Promote Bone Regeneration Research Articles

Mixed-valence vanadium-doped mesoporous bioactive glass for treatment of tumor-associated bone defects.

Vanadium is a bioactive trace element with variable valence. Its pentavalent form has been confirmed to be capable of predominantly regulating the early and mid-stage osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) without tumor inhibition, while its tetravalent form exhibits tumor inhibition but only primarily modulates late osteogenic differentiation and angiogenesis. In this study, a multifunctional bone tissue scaffold consisting of mixed-valence vanadium-doped mesoporous bioactive glass and poly(lactic-co-glycolic acid) (V(IV/V)-MBG/PLGA) was developed to simultaneously inhibit the recurrence of osteosarcoma and promote the regeneration of operative bone defects. The in vitro results showed that the V(IV) and V(V) species could be sustainably released from V(IV/V)-MBG and complementarily enhance the proliferation, osteogenic differentiation, and mineralization of BMSCs by activating multiple signaling pathways throughout the whole osteogenesis process. More importantly, the co-existence of mixed-valent vanadium species was able to continuously stimulate the generation of excessive ROS and the depletion of GSH by synergistically supplying an appropriate ratio of V(IV) and V(V) to thermodynamically and kinetically maintain the stable self-circulation of the valence state alteration, thus inducing UMR-106 cell death. In a rat model, V(IV/V)-MBG/PLGA scaffolds effectively suppressed tumor invasion and promoted bone regeneration. These results suggest that V(IV/V)-MBG/PLGA scaffolds are a promising strategy for treating tumor-associated bone defects, offering dual tumor inhibition and bone regeneration.

A novel ultrasound-driven piezoelectric GBR membrane dispersed with boron nitride nanotubes promotes bone regeneration and anti-bacterial properties.

Bone graft absorption and infection are the major challenges to guided bone regeneration(GBR), yet the GBR membrane is neither osteogenic nor antibacterial. Hence, we followed sono-piezo therapy strategy by fabricating an electrospun membrane dispersed with boron nitride nanotubes. The PLLA/Gelatine/PDA@BNNT (PGBT) membrane has improved mechanical and biocompatible properties and generate piezovoltages of 130mV when activated by ultrasound stimulation under 100mW/cm2 without extra polarization. The PGBT with ultrasound is conducive to cellular osteogenesis, barrier function, and shows antibacterial rate of about 40%. The rat cranial defect experiments revealed that PGBT with ultrasound could promote osteogenesis in-vivo and show great potentials for vertical bone defect repair.

In situ osteogenic activation of mesenchymal stem cells by the blood clot biomimetic mechanical microenvironment

Blood clots (BCs) play a crucial biomechanical role in promoting osteogenesis and regulating mesenchymal stem cell (MSC) function and fate. This study shows that BC formation enhances MSC osteogenesis by activating Itgb1/Fak-mediated focal adhesion and subsequent Runx2-mediated bone regeneration. Notably, BC viscoelasticity regulates this effect by modulating Runx2 nuclear translocation. To mimic this property, a viscoelastic peptide bionic hydrogel named BCgel was developed, featuring a nanofiber network, Itgb1 binding affinity, BC-like viscoelasticity, and biosafety. The anticipated efficacy of BCgel is demonstrated by its ability to induce nuclear translocation of Runx2 and promote bone regeneration in both in vitro experiments and in vivo bone defect models with blood clot defect, conducted on rats as well as beagles. This study offers insights into the mechano-transduction mechanisms of MSCs during osteogenesis and presents potential guidelines for the design of viscoelastic hydrogels in bone regenerative medicine.

Oriented Cortical-Bone-Like Silk Protein Lamellae Effectively Repair Large Segmental Bone Defects in Pigs.

