SECURING IMPLANTS AND MEDICAL DEVICES

Abstract

A biocompatible material for securing such implantable medical devices, for example by using an adhesive path.

Claims

1. A discrete adhesive unit for securing an implantable medical device to a tissue, comprising an adhesive layer and a non-adhesive layer, said adhesive layer comprising a biocompatible material, wherein said biocompatible material comprises a cross-linkable protein or polypeptide and one or more cross-linking materials, wherein said adhesive layer adheres said implantable medical device to the tissue.

2. The unit of claim 1, in the form of an adhesive patch.

3. The unit of claim 2, wherein said non-adhesive layer comprises a reinforcing backing layer, wherein said reinforcing backing layer comprises at least one water erodible, film-forming polymer.

4. The unit of claim 3, wherein said reinforcing backing layer comprises at least one of cellulose ether derivatives, such as HPMC (hydroxypropyl methylcellulose) or HPC (hydroxypropyl cellulose), HEC (hydroxyethyl cellulose), EC (ethyl cellulose) or crosslinked gelatin, or a combination thereof.

5. The unit of claim 2, wherein said backing layer has a thickness d2, from 50 m to 1000 m.

6. The unit of claim 2, wherein said non-adhesive layer is removable.

7. The unit of claim 2, wherein said non-adhesive layer remains after adhering said implantable medical device to the tissue.

8. The unit of claim 2, wherein said adhesive layer wraps around at least a portion of the implantable medical device.

9. The unit of claim 2, wherein the unit is separately attached to at least a portion of the implantable medical device, separate from said adhesive layer.

10. The unit of claim 2., wherein the biocompatible material comprises an enzymatically crosslinked gelatin matrix.

11. The unit of claim 2, wherein said matrix comprises gelatin and transglutaminase, wherein said transglutaminase cross-links said gelatin.

12. The unit of claim 11, wherein said gelatin is foamed to form gelatin foam.

13. The unit of claim 12, wherein the gelatin foam is in a density range of 5 to 100 mg/cm.sup.3.

14. The unit of claim 13, wherein the density is in the range of 10 to 50 mg/cm.sup.3.

15. The unit of claim 12, wherein said foamed gelatin comprises dried or lyophilized foamed gelatin solution.

16. The unit of claim 12, wherein prior to foaming, the concentration of the gelatin solution is between 0.1% and 30% w/w.

17. The unit of claim 16, wherein prior to foaming, the concentration of the gelatin solution is between 1% and 20% w/w.

18. The unit of claim 17 wherein prior to foaming, the concentration of the gelatin solution is between 5% and 15% w/w.

19. The unit of claim 11, wherein said matrix has a density in a range of from 5 to 100 mg/cm.sup.3.

20. The unit of claim 19, wherein said density is in a range of from 10 to 50 mg/cm.sup.3.

21. The unit of claim 11, wherein the gelatin is incorporated into a gelatin matrix with said transglutaminase such that one or more of the following occur: a majority of enzyme activity is preserved throughout a process of preparation; enzyme is equally distributed across the gelatin matrix surface; and/or enzyme is embedded into the depth of the gelatin matrix (gradient or equal distribution).

22. The unit of claim 11, wherein said transglutaminase is incorporated into said gelatin matrix according to one or more of mixing before drying said matrix or after drying said matrix.

23. The unit of claim 11, wherein said matrix is dried to comprise no more than 10% moisture content.

24. The unit of claim 11, wherein said transglutaminase is present at a concentration of from 0.0006 to 2 mg transglutaminase/cm.sup.3 gelatin matrix.

