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Surface porosity of individual electrospun polymeric fibers provides interesting means for controlling fiber behavior for different biomedical applications. In this study porous polycaprolactone (P...

Theophylline (TEO) nanofibers with polyethylene oxide (PEO) were prepared by conventional electrospinning (ES) and novel needleless ultrasound-enhanced electrospinning (USES). They were compared for Young's modulus, elongation at rupture and rupture stress, tabletability and drug release. Placebo (PEO) or drug-loaded (PEO/TEO 90:10) nanofibers were examined by scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and infrared spectroscopy (ATR-FTIR). Nanofibers prepared by USES were thinner than ES nanofibers and drug-loaded nanofibers thinner than placebo. Drug was mostly amorphous and interacted weakly with PEO. Mats generated by USES and also drug-loaded mats demonstrated higher Young's modulus (stiffness) and higher rupture stress. Under compression, USES and drug-loaded nanofibers demonstrated greater compaction work, higher yield pressure (Heckel and K-L models), and produced stronger tablets than ES and placebo respectively. Principal Component Analysis revealed two significant components explaining 91.05% of the variance. The first comprised the compaction work, yield pressure (ductility) and Young's modulus that were positively intercorrelated and elongation at rupture that was correlated negatively. The second comprised the mat rupture stress and tablet breaking load. Drug release from nanofibrous tablets was faster than tablets of physical mixture but there was no difference between the tablets of the two electrospinning methods.

Berberine (BBR) is a poorly water-soluble quaternary isoquinoline alkaloid of plant origin with potential uses in the drug therapy of hypercholesterolemia. To tackle the limitations associated with the oral therapeutic use of BBR (such as a first-pass metabolism and poor absorption), BBR-loaded liposomes were fabricated by ethanol-injection and thin-film hydration methods. The size and size distribution, polydispersity index (PDI), solid-state properties, entrapment efficiency (EE) and in vitro drug release of liposomes were investigated. The BBR-loaded liposomes prepared by ethanol-injection and thin-film hydration methods presented an average liposome size ranging from 50 nm to 244 nm and from 111 nm to 449 nm, respectively. The PDI values for the liposomes were less than 0.3, suggesting a narrow size distribution. The EE of liposomes ranged from 56% to 92%. Poorly water-soluble BBR was found to accumulate in the bi-layered phospholipid membrane of the liposomes prepared by the thin-film hydration method. The BBR-loaded liposomes generated by both nanofabrication methods presented extended drug release behavior in vitro. In conclusion, both ethanol-injection and thin-film hydration nanofabrication methods are feasible for generating BBR-loaded oral liposomes with a uniform size, high EE and modified drug release behavior in vitro.

The hydration of phospholipids, electrospun into polymeric nanofibers and used as templates for liposome formation, offers pharmaceutical advantages as it avoids the storage of liposomes as aqueous dispersions. The objective of the present study was to electrospin and characterize amphiphilic nanofibers as templates for the preparation of antibiotic-loaded liposomes and compare this method with the conventional film-hydration method followed by extrusion. The comparison was based on particle size, encapsulation efficiency and drug-release behavior. Chloramphenicol (CAM) was used at different concentrations as a model antibacterial drug. Phosphatidylcoline (PC) with polyvinylpyrrolidone (PVP), using ethanol as a solvent, was found to be successful in fabricating the amphiphilic composite drug-loaded nanofibers as well as liposomes with both methods. The characterization of the nanofiber templates revealed that fiber diameter did not affect the liposome size. According to the optical microscopy results, the immediate hydration of phospholipids deposited on the amphiphilic nanofibers occurred within a few seconds, resulting in the formation of liposomes in water dispersions. The liposomes appeared to aggregate more readily in the concentrated than in the diluted solutions. The drug encapsulation efficiency for the fiber-hydrated liposomes varied between 14.9 and 28.1% and, for film-hydrated liposomes, between 22.0 and 77.1%, depending on the CAM concentrations and additional extrusion steps. The nanofiber hydration method was faster, as less steps were required for the in-situ liposome preparation than in the film-hydration method. The liposomes obtained using nanofiber hydration were smaller and more homogeneous than the conventional liposomes, but less drug was encapsulated.

