Combination of simvastatin and hydroxyapatite fiber induces bone augmentation

Shang Gao, Makoto Shiota, Masaki Fujii, Kang Chen, Masahiro Shimogishi, Masashi Sato, Shohei Kasugai

Department of Oral and Maxillofacial Surgery, Tokyo Medical and Dental University, Tokyo, Japan.
Department of Oral Implantology and Regenerative Dental Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Department of Oral Implantology and Regenerative Dental Medicine, Tokyo Medical and Dental University, Tokyo, Japan;.

DOI: 10.4236/ojrm.2013.23009                

Abstract

This study evaluated the capability of hydroxyapatite fiber (HAF) as a carrier and the bone formation by blending simvastatin. The mixture of HAF and simvastatin (0.15, 0.45, 0.75 mg) was placed in 1 ml of tris-buffer and the release of simvastatin from HAF was calculated per 24 hours for 10 days. Bilateral 5 mm-diameter and 3 mm-hight Teflon chambers were fixed on calvaria of adult Japanese white rabbits and filled with 40 mg HAF which containing simvastatin (0, 0.15, 0.45, 0.75 mg). The animals were sacrificed at 4 and 8 weeks and calculated radiologically by Micro-CT. After dyeing by toluidine blue the samples were analyzed histologically. In all of the study groups approximately 25% of simvastatin was released until 10 days. The new bone volume ratio measured by Micro-CT of 4 and 8 weeks group was (22.4%, 21.3%, 41.6%, 26.3%) and (20.2%, 11.7%, 42.1%, 31.2%) in different doses respectively. The 0.45 mg group showed significantly higher new bone volume ratio than 0 mg group and 0.15 mg group. The histological measurement and observations also supported these results. In conclusion, the HAF could be used as a carrier for simvastatin. Combinations of HAF and simvastatin have the potentiality to stimulate new bone formation and approximately 0.45 mg simvastatin in 40 mg HAF is the optimal dose in rabbit chamber model.

