Glycerol-based sustainably sourced resin for volumetric printing.

Volumetric Additive Manufacturing (VAM) represents a revolutionary advancement in the field of Additive Manufacturing, as it allows for the creation of objects in a single, cohesive process, rather than in a layer-by-layer approach. This innovative technique offers unparalleled design freedom and significantly reduces printing times. A current limitation of VAM is the availability of suitable resins with the required photoreactive chemistry and from sustainable sources. To support the application of this technology, we have developed a sustainable resin based on polyglycerol, a bioderived (e.g., vegetable origin), colourless, and easily functionisable oligomer produced from glycerol. To transform polyglycerol-6 into an acrylate photo-printable resin we adopted a simple, one-step, and scalable synthesis route. Polyglycerol-6-acrylate fulfils all the necessary criteria for volumetric printing (transparency, photo-reactivity, viscosity) and was successfully used to print a variety of models with intricate geometries and good resolution. The waste resin was found to be reusable with minimal performance issues, improving resin utilisation and minimising waste material. Furthermore, by incorporating dopants such as poly(glycerol) adipate acrylate (PGA-A) and 10,12-pentacosadyinoic acid (PCDA), we demonstrated the ability to print objects with a diverse range of functionalities, including temperature sensing probes and a polyester excipient, highlighting the potential applications of these new resins.

Cyclosporine A micellar nasal spray characterization and antiviral action against SARS-CoV-2.

The upper airways represent the point of entrance from where Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection spreads to the lungs. In the present work, α-tocopheryl-polyethylene-glycol succinate (TPGS) micelles loaded with cyclosporine A (CSA) were developed for nasal administration to prevent or treat the viral infection in the very first phases. The behavior of the micelles in presence of simulated nasal mucus was investigated in terms of stability and mucopenetration rate, evidencing long-term stability and fast diffusion across the glycoproteins matrix. Moreover, the spray characteristics of the micellar formulation and deposition profile in a silicon nasal model were studied using three nasal spray devices. Results allowed to identify the nasal spray pump (BiVax, Aptar) able to provide the wider and uniform deposition of the nasal cavity. The cyclosporine A micelles antiviral activity against SARS-CoV-2 was tested on the Omicron BA.1 variant using Vero E6 cells with protocols simulating treatment before, during and after the infection of the upper airways. Complete viral inactivation was observed for the cyclosporine-loaded micelles while a very low activity was evidenced for the non-formulated drug, suggesting a synergistic activity of the drug and the formulation. In conclusion, this work showed that the developed cyclosporine A-loaded micellar formulations have the potential to be clinically effective against a wide spectrum of coronavirus variants.

Neem Oil or Almond Oil Nanoemulsions for Vitamin E Delivery: From Structural Evaluation to in vivo Assessment of Antioxidant and Anti-Inflammatory Activity.

Purpose: Vitamin E (VitE) may be classified in "the first line of defense" against the formation of reactive oxygen species. Its inclusion in nanoemulsions (NEs) is a promising alternative to increase its bioavailability. The aim of this study was to compare O/W NEs including VitE based on Almond or Neem oil, showing themselves antioxidant properties. The potential synergy of the antioxidant activities of oils and vitamin E, co-formulated in NEs, was explored. Patients and Methods: NEs have been prepared by sonication and deeply characterized evaluating size, ζ-potential, morphology (TEM and SAXS analyses), oil nanodroplet feature, and stability. Antioxidant activity has been evaluated in vitro, in non-tumorigenic HaCaT keratinocytes, and in vivo through fluorescence analysis of C. elegans transgenic strain. Moreover, on healthy human volunteers, skin tolerability and anti-inflammatory activity were evaluated by measuring the reduction of the skin erythema induced by the application of a skin chemical irritant (methyl-nicotinate). Results: Results confirm that Vitamin E can be formulated in highly stable NEs showing good antioxidant activity on keratinocyte and on C. elegans. Interestingly, only Neem oil NEs showed some anti-inflammatory activity on healthy volunteers. Conclusion: From the obtained results, Neem over Almond oil is a more appropriate candidate for further studies on this application.

