WO2016097040A1 - Multi-component adhesive for producing an adhesive hydrogel - Google Patents

Abstract

The present invention primarily relates to a multi-component adhesive for producing an adhesive hydrogel, comprising the following defined compound of formula (I) and one, two, three, four or more further components. The invention also relates to the use of said multi-component adhesive and corresponding methods for glueing together two surfaces. The present invention further relates to a method for producing a corresponding adhesive hydrogel. In addition, the invention relates to a kit comprising a corresponding multi-component adhesive and one or more further components. Furthermore, the invention relates to articles comprising a multi-component adhesive according to the invention or an adhesive hydrogel produced therefrom.

Description

 Multi-component adhesive for the production of an adhesive hydrogel

The present invention primarily relates to a multi-component adhesive for producing an adhesive hydrogel, comprising the compound of the formula (I) defined below and one, two, three, four or more further component (s). The invention also relates to the use of the said multicomponent adhesive and to corresponding methods for bonding two surfaces together. Furthermore, the present invention relates to a method for producing a corresponding adhesive hydrogel. The invention also relates to a kit comprising a corresponding multicomponent adhesive and one or more further component (s). The invention likewise relates to articles which comprise a multicomponent adhesive according to the invention or an adhesive hydrogel prepared therefrom.

Further aspects of the present invention will become apparent from the following description and in particular from the appended claims.

In modern surgery there is a constant need for new biocompatible adhesives for bonding tissue. An important field of application for such biocompatible adhesives is in the field of dental implantology. The use of implants always involves the risk of bacteria penetrating into the interface between the implant and the tissue surrounding the implant (eg peri-implant mucosa) despite careful handling by the (dental) doctor and leading to infections. Infections of the peri-implant mucosa (mucosa) without the involvement of the reversible and are called mucositis. Progressive inflammation with progressive, irreversible bone loss is called peri-implantitis. Due to the bone loss in peri-implantitis, this leads to an implant loosening and ultimately can lead to implant loss. Both mucositis and peri-implantitis can currently only be avoided through regular monitoring and appropriate therapeutic measures after the first signs of mucositis are diagnosed. This is associated with a high treatment costs for the treating (dental) doctor and patients and at high costs.

Stabilization or sealing of the mucosa and tissue layers on the implant body, which is achieved by the use of biocompatible adhesives, not only leads to a greatly reduced risk of mucositis or peri-implantitis, but also reduces the healing time of the implants on the tissue surrounding the implant ( eg peri-implant supporting tissue). An important prerequisite for a successful implantation is that the implant has sufficient primary stability after being introduced into the bone. This means that it must not sit loose immediately after insertion, but absolutely, d. H. to the maximum extent possible, firmly anchored in the bone. Excessive chewing forces on the implant bone structure, which is in the construction and conversion after implant placement, do not significantly affect newly formed tissue due to stabilization, so that it is not destroyed again. By stabilizing or sealing the implants on the tissue surrounding the implant, oral reconstruction has a very good starting position for a complete rehabilitation in the long term. As a result, the hitherto customary treatment expense of a peri-implant supportive tissue intrusion and the associated costs can be reduced or completely avoided. Compared with the implantation lifetimes of previous treatment methods without biocompatible adhesives, the use of biocompatible adhesives also leads to significantly longer implant survival times.

In addition to the use of biocompatible adhesives in implantology, other surgical, therapeutic and other applications are possible. For example, cuts can be made by applying appropriate adhesives. The bonding of bone, cartilage and / or soft tissue is possible.

Thus, z. As a fixation of bone fractures can be achieved, in which the subsequent healing processes can proceed much faster. At the same time, the self-loading capacity of the bone tissue gradually increases and the biocompatible adhesive is gradually degraded until only pure cell tissue, or bone material is present.

Numerous adhesives and sealing materials suitable for medical use are disclosed in the literature. EP 1 609 431 B1 discloses a cell-enclosed membrane obtained by reaction of at least two precursor molecules. The described cell-cellosive membrane is not an adhesive, however, the membrane may also be used in bone regeneration or in tissue regeneration.

In Brubaker et al., Biomaterials 31 (2010) 420, a medical adhesive is disclosed. The adhesive described can be converted into a hydrogel by oxidation with sodium periodate. The adhesion of Langerhans cells to adipose tissue and liver tissue in mice is also described.

Bruce Lee et al., Macromolecules 39 (2006) 1740 discloses an adhesive which can be gel-cured by photocuring. The adhesive and the resulting gel have a high content of 3,4-dihydroxyphenylanaline (DOPA). As a possible application example of the disclosed adhesives or the gels formed therefrom, the use as bioadhesive is described.

The object of the present invention was to provide an adhesive which, after curing (setting), has at least one, but preferably several, of the following properties:

 good biocompatibility

 no or low toxicity

 biodegradability

 Ability to absorb and / or embed drugs and, where appropriate, ability to release (re) release ingested or embedded drugs

 no immune reaction in the animal and / or human body

good adhesion to biological tissue of allogeneic, heterogeneous or synthetic origin and / or to medical implants good barrier against bacteria.

This object is achieved by a multi-component adhesive for producing an adhesive hydrogel, comprising

a) a compound of the formula (I)

wobei

in which

R, R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} each independently H, OH or LX, wherein

X is selected from the group consisting of SH, NH ₂ and alpha, beta-unsaturated carbonyl groups and

L is a linker linking the phenyl moiety of formula (I) to X, with the proviso that two or three of R, R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} each LX and two or three R, R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} each OH,

 and

 one, two, three, four or more connections,

 each containing one, two, three, four, five, six, seven, eight or more structural units (II)

 B-L-Y (II)

 wherein in each of the structural units (II), independently of the meaning in other structural units (II)

 B is a node,

 L 'is a linker and

Y is selected from the group consisting of SH, NH ₂ and alpha, beta-unsaturated carbonyl groups and can be reacted with the group X to form at least one covalent bond, in which

(i) one, two, three, four or more of the compounds each containing one, two, three, four, five, six, seven, eight or more structural units (II) each additionally comprise a radical Z, which is independent of each other radical Z of another compound is selected from the group consisting of SH, NH ₂ and alpha, beta-unsaturated carbonyl groups and can be reacted with a group Y to form at least one covalent bond

 and or

 (ii) the multicomponent adhesive additionally comprises one, two, three, four or more compounds which independently of one another each have two, three, four, five, six, seven, eight or more structural units (III)

 B'-L "-Z '(III)

 in which each of the structural units (III) is independent of the meaning in other structural units (III)

 B 'is a node,

 L "is a linker and

Z 'is selected from the group consisting of SH, NH ₂ and alpha, beta-unsaturated carbonyl groups and is reactable with a group Y to form at least one covalent bond.