Electrospun fiber scaffolds have a huge potential for the successful treatment of infected wounds based on their unique properties. Although several studies report novel drug-loaded electrospun fiber-based biomaterials, many of these do not provide information on their interactions with eukaryotic and bacterial cells. The main aim of this study was to develop antibacterial drug-loaded porous biocompatible polycaprolactone (PCL) fiber scaffolds mimicking the native extracellular matrix for wound healing purposes. Mechanical property evaluation and different biorelevant tests were conducted in order to understand the structure-activity relationships and reveal how the surface porosity of fibers and the fiber diameter affect the scaffold interactions with the living bacterial and eukaryotic fibroblast cells. Cell migration and proliferation assays and antibiofilm assays enabled us to enlighten the biocompatibility and safety of fiber scaffolds and their suitability to be used as scaffolds for the treatment of infected wounds. Here, we report that porous PCL microfiber scaffolds obtained using electrospinning at high relative humidity served as the best surfaces for fibroblast attachment and growth compared to the nonporous microfiber or nonporous nanofiber PCL scaffolds. Porous chloramphenicol-loaded microfiber scaffolds were more elastic compared to nonporous scaffolds and had the highest antibiofilm activity. The results indicate that in addition to the fiber diameter and fiber scaffold porosity, the single-fiber surface porosity and its effect on drug release, mechanical properties, cell viability, and antibiofilm activity need to be understood when developing antibacterial biocompatible scaffolds for wound healing applications. We show that pores on single fibers within an electrospun scaffold, in addition to nano- and microscale diameter of the fibers, change the living cell-fiber interactions affecting the antibiofilm efficacy and biocompatibility of the scaffolds for the local treatment of wounds.

Electrospinning (ES) is a convenient and versatile method for the fabrication of nanofibers and has been utilized in many fields including pharmaceutical and biomedical applications. Conventional ES uses a needle spinneret for the generation of nanofibers and is associated with many limitations and drawbacks (i.e., needle clogging, limited production capacity, and low yield). Needleless electrospinning (NLES) has been proposed to overcome these problems. Within the last two decades (2004–2020), many research articles have been published reporting the use of NLES for the fabrication of polymeric nanofibers intended for drug delivery and biomedical tissue engineering applications. The objective of the present mini-review article is to elucidate the potential of NLES for designing such novel nanofibrous drug delivery systems and tissue engineering constructs. This paper also gives an overview of the key NLES approaches, including the most recently introduced NLES method: ultrasound-enhanced electrospinning (USES). The technologies underlying NLES systems and an evaluation of electrospun nanofibers are presented. Even though NLES is a promising approach for the industrial production of nanofibers, it is a multivariate process, and more research work is needed to elucidate its full potential and limitations.

Hot-melt extruded (HME) filaments are an essential intermediate product for the three- dimensional (3D) printing of drug delivery systems (DDSs) by the fused deposition modelling (FDM) process. The aim of this study was to design novel polymeric 3D-printable HME filaments loaded with active pharmaceutical ingredients (APIs). The physical solid-state properties, mechanical properties, drug release and short-term storage stability of the filaments and 3D-printed DDSs were studied. Physical powder mixtures of polycaprolactone (PCL), plasticizer and API were manually blended, extruded by a single-screw extruder, and printed by a table-top FDM 3D-printing system. The composition of PCL and arabic gum (ARA) enabled the incorporation of 20%, 30% and 40% (w/w) of indomethacin (IND) and theophylline (THEO) into the HME filaments. The uneven distribution of API throughout the filaments impaired 3D printing. The HME filaments loaded with 20% IND or THEO were selected for the further analysis and printing tests (the ratio of PCL, ARA and IND or THEO was 7:1:2, respectively). The IND filaments were yellowish, mechanically strong and flexible, and they had a uniform filament diameter and smooth outer surface. The filaments containing THEO were smooth and off-white. The 3D-printed tablets fabricated from IND or THEO-loaded filaments showed sustained drug release in vitro. The drug release rate, however, significantly increased by changing the geometry of 3D-printed tablets from a conventional tablet structure to an unorthodox lattice ("honeycomb") structure. Overall, the combination of PCL and ARA provides an interesting novel polymeric carrier system for 3D-printable HME filaments and tablets.

Crosslinking is an established treatment to alter the physicochemical and functional properties of polymers through the creation of bonds between the polymer chains. Polymers can be crosslinked via radiation in the presence of photo-initiator. The aim of the present study was to formulate 3D-printed theophylline (THEO) tablets using polyethylene oxide (PEO) as a carrier polymer, and to study the influence of crosslinking on the drug release behavior. The tablets were 3D-printed using the aqueous solution of PEO and THEO (80:20 w/w) with a micro-extrusion-based printing setup. A photo-initiator (4-hydroxybenzophenone) was added into the printing solutions, and the injectability of the solutions was investigated prior to printing. The 3D-printed tablets were crosslinked after printing using ultraviolet (UV) or gamma-radiation, and crosslinking was verified by means of Fourier-transform infrared (FTIR) spectroscopy. The maximum injection force of aqueous printing solutions of PEO and THEO was close to that observed with the pure PEO solution. Increasing the number of printing layers in the 3D-printed tablets resulted in a slower drug release in vitro. Gamma-radiation in a nitrogen environment and UV-crosslinking made the carrier polymer (PEO) less water-soluble, but such crosslinking did not affect the release rate of the tablets. Surprisingly, even faster drug release behavior was found with the crosslinked 3D-printed tablets compared to that of non-crosslinked tablets. More research work is needed on the impact of 3D-printed tablet layering thickness and crosslinking for tailoring drug release behavior.

