Local Delivery of Controlled-release Simvastatin/PLGA/HAp Microspheres Enhances Bone Repair

Overview

Journal Int J Nanomedicine

Publisher Dove Medical Press

Specialty Biotechnology

Date 2013 Oct 22

PMID 24143094

Citations 31

Authors

I-Chun Tai

Yin-Chih Fu

Chih-Kuang Wang

Je-Ken Chang

Mei-Ling Ho

Affiliations

Soon will be listed here.

Abstract

Statins are used clinically for reduction of cholesterol synthesis to prevent cardiovascular disease. Previous in vitro and in vivo studies have shown that statins stimulate bone formation. However, orally administered statins may be degraded during first-pass metabolism in the liver. This study aimed to prevent this degradation by developing a locally administered formulation of simvastatin that is encapsulated in poly(lactic-co-glycolic acid)/hydroxyapatite (SIM/PLGA/HAp) microspheres with controlled-release properties. The effect of this formulation of simvastatin on bone repair was tested using a mouse model of gap fracture bridging with a graft of necrotic bone. The simvastatin released over 12 days from 3 mg and 5 mg of SIM/PLGA/HAp was 0.03-1.6 μg/day and 0.05-2.6 μg/day, respectively. SIM/PLGA/HAp significantly stimulated callus formation around the repaired area and increased neovascularization and cell ingrowth in the grafted necrotic bone at week 2 after surgery. At week 4, both 3 mg and 5 mg of SIM/PLGA/HAp increased neovascularization, but only 5 mg SIM/PLGA/HAp enhanced cell ingrowth into the necrotic bone. The low dose of simvastatin released from SIM/PLGA/HAp enhanced initial callus formation, neovascularization, and cell ingrowth in the grafted bone, indicating that SIM/PLGA/HAp facilitates bone regeneration. We suggest that SIM/PLGA/HAp should be developed as an osteoinductive agent to treat osteonecrosis or in combination with an osteoconductive scaffold to treat severe bone defects.

Citing Articles

Prospective and challenges of locally applied repurposed pharmaceuticals for periodontal tissue regeneration.

El-Nablaway M, Rashed F, Taher E, Abdeen A, Taymour N, Soliman M Front Bioeng Biotechnol. 2024; 12:1400472.

PMID: 39605747 PMC: 11600316. DOI: 10.3389/fbioe.2024.1400472.

Recent progress in the manipulation of biochemical and biophysical cues for engineering functional tissues.

Bakhshandeh B, Ranjbar N, Abbasi A, Amiri E, Abedi A, Mehrabi M Bioeng Transl Med. 2023; 8(2):e10383.

PMID: 36925674 PMC: 10013802. DOI: 10.1002/btm2.10383.

Bone-Targeting Nanoparticles of a Dendritic (Aspartic acid)-Functionalized PEG-PLGA Biopolymer Encapsulating Simvastatin for the Treatment of Osteoporosis in Rat Models.

Lin C, Lee C, Lin S, Kang L, Fu Y, Chen C Int J Mol Sci. 2022; 23(18).

PMID: 36142447 PMC: 9503052. DOI: 10.3390/ijms231810530.

Anabolic Effects of a Novel Simvastatin Derivative on Treating Rat Bone Defects.

Lee T, Chen H, Tai I, Kao L, Hung M, Chen C Biomedicines. 2022; 10(8).

PMID: 36009462 PMC: 9405916. DOI: 10.3390/biomedicines10081915.

Tri-Layered Doxycycline-, Collagen- and Bupivacaine-Loaded Poly(lactic--glycolic acid) Nanofibrous Scaffolds for Tendon Rupture Repair.

Yu Y, Shen S, Hsu Y, Chou Y, Yu P, Liu S Polymers (Basel). 2022; 14(13).

PMID: 35808704 PMC: 9269609. DOI: 10.3390/polym14132659.

References

Montagnani A, Gonnelli S, Cepollaro C, Pacini S, Campagna M, Franci M . Effect of simvastatin treatment on bone mineral density and bone turnover in hypercholesterolemic postmenopausal women: a 1-year longitudinal study. Bone. 2003; 32(4):427-33. DOI: 10.1016/s8756-3282(03)00034-6. View

Skoglund B, Forslund C, Aspenberg P . Simvastatin improves fracture healing in mice. J Bone Miner Res. 2002; 17(11):2004-8. DOI: 10.1359/jbmr.2002.17.11.2004. View

Pasco J, Kotowicz M, Henry M, Sanders K, Nicholson G . Statin use, bone mineral density, and fracture risk: Geelong Osteoporosis Study. Arch Intern Med. 2002; 162(5):537-40. DOI: 10.1001/archinte.162.5.537. View

