中国神经再生研究(英文版) ›› 2025, Vol. 20 ›› Issue (1): 291-304.doi: 10.4103/NRR.NRR-D-22-01198

• 原著:周围神经损伤修复保护与再生 • 上一篇    

功能性他克莫司释放神经包膜增强手术神经修复后的神经再生能力

  

  • 出版日期:2025-01-15 发布日期:2025-01-15

A functional tacrolimus-releasing nerve wrap for enhancing nerve regeneration following surgical nerve repair

Simeon C. Daeschler1, *, #, Katelyn J.W. So1, 2, #, Konstantin Feinberg1, 3, Marina Manoraj1, Jenny Cheung1, Jennifer Zhang1, 4, Kaveh Mirmoeini1, J. Paul Santerre5, Tessa Gordon1, 4, Gregory H. Borschel1, 2, 3, 4   

  1. 1SickKids Research Institute, Neuroscience and Mental Health Program, Toronto, ON, Canada; 2Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada; 3Indiana University School of Medicine, Indianapolis, IN, USA; 4Division of Plastic and Reconstructive Surgery, the Hospital for Sick Children, Toronto, ON, Canada; 5Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, Institute of Biomedical Engineering, Faculty of Dentistry, University of Toronto, Toronto, ON, Canada
  • Online:2025-01-15 Published:2025-01-15
  • Contact: Simeon C. Daeschler, MD, simeondaeschler@gmail.com.
  • Supported by:
    This work was supported by the German Research Foundation (DA 2255/1-1; to SCD); a SickKids Research Training Competition (RESTRACOMP) Graduate Scholarship (to KJWS), an Ontario Graduate Scholarship (to KJWS); a grant from Natural Sciences and Engineering Research Council of Canada (NSERC) (to KJWS) and a Kickstarter grant from the Institute of Biomedical Engineering (BME) at the University of Toronto (to KJWS); and the Abe Frank Fund from the Riley’s Children Foundation (GHB).

摘要:

手术神经修复后的轴突再生缓慢且往往不完全,导致功能恢复不佳,有时甚至会造成终身残疾。目前,美国食品和药物管理局尚未批准促进神经再生的疗法。他克莫司可加速轴突再生,但目前其全身副作用超过了其对周围神经手术的潜在益处。实验描述了一种基于聚氨酯的可生物降解给药系统,该系统可在神经修复部位局部持续释放他克莫司,具有适合规模化生产和临床应用的特性,旨在促进神经再生和功能恢复,同时尽量减少全身性药物暴露。将他克莫司封装在同轴电纺聚碳酸酯-聚氨酯纳米纤维中,生成一种在 31 天内释放治疗剂量的生物活性他克莫司的可植入神经包膜。这种包膜可在 120 天内降解为生物相容性副产物。从神经包膜中释放的他克莫司可促进体外轴突的伸长,并加速临床前神经修复模型的神经再生和功能恢复,同时与全身给药相比,脱靶的全身药物暴露减少了 80%。鉴于该系统的手术适用性、临床前疗效和安全性,它可以为接受神经手术的患者提供一种易于转化的支持轴突再生和恢复的方法。

https://orcid.org/0000-0001-8130-7714 (Simeon C. Daeschler)

Abstract: Axonal regeneration following surgical nerve repair is slow and often incomplete, resulting in poor functional recovery which sometimes contributes to lifelong disability. Currently, there are no FDA-approved therapies available to promote nerve regeneration. Tacrolimus accelerates axonal regeneration, but systemic side effects presently outweigh its potential benefits for peripheral nerve surgery. The authors describe herein a biodegradable polyurethane-based drug delivery system for the sustained local release of tacrolimus at the nerve repair site, with suitable properties for scalable production and clinical application, aiming to promote nerve regeneration and functional recovery with minimal systemic drug exposure. Tacrolimus is encapsulated into co-axially electrospun polycarbonate-urethane nanofibers to generate an implantable nerve wrap that releases therapeutic doses of bioactive tacrolimus over 31 days. Size and drug loading are adjustable for applications in small and large caliber nerves, and the wrap degrades within 120 days into biocompatible byproducts. Tacrolimus released from the nerve wrap promotes axon elongation in vitro and accelerates nerve regeneration and functional recovery in preclinical nerve repair models while off-target systemic drug exposure is reduced by 80% compared with systemic delivery. Given its surgical suitability and preclinical efficacy and safety, this system may provide a readily translatable approach to support axonal regeneration and recovery in patients undergoing nerve surgery.

Key words: biodegradable, local drug delivery, nerve injury, nerve regeneration, nerve wrap, tacrolimus