Spinal cerrahide istenmeyen kemik dokusu oluşumunun inhibisyonunda 5-florourasilin etkinliği: Spontan spinal füzyonun sıçan modelinde histolojik değerlendirmesi

Abstract

Amaç: Bu çalışmanın amacı, antiproliferatif bir ajan olan 5-florourasilin (5FU) deneysel sıçan modelinde spinal kemik oluşumunun inhibisyonuna etkisinin araştırılması idi. Çalışma planı: Altı aylık 30 adet Sprague-Dawley sıçan çalışmaya alındı ve 3 grup oluşturuldu. Spontan füzyon modelinde L4-L5 omurlarının posterior elemanlarında noktasal kanama oluşturmak için bisturi ile agresif periostal soyma işlemi gerçekleştirildi. Spinöz çıkıntılar tellerle tespit edildi ve herhangi bir greft materyali uygulanmadı. Grup 1’e Adcon-L, Grup 2’ye tek dokunuş tekniği ile 5FU uygulanırken, Grup 3 kontrol grubunu oluşturdu. Dört hafta sonra sıçanlar sakrifiye edildi ve histolojik inceleme için örnekler alındı. Bulgular: Bu çalışmada 5FU’nun, kontrol grubuna kıyasla, fibroblast ve enflamatuvar hücre yoğunluğu ve kemik formasyonunu önemli ölçüde inhibe ettiği gözlendi. Ayrıca, 5FU’nun kemik formasyonu ve enflamatuvar hücrelerin inhibisyonu açısından Adcon-L’ye göre belirgin şekilde üstün olduğu saptandı (p=0.0001). Çıkarımlar: Çalışmamız 5FU’nun spinal cerrahide füzyon, fibrozis ve istenmeyen skar doku oluşumunu inhibe edebildiğini göstermiştir. 5FU’nun lokal uygulama dozuyla ilgili gelecekteki çalışmalar sonrası insanlarda istenmeyen füzyonun inhibisyonu için kullanılabileceği düşüncesindeyiz.

Keywords

• 5-florourasil; spinal füzyonun inhibisyonu; spontan spinal füzyon

Efficacy of 5-Fluorouracil in inhibition of unintended bone formation in spinal surgery: a histological evaluation on a rat model of spontaneous spinal fusion

Abstract

Objective: The aim of this study was to investigate the influence of the antiproliferative agent 5-Fluorouracil (5FU) over inhibition of spinal bone formation in an experimental rat model.
Methods: The study included 30 6-month-old Sprague-Dawley rats divided into 3 groups. Aggressive periosteal denuding was performed by scalpel to induce punctuate bleeding in the posterior elements of the L4-L5 vertebrae in the spontaneous fusion model. Spinous processes were fixated by wires and no graft substitute was applied. Adcon-L was applied in Group 1, single-touch technique 5FU in Group 2. Group 3 was the control group. Rats were sacrificed at 4 weeks and specimens acquired for histological examination.
Results: 5FU substantially inhibited fibroblast and inflammatory cell densities as well as bone formation compared to the control group. 5FU was considerably superior to Adcon-L with regard to inhibition of bone formation and inflammatory cells (p=0.0001).
Conclusion: 5FU can inhibit fusion, fibrosis and unwanted scar tissue in spinal surgery. We believe that after further studies on its local delivery dose, it can be used in humans for inhibition of unintended fusion.

Keywords

• 5-Fluorouracil
• inhibition of spinal fusion
• spontaneous spinal fusion

References

1. Mardjetko SM, Hammerberg KW, Lubicky JP, Fister JS. The Luque trolley revisited. Review of nine cases requiring revision. Spine 1992;17:582-9. CrossRef
2. Blakemore LC, Scoles PV, Poe-Kochert C, Thompson GH. Submuscular Isola rod with or without limited apical fusion in the management of severe spinal deformities in young children: preliminary report. Spine 2001;26:2044- 8. CrossRef
3. Acaroglu E, Yazici M, Alanay A, Surat A. Three-dimen- sional evolution of scoliotic curve during instrumenta- tion without fusion in young children. J Pediatr Orthop 2002;22:492-6. CrossRef
4. Moe JH, Kharrat K, Winter RB, Cummine JL. Harrington instrumentation without fusion plus external orthotic support for the treatment of difficult curvature problems in young children. Clin Orthop Relat Res 1984;185:35- 45.
5. Eberle CF. Failure of fixation after segmental spinal instru- mentation without arthrodesis in the management of par- alytic scoliosis. J Bone Joint Surg Am 1988;70:696-703.
6. Fisk JR, Peterson HA, Laughlin R, Lutz R. Spontaneous fusion in scoliosis after instrumentation without arthrod- esis. J Pediatr Orthop 1995;15:182-6. CrossRef
7. Cahill PJ, Marvil S, Cuddihy L, Schutt C, Idema J, Clem- ents DH, et al. Autofusion in the immature spine treated with growing rods. Spine 2010;35:E1199-203. CrossRef
8. Poynton AR, Lane JM. Safety profile for the clinical use of bone morphogenetic proteins in the spine. Spine 2002;27(16 Suppl 1):40-8. CrossRef