In the context of this text, an adhesive is understood to mean a substance mixture which sets by chemical reaction of its constituents and / or by the action of external substances and can thus bond materials and / or tissue by adhesion to the surface in such a way that the compound has sufficient internal strength (adhesion). Cohesion).

A "multicomponent adhesive" is generally understood to mean an adhesive which consists of two or more spatially separate, reactive components which are mixed for reaction and, if necessary, further treated. of the multicomponent adhesive according to the invention are thus divided into two, three or more separate components, wherein preferably constituents in which X, Y, Z or Z 'are SH and / or NH ₂ are separated from constituents in which it is at X, Y, Z or Z 'is an alpha, beta-unsaturated carbonyl group. In certain embodiments of inventive multi-component adhesives, for. For example, when a separation of constituents intended for reaction in which X, Y, Z or Z 'are SH and / or NH ₂ , of constituents in which X, Y, Z or Z' is an alpha, beta-unsaturated carbonyl group, is not possible or expedient, the other constituents of the multicomponent adhesive are so divided that nevertheless a formation of the adhesive Hydrogel (by setting) does not occur before mixing the components. This can be done, for example, by adjusting the pH of individual or all components of the multicomponent adhesive in such a way that the adhesive hydrogel is formed only after the components have been mixed or after application of the multicomponent adhesive to a corresponding medium which has a corresponding pH Value (eg mouth cavity).

The term "hydrogels" as used herein refers to gels based on hydrophilic but water-insoluble polymers that exist as three-dimensional networks.The hydrophilic nature of three-dimensional networks allows hydrogels to absorb water, preferably hydrogels Textes, however, are understood as hydrogel also dried hydrogels containing no or only traces of water, provided that they are able to absorb (additional) water.

By "adhesive hydrogel" is meant a hydrogel that has both the properties of a hydrogel and that can bond materials and / or tissue by surface adhesion so that the compound has sufficient internal strength (cohesion) after mixing the components a multi-component adhesive according to the invention is formed by chemical reaction of the constituents of the individual components an adhesive hydrogel.

In some cases, it may be preferred that when X = NH ₂ , the chain of the linker L linking X to the phenyl moiety of formula (I) is not exclusively carbon atoms. In this context, it does not matter if the linking chain is substituted or not.

Furthermore, alternatively or additionally, in the event that X is an alpha, beta-unsaturated carbonyl group, it may not be part of an acryloyl, methacryloyl, acrylamide or methacrylamide group. According to a first preferred embodiment of the present invention, a multicomponent adhesive according to the invention for producing an adhesive hydrogel comprises a) a compound of the formula (I)

wobei

in which

R, R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} each independently H, OH or LX, wherein

X is selected from the group consisting of SH, NH ₂ and alpha, beta-unsaturated carbonyl groups and

L is a linker linking the 1,2-dihydroxyphenyl moiety to X, with the proviso that two or three of R, R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} each LX and two or three of R, R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} each OH,

 and

 one, two, three, four or more connections,

 each containing one, two, three, four, five, six, seven, eight or more structural units (II)

 B-L-Y (II)

 wherein in each of the structural units (II), independently of the meaning in other structural units (II)

 B is a node,

 L 'is a linker and

Y is selected from the group consisting of SH, NH ₂ and alpha, beta-unsaturated carbonyl groups and can be reacted with the group X to form at least one covalent bond,

in which (i) one, two, three, four or more of the compounds each containing one, two, three, four, five, six, seven, eight or more structural units (II) each additionally comprise a radical Z, which is independent of each other radical Z of another compound is selected from the group consisting of SH, NH ₂ and alpha, beta-unsaturated carbonyl groups and is convertible with a group Y to form at least one covalent bond.

According to a second, equally preferred embodiment of the present invention, a multi-component adhesive according to the invention comprises for the production of an adhesive hydrogel

a) a compound of the formula (I)

in which

R, R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} each independently H, OH or LX, wherein

X is selected from the group consisting of SH, NH ₂ and alpha, beta-unsaturated carbonyl groups and

L is a linker linking the 1,2-dihydroxyphenyl moiety to X, with the proviso that two or three of R, R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} each LX and two or three of R, R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} each OH,

 and

 one, two, three, four or more connections,

 each containing one, two, three, four, five, six, seven, eight or more structural units (II)

 B-L-Y (II)

wherein in each of the structural units (II), independently of the meaning in other structural units (II) B is a node,

 L 'is a linker and

Y is selected from the group consisting of SH, NH ₂ and alpha, beta-unsaturated carbonyl groups and can be reacted with the group X to form at least one covalent bond,

and

 (ii) additionally one, two, three, four or more compounds which independently of one another each have two, three, four, five, six, seven, eight or more structural units (III)

 B'-L "-Z '(III)

 in which each of the structural units (III) is independent of the meaning in other structural units (III)

 B 'is a node,

 L "is a linker and

Z 'is selected from the group consisting of SH, NH ₂ and alpha, beta-unsaturated carbonyl groups and is reactable with a group Y to form at least one covalent bond.

It has been found that multicomponent adhesives according to the invention have particularly good properties if at least one component of the multicomponent adhesive has a specific pH. After mixing the components for the purpose of forming an adhesive hydrogel, in particular in the preferred presence of SH groups (Y, X and / or Z 'then SH in the respective corresponding compound or structural unit of the formula (I), (II) or (III)) occur at a pH of> 8 side reactions that can adversely affect the production of adhesive Hydrogel. At a pH of <6, the reaction rate of the reaction mixture obtained by mixing the components in the formation of the adhesive hydrogel is often lowered, so that the formation of the adhesive hydrogel is slowed down. Preference is therefore given to a multicomponent adhesive according to the invention in which one, two, three or all components have a pH in the range from 6 to 8, preferably in the range from 7 to 8, particularly preferably in the range from 7.5 to 7.8. According to a first preferred embodiment of the present invention, the components of the multicomponent adhesive according to the invention are designed so that after mixing all components together in the resulting reaction mixture, a pH in the range of 6 to 8, preferably in the range of 7 to 8, particularly preferably in Range from 7.5 to 7.8.

According to a second, equally preferred embodiment of the present invention, the components of the multicomponent adhesive according to the invention are designed so that after mixing all components together in the resulting reaction mixture a pH in the range of 6.5 to 7.2, preferably in the range from 6.9 to 7.0.

This applies in particular to the preferred presence of SH groups (Y, X and / or Z 'then mean SH in the respectively corresponding compound or structural unit of the formula (I), (II) or (III)).

The abovementioned ranges of pH are physiologically very well tolerated and are usually present, for example, in the oral cavity. Therefore, the preferred multicomponent adhesives according to the invention have a particularly good biocompatibility. In addition, the formation of an adhesive hydrogel in these pH ranges is particularly well, especially in the preferred presence of SH groups.

