Mucoadhesive, antioxidant, and lubricant catechol-functionalized poly(phosphobetaine) as biomaterial nanotherapeutics for treating ocular dryness.

Dry eye disease (DED) is associated with ocular hyperosmolarity and inflammation. The marketed topical eye drops for DED treatment often lack bioavailability and precorneal residence time. In this study, we investigated catechol-functionalized polyzwitterion p(MPC-co-DMA), composed of 2-methacryloyloxyethyl phosphorylcholine (MPC) and dopamine methacrylamide (DMA) monomers, as potential topical nanotherapeutics for DED. The copolymers were synthesized via random free-radical copolymerization, producing different proportions of catecholic functionalization. All as-prepared polymer compositions displayed good ocular biocompatibility. At a feeding ratio of 1:1, p(MPC1-co-DMA1) can facilitate a robust mucoadhesion via Michael addition and/or Schiff base reaction, thus prolonging ocular residence time after 4 days of topical instillation. The hydration lubrication of MPC and radical-scavenging DMA endow the nano-agent to ease tear-film hyperosmolarity and corneal inflammation. A single dose of p(MPC1-co-DMA1) (1 mg/mL) after 4 days post-instillation can protect the cornea against reactive oxygen species, inhibiting cell apoptosis and the over-expression of pro-inflammatory factors (IL-6 and TNF-α). In clinical assessment, DED-induced rabbit eyes receiving p(MPC1-co-DMA1) could increase lacrimal fluid secretion by 5-fold higher than cyclosporine A. The catechol-functionalized polyzwitterion with enhanced lubricity, mucoadhesion, and anti-oxidation/anti-inflammation properties has shown high promise as a bioactive eye drop formulation for treating DED.

Fluorescent carbon dots for labeling of bacteria: mechanism and prospects-a review.

The search for bacteria-labeling agents that are more efficient and less toxic compared to existing staining dyes is ongoing. Fluorescent quantum dots and carbon dots (CDs) have been extensively researched for various bioimaging applications. Priority is given to CDs due to several advantages, including lower toxicity, versatility in tuning their properties, and better photostability compared to metal-based quantum dots. Although significant progress is still needed to replace existing dyes with CDs for bacteria labeling, they offer promising potential for further improvement in efficiency. Surface charges and functional groups have been reported as decisive factors for bacterial discrimination and live/dead assays; however, a complete guideline for preparing CDs with optimum properties for efficient staining and predicting their labeling performance is lacking. In this review, we discuss the application of fluorescent CDs for bacterial labeling and the underlying mechanisms and principles. We primarily focus on the application and mechanism of CDs for Gram differentiation, live imaging, live/dead bacteria differentiation, bacterial viability testing, biofilm imaging, and the challenges associated with application of CDs. Based on proposed mechanisms of bacterial labeling and ambiguous results reported, we provide our view and guidelines for the researchers in this field to overcome the challenges associated with bacteria labeling using fluorescent CDs.

An insight into the dual role of MoS2-based nanocarriers in anticancer drug delivery and therapy.

