Alkali Burn Research Articles

Exploring the Role of Lycium barbarum Polysaccharide in Corneal Injury Repair and Investigating the Relevant Mechanisms through In Vivo and In Vitro Experiments.

Lycium barbarum polysaccharide (LBP) is the main active component of Fructus Lycii, exhibiting various biological activities. This study aims to explore the protective effects of LBP on human corneal epithelial cells (HCEC) and a rat corneal injury model. Potential target points for LBP improving corneal injury repair were screened from public databases, and functional and pathway enrichment analyses of core targets were conducted using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Rat corneal alkali burns and HCEC oxidative stress injury models were established, and the results were validated through slit lamp examination, HE staining, TUNEL assay, immunofluorescence, CCK-8 assay, flow cytometry, scratch assay, and qRT-PCR methods. In the context of database retrieval, identification of 10 LBP monosaccharide components and 50 corneal injury repair-related targets was achieved. KEGG pathway analysis suggested that LBP might regulate the IL-17 and TNF signaling pathways through targets such as JUN, CASP3, and MMP9, thereby improving corneal damage. In vivo and in vitro experimental results indicated that LBP could reduce the increase of inflammation index scores (p < 0.05), inflammatory cell density (p < 0.01), TUNEL-positive cells (p < 0.01), corneal opacity scores (p < 0.01), and expression of corneal stromal fibrosis-related proteins α-SMA, FN, and COL (p < 0.01) caused by chemical damage to rat corneas. LBP inhibited oxidative stress-induced decreases in cell viability (p < 0.001) and migration healing ability (p < 0.01) in HCECs, reducing apoptosis rates (p < 0.001), ROS levels (p < 0.001), and the expression of inflammatory factors TNF-α and IL-6 (p < 0.01). qRT-PCR results demonstrated that LBP intervention decreased the mRNA levels of JUN, CASP3, and MMP9 in H2O2-induced alkaline-burned corneas and HCECs (p < 0.01).The integrated results from network pharmacology and validation experiments suggest that the inhibitory effects of LBP on apoptosis, inflammation, and fibrosis after corneal injury may be achieved through the suppression of the TNF and IL-17 signaling pathways mediated by JUN, CASP3, and MMP9.

Novel micellar CB2 receptor agonist with anti-inflammatory action for treating corneal alkali burns in a mouse model.

Introduction: Moderate corneal alkali burns such as those sustained from accidental exposure to household chemicals are treated with topical corticosteroids. Side effects include increased intraocular pressure and slowing of wound healing. Here, we compare the effects of a cannabinoid receptor 2 (CB2r) agonist, TA-A001, that is involved in wound healing with that of the corticosteroid, prednisolone. Methods: TA-A001 was encapsulated with a polymeric micelle comprising polyvinylpyrrolidone: polylactide block copolymers referred to as SmartCelle™ to allow delivery of the very hydrophobic drug. Mouse corneas were given moderate alkali burns. Different doses of TA-A001 of 0.125%, 0.25% and 0.5% were used to treat the burns in comparison to the corticosteroid, prednisolone. Results: TA-A001 at 0.25% and 0.5% allowed for faster wound closure. However, the higher 0.5% dose also induced unwanted neovascularization. By comparison, burned corneas treated with prednisolone showed slower healing as well as disorganization of the cornea. Although 0.25% TA-A001 appeared to produce the most-optimal responses, this dose resulted in marked expression of the macrophage chemoattractant protein, MCP-1. However, there was also an increase in CD163 positive stained M2 anti-inflammatory macrophages in the TA-A001 corneas. TA-A001 treated corneas showed the presence of sensory nerve fibers throughout the corneal epithelium including the superficial cell layers as did Substance P staining. Discussion: We found that TA-A001 at the 0.25% doses was able to modulate inflammation resulting from a moderate alkali burn to the cornea. With more extensive testing, TA-A001 might prove to be a potential alternative to corticosteroids for treating alkali burns or other causes of corneal inflammation.

