Optimized, visible light-induced crosslinkable hybrid gelatin/hyaluronic acid scaffold promotes complete spinal cord injury repair

2021 ◽  
Author(s):  
Xinhao Zhao ◽  
Huiru Wang ◽  
Yunlong Zou ◽  
Weiwei Xue ◽  
Yang Zhuang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Hyaluronic Acid ◽  
Visible Light ◽  
Inflammatory Responses ◽  
Neural Regeneration ◽  
Dependent Manner ◽  
Hydrogel Scaffold ◽  
Hybrid Hydrogel ◽  
Cord Injury

Abstract Severe microenvironmental changes after spinal cord injury (SCI) present serious challenges in neural regeneration and tissue repair. Gelatin (GL)- and hyaluronic acid (HA)-based hydrogels are attractive scaffolds because they are major components of the extracellular matrix and can provide a favorable adjustable microenvironment for neurogenesis and motor function recovery. In this study, three-dimensional hybrid GL/HA hydrogel scaffolds were prepared and optimized. The hybrid hydrogels could undergo in-situ gelation and fit the defects perfectly via visible light- induced crosslinking in the complete SCI rats. We found that the transplantation of the hybrid hydrogel scaffold significantly reduced the inflammatory responses and suppressed glial scar formation in an HA concentration-dependent manner. Moreover, the hybrid hydrogel with GL/HA ratios less than 8/2 effectively promoted endogenous neural stem cell migration and neurogenesis, as well as improved neuron maturation and axonal regeneration. The results showed locomotor function improved 60 days after transplantation, thus suggesting that GL/HA hydrogels can be considered as a promising scaffold for complete SCI repair.

scholarly journals pH-responsive delivery of H2 through ammonia borane-loaded mesoporous silica nanoparticles improves recovery after spinal cord injury by moderating oxidative stress and regulating microglial polarization

2021 ◽  
Author(s):  
Yi Liu ◽  
Yeying Wang ◽  
Bing Xiao ◽  
Guoke Tang ◽  
Jiangming Yu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Mesoporous Silica ◽  
Silica Nanoparticles ◽  
Mesoporous Silica Nanoparticles ◽  
Ammonia Borane ◽  
Neural Regeneration ◽  
Dependent Manner ◽  
Cord Injury

Abstract Imbalance of oxidative and inflammatory regulation is the main contributor to neurofunctional deterioration and failure of rebuilding spared neural networks after spinal cord injury (SCI). As an emerging biosafe strategy for protecting against oxidative and inflammatory damage, hydrogen (H2) therapy is a promising approach for improving the microenvironment to allow neural regeneration. However, achieving release of H2 at sufficient concentrations specifically into the injured area is critical for the therapeutic effect of H2. Thus, we assembled SiO2@mSiO2 mesoporous silica nanoparticles and loaded them with ammonia borane (AB), which has abundant capacity and allows controllable release of H2 in an acid-dependent manner. The release of H2 from AB/SiO2@mSiO2 was satisfactory at pH 6.6, which is approximately equal to the microenvironmental acidity after SCI. After AB/SiO2@mSiO2 were intrathecally administered to rat models of SCI, continuous release of H2 from these nanoparticles synergistically enhanced neurofunctional recovery, reduced fibrotic scar formation and promoted neural regeneration by suppressing oxidative stress reaction. Furthermore, in the subacute phase of SCI, microglia were markedly polarized toward the M2 phenotype by H2 via inhibition of TLR9 expression in astrocytes. In conclusion, H2 delivery through AB/SiO2@mSiO2 has the potential to efficiently treat SCI through comprehensive modulation of the oxidative and inflammatory imbalance in the microenvironment.

scholarly journals Photobiomodulation Promotes Repair Following Spinal Cord Injury by Regulating the Transformation of A1/A2 Reactive Astrocytes