Over the years, nanomaterials have been exploited as drug delivery systems and therapeutic agents in cancer treatment. Special emphasis has been placed on structure and shape-mediated drug loading and release. Functional materials, including molybdenum disulfide (MoS2), have shown promising results because of their tunable structure and unmatched physicochemical properties. Specifically, easy surface functionalization and high drug adsorption ability make them ideal candidates. Although the large surface area of nanosheets/nanoflakes may result in high drug loading, the encapsulation efficiency is better for MoS2 nanoflower structures. Due to its high targeting abilities, the loading of chemotherapeutic drugs onto MoS2 may minimize nonspecific cellular death and undesired side effects. Furthermore, due to their strong light-absorption ability, MoS2 nanostructures have been widely exploited as photothermal and photodynamic therapeutic agents. The unexplored dimensions of cancer therapy, including chemodynamic (Fenton-like reaction) and piezo-catalytic (ultrasound-mediated reactive oxygen generation), have been recently unlocked, in which the catalytic properties of MoS2 are utilized to generate toxic free radicals to eliminate cancer. Intriguingly, combining these therapeutic modalities often results in high therapeutic efficacy at low doses and minimizes side effects. With a plethora of recent studies, a thorough analysis of current findings is crucial. Therefore, this review discusses the major advances in this field of research. A brief commentary on the limitations/future outlook/ethical issues of the clinical translation of MoS2-mediated cancer treatments is also deliberated. Overall, in our observations, the MoS2-based nanoformulations hold great potential for future cancer therapy applications. STATEMENT OF SIGNIFICANCE: Development of nanomedicines based on MoS2 has opened new avenues in cancer treatment. The MoS2 with different morphologies (nanosheet/nanoflower/QDs) has shown promising results in controlled and targeted drug delivery, leading to minimized side effects and increased therapeutic efficacy. While existing reviews have primarily focused on the optical/thermal properties utilized in photodynamic/photothermal therapy, the outstanding catalytic properties of MoS2 utilized in cancer therapies (chemodynamic/piezo-catalytic) are often overlooked. This review critically highlights and praises/criticizes individual articles reporting the MoS2-based nanoplatforms for cancer therapy applications. Additionally, MoS2-based combined therapies for synergistic effects are discussed. Furthermore, a brief commentary on the future prospects for clinical translations is also deliberated, which is appealing to various research communities engaged in cancer theranostics and biomedical sciences research.

Optically active two-dimensional MoS2-based nanohybrids for various biosensing applications: A comprehensive review.

Following the discovery of graphene, there has been a surge in exploring other two-dimensional (2D) nanocrystals, including MoS2. Over the past few decades, MoS2-based nanocrystals have shown great potential applications in biosensing, owing to their excellent physico-chemical properties. Unlike graphene, MoS2 shows layer-dependent finite band gaps (∼1.8 eV for a single layer and ∼1.2 for bulk) and relatively strong interaction with the electromagnetic spectrum. The tunability of the size, shape, and intrinsic properties, such as high optical absorption, electron mobility, mechanical strength and large surface area, of MoS2 nanocrystals, make them excellent alternative probe materials for preparing optical, photothermal, and electrical bio/immunosensors. In this review, we will provide insights into the rapid evolutions in bio/immunosensing applications based on MoS2 and its nanohybrids. We emphasized the various synthesis, characterization, and functionalization routes of 2D MoS2 nanosheets/nanoflakes. Finally, we discussed various fabrication techniques and the critical parameters, including the limit of detection (LOD), linear detection range, and sensitivity of the biosensors. In addition, the role of MoS2 in enhancing the performance of biosensors, the limitations associated with current biosensing technologies, future challenges, and clinical implications are addressed. The advantages/disadvantages of each biosensor technique are also summarized. Collectively, we believe that this review will encourage resolute researchers to follow up further with the state-of-the-art MoS2-based biosensing technology.

Ultrahigh-Efficacy VEGF Neutralization Using Carbonized Nanodonuts: Implications for Intraocular Anti-Angiogenic Therapy.

