Keywords
nerve gap - nerve repair - nerve guides - neurotrophic factors
Although Paulus Aegineta (626–696 AD) is the first physician who postulated the restoration
of severed nerves,[1] before the 1700s surgeons were generally afraid to manipulate nerves. Introduction
of microsurgical techniques[2] in peripheral nerve surgery and the establishment of the principle of tension-free
repair[3] allowed inspired surgeons such as Narakas, Millesi, Allieu, Brunelli, Terzis, Doi,
Gu, and others to suggest several new approaches to nerve reconstruction.
With the further accumulation of knowledge and an increasing understanding of nerve
anatomy, function, and physiology, a more precise understanding of the process of
nerve healing ensued that initiated the establishment of rational strategies for nerve
repair, taking it from wild speculation to a more predictable reality. Many factors
influence the success of nerve repair and reconstruction. The age of the patient,
the timing of nerve repair, the level of injury, the extent of the zone of injury,
the technical skill of the surgeon, and the method of repair all contribute to the
functional outcome after nerve injury.[4]
Injured nerves do not spontaneously restore their function. Continuity of the nerve
has to be reestablished first by microsurgical intervention such as end-to-end repair.
When nerve endings cannot be rejoined without tension, interposition nerve grafts
are used for nerve reconstruction. The purpose of using a nerve graft is to provide
a conduit consisting of a basal lamina scaffold together with their corresponding
Schwann cells. However, autologous nerve grafting is associated with morbidity, including
potential neuroma formation at the donor site, as well as frequent disappointing functional
outcomes.[5] Furthermore, donor nerves are often of small caliber and limited in number.
For these reasons, increasing efforts have been made over the last three decades to
seek effective alternatives to autologous nerve grafts. In long nerve defects, nerve
allografts may be a suitable alternative when the length of an autologous nerve graft
is a limiting factor.[6] Although the use of nerve allografts prevents the possible donor-site morbidity
following harvest of an autologous nerve graft, systemic immunosuppression is required
for 18 months.[7]
The tubulization technique with nonabsorbable or absorbable tubes has shown promising
results experimentally and clinically when used to bridge nerve gaps, or to enclose
the nerve suture site.[8]
[9]
[10]
[11] A nerve tube is a tubular structure designed to bridge the gap of a sectioned nerve,
protect the nerve from the surrounding tissue (e.g., scar formation), and guide the
regenerating axons into the distal nerve stump.
Although their clinical use has been limited mainly to the repair of relatively small
defects (less than 3 cm) in small-caliber digital nerves,[12]
[13]
[14] the potential for extending clinical applications to the repair of larger defects
and larger mixed or motor nerves[15] has made the development of an ideal nerve tube appealing for both scientists and
the medical device industry. The basic design of these tubes is similar, but they
are made of different biomaterials using various fabrication techniques. As a result,
these nerve tubes also differ in physical properties.
The purpose of this review is to present an overview of the literature on the applications
of nerve conduits in peripheral nerve repair. Moreover, the different steps that are
involved in the design of an ideal nerve conduit for peripheral nerve repair, including
the choice of biomaterial, fabrication technique, and the various potential modifications
to the common hollow nerve tube, are also discussed.
Historical Background
The employment of tubulization techniques has seen major advances over the past 30
years, and this approach to peripheral nerve surgery has a long history. Throughout
the 19th century scientists had experimentally investigated the possibility of using
a non-nervous conduit for bridging a nerve defect.[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
In 1880, Glück[16] first used the central canal of decalcified bone to provide a pathway between the
severed stumps of a divided nerve. Based on this study, Vanlair,[17]
[18] in 1882 used decalcified bone as tubes for bridging a 3-cm gap of the sciatic nerve
in the dog. Histological examination showed nerve regeneration, which replaced the
resorbed bone distally. Bügner,[19] in 1891, reported the utilization of human arterial grafts to bridge nerve gaps
in the dog.
Notthaft,[20] in 1893, attempted to bridge a gap in the sciatic nerve of rabbits using rabbit
aorta, but without any sign of regeneration. Willard,[21] in 1894, performed a tubulization procedure using decalcified bone. In 1904, Foramitti,[22] and in 1915, Nageotte[23] observed initial nerve regeneration in an arterial and vein graft followed by subsequent
graft disintegration.
Wrede,[24] in 1909, introduced the use of vein conduit to support nerve regeneration across
nerve gaps. Weiss and Taylor,[25]
[26] in the middle of the past century, in an attempt to prove that nerve regeneration
was independent of tropic and trophic factors, used biological (from artery, either
fresh or freeze-dried and rehydrated) along with artificial conduits from tantalum
in their experiments.
The century-old search for the ideal nerve conduit has encompassed the use of autogenous
and exogenous biological materials and the use of artificial materials. Since the
first attempts, many different materials have been used to fashion nerve guides. The
categories of nerve conduits include autogenous biological conduits, nonautogenous
biological conduits, and nonbiological conduits.
Mackinnon and Dellon were the first to study nerve regeneration in monkeys to compare
the electrophysiologic results of nerve graft versus polyglycolic acid conduit repairs,
using bioabsorbable conduits of various lengths.[27]
[28] Both of their studies demonstrated that the primate peripheral nerve can regenerate
across 3-cm nerve gaps when guided by an appropriate nerve conduit.
Contemporary nerve guides are mostly made of biodegradable materials such as aliphatic
polyesters or polyurethanes, collagen, chitosan, or excised vein. Nonetheless, silicone
has long been the most frequently used material for fabrication of nerve guides, but
its nondegradability and relative stiffness have limited its use.
In more recent years, research has been focused mainly on improving single-lumen nerve
guides to bridge larger nerve gaps (longer than 3 cm). Different techniques have been
applied to make nerve tubes permeable. Nerve tubes have been filled with collagen-
and laminin-containing gels, Schwann cells, and growth factors.
The Problem
A nerve injury differs from most other types of tissue injury in the body, since not
only a local repair process is required. Transection of axons has implications for
the whole length of the neuron, and the repair process involves outgrowth of axons
over very long distances. Following peripheral nerve injury, morphologic and metabolic
changes occur. End organs also undergo changes after nerve injury.
Within the first few hours to days, morphologic changes occur in the corresponding
neurons, including swelling of the cell body, displacement of the nucleus to the periphery,
and disappearance of basophilic material from the cytoplasm, a phenomenon termed chromatolysis.
