In vivo study of ethyl-2-cyanoacrylate applied in direct contact with nerves regenerating in a novel nerve-guide

  • A. Merolli
  • S. Marceddu
  • L. Rocchi
  • F. Catalano


Stitch suture is still the most recommended method to hold a nerve-guide in place but stitch suture is a well known cause of local inflammatory response. Glues of several kinds have been proposed as an alternative but they are not easy to apply in a real surgical setting. In 2006 authors developed a new concept of nerve-guide termed “NeuroBox” which is double-halved, not-degradable and rigid, and allows the use of cyanoacrylic glues. In this study, Authors analyzed histologically the nerve-glue interface. Wistar rats were used as animal model. In group 1, animals were implanted a NeuroBox to promote the regeneration of an experimentally produced 4 mm gap in the sciatic nerve. In group 2, the gap was left without repair (“sham-operated” group). Group 3 was assembled by harvesting 10 contralateral intact nerves to document the normal anatomy. Semi-thin sections for visible light microscopy and ultra-thin sections for Transmission Electron Microscopy were analyzed. Results showed that application of ethyl-2-cyanoacrylate directly to the epineurium produced no significative insult to the underlining nerve fibers nor impaired nerve regeneration. No regeneration occurred in the “sham-operated” group.


Sciatic Nerve Nerve Stump Nerve Guide Regeneration Chamber Acrylic Glue 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The NeuroBox is an international patent of the Catholic University in Rome (WO/2008/029373).


  1. 1.
    Sinis N, Schaller HE, Schulte-Eversum C, Lanaras T, Schlosshauer B, Doser M, et al. Comparative neuro tissue engineering using different nerve guide implants. Acta Neurochir Suppl. 2007;100:61–4.PubMedGoogle Scholar
  2. 2.
    Rappaport WD, Valente J, Hunter G. Clinical utilization and complications of sural nerve biopsy. Am J Surg. 1993;166:252–6.CrossRefPubMedGoogle Scholar
  3. 3.
    Taras JS, Nanavati V, Steelman P. Nerve conduits. J Hand Ther. 2005;18:191–7.CrossRefPubMedGoogle Scholar
  4. 4.
    Bora FW Jr. Peripheral nerve repair in cats. The fascicular stitch. J Bone Joint Surg Am. 1967;49:659–66.PubMedGoogle Scholar
  5. 5.
    Dahlin LB. Nerve injuries. Curr Orthop. 2008;22:9–16.CrossRefGoogle Scholar
  6. 6.
    Neubauer D, Graham JB, Muir D. Chondroitinase treatment increases the effective length of acellular nerve grafts. Exp Neurol. 2007;207:163–70.CrossRefPubMedGoogle Scholar
  7. 7.
    Ijkema-Paassen J, Jansen K, Gramsbergen A, Meek MF. Transection of peripheral nerves, bridging strategies and effect evaluation. Biomaterials. 2004;25(9):1583–92.CrossRefPubMedGoogle Scholar
  8. 8.
    Sinis N, Schaller HE, Schulte-Eversum C, Schlosshauer B, Doser M, Dietz K, et al. Nerve regeneration across a 2-cm gap in the rat median nerve using a resorbable nerve conduit filled with Schwann cells. J Neurosurg. 2005;103(6):1067–76.CrossRefPubMedGoogle Scholar
  9. 9.
    Schlosshauer B, Dreesmann L, Schaller HE, Sinis N. Synthetic nerve guide implants in humans: a comprehensive survey. Neurosurgery. 2006;59(4):740–7.CrossRefPubMedGoogle Scholar
  10. 10.
    Meek MF, Coert JH. US Food and Drug Administration/Conformit Europe-approved absorbable nerve conduits for clinical repair of peripheral and cranial nerves. Ann Plast Surg. 2008;60(1):110–6.CrossRefPubMedGoogle Scholar
  11. 11.
    Ahmed MR, Vairamuthu S, Shafiuzama M, Basha SH, Jayakumar R. Microwave irradiated collagen tubes as a better matrix for peripheral nerve regeneration. Brain Res. 2005;1046(1–2):55–67.CrossRefPubMedGoogle Scholar
  12. 12.
    Bertleff MJ, Meek MF, Nicolai JP. A prospective clinical evaluation of biodegradable neurolac nerve guides for sensory nerve repair in the hand. J Hand Surg [Am]. 2005;30(3):513–8.CrossRefGoogle Scholar
  13. 13.