Song C, Guo Z, Ma Q, Chen Z, Liu Z, Jia H . Simvastatin induces osteoblastic differentiation and inhibits adipocytic differentiation in mouse bone marrow stromal cells. Biochem Biophys Res Commun. 2003; 308(3):458-62. DOI: 10.1016/s0006-291x(03)01408-6. View

Maritz F, Conradie M, Hulley P, Gopal R, Hough S . Effect of statins on bone mineral density and bone histomorphometry in rodents. Arterioscler Thromb Vasc Biol. 2001; 21(10):1636-41. DOI: 10.1161/hq1001.097781. View

Heckman J . The economics of treating tibia fractures. The cost of delayed unions. Bull Hosp Jt Dis. 1997; 56(1):63-72. View

Jacobson R, Wang P, Glueck C . Myositis and rhabdomyolysis associated with concurrent use of simvastatin and nefazodone. JAMA. 1997; 277(4):296-7. DOI: 10.1001/jama.277.4.296. View

Kandziora F, Bail H, Schmidmaier G, Schollmeier G, Scholz M, Knispel C . Bone morphogenetic protein-2 application by a poly(D,L-lactide)-coated interbody cage: in vivo results of a new carrier for growth factors. J Neurosurg. 2002; 97(1 Suppl):40-8. DOI: 10.3171/spi.2002.97.1.0040. View

Thylin M, McConnell J, Schmid M, Reckling R, Ojha J, Bhattacharyya I . Effects of simvastatin gels on murine calvarial bone. J Periodontol. 2002; 73(10):1141-8. DOI: 10.1902/jop.2002.73.10.1141. View

10.

Wang C, Ho M, Wang G, Chang J, Chen C, Fu Y . Controlled-release of rhBMP-2 carriers in the regeneration of osteonecrotic bone. Biomaterials. 2009; 30(25):4178-86. DOI: 10.1016/j.biomaterials.2009.04.029. View

11.

Ho M, Fu Y, Wang G, Chen H, Chang J, Tsai T . Controlled release carrier of BSA made by W/O/W emulsion method containing PLGA and hydroxyapatite. J Control Release. 2008; 128(2):142-8. DOI: 10.1016/j.jconrel.2008.02.012. View

12.

van Staa T, Wegman S, de Vries F, Leufkens B, Cooper C . Use of statins and risk of fractures. JAMA. 2001; 285(14):1850-5. DOI: 10.1001/jama.285.14.1850. View

13.

Hwang R, Lee E, Kim M, Li S, Jin Y, Rhee Y . Calcyclin, a Ca2+ ion-binding protein, contributes to the anabolic effects of simvastatin on bone. J Biol Chem. 2004; 279(20):21239-47. DOI: 10.1074/jbc.M312771200. View

14.

Tikiz C, Tikiz H, Taneli F, Gumuser G, Tuzun C . Effects of simvastatin on bone mineral density and remodeling parameters in postmenopausal osteopenic subjects: 1-year follow-up study. Clin Rheumatol. 2005; 24(5):447-52. DOI: 10.1007/s10067-004-1053-x. View

15.

Schachter M . Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol. 2005; 19(1):117-25. DOI: 10.1111/j.1472-8206.2004.00299.x. View

16.

Skoglund B, Aspenberg P . Locally applied Simvastatin improves fracture healing in mice. BMC Musculoskelet Disord. 2007; 8:98. PMC: 2200653. DOI: 10.1186/1471-2474-8-98. View

17.

Wang J, Xu S, Yang D, Lv R . Locally applied simvastatin promotes fracture healing in ovariectomized rat. Osteoporos Int. 2007; 18(12):1641-50. DOI: 10.1007/s00198-007-0412-2. View

18.

Bax B, Wozney J, Ashhurst D . Bone morphogenetic protein-2 increases the rate of callus formation after fracture of the rabbit tibia. Calcif Tissue Int. 1999; 65(1):83-9. DOI: 10.1007/s002239900662. View

19.

Garrison K, Donell S, Ryder J, Shemilt I, Mugford M, Harvey I . Clinical effectiveness and cost-effectiveness of bone morphogenetic proteins in the non-healing of fractures and spinal fusion: a systematic review. Health Technol Assess. 2007; 11(30):1-150, iii-iv. DOI: 10.3310/hta11300. View

20.

Fuentes I, Aguilera C . [Myopathy secondary to the treatment with inhibitors of HMG-CoA reductase]. Med Clin (Barc). 1999; 111(18):700. View