Search Results (102)

This study investigates the flow behavior of gyroid scaffolds using computational fluid dynamics (CFD) and three rheological models, Newtonian, Power-law, and Carreau, to assess the influence of pore size, inlet velocity, and scaffold size on wall shear stress (WSS) and permeability. The results show that non-Newtonian models yield substantially higher and broader WSS distributions than the Newtonian model, reflecting the importance of shear-dependent viscosity for physiologically realistic simulations. Larger pore size reduces the WSS and increases the permeability. Nevertheless, localized high-shear regions persist, particularly for the non-Newtonian fluids. Higher inlet velocities produce an increase in both WSS and permeability. However, this effect is lees remarkable for the Newtonian model. Comparisons between small and large scaffolds show lower wall shear stress levels in the larger geometry due to reduced local velocity gradients and a more evenly distributed flow field. Overall, rheological models influence the magnitude and heterogeneity of WSS. These findings highlight the need to incorporate non-Newtonian models when evaluating the scaffold performance in tissue engineering applications. Full article

Laceration is one of the most common meniscus injuries, which can cause knee joint dysfunction. The treatment of meniscus injuries remains one of the greatest challenges in orthopedics. In this study, a three-dimensional sponge-like Poly(lactic acid)/Poly(3-hydroxybutyrate-co-4-hydroxybutyrate) (PLA/P(3HB-co-4HB)) scaffold with oriented microtubules was fabricated using an improved gradient thermal phase separation technique. The scaffold surface was modified by adsorbing gelatin. The surface-modified scaffolds and the unmodified scaffolds were divided into two groups. All preparation parameters were adjusted to meet tissue engineering requirements. The prepared scaffolds were tested for porosity, compression modulus, hydrophilicity, and degradability. Following scaffold preparation, induced differentiated rabbit bone marrow mesenchymal stem cells (BMSCs) were seeded to evaluate scaffold cytocompatibility. Cell proliferation was observed in the two scaffold groups, and cell viability was analyzed using CCK-8 assay, scanning electron microscopy (SEM), and confocal microscopy. Histological staining was performed to comparatively study cell synthetic function. Subsequently, tissue reconstruction and regeneration were evaluated following subcutaneous implantation of gelatin/PLA/P(3HB-co-4HB) scaffolds loaded with induced differentiated BMSCs in the dorsal regions of athymic nude mice. Results demonstrated that the gelatin/PLA/P(3HB-co-4HB) scaffold exhibited good cell compatibility, providing a suitable microenvironment for cell proliferation and differentiation. Furthermore, the scaffold supported the growth of seeded induced differentiated rabbit MSCs in vivo, maintaining meniscus cell phenotyping and function. The cell-laden scaffold has the potential to generate meniscus fibrocartilage. Full article

This study investigates and compares properties of various P-type Triply Periodic Minimal Surface (TPMS) porous structures for bone scaffold design. At first, six cases of homogeneous single/dual-layer structures, axial single/dual-layer gradient structures and radial single/dual-layer gradient structures with the same average porosity are developed. Dual-layer gradient structures are selected for further design due to more similar pore and stress distributions to human bones, reduced maximum stress, higher yield strength and greater variations in yield strength and elastic modulus (E). The mechanical and permeability properties of ten cases of axial and radial dual-layer gradient structures with the same overall porosity but different inner and outer layer porosities are then further designed and studied. The results show that yield strength is within 112.75–139.97 MPa, E ranges from 11.15 to 13.01 GPa, the permeability (K) falls within 1.51–10.01 × 10⁻⁹ m² and the average wall shear stress (WSS_avg) varies between 6.18 and 9.11 mPa. The yield strength, E and K of radial dual-layer gradient structures are higher and WSS_avg is lower than those of axial dual-layer gradient structures. Moreover, with increase in inner average porosity ($\overline{P}$) and decrease in outer $\overline{P}$, the yield strength, E and K gradually decrease while WSS_avg gradually increases for both types of structures. In particular, the radial dual-layer structure with the lowest porosity of 27.5% in the inner layer and highest porosity of 42.5% in the outer layer has superior mechanical and permeability properties. The findings offer direct guidance for the structural design of bone implants, enabling performance customization for different applications. Full article

