Models for purulent septic inflammation of the tibia in rats to assess the effect of bioresorbable materials with antimicrobial drugs

Introduction A brief review of modeling purulent septic inflammation in rats, including with the help of an active bacterial agent, and methods for diagnosing inflammation are given.

The aim of the study was to demonstrate the results of the development of an effective experimental model of purulent septic inflammation of the tibia in rats using minimally invasive methods for diagnosing infection in vivo.

Materials and methods Various models of purulent septic inflammation were studied in four groups of small laboratory animals, when using the inoculation of Staphylococcus aureus. Methods for assessing purulent-septic inflammation that are not destructible by the object have been worked out: microbiological, tomographic, morphological.

Results The results of the study indicate the possibility of creating experimental purulent-septic inflammation in rats by 14-60 days using S. aureus inoculation, which is a severe, rapidly progressive purulent infection that leads to extensive destruction of the bone with the formation of sequesters.

Discussion To guarantee the formation of a purulent-inflammatory process of bone tissue in a shorter period of observation, a quantitatively controlled invasion of an active bacterial agent is necessary. A sclerosing agent and formation of a fistulous tract are not essential in creating inflammation.

Conclusion The results of the development of experimental models for the creation of purulent-septic inflammation using minimally invasive in vivo diagnostic methods are demonstrated, which will allow an adequate assessment of the degree of infection before treatment.

1. Lew DP, Waldvogel FA. Osteomyelitis. Lancet. 2004;364(9431):369-79. doi: 10.1016/S0140-6736(04)16727-5

2. Inzana JA, Schwarz EM, Kates SL, Awad HA. Biomaterials approaches to treating implant-associated osteomyelitis. Biomaterials. 2016;81:58-71. doi: 10.1016/j.biomaterials.2015.12.012

3. Rao N, Lipsky BA. Optimising antimicrobial therapy in diabetic foot infections. Drugs. 2007;67(2):195-214. doi: 10.2165/00003495-200767020-00003

4. Cram P, Lu X, Kates SL, Singh JA, Li Y, Wolf BR. Total knee arthroplasty volume, utilization, and outcomes among Medicare beneficiaries, 1991-2010. JAMA. 2012;308(12):1227-36. doi: 10.1001/2012.jama

5. Rosas S, Ong AC, Buller LT, Sabeh KG, Law TY, Roche MW, Hernandez VH. Season of the year influences infection rates following total hip arthroplasty. World J Orthop. 2017;8(12):895-901. doi: 10.5312/wjo.v8.i12.895

6. Geurts JAP, van Vugt TAG, Arts JJC. Use of contemporary biomaterials in chronic osteomyelitis treatment: Clinical lessons learned and literature review. J Orthop Res. 2021;39(2):258-264. doi: 10.1002/jor.24896

7. Schwarz EM, Parvizi J, Gehrke T, Aiyer A, Battenberg A, Brown SA, Callaghan JJ, Citak M, Egol K, Garrigues GE, Ghert M, Goswami K, Green A, Hammound S, Kates SL, McLaren AC, Mont MA, Namdari S, Obremskey WT, O'Toole R, Raikin S, Restrepo C, Ricciardi B, Saeed K, Sanchez-Sotelo J, Shohat N, Tan T, Thirukumaran CP, Winters B. 2018 International Consensus Meeting on Musculoskeletal Infection: Research Priorities from the General Assembly Questions. J Orthop Res. 2019;37(5):997-1006. doi: 10.1002/jor.24293

8. Sheehy SH, Atkins BA, Bejon P, Byren I, Wyllie D, Athanasou NA, Berendt AR, McNally MA. The microbiology of chronic osteomyelitis: prevalence of resistance to common empirical anti-microbial regimens. J Infect. 2010;60(5):338-43. doi: 10.1016/j.jinf.2010.03.006

9. Trampuz A, Zimmerli W. Diagnosis and treatment of infections associated with fracture-fixation devices. Injury. 2006;37 Suppl 2:S59-66. doi: 10.1016/j.injury.2006.04.010

