RESORBABLE COVERING MEMBRANE FOR MEDICAL WOUND AREA TREATMENT

Abstract

A covering membrane for medical wound area treatment is disclosed for burns or for preventing adhesion. The covering membrane has a substrate layer including a polymer material as well as collagen particles which have a particle size I of more than 80 μm and are disposed in such a way as to be fixedly embedded in at least some portions of the polymer material of the substrate layer. The covering membrane further relates to a process for manufacturing such a covering membrane.

Claims

1. A covering membrane configured for medical wound area treatment including for burns or for preventing adhesion, comprising: a substrate layer comprising a resorbable polymer material; and collagen particles which have a particle size I>80 μm and are disposed fixedly embedded in at least some portions of the resorbable polymer material of the substrate layer.

2. The covering membrane according to claim 1, wherein the collagen particles have an average particle size in the range between 80 μm and 500 μm.

3. The covering membrane according to claim 1, wherein the collagen particles have an average particle size in the range between 100 μm and 250 μm.

4. The covering membrane according to claim 1, wherein the collagen particles have an average particle size in the range between 100 μm and 150 μm.

5. The covering membrane according to claim 1, wherein the covering membrane comprises between 0.4 and 80 weight percent collagen particles.

6. The covering membrane according to claim 1, wherein the covering membrane comprises between 0.4 and 25 weight percent collagen particles.

7. The covering membrane according to claim 1, wherein the covering membrane comprises between 0.4 and 2% collagen particles.

8. The covering membrane according to claim 1, wherein at least some of the collagen particles bulge over a surface region of the substrate layer surrounding the respective collagen particle or extend away from the substrate layer to form a collagen pole.

9. The covering membrane according to claim 8, wherein, in the ready-to-use state of the covering membrane, the collagen pole has a structure height h of more than 10% of the nominal thickness d of the substrate layer.

10. The covering membrane according to claim 8, wherein, in the ready-to-use state of the covering membrane, the collagen pole has a structure height h of more than 20% of the nominal thickness d of the substrate layer.

11. The covering membrane according to claim 8, wherein the substrate layer has the collagen pole on both sides.

12. The covering membrane according to claim 1, wherein the collagen particles are produced from native bovine, type I and/or type III collagen.

13. The covering membrane according to claim 1, wherein the substrate layer comprises: a copolymer based on the monomers lactide, trimetalcarbonate, glycolide, ε-caprolactone and/or 1,4-dioxan-2-one, or polyhydroxybutyrate (PHB); or mixtures of these polymers.

14. The covering membrane according to claim 13, wherein the substrate layer comprises a terpolymer of 65 to 87 weight percent lactide, 5 to 20 weight percent trimethyl carbonate, and 5 to 20 weight percent E-caprolactone.

15. The covering membrane according to claim 14, wherein the monomers lactide, trimethylene carbonate and ε-caprolactone are present in the terpolymer, in the range of 87/8/5 to 70/20/10 weight percent.

16. The covering membrane according to claim 1, wherein the substrate layer has a nominal thickness d of 50 μm to 3000 μm.

17. The covering membrane according to claim 1, wherein the substrate layer has a nominal thickness d of 80 μm to 500 μm.

18. The covering membrane according to claim 1, wherein the substrate layer has a nominal thickness d of 1000 μm to 2500 μm.

19. A process for manufacturing the covering membrane according to claim 1, comprising the steps of: comminuting provided and dried native collagen to collagen particles having an average particle size greater than 80 μm; preparing a polymer solution of a resorbable polymer and a suitable solvent; a) suspending the collagen particles in the polymer solution and applying the collagen suspension thus obtained, with the collagen particles suspended therein, onto a flat substrate; or b) applying the polymer solution to a planar substrate after previous sprinkling of the substrate with the collagen particles or with subsequent sprinkling of the polymer solution with the collagen particles; and removing the solvent by drying.

20. The process according to claim 19, wherein the step of comminuting provided and dried native collagen to collagen particles having an average particle size is greater than 100 μm.

