WO1991010470A1 - Devices and methods for enhanced delivery of active factors - Google Patents

Devices and methods for enhanced delivery of active factors

Info

Publication number
WO1991010470A1
WO1991010470A1 PCT/US1991/000155 US9100155W WO1991010470A1 WO 1991010470 A1 WO1991010470 A1 WO 1991010470A1 US 9100155 W US9100155 W US 9100155W WO 1991010470 A1 WO1991010470 A1 WO 1991010470A1
Authority
WO
Grant status
Application
Patent type
Prior art keywords
factor
active
membrane
cell
cells
Prior art date
Application number
PCT/US1991/000155
Other languages
French (fr)
Inventor
Patrick Aebischer
Giorgio Soldani
Original Assignee
Brown University Research Foundation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, E.G. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/022Artificial gland structures using bioreactors
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0085Brain, e.g. brain implants; Spinal cord
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M31/00Devices for introducing or retaining media, e.g. remedies, in cavities of the body
    • A61M31/002Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time

Abstract

Methods and devices (10, 20, 30) are disclosed for the enhanced delivery of an active factor from an implanted, active factor-secreting cell culture to a target region in a subject. The cell culture (25) is maintained within a biocompatible, semipermeable electrically charged membrane (22) which generates electric charges on its surface, thereby resulting in enhanced delivery of active factor therefrom. The membrane permits the diffusion of active factor and metabolites therethrough, while excluding viruses, antibodies, and other detrimental agents present in the external environment from gaining access. In addition, implantable cell culture devices are disclosed which may be retrieved from the subject, replaced, or recharged with new, active factor-secreting cell cultures, and reimplanted.

Description

DEVICES AND METHODS FOR ENHANCED DELIVERY OF ACTIVE FACTORS

Background of the Invention

The technical field of this invention is the treatment of deficiency diseases and, in particular, the treatment of diseases or disorders resulting from an inadequacy or lack of a neurotransmitter, growth factor, or hormone.

Neurotransmitters, growth factors, and hormones are soluble, "trans-acting" molecules that are elicited by one cell and affect another cell. For example, neurotransmitters act as chemical means of communication between neurons. They are synthesized by the presynaptic neuron and released into the synaptic space where they are then taken up by postsynaptic neurons. Lack of neurotransmitter- mediated synaptic contact causes neuropathological symptoms, and can also lead to the ultimate destruction of the neurons involved. In fact, neurotransmitter deficits have been implicated in a number of neurological diseases.

It has been discovered that localized delivery of the relevant neurotransmitter to the target tissue may reverse the symptoms without the need for specific synaptic contact. 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. These clinical symptoms can be improved by the systemic administration of dopamine precursors, such as L-dopa (Calne et al., (1969) Lancet ii:973-976) . which are able to cross the blood-brain barrier and there to be converted into dopamine, or agonists such as bromocriptine (Calne et al., (1974) Bri. Med. J. 4 :442-444) which elicit a dopamine response.

Dopamine, itself, cannot be administered systemically because of its inability to cross the blood-brain barrier.

One of the drawbacks of direct systemic therapy is that other neighboring organs or tissues that respond to the administered compound are also affected. In addition, it may become increasingly difficult to administer the correct dosage of compound with time because the "therapeutic window" narrows. For example, just after L-dopa administration, the patient is overdosed, exhibiting excessive spontaneous movement; some time thereafter the drug level may become insufficient, causing the patient to again express Parkinsonian symptoms.

Therefore, what is needed is a method of delivering an appropriate concentration of a needed compound or "active factor" to a target region of the body which is deficient in that factor.

The constitutive provision of the needed quantity of active factor has been proposed to alleviate the aforementioned problems. To this end, the transplantation of neurotransmitter- or growth factor-secreting cells has been attempted. For example, dopamine-secreting tissue has been transplanted into the brain to treat Parkinsonian symptoms. However, recent studies have shown that although the brain is considered "immuno- priviledged", rejection ultimately occurs with both allografts (identical tissue from another of the same species) and xenografts (similar tissue from another of a different species) . The rejection problem necessitates the co-adminstration of immuno- suppressors, the use of which renders their own set of complications and deleterious side-effects.

To prevent the elicitation of an immune response, remedial transplantation of neuro- transmitter-secreting tissue has been tried using the patient's own tissue. For example, dopamine- secreting tissue from the adrenal medulla of patients suffering from Parkinson's disease has been implanted in their striatum with reasonable 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 this procedure as a remedy since the disease often affects older people.

An alternative way of alleviating an immune reaction in response to tissue transplantation involves protecting the cells to be implanted in a selectively permeable membrane. Such a membrane allows the diffusion therethrough of metabolites and active factors, while preventing the passage of antibodies and complement as well as viruses. However, in some systems, cell-to-cell contact is thought to be a prerequisite for the elicitation of active factor in the concentration normally required by a target tissue. In addition, diffusion rates through the membrane may change the delivery rate of an active factor from the cell culture to the target tissue.

Therefore, there exists a need for improved therapies for various deficiency diseases in general, and in particular, a need for systems which can augment or replace dysfunctional areas of an active factor-producing tissue. More specifically, there exists a need for a method of providing an active factor to a localized area of the body of a subject, the correct dosage of which will be constitutively delivered over time.

Accordingly, it is an object of the present invention to provide a method for delivering an active factor to a localized region of a subject. It is another object of the present invention to provide a method of enhancing the delivery of active factor from encapsulated cells. Another object is to provide a method of constitutively delivering the needed dosage of an active factor to a subject deficient in that factor.

Another object is to provide an implantable cell culture device which allows for the enhanced delivery of an active factor from the cells cultured within. Yet another object is to provide a cell culture device which is retrievable, and whose contents are renewable with new and/or additional neurotransmitter-secreting cells. A further object is to provide a cell culture device which protects the cells therein from an immunological response or from viral infection, while allowing the delivery of an active factor and metabolites therefrom.

Summary of the Invention

Methods and devices are disclosed herein for the constitutive and enhanced delivery of an active factor to a subject suffering from a deficiency or dysfunction. The term "active factor" is used herein to describe neurotransmitters, growth factors, peptide hormones, trophic factors, lymphokines, and any molecule synthesized and secreted by a cell and required for the proper function and maintenance of a tissue.

It has been discovered that the delivery of an active factor from active factor-secreting cells can be greatly enhanced by encapsulating the cells in a semipermeable, electrically-charged or conductive membrane. This membrane produces surface electric charges that depolarize the encapsulated cells therein, thereby enhancing the delivery of active factor therefrom.