Ultrastable shelled PFC nanobubbles: A platform for ultrasound-assisted diagnostics, and therapy.

Nanoscale echogenic bubbles (NBs), can be used as a theranostic platform for the localized delivery of encapsulated drugs. However, the generation of NBs is challenging, because they have lifetimes as short as milliseconds in solution. The aim of this work has been the optimization of a preparation method for the generation of stable NBs, characterized by measuring: a) acoustic efficiency, b) nano-size, to ensure passive tumour targeting, c) stability during storage and after injection and d) ability to entrap drugs. NBs are monodisperse and ultra-stable, their stability achieved by generation of an amphiphilic multilamellar shell able to efficiently retain the PFC gas. The NBs perform as good acoustic enhancers over a wide frequency range and out of resonant conditions, as tested in both in vitro and in vivo experiments, proving to be a potential platform for the production of versatile carriers to be used in ultrasound-assisted diagnostic, therapeutic and theranostic applications.

Dysmyelination and glycolipid interference caused by phenylalanine in phenylketonuria.

Phenylketonuria (PKU) is a metabolic disorder connected to an excess of phenylalanine (Phe) in the blood and tissues, with neurological consequences. The disease's molecular bases seem to be related to the accumulation of Phe at the cell membrane surface. Radiological outcomes in the brain demonstrate decreased water diffusivity in white matter, involving axon dysmyelination of not yet understood origin. We used a biophysical approach and model membranes to extend our knowledge of Phe-membrane interaction by clarifying Phe's propensity to affect membrane structure and dynamics based on lipid composition, with emphasis on modulating cholesterol and glycolipid components to mimic raft domains and myelin sheath membranes. Phe showed affinity for the investigated membrane mimics, mainly affecting the Phe-facing membrane leaflet. The surfaces of our neuronal membrane raft mimics were strong anchoring sites for Phe, showing rigidifying effects. From a therapeutic perspective, we further investigated the role of doxycycline, known to disturb Phe packing, unveiling its action as a competitor in Phe interactions with the membrane, suggesting its potential for treatment in the early stages of PKU. Our results suggest how Phe accumulation in extracellular fluids can impede normal growth of myelin sheaths by interfering with membrane slipping and by remodulating free water and myelin-associated water contents.

Smart nano-in-microparticles to tackle bacterial infections in skin tissue engineering.

Chronic wounds (resulting from underlying disease, metabolic disorders, infections, trauma, and even tumours) pose significant health problems. In this work, microparticles, based on polysaccharides (maltodextrin or dextran) and amino acids, and doped with antibacterial nanoparticles (CuO or ZnO NPs) are designed. Smart nano-in-microparticles with a hierarchical 3D structure are developed. The ultimate goal aims at an innovative platform to achieve skin repair and to manage skin colonization by avoiding infection that could delay and even impair the healing process. The microparticles are prepared by spray-drying and cross-linked by heating, to obtain insoluble scaffolds able to facilitate cell proliferation in the wound bed. The nano-in-microparticles are characterized using a multidisciplinary approach: chemico-physical properties (SEM, SEM-EDX, size distribution, swelling and degradation properties, structural characterization - FTIR, XRPD, SAXS - mechanical properties, surface zeta potential) and preclinical properties (in vitro biocompatibility and whole-blood clotting properties, release studies and antimicrobial properties, and in vivo safety and efficacy on murine burn/excisional wound model) were assessed. The hierarchical 3D nano-in microparticles demonstrate to promote skin tissue repair in a preclinical study, indicating that this platform deserves particular attention and further investigation will promote the prototypes translation to clinics.

Biochemical and biophysical features of disease-associated tau mutants V363A and V363I.

