Nanoengineered 3D-printing scaffolds prepared by metal-coordination self-assembly for hyperthermia-catalytic osteosarcoma therapy and bone regeneration.

The integration of functional nanomaterials with tissue engineering scaffolds has emerged as a promising solution for simultaneously treating malignant bone tumors and repairing resected bone defects. However, achieving a uniform bioactive interface on 3D-printing polymer scaffolds with minimized microstructural heterogeneity remains a challenge. In this study, we report a facile metal-coordination self-assembly strategy for the surface engineering of 3D-printed polycaprolactone (PCL) scaffolds with nanostructured two-dimensional conjugated metal-organic frameworks (cMOFs) consisting of Cu ions and 2,3,6,7,10,11-hexahydroxytriphenylene (HHTP). A tunable thickness of Cu-HHTP cMOF on PCL scaffolds was achieved via the alternative deposition of metal ions and HHTP. The resulting composite PCL@Cu-HHTP scaffolds not only demonstrated potent photothermal conversion capability for efficient OS ablation but also promoted the bone repair process by virtue of their cell-friendly hydrophilic interfaces. Therefore, the cMOF-engineered dual-functional 3D-printing scaffolds show promising potential for treating bone tumors by offering sequential anti-tumor effects and bone regeneration capabilities. This work also presents a new avenue for the interface engineering of bioactive scaffolds to meet multifaceted demands in osteosarcoma-related bone defects.

Cyaonoside A-loaded composite hydrogel microspheres to treat osteoarthritis by relieving chondrocyte inflammation.

Cyaonoside A (CyA), derived from the natural Chinese medicine, Cyathula officinalis Kuan, which was for a long time used to treat knee injuries and relieve joint pain in traditional Chinese medicine, showed an unclear mechanism for protecting cartilage. In addition, CyA was poorly hydrosoluble and incapable of being injected directly into the joint cavity, which limited its clinical application. This study reveals that CyA resisted IL-1ß-mediated chondrogenic inflammation and apoptosis. Next, transcriptome sequencing is used to explore the potential mechanisms underlying CyA regulation of MSC chondrogenic differentiation. Based on these findings, CyA-loaded composite hydrogel microspheres (HLC) were developed and they possessed satisfactory loading efficiency, a suitable degradation rate and good biocompatibility. HLC increased chondrogenic anabolic gene (Acan, COL2A, and SOX9) expression, while downregulating the expression of the catabolic marker MMP13 in vitro. In the osteoarthritis mouse model, HLC demonstrated promising therapeutic capabilities by protecting the integrity of articular cartilage. In conclusion, this study provides insights into the regulatory mechanisms of CyA for chondrocytes and proposes a composite hydrogel microsphere-based advanced therapeutic strategy for osteoarthritis.

Functional anti-bone tumor biomaterial scaffold: construction and application.

Bone tumors, including primary bone tumors and bone metastases, have been plagued by poor prognosis for decades. Although most tumor tissue is removed, clinicians are still confronted with the dilemma of eliminating residual cancer cells and regenerating defective bone tissue after surgery. Therefore, functional biomaterial scaffolds are considered to be the ideal candidates to bridge defective tissues and restrain cancer recurrence. Through functionalized structural modifications or coupled therapeutic agents, they provide sufficient mechanical strength and osteoinductive effects while eliminating cancer cells. Numerous novel approaches such as photodynamic, photothermal, drug-conjugated, and immune adjuvant-assisted therapies have exhibited remarkable efficacy against tumors while exhibiting low immunogenicity. This review summarizes the progress of research on biomaterial scaffolds based on different functionalization strategies in bone tumors. We also discuss the feasibility and advantages of the combined application of multiple functionalization strategies. Finally, potential obstacles to the clinical translation of anti-tumor bone bioscaffolds are highlighted. This review will provide valuable references for future advanced biomaterial scaffold design and clinical bone tumor therapy.

Advances in cell membrane-coated nanoparticles and their applications for bone therapy.