Artesunate (ART) is proven to have potential anti-proliferative activities, but its instability and poor aqueous solubility limit its application as an anti-cancer drug. The present study was undertaken to develop coaxial electrospraying as a novel technique for fabricating nanoscale drug delivery systems of ART as the core-shell nanostructures.The core-shell nanoparticles (NPs) were fabricated with coaxial electrospraying and the formation mechanisms of NPs were examined. The physical solid state and drug-polymer interactions of NPs were characterized by X-ray powder diffraction (XRPD) and Fourier transform infrared (FTIR) spectroscopy. The effects of materials and electrospraying process on the particle size and surface morphology of NPs were investigated by scanning electron microscopy (SEM). The drug release from NPs was determined in vitro by a dialysis method.The ART/poly(lactic-co-glycolic) acid (PLGA) chitosan (CS) NPs exhibited the mean particle size of 303 ± 93 nm and relatively high entrapment efficiency (80.5%). The release pattern showed an initial rapid release within two hours followed by very slow extended release. The release pattern approached the Korsmeyer-Peppas model.The present results suggest that the core-shell NPs containing PLGA and CS have a potential as carriers in the anticancer drug therapy of ART.

Amorphous solid dispersions (SDs) are a promising approach to improve the dissolution rate of and oral bioavailability of poorly water-soluble drugs. In some cases multi-phase, instead of single-phase, SD systems with amorphous drug are obtained. While it is widely assumed that one-phase amorphous systems are desirable, two-phase systems may still potentially exhibit enhanced stability and dissolution advantages over undispersed systems. The objective of the present study was to understand the solid-state properties of two-phase SDs with amorphous drug and their relation to physical stability. Two different types of excipients for SD formation were used, one being a polymer and the other a small molecule excipient. The supercooled molten SDs of a poorly water-soluble indomethacin (IND) with a graft copolymer, Soluplus® (SOL) and sugar alcohol, xylitol (XYL) were prepared. Supercooled molten SDs of IND with SOL were two-phase glassy suspension in which the amorphous drug was dispersed in an amorphous polymer matrix. A short-term aging of the SDs led to the formation of glassy suspensions where the crystalline drug was dispersed in an amorphous polymer matrix. These were physically stable at room temperature for the time period studied (RT, 23 ± 2 °C), but aging at high-humidity conditions (75% RH) recrystallization to metastable α-IND occurred. Interestingly, the SDs with XYL were two-phase amorphous precipitation systems in which the drug was in an amorphous form in the crystalline sugar alcohol matrix. The SDs of IND and XYL exhibited fast drug recrystallization. In conclusion, the preparation method of two-phase systems via co-melting in association with the rapid quench cooling is a feasible method for the formulation of poorly water-soluble drugs. The physical stability of these two-phase systems, however, is dependent on the carrier material and storage conditions.

We investigated nozzleless ultrasound-enhanced electrospinning (USES) as means to generate nanofibrous drug delivery systems (DDSs) for pharmaceutical and biomedical applications. Traditional electrospinning (TES) equipped with a conventional spinneret was used as a reference method. High-molecular polyethylene oxide (PEO) and chitosan were used as carrier polymers and theophylline anhydrate as a water-soluble model drug. The nanofibers were electrospun with the diluted mixture (7:3) of aqueous acetic acid (90% v/v) and formic acid solution (90% v/v) (with a total solid content of 3% w/v). The fiber diameter and morphology of the nanofibrous DDSs were modulated by varying ultrasonic parameters in the USES process (i.e., frequency, pulse repetition frequency and cycles per pulse). We found that the USES technology produced nanofibers with higher fiber diameter (402 &plusmn, 127 nm) than TES (77 &plusmn, 21 nm). An increase of a burst count in USES increased the fiber diameter (555 &plusmn, 265 nm) and the variation in fiber size. The slight-to-moderate changes in a solid state (crystallinity) were detected when compared the nanofibers generated by TES and USES. In conclusion, USES provides a promising alternative for aqueous-based fabrication of nanofibrous DDSs for pharmaceutical and biomedical applications.

