An in vitro spinal cord injury model to screen neuroregenerative materials

Weightman, Alan P.; Pickard, Michael A.; Yang, Ying; Chari, Divya M.

doi:10.1016/j.biomaterials.2014.01.022

Cited by 46 publications

(54 citation statements)

References 62 publications

(70 reference statements)

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“…This model is based on the use of 3-D spinal cord tissue arrays within which a focal, traumatic injury can be induced severing the nerve fibres, mimicking for example injuries due to knife/gunshot wounds. We previously demonstrated that major pathological features of neurological injury in vivo, such as the formation of a glial cell scar and an age related decline in nerve fibre regeneration were all mimicked in the injury foci-highlighting the model's relevance to CNS injury in vivo [20]. Importantly, injury foci were found to 3 Nano Res.…”

Section: Introductionmentioning

confidence: 99%

“…This allows for easy visualisation of cellular NP uptake dynamics within the injury site. Spinal cord slices were lesioned at 1 DIV then main-tained until 6 DIV for all experiments, as a peak in microglial infiltration has previously been shown by ourselves to occur at five days postlesioning [20].…”

Section: Preparation and Lesioning Of Organotypic Spinal Cord Slice Cmentioning

confidence: 99%

“…Spinal cord slice cultures were generated and lesioned as described previously [20,22,23]. Briefly, mouse pups aged 1-3 postnatal days (P1-3) were terminally anaesthetised, decapitated and a midline incision was made along the length of each spine.…”

Section: Preparation and Lesioning Of Organotypic Spinal Cord Slice Cmentioning

confidence: 99%

“…Corrected integrated density measurements were performed using ImageJ software (version 1.45s; NIH) and the values for the live stained micrograph expressed as a percentage of the sum total from both [20,26].…”

Section: Assessment Of Lesioned Slice Viability Postlive Cell Imagingmentioning

confidence: 99%

“…In this context, a novel in vitro model of SCI described by ourselves recently could provide a technically facile but valuable experimental tool for studying microglial particle uptake dynamics within an injury-simulated environment [20]. This model is based on the use of 3-D spinal cord tissue arrays within which a focal, traumatic injury can be induced severing the nerve fibres, mimicking for example injuries due to knife/gunshot wounds.…”

Section: Introductionmentioning

confidence: 99%

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Using a 3-D multicellular simulation of spinal cord injury with live cell imaging to study the neural immune barrier to nanoparticle uptake

2016

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Development of nanoparticle (NP) based therapies to promote regeneration in sites of central nervous system (CNS; i.e. brain and spinal cord) pathology relies critically on the availability of experimental models that offer biologically valid predictions of NP fate in vivo. However, there is a major lack of biological models that mimic the pathological complexity of target neural sites in vivo, particularly the responses of resident neural immune cells to NPs. Here, we have utilised a previously developed in vitro model of traumatic spinal cord injury (based on 3-D organotypic slice arrays) with dynamic time lapse imaging to reveal in real-time the acute cellular fate of NPs within injury foci. We demonstrate the utility of our model in revealing the well documented phenomenon of avid NP sequestration by the intrinsic immune cells of the CNS (the microglia). Such immune sequestration is a known translational barrier to the use of NP-based therapeutics for neurological injury. Accordingly, we suggest that the utility of our model in mimicking microglial sequestration behaviours offers a valuable investigative tool to evaluate strategies to overcome this cellular response within a simple and biologically relevant experimental system, whilst reducing the use of live animal neurological injury models for such studies.

