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Regenerative Medicine for Peripheral Nerve Injury: Recent Advances, Emerging Therapies and Future Directions

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Materials Science".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 70340

Special Issue Editors

Dr. Giulia Ronchi

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Guest Editor
Department of Clinical and Biological Sciences, University of Turin & Neuroscience Institute of the “Cavalieri Ottolenghi” Foundation (NICO), Regione Gonzole 10, 10043 Orbassano, Turin, Italy
Interests: peripheral nerve regeneration; translational research; biomaterials; tissue engineering; neuregulin1/ErbB system; stereology
Dr. Ilaria Tonazzini

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Guest Editor
National Enterprise for Nanoscience and Nanotechnology (NEST), Istituto Nanoscienze Consiglio Nazionale delle Ricerche (CNR) and Scuola Normale Superiore Pisa, Piazza San Silvestro 12, 56127 Pisa, Italy
Interests: nanoscience; neuroscience; nano/microstructured materials; scaffolds; nanoparticles; mechanotrasduction; mechanobiology

Special Issue Information

Dear Colleagues,

Peripheral nerves are widely spread throughout the body and can be damaged in several ways: as a result of a car crash, domestic or sport falls, work accidents, war wounds, or as a consequence of direct surgical trauma, anesthetic interventions, or radical tumor resection (iatrogenic injuries).

Injury to peripheral nerves represents a major cause of morbidity and negatively impacts the quality of life of an increasing number of patients, bringing about physical disability and total or partial loss of their productive activities with important related social and economic consequences.

Nowadays, there are no repair or reconstruction techniques that can ensure the full restoration of sensorimotor functions of patients following severe nerve injuries. Therefore, the repair, reconstruction, and regeneration of peripheral nerve injuries represents a major field where innovative therapies should be investigated.

In recent years, there have been many advances in different areas of regenerative medicine, including reconstructive microsurgery techniques, tissue engineering, nanomedicine, material science, regenerative 2/3D scaffolds (microfabrication techniques, microstructured substrates, functionalization), gene therapy, stem cell biology, and cell transplantation.

This Special Issue of IJMS will focus on recent advances in regenerative medicine for peripheral nerve injury, both in basic and translational research. We invite researchers to contribute by submitting both original research articles and reviews of the literature. We are interested in articles that outline the latest advances in nerve regeneration research as well as that explore novel therapies and approaches for promoting peripheral nerve regeneration (e.g., new biomaterials and their functionalization/nano–microstructuration, 2/3D engineered scaffolds and innovative fabrication techniques, innovative gene therapy approaches, delivery of growth factors, and involvement of new molecules in the process of nerve regeneration). Interdisciplinary approaches, even computational, that bring together different aspects of regenerative medicine are welcome.

Dr. Giulia Ronchi
Dr. Ilaria Tonazzini
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Peripheral nerve injury and regeneration
  • Regenerative medicine
  • Schwann cells
  • Biomaterials
  • Functionalization
  • Gene therapy
  • Cell therapy
  • Growth factors
  • Translational research
  • Stem cells
  • 2/3D scaffolds
  • Nano–microfabrication
  • Nano–microstructured materials
  • 3D printing

Published Papers (19 papers)

