3. Pharmacological aids to enhance regeneration after nerve root reimplantation

time the regenerating axonal sprouts reach the motor end plates [72, 73]. In rats, functional recovery is seen only in cervical but not in lumbosacral avulsion models as the distance to cover is much shorter for the cervical NRs [9, 40, 85–87], and in any case only proximal limb muscle recovery is seen [86–89]. Third, the regenerating fibers may reach the wrong target due to misrouting [53], and in the absence of NG or conduit, the regenerating axons will grow along the surface of the SC [27, 43, 53, 83, 87]. The misrouting is responsible for simultaneous contractures in agonist and antagonist muscles leading to ineffective limb movements [30]. Fourth, there is severe muscular atrophy due to lack of use [74]. Hence, for a successful clinical result, MN survival must be improved, axonal regeneration has to be enhanced and accelerated, misrouting should be minimized and muscle atrophy should be prevented [15, 72].

Although the MN cell body can regenerate and grow a new axon after this is torn [69, 90], many MNs apoptose [13, 65, 69], and only 80% of the surviving MNs do finally project a regenerating axon in the reimplanted ventral root or NG [26, 27, 31, 86]. Reimplantation of avulsed NRs either directly or by means of a peripheral NG helps to reduce the number of MNs undergoing apoptosis, probably because of local NF production [69, 77, 89, 91–93]. Exogenous NFs can be administered to enhance the regenerating capacity of cells [47, 94, 95]. Historically, the first attempts were directed at motor recovery with ventral rootlet reimplantantion [96], but recently sensory recovery has been proved possible by reimplanting dorsal rootlets [97]. The results of dorsal rootlet repair are dismal because the SC glial proliferation creates barriers that prevent the regenerating DRG axons from reaching the posterior SC horn [81]. The lack of sensory recovery induces chronic neuropathic pain [49, 98], and the lack of proprioception causes limb clumsiness [30]. This has been partially avoided by direct implantation of the dorsal rootlets or their NGs' extensions inside the posterior horn itself rather than on the surface of the SC [81, 99]. The repair of both motor and sensory NRts leads to better functional results with more accurate movements and less muscular synkinesis [100]. Functional MRI studies have corroborated affected limb sensory cortex function recovery in

The timing of NR reimplantation is crucial, as a longer waiting period will correlate with a greater amount of MNs undergoing apoptosis [20, 27, 91, 93, 101–103]. The percentage of dead MNs increases from 20% by 10–12 days post-avulsion [13, 65, 69] to 50% by 4 weeks [104, 105], 85% by 6 weeks [106] and 90% by 20 weeks [27, 83, 93, 107]. Early NR reimplantation seems to have neuroprotective effects [27, 83, 89, 93, 108, 109], but some MN loss will happen even if repair occurs immediately after avulsion [93, 101]. In animal models, NRA followed by immediate reimplantation in the same surgical procedure minimizes MN apoptosis and achieves muscle reinnervation with some limited functional recovery, which is better in the brachial plexus than in the lumbosacral plexus [27, 69, 83, 110]. Ideally, the surgical repair must be performed no later than 10 days post-injury [65] as a delay over 2 weeks will lead to poor clinical results [20, 26, 27]. In clinical practice, patients suffering from brachial or lumbosacral plexus avulsions often experience other concomitant injuries, sometimes quite serious, that force delaying NR repair [111]. Another common scenario is that the precise diagnosis takes weeks or even months [3]. In any case, in human beings NRA repair has to occur no later than 1 month after the injury to allow any motor function recovery [45, 74, 97, 100]. NGs are almost

the area corresponding to the reimplanted NR [100].

48 Treatment of Brachial Plexus Injuries

Several pharmacological aids have been introduced to improve MN survival and axonal regeneration after anterior spinal NRt reimplantation. They can be classified into NFs, drugs and cell-derived products (Table 1).