URP20 improves corneal injury caused by alkali burns combined with pathogenic bacterial infection in rats

Corneal alkali burns often occur in industrial production and daily life, combined with infection, and may cause severe eye disease. Oxidative stress and neovascularization (NV) are important factors leading to a poor prognosis. URP20 is an antimicrobial peptide that has been proven to treat bacterial keratitis in rats through antibacterial and anti-NV effects. Therefore, in this study, the protective effect and influence mechanism of URP20 were explored in a rat model of alkali burn together with pathogenic bacteria (Staphylococcus aureus and Escherichia coli) infection. In addition, human umbilical vein endothelial cells (HUVECs) and human corneal epithelial cells (HCECs) were selected to verify the effects of URP20 on vascularization and oxidative stress. The results showed that URP20 treatment could protect corneal tissue, reduce corneal turbidity, and reduce the NV pathological score. Furthermore, URP20 significantly inhibited the expression of the vascularization marker proteins VEGFR2 and CD31. URP20 also reduced the migration ability of HUVECs. In terms of oxidative stress, URP20 significantly upregulated SOD and GSH contents in corneal tissue and HCECs (treated with 200 μM H2O2) and promoted the expression of the antioxidant protein Nrf2/HO-1. At the same time, MDA and ROS levels were also inhibited. In conclusion, URP20 could improve corneal injury combined with bacterial infection in rats caused by alkali burns through antibacterial, anti-NV, and antioxidant activities.

Research progress on animal models of corneal epithelial-stromal injury.

A corneal epithelial-stromal defect is recognized as a major contributor to corneal scarring. Given the rising prevalence of blindness caused by corneal scarring, increasing attention has been focused on corneal epithelial-stromal defects. Currently, the etiology and pathogenesis of these defects remain inadequately understood, necessitating further investigation through experimental research. Various modeling methods exist both domestically and internationally, each with distinct adaptive conditions, advantages, and disadvantages. This review primarily aims to summarize the techniques used to establish optimal animal models of corneal epithelial-stromal injury, including mechanical modeling, chemical alkali burns, post-refractive surgery infections, and genetic engineering. The intention is to provide valuable insights for studying the mechanisms underlying corneal epithelial-stromal injury and the development of corresponding therapeutic interventions.

Development of injectable hyaluronic acid-based hydrogels with antioxidant activity for the treatment of corneal neovascularization

Corneal neovascularization (CNV) is a condition that can severely adversely affect corneal transparency, culminating in visual disturbances and potential blindness. The need to manage this condition by frequently administering glucocorticoid eye drops can increase the risk of adverse side effects while reducing the odds that patients will comply with treatment regimens. Given that CNV often coincides with elevated levels of reactive oxygen species (ROS) production, in this study a sunitinib-loaded injectable antioxidant hydrogel was developed using hyaluronic acid and tannic acid. This hydrogel was effectively able to eliminate free radicals including ABTS and DPPH, normalizing intracellular ROS levels while protecting against H2O2-induced apoptosis. This sunitinib-loaded hydrogel also effectively inhibited the proliferation and tube formation activity of endothelial cells, while also inhibiting oxidative stress, inflammatory activity, and CD31 expression, thereby effectively preserving corneal transparency, promoting more rapid epithelialization, and inhibiting alkali burn-induced CNV in vivo. This sunitinib-loaded hydrogel may thus hold great promise as a novel tool for treating CNV and corneal alkali burns.

Tetramethylpyrazine inhibits keratitis and neovascularization induced by corneal alkali burn by suppressing the TLR4/NF-κB pathway activation and NLRP1/NLRP3 inflammasomes in rats

