Mædica - a Journal of Clinical Medicine

MAEDICA – a Journal of Clinical Medicine

2015; 10(1): 65-68

S TATE OF THE ART

Peripheral Nerve Regeneration –

an Appraisal of the Current
Treatment Options
Dragoş CINTEZAa,b; Iulia PERŞINARUa; Bogdan Mircea MACIUCEANU
ZARNESCUa,b; Dan IONESCUa; Ioan LASCARa,b
a
Department of Plastic and Reconstructive Surgery, Emergency Clinical Hospital,
Bucharest, Romania
b
“Carol Davila” University of Medicine and Pharmacy Bucharest, Romania

ABSTRACT
During the last decades significant progress was made in the understanding of the physiopathology
of the peripheral nerve regeneration. Although the evolution of therapy is not as spectacular, a series of
new treatment solutions were developed. The gold standard in therapy remains the use of autografts.
We present the current concepts and therapeutic options available.

Keywords: nerve regeneration, autograft, conduit, bioengineering

INTRODUCTION Depending on the type and the extent of

the damage on the peripheral nerve, the injury

T
he peripheral nerve injury, most
commonly post-traumatic, has an
incidence of 300.000 new cases/
year in Europe (1). After mechani-
cal, chemical or thermic injury, a
gap in the nerve structure results with subse-
quent loss of innervation of the target organ (2).
The regeneration is influenced by factors
depending on the patient’s biological status
(co-morbidities, age), on the mechanism of in-
jury and on the level of the injury (more distal
injuries have better clinical outcome) (3).
Although physiopathological mechanism of
the nerve regeneration is better understood
now than it was 30 years ago, the clinical treat-
ment has not significantly improved, and the
clinical outcome is still unsatisfactory (4).
was classified by Seddon and Sunderland as
neuropraxia (the nerve structure is still in conti-
nuity; the recovery occurs in days/weeks), axo-
notmesis (the nerve structure is still in continu-
ity, but the axons are interrupted and surgical
intervention is not necessary needed; the re-
covery occurs in weeks/years), neurotmesis
(complete interruption of the nerve; surgical
repair of the nerve is mandatory; complete re-
covery is never achieved) (5).
Following the injury, the distal nerve stump
undergoes a complex process, known as the
Wallerian degeneration, initiated by the
Schwann cells deriving from the myelin sheath,
which trans-differentiate into a phenotype
characterized by phagocytic activity and in-

Address for correspondence:

Dragos Cinteza, Department of Plastic and Reconstructive Surgery, Emergency Clinical Hospital, 8th Floreasca Avenue, 1st District,
Bucharest, Romania
E-mail: dragoscinteza@gmail.com

Article received on the 3rd of March 2015. Article accepted on the 8th of March 2015.

