Evaluation of synergistic osteogenesis between icariin and BMP2 through a micro/meso hierarchical porous delivery system

International Journal of Nanomedicine Dovepress open access to scientific and medical research O r i g in a l R e s e a r c h International Journal of Nanomedicine downloaded from https://www.dovepress.com/ by 51.38.247.138 on 12-Jul-2018 For personal use only. Open Access Full Text Article Evaluation of synergistic osteogenesis between icariin and BMP2 through a micro/meso hierarchical porous delivery system This article was published in the following Dove Press journal: International Journal of Nanomedicine 19 October 2017 Number of times this article has been viewed Qian Wang 1–4 Lingyan Cao 4,5 Yang Liu 6 Ao Zheng 4,5 Jiannan Wu 4,5 Xinquan Jiang 4,5 Ping Ji 1–3 Department of Oral and Maxillofacial Surgery, Stomatological Hospital of Chongqing Medical University, 2 Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, 3 Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, 4Oral Bioengineering and Regenerative Medicine Lab, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center of Stomatology, 5Department of Prosthodontics, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, 6The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, People’s Republic of China 1 Abstract: BMP2 is well known as an outstanding growth factor for inducing new bone formation. However, improvements are still required to use BMP2 effectively and expand its clinical application due to the potential side effects at high doses. In this study, icariin (IC), a type of traditional Chinese medicine, was originally proposed to be a cooperative factor for BMP2. An alkaline phosphatase (ALP) activity assay showed that IC promoted BMP2 osteogenesis in a concentration-dependent manner with significant enhancement at 38.4 µM versus that for BMP2 at 0.8 µg/mL. Furthermore, we developed a composite hierarchical porous scaffold (SF/SBA15; composed of micropores of silk fibroin [SF] scaffold and mesopores of SBA15) for the controlled delivery of BMP2 and IC. This composite scaffold was investigated by a series of physical characterizations and displayed good in vitro cell biocompatibility. In addition, the composite scaffold also showed the degradation rate of 12% dry weight loss and a slight change in the microstructures within 10 days. Moreover, BMP2 and IC were loaded into the SF and SBA15 structures, respectively, of the SF/SBA15 scaffold. This protein/drug loading system (SFBMP2/SBA15IC) provided delivery of BMP2 with an initial burst release of 60.9%±0.9% in the first 24 hours and a gradual release over the subsequent 6 days to 97.9%±0.8%, whereas IC exhibited a burst release of 64.2%±0.7% in the first 24 hours, followed by a sustained release to 92.4%±0.8% over 10 days. With the prolonged local retention and interaction duration of BMP2 and IC, the SFBMP2/SBA15IC scaffold provided better osteogenic differentiation than other groups with different loading modes of BMP2 or IC, as determined by ALP staining and quantitation and Alizarin red staining. Finally, the results of quantitative real-time polymerase chain reaction analysis indicated that the SFBMP2/SBA15IC scaffold induced a significantly higher increase in the RUNX2, ALP, COL I, and OCN expression levels of cocultured bone marrow mesenchymal stem cells than other payload composite scaffolds. This study suggests that a micro/meso hierarchical porous delivery system of BMP2 and IC ensures osteogenic synergy and demonstrates promise for bone tissue engineering. Keywords: synergistic delivery, hierarchical structure, controlled release, porous scaffold, mesopore, growth factor Introduction Correspondence: Xinquan Jiang; Ping Ji Department of Oral and Maxillofacial Surgery, Stomatological Hospital of Chongqing Medical University, 426 Jinlong Road, Chongqing 402160, People’s Republic of China Email ; 7721 submit your manuscript | www.dovepress.com International Journal of Nanomedicine 2017:12 7721–7735 Dovepress © 2017 Wang et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). http://dx.doi.org/10.2147/IJN.S141052 Powered by TCPDF (www.tcpdf.org) Bone defects, especially large-volume defects, often arise from trauma, skeletal diseases, congenital malformations, and tumor resections1 and remain challenging to surgeons. Traditional approaches for bone reconstruction include autologous bone grafting and alloplastic implants. However, the risks of limited supply, secondary traumatization, disease transmission, and immunogenicity still exist.2,3 The limitations of autografts and allografts have compelled the development of artificial materials that can stimulate Dovepress International Journal of Nanomedicine downloaded from https://www.dovepress.com/ by 51.38.247.138 on 12-Jul-2018 For personal use only. Wang et al natural bone tissue formation and repair.4 Tissue engineering approaches for bone regeneration based on the potent osteoinductive activity of BMPs have been proposed. Among BMPs, BMP2 has exhibited great potential for the regeneration of bone defects due to its remarkable ability to gather osteoprogenitor cells and induce osteogenic differentiation.4 To efficiently promote bone healing, the application of BMP2 has been widely used and is approved by the US Food and Drug Administration.4,5 However, despite its clinical efficacy in bone regeneration, BMP2 is limited by its short duration of bioactivity, highly preserved condition, and high production costs. Furthermore, at high doses, BMP2 is associated with risks and side effects, such as excessive bone resorption6 and the promotion of tumor angiogenesis.7,8 Therefore, it is necessary to find effective biomolecules that can synergistically promote the osteogenic bioactivity of BMP2. Osteogenic bioactivity can also be enhanced through biochemical cues via the combination of effective biomolecules, such as heparin,9 2-N,6-O-sulfated chitosan,10 dexamethasone,3 and vascular endothelial growth factor.4,11 Traditional Chinese medicines characterized by high production rates and low cost could be used in the synergy with BMP2. However, there are few studies regarding traditional Chinese medicines that may coordinate with BMP2. Among the traditional Chinese medicines, icariin (IC), which is extracted from Epimedium, (...truncated)