Abstract
In recent times, notable advancement has been made in the field of electrospinning for the fabrication of numerous types of nanofiber scaffolds. Due to the ultrathin fiber diameter, electrospun nanofiber scaffolds are considered to be an operational delivery system for biomolecules, genes, as well as drugs due to the high specific surface area and stereological porous structure. Here, we introduce some of methods for the integration of drugs and biomolecules within electrospun nanofiber scaffolds, such as blending, surface modification, coaxial process, and emulsion methods. Then, we describe some important biomedical applications of nanofibers in drug delivery systems along with their suitable examples in transdermal systems and wound dressings, cancer therapy, growth factor delivery, nucleic acid delivery, and stem cell delivery.
Introduction
Electrostatic spinning or electrospinning technology has been used for the fabrication of nanofibers with diameters 10s of nanometers to microns and make nanofiber with properties such as ultrafine nanoscale and nonwoven fibers. There are several approaches to yield nanofibers, such as template synthesis, drawing (Guarino et al. Citation2014, Zhong et al. Citation2011), electrospinning, phase separation (Ma et al. Citation2005, Widmer et al. Citation1998), and self-assembly (Naik et al. Citation2003, Williamson and Coombes Citation2004).
To fabricate drug delivery systems based on this approaches, a drug is combined along with the polymer in the solution to be electrospun. In this procedure, the diameter and morphology of the filaments is determined by three general types of variable: environmental parameters (temperature, humidity, and air velocity in the spinning chamber), equipment-controlled parameters (flow rate of the solution, hydrostatic pressure in the spinneret, applied electric field, and tip-to-collector distance), and solution parameters (solution dielectric constant, conductivity, polymer type and concentration, and surface tension) (Chronakis Citation2005).
Electrospinning methods offer great elasticity in choosing materials for drug delivery applications. By using appropriate polymers, the drug release profile can be personalized either by diffusion followed or diffusion alone by scaffold degradation. Recent studies indicated that all types of drugs, such as anticancer agents, antibiotics, proteins, DNA, and RNA, can be combined into electrospun scaffolds (Chronakis Citation2005, Khan et al. Citation2001). Due to simplicity of their design, these nanofibers were viewed as vectors for drug delivery that improved pharmacokinetic parameters, such as blood residence times, providing an effective means to an end. In this review, first, the mechanisms of drug loading in nanofibers were discussed, and then, the application of nanofiber in drug delivery was categorized in five classes: transdermal systems and wound dressings, cancer therapy, growth-factor delivery, nucleic acid delivery, and stem cell delivery.
Mechanisms of drug loading
Employing different techniques, such as blending, surface modification, coaxial process, and emulsion methods (Zamani et al. Citation2013), there is a great opportunity of incorporating drugs into the nanofibers via electrospinning techniques.
Blending
Among all the advanced approaches for drug loading and integration into nanofibers, blending of the drug with nanofibers and polymeric solutions remains the most principal. For this purpose, the drug is dispersed or dissolved in the polymer solution to prepare encapsulated drug through a one-phase electrospinning technique. With the aim of achieve sustained release, blending and incorporating of hydrophilic/hydrophobic polymers using different polymer blends has been carried out by many investigators, and the observations indicated that addition of hydrophilic polymers, such as polyethylene glycol (PEG) (Cao et al. Citation2010), gelatin (Meng et al. Citation2011), or polyvinyl alcohol (PVA) (Jannesari et al. Citation2011), amphiphilic copolymers such as PEG-b-PLA diblock copolymer (Kim et al. Citation2004) could meaningfully improve drug-loading efficiency and subsequently decrease the eruption release of drugs. The positive interface of polymer and hydrophilic drug might limit the tendency of the drug molecules to transfer to the nanofibers surface (Zamani et al. Citation2010). On the other hand, polymer modification and copolymerization (Cui et al. Citation2008, Rujitanaroj et al. Citation2011) have also been demonstrated to improve the hydrophilic properties of polymeric carriers.
Surface modification
Another favorable technique, for bring together biofunctionality into nanofibers, is surface modification with target biomolecules. Using this method, the therapeutic agent and drugs is conjugated or bound to the nanofiber surfaces, making it biochemically and structurally similar to the natural tissue (Zamani et al. Citation2013). This approach is frequently used to solve the problem of short release time as well as initial burst release (Im et al. Citation2010). In this method, the release capacity of the therapeutics agents and drugs would be decreased, and the functionality of the surface-immobilized biomolecules could be well maintained (Volpato et al. Citation2012). Because of this property, surface modification technique would be more appropriate for growth factor or gene delivery, where a prolonged and slow release of the therapeutic agent and drugs is required .Another application of this method is for the delivery of biomolecules such as enzymes, growth factors (GFs), or DNA that degrade within a few days and lose bioactivity, bioconjugating the biomolecules and drugs to the nanofiber surfaces and gradually releasing them into the neighboring tissue and cells would meaningfully preserve their biofunctionality (Zamani et al. Citation2013).
