Supramolecular Polyelectrolyte Complexes of Bone Morphogenetic Protein‐2 with Sulfonated Polyrotaxanes to Induce Enhanced Osteogenic Differentiation

Abstract

Although bone morphogenetic protein-2 (BMP-2) has received considerable attention because of its strong osteoinductivity, the clinical application of BMP-2 is limited due to its degradation and deactivation under physiological conditions. Negatively charged heparin is known to form polyelectrolyte complexes with BMP-2 to prevent deactivation and enhance the osteoinduction capability of BMP-2. Herein, we report the sulfonated polyrotaxanes (S-PRX) composed of α-cyclodextrin threaded onto a linear polymer for the protection of BMP-2 through the polyelectrolyte complex formation. When MC3T3-E1 osteoprogenitor cells were treated with the S-PRX/BMP-2 complexes, significantly high alkaline phosphatase production and mineralized matrix deposition were observed compared with that of free BMP-2 and heparin/BMP-2 complexes. Note that the S-PRXs showed negligible anticoagulant activity and cytotoxicity, whereas heparin showed strong anticoagulant activity. Accordingly, the S-PRXs are promising candidates for enhanced osteoinduction ability of BMP-2 without toxicity and anticoagulant activity and could contribute to clinical bone regeneration.

Potentiating bioactivity of BMP‐2 by polyelectrolyte complexation with sulfonated polyrotaxanes to induce rapid bone regeneration in a mouse calvarial defect

“…The heparin/BMP‐2 complex‐treated cells secreted greater amount of ALP than free BMP‐2‐treated cells (Figure A). Note that all the SPE‐PRXs/BMP‐2 complexes induced significantly higher ALP production in MC3T3‐E1 cells than the heparin/BMP‐2 complex or free BMP‐2, which is consistent with our previous study …”

“…The sulfonated PRXs form a polyelectrolyte complex with positively charged BMP‐2, which contributes to protecting BMP‐2 from deactivation by Noggin. The sulfonated PRX/BMP‐2 complexes showed enhanced osteogenetic differentiation in MC3T3‐E1 cells in comparison to heparin/BMP‐2 complexes or free BMP‐2 . Furthermore, it is important to note that the sulfonated PRXs show negligible deactivation of factor Xa.…”

“…Also, the PRXs modified with cationic or anionic functional groups form polyelectrolyte complexes with oppositely charged proteins, in which the movable character of CDs or rod‐like structure of the PRXs can provide a benefit on the complexation behavior and the properties of the complexes. Taking these unique characters into consideration, we have developed sulfonated PRXs for the complexation with BMP‐2 . The sulfonated PRXs form a polyelectrolyte complex with positively charged BMP‐2, which contributes to protecting BMP‐2 from deactivation by Noggin.…”

“…In this regard, the main aim of this study is to validate the bone regeneration ability of the polyelectrolyte complexes between BMP‐2 and the sulfonated PRXs under in vivo conditions. To achieve this objective, sulfopropyl ether‐modified PRXs (SPE‐PRXs) with different molecular weights of axle polymer (i.e., PEG) were newly synthesized because our previously designed sulfonated PRXs have ester linkages for introducing sulfonate groups into α‐CDs, which are susceptible to be hydrolyzed . The in vitro osteogenetic differentiation ability of the SPE‐PRX/BMP‐2 polyelectrolyte complexes was investigated to clarify the effect of the molecular weight of the SPE‐PRXs on the osteogenetic differentiation.…”

“…Taking these unique characters into consideration, we have developed sulfonated PRXs for the complexation with BMP-2. 31 The sulfonated PRXs form a polyelectrolyte complex with positively charged BMP-2, which contributes to protecting BMP-2 from deactivation by Noggin. The sulfonated PRX/BMP-2 complexes showed enhanced osteogenetic differentiation in MC3T3-E1 cells in comparison to heparin/BMP-2 complexes or free BMP-2.…”