Porous microneedle patch with sustained delivery of extracellular vesicles mitigates severe spinal cord injury.

The transplantation of mesenchymal stem cells-derived secretome, particularly extracellular vesicles is a promising therapy to suppress spinal cord injury-triggered neuroinflammation. However, efficient delivery of extracellular vesicles to the injured spinal cord, with minimal damage, remains a challenge. Here we present a device for the delivery of extracellular vesicles to treat spinal cord injury. We show that the device incorporating mesenchymal stem cells and porous microneedles enables the delivery of extracellular vesicles. We demonstrate that topical application to the spinal cord lesion beneath the spinal dura, does not damage the lesion. We evaluate the efficacy of our device in a contusive spinal cord injury model and find that it reduces the cavity and scar tissue formation, promotes angiogenesis, and improves survival of nearby tissues and axons. Importantly, the sustained delivery of extracellular vesicles for at least 7 days results in significant functional recovery. Thus, our device provides an efficient and sustained extracellular vesicles delivery platform for spinal cord injury treatment.

Controlled delivery of a neurotransmitter-agonist conjugate for functional recovery after severe spinal cord injury.

Despite considerable unmet medical needs, effective pharmacological treatments that promote functional recovery after spinal cord injury remain limited. Although multiple pathological events are implicated in spinal cord injuries, the development of a microinvasive pharmacological approach that simultaneously targets the different mechanisms involved in spinal cord injury remains a formidable challenge. Here we report the development of a microinvasive nanodrug delivery system that consists of amphiphilic copolymers responsive to reactive oxygen species and an encapsulated neurotransmitter-conjugated KCC2 agonist. Upon intravenous administration, the nanodrugs enter the injured spinal cord due to a disruption in the blood-spinal cord barrier and disassembly due to damage-triggered reactive oxygen species. The nanodrugs exhibit dual functions in the injured spinal cord: scavenging accumulated reactive oxygen species in the lesion, thereby protecting spared tissues, and facilitating the integration of spared circuits into the host spinal cord through targeted modulation of inhibitory neurons. This microinvasive treatment leads to notable functional recovery in rats with contusive spinal cord injury.

Glucose trajectory prediction by deep learning for personal home care of type 2 diabetes mellitus: modelling and applying.

Glucose management for people with type 2 diabetes mellitus is essential but challenging due to the multi-factored and chronic disease nature of diabetes. To control glucose levels in a safe range and lessen abnormal glucose variability efficiently and economically, an intelligent prediction of glucose is demanding. A glucose trajectory prediction system based on subcutaneous interstitial continuous glucose monitoring data and deep learning models for ensuing glucose trajectory was constructed, followed by the application of personalised prediction models on one participant with type 2 diabetes in a community. The predictive accuracy was then assessed by RMSE (root mean square error) using blood glucose data. Changes in glycaemic parameters of the participant before and after model intervention were also compared to examine the efficacy of this intelligence-aided health care. Individual Recurrent Neural Network model was developed on glucose data, with an average daily RMSE of 1.59 mmol/L in the application segment. In terms of the glucose variation, the mean glucose decreased by 0.66 mmol/L, and HBGI dropped from 12.99 × 102 to 9.17 × 102. However, the participant also had increased stress, especially in eating and social support. Our research presented a personalised care system for people with diabetes based on deep learning. The intelligence-aided health management system is promising to enhance the outcome of diabetic patients, but further research is also necessary to decrease stress in the intelligence-aided health management and investigate the stress impacts on diabetic patients.

A biocompatible two-photon absorbing fluorescent mitochondrial probe for deep in vivo bioimaging.

Mitochondria, key organelles which keep in tune with energy demands for eukaryotic cells, are firmly associated with neurological conditions and post-traumatic rehabilitation. In vivo fluorescence imaging of mitochondria, especially with deep tissue penetration, would open a window to investigate the actual context of the brain. However, the depth of traditional two-photon mitochondrial fluorescence imaging is still limited due to the poor biological compatibility or low two-photon absorption cross-sections. A biocompatible mitochondria-targeted two-photon fluorescent dye (FO2) with an excellent two-photon absorption cross-section (the maximum of 1184 GM at 790 nm) and low cellular toxicity was designed and synthesized to overcome this problem. With this dye, we reached an imaging depth of ca. 640 µm during mitochondrial imaging of cortical cells in live animals. FO2 could be an excellent mitochondrial probe for live animal neural imaging to investigate the function and dysfunction of mitochondria in the brain.

Correction: A biocompatible two-photon absorbing fluorescent mitochondrial probe for deep in vivo bioimaging.