Due to the specific structure of natural bone, most of the therapeutics are incapable to be delivered into the targeted site with effective concentrations. Nanotechnology has provided a good way to improve this issue, cell membrane mimetic nanoparticles (NPs) have been emerging as an ideal nanomaterial which integrates the advantages of natural cell membranes with synthetic NPs to significantly improve the biocompatibility as well as achieving long-lasting circulation and targeted delivery. In addition, functionalized modifications of the cell membrane facilitate more precise targeting and therapy. Here, an overview of the preparation of cell membrane-coated NPs and the properties of cell membranes from different cell sources has been given to expatiate their function and potential applications. Strategies for functionalized modification of cell membranes are also briefly described. The application of cell membrane-coated NPs for bone therapy is then presented according to the function of cell membranes. Moreover, the prospects and challenges of cell membrane-coated NPs for translational medicine have also been discussed.

Stat3 Signaling Pathway: A Future Therapeutic Target for Bone-Related Diseases.

Signal transducer and activator of transcription 3 (Stat3) is activated by phosphorylation and translocated to the nucleus to participate in the transcriptional regulation of DNA. Increasing evidences point that aberrant activation or deletion of the Stat3 plays a critical role in a broad range of pathological processes including immune escape, tumorigenesis, and inflammation. In the bone microenvironment, Stat3 acts as a common downstream response protein for multiple cytokines and is engaged in the modulation of cellular proliferation and intercellular interactions. Stat3 has direct impacts on disease progression by regulating mesenchymal stem cells differentiation, osteoclast activation, macrophage polarization, angiogenesis, and cartilage degradation. Here, we describe the theoretical basis and key roles of Stat3 in different bone-related diseases in combination with in vitro experiments and animal models. Then, we summarize and categorize the drugs that target Stat3, providing potential therapeutic strategies for their use in bone-related diseases. In conclusion, Stat3 could be a future target for bone-related diseases.

RANKL from bone marrow adipose lineage cells promotes osteoclast formation and bone loss.

Receptor activator of NF-κB ligand (RANKL) is essential for osteoclast formation and bone remodeling. Nevertheless, the cellular source of RANKL for osteoclastogenesis has not been fully uncovered. Different from peripheral adipose tissue, bone marrow (BM) adipose lineage cells originate from bone marrow mesenchymal stromal cells (BMSCs). Here, we demonstrate that adiponectin promoter-driven Cre expression (AdipoqCre ) can target bone marrow adipose lineage cells. We cross the AdipoqCre mice with ranklfl/fl mice to conditionally delete RANKL from BM adipose lineage cells. Conditional deletion of RANKL increases cancellous bone mass of long bones in mice by reducing the formation of trabecular osteoclasts and inhibiting bone resorption but does not affect cortical bone thickness or resorption of calcified cartilage. AdipoqCre ; ranklfl/fl mice exhibit resistance to estrogen deficiency and rosiglitazone (ROS)-induced trabecular bone loss but show bone loss induced by unloading. BM adipose lineage cells therefore represent an essential source of RANKL for the formation of trabecula osteoclasts and resorption of cancellous bone during remodeling under physiological and pathological conditions. Targeting bone marrow adiposity is a promising way of preventing pathological bone loss.

Bone Marrow Mesenchymal Stromal Cells: Identification, Classification, and Differentiation.

Bone marrow mesenchymal stromal cells (BMSCs), identified as pericytes comprising the hematopoietic niche, are a group of heterogeneous cells composed of multipotent stem cells, including osteochondral and adipocyte progenitors. Nevertheless, the identification and classification are still controversial, which limits their application. In recent years, by lineage tracing and single-cell sequencing, several new subgroups of BMSCs and their roles in normal physiological and pathological conditions have been clarified. Key regulators and mechanisms controlling the fate of BMSCs are being revealed. Cross-talk among subgroups of bone marrow mesenchymal cells has been demonstrated. In this review, we focus on recent advances in the identification and classification of BMSCs, which provides important implications for clinical applications.

Tailored Mesoporous Inorganic Biomaterials: Assembly, Functionalization, and Drug Delivery Engineering.