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15 pages, 16043 KiB  
Article
Blood Vessels: The Pathway Used by Schwann Cells to Colonize Nerve Conduits
by Benedetta Elena Fornasari, Federica Zen, Giulia Nato, Marco Fogli, Federico Luzzati, Giulia Ronchi, Stefania Raimondo and Giovanna Gambarotta
Int. J. Mol. Sci. 2022, 23(4), 2254; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042254 - 18 Feb 2022
Cited by 12 | Viewed by 2204
Abstract
The repair of severe nerve injuries requires an autograft or conduit to bridge the gap and avoid axon dispersion. Several conduits are used routinely, but their effectiveness is comparable to that of an autograft only for short gaps. Understanding nerve regeneration within short [...] Read more.
The repair of severe nerve injuries requires an autograft or conduit to bridge the gap and avoid axon dispersion. Several conduits are used routinely, but their effectiveness is comparable to that of an autograft only for short gaps. Understanding nerve regeneration within short conduits could help improve their efficacy for longer gaps. Since Schwann cells are known to migrate on endothelial cells to colonize the “nerve bridge”, the new tissue spontaneously forming to connect the injured nerve stumps, here we aimed to investigate whether this migratory mechanism drives Schwann cells to also proceed within the nerve conduits used to repair large nerve gaps. Injured median nerves of adult female rats were repaired with 10 mm chitosan conduits and the regenerated nerves within conduits were analyzed at different time points using confocal imaging of sequential thick sections. Our data showed that the endothelial cells formed a dense capillary network used by Schwann cells to migrate from the two nerve stumps into the conduit. We concluded that angiogenesis played a key role in the nerve conduits, not only by supporting cell survival but also by providing a pathway for the migration of newly formed Schwann cells. Full article
(This article belongs to the Special Issue Regenerative Medicine for Peripheral Nerve Injury: Recent Advances, Emerging Therapies and Future Directions)
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14 pages, 4206 KiB  
Article
Validation of a Cleanroom Compliant Sonication-Based Decellularization Technique: A New Concept in Nerve Allograft Production
by Federico Bolognesi, Nicola Fazio, Filippo Boriani, Viscardo Paolo Fabbri, Davide Gravina, Francesca Alice Pedrini, Nicoletta Zini, Michelina Greco, Michela Paolucci, Maria Carla Re, Sofia Asioli, Maria Pia Foschini, Antonietta D’Errico, Nicola Baldini and Claudio Marchetti
Int. J. Mol. Sci. 2022, 23(3), 1530; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031530 - 28 Jan 2022
Cited by 1 | Viewed by 2103
Abstract
Defects of the peripheral nervous system are extremely frequent in trauma and surgeries and have high socioeconomic costs. If the direct suture of a lesion is not possible, i.e., nerve gap > 2 cm, it is necessary to use grafts. While the gold [...] Read more.
Defects of the peripheral nervous system are extremely frequent in trauma and surgeries and have high socioeconomic costs. If the direct suture of a lesion is not possible, i.e., nerve gap > 2 cm, it is necessary to use grafts. While the gold standard is the autograft, it has disadvantages related to its harvesting, with an inevitable functional deficit and further morbidity. An alternative to autografting is represented by the acellular nerve allograft (ANA), which avoids disadvantages of autograft harvesting and fresh allograft rejection. In this research, the authors intend to transfer to human nerves a novel technique, previously implemented in animal models, to decellularize nerves. The new method is based on soaking the nerve tissues in decellularizing solutions while associating ultrasounds and freeze–thaw cycles. It is performed without interrupting the sterility chain, so that the new graft may not require post-production γ-ray irradiation, which is suspected to affect the structural and functional quality of tissues. The new method is rapid, safe, and inexpensive if compared with available commercial ANAs. Histology and immunohistochemistry have been adopted to evaluate the new decellularized nerves. The study shows that the new method can be applied to human nerve samples, obtaining similar, and, sometimes better, results compared with the chosen control method, the Hudson technique. Full article
(This article belongs to the Special Issue Regenerative Medicine for Peripheral Nerve Injury: Recent Advances, Emerging Therapies and Future Directions)
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13 pages, 2262 KiB  
Article
Early Intervention of Cold-Water Swimming on Functional Recovery and Spinal Pain Modulation Following Brachial Plexus Avulsion in Rats
by Yueh-Ling Hsieh, Nian-Pu Yang, Shih-Fong Chen, Yu-Lin Lu and Chen-Chia Yang
Int. J. Mol. Sci. 2022, 23(3), 1178; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031178 - 21 Jan 2022
Cited by 3 | Viewed by 2291
Abstract
Brachial plexus avulsion (BPA) causes peripheral nerve injury complications with motor and sensory dysfunction of the upper limb. Growing evidence has shown an active role played by cold-water swimming (CWS) in alleviating peripheral neuropathic pain and functional recovery. This study examined whether CWS [...] Read more.
