Nanodevices for deep cartilage penetration.

Osteoarthritis (OA) is a degenerative joint disease and is the main cause of chronic pain and functional disability in adults. Articular cartilage is a hydrated soft tissue that is composed of normally quiescent chondrocytes at a low density, a dense network of collagen fibrils with a pore size of 60-200 nm, and aggrecan proteoglycans with high-density negative charge. Although certain drugs, nucleic acids, and proteins have the potential to slow the progression of OA and restore the joints, these treatments have not been clinically applied owing to the lack of an effective delivery system capable of breaking through the cartilage barrier. Recently, the development of nanotechnology for delivery systems renders new ideas and treatment methods viable in overcoming the limited penetration. In this review, we focus on current research on such applications of nanotechnology, including exosomes, protein-based cationic nanocarriers, cationic liposomes/solid lipid nanoparticles, amino acid-based nanocarriers, polyamide derivatives-based nanocarriers, manganese dioxide, and carbon nanotubes. Exosomes are the smallest known nanoscale extracellular vesicles, and they can quickly deliver nucleic acids or proteins to the required depth. Through electrostatic interactions, nanocarriers with appropriate balance in cationic property and particle size have a strong ability to penetrate cartilage. Although substantial preclinical evidence has been obtained, further optimization is necessary for clinical transformation. STATEMENT OF SIGNIFICANCE: The dense cartilage matrix with high-negative charge was associated with reduced therapeutic effect in osteoarthritis patients with deep pathological changes. However, a systematic review in nanodevices for deep cartilage penetration is still lacking. Current approaches to assure penetration of nanosystems into the depth of cartilage were reviewed, including nanoscale extracellular vesicles from different cell lines and nanocarriers with appropriate balance in cationic property and size particle. Moreover, nanodevices entering clinical trials and further optimization were also discussed, providing important guiding significance to future research.

Recent advances in enzyme-related biomaterials for arthritis treatment.

Arthritis is a group of highly prevalent joint disorders, and osteoarthritis (OA) and rheumatoid arthritis are the two most common types. The high prevalence of arthritis causes severe burdens on individuals, society and the economy. Currently, the primary treatment of arthritis is to relieve symptoms, but the development of arthritis cannot be effectively prevented. Studies have revealed that the disrupted balance of enzymes determines the pathological changes in arthritis. In particular, the increased levels of matrix metalloproteinases and the decreased expression of endogenous antioxidant enzymes promote the progression of arthritis. New therapeutic strategies have been developed based on the expression characteristics of these enzymes. Biomaterials have been designed that are responsive when the destructive enzymes MMPs are increased or have the activities of the antioxidant enzymes that play a protective role in arthritis. Here, we summarize recent studies on biomaterials associated with MMPs and antioxidant enzymes involved in the pathological process of arthritis. These enzyme-related biomaterials have been shown to be beneficial for arthritis treatment, but there are still some problems that need to be solved to improve efficacy, especially penetrating the deeper layer of articular cartilage and targeting osteoclasts in subchondral bone. In conclusion, enzyme-related nano-therapy is challenging and promising for arthritis treatment.

Recent Advances in Reactive Oxygen Species (ROS)-Responsive Polyfunctional Nanosystems 3.0 for the Treatment of Osteoarthritis.

Osteoarthritis (OA) is an inflammatory and degenerative joint disease with severe effects on individuals, society, and the economy that affects millions of elderly people around the world. To date, there are no effective treatments for OA; however, there are some treatments that slow or prevent its progression. Polyfunctional nanosystems have many advantages, such as controlled release, targeted therapy and high loading rate, and have been widely used in OA treatment. Previous mechanistic studies have revealed that inflammation and ROS are interrelated, and a large number of studies have demonstrated that ROS play an important role in different types of OA development. In this review article, we summarize third-generation ROS-sensitive nanomaterials that scavenge excessive ROS from chondrocytes and osteoclasts in vivo. We only focus on polymer-based nanoparticles (NPs) and do not review the effects of drug-loaded or heavy metal NPs. Mounting evidence suggests that polyfunctional nanosystems will be a promising therapeutic strategy in OA therapy due to their unique characteristics of being sensitive to changes in the internal environment.