The term "electret" as used herein is intended to encompass natural and synthetic materials capable of generating electrical charges on their surface. Piezoelectric materials are one type of electret which generates a transient electric surface charge upon mechanical stress or deformation. Medical devices employing such electret membranes are disclosed for use in implantable cell culture devices.

The membranes of the present invention are also "semipermeable", or selectively permeable to nutrients, metabolites, and active factors having molecular weights of about 50,000 daltons or less; excluded from passage are cells, antibodies, complement, virus and other agents harmful to the cells encapsulated therein.

In one preferred embodiment of the invention, the electret membrane is a tube composed of a piezoelectric material such as polyvinylidene difluoride (PVDF) , trifluoroethylene (TrFE) , or a copolymer thereof (PVDF-TrFE) . Alternatively, the membrane can comprise a permanent poled polymeric material or may be fabricated in whole or in part of a conductive polymer.

In accordance with the method of present invention, at least one active factor-secreting cell, such as a neuron, is encapsulated within such a membrane and implanted into a subject where it is maintained protectively while delivering active factor to the local internal environment of that subject.

The cells to be implanted may be any cells which synthesize and secrete a desired active factor. Preferred active factors include neurotransmitters, growth factors, and active analogs, fragments, and derivatives thereof. One particularly useful active factor is the neurotransmitter, dopamine, which is secreted by cells of the adrenal medulla, embryonic ventral mesencephalic tissue, and neuroblastic cell lines such as PC12, a cell line derived from a rat pheochromacytoma. Other useful active factors include the dopamine precursor, L-dopa, and the dopamine agonist, bromocriptine. A preferred growth factor is fibroblast growth factor (FGF) in either its acidic or basic form.

In one aspect of the invention the encapsulating membrane is a tube preferably having a diameter of about 200 - 600 mm, and a wall thickness ranging from about 50 - 100 mm. The openings of the tube may be covered by removable plugs or caps. Such a construct enables the easy replacement of cells within the membrane with other cells through the uncovered tube openings after retrieval from the subject via the attached guide wire.

Also disclosed is a method for enhancing the secretion of an active factor from an active-factor secreting cell. The method includes the steps of encapsulating the active factor-secreting cell in a semipermeable, electret membrane, and allowing the membrane to generate an electric surface charge, thereby causing the encapsulated cells to become depolarized and to secrete active factor. In a preferred embodiment, the cells is encapsulated within a piezoelectric membrane which generates the depolarizing surface charge upon mechanical stress.

Further a method for providing an active factor to a target region of the body is disclosed. In this method, an active factor-secreting cell is encapsulated within a semipermeable, electret membrane that is permeable to the active factor. The encapsulated cell is implanted in a target region of the body. Enhanced secretion of the active factor from the encapsulated cell results when the encapsulating membrane generates a surface charge and depolarizes the cells therein.

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. The present invention should not be read to require, or be limited to, particular cell lines or electret materials described by way of sample or illustration. Additionally, although the culture devices described below are generally tubular in shape, it should be clear that various alternative shapes can be employed as well. Moreover, the electrically charged or conductive materials employed in the present invention need not form the entire encapsulating membrane but rather can be interspersed within an otherwise inactive membrane matrix.

Brief Description of the Drawings

The invention itself can be more fully understood from the following description when read together with the accompanying drawings in which:

FIG. 1 is a schematic illustration of an implantable cell culture device for delivering a active factor, according to one aspect of the invention;

FIG. 2 is a schematic illustration of an implantable and retrievable cell culture device for delivering an active factor, according to another aspect of the invention; and

FIG. 3 is a schematic illustration of an implantable, retrievable, and rechargeable cell culture device for delivering an active factor, according to yet another aspect of the invention.

Detailed Description

Methods and devices are disclosed herein for the enhanced delivery of an active factor from an implanted, active factor-secreting cell culture to a target region in a subject. This invention exploits the discovery that upon depolarization, nerve cells may be induced to release neurotransmitter from secretory granules in their cytoplasm.

In the present invention, a cell culture is maintained within a biocompatible, semipermeable electret membrane. The surface charges generated by the membrane causes the encapsulated cells therein to become depolarized and to secrete active factor. The electret membrane is also semipermeable, permitting the diffusion of active factor and metabolites therethrough, while excluding viruses, antibodies, and other detrimental agents present in the external environment from gaining access. In addition, implantable cell culture devices are disclosed which may be retrieved from the subject, replaced, or recharged with new, active factor-secreting cell cultures, and reimplanted.

Any cell line or tissue which secretes a needed active factor can be encapsulated for use in the present invention. These include tissue fragments and established cell lines that secrete active factors _in vivo such as adrenal medulla, embryonic ventral mesencephalic tissue, neuroblastic cell lines, and PC.12 cells, all of which secrete dopamine. Other useful neurotransmitters include gamma aminobutyric acid (GABA), serotonin. acetylcholine, noradrenaline, and other compounds necessary for normal nerve functions. Preferred active factors is fibroblast growth factor in either its acidic or basic form and various peptide hormones.

In addition, any cell which secretes a precursor, analog, derivative, agonist or fragment of a desired active factor having similar activity can be used, including, for example, cells which elicit L-dopa, a precursor of dopamine, or bromocriptine, a dopamine agonist.

The cells to be encapsulated may be allografts, or cells from another of the same species as the subject in which they are to be implanted, or they may be xenografts, or those from another of a different species. They may be derived from, or are a component of an adult body organ or tissue which normally secretes a particular active factor in vivo. Alternatively, useful cells include embryonic active factor-secreting cells from, for example, the embryonic ventral mesencephalon, neuroblastoid cell lines, or the adrenal medulla.

Further, any cells which have been genetically engineered to express an active factor or its agonist, precursor, derivative, analog, or fragment thereof which has similar neurotransmitter activity are also useful in practicing this invention. Thus, in such an approach, the gene which encodes the active factor, or an analog, precursor, or fragment thereof, is either isolated from a cell line or constructed by various known engineering methods. The gene is then incorporated into a vector, which, in turn, is transfected into a host cell for expression (see, e.g., Maniatis et al., Molecular Cloning (1982), herein incorporated by reference for further discussion of cloning vehicles and gene manipulation procedures) . Appropriately transformed cells which express the active factor can be cultured .in vitro until a suitable density is achieved.

The active factor-secreting cells are then placed into the cell culture device prior to implantation, either as tissue fragments or as seed cultures.

