Electrospinning is a simple and versatile method to produce fibers using charged polymer solutions. As drug delivery systems, electrospun fibers are an excellent choice because of easy drug entrapment, high surface area, morphology control and biomimetic characteristics. Various drugs and biomolecules can be easily encapsulated inside or on fiber surface either during electrospinning or through post-processing of the fibers. Multicomponent fibers have attracted special attention because new

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... erties and morphologies can be easily obtained through the combination of different polymers. The factors that affect the drug release such as construct geometry and thickness, diameter and porosity, composition, crystallinity, swelling capacity, drug loading, drug state, drug molecular weight, drug solubility in the release medium, drug-polymerelectrospinning solvent interactions are discussed. Mathematical models of drug release from electrospun fibers are reviewed and strategies to attain zero-order release and control of burst stage are considered. Finally, some results concerning release control in bicomponent fibers composed of poly(E-caprolactone) and Lutrol F127 (poly(oxyethylene-b-oxypropylene-b-oxyethylene) are presented. The properties of the bicomponent fibers were studied in order to determine the effect of electrospinning processing on crystallinity, hydrophilicity and degradation. Acetazolamide and timolol maleate were loaded in the fibers in different concentrations in order to determine the effect of drug solubility in polymer, drug state, drug loading and fiber composition on morphology, drug distribution and release kinetics. Such electrospun drug eluting fibers can be used as basic elements of various implants and scaffolds for tissue regeneration. Abstract Electrospinning is a simple and versatile method to produce fibers using 5 charged polymer solutions. As drug delivery systems, electrospun fibers are an 6 excellent choice because of easy drug entrapment, high surface area, morphology 7 control and biomimetic characteristics. Various drugs and biomolecules can be 8 easily encapsulated inside or on fiber surface either during electrospinning or 9 through post-processing of the fibers. Multicomponent fibers have attracted special 10 attention because new properties and morphologies can be easily obtained through 11 the combination of different polymers. The factors that affect the drug release such 12 as construct geometry and thickness, diameter and porosity, composition, crys-13 tallinity, swelling capacity, drug loading, drug state, drug molecular weight, drug 14 solubility in the release medium, drug-polymer-electrospinning solvent interac-15 tions are discussed. Mathematical models of drug release from electrospun fibers 16 are reviewed and strategies to attain zero-order release and control of burst stage 17 are considered. Finally, some results concerning release control in bicomponent 18 fibers composed of poly(e-caprolactone) and Lutrol F127 (poly(oxyethylene-b-19 oxypropylene-b-oxyethylene) are presented. The properties of the bicomponent 20 fibers were studied in order to determine the effect of electrospinning processing 21 on crystallinity, hydrophilicity and degradation. Acetazolamide and timolol 22 maleate were loaded in the fibers in different concentrations in order to determine 23 the effect of drug solubility in polymer, drug state, drug loading and fiber composition on morphology, drug distribution and release kinetics. Such elec-25 trospun drug eluting fibers can be used as basic elements of various implants and 26 scaffolds for tissue regeneration. 27 28 1 What is Electrospinning? 29 Electrospinning is a method of producing fibers with diameters ranging from 30 micrometer to nanometer scale by accelerating a jet of charged polymer solution/ 31 melt in an electric field. Recently, this technology has been expanding due to the 32 simplicity of the process and the various materials that can be used. Fibers can be 33 produced from either natural or synthetic polymers. Such fibers have diverse 34 applications including filtration, catalysis, textiles, composite materials, biomed-35 icine (wound dressings, drug delivery, tissue engineering, cosmetics), sensors, 36 electronic devices, liquid crystals, photovoltaic cells and much more [1, 2]. 37 Usually, the experimental set-up consists of a high voltage power supply 38 connecting an electrode with needle-like geometry (through which the polymer 39 solution is ejected) to the collector electrode. The polymer solution is pumped at 40 the desired flow rate using a syringe pump. A diagram presenting the most 41 common electrospinning set-up is shown in Fig. 1. 42 Recent works suggest that the most important mechanism of electrospinning is 43 a rapidly whipping/bending fluid jet [3]. The jet instability is produced by the 44 competition between surface tension and charge repulsion, in which the destabi-45 lizing effect of charge repulsion is responsible for the stretching of the fluid jet and 46 simultaneous decrease in the jet diameter. Surface tension has a stabilizing effect 47 M. V. Natu et al. Layout: T1 Standard SC fiber collection [4]. Several process parameters (voltage, nozzle to collector dis-51 tance, polymer flow rate, spinning environment) and solution parameters (con-52 centration-viscosity, conductivity, surface tension, solvent volatility) can be 53 manipulated in order to obtain the desired properties of the fibers such as fiber 54 diameter and morphology. Moreover, the fibers can be collected with a multitude 55 of collectors producing fiber mats that contain either aligned or unoriented fibers 56 [5]. 57 2 Electrospun Fibers as Drug Delivery Systems 58 Electrospun fibers have been shown to function as drug delivery systems because 59 of high surface area (which enhances mass transfer), similar topography and 60 porosity to the extracellular matrix making them ideal candidates as active 61 implants/scaffolds. The easy control of the macrostructure (oriented or arranged 62 randomly, fiber mat porosity) and the microstructure (individual fiber porosity) 63 will determine both the bulk physico-chemical properties and the biological 64 response to the implant/scaffold. Variuos drugs ranging from low molecular agents 65 to proteins and even cells [6] can be easily encapsulated inside or on the surface of 66 the fibers depending on the application. Some disadvantages include drug loading 67 that is limited by the drug solubility in the electrospining solution or burst effect 68 due to surface deposited drug. 69 Drug delivery systems can be classified according to different criteria [7, 8]. 70 The most common one is to classify with respect to the rate control mechanism. 71 These classifications may also be applied to drug-containing polymeric fibers: 72 • Drug diffusion controlled systems: diffusion can take place either through the 73 bulk polymer as in bicomponent mixed fibers or through a barrier as in core-74 shell fibers 75 • Solvent diffusion controlled systems: drug release is determined by the rate of 76 polymer swelling 77 • Chemically controlled systems: either polymer erosion or enzymatic/hydrolytic 78 polymer degradation control the drug release rate 79 • Regulated systems: the application of a magnetic field or another external 80 stimulus can trigger the release (as in composite fibers containing magnetic 81 particles) 82 The active ingredient can be loaded either during electrospinning or during 83 post-processing of the electrospun fibers. In the former case, the drug is either co-84 dissolved with the polymers in the electrospinning solution or the drug is loaded in 85 particles that will be co-electrospun with the polymers [9-11]. The later case 86 includes various modalities of drug loading: fiber soaking in the drug solution, 87 drug impregnation using supercritical fluids technology [12], loading in previously 88 molecular imprinted fibers [13, 14], functionalization of the fiber surface through 89 grafting copolymerization [15] and subsequent drug/protein binding [16, 17]. By electrospinning, the drug is usually entrapped as solid particles inside or on 91 the surface of the fibers. According to the type of solid-solid or polymer-drug 92 mixture, the drug loaded fibers can be classified as: 93 • Solid solutions: the drug is dissolved at molecular level in the polymer 94 • Solid dispersions: the drug is distributed in the polymer as either crystalline or 95 amorphous aggregates 96 • Phase-separated systems or reservoir systems: the drug is contained inside the 97 core of the fiber or encapsulated in particles, that are surrounded by a polymer 98 shell (as in core-shell constructs or composite fibers, see Sect. 2.1) 99 2.1 Multicomponent Fibers 100 Multicomponent fibers have attracted special attention because new properties can 101 be obtained through the combination of different materials. Synthetic polymers 102 with good processability and good mechanical properties can be mixed with 103 natural hydrophilic polymers producing an increase in cellular attachment and 104 biocompatibility [5]. Unfortunately, sometimes the solvent that is used to dissolve 105 both polymers can damage the structure of the natural polymer or phase separation 106 can worsen the mechanical properties. One possible solution is to incorporate 107 function-regulating biomolecules (DNA, growth factors) in synthetic polymers to 108 increase bioactivity [17] or to modify the structure of the polymer before elec-109 trospinning [18]. 110 Multicomponent fibers can be obtained mainly by two techniques [19, 20] as 111 shown in Fig. 2: electrospinning of polymers solution in a single-needle config-112 uration (if a mixture of polymers is co-dissolved in the electrospinning solution) or 113 a multi-needle configuration (in which the polymer solutions are separated in 114 parallel or concentric syringes) and post-treatment of the electrospun fibers (which 115 can include either coating with other inorganic/polymer layers [16, 21], grafting 116 [15], crosslinking [22], chemical vapour deposition [23] or functionalization with 117 other (bio)polymers [17]). 118 In addition to the combination of physico-chemical properties that arise from 119 using various components, there can be obtained a variety of fiber morphologies as 120 presented in Fig. 3 such as core-shell fibers, micro/nanotubes, interpenetrating 121 phase morphologies (matrix dispersed or co-continuous fibers) [24, 25], nanoscale 122 morphologies (spheres, rods, micelles, lamellae, vesicle tubules, and cylinders) 123 obtained by self-assembly of block copolymers [26], multilayers (either with 124 different composition or different fiber diameter) [27, 28]. Moreover, the fiber 125 morphology can be further controlled after electrospinning by selective removal of 126 one component using thermal treatment [29] or dissolution [30]. 127 Many of the fiber constructs are supposed to work as implants/tissue scaffolds 128 besides functioning as drug delivery devices. Good mechanical properties are 129 required in order to preserve the structural integrity of the implant. Crosslinking M. V. Natu et al. Layout: T1 Standard SC 548 3. Hohman, M.M., Shin, M., Rutledge, G., Brenner, M.P.: Electrospinning and electrically 549 forced jets. I. Stability theory. and random polydioxanone-polycaprolactone-silk fibroin-blended scaffolds: geometry for a 554 vascular matrix.