Cutting-Edge Technologies for Inflamed Joints on Chip: How Close Are We?

Osteoarthritis (OA) is a painful and disabling musculoskeletal disorder, with a large impact on the global population, resulting in several limitations on daily activities. In OA, inflammation is frequent and mainly controlled through inflammatory cytokines released by immune cells. These outbalanced inflammatory cytokines cause cartilage extracellular matrix (ECM) degradation and possible growth of neuronal fibers into subchondral bone triggering pain. Even though pain is the major symptom of musculoskeletal diseases, there are still no effective treatments to counteract it and the mechanisms behind these pathologies are not fully understood. Thus, there is an urgent need to establish reliable models for assessing the molecular mechanisms and consequently new therapeutic targets. Models have been established to support this research field by providing reliable tools to replicate the joint tissue in vitro. Studies firstly started with simple 2D culture setups, followed by 3D culture focusing mainly on cell-cell interactions to mimic healthy and inflamed cartilage. Cellular approaches were improved by scaffold-based strategies to enhance cell-matrix interactions as well as contribute to developing mechanically more stable in vitro models. The progression of the cartilage tissue engineering would then profit from the integration of 3D bioprinting technologies as these provide 3D constructs with versatile structural arrangements of the 3D constructs. The upgrade of the available tools with dynamic conditions was then achieved using bioreactors and fluid systems. Finally, the organ-on-a-chip encloses all the state of the art on cartilage tissue engineering by incorporation of different microenvironments, cells and stimuli and pave the way to potentially simulate crucial biological, chemical, and mechanical features of arthritic joint. In this review, we describe the several available tools ranging from simple cartilage pellets to complex organ-on-a-chip platforms, including 3D tissue-engineered constructs and bioprinting tools. Moreover, we provide a fruitful discussion on the possible upgrades to enhance the in vitro systems making them more robust regarding the physiological and pathological modeling of the joint tissue/OA.

A rare case of a nasal cavity fungus ball due to Aspergillus niger.

Background and Purpose: Fungus Ball (FB) is a non-invasive fungal infection caused mainly by Aspergillus species. It can occur after root canal treatments are applied to the teeth adjacent to the maxillary sinus. These balls are commonly seen in the paranasal sinuses and rarely observed in the nasal cavity. This report attempted in to highlight such a rare case of fungal infection which requires accurate observation. Moreover, it highlights the importance of careful microbiological and histopathological examinations that were combined with imaging and can lead to a definitive diagnosis. Case report: Herein, we report a rare case of a FB found in the vicinity of the nasal cavity of a 73-year-old male patient. Microbiological examination supported by radiographic and histopathological results indicated that the FB is due to Aspergillus niger. Excised surgery was done to the FB area, and the patient was referred to the post-operation room with the proper recommendations. After the wound healed, the total denture was performed as requested by the patient, and his overall oral health was improved. Conclusion: In this article, we report the first case of a rare FB in the vicinity of the nasal cavity of a 73-year-old male patient. The appropriate investigation is an essential step in the diagnostic process for these infections and requires effective communication and collaboration.

Posaconazole micelles for ocular delivery: in vitro permeation, ocular irritation and antifungal activity studies.

Posaconazole (PSC) is a triazole group anti-fungal agent with the widest spectrum. Although there is no commercially available ocular dosage form, its diluted oral suspension preparation (Noxafil®) is used as off-label in topical treatment of severe keratitis and sclerokeratitis in the clinic. However, ocular bioavailability of PSC suspension form is extremely low due to its highly lipophilic character. Thus, there is a clinical need to improve its ocular bioavailability and to develop novel delivery system for the treatment of ocular fungal infections. Herein, we studied ex vivo permeation, penetration, anti-fungal activity, and Hen's Egg Test-Chorioallantoic Membrane (HET-CAM) toxicity tests in order to assess ocular targeting of PSC micelles, which were optimized in our previous study. The results indicated that micellar carrier system increased the permeability of PSC to eye tissues. Micelles showed higher affinity to ocular tissues than that of commercial oral suspension of PSC (Noxafil®). In vitro anti-fungal activity data also confirmed the efficacy of PSC loaded micellar formulations against Candida. albicans strains. The relative safety of the optimized micelles on the ocular tissue was shown with the HET-CAM toxicity test. In conclusion, micellar systems could be a promising strategy for the effective and safe delivery of PSC in the treatment of ocular fungal infections.

Nanocarriers Mediated Cutaneous Drug Delivery.

The cutaneous drug delivery represents an attractive option for the management of skin diseases. However, the skin has a very complex morphological structure, although the skin barrier is disrupted in some of dermatological diseases. Therefore, to safely overcome the skin barrier and to deliver drugs across the skin efficiently is still remain as a challenge in the management of dermatological diseases. The nanocarrier mediated cutaneous delivery appears to offer a hope to provide targeting potential of the drugs into specific sites of the skin with minimizing side effects. This review highlights the human structure and diseased skin barrier, and possible therapeutic outcomes of nanocarrier based drug delivery in the treatment of skin diseases due to their skin transport and follicular targeting mechanisms, and summarizes recent studies in which polymer, lipid and surfactant based nanocarriers of drugs used in the skin diseases.

