scholarly journals Molecular and cellular correlates of human nerve regeneration: ADCYAP1 encoding PACAP enhances sensory neuron outgrowth

2019 ◽  
Author(s):  
Annina B Schmid ◽  
Georgios Baskozos ◽  
Katherine Windsor ◽  
Pall Karlsson ◽  
Oliver Sandy-Hindmarch ◽  
...  
Keyword(s):  
Nerve Regeneration ◽  
Sensory Nerve ◽  
Neural Regeneration ◽  
Human Model ◽  
Symptom Improvement ◽  
Decompression Surgery ◽  
Partial Recovery ◽  
Post Surgery ◽  
Human Nerve

AbstractWe only have a rudimentary understanding of the molecular and cellular determinants of human nerve regeneration. Here, we use carpal tunnel syndrome (CTS) as a human model system to prospectively evaluate correlates of neural regeneration and their relationship with clinical recovery after decompression surgery. At 6 months post-surgery, we noted a significant improvement of median nerve neurophysiological and somatosensory function. Serial skin biopsies revealed a partial recovery of intraepidermal innervation, whose extent correlated with symptom improvement. In myelinated afferents, nodal length increased postoperatively. Transcriptional profiling of the skin revealed 23 differentially expressed genes following decompression, with ADCYAP1 (encoding PACAP) being the most strongly upregulated and showing an association with regeneration of intraepidermal nerve fibres. Using human induced pluripotent stem cell-derived sensory neurons, we confirmed that PACAP significantly enhances axon outgrowth in vivo. Since PACAP signals through G-protein receptors, this pathway provides an interesting therapeutic target for human sensory nerve regeneration.

scholarly journals Probabilistic Assessment of Nerve Regeneration with Diffusion MRI in Rat Models of Peripheral Nerve Trauma

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Isaac V. Manzanera Esteve ◽  
Angel F. Farinas ◽  
Alonda C. Pollins ◽  
Marlieke E. Nussenbaum ◽  
Nancy L. Cardwell ◽  
...  
Keyword(s):  
Nerve Regeneration ◽  
Diffusion Mri ◽  
Diffusion Tensor ◽  
Ex Vivo ◽  
Behavioral Data ◽  
Diffusion Kurtosis Imaging ◽  
Partial Recovery ◽  
Limited Information ◽  
Sprague Dawley ◽  
Post Surgery

AbstractNerve regeneration after injury must occur in a timely fashion to restore function. Unfortunately, current methods (e.g., electrophysiology) provide limited information following trauma, resulting in delayed management and suboptimal outcomes. Herein, we evaluated the ability of diffusion MRI to monitor nerve regeneration after injury/repair. Sprague-Dawley rats were divided into three treatment groups (sham = 21, crush = 23, cut/repair = 19) and ex vivo diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) was performed 1–12 weeks post-surgery. Behavioral data showed a distinction between crush and cut/repair nerves at 4 weeks. This was consistent with DTI, which found that thresholds based on the ratio of radial and axial diffusivities (RD/AD = 0.40 ± 0.02) and fractional anisotropy (FA = 0.53 ± 0.01) differentiated crush from cut/repair injuries. By the 12th week, cut/repair nerves whose behavioral data indicated a partial recovery were below the RD/AD threshold (and above the FA threshold), while nerves that did not recover were on the opposite side of each threshold. Additional morphometric analysis indicated that DTI-derived normalized scalar indices report on axon density (RD/AD: r = −0.54, p < 1e-3; FA: r = 0.56, p < 1e-3). Interestingly, higher-order DKI analyses did not improve our ability classify recovery. These findings suggest that DTI may provide promising biomarkers for distinguishing successful/unsuccessful nerve repairs and potentially identify cases that require reoperation.

scholarly journals Protocol for a phase I trial of a novel synthetic polymer nerve conduit 'Polynerve' in participants with sensory digital nerve injury (UMANC)