In some embodiments, it has proved to be advantageous to stabilize the pH range or value of the reaction mixture resulting from a multicomponent adhesive according to the invention by adding a buffer system. Preference is therefore given to a multicomponent adhesive according to the invention comprising c) a buffer consisting of a buffer acid and a corresponding buffer base, wherein the pK _{B of} the buffer base is not smaller than 2, preferably not smaller than 4. The use of a buffer system leads to a stabilization of the pH. Range or value in the reaction mixture of a multicomponent adhesive according to the invention. As a result, for example, possible side reactions which may otherwise occur during the formation of an adhesive hydrogel at pH values of> 8 can be avoided. This applies in particular to the preferred presence of SH groups (Y, X and / or Z 'then signify SH in the respectively corresponding compound or structural unit of the formula (I), (II) or (III)). In addition, by using a Buffer system, the pH values of the components and the pH of the mixture resulting from mixing all components very accurately.

In particular, a multicomponent adhesive according to the invention in which the molar ratio of buffer acid to buffer base is in the range from 1:10 to 10: 1 is preferred, preferably in the range from 1: 8 to 8: 1, particularly preferably in the range from 1: 5 to 5 : 1. In this range of the molar ratio of buffer acid to the buffer base, the buffer regularly has sufficient buffer capacity.

Numerous buffer systems which can be adjusted to a desired pH in the range between 6 and 8 are known to those skilled in the art. In our own investigations, it has been shown that buffer systems, the primary amine groups and / or buffer systems containing 3- (A / -Morpholino) propanesulfonic acid (MOPS), the formation of an adhesive hydrogel according to the invention from the multi-component adhesive according to the invention in some cases in relevant Hinder dimensions; the presence of sulfonic acid groups does not appear to be generally preferred. It is likely that side reactions between the amine groups and / or sulfonic acid groups of the buffer and the further constituents of the multicomponent adhesive intended for reaction take place. Accordingly, a multi-component adhesive according to the invention is particularly preferred in which the buffer acid and / or buffer base do not undergo any formation of an adhesive hydrogel interfering with the components of the multi-component adhesive. In particular, a multi-component adhesive according to the invention is particularly preferred in which the buffer acid and / or buffer base contains no amine groups and / or sulfonic acid groups.

In our own investigations, numerous buffer systems could be identified whose pH can be adjusted in the range between 6 and 8 and which do not undergo any undesired interactions (eg chemical reactions) with the constituents of the multicomponent adhesive according to the invention. Preference is therefore given to an inventive multicomponent adhesive comprising one or more buffers (buffer systems) selected from the group consisting of maleate buffer, citrate buffer, bis (2-hydroxyethyl) amino-tris (hydroxymethyl) methane buffer (Bis-Tris buffer) , Phosphate buffer, N- (2-acetamido) -iminodiacetic acid (ADA), carbonate buffer, imidazole buffer, 1, 3-bis [tris (hydroxymethyl) -methylamino] propane buffer (bis-tris-propane Buffer), triethanolamine buffer, tricine buffer and bicin buffer. The formation of an adhesive hydrogel according to the invention takes place by chemical reaction of the constituents of the multicomponent adhesive according to the invention. In this case, preferably react the SH and / or NH ₂ groups with the alpha, beta-unsaturated carbonyl groups in the context of a Michael addition. The SH and / or NH ₂ groups act as Michael donors and the alpha, beta-unsaturated carbonyl groups as Michael acceptors. This Michael addition proceeds particularly well in the presence of a strong base. Preference is therefore given to a multicomponent adhesive according to the invention which comprises as component d) one or more bases having a pK _B <1.

Particular preference is given to such a multicomponent adhesive according to the invention, in which the one or the bases having a pK _B <1 are ammonia, ammonium hydroxide and / or hydroxides of the alkali metals or alkaline earth metals, preferably sodium hydroxide or potassium hydroxide. The resulting multicomponent adhesives according to the invention have very good biocompatibility.

Component a), compound of the formula (I): The compound of the formula (I) in a multicomponent adhesive according to the invention is jointly responsible for excellent adhesion of the adhesive hydrogel resulting from the multicomponent adhesive according to the invention. The 1,2-dihydroxyphenyl moiety of the compound of formula (I) is capable of forming strong adhesion forces to other surfaces (e.g., biological tissues or titanium surfaces). Our own investigations have shown that the linker L in the compound of the formula (I) has an influence on the properties of the multicomponent adhesive or of the resulting adhesive hydrogel (eg biocompatibility, biodegradability, good adhesion to biological tissue allogeneic , heterogeneous or synthetic origin and / or on medical implants). According to a preferred embodiment of the multicomponent adhesive according to the invention, the linker L of the compound of the formula (I) is an organic molecular unit whose chain members consist of (a) exclusively carbon atoms or (b) carbon atoms and heteroatoms. As a result, the multicomponent adhesive according to the invention or the resulting adhesive hydrogel according to the invention has good biocompatibility, biodegradability and / or no or low toxicity. In certain embodiments of the multicomponent adhesive according to the invention, it has proved to be advantageous to provide the linker L in a specific length. Preference is given to a multicomponent adhesive according to the invention, the number of chain links of the linker L being in the range from 5 to 65, preferably from 6 to 60, preferably from 24 to 36. It has been shown in our own investigations that the adhesive hydrogels resulting from such novel multicomponent adhesives have good adhesion to biological tissue of allogeneic, heterogeneous or synthetic origin and / or to medical implants.

In the context of the present text, a chain member of the linker L is understood as meaning a single atom (chain atom or chain member) which, in combination with other atoms (further chain atoms or chain members) arranged together by covalent bonds, represents the 1,2-dihydroxyphenyl unit of the compound of the formula (I) linked by the shortest route to the functional group X. Only the atoms are counted as chain members lying on the shortest path between the 1, 2-dihydroxyphenyl unit of the compound of formula (I) and X; Atoms in side chains are not considered. In the event that a compound of the formula (I) comprises both one or more SH groups and one or more NH ₂ groups, only the SH group (s) is (are) taken into account. In the event that a compound of formula (I) comprises two or more SH groups or (in the absence of SH groups) NH ₂ groups, the group SH or NH _{2 is} considered as X, which by the shortest route the 1, 2-dihydroxyphenyl unit and the SH or NH ₂ group is linked.

The linker L can be designed in many ways. However, a multi-component adhesive according to the invention in which the linker L is a hydrocarbon, a polyether or a peptide or comprises such a group is particularly preferred. The adhesive hydrogels resulting from such novel multicomponent adhesives have very good biocompatibility.

