Tantalum Particles Promote M2 Macrophage Polarization and Regulate Local Bone Metabolism via Macrophage-Derived Exosomes Influencing the Fates of BMSCs.

In this study, the regulatory role and mechanisms of tantalum (Ta) particles in the bone tissue microenvironment are explored. Ta particle deposition occurs in both clinical samples and animal tissues following porous Ta implantation. Unlike titanium (Ti) particles promoting M1 macrophage (Mϕ) polarization, Ta particles regulating calcium signaling pathways and promoting M2 Mϕ polarization. Ta-induced M2 Mϕ enhances bone marrow-derived mesenchymal stem cells (BMSCs) proliferation, migration, and osteogenic differentiation through exosomes (Exo) by upregulating miR-378a-3p/miR-221-5p and downregulating miR-155-5p/miR-212-5p. Ta particles suppress the pro-inflammatory and bone resorption effects of Ti particles in vivo and in vitro. In a rat femoral condyle bone defect model, artificial bone loaded with Ta particles promotes endogenous Mϕ polarization toward M2 differentiation at the defect site, accelerating bone repair. In conclusion, Ta particles modulate Mϕ polarization toward M2 and influence BMSCs osteogenic capacity through Exo secreted by M2 Mϕ, providing insights for potential bone repair applications.

Cobalt-doped layered hydroxide coating on titanium implants promotes vascularization and osteogenesis for accelerated fracture healing.

Angiogenesis at the fracture site plays crucial roles in the endogenous osteogenesis process and is a prerequisite for the efficient repair of implant fixed bone defects. To improve the peri-implant vascularization of titanium implant for accelerating defect healing, we developed a Co-doped Mg-Al layered hydroxide coating on the surface of titanium using hydrothermal reaction and then modified the surface with gallic acid (Ti-LDH/GA). Gallic acid coating enabled the sustained release of Co2+ and Mg2+ to the defect site over a month. Ti-LDH/GA treatment profoundly stimulated the angiogenic potential of endothelial cells by upregulating the vascularization regulators such as vascular endothelial growth factor VEGF) and hypoxia-inducible factor-1α (HIF-1α), leading to enhanced osteogenic capability of mesenchymal stem cells (MSCs). These pro-bone healing benefits were attributed to the synergistic effects of Co ions and Mg ions in promoting angiogenesis and new bone formation. These insights collectively suggested the potent pro-osteogenic effect of Ti-LDH/GA through leveraging peri-implant vascularization, offering a new approach for developing biofunctional titanium implants.

Osteogenic differentiation of the MSCs on silk fibroin hydrogel loaded Fe3O4@PAA NPs in static magnetic field environment.

The combination of static magnetic field and magnetic materials for bone tissue repair provides a remote, minimally invasive, and uncomplicated treatment method. Although materials based on Fe3O4 nanoparticles (Fe3O4 NPs) have been widely applied in bone tissue regeneration, the high mobility of Fe3O4 NPs and the oxidative stress involving hydrogen peroxide (H2O2) limit its applications. In this work, silk fibroin (SF) hydrogel was selected to astrict the flowability of Fe3O4 NPs. SF has strong biocompatibility and inducement to the osteogenic differentiation of mesenchymal stem cells (MSCs). In order to reduce the influence of oxidative stress, polyacrylic acid (PAA) was employed to modify the Fe3O4 NPs. The results indicated that Fe3O4@PAA nanoparticles (Fe3O4@PAA NPs) eliminated about 40 % H2O2 in 3 hrs and reduced hydroxyl radicals produced by Fenton reaction. Intracellular studies have shown that SF hydrogel contained Fe3O4@PAA NPs reduced intracellular ROS-induced damage and thus improved cell activity. Compared with other groups, the ALP activity, mineralization ability and collagen secretion level of MSCs on SF hydrogel with Fe3O4@PAA NPs were higher when magnetic field exists.

Multifunctional silicon calcium phosphate composite scaffolds promote stem cell recruitment and bone regeneration.

A scaffold is one of the most significant implants for treating bone injury, while the precise control of stem cell proliferation and differentiation within a scaffold is still challenging. In this work, a composite scaffold was designed to be capable of recruiting endogenous stem cells, stimulating osteogenic differentiation and achieving significant bone repair function. The designed SiCP + SF@PFS silica-calcium phosphate composite scaffold was obtained by mixing the peptide PFS containing silk fibroin solution with the SiCP scaffold, and treating with horseradish peroxidase and H2O2. The results showed that the composite scaffold was able to release the PFS peptide continuously to induce the migration of mesenchymal stem cells. Meanwhile, cell proliferation and osteogenic differentiation were also improved after being seeded on the scaffold. In the cranial defect rat model, the composite scaffold was able to recruit CD29+ and CD90+ cells one week after implantation around the injury sites. The results of Micro-CT, H&E staining, Masson's staining and immunohistochemical staining indicated that the composite scaffold was able to promote new bone formation significantly.

