ESF1 positively regulates MDM2 and promotes tumorigenesis.

Eighteen S rRNA factor 1 (ESF1) is a predominantly nucleolar protein essential for embryogenesis. Our previous studies have suggested that Esf1 is a negative regulator of the tumor suppressor protein p53. However, it remains unclear whether ESF1 contributes to tumorigenesis. In this current research, we find that increased ESF1 expression correlates with poor survival in multiple tumors including pancreatic cancer. ESF1 is able to regulate cell proliferation, migration, DNA damage-induced apoptosis, and tumorigenesis. Mechanistically, ESF1 physically interacts with MDM2 and is essential for maintaining the stability of MDM2 protein by inhibiting its ubiquitination. Additionally, ESF1 also prevented stress-induced stabilization of p53 in multiple cancer cells. Hence, our findings suggest that ESF1 is a potent regulator of the MDM2-p53 pathway and promotes tumor progression.

[Development and Challenges of Additive Manufactured Customized Implant].

Additive manufacturing (3D printing) technology aligns with the direction of precision and customization in future medicine, presenting a significant opportunity for innovative development in high-end medical devices. Currently, research and industrialization of 3D printed medical devices mainly focus on nondegradable implants and degradable implants. Primary areas including metallic orthopaedic implants, polyether-ether-ketone (PEEK) bone implants, and biodegradable implants have been developed for clinical and industrial application. Recent research achievements in these areas are reviewed, with a discussion on the additive manufacturing technologies and applications for customized implants. Challenges faced by different types of implants are analyzed from technological, application, and regulatory perspectives. Furthermore, prospects and suggestions for future development are outlined.

Biotribological properties of 3D printed high-oriented short carbon fiber reinforced polymer composites for artificial joints.

Short carbon fiber (SCF) reinforced polymer composites are expected to possess outstanding biotribological and mechanical properties in certain direction, while the non-oriented SCF weakens its reinforcing effect in the matrix. In this work, high-oriented SCF was achieved during nozzle extrusion, and then SCF reinforced polyether-ether-ketone (PEEK) composites were fabricated by fused deposition modeling (FDM). The concrete orientation process of SCF was theoretically simulated, and significant shear stress difference was generated at both ends of SCF. As a result, the SCF was distributed in the matrix in a hierarchical structure, containing surface layer I, II and core layer. Moreover, the SCF was oriented highly along the printing direction and demonstrated a more competitive orientation distribution compared to other studies. The SCF/PEEK composites showed a considerable improvement in wear resistance by 44 % due to self-lubricating and load-bearing capability of SCF. Besides, it demonstrated enhancements in Brinell hardness, compressive and impact strength by 48.52 %, 16.42 % and 53.64 %, respectively. In addition, SCF/PEEK composites also showed good cytocompatibility. The findings gained herein are useful for developing the high-oriented SCF reinforced polymer composites with superior biotribological and mechanical properties for artificial joints.

TMED2 promotes glioma tumorigenesis by being involved in EGFR recycling transport.

Aberrant epidermal growth factor receptor (EGFR) signaling is the core signaling commonly activated in glioma. The transmembrane emp24 protein transport domain protein 2 (TMED2) interacts with cargo proteins involved in protein sorting and transport between endoplasmic reticulum (ER) and Golgi apparatus. In this study, we found the correlation between TMED2 with glioma progression and EGFR signaling through database analysis. Moreover, we demonstrated that TMED2 is essential for glioma cell proliferation, migration, and invasion at the cellular levels, as well as tumor formation in mouse models, underscoring its significance in the pathobiology of gliomas. Mechanistically, TMED2 was found to enhance EGFR-AKT signaling by facilitating EGFR recycling, thereby providing the initial evidence of TMED2's involvement in the membrane protein recycling process. In summary, our findings shed light on the roles and underlying mechanisms of TMED2 in the regulation of glioma tumorigenesis and EGFR signaling, suggesting that targeting TMED2 could emerge as a promising therapeutic strategy for gliomas and other tumors associated with aberrant EGFR signaling.

Microstructure Optimization for Design of Porous Tantalum Scaffolds Based on Mechanical Properties and Permeability.

