Tissue-Adhesive Hydrogels

Abstract

The invention is directed to a tissue-adhesive multi-arm polymer comprising a core from which polymeric arms extent, which polymeric arms are substituted with a hydroxyl-substituted aromatic group based on compounds such as dopamine, L-DOPA, D-DOPA, tyramine, noradrenaline and/or serotonin. In addition, the invention is directed to a caprolactam blocked hydroxyl-substituted aromatic compound, suitable for the preparation of the tissue-adhesive multi-arm polymer and to the method for the preparation of the tissue-adhesive multi-arm polymer.

Claims

1. A method for preparing a tissue-adhesive multi-arm polymer having a structure according to formula I ##STR00019## wherein Q represent a core; the polymeric chain comprises one or more polymeric groups; X represents O, S or NH; the spacer represents a linear or branched C.sub.1-C.sub.8 hydrocarbon, optionally substituted with one or more OH, SH, halide, amide and/or carboxylate; ArOH represents a hydroxyl-substituted aromatic group; m represents the number of functionalized polymer arms and is 2 or more; and n represents the number of non-functionalized polymer arms and is a number in the range of less than m, wherein said method comprises reacting a multi-arm polymer having a structure according to formula II with the caprolactam blocked hydroxyl-substituted aromatic compound according to formula III.

2. The method according to claim 1 wherein the ArOH is selected from the group consisting of phenol, catechol, 3-hydroxyphenol, 4-hydroxyphenol, 2-aminophenol, 3-aminophenol, 4-aminophenol, 4-hydroxyindole, 5-hydroxyindole, 6-hydroxyindole, 7-hydroxyindole, and combinations thereof ##STR00020##

3. The method according to claim 1, wherein the polymeric chain comprises polyethers, polyesters, poly(ester ethers), polyamides, polycarbonates, polyurethanes, or a combination thereof

4. The method according to claim 1 wherein the spacer represents a linear or branched C.sub.1-C.sub.6 alkylene, and is optionally substituted with an hydroxyl and/or a carboxylic acid group.

5. The method according to claim 1 wherein the moiety NH-spacer-ArOH is based on dopamine, L-DOPA, D-DOPA, tyramine, noradrenaline and/or serotonin.

6. The method according to claim 1, wherein the polymeric chain is based on a polyether and/or a polyester.

7. The method according to claim 1, wherein the tissue-adhesive multi-arm polymer has a structure according to formula Ib, ##STR00021## wherein Q, m and n are as defined for formula I; R.sup.1 represents linear or branched C.sub.1-C.sub.4 alkylene and/or —C(O)—C.sub.1-C.sub.5 alkylene; R.sup.2 represents H, OH, CH.sub.3, or CO.sub.2H or esters thereof such as CO.sub.2Me or CO.sub.2Et; k represents the number of polymer units of each arm and proportional to the molecular weight of each arm.

8. The method according to claim 1, wherein the tissue-adhesive polymer has a number-average molecular weight in the range of 500 Da to 100 kDa.

9. The method in accordance with claim 1, wherein the core is based on a polyol selected from the group consisting of ethylene glycol, glycerol (GL), pentraerythritol (P), hexaglycerol (HG), tripentaerytritol (TP), trimethylolpropane (TMP), dipentaerythritol (DP) and combinations thereof.

10. The method in accordance with claim 1, wherein m is 4 to 10.

11. The method in accordance with claim 1, wherein the tissue-adhesive polymer has a substitution degree of the arms as defined by m divided by (m+n) of more than 60% as determined by .sup.1H-NMR.

12. A tissue-adhesive multi-arm polymer having a structure according to formula I, wherein said polymer is obtainable according to claim 1.

13. The tissue-adhesive multi-arm polymer according to claim 12, having a number-average molecular weight in the range of 15 kDa to 100 kDa, and wherein n is more than 4.

14. A kit of parts comprising a first container comprising the tissue-adhesive polymer in accordance with claim 12 and a second container comprising an oxidizing agent.

15. An injectable hydrogel, based on an oxidized tissue-adhesive polymer in accordance with claim 12, said hydrogel having a lap shear adhesion strength of more than 0.50 N as determined by ASTM F2255-05.38 and/or said hydrogel having a burst pressure of more than 15 mbar as determined by ASTM F2392-04.

16. The tissue-adhesive polymer in accordance with claim 12 for use sealing or closing of a tissue.

17. A caprolactam blocked hydroxyl-substituted aromatic compound, suitable for the preparation of the tissue-adhesive multi-arm polymer, said caprolactam blocked compound having a structure according to formula IIIb ##STR00022## wherein the spacer represents a linear or branched C.sub.1-C.sub.8 hydrocarbon, optionally substituted with one or more OH, SH, halide, amide and/or carboxylate and R.sup.2 is H, OH or CO.sub.2H or esters thereof such as CO.sub.2Me or CO.sub.2Et.