In regenerative medicine, three-dimensional (3D) printing provides precise spatial control over the fabrication of complex, biomimetic tissue constructs, enabling the production of architecturally defined and functionally tailored scaffolds. By enabling precise layer-by-layer deposition of cells, biomaterials, and bioactive compounds, 3D printing overcomes many limitations associated with conventional scaffold fabrication methods. This approach facilitates the development of tailored structures that mimic the mechanical, biological, and structural characteristics of native tissues, thereby enhancing cellular organization, proliferation, and differentiation. Extensive research in tissue engineering has led to the development of 3D-printed scaffolds for the regeneration of vascular, skin, bone, cartilage, and soft tissues. Advances in bioink formulations—including growth factor-loaded systems, decellularized extracellular matrix components, and natural and synthetic polymers—have further improved tissue-specific functionality. Moreover, multimaterial and multiscale printing strategies enable the fabrication of heterogeneous constructs with controlled porosity, mechanical gradients, and spatially regulated biological cues. Although vascularized tissue constructs remain a major challenge for clinical translation, recent bioprinting advancements have significantly accelerated progress in this area. Integration of computer-aided design with patient-specific imaging data has further strengthened the potential of 3D printing for personalized regenerative therapies. Despite these advances, challenges related to scalability, regulatory approval, and long-term functionality persist. Nevertheless, continued progress in printing technologies, biomaterials, and regulatory and standards frameworks is expected to drive the clinical adoption of 3D printing. Ultimately, 3D printing represents a transformative approach in tissue engineering, redefining strategies for functional tissue regeneration and translational regenerative medicine. Full article

Culturing cells and micro-tissue samples in 3D bio-scaffolding structures is gaining popularity; however, precise control of tissue micro-environment in such systems remains challenging. We describe a family of new hybrid bio-scaffolds with 3D O₂-sensing ability, produced by simple means from readily available bio-scaffolding and O₂-sensing materials. Three different types of phosphorescent O₂-sensing materials—polymeric microparticles (MPs), supramolecular probe MitoXpress and nanoparticulate probes NanO2 and Nano-IR (NPs)—were integrated in Matrigel and agarose scaffolding materials and evaluated. Key working characteristics of such hybrid scaffolds, including heterogeneity, stability, cytotoxicity, optical signals and O₂-sensing properties, ease of fabrication and use, were compared. The results show superiority of the Matrigel hybrids with NanO2 and Nano-IR probes. Demonstration experiments were conducted with HCT116 cells and individual spheroids derived from these cells, culturing them in the Matrigel–NP hybrid scaffolds and monitoring oxygenation and local O₂ gradients on a time-resolved fluorescence plate reader and by phosphorescence lifetime imaging microscopy (PLIM). Full article

The regeneration of bone and the repair of large segmental bone defects represent critical challenges in regenerative medicine. Natural bone tissue is an anisotropic material characterized by an intricate gradient distribution in structure, mechanical properties, and biochemical composition; this multi-dimensional heterogeneity is crucial for maintaining its physiological functions and guiding regeneration. Although tissue engineering scaffolds have demonstrated significant potential in the treatment of bone defects, homogeneous or single-gradient scaffolds often struggle to precisely recapitulate the high degree of heterogeneity and anisotropy of natural bone from the macroscopic to the microscopic level, thereby limiting their capability in repairing complex bone defects. In recent years, biomimetic gradient scaffolds—particularly those employing multi-gradient synergistic designs that integrate physical structure, biochemical composition, and mechanical properties—have emerged as a research frontier in this field due to their ability to accurately mimic the natural bone microenvironment and regulate cellular behavior. This research aims to systematically review the latest research progress in gradient scaffolds for bone tissue engineering. First, gradient characteristics of biomimetic gradient bone scaffolds are summarized; second, the design strategies for gradient scaffolds are discussed in depth, with a focus on the applications and advantages of advanced fabrication techniques, such as additive manufacturing, in constructing multi-dimensional gradient structures; finally, based on current research findings, the emerging development trends and future research directions of biomimetic gradient bone scaffolds are outlined to provide a reference for innovative breakthroughs in the field of bone tissue engineering. Full article