Maedica A Journal of Clinical Medicine, Volume 10 No.1 2015 65

PERIPHERAL NERVE REGENERATION – AN APPRAISAL OF THE CURRENT TREATMENT OPTIONS
Nerve grafts Conduits
Autograft: Biological conduits:
• sural nerve • artery
• medial cutaneous antebrachial • vein
nerve • muscle
• terminal branch of the posterior • composed
interosseous nerve
• lateral cutaneous antebrachial
nerve
• saphenous nerve
• superficial branch of the radial
nerve
Allograft Artificial:
• biodegradable
- collagen
- gelatin
- fibrin
- polyglycolic acid
- polylactic acid
- polylactide-caprolactone
• non-biodegradable
- polyvynil alcohol
- silicone
- poly- tetra-fluoroethylene
TABLE 1. Type of grafts used in peripheral nerve reconstruction.
creased expression of neurotrophic factors (6).
After removal of the resulting debris by the
Schwann cells and the macrophages, Schwann
cells tend to align forming columns of cells
known as bands of Büngner which provide an
adequate environment for regeneration and
serve as guidance for axonal growth (7).
Although the peripheral nervous system has
the regeneration capacity, external intervention
is mandatory for sustaining it.
Treatment options
The current methods developed for the
treatment of the peripheral nerve injuries can
be classified into two major groups: direct co-
aptation and indirect coaptation.
The direct coaptation is the most frequent
method used (performed in 82% of cases), and
should be performed in the first 24 h post in-
jury (1,8). This can be applied in an ideal situa-
tion, when the gap between the nerve stumps
does not exceed 8 mm (1) and the microsurgi-
cal repair of the nerve can be performed with-
out any tension in the suturing site. When the
gap exceeds 8 mm, the tension in the suturing
site determines an impairment of the blood
flow with subsequent inhibition of nerve rege-
neration (2).
The indirect coaptation implies the interpo-
sition of a graft between the nerve stumps
66 Maedica A Journal of Clinical Medicine, Volume 10 No.1 2015
which acts as a regeneration chamber. This
provides an adequate environment for the
growing axons until they reach the distal ner-
vous stump. The grafts used could be auto-
grafts, allografts or nerve conduits.
The nerve grafting remains the “gold stan-
dard” clinical treatment for peripheral nerve
defects, regardless the size of the gap (2). How-
ever, several studies demonstrate that for grafts
of 4 cm length, only a small number of axons
regenerate across the graft, and for those that
surpass 10 cm none of the axons from the
proximal stump reaches the distal one (9). The
standard technique implies the harvesting of a
pure sensory nerve, most commonly being
used the sural nerve, and its employment to
bridge the nerve gap using microsurgical anas-
tomosis. The disadvantage of this method is the
morbidity of the donor site, additional intra-
and postoperative risks, the limited graft avail-
ability and the limitation of use in motor or
mixed (motor and sensory), nerve defects. Mo-
tor nerve grafts are more suited for these situa-
tions, but the benefit does not surpass the dis-
advantage of sacrificing the motor function
(10).
A method that eliminates most of the auto-
graft disadvantages is the use of allografts- nerve
grafts harvested from cadavers, but it comes
with the price of the associated risks of immu-
nosuppression (11).
Recently AxoGen© claimed that their al-
lograft named Avance® Nerve Graft has no dis-
advantages related to immunogenicity due to
their decellularized and cleansed extracellular
matrix. Their on-going study, the Ranger® Study
had more than 600 nerve repairs enrolled in
January 2015. The preliminary data showed
good recovery rates (with an average of over
78%) in a group of 109 subjects, with 151
nerve repairs performed using Avance® Nerve
Graft (12).
The nerve conduits were developed in or-
der to overcome nerve grafting inconvenien-
ces.
Initial attempts were made to easily achieve
a conduit using various types of tissues avail-
able at the injury site, such as arteries, veins or
skeletal muscle. The inconvenience of this
method was that when arteries or veins were
used, the conduit collapsed due to the sur-
rounding structures and when only skeletal
muscle was used massive fibrous tissue was
formed, impairing the regeneration process (2).
 PERIPHERAL NERVE REGENERATION – AN APPRAISAL OF THE CURRENT TREATMENT OPTIONS
In order to surpass these inconveniences
the vein or the artery were filled with skeletal
muscle, the vessel providing the appropriate
environment for the regeneration, limiting the
interference of adjacent tissues, and the actin/
myosin cytoskeleton of the muscle serving as a
guide for axonal growth. Several experimental
studies on rats were conducted to prove the
utility of this composite biological conduit and
of its improved versions by adding bone mar-
row stromal cells or adipose-derived stem cells
in its structure (13,14).
Due to the unsatisfactory results achieved
