Methods and compositions to prevent formation of adhesions...

Details Methods and compositions to prevent formation of adhesions... Methods and compositions to prevent formation of adhesions...

1998-08-27

2003-07-22

Webman, Edward J. (Department: 1617)

Drug, bio-affecting and body treating compositions

Solid synthetic organic polymer as designated organic active...

Aftertreated polymer

C424S078170, C424S078240, C424S078310, C424SDIG001, C525S054110, C525S389000, C525S337000, C525S326900, C525S326800, C525S330200, C525S054200, C525S056000, C525S063000, C525S088000, C525S330300, C525S937000

Reexamination Certificate

active

06596267

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to methods and polymeric compositions for preventing the formation of tissue adhesions following surgical procedures or injury.
BACKGROUND OF THE INVENTION
Many pathological conditions result from the adhesion of proteins or cells to extracellular matrix, membranes, or other surfaces in the body. For example, damage to tissue surfaces after peritoneal surgery can result in formation of fibrinous attachments between tissues. G. dizerega,
Fertility and Sterility
61:219-235 (1994); G. Holtz,
Fertility and Sterility
41:497-507 (1984). These adhesions can have severe consequences including pain, bowel obstruction, and infertility. Adhesion can also occur as a result of cataract surgery. Residual lens epithelial cells migrate onto the posterior lens capsule, resulting in formation of a secondary cataract, referred to as posterior capsule opacification, and subsequent reduction in vision. D. Apple et al.,
Survey of Ophthalmology
37:73-116 (1992).
These conditions result from disruption of the naturally occurring surface of a biological tissue through surgical manipulation or external injury, followed by direct contact of one such disrupted biological surface with another biological surface, and then formation of a cellular adhesion that connects the adjacent tissues. Adhesions are scar tissue bridges that often connect to opposing organs, for example, restricting organ movement and function as well as causing pain.
One approach to prevention of adhesions has involved using a physical barrier that isolates the biological surfaces from each other. Attempts to prevent surface to surface contact of tissues have met with varying levels of success. In some cases, the materials did not remain in intimate contact with the treated biological surface for a sufficient period of time. In other cases, application of the barrier materials required extensive surgical manipulation in order to cover inaccessible tissue surfaces.
Most previous work in preventing adhesions has been in the field of gynecological surgery. Solid, liquid, and gel materials have been used. Solid treatments presumably work by providing a barrier between the damaged surface and other cells. The most popular of these materials are oxidized regenerated cellulose and expanded polytetrafluoroethylene, but use of these barriers has resulted in questionable efficacy, due to the requirement for extensive surgical manipulation, sometimes including additional surgery, nonadherence of the barrier to the surface, and immune response.
Liquid materials have included high molecular weight dextran solutions, hyaluronic acid, in liquid or gel form, and Ringer's lactate. These materials may work by preventing tissue damage in the first place and/or by “floating” the tissues, but the materials can make surgical manipulation difficult and all of the materials have shown questionable efficacy.
Gel materials have included fibrin glues, a triblock copolymer of polyethylene glycol (PEG) and polypropylene glycol (PPG) which gels at physiological temperatures, and a PEG-co-lactic acid (PEG-PLA) hydrogel. U.S. Pat. Nos. 5,410,016, 5,626,863, and 5,567,435, to Hubbell et al., disclose PEG-PLA hydrogels useful for adhesion prevention. These treatments presumably work by forming a barrier over the injured surface. The fibrin glue has not been tested on lysed adhesions and it may induce inflammatory response. P. De Iaco et al.,
Fertility and Sterility
62:400-404 (1994); L. Adamyan et al.,
International Journal of Fertility
36:76-88 (1991). The triblock copolymer may be cleared from the wound site too quickly because it does not adhere specifically to surfaces. V. Montgomery Rice et al.,
Fertility and Sterility
59:901-906 (1993); A. Steinleitner et al.,
Fertility and Sterility
57:305-308 (1992). Application of the PEG-PLA hydrogel requires access to and specific treatment of each surface involved, as well as UV irradiation for the gel to form. J. West et al.,
Biomaterials
16:1153-1156 (1995).
Research on the prevention of posterior capsule opacification by blocking adhesion of epithelial cells to the posterior capsule has focused on causing firm contact between an implanted intraocular lens and the posterior capsule, presumably mechanically blocking the migration of cells into the visual axis of the posterior capsule. D. Apple et al.,
Survey of Ophthalmology
37:73-116 (1992); C. Ohadi et al.,
Current Opinion in Ophthalmology
2:46-52 (1991). The mechanism of this technique has yet to be confirmed, and clinical results vary.
Elbert has investigated self assembling treatments which sterically protect the underlying surfaces to allegedly prevent adhesions. D. L. Elbert et al.,
Chemistry and Biology
5:177-183 (1998). Elbert used copolymers containing PEG and lysine, having a comb geometry of a poly(lysine) backbone with PEG sidechains or a dendrimer geometry of PEG attached to a lysine dendrimer. The cationic copolymers may adsorb to many biological surfaces, presumably due to electrostatic interactions, while the PEG molecules presumably sterically hinder the approach of proteins and cells to the surfaces. Other research in the area has included using PEG to sterically protect surfaces by covalently adding PEG to the surface (S. Dunn et al.,
Pharmaceutical Research
11:1016-1022 (1994)), entrapping PEG in the surface (N. Desai et al.,
Biomaterials
13:505-510 (1992)), applying PEG to the surface within a gel (A. Steinleitner et al.,
Fertility and Sterility
57:305-308 (1992); J. West et al.,
Biomaterials
16:1153-1156 (1995)), PEG copolymers to surfaces by adding cationic moieties to the PEG (D. L. Elbert et al.,
Chemistry and Biology
5:177-183 (1998)).
A biocompatible material that would prevent surface to surface contact by spontaneously adhering directly to a biological surface, in sufficient quantities to protect the surface, would provide a great advantage over all of the aforementioned treatments. The material would also present a cell and protein resistant outer layer that would minimize interactions with other surfaces during healing.
It is therefore an object of the present invention to provide polymeric materials that can be applied to tissues, in a very short time period, to protect the tissues from tissue to tissue interactions, such as adhesion.
It is a further object of the present invention to provide polymeric materials which are biocompatible and resistant to degradation for a specific time period.
It is a further object of the present invention to provide methods for making and using compositions for inhibiting tissue to tissue contact and adhesion within the body.
SUMMARY OF THE INVENTION
Methods and compositions are provided that form a self assembling layer on biological surfaces. The materials prevent adhesion via steric hindrance and inhibit direct contact between adjacent tissues. The materials are easy to apply to the tissue surface and exhibit lasting intimate contact with the tissue surface. These materials are copolymers of a polymer including boronate groups such as phenylboronic acid, which adsorb onto biological surfaces, and a polymer which is nonadsorbing, and adhesion resistant, such as polyethylene glycol, which interferes sterically with surface contact between tissues. The copolymers spontaneously adsorb to many biological surfaces containing acid or hydroxyl groups and remain for a finite period of time, preferably a matter of days, to sterically protect the surface while it heals.
The compositions can be applied to isolated tissue or to tissue during surgery or by means of a catheter or other less invasive device, for example during angioplasty or atherosclerosis surgery. The compositions are useful for blocking adhesion and immune recognition and thereby aid in the prevention of postoperative adhesions, protection of injured blood vessels from thrombosis and intimal thickening relating to restenosis, and decrease the extent of metastasis of tumor cells. The materials can be used as barriers to prevent the interaction of one cell or tis

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