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.

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.

eGAC3D: enhancing depth adaptive convolution and depth estimation for monocular 3D object pose detection.

Many alternative approaches for 3D object detection using a singular camera have been studied instead of leveraging high-precision 3D LiDAR sensors incurring a prohibitive cost. Recently, we proposed a novel approach for 3D object detection by employing a ground plane model that utilizes geometric constraints named GAC3D to improve the results of the deep-based detector. GAC3D adopts an adaptive depth convolution to replace the traditional 2D convolution to deal with the divergent context of the image's feature, leading to a significant improvement in both training convergence and testing accuracy on the KITTI 3D object detection benchmark. This article presents an alternative architecture named eGAC3D that adopts a revised depth adaptive convolution with variant guidance to improve detection accuracy. Additionally, eGAC3D utilizes the pixel adaptive convolution to leverage the depth map to guide our model for detection heads instead of using an external depth estimator like other methods leading to a significant reduction of time inference. The experimental results on the KITTI benchmark show that our eGAC3D outperforms not only our previous GAC3D but also many existing monocular methods in terms of accuracy and inference time. Moreover, we deployed and optimized the proposed eGAC3D framework on an embedded platform with a low-cost GPU. To the best of the authors' knowledge, we are the first to develop a monocular 3D detection framework on embedded devices. The experimental results on Jetson Xavier NX demonstrate that our proposed method can achieve nearly real-time performance with appropriate accuracy even with the modest hardware resource.

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.

Preparation and Photocatalytic Characterization of Modified Nano TiO2/Nd/Rice Husk Ash Material for Rifampicin Removal in Aqueous Solution.

Antibiotics like rifampicin are often persistent in the environment. When entering the water, it causes antimicrobial resistance that affects the ecosystem and accumulates in the aquatic organisms and affects human health through the food chain. In this study, titanium dioxide was doped with neodymium (0.01 to 0.8%) using the sol-gel hydrothermal method. TiO2/Nd was then coated on rice husk ash to produce a modified TiO2/Nd/rice husk ash material containing 0.36% (w/w) Nd. The structural characteristics and photocatalytic properties of the materials were analyzed by X-ray diffraction, energy dispersive X-ray, transmission electron microscopy, scanning electron microscopy, forbidden zone energy, and specific surface area. The TiO2/Nd material exhibited a higher photocatalytic decomposition capacity than TiO2 and depended on the Nd content. The rifampicin removal efficiency of TiO2/Nd materials with 0.36 to 0.80% Nd contents was approximately 40% higher than that of TiO2/Nd containing 0.01 to 0.28% Nd. A new photocatalytic TiO2/Nd/rice husk ash material was developed to decompose rifampicin. The rifampicin-degrading efficiency of TiO2/Nd and TiO2/Nd/rice husk ash material reached approximately 86 and 75%, respectively, within 90 min under sunlight. Although a lower efficiency was obtained, the TiO2/Nd/rice husk ash material was selected to degrade rifampicin residue in water via the photocatalytic process (under sunlight) because of its advantages such as requirement of a small amount and easy recovery. In the rifampicin removal process, k values were found to match the zero- and first-order kinetics. In particular, for TiO2/Nd and TiO2/Nd/rice husk ash under solar irradiation, R 2 values reached approximately 0.98. These results have been previously published as a preprint.

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.

The characteristics of coalbed water and coal in a coal seam situated in the Red River Basin, Vietnam.

An in-depth understanding of the hydrogeochemical characteristics of coal mines is helpful in establishing an effective and successful exploration program of coalbed methane (CBM). This study provides a comprehensive analysis of hydrogeological characteristics, characteristics of coalbed water, and characteristics of the coal sample from a coal seam located in the Red River Basin (RRB). These physicochemical characteristics along with the microbial composition of coalbed water were critically analyzed. A high concentration of chloride and sodium was found in the coalbed water, presumably due to the coal mine's stratigraphic association with marine or marine-transitional beds. A correlation between the occurrence of microbes and the chemical components in the coalbed water was established. The characteristics of the coal were systematically analyzed, including proximate, ultimate, and petrographic analyses. Based on the coal macerals, coal rank is classified as low-rank (sub-bituminous) with a vitrinite reflectance (Ro, max) of 0.36%, suggesting that this type of low-rank coal is favorable for biogenic methane generation. Pore structures and pore types were characterized using different methods, including low-temperature nitrogen adsorption/desorption (LTNA), mercury intrusion porosimetry (MIP), and scanning electron microscopy (SEM). Coal from the study area has microporous and macroporous features. Pore types of the coal were also characterized using SEM. The primary genetic pore types of the Red River coal include plant tissue holes and blowholes.

