Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-01-04
2003-10-07
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S443000, C424S488000, C435S001100, C435S001200, C514S054000, C514S055000, C514S056000
Reexamination Certificate
active
06630154
ABSTRACT:
FIELD OF THE INVENTION
The greatest obstacle to the field of cell and tissue encapsulation/immunoisolation has historically been the lack of sufficient oxygen and nutrient transport across the polymer membranes used to encapsulate cells and tissues. The result of this insufficient gas and nutrient exchange is cell death and lowered metabolic activity. Given that most of these encapsulation devices are used in hormone replacement therapies, such as encapsulated islet cells to treat Diabetes Mellitus, a lowered metabolic activity increases many fold the tissue requirement needed to therapeutically treat the hormone deficiency and, to date, has not generated any devices with clinical applicability to treat the many millions of diabetics throughout the world. The present invention relates to a novel device within which tissue density could be increased and gas and nutrient exchange could be improved thus greatly benefit the field of immunoisolation.
After nearly thirty years of extensive research in the field of islet cell encapsulation, most of the primary contributors in this specialized area agree upon three important tenets (See References cited 1 to 19). First, that in any geometrical style of immunoisolation device, no one dimension can exceed a value of 1 mm. Second, that no device can be loaded with cells at a tissue density higher than 5-10% v/v. Third, regardless of matrix structure, diffusion of metabolites into and insulin out of such devices is often delayed and is governed by simple diffusion gradients across the distance between the cells and the periphery of the capsule. The end results of such limitations are numerous. First, in order to achieve clinical success with any such devices, the ratio of polymer to tissue that would need to be transplanted into a diabetic patient of average weight would rapidly fill the intraperitoneal cavity of a transplant recipient. Second, if any of the above outlined tenets are modified, the result is often catastrophic to the encapsulated islets. The incidence of graft failure increases dramatically, with subclinical performances in functional tests, and the evidence of device-wide cell necrosis is prevalent upon post-explant histological examination. The primary cause for these results is frequently confirmed as the hypoxic environment of isolated and further, immunoisolated islet cells. Given the increased metabolic demands of islet cells in comparison to other somatic cells, the need for improving their oxygen supply after isolation, immunoisolation, and transplantation is of the utmost importance to the possibility of such devices having clinical relevance.
Colton and another group under Per-Ola Carlsson have implemented microelectrodes to measure oxygen partial pressures within islets, in their native environment, after isolation, and post-transplant in polymer devices and free, under the kidney capsule. Both groups found similarly (See references cited 19 and 20). The oxygen partial pressures in the native pancreatic islets are the highest of any organ within the body, measuring 37-46 mmHg (compare this to the value of 13-21 mmHg for cells within the renal cortex). Upon isolation, these values fall between 14-19 mm Hg. Upon transplantation in normoglycemic animals under the kidney capsule, the values fall slightly to 9-15 mmHg. If transplanted into severely hyperglycemic animals (above 350 mg/dL) these values fall between 6-8 mmHg. When the cells are immunoisolated and, therefore, do not lend themselves easily to transplant in a vascularized region such as the kidney capsule, the oxygen values drop even further. In fact, in hyperglycemic animals, the oxygen partial pressures of islets within polymer capsules can drop to values as low as 1-2 mmHg. These nearly anoxic conditions can result in quick cell death, particularly the nearer the cell to the core of the polymer device.
The invention further relates to the inclusion of perfluorinated substances in the Biodritin polymer formulations, in order to achieve better oxygen availability for encapsulated cells or tissues. Perfluoro organic compounds are excellent solvents for oxygen, having several fold higher solubility for oxygen than water. These compounds are largely used as blood substitutes and more recently, have been used for tissue preservation after removal from animals, as well as to improve islet isolations from pancreas.
Thus, the invention especially relates to adding perfluorinated substances in the 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 adding the perfluorinated substances to a composition herein termed “Biodritin polymer network”, and to methods and formulations for preparing a Biodritin polymer network. A Biodritin polymer network can comprise 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. (See U.S. application Ser. No. 08/877,682, now U.S. Pat. No. 6,281,341, filed Jun. 17, 1997 and WO98/49202 with respect to “Biodritin” and “Biodritin Polymer Network”). 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 Biodritin 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 employ 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
Fraker Christopher
Inverardi Luca
Mares-Guia Marcos
Ricordi Camillo
Biomm, Inc.
Frommer & Lawrence & Haug LLP
Maier Leigh C
Pan Grace L.
Wilson James O.
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