Brachial plexus avulsion (BPA) causes peripheral nerve injury complications with motor and sensory dysfunction of the upper limb. Growing evidence has shown an active role played by cold-water swimming (CWS) in alleviating peripheral neuropathic pain and functional recovery. This study examined whether CWS could promote functional recovery and pain modulation through the reduction of neuroinflammation and microglial overactivation in dorsal horn neurons at the early-stage of BPA. After BPA surgery was performed on rats, they were assigned to CWS or sham training for 5 min twice a day for two weeks. Functional behavioral responses were tested before and after BPA surgery, and each week during training. Results after the two-week training program showed significant improvements in BPA-induced motor and sensory loss (p < 0.05), lower inflammatory cell infiltration, and vacuole formation in injured nerves among the BPA–CWS group. Moreover, BPA significantly increased the expression of SP and IBA1 in dorsal horn neurons (p < 0.05), whereas CWS prevented their overexpression in the BPA–CWS group. The present findings evidenced beneficial rehabilitative effects of CWS on functional recovery and pain modulation at early-stage BPA. The beneficial effects are partially related to inflammatory suppression and spinal modulation. The synergistic role of CWS combined with other management approaches merits further investigation. Full article
(This article belongs to the Special Issue Regenerative Medicine for Peripheral Nerve Injury: Recent Advances, Emerging Therapies and Future Directions)
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16 pages, 60672 KiB  
Article
Gellan-Xanthan Hydrogel Conduits with Intraluminal Electrospun Nanofibers as Physical, Chemical and Therapeutic Cues for Peripheral Nerve Repair
by Poornima Ramburrun, Pradeep Kumar, Elias Ndobe and Yahya E. Choonara
Int. J. Mol. Sci. 2021, 22(21), 11555; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111555 - 26 Oct 2021
Cited by 9 | Viewed by 1956
Abstract
Optimal levels of functional recovery in peripheral nerve injuries remain elusive due to the architectural complexity of the neuronal environment. Commercial nerve repair conduits lack essential guidance cues for the regenerating axons. In this study, the regenerative potential of a biosimulated nerve repair [...] Read more.
Optimal levels of functional recovery in peripheral nerve injuries remain elusive due to the architectural complexity of the neuronal environment. Commercial nerve repair conduits lack essential guidance cues for the regenerating axons. In this study, the regenerative potential of a biosimulated nerve repair system providing three types of regenerative cues was evaluated in a 10 mm sciatic nerve-gap model over 4 weeks. A thermo-ionically crosslinked gellan-xanthan hydrogel conduit loaded with electrospun PHBV-magnesium oleate-N-acetyl-cysteine (PHBV-MgOl-NAC) nanofibers was assessed for mechanical properties, nerve growth factor (NGF) release kinetics and PC12 viability. In vivo functional recovery was based on walking track analysis, gastrocnemius muscle mass and histological analysis. As an intraluminal filler, PHBV-MgOl-NAC nanofibers improved matrix resilience, deformation and fracture of the hydrogel conduit. NGF release was sustained over 4 weeks, governed by Fickian diffusion and Case-II relaxational release for the hollow conduit and the nanofiber-loaded conduit, respectively. The intraluminal fibers supported PC12 proliferation by 49% compared to the control, preserved up to 43% muscle mass and gradually improved functional recovery. The combined elements of physical guidance (nanofibrous scaffolding), chemical cues (N-acetyl-cysteine and magnesium oleate) and therapeutic cues (NGF and diclofenac sodium) offers a promising strategy for the regeneration of severed peripheral nerves. Full article
(This article belongs to the Special Issue Regenerative Medicine for Peripheral Nerve Injury: Recent Advances, Emerging Therapies and Future Directions)
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26 pages, 23895 KiB  
Article
Injury-Induced HSP27 Expression in Peripheral Nervous Tissue Is Not Associated with Any Alteration in Axonal Outgrowth after Immediate or Delayed Nerve Repair
by Lena Stenberg, Derya Burcu Hazer Rosberg, Sho Kohyama, Seigo Suganuma and Lars B. Dahlin
Int. J. Mol. Sci. 2021, 22(16), 8624; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168624 - 11 Aug 2021
Cited by 4 | Viewed by 1728
Abstract
We investigated injury-induced heat shock protein 27 (HSP27) expression and its association to axonal outgrowth after injury and different nerve repair models in healthy Wistar and diabetic Goto-Kakizaki rats. By immunohistochemistry, expression of HSP27 in sciatic nerves and DRG and axonal outgrowth (neurofilaments) [...] Read more.
We investigated injury-induced heat shock protein 27 (HSP27) expression and its association to axonal outgrowth after injury and different nerve repair models in healthy Wistar and diabetic Goto-Kakizaki rats. By immunohistochemistry, expression of HSP27 in sciatic nerves and DRG and axonal outgrowth (neurofilaments) in sciatic nerves were analyzed after no, immediate, and delayed (7-day delay) nerve repairs (7- or 14-day follow-up). An increased HSP27 expression in nerves and in DRG at the uninjured side was associated with diabetes. HSP27 expression in nerves and in DRG increased substantially after the nerve injuries, being higher at the site where axons and Schwann cells interacted. Regression analysis indicated a positive influence of immediate nerve repair compared to an unrepaired injury, but a shortly delayed nerve repair had no impact on axonal outgrowth. Diabetes was associated with a decreased axonal outgrowth. The increased expression of HSP27 in sciatic nerve and DRG did not influence axonal outgrowth. Injured sciatic nerves should appropriately be repaired in healthy and diabetic rats, but a short delay does not influence axonal outgrowth. HSP27 expression in sciatic nerve or DRG, despite an increase after nerve injury with or without a repair, is not associated with any alteration in axonal outgrowth. Full article
