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Lead-free piezoelectric ceramics can generate electrical signals to promote bone defect repair, but they suffer from low bioreactivity. In this study, K 0.48 Na 0.52 NbO 3 & akermanite composite ceramic (KNN & AK) was prepared using digital light processing (DLP). The influence of sintering temperature and AK content was investigated. With the increase of sintering temperature, the piezoelectric coefficient d 33 of the composite ceramics first increased and then decreased, reaching a maximum of 7.80 pC/N at 1070 °C. The doping of AK would lead to a significant decrease in the piezoelectric property, and the AK content should not exceed 10 wt% to achieve the piezoelectric coefficient of human bone. After immersion in Tris-HCl solution for 28 days, the weight loss rate of the composite ceramics doped with 15 wt% AK could reach 8.36 %. The combination of KNN and AK promotes the application of piezoelectric bone scaffolds in the field of bone repair. [ABSTRACT FROM AUTHOR]

The treatment of vertebral compression fractures of the spinal necessitates the use of injectable bone repair materials with the adaptive modulus of elasticity. Currently, newly developed injectable self-curing materials for minimally invasive surgery are primarily categorized into calcium phosphate and calcium silicate systems, both of which exhibit excellent biocompatibility. However, calcium phosphate bone cement lacks adequate mechanical properties and the stress does not match between bone and material. Calcium silicate cement has a long curing time, low mechanical strength, and high alkalinity. These deficiencies render them inadequate for meeting clinical requirements. Therefore, we incorporated inorganic disodium phosphate, organic polyvinyl alcohol, and solid component cerium oxide into the matrix phase of tricalcium silicate bone cement to establish a ternary self-curing hydration reinforcement system and produced an organic-inorganic composite injectable bone cement. Even though the composite bone cement has a longer setting time, it exhibited high compressive strength (61.9Mpa) and fracture strain (7.88 %), demonstrating excellent mechanical properties. Furthermore, it also demonstrates good injectable properties (86 %), anti-collapse properties, good biological activity, and outstanding antibacterial properties. The composite bone cement has great potential to develop a new injectable self-curing material to replace PMMA bone cement in clinical vertebral compression fractures. [ABSTRACT FROM AUTHOR]

Background: Angiogenesis is essential for repairing critical-sized bone defects. Although adipose-derived stem cell (ADSC)-derived exosomes have been shown to enhance the angiogenesis of endothelial progenitor cells (EPCs), the underlying mechanisms remain unclear. This study aims to explore the effects and mechanisms of ADSC-derived exosomes in enhancing bone repair by promoting EPC angiogenesis. Methods: Transmission electron microscopy, nanoparticle tracking analysis, and Dil reagent kit were employed to identify ADSC-derived exosomes and their internalization by EPCs. Micro-CT analysis, H&E staining, and Masson staining were used to assess bone mineral density (BMD), bone volume fraction (BV/TV), trabecular thickness (Tb.Th), and trabecular number (Tb.N), as well as the pathological changes and fibrosis at defect sites. Cell viability, migration, invasion, and tube formation of EPCs were evaluated using CCK-8, wound healing, Transwell, and tube formation assays. Immunohistochemical staining, RT-PCR, and Western blotting were utilized to measure the gene and protein expression of markers such as CD31, VEGFA, OCN, RUNX2, NOTCH1, and DLL4. Gene sequencing and bioinformatics analyses were conducted to identify the most highly expressed miRNA in exosomes, while miRDB and dual-luciferase reporter assays were used to explore the interaction between miR-21-5p and NOTCH1. Results: The ADSC-derived exosomes, averaging 126 nm in diameter, were internalized by EPCs. In vivo, these exosomes promoted new bone formation, increased BMD, BV/TV, Tb.Th, and Tb.N, reduced pathological damage to cranial defect tissues, enhanced vascular and bone tissue regeneration, and upregulated OCN and RUNX2 expression. In vitro, ADSC-derived exosomes enhanced EPC viability, migration, invasion, and tube formation. Both in vivo and in vitro experiments demonstrated that ADSC-derived exosomes upregulated CD31 and VEGFA expression. miR-21-5p, the most highly expressed miRNA in ADSC-derived exosomes, was found to target NOTCH1. Overexpression of miR-21-5p in these exosomes facilitated EPC migration, tube formation, and VEGFA expression while downregulating NOTCH1 and DLL4 expression. Inhibition of miR-21-5p produced opposite effects on EPCs. Conclusions: These findings indicate that miR-21-5p in ADSC-derived exosomes promotes angiogenesis in EPCs to accelerate bone repair by targeting the NOTCH1/DLL4/VEGFA signaling pathway, offering a potential therapeutic strategy for bone defect treatment. [ABSTRACT FROM AUTHOR]

AbstractPoly (lactic-co-glycolic acid) (PLGA) has been widely used as drug delivery carrier or scaffold for bone repair due to its good biocompatibility, biodegradability, and degradation rate controllability. However, defects, like acidic degradation by-products, are associated with PLGA and restrict its practical applications. Jade powder, leftover from jade polishing process, is a natural material rich in elements of Ca, Si, and Mg while biocompatible and antibacterial. Herein, jade powder/PLGA composite microspheres with different mass ratios were prepared by emulsion solvent evaporation method under the optimized conditions. Characterization from SEM, EDS, FTIR, and surface water contact angle measurements indicated jade powder was successfully combined with PLGA and improved the surface wettability of the microspheres. Moreover, it was proved, through in vitro simulated body fluid test as well as adipose stem cell osteogenesis analysis, that jade powder addition enhanced the pH buffering capacity of the composite microsphere for simulated body fluid, and promoted the in vitro osteogenic activity of adipose stem cells at a certain amount. This study provides new ideas to employ jade powder, a natural material otherwise thrown away as solid waste, for improvement on PLGA performance in bone repair or potentially other biomedical fields. [ABSTRACT FROM AUTHOR]

One of the critical factors that determines the biological properties of scaffolds is their structure. Due to the mechanical and structural discrepancies between the target bone and implants, the poor internal architecture design and difficulty in degradation of conventional bone implants may cause several adverse outcomes. To date, many scaffolds, such as 3-D printed sandwich structures, have been successfully developed for the repair of bone defects; however, the steps of these methods are complex and costly. Hydrogels have emerged as a unique scaffold material for repairing bone defects because of their good biocompatibility and excellent physicochemical properties. However, studies exploring bioinspired hydrogel scaffolds with hierarchical structures are scarce. More efforts are needed to incorporate bioinspired structures into hydrogel scaffolds to achieve optimal osteogenic properties. In this study, we developed a low-cost and easily available hydrogel matrix that mimicked the natural structure of the bone's porous sandwich to promote new bone growth and tissue integration. A comprehensive evaluation was conducted on the microstructure, swelling rate, and mechanical properties of this hydrogel. Furthermore, a 3D finite element analysis was employed to model the structure-property relationship. The results indicate that the sandwich-structured hydrogel is a promising scaffold material for bone injury repair, exhibiting enhanced compressive stress, elastic modulus, energy storage modulus, and superior force transmission. [ABSTRACT FROM AUTHOR]

