Near-infrared hemicyanine photosensitizer for targeted mitochondrial viscosity imaging and efficient photodynamic therapy.

As a severe threat to human health, cancer has always been one of the most significant challenges facing the medical field. However, there is currently no effective technology or method to diagnose and treat cancer simultaneously. Therefore, developing a new approach that integrates diagnosis and treatment holds promise as a means of achieving personalized and precise cancer therapy. In this study, we developed a novel dual-functional near-infrared mitochondrial-targeted photosensitizer, Hcy-I, which is capable of simultaneously monitoring cellular viscosity and specifically targeting mitochondria for photodynamic therapy. Compared with traditional hemicyanine dyes, the introduction of iodine atoms in Hcy-I enhanced spin-orbit coupling (SOC) and promoted the intersystem crossing (ISC) rate, thereby increasing the efficiency of singlet oxygen (1O2) generation. In vitro experiments demonstrated that Hcy-I exhibited high sensitivity to viscosity variations and efficiently generated 1O2 under 638 nm laser irradiation, with an 1O2 quantum yield of up to 48.9 %. Cell experiments further revealed that this photosensitizer could effectively target mitochondria for photodynamic therapy, disrupting mitochondrial membrane potential and inducing cell death. When treated with Hcy-I at a concentration of 0.8 µM, the survival rate of HepG-2 cells was only 13 %. These results suggested that Hcy-I had the potential to integrate cancer diagnosis and treatment. The research not only promotes the development of photodynamic thereby technology, but also opens up new avenues for the diagnosis and treatment of cancer.

Molecularly Imprinted Polymers for Highly Specific Bioorthogonal Catalysis inside Cells.

Transition metal catalysts (TMCs) mediated bioorthogonal catalysis expand the chemical possibilities within cells. Developing synthetic TMCs tools that emulate the efficiency and specificity of natural metalloenzymes is a rewarding yet challenging endeavor. Here, we highlight the potential of molecularly imprinted enzyme mimics (MIEs) containing a Cu center and specific substrate binding domain, for conducing dimethylpropargyloxycarbonyl (DmProc) cleavage reactions within cells. Our studies reveal that the Cu-MIEs act as highly specific guides, precisely catalyzing target substrates, even in glutathione (GSH)-rich cellular environments. By adapting templates similar to the target substrates, we evolved Cu-MIEs activity to a high level and provided a method to broaden its scope to other unique substrates. This system was applied to a thyroid hormone (T3)-responsive gene switch model, inducing firefly luciferase expression by T3 in cells. This approach verifies that MIEs effectively rescue DmProc-bearing T3 prodrugs and seamlessly integrating themself into cellular biocatalytic networks.

Supramolecular Assembly in Live Cells Mapped by Real-Time Phasor-Fluorescence Lifetime Imaging.

The complex dynamics and transience of assembly pathways in living systems complicate the understanding of these molecular to nanoscale processes. Current technologies are unable to track the molecular events leading to the onset of assembly, where real-time information is imperative to correlate their rich biology. Using a chemically designed pro-assembling molecule, we map its transformation into nanofibers and their fusion with endosomes to form hollow fiber clusters. Tracked by phasor-fluorescence lifetime imaging (phasor-FLIM) in epithelial cells (L929, A549, MDA-MB 231) and correlative light-electron microscopy and tomography (CLEM), spatiotemporal splicing of the assembly events shows time-correlated metabolic dysfunction. The biological impact begins with assembly-induced endosomal disruption that reduces glucose transport into the cells, which, in turn, stymies mitochondrial respiration.

Transition Metal Ru(II) Catalysts Immobilized Nanoreactors for Conditional Bioorthogonal Catalysis in Cells.

Employing transition metal catalysts (TMCs) to perform bioorthogonal activation of prodrugs and pro-fluorophores in biological systems, particularly in a conditional fashion, remains a challenge. Here, we used a mesoporous organosilica nanoscaffold (RuMSN), which localizes Ru(II) conjugates on the pore wall, enabling the biorthogonal photoreduction reactions of azide groups. Due to easily adjustable surface charges and pore diameter, this efficiently engineering RuMSN catalyst, with abundant active sites on the inner pore well, could spontaneously repel or attract substrates with different molecular sizes and charges and thus ensure selective bioorthogonal catalysis. Depending on it, engineering RuMSN nanoreactors showed fascinating application scales from conditional bioorthogonal activation of prodrugs and pro-fluorophores in either intra- or extracellular localization to performing intracellular concurrent and tandem catalysis together with natural enzymes.

