The Influence of Electrospinning Parameters and Drug Loading on Polyhydroxyalkanoate (PHA) Nanofibers for Drug Delivery


  • Yan-Fen Lee Ecobiomaterial Research Laboratory, School of Biological Sciences, Universiti Sains Malaysia
  • Nanthini Sridewi Department of Maritime Science and Technology, Faculty of Defence Science and Technology, National Defense University of Malaysia
  • Surash Ramanathan Centre for Drug Research, Universiti Sains Malaysia
  • Kumar Sudesh Ecobiomaterial Research Laboratory, School of Biological Sciences, Universiti Sains Malaysia



polyhydroxyalkanoate, electrospinning, nanofibers, drug loading, biocompatibility


The impact of polymer concentration and drug loading on nanofiber morphology and diameter were investigated during electrospinning of polyhydroxyalkanoate nanofibrous films. Low molecular weight poly(3-hydroxybutyrate-co-4-hydroxybutyrate) [P(3HB-co-95 mol% 4HB)] required a 5-fold higher solution concentration than high molecular weight poly(3-hydroxybutyrate) [P(3HB)] to produce bead-free nanofibers. Loading the films with paclitaxel increased the initial polymer solution viscosity allowing larger diameter nanofibers to form. Furthermore, paclitaxel added at 1% (w/w) into 8 % (w/v) P(3HB-co-95 mol% 4HB) solution eliminated the formation of beads seen in solutions without the drug, at the same initial polymer solution concentration. In preliminary drug release studies, nanofiber mats consisting of large-diameter nanofibers with high drug loading released paclitaxel at a faster rate due to larger pore sizes. This was a consequence of the random packing of larger diameter nanofibers. However, the release pattern of nanofibers with low drug loading was much more consistent and controlled. Lastly, we have shown the potential applications of P(3HB-co-4HB) drug loaded nanofibers in the development of biocompatible drug eluting stents by directly coating a metal stent with a homogeneous layer of electrospun polymer.


[1] Yoo HS, Kim TG, Park, TG. Surface-funtionalized electrospun nanofibers for tissue engineering and drug delivery. Adv Drug Deliv Rev 2009; 61: 1033-42.
[2] Vasita R, Katti DS. Nanofibers and their applications in tissue engineering. Int J Nanomedicine 2006; 1: 15-30.
[3] Greiner A, Wendorff JH. Electrospinning: a fascinating method for the preparation of ultrathin fibers. Angew Chem Int Ed Engl 2007; 46: 5670-703.
[4] Liang D, Hsiao BS, ChuB. Functional electrospun nanofibrous scaffolds for biomedical applications. Adv Drug Deliv Rev 2007; 59: 1392-412.
[5] Pillay V, Dott C, Choonara YE, et al. A review of the effect of processing variables on the fabrication of electrospun nanofibers for drug delivery applications. J Nanomater 2013 Article ID 789289, 22 pages.
[6] Joyyi L, Sridewi N, Abdullah AAA, Kasuya K, Sudesh K. Fabrication and degradation of electrospun polyhydroxyalkanoate film. J Sib Fed Univ Biol 2015; 8: 236-53.
[7] Brigham CJ, Sinskey AJ. Applications of polyhydroxyalkanoates in the medical industry. Int J Biotech Well Indus 2012; 1: 53-60.
[8] Sudesh K, Abe H, Doi Y. Synthesis, structure and properties of polyhydroxyalkanoates: biological polyesters. Prog Polym Sci 2000; 25: 1503-55.
[9] Thomson N, Summers D, Sivaniah E. Synthesis, properties and uses of bacterial storage lipid granules as natural occurring nanoparticles. Soft Matter 2010; 6: 4045-57.
[10] Bhubalan K, Lee WH, Sudesh K. Polyhydroxyalkanoate. In: AJ Domb, N Kumar, A. Ezra, John Wiley & Sons, Inc. Biodegradable polymers in clinical use and clinical development. Hoboken: New Jersey 2011; pp. 249-315.