Within 2 to 3 days of injury, edema forms in the distal axonal stump. This degenerative
process is called Wallerian degeneration after Augustus Volney Waller, who first characterized
morphological changes in sectioned frog glossopharyngeal and hypoglossal nerves 160
years ago.[29] The proximal portion retracts, and the neuron, now deprived of its normal synaptic
targets, is vulnerable to retrograde death by apoptosis.
During Wallerian degeneration, Schwann cells from the distal stump proliferate, help
inflammatory infiltrating cells to eliminate debris, and upregulate the synthesis
of trophic and tropic factors. The Schwann cells close to the site of transection
go through the same type of changes as the Schwann cells in the distal nerve segment.
After 3 to 6 weeks, endoneurial tubes are left behind that consist of basement membranes
lined with Schwann cells, which proliferate and organize into columns, guiding the
regenerating axonal sprouts within the basement membranes to their targets. Metabolic
changes within the neuronal cell body involve switching the machinery normally set
up to transmit nerve impulses to manufacturing structural components needed for reconstruction
and repair of the damaged nerve.
When axons remain without connection to their target tissue over significant periods
of time they lose the ability to regenerate, and the possibility for functional recovery
is lost. Complete atrophy occurs within 2 to 6 weeks of denervation. Fibrosis occurs
in motor fibers at 1 to 2 years and fragmentation and disintegration occur by 2 years.
It is generally agreed that functional recovery is diminished if the nerve does not
reach the motor end plate by 12 months.
In contrast, it has been long known that although axons in the peripheral nervous
system (PNS) are able to regenerate after being severed, this does not hold true for
injured central nervous system (CNS) axons. Studies in the early 1980s[30]
[31]
[32]
[33]
[34]
[35] suggested that the environmental milieu available to injured PNS axons might be
more favorable than that encountered by injured CNS axons. Moreover, these studies
demonstrated that when injured CNS axons are provided with a supportive substratum,
such as a segment of peripheral nerve, they are capable of regenerating for long distances
and of being directed toward a specific targeted area.
After traumatic injury to the spinal cord, two events take place that have been associated
with impaired neurological function and ineffective attempts at axon regeneration:
the acute primary mechanical insult and the chronic secondary reactive damage, the
hallmark of which is molecular inhibitors.[36] Attempts of CNS axons to regenerate after axon injury are partially suppressed by
inhibitory signals in the injured axon tip.
Molecular inhibitors of axon growth have been particularly linked to three main components
of the lesion: the fibrotic scar, the glial scar tissue, and the damaged myelin.[37] The two major classes of CNS regeneration inhibitors are the myelin-associated inhibitors
(MAIs) and the chondroitin sulfate proteoglycans (CSPGs). These molecules limit axon
regeneration, and, by interfering with their function, achieve some degree of growth
in the adult CNS.[38] Thus, the lack of neurotrophic support contributes to the absence of spontaneous
regeneration in the CNS.
When a nerve gap is incurred that cannot be repaired by end-to-end suture without
tension, the current repair method is a sutured autologous graft from another nerve
of lesser functional importance. However, the use of autologous grafts has some disadvantages
such as the need of a second surgical site, loss of the donor nerve function, a limited
supply of donor nerves, and the mismatch between nerve and graft dimensions.
Development of alternative treatments, especially for larger defects, is necessary
to bridge the gap between the proximal and the distal nerve stumps. Tubulization,
which involves enclosure of the ends of a severed nerve by a tube, offers a guide
to regenerating axons to the distal stump.[39] The tube concept is based on the following principles: (1) nerve regeneration will
be favored if the surgical trauma is minimized; (2) a short gap between the nerve
ends inside the tube will increase the possibilities for neurotrophic and neurotropic
mechanisms to act; and (3) a closed tube system will allow accumulation of neurotrophic
factors that are normally synthesized in a nerve trunk after trauma (and prevent interference
from the surrounding milieu).[40]
Many attempts have been made to bridge peripheral nerve gaps by various nerve conduits.
Most studies have used short-gap models of less than 25 mm.[41]
[42]
[43]
[44]
[45]
[46] The few studies of longer gaps[8]
[28]
[47]
[48]
[49]
[50]
[51]
[52]
[53]
[54] resulted in poor outcomes similar to allografts. There has been only one report
of functionally successful artificial conduit applied to a gap of 80 mm in dogs.[48] In this study, Matsumoto et al[48] reported successful nerve regeneration, using a polyglycolic acid (PGA)-collagen
tube filled with laminin-coated collagen fibers, across an 80-mm nerve gap in the
dog peroneal nerve after 12-month follow-up.
Successful regeneration after tubulization depends on the formation of a new extracellular
matrix scaffold, over which blood vessels, fibroblasts, and Schwann cells migrate
and form a new nerve structure.[55] Regeneration fails through long gaps (longer than 3 cm) most likely because the
regenerative capabilities of the nerve stumps have been exceeded and Schwann cells
are not able to provide a permissive environment for axonal elongation.[56]
By using a nerve guide, guidance of regenerating axons is not only achieved by a mechanical
effect (the wall and lumen of the nerve guide), but also by a chemical effect (accumulation
of neurotrophic and neurotropic factors). This combination of chemical, physical,
and biological factors has made the development of a nerve tube into a complex process
that requires close collaboration of bioengineers, neuroscientists, and peripheral
nerve surgeons. Engineering the ideal tube for bridging large nerve defects remains
a challenge.
Designing the Ideal Nerve Tube
Designing the Ideal Nerve Tube
Hudson et al[57] listed several important properties that nerve conduits should possess: easily fabricated
with the desired dimensions and topography, implanted with relative ease, and sterilizable.
The ideal nerve tube should also be nonimmunogenic, causing neither local tissue irritation
nor allergic response.[58]
The categories of nerve conduits include autogenous biological conduits, nonautogenous
biological conduits, and nonbiological conduits. Several materials, either of biologic
origin[28] or synthetically-fabricated,[50] have been used for designing nerve tubes.
The choice of biomaterial and fabrication technique is an important first step in
the development of a nerve tube. Ideally, the nerve conduit should be porous to allow
and control nutrient exchange, and biodegradable to eliminate the need for its removal.[59] Moreover, the tube material must strike a balance between an appropriate rate of
degradation and its intrinsic mechanical properties, which should minimize inflammatory
responses and prevent nerve compression.
