3D-printed BaTiO3-modified PCL/β-TCP scaffolds with multimodal optimization for enhanced critical-size bone regeneration.

Cryogenic 3D-Printed PLGA/Nano-selenium Scaffold for Bone Regeneration: A Dual-Functional Strategy Synergistically Regulating Macrophage Polarization and Osteogenic Differentiation

Autologous and allogeneic bone grafts are primarily used for bone tissue defects; however, they have limitations such as limited supply, donor site morbidity, and immune rejection risks. Therefore, substitute synthetic bone grafts are required. Using low-temperature 3D printing combined with freeze-drying technology, a hierarchically porous PLGA/HA@SeNPs composite scaffold was fabricated by compositing poly(lactic-co-glycolic acid) (PLGA) with hyaluronic acid-modified selenium nanoparticles (HA@SeNPs), enabling sustained immunomodulation and osteogenic activity through its engineered microtopography and bioactive components. In vitro evaluations confirmed that the unique microstructure and sustained selenium release from HA@SeNPs synergistically promoted macrophage polarization toward the M2 phenotype, accompanied by enhanced osteogenic differentiation as shown by upregulation of Runx2 and OCN and accelerated matrix mineralization. Implantation into a rat femoral critical-sized defect model resulted in substantially improved bone repair and architectural restoration. These findings indicate that the intrinsic physicochemical properties of the PLGA/HA@SeNPs scaffold orchestrate a favorable osteo-immune environment, positioning it as a promising platform for bone regeneration.

3D-printed graphene oxide/bioactive glass/BMP-2 composite scaffolds enhance osteogenesis in bone defect repair.

Clinical repair of critical-sized bone defects is currently hindered by the insufficient bioactivity of existing materials and mechanical property mismatches. This study aims to develop a 3D-printed graphene oxide (GO)/bioactive glass (BG)/bone morphogenetic protein-2 (BMP-2) composite biomimetic scaffold that integrates structural support with biochemical induction. In this work, polycaprolactone-based scaffolds loaded with different gradients of GO (1, 5, 10 wt.%) were fabricated using 3D printing technology, and surface functionalization of BMP-2 was achieved through EDC/NHS coupling. The optimal composition (5% GO) was determined through electron microscopy and mechanical screening, and a rat proximal femoral penetrating defect model was established. Micro-CT, Masson staining, and molecular biology techniques (IHC/WB) were utilized to evaluate its multidimensional regulatory effects on bone regeneration. Results showed that the 5% GO/BG/BMP-2 scaffold exhibited excellent mechanical stability and an appropriate porous structure, with compressive strength and modulus superior to other formulations. Animal experiments confirmed that the bone mineral density (BMD) and bone volume fraction (BV/TV) of the GO/BG/BMP-2 group were significantly higher than those of other groups (p < 0.001). At 4 weeks post-operation, the new bone area fraction reached 75.50% ± 3.17%, achieving high mineralization and functional remodeling of the bone tissue. Molecular mechanism studies indicated that the scaffold induces efficient osteogenic differentiation of mesenchymal stem cells by strongly activating core signaling pathways such as BMP-2, RUNX2, and EGFR during the early stages of repair. In conclusion, the 5% GO/BG/BMP-2 composite scaffold possesses both precise mechanical support and powerful molecular regulatory capabilities, providing a highly promising biomimetic alternative for the clinical treatment of complex bone defects.

A hybrid 3D-printed/electrospun biodegradable drug-eluting scaffold for heterotopic ossification-related local drug delivery

Heterotopic ossification (HO) is a clinically challenging complication after trauma or orthopedic surgery. This study evaluated a hybrid biodegradable scaffold for localized peri-osseous delivery of agents relevant to HO-risk and bone-healing environments. Polycaprolactone (PCL) mesh scaffolds were fabricated using solvent-cast additive manufacturing as flexible macro-scale barriers, while poly(lactic-co-glycolic acid) (PLGA) nanofibers incorporating indomethacin, teicoplanin, and bone morphogenetic protein-2 (BMP-2) were prepared using electrospinning and coaxial electrospinning. Scaffold morphology, wettability, mechanical behavior, Fourier-transform infrared spectroscopy and differential scanning calorimetry profiles, in vitro release, rabbit local/systemic release, and peri-implant histology were evaluated. The PCL mesh showed an ultimate tensile strength of 26.2 ± 2.6 MPa and a maximum strain of 337%. After 3 days in phosphate-buffered saline, the assembled PCL mesh/PLGA nanofiber scaffold retained comparable tensile properties, with an ultimate tensile strength of 24.8 ± 2.0 MPa and maximum strain of 334 ± 6%, indicating preserved flexibility under hydrated conditions. Drug-loaded PLGA nanofibers showed reduced tensile strength compared with pristine PLGA fibers, indicating that drug incorporation affected nanofiber handling and durability. In vitro testing demonstrated initial burst release of indomethacin and teicoplanin followed by sustained release, whereas BMP-2 release persisted for more than 30 days. In healthy rabbits, local teicoplanin and indomethacin levels were sustained for 28 days with substantially lower systemic levels. Histology demonstrated an early peri-implant inflammatory response that decreased over time. As no validated HO model or ectopic bone quantification was used, the findings support scaffold feasibility and localized delivery, not proven HO prevention. Further disease-model efficacy, biological activity, dose optimization, degradation, and safety studies are required before clinical translation.

