Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1997-06-17
2001-08-28
Fonda, Kathleen K. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S018700, C536S123000, C536S123100, C536S124000, C424S093700, C424S423000, C424S488000, C424S493000, C424S499000
Reexamination Certificate
active
06281341
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to: a novel hetero-polysaccharide conjugate or complex, gels therefrom and/or a composition, e.g., solutions having adjustable viscosity, prepared by manipulating the concentration of hetero-polysaccharide conjugate or complex, and/or ion concentrations, e.g., calcium; and/or a gel or sol comprising the hetero-polysaccharide conjugate; the synthesis, purification and utilization of a novel glycopolymer and/or hetero-polysaccharide and/or gels, solutions and/or sols; and especially, a neo-heteropolysaccharide conjugate or complex, herein referred to as “Biodritin heteropolysaccharide”, comprising a heteropolysaccharide from covalent bonding between at least one glycosaminoglycan, e.g., chondroitin sulfate-4 and/or 6, and at least one alginic acid salt, e.g., sodium alginate, preferably via a coupling reaction via a linking molecule such as divinyl sulfone.
Thus, the invention especially relates to Biodritin heteropolysaccharide, gels therefrom and/or a composition, e.g., solutions having adjustable viscosity, prepared by manipulating the concentration of Biodritin heteropolysaccharide, and/or ion concentrations, e.g., calcium; and/or a gel or sol comprising the Biodritin heteropolysaccharide; the synthesis, purification and utilization of Biodritin heteropolysaccharide as a novel glycopolymer and/or heteropolysaccharide and/or gels, solutions and/or sols comprising Biodritin heteropolysaccharide. Gels are obtained by adding an inorganic ion, such as calcium ions, to Biodritin heteropolysaccharide. Sols can be obtained by treatment of a gel with a suitable agent such as a sodium salt, e.g., citrate salts or ethylene-diamine-tetraacetic (EDTA) as sodium salt. Gels can have varying viscosity by varying the amount of Biodritin heteropolysaccharide and/or inorganic ion, e.g., calcium ion; and with an amount of calcium ions, infinite gels can be obtained.
The invention further relates to a composition herein termed “Biodritin polymer network”, and to methods and formulations for preparing a Biodritin polymer network. A Biodritin polymer network comprises at least one glycosaminoglycan, e.g., chondroitin sulfate-4 and/or 6, and at least one alginic acid salt, e.g., sodium alginate, wherein at least one of the glycosaminoglycan and alginic acid salt is cross-linked. And, the methods and formulations for preparing a Biodritin polymer network comprises admixing the glycosaminoglycan and alginic acid salt and adding at least one cross-linking agent, e.g., an inorganic ion. For instance, a Biodritin polymer network which is believed, without necessarily wishing to be bound by any one particular theory, to be a semi-interpenetrating polymer network (s-IPN), is formed by addition of inorganic ions to a solution of a glycosaminoglycan and an alginic acid salt, e.g., calcium ions added to a solution of chondroitin sulfate-4 and/or -6 and sodium alginate (wherein sodium alginate is cross linked and has pockets of chondroitin sulfate-4 and/or -6 and/or non-cross-linked sodium alginate).
Of course, a Biodritin polymer network containing at least one Bioditrin heteropolysaccharide can be obtained by covalently bonding the glycosaminoglycan and alginic acid salt present in a Biodritin polymer network, e.g., subjecting a Biodritin polymer network to a coupling reaction involving a linker molecule; for instance, forming network by addition of inorganic ions to a solution of a glycosaminoglycan and an alginic acid salt, e.g., calcium ions added to a solution of chondroitin sulfate-4 and/or -6 and sodium alginate, and subjecting network to coupling reaction, e.g., subjecting network to coupling reaction involving divinyl sulfone.