Assembling natural proteins into large, strong, bone-mimetic scaffolds for repairing bone defects in large-animal load-bearing sites remain elusive. Here this challenge is tackled by assembling pure silk fibroin (SF) into 3D scaffolds with cortical-bone-like lamellae, superior strength, and biodegradability through freeze-casting. The unique lamellae promote the attachment, migration, and proliferation of tissue-regenerative cells (e.g., mesenchymal stem cells [MSCs] and human umbilical vein endothelial cells) around them, and are capable of developing in vitro into cortical-bone organoids with a high number of MSC-derived osteoblasts. High-SF-content lamellar scaffolds, regardless of MSC inoculation, regenerated more bone than non-lamellar or low-SF-content lamellar scaffolds. They accelerated neovascularization by transforming macrophages from M1 to M2 phenotype, promoting bone regeneration to repair large segmental bone defects (LSBD) in minipigs within three months, even without growth factor supplements. The bone regeneration can be further enhanced by controlling the orientation of the lamella to be parallel to the long axis of bone during implantation. This work demonstrates the power of oriented lamellar bone-like protein scaffolds in repairing LSBD in large animal models.

Evenly Distributed Microporous Structure and E7 Peptide Functionalization Synergistically Accelerate Osteogenesis and Angiogenesis in Engineered Periosteum.

Repairing large bone defects remains a significant clinical challenge. Stem cell is of great importance in bone regeneration, and periosteum is rich in periosteal stem cell, which has a great influence on repairing bone defects. Bioengineered periosteum with excellent biocompatibility and stem cell homing capabilities to promote bone regeneration is of great clinical significance. The E7 peptide (EPLQLKM), which exhibits a specific affinity for mesenchymal stem cells (MSCs), is beneficial for modulating cellular functions. In this study, a unique microporous structured carboxymethyl chitosan/sodium alginate membrane with a proper mass ratio is developed by the addition of Poloxam 407 （P407）, which is then functionalized with the E7 affinitive peptide. This membrane, characterized by its microporous structure and E7 peptide functionalization (CSSA/P/E), not only demonstrated favorable mechanical properties, enhanced hydrophilicity, satisfactory biodegradation profile, and excellent biocompatibility, but also synergistically enhanced MSCs recruitment. It is found to promote the proliferation, spreading, and osteogenic differentiation of MSCs in vitro and to accelerate early periosteal regeneration, bone matrix deposition, and vascularization in vivo, leading to effective regeneration of critical-sized bone defects. Overall, this study presents a robust, cell and growth factor-free strategy for bioengineering periosteum, offering a potential solution for the challenging large size bone defects.

Enhancer-driven Shh signaling promotes glia-to-mesenchyme transition during bone repair

Plp1-lineage Schwann cells (SCs) of peripheral nerve play a critical role in vascular remodeling and osteogenic differentiation during the early stage of bone healing, and the abnormal plasticity of SCs would jeopardize the bone regeneration. However, how Plp1-lineage cells respond to injury and initiate the vascularized osteogenesis remains incompletely understood. Here, by employing single-cell transcriptional profiling combined with lineage-specific tracing models, we uncover that Plp1-lineage cells undergoing injury-induced glia-to-MSCs transition contributed to osteogenesis and revascularization in the initial stage of bone injury. Importantly, our data demonstrated that the Sonic hedgehog (Shh) signaling was responsible for the transition process initiation, which was strongly activated by c-Jun/SIRT6/BAF170 complex-driven Shh enhancers. Collectively, these findings depict an injury-specific niche signal-mediated Plp1-lineage cells transition towards Gli1+ MSCs and may be instructive for approaches to promote bone regeneration during aging or other bone diseases.

Zinc Doped Akermanite: A Promising Biomaterial for Orthopedic Application with Enhanced Bioactivity, Mechanical Strength, and Bacterial Study.