Formulas calculating the reactance of tubular busbars and their derivation in primary electrical connection schemes.

Electrical switching operation in a substation which locates in a high-voltage transmission system alters operating modes of main wiring in either the substation or the system. Major alterations may have negative influences on the switchgear of main wiring in a short time. The quantitative study of this problem has to be based on establishing equivalent circuits of main wiring, when there rarely are formulas to calculate the reactance of tubular busbars. In this paper on the basis of the electromagnetic field theory, the magnetic induction and flux linkages outside and inside tubular conductors are obtained from the Ampere Loop Theorem, and then the formulas to calculate approximately the reactance of tubular busbars with a three-phase parallel arrangement are derived. From the process and results of the calculation in an example it may be seen that the formulas are applied simply, conveniently and rapidly, and may be valuably spread in practical electrical engineering.

Cartilage-Inspired Hydrogel with Mechanical Adaptability, Controllable Lubrication, and Inflammation Regulation Abilities.

Cartilage is a key component in joints because of its load-bearing and lubricating abilities. However, osteoarthritis often leads to afunction of load-bearing/lubrication and occurrence of inflammation with overexpressed reactive oxygen species (ROS) and nitric oxide (NO). To address these issues, we fabricated a novel polyanionic hydrogel with abundant carboxylates/sulfonates ("CS" hydrogel), inspired by normal cartilage rich in anionic hyaluronate/sulfonate glycosaminoglycan/lubricin, and crosslinked it tightly by Fe3+ ("CS-Fe" hydrogel). The "CS-Fe" hydrogel displayed mechanical adaptability and shear resistance. A low coefficient of friction (∼0.02) appeared when a loose hydrogel layer was generated because of the photoreduction of Fe3+ to Fe2+ by UV irradiation. This biocompatible "CS-Fe" hydrogel suppressed the overexpressed hydroxyl radical (·OH) and NO in macrophages and protected chondrocytes/fibroblasts from aggressive inflammation. Moreover, the layered "CS-Fe" hydrogel avoided cell death of chondrocytes in sliding tests. The results demonstrate that this cartilage-inspired hydrogel is a promising candidate material in cartilage tissue engineering to especially address inflammation.

An Improved Incipient Fault Diagnosis Method of Bearing Damage Based on Hierarchical Multi-Scale Reverse Dispersion Entropy.

The amplitudes of incipient fault signals are similar to health state signals, which increases the difficulty of incipient fault diagnosis. Multi-scale reverse dispersion entropy (MRDE) only considers difference information with low frequency range, which omits relatively obvious fault features with a higher frequency band. It decreases recognition accuracy. To defeat the shortcoming with MRDE and extract the obvious fault features of incipient faults simultaneously, an improved entropy named hierarchical multi-scale reverse dispersion entropy (HMRDE) is proposed to treat incipient fault data. Firstly, the signal is decomposed hierarchically by using the filter smoothing operator and average backward difference operator to obtain hierarchical nodes. The smoothing operator calculates the mean sample value and the average backward difference operator calculates the average deviation of sample values. The more layers, the higher the utilization rate of filter smoothing operator and average backward difference operator. Hierarchical nodes are obtained by these operators, and they can reflect the difference features in different frequency domains. Then, this difference feature is reflected with MRDE values of some hierarchical nodes more obviously. Finally, a variety of classifiers are selected to test the separability of incipient fault signals treated with HMRDE. Furthermore, the recognition accuracy of these classifiers illustrates that HMRDE can effectively deal with the problem that incipient fault signals cannot be easily recognized due to a similar amplitude dynamic.

Gellan gum modified hyaluronic acid hydrogels as viscosupplements with lubrication maintenance and enzymatic resistance.

