Bioactive nanocomposite hydrogel enhances postoperative immunotherapy and bone reconstruction for osteosarcoma treatment.

Osteosarcoma, a malignant bone tumor often characterized by high hedgehog signaling activity, residual tumor cells, and substantial bone defects, poses significant challenges to both treatment response and postsurgical recovery. Here, we developed a nanocomposite hydrogel for the sustained co-delivery of bioactive magnesium ions, anti-PD-L1 antibody (αPD-L1), and hedgehog pathway antagonist vismodegib, to eradicate residual tumor cells while promoting bone regeneration post-surgery. In a mouse model of tibia osteosarcoma, this hydrogel-mediated combination therapy led to remarkable tumor growth inhibition and hence increased animal survival by enhancing the activity of tumor-suppressed CD8+ T cells. Meanwhile, the implanted hydrogel improved the microenvironment of osteogenesis through long-term sustained release of Mg2+, facilitating bone defect repair by upregulating the expression of osteogenic genes. After 21 days, the expression levels of ALP, COL1, RUNX2, and BGLAP in the Vis-αPD-L1-Gel group were approximately 4.1, 5.1, 5.5, and 3.4 times higher than those of the control, respectively. We believe that this hydrogel-based combination therapy offers a potentially valuable strategy for treating osteosarcoma and addressing the tumor-related complex bone diseases.

An Antibacterial Bionic Periosteum with Angiogenesis-Neurogenesis Coupling Effect for Bone Regeneration.

The periosteum, rich in neurovascular networks, bone progenitor cells, and stem cells, is vital for bone repair. Current artificial periosteal materials face challenges in mechanical strength, bacterial infection, and promoting osteogenic differentiation and angiogenesis. To address these issues, we adjusted the electrospinning ratio of poly-ε-caprolactone and chitosan and incorporated Zn doping whitlockite with polydopamine coating into a nanofiber membrane. After a series of characterizations, optimal results were achieved with a poly-ε-caprolactone: chitosan ratio of 8:1 and 5% nanoparticle content. In vitro cell experiments and in vivo calvarial defect models, the sustained release of Mg2+ and Ca2+ promoted vascularization and new bone formation, respectively, while the release of Zn2+ was conducive to antibacterial and cooperated with Mg2+ to promote neurovascularization. Consequently, this antibacterial bionic periosteum with an angiogenesis-neurogenesis coupling effect demonstrates a promising potential for bone repair applications.

Supramolecular Assembly Based on Calix(4)arene and Aggregation-Induced Emission Photosensitizer for Phototherapy of Drug-Resistant Bacteria and Skin Flap Transplantation.

Photodynamic therapy as a burgeoning and non-invasive theranostic technique has drawn great attention in the field of antibacterial treatment but often encounters undesired phototoxicity of photosensitizers during systemic circulation. Herein, a supramolecular substitution strategy is proposed for phototherapy of drug-resistant bacteria and skin flap repair by using macrocyclic p-sulfonatocalix(4)arene (SC4A) as a host, and two cationic aggregation-induced emission luminogens (AIEgens), namely TPE-QAS and TPE-2QAS, bearing quaternary ammonium group(s) as guests. Through host-guest assembly, the obtained complex exhibits obvious blue fluorescence in the solution due to the restriction of free motion of AIEgens and drastically inhibits efficient type I ROS generation. Then, upon the addition of another guest 4,4'-benzidine dihydrochloride, TPE-QAS can be competitively replaced from the cavity of SC4A to restore its pristine ROS efficiency and photoactivity in aqueous solution. The dissociative TPE-QAS shows a high bacterial binding ability with an efficient treatment for methicillin-resistant Staphylococcus aureus (MRSA) in dark and light irradiation. Meanwhile, it also exhibits an improved survival rate for MRSA-infected skin flap transplantation and largely accelerates the healing process. Thus, such cascaded host-guest assembly is an ideal platform for phototheranostics research.

Biofunctionalization of 3D Printed Porous Tantalum Using a Vancomycin-Carboxymethyl Chitosan Composite Coating to Improve Osteogenesis and Antibiofilm Properties.

3D-printed porous tantalum scaffold has been increasingly used in arthroplasty due to its bone-matching elastic modulus and good osteoinductive ability. However, the lack of antibacterial ability makes it difficult for tantalum to prevent the occurrence and development of periprosthetic joint infection. The difficulty and high cost of curing periprosthetic joint infection (PJI) and revision surgery limit the further clinical application of tantalum. Therefore, we fabricated vancomycin-loaded porous tantalum scaffolds by combining the chemical grafting of (3-aminopropyl)triethoxysilane (APTES) and the electrostatic assembly of carboxymethyl chitosan and vancomycin for the first time. Our in vitro experiments show that the scaffold achieves rapid killing of initially adherent bacteria and effectively prevents biofilm formation. In addition, our modification preserves the original excellent structure and biocompatibility of porous tantalum and promotes the generation of mineralized matrix and osteogenesis-related gene expression by mesenchymal stem cells on the surface of scaffolds. Through a rat subcutaneous infection model, the composite bioscaffold shows efficient bacterial clearance and inflammation control in soft tissue and creates an immune microenvironment suitable for tissue repair at an early stage. Combined with the economic friendliness and practicality of its preparation, this scaffold has great clinical application potential in the treatment of periprosthetic joint infection.

Differential effect of tantalum nanoparticles versus tantalum micron particles on immune regulation.

The inflammatory microenvironment created by macrophages has been proven critical for bone regeneration. Both tantalum nanoparticles and micron particles have been applied to bone tissue engineering and have achieved good efficacy, but their effects on immune microenvironment remain unclear. Herein, we explored the different effects between nano- and micro-tantalum particles on the innate immunity of macrophages in vitro and in vivo. RAW 264.7 â€‹cells were co-cultured with nano- and micro-tantalum particles under inflammatory conditions to evaluate the effects on the morphology and behavior of macrophages. Air pouch model was used to evaluate the material-induced macrophage polarization in vivo. Compared to the tantalum micron particles (TaMPs), the morphology of macrophages was more similar to the M2 phenotype in co-culture with tantalum nanoparticles (TaNPs). At the same time, the TaNPs could also decrease the gene expression of interleukin-1ß (IL-1ß), tumor necrosis factor-α(TNF-α), inducible nitric oxide synthase (iNOS), and increase the expression of transforming growth factor-ß1 (TGF-ß1) and interleukin-10 (IL-10). Furthermore, the air pouch model showed more M2 macrophage infiltration under the intervention of TaNPs. Our findings demonstrated that TaNPs could significantly increase the polarization of M2 macrophages and decrease the macrophage polarization to the M1 phenotype under the inflammatory microenvironment, showing better immunomodulatory properties.