Drug-loaded Fibers Research Articles

Interactions between Chloramphenicol, Carrier Polymers, and Bacteria-Implications for Designing Electrospun Drug Delivery Systems Countering Wound Infection.

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 of alginate/soy protein isolated nanofibers and their release characteristics for biomedical applications

Abstract Natural polymer-based nanofibers with functions of loading and releasing bioactive cues or drugs have recently gained interest for biomedical applications. Nanotopography and large surface area to volume ratio of hydrophilic polymer fibers promote their use as carriers of hydrophilic drugs. Here, sodium alginate (SA) and soy protein isolated (SPI) blended fibers encapsulated with vancomycin were fabricated via electrospinning with the assistance of poly(ethylene oxide) (PEO). Morphological results showed submicron-sized, smooth and uniform as-spun SA/PEO/SPI fibers with an average diameter of 200 nm. Beads on the fiber mats were formed with increasing SPI content in the blending system. The optimal polymer composition of the electrospinning solution was determined as 5.6/2.4/2 SA/PEO/SPI. Polymer blends were maintained after ionic “cross-linking”, as indicated by the FTIR result. Investigation of release characteristic of vancomycin-loaded SA/PEO/SPI electrospun fibers exhibited initial burst release followed by a controlled release after 2 days of immersion in a phosphate buffered saline. The release rate of SA/PEO/SPI fibers was significantly slower than that of SA/PEO fibers, and drug-loaded fibers inhibited bacterial growth against Staphylococcus aureus after 24 h of incubation. Non-toxicity and biocompatibility of the fibers were confirmed by an indirect cytotoxicity test using human dermal fibroblasts. These results suggest that the vancomycin-loaded SA/PEO/SPI blended fibers are a promising nanomaterial for use in biomedical fields such as scaffolds for tissue engineering and drug delivery systems.

Melt electrospinning of daunorubicin hydrochloride-loaded poly (ε-caprolactone) fibrous membrane for tumor therapy

Daunorubicin hydrochloride is a cell-cycle non-specific antitumor drug with a high therapeutic effect. The present study outlines the fabrication of daunorubicin hydrochloride-loaded poly (ε-caprolactone) (PCL) fibrous membranes by melt electrospinning for potential application in localized tumor therapy. The diameters of the drug-loaded fibers prepared with varying concentrations of daunorubicin hydrochloride (1, 5, and 10 wt%) were 2.48 ± 1.25, 2.51 ± 0.78, and 2.49 ± 1.58 μm, respectively. Fluorescence images indicated that the hydrophobic drug was dispersed in the hydrophilic PCL fibers in their aggregated state. The drug release profiles of the drug-loaded PCL melt electrospun fibrous membranes were approximately linear, with slow release rates and long-term release periods, and no observed burst release. The MTT assay was used to examine the cytotoxic effect of the released daunorubicin hydrochloride on HeLa and glioma cells (U87) in vitro. The inhibition ratios of HeLa and glioma cells following treatment with membranes prepared with 1, 5, and 10 wt% daunorubicin hydrochloride were 62.69%, 76.12%, and 85.07% and 62.50%, 77.27%, and 84.66%, respectively. Therefore, PCL melt electrospun fibrous membranes loaded with daunorubicin hydrochloride may be used in the local administration of oncotherapy.

Nanosized sustained-release drug depots fabricated using modified tri-axial electrospinning.

Nanoscale drug depots with a drug reservoir surrounded by a carrier are highly attractive in biomedicine. A cellulose acetate based drug depot was investigated in detail, starting with the design of the nanostructure, and moving through its fabrication using a modified tri-axial electrospinning process and a series of characterizations. The core-shell fiber-based drug depots can provide a more sustained release profile with no initial burst effect and less tailing-off than equivalent monolithic drug-loaded fibers. The drug release mechanisms are also distinct in the two systems. This proof-of-concept work can be further expanded to conceive a series of new structural biomaterials with improved or new functional performance.