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 959 ◽  
Author(s):  
Ralph Murphy ◽  
Alessandro Faroni ◽  
Jason Wong ◽  
Adam Reid
Keyword(s):  
Phase I ◽  
Nerve Regeneration ◽  
Treatment Options ◽  
Donor Site ◽  
Sensory Nerve ◽  
Sensory Nerves ◽  
Nerve Conduit ◽  
Nerve Injuries ◽  
Post Surgery ◽  
The Uk

Background: Peripheral nerve injuries are common, with approximately 9,000 cases in the UK annually. Young working individuals are predominantly affected, leading to significant health and social implications. Functional recovery is often poor with impaired hand sensation, reduced motor function and pain and cold intolerance. Where a nerve gap exists, nerve grafting remains the gold-standard treatment but creates a second surgical site, sensory deficit at the donor site, possible neuroma formation and has limited availability. Current commercially available synthetic and resorbable nerve conduit alternatives are reported to be rigid and inflexible. This study will set out to examine the first-in-man use of a new nerve conduit device ‘Polynerve’ to repair small nerve gaps in digital sensory nerves of the hand. Polynerve is a degradable co-polymer of poly-ε-caprolactone and poly-l-lactic acid, which is shaped as a cylinder that has greater tensile strength, flexibility and less acidic degradation compared with current commercially available synthetic nerve conduits. In addition, it has a novel micro-grooved internal lumen that aids Schwann cell ingress and alignment to improve nerve regeneration. Methods: In total, 17 eligible participants will be recruited to undergo repair of a transected sensory nerve of the hand using the Polynerve device. All participants that receive the nerve conduit device will be followed for a period of 12 months post-surgery. The primary endpoint is safety of the device and the secondary endpoint is degree of sensory nerve regeneration through the conduit assessed using standard sensory testing (2-PD, WEST monofilament testing and locognosia). Discussion: The ‘UMANC’ trial is a single-centre UK-based, prospective, unblinded, phase I clinical trial of a novel nerve conduit device. We aim to demonstrate the safety of Polynerve as a synthetic, biodegradable nerve conduit and improve the treatment options available to patients with significant nerve injuries. Registration: Clinicaltrials.gov: NCT02970864; EudraCT: 2016-001667-37.

scholarly journals Molecular and cellular correlates of human nerve regeneration: ADCYAP1/PACAP enhance nerve outgrowth

Brain ◽  
2020 ◽  
Vol 143 (7) ◽  
pp. 2009-2026 ◽  
Author(s):  
Georgios Baskozos ◽  
Oliver Sandy-Hindmarch ◽  
Alex J Clark ◽  
Katherine Windsor ◽  
Pall Karlsson ◽  
...  
Keyword(s):  
Standard Deviation ◽  
Nerve Regeneration ◽  
Nerve Fibre ◽  
Carpal Tunnel ◽  
Quantitative Sensory Testing ◽  
Human Model ◽  
Partial Recovery ◽  
Dependent Manner ◽  
Sensory Testing ◽  
Clinical Recovery