25. The unit of claim 1, wherein said adhesive layer has a thickness of from 0.6 cm to 2 cm.

26. The unit of claim 1, wherein said unit is in the form of a patch and has a surface area from 2-600 cm.sup.2.

27. The unit of claim 26, wherein said patch is in a shape of a square, rectangle, circle, or oval.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0030] The invention is herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of the preferred embodiments of the present invention only, and are presented in order to provide what is believed to be the most useful and readily understood description of the principles and conceptual aspects of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for a fundamental understanding of the invention, the description taken with the drawings making apparent to those skilled in the art how the several forms of the invention may be embodied in practice. In the drawings:

[0031] FIG. 1 represents a side schematic view of a non-limiting, exemplary, illustrative implementation of the adhesive material provided as a discrete unit;

[0032] FIGS. 2A and 2B show non-limiting, exemplary embodiment of an adhesive material, provided as a discrete unit, with various placements in relation to the tissue and the implantable device;

[0033] FIGS. 3A and 3B show schematic diagrams of a non-limiting example: of an adhesive patch, adhering to an implantable device such as a collagen scaffold for example;

[0034] FIG. 4: Adhesion of a collagen scaffold using a gelatin-based dry patch on a pork abdominal muscle at: (a) time 0 and (b) after 4 minutes;

[0035] FIG. 5: Schematic representing the fixation of a surgical mesh using an adhesive dry patch: (a) top view; (b) side view; and

[0036] FIG. 6: Securing a surgical mesh using a gelatin-based dry patch on a porcine abdominal muscle, (a) at time 0, (b) after 4 minutes.

DESCRIPTION OF PREFERRED EMBODIMENTS

[0037] The present invention is of compositions comprising a cross-linkable protein or polypeptide, and an agent which induces cross-linking of the cross-linkable protein, which are suitable for attaching a medical device to tissue.

[0038] According to preferred embodiments of the present invention, there is provided a composition for tissue adhesive in which the cross-linking material comprises transglutaminase and the cross-linkable protein comprises gelatin, in an attachment form that is suitable for attaching a medical device to tissue. For example, the attachment form may comprise a discrete unit, such as a patch for example. The cross-linked gelatin may form a matrix for example, which in turn may comprise an adhesive layer of the discrete unit. Optionally and preferably, the discrete unit also comprises a non-adhesive layer, such as a backing layer for example.

[0039] Suitable gelatin and transglutaminase can be obtained by any of the methods known and available to those skilled in the art. Gelatin may optionally comprise any type of gelatin which comprises protein that is known in the art, preferably including but not limited to gelatin obtained by partial hydrolysis of animal tissue and/or collagen obtained from animal tissue, including but not limited to animal skin, connective tissue (including but not limited to ligaments, cartilage and the like), antlers or horns and the like, and/or bones, and/or fish scales and/or bones or other components; and/or a recombinant gelatin produced using bacterial, yeast, animal, insect, or plant systems or any type of cell culture.

[0040] According to preferred embodiments of the present invention, gelatin from animal origins preferably comprises gelatin from mammalian origins and more preferably comprises one or more of pork skins, pork and cattle bones, or split cattle hides, or any other pig or bovine source. More preferably, such gelatin comprises porcine gelatin since it has a lower rate of anaphylaxis. Gelatin from animal origins may optionally be of type A (Acid Treated) or of type B (Alkaline Treated), though it is preferably type A.

[0041] Preferably, gelatin from animal origins comprises gelatin obtained during the first extraction, which is generally performed at lower temperatures (50-60 C., although this exact temperature range is an optional limitation).

[0042] The transglutaminase may optionally comprise any plant, animal, or microbe derived transglutaminase. Preferably the transglutaminase derived from Streptoverticillium mobaraensis is used.

[0043] The transglutaminase may optionally be in a composition comprising at least one other substance, such as a stabilizer or filler for example. Non-limiting examples of such materials include maltodextrin, hydrolyzed skim milk protein or any other protein substance, sodium chloride, safflower oil, trisodium phosphate, sodium caseinate or lactose, or a combination thereof preferably other than blood derived Factor XIII.

[0044] Although the optimal pH for activity of crude transglutaminase is 6.0, it also functions with high activity in the range of pH 5.0 to pH 8.0. Therefore, a composition according to the present invention for implant fixation preferably has a pH value in a range of from about 5 to about 8.

