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DOI: 10.1055/s-0042-1747959
A Rabbit Model for Peripheral Nerve Reconstruction Studies Avoiding Automutilation Behavior
Funding This study was supported by the German-Israeli Foundation for Scientific Research and Development, grant number: G-1350-409.10/2016![](https://www.thieme-connect.de/media/10.1055-s-00027212/202201/lookinside/thumbnails/10-1055-s-0042-1747959_2100004-1.jpg)
Abstract
Background The rabbit sciatic nerve injury model may represent a valuable alternative for critical gap distance seen in humans but often leads to automutilation. In this study, we modified the complete sciatic nerve injury model for avoiding autophagy.
Materials and Methods In 20 adult female New Zealand White rabbits, instead of transecting the complete sciatic nerve, we unilaterally transected the tibial portion and preserved the peroneal portion. Thereby loss of sensation in the dorsal aspect of the paw was avoided. The tibial portion was repaired in a reversed autograft approach in a length of 2.6 cm. In an alternative repair approach, a gap of 2.6 cm in length was repaired with a chitosan-based nerve guide.
Results During the 6-month follow-up period, there were no incidents of autotomy. Nerve regeneration of the tibial portion of the sciatic nerve was evaluated histologically and morphometrically. A clear difference between the distal segments of the healthy contralateral and the repaired tibial portion of the sciatic nerve was detectable, validating the model.
Conclusion By transecting the isolated tibial portion of the rabbit sciatic nerve and leaving the peroneal portion intact, it was possible to eliminate automutilation behavior.
* Equally contributed.
Publication History
Received: 06 March 2021
Accepted: 08 June 2021
Article published online:
21 June 2022
© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
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References
- 1 Siemionow M, Brzezicki G. Chapter 8: current techniques and concepts in peripheral nerve repair. Int Rev Neurobiol 2009; 87: 141-172
- 2 Kim DH, Midha R, Murovic JA, Spinner RJ. Kline & Hudson's Nerve Injuries. Operative Results for Major Nerve Injuries, Entrapments, and Tumors. Philadelphia, PA: Saunders Elsevier; 2008: 505
- 3 Geuna S. The sciatic nerve injury model in pre-clinical research. J Neurosci Methods 2015; 243: 39-46
- 4 Nichols CM, Myckatyn TM, Rickman SR, Fox IK, Hadlock T, Mackinnon SE. Choosing the correct functional assay: a comprehensive assessment of functional tests in the rat. Behav Brain Res 2005; 163 (02) 143-158
- 5 Angius D, Wang H, Spinner RJ, Gutierrez-Cotto Y, Yaszemski MJ, Windebank AJ. A systematic review of animal models used to study nerve regeneration in tissue-engineered scaffolds. Biomaterials 2012; 33 (32) 8034-8039
- 6 Malik S, Ahmed S, Azeem MA, Noushad S, Sherwani SK. Comparison of sciatic nerve course in amphibians, reptiles and mammals. FUUAST J Biol 2011; 1 (02) 7-14
- 7 Amillo S, Yáñez R, Barrios RH. Nerve regeneration in different types of grafts: experimental study in rabbits. Microsurgery 1995; 16 (09) 621-630
- 8 Barmpitsioti A, Konofaos P, Ignatiadis I, Papalois A, Zoubos AB, Soucacos PN. Nerve growth factor combined with an epineural conduit for bridging a short nerve gap (10 mm). A study in rabbits. Microsurgery 2011; 31 (07) 545-550
- 9 Bayram B, Akdeniz SS, Diker N, Helvacioğlu F, Erdem SR. Effects of platelet-rich fibrin membrane on sciatic nerve regeneration. J Craniofac Surg 2018; 29 (03) e239-e243
- 10 Boriani F, Fazio N, Fotia C. et al. A novel technique for decellularization of allogenic nerves and in vivo study of their use for peripheral nerve reconstruction. J Biomed Mater Res A 2017; 105 (08) 2228-2240
- 11 Bulstra LF, Hundepool CA, Friedrich PF, Nijhuis THJ, Bishop AT, Shin AY. Motor nerve recovery in a rabbit model: description and validation of a noninvasive ultrasound technique. J Hand Surg Am 2016; 41 (01) 27-33
