Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1995-04-05
2001-07-17
Fonda, Kathleen K. (Department: 1211)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S054000, C536S055100, C536S055300, C536S056000, C536S123100, C536S124000, C514S054000, C514S057000, C424S443000, C424S488000
Reexamination Certificate
active
06262255
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to non-immunogenic biocompatible macromolecular membrane compositions and methods for making and using the same. The non-immunogenic biocompatible macromolecular composition is preferably comprised of a membrane, more preferably, a cellulosic membrane, having bound, preferably covalently at, or on its surface to, one or more type of glycosaminoglycan, through one or more types of a binding moiety. The binding moiety preferably has a plurality of functional groups; more preferably, at least two functional groups, most preferably two functional groups. The cellulosic membrane is preferably covalently bound to one functional group of the binding moiety. The glycosaminoglycan (GAG) is preferably covalently bound to the other functional group of the binding moiety.
The invention therefore also relates to such selective membranes and methods of making and using them.
Certain documents are cited herein and, are incorporated herein by reference.
BACKGROUND OF THE INVENTION
A non-immunogenic biocompatible macromolecular molecular membrane composition is preferably substantially insoluble in bodily fluids, thus, non-biodegradable. Yet, it is also preferably suitable for contact with body fluids in or on the body. Ideally, such membrane composition has all or some of the following characteristics:
1. The membrane composition should avoid inducing undesirable reactions in the body (such as blood clotting, tissue death, tumor formation, allergy reaction, immune response or an inflammatory reaction).
2. The membrane composition should have desirable physical properties (such as strength, elasticity, permeability, and necessary flexibility).
3. The membrane composition should also be purified, fabricated, and sterilized easily.
4. The membrane composition should be able to maintain its physical properties and functions during the time the membrane composition remains implanted in or in contact with the host body.
While there are biocompatible macromolecular skin graft, or skin substitute compositions in the literature, an impediment for in vivo implantation (both cutaneously and in any degree more internal than cutaneous, e.g., subcutaneous or intraperitoneal application) of biocompatible implants is lack of reliability. Another deficiency of these implants is that they are often not retrievable after implantation. This deficiency is significant, particularly when combined with yet a further deficiency of these implants, namely that they can lose physical properties. For instance, implants made from biodegradable materials degrade over time and thereby induce a local or a systemic immune response in a host system. Further, another deficiency of implants is the difficulty to monitor and inspect such implants.
A number of approaches have been taken to improve the biocompatibility of implantable items. One approach was to prevent undesirable protein adhesion by providing a biomaterial with a low polarity surface, a negatively charged surface, or a surface coated with biological materials such as enzymes, endothelial cells, or proteins. Another approach was to coat solid surfaces with heparin, albumin, or streptokinase to enhance thromboresistance. However, these approaches have failed to teach or suggest the preferably covalent bonding of the present invention or the binding agent of the present invention, or the methods of making and using the invention including the pouch embodiments on structures.
Several researchers have proposed different approaches to protecting islet tissue from host attack after transplantation; these included encapsulation of islets in different materials such that insulin may be secreted but the beta-cells in the islet tissue will be immunologically isolated from the host. Polysaccharides have been proposed to form membranes, as is the case of agarose, by Howell, Ishaq and Tyhurst (Journal of Physiology 324, 20-21, 1982) or alginate, by Tze and Tai (Transplantation 33, 563-564, 1982). Search of the more recent literature indicates that the effort to develop new membrane materials for cell encapsulation for implants keeps a strong and steady pace. These include synthetic poly-acids and poly-bases (Bader et al., 1988 Eur. Pat. App. EP 280,155), gelatin and polyamino acids (Young et al., Biopharm 2, 34, 36, 38, 40-46, 1989) as well as different polysaccharides; chemically modified dextran, to form poly-ionically bonded capsules (Lim and Hall, 1988, PCT Int. Appl. WO 88 00, 327), entrapment in alginate followed by stabilization with poly-lysine and alginate (Chang and Wong, 1992, U.S. U.S. Pat. No. 5,084,350, as well as a combination of chitosan and carboxy-methyl cellulose to form capsules of controlled permeability (Shioyo and Hirano, 1990, U.S. Pat. No. 5,089,272). A recent review by Mikos et al. (Biotechnol. & Bioeng. 43, 673-677, 1994) discusses other alternatives, all with emphasis on synthetic materials as membrane components.
On the other hand, recent work bearing on regeneration of skin in culture has pointed out the important role of GAG's in the process, in studies where mixtures of collagen and GAG were used to support it (Murphy et al., Lab. Invest. 62, 305-313, 1990; Yannas et al., Polym. Mater. Sci. Eng. 62 801-803, 1990). Along the same line, but coming from another direction, keratinocytes and fibroblasts grown on a nylon mesh produced a dermal-like matrix containing heparan sulfate proteoglycans (Slivka et al., J. Invest. Dermatol. 100, 40-46, 1993).
These works, that show the importance of the extracellular matrix components in the normal development of the skin system, support the basis of our invention, that foreign membranes lined or structured with GAG's may constitute ideal materials for devices aiming at transplantation of cells or tissues of human or animal origin, with the purpose of treating or controlling disease. Their surfaces will contain critical elements for successful interaction with the host organism. Although GAG's occur in the organism mostly linked to proteins, as proteo-glycans, it has been demonstrated that the protein part only is immunogenic; the glycosaminoglycan component is not immunogenic by itself (Hirschmann and Dziewiatkowski, Science 154, 393-395, 1966; Loewi and Muir, Immunology 9, 119-127, 1965).
The extent of the interest in discovering the best way to use islets in transplantation is given by two recently published papers, one dealing with storage and preservation of islets (Jindal and Gray, Transplantation 57, 317-321, 1994) and the other with the action of prednisone on the islet autograft function (Rodrigues Rilo et al., Transplantation 57, 181-187, 1994). However, none of this work teaches or suggests the pouch system of the present invention where in cellulose macromolecular membrane is bound with GAG, formed into a pouch and cells are inserted into it.
Likewise, species within the term glycosaminoglycan (“GAG”) may have been mentioned in connection with compositions, but these compositions are unlike the present invention, and, so too are the prior approaches to improve biocompatibility.
For instance, Guire, U.S. Pat. Nos. 4,979,959 and 5,263,992, relate to materials having a surface coating which is a covalently bound biocompatible agent. While cellulose is included in a long list of allegedly possible materials and heparin is included in a long list of allegedly possible agents, there is no teaching or suggestion to specifically select the combination of cellulose and heparin or, any working example thereof. Further, Guire's reagents require activation by light in order for the reaction to proceed. A “dark room” type of reaction with subsequent light activation is thus required; and, this is complicated and presents economic deficiencies and industrial scale-up or other preparation or utility problems. In contrast, the present invention specifically calls for a cellulose membrane having glycosaminoglycan covalently surface bound via a linker molecule, a binding agent bound without any need for light activation. For instance, conditions
BIOMM, Inc.
Fonda Kathleen K.
Frommer Lawrence & Haug
Kowalski Thomas J.
Pan Grace L.
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