University of California

University of Michigan

The United States Government As Represented by the Department of Veterans Affairs

California Institute of Technology

Michigan State University

The United States of America As Represented by the Department of Veterans Affair

Mark Henry Tuszynski

Jeffrey S Sakamoto

Yacov M Koffler

Wendy Campana

Dena Shahriari

Michael J Sailor

Fred Harrison Gage

Jeff S Sakamoto

Jonathan Zuidema

Kendell M Pawelec

Jean-Pierre Fleurial

Shaochen Chen

David James Welker

Wei Zhu

Adam Kisor

James R Weiss

Todd Edward Holt

Christopher David Breckon

Shula Stokols

Paul Lu

Armin Blesch

Thomas Gros

Rav Grill

Christina Chan

Hiromi Kumamaru

Yacov Koffler

Sumit Mehrotra

Tissue scaffolds for neural tissue growth have a plurality of microchannels disposed within a sheath. Each microchannel comprises a porous wall having a thickness of ≤about 100 μm that is formed from a biocompatible and biodegradable material comprising a polyester polymer. The polyester polymer may be polycaprolactone, poly(lactic-co-glycolic acid) polymer, and combinations thereof. The tissue scaffolds have high open volume % enabling superior (linear and high fidelity) neural tissue growth, while minimizing inflammation near the site of implantation in vivo. In other aspects, methods of making such tissue scaffolds are provided. Such a method may include mixing a reduced particle size porogen with a polymeric precursor solution. The material is cast onto a template and then can be processed, including assembly in a sheath and removal of the porogen, to form a tissue scaffold having a plurality of porous microchannels.

Nerve repair scaffolds having high microchannel volume and methods for making the same

Implantable devices for spinal cord and peripheral nerve injury are described. The implants include a three-dimensional printed structure having stem cells disposed therein. Also disclosed are methods of treating neuronal injuries with the disclosed implants.

Biomimetic implants

Provided herein is technology relating to materials having microscale and/or nanoscale features and particularly, but not exclusively, to porous materials comprising microscale features, methods for producing porous materials comprising microscale features, drug delivery vehicles, and related kits, systems, and uses.

Porous material with microscale features

Spinal cord neural stem cells (NSCs) have great potential to reconstitute damaged spinal neural circuitry. In some embodiments, derivation of spinal cord NSCs from human pluripotent stem cells (hPSCs) is described. These spinal cord NSCs can differentiate into a diverse population of spinal cord neurons comprising multiple positions in the dorso-ventral axis, and can be maintained for prolonged time periods. After grafting into injured spinal cords, grafts may be rich with excitatory neurons, extend large numbers of axons over long distances, innervate their target structures, and enable robust corticospinal regeneration. In some embodiments, hPSC-derived spinal cord NSCs enable a broad range of biomedical applications for in vitro disease modeling, and can provide a clinically-translatable cell source for spinal cord 'replacement' strategies in several spinal cord disorders.

Generation of human spinal cord neural stem cells

Tissue scaffolds for neural tissue growth have a plurality of microchannels disposed within a sheath. Each microchannel comprises a porous wall having a thickness of &#x2264;about 100 &#x3bc;m that is formed from a biocompatible and biodegradable material comprising a polyester polymer. The polyester polymer may be polycaprolactone, poly(lactic-co-glycolic acid) polymer, and combinations thereof. The tissue scaffolds have high open volume % enabling superior (linear and high fidelity) neural tissue growth, while minimizing inflammation near the site of implantation in vivo. In other aspects, methods of making such tissue scaffolds are provided. Such a method may include mixing a reduced particle size porogen with a polymeric precursor solution. The material is cast onto a template and then can be processed, including assembly in a sheath and removal of the porogen, to form a tissue scaffold having a plurality of porous microchannels.

Methods for inducing non-embryonic lesioned central nervous system neurons to survive, integrate, extend axons over long distances, induce intra-lesion ingrowth of neurons into the lesion from host tissue and form synapses in vivo. Pluripotent neural stem cells are grafted into the lesioned CNS tissue within a tissue adhesive suspension, optionally in the presence of growth factors. No modification of the neuronal regenerative inhibitory environment of the CNS is necessary.

Methods for use of neural stem cell compositions for treatment of central nervous system lesions

A specific clinical protocol for use toward therapy of defective, diseased and damaged neurons in the mammalian brain by delivering a definite concentration of recombinant neurotrophin, into a targeted region of the brain using a lentiviral expression vector. The neurotrophin is delivered to, or within close proximity of, identified defective, diseased or damaged brain cells. Growth of targeted neurons, and reversal of functional deficits associated with the neurodegenerative disease being treated is provided.

