Tajdaran Kasra, Gordon Tessa, Wood Mathew D, Shoichet Molly S, Borschel Gregory H
Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario M5G1X8, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.
Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario M5G1X8, Canada; Division of Plastic and Reconstructive Surgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada; Program in Neuroscience, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.
Acta Biomater. 2016 Jan;29:62-70. doi: 10.1016/j.actbio.2015.10.001. Epub 2015 Oct 9.
Acellular nerve allografts (ANAs) are used clinically to bridge nerve gaps but these grafts, lacking Schwann cells and therapeutic levels of neurotrophic factors, do not support regeneration to the same extent as autografts. Here we investigated a local drug delivery system (DDS) for glial cell line-derived neurotrophic factor (GDNF) controlled release to implanted ANAs in rats using drug-loaded polymeric microspheres (MSs) embedded in a fibrin gel. In a rat hindlimb nerve gap model, a 10mm ANA was used to bridge a 5mm common peroneal (CP) nerve gap. Experimental groups received DDS treatment at both suture sites of the allografts releasing GDNF for either 2 weeks or 4 weeks. In negative control groups, rats received no DDS treatment or empty DDS. Rats receiving nerve isografts served as the positive control group. The numbers of motor and sensory neurons that regenerated their axons in all the groups with GDNF MS and isograft treatment were indistinguishable and significantly higher as compared to the negative control groups. Nerve histology distal to the nerve graft demonstrated increased axon counts and a shift to larger fiber diameters due to GDNF MS treatment. The sustained delivery of GDNF to the implanted ANA achieved in this study demonstrates the promise of this DDS for the management of severe nerve injuries in which allografts are placed.
This work addresses the common clinical situation in which a nerve gap is bridged using acellular nerve allografts. However, these allografts are not as effective in supporting nerve regeneration as the gold standard method of autografting. The novel local drug delivery system used in this study provides sustained and controlled release of glial cell line-derived neurotrophic factor (GDNF), one of the most potent neurotrophic factors, which significantly improves nerve regeneration following severe nerve injuries. Results from this research will provide a mean of improving nerve allografts with locally delivered GDNF. This strategy may lead to a novel "off the shelf" alternative to the current management of severe nerve injuries.
脱细胞神经同种异体移植物（ANA）在临床上用于桥接神经间隙，但这些移植物缺乏施万细胞和神经营养因子的治疗水平，在支持再生方面不如自体移植物。在此，我们研究了一种局部药物递送系统（DDS），用于将胶质细胞系源性神经营养因子（GDNF）控释至植入大鼠体内的ANA，该系统使用嵌入纤维蛋白凝胶中的载药聚合物微球（MS）。在大鼠后肢神经间隙模型中，使用10mm的ANA桥接5mm的腓总神经（CP）间隙。实验组在同种异体移植物的两个缝合部位接受DDS治疗，释放GDNF持续2周或4周。在阴性对照组中，大鼠未接受DDS治疗或接受空的DDS。接受神经同基因移植的大鼠作为阳性对照组。与阴性对照组相比，所有接受GDNF MS和同基因移植治疗的组中，再生轴突的运动和感觉神经元数量无差异且显著更高。神经移植物远端的神经组织学显示，由于GDNF MS治疗，轴突数量增加且纤维直径向更大尺寸转变。本研究中实现的GDNF向植入ANA的持续递送证明了这种DDS在处理植入同种异体移植物的严重神经损伤方面的前景。
本研究针对使用脱细胞神经同种异体移植物桥接神经间隙的常见临床情况。然而，这些同种异体移植物在支持神经再生方面不如自体移植这一金标准方法有效。本研究中使用的新型局部药物递送系统可实现胶质细胞系源性神经营养因子（GDNF，最有效的神经营养因子之一）的持续控释，显著改善严重神经损伤后的神经再生。本研究结果将提供一种通过局部递送GDNF来改善神经同种异体移植物的方法。该策略可能会为当前严重神经损伤的治疗带来一种新型的“现货供应”替代方案。
