In-Situ Thermoresponsive Hydrogel Containing Resveratrol-Loaded Nanoparticles as a Localized Drug Delivery Platform for Dry Eye Disease.

Dry eye disease (DED) is a dynamic and complex disease that can cause significant damage to the ocular surface and discomfort, compromising the patient's quality of life. Phytochemicals such as resveratrol have received increasing attention due to their ability to interfere with multiple pathways related to these diseases. However, the low bioavailability and the poor therapeutic response of resveratrol hinder its clinical applications. Cationic polymeric nanoparticles, in combination with in situ gelling polymers, could represent a promising strategy to prolong drug corneal residence time reducing the frequency of administration and increasing the therapeutic response. Eyedrop formulations, based on acetylated polyethyleneimine-modified polylactic-co-glicolyc acid- (PLGA-PEI) nanoparticles loaded with resveratrol (RSV-NPs) were dispersed into poloxamer 407 hydrogel and characterized in terms of pH, gelation time, rheological properties, in vitro drugs release, and biocompatibility. Moreover, the antioxidant and anti-inflammatory effects of RSV were assessed in vitro by mimicking a DED condition through the exposition of epithelial corneal cells to a hyperosmotic state. This formulation exhibited sustained release of RSV for up to 3 days, exerting potent antioxidant and anti-inflammatory effects on corneal epithelial cells. In addition, RSV reversed the mitochondrial dysfunction mediated by high osmotic pressure, leading to upregulated sirtuin-1 (SIRT1) expression, an essential regulator of mitochondrial function. These results suggest the potential of eyedrop formulation as a platform to overcome the rapid clearance of current solutions for treating various inflammation- and oxidative stress-related diseases such as DED.

Regeneration of dentin-pulp complex: Effect of calcium-based materials on hDPSCs differentiation and gene expression.

OBJECTIVE: Dentin-pulp complex is object of interest in the regenerative endodontic field as well as the natural function of human dental pulp stem cells (hDPSCs) that may differentiate into specific cells able to repair and/or regenerate both hard and soft dental structures. The aim of the present study was to evaluate the capacity of hDPSCs to differentiate in odontoblastic-like cells by evaluating the expression of specific odontogenic-related genes and to prove the ability of treatment with calcium-based materials such as calcium carbonate (CaCO3), calcium hydroxide (Ca(OH)2), and mineral trioxide aggregate (MTA). METHODS: hDPSCs were obtained and isolated from a third molar of a young patient. Odontogenic-related gene expression was assessed unti1 28 days of culture as well as alkaline phosphatase activity (ALP). hDPSCs were cultured in odontoblastic-induction medium used as control, and in presence of different concentrations of CaCO3, Ca(OH)2, and MTA. RESULTS: The results demonstrated an upregulation in odontoblastic cell-related genes, in particular of the early differentiation marker known as matrix extracellular phosphoglycoprotein (MEPE), as well as increased ALP activity and the presence of calcium deposits, mainly by stimulation with calcium derivatives. In this regard, treatment of pulp tissue with CaCO3, Ca(OH)2 and even better with MTA seemed to be effective for dentinogenesis. SIGNIFICANCE: The ease of isolation of hDPSCs from discarded or extracted teeth offers a promising source of autologous cells that may be applied for regenerative purpose in combination with selected bioactive materials. However, further investigations should be conducted to confirm the obtained results.

Polylactic Acid/Poly(vinylpyrrolidone) Co-Electrospun Fibrous Membrane as a Tunable Quercetin Delivery Platform for Diabetic Wounds.

Diabetic wound infections (DWI) represent one of the most costly and disruptive complications in diabetic mellitus. The hyperglycemic state induces a persistent inflammation with immunological and biochemical impairments that promotes delayed wound healing processes and wound infection that often results in extended hospitalization and limb amputations. Currently, the available therapeutic options for the management of DWI are excruciating and expensive. Hence, it is essential to develop and improve DWI-specific therapies able to intervene on multiple fronts. Quercetin (QUE) exhibits excellent anti-inflammatory, antioxidant, antimicrobial and wound healing properties, which makes it a promising molecule for the management of diabetic wounds. In the present study, Poly-lactic acid/poly(vinylpyrrolidone) (PP) co-electrospun fibers loaded with QUE were developed. The results demonstrated a bimodal diameter distribution with contact angle starting from 120°/127° and go to 0° in less than 5 s indicating the hydrophilic nature of fabricated samples. The release QUE kinetics, analyzed in simulated wound fluid (SWF), revealed a strong initial burst release, followed by a constant and continuous QUE release. Moreover, QUE-loaded membranes present excellent antibiofilm and anti-inflammatory capacity and significantly reduce the gene expression of M1 markers tumor necrosis factor (TNF)-α, and IL-1ß in differentiated macrophages. In conclusion, the results suggested that the prepared mats loaded with QUE could be a hopeful drug-delivery system for the effective treatment of diabetic wound infections.

