Dual-controlled release of PTH(1–34) via microsphere-hydrogel scaffold promotes early bone regeneration in osteoporosis

This study developed a three-dimensional (3D)-printed dual-controlled release scaffold for localized, sustained parathyroid hormone 1–34 (PTH 1–34) delivery to overcome systemic limitations (inadequate spatiotemporal control, poor anatomical matching) and enhance early bone regeneration in osteoporotic defects. PTH(1–34)-loaded poly(lactic- co -glycolic acid) (PLGA) microspheres (68.2 % efficiency) were incorporated into chitosan (CS) /short rod-shaped nano-hydroxyapatite (nHA) hydrogel ink and 3D-printed (300 μm nozzle). In vitro, scaffolds exhibited sustained biphasic release (19.4 ± 2.1 % initial burst within 24 h and 71.8 ± 1.7 % cumulative release over 30 days), significantly promoting MC3T3-E1 proliferation, alkaline phosphatase (ALP) activity (3.08-fold vs control, day 14; p < 0.01), and runt-related transcription factor 2 (Runx2) expression (8.13-fold; p < 0.001). In vivo (Ovariectomy rats, 5-mm calvarial defects; n = 5/group), Micro-computed tomography (micro-CT) at 4 weeks showed 2.22-fold higher trabecular bone volume fraction (BV/TV) ( p < 0.001) with 73 % greater trabecular thickness ( p < 0.001), confirmed histologically by accelerated mineralization/osteoblast activation. The PTH(1–34)@PLGA/CS-nHA scaffold integrates spatiotemporal drug delivery and biomimetic architecture, offering a promising strategy for early-phase bone regeneration in osteoporosis. • Sustained biphasic PTH(1–34) release (71.8 % over 30 days) enhances early osteogenesis. • 3D-printed scaffold improves osteoporotic bone volume 2.22-fold (BV/TV) in vivo . • Rod-shaped nHA reinforces mechanics and synergizes with PTH(1–34) for bone repair. • Scaffold degradation aligns with bone healing phases, resolving regeneration mismatch.