Porous tantalum (Ta) implants have important clinical application prospects due to their appropriate elastic modulus, and their excellent bone growth and bone conduction ability. However, porous Ta microstructure designs generally mimic titanium (Ti) implants commonly used in the clinic, and there is a lack of research on the influence of the microstructure on the mechanical properties and penetration characteristics, which will greatly affect bone integration performance. This study explored the effects of different microstructure parameters, including the fillet radius of the middle plane and top planes, on the mechanics and permeability properties of porous Ta diamond cells through simulation, and put forward an optimization design with a 0.5 mm midplane fillet radius and 0.3 mm top-plane fillet radius in order to significantly decrease the stress concentration effect and improve permeability. On this basis, the porous Ta structures were prepared by Laser Powder Bed Fusion (LPBF) technology and evaluated before and after microstructural optimization. The elastic modulus and the yield strength were increased by 2.31% and 10.39%, respectively. At the same time, the permeability of the optimized structure was also increased by 8.25%. The optimized microstructure design of porous Ta has important medical application value.

Mechanical Properties Directionality and Permeability of Fused Triply Periodic Minimal Surface Porous Scaffolds Fabricated by Selective Laser Melting.

Titanium alloy porous scaffolds possess excellent mechanical properties and biocompatibility, making them promising for applications in bone tissue engineering. The integration of triply periodic minimal surface (TPMS) with porous scaffolds provides a structural resemblance to the trabecular and cortical bone structures of natural bone tissue, effectively reducing stress-shielding effects, enabling the scaffold to withstand complex stress environments, and facilitating nutrient transport. In this study, we designed fused porous scaffolds based on the Gyroid and Diamond units within TPMS and fabricated samples using selective laser melting technology. The effects of the rotation direction and angle of the inner-layer G unit on the elastic modulus of the fused TPMS porous scaffold were investigated through quasi-static compression experiments. Furthermore, the influence of the rotation direction and angle of the inner-layer G unit on the permeability, pressure, and flow velocity of the fused TPMS porous scaffold structure was studied using computational fluid dynamics (CFD) based on the Navier-Stokes model. The quasi-static compression experiment results demonstrated that the yield strength of the fused TPMS porous scaffold ranged from 367.741 to 419.354 MPa, and the elastic modulus ranged from 10.617 to 11.252 GPa, exhibiting stable mechanical performance in different loading directions. The CFD simulation results indicated that the permeability of the fused TPMS porous scaffold model ranged from 5.70015 × 10-8 to 6.33725 × 10-8 m2. It can be observed that the fused porous scaffold meets the requirements of the complex stress-bearing demands of skeletal structures and complies with the permeability requirements of human bone tissue.

Reconstructing avascular necrotic femoral head through a bioactive ß-TCP system: From design to application.

A variety of techniques have been used for treating avascular necrosis of the femoral head (ANFH), but have frequently failed. In this study, we proposed a ß-TCP system for the treatment of ANFH by boosting revascularization and bone regeneration. The angio-conductive properties and concurrent osteogenesis of the highly interconnected porous ß-TCP scaffold were revealed and quantified through an in vivo model that simulated the ischemic environment of ANFH. Mechanical test and finite element analysis showed that the mechanical loss caused by tissue necrosis and surgery was immediately partially compensated after implantation, and the strength of the operated femoral head was adaptively increased and eventually returned to normal bone, along with continuous material degradation and bone regeneration. For translational application, we further conducted a multi-center open-label clinical trial to assess the efficacy of the ß-TCP system in treating ANFH. Two hundred fourteen patients with 246 hips were enrolled for evaluation, and 82.1% of the operated hips survived at a 42.79-month median follow-up. The imaging results, hip function, and pain scores were dramatically improved compared to preoperative levels. ARCO stage Ⅱ disease outperformed stage Ⅲ in terms of clinical effectiveness. Thus, bio-adaptive reconstruction using the ß-TCP system is a promising hip-preserving strategy for the treatment of ANFH.

Stress-dependent design and optimization methodology of gradient porous implant and application in femoral stem.

Gradient porous structure made by additive manufacturing (AM) technology is potential to improve the long-term stability of orthopaedic implants through bone ingrowth while maintaining mechanical safety. In this study, a parametrical optimization methodology for the customized gradient porous implants was developed based on a stress-dependent design algorithm. Clinical requirements and manufacturing capabilities of AM were considered in the design procedure. A femoral stem with a minimum bone loss proportion of 2.4% by optimizing the control parameters. This study provided a feasible and flexible design approach for the customized implant with gradient porous structure or material components.

