Chemistry: molecular biology and microbiology – Carrier-bound or immobilized enzyme or microbial cell;... – Enzyme or microbial cell is immobilized on or in an organic...
Reexamination Certificate
2001-07-05
2003-11-18
Naff, David M. (Department: 1651)
Chemistry: molecular biology and microbiology
Carrier-bound or immobilized enzyme or microbial cell;...
Enzyme or microbial cell is immobilized on or in an organic...
C424S423000, C424S093700, C435S182000, C435S382000, C435S395000, C435S283100
Reexamination Certificate
active
06649384
ABSTRACT:
FIELD OF THE INVENTION
This invention describes a method and system for the consistent and effective encapsulation of viable biological material (e.g., individual living cells, cell clusters, or organ tissue) with a polymeric coating material.
BACKGROUND OF THE INVENTION
Transplantation of organ tissue (e.g., pancreatic islets) into genetically dissimilar hosts has gained a significant interest in the treatment for functional deficiencies of secretory and other biological organs. Transplantation, however, generally requires the continuous use of immunosuppressive agents by the transplant recipient in order to forestall rejection of the transplanted tissue by the recipient's immune system. Unfortunately, these immunosuppressive agents can deprive the recipient of adequate protective immune function against diseases.
A potential solution that avoids the need for such immunosuppressive agents is the encapsulation of the tissue material so as to protect the transplanted tissue from the recipient's immune system. Encapsulation generally eliminates the need for immunosuppressive agents to prevent adverse immune system response and rejection of the implant. Encapsulation with a sufficiently semi-permeable protective barrier coating not only generally prevents an immune response, but also provides for diffusion of oxygen into the encapsulated material along with the transfer of nutrients, ions, glucose, and hormones, as well as the excretion of metabolic waste. This maintains the health of the encapsulated tissue material.
One promising approach for the encapsulation of tissue material such as pancreatic islets involves the use of coatings formed of a non-fibrogenic alginate, a gelatinous substance that can be derived from certain kinds of kelp. The islets are suspended in a viscous, liquid alginate, which is then atomized by any of a number of different arrangements into droplets of suitable size to encapsulate the islets. Once the droplets come into contact with a gelling solution, such as calcium chloride or barium chloride, a single layer alginate coating is created around the islets. Examples of this approach for creating single layer alginate coatings using an electrostatic coating process are shown in U.S. Pat. No. 4,789,550 (Hommel et al.), U.S. Pat. No. 4,956,128 (Hommel et al.), U.S. Pat. No. 5,429,821 (Dorian et al.), U.S. Pat. No. 5,639,467 (Dorian et al.), U.S. Pat. No. 5,656,468 (Dorian et al.) and U.S. Pat. No. 5,693,514 (Dorian et al.). An example for creating a single layer alginate coating using an air knife process is shown in U.S. Pat. No. 5,521,079 (Dorian et al.). A pressurized process for coating droplets is described in U.S. Pat. No. 5,260,002 (Wang) and U.S. Pat. No. 5,462,866 (Wang). Other examples for creating a single layer alginate coating using a spinning disk arrangement are shown in U.S. Pat. No. 5,643,594 (Dorian et al.) and U.S. Pat. No. 6,001,387 (Cochrum). Examples for creating a single layer alginate coating using a piezoelectric nozzle are shown in U.S. Pat. No. 5,286,496 (Batich et al.), U.S. Pat. No. 5,648,099 (Batich et al.) and U.S. Pat. No. 6,033,888 (Batich et al.)
A problem common to all of these techniques for creating single layer alginate coatings is the formation of non-encapsulated or partially encapsulated islets. Any non-encapsulated biological material or capsules that are only partially coated or that have too thin of a coating will lead to an adverse immunological response when transplanted into the recipient. One way to decrease this problem is to increase the diameter of the single coating so that the capsules have diameters in the range of 700-800 microns. Unfortunately, these large-sized capsules tend to be less effective when transplanted into a recipient because the larger diameter diminishes the ability of oxygen to penetrate completely into the interior of the capsule. It has also been found that large-sized capsules tend to increase the potential for macrophage attack by the recipient's immune system and can limit the potential transplantation sites as compared to smaller-sized capsules.
It has been discovered that encapsulation of tissue material such as pancreatic islets with a second coating of a cross-linkable polymer can provide substantially complete coverage of the islets in order to minimize or eliminate the possibility of adverse immune reactions, while at the same time providing a capsule having a dimension on the order of 400-500 microns. The multiple coatings of the individual capsules containing the core of living tissue serve as an additional means for assisting in the resistance to chemical, mechanical, or immune destruction by the host. The smaller-sized capsule is believed to permit oxygen to better permeate into the interior of the capsule as oxygen can normally permeate up to about 200-250 microns into encapsulated tissue material.
U.S. Pat. No. 5,470,731 (Cochrum) and U.S. Pat. No. 5,531,997 (Cochrum) describe a double layer coating for tissue that comprises a first layer of a gellable organic polymer and a cationic polymer and a second water-soluable, semi-permeable layer chemically bonded to the first layer. U.S. Pat. No. 6,020,200 (Enevold) describes a dual layer coating having a stabilized outer layer formed of a cross-linked polmer matrix. U.S. Pat. No. 5,227,298 (Weber at al.) describes a double walled alginate coating. U.S. Pat. No. 5,578,314 (Cochrum et al.) teaches such a method for applying multiple layers of alginate onto biological material (e.g., pancreatic islets). In this method, a first layer of a multiple layer alginate coating is applied using a solution of an alginate containing a high ratio of guluronate to manuronate, and the second layer is applied using a solution of an alginate containing a high ratio of mannuronate to guluronate. U.S. Pat. No. 5,876,742 (Cochrum et al.) teaches a multiple layer alginate coating where an intermediary halo layer of a soft gel is formed between the inner and outer alginate coating layers.
While the use of multiple layer alginate coatings solves many of the problems associated with single layer coatings, the existing techniques for generating such multiple layer alginate coatings are not well suited to large scale manufacturing systems that can consistently and reliably produce large amounts of encapsulated material. In order to obtain amounts of encapsulated islets, for example, necessary for a single human transplantation procedure, as many as 500,000 to 1,000,000 encapsulated islet equivalents (one islet equivalent is equal to a cell cluster of islets having a diameter of 150 microns), or at least 8000 islet equivalents per kilogram of body weight may be required.
Several problems with the existing techniques have generally prevented the large-scale manufacture of encapsulated islets to meet these needs. First, the existing techniques tend to generate a very large number of empty capsules or “blanks”. While such blanks can be created in either the first coating process or the second process, the problem is most noticeable where a droplet is produced during the second coating process that does not contain an islet. Second, the existing techniques also tend to create encapsulated islets in which multiple single coated islets either stick together during the coating process or end up with more than about ten islets being contained within the same second coating encapsulation, conditions which are referred to as “clumping”. When clumping occurs during the coating process, the entire batch of capsules being processed can be destroyed. Single-coated capsules can bind together into clumps that are subsequently coated a second time during the encapsulation process. Depending upon the number of single-coated capsules in a particular clump, the coated clumps do not function as effectively as a double-coated capsule containing only one or up to four single-coated capsules, most likely because the size of the resultant capsule of clumped single-coated capsules is too large.
Most importantly, the entire encapsulation process for biological ma
Canfield Monte R.
Drake Nancy J.
Walsh Stephen E.
Islet Technology Inc.
Naff David M.
Patterson Thuente Skaar & Christensen P.A.
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