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annually more than half a million peripheral nerve injury cases are reported worldwide ( daly et al . , 2012 ) .
gold standard technique to repair a completely transected nerve with gap size larger than 30 mm .
however , anaesthesia , denervation and numbness of the donor site , painful neuroma formation and time consuming operations are main limitations of this technique ( hood et al . , 2009 ) .
in the last few years , numerous micro - surgical techniques ( tsintou et al . , 2015 ) have been developed to reconstruct a long segment of a damaged peripheral nerve ( sedaghati et al . , 2014 ) .
advancements in the field of tissue engineering and biomaterial science ( tsintou et al . ,
2015 ) have led researchers to develop synthetic nerve conduits as an alternative to nerve autografting . however , to date , the clinical use of the clinically approved nerve conduits is limited to small diameter nerves with short gaps ( < 30 mm ) as their basic hollow tube designs fail to mimic extracellular matrix ( ecm ) nanostructure ( moore et al . ,
so , they become incompetent to support axonal regeneration in defects with longer gaps and larger diameter ( matsumoto et al . , 2000 ) .
extracellular matrix ( ecm ) is one of the important components that influence neural repair and regeneration .
ecm molecules regulate schwann cells ( scs ) morphology , migration and myelination by providing support and anchorage site for these cells ( platt et al . , 2003 ; armstrong et al . , 2007
it is well documented that ecm regulates axonal growth via providing binding sites and guides the growing axons during development and regeneration ( baron - van evercooren et al . , 1982 ;
furthermore , it has been discovered that the interaction between scs and ecm molecules is essential for the release of diffusible nerve growth factors from scs which are crucial for neurite outgrowth ( armstrong et al . , 2007 ) .
they not only have effect on the cell adhesion but also on transducing growth related signals by influencing intracellular signalling , particularly through the mitogen - activated protein kinase kinase ( mek ) pathway ( juliano et al . , 2004 ;
it has been revealed that scs up - regulate expression of integrins on contact with dorsal root ganglion neurons ( einheber et al . , 1993 ) .
several isolated and purified forms of ecm peptide sequences , like rgd , have been used experimentally to enhance neural regeneration ( rogers et al . , 1983 ; santiago et al . , 2006
many adhesive proteins present in ecm , such as fibronectin , vitronectin , collagen and laminin , contain rgd cell adhesion sequence in their integrin recognition sites , which is cell surface receptor that recognizes the rgd sequence of various proteins .
when this sequence is recognised by its integrin , it provides signals for cell attachment , growth , maturation and differentiation ( hersel et al . , 2003 ) .
extensive research over the last decade has revealed that the ecm derived rgd sequence , can act as an integral cell adhesion recognition sequence which interacts with a variety of integrins and promote cell attachment , neurite outgrowth and differentiation ( ruoslahti , 1996 ; plow et al . , 2000 ; rashid et al . , 2004 ) . as a result of these molecular changes ,
scs proliferate and develop a scaffold ahead of the re - growing axon fibers which encourage nerve regeneration ( webber and zochodne , 2010 ) .
incorporation of a small amount of rgd peptide , for instance 1 fmol / cm , has shown effectively improved cell adhesion to the non - adherent surface ( rafiuddin ahmed and jayakumar , 2003 ) .
rgd peptide facilitates sc outgrowth at low doses but will disrupt endogenous fibronectin signalling and regeneration at higher doses ( liu et al . ,
addition of rgd has shown to affect the physiochemical properties of neural scaffold 's surface .
surface topography and chemistry of biomaterial have been shown to be extremely important in determining cell - material interactions by influencing cellular properties such as cell adhesion , proliferation , differentiation , cell - cell reactions and cytoskeleton organisation ( jell et al . , 2009 ) .
schematic diagram of cell attachment and spreading on un - coated ( a ) and arginine - glycine - aspartic acid ( rgd)-coated ( b ) surfaces ( adapted from sedaghati et al . , 2014 ) .
the interaction between cellular integrin receptor and rgd sequence on the surface of a biomaterial is important in controlling the intracellular signalling pathway .
for instance , a significant reduction in water contact angle of rgd - poss - pcl ( polyhedral oligomeric silsesquioxane modified poly ( caprolactone ) urea urethane ) sample compared to poss - pcl sample is a good indication of a decrease in the surface hydrophobicity of the rgd - poss - pcl samples ( sedaghati et al . , 2014 ) .
this peptide may alter nanocomposite surface hydrophobicity to a more polar surface by introducing charged functional groups on polymer surface whereby water molecules in the proximity of the polymer surface bind strongly onto it ( jell et al . , 2009 ) .
hydrophilicity is known to promote schwann cell attachment by influencing the adsorption of cell adhesion ligands present in the ecm ( lee et al . , 2003 ; sun and downes , 2009 ; hong and kim , 2010 ) .
scs morphology and process outgrowth on rgd - poss - pcl revealed a significant increase in the sc spreading and process at day 3 of cell culture studied by s100 immuno - staining and haematoxylin . whilst cells grown on tricalcium phosphate ( tcp ) sample retained their undifferentiated flat polyhedral morphology with no measurable process and tended to cluster together and rather than spreading .
it is therefore speculated that rgd - poss - pcl surface with less hydrophobicity not only favours better cell attachment but also enhances further morphological differentiation and spreading of neural cells .
these findings confirm that recognition of rgd peptide by its integrin on cell membrane may provide signals for neural cell spreading , migration and differentiation ( jifeng et al . , 2010 ;
( 2014 ) showed that incorporation of rgd and -tcp in the pdlla conduit resulted in the microenvironment rich in nerve growth factor ( ngf ) and brain - derived neurotrophic factor ( bdnf ) , which assist to neutralize the oxidative stress and to improve the cytoskeletal protein expressions in vivo .
