Implantable therapy systems and methods

Details Implantable therapy systems and methods Implantable therapy systems and methods

1996-10-29

2001-01-30

Bockelman, Mark (Department: 3762)

Surgery

Means for introducing or removing material from body for...

Treating material introduced into or removed from body...

C424S570000, C604S093010

Reexamination Certificate

active

06179826

ABSTRACT:

BACKGROUND OF THE INVENTION
The technical field of this invention includes the treatment of neurological disorders and treatment of acute and/or chronic pain. In particular, the invention concerns the treatment of diseases and disorders which may be remedied by treatment with secretory substances, such as neurotransmitters, neuromodulators, hormones, trophic factors, or growth factors, as well as the reduction of pain sensitivity by the provision of a sustained local delivery of neuroactive substances, particularly catecholamines and opioid peptides. All these substances are characterized by the fact they are secreted by “source” cells and produce a specific change in the source cell itself or in a “target” cell (i.e., they are biologically active).
Deficits in secretory substances have been implicated in various neurological diseases. Lack of neurotransmitter-mediated synaptic contact causes neuropathological symptoms, and can also lead to the ultimate destruction of the neurons involved.
For example, paralysis agitans, more commonly known as Parkinson's disease, is characterized by a lack of the neurotransmitter, dopamine, within the striatum of the brain, secondary to the destruction of the dopamine secreting cells of the substantia nigra. Affected subjects demonstrate a stooped posture, stiffness and slowness of movement, and rhythmic tremor of limbs, with dementia being often encountered in very advanced stages of the disease.
The direct administration of purified or synthetic dopamine, its precursors, analogs and inhibitors has been studied for therapeutic value in the treatment of Parkinson's disease. These studies have revealed various problems with delivery, stability, dosage, and cytotoxicity of the applied compounds. To date, none of these approaches has demonstrated more than marginal therapeutic value. Brain derived growth factor also may have potential value in the treatment of Parkinson's disease since it has been demonstrated to maintain the viability of striatal neurons in vitro.
Many other diseases, especially neurological disorders appear to be based in whole, or in part, on the absence or limited availability, to target cells or regions, of a critical biological factor.
It is also fairly well established that the activation of noradrenergic or opioid receptors in the spinal cord by direct intrathecal injection of &agr;-adrenergic or opioid agonists produces antinociception, and that the co-administration of subeffective doses of these agents can produce potent analgesia. The presence of enkephalin-secreting neurons and opiate receptors in high densities in the substantia gelatinosa of the spinal cord and the resultant analgesia observed following local injection of opiates into the spinal cord have suggested a role for opioid peptides in modulating the central transmission of nociceptive information. In addition, catecholamines also appear to be important in modulating pain sensitivity in the spinal cord since injection of noradrenergic agonists into the subarachnoidal space of the spinal cord produces analgesia, while the injection of noradrenergic antagonists produces increased sensitivity to noxious stimuli.
In an attempt to provide a continuous supply of drugs or other factors to the brain and other tissues at a controlled rate, miniature osmotic pumps have been used. However, limited solubility and stability of certain drugs, as well as reservoir limitations, have restricted the usefulness of this technology. For example, controlled sustained release of dopamine has been attempted by implanting dopamine encapsulated within bioresorbable microcapsules (McRae-Degueurce et al. (1988) Neurosci. Lett. 92:303-309). However, controlled sustained release of a drug from a bioresorbable polymer may rely, e.g., on bulk or surface erosion, which may be due to various hydrolytic events, increasing the likelihood of drug degradation, and rendering predictable release rates difficult. Others may be limited to finite loading of the polymer, and may lack any cellular feedback regulation.
Many drugs have been administered intraspinally in the clinical setting, and numerous methods are available to deliver intraspinal medications. For instance, the most common method of intraspinal drug delivery, particularly anesthetics, is continuous infusion by way of spinal catheters. However, the use of these catheters, particularly small-bore catheters, has been implicated in such complications as cauda equina syndrome, a neurological syndrome characterized by loss of sensation or mobility of the lower limbs. In fact, the FDA was prompted to issue a safety alert in May, 1992, alerting Anesthesia Care Providers to the serious hazard associated with continuous spinal anesthesia by small-bore catheters and has taken action to remove all small-bore catheters from the market.
The implantation of cells capable of constitutively producing and secreting neuroactive factors has also been attempted. Recently, remedial transplantation of neurotransmitter-secreting tissue has been accomplished using the patient's own tissue so as not to elicit an immune response. For example, dopamine-secreting tissue from the adrenal medulla of patients suffering from Parkinson's disease has been implanted in their striatum with some success. However, this procedure is only used in patients less than 60 years of age, as the adrenal gland of older patients may not contain sufficient dopamine-secreting cells. This restriction limits the usefulness of the procedure as a remedy since the disease most often affects older people. A further problem associated with this procedure is that it requires an additional, distinct surgical procedure.
Other transplantation approaches have demonstrated that even though the Central Nervous System (CNS), e.g. the brain and spinal cord, is considered “immuno-privileged”, rejection ultimately occurs with both allografts and xenografts. This problem necessitates the co-adminstration of immuno-suppressors, the use of which renders their own set of complications and deleterious side-effects. For example, human medullary tissue has been implanted into the subarachnoid space of patients suffering from terminal cancer and has been shown to reduce both acute and chronic pain. However, the limited availability of human donor tissue for allografts reduces the potential for its large scale use, suggesting the need to utilize zenographic donors. It is clear that the use of widely disparate histoincompatible species (i.e. bovine and human) can result in severe immunological responses, which can cause the ultimate destruction of the graft. The immunosuppresent cyclosporine A has been used to prolong bovine adrenal medullary chromaffin cell xenografts in the rat CNS, but survival is variable and cyclosporine A can be toxic with potentially serious complications including hepatotoxicity and nephrotozicity, as well as tumorogenicity. With regard to the use of cyclosporine A in humans, the serious side effects associated with its use have precluded its administration to otherwise healthy patients.
A number of researchers have proposed the use of microcapsules, i.e., tiny spheres which encapsulate a microscopic droplet of a cell solution, for both therapeutic implantation purposes and large scale production of biological products. However, there are a number of shortcomings to the microencapsulation approach. For example, the microcapsules can be extremely difficult to handle, including being difficult to retrieve after implantation. The types of encapsulating materials which can be used are constrained by the formation process to polymers which can dissolve in biocompatible solvents. Furthermore, due to the limited diffusional surface area per unit volume of larger size spheres, only a limited amount of tissue can be loaded into a single microcapsule.
An alternative approach has been macroencapsulation, which typically involves loading cells into hollow fibers and then sealing the extremities. In contrast to microcapsules, macrocapsules offer the advantage of easy retriev

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