Recent advances in 3D hydrogel culture systems for mesenchymal stem cell-based therapy and cell behavior regulation.

Mesenchymal stem cells (MSCs) have been increasingly recognized as a resource for disease treatment and regenerative medicine. Meanwhile, the unique chemical and physical properties of hydrogels provide innate advantages to achieve high quality MSCs on a large scale. Tremendous kinds of biomaterials have been employed to form hydrogels providing a controllable microenvironment for culturing MSCs. The development of materials science makes it possible to mimic the natural extracellular matrix (ECM), providing an effective means to understand mechanisms such as sensing and remodeling of the different microenvironments by MSCs. The mechanical cues, the formation mechanisms, material types and combination hydrogels are all discussed in this review for three-dimensional (3D) hydrogel culture systems. This article also focuses on the latest development of hydrogel culture systems applied both in vivo and in vitro. Besides the innovation of materials, the culture methods and spatiotemporal cues during the culture stage are other directions of exploration for 3D culture systems. The ultimate goal of hydrogel 3D culture systems is to perfectly mimic the native microenvironment for the study of MSC behavior or the applications of MSC-based therapies.

Self-renewal or quiescence? Orchestrating the fate of mesenchymal stem cells by matrix viscoelasticity via PI3K/Akt-CDK1 pathway.

To control the fate of mesenchymal stem cells (MSCs) in a 3D environment by adjusting the mechanical parameters of MSC-loading scaffolds, is one of the hot topics in the field of regenerative biomaterials. However, a thorough understanding of the relevant MSCs behaviors affected by viscoelasticity, a dynamic physical parameter of scaffolds, is still lacking. Herein, we established an alginate hydrogel system with constant stiffness and tunable stress relaxation rate, which is a key parameter for the viscoelastic property of material. MSCs were cultured inside three groups of alginate hydrogels with various stress relaxation rates, and then RNA-seq analysis of cells was performed. Results showed that the change of stress relaxation rates of hydrogels regulated the most of the different expression genes of MSCs, which were enriched in cell proliferation-related pathways. MSCs cultured in hydrogels with fast stress relaxation rate presented a high self-renewal proliferation profile via activating phosphatidylinositol 3- kinase (PI3K)/protein kinase B (Akt) pathway. In contrast, a slow stress relaxation rate of hydrogels induced MSCs to enter a reversible quiescence state due to the weakened PI3K/Akt activation. Combined with a further finite element analysis, we speculated that the quiescence of MSCs could be served as a positive strategy for MSCs to deal with the matrix with a low deformation to keep stemness. Based on the results, we identified that stress relaxation rate of hydrogel was a potential physical factor of hydrogel to regulate the self-renewal or quiescence of MSCs. Thus, our findings provide a significant guiding principle for the design of MSCs-encapsulated biomaterials.

Engineering of Cascade-Responsive Nanoplatform to Inhibit Lactate Efflux for Enhanced Tumor Chemo-Immunotherapy.

As an increased product of high-rate aerobic glycolysis in tumors, lactate could regulate the immunosuppressive tumor microenvironment (TME). A PEG-CDM surface modified, GSH-dependent responsive hollow mesoporous organosilica nanoplatform loaded with hydroxycamptothecin (HCPT) and siMCT-4 was administrated for synergistic tumor chemo-immunotherapy. The nanoplatform cascaded responded to the weak acid TME and the high level of GSH in tumor cells. HCPT and siMCT-4 were continuously released from the nanoplatform for chemotherapy and inhibiting intracellular lactate efflux. The increased intracellular lactate and HCPT effectively induced tumor cell apoptosis. Moreover, the decreased extracellular lactate polarized tumor-associated macrophages (TAMs) phenotype from M2 type to M1 type and restored CD8+ T cell activity in vivo. The results demonstrated that the nanoplatform effectively removed the immunosuppressive TME, inhibited tumor growth, and suppressed lung metastasis of B16F10 cells and 4T1 cells via the combination of inhibiting lactate efflux and chemotherapy. Accordingly, it suggested a strategy to transform immunosuppressive tumors into "hot" tumors and inhibit the tumor growth with high efficiency in vivo.

A facile and novel design of multifunctional electronic skin based on polydimethylsiloxane with micropillars for signal monitoring.

