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      Injectable hydrogels in stroke and spinal cord injury treatment: a review on hydrogel materials, cell–matrix interactions and glial involvement

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          Abstract

          Cell–matrix interactions and glia involvement are crucial factors to be considered for the design of injectable hydrogels in the treatment of central nervous system pathologies.

          Abstract

          Central nervous system (CNS) pathologies, such as stroke and spinal cord injury, remain debilitating issues due to the inhibitory environment in the CNS. Many research works have focused on combinatorial therapeutic approaches, such as biomaterial scaffolding, cell transplantation and biomolecule delivery, in the hope of effectively improving functional recovery in vivo. Unfortunately, to date, there is still no effective treatment to regain mobility post-injury. In search of better therapeutic strategies, injectable hydrogels are becoming a popular treatment option for CNS diseases due to their tuneable mechanical properties and the minimally invasive nature of administration. Moreover, the ability to encapsulate exogenous cells and therapeutic molecules while providing an environment that is permissive to cells and promote cell survival incentivises the use of injectable hydrogels in CNS disease treatment. In this review, we will discuss the advances that have been achieved in the recent decade in injectable hydrogel systems for tissue regeneration after stroke and spinal cord injuries. In particular, we focus on the cellular response and tissue integration related to these hydrogel systems. We hope to provide useful insights on materials choices for future research work in injectable hydrogels for stroke and spinal cord regeneration.

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          Most cited references160

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          CD44: from adhesion molecules to signalling regulators.

          Cell-adhesion molecules, once believed to function primarily in tethering cells to extracellular ligands, are now recognized as having broader functions in cellular signalling cascades. The CD44 transmembrane glycoprotein family adds new aspects to these roles by participating in signal-transduction processes--not only by establishing specific transmembrane complexes, but also by organizing signalling cascades through association with the actin cytoskeleton. CD44 and its associated partner proteins monitor changes in the extracellular matrix that influence cell growth, survival and differentiation.
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            A sensitive and reliable locomotor rating scale for open field testing in rats.

            Behavioral assessment after spinal cord contusion has long focused on open field locomotion using modifications of a rating scale developed by Tarlov and Klinger (1954). However, on-going modifications by several groups have made interlaboratory comparison of locomotor outcome measures difficult. The purpose of the present study was to develop an efficient, expanded, and unambiguous locomotor rating scale to standardize locomotor outcome measures across laboratories. Adult rats (n = 85) were contused at T7-9 cord level with an electromagnetic or weight drop device. Locomotor behavior was evaluated before injury, on the first or second postoperative day, and then for up to 10 weeks. Scoring categories and attributes were identified, operationally defined, and ranked based on the observed sequence of locomotor recovery patterns. These categories formed the Basso, Beattie, Bresnahan (BBB) Locomotor Rating Scale. The data indicate that the BBB scale is a valid and predictive measure of locomotor recovery able to distinguish behavioral outcomes due to different injuries and to predict anatomical alterations at the lesion center. Interrater reliability tests indicate that examiners with widely varying behavioral testing experience can apply the scale consistently and obtain similar scores. The BBB Locomotor Rating Scale offers investigators a more discriminating measure of behavioral outcome to evaluate treatments after spinal cord injury.
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              Astrocyte scar formation aids central nervous system axon regeneration.

              Transected axons fail to regrow in the mature central nervous system. Astrocytic scars are widely regarded as causal in this failure. Here, using three genetically targeted loss-of-function manipulations in adult mice, we show that preventing astrocyte scar formation, attenuating scar-forming astrocytes, or ablating chronic astrocytic scars all failed to result in spontaneous regrowth of transected corticospinal, sensory or serotonergic axons through severe spinal cord injury (SCI) lesions. By contrast, sustained local delivery via hydrogel depots of required axon-specific growth factors not present in SCI lesions, plus growth-activating priming injuries, stimulated robust, laminin-dependent sensory axon regrowth past scar-forming astrocytes and inhibitory molecules in SCI lesions. Preventing astrocytic scar formation significantly reduced this stimulated axon regrowth. RNA sequencing revealed that astrocytes and non-astrocyte cells in SCI lesions express multiple axon-growth-supporting molecules. Our findings show that contrary to the prevailing dogma, astrocyte scar formation aids rather than prevents central nervous system axon regeneration.
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                Author and article information

                Contributors
                (View ORCID Profile)
                Journal
                MAADC9
                Materials Advances
                Mater. Adv.
                Royal Society of Chemistry (RSC)
                2633-5409
                April 26 2021
                2021
                : 2
                : 8
                : 2561-2583
                Affiliations
                [1 ]School of Chemical and Biomedical Engineering
                [2 ]Nanyang Technological University
                [3 ]Singapore 637459
                [4 ]Singapore
                [5 ]Department of Cardiology
                [6 ]The Second Affiliated Hospital of Nanchang University
                [7 ]China
                [8 ]Lee Kong Chian School of Medicine
                Article
                10.1039/D0MA00732C
                e0e01a96-ccd6-45b9-9c5d-6fd6a1fa1ac2
                © 2021

                http://creativecommons.org/licenses/by-nc/3.0/

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