CA2128463A1

CA2128463A1 - Adhesive compositions for surgical use

Info

Publication number: CA2128463A1
Application number: CA002128463A
Authority: CA
Inventors: Alain Constancis; Gerard Soula; Jean-Louis Tayot; Jerome Tiollier
Original assignee: Imedex SA
Current assignee: Imedex SA
Priority date: 1993-07-21
Filing date: 1994-07-20
Publication date: 1995-01-22
Also published as: FR2707878B1; BR9402861A; FR2707878A1; US5496872A; EP0635276A1; AU6757994A; JPH07163650A

Abstract

ABSTRACT
New adjesove compositions for surgical use The invention relates to an adhesive, biocompatible, biodegradable and non-toxic composition for surgical use, in particular for binding tissues, which composition is of the following general formula:

(I) in which:
- R is a hydrocarbon chain containing from 1 to 50 carbon atoms, - R1 and R2 are identical or different and are chosen from the following groups:
; ; - R3, R4, R5, R6 and R7 independently represent hydrogen or an aliphatic and/or alicyclic and/or aromatic group, -CH3 ; -CH2-CH3 ; -CH2-? ;

Description

~ 212~4~3 New adhesive compositions for surgi~al use The present invention relates to new adhesi~e compo~itions comprising compounds resulting, for example, from the conde~ation of a carboxylic diacid with a sulphur-containing amino acid or o~e of it~ deri~atives.
These products contain reactive thiol S~ functions which may oxidize to form disulphide bridges, leading to polymers which may or ~ay not be crossli~ked.
3iodegradab1e sy~thetic oligomers and polymers are already known, which ~ery often consist of simple hydrolysable (ester or am~ de~ chains of compounds capable of being degraded, forming metabolite~.
Thus, Patent Application EP 0,332,530 describe~
hydrophilic polymers with a degree of polymerization of 15 less than 1000, preferably between 20 and 300, and which consist of the polyamides resulting from the conden~ation of citric acid with diami~e~, such as lysine, cystamine and cystine.
The synthesis of these polyamides present~ real difficultie~ associated with the protection and then the deprotecticn of citric acid.
The~e biodegradable polyamides may be u~ed ~or the preparation of medicament carriers, sutures, liga~
tures or prostheses, or alternatively of surgical adhesives.
If, for certain applications, the use of polymers of relatively high mas~, of the type of those described in Patent Application EP 0,332 530, i~ advantagQous for other uses, the use of monomers or oligom0rs bearing reactive or polymerizable functions (prepolymers) is preferable. This is particularly the ca3e in reparatory surgery (bone-filling, surgical c~ments, biological ~ adhesives etc.) or in dental surgery (dental ceme~ts etc.). In these applications, it i8 advantageous for the monomer or prepolymer to be able to defu~o very readily into tho tissue to be repaired and thus to penetrate into all the interstitial spaces. The polymerization may then occur n in situ" and gi~e ri~e to an interlocking of the ~ u , . , ~ - , , , : .

- - 2 - 212~63 polymer chains which have the de~ired filling, cohesion or adhesion propertie~.
In this state of the art, one of the e~ential aims of the invention is to provide synthetic organic products which are biocompatible and biodegradable ~urgical adhesi~es ba~ed on non-toxic products.
Another es~ential aim of the in~ention i8 to provide such products compri ing synthetic organic products which are found in the form o~ prepolymers and/or monom~rs, capable of diffusing readily into biological tissue~ and of polymerizing in situ, or even in vivo, in order satiafactorily to ensure the adhesion functions.
These aims and othars are achieved by the pre~ent invention which relates, in the fir~t place, to a bio-compatible, biodegradable and non-toxic adhesive composi-tion for internal or external surgical use, which com-prises an organic product containing at least two thiol functions or derivatives and carboxylic functions, which may be protected or unprotected, and/or carbonyl func-tions, of the following general formula:
R3-S-(c~2)x-lH-NH-c-R-c-NH-cl~-(cH2)y~S~~4 O O O l=O
Rl R2 in which:
- R is a hydrocarbon, preferably alkylated, chain containing from l to 50 carbon atom~ and e~en more preferably an aliphatic chain ha~ing from 1 to 10 carbon ato~s, - R1 and R2 are identical or different and are chosen from the following group~:
O-R ; -N~-C~-(C~2) -5-R6 ; -NH-(C~2~y~S~R6 - R3, R4, ~5, R6 and R7 independently repre~ent , ... .

.,'J, ,' ' ' ' . . - , ' . . : - ~
':,~., . ', , ,, , " . :', ' :

- ~ 3 - 2 128~ ~3 hydrogen or an aliphatic and/or alicyclic and/or aromatic group, preferably a lower alkyl group and/or an aromatic group and, even more preferably, one of the following groups:
/ ~
-CH3 ; -CH2-CH3 ; -C~

~ , - x, y and z = 1 or 2.
For rea~on~ of aimplicity, t e aromatic rings are denoted by the Greek letter ~ throughout the pxesent O account.
In the sen~e of the present in~ention, the term "lower alkyl" denotes radicals containing from 1 to 6 carbon atoms.
The b~ological com~ou~ds corresponding to this ormula advantageously have a relatively low molecular weight (le~ than 2000) and may thus diffuse readily through the protein networks (collagen, elastin etc.~ or glycoprotein networks constituting the tissues. This i~
a property which it i8 adva~tageous to exploit in the field of adhesives.
A first sub-class o~ the products used in the context of the invention comprises those in which the radicals R1 and R2 represent OR5.
Even more precisely, when R3 and R4 correspond to hydrogen, this give~ an oligo~er which has, at each of its two end~, an S~ function borne by a cysteine unit or derivative ("di S~ oligo~er).
The~e S~ functions have the capacity to react with the~selves, in order to form disulphide bridges and to allow long chains to be obtained. This property may be exploited in order to prepare various adhesive products - ~uch as threads, films or viscous solutions which are biodegradable.
The prese~ce of carboxylic function~ on these di S~ compounds mak6s it pos~ible to e~visage inter-actions wlth other molecule~ (~or example natural macromolecule~). This tends toward~ an improvement in the 21284~3 4 _ adhesive properties. In addition, these carboxylic ~u~ctions lead to a hydrophilic nature and a capacity to bind active principles.
A second sub-clas~ which i9 typical of the products used in the context of the i~vention regroups the products corresponding to the general formula indicated abov~, in which the radical R1 repre~ents:
-NH-IH-(C~2)z-s-R6 a~d R2 represents -O-R5 or vice ~er~a.
When R5 and R6 consist Of hydrogen, these oligomer co~pounds may be termed a~ "tri SH~ oligomers.
Theao oligomers, the S~ end~ of which are capable of reacting to form disulphide bridg~s, allow po~sibilities of developmant of multidirectional networks to be glimpsed, which ca~ fmprove the ~echanical prop-ertiea, th~ virtueQ of adhe~ion and th~ raslstance tobiodegradation of the products accordi~g to the i~ven-tion.
A third sub-class of organic product~ which are used in the context of the invention con~ist~ of the products in which the radicals Rl a~d R2 consist of the radical:
-N~-f~- ' C~2 ) z-s R6 When R3, R~ and R6 correspond to hydrogen, a t~trafunctional oligom~r i8 defined which contains ~our SE units at its ends ( n tetra S~" oligomer). Thi8 multi-plicity of potential attachment points may be exploitedadvantageou~ly in the field of biomaterials. This i~ a~
~xten~ion of that which has been indicated above for the di- and trifunctional oligomer~.
The cysteic u~it used may be formed by cy~tei~e itself: x, y and z = 1 or by homocystein~: x, y and z 2, which may optionally originate from cy~tine or homo-cysti~e.

