Sufficient bone mass plays a vital role in dental implant fixation and durability. However, bone deficiency is common clinically, and peri-implant infection causes alveolar bone to further resorb. Therefore, inhibiting bone resorption and promoting peri-implant bone regeneration are highly desirable. For this purpose, functional pH-sensitive double-layered nanoparticles were fabricated for application on dental implant surface. These double-layered nanoparticles were composed of a poly(L-lactic acid) inner layer and a chitosan outer shell. Recombinant human bone morphogenetic protein-2-loaded poly(L-lactic acid) nanoparticles were prepared by the emulsification-solvent evaporation method. Osteoprotegerin was conjugated to the chitosan backbone via a pH-sensitive hydrazone bond. The release profile consisted of an initial fast release and a more continuous slow release for at least 30 days. Moreover, the cumulative osteoprotegerin release increased significantly with decreasing pH (p < 0.05). The results from biological studies indicated that the double-layered nanoparticles could inhibit the generation of osteoclasts, recruit bone marrow-derived mesenchymal stem cells (BMSCs), and promote BMSCs to differentiate into osteoblasts. Meanwhile, the inhibitory effect on osteoclasts increased with decreasing pH (p < 0.05). It can be concluded that the pH-sensitive double-layered nanoparticles, which had a significant effect on inhibiting bone resorption and promoting bone regeneration, are ideal nanoparticles to be applied on dental implant surface.
LiJYinXHuangL, et al.
Relationships among bone quality, implant osseointegration, and Wnt signaling. J Dent Res2017;
96: 822–831.
2.
TolstunovLHamrickJFEBroumandV, et al.
Bone augmentation techniques for horizontal and vertical alveolar ridge deficiency in oral implantology. Oral Maxillofac Surg Clin North Am2019;
31: 163–191.
3.
DuanDHFuJHQiW, et al.
Graft-free maxillary sinus floor elevation: a systematic review and meta-analysis. J Periodontol2017;
88: 550–564.
4.
PokrowieckiRMielczarekAZarębaT, et al.
Oral microbiome and peri-implant diseases: where are we now?Ther Clin Risk Manag2017;
13: 1529–1542.
5.
SalviGECosgareaRSculeanA, et al.
Prevalence and mechanisms of peri-implant diseases. J Dent Res2017;
96: 31–37.
6.
LiuWZhangX.Receptor activator of nuclear factor-κB ligand (RANKL)/RANK/osteoprotegerin system in bone and other tissues (review). Mol Med Rep2015;
11: 3212–3218.
7.
TaylorCRBranstetterDMannaE, et al.
Distribution of RANK and RANK ligand in normal human tissues as determined by an optimized immunohistochemical method. Appl Immunohistochem Mol Morphol2017;
25: 299–307.
8.
WeitzmannMN.Bone and the immune system. Toxicol Pathol2017;
45: 911–924.
9.
KapasaERGiannoudisPVJiaX, et al.
The effect of RANKL/OPG balance on reducing implant complications. J Funct Biomater2017;
8: 42.
10.
AbbasM.Combination of bone marrow mesenchymal stem cells and cartilage fragments contribute to enhanced repair of osteochondral defects. Bioinformation2017;
13: 196–201.
11.
WangYSunXLvJ, et al.
Stromal cell-derived factor-1 accelerates cartilage defect repairing by recruiting bone marrow mesenchymal stem cells and promoting chondrogenic differentiation. Tissue Eng Part A2017;
23: 1160–1168.
12.
LinHSohnJShenH, et al.
Bone marrow mesenchymal stem cells: aging and tissue engineering applications to enhance bone healing. Biomaterials2019;
203: 96–110.
13.
WangCWangYMengHY.Application of bone marrow mesenchymal stem cells to the treatment of osteonecrosis of the femoral head. Int J Clin Exp Med2015;
8: 3127–3135.
14.
LiJGuoWXiongM, et al.
Effect of SDF-1/CXCR4 axis on the migration of transplanted bone mesenchymal stem cells mobilized by erythropoietin toward lesion sites following spinal cord injury. Int J Mol Med2015;
36: 1205–1214.
15.
YuYYLieuSLuC, et al.
Bone morphogenetic protein 2 stimulates endochondral ossification by regulating periosteal cell fate during bone repair. Bone2010;
47: 65–73.
16.
LeeSHParkYSongM, et al.
Orai1 mediates osteogenic differentiation via BMP signaling pathway in bone marrow mesenchymal stem cells. Biochem Biophys Res Commun2016;
473: 1309–1314.
17.
LiuSLiuYJiangL, et al.