[11] Martin DP, Williams, SF. Medical application of poly-4-hydroxybutyrate: a strong flexible absorbable biomaterial. Biochem Eng J 2003; 16: 97-105.
[12] Siew EL, Rajab NF, Annear BO, Sudesh K, Inayat-Hussain, SH. In vitro biocompatibility evaluation of poly(3-hydroxybutyrate-co-4-hydroxybutyrate) copolymer in fibroblast cells. J Biomed Mater Res 2007; 81A: 317-25.
[13] Siew EL, Rajab NF, Annear BO, Sudesh K, Inayat-Hussain SH. Mutagenesis and clastogenic characterization of post sterilized poly(3-hydroxybutyrate-co-4-hydroxybutyrate) copolymer biosynthesized by Delftia acidovorans. J Biomed Mater Res A 2009; 91A: 786-94.
[14] Nelson T, Kaufman E, Kline J, Sokoloff L. The extraneural distribution of -hydroxybutyrate. J Neurochem 1981; 37: 1345-8.
[15] Sendelbeck SL, Girdis GL. Disposition of a 14C-labeled bioerodible polyorthoester and its hydrolysis products, 4-hydroxybutyrate and cis, trans-1,4-bis(hydroxymethyl) cyclohexane, in rats. Drug Metab Dispos 1985; 13: 291-5.
[16] Yu D, Zhu L, White K, Branford-White C. Electrospun nanofiber-based drug delivery systems. Health 2009; 1: 67-75.
[17] Long HJ. Paclitaxel (Taxol): a novel anticancer chemo-therapeutic drug. Mayo Clin Proc 1994; 69: 341-5.
[18] Cahan MA, Walter KA, Colven OM, Brem H. Cytotoxicity of taxol in vitro against human and rat malignant brain tumors. Cancer Chemother Pharmacol 1994; 33: 441-4.
[19] Arbuck SG, Christian MC, Fisherman JS, et al. Clinical development of Taxol. J Natl Cancer Inst Monogr 1993; 15: 11-24.
[20] Foa R, Norton L, Seidman AD. Taxol (paclitaxel) a novel micro-tubule agent with remarkable anti-neoplastic activity. Int J Clin Lab Res 1994; 24: 6-14.
[21] Rowinsky EK, Donehower RC. Paclitaxel (Taxol). N Engl J Med 1995; 332: 1004-14.
[22] Singla AK, Garg A, Aggarwal D. Palitaxel and its formulations. Int J Pharm 2002; 235: 179-92.
[23] Lee WH, Azizan MNM, Sudesh K. Effects of culture conditions on the composition of poly(3-hydroxybutyrate-co-4-hydroxybutyrate) synthesized by Comamonas acidovorans. Polym Degrad Stab 2004; 84: 129-34.
[24] Braunegg G, Sonnleitner B, Lafferty RM. A rapid gas chromatographic method for the determination of poly--hydroxybutyric acid in microbial biomass. Eur J Microbiol Biotechnol 1978; 6: 29-37.
[25] Bhardwaj N, Kundu SC. Electrospinning: A fascinating fiber fabrication technique. Biotechnol Adv 2010; 28: 325-47.
[26] Luo CJ, Nangrejo M, Edirisinghe MA. Novel method of selecting solvents for polymer electrospinning. Polymer 2010; 51: 1654-62.
[27] Shenoy SL, Bates WD, Frisch HL, Wnek GE. Role of chain entanglement on fiber formation during electrospinning of polymer solutions: good solvent, non-specific polymer-polymer interaction limit. Polymer 2005; 46: 3372-84.
[28] Ramakrishna S, Fujihara K, Teo WE, Lim TC, Ma Z. An introduction to electrospinning and nanofibers. Singapore: World Scientific; 2005
[29] Tan SH, Inai R, Kotaki M, Ramakrishna S. Systematic parameter study for ultra-fine fiber fabrication via electrospinning process. Polymer 2005; 46: 6128-34.
