Comparison the effects of chitosan and hyaluronic acid-based thermally sensitive hydrogels containing rosuvastatin on human osteoblast-like MG-63 cells

Vajihe Akbari , Mahboubeh Rezazadeh , Zahra Ebrahimi

Abstract


Background and purpose: Bone regeneration can be accelerated by localized delivery of statins.                        Here, we aimed to evaluate the effect of two thermosensitive hydrogels containing rosuvastatin (RSV) on proliferation and differentiation of human osteoblast-like MG-63 cells.

Experimental approach: Firstly, chitosan (CTS)/glycerophosphate (GP)/gelatin (G) thermosensitive hydrogel was prepared and characterized based on rheological properties, in vitro erosion, and release pattern of RSV and then the optimized mixture was loaded with nanoparticles containing RSV(NRSV).                   Secondly, the effect of NRSV-embedded in CTS/GP/G on cell viability, alkaline phosphate activity,                       and cell calcification was evaluated using MG-63 cells and compared with RSV-embedded into hyaluronic acid (HA)/Pluronic® F127 (PF127) hydrogel. 

Findings / Results: CTS/GP mixtures with 1 and 1.5 % gelatin existing in solution with low viscosity at              4 °C were solidified at 32-34 °C while the mixture containing 2% gelatin was jellified at room temperature. The gelation times of CTS/GP/G with 1 and 1.5% gelatin were 72 and 44 s, respectively. The hydrogel containing 3% w/v NRSV was also converted to a semisolid upon increasing the temperature to 33-36 °C. Due to the higher gel strength of CTS/GP/G compared to HA/PF127 hydrogel, the release rate of RSV from the NRSV-embedded CTS/GP/G hydrogel was significantly slower than that of HA/PF127 system.                      As revealed by alkaline phosphatase and mineralization assays, NRSV-embedded in CTS/GP/G hydrogel had the most promotive effect on differentiation of osteoblasts among other mixtures.

Conclusion and implication: NRSV-embedded in CTS/GP/G hydrogel could be efficiently used in                       the future for bone defects such as osteoporosis and bone fractures.


Keywords


Rosuvastatin; Thermosensitive hydrogel; Tissue engineering.

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References


Gittens SA, Uludag H. Growth factor delivery for bone tissue engineering. J Drug Target. 2001;9(6):407-429.

Bessa PC, Casal M, Reis RL. Bone morphogenetic proteins in tissue engineering: the road from laboratory to clinic, part II (BMP delivery). J Tissue Eng Regen Med. 2008;2(2-3):81-96.

Shields LB, Raque GH, Glassman SD, Campbell M, Vitaz T, Harpring J, et al. Adverse effects associated with high-dose recombinant human bone morphogenetic protein-2 use in anterior cervical spine fusion. Spine (Phila Pa 1976). 2006;31(5):542-547.

Park YS, David AE, Park KM, Lin CY, Than KD, Lee K, et al. Controlled release of simvastatin from in situ forming hydrogel triggers bone formation in MC3T3-E1 cells. AAPS J. 2013;15(2):367-376.

Yue J, Zhang X, Dong B, Yang M. Statins and bone health in post-menopausal women: a systematic review of randomized controlled trials. Menopause. 2010;17(5):1071-1079.

Toh S, Hernández-Díaz S. Statins and fracture risk. A systematic review. Pharmacoepidemiol Drug Saf. 2007;16(6):627-640.

Maeda T, Matsunuma A, Kawane T, Horiuchi N. Simvastatin promotes osteoblast differentiation and mineralization in MC3T3-E1 cells. Biochem Biophys Res Commun. 2001;280(3):874-877.

Ayukawa Y, Yasukawa E, Moriyama Y, Ogino Y, Wada H, Atsuta I, et al. Local application of statin promotes bone repair through the suppression of osteoclasts and the enhancement of osteoblasts at bone-healing sites in rats. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;107(3):336-342.

Nyan M, Sato D, Oda M, Machida T, Kobayashi H, Nakamura T, et al. Bone formation with the combination of simvastatin and calcium sulfate in critical-sized rat calvarial defect. J Pharmacol Sci. 2007;104(4):384-386.

Moriyama Y, Ayukawa Y, Ogina Y, Atsuta I, Koyano K. Topical application of statin affects bone healing around implants. Clin Oral Implants Res. 2008;19(6):600-605.

Lee Y, Chung HJ, Yeo S, Ahn CH, Lee H, Messersmith PB, et al. Thermosensitive injectable and tissue adhesive sol-gel transition hyaluronic acid/pluronic composite hydrogel prepared from bio-inspired catechol-thiol reaction. Soft Matter. 2010;6(5):977-983.