In order to improve the adhesion of the adhesive hydrogel prepared from the multicomponent adhesive according to the invention, it has proved to be advantageous if, in addition to the 1,2-dihydroxyphenyl unit, alkylamines are also present in the compound of formula (I). Accordingly, a multi-component adhesive according to the invention is preferred, wherein the linker L contains one, two, three, four or more alkylamines as side chain. Also preferred is a multicomponent adhesive according to the invention, wherein the linker L is or comprises a peptide, wherein the peptide comprises at least 2 N atoms in the X connecting with the 1, 2-dihydroxyphenyl unit, preferably 2 to 20, more preferably 5 to 15, more preferably 8 to 12 N atoms in the X connected to the 1, 2-dihydroxyphenyl unit chain comprises. In this case, only N atoms are counted, which are chain links. When using peptides in or as linker L, multicomponent adhesives according to the invention or the resulting adhesive hydrogel according to the invention have particularly good biocompatibility and / or biodegradability.

In some applications, a multi-component adhesive according to the invention has proven to be particularly suitable, in which the compound of the formula (I) contains specific amino acid units or combinations of specific amino acid units. Particular preference is given to a multicomponent adhesive according to the invention, wherein the compound of the formula (I) contains at least one cysteine unit, preferably an L-cysteine unit (formula X).

At least one of the dashed lines in formula (X) represents a covalent bond to further structural units. In the case where the cysteine unit is terminal in the compound of the formula (I), one of the dashed lines corresponds to hydrogen or -OH, depending on whether the cysteine unit is covalent via the carboxylic acid function or via the amine function with further structural units connected is.

Inventive multicomponent adhesives in which the compound of the formula (I) contains specific amino acid units or combinations of specific amino acid units are distinguished by particularly good biocompatibility and / or are biodegradable.

Preference is given to a multicomponent adhesive according to the invention, where the linker L in the compound of the formula (I) contains one, two or more structural units selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, methionine, phenol nylalanine, tryptophan, proline, hydroxyproline, serine, phosphoserine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, preferably selected from the group consisting of cysteine, alanine, lysine, proline, hydroxyproline, serine , Phosphoserine, tyrosine and threonine. Particular preference is given to a multicomponent adhesive according to the invention in which the linker L in the compound of the formula (I) contains one, two or more structural units selected from the group of amino acid sequences consisting of alanine-lysine, lysine-proline, proline-serine, serine Tyrosine, Tyrosine Proline, Proline Proline, Proline Threonine, Alanine Lysine Proline, Lysine Proline Serine, Proline Serine Tyrosine, Serine Tyrosine Proline, Tyrosine Proline Proline, Proline Proline Threonine, alanine-lysine-proline-serine (SEQ ID NO: 1), lysine-proline-serine-tyrosine (SEQ ID NO: 2), proline-serine-tyrosine-proline (SEQ ID NO: 3), serine tyrosine Proline-proline (SEQ ID NO: 4), tyrosine-proline-proline-threonine (SEQ ID NO: 5), alanine-lysine-proline-serine-tyrosine (SEQ ID NO: 6), lysine-proline-serine Tyrosine Proline (SEQ ID NO: 7), Proline Serine Tyrosine Proline Proline (SEQ ID NO: 8), Serine Tyrosine Proline Proline Threonine (SEQ ID NO: 9), Alanine Lysine Proline Serine tyrosine proline (SEQ ID NO: 10), lysine proline serine tyrosine proline Proline (SEQ ID NO: 11), proline-serine-tyrosine-proline-proline-threonine (SEQ ID NO: 12), alanine-lysine-proline-serine-tyrosine-proline-proline (SEQ ID NO: 13), Lysine proline serine tyrosine proline proline threonine (SEQ ID NO: 14) and alanine lysine proline serine tyrosine proline proline threonine (SEQ ID NO: 15). In the aforementioned amino acid sequences, the structural units serine may be independently replaced by phosphoserine. Likewise, in the abovementioned amino acid sequences, the structural units proline can be replaced independently of one another by hydroxyproline.

The "SEQ ID NO" refer to the attached Sequence Listing, which is part of the present specification.

Preference is given to a novel multicomponent adhesive in which, if X in the compound of the formula (I) is an alpha, beta-unsaturated carbonyl group, X is selected from the group consisting of alpha, beta-unsaturated aldehydes, alpha, beta-unsaturated ketones, alpha, beta-unsaturated esters, preferably acrylic acid esters and methacrylic esters, alpha, beta-unsaturated carboxylic acids, preferably acrylic acid and methacrylic acid, and alpha, beta-unsaturated carboxylic acid amides, preferably maleimide. Component b), compound containing the structural unit B-L'-Y (II):

In our own investigations, it has also been found that the linker L 'in the structural unit B-L'-Y (II) has an influence on the properties (eg biocompatibility, biodegradability, good adhesion to biological tissue allogeneic, heterogeneous or of synthetic origin and / or on medical implants) of the multicomponent adhesive or of the adhesive hydrogel resulting therefrom. A multi-component adhesive according to the invention is preferred in which the linker L 'in the structural unit B-L-Y (II) is an organic molecular unit whose chain members consist of (a) exclusively carbon atoms or (b) carbon atoms and heteroatoms. Such a multi-component adhesive according to the invention or the adhesive hydrogel resulting therefrom has good biocompatibility, biodegradability and / or no or low toxicity.

In the context of the present text, a chain link of the linker L 'is understood as meaning a single atom (chain atom or chain link) which, in combination with further atoms (further chain atoms or chain links) which are aligned by covalent bonds B, can be replaced by the functional group Y. connected. Only the atoms are counted as chain links lying on the shortest path between B and X; Atoms in side chains are not considered. For example, the number of chain members of a linker L 'in the following compound of the formula (V) is 7 when n is 1 and m is 2 (this is the number of atoms between the group Y and the node B).

B is a join point that links individual groups L'-Y. Usually, B is a carbon atom, a nitrogen atom or an oxygen atom. For example, B in the following compound of formula (V) corresponds to the quaternary carbon atom to which four groups L-Y are attached.

Preference is given to a multicomponent adhesive according to the invention in which, if Y in the structural unit B-L-Y (II) is an alpha, beta-unsaturated carbonyl group, Y is selected from the group consisting of alpha, beta-unsaturated aldehydes, alpha, beta unsaturated ketones, alpha, beta-unsaturated esters, preferably acrylic acid esters, and alpha, beta-unsaturated carboxylic acid amides, preferably maleimide. A multi-component adhesive according to the invention is particularly preferred when the linker L 'in the structural unit B-L-Y (II) is or comprises a hydrocarbon, a polyether or a peptide. The adhesive hydrogels resulting from such multicomponent adhesives according to the invention regularly have very good biocompatibility.