New spin on drug-loaded composite fibers

New spin on drug-loaded composite fibers

Rapidly Biodegrading PLGA-Polyurethane Fibers for Sustained Release of Physicochemically Diverse Drugs.

Sustained release of physicochemically diverse drugs from electrospun fibers remains a challenge and precludes the use of fibers in many medical applications. Here, we synthesize a new class of polyurethanes with poly(lactic-co-glycolic acid) (PLGA) moieties that degrade faster than polyurethanes based on polycaprolactone. The new polymers, with varying hard to soft segment ratios and fluorobenzene pendant group content, were electrospun into nanofibers and loaded with four physicochemically diverse small molecule drugs. Polymers were characterized using GPC, XPS, and 19F NMR. The size and morphology of electrospun fibers were visualized using SEM, and drug/polymer compatibility and drug crystallinity were evaluated using DSC. We measured in vitro drug release, polymer degradation and cell-culture cytotoxicity of biodegradation products. We show that these newly synthesized PLGA-based polyurethanes degrade up to 65-80% within 4 weeks and are cytocompatible in vitro. The drug-loaded electrospun fibers were amorphous solid dispersions. We found that increasing the hard to soft segment ratio of the polymer enhances the sustained release of positively charged drugs, whereas increasing the fluorobenzene pendant content caused more rapid release of some drugs. In summary, increasing the hard segment or fluorobenzene pendant content of segmented polyurethanes containing PLGA moieties allows for modulation of physicochemically diverse drug release from electrospun fibers while maintaining a biologically relevant biodegradation rate.

A Luteolin-Loaded Electrospun Fibrous Implantable Device for Potential Therapy of Gout Attacks

The recurrence of acute gout attacks remains an unsolved problem in clinical therapy. In order to tackle this problem, poly(ε-caprolactone) (PCL)/gelatin composite fibrous devices loaded with luteolin are presented via electrospinning for the therapy of gout and its recurrence. The luteolin-loaded fibrous device has the capability of inhibiting metabolic activities and reducing inflammation-associated cytokine productions (TNF-a, IL-1β, IL-6) that are secreted by lipopolysaccharide stimulated RAW 264.7 macrophages. The device can also suppress the reaction activities of xanthine oxidase for 7 d in vitro. In vivo, acute gout model is established by injecting monosodium urate (MSU) crystals into New Zealand rabbits' knees, then the luteolin-loaded PCL/gelatin (5:5) nanofiber device is implanted near the gout sites. The results show that the device can alleviate the acute gouty arthritis. In the mean time, the luteolin-loaded PCL fiber device with a longer drug release profile is implanted in a recurrent gout model, which is constructed by injecting MSU crystals into rabbits' knees three times. The results on day 21 reveal that this device has the potential to overcome the recurrence of gout. Therefore, the drug-loaded polymer fiber device can be an inspiration for potential gout therapy to overcome recurrent attacks.

Electrospun Gelatin Fibers with a Multiple Release of Antibiotics Accelerate Dermal Regeneration in Infected Deep Burns.

Electrospun fibers of hydrophilic polymers meet challenges in a rapid degradation of fiber matrices and discharge of antibiotics to comply with requirements of infection control as a dermal regeneration template. In the current study, a pH conversion process is initially developed to ensure fluent electrospinning, an efficient in situ cross-linking of electrospun gelatin fibers with oxidized alginate and simultaneous loading of gentamicin sulfate (GS) and hydrophobic ciprofloxacin into fibers. The dual drug-loaded fibers indicate a complete release of GS during 6 d and a sustained release of ciprofloxacin for over three weeks, and the antibiotics release indicates significant growth inhibitions on Pseudomonas aeruginosa and Staphylococcus epidermidis. The wound healing efficacy is evaluated on a deep burn model infected with 10(8) CFU of P. aeruginosa. Compared with fibers with loaded individual drugs, the concomitant release of GS and ciprofloxacin significantly reduces the bacteria numbers in wound and livers, at around 2.30 × 10(5) and 1.25 × 10(3) CFU after 3 d, respectively. The wound re-epithelization, blood vessel formation, collagen deposition, and tissue remodeling process are accelerated with a complete healing observed after 21 d. This study provides a feasible strategy to design cross-linked hydrophilic fibers with an extended drug release for biomedical applications.