The comprehension of pathogenetic mechanisms in tauopathy-associated neurodegenerative diseases can be improved by the knowledge of the biochemical and biophysical features of mutated tau proteins. Here, we used the full-length, wild-type tau, the V363A and V363I mutated species, associated with pathology, and the P301L mutated tau as a benchmark. Using several techniques, including small-angle X-ray scattering, atomic force microscopy, thioflavin T binding, and electrophoretic separation, we compared their course from intrinsically disordered monomers in solution to early-stage recruitment in complexes and then aggregates of increasing size over long periods up to the asymptotic aggregative behavior of full-length tau proteins. We showed that diversity in the kinetics of recruitment and aggregate structure occurs from the beginning and spreads all over their pathway to very large objects. The different extents of conformational changes and types of molecular assemblies among the proteins were also reflected in their in vitro toxicity; this variation could correlate with physiopathology in humans, considering that the P301L mutation is more aggressive than V363A, especially V363I. This study identified the presence of aggregation intermediates and corroborated the oligomeric hypothesis of tauopathies.

Polystyrene perturbs the structure, dynamics, and mechanical properties of DPPC membranes: An experimental and computational study.

Synthetic plastic oligomers can interact with the cells of living organisms by different ways. They can be intentionally administered to the human body as part of nanosized biomedical devices. They can be inhaled by exposed workers, during the production of multicomponent, polymer-based nanocomposites. They can leak out of food packaging. Most importantly, they can result from the degradation of plastic waste, and enter the food chain. A physicochemical characterization of the effects of synthetic polymers on the structure and dynamics of cell components is still lacking. Here, we combine a wide spectrum of experimental techniques (calorimetry, x-ray, and neutron scattering) with atomistic Molecular Dynamics simulations to study the interactions between short chains of polystyrene (25 monomers) and model lipid membranes (DPPC, in both gel and fluid phase). We find that doping doses of polystyrene oligomers alter the thermal properties of DPPC, stabilizing the fluid lipid phase. They perturb the membrane structure and dynamics, in a concentration-dependent fashion. Eventually, they modify the mechanical properties of DPPC, reducing its bending modulus in the fluid phase. Our results call for a systematic, interdisciplinary assessment of the mechanisms of interaction of synthetic, everyday use polymers with cell membranes.

Smart Device for Biologically Enhanced Functional Regeneration of Osteo-Tendon Interface.

The spontaneous healing of a tendon laceration results in the formation of scar tissue, which has lower functionality than the original tissue. Moreover, chronic non-healing tendon injuries frequently require surgical treatment. Several types of scaffolds have been developed using the tissue engineering approach, to complement surgical procedures and to enhance the healing process at the injured site. In this work, an electrospun hybrid tubular scaffold was designed to mimic tissue fibrous arrangement and extracellular matrix (ECM) composition, and to be extemporaneously loaded into the inner cavity with human platelet lysate (PL), with the aim of leading to complete post-surgery functional regeneration of the tissue for functional regeneration of the osteo-tendon interface. For this purpose, pullulan (P)/chitosan (CH) based polymer solutions were enriched with hydroxyapatite nanoparticles (HP) and electrospun. The nanofibers were collected vertically along the length of the scaffold to mimic the fascicle direction of the tendon tissue. The scaffold obtained showed tendon-like mechanical performance, depending on HP content and tube size. The PL proteins were able to cross the scaffold wall, and in vitro studies have demonstrated that tenocytes and osteoblasts are able to adhere to and proliferate onto the scaffold in the presence of PL; moreover, they were also able to produce either collagen or sialoproteins, respectively-important components of ECM. These results suggest that HP and PL have a synergic effect, endorsing PL-loaded HP-doped aligned tubular scaffolds as an effective strategy to support new tissue formation in tendon-to-bone interface regeneration.

Hyaluronic Acid-Dexamethasone Nanoparticles for Local Adjunct Therapy of Lung Inflammation.