The device is a membrane adapted to receive the active-factor secreting cells. This membrane is biocompatible and semipermeable so as to protect the cells from deleterious encounters with viruses and elements of the immune system. Such protection is particularly important for preserving allografts or xenografts which are eventually considered foreign even in the "immuno-priviledged" brain. Therefore, the membrane should bar viruses, macrophages, complement, lymphocytes, and antibodies from entry while allowing the passage of nutrients, gases, metabolic breakdown products, other solutes, and the neurotransmitter to pass therethrough. Accordingly, a biocompatible and nonresorbable materials having pores enabling the diffusion therefrom of molecules having a molecular weight of up to about 50,000 daltons are useful for practicing the present invention. Further, the membrane of the cell culture device is made of an electret material, one preferred example of which is a piezoelectric material. Useful piezoelectric membranes are composed of biocompatible, semicrystalline polymers which may have to be poled prior to use, but which need not be stretched prior to poling. Poling can then be performed to align the polymeric chain segments in a particular orientation, thereby establishing a predefined dipole moment. Polarization can be achieved, for example, by disposing one electrode on the inside of a tubular membrane and another electrode on the outside of the tube, and then applying a voltage to one of the electrodes such that an electric field is established. When the membrane is a piezoelectric material, poling preferably establishs a charge generation (polarization constant) ranging from about 0.5 - 35 picoColoumbs per Newton, and, more preferably, from about 1.0 - 20.0 picoColoumbs per Newton.

Piezoelectric materials useful in the present invention include a variety of halogenated polymers, copolymers and polymer blends. The halogenated polymers include polyvinylidene difluoride, polyvinyl fluoride, polyvinyl chloride and derivatives thereof as well as copolymers such as copolymers of the above materials and trifluoroethylene. PVDF-TrFE, for example, is a preferable material for membrane fabrication with adequate mechanical characteristics for cell filling and stereotaxic brain implantation. It need not be stretched prior to poling.

Small tubular membranes of PVDF-TrFE can be constructed by various fabrication techniques known to those skilled in the art, including, for example, the spray-phase inversion technique. In this procedure, the tubular membrane is fabricated using a machine consisting of a small precision lathe in which mandrels of different diameters are rotated using an electronically controlled variable speed motor. A carriage is positioned adjacent to the lathe bed. The carriage can move bidirectionally and in parallel with the rotating mandrel. The carriage is driven by an electronically controlled motor which is automatically reversed by the action of electro¬ mechanical relays controlled by micro-switches. Two spray-guns are mounted on the carriage and can be fixed at different angles to one another, and at different distances between nozzles and mandrel, so that the jet-streams can be directed on a precise point over the mandrel.

The porosity of the membrane may be controlled by the degree of phase inversion. The advantage of PVDF-TrFE resides in its ability to be electrically poled without the need for mechanical stretching.

The cell culture device may take any shape that will accommodate the cells to be encapsulated, and which will not cause undue trauma upon surgical implantation. In addition, to ensure viability of the cells within, only small diffusion distances are established between the implanted tissue and the vascularized surrounding host tissue. To this end, the diameter of the tube should be in the range of about 200 - 600 m, as determined by the observation that oxygen tension, when relying only on diffusion, approaches zero in a vascularized tissue.

A preferable implantable cell culture device 10 shown in FIG. 1 is a tubular, selectively permeable piezoelectric membrane 22 having ends 12 and 14 through which active factor-secreting cells 25 are loaded into cell compartment 16. Ends 12 and 14 may then be permanently occluded with caps 17 and 19 or, alternatively, with an epoxy glue or sutures of a biocompatible and nonresorbable material like polypropylene.

The device 10 as shown in FIG. 1 can be surgically implanted into the target region of a subject such that membrane 22 is in immediate contact with body tissues or fluids. The targeted region may be the _in vivo site of deficiency, need, or the site of synthesis of the factor. For example, this region may be any part of the nervous system, but will most often be the brain, as it is the source of numerous neurological dysfunctions. The site will provide means for the mechanical deformation of the piezoelectric membrane, necessary for generation of the depolarizing charge. Such means includes the pulsation of adjacent blood vessels and natural movements of the body to which the membrane may be attached.

The method of the present invention may include an additional step whereby the initially encapsulated and implanted cells are retrieved from the subject in the event that they cease to produce active factor, expire, or are no longer needed to correct the dysfunction. As illustrated in FIG. 2, retrieval of implanted cell culture device 20 can be accomplished by means of guide wire 18 which is permanently attached to end cap 17 or 19. This wire may be constructed of any nonresorbable, biocompatible material with enough tensile strength to support the cell culture device.

A exemplary cell culture device useful in practicing this method is shown in FIG. 3. Device 30 is tubular, having ends 12 and 14 reversibly covered with removable, friction-fitted caps 22 and 24, respectively, to enable the extraction and replacement of cells 25 in cell compartment 16 with new cells. The device 30 as shown in FIG. 3 can be surgically implanted into the brain of a subject such that guide wire 18 is located directly under the epithelial tissues of the head, and membrane 22 is in immediate contact with brain tissue. Transient charges will be generated by the piezoelectric membrane in response to normal movements of the head and brain.

The invention will next be described in connection with the following non-limiting examples.

EXAMPLES

Piezoelectric semipermeable tubular membranes were fabricated on a rotating polyethylene mandrel of 500 mm diameter using a spraying-phase inversion technique. PVDF-TrFE copolymer (70:30 v/v) was obtained from Autochem, NJ. The fabrication process was undertaken in a chemical hood. A skin was formed by spraying a PVDF-TrFE solution (1% in methyl ethyl ketone (MEK)) or cospraying a 0.5% solution of PVDF-TrFE and a 50% ethanol/water mixture onto the mandrel. Two spray-guns were operated at the same volumetric flux using compressed nitrogen as the transport gas. The spray-guns were positioned at 30°C to one another and aligned so that the jet-streams converged at a distance of 4 cm between the spray-gun nozzles and the rotating mandrel. The mandrel rotation speed and carriage movement speed were fixed at 600 rpm and 70 cm/min, respectively. Upon the completion of 16 passages, a nonsolvent solution of 1:1 H2θ/methanol was simultaneously but separately sprayed by the second spray-gun. The nonsolvent solution allowed the formulation of an outer porous membrane structure which functions as the inner skin structural support.

Following the fabrication process, the polyethylene mandrel was removed and immediately submerged in a bath of 1:1 H2θ/methanol. This step was performed to stabilize the delicate sponge-like structure of the tubular membranes by allowing the solvents to gradually leave and the nonsolvent to enter the porous structure. The tubular membranes were mechanically detached from the mandrel and dried at room temperature.

Cross-section scanning electron micrographs of the tubular membranes showed a thin inner skin surrounded by a porous network.