NF administration improves MN survival as well as synaptic and axonal regrowth [87, 112–115] improving the NR reimplantation results. NFs enhance Schwann cell migration, axonal regeneration and myelination [8, 16, 69, 93, 105, 116–120] and delay MN apoptosis—by 6 weeks 80–90% of them are still alive [8, 69, 116, 118–121]. To be maximally effective, they must be administered locally at the SC-NR interface within the first 3 days and no later than 2 weeks post-avulsion [20, 87, 93, 116]. NFs ought to be applied with Gelfoam or fibrin glue to avoid dilution in the CSF [72], but free intrathecal application by means of an injecting pump is not recommended [122]. Their short half-life limits their use, particularly because NFs have to be applied directly to a surgically exposed SC [123]. Although NFs increase MN survival and axonal regeneration, their effect on muscle recovery and final functional results is very limited [4, 7, 18, 20, 27, 37, 93, 105]. It has been observed that in areas where the concentration of NFs is high, the regenerating axons get trapped and do not grow to reach their final distal targets [18, 102]. Some have cautioned against the possible adverse effects of using NFs in human clinical practice [124]. The currently used NFs are brain-derived neurotrophic factor (BDNF) [115], glial-derived neurotrophic factor (GDNF) [8, 18, 20, 37, 102, 105, 125], ciliary neurotrophic factor (CNTF) [87] and intracellular sigma peptide (ISP) [126]. GDNF shows the strongest action and a single direct application to the SC are enough, provided that they are applied within the first 2 weeks after NRA [18, 20, 37, 102, 116, 127]. GDNF delays MN cell death for 6 weeks, therefore broadening the window for avulsed NR reimplantation [20]. Similarly, the intracellular sigma peptide (ISP) blocks astrocytic inhibitory action, thus facilitating axonal regeneration [126].

Moreover, the distance to cover by the regenerating axons from the SC avulsion site to the muscular end plates is so long that by the time the axons reach their destination, the muscles are atrophic and fibrotic [20, 128]. To avoid and delay this muscle atrophy as much as possible, several strategies have been attempted: manipulating the molecular pathways involved in muscle atrophy [129–131], nerve transfers from neighboring functioning nerves [132–136], direct electrical stimulation of the affected muscles [137–139] and neuronal transplantation inside the denervated muscle [20, 140–142]. In rats, the combination of GDNF at the SC-NR injury site and embryonic spinal foetal neuron transplant inside the target muscles provided the best possible functional result [20]. These embryonic neurons reinnervate the muscle end plates just after the injury, preventing muscle atrophy while the regenerating axons arrived


Agent Lithium Minocycline

Tetracyclyne

Inhibits glial

Orally

Motoneuron

Improves axonal

Neurotoxic

doses.

Prevents and reverses

hypersensitivity

 at high

Rat,

Bacterial infections,

mice

Stroke

sprouting and

migration

survival

487% at

5 weeks. Autonomic

neurons ∅

effect

Recombinant

Drug

 Counteracts

Subcutaneously

survival

51.7 0.8%

at 12 days

postavulsion

Motoneuron

Suppresses

Induces a pro-

Rat

 Anemia

thrombotic

 state. Neuroprotective

microglia

proliferation.

Protects axon

effect NOT long-

regeneration

lasting

glutamate's

effect

 cytotoxic

erythropoietin

FK506-tacrolimus

 Drug

Target heat shock

protein 90

Immunosuppression.

Sublingual

survival not

axons

reported.

penetrating

reaching the

posterior horn

 and

> Used ONLY

in dorsal

nerve root

repair

Geldamycin Acamprosate

 Drug

⇓

Synaptic glutamate

 Orally

Ansamycin

On heat shock protein

Parenteral

⇑ dorsal

axonal

ganglion

regeneration

Toxic at high doses

neuron.

Motoneuron

not studied

Associated

Associated

ribavirin

accelerates

 with

Side effects if ethanol

Rat

 Alcoholism 51

consumption

with

ribavirin ⇑

Survival

Accelerates

No

Rat

 Cancer

Nerve Root Reimplantation in Brachial Plexus Injuries http://dx.doi.org/10.5772/intechopen.82431

immunosuppression.

injection

antibiotic

90. NOT immunosuppression

Motoneuron

⇑

Regenerating

Immunosuppression.

Rat

 Organ transplant immunosuppression

Long-term

administration

needed

derivative

proliferation.