Neuroinflammation and apoptosis after surgery for a rat model of double-level cervical cord compression.

INTRODUCTION: Cervical spondylotic myelopathy (CSM) is the most prevalent type of non-traumatic spinal cord injury. The pathological process of CSM is relatively complicated. Most of the chronic cervical cord compression animal models established using hydrophilic expanding polymer are single-segment compression, which was deviated from clinical practice with double-segment or multi-segment compression. This study aims to better mimic the actual clinical compression by using a new type of hydrophilic expanding polymer to establish an animal model of double-level cervical cord compression. MATERIALS AND METHODS: Progressive cord compression was done with implantation of polyvinyl alcohol-polyacrylamide hydrogel in the spinal canal at the C3-4 and C5-6 levels. Sprague-Dawley rats (n = 32) were divided into three groups: sham (no compression, n = 12) and screw compression group (n = 8), and hydrogel compression group (n = 12). Functional deficits were characterized using motor function scores, forelimb grip strength, hindlimb pain threshold, and gait analysis, while compression was imaged with magnetic resonance imaging. The apoptosis, inflammation, and demyelination were assessed by hematoxylin and eosin staining, Luxol fast blue staining, TUNEL assay, immunofluorescence staining, and Western blot analysis. RESULTS: Motor function scores for rats with cervical cord hydrogel compression were significantly decline in motor function scores, an increase in allodynia, neurons and oligodendrocytes apoptosis related to B cell lymphoma-2 (Bcl-2)/Bcl-2 associated X (Bax)/cleaved caspase-3, and impaired axonal conduction, as well as neuroinflammation zone related to microglia or macrophages aggregation related to the nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3 (NLRP3) inflammasome activation, and activation of astrocytes, as well as oxidative stress were observed. CONCLUSION: We believe that this model utilizing compression on double-level cervical cord will allow researchers to investigate of translationally relevant therapeutic methods for CSM.

Ginseng extract and ginsenosides improve neurological function and promote antioxidant effects in rats with spinal cord injury: A meta-analysis and systematic review.

Spinal cord injury (SCI) is defined as damage to the spinal cord that temporarily or permanently changes its function. There is no definite treatment established for neurological complete injury patients. This study investigated the effect of ginseng extract and ginsenosides on neurological recovery and antioxidant efficacies in rat models following SCI and explore the appropriate dosage. Searches were done on PubMed, Embase, and Chinese databases, and animal studies matches the inclusion criteria were selected. Pair-wise meta-analysis and subgroup analysis were performed. Ten studies were included, and the overall methodological qualities were low quality. The result showed ginseng extract and ginsenosides significantly improve neurological function, through the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale (pooled MD = 4.40; 95% CI = 3.92 to 4.88; p < 0.00001), significantly decrease malondialdehyde (MDA) (n = 290; pooled MD = -2.19; 95% CI = -3.16 to -1.22; p < 0.0001) and increase superoxide dismutase (SOD) levels (n = 290; pooled MD = 2.14; 95% CI = 1.45 to 2.83; p < 0.00001). Both low (<25 mg/kg) and high dosage (≥25 mg/kg) showed significant improvement in the motor function recovery in SCI rats. Collectively, this review suggests ginseng extract and ginsenosides has a protective effect on SCI, with good safety and a clear mechanism of action and may be suitable for future clinical trials and applications.

An Analysis of the Anti-Neuropathic Effects of Qi She Pill Based on Network Pharmacology.