One of main disadvantage of this technique is drugs that require interaction with the cell nucleus or that are required to be endocytosed cannot be immobilized in this way (Zamani et al. Citation2013). For overcoming this problem, the release rate of immobilized drug molecules could be exactly regulated via introduction of responsive materials to local external cues (Kim and Yoo Citation2010).
As well as immobilization and integration of drug molecules, nanofibers surface modification with several chemical compounds can be used to modify drug-release profiles from drug-integrated nanofibers. As an example, the nanofiber surfaces fluorination caused controlled drug-release rate by presenting hydrophobic functional groups onto the nanofibers surface (Im et al. Citation2010).
Coaxial process
An improved version of electrospinning that permits fabrication of nanofibers with core–shell morphology is coaxial process. Combination of biomolecules, such as DNA, RNA, or drugs, by incorporation with polymer solutions caused localization of DNA, RNA, or drugs molecules on the surface of nanofibers, more willingly than being encapsulated indoors the nanofibers (Luu et al. Citation2003).
Coaxial electrospinning was performed to improve the functionality of biomolecules, where the biomolecule solution shaped the inner jet and it was coelectrospun with a polymer solution that shaped the outer jet (Liao et al. Citation2009).
Compared to the commonly used electrospinning device, one of the main advantage of this method is that the nanofibers are produced from two separate solutions. This property minimize the collaboration between the organic solvents in which the polymer is mainly dissolved and aqueous-based biological molecules (Zamani et al. Citation2013). As a result of this modification, the bioactivity of the unstable biological molecules, such as drugs, can be conserved and can be avoided additional modification processes like lyophilization of plasmid DNA (pDNA) (Saraf et al. Citation2010).
The nanofibers, which produced by coaxial electrospun, presented a novel generation of scaffolds for tissue engineering that can succeed local, efficient and constant growth factor and gene delivery to cells seeded on the scaffold. It was also informed that the growth factors released from these coaxially fabricated nanofibers sustained the same level of bioactivity as fresh growth factors (Liao and Leong Citation2011). Other types of pharmaceutical compounds, such as antioxidant drugs or antibiotic, were also blended into coaxially electrospun nanofibers for different applications.
The main disadvantage of this method is the difficulty in the design and electrohydrodynamic behavior of the process, whereby the viscoelasticity of the two polymers, interfacial tension, and parameters of spinning must be exactly controlled (Yang et al. Citation2008). Compared to electrospinning of polymer solution which contains drug dispersions, the hydrophilic biomolecule is anticipated to be encapsulated inside the nanofibers instead of evading onto the surface of nanofiber using emulsion electrospinning (He et al. Citation2012).
Emulsion
In emulsion electrospinning methods, the aqueous protein or drug solution is blended within a polymer solution, which is mentioned as the oil phase, and after electrospinning, the biomolecule-loaded phase can be dispersed within the nanofibers if a low-molecular-weight drug is used (Xu et al. Citation2005) or form a core–shell nanofibrous structure when macromolecules are integrated in the aqueous phase.
As compared to the conventional blending technique, the main promising advantage of emulsion electrospinning is that the polymer and drug are dissolved in suitable solvents, eliminating the requirement for a common solvent, as well as, several hydrophobic polymeric and hydrophilic drugs combinations can be used, and during this procedure, the drug contact with organic solvent is minimal (Xu et al. Citation2005). But, as compared to coaxial electrospinning, emulsion electrospinning would still result in degradation or damage of unstable macromolecules such as pDNA, undoubtedly because of the interface tension or shearing force between the organic and aqueous phases of the emulsion (He et al. Citation2012, Yang et al. Citation2011).
Another drawback of emulsion electrospinning is that the ultrasonication and emulsification processes would improve the (protein or drug) core contact with the solvent by interference of the aqueous protein droplets, thus improving the possibility of protein or drug damage (Yang et al. Citation2008).
Applications of nanofiber scaffold in delivery systems
Nanofibers have enormous applications: as wound dressing (Riboldi et al. Citation2005), in medicine (Fujihara et al. Citation2005), as protective materials (Blanco et al. Citation2015), in sensor devices, as medical textile materials (Yang et al. Citation2006), in the textile industry, in pigments for cosmetics (Li et al. Citation2002), in filtration system, in energy applications, etc.
Because of the unique properties of nanofibers, it extensively applied for regulating drug delivery from hydrophilic polymers as well as biodegradable in medical therapy. Nanofibers are applied for the delivery of an extensive range of drugs such as water-insoluble drugs, water soluble, poor-water soluble, and macromolecules, such as bioactive proteins and DNA.
Here, we describe some important biomedical applications of nanofibers in drug delivery systems along with their suitable examples in transdermal systems and wound dressings, cancer therapy, growth-factor delivery, nucleic acid delivery, and stem cell delivery.