Piezoelectric ceramics are piezoelectric materials with polycrystalline structure and have been widely used in many fields such as medical imaging and sound sensors. As knowledge about this kind of material develops, researchers find piezoelectric ceramics possess favorable piezoelectricity, biocompatibility, mechanical properties, porous structure and antibacterial effect and endeavor to apply piezoelectric ceramics to the field of bone tissue engineering. However, clinically no piezoelectric ceramics have been exercised so far. Therefore, in this paper we present a comprehensive review of the research and development of various piezoelectric ceramics including barium titanate, potassium sodium niobate and zinc oxide ceramics and aims to explore the application of piezoelectric ceramics in bone regeneration by providing a detailed overview of the current knowledge and research of piezoelectric ceramics in bone tissue regeneration. [ABSTRACT FROM AUTHOR]

Implant materials with micro/nanostructures bear a closer resemblance with the features of natural bone, which influences the wettability, bone differentiation, and vascularization of materials. However, it is still technically challenging to design the inner wall and surface micro/nanostructures on macroporous bioceramics due to their brittleness. In this work, micro/nanostructured composites with Si3N4 whiskers as a framework, and the (inner) surface covered with SiC nanowires were prepared, denoted as SiC‐nw@Si3N4‐w bioceramics. The synthesis, adopting the green chemistry concept, was utilized from environmental products (carbon evaporated in the furnace at high temperature) and reaction impurities (carbon obtained by polymer pyrolysis and silicon obtained by Si3N4 decomposition) to synthesize SiC nanowires via a vapor‐solid growth mechanism. The prepared SiC‐nw@Si3N4‐w bioceramics have potential applications in bone repair due to their cell adhesion and proliferation. [ABSTRACT FROM AUTHOR]

Electrical stimulation (ES) plays an important role in regulating cell osteoblast differentiation. As a noninvasive rehabilitation therapy method, Es has a unique role in postoperative recovery. Bone morphogenetic protein-2 (BMP-2) is the most commonly used bioactive molecule in in situ tissue engineering scaffolds, and it plays an important regulatory role in the whole process of bone injury repair. In this study, the osteogenic regulation of MC-3T3-E1 cells was studied by combining pulsed electrical stimulation (PES) and different concentrations of BMP-2. The results showed that PES and BMP-2 could synergically promote the proliferation of MC-3T3-E1 cells. The qPCR results of osteoblast-related genes showed that PES was synergistic with BMP-2 to promote osteoblast differentiation mainly through the regulation of the Smad/BMP and insulin like growth factor 1 (IGF1) signaling pathways. The expression level of alkaline phosphatase (ALP) and alizarin red staining further demonstrated the synergistic effect of PES and BMP-2 on promoting osteogenic differentiation and mineralization of cells. PES and BMP-2 could also synergically promote cell proliferation, expression of collagen I (COL-I) and ALP, and cell mineralization on the 3D-printed polylactic acid scaffold. These results suggest that the use of PES can enhance the osteogenic effect of in situ bone repair scaffolds containing BMP-2, reduce the dose of BMP-2 alone, and reduce the possible side effects of high-dose BMP-2 in vivo. [ABSTRACT FROM AUTHOR]

Creating interconnected macropores in calcium phosphate cement (CPC) is an effective strategy to promote its degradation and osteogenesis. However, little attention has been given to the osteogenic effect of the CPC scaffolds with pre-forming and in-situ forming interconnected macropores. Herein, two types of CPC scaffolds were prepared by infiltrating CPC pastes into 3D-printed polycaprolactone (PCL) and poly(lactic-co-glycolic acid) (PLGA) networks. Meanwhile, the sacrificial PCL network within CPC was dissolved to obtain the CPC scaffold with approximately 300 μm macropores, whereas the PLGA network was retained within the CPC to obtain the PLGA/CPC scaffold. The results indicated that the PLGA/CPC scaffold showed higher degradation rate and compressive strength compared to the CPC scaffold with pre-forming interconnected macropores. However, the proliferation rate and alkaline phosphatase activity of mouse bone mesenchymal stem cells cultured with the CPC scaffold were superior to those cultured with the PLGA/CPC scaffold. In addition, greater formation of new bone and material degradation in the CPC scaffold compared to the PLGA/CPC scaffold after implanted in the rabbit femoral defects. [ABSTRACT FROM AUTHOR]

Angiogenesis is crucial for successful bone defect repair. Co‐transplanting Bone Marrow Stromal Cells (BMSCs) and Endothelial Cells (ECs) has shown promise for vascular augmentation, but it face challenges in hostile tissue microenvironments, including poor cell survival and limited efficacy. In this study, the mitochondria of human BMSCs are isolated and transplanted to BMSCs from the same batch and passage number (BMSCsmito). The transplanted mitochondria significantly boosted the ability of BMSCsmito‐ECs to promote angiogenesis, as assessed by in vitro tube formation and spheroid sprouting assays, as well as in vivo transplantation experiments in balb/c mouse and SD rat models. The Dll4‐Notch1 signaling pathway is found to play a key role in BMSCsmito‐induced endothelial tube formation. Co‐transplanting BMSCsmito with ECs in a rat cranial bone defect significantly improves functional vascular network formation, and improve bone repair outcomes. These findings thus highlight that mitochondrial transplantation, by acting through the DLL4‐Notch1 signaling pathway, represents a promising therapeutic strategy for enhancing angiogenesis and improving bone repair. Hence, mitochondrial transplantation to BMSCS as a therapeutic approach for promoting angiogenesis offers valuable insights and holds much promise for innovative regenerative medicine therapies. [ABSTRACT FROM AUTHOR]

Bone defect is a common clinical orthopedic disease. The trend in this field is to develop tissue engineering scaffolds with appropriately designed components and structures for bone repair. Herein, inspired by the organic and inorganic components of bone matrix and the natural biomineralization mechanism, a MgSiO3@Fe3O4 nanoparticle composite polycaprolactone (PCL) hybrid mineralized scaffold for bone repair is developed by microfluidic 3D printing. The incorporation of MgSiO3@Fe3O4 within the PCL scaffold can effectively improve the bioactivity. In addition, a biomimetic mineralized layer is prepared on the surface of the scaffold, which endowed it with unique microstructural characteristics, enhanced cell adhesion and osteogenic activity, and thus improved the bone repair performance. Owing to these advantages, both in vivo and in vitro experiments have demonstrated that the designed scaffold has outstanding biocompatibility and bone repair performance. These features indicate that the organic–inorganic biomineralized hybrid scaffold can be a potential bone graft substitute for clinical bone repair. [ABSTRACT FROM AUTHOR]