The first nerve conduits used in rodent and human trials were composed of nonresorbable
polymers based on silicone and poly-tetrafluoroethylene (Gore-Tex).[60]
[61]
[62] Potential drawbacks of nonresorbable nerve guides are permanent fibrotic encapsulation
of the implant and late loss of functional recovery caused by compression of axons
within the conduit.
With the evolution of tissue engineering, a second generation of nerve guide conduits
has been synthesized from bioresorbable polymers of synthetic or biological origin.
Extensively used synthetic polymers, including polylactic acid (PLA)[32] and poly(d,l-lactide-co-glycolide) (PLGA)[63] are known for their ease of processing, low inflammatory response, and approval
by the U.S. Food and Drug Administration (FDA).
Several nerve tubes are currently being marketed, including Neurotube (Synovis Surgical
Innovations, Deerfield, Illinois, USA), Neurolac (Ascension Orthopedics, Plainsboro,
New Jersey, USA), and NeuraGen (Integra LifeSciences, Plainsboro, New Jersey, USA).
A few of these resorbable conduits have been tested in small cohorts of humans with
short nerve defects.[11]
[14]
[64]
[65] Currently, these nerve conduits can only be used in cases where the nerve gap is
less than 3 cm in length.[66] Additionally, some nerve conduits' designs and regeneration strategies are more
successful than others in yielding functional recovery that is similar to the gold
standard, the nerve autograft. Thus, current research is focused on strategies for
improving nerve conduit design and increasing regeneration potential.
Wall thickness is also an important factor. If the conduit wall is too thick, it will
degrade too slowly, thus lengthening the time of possible foreign body reaction. On
the other hand, a thin-walled guide could degrade too quickly, resulting in loss of
the supportive structure. Empirically, biodegradable nerve guides with an internal
diameter of approximately 1.5 mm and a wall thickness of approximately 0.3 mm have
given optimal results for peripheral nerve regeneration.
Permeability of a conduit is an important nerve tube property because nutrients and
oxygen need to diffuse into the site of regeneration before the tube becomes vascularized.
Absorbable tubes, such as poly-glycolic acid conduits, have increased permeability,
thus improving the interaction of the nerve ends with the surrounding environment.
This interaction has been demonstrated to improve axonal regeneration when compared
with impermeable nerve guides.[58]
[67]
The favorable effects of permeable tubes may be attributed to different reasons, including
metabolic exchange across the tube wall; diffusion into the guide lumen of growth
promoting factors generated in the external environment; retention of trophic factors
secreted by the nerve stumps; or a combination of all these.[67] Hence, the size of the tube wall pores and its stability over time seem to be important
factors determining the flow of different constituents that may promote or inhibit
regeneration. Permeability depends on the hydrophilic properties of the material and
the technique used.[68]
Flexibility is an important nerve tube property, especially in the repair of larger
nerve gaps, because the ends may not be in the same plane/line and the gap that needs
to be bridged may cross a joint.[69] Nerve conduits should be pliable enough to glide and bend with the limb's movements,
yet stiff enough not to collapse in vivo.
Moreover, the ideal nerve tube should remain intact for the time axons need to regenerate
across the nerve gap and then degrade gradually with minimal swelling and foreign
body reaction.[69] Bioreabsorbable tubes that degrade too quickly may not survive for a long enough
time for nerve regeneration and maturation. If the nerve guide breaks down at an early
stage, fibrous tissue can be formed inside the tube and impair further maturation
of the regenerated nerve.[70]
Surgical Technique
An assessment of the soft tissues at the injury site is a mandatory step to determine
whether reconstruction should be performed before, or concomitant with, the nerve
repair. Exploration of the injured nerve takes place proximal and distal to the lesion
site until normal nerve to inspection and palpation is reached.
The surgeon then trims back the nerve ends to a level where there is neither intraneural
hemorrhage for an acute injury nor interfascicular scarring for a subacute injury.
The proximal and distal stumps of the nerve are approximated without tension to prevent
torsion, which can change the orientation of fascicles in the two nerve stumps.
Commercially available conduits range from 1.5 mm to 10.0 mm in diameter. The chosen
conduit should be slightly larger than the diameter of the nerve. The technique for
preparing the tube varies considerably in relation to the type of material employed.
In general, the tube is soaked in plain or heparinized saline before use.
After the correct-sized conduit is chosen, the nerve tube is stabilized to the neighboring
soft tissues with interrupted sutures and sewn in a u-shaped fashion over the tube. Anchoring of the tube facilitates insertion and suturing
of the nerve stumps in the tube ends. Both nerve stumps are inserted 2 mm into each
end of the tube and fixed by means of two or three interrupted epineurial stitches
(9–0 or 10–0 nylon suture) under adequate magnification.
The technique of anchoring the nerve ends to the tube is as follows: the nylon is
passed through the wall of the tube, at least 1 mm from its end. The stitch is passed
in and out through the epineurium, 2 to 3 mm from the cut end. Then, the suture is
passed through the tube wall, close to the point where the suture is first penetrated.
Finally, the nerve end is gently inserted into the tube by tension on the nylon and
fixed in place by means of a knot on the outside of the tube.
The conduit's lumen is filled with sterile saline to prevent blood products and clot
from forming within its lumen. Some studies suggested the use of heparin at this step,
instead of saline, to decrease blood clot formation, which can impede axonal regeneration
by blocking the axon's advancing growth cone.[18]
[23] Closure of well-vascularized soft tissues over the tube is critical to achieve uninterrupted
wound healing.
Autogenous Biological Conduits
Autogenous Biological Conduits
Among the various different types of biological tubes that have been used for bridging
a peripheral nerve defect, veins and skeletal muscles are the organs that receive
the most attention by researchers.
Artery: The idea of using nerve conduits from vascular origins is not new and has been studied
since the end of the 19th century. Conduits made by small segments of artery were
first employed by Bünger in 1891,[19] who obtained successful nerve regeneration. Despite the experimental use of artery
as a nerve guide, this technique has not been implemented in clinical practice, likely
due to a lack of suitable donor vessels.
Vein: The first employment of veins as nerve conduits was reported by Wrede in 1909,[24] who successfully repaired the median nerve of a male by means of a 45-mm-long vein
tube. Strauch et al,[71] in an experimental rabbit model, determined that good axonal regrowth occurred in
a vein nerve conduit of 3 cm in length. For lengths between 3.5 and 5.25 cm, rare
regrowth was evident, whereas with gaps measuring 6 cm, nerve regeneration was found
for a length of only 1.45 cm.
