Injectable simvastatin gel for minimally invasive periosteal distraction: In vitro and in vivo studies in rat.

Hao, Jia; Chou, Joshua; Kuroda, Shinji; Otsuka, Makoto; Kasugai, Shohei; Lang, Niklaus Peter (2018). Injectable simvastatin gel for minimally invasive periosteal distraction: In vitro and in vivo studies in rat. Clinical oral implants research, 29(2), pp. 227-234. Wiley-Blackwell 10.1111/clr.13105

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To evaluate whether the subperiosteal injection of simvastatin (SIM) with a novel in situ gel-forming system, SrHA/Alg (strontium hydroxyapatite/alginate), can stimulate vertical bone augmentation in a rat calvarial model.


The SrHA/Alg solution was synthesized and combined with different doses of SIM (0.01, 0.02, 0.1, and 0.2 mg) to form the following groups: (1) SrHA/Alg only, (2) SrHA/Alg/0.01, (3) SrHA/Alg/0.02, (4) SrHA/Alg/0.1, and (5) SrHA/Alg/0.2. The SIM release pattern was analyzed, and rat primary periosteum-derived cell (PDC) responses were investigated. Twenty male Wistar rats were enrolled in the calvarial subperiosteal injection experiment with each animal receiving a 200-μl single subperiosteal injection of SrHA/Alg with different amounts of SIM (0, 0.01, 0.02, and 0.1 mg) incorporated (n = 5). The 0.2 mg dose group was not tested in vivo due to the severe toxicity found in vitro. The new bone formation was assessed histologically and radiologically at 8 weeks.


The slow release of SIM was confirmed, and PDC viability decreased in the SrHA/Alg/0.2 group. Alkaline phosphatase positive areas and mineralization areas were significantly greater in the SrHA/Alg/0.01 and SrHA/Alg/0.02 groups (p < .05). The mRNA expression level of Runx2 significantly increased in the SrHA/Alg/SIM-0.02 group by day 7 (p < .05) and significantly higher levels of VEGF were found in the SrHA/Alg/0.01 and SrHA/Alg/0.02 groups at different time points (p < .05). In vivo, no prominent clinical sign of inflammation was observed, and the most significant bone gain was shown in the SrHA/Alg/0.02 group (p < .05). The osteoclast formation within the newly formed bone area was reduced in the SrHA/Alg/0.1 group (p < .05).


When combined with SrHA/Alg system, the 0.02 mg SIM seemed to be the optimal dose to stimulate subperiosteal bone formation without inducing inflammation. This combination may hold potential therapeutic benefits for clinical bone augmentation in a minimally invasive manner.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > School of Dental Medicine > Department of Periodontology
04 Faculty of Medicine > School of Dental Medicine > School of Dental Medicine, Periodontics Research

UniBE Contributor:

Lang, Niklaus Peter


600 Technology
600 Technology > 610 Medicine & health








Doris Burri

Date Deposited:

03 Jul 2019 11:01

Last Modified:

27 Oct 2019 01:11

Publisher DOI:


PubMed ID:


Uncontrolled Keywords:

bone augmentation periosteal distraction simvastatin strontium




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