Transdermal systems and wound dressings
Wound dressings help in shielding the wound from absorbing exudates, external microorganisms, accelerate the wound-healing process, and lastly improving surface manifestation (Khil et al. Citation2003, Zhang et al. Citation2005).
Electrospun nanofibers are good wound-dressing candidate because of very high specific surface area, well interconnectivity, and high porous structure (Garg and Kumar Goyal Citation2012). Nanofibers are used not only for remove extra body fluids from the wound area but also for wound healing.
Cejkova et al (Citation2013) examined that nanofiber scaffolds loaded with rabbit bone marrow derived MSCs effectively lowered apoptotic cell death, reduce alkali-induced oxidative stress in the rabbit cornea, decreased pro-inflammatory, and cytokine matrix metalloproteinase production (Cejkova et al. Citation2013). Nanofibers also assistance in rinsing the exogenous micro-organism and accelerating the healing process (Garg and Goyal Citation2014). Ahire and Dicks (Citation2014) produced nanofibers loading with 2, 3-dihydroxybenzoic acid (DHBA). The data indicated that fabricated nanofibers inhibited cell growth for at least 4 h and could be developed as wound-dressing scaffolds to treat topical infections caused by P. aeruginosa (Ahire and Dicks Citation2014). Fabricated electrospun polymer ultrafine nanofiber scaffolds for the codelivery of green tea polyphenols (GTP) and dexamethasone (DEX) in order to obtain an appropriate balance between effective treatment of keloid and safety to the skin. The histological analysis showed that the GTP/DEX-loaded nanofiber scaffolds meaningfully encourage the degradation of collagen fibers in keloid on the back of nude mice compared with the traditional treatment (Shen et al. Citation2014). Some important applications of nanofibers in transdermal systems and wound dressings are discussed in .
Table 1. Some examples of transdermal systems and wound dressings using nanofiber.
Cancer therapy
The use of electrospun nanofiber scaffolds as drug delivery systems seems to be a promising technique for the delivery of anticancer drugs, particularly in chemotherapy of postoperative local, due to their frequent advantages, such as handling convenience, reduced toxicity, and improved therapeutic effect.
Zeng et al (Citation2003) studied the influence of surfactants and anti-cancer drugs on the diameter and uniformity of electrospun PLLA fibers. Various types of anti-cancer drugs, including doxorubicin hydrochloride (Dox, an anticancer drug) and paclitaxel (PTX, an anticancer drug), were also studied. The results indicated that the anticancer drugs were encapsulated inside the nanofibers and that drug release in the existence of proteinase K followed nearly zero-order kinetics because of the degradation of PLLA nanofibers.
Zeng et al (Citation2005) demonstrated the influence of compatibility and solubility of drugs in the drug–polymer system. PLLA fiber mats were used as carriers to integrate various types of drugs including the anticancer drugs Dox and PTX. The results indicated that there was good compatibility of Dox and PTX with PLLA.
Using water-in-oil emulsion electrospinning, the electrospun amphiphilic PEG-PLLA diblock copolymer fiber mats containing Dox were successfully prepared (Xu et al. Citation2005). The results indicated that in comparison with the suspension electrospun fiber mats, the continuous release of Dox was detected for emulsion–electrospun fiber mats.
1, 3-Bis (2-chloroethyl)-1-nitrosourea (BCNU) is one of the most extensively used antineoplastic agents for the treatment of malignant gliomas (Loo et al. Citation1966). Xu et al assayed the long-term delivery of BCNU using the fabrication of electrospun-biodegradable PEG–PLLA diblock copolymer fiber carrier (Xu et al. Citation2006). These results significantly propose that the BCNU/PEG–PLLA fibers have an effect of controlled release of BCNU and are appropriate for postoperative chemotherapy of cancers. Some important applications of nanofibers in cancer drug delivery and therapy are discussed in .
Table 2. Some examples of cancer drug delivery and therapy using nanofiber.
Growth factor delivery
Growth factor (GF) is one of endogenous proteins with ability to bind cell surface receptors and leading cellular activities elaborate in the regeneration of new tissue (Varkey et al. Citation2004). Delivery of exogenous growth factors to local of interest (depends on the large-scale production of recombinant growth factors) is recommended to be therapeutically effective for the production of cellular components complicated in the healing process and tissue development, thus introducing them significant factors for tissue regeneration and other applications (Chen et al. Citation2010).
Chew et al examined the probability of encapsulating human b-nerve growth factor (NGF) that was stable in the carrier protein, bovine serum albumin (BSA) in a copolymer of ethyl ethylene phosphate and e-caprolactone (Chew et al. Citation2005). The continuous release of NGF by diffusion was gained for at least 3 months.
In one study, Patel et al examined the effects of immobilizing basic fibroblast growth factor (bFGF) onto nanofibers on neurite extension in vitro (Patel et al. Citation2007), and delivering bFGF in a soluble manner, the conjugated nanofibers presented several advantages, such as (1) the electrospun fibrous scaffolds can act as a delivery vehicle for specific targets, without inducing systemic effects, (2) only a small amount of bFGF was required to achieve effects similar to those achieved with soluble bFGF in medium.