21. The process according to claim 19, wherein removing the solvent by drying is by freeze-drying.

22. The process according to claim 19, wherein a copolymer based on the monomers lactide, trimetal carbonate, glycolide, ε-caprolactone and/or 1,4-dioxan-2-one or polyhydroxybutyrate (PHB) or mixtures of these polymers is used.

23. The process according to claim 19, wherein the collagen particles are dispersed in the polymer solution by stirring for a maximum of two minutes.

24. The process according to claim 19, wherein the collagen particles are dispersed in the polymer solution by stirring for a maximum of one minute.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0031] In the drawings:

[0032] FIG. 1 is a schematic sectional view of a covering membrane having a substrate layer in which collagen particles having a particle size of greater than 80 μm are anchored;

[0033] FIG. 2 is a side view of a covering membrane;

[0034] FIG. 3 is a plan view of the covering membrane according to FIG. 2, showing a collagen particle completely fixedly embedded in the polymer material of the substrate layer, which bulges over the (planar) surface region of the substrate layer that surrounds the collagen particle in each case;

[0035] FIG. 4 shows the covering membrane according to FIG. 2 after several hours of swelling in water at 37° Celsius;

[0036] FIG. 5 is a block diagram of a process according to the invention for manufacturing a covering membrane according to the invention; and

[0037] FIG. 6 shows an SDS-PAGE test for detecting an undesired degradation of collagen particles depending on the mixing time when mixing the collagen particles with a polymer solution.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0038] FIG. 1 shows a covering membrane 10 for medical wound area treatment, which is also suitable in particular for intraperitoneal adhesion prevention. The covering membrane 10 comprises a substrate layer 12 having a front and a rear side 12a, 12b. The substrate layer 12 is formed here structurally by a copolymer based on the monomers lactide, trimethylene carbonate, e-caprolactone and/or 1,4-dioxan-2-one, or polyhydroxybutyrate (PHB) or mixtures of these polymers. The substrate layer 12 is therefore biocompatible and degradable and completely resorbable hydrolytically and/or by the body's own enzymes.

[0039] The substrate layer has a nominal thickness d which can be from 50 to 3000 μm, preferably from 80 to 500 μm, or from 1000 to 2500 μm, depending on the mechanical application requirements placed on the covering membrane 10.

[0040] For improved hemostasis or faster absorption of blood and wound fluid, collagen particles 14 are fixedly embedded in at least some portions of the material of the substrate layer 12. In other words, the collagen particles 14 are anchored in the material of the substrate layer 12. The collagen particles 14 can be fixedly embedded in their entirety in the polymer material of the substrate layer and, according to FIG. 1, extend away from the substrate layer 12, or bulge over the front side, at least in part, as explained further below in connection with FIG. 4. If the collagen particles 14 extend away from the substrate layer, they can together form a collagen pole 16 of the substrate layer 12. In the ready-to-use state of the covering membrane 10, the structure height h of the collagen pole 16 can be more than 10%, preferably more than 20%, of the nominal thickness d of the substrate layer 12.

[0041] The collagen particles 14 all consist of comminuted native collagen, for example Type I and/or Type III collagen, and can, in particular, be of bovine, murine or porcine origin. The collagen particles 14 have a particle size I of more than 80 μm, preferably between 100 μm and 500 μm, particularly preferably between 100 μm and 250 μm.

[0042] In the embodiment shown in FIG. 1, due to the collagen pole 16 the covering membrane 10 has two different wear faces 18, 20. If the covering membrane 10 is applied with its pole-side wear face 18 to a wound area (not shown), a direct contacting of the wound area by the collagen particles 14 is made possible. In this way, a particularly high bioavailability of the collagen is ensured and its functional advantages in wound area treatment are exhausted at an early stage and comprehensively. These include, in particular, the known hemostatic properties of fibrillar collagen, the swelling capacity of which is due to a pronounced absorption capacity of blood and wound exudate, and the favorable effects thereof with respect to rapid vascularization of the wound area and wound healing. In practice, it has been shown that even low mass fractions of the collagen particles 14 favor the aforementioned effects. In this respect, the covering membrane 10 can comprise between 0.5 and 80 wt % (i.e., weight percent) collagen particles 14, preferably between 0.8 and 25 wt % collagen particles 14.

