ROS-responsive celastrol-nanomedicine alleviates inflammation for dry eye disease.

Dry eye disease (DED) is a major global eye disease leading to severe eye discomfort and even vision impairment. The incidence of DED has been gradually increasing with the high frequency of use of electronic devices. It has been demonstrated that celastrol (Cel) has excellent therapeutic efficacy in ocular disorders. However, the poor water solubility and short half-life of Cel limit its further therapeutic applications. In this work, a reactive oxygen species (ROS) sensitive polymeric micelle was fabricated for Cel delivery. The micelles improve the solubility of Cel, and the resulting Cel loaded micelles exhibit an enhanced intervention effect for DED. Thein vitroresults demonstrated that Cel-nanomedicine had a marked ROS responsive release behavior. The results ofin vitroandin vivoexperiments demonstrated that Cel has excellent biological activities to alleviate inflammation in DED by inhibiting TLR4 signaling activation and reducing pro-inflammatory cytokine expression. Therefore, the Cel nanomedicine can effectively eliminate ocular inflammation, promote corneal epithelial repair, and restore the number of goblet cells and tear secretion, providing a new option for the treatment of DED.

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.

Pantoprazole suppresses carcinogenesis and growth of hepatocellular carcinoma by inhibiting glycolysis and Na+/H+ exchange.

Hepatocellular carcinoma (HCC) is one of the deadliest cancers. The prevention and therapy for this deadly disease remain a global medical challenge. In this study, we investigated the effect of pantoprazole (PPZ) on the carcinogenesis and growth of HCC. Both diethylnitrosamine (DEN) plus CCl4-induced and DEN plus high fat diet (HFD)-induced HCC models in mice were established. Cytokines and cell proliferation-associated gene in the liver tissues of mice and HCC cells were analyzed. Cellular glycolysis and Na+/H+ exchange activity were measured. The preventive administration of pantoprazole (PPZ) at a clinically relevant low dose markedly suppressed HCC carcinogenesis in both DEN plus CCl4-induced and HFD-induced murine HCC models, whereas the therapeutic administration of PPZ at the dose suppressed the growth of HCC. In the liver tissues of PPZ-treated mice, inflammatory cytokines, IL1, CXCL1, CXCL5, CXCL9, CXCL10, CCL2, CCL5, CCL6, CCL7, CCL20, and CCL22, were reduced. The administration of CXCL1, CXCL5, CCL2, or CCL20 all reversed PPZ-suppressed DEN plus CCL4-induced HCC carcinogenesis in mice. PPZ inhibited the expressions of CCNA2, CCNB2, CCNE2, CDC25C, CDCA5, CDK1, CDK2, TOP2A, TTK, AURKA, and BIRC5 in HCC cells. Further results showed that PPZ reduced the production of these inflammatory cytokines and the expression of these cell proliferation-associated genes through the inhibition of glycolysis and Na+/H+ exchange. In conclusion, PPZ suppresses the carcinogenesis and growth of HCC, which is related to inhibiting the production of inflammatory cytokines and the expression of cell proliferation-associated genes in the liver through the inhibition of glycolysis and Na+/H+ exchange.

Diffusional Electron Transport Coupled to Thermodynamically Driven Electron Transfers in Redox-Conductive Multivariate Metal-Organic Frameworks.

The development of redox-conductive metal-organic frameworks (MOFs) and the fundamental understanding of charge propagation through these materials are central to their applications in energy storage, electronics, and catalysis. To answer some unresolved questions about diffusional electron hopping transport and redox conductivity, mixed-linker MOFs were constructed from two statistically distributed redox-active linkers, pyromellitic diimide bis-pyrazolate (PMDI) and naphthalene diimide bis-pyrazolate (NDI), and grown as crystalline thin films on conductive fluorine-doped tin oxide (FTO). Owing to the distinct redox properties of the linkers, four well-separated and reversible redox events are resolved by cyclic voltammetry, and the mixed-linker MOFs can exist in five discrete redox states. Each state is characterized by a unique spectroscopic signature, and the interconversions between the states can be followed spectroscopically under operando conditions. With the help of pulsed step-potential spectrochronoamperometry, two modes of electron propagation through the mixed-linker MOF are identified: diffusional electron hopping transport between linkers of the same type and a second channel that arises from thermodynamically driven electron transfers between linkers of different types. Corresponding to the four redox events of the mixed-linker MOFs, four distinct bell-shaped redox conductivity profiles are observed at a steady state. The magnitude of the maximum redox conductivity is evidenced to be dependent on the distance between redox hopping sites, analogous to the situation for apparent electron diffusion coefficients, Deapp, that are obtained in transient experiments. The design of mixed-linker redox-conductive MOFs and detailed studies of their charge transport properties present new opportunities for future applications of MOFs, in particular, within electrocatalysis.

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.

Novel nanomicelle butenafine formulation for ocular drug delivery against fungal keratitis: In Vitro and In Vivo study.