10. Murray CK, Hsu JR, Solomkin JS, Keeling JJ, Andersen RC, Ficke JR, Calhoun JH. Prevention and management of infections associated with combat-related extremity injuries. J Trauma. 2008;64(3 Suppl):S239-51. doi: 10.1097/TA.0b013e318163cd14

11. Reizner W, Hunter JG, O'Malley NT, Southgate RD, Schwarz EM, Kates SL. A systematic review of animal models for Staphylococcus aureus osteomyelitis. Eur Cell Mater. 2014 25;27:196-212. doi: 10.22203/ecm.v027a15

12. Histing T, Garcia P, Holstein JH, Klein M, Matthys R, Nuetzi R, Steck R, Laschke MW, Wehner T, Bindl R, Recknagel S, Stuermer EK, Vollmar B, Wildemann B, Lienau J, Willie B, Peters A, Ignatius A, Pohlemann T, Claes L, Menger MD. Small animal bone healing models: standards, tips, and pitfalls results of a consensus meeting. Bone. 2011;49(4):591-9. doi: 10.1016/j.bone.2011.07.007

13. Lindsey BA, Clovis NB, Smith ES, Salihu S, Hubbard DF. An animal model for open femur fracture and osteomyelitis: Part I. J Orthop Res. 2010;28(1):38-42. doi: 10.1002/jor.20960

14. Li B, Jiang B, Dietz MJ, Smith ES, Clovis NB, Rao KM. Evaluation of local MCP-1 and IL-12 nanocoatings for infection prevention in open fractures. J Orthop Res. 2010;28(1):48-54. doi: 10.1002/jor.20939

15. Buxton TB, Travis MT, O'Shea KJ, McPherson JC 3rd, Harvey SB, Plowman KM, Walsh DS. Low-dose infectivity of Staphylococcus aureus (SMH strain) in traumatized rat tibiae provides a model for studying early events in contaminated bone injuries. Comp Med. 2005;55(2):123-128.

16. Antoci V Jr, Adams CS, Hickok NJ, Shapiro IM, Parvizi J. Vancomycin bound to Ti rods reduces periprosthetic infection: preliminary study. Clin Orthop Relat Res. 2007;461:88-95. doi: 10.1097/BLO.0b013e318073c2b2

17. Holt J, Hertzberg B, Weinhold P, Storm W, Schoenfisch M, Dahners L. Decreasing bacterial colonization of external fixation pins through nitric oxide release coatings. J Orthop Trauma. 2011;25(7):432-437. doi: 10.1097/BOT.0b013e3181f9ac8a

18. Hienz SA, Sakamoto H, Flock JI, Mörner AC, Reinholt FP, Heimdahl A, Nord CE. Development and characterization of a new model of hematogenous osteomyelitis in the rat. J Infect Dis. 1995;171(5):1230-1236. doi: 10.1093/infdis/171.5.1230

19. Itokazu M, Yamamoto K, Yang WY, Aoki T, Kato N, Watanabe K. The sustained release of antibiotic from freeze-dried fibrin-antibiotic compound and efficacies in a rat model of osteomyelitis. Infection. 1997;25(6):359-363. doi: 10.1007/BF01740818

20. Mendel V, Simanowski HJ, Scholz HC, Heymann H. Therapy with gentamicin-PMMA beads, gentamicin-collagen sponge, and cefazolin for experimental osteomyelitis due to Staphylococcus aureus in rats. Arch Orthop Trauma Surg. 2005;125(6):363-368. doi: 10.1007/s00402-004-0774-2

21. Cevher E, Orhan Z, Mülazimoğlu L, Sensoy D, Alper M, Yildiz A, Ozsoy Y. Characterization of biodegradable chitosan microspheres containing vancomycin and treatment of experimental osteomyelitis caused by methicillin-resistant Staphylococcus aureus with prepared microspheres. Int J Pharm. 2006;317(2):127-135. doi: 10.1016/j.ijpharm.2006.03.014