Hyaluronic Acid Hydrogel Containing Resveratrol-Loaded Chitosan Nanoparticles as an Adjuvant in Atopic Dermatitis Treatment.

Atopic dermatitis (AD) is a common disease-causing skin inflammation, redness, and irritation, which can eventually result in infection that drastically impacts patient quality of life. Resveratrol (Res) is a natural phytochemical famed for its excellent anti-inflammatory and antioxidant activities. However, it is poorly bioavailable. Thus, a drug delivery system is needed to enhance in vivo bioactivity. Herein, we report the preparation of hyaluronic acid (HA) hydrogels containing resveratrol-loaded chitosan (CS) nanoparticles, their physicochemical analysis, and their potential therapeutic effects in the treatment of AD. Positively charged CS nanoparticles prepared by tripolyphosphate (TPP) gelation showed sizes ranging from 120 to around 500 nm and Res encapsulation efficiency as high as 80%. Embedding the nanoparticles in HA retarded their hydrolytic degradation and also slowed resveratrol release. Resveratrol released from nanoparticle-loaded hydrogel counteracted the oxidative damage induced by ROS generation in TNF-α/INF-γ-treated human keratinocytes (HaCaT) used as an AD in vitro model. Moreover, pre-treatment with Res@gel reduced secretion and gene expression of proinflammatory cytokines in HaCaT cells. The physicochemical analysis and in vitro assay confirmed that the formulated hydrogel could be considered an efficient and sustained resveratrol delivery vector in AD treatment.

Thermo-Responsive Gel Containing Hydroxytyrosol-Chitosan Nanoparticles (Hyt@tgel) Counteracts the Increase of Osteoarthritis Biomarkers in Human Chondrocytes.

Although osteoarthritis (OA) is a chronic inflammatory degenerative disease affecting millions of people worldwide, the current therapies are limited to palliative care and do not eliminate the necessity of surgical intervention in the most severe cases. Several dietary and nutraceutical factors, such as hydroxytyrosol (Hyt), have demonstrated beneficial effects in the prevention or treatment of OA both in vitro and in animal models. However, the therapeutic application of Hyt is limited due to its poor bioavailability following oral administration. In the present study, a localized drug delivery platform containing a combination of Hyt-loading chitosan nanoparticles (Hyt-NPs) and in situ forming hydrogel have been developed to obtain the benefits of both hydrogels and nanoparticles. This thermosensitive formulation, based on Pluronic F-127 (F-127), hyaluronic acid (HA) and Hyt-NPs (called Hyt@tgel) presents the unique ability to be injected in a minimally invasive way into a target region as a freely flowing solution at room temperature forming a gel at body temperature. The Hyt@tgel system showed reduced oxidative and inflammatory effects in the chondrocyte cellular model as well as a reduction in senescent cells after induction with H2O2. In addition, Hyt@tgel influenced chondrocytes gene expression under pathological state maintaining their metabolic activity and limiting the expression of critical OA-related genes in human chondrocytes treated with stressors promoting OA-like features. Hence, it can be concluded that the formulated hydrogel injection could be proposed for the efficient and sustained Hyt delivery for OA treatment. The next step would be the extraction of "added-value" bioactive polyphenols from by-products of the olive industry, in order to develop a green delivery system able not only to enhance the human wellbeing but also to promote a sustainable environment.

Food-Derived Bioactive Molecules from Mediterranean Diet: Nanotechnological Approaches and Waste Valorization as Strategies to Improve Human Wellness.