Abstract We only have a rudimentary understanding of the molecular and cellular determinants of nerve regeneration and neuropathic pain in humans. This cohort study uses the most common entrapment neuropathy (carpal tunnel syndrome) as a human model system to prospectively evaluate the cellular and molecular correlates of neural regeneration and its relationship with clinical recovery. In 60 patients undergoing carpal tunnel surgery [36 female, mean age 62.5 (standard deviation 12.2) years], we used quantitative sensory testing and nerve conduction studies to evaluate the function of large and small fibres before and 6 months after surgery. Clinical recovery was assessed with the global rating of change scale and Boston Carpal Tunnel Questionnaire. Twenty healthy participants provided normative data [14 female, mean age 58.0 (standard deviation 12.9) years]. At 6 months post-surgery, we noted significant recovery of median nerve neurophysiological parameters (P &lt; 0.0001) and improvements in quantitative sensory testing measures of both small and large nerve fibre function (P &lt; 0.002). Serial biopsies revealed a partial recovery of intraepidermal nerve fibre density [fibres/mm epidermis pre: 4.20 (2.83), post: 5.35 (3.34), P = 0.001], whose extent correlated with symptom improvement (r = 0.389, P = 0.001). In myelinated afferents, nodal length increased postoperatively [pre: 2.03 (0.82), post: 3.03 (1.23), P &lt; 0.0001] suggesting that this is an adaptive phenomenon. Transcriptional profiling of the skin revealed 31 differentially expressed genes following decompression, with ADCYAP1 (encoding pituitary adenylate cyclase activating peptide, PACAP) being the most strongly upregulated (log2 fold-change 1.87, P = 0.0001) and its expression was associated with recovery of intraepidermal nerve fibres. We found that human induced pluripotent stem cell-derived sensory neurons expressed the receptor for PACAP and that this peptide could significantly enhance axon outgrowth in a dose-dependent manner in vitro [neurite length PACAP 1065.0 µm (285.5), vehicle 570.9 μm (181.8), P = 0.003]. In conclusion, carpal tunnel release is associated with significant cutaneous reinnervation, which correlates with the degree of functional improvement and is associated with a transcriptional programme relating to morphogenesis and inflammatory processes. The most highly dysregulated gene ADCYAP1 (encoding PACAP) was associated with reinnervation and, given that this peptide signals through G-protein coupled receptors, this signalling pathway provides an interesting therapeutic target for human sensory nerve regeneration.

scholarly journals Probabilistic Assessment of Nerve Regeneration with Diffusion MRI: Validation in Rat Models of Peripheral Nerve Trauma

2019 ◽  
Author(s):  
Isaac V. Manzanera Esteve ◽  
Angel F. Farinas ◽  
Alonda C. Pollins ◽  
Marlieke E. Nussenbaum ◽  
Nancy L. Cardwell ◽  
...  
Keyword(s):  
Nerve Regeneration ◽  
Diffusion Mri ◽  
Diffusion Tensor ◽  
Ex Vivo ◽  
Behavioral Data ◽  
Diffusion Kurtosis Imaging ◽  
Partial Recovery ◽  
Limited Information ◽  
Sprague Dawley ◽  
Post Surgery

ABSTRACTNerve regeneration after injury must occur in a timely fashion to restore function. Unfortunately, current methods (e.g., electrophysiology) provide limited information following trauma, resulting in delayed management and suboptimal outcomes. Herein, we evaluated the ability of diffusion MRI to monitor nerve regeneration after injury/repair. Sprague-Dawley rats were divided into three treatment groups (sham=21, crush=23, cut/repair=19) and ex vivo diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) was performed 1-12 weeks post-surgery. Behavioral data showed a distinction between crush and cut/repair nerves at 4 weeks. This was consistent with DTI, which found that thresholds based on the ratio of radial and axial diffusivities (RD/AD=0.40±0.02) and fractional anisotropy (FA=0.53±0.01) differentiated crush from cut/repair injuries. By the 12th week, cut/repair nerves whose behavioral data indicated a partial recovery were below the RD/AD threshold (and above the FA threshold), while nerves that did not recover were on the opposite side of each threshold. Additional morphometric analysis indicated that DTI-derived normalized scalar indices report on axon density (RD/AD: r=−0.54, p<1e-3; FA: r=0.56, p<1e-3). Interestingly, higher-order DKI analyses did not improve our ability classify recovery. These findings suggest that DTI can distinguish successful/unsuccessful nerve repairs and potentially identify cases that require reoperation.