Chiu and Strauch, in 1990, validated the clinical application of autogenous venous
nerve conduits.[72] They reported 15 secondary reconstructions after resection of symptomatic neuromas
in the hand and forearm using either a vein graft or a conventional nerve graft. Although
superior results were obtained from nerve grafting, in vein conduit patients there
was successful return of two-point discrimination. Although Chiu[73] demonstrated the efficacy of autogenous venous nerve conduits in both acute and
delayed nerve repairs of digital nerves, Walton et al[74] suggested that veins were not successful as nerve guides in delayed nerve repairs.
Tang et al,[75] in 1993, used autologous vein grafts to bridge 18 digital nerves during tendon surgery
in zone II. Interestingly, the vein lumen was seeded with nerve slices. Recovery of
sensibility was evaluated as good or excellent in 11 digital nerves. Two years later,
the same author[76] reported another series of 16 patients with the same method. This clinical study
suggested that vein conduits with the interposition of nerve tissue is a practical
and reliable procedure for nerve defects between 2.0 cm and 4.5 cm.
In general, vein conduits have not been recommended for clinical use, as there is
always the possibility of collapsing because their thin walls can be constricted from
surrounding tissues. However, Tseng et al[77] have demonstrated in the rat that hematoma and thrombin within the vein can conversely
keep the conduit patent.
Muscle: The rationale for the use of skeletal muscle as a nerve conduit is the availability
of a longitudinally oriented basal lamina and extracellular matrix components that
direct and enhance regenerating nerve fibers.[78]
[79] These factors are not available in vein grafts or in degradable or nondegradable
nerve conduits when used for bridging. Also, donor sites for muscle grafts are numerous.
The main disadvantages of this technique are the risk that nerve fibers can grow out
of the muscle tissue during nerve regeneration and that a donor site is necessary
to harvest the muscle tissue.[80]
The use of skeletal muscle autografts for nerve repair was first reported in 1940.[81] Studies in animals and humans have demonstrated that both fresh and denatured muscle
conduits can lead to successful regeneration and even lead to superior results when
compared with end-to-end sutures.[82]
[83]
[84]
[85] Most studies suggest an upper limit of 5 cm for the largest animal models (sheep
femoral nerve) and 2 cm in rat sciatic nerve. However, in longer nerve defects, the
effectiveness of skeletal muscle autografts may be progressively reduced.
Pereira et al[84]
[85] in two studies used denatured muscle grafts for nerve defect reconstruction. In
a series of 12 patients with leprosy,[84] they bridged defects between 25 to 60 mm in nine posterior tibial and three median
nerves. They reported encouraging results. In the second study,[85] they described 24 digital nerve defects between 15 to 28 mm. They reported better
results than with nerve grafting.
Tendon: Brandt et al,[86] using the rat sciatic nerve model, suggested that tendon grafts can be used as nerve
conduits for bridging defects of 10 mm. The extracellular matrix components of the
rat tail tendon, along with the longitudinal arrangement of the collagen bundles in
the graft, constitute a favorable substrate for regenerating axons and other cellular
elements involved in the regeneration process. Furthermore, Brandt et al[87]
[88] suggested that based on functional and morphometric evaluation, the tendon autograft
does not differ from the freeze-thawed muscle graft in supporting axonal regeneration
across an extended defect. Nishiura et al[89] suggested that the main advantage of this technique is that there is abundant graft
material with limited loss of function.
Nonautogenous Biological Conduits
Nonautogenous Biological Conduits
Collagen: Collagen is the major component of the extracellular matrix and is known to promote
cellular proliferation and tissue healing.[90]
[91]
[92] It has been described that extracellular matrix components (mainly collagen, laminin,
and fibronectin) localized in the endoneurium and basal membranes are presumptive
trophic factors that guide the growth cones.[93]
Archibald et al[92] have demonstrated the effectiveness of nerve guides constructed from purified type
I bovine collagen in the regeneration of a 5-mm nerve gap in the nonhuman primate.
Keilhoff et al,[94] using the rat sciatic nerve model, tested collagen type I/III tubes as a potential
nerve guiding matrix. They suggested that collagen-type I/III can serve as template
to design “living” nerve conduits, which may be able to ensure nerve regeneration
through extended nerve gaps.
Ashley et al[95] used collagen matrix tubes (Neurogen) instead of autologous nerve graft material
in five patients with obstetrical brachial plexus palsy. They used the collagen tubes
for gaps smaller than 2 cm and diameters less than 5 mm. According to their results,
four out of the five patients made a good recovery and were functional by 2 years
postoperatively.
Nerve allografts: The earliest report of clinical nerve allografting was in 1885 by Albert.[96] However, the results were disappointing. Renewed interest in this technique was
not seen until investigators began to understand the immunological responses to nerve
allografts and developed techniques to combat antigenicity, such as pretreatment with
irradiation and lyophilization.[97]
Allografts have been broadly studied as a potential alternative reconstructive material.
This tissue has met with moderate success in its clinical application[98] serving as a temporary scaffold for regenerating fibers. Allograft can provide an
abundant supply of donor nerves. However, significant potential side effects of necessary
immunosuppression[99]
[100] and the risk of disease transmission[101] limit their application to only the most severe injuries.
In contrast to autografts, the use of nerve allografts relies upon the viability of
both host and donor Schwann cells. The donor Schwann cells act as support cells for
remyelination and as facultative antigen-presenting cells. This dual role prohibits
a complete removal of these presumed primary sources of major histocompatibility complex
(MHC) II molecules and simultaneously maintains the requirement for systemic immunosuppression.[102]
[103]
Multiple studies in rat and primate models have analyzed the short nerve allograft
response with and without systemic immunosuppression.[104]
[105]
[106]
[107]
[108] MacKinnon et al[109] suggested that the immunosuppressed allograft functions as a structural scaffold
for regenerating host nerve fibers. As regeneration proceeds, donor Schwann cells
are lost and replaced by host Schwann cells. On the contrary, a nonimmunosuppressed
allograft undergoes scarring and fibrosis, providing a mechanical barrier to regenerating
host fibers.
In 1992, Mackinnon et al[109] reported the clinical outcome of seven patients who underwent reconstruction of
long upper- and lower-extremity peripheral nerve gaps with interposition peripheral
nerve allografts. Six patients demonstrated return of motor function and sensation
in the affected limb, and one patient experienced rejection of the allograft secondary
to subtherapeutic immunosuppression.