Fused Deposition Modeling PEEK Implants for Personalized Surgical Application: From Clinical Need to Biofabrication.

Three-dimensional printing (3DP) technology is suitable for manufacturing personalized orthopedic implants for reconstruction surgery. Compared with traditional titanium, polyether-ether-ketone (PEEK) is the ideal material for 3DP orthopedic implants due to its various advantages, including thermoplasticity, thermal stability, high chemical stability, and radiolucency suitable elastic modulus. However, it is challenging to develop a well-designed method and manufacturing technique to meet the clinical needs because it requires elaborate details and interplays with clinical work. Furthermore, establishing surgical standards for new implants requires many clinical cases and an accumulation of surgical experience. Thus, there are few case reports on using 3DP PEEK implants in clinical practice. Herein, we formed a team with a lot of engineers, scientists, and doctors and conducted a series of studies on the 3DP PEEK implants for chest wall reconstruction. First, the thoracic surgeons sort out the specific types of chest wall defects. Then, the engineers designed the shape of the implant and performed finite element analysis for every implant. To meet the clinical needs and mechanical requirements of implants, we developed a new fused deposition modeling technology to make personalized PEEK implants. Overall, the thoracic surgeons have used 114 personalized 3DP PEEK implants to reconstruct the chest wall defect and further established the surgical standards of the implants as part of the Chinese clinical guidelines. The surface modification technique and composite process are developed to overcome the new clinical problems of implant-related complications after surgery. Finally, the major challenges and possible solutions to translating 3DP PEEK implants into a mature and prevalent clinical product are discussed in the paper.

Stress Shielding and Bone Resorption of Press-Fit Polyether-Ether-Ketone (PEEK) Hip Prosthesis: A Sawbone Model Study.

Stress shielding secondary to bone resorption is one of the main causes of aseptic loosening, which limits the lifespan of the hip prostheses and increases the rates of revision surgery. This study proposes a low stiffness polyether-ether-ketone (PEEK) hip prostheses, produced by fused deposition modelling to minimize the stress difference after the hip replacement. The stress shielding effect and the potential bone resorption of the PEEK implant was investigated through both experimental tests and FE simulation. A generic Ti6Al4V implant was incorporated in this study to allow fair comparison as control group. Attributed to the low stiffness, the proposed PEEK implant showed a more natural stress distribution, less stress shielding (by 104%), and loss in bone mass (by 72%) compared with the Ti6Al4V implant. The stiffness of the Ti6Al4V and the PEEK implant were measured through compression tests to be 2.76 kN/mm and 0.276 kN/mm. The factor of safety for the PEEK implant in both static and dynamic loading scenarios were obtained through simulation. Most of the regions in the PEEK implant were tested to be safe (FoS larger than 1) in terms of representing daily activities (2300 N), while the medial neck and distal restriction point of the implant attracts large von Mises stress 82 MPa and 76 MPa, respectively, and, thus, may possibly fail during intensive activities by yield and fatigue. Overall, considering the reduction in stress shielding and bone resorption in cortical bone, PEEK could be a promising material for the patient-specific femoral implants.

Mechanical Characterisation and Numerical Modelling of TPMS-Based Gyroid and Diamond Ti6Al4V Scaffolds for Bone Implants: An Integrated Approach for Translational Consideration.

Additive manufacturing has been used to develop a variety of scaffold designs for clinical and industrial applications. Mechanical properties (i.e., compression, tension, bending, and torsion response) of these scaffolds are significantly important for load-bearing orthopaedic implants. In this study, we designed and additively manufactured porous metallic biomaterials based on two different types of triply periodic minimal surface structures (i.e., gyroid and diamond) that mimic the mechanical properties of bone, such as porosity, stiffness, and strength. Physical and mechanical properties, including compressive, tensile, bending, and torsional stiffness and strength of the developed scaffolds, were then characterised experimentally and numerically using finite element method. Sheet thickness was constant at 300 µm, and the unit cell size was varied to generate different pore sizes and porosities. Gyroid scaffolds had a pore size in the range of 600-1200 µm and a porosity in the range of 54-72%, respectively. Corresponding values for the diamond were 900-1500 µm and 56-70%. Both structure types were validated experimentally, and a wide range of mechanical properties (including stiffness and yield strength) were predicted using the finite element method. The stiffness and strength of both structures are comparable to that of cortical bone, hence reducing the risks of scaffold failure. The results demonstrate that the developed scaffolds mimic the physical and mechanical properties of cortical bone and can be suitable for bone replacement and orthopaedic implants. However, an optimal design should be chosen based on specific performance requirements.