Ocular angiogenesis, associated with diseases such as retinopathy of prematurity and diabetic retinopathy, is a leading cause of irreversible vision loss. Herein, carbon nanodonuts (CNDs) with a donut-shaped structure are synthesized using sodium alginate (SA) and 1,8-diaminooctane (DAO) through a one-step thermal process. The formation of SA/DAO-CNDs occurs through a crosslinking reaction between SA and DAO, creating amide bonds followed by partial carbonization. In human retinal pigment epithelial cells exposed to H2 O2 or lipopolysaccharide, the SA/DAO-CNDs display a more than fivefold reduction in reactive oxygen species and proinflammatory cytokines, such as IL-6 and IL-1ß, when compared to carbonized nanomaterials produced exclusively from SA. Furthermore, the CNDs effectively inhibit vascular endothelial growth factor A-165 (VEGF-A165 )-induced cell migration and tube formation in human umbilical vein endothelial cells due to their strong affinity for VEGF-A165 , with a dissociation constant of 2.2 × 10-14  M, over 1600 times stronger than the commercial drug bevacizumab (Avastin). Trypsin digestion coupled with LC-MS/MS analysis reveals that VEGF-A165 interacts with SA/DAO-CNDs through its heparin-binding domain, leading to activity loss. The SA/DAO-CNDs demonstrate excellent biocompatibility and potent anti-angiogenic effects in chicken embryos and rabbit eyes. These findings suggest that SA/DAO-CNDs hold promise as a therapeutic agent for treating various angiogenesis-related ocular diseases.

Unveiling the Power of Gabapentin-Loaded Nanoceria with Multiple Therapeutic Capabilities for the Treatment of Dry Eye Disease.

Dry eye (DE) disease, which is primarily linked to aqueous deficiency, is an escalating health issue worldwide, mainly due to the widespread use of electronic devices. The major obstacles in DE pharmacotherapy include insufficient therapeutic efficacy and low ocular bioavailability. This study presents the development of a ceria-based nanosystem to carry gabapentin (GBT), aiming to offer comprehensive relief from DE symptoms. We prepared multifunctional nanoceria capped with thiolated gelatin followed by cross-linking with glutaraldehyde, yielding a nanocarrier with desirable biocompatibility and antioxidant, anti-inflammatory, antiangiogenic, antiapoptotic, and neuronal protective activities. Specifically, the highly abundant thiol groups on gelatin increased the cellular uptake of the nanocarrier by 2.3-fold and its mucin-binding efficiency by 10-fold, thereby extending ocular retention and amplifying therapeutic activity. Moderate cross-linking of the thiolated gelatin not only enhanced the ocular bioavailability of the nanoceria but also provided slow, degradation-controlled release of GBT to promote the lacrimal stimulation to restore the tear film. In a rabbit model of DE, topical administration of our GBT/nanoceria nanoformulation resulted in comprehensive alleviation of symptoms, including repairing corneal epithelial damage, preserving corneal nerve density, and stimulating tear secretion, demonstrating superior performance in comparison to the free drug. These results underscore the safety and potential of this innovative nanoformulation for DE pharmacotherapy.

Recent advances in the design of intracellular pH sensing nanoprobes based on organic and inorganic materials.

In the biological system, the intracellular pH (pHi) plays an important role in regulating diverse physiological activities, including enzymatic action, ion transport, cell proliferation, metabolism, and programmed cell death. The monitoring of pH inside living cells is also crucial for studying cellular events such as phagocytosis, endocytosis, and receptor-ligand internalization. Furthermore, some organelles, viz., endosomes and lysosomes, have intracompartmental pH, which is critical for maintaining the stability of protein structure and function. The dysfunction and abnormal pH regulation can result in terminal diseases such as cancer, Alzheimer, and so forth. Therefore, the accuracy of intracellular pH measurement is always the top priority and demands cutting-edge research and analysis. Such techniques, such as Raman spectroscopy and fluorescence imaging, preferably use nanotechnology due to their remarkable advantages, such as a non-invasive approach and providing accuracy, repeatability, and reproducibility. In the past decades, there have been numerous attempts to design and construct non-invasive organic and inorganic materials-based nanoprobes for pHi sensing. For Raman-based techniques, metal nanostructures such as Au/Ag/Cu nanoparticles are utilized to enhance the signal intensity. As for the fluorescence-based studies, the organic-based small molecules, such as dyes, show higher sensitivity toward pH. However, they possess several drawbacks, including high photobleaching rate, and autofluorescence background signals. To this end, there are alternative nanomaterials proposed, including semiconductor quantum dots (QDs), carbon QDs, upconversion nanoparticles, and so forth. Moreover, the fluorescence technique allows for ratiometric measurement of pHi, which as a result, offers a reliable calibration curve. This timely review will critically examine the current progression in the existing nanoprobes. In addition, based on our knowledge and available research findings, we provide a brief future outlook that may advance the state-of-the-art methodologies for pHi sensing.