Keywords

Biomaterial; Bone Substitutes; Bone Formation; Drug Delivery; Growth Factors

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Hermann, J.S. and Buser, D. (1996) Guided bone regeneration for dental implants. Current Opinion in Periodontology, 3, 168-77.
[2]	Becker, W. and Becker, B.E. (1990) Guided tissue regeneration for implants placed into extraction sockets and for implant dehiscences: Surgical techniques and case report. The International Journal of Periodontics and Restorative Dentistry, 10, 376-91.
[3]	Porter, J.R., Ruckh, T.T. and Popat, K.C. (2009) Bone tissue engineering: A review in bone biomimetics and drug delivery strategies. Biotechnology Progress, 25, 1539-1560.
[4]	Rogers, G.F. and Greene, A.K. (2012) Autogenous bone graft: Basic science and clinical implications. Journal of Craniofacial Surgery, 23, 323-327. doi:10.1097/SCS.0b013e318241dcba
[5]	Bucholz, R.W., Carlton, A. and Holmes, R. (1989), Interporous hydroxyapatite as a bone graft substitute in tibial plateau fractures. Clinical Orthopaedics and Related Research, 240, 53-62.
[6]	LeGeros, R.Z. (2002) Properties of osteoconductive biomaterials: Calcium phosphates. Clinical Orthopaedics and Related Research, 395, 81-98. doi:10.1097/00003086-200202000-00009
[7]	Kunert-Keil, C., et al. (2009) Morphological evaluation of bone defect regeneration after treatment with two different forms of bone substitution materials on the basis of BONITmatrix. Canadian Journal of Physiology and Pharmacology, 60, 57-60.
[8]	Grageda, E. (2004) Platelet-rich plasma and bone graft materials: A review and a standardized research protocol. Implant Dentistry, 13, 301-309.
[9]	Faratzis, G., et al. (2012) Effect of autologous platelet-rich plasma in combination with a biphasic synthetic graft material on bone healing in critical-size cranial defects. Journal of Craniofacial Surgery, 23, 1318-1323. doi:10.1097/SCS.0b013e31825c76e5
[10]	Dimitrievska, S., et al. (2008) Biocompatibility of novel polymer-apatite nanocomposite fibers. Journal of Biomedical Materials Research Part A, 84, 44-53. doi:10.1002/jbm.a.31338
[11]	Stanishevsky, A., et al. (2008) Hydroxyapatite nanoparticle loaded collagen fiber composites: Microarchitecture and nanoindentation study. Journal of Biomedical Materials Research Part A, 86, 873-882. doi:10.1002/jbm.a.31657
[12]	Kimura, J., et al. (2012) Effect of hydroxyapatite fiber material with autogenous bone graft on vertical bone augmentation. Journal of Oral Tissue Engineering, 9, 136-146.
[13]	Machida, T., et al. (2010) Effect of hydroxyapatite fiber material on rat incisor socket healing. Journal of Oral Tissue Engineering, 7, 153-162.
[14]	Oda, M., et al. (2009) Hydroxyapatite fiber material with BMP-2 gene induces ectopic bone formation. Journal of Biomedical Materials Research Part B, 90, 101-109.
[15]	Hollinger, J.O., et al. (2008) Recombinant human platelet-derived growth factor: Biology and clinical applications. The Journal of Bone & Joint Surgery, 90, 48-54. doi:10.2106/JBJS.G.01231
[16]	Bernstein, A., Mayr, H.O. and Hube, R. (2010) Can bone healing in distraction osteogenesis be accelerated by local application of IGF-1 and TGF-beta1? Journal of Biomedical Materials Research Part B, 92, 215-225. doi:10.1002/jbm.b.31508
[17]	Shimizu, E., et al. (2006) Fibroblast growth factor 2 and cyclic AMP synergistically regulate bone sialoprotein gene expression. Bone, 39, 42-52. doi:10.1016/j.bone.2005.12.011
[18]	Visser, R., et al. (2009) The effect of an rhBMP-2 absorbable collagen sponge-targeted system on bone formation in vivo. Biomaterials, 30, 2032-2037. doi:10.1016/j.bone.2005.12.011
[19]	Hunninghake, D., et al. (1998) Treating to meet NCEP-recommended LDL cholesterol concentrations with atorvastatin, fluvastatin, lovastatin, or simvastatin in patients with risk factors for coronary heart disease. The Journal of Family Practice, 47, 349-356.
[20]	Mundy, G., et al. (1999) Stimulation of bone formation in vitro and in rodents by statins. Science, 286, 1946-1949. doi:10.1126/science.286.5446.1946
[21]	Garrett, I.R., Gutierrez, G., and Mundy, G.R. (2001) Statins and bone formation. Current Pharmaceutical Design, 7, 715-736. doi:10.2174/1381612013397762.