On the mechanical aspect of additive manufactured polyether-ether-ketone scaffold for repair of large bone defects.

Polyether-ether-ketone (PEEK) is widely used in producing prosthesis and have gained great attention for repair of large bone defect in recent years with the development of additive manufacturing. This is due to its excellent biocompatibility, good heat and chemical stability and similar mechanical properties which mimics natural bone. In this study, three replicates of rectilinear scaffolds were designed for compression, tension, three-point bending and torsion test with unit cell size of 0.8 mm, a pore size of 0.4 mm, strut thickness of 0.4 mm and nominal porosity of 50%. Stress-strain graphs were developed from experimental and finite element analysis models. Experimental Young's modulus and yield strength of the scaffolds were measured from the slop of the stress-strain graph to be 395 and 19.50 MPa respectively for compression, 427 and 6.96 MPa respectively for tension, 257 and 25.30 MPa respectively for three-point bending and 231 and 12.83 MPa respectively for torsion test. The finite element model was found to be in good agreement with the experimental results. Ductile fracture of the struct subjected to tensile strain was the main failure mode of the PEEK scaffold, which stems from the low crystallinity of additive manufacturing PEEK. The mechanical properties of porous PEEK are close to those of cancellous bone and thus are expected to be used in additive manufacturing PEEK bone implants in the future, but the lower yield strength poses a design challenge.

Additive manufactured polyether-ether-ketone implants for orthopaedic applications: a narrative review.

Polyether-ether-ketone (PEEK) is believed to be the next-generation biomedical material for orthopaedic implants that may replace metal materials because of its good biocompatibility, appropriate mechanical properties and radiolucency. Currently, some PEEK implants have been used successfully for many years. However, there is no customised PEEK orthopaedic implant made by additive manufacturing licensed for the market, although clinical trials have been increasingly reported. In this review article, design criteria, including geometric matching, functional restoration, strength safety, early fixation, long-term stability and manufacturing capability, are summarised, focusing on the clinical requirements. An integrated framework of design and manufacturing processes to create customised PEEK implants is presented, and several typical clinical applications such as cranioplasty patches, rib prostheses, mandibular prostheses, scapula prostheses and femoral prostheses are described. The main technical challenge faced by PEEK orthopaedic implants lies in the poor bonding with bone and soft tissue due to its biological inertness, which may be solved by adding bioactive fillers and manufacturing porous architecture. The lack of technical standards is also one of the major factors preventing additive-manufactured customised PEEK orthopaedic implants from clinical translation, and it is good to see that the abundance of standards in the field of additive-manufactured medical devices is helping them enter the clinical market.

Additive manufactured polyether-ether-ketone composite scaffolds with hydroxyapatite filler and porous structure promoted the integration with soft tissue.

Additive Manufactured (AM) Polyether-ether-ketone (PEEK) orthopaedic implants offer new opportunities for bone substitutes. However, owing to its chemical inertness, the integration between PEEK implants and soft tissue represents a major challenge threatening the early success of the PEEK implants. Here we investigated the influence of hydroxyapatite (HA) fillers and porous structure of AM HA/PEEK scaffolds on the integration with soft tissue through in-vitro cellular experiments and in-vivo rabbit experiments. Among the animal experiments, HA/PEEK composite scaffolds with HA contents of 0, 20 wt%, 40 wt% and pore sizes of 0.8 mm, 1.6 mm were manufactured by fused filament fabrication. The results indicated that HA promoted the proliferation and adhesion of myofibroblasts on PEEK-based composites by releasing Ca2+ to active FAK and its downstream proteins, while the surface morphology of the scaffolds was also roughened by the HA particles, both of which led to the tighter adhesion between HA/PEEK scaffolds and soft tissue in-vivo. The macroscopic bonding force between soft tissue and scaffolds was dominated by the pore size of the scaffolds but was hardly affected by neither the HA content and nor the surface morphology. Scaffolds with larger pore size bonded more strongly to the soft tissue, and the maximum bonding force reached to 5.61 ± 2.55 N for 40 wt% HA/PEEK scaffolds with pore size of 1.6 mm, which was higher than that between natural bone and soft tissue of rabbits. Although the larger pore size and higher HA content of the PEEK-based scaffolds facilitated the bonding with the soft tissue, the consequent outcome of reduced mechanical properties has to be compromised in the design of the porous PEEK-based composite implants. The present study provides engineering-accessible synergistic strategies on material components and porous architecture of AM PEEK orthopaedic implants for improving the integration with soft tissue.