[0043] In practice, the covering membrane 10 can be folded and respective folding portions (not shown) can be placed on top of each other, e.g., by their mutually facing rear side 12b. This offers the advantage, in particular, in the case of preventing adhesion, of a particularly large fluid absorption capacity based on the surface unit 22 of the folded covering membrane 10 contacting the wound area in each case. In addition, a laparoscopic application of the covering membrane can thereby be facilitated.

[0044] According to an embodiment not shown in the drawings, the covering membrane can also have a collagen pole 16 of collagen particles 14 on both sides. This can, in practice, firstly counteract an accidental inverted application of the covering membrane and provide a collagen wear face 20 on both sides. At the same time, in the case of the wound application of the covering membrane, onerous adhesion of the covering membrane 10 to itself can be counteracted. It should be noted that the collagen poles 16 of the front and rear sides 12a, 12b of the substrate layer 12 can differ from one another in the average density of their collagen particles 14 per unit area 22 of the covering membrane 10 and/or the size of their collagen particles 14 or their structure height h. As a result, a covering membrane 10 having different collagen wear faces 18, can be provided, and thus the possible range of use of the covering membrane 10 during wound area treatment can be expanded.

[0045] FIGS. 2 to 4 show a further covering membrane 10 in its ready-to-use state. This covering membrane differs from the embodiment explained above in connection with FIG. 1 essentially in that the collagen particles 14 are completely fixedly embedded in the polymer material of the substrate layer 12. In other words, in this case the collagen particles 14 are completely surrounded or enveloped by the polymer material of the substrate layer. FIG. 2 shows a side view of the covering membrane, in which the nominal thickness d of the substrate layer can be clearly seen.

[0046] FIG. 3 shows the ready-to-use covering membrane 10 in the region of a collagen particle 14 in a microscopic plan view and having a height profile along the measuring section designated S. The collagen particle 14 bulges together with the polymer material (in a locally delimited manner) over the surface region 24 the front face 12a of the substrate layer 12 surrounding the collagen particle 14. In this case, the surface region 24 of the substrate layer 12 is planar or substantially planar.

[0047] If the covering membrane 10 shown in FIG. 3 is inserted in water and subsequently investigated by measurement, then increased swelling of the covering membrane 10 compared to collagen-free substrate layer portions of the covering membrane or of the surface region of the substrate layer 12 surrounding the collagen particle 14 is found in the region of a collagen particle 14, i.e., in a locally limited manner. FIG. 4 shows, in this respect, a microscope image of the covering membrane 10 after a water bath at 37° C. for 22 hours. The nominal thickness d (cf. FIG. 1) of the covering membrane 10 is approximately 250 μm on average, according to the height profile image, the collagen particle 14 shown (see FIG. 1) protruding approximately 350 μm beyond the surface region 24 of the substrate layer 12 (collagen particle-free substrate layer portion) encompassing the collagen particle 14.

[0048] Water contacting the covering membrane 10 diffuses through the polymer material of the substrate layer that covers the collagen particles 14 and is taken up by the collagen particles 14. The collagen particles 14 thus extract water from a bleeding wound and thus accelerate the hemostasis. The combination of the collagen particles 14 and the synthetic resorbable polymer (e.g., poly-lactide-caprolactone-trimethylene carbonate) combines the positive properties of both materials. The resorbable polymer material of the substrate layer 12 is in direct contact with the wound (e.g., burn wound) and can improve wound healing by enzymatic release of lactic acid and develop a pain-relieving and anti-infections effect.

[0049] Manufacturing Process:

[0050] In the following embodiments of a process 100 for manufacturing the covering membrane 10 according to the invention, reference is additionally made to the block diagram, with individual process steps of the process 100, shown in FIG. 5.