Sahoo et al introduced two types of PLGA nanofiber scaffolds integrated with bFGF. These nanofibers were produced using the facile method of electrospinning and blending (group I) and by the more complex method of coaxial electrospinning (group II) (Sahoo et al. Citation2010). Although both scaffold groups favored bone marrow stem cell (BMSC) attachment and consequent proliferation, cells cultured on group I nanofiber scaffolds revealed amplified collagen construction and upregulated gene expression of specific extracellular matrix (ECM) proteins, which as representative of fibroblastic differentiation. The results of this study illustrates that the electrospinning method could be used to extend growth factor release from scaffolds. Some important applications of nanofibers in growth factor delivery are listed in .
Table 3. Some examples of growth factor delivery using nanofiber.
Nucleic acid delivery
Nanofibrous scaffolds introduced as a novel class of potent materials for nucleic acid delivery applications. Saraf et al fabricated the fiber mesh scaffolds using coaxial electrospinning for the encapsulation and subsequent release of a nonviral gene delivery vector over a period of up to 60 days (Schneider et al. Citation2009). In this work, numerous nanofiber mesh scaffolds containing the nonviral gene delivery vector poly (ethylenimine)-hyaluronic acid (PEI-HA) within the sheath of coaxial fibers and plasmid DNA (pDNA) within the core, were produced on the basis of a fractional factorial design that examined the effects of four processing parameters at two levels. The release kinetics of PEIHA from the nanofibers was establish to be affected by the loading concentration of pDNA. The results revealed that complexes of pDNA with PEI-HA released from fiber mesh scaffolds could successfully induces expression of enhanced green fluorescent protein (EGFP) and transfect cells.
Liang et al have introduced a novel core–shell DNA nanoparticle by entreating solvent-induced condensation of pDNA (b-galactosidase or GFP) in a solvent mixture (94% DMF +6% Tris/EDTA buffer) and following encapsulation of the condensed DNA globule in a triblock copolymer, PLLA–PEG–PLLA, in the same solvent environment (Im et al. Citation2010). The data indicated that the polylactide shell shields the encapsulated DNA from degradation during electrospinning of a combination of encapsulated DNA nanoparticles and biodegradable PLGA to form a nanofibrous nonwoven scaffold using the same solution mixture. Some important applications of nanofibers in nucleic acid delivery are listed in .
Table 4. Some examples of nucleic acid delivery using nanofiber.
Stem cell delivery
Deficiency in the selection of a suitable carrier to transfer stem cells to exact tissue location is one of the main problems related to stem cell therapy. For the transfer of stem cells, numerous materials and scaffolds, such as fibrin glue used for cell transfer on the ocular surface (Schwab et al. Citation2006), macroporous hydrogels used to transfer SCs for spinal cord injury repair (Syková et al. Citation2006), polymers and collagen sponges (Rama et al. Citation2001), and self-assembling peptide nanofibers studied for cell-based therapy on infarcted myocardium, have been used (Dubois et al. Citation2008). Some important applications of nanofibers in stem cell delivery are listed in .
Table 5. Some examples of stem cell delivery using nanofiber.
Conclusion
To the best of our knowledge, most of the researches on drug releases and therapeutic use of nanofibers have been carried out in vitro. Many in vivo researches will be necessary before electrospun nanofiber-based drug delivery systems can be taken forward into clinical trials. Although electrospun nanofibers have revealed abundant possibility in drug delivery, there are also an amount of challenges that are yet to be overwhelmed, such as scaling up.
The benefits of engaging electrospinning technology to prepare nanofibers as drug delivery systems are not as yet fully exploited. Nanotechnology is now having a significant impact in medical diagnostics sciences, pharmaceutical, and biotechnology. Biomolecules and drugs can be combined within electrospun nanofiber scaffolds by blending, surface modification, coaxial process, and emulsion methods. Due to simplify in their design, these nanofibers were viewed as vectors for drug delivery that improved pharmacokinetic parameters, such as blood-residence times, providing an effective means to an end (Blanco et al. Citation2015). The mechanisms of drug loading in nanofibers were discussed and then the application of nanofiber in drug delivery were categorized in five classes: Transdermal systems and wound dressings, cancer therapy, growth-factor delivery, nucleic acid delivery, and stem cell delivery. Still several difficulties must be fixed for additional applications, such as the residual organic solvent, the combined usage of new biocompatible polymers, the drug loading, the initial burst effect, and the stability of active agents
Disclosure statement
The authors report no conflicts of interests. The authors alone are responsible for the content and writing of this article.
References
- Ahire JJ, Dicks LM. 2014. 2, 3-Dihydroxybenzoic acid-containing nanofiber wound dressings inhibit biofilm formation by pseudomonas aeruginosa. Antimicrob Agents Chemotherapy. 58:2098–2104.