 Strong

anti-inflammatory

effect

Drug

⇑

Endogenous

secretion

 BDNF

Orally

Group

Mechanism

 of action

Administration

Motoneuron

Axonal

Observation

 Applied

Current human

to

clinical use

regeneration

survival

post-injury

Motoneuron

⇑

Myelinated

Helps prevent muscle

Rat

 Bipolar disorder

atrophy

survival 69%

axons inside reimplanted nerve

by 12 weeks

postavulsion

root

route


Agent Brain-

NF

Reverses cholinergic

Intrathecal

survival 53%

by 16 weeks

fibers reaching

cord-avulsed

root interface

Motoneuron

Abundant regenerating

Active against many

Rat

 None

50 Treatment of Brachial Plexus Injuries

neurodegenerative

disorders

transmitter-related

enzyme deficiency

derived-neurotrophic-

factor (BDNF)

Glial-

NF

⇑

Survival of

Direct

Completely

⇑ Axonal

Strongest NF.

combined with

Riluzole

Administration

⇑ Effect

Rat

 None

prevents

regeneration

motoneuron

and coiling and

regeneration

Schwann cells

before 2 week post-

avulsion

loss at 16 weeks postavulsion

administration

dopaminergic

neurons

on spinal cord

derived-neurotrophic-

factor (GDNF) Ciliary NF (CNTF)

 NF

Activates motor

Direct

Motoneuron

⇑ Axon

Conjugation

transferrin prolongs

 it with

Rabbit

 None

administration

survival 23

4.3% by 3 weeks post-

avulsion

regeneration

across interface

its action

> spinal cord/

nerve root

neuron signal

transducer

 and

on spinal cord

transcription

activator(STAT3)

Intracellular

peptide (ISP)

Resveratrol

Riluzole

Drug

 Inhibitor presynaptic

Orally

Motoneuron

⇑

Myelinated

Administration

Rat

sclerosis, Nervous

Depression,

Cord Injury

 Spinal

Amyotrophic

 lateral

> before 2 week after

injury. Maximum

survival 70%

axons in reimplanted nerve

> by 5 weeks

postavulsion

root.

⇓ hypersensitivity

and allodynia

Sensory

effect combined with

GDNF

glutamate release

Drug

inhibitor

Topoisomerase

 II

Added to nerve

Motoneuron

⇑ Axonal

Only tried on

Rat

 Cancer, Chronic

diseases, Aging

autologous

graft cultures

 nerve

survival 69%

regeneration,

Schwann cell migration and

myelination

at 8 weeks

postavulsion

graft culture

 sigma

NF

⇓

Inhibition of

Subcutaneous

Motoneuron

⇑

Amount and

Act as synapse

Rat

 None

organizing

 agent

survival

size of regenerated

axons

61.2% at 12 weeks postavulsion

injection

astrocyte secreted

chon-droitin

proteoglycans

 sulfate

 3

Group

Mechanism

 of action

Administration

Motoneuron

Axonal

Observation

 Applied

Current human

to

clinical use

regeneration

survival

post-injury

route


Table 1. NFs (neurotrophic factors) and drugs used in nerve root reimplantation with their effects.

[20]. However, when the regenerating axons reached the muscular end plates, they had to compete with the already existing axons coming from the locally injected embryonic foetal

Some drugs have been administered to minimize MN apoptosis and improve NR regenera-

zothiazole) [8, 69, 121], lithium [146, 147], minocycline [119], recombinant erythropoietin

[154], N-acetyl cysteine [155] and glatiramer [156]. Some researchers have administered combinations such as acamprosate and ribavirin [154] or riluzole and GDNF [8]. The main advantage of acamprosate, ribavirin, and riluzole is that they can be administered orally

Resveratrol has been added to the autologous NG culture for a week in the rat experimental C6 NRA and reimplantation model [145], finding that it improves axonal regeneration,

In experimental brachial plexus avulsion (BPA) rat models, riluzole has been proved to improve MN survival, prolonging the time period at which reimplantation can be successful [65, 69, 101, 121]. If administered within 2 weeks post-avulsion, riluzole helps to keep 70% of the MNs [65, 69, 121] alive and minimizes the sensory hypersensitivity and allodynia [119]. Its maximum effect is achieved when combined with GDNF [8], and it can be administered

In rat, experimental avulsion models and at doses used in the treatment of mood disorders, lithium improves neuronal survival, axonal regeneration and myelination, allowing an earlier and better functional recovery [146, 147]. One of its mechanisms of action is by increasing endogenous BDNF secretion [158]. Its effect on growing axon myelination starts 4 weeks post-NR reimplantation, reaching its pinnacle at 6 weeks and slowing down by 12 weeks [146].

properties [120]. In rats, it has been administered intraperitoneally and intrathecally, with better results through the latter route [106]. At low doses, minocycline has neuroprotective properties, but at high concentrations it is neurotoxic [164], among other reasons, because glial proliferation and Wallerian degeneration are a sine qua non for nerve regeneration [106].

