Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
1999-03-09
2002-12-17
Jones, Dameron L. (Department: 1619)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S450000
Reexamination Certificate
active
06495161
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to new forms of biocompatible containment systems that envelop encapsulated or free cells or other biologically active materials. In a particular aspect, the present invention relates to a system that provides an immune barrier for the cells or other biologically active materials. In another aspect, the present invention relates to a system that provides enhanced migration and aggregation of the cells or other biologically active materials within the containment system. In a further aspect, the present invention relates to a system that provides enhanced transfer of the secretions of cells or other biologically active materials out of the containment system.
BACKGROUND OF THE INVENTION
Microencapsulation of cells (e.g., pancreatic islets) by an alginate-PLL-alginate membrane (i.e., an alginate-poly-L-lysine-alginate membrane) is a potential method for prevention of rejection of foreign cells by the host's immune system. By this technique, researchers are able to encapsulate living islets in a protective membrane that allows insulin to be secreted, yet prevents antibodies from reaching the islets, causing rejection of the cells. This membrane (or microcapsule) protects the islet from rejection and allows insulin to be secreted through its “pores” to maintain the diabetic in normal glucose control.
Successful transplants of microencapsulated cells have not been clinically feasible to date due to fundamental problems of transplant rejection and/or fibrotic reaction to the microcapsule. In the treatment of diabetes, Lim and Sun, 1980; Science 210:908, reported the first successful implantation of microencapsulated islets and described normalization of blood sugar in diabetic rats.
However, for microencapsulated cells to be clinically useful and applicable in humans, it is important that the capsule be biocompatible, allow adequate diffusion for the encapsulated cells to respond appropriately to a stimulatory signal and to provide the encapsulated cells with necessary nutrients, and optionally be retrievable. Retrievability is desirable for a variety of reasons, e.g., so that accumulation of the implanted materials can be avoided, so that encapsulated cells can be removed from the recipient when no longer needed or desired (e.g., when the product(s) of the encapsulated cells are no longer needed, if the encapsulated cells fail to perform as desired, etc.), so that encapsulated cells can be removed if/when they become non-viable, and the like.
Biocompatibility of encapsulated islets remains a fundamental problem. The term “biocompatible” is used herein in its broad sense, and relates to the ability of the material to result in long-term in vivo function of transplanted biological material, as well as its ability to avoid a foreign body, fibrotic response. A major problem with microencapsulation technology has been the occurrence of fibrous overgrowth of the epicapsular surface, resulting in cell death and early graft failure. Despite extensive studies, the pathological basis of this phenomenon in alginate based capsules remains poorly understood. However, several factors have recently been identified as being involved in graft failure, e.g., the guluronic acid/mannuronic acid content of the alginate employed, imperfections in the microcapsule membrane (allowing exposure of poly-L-lysine to the in vivo environment), failure of the microcapsule membrane to completely cover the cells being encapsulated (thereby allowing exposure of the cells to the in vivo environment), and the like.
Accordingly, there is a need in the art for new and better capsules for the encapsulation of biologically active materials. In addition, there is a need for new methods of making capsules that encapsulate biologically active materials while permitting variation of certain properties (e.g., mechanical strength, capsule permeability and porosity, desired controlled release rates of the biologic or components secreted by the biologic, and immunoreactivity) across broad performance ranges to address variable physiological conditions. Further, there is a need for new methods of facilitating formation of and delivery systems for cell aggregates.
BRIEF DESCRIPTION OF THE INVENTION
In accordance with the present invention, capsules (e.g., microcapsules and macrocapsules) have been developed for the encapsulation of biologically active materials therein. Invention capsules comprise at least one biocompatible gellable material, wherein at least the outer layer of the capsule is covalently crosslinked and optionally polyionically crosslinked (or, in the case of macrocapsules comprising microcapsules therein, either polyionically crosslinked, covalently crosslinked, or both polyionically crosslinked and covalently crosslinked), but not ionically crosslinked. Surprisingly, invention capsules permit enhanced migration and aggregation of the biologically active material within the capsule and enhanced control over the release rates of the biologically active material or components secreted by the biologically active material, while decreasing the risk of biomineralization due to ions required for ionic crosslinking and enabling the biologically active material contained within the capsule to retain a significant proportion of the functionality of the unencapsulated biologically active material.
In a further aspect of the present invention, there also have been developed methods of making invention capsules. One of the invention methods comprises subjecting a capsule whose outer layer is ionically crosslinked and covalently crosslinked, and optionally polyionically crosslinked (or, in the case of macrocapsules comprising microcapsules therein, ionically crosslinked and either polyionically crosslinked, covalently crosslinked, or both polyionically crosslinked and covalently crosslinked), to conditions sufficient to disrupt ionic crosslinking in at least the outer layer thereof. Surprisingly, invention methods facilitate the relatively rapid formation of invention capsules under conditions which are not cytotoxic, while decreasing the risk of biomineralization caused by the presence of ions required for ionic crosslinking and enabling the biologically active material contained within the capsule to retain a significant proportion of the functionality of the unencapsulated biologically active material.
Additional methods of making invention capsules comprise simultaneously subjecting a droplet comprising a suspension of biologically active materials in a covalently crosslinkable carrier to conditions sufficient to prevent substantial dissociation thereof and subjecting the droplet to conditions sufficient to induce substantial covalent crosslinking thereof. Surprisingly, these invention methods facilitate the relatively rapid formation of invention capsules under conditions which are not cytotoxic, while reducing to substantially zero the risk of biomineralization caused by the presence of ions required for ionic crosslinking and while enabling the biologically active material contained within the capsule to retain a significant proportion of the functionality of the unencapsulated biologically active material.
In a further aspect of the present invention, there also have been developed capsules containing cell aggregates therein, and methods for the production thereof. Invention capsules comprise a biocompatible gellable material, and have a core which is not ionically crosslinked, and at least an outer layer thereof which is covalently crosslinked, polyionically crosslinked, or both covalently crosslinked and polyionically crosslinked. Surprisingly, invention capsules permit enhanced migration and aggregation of the cell aggregates and constituent cells within the capsule and enhanced control over the release rates of the components secreted by the cell aggregates, while decreasing the risk of biomineralization due to ions required for ionic crosslinking and enabling the cell aggregates contained within the capsule to retain a significant proportion of the functio
Curcio Francesco
Desai Neil
Heintz Roswitha
Ron Nilesh
Sojomihardjo S. Andrew
Jones Dameron L.
Reiter Stephen E.
VivoRx, Inc.
LandOfFree
Cytoprotective biocompatible containment systems for... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Cytoprotective biocompatible containment systems for..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Cytoprotective biocompatible containment systems for... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2970038