Methods for therapy of neurodegenerative disease of the brain

A specific clinical protocol for use toward therapy of defective, diseased and damaged cholinergic neurons in the mammalian brain, of particular usefulness for treatment of neurodegenerative conditions such as Alzheimer's disease. The protocol is practiced by delivering a definite concentration of recombinant neurotrophin into, or within close proximity of, identified defective, diseased or damaged brain cells. Using a viral vector, the concentration of neurotrophin delivered as part of a neurotrophic composition varies from 10to 10neurotrophin encoding viral particles/ml of composition fluid. Each delivery site receives form 2.5 &#x3bc;l to 25 &#x3bc;l of neurotrophic composition delivered slowly, as in over a period of time ranging upward of 10 minutes/delivery site. Each delivery site is at, or within 500 &#x3bc;m of, a targeted cell, and no more than about 10 mm from another delivery site. Stable in situ neurotrophin expression can be achieved for 12 months, or longer.

Millimeter to nano-scale structures manufactured using a multi-component polymer fiber matrix are disclosed. The use of dissimilar polymers allows the selective dissolution of the polymers at various stages of the manufacturing process. In one application, biocompatible matrixes may be formed with long pore length and small pore size. The manufacturing process begins with a first polymer fiber arranged in a matrix formed by a second polymer fiber. End caps may be attached to provide structural support and the polymer fiber matrix selectively dissolved away leaving only the long polymer fibers. These may be exposed to another product, such as a biocompatible gel to form a biocompatible matrix. The polymer fibers may then be selectively dissolved leaving only a biocompatible gel scaffold with the pores formed by the dissolved polymer fibers. The scaffolds may be used in, among other applications, the repair of central and peripheral nerves. Scaffolds for the repair of peripheral nerves may include a reservoir for the sustained release of nerve growth factor. The scaffolds may also include a multifunctional polyelectrolyte layer for the sustained release of nerve growth factor and enhance biocompatibility.

High aspect ratio template and method for producing same for central and peripheral nerve repair

Millimeter to nano-scale structures manufactured using a multi-component polymer fiber matrix are disclosed. The use of dissimilar polymers allows the selective dissolution of the polymers at various stages of the manufacturing process. In one application, biocompatible matrixes may be formed with long pore length and small pore size. The manufacturing process begins with a first polymer fiber arranged in a matrix formed by a second polymer fiber. End caps may be attached to provide structural support and the polymer fiber matrix selectively dissolved away leaving only the long polymer fibers. These may be exposed to another product, such as a biocompatible gel to form a biocompatible matrix. The polymer fibers may then be selectively dissolved leaving only a biocompatible gel scaffold with the pores formed by the dissolved polymer fibers.

High aspect ratio template and method for producing same

A protocol for use of growth factors to stimulate neuronal cell growth and activity in trkB receptor containing cortical tissues, including the entorhinal and hippocampal cortices. The method introduces exogenous growth factor, such as BDNF, NT-4/5 and NT-3, into the EC. The method is useful in therapy of defective, diseased and damaged neurons in the mammalian brain, of particular usefulness for treatment of neurodegenerative conditions such as Alzheimer's disease or for normal aging.

Methods for therapeutic use of brain derived neurotrophic factor in the entorhinal cortex

A specific clinical protocol for use toward therapy of defective, diseased and damaged cholinergic neurons in the mammalian brain, of particular usefulness for treatment of neurodegenerative conditions such as Alzheimer's disease. The protocol is practiced by delivering a definite concentration of recombinant neurotrophin into, or within close proximity of, identified defective, diseased or damaged brain cells. Using a viral vector, the concentration of neurotrophin delivered as part of a neurotrophic composition varies from 10to 10neurotrophin encoding viral particles/ml of composition fluid. Each delivery site receives from 2.5 &#x3bc;l to 25 &#x3bc;l of neurotrophic composition, delivered slowly, as in over a period of time ranging upwards of 10 minutes/delivery site. Each delivery site is at, or within 500 &#x3bc;m of, a targeted cell, and no more than about 10 mm from another delivery site. Stable in situ neurotrophin expression can be achieved for 12 months, or longer.

The invention provides a clinically useful protocol for delivery of recombinant nervous system growth factors into the aging mammalian brain. The invention is particularly useful in tempering and reversing the loss of neurological function in the aging mammalian brain, by (a) correlating loss of cortical fiber density to impairment of neurological function in the normal, aging brain; and (b) providing minimally invasive means by which such losses may be reversed. To these ends, a method is provided by which a growth factor-encoding transgene is delivered to, and expressed in, preselected sites within the brain, to stimulate growth of neurons at, and at a distance from, each delivery site.

Growing community of inventors

La Jolla, CA, United States of America

Mark Henry Tuszynski