Tissue engineering of the peripheral nervous system.

Expert Review of Neurotherapeutics

ISSN: 1473-7175 (Print) 1744-8360 (Online) Journal homepage: http://www.tandfonline.com/loi/iern20

Tissue engineering of the peripheral nervous system Víctor Carriel, Miguel Alaminos, Ingrid Garzón, Antonio Campos & Maria Cornelissen To cite this article: Víctor Carriel, Miguel Alaminos, Ingrid Garzón, Antonio Campos & Maria Cornelissen (2014) Tissue engineering of the peripheral nervous system, Expert Review of Neurotherapeutics, 14:3, 301-318, DOI: 10.1586/14737175.2014.887444 To link to this article: http://dx.doi.org/10.1586/14737175.2014.887444

Published online: 10 Feb 2014.

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Tissue engineering of the peripheral nervous system

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Expert Rev. Neurother. 14(3), 301–318 (2014)

Vıćtor Carriel*1,2, Miguel Alaminos1, Ingrid Garzoń1, Antonio Campos1 and Maria Cornelissen2 1 Department of Histology (Tissue Engineering Group), University of Granada, Avenida de Madrid 11, 18012 Granada, Spain 2 Department of Basic Medical Sciences (Histology and Tissue Engineering Group), Ghent University, De Pintelaan 185 B3, 9000 Ghent, Belgium *Author for correspondence: Tel.: +34 958 243 515 Fax: +34 958 244 034 [email protected]; [email protected]

The structure and function of peripheral nerves can be affected by a range of conditions with severe consequences in these patients. Currently, there are several surgical techniques available to treat peripheral nerve defects. Direct repair is the preferred treatment for short nerve gaps, and nerve autografting is the gold standard in critical nerve defects. The autografting is not always available, and the use of allograft, decellularized allograft and nerve conduits are often used with variable success. During the recent years, several outcomes were achieved in peripheral nerve tissue engineering. Promising experimental results have been demonstrated with this novel generation of nerve conduits, mainly composed by biodegradables materials in combination with intraluminal fillers, growth factors and different cell sources. KEYWORDS: biomaterials • cell-based therapy • graft-based repair • surgical nerve repair • tissue engineering • traumatic nerve injuries • tubulization

Structure & regeneration of the PNS

The PNS is composed of delicate organs called peripheral nerves (PN), which form a highly complex and organized network throughout the body. PN connect the CNS to the distal target organs of the motor and sensory pathways. They emerge from the CNS, forming specialized nerve trunks, and can be anatomically divided in cranial and spinal nerves [1,2]. They present a relatively similar histological structure, with the exception of the olfactory and optic nerves [3]. Histologically, PN are organized into two main components, a functional unit or parenchyma and the stroma. The parenchyma is composed of the nerve fibers, formed by the axons and the surrounding Schwann cells (SC), while the stroma is composed of a specialized connective tissue. The SC can interact with a single axon forming a myelinated nerve fiber, or a single SC can interact with several axons forming unmyelinated nerve fibers. In the case of the stroma, it is a vascularized structure that regulates the compartmentalization of these organs. Transverse histological sections of PN show how the endoneurial compartments containing nerve fibers are surrounded by perineurium to form individual fascicles embedded in epineurial connective tissue. The proportion of myelinated and/or unmyelinated nerve fibers or the informahealthcare.com

10.1586/14737175.2014.887444

number of nerve fascicles widely differ among organs [1,2]. Based on their functions and fiber type composition, they can be divided in three main categories: sensory, motor and mixed nerves; the PNS is also divided into somatic and autonomic nervous system [2]. The normal structure and functions of these organs can be affected by several conditions and many patients remain disabled for the rest of their lives [2–6]. However, in comparison with the CNS, the PNS has a better physiological capability to regenerate its distal components following structural disruption. Ramoń y Cajal was one of the first researchers to suggest that both cellular and diffusible factors contribute to nerve regeneration in the PNS [7]. The large extension of these organs makes them vulnerable to damage from traumatic injury at any anatomic site [2,3]. The etiology of this damage ranges from nerve compression and traction, to severe rupture, lacerations and avulsion of spinal nerve roots [4,8–10]. The incidence of peripheral nerve injuries is high, and often results in serious physical and psychological consequences for these patients. In the USA, it is estimated that around 2.8% of the traumatic injuries affect the PN [11], and this occurs in 73% of the patients with upper limb affection. In fact, over 200,000 peripheral nerve repair procedures are performed annually only in the USA [12]. Motor vehicle accidents,

