Abstract
Purpose
Scar formation after injured peripheral nerve repair is a significant clinical problem because it prevents nerve regeneration. The aim of this study was to investigate and compare the effects of hyaluronic acid (HA) and tacrolimus (FK506) on peripheral nerve regeneration in rabbits after the drugs were topically applied at the site of nerve repair.
Methods
Thirty adult male European rabbits (Oryctolagus cuniculus), ranging in weight from 2.5 to 3 kg, were randomly assigned to three groups: the HA and FK506 groups comprised the experimental groups, while the saline group served as the control. At week 12, macroscopic and microscopic evaluations were performed and analyzed.
Results
In general, the macroscopic evaluations (skin and muscle fascia closure and nerve adherence), microscopic evaluations (cellular components, scar tissue formation index, and histomorphological organization), and measurements of nerve diameter and gastrocnemius muscle wet weight demonstrated the positive effects of topical application of these pharmacological agents (HA and FK506); HA and FK506 prevented scar formation and enhanced nerve regeneration. No significant differences in the parameters described above were observed between the HA and FK506 groups (P > 0.05). However, significant differences were observed between both the HA and FK506 groups and the saline group (P < 0.05).
Conclusion
Based on our findings, topical application of HA and FK506 exhibits equally positive effects, preventing perineural scar formation and enhancing nerve regeneration after peripheral nerve repair.
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References
Siemionow M, Brzezicki G. Chapter 8: current techniques and concepts in peripheral nerve repair. Int Rev Neurobiol. 2009;87:141–72.
Kouyoumdjian JA. Peripheral nerve injuries: a retrospective survey of 456 cases. Muscle Nerve. 2006;34:785–8.
Stanec S, Tonković I, Stanec Z, Tonković D, Dzepina I. Treatment of upper limb nerve war injuries associated with vascular trauma. Injury. 1997;28:463–8.
Grinsell D, Keating CP. Peripheral nerve reconstruction after nerve injury: a review of clinical and experimental therapies. Biomed Res Int. 2014;2014:698256.
Kucuk L, Gunay H, Erbas O, Kucuk U, Atamaz F, Coskunol E. Effects of platelet-rich plasma on nerve regeneration in a rat model. Acta Orthop Traumatol Turc. 2014;48:449–54.
Mekaj AY, Morina AA, Bytyqi CI, Mekaj YH, Duci SB. Application of topical pharmacological agents at the site of peripheral nerve injury and methods used for evaluating the success of the regenerative process. J Orthop Surg Res. 2014;9:94.
Necas J, Bartosikova P, Brauner J, Kolar. Hyaluronic acid (hyaluronan): a review. Vet Med. 2008;52:397–411.
Weigel PH, Fuller GM, LeBoeuf RD. A model for the role of hyaluronic acid in fibrin in the early events during the inflammatory response and wound healing. J Theor Biol. 1986;119:219–34.
Burd DA, Greco RM, Regauer S, Longaker MT, Siebert JW, Garg HG. Hyaluronan and wound healing: a new perspective. Br J Plast Surg. 1991;44:579–84.
Ozgenel GY. Effects of hyaluronic acid on the peripheral nerve scarring regeneration in rats. Microsurgery. 2003;23:575–81.
Li X, Wang W, Wei G, Wang G, Zhang W, Ma X. Immunophilin FK506 loaded in chitosan guide promotes peripheralnerve regeneration. Biotechnol Lett. 2010;32:1333–7.
Shahraki M, Mohammadi R, Najafpour A. Influence of tacrolimus (FK506) on nerve regeneration using allografts: a rat sciatic nerve model. J oral Maxillofac Surg. 2015;73:1438 e1–9.
Chen B, Song YX, Liu ZJ. Promotion of nerve regenerationin peripheral nerve by short-course FK506 after end-to-sideneurorrhaphy. J Surg Res. 2009;152:303–10.
Azizi S, Mohammadi R, Amini K, Fallah R. Effects of topically administered FK506 on sciatic nerve regeneration and reinnervation after vein graft repair of short nerve gaps. Neurosurg Focus. 2012;32:E5.