Correction for 'A biocompatible two-photon absorbing fluorescent mitochondrial probe for deep in vivo bioimaging' by Lingmin Lin et al., J. Mater. Chem. B, 2022, DOI: 10.1039/d1tb02040d.

Single-cell RNA-seq reveals the transcriptional landscape in ischemic stroke.

Ischemic stroke (IS) is a detrimental neurological disease with limited treatments options. It has been challenging to define the roles of brain cell subsets in IS onset and progression due to cellular heterogeneity in the CNS. Here, we employed single-cell RNA sequencing (scRNA-seq) to comprehensively map the cell populations in the mouse model of MCAO (middle cerebral artery occlusion). We identified 17 principal brain clusters with cell-type specific gene expression patterns as well as specific cell subpopulations and their functions in various pathways. The CNS inflammation triggered upregulation of key cell type-specific genes unpublished before. Notably, microglia displayed a cell differentiation diversity after stroke among its five distinct subtypes. Importantly, we found the potential trajectory branches of the monocytes/macrophage's subsets. Finally, we also identified distinct subclusters among brain vasculature cells, ependymal cells and other glia cells. Overall, scRNA-seq revealed the precise transcriptional changes during neuroinflammation at the single-cell level, opening up a new field for exploration of the disease mechanisms and drug discovery in stroke based on the cell-subtype specific molecules.

Association of Fibroblast Growth Factor 23 With Ischemic Stroke and Its Subtypes: A Mendelian Randomization Study.

Fibroblast growth factor 23 (FGF23), which is involved in the regulation of vitamin D, is an emerging independent risk factor for cardiovascular diseases. Previous studies have demonstrated a positive association between FGF23 and stroke. In this study, we aimed to assess the association of FGF23 with ischemic stroke and its subtypes by applying a Mendelian randomization (MR) framework. Five genetic variants obtained from a genome-wide association study involving 16,624 European subjects were used as valid instruments of circulating FGF23 levels. MR was applied to infer the causality of FGF23 levels and the risk of ischemic stroke using data from the MEGASTROKE consortium. Subsequently, several MR analyses, including inverse-variance weighted meta-analysis, MR-Egger, weighted median estimate (WME), MR Pleiotropy Residual Sum and Outlier were performed. The heterogeneity test analysis, including Cochran's Q, I 2 test and leave-one-out analysis were also applied. Furthermore, potential horizontal/vertical pleiotropy was assessed. Lastly, the power of MR analysis was tested. Three validated variants were found to be associated with circulating FGF23 levels and were used for further investigation. We found that high expression level of FGF23 was not associated with any ischemic stroke. However, a causal association between genetically predicted FGF23 levels and the risk of large-artery atherosclerotic stroke (LAS) was significant, with an odds ratio of 1.74 (95% confidence interval = 1.08-2.81) per standard deviation increase in circulating FGF23 levels. Our findings provide support for the causal association between FGF23 and LAS, and therefore, offer potential therapeutic targets for LAS. The specific roles of FGF23 in LAS and associated molecules require further investigation.

[Effect of transcutaneous electrical acupoint stimulation on gastric emptying in patients undergoing surgery].

OBJECTIVE: To observe the effects of transcutaneous electrical acupoint stimulation (TEAS) on gastric emptying in patients undergoing selective surgery based on velocity of gastric emptying by ultrasonography. METHODS: A total of 75 patients with selective operation of subarachnoid block at lower limb in the afternoon were randomly assigned to a TEAS group, a sham group and a control group, 25 patients in each one. All the patients were provided with semi-fluid diet at 8 a.m. The TEAS group was treated with TEAS 5 min after semi-fluid diets at bilateral Zusanli (ST 36) and Neiguan (PC 6) for 30 min, with frequency of 5 Hz and intensity which was 1 mA lower than the tolerance threshold. The sham group patients were stimulated at the same acupoints with current intensity which was 1 mA lower than the sensory threshold. The control group received no treatment. On the day of operation, and ultrasonography was given at time of empty stomach (T0), immediately after the semi-fluid diets (T1), and every 30 min after diets (T2-T6), respectively, to measure the gastric content and emptying time at semire-clining position and right lateral position. RESULTS: The volume of gastric content in the three groups at T3-T6 was significantly less than that at T1 (all P<0.05). The volume of gastric content at T4-T6 at semire-clining position in the TEAS group was significantly less than that in the control group and sham group (all P<0.05). The volume of gastric content at T5-T6 at right lateral position in the TEAS group was significantly less than that in the control group and sham group (all P<0.05). The gastric emptying time in the TEAS group was significantly less than that in the control group and sham group (both P<0.05). CONCLUSION: The gastric emptying velocity could be evaluated by ultrasonography. TEAS could improve the velocity of gastric emptying and reduce the gastric emptying time.