Thread-structural microneedles loaded with engineered exosomes for annulus fibrosus repair by regulating mitophagy recovery and extracellular matrix homeostasis.

Low back pain is among the most grave public health concerns worldwide and the major clinical manifestation of intervertebral disc degeneration (IVDD). The destruction of annulus fibrosus (AF) is the primary cause of IVDD. A sustainable and stable treatment system for IVDD is lacking because of the special organizational structure and low nutrient supply of AF. We here found that IVDD results in the impaired mitochondrial function of AF tissue, and mitochondrial autophagy (mitophagy) plays a protective role in this process. We therefore reported a thread-structural microneedle (T-MN) matching the ring structure of AF. Based on the adsorption effect of laminin, our T-MN could load with bone marrow mesenchymal stem cell-derived exosomes to envelope the regulating mitophagy microRNA (miRNA 378), named as T-MN@EXO@miR-378. In general, we offered in situ locking in the defect site of AF to prevent nucleus pulposus leakage and promoted AF repair. The design of the thread structure was aimed at bionically matching the layered AF structure, thereby providing stronger adhesion. The T-MN@EXO@miR-378 effectively attached to AF and slowly released therapeutic engineered exosomes, and prevented IVDD progression by restoring mitophagy, promoting AF cell proliferation and migration, and inhibiting the pathological remodeling of the extracellular matrix. This functional system can be used as an excellent tool for sustained drug release and has a certain prospect in substituting the conventional treatment of IVDD.

A trinity strategy enabled by iodine-loaded nitrogen-boron-doped carbon protective layer for dendrite-free zinc-ion batteries.

Although aqueous zinc ion batteries (AZIBs) have the merits of environmental friendliness, high safety and theoretical capacity, the slow kinetics associated with zinc deposition and unavoidable interfacial corrosion have seriously affected the commercialization of aqueous zinc ion batteries. In this work, an ingenious "trinity" design is proposed by applying a porous hydrophilic carbon-loaded iodine coating to the zinc metal surface (INBC@Zn), which simultaneously acts as an artificial protective layer, electrolyte additive and anode curvature regulator, so as to reduce the nucleation overpotential of Zn and promote the preferential deposition of (002) planes to some extent. With this synergistic effect, INBC@Zn exhibits high reversibility and strong side reaction inhibition. As a result, INBC@Zn shows high symmetric cycling stability up to 4500 h at 1 mA cm-2. An ultra-long cycle stability of 1500 cycles with high Coulombic efficiency (99.8 %) is achieved in the asymmetric cell. In addition, the INBC@Zn//NVO full cells exhibit impressive capacity retention (96 % after 1000 cycles at 3 A/g). Importantly, the designed pouch cell demonstrates stable performance and shows certain prospects for application. This work provides a facile and instructive approach toward the development of high-performance AZIBs.

Causal associations between gut microbiota with intervertebral disk degeneration, low back pain, and sciatica: a Mendelian randomization study.

PURPOSE: Although studies have suggested that gut microbiota may be associated with intervertebral disk disease, their causal relationship is unclear. This study aimed to investigate the causal relationship between the gut microbiota and its metabolic pathways with the risk of intervertebral disk degeneration (IVDD), low back pain (LBP), and sciatica. METHODS: Genetic variation data for 211 gut microbiota taxa at the phylum to genus level were obtained from the MiBioGen consortium. Genetic variation data for 105 taxa at the species level and 205 metabolic pathways were obtained from the Dutch Microbiome Project. Genetic variation data for disease outcomes were obtained from the FinnGen consortium. The causal relationships between the gut microbiota and its metabolic pathways and the risk of IVDD, LBP, and sciatica were evaluated via Mendelian randomization (MR). The robustness of the results was assessed through sensitivity analysis. RESULTS: Inverse variance weighting identified 46 taxa and 33 metabolic pathways that were causally related to IVDD, LBP, and sciatica. After correction by weighted median and MR-PRESSO, 15 taxa and nine pathways remained stable. After FDR correction, only the effect of the genus_Eubacterium coprostanoligenes group on IVDD remained stable. Sensitivity analyses showed no evidence of horizontal pleiotropy, heterogeneity, or reverse causation. CONCLUSION: Some microbial taxa and their metabolic pathways are causally related to IVDD, LBP, and sciatica and may serve as potential intervention targets. This study provides new insights into the mechanisms of gut microbiota-mediated development of intervertebral disk disease.

Effects of Catalpol from Rehmannia glutinosa Extract on Skin Flaps.

