Tissue-Adhesive Material

Abstract

The invention is directed to a tissue-adhesive polymer blend comprising a bioresorbable carrier polymer and a bioresorbable synthetic tissue-reactive polymer as well as to a tissue-adhesive device for sealing dura mater comprising said tissue-adhesive polymer blend.

Claims

1.-17. (canceled)

18. A tissue-adhesive polymer blend comprising a bioresorbable carrier polymer and a bioresorbable synthetic tissue-reactive polymer, wherein the synthetic tissue-reactive polymer is based on a multi-arm polyethylene glycol and is functionalized with at least one tissue-reactive group that comprises an activated ester, wherein the tissue-reactive polymer has a molecular weight of 20000 g/mol or more.

19. Tissue-adhesive polymer blend according to claim 18, wherein the carrier polymer is a synthetic carrier polymer comprising polyesters, polyethers, polyhydroxyacids, polylactones, polyetheresters, polycarbonates, polydioxanes, polyanhydrides, polyurethanes, polyester(ether)urethanes, polyurethane urea, polyamides, polyesteramides, poly-orthoesters, polyaminoacids, polyphosphonates, polyphosphazenes and combinations thereof.

20. Tissue-adhesive polymer blend according to claim 19, wherein the synthetic carrier polymer comprises a poly(DL-lactide-co--caprolactone) copolymer obtainable by the copolymerizaton of DL-lactide and -caprolactone.

21. Tissue-adhesive polymer blend according to claim 18, wherein the carrier polymer is a biological polymer comprising a polysaccharide.

22. Tissue-adhesive polymer blend according to claim 18, wherein the activated ester is selected from the group consisting of a thioester, a perfluoroalkyl ester, pentafluorophenol ester, N-hydroxysuccinimide ester and derivatives thereof.

23. Tissue-adhesive polymer blend according to claim 18, wherein the tissue-reactive polymer is based on a 4-arm or an 8-arm polyethylene glycol.

24. Tissue-adhesive polymer blend according to claim 18, wherein the tissue-reactive polymer has a molecular weight of up to to 100000 g/mol.

25. Tissue-adhesive polymer blend claim 18, wherein the weight ratio of the carrier polymer to the tissue-reactive polymer in the material is 1:10 to 10:1.

26. Tissue-adhesive polymer blend according to claim 18, further comprising a filler polymer that is typically based on polyethylene glycol that is not functionalized with the tissue-reactive functional group.

27. Tissue-adhesive polymer blend according to claim 18, further comprising a buffering agent which is preferably selected from the group consisting of phosphates, carbonates, acetates, citrates, Good's buffers and combinations thereof.

28. (canceled)

29. Tissue-adhesive device for sealing dura mater comprising the tissue-adhesive polymer blend in accordance to claim 18, preferably having a foam structure, a sheet structure, a gel-like structure or combinations thereof.

30. Tissue-adhesive device for sealing dura mater according to claim 29 comprising a foam structure.

31. Tissue-adhesive device for sealing dura mater according to claim 29, having a multilayered structure comprising at least two layers of which a first layer which comprises a foam structure that comprises a tissue-adhesive polymer blend in accordance to claim 18 and a second layer which comprises a sheet structure.

32. Tissue-adhesive device for sealing dura mater according to claim 29, having a multilayered structure comprising at least two layers of which a first layer comprises a tissue-adhesive polymer blend in accordance to claim 18 and a second layer essentially consisting of the carrier polymer in accordance to claim 18.

33. Tissue-adhesive device for sealing dura mater according to claim 29, having an adhesive strength of more than 1 N.

34. Tissue-adhesive device for sealing dura mater according to claim 29, having a burst-resistance of at least 8 mmHg.

35. Tissue-adhesive device for sealing dura mater according to claim 29, having a burst-resistance of at least 15 mmHg.

36. Tissue-adhesive device for sealing dura mater according to claim 29, having a burst-resistance of at least 30 mmHg.

37. Tissue-adhesive device for sealing dura mater according to claim 29, having a burst-resistance of at least 45 mmHg.

38. Tissue-adhesive polymer blend according to claim 24, wherein the tissue-reactive polymer has a molecular weight of up to to 80000 g/mol.

39. Tissue-adhesive polymer blend according to claim 24, wherein the tissue-reactive polymer has a molecular weight of 20000 to 60000 g/mol.

40. Tissue-adhesive polymer blend according to claim 27, wherein the buffering agent is selected from the group consisting of phosphates, carbonates, acetates, citrates, Good's buffers and combinations thereof.

41. Method for sealing dura mater of the human body by sealing the dura mater with a tissue-adhesive polymer blend in accordance with claim 18.

