Title:  Implantable therapy systems and methods

United States Patent:  6,179,826

Assignee:  Brown University Research Foundation (Providence, RI)

Filed:  October 29, 1996

Implantable therapy systems are disclosed for the local and controlled delivery of a biologically active factor to the brain, spinal cord and other target regions of a subject suffering from a dibilatating condition. The method of the invention involves surgically exposing an insertion site, generally located above a predetermined treatment site (12), in a patient. A cannula (20), having an obturator (30) or dilator (104) positioned therein, is inserted at the insertion site, defining a pathway to the treatment site. In some instances, the cannula can be inserted along the path of a guidewire (102) previously positioned at the treatment site. The cannula (20) is preferably a low friction polymeric material such as polytetrafluoroethylene. The cannula (20) generally has an open proximal end for receiving the obturator (30) or dilator (104), and an open distal end, preferably a tapered end, for delivery of neurologically active factors to the treatment site (12). The obturator (30) is then removed from the cannula (20), and a biocompatible tethered vehicle (40) containing a biologically active material is inserted into the cannula along the passageway. A pusher can be inserted within the cannula, behind the vehicle (40), to position the proximal end of the vehicle at the proximal tip of the cannula (20b). Once the vehicle (40) is positioned near the proximal end of the cannula (20), the cannula is removed from the passageway, followed by the pusher, leaving the vehicle (40) positioned at the treatment site (12).

SUMMARY OF THE INVENTION

Neurological therapy methods and systems are disclosed for the local and controlled delivery of a biologically active factor to the brain, or other portion of the CNS, or other organ of a subject. The methods and systems are useful for treating subjects suffering from a deficiency or organ dysfunction, or suffering from acute and/or chronic pain.

A method of the invention involves surgically exposing an insertion site generally located above a predetermined treatment site, which site may be within brain tissue or other target organ tissue. The precise location of the treatment site, and the subsequent insertion site location may be stereotazically ascertained. A cannula, having an obturator positioned therein, is inserted at the insertion site, defining a passageway to the treatment site. The cannula generally has an open proximal end for receiving the obturator, and an open distal end for delivery of biologically active factors to the treatment site.

The method further involves removing the obturator from the cannula once the passageway is defined and the cannula is in the desired position. After the obturator is removed, a biocompatible vehicle containing a biologically active factor is inserted into the cannula along the passageway. Once the vehicle is positioned near the distal end of the cannula, the cannula is removed from the passageway, leaving the vehicle positioned at the treatment site.

The obturator may be re-inserted into the cannula after the vehicle is initially placed in the cannula to position the vehicle at the distal end. This may be necessary if, for example, the vehicle does not slidably fit within the cannula. The obturator used for thus positioning the vehicle may be the same as or different from the obturator initially positioned in the cannula. If an obturator is used to position the vehicle, it is removed following removal of the cannula to further assist in retaining the desired position of the vehicle at the treatment site.

Another form of the invention involves making an insertion site proximal to the treatment site, and introducing a guidance needle, optionally with an obturator positioned in its central bore, into the area of the treatment site. The needle lumen is opened by removing the obturator if any is present, and a guidewire is introduced into the lumen of the needle and is fed through until it enters the treatment site. Once the guidewire is contacting the treatment site, the guidance needle is removed and replaced with a cannula. The cannula is ideally dimensioned for providing an insertion path for positioning a biocompatible vehicle containing biologically active factors at the desired treatment site. The guidewire is removed, and the vehicle is inserted into the cannula and guided along the passageway of the cannula towards the treatment site. Once the vehicle is positioned near the distal end of the cannula (i.e. at the treatment site), the cannula is removed from the passageway, leaving the vehicle at the treatment site.

A pusher can be inserted into the cannula after the vehicle is initially placed in the cannula so as to aid in positioning the vehicle at the distal end. As above, this may be necessary if, for example, the vehicle does not slide freely within the lumen of the cannula.

In another form of the invention, the insertion site is enlarged by introducing at least one dilator over the guidewire before the insertion of the cannula.

In another form of the invention, the cannula is filled with a physiologically compatible solution following removal of an obturator or a dilator and prior to inserting the vehicle. In this manner, the fluid serves as a lubricant to assist in positioning the vehicle at the distal end of the cannula.

The vehicles used in practicing the method of the invention, include capsules containing biologically active factors. These capsules may include an integral tether that extends from the capsule. The tether preferably is of a length sufficient to reach at least from the treatment site to the proximity of the insertion site. The tether may also be a part of the cell capsule itself that extends above the insertion site. In addition, the tether may form a secondary seal on the capsule. Once the vehicle capsule is positioned in the passageway to the treatment site, the tether may then be secured at the insertion site, e.g., by securing the tether to the outer surface of the skull proximal to the insertion site by means of surgical staples, biocompatible adhesive, and the other methods available and known to those skilled in the art. Following positioning of the vehicle at the treatment site, the insertion site may be closed or capped to prevent introduction of extraneous material to the passageway and the treatment site.

In one aspect of the invention, the vehicle may include an amount of a detectable marker, such as a radio-opaque material, to facilitate in situ monitoring of the vehicle at the treatment site. The vehicle may then post-operatively be monitored in the patient through the use of CAT scan, MRI or the like.

Systems for providing encapsulated biological material to a selected treatment site are also disclosed. A system that can be used to practice the method of the invention includes a cannula, an obturator, and a biological vehicle. The cannula is adapted to receive the vehicle, having an open proximal end for receiving the obturator and the vehicle, and an open distal end for delivering the vehicle to the treatment site. The obturator is of the type designed for insertion within and along a substantial length of the cannula to prevent backfill of materials, such as dura, into the cannula during insertion of the cannula to the treatment site. The obturator is also adapted to assist in positioning the encapsulated neuroactive factors within the cannula.