2128~63 ~he alkylated chain R, which i8 optionally -~ubstituted, de~ines the radical~
-C-R-C-11 11 ~ .
o O
in the formula (I), sueh that it belong~ to the cla~s of polyearboxylic, advantageously diearbo~ylie, aeid residue~, with the exclusion of citric acid, R preferably being ~eleeted from the following groups:

(CH2)p ; -fH~(CH2)q ; -fH-(CH2) with:
- p 5 5, preferably equal to 2 (sueeinic aeid) or 3 :
(glutarie aeid~, -0 - q 5 5, preferably equal to 1 (a~partic aeid) or 2 (glutamie aeid), - and fi~ally r 5 5, pre~erably equal to 1 (malie aeid).
R may al~o be eomposed of low-molecular-weight 1~ polylaetie and/or polyglyeolie and/or polyamino aeid ehains.
The~e oligomers whieh ar~ u~ed in the eo~text of the invention bear S~ funetione whieh impart to them eapaeitie~ for polymerization and/or eros~linking, 20 optionally in the presenee of an oxidizing agent. They :~
thus make it possible to obtain, a$ter oxidation, poly-mers whieh may or may not be erosslinked, whieh ~ay be used as biomaterials and may possibly be degraded to natural metabolites, i.~. which are in~olved in the 25 biological cycles of mammals. ~
Moreover, their size and thoir strueture are such ~ :
- that they ~ay readily migrate and penetrzte into mammalia~ biological tissues.
It follows that these oligomer~ may gain aecess without diffieulty to the target biologieal site~ and may polymerize "in situ" oo as to form an int~rlocking ~y~te~
and/or a network of polymer ehain~.

212~4 63 These oligomers thus ind their use as consti-tuents of the adhesive materials or compositions accord-ing to the i~vention.
In addition, the polymerization of the~e products by oxidation of t~e SH's to disulphide bridges may also be carried out in vitro and may thus allow the formation of mouldable articles or films, which may be used as biomaterials remaining adhesive.
The present invention also relates to an adhesive biomaterial comprising one or more polymers whlch are capable of being obtained from oligomer~, as described above and which correspond to the following general formula:

II) ~5 (CH2)x IH-NH-~CI-R-ICl-NH-7H-(c~2)y_S]
c=o o o 7=o ~1 R2 in which:
- R1 and R2 are identical or different and are chosen from the following groups:
-O-R5 ; -NH-CH-~CH2~ -S-R6 ; -NH-CH2-CH -S-R6 ;

with R5, R6 and R7 independently representing hydrogen or an aliphatic and/or alicyclic and/or aromatic group, preferably a lower alkyl group and/or an aromatic group and, even more preferably, one of the following groups:

-CH3 ; -C~2c~3 ; -C~2 ~
~: :
- R is cho~en such that the radical:
-C-R-C-O O

..... . . .

~ ~ 7 ~ 2~2~6~
of the formula (I) i8 a radical belonging to the class of polycarboxylic, adva~tageously dicarboxylic, acids with the exclusion of citric acid, preferably selected from the followi~g group~:
-~CH2)p~ -(C~z)~ C~2)r with:
- p 5 5, pre~erably equal to 2 os 3, - q 5 5, preferably equal to 1 or 2, - and r s 5, preferably equal to 1, - n being betwee~ 1 and 100, preferably between 2 and 50 and, even more preerably between 4 a~d 30, - and x and y corresponding to 1 or 2 as above.
R may also be composed of low-molecular-weight polylactic and/or polyglycolic and/or poly~lno acid chains.
The~e polymers are polysulphides in which the recurring unit preferably re~ults from the combination of succinic acid and cysteine.
These poly~ers may serve as a base for obtaining other adhesive product~ in accordance with the invention by constitut~ng cro~slin~ed materials (III). This cro~
linking is carried out, for example, by ~m~ dation and/or esterification, using at lQast oce brid~ing agent, prefarably chosen from the following producks: cy~tine, lysine, cy~tamine and their derivativas, mono~accharides and their hydrogenated derivatives, and other polyol~
(glycerolJ.
The i~vention also relates to, as new product~, th~ adhe~ive bio_aterial~ containing the cro~slinXed matorials (III) which have been cro~linked by bridge~
30 - originating from at least one bridging agent of the type of that mentioned above.
G~ven that all the product~ in accordance with the invention de~cribod above may be incorporated into the same preparation chain, it i~ clear that the pre~ent in~ention also relate~ to any bioadhesive composition ~ - 8 - 2128~63 consi~ting of a mixture of at least two of the abovementioned products, including the mixture of a polymer or of a crosslinked material with a non-solid product as de~cribed abov~, or by impregnation of ~uch a polymer or crosslinked material u~ing such a non-~olid product.
The glues according to the invention are bio-compatible and have pro~ed to be particularly suitable for entry into the biomaterials composition.
Another subject of the present inventlon is thus any adhesi~e biomaterial formed from a mixture and/or a combination of at least one of the oligomers (I) and/or polymers (II) and/or cros~linked material~ (III) and/or compositions described above with biological macromolecules, biodogradable, synthetic or natural polypeptides such as:
- poly~accharide~; e.g. starch, cellulose, chitosan, d~xtran, mucopolysaccharides ~uch as hyaluronic acid or chondroitin sulphate;
20 - protein~; e.g. collagen, gelatin, albu~in, globulins;
- polyamino acids;
- polyesters (in particular lactic and/or glycolic polyesters), polyortho esters, polyanhydrid~s, poly-pho~phazines;
- and lipids and phospholipids.
In the~e mixtures and/or combination~, these macromolecules may be engaged in physical and/or chemical bonds with the products I, II, III and the compo~itiona according to the i~ention.
The~e a & esive biomaterial~ may be glues or gluing materials in any physical form, including the solid form.
The compositions according to the in~e~tion may be used, in vitro or in vtvo, for binding biological tissues to each other or for binding between a biological tis~ue and an implantod bio~aterial, including when th~
biological tissue ~8 highly hydrated.
In a first embodim~nt, the composition is .

