Brown University

Cytotherapeutics, Inc.

Neurotech S.a.

Boston University

Ecole Polytechnique Federale De Lausanne

Pfizer Hospital Products Group, Inc.

Patrick Aebischer

Frank T Gentile

Paul R Sanberg

Shelley R Winn

Dwaine F Emerich

Keith E Dionne

Edward J Doherty

Michael J Lysaght

Orion D Hegre

Alfred V Vasconcellos

Paul E Lacy

Diane Hoffman

Lisa Christenson

Joseph P Hammang

David W Scharp

Molly S Shoichet

Brian M Cain

Laura M Holland

Malcolm Schinstine

Lars Wahlberg

Patrick A Tresco

Pierre M Galletti

Robert F Valentini

Paul J Mulhauser

Moses Goddard

Nicholas F Warner

Ravi Bellamkonda

John F Mills

Anne M Rathbun

John G Moldauer

John P Ranieri

Beth A Zielinski

Paul C DiCesare

Paolo Dario

Luigi Miracoli

Anastassios N Salessiotis

Angelo Sabatini

Jeffrey H Kordower

David W Sharp

Alfred V Vasooncellos

Alfred V Vasoohcellos

Olivier Jordan

Jean-Francois Clemence

George Panol

An immunoisolatory vehicle for the implantation into an individual of cells which produce a needed product or provide a needed metabolic function. The vehicle is comprised of a core region containing isolated cells and materials sufficient to maintain the cells, and a permselective, biocompatible, peripheral region free of the isolated cells, which immunoisolates the core yet provides for the delivery of the secreted product or metabolic function to the individual. The vehicle is particularly well-suited to delivery of insulin from immunoisolated islets of Langerhans, and can also be used advantageously for delivery of high molecular weight products, such as products larger than IgG. A method of making a biocompatible, immunoisolatory implantable vehicle, consisting in a first embodiment of a coextrusion process, and in a second embodiment of a stepwise process. A method for isolating cells within a biocompatible, immunoisolatory implantable vehicle, which protects the isolated cells from attack by the immune system of an individual in whom the vehicle is implanted. A method of providing a needed biological product or metabolic function to an individual, comprising implanting into the individual an immunoisolatory vehicle containing isolated cells which produce the product or provide the metabolic function.

Implantable biocompatible immunoisolatory vehicle for delivery of selected therapeutic products

An immunoisolatory vehicle for the implantation into an individual of cells which produce a needed product or provide a needed metabolic function. The vehicle is comprised of a core region containing isolated cells and materials sufficient to maintain the cells, and a permselective, biocompatible, peripheral region free of the isolated cells, which immunoisolates the core yet provides for the delivery of the secreted product or metabolic function to the individual.

Implantable biocompatible immunoisolatory vehicle for the delivery of selected therapeutic products

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 (,), in a patient. A cannula (,), having an obturator (,) or dilator (,) 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 (,) previously positioned at the treatment site. The cannula (,) is preferably a low friction polymeric material such as polytetrafluoroethylene. The cannula (,) generally has an open proximal end for receiving the obturator (,) or dilator (,), and an open distal end, preferably a tapered end, for delivery of neurologically active factors to the treatment site (,). The obturator (,) is then removed from the cannula (,), and a biocompatible tethered vehicle (,) containing a biologically active material is inserted into the cannula along the passageway. A pusher can be inserted within the cannula, behind the vehicle (,), to position the proximal end of the vehicle at the proximal tip of the cannula (,). Once the vehicle (,) is positioned near the proximal end of the cannula (,), the cannula is removed from the passageway, followed by the pusher, leaving the vehicle (,) positioned at the treatment site (,).