Hollow polycaprolactone composite fibers for controlled magnetic responsive antifungal drug release

Hollow magnetic fibers for trigger based drug release were synthesized using one-step co-axial electrospinning (COX-ES). This was achieved by encapsulating the antifungal active ‘ketoconazole’ (KCZ) and iron oxide (Fe3O4) nanoparticles (NPs) in composite form within the core shell polymeric matrix material (polycaprolactone, PCL) during the COX-ES process. Dimethyl silicone oil was used as the inner core (liquid) of co-flowing solutions, which subsequently perfused out of the two-phase electrospun microstructures to form hollow fibers. Resulting drug-loaded magnetic hollow fibers were characterized using optical microscopy, scanning electron microscopy and Fourier Transform Infra-Red. The tensile strength and magnetization properties of composite fibers were also assessed. KCZ drug concentration in electrospinning solutions strongly influenced resulting fiber morphology, drug loading efficiency and release. Expedited drug release during a slow-sustained phase was demonstrated through the application of an auxiliary magnetic field. Variations in tensile strength (∼1.3–6.3MPa) were due to composite fiber components compromising polymer chain integrity. In-vitro cell studies (using human cervical carcinoma cell lines) demonstrated fiber biocompatibility. The present study demonstrates the potential application of magnetic hollow fibers for controlled treatment of fungal infections and antimicrobial indications.

Time-programmed DCA and oxaliplatin release by multilayered nanofiber mats in prevention of local cancer recurrence following surgery

Local recurrence following surgery in cancer treatment remains a major clinical challenge. To increase antitumor activity but maintain toxicity in an acceptable level in prevention of local cancer recurrence, we demonstrated a dual drug-loaded multilayered fiber mats strategy, in which DCA and oxaliplatin were co-electrospun into the distinct layer of resultant fabrics and the oxaliplatin-loaded fibers layer was sealed between the basement film layer and other two fibers layers. The dual drug-loaded multilayered fiber mats exhibit time-programmed dual release behavior and synergistic effect upon cancer cells. Nontoxic DCA selectively promotes apoptosis of cancer cells through modulating cellular metabolism, and oxaliplatin subsequently kills the remained cancer cells in a low concentration. After implantation on the resection margin of cervical carcinoma on a murine model, the dual drug-loaded multilayered fiber mats displayed enhanced anti-recurrence efficacy and decreased side toxic effects over 30days compared with drug-loaded monolayered fiber mats. The time-programmed combination of DCA and oxaliplatin within multilayered nanofiber mats appears to be a promising strategy for local cancer treatment following resection.

Surfactant-assisted water exposed electrospinning of novel super hydrophilic polycaprolactone based fibers

Hybrid scaffolds prepared by blend electrospinning of Polycaprolactone and Pluronic solution benefit from enhanced fiber hydrophilicity and may offer satisfactory cell attachment and proliferation. To improve hybrid scaffold wettability and water swelling ratio, adequate amount of hydrophilic polymer is required; though this amount is limited by fiber surface enrichment of Pluronic and cannot be exceeded without affecting the scaffold mechanical properties. To overcome this problem, a routine blend electrospinning setup was modified by exposing the blend solution to water in order to attract Pluronic chains toward the surface of the charged jet. Morphology of scaffolds produced by the routine blend electrospinning and modified method was studied. A 50 nm thick Pluronic layer with linty appearance on the surface of the fibers fabricated by the modified method was detected. Drug-loaded fibers from modified method showed a moderate initial burst and then a prolonged release period while an abnormal two-stage phased release profile was observed for the routine blend method. The latter was associated to Pluronic/drug accumulations within the fibers fabricated by the routine method which resulted in fiber disintegration and a subsequent second burst release.

