Cyclodextrin-Based Supramolecular Complexes of Osteoinductive Agents for Dental Tissue Regeneration

Abstract

Oral tissue regeneration has received growing attention for improving the quality of life of patients. Regeneration of oral tissues such as alveolar bone and widely defected bone has been extensively investigated, including regenerative treatment of oral tissues using therapeutic cells and growth factors. Additionally, small-molecule drugs that promote bone formation have been identified and tested as new regenerative treatment. However, treatments need to progress to realize successful regeneration of oral functions. In this review, we describe recent progress in development of regenerative treatment of oral tissues. In particular, we focus on cyclodextrin (CD)-based pharmaceutics and polyelectrolyte complexation of growth factors to enhance their solubility, stability, and bioactivity. CDs can encapsulate hydrophobic small-molecule drugs into their cavities, resulting in inclusion complexes. The inclusion complexation of osteoinductive small-molecule drugs improves solubility of the drugs in aqueous solutions and increases in vitro osteogenic differentiation efficiency. Additionally, various anionic polymers such as heparin and its mimetic polymers have been developed to improve stability and bioactivity of growth factors. These polymers protect growth factors from deactivation and degradation by complex formation through electrostatic interaction, leading to potentiation of bone formation ability. These approaches using an inclusion complex and polyelectrolyte complexes have great potential in the regeneration of oral tissues.

Keywords: biomaterials; cyclodextrin; inclusion complex; polyrotaxane; regenerative medicine.

Figure 1

Chemical structure of small-molecule drugs that stimulate bone formation.

Figure 2

Chemical structures of cyclodextrins and representative chemically modified cyclodextrin derivatives.

Figure 3

(A) Relative ALP activity in MC3T3-E1 cells after treatment with free SV (100 nM), HP-β-CD/SV inclusion complexes (SV: 100 nM, HP-β-CD: 1 μM), and RM-β-CD/SV inclusion complexes (SV: 100 nM, RM-β-CD: 1 μM) for 14 days. (B) Relative ALP activity in MC3T3-E1 cells after treatment with free SV (100 nM), HP-β-CD (1 μM), and RM-β-CD (1 μM) for 14 days. Data are expressed as the mean ± S.D. (n = 3, * p < 0.05). Reproduced with permission from [74] © 2016 Elsevier.

Figure 4

(A) Intracellular amount of melatonin (MLT) in MC3T3-E1 cells treated with free MLT (MLT: 1 μM) and HP-β-CD/MLT inclusion complexes (MLT: 1 μM, HP-β-CD: 1 μM) for 24 h. Data are expressed as the mean ± S.D. (n = 3, * p < 0.05). (B) Relative ALP activities in MC3T3-E1 cell treated with free MLT (100 nM) and HP-β-CD/MLT inclusion complexes (MLT: 100 nM, HP-β-CD: 100 nM) for 3, 6, and 9 days. Data are expressed as the mean ± S.D. (n = 3, * p < 0.05, *** p < 0.005). (C) Mineralized matrix formation of MC3T3-E1 cells as detected by staining with alizarin red. The cells were treated with free MLT (MLT: 100 nM) and HP-β-CD/MLT inclusion complexes (MLT: 100 nM, HP-β-CD: 100 nM) for 28 days (scale bars: 500 μm). Reproduced with permission from [79] © 2018 Elsevier.

Figure 5

Chemical structure of sulfonated polyrotaxane (S-PRX), and the formation of a polyelectrolyte complex with BMP-2. Reproduced with permission from [127] © 2015 Wiley.

Figure 6

(A) Amount of ALP production in MC3T3-E1 cells after treatment with free BMP-2, heparin/BMP-2, and S-PRX/BMP-2 for 72 h. The concentrations of BMP-2 and the SPE-PRXs were 100 ng/mL and 1,000 μg/mL, respectively. The data are expressed as the mean ± S.D. (n = 3, *** p < 0.005, **** p < 0.001). (B) Alizarin red stained images for MC3T3-E1 cells after treatment with free BMP-2, heparin/BMP-2, and S-PRX/BMP-2 for 21 days. (C) X-ray μ-CT images of the mouse calvarial defect treated with free BMP-2, heparin/BMP-2, and S-PRX/BMP-2 complexes embedded into collagen sponges. The concentrations of BMP-2 and S-PRX were 100 ng/mouse and 1000 μg/mouse, respectively. The amount of implanted heparin was 100 μg/mouse. Reproduced with permission from [127] © 2015 Wiley and [128] © 2017 Wiley.