Tenogenic effects of silymarin following experimental Achilles tendon ‎transection in rats

Document Type : Original Article

Authors

1 DVM Graduate, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran

2 Department of Surgery and Diagnostic Imaging, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran

3 Department of Pathobiology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran

Abstract

Tendon healing is prolonged due to the small number of cells, poor circulation, and low metabolism. The optimal tendon healing and its complete functional recovery have always been a challenge for researchers. Silymarin possesses anti-inflammatory, anti-oxidant, analgesic, and regenerative properties. The present study aimed to investigate the effects of silymarin on healing the Achilles tendon in rats. Twenty-four male Wistar rats were divided into two groups of control and treatment. After surgical preparation, a complete transverse incision was made in the middle part of the Achilles tendon, and then a modified Kessler suture was placed. The control group received 1.00 mL normal saline for five consecutive days, and the treatment group received 50.00 mg kg-1 of silymarin suspended in 1.00 mL normal saline for five days, orally. During the experimental period, Achilles functional index (AFI) was recorded. Six weeks after surgery, sampling was done. Histopathologically, a significant increase in the density of collagen fibers and reduction in neovascularization and inflammatory cells infiltration were observed in the treatment group. The biomechanical evaluation showed a significant increase in tensile strength of the tendon in the treatment group compared to the control group. The AFI results were concomitant with the results stated above, indicating an improvement in the AFI of rats in the treatment group. The present study results showed that oral administration of silymarin improved tissue healing indices, biomechanical properties, and functional index, leading to optimal healing of experimental Achilles tendon injury in the rat.