- 12 Donzelli R, Capone C, Sgulò FG, Mariniello G, Maiuri F. Vascularized nerve grafts: an experimental study. Neurol Res 2016; 38 (08) 669-677
- 13 Gao H, You Y, Zhang G, Zhao F, Sha Z, Shen Y. The use of fiber-reinforced scaffolds cocultured with Schwann cells and vascular endothelial cells to repair rabbit sciatic nerve defect with vascularization. BioMed Res Int 2013; 2013: 362918
- 14 Geuna S, Tos P, Battiston B, Giacobini-Robecchi MG. Bridging peripheral nerve defects with muscle-vein combined guides. Neurol Res 2004; 26 (02) 139-144
- 15 Giovanoli P, Koller R, Meuli-Simmen C. et al. Functional and morphometric evaluation of end-to-side neurorrhaphy for muscle reinnervation. Plast Reconstr Surg 2000; 106 (02) 383-392
- 16 Heijke GC, Klopper PJ, Van Doorn IB, Baljet B. Processed porcine collagen tubulization versus conventional suturing in peripheral nerve reconstruction: an experimental study in rabbits. Microsurgery 2001; 21 (03) 84-95
- 17 Henry FP, Goyal NA, David WS. et al. Improving electrophysiologic and histologic outcomes by photochemically sealing amnion to the peripheral nerve repair site. Surgery 2009; 145 (03) 313-321
- 18 Hill PS, Apel PJ, Barnwell J. et al. Repair of peripheral nerve defects in rabbits using keratin hydrogel scaffolds. Tissue Eng Part A 2011; 17 (11,12): 1499-1505
- 19 Hsu SH, Chan SH, Chiang CM, Chen CC, Jiang CF. Peripheral nerve regeneration using a microporous polylactic acid asymmetric conduit in a rabbit long-gap sciatic nerve transection model. Biomaterials 2011; 32 (15) 3764-3775
- 20 Hu C, Zhang T, Deng Z. et al. Study on the effect of vacuum sealing drainage on the repair process of rabbit sciatic nerve injury. Int J Neurosci 2015; 125 (11) 855-860
- 21 Ignatiadis IA, Yiannakopoulos CK, Barbitsioti AD. et al. Diverse types of epineural conduits for bridging short nerve defects. An experimental study in the rabbit. Microsurgery 2007; 27 (02) 98-104
- 22 Ikumi A, Hara Y, Yoshioka T, Kanamori A, Yamazaki M. Effect of local administration of platelet-rich plasma (PRP) on peripheral nerve regeneration: An experimental study in the rabbit model. Microsurgery 2018; 38 (03) 300-309
- 23 Kakinoki S, Nakayama M, Moritan T, Yamaoka T. Three-layer microfibrous peripheral nerve guide conduit composed of elastin-laminin mimetic artificial protein and poly(L-lactic acid). Front Chem 2014; 2: 52
- 24 Lasso JM, Pérez Cano R, Castro Y, Arenas L, García J, Fernández-Santos ME. Xenotransplantation of human adipose-derived stem cells in the regeneration of a rabbit peripheral nerve. J Plast Reconstr Aesthet Surg 2015; 68 (12) e189-e197
- 25 Li YJ, Zhao BL, Lv HZ, Qin ZG, Luo M. Acellular allogeneic nerve grafting combined with bone marrow mesenchymal stem cell transplantation for the repair of long-segment sciatic nerve defects: biomechanics and validation of mathematical models. Neural Regen Res 2016; 11 (08) 1322-1326
- 26 Lutz BS, Chuang DC, Chuang SS, Hsu JC, Ma SF, Wei FC. Nerve transfer to the median nerve using parts of the ulnar and radial nerves in the rabbit–effects on motor recovery of the median nerve and donor nerve morbidity. J Hand Surg [Br] 2000; 25 (04) 329-335
- 27 Matsuzaki H, Shibata M, Jiang B, Takahashi HE. Distal nerve elongation vs nerve grafting in repairing segmental nerve defects in rabbits. Microsurgery 2004; 24 (03) 207-212
- 28 Mekaj AY, Manxhuka-Kerliu S, Morina AA, Duci SB, Shahini L, Mekaj YH. Effects of hyaluronic acid and tacrolimus on the prevention of perineural scar formation and on nerve regeneration after sciatic nerve repair in a rabbit model. Eur J Trauma Emerg Surg 2017; 43 (04) 497-504
- 29 Mekaj AY, Morina AA, Manxhuka-Kerliu S. et al. Electrophysiological and functional evaluation of peroneal nerve regeneration in rabbit following topical hyaluronic acid or tacrolimus application after nerve repair. Niger Postgrad Med J 2015; 22 (03) 179-184