Tubular membrane segments (1 cm) were cut and one of their extremities capped with a fast curing acrylic polymer glue. The tubular membranes were either left empty or filled with PC12 cells. The second extremity of the tubes was then capped with the same acrylic polymer glue.

Empty PVDF-TrFE cell culture devices implanted stereotaxically in the striatum of rats, the target structure for dopamine in Parkinson's disease, displayed a mild tissue reaction consisting primarily of microglia and reactive astrocytes.

With the cell-filled devices, intact PC12 cells were observed after 7 days in vitro. TEM micrographs showed the presence of well preserved dopamine-containing secretory granules. Intact viability of macroencapsulated PC12 cells and limited host tissue reaction to the membranes confirmed the utility of PVDF-TrFE as an encapsulation material.

We claim:

Claims

1. A medical device for use in providing an active factor to a target region of the body, said device comprising: a semipermeable, electrically charged membrane; and at least one active factor-secreting cell encapsulated within said membrane, said membrane being permeable to said active factor, and impermeable to cells, virus, complement, antibodies and other factors detrimental to said cells.
2. The device of claim 1 wherein said semipermeable membrane is permeable to molecules having a molecular weight of about 50,000 daltons or less.
3. The device of claim 1 wherein said membrane comprises a tube.
4. The device of claim 3 wherein said tube has a diameter of about 200 - 600 mm.
5. The device of claim 1 wherein said membrane has a wall thickness ranging from about 50 - 100 mm.
6. The device of claim 1 wherein said membrane comprises an electret material.
7. The device of claim 1 wherein said membrane comprises a piezoelectric material.
8. The device of claim 1 wherein said membrane comprises polyvinylidene difluoride.
9. The device of claim 1 wherein said membrane 5 comprises trifluoroethylene.
10. The device of claim 1 wherein said membrane comprises a polyvinylidene difluoride-trifluroro- ethylene copolymer. 0
11. The device of claim 1 wherein said membrane comprises a conductive polymer.
12. The device of claim 1 wherein said active 15 factor-secreting cell is a neuron.
13. The device of claim 1 wherein said active factor is selected from the group consisting of neurotransmitters and precursors, active fragments,
20 analogs, and derivatives thereof.
14. The device of claim 13 wherein said neurotransmitter comprises dopamine.
25 15. The device of claim 13 wherein said precursor comprises L-dopa.
16. The device of claim 1 wherein said active factor is selected from the group consisting of a
30 growth factor and an active fragment, analog, and derivative thereof.
17. The device of claim 16 wherein said growth factor comprises fibroblast growth factor.
35
18. The device of claim 17 wherein said fibroblast growth factor comprises basic fibroblast growth factor.
19. The device of claim 18 wherein said fibroblast growth factor comprises acidic fibroblast growth factor.
20. The device of claim 1 wherein said active factor is selected from the group consisting of a hormone and an active fragment, analog, and derivative thereof.
21. A method for enhancing the secretion of an active factor from an active-factor secreting cell, said method comprising the steps of: encapsulating said active factor-secreting cell in a semipermeable, electrically charged membrane; and allowing said membrane to generate an electric surface charge, said charge causing said encapsulated cell to become depolarized, thereby inducing the secretion of said active factor therefrom.
22. The method of claim 21 wherein said encapsulating step further comprises encapsulating said active factor-secreting cell in a semipermeable, membrane, said membrane being permeable to molecules having a molecular weight of about 50,000 daltons or less.
23. The method of claim 21 wherein said encapsulating step further comprises encapsulating said active factor-secreting cell in a semipermeable, electret membrane, said membrane having a substantially tubular shape.
24. The method of claim 21 wherein said encapsulating step further comprises encapsulating said active factor-secreting cell in a tube having a diameter of about 200 - 600 mm.
25. The device of claim 21 wherein said encapsulating step further comprises encapsulating said active factor-secreting cell in a membrane having a wall thickness ranging from about 50 - 100 mm.
26. The method of claim 21 wherein said encapsulating step further comprises encapsulating said active factor-secreting cell in a semipermeable, piezoelectric membrane, and said allowing step further comprises subjecting said piezoelectric membrane to mechanical stress, said stressed membrane generating a transient electric surface charge, said charge causing said encapsulated cell to become depolarized, thereby inducing the secretion of said active factor therefrom.
27. The device of claim 26 wherein said encapsulating step further comprises encapsulating said active factor-secreting cell in a semipermeable, piezoelectric membrane, said membrane including a polyvinylidene difluoride-trifluroroethylene copolymer.
28. The method of claim 21 wherein said encapsulating step further comprises encapsulating said active factor-secreting cell in a semipermeable membrane, said membrane including a conductive polymer.
29. A method for providing an active factor to a target region of the body, said method comprising the steps of: encapsulating an active factor-secreting cell in a semipermeable, electret membrane, said membrane being permeable to said active factor; implanting said membrane in said target region; and allowing said electret membrane to generate an electric surface charge, said charge causing said encapsulated cell to become depolarized, thereby inducing the secretion of said active factor therefrom.
30. The method of claim 29 wherein said encapsulating step further comprises encapsulating said active factor-secreting cell in a semipermeable, membrane, said membrane being permeable to molecules having a molecular weight of about 50,000 daltons or less.
31. The method of claim 29 wherein said encapsulating step further comprises encapsulating said active factor-secreting cell in a semipermeable, electret membrane, said membrane having a substantially tubular shape.
32. The method of claim 31 wherein said encapsulating step further comprises encapsulating said active factor-secreting cell in a tube having a diameter of about 200 - 600 mm.
33. The device of claim 29 wherein said encapsulating step further comprises encapsulating said active factor-secreting cell in a membrane having a wall thickness ranging from about 50 - 100 mm.
PCT/US1991/000155 1990-01-08 1991-01-08 Devices and methods for enhanced delivery of active factors WO1991010470A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US46210790 true 1990-01-08 1990-01-08
US462,107 1990-01-08

Publications (1)

Publication Number Publication Date
WO1991010470A1 true true WO1991010470A1 (en) 1991-07-25

Family

ID=23835194

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1991/000155 WO1991010470A1 (en) 1990-01-08 1991-01-08 Devices and methods for enhanced delivery of active factors

Country Status (1)

Country Link
WO (1) WO1991010470A1 (en)

