Drug design, development and therapy · 2026
Tideglusib-Preactivated Osteoblasts Encapsulated in Ceramic Particle-Reinforced GelMA Hydrogel for Enhanced Critical-Size Bone Defect Regeneration.
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Cao Keqin, Shang Hongxu, Li Yexin, Tan Yanfei, Li Molin, Ma Yufei, Cai Xue, Tang Zhurong
Аннотация
PURPOSE: Critical-size bone defects remain a clinical challenge due to limited intrinsic bone regeneration. This study developed a composite scaffold composed of osteoinductive biphasic calcium phosphate (BCP) ceramic particles and gelatin methacryloyl (GelMA) hydrogel, loaded with calvarial osteoblasts (OBs) pretreated with the glycogen synthase kinase-3β (GSK-3β) inhibitor Tideglusib on surface of BCP particles, and evaluated its bone regenerative efficacy.
METHODS: BCP particles were characterized by X-ray diffraction and scanning electron microscopy. GelMA was synthesized and characterized by FTIR and 1H-NMR spectroscopy. Mechanical properties were assessed by compression testing. OBs were treated with Tideglusib to determine optimal concentration via CCK-8, scratch assays, qPCR, ALP and Alizarin Red S staining. Tideglusib-pretreated OBs seeded on BCP particles were evaluated for viability, proliferation, and osteogenic gene expression (COL-I, ALP). In vivo, 3.5 mm rat femoral defects were used to assess the bone regeneration potential of T-OB/BCP particle/GelMA (GPCT) composites in comparison with other groups by micro-CT and histology at 4 and 8 weeks.
RESULTS: BCP (200-300 μm, HA/β-TCP ~30:70) incorporation enhanced GelMA compressive modulus ~4-fold. In vitro, 1 μM Tideglusib optimally activated Wnt/β-catenin signaling and promoted OB proliferation, migration, and osteogenic differentiation, with sustained effects after drug removal. OBs on BCP particles showed time-dependent upregulation of osteogenic genes, and Tideglusib pretreatment further elevated this expression. In vivo, micro-CT revealed significantly higher BV/TV, Tb.N, Tb.Th, and BMD in the GPCT group versus others. Histology showed more mature bone with numerous osteocytes, partial degradation of BCP particles, and new bone area fraction >70% in GPCT.
CONCLUSION: The composite BCP particle/GelMA scaffold with Tideglusib-pretreated OBs provides mechanical reinforcement and sustained osteogenic stimulation, effectively accelerating critical-size bone defect regeneration. This ex vivo pharmacological priming strategy represents a promising translational approach for bone tissue engineering.
METHODS: BCP particles were characterized by X-ray diffraction and scanning electron microscopy. GelMA was synthesized and characterized by FTIR and 1H-NMR spectroscopy. Mechanical properties were assessed by compression testing. OBs were treated with Tideglusib to determine optimal concentration via CCK-8, scratch assays, qPCR, ALP and Alizarin Red S staining. Tideglusib-pretreated OBs seeded on BCP particles were evaluated for viability, proliferation, and osteogenic gene expression (COL-I, ALP). In vivo, 3.5 mm rat femoral defects were used to assess the bone regeneration potential of T-OB/BCP particle/GelMA (GPCT) composites in comparison with other groups by micro-CT and histology at 4 and 8 weeks.
RESULTS: BCP (200-300 μm, HA/β-TCP ~30:70) incorporation enhanced GelMA compressive modulus ~4-fold. In vitro, 1 μM Tideglusib optimally activated Wnt/β-catenin signaling and promoted OB proliferation, migration, and osteogenic differentiation, with sustained effects after drug removal. OBs on BCP particles showed time-dependent upregulation of osteogenic genes, and Tideglusib pretreatment further elevated this expression. In vivo, micro-CT revealed significantly higher BV/TV, Tb.N, Tb.Th, and BMD in the GPCT group versus others. Histology showed more mature bone with numerous osteocytes, partial degradation of BCP particles, and new bone area fraction >70% in GPCT.
CONCLUSION: The composite BCP particle/GelMA scaffold with Tideglusib-pretreated OBs provides mechanical reinforcement and sustained osteogenic stimulation, effectively accelerating critical-size bone defect regeneration. This ex vivo pharmacological priming strategy represents a promising translational approach for bone tissue engineering.