Recombinant erythropoietin injected subcutaneously once a day for 3 days has shown neuroprotective properties in a rat NRA experimental model [118]. These neuroprotective properties are short lasting but can help to delay motor neuron apoptosis after NRA, increasing the period in which a NR reimplantation can be undertaken [118]. Recombinant erythropoietin seems to counteract the cytotoxic effect of glutamate, block free radicals, increase the release of neurotransmitters and decrease microglial activation [165]. The positive effects of recombinant erythropoietin are maximal when its administration is started within 96 hours (4 days) after NRA and reimplantation [118]. The side effects related with the administration of

Minocycline is a tetracycline derivative that inhibits glial proliferation [159]

Schwann cell migration and myelination and MN survival

,5-trihydroxystilbene) [145], riluzole (2-amino-6-trifluoromethoxyben-

–151], geldanamycin [152, 153], acamprosate [67, 154], ribavirin

—and decreases neuronal [161] and oligodendrocyte cell loss

–brain barrier and has anti-inflammatory

—69% surviving 8 weeks after

Nerve Root Reimplantation in Brachial Plexus Injuries http://dx.doi.org/10.5772/intechopen.82431 53

—a barrier against

neurons [20, 140, 143, 144].

[118], FK506-tacrolimus [148

.

axonal and dendrite growth [160]

[120, 162, 163]. Minocycline can cross the blood

tion: resveratrol (3,4<sup>0</sup>

[67, 154, 157]

NR repair.

orally [157].

[20]. However, when the regenerating axons reached the muscular end plates, they had to compete with the already existing axons coming from the locally injected embryonic foetal neurons [20, 140, 143, 144].

Some drugs have been administered to minimize MN apoptosis and improve NR regeneration: resveratrol (3,4<sup>0</sup> ,5-trihydroxystilbene) [145], riluzole (2-amino-6-trifluoromethoxybenzothiazole) [8, 69, 121], lithium [146, 147], minocycline [119], recombinant erythropoietin [118], FK506-tacrolimus [148–151], geldanamycin [152, 153], acamprosate [67, 154], ribavirin [154], N-acetyl cysteine [155] and glatiramer [156]. Some researchers have administered combinations such as acamprosate and ribavirin [154] or riluzole and GDNF [8]. The main advantage of acamprosate, ribavirin, and riluzole is that they can be administered orally [67, 154, 157].

Resveratrol has been added to the autologous NG culture for a week in the rat experimental C6 NRA and reimplantation model [145], finding that it improves axonal regeneration, Schwann cell migration and myelination and MN survival—69% surviving 8 weeks after NR repair.

In experimental brachial plexus avulsion (BPA) rat models, riluzole has been proved to improve MN survival, prolonging the time period at which reimplantation can be successful [65, 69, 101, 121]. If administered within 2 weeks post-avulsion, riluzole helps to keep 70% of the MNs [65, 69, 121] alive and minimizes the sensory hypersensitivity and allodynia [119]. Its maximum effect is achieved when combined with GDNF [8], and it can be administered orally [157].

In rat, experimental avulsion models and at doses used in the treatment of mood disorders, lithium improves neuronal survival, axonal regeneration and myelination, allowing an earlier and better functional recovery [146, 147]. One of its mechanisms of action is by increasing endogenous BDNF secretion [158]. Its effect on growing axon myelination starts 4 weeks post-NR reimplantation, reaching its pinnacle at 6 weeks and slowing down by 12 weeks [146].

Minocycline is a tetracycline derivative that inhibits glial proliferation [159]—a barrier against axonal and dendrite growth [160]—and decreases neuronal [161] and oligodendrocyte cell loss [120, 162, 163]. Minocycline can cross the blood–brain barrier and has anti-inflammatory properties [120]. In rats, it has been administered intraperitoneally and intrathecally, with better results through the latter route [106]. At low doses, minocycline has neuroprotective properties, but at high concentrations it is neurotoxic [164], among other reasons, because glial proliferation and Wallerian degeneration are a sine qua non for nerve regeneration [106].