Bone grafting in oral and maxillofacial surgery has evolved significantly due to developments in materials science, offering innovative alternatives for the repair of bone defects. A few grafts are currently used in clinical settings, including autografts, xenografts, and allografts. However, despite their benefits, they have some challenges, such as limited availability, the possibility of disease transmission, and lack of personalization for the defect. Synthetic bone grafts have gained attention since they have the potential to overcome these limitations. Moreover, new technologies like nanotechnology, 3D printing, and 3D bioprinting have allowed the incorporation of molecules or substances within grafts to aid in bone repair. The addition of different moieties, such as growth factors, stem cells, and nanomaterials, has been reported to help mimic the natural bone healing process more closely, promoting faster and more complete regeneration. In this regard, this review explores the currently available bone grafts, the possibility of incorporating substances and molecules into their composition to accelerate and improve bone regeneration, and advanced graft manufacturing techniques. Furthermore, the presented current clinical applications and success stories for novel bone grafts emphasize the future potential of synthetic grafts and biomaterial innovations in improving patient outcomes in oral and maxillofacial surgery. [ABSTRACT FROM AUTHOR]

The design and construction of a new and excellent synthetic graft is of great significance in the field of bone defect repair and reconstruction. In this study, a dopamine modified chitosan hydrogel doped with Cu ions with a mild photothermal effect was designed to provide a better microenvironment to advance the bone repair via promote the angiogenesis and osteogenesis. Characterizations showed the successful synthesis of the material while it also presented excellent biocompatibility and mild photothermal effect under the irradiation of near-infrared light. Further, it could enhance the angiogenesis of HUVECs cells through promoting the ability of migration and tube formation and enhance the osteogenic differentiation of MC3T3-E1 cells via increasing the content of vital osteogenic factors including Runx2, Col-1, OPN, OCN, OSX, etc. The in vivo experiment also testified that it could promote the bone defect repair in rat models. These results indicate the multifunctional hydrogel is an ideal material for the treatment of bone defects and has good clinical application potential. [ABSTRACT FROM AUTHOR]

The treatment of infective bone defects remains a considerable challenge for orthopedic surgeons, primarily due to the complexities of infection control and the unsatisfactory healing of bone tissue. To solve this challenge, we have designed core/shell nanoparticles to loaded with antibacterial and osteogenic agents. Specifically, magnetocaloric CoFe2O4 (CF) nanoparticles loaded with naringin (NG) and coated with mesoporous silica (MS) were developed to construct NG-CF@MS nanoparticles. Subsequently, levofloxacin (LEV) was loaded into the MS coating, yielding NG-CF@MS-LEV nanoparticles capable of dual drug delivery. These nanoparticles were then incorporated into poly l-lactide (PLLA) powder to fabricate magnetically responsive scaffolds, which demonstrated enhanced osteogenesis and antibacterial activity under alternating magnetic field (AMF) conditions. Drug release studies showed a significant increase in NG and LEV release efficiency in the AMF setting, with a 337% increase in NG release and a 196% increase in LEV compared to non-AMF conditions. In vitro experiments further demonstrated that NG-CF@MS-LEV/PLLA scaffolds exhibited excellent osteogenic and antibacterial properties. Under the intervention of the AMF, the scaffolds displayed antibacterial rates of 98.67% and 99.38% against Escherichia coli and Staphylococcus aureus , respectively. Moreover, the scaffolds significantly promoted osteogenic differentiation and mineralization of mouse bone marrow mesenchymal stromal cells (mBMSCs), highlighting their potential as a promising therapeutic approach for repair of infected bone defects. [ABSTRACT FROM AUTHOR]

Hydroxyapatite (HA), a commonly used material for bone repair, can enhance its biological properties through the modulation of its crystallinity. Exploring the variations in physicochemical and biological properties associated with different degrees of crystallinity is crucial for advancing the applications of HA. In this study, stoichiometric nano-apatite precursors were initially synthesized using chemical precipitation. Subsequently, four groups of HA ceramics with varying degrees of crystallinity (24 %, 42 %, 72 %, 100 %) were produced by adjusting the calcination temperature, as confirmed through comprehensive characterizations. A systematic investigation was then conducted to examine the impact of crystallinity on the physicochemical, cytological, and in vivo osteogenic properties of HA ceramics, elucidating the influence of crystallinity on the osteogenic potential of HA. Results indicated that higher crystallinity in HA ceramics enhanced mechanical strength and hardness while reducing surface roughness, hydrophilicity, and protein affinity. Cytological studies revealed that decreased crystallinity led to lower cell proliferation rates but facilitated cell adhesion, spreading, and increased expression of osteogenic genes. Moreover, cell experiments with extracts further supported the significant role of surface properties of HA ceramics in modulating cell behavior. In vivo osteogenic assays demonstrated that reduced crystallinity notably stimulated new bone formation. Overall, by integrating the results of in vitro and in vivo experiments, it can be concluded that reducing the crystallinity of HA ceramics, the biological properties of HA ceramics can be significantly enhanced while maintaining a certain level of mechanical strength, such as HA2 group (42 % crystallinity). This study highlights the substantial impact of crystallinity and surface characteristics of HA ceramics on cell behavior, offering valuable insights and strategies for enhancing and optimizing bone repair materials in future applications. [ABSTRACT FROM AUTHOR]

Bone extracellular matrix (ECM) has been shown to mimic aspects of the tissue's complex microenvironment, suggesting its potential role in promoting bone repair. However, current ECM-based therapies suffer from limitations such as inefficient scale-up, lack of mechanical integrity, and sub-optimal efficacy. Here, we fabricated hydrogels from decellularized ECM (dECM) from wild type (WT) and thrombospondin-2 knock-out (TSP2KO) mouse bones. TSP2KO bone ECM hydrogel was found to have distinct mechanical properties and collagen fibril assembly from WT. Furthermore, TSP2KO hydrogel promoted mesenchymal stem cell (MSC) attachment, spreading, and invasion in vitro. Similarly, it promoted formation of tube-like structures by human umbilical vein endothelial cells (HUVECs). When applied to a murine calvarial defect model, TSP2KO hydrogel enhanced repair, in part, due to increased angiogenesis. Our study suggests the pro-angiogenic therapeutic potential of TSP2KO bone ECM hydrogel in bone repair. The study describes the first successful preparation of a novel hydrogel made from decellularized bones from wild-type mice and mice lacking thrombospondin-2 (TSP2). Hydrogels from TSP2 knock-out (TSP2KO) bones have unique characteristics in structure and biomechanics. These gels interacted well with cells in vitro and helped repair damaged bone in a mouse model. Therefore, TSP2KO bone-derived hydrogel has translational potential for accelerating repair of bone defects that are otherwise difficult to heal. This study not only creates a new material with promise for accelerated healing, but also validates tunability of native biomaterials by genetic engineering. [Display omitted] [ABSTRACT FROM AUTHOR]