Implantable therapy systems and methods

A bioartificial extracellular matrix for use in tissue regeneration or replacement is provided by derivatizing a three-dimensional hydrogel matrix with a cell adhesive extracellular matrix protein or cell adhesive peptide fragment of the protein. Preferably, derivatizing is by covalent immobilization of a cell adhesive peptide fragment having the amino acid sequence, ArgGlyAsp, TyrIleGlySerArg or IleLysValAlaVal. Cartilage or tendon can be regenerated by implanting a matrix containing an adhesive peptide fragment that favors chondrocyte invasion. The matrix can be pre-seeded with cells, and tissue can be reconstituted in vitro and then implanted. A cell-seeded matrix can be encapsulated in a semi-permeable membrane to form a bioartificial organ. An agarose hydrogel matrix having an agarose concentration of 0.5-1.25% (w/v) and an average pore radius between 120 nm and 290 nm is preferred. A nerve guidance channel for use in regenerating severed nerve is prepared containing a tubular semi-permeable membrane having openings adapted to receive ends of a severed nerve, and an inner lumen containing the hydrogel matrix having a bound cell adhesive peptide fragment through which the nerve can regenerate.

Bioartificial extracellular matrix containing hydrogel matrix

Encapsulated viable cells for implanting are prepared having cells dispersed in a particulate, essentially non cross-linked chitosan core matrix that is enclosed within a semipermeable membrane. The cells are entrapped between chitosan particles of the core matrix and there is essentially no interfacial cross-linking between the core matrix and the membrane. The core matrix provides a physical support for the cells such that the cells are evenly dispersed throughout the core matrix so as to allow their maintenance, growth, proliferation and differentiation. The encapsulated cells may be prepared by mixing viable cells with a solution of chitosan, encapsulating the resultant mixture in a thermoplastic semipermeable membrane, and causing the chitosan to precipitate such as by changing the pH to form the core matrix. Alternatively, the chitosan in solution is precipitated to form the core matrix containing cells, and the core matrix is encapsulated in a semipermeable membrane. Cells encapsulated include neurosecretory cell lines, .beta.-cell-derived cells lines, fibroblasts, myocytes and glial cells.

Chitosan core matrix containing cells encapsulated in a thermoplastic

Implantable biocompatable immunoisolatory vehicle for delivery of

A method of producing a microencapsulated pharmaceutical formulation is disclosed comprising causing a dye to be attached to the surface of pharmaceutical particles or particle clusters and applying a source of radiant energy to the dye in the presence of a liquid polymeric or polymerisable material so as to cause the material to cross-link, producing a conformal layer of cross-linked polymer on the particulate surfaces. Preferably, the polymer provides an immuno-protective layer around the particles, while allowing therapeutic components to exit the microcapsules. Microencapsulated pharmaceutical formulations and their medical use are also disclosed, especially for the treatment of diabetes by encapsulating insulin secreting cells.

Pharmaceutical microencapsulation

Methods and devices are provided for gene therapy using encapsulated packaging cell lines to deliver viral particles carrying at least one heterologous gene encoding at least one biologically active molecule.

Device and method for encapsulated gene therapy

This invention relates to methods and compositions of controlling cell distribution within a bioartificial organ by exposing the cells to a treatment that inhibits cell proliferation, promotes cell differentiation, or affects cell attachment to a growth surface within the bioartificial organ. Such treatments include (1) genetically manipulating cells, (2) exposing the cells to a proliferation-inhibiting compound or a differentiation-inducing compound or removing the cells from exposure to a proliferation-stimulating compound or a differentiation-inhibiting compound; exposing the cells to irradiation, and (3) modifying a growth surface of the BAO with ECM molecules, molecules affecting cell proliferation or adhesion, or an inert scaffold, or a combination thereof. These treatments may be used in combination.

Methods and compositions of growth control for cells encapsulated within

A method of forming an implantable and retrievable immunoisolatory vehicles is disclosed, the method comprising the steps of first forming a core comprising a volume of at least 1 .mu.l and at least 10.sup.4 cells capable of providing a biologically active product or metabolic or immunologic function, said cells being dispersed in a biocompatible hydrogel or extracellular matrix, and then forming around the core a surrounding external biocompatible thermoplastic or hydrogel jacket free of said cells projecting externally thereof, said jacket having molecular weight cutoff permitting passage of molecules to and from the core through said jacket to provide said biologically active product or function.