The delivery of a dexamethasone formulation directly into the lung appears as an appropriate strategy to strengthen the systemic administration, reducing the dosage in the treatment of lung severe inflammations. For this purpose, a hyaluronic acid-dexamethasone formulation was developed, affording an inhalable reconstituted nanosuspension suitable to be aerosolized. The physico-chemical and biopharmaceutical properties of the formulation were tested: size, stability, loading of the spray-dried dry powder, reconstitution capability upon redispersion in aqueous media. Detailed structural insights on nanoparticles after reconstitution were obtained by light and X-ray scattering techniques. (1) The size of the nanoparticles, around 200 nm, is in the proper range for a possible engulfment by macrophages. (2) Their structure is of the core-shell type, hosting dexamethasone nanocrystals inside and carrying hyaluronic acid chains on the surface. This specific structure allows for nanosuspension stability and provides nanoparticles with muco-inert properties. (3) The nanosuspension can be efficiently aerosolized, allowing for a high drug fraction potentially reaching the deep lung. Thus, this formulation represents a promising tool for the lung administration via nebulization directly in the pipe of ventilators, to be used as such or as adjunct therapy for severe lung inflammation.

Bespoke 3D-Printed Polydrug Implants Created via Microstructural Control of Oligomers.

Controlling the microstructure of materials by means of phase separation is a versatile tool for optimizing material properties. Phase separation has been exploited to fabricate intricate microstructures in many fields including cell biology, tissue engineering, optics, and electronics. The aim of this study was to use phase separation to tailor the spatial location of drugs and thereby generate release profiles of drug payload over periods ranging from 1 week to months by exploiting different mechanisms: polymer degradation, polymer diluent dissolution, and control of microstructure. To achieve this, we used drop-on-demand inkjet three-dimensional (3D) printing. We predicted the microstructure resulting from phase separation using high-throughput screening combined with a model based on the Flory-Huggins interaction parameter and were able to show that drug release from 3D-printed objects can be predicted from observations based on single drops of mixtures. We demonstrated for the first time that inkjet 3D printing yields controllable phase separation using picoliter droplets of blended photoreactive oligomers/monomers. This new understanding gives us hierarchical compositional control, from droplet to device, allowing release to be "dialled up" without manipulation of device geometry. We exemplify this approach by fabricating a biodegradable, long-term, multiactive drug delivery subdermal implant ("polyimplant") for combination therapy and personalized treatment of coronary heart disease. This is an important advance for implants that need to be delivered by cannula, where the shape is highly constrained and thus the usual geometrical freedoms associated with 3D printing cannot be easily exploited, which brings a hitherto unseen level of understanding to emergent material properties of 3D printing.

Hyaluronic Acid Derivative Effect on Niosomal Coating and Interaction with Cellular Mimetic Membranes.

Hyaluronic acid (HA) is one of the most used biopolymers in the development of drug delivery systems, due to its biocompatibility, biodegradability, non-immunogenicity and intrinsic-targeting properties. HA specifically binds to CD44; this property combined to the EPR effect could provide an option for reinforced active tumor targeting by nanocarriers, improving drug uptake by the cancer cells via the HA-CD44 receptor-mediated endocytosis pathway. Moreover, HA can be easily chemically modified to tailor its physico-chemical properties in view of specific applications. The derivatization with cholesterol confers to HA an amphiphilic character, and then the ability of anchoring to niosomes. HA-Chol was then used to coat Span® or Tween® niosomes providing them with an intrinsic targeting shell. The nanocarrier physico-chemical properties were analyzed in terms of hydrodynamic diameter, ζ-potential, and bilayer structural features to evaluate the difference between naked and HA-coated niosomes. Niosomes stability was evaluated over time and in bovine serum. Moreover, interaction properties of HA-coated nanovesicles with model membranes, namely liposomes, were studied, to obtain insights on their interaction behavior with biological membranes in future experiments. The obtained coated systems showed good chemical physical features and represent a good opportunity to carry out active targeting strategies.

Structure and Fate of Nanoparticles Designed for the Nasal Delivery of Poorly Soluble Drugs.