    Bozkurt A, Brook GA, Moellers S, Lassner F, Sellhaus B, Weis J, et al. In vitro assessment of axonal growth using dorsal root ganglia explants in a novel three-dimensional collagen matrix. Tissue Eng. 2007;13(12):2971–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Bunting S, Di Silvio L, Deb S, Hall S. Bioresorbable glass fibres facilitate peripheral nerve regeneration. J Hand Surg [Br]. 2005;30(3):242–7.Google Scholar
  15. 15.
    Chang CJ, Hsu SH, Yen HJ, Chang H, Hsu SK. Effects of unidirectional permeability in asymmetric poly(dl-lactic acid-co-glycolic acid) conduits on peripheral nerve regeneration: an in vitro and in vivo study. J Biomed Mater Res B Appl Biomater. 2007;83(1):206–15.PubMedGoogle Scholar
  16. 16.
    Chang JY, Lin JH, Yao CH, Chen JH, Lai TY, Chen YS. In vivo evaluation of a biodegradable EDC/NHS-cross-linked gelatin peripheral nerve guide conduit material. Macromol Biosci. 2007;7(4):500–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Chavez-Delgado ME, Gomez-Pinedo U, Feria-Velasco A, Huerta-Viera M, Castaneda SC, Toral FA, et al. Ultrastructural analysis of guided nerve regeneration using progesterone- and pregnenolone-loaded chitosan prostheses. J Biomed Mater Res B Appl Biomater. 2005;74(1):589–600.PubMedGoogle Scholar
  18. 18.
    Chen YS, Chang JY, Cheng CY, Tsai FJ, Yao CH, Liu BS. An in vivo evaluation of a biodegradable genipin-cross-linked gelatin peripheral nerve guide conduit material. Biomaterials. 2005;26(18):3911–8.CrossRefPubMedGoogle Scholar
  19. 19.
    Huang YC, Huang YY, Huang CC, Liu HC. Manufacture of porous polymer nerve conduits through a lyophilizing and wire-heating process. J Biomed Mater Res B Appl Biomater. 2005;74(1):659–64.PubMedGoogle Scholar
  20. 20.
    Inada Y, Hosoi H, Yamashita A, Morimoto S, Tatsumi H, Notazawa S, et al. Regeneration of peripheral motor nerve gaps with a polyglycolic acid-collagen tube: technical case report. Neurosurgery. 2007;61(5):E1105–7.CrossRefPubMedGoogle Scholar
  21. 21.
    Jansen K, Meek MF, van der Werff JF, van Wachem PB, van Luyn MJ. Long-term regeneration of the rat sciatic nerve through a biodegradable poly(dl-lactide-epsilon-caprolactone) nerve guide: tissue reactions with focus on collagen III/IV reformation. J Biomed Mater Res A. 2006;69(2):334–41.Google Scholar
  22. 22.
    Lietz M, Ullrich A, Schulte-Eversum C, Oberhoffner S, Fricke C, Muller HW, et al. Physical and biological performance of a novel block copolymer nerve guide. Biotechnol Bioeng. 2006;93(1):99–109.CrossRefPubMedGoogle Scholar
  23. 23.
    Lietz M, Dreesmann L, Hoss M, Oberhoffner S, Schlosshauer B. Neuro tissue engineering of glial nerve guides and the impact of different cell types. Biomaterials. 2006;27(8):1425–36.CrossRefPubMedGoogle Scholar
  24. 24.
    Madaghiele M, Sannino A, Yannas IV, Spector M. Collagen-based matrices with axially oriented pores. J Biomed Mater Res A. 2008;85(3):757–67.PubMedGoogle Scholar
  25. 25.
    Marchesi C, Pluderi M, Colleoni F, Belicchi M, Meregalli M, Farini A, et al. Skin-derived stem cells transplanted into resorbable guides provide functional nerve regeneration after sciatic nerve resection. Glia. 2007;55(4):425–38.CrossRefPubMedGoogle Scholar
  26. 26.
    Merolli A, Rocchi L, Catalano F, Planell J, Engel E, Martínez E, et al. In vivo regeneration of rat sciatic nerve in a double-halved stitch-less guide: a pilot-study. Microsurgery. 2009;29(4):310–8.CrossRefPubMedGoogle Scholar
  27. 27.
    Oh SH, Lee JH. Fabrication and characterization of hydrophilized porous PLGA nerve guide conduits by a modified immersion precipitation method. J Biomed Mater Res A. 2007;80(3):530–8.PubMedGoogle Scholar
  28. 28.
    Patel M, Vandevord PJ, Matthew H, Wu B, DeSilva S, Wooley PH. Video-gait analysis of functional recovery of nerve repaired with chitosan nerve guides. Tissue Eng. 2006;12(11):3189–99.CrossRefPubMedGoogle Scholar
  29. 29.