The cell (plasma) membrane is enriched with numerous receptors, ligands, enzymes, and phospholipids that play important roles in cell-cell and cell-extracellular matrix interactions governing, for instance, tissue development and repair. We previously showed that plasma membrane nanofragments (PMNFs) act as nucleation sites for bone formation in vivo , and induce in vitro mineralization within 1 day. In this study, we optimized the methods for generating, isolating, and applying PMNFs as a cell-free therapeutic to expedite bone defect repair. The PMNFs were isolated from different mouse cell lines (chondrocytes, osteoblasts, and fibroblasts), pre-conditioned, lyophilized, and subsequently transplanted into 2 mm critical-sized calvarial defects in mice (n = 75). The PMNFs from chondrocytes, following a 3-day pre-incubation, significantly accelerated bone repair within 2 weeks, through a coordinated attraction of macrophages, endothelial cells, and osteoblasts to the healing site. In vitro experiments confirmed that PMNFs enhanced cell adhesion. Comparison of the PMNF efficacy with phosphatidylserine, amorphous calcium phosphate (ACP), and living cells confirmed the unique ability of PMNFs to promote accelerated bone repair. Importantly, PMNFs promoted nearly complete integration of the regenerated bone with native tissue after 6 weeks (% non-integrated bone area = 15.02), contrasting with the partial integration (% non-integrated bone area = 56.10; p < 0.01, Student's test) with transplantation of ACP. Vickers microhardness tests demonstrated that the regenerated bone after 6 weeks (30.10 ± 1.75) exhibited hardness similar to native bone (31.07 ± 2.46). In conclusion, this is the first study to demonstrate that cell membrane can be a promising cell-free material with multifaceted biofunctional properties that promote accelerated bone repair. • For the first time, the cell (plasma) membrane is used as material for bone repair. • The plasma membrane from chondrocytes promoted rapid bone repair within 2 weeks, with complete integration of the newly formed bone with the surrounding native tissue. • The plasma membrane from chondrocytes presented multifaceted effects, strongly promoting the attraction of macrophages, endothelial cells and osteoblasts to the healing site. [Display omitted] [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is a chronic metabolic disorder that can affect the balance of bone metabolism and bone microenvironment, leading to impaired fracture healing. There are several underlying mechanisms which contributing to the impaired diabetic bone microenvironment such as hyperglycemia, the production of advanced glycation end products (AGEs), inflammation, and oxidative stress, etc. Recent studies have achieved great progress in developing novel smart biomaterials in improving the diabetic bone microenvironment to promote diabetic fracture healing. In this paper, we reviewed the mechanisms on DM-induced impaired fracture healing. Meanwhile, we also summarized the smart biomaterials used to improve the local microenvironment of diabetic fractures healing, which provides a novel perspective for the future treatment of fractures in diabetic patients. [ABSTRACT FROM AUTHOR]

Degenerative scoliosis (DS), encompassing conditions like spondylolisthesis and spinal stenosis, is a common type of spinal deformity. Lumbar interbody fusion (LIF) stands as a conventional surgical intervention for this ailment, aiming at decompression, restoration of intervertebral height, and stabilization of motion segments. Despite its widespread use, the precise mechanism underlying spinal fusion remains elusive. In this review, our focus lies on endochondral ossification for spinal fusion, a process involving vertebral development and bone healing. Endochondral ossification is the key step for the successful vertebral fusion. Endochondral ossification can persist in hypoxic conditions and promote the parallel development of angiogenesis and osteogenesis, which corresponds to the fusion process of new bone formation in the hypoxic region between the vertebrae. The ideal material for interbody fusion cages should have the following characteristics: (1) Good biocompatibility; (2) Stable chemical properties; (3) Biomechanical properties similar to bone tissue; (4) Promotion of bone fusion; (5) Favorable for imaging observation; (6) Biodegradability. Utilizing cartilage-derived bone-like constructs holds promise in promoting bony fusion post-operation, thus warranting exploration in the context of spinal fusion procedures. [ABSTRACT FROM AUTHOR]

The demand for novel tissue grafting and regenerative wound care biomaterials is growing as traditional options often fall short in biocompatibility, functional integration with human tissue, associated cost(s), and sustainability. Salmon aquaculture generates significant volumes of waste, offering a sustainable opportunity for biomaterial production, particularly in osteo-conduction/-induction, and de novo clinical/surgical bone regeneration. Henceforth, this study explores re-purposing salmon waste through a standardized pre-treatment process that minimizes the biological waste content, followed by a treatment stage to remove proteins, lipids, and other compounds, resulting in a mineral-rich substrate. Herein, we examined various methods—alkaline hydrolysis, calcination, and NaOH hydrolysis—to better identify and determine the most efficient and effective process for producing bio-functional nano-sized hydroxyapatite. Through comprehensive chemical, physical, and biological assessments, including Raman spectroscopy and X-ray diffraction, we also optimized the extraction process. Our modified and innovative alkaline hydrolysis–calcination method yielded salmon-derived hydroxyapatite with a highly crystalline structure, an optimal Ca/P ratio, and excellent biocompatibility. The attractive nano-scale cellular/tissular properties and favorable molecular characteristics, particularly well-suited for bone repair, are comparable to or even surpass those of synthetic, human, bovine, and porcine hydroxyapatite, positioning it as a promising candidate for use in tissue engineering, wound healing, and regenerative medicine indications. [ABSTRACT FROM AUTHOR]

The development of hydroxyapatite (HAp) and polyether ether ketone (PEEK) biocomposites has been extensively studied for bone repair applications due to the synergistic properties of the involved materials. In this study, we aimed to develop HAp/PEEK biocomposites using high-energy ball milling, with HAp concentrations (20%, 40%, and 60% w/v) in PEEK, to evaluate their physicochemical, mechanical, cytotoxicity, and antimicrobial properties for potential applications in Tissue Engineering (TE). The biocomposites were characterized by structure, morphology, apparent porosity, diametral compression strength, cytotoxicity, and antimicrobial activity. The study results demonstrated that the HAp/PEEK biocomposites were successfully synthesized. The C2 biocomposite, containing 40% HAp, stood out due to the optimal distribution of HAp particles in the PEEK matrix, resulting in higher compression strength (246 MPa) and a homogeneous microstructure. It exhibited antimicrobial activity against Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli, with no cytotoxicity observed. These properties make the C2 biocomposite promising for regenerative medicine applications, combining mechanical strength, bioactivity, and biocompatibility. [ABSTRACT FROM AUTHOR]

Biometal ions are crucial in the structure and function of living organisms and have extensively been employed to promote bone tissue regeneration. Nevertheless, the biological functions of biometal ions and the underlying mechanisms responsible for their pro-regenerative effects remain incompletely understood, since bone repair is an intricate physiological process involving multiple cell types and signals. Recent accomplishments in the osteoimmunological field have revealed the momentous involvement of the immune system in mediating the therapeutic effects of biometal ions. The inflammatory factors secreted by immune cells contribute to bone cell migration, activation, and proliferation. This review summarizes the immune system and its constituent cells, followed by the current perspective on immunomodulation during bone healing. Next, the physicochemical and physiological properties of various biometal ions, including lithium, sodium, potassium, magnesium, calcium, strontium, vanadium, iron, cobalt, copper, and zinc, are thoroughly reviewed. In addition, the interactions between biometal ions, immune cells, and bone tissue are discussed, aiming to provide insights into the prospective development of novel approaches to bone tissue regeneration by harnessing the therapeutic potential of these biometal ions. [ABSTRACT FROM AUTHOR]