BACKGROUND: Flaps are commonly used for repairing tissues and wounds in surgery. However, various factors can cause postoperative necrosis in these flaps. Catalpol is a bioactive component in extracts from Rehmannia glutinosa , which has pharmacologic characteristics that may improve flap survival. METHODS: The experiments were performed in 36 male Sprague-Dawley rats divided into three groups: control, low-dose catalpol, and high-dose catalpol. The flap survival rate, neutrophil density, microvessel density, superoxide dismutase, and malondialdehyde levels were measured; histopathologic analysis was performed 7 days after surgery. Blood flow was measured by laser Doppler flowmetry and lead oxide-gelatin angiography. The levels of vascular endothelial growth factor, toll-like receptor 4, nuclear factor-kappa B, tumor necrosis factor-α, interleukin (IL)-6, nod-like receptor 3, cysteinyl aspartate specific proteinase-1 (caspase-1), IL-1ß, and IL-18 were determined by immunohistochemistry. RESULTS: Catalpol treatment increased flap survival, reduced neutrophil recruitment and release, decreased malondialdehyde levels, and increased superoxide dismutase levels; thus, it effectively reduced oxidative stress, up-regulated the expression of vascular endothelial growth factor, and increased microvessel density. Laser Doppler flowmetry and lead oxide-gelatin angiography showed that catalpol treatment improved angiogenesis. Immunohistochemical analyses showed that catalpol inhibited the production of inflammatory factors, such as tumor necrosis factor-α and IL-6, by down-regulating toll-like receptor 4 and nuclear factor-κB. Furthermore, catalpol reduced cell pyroptosis by inhibiting the production of nod-like receptor 3 inflammasomes, thereby down-regulating the release of IL-1ß and IL-18. CONCLUSION: Catalpol can improve the rate of flap survival. CLINICAL RELEVANCE STATEMENT: The research verified that the Rehmannia extract catalpol, through angiogenesis, inflammatory response, ischemia-reperfusion injury, and pyroptosis-related pathways, effectively improved the flap survival rate, which will provide new ideas for clinical medication.

Effects of Apigenin Treatment on Random Skin Flap Survival in Rats.

Random skin flaps are often used in plastic surgery, but the complications of marginal flap ischemia and necrosis often limit their wider clinical application. Apigenin (Api) is a flavonoid found in various fruits and vegetables. Api has been shown to promote angiogenesis, as well as reduce oxidative stress, membrane damage, and inflammation. In this study, we assessed the effects of Api treatment on random skin flap survival. Dorsal McFarlane skin flaps were transplanted into rats, which were randomly divided into three groups: control (normal saline), low-dose Api (20 mg/kg), and high-dose Api (50 mg/kg). Seven days after the surgery, the activity of superoxide dismutase (SOD) and the level of malondialdehyde (MDA) were measured. Histological analyses were performed to determine flap survival and tissue edema. H&E staining was performed to assess the histopathological changes in skin flaps, and the levels of microvascular density (MVD) were determined. Laser doppler flowmetry was used to assess microcirculation blood flow. Flap angiography was performed by injection of lead oxide/gelatin. The expression levels of vascular endothelial growth factor (VEGF), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interlukin-1ß (IL-lß) were evaluated by immunohistochemistry. Rats in the high-dose Api group exhibited higher average flap survival area, microcirculatory flow, increased SOD activity, and higher VEGF expression levels compared with the other two groups. Furthermore, the levels of MDA and pro-inflammatory cytokines were significantly decreased in rats treated with high-dose Api. Our findings suggest the potential usefulness of Api in preventing skin flap tissue necrosis.

Angiogenic and anti-inflammatory properties of azadirachtin A improve random skin flap survival in rats.

Random skin flaps are widely used to repair tissue defects. However, the distal flap regions are prone to ischemic necrosis, limiting clinical applications. Azadirachtin A, a fruit extract from the neem, improves tissue blood supply and metabolism, reduces cell swelling, promotes tissue healing, and prevents venous thrombosis. We explored whether it enhances random skin flap survival. Fifty-four Sprague-Dawley rats were divided into control, low-dose, and high-dose Azadirachtin A-treated groups using a random number table. We used an improved version of the McFarlane technique to create flaps. On day 2, superoxide dismutase and malondialdehyde levels were measured. Tissue slices prepared on day 7 were stained with hematoxylin and eosin. The expression levels of vascular endothelial growth factor (VEGF), toll-like receptor 4 (TLR4), nuclear factor kappa-B (NF-kB), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were immunohistochemically assayed. Microcirculatory blood flow was measured via laser Doppler blood flowmetry. Flap angiography was performed using the lead-oxide gelatin injection technique. And the azadirachtin A groups exhibited a greater mean flap survival area, an improved mean blood vessel density, a greater blood flow, and higher superoxide dismutase and VEGF levels, especially at the high dose. Azadirachtin A markedly reduced the levels of TNF-α, IL-6, IL-1ß, TLR4, and NF-kB. These findings suggest that azadirachtin A promotes random skin flap survival by improving the blood supply, reducing tissue inflammation, and inhibiting flap ischemia reperfusion injury.