[0051] The process 100 has the following process steps:

[0052] In a first step 102, provided and preferably dried native collagen 200 is comminuted to collagen particles 14 having a particle size greater than 80 μm, preferably greater than 100 μm.

[0053] The collagen particles 14 can, in a subsequent optional step 104, be suspended in an organic solvent 202, for example dimethyl sulfoxide (DMSO), forming a collagen stock suspension 204. Surprisingly, the collagen particles 14 are stable or largely stable in pure DMSO, such that the collagen particles 14 suspended in DMSO do not degrade.

[0054] In a further step 106, a polymer solution 206 is prepared from a resorbable polymer 208 and a suitable solvent 210.

[0055] In step 108, the collagen particles 14 or the collagen particles 14 contained in the collagen stock suspension 204 are suspended/dispersed in the polymer solution 206 such that a collagen suspension 212 is obtained.

[0056] Here, care must be taken that the size and functionality of the collagen particles 14 (i.e. structural integrity with detectability of α- and β-bands in SDS PAGE test) is/are preserved. Thus, it has surprisingly been found that the collagen particles 14 are, for example, not stable in a solution 206 of a statistical terpolymer of D, L-lactide-trim ethylene carbonate caprolactone and can degrade over time to form collagen particles 14 having a particle size <50 μm. In this respect, on the one hand rapid processing of the collagen suspension 212 is advisable. Furthermore, when the collagen particles 14 are mixed with the polymer solution 206, extremely gentle, in particular temporally limited, stirring is advisable, in order not to further comminute or destroy the collagen particles 14, directly or by shearing. For this purpose, for example a dispersing device of the Ultra Turrax® series from IKA®-Werke GmbH & CO. KG, Germany can be used.

[0057] FIG. 6 shows the result of an SDS-PAGE test (sodium dodecyl sulfate polyacrylamide gel electrophoretic test) of the collagen suspension 212, depending on the stirring time by means of an aforementioned Ultra Turrax® stirrer. In the first (left-hand) trace, a protein marker PM (protein marker: “Precision Plus Protein Standard” from BioRad having defined molar weights between 10 and 250 kDa; 10 μl sample volume) was applied. The reference bands typical for the protein marker PM are found. A solution comprising native bovine collagen (sample volume 4 μl) was applied in the second trace. A sample (sample volume 33 μl) of the collagen suspension 212 having a stirring time of 2×15 s (trace 7), 2×30 s (trace 8), 2×60 s (trace 9) and 2×5 min (trace 10) was applied in the trace nos. 7 to 10 in each case.

[0058] The collagen bands typical for collagen particles 14 (α, β and γ regions) are clearly visible at an Ultra Turrax® mixing time of 2×15 s (trace 7). The intensity of the bands in the γ- and β region already decreases increasingly at a mixing time of 2×30 s and 2×60 s. In the case of a mixing time of 2×5 min, the bands in the γ region are almost no longer discernible and the bands in the α- and β region are markedly less pronounced. Surprisingly, the reduction of the intensity of the α-, β-, and γ regions thus clearly shows a degradation of the collagen even after stirring for 5 minutes. In the case of even longer stirring, the alpha and beta bands in the collagen suspension 212 are no longer discernible either (not shown). For the above reasons, the collagen particles 14 are preferably dispersed/suspended in the respective polymer solution 206 for less than 2 minutes, very particularly preferably at most 1 minute.

[0059] The collagen suspension 212 thus obtained is preferably applied, in step 110, to a flat substrate 216 by means of a doctor blade 214. As a flat substrate 216, in particular a glass plate can be used.

[0060] In a final step 112, the collagen suspension 212 is dried, in particular freeze-dried, and the solvent 210 is thereby removed.

