Nerve Wrap for Local Delivery of FK506/Tacrolimus Accelerates Nerve Regeneration
Peripheral nerve injuries (PNIs) occur frequently and can lead to devastating and permanent sensory and motor function disabilities. Systemic tacrolimus (FK506) administration has been shown to hasten recovery and improve functional outcomes after PNI repair. Unfortunately, high systemic levels of F...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2024-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/25/2/847 |
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| author | Bo Xiao Firuz Feturi An-Jey A. Su Yolandi Van der Merwe Joshua M. Barnett Kayvon Jabbari Neil J. Khatter Bing Li Evan B. Katzel Raman Venkataramanan Mario G. Solari William R. Wagner Michael B. Steketee Daniel J. Simons Kia M. Washington |
| author_facet | Bo Xiao Firuz Feturi An-Jey A. Su Yolandi Van der Merwe Joshua M. Barnett Kayvon Jabbari Neil J. Khatter Bing Li Evan B. Katzel Raman Venkataramanan Mario G. Solari William R. Wagner Michael B. Steketee Daniel J. Simons Kia M. Washington |
| author_sort | Bo Xiao |
| collection | DOAJ |
| description | Peripheral nerve injuries (PNIs) occur frequently and can lead to devastating and permanent sensory and motor function disabilities. Systemic tacrolimus (FK506) administration has been shown to hasten recovery and improve functional outcomes after PNI repair. Unfortunately, high systemic levels of FK506 can result in adverse side effects. The localized administration of FK506 could provide the neuroregenerative benefits of FK506 while avoiding systemic, off-target side effects. This study investigates the utility of a novel FK506-impregnated polyester urethane urea (PEUU) nerve wrap to treat PNI in a previously validated rat infraorbital nerve (ION) transection and repair model. ION function was assessed by microelectrode recordings of trigeminal ganglion cells responding to controlled vibrissae deflections in ION-transected and -repaired animals, with and without the nerve wrap. Peristimulus time histograms (PSTHs) having 1 ms bins were constructed from spike times of individual single units. Responses to stimulus onsets (ON responses) were calculated during a 20 ms period beginning 1 ms after deflection onset; this epoch captures the initial, transient phase of the whisker-evoked response. Compared to no-wrap controls, rats with PEUU-FK506 wraps functionally recovered earlier, displaying larger response magnitudes. With nerve wrap treatment, FK506 blood levels up to six weeks were measured nearly at the limit of quantification (LOQ ≥ 2.0 ng/mL); whereas the drug concentrations within the ION and muscle were much higher, demonstrating the local delivery of FK506 to treat PNI. An immunohistological assessment of ION showed increased myelin expression for animals assigned to neurorrhaphy with PEUU-FK506 treatment compared to untreated or systemic-FK506-treated animals, suggesting that improved PNI outcomes using PEUU-FK506 is mediated by the modulation of Schwann cell activity. |
| first_indexed | 2024-03-08T09:53:36Z |
| format | Article |
| id | doaj.art-2890ea77e778463f888ea1bde28ec1ee |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-08T09:53:36Z |
| publishDate | 2024-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-2890ea77e778463f888ea1bde28ec1ee2024-01-29T13:54:53ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-01-0125284710.3390/ijms25020847Nerve Wrap for Local Delivery of FK506/Tacrolimus Accelerates Nerve RegenerationBo Xiao0Firuz Feturi1An-Jey A. Su2Yolandi Van der Merwe3Joshua M. Barnett4Kayvon Jabbari5Neil J. Khatter6Bing Li7Evan B. Katzel8Raman Venkataramanan9Mario G. Solari10William R. Wagner11Michael B. Steketee12Daniel J. Simons13Kia M. Washington14Department of Plastic Surgery, University of Pittsburgh School of Medicine, Veterans Administration Healthcare System, Pittsburgh, PA 15213, USADepartment of Plastic Surgery, University of Pittsburgh School of Medicine, Veterans Administration Healthcare System, Pittsburgh, PA 15213, USADepartment of Plastic Surgery, University of Pittsburgh School of Medicine, Veterans Administration Healthcare System, Pittsburgh, PA 15213, USADepartment of Ophthalmology, University of California, San Diego, CA 90095, USADepartment of Plastic Surgery, University of Pittsburgh School of Medicine, Veterans