Protective effects of dexmedetomidine on the survival of random flaps.

BACKGROUND: Random flaps can be used to repair wounds and improve shape and functional reconstruction, but inflammation and necrosis limit their application. Modified McFarlane flap models were constructed on the backs of rats. We hypothesized that dexmedetomidine (DEX) could improve the survival rate of ischemic random flaps. METHODS: Sixty rats were randomly divided into three groups: a low-dose DEX group (DEX-L group, 10 µg/kg/D), a high-dose DEX group (DEX-H group, 20 µg/kg/D) and a control group (0.9 % saline equivalent). On day 7 after flap construction, the survival percentage of the flap model was calculated. Hematoxylin and eosin staining (H&E) was used to evaluate the histopathological status of the flaps and microvessel density (MVD). Lead oxide/gelatin angiography was used to detect angiogenesis, and laser Doppler flow imaging (LDF) was used to detect blood perfusion. The levels of superoxide dismutase (SOD) and malondialdehyde (MDA) in the middle areas of the flaps were measured to show the level of oxidative stress. The expressions of Toll-like receptor (TLR4), nuclear factor-kappa B (NF-κB), interleukin (IL)-1ß, IL-6, tumor necrosis factor-α (TNF-α) and vascular endothelial growth factor (VEGF) were detected by immunohistochemistry. RESULTS: DEX significantly increased the average survival percentage of the flaps and reduced ischemia and necrosis of the distal end of the flaps. SOD activity significantly increased, while MDA significantly decreased, indicating that DEX reduces oxidative damage. The expression of inflammatory immunoregulatory proteins (TLR4, NF-κB) was downregulated, and the levels of inflammatory factors (IL-1ß, IL-6 and TNF-α) were lower. In addition, DEX upregulated VEGF expression, promoted angiogenesis, and increased blood perfusion. CONCLUSION: In random flap transplantation, a high dose of DEX is beneficial to flap survival.

Protective effect of citicoline on random flap survival in a rat mode.

BACKGROUND: Medical therapy for flap survival has been extensively investigated. In this study, we explored the effect of citicoline (CDP-choline, CDPC), used for clinical treatment of cerebral trauma, on random skin flap survival in rats. MATERIALS AND METHODS: Sixty rats were divided into three groups: low-dose (CDPC-L), high-dose (CDPC-H), and control. The CDPC-L and CDPC-H groups were intraperitoneally injected with 100 mg/kg and 300 mg/kg CDPC every day, respectively; the control group was injected with an equivalent volume of normal saline. The survival region was assessed on the 7th day after the flap operation. The microvascular density and neutrophil density were measured by hematoxylin and eosin staining. Lead angiography was used to detect angiogenesis, and laser Doppler was used to detect blood perfusion. Expression levels of vascular endothelial growth factor (VEGF), interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α, Toll-like receptor (TLR) 4, and nuclear factor kappa B (NF-κB) were detected by immunohistochemistry. Malondialdehyde and superoxide dismutase were used to determine the lipid peroxidation level. RESULTS: The average survival region of the flap was significantly larger in the CDPC-H group than in CDPC-L and control groups, with less ischemic necrosis. VEGF expression, microvascular density, angiogenesis, blood perfusion, and superoxide dismutase in the flap were higher in the CDPC-H group than in the CDPC-L and control groups. In addition, levels of neutrophil density, IL-1ß, IL-6, TNF-α, TLR4, NF-κB, and malondialdehyde decreased significantly in the CDPC-H group. CONCLUSION: High-dose CDPC injection after a random flap operation is beneficial for flap survival.

Protective effects of icariin on dorsal random skin flap survival: An experimental study.

This study was performed to examine the protective effects of icariin (ICA) on ischemic random skin flaps. A rat random-pattern skin flap model was established, and animals in the low-dose and high-dose experimental groups were administered ICA intraperitoneally at doses of 40 and 80 mg/kg, respectively, once daily for 7 days after the initial surgery. Control rats received vehicle according to the same schedule. Survival rates were observed and recorded using transparent graph paper, and flaps were obtained and stained with hematoxylin and eosin (H&E). The malondialdehyde (MDA) content and superoxide dismutase (SOD) activity in the flap tissue were assessed. The blood flow volume was determined by the laser Doppler method, and tissue expression levels of vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), interleukin-1ß, and phosphodiesterase 5 (PDE5) were scored immunohistochemically. The levels of proinflammatory cytokines, including tumor necrosis factor-α and IL-6, were determined by enzyme-linked immunosorbent assay. The main flap survival area was significantly larger in rats treated with ICA than in vehicle-treated controls. H&E staining showed an inhibitory effect of ICA on inflammation, especially at the high dose. In addition, ICA treatment was associated with decreases in the tissue MDA level, proinflammatory cytokine production, and the level of PDE5, but increases in SOD activity, blood flow volume, and the level of VEGF expression. The findings of the present study suggest that ICA is a potential therapeutic agent for random-pattern skin flap necrosis in the clinical setting.