A multi-component adhesive of the invention is also particularly preferred when the structural unit (II) has the following structure (IIa):

wobei n eine ganze Zahl größer oder gleich 1 ist, x 0, 1 , 2, 3, 4, 5, 6, 7, oder 8 ist und m 0, 1 , 2, 3, 4, 5, 6, 7, oder 8 ist. Die aus solchen erfindungsgemäßen Mehrkomponentenklebstoffen resultierenden Adhäsivhydrogele, weisen eine sehr gutes Wasseraufnahmevermögen und eine sehr gute Biokompatibilität auf.

where n is an integer greater than or equal to 1, x is 0, 1, 2, 3, 4, 5, 6, 7, or 8, and m is 0, 1, 2, 3, 4, 5, 6, 7, or 8 is. The adhesive hydrogels resulting from such novel multicomponent adhesives have very good water absorption capacity and very good biocompatibility.

The structural unit (IIa) is a preferred example of one of the structural unit B-L'-Y (II).

Particular preference is given to multicomponent adhesives according to the invention comprising, in or as constituent (b), one, two, three, four or more compounds selected from compounds of the formula (V)

 (V) where

n is an integer greater than or equal to 1 in each of the four side chains, regardless of the meaning of n in the other side chains, and m in each of the four side chains is independent of the meaning of m in the other side chains 0, 1, 2, 3, 4, 5, 6, 7, or 8

and

Y in each of the four side chains, independently of the meaning of Y in the other side chains, is selected from the group consisting of SH, NH ₂ and alpha, beta-unsaturated carbonyl groups and is convertible with the group X to form at least one covalent bond.

The compound of the formula (V) is a preferred example of a compound containing the structural unit B-L'-Y (II) or a compound containing the structural unit (IIa).

Very particular preference is given to a multicomponent adhesive according to the invention as just defined, where in the compound of the formula (V)

m is identical in each of the four side chains

and or

Y is identical in each of the four side chains.

Since the compound of the formula (V) in the particularly preferred embodiments has a high degree of symmetry and all side arms (as an example of structural units (II)) are identical, this compound can be produced particularly easily. As a result, for example, the cost of the compound of the formula (V) and thus also the cost of a multi-component adhesive according to the invention can be reduced. Due to the simple synthetic approach to compounds of formula (V) in a few reaction steps, the compound of formula (V) can also be obtained in high purity. Impurities and by-products that would inevitably arise in reactions with many synthetic steps and can not be separated are avoided. As a result, a multicomponent adhesive according to the invention can be obtained in very good purity and quality.

Particular preference is given to a novel multicomponent adhesive as just defined, comprising in or as component (b) a compound of the formula (VI)

 Where VI

n is an integer greater than or equal to 1 in each of the four side chains regardless of the meaning of n in the other side chains. The compound of the formula (VI) is a particularly preferred example of a compound of the formula (V) and a particularly preferred embodiment of a compound containing the structural unit B-L-Y (II) or the structural unit (IIa).

The SH groups of the compound of formula (VI) (and similar compounds) react very selectively, in high yields and under mild conditions with alpha, beta-unsaturated carbonyl groups. Thus, the corresponding multi-component adhesives according to the invention and the resulting adhesive hydrogels according to the invention have a very high quality.

Particular preference is given to a multicomponent adhesive according to the invention, one, two, three, four or all compounds which independently of one another comprise in each case two, three, four, five, six, seven, eight or more structural units (II), (a) a weight average of Have molecular weight (M _w ) in the range of 500 to 40,000 g / mol, preferably in the range of 500 to 25,000 g / mol, more preferably in the range of 1000 to 15000 g / mol, particularly preferably in the range of 2000 to 8000 g / mol and / or (b) have a polydispersity of less than 4, preferably less than 3, more preferably less than 2, most preferably less than 1.5.

Component (ii), compound containing the structural unit B'-L "-Z '(III):

In our own investigations it has also been found that the linker L "in structural unit B'-L" -Z '(III) has an influence on the properties (eg biocompatibility, biodegradability, good adhesion to biological tissue allogeneic, of heterogeneous or synthetic origin and / or on medical implants) of the multicomponent adhesive or of the adhesive hydrogel resulting therefrom. A multi-component adhesive according to the invention is preferred when the linker L "in the structural unit B'-L" -Z '(III) is an organic molecular unit whose chain members consist of (a) exclusively carbon atoms or (b) carbon atoms and heteroatoms. As a result, the multicomponent adhesive according to the invention or the resulting adhesive hydrogel according to the invention has good biocompatibility, biodegradability and / or no or low toxicity.

In the context of the present text, a chain link of the linker L "is understood as meaning a single atom (chain atom or chain link) which, in combination with other atoms (further chain atoms or chain links) which are aligned by covalent bonds, links B to the functional group Z 'by the shortest path Only the atoms are counted as chain members lying on the shortest path between the B 'and Z', atoms in side chains are not taken into account, for example, the number of chain members of a linker L "in the following compound of the formula (VII) 5, if o equals 1.

B 'is a point of attachment connecting individual groups L "-Z', and usually B is a carbon atom, a nitrogen atom or an oxygen atom. For example, B 'in the following compound of the formula (VII ) the oxygen to which two structural units (III) are bonded.

Preference is given to a multicomponent adhesive according to the invention in which, if Z 'in structural unit B'-L "-Z' (III) is an alpha, beta-unsaturated carbonyl group, Z 'is selected from the group consisting of alpha, beta unsaturated aldehydes, alpha, beta-unsaturated ketones, alpha, beta-unsaturated esters, preferably acrylic acid esters, and alpha, beta-unsaturated carboxylic acid amides, preferably maleimide.

wobei o eine ganze Zahl größer oder gleich 1 ist, q 0, 1 , 2, 3, 4, 5, 6, 7, oder 8 ist und p 0, 1 , 2, 3, 4, 5, 6, 7, oder 8 ist. Die aus diesen erfindungsgemäßen Mehrkomponentenklebstoffen resultierenden Adhäsivhydrogele, weisen eine sehr gutes Wasseraufnahmevermögen und eine sehr gute Biokompatibilität auf. A multi-component adhesive according to the invention is particularly preferred when the linker L "in the structural unit B'-L" -Z '(III) is or comprises a hydrocarbon, a polyether or a peptide. The adhesive hydrogels resulting from these novel multicomponent adhesives have very good biocompatibility. A multi-component adhesive according to the invention is likewise particularly preferred if the structural unit (III) has the following structure (IIIa):

where o is an integer greater than or equal to 1, q is 0, 1, 2, 3, 4, 5, 6, 7, or 8, and p is 0, 1, 2, 3, 4, 5, 6, 7, or 8 is. The Adhäsivhydrogele resulting from these novel multicomponent adhesives, have a very good water absorption capacity and a very good biocompatibility.