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ń, Campos & Cornelissen Carriel, Alaminos, Garzo

particularly motorcycles crashes, were the most common cause of severe peripheral nerve injuries (SPNI) [4]. These injuries affect a large number of patients in their productive years, and they not only cause problems in their lives but also in their professional and leisure activities, with a high economical cost for the society [13]. These injuries can produce different degrees of structural damage and/or dysfunction of the PN, and they are classified by the Seddon and/or Sunderland (first- to fifthdegree injuries) classification. In first-degree injuries, the anatomy of the nerve is continuous with all the layers of the connective tissue preserved, but with the axon’s conduction capability affected. There is motor and sensory loss due to the demyelination process. This nerve conduction impairment usually affects motor fibers more than sensory fibers. In these cases, the management of the patients is conservative, and full recovery is expected. In the second- and third-degree injuries, the axonal continuity is disrupted within Wallerian degeneration [4]. The stroma is partially conserved, and the nerve regeneration will depend on the stromal disorganization and the distance to the distal muscle. Clinically, the patients show the Tinel’s sign, and both degrees of injuries are managed conservatively. Fourth- and fifth-degree lesions are considered as SPNI, and surgical treatment is required [4,9,14]. The fourth-degree lesions are characterized by internal disruptions that mainly affect the nerve fibers. The stroma is damaged but continuity of the nerve trunk is partially preserved, with limited spontaneous regeneration capability. In the case of fifth-degree injuries, there is a severe damage of the nerve trunk with a complete disruption of all the structures, and reinnervation does not occur without surgery [4,15,16]. There are several factors that influence recovery following a nerve injury, including the time elapsed, patient’s age, type of injury and surgical treatment. Following peripheral nerve injury and surgical repair, spontaneous nerve regeneration starts accompanied by cellular and molecular processes from the CNS to the peripheral levels, including the target organs [2,7,17]. SC play a key role and participate actively in both Wallerian degeneration (contributing to the phagocytosis of myelin and axon debris) and axon regeneration. SC proliferates and begins to form continuous cellular structures called bands of Bu¨ngner, which are guidance cues for axonal growth with a basement membrane [2,3]. Complete and detailed information on these processes has been comprehensively discussed in other review articles [2,3,17–19], and will not be considered for discussion in this review. Nerve reconstruction & tissue engineering

Microsurgery is the key scientific discipline in surgical nerve reconstruction and nerve tissue engineering (TE). Currently, there is a variety of microsurgical repair techniques and devices available to treat SPNI, and their application will depend of the state of the patient, nature and severity of the injury [9,20,21]. The main objective of all these techniques is re-establishment of the nerve continuity by direct microsurgical repair employing an adequate surgical technique. In cases when the nerves cannot be surgically reconnected, interposition of nerve grafts is 302

often used for nerve reconstruction [12,21,22]. Unfortunately, the graft material is limited and it has some associated disadvantages, opening a new era in nerve reconstruction and TE. Nowadays, it is possible to reconstruct nerves clinically and experimentally, by using non-nervous materials and/or different hollow nerve conduits (NC), and its approach is denominated tubulization [3,15,20,21,23,24], and has a long history starting from the 19th century. Since the first attempts, many different materials have been used as NC, but the tubulization technique still represents a great challenge for TE [20]. Some biological materials, including decalcified bones, blood vessels and muscle were first used to bridge nerve gaps, and the efficiency of the tubulization was demonstrated [21]. TE is a contemporary scientific discipline that combines the principles and methods of engineering, medicine and biology [25–27]. It offers the possibility to premanipulate different kinds of tissues and/or biomaterials in the laboratory in order to design biomimetic NC promoting the nerve regeneration [28–30]. In more recent years, the TE techniques showed a positive impact in the development of processed nerve allografts and, specially, NC [12,20,21,28]. Tubulization technique & TE