Electronic skins (e-skins) with monitoring capabilities have attracted extensive attention and are being widely employed in wearable devices for medical diagnosis. In particular, e-skins based on strain sensors have been reported extensively due to their simple structure and efficient performance in collecting human physiological information. Flexible sensors with high sensitivity, simplified fabrication, and low-cost are highly desired for human signal monitoring; this work provides a novel strain-sensing e-skin with micro-structures, which is simply made of modified polydimethylsiloxane (PDMS) and silver nanowires (AgNWs). The fabricated e-skin has great sensitivity towards strain changes, and its mechanical properties and sensitivity could be regulated by varying the micro-structures. Furthermore, the e-skin demonstrated significant capacity for monitoring human body movements, temperature changes, and spatial resolution, highlighting its great potential in personalized medicine.

A dynamic matrix potentiates mesenchymal stromal cell paracrine function via an effective mechanical dose.

The paracrine function of mesenchymal stromal cells (MSCs) contributes a lot to tissue development, and it is regulated by various physical factors. Moreover, the extracellular matrix (ECM) of MSCs is dynamic, and its remodeling is always occurring. In particular, stiffness changes are prevalent. Accordingly, ECM stiffness changes may affect the paracrine function of MSCs, which has not been investigated much. In this study, for the first time, alginate hydrogels with different stiffening times were used to assess the influence of dynamic ECM stiffness changes on the paracrine function of MSCs. It was found that a stiffer matrix (14.72 ± 1.44 kPa) under static conditions without any additional treatment could significantly potentiate the paracrine function of MSCs compared to a soft matrix (2.44 ± 0.23 kPa). Furthermore, this promotion was regulated by the activation of Yes-associated protein (YAP), which was caused by the polymerization of F-actin. Intriguingly, in a dynamic system, the MSC-encapsulating matrix that stiffened on the third day had stronger YAP activation than the Static-Stiff matrix. However, this activation was weakened when MSCs were cultured in a matrix that stiffened on the fifth day. The results show that an increase in ECM mechanical dosing levels would promote the paracrine function of MSCs. Moreover, an effective mechanical dose that can influence the paracrine function of MSCs indeed exists.

Redox-responsive amphiphilic camptothecin prodrug nanoparticles for targeted liver tumor therapy.

Tumor cell-targeting drug delivery systems are of great importance to anti-tumor therapy in clinics. Owing to the overexpression of the asialoglycoprotein receptor (ASGPR) on the membrane of hepatoma carcinoma cells, the conjugation of lactose on the surface of drug delivery systems has already shown significant advantages for targeting tumor cells. In this study, a disulfide bond-conjugated prodrug targeting delivery system consisting of camptothecin (CPT) and lactose (LA) was synthesized, which was denoted as CPT-S-S-LA. Camptothecin and lactose act as the chemotherapy drug and targeting ligand in the drug delivery system, respectively. Since CPT-S-S-LA is an amphiphilic compound, it can self-assemble into nanoparticles with a diameter of around 110 nm. The CPT-S-S-LA nanoparticles displayed controllable drug release behavior in the physiological environment. Unlike the free CPT, the CPT-S-S-LA nanoparticles firstly assembled at the tumor sites via the enhanced permeability and retention (EPR) effect, and then were phagocytized by the tumor cells with ASGP receptor-mediated endocytosis. Finally, the antitumor agent CPT was released for killing tumor cells, which have a high glutathione (GSH) concentration environment. The nanoparticles displayed favorable ability to target hepatoma carcinoma cells rather than the normal HUVEC cells in vitro. Both the in vitro and in vivo studies demonstrated that the CPT-S-S-LA nanoparticles display enhanced antitumor ability and reduced side effects. Thus, active targeting prodrug delivery systems should be a promising strategy for liver tumor therapy.

Rapid and sensitive detection of Salmonella Typhimurium using nickel nanowire bridge for electrochemical impedance amplification.

Rapid detection of foodborne pathogens is crucial to prevent the outbreaks of foodborne illnesses. In this study, a sensitive electrochemical aptasensor was developed using aptamer coated gold interdigitated microelectrode for target capture and impedance measurement, and antibody modified nickel nanowires (NiNWs) for target separation and impedance amplification. First, the interdigitated microelectrode was modified with the biotinylated aptamers against Salmonella typhimurium through electrostatic absorption of streptavidin onto the microelectrode and streptavidin-biotin binding. Then, the target Salmonella cells were magnetically separated and concentrated using the NiNWs modified with the anti-Salmonella typhimurium antibodies to form the bacteria-NiNW complexes, and incubated on the microelectrode to form the aptamer-bacteria-NiNW complexes. After an external arc magnetic field was developed and applied to control the NiNWs to form conductive NiNW bridges across the microelectrode, the enhanced impedance change of the microelectrode was measured and used to determine the amount of target bacteria. This electrochemical aptasensor was able to quantitatively detect Salmonella ranging from 102 to 106 CFU/mL in 2 h with the detection limit of 80 CFU/mL. The mean recovery for the spiked chicken samples was 103.2%.