2021 ◽  
Vol 15 ◽  
Author(s):  
Xuankang Wang ◽  
Zhihao Zhang ◽  
Zhijie Zhu ◽  
Zhuowen Liang ◽  
Xiaoshuang Zuo ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Growth Factor ◽  
Motor Function ◽  
Function Analysis ◽  
Reactive Astrocytes ◽  
Male Rats ◽  
Dependent Manner ◽  
Astrocyte Activation ◽  
Cord Injury

After spinal cord injury (SCI), reactive astrocytes can be classified into two distinctive phenotypes according to their different functions: neurotoxic (A1) astrocytes and neuroprotective (A2) astrocytes. Our previous studies proved that photobiomodulation (PBM) can promote motor function recovery and improve tissue repair after SCI, but little is known about the underlying mechanism. Therefore, we aimed to investigate whether PBM contributes to repair after SCI by regulating the activation of astrocytes. Male rats subjected to clip-compression SCI were treated with PBM for two consecutive weeks, and the results showed that recovery of motor function was improved, the lesion cavity size was reduced, and the number of neurons retained was increased. We determined the time course of A1/A2 astrocyte activation after SCI by RNA sequencing (RNA-Seq) and verified that PBM inhibited A1 astrocyte activation and promoted A2 astrocyte activation at 7 days postinjury (dpi) and 14 dpi. Subsequently, potential signaling pathways related to A1/A2 astrocyte activation were identified by GO function analysis and KEGG pathway analysis and then studied in animal experiments and preliminarily analyzed in cultured astrocytes. Next, we observed that the expression of basic fibroblast growth factor (bFGF) and transforming growth factor-β (TGF-β) was upregulated by PBM and that both factors contributed to the transformation of A1/A2 astrocytes in a dose-dependent manner. Finally, we found that PBM reduced the neurotoxicity of A1 astrocytes to dorsal root ganglion (DRG) neurons. In conclusion, PBM can promote better recovery after SCI, which may be related to the transformation of A1/A2 reactive astrocytes.

scholarly journals The human ApoE4 variant reduces functional recovery and neuronal sprouting after incomplete spinal cord injury in male mice

2020 ◽  
Author(s):  
Carlos A. Toro ◽  
Jens Hansen ◽  
Mustafa M. Siddiq ◽  
Kaitlin Johnson ◽  
Wei Zhao ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Inflammatory Responses ◽  
Synaptic Activity ◽  
Cord Injury ◽  
Hospital Stays ◽  
Human Apoe3 ◽  
Neuronal Sprouting ◽  
Apoe Genotypes ◽  
Upregulated Genes

AbstractSpinal cord injury (SCI) is a devastating form of neurotrauma. Patients who carry one or two ApoE4 alleles show worse functional outcomes and longer hospital stays after SCI but the cellular and molecular underpinnings for this genetic link remain poorly understood. Thus, there is a great need to generate animal models to accurately replicate the genetic determinants of outcomes after SCI to spur development of treatments that improve physical function. Here, we examined outcomes after a moderate contusion SCI of transgenic mice expressing human ApoE3 or ApoE4. ApoE4 mice have worse locomotor function and coordination after SCI. Histological examination revealed greater glial staining in ApoE4 mice after SCI associated with reduced levels of neuronal sprouting markers. Bulk RNA sequencing revealed that subcellular processes (SCPs), such as extracellular matrix organization and inflammatory responses, were highly-ranked among upregulated genes at 7 days after SCI in ApoE4 variants. Conversely, SCPs related to neuronal action potential and neuron projection development were increased in ApoE3 mice at 21 days. In summary, our results reveal a clinically relevant SCI mouse model that recapitulates the influence of ApoE genotypes on post-SCI function in individuals who carry these alleles and suggest that the mechanisms underlying worse recovery for ApoE4 animals involve glial activation and loss of sprouting and synaptic activity.

scholarly journals Multipotent Neurotrophic Effects of Hepatocyte Growth Factor in Spinal Cord Injury