sciatic nerve regeneration was faster when the rgd peptide was present in a rat model ( xiao et al . , 2013 ) .
addition of other bioactive molecules such as ngf and fk506 into conduit containing rgd motifs enhanced functional outcome similar to that of a nerve autograft following neural repair ( yan et al . , 2012 ) .
nerve conduits have emerged as alternatives to the nerve autografting for defects with a gap length of up to 30 mm in order to eliminate its drawbacks such as unavailability of appropriate - sized nerves and donor site morbidities .
several biological and synthetic materials have been tested for development of nerve conduits with different physiochemical properties ( sedaghati et al . , 2011 ) .
nanotechnology and nano - based materials have attracted considerable amount of attention among researchers in last three decades .
a nanocomposite is a multi - phase compact material where the dimension of the one of its phases is in the size range of 1100 nm . these nanoparticles can be used as the link between the molecules of different composite polymers due to their advantageous size and directly affect nanocomposite 's thermal , mechanical , electrical , catalytic , optical and chemical properties ( sun and downes , 2009 ; torabinejad et al . , 2014 ; yazdimamaghani et al . , 2014
furthermore , considerable increase in the surface to volume ratio of nanocomposite in addition to the decrease in the volume distinguishes this material from usual composites ( figure 2 ) .
these features allow a higher number of reactions happen on the surface of a nanocomposite .
there is a great hope that bio - nanocomposite materials can potentially resemble the characteristic of native ecm ( shekaran and garcia , 2011 ) .
natural ecm proteins , such as collagen and laminin molecules , exhibit specific nano - structural features ( i.e. , nano - meter scale ( 10 - 9 ) ) .
surface modificantion of conevsntional composite biomaterial including topography and chemistry by incorporating nanoparticles can influence cell attachment , growth and differentiation during tissue regeneration .
poss nanoparticles are one of the most promising nanomaterials for medical applications ( kannan et al . , 2005 ; ghanbari et al . , 2011b ) , consisting of a distinctive nanocage structure comprising an inner inorganic framework of silicon and oxygen atoms and an outer shell of organic functional groups
the chemical composition of this nanoparticle makes it a unique nanoparticle that could potentially be used to improve the physiochemical properties of the copolymers ( ghanbari et al . , 2011a ) .
incorporation of this nanoparticle into poly - caprolactone ( pcl ) resulted in the synthesis of poss- incorporated poly ( caprolactone ) urea / urethane ( poss - pcl ) nanocomposite polymer with considerably enhanced physiochemical properties including increased in tensile strength and surface roughness compared to conventional pcl ( chawla et al . , 2014 ) .
scaffold made of this nanocomposite are currently under investigation for nerve ( sedaghati et al . , 2014 ) and skin ( yildirimer and seifalian , 2015 ) tissue regeneration and implants needed for paediatric cases .
nano - fibrous scaffolds also offer great potential in the field of neural tissue engineering ( olakowska et al . , 2010 ) .
nano - fibrous scaffolds can be produced by different fabrication technique such as electrospinning and self - assembly ( ellis - behnke et al .
2009 ) using numerous materials , such as synthetic polymers , proteins , lipids , dna and glass .
processing parameters such as solution - flow rate , applied voltage , polymer concentration and molecular weight and the distance between the needle tip to the ground collection plate can directly or indirectly affect the properties of nano - fibrous scaffolds ( hu et al .
nano - fibers have larger surface area relative to their dimensions ( biazar et al . , 2010 )
. this feature can enhance tissue regeneration where it provides the possibility of coating the outside of a nano - fiber with various biochemical substances essential for cell survival , growth and differentiation ( tysseling - mattiace et al .
pc12 cells grown on fibrous scaffold secreted a higher amount of dopamine compared to the control tissue cultures .
furthermore , neurites of differentiated pc12 cells were highly aligned and longer on parallel phb fibres than random fibres , thereby indicating the importance of fiber orientation for neural regeneration ( figure 3 ) .
schematic diagram of parallel ( a ) and randomly ( b ) aligned electrospun nano - fibers .
nano - fiber alignment , orinetation and chemistry can control cellular behaviour such as proliferation and differentiation .
ecm components , especially rgd peptide sequence , have been exhibited to promote neural tissue regeneration by providing a favourable environment in animal models .
potential treatments under research including alteration of the intrinsic ecm and incorporation of nanoparticles into the scaffolds allow the delivery of combination of neurotrophic factors and cells . nanotubes and nano - fibres
also have shown to be promising strategies for neural tissue engineering in which they support and enhance axonal growth based on their nanometre - scale physiochemical properties .
many of these changes have demonstrated noticeable ability to enhance neural regeneration in vivo . whilst there is potential of using such scaffolds and biomolecules for therapeutic improvements in clinical setting , no clinical study is published yet .
there is a high clinical demand for new smart biomaterials , which stimulate neuronal cell proliferation , migration and increase cell - material interaction to facilitate nerve regeneration across these critical - sized defects . 
 this article briefly reviews several up - to - date published studies using arginine - glycine - aspartic acid peptide sequence , nanocomposite based on polyhedral oligomeric silsesquioxane nanoparticle and nanofibrous scaffolds as promising strategies to enhance peripheral nerve regeneration by influencing cellular behaviour such as attachment , spreading and proliferation . 
 the aim is to establish the potent manipulations , which are simple and easy to employ in the clinical conditions for nerve regeneration and repair .