The Promotion of Mechanical Properties by Bone Ingrowth in Additive-Manufactured Titanium Scaffolds.

Although the initial mechanical properties of additive-manufactured (AM) metal scaffolds have been thoroughly studied and have become a cornerstone in the design of porous orthopaedic implants, the potential promotion of the mechanical properties of the scaffolds by bone ingrowth has barely been studied. In this study, the promotion of bone ingrowth on the mechanical properties of AM titanium alloy scaffolds was investigated through in vivo experiments and numerical simulation. On one hand, the osseointegration characteristics of scaffolds with architectures of body-centred cubic (BCC) and diamond were compared through animal experiments in which the mechanical properties of both scaffolds were not enhanced by the four-week implantation. On the other hand, the influences of the type and morphology of bone tissue in the BCC scaffolds on its mechanical properties were investigated by the finite element model of osseointegrated scaffolds, which was calibrated by the results of biomechanical testing. Significant promotion of the mechanical properties of AM metal scaffolds was only found when cortical bone filled the pores in the scaffolds. This paper provides a numerical prediction method to investigate the effect of bone ingrowth on the mechanical properties of AM porous implants, which might be valuable for the design of porous implants.

The development of catalysts for electrochemical nitrogen reduction toward ammonia: theoretical and experimental advances.

Ammonia (NH3) is essential for the industrial production of fertilizers, pharmaceuticals, plastics, synthetic fibers, resins, and chemicals, and it is also a promising carbon-free energy carrier. The electrocatalytic nitrogen reduction reaction (eNRR) driven by renewable energy sources at ambient temperature and atmospheric pressure is an alternative approach to the Haber-Bosch process for NH3 synthesis. However, the efficient electrocatalytic reduction of nitrogen (N2) to NH3 is challenging due to the lack of effective electrocatalysts. Tremendous effort has been made to develop high-performance electrocatalysts for the eNRR in the past few years. In this review, we summarize recent progress relating to electrocatalysts for the eNRR from both theoretical and experimental aspects. Remaining challenges and perspectives for promoting the eNRR to generate NH3 are also discussed. This review hopes to guide the design and development of efficient electrocatalysts for the eNRR for NH3 synthesis.

New brefeldin A-cinnamic acid ester derivatives as potential antitumor agents: Design, synthesis and biological evaluation.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and ranks third in mortality rate worldwide. Brefeldin A (BFA, 1), a natural Arf1 inhibitor, qualifies extremely superior antitumor activity against HCC while its low aqueous solubility, poor bioavailability, and high toxicity have greatly hindered its translation to the clinic. Herein, a series of BFA-cinnamic acid ester derivatives was rationally designed and synthesized via introducing active cinnamic acid and its analogues into the structure of 1. Their in vitro cytotoxic activities on five cancer cell lines, including HepG2, BEL-7402, HeLa, Eca-109 and PANC-1, were evaluated using MTT assay. As expected, favorable cytotoxic activity was observed on majority of the mono-substituted derivatives. Especially, the most potent brefeldin A 4-O-(4)-dimethylaminocinnamate (CHNQD-01269, 33) with improved aqueous solubility, demonstrated the strong cytotoxic activity against HepG2 and BEL-7402 cell lines with IC50 values of 0.29 and 0.84 µM, respectively. More importantly, 33 performed low toxicity on normal liver cell line L-02 with the selectivity index (SI) of 9.69, which was more than 17-fold higher than that of 1. Results from mechanistic studies represented that 33 blocked the cell cycle in the G1 phase, and induced apoptosis via elevating reactive oxygen species (ROS) production and increasing expression of apoptosis-related proteins of HepG2 cells. Docking experiment also suggested 33 a promising Arf1 inhibitor, which was confirmed by the cellular thermal shift assay that 33 displayed a significant effect on the stability of Arf1 protein. Furthermore, 33 possessed high safety profile (MTD >100 mg/kg, ip) and favorable pharmacokinetic properties. Notably, the superior antiproliferative activity was verified in HepG2 tumor-bearing xenograft model in which 33 markedly suppressed the tumor growth (TGI = 46.17%) in nude mice at a dose of 10 mg/kg once a day for 16 d. The present study provided evidence of exploiting this series of highly efficacious derivatives, especially 33, for the treatment of HCC.