The role and related mechanisms of tetramethylpyrazine (TMP) in corneal alkali burn in rats were expected to be explored in this article. After construction of corneal alkali burn rat models, TMP eye drops were given four times daily for consecutive 7 days. H&E staining was utilized for observing the histopathological changes of corneas on the 3rd and 7th days of treatment; immunohistochemistry for detecting the Nestin protein expression changes; qRT-PCR for determining the expression changes of genes correlated with neovascularization [C-X-C Motif Chemokine Ligand 1 (CXCL-1), vascular endothelial growth factor A (VEGFA) and CD31] and inflammation-related factors [monocyte chemoattractant protein-1 (MCP-1), interleukin-1β (IL-1β), tumour necrosis factor α (TNF-α), and IL-6]; Western blot for testing NLR Family Pyrin Domain Containing 1 (NLRP1)/NLRP3 inflammasomes and toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) pathway-related protein expression changes. All above trials were completed based on rat corneal tissue. TMP ameliorated the pathological damage in alkali-burned rat corneal tissue. Specifically, TMP treatment decreased Nestin-positive cell expression and the CXCL-1, VEGFA and CD31 mRNA expression in alkali-burned rat corneal tissue dose-dependently. TMP also down-regulated the IL-1β, TNF-α, MCP-1 and IL-6 mRNA expression and inhibited the NLRP1, caspase-1, NLRP3, pro-IL-1β and mature IL-1β protein expression in the alkali-burned rat corneal tissue. In addition, TMP treatment down-regulated the myeloid differentiation factor 88 (MyD88) and TLR4 protein expression and decreased the p–NF–κB p65/NF-κB p65 ratio in the alkali-burned rat corneal tissue. The mechanism of TMP relieving the inflammatory response and inhibiting neovascularization caused by corneal alkali burn in rats might have a correlation with the suppression of acitivation of TLR4/NF-κB pathway and NLRP1/NLRP3 inflammasomes in rats.

Emerging Strategies in Treating Corneal Alkali Burns: A Narrative Review.

Corneal alkali burns represent a complex and debilitating ocular injury, necessitating innovative strategies for effective management. This narrative medical review seeks to provide a comprehensive exploration of emerging approaches in the treatment of corneal alkali burns. The primary objectives of this review are multifaceted. First, we aim to unravel the intricate pathophysiology of corneal alkali burns, delving into the immediate and long-term consequences of alkali exposure on ocular tissues. Understanding the underlying mechanisms, including oxidative stress, inflammation, and neovascularization, is essential for the development of targeted therapeutic interventions. Second, we assess the efficacy of novel treatment modalities, encompassing pharmacological agents and surgical techniques, with a focus on their ability to mitigate corneal damage, facilitate tissue regeneration, and preserve visual function. By analyzing the latest clinical findings, we aim to identify promising avenues for improved patient outcomes. Temporal dynamics play a crucial role in the healing process, and thus our review investigates the progression of corneal lymphangiogenesis and the expression patterns of key growth factors, such as vascular endothelial growth factor-C (VEGF-C). These insights into the timing of corneal healing provide valuable guidance for tailoring therapeutic interventions to specific stages of injury. Finally, we delve into regenerative therapies, particularly the potential of mesenchymal stem cells (MSCs) and their secretome as anti-inflammatory and antiangiogenic agents. By summarizing the promising results from preclinical and clinical studies, we illuminate the prospects of regenerative approaches in corneal alkali burn management. This narrative review aspires to serve as an indispensable resource for clinicians, researchers, and healthcare professionals involved in the treatment of corneal alkali burns. By addressing these objectives, we aim to foster a deeper understanding of this challenging condition, facilitate the development of innovative strategies, and ultimately enhance patient outcomes in the realm of corneal health and vision preservation.

Biofunctionalization of nanoceria with sperminated hyaluronan enhances drug delivery performance for corneal alkali burn therapy

Corneal alkali burn (AB) injury is the most common sight-threatening injury that is highly associated with oxidative stress, inflammation, apoptosis, angiogenesis, and cell deficiency. Most therapeutic options are ineffective in improving and reversing pathological conditions. This study aims to develop a delivery system based on sperminated hyaluronan (sH)-functionalized nanoceria (Ce-sH nanoparticles (NPs)) with enhanced barrier penetration capability and increased ocular drug bioavailability. The functional surface properties and therapeutic bioactivities of Ce-sH NPs were evaluated. We observed a high tight-junction opening capacity with higher spermine content, resulting in excellent permeability and cellular uptake efficiency (fourfold that of bare Ce NPs). The NPs exhibited high drug (insulin-like growth factor 1, IGF-1) entrapment efficiency (10-fold) and hyaluronidase-triggered controlled slow release (up to 168 h) compared with bare Ce NPs. The IGF-1-loaded Ce-hsH NPs (I@Ce-hsH) had the best wound healing rate (>90 %). In contrast to a clinically used eye drop (dexamethasone), the I@Ce-hsH significantly reduced corneal defects to <1 % and restored the tissue transparency to a normal range within 7 d post-instillation in a rat model of AB. In summary, our bioactive nanoformulations successfully reversed corneal injury and has great potential in the design of biomaterials for ocular therapeutics.