Administration Healthcare System, Pittsburgh, PA 15213, USADepartment of Surgery, Division of Plastic Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Surgery, Division of Plastic Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Surgery, Division of Plastic Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Plastic Surgery, University of Pittsburgh School of Medicine, Veterans Administration Healthcare System, Pittsburgh, PA 15213, USAUniversity of Pittsburgh School of Pharmacy, Pittsburgh, PA 15213, USADepartment of Plastic Surgery, University of Pittsburgh School of Medicine, Veterans Administration Healthcare System, Pittsburgh, PA 15213, USAMcGowan Institute for Regenerative Medicine, Pittsburgh, PA 15219, USADepartment of Ophthalmology, University of California, San Diego, CA 90095, USAMcGowan Institute for Regenerative Medicine, Pittsburgh, PA 15219, USADepartment of Plastic Surgery, University of Pittsburgh School of Medicine, Veterans Administration Healthcare System, Pittsburgh, PA 15213, USAPeripheral nerve injuries (PNIs) occur frequently and can lead to devastating and permanent sensory and motor function disabilities. Systemic tacrolimus (FK506) administration has been shown to hasten recovery and improve functional outcomes after PNI repair. Unfortunately, high systemic levels of FK506 can result in adverse side effects. The localized administration of FK506 could provide the neuroregenerative benefits of FK506 while avoiding systemic, off-target side effects. This study investigates the utility of a novel FK506-impregnated polyester urethane urea (PEUU) nerve wrap to treat PNI in a previously validated rat infraorbital nerve (ION) transection and repair model. ION function was assessed by microelectrode recordings of trigeminal ganglion cells responding to controlled vibrissae deflections in ION-transected and -repaired animals, with and without the nerve wrap. Peristimulus time histograms (PSTHs) having 1 ms bins were constructed from spike times of individual single units. Responses to stimulus onsets (ON responses) were calculated during a 20 ms period beginning 1 ms after deflection onset; this epoch captures the initial, transient phase of the whisker-evoked response. Compared to no-wrap controls, rats with PEUU-FK506 wraps functionally recovered earlier, displaying larger response magnitudes. With nerve wrap treatment, FK506 blood levels up to six weeks were measured nearly at the limit of quantification (LOQ ≥ 2.0 ng/mL); whereas the drug concentrations within the ION and muscle were much higher, demonstrating the local delivery of FK506 to treat PNI. An immunohistological assessment of ION showed increased myelin expression for animals assigned to neurorrhaphy with PEUU-FK506 treatment compared to untreated or systemic-FK506-treated animals, suggesting that improved PNI outcomes using PEUU-FK506 is mediated by the modulation of Schwann cell activity.https://www.mdpi.com/1422-0067/25/2/847peripheral nerve injurytacrolimusneuroregenerationimmunologyinfraorbital nervebiopolymer |
| spellingShingle | Bo Xiao Firuz Feturi An-Jey A. Su Yolandi Van der Merwe Joshua M. Barnett Kayvon Jabbari Neil J. Khatter Bing Li Evan B. Katzel Raman Venkataramanan Mario G. Solari William R. Wagner Michael B. Steketee Daniel J. Simons Kia M. Washington Nerve Wrap for Local Delivery of FK506/Tacrolimus Accelerates Nerve Regeneration International Journal of Molecular Sciences peripheral nerve injury tacrolimus neuroregeneration immunology infraorbital nerve biopolymer |
| title | Nerve Wrap for Local Delivery of FK506/Tacrolimus Accelerates Nerve Regeneration |
| title_full | Nerve Wrap for Local Delivery of FK506/Tacrolimus Accelerates Nerve Regeneration |
| title_fullStr | Nerve Wrap for Local Delivery of FK506/Tacrolimus Accelerates Nerve Regeneration |
| title_full_unstemmed | Nerve Wrap for Local Delivery of FK506/Tacrolimus Accelerates Nerve Regeneration |
| title_short | Nerve Wrap for Local Delivery of FK506/Tacrolimus Accelerates Nerve Regeneration |
| title_sort | nerve wrap for local delivery of fk506 tacrolimus accelerates nerve regeneration |
| topic | peripheral nerve injury tacrolimus neuroregeneration immunology infraorbital nerve biopolymer |
| url | https://www.mdpi.com/1422-0067/25/2/847 |
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