Efficient Electrocatalytic Nitrogen Reduction to Ammonia on Ultrafine Sn Nanoparticles.

Electrocatalytic nitrogen reduction reaction (NRR) at ambient conditions is a promising route for ammonia (NH3) synthesis but still suffers from low activity and selectivity. Here, ultrafine Sn nanoparticles (NPs) grown on carbon blacks (SnSC/C) have been synthesized through a wet-chemical method using sodium citrate dehydrate as a stabilizing agent. Benefiting from the small sizes of Sn NPs, the SnSC/C catalyst exhibits excellent electrocatalytic performance for NRR with a high Faradaic efficiency of 22.76% and an NH3 yield rate of 17.28 µg h-1 mg-1 in the 0.1 M Na2SO4 electrolyte, outperforming many reported electrocatalysts for NRR under similar conditions. Density functional theory calculation results reveal that the potential-determining step on Sn NPs is the generation of NHNH* through simultaneous hydrogenation of N2* by a H* and a H+/e- pair via Langmuir-Hinshelwood plus Eley-Rideal mechanisms.

Tuning the electronic structure of NiCoVOx nanosheets through S doping for enhanced oxygen evolution.

It is of great importance to develop efficient and low-cost oxygen evolution reaction (OER) electrocatalysts for electrochemical water splitting. Herein, S doped NiCoVOx nanosheets grown on Ni-Foam (S-NiCoVOx/NF) with a modified electronic structure have been prepared through a facile one-step hydrothermal method. The as-prepared S4.06-NiCoVOx/NF exhibits outstanding OER activity with low overpotentials of 248 mV and 289 mV to deliver current densities of 10 mA cm-2 and 100 mA cm-2, respectively, and a small Tafel slope of 46.2 mV dec-1 in 1.0 M KOH electrolyte. These values are much lower than those obtained for most of the recently reported non-noble metal-based electrocatalysts under similar experimental conditions. This study provides a simple approach to rational design of efficient and cost-effective OER electrocatalysts for practical application of electrochemical water splitting.

Additively-manufactured PEEK/HA porous scaffolds with highly-controllable mechanical properties and excellent biocompatibility.

Polyetheretherketone (PEEK) was widely applied into fabricating of orthopaedic implants, benefitting its excellent biocompatibility and similar mechanical properties to native bones. However, the inertness of PEEK hinders its integration with the surrounding bone tissue. Here PEEK scaffolds with a series of hydroxyapatite (HA) contents in gradient were manufactured via fused filament fabrication (FFF) 3D printing techniques. The influence of the pore size, HA content and printing direction on the mechanical properties of the PEEK/HA scaffolds was systematically evaluated. By adjusting the pore size and HA contents, the elastic modulus of the PEEK/HA scaffolds can be widely tuned in the range of 624.7-50.6 MPa, similar to the variation range of natural cancellous bone. Meanwhile, the scaffolds exhibited higher Young's modulus and lower compressive strength along Z printing direction. The mapping relationship among geometric parameters, HA content, printing direction and mechanical properties was established, which gave more accurate predictions and controllability of the modulus and strength of scaffolds. The PEEK/HA scaffolds with the micro-structured surface could promote cell attachment and mineralization in vitro. Therefore, the FFF-printed PEEK/HA composites scaffolds can be a good candidate for bone grafting and tissue engineering.