Smooth muscle cells-specific loss of OCT4 accelerates neointima formation after acute vascular injury.

There is growing evidence that smooth muscle cell (SMC) phenotypic transitions play critical roles during normal developmental and tissue recovery processes and in pathological conditions such as atherosclerosis. However, the molecular mechanisms responsible for these transitions are not well understood. Recently, we found that the embryonic stem cell/induced pluripotent stem cell (iPSC) factor OCT4, which was believed to be silenced in somatic cells, plays an atheroprotective role in SMC, and regulates angiogenesis after corneal alkali burn and hindlimb ischemia by mediating microvascular SMC and pericyte migration. However, the kinetics of OCT4 activation in arterial SMC and its role in acute pathological conditions are still unknown. Here, using an Oct4-IRES-GFP reporter mouse model, we found that OCT4 is reactivated in the carotid artery 18 hours post-acute ligation-induced injury, a common in vivo model of the SMC phenotypic transitions. Next, using a tamoxifen-inducible Myh11-CreERT2 Oct4 knockout mouse model, we found that the loss of OCT4, specifically in SMC, led to accelerated neointima formation and increased tunica media following carotid artery ligation, at least in part by increasing SMC proliferation within the media. Bulk RNA sequencing analysis on the cultured SMC revealed significant down-regulation of the SMC contractile markers and dysregulation of the genes belonging to the regulation of cell proliferation and, positive and negative regulation for cell migration ontological groups following genetic inactivation of Oct4. We also found that loss of Oct4 resulted in suppression of contractile SMC markers after the injury and in cultured aortic SMC. Further mechanistic studies revealed that OCT4 regulates SMC contractile genes, ACTA2 and TAGLN, at least in part by direct binding to the promoters of these genes. These results demonstrate that the pluripotency factor OCT4 is quickly activated in SMC after the acute vascular injury and inhibits SMC hyperproliferation, which may be protective in preventing excessive neointima formation.

Smart coating by thermo-sensitive Pluronic F-127 for enhanced corneal healing via delivery of biological macromolecule progranulin

As a leading cause of vision impairment and blindness, corneal alkali burns lead to long-term visual deterioration or even permanent visual impairment while effective treatment strategies remain a challenge. Herein, a thermo-sensitive hydrogel with the combination of multi-functional protein progranulin (PGRN), a biological macromolecule consisting of several hundred amino acids and possessing a high molecular weight, is efficiently prepared through a convenient stirring and mixing at the low temperature. The hydrogel can be easily administrated to the ocular surface contacting with the cornea, which can be immediately transformed into gel-like state due to the thermo-responsive behavior, realizing a site-specific coating to isolate further external stimulation. The smart coating not only exhibits excellent transparency and biocompatibility, but also presents a constant delivery of PGRN, creating a nutritious and supportive micro-environment for the ocular surface. The results show that the prepared functional hydrogel can efficiently suppress inflammation, accelerate re-epithelization, and intriguingly enhance axonal regeneration via modulation of multiple signaling pathways, indicating the novel designed HydrogelPGRN is a promising therapy option for serious corneal injury.

The prophylactic value of TNF-α inhibitors against retinal cell apoptosis and optic nerve axon loss after corneal surgery or trauma.