Infectious or immune diseases have caused serious threat to human health due to their complexity and specificity, and emerging drug delivery systems (DDSs) have evolved into the most promising therapeutic strategy for drug-targeted therapy. Various mesoporous biomaterials are exploited and applied as efficient nanocarriers to loading drugs by virtue of their large surface area, high porosity, and prominent biocompatibility. Nanosized mesoporous nanocarriers show great potential in biomedical research, and it has become the research hotspot in the interdisciplinary field. Herein, recent progress and assembly mechanisms on mesoporous inorganic biomaterials (e.g., silica, carbon, metal oxide) are summarized systematically, and typical functionalization methods (i.e., hybridization, polymerization, and doping) for nanocarriers are also discussed in depth. Particularly, structure-activity relationship and the effect of physicochemical parameters of mesoporous biomaterials, including morphologies (e.g., hollow, core-shell), pore textures (e.g., pore size, pore volume), and surface features (e.g., roughness and hydrophilic/hydrophobic) in DDS application are overviewed and elucidated in detail. As one of the important development directions, advanced stimuli-responsive DDSs (e.g., pH, temperature, redox, ultrasound, light, magnetic field) are highlighted. Finally, the prospect of mesoporous biomaterials in disease therapeutics is stated, and it will open a new spring for the development of mesoporous nanocarriers.

Targeting actin-bundling protein L-plastin as an anabolic therapy for bone loss.

The actin-bundling protein L-plastin (LPL) mediates the resorption activity of osteoclasts, but its therapeutic potential in pathological bone loss remains unexplored. Here, we report that LPL knockout mice show increased bone mass and cortical thickness with more mononuclear tartrate-resistant acid phosphatase-positive cells, osteoblasts, CD31hiEmcnhi endothelial vessels, and fewer multinuclear osteoclasts in the bone marrow and periosteum. LPL deletion impeded preosteoclasts fusion by inhibiting filopodia formation and increased the number of preosteoclasts, which release platelet-derived growth factor-BB to promote CD31hiEmcnhi vessel growth and bone formation. LPL expression is regulated by the phosphatidylinositol 3-kinase/AKT/specific protein 1 axis in response to receptor activator of nuclear factor-κB ligand. Furthermore, we identified an LPL inhibitor, oroxylin A, that could maintain bone mass in ovariectomy-induced osteoporosis and accelerate bone fracture healing in mice. In conclusion, we showed that LPL regulates osteoclasts fusion, and targeting LPL serves as a novel anabolic therapy for pathological bone loss.

New insight into unexpected bone formation by denosumab.

Denosumab (Dmab) was the first monoclonal antibody (mAb) approved for the treatment of osteoporosis. It blocks the receptor activator for nuclear factor κB ligand (RANKL) and acts as a potent antiresorptive agent. In contrast to classic antiresorptive agents, Dmab treatment leads to a progressive increase in bone mass, but the mechanisms remain controversial. Recently, RANKL signaling in osteoblastogenesis and bone formation and RANKL reverse signaling in coupling bone resorption and formation were demonstrated. Thus, here we discuss the roles of RANKL signaling and RANKL reverse signaling in the bone-forming effects of Dmab.

Triptolide prevents bone loss via suppressing osteoclastogenesis through inhibiting PI3K-AKT-NFATc1 pathway.

Bone loss (osteopenia) is a common complication in human solid tumour. In addition, after surgical treatment of gynaecological tumour, osteoporosis often occurs due to the withdrawal of oestrogen. The major characteristic of osteoporosis is the low bone mass with micro-architectural deteriorated bone tissue. And the main cause is the overactivation of osteoclastogenesis, which is one of the most important therapeutic targets. Inflammation could induce the interaction of RANKL/RANK, which is the promoter of osteoclastogenesis. Triptolide is derived from the traditional Chinese herb lei gong teng, presented multiple biological effects, including anti-cancer, anti-inflammation and immunosuppression. We hypothesized that triptolide could inhibits osteoclastogenesis by suppressing inflammation activation. In this study, we confirmed that triptolide could suppress RANKL-induced osteoclastogenesis in bone marrow mononuclear cells (BMMCs) and RAW264.7 cells and inhibited the osteoclast bone resorption functions. PI3K-AKT-NFATc1 pathway is one of the most important downstream pathways of RANKL-induced osteogenesis. The experiments in vitro indicated that triptolide suppresses the activation of PI3K-AKT-NFATc1 pathway and the target point located at the upstream of AKT because both NFATc1 overexpression and AKT phosphorylation could ameliorate the triptolide suppression effects. The expression of MDM2 was elevated, which demonstrated the MDM-p53-induced cell death might contribute to the osteoclastogenesis suppression. Ovariectomy-induced bone loss and inflammation activation were also found to be ameliorated in the experiments in vivo. In summary, the new effect of anti-cancer drug triptolide was demonstrated to be anti-osteoclastogenesis, and we demonstrated triptolide might be a promising therapy for bone loss caused by tumour.