22. Orhan Z, Cevher E, Mülazimoglu L, Gürcan D, Alper M, Araman A, Ozsoy Y. The preparation of ciprofloxacin hydrochloride-loaded chitosan and pectin microspheres: their evaluation in an animal osteomyelitis model. J Bone Joint Surg Br. 2006;88(2):270-275. doi: 10.1302/0301-620X.88B2.16328

23. Cevher E, Orhan Z, Sensoy D, Ahiskali R, Kan PL, Sağirli O, Mülazimoğlu L. Sodium fusidate-poly(D,L-lactide-co-glycolide) microspheres: preparation, characterisation and in vivo evaluation of their effectiveness in the treatment of chronic osteomyelitis. J Microencapsul. 2007;24(6):577-595. doi: 10.1080/02652040701472584

24. Orhan Z, Cevher E, Yildiz A, Ahiskali R, Sensoy D, Mülazimoğlu L. Biodegradable microspherical implants containing teicoplanin for the treatment of methicillin-resistant Staphylococcus aureus osteomyelitis. Arch Orthop Trauma Surg. 2010;130(1):135-142. doi: 10.1007/s00402-009-0886-9

25. Solberg BD, Gutow AP, Baumgaertner MR. Efficacy of gentamycin-impregnated resorbable hydroxyapatite cement in treating osteomyelitis in a rat model. J Orthop Trauma. 1999;13(2):102-106. doi: 10.1097/00005131-199902000-00006

26. Zelken J, Wanich T, Gardner M, Griffith M, Bostrom M. PMMA is superior to hydroxyapatite for colony reduction in induced osteomyelitis. Clin Orthop Relat Res. 2007;462:190-194. doi: 10.1097/BLO.0b013e3180ca9521

27. Norden CW. Experimental osteomyelitis. I. A description of the model. J Infect Dis. 1970;122(5):410-418. doi: 10.1093/infdis/122.5.410

28. Subasi M, Kapukaya A, Kesemenli C, Kaya H, Sari I. Effect of granulocyte-macrophage colony-stimulating factor on treatment of acute osteomyelitis. An experimental investigation in rats. Arch Orthop Trauma Surg. 2001;121(3):170-173. doi: 10.1007/s004020000209

29. Burch S, Bisland SK, Bogaards A, Yee AJ, Whyne CM, Finkelstein JA, Wilson BC. Photodynamic therapy for the treatment of vertebral metastases in a rat model of human breast carcinoma. J Orthop Res. 2005;23(5):995-1003. doi: 10.1016/j.orthres.2004.12.014

30. Ersoz G, Oztuna V, Coskun B, Eskandari MM, Bayarslan C, Kaya A. Addition of fusidic acid impregnated bone cement to systemic teicoplanin therapy in the treatment of rat osteomyelitis. J Chemother. 2004;16(1):51-55. doi: 10.1179/joc.2004.16.1.51

31. Lucke M, Schmidmaier G, Sadoni S, Wildemann B, Schiller R, Stemberger A, Haas NP, Raschke M. A new model of implant-related osteomyelitis in rats. J Biomed Mater Res B Appl Biomater. 2003;67(1):593-602. doi: 10.1002/jbm.b.10051

32. Bisland SK, Chien C, Wilson BC, Burch S. Pre-clinical in vitro and in vivo studies to examine the potential use of photodynamic therapy in the treatment of osteomyelitis. Photochem Photobiol Sci. 2006;5(1):31-38. doi: 10.1039/b507082a

33. García-Alvarez F, Navarro-Zorraquino M, Castro A, Grasa JM, Pastor C, Monzón M, Martínez A, García-Alvarez I, Castillo J, Lozano R. Effect of age on cytokine response in an experimental model of osteomyelitis. Biogerontology. 2009;10(5):649-658. doi: 10.1007/s10522-008-9211-1

