Dual-ROS-scavenging and dual-lingering nanozyme-based eye drops alleviate dry eye disease.

Efficiently removing excess reactive oxygen species (ROS) generated by various factors on the ocular surface is a promising strategy for preventing the development of dry eye disease (DED). The currently available eye drops for DED treatment are palliative, short-lived and frequently administered due to the short precorneal residence time. Here, we developed nanozyme-based eye drops for DED by exploiting borate-mediated dynamic covalent complexation between n-FeZIF-8 nanozymes (n-Z(Fe)) and poly(vinyl alcohol) (PVA) to overcome these problems. The resultant formulation (PBnZ), which has dual-ROS scavenging abilities and prolonged corneal retention can effectively reduce oxidative stress, thereby providing an excellent preventive effect to alleviate DED. In vitro and in vivo experiments revealed that PBnZ could eliminate excess ROS through both its multienzyme-like activity and the ROS-scavenging activity of borate bonds. The positively charged nanozyme-based eye drops displayed a longer precorneal residence time due to physical adhesion and the dynamic borate bonds between phenyboronic acid and PVA or o-diol with mucin. The in vivo results showed that eye drops could effectively alleviate DED. These dual-function PBnZ nanozyme-based eye drops can provide insights into the development of novel treatment strategies for DED and other ROS-mediated inflammatory diseases and a rationale for the application of nanomaterials in clinical settings.

An injectable thermoresponsive-hydrogel for lamellar keratoplasty: In-situ releases celastrol and hampers corneal scars.

Corneal stromal fibrosis is a common cause of visual impairment resulting from corneal injury, inflammation and surgery. Therefore, there is an unmet need for inhibiting corneal stromal fibrosis. However, bioavailability of topical eye drops is very low due to the tear and corneal barriers. In situ delivery offers a unique alternative to improve efficacy and minimize systemic toxicity. Herein, a drug delivery platform based on thermoresponsive injectable hydrogel/nano-micelles composite with in situ drug-controlled release and long-acting features is developed to prevent corneal scarring and reduce corneal stromal fibrosis in lamellar keratoplasty. The in-situ gelation hydrogels enabled direct delivery of celastrol to the corneal stroma. In vivo evaluation with a rabbit anterior lamellar keratoplasty model showed that hydrogel/micelles platform could effectively inhibit corneal stromal fibrosis. This strategy achieves controlled and prolonged release of celastrol in the corneal stroma of rabbit. Following a single corneal interlamellar injection, celastrol effectively alleviated fibrosis via mTORC1 signal promoting autophagy and inhibiting TGF-ß1/Smad2/3 signaling pathway. Overall, this strategy demonstrates promise for the clinical application of celastrol in preventing corneal scarring and reducing corneal stromal fibrosis post-lamellar keratoplasty, highlighting the potential benefits of targeted drug delivery systems in ocular therapeutics.

Biophilic Positive Carbon Dot Exerts Antifungal Activity and Augments Corneal Permeation for Fungal Keratitis.

Fungal keratitis (FK) is an infectious eye disease that poses a significant risk of blindness. However, the effectiveness of conventional antifungal drugs is limited due to the intrinsic ocular barrier that impedes drug absorption. There is an urgent need to develop new therapeutic strategies to effectively combat FK. Herein, we synthesized an ultrasmall positively charged carbon dot using a simple stage-melting method. The carbon dot can penetrate the corneal barrier by opening the tight junctions, allowing them to reach the lesion site and effectively kill the fungi. The results both in vitro and in vivo demonstrated that it exhibited good biocompatibility and antifungal activity, significantly improving the therapeutic effect in a mouse model of FK. Therefore, this biophilic ultrasmall size and positive carbon dot, characterized by its ability to penetrate the corneal barrier and its antifungal properties, may offer valuable insights into the design of effective ocular nanomedicines.

Dual-Atom Nanozyme Eye Drops Attenuate Inflammation and Break the Vicious Cycle in Dry Eye Disease.