Cited By (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0604571A1 (en) * 1991-09-20 1994-07-06 THE GOVERNMENT OF THE UNITED STATES OF AMERICA as represented by the SECRETARY OF THE DEPARTMENT OF HEALTH AND HUMAN SERVICES cDNA ENCODING A DOPAMINE TRANSPORTER AND PROTEIN ENCODED THEREBY
US5639275A (en) * 1993-08-12 1997-06-17 Cytotherapeutics, Inc. Delivery of biologically active molecules using cells contained in biocompatible immunoisolatory capsules
US5641749A (en) * 1995-11-29 1997-06-24 Amgen Inc. Method for treating retinal ganglion cell injury using glial cell line-derived neurothrophic factor (GDNF) protein product
US5641750A (en) * 1995-11-29 1997-06-24 Amgen Inc. Methods for treating photoreceptors using glial cell line-derived neurotrophic factor (GDNF) protein product
US5731284A (en) * 1995-09-28 1998-03-24 Amgen Inc. Method for treating Alzheimer's disease using glial line-derived neurotrophic factor (GDNF) protein product
US5798113A (en) * 1991-04-25 1998-08-25 Brown University Research Foundation Implantable biocompatible immunoisolatory vehicle for delivery of selected therapeutic products
US5800829A (en) * 1991-04-25 1998-09-01 Brown University Research Foundation Methods for coextruding immunoisolatory implantable vehicles with a biocompatible jacket and a biocompatible matrix core
US5837681A (en) * 1996-02-23 1998-11-17 Amgen Inc. Method for treating sensorineural hearing loss using glial cell line-derived neurotrophic factor (GDNF) protein product
US5902745A (en) * 1995-09-22 1999-05-11 Gore Hybrid Technologies, Inc. Cell encapsulation device
US5908623A (en) * 1993-08-12 1999-06-01 Cytotherapeutics, Inc. Compositions and methods for the delivery of biologically active molecules using genetically altered cells contained in biocompatible immunoisolatory capsules
US5929041A (en) * 1996-02-23 1999-07-27 Amgen Inc. Method for preventing and treating sensorineural hearing loss and vestibular disorders using glial cell line-derived neurotrophic factor(GDNF) protein product
US5935795A (en) * 1991-09-20 1999-08-10 Amgen Inc. Glial cell line-derived neurotrophic factor antibody
US5964745A (en) * 1993-07-02 1999-10-12 Med Usa Implantable system for cell growth control
US5980889A (en) * 1993-08-10 1999-11-09 Gore Hybrid Technologies, Inc. Cell encapsulating device containing a cell displacing core for maintaining cell viability
US6043221A (en) * 1997-07-30 2000-03-28 Amgen Inc. Method for preventing and treating hearing loss using a neuturin protein product
WO2000047219A2 (en) 1999-02-10 2000-08-17 Ontogeny, Inc. Methods and reagents for treating glucose metabolic disorders
US6110707A (en) * 1996-01-19 2000-08-29 Board Of Regents, The University Of Texas System Recombinant expression of proteins from secretory cell lines
US6194176B1 (en) 1996-01-19 2001-02-27 Board Of Regents, The University Of Texas System Recombinant expression of proteins from secretory cell lines
US6322962B1 (en) 1998-08-14 2001-11-27 Board Of Regents, The University Of Texas System Sterol-regulated Site-1 protease and assays of modulators thereof
WO2005014022A1 (en) 2003-07-16 2005-02-17 Develogen Aktiengesellschaft Use of pleitrophin for preventing and treating pancreatic diseases and/or obesity and/or metabolic syndrome
US7001371B1 (en) 1993-07-02 2006-02-21 Med Usa Porous drug delivery system
EP1632238A1 (en) * 1994-04-15 2006-03-08 Neurotech S.A. Encapsulated cells adapted for implantation into the aqueous and vitreous humor of the eye
WO2006117212A2 (en) 2005-05-04 2006-11-09 Develogen Aktiengesellschaft Use of gsk-3 inhibitors for preventing and treating pancreatic autoimmune disorders
WO2007068803A1 (en) 2005-12-14 2007-06-21 Licentia Ltd Novel neurotrophic factor protein and uses thereof
US7390781B2 (en) 1995-09-28 2008-06-24 Amgen Inc. Methods of using truncated glial cell line-derived neurotrophic factor
WO2008088738A2 (en) 2007-01-17 2008-07-24 Stemnion, Inc. Novel methods for modulating inflammatory and/or immune responses
US7408047B1 (en) 1999-09-07 2008-08-05 Amgen Inc. Fibroblast growth factor-like polypeptides
US7459540B1 (en) 1999-09-07 2008-12-02 Amgen Inc. Fibroblast growth factor-like polypeptides
EP2077279A1 (en) 2000-06-28 2009-07-08 Amgen Inc. Thymic stromal lymphopoietin receptor molecules and uses thereof
US7579180B2 (en) 1999-03-26 2009-08-25 Amgen Inc. Beta secretase polypeptides
WO2009133247A1 (en) 2008-04-30 2009-11-05 Licentia Oy Neurotrophic factor manf and uses thereof
US7662924B2 (en) 2002-02-22 2010-02-16 The Board Of Trustees Of The University Of Illinois Beta chain-associated regulator of apoptosis
US7723471B2 (en) 2004-02-11 2010-05-25 Amylin Pharmaceuticals, Inc. Pancreatic polypeptide family motifs, polypeptides and methods comprising the same
US7745216B2 (en) 1999-02-10 2010-06-29 Curis, Inc. Methods and reagents for treating glucose metabolic disorders
US8119398B2 (en) 2004-12-30 2012-02-21 Primegen Biotech Llc Adipose-derived stem cells for tissue regeneration and wound healing
EP2460875A1 (en) 2005-03-31 2012-06-06 Stemnion, Inc. Amnion-derived cell compositions, methods of making and uses thereof
US8273713B2 (en) 2000-12-14 2012-09-25 Amylin Pharmaceuticals, Llc Methods of treating obesity using PYY[3-36]
WO2012145384A1 (en) 2011-04-20 2012-10-26 University Of Washington Through Its Center For Commercialization Beta-2 microglobulin-deficient cells
EP2551281A1 (en) 2007-10-25 2013-01-30 Nevalaita, Lina Splice variants of GDNF and uses thereof
WO2013106547A1 (en) 2012-01-10 2013-07-18 President And Fellows Of Harvard College Beta-cell replication promoting compounds and methods of their use
WO2013158292A1 (en) 2012-04-17 2013-10-24 University Of Washington Through Its Center For Commercialization Hla class ii deficient cells, hla class i deficient cells capable of expressing hla class ii proteins, and uses thereof
US8835385B2 (en) 2009-05-05 2014-09-16 Amgen Inc. FGF21 polypeptides comprising two or more mutations and uses thereof
US9144584B2 (en) 2008-06-11 2015-09-29 Cell4Vet Corporation Adipose tissue-derived stem cells for veterinary use
US9273106B2 (en) 2008-06-04 2016-03-01 Amgen Inc. FGF mutants with reduced proteolysis and aggregation
US9279013B2 (en) 2008-10-10 2016-03-08 Amgen Inc. FGF-21 mutants comprising polyethylene glycol and uses thereof
US9284378B2 (en) 2009-12-07 2016-03-15 Shaw-Fen Sylvia Hu Human antigen binding proteins that bind β-Klotho, FGF receptors and complexes thereof
US9493530B2 (en) 2009-05-05 2016-11-15 Amgen Inc. FGF21 mutants comprising a mutation at position 98, 171 and/or 180
US9517264B2 (en) 2010-04-15 2016-12-13 Amgen Inc. Human FGF receptor and β-Klotho binding proteins