by the use of natural conduits, attempts were
made to develop a better conduit which can
support the adhesion, migration and function
of the local cell (15) and can respect as many
properties as possible of an ideal nerve con-
duit, such as (16):
• biocompatibility
• biodegradability
• permeability and porosity
• protection for axonal growth
• adequate size
• adequate flexibility
One of the first artificial conducts used were
non-biodegradable, tubes made of biologically
inert silicone, which had the advantage of a
very good contention due to their imperme-
ability, but they had high rigidity and deter-
mined a foreign body-reaction (11). In addi-
tion, the patient had to undergo another
surgical intervention for removal of the con-
duit.
Along with the development of tissue bio-
engineering, the focus was on creating biocom-
patible and biodegradable conduits. Currently,
conduits are being synthetized from natural
derived polymers such as animal collagen (usu-
ally type I), laminin, fibrin, fibronectin, hyaluro-
nan, polysaccharides derivates such as chito-
san, alginate, agarose. Most of the conduits the
FDA or Conformit Europe approved for clinical
use are made of type I collagen, such as Neura-
Gen®, NeuroFlex™, NeuroWrap™, but there
are also available conduits synthetized of poly-
glycolic acid and polylactide-caprolactone
(Neurotube®, Neurolac®). Other types of poly-
mer are tested for including them in the struc-
ture of various conducts: biodegradable glass
and magnesium alloys, nanostructured ZnO
ceramic, carbon or Al/Al2O3 nanostructures
(15). However, studies on nerve regeneration
using FDA approved devices show poor results
in clinical recovery compared with autologous
nerve graft, and their use is limited to defects
under 2 cm (17).
The conduits alone are not sufficient for the
nervous regeneration which is why for creating
the optimal environment, growth factors and
different types of cells are packed within the
conduit.
The growth factors influence the phenotyp-
ic expression of neural cells, supporting the
axonal growth. They can be classified into two
categories: neurotrophins (brain-derived neu-
rotrophic factor, nerve growth factor, neuregu-
lin, neurotrophin-3) and growth-factors with
neurotrophic action (fibroblast growth factor,
insulin growth factor-1, ciliary neurotrophic
factor) (3,15).
The cellular component of the artificial
nerve graft adds trophic support to the regen-
eration process in order to enhance the out-
come. Initially were used the Schwann cells
and olfactory ensheathing cells, but they have
limited capacities of expansion. That is why re-
searchers appealed to stem cells of different
sources, with unlimited capacity of regenera-
tion and possibility of multilineage differentia-
tion. The most attractive type of cells used are
the bone marrow mesenchymal stem cells, ad-
ipose-derived stem cells and skin-derived pre-
cursor cells (15).
There are some alternative methods under
study for enhancing the axonal regeneration.
Electrical stimulation of the proximal nervous
stump in rats stimulates the Schwann cells pro-
liferation and releasing of neurotrophic factors.
Administration of -D-xyloside inhibits the syn-
thesis of chondroitin sulfate proteoglycan, pro-
duced by the Schwann cells immediately after
injury which retards axonal growth. Within 4
days after de administration the level of chon-
droitin sulfate proteoglycan reduces by 90%.
Studies regarding administration of immuno-
suppressants (tacrolimus) in lower doses than
required show an increased speed of regenera-
tion, the myelin sheath is by 40% thicker, the
number of axons that regenerate increases
(10).
A new approach on modulating the regen-
eration process is the interference with the in-
trinsic growth mechanism, with molecular tar-
geting strategies by use of RNA with the help of
genetic engineering (15).
Maedica A Journal of Clinical Medicine, Volume 10 No.1 2015 67
PERIPHERAL NERVE REGENERATION – AN APPRAISAL OF THE CURRENT TREATMENT OPTIONS

CONCLUSION Conflict of interests: none declared.

Acknowledgement: This paper was co-finan-

D espite major progress in understanding pe-

ripheral nerve regeneration, the gold stan-
dard for repairing a nerve defect remains auto-
grafting. Until now there are no studies to
prove better outcomes than nerve grafting.
However there are many ongoing trials that
show promising results using various artificial
conduits, as well “in vitro” as “in vivo”. Bio and
genetic engineering will play an essential role
in the progress of peripheral nerve repair.
ced from the European Social Fund, through the
Sectorial Operational Programme Human Re-
sources Development 2007-2013, project
number POSDRU/159/1.5/S/138907 “Excellen-
ce in scientific interdisciplinary research, docto-
ral and postdoctoral, in the economic, social
and medical fields -EXCELIS”, coordinator of the
University of Economic Studies, Bucharest.

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