Incorporating zinc into biocompatible materials has been identified as a potential strategy for promoting bone regeneration and osteogenic activity during hard tissue regeneration. This work aimed to investigate the impact of zinc doping on the structure of akermanite, which was synthesized using the sol-gel combustion method, with the goal of improving the biological response. Powder XRD and FT-IR analysis confirmed the phase purity and the respective functional groups associated with Zn-doped akermanite. Further XPS analysis confirmed the presence of zinc with the respective binding energies in the akermanite matrix. According to the results obtained from the analysis, the apatite-forming ability of Zn-doped akermanite demonstrated enhanced apatite deposition on the surface of the pellet after 9 days of immersion in the SBF medium. The measured mechanical parameters, including compressive strength (140-189 MPa) and Young's modulus (2505-3599 MPa), fall within the range of human cortical bone. Antimicrobial results showed an improved inhibition rate of the doped ceramics compared to pure akermanite with an inhibition percentage of 87% even at lower concentrations. The hemocompatibility of the materials showed hemolysis of human blood cells within the acceptable range without exhibiting toxicity. Cytotoxicity results demonstrate the biocompatibility of the materials with the MG-63 cell line. Based on the results, akermanite doped with zinc at optimal concentrations was found to be compatible and nontoxic promoting it as a potential alternative for bone regeneration in orthopedic applications.

The ability of different forms of autogenous tooth graft to promote bone regeneration: a network meta-analysis.

Several forms of autogenous tooth graft have been presented. However, it is still unclear which form provides better bone formation and is the best to use clinically. This network meta-analysis aimed to thoroughly evaluate the available literature on the ability of different forms of the autogenous tooth graft to promote bone regeneration, in order to explore if any specific type or method of processing would result in better overall outcomes. MEDLINE/PubMed, Cochrane library, and Scopus databases were searched, to find randomized clinical trials, published up to November 29, 2023, which compared two forms of autogenous tooth graft or any form of this material with other bone grafts or with empty sockets and reported the percentage of bone formation in the grafted sites. Of 1129 articles found, nine were included. The outcomes of this meta-analysis indicated that demineralized dentin, demineralized root with BMP-2 and undemineralized tooth all showed significantly higher bone formation, compared to xenograft; Mean difference (MD) = 23.25, 95% Confidence interval (CI) = 7.42 to 39.08, MD = 17.09, 95% CI = 4.03 to 30.15, and MD = 12.40, 95% CI = 5.64 to 19.16, respectively. Following the GRADE system, the level of evidence was judged to be low/very low. Choosing the undemineralized tooth could be a better option than other forms of this material, considering the complexity, time, and cost of the other forms of autogenous tooth graft. Nevertheless, future investigations with more direct comparisons are highly needed, considering the small number of included studies and the low level of evidence obtained from this meta-analysis.

Hydroxyapatite Chitosan Gradient Pore Scaffold Activates Oxidative Phosphorylation Pathway to Induce Bone Formation.

In this study, we prepared a porous gradient scaffold with hydroxyapatite microtubules (HAMT) and chitosan (CHS) and investigated osteogenesis induced by these scaffolds. The arrangement of wax balls in the mold can control the size and distribution of the pores of the scaffold, and form an interconnected gradient pore structure. The scaffolds were systematically evaluated in vitro and in vivo for biocompatibility, biological activity, and regulatory mechanisms. The porosity of the four scaffolds was more than 80%. The 50% and 70% HAMT-CHS scaffolds formed an excellent gradient pore structure, with interconnected pores. Furthermore, the 70% HAMT-CHS scaffold showed better anti-compressive deformation ability. In vitro experiments indicated that the scaffolds had good biocompatibility, promoted the expression of osteogenesis-related genes and proteins, and activated the oxidative phosphorylation pathway to promote bone regeneration. Eight weeks after implanting the HAMT-CHS scaffold in rat skull defects, new bone formation was observed in vivo by micro-computed tomographic (CT) staining. The obtained data were statistically analyzed, and the p-value < 0.05 was statistically significant. HAMT-CHS scaffolds can accelerate osteogenesis in bone defects, potentially through the activation of the oxidative phosphorylation pathway. These results highlight the potential therapeutic application of HAMT-CHS scaffolds.