. ~, . . .

` 212~4~3 g provided in liquid solution form, for example in bottle or spray ~orm, or in a form analogous to the liquid ~orm, for example in gel form or in the form of very small-sized particles. In this embodiment, the adhe~ion functionality is ensured by a polyfunctional monomer (multi-S~ and multi-COO~) which can diffuse into the biological tissue~ to be stuck.
In order to ensure ~etting of the glue thus produced, an oxidizing agent capable of inducing the polymerization of this monomer is brought in. Thi~
oxidizing agent may be, for example, a solution of iodine, of hydrogen peroxide, an oxidizing enzyme (oxidase) or even oxygen itself, in pure form or in atmospheric form.
The composition may be provided, for example, in kit form comprising, in one container, the adhesive composition and, in the other, an oxidizing agent.
For the binding together of tissues or or the binding of a ti88ue and a~ implanted biomaterial, con-sisting in applying the two surfaces to be joined oneagainst the other, a composition and/or an oxidizing agent is applied or allowed to diffuse over at least one of the said ~urfaces, under conditions such that the oxidizing agent bring~ about a polymeri~ation o~ the composition at the moment the said surfzces are applied one against thc other. For example, the composition may be applied to one surface and the oxidizing agent to the other. Or alternatively, the oxidizing agent is applied first only on one or the two surface~ and then the composition i~ ~ubsequently applied between the two tissue~.
It i~ also possible to mix the compo~ition and the oxidizing agent at the time of introduction, or ~slightly before this moment, for example by using a double syringe or any other devic~ for extemporaneous mixing.
Irrespective of the load and the sequence of the applicat~o~ to the surfaces, the result should be ~uch that the oxidizing agent and the compo~ition are in ... . . .

o - 2128~63 intimate contact at the two surfaces to be joined, the compo~ition and/or the agent preferably being designed in a form which allow~ a certain diffusion ~rom the 3urface towards the interior of the tissue.
In another e~bodiment, the composition is pro-vided in the form of a bulk material, the geometrical form of which may be very variable. It may be, for example, a film or a textile, a sponge, a patch or any other form. In this embodiment, in which the compo~ition is in bulk solid form, the organic product is adva~tageously a polymer according to the formula (II) ~hich has adhe~i~e properties.
The compo3ition~ according to the invention may be combined with a bioDaterial, which i8 preferably ~e~orbable, in order to form a biomaterial complex presenting, superficially or within its depth, an adhesive composition according to the invention~ The composition ~ay be provided in or on the biomaterial, either by being i~corporated during th~ ma~ufacture of the biomRterial or by impregnation, coating or any other process.
The biomaterial, with which the compo~ition i8 combined, may form only one bioresorbable carrier, for example one made of collagen, which may hav~ any physical form, or exa~ple a suspension, ballotini, gel, film, ~ponge or patch form, i~ order to form, with the composi-tion, the biomaterial complex intended to be applied between the tissues. ~owevor, a8 a variant, this bio-material may form a prosthe~i~ or another, more hard-wearing component, for example a filling agent, combined with the compozition according to the in~ention, allowing it to be stuck to one or more ti~sues. Theae bio~aterial complexss are introduced into the ti~ue, or between the tissues, in the pre~ence of an oxidizing agent.
The invention al80 relates to the abovementioned biomaterial~, lacking any composition according to the i~vention, these biomaterials presenting, ~uperficially or within their depth, an oxidizing agent which is intended to react with a compo~ition accord~ng to the . , 2128~ ~3 in~ention. In thi~ ca~e, the gluing i8 carried out bybringing a composition which i8, for example, liquid or in gel form, in contact with the biomaterial or with the tissue surface against which the biomaterial is applied, 80 as to bring a~out the reaction between the oxidizing agent and the composition.
The non-adhesive biomaterial with which the adhesive compoQition according to the invention is combined in order to form a co~plete adhesi~e bio-material may consist of or contain any biocompatiblematerial, and preferably made of collagen. ~owever, in an advantageous variant, this biomaterial may itself consist mainly or entirely of a polymer, which i~ adhesive or non-adhesive, according to the formula (II) or of a crosslinked material (III) with which an adhesive composition or material according to the in~ention is combined by mixing or by any other mean~.
Indeed, the polymer according to the formula (II) may be produced under conditions leading to a polymerization which lea~ea behind few or no a& es~e functions. -`
The production of the adhesive products (I), (II) and (III) is incorporated into a reaction scheme deve-loped by the French compa~y FLAMEL TECENOLOGIES SA and which is as ~ollows: the first step is the preparation of polymer~ including, in particular, those corre~ponding to the formula (II), which subsequently give access to the products (I), which thQm~elves may be reconverted to ~-polymer~ (II) or to crosslinked materials (III).
This preparation pre~erably con~i~t~ in carrying out:
a) a polyconden~ation between:
- on the one hand, a reactan~ of formula A:
X-C-R-C-Y
O O
with X and Y, which may be identical or diff~
rent and represent a halogen, preferably chlorine, or a radical -OR8, in which R8 corresponds to hydrogen or to 2~28~ 63 an alicyclic or aliphatic radical, preferably chosen from the ~ollowing list of radicals:

O o Il ll -C-C(CH3)3 ; C-fH2 ; -C-C2H5 -N\ I O
C-C~t2 o and with a radical R which i~ a hydrocarbon, ~:
preferably alkylated, chain containing ~rom 1 to 50 carbon atoms and, even more preferably, an aliphatic chain having from 1 to 10 carbon atoms, and, on the other hand, a reactant o~ formula B:
RgHN~CH~~CH2)x~S~S~(c~2)y-cH-N~Rlo ::

