Search

Injectable granular gels consisting of densely packed microgels serving as scaffolding biomaterial have recently shown great potential for applications in tissue regeneration, which allow administration via minimally invasive surgery, on-target cargo delivery, and high efficiency in nutrient/waste exchange. However, limitations such as insufficient mechanical strength, structural integrity, and uncontrollable differentiation of the encapsulated cells in the scaffolds hamper their further applications in the biomedical field. Herein, we developed a new class of granular gels via bottom-up assembly of cell-laden microgels via photo-triggered imine-crosslinking (PIC) chemistry based on the microfluidic technique. The particulate nature of the granular gels rendered them with shear-thinning and self-healing behavior, thereby functioning as an injectable and adaptable cellularized scaffold for bone tissue regeneration. Specifically, single cell-laden, monodisperse microgels composed of methacrylate- and o-nitrobenzene-functionalized hyaluronic acid and gelatin were prepared using a high-throughput microfluidic technique with a production rate up to 3.7 × 108 microgels/hr, wherein the PIC chemistry alleviated the oxygen inhibition on free-radical polymerization and facilitated enhanced fabrication accuracy, accelerated gelation rate, and improved network strength. Further in vitro and in vivo studies demonstrated that the microgels can serve as carriers to support the activity of the encapsulated mesenchymal stem cells; these cell-laden microgels can also be used as cellularized bone fillers to induce the regeneration of bone tissues as evidenced by the in vivo experiment using the rat femoral condyle defect model. In general, these results represent a significant step toward the precise fabrication of engineered tissue mimics with single-cell resolution and high cell-density and can potentially offer a powerful tool for the design and applications of a next generation of tissue engineering strategy. Statement of significance: Using microfluidic droplet-based technology, we hereby developed a new class of injectable and moldable granular gels via bottom-up assembly of cell-laden microgels as a versatile platform for tissue regeneration. Phototriggered imine-crosslinking chemistry was introduced for microgel cross-linkage, which allowed for the fabrication of microgels with improved matrix homogeneity, accelerated gelation process, and enhanced mechanical strength. We demonstrated that the microgel building blocks within the granular gels facilitated the proliferation and differentiation of the encapsulated mesenchymal stem cells, which can further serve as a cellularized scaffold for the treatment of bone defects.

Cooperatively enhanced photothermal-chemotherapy via simultaneously downregulating heat shock proteins and promoting DNA alkylation to achieve efficient cancer therapy.

As a controllable biological process, regulated cell death (RCD) extensively participates in cellular homeostasis, organismal development, and the pathogenesis of diseases. This review addresses the research gaps by synthesising the findings on the complexity of RCD modes and their role in disc degeneration, and summarises the preclinical strategies to alleviate disc degeneration and promote disc repair by regulating RCD.Intervertebral disc degeneration (IDD) is the major source of chronic low back pain. As a controllable biological process, regulated cell death (RCD) extensively participates in the pathogenesis of IDD. Nevertheless, the initiation and progression of RCD remain unclear, and more importantly, the interaction between different RCD modes during IDD and therapy is far from well understood.Literature search was performed using "regulated cell death AND intervertebral disc degeneration" in PubMed, Embase, and Web of Science. Meanwhile, relevant findings have been reviewed and quoted.In this review, we discuss the inducing factors of IDD, various modes of RCD in intervertebral disc, the interactions between different RCD modes, as well as the obstacles to achieve disc regeneration. Meanwhile, the research gaps and perspective in studies that targeting RCD are also presented.Increasing evidence demonstrated the presence of different RCD modes in intervertebral disc during the progression of IDD. RCD in the resident disc cells is probably induced by the multiple factors such as abnormal mechanical loading, nutritional imbalance, inflammation microenvironment, circadian rhythm changes, withdraw of hormones, and other biomechanical factors. A better understanding of the fundamental mechanisms and the interactions between different RCD modes might contribute to the rescuing of disc degeneration and development of promising therapeutics.The Translational potential of this article. This review aims to demonstrate a better understanding of the fundamental mechanisms governing RCD, which might contribute to the rescuing of disc degeneration and to the development of promising therapeutics in a clinical setting.