Preparation and characterization of naproxen-loaded electrospun thermoplastic polyurethane nanofibers as a drug delivery system

The design and production of drug-loaded nanofiber based materials produced by electrospinning is of interest for use in innovative drug delivery systems. In the present study, ultra-fine fiber mats of thermoplastic polyurethane (TPU) containing naproxen (NAP) were successfully prepared by electrospinning from 8 and 10% (w/w) TPU solutions. The amount of NAP in the solutions was 10 and 20% based on the weight of TPU. The collection period of the drug-loaded electrospun TPU fibers was 5, 10 and 20h, and they were characterized by FTIR, DSC and TGA analysis. The morphology of the NAP-loaded electrospun TPU fiber mats was smooth, and the average diameters of these fibers varied between 523.66 and 723.50nm. The release characteristics of these fiber mats were determined by the total immersion method in the phosphate buffer solution at 37°C. It was observed that the collection period in terms of the mat thickness played a major role in the release rate of NAP from the electrospun TPU mats.

AC and DC electrospinning of hydroxypropylmethylcellulose with polyethylene oxides as secondary polymer for improved drug dissolution

Alternating current electrospinning (ACES) capable to reach multiple times higher specific productivities than widely used direct current electrospinning (DCES) was investigated and compared with DCES to prepare drug-loaded formulations based on one of the most widespread polymeric matrix used for commercialized pharmaceutical solid dispersions, hydroxypropylmethylcellulose 2910 (HPMC). In order to improve the insufficient spinnability of HPMC (both with ACES and DCES) polyethylene oxide (PEO) as secondary polymer with intense ACES activity was introduced into the electrospinning solution. Different grades of this polymer used at as low concentrations in the fibers as 0.1% or less enabled the production of high quality HPMC-based fibrous mats without altering its physicochemical properties remarkably. Increasing concentrations of higher molecular weight PEOs led to the thickening of fibers from submicronic diameters to several microns of thickness. ACES fibers loaded with the poorly water-soluble model drug spironolactone were several times thinner than drug-loaded fibers prepared with DCES in spite of the higher feeding rates applied. The amorphous HPMC-based fibers with large surface area enhanced the dissolution of spironolactone significantly, the presence of small amounts of PEO did not affect the dissolution rate. The presented results confirm the diverse applicability of ACES, a novel technique to prepare fibrous drug delivery systems.

Doxorubicin release from optimized electrospun polylactic acid nanofibers

Electrospinning has been known as an efficient method for fabrication of polymer nanofibers. In this study, an electrospun nanofibrous mats based on polylactic acid with a defined release using doxorubicin was developed. The effects of process parameters, such as concentration, distance, applied voltage, temperature and flow rate on the mean diameter of electrospun doxorubicin-loaded polylactic acid nanofibers were investigated. The fiber morphology and mean fiber diameter of prepared nanofibers were investigated by scanning electron microscopy. Differential scanning calorimetry was employed to identify the presence of doxorubicin within nanofibers. Response surface methodology based on a five-level, five-variable central composite design was used to model the average diameter of electrospun polylactic acid/doxorubicin nanofibers. Mean fiber diameter was correlated to these variables by using a polynomial function at a 95% confidence level. The coefficient of determination of the model was found to be 0.93. The predicted fiber diameter was in good agreement with the experimental result. Differential scanning calorimetry results showed that the doxorubicin was loaded into the nanofibers successfully. In vitro drug release in phosphate-buffered solution and acetate buffer for the optimized and non-optimized samples demonstrated that diffusion is the dominant drug release mechanism for drug-loaded fibers. The initial burst release was observed for non-optimized nanofibers compared to optimized nanofibers. Optimized drug-loaded polylactic acid nanofibers could be good candidates for biomedical applications.