Haemanthamine (HAE) has been proven as a potential anticancer agent. However, the therapeutic use of this plant-origin alkaloid to date is limited due to the chemical instability and poorly water-soluble characteristics of the agent. To overcome these challenges, we developed novel amphiphilic electrospun nanofibers (NFs) loaded with HAE, phosphatidylcholine (PC) and polyvinylpyrrolidone (PVP), and intended for a stabilizing platform (template) of self-assembled liposomes of the active agent. The NFs were fabricated with a solvent-based electrospinning method. The chemical structure of HAE and the geometric properties, molecular interactions and physical solid-state properties of the NFs were investigated using nuclear magnetic resonance (NMR) spectroscopy, scanning electron microscopy (SEM), photon correlation spectroscopy (PCS), Fourier transform infrared (FTIR) spectroscopy, X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC), respectively. An in-house dialysis-based dissolution method was used to investigate the drug release in vitro. The HAE-loaded fibers showed a nanoscale size ranging from 197 nm to 534 nm. The liposomes with a diameter between 63 nm and 401 nm were spontaneously formed as the NFs were exposed to water. HAE dispersed inside liposomes showed a tri-modal dissolution behavior. In conclusion, the present amphiphilic NFs loaded with HAE are an alternative approach for the formulation of a liposomal drug delivery system and stabilization of the liposomes of the present alkaloid.

We utilized an ultrasound enhanced electrospinning (USES) technique to produce a four-layer nanofiber scaffold. In contrast to ordinary electrospinning (ES), in the USES process, acoustic radiation pressure generates a cone at the free surface of the polymer solution (4-wt% polyethylene oxide (PEO); aqueous solution), which replaces the need for the needle employed in traditional ES. The cone shape and size were modified by changing the ultrasound parameters (pulse repetition rate, cycles per pulse, and amplitude) during the electrospinning process. A four-layer sample was generated and imaged using scanning electron microscope. The produced nanofiber construct is the first demonstration of a needle-free electrospinning process featuring accurate control of fiber diameter without changes in the sample chemistry. These kinds of gradient structures could be utilized for generation of precision tailored wound pads.

We present simulation efforts towards trying to understand ultrasound enhanced electrospinning (USES). Compared to traditional electrospinning this method uses ultrasound to produce an acoustic fountain on the free surface of the spinning liquid. This fountain is used as a base for the electrospinning process by applying a high-voltage between a collector plate and the liquid. The simulation predictions for the acoustic fountain height as a function of acoustic power are compared to measured values. Then, the effect of electrostatic deformation of the fountain, when a high-voltage is applied, is studied by simulations as a function of initial fountain height.

Electrospinning is commonly used to produce polymeric nanofibers. Potential applications for such fibers include novel drug delivery systems, tissue engineering scaffolds, and filters. Electrospinning, however, has shortcomings such as needle clogging and limited ability to control the fiber-properties in a non-chemical manner. This study reports on an orifice-less technique that employs high-intensity focused ultrasound, i.e. ultrasound-enhanced electrospinning. Ultrasound bursts were used to generate a liquid protrusion with a Taylor cone from the surface of a polymer solution of polyethylene oxide. When the polymer was charged with a high negative voltage, nanofibers jetted off from the tip of the protrusion landed on an electrically grounded target held at a constant distance from the tip. Controlling the ultrasound characteristics permitted physical modification of the nanofiber topography at will without using supplemental chemical intervention. Possible applications of tailor-made fibers generated by ultrasound-enhanced electrospinning include pharmaceutical controlled-release applications and biomedical scaffolds with spatial gradients in fiber thickness and mechanical properties.

3D fibrous scaffolds have received much recent attention in regenerative medicine. Use of fibrous scaffolds has shown promising results in tissue engineering and wound healing. Here we report the development and properties of a novel fibrous scaffold that is useful for promoting wound healing. A scaffold made of salmon fibrinogen and chitosan is produced by electrospinning, resulting in a biocompatible material mimicking the structure of the native extracellular matrix (ECM) with suitable biochemical and mechanical properties. The scaffold is produced without the need for enzymes, in particular thrombin, but is fully compatible with their addition if needed. Human dermal fibroblasts cultured on this scaffold showed progressive proliferation for 14 days. Split-thickness experimental skin wounds treated and untreated were compared in a 10-day follow-up period. Wound healing was more effective using the fibrinogen-chitosan scaffold than in untreated wounds. This scaffold could be applicable in various medical purposes including surgery, tissue regeneration, burns, traumatic injuries, and 3D cell culture platforms.