Methods for making immunoisolatary implantable vehicles with a

A method for treatment of a neurodegenerative condition in a patient comprising implanting in the patient at least one immunoisolatory vehicle comprising a corc comprising a volume of at least 1 .mu.l and at least 10.sup.4 living cells which secrete at least one biologically active product, said cells being dispersed in a biocompatible matrix comprising a hydrogel or extracellular matrix components, and an external jacket surrounding the core, the jacket comprising a biocompatible hydrogel or thermoplastic, the jacket being free of cells projecting externally thereof, said jacket having a molecular weight cutoff permitting the passage of the biologically active product from the core through the jacket.

Methods for treatment or prevention of neurodegenerative conditions

Vehicles containing cells for implanting in the tissue of an individual are prepared having cells dispersed in a particulate, essentially non cross-linked chitosan core matrix that is enclosed within a semipermeable membrane. The cells are entrapped between chitosan particles of the core matrix and there is essentially no interfacial cross-linking between the core matrix and the membrane. The core matrix provides a physical support for viable cells within the vehicle such that the cells are evenly dispersed throughout the core matrix so as to allow their maintenance, growth, proliferation and differentiation. The vehicle can be prepared by mixing viable cells with a solution of chitosan, encapsulating the resultant mixture in a semipermeable membrane and causing the chitosan to precipitate such as by changing the pH to form the core matrix. Alternatively, the chitosan is precipitated to form the core matrix containing cells and then the core matrix is encapsulated in a semipermeable membrane. Cells within the core matrix may be neurosecretory cell lines, .beta.-cell-derived cells lines, fibroblasts, myocytes and glial cells.

Particulate non cross-linked chitosan core matrices for encapsulated

Methods are disclosed for the alleviation of movement disorders via the implantation of static devices which focally release neuroinhibitory compounds to preselected brain areas. Pathological conditions to be treated by these methods include parkinsonian movement disorders, Huntington's chorea, and epileptiform seizure activity. In the treatment of parkinsonism, target areas implantation include the subthalamic nucleus, the globus pallidus internus, and the substantia nigra pars reticulata. In the treatment of epilepsy, implants may be placed in an epileptogenic focus area of neural over-activity. The devices may be polymeric implants that release neuroinhibitory compounds such as GABA, GABA agonists, GABA potentiators, action potential blockers and voltage dependent calcium channel blockers, and glutamate antagonists. Alternatively, the devices may contain living cells which secrete neuroinhibitory compounds.

Planting devices for the focal release of neuroinhibitory compounds

A method for treating diabetes in a patient comprising subcutaneously implanting in the patient at least one immunoisolatory vehicle comprising a core comprising a volume of at least 1 .mu.l and at least about 10.sup.4 living cells which secrete insulin, said cells being dispersed in a biocompatible matrix comprising a hydrogel or extracellular matrix components, and a surrounding external jacket of a biocompatible thermoplastic or hydrogel free of said cells projecting externally thereof, said jacket being permselective and immunoisolatory, said jacket having a molecular weight cutoff permitting passage of molecules between the patient and core through said jacket wherein the insulin is released from the immunoisolatory vehicle into the patient's body to treat diabetes.

Methods for treating diabetes by delivering insulin from biocompatible

Methods and compositions are provided for controlling cell distribution within an implantable bioartificial organ by exposing the cells to a treatment that inhibits cell proliferation, promotes cell differentiation, or affects cell attachment to a growth surface within the bioartificial organ. Such treatments include (1) genetically manipulating cells, (2) exposing the cells to a proliferation-inhibiting compound or a differentiation-inducing compound or removing the cells from exposure to a proliferation-stimulating compound or a differentiation-inhibiting compound; exposing the cells to irradiation, and (3) modifying a growth surface of the bioartificial organ with extracellular matrix molecules, molecules affecting cell proliferation or adhesion, or an inert scaffold, or a combination thereof. These treatments may be used in combination. The bioartificial organ typically has a semipermeable membrane encapsulating a cell-containing core, and is preferably immunoisolatory. Cells can be grown on microcarriers and then loaded into the bioartificial organ. The microcarriers may be coated with an extracellular matrix component such as collagen to cause decreased cell proliferation or increased cell differentiation. Microcarriers containing cells can be suspended in a proliferation inhibiting hydrogel matrix prior to encapsulation.

Control of cell growth in a bioartificial organ with extracellular

Growing community of inventors

Lutry, Switzerland

Patrick Aebischer