Konofaos P, Terzis JK. FK506 and nerve regeneration: past, present and future. J Reconstr Microsurg. 2013;29:141–8.
Que J, Cao Q, Sui T, Du S, Kong D, Cao X. Effect of FK506 in reducing scar formation by inducing fibroblast apoptosis after sciatic nerve injury in rats. Cell Death Dis. 2013;4:e526.
Shen J, Zhou CP, Zhong XM, Guo RM, Griffith JF, Cheng LN, Duan XH, Liang BL. MR neurography: T1 and T2 measurements in acute peripheral nerve traction injury in rabbits. Radiology. 2010;254:729–38.
Petersen J, Russell L, Andrus K, MacKinnon M, Silver J, Kliot M. Reduction of extraneural scarring by ADCON-T/N after surgical intervention. Neurosurgery. 1996;38:976–83.
Brown RE, Erdmann D, Lyons SF, Suchy H. The use of cultured Schwann cells in nerve repair in rabbit hind-limb model. J Reconstr Microsurg. 1996;12:149–52.
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;44:59–64.
Wang KK, Nemeth IR, Seckel BR, Chakalis-Haley DP, Swann DA, Kuo JW, Bryan DJ, Cetrulo CL Jr. Hyaluronic acid enhances peripheral nerve regeneration in vivo. Microsurgery. 1998;18:270–5.
Zor F, Deveci M, Kilic A, Ozdag MF, Kurt B, Sengezer M, Sönmez TT. Effect of VEGF gene therapy and hyaluronic acid film sheath on peripheral nerve regeneration. Microsurgery. 2014;34:209–16.
Yeh C, Browers D, Hadlock TA. Effect of FK506 on functional recovery after facial nerve injury in the rat. Arch Facial Plast Surg. 2007;9:333–9.
Mekaj Y, Mekaj A. Prevention of failed back surgery syndrome with applications of different pharmacological agents: a review article. Ther Targets Neurol Dis. 2015;2:e507.
Adanali G, Verdi M, Tuncel A, Erdogan B, Kargi E. Effect of hyaluronic acid-carboxymethylcellulose membrane on extraneural adhesion formation and peripheral nerve regeneration. J Reconstr Microsurg. 2003;19:29–36.
Park JS, Lee JH, Han CS, Chung DW, Kim GY. Effect of hyaluronic acid-carboxymethylcellulose solution on perineural scar formation after sciatic nerve repair in rats. Clinin Orthop Surg. 2011;3:315–24.
Ikeda K, Yamauchi D, Osamura N, Hagiwara N, Tomita K. Hyaluronic acid prevents peripheral nerve adhesion. Br J Plast Surg. 2003;56:341–7.
Mekaj AY, Morina AA, Manxhuka-Kerliu S, Neziri B, Duci SB, Kukaj V, Miftari I. 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;22:179–84.
Mekaj AY, Morina AA, Lajqi S, Manxhuka-Kerliu S, Kelmendi FM, Duci SB. Biomechanical properties of the sciatic nerve following repair: effects of topical application of hyaluronic acid or tacrolimus. Int J Clin Exp Med. 2015;8:20218–26.
Que J, Cao Q, Sui T, Du S, Zhang A, Kong D, Cao X. Tacrolimus reduces scar formation and promotes sciatic nerve regeneration. Neural Regen Res. 2012;7:2500–6.
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This work is in compliance with all ethical requirements. This study was approved by the Animal Experimental Ethics Committee of the Medical Faculty, University of Prishtina, Kosovo (No.1551).
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Agon Y. Mekaj, Suzana Manxhuka-Kerliu, Arsim A. Morina, Shkelzen B. Duci, Labinot Shahini, and Ymer H. Mekaj declare that they have no conflict of interest.
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Mekaj, A.Y., Manxhuka-Kerliu, S., Morina, A.A. et al. 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 43, 497–504 (2017). https://doi.org/10.1007/s00068-016-0683-4
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DOI: https://doi.org/10.1007/s00068-016-0683-4