The use of artificial NC to bridge nerve gap is a clinical alternative when nerve autograft is not suitable [12,21,28,29,31]. NC can be fabricated by using synthetic polymers and/or natural biomaterials [28–32]. They were designed to increase the number, speed and length of the regenerating axons. NC provide mechanical support, directing the axonal growth from the proximal to the distal nerve stumps [28,30,31]. From the physical and structural point of view, NC must have the appropriate dimensions to bridge the nerve gap under tension-free suturing, avoiding any compression of the regenerating tissue. Indeed, there are a number of criteria for the ideal NC. The biomaterials used must be biocompatible and biodegradable; flexible and mechanically stable, with an appropriate rate of biodegradation; and semi-permeable to allow and control nutrient exchange, but conserving the regenerative microenvironment and suitable for their production, sterilization and surgical handling [12,21]. However, the ideal nerve conduit does not exist and certain key elements are missing from most NC. The first generation of NC was simple and based on the use of synthetic non-resorbable materials such as silicone. With the recent advances in TE and material sciences, a second generation of NC was developed. This second generation was mostly made of synthetic and natural biodegradable biomaterials [20,28,30]. Currently, a number of NC based on synthetic and natural biomaterials have been approved for clinical use by the US FDA [12]. Over recent years, different bioartificial nerve conduits (BNC) were developed by TE techniques. These BNC consist of functionalized biodegradable conduits filled with different biomaterials, growth factors, cells or a combination of all these elements [28–32]. These novel TE approaches showed better experimental results in comparison with the use of conventional hollow NC, but they are still under preclinical research. Expert Rev. Neurother. 14(3), (2014)

Tissue engineering of the PNS

The aim of the prior sections was to provide additional context in peripheral nerve structure, injuries and alternatives of nerve repair. The following sections provide the review of the current clinical management of SPNI, with special attention to clinical nerve reconstruction by TE. Finally, the experimental advances in peripheral nerve TE will be reviewed comprehensively.

A Direct repair, end-to-end neurorrhaphy Short nerve gaps Under tension free manner B Neurotization

C End-to-side neurorrhaphy

Donor nerve Injured nerve Donor nerve injury site


Current clinical management of peripheral nerve injuries

Currently, peripheral nerve injuries can be clinically managed by surgical techniques, the use of grafts and tubulization techniques.

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Key issues D The nerve autograft and allograft

Viable Schwann cells Growth factors Natural ECM

E Autologous muscle–vein-combined method

Surgical techniques

Vein conduit

There are several primary surgical techniSkeletal muscle Natural ECM ques, and they are well described and F Decellularized allograft addressed in some reviews [4,9,14–16]. Briefly, Acellular and purified ECM the primary surgical techniques currently used include neurolysis, end-to-end neuroG Tubulization technique rrhaphy, nerve transfer and end-to-side neuBiodegradable conduit rorrhaphy. In cases with loss of substance, Synthetic or natural nerve reconstruction can be performed with the use of autologous or allogenous grafts Figure 1. Current surgical management of peripheral nerve injuries. and tubulization (FIGURE 1) [4,5]. ECM: Extracellular matrix. First, neurolysis is essentially indicated for internal and/or external decompression of injured nerves. healthy donor nerve are transected, intraneurally dissected, This method is used in injuries corresponding to the first to redirected and anastomosed to a functionally more important third degrees of Sunderland, and a complete recovery of these injured distal nerve segment (FIGURE 1B) [9,16,33]. The main disadpatients is commonly expected. Second, direct nerve repair or vantage of neurotization is the possible loss of function from end-to-end neurorrhaphy is the most effective and preferred the donor nerve. This is a complicated surgical procedure, and method after nerve transection (FIGURE 1A) [9,14,28]. This method is there are no definitive guidelines for when to use nerve translimited to the treatment of short defects (15% of density) may trigger a significant reduction and/or inhibition of nerve regeneration [130,137]. In the case of filaments, fibers and films, the incorrect and heterogeneous distribution of these components into the NCs lumen also results in an inefficient or inhibition of the regeneration [127,135]. Finally, based on these studies, intraluminal fillers at low densities, homogeneously distributed and used in combination with permeable NC are considered optimal for their use in peripheral nerve regeneration [127,130,136,137]. All of these works confirm that the incorporation of a secondary scaffold as fillers is an efficient strategy to increase the nerve regeneration in comparison with empty NC. In this sense, fillers based on biodegradable biomaterials (natural or synthetic) are preferred, thanks to their high biocompatibility and biodegradability; thus, they have the advantage of not being permanent. Hydrogels are efficient physical support mainly composed of randomly oriented fibers, which have the advantage to increase the hydration rate of the microenvironment, favoring the concentration and diffusion of the local NF [101,120,125]. In the case of aligned intraluminal fillers, they mimic the native ECM orientation and have the advantage to guide and properly orient the regeneration front to the distal nerve stumps [117,127–133]. The use of growth factors

Following a nerve injury, several NF are released from the injured nerve stumps, triggering the complex process of nerve regeneration [17–19,138]. They can be classified into three groups: neurotrophins (including the NGF, brain-derived neurotrophic factor [BDNF], neurotrophin-3 [NT3] and neurotrophin-4 [NT4]), glial-cell-derived neurotrophic factor [GDNF]) and neuropoietic cytokines (include ciliary neurotrophic factor 308