An injectable multi-functional composite bioactive hydrogel for bone regeneration via immunoregulatory and osteogenesis effects

Bone defects represent a prevalent and significant challenge in clinical practice. Given the inflammatory microenvironment at injury sites and the requirement for endogenous cell and tissue infiltration, there is an urgent need for an ideal biomaterial that can modulate inflammation and promote bone regeneration. We developed an innovative injectable hydrogel (CH@PUE&MSN) designed for immunomodulation and bone regeneration through in situ self-assembly, incorporating puerarin and chitosan with mesoporous silica nanoparticles. In vitro experiments demonstrated that this multifunctional injectable hydrogel promotes tissue cell regeneration, reduces inflammation, inhibits osteoclast formation, induces the migration and differentiation of bone marrow mesenchymal stem cells, and facilitates bone regeneration. Furthermore, we conducted an extensive in vivo evaluation using a bone defect model, employing advanced imaging and histological analyses. Our findings indicate that this multifunctional injectable hydrogel is a promising bioactive material for bone regeneration and presents a novel strategy for the clinical management of bone defects.

Mechanical Stimulus and Metabolic Responses by Cryo‐Printing Anisotropic Scaffolds for Achieving Promoted Bone Regeneration

Mechanical Stimulus and Metabolic Responses by Cryo‐Printing Anisotropic Scaffolds for Achieving Promoted Bone Regeneration

Research progress of bioactive scaffolds in repair and regeneration of osteoporotic bone defects

To summarize the research progress of bioactive scaffolds in the repair and regeneration of osteoporotic bone defects. Recent literature on bioactive scaffolds for the repair of osteoporotic bone defects was reviewed to summarize various types of bioactive scaffolds and their associated repair methods. The application of bioactive scaffolds provides a new idea for the repair and regeneration of osteoporotic bone defects. For example, calcium phosphate ceramics scaffolds, hydrogel scaffolds, three-dimensional (3D)-printed biological scaffolds, metal scaffolds, as well as polymer material scaffolds and bone organoids, have all demonstrated good bone repair-promoting effects. However, in the pathological bone microenvironment of osteoporosis, the function of single-material scaffolds to promote bone regeneration is insufficient. Therefore, the design of bioactive scaffolds must consider multiple factors, including material biocompatibility, mechanical properties, bioactivity, bone conductivity, and osteogenic induction. Furthermore, physical and chemical surface modifications, along with advanced biotechnological approaches, can help to improve the osteogenic microenvironment and promote the differentiation of bone cells. With advancements in technology, the synergistic application of 3D bioprinting, bone organoids technologies, and advanced biotechnologies holds promise for providing more efficient bioactive scaffolds for the repair and regeneration of osteoporotic bone defects.

Cellulose nanofiber reinforced curcumin-infused calcium phosphate silicate cement for various bone-tissue engineering application.

This study utilized a injectable curcumin (Cur)-infused calcium phosphate silicate cement (CPSC) for addressing defects caused by bone cancer, and evaluated its promoting bone regeneration and exerting cytotoxic effects on osteosarcoma cells. The material's physicochemical properties, biocompatibility with osteoblasts, and cytotoxicity toward osteosarcoma cells were rigorously analyzed. The findings demonstrate that CPSC-Cur signicantly prolongs the setting time, which can be optimized by adding silanized cellulose nanober (CNF-SH) to achieve a balance between workability and mechanical strength. Biological assessments reveal a pronounced cytotoxic effect on osteosarcoma cells while maintaining minimal toxicity toward pre-osteoblasts, highlighting CPSC-Cur's potential as a promising material for repairing bone defects following cancer removal. This study lays the groundwork for future investigations into CPSC-Cur's in vivo efficacy and its role in the clinical treatment of bone cancer.