Description

EXAMPLE 1: PREPARATION OF POLYESTER FOAM DEVICE

[0043] A device based on a polymer blend comprising poly(DL-lactide-co--caprolactone) copolymer and tissue-reactive polymer 8-arm NHS-functionalized PEG of 40 kD with a glutarate spacer (8APEGNHS40k) was prepared as follows.

[0044] Poly(DL-lactide-co--caprolactone) copolymer (LLC) was prepared by copolymerization of DL-lactide and -caprolactone as described in WO2003/066705. 8APEGNHS40k was purchased from Jenkem Technologies.

[0045] The copolymer was dissolved in dioxane in a concentration of 2.5 wt % with cyclohexane (2 wt %) as porogen. 8APEGNHS40k was added to yield concentration of 50 mg/mL. The solution was poured in a mold (221.5 cm)_and cooled at 24 C. Freeze-drying of the solidified solutions provided the foam device. In another example molds of 55 cm and 1010 cm were used with the appropriate amount of the solutions.

EXAMPLE 2: PREPARATION OF A MULTILAYERED POLYESTER FOAM DEVICE

[0046] A solution is prepared according to Example 1, 1 mL from this solution is poured in a mold (221.5 cm) and the mold is subsequently cooled (24 C.) until the solution has solidified. On top of the frozen solution 1 mL of a second solution containing PEG-OH (20 k) in 1,4-dioxane (conc.) is added. The mold is placed at 24 C. until the entire content of the mold has solidified. The mold is placed in the freeze-dryer and the solvent is removed overnight.

EXAMPLE 3: PREPARATION OF A POLYESTER FOAM DEVICE WITH A DENSE SHEET ON ONE SIDE

[0047] A solution of polyurethane (about 2 wt %) in chloroform is cast in a mold as described in example 2. After evaporation of the solvent a sheet is obtained. The mold and the sheet are cooled at 24 C.

[0048] The LCC copolymer of Example 1 was dissolved in dioxane in a concentration of 2.5 wt % with cyclohexane (2 wt %) as porogen. 8APEGNHS40k was added to yield concentration of 50 mg/mL. The solution was poured on top of the cooled sheet in the mold (221.5 cm) and subsequently cooled at 24 C. Freeze-drying of the solidified solutions provided the foam device. In other examples molds of 55 cm and 1010 cm were used with the appropriate amount of the solutions.

EXAMPLE 4: PREPARATION OF A POLYESTER FOAM DEVICE WITH A SHEET ON ONE SIDE AND CONTAINING BUFFER SALT

[0049] A solution of polyurethane (about 3 wt %) in chloroform was cast in a mold. After evaporation of the solvent a sheet was obtained. The mold and the sheet were cooled at 24 C.

[0050] The LCC copolymer of Example 1 was dissolved in dioxane in a concentration of 2.5 wt %. 8APEGNHS40k was added to yield concentration of 40 mg/mL. To this, disodium hydrogen phosphate was added in 3 mg/mL concentration. The obtained solution was poured on top of the cooled sheet in the mold (771.5 cm) and subsequently cooled at 24 C. Freeze-drying of the solidified solutions provided the foam device.

EXAMPLE 5: PREPARATION OF AMYLOPECTINE FOAM DEVICE

[0051] Amylopectine was mixed with water in a ratio of 1:7 by weight. By heating the suspension (95 C.) under vigorous stirring for 60 minutes a gel was obtained. The gel was poured in a mold (221.5 cm), cooled (24 C.) and after freeze-drying a foam of amylopectine was obtained.

EXAMPLE 6 AMYLOPECTIN FOAM DEVICE IMPREGNATED WITH 8APEGNHS COVERED WITH COPOLYESTER SHEET

[0052] A foam of amylopectin prepared according to example 5 was impregnated with a solution of tissue reactive polymer (8APEGNHS10k) in chloroform. To obtain a loading of 80 mg tissue reactive polymer in the foam. After evaporation of the solvent the foam is covered with a sheet of copolyester poly(DL-lactide-co--caprolactone) copolymer.

[0053] The sheet of the poly(DL-lactide-co--caprolactone) copolymer is covered with a 2 wt % solution of the copolymer in chloroform and the amylopectine foam with tissue reactive polymer is pressed on the sheet. After evaporation of the solvent a foam with a dense sheet on top is obtained.

EXAMPLE 7: DETERMINATION OF ADHESIVE STRENGTH

[0054] The adhesive strength of is determined by slicing a piece of porcine dura mater into two slices and adhering the device to both slices such that the slices are joined at their point of slicing. Adherence is achieved by applying a force of 9.8 N for 2 minutes.

[0055] By using a universal testing machine, the joined slices are pulled apart at 10 mm/min to determined the force required to break the bonding of the device with the dura mater. The adhesive strength is defined as the maximum load before failure of the bond between the device and the dura mater.