9. Patel VV, Zhao L, Wong P, Kanim L, Bae HW, Pradhan BB, et al. Controlling bone morphogenetic protein diffu- sion and bone morphogenetic protein-stimulated bone growth using fibrin glue. Spine 2006;31:1201-6. CrossRef
10. Patel VV, Zhao L, Wong P, Pradhan BB, Bae HW, Kanim L, et al. An in vitro and in vivo analysis of fibrin glue use to control bone morphogenetic protein diffusion and bone morphogenetic protein-stimulated bone growth. Spine J 2006;6:397-404. CrossRef
11. Zou X, Li H, Egund N, Lind M, Bünger C. Inhibition of spinal fusion by use of a tissue ingrowth inhibitor. Eur Spine J 2004;13:157-63. CrossRef
12. Abiraman S, Varma HK, Umashankar PR, John A. Fibrin glue as an osteoinductive protein in a mouse model. Bio- materials 2002;23:3023-31. CrossRef
13. Khan U, Occleston NL, Khaw PT, McGrouther DA. Single exposures to 5-fluorouracil: a possible mode of tar- geted therapy to reduce contractile scarring in the injured tendon. Plast Reconstr Surg 1997;99:465-71. CrossRef
14. He Y, Revel M, Loty B. A quantitative model of post-lam- inectomy scar formation. Effects of a nonsteroidal anti- inflammatory drug. Spine 1995;20:557-63; discussion 579-80. CrossRef
15. Emery SE, Brazinski MS, Koka A, Bensusan JS, Steven- son S. The biological and biomechanical effects of irra- diation on anterior spinal bone grafts in a canine model. J Bone Joint Surg Am 1994;76:540-8.
16. Rinsky LA, Gamble JG, Bleck EE. Segmental instrumen- tation without fusion in children with progressive scolio- sis. J Pediatr Orthop 1985;5:687-90. CrossRef
17. Tello CA. Harrington instrumentation without arthrode- sis and consecutive distraction program for young children with severe spinal deformities. Experience and technical details. Orthop Clin North Am 1994;25:333-51.
18. Morin MR. Pediatric Cotrel-Dubousset instrumentation system. In: Bridwell KH, DeWald RL, editors. Spinal sur- gery. Philadelphia, PA: JB Lippincott; 1991. p. 212-7.
19. Anand N, Sahni K, Menage MJ. Modification of trabecu- lectomy with single-dose intraoperative 5-Fluorouracil ap- plication. Acta Ophthalmol Scand 1998;76:83-9. CrossRef
20. Mora JS, Nguyen N, Iwach AG, Gaffney MM, Hether- ington J Jr, Hoskins HD Jr, et al. Trabeculectomy with intraoperative sponge 5-fluorouracil. Ophthalmology 1996;103:963-70. CrossRef
21. Zhao C, Zobitz ME, Sun YL, Predmore KS, Amadio PC, An KN, et al. Surface treatment with 5-fluorouracil after flexor tendon repair in a canine in vivo model. J Bone Joint Surg Am 2009;91:2673-82. CrossRef
22. Moran SL, Ryan CK, Orlando GS, Pratt CE, Michalko KB. Effects of 5-fluorouracil on flexor tendon repair. J Hand Surg Am 2000;25:242-51. CrossRef
23. Khaw PT, Sherwood MB, MacKay SL, Rossi MJ, Schultz G. Five-minute treatments with fluorouracil, floxuridine, and mitomycin have long-term effects on human Tenon’s capsule fibroblasts. Arch Ophthalmol 1992;110:1150-4.
24. Akali A, Khan U, Khaw PT, McGrouther AD. Decrease in adhesion formation by a single application of 5-fluo- rouracil after flexor tendon injury. Plast Reconstr Surg 1999;103:151-8. CrossRef
25. Geisler FH. Prevention of peridural fibrosis: current methodologies. Neurol Res 1999;21 Suppl 1:S9-22.
26. Zhu W, Rawlins BA, Boachie-Adjei O, Myers ER, Arimizu J, Choi E, et al. Combined bone morphogenetic protein-2 and -7 gene transfer enhances osteoblastic dif- ferentiation and spine fusion in a rodent model. J Bone Miner Res 2004;19:2021-32. CrossRef