Osteoarthritis (OA) is a common disease caused by damage to articular cartilage and underlying bone tissues. Early OA can be treated by intra-articular injection of viscosupplements to restore the lost viscoelasticity and lubricity of synovial fluid. Hyaluronic acid (HA), as a most standard synovial fluid supplementation, can be easily degraded in vivo, bringing about lower viscoelasticity and increased injection frequency. In this study, we focus on products with reasonable viscoelasticity and long-lasting action time and develop a kind of polysaccharide-based hydrogel viscosupplement (HEG) based on HA chemically modified gellan gum (GG), which can maintain stable viscoelasticity with hyaluronidase for 1 week owing to the fact that the main component of GG still maintains a stable three-dimensional network structure after enzyme treatment. The as-developed injectable HEG hydrogel possesses good biocompatibility, excellent injectability, suitable viscoelasticity, satisfactory lubricity, and enzymatic resistance, demonstrating great potential to intervene in the development of OA.

Zwitterionic polymer modified xanthan gum with collagen II-binding capability for lubrication improvement and ROS scavenging.

High friction of damaged cartilage requires long-acting lubricated additive, which can also effectively scavenge reactive oxidative species (ROS) produced by mechanically stimulated chondrocytes. In this study, xanthan gum (XG) was grafted by poly (sulfobetaine methacrylate) (PSBMA) (the [XG]/[SBMA] molar ratio is 1:5 or 1:10), forming nanoparticles and then conjugated with collagen II-binding peptide, finally obtaining CBPXGSB1/5 or CBPXGSB1/10. Therein, the CBPXGSB1/5 was chosen as optimal lubricated additive. The results show that hydrated effect of PSBMA side chains endows CBPXGSB1/5 with favorable lubrication property (COF is 0.063). Furthermore, the CBPXGSB1/5 combining lubrication property and specific binding capability together may achieve the long-acting lubrication for injured cartilage in medical field. The CBPXGSB1/5 also possesses antioxidation verified by DPPH assay and exhibits synergistically enhanced ROS (OH, O2- and H2O2) scavenging. Besides, cytotoxicity experiment demonstrates that CBPXGSB1/5 has good biocompatibility. Therefore, multifunctional CBPXGSB1/5 developed here may have promising application potential in osteoarthritis treatment.

Gellan gum/alginate-based Ca-enriched acellular bilayer hydrogel with robust interface bonding for effective osteochondral repair.

The treatment of osteochondral (OC) defects remains challenging because of the lack of economical and feasible therapeutic strategies for OC repair and reconstruction. In this study, we report an integrated bilayer hydrogel with robust interface binding force (40 kPa) by facilitating the diffusion of calcium ions to the secondary crosslink of the bilayer hydrogel, in which gellan gum and sodium alginate acted as the chondral layer, gellan gum and hydroxyapatite acted as subchondral layer. This integrated construct has high cytocompatibility, and can seed with mesenchymal stem cells (MSCs) related to different functional protein expression for cartilage and bone formation, respectively. Furthermore, in the rabbit critical-sized osteochondral defect model (4.0 mm in diameter and 8.0 mm in depth), the calcium enriched hydrogel act as a calcium reservoir, promote neovascularization at week 4, and repair the critical defect at week 8, demonstrating the feasible preparation of an acellular hydrogel for OC repair.

Preparation and characterisation of a gellan gum-based hydrogel enabling osteogenesis and inhibiting Enterococcus faecalis.

Infections are the leading cause of failure of osteogenic material implantation. Antibiotic treatment, treatment with bone cement, or collagen sponge placement can result in drug resistance and difficulties in operation. To address this, gellan gum (GG) was selected in this study and prepared as an injectable hydrogel containing chlorhexidine (CHX) and nanohydroxyapatite (nHA) that overcomes these intractable problems. Scanning electron microscopy and micro-computed tomography revealed a three-dimensional polymeric network of the hydrogel. The hydrogel had excellent biocompatibility, as detected by cell counting kit-8 and Live/Dead assay. Bone marrow mesenchymal stem cells could be encapsulated into the network, showing that the structure was suitable for cell growth. Additionally, loading the hydrogel with nHA improved its mechanical, biodegradable, and osteogenic properties. Quantitative alkaline phosphatase and Alizarin Red S staining validated its osteogenic ability. Furthermore, antibacterial activity assessment showed that the hydrogel loaded with 50 µg/mL CHX inhibited Enterococcus faecalis in a concentration-dependent manner. Thus, we report an injectable GG-based hydrogel with superior antibacterial effect against E. faecalis and osteogenesis, which holds promise for treating infectious bone defects caused by refractory periradicular periodontitis.