COMPARATIVE EXAMPLE 1: DETERMINATION OF ADHESIVE STRENGTH OF COMMERCIALLY AVAILABLE SEALANTS

[0056] In a comparative example, the adhesive strength of commercially available sealants are determined as described in example 7. The results are provided in Table 1.

[0057] TissuePatchDural is commercially available from Tissuemed, Hemopatch and TachoSil are commercially available from Baxter.

TABLE-US-00001 TABLE 1 Device Adhesive strength (N) Example 1 (LCC + 8APEGNHS40k) 1.373 Example 2 multilayered device 1.560 Example 4 (LCC/8APEGNHS40k/ 6.9 Na.sub.2HPO.sub.4 buffer) + copolyurethane sheet Example 5 amylopectin device 0.13 Example 6 (amylopectin/8APEGNHS10k) + 1.824 copolyester sheet Comparative examples TissuePatchDural 0.439 Hemopatch 0.487 Tachosil 0.850

EXAMPLE 8: DETERMINATION OF DURABLE ADHESIVE STRENGTH

[0058] Devices given in table 2 were prepared comparable to example 1, but with tissue-reactive polymers with a different number of arm and a different molecular weight.

[0059] The durable adhesive strengths of the devices were tested in a method comparable to example 7, with the difference that the slices joined by the adhering device are submerged and stored in a saline solution for a certain time period (0-168 h, as indicated in table 2) before the adhesive strength of the device with the dura mater is determined. The results are given in table 2.

TABLE-US-00002 TABLE 2 Devices Comp. Time LCC + LCC + LCC + device (h) 8APEGNHS40k 4APEGNHS10k 8APEGNHS10k Tachosil 0 1.37 0.98 0.7 0.85 24 2.44 0 96 2.17 1.71 1.02 0 168 1.61 1.74 1.46 0

EXAMPLE 9: DETERMINATION OF ADHESIVE STRENGTH DEPENDENT IN PEG MULTI-ARM BASED DEVICES

[0060] Three different devices (devices #1-3), each comprising the same concentration of a different tissue-adhesive polymer having a NHS-comprising PEG arms were provided as described in Example 1.

[0061] The adhesive strength of each device on dura mater was determined as described in Example 7. [0062] Device #1-1 arm: 1PEGNHS2k (1 mmol NHS per gram polymer) [0063] Device #2-4 arms: 4PEGNHS10k (0.4 mmol NHS per gram polymer) [0064] Device #3-8 arms: 8PEGNHS40k (0.2 mmol NHS per gram polymer)

[0065] The adhesive strength is provided in FIG. 3. The results show that, despite less NHS per gram of polymer, multi-arm PEG tissue-adhesive polymer devices demonstrate a relatively high adhesive strength to dura mater.

EXAMPLE 10: BURST-RESISTANCE

[0066] The burst-resistance of devices obtained from examples 1 and 2 were determined by closing a container containing a liquid with dura mater. The dura mater is punctured such that a puncture with a 3 mm diameter is obtained. The puncture is covered with the device that adheres to the dura matter surrounding the puncture by applying a force of 9.8 N for 2 minutes. Then, the pressure in the container is increased such that the liquid contained in the contained exerts a pressure on the device sealing the puncture. The burst-resistance is the point at which the device bursts.

[0067] Results are provided in table 3.

COMPARATIVE EXAMPLE 2: BURST-RESISTANCE OF COMMERCIALLY AVAILABLE SEALANTS

[0068] In a comparative example, the burst-resistance of commercially available sealants are determined as described in example 10. The results are provided in Table 3.

TABLE-US-00003 TABLE 3 Device burst-resistance (mmHg) Example 1 LCC + 8APEGNHS40k 59 Example 1 LCC + 8APEGNHS40k 16 (after 24 h in saline) Example 4 (LCC + 8APEGNHS40k + 106 Na.sub.2HPO.sub.4 buffer) + copolyester sheet Example 5 Amylopectine 14 Example 6 (amylopectin/8APEGNHS10k) + 51 copolyester sheet Comparative devices Hemopatch 19 TissuePatchDural 7

EXAMPLE 11: EFFECT OF BUFFER ON DEGRADATION OF POLY(DL-LACTIDE-CO--CAPROLACTONE) COPOLYMER (LLC)

[0069] The poly(DL-lactide-co--caprolactone) copolymer (LLC) as prepared in Example 1 was dissolved in dioxane in a concentration of 2.5 wt and one of three different buffer solutions (phosphate, bicine, carbonate) was added in 3 mg/mL concentration. The obtained solution cooled at24 C and freeze-dried to provided the foam device.

[0070] The foam device was placed in a physiological solution at 40 C., 80% relative humidity and the degradation of the LCC copolymer was monitored in time.

[0071] The results are provided in FIG. 4. The presence of the buffer in the foam does not have a detrimental negative effect on the degradation of the foam.