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2094833A (en) * 1981-03-13 1982-09-22 Damon Corp Process and system for producing biological materials from encapsulated cells
US4364385A (en) * 1981-03-13 1982-12-21 Lossef Steven V Insulin delivery device
US4407957A (en) * 1981-03-13 1983-10-04 Damon Corporation Reversible microencapsulation of a core material
EP0127713A2 (en) * 1983-06-01 1984-12-12 Connaught Laboratories Limited Microencapsulation of living tissue and cells
EP0274911A1 (en) * 1987-01-12 1988-07-20 Pall Corporation Diagnostic device, method for making, and method for using
EP0290891A1 (en) * 1987-04-29 1988-11-17 Massachusetts Institute Of Technology Controlled drug delivery system for treatment of neural disorders
WO1989012464A1 (en) * 1988-06-14 1989-12-28 Massachusetts Institute Of Technology Controlled release systems containing heparin and growth factors
WO1990005552A1 (en) * 1988-11-18 1990-05-31 Brown University Research Foundation Composite nerve guidance channels

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2094833A (en) * 1981-03-13 1982-09-22 Damon Corp Process and system for producing biological materials from encapsulated cells
US4364385A (en) * 1981-03-13 1982-12-21 Lossef Steven V Insulin delivery device
US4407957A (en) * 1981-03-13 1983-10-04 Damon Corporation Reversible microencapsulation of a core material
EP0127713A2 (en) * 1983-06-01 1984-12-12 Connaught Laboratories Limited Microencapsulation of living tissue and cells
EP0274911A1 (en) * 1987-01-12 1988-07-20 Pall Corporation Diagnostic device, method for making, and method for using
EP0290891A1 (en) * 1987-04-29 1988-11-17 Massachusetts Institute Of Technology Controlled drug delivery system for treatment of neural disorders
WO1989012464A1 (en) * 1988-06-14 1989-12-28 Massachusetts Institute Of Technology Controlled release systems containing heparin and growth factors
WO1990005552A1 (en) * 1988-11-18 1990-05-31 Brown University Research Foundation Composite nerve guidance channels