Computational Assessment of Biocompatibility and Toxicity of Graphene and Its Derivatives for Dental Adhesives

Background/Objectives: Graphene and its derivatives have garnered attention for their unique properties that could enhance dental biomaterials. Understanding their interactions with biological systems is crucial for optimizing their application in dentistry. This study aimed to comprehensively evaluate the biocompatibility, molecular interactions, and toxicity profiles of graphene and its derivatives for potential dental applications using in silico approaches. Methods: The study employed molecular-docking simulations, 100 ns molecular dynamics (MD) simulations, pharmacophore modeling, and in silico toxicity assessments. Key bone-related proteins and receptors were selected to assess the potential of graphene-based materials in dental restorative and regenerative therapies. Results: Molecular-docking simulations revealed strong interactions of Graphene Quantum Dots (GQDs) and sulfur-doped graphene with critical bone-related receptors, suggesting their potential for reinforcing dentin and promoting bone regeneration. MD simulations demonstrated stable complex formations, with occasional fluctuations indicating areas for material optimization. In silico toxicity assessments indicated favorable profiles for high-purity graphene and selected doped graphenes (nitrogen-, fluorine-, and sulfur-doped), while graphene oxide (GO) exhibited concerning toxicity levels, highlighting the importance of mitigating strategies. Conclusions: Graphene and its derivatives exhibit promising biocompatibility and molecular interaction profiles relevant to dental applications. Challenges such as GO’s toxicity and occasional instability in simulations suggest the need for further research into surface modifications and material refinement. These findings pave the way for advancing graphene-based dental materials toward clinical implementation, potentially revolutionizing dental prosthetics and treatments.

Recent Advances in Promoting Bone Regeneration in Type 2 Diabetes Using Drug Delivery Vehicles and Vehicle‐Free Therapeutics

AbstractThe incidence of type 2 diabetes (T2DM) increases significantly worldwide. Due to consistent hyperglycemia, insulin resistance, and chronic inflammation, T2DM patients encounter osteoporosis and induced osteoporotic fracture risks. Antidiabetic drugs have been traditional therapies that seek to control blood glucose, balance bone metabolism, and favor systemic immunosuppression. However, such drugs impact bone quality and its nano‐scale features in the long‐term. Today, biomedical experts are continuously advancing drug delivery tools for local delivery of osteo‐immunomodulatory agents in T2DM. It is demonstrated that bioavailability and release profile determine osteo‐immunomodulatory and osteoconductivity outcomes of such therapeutics. This review focuses on introducing currently used local drug delivery vehicles in T2DM. The fabrication techniques of such biomaterial‐based systems are thoroughly examined. Furthermore, the feasibility and the potential factors contributing to consistent release of bioactive agents are surveyed. Furthermore, the extent of in vivo responses is described in the context of current research examples. Targeted signaling mechanisms are also assessed in detail to elucidate the activated healing routes.

Tenascin-C promotes bone regeneration via inflammatory macrophages.

During the early stage of tissue injury, macrophages play important roles in the activation of stem cells for further regeneration. However, the regulation of macrophages during bone regeneration remains unclear. Here, the extracellular matrix (ECM) tenascin-C (TNC) is found to express in the periosteum and recruit inflammatory macrophages. TNC-deficiency in the periosteum delays bone repair. Transplantation of macrophages derived from injured periosteum is able to rescue the decreased skeletal stem cells and impaired bone regeneration caused by TNC deficiency. The cell communication analysis identifies ITGA7 as a TNC receptor contributing to the recruitment of inflammatory macrophages. TNC expression declines in aged mice and the exogenous delivery of TNC significantly promotes bone regeneration after aging through the recruitment of macrophages. Taken together, this study reveals the regulation of macrophage recruitment and its function in the activation of skeletal stem cells after bone injury, providing a strategy to accelerate bone regeneration by TNC delivery.

Concurrently bioprinted scaffolds with autologous bone and allogeneic BMSCs promote bone regeneration through native BMSC recruitment

Concurrently bioprinted scaffolds with autologous bone and allogeneic BMSCs promote bone regeneration through native BMSC recruitment

The TACOS Technique: A Stepwise Protocol for Alveolar Ridge Augmentation Using Customized Titanium Mesh.