Another system that can be used to practice the method of the invention includes a guidance needle, a guidewire, a cannula, and a biological vehicle. The guidance needle has a lumen adapted to receive the guidewire, such that the guidewire can be fed therethrough from an open proximal end adapted for receiving the guidewire to an open distal end which can be placed at or proximate the treatment site. The guidance needle is removable from the insertion site and disconnectable from the guidewire without effecting the guidewires ultimate position at the desired treatment site. The cannula has a bore adapted for receiving the vehicle and the guidewire, having an open proximal end for receiving the vehicle, and an open distal end for delivering the vehicle to the treatment site. The system can further include an obturator for reversibly blocking the lumen of the guidance needle, as well as dilators adapted for receiving the guidewire and slidable therealong. A pusher can also be used with the system, the pusher adapted for passing through the lumen of the cannula and pushing the vehicle to the distal end of the cannula.

The vehicles of the system of the invention can include a cell capsule having a biocompatible permselective outer membrane encapsulating cells capable of releasing active factors. The vehicle generally has a shape which enables insertion within and movement along the cannula. In one form, the vehicles are smooth, seamless capsules formed by extrusion through a multilumen spinneret. In that form, the capsules are formed from a biocompatible, permselective thermoplastic, encapsulating a suspension of cells that secrete a biologically active factor. Exemplary classes of active factors include neurotransmitters, neuropeptides including opioid peptides, growth factors, trophic factors, and analgesic factors such as catecholamines. In another form, the vehicles are hollow fibers filled with the factor-secreting cells.

The vehicles of the present system further include a tether extending from the capsule for securing the vehicle at the treatment site following insertion. The tether may be integral with the capsule, or may be attached by methods available and known to those skilled in the art.

The term "biologically active factors" used herein includes: neurotransmitters such as gamma aminobutyric acid, serotonin, acetylcholine, glutamic acid and dopamine; and neuroactive analgesic factors such as catecholamines (e.g. epinephrine and norepinephrine) and opioid peptides. The term also includes precursors, agonists, active analogs, and active fragments of these neurotransmitters (e.g. dopamine precursor L-dopa and dopamine agonist bromocriptine). Cells that secrete neuroactive factors such as peptide neurotransmitters, growth factors, trophic factors, catecholamines, opioid peptides, and/or hormones may also be useful. These include: insulin, Factor VIII, trophic factors such as erythropoeitin and growth hormones, biological response modifiers such as lymphokines and cytokines, enzymes, and antibodies from antibody-secreting cells, neuropeptides such as enkephalins, dynorphins, Substance P, Met-enkephalin, neuropeptide Y, vasoactive intestinal polypeptide, neurotensin, somatostania, and endorphins, catecholamines such as epinephrine and norepinephrine, as well as factors such as nerve growth factor (NGF), brain-derived neurotophic factor (BDNF), neurotrophin-3 (NT-3), an array of fibroblast growth factors, and an array of neurotrophic factors.

The term "semipermeable" is used herein to describe biocompatible membranes that allow the diffusion therethrough of molecules having a relatively low molecular weight, i.e., approximately 150 kD, while excluding the passage of those having a relatively high molecular weight.

In one embodiment of the invention, the semipermeable membrane of the receptacle preferably contains pores having a molecular weight exclusion of about 150 kD. This membrane excludes the passage therethrough of large particles such as those which are capable of degrading the neurotransmitter or injuring the neurotransmitter-producing cells (e.g. viruses, antibodies, complement, and various proteases). The semipermeable membrane can be made of various polymeric compositions such as a polyvinylchloride, polyacrylonitrile, polyvinylidene fluoride, polystyrene, polyurethane, polyamides, cellulose acetates and nitrates, polymethylmethacrylate, polysulfones, polyacrylates including acrylic copolymers, and derivatives, copolymers, and mixtures thereof.

The encapsulated cells may include secretory cells which have been isolated from natural sources, or have been genetically engineered to produce neuroactive factors, growth factors or agonists, precursors, active analogs, or active fragments thereof. For example, chromaffin cells of the adrenal medulla, embryonic ventral mesencephalic tissue, and various neuroblastic cell lines such as PC12 function to supply dopamine and other active factors, and therefore, are preferred for incorporation into the device. In some aspects of the invention, the cell is an allograft (i.e., cells from another of the same species as the subject in which it is to be implanted) or a zenograft (i.e., cells from another of a different species).

The invention will next be described in connection with certain illustrated embodiments. However, it should be clear that various modifications, additions, and subtractions can be made without departing from the spirit or scope of the invention. For example, the present invention should not be read to require, or be limited to, a particular device shape, material, neuroactive factors, growth factor, or cell line described by way of example or illustration.

Claim 1 of 9 Claims

What is claimed is:

1. A method for delivering a biologically active factor to a patient, comprising

introducing through the bore of a single cannula into the subarachnoid space of a spinal column at least one vehicle comprising a biocompatible semipermeable outer membrane and which encapsulates cells that produce the biologically active factor, wherein the cannula is adapted for penetration through tissue, the cannula having a bore with a substantially smooth surface running axially therethrough through which a vehicle may slidably move, an open, proximal end into which the vehicle may be slidably inserted and a distal end having an opening through which the vehicle may slidably move wherein the external diameter and bore diameter are tapered toward the distal tip

whereby the biologically active factor is released from the cells through the semipermeable membrane of the vehicle into the central nervous system of the patient.

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