- 30 Meng WK, Huang Z, Tan Z. et al. [Vein nerve conduit supported by vascular stent in the regeneration of peripheral nerve in rabbits] (in Chinese). Sichuan Da Xue Xue Bao Yi Xue Ban 2017; 48 (05) 687-692
- 31 Mligiliche NL, Tabata Y, Kitada M. et al. Poly lactic acid–caprolactone copolymer tube with a denatured skeletal muscle segment inside as a guide for peripheral nerve regeneration: a morphological and electrophysiological evaluation of the regenerated nerves. Anat Sci Int 2003; 78 (03) 156-161
- 32 Mohammad JA, Warnke PH, Pan YC, Shenaq S. Increased axonal regeneration through a biodegradable amnionic tube nerve conduit: effect of local delivery and incorporation of nerve growth factor/hyaluronic acid media. Ann Plast Surg 2000; 44 (01) 59-64
- 33 Mohanna PN, Young RC, Wiberg M, Terenghi G. A composite poly-hydroxybutyrate-glial growth factor conduit for long nerve gap repairs. J Anat 2003; 203 (06) 553-565
- 34 Piskin A, Altunkaynak BZ, Çitlak A, Sezgin H, Yazιcι O, Kaplan S. Immediate versus delayed primary nerve repair in the rabbit sciatic nerve. Neural Regen Res 2013; 8 (36) 3410-3415
- 35 Ruch DS, Deal DN, Ma J. et al. Management of peripheral nerve defects: external fixator-assisted primary neurorrhaphy. J Bone Joint Surg Am 2004; 86 (07) 1405-1413
- 36 Sahakyants T, Lee JY, Friedrich PF, Bishop AT, Shin AY. Return of motor function after repair of a 3-cm gap in a rabbit peroneal nerve: a comparison of autograft, collagen conduit, and conduit filled with collagen-GAG matrix. J Bone Joint Surg Am 2013; 95 (21) 1952-1958
- 37 Schmitz HC, Beer GM. The toe-spreading reflex of the rabbit revisited–functional evaluation of complete peroneal nerve lesions. Lab Anim 2001; 35 (04) 340-345
- 38 Sharula, Hara Y, Nishiura Y, Saijilafu, Kubota S, Ochiai N. Repair of the sciatic nerve defect with a direct gradual lengthening of proximal and distal nerve stumps in rabbits. Plast Reconstr Surg 2010; 125 (03) 846-854
- 39 Shibata M, Breidenbach WC, Ogden L, Firrell J. Comparison of one- and two-stage nerve grafting of the rabbit median nerve. J Hand Surg Am 1991; 16 (02) 262-268
- 40 Strauch B, Ferder M, Lovelle-Allen S, Moore K, Kim DJ, Llena J. Determining the maximal length of a vein conduit used as an interposition graft for nerve regeneration. J Reconstr Microsurg 1996; 12 (08) 521-527
- 41 Strauch B, Rodriguez DM, Diaz J, Yu HL, Kaplan G, Weinstein DE. Autologous Schwann cells drive regeneration through a 6-cm autogenous venous nerve conduit. J Reconstr Microsurg 2001; 17 (08) 589-595 , discussion 596–597
- 42 Wang Y, Li ZW, Luo M, Li YJ, Zhang KQ. Biological conduits combining bone marrow mesenchymal stem cells and extracellular matrix to treat long-segment sciatic nerve defects. Neural Regen Res 2015; 10 (06) 965-971
- 43 Whitworth IH, Doré CJ, Green CJ, Terenghi G. Increased axonal regeneration over long nerve gaps using autologous nerve-muscle sandwich grafts. Microsurgery 1995; 16 (12) 772-778
- 44 Yin D, Wang XH, Yan Y, Zhang R. Preliminary studies on peripheral nerve regeneration using a new polyurethane conduit. J Bioact Compat Polym 2007; 22: 143-159
- 45 Young RC, Wiberg M, Terenghi G. Poly-3-hydroxybutyrate (PHB): a resorbable conduit for long-gap repair in peripheral nerves. Br J Plast Surg 2002; 55 (03) 235-240
- 46 Zhang Z, Johnson EO, Vekris MD. et al. Repair of the main nerve trunk of the upper limb with end-to-side neurorrhaphy: an experimental study in rabbits. Microsurgery 2006; 26 (04) 245-252
- 47 Kollitz KM, Giusti G, Friedrich PF, Bishop AT, Shin AY. The rabbit brachial plexus as a model for nerve injury and repair part 1: anatomic study of the biceps and triceps innervation. Microsurgery 2020; 40 (02) 183-188
