Highlights Routes of administration to retinal photoreceptors. The blood–retinal barrier as a challenge for photoreceptor drug delivery. Review of nanoparticle drug delivery systems used for intraocular applications. Perspectives for topical drug delivery to the retina.

The large-scale continuous production of niosomes remains challenging. The inherent drawbacks of batch processes such as large particle polydispersity and reduced batch-to-batch reproducibility are here overcome by using commercially available microfluidic reactors. Compared to the traditional batch-based film hydration method, herein, we demonstrate that it is possible to carry out the homogeneous, large-scale (up to 120 mg/min) production of niosomes using two different synthesis techniques (the thin film hydration method and the emulsification technique). Niosomes particle size can be controlled depending on the need by varying the synthesis temperature. The high cytocompatibility of the resulting niosomes was also demonstrated in this work on three different somatic cell lines. For the first time, the structure of the niosome multilamellar shell was also elucidated using high-resolution transmission electron microscopy (HR-STEM) as well as their colloidal stability over time (6 weeks) under different storage conditions. The morphology of cryo-protected or as-made niosomes was also evaluated by HR-STEM after freeze-drying. Finally, the dual ability of those synthetic, nonionic, surfactant-based vesicles to carry both hydrophilic and hydrophobic molecules was also here demonstrated by using laser scanning confocal microscopy.

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The treatment of osteochondral defects remains a challenge. Four scaffolds were produced using Food and Drug Administration (FDA)-approved polymers to investigate their therapeutic potential for the regeneration of the osteochondral unit. Polycaprolactone (PCL) and poly(vinyl-pyrrolidone) (PVP) scaffolds were made by electrohydrodynamic techniques. Hydroxyapatite (HAp) and/or sodium hyaluronate (HA) can be then loaded to PCL nanofibers and/or PVP particles. The purpose of adding hydroxyapatite and sodium hyaluronate into PCL/PVP scaffolds is to increase the regenerative ability for subchondral bone and joint cartilage, respectively. Human bone marrow-derived mesenchymal stem cells (hBM-MSCs) were seeded on these biomaterials. The biocompatibility of these biomaterials in vitro and in vivo, as well as their potential to support MSC differentiation under specific chondrogenic or osteogenic conditions, were evaluated. We show here that hBM-MSCs could proliferate and differentiate both in vitro and in vivo on these biomaterials. In addition, the PCL-HAp could effectively increase the mineralization and induce the differentiation of MSCs into osteoblasts in an osteogenic condition. These results indicate that PCL-HAp biomaterials combined with MSCs could be a beneficial candidate for subchondral bone regeneration.

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In this study, we developed a novel solid lipid nanoparticle (SLN) formulation for drug delivery of small hydrophilic cargos to the retina. The new formulation, based on a gel core and composite shell, allowed up to two-fold increase in the encapsulation efficiency. The type of hydrophobic polyester used in the composite shell mixture affected the particle surface charge, colloidal stability, and cell internalization profile. We validated SLNs as a drug delivery system by performing the encapsulation of a hydrophilic neuroprotective cyclic guanosine monophosphate analog, previously demonstrated to hold retinoprotective properties, and the best formulation resulted in particles with a size of ±250 nm, anionic charge > −20 mV, and an encapsulation efficiency of ±60%, criteria that are suitable for retinal delivery. In vitro studies using the ARPE-19 and 661W retinal cell lines revealed the relatively low toxicity of SLNs, even when a high particle concentration was used. More importantly, SLN could be taken up by the cells and the release of the hydrophilic cargo in the cytoplasm was visually demonstrated. These findings suggest that the newly developed SLN with a gel core and composite polymer/lipid shell holds all the characteristics suitable for the drug delivery of small hydrophilic active molecules into retinal cells.

Delivering small hydrophilic drug molecules to the retina is a challenging task in ophthalmology. A solid lipid nanoparticle (SLP) with a composite shell and hydrogel core as delivery system of a hydrophilic cargo to retinal cells has been developed in this work to meet the challenge. The composite shell formed by lipid and hydrophobic polyesters improves polydispersity while the hydrogel core enhances the encapsulation efficiency when compared to conventional SLP. In vitro studies tracking internalization and release of hydrophilic fluorescent dyes in retinal pigment epithelium and photoreceptor cell lines, showed a successful uptake and release of the hydrophilic cargo inside the cells. Validation of SLP encapsulation capability using a neuroprotective cGMP analogue resulted in a SLP size < 250 nm, negative surface charge > -20 mV, and encapsulation efficiency value of 60%. This formulation shows a potential to be applied as ocular drug delivery system and may open new perspectives for developing a treatment for retinal diseases.