Background: Alveolar ridge resorption following tooth loss poses a significant challenge for successful dental implant placement. In cases of severe atrophy, bone augmentation is required to restore sufficient bone volume. This technical note outlines a detailed, stepwise surgical protocol for horizontal and vertical alveolar ridge augmentation using customized titanium mesh. Materials and Methods: The procedure includes precise mesh fitting, autologous bone grafting, and the application of bioactive agents to promote bone regeneration. Emphasis is placed on the technique's feasibility, predictability, and the critical steps necessary for preventing complications. Results: The use of customized mesh ensures stability and improved bone regeneration outcomes, enabling clinicians to achieve successful implant placement even in severely atrophic ridges. Conclusions: The described protocol has demonstrated predictable results in both clinical and radiographic evaluations, offering an effective solution for complex bone augmentation cases.

T Cell-Derived Apoptotic Extracellular Vesicles Ameliorate Bone Loss via CD39 and CD73-Mediated ATP Hydrolysis.

Osteoporosis is a major public health concern characterized by decreased bone density. Among various therapeutic strategies, apoptotic extracellular vesicles (ApoEVs) have emerged as promising agents in tissue regeneration. Specifically, T cell-derived ApoEVs have shown substantial potential in facilitating bone regeneration. However, it remains unclear whether ApoEVs can promote bone mass recovery through enzymatic activity mediated by membrane surface molecules. Therefore, this study aimed to investigate whether T cell-derived ApoEVs could promote bone mass recovery in osteoporosis mice and reveal the underlying mechanisms. ApoEVs were isolated through sequential centrifugation, and their proteomic profiles were identified via mass spectrometry. Western blot and immunogold staining confirmed the enrichment of CD39 and CD73 on ApoEVs. The role of CD39 and CD73 in hydrolyzing adenosine triphosphate (ATP) to adenosine was evaluated by quantifying the levels of ATP and adenosine. Inhibitors of CD39 and CD73, and an A2BR antagonist were used to explore the molecular mechanism of ApoEVs in promoting bone regeneration. ApoEVs significantly reduced bone loss and promote the osteogenic differentiation of BMMSCs in ovariectomy (OVX) mice. We observed increased levels of extracellular ATP and a decrease in CD39 and CD73, key enzymes in ATP-to-adenosine conversion in bone marrow of OVX mice. We found that ApoEVs are enriched with CD39 and CD73 on their membranes, which enable the hydrolysis of extracellular ATP to adenosine both in vitro and in vivo. The adenosine generated by ApoEVs inhibits the inflammatory response and promotes osteogenesis through A2BR and downstream PKA signaling. T cell-derived ApoEVs are enriched with CD39 and CD73, enabling them to hydrolyze extracellular ATP to adenosine, thereby promoting bone regeneration via A2BR and PKA signaling pathway. Our data underscore the substantive role of T cell-derived ApoEVs to treat osteoporosis, thus providing new ideas for the development of ApoEVs-based therapies in tissue regeneration.

Regulation of the diabetic immune microenvironment by metformin-loaded strontium-doped mesoporous bioactive glass facilitates bone regeneration.

Chronic inflammation and oxidative stress in the diabetic microenvironment often hinder the healing of bone defects. Metformin (MET), the first-line diabetes medication, was shown to alter macrophage polarization toward an anti-inflammatory M2 phenotype, while simultaneously suppressing excessive reactive oxygen species (ROS) generation. Strontium-doped mesoporous bioactive glasses (SrMBG) also showed promising benefits in promoting bone regeneration. Aiming to improve the diabetic immune microenvironment within bone defects, in this study we loaded SrMBG mesopores with increasing amounts of MET. MET-loaded SrMBG (MET/SrMBG) extracts promoted macrophage differentiation toward the M2 phenotype and reduced ROS production in vitro. The possibility of facilitating osteogenic differentiation of bone marrow stromal cells (BMSCs) in vivo led us to develop 3D-printed MET/SrMBG scaffolds. Experiments utilizing a critical-size calvarium defect model in diabetic rats confirmed that implanting the MET/SrMBG scaffold enhanced bone repair owing to the effects of MET regulating M2 type macrophage polarization and mitigating oxidative stress to improve the inflammatory microenvironment.