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The aim of this study was to verify the effectiveness of attenuated total reflectance‐fourier transform infrared (ATR‐FTIR) spectroscopy in the characterization of bone repair in mandibular osteotomy using erbium, chromium‐doped yttrium, scandium, gallium and garnet (Er,Cr:YSGG) laser and multilaminate drill on each side. Two mandible bone fragments were removed from 30 rabbits, and the process of bone repair was studied immediately, 3, 7, 15, 21, and 28 days after the surgery. The histological analysis allowed detecting differences in the early stages of tissue repair after bone cutting performed with the Er,Cr:YSGG laser or multilaminate drill. The ATR‐FTIR spectroscopy technique was sensitive to changes in the organic content of bone tissue repair process. [ABSTRACT FROM AUTHOR]

Abstract Background Angiogenesis is essential for repairing critical-sized bone defects. Although adipose-derived stem cell (ADSC)-derived exosomes have been shown to enhance the angiogenesis of endothelial progenitor cells (EPCs), the underlying mechanisms remain unclear. This study aims to explore the effects and mechanisms of ADSC-derived exosomes in enhancing bone repair by promoting EPC angiogenesis. Methods Transmission electron microscopy, nanoparticle tracking analysis, and Dil reagent kit were employed to identify ADSC-derived exosomes and their internalization by EPCs. Micro-CT analysis, H&E staining, and Masson staining were used to assess bone mineral density (BMD), bone volume fraction (BV/TV), trabecular thickness (Tb.Th), and trabecular number (Tb.N), as well as the pathological changes and fibrosis at defect sites. Cell viability, migration, invasion, and tube formation of EPCs were evaluated using CCK-8, wound healing, Transwell, and tube formation assays. Immunohistochemical staining, RT-PCR, and Western blotting were utilized to measure the gene and protein expression of markers such as CD31, VEGFA, OCN, RUNX2, NOTCH1, and DLL4. Gene sequencing and bioinformatics analyses were conducted to identify the most highly expressed miRNA in exosomes, while miRDB and dual-luciferase reporter assays were used to explore the interaction between miR-21-5p and NOTCH1. Results The ADSC-derived exosomes, averaging 126 nm in diameter, were internalized by EPCs. In vivo, these exosomes promoted new bone formation, increased BMD, BV/TV, Tb.Th, and Tb.N, reduced pathological damage to cranial defect tissues, enhanced vascular and bone tissue regeneration, and upregulated OCN and RUNX2 expression. In vitro, ADSC-derived exosomes enhanced EPC viability, migration, invasion, and tube formation. Both in vivo and in vitro experiments demonstrated that ADSC-derived exosomes upregulated CD31 and VEGFA expression. miR-21-5p, the most highly expressed miRNA in ADSC-derived exosomes, was found to target NOTCH1. Overexpression of miR-21-5p in these exosomes facilitated EPC migration, tube formation, and VEGFA expression while downregulating NOTCH1 and DLL4 expression. Inhibition of miR-21-5p produced opposite effects on EPCs. Conclusions These findings indicate that miR-21-5p in ADSC-derived exosomes promotes angiogenesis in EPCs to accelerate bone repair by targeting the NOTCH1/DLL4/VEGFA signaling pathway, offering a potential therapeutic strategy for bone defect treatment. Graphical Abstract

Objective To study the effect of the combinational use of miR-34a-functionalized Bio-Oss® bone powder with transglutaminase crosslinked gelatin (Col-Tgel) on the osteoblastic differentiation of bone marrow mesenchymal stem cells (BMSCs) and bone defect healing after irradiation. Methods The experiment was approved by the Animal Ethics Committee. BMSCs were isolated from the bone marrow of 2-week-old Sprague-Dawley (SD) rats and identified. After reaching 80% confluence, BMSCs were irradiated with 2 Gy of X-ray radiation to establish a radiation-damaged BMSC model for further experimentation. 2.5 μL or 5 μL of Col-Tgel was mixed with 10 mg of Bio-Oss® (P) to prepare PG-2.5 and PG-5. The optimal proportion of Bio-Oss® (P) and Col-Tgel was determined through in vitro and in vivo experiments. Cy3-labeled agomiR-34a, agomiR-34a, or agomiR NC was mixed with lipofectamine 2000 and added to 10 mg of Bio-Oss® (P). The mixtures were lyophilized, and 2.5 μL Col-Tgel was added to each group of lyophilized Bio-Oss®/lipofectamine/miRNA complexes or to 10 mg of Bio-Oss® to obtain PG-Cy3-miR-34a, PG-miR-34a, PG-miR NC, and PG. Irradiated BMSCs were cocultured with PG-Cy3-miR-34a to evaluate cellular uptake of Cy3-agomiR-34a using confocal microscopy. Then, irradiated BMSCs were cocultured with PG-miR-34a, PG-miR NC, and PG. The expression of miR-34a was tested by RT-qPCR and cell proliferation was tested by CCK-8 assay. After 14 days of osteogenic induction, the mRNA expression of Runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP), and osteocalcin (OCN) was tested by RT-qPCR. The bilateral tibias of 8-week-old SD rats were irradiated with a single dose of 15 Gy of X-ray radiation. Three weeks later, tibial defects with a diameter of 3 mm and a depth of 2 mm were created 2-3 mm below the epiphyseal line in the tibial metaphysis. The composite bone substitute materials of PG-miR-34a, PG-miR NC, and PG were implanted into the defect area. Eight weeks after implantation, the tibias were harvested and evaluated for bone regeneration using micro-CT analysis and HE staining. Results The results demonstrated that 2 Gy irradiation adversely affected the osteogenic differentiation capacity of BMSCs, evidenced by the decreased ALP staining and number of mineralized nodules stained with Alizarin red in the irradiated group compared to the non-irradiated group. The composite material consisting of 10 mg Bio-Oss® and 2.5 μL Col-Tgel exhibited good osteogenic induction capability and handling properties and was used for subsequent experiments. The PG-Cy3-miR-34a could deliver the loaded Cy3-agomiR-34a into irradiated BMSCs. PG-miR-34a enhanced the expression of miR-34a in irradiated BMSCs without affecting cell proliferation. PG-miR-34a significantly upregulated the expression of osteogenic-related genes, including Runx2, ALP, and OCN. In the experiment of bone defect healing in irradiated tibias, micro-CT analysis showed that PG-miR-34a group had a higher bone volume in the bone defect area compared to other groups. The HE staining results also confirmed that implantation of PG-miR-34a can promote the healing of bone defects in irradiated tibias. Conclusion The combinational use of miR-34a-functionalized Bio-Oss® bone powder with Col-Tgel could promote the osteogenic differentiation of irradiated BMSCs and enhance bone regeneration in irradiated bone defects.

The bone morphogenetic protein (BMP) signaling pathway plays a crucial role in bone development and regeneration. While BMP-2 is widely used as an alternative to autograft, its clinical application has raised concerns about adverse side effects and deteriorated bone quality. Therefore, there is a need to develop more sophisticated approaches to regulate BMP signaling and promote bone regeneration. Here, we present a novel complementary strategy that targets both BMP antagonist noggin and agonist Trb3 to enhance bone defect repair without the application of exogenous BMP-2. In vitro studies showed that overexpression of Trb3 with simultaneous noggin suppression significantly promotes osteogenic differentiation of mesenchymal stem cells. This was accompanied by increased BMP/Smad signaling. We also developed sterosome nanocarriers, a non-phospholipid liposomal system, to achieve non-viral mediated noggin suppression and Trb3 overexpression. The gene-loaded sterosomes were integrated onto an apatite-coated polymer scaffold for in vivo calvarial defect implantation, resulting in robust bone healing compared to BMP-2 treatments. Our work provides a promising alternative for high-quality bone formation by regulating expression of BMP agonists and antagonists.