[CNTF]) [138]. Based on this knowledge and trying to improve the nerve regeneration, a number of studies have successfully used different types of NF and exogenous growth factors (e.g., VEGF and acidic FGF-1) [21,28,30,31,72,120]. They can be incorporated into NCs lumen directly (in solution) or by the use of carriers or delivery systems [21,28,120]. In general, the growth factors have a short half-life and often their effects are dose-dependent, requiring a sustained release over the time. These two factors limit their direct addition into the NCs lumen, and delivery systems are generally preferred. In this sense, they were successfully incorporated into NC through the use of intraluminal fillers such as hydrogels, sponges, microspheres and different kind of filaments and/or fibers. Hydrogels were combined with delivery systems for the slow release of growth factors into the regenerative microenvironment. Silicone-based NC was filled with fibrin hydrogels containing a heparin-delivery system for the slow release of NGF. This approach was applied to bridge a critical nerve gap of 1.3 cm obtaining comparable nerve fibers densities to the nerve autograft after 6 weeks [139]. Similarly, in a comparative study, it was demonstrated that the use of GDNF was superior to the effect of NGF and nerve autograft after 6 [140] and 12 weeks [141]. Collagen matrix was also used to incorporate growth factors into synthetic NCs lumen. In a comparative study, NT3, BDNF and FGF-1 were evaluated bridging 1 cm of nerve gap. This study demonstrated an improvement of the nerve regeneration by the incorporation of growth factors in comparison with the use of empty or collagen-filled NC. Interestingly, FGF-1 was superior to the use of the other growth factors, with comparable results to the nerve autograft [142]. Collagen matrix was also enriched with BDNF and used to fill collagen-based NC. This strategy applied to bridge 1.5 cm of the rabbit facial nerve obtained comparable results to the nerve autograft [143]. These studies demonstrated that the use of NC filled with growth factors-functionalized hydrogels supports a significant improvement of the nerve regeneration with comparable results to autograft in more critical nerve gaps. NC were also functionalized by the incorporation of growth factors and/or essential ECM and/or peptide sequences within the biomaterials. These growth factors were incorporated within the NCs wall [144–148], encapsulated into intraluminal biodegradable microspheres [149–152] and combined with aligned biomaterials [68,117,153–155]. The incorporation of chitosan and chondroitin sulfate into the wall of the poly-DL-lactic acid based NC showed an improvement of the nerve regeneration, but comparable results to the autograft were only obtained by the immobilization of NGF into the inner NCs wall [148]. NGF was also successfully cross-linked into chitosan-based NCs wall, supporting the nerve regeneration [144]. Both studies demonstrated an increase in the nerve regeneration by the use of NGF in 1 cm of nerve gap. However, the real efficiency of these novel models in critical nerve gaps is unknown. In this regard, a critical nerve gap of 1.4 cm was successfully bridged with comparable results to autografting by the immobilization of NGF at gradient concentration into PCLA-based NCs Expert Rev. Neurother. 14(3), (2014)



wall [145]. Recently, the incorporation of RGD peptide (that favors the cellular attachment and migration) in combination with NGF showed promising results bridging a critical nerve gap of 3 cm in the tibial nerve of dogs [156]. Regarding to the aligned intraluminal fillers, they were functionalized with essential ECM molecules and growth factors to provide a synergistic effect to the nerve regeneration. Linear collagen scaffold were loaded with laminin and CNTF and used as intraluminal fillers inside silicone-based NC with a significant improvement on the nerve regeneration along a short nerve gap [68]. Promising results were obtained bridging 1 cm of nerve gap by the implantation of a novel NC composed of poly (L-lactic acid) nanofibrous blended with laminin and filled with PLGA fibers containing NGF [117]. A combined strategy showed interesting results following the implantation of poly-L-lactide-co-caprolactone (PLCL)-based NC filled with a composite hydrogel containing aligned PLCL fibers blended or not with NGF. In this study, positive outcomes were obtained with the use of hydrogels containing aligned PLCL fibers, but the incorporation of NGF did not have a significant effect on nerve regeneration. This study demonstrated that the use of two combined physical fillers promotes an efficient nerve regeneration and sensory recovery [157]. Growth factors can also be used in combination providing a synergetic effect to the nerve regeneration [158–160]. The use of a codelivery system for the slow release of both GDNF and NGF showed a significant improvement of the nerve regeneration [147]. The incorporation of growth factors is an efficient experimental alternative to improve the nerve regeneration of NC [68,141,142,146–149]. These growth factors have some limitations that could be solved by the use of controlled delivery systems, where they are efficiently immobilized or cross-linked into NC and/or intraluminal fillers [139,145,147,152–155]. These studies also demonstrate that the combined use of physical fillers and growth factors or the combination of two growth factors provide a synergetic effect to the regenerative microenvironment, promoting a comparable nerve regeneration to the use of autograft [140,141,146,148,153,158,160]. Cell therapy in peripheral nerve TE