Fungal keratitis (FK) is a serious infectious corneal disease that leads to blindness. Butenafine (BTF) is an allylamine drug with high antifungal activity, but its poor water solubility and low bioavailability limit its clinical application in ophthalmology. To increase its aqueous solubility and corneal permeability, butenafine was encapsulated in d-ɑ-tocopheryl polyethylene glycol succinate (TPGS) polymeric nanomicelles to improve the bioavailability of the drug for the treatment of FK. Butenafine was successfully fabricated into nanomicelles with a high EE of 96.34 ± 1.65 % and DL of 6.71 ± 0.099 %. The BTF-NM showed an average particle size of 13.12 ± 0.24 nm, a zeta potential of -0.56 ± 0.44 mV and a narrow PDI of 0.12 ± 0.02 with a nearly spherical shape. The characterization results of FTIR, XRD and DSC indicated that BTF was encapsulated in the TPGS nanomicelles. The BTF-NM formulation also showed high storage stability, and the in vitro drug release study showed typical biphasic-release characteristics. In addition, the BTF-NM formulation displayed good cellular tolerance and excellent ocular tolerance in rabbits. Significantly elevated in vitro antifungal activity was also observed in the BTF-NM formulation, and remarkable improvements regarding in vivo corneal permeation were observed compared with the BTF suspension formulation. Finally, the in vivo antifungal activity studies indicated that the BTF-NM formulation had a good therapeutic effect on FK and had similar efficacy to that of commercial natamycin suspension eye drops. These results suggest that the BTF-NM ophthalmic formulation could be a promising ocular drug delivery system for the treatment of FK.

Phloretin Inhibits Quorum Sensing and Biofilm Formation in Serratia marcescens.

This study investigated the antivirulence capacity and mechanism of apple-skin-derived phloretin against Serratia marcescens NJ01, a vegetable spoilage bacterium. At 0.5 to 2 mg/mL doses, phloretin considerably inhibited the secretion of acyl homoserine lactones (AHLs), indicating that phloretin disrupted quorum sensing (QS) in S. marcescens NJ01. The dysfunction of QS resulted in reduced biofilms and the decreased production of protease, prodigiosin, extracellular polysaccharides (EPSs), and swimming and swarming motilities. Dysfunctional QS also weakened the activity of antioxidant enzymes and improved oxidative injury. The improved oxidative injury changed the composition of the membrane, improved membrane permeability, and eventually increased the susceptibility of biofilm cells to amikacin, netilmicin, and imipenem. The disrupted QS and enhanced oxidative stress also caused disorders of amino acid metabolism, energy metabolism, and nucleic acid metabolism, and ultimately attenuated the ability of S. marcescens NJ01 to induce spoilage. Our results indicated that phloretin can act as a potent drug to defend against spoilage by S. marcescens.

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.

Hollow CuS nanoparticles equipped with hydroxyapatite/hyaluronic acid coating for NIR/pH dual-responsive drug delivery.

The near-infrared (NIR)/pH dual-responsive nanoplatform shows great potential in remote photothermal therapy for tumor on account of the near-infrared window in biological tissue and the mild acidic environment in tumor cells. CuS nanoplatform has become a rising star in the field of photothermal agents due to its excellent NIR responsiveness and photostability. In this work, hollow CuS nanoparticles with high photothermal conversion efficiency (42.42 %) were synthesized through a novel surfactant micelle-assisted method. Then, CuS@hydroxyapatite (HAP)/hyaluronic acid (HA) nanoclusters with controllable drug release property were prepared by capping HAP and HA on the surface of CuS via electrostatic self-assembly approach. The hollow structure of CuS and the large specific surface area of HAP ensure an outstanding doxorubicin hydrochloride (DOX) loading efficiency of 99.2 % in CuS@HAP/HA nanoclusters. The introduction of HA effectively retards the initial burst release of DOX and ensures the excellent biocompatibility of nanoclusters. More importantly, CuS@HAP/HA displays distinct NIR/pH dual-responsive drug release properties owing to the excellent NIR responsiveness of hollow CuS and the gradual dissolution of HAP under acidic conditions. This work provides an environmentally benign method to prepare CuS-based nanoclusters with excellent NIR/pH responsive drug delivery properties, which has great potential in remote photothermal therapy.

Electrochromism in Isoreticular Metal-Organic Framework Thin Films with Record High Coloration Efficiency.