Yiran Zhang,1– 4,* Hongzhi Hu,5,* Xiangtian Deng,6,* Qingcheng Song,2 Xin Xing,2,3 Weijian Liu,5 Yingze Zhang1– 3 1School of Medicine, Nankai University, Tianjin, 300071, People’s Republic of China; 2Department of Orthopaedic Surgery, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050051, People’s Republic of China; 3NHC Key Laboratory of Intelligent Orthopaedic Equipment, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 4HeBei Ex&Invivo Biotechnology Co. Ltd, Shijiazhuang, Hebei, 050051, People’s Republic of China; 5Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 6Orthopaedics Research Institute, Department of Orthopaedics, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yingze Zhang; Weijian Liu, Email yzling_liu@163.com; xh_liuweijian@hust.edu.cnBackground: Although chemodynamic therapy (CDT) has attracted enormous attention in anti-tumor studies for converting endogenous hydrogen peroxide (H2O2) into toxic hydroxyl radicals (•OH) by Fenton-type reaction, the treating effects of using CDT alone is still unsatisfying. Recently, glucose oxidase (GOx) was reported to be co-delivered with Fenton agent for synergistic starvation therapy (ST) and CDT. However, the overexpressed glutathione (GSH) and hypoxia in tumor microenvironment (TME) restrict the therapeutic efficacy of ST/CDT.Methods and Results: In this work, a novel nanoplatform composed of GOx plus Fenton agent (Cu2+) encapsulated core and metformin (MET)-loaded manganese dioxide nanosheets (MNSs) shell was prepared and further functionalized by arginine-glycine-aspartate (RGD). With the RGD-mediated affinity with cancer cells, the nanocomposite (GOx-CuCaP@MNSs-MET@PEG-RGD, GCMMR) could accomplish targeting delivery and TME-activated release of cargos. The intracellular GSH was depleted by MnO2/Cu2+ and abundant H2O2 was generated along with the GOx-induced glucose deprivation, which process was further enhanced by MET-mediated hypoxia relief via inhibiting mitochondria-associated respiration. Subsequently generated •OH from Cu+-mediated Fenton-like reaction exerts severe intracellular oxidative stress and cause apoptosis. Moreover, significant inhibition of tumor growth was detected in a subcutaneous xenograft model of osteosarcoma (OS) after GCMMR treatment.Conclusion: The excellent therapeutic efficacy and biosafety of the nanoplatform were confirmed both in vitro and in vivo. Collectively, this study provides an appealing strategy with catalytic cascade enhancement on targeted ST/CDT for cancer treatment, especially for hypoxic solid tumors.Graphical Abstract: Keywords: chemodynamic therapy, starvation therapy, glucose oxidase, Fenton reaction, biomineralization, metformin

Intervertebral disc (IVD) degeneration (IVDD) is the most common spinal disorder, which can lead to the symptoms of neck pain or low back pain. In healthy mature IVD tissues, extracellular matrix (ECM) complex possesses favorable biochemical and biomechanical properties, withstanding compression and torsion forces. IVD cells and ECM associate with each other to form a coordinated functional system. IVD cells are the main producers of ECM components, while ECM could modulate the viability and phenotype of IVD cells via direct interactions or indirect regulations. However, with the process of IVDD and ageing, ECM of IVD undergoes content loss and structure degeneration. Moreover, the accumulation of catabolic products may further deteriorate the IVD microenvironment. A better understanding of the physiology and the pathology of ECM within the IVD provides new insight into potential IVD regeneration strategies. Natural ECM components, functional motifs, or mimetic peptides are widely used in IVD repair by not only restoring structural support but also regulating cell fate and tissue microenvironment. Herein, we reviewed recent advances in the involvement of ECM in IVD health and disease, with an emphasis on ECM composition and organization, cell-matrix interactions, pathological ECM degradation, and promising matrix-based biomaterials for IVD regeneration.

