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      Synthesis and Characterization of a Silica-Based Drug Delivery System for Spinal Cord Injury Therapy

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          Highlights

          • With good biocompatibility, a silica-based drug delivery system was prepared and used effectively in vivo to prolong the duration of drug treatment.

          • The prepared system can target spinal cord injury directly. Additionally, due to its small size (approximately 100 nm), it can penetrate the blood-spinal cord barrier.

          • This system reduced the expression of interleukin-17 (IL-17) and IL-17-related inflammatory factors and can protect neurons and promote the recovery of spinal cord injury.

          Electronic supplementary material

          The online version of this article (10.1007/s40820-019-0252-6) contains supplementary material, which is available to authorized users.

          Abstract

          Acute inflammation is a central component in the progression of spinal cord injury (SCI). Anti-inflammatory drugs used in the clinic are often administered systemically at high doses, which can paradoxically increase inflammation and result in drug toxicity. A cluster-like mesoporous silica/arctigenin/CAQK composite (MSN-FC@ARC-G) drug delivery system was designed to avoid systemic side effects of high-dose therapy by enabling site-specific drug delivery to the spinal cord. In this nanosystem, mesoporous silica was modified with the FITC fluorescent molecule and CAQK peptides that target brain injury and SCI sites. The size of the nanocarrier was kept at approximately 100 nm to enable penetration of the blood–brain barrier. Arctigenin, a Chinese herbal medicine, was loaded into the nanosystem to reduce inflammation. The in vivo results showed that MSN-FC@ARC-G could attenuate inflammation at the injury site. Behavior and morphology experiments suggested that MSN-FC@ARC-G could diminish local microenvironment damage, especially reducing the expression of interleukin-17 (IL-17) and IL-17-related inflammatory factors, inhibiting the activation of astrocytes, thus protecting neurons and accelerating the recovery of SCI. Our study demonstrated that this novel, silica-based drug delivery system has promising potential for clinical application in SCI therapy.

          Electronic supplementary material

          The online version of this article (10.1007/s40820-019-0252-6) contains supplementary material, which is available to authorized users.

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          Astrocyte scar formation aids central nervous system axon regeneration.

          Mark A Anderson, Joshua Burda, Yilong Ren … (2016)
          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.
          Article 0 comments Cited 467 times – based on 0 reviews     Review now
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            Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury.

            Takashi Shichita, Yuki Sugiyama, Hiroaki Ooboshi … (2009)
            Lymphocyte recruitment and activation have been implicated in the progression of cerebral ischemia-reperfusion (I/R) injury, but the roles of specific lymphocyte subpopulations and cytokines during stroke remain to be clarified. Here we demonstrate that the infiltration of T cells into the brain, as well as the cytokines interleukin-23 (IL-23) and IL-17, have pivotal roles in the evolution of brain infarction and accompanying neurological deficits. Blockade of T cell infiltration into the brain by the immunosuppressant FTY720 reduced I/R-induced brain damage. The expression of IL-23, which was derived mostly from infiltrated macrophages, increased on day 1 after I/R, whereas IL-17 levels were elevated after day 3, and this induction of IL-17 was dependent on IL-23. These data, together with analysis of mice genetically disrupted for IL-17 and IL-23, suggest that IL-23 functions in the immediate stage of I/R brain injury, whereas IL-17 has an important role in the delayed phase of I/R injury during which apoptotic neuronal death occurs in the penumbra. Intracellular cytokine staining revealed that gammadeltaT lymphocytes, but not CD4(+) helper T cells, were a major source of IL-17. Moreover, depletion of gammadeltaT lymphocytes ameliorated the I/R injury. We propose that T lymphocytes, including gammadeltaT lymphocytes, could be a therapeutic target for mitigating the inflammatory events that amplify the initial damage in cerebral ischemia.
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              Basso Mouse Scale for locomotion detects differences in recovery after spinal cord injury in five common mouse strains.

