Abstract Human physical and mental health are significantly impacted by maxillofacial alveolar bone defects. The emergence of additive manufacturing metamaterial scaffolds provides a new treatment strategy for this. Due to the complexity of the jawbone and the difficulty in preparing bionic hierarchical gradient scaffolds, most current research focuses on human long bones. This study first proposes a metamaterial scaffold that simulates the jawbone. The stratified scaffolds (G300–600, G300–750,G300–900) adopt the Gyroid structure of the triply periodic minimum surfaces, with the upper and lower layers respectively simulating the cortical bone and cancellous bone of the jawbone. And a large-aperture uniform scaffold (G750) was designed as a control. And it is prepared through digital light processing 3D printing technology. The results show that sintering the scaffold to 1170 °C and holding it for 48 h can improve the mechanical properties and biocompatibility of the scaffold, making it match. G300–600 not only improves in vitro neovascularization and new bone formation, but also features a high level of compressive strength (9.86 MPa) and outstanding degradability. This gradient metamaterial scaffold has a structure, mechanical properties and biological activity that conform to the jawbone, providing a new strategy for bone defects in the maxillofacial region.
Abstract Decellularized extracellular matrix (dECM)-based hydrogels in previous research demonstrated as promising biomimetic scaffolds. However, conventional decellularization protocols are commonly based on harsh detergents that disrupt extracellular matrix (ECM) integrity. While milder detergents such as sodium lauryl ether sulfate (SLES) and physical methods like ultrasonication have been proposed to reduce these negative effects, their combined application and the influence of ultrasonication parameters remain insufficiently explored. In this study, we systematically investigated the effect of ultrasonication-assisted decellularization on porcine liver tissue treated with SLES, with particular emphasis on ultrasonication exposure time. Decellularization efficiency and ECM preservation were evaluated through DNA, collagen, and glycosaminoglycan quantification, and structural integrity analysis. The impact of processing conditions on downstream applications was assessed by characterizing the gelation behavior, rheological properties, molecular weight distribution, and microstructure of the resulting dECM-based hydrogels. Biocompatibility was evaluated using HaCaT cells through metabolic assay and adhesion. Ultrasonication-assisted decellularization improved ECM preservation while maintaining effective decellularization, as all samples had < 50 ng of DNA per mg of dry tissue. Furthermore, it enabled the formation of hydrogels with enhanced physicochemical properties and increased cell viability compared to hydrogels obtained by detergent decellularization only. These findings demonstrate that controlled ultrasonication can reduce the need for harsh chemical treatments and improve scaffold preservation, highlighting its potential for optimizing decellularization protocols in tissue engineering applications.
Abstract Scaffolds have proven useful as matrices for cell culture, tissue ingrowth, organ formation, mechanical support, drug screening platforms, and localized delivery systems. Their performance depends on multiple structural and material properties that determine their suitability for specific applications. In this study, we developed a multifunctional scaffold designed to provide both cell culture support and gradual microRNA (miRNA, miR) delivery. A method was first introduced for generating heterogeneous triply periodic minimal surface (TPMS)-based scaffold architectures. Compared with existing methods, the proposed approach provides a more user-friendly strategy for generating functionally graded structures and enables irregular architectural variations throughout the scaffold. The scaffolds were fabricated using fused filament deposition (FFD) and evaluated for printing fidelity. A gelatin/polyethyleneimine (PEI)-based delivery system was developed to immobilize miRNA on the scaffold surface, and its release profile was optimized. The scaffolds were further evaluated for cell attachment, proliferation, infiltration, and transfection efficiency. The proposed design method successfully generated complex architectural deformations while maintaining printability. The scaffold surface supported favorable cell attachment and proliferation, whereas cell infiltration was influenced by both porosity and geometry. The developed delivery system provided gradual miRNA release over 7 days and effectively transfected primary cells, achieving a transfection efficiency of 67% in human mesenchymal stromal cells without significant cytotoxicity. These findings demonstrate a multifunctional scaffold that combines advanced architectural design with gradual nucleic acid delivery for tissue engineering applications.