Recombinant erythropoietin injected subcutaneously once a day for 3 days has shown neuroprotective properties in a rat NRA experimental model [118]. These neuroprotective properties are short lasting but can help to delay motor neuron apoptosis after NRA, increasing the period in which a NR reimplantation can be undertaken [118]. Recombinant erythropoietin seems to counteract the cytotoxic effect of glutamate, block free radicals, increase the release of neurotransmitters and decrease microglial activation [165]. The positive effects of recombinant erythropoietin are maximal when its administration is started within 96 hours (4 days) after NRA and reimplantation [118]. The side effects related with the administration of

Agent

Group

Mechanism

 of action

Administration

Motoneuron

Axonal

Observation

 Applied

Current human

to

clinical use

52 Treatment of Brachial Plexus Injuries

regeneration

survival

post-injury

motoneuron

axonal

regeneration

survival by

64.62% at

>4 weeks

> 1 week

> > Ribavirin

Drug

 Synthetic guanosine

Orally

Associated

Associated

 with

Can induce anemia

 Rat

 Hepatitis virus C

Acamprosate

accelerates

axonal

with

acamprosate

⇑

motoneuron

regeneration

survival by

>4 weeks

> 64.62% at

1 week

> N-acetyl cysteine

Glatiramer Table 1. NFs

(neurotrophic

 factors) and drugs used in nerve root

Drug

Immunomodulator

Subcutaneously

⇑

Reduction in

⇑ Risk of infection

Rat

 Multiple sclerosis

> and malignancy

Motoneuron

astrocyte

proliferation

survival but

NOT

quantified

reimplantation

 with their effects.

 Drug

 Stabilizes oxidative

Orally

Neuron

Facilitates

Vitamin C

Rat

 Mucolytic

counteracts

effects

 side

survival 26%

axonal

motor, 95%

regeneration

sensory

metabolism

antiviral properties

route

this drug—increase in erythrocyte production and a prothrombotic state—are not problematic because this drug is only administered for 3 days [118]. Perhaps administering this drug for a longer period of time could provide additional neuroprotective effects, but 3 days are enough to prolong the period in which a successful NR reimplantation can be performed [118].

A word of caution is to be said about the materials used to glue the peripheral NGs to the SC. Only Tisseel® causes no long-term histological reaction [180, 181], while other preparations available in the market (BioGlue®, Adherus®) induce local fibrous reaction with SC adherences and at times neurological sequelae [181]. BioGlue® when applied close or in contact with nervous tissues can create serious damages [182]. In rats, some researchers have used snake (Crotalus durissus terrificus) venom-derived fibrin glue and reported excellent results [183, 184].

Nerve Root Reimplantation in Brachial Plexus Injuries http://dx.doi.org/10.5772/intechopen.82431 55

On the other hand, conduits can be used to substitute autologous NGs. They have been extensively tried in peripheral nerve repairs [186, 187], but in NR reimplantation the data available are more limited [188, 189]. In peripheral nerve repair, these conduits have proved useful up to distances of 70 mm in length [37, 38, 190]. Certainly, the central-peripheral nervous tissue interface is a place in which autologous NFs provided by the autologous NGs play a pivotal role in regeneration of the reimplanted NR [69, 77, 89, 91–93]. Some researchers have tried nerve conduits enriched with BDNF that have had a good result in a rabbit experimental model [191]. In human clinical practice, there are currently no published

However, the applicability of all these studies is limited since they were generated with experimental animal models and with reimplantation immediately following the avulsion. On top of that, the regenerating capacities of the human nervous system are much less than that observed in research animals (the rat especially [73]), and the reimplantation of an avulsed NR has to be delayed weeks or even months until the patient is stabilized from other traumatic

Surgical techniques can be useful, particularly in complete BPA and with a delay between the injury and the surgical repair of no longer than 4 weeks [45]. Some significant problems are that MN apoptosis is greater as the time goes by [20, 27, 91, 93, 101–103] and that by 4 weeks, there is a dense scar around the BP as well as the avulsed NRs and in their intervertebral

The surgical approaches described can be summarized into posterior subscapular [192], lateral [193], anterolateral [194, 195] and single-stage combined anterior (first) and posterior

With the patient in the prone position, a longitudinal incision is made halfway between the spine and the scapula [39, 192, 196]. The trapezius muscle is sectioned transversally in the direction of its fibers. The rhomboid major and minor muscles are also divided following the direction of their fibers. The T1 transverse process is identified and removed with the aid of a drill. A section of the first rib is also removed. A laminectomy and facetectomy are needed to

lesions and when an adequate diagnosis and treatment strategy are well defined [111].

4. Surgical technique of human NR reimplantation

foramina that hinders any surgical manoeuvres [45, 74].

In clinical practice, fibrin glue from human origin is usually used [15, 30, 33, 45, 185].

reports [45, 74].

(second) [33].