- Blanco E, Shen H, Ferrari M. 2015. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nature Biotechnol. 33:941–951.
- Cao H, Jiang X, Chai C, Chew SY. 2010. RNA interference by nanofiber-based siRNA delivery system. J Control Release. 144:203–212.
- Cejkova J, Trosan P, Cejka C, Lencova A, Zajicova A, Javorkova E. 2013. Suppression of alkali-induced oxidative injury in the cornea by mesenchymal stem cells growing on nanofiber scaffolds and transferred onto the damaged corneal surface. Exp Eye Res. 116:312–323.
- Chen FM, Zhang M, Wu ZF. 2010. Toward delivery of multiple growth factors in tissue engineering. Biomaterials. 31:6279–6308.
- Chen P, Wu QS, Ding YP, Chu M, Huang ZM, Hu W. 2010. A controlled release system of titanocene dichloride by electrospun fiber and its antitumor activity in vitro. Eur J Pharm Biopharm. 76:413–420.
- Chen M, Gao S, Dong M, Song J, Yang C, Howard KA, Kjems J, Besenbacher F. 2012. Chitosan/siRNA nanoparticles encapsulated in PLGA nanofibers for siRNA delivery. ACS Nano. 6:4835–4844.
- Chew SY, Wen J, Yim EK, Leong KW. 2005. Sustained release of proteins from electrospun biodegradable fibers. Biomacromolecules. 6:2017–2024.
- Chronakis IS. 2005. Novel nanocomposites and nanoceramics based on polymer nanofibers using electrospinning process—a review. J Material Processing Tech. 167:283–293.
- Cui W, Qi M, Li X, Huang S, Zhou S, Weng J. 2008. Electrospun fibers of acid-labile biodegradable polymers with acetal groups as potential drug carriers. Int J Pharm. 361:47–55.
- Dubey P, Bhushan B, Sachdev A, Matai I, Kumar SU, Gopinath P. 2015. Silver‐nanoparticle‐Incorporated composite nanofibers for potential wound‐dressing applications. J ApplPolymer Sci. 132:1–12.
- Dubois G, Segers VF, Bellamy V, Sabbah L, Peyrard S, Bruneval P. 2008. Self‐assembling peptide nanofibers and skeletal myoblast transplantation in infarcted myocardium. J Biomed Mater Res B: Appl Biomater. 87:222–228.
- Fujihara K, Kotaki M, Ramakrishna S. 2005. Guided bone regeneration membrane made of polycaprolactone/calcium carbonate composite nano-fibers. Biomaterials. 26:4139–4147.
- Garg T, Goyal AK. 2014. Liposomes: targeted and controlled delivery system. Drug Delivery Lett. 4:62–71.
- Garg T, Kumar Goyal A. 2012. Iontophoresis: drug delivery system by applying an electrical potential across the skin. Drug Delivery Lett. 2:270–280.
- Gil ES, Panilaitis B, Bellas E, Kaplan DL. 2013. Functionalized silk biomaterials for wound healing. Adv Healthc Mater. 2:206–217.
- Guarino V, Cirillo V, Altobelli R, Ambrosio L. 2014. Polymer-based platforms by electric field-assisted techniques for tissue engineering and cancer therapy. Expert Rev Med Devices. 12:113–129.
- He S, Xia T, Wang H, Wei L, Luo X, Li X. 2012. Multiple release of polyplexes of plasmids VEGF and bFGF from electrospun fibrous scaffolds towards regeneration of mature blood vessels. Acta Biomater. 8:2659–2669.
- Im JS, Bai BC, Lee YS. 2010. The effect of carbon nanotubes on drug delivery in an electro-sensitive transdermal drug delivery system. Biomaterials. 31:1414–1419.
- Im JS, Yun J, Lim YM, Kim HI, Lee YS. 2010. Fluorination of electrospun hydrogel fibers for a controlled release drug delivery system. Acta Biomater. 6:102–109.
- Jannesari M, Varshosaz J, Morshed M, Zamani M. 2011. Composite poly (vinyl alcohol)/poly (vinyl acetate) electrospun nanofibrous mats as a novel wound dressing matrix for controlled release of drugs. Int J Nanomedicine. 6:993–1003.
- Jin G, Prabhakaran MP, Kai D, Annamalai SK, Arunachalam KD, Ramakrishna S. 2013. Tissue engineered plant extracts as nanofibrous wound dressing. Biomaterials. 34:724–734.
- Jung SM, Yoon GH, Lee HC, Shin HS. 2015. Chitosan nanoparticle/PCL nanofiber composite for wound dressing and drug delivery. J Biomater Sci Polym Ed. 26:252–263.
- Khan SP, Bhasin K, Newaz GM. 2001. Optimizing process variables to control fiber diameter of electrospun polycaprolactone nanofiber using factorial design. In MRS Proceedings. Cambridge, United Kingdom: Cambridge Univ Press.
