Jul 2026· International Journal of Bioprinting· 0 citations
TL;DR
The feasibility of integrating DEXA into a controlled drug release system for bone tissue engineering applications is demonstrated, and the FFF-compatible 1% DEXA–PLA CF retains physicochemical integrity after DEXA incorporation and enables sustained local DEXA delivery within a biologically active concentration range, achieving dual osteogenic and immunomodulatory effects.
Abstract
Critical-sized bone defects remain a major therapeutic challenge. Among additive manufacturing approaches, fused filament fabrication provides a scalable alternative to autografting by enabling the production of patient-specific scaffolds with integrated bioactive functionality. Given the osteogenic and immunomodulatory properties of dexamethasone (DEXA), this study aimed to develop a 3D-printable DEXA-loaded polylactic acid (PLA) composite filament for controlled local drug delivery and to assess its osteogenic and immunomodulatory effects in vitro. DEXA–PLA composite filaments (0.1% and 1% w/w) were fabricated by melt extrusion. Thermal, chemical, surface, and mechanical characterization were performed using thermogravimetric analysis, differential scanning calorimetry, dynamic mechanical analysis, Fourier-transform infrared spectroscopy, contact angle, and three-point bending tests. DEXA release over 28 days was quantified by ELISA. Human mesenchymal stromal cells (MSCs) or THP-1–derived macrophages (TDM) were cultured in indirect contact with PLA or DEXA–PLA (0.1% or 1%) test specimens or treated with soluble DEXA as positive control. Osteogenic and immunomodulatory effects were assessed by metabolic activity (resazurin assay), gene expression (RT-qPCR), extracellular matrix (ECM) mineralization (Alizarin Red quantification), and cytokine secretion (Cytometric Bead Array). Statistical analysis was performed using two-way ANOVA followed by Tukey’s multiple comparisons test, and Kruskal–Wallis/Dunn (n = 4; α = 0.05). Thermal, chemical, surface, and mechanical properties of CF are largely preserved after DEXA incorporation. Both formulations exhibited distinct, concentration-dependent release kinetics. While the 0.1% DEXA–PLA showed a transient increase in DEXA concentration up to 72 h followed by decline, the 1% DEXA–PLA established a sustained plateau (~143 ng of DEXA per g of test specimen) over 28 days. Neither composite affected MSC metabolic activity. After 14 days, the 1% DEXA–PLA significantly enhanced ALPL expression and ECM mineralization compared with the 0.1% DEXA–PLA and PLA, reaching levels comparable to osteogenic differentiation medium (10 nM DEXA). In macrophages, the 1% DEXA–PLA selectively reduced in M1 cells metabolic activity, IL1B expression and secretion of IL-1β, IL-6, and TNF-α, while upregulating CD163 and PPARG. The FFF-compatible 1% DEXA–PLA CF retains physicochemical integrity after DEXA incorporation and enables sustained local DEXA delivery within a biologically active concentration range, achieving dual osteogenic and immunomodulatory effects, as evidenced by attenuated M1 macrophage activation. These findings demonstrate the feasibility of integrating DEXA into a controlled drug release system for bone tissue engineering applications.
