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Identifier 000434960
Title Effects of BNN27 microneurotrophin delivery on tissue regeneration after optic nerve injury
Alternative Title Η Επίδραση της χορήγησης της μικρονευροτροφίνης BNN27 στην αναγέννηση ιστού μετά από τραύμα οπτικού νεύρου
Author Μάλλιος, Ξενοφών
Thesis advisor Χαραλαμπόπουλος, Ιωάννης
Γραβάνης, Αχιλλέας
Τζεράνης, Δημήτριος
Abstract Traumatic Optic Neuropathy (TON) refers to a condition of optic nerve injury caused by direct or indirect head and/or facial trauma. Indirect TON is more common than direct, having as more usual causes road-traffic accidents (21.5%), falls (25.6%) and assaults (20.7%). Our vision depends on the successful and high-quality signal conduction from the retina to subcortical target areas of the brain via the optic nerve, which is formed by RGC axons. Taking into account that RGCs cannot regenerate their axons upon injury, as the majority of CNS neurons, TON could result in vision impairment or permanent vision loss. To this day there is no treatment available, able to prevent ONI-induced RGC loss or to stimulate efficient RGC axon elongation. Current clinical treatments include corticosteroid administration and surgical decompression of the optic canal, presenting limited results and a number of side-effects (hypertension, insomnia, hyperglycemia, etc.). Research TON treatments include the use of eye drops and intravitreal injections for the delivery of NTs and NTFs, drugs and peptides as well as biomaterial-based drug delivery strategies. Literature reports the use of grafts in combination with cells, NTs or other molecules; administration of micro- / nanospheres and liposomes containing NTs or drugs; the use of other delivery systems (e.g. reverse thermal gel). This study aims to quantify the effects of the microneurotrophin BNN27 on key cell phenotypes (RGC survival, astroglial activation) after ONC injury in mice, pursuing two BNN27 delivery strategies. The first strategy comprises administration of BNN27 via eye drops for 7 and 14 days after injury. The second strategy includes BNN27 delivery via biomaterials; BNN27 is entrapped in a peptide gel formed inside a porous collagen-GAG scaffold, placed directly at the injury site. Characterization of the developed ONC model revealed that ONC induced reduction in RGC survival, astroglial (GFAP) and microglial (IBA1) activation, as well as a trend for TrkC downregulation 7 and 14 days after injury. For the rest NT receptors studied (p75NTR, TrkA, TrkB), no statistically significant alterations in their expression were observed 1 and 2 weeks after injury. Concerning the first strategy, BNN27 displayed a trend for RGCs protection from ONC-induced apoptosis 7 and 14 days post injury, whereas no effect was observed on astroglial activation (GFAP). Regarding the second strategy, BNN27 did not present any neuroprotective effects on RGC survival or astroglial activation 2 weeks after ONC, when delivered via a peptide gel formed in a collagen-GAG scaffold, possibly due to administration of insufficient BNN27 dose. Furthermore, BNN27 delivery via covalent conjugation on collagen-GAG scaffold using a novel linker (SPDP) was pursued through in vitro experiments. TC447 was successfully conjugated on collagen-GAG scaffold via covalent bond, although some amount of non-specific conjugation was observed. Finally, a significant finding of this study is that TC447 conjugation was highly enhanced on SPDP-activated scaffolds treated with DTT prior TC447, suggesting that chemical interactions among SPDP, collagen-GAG and DTT lead to the generation of a microenvironment that promotes TC447 conjugation on this scaffold more efficiently compared to TC447 conjugation on SPDP-activated scaffold alone.
Language English
Subject Biomaterials
Drug delivery
Neuroprotection
Optic nerve cruch
Retinal ganglion cells
Traumatic optic neuropathy
Βιουλικά
Γαγγλιακά κύτταρα αμφιβληστροειδούς
Νευροπροστασία
Νευροτροφίνες
Τραυματική οπτική νευροπάθεια
Υποδοχείς κινάσες τυροσίνης
Χορήγηση φαρμάκου
Issue date 2020-12-17
Collection   School/Department--School of Medicine--Department of Medicine--Post-graduate theses
  Type of Work--Post-graduate theses
Permanent Link https://elocus.lib.uoc.gr//dlib/d/0/2/metadata-dlib-1608117863-271828-7077.tkl Bookmark and Share
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