Adhesive protein foam for surgical and/or therapeutic uses

Details Adhesive protein foam for surgical and/or therapeutic uses Adhesive protein foam for surgical and/or therapeutic uses

2001-03-20

2004-05-04

Foelak, Morton (Department: 1711)

Drug, bio-affecting and body treating compositions

Fermentate of unknown chemical structure

Having a known elemental analysis

C424S124000, C424S177100, C424S200100

Reexamination Certificate

active

06730299

ABSTRACT:

The present invention lies within the domain of biological adhesives, which are biodegradable and nontoxic, intended for surgical and/or therapeutic use.
More specifically, the present invention relates to a biocompatible fluid adhesive protein foam, which is bioresorbable and nontoxic, for surgical and/or therapeutic use.
It also relates to such a foam containing bioactive substances which can be released in a given site.
The invention relates, moreover, to a process for producing such an adhesive foam and to a kit for the preparation thereof.
It also relates to the use of the adhesive foam in surgery and/or for therapeutic purposes, in particular for protecting wounds and attaching biological tissues to each other or to an implanted biomaterial.
Biological glues which can adhere to tissues or attach them to each other, in a few minutes, without using staples or sutures are known. These glues are eliminated, in general after the cicatrization of the wound, by biodegradation, resorption or by simple detachment in the form of scabs.
Various technologies have been developed for the formulation of tissue adhesives. Some of them are of synthetic origin, such as the glues based on cyanoacrylates (2-butyl cyanoacrylate, 2-octyl cyanoacrylate), or on synthetic polymers, and others contain biological materials such as collagen or fibrin.
In general, the synthetic adhesives are used for the tight sealing of vessels or of lungs and for “gluing” the edges of skin incisions. The adhesive biological derivatives such as collagen and fibrin in addition have hemostatic properties and also act by controlling bleeding.
The cyanoacrylate glues form toxic products when degrading, even though the glues recently developed are less harmful.
They lead to products which are brittle after polymerization on the site of application. They remain in place 7 to 10 days and are eliminated by simple detachment, after cicatrization. Their polymerization time is relatively unmodifiable, less than 1 minute, and does not allow flexible use of these glues. They can also easily run and, consequently, glue tissues adjacent to the desired site.
FOCAL (U.S. Pat. No. 5,844,016) has described synthetic adhesives based on the photochemical polymerization of hydrogel made of polyethylene glycol (PEG). Their method of use is not practical. Specifically, they involve application in several steps, to the operating site, of the solution containing the photochemical initiator (eosin Y) and of the monomer (derivative of PEG and of acrylate) solution possibly containing a biologically active substance, and then irradiation with light until a solid transparent and adherent gel is obtained, after 40 to 60 seconds. This type of adhesive thus requires the application of several solutions which, because of their fluidity, can easily spread over sites adjacent to the target site.
These adhesives have also been described for the targeted delivery of biologically active substances (vascular endothelial growth factor [VEGF], endothelial cell growth factor (ECGF], basic fibroblast growth factor [bFGF], bone morphogenic protein [BMP], etc) contained in their microparticulate network (FOCAL U.S. Pat. No. 5,879,713).
BARD (WO 97/42986) has described an adhesive similar to that of FOCAL, mentioned above, for which the polymerization is induced by ultraviolet rays.
COHESION TECHNOLOGIES (U.S. Pat. No. 5,874,500; U.S. Pat. No. 5,744,545; U.S. Pat. No. 5,550,187) has also described liquid glues based on activated PEG (ex. PEG comprising succinimidyl and maleimidyl groups) which polymerize after simple application to the target site of application, in a varying amount of time. These glues are potentially toxic and have the drawback of being fluids, which prevents accurate application to the site of intervention.
CRYOLIFE has developed another type of adhesive, based on a mixture of bovine albumin and of glutaraldehyde. Besides the known toxic effects of this crosslinking agent and of the antigenic nature of the bovine albumin, this adhesive also has the abovementioned problems of fluidity.
Fibrin glues, a mixture of concentrated fibrinogen and of thrombin, create a fibrin matrix which is slowly degraded by the endogenous fibrinolytic system. Before polymerization, they are very fluid and can easily run, even though their reaction time can be adjusted by modifying the total amount of thrombin. They can release active biological substances (ex. Zarge et al., J. Surg. Res., 1997, 67, 4-8; Greisler et al., Surgery, 1992, 112, 244-255; Gray et al., Surg. Forum, 1993, 44, 394-396; Clinica, 1999, 848, 18).
Devices combining fibrin glues with liposomes have also been described (U.S. Pat. No. 5,651,982).
Fibrin glues can be vaporized onto the site of application, using a spray, and can form a foamy coagulum film (U.S. Pat. No. 5,607,694; WO 97/33646).
Complex devices combining a synthetic polymer protein with a crosslinking agent have been provided as biological adhesives (U.S. Pat. No. 5,817,303).
Finally, several adhesives based on collagen or on gelatin have been described in the literature. Very early on, gelatin was combined with resorcinol and with formaldehyde or with glutaraldehyde to produce an adhesive also having hemostatic properties (Tatooles et al., Surgery, 1966, 60, 857-861; Braunwald et al., Surgery, 1966, 59, 1024-1030; Guilmet et al., J. Thorac. Cardiovasc. Surg., 1979, 77, 516-521). With this type of adhesive, there is, however, a risk of release of formaldehyde or of glutaraldehyde causing toxic reactions, leading to tissue necroses or less severe reactions, producing poor cicatrization or the slowing down thereof.
In certain formulations, the collagen is closely associated with thrombin (CoStasis from Cohesion technol. and Flo-Seal from Fusion).
For applications in surgery, it can also be modified chemically with acylation or sulfonation agents so that the collagen thus transformed can polymerize on the site of application, in the presence or absence of an initiator (U.S. Pat. No. 5,874,537; WO 97/42986).
An adhesive obtained using heated collagen and, as crosslinking agent, a biodegradable macromolecular polyaldehyde has also been described (FR 2,754,267; FR 2,754,268).
The glues for surgical and/or therapeutic use, described in the literature, are essentially in liquid form.
A noninjectable lyophilized material comprising the elements of the fibrin glue (thrombin and fibrinogen) has been described (U.S. Pat. No. 4,442,655). An inert gas is optionally introduced into the fibrinogen/thrombin reactive aqueous solution in order to lighten the material which has a hemostatic role or a role of support for the delivery of cicatrizing substances, and is mainly intended for the cleaning of wounds. Another noninjectable lyophilized material comprising, inter alia, the elements of the fibrin glue and collagen has also been described in the literature, as an effective hemostatic agent and an adhesive (Nishida et al., Geka Shinryo [Surgical Diagnosis Treatment], 1994, 36, 1449-1459; Ochiai et al., Sanpujinka no Jissai [Obstetric and Gynecologic Practice], 1995, 44, 253-262; Schelling et al., Ann. Surg., 1987, 205, 432-435; Shimamura et al., The Clinical Report, 1994, 28, 2994-2507).
Some adhesives have also been proposed in the form of a spray so as to allow a more homogeneous and more discreet application over a considerable surface area. However, the use of a spray has drawbacks, including:
i) the contribution of not insignificant amounts of carbon dioxide or of other gases, leading to risks of dangerous very high pressure and possibly proving to be toxic for applications in noninvasive surgery,
ii) the considerable displacement of the adhesive mixture over the site of deposit by the propellent gas of the applicator,
iii) the development of a special spray applicator, markedly increasing the cost price of the adhesive device and:possibly requiring a more complex environment, in particular because of the connection of the device to a source of propellent gas.
Moreover, rigid protein foams

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