A Novel Injectable Chitosan Sponge Containing Brain Derived Neurotrophic Factor (BDNF) to Enhance Human Oligodendrocyte
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A Novel Injectable Chitosan Sponge Containing Brain Derived Neurotrophic Factor (BDNF) to Enhance Human Oligodendrocyte Progenitor Cells' (OPC) Differentiation
Mina Mekhail1, Qiao-Ling Cui2, Guillermina Almazan3, Jack Antel2, Maryam Tabrizian1 1
Biomedical Engineering, Faculty of Medicine, McGill University, Montreal, QC, Canada Neurology and Neurosurgery, Faculty of Medicine, McGill University, Montreal, QC 3 Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, QC 2
ABSTRACT We developed a rapidly-gelling chitosan sponge crosslinked with Guanosine 5'-Diphosphate (GDP). GDP has not been previously explored as an anionic crosslinker, and it was used in this application since the nucleoside guanosine has been shown to improve remyelination in situ, and thus its presence in the sponge composition was hypothesized to induce Oligodendrocyte Progenitor Cells' (OPC) differentiation. In addition to the chemical composition tailored to target OPCs, the developed chitosan sponge possesses a wide range of desirable physicochemical properties such as: rapid gelation, high porosity with interconnected pores, moduli of elasticity resembling that of soft tissue and cytocompatibility with many cell types. Moreover, protein encapsulation into the sponges was possible with high encapsulation efficiencies (e.g. BMP-7 and NT-3). In this study, BDNF was encapsulated in the chitosan sponges with an encapsulation efficiency greater than 80% and a sustained release over a 16-day period was achieved. We demonstrate here for the first time, the attachment of human fetal OPCs to the sponges and their differentiation after 12 days of culture. Overall, this newly-introduced injectable sponge is a promising therapeutic modality that can be used to enhance remyelination post-spinal cord injuries. INTRODUCTION Approximately 2.5 million people world-wide are living with paralysis caused by spinal cord injuries (SCI). Demyelination, or the loss of myelin sheaths surrounding axons, is one of the adverse outcomes that occurs early post-SCI due to oligodendrocyte (OG) death [1]. Demyelinated axons are not capable of transmitting action potentials, and will therefore degenerate if myelin is not re-instated. OPCs are endogenous precursors that migrate to the site of injury and remyelinate axons. However, the myelin produced is thinner compared to normal myelin, and is thus insufficient. Failure to fully remyelinate has been attributed to the inability of OPCs to fully differentiate into mature OGs [2]. The aim of this work was to address this issue through developing a rapidly-gelling, injectable chitosan sponge that is crosslinked using Guanosine 5’-diphosphate (GDP) to promote human OPC differentiation [3]. The rapid gelation (Tgel < 2 seconds) occurs due to the electrostatic interactions between cationic amine groups in chitosan and anionic phosphate groups in GDP. Guanosine (present in GDP) has been shown to induce remyelination post-SCI in animal models and was thus hypothesized to improve OPC attachment and differenti
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