[22]	Nyan, M., et al. (2007) Bone formation with the combination of simvastatin and calcium sulfate in critical-sized rat calvarial defect. Journal of Pharmacological Sciences, 104, 384-386. doi:10.1254/jphs.SC0070184
[23]	Stein, D., et al. (2005) Local simvastatin effects on mandibular bone growth and inflammation. Journal of Periodontology, 76, 1861-1870. doi:10.1902/jop.2005.76.11.1861
[24]	Ohnaka, K., et al. (2001) Pitavastatin enhanced BMP-2 and osteocalcin expression by inhibition of Rho-associated kinase in human osteoblasts. Biochemical and Biophysical Research Communications, 287, 337-342. doi:10.1006/bbrc.2001.5597.
[25]	Maeda, T., Kawane T. and Horiuchi, N. (2003) Statins augment vascular endothelial growth factor expression in osteoblastic cells via inhibition of protein prenylation. Endocrinology, 144, 681-692. doi:10.1210/en.2002-220682
[26]	Junqueira, J.C., et al. (2002) Effects of simvastatin on bone regeneration in the mandibles of ovariectomized rats and on blood cholesterol levels. Oral Science International, 44, 117-124. doi:10.2334/josnusd.44.117
[27]	Pytlik, M., et al. (2003) Effects of simvastatin on the development of osteopenia caused by ovariectomy in rats. Polish Journal of Pharmacology, 55, 63-71.
[28]	Morris, M.S., et al. (2008) Injectable simvastatin in periodontal defects and alveolar ridges: Pilot studies. Journal of Periodontology, 79, 1465-1473. doi:10.1902/jop.2008.070659
[29]	Todd, P.A. and Goa, K.L. (1990) Simvastatin. A review of its pharmacological properties and therapeutic potential in hypercholesterolaemia. Drugs, 40, 583-607. doi:10.2165/00003495-199040040-00007
[30]	Tikiz, C., et al. (2005) Effects of simvastatin on bone mineral density and remodeling parameters in postmenopausal osteopenic subjects: 1-year follow-up study. Clinical Rheumatology, 24, 447-52. doi:10.1007/s10067-004-1053-x
[31]	Skoglund, B. and Aspenberg, P. (2007) Locally applied Simvastatin improves fracture healing in mice. BMC Musculoskeletal Disorders, 8, 98. doi:10.1186/1471-2474-8-98
[32]	Pradeep, A.R. and Thorat, M.S. (2010) Clinical effect of subgingivally delivered simvastatin in the treatment of patients with chronic periodontitis: A randomized clinical trial. Journal of Periodontology, 81, 214-222. doi:10.1902/jop.2009.090429
[33]	Tanigo, T., Takaoka R. and Tabata, Y. (2010) Sustained release of water-insoluble simvastatin from biodegradable hydrogel augments bone regeneration. Journal of Controlled Release, 143, 201-206. doi:10.1016/j.jconrel.2009.12.027
[34]	Nyan, M., et al. (2010) Molecular and tissue responses in the healing of rat calvarial defects after local application of simvastatin combined with alpha tricalcium phosphate. Journal of Biomedical Materials Research Part B: Applied Biomaterials, 93, 65-73.
[35]	Monjo, M., et al. (2010) In vivo performance of absorbable collagen sponges with rosuvastatin in criticalsize cortical bone defects. Acta Biomaterialia, 6, 1405-1412. doi:10.1016/j.actbio.2009.09.027
[36]	Wadagaki, R., et al. (2011) Osteogenic induction of bone marrow-derived stromal cells on simvastatin-releasing, biodegradable, nanoto microscale fiber scaffolds. Annals of Biomedical Engineering, 39, 1872-1881. doi:10.1007/s10439-011-0327-0
[37]	Nyan, M., et al. (2009) Effects of the combination with alpha-tricalcium phosphate and simvastatin on bone regeneration. Clinical Oral Implants Research, 20, 280-287. doi:10.1111/j.1600-0501.2008.01639.x
[38]	Sakai, K., et al. (2011) Effects on bone regeneration when collagen model polypeptides are combined with various sizes of alpha-tricalcium phosphate particles. Dental Materials, 2011. doi:10.4012/dmj.2011-126
[39]	Batista, M.A., et al. (2011) Comparison between the effects of platelet-rich plasma and bone marrow concentrate on defect consolidation in the rabbit tibia. Clinics (Sao Paulo), 66, 1787-92.
[40]	Hong, H.H., et al. (2012) The potential effects of cholecalciferol on bone regeneration in dogs. Clinical Oral Implants Research, 23, 1187-1192. doi:10.1111/j.1600-0501.2011.02284.x
[41]	Schmitz, J.P. and Hollinger, J.O. (1986) The critical size defect as an experimental model for craniomandibulofacial nonunions. Clinical Orthopaedics and Related Research, 205, 299-308.
[42]	Lee, Y., et al. (2008) The effect of local simvastatin delivery strategies on mandibular bone formation in vivo. Biomaterials, 29, 1940-1949. doi:10.1016/j.biomaterials.2007.12.045