A review of electronic skin: soft electronics and sensors for human health.

This article reviews several categories of electronic skins (e-skins) for monitoring signals involved in human health. It covers advanced candidate materials, compositions, structures, and integrate strategies of e-skin, focusing on stretchable and wearable electronics. In addition, this article further discusses the potential applications and expected development of e-skins. It is possible to provide a new generation of sensors which are able to introduce artificial intelligence to the clinic and daily healthcare.

Polarization of tumor-associated macrophage phenotype via porous hollow iron nanoparticles for tumor immunotherapy in vivo.

Tumor-associated macrophages (TAMs) are the most important components in the tumor immunosuppressive microenvironment, promoting tumor growth and metastasis. Although TAMs have become one of the hot topics of tumor immunotherapy, challenges still remain to achieve TAM-targeted re-polarization therapy. In this work, porous hollow iron oxide nanoparticles (PHNPs) were synthesized for loading a P13K γ small molecule inhibitor (3-methyladenine, 3-MA) and further modified by mannose to target TAMs. The delivery system named PHNPs@DPA-S-S-BSA-MA@3-MA showed good efficiency for targeting TAMs. The inflammatory factor NF-κB p65 of macrophages was activated by the combination of PHNPs and 3-MA, which synergistically switched TAMs to pro-inflammatory M1-type macrophages. As a result, it activated immune responses and inhibited tumor growth in vivo. The study provides an intracellular switch of the TAM phenotype for targeted TAM therapy.

Regulation of MSC and macrophage functions in bone healing by peptide LL-37-loaded silk fibroin nanoparticles on a titanium surface.

Titanium-based materials have been long regarded as effective bone implants for clinical use, yet the corresponding osteointegration ability needs to be optimized. This challenge can be overcome by fabricating titanium (Ti) materials with physiological functions. In this study, peptide LL-37-loaded silk fibroin nanoparticles (SFNPs) were immobilized on a titanium surface to facilitate osteointegration by regulating the physiological functions of mesenchymal stem cells (MSCs) and macrophages. According to our results, the cell viability, recruitment and paracrine responses of MSCs and macrophages were improved by the modified Ti samples. MSC differentiation was promoted by the macrophages incubated on the modified Ti samples, and the phenotype switch of macrophages was also modulated by the MSCs incubated on the modified Ti samples. In vivo studies proved that the modified Ti implant induced MSC and macrophage recruitments to injury sites and the inflammatory response was positively regulated. Moreover, better bone formation was achieved around the modified Ti implant 28 days after surgery. This suggested that the immobilization of peptide LL-37-loaded SFNPs on a titanium surface improves osteointegration via the regulation of physiological functions of MSCs and macrophages.

Continuous-Flow Separation and Efficient Concentration of Foodborne Bacteria from Large Volume Using Nickel Nanowire Bridge in Microfluidic Chip.

Separation and concentration of target bacteria has become essential to sensitive and accurate detection of foodborne bacteria to ensure food safety. In this study, we developed a bacterial separation system for continuous-flow separation and efficient concentration of foodborne bacteria from large volume using a nickel nanowire (NiNW) bridge in the microfluidic chip. The synthesized NiNWs were first modified with the antibodies against the target bacteria and injected into the microfluidic channel to form the NiNW bridge in the presence of the external arc magnetic field. Then, the large volume of bacterial sample was continuous-flow injected to the channel, resulting in specific capture of the target bacteria by the antibodies on the NiNW bridge to form the NiNW-bacteria complexes. Finally, these complexes were flushed out of the channel and concentrated in a lower volume of buffer solution, after the magnetic field was removed. This bacterial separation system was able to separate up to 74% of target bacteria from 10 mL of bacterial sample at low concentrations of ≤102 CFU/mL in 3 h, and has the potential to separate other pathogenic bacteria from large volumes of food samples by changing the antibodies.

Matrix promote mesenchymal stromal cell migration with improved deformation via nuclear stiffness decrease.

