**1. Introduction**

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184 Advances in Nanofibers

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#### **1.1. Central nervous system injury**

Traumatic brain injury (TBI) and spinal cord injury (SCI) are serious health problems in society. It is estimated that approximately 1.7 million TBI (Ghajar, 2000) and 12,000 new cases of SCI (https://www.nscisc.uab.edu, 2011) occur each year in the U.S. TBI is the leading cause of death and permanent severe neurological disabilities in individuals aged below 45 years in the western world. Similarly, SCI affects young adults with an average age of 40.7 years, and is predominantly caused by motor vehicle accidents. Both types of central nervous system (CNS) injuries commonly result in significant sensorimotor deficits as well as psychological and cognitive impairments. The associated social-economic burden is significant.

#### **1.2. Peripheral nervous system injury**

Peripheral nervous injuries (PNI) are most primarily caused by traffic accident, bone fractures and joint dislocations (Millesi et al., 1998). Additionally, complications of region‐ al anesthesia and some neuropathic or metabolic disorders may also cause PNI. The incidence is around 2.8% of trauma patients per year. Injuries to the peripheral nerves may lead to partial or complete loss of sensory, motor or autonomic functions that can serious‐ ly compromise the life quality of the patients and result in significant socioeconomic loss (Noble et al., 1998; Taylor et al., 2008).

© 2013 Gao et al.; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **1.3. current neural tissue engineering**

#### *1.3.1. Tissue engineering for the repair of central nerve injury*

CNS injuries are characterized by the permanent loss of neural tissues as the result of apoptosis, axonal damage, as well as acute and chronic neural degeneration. These primary and secon‐ dary neuropathological cascades lead to severe destruction of neuronal circuitry. Subsequent significant astrogliosis may also constitute a microenvironment that is inhibitory to regener‐ ation. The capacity for self-repair within the adult CNS after injury is poor, and numerous reparative strategies have been developed to enhance axonal regrowth, reactivate the plasticity of the spared neural tissue, and replace lost tissue by means of cell transplantation (Kim et al., 2012). Of these, neural bioengineering adopts a multifaceted approach in providing both a permissive microenvironment and a suitable three-dimensional scaffold that integrates transplantable cells with bioactive factors. By modifying the components, morphology, and architecture of biodegradable and biocompatible materials, a number of scaffolds have been developed to tailor to the desired physical and chemical properties required for neural repair. Both natural and artificial polymers such as collagen, chitosan, PLGA (poly lactic-co-glycolic acid ), and nanofiberous scaffold have been tested in TBI and SCI models (Peter et al.,2009; Wang et al.,2011). When combined with engrafted stem cells and surface modification, these bioengineered scaffolds represent some of the most promising materials in neuro-regenerative therapy. A wide range of transplantable cells have been used in combination with these scaffolds, including embryonic stem cells, neural stem cells, mesenchymal stem cells, Schwann cells and a variety of adult multipotent stem cell types. The underlying principle is that these engrafted cells may promote neural repair and regeneration by means of growth factor production, neuronal replacement and remyelination. Similarly, enhancement with integrated bioactive factor or oligopeptide motifs may provide a more conducive environment for the survival of the engrafted cells and their integration with the host tissue-scaffold. More importantly, novel controllable release techniques can potentially facilitate the delivery of embedded tissue factors that counteract or neutralize the local inhibitory signals, and degrade glioscar. Given the complexity in anatomical organization and functional communication within the CNS, bioengineered scaffold-based is an reparative strategy of significant potential. PNS bioengineering is to develop bioengineered nerve implant that could match or exceed the performance of autograft. Currently, various conduits made of diverse synthetic or natural biomaterials have been exploited to bridge experimental nerve transection gaps of between 10mm and 80mm in experimental rodent and primate models. The most commonly used biomaterials are biodegradable polymers such as PLGA, type I Collagen and chitosan. The engrafted cells may include Schwann cells, neural stem cells and olfactory ensheathing cells (OECs). However, the degree of axonal regeneration and functional recovery has so far been found to be limited, and inferior to nerve grafting control. Further studies are required to

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Various promising biomaterials have been exploited to meet the diverse needs for specific bioengineering applications. The fundamental requirements of biomaterials utilized in neural tissue engineering include biodegradability, neural bioactivity and neural tissue-matched