Background/Objectives: The development of multifunctional biomaterials for bone regeneration remains a key challenge in additive manufacturing. Although polylactic acid (PLA) is widely used in fused deposition modeling (FDM), its limited bioactivity and lack of intrinsic antibacterial functionality restrict its application in implantable constructs. This study aimed to develop a PLA-based composite filament combining ion-mediated bioactive potential and local antibacterial functionality using a Quality by Design (QbD) approach. Methods: PLA-based composite filaments incorporating a mollusk shell-derived biogenic calcium-containing filler (20 wt.%) and gentamicin (5 wt.%) were fabricated by solvent-free melt extrusion. A QbD framework was applied to define the Quality Target Product Profile (QTPP), identify critical quality attributes (CQAs), and assess critical material attributes (CMAs) and critical process parameters (CPPs). The material was characterized by SEM–EDS combined with ImageJ-based quantitative image analysis, TGA/DSC, mechanical testing, ICP-AES analysis of aqueous extracts, agar diffusion antibacterial assays, FDM printability assessment, and in vivo biocompatibility testing in a rat subcutaneous implantation model. Results: The developed PLA–Gen–MS material was obtained as a continuous filament with a diameter of 1.75 ± 0.05 mm and was successfully used for FDM printing of model scaffold structures. SEM–EDS confirmed matrix continuity and distribution of the calcium-containing mineral phase. ICP-AES revealed a calcium-dominant multicomponent ion release profile, with Ca as the predominant element and measurable levels of Sr, Mg, P, Mn, and Fe. TGA/DSC confirmed thermal compatibility of the components under melt-processing conditions. PLA–Gen–MS demonstrated antibacterial activity against all tested strains, with inhibition zones of approximately 20–21 mm. In vivo, the material showed a favorable preliminary tissue response compared with TiLOOP®, including faster reduction of inflammatory infiltration and absence of foreign body giant cells by day 14. Conclusions: The QbD-guided strategy enabled the development of a multifunctional PLA-based filament integrating melt processability, structural integrity, ion-mediated bioactive potential, antibacterial functionality, printability, and favorable preliminary biocompatibility. PLA–Gen–MS can be considered a promising platform for further development of personalized bioactive and antibacterial scaffold constructs for bone regeneration.
A. Khrustaleva, A. Yedrissov, D. Khrustalev et al.· Pharmaceutics· 0 citations
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.
Chih-Yang Lai, Po-Ju Lai, Szu-Yao Wang et al.· Materials Science in Additiv...· 0 citations
Overall, PTB4 achieved the best balance among printability, mechanical compatibility, cytocompatibility, angiogenesis-related activity, and osteogenic performance, supporting low-dose BT modification as a promising strategy for safe, printable scaffolds for critical-size craniofacial and oral bone defect repair.
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.
Shengwen Cheng, Yuqiao Wang, Yu Zhai et al.· Burns & Trauma· 0 citations
The scaffold showed the highest osteoinduction, and the scaffold with 530 ± 56 μm average pore diameter demonstrated the highest expression of osteodifferentiation marker genes in DPSCs, and the addition of nanoparticles into the polymer matrix led to the decrease in the expression of pro-inflammatory genes in macrophages.
A. V. Yushkov, E. A. Kuvshinova, I. Bulygina et al.· Biomedical Materials· 0 citations
The persistent inflammatory microenvironment during bone defect repair can inhibit osteogenic differentiation, delay angiogenesis, and reduce the reparative efficacy of implanted materials. Therefore, developing biomaterials that combine immunomodulatory functions with bone-regenerative capacity is of great significance. In this study, composite scaffolds with anti-inflammatory and bone-repair-promoting properties were fabricated through surface functionalization and 3D printing. The structural and physicochemical properties of the scaffolds were systematically characterized by scanning electron microscopy (SEM), elemental mapping, X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), contact angle measurement, and mechanical testing. Transmission electron microscopy and related analyses were further used to evaluate their microstructure and surface characteristics. The degradation behavior, pH variation, ion release profile, and antioxidant performance of the scaffolds under inflammatory conditions were then investigated to verify their ability to regulate the local microenvironment. In vitro, cytocompatibility was evaluated using CCK-8 assays, live/dead staining, and immunofluorescence staining. The effects of the scaffolds on macrophage polarization and inflammatory factor expression were further analyzed. Their osteogenic differentiation potential was assessed by alkaline phosphatase (ALP) staining, Alizarin Red staining, and osteogenesis-related gene expression analysis. In addition, Micro-CT, hematoxylin and eosin (HE) staining, and Masson's trichrome staining were performed in a bone defect animal model to evaluate bone regeneration and tissue repair. The results showed that the composite scaffolds effectively improved the inflammatory microenvironment in the defect region, promoted macrophage polarization toward an anti-inflammatory phenotype, enhanced cellular osteogenic activity and mineralization, and facilitated new bone formation and tissue reconstruction. This study provides a theoretical basis and experimental evidence for the design and application of bone repair materials under inflammatory conditions.
Fang Tong, Ting-Ting Lu, Lu Tang et al.· Journal of materials chemist...· 0 citations