Regulating Chondro-Bone Metabolism for Treatment of Osteoarthritis via High-Permeability Micro/Nano Hydrogel Microspheres.

Destruction of cartilage due to the abnormal remodeling of subchondral bone (SB) leads to osteoarthritis (OA), and restoring chondro-bone metabolic homeostasis is the key to the treatment of OA. However, traditional intra-articular injections for the treatment of OA cannot directly break through the cartilage barrier to reach SB. In this study, the hydrothermal method is used to synthesize ultra-small size (≈5 nm) selenium-doped carbon quantum dots (Se-CQDs, SC), which conjugated with triphenylphosphine (TPP) to create TPP-Se-CQDs (SCT). Further, SCT is dynamically complexed with hyaluronic acid modified with aldehyde and methacrylic anhydride (AHAMA) to construct highly permeable micro/nano hydrogel microspheres (SCT@AHAMA) for restoring chondro-bone metabolic homeostasis. In vitro experiments confirmed that the selenium atoms scavenged reactive oxygen species (ROS) from the mitochondria of mononuclear macrophages, inhibited osteoclast differentiation and function, and suppressed early chondrocyte apoptosis to maintain a balance between cartilage matrix synthesis and catabolism. In vivo experiments further demonstrated that the delivery system inhibited osteoclastogenesis and H-vessel invasion, thereby regulating the initiation and process of abnormal bone remodeling and inhibiting cartilage degeneration in SB. In conclusion, the micro/nano hydrogel microspheres based on ultra-small quantum dots facilitate the efficient penetration of articular SB and regulate chondro-bone metabolism for OA treatment.

Seamlessly Adhesive Bionic Periosteum Patches Via Filling Microcracks for Defective Bone Healing.

Current artificial designs of the periosteum focus on osteogenic or angiogenic properties, while ignoring the filling and integration with bone microcracks, which trigger a prolonged excessive inflammatory reaction and lead to failure of bone regeneration. In this study, seamless adhesive biomimetic periosteum patches (HABP/Sr-PLA) were prepared to fill microcracks in defective bone via interfacial self-assembly induced by Sr ions mediated metal-ligand interactions among pamidronate disodium-modified hyaluronic acid (HAPD), black phosphorus (BP), and hydrophilic polylactic acid (PLA). In vitro, HABP/Sr-PLA exhibited excellent self-healing properties, seamlessly filled bone microcracks, and significantly enhanced osteogenesis and angiogenesis. Furthermore, in a rat cranial defect model, HABP/Sr-PLA was demonstrated to significantly promote the formation of blood vessels and new bone under mild 808 nm photothermal stimulation (42.8 °C), and the highest protein expression of CD31 and OPN was five times higher than that of the control group and other groups. Therefore, the proposed seamless microcrack-filled bionic periosteum patch is a promising clinical strategy for promoting bone repair.

FePSe3 -Nanosheets-Integrated Cryogenic-3D-Printed Multifunctional Calcium Phosphate Scaffolds for Synergistic Therapy of Osteosarcoma.

Clinical treatment of osteosarcoma encounters great challenges of postsurgical tumor recurrence and extensive bone defect. To develop an advanced artificial bone substitute that can achieve synergistic bone regeneration and tumor therapy for osteosarcoma treatment, a multifunctional calcium phosphate composite enabled by incorporation of bioactive FePSe3 -nanosheets within the cryogenic-3D-printed α-tricalcium phosphate scaffold (TCP-FePSe3 ) is explored. The TCP-FePSe3 scaffold exhibits remarkable tumor ablation ability due to the excellent NIR-II (1064 nm) photothermal property of FePSe3 -nanosheets. Moreover, the biodegradable TCP-FePSe3 scaffold can release selenium element to suppress tumor recurrence by activating of the caspase-dependent apoptosis pathway. In a subcutaneous tumor model, it is demonstrated that tumors can be efficiently eradicated via the combination treatment with local photothermal ablation and the antitumor effect of selenium element. Meanwhile, in a rat calvarial bone defect model, the superior angiogenesis and osteogenesis induced by TCP-FePSe3 scaffold have been observed in vivo. The TCP-FePSe3 scaffold possesses improved capability to promote the repair of bone defects via vascularized bone regeneration, which is induced by the bioactive ions of Fe, Ca, and P released during the biodegradation of the implanted scaffolds. The TCP-FePSe3 composite scaffolds fabricated by cryogenic-3D-printing illustrate a distinctive strategy to construct multifunctional platform for osteosarcoma treatment.

Multifunctional Scaffold for Osteoporotic Pathophysiological Microenvironment Improvement and Vascularized Bone Defect Regeneration.