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Section: Introductionmentioning

confidence: 99%

Section: Preparation and Lesioning Of Organotypic Spinal Cord Slice Cmentioning

confidence: 99%

Section: Preparation and Lesioning Of Organotypic Spinal Cord Slice Cmentioning

confidence: 99%

Section: Assessment Of Lesioned Slice Viability Postlive Cell Imagingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Using a 3-D multicellular simulation of spinal cord injury with live cell imaging to study the neural immune barrier to nanoparticle uptake

2016

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An In Vitro and Ex Vivo Analysis of the Potential of GelMA Hydrogels as a Therapeutic Platform for Preclinical Spinal Cord Injury

Walsh

Wychowaniec

Costello

et al. 2023

Adv Healthcare Materials

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Spinal cord injury (SCI) is a devastating condition with no curative therapy currently available. Immunomodulation can be applied as a therapeutic strategy to drive alternative immune cell activation and promote a proregenerative injury microenvironment. Locally injected hydrogels carrying immunotherapeutic cargo directly to injured tissue offer an encouraging treatment approach from an immunopharmacological perspective. Gelatin methacrylate (GelMA) hydrogels are promising in this regard, however, detailed analysis on the immunogenicity of GelMA in the specific context of the SCI microenvironment is lacking. Here, the immunogenicity of GelMA hydrogels formulated with a translationally relevant photoinitiator is analyzed in vitro and ex vivo. 3% (w/v) GelMA, synthesized from gelatin type‐A, is first identified as the optimal hydrogel formulation based on mechanical properties and cytocompatibility. Additionally, 3% GelMA‐A does not alter the expression profile of key polarization markers in BV2 microglia or RAW264.7 macrophages after 48 h. Finally, it is shown for the first time that 3% GelMA‐A can support the ex vivo culture of primary murine organotypic spinal cord slices for 14 days with no direct effect on glial fibrillary acidic protein (GFAP+) astrocyte or ionized calcium‐binding adaptor molecule 1 (Iba‐1+) microglia reactivity. This provides evidence that GelMA hydrogels can act as an immunotherapeutic hydrogel‐based platform for preclinical SCI.

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Epidermal neural crest stem cell‐derived glia enhance neurotrophic elements in an ex vivo model of spinal cord injury

Pandamooz

Salehi

Zibaii

et al. 2018

J of Cellular Biochemistry

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Growing evidence that cell-based therapies can improve recovery outcome in spinal cord injury (SCI) models substantiates their application for treatment of human with SCI. To address the effectiveness of these stem cells, potential candidates should be evaluated in proper SCI platform that allows direct real-time monitoring. In this study, the role of epidermal neural crest stem cells (EPI-NCSCs) was elucidated in an ex vivo model of SCI, and valproic acid (VPA) was administered to ameliorate the inhospitable context of injury for grafted EPI-NCSCs. Here the contusion was induced in organotypic spinal cord slice culture at day seven in vitro using a weight drop device and one hour post injury the GFP- expressing EPI-NCSCs were grafted followed by VPA administration. The evaluation of treated slices seven days after injury revealed that grafted stem cells survived on the injured slices and expressed GFAP, whereas they did not express any detectable levels of the neural progenitor marker doublecortin (DCX), which was expressed prior to transplantation. Immunoblotting data demonstrated that the expression of GFAP, BDNF, neurotrophin-3 (NT3), and Bcl2 increased significantly in stem cell treated slices. This study illustrated that the fate of transplanted stem cells has been directed to the glial lineage in the ex vivo context of injury and EPI-NCSCs may ameliorate the SCI condition through releasing neurotrophic factors directly and/or via inducing resident spinal cord cells.

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An in vitro spinal cord injury model to screen neuroregenerative materials

Cited by 46 publications

References 62 publications

Using a 3-D multicellular simulation of spinal cord injury with live cell imaging to study the neural immune barrier to nanoparticle uptake

Using a 3-D multicellular simulation of spinal cord injury with live cell imaging to study the neural immune barrier to nanoparticle uptake

An In Vitro and Ex Vivo Analysis of the Potential of GelMA Hydrogels as a Therapeutic Platform for Preclinical Spinal Cord Injury

Epidermal neural crest stem cell‐derived glia enhance neurotrophic elements in an ex vivo model of spinal cord injury

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