BACKGROUND: Magnetic nanomaterials have biological activities such as promoting osteogenic differentiation of stem cells and inhibiting osteoclast formation, and can effectively promote the healing of injured bone tissue under the synergistic effect of magnetic fields. They have a very broad application prospect in bone injury repair. OBJECTIVE: To review the mechanism of magnetic nanomaterials and magnetic fields promoting bone repair, as well as their research progress in the field of bone injury repair. METHODS: Relevant literature search was conducted in PubMed and Web of Science databases with the search terms "magnetic nanomaterials, magnetic field, bone repair, bone tissue engineering, stem cell, osteoblast, osteoclast." The time limit of literature search was from 2003 to 2023, which was screened and analyzed. Some classic articles were manually retrieved, and 98 articles were finally included for RESULTS AND CONCLUSION: (1) Magnetic nanomaterials have biological effects such as promoting osteoblast differentiation, inhibiting osteoclast formation and regulating the immune microenvironment. In addition, magnetic nanomaterials can regulate the physicochemical properties of tissue engineering scaffolds, such as mechanical properties and surface morphology, and endowed with magnetic properties, which is conducive to the regulation of the adhesion, proliferation and osteogenic differentiation of stem cells. (2) The magnetic field has the ability to regulate multiple cell signaling pathways to promote osteoblast differentiation, inhibit osteoclast formation, stimulate angiogenesis and other biological effects, thus accelerating the healing of damaged bone tissue. (3) The joint application of magnetic nanomaterials and magnetic field accelerates the repair of bone damage by activating mechanotransduction, increasing the content of intracellular magnetic nanoparticles, and enhancing the effect of micro-magnetic field, which provides a new idea for the research of bone tissue engineering. (4) Magnetic field has demonstrated definite efficacy in the treatment of clinical fractures, osteoporosis, and osteoarthritis diseases, which is beneficial for bone tissue growth, reducing bone loss, alleviating pain, and improving the quality of life of patients. (5) Magnetic nanomaterials and magnetic fields have great potential for application in bone damage repair and regeneration, but the interaction mechanism between magnetic nanomaterials, magnetic fields, and cells has not been fully elucidated. Moreover, the key parameters of magnetic fields that regulate intracellular molecular events, including the type, intensity, frequency, duration, and mode of the magnetic field, as well as the precise biological effects of a specific magnetic field on osteoblasts and the underlying mechanisms, have yet to be defined. (6) Further attention needs to be paid to the effects on osteoclasts, nerves, blood vessels, and immune cells in the microenvironment of damaged tissues. Finally, the safety of magnetic materials for human use is yet to be systematically studied in terms of their distribution, metabolism, and acute and chronic toxicities. [ABSTRACT FROM AUTHOR]

Isotretinoin is an oral medication commonly utilized to treat severe acne. It belongs to the class of retinoids and is a synthetic form of vitamin A. Possible changes in bone tissue associated with the systemic administration of Isotretinoin for long periods and in high doses, such as hypercalcemia, osteopenia, diffuse hyperostosis, or even skeletal deformities, are reported in scientific studies. The objective of this literature review was to analyze the available scientific literature on the systemic administration of Isotretinoin and its effects on bone tissue. To this end, articles that demonstrate effects of Isotretinoin on bone metabolism, bone mineral density, bone formation, and resorption, in addition to possible changes generated in this tissue were considered valid for inclusion in this literature review. The search for articles that fit the premise of this work was carried out in the PubMed/MEDLINE database. In a preliminary search, 85 articles were obtained; after in-depth investigation and checking of the inclusion and exclusion criteria, 21 articles were selected, with 17 articles reporting the effect of systemic administration of Isotretinoin in humans and four articles analyzing the effect generated by this substance systemically administrated in animals, more specifically in rats. After analyzing the selected articles, it was possible to observe several reports on hyperostosis or even changes in the formation of bone structures in human patients. Concerning animals, the largest number of studies addressed the changes caused in the formation or development of bone structures by the systemic administration of Isotretinoin. From the current analyses, and given the wide use of Isotretinoin, it is necessary to know its viability and influence on tissues. Its clinical efficacy seems to overcome any of the skeletal side effects observed; however, more studies are necessary to properly evaluate and prove the effects generated on bone tissues as well as other structures.

Abstract Simultaneously modulating the inflammatory microenvironment and promoting local bone regeneration is one of the main challenges in treating bone defects. In recent years, osteoimmunology has revealed that the immune system plays an essential regulatory role in bone regeneration and that macrophages are critical components. In this work, a mussel-inspired immunomodulatory and osteoinductive dual-functional hydroxyapatite nano platform (Gold/hydroxyapatite nanocomposites functionalized with polydopamine - PDA@Au-HA) is developed to accelerate bone tissues regeneration by regulating the immune microenvironment. PDA coating endows nanomaterials with the ability to scavenge reactive oxygen species (ROS) and anti-inflammatory properties, and it also exhibits an immunomodulatory ability to inhibit M1 macrophage polarization and activate M2 macrophage secretion of osteogenesis-related cytokines. Most importantly, this nano platform promotes the polarization of M2 macrophages and regulates the crosstalk between macrophages and pre-osteoblast cells to achieve bone regeneration. Au-HA can synergistically promote vascularized bone regeneration through sustained release of Ca and P particles and gold nanoparticles (NPs). This nano platform has a synergistic effect of good compatibility, scavenging of ROS, and anti-inflammatory and immunomodulatory capability to accelerate the bone repair process. Thus, our research offers a possible therapeutic approach by exploring PDA@Au-HA nanocomposites as a bifunctional platform for tissue regeneration.