Recent Approaches on Novel Topical Delivery Systems for Atopic Dermatitis Treatment.

Atopic dermatitis is a chronic inflammatory disease of the skin, which is characterized by itching, erythema, and eczematous lacerations. It affects about 10 % of adults and approximately 15-20 % of children worldwide. As a result of genetic, immunologic, and environmental factors, the disease manifests itself with the impaired stratum corneum barrier and then immunological responses. Topical administration of corticosteroids and calcineurin inhibitors are currently used as the first strategy in the management of the disease. However, they have low skin bioavailability and some side effects. The nanocarriers as novel drug delivery systems could overcome limitations of conventional dosage forms, owing to increment of poorly soluble drug' solubility, then its thermodynamic activity and, consequently, its skin permeation. Also, side effects of the drug substances on the skin could be reduced by the nano-sized drug delivery systems due to encapsulation of the drug in the nanocarriers and targeted drug delivery of drug substances to the inflammated skin areas. Thereby, there have been available numerous research studies and patents regarding the use of nanocarriers in the management of atopic dermatitis. This review focuses on the mechanism of disease and development of nanocarrier based on novel drug release systems in the management of atopic dermatitis.

Optimization and Characterization of Aqueous Micellar Formulations for Ocular Delivery of an Antifungal Drug, Posaconazole.

BACKGROUND: Topical therapy is preferred for the management of ocular fungal infections due to its superiorities which include overcoming potential systemic side effects risk of drugs, and targeting of drugs to the site of disease. However, the optimization of effective ocular formulations has always been a major challenge due to restrictions of ocular barriers and physiological conditions. Posaconazole, an antifungal and highly lipophilic agent with broad-spectrum, has been used topically as off-label in the treatment of ocular fungal infections due to its highly lipophilic character. Micellar carriers have the potential to improve the solubility of lipophilic drugs and, overcome ocular barriers. OBJECTIVE: In the current study, it was aimed optimization of posaconazole loaded micellar formulations to improve aqueous solubility of posaconazole and to characterize the formulations and to investigate the physical stability of these formulations at room temperature (25°C, 60% RH), and accelerated stability (40°C, 75% RH) conditions. METHODS: Micelles were prepared using a thin-film hydration method. Pre-formulation studies were firstly performed to optimize polymer/surfactant type and to determine their concentration in the formulations. Then, particle size, size distribution, and zeta potential of the micellar formulations were measured by ZetaSizer Nano-ZS. The drug encapsulation efficiency of the micelles was quantified by HPLC. The morphology of the micelles was depicted by AFM. The stability of optimized micelles was evaluated in terms of particle size, size distribution, zeta potential, drug amount and pH for 180 days. In vitro release studies were performed using Franz diffusion cells. RESULTS: Pre-formulation studies indicated that single D-ɑ-tocopheryl polyethylene glycol succinate (TPGS), a combination of it and Pluronic F127/Pluronic F68 are capable of formation of posaconazole loaded micelles at specific concentrations. Optimized micelles with high encapsulation efficiency were less than 20 nm, approximately neutral, stable, and in aspherical shape. Additionally, in vitro release data showed that the release of posaconazole from the micelles was higher than that of suspension. CONCLUSION: The results revealed that the optimized micellar formulation of posaconazole offers a potential approach for topical ocular administration.

Effects of Polyvinylpyrrolidone and Ethyl Cellulose in Polyurethane Electrospun Nanofibers on Morphology and Drug Release Characteristics.

OBJECTIVES: Polyurethanes (PUs) are a popular choice for composing nanofibers due to their spinnability, biocompatibility, high chemical stability, and good mechanical and elasticity properties. The desired release behaviors are also achieved by using combinations of PUs and various polymers. In this study, we investigated effects of polyvinylpyrrolidone (PVP) and ethyl cellulose (EC) on PU electrospun nanofibers in terms of morphological structures and drug release characteristics. MATERIALS AND METHODS: Nanofibers were prepared using blends of PU with either EC or PVP in different ratios by electrospinning. The effects of PVP or EC on the morphology and diameter of the prepared nanofibers were examined with scanning electron microscope (SEM). The compatibility of the components used in the formulations of nanofibers was determined by attenuated total reflection (ATR)-fourier-transform infrared (FTIR). Donepezil hydrochloride (DNP), a water soluble compound, was selected as a model drug to examine its release characteristics from both PU/PVP and PU/EC electrospun nanofibers. In vitro drug release studies from electrospun nanofibers were performed according to the method defined in the monograph as the "paddle over disk method" of United States Pharmacopeia 38. RESULTS: The SEM images showed that addition of EC or PVP to PU solutions did not affect the generation of nanofibers, and those formed had a smooth surface without beads in nanoscale. The ATR-FTIR spectra disclosed that EC and PVP were separately incorporated into the PU matrix. The in vitro release data indicated that the presence of EC or PVP in PU nanofibers dramatically changed the release behavior of DNP. PU/EC nanofibers (F4) provided sustained drug release with the Korsmeyer-Peppas drug release kinetic mechanism, in which the release rate was controlled by diffusion of the drug, while all of the PU/PVP nanofibers exhibited fast drug release. CONCLUSION: Overall, these characteristics of PU/EC (10/8) electrospun nanofibers has suggested their potential use as a drug carrier from which water-soluble drug release may occur in a sustained fashion.