Dry eye disease (DED) is a major ocular pathology worldwide, causing serious ocular discomfort and even visual impairment. The incidence of DED is gradually increasing with the high-frequency use of electronic products. Although inflammation is core cause of the DED vicious cycle, reactive oxygen species (ROS) play a pivotal role in the vicious cycle by regulating inflammation from upstream. Therefore, current therapies merely targeting inflammation show the failure of DED treatment. Here, a novel dual-atom nanozymes (DAN)-based eye drops are developed. The antioxidative DAN is successfully prepared by embedding Fe and Mn bimetallic single-atoms in N-doped carbon material and modifying it with a hydrophilic polymer. The in vitro and in vivo results demonstrate the DAN is endowed with superior biological activity in scavenging excessive ROS, inhibiting NLRP3 inflammasome activation, decreasing proinflammatory cytokines expression, and suppressing cell apoptosis. Consequently, the DAN effectively alleviate ocular inflammation, promote corneal epithelial repair, recover goblet cell density and tear secretion, thus breaking the DED vicious cycle. Our findings open an avenue to make the DAN as an intervention form to DED and ROS-mediated inflammatory diseases.

M2 macrophages promote subconjunctival fibrosis through YAP/TAZ signalling.

PURPOSE: To evaluate the role of M2 macrophages in subconjunctival fibrosis after silicone implantation (SI) and investigate the underlying mechanisms. MATERIALS AND METHODS: A model of subconjunctival fibrosis was established by SI surgery in rabbit eyes. M2 distribution and collagen deposition were evaluated by histopathology. The effects of M2 cells on the migration (using wound-scratch assay) and activation (by immunofluorescence and western blotting) of human Tenon's fibroblasts (HTFs) were investigated. RESULTS: There were more M2 macrophages (CD68+/CD206+ cells) occurring in tissue samples around silicone implant at 2 weeks postoperatively. Dense collagen deposition was observed at 8 weeks after SI. In vitro experiment showed M2 expressed high level of CD206 and transforming growth factor-ß1 (TGF-ß1). The M2-conditioned medium promoted HTFs migration and the synthesis of collagen I and fibronectin. Meanwhile, M2-conditioned medium increased the protein levels of TGF-ß1, TGF-ßR II, p-Smad2/3, yes-associated protein (YAP), and transcriptional coactivator with PDZ-binding motif (TAZ). Verteporfin, a YAP inhibitor, suppressedTGF-ß1/Smad2/3-YAP/TAZ pathway and attenuated M2-induced extracellular matrix deposition by HTFs. CONCLUSIONS: TGF-ß1/Smad2/3-YAP/TAZ signalling may be involved in M2-induced fibrotic activities in HTFs. M2 plays a key role in promoting subconjunctival fibrosis and can serve as an attractive target for anti-fibrotic therapeutics.

Characteristics of Quinoa Protein Isolate Treated by Pulsed Electric Field.

The aim of this study was to investigate the impact of a pulsed electric field (PEF) on the structural and functional properties of quinoa protein isolate (QPI). The findings revealed a significant alteration in the secondary structure of QPI following PEF treatment, converting the random coil into the ß-sheet, resulting in an improvement in structure orderliness and an enhancement of thermal stability. The PEF treatment led to a reduction in particle size, induced structural unfolding, and increased the surface hydrophobicity, resulting in a statistically significant enhancement in the solubility, foaming, and emulsifying properties of QPI (p < 0.05). Specifically, PEF treatment at 7.5 kV/cm for 30 pulses was identified as the optimal condition for modifying QPI. This study provides a basis for the precision and range of application of pulsed electric field treatment and offers the possibility of improving the physical and chemical properties of quinoa protein.

Effect of Starch on the Solubility of Quinoa Protein Isolates during Heat Treatment.