Suberin fatty acids (SFAs) isolated from outer birch bark were investigated as an antimicrobial agent and biomaterial in nanofibrous mats intended for wound treatment. Electrospinning (ES) was used in preparing the composite nonwoven nanomats containing chloramphenicol (CAM; as a primary antimicrobial drug), SFAs, and polyvinylpyrrolidone (as a carrier polymer for ES). The X-ray powder diffraction, differential scanning calorimetry, scanning electron microscopy, atomic force microscopy, and texture analysis were used for the physicochemical and mechanical characterization of the nanomats. ES produced nanofibrous mats with uniform structure and with an average fiber diameter ranging from 370 to 425 nm. Microcrystalline SFAs and crystalline CAM were found to undergo a solid-state transformation during ES processing. The ES process caused also the loss of CAM in the final nanofibers. In the texture analysis, the SFAs containing nanofibers exhibited significantly higher maximum detachment force to an isolated pig skin (p < 0.05) than that obtained with the reference nanofibers. CAM exists in an amorphous form in the nanofibers which needs to be taken into account in controlling the physical storage stability. In conclusion, homogeneous composite nanofibrous mats for wound healing can be electrospun from the ternary mixture(s) of CAM, SFAs, and polyvinylpyrrolidone.

The present study introduces a modified melt-electrospinning (MES) method for fabricating the melt-electrospun fibers (MSFs) of a poorly water-soluble drug and carrier polymer. The MES of poorly water-soluble model drug indomethacin (IND) and hydrophilic carrier polymer, Soluplus (R) (SOL) were prepared at a 1:3 drug-polymer weight ratio. Water was used as an external plasticizer to regulate a MES processing temperature and to improve fiber formation. The fiber size, surface morphology, physical solid state, drug-polymer (carrier) interactions, thermal and chemical stability and dissolution behavior of MSFs were investigated. Solid state nuclear magnetic resonance spectroscopy (NMR) was used to measure T1(H-1), and the domain size of IND in MSFs (25-100 nm) was calculated from these results. Solid-state and thermal analysis confirmed the presence of amorphous solid dispersions of IND and SOL. IND was found to be chemically stable during an entire MES process. Only small drug content variability of different MSF batches was detected with high performace liquid chromatography (HPLC). Given findings were verified with the liquid NMR spectroscopy. The dissolution of MSFs was significantly faster than that of physical mixtures (PMs) or pure drug. The enhanced dissolution of MSFs was caused by high surface area, amorphous state of the drug and solubilizing properties of the carrier polymer (SOL).

Printing technologies combined with a computer-aided design (CAD) have found an increasing number of uses in pharmaceutical applications. In extrusion-based printing, the material is forced through a nozzle to form a three-dimensional (3D) structure pre-designed by CAD. The aim of this study was to evaluate the 3D-printability of biocompatible aqueous poly(ethylene oxide) (PEO) gels and to investigate the effects of three formulation parameters on the 3D printing process. The impact of PEO concentration (gel viscosity), printing head speed and printing plate temperature was investigated at three different levels using a full factorial experimental design. The aqueous PEO gels were printed with a bench-top extrusion-based 3D printing system at an ambient room temperature. The viscosity measurements confirmed that the aqueous PEO gels follow a shear-thinning behaviour suitable for extrusion-based printing. Heating the printing plate allowed the gel to dry faster resulting in more precise printing outcome. With the non-heated plate, the gel formed a dumbbell-shaped grid instead of straight lines. Higher concentration and more viscous PEO gels formed the best structured 3D-printed lattices. In conclusion, the accuracy and precision of extrusion-based 3D printing of aqueous PEO gels is highly dependent on the formulation (PEO concentration) and printing parameters (printing head speed, plate temperature). By optimizing these critical process parameters, PEO may be suitable for printing novel drug delivery systems.

Recently, 3D label-free super-resolution profilers based on microsphere-assisted scanning white light interferometry were introduced having vertical resolution of few angstroms (angstrom) and a lateral resolution approaching 100 nm. However, the use of a single microsphere to generate the photonic nanojet (PNJ) limits their field of view. We overcome this limitation by using polymer microfibers to generate the PNJ. This increases the field of view by order of magnitude in comparison to the previously developed solutions while still resolving sub 100 nm features laterally and keeping the vertical resolution in 1 nm range. To validate the capabilities of our system we used a recordable Blu-ray disc as a sample. It features a grooved surface topology with heights in the range of 20 nm and with distinguishable sub 100 nm lateral features that are unresolvable by diffraction limited optics. We achieved agreement between all three measurement devices across lateral and vertical dimensions. The field of view of our instrument was 110 mu m by 2 mu m and the imaging time was a couple of seconds.