The structural unit (IIIa) is a preferred example of one of the structural units B'-L "-Z '(III), particularly preferred is a multicomponent adhesive according to the invention comprising, in or as a compound comprising the structural unit (III) one, two, three, four or more compounds selected from compounds of the formula (VII)

wobei o in jeder der zwei Seitenketten unabhängig von der Bedeutung von o in den jeweils anderen Seitenketten eine ganze Zahl größer oder gleich 1 ist und

where o in each of the two side chains regardless of the meaning of o in the other side chains is an integer greater than or equal to 1, and

Z 'each of the two side chains, independently of the meaning of Z' in the other side chains, is selected from the group consisting of SH, NH ₂ and alpha, beta-unsaturated carbonyl groups and is convertible with a group Y forming at least one covalent bond. The compound of the formula (VII) is a preferred example of a compound containing the structural unit B'-L "-Z '(III) or a compound containing the structural unit (IIIa).

Since the compound of the formula (VII) has high symmetry and both side arms (structural units (III)) are identical, this compound is particularly easy to produce. This allows, for example, the cost of the compound with the formula (VII) and thus reduce the cost of a multi-component adhesive according to the invention. Due to the simple synthetic approach to compounds of formula (VII) in a few reaction steps, the compound of formula (VII) can also be obtained in high purity. Impurities and by-products that would inevitably arise in reactions with many synthetic steps and can not be separated are avoided. As a result, an inventive multicomponent adhesive can be obtained in very good purity and quality.

Very particular preference is given to a novel multicomponent adhesive comprising, in or as component (ii), a compound of the formula (VIII)

where o is an integer greater than or equal to 1.

The compound of the formula (VIII) is a particularly preferred example of a compound of the formula (VII) and a particularly preferred embodiment of a compound comprising the structural unit B'-L "-Z '(III) or the structural unit (IIIa) ).

The alpha, beta-unsaturated carbonyl groups of the compound of the formula (VIII) are maleimide groups. These maleimide groups react very selectively, in high yields and under mild conditions, with Michael donors such as SH and NH ₂ , especially with SH. Accordingly, the resulting multicomponent adhesives according to the invention and the resulting adhesive hydrogels according to the invention have a very high quality.

Particular preference is given to a multicomponent adhesive according to the invention, one, two, three, four or all compounds which independently of one another comprise in each case two, three, four, five, six, seven, eight or more structural units (III), (a) a weight average of Have molecular weight (M _w ) in the range of 500 to 40,000 g / mol, preferably in the range of 500 to 25,000 g / mol, particularly preferably in the range of 1000th to 15000 g / mol, more preferably in the range of 2000 to 8000 g / mol and / or (b) have a polydispersity of less than 4, preferably less than 3, more preferably less than 2, especially preferably less than 1.5.

The weight average molecular weight (M _w ) is determined by gel permeation chromatography with polystyrene (PS) as the standard. The polydispersity corresponds to the quotient of the weight average molecular weight (M _w ) and the number average molecular weight (M _n ).

The individual (in particular the preferred) embodiments (as described above) of the constituents a), b), c), d) and (ii) of a multicomponent adhesive according to the invention discussed in detail above can be combined with one another.

Preference is given to a multicomponent adhesive according to the invention which is biocompatible and / or biodegradable.

In this context, the term "biocompatible" is understood to mean the ability of the multicomponent adhesive to have no or only a slight negative influence on living tissue in the environment of the multicomponent adhesive. "Biocompatible" are, on the one hand, multicomponent adhesives, in the biological assessment according to DIN EN ISO 10993- 1: 2010-04 no chronic toxicity, carcinogenicity, toxicokinetics, immunotoxicity, reproductive / developmental toxicity and other organ-specific toxicities; other biocompatible multi-component adhesives, in particular those multi-component adhesives in which negative effects are at least offset by positive effects.

The term "biodegradable" in this context means the ability of the multicomponent adhesive to biodegrade. "Biodegradable" are on the one hand "enzymatically degradable", ie decomposable by enzymes multicomponent adhesives, on the other hand biodegradable multicomponent adhesives, in particular biologically hydrolytic degradable multicomponent adhesives.

A preferred biodegradable multicomponent adhesive of the invention has inherent degradability (preferably according to the Organization for Economic Co-operation and Development (OECD 302) method of testing). A multicomponent adhesive according to the invention is preferred for use in a method for the surgical or therapeutic treatment of the human or animal body.

Likewise preferred is a multicomponent adhesive according to the invention for adhering (a) medical and / or (b) metallic implants, preferably medical, metallic implants, which preferably have a titanium content of more than 89% by weight, based on the total mass of the implant , human or animal tissue, wherein the tissue is preferably selected from the group consisting of bone, mucous membrane, gingiva, skin, cartilage, tooth, periodontal, connective tissue, muscle tissue, nerve tissue and epithelial tissue.

Likewise preferred is a multicomponent adhesive according to the invention for gluing together two parts of human or animal tissue, wherein (i) each of the two tissues, independently of the respective other tissue, is preferably selected from the group consisting of bone, mucous membrane, gingiva, skin, cartilage, tooth substance , Periodontal, connective tissue, muscle tissue, nerve tissue and epithelial tissue, and / or (ii) the tissue is allogeneic, heterogeneous or at least one tissue is synthetically or biologically producible. A purely artificially produced tissue without living additives (e.g., proteins) and starting materials (e.g., cells) is a synthetic tissue; a tissue manufacturing method using living cells or e.g. Bacteria are used, is a biological production process that leads to biologically producible tissue.

Also preferred is a multi-component adhesive according to the invention for gluing together (a) an implant with gingiva, (b) an implant with a biomaterial (allogeneic, heterogeneous or synthetic), (c) an implant with bone, (d) a biomaterial (allogeneic, heterogeneous or (c) a biomaterial (allogeneic, heterogeneous or synthetic) with bone, (d) a biomaterial (allogeneic, heterogeneous or synthetic) with tooth substance, (e) a biomaterial (allogeneic, heterogeneous or synthetic) with periodontal ligament, (f) bone with gingiva, (g) bone with periodontal, (h) tooth substance with gingiva, (i) tooth substance with periodontium, (j) periodontal with gingiva, (k) an implant with a chemical or biological Treatment substance, (I) a biomaterial (allogeneic, heterogeneous or synthetic) with a chemical or biological treatment substance, (m) of bone with a chemical or biological treatment substance, (n) of tooth substance with a chemical or biological treatment substance or (o) of periodontal with a chemical or biological treatment substance.