    Patel M, Mao L, Wu B, Vandevord PJ. GDNF-chitosan blended nerve guides: a functional study. J Tissue Eng Regen Med. 2007;1(5):360–7.CrossRefPubMedGoogle Scholar
  30. 30.
    Pereira Lopes FR, Camargo de Moura Campos L, Dias Corrêa J Jr, Balduino A, Lora S, Langone F, et al. Bone marrow stromal cells and resorbable collagen guidance tubes enhance sciatic nerve regeneration in mice. Exp Neurol. 2006;198(2):457–68.CrossRefPubMedGoogle Scholar
  31. 31.
    Phillips JB, Bunting SC, Hall SM, Brown RA. Neural tissue engineering: a self-organizing collagen guidance conduit. Tissue Eng. 2005;11(9–10):1611–7.CrossRefPubMedGoogle Scholar
  32. 32.
    Scherman P, Kanje M, Dahlin LB. Sutures as longitudinal guides for the repair of nerve defects—influence of suture numbers and reconstruction of nerve bifurcations. Restor Neurol Neurosci. 2005;23(2):79–85.PubMedGoogle Scholar
  33. 33.
    Stokols S, Tuszynski MH. Freeze-dried agarose scaffolds with uniaxial channels stimulate and guide linear axonal growth following spinal cord injury. Biomaterials. 2006;27(3):443–51.CrossRefPubMedGoogle Scholar
  34. 34.
    Stokols S, Sakamoto J, Breckon C, Holt T, Weiss J, Tuszynski MH. Templated agarose scaffolds support linear axonal regeneration. Tissue Eng. 2006;12(10):2777–87.CrossRefPubMedGoogle Scholar
  35. 35.
    Sundback CA, Shyu JY, Wang Y, Faquin WC, Langer RS, Vacanti JP, et al. Biocompatibility analysis of poly(glycerol sebacate) as a nerve guide material. Biomaterials. 2005;26(27):5454–64.CrossRefPubMedGoogle Scholar
  36. 36.
    Tos P, Battiston B, Nicolino S, Raimondo S, Fornaro M, Lee JM, et al. Comparison of fresh and predegenerated muscle-vein-combined guides for the repair of rat median nerve. Microsurgery. 2007;27(1):48–55.CrossRefPubMedGoogle Scholar
  37. 37.
    Tyner TR, Parks N, Faria S, Simons M, Stapp B, Curtis B, et al. Effects of collagen nerve guide on neuroma formation and neuropathic pain in a rat model. Am J Surg. 2007;193(1):e1–6.CrossRefPubMedGoogle Scholar
  38. 38.
    Uebersax L, Mattotti M, Papaloizos M, Merkle HP, Gander B, Meinel L. Silk fibroin matrices for the controlled release of nerve growth factor (NGF). Biomaterials. 2007;28(30):4449–60.CrossRefPubMedGoogle Scholar
  39. 39.
    Yoshitani M, Fukuda S, Itoi S, Morino S, Tao H, Nakada A, et al. Experimental repair of phrenic nerve using a polyglycolic acid and collagen tube. J Thorac Cardiovasc Surg. 2007;133(3):726–32.CrossRefPubMedGoogle Scholar
  40. 40.
    Wieken K, Angioi-Duprez K, Lim A, Marchal L, Merle M. Nerve anastomosis with glue: comparative histologic study of fibrin and cyanoacrylate glue. J Reconstr Microsurg. 2003;19(1):17–20.CrossRefPubMedGoogle Scholar
  41. 41.
    Klein SM, Nielsen KC, Buckenmaier CC III, Kamal AS, Rubin Y, Steele SM. 2-Octyl cyanoacrylate glue for the fixation of continuous peripheral nerve catheters. Anesthesiology. 2003;98(2):590–1.CrossRefPubMedGoogle Scholar
  42. 42.
    Choi BH, Kim BY, Huh JY, Lee SH, Zhu SJ, Jung JH, et al. Microneural anastomosis using cyanoacrylate adhesives. Int J Oral Maxillofac Surg. 2004;33(8):777–80.PubMedGoogle Scholar
  43. 43.
    Piñeros-Fernández A, Rodeheaver PF, Rodeheaver GT. Octyl 2-cyanoacrylate for repair of peripheral nerve. Ann Plast Surg. 2005;55(2):188–95.CrossRefPubMedGoogle Scholar
  44. 44.
    Landegren T, Risling M, Brage A, Persson JK. Long-term results of peripheral nerve repair: a comparison of nerve anastomosis with ethyl-cyanoacrylate and epineural sutures. Scand J Plast Reconstr Surg Hand Surg. 2006;40(2):65–72.CrossRefPubMedGoogle Scholar
  45. 45.