Elkwood et al[110] reported a series of eight patients with multilevel brachial plexus injuries that
were selected for transplantation using either cadaveric allografts or living-related
donors. Seven patients showed signs of regeneration, demonstrated by return of sensory
and motor function and/or a migrating Tinel sign. One patient was noncompliant with
the postoperative regimen and experienced minimal return of function despite a reduction
in pain.
Nonbiological Conduits
Several reports on the employment of nonbiological materials for tubulization were
published during the 20th century.[111] Garrity,[112] in 1955, reported on the unsuccessful employment of polyethylene, polyvinyl, and
rubber in three patients with very long (>7 cm) nerve defects. Also, the widespread
use of tantalum metal cuffs on soldiers during World War II led to unsatisfactory
clinical results.[113]
Nonbiological conduits are divided in nonabsorbable and absorbable ones. Both have
been proven to permit nerve regeneration through the conduit. However, nonabsorbable
nerve guides have the disadvantage that they remain in situ as foreign bodies with
subsequent scar tissue formation, which results in compression of the newly formatted
nerve.[114]
Nonabsorbable Nerve Conduits
Silicone: Merle et al[115] were the first to use silicone nerve guides clinically and reported successful nerve
regeneration in three patients. Silicone is not biodegradable, nor is it permeable
to large molecules. Chen et al[116] showed that silicone nerve guides filled with a collagen-, laminin-, and fibronectin-based
gel resulted in a more mature organization of regenerating axons when compared with
controls.
Lundborg et al[10]
[61]
[117] presented three prospective studies with successful regeneration through silicone
guides in short gaps of less than 5 mm. Long-term follow-up of patients treated for
median and ulnar nerve deficits demonstrated that the use of a silicone tube was at
least as good as direct suture repair. However, some of the patients in these studies
required removal of the silicone because of irritation.
In 1999, Braga-Silva[118] described the use of silicone tubes for late repair of median and ulnar nerves in
26 patients. He suggested that silicone tubes were effective in the repair of peripheral
nerve injuries with gaps of up to 3 cm, with better results in the ulnar nerves than
in the median nerves. However, the silicone tubes had to be removed in seven patients
because of irritation at the implantation site as well as loss of nerve function.
Other materials: Stanec et al[119] evaluated the effectiveness of the expanded polytetrafluoroethylene (ePTFE) tube
in clinical repair of median and ulnar nerves in 43 patients. According to them, the
ePTFE conduit is a reliable and successful surgical procedure for nerve repair in
reconstruction of nerve gaps up to 4 cm between the ends of median and ulnar nerves
at various levels of the upper extremity.
Pitta et al[120] evaluated regeneration associated with the use of Gore-Tex (GT; WL Gore & Associates,
Flagstaff, Arizona, USA) vein graft tubes for repair of the inferior alveolar nerve
and lingual nerves lesions in seven patients. The nerve defects were all smaller than
3 mm. Only two patients had any return of sensation. The authors suggested that Gore-Tex
tubes are not recommended for nerve reconstruction of the inferior alveolar nerve
and lingual nerve lesions.
Absorbable Nerve Conduits
Polyglycolic acid: PGA conduits are the most commonly used guides, both experimentally and clinically.
PGA is a bioabsorbable substance that is currently used as a commonly chosen suture
material for wound closure.[50]
[121] It is absorbed in the body by hydrolysis within 90 days of implantation.[122] The PGA conduit unfortunately has two drawbacks. First, these tubes cost more than
the suture used in a standard repair. Second, it is reported that extrusion of the
tube can be encountered due to the poor quality of the skin overlying the tube. In
1999, the U.S. Food and Drug Administration approved the use of PGA tubes (Neurotube;
Neuroregen LLC, Bel Air, Maryland, USA) in humans in the United States.
Early support for the PGA tube was provided by Dellon et al,[8] who compared the regeneration achieved after 1 year in a 3-cm ulnar nerve gap in
monkeys using a PGA conduit compared with an interfascicular sural nerve graft. The
results suggest that PGA conduits are a good alternative to short nerve grafts.
Matsumoto et al[48] reported successful nerve regeneration, using a PGA-collagen tube filled with laminin-coated
collagen fibers, across an 80-mm nerve gap in the dog peroneal nerve after 12-month
follow-up. The tube was made of cylindrically woven PGA mesh and its outer and inner
surface were coated with amorphous collagen layers. The conduit was reinforced with
PGA mesh, as it was believed that if the outer tube was made from collagen alone,
it might degrade too quickly to maintain enough space for good axonal outgrowth and
the ingrowth of scar tissue might prevent nerve regeneration in the case of a long
gap. The authors provided evidence that this conduit effectively guided peripheral
nerve elongation with good function recovery across a wider gap than previously reported
for artificial nerve conduits.
Weber et al[14] described a prospective, randomized, multicenter study of the use of PGA tubes versus
standard repair. They studied 136 nerve transections in the hand in 96 patients and
found that repair with PGA conduit produced superior results for short gaps of less
than 4 mm when compared with end-to-end repair. For longer defects of up to 30 mm,
they demonstrated superior results when compared with nerve autografts.
Polyesters: PLGA and poly(caprolactone) (PCL) are FDA-approved biodegradable polymers that are
currently being examined as matrices for tissue-engineered applications.[50]
[123] Copolymerization has been used to obtain these materials with characteristics tailored
to degradation behavior, mechanical performance, thermal properties, and wettability.
Polymer crystallinity affects permeability and biodegradation of nerve guides. The
crystalline phase is inaccessible to water and other permeable molecules. Biodegradation
and permeation decrease with an increase in crystallinity.[124] Crystalline debris formed during degradation may cause an inflammatory response,
which may jeopardize the regeneration process and the recovery of nerve function.
Pêgo et al[125] investigated the physicochemical properties of synthetized copolymers of trimethylene
carbonate (TMC) and e-caprolactone with the aim of assessing their potential in the
development of flexible and slowly degrading artificial nerve guides. They suggested
that poly(trimethylene carbonate) and poly(trimethylene carbonate-co-epsilon-caprolactone)
copolymers with high epsilon-caprolactone content possess good physical properties
that make them suitable for the preparation of porous artificial nerve guides.