These are mainly natural polymers such as collagen, laminin, fibronection, fibin, hyaluronic acid. agarose, alginate, and chitosan. The majority of them are derived directly from ECM and have been extensively studied due to their inherent merits including the presentation of biological receptor-binding ligands, the susceptibility to proteolytic degradation and remod‐ eling in vivo (Ma et al., 2008). These natural macromolecules can be hydrated, and serve as bioscaffolds for various cells *in vivo* and *in vitro*. For example, collagen is the most abundant protein from natural ECM in connective tissue. In mammalian tissues, the primary structural collagen is type I collagen. The collagen conduit made of type 1 collagen such as NeuraGen conduit has been approved by the United States Food and Drug Administration (FDA) and is commercially available for clinical use practice, whereas limited in field of the peripheral nerve repair (Kehoe et al., 2012). Major concerns regarding the clinical application of biologically derived materials, include the problems with sustainable production, immunogenicity, and

Compared to the natural polymers, artificial biomaterials or biomimetic materials, could be designed and synthesized to mimic one or multiple desired characteristics of the natural ECM for specific purposes. For reparative applications, artificial polymers have the advantages of having great flexibility for design and modification so as to allow for the control of orientation

Biodegradability is an important property of biomaterials in tissue engineering. Due to the well-accepted biodegradability and biocompatibility, linear aliphatic polyesters including

explore the applications of other novel materials. (Battiston et al., 2009).

**1.4. Biomaterials developed in the field of Neural Tissue Engineering**

pathogen transmission as well as weak mechanical *in vivo* strength.

and development of new-born tissue for better functional outcomes.

mechanical module.

*1.4.1. Biological biomaterials*

*1.4.2. Artificial biomaterials*

*1.4.2.1. Degradable materials*

#### *1.3.2. Tissue engineering for repair of peripheral nerve injury*

When compared with the CNS, the PNS has a much greater capacity for regeneration after traumatic injury. For lesion gaps of over 5cm in length, autologous nerve grafting is a treatment of choice. However, the recovery of sensory and motor function is often slow and incomplete. Nerve grafting is limited by the availability of the donor nerve, the loss of donor nerve function, and the additional surgical trauma and complications (Gordon et al., 2003). Peripheral nerve is mainly constituted by fascicles of myelinated and unmyelinated nerve fibers as well as multiple layers of connective tissue and blood vessels. PNS bioengineering approaches therefore require longitudinally orientated conduits to provide the physical support and contact guidance for neurite regrowth, while maintaining the biological and functional viability of the distal denervated targets during the regenerative process. The ultimate goal of PNS bioengineering is to develop bioengineered nerve implant that could match or exceed the performance of autograft. Currently, various conduits made of diverse synthetic or natural biomaterials have been exploited to bridge experimental nerve transection gaps of between 10mm and 80mm in experimental rodent and primate models. The most commonly used biomaterials are biodegradable polymers such as PLGA, type I Collagen and chitosan. The engrafted cells may include Schwann cells, neural stem cells and olfactory ensheathing cells (OECs). However, the degree of axonal regeneration and functional recovery has so far been found to be limited, and inferior to nerve grafting control. Further studies are required to explore the applications of other novel materials. (Battiston et al., 2009).

#### **1.4. Biomaterials developed in the field of Neural Tissue Engineering**

Various promising biomaterials have been exploited to meet the diverse needs for specific bioengineering applications. The fundamental requirements of biomaterials utilized in neural tissue engineering include biodegradability, neural bioactivity and neural tissue-matched mechanical module.