(This article belongs to the Special Issue Regenerative Medicine for Peripheral Nerve Injury: Recent Advances, Emerging Therapies and Future Directions)
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21 pages, 6964 KiB  
Article
Chitosan Micro-Grooved Membranes with Increased Asymmetry for the Improvement of the Schwann Cell Response in Nerve Regeneration
by Luca Scaccini, Roberta Mezzena, Alessia De Masi, Mariacristina Gagliardi, Giovanna Gambarotta, Marco Cecchini and Ilaria Tonazzini
Int. J. Mol. Sci. 2021, 22(15), 7901; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157901 - 23 Jul 2021
Cited by 17 | Viewed by 2653
Abstract
Peripheral nerve injuries are a common condition in which a nerve is damaged, affecting more than one million people every year. There are still no efficient therapeutic treatments for these injuries. Artificial scaffolds can offer new opportunities for nerve regeneration applications; in this [...] Read more.
Peripheral nerve injuries are a common condition in which a nerve is damaged, affecting more than one million people every year. There are still no efficient therapeutic treatments for these injuries. Artificial scaffolds can offer new opportunities for nerve regeneration applications; in this framework, chitosan is emerging as a promising biomaterial. Here, we set up a simple and effective method for the production of micro-structured chitosan films by solvent casting, with high fidelity in the micro-pattern reproducibility. Three types of chitosan directional micro-grooved patterns, presenting different levels of symmetricity, were developed for application in nerve regenerative medicine: gratings (GR), isosceles triangles (ISO) and scalene triangles (SCA). The directional patterns were tested with a Schwann cell line. The most asymmetric topography (SCA), although it polarized the cell shaping less efficiently, promoted higher cell proliferation and a faster cell migration, both individually and collectively, with a higher directional persistence of motion. Overall, the use of micro-structured asymmetrical directional topographies may be exploited to enhance the nerve regeneration process mediated by chitosan scaffolds. Full article
(This article belongs to the Special Issue Regenerative Medicine for Peripheral Nerve Injury: Recent Advances, Emerging Therapies and Future Directions)
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17 pages, 4901 KiB  
Article
Toll-Like Receptor 9-Mediated Neuronal Innate Immune Reaction Is Associated with Initiating a Pro-Regenerative State in Neurons of the Dorsal Root Ganglia Non-Associated with Sciatic Nerve Lesion
by Petr Dubový, Ivana Hradilová-Svíženská, Václav Brázda and Marek Joukal
Int. J. Mol. Sci. 2021, 22(14), 7446; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147446 - 12 Jul 2021
Cited by 8 | Viewed by 2345
Abstract
One of the changes brought about by Wallerian degeneration distal to nerve injury is disintegration of axonal mitochondria and consequent leakage of mitochondrial DNA (mtDNA)—the natural ligand for the toll-like receptor 9 (TLR9). RT-PCR and immunohistochemical or Western blot analyses were used to [...] Read more.
One of the changes brought about by Wallerian degeneration distal to nerve injury is disintegration of axonal mitochondria and consequent leakage of mitochondrial DNA (mtDNA)—the natural ligand for the toll-like receptor 9 (TLR9). RT-PCR and immunohistochemical or Western blot analyses were used to detect TLR9 mRNA and protein respectively in the lumbar (L4-L5) and cervical (C7-C8) dorsal root ganglia (DRG) ipsilateral and contralateral to a sterile unilateral sciatic nerve compression or transection. The unilateral sciatic nerve lesions led to bilateral increases in levels of both TLR9 mRNA and protein not only in the lumbar but also in the remote cervical DRG compared with naive or sham-operated controls. This upregulation of TLR9 was linked to activation of the Nuclear Factor kappa B (NFκB) and nuclear translocation of the Signal Transducer and Activator of Transcription 3 (STAT3), implying innate neuronal immune reaction and a pro-regenerative state in uninjured primary sensory neurons of the cervical DRG. The relationship of TLR9 to the induction of a pro-regenerative state in the cervical DRG neurons was confirmed by the shorter lengths of regenerated axons distal to ulnar nerve crush following a previous sciatic nerve lesion and intrathecal chloroquine injection compared with control rats. The results suggest that a systemic innate immune reaction not only triggers the regenerative state of axotomized DRG neurons but also induces a pro-regenerative state further along the neural axis after unilateral nerve injury. Full article
(This article belongs to the Special Issue Regenerative Medicine for Peripheral Nerve Injury: Recent Advances, Emerging Therapies and Future Directions)
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17 pages, 2403 KiB  
Article
Bioluminescent Optogenetics: A Novel Experimental Therapy to Promote Axon Regeneration after Peripheral Nerve Injury
by Arthur W. English, Ken Berglund, Dario Carrasco, Katharina Goebel, Robert E. Gross, Robin Isaacson, Olivia C. Mistretta and Carly Wynans
Int. J. Mol. Sci. 2021, 22(13), 7217; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22137217 - 05 Jul 2021
Cited by 8 | Viewed by 3064
Abstract
