Abstract
This is the first report on the development of a covalently bone morphogenetic protein-2 (BMP2)-immobilized hydrogel that is suitable for osteogenic differentiation of human periodontal ligament stem cells (hPLSCs). O-propargyl-tyrosine (OpgY) was site-specifically incorporated into BMP2 to prepare BMP2-OpgY with an alkyne group. The engineered BMP2-OpgY exhibited osteogenic characteristics after in vitro osteogenic differentiation of hPLSCs, indicating the osteogenic ability of BMP2-OpgY. A methoxy polyethylene glycol-(polycaprolactone-(N3)) block copolymer (MC-N3) was prepared as an injectable in situ-forming hydrogel. BMP2 covalently immobilized on an MC hydrogel (MC-BMP2) was prepared quantitatively by a simple biorthogonal reaction between alkyne groups on BMP2-OpgY and azide groups on MC-N3 via a Cu(I)-catalyzed click reaction. The hPLSCs-loaded MC-BMP2 formed a hydrogel almost immediately upon injection into animals. In vivo osteogenic differentiation of hPLSCs in the MC-BMP2 formulation was confirmed by histological staining and gene expression analyses. Histological staining of hPLSC-loaded MC-BMP2 implants showed evidence of mineralized calcium deposits, whereas hPLSC-loaded MC-Cl or BMP2-OpgY mixed with MC-Cl, implants showed no mineral deposits. Additionally, MC-BMP2 induced higher levels of osteogenic gene expression in hPLSCs than in other groups. In conclusion, BMP2-OpgY covalently immobilized on MC-BMP2 induced osteogenic differentiation of hPLSCs as a noninvasive method for bone tissue engineering.
Highlights
This is the first report on the development of a covalently bone morphogenetic protein-2 (BMP2)immobilized hydrogel that is suitable for osteogenic differentiation of human periodontal ligament stem cells
The objectives of the current study were (1) to prepare BMP2-OpgY with an alkyne group and to examine the osteogenic differentiation of human periodontal ligament stem cells (hPLSCs) induced by BMP2-OpgY, (2) to evaluate whether covalently immobilized MC-BMP2 formulated by a quick click reaction can be injected to produce a hydrogel (Fig. 1b), and (3) to determine whether the injectable MC-BMP2 can induce synergistic osteogenic differentiation of hPLSCs that is greater than that of a physically BMP2-loaded MC hydrogel (MC-Cl [+BMP2-OpgY])
Using the engineered MjTyrRS - MjtRNACUA described in the experimental section, OpgY was incorporated into the TAG position
Summary
This is the first report on the development of a covalently bone morphogenetic protein-2 (BMP2)immobilized hydrogel that is suitable for osteogenic differentiation of human periodontal ligament stem cells (hPLSCs). In vivo osteogenic differentiation of hPLSCs in the MC-BMP2 formulation was confirmed by histological staining and gene expression analyses. BMP2-OpgY covalently immobilized on MC-BMP2 induced osteogenic differentiation of hPLSCs as a noninvasive method for bone tissue engineering. Clinical administration of BMP2 has sometimes required focal repeated exposures to BMP2 at supra-physiological doses to achieve the biologic activity needed for remedial effects because of its comparatively short half-life in vivo[6] This repeated administration at supra-physiological doses is costly and may lead to unfavorable side effects, including excessive remedial effects and adverse immune responses[7]. Physical adsorption may not provide BMP2 efficacy and stability for the needed period of time[14]
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