BACKGROUND: Bone has bioelectric effects. However, bone defects can lead to loss of endogenous bioelectricity in bone. The implantation of bone tissue engineering scaffolds with bioelectric effect into bone defects will replenish the missing electrical signals and accelerate the repair of bone defects. OBJECTIVE: To introduce the bioelectric effect of bone tissue and expound the repair effect of electrical stimulation on bone defects, summarize the research progress of bioelectric effect applied to bone tissue engineering, in order to provide new ideas for the research of bone tissue engineering. METHODS: Relevant articles were searched on CNKI, WanFang, PubMed, Web of Science and ScienceDirect databases, using “bioelectrical effect, bioelectrical materials, electrical stimulation, bone tissue engineering, bone scaffold, bone defect, bone repair, osteogenesis” as the English and Chinese search terms. Finally, 87 articles were included for analysis. RESULTS AND CONCLUSION: (1) Bioelectrical effect combined with ex vivo electrical stimulation to design bone tissue engineering scaffolds is an ideal and feasible approach, and the main materials involved include metallic materials, graphene materials, natural bio-derived materials, and synthetic biomaterial. At present, the most widely used conductive material is graphene material, which benefits from its super conductivity, large specific surface area, good biocompatibility with cells and bones, and excellent mechanical properties. (2) Graphene materials are mainly introduced into the scaffold as modified materials to enhance the conductivity of the overall scaffold, while its large surface area and rich functional groups can promote the loading and release of bioactive substances. (3) However, there are still some major challenges to overcome for bioelectrically effective bone tissue engineering scaffolds: not only electrical conductivity but also the overall performance of the bracket needs to be considered; lack of uniform, standardized preparation of bioelectrically effective bone tissue engineering scaffolds; extracorporeal electrical stimulation intervention systems are not yet mature enough; lack of individualized guidance on stent selection to enable the selection and design of the most appropriate stent for patients with different pathologies. (4) When designing conductive scaffolds, researchers have to deeply consider the comprehensive effects of the scaffolds, such as biocompatibility, mechanical properties, and biodegradability. This combination of properties can be achieved by combining multiple materials. (5) Beyond that, clinical translation should be the ultimate consideration for conductive stent design. On the basis of evaluating the safe current threshold for electrical stimulation to act on the human body and facilitate the repair of bone defects, animal experiments as well as basic experiments are designed and then applied to the clinic to achieve the ultimate goal of applying bioelectrical effect bone tissue engineering scaffolds in the clinic. [ABSTRACT FROM AUTHOR]

Due to the limited supply of autologous bone grafts, there is a need to develop more bone matrix materials to repair bone defects. Xenograft bone is expected to be used for clinical treatment due to its exact structural similarity to natural bone and its high biocompatibility. In this study, decellularized antler cancellous bone matrix (DACB) was first prepared, and then the extent of decellularization of DACB was verified by histological staining, which demonstrated that it retained the extracellular matrix (ECM). The bioactivity of DACB was assessed using C3H10T1/2 cells, revealing that DACB enhanced cell proliferation and facilitated cell adhesion and osteogenic differentiation. When evaluated by implanting DACB into nude mice, there were no signs of necrosis or inflammation in the epidermal tissues. The bone repair effect of DACB was verified in vivo using sika deer during the antler growth period as an animal model, and the molecular mechanisms of bone repair were further evaluated by transcriptomic analysis of the regenerated tissues. Our findings suggest that the low immunogenicity of DACB enhances the production of bone extracellular matrix components, leading to effective osseointegration between bone and DACB. This study provides a new reference for solving bone defects. [ABSTRACT FROM AUTHOR]

Postoperative pain is a major clinical problem imposing a significant burden on patients and society. In a survey 2 years after orthopedic surgery, 57%of patients reported persisting postoperative pain. However, only limited progress has been made in the development of safe and effective therapies to prevent the onset and chronification of pain after orthopedic surgery. We established a tibial fracturemouse model that recapitulates clinically relevant orthopedic trauma surgery, which causes changes in neuropeptide levels in dorsal root ganglia and sustained neuroinflammation in the spinal cord. Here, we monitored extended pain behavior in this model, observing chronic bilateral hindpaw mechanical allodynia in both male and female C57BL/6J mice that persisted for .3 months after surgery. We also tested the analgesic effects of a novel, minimally invasive, bioelectronic approach to percutaneously stimulate the vagus nerve (termed percutaneous vagus nerve stimulation [pVNS]). Weekly pVNS treatment for 30 minutes at 10 Hz for 3 weeks after the surgery strongly reduced pain behaviors comparedwith untreated controls. Percutaneous vagus nerve stimulation also improved locomotor coordination and accelerated bone healing. In the dorsal root ganglia, vagal stimulation inhibited the activation of glial fibrillary acidic protein-positive satellite cells but without affectingmicroglial activation. Overall, these data provide novel evidence supportive of theuseof pVN Stop revent post operative pain and inform translational studies to test antinociceptive effects of bioelectronic medicine in the clinic. [ABSTRACT FROM AUTHOR]

Aim: To assess the efficacy of heterologous fibrin biopolymer (HFB) in promoting alveolar bone healing after tooth extraction in rats. Materials and Methods: The upper right incisors of 48 Wistar rats were extracted. Toothless sockets were filled with HFB (HFBG, n = 24) or blood clot (BCG, n = 24). The tooth extraction sites were subjected to micro‐computed tomography (micro‐CT), histological, histomorphometric and immunohistochemical (for Runt‐related transcription factor 2/Runx2 and tartrate‐resistant acid phosphatase/TRAP) analyses on days 0, 7, 14 and 42 after extraction. Results: Socket volume remained similar between days 0 and 14 (69 ± 5.4 mm3), except in the BCG on day 14, when it was 10% lower (p =.043). Although the number of Runx2+ osteoblasts was high and similar in both groups (34 × 102 cells/mm2), the HFBG showed lower inflammatory process and osteoclast activity than BCG at 7 days. On day 14, the number of Runx2+ osteoblasts remained high and similar to the previous period in both groups. However, osteoclast activity increased. This increase was 55% lower in the HFBG than BCG. In the BCG, the presence of an inflammatory process and larger and numerous osteoclasts on day 14 led to resorption of the alveolar bone ridge and newly formed bone. On day 42, numbers of Runx2+ osteoblast and TRAP+ osteoclasts decreased dramatically in both groups. Although the BCG exhibited a more mature cortical bone formation, it exhibited a higher socket reduction (28.3 ± 6.67%) and smaller bone volume (37 ± 5.8 mm3) compared with HFBG (socket reduction of 14.8 ± 7.14% and total bone volume of 46 ± 5.4 mm3). Conclusions: HFB effectively suppresses osteoclast activity and reduces alveolar bone resorption compared with blood clot, thus preventing three‐dimensional bone loss, particularly during the early healing period. HFB emerges as a promising biopharmaceutical material for enhancing healing processes after tooth extraction. [ABSTRACT FROM AUTHOR]

Structural alteration of synthetic implants aims to achieve better bioactivity, higher cellular response, and regulated degradability, all of which are critical criteria for a biomaterial to serve as a graft in bone regeneration. The aim of this work was to synthesize silicon-substituted hydroxyapatite and test its bioactivity in simulated body fluid (SBF) by proving the use of sodium metasilicate (Na2SiO3.9H2O) as an affordable precursor of silica. Thus, the study evaluated the in vitro bone-bonding capacity of hydroxyapatite (Ca10(PO4)6(OH)2) (HA) substituted with silicate ion (Ca10(PO4)6−x(SiO4)x(OH)2−x; SixHA). The SixHA with x = 0.4 was synthesized by utilizing a wet precipitation method with sodium metasilicate as a low-cost silica alternative for alkoxysilane precursors. The SixHA was then examined for properties such as morphology, elemental composition, phase composition, and the nature of chemical bonds using scanning electron microscopy (SEM), energy dispersive X-ray analysis (EDX), X-ray diffractometry (XRD), and Fourier transformed infrared spectroscopy (FTIR), respectively. An in vitro bioactivity experiment was also carried out by incubating the SixHA in simulated body fluid (SBF) at 36.5 ◦C for 7 and 14 days. The obtained results revealed the substitution of SiO44− for some PO4 3− groups in the hydroxyapatite structure. The SixHA nucleated more apatite crystals on its surface and demonstrated some degradability during the periods of immersion in SBF. The characteristics of the SixHA imply that it could be used as a graft in bone restoration applications, thus signifying that sodium metasilicate could serve as an economic silica source for silicon-substituted hydroxyapatite production. [ABSTRACT FROM AUTHOR]