Den Dunnen et al[70]
[126]
[127] evaluated poly(d,l-lactide)-E-caprolactone (DLLA-E-CL) nerve guides to bridge a 10-mm nerve gap. The
conduit was composed of 50% DL-lactide and 50% E-caprolactone, with the lactide component
containing 85% l-lactide (LLA) and 15% d-lactide (DLA). The authors reported that nerve regeneration through DLLA-E-CL guide
was faster and qualitatively better when compared with an autologous nerve graft.
Meek et al[128] evaluated, using the rat sciatic nerve model, nerve regeneration after bridging
a 15-mm gap with either a DLLA-E-CL nerve guide or an autologous nerve graft. They
suggested that return of motor function is better after bridging the gap with a DLLA-E-CL
nerve guide, compared with autologous nerve grafts.
Chitosan: Chitosan is a polysaccharide obtained from N-deacetylation of chitin and is a copolymer
of d-glucosamine and N-acetyl-d-glucosamine. Hsu et al[129] suggested that gene expression for neurotrophic factors in Schwann cells is upregulated
on chitosan substrate compared with that on polylactide. Various researchers[130]
[131]
[132]
[133] demonstrated that chitosan has a good affinity for nerve cells and promotes the
survival and neurite outgrowth of nerve cells in vitro, which suggests that chitosan
might be applicable as a scaffold for axonal regeneration in peripheral nerves.
Wang et al[134] used chitosan as a dual-component nerve graft for bridging a 30-mm gap in the sciatic
nerve of beagles. In this application, the external part of graft consisted of chitosan,
and the internal part consisted of PGA. According to their results, in the chitosan/PGA
graft group, the dog sciatic nerve trunk had been reconstructed with restoration of
nerve continuity and functional recovery, and its target skeletal muscle had been
re-innervated, improving locomotion activities of the operated limb.
Chávez-Delgado et al[135] evaluated nerve regeneration in chitosan prostheses used as in situ delivery vehicles
for progesterone in bridging a 10-mm gap defects in the facial nerves of rabbits.
The lack of inflammation, wound infection, or local destruction at the implantation
site showed that chitosan prostheses were promising for nerve regeneration. Progesterone-releasing
chitosan scaffolds positively affected the regenerative response of rabbit facial
nerves, significantly increasing the number of myelinated fibers and the regenerated
area when compared with chitosan scaffolds alone.
Zhang et al[136] investigated, using the rat sciatic nerve model, nerve regeneration following application
of de-acetyl chitin conduits for bridging a 10-mm gap. According to their results,
the combination of chitin conduits with nerve fibers inside can be successfully used
for bridging nerve defects of 10 mm. Moreover, using the above-mentioned combination,
nerve regeneration is better than using either chitin conduits alone or autologous
nerve grafts.
Combined Tubes and Tissue Engineering
Combined Tubes and Tissue Engineering
Tissue engineering has focused on developing alternative treatments to the autologous
nerve graft, especially for larger defects, and improving recovery rates and functional
outcome. The application of tissue engineering techniques in the field of nerve tubulization
is based on the belief that conduits can be manipulated in the laboratory to mimic
important biological features in the nerve microenvironment. Moreover, using these
advanced techniques can produce tubes, whether biological or synthetic, enriched with
various elements promoting regeneration of the peripheral nerve that previously were
not possible in nonautogenous conduits.
When considering substrate materials, it is imperative to choose one that exhibits
good biocompatibility. The materials must be strong enough that they will not collapse
during the patient's normal activities. Moreover, they must also contain a biodegradable
and porous channel wall, be able to deliver bioactive factors, enable the incorporation
of support cells, have an internal oriented matrix to support cell migration, and
intraluminal channels to mimic the structure of nerve fascicles and electrical activities.
Two bioengineered grafts that have been successful in human and animal studies are
the nerve/vein combined graft and the muscle/vein combined graft. Tang[76]
[137] evaluated, in humans, nerve regeneration by means of autogenous vein graft with
slices of normal nerve graft in the lumen. According to these studies, the nerve/vein
combined graft may be a promising alternative to group fascicular nerve grafting for
nerve defects between 20 and 45 mm.
Meek et al,[138]
[139]
[140] using the rat sciatic nerve model, evaluated nerve regeneration by means of a thin-walled
biodegradable nerve guide with denatured muscle tissue inside the lumen. The placement
of modified denatured skeletal muscle inside the nerve guide prevented the collapse
of the conduits and led to good, and faster, sciatic nerve fiber regeneration and
functional recovery in a rat as compared with conduit without denatured muscle.
Brunelli et al[141] compared nerve regeneration in nerve grafts, free fresh muscle grafts, vein conduits
filled with muscle, and empty vein grafts for bridging nerve gaps of 1.0 and 2.0 cm.
They suggested that vein filled with muscle might serve as a grafting conduit for
the repair of peripheral nerve injuries and could give better results than traditional
nerve grafting.
Battiston et al[142]
[143] used the muscle-vein-combined grafts for bridging both sensory and mixed nerve defects
in 21 patients. The nerve defects ranged from 0.5 to 6 cm in length. They suggested
that muscle-vein-combined grafts seem to be superior to other kinds of artificial
or biological conduits.
Recently, tissue engineering has started to use polymeric biomaterials with or without
living precursor cells for nerve regeneration. Polymers can be used as scaffold to
promote cell adhesion and maintenance of differentiated cell function without hindering
proliferation. They also serve as template for organizing and directing the growth
of cells, and they assist in the function of an extracellular matrix.[144] Some disadvantages of these polymers in tissue engineering applications are their
poor biocompatibility, release of acidic degradation products, poor processing characteristics,
and loss of mechanical properties very early during degradation. For this reason,
these materials must be modified to become more “cell-friendly.”[145]
The tissue engineering approach for nerve regeneration includes scaffolds for axonal
proliferation, support cells such as Schwann cells, growth factors, and an extracellular
matrix. Variations of artificial material properties allow alterations in geometric
configuration, biocompatibility, porosity, degradation, electrical conductivity, and
mechanical strength. These variations in the aforementioned parameters can dramatically
alter the ability of axons to proliferate. Moreover, porosity and pore size are often
dependent on the method of scaffold fabrication.[146]
The physical structure of conduit channels also dramatically affects the quality of
nerve regeneration. Because the total surface area of an oriented intraluminal framework
or filament is larger than that of an empty tube, there is a common belief that fiber-filled
devices or intraluminal scaffolds may improve nerve regeneration.[147]
[148] McCaig[149] suggested that the use of an applied electric field in conjunction with pharmacological
agents (such as dimethyl sulfoxide, forskolin, and ganglioside GM1) might enhance nerve regeneration in vivo.
