Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Animal or plant cell
Reexamination Certificate
1999-07-16
2002-04-09
Naff, David M. (Department: 1651)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Animal or plant cell
C424S423000, C435S325000, C435S382000, C435S383000, C435S289100, C435S297100
Reexamination Certificate
active
06368592
ABSTRACT:
FIELD OF THE INVENTION
The invention relates generally to devices for delivering oxygen to cells and more specifically to devices which deliver oxygen in situ to cells in the body of an organism.
BACKGROUND
Techniques to transplant cells into people in need of the functions that these cells provide have application in the treatment of a variety of chronic conditions including diabetes, hemophilia, dwarfism, anemia, kidney failure, hepatic failure, familial hypercholesterolemia, immunodeficiency disorders, pituitary disorders, and central nervous system disorders.
Cell implantation techniques are typically limited by shortages of cells. For example, successful transplantation of insulin-secreting cells or tissue into people with diabetes has been a challenge because of the obvious shortage of human islet tissue. The approximately 3000 cadaver pancreases that could be available each year in the U.S.A. come nowhere near to meeting the needs of people with Insulin Dependent Diabetes Mellitus (IDDM). Use of cells/tissue from other species as xenogeneic cells may therefore provide the fastest path to clinical application.
Immunobarrier devices have been developed as a means of protecting xenogeneic cells from transplantation rejection by a host organism. The xenogeneic cells are encapsulated at a high, tissue-like density or are dispersed in the form of individual cells or cell aggregates (e.g., islets of Langerhans) in an extracellular gel matrix such as agar, alginate, or chitosan, within these devices.
High-density culture, if attainable, is advantageous because it minimizes the size of the implanted device used in a particular application. This is desirable because the complexity and difficulty of the application increases with the volume of implanted cells/tissue. Consequently, applications which have tended to require the least amount of transplanted cells/tissue, such as central nervous system applications, have been the first to advance to clinical testing.
Maintenance of the viability and function of implanted cells within an immunobarrier device is essential and limited by the supply of nutrients and oxygen which can be provided to the cells from the host. Apoptosis in transplanted tissues has been observed and may be a general response to severe hypoxia, as well as to methods of isolation and culture, glycemic state, and the nonspecific inflammatory reaction associated with the transplantation procedure.
The impact of hypoxia is also influenced by the type of cells/tissues being implanted. For example, pancreatic islet cells are especially prone to oxygen supply limitations because they have a relatively high oxygen consumption rate. They are normally highly vascularized and are supplied blood at arterial pO
2
. When cultured in vitro under normoxic conditions, islets develop a necrotic core, the size of which increases with increasing islet size, as is to be expected as a result of oxygen diffusion and consumption within the islet. However, the death of implanted cells due to hypoxia is not the only concern. Oxygen levels high enough to keep cells alive can nonetheless have deleterious effects on cell functions that require higher cellular ATP concentrations, for example, ATP-dependent insulin secretion.
Only scant attention has been paid to the issue of islet viability within implanted immunobarrier devices. However, recently, critical parameters such as the number and volume of viable islet cells that can be supported by such devices, and the development of islet necrosis and fibrosis in such devices has begun to be examined. It is clear from these recent studies that all attempts to support larger volumes of islet tissue in high-density culture (i.e., where all or most of the internal device volume is occupied by viable islet tissue) have led to massive islet necrosis, invariably in regions furthest from the oxygen source. As with transplantation of naked cells, the hypoxic environment for several days following transplantation appears to be a critical problem. For example, most of the loss of viable &bgr;-cell mass undoubtedly occurs during the first few days after transplantation within these devices.
With few exceptions, only by suspending islets in an extracellular gel matrix at very low islet volume fractions (e.g., 1 to 5%), which greatly increases the size of the implanted device, have investigators been able to maintain the viability of the initially loaded islets. However, use of such low tissue density puts undesirable constraints on the maximum number of islets that can be supported in a device of a size suitable for surgical implantation.
Attempts to modify the design of immunobarrier devices have been made to try to overcome these limitations. A biohybrid artificial pancreas for insulin secretion known in the art consists of a semipermeable membrane tube through which arterial blood flows. The membrane tube is surrounded by the implanted tissue which is, in turn, contained in a housing. This approach provides the highest available pO
2
(100 mm Hg) but suffers from the need to open the cardiovascular system; thus, it may be limited to only a small fraction of patients.
One alternative is an extravascular device in the form of a planar or cylindrical diffusion chamber implanted, for example, in subcutaneous tissue or intraperitoneally. Such devices are exposed to the mean pO
2
of the microvasculature (about 40 mm Hg) limiting the steady state thickness of viable tissue that can be supported. Further limits are imposed when such devices are implanted into soft tissue. If a foreign body response occurs, an avascular fibrotic tissue layer adjacent to the chamber can be produced, typically on the order of 100 &mgr;m thick. This fibrotic tissue increases the distance between blood vessels and implant, and the fibroblasts in fibrotic tissue layer also consume oxygen. Oxygen deficits are especially likely during the first few days after implantation before neovascularization has a chance to occur. Anoxia may exist within regions of the device, leading to death of a substantial fraction of the initially implanted tissue.
Microporous membranes that induce neovascularization at the device-host tissue interface have also been used. This angiogenic process takes 2-3 weeks for completion, and the vascular structures induced remain indefinitely. By bringing some blood vessels close to the implant, oxygen delivery is improved. Oxygen delivery also may be improved by prevascularizing the device, e.g, by infusion of an angiogenic factor(s) through the membranes into the surrounding tissue.
Another means of implanting cells in an extravascular environment involves the use of spherical microcapsules. The microcapsules comprise small quantities of cells enclosed in a semipermeable membrane and can be implanted in an extravascular space, for example, in the peritoneal space. However, the large volume of microcapsules employed, and the tendency for most to permanently attach to peritoneal surfaces, may lead to clinical problems. Thus, despite encouraging results with various tissues and applications, the problem of oxygen transport limitations remain.
The present invention improves the viability and function of encapsulated tissue.
SUMMARY OF THE INVENTION
The invention provides an oxygen generator device for delivering oxygen to cells or to a cell compatible fluid. The oxygen generator device disclosed herein has application for in vitro or in vivo use. In one aspect the device is placed in proximity to a cell compatible fluid. In another aspect, the oxygen generator is placed in proximity to cells for which supplemental oxygen is desired. In a further aspect of the invention, the oxygen generator is placed in proximity to a cell encapsulating device. The oxygen generator disclosed herein provides a system to deliver oxygen to cells in situ in the body of an organism.
In one embodiment of the invention, the oxygen generator is an electrolyzer device which electrolyzes water into oxygen and hydrogen. In another embodiment of the invention, the oxygen generator is in the form
Colton Clark K.
Swette Larry L.
Massachusetts Institute of Technology
Naff David M.
Testa Hurwitz & Thibeault LLP
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