The power of isoreticular chemistry has been widely exploited to engineer metal-organic frameworks (MOFs) with fascinating molecular sieving and storage properties but is underexplored for designing MOFs with tunable optoelectronic properties. Herein, three dipyrazole-terminated XDIs (X = PM (pyromellitic), N (naphthalene), or P (perylene); DI = diimide) with different lengths and electronic properties are prepared and employed as linkers for the construction of an isoreticular series of Zn-XDI MOFs with distinct electrochromism. The MOFs are grown on fluorine-doped tin oxide (FTO) as high-quality crystalline thin films and characterized by X-ray diffraction (XRD) and scanning electron microscopy (SEM). Due to the constituting electronically isolated XDI linkers, each member of the isoreticular thin film series exhibits two reversible one-electron redox events, each at a distinct electrochemical potential. The orientation of the MOFs as thin films as well as their isoreticular nature results in identical cation-coupled electron hopping transport rates in all three materials, as demonstrated by comparable apparent electron diffusion coefficients, Deapp. Upon electrochemical reduction to either the [XDI]•- or [XDI]2- state, each MOF undergoes characteristic changes in its optical properties as a function of linker length and redox state of the linker. Operando spectroelectrochemistry measurements reveal that Zn-PDI@FTO (PDI = perylene diimide) thin films exhibit a record high coloration efficiency of 941 cm2 C-1 at 746 nm, which is attributed to the maximized Faradaic transformations at each electronically isolated PDI unit. The electrochromic response of the thin film is retained to more than 99% over 100 reduction-oxidation cycles, demonstrating the applicability of the presented materials.

Organic Polymer Dots Photocatalyze CO2 Reduction in Aqueous Solution.

Developing low-cost and efficient photocatalysts to convert CO2 into valuable fuels is desirable to realize a carbon-neutral society. In this work, we report that polymer dots (Pdots) of poly[(9,9'-dioctylfluorenyl-2,7-diyl)-co-(1,4-benzo-thiadiazole)] (PFBT), without adding any extra co-catalyst, can photocatalyze reduction of CO2 into CO in aqueous solution, rendering a CO production rate of 57 µmol g-1 h-1 with a detectable selectivity of up to 100 %. After 5 cycles of CO2 re-purging experiments, no distinct decline in CO amount and reaction rate was observed, indicating the promising photocatalytic stability of PFBT Pdots in the photocatalytic CO2 reduction reaction. A mechanistic study reveals that photoexcited PFBT Pdots are reduced by sacrificial donor first, then the reduced PFBT Pdots can bind CO2 and reduce it into CO via their intrinsic active sites. This work highlights the application of organic Pdots for CO2 reduction in aqueous solution, which therefore provides a strategy to develop highly efficient and environmentally friendly nanoparticulate photocatalysts for CO2 reduction.

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.

Experimental manifestation of redox-conductivity in metal-organic frameworks and its implication for semiconductor/insulator switching.

Electric conductivity in metal-organic frameworks (MOFs) follows either a band-like or a redox-hopping charge transport mechanism. While conductivity by the band-like mechanism is theoretically and experimentally well established, the field has struggled to experimentally demonstrate redox conductivity that is promoted by the electron hopping mechanism. Such redox conductivity is predicted to maximize at the mid-point potential of the redox-active units in the MOF, and decline rapidly when deviating from this situation. Herein, we present direct experimental evidence for redox conductivity in fluorine-doped tin oxide surface-grown thin films of Zn(pyrazol-NDI) (pyrazol-NDI = 1,4-bis[(3,5-dimethyl)-pyrazol-4-yl]naphthalenediimide). Following Nernstian behavior, the proportion of reduced and oxidized NDI linkers can be adjusted by the applied potential. Through a series of conductivity measurements, it is demonstrated that the MOF exhibits minimal electric resistance at the mid-point potentials of the NDI linker, and conductivity is enhanced by more than 10000-fold compared to that of either the neutral or completely reduced films. The generality of redox conductivity is demonstrated in MOFs with different linkers and secondary building units, and its implication for applications that require switching between insulating and semiconducting regimes is discussed.

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.

The effect of charges on the corneal penetration of solid lipid nanoparticles loaded Econazole after topical administration in rabbits.

Fungal keratitis is an infectious disease caused by pathogenic fungi with a high blindness rate. Econazole (ECZ) is an imidazole antifungal drug with insoluble ability. Econazole-loaded solid lipid nanoparticles (E-SLNs) were prepared by microemulsion method, then modified with positive and negative charge. The mean diameter of cationic E-SLNs, nearly neutral E-SLNs and anionic E-SLNs were 18.73±0.14, 19.05±0.28, 18.54±0.10 nm respectively. The Zeta potential of these different charged SLNs formulations were 19.13±0.89, -2.20±0.10, -27.40±0.67 mV respectively. The Polydispersity Index (PDI) of these three kinds of nanoparticles were all about 0.2. The Transmission Electron Microscopy (TEM) and Differential Scanning Calorimetry (DSC) analysis showed that the nanoparticles were a homogeneous system. Compared with Econazole suspension (E-Susp), SLNs exhibited sustained release capability, stronger corneal penetration and enhanced inhibition of pathogenic fungi without irritation. The antifungal ability was further improved after cationic charge modification compared with E-SLNs. Studies on pharmacokinetics showed that the order of the AUC and t1/2 of different preparations was cationic E-SLNs > nearly neutral E-SLNs > anionic E-SLNs > E-Susp in cornea and aqueous humor. It was shown that SLNs could increase corneal penetrability and ocular bioavailability while these capabilities were further enhanced with positive charge modification compared with negative charge ones.

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.