There is increasing interest in developing quinoa products due to their unique nutritional value. Starch and protein are the primary components in quinoa, and the interaction between them affects the quality of quinoa products. This study extracted the starch and protein from quinoa and simulated the thermal processing of quinoa to investigate the effects of starch on the solubility and structure of quinoa protein isolates during heat treatment. The structure of quinoa protein isolates was characterized by fluorescence spectroscopy, Fourier transform infrared spectroscopy, laser particle size analysis, and scanning electron microscopy. The results showed that starch decreased protein solubility, and the maximum solubility was obtained after heating for 5 min. After starch addition during heat treatment, the surface charge distribution of protein changed, the degree of protein aggregation increased, the particle size of proteins increased, the thermal stability increased, and the ß-sheet ratio of the proteins increased, suggesting that the protein structure is more ordered, which is the structural foundation of protein solubility decreasing. The research about the interaction between starch and protein and the effects on the solubility of protein could provide a reference for quinoa products processing.

Sustainable ultrasound-assisted extraction of Polygonatum sibiricum saponins using ionic strength-responsive natural deep eutectic solvents.

The sustainable extraction of saponins was investigated using natural deep eutectic solvents (NADESs) combined with ultrasound-assisted extraction. A novel NADES (butyric acid-urea) that was responsive to ionic strength was designed and used as the extractant. Ultrasound treatment and a catalyst ferric chloride with plant cell wall breaking function were applied to improve the extraction efficiency.Since the solubility of the NADES varied significantly with ionic strength, 95% of NADES was readily separated from the water phase after the addition of sodium chloride, while saponins remained in the water phase for easy collection. The reuse capacity of NADES, the eco-friendliness of the extraction method, and the antioxidant activity of the extract were further evaluated.NADES was continuously recovered and used to extract Polygonatum sibiricum powder: the yield of saponins did not decrease after five cycles of recovery and re-extraction. The penalty point on the "Eco-scale" suggested that the extraction method was "green" (i.e. eco-friendly).Compared with ethanol extracts, the NADES extracts showed a higher saponin concentration and antioxidant activity.The study can contribute to the sustainable and green extraction of hydrophilic active substances in the food and pharmaceutical industries.

Antibiotic Delivery System for Treating Bacteria-Induced Anterior Blepharitis.

The eyelid-related disease of blepharitis remains a tricky ocular disorder and affects patient compliance. However, there is no available and effective treatment, making it extremely challenging. Herein, an antibacterial system based on antibiotic delivery was developed and applied in a blepharitis model induced by bacteria. The antibacterial tests against Staphylococcus aureus both in vitro and in vivo demonstrated that the system shows a favorable bactericidal effect. Then, histological evaluation indicated that the system shows both antibacterial and anti-inflammatory effects. This facile design provided an effective ocular infection management, which displays a promising prospect while addressing other complex ocular disorders.

Novel technique for amniotic membrane transplantation for acute Stevens-Johnson syndrome/toxic epidermal necrolysis patients.

Purpose: To report a novel technique to facilitate amniotic membrane transplantation (AMT) for acute stage Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Design: Laboratory investigation and retrospective, single-center case series. Methods: The polylactic acid (PLA) amniotic fornical ring (AFR) have been successfully manufactured by three-dimensional (3D) printing technology for AMT. This study retrospectively analyzed the medical records of 5 SJS/TEN patients at the acute stage between 2019 and 2023. Patients were surgically treated with AFR or sutured amniotic membrane transplant (SAMT). Epidemiology, best-corrected visual acuity (BCVA), acute ocular severity score, operative duration, epithelial healing time, amniotic dissolution and follow-up time were evaluated. Results: Of all five patients, three patients (6 eyes) received AFR/AMT (Group A), and 2 patients (4 eyes) received SAMT (Group B). There were no significant differences between two groups in the mean preoperative days and vision changes. The mean operation duration was 11.7 ± 3.8 mins in group A. Compared with the SAMT (48.8 ± 5.3 mins), the operation duration was reduced by 76.02%. The mean times for epithelial healing were 32.5 ± 29.2 days in group A and 12.0 ± 0.0 days in group B. In addition, there were no significant side effects of 3D-printed sterile AFR on the eyes. Conclusions: 3D-printed PLA scaffolds could be used as an AFR device for acute SJS/TEN. In addition, personalized 3D-printed AFR is superior to conventional SAMT in operation duration.