Various studies[150]
[151]
[152] support the concept that Schwann cells offer a highly preferred substrate for axon
migration and release bioactive factors that further enhance nerve migration. Moreover,
Schwann cells synthesize and secrete a cocktail of neurotrophic molecules such as
nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and ciliary neurotrophic
factor (CNTF), which enhance nerve regeneration.
Enrichment of conduits of various origins with Schwann cells has proved to significantly
improve the morphological and functional restoration of the injured nerve. Zhang et
al[153] and Strauch et al[154] suggested that a vein conduit filled with Schwann cells allowed successful bridging
of rabbit nerve defects up to 40 and 60 mm, respectively.
The influence of neurotrophic factors in neural development, survival, outgrowth,
and branching was explored at various levels, from molecular interactions to macroscopic
tissue responses.[155] Controlled release is one means of supplying factors to enhance nerve regeneration.
Biodegradable nerve guidance channels serve as a vehicle for delivery of bioactive
factors to manipulate cellular processes within the scaffold microenvironment. They
can be made to release growth or trophic factors trapped in or adsorbed to the polymer.[156] There are several delivery devices used in neural applications, including polymer
matrices,[157] microspheres,[158]
[159] viral vectors,[160]
[161] and liposomes.[162] Rich et al,[163] using the rat sciatic nerve model, studied the effect of exogenous NGF on axonal
growth across a gap that was bridged with silicone chambers. They demonstrated that
the myelinated axons in the chamber approximately doubled and that the myelin sheath
doubled in size.
Insoluble extracellular matrix molecules, including laminin, fibronectin, and some
forms of collagen, promote axonal extension and, therefore, are excellent candidates
for incorporation into the lumen of guidance channels.[164] Alternatively, these molecules could be placed on natural biological conduits through
adhesion molecules or similar processes. Components of the extracellular matrix and
matrix analogues have also demonstrated promise in nerve replacement.[165] Labrador et al,[166] using the mouse sciatic nerve model, assessed the usefulness of nerve chambers prefilled
with collagen and laminin gels to enhance nerve regeneration. They found that both
matrices allowed for higher levels of recovery and for successful regeneration in
a higher proportion of mice than saline solution. Furthermore, the laminin gel performed
slightly better than the collagen gel.
Nerve Growth Factors
Nerve growth factors are molecules that are naturally released in the process of nerve
regeneration.[167] They are released from the nerve ending especially following a nerve injury and
have an effect on nerve growth, differentiation, and surveillance.[168]
[169] This knowledge has led to studies related to the application of factors that increase
nerve regeneration through the conduit lumen.
The basic neurotrophic factor concept is defined by the hypothesis that trophic proteins
are synthesized in the target tissues and delivered to the neuronal soma via retrograde
transport, where they exert a trophic and survival effect.[170]
[171]
[172] The influence of growth factors is exerted via their binding to particular classes
of tyrosine kinase receptors present on the surface of the responsive cells.[40]
Different growth factors, including NGF, glia cell-derived neurotrophic factor (GDNF),
neurotrophin-3 (NT-3), and fibroblast neurotrophic factor (FGF) have been added to
single-lumen nerve tubes.[173]
[174]
[175]
[176] They can be incorporated directly (in solution) into the tube's lumen or through
a delivery system. Due to the fact that the effect of growth factors is often dose-dependent
and requires their release over extended periods of time, delivery systems are generally
preferred. Besides, solutions may leak from the nerve tube. Different carriers and
delivery systems have been used, including absorption to fibronectin mats, collagen
matrices, bovine serum albumin (BSA), and microspheres.[173]
[175]
[176]
[177]
Nerve growth factor: NGF is present at low concentrations in healthy nerves. Following nerve injury, NGF
is upregulated in the distal nerve stump[178] and plays an important role in the survival of sensory neurons and outgrowth of
their neurites. Moreover, the concentration of NGF receptors is increased in the Schwann
cells in the distal nerve segment.[179] Conversely, NGF has little or no influence on motor neurons and their neurite outgrowth.[180]
He et al[181] suggested that the mere inclusion of NGF–saline solution into plain silicone nerve
guides can enhance the magnitude of motor nerve conduction velocities in rats 6 weeks
after a 5-mm sciatic nerve injury. Rich et al[182] reported that a silicone tube filled with NGF and implanted in a rat sciatic nerve
gap yielded significantly more myelinated axons in the distal part of the defect at
4 weeks after surgery than a NGF-free control silicone tube.
Lee et al[174] used heparin to immobilize NGF and slow its diffusion from a fibrin matrix inside
a conduit bridging a 13-mm rat sciatic nerve defect to produce similar numbers of
nerve fibers to isografts. They demonstrated that the delivery system used in their
study revealed a marked dose-dependent effect and also enhanced peripheral nerve regeneration.
One of the few studies that compared NGF-loaded tubes against an autograft found significantly
more myelinated fibers in the autograft than in the NGF-tube group after 5 weeks.[183] Although the number of regenerating myelinated axons within the nerve grafts was
greater than that of axons within silicone tube implants, functional recovery of autologous
nerve graft repairs may not be superior to that of tube repairs.
Glial growth factor (GGF): GGF is a trophic factor specific for Schwann cells rather than neurons, but it has
a significant role in the interaction of the two cell types.[184] Mahanthappa et al[185] suggested that GGF increases Schwann cell motility and proliferation, and these
two effects are dependent on the concentration of growth factor available to the glial
cells.
Mohanna et al,[186] using the rabbit common peroneal nerve transection model, demonstrated that the
presence of GGF in poly-3-hydroxybutyrate (PHB) conduits produced a progressive and
sustainable increase in the distance and quantity of Schwann cells and axonal regeneration
for up to 63 days. When the GGF is applied into PHB conduits for bridging nerve gaps
of 2 to 4 cm in rabbit peroneal nerves, it increased the number of Schwann cells and
improved the axonal regeneration, whereas it decreased the muscle mass lost in comparison
with the control group.[187]
Fibroblast growth factor: FGFs are a family of at least 23 cytokines that are involved in cell growth and regeneration
and are naturally secreted by damaged nerve ends after injury.[188] The earliest published study showing the regenerative effect of FGF was in 1992,
in which it was demonstrated that addition of FGF is a successful method of salvaging
penile erectile function after division of the cavernous nerves.[189]
Walter et al,[190] using the rat sciatic nerve model, studied the effect of recombinant acidic FGF
into a synthetic conduit bridging a 15-mm nerve gap. They observed that functional
motor return, nerve amplitude, and muscle action potential increased in the FGF group
in comparison with the control group. Midha et al,[191] using poly (2-hydroxyethyl methacrylate-co-methyl methacrylate) (PHEMA-MMA) porous
tubes filled with 10 μg/mL of acidic FGF (dispersed within a collagen matrix) to bridge
a 10-mm rat sciatic nerve gap and demonstrated enhanced nerve regeneration at 8 weeks
postsurgery.
Similarly, the efficacy of basic FGF in enhancing peripheral nerve regeneration has
also been demonstrated. Wang et al[192] used poly (d,l-lactide) (PDLLA) tubes containing basic FGF to repair a 15-mm gap in the rat sciatic
nerve. They concluded that basic FGF enhances the regeneration of peripheral nerves,
retains its bioactivity after being embedded in PDLLA matrix, and can be released
continuously from the polymeric matrix for a prolonged time.
Glial cell-derived neurotrophic factor: GDNF is a neurotrophic factor secreted by Schwann cells after nerve injury, which
is known to improve motor/sensory neuron survival, neurite outgrowth, Schwann cell
migration and, in particular, the survival of dopaminergic neurons.[193] GDNF has a beneficial effect on axonal regeneration, as assessed by the nerve pinch
test.[194] GDNF also improves the conduction velocity of motoneurons following regeneration,[195] and that of small-diameter sensory neurons.[196]
Fine et al[173] demonstrated enhanced motor and sensory neuronal regeneration across a 15-mm synthetic
nerve tube in the rat sciatic nerve defect gap using GDNF, as compared with the inclusion
of NGF, at 7 weeks postimplantation. Chew et al[197] reported, by using a copolymer of caprolactone and ethyl ethylene phosphate (PCLEEP)
tubes with GDNF encapsulated within electrospun polymer fibers, enhanced nerve regeneration
and functional recovery at 3 months postimplantation across a 15-mm critical defect
gap in rats as compared with nerve guides without GDNF inclusion. From the comparative
studies performed thus far, it appears that GDNF is a potent candidate for inclusion
into tubes for enhancing nerve regeneration.
Neurotrophin-3: Following nerve injury, continuous infusion of NT-3 has proved to be effective in
restoring sensory and motor conduction velocity in a dose-dependent manner,[194] consistent with the neuroprotective role of NT-3 in sensory neuropathy.[197] The strong trophic effect on muscle sensory afferent fibers is evident following
exogenous administration of NT-3, even in the absence of the target organ.[198]
The exogenous administration of NT-3 restores muscle mass and is selectively beneficial
for the reinnervation of type 2b fast muscle fibers.[199]
[200] Sterne et al,[201] by using the rat sciatic nerve model, investigated the effect of NT-3 delivered
via fibronectin mats, which were grafted into 1-cm sciatic nerve defects. In the presence
of NT-3, axonal regeneration was significantly increased at day 15 as compared with
the control group (comprised of plain fibronectin mats). By 8 months after surgery,
although both NT-3 and control groups resulted in the formation of axons of similar
diameters, the presence of NT-3 supported a significantly greater number of myelinated
axons.
Other factors: Several other growth and neurotrophic factors, although less commonly used in peripheral
nerves, also have demonstrated efficacy in enhancing peripheral nerve regeneration.
Such factors include CNTF,[202] vascular endothelial growth factor (VEGF),[203] leukemia inhibitory factor (LIF),[204] insulin-like growth factor I (IGF-I)[205] and platelet-derived growth factor (PDGF).[206] In general, these proteins are either injected directly into the lumen of nerve
conduits, or embedded within a hydrogel as nerve guide lumen fillers. Moreover, the
combination of two or more growth factors may offer additional benefits. It is apparent
that more detailed understanding of neurotrophic factor dose response and their combinations
on nerve regeneration is necessary for optimal scaffold designs.
The Future
Today, tubulization represents, in selected clinical situations, a possible alternative
to autogenous nerve grafts for peripheral nerve repair. Although research efforts
in nerve regeneration have been extensive, we are still hindered by a lack of knowledge
of the underlying mechanism for axonal proliferation.
Clinical data indicate that simple monotissue biological conduits such as veins or
skeletal muscle hold a good chance of succeeding if they are used for short gaps.
This is also true for silicone tubes. If longer defects require bridging, combined
biologic tubes (vein plus muscle or vein plus nerve) can be employed.
The era of molecular nerve repair holds much promise for the future of peripheral
nerve surgery. The expanding knowledge and advances in nerve biology will lead us
to more insights in the specificity of nerve fiber growth toward their target organs.
Despite the multiple studies describing the utilization of growth-promoting factors
inside the lumens of nerve conduits, they have not been introduced to clinical practice.
Utilizing biodegradable synthetic and natural polymers could be good options for nerve
regeneration, and for the design and engineering of hollow tubes filled with different
materials, thus achieving optimal porosity, pore size, morphology, and strength. The
most important developmental field from a future perspective will be tissue-engineering
conduits enriched with either neurotrophic factors and/or support cells of nerve regeneration
(e.g., Schwann cells). The increased understanding of the underlying mechanisms of
peripheral nerve regeneration will allow scientists to devise more appropriate nerve
conduits with integrated growth factor delivery systems and/or cellular components.
The potential to release growth or trophic factors inside the conduit lumen, to reduce
nerve cell death, and to improve the outgrowth of axons after nerve injury, is an
area in which considerable achievement will be expected.
The combination of two or more growth factors will likely exert a synergistic effect
on nerve regeneration, especially when the growth factors belong to different families
and act via different mechanisms. Combinations of growth factors can be expected to
enhance further nerve regeneration, particularly when each of them is delivered at
individually tailored kinetics. The combination of Schwann cells with growth factors
may further improve nerve regeneration. Such a system may be engineered from longitudinally
aligned fibers that contain and deliver the growth factor(s) and act as support for
Schwann cells.
Experiments have demonstrated that tissue-engineered tubes are effective in nerve
repair for gaps longer than 4 cm. These results were previously thought to be possible
only with autogenous nerve grafts. Thus, in selected clinic situations, tubulization
represents a viable alternative to autogenous nerve grafts. Future studies need to
provide us with information regarding the effectiveness of different tubulization
techniques.
