Prosthesis (i.e. – artificial body members) – parts thereof – or ai – Implantable prosthesis
Reexamination Certificate
1994-12-12
2004-08-10
Isabella, David J. (Department: 3738)
Prosthesis (i.e., artificial body members), parts thereof, or ai
Implantable prosthesis
C623S023720, C424S422000
Reexamination Certificate
active
06773458
ABSTRACT:
FIELD OF THE INVENTIONS
The inventions relate to systems and methods for implanting living cells within a host.
BACKGROUND OF THE INVENTIONS
For several years, researchers have been trying to surgically implant living cells in a host to treat various cell and molecular deficiency diseases. In theory, the implanted cells will generate biological products that the host, because of disease or injury, cannot produce for itself. For example, the implant assembly can contain pancreatic cells (clusters of which are called “islets”), which generate insulin that a diabetic host lacks.
Yet, in practice, conventional implant assemblies and methodologies usually fail to keep the implanted cells alive long enough to provide the intended therapeutic benefit. For example, pancreatic cells implanted for the treatment of diabetes usually die or become dysfunctional within a few days or weeks after implantation.
For a period after implantation, the region of the host tissue next to the implant assembly can be characterized as ischemic. “Ischemic” means that there is not a sufficient flow of blood in the tissue region closely surrounding the implant assembly. Usually, this ischemic condition exists during the first two weeks of implantation. Most implanted cells fail to live through this period.
During the ischemic period, a foreign body capsule forms around the implanted cells. The capsule consists of flattened macrophages, foreign body giant cells, and fibroblasts. Conventional hypotheses blame the foreign body capsule for causing implanted cells to die or become dysfunctional during the ischemic period.
The inventors have discovered that these widely held hypotheses are wrong. The inventors have discovered that the cells do not die because of the intervention of the foreign body capsule. Instead, the cells die because conventional implant assemblies and methodologies themselves lack the innate capacity to support the implanted cells' ongoing life processes during the critical ischemic period, when the host's vascular structures are not nearby. Because of this, the implanted cells perish before the host can grow new vascular structures close enough to sustain them.
When implanted cells die during the ischemic period, a classical foreign body capsule inevitably forms around the implant. The persistent presence of this capsule led previous researchers to the false conclusion that the host's foreign body reaction was the cause of implanted cell death, rather than its result.
The invention corrects these and other problems in existing implant assemblies and methodologies.
Many previous implant assemblies have also failed to be useful in a clinical setting, because they cannot be practically implanted and tolerated by the host without danger or discomfort.
For example, an implant assembly that housed cells within hollow fibers was recently used by CytoTherapeutics to successfully treat diabetes in rats. The assembly consisted of 7 fibers, each being 2 cm long and 0.073 cm in diameter. The pancreatic cells were present within the fibers at a density of about 25,000 cells per cm
3
. For this assembly to be clinically useful for the treatment of diabetes in humans, it would have to contain at least about 250,000 pancreatic islets (each islet contains about 1000 cells). This means that, to hold enough pancreatic cells to treat human diabetes, the assembly would have to be about 117 feet long. This makes the assembly unusable for clinical use in humans.
Recently, cells have also been encapsulated in tiny hydrogel vessels, called microcapsules. These tiny vessels cannot be implanted within the host's soft tissues, because they lack the physical strength to withstand the physiological stresses normally encountered close to the host tissue. Instead, the microcapsules are suspended in a free floating state within a solution that is infused into the host's peritoneal cavity.
In reality, the microcapsules have only limited clinical application. Not all persons can tolerate their injection free of danger or discomfort. Microcapsules are non-adhesive, and they do not stick to organs. Instead, they settle in large masses at the bottom of the peritoneal cavity. And, if implanted directly within the host's tissue, the microcapsules will rupture, and the contained cells would perish. For these reasons, microcapsules fail to provide a widely usable clinical solution to the problems surrounding the therapeutic implantation of cells.
The inventions have as an important objective the design of implant assemblies and methodologies that combine effectiveness and practicality required for widespread clinical use.
SUMMARY OF THE INVENTIONS
To meet these and other objectives, the inventions provide improved implant assemblies and methodologies that can carry enough cells to be of therapeutic value to the host, yet occupy a relatively small, compact area within the host. The implant assemblies and methodologies that the inventions provide also establish an improved boundary between the implanted cells and the host. The improved boundary sustains the viability of the implanted cells, both before and after the growth of vascular structures by the host.
To assure the long term survival and functionality of implanted cells, the host must grow new vascular structures to serve them. The inventors have discovered that an animal host will not naturally provide these new vascular structures. It must be stimulated to do so.
The implant assembly itself must provide this crucial stimulation to the host. Otherwise, new vascular structures will not form close to the boundary. The implanted cells will die or will not function as expected.
The inventors have found that some cells implanted for therapeutic reasons, like pancreatic islets, naturally secrete angiogenic material. “Angiogenic” identifies a type of material that has the characteristic of stimulating the growth of new vascular structures by the host close to the boundary that separates the implanted cells from the host. “Close” means that the vascular structures generally lie within about one cell layer away from the boundary, which is usually less than about 15 microns.
These angiogenic source cells, if implanted, create their own stimulation for close neovascular growth. Yet, other cells do not naturally secrete angiogenic materials. These cells, if implanted alone, will not induce vascularization. If these cells are implanted, the implant assembly should include a separate angiogenic source for them.
Still, the presence of an angiogenic source does not assure cell survival during the ischemic period, before the close vascular structures form. Even cells that naturally secrete angiogenic material often die or become dysfunctional soon into the ischemic period. Their release of angiogenic material stops, too, bringing vascularization to a halt.
The inventors have discovered that implanted cells perish during the ischemic period, because the assemblies housing them lack the intrinsic capacity to bring in enough nutrients and let out enough wastes to support their ongoing metabolic processes when the host's vascular structures are absent. This capacity will be referred to as “metabolic transit.”
It is the lack of sufficient metabolic transit innate in prior implant assemblies and methodologies, and not the formation of the foreign body capsule, that causes the implanted cells to expire or become dysfunctional during the ischemic period. It is the lack of sufficient metabolic transit by the boundary that stymies the formation of close vascular structures and causes the implant to fail.
The inventors have discovered that an implant assembly will support the ongoing metabolic processes of implanted cells during the ischemic period, even when a foreign body capsule forms, if the assembly has a sufficient metabolic transit value to support these processes in the absence of close vascular structures. With their metabolic processes supported, the cells survive the ischemic period. When the assembly includes implanted angiogenic source cells, they also r
Brauker James H.
Hill Ronald S.
Johnson Robert C.
Johnston William D.
Martinson Laura A.
Baxter International Inc.
Isabella David J.
McDonnell & Boehnen Hulbert & Berghoff
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