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R. P. Shupak et al.
Introduction
Surgeons often encounter peripheral nerve injuries in practice. This is especially
true when operating in the head and neck region where there is a rich supply of
cranial and spinal nerves. As the largest cranial and peripheral sensory nerve, the
trigeminal nerve is one of the most commonly injured [1, 2]. Main branches of the
trigeminal nerve, namely, the mental, inferior alveolar, lingual, and infraorbital
nerves, are highly susceptible to damage. Injury often results from trauma, iatrogenic injury following routine surgery, or planned ablative procedures. Regardless
of the etiology, trigeminal nerve injury results in neurosensory disturbances that
have detrimental effects on patients’ quality-of-life.
Damage to the trigeminal nerve can result in worrisome dysesthesias (pain,
hypersensitivity, burning, numbness, tingling, and itching) that signicantly affect
patients’ well-being [3]. Dysesthesias can alter normal functions such as speech,
taste, swallowing, mastication, and maintenance of saliva within the oral cavity [4].
Additionally, pain catastrophizing, depression, psychological disability, and discomfort have been associated with inferior alveolar and lingual nerve injury [5].
In order to appropriately treat and rehabilitate patients, accurate classication of
trigeminal nerve injury is required. Currently, there is inconsistency in the clinical
grading of trigeminal nerve injury with several classication systems used for clinical care and research including Seddon, Sunderland, and the Medical Research
Council Scale. In a recent study, Miloro etal. surveyed oral and maxillofacial surgeons and found inconsistency, lack of surgeon condence, and need for a uniform
grading system to communicate and guide trigeminal nerve injury and treatment
[6]. Expert consensus suggests that clinicians utilize neurosensory testing to calculate Medical Research Council Scale (MRCS) grading scores, allowing for valid
comparison and outcome measurement [6]. The objective of trigeminal reconstructive surgery is to meaningfully restore patient sensation with consistent and reliable
protocols to achieve functional sensory recovery (FSR). This correlates to an MRCS
grade 3.0 or greater [3].
Historical Perspective onTrigeminal Nerve Reconstruction
andRepair
Historical mention of nerve anatomy and injury dates back to Greco-Roman times
with descriptions from Hippocrates (460–370). At that time, it was universally
believed that nerve tissue could not unite, and therefore, early attempts of nerve
repair were not undertaken [7, 8]. It was not until the seventh century with Paul of
Aegina (626–696) that text descriptions of nerve handling and postulations of
nerve repair exist. The rst suitable description of direct nerve suturing techniques
was in the thirteenth century by Lanfranchi at Bologna Medical School. Centuries
then passed without signicant evolution from these early descriptions.
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Modern nerve surgery evolved quickly during the nineteenth and twentieth century in part due to increased traumatic nerve injury occurring during wartime. In
their descriptions and texts, individuals such as Langenbeck, Vulpian, and Létiévant
advanced the eld of peripheral nerve repair, thus setting the foundation for those to
follow [7]. Further work by individuals such as Mitchell, Woolsey, Tinel, Elsberg,
Babcock, Dandy, Seddon, and Sunderland laid the foundation of how we currently
understand, classify, and surgically treat peripheral nerve injury [7].
Within the scope of oral and maxillofacial surgery, cranial nerve repair literature
began to appear during the mid-twentieth century. Surgeons began to push the forefront of peripheral nerve repair with the advent and renement of microsurgical
techniques in the 1950s and 1960s. Case series of direct nerve repair and autogenous nerve grafting techniques for trigeminal and facial nerve repair detailed promising results [9–11]. During the latter part of the twentieth and early twenty-rst
century, surgical approaches, materials, and techniques continued to advance. Many
utilized autogenous sources as interpositional grafts when direct nerve repair was
impossible. Most recently, nerve allografts became available, which reduced donor
site morbidity. Commercially available allografts and scaffold connectors/protectors now play a major role in trigeminal nerve microneurosurgery.
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Current Practices andOutcomes ofPeripheral Trigeminal
Nerve Repair
Pathophysiology ofNerve Damage
Peripheral nerve damage can result from trauma, tumor, thermal, ischemic, chemical, infectious, inammatory, or iatrogenic injury. Seddon describes three degrees
of nerve injury [12]. The least severe form of nerve injury, neuropraxia, results
in localized reversible conduction blockade. Complete nerve recovery can be
expected within weeks to months. More severe damage results in axonotmesis. This
is characterized by axonal and myelin disruption with its connective tissue framework preservation. These forms of injury are more severe and result in varying
degrees of recovery. Neurotmesis is the most severe and results from contusion,
stretch, or laceration. With this form of injury, there is little to no potential for full
recovery when left untreated.
In axonotmesis and neurotmesis, Wallerian degeneration occurs shortly after
injury. Wallerian degeneration describes the process of retrograde degeneration of
the distal end of the injured nerve. This results in disruption of the distal axonal
skeleton and membrane. This is followed by myelin sheath degradation clearance
by macrophages and Schwann cells. If terminally injured, the nerve cell undergoes
apoptosis; otherwise, it enters the regeneration phase. This phase is a complex multifactorial process resulting in a growth cone at the distal aspect of injury to support
axonal branching and outgrowth. If the distal endoneurium remains in close
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approximation after injury, it can direct axonal growth back to its target. If not, there
is potential for incomplete functional regeneration and neuroma formation. Unlike
the central nervous system (CNS), peripheral nerve injury lends itself to a better
environment for axonal regeneration [13].
R. P. Shupak et al.
Current Options forTrigeminal Nerve Repair
andReconstruction
Surgeons have multiple options when repairing trigeminal nerve injuries. The type
of repair is dictated by the type, severity, and size of defect. When direct repair is
feasible, end-to end coaptation (i.e., neurorrhaphy) is performed under magnication utilizing non-tissue reactive microsuture (e.g., 8-0 to 10-0 Nylon) in a tensionfree manner [2, 3, 14]. More recently, the literature supports the utilization of
connectors to protect the direct repair as it shields the regeneration process from the
deleterious effects of the wound bed [15]. When direct repair is not possible
(extended continuity defects or repairs under tension), interpositional grafts are
required.
Saphenous, medial antebrachial cutaneous, sural, or greater auricular nerves
were historically utilized as interpositional grafts. Donor site morbidity, incomplete
functional return, and the increasing availability of alternative options have
decreased the use of autografts [13]. First-generation nerve conduits (silicone/
polytetrauoroethylene) were introduced to guide axonal regrowth and protect from
the inltration of connective tissue in the wound bed. These conduits often require
secondary removal and can result in nerve compression syndromes.
Second-generation nerve conduits were subsequently developed to mitigate the
pitfalls of non-resorbable materials. These conduits are both resorbable and biocompatible avoiding a second-stage procedure. Materials such as polyglycolic acid,
type I collagen, polycaprolactone, and N-broin have been studied as conduits for
peripheral nerve repair with mixed efcacy [13]. Third-generation nerve conduits
containing neurotrophic factors, stem cells, extracellular matrix (ECM) proteins,
and other neuroactive substances are being studied and may guide and stimulate
peripheral nerve repair.
There has been a signicant trend in current practice to repair and reconstruct
trigeminal nerve injury with nerve allograft (AxoGen, Alachua, FL) [2–4, 14, 16].
Avance™ is a processed human nerve that is treated via a combination of detergent
decellularization, chondroitin sulfate proteoglycan degradation, chondroitinase
treatment, and gamma-irradiation sterilization [17]. The nerve allograft is brought
into the operative eld and neurorrhaphy is performed at the proximal and distal
nerve stump via AxoGuard™ nerve connectors. The connector is comprised of porcine small intestinal submucosa, which allows for a tension-free coaptation. It can
prevent aberrant axonal growth and protects the nerve regeneration process from
inammation at the repair site [2, 17].
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Surgeons must also consider the timing of trigeminal nerve reconstruction.
Timing to repair/reconstruction remains controversial in the literature [18–20].
Consensus dictates that the surgeon immediately repairs a witnessed trigeminal
nerve injury. There is also a trend toward immediate reconstruction of planned ablative defects when feasible. Early repair (i.e., within 3–6months from injury) of trigeminal nerve injuries and its effect on neurosensory recovery was studied in a
recent systematic review and meta-analysis [19]. The review showed mixed results
in obtaining functional sensory recovery with early intervention. However, the
meta-analysis showed higher combined success rates (93% versus 78.5%) and
higher odds of improvement in the early versus late (>6months) group. The optimal
time for repair is still being elucidated [19].
Current Practices: Inferior Alveolar, Long Buccal, andMental
Nerve Repair andReconstruction
The inferior alveolar nerve (IAN) and mental nerve (MN) are among the most commonly reconstructed divisions of the trigeminal nerve. The authors’ preference is
direct tension-free repair utilizing AxoGuard connectors when possible (Fig.19.1).
Approaches to the IAN are performed both intraorally or transcutaneous based on
extent and position of injury. Virtual surgical planning can be employed to aid in
nerve locating, repair, and reconstruction. The authors utilize a combination of
interposition allograft (Avance™, AxoGen) with proximal and distal nerve connectors in situations where a segmental nerve defect exists (AxoGuard™, AxoGen)
(Figs.19.2 and 19.3).
Fig. 19.1 A transected trigeminal nerve branch showing proximal and distal nerve stumps within
proximity for direct repair. The site of injury is identied, dissected, and prepared for primary
neurorrhaphy. If the proximal and distal ends of the nerve can be coapted in a tension free manner,
a direct repair or preferentially a nerve connector can be utilized. Care is taken to not cause additional axonal damage during manipulation. The epineurium is handled with microsurgical
instrumentation
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Fig. 19.2 A planned ablative procedure with immediate nerve reconstruction of the inferior alveolar nerve. (a) The proximal inferior alveolar nerve is identied after mandibulectomy. Avance™
nerve graft is used with proximal and distal Axoguard™ nerve connectors. The proximal nerve
coaptation is performed rst. (b) The mental nerve stump is identied and neurorrhaphy is performed. (c) A bula free ap is inset around the segmental inferior alveolar nerve reconstruction
R. P. Shupak et al.
abc
Fig. 19.3 A mental nerve injury is identied. (a) The proximal and distal nerve stumps are dissected and identied. (b) A buccal decortication is performed to gain access to additional length of
inferior alveolar nerve. (b) The inferior alveolar nerve is removed from the canal and trimmed to
healthy nerve tissue. (c) An interpositional allogenic nerve graft is used via a connector-assisted
repair to reconstruct the mental nerve injury
There have been multiple studies and systematic reviews focusing on inferior
alveolar nerve repair and reconstruction outcomes [1, 4, 16, 19–21]. Rates in the
literature support 80% or more excellent FSR when direct repair is undertaken [4,
20]. When interpositional grafts are utilized, nerve autografts appear to have slightly
lower rates of FSR in comparison to direct repair [4, 20]. Allogenic nerve sources
for inferior alveolar nerve reconstruction have received much attention. FSR rates
for IAN reconstructions utilizing allogenic sources are reported from 88% to 100%.
The success rates appear to be higher when immediate reconstruction is performed
[4, 16, 21].
The long buccal nerve is a terminal sensory branch of the mandibular division of
the trigeminal nerve. It is close to local and regional inltrative techniques routinely
used in oral maxillofacial surgery. It runs on the surface of the buccinator muscle
with sensory innervation from the commissure of the mouth and the buccal mucosa
and around the posterior dental segment of the mandible. Anatomically the buccal
nerve passes between the superior and inferior heads of the lateral pterygoid muscles and descends on the mandibular ramus onto the buccinator. Its nal sensory
plexus is with the facial nerve and the infraorbital nerve and the mental nerve.
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Current Practices: Lingual Nerve Repair andReconstruction
Damage to the lingual nerve affects tongue sensation, taste, and speech. The lingual
nerve is typically approached intraorally when the repair is secondary to damage from
dentoalveolar surgery (Fig.19.4). The lingual nerve can also be approached in transcervical fashion when damaged or sacriced during an ablative procedure (Fig.19.5).
Like the IAN, lingual nerve repair has shown to be successful in providing patients
with functional sensory recovery [1, 4, 20]. Direct repair has shown success rates as
high as 95% in the literature. Both autografts and allografts have also demonstrated
success above 80–90%. Non-biological conduits have lower success rates than direct
repair or grafting (need reference(s)—such as pogrel using vein grafts).
abc
Fig. 19.4 Lingual nerve injury following third molar surgery. (a) The lingual nerve is approached
intraorally. A lingual ap is elevated and the proximal and distal ends of the injured lingual nerve
are identied. (b) An allogenic interpositional nerve graft is prepared with two nerve connectors
prior to being brought into the surgical eld. (c) The interpositional graft is secured to the proximal
and distal nerve stumps
ab
Fig. 19.5 Transcervical approach to a planned lingual nerve resection associated with an ablative
procedure. (a) The proximal and distal lingual nerve stumps are identied and preserved. (b) The
sacriced lingual nerve is reconstructed with a combination of Avance™ and Axoguard™ products
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R. P. Shupak et al.
Current Practices: Infraorbital Nerve (IO) Repair
andReconstruction
Recent reports detail immediate reconstruction of the second division of the trigeminal nerve. Infraorbital nerve repair planning and technique are similar to the
inferior alveolar and lingual nerve. Aside from direct repair, studies have emerged
detailing successful neurosensory recovery utilizing nerve allografts at the time of
ablative maxillary procedures [18, 22]. In a small retrospective cohort, one group
reported 100% FSR of three patients undergoing immediate allograft reconstruction
of the infraorbital nerve at 6months [18].
Measuring Outcomes andControversies inTrigeminal
Nerve Reconstruction
Peripheral trigeminal nerve repair and reconstruction have come a long way since
Hippocrates. However, controversies still exist, and further research is needed to
optimize patient outcomes. There is continued need for adequately powered prospective, multicenter studies. The Registry of Avance® Nerve Graft’s Utilization and
Recovery Outcomes Post Peripheral Nerve Reconstruction (RANGER®) has been
established in one such attempt. This registered clinical trial (NCT01526681) aims
to provide data for outcome analysis Avance™ assisted repairs. Trigeminal nerve
reconstruction is included in the registry, which will hopefully aid in answering
some of the clinical questions that still exist.
In a recent article by Pogrel, the author reports on long-term outcome data following the sacrice of the inferior alveolar nerve during mandibular resection [23].
In his retrospective review, the author reports on sensation recovery without nerve
reconstruction in 30 patients. The author found 29 of the 30 patients regained some
sensation in the IAN distribution. Additionally, 70% of the subjects had a return of
function at the MRCS S3 level. The author noted that subjects adapted well to the
loss of sensation and had little effect on quality of life. Even though the author asks
readers to interpret the results with caution, the study highlights the need for welldesigned studies evaluating both the short-term and long-term benets of trigeminal
reconstruction after ablation utilizing the latest tools and techniques.
Future Developments
The use of autografts and allografts to repair human trigeminal nerve injuries has
resulted in 70–90% successful recovery that surpasses the performance of any
second- generation nerve conduit [4, 24]. However, autografts have multiple limitations including the sensory loss of secondary surgical sites and the risk of neuroma
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formation [25, 26]. Allografts, on the other hand, have high costs and potential
limited availability, particularly on demand. Hence, third-generation nerve conduits
are being actively studied with potential to replace autografts and allografts to
achieve optimal surgical outcomes.
As successful peripheral nerve regeneration requires biochemical and structural
cues, the main objectives of third-generation nerve conduits involve initiating/
extending the regenerative phase after nerve injuries and recapitulating the native
environment of nerve tissues [26, 27]. Many tissue engineering strategies such as
growth factors, stem cell therapy, and intraluminal architecture are currently
employed to enhance the rate of nerve regeneration. Each methodology plays a vital
role in developing future treatments, with its advantages/limitations summarized in
Table19.1.
Growth factors facilitate nerve regeneration via their interactions with cell surface receptors, which trigger intracellular signal transduction, including the
mitogen- activated protein kinase pathway [26, 28, 29]. As a result, neurons undergo
axonal outgrowth and less apoptosis. After nerve injuries, the production of neurotrophic factors is only upregulated for a few hours to days, insufcient for regenerating larger nerve defects [27, 30]. In rabbit IAN injury models, injections of human
Table 19.1 Overview of common tissue engineering strategies found in third-generation nerve
conduits
Strategy Working principle Advantages Limitations
Growth factors (NGF/
hbFGF)
Interact with cell
surface receptors to
stimulate axonal
outgrowths
1. Easy to use 1. Short shelf-lives
2. Readily available 2. Tumorigenesis
3. Hyperalgesia
Stem cells (ADSCs/
NSCs)
Intraluminal
architecture (matrices/
hydrogels)
Dynamic and
long-term release of a
combination of
neurotrophic factors
Provide directional
guidance/structural
support for axon
elongation/adhesion
1. Self-renewal 1. Unclear
2. Able to differentiate
into specialized cells
1. Mimic native
microenvironment
2. Low cost
3. Low immunogenicity
4. Few side effects
long-term metabolic
activities
2. High costs
3. Time-consuming
4. Tumorigenesis
1. Low bioactivity
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nerve growth factor and basic broblast growth factor (FGF) near surgical sites
show limited improvement in myelination and jaw-opening reex thresholds,
respectively [31–33]. It is hypothesized that the supplemental growth factors quickly
decrease in concentration below the triggering threshold of surface receptors. To
improve the efcacy of growth factor treatments, researchers have investigated different entrapment strategies to control the release of growth factors [26, 34]. Growth
factors can be chemically attached to the nerve conduits to prolong their release [35,
36]. Multiple vehicles including microspheres [37, 38] and nanoparticles [39–41]
have been loaded with growth factors and localized within nerve conduits for sustained delivery. Furthermore, matrix-like materials can mix with neurotrophic factors before in situ injection within the nerve conduits to achieve physical entrapment
[42, 43]. In rat sciatic nerve resection models, these spatiotemporal delivery
approaches lead to better axon counts, gastrocnemius muscle retention, and electrical conduction [35–43]. The use of growth factors is quick and simple but unsuitable for long-term regeneration due to short shelf-lives. The common side effects
found in preclinical studies consist of tumorigenesis and hyperalgesia at surgical
sites [28, 44, 45].
Peripheral nerve regeneration is complex and difcult to mimic by the controlled
release of growth factors alone [26, 27]. In vivo, regeneration involves interaction
between multiple neurotropic factors, cytokines, Schwann cells, and macrophages.
Introducing stem cells to surgical sites replenishes damaged cells during nerve
injures and supports continuous release of multiple growth factors that facilitate
nerve regeneration and angiogenesis [46]. Adipose stem cells (ADSCs), harvested
from patients’ fat tissues, have been reported to accelerate sciatic nerve regeneration
in rodent models [47–49]. When encapsulated in gelatin methacrylate (GelMA)
gels, ADSCs resulted in better electrophysiological performance and myelination
than acellular conduits after 16-week implantation [48]. Similar improvements
were also observed in another study that embedded ADSCs within dual-layer conduits made of poly(caprolactone) and GelMA [49]. Further immunouorescence
staining showed that some ADSCs stayed well encapsulated for 6weeks [49]. In
addition to these direct encapsulation methodologies, ADSCs can be differentiated
to express Schwann cell-like behaviors and biomarkers before use [47, 50, 51].
These differentiated ADSCs and autografts shared comparable measurements in
nerve density and the amplitude of compound muscle action potential (CMAP) in a
16-week study [50]. Alternatively, neural stem cells (NSCs), derived from induced
pluripotent stem cells, can differentiate into Schwann-like cells and enhance functional recovery and axon count of resected rat sciatic nerves after 12weeks [52].
When encapsulated into GelMA and implanted into injured spinal cords, NSCs promote axonal regeneration and inhibit glial scar formation [53]. The self-renewal and
multipotent characteristics of ADSCs and NSCs allow them to be cultured into large
quantities of specialized cells [26, 47]. Harvesting patients’ own stem cells also
reduces the risk of immune rejection. However, stem cells’ long-term metabolic
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activity and viability after invivo implantations remain unclear. High costs, timeconsuming procedures, and the inherent tumorigenicity associated with stem cell
therapy are challenging roadblocks that need to be overcome before clinical use [26,
47, 54].
Intraluminal architecture, present in autografts and allografts, is not present in
second-generation conduits. Some research in third-generation conduits focuses on
adding solid structures [55–57], microporous matrices [58, 59], and nanobrous
hydrogels [60–67] within the conduits to promote cellular adhesions and direct axonal outgrowth. Regenerated axons can orient themselves and grow within spaces
between solid structures such as multichannels [55, 56] and bundled rods [57]. Yet,
solid structures reduce cross-sectional area that could be occupied by axons.
Microporous matrices maximize the available area by creating a greater number of
micro-size canals. For example, a honeycomb architecture fabricated from unidirectional freezing demonstrated accelerated sciatic nerve regeneration [58, 59].
Moreover, nanobrous hydrogels better mimic the characteristics of uninjured
nerve tissues due to their resemblance to extracellular matrix, large water content,
and physiologically relevant material stiffness [68–70]. In rodent sciatic nerve transection models, the use of brin and silk hydrogels in conduits results in faster
neurite elongation and greater amplitude of CMAP respectively after 4-week
implantation when compared to hollow conduits [60–63]. Alternatively, some studies investigate the neuroregenerative potential of self-assembling peptides, customized with biomimetic motifs from growth factors that introduce bioactivity in
synthetic hydrogels [70]. Peptide amphiphiles with RGDS (integrin binding) and
Ile-Lys-Val-ala-Val (IKVAV) (laminin-mimetic) peptide sequences have more cell
density than the negative control after 12weeks in sciatic nerve regeneration [64].
Álvarez etal. ne-tuned the linkage sequence of peptide amphiphiles and added a
FGF mimetic sequence, which yielded better neuronal extension and motor functional recovery in a murine spinal cord injury model [65]. In a study from our lab
using a nerve crush injury model in rats, multidomain peptide hydrogels showed
improved motor recovery and signicant remyelination after 15days [66]. The
internal modication of third-generation conduits has potentially fewer side effects
than growth factors and cell therapies, but faces challenges with reduced
bioactivity.
The future of trigeminal nerve reconstruction will involve third-generation nerve
conduits with the implementations of growth factors, stem cells, and/or internal
architecture, along with 3D bioprinting to regenerate convoluted and large-scale
nerve defects. Further advancement and combinations of these approaches would
supersede the clinical outcomes of autografts and allografts with fewer side effects.
Most of the nerve conduit research is tested in rodent models, with a few exceptions
in canine, feline, and leporine models [33, 71–73]. As the pathophysiology and
recovery process of large animal and primate resemble those of humans, third-generation nerve conduits must be validated by large animal studies before human
clinical trials to ensure the safety and efcacy of these conduits [74].
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