The beneficial effects of the Mediterranean diet (MedDiet), the most widely followed healthy diet in the world, are principally due to the presence in the foods of secondary metabolites, mainly polyphenols, whose healthy characteristics are widely recognized. However, one of the biggest problems associated with the consumption of polyphenols as nutraceutical adjuvant concerns their bioavailability. During the last decades, different nanotechnological approaches have been developed to enhance polyphenol bioavailability, avoiding the metabolic modifications that lead to low absorption, and improving their retention time inside the organisms. This review focuses on the most recent findings regarding the encapsulation and delivery of the bioactive molecules present in the foods daily consumed in the MedDiet such as olive oil, wine, nuts, spice, and herbs. In addition, the possibility of recovering the polyphenols from food waste was also explored, taking into account the increased market demand of functional foods and the necessity to obtain valuable biomolecules at low cost and in high quantity. This circular economy strategy, therefore, represents an excellent approach to respond to both the growing demand of consumers for the maintenance of human wellness and the economic and ecological exigencies of our society.

PLA Nanofibers for Microenvironmental-Responsive Quercetin Release in Local Periodontal Treatment.

The management of periodontitis remains a vital clinical challenge due to the interplay between the microorganisms of the dental biofilm and the host inflammatory response leading to a degenerative process in the surrounding tissues. Quercetin (QUE), a natural flavonol found in many foods, including apples, onions and tea, has exhibited prolonged and strong antibiofilm and anti-inflammatory effects both in vitro and in vivo. However, its clinical application is limited by its poor stability and water solubility, as well as its low bioavailability. Thus, in the present study, electrospun polylactic acid (PLA) nanofibers loaded with different amounts (5−10% w/w) of QUE were produced to rapidly respond to the acidic microenvironment typical of periodontal pockets during periodontal disease. This strategy demonstrated that PLA-QUE membranes can act as a drug reservoir releasing high QUE concentrations in the presence of oral bacterial infection (pH < 5.5), and thus limiting Pseudomonas aeruginosa PAO1 and Streptococcus mutans biofilm maturation. In addition, released QUE exerts antioxidant and anti-inflammatory effects on P. gingivalis Lipopolysaccharide (LPS)-stimulated human gingival fibroblast (HGFs). The reported results confirmed that PLA-QUE membranes could inhibit subgingival biofilm maturation while reducing interleukin release, thereby limiting host inflammatory response. Overall, this study provided an effective pH-sensitive drug delivery system as a promising strategy for treating periodontitis.

Antimicrobial and physicochemical characterization of 2,3-dialdehyde cellulose-based wound dressings systems.

Biobased and biodegradable films were prepared by physically mixing 2,3-dialdehyde cellulose (DAC) with two other biopolymers, zein and gelatin, in three different proportions. The antimicrobial activities of the composite blends against Gram-positive and Gram-negative bacteria increase with the increase of DAC content. Cell viability tests on mammalian cells showed that the materials were not cytotoxic. In addition, DAC and gelatin were able to promote thermal degradation of the blends. However, DAC increased the stiffness and decreased the glass transition temperature of the blends, while gelatin was able to decrease the stiffness of the film. Morphological analysis showed the effect of DAC on the surface smoothness of the blends. The contact angle confirmed that all blends were within the range of hydrophilic materials. Although all the blends showed impressive performance for wound dressing application, the blend with gelatin might be more suitable for this purpose due to its better mechanical performance and antibacterial activity.

Positively charged polymers modulate the fate of human mesenchymal stromal cells via ephrinB2/EphB4 signaling.

Understanding the mechanisms by which mesenchymal stromal cells (MSCs) interact with the physical properties (e.g. topography, charge, ζ-potential, and contact angle) of polymeric surfaces is essential to design new biomaterials capable of regulating stem cell behavior. The present study investigated the ability of two polymers (pHM1 and pHM3) with different positive surface charge densities to modulate the differentiation of MSCs into osteoblast-like phenotype via cell-cell ephrinB2/EphB4 signaling. Although pHM1 promoted the phosphorylation of EphB4, leading to cell differentiation, pHM3, characterized by a high positive surface charge density, had no significant effect on EphB4 activation or MSCs differentiation. When the MSCs were cultured on pHM1 in the presence of a forward signaling blocking peptide, the osteoblast differentiation was compromised. Our results demonstrated that the ephrinB2/EphB4 interaction was required for MSCs differentiation into an osteoblast-like phenotype and that the presence of a high positive surface charge density altered this interaction.