Local cells drive the complex process of peripheral nerve regeneration. Following a nerve injury, they release a wide range of growth factors (neurotrophic and angiogenic factors), ECM molecules and cytokines creating an optimal regenerative microenvironment to trigger and support the nerve regeneration [2,17,19]. The SC proliferate increasing its number (between 4- and 17-times), providing a stable physical and molecular support to the axonal regrowth and final stabilization in short nerve gaps [28,161]. For this reason, the SC’s proliferation and migration is considered indispensable for the success of the regeneration, but they remain insufficient to repair critical nerve gaps. In attempts to reinforce the regenerative cellular response, cell-based therapy emerges as an efficient alternative to the use of growth factors in peripheral nerve TE [28,32,77,119,120,161–165]. SC and different stem cells were successfully incorporated into NC giving rise to a new generation of BNC with promising results. These cells informahealthcare.com

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can be incorporated by direct injection, combined with soft materials and/or hydrogels, attached within aligned biomaterials and/or incorporated to the inner surface of the NCs wall. Schwann cells

Currently, the addition of autologous SC is considered the gold standard of the cellular-based therapy in experimental peripheral nerve regeneration. They drive the nerve regeneration by the production of essential NF, ECM molecules and also by their active participation in the Wallerian degeneration [28,101,120,166,167]. Previous studies demonstrated the positive impact of the BNC containing SC. In this sense, different SC types (autologous, syngeneic, allogeneic and transducted SC) were tested. As a result, a significant increase of the nerve regeneration and less adverse effects was achieved by the use of allogeneic and autologous SC [168–171]. In another study, the allogeneic SC were retrovirally labeled (for the expression of the green fluorescent protein) and implanted into silicone-based NC. This study demonstrated the integration of the implanted cells into the host regenerative process, doubling the rate of nerve regeneration in comparison with the empty NC. Additionally, these authors evaluated the impact of different cellular densities, and they found an optimal cellular density (80 106 cell/ml) with maximal nerve regeneration [161]. In another study, impressive histological results were achieved when 6 cm of vein graft filled with matrigel containing purified autologous SC was used to bridge 6 cm of nerve gap in rabbits [169]. Other outcomes were addressed, and SC were successfully used in combination with fibronectin/alginate scaffold [172], collagen/ hyaluronic acid/laminin hydrogel [173], muscle-vein-combined technique [42] and seeded within micropatterned biodegradable NC [174]. Recently, a biodegradable collagen/chitosan-based scaffold containing longitudinally oriented micro-channels was successfully combined with SC. In this study, the authors bridged 1.5 cm with comparable nerve regeneration and functional recovery to nerve autograft [175]. All of these studies demonstrate the effectiveness of the SC’s incorporation into BNC. They provide growth factors (NGF, BDNF, NT-3, CNTF and GDNF) and ECM molecules (collagens and basal membrane’s component) that enrich the regenerative microenvironment resulting in a significant increase of the nerve regeneration in short and larger nerve gaps [167]. In addition, these cells should be combined with intraluminal fillers and/or NCs wall modification to ensure their survival and function [72,169,170,174,175]. Unfortunately, autologous or allogeneic SC present comparable disadvantages than the use of nerve autograft and/or allograft (described above), besides they are only available after a difficult and lengthy expansion time in vitro. For all these reasons, their clinical application remains a non-viable option [28,72,165,176,177]. Stem cells

Due to the limitations of the SC, different kinds of mesenchymal stem cells (MSCs) have been used within BNC. These stem cells are characterized by their hypo-immunogenicity, 309


