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      International Journal of Nanomedicine (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on the application of nanotechnology in diagnostics, therapeutics, and drug delivery systems throughout the biomedical field. Sign up for email alerts here.

      105,621 Monthly downloads/views I 7.033 Impact Factor I 10.9 CiteScore I 1.22 Source Normalized Impact per Paper (SNIP) I 1.032 Scimago Journal & Country Rank (SJR)

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      An anti-inflammatory peptide and brain-derived neurotrophic factor-modified hyaluronan-methylcellulose hydrogel promotes nerve regeneration in rats with spinal cord injury

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          Abstract

          Background

          Traumatic spinal cord injury (SCI) causes neuronal death, demyelination, axonal degeneration, inflammation, glial scar formation, and cystic cavitation resulting in interruption of neural signaling and loss of nerve function. Multifactorial targeted therapy is a promising strategy for SCI.

          Methods

          The anti-inflammatory peptide KAFAKLAARLYRKALARQLGVAA (KAFAK) and brain-derived neurotrophic factor (BDNF)-modified hyaluronan-methylcellulose (HAMC) hydrogel was designed for minimally invasive, localized, and sustained intrathecal protein delivery. The physical and biological characteristics of HAMC-KAFAK/BDNF hydrogel were measured in vitro. SCI model was performed in rats and HAMC-KAFAK/BDNF hydrogel was injected into the injured site of spinal cord. The neuronal regeneration effect was evaluated by inflammatory cytokine levels, behavioral test and histological analysis at 8 weeks post operation.

          Results

          HAMC-KAFAK/BDNF hydrogel showed minimally swelling property and sustained release of the KAFAK and BDNF. HAMC-KAFAK/BDNF hydrogel significantly improved the proliferation of PC12 cells in vitro without cytotoxicity. Significant recovery in both neurological function and nerve tissue morphology in SCI rats were observed in HAMC-KAFAK/BDNF group. HAMC-KAFAK/BDNF group showed significant reduction in proinflammatory cytokines expression and cystic cavitation, decreased glial scar formation, and improved neuronal survival in the rat SCI model compared to HAMC group and SCI group.

          Conclusion

          The HAMC-KAFAK/BDNF hydrogel promotes functional recovery of rats with spinal cord injury by regulating inflammatory cytokine levels and improving axonal regeneration.

          Most cited references40

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          Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice.

          T Bush, N Puvanachandra, C Horner … (1999)
          Reactive astrocytes adjacent to a forebrain stab injury were selectively ablated in adult mice expressing HSV-TK from the Gfap promoter by treatment with ganciclovir. Injured tissue that was depleted of GFAP-positive astrocytes exhibited (1) a prolonged 25-fold increase in infiltration of CD45-positive leukocytes, including ultrastructurally identified monocytes, macrophages, neutrophils, and lymphocytes, (2) failure of blood-brain barrier (BBB) repair, (3) substantial neuronal degeneration that could be attenuated by chronic glutamate receptor blockade, and (4) a pronounced increase in local neurite outgrowth. These findings show that genetic targeting can be used to ablate scar-forming astrocytes and demonstrate roles for astrocytes in regulating leukocyte trafficking, repairing the BBB, protecting neurons, and restricting nerve fiber growth after injury in the adult central nervous system.
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            Spinal Cord Injury Scarring and Inflammation: Therapies Targeting Glial and Inflammatory Responses

            Michael B. Orr, John C. Gensel (2018)
            Deficits in neuronal function are a hallmark of spinal cord injury (SCI) and therapeutic efforts are often focused on central nervous system (CNS) axon regeneration. However, secondary injury responses by astrocytes, microglia, pericytes, endothelial cells, Schwann cells, fibroblasts, meningeal cells, and other glia not only potentiate SCI damage but also facilitate endogenous repair. Due to their profound impact on the progression of SCI, glial cells and modification of the glial scar are focuses of SCI therapeutic research. Within and around the glial scar, cells deposit extracellular matrix (ECM) proteins that affect axon growth such as chondroitin sulfate proteoglycans (CSPGs), laminin, collagen, and fibronectin. This dense deposition of material, i.e., the fibrotic scar, is another barrier to endogenous repair and is a target of SCI therapies. Infiltrating neutrophils and monocytes are recruited to the injury site through glial chemokine and cytokine release and subsequent upregulation of chemotactic cellular adhesion molecules and selectins on endothelial cells. These peripheral immune cells, along with endogenous microglia, drive a robust inflammatory response to injury with heterogeneous reparative and pathological properties and are targeted for therapeutic modification. Here, we review the role of glial and inflammatory cells after SCI and the therapeutic strategies that aim to replace, dampen, or alter their activity to modulate SCI scarring and inflammation and improve injury outcomes. Electronic supplementary material The online version of this article (10.1007/s13311-018-0631-6) contains supplementary material, which is available to authorized users.
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              Fast-gelling injectable blend of hyaluronan and methylcellulose for intrathecal, localized delivery to the injured spinal cord.