Late secondary glaucoma is an often-severe complication after acute events like anterior segment surgery, trauma and infection. TNF-α is a major mediator that is rapidly upregulated, diffusing also to the retina and causes apoptosis of the ganglion cells and degeneration of their optic nerve axons (mediating steps to glaucomatous damage). Anti-TNF-α antibodies are in animals very effective in protecting the retinal cells and the optic nerve-and might therefore be useful prophylactically against secondary glaucoma in future such patients. Here we evaluate (1) toxicity and (2) efficacy of two TNF-α inhibitors (adalimumab and infliximab), in rabbits by subconjunctival administration. For drug toxicity, animals with normal, unburned corneas were injected with adalimumab (0.4, 4, or 40 mg), or infliximab (1, 10, or 100 mg). For drug efficacy, other animals were subjected to alkali burn before such injection, or steroids (for control). The rabbits were evaluated clinically with slit lamp and photography, electroretinography, optical coherence tomography, and intraocular pressure manometry. A sub-set of eyes were stained ex vivo after 3 days for retinal cell apoptosis (TUNEL). In other experiments the optic nerves were evaluated by paraphenylenediamine staining after 50 or 90 days. Loss of retinal cells and optic nerve degeneration were quantified. Subconjunctival administration of 0.4 mg or 4.0 mg adalimumab were well tolerated, whereas 40.0 mg was toxic to the retina. 1, 10, or 100 mg infliximab were also well tolerated. Analysis of the optic nerve axons after 50 days confirmed the safety of 4.0 mg adalimumab and of 100 mg infliximab. For efficacy, 4.0 mg adalimumab subconjunctivally in 0.08 mL provided practically full protection against retinal cell apoptosis 3 days following alkali burn, and infliximab 100 mg only slightly less. At 90 days following burn injury, control optic nerves showed about 50% axon loss as compared to 8% in the adalimumab treatment group. Subconjunctival injection of 4.0 mg adalimumab in rabbits shows no eye toxicity and provides excellent neuroprotection, both short (3 days) and long-term (90 days). Our total. accumulated data from several of our studies, combined with the present paper, suggest that corneal injuries, including surgery, might benefit from routine administration of anti-TNF-α biologics to reduce inflammation and future secondary glaucoma.

Development of dual-functional core-shell electrospun mats with controlled release of anti-inflammatory and anti-bacterial agents for the treatment of corneal alkali burn injuries

In this study, a novel dual-drug carrier for the co-administration of an anti-inflammatory and antibiotic agent consisting of core-shell nanofibers for the treatment of cornea alkali burns was designed. The core-shell nanofibers were prepared via coaxial electrospinning of curcumin-loaded silk fibroin as the core and vancomycin-loaded chitosan/polyvinyl alcohol (PVA) as the shell.Electron microscopy (SEM and TEM) images confirmed the preparation of smooth, bead-free, and continuous fibers that formed clear core-shell structures. For further studies, nanofiber mats were cross-linked by heat treatment to avoid rapid disintegration in water and improve both mechanical properties and drug release. The release profile of curcumin and vancomycin indicated an initial burst release, continued by the extended release of both drugs within 72 hours. Rabbit corneal cells demonstrated high rates of proliferation when evaluated using a cell metabolism assay. Finally, the therapeutic efficiency of core/shell nanofibers in healing cornea alkali burn was studied by microscopic and macroscopic observation, fluorescence staining, and hematoxylin-eosin assay on rabbit eyes. The anti-inflammatory activity of fabricated fibers was evaluated by enzyme-linked immunosorbent assay and Immunofluorescence analysis. In conclusion, using a robust array of in vitro and in vivo experiments this study demonstrated the ability of the dual-drug carriers to promote corneal re-epithelialization, minimize inflammation, and inhibit corneal neovascularization. Since these parameters are critical to the healing of corneal wounds from alkali burns, we suggest that this discovery represents a promising future therapeutic agent that warrants further study in humans.