- 48 Boriani F, Savarino L, Fazio N. et al. Auto-allo graft parallel juxtaposition for improved neuroregeneration in peripheral nerve reconstruction based on acellular nerve allografts. Ann Plast Surg 2019; 83 (03) 318-325
- 49 Weber RA, Proctor WH, Warner MR, Verheyden CN. Autotomy and the sciatic functional index. Microsurgery 1993; 14 (05) 323-327
- 50 Wall PD, Devor M, Inbal R. et al. Autotomy following peripheral nerve lesions: experimental anaesthesia dolorosa. Pain 1979; 7 (02) 103-113
- 51 Magnusson JE, Vaccarino AL. Reduction of autotomy following peripheral neurectomy by a single injection of bupivacaine into the cingulum bundle of rats. Brain Res 1996; 723 (1,2): 214-217
- 52 Vachon P. Self-mutilation in rabbits following intramuscular ketamine-xylazine-acepromazine injections. Can Vet J 1999; 40 (08) 581-582
- 53 Calasans-Maia MD, Monteiro ML, Ascoli FO, Granjeiro JM. The rabbit as an animal model for experimental surgery. Acta Cir Bras 2009; 24 (04) 325-328
- 54 Robinson V. Finding alternatives: an overview of the 3Rs and the use of animals in research. Sch Sci Rev 2005; 87: 111-114
- 55 Russell WMS, Burch RL. The Principles of Humane Experimental Technique. Wheathampstead, United Kingdom: Universities Federation for Animal Welfare; 1992: 238
- 56 Stößel M, Rehra L, Haastert-Talini K. Reflex-based grasping, skilled forelimb reaching, and electrodiagnostic evaluation for comprehensive analysis of functional recovery-The 7-mm rat median nerve gap repair model revisited. Brain Behav 2017; 7 (10) e00813
- 57 Dietzmeyer N, Förthmann M, Leonhard J. et al. Two-chambered chitosan nerve guides with increased bendability support recovery of skilled forelimb reaching similar to autologous nerve grafts in the rat 10 mm median nerve injury and repair model. Front Cell Neurosci 2019; 13: 149
- 58 Dietzmeyer N, Huang Z, Schüning T. et al. In vivo and in vitro evaluation of a novel hyaluronic acid-laminin hydrogel as luminal filler and carrier system for genetically engineered Schwann cells in critical gap length tubular peripheral nerve graft in rats. Cell Transplant 2020; 29: 963689720910095
- 59 Korte N, Schenk HC, Grothe C, Tipold A, Haastert-Talini K. Evaluation of periodic electrodiagnostic measurements to monitor motor recovery after different peripheral nerve lesions in the rat. Muscle Nerve 2011; 44 (01) 63-73
- 60 Geuna S, Tos P, Battiston B, Guglielmone R. Verification of the two-dimensional disector, a method for the unbiased estimation of density and number of myelinated nerve fibers in peripheral nerves. Ann Anat 2000; 182 (01) 23-34
- 61 Rochkind S, Astachov L, el-Ani D. et al. Further development of reconstructive and cell tissue-engineering technology for treatment of complete peripheral nerve injury in rats. Neurol Res 2004; 26 (02) 161-166
- 62 Rochkind S, Nevo Z. Recovery of peripheral nerve with massive loss defect by tissue engineered guiding regenerative gel. BioMed Res Int 2014; 2014: 327578
- 63 Shapira Y, Tolmasov M, Nissan M. et al. Comparison of results between chitosan hollow tube and autologous nerve graft in reconstruction of peripheral nerve defect: An experimental study. Microsurgery 2016; 36 (08) 664-671
- 64 Bozkurt A, Deumens R, Scheffel J. et al. CatWalk gait analysis in assessment of functional recovery after sciatic nerve injury. J Neurosci Methods 2008; 173 (01) 91-98
- 65 Bozkurt A, Tholl S, Wehner S. et al. Evaluation of functional nerve recovery with Visual-SSI–a novel computerized approach for the assessment of the static sciatic index (SSI). J Neurosci Methods 2008; 170 (01) 117-122
- 66 Tos P, Ronchi G, Papalia I. et al. Chapter 4: methods and protocols in peripheral nerve regeneration experimental research: part I-experimental models. Int Rev Neurobiol 2009; 87: 47-79
- 67 Varejão AS, Melo-Pinto P, Meek MF, Filipe VM, Bulas-Cruz J. Methods for the experimental functional assessment of rat sciatic nerve regeneration. Neurol Res 2004; 26 (02) 186-194