## *1.4.1. Biological biomaterials*

**1.3. current neural tissue engineering**

186 Advances in Nanofibers

*1.3.1. Tissue engineering for the repair of central nerve injury*

*1.3.2. Tissue engineering for repair of peripheral nerve injury*

CNS injuries are characterized by the permanent loss of neural tissues as the result of apoptosis, axonal damage, as well as acute and chronic neural degeneration. These primary and secon‐ dary neuropathological cascades lead to severe destruction of neuronal circuitry. Subsequent significant astrogliosis may also constitute a microenvironment that is inhibitory to regener‐ ation. The capacity for self-repair within the adult CNS after injury is poor, and numerous reparative strategies have been developed to enhance axonal regrowth, reactivate the plasticity of the spared neural tissue, and replace lost tissue by means of cell transplantation (Kim et al., 2012). Of these, neural bioengineering adopts a multifaceted approach in providing both a permissive microenvironment and a suitable three-dimensional scaffold that integrates transplantable cells with bioactive factors. By modifying the components, morphology, and architecture of biodegradable and biocompatible materials, a number of scaffolds have been developed to tailor to the desired physical and chemical properties required for neural repair. Both natural and artificial polymers such as collagen, chitosan, PLGA (poly lactic-co-glycolic acid ), and nanofiberous scaffold have been tested in TBI and SCI models (Peter et al.,2009; Wang et al.,2011). When combined with engrafted stem cells and surface modification, these bioengineered scaffolds represent some of the most promising materials in neuro-regenerative therapy. A wide range of transplantable cells have been used in combination with these scaffolds, including embryonic stem cells, neural stem cells, mesenchymal stem cells, Schwann cells and a variety of adult multipotent stem cell types. The underlying principle is that these engrafted cells may promote neural repair and regeneration by means of growth factor production, neuronal replacement and remyelination. Similarly, enhancement with integrated bioactive factor or oligopeptide motifs may provide a more conducive environment for the survival of the engrafted cells and their integration with the host tissue-scaffold. More importantly, novel controllable release techniques can potentially facilitate the delivery of embedded tissue factors that counteract or neutralize the local inhibitory signals, and degrade glioscar. Given the complexity in anatomical organization and functional communication within the CNS, bioengineered scaffold-based is an reparative strategy of significant potential.

When compared with the CNS, the PNS has a much greater capacity for regeneration after traumatic injury. For lesion gaps of over 5cm in length, autologous nerve grafting is a treatment of choice. However, the recovery of sensory and motor function is often slow and incomplete. Nerve grafting is limited by the availability of the donor nerve, the loss of donor nerve function, and the additional surgical trauma and complications (Gordon et al., 2003). Peripheral nerve is mainly constituted by fascicles of myelinated and unmyelinated nerve fibers as well as multiple layers of connective tissue and blood vessels. PNS bioengineering approaches therefore require longitudinally orientated conduits to provide the physical support and contact guidance for neurite regrowth, while maintaining the biological and functional viability of the distal denervated targets during the regenerative process. The ultimate goal of

These are mainly natural polymers such as collagen, laminin, fibronection, fibin, hyaluronic acid. agarose, alginate, and chitosan. The majority of them are derived directly from ECM and have been extensively studied due to their inherent merits including the presentation of biological receptor-binding ligands, the susceptibility to proteolytic degradation and remod‐ eling in vivo (Ma et al., 2008). These natural macromolecules can be hydrated, and serve as bioscaffolds for various cells *in vivo* and *in vitro*. For example, collagen is the most abundant protein from natural ECM in connective tissue. In mammalian tissues, the primary structural collagen is type I collagen. The collagen conduit made of type 1 collagen such as NeuraGen conduit has been approved by the United States Food and Drug Administration (FDA) and is commercially available for clinical use practice, whereas limited in field of the peripheral nerve repair (Kehoe et al., 2012). Major concerns regarding the clinical application of biologically derived materials, include the problems with sustainable production, immunogenicity, and pathogen transmission as well as weak mechanical *in vivo* strength.

#### *1.4.2. Artificial biomaterials*

Compared to the natural polymers, artificial biomaterials or biomimetic materials, could be designed and synthesized to mimic one or multiple desired characteristics of the natural ECM for specific purposes. For reparative applications, artificial polymers have the advantages of having great flexibility for design and modification so as to allow for the control of orientation and development of new-born tissue for better functional outcomes.

#### *1.4.2.1. Degradable materials*

Biodegradability is an important property of biomaterials in tissue engineering. Due to the well-accepted biodegradability and biocompatibility, linear aliphatic polyesters including poly(lactic acid) (PLA), poly(glycolic acid) (PGA), and their copolymers poly(lactic acid-coglycolic acid) (PLGA) have been widely utilized to reconstruct bioscaffold in diverse condi‐ tions of neural repair. To facilitate host-material integration, biomaterial candidates must also possess the appropriate elastic module. For instance, hydrogel made of poly(2-hydroxyethyl methacrylate-co-methyl methacrylate) (p(HEMA-co-MMA)) has similar mechanical proper‐ ties to the mammalian spinal cord (elastic modulus of 200 to 600 kPa), and could be customized by altering the ratio of co-monomers (Dalton et al.,2002). The hydrophobic surface properties in most of the synthetic biodegradable materials such as PLGA, PCL and PHB, may be modified by coating them with ECM proteins components like laminin, fibronectin, collagen. Specific adhesion oligopeptide such as RGD and IKVAV, YIGSR may also be added to improve their adhesion properties for seeded cells. Several studies showed that the cellular adhesion performance of these artificial biomaterials including methyl cellulose, alginate, poly (hy‐ droxyethyl methacrylate) (PHEMA), poly (hydroxybutyrate) (PHB) (Samadikuchaksaraei, 2007), could be significantly improved by surface modifications. Another category of synthetic biomaterial is related to the nanofibre scaffold which will be discussed in later sections.

