Nerve Wrap for Local Delivery of FK506/Tacrolimus Accelerates Nerve Regeneration.

Peripheral nerve injuries (PNIs) occur frequently and can lead to devastating and permanent sensory and motor function disabilities. Systemic tacrolimus (FK506) administration has been shown to hasten recovery and improve functional outcomes after PNI repair. Unfortunately, high systemic levels of FK506 can result in adverse side effects.

Author Correction: Matrix-bound nanovesicles prevent ischemia-induced retinal ganglion cell axon degeneration and death and preserve visual function.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Matrix-bound nanovesicles prevent ischemia-induced retinal ganglion cell axon degeneration and death and preserve visual function.

Injury to retinal ganglion cells (RGC), central nervous system neurons that relay visual information to the brain, often leads to RGC axon degeneration and permanently lost visual function. Herein this study shows matrix-bound nanovesicles (MBV), a distinct class of extracellular nanovesicle localized specifically to the extracellular matrix (ECM) of healthy tissues, can neuroprotect RGCs and preserve visual function after severe, intraocular pressure (IOP) induced ischemia in rat. Intravitreal MBV injections attenuated IOP-induced RGC axon degeneration and death, protected RGC axon connectivity to visual nuclei in the brain, and prevented loss in retinal function as shown by histology, anterograde axon tracing, manganese-enhanced magnetic resonance imaging, and electroretinography.

Fetal extracellular matrix nerve wraps locally improve peripheral nerve remodeling after complete transection and direct repair in rat.

In peripheral nerve (PN) injuries requiring surgical repair, as in PN transection, cellular and ECM remodeling at PN epineurial repair sites is hypothesized to reduce PN functional outcomes by slowing, misdirecting, or preventing axons from regrowing appropriately across the repair site. Herein this study reports on deriving and analyzing fetal porcine urinary bladder extracellular matrix (fUB-ECM) by vacuum assisted decellularization, fabricating fUBM-ECM nerve wraps, and testing fUB-ECM nerve wrap biocompatibility and bioactivity in a trigeminal, infraorbital nerve (ION) branch transection and direct end-to-end repair model in rat. FUB-ECM nerve wraps significantly improved epi- and endoneurial organization and increased both neovascularization and growth associated protein-43 (GAP-43) expression at PN repair sites, 28-days post surgery.

Extracellular Vesicles: Biomarkers, Therapeutics, and Vehicles in the Visual System.

Purpose: We discuss recent advances in extracellular vesicle (EV) technology as biomarkers, therapeutics, and drug delivery vehicles in the visual system with an emphasis on the retina.

Recent Findings: Retinal cell-type specific EVs can be detected in the blood and in the aqueous humor and EV miRNA cargoes can be used diagnostically to predict retinal disease progression. Studies have now shown EVs can deliver bioactive miRNA and AAV cargoes to the inner retinal cell layers and, in some models, improve retinal ganglion cell (RGC) survival and axon regeneration.

Correction to: Extracellular Vesicles: Biomarkers, Therapeutics, and Vehicles in the Visual System.

[This corrects the article DOI: 10.1007/s40135-017-0153-0.].

An Elastomeric Polymer Matrix, PEUU-Tac, Delivers Bioactive Tacrolimus Transdurally to the CNS in Rat.

Central nervous system (CNS) neurons fail to regrow injured axons, often resulting in permanently lost neurologic function. Tacrolimus is an FDA-approved immunosuppressive drug with known neuroprotective and neuroregenerative properties in the CNS. However, tacrolimus is typically administered systemically and blood levels required to effectively treat CNS injuries can lead to lethal, off-target organ toxicity.

Urinary bladder extracellular matrix hydrogels and matrix-bound vesicles differentially regulate central nervous system neuron viability and axon growth and branching.

Central nervous system neurons often degenerate after trauma due to the inflammatory innate immune response to injury, which can lead to neuronal cell death, scarring, and permanently lost neurologic function. Extracellular matrix bioscaffolds, derived by decellularizing healthy tissues, have been widely used in both preclinical and clinical studies to promote positive tissue remodeling, including neurogenesis, in numerous tissues, with extracellular matrix from homologous tissues often inducing more positive responses. Extracellular matrix hydrogels are liquid at room temperature and enable minimally invasive extracellular matrix injections into central nervous system tissues, before gelation at 37℃.