Accurately identifying drug off-targets is essential for reducing toxicity and improving the success rate of pharmaceutical discovery pipelines. However, current deep learning approaches often struggle to fuse chemical structure, protein biology, and multi-target context. Here, we introduce HDPC-LGT (Hybrid Dual-Prompt Cross-Attention Ligand–Protein Graph Transformer), a framework designed to predict ligand binding across sixteen human translation-related proteins clinically associated with antibiotic toxicity. HDPC-LGT combines graph-based chemical reasoning with protein language model embeddings and structural priors to capture biologically meaningful ligand–protein interactions. The model was trained on 216,482 experimentally validated ligand–protein pairs from the Chemical Database of Bioactive Molecules (ChEMBL) and the Protein–Ligand Binding Database (BindingDB) and evaluated using scaffold-level, protein-level, and combined holdout strategies. HDPC-LGT achieves a macro receiver operating characteristic–area under the curve (macro ROC–AUC) of 0.996 and a micro F1-score (micro F1) of 0.989, outperforming Deep Drug–Target Affinity Model (DeepDTA), Graph-based Drug–Target Affinity Model (GraphDTA), Molecule–Protein Interaction Transformer (MolTrans), Cross-Attention Transformer for Drug–Target Interaction (CAT–DTI), and Heterogeneous Graph Transformer for Drug–Target Affinity (HGT–DTA) by 3–7%. External validation using the Papyrus universal bioactivity resource (Papyrus), the Protein Data Bank binding subset (PDBbind), and the benchmark Yamanishi dataset confirms strong generalisation to unseen chemotypes and proteins. HDPC-LGT also provides biologically interpretable outputs: cross-attention maps, Integrated Gradients (IG), and Gradient-weighted Class Activation Mapping (Grad-CAM) highlight catalytic residues in aminoacyl-tRNA synthetases (aaRSs), ribosomal tunnel regions, and pharmacophoric interaction patterns, aligning with known biochemical mechanisms. By integrating multimodal biochemical information with deep learning, HDPC-LGT offers a practical tool for off-target toxicity prediction, structure-based lead optimisation, and polypharmacology research, with potential applications in antibiotic development, safety profiling, and rational compound redesign. Full article

A biomimetic cartilage scaffold featuring a continuous hydroxyapatite (HA) concentration gradient and a spatially curved architecture was developed using a dual-channel mixing extrusion-based 3D printing approach. By dynamically regulating the feeding rates of two bioinks during printing, a continuous HA gradient decreasing from the bottom to the top of the scaffold was precisely achieved, mimicking the compositional transition from the calcified to the non-calcified cartilage region in native articular cartilage. The integration of gradient material deposition with synchronized multi-axis motion enabled accurate fabrication of curved geometries with high structural fidelity. The printed scaffolds exhibited stable swelling and degradation behavior and showed improved compressive performance compared with step-gradient counterparts. Rheological analysis confirmed that the bioinks possessed suitable shear-thinning and recovery properties, ensuring printability and shape stability during extrusion. In vitro evaluations demonstrated good cytocompatibility, supporting bone marrow mesenchymal stem cell (BMSC) adhesion and proliferation. Chondrogenic assessment based on scaffold extracts indicated that the incorporation of HA and its gradient distribution did not inhibit cartilage-related extracellular matrix synthesis, confirming the biosafety of the composite hydrogel system. Overall, this study presents a controllable and versatile fabrication strategy for constructing curved, compositionally graded cartilage scaffolds, providing a promising platform for the development of biomimetic cartilage tissue engineering constructs. Full article

Additive manufacturing has been adopted in several industries including the medical field to develop new personalised medical implants including tissue engineering scaffolds. Custom patient-specific scaffolds can be additively manufactured to speed up the wound healing process. The aim of this study was to design, fabricate, and evaluate a range of materials and scaffold architectures for 3D-printed wound dressings intended for soft tissue applications, such as skin repair. Multiple biocompatible polymers, including polylactic acid (PLA), polyvinyl alcohol (PVA), butenediol vinyl alcohol copolymer (BVOH), and polycaprolactone (PCL), were fabricated using a material extrusion additive manufacturing technique. Eight scaffolds, five with circular designs (knee meniscus angled (KMA), knee meniscus stacked (KMS), circle dense centre (CDC), circle dense edge (CDE), and circle no gradient (CNG)), and three square scaffolds (square dense centre (SDC), square dense edge (SDE), and square no gradient (SNG), with varying pore widths and gradient distributions) were designed using an open-source custom toolpath generator to enable precise control over scaffold architecture. An in vitro degradation study in phosphate-buffered saline demonstrated that PLA exhibited the greatest material stability, indicating minimal degradation under the tested conditions. In comparison, PVA showed improved performance relative to BVOH, as it was capable of absorbing a greater volume of exudate fluid and remained structurally intact for a longer duration, requiring up to 60 min to fully dissolve. Tensile testing of PLA scaffolds further revealed that designs with increased porosity towards the centre exhibited superior mechanical performance. The strongest scaffold design exhibited a Young’s modulus of 1060.67 ± 16.22 MPa and withstood a maximum tensile stress of 21.89 ± 0.81 MPa before fracture, while maintaining a porosity of approximately 52.37%. This demonstrates a favourable balance between mechanical strength and porosity that mimics key properties of engineered tissues such as the meniscus. Overall, these findings highlight the potential of 3D-printed, patient-specific scaffolds to enhance the effectiveness and customisation of tissue engineering treatments, such as meniscus repair, offering a promising approach for next-generation regenerative applications. Full article