Intervertebral disc (IVD) degeneration (IDD), the leading cause of low back pain (LBP), remains intractable due to a lack of effective therapeutic strategies. Several lines of studies have documented that nucleus pulposus cell (NPC) death induced by excessive oxidative stress is a crucial contributor to IDD. However, the concrete role and regulation mechanisms have not been fully clarified. Selenium (Se), a vital prosthetic group of antioxidant enzymes, is indispensable for maintaining redox homeostasis and promoting cell survival. However, no light was shed on the role of Se on IDD progression, especially regulation on mitochondrial dynamics and homeostasis. To fill this research gap, the current study focuses on the effects of Se, including sodium selenite (SS) and selenomethionine (Se-Met), on IDD progression and the underlying mechanisms. In vitro, we found that both SS and Se-Met alleviated tert-butyl hydroperoxide- (TBHP-) induced oxidative stress, protected mitochondrial function, and inhibited apoptosis of NPCs. Further experiments indicated that Se suppressed TBHP-induced mitochondrial fission and rescued the imbalance of mitochondrial dynamics. Promoting mitochondrial fission by carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP) partially counteracted the cytoprotective effects of Se. Moreover, blocking nuclear factor erythroid 2-related factor 2 (Nrf2) with ML385 proved that the effect of Se on regulating mitochondrial dynamics was attributed to the activation of the Nrf2 pathway. In the puncture-induced rat IDD model, a supplement of Se-Met ameliorated degenerative manifestations. Taken together, our results demonstrated that Se suppressed TBHP-induced oxidative stress and mitochondrial fission by activating the Nrf2 pathway, thereby inhibiting the apoptosis of NPCs and ameliorating IDD. Regulation of mitochondrial dynamics by Se may have a potential application value in attenuating the pathological process of IDD.

Ketamine was proven to have short-term antidepressant effects. There is a paucity of studies focused on the long-term outcomes of repeated infusions of ketamine. This study aimed to examine the long-term outcomes of repeated ketamine infusions in patients with unipolar and bipolar depression METHODS: One hundred and eight patients with unipolar and bipolar depression completed the repeated treatment phase (administered ketamine three times weekly over a 12-day) and entered a 9-month naturalistic follow-up phase. Assessments were obtained at week 2, month 6, and month 9 after the repeated treatment phase. The Patient Health Questionnaire-9 (PHQ-9) Scale and the Global Assessment of Functioning (GAF) Scale were used to assess depressive symptoms and global functional status, respectively.Seventy-one (65.7%) of patients completed the 9-month follow-up. On month 9, the response and remission rate were 80.3% and 78.9%, respectively. Among 56 patients who achieved response after the repeated treatment phase, 26 (46.4%) of patients sustained response during 9-month follow-up and their GAF score remained over 70. Sixteen patients relapsed during the 9-month follow-up and 14 (85.7%) of the relapse occurred during the first 2-week follow-up.The major limitation of this study is the open-label design.This small sample study suggested that patients with unipolar and bipolar depression who response to repeated treatment with continued oral antidepressant may be a viable treatment option, and their global functional status improved with a follow-up. Relapse of depression tended to occur during the 2 weeks follow-up.

Traditional "one for one channel" long-wavelength probes in hematology analyzers limit their resolution and detection efficiency. In this study, we developed a "one for two channels" probe named NATO, which shows a short wavelength (λ

It is ideal yet challenging to achieve precise tumor targeting and high-quality imaging guided combined photodynamic and photothermal therapy (PDT and PTT). In this study, we synthesized a series of D-π-A-type single-molecule photosensitizers (CyE-TT, CyQN-TT, and CyQN-BTT) based on quaternized 1,1,2-trimethyl-1

Recently, an animal model for depression has shown that ketamine, an N-methyl- d-aspartate receptor (NMDAR) antagonist, elicits a rapid-acting antidepressant effect by blocking NMDAR-dependent bursting in the lateral habenula (Hb). However, evidence from human studies remains scarce.This study explored the changes of resting-state functional connectivity (FC) of the Hb in responders and nonresponders who was diagnosed with unipolar or bipolar depression before and after ketamine treatment. The response was defined as a ≥50% reduction in the total MADRS score at Day 13 (24 h following the sixth infusion) in comparison with the baseline score. Correlation analyses were performed to identify an association between symptom improvement and the signals of the significantly different brain regions detected in the above imaging analysis.In the post-hoc region-of-interest analysis, an enhanced baseline FC between Hb and several hubs of the default mode network (including angulate cortex, precuneus, medial prefrontal cortex, and middle temporal cortex) was observed in responders (≥50% decrease in the Montgomery-Asberg Scale at 2 weeks) compared with nonresponders.These pilot findings may suggest a potential neural mechanism by which ketamine exerts its robust antidepressant efficacy via downregulation of aberrant habenular FC with parts of the default mode network.

