Hyaluronate loaded advanced wound dressing in form of in situ forming hydrogel powders: Formulation, characterization, and therapeutic potential.

In this paper, a blend composed of alginate-pectin-chitosan loaded with sodium hyaluronate in the form of an in situ forming dressing was successfully developed for wound repair applications. This complex polymeric blend has been efficiently used to encapsulate hyaluronate, forming an adhesive, flexible, and non-occlusive hydrogel able to uptake to 15 times its weight in wound fluid, and being removed without trauma from the wound site. Calorimetric and FT-IR studies confirmed chemical interactions between hyaluronate and polysaccharides blend, primarily related to the formation of a polyelectrolytic complex between hyaluronate and chitosan. In vivo wound healing assays on murine models highlighted the ability of the loaded hydrogels to significantly accelerate wound healing compared to a hyaluronic-loaded ointment. This was evident through complete wound closure in <10 days, accompanied by fully restored epidermal functionality and no indications of the site of excision or treatment. Therefore, all these results suggest that hyaluronate-loaded powders could be a very promising conformable dressing in several wound healing applications where exudate is present.

3D printed macroporous scaffolds of PCL and inulin-g-P(D,L)LA for bone tissue engineering applications.

Bone repair and tissue-engineering (BTE) approaches require novel biomaterials to produce scaffolds with required structural and biological characteristics and enhanced performances with respect to those currently available. In this study, PCL/INU-PLA hybrid biomaterial was prepared by blending of the aliphatic polyester poly(ε-caprolactone) (PCL) with the amphiphilic graft copolymer Inulin-g-poly(D,L)lactide (INU-PLA) synthetized from biodegradable inulin (INU) and poly(lactic acid) (PLA). The hybrid material was suitable to be processed using fused filament fabrication 3D printing (FFF-3DP) technique rendering macroporous scaffolds. PCL and INU-PLA were firstly blended as thin films through solvent-casting method, and then extruded by hot melt extrusion (HME) in form of filaments processable by FFF-3DP. The physicochemical characterization of the hybrid new material showed high homogeneity, improved surface wettability/hydrophilicity as compared to PCL alone, and right thermal properties for FFF process. The 3D printed scaffolds exhibited dimensional and structural parameters very close to those of the digital model, and mechanical performances compatible with the human trabecular bone. In addition, in comparison to PCL, hybrid scaffolds showed an enhancement of surface properties, swelling ability, and in vitro biodegradation rate. In vitro biocompatibility screening through hemolysis assay, LDH cytotoxicity test on human fibroblasts, CCK-8 cell viability, and osteogenic activity (ALP evaluation) assays on human mesenchymal stem cells showed favorable results.

In Situ Hydrogel Formulation for Advanced Wound Dressing: Influence of Co-Solvents and Functional Excipient on Tailored Alginate-Pectin-Chitosan Blend Gelation Kinetics, Adhesiveness, and Performance.

Chronic skin wounds affect more than 40 million patients worldwide, representing a huge problem for healthcare systems. This study elucidates the optimization of an in situ gelling polymer blend powder for biomedical applications through the use of co-solvents and functional excipients, underlining the possibility of tailoring microparticulate powder properties to generate, in situ, hydrogels with advanced properties that are able to improve wound management and patient well-being. The blend was composed of alginate, pectin, and chitosan (APC). Various co-solvents (ethanol, isopropanol, and acetone), and salt excipients (sodium bicarbonate and ammonium carbonate) were used to modulate the gelation kinetics, rheology, adhesiveness, and water vapor transmission rate of the gels. The use of co-solvents significantly influenced particle size (mean diameter ranging from 2.91 to 5.05 µm), depending on the solvent removal rate. Hydrogels obtained using ethanol were able to absorb over 15 times their weight in simulated wound fluid within just 5 min, whereas when sodium bicarbonate was used, complete gelation was achieved in less than 30 s. Such improvement was related to the internal microporous network typical of the particle matrix obtained with the use of co-solvents, whereas sodium bicarbonate was able to promote the formation of allowed particles. Specific formulations demonstrated an optimal water vapor transmission rate, enhanced viscoelastic properties, gel stiffness, and adhesiveness (7.7 to 9.9 kPa), facilitating an atraumatic removal post-use with minimized risk of unintended removal. Microscopic analysis unveiled that porous inner structures were influencing fluid uptake, gel formation, and transpiration. In summary, this study provided valuable insights for optimizing tailored APC hydrogels as advanced wound dressings for chronic wounds, including vascular ulcers, pressure ulcers, and partial and full-thickness wounds, characterized by a high production of exudate.