Recombinant human BMP-2 accelerates the migration of bone marrow mesenchymal stem cells via the CDC42/PAK1/LIMK1 pathway in vitro and in vivo. Biomater Sci2018;
7: 362–372.
18.
HrehaJKrellESBibboC.Role of recombinant human bone morphogenetic protein-2 on hindfoot arthrodesis. Foot Ankle Clin2016;
21: 793–802.
19.
Gomes-FerreiraPHOkamotoRFerreiraS, et al.
Scientific evidence on the use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in oral and maxillofacial surgery. Oral Maxillofac Surg2016;
20: 223–232.
20.
LeeCHJinMUJungHM, et al.
Effect of dual treatment with SDF-1 and BMP-2 on ectopic and orthotopic bone formation. PLoS One2015;
10: e0120051.
21.
RatanavarapornJFuruyaHKoharaH, et al.
Synergistic effects of the dual release of stromal cell-derived factor-1 and bone morphogenetic protein-2 from hydrogels on bone regeneration. Biomaterials2011;
32: 2797–2811.
22.
HwangHDLeeJTKohJT, et al.
Sequential treatment with SDF-1 and BMP-2 potentiates bone formation in calvarial defects. Tissue Eng Part A. 2015;
21: 2125–2135.
23.
ChengYWuJGaoB, et al.
Fabrication and in vitro release behavior of a novel antibacterial coating containing halogenated furanone-loaded poly(L-lactic acid) nanoparticles on microarc-oxidized titanium. Int J Nanomed2012;
7: 5641–5652.
24.
ChengYZhaoXLiuX, et al.
Antibacterial activity and biological performance of a novel antibacterial coating containing a halogenated furanone compound loaded poly(L-lactic acid) nanoparticles on microarc-oxidized titanium. Int J Nanomed2015;
10: 727–737.
25.
ChengYGaoBLiuX, et al.
In vivo evaluation of an antibacterial coating containing halogenated furanone compound-loaded poly(l-lactic acid) nanoparticles on microarc-oxidized titanium implants. Int J Nanomed2016;
11: 1337–1347.
26.
YangSLiYP.RGS12 is essential for RANKL-evoked signaling for terminal differentiation of osteoclasts in vitro. J Bone Miner Res2007;
22: 45–54.
27.
HuYLouBWuX, et al.
Comparative study on in vitro culture of mouse bone marrow mesenchymal stem cells. Stem Cells Int2018;
2018: 6704583
28.
DinFUKimDWChoiJY, et al.
Irinotecan-loaded double-reversible thermogel with improved antitumor efficacy without initial burst effect and toxicity for intramuscular administration. Acta Biomater2017;
54: 239–248.
29.
FuKPackDWKlibanovAM, et al.
Visual evidence of acidic environment within degrading poly(lactic-co-glycolic acid) (PLGA) microspheres. Pharm Res2000;
17: 100–106.
30.
LvYWangGXuW, et al.
Tartrate-resistant acid phosphatase 5b is a marker of osteoclast number and volume in RAW 264.7 cells treated with receptor-activated nuclear kappaB ligand. Exp Ther Med2015;
9: 143–146.
31.
FriedrichMJWimmerMDSchmoldersJ, et al.
RANK-ligand and osteoprotegerin as biomarkers in the differentiation between periprosthetic joint infection and aseptic prosthesis loosening. World J Orthop2017;
8: 342–349.
32.
KomaroffAL.Modern biological research, medical practice, and human knowledge. JAMA2015;
314: 1133–1135.
33.
KanamalaMWilsonWRYangM, et al.
Mechanisms and biomaterials in pH-responsive tumour targeted drug delivery: a review. Biomaterials2016;
85: 152–167.
34.
DongYYeHLiuY, et al.
pH dependent silver nanoparticles releasing titanium implant: a novel therapeutic approach to control peri-implant infection. Colloids Surf B Biointerf2017;
158: 127–136.
35.
LimEKChungBHChungSJ.Recent advances in pH-sensitive polymeric nanoparticles for smart drug delivery in cancer therapy. Curr Drug Targets2018;
19: 300–317.
36.
HerbergSAguilar-PerezAHowieRN, et al.
Mesenchymal stem cell expression of SDF-1beta synergizes with BMP-2 to augment cell-mediated healing of critical-sized mouse calvarial defects. J Tissue Eng Regen Med2017;
11: 1806–1819.
37.
WangZWangKLuX, et al.
BMP-2 encapsulated polysaccharide nanoparticle modified biphasic calcium phosphate scaffolds for bone tissue regeneration. J Biomed Mater Res A2015;
103: 1520–1532.