GAC3D: improving monocular 3D object detection with ground-guide model and adaptive convolution.

Monocular 3D object detection has recently become prevalent in autonomous driving and navigation applications due to its cost-efficiency and easy-to-embed to existent vehicles. The most challenging task in monocular vision is to estimate a reliable object's location cause of the lack of depth information in RGB images. Many methods tackle this ill-posed problem by directly regressing the object's depth or take the depth map as a supplement input to enhance the model's results. However, the performance relies heavily on the estimated depth map quality, which is bias to the training data. In this work, we propose depth-adaptive convolution to replace the traditional 2D convolution to deal with the divergent context of the image's features. This lead to significant improvement in both training convergence and testing accuracy. Second, we propose a ground plane model that utilizes geometric constraints in the pose estimation process. With the new method, named GAC3D, we achieve better detection results. We demonstrate our approach on the KITTI 3D Object Detection benchmark, which outperforms existing monocular methods.

Visible-Light-Assisted Photoelectrochemical Biosensing of Uric Acid Using Metal-Free Graphene Oxide Nanoribbons.

In this study, we demonstrate the visible-light-assisted photoelectrochemical (PEC) biosensing of uric acid (UA) by using graphene oxide nanoribbons (GONRs) as PEC electrode materials. Specifically, GONRs with controlled properties were synthesized by the microwave-assisted exfoliation of multi-walled carbon nanotubes. For the detection of UA, GONRs were adopted to modify either a screen-printed carbon electrode (SPCE) or a glassy carbon electrode (GCE). Cyclic voltammetry analyses indicated that all Faradaic currents of UA oxidation on GONRs with different unzipping/exfoliating levels on SPCE increased by more than 20.0% under AM 1.5 irradiation. Among these, the GONRs synthesized under a microwave power of 200 W, namely GONR(200 W), exhibited the highest increase in Faradaic current. Notably, the GONR(200 W)/GCE electrodes revealed a remarkable elevation (~40.0%) of the Faradaic current when irradiated by light-emitting diode (LED) light sources under an intensity of illumination of 80 mW/cm2. Therefore, it is believed that our GONRs hold great potential for developing a novel platform for PEC biosensing.

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.

Edge-Rich Interconnected Graphene Mesh Electrode with High Electrochemical Reactivity Applicable for Glucose Detection.

The development of graphene structures with controlled edges is greatly desired for understanding heterogeneous electrochemical (EC) transfer and boosting EC applications of graphene-based electrodes. We herein report a facile, scalable, and robust method to produce graphene mesh (GM) electrodes with tailorable edge lengths. Specifically, the GMs were fabricated at 850 °C under a vacuum level of 0.6 Pa using catalytic nickel templates obtained based on a crack lithography. As the edge lengths of the GM electrodes increased from 5.48 to 24.04 m, their electron transfer rates linearly increased from 0.08 to 0.16 cm∙s-1, which are considerably greater than that (0.056 ± 0.007 cm∙s-1) of basal graphene structures (defined as zero edge length electrodes). To illustrate the EC sensing potentiality of the GM, a high-sensitivity glucose detection was conducted on the graphene/Ni hybrid mesh with the longest edge length. At a detection potential of 0.6 V, the edge-rich graphene/Ni hybrid mesh sensor exhibited a wide linear response range from 10.0 µM to 2.5 mM with a limit of detection of 1.8 µM and a high sensitivity of 1118.9 µA∙mM-1∙cm-2. Our findings suggest that edge-rich GMs can be valuable platforms in various graphene applications such as graphene-based EC sensors with controlled and improved performance.

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.

Preoperative embolization of high-flow peripheral AVMs using plug and push technique with low-density NBCA/Lipiodol.