The combination of nanomicelles with terpenes for enhancement of skin drug delivery.

The nanomicelles have recently drawn a great deal of attention for drug delivery into the skin. However, these carriers have only deposited in hair follicles and furrows, and drug in the micelles may not therapeutically reach into viable skin layers. The aim of this study was to formulate a combination of nanomicelles with terpenes to overcome this challenge and evaluate their potential for topical drug delivery into the skin. The nanomicelles were characterised with respect to size, size distribution (PDI), zeta potential, morphology and encapsulation efficiency (%). The drug accumulation and penetration were examined by tape stripping method in the skin. The colloidal stability of nanomicelles was followed with respect to size and PDI values. The nanomicelles were about 25-30 nm in size with narrow distribution. All of them had slightly negative surface charge, spherical shapes and high encapsulation efficiency (%). The tape stripping data revealed that nanomicelles consisting of terpinolene led to accumulation of more drug in the stripped skin as compared with commercial product and nanomicelles without terpene. Also, micelle formulations consisting of terpinolene (2.0%) had the highest colloidal stability. Consequently, combination of nanomicelles with terpinolene could be a feasible approach for enhancement of skin drug delivery.

Potential enhancement and targeting strategies of polymeric and lipid-based nanocarriers in dermal drug delivery.

Nanocarriers used for alternative drug-delivery strategies have gained interest due to improved penetration and delivery of drugs into specific regions of the skin in recent years. Dermal drug delivery via polymeric-based nanocarriers (polymeric nanoparticles, micelles, dendrimers) and lipid-based nanocarriers (solid-lipid nanoparticles and nanostructured lipid carriers, vesicular nanocarriers including liposomes, niosomes, transfersomes and ethosomes) has been widely investigated. Although penetration of nanocarriers through the intact skin could be restricted, these carriers are particularly considered as feasible for the treatment of dermatological diseases in which the skin barrier is disrupted and also for follicular delivery of drugs for management of skin disorders such as acne. This review mainly highlights the recent approaches on potential penetration enhancement and targeting mechanisms of these nanocarriers.

Polymeric micellar nanocarriers of benzoyl peroxide as potential follicular targeting approach for acne treatment.

The aim of this work was to optimize polymeric nano-sized micellar carriers of the anti-acne compound benzoyl peroxide (BPO) and to examine the ability of these carriers to deposit into hair follicles with the objective of improving skin delivery of BPO. BPO loaded polymeric micelles composed of Pluronic(®) F127 were prepared by the thin film hydration method and characterized in terms of size, loading capacity, morphology and physical stability. The optimized micelle formulation was then selected for skin delivery studies. The penetration of BPO loaded micellar carriers into skin and skin appendages across full thickness porcine skin was examined in vitro. Confocal microscopy images confirmed the penetration of Nile Red into hair follicles, which was loaded into micellar carriers as a model fluorescent compound. The relative safety of the polymeric micelles was evaluated with the MTT viability test using mouse embryonic fibroblasts. The results indicated that nano-sized polymeric micelles of BPO composed of Pluronic(®) F127 offer a potential approach to enhance skin delivery of BPO and that targeting of micelles into hair follicles may be an effective and safe acne treatment.

Polyethylenimine Modified and Non-Modified Polymeric Micelles Used for Nasal Administration of Carvedilol.

This study evaluates the ability of polyethylenimine-modified and non-modified polymeric micelles to enhance permeation through the nasal mucosa for a highly hydrophobic model drug. Carvedilol was loaded into polyethylenimine-modified and non-modified micelles by direct dissolution. Formulations were characterised by critical micelle concentration, micelle particle size and distribution, zeta potential, morphological structure and entrapment efficiency. The drug entrapment efficiency was determined to be as high as 77.14%, while micelle particle sizes and zeta potentials were within the range of 140.0-279.9 nm and (- 40.6)-(+ 25.9) mV, respectively. In vitro studies showed 100% release of carvedilol from micelles in 120 hours. Ex vivo permeation studies showed that the drug in polyethylenimine non-modified micelles passed more efficiently than the drug in polyethylenimine modified micelles. These results demonstrated that polyethylenimine modified micelles did not significantly affect the permeation of the drug when compared to polyethylenimine non-modified micelles. On the contrary, the drug in poly(L-lactide)-block-methoxy poly(ethylene glycol)5000 micelles, the polyethylenimine non-modified micelles, showed the highest permeation rate through bovine nasal mucosa. In conclusion, poly(L-lactide)-block- methoxy poly(ethylene glycol)5000 polymeric micelles maybe useful as novel drug carriers that increase the permeation through the nasal mucosa.