- Khil MS, Cha DI, Kim HY, Kim IS, Bhattarai N. 2003. Electrospun nanofibrous polyurethane membrane as wound dressing. J Biomed Mater Res Part B Appl Biomater. 67:675–679.
- Kim HS, Yoo HS. 2010. MMPs-responsive release of DNA from electrospun nanofibrous matrix for local gene therapy: in vitro and in vivo evaluation. J Control Release. 145:264–271.
- Kim H, Yoo H. 2013. Matrix metalloproteinase-inspired suicidal treatments of diabetic ulcers with siRNA-decorated nanofibrous meshes. Gene Ther. 20:378–385.
- Kim K, Luu YK, Chang C, Fang D, Hsiao BS, Chu B, Hadjiargyrou M. 2004. Incorporation and controlled release of a hydrophilic antibiotic using poly (lactide-co-glycolide)-based electrospun nanofibrous scaffolds. J Control Release. 98:47–56.
- Kim TH, Kim JJ, Kim HW. 2014. Basic fibroblast growth factor-loaded, mineralized biopolymer-nanofiber scaffold improves adhesion and proliferation of rat mesenchymal stem cells. Biotechnology Lett. 36:383–390.
- Li WJ, Laurencin CT, Caterson EJ, Tuan RS, Ko FK. 2002. Electrospun nanofibrous structure: a novel scaffold for tissue engineering. J Biomed Mater Res. 60:613–621.
- Li WJ, Danielson KG, Alexander PG, Tuan RS. 2003. Biological response of chondrocytes cultured in three‐dimensional nanofibrous poly (ε‐caprolactone) scaffolds. J Biomed Mater Res A. 67:1105–1114.
- Li C, Vepari C, Jin HJ, Kim HJ, Kaplan DL. 2006. Electrospun silk-BMP-2 scaffolds for bone tissue engineering. Biomaterials. 27:3115–3124.
- Liao IC, Leong KW. 2011. Efficacy of engineered FVIII-producing skeletal muscle enhanced by growth factor-releasing co-axial electrospun fibers. Biomaterials. 32:1669–1677.
- Liao IC, Chen S, Liu JB, Leong KW. 2009. Sustained viral gene delivery through core-shell fibers. J Control Release. 139:48–55.
- Liu D, Liu S, Jing X, Li X, Li W, Huang Y. 2012a. Necrosis of cervical carcinoma by dichloroacetate released from electrospun polylactide mats. Biomaterials. 33:4362–4369.
- Liu X, Lin T, Gao Y, Xu Z, Huang C, Yao G. 2012b. Antimicrobial electrospun nanofibers of cellulose acetate and polyester urethane composite for wound dressing. J Biomed Mater Res B Appl Biomater. 100:1556–1565.
- Liu S, Wang X, Zhang Z, Zhang Y, Zhou G, Huang Y, Xie Z, Jing X. 2015. Use of asymmetric multilayer polylactide nanofiber mats in controlled release of drugs and prevention of liver cancer recurrence after surgery in mice. Nanomedicine. 11:1047–1056.
- Loo TL, Dion RL, Dixon RL, Rall DP. 1966. The antitumor agent, 1, 3‐bis (2‐chloroethyl)‐1‐nitrosourea. J Pharm Sci. 55:492–497.
- Luu Y, Kim K, Hsiao BS, Chu B, Hadjiargyrou M. 2003. Development of a nanostructured DNA delivery scaffold via electrospinning of PLGA and PLA-PEG block copolymers. J Control Release. 89:341–353.
- Ma Z, He W, Yong T, Ramakrishna S. 2005. Grafting of gelatin on electrospun poly(caprolactone) nanofibers to improve endothelial cell spreading and proliferation and to control cell orientation. Tissue Eng. 11:1149–1158.
- Ma G, Fang D, Liu Y, Zhu X, Nie J. 2011. Paclitaxel loaded electrospun porous nanofibers as mat potential application for chemotherapy against prostate cancer. Carbohydr Polym. 86:505–512.
- Meng Z, Xu XX, Zheng W, Zhou HM, Li L, Zheng YF, Lou X. 2011. Preparation and characterization of electrospun PLGA/gelatin nanofibers as a potential drug delivery system. Colloids Surf B Biointerfaces. 84:97–102.
- Merrell JG, McLaughlin SW, Tie L, Laurencin CT, Chen AF, Nair LS. 2009. Curcumin‐loaded poly (ɛ‐caprolactone) nanofibres: Diabetic wound dressing with anti‐oxidant and anti‐inflammatory properties. Clin Exp Pharmacol Physiol. 36:1149–1156.
- Mi K, Xing Z. 2015. CD44+/CD24− breast cancer cells exhibit phenotypic reversion in three-dimensional self-assembling peptide RADA16 nanofiber scaffold. Int J Nanomed. 10:3043.