Arteriovenous malformations (AVMs) embolization is considered as a promising option either its single treatment or in combination with surgery, and the use of low-density N-butyl cyanoacrylate (NBCA)/Lipiodol is acceptable mixture agents but its application should be performed by experienced endovascular teams. We describe a successful case preoperative embolization of high-flow AVMs with low-density NBCA/Lipiodol. A 26-year-old male patient was hospitalized with a big pulsatile mass at the right thigh. Doppler ultrasound showed a mass with high systolic, and diastolic velocities coming from the right superficial femoral artery. Angiogram showed a large and high-flow AVM type IV, according to Yakes classification. Low-density NBCA/Lipiodol 12.5% were performed to obstruct all the nidus and feeding arteries. Extirpation surgery was implemented 4 days after the complete embolization procedure.

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.

Effects of shell thickness of hollow poly(lactic acid) nanoparticles on sustained drug delivery for pharmacological treatment of glaucoma.

Structural designing of carriers with extended drug release profiles is critically important for achieving long-acting drug delivery systems toward efficient managements of chronic diseases. Here, we present a strategy to exploit the effects of the shell thickness of hollow poly(lactic acid) nanoparticles (HPLA NPs) in sustained glaucoma therapy. Formulations based on pilocarpine-loaded HPLA NPs with tailorable shell thickness ranging from 10 to 100 nm were shown to be highly compatible with human lens epithelial cells in vitro and with rabbit eyes in vivo. Specifically, shell thickness regulated the release of pilocarpine, with thick shells (~70 to 100 nm) providing sustained drug release performance but limited drug-loading efficiency, whereas ultrathin shells (~10 nm) induced the opposite effects. Remarkably, moderately thick shells (~40 nm) showed the most effective release profile of pilocarpine (above the therapeutic levels of ~10 µg/mL for over 56 days). In a rabbit model of glaucoma, single intracameral administration of an HPLA NP-based formulation with shell thickness of ~40 nm sustainably alleviated ocular hypertension for over 56 days, consequently protecting the structural integrity of the corneal endothelium, preserving the electrophysiological functions of the retina, and attenuating retinal and optic nerve degeneration in progressively glaucomatous eyes. The findings therefore implied a promising use of shell thickness effects in the development of long-acting drug delivery systems for pharmacological treatment of chronic ocular diseases. STATEMENT OF SIGNIFICANCE: Owing to their large surface areas and modifiable structures, nanoparticles have been considered as a promising platform for drug delivery; however, achieving drug nanocarrier systems with reduced burst release and sustained therapeutic efficacy remains challenges. This work presents the first report on rational design of hollow poly(lactic acid) nanocarriers for tailoring the structure-property-function relationships toward effective treatment of glaucoma. The shell thickness of the hollow nanocarriers is demonstrated to have influential impacts on pilocarpine encapsulation efficiency and release profile, indicating that the most sustained delivery performance (maintaining the release of pilocarpine above therapeutic level over 56 days) can be obtained for the polymeric nanoparticles with moderate shell thickness of ~40 nm.

Dually functional hollow ceria nanoparticle platform for intraocular drug delivery: A push beyond the limits of static and dynamic ocular barriers toward glaucoma therapy.

Delivery of ophthalmic drugs to the interior parts of the eye for effective treatment of glaucoma (i.e., a chronic disease) remains a huge challenge because of the well-known static and dynamic ocular barriers. Herein, we present a new antiglaucoma formulation based on the development of a dual-functional therapeutic nanocarrier platform for intraocular targeted and sustained delivery of pilocarpine. Specifically, chitosan and ZM241385 are functionalized onto surfaces of hollow ceria nanoparticles (hCe NPs), thereby endowing the nanocarriers with a strong capability to open corneal epithelial tight junctions and deliver drug molecules to the targeted intraocular tissue (i.e., ciliary body). Moreover, the nanocarriers are demonstrated in vitro and in vivo to possess potent anti-oxidant and anti-inflammatory properties, which are beneficial to simultaneously alleviate glaucomatous damage. Single topical instillation of the pilocarpine-loaded dual-functional therapeutic nanocarriers with optimized delivery performance onto experimentally glaucomatous eyes can effectively mitigate disease progression for 7 days while that employing the traditional commercial eye drops only provides a moderate treatment efficacy for 4 h, possibly due to improved intraocular drug delivery (~250-fold greater bioavailability in the ciliary body) and intrinsic therapeutic activity of the ophthalmic formulation. These findings show great promise for the development of advanced nano eye drops toward efficient management of ocular diseases occurred in the inner segments of the eye.