EXAMPLES

Example 1

[0045] Various exemplary implementations of the structure featuring the tissue adhesive composition are possible and are considered to fall within the present invention. FIG. 1 represents a side schematic view of a non-limiting, exemplary, illustrative implementation of the adhesive material provided as a discrete unit, in this case a patch 100, showing view of the layers. In this non-limiting example, two layers are provided, an adhesive layer 102 and a backing 104. As previously noted, backing 104 preferably is temporarily used in order for adhesive layer 102 (or layers) to be applied to both the tissue and to the implantable device (not shown). Such temporary use prevents having adhesive layer 102 (or layers) inadvertently adhere to an undesirable surface that is not the intended tissue and/or implantable device. Alternatively, the backing 104 or other non-adhesive layer remains after the implantable medical device is adhered to the tissue.

[0046] Each layer has a thickness d. In this non-limiting example, adhesive layer 102 has a thickness d1, which is optionally from 0.6 cm to 2 cm. Backing 104 has a thickness d2, which is optionally from 50 m to 1000 m.

Example 2

[0047] The adhesive can be used in various ways. FIGS. 2A and 2B show non-limiting, exemplary embodiments of an adhesive material, provided as a discrete unit, with various placements in relation to the tissue and the implantable device. In the configuration shown in FIG. 2A, an adhesive material 200 features an adhesive layer 202 and a backing 204. Adhesive layer 202 is placed to adhere to an implantable device 206 which in turn is placed against the tissue 208. Adhesive layer 202 then wraps over and around at least a portion of implantable device 206 as shown, so as to contact tissue 208 that surrounds implantable device 206. The contact points at tissue 208 that surrounds implantable device 206 act to fixate adhesive layer 202 to tissue 208, while the contact points to implantable device 206 act to fixate adhesive layer 202 to implantable device 206. Backing 204 is non-adhesive and may be removed after place of adhesive layer 202 and implantable device 206, or may alternatively remain, to avoid attachment of any other undesirable surface to adhesive layer 202.

[0048] In the configuration shown in FIG. 2B, an adhesive material 220 features an adhesive layer 224. An implantable device 222 is adhered to a tissue 226, by placing adhesive layer 224 against tissue 226 and then placing implantable device 222 on adhesive layer 224. In this non-limiting example, optionally a backing is not provided, because the adhering surfaces of adhesive layer 224 are at least partially covered by contact with tissue 226 and implantable device 222.

Example 3

[0049] Various non-limiting examples of implementations of the adhesive material as a patch or other discrete unit are possible. For example, the adhesive can be a gelatin-based dry patch prepared from a 16% gelatin and 80 U/g_gelatin mTG solution. The solution is foamed at low pH (3.8) in order to inhibit the enzymatic crosslinking, and dried by lyophilisation. The crosslinking is activated by wetting the patch when the latter is in contact with the muscle. Above it, a medical device is added. It can be, for example, a collagen scaffold (such as for example Ossix Volumax, a thick dental regeneration product).

[0050] FIGS. 3A and 3B show schematic diagrams of a non-limiting example of an adhesive patch which may be implemented according to the above description, adhering to an implantable device such as a collagen scaffold for example. FIG. 3A shows the top view and FIG. 3B shows the side view.

[0051] As shown, an adhesive patch 300 is provided which may be implemented as described with regard to FIG. 2B for example. Adhesive patch 300 is attached to a tissue 304, such as muscle for example. An implantable device 302 is then attached to adhesive patch 300, which in this non-limiting example is a collagen scaffold, such as the previously described Volumax product.

[0052] Optionally and alternatively the discrete unit, such as the adhesive patch, is separately attached to at least a portion of the implantable medical device, separate from the adhesive layer (not shown).

[0053] As another non-limiting example, the adhesive can be implemented as a gelatin-based dry patch prepared from a 2.5% gelatin and 80 U/g_gelatin mTG solution. The solution is foamed at low pH (3.8) in order to inhibit the enzymatic crosslinking, and dried by lyophilisation. It can be used in order to secure a surgical mesh on a muscle to prevent or repair a hernia.

