Mehmet YALÇINOZAN, Mehmet TÜRKER, Meriç ÇIRPAR

Effects of a novel biodegredable implant system on a rat tibia fracture model

Objective: This study aimed to determine the effects of a novel biodegradable implant releasing platelet-derived growth factor (PDGF) at the fracture site on fracture healing in a rat tibia fracture model. Methods: In this study, 35 male Sprague-Dawley rats weighing between 300 and 350g were used. The rats were divided into four groups: Group A (control group without any treatment, n=10), Group B (spacer without PDGF Group, n=10), Group C (spacer with PDGF group, n=10), and Group D (healthy rat Group, n=5). Standardized fractures were created in the right tibias of rats, and then biodegradable implants made of poly-β-hydroxybutyrate-co-3-hydroxy valerate were implanted at the fracture sites in Groups B and C. In Group C, implants were loaded with 600 ng of PDGF. Animals were sacrificed 30 days after the operation, and fracture healing in each group was assessed radiologically based on the Goldberg score. Furthermore, the anteroposterior (AP) and mediolateral (ML) callus diameters were measured macroscopically, and fracture sites were mechanically tested. Results: In the radiological assessment, Group C showed higher fracture healing rate than Groups A and B (p=0.001), whereas no significant difference was found between group C and Group D (p>0.05). In the macroscopic assessment, while Group C exhibited the thickest AP callus diameter (p=0.02), no significant differences in ML callus diameters existed among the groups (p>0.05). Mechanical testing revealed that Group C had higher torsional strength (p=0.001) and stiffness than Groups A and B (p=0.001) while there was no significant difference between Groups C and D (p>0.05).

___

1. Claes L, Ignatius A. Development of new, biodegradable implants. Chirurg 2002; 73: 990-6. [Crossref]

2. Elmowafy E, Abdal-Hay A, Skouras A, Tiboni M, Casettari L, Guarino V. Polyhydroxyalkanoate (PHA): applications in drug delivery and tissue engineering. Expert Rev Med Devices 2019; 16: 467-82. [Crossref]

3. Li C, Zhang J, Li Y, Moran S, Khang G, Ge Z. Poly (l-lactide-co-caprolactone) scaffolds enhanced with poly (beta-hydroxybutyrate-co-beta-hydroxyvalerate) microspheres for cartilage regeneration. Biomed Mater 2013; 8: doi: 10.1088/1748-6041/8/2/025005. Epub 2013 Feb 5. [Crossref]

4. Dimitriou R, Jones E, McGonagle D, Giannoudis PV. Bone regeneration: current concepts and future directions. BMC Med 2011; 9: doi: 10.1186/1741-7015-9-66. [Crossref]

5. Lichte P, Pape HC, Pufe T, Kobbe P, Fischer H. Scaffolds for bone healing: concepts, materials and evidence. Injury 2011; 42: 569-73. [Crossref]

6. Majidinia M, Sadeghpour A, Yousefi B. The roles of signaling pathways in bone repair and regeneration. J Cell Physiol 2018; 233: 2937-48 [Crossref]

7. Pacifici L, Casella F, Ripari M. The principles of tissue engineering: role of growth factors in the bone regeneration. Minerva Stomatol 2002; 51: 351-9.

8. Li A, Xia X, Yeh J, et al. PDGF-AA promotes osteogenic differentiation and migration of mesenchymal stem cell by down-regulating PDGFRalpha and derepressing BMPSmad1/5/8 signaling. PLoS One 2014; 9: doi: 10.1371/journal. pone.0113785. eCollection 2014. [Crossref]

9. Al-Zube L, Breitbart EA, O’Connor JP, et al. Recombinant human platelet-derived growth factor BB (rhPDGF-BB) and beta-tricalcium phosphate/collagen matrix enhance fracture healing in a diabetic rat model. J Orthop Res 2009; 27: 1074-81. [Crossref]

10. Hengartner NE, Fiedler J, Ignatius A, Brenner RE. IL-1beta inhibits human osteoblast migration. Mol Med 2013; 19: 36- 42. [Crossref]

11. Hollinger JO, Onikepe AO, MacKrell J, et al. Accelerated fracture healing in the geriatric, osteoporotic rat with recombinant human platelet-derived growth factor-BB and an injectable beta-tricalcium phosphate/collagen matrix. J Orthop Res 2008; 26: 83-90. [Crossref]