Osteoporosis is a degenerative bone disease resulting from bone homeostasis imbalance regulated by osteoblasts and osteoclasts. Treating osteoporotic bone defects tends to be more difficult due to suppressed osteogenic differentiation, hyperactive osteoclastogenesis, and impaired angiogenesis. Hence, a drug carrier system composed of gelatin-coated hollow mesoporous silica nanoparticles (HMSNs/GM) loaded with pro-osteogenic parathyroid (PTH) and anti-osteoclastogenic alendronate (ALN) is constructed and compounded into calcium magnesium phosphate cement (MCPC). The spatial-temporal release of ions and drugs, controllable degradation rate, and abundant pore structure of MCPC composites enhance osteoporotic bone regeneration in ovariectomized rats by accelerating vascularization, promoting osteogenic differentiation and mineralization, and inhibiting osteoclastogenesis and bone resorption. The MCPC/HMSNs@ALN-PTH/GM demonstrates a synergistic threefold effect on osteogenesis, osteoclastogenesis, and angiogenesis. It improves the osteoporotic pathophysiological microenvironment and promotes osteoporotic vascularized bone defect regeneration, holding huge potential for other functional biomaterials design and clinical management.

Mesoporous bioglass capsule composite injectable hydrogels with antibacterial and vascularization promotion properties for chronic wound repair.

Building an angiogenesis microenvironment and inhibiting wound infection are of great significance for chronic wound repair. In this paper, polydopamine-encapsulated mesoporous bioglass (MBG@PDA) capsules were constructed to realize the integration of angiogenesis and infection inhibition through the formation of a composite hydrogel with modified hyaluronic acid (HAMA) to promote wound healing. The experiments showed that the composite hydrogel had good adhesion and toughness and promoted the migration of fibroblasts to accelerate the epithelialization process. In addition, in the composite hydrogel, MBG@PDA could release Mg2+ to promote the proliferation and migration of vascular endothelial cells for angiogenesis. At the same time, MBG@PDA in the composite hydrogel could facilitate the long-term release of drugs to inhibit the growth of Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) for reducing the possibility of wound infection. Finally, the results of in vivo experiments showed that a multifunctional dressing could repair wounds more quickly by promoting angiogenesis and reducing the pathological areas. In summary, the construction of these composite hydrogels can provide a repair method in the wound-repair field.

Photothermal Hydrogel Encapsulating Intelligently Bacteria-Capturing Bio-MOF for Infectious Wound Healing.

Chronic wounds are characterized by long-term inflammation and persistent infection, which make them difficult to heal. Therefore, an urgent desire is to develop a multifunctional wound dressing that can prevent wound infection and promote wound healing by creating a favorable microenvironment. In this study, a curcumin-based metal-organic framework (QCSMOF-Van), loaded with vancomycin and coated with quaternary ammonium salt chitosan (QCS), was prepared. Multifunctional composite hydrogels were conveniently synthesized by combining methacrylic anhydride modified gelatin and methacrylic anhydride modified oxidized sodium alginate with QCSMOF-Van through radical polymerization and Schiff base reaction. It is important to note that the QCSMOF-Van could capture bacteria through the positive charges on the surface of QCS. In this process, due to the synergistic effect of broad-spectrum antibacterial Zn2+ and vancomycin, the metabolism of bacteria was well inhibited, and the efficient capturing and rapid killing of bacteria were achieved. The QCSMOF-Van hydrogels could precisely regulate the balance of M1/M2 phenotypes of macrophages, thereby promoting the regeneration of nerves and blood vessels, which promotes the rapid healing of chronic wounds. This advanced cascade management strategy for tissue regeneration highlights the potential of multifunctional composite hydrogels in chronic wound dressings.

Progress of delivery methods for CRISPR-Cas9.

INTRODUCTION: Gene therapy is becoming increasingly common in clinical practice, giving hope for the correction of a wide range of human diseases and defects. The CRISPR/Cas9 system, consisting of the Cas9 nuclease and single-guide RNA (sgRNA), has revolutionized the field of gene editing. However, efficiently delivering the CRISPR-Cas9 to the target organ or cell remains a significant challenge. In recent years, with rapid advances in nanoscience, materials science, and medicine, researchers have developed various technologies that can deliver CRISPR-Cas9 in different forms for in vitro and in vivo gene editing. Here, we review the development of the CRISPR-Cas9 and describe the delivery forms and the vectors that have emerged in CRISPR-Cas9 delivery, summarizing the key barriers and the promising strategies that vectors currently face in delivering the CRISPR-Cas9. AREAS COVERED: With the rapid development of CRISPR-Cas9, delivery methods are becoming increasingly important in the in vivo delivery of CRISPR-Cas9. EXPERT OPINION: CRISPR-Cas9 is becoming increasingly common in clinical trials. However, the complex nuclease and protease environment is a tremendous challenge for in vivo clinical applications. Therefore, the development of delivery methods is highly likely to take the application of CRISPR-Cas9 technology to another level.