Additive Manufacturing Strategies for Personalized Drug Delivery Systems and Medical Devices: Fused Filament Fabrication and Semi Solid Extrusion.

Novel additive manufacturing (AM) techniques and particularly 3D printing (3DP) have achieved a decade of success in pharmaceutical and biomedical fields. Highly innovative personalized therapeutical solutions may be designed and manufactured through a layer-by-layer approach starting from a digital model realized according to the needs of a specific patient or a patient group. The combination of patient-tailored drug dose, dosage, or diagnostic form (shape and size) and drug release adjustment has the potential to ensure the optimal patient therapy. Among the different 3D printing techniques, extrusion-based technologies, such as fused filament fabrication (FFF) and semi solid extrusion (SSE), are the most investigated for their high versatility, precision, feasibility, and cheapness. This review provides an overview on different 3DP techniques to produce personalized drug delivery systems and medical devices, highlighting, for each method, the critical printing process parameters, the main starting materials, as well as advantages and limitations. Furthermore, the recent developments of fused filament fabrication and semi solid extrusion 3DP are discussed. In this regard, the current state of the art, based on a detailed literature survey of the different 3D products printed via extrusion-based techniques, envisioning future directions in the clinical applications and diffusion of such systems, is summarized.

Floating Ricobendazole Delivery Systems: A 3D Printing Method by Co-Extrusion of Sodium Alginate and Calcium Chloride.

At present, the use of benzimidazole drugs in veterinary medicine is strongly limited by both pharmacokinetics and formulative issues. In this research, the possibility of applying an innovative semi-solid extrusion 3D printing process in a co-axial configuration was speculated, with the aim of producing a new gastro-retentive dosage form loaded with ricobendazole. To obtain the drug delivery system (DDS), the ionotropic gelation of alginate in combination with a divalent cation during the extrusion was exploited. Two feeds were optimized in accordance with the printing requirements and the drug chemical properties: the crosslinking ink, i.e., a water ethanol mixture containing CaCl2 at two different ratios 0.05 M and 0.1 M, hydroxyethyl cellulose 2% w/v, Tween 85 0.1% v/v and Ricobendazole 5% w/v; and alginate ink, i.e., a sodium alginate solution at 6% w/v. The characterization of the dried DDS obtained from the extrusion of gels containing different amounts of calcium chloride showed a limited effect on the ink extrudability of the crosslinking agent, which on the contrary strongly influenced the final properties of the DDS, with a difference in the polymeric matrix toughness and resulting effects on floating time and drug release.

Advanced printable hydrogels from pre-crosslinked alginate as a new tool in semi solid extrusion 3D printing process.

With the aim to overcome alginate shape fidelity issue during the semisolid extrusion 3D printing and matrix collapsing after drying, we speculated that a pre-crosslinking step of the alginate ink-gel with low amount of Ca+2 could improve the hydrogel performance. To verify this, the influence of pre-crosslinker concentration (10-25 mM) on the ink gel rheological properties were studied and flow behaviour and viscoelastic properties were determined. The developed ink gels were fully characterised by DSC and Magnetic Resonance Imaging (MRI). Moreover, extrudability and the shape retention of extruded forms after printing and after drying were studied. The rheological and MRI data, combined with the morphological analysis of printed forms allowed us to identify the relationship between printability, shape retention and shear thinning behaviour of gels, showing good extrudability for all the pre-crosslinked gels with a calcium concentration between 0.15 and 0.25, corresponding to both egg-box dimers and multimers interactions.

Development and analysis of a novel loading technique for FDM 3D printed systems: Microwave-assisted impregnation of gastro-retentive PVA capsular devices.