Solid dispersions (SDs) hold a proven potential in formulating poorly water-soluble drugs. The present paper investigates the interfacial phenomena associated with the bulk powder flow, water sorption, wetting and dissolution of the SDs prepared by a modified melt and quench-cooling (QC) method. Poorly water-soluble indomethacin (IND) was QC molten with solubilizing graft copolymer (Soluplus (R)) or polyol sugar alcohol (xylitol, XYL). The interfacial interactions of SDs with air/water were found to be reliant on the type (amorphous/crystalline) and amount of the carrier material used. The final SDs were composed of fused agglomerates (SOL) or large jagged particles (XYL) with good wetting and powder flow properties. The initial dissolution of IND was accelerated by both carrier materials studied. The QC molten SDs with amorphous Soluplus (R) significantly improved the dissolution rate of IND at pH 6.8 (79.9 +/- 0.2% at 30 min) compared to that of pure crystalline drug. The substantial improvement in the dissolution rate of IND was in connection with the amorphous state of the drug being stabilized by Soluplus (R) in the QC molten SDs. However, it is evident that a strong H-bond formation between the components in some regions of the QC molten SDs can limit the dissolution of IND. The QC molten two-phase SDs with a polyol carrier (XYL) showed rapid and continuous drug release without reaching a plateau.

Antibacterial drug-loaded electrospun nano- and microfibrous dressings are of major interest as novel topical drug delivery systems in wound care. In this study, chloramphenicol (CAM)-loaded polycaprolactone (PCL) and PCL/poly(ethylene oxide) (PEO) fiber mats were electrospun and characterized in terms of morphology, drug distribution, physicochemical properties, drug release, swelling, cytotoxicity, and antibacterial activity. Computational modeling together with physicochemical analysis helped to elucidate possible interactions between the drug and carrier polymers. Strong interactions between PCL and CAM together with hydrophobicity of the system resulted in much slower drug release compared to the hydrophilic ternary system of PCL/PEO/CAM. Cytotoxicity studies confirmed safety of the fiber mats to murine NIH 3T3 cells. Disc diffusion assay demonstrated that both fast and slow release fiber mats reached effective concentrations and had similar antibacterial activity. A biofilm formation assay revealed that both blank matrices are good substrates for the bacterial attachment and formation of biofilm. Importantly, prolonged release of CAM from drug-loaded fibers helps to avoid biofilm formation onto the dressing and hence avoids the treatment failure.

Electrospinning was introduced as a novel technique for preparing controlled-release (CR) amorphous solid dispersions (SD) and polymeric nanofibers of a poorly water-soluble drug. Piroxicam (PRX) was used as a low-dose poorly-soluble drug and hydroxypropyl methylcellulose (HPMC) as an amorphous-state stabilising carrier polymer in nanofibers. Raman spectroscopy, X-ray powder diffraction (XPRD), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM) were used in the physical characterisation of the CR–SD nanofibers. Special attention was paid on the effects of a polymer and solvent system on the solid-state properties and physical stability of nanofibers. The average dry diameter of the electrospun CR–SD nanofibers ranged from 400 to 600 nm (SEM). PRX existed in amorphous form in the nanofibers immediately after fabrication and after a short-term (3-month) aging at low temperature (6–8 °C/0% RH) and ambient room temperature (22 °C/0% RH). At higher temperature and humidity (30 °C/85% RH), however, amorphous PRX in the nanofibers tended to slowly recrystallise to PRX form III. The electrospun CR–SD nanofibers exhibited a short lag-time, the absence of initial burst release and zero-order linear CR dissolution kinetics. In conclusion, electrospinning can be used to fabricate supersaturating CR–SD nanofibers of PRX and HPMC, and to stabilise the amorphous state of PRX.

Printing technology has been shown to enable flexible fabrication of solid dosage forms for personalized drug therapy. Several methods can be applied for tailoring the properties of the printed pharmaceuticals. In this study, the use of electrospun fibrous substrates in the fabrication of inkjet-printed dosage forms was investigated. A single-drug formulation with lidocaine hydrochloride (LH) and a combination drug system containing LH and piroxicam (PRX) for oromucosal administration were prepared. The LH was deposited on the electrospun and cross-linked gelatin substrates by inkjet printing, whereas PRX was incorporated within the substrate fibers during electrospinning. The solid state analysis of the electrospun substrates showed that PRX was in an amorphous state within the fibers. Furthermore, the results indicated the entrapment and solidification of the dissolved LH within the fibrous gelatin matrix. The printed drug amount (2-3 mg) was in good correlation with the theoretical dose calculated based on the printing parameters. However, a noticeable degradation of the printed LH was detected after a few months. An immediate release (over 85% drug release after 8 min) of both drugs from the printed dosage forms was observed. In conclusion, the prepared electrospun gelatin scaffolds were shown to be suitable substrates for inkjet printing of oromucosal formulations. The combination of electrospinning and inkjet printing allowed the preparation of a dual drug system.