BACKGROUND: Qi She Pill (QSP) is a traditional prescription for the treatment of neuropathic pain (NP) that is widely used in China. However, no network pharmacology studies of QSP in the treatment of NP have been conducted to date. OBJECTIVE: To verify the potential pharmacological effects of QSP on NP, its components were analyzed via target docking and network analysis, and network pharmacology methods were used to study the interactions of its components. MATERIALS AND METHODS: Information on pharmaceutically active compounds in QSP and gene information related to NP were obtained from public databases, and a compound-target network and protein-protein interaction network were constructed to study the mechanism of action of QSP in the treatment of NP. The mechanism of action of QSP in the treatment of NP was analyzed via Gene Ontology (GO) biological process annotation and Kyoto Gene and Genomics Encyclopedia (KEGG) pathway enrichment, and the drug-like component-target-pathway network was constructed. RESULTS: The compound-target network contained 60 compounds and 444 corresponding targets. The key active compounds included quercetin and beta-sitosterol. Key targets included PTGS2 and PTGS1. The protein-protein interaction network of the active ingredients of QSP in the treatment of NP featured 48 proteins, including DRD2, CHRM, ß2-adrenergic receptor, HTR2A, and calcitonin gene-related peptide. In total, 53 GO entries, including 35 biological process items, 7 molecular function items, and 11 cell related items, were identified. In addition, eight relevant (KEGG) pathways were identified, including calcium, neuroactive ligand-receptor interaction, and cAMP signaling pathways. CONCLUSION: Network pharmacology can help clarify the role and mechanism of QSP in the treatment of NP and provide a foundation for further research.

Muscone suppresses inflammatory responses and neuronal damage in a rat model of cervical spondylotic myelopathy by regulating Drp1-dependent mitochondrial fission.

Cervical spondylotic myelopathy (CSM) is a common cause of disability with few treatments. Aberrant mitochondrial dynamics play a crucial role in the pathogenesis of various neurodegenerative diseases. Thus, regulation of mitochondrial dynamics may offer therapeutic benefit for the treatment of CSM. Muscone, the active ingredient of an odoriferous animal product, exhibits anti-inflammatory and neuroprotective effects for which the underlying mechanisms remain obscure. We hypothesized that muscone might ameliorate inflammatory responses and neuronal damage by regulating mitochondrial dynamics. To this end, the effects of muscone on a rat model of chronic cervical cord compression, as well as activated BV2 cells and injured neurons, were assessed. The results showed that muscone intervention improved motor function compared with vehicle-treated rats. Indeed, muscone attenuated pro-inflammatory cytokine expression, neuronal-apoptosis indicators in the lesion area, and activation of the nod-like receptor family pyrin domain-containing 3 inflammasome, nuclear transcription factor-κB, and dynamin-related protein 1 in Iba1- and ßIII-tubulin-labeled cells. Compared with vehicle-treated rats, compression sites of muscone-treated animals exhibited elongated mitochondrial morphologies in individual cell types and reduced reactive oxygen species. In vitro results indicated that muscone suppressed microglial activation and neuronal damage by regulating related-inflammatory or apoptotic molecules. Moreover, muscone inhibited dynamin-related protein 1 activation in activated BV2 cells and injured neurons, whereby it rescued mitochondrial fragmentation and reactive oxygen species production, which regulate a wide range of inflammatory and apoptotic molecules. Our findings reveal that muscone attenuates neuroinflammation and neuronal damage in rats with chronic cervical cord compression by regulating mitochondrial fission events, suggesting its promise for CSM therapy.

Effect of docosahexaenoic acid on the recovery of motor function in rats with spinal cord injury: a meta-analysis.