[0061] Alternatively or in addition to steps 104 and 108, the collagen particles 14 may, in step 114, also be applied or scattered on the flat substrate 210 before application of the solution 206 or the collagen stock suspension 212 to the flat substrate 216, or applied or scattered on the solution 206/collagen suspension 212 after the application of the solution 206/collagen suspension 212 to the flat substrate 210. In the latter case, this can be done by means of a compressed gas or by means of compressed air, in order to introduce the collagen particles 14 into the solution 206 or the collagen suspension 212 at least in portions.

Example 1

[0062] In step 102, 0.5 g of dried bovine collagen 200 is comminuted to collagen particles 14 having a particle size >80 μm. The collagen particles 14 are subsequently dispersed in step 104 in an organic solvent 202 to obtain a collagen stock suspension 204. For this purpose, the collagen particles 14 are added for example to 49.5 g of dimethyl sulfoxide (DMSO) and dispersed gently therein over 15 sec. This gives a 1 collagen stock suspension 204.

[0063] In the subsequent step 106, in this case by way of example 150 g of a 23% solution 206 of a statistical terpolymer of D, L-lactide-trimethylene carbonate caprolactone in a solvent 208 is provided.

[0064] Subsequently, in step 108, a total of 50 g of the 1% DMSO-collagen stock suspension 204 is mixed with 150 g of the 23% solution of a statistical terpolymer of D, L-lactide-trimethylene-carbonate-caprolactone to form the collagen suspension 212, and homogenized twice, over 15 sec in each case, by means of stirring.

[0065] In step 110, the collagen suspension 212 is spread onto the substrate 216, for example a glass plate, using a doctor blade 214 having a doctor blade gap of 250 μm, and then freeze-dried in step 112. This results in a covering membrane 10 of approximately 120 μm nominal thickness d consisting of 98.6% lactide trimethylene carbonate caprolactone terpolymer and 1.4% bovine collagen particles 14.

Example 2

[0066] In step 108, a total of 1.15 g of ground collagen particles 14 having a particle size >80 μm is added to 100 ml of a 23% polymer solution 206 of a statistical terpolymer of D, L-lactide trimethylene carbonate caprolactone in DMSO, and stirred gently to form the collagen suspension 212.

[0067] The collagen suspension 212 is subsequently spread onto the flat substrate 216 in step 110, using a doctor blade 214 having a doctor blade gap of 500 μm. Finally, the solvent 210 is removed from the collagen suspension 212 by freeze-drying the collagen suspension 212. This results in an approximately 100-250 μm thick covering membrane in the form of a collagen composite membrane composed of 95% of a statistical terpolymer consisting of lactide-trimethylene-carbonate-caprolactone and 5% collagen particles 14 having a particle size >80 μm.

Example 3

[0068] If, according to example 2, a total of 4.6 g collagen particle 14 having a particle size >80 μm is suspended in the polymer solution 206 then, with otherwise unchanged further process steps, an approximately 100-250 μm thick covering membrane 10 consisting of 80% of a statistical terpolymer of D, L-lactide-trimethylene carbonate-caprolactone and 20% bovine collagen particles 14 of a particle size above 80 μm is obtained.

Example 4

[0069] In the first step 102, native bovine collagen is comminuted to collagen particles 14 having an average particle size >80 μm. Thereafter, in step 104, 0.25 g of the dried collagen particles 14 is added to 49.5 g DMSO and dispersed gently for 15 sec. A 1% collagen stock suspension 204 is obtained in the process. In step 108, 50 g of the 1% DMSO collagen stock suspension 204 are mixed with 150 g of a 12.5% solution of a statistical terpolymer of D, L-lactide-trimethylene-carbonate-caprolactone, and homogenized by stirring for 2×15 sec. The collagen suspension 212 thus obtained is spread onto the flat substrate 216 using a doctor blade 214 having a doctor blade gap of 600 μm.

[0070] In step 112, the collagen suspension 212 is freeze-dried, such that a covering membrane of approximately 180 μm nominal thickness d consisting of 98.6% lactide trimethylene carbonate caprolactone terpolymer and 1.4% bovine collagen particles 14 of a particle size >80 μm is obtained.