Functional recovery after peripheral nerve injury (PNI) is poor, mainly due to the slow and incomplete regeneration of injured axons. Experimental therapies that increase the excitability of the injured axons have proven remarkably successful in promoting regeneration, but their clinical applicability has been [...] Read more.
Functional recovery after peripheral nerve injury (PNI) is poor, mainly due to the slow and incomplete regeneration of injured axons. Experimental therapies that increase the excitability of the injured axons have proven remarkably successful in promoting regeneration, but their clinical applicability has been limited. Bioluminescent optogenetics (BL-OG) uses luminopsins, fusion proteins of light-generating luciferase and light-sensing ion channels that could be used to increase neuronal excitability if exposed to a suitable substrate. Excitatory luminopsins were expressed in motoneurons of transgenic mice and in wildtype mice transduced with adeno-associated viral vectors. Intraperitoneal administration of coelenterazine (CTZ), a known luciferase substrate, generated intense bioluminescence in peripheral axons. This bioluminescence increased motoneuron excitability. A single administration of CTZ immediately after sciatic nerve transection and repair markedly enhanced motor axon regeneration. Compound muscle action potentials were 3–4 times larger than controls by 4 weeks after injury. The results observed with transgenic mice were comparable to those of mice in which the luminopsin was expressed using viral vectors. Significantly more motoneurons had successfully reinnervated muscle targets four weeks after nerve injury in BL-OG treated mice than in controls. Bioluminescent optogenetics is a promising therapeutic approach to enhancing axon regeneration after PNI. Full article
(This article belongs to the Special Issue Regenerative Medicine for Peripheral Nerve Injury: Recent Advances, Emerging Therapies and Future Directions)
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25 pages, 7232 KiB  
Article
Gold and Cobalt Oxide Nanoparticles Modified Poly-Propylene Poly-Ethylene Glycol Membranes in Poly (ε-Caprolactone) Conduits Enhance Nerve Regeneration in the Sciatic Nerve of Healthy Rats
by Derya Burcu Hazer Rosberg, Baki Hazer, Lena Stenberg and Lars B. Dahlin
Int. J. Mol. Sci. 2021, 22(13), 7146; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22137146 - 01 Jul 2021
Cited by 8 | Viewed by 2213
Abstract
Reconstruction of nerve defects is a clinical challenge. Autologous nerve grafts as the gold standard treatment may result in an incomplete restoration of extremity function. Biosynthetic nerve conduits are studied widely, but still have limitations. Here, we reconstructed a 10 mm sciatic nerve [...] Read more.
Reconstruction of nerve defects is a clinical challenge. Autologous nerve grafts as the gold standard treatment may result in an incomplete restoration of extremity function. Biosynthetic nerve conduits are studied widely, but still have limitations. Here, we reconstructed a 10 mm sciatic nerve defect in healthy rats and analyzed nerve regeneration in poly (ε-caprolactone) (PCL) conduits longitudinally divided by gold (Au) and gold-cobalt oxide (AuCoO) nanoparticles embedded in poly-propylene poly-ethylene glycol (PPEG) membranes (AuPPEG or AuCoOPPEG) and compared it with unmodified PPEG-membrane and hollow PCL conduits. After 21 days, we detected significantly better axonal outgrowth, together with higher numbers of activated Schwann cells (ATF3-labelled) and higher HSP27 expression, in reconstructed sciatic nerve and in corresponding dorsal root ganglia (DRG) in the AuPPEG and AuCoOPPEG groups; whereas the number of apoptotic Schwann cells (cleaved caspase 3-labelled) was significantly lower. Furthermore, numbers of activated and apoptotic Schwann cells in the regenerative matrix correlated with axonal outgrowth, whereas HSP27 expression in the regenerative matrix and in DRGs did not show any correlation with axonal outgrowth. We conclude that gold and cobalt-oxide nanoparticle modified membranes in conduits improve axonal outgrowth and increase the regenerative performance of conduits after nerve reconstruction. Full article
(This article belongs to the Special Issue Regenerative Medicine for Peripheral Nerve Injury: Recent Advances, Emerging Therapies and Future Directions)
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26 pages, 4320 KiB  
Article
Modified Hyaluronic Acid-Laminin-Hydrogel as Luminal Filler for Clinically Approved Hollow Nerve Guides in a Rat Critical Defect Size Model
by Zhong Huang, Svenja Kankowski, Ella Ertekin, Mara Almog, Zvi Nevo, Shimon Rochkind and Kirsten Haastert-Talini
Int. J. Mol. Sci. 2021, 22(12), 6554; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126554 - 18 Jun 2021
Cited by 5 | Viewed by 2292
Abstract
Hollow nerve guidance conduits are approved for clinical use for defect lengths of up to 3 cm. This is because also in pre-clinical evaluation they are less effective in the support of nerve regeneration over critical defect lengths. Hydrogel luminal fillers are thought [...] Read more.