2019 ◽  
Vol 20 (23) ◽  
pp. 6078 ◽  
Author(s):  
Kentaro Yamane ◽  
Haruo Misawa ◽  
Tomoyuki Takigawa ◽  
Yoshihiro Ito ◽  
Toshifumi Ozaki ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Stem Cell Differentiation ◽  
Neural Regeneration ◽  
Therapeutic Effects ◽  
Positive Effects ◽  
Cord Injury ◽  
Hepatocyte Growth

Spinal cord injury (SCI) results in neural tissue loss and so far untreatable functional impairment. In addition, at the initial injury site, inflammation induces secondary damage, and glial scar formation occurs to limit inflammation-mediated tissue damage. Consequently, it obstructs neural regeneration. Many studies have been conducted in the field of SCI; however, no satisfactory treatment has been established to date. Hepatocyte growth factor (HGF) is one of the neurotrophic growth factors and has been listed as a candidate medicine for SCI treatment. The highlighted effects of HGF on neural regeneration are associated with its anti-inflammatory and anti-fibrotic activities. Moreover, HGF exerts positive effects on transplanted stem cell differentiation into neurons. This paper reviews the mechanisms underlying the therapeutic effects of HGF in SCI recovery, and introduces recent advances in the clinical applications of HGF therapy.

High molecular weight hyaluronic acid limits astrocyte activation and scar formation after spinal cord injury

2011 ◽  
Vol 8 (4) ◽  
pp. 046033 ◽  
Author(s):  
Zin Z Khaing ◽  
Brian D Milman ◽  
Jennifer E Vanscoy ◽  
Stephanie K Seidlits ◽  
Raymond J Grill ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Molecular Weight ◽  
Spinal Cord Injury ◽  
Hyaluronic Acid ◽  
High Molecular Weight ◽  
Scar Formation ◽  
Astrocyte Activation ◽  
Cord Injury

Influence of cross-linked hyaluronic acid hydrogels on neurite outgrowth and recovery from spinal cord injury

2007 ◽  
Vol 6 (2) ◽  
pp. 133-140 ◽  
Author(s):  
Eric M. Horn ◽  
Michael Beaumont ◽  
Xiao Zheng Shu ◽  
Adrian Harvey ◽  
Glenn D. Prestwich ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Hyaluronic Acid ◽  
Neurite Outgrowth ◽  
Motor Evoked Potentials ◽  
Neurite Growth ◽  
Thoracic Spinal Cord ◽  
Bioactive Materials ◽  
Thoracic Spinal ◽  
Cord Injury

Object Therapies that use bioactive materials as replacement extracellular matrices may hold the potential to mitigate the inhibition of regeneration observed after central nervous system trauma. Hyaluronic acid (HA), a nonsulfated glycosaminoglycan ubiquitous in all tissues, was investigated as a potential neural tissue engineering matrix. Methods Chick dorsal root ganglia were cultured in 3D hydrogel matrices composed of cross-linked thiol-modified HA or fibrin. Samples were cultured and images were acquired at 48-, 60-, and 192-hour time points. Images of all samples were analyzed at 48 hours of incubation to quantify the extent of neurite growth. Cultures in cross-linked thiolated HA exhibited more than a 50% increase in neurite length compared with fibrin samples. Furthermore, cross-linked thiolated HA supported neurites for the entire duration of the culture period, whereas fibrin cultures exhibited collapsed and degenerating extensions beyond 60 hours. Two concentrations of the thiolated HA (0.5 and 1%) were then placed at the site of a complete thoracic spinal cord transection in rats. The ability of the polymer to promote regeneration was tested using motor evoked potentials, retrograde axonal labeling, and behavioral assessments. There were no differences in any of the parameters between rats treated with the polymer and controls. Conclusions The use of a cross-linked HA scaffold promoted robust neurite outgrowth. Although there was no benefit from the polymer in a rodent spinal cord injury model, the findings in this study represent an early step in the development of semisynthetic extracellular matrice scaffolds for the treatment of neuronal injury.

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