Topical formulations of Aprepitant are safe and effective in relieving pain and inflammation, and drive neural regeneration

PurposeTo test long-term ocular toxicity and analgesic/anti-inflammatory efficacy of two novel ocular formulations of neurokinin 1 receptor (NK1R) antagonist Aprepitant. Methodsfor toxicity studies, two Aprepitant formulations (X and Y) were tested on C57BL/6 N mice. Gold standards were 0.4% Oxybuprocaine, 0.1% Diclofenac, or saline. For efficacy studies, C57BL/6 N mice underwent corneal alkali burn, and then received Aprepitant formulation X, Dexamethasone or saline. Eye-drops were applied 3 times/day for 90 days (toxicity) and 14 days (efficacy). Stromal opacity, corneal epithelial damage, nociception and sensitivity were assessed in vivo. The eye-wiping test and corneal sensitivity were assessed to evaluate analgesic efficacy and nerve function. At the end of the experiments mice were euthanized, and corneas were dissected for immunohistochemistry and RT-PCR analyses. ResultsIn normal mice, formulation X was not toxic when topically administered for 90 days. Formulation Y was associated with increased leukocyte infiltration in the cornea (p < 0.001). X1 and X2 formulations significantly reduced corneal pain, as Diclofenac and Oxybuprocaine, but did not reduce corneal sensitivity. Formulation Y, instead, was not analgesic at any time point. In the alkali burn model, X1 and X2 formulation enhanced epithelial damage recovery, and reduced inflammation both at day 7 and 14. Moreover, formulation X showed a stronger analgesic effect when compared to the saline and Dexamethasone groups (p < 0.01). Finally, formulation X1 and X2 restored corneal sensitivity by promoting corneal nerve regeneration. ConclusionsAprepitant X formulation is a promising candidate for the treatment of pain associated with inflammation of the ocular surface.

Composite Hydrogel Modulates Intrinsic Immune-Cascade Neovascularization for Ocular Surface Reconstruction after Corneal Chemical Injury.

Ocular alkali burns recruit neutrophils and triggers neutrophil extracellular trap (NET)-neovascularization cascade effects that limit ocular surface reconstruction and functional repair. However, effective inhibition of the release of neutrophil extracellular traps after a corneal chemical injury, coordination of intrinsic immunity with corneal repair, and exploration of more effective and non-invasive drug-delivery modes are still urgently needed. Using an in vitro coculture system, we found that an alkaline environment stimulates neutrophils to release NETs, which can be regulated by deoxyribonuclease I (DNase I). Inspired by this, we loaded DNase I, which effectively regulates NETs, onto chitosan nanoparticles and combined them with silk fibroin to construct a composite hydrogel that can sustainably regulate NETs. The hydrogel reduced neutrophil extracellular trap production by 50% and neovascularization by approximately 70% through sustained DNase I release after a corneal alkali burn. The complex hydrogel promotes ocular surface reconstruction by modulating the intrinsic immune-cascade neovascularization effect, providing a new research basis for the construction of nanobiomaterials that modulate pathological neovascularization.

Expressions of Matrix Metalloproteinase-3 and Tissue Inhibitor Metalloproteinase-1 in Corneal Tissue Post Alkali Burn Treated with Topical Medroxyprogesterone Acetate and Doxycycline

Expressions of Matrix Metalloproteinase-3 and Tissue Inhibitor Metalloproteinase-1 in Corneal Tissue Post Alkali Burn Treated with Topical Medroxyprogesterone Acetate and Doxycycline

Myeloid-derived suppressor cells ameliorate corneal alkali burn through IL-10-dependent anti-inflammatory properties