Developing Extracellular Matrix Technology to Treat Retinal or Optic Nerve Injury(1,2,3).

Adult mammalian CNS neurons often degenerate after injury, leading to lost neurologic functions. In the visual system, retinal or optic nerve injury often leads to retinal ganglion cell axon degeneration and irreversible vision loss. CNS axon degeneration is increasingly linked to the innate immune response to injury, which leads to tissue-destructive inflammation and scarring.

Promoting filopodial elongation in neurons by membrane-bound magnetic nanoparticles.

Filopodia are 5-10 μm long processes that elongate by actin polymerization, and promote axon growth and guidance by exerting mechanical tension and by molecular signaling. Although axons elongate in response to mechanical tension, the structural and functional effects of tension specifically applied to growth cone filopodia are unknown. Here we developed a strategy to apply tension specifically to retinal ganglion cell (RGC) growth cone filopodia through surface-functionalized, membrane-targeted superparamagnetic iron oxide nanoparticles (SPIONs).

Regulation of intrinsic axon growth ability at retinal ganglion cell growth cones.

Purpose: Mammalian central nervous system neurons fail to regenerate after injury or disease, in part due to a progressive loss in intrinsic axon growth ability after birth. Whether lost axon growth ability is due to limited growth resources or to changes in the axonal growth cone is unknown.

Methods: Static and time-lapse images of purified retinal ganglion cells (RGCs) were analyzed for axon growth rate and growth cone morphology and dynamics without treatment and after manipulating Kruppel-like transcription factor (KLF) expression or applying mechanical tension.

Mitochondrial Dynamics in Retinal Ganglion Cell Axon Regeneration and Growth Cone Guidance.

Failed axon regeneration and retinal ganglion cell (RGC) death after trauma or disease, including glaucomatous and mitochondrial optic neuropathies, are increasingly linked to mitochondrial dysfunction. Mitochondria are highly dynamic organelles whose size, organization, and function are regulated by a balance between mitochondrial fission and fusion. Mitochondria are ubiquitous in axonal growth cones both in vitro and in vivo and during development and regeneration.

Signaling endosomes and growth cone motility in axon regeneration.

During development and regeneration, growth cones guide neurites to their targets by altering their motility in response to extracellular guidance cues. One class of cues critical to nervous system development is the neurotrophins. Neurotrophin binding to their cognate receptors stimulates their endocytosis into signaling endosomes.

Mitochondrial dynamics regulate growth cone motility, guidance, and neurite growth rate in perinatal retinal ganglion cells in vitro.

Purpose: Retinal ganglion cell (RGC) death and failed axonal regeneration after trauma or disease, including glaucomatous and mitochondrial optic neuropathies, are linked increasingly to dysfunctional mitochondrial dynamics. However, how mitochondrial dynamics influence axon growth largely is unstudied. We examined intrinsic mitochondrial organization in embryonic and postnatal RGCs and the roles that mitochondrial dynamics have in regulating neurite growth and guidance.

Nanoparticle-mediated signaling endosome localization regulates growth cone motility and neurite growth.

Understanding neurite growth regulation remains a seminal problem in neurobiology. During development and regeneration, neurite growth is modulated by neurotrophin-activated signaling endosomes that transmit regulatory signals between soma and growth cones. After injury, delivering neurotrophic therapeutics to injured neurons is limited by our understanding of how signaling endosome localization in the growth cone affects neurite growth.

Three functionally distinct adhesions in filopodia: shaft adhesions control lamellar extension.

In this study, adhesions on individual filopodial shafts were shown to control veil (lamellar) advance and to be modulated by guidance cues. Adhesions were detected in individual filopodia of sensory growth cones using optical recordings, adhesion markers, and electron microscopy. Veils readily advanced along filopodia lacking shaft adhesions but rarely advanced along filopodia displaying shaft adhesions.