Preference is given to a multicomponent adhesive according to the invention comprising the compound of the formula (I) in an amount of from 1 to 15% by weight, preferably in an amount of from 3 to 10% by weight, preferably in an amount of from 4 to 7% by weight. %, based on the total mass of the compound of the formula (I), of the compound (s), each containing one, two, three, four, five, six, seven, eight or more structural units (II), and the compound (s) each containing one, two, three, four, five, six, seven, eight or more structural units (III). Particular preference is given to a novel multicomponent adhesive comprising the compound of the formula (I) where the total amount of the compound of the formula (I) is in the range from 1 to 15% by weight, preferably in the range from 3 to 10% by weight, preferably in the range of 4 to 7 wt .-%, based on the total mass of the compound of formula (I), the compound (s), each containing one, two, three, four, five, six, seven, eight or more structural units (II), and the compounds) each containing one, two, three, four, five, six, seven, eight or more structural units (III),

 one, two, three, four or more compounds each containing one, two, three, four, five, six, seven, eight or more structural units (II), wherein the total amount of the compounds containing one, two, three, four or more structural units (II) in the range of 55 to 70 wt .-%, preferably in the range of 60 to 67 wt .-%, preferably in the range of 63 to 66 wt .-%, based on the total mass of the compound of formula (I), the compound (s) each containing one, two, three, four, five, six, seven, eight or more structural units (II), and the compound (s) each containing one, two, three, four , five, six, seven, eight or more structural units (III), and

 additionally comprises one, two, three, four or more compounds which independently of one another contain in each case two, three, four, five, six, seven, eight or more structural units (III), the total amount of the compound containing in each case two or three , four, five, six, seven, eight or more structural units (III) in the

Range of from 20 to 44 wt .-%, preferably in an amount of 27 to 35 wt .-%, preferably in an amount of 28 to 31 wt .-%, based on the total mass of the compound of formula (I), the Compound (s) each containing one, two, three, four, five, six, seven, eight or more structural units (II), and the compound (s), each containing one, two, three, four, five, six, seven, eight or more structural units (III).

In the total mass of the compound of formula (I), the compound (s), each containing one, two, three, four, five, six, seven, eight or more structural units (II), and the compound (s), each containing One, two, three, four, five, six, seven, eight or more structural units (III) are the (total) sum of the masses of these compounds.

The invention also relates to the use of a multi-component adhesive according to the invention for the non-therapeutic bonding together of two surfaces.

The invention also relates to a process for producing an adhesive hydrogel comprising the following steps:

 Providing or producing a multicomponent adhesive according to the invention (as described above, preferably as referred to above as preferred, with respect to preferred constituents, what has been said above),

 Allow the components of the multi-component adhesive to react so that the adhesive hydrogel is formed.

For the process according to the invention described above, the adhesive hydrogel formation preferably takes place by crosslinking of the abovementioned groups X, Y, Z and Z 'of the constituents of the multicomponent adhesive.

It has been found that adhesive hydrogels of the invention can be crosslinked without having to resort to an oxidizing agent.

Particularly preferred, therefore, that the Adhäsivhydrogel formed is then cross-linked, without it (with an oxidizing agent, for example with Nal0 _4, H ₂ 0 _2, or an oxidoreductase, such as a with the EC-point 1.10 applies to the inventive process described above, especially laccase, catechol oxidase, tyrosinase, phenol oxidase).

It has also been found that the more crosslinking takes place the more groups R, R ² , R ³ and R ⁴ in the compound of the formula (I) are each LX. Therefore, a multi-component adhesive according to the invention in which in the compound of the formula (I) three of R, R ² , R ³ and R ^{4 are} each LX is particularly preferred.

In some embodiments, however, it may be preferable to add a corresponding oxidizing agent when mixing or shortly after mixing all the components of the multicomponent adhesive according to the invention.

The crosslinked adhesive hydrogel has particularly good properties. In particular, a good adhesion to biological tissue of allogeneic, heterogeneous or synthetic origin and to medical implants and a good barrier effect against bacteria is achieved. The invention also relates to a kit comprising a multicomponent adhesive according to the invention (as described above, preferably as referred to above as preferred, with regard to preferred constituents, what has been said above) and one or more further constituents.

Preferred is a kit according to the invention, wherein the one or more further components is or are selected from the group consisting of syringes, cannulas, implants, stents, catheters, applicator, mixing device (eg static or dynamic mixers) and oxidizing agents for cross-linking a Adhesive hydrogel prepared from the multi-component adhesive.

The invention also relates to a method for the therapeutic or non-therapeutic sticking together of two or more surfaces, comprising the following steps:

 Providing or producing a multicomponent adhesive according to the invention (as described above, preferably as referred to above as preferred, with respect to preferred constituents, what has been said above),

Providing or producing two or more surfaces,

 Applying a mixture of the components of the prepared or provided multicomponent adhesive to one, two or more of the provided or prepared surfaces,

Producing a composite comprising two and more of the provided or manufactured surfaces and connecting between these surfaces a mixture of the components of the prepared or provided multi-component adhesive

 Allow the mixture of components of the multicomponent adhesive in the said composite to react so that an adhesive hydrogel is formed and the surfaces of the composite are glued together.

Preferred is a method according to the invention, wherein at least one of the provided or prepared surfaces is the surface of an element with a titanium content of more than 89% by weight, based on the total mass of the element.

The invention also relates to an adhesive hydrogel preparable from a multiplicity of inventive multicomponent adhesive (as described above, preferably as described above as preferred, with regard to preferred constituents, what has been said above), or (preferably) prepared by a process according to the invention for the preparation of a Adhesive hydrogel, wherein at least two linkers L are bound to each of the phenyleinheit derived from formula (I). Among a large number in this context is preferably a number of> 1000, preferably> 1 * 10 ⁶ , more preferably> 1 * 10 ⁹ , more preferably> 1 * 10 ¹² , more preferably> 1 * 10 ¹⁵ and particularly preferably> 1 * 10 ¹⁸ to understand.

A multitude of multicomponent adhesives according to the invention means that the amount corresponding to the multitude is contained in each individual component of the multicomponent adhesive.

The invention also relates to an article comprising two glued-together surfaces, between which an adhesive hydrogel preparable from a multi-component adhesive according to the invention (as described above, preferably as described above with regard to preferred constituents, as described above) and which effects the adhesive bond.

The invention also relates to an article comprising a surface on which an adhesive hydrogel preparable in a adhesive compound from a multicomponent adhesive according to the invention (as described above, preferably as described above as preferred, with regard to preferred constituents, as described above). The following examples illustrate the invention; Unless otherwise indicated, all figures are by weight.

Example 1 :

In each case a 50C ^ I microreaction vessel 15 mg (about 7.5 μιηοΙ) 4-arm PEG-SH (compound of formula (VI)) in 150 μΙ 0, 1 M carbonate buffer (with 1 M HCl to pH 7 , 5) and 7 mg (about 3.5 μιηοΙ) of Mal-PEG-Mal (compound of formula (VIII)) in 200 μΙ 0, 1 M carbonate buffer (adjusted to pH 7.5 with 1 M HCl). To the solution of Mal-PEG-Mal, a further solution consisting of 1 mg (0.7 μητιοΙ) decapeptide (compound of formula (IX)) dissolved in 50 μΙ 0, 1 M carbonate buffer (the pH of the final solution is with about 1 μΙ NaOH solution adjusted to pH 7.5) and stirred well with a vortex mixer. After 10 minutes reaction time, the two solutions consisting of the decapeptide and Mal-PEG-Mal and 4-arm PEG-SH with the aid of two pipettes as possible applied simultaneously to the gingiva substrate. Immediately after application, the titanium substrate is stuck to the solutions. After about 5 minutes, the gel has reached its final strength.