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.

In Situ Hybridization of Polymeric Curcumin to Arginine-Derived Carbon Quantum Dots for Synergistic Treatment of Bacterial Infections.

Effective infectious keratitis treatment must eliminate the pathogen, reduce the inflammatory response, and prevent persistent damage to the cornea. Infectious keratitis is generally treated with broad-spectrum antibiotics; however, they have the risk of causing corneal epithelial cell damage and drug resistance. In this study, we prepared a nanocomposite (Arg-CQDs/pCur) from arginine (Arg)-derived carbon quantum dots (Arg-CQDs) and polymeric curcumin (pCur). Partial carbonization of arginine hydrochloride in the solid state by mild pyrolysis resulted in the formation of CQDs, which exhibited enhanced antibacterial activity. pCur was formed by the polymerization of curcumin, and further crosslinking reduced its cytotoxicity and improved antioxidative, anti-inflammatory, and pro-proliferative activities. The pCur in situ conjugated with Arg-CQDs to form the Arg-CQDs/pCur nanocomposite, which showed a minimum inhibitory concentration of ca. 10 µg mL-1, which was >100-fold and >15-fold lower than that of the precursor arginine and curcumin, respectively, against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. The Arg-CQDs/pCur nanocomposite with combined antibacterial, antioxidative, anti-inflammatory, pro-proliferative properties, and long-term retention on cornea enabled synergistic treatment of bacterial keratitis. In a rat model, it can effectively treat P. aeruginosa-induced bacterial keratitis at a concentration 4000-fold lower than the commercially used drug, Sulmezole eye drops. Arg-CQDs/pCur nanocomposites have great potential for application in antibacterial and anti-inflammatory nanoformulations for clinical use to treat infectious diseases.

Highly Retina-Permeating and Long-Acting Resveratrol/Metformin Nanotherapeutics for Enhanced Treatment of Macular Degeneration.

The development of therapeutics for effective treatments of retinal diseases is significantly constrained by various biological barriers. We herein report a nanomedicine strategy to develop nanotherapeutics featured with not only high retinal permeability but also sustained bioactive delivery. Specifically, the nanotherapeutics are rationally designed via aminolysis of resveratrol-encapsulated polycaprolactone nanoparticles (R@PCL NPs), followed by the formation of amide linkages with carboxyl-terminated transacting activator of transcription cell penetrating peptide (T) and metformin (M). The R@PCL-T/M NP nanotherapeutics are demonstrated in vitro to possess persistent drug release profiles, good ocular biocompatibility, and potent bioactive activities for targeting prevailing risk factors associated with retinal diseases. In vivo studies indicate that single-dose intravitreal administration of the R@PCL-T/M NPs can effectively improve retinal permeability (∼15-fold increase), prevent loss of endogenous antioxidants, and suppress the growth of abnormal vessels in the retina with macular degeneration for 56 days. This high treatment efficacy can be ascribed to the enhanced retinal permeability of the nanotherapeutics in conjunction with the sustained pharmacological activity of the dual drugs (R and M) in the retinal pigment epithelial region. These findings show a great promise for the development of pharmacological nanoformulations capable of targeting the retina and thereby treating complex posterior segment diseases with improved efficacies.

Oxidation-mediated scaffold engineering of hyaluronic acid-based microcarriers enhances corneal stromal regeneration.