The role of aromatic ring number in phenolic compound-conjugated chitosan injectables for sustained therapeutic antiglaucoma efficacy.

The development of long-lasting therapeutic drug delivery system is greatly desired for effective treatment of glaucoma, a chronic and multifactorial disease. Herein, the roles of aromatic ring number in phenolic compound-conjugated chitosan injectables are exploited for achieving an advanced drug carrier with potent anti-inflammatory and anti-oxidant properties. Low and high number of aromatic rings can induce deleterious impacts on the pharmaceutical applications of injectables, whereas the compound with a moderate ring number is proved as the most efficient agent for boosting drug delivery performances and endowing the chitosan injectables with therapeutic properties. Kaempferol-conjugated injectable formulation reveals a remarkable effectiveness for intracameral pilocarpine administration, which can alleviate progressive glaucoma via simultaneously exerting multiple pharmacological activities to suppress ocular hypertension, inflammation, and oxidative stress. These findings provide a significant advance in understanding structure-property relationship of the phenolic compound-conjugated chitosan injectables as long-lasting therapeutic drug delivery systems for medical management of glaucoma.

Benzoic acid derivative-modified chitosan-g-poly(N-isopropylacrylamide): Methoxylation effects and pharmacological treatments of Glaucoma-related neurodegeneration.

Long-acting drug delivery systems with advanced functionalities are critically important to pharmacologically treat glaucomatous optic neuropathy, a chronic and multifactorial neurodegenerative disease. Here, a novel strategy based on the methoxylation effects of benzoic acid derivatives was exploited to rationally design a biodegradable and injectable thermogel, which possesses potent antioxidant activities and sustained drug delivery abilities for treating glaucomatous nerve damage. In particular, 4-hydroxy-3,5-dimethoxybenzoic acid, consisting of two methoxyl groups and one hydroxyl group at the position para to the carboxylic group, was demonstrated to contribute to the strong antioxidant activities of a chitosan-g-poly(N-isopropylacrylamide) biomaterial while maintaining the drug encapsulation/release efficiencies of the thermogel. The pharmacological treatment relies on the intracameral injection of the thermogel coloaded with pilocarpine and RGFP966 and exhibits significant improvement in the attenuation of neurodegeneration via suppressing oxidative stress, lowering ocular hypertension, reducing retinal ganglion cell loss and enhancing myelin growth and neuron regeneration. These findings on the development of long-acting drug delivery systems with extended functions show great promise for the management of glaucoma-related neurodegeneration.

Dendritic Effects of Injectable Biodegradable Thermogels on Pharmacotherapy of Inflammatory Glaucoma-Associated Degradation of Extracellular Matrix.

The development of advanced drug delivery systems with extensively sustained release and multiple functions is highly imperative for effective attenuation of the degradation of ocular extracellular matrix that is associated with inflammatory glaucoma. Here, the generation of amine-terminated polyamidoamine dendrimers in an injectable biodegradable thermogel is demonstrated to be important for achieving prolonged drug release profiles and potent anti-inflammatory effects. Among various generations (Gx, x = 0, 1, 3, 5), third-generation G3 is proved as the most effective material for optimizing the synergistic effects of gelatin and poly(N-isopropylacrylamide) and generating a thermogel with the highest biodegradation resistance, the best drug encapsulation/extended-release performance, and the best ability to reduce the elevated expression of inflammatory molecules. A pharmacotherapy based on intracameral injection of thermogels coloaded with pilocarpine and ascorbic acid results in effective alleviation of progressive glaucoma owing to the anti-inflammatory activity and long-acting drug release (above a therapeutic level of 10 µg mL-1 over 80 days) of thermogels, which simultaneously suppress inflammation and stimulate regeneration of stromal collagen and retinal laminin. These findings on the dendritic effects of rationally designed injectable biomaterials with potent anti-inflammatory effects and controlled drug release demonstrate great promise of their use for pharmacological treatment of progressive glaucoma.