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adhesive behavior and by a panel of positive and negative cell surface markers. Under specific culture conditions, they can differentiate into multiple mesodermal [178–181], neural and glial cell lineages [182–184]. Bone marrow-derived mesenchymal stem cells (BMSCs) [162,182,185,186] and adipose-derived mesenchymal stem cells (ADMSCs) [32,165,187–190] have been widely used in peripheral nerve TE. Other stem cells have been less explored, but an increase in the nerve regeneration was achieved with dental pulp-derived mesenchymal stem cells [191,192], Wharton’s jelly-derived mesenchymal stem cells [183,193] and embryonic stem cells [194]. BMSCs can be obtained from the bone marrow through an invasive procedure obtaining large amounts. Undifferentiated BMSCs were efficiently implanted into biodegradable chitinbased NC and injected into epineurial tubes showing a significant improvement of the nerve regeneration at the histological and functional levels [186,195]. BMSCs were successfully stimulated for their differentiation into SC-phenotype (expressing SC’s markers) and injected into collagen-based NC to bridge 1.2 cm of nerve gap. These cells promoted a significant improvement of the nerve regeneration with similar results to SC, and better than NC filled with undifferentiated BMSCs and empty NC. However, these results were poor in comparison with the use of the nerve autograft [182]. Better results were obtained when a fibrin matrix was combined with differentiated BMSCs and used to fill a biodegradable NC. In this study, this combined strategy promoted a significant increase of the nerve regeneration. As a result, differentiated BMSCs showed comparable results to the use of SC, and both cells were superior to the use of undifferentiated BMSCs and empty NC [185]. Currently, the ADMSCs are considered one of the most promising alternatives in peripheral nerve TE. These cells can be autologously obtained in higher number, and are preferred for TE applications in comparison with other sources of MSCs [31,32,70,165,188,196–198]. ADMSCs were differentiated into SC phenotype and compared with differentiated BMSCs and SC. It was demonstrated that both differentiated MSCs promoted a comparable increase of the nerve regeneration at the histological level [165]. These cells were also successfully used undifferentiated, and it was demonstrated that they have the capacity to release BDNF, stimulating the regeneration of peripheral nerves [188]. Based on their adhesive behavior, they were seeded into chitosan/silk scaffold and implanted in vivo to bridge 1 cm of nerve gap. This study showed a positive impact of these cells with a progressive enhancement of the nerve regeneration and functional recovery after 12 and 24 weeks [187]. Recently, the potential usefulness of the ADMSCs in combination with fibrin-agarose hydrogel was tested with success in nerve regeneration. In this study, collagen-based NC filled with saline or acellular fibrin-agarose or fibrin-agarose containing autologous ADMSCs was used to repair 1 cm of the rat sciatic nerve. The use of acellular fibrin-agarose hydrogels showed a significant improvement of the nerve regeneration and functional recovery compared with saline-filled NC. Even more 310

significant outcomes were achieved after 12 weeks when the ADMSCs were used in combination with fibrin-agarose hydrogels. This improvement was attributed on the one hand to the enriched environment provided by the hydrogels containing ADMSCs, and on the other hand to the increase of the collagen fibers and laminin [32]. Cell-based therapies were also successfully combined with the use of decellularized nerves grafts. BMSCs were mixed with fibrin and injected into a decellularized nerve graft to treat a critical nerve gap of 1.5 cm with success [199]. ADMSCs were characterized, differentiated into neural phenotype and seeded into a xenogeneic (porcine origin) nerve graft to bridge 1 cm of nerve gap. Axonal regeneration was demonstrated after 28 days, and the differentiated ADMSCs expressed NGF, GDNF, BDNF and the markers glialfibrillar acidic protein and S-100 [200]. These results confirm the capacity of these cells to release essential NF, which supports the nerve regeneration. In other recent study, it was demonstrated that both BMSCs and ADMSCs are effective to recellularize nerve allograft and support the nerve regeneration [163]. There is evidence supporting that the use of MSCs are an efficient and comparable alternative to SC in experimental nerve TE [163,164,182,186,188–190,193,199,201–203]. They can be easily obtained in large amounts, especially the ADMSCs [32,165,189,190]. MSCs promote a significant increase of the nerve regeneration and avoid the drawbacks associated with the use of SC [32,177,189]. These cells were efficiently used in peripheral nerve TE at both undifferentiated and differentiate states. The incorporation of undifferentiated MSCs is an effective alternative, where the local regenerative microenvironment exerts an important role stimulating these cells to differentiate in vivo into multiple pathways and in accordance with the local necessities [28,189]. However, the complex mechanisms related with the success of the nerve regeneration using undifferentiated MSCs are still unknown, limiting their potential clinical use. The differentiation of these MSCs decreases its uncontrolled behavior and variable results were often observed with their use. They can be differentiated into SC or neural phenotype, showing a slight or significant improvement on the nerve regeneration [163,165,182,189,190]. In cell-based therapies, the use of biodegradable-based NC filled with soft materials supporting the cells is recommended to ensure the effectiveness of the cellbased therapies in peripheral nerve TE [72,169,170,174,175]. Although recent studies have demonstrated the positive impact of the MSCs in nerve regeneration, considerable optimization of these cell-based strategies is still required for their future clinical application. Expert commentary