The functional design of scaffolding biomaterials with potent capabilities of promoting cell adhesion and proliferation is critically important for tissue repair and regeneration. Here, we exploit the effects of oxidation level of aldehyde hyaluronic acid (oHA) on gelatin microcarriers for repairing corneal injuries. Specifically, high oxidation levels can endow the microcarrier surface with large oHA grafting amount, smooth topography, and strong stiffness, consequently formulating biocompatible scaffolding materials with superior affinities for keratocyte attachment and growth. In a rabbit model of corneal alkali burn injury, single intracorneal injection of keratocytes/functionalized microcarriers with an appropriate oxidation level could effectively reduce corneal swelling (~62-fold improvement), recover ~94% collagen production and ~89% keratocan expression, and repair disordered collagenous stromal architecture after 4 weeks. These findings on the oxidation level effects of the aldehyde polysaccharide show a great potential use in the development of advanced scaffolds for efficient tissue engineering.

Carbon-based low-pressure filtration membrane for the dynamic disruption of bacteria from contaminated water.

Carbon-based materials, especially graphene oxide (GO) and carbon dots possessing antibacterial properties, are widely used for various applications. Recently, we reported the antibacterial and antioxidant properties of carbonized nanogels (CNGs) for the treatment of bacterial keratitis, and as a virostatic agent against infectious bronchitis virus. In this work, we demonstrate the use of CNGs/GO nanocomposite (GO@CNGs) membrane for the efficient removal of Gram-negative (E. coli) and Gram-positive (S. aureus) bacteria from contaminated water. The GO@CNGs composite membrane with an optimized ratio of GO to CNGs could achieve more than 99% removal efficiency toward E. coli and S. aureus. Various strains of bacteria interact differently with the membrane, and hence the membrane shows different removal rate, which can be optimized by controlling the interaction time through regulating the water flux. The GO@CNGs membrane with an active area of 2.83 cm2 achieved > 99% bacterial removal efficiency at a water flux of 400 mL min-1 m-2. The dynamic disruption of bacteria by GO@CNGs plays a crucial role in eliminating the bacteria. Rather than filtering out the bacteria, GO@CNGs membrane allows them to pass through it, interact with the bacteria and rupture the bacterial cell membranes. Our GO@CNGs membrane shows great potential as a filter to remove bacteria from contaminated water samples, operating under tap water pressure without any extra power consumption.

Alleviation of dry eye syndrome with one dose of antioxidant, anti-inflammatory, and mucoadhesive lysine-carbonized nanogels.

Most dry eye syndromes (DES) are caused by oxidative stress and an overactive inflammatory response, leading to tear deficiency and excessive tear evaporation. Conventional eye drops for DES treatment require high doses and frequent administration due to their insufficient precorneal residence time. To overcome these problems, in this study, we have developed carbonized nanogels (CNGs) via the straightforward pyrolysis of lysine hydrochloride (Lys) to provide a long-lasting eye drop formulation for topical DES therapy. This methodology thermally converts Lys-into nitrogen-doped crosslinked polymers with embedded nanographitic structures, which enable efficient free radical scavenging. The cationic and crosslinked polymeric features of the Lys-CNGs also prolong the precorneal retention time and improve ocular bioavailability. These Lys-CNGs exhibit high biocompatibility with corneal epithelial cells both in vitro and in vivo, indicating their safety as eye drops. In a DES rabbit model, a single dose of Lys-CNGs (50 µg mL-1) can effectively alleviate the signs of DES within 4 days, whereas multiple treatments of 10-fold higher concentration of cyclosporine A are needed to achieve similar therapeutic effects (one dose every 12 h; 500 µg mL-1). The topical administration of Lys-CNGs enable a reduced therapeutic dose and extended dosing interval, thereby demonstrating a superior therapeutic efficacy compared to the commercial cyclosporine A eye drops. These Lys-CNGs, which exhibit significant free radical scavenging, anti-inflammatory activity, high biocompatibility, and a remarkable ocular bioadhesive property, hold great potential as a long-lasting eye drop formulation for the treatment of dry eye disease. STATEMENT OF SIGNIFICANCE: Multifunctional nanobiomaterial-based eye drops can render an ideal pharmaceutical formulation for the treatment of a variety of ocular surface diseases. To our knowledge, this is the first report describing the development of carbonized nanogels as topically administered therapeutics for alleviating dry eye syndrome (DES). We present evidence that the thermal transformation of lysine hydrochloride into carbonized nanogels (Lys-CNGs) endows superior antioxidant, anti-inflammatory, and bioadhesive properties. While a single dose of Lys-CNGs (50 µg mL-1) is sufficient to relieve the symptoms of DES for 4 days, multiple treatments of 10-fold higher concentration of commercially available cyclosporine eye drops are needed to achieve similar therapeutic outcomes (one dose every 12 h; 500 µg mL-1), suggesting an effective and long-lasting ocular carbonized nanomedicine.