Background: The Na⁺/K⁺-ATPase (NKA) maintains electrochemical gradients by exporting Na+ and importing K⁺ at the expense of ATP hydrolysis. Although NKA inhibition is a well-established strategy for increasing cardiac contractility, existing inhibitors such as cardiotonic steroids (CTS) are limited by serious adverse effects. N106 is a small molecule previously shown to enhance cardiac lusitropy by promoting SERCA2a SUMOylation and, intriguingly, also exerts positive inotropic effects, suggesting additional mechanisms of action. Methods: To test whether N106 directly modulates NKA, we combined ATPase activity assays with molecular docking and microsecond-scale molecular dynamics simulations. Results: Biochemical measurements showed that N106 partially inhibits NKA, achieving ~80% maximal inhibition with an IC50 of 7 ± 1 µM, while leaving the pump’s apparent affinity for Na⁺, K⁺, and ATP unchanged. Computational analyses suggest that N106 binds within the canonical CTS-binding pocket but undergoes intermittent unbinding events, consistent with the partial inhibition observed experimentally. Conclusions: These findings identify N106 as a first-in-class dual modulator of cardiac ion pumps, partially inhibiting NKA while previously shown to activate SERCA2a through enhanced SUMOylation. This combined mechanism likely underlies its positive inotropic and lusitropic effects and positions the N106 scaffold as a promising lead for developing next-generation dual-target therapeutics for heart failure. Full article

Tissue engineering offers a promising solution by developing scaffolds that mimic the extracellular matrix and guide cellular growth and differentiation. Recent evidence suggests that scaffolds must provide not only biocompatibility and appropriate mechanical properties, but also the structural complexity and heterogeneity characteristic of natural tissues. Particle-based scaffolds represent an emerging paradigm in regenerative medicine, wherein micro- and nanoparticles serve as primary building blocks rather than minor additives. This approach offers exceptional control over scaffold properties through precise selection and combination of particles with varying composition, size, rigidity, and surface characteristics. The presented review examines the fundamental principles, fabrication methods, and properties of particle-based scaffolds. It discusses how interparticle connectivity is achieved through techniques such as selective laser sintering, colloidal gel formation, and chemical cross-linking, while scaffold architecture is controlled via molding, templating, cryogelation, electrospinning, and 3D printing. The resulting materials exhibit tunable mechanical properties ranging from soft injectable gels to rigid load-bearing structures, with highly interconnected porosity that is essential for cell infiltration and vascularization. Importantly, particle-based scaffolds enable sophisticated pharmacological functionality through controlled delivery of growth factors, drugs, and bioactive molecules, while their modular nature facilitates the creation of spatial gradients mimicking native tissue complexity. Overall, the versatility of particle-based approaches positions them as prospective tools for tissue engineering applications spanning bone, cartilage, and soft tissue regeneration, offering solutions that integrate structural support with biological instruction and therapeutic delivery on a single platform. Full article

Tissue engineering approaches for cartilage tissue regeneration are expanding to include the complex features of the tissue, such as the biological and mechanical gradients. Many of these approaches are, however, based on the use of multiple biomaterials or concentrations, and crosslinking methods that make it difficult to integrate and control the properties of the resulting scaffolds. In this study, a 3D bioprinted scaffold with a stiffness gradient was fabricated by using a single biomaterial type and concentration combined with a directional ionic crosslinking method. The scaffolds revealed a gradient in stiffness from 39.8 ± 6.6 kPa at the top to 60.6 ± 10.9 kPa at the bottom of the scaffolds. Live/dead analysis of human chondrocytes embedded in the scaffolds showed no negative effects of the stiffness gradient on cell viability over 28 days. The induced stiffness gradient led to a gradient in cell density and sulfated glycosaminoglycan deposition in the bioprinted tissue constructs with enhanced values in the softer top region of the scaffolds as compared to the stiffer bottom part. This study showed a novel method to generate scaffolds with stiffness gradients from a single biomaterial and indicates that such scaffolds could be used to spatially regulate the behavior of chondrocytes and the associated deposition of the cartilage matrix. Full article