[30] Deitzel JM, Kleinmeyer J, Harris D, Beck Tan NC. The effect of processing variables on the morphology of electrospun nanofibers and textiles. Polymer 2001; 42: 261-72.
[31] Reneker DH, Chun I. Nanometre diameter fibres of polymer, produced by electrospinning. Nanotechnology 1996; 7: 216-23.
[32] Demir MM, Yilgor I, Yilgor E, Erman B. Electrospinning of polyurethane fibers. Polymer 2002; 43: 3303-9.
[33] Ki CS, Baek DH, Gang KD, Lee KH, Um IC, Park YH. Characterization of gelatin nanofiber prepared from gelatin-formic acid solution. Polymer 2005; 46: 5094-102.
[34] Zeng J, Xu X, Chen X, et al. Biodegradable electrospun fibers for drug delivery. J Control Release 2003; 92: 227-31.
[35] Ch’ng DHE, Sudesh K. Densitometry based microassay for the determination of lipase depolymerizing activity on polyhydroxyalkanoate. AMB Express 2013; 3: 22.
[36] Ch’ng DHE, Lee WH, Sudesh K. Biosynthesis and lipase-catalysed hydrolysis of 4-hydroxybutyrate-containing polyhydroxyalkanoates from Delftia acidovorans. Mal J Microbiol 2012; 8: 156-63.
[37] Mukai K, Doi Y, Sema Y, Tomita K. Substrate specificities in hydrolysis of polyhydroxyalkanoates by microbial esterases. Biotechnol Lett 1993; 15: 601-4.
[38] Hsieh WC, Wada Y, Chang CP. Fermentation, biodegradation and tensile strength of poly(3-hydroxybutyrate-co-4-hydroxybutyrate) synthesized by Delftia acidovorans. J Taiwan Inst Chem Eng 2009; 40: 143-7.
[39] Okuda T, Tominaga K, Kidoaki S. Time-programmed dual release formulation by multilayered drug-loaded nanober meshes. J Control Release 2009; 143: 258-64.
[40] Cui W, Li X, Zhu X, Yu G, Zhou S, Weng J. Investigation of drug release and matrix degradation of electrospun poly(DL-lactide) fibers with paracetanol inoculation. Biomacromolecules 2006; 7: 1623-9.
[41] Xie Z, Buschle-Diller G. Electrospun poly(D,L-lactide) fibers for drug delivery: The influence of cosolvent and the mechanism of drug release. J Appl Polym Sci 2010; 115: 1-8.
[42] Kenawy ER, Bowlin GL, Mansfield K, et al. Release of tetracycline hydrochloride from electrospun poly(ethylene-co-vinylacetate), poly(lactic acid), and a blend. J Control Release 2002; 81: 57-64.
[43] Buschle-Diller G, Cooper J, Xie Z, Wu Y, Waldrup J, Ren X. Release of antibiotics from electrospun bicomponent fibers. Cellulose 2007; 14: 553-62.
[44] Zamani M, Morshed M, Varshosaz J, Jannesari M. Controlled release of metronidazole benzoate from poly epsilon-caprolactone electrospun nanobers for periodontal diseases. Eur J Pharm Biopharm 2010; 75: 179-85.
[45] Zeng J, Yang L, Liang Q, et al. Influence of the drug compatibility with polymer solution on the release kinetics of electrospun fiber formulation. J Control Release 2005; 105: 43-51.
[46] Goonoo N, Bhaw-Luximon A, Jhurry D. Drug loading and release from electrospun biodegradable nanofibers. J Biomed Nanotechnol 2014; 10: 2173-99.
[47] Meng ZX, Zheng W, Li L, Zheng YF. Fabrication, characterization and in vitro drug release behavior of electrospun PLGA/chitosan nanofibrous scaffold. Mater Chem Phys 2011; 125: 606-11.