(IX) Example 2:

In a δΟΟμΙ-ΜίΙ οΓβθΜοηεςβίθβ 15 mg (about 7.5 μιηοΙ) 4-arm PEG-SH (compound of formula (VI)) in 150 μΙ 0, 1 M carbonate buffer (with 1 M HCl to pH 7.5 adjusted) and 1 mg (0.7 μητιοΙ) decapeptide (compound of formula (IX)) dissolved in 50 μΙ 0.1 M carbonate buffer (the pH of the final solution is adjusted to pH 7 with about 1 μΙ NaOH solution, 5 set) and). In another 500 μl microreaction vessel 7 mg (about 3.5 μηηοΙ) times PEG-Mal (compound of formula (VIII)) in 200 .mu.l 0.1 M carbonate buffer dissolved (adjusted with 1 M HCl to pH 7.5 ). After 10 min reaction time of the peptide / PEG-SH solution, the contents of both solutions are applied to the gingiva substrate as simultaneously as possible using two pipettes. Immediately after application, the titanium substrate is stuck to the solution. After about 5 minutes, the gel has reached its final strength.

Claims

Claims: 1. A multi-component adhesive for the preparation of an adhesive hydrogel comprising a) a compound of the formula (I)

in which R, R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} each independently H, OH or LX, wherein X is selected from the group consisting of SH, NH ₂ and alpha, beta-unsaturated carbonyl groups and L is a linker linking the phenyl moiety of formula (I) to X, with the proviso that two or three of R, R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} each LX and two or three R, R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} each OH, and  b) one, two, three, four or more compounds,  each containing one, two, three, four, five, six, seven, eight or more structural units (II)  B-L-Y (II)  wherein in each of the structural units (II), independently of the meaning in other structural units (II)  B is a node,  L 'is a linker and Y is selected from the group consisting of SH, NH ₂ and alpha, beta-unsaturated carbonyl groups and can be reacted with the group X to form at least one covalent bond, in which (i) one, two, three, four or more of the compounds each containing one, two, three, four, five, six, seven, eight or more structural units (II) each additionally comprise a radical Z, which is independent of each other radical Z of another compound is selected from the group consisting of SH, NH ₂ and alpha, beta-unsaturated carbonyl groups and is convertible with a group Y to form at least one covalent bond  and or  (ii) the multicomponent adhesive additionally comprises one, two, three, four or more compounds which independently of one another each have two, three, four, five, six, seven, eight or more structural units (III)  B'-L "-Z '(III)  in which each of the structural units (III) is independent of the meaning in other structural units (III)  B 'is a node,  L "is a linker and Z 'is selected from the group consisting of SH, NH ₂ and alpha, beta-unsaturated carbonyl groups and is reactable with a group Y to form at least one covalent bond. A multi-component adhesive according to claim 1, wherein in the compound of formula (I) three of R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} each LX and / or three of R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} each OH. A multicomponent adhesive according to any one of claims 1 or 2, comprising c) a buffer consisting of a buffer acid and a corresponding buffer base, wherein the pK _{B of} the buffer base is not smaller than 2, preferably not smaller than 4 and or d) one or more bases with a pK _B <1. multicomponent adhesive according to any one of claims 1 to 3, wherein the linker L of the compound of the formula (I) is an organic molecular unit whose chain members consist of (a) exclusively carbon atoms or (b) carbon atoms and heteroatoms  and or  the linker L 'in the structural unit B-L-Y (II) is an organic molecular unit whose chain members consist of (a) exclusively carbon atoms or (b) carbon atoms and heteroatoms  and or  the linker L "in the structural unit B'-L" -Z '(III) is an organic molecular unit whose chain members consist of (a) exclusively carbon atoms or (b) carbon atoms and heteroatoms. 5. Multi-component adhesive according to one of claims 1 to 4, wherein the structural unit (II) has the following structure (IIa):

where n is an integer greater than or equal to 1, x is 0, 1, 2, 3, 4, 5, 6, 7, or 8, and m is 0, 1, 2, 3, 4, 5, 6, 7, or 8 is. 6. A multi-component adhesive according to any one of claims 1 to 5, comprising in or as component (b) one, two, three, four, five, six, seven, eight or more compounds selected from compounds of formula (V)

(V) where n is an integer greater than or equal to 1 in each of the four side chains, regardless of the meaning of n in the other side chains, and m in each of the four side chains is independent of the meaning of m in the other side chains 0, 1, 2, 3, 4, 5, 6, 7, or 8 and Y in each of the four side chains, independently of the meaning of Y in the other side chains, is selected from the group consisting of SH, NH ₂ and alpha, beta-unsaturated carbonyl groups and is convertible with the group X to form at least one covalent bond. A multi-component adhesive according to any one of claims 1 to 6, wherein the structural unit (III) has the following structure (IIIa):

where o is an integer greater than or equal to 1, q is 0, 1, 2, 3, 4, 5, 6, 7, or 8, and p is 0, 1, 2, 3, 4, 5, 6, 7, or 8 is. A multi-component adhesive according to any one of claims 1 to 7, comprising in or as a compound comprising the structural unit (III) one, two, three, four or more compounds selected from compounds of the formula (VII)

 (VII) wherein o in each of the two side chains regardless of the meaning of o in the other side chains is an integer greater than or equal to 1, and Z 'each of the two side chains, independently of the meaning of Z' in the other side chains, is selected from the group consisting of SH, NH ₂ and alpha, beta-unsaturated carbonyl groups and is convertible with a group Y forming at least one covalent bond. 9. Multi-component adhesive according to one of claims 1 to 8, for use in a method for the surgical or therapeutic treatment of the human or animal body. 10. Use of a multi-component adhesive according to one of claims 1 to 9 for non-therapeutic bonding together of two surfaces. 1 1. A process for the preparation of an adhesive Hydrogel comprising the following steps:  Provision or production of a multicomponent adhesive according to one of claims 1 to 9,  Allow the components of the multicomponent adhesive to react to form the adhesive hydrogel. 12. Kit comprising a multi-component adhesive according to one of claims 1 to 9 and one or more further constituents. The kit of claim 12, wherein the one or more further ingredients are selected from the group consisting of syringes, cannulas, implants, stents, catheters, and oxidants for crosslinking an adhesive hydrogel prepared from the multicomponent adhesive. 14. Adhesive hydrogel preparable from a plurality of multi-component adhesive according to one of claims 1 to 9, or prepared with a plurality of multi-component adhesive according to one of claims 1 to 9, according to a method of claim 1 1, wherein each of the formula (I) originating Phenyleinheit at least two linkers L are bound.