,:
with Rl and R2 corresponding to an identical definition to that given above, with Rg and R1o identical or different and .
cho~en from the following radical~: ~,aliphatic~, prefe-rably alkyles, hydrogen being ~till the most preferably retained, and with x and y being, i~ a conventional manner, equal to 1 or 2, b) a reduction of the polymer obtained, which may or may not be sub~equently convarted.
In practice, it i~ preferable for the compou~d o formula A to be in the form of an acid halide, for ex~mple an acid chloride, and for the compou~d B of cy~teic nature to be o~teri~iod with alkyl radical~ R
~and R2 which preferably consist of methyl radicals.
Two polycondensation techniquee may be envisaged in order to obtain polymora including tho~e o formula ~ solutlon polycondonsation or interfacial polyco~-den~ation.
The~e technique~ will be viewed in detail in the ~ - 13 - 212~4~3 examples below.
Once the polymer has been obtained, it i8 advantageouR to hydrolyse the ester functions carried by this polymer. This hydrolysis is performed in water, in a mildly alkaline medium, in order to maintain control over the functions other than the ester functions of the polymer (saponification~.
According to a first variant of the process, the polymer, which may or may ~ot have undergone a hydrolysis of its ester functions, i8 subjected to a reduction of the disulphide bridge~ which it contain~, thus mainly allowing difunctional oli~omers bearing an S~ unit at each of their ends to be obtained.
Standard reduction technique~ are used. They may be, for example, those de~cribed in METXODS I~
ENZYMOLOGY, vol. 143, "Sulfur and sulfur amino-acids", W.B. JAROBY, O.W. GRIFFITH, Academic Press Inc., Orlando, (1987).
According to a second variant of the process, the polymer which has been partially or totally 3aponified i8 subjected to a cro~linking. This polymer may be the polycondensate as it iR or reduced in accordance with the first ~ariant of the proces~, which corresponds to the di-S~ difunctio~al oligomers. The cros~linking iB per-i 25 formed using at least one ~ridging agent and preferably in the presence of a coupling agent.
The bridging agent is preferably a diol or adiamine which has at least o~e -S-S- bond, such a~ for example the Gystine dialkyl ester (methyl or ethyl ester).
The coupling agent is advantageously chosen from the following list of compounds: ethyldiaminopropyl-carbodiimide (EDC), carbonyldiimidazole (CDI).
The degree of cros~liDking may be made to vary by acting upon t~e-amount of bridging agent used relative to the nu~ber of acid functions of the polymer.
The concentration of bridging agent is defined by the following ratio:

2128~

number of NH2, OH, etc. functions of the bridging agent ~-number of COOH function~ of the polymer ~:

This ratio is between 0.01 and 1.
The crosalinked materials (III) obtained may be represented symbolically as follows:

W~s-s~As-s~s-s~ -; . ~, ~0 V~s-s~As-s~ s-sWW\
co COOH Ico I
t I ~
CO CO COOH
V\s-S\~\S-S\~/S-S~ :~' wit~ Z = O or NH.
-Z-P-Z- is a bridge derived from polyol~ (Z = 0):
OH-P-OH or from polyamides (Z = N~ 2N-P-NH2.
The reduction of ~uch a cro~linked material may be performed in su~pension in water, in the pre~ence of dithiothreitol or tributylphosphine. It leads to a - mixture of molecule~ containing se~eral -S~ functions which may be isolated, ~reeze-dried and ~tored under nitrogen at a temperature below 0C. It i~ subseque~tly pou~ble, under mild oxidation co~dition~, to re~or~ the disulphide bridge~ in order to obtain a cro~linXed material slmllar to (III).

:

` _ - 15 - 2128~6~
In the particular case in which the bridging agent i8 cho~en from the following products: cystamine or esters of cy~ti~e or of homocystina, the P group~ o~ Ihe crosslinked material (III) also contain di~ulphide bridges and the reduction of the crosslinked material then lead~ to a mixture mainly composed o~ the di-, tri-and tetra-SH molecules described above (formula I).
The la~t phase of the proce~s, which is common to the two abo~ementioned variants, consists in oxidizing the SH oligomers obtained in the above step, 80 as to produce polymers, i~cluding in particular those of formula (II), and/or cros~linked materials (III), by (re)forming the disulphid~ bridge~. ~
This oxidation is carried out either, and prerer-ably, in the presence of at least one oxidizing systemc~mprising, for example, iodine and/or its deri~ative~
and/or hydrogen peroxide or an enzymatic ~ystem, or by electroch~ try, or directly in air.
The object of the pre~ent in~ention i5 al~o any afihesive composition formed by a mixture of at least two products of for~ula (I) and/or (II) and/or (III).
In particular, the ad~antageou~ compositions are tho~e comprising mixture~ of oligomers (I), because once reoxidized they lead to the biomaterials, gels and multi-S~ coating~ de~cri~ed above. Th2se reoxidized compound~should exhibit a certain number of mechanical properties, in relation with their usual characteristics. The level of the mechanical propestie~ esse~tially depends on the structure of the network formed and on the control o~er 30 the cros~linking of the multi-function~, preforably the -~
multi-SE functions, of the oligomers. In theory, any multi-SH compo~ition with a mean S~ functionality which is strictly greater than 2 may gi~e an i~soluble cro~s-- linked material. The mean SH functionality may be defined as follows:
Fmoan = number of S~ units per molecule = -B

with:

.; . ~ , - ~: , . : , '. ..
.-' ' ' .'. ' ' ' ~ ' . .~ . . ,.' ' , - :

2128~ 6.~

- A = 1. number of mono-SH molecule~ + 2. number of di-SH molecules ~ 3. number of tri-S~ molecule~ ~ 4.
number of tetra-S~ molecules, - B = number of mono-S~ molecules ~ number of di-S~
molecule~ + number of tri-SX molecules ~ number of tetra-S~ ~olecules.
Taking into account the possibility of intramolecular reactions which disrup~ the formation of the network by consuming potential nodes, it is prefer-able to aim for Fm~ for the oligomer mixture~ of the order of 2.1 to 2.5, in order to ensure the f ormation of the network. Generally speaking, the elasticity and the swelling (gel aspect) of the crosslinked material decreaseo when Fmoan increa~e~.
A desired mean functionality (for example 2.3) may be obtained directly or indirectly.
According to the direct method, linear polycon-densates of known length are crosslinked in ordex to estimate the relative proportion of mono-S~ relative to the di-S~'s, with an adapted amou~t of bridging agent, such a~ cy~tine dimethyl ester. After reduction of the cro~slinked material obtained, this pro~ides a mono-, di-, tri- and tetra-S~ mixture for which the Fme~ will be close to that desired. It is necessary to ensure, how-ever, that the bridging agent has totally reacted andthat the SS bridges have been totally reduced.
The indirect method con~i~t~ in "o~er-crosslink-ing" a linear polymer by aiming for a theoretical Fmean, for example in the region Of 3, in reducing thi~ cross-linked material, in determining the Fma~ obtained bya6say, in preparing, by reduction of a linear polyco~den-sate, a mono- and di-S~ mixturs which i8 close to 2 ~nd in obtaining, by mixing the two assayed compositions in the do~ired proportio~B~ the Fm~
corre~ponding to a~ optimum for the properties sought.
For the applications of biomaterial~ requiring the formation o~ a gel, it would appear to be de~irable to start from a compo~ition, i.e. a~ oligomer mixture having an Fm~a~ greater than or equal to 2, preferably ~- : ', :

