Stimuli responsive co-delivery of celecoxib and BMP2 from micro-scaffold for periodontal disease treatment

doi:10.1016/j.jmst.2020.10.027

J. Mater. Sci. Technol. ›› 2021, Vol. 75: 216-224.DOI: 10.1016/j.jmst.2020.10.027

• Research Article • Previous Articles Next Articles

Stimuli responsive co-delivery of celecoxib and BMP2 from micro-scaffold for periodontal disease treatment

Yi Hao^a^,^*,1(), Ran Tian^b,1, Kaige Lv^a, Zhongning Liu^c, Jing Ni^a, Pingyun Yuan^b, Yongkang Bai^b, Xin Chen^b^,^*()

^a Department of Prosthodontics, Shanghai Ninth People’s Hospital College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center of Stomatology, Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Shanghai 200240, China
^b Department of Chemical Engineering, Shaanxi Key Laboratory of Energy Chemical Process Intensification, Institute of Polymer Science in Chemical Engineering, School of Chemical Engineering and Technology, Xi’an Jiaotong University, Xi’an, 710049, China
^c Department of Prosthodontics, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing, 100081, China

Received:2020-06-26 Revised:2020-07-29 Accepted:2020-07-30 Published:2021-06-10 Online:2020-10-27
Contact: Yi Hao,Xin Chen
About author:*E-mail addresses: haoyi5315@163.com (Y. Hao),
First author contact:
¹These authors contributed equally to this work.

Abstract

Abstract:

Controlling inflammation meanwhile facilitating tissue regeneration has been considered as a promising strategy to treat inflammatory bone defect. Herein, we describe the synthesis of a bio-sensitive poly(lactic-co-glycolic acid)/mesoporous silica nanocarriers core-shell porous microsphere (PLGA/MSNs-PMS) encapsulated poly(L-lactic acid) (PLLA) spongy nanofibrous micro-scaffold as a new generation of therapeutic platform for effective reconstruction of bone defects caused by periodontal diseases. The PLGA/MSNs-PMS were designed as stimuli-responsive carriers for on-demand co-delivery of multiple biomolecules to provide proper physiological environment, while the multi-level (from macro-, micro- to nanometers) nanofibrous and porous structures in PLLA micro-scaffold were in charge of the reconstruction of ECM, which synergistically contribute to the enhancement of new tissue formation under inflammatory condition. After local injection into periodontal tissue, this construct could sequentially release bone growth factor (BMP-2) as well as anti-inflammatory drug (celecoxib) loaded MSNs in response to the over-expressed matrix metalloproteinases (MMP) in periodontal region. During alveolar bone regeneration induced by BMP-2 and ECM like structure, the MSNs would further deliver celecoxib in target cells to achieve inflammation inhibition, resulting in effective treatment of periodontal disease.

Yi Hao, Ran Tian, Kaige Lv, Zhongning Liu, Jing Ni, Pingyun Yuan, Yongkang Bai, Xin Chen. Stimuli responsive co-delivery of celecoxib and BMP2 from micro-scaffold for periodontal disease treatment[J]. J. Mater. Sci. Technol., 2021, 75: 216-224.

Figures/Tables 6

Fig. 1. Schematic illustration of multilevel structure of PLGA/MSNs-PMS immobilized PLLA spongy nanofibrous micro-scaffold and dual responsive bio- molecules delivery based on this designed complex.

Fig. 2. TEM images of MSN clusters connected by disulfide bond (MSNs-Peptide, a), porous PLGA microspheres containing MSN clusters (PLGA/MSNs-PMS, b) and PLGA/MSNs-PMS immobilized PLLA spongy nanofibrous micro-scaffold (c). (d) Dynamic light scattering (DLS) of thiol functionalized MSNs (MSN-SH), MSNs-Peptide and PLGA/MSNs-PMS.

Fig. 3. Encapsulation of rhodamine-labeled BSA (model growth factor) and coumarin-6 (model drug) in porous PLGA microspheres containing MSN clusters (PLGA/MSNs-PMS, a) and PLGA/MSNs-PMS immobilized PLLA spongy nanofibrous micro-scaffold (b). The figure is presented by representative fluorescence microscope images.

Fig. 4. (a) UV-vis spectrum of the pure rhodamine-labeled BSA, pure coumarin-6/β-CD complex and the mixture of BSA/coumarin-6 in PBS (pH 7.4). (b) The UV-vis absorption spectrum of rhodamine-labeled BSA and coumarin-6/β-CD complex co-loaded micro-scaffold after different treatments.(c) Release kinetics of rhodamine-labeled BSA and coumarin-6/β-CD complex loaded micro-scaffold in PBS. (d) Matrix metallo proteinases (MMP) and glutathione (GSH) multiple-dependent release kinetics of rhodamine-labeled BSA and coumarin-6/β-CD complex loaded micro-scaffold. The figure c and d are represented by the black curve (MMP responsive release of BSA) and red curve (GSH responsive release of coumarin-6).

Fig. 5. The in vitro therapeutic effects of different formulations on inflamed D1 cells (i: Control; ii: LPS; iii: celecoxib (CE) loaded micro-scaffold + LPS; iv: BMP2 loaded micro-scaffold + LPS; v: CE/BMP-2 loaded micro-scaffold + LPS). (a-c) The gene expression of bone related marker ALP, BSP and RUNX2 after treatment by different formulations. (d) The ALP activity of inflamed D1 cells after treatment by different formulations. (e) The formation of mineralized nodules of inflamed D1 cells after treatment by different formulations, which was detected by alizarin red staining.

Fig. 6. The in vitro therapeutic effects of celecoxib/ Bone Morphogenetic protein-2 (CE/BMP-2) loaded micro-scaffold on mouse model of periodontitis, which is determined by Micro CT.

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Stimuli responsive co-delivery of celecoxib and BMP2 from micro-scaffold for periodontal disease treatment

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