18. A method of functionalizing an activated material A, which surface comprises at least one hydroxyl, sulfhydryl and/or amine reactive group, with a catechol derivative, said method comprising contacting said activated material A with the caprolactam blocked hydroxyl-substituted aromatic compound according claim 17 to provide functional material B, ##STR00023## wherein XH is the hydroxyl, sulfhydryl and/or amine reactive group.

19. The functionalized material obtainable by the method according to claim 18.

20. The injectable hydrogel of claim 15 for use in sealing or closing of a tissue.

Description

EXAMPLE 1

Preparation of a Caprolactam Blocked Dopamine (CABDA)

[0062] ##STR00017##

[0063] In a chloroform chloroform solution at a temperature of 90° C., dopamine hydrochloride (1.5 equivalents) and CBC were reacted in the presence of triethylamine (3 equivalents) for 48 h. CABDA was obtained in a yield of 92%.

[0064] At a round-bottom flask was added carbonyl bis caprolactam (1.0 eq; 19.82 mmol; 5.0 g) and dissolved in CHCl.sub.3 (50 mL). The mixture was stirred at room temperature until dissolved, and of all times kept under inert conditions. Dopamine hydrochloride (1.5 eq; 29.73 mmol; 5.64 g) was added to the mixture and heated to 40° C. and followed by the addition of triethylamine (3.0 eq; 59.46 mmol; 6.02 g; 8.29 mL). The reaction mixture was heated to 90° C. and stirred for 48 h. The mixture was slowly cooled to room temperature. The white precipitation in the mixture was removed by Buchner filtration. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate/hexane (2/1; 90 mL). The mixture was treated with a solution of 0.5 M HCl/5% CaCl.sub.2 and 5% NaCl (90 mL), 5% CaCl.sub.2 (90 mL), 1M Na.sub.2CO.sub.3 (90 mL) and brine (90 mL). The organic layer was dried with MgSO.sub.4 and filtrated. The solvents were removed in vacuo. To give a yellow solid (yield 92%).

EXAMPLE 2

Functionalization of Multi-arm PEG Polymers

[0065] ##STR00018##

[0066] An 8-arm poly(ethylene glycol) polymer (PEG), 6-arm PEG and 4-arm PEG, having a molecular weight of 40 kDa, 30 kDa and 20 kDa respectively (8-arm-PEG40k, 6-arm-PEG30k and 4-arm-PEG20k respectively) were separately reacted with CABDA (1 equiv.) at 145° C. for 48 h under vacuum. Tissue-adhesive multi-arm polymers based on multi-arm-PEG40k and dopamine 8-ArmPEG40k-DA, 6-armPEG30k-DA and 4-armPEG20k-DA were individually obtained.

EXAMPLE 3

Gelation Time of 8-ArmPEG40k-DA, 6-armPEG30k-DA and 4-armPEG20k-DA

[0067] The polymers prepared according to Example 2 were mixed with NaIO.sub.4 in order to oxidize the catechol hydroxyl groups. This resulted in the formation of reactive quinone moieties which gives intermolecular crosslinking or gelation. The results are depicted in FIG. 1.

[0068] It was found that faster gelation occurs for 8-ArmPEG40k-DA>6-armPEG30k-DA>4-armPEG20k-DA. In addition, faster gelation occurs with increasing relative amounts of oxidation agent NaIO.sub.4.

EXAMPLE 4

Lap Shear Adhesion of 8-ArmPEG40k-DA, 6-armPEG30k-DA and 4-armPEG20k-DA

[0069] The tissue adhesive properties of the multi-arm PEG-DA polymers prepared according to Example 2 were determined on porcine dura mater. Lap shear adhesion test were carried out according to ASTM F2255-05.38. The results are depicted in Table 1 and are compared with commercially available DuraSeal™. Results show that the lap shear strength of the 8-ArmPEG40k-DA is much higher than with DuraSeal™.

TABLE-US-00001 TABLE 1 Tissue adhesive material Lap shear strength (N) (n = 5) 4-armPEG20k-DA 0.00 6-armPEG30k-DA 0.55 8-ArmPEG40k-DA 2.28 DuraSeal ™ 0.66

EXAMPLE 5

In Vitro Burst Pressure Test of 8-ArmPEG40k-DA, 6-armPEG30k-DA and 4-armPEG20k-DA

[0070] The tissue adhesive properties of the multi-arm PEG-DA polymers prepared according to Example 2 were determined on porcine dura mater. The in vitro burst pressure test was performed according to ASTM F2392-04 (Standard Test Method for Burst Strength of Surgical Sealants). The results are depicted in Table 2 and are compared with commercially available DuraSeal™. Results show that the burst pressure of the 8-ArmPEG40k-DA is higher than commercially available DuraSeal™.

TABLE-US-00002 TABLE 2 Tissue adhesive material Burst pressure (mbar) (n = 5) 4-armPEG20k-DA 0.00 6-armPEG30k-DA 25.4 8-ArmPEG40k-DA 29.3 DuraSeal ™ 10.4