Hollow nerve guidance conduits are approved for clinical use for defect lengths of up to 3 cm. This is because also in pre-clinical evaluation they are less effective in the support of nerve regeneration over critical defect lengths. Hydrogel luminal fillers are thought to improve the regeneration outcome by providing an optimized matrix inside bioartificial nerve grafts. We evaluated here a modified hyaluronic acid-laminin-hydrogel (M-HAL) as luminal filler for two clinically approved hollow nerve guides. Collagen-based and chitosan-based nerve guides were filled with M-HAL in two different concentrations and the regeneration outcome comprehensively studied in the acute repair rat sciatic nerve 15 mm critical defect size model. Autologous nerve graft (ANG) repair served as gold-standard control. At 120 days post-surgery, all ANG rats demonstrated electrodiagnostically detectable motor recovery. Both concentrations of the hydrogel luminal filler induced improved regeneration outcome over empty nerve guides. However, neither combination with collagen- nor chitosan-based nerve guides resulted in functional recovery comparable to the ANG repair. In contrast to our previous studies, we demonstrate here that M-HAL slightly improved the overall performance of either empty nerve guide type in the critical defect size model. Full article
(This article belongs to the Special Issue Regenerative Medicine for Peripheral Nerve Injury: Recent Advances, Emerging Therapies and Future Directions)
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21 pages, 36954 KiB  
Article
Bioactive Nanofiber-Based Conduits in a Peripheral Nerve Gap Management—An Animal Model Study
by Tomasz Dębski, Ewa Kijeńska-Gawrońska, Aleksandra Zołocińska, Katarzyna Siennicka, Anna Słysz, Wiktor Paskal, Paweł K. Włodarski, Wojciech Święszkowski and Zygmunt Pojda
Int. J. Mol. Sci. 2021, 22(11), 5588; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115588 - 25 May 2021
Cited by 14 | Viewed by 2950
Abstract
The aim was to examine the efficiency of a scaffold made of poly (L-lactic acid)-co-poly(ϵ-caprolactone), collagen (COL), polyaniline (PANI), and enriched with adipose-derived stem cells (ASCs) as a nerve conduit in a rat model. P(LLA-CL)-COL-PANI scaffold was optimized and electrospun into a tubular-shaped [...] Read more.
The aim was to examine the efficiency of a scaffold made of poly (L-lactic acid)-co-poly(ϵ-caprolactone), collagen (COL), polyaniline (PANI), and enriched with adipose-derived stem cells (ASCs) as a nerve conduit in a rat model. P(LLA-CL)-COL-PANI scaffold was optimized and electrospun into a tubular-shaped structure. Adipose tissue from 10 Lewis rats was harvested for ASCs culture. A total of 28 inbred male Lewis rats underwent sciatic nerve transection and excision of a 10 mm nerve trunk fragment. In Group A, the nerve gap remained untouched; in Group B, an excised trunk was used as an autograft; in Group C, nerve stumps were secured with P(LLA-CL)-COL-PANI conduit; in Group D, P(LLA-CL)-COL-PANI conduit was enriched with ASCs. After 6 months of observation, rats were sacrificed. Gastrocnemius muscles and sciatic nerves were harvested for weight, histology analysis, and nerve fiber count analyses. Group A showed advanced atrophy of the muscle, and each intervention (B, C, D) prevented muscle mass decrease (p < 0.0001); however, ASCs addition decreased efficiency vs. autograft (p < 0.05). Nerve fiber count revealed a superior effect in the nerve fiber density observed in the groups with the use of conduit (D vs. B p < 0.0001, C vs. B p < 0.001). P(LLA-CL)-COL-PANI conduits with ASCs showed promising results in managing nerve gap by decreasing muscle atrophy. Full article
(This article belongs to the Special Issue Regenerative Medicine for Peripheral Nerve Injury: Recent Advances, Emerging Therapies and Future Directions)
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18 pages, 6286 KiB  
Article
Comparison of Decellularization Protocols to Generate Peripheral Nerve Grafts: A Study on Rat Sciatic Nerves
by Marwa El Soury, Óscar Darío García-García, Matteo Moretti, Isabelle Perroteau, Stefania Raimondo, Arianna Barbara Lovati and Víctor Carriel
Int. J. Mol. Sci. 2021, 22(5), 2389; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052389 - 27 Feb 2021
Cited by 11 | Viewed by 3267
Abstract
In critical nerve gap repair, decellularized nerve allografts are considered a promising tissue engineering strategy that can provide superior regeneration results compared to nerve conduits. Decellularized nerves offer a well-conserved extracellular matrix component that has proven to play an important role in supporting [...] Read more.
In critical nerve gap repair, decellularized nerve allografts are considered a promising tissue engineering strategy that can provide superior regeneration results compared to nerve conduits. Decellularized nerves offer a well-conserved extracellular matrix component that has proven to play an important role in supporting axonal guiding and peripheral nerve regeneration. Up to now, the known decellularized techniques are time and effort consuming. The present study, performed on rat sciatic nerves, aims at investigating a novel nerve decellularization protocol able to combine an effective decellularization in short time with a good preservation of the extracellular matrix component. To do this, a decellularization protocol proven to be efficient for tendons (DN-P1) was compared with a decellularization protocol specifically developed for nerves (DN-P2). The outcomes of both the decellularization protocols were assessed by a series of in vitro evaluations, including qualitative and quantitative histological and immunohistochemical analyses, DNA quantification, SEM and TEM ultrastructural analyses, mechanical testing, and viability assay. The overall results showed that DN-P1 could provide promising results if tested in vivo, as the in vitro characterization demonstrated that DN-P1 conserved a better ultrastructure and ECM components compared to DN-P2. Most importantly, DN-P1 was shown to be highly biocompatible, supporting a greater number of viable metabolically active cells. Full article