2128~ ~3 less than or equal to 2.6 and, even more preferably, less than or equal to 2.3.
For harder adhesive biomaterial~, it would appear to be desirable to aim for Fmean'~ greatex than or egual to 2.3 and preferably greater than or equal to 2.5.
The oligomers (I), polymers ~II) inter alia, and crosslinked materials (III), which may or may not be functionalized, ars compound~ which exhibit no direct or indirect toxicity: they are not carcinogenic, teratoge~ic, immunogenic or mutagenic. Moreover, they are perfectly biodegradable, that i8 to Ray that they consist of products which are integrated per~ectly well into metabolic pathways (in particular the Rrebs cycle) of man or animals. The degradation products of the~e compounds are, ipso facto, perfectly tolerated.
In particular, it iR interesting to note that the oligomers (I) are of low molecular weight (lower than 1000 Da) and they are thus capabla of diffusing into the interior of biological tissues to be subsequently polymerized and/or crosslinked therein. The interlocki~g which may then for~ with the glycoprotein~ ensure~ a 301id adhesi~e bond.
I~ reduced fonm and combined with an oxidizing system, the~e products and/or their mixtures are very suitable as adhesive biomateriala or as biological glue~.
These con~tituents enter into the field of the invention.
In oxidized form, these constituents are cohesive networks, dotted with di~ulphide bridges a~d havi~g between them variable mechanical and biological properties.
Another ~ubject o~ the inYention is the use~o~
the products of formula (I) or (II), or of the cros~-link~d materials (III) for the preparation of an adhe-si~e, biocompatible, biodegradable and non-toxic composi-tion, for surgical use.
~ xamples 1 to 20 which follow are an illu~trationo4 the properties and of the variants o~ the adhesives according to the invention. They also describe the structures and the methods for preparing the products ~ - 18 - 2123~63 entering into the adhesive composition a~cording to the invention.
EXAMæLES
EXAMPLE 1: SYNTHESIS OF THE POLYMER 11) BY SOL~TION
POLYCOND~NSATION IN DIMET~YLACETAMIDE (DMAC) OF CYSTINE DINET~YL ESTER ~YDROCHLORIDE AND
SUCCINYL CXLORIDE.

11) ~ -CH2-C~2~ -N ~ H~C~2-5-5-C~2~ ~-N~
L o COOCH3 COOC~3~

25 g (0.073 mol) of cysti~e di~ethyl ~st~r hydrochlorid~ and 400 ml of D~AC are placed in a 1 1 reactor. 41.2 ml of triathylamine (0.293 mol) are then added. 8.1 ml of freshly distilled succinyl chloride are diluted in 100 ~1 of DMAC and this i8 all added to the reaction mixture using a dropping funn~l. The reaction mixture ia th~n stirred for 24 hours at room temperature.
15 The precipitated triethylam~onium nalt i8 removed by -filtration and the ~eaction mlxture i8 then precipitated in 5 1 of water. The polym~r is recovered by filtration and oven-dried under vacuum: 13 g of a white (slightly pink-coloured) powd~r are thus obtained. The lH NMR (in deuterated trifluoroacetic acid (~FA~) and IR spectra are in accordance. The molecular weights, determined by -~
steric exclu~ion chromatography (SEC) in DMAC and expressed as polystyrene equivalente, are a3 follow~: ~
Ma = 6200, M~,, = 9600 ~:
E~ANPLB 2: SYNT~ESIS OF THE POLYMER (1) BY WAT~R~TOLUENE
INTRRFACIAL POLYCONDENSATION OF CYSTIME
DIM~T~YL ESTER HYDRO~TORIDE AND S~CCINY*
CHLORIDE. -~
25 g (0.073 mol) of cy~tine dimethyl e3ter hydrochloride and 200 ml of DMAC are placed in a 1 1 reactor. 31.06 g of auhydrou~ ~odium carbona~e (0.293 mol) ars then added. A pre-emulsion is sub~equently form0d by addition of 100 ml of toluene.
8.1 ml of freshly distilled ~uccinyl chloride are the~

"~ . - . , - - lg - 212~63 diluted in 100 ml of toluene and this i8 all added to the reaction mixture uuing a dropping f~nnel. The reaction mixture i8 then ~tirred for 4 hours at room temperature.
The polymer, which ha~ precipitated during the reaction, 5 i8 reco~ered by filtration and washed with acetone, then with water. It is oven-dried under vacuum: 14 g of a white (slightly pink-coloured) powder are thus obtained.
The lH NMR (in TFA) and IR spectra are in accordance and are analogous to those obtained for the polymer of Example 1. The molecular weights, determined by SEC in DNAC and expressed as polystyrenQ equivalents, are as follows:
Ma = 5700~ Nw - 11,500 EXANPLæ 3: HYDROLYSIS OF T~E ESTER F~NCTIONS OF THE
POLYMER (1): PRODUCTION OF POLYMER (2 ) (2) ~C--CH2--C~3--lCI--NH--~ 2--5--S--C~2--IH NH~r L COOH COOH J

5 g of polymer (1) obtained by solution or interfacial polycondensation are suspended in 1 1 of water. The pH is adjusted to 10.5 with 1 M sodium hydroxide and i8 maintained at this value throughout the hydrolysi~. The addition of sodium hydroxid~ is ~topped when the solution become~ clear. The so~ution is then acidified to a p$ ~ 3 by an acidic ion-exchange resin. It i8 concentrated, frozen and then freeze-dried. 4.6 g of a white powder are obtained. The lH NMR (in TFA and in D20) and IR spectra are in accordance and show that the hydrolysis of the ester function~ is total.
E~AMPLF 4: RED~CTION OF TH~ POLYNER (2) ~Y DIT~IO-THREITOL: PROD~CTION OF T~E MOLEC~LE ( 3 ) H CH2 C~--NH--C--CH2--CH2--C--NH--C~--CH SH
~OOH I 1 ~OOH