In preparing a Biodritin heteropolysaccharide or Biodritin polymer network comprising a Biodritin heteropolysaccharide, a solution of GAG, e.g., chondroitin sulfate-4 and/or -6 is linked to alginate, e.g., sodium alginate by covalent bonding via reaction with a linker molecule such as divinyl sulfone; the reaction is preferably in alkaline medium. In practicing the invention, one can emploly a process to protect the calcium binding sites of alginate, also known as “egg-box” sites, such that no reaction occurs to these sites during the linking reaction with the linker molecule, e.g., divinyl sulfone, and GAG, e.g., chondroitin sulfate. One can also employ a process to eliminate remaining active vinyl groups in Biodritin, after linking, by reaction with an alkanolamine such as ethanolamine, preferably at alkaline pH. And, one can employ a process to purify Biodritin after the synthesis reaction which involves removal of calcium with molecule which binds to or conjugates with calcium, e.g., EDTA, preferably followed by precipitation(s) with an alchol such as ethanol.
The invention also relates to an additional process to prepare a Biodritin polymer network comprising dehydrothermal cross-linking of a mixture of the polymers that form a Biodritin heteropolysaccharide. The dehydrothermal reaction can be of a dry cake containing GAG, e.g., chondroitin sulfate and alginate, e.g., sodium alginate. The cake can be produced by freeze-drying a solution containing chondroitin sulfate and sodium alginate in proper concentrations. The calcium binding sites of alginate can be protected prior to the dehydrothermal treatment by adding calcium ions to bind to the “egg-box” sites of alginate. The calcium can be removed from the “egg-box” complexes by treatment of the dehydrothermal reaction product with a material which complexes or conjugates or binds with calcium, e.g., sodium EDTA. Purification can be as discussed above.
For ease of reference, Biodritin polymer networks and Biodritin heteropolysaccharides may be termed “Biodritin” or “Biodritin products”.
A primary use of Biodritin products and/or products derived therefrom is in applications where biocompatibility with host tissues and/or immunoisolation are issues, for example, in cell encapsulation, such as immunoisolation by microencapsulation of islets of Langerhans for diabetes control, or of other cells types or tissues. A Biodritin gel formed from Biodritin heteropolysaccharide or comprised of a Biodritin polymer network (e.g., a gel comprising at least one glycosaminoglycan, e.g., chondroitin-4 and/or -6 and at least one alginic acid salt wherein at least one of the glycosaminoglycan and alginic acid salt are cross-linked and the gycosaminoglycan and alginic acid salt are optionally (and preferably) covalently bound, preferably via a reaction involving a linker molecule such as divinyl sulfone, and the cross-linking can be performed after the covalent binding or prior thereto; generally, a Biodritin product or a product from reaction with Biodritin) can be used to form beads or microcapsules containing cells or tissues for implantation. And thus, the invention relates to such beads or microcapsules, and methods for making and using such beads or microcapsules.
Biodritin products and/or products therefrom can also be “painted”, sprayed or applied to or on top of wounds, e.g., surgical wounds or sutures, and can be used to coat surgical, monitoring, or other equipment to avoid local reaction, injury or irritation. The skilled artisan can apply such without undue experimentation considering the disclosure herein and the knowledge in the art, and typical factors such as the age, sex, weight, condition of the patient, etc. or the nature of the equipment to be coated. Biodritin products and/or products therefrom serves as a matrix material for supporting cells for culturing or other applications in which cells must maintain a suspended or non-aggregated state. Accordingly, the invention relates to “paints”, sprays, and matrices comprising Biodritin products and/or products therefrom, and to methods for making and using them.
The novel heteropolysaccharide and products therefrom, as well as the semi-interpenetrating polymer network, i.e., Biodritin heteropolysaccharide and products therefrom and the Biodritin polymer network, make use of: the biocompatibility of glycosaminoglycans (GAGs), prefe
Mares-Guia Marcos
Ricordi Camillo
Biomm, Inc. & University of Miami
Fonda Kathleen K.
Frommer Lawrence & Haug
Pan Grace L.
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