Yoshii T, Hafeman AE, Esparza JM, Okawa A, Gutierrez G, Guelcher SA. Local injection of lovastatin in biodegradable polyurethane scaffolds enhances bone regeneration in a critical-sized segmental defect in rat femora. J Tissue Eng Regen Med. 2014;8(8):589-595.

Dolkart O, Pritsch T, Sharfman Z, Somjen D, Salai M, Maman E, et al. The effects of lipophilic and hydrophilic statins on bone tissue mineralization in saos2 human bone cell line-in vitro comparative study. Pharm Anal Acta. 2015;6(5):1-4.

Ertugrul DT, Yavuz B, Cil H, Ata N, Akin KO, Kucukazman M. STATIN-D study: comparison of the influences of rosuvastatin and fluvastatin treatment on the levels of 25-hydroxyvitamin D. Cardiovasc Ther. 2011;29(2):146-152.

Lee Y, Schmid MJ, Marx DB, Beatty MW, Cullen DM, Collins ME, et al. The effect of local simvastatin delivery strategies on mandibular bone formation in vivo. Biomaterials. 2008;29(12):1940-1949.

Monjo M, Rubert M, Ellingsen JE, Lyngstadaas SP. Rosuvastatin promotes osteoblast differentiation and regulates SLCO1A1 transporter gene expression in MC3T3-E1 cells. Cell Physiol Biochem. 2010;26(4-5):647-656.

Ibrahim HK, Fahmy RH. Localized rosuvastatin via implantable bioerodible sponge and its potential role in augmenting bone healing and regeneration. Drug Deliv. 2016;23(9):3181-3192.

Dong C, Yu B, Hu ZB, Zhou ZL, Yang H, Jin AM. Rosuvastatin implant for local bone specific drug delivery in osteoporotic bone fracture. J Biomater Tissue Eng. 2015;5(7):565-569.

Porter JR, Ruckh TT, Popat KC. Bone tissue engineering: a review in bone biomimetics and drug delivery strategies. Biotechnol Prog. 2009;25(6):1539-1560.

Rezazadeh M, Parande M, Akbari V, Ebrahimi Z, Taheri A. Incorporation of rosuvastatin-loaded chitosan/chondroitin sulfate nanoparticles into a thermosensitive hydrogel for bone tissue engineering: preparation, characterization, and cellular behavior. Pharm Dev Technol. 2019;24(3):357-367.

Cheng YH, Yang SH, Su WY, Chen YC, Yang KC, Cheng WT, et al. Thermosensitive chitosan-gelatin-glycerol phosphate hydrogels as a cell carrier for nucleus pulposus regeneration: an in vitro study. Tissue Eng Part A. 2010;16(2): 695-703.

Rezazadeh M, Akbari V, Amuaghae E, Emami J. Preparation and characterization of an injectable thermosensitive hydrogel for simultaneous delivery of paclitaxel and doxorubicin. Res Pharm Sci. 2018;13(3):181-191.

Martin PD, Warwick MJ, Dane AL, Brindley C, Short T. Absolute oral bioavailability of rosuvastatin in healthy white adult male volunteers. Clin Ther. 2003;25(10):2553-2563.

Croisier F, Jérôme C. Chitosan-based biomaterials for tissue engineering. Eur Polym J. 2013;49:780-792.

Yu P, Bao RY, Shi XJ, Yang W, Yang MB. Self-assembled high-strength hydroxyapatite/graphene oxide/chitosan composite hydrogel for bone tissue engineering. Carbohydr Polym. 2017;155:507-515.

Perez RA, Del Valle S, Altankov G, Ginebra MP. Porous hydroxyapatite and gelatin/hydroxyapatite microspheres obtained by calcium phosphate cement emulsion. J Biomed Mater Res B Appl Biomater. 2011;97(1):156-166.

Kogan G, Šoltés L, Stern R, Gemeiner P. Hyaluronic acid: a natural biopolymer with a broad range of biomedical and industrial applications. Biotechnol Lett. 2007;29:17-25.

Park YD, Tirelli N, Hubbell JA. Photopolymerized hyaluronic acid-based hydrogels and interpenetrating networks. Biomaterials. 2003;24(6):893-900.

Büttner M, Möller S, Keller M, Huster D, Schiller J, Schnabelrauch M, et al. Over-sulfated chondroitin sulfate derivatives induce osteogenic differentiation of hMSC independent of BMP-2 and TGF-β1 signalling. J Cell Physiol. 2013;228(2):330-340.


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