12. Canalis E. Growth factor control of bone mass. J Cell Biochem 2009; 108: 769-77. [Crossref]

13. Caplan AI, Correa D. PDGF in bone formation and regeneration: new insights into a novel mechanism involving MSCs. J Orthop Res 2011; 29: 1795-803. [Crossref]

14. Grageda E. Platelet-rich plasma and bone graft materials: a review and a standardized research protocol. Implant Dent 2004; 13: 301-9. [Crossref]

15. Thoma DS, Jung RE, Hanseler P, Hammerle CHF, Cochran DL, Weber FE. Impact of recombinant platelet-derived growth factor BB on bone regeneration: a study in rabbits. Int J Periodontics Restorative Dent 2012; 32: 195-202.

16. Andre J, Gallini R, Betsholtz C. Role of platelet-derived growth factors in physiology and medicine. Genes Dev 2008; 22: 1276- 312.[Crossref]

17. DiGiovanni CW, Lin SS, Baumhauer JF, et al. Recombinant human platelet-derived growth factor-BB and beta-tricalcium phosphate (rhPDGF-BB/beta-TCP): an alternative to autogenous bone graft. J Bone Joint Surg Am 2013; 95: 1184-92. [Crossref]

18. Kim JH, Kim HW. Rat defect models for bone grafts and tissue engineered bone constructs. Tissue Eng Regen Med 2013; 10: 310-6. [Crossref]

19. Bernabe PFE, Melo LGN, Cintra LTA, Gomes JE, Dezan E, Nagata MJH. Bone healing in critical-size defects treated with either bone graft, membrane, or a combination of both materials: a histological and histometric study in rat tibiae. Clin Oral Implants Res 2012; 23: 384-8. [Crossref]

20. Goldberg VM, Powell A, Shaffer JW, Zika J, Bos GD, Heiple KG. Bone grafting: role of histocompatibility in transplantation. J Orthop Res 1985; 3: 389-404. [Crossref]

21. Huo MH, Troiano NW, Pelker RR, Gundberg CM, Friedlaender GE. The influence of ibuprofen on fracture repair: Biomechanical, biochemical, histologic, and histomorphometric parameters in rats. J Orthop Res 1991; 9: 383-90. [Crossref]

22. Kılıçoğlu SS. Mikroskobi düzeyinde kırık iyileşmesi. Ankara Üniversitesi Tıp Fakültesi Mecmuası 2002; 55: 143-50. [Crossref]

23. Luginbuehl V, Meinel L, Merkle HP, Gander B. Localized delivery of growth factors for bone repair. Eur J Pharm Biopharm 2004; 58: 197-208. [Crossref]

24. Mitlak BH, Finkelman RD, Hill EL, et al. The effect of systemically administered PDGF-BB on the rodent skeleton. J Bone Miner Res 1996; 11: 238-47. [Crossref]

25. Nash TJ, Howlett CR, Martin C, Steele J, Johnson KA, Hicklin DJ. Effect of platelet-derived growth factor on tibial osteotomies in rabbits. Bone 1994; 15: 203-8. [Crossref]

26. Terzioğlu A, Aslan G, Tuncalı D, Elagöz Ş, Hasırcı V, Gürsel İ. Transforming Growth Factor β-1 Incorporating Biodegradable Polyhydroxybutyrate-co-Hydroxyvalerate Rods: Effects of Controlled Delivery System on Bone Healing. Türk Plast Rekonstr Est Cer Derg 2005; 13: 4.

27. Aghaloo TL, Moy PK, Freymiller EG. Investigation of platelet-rich plasma in rabbit cranial defects: A pilot study. J Oral Maxillofac Surg 2002; 60: 1176-81. [Crossref]

28. Kumarasuriyar A, Jackson RA, Grondahl L, Trau M, Nurcombe V, Cool SM. Poly (beta-hydroxybutyrate-co-beta-hydroxyvalerate) supports in vitro osteogenesis. Tissue Eng 2005; 11: 1281-95. [Crossref]

29. Kumarasuriyar A, Grondahl L, Nurcombe V, Cool SM. Osteoblasts up-regupregulate the expression of extracellular proteases following attachment to Poly (beta-hydroxybutyrate-co-beta-hydroxyvalerate). Gene 2009; 428: 53-8. [Crossref]