- Mottaghitalab F, Farokhi M, Mottaghitalab V, Ziabari M, Divsalar A. 2011. Enhancement of neural cell lines proliferation using nano-structured chitosan/poly (vinyl alcohol) scaffolds conjugated with nerve growth factor. Carbohydr Polym. 86:526–535.
- Naik S, Chiang AST, Thompson RW, Huang FC. 2003. Formation of silicalite-1 hollow spheres by the self-assembly of nanocrystals. Chem Mater. 15:787–792.
- Nguyen TT, Ghosh C, Hwang SG, Chanunpanich N, Park JS. 2012. Porous core/sheath composite nanofibers fabricated by coaxial electrospinning as a potential mat for drug release system. Int J Pharm. 439:296–306.
- Nie H, Wang CH. 2007. Fabrication and characterization of PLGA/HAp composite scaffolds for delivery of BMP-2 plasmid DNA. J Control Release. 120:111–121.
- Patel S, Kurpinski K, Quigley R, Gao H, Hsiao BS, Poo MM, Li S. 2007. Bioactive nanofibers: synergistic effects of nanotopography and chemical signaling on cell guidance. Nano Lett. 7:2122–2128.
- Rama P, Bonini S, Lambiase A, Golisano O, Paterna P, De Luca M, Pellegrini G. 2001. Autologous fibrin-cultured limbal stem cells permanently restore the corneal surface of patients with total limbal stem cell deficiency1. Transplantation. 72:1478–1485.
- Riboldi SA, Sampaolesi M, Neuenschwander P, Cossu G, Mantero S. 2005. Electrospun degradable polyesterurethane membranes: potential scaffolds for skeletal muscle tissue engineering. Biomaterials. 26:4606–4615.
- Rujitanaroj PO, Wang YC, Wang J, Chew SY. 2011. Nanofiber-mediated controlled release of siRNA complexes for long term gene-silencing applications. Biomaterials. 32:5915–5923.
- Sadri M, Arab-Sorkhi S, Vatani H, Bagheri-Pebdeni A. 2015. New wound dressing polymeric nanofiber containing green tea extract prepared by electrospinning method. Fibers Polym. 16:1742–1750.
- Sahoo S, Ang LT, Goh JC, Toh SL. 2010. Growth factor delivery through electrospun nanofibers in scaffolds for tissue engineering applications. J Biomed Mater Res A. 93:1539–1550.
- Said SS, Aloufy AK, El-Halfawy OM, Boraei NA, El-Khordagui LK. 2011. Antimicrobial PLGA ultrafine fibers: Interaction with wound bacteria. Eur J Pharm Biopharm. 79:108–118.
- Said SS, El-Halfawy OM, El-Gowelli HM, Aloufy AK, Boraei NA, El-Khordagui LK. 2012. Bioburden-responsive antimicrobial PLGA ultrafine fibers for wound healing. Eur J Pharm Biopharm. 80:85–94.
- Saraf A, Baggett LS, Raphael RM, Kasper FK, Mikos AG. 2010. Regulated non-viral gene delivery from coaxial electrospun fiber mesh scaffolds. J Control Release. 143:95–103.
- Schneider A, Wang XY, Kaplan DL, Garlick JA, Egles C. 2009. Biofunctionalized electrospun silk mats as a topical bioactive dressing for accelerated wound healing. Acta Biomater. 5:2570–2578.
- Schwab IR, Johnson NT, Harkin DG. 2006. Inherent risks associated with manufacture of bioengineered ocular surface tissue. Arch Ophthalmol. 124:1734–1740.
- Shao S, Li L, Yang G, Li J, Luo C, Gong T, Zhou S. 2011. Controlled green tea polyphenols release from electrospun PCL/MWCNTs composite nanofibers. Int J Pharm. 421:310–320.
- Shen X, Xu Q, Xu S, Li J, Zhang N, Zhang L. 2014. Preparation and transdermal diffusion evaluation of the prazosin hydrochloride-loaded electrospun poly (vinyl alcohol) fiber mats. J Nanosci Nanotechnol. 14:5258–5265.
- Syková E, Jendelová P, Urdzíková L, Lesný P, Hejcl A. 2006. Bone marrow stem cells and polymer hydrogels—two strategies for spinal cord injury repair. Cell Mol Neurobiol. 26:1111–1127.
- Unnithan AR, Sasikala AR, Murugesan P, Gurusamy M, Wu D, Park CH, Kim CS. 2015. Electrospun polyurethane-dextran nanofiber mats loaded with Estradiol for post-menopausal wound dressing. Int J Biol Macromol. 77:1–8.
- Varkey M, Gittens SA, Uludag H. 2004. Growth factor delivery for bone tissue repair: an update. Expert Opin Drug Deliv. 1:19–36.
- Volpato FZ, Almodóvar J, Erickson K, Popat KC, Migliaresi C, Kipper MJ. 2012. Preservation of FGF-2 bioactivity using heparin-based nanoparticles, and their delivery from electrospun chitosan fibers. Acta Biomater. 8:1551–1559.