Nanoparticles are promising mediators to enable nasal systemic and brain delivery of active compounds. However, the possibility of reaching therapeutically relevant levels of exogenous molecules in the body is strongly reliant on the ability of the nanoparticles to overcome biological barriers. In this work, three paradigmatic nanoformulations vehiculating the poorly soluble model drug simvastatin were addressed: (i) hybrid lecithin/chitosan nanoparticles (LCNs), (ii) polymeric poly-ε-caprolactone nanocapsules stabilized with the nonionic surfactant polysorbate 80 (PCL_P80), and (iii) polymeric poly-ε-caprolactone nanocapsules stabilized with a polysaccharide-based surfactant, i.e., sodium caproyl hyaluronate (PCL_SCH). The three nanosystems were investigated for their physicochemical and structural properties and for their impact on the biopharmaceutical aspects critical for nasal and nose-to-brain delivery: biocompatibility, drug release, mucoadhesion, and permeation across the nasal mucosa. All three nanoformulations were highly reproducible, with small particle size (∼200 nm), narrow size distribution (polydispersity index (PI) < 0.2), and high drug encapsulation efficiency (>97%). Nanoparticle composition, surface charge, and internal structure (multilayered, core-shell or raspberry-like, as assessed by small-angle neutron scattering, SANS) were demonstrated to have an impact on both the drug-release profile and, strikingly, its behavior at the biological interface. The interaction with the mucus layer and the kinetics and extent of transport of the drug across the excised animal nasal epithelium were modulated by nanoparticle structure and surface. In fact, all of the produced nanoparticles improved simvastatin transport across the epithelial barrier of the nasal cavity as compared to a traditional formulation. Interestingly, however, the permeation enhancement was achieved via two distinct pathways: (a) enhanced mucoadhesion for hybrid LCN accompanied by fast mucosal permeation of the model drug, or (b) mucopenetration and an improved uptake and potential transport of whole PCL_P80 and PCL_SCH nanocapsules with delayed boost of permeation across the nasal mucosa. The correlation between nanoparticle structure and its biopharmaceutical properties appears to be a pivotal point for the development of novel platforms suitable for systemic and brain delivery of pharmaceutical compounds via intranasal administration.

Aß Beyond the AD Pathology: Exploring the Structural Response of Membranes Exposed to Nascent Aß Peptide.

The physiological and pathological roles of nascent amyloid beta (Aß) monomers are still debated in the literature. Their involvement in the pathological route of Alzheimer's Disease (AD) is currently considered to be the most relevant, triggered by their aggregation into structured oligomers, a toxic species. Recently, it has been suggested that nascent Aß, out of the amyloidogenic pathway, plays a physiological and protective role, especially in the brain. In this emerging perspective, the study presented in this paper investigated whether the organization of model membranes is affected by contact with Aß in the nascent state, as monomers. The outcome is that, notably, the rules of engagement and the resulting structural outcome are dictated by the composition and properties of the membrane, rather than by the Aß variant. Interestingly, Aß monomers are observed to favor the tightening of adjacent complex membranes, thereby affecting a basic structural event for cell-cell adhesion and cell motility.

Baseline well-being, perceptions of critical incidents, and openness to debriefing in community hospital emergency department clinical staff before COVID-19, a cross-sectional study.