Bone marrow derived mesenchymal stromal cells (BMSCs) migration to injury site is a prevalent event in tissue repair process after damage occurrence. The migration process is always accompanied with matrix stiffness change. In this study, sodium alginate hydrogels with different stiffness and Transwell chambers with gradient chemical factors were employed to mimic tissue repair in vivo. In this work, in the stiffness range of 1-20 kPa, BMSCs in stiffer matrix showed higher migration speed compared to those in softer matrix. Moreover, stiffer matrix decreased the nuclear stiffness of BMSCs and reduced the expression of lamin A/C, which playing a main role in the regulation of nuclear stiffness. Furthermore, it was found that BMSCs fitted environment by selecting migration strategy. This study provides a novel platform for the investigation of BMSCs migration to mimic the natural tissue repair process.

Zn-incorporation with graphene oxide on Ti substrates surface to improve osteogenic activity and inhibit bacterial adhesion.

The poor osseointegration and postoperative bacterial infection are prominently responsible for the failure of titanium (Ti)-based implant in clinic. To address above issues, methacryloyl modified graphene oxide (GOMA) as zinc ions (Zn2+ ) reservoir and release platform was fabricated on the Ti substrates with cathode electrophoresis deposition (EPD). Afterward, phenylboronic acid (PBA) functionalization methacryloyl-gelatin (GelMA-PBA) was reacting with GOMA through in situ free-radical polymerization to prepare GO-Zn/GelMA-PBA coating. The obtained coating was confirmed by scanning electron microscopy, X-ray photoelectron spectroscopy, and Zn ions release property, respectively. in vitro cellular experiments including cell activity, alkaline phosphatase, collagen secretion, extracellular matrix (ECM) mineralization, osteogenic genes and proteins, revealed that GO-Zn/GelMA-PBA coating was beneficial for enhancing the adhesion, proliferation, and differentiation of osteoblasts. The positive results were related to the existence of gelatin, formation of boronic ester between PBA groups, and carbohydrates of osteoblasts surface. Meanwhile, antibacterial assay against Staphylococcus aureus and Pseudomonas aeruginosa confirmed that GO-Zn/GelMA-PBA coating on Ti substrates had superior antibacterial capacity, availably inhibited the bacterial adhesion, and prevented formation of biofilm. Hence, the study provides a promising strategy for designing pro-osteogenesis and antibacterial coating on Ti substrates for orthopedic applications.

Type-II Dirac Photons at Metasurfaces.

Topological characteristics of energy bands, such as Dirac and Weyl nodes, have attracted substantial interest in condensed matter systems as well as in classical wave systems. Among these energy bands, the type-II Dirac point is a nodal degeneracy with tilted conical dispersion, leading to a peculiar crossing dispersion in the constant-energy plane. Such nodal points have recently been found in electronic materials. The analogous topological feature in photonic systems remains a theoretical curiosity, with experimental realization expected to be challenging. Here, we experimentally realize the type-II Dirac point using a planar metasurface architecture, where the band degeneracy point is protected by the underlying mirror symmetry of the metasurface. Gapless edge modes are found and measured at the boundary between the different domains of the symmetry-broken metasurface. Our Letter shows that metasurfaces are simple and practical platforms for realizing electromagnetic type-II Dirac points, and their planar structure is a distinct advantage that facilitates applications in two-dimensional topological photonics.

Shape-Controlled Synthesis of Pt Nanopeanuts.

Exploring the novel shape of Pt nanoparticles is one of the most useful ways to improve the electrocatalytic performance of Pt in fuel cells. In this work, the Pt nanopeanuts consisting of two nanospheres grown together have been fabricated through a two-step polyol method. The high resolution scanning electron microscope (SEM) images and energy dispersive x-ray (EDX) spectrum collected at adjacent part point out the Pt nanopeanut is apparently different from the two physical attached nanospheres. To understand the growth mechanism of this nanopeanut, the final products in different synthesis situations are studied. The results indicate the interesting morphology of Pt nanopeanuts mainly benefit from the chemical reagent (FeCl3) while the size and homogeneity are greatly affected by the temperature. Furthermore, the electrocatalytic activity of the Pt nanopeanuts has also been demonstrated here. Our two-step synthesis of Pt nanopeanuts not only enlarges the group of Pt nanoparticles, but also provides a beneficial strategy for the synthesis of novel metal nanoparticles.

Synthesis of Nickel Nanowires with Tunable Characteristics.

A one-step synthesis of magnetic nickel nanowires (NiNWs) with tunable characteristics is reported. The method is simple and easy to be conducted, leading to high compatibility with scaling-up. It is discovered that the size and morphology of NiNWs can be adjusted by tuning the reaction temperature, time length, as well as surfactant concentration. It is found that the products have shown high purity which remained after being stored for several months. A remarkable enhanced saturation magnetization of the product was also observed, compared to that of bulk nickel. By providing both practical experimental details and in-depth mechanism, the work introduced in this paper may advance the mass production and further applications of NiNWs.