    Landegren T, Risling M, Persson JK. Local tissue reactions after nerve repair with ethyl-cyanoacrylate compared with epineural sutures. Scand J Plast Reconstr Surg Hand Surg. 2007;41(5):217–27.CrossRefPubMedGoogle Scholar
  46. 46.
    Elgazzar RF, Abdulmajeed I, Mutabbakani M. Cyanoacrylate glue versus suture in peripheral nerve reanastomosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007;104(4):465–72.CrossRefPubMedGoogle Scholar
  47. 47.
    Rickett T, Li J, Patel M, Sun W, Leung G, Shi R. Ethyl-cyanoacrylate is acutely nontoxic and provides sufficient bond strength for anastomosis of peripheral nerves. J Biomed Mater Res A. 2009;90(3):750–4.PubMedGoogle Scholar
  48. 48.
    Li J, Yan JG, Ai X, Hu S, Gu YD, Matloub HS, et al. Ultrastructural analysis of peripheral-nerve regeneration within a nerve conduit. J Reconstr Microsurg. 2004;20(7):565–9.CrossRefPubMedGoogle Scholar
  49. 49.
    Merolli A, Rocchi L. Peripheral nerve regeneration by artificial nerve guides. In: Merolli A, Joyce TJ, editors. Biomaterials in hand surgery. Heidelberg: Springer; 2009. p. 127–43.CrossRefGoogle Scholar
  50. 50.
    Millesi H. Reappraisal of nerve repair. Surg Clin North Am. 1981;61(2):321–40.PubMedADSGoogle Scholar
  51. 51.
    Millesi H, Meissl G, Berger A. Further experience with interfascicular grafting of the median, ulnar and radial nerves. J Bone Joint Surg Am. 1976;58(2):209–18.PubMedGoogle Scholar
  52. 52.
    Yannas IV, Zhang M, Spilker MH. Standardized criterion to analyze and directly compare various materials and models for peripheral nerve regeneration. J Biomater Sci Polym Ed. 2007;18(8):943–66.CrossRefPubMedGoogle Scholar
  53. 53.
    Belsito DV. Contact dermatitis to ethyl-cyanoacrylate-containing glue. Contact Dermat. 1987;17(4):234–6.CrossRefGoogle Scholar
  54. 54.
    Bruze M, Bjorkner BM, Lepoittvin JP. Occupational allergic contact dermatitis from ethyl cyanoacrylate. Contact Dermat. 1995;32(3):156–9.CrossRefGoogle Scholar
  55. 55.
    Conde-Salazar L, Rojo S, Guimaraens D. Occupational contact dermatitis from cyanoacrylates. Am J Contact Dermat. 1998;9(3):188–9.CrossRefPubMedGoogle Scholar
  56. 56.
    Nakazawa T. Occupational asthma due to alkyl cyanoacrylate. J Occup Med. 1990;32(8):709–10.PubMedMathSciNetGoogle Scholar
  57. 57.
    Savonius B, Keskin H, Tuppurainen M, Kanerva L. Occupational respiratory disease caused by acrylates. Clin Exp Allergy. 1993;23:416–24.CrossRefPubMedGoogle Scholar
  58. 58.
    Chan CC, Cheong TH, Lee HS, Wang YT, Poh SC. Case of occupational asthma due to glue containing cyanoacrylate. Ann Acad Med Singap. 1994;23:731–3.PubMedGoogle Scholar
  59. 59.
    Hanft JR, Kashuk KB, Toney ME, McDonald TD. Peripheral neuropathy as a result of cyanoacrylate toxicity. J Am Pediatr Med Assoc. 1991;12:653–5.Google Scholar
  60. 60.
    Page EH, Pajeau AK, Arnold TC, Fincher AR, Goddard MJ. Peripheral neuropathy in workers exposed to nitromethane. Am J Ind Med. 2001;40(1):107–13.CrossRefPubMedGoogle Scholar
  61. 61.
    Kuroki T, Aoki K, Aoki Y, Nemoto A, Yamazaki T, Katsume M, et al. Cranial nerve pareses following wrapping of a ruptured dissecting vertebral artery aneurysm: a possible complication of cyanoacrylate glue—case report. Neurol Med Chir. 2003;43(1):35–7.CrossRefGoogle Scholar
  62. 62.
    Vinters HV, Galil KA, Lundie MJ, Kaufmann JC. The histotoxicity of cyanoacrylates. A selective review. Neuroradiology. 1985;27(4):279–91.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • A. Merolli
    • 1
  • S. Marceddu
    • 2
  • L. Rocchi
    • 1
  • F. Catalano
    • 1
  1. 1.Orthopaedics and Hand Surgery UnitThe Catholic University School of Medicine in RomeRomeItaly
  2. 2.National Research CouncilISPA-CNRSassariItaly

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