Breast cancer remains the leading cause of cancer-related death in women worldwide. This disease is characterized by its molecular and phenotypic heterogeneity, which hinders the development of effective therapies. While two-dimensional (2D) monolayer cell cultures are widely used, they are insufficient to reproduce the characteristics of the tumor microenvironment, thus limiting our understanding of cancer biology. In this context, three-dimensional (3D) models have emerged as representative tools that more accurately reproduce tissue architecture, cell signaling, and nutrients and oxygen gradients. These cellular models offer greater similarity to primary tissues, improving the study of relevant biological processes. Although 3D cultures provide numerous advantages in cancer research, there is no unified model that standardizes the matrix type and parameters such as gelation time or porosity, hindering the reproducibility and interpretability of the data. This review integrates evidence from various studies to evaluate the effect of epigenetic variations generated by 3D culture methods, which are regulated by mechanotransduction and, consequently, by signaling pathways such as integrin/FAK-ILK/Rho-YAP derived from interactions of cells with extracellular matrix-enriched scaffolds. This affects processes such as DNA methylation, histone coding, and the regulation of non-coding RNAs such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) in different molecular subtypes of breast cancer. Overall, the evidence highlights that 3D culture methods are not equivalent but rather generate distinct epigenetic signatures at the non-coding RNA level that influence the proliferation, differentiation, therapeutic resistance, and metastatic potential of tumor cells. Furthermore, the evidence suggests that histone coding patterns, primarily through the reduction of acetylation marks, are conserved regardless of the type of 3D culture. In summary, the study highlights that the microarchitectural and compositional characteristics of 3D scaffolds are key determinants of epigenetic plasticity. Full article

We propose Federated Entropic High-Order Descent (FedEHD), a drop-in client optimizer that augments local SGD with (i) an entropy (sign) term and (ii) quadratic and cubic gradient components for drift control and implicit clipping. Across non-IID CIFAR-10 and CIFAR-100 benchmarks (100 clients, 10% sampled per round), FedEHD achieves faster and higher convergence than strong baselines including FedAvg, FedProx, SCAFFOLD, FedDyn, MOON, and FedAdam. On CIFAR-10, it reaches 70% accuracy in approximately 80 rounds (versus 100 for MOON and 130 for SCAFFOLD) and attains a final accuracy of 72.5%. On CIFAR-100, FedEHD surpasses 60% accuracy by about 150 rounds (compared with 250 for MOON and 300 for SCAFFOLD) and achieves a final accuracy of 68.0%. In an environmental monitoring case study involving four distributed air-quality stations, FedEHD yields the highest macro AUC/F1 and improved calibration (ECE 0.183 versus 0.186–0.210 for competing federated methods) without additional communication and with only $\mathcal{O}(d)$ local overhead. The method further provides scale-invariant coefficients with optional automatic adaptation, theoretical guarantees for surrogate descent and drift reduction, and convergence curves that illustrate smooth and stable learning dynamics. Full article

Tendon injuries affect millions of people globally and are among the most prevalent musculoskeletal conditions, frequently resulting in chronic pain, reduced mobility, and functional impairment. While conservative and surgical treatments are available, limitations such as low healing capacity, scar formation, and reduced biomechanics necessitate alternative approaches. Tissue engineering offers a promising solution by combining cells, scaffolds, and bioactive molecules to regenerate tendon tissue. This review presents key concepts and emerging trends, highlighting the cellular components, scaffold materials, and manufacturing processes. Tenocytes and mesenchymal stem cells are fundamental for tissue regeneration, as they synthesize extracellular matrix components and regulate inflammatory responses. Various natural and synthetic polymers have been fabricated into scaffolds that mimic the structure and biomechanics of natural tendons. Composite and hybrid scaffolds are utilized to improve the biocompatibility of natural materials with the mechanical stability of synthetic materials. Advanced technologies, such as electrospinning, freeze-drying, and 3D bioprinting, enable the creation of scaffolds with defined architecture and functional gradients, improving cell alignment, differentiation, and tendon–bone integration. Although promising preclinical data exists, major challenges remain in translating these strategies clinically, particularly vascularization, immune rejection, and mechanical stability. Continued interdisciplinary attempts in biomaterials science, cellular biology, and engineering are crucial to advancing clinically viable tendon tissue engineering. Full article