Development of Controllable Simvastatin-Releasing PLGA/β-TCP Composite Microspheres Sintered Scaffolds as Synthetic Bone Substitutes

Abstract:

The bone remodeling process plays an essential part of the calcium homeostatic system and provides a crucial mechanism for adaptation to physical stress, the repair of damaged bone and the removal of old bone. We reported previously that sustainable release of simvastatin (SIM) from poly (lactic-co-glycolic acid) (PLGA) formulations could induce bone formation. The aim of this study was to develop a simvastatin-releasing PLGA/β-TCP composite microspheres (β-SPMs) sintered scaffolds (β-SPMSS) as a synthetic bone substitute, and investigate the influence of the dissolution medium on the drug release capabilities of these device based on a physicochemical model for bone remodeling. X-ray diffraction analysis (XRD) results showed β-TCP and SIM could be encapsulated into the PLGA microspheres. The β-SPMs and the β-SPMSS were able to produce sustained release of SIM for 1 month in simulated body fluid (SBF), whereas these composites released SIM for 10 days in acetate buffer (AB). The release rate of SIM from β-SPMSS in AB was faster than in SBF, indicating that the β-SPMSS could control drug release with bone cells activity response, and could be used as a scaffold in bone remodeling area. These results suggested that the β-SPMSS could release SIM sustainably, with bone cells activity response, and could be used as a scaffold in bone remodeling area.

• Periodical: Key Engineering Materials (Volume 758)
• Pages: 126-131
• DOI: https://doi.org/10.4028/www.scientific.net/KEM.758.126
• Online since: November 2017
• Authors: Takayuki Terukina*, Takanori Numaguchi, Yusuke Hattori, Makoto Otsuka
• Keywords: Bone Substitute, Drug Delivery System, PLGA, Simvastatin, β-Tricalcium Phosphate

References

[1] SIMS, Natalie A.; MARTIN, T. John. Coupling the activities of bone formation and resorption: a multitude of signals within the basic multicellular unit. BoneKEy reports, 2014, 3.

DOI: 10.1038/bonekey.2013.215

[2] ROSS, J. A., et al. The macrophage. UK. (2nd) The biology of the macrophage. Oxford University Press, New York, 2002, 3-24.

[3] Everts, V., et al. The bone lining cell: its role in cleaning Howship's lacunae and initiating bone formation. Journal of Bone and Mineral Research, 2002, 17. 1: 77-90.

DOI: 10.1359/jbmr.2002.17.1.77

[4] Mundy, G., et al. Stimulation of bone formation in vitro and in rodents by statins., Science 286. 5446 (1999): 1946-(1949).

DOI: 10.1126/science.286.5446.1946

[5] Terukina, T, et al. The effect of the release behavior of simvastatin from different PLGA particles on bone regeneration in vitro and in vivo: Comparison of simvastatin-loaded PLGA microspheres and nanospheres., Journal of Drug Delivery Science and Technology 33 (2016).

DOI: 10.1016/j.jddst.2016.03.005

[6] Terukina, T, et al. Development and effect of a sustainable and controllable simvastatin-releasing device based on PLGA microspheres/carbonate apatite cement composite: In vitro evaluation for use as a drug delivery system from bone-like biomaterial., Journal of Drug Delivery Science and Technology 37 (2017).

DOI: 10.1016/j.jddst.2016.10.007

[7] Xia, Zhidao, et al. Macrophage‐mediated biodegradation of poly (DL‐lactide‐co‐glycolide) in vitro., Journal of Biomedical Materials Research Part A 79. 3 (2006): 582-590.

DOI: 10.1002/jbm.a.30853

[8] Anderson, James M., and Matthew S. Shive. Biodegradation and biocompatibility of PLA and PLGA microspheres., Advanced drug delivery reviews 64 (2012): 72-82.

DOI: 10.1016/j.addr.2012.09.004

[9] Liu, Huinan, Elliott B. Slamovich, and Thomas J. Webster. Less harmful acidic degradation of poly (lactic-co-glycolic acid) bone tissue engineering scaffolds through titania nanoparticle addition., International journal of nanomedicine 1. 4 (2006).

DOI: 10.2147/nano.2006.1.4.541

[10] Otsuka, M, and Hirano R. Bone cell activity responsive drug release from biodegradable apatite/collagen nano-composite cements—In vitro dissolution medium responsive vitamin K2 release., Colloids and Surfaces B: Biointerfaces 85. 2 (2011).

DOI: 10.1016/j.colsurfb.2011.03.006

[11] Otsuka, M, et al. Dissolution Medium Responsive Simvastatin Release from Biodegradable Apatite Cements Drug Delivery System-The Therapeutically Effect and their Histology in Osteoporosis Rats., Key Engineering Materials. Vol. 493. Trans Tech Publications, (2012).

DOI: 10.4028/www.scientific.net/kem.493-494.684

[12] Borden, Mark, et al. Tissue engineered microsphere-based matrices for bone repair: design and evaluation., Biomaterials 23. 2 (2002): 551-559.

DOI: 10.1016/s0142-9612(01)00137-5

[13] Borden, Mark, Mohamed Attawia, and Cato T. Laurencin. The sintered microsphere matrix for bone tissue engineering: in vitro osteoconductivity studies., Journal of biomedical materials research 61. 3 (2002): 421-429.

DOI: 10.1002/jbm.10201