- Wang J, An Q, Li D, Wu T, Chen W, Sun B, El-Hamshary H. 2015. Heparin and vascular endothelial growth factor loaded poly (L-lactide-co-caprolactone) nanofiber covered stent-graft for aneurysm treatment. J Biomed Nanotechnol. 11:1947–1960.
- Widmer MS, Gupta PK, Lu L, Meszlenyi RK, Evans GR, Brandt K, et al. 1998. Manufacture of porous biodegradable polymer conduits by an extrusion process for guided tissue regeneration. Biomaterials. 19:1945–1955.
- Williamson MR, Coombes AG. 2004. Gravity spinning of polycaprolactone fibres for applications in tissue engineering. Biomaterials. 25:459–465.
- Xie C, Li X, Luo X, Yang Y, Cui W, Zou J, Zhou S. 2010. Release modulation and cytotoxicity of hydroxycamptothecin-loaded electrospun fibers with 2-hydroxypropyl-β-cyclodextrin inoculations. Int J Pharm. 391:55–64.
- Xu X, Yang L, Xu X, Wang X, Chen X, Liang Q, Zeng J, Jing X. 2005. Ultrafine medicated fibers electrospun from W/O emulsions. J Control Release. 108:33–42.
- Xu X, Chen X, Xu X, Lu T, Wang X, Yang L, Jing X. 2006. BCNU-loaded PEG-PLLA ultrafine fibers and their in vitro antitumor activity against glioma C6 cells. J Control Release. 114:307–316.
- Xu F, Weng B, Gilkerson R, Materon LA, Lozano K. 2015. Development of tannic acid/chitosan/pullulan composite nanofibers from aqueous solution for potential applications as wound dressing. Carbohydr Polym. 115:16–24.
- Yang Y, Li X, Qi M, Zhou S, Weng J. 2008. Release pattern and structural integrity of lysozyme encapsulated in core–sheath structured poly (DL-lactide) ultrafine fibers prepared by emulsion electrospinning. Eur J Pharm Biopharm. 69:106–116.
- Yang Y, Li X, Cheng L, He S, Zou J, Chen F, Zhang Z. 2011. Core–sheath structured fibers with pDNA polyplex loadings for the optimal release profile and transfection efficiency as potential tissue engineering scaffolds. Acta Biomater. 7:2533–2543.
- Yang G, Wang J, Wang Y, Li L, Guo X, Zhou S. 2015. An implantable active-targeting micelle-in-nanofiber device for efficient and safe cancer therapy. ACS Nano. 9:1161–1174.
- Yang Y, Nikkola L, Ylikauppila H, Ashammakhi N. 2006. Investigation of cell attachment on the scaffolds manufactured by electrospun PCL-hyaluronan blend. Paper presented at: TNT2006 “Trends in Nanotechnology” Conference (pp. 4–8).
- Yoshimoto H, Shin YM, Terai H, Vacanti JP. 2003. A biodegradable nanofiber scaffold by electrospinning and its potential for bone tissue engineering. Biomaterials. 24:2077–2082.
- Yu YQ, Jiang XS, Gao S, Ma R, Jin Y, Jin X. 2014. Local delivery of vascular endothelial growth factor via nanofiber matrix improves liver regeneration sfter extensive hepatectomy in rats. J Biomed Nanotechnol. 10:3407–3415.
- Yun J, Im JS, Lee YS, Kim HI. 2011. Electro-responsive transdermal drug delivery behavior of PVA/PAA/MWCNT nanofibers. Eur Polymer J. 47:1893–1902.
- Zamani M, Morshed M, Varshosaz J, Jannesari M. 2010. Controlled release of metronidazole benzoate from poly ɛ-caprolactone electrospun nanofibers for periodontal diseases. Eur J Pharm Biopharm. 75:179–185.
- Zamani M, Prabhakaran MP, Ramakrishna S. 2013. Advances in drug delivery via electrospun and electrosprayed nanomaterials. Int J Nanomedicine. 8:2997.
- Zeng J, Yang L, Liang Q, Zhang X, Guan H, Xu X, Chen X, Jing X. 2005. Influence of the drug compatibility with polymer solution on the release kinetics of electrospun fiber formulation. J Control Release. 105:43–51.
- Zeng J, Xu X, Chen X, Liang Q, Bian X, Yang L, Jing X. 2003. Biodegradable electrospun fibers for drug delivery. J Control Release. 92:227–231.
- Zhang Y, Lim CT, Ramakrishna S, Huang ZM. 2005. Recent development of polymer nanofibers for biomedical and biotechnological applications. J Mater Sci Mater Med. 16:933–946.
- Zhong S, Zhang Y, Lim CT. 2011. Fabrication of large pores in electrospun nanofibrous scaffolds for cellular infiltration: a review. Tissue Eng Part B Rev. 18:77–87.