We showed that scanning white light interferometry (SWLI) can provide nanometer depth resolution in 3D topographic analysis of electrospun drug-loaded nanofibrous mats without sample preparation. The method permits rapidly investigating geometric properties (e.g. fiber diameter, orientation and morphology) and surface topography of drug-loaded nanofibers and nanomats. Electrospun nanofibers of a model drug, piroxicam (PRX), and hydroxypropyl methylcellulose (HPMC) were imaged. Scanning electron microscopy (SEM) served as a reference method. SWLI 3D images featuring 29 nm by 29 nm active pixel size were obtained of a 55 μm × 40 μm area. The thickness of the drug-loaded non-woven nanomats was uniform, ranging from 2.0 μm to 3.0 μm (SWLI), and independent of the ratio between HPMC and PRX. The average diameters (n = 100, SEM) for drug-loaded nanofibers were 387 ± 125 nm (HPMC and PRX 1:1), 407 ± 144 nm (HPMC and PRX 1:2), and 290 ± 100 nm (HPMC and PRX 1:4). We found advantages and limitations in both techniques. SWLI permits rapid non-contacting and non-destructive characterization of layer orientation, layer thickness, porosity, and surface morphology of electrospun drug-loaded nanofibers and nanomats. Such analysis is important because the surface topography affects the performance of nanomats in pharmaceutical and biomedical applications.

The aim of this study was to gain understanding about the effects of different solid-state forms of a poorly water-soluble piroxicam on drug dissolution and oral bioavailability in rats. Three different solid-state forms of piroxicam were studied: anhydrate I (AH), monohydrate (MH), and amorphous form in solid dispersion (SD). In addition, the effect of a new polymeric excipient Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer) on oral bioavailability of piroxicam was investigated. Significant differences in the dissolution and oral bioavailability were found between the solid-state forms of piroxicam. Amorphous piroxicam in SD showed the fastest dissolution in vitro and a solid-state transformation to MH in the dissolution medium. Despite the presence of solid-state transformation, SD exhibited the highest rate and extent of oral absorption in rats. Oral bioavailability of other two solid-state forms decreased in the order AH and MH. The use of Soluplus® was found to enhance the dissolution and oral bioavailability of piroxicam in rats. The present study shows the importance of solid-state form selection for oral bioavailability of a poorly water-soluble drug.

Electrospinning was used as a novel technique for fabricating polymeric nanofibers of a serum cholesterol lowering and poorly water-soluble plant sterol, β-sitosterol. Chitosan was used as a stabilizer/carrier polymer. The mean diameters of nanofibers ranged from 150 nm to 218 nm. β-sitosterol was in an amorphous form and homogeneously dispersed in the nanofibers. The β-sitosterol-loaded nanofibers were freely water-soluble and exhibited very short lag-time in releasing the plant sterol. The dissolution was associated with an immediate recrystallization of β-sitosterol in submicron level. In conclusion, electrospinning is a promising future technology for the formulation of poorly water-soluble plant sterols.

Electrospinning is an effective method in preparing polymeric nanofibrous drug delivery systems (DDSs) for topical wound healing and skin burn therapy applications. The aim of the present study was to investigate a new synthetic graft copolymer (Soluplus) as a hydrophilic carrier polymer in electrospinning of nanofibrous DDSs. Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)) was applied in the nonwoven nanomats loaded with piroxicam (PRX) as a poorly water-soluble drug. Raman spectroscopy, X-ray powder diffraction, differential scanning calorimetry, and scanning electron microscopy (SEM) were used in the physical characterization of nanofibrous DDSs. According to the SEM results, the drug-loaded PCL-PVAc-PEG nanofibers were circular in cross-section with an average diameter ranging from 500 nm up to 2 µm. Electrospinning stabilized the amorphous state of PRX. In addition, consistent and sustained-release profile was achieved with the present nanofibrous DDSs at the physiologically relevant temperature and pH applicable in wound healing therapy. In conclusion, electrospinning can be used to prepare nanofibrous DDSs of PCL-PVAc-PEG graft copolymer (Soluplus) and to stabilize the amorphous state of a poorly water-soluble PRX. The use of this synthetic graft copolymer can open new options to formulate nanofibrous DDSs for wound healing.