An Efficacy Predictive Method for Diabetic Ulcers Based on Higher-Order Markov Chain-Set Pair Analysis.

BACKGROUND: Clinical comprehensive decision-making of diabetic ulcers includes curative effect evaluation and curative effect prediction. Nevertheless, there are few studies on the prediction of diabetic ulcers. METHODS: Set pair analysis (SPA) was used to assess the curative effect evaluation, and therapeutic effect was evaluated by connection degree (CD). The higher-order Markov chain-SPA curative effect prediction model was established to predict the future curative effect development. The predicted results with higher-order Markov chain-SPA and traditional first-order Markov-SPA model were compared with the actual results of the patients to verify the effectiveness of prediction. RESULTS: The connection degree of index levels I and II of 15 patients with diabetic ulcers after traditional Chinese medicine (TCM) treatment increased with time, while that of index levels IV and V decreased, indicating that the curative effect tends to improve. The higher-order Markov chain-SPA model was used to predict the curative effect. The results showed that the relative errors were fewer than the traditional first-order Markov-SPA model. CONCLUSIONS: The present study suggests that a method of SPA combined with higher-order Markov-SPA is relatively effective and can be applied to the clinical prediction of diabetic ulcers, which has higher accuracy than traditional first-order curative effect prediction model.

Thermosensitive Polysaccharide Hydrogel As a Versatile Platform for Prolonged Salmon Calcitonin Release and Calcium Regulation.

The common pathological characteristic of osteoporosis and hypercalcemia is the disorder of calcium homeostasis. Currently, salmon calcitonin (sCT), a clinical regenerative medicine, is an attractive chioice to regulate calcium metabolism for alleviation of osteoporosis and hypercalcemia. Unfortunately, serum sCT is quickly cleared in vivo, leading to its short half-life. Here, we designed a versatile hydrogel, based on salmon calcitonin-oxidized calcium alginate (sCT-OCA) conjugate and hydroxypropyl chitin (HPCH). The release profile showed that sCT could be released from HPCH hydrogels loaded with sCT-OCA conjugate (sCT-OCA-HPCH) for at least 28 days with conformation stability. The cellular test demonstrated that the biocompatible sCT-OCA-HPCH, compared with sCT formulation, had capacity in up-regulating alkaline phosphatase activity (∼63% increase) and promoting calcium to deposit into extracellular matrix (∼42% increase). These results indicated that thermosensitive sCT-OCA-HPCH hydrogel herein is a versatile platform for many applications such as calcium metabolism regulation, osteoporosis treatment, and hypercalcemia therapy.

Application of a Cloud Model-Set Pair Analysis in Efficacy Assessment for Diabetic Ulcers.

Because treatment of diabetic ulcers includes various uncertainties, efficacy assessments are needed and significant. In previous studies, set pair analysis (SPA) has been applied to the efficacy assessments of traditional Chinese medicine (TCM) that pick out uncertainties related to the development and prognosis of disease. Optimized clinical protocols of SPA improve clinical efficacy. In the article, cloud model (CM) is employed to improve SPA, and a novel efficacy assessment method for a treatment of diabetic ulcers is proposed based on the cloud model-set pair analysis (CM-SPA). It is recommended to replace connection degree (CD) with cloud connection degree (CCD) that the efficacy assessment results are shown as normal clouds. Then, three diabetic ulcers patients treated with TCM made importance assessment by both CM-SPA and AHP based SPA. The comparison of assessment results shows that the CM-SPA is efficacious for the efficacy assessment of a treatment for diabetic ulcers and the results will be more scientific and accurate via CM-SPA.