3 g of polymer (2) and 2.87 g of dithiothreitol (DTT) are dissolved in 70 ml of water ~nder a nitrogen atmosphere. The pH is adjusted to 8.5 by addition of 1 sodiu~ hydroxide and the solution is stirred ~or 3 hours 212~4 ~

under bubbling with nitrogen. The mixture is then extracted twice with 100 ml of ethyl acetate. The aqueous pha~e is subsequently acidi~i~d by an acidic ion-exchange resin to p~ = 4.5, then concentrated and precipitated in an exce~s of acetone. ~he ~tic~y precipitate o~tained i~
redissol~ed in a minimum amount of water and reprecipi-tated in acetone. It is finally redissolved in water and ~reeze-dried. 2 g of a slightly yellow product are recovered. The 1~ NNR spectrum (in D20) obtained is in a~cordance with the formula (3), the carboxylic group~
being i~ ionized form.
EXA~æL~ 5~ ~EDUCTION OF T~E POLYMER (2) BY TRI(n-~UTYL)~
P~OSP~INE: PRODUCTION OF T~ NOLECULE (3) 2.4 g of polymer (2) are dissolved in 30 ml of water under a nitrogen at~osphere. 120 ml of methanol, degassed beforehand, are then added. Next, 2 ml of tri(n-butyl)phosphine are injected into the reaction mixture. After reacting for 3 hours, the methanol i8 evaporated off using a rotary evaporator. 50 ml of water are added to the residual aqu~ous ~olution, which is subsequently extracted twice with 200 ml of ethyl acetate. The aqueous solution is subseguently acidified and precipitated in acetone, as described in Example 4.
The 1~ NMR spectrum in D20 i8 identical to that of the product obtained in Exampla 4.
E~ANæLE 6: CROSS~INRING OF TXE POhY~$R (2) BY CYSTINE
DIMETHYL ESTER
5 g of polymer (2) and 5.3 g of cystin~ dimethyl ester hydrochloride are dissolved in 100 ml o4 water. 6 g of N-dimethylaminopropyl-N'-ethylcarbodiLmide (EDC) are then dissolved in 5 ml of water and immediately added~to the ~eaction mixture. The mixture immediatoly turns dark rod and, after a few ~econds, a pink precipitate is then formed. The reactio~ is stopped after 3 hours and 200 ml of water are added. The precipitate i8 recovered by filt~atio~, washed several times with water and then oven-dried under vacuum.
EXAMPL~ 7: CROSSLINRING OF T~E POLYNER (2) BY CYSTINE
DIET~YL ESTER

21284 ~3 5 g of polymer (2) and 5.73 g of cystine diethyl e~ter hydrochloride are di~solved in 100 ml of water. 6 g of N-dimethylaminopropyl-N'-othylcarbodiimide (EDC) are then dissolved in 5 ml of water a~d immediately added to the reaction mixture. The reaction i8 stopped a~ter 3 hours and 200 ml of water are added. The precipitate i8 recovered by filtration, washed several times with water and then o~en-dried under vacuum.
13~a~I~15 8: REDIJCTION BY DITHIOl~REITO~ OF T~IE CROSSLINRED
PO~YMER OF EXANPLE 6 1 g of the cro~slinked polymer of Example 7 and 1.1 g of dithiothreitol are dissolved in 50 ml of water, which has been flu~hed beforehand with a stream of nitrogen. The pH i~ adjusted to 9.5 by 1 M ~odium hydroxide. The reaction ~ixture becomes clear and the reaction i8 stopped at the end of one hour. After BiX
extractions with 50 ~1 of ethyl acetate, the aqueous solution i~ acidified to pH = 5 by an exchange resin, reextracted with twice 50 ~1 of ethyl acetate and then freeze-dried. The product obtained is a mixture mainly comprising the followi~g molecules (3), (4) and (5):

~31 S~-C~2-C~-NH-ICl-CH2-C~2-C-NH-CH-C~2-SH
~OOH 0 ~ ~OOH

H

l~2 S~

SH--CH2 1 H--NH--ICI--CH2--CH2--ll--NH I H--CH2--SH
C=O O O IC=O
H NH
IH-COOCH3 IH-COOC~3 f~2 f~2 SH SH

.~ ...................... . ... ~ . . .

212~ 63 The carboxylic functiona are in ionized form (-COO~, Na+). The ~ xture i8 no longer fully soluble in water when the pH i8 ~ 3.
Y~aMæ~æ 9: REDUCTION 3Y DITHIOl~KEITOL OF T~E CROSSLINRED ~:
P9~YMER OF EXANP~E 6 - ~YDRO~YSIS OF THE ESTER
FUNCTIONS OF ln~ PRODUCT OBTAINED

The reactio~ i8 per$ormed as de~cribed in Rxample 8, but the reduced solution i8 maintained at pH = 9.5 for 24 hours at 35C. A~ter six extraction~ with 50 ml of ethyl acetate, the aqueous solution is acidi~ied to pH = S by an exchange resin, re-extracted with twice 50 ml of ethyl acetate and then freeze-dried. The product ~- :
obtained i8 a mixture mainly compri~ing the following ::
molecules (3), (6) and (7):
SH-CH2-C~-NH-ICl-CH2-CH2 ll_NH_CH_CH2_SH -COOH O 0 ~00 SH-CH2-lH-NH-Il-CH2-CH2-ll-NH-lC~-CH2-SH ;~
~6) f =o o o COOH
NH
IH-COOH
fH2 SH

SH--C~2--fH NH--ICI--CH2--CH2--1CI--N~--I ~CH2--SH

IH IH
f H-COOH f H-COOH
~2 fH2 M SH
:
The carboxylic ~u~ctions are in ionized form (-COO~, Na~). Ths mixture may be acidiied (to pK = 2.5) by passing through an ion-exchange re~in. In this case, the water-~olubility ia conserved.

` ~ - 23 - 212~
E~MPL~ 10: REDUCTION BY DITHIOTXREITOL OF THE CROSS-LINRED PO~YMER OF EXAMPLE 7 1 g of the crosslinked polymer of Example 7 and 1.1 g of dithiothreitol are di~solved in 50 ml o~ water, which has been flushed beforehand with a stream of nitrogen. The pH is adju~ted to 9.5 by 1 M ~odium hydroxide. The reaction mixture becomes clear and the reaction is ~topped at the end of one hour. After ~ix extractions with 50 ml of cthyl acetate, the aqueous ~olution i~ acidified to p~ = 4 with lN ~Cl solution. A
sticky, slightly brown precipitate i8 obtained. Thi~ is a mixture consisting mainly of the following molecules (3), (8) and (9~
SH-CH -C~-NH-C-CH -CH -C-NH-CH-CH -SH
~3) 2 1 ll 2 2 ll 1 2 COOH O O COOH