OBJECTIVE: Studies have shown that docosahexaenoic acid (DHA) has a beneficial effect in the treatment of spinal cord injury. A meta-analysis was used to study the effect of DHA on the neurological recovery in the rat spinal cord injury model, and the relationship between the recovery of motor function after spinal cord injury and the time and method of administration and the dose of DHA. DATA SOURCE: Published studies on the effect of DHA on spinal cord injury animal models from seven databases were searched from their inception to January 2019, including PubMed, MEDLINE, EMBASE, the China National Knowledge Infrastructure, Wanfang, VIP, and SinoMed databases. The search terms included "spinal cord injury" "docosahexaenoic acid", and "rats". DATA SELECTION: Studies that evaluated the influence of DHA in rat models of spinal cord injury for locomotor functional recovery were included. The intervention group included any form of DHA treatment and the control group included treatment with normal saline, vehicle solution or no treatment. The Systematic Review Centre for Laboratory animal Experimentation's risk of bias assessment tool was used for the quality assessment of the included studies. Literature inclusion, quality evaluation and data extraction were performed by two researchers. Meta-analysis was then conducted on all studies that met the inclusion criteria. Statistical analysis was performed on the data using RevMan 5.1.2. software. OUTCOME MEASURES: The primary outcome measure was the score on the Basso, Beattie, and Bresnahan scale. Secondary outcome measures were the sloping plate test, balance beam test, stair test and grid exploration test. RESULTS: A total of 12 related studies were included, 3 of which were of higher quality and the remaining 9 were of lower quality. The highest mean Basso, Beattie, and Bresnahan scale score occurred at 42 days after DHA treatment in spinal cord injury rats. At 21 days after treatment, the mean difference in Basso, Beattie, Bresnahan scores between the DHA group and the control group was the most significant (pooled MD = 4.14; 95% CI = 3.58-4.70; P < 0.00001). In the subgroup analysis, improvement in the Basso, Beattie, and Bresnahan scale score was more significant in rats administered DHA intravenously (pooled MD = 2.74; 95% CI = 1.41-4.07; P < 0.0001) and subcutaneously (pooled MD = 2.99; 95% CI = 2.29-3.69; P < 0.00001) than in the groups administered DHA orally (pooled MD = 3.04; 95% CI = -1.01 to 7.09; P = 0.14). Intravenous injection of DHA at 250 nmol/kg (pooled MD = 2.94; 95% CI = 2.47-3.41; P < 0.00001] and 1000 nmol/kg [pooled MD = 3.60; 95% CI = 2.66-4.54; P < 0.00001) significantly improved the Basso, Beattie, and Bresnahan scale score in rats and promoted the recovery of motor function. CONCLUSION: DHA can promote motor functional recovery after spinal cord injury in rats. The administration of DHA by intravenous or subcutaneous injection is more effective than oral administration of DHA. Intravenous injection of DHA at doses of 250 nmol/kg or 1000 nmol/kg is beneficial. Because of the small number and the low quality of the included studies, more high-quality research is needed in future to substantiate the results.

MK-801 attenuates lesion expansion following acute brain injury in rats: a meta-analysis.

OBJECTIVE: To evaluate the efficacy and safety of MK-801 and its effect on lesion volume in rat models of acute brain injury. DATA SOURCES: Key terms were "stroke", "brain diseases", "brain injuries", "brain hemorrhage, traumatic", "acute brain injury", "dizocilpine maleate", "dizocilpine", "MK-801", "MK801", "rat", "rats", "rattus" and "murine". PubMed, Cochrane library, EMBASE, the China National Knowledge Infrastructure, WanFang database, the VIP Journal Integration Platform (VJIP) and SinoMed databases were searched from their inception dates to March 2018. DATA SELECTION: Studies were selected if they reported the effects of MK-801 in experimental acute brain injury. Two investigators independently conducted literature screening, data extraction, and methodological quality assessments. OUTCOME MEASURES: The primary outcomes included lesion volume and brain edema. The secondary outcomes included behavioral assessments with the Bederson neurological grading system and the water maze test 24 hours after brain injury. RESULTS: A total of 52 studies with 2530 samples were included in the systematic review. Seventeen of these studies had a high methodological quality. Overall, the lesion volume (34 studies, n = 966, MD = -58.31, 95% CI: -66.55 to -50.07; P < 0.00001) and degree of cerebral edema (5 studies, n = 75, MD = -1.21, 95% CI: -1.50 to -0.91; P < 0.00001) were significantly decreased in the MK-801 group compared with the control group. MK-801 improved spatial cognition assessed with the water maze test (2 studies, n = 60, MD = -10.88, 95% CI: -20.75 to -1.00; P = 0.03) and neurological function 24 hours after brain injury (11 studies, n = 335, MD = -1.04, 95% CI: -1.47 to -0.60; P < 0.00001). Subgroup analysis suggested an association of reduction in lesion volume with various injury models (34 studies, n = 966, MD = -58.31, 95% CI: -66.55 to -50.07; P = 0.004). Further network analysis showed that 0-1 mg/kg MK-801 may be the optimal dose for treatment in the middle cerebral artery occlusion animal model. CONCLUSION: MK-801 effectively reduces brain lesion volume and the degree of cerebral edema in rat models of experimental acute brain injury, providing a good neuroprotective effect. Additionally, MK-801 has a good safety profile, and its mechanism of action is well known. Thus, MK-801 may be suitable for future clinical trials and applications.