Erratic rainfall and misalignment between the rainy season and the growing season of winter wheat greatly limit rainfed winter wheat yield in the Loess Plateau of China. To increase the grain yield of winter wheat in this region, the effects of different agronomic practices, including adjusting planting pattern (NR, narrow row spacing), increasing seeding rate (high seeding rate, HS), decreasing basal nitrogen rate and increasing top-dressed nitrogen rate (DBN), and replacing an old cultivar with a new cultivar (NC) on wheat yield were investigated for two consecutive years. The results showed that the current grain yield of rainfed winter wheat in the Loess Plateau could be increased to 5879–7093 kg ha−1 by HS, DBN and NC practices relative to the practice of high-yielding farmers (PF). The increased yield due to HS, DBN and NC was attributed to the higher number of spikes ha−1, 1000-grain weight, and kernels spike−1. Before the flowering stage, HS increased soil water consumption (SWC) in 1–3 m subsoil due to the higher plant population compared with that of PF, whereas DBN decreased SWC in the 0–2 m soil layer compared with that of PF. After the flowering stage, HS, DBN, and NC increased SWC by 8–16 mm in 2–3 m subsoil compared to PF. The water use efficiency (WUE) was increased under DBN and NC in comparison with PF. However, the WUE did not increase under HS as it had the highest evapotranspiration among the five treatments. Increasing the use of subsoil water during the late growth stage by optimizing agronomic practices or applying new cultivars with expansive roots should be the primary approach to increase rainfed winter wheat yield in this region.

In this study, a data analysis method for the relaxation test was proposed under step loading by conducting creep and stress relaxation tests of dentate discontinuity poured by cement mortar using biaxial creep machine under step loading and single-stage loading. First, a superposition method for the stress relaxation curve was deduced based on the data processing method of creep test by considering the effect of loading history on the relaxation curve and the characteristic of relaxation was analyzed. Second, this superposition method was verified by testing data under step loading and single-stage loading. Finally, this paper indicate the accurate way for the processing of relaxation test data under step loading. The results show that under the same stress level, the values of relaxation curve after the superposition are different from that under the single-stage loading test. Furthermore, the relaxation curves in the step loading test under different stress levels are similar to those in single-stage loading under the same stress level. Furthermore, creep deformation increase monotonically during the creep, but stress do not exhibit such a trend during relaxation, which is inconsistent with the Boltzmann superposition principle. The relaxation curve in the step loading test under different shear stress could reflect the relaxation properties of the single-stage loading test under the same shear stress, and unlike the data processing method of step loading creep test, superimposition is not needed.

BACKGROUND Existing therapeutic efficacy of chemotherapy and photodynamic therapy (PDT) is always affected by some resistance factors from tumour environment (TME), such as hypoxia and the antioxidant defense system. PURPOSE This study aims at developing a cascaded intelligent multifunctional nanoplatforms to modulate the TME resistance for synergistically enhanced chemo- and photodynamic therapies. METHODS In this study, we synthesised hollow manganese dioxide nanoparticles (HMDNs) loaded with the hydrophilic chemotherapeutic drug (acriflavine, ACF) and the hydrophobic photosensitizer (chlorine6, Ce6), which was further encapsulated by pH-sensitive liposome to form core-shell nanocomposite, with surface modified with arginine-glycine-aspartic acid (RGD) peptide to achieve tumour targeting. RESULTS After uptake by tumour cells, the liposome shell was rapidly degraded by the low pH, and the inner core could be released from the liposome. Then, the released HMDNs/ACF/Ce6 would be dissociated by low pH and high levels of intracellular GSH within TME to release encapsulated drugs, thereby resulting in synergistic effects of chemotherapy and PDT. Meanwhile, the released ACF could bind with HIF-1a and then inhibit the expression levels of HIF-1's downstream signalling molecules P-gp and VEGF, which could further strengthen the antitumor effects. As a result, HMDNs/ACF/Ce6@Lipo-RGD NPs with laser irradiation exhibited superior anti-tumour therapeutic efficiency.