulose.  8. Collagenic material according to any one of the preceding claims, characterized in that it comprises collagen and at least one hydrophilic macromolecular additive according to a collagen / hydrophilic additive (s) ratio ranging from 1/1 to 9 / 1, preferably from 2/1 to 4/1 and even more preferably from 3/1.  9. Collagenic material according to any of the preceding claims, characterized in that it also contains glycerin.  10. Collagenic material according to any one of the preceding claims, characterized in that it is in the form of a film.  11. Method for obtaining a biocompatible, non-toxic, potentially adherent and biodegradable collagen material in less than a week, characterized in that it comprises  a) the preparation of a modified collagen solution by oxidative cleavage  b) treatment by heating at a temperature above  37 "C, of said solution  c) mixing the resulting collagen solution with a  solution containing at least one hydrophilic additive  macromolecular, chemically non-reactive towards  collagen present;  d) neutralization of said mixture until neutral pH.  1 2. Method according to claim 11, characterized in that, in step a) an acid collagen solution is prepared, at a concentration between 5 and 50 g / l, and it is mixed at room temperature, with a periodic acid solution or one of its salts, at a concentration between 1 and 10-5 M.  1 3. Method according to any one of claims 1 1 and 12, characterized in that, in step b), the modified collagen solution is heated by oxidative cleavage, to a temperature between 40 and 50 C.  1 4. Method according to any one of claims 11 to 13, characterized in that in step c), the hydrophilic additive has a molecular weight greater than 3000 Daltons.  1 5. Method according to any one of claims 1 1 to 14, characterized in that in step c), the hydrophilic additive is a hydrophilic polymer of molecular weight between 3,000 and 20,000 Daltons.  1 6. Method according to any one of claims 1 1 to 15, characterized in that in step c), the hydrophilic additive is polyethylene glycol.  1 7. Method according to any one of claims 1 1 to 16, characterized in that in step c), the hydrophilic additive is a polysaccharide preferably chosen from starch, dextran and cellulose.  1 8. A method according to any one of claims 1 1 to 17, characterized in that, in step c), the concentration of hydrophilic additive is 2 to 10 times lower than that of collagen.  19. Method according to any one of claims 11 to 18, characterized in that in step c), glycerin is also added.  20. The method of claim 19, characterized in that the glycerin concentration is between 3 and 8 g / l.  21. Method according to any one of claims 1 1 to 20, characterized in that a film is formed from the solution containing the modified collagen by oxidative cleavage and heating, at least one hydrophilic additive and optionally glycerin .  22. The method of claim 21, characterized in that the solution is applied in a thin layer, in a substantially uniform manner, on a substantially flat inert support, the crosslinking of the collagen is allowed to take place and then the film is separated from the support. form.  23. Method according to any one of claims 21 and 22, characterized in that the solution contains 2 to 6% of collagen, 0.6 to 2% of hydrophilic additive, 0.3 to 0.8% of glycerin and the thin layer applied to said inert support has a density of between 0.05 and 0.3 g / cm2.