(This article belongs to the Special Issue Regenerative Medicine for Peripheral Nerve Injury: Recent Advances, Emerging Therapies and Future Directions)
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27 pages, 14852 KiB  
Article
Establishment of a Sheep Model for Hind Limb Peripheral Nerve Injury: Common Peroneal Nerve
by Rui D. Alvites, Mariana V. Branquinho, Ana C. Sousa, Federica Zen, Monica Maurina, Stefania Raimondo, Carla Mendonça, Luís Atayde, Stefano Geuna, Artur S.P. Varejão and Ana C. Maurício
Int. J. Mol. Sci. 2021, 22(3), 1401; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031401 - 30 Jan 2021
Cited by 12 | Viewed by 3385
Abstract
Thousands of people worldwide suffer from peripheral nerve injuries and must deal daily with the resulting physiological and functional deficits. Recent advances in this field are still insufficient to guarantee adequate outcomes, and the development of new and compelling therapeutic options require the [...] Read more.
Thousands of people worldwide suffer from peripheral nerve injuries and must deal daily with the resulting physiological and functional deficits. Recent advances in this field are still insufficient to guarantee adequate outcomes, and the development of new and compelling therapeutic options require the use of valid preclinical models that effectively replicate the characteristics and challenges associated with these injuries in humans. In this study, we established a sheep model for common peroneal nerve injuries that can be applied in preclinical research with the advantages associated with the use of large animal models. The anatomy of the common peroneal nerve and topographically related nerves, the functional consequences of its injury and a neurological examination directed at this nerve have been described. Furthermore, the surgical protocol for accessing the common peroneal nerve, the induction of different types of nerve damage and the application of possible therapeutic options were described. Finally, a preliminary morphological and stereological study was carried out to establish control values for the healthy common peroneal nerves regarding this animal model and to identify preliminary differences between therapeutic methods. This study allowed to define the described lateral incision as the best to access the common peroneal nerve, besides establishing 12 and 24 weeks as the minimum periods to study lesions of axonotmesis and neurotmesis, respectively, in this specie. The post-mortem evaluation of the harvested nerves allowed to register stereological values for healthy common peroneal nerves to be used as controls in future studies, and to establish preliminary values associated with the therapeutic performance of the different applied options, although limited by a small sample size, thus requiring further validation studies. Finally, this study demonstrated that the sheep is a valid model of peripheral nerve injury to be used in pre-clinical and translational works and to evaluate the efficacy and safety of nerve injury therapeutic options before its clinical application in humans and veterinary patients. Full article
(This article belongs to the Special Issue Regenerative Medicine for Peripheral Nerve Injury: Recent Advances, Emerging Therapies and Future Directions)
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21 pages, 5074 KiB  
Article
Histological, Biomechanical, and Biological Properties of Genipin-Crosslinked Decellularized Peripheral Nerves
by Óscar Darío García-García, Marwa El Soury, David González-Quevedo, David Sánchez-Porras, Jesús Chato-Astrain, Fernando Campos and Víctor Carriel
Int. J. Mol. Sci. 2021, 22(2), 674; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020674 - 12 Jan 2021
Cited by 16 | Viewed by 2385
Abstract
Acellular nerve allografts (ANGs) represent a promising alternative in nerve repair. Our aim is to improve the structural and biomechanical properties of biocompatible Sondell (SD) and Roosens (RS) based ANGs using genipin (GP) as a crosslinker agent ex vivo. The impact of two [...] Read more.
Acellular nerve allografts (ANGs) represent a promising alternative in nerve repair. Our aim is to improve the structural and biomechanical properties of biocompatible Sondell (SD) and Roosens (RS) based ANGs using genipin (GP) as a crosslinker agent ex vivo. The impact of two concentrations of GP (0.10% and 0.25%) on Wistar rat sciatic nerve-derived ANGs was assessed at the histological, biomechanical, and biocompatibility levels. Histology confirmed the differences between SD and RS procedures, but not remarkable changes were induced by GP, which helped to preserve the nerve histological pattern. Tensile test revealed that GP enhanced the biomechanical properties of SD and RS ANGs, being the crosslinked RS ANGs more comparable to the native nerves used as control. The evaluation of the ANGs biocompatibility conducted with adipose-derived mesenchymal stem cells cultured within the ANGs confirmed a high degree of biocompatibility in all ANGs, especially in RS and RS-GP 0.10% ANGs. Finally, this study demonstrates that the use of GP could be an efficient alternative to improve the biomechanical properties of ANGs with a slight impact on the biocompatibility and histological pattern. For these reasons, we hypothesize that our novel crosslinked ANGs could be a suitable alternative for future in vivo preclinical studies. Full article
(This article belongs to the Special Issue Regenerative Medicine for Peripheral Nerve Injury: Recent Advances, Emerging Therapies and Future Directions)
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Review