hydrophobic interactions. To recapitulate the bioactive motif of laminin, Stupp and coworkers designed a self-assembling peptide amphiphile (PA) that consisted of the laminin-derived peptide IKVAV (Ile-Lys-Val-Ala-Val). The self-assembly of IKVAV could be initiated sponta‐ neously upon the introduction of physiological buffer which leads to the formation of

Use of Self-Assembly Nanofibre Biomaterials for Neural Repair After Injury

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189

Electrospinning was a traditional industrial fabrication technique used widely in 1930s. Due to its effectiveness of producing microfibers with diameters of sub-micron or nanometer scale, it has been utilized to process a number of natural and synthetic polymers such as collagen, fibroin, PLLA, PLGA, and PCL. The electrospun nanofiber matrices resemble the structural morphology of ECM with a high surface area–to-volume ratio, which has been shown to greatly facilitate cellular attachment, proliferation and differentiation. Recent studies continue to report the development of novel electrospun nanofibers, and the introduction of bioactive molecules such as growth factors during the fabrication process of nanofibers for peripheral nerve regeneration (Prabhakaran et al., 2008). The intrinsic limitations of this technique include the degradation of bioactive factors during procedure, the inability to fabricate complex 3D

Phase separation, or thermally induced liquid–liquid phase separation, was developed by Ma and Zhang to produce a nanofibrous foam materials. Polymer scaffolds generated by phase separation normally have a sponge-like porous morphology with spherical pores 50–500 nm in diameter. Phase separation system consists of a polymer-rich component and a polymerlean/solvent-rich component, by which the polymer morphology can solidify by quenching under low temperature. A few nanofibre scaffold from artificial biodegradable polymers have been produced with phase separation including PLLA, which was studied as a suitable matrices in which NSCs can grow and differentiate (Yang et al., 2004). Compared with other techniques previously discussed phase separation has simpler and the need for specialized equipment is minimal. However, due to the small number of candidate polymers suitable for *in vivo* study, reports on nanofiber scaffold generated by phase separation in neural tissue

The applications of RADA16-I, a representative SAPNS, in 3D cell culturing, wound hemo‐ stasis and healing has been well described in a series of studies. The initial research of RADA16- I in experimental TBI was conducted by Ellis-Behnke et al. (Ellis-Behnke et al. 2006). Using an acute TBI model in which the midbrain of P2 hamsters was injured surgically with a knife wound (1.5 mm deep and 2.0 mm wide), 10µl of 1% SAPNS was applied to bridge the injury gap. The central traumatic lesion showed restoration in all SAPNS-treated animal subjects

nanofibers with diameter ranging from 6 to 8 nm (Tysseling-Mattiace, 2008).

structures or specific microstructure with designed internal pore size.

**2.2. Current application of SAPNS for the repair of injured CNS**

*2.1.2. Eletrospun nanofiber scaffolds*

*2.1.3. Phase separation*

engineering are limited.

*2.2.1. Traumatic brain injury*

#### *1.4.2.2. Nondegradable materials*

The use of synthetic nondegradable materials in neural repair is limited by their nondegrada‐ blilty and unbioabsorbility. The majority of reported studies involved PNI. For example, poly (2-hydroxyethyl methacrylate) has been demonstrated to support regeneration of injured axons in a rat SCI model (Tsai et al. 2006). Recently, electroactive polymer like polypyrole or hybrid conduct materials showed neuronal attachment and growth. The major concerns regarding these materials are related to immunorejection, chronic inflammatory responses, fibrous scarring, and the associated problems of neural compression and need for re-operation. These render nondegradable materials unsuitable for CNS repair (Cullen et al., 2008).