Carboxymethyl chitosan regulates macrophages polarization to inhibit early subconjunctival inflammation in conjunctival injury.

Persistent subconjunctival inflammation leads to subconjunctival fibrosis and eventual visual impairment. There is an unmet need for how to effectively inhibit subconjunctival inflammation. Herein, the effect of carboxymethyl chitosan (CMCS) on subconjunctival inflammation was investigated and the mechanism was involved. The evaluation of cytocompatibility demonstrated that CMCS had good biocompatibility. The in vitro results showed that CMCS inhibited secretions of pro-inflammatory cytokines (IL-6, TNF-α, IL-8 and IFN-γ) and chemokines (MCP-1), and downregulated TLR4/MyD88/NF-κB pathway in M1. The in vivo results displayed that CMCS alleviated conjunctival edema and congestion, and improved conjunctival epithelial reconstruction significantly. Both in vitro and in vivo results demonstrated that CMCS inhibited the infiltration of macrophages and reduced the expressions of iNOS, IL-6, IL-8 and TNF-α in the conjunctiva. Given that CMCS indicated the activities of inhibiting M1 polarization, NF-κB pathway, and subconjunctival inflammation, which may be employed as a potent treatment for subconjunctival inflammation.

Personalized 3D-printed amniotic fornical ring for ocular surface reconstruction.

In the present work, we used three-dimensional (3D) printing technology to make a polylactic acid (PLA) amniotic fornical ring (AFR) for ocular surface reconstruction. This work is a retrospective and interventional case series of patients with ocular surface diseases who underwent either personalized 3D-printed AFR-assisted amniotic membrane transplantation (AMT) or sutured AMT (SAMT). Patient epidemiology, treatment, operative duration, epithelial healing time, retention time, vision changes, morbidity, and costs were analyzed. Thirty-one patients (40 eyes) and 19 patients (22 eyes) were enrolled in the 3D-printed AFR group and the SAMT group, respectively. The clinical indications of AFR and SAMT were similar, such as corneal and/or conjunctival epithelial defects due to chemical burns, thermal burns, Stevens-Johnson syndrome (SJS), or toxic epidermal necrolysis (TEN). The mean dissolution time was 15 ± 11 days in the AFR group, compared with 14 ± 7 days in the SAMT group. The percentage of healed corneal area was 90.91% (66.10%-100.00%) for AFR and 93.67% (60.23%-100.00%) for SAMT. The median time for corneal epithelial healing was 14 (7-75) days in the AFR group and 30 (14-55) days in the suture AMT group. There were no significant differences in the initial visual acuity, final visual acuity, or improvement in visual acuity between the two groups. The operation duration in the AFR group was significantly shorter than that in the SAMT group. Regarding the cost analysis, the average cost per eye in the AFR group was significantly lower than that in the SAMT group. Furthermore, 3D-printed and sterile AFR showed no obvious side effects on the eyes. Our results suggested that 3D-printed PLA scaffolds could be used as an AFR device for ocular surface disease. In addition, personalized 3D-printed AFR is superior to conventional AMT in operation duration and cost effectiveness, thereby reducing the financial burden on our health care system.

Celastrol Alleviates Corneal Stromal Fibrosis by Inhibiting TGF-ß1/Smad2/3-YAP/TAZ Signaling After Descemet Stripping Endothelial Keratoplasty.