The effect of Rho Kinase inhibition on corneal nerve regeneration in vitro and in vivo

2021 ◽  
Author(s):  
Sonja Mertsch ◽  
Inga Neumann ◽  
Cosima Rose ◽  
Marc Schargus ◽  
Gerd Geerling ◽  
...  
Keyword(s):  
Nerve Regeneration ◽  
Rho Kinase ◽  
Kinase Inhibition ◽  
Corneal Nerve ◽  
Regeneration In Vitro

scholarly journals Transcription of Candidate Virulence Genes ofHaemophilus ducreyi during Infection of Human Volunteers

2001 ◽  
Vol 69 (3) ◽  
pp. 1483-1487 ◽  
Author(s):  
Robert E. Throm ◽  
Stanley M. Spinola
Keyword(s):  
Experimental Infection ◽  
Virulence Genes ◽  
Human Model ◽  
Specific Gene ◽  
Gene Products ◽  
Virulence Determinants ◽  
Reverse Transcription Pcr ◽  
Human Volunteers

ABSTRACT Haemophilus ducreyi expresses several putative virulence factors in vitro. Isogenic mutant-to-parent comparisons have been performed in a human model of experimental infection to examine whether specific gene products are involved in pathogenesis. Several mutants (momp, ftpA, losB, lst, cdtC, and hhdB) were as virulent as the parent in the human model, suggesting that their gene products did not play a major role in pustule formation. However, we could not exclude the possibility that the gene of interest was not expressed during the initial stages of infection. Biopsies of pustules obtained from volunteers infected with H. ducreyiwere subjected to reverse transcription-PCR. Transcripts corresponding to momp, ftpA, losB, lst, cdtB, and hhdA were expressed in vivo. In addition, transcripts for other putative virulence determinants such as ompA2, tdhA, lspA1, andlspA2 were detected in the biopsies. These results indicate that although several candidate virulence determinants are expressed during experimental infection, they do not have a major role in the initial stages of pathogenesis.

Nerve branching is induced and oriented by a small applied electric field

1990 ◽  
Vol 95 (4) ◽  
pp. 605-615
Author(s):  
C.D. McCaig
Keyword(s):  
Electric Field ◽  
Dimethyl Sulfoxide ◽  
Nerve Regeneration ◽  
Applied Electric Field ◽  
Large Majority ◽  
Ganglioside Gm1 ◽  
Pharmacological Agents ◽  
Extrinsic Cues

Nerve branching is controlled by intrinsic and extrinsic cues, one of which may be a small applied electric field. Lateral processes were induced by passing current through a micropipette placed at 90 degrees to the shaft of a developing nerve. The appearance of processes was a polarised event with a large majority arising from the cathodal facing side of nerves. Whilst an electric field alone may promote branching, the presence of dimethyl sulfoxide (DMSO) or the ganglioside GM1 enhanced branching of developing nerves. It is likely that an applied electric field promotes microtubule disassembly locally along the neurite shaft and that this can lead to a polarised rearrangement of the neuronal cyto-skeleton. It is suggested that the use of an applied electric field in conjunction with these pharmacological agents might enhance nerve regeneration in vivo.

scholarly journals 3D Printed Polymeric Hydrogels for Nerve Regeneration

Polymers ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 1041 ◽  
Author(s):  
Binoy Maiti ◽  
David Díaz Díaz
Keyword(s):  
Nerve Regeneration ◽  
Nerve Cell ◽  
Clinical Applications ◽  
Cell Regeneration ◽  
3D Bioprinting ◽  
Ability To Regenerate ◽  
3D Printed ◽  
Polymeric Hydrogels ◽  
Human Nervous System

The human nervous system lacks an inherent ability to regenerate its components upon damage or diseased conditions. During the last decade, this has motivated the development of a number of strategies for nerve regeneration. However, most of those approaches have not been used in clinical applications till today. For instance, although biomaterial-based scaffolds have been extensively used for nerve reparation, the lack of more customized structures have hampered their use in vivo. This highlight focuses mainly on how 3D bioprinting technology, using polymeric hydrogels as bio-inks, can be used for the development of new nerve guidance channels or devices for peripheral nerve cell regeneration. In this concise contribution, some of the most recent and representative examples are highlighted to discuss the challenges involved in various aspects of 3D bioprinting for nerve cell regeneration, specifically when using polymeric hydrogels.

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