              David L Jakeman, Phillip G. Popovich, Dana M. McTigue … (2006)
              Genetically engineered mice are used extensively to examine molecular responses to spinal cord injury (SCI). Inherent strain differences may confound behavioral outcomes; therefore, behavioral characterization of several strains after SCI is warranted. The Basso, Beattie, Bresnahan Locomotor Rating Scale (BBB) for rats has been widely used for SCI mice, but may not accurately reflect their unique recovery pattern. This study's purpose was to develop a valid locomotor rating scale for mice and to identify strain differences in locomotor recovery after SCI. We examined C57BL/6, C57BL/10, B10.PL, BALB/c, and C57BL/6x129S6 F1 strains for 42 days after mild, moderate, and severe contusive SCI or transection of the mid thoracic spinal cord. Contusions were created using the Ohio State University electromagnetic SCI device which is a displacement-driven model, and the Infinite Horizon device, which is a force-driven model. Attributes and rankings for the Basso Mouse Scale for Locomotion (BMS) were determined from frequency analyses of seven locomotor categories. Mouse recovery differed from rats for coordination, paw position and trunk instability. Disagreement occurred across six expert raters using BBB (p < 0.05) but not BMS to assess the same mice. BMS detected significant differences in locomotor outcomes between severe contusion and transection (p < 0.05) and SCI severity gradations resulting from displacement variations of only 0.1 mm (p < 0.05). BMS demonstrated significant face, predictive and concurrent validity. Novice BMS raters with training scored within 0.5 points of experts and demonstrated high reliability (0.92-0.99). The BMS is a sensitive, valid and reliable locomotor measure in SCI mice. BMS revealed significantly higher recovery in C57BL/10, B10.PL and F1 than the C57BL/6 and BALB/c strains after moderate SCI (p < 0.05). The differing behavioral response to SCI suggests inherent genetic factors significantly impact locomotor recovery and must be considered in studies with inbred or genetically engineered mouse strains.
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                Author and article information

                Contributors
                Tao Yu: ytbiom@jnu.edu.cn
                Journal
                Journal ID (nlm-ta): Nanomicro Lett
                Journal ID (iso-abbrev): Nanomicro Lett
                Title: Nano-Micro Letters
                Publisher: Springer Singapore (Singapore )
                ISSN (Print): 2311-6706
                ISSN (Electronic): 2150-5551
                Publication date (Electronic): 11 March 2019
                Publication date PMC-release: 11 March 2019
                Publication date Collection: December 2019
                Volume: 11
                Electronic Location Identifier: 23
                Affiliations
                [1 ]ISNI 0000 0004 1790 3548, GRID grid.258164.c, College of Chemistry and Material Sciences, , Jinan University, ; Guangzhou, 510632 People’s Republic of China
                [2 ]ISNI 0000 0004 1760 3828, GRID grid.412601.0, Department of Orthopedics, , First Affiliated Hospital, Jinan University, ; Guangzhou, 510632 People’s Republic of China
                [3 ]ISNI 0000 0004 1790 3548, GRID grid.258164.c, College of Traditional Chinese Medicine, , Jinan University, ; Guangzhou, 510632 People’s Republic of China
                [4 ]ISNI 0000 0001 0662 3178, GRID grid.12527.33, Tsinghua-Berkeley Shenzhen Institute, , Tsinghua University, ; Shenzhen, 518055 People’s Republic of China
                Article
                Publisher ID: 252
                DOI: 10.1007/s40820-019-0252-6
                PMC ID: 7770885
                PubMed ID: 34137964
                SO-VID: d182a3cf-4b35-4fdb-9816-08452bc160d7
                Copyright © © The Author(s) 2019
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                Date received : 5 January 2019
                Date accepted : 19 February 2019
                Categories
                Subject: Article
                Custom metadata
                issue-copyright-statement © The Author(s) 2019

                Keywords: silica,drug delivery,spinal cord injury,arctigenin,astrocytes
                Data availability:
                Keywords: silica, drug delivery, spinal cord injury, arctigenin, astrocytes

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