AO Spine Reference Centre & Institute of Health & Biomedical Innovation, Queensland University of Technology, Brisbane, Australia. Traumatic spinal cord injury (SCI) is a devastating condition with no curative therapy. Pro-inflammatory therapy has been suggested recently to try and reduce the inhibitory glial scar and promote neural regeneration and healing. The aim of this study is to investigate the potential of sustained delivery of angiogenic/pro-inflammatory growth factors to reduce the secondary degeneration after spinal cord injury. Adult male Wistar Kyoto
Aims. In this investigation, we administered oxidative stress to nucleus pulposus cells (NPCs), recognized DNA-damage-inducible transcript 4 (DDIT4) as a component in intervertebral disc degeneration (IVDD), and devised a hydrogel capable of conveying small interfering RNA (siRNA) to IVDD. Methods. An in vitro model for oxidative stress-induced injury in NPCs was developed to elucidate the mechanisms underlying the upregulation of DDIT4 expression, activation of the reactive oxygen species (ROS)-thioredoxin-interacting protein (TXNIP)-NLRP3 signalling pathway, and nucleus pulposus pyroptosis. Furthermore, the mechanism of action of small interfering DDIT4 (siDDIT4) on NPCs in vitro was validated. A triplex hydrogel named siDDIT4@G5-P-HA was created by adsorbing siDDIT4 onto fifth-generation polyamidoamine (PAMAM) dendrimer using van der Waals interactions, and then coating it with hyaluronic acid (HA). In addition, we established a rat puncture IVDD model to decipher the hydrogel’s mechanism in IVDD. Results. A correlation between DDIT4 expression levels and disc degeneration was shown with human nucleus pulposus and needle-punctured rat disc specimens. We confirmed that DDIT4 was responsible for activating the ROS-TXNIP-NLRP3 axis during oxidative stress-induced pyroptosis in rat nucleus pulposus in vitro. Mitochondria were damaged during oxidative stress, and DDIT4 contributed to mitochondrial damage and ROS production. In addition, siDDIT4@G5-P-HA hydrogels showed good delivery activity of siDDIT4 to NPCs. In vitro studies illustrated the potential of the siDDIT4@G5-P-HA hydrogel for alleviating IVDD in
Aims. Inflammatory response plays a pivotal role in the pathophysiological process of intervertebral disc degeneration (IDD). A20 (also known as tumour necrosis factor alpha-induced protein 3 (TNFAIP3)) is a ubiquitin-editing enzyme that restricts nuclear factor-kappa B (NF-κB) signalling. A20 prevents the occurrence of multiple inflammatory diseases. However, the role of A20 in the initiation of IDD has not been elucidated. The aim of the study was to investigate the effect of A20 in senescence of TNF alpha (TNF-α)-induced nucleus pulposus cells (NPCs). Methods. Immunohistochemical staining was performed to observe the expression of A20 in normal and degenerated human intervertebral discs. The NPCs were dissected from the tail vertebrae of healthy male Sprague-Dawley
Introduction. Melatonin-deficient
This review provides a concise outline of the advances made in the care of patients and to the quality of life after a traumatic spinal cord injury (SCI) over the last century. Despite these improvements reversal of the neurological injury is not yet possible. Instead, current treatment is limited to providing symptomatic relief, avoiding secondary insults and preventing additional sequelae. However, with an ever-advancing technology and deeper understanding of the damaged spinal cord, this appears increasingly conceivable. A brief synopsis of the most prominent challenges facing both clinicians and research scientists in developing functional treatments for a progressively complex injury are presented. Moreover, the multiple mechanisms by which damage propagates many months after the original injury requires a multifaceted approach to ameliorate the human spinal cord. We discuss potential methods to protect the spinal cord from damage, and to manipulate the inherent inhibition of the spinal cord to regeneration and repair. Although acute and chronic SCI share common final pathways resulting in cell death and neurological deficits, the underlying putative mechanisms of chronic SCI and the treatments are not covered in this review.
Non-coding microRNA (miRNA) in extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) may promote neuronal repair after spinal cord injury (SCI). In this paper we report on the effects of MSC-EV-microRNA-381 (miR-381) in a rodent model of SCI. In the current study, the luciferase assay confirmed a binding site of bromodomain-containing protein 4 (BRD4) and Wnt family member 5A (WNT5A). Then we detected expression of miR-381, BRD4, and WNT5A in dorsal root ganglia (DRG) cells treated with MSC-isolated EVs and measured neuron apoptosis in culture by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. A rat model of SCI was established to detect the in vivo effect of miR-381 and MSC-EVs on SCI.Aims
Methods
Objectives. In order to elucidate the influence of sympathetic nerves on
lumbar radiculopathy, we investigated whether sympathectomy attenuated
pain behaviour and altered the electrical properties of the dorsal
root ganglion (DRG) neurons in a rat model of lumbar root constriction. Methods. Sprague-Dawley
Background. We have reported an injectable L-pNIPAM-co-DMAc hydrogel with hydroxyaptite nanoparticles (HAPna) which promotes mesenchymal stem cell (MSC) differentiation to bone cells without the need for growth factors. This hydrogel could potentially be used as an osteogenic and osteoconductive bone filler of spinal cages to improve vertebral body fusion. Here we investigated the biocompatibility and efficacy of the hydrogel in vivo using a proof of concept femur defect model. Methods. Rat sub-cut analysis was performed to investigate safety in vivo. A rat femur defect model was performed to evaluate efficacy. Four groups were investigated: sham operated controls; acellular L-pNIPAM-co-DMAc hydrogel; acellular L-pNIPAM-co-DMAc hydrogel with HAPna; L-pNIPAM-co-DMAc hydrogel with rat MSCs and HAPna. Following 4 weeks, defect site and organs were histologically examined to determine integration, repair and inflammatory response, as well as Micro-CT to assess mineralisation. Results. No inflammatory reactions or toxicity were seen in any animal. Enhanced bone healing was observed in aged exbreeder female
Introduction. The response of the intervertebral disc to asymmetric forces may accelerate degeneration through changes in the matrix. Macroscopically, the disc sustains structural changes that may play a part in the progression of a scoliotic curve. Molecularly, disc degeneration is the outcome of the action of matrix metalloproteases (MMPs), members of a family of enzymes that bring about the degradation of extracellular matrix components. In this study we measured in vivo the expression of MMPs in a rat scoliotic intervertebral disc and studied the effect of the degree of the deformity on their production. Methods. Asymmetric forces were applied in the intervertebral disc between the ninth and tenth vertebrae at the base of a rat tail with the use of a mini Ilizarov external fixator, under anaesthesia. Animals were categorised into three groups according to the degree of the deformity. In group I, the deformity that was applied on the intervertebral disc was 10°, in group II 30°, and in group III 50°. All the animals used were female Wistar
Mesenchymal stem-cell based therapies have been
proposed as novel treatments for intervertebral disc degeneration,
a prevalent and disabling condition associated with back pain. The
development of these treatment strategies, however, has been hindered
by the incomplete understanding of the human nucleus pulposus phenotype
and by an inaccurate interpretation and translation of animal to
human research. This review summarises recent work characterising
the nucleus pulposus phenotype in different animal models and in
humans and integrates their findings with the anatomical and physiological
differences between these species. Understanding this phenotype
is paramount to guarantee that implanted cells restore the native
functions of the intervertebral disc. Cite this article: