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Diffusion tensor tractography to visualize axonal outgrowth and regeneration in a 4-cm reverse autograft sciatic nerve rabbit injury model.
Farinas AF, Pollins AC, Stephanides M, O'Neill D, Al-Kassis S, Esteve IVM, Colazo JM, Keller PR, Rankin T, Wormer BA, Kaoutzanis C, Dortch RD, Thayer WP
(2019) Neurol Res 41: 257-264
MeSH Terms: Animals, Axons, Diffusion Tensor Imaging, Imaging, Three-Dimensional, Nerve Regeneration, Peripheral Nerve Injuries, Rabbits, Sciatic Nerve, Transplantation, Autologous
Show Abstract · Added November 7, 2019
BACKGROUND - Diffusion tensor tractography (DTT) has recently been shown to accurately detect nerve injury and regeneration. This study assesses whether 7-tesla (7T) DTT imaging is a viable modality to observe axonal outgrowth in a 4 cm rabbit sciatic nerve injury model fixed by a reverse autograft (RA) surgical technique.
METHODS - Transection injury of unilateral sciatic nerve (4 cm long) was performed in 25 rabbits and repaired using a RA surgical technique. Analysis of the nerve autograft was performed at 3, 6, and 11 weeks postoperatively and compared to normal contralateral sciatic nerve, used as control group. High-resolution DTT from ex vivo sciatic nerves were obtained using 3D diffusion-weighted spin-echo acquisitions at 7-T. Total axons and motor and sensory axons were counted at defined lengths along the graft.
RESULTS - At 11 weeks, histologically, the total axon count of the RA group was equivalent to the contralateral uninjured nerve control group. Similarly, by qualitative DTT visualization, the 11-week RA group showed increased fiber tracts compared to the 3 and 6 weeks counterparts. Upon immunohistochemical evaluation, 11-week motor axon counts did not significantly differ between RA and control; but significantly decreased sensory axon counts remained. Nerves explanted at 3 weeks and 6 weeks showed decreased motor and sensory axon counts.
DISCUSSION - 7-T DTT is an effective imaging modality that may be used qualitatively to visualize axonal outgrowth and regeneration. This has implications for the development of technology that non-invasively monitors peripheral nerve regeneration in a variety of clinical settings.
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A novel conduit-based coaptation device for primary nerve repair.
Bamba R, Riley DC, Kelm ND, Cardwell N, Pollins AC, Afshari A, Nguyen L, Dortch RD, Thayer WP
(2018) Int J Neurosci 128: 563-569
MeSH Terms: Animals, Diffusion Tensor Imaging, Disease Models, Animal, Extracellular Matrix, Female, Microsurgery, Nerve Regeneration, Peripheral Nerve Injuries, Rats, Rats, Sprague-Dawley, Sciatic Nerve
Show Abstract · Added October 24, 2018
BACKGROUND - Conduit-based nerve repairs are commonly used for small nerve gaps, whereas primary repair may be performed if there is no tension on nerve endings. We hypothesize that a conduit-based nerve coaptation device will improve nerve repair outcomes by avoiding sutures at the nerve repair site and utilizing the advantages of a conduit-based repair.
METHODS - The left sciatic nerves of female Sprague-Dawley rats were transected and repaired using a novel conduit-based device. The conduit-based device group was compared to a control group of rats that underwent a standard end-to-end microsurgical repair of the sciatic nerve. Animals underwent behavioral assessments at weekly intervals post-operatively using the sciatic functional index (SFI) test. Animals were sacrificed at four weeks to obtain motor axon counts from immunohistochemistry. A sub-group of animals were sacrificed immediately post repair to obtain MRI images.
RESULTS - SFI scores were superior in rats which received conduit-based repairs compared to the control group. Motor axon counts distal to the injury in the device group at four weeks were statistically superior to the control group. MRI tractography was used to demonstrate repair of two nerves using the novel conduit device.
CONCLUSIONS - A conduit-based nerve coaptation device avoids sutures at the nerve repair site and leads to improved outcomes in a rat model. Conduit-based nerve repair devices have the potential to standardize nerve repairs while improving outcomes.
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Immediate Enhancement of Nerve Function Using a Novel Axonal Fusion Device After Neurotmesis.
Riley DC, Boyer RB, Deister CA, Pollins AC, Cardwell NL, Kelm ND, Does MD, Dortch RD, Bamba R, Shack RB, Thayer WP
(2017) Ann Plast Surg 79: 590-599
MeSH Terms: Animals, Axons, Disease Models, Animal, Drug Delivery Systems, Electromyography, Female, Immunohistochemistry, Male, Nerve Regeneration, Neurosurgical Procedures, Peripheral Nerve Injuries, Polyethylene Glycols, Random Allocation, Rats, Rats, Sprague-Dawley, Recovery of Function, Sciatic Nerve, Trauma, Nervous System
Show Abstract · Added October 24, 2018
BACKGROUND - The management of peripheral nerve injuries remains a large challenge for plastic surgeons. With the inability to fuse axonal endings, results after microsurgical nerve repair have been inconsistent. Our current nerve repair strategies rely upon the slow and lengthy process of axonal regeneration (~1 mm/d). Polyethylene glycol (PEG) has been investigated as a potential axonal fusion agent; however, the percentage of axonal fusion has been inconsistent. The purpose of this study was to identify a PEG delivery device to standardize outcomes after attempted axonal fusion with PEG.
MATERIALS AND METHODS - We used a rat sciatic nerve injury model in which we completely transected and repaired the left sciatic nerve to evaluate the efficacy of PEG fusion over a span of 12 weeks. In addition, we evaluated the effectiveness of a delivery device's ability to optimize results after PEG fusion.
RESULTS - We found that PEG rapidly (within minutes) restores axonal continuity as assessed by electrophysiology, fluorescent retrograde tracer, and diffusion tensor imaging. Immunohistochemical analysis shows that motor axon counts are significantly increased at 1 week, 4 weeks, and 12 weeks postoperatively in PEG-treated animals. Furthermore, PEG restored behavioral functions up to 50% compared with animals that received the criterion standard epineurial repair (control animals).
CONCLUSIONS - The ability of PEG to rapidly restore nerve function after neurotmesis could have vast implications on the clinical management of traumatic injuries to peripheral nerves.
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A novel therapy to promote axonal fusion in human digital nerves.
Bamba R, Waitayawinyu T, Nookala R, Riley DC, Boyer RB, Sexton KW, Boonyasirikool C, Niempoog S, Kelm ND, Does MD, Dortch RD, Shack RB, Thayer WP
(2016) J Trauma Acute Care Surg 81: S177-S183
MeSH Terms: Adolescent, Historically Controlled Study, Humans, Lacerations, Male, Nerve Regeneration, Peripheral Nerve Injuries, Peripheral Nerves, Polyethylene Glycols, Recovery of Function
Show Abstract · Added October 24, 2018
BACKGROUND - Peripheral nerve injury can have a devastating impact on our military and veteran population. Current strategies for peripheral nerve repair include techniques such as nerve tubes, nerve grafts, tissue matrices, and nerve growth guides to enhance the number of regenerating axons. Even with such advanced techniques, it takes months to regain function. In animal models, polyethylene glycol (PEG) therapy has shown to improve both physiologic and behavioral outcomes after nerve transection by fusion of a portion of the proximal axons to the distal axon stumps. The objective of this study was to show the efficacy of PEG fusion in humans and to retrospectively compare PEG fusion to standard nerve repair.
METHODS - Patients with traumatic lacerations involving digital nerves were treated with PEG after standard microsurgical neurorrhaphy. Sensory assessment after injury was performed at 1 week, 2 weeks, 1 month, and 2 months using static two-point discrimination and Semmes-Weinstein monofilament testing. The Medical Research Council Classification (MRCC) for Sensory Recovery Scale was used to evaluate the level of injury. The PEG fusion group was compared to patient-matched controls whose data were retrospectively collected.
RESULTS - Four PEG fusions were performed on four nerve transections in two patients. Polyethylene glycol therapy improves functional outcomes and speed of nerve recovery in clinical setting assessed by average MRCC score in week 1 (2.8 vs 1.0, p = 0.03). At 4 weeks, MRCC remained superior in the PEG fusion group (3.8 vs 1.3, p = 0.01). At 8 weeks, there was improvement in both groups with the PEG fusion cohort remaining statistically better (4.0 vs 1.7, p = 0.01).
CONCLUSION - Polyethylene glycol fusion is a novel therapy for peripheral nerve repair with proven effectiveness in animal models. Clinical studies are still in early stages but have had encouraging results. Polyethylene glycol fusion is a potential revolutionary therapy in peripheral nerve repair but needs further investigation.
LEVEL OF EVIDENCE - Therapeutic study, level IV.
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4.7-T diffusion tensor imaging of acute traumatic peripheral nerve injury.
Boyer RB, Kelm ND, Riley DC, Sexton KW, Pollins AC, Shack RB, Dortch RD, Nanney LB, Does MD, Thayer WP
(2015) Neurosurg Focus 39: E9
MeSH Terms: Acute Disease, Animals, Anisotropy, Diffusion Tensor Imaging, Disease Models, Animal, Female, Humans, Lower Extremity, Male, Peripheral Nerve Injuries, ROC Curve, Rats, Sprague-Dawley, Sciatic Neuropathy, Sensitivity and Specificity, Statistics as Topic
Show Abstract · Added January 26, 2016
Diagnosis and management of peripheral nerve injury is complicated by the inability to assess microstructural features of injured nerve fibers via clinical examination and electrophysiology. Diffusion tensor imaging (DTI) has been shown to accurately detect nerve injury and regeneration in crush models of peripheral nerve injury, but no prior studies have been conducted on nerve transection, a surgical emergency that can lead to permanent weakness or paralysis. Acute sciatic nerve injuries were performed microsurgically to produce multiple grades of nerve transection in rats that were harvested 1 hour after surgery. High-resolution diffusion tensor images from ex vivo sciatic nerves were obtained using diffusion-weighted spin-echo acquisitions at 4.7 T. Fractional anisotropy was significantly reduced at the injury sites of transected rats compared with sham rats. Additionally, minor eigenvalues and radial diffusivity were profoundly elevated at all injury sites and were negatively correlated to the degree of injury. Diffusion tensor tractography showed discontinuities at all injury sites and significantly reduced continuous tract counts. These findings demonstrate that high-resolution DTI is a promising tool for acute diagnosis and grading of traumatic peripheral nerve injuries.
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15 MeSH Terms
Sensory enrichment after peripheral nerve injury restores cortical, not thalamic, receptive field organization.
Florence SL, Boydston LA, Hackett TA, Lachoff HT, Strata F, Niblock MM
(2001) Eur J Neurosci 13: 1755-66
MeSH Terms: Animals, Brain Mapping, Denervation, Evoked Potentials, Somatosensory, Hypesthesia, Macaca mulatta, Nerve Regeneration, Neuronal Plasticity, Neurons, Perception, Peripheral Nerve Injuries, Peripheral Nerves, Physical Stimulation, Recovery of Function, Somatosensory Cortex, Touch, Ventral Thalamic Nuclei
Show Abstract · Added April 6, 2017
Sensory perception can be severely degraded after peripheral injuries that disrupt the functional organization of the sensory maps in somatosensory cortex, even after nerve regeneration has occurred. Rehabilitation involving sensory retraining can improve perceptual function, presumably through plasticity mechanisms in the somatosensory processing network. However, virtually nothing is known about the effects of rehabilitation strategies on brain organization, or where the effects are mediated. In this study, five macaque monkeys received months of enriched sensory experience after median nerve cut and repair early in life. Subsequently, the sensory representation of the hand in primary somatosensory cortex was mapped using multiunit microelectrodes. Additionally, the primary somatosensory relay in the thalamus, the ventroposterior nucleus, was studied to determine whether the effects of the enrichment were initiated subcortically or cortically. Age-matched controls included six monkeys with no sensory manipulation after median nerve cut and regeneration, and one monkey that had restricted sensory experience after the injury. The most substantial effect of the sensory environment was on receptive field sizes in cortical area 3b. Significantly greater proportions of cortical receptive fields in the enriched monkeys were small and well localized compared to the controls, which showed higher proportions of abnormally large or disorganized fields. The refinements in receptive field size and extent in somatosensory cortex likely provide better resolution in the sensory map and may explain the improved functional outcomes after rehabilitation in humans.
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17 MeSH Terms
Multiexponential T2 relaxation in degenerating peripheral nerve.
Does MD, Snyder RE
(1996) Magn Reson Med 35: 207-13
MeSH Terms: Animals, Female, In Vitro Techniques, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Peripheral Nerve Injuries, Peripheral Nerves, Sciatic Nerve, Wallerian Degeneration, Xenopus laevis
Show Abstract · Added May 27, 2014
The multiexponential T2 relaxation spectrum of peripheral nerve undergoing Wallerian degeneration has been measured both in vivo and in vitro. Degeneration of the sciatic nerve of the amphibian Xenopus laevis was induced by crush injury, and T2 relaxation spectra of the nerve were measured at several times up to 35 days following injury. Histologic evidence verified that the nerve underwent Wallerian degeneration. Relaxation spectra were observed to undergo measurable changes as degeneration progressed, the most evident being a reduction from three well-resolved T2 components to one and a decline in the fraction of the spectra associated with the shortest T2 component. The former appears to reflect the collapse and loss of myelinated fibers, while the latter a combination of interstitial edema and myelin loss.
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10 MeSH Terms