This study aims to investigate the efficiency and the underlying mechanism of myeloid-derived suppressor cells (MDSCs) in corneal alkali burns (CAB). In the study, CD11b+ Gr-1+ cells from C57BL/6J mice bone marrow were cultured and induced. Cell activity and immunoregulatory function were assessed by flow cytometry in vitro. The optimal strategy of MDSCs therapy was assessed by slit-lamp microscopy, and flow cytometry in vivo. The therapeutic effects of MDSCs and the critical signaling pathway were investigated by hematoxylin-eosin (HE) staining, slit-lamp microscopy, flow cytometry, and immunofluorescence. The expression level of the NLRP3 inflammasome pathway was examined. The crucial biochemical parameters of MDSCs were examined by RNA-seq and qPCR to screen out the key regulators. The mechanism of MDSCs’ therapeutic effects was explored using MDSCs with IL-10 knockout/rescue by slit-lamp microscopy, HE staining, and qPCR evaluation. The cell frequencies of macrophages and neutrophils in the cornea were examined by flow cytometry in vivo. The results demonstrated that the induced MDSCs meet the standard of phenotypic and functional characteristics. The treatment of 5 × 105 MDSCs conjunctival injection on alternate days significantly ameliorated the disease development, downregulated the NLRP3 inflammasome pathway, and decreased the cell frequencies of macrophages and neutrophils in vivo significantly. IL-10 was screened out to be the critical factor for MDSCs therapy. The therapeutic effects of MDSCs were impaired largely by IL-10 knock-out and saved by the IL-10 supplement. In conclusion, MDSCs therapy is a promising therapeutic solution for CAB. MDSCs fulfilled immunoregulatory roles for CAB by IL-10-dependent anti-inflammatory properties.

Sustained Inhibition of VEGF and TNF-α Achieves Multi-Ocular Protection and Prevents Formation of Blood Vessels after Severe Ocular Trauma.

This study aimed to develop a clinically feasible and practical therapy for multi-ocular protection following ocular injury by using a thermosensitive drug delivery system (DDS) for sustained delivery of TNF-α and VEGF inhibitors to the eye. A thermosensitive, biodegradable hydrogel DDS (PLGA-PEG-PLGA triblock polymer) loaded with 0.7 mg of adalimumab and 1.4 mg of aflibercept was injected subconjunctivally into Dutch-belted pigmented rabbits after corneal alkali injury. Control rabbits received 2 mg of IgG-loaded DDS or 1.4 mg of aflibercept-loaded DDS. Animals were followed for 3 months and assessed for tolerability and prevention of corneal neovascularization (NV), improvement of corneal re-epithelialization, inhibition of retinal ganglion cell (RGC) and optic nerve axon loss, and inhibition of immune cell infiltration into the cornea. Drug-release kinetics was assessed in vivo using an aqueous humor protein analysis. A single subconjunctival administration of dual anti-TNF-α/anti-VEGF DDS achieved a sustained 3-month delivery of antibodies to the anterior chamber, iris, ciliary body, and retina. Administration after corneal alkali burn suppressed CD45+ immune cell infiltration into the cornea, completely inhibited cornea NV for 3 months, accelerated corneal re-epithelialization and wound healing, and prevented RGC and optic nerve axon loss at 3 months. In contrast, anti-VEGF alone or IgG DDS treatment led to persistent corneal epithelial defect (combined: <1%; anti-VEGF: 15%; IgG: 10%, of cornea area), increased infiltration of CD45+ immune cells into the cornea (combined: 28 ± 20; anti-VEGF: 730 ± 178; anti-IgG: 360 ± 186, cells/section), and significant loss of RGCs (combined: 2.7%; anti-VEGF: 63%; IgG: 45%) and optic nerve axons at 3 months. The aqueous humor protein analysis showed first-order release kinetics without adverse effects at the injection site. Concomitant inhibition of TNF-α and VEGF prevents corneal neovascularization and ameliorates subsequent irreversible damage to the retina and optic nerve after severe ocular injury. A single subconjunctival administration of this therapy, using a biodegradable, slow-release thermosensitive DDS, achieved the sustained elution of therapeutic levels of antibodies to all ocular tissues for 3 months. This therapeutic approach has the potential to dramatically improve the outcomes of severe ocular injuries in patients and improve the therapeutic outcomes in patients with retinal vascular diseases.

ACUTE KERATOUVEITIS WITH CORNEAL GRAFT MELTING AS A LATE COMPLICATION OF MILD CHEMICAL BURN POTENTIALLY ASSOCIATED WITH COVID-19 INFECTION: A CASE REPORT.