Jump to: Research

19 pages, 1779 KiB  
Review
Morphological Methods to Evaluate Peripheral Nerve Fiber Regeneration: A Comprehensive Review
by Giulia Ronchi, Federica Fregnan, Luisa Muratori, Giovanna Gambarotta and Stefania Raimondo
Int. J. Mol. Sci. 2023, 24(3), 1818; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24031818 - 17 Jan 2023
Cited by 7 | Viewed by 3418
Abstract
Regeneration of damaged peripheral nerves remains one of the main challenges of neurosurgery and regenerative medicine, a nerve functionality is rarely restored, especially after severe injuries. Researchers are constantly looking for innovative strategies for tackling this problem, with the development of advanced tissue-engineered [...] Read more.
Regeneration of damaged peripheral nerves remains one of the main challenges of neurosurgery and regenerative medicine, a nerve functionality is rarely restored, especially after severe injuries. Researchers are constantly looking for innovative strategies for tackling this problem, with the development of advanced tissue-engineered nerve conduits and new pharmacological and physical interventions, with the aim of improving patients’ life quality. Different evaluation methods can be used to study the effectiveness of a new treatment, including functional tests, morphological assessment of regenerated nerve fibers and biomolecular analyses of key factors necessary for good regeneration. The number and diversity of protocols and methods, as well as the availability of innovative technologies which are used to assess nerve regeneration after experimental interventions, often makes it difficult to compare results obtained in different labs. The purpose of the current review is to describe the main morphological approaches used to evaluate the degree of nerve fiber regeneration in terms of their usefulness and limitations. Full article
(This article belongs to the Special Issue Regenerative Medicine for Peripheral Nerve Injury: Recent Advances, Emerging Therapies and Future Directions)
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31 pages, 1756 KiB  
Review
The Potential Benefits of Dietary Polyphenols for Peripheral Nerve Regeneration
by Luisa Muratori, Federica Fregnan, Monica Maurina, Kirsten Haastert-Talini and Giulia Ronchi
Int. J. Mol. Sci. 2022, 23(9), 5177; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23095177 - 05 May 2022
Cited by 6 | Viewed by 3272
Abstract
Peripheral nerves are frequently affected by lesions caused by trauma (work accidents, car incidents, combat injuries) and following surgical procedures (for instance cancer resection), resulting in loss of motor and sensory function with lifelong impairments. Irrespective of the intrinsic capability of the peripheral [...] Read more.
Peripheral nerves are frequently affected by lesions caused by trauma (work accidents, car incidents, combat injuries) and following surgical procedures (for instance cancer resection), resulting in loss of motor and sensory function with lifelong impairments. Irrespective of the intrinsic capability of the peripheral nervous system for regeneration, spontaneous or surgically supported regeneration is often unsatisfactory with the limited functional success of nerve repair. For this reason, many efforts have been made to improve the regeneration process. Beyond innovative microsurgical methods that, in certain cases, are necessary to repair nerve injuries, different nonsurgical treatment approaches and adjunctive therapies have been investigated to enhance nerve regeneration. One possibility could be taking advantage of a healthy diet or lifestyle and their relation with proper body functions. Over the years, scientific evidence has been obtained on the benefits of the intake of polyphenols or polyphenol-rich foods in humans, highlighting the neuroprotective effects of these compounds in many neurodegenerative diseases. In order to improve the available knowledge about the potential beneficial role of polyphenols in the process of peripheral nerve regeneration, this review assessed the biological effects of polyphenol administration in supporting and promoting the regenerative process after peripheral nerve injury. Full article
(This article belongs to the Special Issue Regenerative Medicine for Peripheral Nerve Injury: Recent Advances, Emerging Therapies and Future Directions)
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27 pages, 1370 KiB  
Review
Peripheral Nerve Injury Treatments and Advances: One Health Perspective
by Bruna Lopes, Patrícia Sousa, Rui Alvites, Mariana Branquinho, Ana Catarina Sousa, Carla Mendonça, Luís Miguel Atayde, Ana Lúcia Luís, Artur S. P. Varejão and Ana Colette Maurício
Int. J. Mol. Sci. 2022, 23(2), 918; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020918 - 14 Jan 2022
Cited by 71 | Viewed by 10809
Abstract
Peripheral nerve injuries (PNI) can have several etiologies, such as trauma and iatrogenic interventions, that can lead to the loss of structure and/or function impairment. These changes can cause partial or complete loss of motor and sensory functions, physical disability, and neuropathic pain, [...] Read more.
Peripheral nerve injuries (PNI) can have several etiologies, such as trauma and iatrogenic interventions, that can lead to the loss of structure and/or function impairment. These changes can cause partial or complete loss of motor and sensory functions, physical disability, and neuropathic pain, which in turn can affect the quality of life. This review aims to revisit the concepts associated with the PNI and the anatomy of the peripheral nerve is detailed to explain the different types of injury. Then, some of the available therapeutic strategies are explained, including surgical methods, pharmacological therapies, and the use of cell-based therapies alone or in combination with biomaterials in the form of tube guides. Nevertheless, even with the various available treatments, it is difficult to achieve a perfect outcome with complete functional recovery. This review aims to enhance the importance of new therapies, especially in severe lesions, to overcome limitations and achieve better outcomes. The urge for new approaches and the understanding of the different methods to evaluate nerve regeneration is fundamental from a One Health perspective. In vitro models followed by in vivo models are very important to be able to translate the achievements to human medicine. Full article
(This article belongs to the Special Issue Regenerative Medicine for Peripheral Nerve Injury: Recent Advances, Emerging Therapies and Future Directions)
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29 pages, 867 KiB  
Review
The Role of Dietary Nutrients in Peripheral Nerve Regeneration
by Marwa El Soury, Benedetta Elena Fornasari, Giacomo Carta, Federica Zen, Kirsten Haastert-Talini and Giulia Ronchi
Int. J. Mol. Sci. 2021, 22(14), 7417; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147417 - 10 Jul 2021
Cited by 16 | Viewed by 12483
Abstract
Peripheral nerves are highly susceptible to injuries induced from everyday activities such as falling or work and sport accidents as well as more severe incidents such as car and motorcycle accidents. Many efforts have been made to improve nerve regeneration, but a satisfactory [...] Read more.
Peripheral nerves are highly susceptible to injuries induced from everyday activities such as falling or work and sport accidents as well as more severe incidents such as car and motorcycle accidents. Many efforts have been made to improve nerve regeneration, but a satisfactory outcome is still unachieved, highlighting the need for easy to apply supportive strategies for stimulating nerve growth and functional recovery. Recent focus has been made on the effect of the consumed diet and its relation to healthy and well-functioning body systems. Normally, a balanced, healthy daily diet should provide our body with all the needed nutritional elements for maintaining correct function. The health of the central and peripheral nervous system is largely dependent on balanced nutrients supply. While already addressed in many reviews with different focus, we comprehensively review here the possible role of different nutrients in maintaining a healthy peripheral nervous system and their possible role in supporting the process of peripheral nerve regeneration. In fact, many dietary supplements have already demonstrated an important role in peripheral nerve development and regeneration; thus, a tailored dietary plan supplied to a patient following nerve injury could play a non-negotiable role in accelerating and promoting the process of nerve regeneration. Full article
(This article belongs to the Special Issue Regenerative Medicine for Peripheral Nerve Injury: Recent Advances, Emerging Therapies and Future Directions)
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18 pages, 706 KiB  
Review
Reconstruction of Critical Nerve Defects Using Allogenic Nerve Tissue: A Review of Current Approaches
by Tim Kornfeld, Anton Borger and Christine Radtke
Int. J. Mol. Sci. 2021, 22(7), 3515; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073515 - 29 Mar 2021
Cited by 18 | Viewed by 2912
Abstract
Regardless of the nerve defect length, nerve injury is a debilitating condition for the affected patient that results in loss of sensory and motor function. These functional impairments can have a profound impact on the patient’s quality of life. Surgical approaches for the [...] Read more.
Regardless of the nerve defect length, nerve injury is a debilitating condition for the affected patient that results in loss of sensory and motor function. These functional impairments can have a profound impact on the patient’s quality of life. Surgical approaches for the treatment of short segment nerve defects are well-established. Autologous nerve transplantation, considered the gold standard, and the use of artificial nerve grafts are safe and successful procedures for short segment nerve defect reconstruction. Long segment nerve defects which extend 3.0 cm or more are more problematic for repair. Methods for reconstruction of long defects are limited. Artificial nerve grafts often fail to regenerate and autologous nerve grafts are limited in length and number. Cadaveric processed/unprocessed nerve allografts are a promising alternative in nerve surgery. This review gives a systematic overview on pre-clinical and clinical approaches in nerve allograft transplantation. Full article
(This article belongs to the Special Issue Regenerative Medicine for Peripheral Nerve Injury: Recent Advances, Emerging Therapies and Future Directions)
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