Purpose: The purpose of this study was to investigate the effect of celastrol (CEL) on corneal stromal fibrosis after Descemet stripping endothelial keratoplasty (DSEK) and its associated mechanism. Methods: Rabbit corneal fibroblasts (RCFs) were isolated, cultured, and identified. A CEL-loaded positive nanomedicine (CPNM) was developed to enhance corneal penetration. CCK-8 and scratch assays were performed to evaluate cytotoxicity and the effects of CEL on the migration of RCFs. The RCFs were activated by TGF-ß1 with or without CEL treatment, and then the protein expression levels of TGFßRII, Smad2/3, YAP, TAZ, TEAD1, α-SMA, TGF-ß1, FN, and COLI were assessed by immunofluorescence or Western blotting (WB). An in vivo DSEK model was established in New Zealand White rabbits. The corneas were stained using H&E, YAP, TAZ, TGF-ß1, Smad2/3, TGFßRII, Masson, and COLI. H&E staining of the eyeball was performed to assess the tissue toxicity of CEL at 8 weeks after DSEK. Results: In vitro CEL treatment inhibited the proliferation and migration of RCFs induced by TGF-ß1. Immunofluorescence and WB showed that CEL significantly inhibited the protein expression of TGF-ß1, Smad2/3, YAP, TAZ, TEAD1, α-SMA, TGF-ßRII, FN, and COL1 induced by TGF-ß1 in RCFs. In the rabbit DSEK model, CEL significantly reduced the levels of YAP, TAZ, TGF-ß1, Smad2/3, TGFßRII, and collagen. No obvious tissue toxicity was observed in the CPNM group. Conclusions: CEL effectively inhibited corneal stromal fibrosis after DSEK. The TGF-ß1/Smad2/3-YAP/TAZ pathway may be involved in the mechanism by which CEL alleviates corneal fibrosis. The CPNM is a safe and effective treatment strategy for corneal stromal fibrosis after DSEK.

A chitosan-based self-healing hydrogel for accelerating infected wound healing.

Wound infection causes irregular tissue closure, often with prolonged healing. Traditional therapies based on antibiotic delivery have resulted in reduced therapeutic efficiency and drug resistance. Such features make it highly desirable to develop an antibiotic-free material for wound infection in clinical applications. Herein, a self-healing antibacterial hydrogel was designed to realize the treatment of S. aureus-infected wounds. The design of the dynamic imine bond endows hydrogels with self-healing and adaptive properties, which could cover the irregular wound and improve the safety of administration. In addition, benefiting from quaternized chitosan, the designed hydrogels also present fascinating antimicrobial properties and favorable biocompatibility. The evaluation in a rat skin wound infection model indicates that the fascinating antimicrobial effect accelerates wound healing by the designed hydrogels. This facile design of an antibiotic-free material allows effective wound infection management, which may be promising in coping with other complex wound healings.

Celastrol-based nanomedicine hydrogels eliminate posterior capsule opacification.

Aim: To formulate an injectable thermosensitive micelle-hydrogel hybrid system loaded with celastrol (celastrol-loaded micelle hydrogel: CMG) to prevent posterior capsule opacification (PCO). Materials & methods: Celastrol-loaded micelles were embedded in a thermosensitive hydrogel matrix to enable controlled on-demand celastrol delivery into the residual capsule. The efficacy and mechanisms of the system for eliminating PCO were evaluated in rabbits. Results: Celastrol-loaded micelles inhibited the migration and proliferation of lens epithelial cells induced by TGF-ß1. Celastrol prevents epithelial-mesenchymal transition in lens epithelial cells induced by TGF-ß1 through the TGF-ß1/Smad2/3/TEAD1 signaling pathway. In vivo efficiency evaluations showed that CMG demonstrated an excellent inhibitory effect on PCO in rabbits and had no obvious tissue toxicity. Conclusion: Injectable CMG may represent a promising ophthalmic platform for preventing PCO. This versatile injectable micelle-hydrogel hybrid represents a clinically relevant platform to achieve localized therapy and controlled release of drugs in other disease therapies.

Bright CsPbBr3 Perovskite Nanocrystals with Improved Stability by In-Situ Zn-Doping.