Thermogels containing sulfated hyaluronan as novel topical therapeutics for treatment of ocular surface inflammation.

The development of long lasting therapeutic agents is critically important for efficient treatment of chronic diseases. We herein report a rational strategy to develop a therapeutic thermogel featured with prolonged anti-inflammatory and corneal-protective effects. Specifically, a hyaluronic acid with different sulfation degrees and an amine-terminated poly(N-isopropylacrylamide) are conjugated to achieve the thermogels. In vitro studies reveal that the thermogels are highly biocompatible to statens seruminstitut rabbit cornea cells and their anti-inflammatory properties are strongly dependent on the sulfation degree. In a rabbit model of ocular inflammation, single-dose topical administration of a thermogel formulation could repair defects in corneal epithelium (∼99% thickness restored), prevent corneal cell apoptosis (∼68.3% cells recovered), and suppress ocular surface inflammation (∼4-fold decrease) for a follow-up period of 7 days. This high treatment efficacy of the thermogel can be attributed to its potent inhibition in selectin-mediated leukocyte infiltration as well as effective corneal protection. These findings show a great promise for topical treatment of ocular inflammation and advancement of ophthalmic formulations using the bioactive thermogel as a therapeutic component that is not rapidly cleared from the eye and thus considerably reduces administration times.

Ascorbic acid ameliorates corneal endothelial dysfunction and enhances cell proliferation via the noncanonical GLUT1-ERK axis.

BACKGROUND: The pumping function of corneal endothelial cells (CECs) plays a pivotal role in the maintenance of corneal water homeostasis. Corneal endothelial dysfunction (CED) leads to corneal edema and opacity, but with the exception of keratoplasty, no optimal therapeutic strategies have been established for CED. In this study, we aimed to investigate the ameliorative effect of ascorbic acid (AA) on CED and the underlying mechanism of action in the corneal endothelium. METHODS: Rabbit corneal endothelial damage was induced by anterior chamber injection of benzalkonium chloride (BAK). AA was topically administered to the corneal surface, and the transparency and thickness of the cornea were assessed by external eye photography, slit-lamp photography, and ultrasonic pachymetry. To further analyze the mechanism, rabbit CECs and immortalized human CECs (B4G12 cells) were cultured. A ferric reducing/antioxidant and AA (FRASC) assay was performed to measure the AA concentration. Cell proliferation was evaluated by cell counting and bromodeoxyuridine (BrdU) labeling assays, and protein expression was examined by liquid chromatography-mass spectrometry (LC/MS) and immunoblotting. The involvement of glucose transporter 1 (GLUT1) and phospho-ERK was evaluated via GLUT1-siRNA and phospho-ERK inhibitor (PD98059) treatment. INTERPRETATION: We observed that topical AA ameliorates BAK-induced rabbit corneal endothelial damage. Furthermore, we demonstrated that AA is transported into B4G12 cells via GLUT1, and afterward, AA increases ERK phosphorylation and promotes cell proliferation. Our findings indicate that CEC proliferation stimulated via the noncanonical AA-GLUT1-ERK axis contributes to AA-enhanced healing of CED.