4.1. Posterior subscapular approach

FK506-tacrolimus improved the amount of regenerating posterior NR axons penetrating the SC and reaching the posterior horn [151].

Acamprosate is a taurine analogue used to prevent relapse in alcoholic patients that acts as neuroprotective and accelerates axonal regeneration [154, 166].

Ribavirin is a nucleoside antimetabolite antiviral agent that blocks nucleic acid synthesis that is administered together with acamprosate to encourage axonal regeneration [154].

N-Acetyl cysteine administered intraperitoneally and intrathecally in rats enhances the rate of MN survival and facilitates regeneration in case of NR reimplantation [155].

Glatiramer is a polymer of L-alanine, L-glutamic acid, L-lysine and L-tyrosine that structurally resembles the myelin basic protein and that when administered daily reduces the gliosis and the avulsed MN synaptic stripping [156].

To summarize, in NRA reimplantation GDGF applied directly to the anterior SC—to the point where the motor rootlets go out—associated with oral riluzole provides the highest rate of MN survival and axonal regeneration [8]. For the dorsal root, CNTF [87] applied directly to the section of the posterior SC where the sensory rootlets get in combined with oral N-acetyl cysteine [155] allows maximal sensory neuron survival. Other agents could be added, such as oral minocycline [106, 120], tacrolimus [151] or recombinant erythropoietin [118, 165]to reduce the reactive glial proliferation that impairs the axonal regeneration. ISP should be administered subcutaneously to minimize astrocyte inhibition of axonal regeneration [126, 167]. The data are summarized in Table 1.

Another strategy has been to apply pluripotent cells at the SC avulsion site to improve MN survival and axonal regeneration. These have been particularly useful in minimizing neuronal apoptosis. Among them are induced pluripotent stem cells (iPSC) [143], mesenchymal stem cells (MSCs) [168–170], olfactory ensheathing glial cells (OECs) [85, 171], bone marrow stem cells (BMC) [172], human fibroblast growth factor 2 (FGG2) [95], neuroectodermal stem cells (ESC) [143], murine neural crest stem cells (MNCSC) [173], embryonic stem cell-derived neuron precursors (ESCDNP) [173] and neural progenitor cells (NPC) [140, 141, 168, 174]. The human embryonic stem cells overexpressing human fibroblast growth factor 2 (FGG2) applied at the injury site improved MN survival and reduced the glial reactivity, thus improving the regenerating capacities [95]. However, it has unknown effectivity, only shown in animal experimental studies, and its application in the human being creates ethical issues.

Some researchers have found in vivo that a week time gap between NG harvest and its subsequent use in nerve repair improves the regenerating capacities [175] by increasing the number of Schwann cells and macrophages inside the NG [145, 176, 177] as well as by inducing the local GDNF release [145, 178, 179]. This is another possibility but difficult to use in clinical practice.

A word of caution is to be said about the materials used to glue the peripheral NGs to the SC. Only Tisseel® causes no long-term histological reaction [180, 181], while other preparations available in the market (BioGlue®, Adherus®) induce local fibrous reaction with SC adherences and at times neurological sequelae [181]. BioGlue® when applied close or in contact with nervous tissues can create serious damages [182]. In rats, some researchers have used snake (Crotalus durissus terrificus) venom-derived fibrin glue and reported excellent results [183, 184]. In clinical practice, fibrin glue from human origin is usually used [15, 30, 33, 45, 185].

On the other hand, conduits can be used to substitute autologous NGs. They have been extensively tried in peripheral nerve repairs [186, 187], but in NR reimplantation the data available are more limited [188, 189]. In peripheral nerve repair, these conduits have proved useful up to distances of 70 mm in length [37, 38, 190]. Certainly, the central-peripheral nervous tissue interface is a place in which autologous NFs provided by the autologous NGs play a pivotal role in regeneration of the reimplanted NR [69, 77, 89, 91–93]. Some researchers have tried nerve conduits enriched with BDNF that have had a good result in a rabbit experimental model [191]. In human clinical practice, there are currently no published reports [45, 74].

However, the applicability of all these studies is limited since they were generated with experimental animal models and with reimplantation immediately following the avulsion. On top of that, the regenerating capacities of the human nervous system are much less than that observed in research animals (the rat especially [73]), and the reimplantation of an avulsed NR has to be delayed weeks or even months until the patient is stabilized from other traumatic lesions and when an adequate diagnosis and treatment strategy are well defined [111].