In this case report, we describe the course and treatment of a patient with chemical alkali burns of both eyes. This study reports the outcomes of an ocular alkali burn patient who became infected with COVID-19 and where severe keratouveitis with corneal graft melting and hypopyon occurred, ultimately resulting in evisceration of the eye. We report the case of a 35-year-old woman, after an alkali burn of both eyes. Complete re-epithelialization of both corneas occurred within three weeks. Due to this observation, we assumed a satisfactory healing prognosis. However, corneal lysis occurred in the left eye over time. Thecondition was managed, but subsequently severe keratouveitis with hypopyon and corneal lysis occurred in the left eye, apparently in connection with the COVID-19 infection, which ultimately led to the evisceration of the affected eye. In the case report, we describe the management of a mild chemical alkali burn of the right eye and a complicated moderate burn of the left eye with an alkaline chemical. Both eyes were completely healed within three weeks. However, the findings on the left eye became complicated, which ultimately led to the evisceration of the affected eye. The disease of COVID-19 could have contributed to the deterioration of the findings on the cornea, or it could have just been a coincidence of two diseases, with the keratouveitis having a serious course due to the previous difficult course of healing and many complications after the chemical burn.

Poly(l-Histidine)-Mediated On-Demand Therapeutic Delivery of Roughened Ceria Nanocages for Treatment of Chemical Eye Injury.

Development of topical bioactive formulations capable of overcoming the low bioavailability of conventional eye drops is critically important for efficient management of ocular chemical burns. Herein, a nanomedicine strategy is presented to harness the surface roughness-controlled ceria nanocages (SRCNs) and poly(l-histidine) surface coatings for triggering multiple bioactive roles of intrinsically therapeutic nanocarriers and promoting transport across corneal epithelial barriers as well as achieving on-demand release of dual drugs [acetylcholine chloride (ACh) and SB431542] at the lesion site. Specifically, the high surface roughness helps improve cellular uptake and therapeutic activity of SRCNs while exerting a negligible impact on good ocular biocompatibility of the nanomaterials. Moreover, the high poly(l-histidine) coating amount can endow the SRCNs with an ≈24-fold enhancement in corneal penetration and an effective smart release of ACh and SB431542 in response to endogenous pH changes caused by tissue injury/inflammation. In a rat model of alkali burn, topical single-dose nanoformulation can efficaciously reduce corneal wound areas (19-fold improvement as compared to a marketed eye drops), attenuate ≈93% abnormal blood vessels, and restore corneal transparency to almost normal at 4 days post-administration, suggesting great promise for designing multifunctional metallic nanotherapeutics for ocular pharmacology and tissue regenerative medicine.

MiRNA 24-3p-rich exosomes functionalized DEGMA-modified hyaluronic acid hydrogels for corneal epithelial healing.

The damage of corneal epithelium may lead to the formation of irreversible corneal opacities and even blindness. The migration rate of corneal epithelial cells directly affects corneal repair. Here, we explored ocu-microRNA 24-3p (miRNA 24-3p) that can promote rabbit corneal epithelial cells migration and cornea repair. Exosomes, an excellent transport carrier, were exacted from adipose derived mesenchymal stem cells for loading with miRNA 24-3p to prepare miRNA 24-3p-rich exosomes (Exos-miRNA 24-3p). It can accelerate corneal epithelial migration in vitro and in vivo. For application in cornea alkali burns, we further modified hyaluronic acid with di(ethylene glycol) monomethyl ether methacrylate (DEGMA) to obtain a thermosensitive hydrogel, also reported a thermosensitive DEGMA-modified hyaluronic acid hydrogel (THH) for the controlled release of Exos-miRNA 24-3p. It formed a highly uniform and clear thin layer on the ocular surface to resist clearance from blinking and extended the drug-ocular-epithelium contact time. The use of THH-3/Exos-miRNA 24-3p for 28 days after alkali burn injury accelerated corneal epithelial defect healing and epithelial maturation. It also reduced corneal stromal fibrosis and macrophage activation. MiRNA 24-3p-rich exosomes functionalized DEGMA-modified hyaluronic acid hydrogel as a multilevel delivery strategy has a potential use for cell-free therapy of corneal epithelial regeneration.