Electrospun Poly(N-isopropylacrylamide)/Ethyl Cellulose Nanofibers as Thermoresponsive Drug Delivery Systems

Fibers of poly(N-isopropylacrylamide) (PNIPAAm), ethyl cellulose (EC), and a blend of both were successfully fabricated by electrospinning. Analogous drug-loaded fibers were prepared loaded with ketoprofen (KET). Scanning and transmission electron microscopy showed that the fibers were largely smooth and cylindrical, with no phase separation observed. The addition of KET to the spinning solutions did not affect the morphology of resultant fibers, and no drug particles could be observed to separate from the polymer matrix. X-ray diffraction demonstrated that the drug was present in the amorphous physical form in the fiber matrix. There are significant intermolecular interactions between KET and polymers, as evidenced by IR spectroscopy and molecular modeling. Water contact angle measurements proved that the PNIPAAm and PNIPAAm/EC fibers switched from being hydrophilic to hydrophobic when the temperature was increased through the lower critical solution temperature of 32°C. In vitro drug release studies found that the PNIPAAm/EC blend nanofibers were able to synergistically combine the properties of the 2 polymers, giving temperature-sensitive systems with sustained release properties. In addition, they were established to be nontoxic and suitable for cell growth. This study demonstrates that electrospun-blend PNIPAAm/EC fibers comprise effective and biocompatible materials for drug delivery systems and tissue engineering.

Surface biofunctional drug-loaded electrospun fibrous scaffolds for comprehensive repairing hypertrophic scars

Incorporation of bioactive drugs and biofunctionalization of polyester fibrous scaffolds are essential means to improve their bio-functions and histocompatibility for regenerative medicine. However, it is still a challenge to biofunctionalize such drug carriers via traditional biochemical methods while maintaining their properties without changes in drug activity and loading ratio. Here, we demonstrated a facile approach for biofunctionalization of PLGA fibrous scaffolds with various molecules (i.e., PEG polymer, RGD peptide and bFGF growth factor for cell repellent, adhesion and proliferation, respectively) via mussel-Inspired poly(dopamine) (PDA) coating in aqueous solution. By virtue of the mild and efficient nature of this approach, the drug-loaded PLGA fibers could be easily biofunctionalized and showed negligible effects on the scaffold properties, especially drug activity and loading ratio. Further, in vivo study showed that, a ginsenoside-Rg3-loaded fibrous scaffold functionalized with bFGF growth factor could not only promote the early-stage wound healing in rabbit ear wounds (bio-signal from bFGF), but also inhibit later-stage hypertrophic scars formation (release of Rg3 drug). Therefore, the mussel-inspired method for bio-modification provides a facile and effective strategy to combine drug and bio-function in one system, thus facilitating a synergistic effect of drug-therapy and bio-signal when such biomaterial is used for regenerative medicine.

Tunable Release of Multiclass Anti-HIV Drugs that are Water-Soluble and Loaded at High Drug Content in Polyester Blended Electrospun Fibers.

Sustained release of small molecule hydrophilic drugs at high doses remains difficult to achieve from electrospun fibers and limits their use in clinical applications. Here we investigate tunable release of several water-soluble anti-HIV drugs from electrospun fibers fabricated with blends of two biodegradable polyesters. Drug-loaded fibers were fabricated by electrospinning ratios of PCL and PLGA. Fiber morphology was imaged by SEM, and DSC was used to measure thermal properties. HPLC was used to measure drug loading and release from fibers. Cytotoxicity and antiviral activity of drug-loaded fibers were measured in an in vitro cell culture assay. We show programmable release of hydrophilic antiretroviral drugs loaded up to 40 wt%. Incremental tuning of highly-loaded drug fibers within 24 h or >30 days was achieved by controlling the ratio of PCL and PLGA. Fiber compositions containing higher PCL content yielded greater burst release whereas fibers with higher PLGA content resulted in greater sustained release kinetics. We also demonstrated that our drug-loaded fibers are safe and can sustain inhibition of HIV in vitro. These data suggest that we were able to overcome current limitations associated with sustained release of small molecule hydrophilic drugs at clinically relevant doses. We expect that our system represents an effective strategy to sustain delivery of water-soluble molecules that will benefit a variety of biomedical applications.