Effects and mechanism of urinary kallidinogenase in the survival of random skin flaps in rats.

OBJECTIVE: This study explored the effects of urinary kallidinogenase (UK) on ischemia and necrosis of random skin flaps in rats, and the mechanisms thereof. METHODOLOGY: Ischemia and necrosis of random skin flaps were induced by constructing a modified McFarlane flap model on the dorsa of rats. UK (0.016 PNA/kg) or normal saline (10 ml/kg, control) was administered through the tail vein immediately after flap ischemia model construction and then daily for 7 days. After sacrifice, the flap tissue was harvested and stained with hematoxylin and eosin (H&E), and histopathological changes were observed. Lead oxide/gelatin angiography and laser Doppler imaging were performed to demonstrate angiogenesis and changes in blood flow. Immunohistochemical analysis of the H&E-stained slices was performed to detect the expression of vascular endothelial growth factor (VEGF), interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α (TNF-α). The TNF-α and IL-6 levels were also detected by enzyme-linked immunosorbent assays. The activity of superoxide dismutase (SOD) and the malondialdehyde (MDA) content were measured to represent the oxidative damage level. RESULTS: UK significantly alleviated ischemia and necrosis of random skin flaps, as evidenced by improved general results and histopathological manifestations, and markedly increased the mean survival area. UK prompted angiogenesis, increased blood flow and VEGF expression. The levels of TNF-α, IL-6, and IL-1ß were declined. Furthermore, UK increased SOD activity and decreased MDA content, suggesting that it has the capacity to alleviate oxidative damage. CONCLUSION: These findings suggest that UK sufficiently attenuated flap ischemia and increased the survival of random skin flaps in rats.

Effects of batroxobin treatment on the survival of random skin flaps in rats.

OBJECTIVE: Batroxobin is a medicinal preparation extracted from the venom of the Fer-de-Lance snake, and is used to lower blood viscosity, promote blood fibrinogen decomposition, and inhibit thrombosis. This research is to investigate whether batroxobin can improve the survival of random skin flaps in a rat model. MATERIALS AND METHODS: Dorsal McFarlane flaps were harvested from 36 rats divided into two groups. Experimental group: Batroxobin was administered via the tail vein once daily. CONTROL GROUP: The same amount of normal saline was injected instead. On day 2, superoxide dismutase (SOD) and malondialdehyde (MDA) levels were measured. On day 7, tissue slices were stained with haematoxylin and eosin. Expression of vascular endothelial growth factor (VEGF) was immunohistochemically evaluated. Microcirculatory flow was measured by laser Doppler flowmetry. Flap angiography, using the lead oxide-gelatin injection technique, was performed with the aid of a soft X-ray machine. RESULTS: The batroxobin group exhibited a greater mean flap survival area, a better microcirculatory flow, and higher-level expression of SOD and VEGF compared with the control group. However, the MDA level was significantly reduced. CONCLUSION: Batroxobin effectively improved the survival of random skin flaps.

Effect of oxytocin on the survival of random skin flaps.

Random flap transplantation is widely used to repair and rebuild skin soft tissue. However, such flaps exhibit poor survival. Plastic surgeons seek to improve flap survival. We explored whether oxytocin improved skin flap survival. Overlength random skin flaps (9 × 3 cm) were established on backs of 80 healthy male SD rats randomly divided into two groups. One group was injected daily with oxytocin (1 mg/kg; test group) and the other with normal saline (control group). On postoperative day 2, malondialdehyde (MDA) and superoxide dismutase (SOD) levels were measured. On postoperative day 7, the flap survival area was measured using transparent graph paper. Microvessel numbers were evaluated histologically by hematoxylin and eosin staining. VEGF expression was assessed immunohistochemically. Angiogenesis was evaluated via lead oxide-gelatin angiography and blood flow via laser Doppler flowmetry. In the test group compared with the control group, the flap survival rate and SOD activity were increased markedly, the MDA level was decreased, and according to hematoxylin and eosin staining, inflammation was significantly attenuated. In addition, the test group exhibited higher levels of VEGF and skin flap angiogenesis. Oxytocin improved flap survival rate by increasing microcirculation and angiogenesis and attenuating ischemia-reperfusion injury.