Currently, there are several surgical methods available for the treatment of peripheral nerve injuries. In the case of short nerve gaps, the direct repair is a well-established method and it is considered the most effective and preferred alternative among surgeons. This method should be performed as soon as possible following its four surgical steps, and good to excellent recovery of these patients could be obtained. In cases when the direct Expert Rev. Neurother. 14(3), (2014)



repair is not available, the neurotization and end-to-side neurorrhaphy could be performed. These methods were described for the treatment of upper limb injuries with promising results, and for their success surgical expertise is required. However, the possibility of loss of function of the donor nerve exists. In the treatment of critical nerve gaps, the nerve autograft is the most effective alternative, with good to excellent sensory recovery, but its effectiveness is variable in the reconstruction of motor nerves. The allograft is an effective alternative to the autograft, and critical nerve gaps reconstructions were achieved with success. Unfortunately, there are several associated disadvantages to the use of nerve autograft and allograft that limit their use, and frequently they are not clinically available. Some interesting outcomes were developed with comparable results to the use of the gold standard nerve autograft and allograft. In the case of allograft, their adequate cryopreservation reduces its associated immunogenicity retaining its physical and molecular structure. Cryopreserved nerve allografts have been used clinically in the treatment of large nerve gaps with good results, avoiding the disadvantages associated with the nerve autograft and especially allograft. In the last years, different decellularized allografts have been approved by the FDA for their clinical use. Decellularized allograft provides a natural ECM that supports nerve regeneration with a sensory recovery closely near to the normal levels. Based on the clinical evidence, both allograftbased methods are recommended to bridge short sensory or digital nerve gaps. Nowadays, there is not enough published evidence to demonstrate the effectiveness and possible applications of these allograft-based methods, and more research and clinical evidences are needed. The tubulization technique surged as one of the most promising alternatives for treatment of nerve gaps. They were designed and fabricated based on natural and/or synthetic biomaterials, to provide a close environment to guide, support and protect the nerve regeneration. Some NC were approved for their clinical use by the FDA, and natural as well as synthetic NC showed good results in the treatment of short nerve gaps. From the surgical point of view, the implantation of NC is a simple and fast procedure, where fewer sutures are needed, with the consequent reduction of the episodes of neuropathies. Collagen-based NC and PGA-based NC are the most used with more experimental and clinical data available. On the one hand, collagen-based NC are probably one of the most biocompatible devices, which support and also promote the nerve regeneration. On the other hand, PGA-based NC are less biocompatible than collagen NC, but offer good mechanical stability, and are the preferred synthetic NC among surgeons. Tubulization technique was clinically applied to treat short and critical nerve gaps, and just acceptable results were achieved in short nerve gaps. At the present, it is accepted that the tubulization technique is a safe and effective alternative limited to bridge non-critical sensory nerve gaps with a maximum length of 3 cm. Despite these advances in surgery and TE, the nerve autograft remains as the gold standard for the treatment of critical nerve gaps. Optimal regeneration was not achieved using single informahealthcare.com

