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(L-Lactic Acid) Composite Scaffold Intended for Nerve Tissue Engineering

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(L-Lactic Acid) Composite Scaffold Intended for Nerve Tissue Engineering EXCLI Journal 2015;14:851-860 – ISSN 1611-2156 Received: April 19, 2015, accepted: May 28, 2015, published: July 27, 2015 Original article: CYTOCOMPATIBILITY OF A CONDUCTIVE NANOFIBROUS CARBON NANOTUBE/POLY (L-LACTIC ACID) COMPOSITE SCAFFOLD INTENDED FOR NERVE TISSUE ENGINEERING Mahboubeh Kabiri1,2,3,*, Saeed Oraee-Yazdani2,4, Masumeh Dodel3,5, Hana Hanaee-Ahvaz2, Sara Soudi2,6, Ehsan Seyedjafari1,3, Mohammad Salehi2,7, Masoud Soleimani8,* 1 Department of Biotechnology, College of Science, University of Tehran, Tehran, Iran 2 Department of Stem Cell Biology, Stem Cell Technology Research Center, Tehran, Iran 3 Department of Nanotechnology and Tissue Engineering, Stem Cell Technology Research Center, Tehran, Iran 4 Functional Neurosurgery Research Center, Shohada Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran 5 Department of Textile Engineering, Amirkabir University of Technology, Tehran, Iran, Stem Cell Technology Research Center, Tehran, Iran 6 Department of Immunology, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran 7 Department of Biotechnology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran 8 Department of Hematology, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran * Corresponding authors: Dr Mahboubeh Kabiri, Department of Biotechnology, College of Science, University of Tehran, P.O.Box: 14155-6455, Tehran, Iran, Tel: (98) 21 66491622, Mobile: +98 9122116831; E-mail: mkabiri@ut.ac.ir Dr Masoud Soleimani, Hematology Department, Faculty of Medical Science, Tarbiat Modares University, P.O.Box: 14115-111, Tehran, Iran, Tel: (98) 21 88861065-7; Mobile: +98122875993; E-mail: soleim_m@modares.ac.ir http://dx.doi.org/10.17179/excli2015-282 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/). ABSTRACT The purpose of this study was to fabricate a conductive aligned nanofibrous substrate and evaluate its suitability and cytocompatibility with neural cells for nerve tissue engineering purposes. In order to reach these goals, we first used electrospinning to fabricate single-walled carbon-nanotube (SWCNT) incorporated poly(L-Lactic acid) (PLLA) nanofibrous scaffolds and then assessed its cytocompatibility with olfactory ensheathing glial cells (OEC). The plasma treated scaffolds were characterized using scanning electron microscopy and water contact angle. OECs were isolated from olfactory bulb of GFP Sprague-Dawley rats and characterized using OEC spe- cific markers via immunocytochemistry and flow cytometery. The cytocompatibility of the conductive aligned nano-featured scaffold was assessed using microscopy and MTT assay. We indicate that doping of PLLA poly- mer with SWCNT can augment the aligned nanosized substrate with conductivity, making it favorable for nerve tissue engineering. Our results demonstrated that SWCNT/PLLA composite scaffold promote the adhesion, growth, survival and proliferation of OEC. Regarding the ideal physical, topographical and electrical properties of the scaffold and the neurotrophic and migratory features of the OECs, we suggest this scaffold and the cell/scaffold construct as a promising platform for cell delivery to neural defects in nerve tissue engineering ap- proaches. 851 EXCLI Journal 2015;14:851-860 – ISSN 1611-2156 Received: April 19, 2015, accepted: May 28, 2015, published: July 27, 2015 Keywords: Nerve tissue engineering, olfactory ensheathing cells, carbon nanotube, composite scaffold, electrospun nanofiber INTRODUCTION developmental heritage with SC is olfactory ensheathing glial cell (OEC). Normally, their Cell therapy has a promising potential for main role in the olfactory system is to facili- the treatment of neurodegenerative diseases tate and guide olfactory axons to the hostile or trauma-related injuries that are otherwise very difficult to cure by conventional ap- olfactory bulb throughout the life ( Ramón- proaches. Damages to nervous tissues, in- Cueto and Valverde, 1995). They have cluding spinal cord, brain and peripheral shown to express different neurotrophic fac- nerves, can cause debilitating diseases as tors including glial derived neurotrophic fac- they usually lead to progressive functional tor (GDNF), nerve growth factors (NGF), damages. Current approaches basically rely brain-derived neurotrophic factor (BDNF) on reduction or inhibition of gliosis by using and their receptors (Woodhall et al., 2001), steroids (Hall and Springer, 2004), immune- and can myelinate axons indistinguishably modulatory drugs (Bowes and Yip, 2014) or from myelination by Schwann cells (Barraud et al., 2010). The neurotrophic factors ex- administration of chondroitinase (Bradbury pressed and produced by OEC could endow et al., 2002), aiming to minimize secondary these cells with axon regeneration and remy- complications associated with the injury elination potential over several millimeters (Thuret et al., 2006). With the advent of cell- of axons (Imaizumi et al., 1998) and ulti- based therapies, the therapeutic potential of mately restoration of functional synapses different cell types was investigated for (Barnett et al., 2000). Besides, originating nerve regeneration (Hedayatpour et al., from the neural crest, OEC persist in adult 2013). Stem cells from different sources tissues and can be regarded as an abundant such as bone marrow (BM) (Hafizi et al., and accessible source of autologous cells 2015), blastocysts (ESC, embryonic stem throughout the life (Barraud et al., 2010). cells), fetal tissues and neural stem cells have Regarding the availability of patient specific been investigated frequently, with each dis- OEC and their neurotrophic characteristics, playing varying degrees of regeneration and these cells can be considered as great candi- functional restoration. The transplanted stem dates for cell-based therapy of neural inju- cell derived neural or glial cells/progenitors ries. can partially reestablish the neural connec- A wide range of bioengineered scaffolds tions and result in recovery of function have been developed to assist in the im- (Yazdani et al., 2012). provement of neural regeneration. An ideal Schwann cells (SC), the glial cells that synthetic scaffold must have chemical, me- ensheath and myelinate axons in peripheral chanical, morphological and electrical prop- nervous system (PNS), are of most studied erties mimicking the natural ECM of the de- cell types that can repair injuries of central sired neural tissue. Poly(α-hydroxy esters), nervous system (CNS) owing to their capa- such as poly(L-lactic acid) (PLLA) and its bility to produce neurotropic factors and cell breakdown products are shown to be bio- adhesion molecules (Oudega and Xu, 2006). compatible with neural cells and tissues both SC are available autologously by a biopsy in vitro and in vivo (Schmidt and Leach, from a peripheral nerve in the leg. The re- 2003). Their tunable degradation rate, the leased neurotrophics can induce repair and non-immunogenicity and FDA approval has survival of the damaged neurons and attract made them enormously attractive in tissue endogenous stem or glial cells to the lesion engineering approaches (Potter et al., 2008). site (Ogawa et al., 2002). Another cell type Electrospinning these polymers allows for that shares many characteristics and even 852 EXCLI Journal 2015;14:851-860 – ISSN 1611-2156 Received: April 19, 2015, accepted: May 28, 2015, published: July 27, 2015 the generation of aligned fibers with diame- nous suspension, and then combined with ters in the nano-meter range that are suitable DMF and PLLA in the same proportions in directed axonal outgrowth through provi- stated above. The final concentration of sion of appropriate contact guidance (Chew SWCNT in solution was equivalent to 3 % of et al., 2006; Kabiri et al., 2012; Potter et al., the PLLA mass. The polymer solution was 2008). Furthermore, the electrospun nano- ultra-sonicated and stir homogenized over- fibrous sheets have the capacity to be rolled night before electrospinning. A syringe and packed within a defined volume, provid- pump was used to feed the solution through ing enough substrate for cell transplantation an extension tube ended in a blunted 21- (Goto et al., 2010). gauge needle. A voltage potential of 25 kV We hypothesized that further functional- was applied between the needle and the col- izing of the PLLA nanofibers with an elec- lector. The nanofiber jet was collected on a trically conductive compound can aid to stainless steel cylinder rotating at 2400 RPM mimic the inherently conductive nature of at a fixed distance of 15 cm from the spin- the nerve tissues. Electrically conductive ma- neret tip. Oxygen plasma surface treatment terials such as polypyrrole, polyaniline and was performed using a low frequency plasma carbon nanotubes (CNT) have been effec- generator set on 40 kHz (Diener Electronics). tively used in drug delivery and biosensor The hydrophobic/hydrophilic nature of the applications and for the fabrication of nerve nanofiber scaffolds before and after plasma guidance conduits in nerve tissue engineer- treatment was evaluated by measuring the ing (Chronakis et al., 2006; MacDonald et contact angle of water droplets using the ses- al., 2008; Schmidt et al., 1997; Voge et al., sile drop method (G10 contact angle goni- 2008; Zhang et al., 2007). The resultant con- ometer, Kruss). ductive composite would inherit both the The morphology of the nanofibrous scaf- physical
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