Long-term survival of cultivated oral mucosal epithelial cells in human cornea: generating cell sheets using an animal product-free culture protocol.

Previously, we reported a collagenase-based, animal product-free protocol for cultivated oral mucosal epithelial cell sheets for transplantation (COMET). Here, we reported the long-term outcomes of first 2 clinical cases. A 27-year-old man suffered from thermal burn, which resulted in symblepharon of lower fornix OD. COMET was performed, and the cornea remained clear with few peripheral NV and no more symblepharon 34 months postoperatively. Another 42-year-old man suffered from severe alkaline burn OD. He underwent COMET, followed by corneal transplantation half a year later. A biopsy taken two years after COMET showed stratified epithelium positive for keratin 4, 13, and 3 in the suprabasal layer. Staining for p63 and p75NTR was both positive in the basal layer. The graft remained clear up to post-OP 4 years. Our study confirmed the long-term survival of the transplanted OMECs, suggesting that collagenase-based spheroidal suspension culture is a promising technique for COMET.Trial registration ClinicalTrials.gov, ClinicalTrials.gov ID: NCT03943797 Registered 9 May 2019-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03943797 .

Tailoring therapeutic properties of silver nanoparticles for effective bacterial keratitis treatment.

The formulation of nanoparticles with intrinsically therapeutic properties in a tailorable and appropriate manner is critical in nanomedicine for effective treatments of infectious diseases. Here, we present a biomedical strategy to formulate silver nanoparticles (AgNPs) as intrinsically therapeutic agents for the treatment of Staphylococcus aureus (S. aureus) keratitis. Specifically, AgNPs are controllably obtained as spheres, wrapped with a biopolymer, and varied in sizes. in vitro and in vivo studies indicate that biological interactions between the AgNPs and corneal keratocytes, S. aureus bacteria, and blood vessels are strongly determined by the particle sizes. As the size increased from 3.3 ±â€¯0.7 to 37.2 ±â€¯5.3 nm, the AgNPs exhibit better ocular biocompatibility and stronger antiangiogenic activity, but poorer bactericidal performance. In a rabbit model of S. Aureus-induced keratitis, intrastromal injection of AgNP formulations (single dose) show substantial influences of particle size on the treatment efficacy. As the trade-off, AgNPs with medium size of 15.0 ±â€¯3.6 nm reveal as the best therapeutic agent that could offer ∼5.6 and ∼9.1-fold greater corneal thickness recovery respectively compared to those with smaller and larger sizes at 3 days post-administration. These findings suggest an important advance in structural design for formulating intrinsically therapeutic nano-agents toward the efficient management of infectious diseases.

Harnessing the tunable cavity of nanoceria for enhancing Y-27632-mediated alleviation of ocular hypertension.

Background: Y-27632 is a potent ophthalmic drug for the treatment of ocular hypertension, a globally prevalent eye disease. However, the sustained delivery of Y-27632 by a therapeutic carrier to lesion sites located in the inner segments of the eye for effectively treating the ocular disorder still remains challenging. Methods: To realize the goal, a strategy based on solvothermal-assisted deposition/infiltration in combination with surface modification is utilized to synthesize hollow mesoporous ceria nanoparticles (HMCNs) with tailorable shell thicknesses and drug release profiles. The shell thickness of HMCNs is rationally exploited for achieving sustained drug release and advanced therapeutic benefits. Results: The shell thickness can regulate release profiles of Y-27632, displaying that thick and thin (~40 nm and ~10 nm) shelled HMCNs reveal burst release characteristics (within 2 days) or limited drug loading content (~10% for the 40 nm thick). As a compromise, the HMCNs with moderate shell thickness (~20 nm) possess the most sustained drug release over a period of 10 days. In a rabbit model of glaucoma, a single instillation of the optimized Y-27632-loaded HMCNs can effectively treat glaucoma for 10 days via simultaneously repairing the defected cornea (recovery of ~93% ATP1A1 mRNA levels), restoring the reduced thickness of outer nuclear layer to normal (~64 µm), and restoring ~86% of the impaired photoreceptor cells. Conclusion: A comprehensive study on the importance of HMCN shell thickness in developing long-acting nano eye drops for the efficient management of glaucoma is proposed. The findings suggest a central role of nanobiomaterial structural engineering in developing the long-life eye drops for pharmacological treatment of intraocular diseases.