Cited By (93)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6960351B2 (en) 1991-04-25 2005-11-01 Brown University Research Foundation Implantable biocompatible immunoisolatory vehicle for delivery of selected therapeutic products
US5871767A (en) * 1991-04-25 1999-02-16 Brown University Research Foundation Methods for treatment or prevention of neurodegenerative conditions using immunoisolatory implantable vehicles with a biocompatible jacket and a biocompatible matrix core
US6322804B1 (en) 1991-04-25 2001-11-27 Neurotech S.A. Implantable biocompatible immunoisolatory vehicle for the delivery of selected therapeutic products
US5869077A (en) * 1991-04-25 1999-02-09 Brown University Research Foundation Methods for treating diabetes by delivering insulin from biocompatible cell-containing devices
US5834001A (en) * 1991-04-25 1998-11-10 Brown University Research Foundation Methods for making immunoisolatory implantable vehicles with a biocompatiable jacket and a biocompatible matrix core
US5800829A (en) * 1991-04-25 1998-09-01 Brown University Research Foundation Methods for coextruding immunoisolatory implantable vehicles with a biocompatible jacket and a biocompatible matrix core
US6083523A (en) * 1991-04-25 2000-07-04 Brown University Research Foundation Implantable biocompatable immunoisolatory vehicle for delivery of selected therapeutic products
US5798113A (en) * 1991-04-25 1998-08-25 Brown University Research Foundation Implantable biocompatible immunoisolatory vehicle for delivery of selected therapeutic products
US5874099A (en) * 1991-04-25 1999-02-23 Brown University Research Foundation Methods for making immunoisolatary implantable vehicles with a biocompatible jacket and a biocompatible matrix core
EP0604571A1 (en) * 1991-09-20 1994-07-06 THE GOVERNMENT OF THE UNITED STATES OF AMERICA as represented by the SECRETARY OF THE DEPARTMENT OF HEALTH AND HUMAN SERVICES cDNA ENCODING A DOPAMINE TRANSPORTER AND PROTEIN ENCODED THEREBY
US6015572A (en) * 1991-09-20 2000-01-18 Amgen Inc. Implantable device containing GDNF secreting cells for treating nerve damage and methods of use
US6093802A (en) * 1991-09-20 2000-07-25 Amgen Inc. Glial cell line-derived neurotrophic factor
US5935795A (en) * 1991-09-20 1999-08-10 Amgen Inc. Glial cell line-derived neurotrophic factor antibody
US7226758B1 (en) 1991-09-20 2007-06-05 Amgen Inc. Nucleic acids encoding glial cell line-derived neurotrophic factor (GDNF)
EP0604571A4 (en) * 1991-09-20 1995-04-12 Us Health cDNA ENCODING A DOPAMINE TRANSPORTER AND PROTEIN ENCODED THEREBY.
US6362319B1 (en) 1991-09-20 2002-03-26 Amgen Inc. Glial cell line-derived neurotrophic factor
US6221376B1 (en) 1991-09-20 2001-04-24 Amgen Inc. Glial cell line-derived neurotrophic factor
US7001371B1 (en) 1993-07-02 2006-02-21 Med Usa Porous drug delivery system
US5964745A (en) * 1993-07-02 1999-10-12 Med Usa Implantable system for cell growth control
US7037304B2 (en) 1993-07-02 2006-05-02 Materials Evolution And Development Usa, Inc. Implantable system for cell growth control
US6340360B1 (en) 1993-07-02 2002-01-22 Med Usa System for cell growth
US6426214B1 (en) 1993-08-10 2002-07-30 Gore Enterprise Holdings, Inc. Cell encapsulating device containing a cell displacing core for maintaining cell viability
US5980889A (en) * 1993-08-10 1999-11-09 Gore Hybrid Technologies, Inc. Cell encapsulating device containing a cell displacing core for maintaining cell viability
US5908623A (en) * 1993-08-12 1999-06-01 Cytotherapeutics, Inc. Compositions and methods for the delivery of biologically active molecules using genetically altered cells contained in biocompatible immunoisolatory capsules
US5653975A (en) * 1993-08-12 1997-08-05 Cytotherapeutics, Inc. Compositions and methods for the delivery of biologically active molecules using cells contained in biocompatible capsules
US5676943A (en) * 1993-08-12 1997-10-14 Cytotherapeutics, Inc. Compositions and methods for the delivery of biologically active molecules using genetically altered cells contained in biocompatible immunoisolatory capsules
US5656481A (en) * 1993-08-12 1997-08-12 Cyto Therapeutics, Inc. Compositions and methods for the delivery of biologically active molecules using cells contained in biocompatible capsules
US5639275A (en) * 1993-08-12 1997-06-17 Cytotherapeutics, Inc. Delivery of biologically active molecules using cells contained in biocompatible immunoisolatory capsules
US6264941B1 (en) 1993-08-12 2001-07-24 Neurotech S.A. Compositions for the delivery of biologically active molecules using genetically altered cells contained in biocompatible immunoisolatory capsules
EP1632238A1 (en) * 1994-04-15 2006-03-08 Neurotech S.A. Encapsulated cells adapted for implantation into the aqueous and vitreous humor of the eye
US5902745A (en) * 1995-09-22 1999-05-11 Gore Hybrid Technologies, Inc. Cell encapsulation device
US7611865B2 (en) 1995-09-28 2009-11-03 Amgen Inc. Polynucleotides encoding truncated glial cell line-derived neurotrophic factor
US7390781B2 (en) 1995-09-28 2008-06-24 Amgen Inc. Methods of using truncated glial cell line-derived neurotrophic factor
US5731284A (en) * 1995-09-28 1998-03-24 Amgen Inc. Method for treating Alzheimer's disease using glial line-derived neurotrophic factor (GDNF) protein product
US5641749A (en) * 1995-11-29 1997-06-24 Amgen Inc. Method for treating retinal ganglion cell injury using glial cell line-derived neurothrophic factor (GDNF) protein product
US5641750A (en) * 1995-11-29 1997-06-24 Amgen Inc. Methods for treating photoreceptors using glial cell line-derived neurotrophic factor (GDNF) protein product
US6194176B1 (en) 1996-01-19 2001-02-27 Board Of Regents, The University Of Texas System Recombinant expression of proteins from secretory cell lines
US6110707A (en) * 1996-01-19 2000-08-29 Board Of Regents, The University Of Texas System Recombinant expression of proteins from secretory cell lines
US5837681A (en) * 1996-02-23 1998-11-17 Amgen Inc. Method for treating sensorineural hearing loss using glial cell line-derived neurotrophic factor (GDNF) protein product
US5929041A (en) * 1996-02-23 1999-07-27 Amgen Inc. Method for preventing and treating sensorineural hearing loss and vestibular disorders using glial cell line-derived neurotrophic factor(GDNF) protein product
US6274554B1 (en) 1997-07-30 2001-08-14 Amgen Inc. Method for preventing and treating hearing loss using a neurturin protein product
US6043221A (en) * 1997-07-30 2000-03-28 Amgen Inc. Method for preventing and treating hearing loss using a neuturin protein product
US6322962B1 (en) 1998-08-14 2001-11-27 Board Of Regents, The University Of Texas System Sterol-regulated Site-1 protease and assays of modulators thereof
US7807641B2 (en) 1999-02-10 2010-10-05 Curis, Inc. Methods and reagents for treating glucose metabolic disorders
WO2000047219A2 (en) 1999-02-10 2000-08-17 Ontogeny, Inc. Methods and reagents for treating glucose metabolic disorders
US7745216B2 (en) 1999-02-10 2010-06-29 Curis, Inc. Methods and reagents for treating glucose metabolic disorders
US7396809B1 (en) 1999-02-10 2008-07-08 Curis, Inc. Methods and reagents for treating glucose metabolic disorders
US7579180B2 (en) 1999-03-26 2009-08-25 Amgen Inc. Beta secretase polypeptides
US7582465B2 (en) 1999-03-26 2009-09-01 Amgen Inc. Beta secretase genes
EP2258722A2 (en) 1999-09-07 2010-12-08 Amgen, Inc Antibodies to fibroblast growth factor-like (FGF-like) polypeptides
US7887799B2 (en) 1999-09-07 2011-02-15 Amgen Inc. Antibodies to fibroblast growth factor-like polypeptides
US7459540B1 (en) 1999-09-07 2008-12-02 Amgen Inc. Fibroblast growth factor-like polypeptides
US7408047B1 (en) 1999-09-07 2008-08-05 Amgen Inc. Fibroblast growth factor-like polypeptides
US8053408B2 (en) 1999-09-07 2011-11-08 Amgen Inc. Methods for treating obesity using fibroblast growth factor-like polypeptides
US8044024B2 (en) 1999-09-07 2011-10-25 Amgen Inc. Identifying modulators of fibroblast growth factor-like polypeptides
US8030275B2 (en) 1999-09-07 2011-10-04 Amgen Inc. Methods for treating obesity using fibroblast growth factor-like polypeptides
US7667008B2 (en) 1999-09-07 2010-02-23 Amgen, Inc. Fibroblast growth factor-like polypeptides and variants thereof
EP2284189A2 (en) 1999-09-07 2011-02-16 Amgen, Inc Nucleic acid molecules encoding fibroblast growth factor-like (FGF-like) polypeptides
US7695938B2 (en) 1999-09-07 2010-04-13 Amgen Inc. Vectors and recombinant host cells comprising nucleic acid molecules encoding Fibroblast Growth Factor-like polypeptides
US7696172B2 (en) 1999-09-07 2010-04-13 Amgen Inc. Fibroblast growth factor-like polypeptides
US7700558B2 (en) 1999-09-07 2010-04-20 Amgen Inc. Methods for treating diabetes using fibroblast growth factor-like polypeptides
US7704952B2 (en) 1999-09-07 2010-04-27 Amgen Inc. Methods for treating diabetes using fibroblast growth factor-like polypeptides
US7671180B2 (en) 1999-09-07 2010-03-02 Amgen, Inc. Fibroblast growth factor-like polypeptides and variants thereof
EP2189475A2 (en) 1999-09-07 2010-05-26 Amgen Inc. Fibroblast growth factor-like polypeptides
US7727742B2 (en) 1999-09-07 2010-06-01 Amgen Inc. Nucleic acid molecules encoding fibroblast growth factor-like polypeptides
US7879323B2 (en) 1999-09-07 2011-02-01 Amgen Inc. Antibodies to fibroblast growth factor-like polypeptides
EP2077279A1 (en) 2000-06-28 2009-07-08 Amgen Inc. Thymic stromal lymphopoietin receptor molecules and uses thereof
US8273713B2 (en) 2000-12-14 2012-09-25 Amylin Pharmaceuticals, Llc Methods of treating obesity using PYY[3-36]
US7662924B2 (en) 2002-02-22 2010-02-16 The Board Of Trustees Of The University Of Illinois Beta chain-associated regulator of apoptosis
WO2005014022A1 (en) 2003-07-16 2005-02-17 Develogen Aktiengesellschaft Use of pleitrophin for preventing and treating pancreatic diseases and/or obesity and/or metabolic syndrome
US8426361B2 (en) 2004-02-11 2013-04-23 Amylin Pharmaceuticals, Llc Pancreatic polypeptide family motifs, polypeptides and methods comprising the same
US7723471B2 (en) 2004-02-11 2010-05-25 Amylin Pharmaceuticals, Inc. Pancreatic polypeptide family motifs, polypeptides and methods comprising the same
US8906849B2 (en) 2004-02-11 2014-12-09 Amylin Pharmaceuticals, Llc Pancreatic polypeptide family motifs, polypeptides and methods comprising the same
US8603969B2 (en) 2004-02-11 2013-12-10 Amylin Pharmaceuticals, Llc Pancreatic polypeptide family motifs and polypeptides comprising the same
US8119398B2 (en) 2004-12-30 2012-02-21 Primegen Biotech Llc Adipose-derived stem cells for tissue regeneration and wound healing
EP2460875A1 (en) 2005-03-31 2012-06-06 Stemnion, Inc. Amnion-derived cell compositions, methods of making and uses thereof
WO2006117212A2 (en) 2005-05-04 2006-11-09 Develogen Aktiengesellschaft Use of gsk-3 inhibitors for preventing and treating pancreatic autoimmune disorders
WO2007068803A1 (en) 2005-12-14 2007-06-21 Licentia Ltd Novel neurotrophic factor protein and uses thereof
WO2008088738A2 (en) 2007-01-17 2008-07-24 Stemnion, Inc. Novel methods for modulating inflammatory and/or immune responses
EP2551281A1 (en) 2007-10-25 2013-01-30 Nevalaita, Lina Splice variants of GDNF and uses thereof
WO2009133247A1 (en) 2008-04-30 2009-11-05 Licentia Oy Neurotrophic factor manf and uses thereof
US9273106B2 (en) 2008-06-04 2016-03-01 Amgen Inc. FGF mutants with reduced proteolysis and aggregation
US9144584B2 (en) 2008-06-11 2015-09-29 Cell4Vet Corporation Adipose tissue-derived stem cells for veterinary use
US9757421B2 (en) 2008-06-11 2017-09-12 Cell4Vet Corporation Adipose tissue-derived stem cells for veterinary use
US9279013B2 (en) 2008-10-10 2016-03-08 Amgen Inc. FGF-21 mutants comprising polyethylene glycol and uses thereof
US8835385B2 (en) 2009-05-05 2014-09-16 Amgen Inc. FGF21 polypeptides comprising two or more mutations and uses thereof
US9493530B2 (en) 2009-05-05 2016-11-15 Amgen Inc. FGF21 mutants comprising a mutation at position 98, 171 and/or 180
US9284378B2 (en) 2009-12-07 2016-03-15 Shaw-Fen Sylvia Hu Human antigen binding proteins that bind β-Klotho, FGF receptors and complexes thereof
US9493577B2 (en) 2009-12-07 2016-11-15 Amgen Inc. Human antigen binding proteins that bind β-klotho, FGF receptors and complexes thereof
US9517264B2 (en) 2010-04-15 2016-12-13 Amgen Inc. Human FGF receptor and β-Klotho binding proteins
WO2012145384A1 (en) 2011-04-20 2012-10-26 University Of Washington Through Its Center For Commercialization Beta-2 microglobulin-deficient cells
WO2013106547A1 (en) 2012-01-10 2013-07-18 President And Fellows Of Harvard College Beta-cell replication promoting compounds and methods of their use
WO2013158292A1 (en) 2012-04-17 2013-10-24 University Of Washington Through Its Center For Commercialization Hla class ii deficient cells, hla class i deficient cells capable of expressing hla class ii proteins, and uses thereof