In this paper, we describe a modular post-printing loading protocol for a 3D printed gastro-retentive drug delivery system. Fused Deposition Modelling (FDM) 3D printing was exploited for the rapid prototyping of a modular floating system (caps-in-cap). Optimized models were produced as blank PVA scaffolds, and a morphological analysis of the FDM printed models was conducted to develop a straightforward protocol for drug-loading. The 3D printed gastro-retentive systems were then subjected to microwave irradiation in oversaturated solutions of anhydrous caffeine for drug loading, and research focused on an analysis of the impact of microwave irradiation on the chemical and physical properties of the polymer and the drug. The drug-loading efficiency, thermal and chemical characteristics of components, the stability of the drug and the morphology of processed printouts are characterised and described. Parameters of this unexplored microwave-assisted post-printing loading technique were evaluated and adequately set up, and the process resulted in the preservation of the polymeric matrix and enhancement of drug loading. Hence, microwave impregnation confirmed its potential in superseding the traditional pre- and post-printing loading methods, such as soaking techniques, being faster and more efficient and providing a new paradigm approach to personalised drug delivery.

Coaxial semi-solid extrusion and ionotropic alginate gelation: A successful duo for personalized floating formulations via 3D printing.

With the aim to fulfill the patient-centered approach of precision medicine, in this research, innovative floating drug delivery systems have been developed through the use of alginate matrix and fully characterized. Particularly, to exploit the ionotropic gelation of alginate, a customized coaxial extruder for Semi-solid Extrusion 3D printing, has been used for the simultaneous dispensing of ink gel (sodium alginate 6% w/v) and crosslinking gel (hydroxyethyl cellulose 3 %w/v, calcium chloride 0.1M and Tween 85 0.1% v/v). The latter also loaded with Propranolol Hydrochloride 12.5%w/v. A novel single-step process gelation for the extemporaneous gelation of loaded oral systems has been therefore developed. These technologically advanced formulations showed high printing reproducibility in manufacturing different models (mass of a single layer 535.41 ± 40.00 mg with an average drug loading efficiency of 85% w/w) and similar release behavior, paving the way for their customization in terms of drug dosages via this pioneering process.

Statistics of work and orthogonality catastrophe in discrete level systems: an application to fullerene molecules and ultra-cold trapped Fermi gases.

The sudden introduction of a local impurity in a Fermi sea leads to an anomalous disturbance of its quantum state that represents a local quench, leaving the system out of equilibrium and giving rise to the Anderson orthogonality catastrophe. The statistics of the work done describe the energy fluctuations produced by the quench, providing an accurate and detailed insight into the fundamental physics of the process. We present here a numerical approach to the non-equilibrium work distribution, supported by applications to phenomena occurring at very diverse energy ranges. One of them is the valence electron shake-up induced by photo-ionization of a core state in a fullerene molecule. The other is the response of an ultra-cold gas of trapped fermions to an embedded two-level atom excited by a fast pulse. Working at low thermal energies, we detect the primary role played by many-particle states of the perturbed system with one or two excited fermions. We validate our approach through the comparison with some photoemission data on fullerene films and previous analytical calculations on harmonically trapped Fermi gases.

Mapping soil gas radon concentration: a comparative study of geostatistical methods.

Understanding soil gas radon spatial variations can allow the constructor of a new house to prevent radon gas flowing from the ground. Indoor radon concentration distribution depends on many parameters and it is difficult to use its spatial variation to assess radon potential. Many scientists use to measure outdoor soil gas radon concentrations to assess the radon potential. Geostatistical methods provide us a valuable tool to study spatial structure of radon concentration and mapping. To explore the structure of soil gas radon concentration within an area in south Italy and choice a kriging algorithm, we compared the prediction performances of four different kriging algorithms: ordinary kriging, lognormal kriging, ordinary multi-Gaussian kriging, and ordinary indicator cokriging. Their results were compared using an independent validation data set. The comparison of predictions was based on three measures of accuracy: (1) the mean absolute error, (2) the mean-squared error of prediction; (3) the mean relative error, and a measure of effectiveness: the goodness-of-prediction estimate. The results obtained in this case study showed that the multi-Gaussian kriging was the most accurate approach among those considered. Comparing radon anomalies with lithology and fault locations, no evidence of a strict correlation between type of outcropping terrain and radon anomalies was found, except in the western sector where there were granitic and gneissic terrain. Moreover, there was a clear correlation between radon anomalies and fault systems.