Three-Dimensional Printing of Polycaprolactone Scaffolds with Multiscale Porosity for Bone Tissue Engineering.

This study provides a practical framework for creating intrafilamentary porosity into 3D-printed PCL scaffolds with improved surface-mediated biological performance.

Cryogenic 3D-printed gelatin-chondroitin sulfate scaffold embedded with PCA/Cu2+/ε-polylysine-functionalized chitosan microspheres for simultaneous antibacterial, anti-inflammatory, angiogenic, and osteogenic bone regeneration.

3D-printed gelatin scaffolds are widely explored for bone regeneration due to their excellent biocompatibility and biodegradability, yet their clinical translation is severely hindered by several inherent defects, including weak mechanical stability, fast in vivo biodegradation, limited osteogenic capability, and the absence of anti-infective functions. Globally, it remains a key challenge in bone tissue engineering to develop integrated scaffold systems that simultaneously satisfy mechanical matching, long-term biological activity, and anti-pathogenic requirements. To address this challenge, a multifunctional CHm/PCA/Cu2+/ε-PL@Gel-OCS scaffold with enhanced mechanical properties, outstanding antibacterial, anti-inflammatory, pro-vascularization and osteogenic activities was developed via cryogenic 3D printing of a gelatin (Gel)/oxidized chondroitin sulfate (OCS) composite ink loaded with chitosan microspheres surface-functionalized by protocatechuic aldehyde (PCA), copper ions (Cu2+) and ε-polylysine (ε-PL). Scanning electron microscopy and energy-dispersive X-ray analysis confirmed uniform dispersion of the microspheres and sustained release of therapeutic agents as the scaffold degraded. Rheological and mechanical testing demonstrated excellent print fidelity, interconnected porosity (161 ± 37 μm pores), and compressive strengths (100-200 MPa) suitable for cortical bone repair. Such porous structure and mechanical performance are highly compatible with human cortical bone microenvironment, which facilitates cell infiltration, nutrient exchange and mechanical load bearing. In vitro release studies revealed a sequential sustained release profile (OCS > Cu2+ > ε-PL), ensuring a sustainable osteogenic, angiogenic, anti-inflammatory and antibacterial activity. The scaffold achieved 100% bactericidal efficiency against both Staphylococcus aureus and Escherichia coli, suppressed protein denaturation (anti-inflammation), and promoted neovascularization in a chick chorioallantoic membrane assay. Biocompatibility assays using MC3T3-E1 osteoblasts showed enhanced cell adhesion, proliferation, and live/dead viability over 5 days. Osteogenic potential was significantly elevated on the multifunctional scaffold, as evidenced by time-dependent increases in ALP activity, mineral deposition (Alizarin Red S), and upregulated expression of ALP, RUNX2, OPN, and OCN genes compared with Gel and Gel-OCS controls. Taken together, our cryogenic 3D-printed Gel-OCS scaffold incorporating PCA/Cu2+/ε-PL-functionalized chitosan microspheres provides a single-step, customizable platform that combines robust mechanical properties with multi-modal therapeutic functionalities. Different from conventional single-function bone scaffolds reported in most international studies, this multi-component synergistic design successfully realizes the integration of mechanical reinforcement, antibacterial, anti-inflammatory, vascularization and osteogenesis functions in one system. These promising preclinical results highlight a novel therapeutic strategy for bone defect regeneration, it solves the common bottlenecks of traditional gelatin-based bone scaffolds, provides a feasible and universal fabrication strategy for high-performance multifunctional bone repair materials, and offers new insights for the global development and clinical translation of 3D-printed bone tissue engineering scaffolds.

Static Biodegradation of 3D-Printed PLA Scaffolds for Bone with Different Architectures and Nanomaterial Additives