SH--CH2--CH--NH--~ CH2--CH2--lCl--NH--CH--CH2--SH
8 ) ~=0 O O 100R
IH
f~COOC2H5 ~C~2 H

SH--CH2--CIH--N~--ICI--CH2--C~2 Il_N I H-CH2_SH

NH NH

fH2 f~2 SH SR

EXANPL~ EX VIVO EVALUATION OF 'l~E TISS~E AD~BSION
15- Evaluation of the a &eaive properties o~ the composition according to the invention wa~ perorm~d on rabbit muscle tlssues (small of the back). ~hese tissues are stored at 4C in physiological s~rum for a maximum of 48 hours. The rabbit tissue i~ cut up along the sense of the fibres using a~ ~lectric slicar (thickne~s of the ~ - 24 - 2~28463 slices: 2.5 + 0.5 mm), then Rquare~ of 25 mm x 25 mm are cut into the slices obtained.
The tests are performed on a usual traction apparatu~, for example of Adamel Lhomargy type of DY34 type fitted wit~ a 100 N force sen~or. This apparatu~
allows the force-displacement curves to be obtained. It also allows the maximum peel ~trength ~FmaX) and Young's modulus to be obtained, and the energy involved may be calculated ~rom the area under the curve.
In each type of t~t, two test sample~ of rabbit tissue are attached using a cyanoacrylic glue (for example sold under the brand name Loctite ~uperglue, liguid or gel) to inert, gla~ or cardboard supports which are very rigid and of larger size. The tests are performed at the end of 3 ~ nutes after a pressure of 4 N.
The composition used i8 a solution of the poly-mer, in an amount o~ 100 ~1 per sample, (2) according to Example 3, Pt a concentration of 20 to 25 per cent and, aa a variant~ not as a ~olution but directly as a powder onto the rabbit tisaue. After gluing for 3 minutes under pressure, an adhesion val~e (F ~ ) between 1.5 and 2 N is obtai~ed. This value is advantageous a~d may be compared with the equivalent values of 1.5 N to 2.5 N of the conventional biological glues based on fibrin. The same test carried out with commercial carboxylic polymers ~uch as polyacrylic acid and sodium algi~ate ~how~ a low level of adhesion (FmaX ~ 1 N, adhe~ional work ~ 1 J).
EXAMPLE 12: MULTI-SH COMPO~NDS
The tests are carried out on multi-S~ compounds in -C00~ form, namely the compounds ~3), (4), (5), ~6), (7), (8) and (9) of Example~ 4, 5, 8, 9 and 10, prefer-ably (3), (6) and (7).
~ For this, the test sample ti~sues are impregnated beforehand with aqueous-alcoholic iodine solution and the composition dissolved in water, in an amount of 100 ~1 per sample, is then added. Depending on the te~t sample~
and the tests, the peel strength mea~ured are between 1.12 and 3.46 N, the average being 2.04 + 0.62 N.

- : ~

212~4~

These results are thus comparable and even better on average than those of the con~entional glues based on fibrin. In addition, the area under the curve, that i8 to say the energy used, is larger than or equal to that of the best fibrin glues.
The ~e~ts performed after one hour of contact show that the a &esional force increases wit~ time (between 3 and 4 N at the end of one hour).
E$AMPLæ 13 0.1 yram of type IV human collagen (IMEDEX), dissolved in 4 ml of water, i~ reduced at p~ 9 by 10 mg of dithiothreitol (DTT) under inert atmo~phere for 18 hours. After dialysis of the solutlon (3 times 8 hours), 80 mg o~ the "multi-S~" type derivatives preparad in Exa~ple 9 are added. The p~ of the solution i adjusted to 9 by addition of concentrated sodium hydroxide, and 20 microlitres of hydrogen peroxide at a concentration of 35% by weight are added to the ~olution in order to allow partial oxidation of the mixture. After 30 minute~, the reaction mixture i8 tested for a &esion by application to rabbit tissue~ according to the procedure described in Example 12.
After contact ~or 3 minutes under 4 N, the following are record~d:
- a mean adhesive force of 1.9 ~/- 0.4 N and - an adhesional energy of 2.9 +/- 1.2 mJ.
The examples which follow relate to processes for binding tissues together or for bi~ding one tissue to an implanted biomaterial by superposition of two surfaces and in which a composition accordi~g to the invention and/or an oxidizing agent i8 applied or allowed to diffuae over at least one of the surfaces, under condi-tion~ such that the oxidizi~g agent bring~ about a polymerization of the compo~ition when the surfac~s are applied one again~t t~e other. This application may be carried out, for example, by spraying o~ impreg~ating the compo~ition according to the invention, or alternativ~ly a resorbable biomaterial accordlng to the invention containing an oxidizing agent may be interpo~ed between .