Synthesis of Podlike Magnetic Mesoporous Silica Nanochains for Use as Enzyme Support and Nanostirrer in Biocatalysis.

Magnetic mesoporous materials have attracted great interest due to their combined property of magnetic nanomaterials and mesoporous materials as well as their potential applications in catalysis, bioenrichment, drug delivery, nanoreactors, etc. In this study, one-dimensional (1D) podlike magnetic mesoporous silica nanochains with tunable hollow space (Fe3O4@nSiO2@void@mSiO2 nanochain named as podlike 1D magnetic mesoporous silica (PL-MMS) nanochain) are rationally synthesized for the first time through a controlled magnetic-induced interface coassembly approach. The obtained PL-MMS possesses a tunable diameter (300-500 nm), large and perpendicular mesopores (8.2 nm) in the outer shell, a silica-protected magnetic-responsive core, and a high surface area (325 m2/g). Benefiting from the large voids and unique mesopores, these mesoporous nanochains exhibit superior performance in enzyme (lipase with a size of 4.0 nm) immobilization with a high loading capacity of 223 µg/mg, and the immobilized lipase demonstrates enhanced catalytic activity in different pH values and temperatures as well as excellent tolerance of organic solvent.

Matrine prevents bone loss in ovariectomized mice by inhibiting RANKL-induced osteoclastogenesis.

Osteoporosis is a metabolic bone disease characterized by decreased bone density and strength due to excessive loss of bone protein and mineral content. The imbalance between osteogenesis by osteoblasts and osteoclastogenesis by osteoclasts contributes to the pathogenesis of postmenopausal osteoporosis. Estrogen withdrawal leads to increased levels of proinflammatory cytokines. Overactivated osteoclasts by inflammation play a vital role in the imbalance. Matrine is an alkaloid found in plants from the Sophora genus with various pharmacological effects, including anti-inflammatory activity. Here we demonstrate that matrine significantly prevented ovariectomy-induced bone loss and inhibited osteoclastogenesis in vivo with decreased serum levels of TRAcp5b, TNF-α, and IL-6. In vitro matrine significantly inhibited osteoclast differentiation induced by receptor activator for NF-κB ligand (RANKL) and M-CSF in bone marrow monocytes and RAW264.7 cells as demonstrated by tartrate-resistant acid phosphatase (TRAP) staining and actin-ring formation as well as bone resorption through pit formation assays. For molecular mechanisms, matrine abrogated RANKL-induced activation of NF-κB, AKT, and MAPK pathways and suppressed osteoclastogenesis-related marker expression, including matrix metalloproteinase 9, NFATc1, TRAP, C-Src, and cathepsin K. Our study demonstrates that matrine inhibits osteoclastogenesis through modulation of multiple pathways and that matrine is a promising agent in the treatment of osteoclast-related diseases such as osteoporosis.-Chen, X., Zhi, X., Pan, P., Cui, J., Cao, L., Weng, W., Zhou, Q., Wang, L., Zhai, X. Zhao, Q., Hu, H., Huang, B., Su, J. Matrine prevents bone loss in ovariectomized mice by inhibiting RANKL-induced osteoclastogenesis.

A new suture technique avoids rib fractures and intercostal nerve trauma in thoracotomy.

This article describes an alternative suture technique for thoracotomy incisions. A modified mattress suture technique is used to fix the intercostal muscles. The described technique can prevent rib fractures and reduce the incidence of intercostal nerve injury. Also, this technique is easy to perform and is effective.