Integrating a biomimetic extracellular matrix to improve the microenvironment of 3D printing scaffolds is an emerging strategy for bone substitute design. Here, a “soft–hard” bone implant (BM‐g‐DPCL) consisting of a bioactive matrix chemically integrated on a polydopamine (PDA)‐coated porous gradient scaffold by polyphenol groups is constructed. The PDA‐coated “hard” scaffolds promoted Ca2+ chelation and mineral deposition; the “soft” bioactive matrix is beneficial to the migration, proliferation, and osteogenic differentiation of stem cells in vitro, accelerated endogenous stem cell recruitment, and initiated rapid angiogenesis in vivo. The results of the rabbit cranial defect model (Φ = 10 mm) confirmed that BM‐g‐DPCL promoted the integration between bone tissue and implant and induced the deposition of bone matrix. Proteomics confirmed that cytokine adhesion, biomineralization, rapid vascularization, and extracellular matrix formation are major factors that accelerate bone defect healing. This strategy of highly chemically bonded soft–hard components guided the construction of the bioactive regenerative scaffold.
Facilitating cell ingrowth and biomineralized deposition inside filaments of 3DP scaffolds are an ideal bone repair strategy. Here, 3D printed PLGA/HA scaffolds with hydroxyapatite content of 50% (P5H5) and 70% (P3H7) were prepared by optimizing 3D printing inks, which exhibited good tailorability and foldability to meet clinical maneuverability. The supercritical CO2 foaming technology further endowed the filaments of P5H5 with a richer interconnected pore structure (P5H5-C). The finite element and computational fluid dynamics simulation analysis indicated that the porosification could effectively reduce the stress concentration at the filament junction and improved the overall permeability of the scaffold. The results of in vitro experiments confirmed that P5H5-C promoted the adsorption of proteins on the surface and inside of filaments, accelerated the release of Ca and P ions, and significantly upregulated osteogenesis (Col I, ALP, and OPN)- and angiogenesis (VEGF)-related gene expression. Subcutaneous ectopic osteogenesis experiments in nude mice further verified that P5H5-C facilitated cell growth inside filaments and biomineralized deposition, as well as significantly upregulated the expression of osteogenesis- and angiogenesis-related genes (Col I, ALP, OCN, and VEGF) and protein secretion (ALP, RUNX2, and VEGF). The porosification of filaments by supercritical CO2 foaming provided a new strategy for accelerating osteogenesis of 3DP implants.
Intermittent delivery of parathyroid hormone (PTH) could effectively promote bone regeneration, but the need for daily injection administration has limited its further clinical applications. Exposure to magnetic stimulation could regulate cell fate to promote osteogenesis. Herein, we developed a magnetized hydrogel with programmed PTH release and simultaneous magnetic actuation to promote osteogenic commitment. Ag dual-cross-linked hydrogel was formulated as GelMA−PVA (GP) biphasic reservoir with magnetic nanoparticles (GPM) and PTH (GPMP). Macroscopic and microscopic characterizations were performed to optimize the formulations. In vitro release assessment confirmed the programmable release of PTH with a pulsatile profile primed via magnetization in the first 4 days and a sustained release, controlled by an optimized GP matrix, for over a month. Stimulated by an alternating magnetic field, the hydrogels displayed a zigzag-shaped pulsatile release profile, and the cumulative release was enhanced by 8, 28, and 18% in In40, Ab40, and In20Ab20 (loading 40 μg PTH via incorporation, absorption, and their combination) formulations, respectively, compared with the same formulations without magnetic stimulation. An in vitro cytocompatibility test showed that all formulations were biocompatible and that PTH addition significantly promoted the proliferation of MC3T3-E1 pre-osteoblasts. In vivo studies presented enhanced new bone regeneration with significantly improved bone volume and bone mineral density in GPM and GPMP groups (increased by 120 and 251% compared with those of non-treated control), confirming their osteogenic effects and accelerated bone healing. This newly developed GPMP sample provides simultaneous osteogenesis effects via the programmed release of PTH and magnetically promoted bone regeneration and is promising in the facilitation of bone healing and treatment of various delayed/non-union conditions without the burden of daily injection.
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