Similar Documents

Publication Publication Date Title
US3596292A (en) Hair implant structure
US5158881A (en) Method and system for encapsulating cells in a tubular extrudate in separate cell compartments
Campochiaro et al. Vitreous aspirates from patients with proliferative vitreoretinopathy stimulate retinal pigment epithelial cell migration
US5190763A (en) Dosage form indicated for the management of abnormal posture, tremor and involuntary movement
US5545223A (en) Ported tissue implant systems and methods of using same
US6314317B1 (en) Electroactive pore
US6319905B1 (en) Method of controlling L-Dopa production and of treating dopamine deficiency
US7374774B2 (en) Electroprocessed material made by simultaneously electroprocessing a natural protein polymer and two synthetic polymers
US5993848A (en) Dissolution liquid for drug in iontophoresis
US6549811B2 (en) Medical electrical lead having controlled texture surface and method of making same
US4450150A (en) Biodegradable, implantable drug delivery depots, and method for preparing and using the same
Hu et al. Survival and neural differentiation of adult neural stem cells transplanted into the mature inner ear
Menei et al. Intracerebral implantation of NGF-releasing biodegradable microspheres protects striatum against excitotoxic damage
US6497729B1 (en) Implant coating for control of tissue/implant interactions
Luo et al. Controlled DNA delivery systems
Zhang et al. Tissue-engineering approaches for axonal guidance
US5385582A (en) Spinal fluid driven artificial organ
US5092871A (en) Electrically-charged nerve guidance channels
US6126936A (en) Microcapsules and composite microreactors for immunoisolation of cells
US20060009805A1 (en) Neural stimulation device employing renewable chemical stimulation
US5614205A (en) Bioartificial endocrine device
US5283187A (en) Cell culture-containing tubular capsule produced by co-extrusion
US20080312610A1 (en) Microarray Device
US20020123678A1 (en) Device for enhanced delivery of biologically active substances and compounds in an organism
Colton Implantable biohybrid artificial organs

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA FI JP KR NO

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LU NL SE

NENP Non-entry into the national phase in:

Ref country code: CA