Three-dimensional (3D) printing has been increasingly employed to produce advanced bone tissue engineering scaffolds with biomimetic structures and matched mechanical strengths, in order to induce improved bone regeneration in defects with a critical size. Given that the successful bone regeneration requires both excellent osteogenesis and vascularization, endowing scaffolds with both strong bone forming ability and favorable angiogenic potential would be highly desirable to induce improved bone regeneration with required vascularization. In this investigation, customized bone tissue engineering scaffolds with balanced osteoconductivity/osteoinductivity were produced via cryogenic 3D printing of β-tricalcium phosphate and osteogenic peptide (OP) containing water/poly(lactic-co-glycolic acid)/dichloromethane emulsion inks. The fabricated scaffolds had a hierarchically porous structure and were mechanically comparable to human cancellous bone. Angiogenic peptide (AP) containing collagen I hydrogel was then coated on scaffold surface to further provide scaffolds with angiogenic capability. A sequential release with a quick AP release and a slow but sustained OP release was obtained for the scaffolds. Both rat endothelial cells (ECs) and rat bone marrow derived mesenchymal stem cells (MSCs) showed high viability on scaffolds. Improved in vitro migration and angiogenesis of ECs were obtained for scaffolds delivered with AP while enhanced osteogenic differentiation was observed in scaffolds containing OP. The in vivo results showed that, toward scaffolds containing both AP and OP, the quick release of AP induced obvious angiogenesis in vivo, while the sustained OP release significantly improved the new bone formation. This study provides a facile method to produce dual-delivery scaffolds to achieve multiple functions.

As the unique cell type in articular cartilage, chondrocyte senescence is a crucial cellular event contributing to osteoarthritis development. Here we show that clathrin-mediated endocytosis and activation of Notch signaling promotes chondrocyte senescence and osteoarthritis development, which is negatively regulated by myosin light chain 3. Myosin light chain 3 (MYL3) protein levels decline sharply in senescent chondrocytes of cartilages from model mice and osteoarthritis (OA) patients. Conditional deletion of Myl3 in chondrocytes significantly promoted, whereas intra-articular injection of adeno-associated virus overexpressing MYL3 delayed, OA progression in male mice. MYL3 deficiency led to enhanced clathrin-mediated endocytosis by promoting the interaction between myosin VI and clathrin, further inducing the internalization of Notch and resulting in activation of Notch signaling in chondrocytes. Pharmacologic blockade of clathrin-mediated endocytosis-Notch signaling prevented MYL3 loss-induced chondrocyte senescence and alleviated OA progression in male mice. Our results establish a previously unknown mechanism essential for cellular senescence and provide a potential therapeutic direction for OA.

With the continuous progress and development in biomedicine, metallic biomedical materials have attracted significant attention from researchers. Due to the low compatibility of traditional metal implant materials with the human body, it is urgent to develop new biomaterials with excellent mechanical properties and appropriate biocompatibility to solve the adverse reactions caused by long-term implantation. High entropy alloys (HEAs) are nearly equimolar alloys of five or more elements, with huge compositional design space and excellent mechanical properties. In contrast, biological high-entropy alloys (Bio-HEAs) are expected to be a new bio-alloy for biomedicine due to their excellent biocompatibility and tunable mechanical properties. This review summarizes the composition system of Bio-HEAs in recent years, introduces their biocompatibility and mechanical properties of human bone adaptation, and finally puts forward the following suggestions for the development direction of Bio-HEAs: to improve the theory and simulation studies of Bio-HEAs composition design, to quantify the influence of composition, process, post-treatment on the performance of Bio-HEAs, to focus on the loss of Bio-HEAs under actual service conditions, and it is hoped that the clinical application of the new medical alloy Bio-HEAs can be realized as soon as possible.

Medical metal implants are required to have excellent mechanical properties and high biocompatibility to handle the complex human environment, which is a challenge that has always existed for traditional medical metal materials. Compared to traditional medical alloys, high entropy alloys (HEAs) have a higher design freedom to allow them to carry more medical abilities to suit the human service environment, such as low elastic modulus, high biocompatible elements, potential shape memory capability. In recent years, many studies have pointed out that bio-HEAs, as an emerging medical alloy, has reached or even surpassed traditional medical alloys in various medical properties. In this review, we summarized the recent reports on novel bio-HEAs for medical implants and divide them into two groups according the properties, namely mechanical properties and biocompatibility. These new bio-HEAs are considered hallmarks of a historic shift representative of a new medical revolution.

In this study, a β-tricalcium phosphate (β-TCP)/poly (lactic-co-glycolic acid) (PLGA) bone tissue scaffold was loaded with osteogenesis-promoting drug HA15 and constructed by three-dimensional (3D) printing technology. This drug delivery system with favorable biomechanical properties, bone conduction function, and local release of osteogenic drugs could provide the basis for the treatment of bone defects. The biomechanical properties of the scaffold were investigated by compressive testing, showing comparable biomechanical properties with cancellous bone tissue. Furthermore, the microstructure, pore morphology, and condition were studied. Moreover, the drug release concentration, the effect of antituberculosis drugs in vitro and in rabbit radial defects, and the ability of the scaffold to repair the defects were studied. The results show that the scaffold loaded with HA15 can promote cell differentiation into osteoblasts in vitro, targeting HSPA5. The micro-computed tomography scans showed that after 12 weeks of scaffold implantation, the defect of the rabbit radius was repaired and the peripheral blood vessels were regenerated. Thus, HA15 can target HSPA5 to inhibit endoplasmic reticulum stress which finally leads to promotion of osteogenesis, bone regeneration, and angiogenesis in the rabbit bone defect model. Overall, the 3D-printed β-TCP/PLGA-loaded HA15 bone tissue scaffold can be used as a substitute material for the treatment of bone defects because of its unique biomechanical properties and bone conductivity.