BACKGROUND: Emergency department personnel routinely bear witness to traumatic experiences and critical incidents that can affect their own well-being. Peer support through debriefing has demonstrated positive impacts on clinicians' well-being following critical incidents. This study explored community hospital emergency department staff's perceptions of critical incidents, assessed openness to debriefing and measured baseline well-being. Our analysis provides a baseline of provider well-being immediately prior to the local onset of COVID-19. The potential need for additional resources to support frontline providers during the pandemic can be evaluated. METHOD: We conducted a cross-sectional study for 4-weeks prior to the first COVID-19 case in Connecticut using a survey offered to an interprofessional group of emergency department clinical staff. The main outcome measures were the Hospital Anxiety and Depression Scale (HADS) and the Professional Quality of Life (ProQOL) scale. Pearson's chi-square test was used to identify significant differences in perceptions of critical incidents and debriefings between professional categories. One-way ANOVA and Tukey's test were used to analyze significant differences in well-being between professional categories. RESULTS: Thirty-nine clinical personnel from St. Vincent's Emergency Department responded to the survey. Events frequently selected as critical incidents were caring for critically ill children (89.7%), mass casualty events (84.6%), and death of a patient (69.2%). Critical incidents were commonly reported (81.6%) as occurring once per week. Additionally, 76.2% of participants reported wanting to discuss a critical incident with their team. Across all respondents, 45.7% scored borderline or abnormal for anxiety, 55.9% scored moderate for burnout, and 55.8% scored moderate to high for secondary traumatic stress. CONCLUSIONS: At baseline, providers reported caring for critically ill children, mass casualty events, and death of a patient as critical incidents, which typically occurred once per week. Death of a patient occurs at increased frequency during the protracted mass casualty experience of COVID-19 and threatens provider well-being. Receptiveness to post-event debriefing is high but the method is still underutilized. With nearly half of staff scoring borderline or abnormal for anxiety, burnout, and secondary traumatic stress at baseline, peer support measures should be implemented to protect frontline providers' well-being during and after the pandemic.

The similarity of inherited diseases (II): clinical and biological similarity between the phenotypic series.

BACKGROUND: Despite being caused by mutations in different genes, diseases in the same phenotypic series are clinically similar, as reported in Part I of this study. Here, in Part II, we hypothesized that the phenotypic series too might be clinically similar. Furthermore, on the assumption that gene mutations indirectly cause clinical phenotypes by directly affecting biological functions, we hypothesized that clinically similar phenotypic series might be biologically similar as well. METHODS: To test these hypotheses, we generated a clinical similarity network and a set of biological similarity networks. In both types of network, the nodes represent the phenotypic series, and the edges linking the nodes indicate the similarity of the linked phenotypic series. The weight of each edge is proportional to a similarity coefficient, which depends on the clinical phenotypes and the biological features that are shared by the linked phenotypic series, in the clinical and biological similarity networks, respectively. RESULTS: After assembling and analyzing the networks, we raised the threshold for the similarity coefficient, to retain edges of progressively greater weight. This way all the networks were gradually split into fragments, composed of phenotypic series with increasingly greater degrees of similarity. Finally, by comparing the fragments from the two types of network, we defined subsets of phenotypic series with varying types and degrees of clinical and biological correlation. CONCLUSIONS: Like the individual diseases, the phenotypic series too are clinically and biologically similar to each other. Furthermore, our findings unveil different modalities of correlation between the clinical manifestations and the biological features of the inherited diseases.

Human-scale tissues with patterned vascular networks by additive manufacturing of sacrificial sugar-protein composites.

Combating necrosis, by supplying nutrients and removing waste, presents the major challenge for engineering large three-dimensional (3D) tissues. Previous elegant work used 3D printing with carbohydrate glass as a cytocompatible sacrificial template to create complex engineered tissues with vascular networks (Miller et al. 2012, Nature Materials). The fragile nature of this material compounded with the technical complexity needed to create high-resolution structures led us to create a flexible sugar-protein composite, termed Gelatin-sucrose matrix (GSM), to achieve a more robust and applicable material. Here we developed a low-range (25-37˚C) temperature sensitive formulation that can be moulded with micron-resolution features or cast during 3D printing to produce complex flexible filament networks forming sacrificial vessels. Using the temperature-sensitivity, we could control filament degeneration meaning GSM can be used with a variety of matrices and crosslinking strategies. Furthermore by incorporation of biocompatible crosslinkers into GSM directly, we could create thin endothelialized vessel walls and generate patterned tissues containing multiple matrices and cell-types. We also demonstrated that perfused vascular channels sustain metabolic function of a variety of cell-types including primary human cells. Importantly, we were able to construct vascularized human noses which otherwise would have been necrotic. Our material can now be exploited to create human-scale tissues for regenerative medicine applications. STATEMENT OF SIGNIFICANCE: Authentic and engineered tissues have demands for mass transport, exchanging nutrients and oxygen, and therefore require vascularization to retain viability and inhibit necrosis. Basic vascular networks must be included within engineered tissues intrinsically. Yet, this has been unachievable in physiologically-sized constructs with tissue-like cell densities until recently. Sacrificial moulding is an alternative in which networks of rigid lattices of filaments are created to prevent subsequent matrix ingress. Our study describes a biocompatible sacrificial sugar-protein formulation; GSM, made from mixtures of inexpensive and readily available bio-grade materials. GSM can be cast/moulded or bioprinted as sacrificial filaments that can rapidly dissolve in an aqueous environment temperature-sensitively. GSM material can be used to engineer viable and vascularized human-scale tissues for regenerative medicine applications.