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factor strategies such as empty NC. Experimentally, these models have shown an exponential evolution with a significant increase in the nerve regeneration in animal models. Trying to improve the results of empty NC, the incorporation of intraluminal fillers, growth factors and cell-based therapies demonstrated a significant improvement of the nerve regeneration and functional recovery. Different biomaterials were successfully used as intraluminal fillers such as hydrogels, films and aligned fibers. Studies demonstrated an increase of the nerve regeneration by the incorporation of intraluminal fillers at low densities and homogeneously distributed into the lumen of biodegradable NC. Highly aligned filaments, fibers and film are efficient physical support that guide and direct the regeneration front. In the case of hydrogels or soft biomaterials, they provide an efficient physical support for nerve regeneration, and also an adequate hydration rate that favors the diffusion and concentration of essential molecules. In general, these intraluminal fillers are essential during the first stages of the regeneration, after that they could exert an inhibition or a decrease of the nerve regeneration. In this sense, natural biomaterials that are highly biocompatible and fastly absorbed are recommended such as fibrin, fibrin-agarose and soft collagen sponges. NC were functionalized by the incorporation of growth factors or essential ECM molecules. These molecules stimulate the SC proliferation, cellular migration and axonal regrowth, with a significant increase of the nerve regeneration. These molecules were used in solutions and associated with delivery systems. In this sense, good to excellent results were obtained when these molecules were combined with delivery systems and/or soft biomaterials. More recent evidence demonstrated the synergistic impact on nerve regeneration by the use of combinatorial approaches. The use of two or more growth factors in association with intraluminal filler promotes a significant increase of the nerve regeneration with comparable results to the nerve autograft. However, more studies are required to determine the safeness of the in vivo use of growth factors. Cell-based therapies have emerged as a promising alternative to improve the nerve regeneration. The incorporation of SC is considered the gold standard in experimental cell-based therapies in nerve TE. Studies have demonstrated that these cells participate actively, stimulating and supporting the nerve regeneration at the optimal density. Unfortunately, there are several limitations associated with the use of SC, but they have been solved using MSCs. These MSCs can be used undifferentiated and differentiated into SC phenotype, and in both cases an increase of the nerve regeneration could be achieved. MSCs participate in the nerve regeneration and have the capacity to release essential growth factors. To ensure the effectiveness of the cell-based therapies, the use of soft intraluminal fillers is recommended. Finally, all these novel strategies have demonstrated significant improvements of the nerve regeneration, but there are fewer negative results available to help us to understand these complex unsuccessful outcomes. With the data available, it is possible to conclude that the closer we get to the biomimetic regenerative 311

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microenvironment, the better results we obtain. This proves that the correct knowledge of the cellular and molecular processes involved during nerve regeneration is essential to design novel strategies to improve the nerve regeneration.


Five-year view

Currently, the application and limitations of the available surgical alternatives are well established. In addition, it is accepted that NC need additional physical, molecular or cellular factors to provide an adequate regenerative microenvironment, especially in critical nerve gaps. In 5 years, several experimental and clinical outcomes will be addressed. From the experimental point of view, a better understanding of the cellular and molecular processes involved in the nerve regeneration will be addressed. A wide range of biodegradable biomaterials and technologies will be available for their application in nerve TE. In order to provide an adequate microenvironment for nerve regeneration, the appropriate combination of NC, intraluminal fillers and cell sources will be achieved with success. Research will be focused on determining the most effective alternatives to bridge critical nerve gaps and replace the gold standard nerve

autograft. From the clinical point of view, more positive and negative evidence regarding the tubulization technique will be available. Comparative studies will be performed elucidating the most adequate indication of each surgical alternative or neural device. Finally, a novel generation of NC based on novel biomaterials, growth factors and maybe cells sources will be approved for their clinical use by the FDA. Financial & competing interests disclosure

This study was supported by the Spanish Ministry of Economy and Competitiveness, grant IPT-2011-0742-900000 (INNPACTO program), cofinanced by Fondo Europeo de Desarrollo regional (FEDER), EU. V Carriel is supported by the grant of excellence P10-CTS 6060 from the Junta de Andalucıá, Spain. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. The authors are grateful to Ariane Ruyffelaert from the Department of Linguistics, Ghent University, Belgium for assistance with the English of this manuscript.

Key issues • The peripheral nervous system has the capacity to regenerate its distal components following a physical disruption. • According to the structural affection, there are five degrees of nerve injuries, and the surgical nerve reconstruction is the unique alternative to treat severe nerve injuries (fourth and fifth degrees of injuries). • Direct surgical repair is the preferred and most efficient method for the surgical treatment of short nerve defects, but comparable or better results are achieved by the use of tubulization technique. • In case of nerve injuries with loss of substance, the interposition of a nerve autograft or allograft is required. The nerve autograft is the most effective, providing a natural extracellular matrix, growth factors and viable Schwann cells. However, there are several associated disadvantages and they are not always clinically available. • Clinically, decellularized nerve allograft and artificial nerve conduits (NC) are used to bridge different nerve gaps in replacement of the conventional surgical techniques and the use of graft materials. Decellularized nerve allograft is successfully used to bridge critical nerve gaps, while NC are limited to short nerve gaps with a maximum length of 3 cm. • Experimentally, a novel regeneration of NC composed of highly aligned biodegradable biomaterials promotes efficient nerve regeneration. They guide and direct the nerve regeneration and sometimes comparable results to the nerve autograft are obtained. • Cell-based therapy promotes a significant increase of nerve regeneration. The Schwann cells or mesenchymal stem cells are combined with soft biomaterials and are used to fill biodegradable NC. • Mesenchymal stem cells are one of the most promising alternatives to repair nerve defects. They have the capacity to differentiate into Schwann cells phenotype, to release growth factors and to participate in the process of nerve regeneration.

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