Abstract Articular cartilage has a limited intrinsic capacity for self-repair because of its avascular, aneural, and alymphatic nature, making cartilage repair a major clinical challenge. This limitation is particularly important in osteoarthritis (OA), where cartilage loss occurs within a complex whole-joint pathological environment involving inflammation, extracellular matrix (ECM) degradation, oxidative stress, chondrocyte senescence, and altered mechanical loading. Cartilage tissue engineering (CTE) has emerged as a promising strategy to restore cartilage structure and function by integrating cells, biomaterials, and bioactive signals. While traditional bulk hydrogels have been widely explored, injectable microgels assemble into microporous constructs whose interparticle voids support the convective and diffusive mass transport that bulk gels restrict, together with precise control over cell–matrix interactions and release kinetics for optimal therapeutic delivery and tissue regeneration. Natural polymers, including chitosan, alginate, hyaluronic acid (HA), gelatin, collagen, and silk fibroin (SF), are attractive for microgel preparation due to their biocompatibility, biodegradability, structural similarity to native ECM, natural abundance, and tunable chemical groups. Beyond static delivery platforms, stimuli-responsive microgels that respond to disease-relevant cues such as pH, temperature, enzymatic activity, and magnetic or electrical fields add spatiotemporal control over therapeutic release. Compared to conventional intra-articular injections of free drugs or cells, natural polymer microgels prolong local retention and sustain release. Rather than acting only as passive carriers, they can modulate the OA microenvironment by delivering anti-inflammatory agents and supporting matrix regeneration. This review critically discusses recent advances in natural polymer-based microgels for CTE, emphasizing OA-oriented therapeutic applications. We review material selection, design criteria, preparation and crosslinking strategies. Furthermore, we provide specific examples of cell, small-molecule, growth-factor, and gene delivery, including nucleic-acid and exosome-based strategies, and finally discuss current challenges and outline future directions toward clinically relevant microgel-based therapies for OA.
Abstract The development of synthetic bone grafts that integrate osteogenic and immunomodulatory functions represents a critical strategy in regenerative orthopedics. In this study, we fabricated strontium- and magnesium-doped hydroxyapatite (HA/Mg/Sr) scaffolds derived from natural bovine cancellous bone. Physicochemical characterization confirmed the preservation of a three-dimensional interconnected porous architecture (~80% porosity, ~350 μm pore size) with a homogeneous nanoparticulate surface. Doping with Mg and Sr enhanced scaffold degradation, sustained the release of bioactive ions (Ca2+, Mg2+, Sr2+), and significantly increased compressive strength to levels comparable with human cancellous bone. HA/Mg/Sr scaffolds exhibited excellent biocompatibility, promoting adhesion and proliferation of both Bone marrow-derived mesenchymal stem cells (BMSCs) and bone marrow-derived macrophages (BMMs). While Mg primarily facilitated direct osteogenic differentiation of BMSCs, Sr played a dominant role in directing macrophage polarization toward the anti-inflammatory M2 phenotype, as evidenced by increased CD206 and IL-10 expression alongside reduced CCR7 and pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). Notably, macrophage-conditioned medium from HA/Mg/Sr cultures substantially enhanced BMSC osteogenesis, highlighting immunomodulation as a central mechanism. Transcriptomic analysis indicated that the HA/Mg/Sr scaffolds promoted macrophage polarization toward the M2 phenotype and modulated immune responses through the NF-κB signaling pathway, which was validated by Western blot. In a rat femoral condyle defect model, HA/Mg/Sr scaffolds—particularly those with 10% Sr content (HA/Mg/Sr2)—demonstrated superior bone regeneration, characterized by bone volume fraction (BV/TV), trabecular thickness (Tb.Th), and enhanced new bone ingrowth and integration, accompanied by elevated M2 macrophage infiltration in vivo. Overall, these findings establish that HA/Mg/Sr scaffolds promote bone repair not only via direct osteoconduction but, more importantly, through immunomodulation—fostering a pro-healing M2 macrophage microenvironment in an NF-κB-dependent manner, thereby offering a promising dual-functional biomaterial strategy for critical-sized bone defect reconstruction. This study underscores the therapeutic relevance of targeting macrophage polarization in bone repair and delineates a mechanistic framework for Sr-based immunomodulatory biomaterial design.