Toward understanding the purely geometric effects of silver nanoparticles on potential application as ocular therapeutics via treatment of bacterial keratitis.

Understanding a complex interaction between therapeutic nanoparticles and biological entities is crucially important for the development of effective disease treatments in the modern nanopharmaceuticals and nanomedicines. Herein, we present a strategy to thoroughly assess geometrical impacts of silver nanoparticles (AgNPs, one of the most promising nanotherapeutic agents) on their biological activities toward treatment of Staphylococcus aureus (S. aureus)-induced keratitis. Specifically, three types of differently shaped AgNPs including silver nanorods (R-Ag), silver nanotriangles (T-Ag), and silver nanospheres (SAg) are employed and interferences of particle surface area and functionality are eliminated to reflect purely geometric effects. Ocular biocompatibility studies on rabbit corneal keratocytes reveal that SAg is the least cytotoxic agent while R-Ag, because of its strongest cellular uptake, induces highest cytotoxic levels. Moreover, SAg is demonstrated to outperform R-Ag and T-Ag in killing S. aureus, possibly due to a predominance of specific particle density and high-atom-density {111} facets of the SAg when interacting with the bacteria. In contrast, owing to its predominance of sharp-tip effects on vascular endothelial cells, R-Ag can suppress blood vessel development in cornea at a greatest extent. In a rabbit model of S. aureus-induced keratitis, intrastromal administration of the differently shaped AgNPs exhibits critical roles of the particle geometry at comparable conditions (i.e., total surface area and functionality) in attenuating progression of S. aureus-induced keratitis. As a compromise among ocular biocompatibility, anti-bacterial activity, and anti-angiogenic capability, SAg shows as the most effective agent that could repair infectious corneal tissues 1.2 and 4-fold greater than the anisotropic counterparts (R-Ag and T-Ag). These findings therefore suggest a promising strategy for a clear-cut evaluation on geometric effects of therapeutic nanoparticles toward preclinical treatment of eye-related microbial infections.

Long-acting mucoadhesive thermogels for improving topical treatments of dry eye disease.

Dry eye disease (DED) is the most common ocular disorder that causes persistent discomfort and blurry vision in patients. Despite pharmacotherapy strategies, the current topical administration of eye drops remains a great challenge owing to their low bioavailability and short residence time. Herein, we demonstrate an effective topical treatment of DED via rational design of a long-acting and mucoadhesive drug delivery system. Specifically, the drug carrier is a chemically ternary material system consisting of gelatin that serves as an enzyme-mediated degradable matrix, poly(N-isopropylacrylamide) as a thermo-responsive regulator, and lectin Helix pomatia agglutinin as a mucus-binding component. The long-acting drug release performance is exploited via initiator effects during the synthesis of the thermo-responsive polymer, while the mucoadhesive feature is inherited from the mucus-binding material. In a rabbit model of DED, a pharmacotherapy based on one-time topical administration of epigallocatechin gallate-loaded carrier onto the cul-de-sac could effectively repair the defective corneal epithelium via mitigating cellular inflammation, oxidative stress, and cell apoptosis for a sustained period over 14 days. These findings on the initiator and synergy effects in the development of the advanced ophthalmic formulation show great promise for efficient management of complex ocular diseases by a simple topical administration route.