Example 4

[0054] In this non-limiting Example, the adhesive was implemented as a gelatin-based. dry patch prepared from a 16% gelatin and 80 U/g_gelatin mTG solution. The solution was foamed at low pH (3.8) in order to inhibit the enzymatic crosslinking, and dried by lyophilisation. The crosslinking was activated by wetting the patch when the latter is in contact with the muscle. Above it, a collagen scaffold (such as for example Ossix Volumax) was attached to the patch.

[0055] The following procedure was performed with a patch and implantable device that were configured as shown in FIGS. 3A and 3B: [0056] Porcine abdominal wall tissue was heated to around 37 C. using a UV lamp. The temperature was checked using a non-contact IR (infrared) thermometer. [0057] The dry patch was applied on the tissue of the muscle and immediately after the collagen scaffold was added above. [0058] The muscle was covered with a wet gauze and then was placed at 37 C. in an air-incubator for 4 minutes, and then the adhesive strength was qualitatively tested.

[0059] After 4 minutes, it was found that the collagen scaffold was well secured on the abdominal muscle, as shown with regard to FIG. 4.

Example 5

[0060] FIGS. 5A and 5B show schematic diagrams of a non-limiting example of an adhesive patch which may be implemented according to the above description, adhering to an implantable device such as a surgical mesh for example. FIG. 5A shows the top view and FIG. 5B shows the side view.

[0061] As shown, an adhesive patch 500 is provided which may be implemented as described with regard to FIG. 2A for example. Adhesive patch 500 optionally is of a surface area from 2-600 cm.sup.2, optionally in any suitable shape, including but not limited to square, rectangle, circle, oval and the like. Adhesive patch 500 is attached to an implantable device 502, which in turn is attached to a tissue 504, such as muscle for example. Implantable device 502 in this non-limiting example is a surgical mesh.

[0062] In this non-limiting Example, the adhesive was implemented as a gelatin-based dry patch prepared from a 2.5% gelatin and 80 U/g_gelatin mTG solution. The solution was foamed at low pH (3.8) in order to inhibit the enzymatic crosslinking, and dried by lyophilisation. In this example, the adhesive patch was used in order to secure a surgical mesh on a muscle, for example to prevent or repair hernia.

[0063] The following procedure was performed with a patch and implantable device that were configured as shown in FIGS. 5A and 5B: [0064] The muscle was heated to around 37 C. using a UV lamp. The temperature was checked using a non-contact IR thermometer. [0065] The surgical mesh was placed on a porcine abdominal muscle and the dry patch was added above it to fixate it to the target tissue. [0066] The muscle was covered with a wet gauze and then was placed at 37 C. in an air-incubator for 4 minutes, afterward the adhesive strength was quantitatively measured using a force gage instrument in a lap shear test.

[0067] After 4 minutes at 37 C., it was found that the surgical mesh was well attached to the muscle. The adhesive strength measured using the gage force instrument was: 2.89 N=1.16 N/cm. The results are shown in FIG. 6.

REFERENCES

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[0069] [2] Tissue Adhesives in Clinical Medicine; 2nd ed.; Quinn, J. V., Ed.; B C Decker: Hamilton, Ontario Canada, 2005. Tissue Glue in Cosmetic Surgery; Saltz, R.; Toriumi, D. M., Eds. Quality Medical Publishing, Inc.: St. Louis, Mo., USA 2004.

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[0071] [4] Wassenaar, E., et al., Mesh-fixation method and pain and quality of life after laparoscopic ventral or incisional hernia repair: a randomized trial of three fixation techniques. Surgical endoscopy, 2010. 24(6): p. 1296-1302.

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[0074] [7] White, G. H., Yu, W., May, J., Chaufour, X., & Stephen, M. S. (1997). Endoleak as a Complication of Endoluminal Grafting of Abdominal Aortic Aneurysms: Classification, Incidence, Diagnosis, and Management. Journal of Endovascular Surgery, 4(2), 152-168. https://doi.org/10.1583/1074-6218(1997)004<0152:EAACOE>2.0. CO;2

[0075] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.

[0076] Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims. All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention.