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1. Introduction
One-dimensional nanofibers have found broad applications due to their intrinsic properties and easily tunable features including high aspect ratio, flexible fabrication techniques, functionalities, and large arrays of source materials. Nanofibers have found applications especially in biomedical [1], self-cleaning [2], reinforcement composites [3,4,5,6], sensing [7,8,9], and energy devices [10]. In this review, we mainly focus on detailing the requirements, strategies, and up-to-date developments of biomedical applications of nanofibers in tissue engineering, drug delivery, and wound dressing. In general, the first and foremost requirement for nanofibers to serve as biomaterials is the biocompatibility, so that they will not cause any toxicity or inflammation to the tissue/organ. The nanofibers can be biodegradable or non-biodegradable, depending upon the kind of specific applications they are placed in. Conventionally, they are preferred to be biodegradable so as to avoid the post-removal process after application of the nanofibers into the biological system. Recently, some nanofibers have been found to be inert in the biological system, i.e., they will not cause any immune response/biological reactions or harm to the host organism [11]. Some reviews [1,11,12] have discussed the preparations and applications of nanofibers, but few have been focused on biomedical uses, especially wound dressing. Herein, most recent advances of biomedical applications of nanofibers are reviewed.
2. Methods of Preparing Nanofibers
Currently there are four major techniques available for the preparation of nanofibers: electrospinning [12,28], self-assembly [28,29], phase separation [30,31], and template synthesis [32,33]. Of these, electrospinning is the only one that can produce at a large scale continuous nanofibers for industrial applications [29], while other techniques may generate more sophisticated structures and more versatile functionalities. Nanofibers synthesized by self-assembly and phase separation have had relatively limited studies that explored their application as scaffolds for drug delivery [12].
Figure 1. Electrospinning setup with (a) flat stationary collector; (b) rotating disc collector. Reprinted with permission from [28], Copyright© 2011 Elsevier.
Solution parameters and processing parameters can greatly affect the diameters and morphologies of the electrospun fibers. Solution parameters usually include viscosity, surface tension, and electrical conductivity. They are strongly determined by polymer molecular weight, polymer concentration, solvent and additives [35,36]. If the solution has a very low viscosity, electrospray occurs instead of electrospinning. A very high viscosity is also detrimental for electrospinning. A hard ejection or micro-ribbon will be obtained in this situation. Surface tension is another important parameter in electrospinning. A higher surface tension will increase the bending-instability, thus producing beaded fibers. For conductivity, it can be tuned by adding ionic salts. With a higher conductivity, the electrospun fibers will have a smaller diameter. However, a very high conductivity can largely increase instability, which results in beaded fibers with a broad diameter distribution. Processing parameters usually include high voltage, flow rate, and the tip-to-collector distance.
Figure 2. Application and preparation of electrospun drug loaded nanofibers. Reprinted with permission from [47], Copyright© 2009 SciRes.
Tissue engineering is one of the most desirable techniques for tissue regeneration. Generally, tissue repair is done using autografts or allografts. However, these two tissue repair techniques have their own disadvantages. An alternative to these two techniques is tissue engineering. The basic requirements for tissue engineering are a suitable cell source, optimal biochemical conditions and a biocompatible scaffold [48]. The scaffolds should be biodegradable, biocompatible and should serve as a framework for cell adhesion, proliferation, and differentiation. In general, scaffolds are expected to mimic the activity of extra cellular matrices (ECM). ECM is composed of several fibrous macromolecules with a length/thickness ratio greater than 100.
Unlike electrospinning, which is a top-down method to break down a macroscale liquid into nanoscale fibers, self-assembly is a bottom up technique for the formation of nanofibers. In this technique, individual molecules arrange themselves in certain patterns to form macromolecular nanofibers. The shape of the nanofiber depends upon the structure of the building blocks, i.e., the smaller units of individual molecules participating in self-assembly and the intermolecular forces connecting these molecules [29]. These molecules can assemble into ordered structures like monolayers, super lattices, tubes or honey comb micro porous films, shown in Figure 3 [30].
Figure 3. Scanning electron microscope (SEM) images showing honeycomb-like structures of poly(vinyl acetate) (PVA) and poly(ethylene oxide) (PEO). Reprinted with permission from [30], Copyright© 2011, American Chemical Society.
Patterning on a microscale may extend order in a predictable manner over large areas, expanding properties and performances. Hung et al. [51] used a sonication-assisted solution embossing self-assembly technique to prepare cylindrical 3D peptide amphiphiles (PAs). These self-assembled nanofibers had their alkyl segments in the core and the peptide sequences on the surface. Koga et al. [52] developed shape specific nanofibers with morphologically kinked structures via self-assembly of three armed peptides forming a β-pleated sheet. Rose thorn like nanofiber composites of Polyarylene ether nitriles (PEN) and iron phthalocyanine (FePc) were prepared by Meng et al. [53] using a combination of electrospinning and self-assembly techniques. The electrospun composite fibers were subjected to solvent removal and subsequent temperature treatment to form rose thorn like structures composed of FePc over the PEN nanofiber. Thus the self-assembly technique finds its application in designing novel scaffolds for drug delivery and tissue engineering.
Figure 4. SEM studies of polyhydroxybutyrate (PHB) matrices formation under different solvent addition to the PHB/chloroform solution. Reprinted with permission from [32], Copyright© 2008 Elsevier.
Nanofibers can also be prepared by a template based synthesis; first a nanostructured ceramic or polymeric membrane is prepared to serve as the template, the targeting material is then added in contact with the nanostructure to form nanofibers, and finally the template is removed to leave free nanofibers. Anodized aluminum oxide (AAO) is one of the popular ceramic templates that has been used to synthesize a variety of nanostructured fibers, including conducting polymers [54,55] and carbon [56], metals [57], and other ceramics [58]. Another frequently used ceramic template is silica, which has been used widely in fabrication of polymer nanofibers [33,59].
Figure 5. (a) Transmission electron micrograph (TEM) of a microtomed section of an alumina template membrane showing 70 nm diameter Au nanofibrils within the pores; (b) Transmission electron micrograph of three polypyrrole nanotubules. The outside diameter is ~90 nm; the inside diameter is ~20–30 nm. Adapted with permission from [61], Copyright© 1996 American Chemical Society.
A novel method for production of nanofibers/nanotubes containing living cells was reported which is efficient mechanically and has a low cost. High pressure gas was used to extrude viscous precursors through a microscale spray into air. The sprayed micro-sized droplets had a high velocity and were continuously elongated into uniform nanofibers/nanotubes. Nanofibers containing living cells produced from this method have high survival rate and can be used in bioengineering [62]. In addition, there are several other methods for production of small diameter fibers using high-volume production methods, such as fibrillation, island-in-sea, and the novel melt-blowing system. The fibrillation method is mostly used for the preparation of cellulose nanofibers from two commercial hard and soft wood pulps, which consists of initial refining and subsequent high-pressure homogenization. The process in fibrillation was studied using different microscopy techniques, mechanical testing, and fiber density measurements of cellulose films prepared after different processing stages.
Figure 6. Different modification techniques using (A) plasma treatment (B) surface graft polymerization (C) Co-electrospinning. Reprinted with permission from [72]. Copyright© 2009 Elsevier B.V.
Nanofibers used as a drug delivery carrier need to accomplish two steps; one is to load the drug cargo, and the other is the controlled release of the drugs. Loading drugs into the nanofibers can be achieved via various ways depending on the material choices of the nanofibers; the drug could be loaded through chemical or physical binding between the drug and the nanofiber materials, it can also use the cross-linking of the polymeric nanofiber materials to encapsulate the drugs, and nanofibers can be made into layers with drugs contained inside the layer. Release of drugs in a controlled fashion could be achieved by controlling the nanofiber membrane structure (porosity), thickness of membrane, and membrane biodegradability (time). The high surface area-volume ratio of electrospun scaffolds allows the efficient delivery of a loading drug.