The neural degeneration caused by spinal cord injury leaves a cavity at the injury site that greatly inhibits repair. One approach to promoting repair is to fill the cavity with a scaffold to limit further damage and encourage regrowth. Injectable materials are advantageous scaffolds because they can be placed as a liquid in the lesion site then form a solid in vivo that precisely matches the contours of the lesion. Fibrin is one type of injectable scaffold, but risk of infection from blood borne pathogens has limited its use. We investigated the potential utility of salmon fibrin as an injectable scaffold to treat spinal cord injury since it lacks mammalian infectious agents and encourages greater neuronal extension in vitro than mammalian fibrin or Matrigel®, another injectable material. Female rats received a T9 dorsal hemisection injury and were treated with either salmon or human fibrin at the time of injury while a third group served as untreated controls. Locomotor function was assessed using the BBB scale, bladder function was analyzed by measuring residual urine, and sensory responses were tested by mechanical stimulation (von Frey hairs). Histological analyses quantified the glial scar, lesion volume, and serotonergic fiber density. Rats that received salmon fibrin exhibited significantly improved recovery of both locomotor and bladder function and a greater density of serotonergic innervation caudal to the lesion site without exacerbation of pain. Rats treated with salmon fibrin also exhibited less autophagia than those treated with human fibrin, potentially pointing to amelioration of sensory dysfunction. Glial scar formation and lesion size did not differ significantly among groups. The pattern and timing of salmon fibrin's effects suggest that it acts on neuronal populations but not by stimulating long tract regeneration. Salmon fibrin clearly has properties distinct from those of mammalian fibrin and is a beneficial injectable scaffold for treatment of spinal cord injury.

Fibrin sealants and topical thrombin preparations are often used for haemostatic and sealing applications in clinical practice. Some of these preparations contain coagulation factors from bovine sources. To minimize the risk of infection and immunogenicity connected with mammalian blood products, proteins derived from the plasma of farmed Atlantic salmon have been considered as an alternative to these mammalian sources. The purpose of this study is to characterize the immunogenicity of salmon fibrin glue in an animal model focusing on crossreactivity of IgG antibodies to host endogenous counterparts. After two immunizations with salmon fibrin glue, rats developed antibodies of IgG and IgM type to both fibrin glue components. Weak crossreactivity to endogenous fibrinogen and thrombin was seen in a subset of rats after the second application of salmon proteins. Coagulation tests showed that salmon fibrin application has no effect on coagulation profiles in mammalian hosts, consistent with previous reports that found no evidence of significant crossreactivity with host proteins. These studies support the potential suitability of salmon fibrin glue for the development of preparations with clinical impact. Before human use can be considered, however, additional data about safety of this preparation in other animal models, including large animal studies, should be obtained.

Fibrin sealants made by polymerization of fibrinogen activated by the protease thrombin have many applications in hemostasis and wound healing. In treatments of acute injury or surgical wounds, concentrated fibrin preparations mimic the initial matrix that normally prevents bleeding and acts as a scaffold for cells that initiate tissue repair. However risks of infectious disease, immunogenic reaction, and the high cost of purified human or other mammalian blood proteins limit widespread use of these materials. Purified coagulation proteins from Atlantic salmon represent a potentially safer, equally effective, and less costly alternative in part because of the low ambient temperature of these farmed animals and the absence of endogenous agents known to be infectious in mammalian hosts. This study reports rheologic measurements of lyophilized salmon fibrinogen and thrombin that demonstrate stability to prolonged storage and gamma irradiation sufficient to reduce viral loads by over five orders of magnitude. Coagulation and immunologic studies in rats and rabbits treated intraperitoneally with salmon fibrin show no deleterious effects on coagulation profiles and no cross reactivity with host fibrinogen or thrombin. The results support the potential of salmon fibrin as an alternative to mammalian proteins in clinical applications.

Polymeric scaffolds formed from synthetic or natural materials have many applications in tissue engineering and medicine, and multiple material properties need to be optimized for specific applications. Recent studies have emphasized the importance of the scaffolds' mechanical properties to support specific cellular responses in addition to considerations of biochemical interactions, material transport, immunogenicity, and other factors that determine biocompatibility. Fibrin gels formed from purified fibrinogen and thrombin, the final two reactants in the blood coagulation cascade, have long been shown to be effective in wound healing and supporting the growth of cells in vitro and in vivo. Fibrin, even without additional growth factors or other components has potential for use in neuronal wound healing in part because of its mechanical compliance that supports the growth of neurons without activation of glial proliferation. This review summarizes issues related to the use of fibrin gels in neuronal cell contexts, with an emphasis on issues of immunogenicity, and considers the potential advantages and disadvantages of fibrin prepared from non-mammalian sources.