Riluzole promotes neurological function recovery and inhibits damage extension in rats following spinal cord injury: a meta-analysis and systematic review.

Spinal cord injury (SCI) is a devastating condition that has few treatment options. Riluzole, a sodium channel blocker used to treat amyotrophic lateral sclerosis, has been initially trialed in human SCI. We performed a systematic review to critically assess the efficacy of riluzole in locomotor recovery and damage extension in SCI rat models, and the potential for clinical translation. PubMed, Embase, Cochrane Library, and Chinese databases were searched from their inception date to March 2018. Two reviewers independently selected animal studies that evaluated neurological recovery and lesion area following riluzole treatment in SCI rat models, extracted data and assessed methodological quality. Pairwise meta-analysis, subgroup analysis, and network meta-analysis were performed to assess the effects of riluzole on SCI. Ten eligible studies were included. Two studies had high methodological quality. Overall, the Basso, Beattie, and Bresnahan scores were increased in riluzole-treated animals versus controls, and effect sizes showed a gradual increase from the 1st (five studies, n = 104, mean difference = 1.24, 95% CI = 0.11 to 2.37, p = 0.03) to 6th week after treatment (five studies, n = 120, mean difference = 2.34, 95% CI = 1.26 to 3.42, p < 0.0001). Riluzole was associated with improved outcomes in the inclined plane test and the tissue preservation area. Subgroup analyses suggested an association of locomotor recovery with riluzole dose. Network meta-analysis showed that 5 mg/kg riluzole exhibited greater protection than 2.5 and 8 mg/kg riluzole. Collectively, this review suggests that riluzole has a protective effect on SCI, with good safety and a clear mechanism of action and may be suitable for future clinical trials or applications. However, animal results should be interpreted with caution given the known limitations in animal experimental design and methodological quality.

Cross-cultural adaptation of Roland-Morris Disability Questionnaire needs to assess the measurement properties: a systematic review.

OBJECTIVE: To assess the cross-cultural adaptations of the Roland-Morris Disability Questionnaire (RMDQ). STUDY DESIGN AND SETTING: English and Chinese databases were searched through December 2017. Cross-cultural adaptation and measurement properties were evaluated using the Guidelines for the Process of Cross-Cultural Adaptation of Self-Report Measures and the Quality Criteria for Psychometric Properties of Health Status Questionnaire. RESULTS: Among 34 studies, there were 31 RMDQ adaptations for 26 different languages/cultures. In the cross-cultural adaptation process, few studies reported expert committees completely constituted (3/31), and only 10 studies completed the test of the prefinal version (10/31) due to insufficient sample sizes. As for the measurement properties, content validity (31/31) and construct validity (24/31) were assessed in most of the adaptations, whereas internal consistency (0/31), agreement (5/31), responsiveness (3/31), interpretability (6/31), and floor and ceiling effects (6/31) were not. CONCLUSION: The Hungarian and Moon's Korean adaptations were the highest quality translations. Where there were multiple adaptations for a language/culture, the Moon's Korean and Fan's simplified Chinese-Chinese Mainland adaptations are recommended over the other Korean or simplified Chinese-Chinese Mainland adaptations. Further studies are required to fully assess the measurement properties of the Arabic-Moroccan, Arabic-Tunisian, German-Austrian, Greek, Gujarati, Kim's Korean, Persian-Iranian, Polish, He's simplified Chinese-Chinese Mainland, Spanish, Spanish-Chilean, Thai, traditional Chinese-Taiwan, and Turkish adaptations of the RMDQ.