Tumor-Triggered Controlled Drug Release from Electrospun Fibers Using Inorganic Caps for Inhibiting Cancer Relapse.

A smart, tumor-trigged, controlled drug release using inorganic "caps" with CO3 (2-) functional groups in electrospun fibers is presented for inhibiting cancer relapse. When the drug-loaded intelligent electrospun fibers encounter pathological acidic environments, the inorganic gates react with the acids and produce CO2 gas, which enables water penetration into the core of the fibers to induce rapid drug release.

Spatial distribution and antitumor activities after intratumoral injection of fragmented fibers with loaded hydroxycamptothecin

There was only a small percentage of drug delivered to tumors after systemic administration, and solid tumors also have many barriers to prevent drug penetration within tumors. In the current study, intratumoral injection of drug-loaded fiber fragments was proposed to overcome these barriers, allowing drug accumulation at the target site to realize the therapeutic efficacy. Fragmented fibers with hydroxycamptothecin (HCPT) loaded were constructed by cryocutting of aligned electrospun fibers, and the fiber lengths of 5 (FF-5), 20 (FF-20), and 50μm (FF-50) could be easily controlled by adjusting the slice thickness. Fragmented fibers were homogeneously dispersed into 2% sodium alginate solution, and could be smoothly injected through 26G1/2 syringe needles. FF-5, FF-20 and FF-50 fiber fragments indicated similar release profiles except a lower burst release from FF-50. In vitro viability tests showed that FF-5 and FF-20 fiber fragments caused higher cytotoxicity and apoptosis rates than FF-50. After intratumoral injection into murine H22 subcutaneous tumors, fragmented fibers with longer lengths indicated a higher accumulation into tumors and a better retention at the injection site, but showed less apparent diffusion within tumor tissues. In addition to the elimination of invasive surgery, HCPT-loaded fiber fragments showed superior in vivo antitumor activities and fewer side effects than intratumoral implantation of drug-loaded fiber mats. Compared with FF-5 and FF-50, FF-20 fiber fragments indicated optimal spatial distribution of HCPT within tumors and achieved the most significant effects on the animal survival, tumor growth inhibition and tumor cell apoptosis induction. It is suggested that the intratumoral injection of drug-loaded fiber fragments provided an efficient strategy to improve patient compliance, allow the retention of fragmented fibers and spatial distribution of drugs within tumor tissues to achieve a low systemic toxicity and an optimal therapeutic efficacy.

Overcoming drug crystallization in electrospun fibers – Elucidating key parameters and developing strategies for drug delivery

For the development of novel therapeutics, uncontrolled crystallization of drugs within delivery systems represents a major challenge. Especially for thin and flexible polymeric systems such as oral films or dermal wound dressings, the formation and growth of drug crystals can significantly affect drug distribution and release kinetics as well as physical storage stability. In this context, electrospinning was introduced as a fabrication technique with the potential to encapsulate drugs within ultrafine fibers by rapid solvent evaporation overcoming drug crystallization during fabrication and storage. However, these effects could so far only be shown for specific drug-polymer combinations and an in-depth understanding of the underlying processes of drug-loaded fiber formation and influencing key parameters is still missing.In this study, we systematically investigated crystal formation of caffeine as a model drug in electrospun fibers comparing different polymers. The solvent polarity was found to have a major impact on the drug crystal formation, whereas only a minor effect was attributed to the electrospinning process parameters.Based on an in-depth understanding of the underlying processes determining drug crystallization processes in electrospun fibers, key parameters could be identified which allow for the rational development of drug-loaded electrospun fibers overcoming drug crystallization.