Multi-material 3D bioprinting of porous constructs for cartilage regeneration.

The current gold standard for nasal reconstruction after rhinectomy or severe trauma includes transposition of autologous cartilage grafts in conjunction with coverage using an autologous skin flap. Harvesting autologous cartilage requires a major additional procedure that may create donor site morbidity. Major nasal reconstruction also requires sculpting autologous cartilages to form a cartilage framework, which is complex, highly skill-demanding and very time consuming. These limitations have prompted facial reconstructive surgeons to explore different techniques such as tissue engineered cartilage. This work explores the use of multi-material 3D bioprinting with chondrocyte-laden gelatin methacrylate (GelMA) and polycaprolactone (PCL) to fabricate constructs that can potentially be used for nasal reconstruction. In this study, we have investigated the effect of 3D manufacturing parameters including temperature, needle gauge, UV exposure time, and cell carrier formulation (GelMA) on the viability and functionality of chondrocytes in bioprinted constructs. Furthermore, we printed chondrocyte-laden GelMA and PCL into composite constructs to combine biological and mechanical properties. It was found that 20% w/v GelMA was the best concentration for the 3D bioprinting of the chondrocytes without comprising the scaffold's porous structure and cell functionality. In addition, the 3D bioprinted constructs showed neocartilage formation and similar mechanical properties to nasal alar cartilage after a 50-day culture period. Neocartilage formation was also observed in the composite constructs evidenced by the presence of glycosaminoglycans and collagen type II. This study shows the feasibility of manufacturing neocartilage using chondrocytes/GelMA/PCL 3D bioprinted porous constructs which could be applied as a method for fabricating implants for nose reconstruction.

Ex Vivo Conjunctival Retention and Transconjunctival Transport of Poorly Soluble Drugs Using Polymeric Micelles.

This paper addresses the problem of ocular delivery of lipophilic drugs. The aim of the paper is the evaluation of polymeric micelles, prepared using TPGS (d-α-Tocopheryl polyethylene glycol 1000 succinate), a water-soluble derivative of Vitamin E and/or poloxamer 407, as a vehicle for the ocular delivery of dexamethasone, cyclosporine, and econazole nitrate. The research steps were: (1) characterize polymeric micelles by dynamic light scattering (DLS) and X-ray scattering; (2) evaluate the solubility increase of the three drugs; (3) measure the in vitro transport and conjunctiva retention, in comparison to conventional vehicles; (4) investigate the mechanisms of enhancement, by studying drug release from the micelles and transconjunctival permeation of TPGS; and (5) study the effect of micelles application on the histology of conjunctiva. The data obtained demonstrate the application potential of polymeric micelles in ocular delivery, due to their ability to increase the solubility of lipophilic drugs and enhance transport in and across the conjunctival epithelium. The best-performing formulation was the one made of TPGS alone (micelles size ≈ 12 nm), probably because of the higher mobility of these micelles, an enhanced interaction with the conjunctival epithelium, and, possibly, the penetration of intact micelles.