212~6~

t~e two surfaces, the two ~urface3 having been impreg-nated with the composition according to the invention, or alternatively a composition in the form of a biomaterial according to the invention may be interpo~ed between the two surfaces to be joined together.
EX~MPLE 14 150 microlitre~ of a solution of adhe~ive monomer (3), (4), (5), (6), (7), (8) or (9), (60 mg) according to one of Examples 4, 5, 8, 9 and 10, preferably 9, are deposited. A compres~ containing an oxidizing ~olution, for example iodine solution or hydrogen peroxide solutio~, is placed between the two tissues and the two ti~sues are joined together on either ~ide of the collagen compress while maintai~ing a pressure, preferably for a period of a few minutes. In3tead of being made o collagen, the compress may, for example, be made of alginate, of hyaluronic acid or of oxidized cellulose.
E$A~PLE 15: ADHESION OF THE SgIN IN PLASTIC ~ND
R~PARATORY S~RG~RY
The muscle area i8 brushed with the oxidizing solution and, after the surplus ~olution has been removed using a compress, a liquid a & ~sive composition according to the in~ention is the~ sprayed onto the muscle area, after which tha two tissues are joined together.
This example may be applied to any surgery for ma~ntaining two tissue~ in a cohesi~e m~ner, it being possible for one or both of the surfaces to be bru~hed, either with oxidizing solution or with the composition according to the i~vention, after which a spraying is carried out, either with the compositio~ or with the oxidizing solution, before joining the tissues together.
ESAMPLE 16: PROTECTION OF AN~STOMOSES
The invention may be used for protecting anaatomoses during vascular, ~i~ceral, gynaecological or urological Eurgery. After sprayi~g a solution of adhesive monomer composition according to the i~vention o~ the surfac2 of the anastomosi~, an anastomosis compres~ or co~pressio~ patch impregnated with the oxidizing solution ~ - 27 - 2128~63 is placed on the tis~ue t~u~ covered with adhesive monomer.
As a variant, t~e anastomosis may be surrounded by an anastomosis patch or compress which ha~ been preimpregnated with adhesive monomer, followed by spraying the oxidizing solution onto the material in order to obtain its adhesion to the tissue.
E~MPL~ 17: TISSUE FILLING
Following an exeresis of soft ti~sue or bone ti~sue, the cavity to be filled i8 covered with adhe~ive monomer according to Example 9 and a suspension of collagen ballotini which ha~ been partially imprsgnated with the oxidizing solution is then introduced in order to fill the caYity.
As a variant, the ca~ity may be filled with a suspen~ion of ballotini or a collagen solution which has been impregnated with the adhesive monomer, followed by in;ection of an oxidizing solution of aqueous iodine into the filled volume.
EXANoeLE 18: TISSUE RECONSTIT~TION
During ~urgery on the dura ~ater, after exeresis of the pathological tissue, a patch, for example a collagen patch, i~ in~roduced in order to replace the excised tissue and to allow the formation of new tissue.
Adhesive monomer composition is deposlted around the edge of the patch and it is then placed in position and sprayed with the oxidizing solution in order to en~ure adhesion and sealing of the gluing.
EXAMPLE 19: TISS~E PROTECTION
In order to protoct an internal tissue ~uch a~ a mucous me~brane or an external tissue, or in order to improve a cicatrizatio~, the ti~sue is ~mpregnated with the oxidizing preparation, the ~urplu~ oxidizing ~olution i~ re~oved, if necessary, and a~ adhesive monomer composition is sprayed on. It is subsequently possible to introduce a prot~ctive compress, for e~ample one made of collagen.
EXANPL~ 20: ~AEMOSTASIS PROCESS
In case of ~erious bleeding in cardiovascular, abdominal or thoracic surgery, for exa~ple during ~ 2128463 hepatectomy, a ~olution of adhe~ive monomer according to the invention is sprayed onto the ti~sue slice and a compress which has been preimpregnated with oxidizing solution is applied, and the compression is maintained until haemostasis is obtained.
Where appropriate, in particular in the case of light bleeding, haemostasi~ may be achieved by the simple application of adhesive monomer and of the oxidizing solution by ~praying in a successi~e or concomitant man~er.

Claims

1. Adhesive, biocompatible, biodegradable and non-toxic composition for surgical use, in particular for binding biological tissues together or for binding a tissue and an implanted biomaterial, characterized in that it includes an organic product containing at least two thiol functions or derivatives and carboxylic functions, which may be protected or unprotected, and/or carbonyl functions, of the following general formula:

(I) in which: x, y and z = 1 or 2 and ? is an aromatic ring, - R is a hydrocarbon, preferably alkylated, chain containing from 1 to 50 carbon atoms and even more preferably an aliphatic chain having from 1 to 10 carbon atoms, - R1 and R2 are identical or different and are chosen from the following groups:

-O-R5 ; ; - NH-(CH2)y-S-R6 - R3, R4, R5, R6 and R7 independently represent hydrogen or an aliphatic and/or alicyclic and/or aromatic group, preferably a lower alkyl group and/or an aromatic group and, even more preferably, one of the following groups:

-CH3 ; -CH2-CH3 ; CH2-? ;

2. Composition according to Claim 1, characterized in that R1 and R2 represent - O - R5.

3. Composition according to Claim 1, characterized in that R1 represents:
and R2 represent - O - R5 or vice versa.

4. Composition according to Claim 1, characterized in that R1 and R2 consist of the radical

5. Composition according to any one of Claims 1 to 4, characterized in that R is chosen such that the radical:
in the formula (I) is a radical belonging to the class of the polycarboxylic, advantageously dicarboxylic, acid residues, with the exclusion of citric acid, R preferably being selected from the following groups:
-(CH2)p ; ; with:
- p ? 5, preferably equal to 2 or 3, - q ? 5, preferably equal to 1 or 2, - and finally r ? 5, preferably equal to 1.

6. Composition according to any one of Claims 1 to 4, characterized in that R is composed of low-molecular-weight polylactic and/or polyglycolic and/or polyamino acid chains.

7. Composition according to one of Claims 1 to 6, characterized in that it is provided in bioresorbable liquid solution, spray, gel or particle form or in the form of a bulk material.

8. Biomaterial which may or may not be in the form of a prosthesis, characterized in that it has, superficially or within its depth, a composition according to one of Claims 1 to 7, which makes it possible to ensure adhesion of the said biomaterial to a biological tissue.

9. Biomaterial which may or may not be in the form of a prosthesis, characterized in that it has, superficially or within its depth, an oxidizing agent intended to react with the composition according to one of Claims 1 to 7, in order to ensure adhesion of the said biomaterial to a biological tissue, the said oxidizing agent preferably comprising iodine and/or its derivatives and/or hydrogen peroxide.

10. Biomaterial according to either of Claims 8 and 9, characterized in that it is provided in patch, compress, filling material, surgical cement or prosthesis form, in particular vascular, bone, tissue or ligament prosthesis, or implant form.

11. Biomaterial according to any one of Claims 8 to 10, characterized in that it consists, at least in part, of a polymer which corresponds to the following general formula:

(II) n is between 1 and 100 and in which R1 and R2 are as defined above according to any one of Claims 1 to 4 and R is as defined according to either of Claims 5 and 6.

12. Biomaterial according to any one of Claims a to 10, characterized in that it consists, at least in part, of a crosslinked material consisting of one or more polymers defined in Claim 8, crosslinked by bridges originating from at least one bridging agent, preferably chosen from polyols and/or polyamines and, even more preferably, from the following products: cystine and its derivatives, monosaccharides and their hydrogenated derivatives, and other polyols (glycerol).

13. Biomaterial, characterized in that it consists of a mixture of at least two of the products defined in any one of Claims 1 to 12 in order to ensure adhesion of the said biomaterial to a biological tissue.

14. Biomaterial according to Claim 13, characterized in that the constituent monomers contain a mean SH number greater than or equal to 2.

15. Adhesive material according to any one of Claims 1 to 8 and 10 to 14, characterized by a combination of at least one of the products and/or polymers and/or crosslinked materials and/or compositions according to at least one of Claims 1 to 7 with biological macromolecules, or synthetic or natural biodegradable polymers such as:
- polysaccharides; e.g. starch, cellulose, chitosan, dextran, mucopolysaccharides such as hyaluronic acid or chondroitin sulphate;
- proteins; e.g. collagen, gelatin, albumin, globulins;
- polyamino acids;
- polyesters (in particular lactic and/or glycolic polyesters), polyortho esters, polyanhydrides, poly-phosphazines;
- and lipids and phospholipids.