Keywords


  1. Sharma P, Maffulli N. Tendon injury and tendinopathy: healing and repair. J Bone Joint Surg Am 2005; 87(1):187-202.
  2. Liu C, Yu K, Bai J, et al. Experimental study of tendon sheath repair via decellularized amnion to prevent tendon adhesion. PLoS ONE 2018;13(10):e0205811. doi:10.1371/journal.pone.0205811.
  3. Connizzo BK, Yannascoli SM, Tucker JJ, et al. The detrimental effects of systemic Ibuprofen delivery on tendon healing are time-dependent. Clin Orthop Relat Res. 2014;472(8):2433-2439.
  4. Lisboa FA, Bradley MJ, Hueman MT, et al. Nonsteroidal anti-inflammatory drugs may affect cytokine response and benefit healing of combat-related extremity wounds. Surgery 2017; 161(4):1164-1173.
  5. Chan K-M, Fu S-C. Anti-inflammatory management for tendon injuries - friends or foes? Sports Med Arthrosc Rehabil Ther Technol 2009; 1(1):23. doi:10.1186/ 1758-2555-1-23.
  6. Rouhani A, Tabrizi A, Ghavidel E. Effects of non-steroidal anti-inflammatory drugs on flexor tendon rehabilitation after repair. Arch Bone Jt Surg. 2013;1(1):28-30.
  7. Dakin SG, Martinez FO, Yapp C, et al. Inflammation activation and resolution in human tendon disease. Sci Transl Med 2015;7(311):311ra173. doi:10.1126/ scitranslmed.aac4269.
  8. Dimmen S, Engebretsen L, Nordsletten L, et al. Negative effects of parecoxib and indomethacin on tendon healing: an experimental study in rats. Knee Surg Sports Traumatol Arthrosc 2009; 17(7):835-839.
  9. Meunier L, Larrey D. Recent advances in hepatotoxicity of non-steroidal anti-inflammatory drugs. Ann Hepatol 2018; 17(2):187-191.
  10. Dixit M, Doan T, Kirschner R, et al. Significant acute kidney injury due to non-steroidal anti-inflammatory drugs: Inpatient setting. Pharmaceuticals (Basel) 2010;3(4):1279-1285.
  11. Zhao-Fleming H, Hand A, Zhang K, et al. Effect of non-steroidal anti-inflammatory drugs on post-surgical complications against the backdrop of the opioid crisis. Burns Trauma 2018; 6:25. doi: 10.1186/s41038-018-0128-x.
  12. García-Poza P, de Abajo FJ, Gil MJ, et al. Risk of ischemic stroke associated with non-steroidal anti-inflammatory drugs and paracetamol: a population-based case-control study. J Thromb Haemost 2015; 13(5):708-718.
  13. Sostres C, Gargallo CJ, Lanas A. Nonsteroidal anti-inflammatory drugs and upper and lower gastrointestinal mucosal damage. Arthritis Res Ther 2013; 15(Suppl 3). doi:10.1186/ar4175.
  14. Ramezannezhad P, Nouri A, Heidarian E. Silymarin mitigates diclofenac-induced liver toxicity through inhibition of inflammation and oxidative stress in male rats. J Herbmed Pharmacol 2019;8(3):231-237.
  15. Ashkani-Esfahani S, Emami Y, Esmaeilzadeh E, et al. Silymarin enhanced fibroblast proliferation and tissue regeneration in full thickness skin wounds in rat models; a stereological study. J Dermatol Dermatol Surg. 2013;17(1):7-12.
  16. Oryan A, Tabatabaei Naeini A, Moshiri A, et al. Modulation of cutaneous wound healing by silymarin in rats. J Wound Care 2012; 21(9):457-464.
  17. Kim J-L, Park S-H, Jeong D, et al. Osteogenic activity of silymarin through enhancement of alkaline phosphatase and osteocalcin in osteoblasts and tibia-fractured mice. Exp Biol Med (Maywood) 2012; 237(4):417-428.
  18. Karimi G, Vahabzadeh M, Lari P, et al. "Silymarin", a promising pharmacological agent for treatment of diseases. Iran J Basic Med Sci 2011;14(4):308-317.
  19. Murrell GA, Lilly EG, Davies H, et al. The Achilles functional index. J Orthop Res 1992; 10(3): 398-404.
  20. Steyaert AE, Burssens PJ, Vercruysse CW, et al. The effects of substance P on the biomechanic properties of ruptured rat Achilles’ tendon. Arch Phys Med Rehabil 2006;87(2):254-258.
  21. Tang JB, Shi D, Zhang QG. Biomechanical and histologic evaluation of tendon sheath management. J Hand Surgery Am 1996; 21(5): 900-908.
  22. Alaseirlis DA, Li Y, Cilli F, et al. Decreasing inflammatory response of injured patellar tendons results in increased collagen fibril diameters. Connect Tissue Res 2005; 46(1): 12-17.
  23. Altaei T. Protective effect of silymarin during coronary artery bypass grafting surgery. Exp Clin Cardiol 2012;17(1):34-38.
  24. Hussain SA, Jassim NA, Numan IT, et al. Anti-inflammatory activity of silymarin in patients with knee osteoarthritis. A comparative study with piro-xicam and meloxicam. Saudi Med J 2009;30(1):98-103.
  25. Yang G, Rothrauff BB, Tuan RS. Tendon and ligament regeneration and repair: clinical relevance and developmental paradigm. Birth Defects Res C Embryo Today. 2013;99(3):203-222.
  26. Docheva D, Müller SA, Majewski M, et al. Biologics for tendon repair. Adv Drug Deliv Rev 2014; 84:222-239.
  27. Wu F, Nerlich M, Docheva D. Tendon injuries: Basic science and new repair proposals. EFORT Open Rev 2017;2(7):332-342.
  28. Sharifi R, Pasalar P, Kamalinejad M, et al. The effect of silymarin (Silybum marianum) on human skin fibroblasts in an in vitro wound healing model. Pharm Biol 2013; 51(3):298-303.
  29. Maffulli N, Renstrom P, Leadbetter WB. Tendon injuries: Basic science and clinical medicine. London, UK: Springer-Verlag 2005:304-306.
  30. Uysal AC, Mizuno H. Tendon regeneration and repair with adipose derived stem cells. Curr Stem Cell Res Ther 2010; 5(2): 161-167.
  31. Liu HY. In vivo evaluation of the stiffness of the patellar tendon. Doctoral Thesis. University of North Carolina; USA 2008.
  32. Ratner B, Hoffman AS, Schoen F, et al. Biomaterials science: An introduction to materials in medicine. 3rd ed. New York, USA: Academic Press 2013;1-55.
  33. Konow N, Roberts TJ. The series elastic shock absorber: tendon elasticity modulates energy dissipation by muscle during burst deceleration. Proc Biol Sci 2015; 282(1804):20142800. doi:10.1098/rspb.2014.2800.
  34. Kirkendall DT, Prentice WE, Garrett WE. Rehabilitation of muscle injuries. In: ‎Puddu G, Giombini A, Selvanetti A (Eds). Rehabilitation of sports injuries: Current ‎Concepts. Berlin, Germany: Springer 2001 185-194.‎
  35. Witvrouw E, Mahieu N, Roosen P, et al. The role of stretching in tendon ‎injuries. Br J Sports Med 2007; 41(4):224-226.‎
  36. Aparecida de Aro A, Vidal B de C, Pimentel ER. Biochemical and anisotropical ‎properties of tendons. Micron 2012; 43(2-3):205-214.‎
  37. Young RG, Butler DL, Weber W, et al. Use of mesen-chymal stem cells in a collagen matrix for Achilles tendon repair. J Orthop Res 1998; 16(4):406-413.
  38. Oryan A, Monazzah S, Bigham-Sadegh A. Bone injury and fracture healing biology. Biomed Environ Sci 2015; 28(1):57-71.
  39. Best TM, Collins A, Lilly EG, et al. Achilles tendon healing: a correlation between functional and mechanical performance in the rat. J Orthop Res 1993; 11(6):897-906.
  40. Staresinic M, Sebecic B, Patrlj L, et al. Gastric penta-decapeptide BPC 157 accelerates healing of transected rat Achilles tendon and in vitro stimulates tendocytes growth. J Orthop Res 2003; 21(6):976-983.
  41. Killian ML, Cavinatto L, Galatz LM, et al. The role of mechanobiology in tendon healing. J Shoulder Elbow Surg 2012; 21(2):228-237.
  42. Khanna A, Friel M, Gougoulias N, et al. Prevention of adhesions in surgery of the flexor tendons of the hand: what is the evidence? Br Med Bull 2009; 90:85-109.
  43. Jacobs MA, Austin NM. Orthotic intervention of the hand and upper extremity: Splinting principles and process. 2nd ed. Philadelphia, USA: Lippincott Williams & Wilkins 2013; 47-65.