              Dimpy Gupta, Charles H. Tator, Molly Shoichet (2006)
              Strategies for spinal cord injury repair are limited, in part, by poor drug delivery techniques. A novel drug delivery system (DDS) is being developed in our laboratory that can provide localized release of growth factors from an injectable gel. The gel must be fast-gelling, non-cell adhesive, degradable, and biocompatible as an injectable intrathecal DDS. A gel that meets these design criteria is a blend of hyaluronan and methylcellulose (HAMC). Unlike other injectable gels, HAMC is already at the gelation point prior to injection. It is injectable due to its shear-thinning property, and its gel strength increases with temperature. In vivo rat studies show that HAMC is biocompatible within the intrathecal space for 1 month, and may provide therapeutic benefit, in terms of behavior, as measured by the Basso, Beattie and Bresnahan (BBB) locomotor scale, and inflammation. These data suggest that HAMC is a promising gel for localized delivery of therapeutic agents to the injured spinal cord.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Nanomedicine
                Journal ID (iso-abbrev): Int J Nanomedicine
                Journal ID (publisher-id): International Journal of Nanomedicine
                Title: International Journal of Nanomedicine
                Publisher: Dove Medical Press
                ISSN (Print): 1176-9114
                ISSN (Electronic): 1178-2013
                Publication date Collection: 2019
                Publication date (Electronic): 18 January 2019
                Volume: 14
                Pages: 721-732
                Affiliations
                [1 ]Logistics University of Chinese People’s Armed Police Force (PAP), Tianjin 300309, China
                [2 ]Department of Nursing, Characteristic Medical Center of Chinese People’s Armed Police Force (PAP), Tianjin 300162, China
                [3 ]Department of Orthopaedics Characteristic Medical Center of Chinese People’s Armed Police Force (PAP), Tianjin 300162, China
                [4 ]Institute of TBI and Neuroscience, Characteristic Medical Center of Chinese People’s Armed Police Force (PAP), Tianjin Key Laboratory of Neurotrauma Repair, Tianjin 300162, China, zhangsai718@ 123456vip.126.com ; shixiangcheng@ 123456vip.126.com
                Author notes
                Correspondence: Sai Zhang; Shixiang Cheng, Institute of TBI and Neuroscience, Characteristic Medical Center of Chinese People’s Armed Police Force (PAP), Tianjin Key Laboratory of Neurotrauma Repair, No. 220 ChengLin Road, Tianjin 300162, China, Tel +86 22 6057 7101; +86 22 6057 7171, Fax +86 22 2471 5698; +86 22 2471 5698, Email zhangsai718@ 123456vip.126.com ; shixiangcheng@ 123456vip.126.com
                [*]

                These authors contributed equally to this work

                Article
                Publisher ID: ijn-14-721
                DOI: 10.2147/IJN.S187854
                PMC ID: 6342221
                PubMed ID: 30705588
                SO-VID: f00235a0-3ab1-4211-b287-0f2f36f3a53b
                Copyright © © 2019 He et al. This work is published and licensed by Dove Medical Press Limited
                License:

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                History
                Categories
                Subject: Original Research

                ScienceOpen disciplines: Molecular medicine
                Keywords: hyaluronan-methylcellulose hydrogel,anti-inflammatory peptide,neuroprotection,spinal cord injury
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: hyaluronan-methylcellulose hydrogel, anti-inflammatory peptide, neuroprotection, spinal cord injury

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