34. Darouiche RO. Treatment of infections associated with surgical implants. N Engl J Med. 2004;350(14):1422-1429. doi: 10.1056/NEJMra035415

35. Smeltzer MS, Thomas JR, Hickmon SG, Skinner RA, Nelson CL, Griffith D, Parr TR Jr, Evans RP. Characterization of a rabbit model of staphylococcal osteomyelitis. J Orthop Res. 1997;15(3):414-421. doi: 10.1002/jor.1100150314

36. Norden CW, Myerowitz RL, Keleti E. Experimental osteomyelitis due to Staphylococcus aureus or Pseudomonas aeruginosa: a radiographic-pathological correlative analysis. Br J Exp Pathol. 1980;61(4):451-460.

37. Inzana JA, Trombetta RP, Schwarz EM, Kates SL, Awad HA. 3D printed bioceramics for dual antibiotic delivery to treat implant-associated bone infection. Eur Cell Mater. 2015;30:232-247. doi: 10.22203/ecm.v030a16

38. Koort JK, Mäkinen TJ, Suokas E, Veiranto M, Jalava J, Knuuti J, Törmälä P, Aro HT. Efficacy of ciprofloxacin-releasing bioabsorbable osteoconductive bone defect filler for treatment of experimental osteomyelitis due to Staphylococcus aureus. Antimicrob Agents Chemother. 2005;49(4):1502-1508. doi: 10.1128/AAC.49.4.1502-1508.2005

39. Li D, Gromov K, Søballe K, Puzas JE, O'Keefe RJ, Awad H, Drissi H, Schwarz EM. Quantitative mouse model of implant-associated osteomyelitis and the kinetics of microbial growth, osteolysis, and humoral immunity. J Orthop Res. 2008;26(1):96-105. doi: 10.1002/jor.20452

40. Kadurugamuwa JL, Sin L, Albert E, Yu J, Francis K, DeBoer M, Rubin M, Bellinger-Kawahara C, Parr TR Jr, Contag PR. Direct continuous method for monitoring biofilm infection in a mouse model. Infect Immun. 2003;71(2):882-890. doi: 10.1128/IAI.71.2.882-890.2003

41. Королев С.Б., Митрофанов В.Н., Живцов О.П., Орлинская Н.Ю., Юлина Д.П. Моделирование хронического остеомиелита в эксперименте. Гений ортопедии. 2022;28(2):223-227. doi: 10.18019/1028-4427-2022-28-2-223-227

42. Waeiss RA, Negrini TC, Arthur RA, Bottino MC. Antimicrobial effects of drug-containing electrospun matrices on osteomyelitis-associated pathogens. J Oral Maxillofac Surg. 2014;72(7):1310-1319. doi: 10.1016/j.joms.2014.01.007

43. Rani SA, Pitts B, Beyenal H, Veluchamy RA, Lewandowski Z, Davison WM, Buckingham-Meyer K, Stewart PS. Spatial patterns of DNA replication, protein synthesis, and oxygen concentration within bacterial biofilms reveal diverse physiological states. J Bacteriol. 2007;189(11):4223-4233. doi: 10.1128/JB.00107-07

44. Mihailescu R, Furustrand Tafin U, Corvec S, Oliva A, Betrisey B, Borens O, Trampuz A. High activity of Fosfomycin and Rifampin against methicillin-resistant staphylococcus aureus biofilm in vitro and in an experimental foreign-body infection model. Antimicrob Agents Chemother. 2014;58(5):2547-2553. doi: 10.1128/AAC.02420-12

45. O'Reilly T, Mader JT. Rat model of bacterial osteomyelitis of the tibia. In: Zak O, Sande MA, editors. Handbook of Animal Models of Infection: Experimental Models in Antimicrobial Chemotherapy. San Diego, CA: Academic Press. (1999), p. 561-575. doi: 10.1016/B978-012775390-4/50205-0