Ibuprofen-Immobilized Thin Films: A Novel Approach to Improve the Clearance of Protein-Bound Uremic Toxins.

Chronic kidney disease (CKD), a pressing global health issue, affects millions and leads to end-stage renal disease (ESRD). Hemodialysis (HD) is a crucial treatment for ESRD, yet its limited efficiency in removing protein-bound uremic toxins (PBUTs) results in high morbidity and mortality rates. A high affinity of pharmaceutical drugs for human serum albumin (HSA) can be leveraged to compete effectively with PBUTs for the same HSA binding sites, thereby enabling them to be capable of displacing these toxins. One such drug is ibuprofen (IBF), known for its very high affinity for HSA and sharing the same binding site as indoxyl sulfate (IS). This study explores the development of IBF-immobilized cellulose acetate-based (CA-based) thin films. The films were created by reacting CA with IBF-modified silica precursors at varying concentrations. The presence of IBF in CA/TEOS/APTES-IBF-3 and CA/TEOS-IBF-25 films, containing 3 and 25 wt % IBF, respectively, was confirmed through 1H NMR spectra. Competitive displacement binding assays indicated that while the incorporation of 3 wt % IBF showed no significant enhancement in IS displacement, the 25 wt % IBF film increased the dialyzed IS by 1.3 when normalized to non-IBF films. Furthermore, there was a 1.2-fold decrease in the total percentage of IS, and the free percentage of IS increased 1.3 to 3.0 times. Although direct systemic infusion of IBF in HD patients achieves a 2.4 times higher removal of IS, it is impractical due to the risks it poses to ESRD patients. The IBF-immobilized films offer the advantage of localized binding, thus eliminating the need for systemic exposure. This innovative approach lays a foundation for developing more efficient HD membranes, aiming to address the challenging issue of PBUT elimination and potentially enhance the quality of life and treatment outcomes for ESRD patients.

Adsorption- and Displacement-Based Approaches for the Removal of Protein-Bound Uremic Toxins.

End-stage renal disease (ESRD) patients rely on renal replacement therapies to survive. Hemodialysis (HD), the most widely applied treatment, is responsible for the removal of excess fluid and uremic toxins (UTs) from blood, particularly those with low molecular weight (MW < 500 Da). The development of high-flux membranes and more efficient treatment modes, such as hemodiafiltration, have resulted in improved removal rates of UTs in the middle molecular weight range. However, the concentrations of protein-bound uremic toxins (PBUTs) remain essentially untouched. Due to the high binding affinity to large proteins, such as albumin, PBUTs form large complexes (MW > 66 kDa) which are not removed during HD and their accumulation has been strongly associated with the increased morbidity and mortality of patients with ESRD. In this review, we describe adsorption- and displacement-based approaches currently being studied to enhance the removal of PBUTs. The development of mixed matrix membranes (MMMs) with selective adsorption properties, infusion of compounds capable of displacing UTs from their binding site on albumin, and competitive binding membranes show promising results, but the road to clinical application is still long, and further investigation is required.

Novel Cellulose Acetate-Based Monophasic Hybrid Membranes for Improved Blood Purification Devices: Characterization under Dynamic Conditions.

A novel cellulose acetate-based monophasic hybrid skinned amine-functionalized CA-SiO2-(CH2)3NH2 membrane was synthesized using an innovative method which combines the phase inversion and sol-gel techniques. Morphological characterization was performed by scanning electron microscopy (SEM), and the chemical composition was analyzed by Fourier transform infrared spectroscopy in attenuated total reflection mode (ATR-FTIR). The characterization of the monophasic hybrid CA-SiO2-(CH2)3NH2 membrane in terms of permeation properties was carried out in an in-house-built single hemodialysis membrane module (SHDMM) under dynamic conditions. Permeation experiments were performed to determine the hydraulic permeability (Lp), molecular weight cut-off (MWCO) and the rejection coefficients to urea, creatinine, uric acid, and albumin. SEM confirmed the existence of a very thin (<1 µm) top dense layer and a much thicker bottom porous surface, and ATR-FTIR showed the main bands belonging to the CA-based membranes. Permeation studies revealed that the Lp and MWCO of the CA-SiO2-(CH2)3NH2 membrane were 66.61 kg·h-1·m-2·bar-1 and 24.5 kDa, respectively, and that the Lp was 1.8 times higher compared to a pure CA membrane. Furthermore, the CA-SiO2-(CH2)3NH2 membrane fully permeated urea, creatinine, and uric acid while completely retaining albumin. Long-term filtration studies of albumin solutions indicated that fouling does not occur at the surface of the CA-SiO2-(CH2)3NH2 membrane.

Emerging Trends in Nanomedicine for Improving Ocular Drug Delivery: Light-Responsive Nanoparticles, Mesoporous Silica Nanoparticles, and Contact Lenses.

Vision is the most dominant of our senses, and it is crucial in every stage of our lives. Ocular diseases, regardless of whether they cause vision impairment or not, lead to personal and financial hardships. The anatomy and physiology of the eye strongly limit the efficacy of current ocular drug delivery strategies. Nanotechnology has been the ground for the development of powerful strategies in several fields, namely in medicine. This review highlights emerging nanotechnology-based solutions for improving ocular drug delivery and thus the bioavailability and efficacy of drugs. We focus our review on ambitious but promising approaches currently emerging to leverage the efficacy of nanoparticle-based systems in ocular therapy: (i) light-responsive nanoparticles, which enable spatiotemporal control of drug release; (ii) mesoporous silica nanoparticles, which offer high surface area-to-volume ratio, simple surface modification, good biocompatibility, and improved bioavailability; and (iii) contact lenses, which serve as a compliant method of nanoparticles use and as drug delivery systems for the treatment of ocular diseases.

Inflammatory cells proliferate in the choroid and retina without choroidal thickness change in early Type 1 diabetes.

Increasing evidence points to inflammation as a key factor in the pathogenesis of diabetic retinopathy (DR). Choroidal inflammatory changes in diabetes have been reported and in vivo choroidal thickness (CT) has been searched as a marker of retinopathy with contradictory results. We aimed to investigate the early stages in the retina and choroid in an animal model of Type 1 diabetes. Type 1 diabetes was induced in male Wistar rats via a single i.p. streptozotocin injection. At 8 weeks after disease onset, CT, choroidal vascular density, VEGF and VEGFR2 expression, microglial cell and pericyte distribution were evaluated. Diabetic rats showed no significant change in CT and choroidal vascular density. A widened pericyte-free gap between the retinal pigment epithelium and the choroid was observed in diabetic rats. The immunoreactivity of VEGFR2 was decreased in the retina of diabetic rats, despite no statistically significant difference in the immunoreactivity of VEGF. The density of microglial cells significantly increased in the choroid and retina of diabetic rats. Reactive microglial cells were found to be more abundant in the choroid of diabetic rats. Evidences of the interconnection between the superficial, intermediate, and deep plexuses of the retina were also observed. At early stages, Type 1 diabetes does not affect choroidal thickness and choroidal vascular density. Proliferation and reactivity of microglial cells occurs in the choroidal stroma and the retina. The expression of VEGFR2 decreases in the retina.