In this study, facile synthesis, characterization, and stability tests of highly luminescent Zn-doped CsPbBr3 perovskite nanocrystals (NCs) were demonstrated. The doping procedure was performed via partial replacement of PbBr2 with ZnBr2 in the precursor solution. Via Zn-doping, the photoluminescence quantum yield (PLQY) of the NCs was increased from 41.3% to 82.9%, with a blue-shifted peak at 503.7 nm and narrower spectral width of 18.7 nm which was consistent with the highly uniform size distribution of NCs observed from the TEM image. In the water-resistance stability test, the doped NCs exhibited an extended period-over four days until complete decomposition, under the harsh circumstances of hexane-ethanol-water mixing solution. The Zn-doped NC film maintained its 94% photoluminescence (PL) intensity after undergoing a heating/cooling cycle, surpassing the un-doped NC film with only 67% PL remaining. Based on our demonstrations, the in-situ Zn-doping procedure for the synthesis of CsPbBr3 NCs could be a promising strategy toward robust and PL-efficient nanomaterial to pave the way for realizing practical optoelectronic devices.

A dual-functional chitosan derivative platform for fungal keratitis.

Fungal keratitis remains a serious infectious ocular disease, and the traditional administration of eye drops is limited by ocular intrinsic barriers and drug shortages. Herein, we fabricated a chitosan-based dual-functional platform for ocular topical delivery of econazole. The platform can prolong the residence time on the ocular surface due to its strong interaction with the mucin layer by physical adhesion and covalent bonding, and also open corneal epithelial tight junctions for being positively charged, thereby enhancing corneal penetration of drug. Using these strategies, dosing concentration was reduced from 0.3 wt% to 0.1 wt%, dosing frequency was reduced from once-an-hour to twice-daily, in vitro and in vivo antifungal therapeutic effects were achieved and patient compliance could be improved. Given its high structural adaptability, many other ocular anterior segment-related diseases would benefit from this platform.

MXene-based hybrid system exhibits excellent synergistic antibiosis.

MXenes are a group of inorganic two-dimensional (2D) nanomaterial, and have raised significant interests in biomedical areas. Ti3C2Tx, as an important member of MXene family, is widely studied because of its biodegradability and low-cytotoxicity. However, their single antibacterial mechanism and poor stability in aqueous solution need to be improved, especially for the antimicrobial applications. In this work, a MXene-based hybrid antibacterial system (M-HAS) was developed and its synergistic antibacterial activity was investigated. In the M-HAS, 2D few-layer Ti3C2Tx(FL-Ti3C2Tx) was modified with hydrophilic polymers and thereby used as carriers for silver nanoparticles (Ag NPs). By assembling these two substrates, photodynamic performance of the prepared system is significantly improved with a large amount of reactive oxygen species produced under 660 nm laser. Antibacterial effects of the M-HAS are enhanced by over 4 times with irradiation. In another word, the developed hybrid system displays excellent photodynamic antibacterial synergistic properties. This work takes advantage of the photodynamic properties of each component in the M-HAS to achieve efficient antibacterial activity and proposes an innovative approach to develop the 2D FL-Ti3C2Tx-based antibacterial platform.

A lingering mouthwash with sustained antibiotic release and biofilm eradication for periodontitis.

Dental plaque biofilms are believed to be one of the principal virulence factors in periodontitis resulting in tooth loss. Traditional mouthwashes are limited due to the continuous flow of saliva and poor drug penetration ability in the biofilm. Herein, we fabricated an antibiotic delivery platform based on natural polysaccharides (chitosan and cyclodextrin) as a novel mouthwash for the topical cavity delivery of minocycline. The penetration and residence mechanisms demonstrate that the platform can prolong the residence time up to 12 h on biofilms. Furthermore, sustained release can enhance the penetration of drugs into biofilms. In vitro antibiofilm experimental results indicated that the mouthwash effectively kills bacteria and eradicate biofilms. Effective treatment in vivo was confirmed by the significantly reduced dental plaque and alleviated inflammation observed in a rat periodontitis model. In summary, this novel platform can improve antibiofilm efficiency and prevent drugs from being washed away by saliva, which may provide benefits for many oral infectious diseases.