[Display omitted] Orderly hierarchical structure with balanced mechanical, chemical, and electrical properties is the basis of the natural bone microenvironment. Inspired by nature, we developed a piezocatalytically-induced controlled mineralization strategy using piezoelectric polymer poly-L-lactic acid (PLLA) fibers with ordered micro-nano structures to prepare biomimetic tissue engineering scaffolds with a bone-like microenvironment (pcm-PLLA), in which PLLA-mediated piezoelectric catalysis promoted the in-situ polymerization of dopamine and subsequently regulated the controllable growth of hydroxyapatite crystals on the fiber surface. PLLA fibers, as analogs of mineralized collagen fibers, were arranged in an oriented manner, and ultimately formed a bone-like interconnected pore structure; in addition, they also provided bone-like piezoelectric properties. The uniformly sized HA nanocrystals formed by controlled mineralization provided a bone-like mechanical strength and chemical environment. The pcm-PLLA scaffold could rapidly recruit endogenous stem cells, and promote their osteogenic differentiation by activating cell membrane calcium channels and PI3K signaling pathways through ultrasound-responsive piezoelectric signals. In addition, the scaffold also provided a suitable microenvironment to promote macrophage M2 polarization and angiogenesis, thereby enhancing bone regeneration in skull defects of rats. The proposed piezocatalytically-induced controllable mineralization strategy provides a new idea for the development of tissue engineering scaffolds that can be implemented for multimodal physical stimulation therapy. [ABSTRACT FROM AUTHOR]

Simultaneously modulating the inflammatory microenvironment and promoting local bone regeneration is one of the main challenges in treating bone defects. In recent years, osteoimmunology has revealed that the immune system plays an essential regulatory role in bone regeneration and that macrophages are critical components. In this work, a mussel-inspired immunomodulatory and osteoinductive dual-functional hydroxyapatite nano platform (Gold/hydroxyapatite nanocomposites functionalized with polydopamine - PDA@Au-HA) is developed to accelerate bone tissues regeneration by regulating the immune microenvironment. PDA coating endows nanomaterials with the ability to scavenge reactive oxygen species (ROS) and anti-inflammatory properties, and it also exhibits an immunomodulatory ability to inhibit M1 macrophage polarization and activate M2 macrophage secretion of osteogenesis-related cytokines. Most importantly, this nano platform promotes the polarization of M2 macrophages and regulates the crosstalk between macrophages and pre-osteoblast cells to achieve bone regeneration. Au-HA can synergistically promote vascularized bone regeneration through sustained release of Ca and P particles and gold nanoparticles (NPs). This nano platform has a synergistic effect of good compatibility, scavenging of ROS, and anti-inflammatory and immunomodulatory capability to accelerate the bone repair process. Thus, our research offers a possible therapeutic approach by exploring PDA@Au-HA nanocomposites as a bifunctional platform for tissue regeneration. [ABSTRACT FROM AUTHOR]

3D printing was widely used for the modification of bioceramic structures. Here, Bioactive titanium dioxide (TiO 2) ceramics with macropore structures were prepared by controlling the pore size through 3D printing, and further obtained secondary micropores by altering the sintering temperature. The structures and in vitro bioactivity of materials were characterized, and the properties of the ceramics for osteogenic differentiation of rabbits bone marrow mesenchymal stem cells (rBMSCs) were investigated. The results showed that titanium dioxide ceramics could induce apatite formation in SBF, which indicated it is bioactive. All materials exhibited porous structures, which could promote the proliferation and osteogenic differentiation of rBMSCs. Importantly, the structure with 200 μm pore size significantly promoted the proliferation and adhesion of cells. Furthermore, more secondary micropores formed on the surface of materials with the decreased sintering temperature, which promoted cell proliferation. The pore size of 400 μm significantly upregulated the expression of osteogenesis-related genes, including Col I, ALP, Runx2, and OPN. It had the strongest osteogenic ability when sintered at 1100 °C compared to other groups. This implies that the 3D-printed TiO 2 ceramics have good osteogenic properties, and the hierarchical structure consisting of macroscopic pores and secondary micropores can control it well. [Display omitted] [ABSTRACT FROM AUTHOR]

Continuous administration of low‐intensity whole‐body vibration (WBV) gradually diminishes bone mechanosensitivity over time, leading to a weakening of its osteogenic effect. We investigated whether discretizing WBV into bouts with short rest intervals was effective in enhancing osteoporotic bone repair. Ten‐week‐old female mice were ovariectomized and underwent drill‐hole defect surgery (Day 0) on the right tibial diaphysis at 11 weeks of age. The mice underwent one of three regimens starting from Day 1 for 5 days/week: continuous WBV at 45 Hz and 0.3 g for 7.5 min/day (cWBV); 3‐s bouts of WBV at 45 Hz, 0.3 g followed by 9‐s rest intervals, repeated for 30 min/day (repeated bouts of whole‐body vibration with short rest intervals [rWBV]); or a sham treatment. Both the cWBV and rWBV groups received a total of 20,250 vibration cycles per day. On either Day 7 or 14 posteuthanasia (n = 6/group/timepoint), the bone and angiogenic vasculature in the defect were computed tomography imaged using synchrotron light. By Day 14, the bone repair was most advanced in the rWBV group, showing a higher bone volume fraction and a more uniform mineral distribution compared with the sham group. The cWBV group exhibited an intermediate level of bone repair between the sham and rWBV groups. The rWBV group had a decrease in large‐sized angiogenic vessels, while the cWBV group showed an increase in such vessels. In conclusion, osteoporotic bone repair was enhanced by WBV bouts with short rest intervals, which may potentially be attributed to the improved mechanosensitivity of osteogenic cells and alterations in angiogenic vasculature. [ABSTRACT FROM AUTHOR]

Some studies have reported that tacrolimus (FK506), an immunosuppressant, may have positive effects on bone formation. However, the precise effects of FK506 on bone repair or osteoblasts remain inadequately elucidated, and limited research has explored the outcomes of its use in an in vivo mouse model. This study aims to examine the effects of FK506 on bone repair and osteoblast functions using bone defect and BMP-2-induced ectopic ossification mouse models, as well as cultured primary mouse osteoblasts treated with FK506. We established mouse models of femur bone defect and BMP-2-induced ectopic ossification to evaluate the effect of FK506 on new bone formation, respectively. Additionally, primary mouse osteoblasts were cultured with FK506 and examined for gene expressions related to osteoblast differentiation. While FK506 promoted the repair of bone defect areas in the femur of the bone defect mouse model, it also led to widespread abnormal bone formation outside the intended area. Additionally, following the implantation of a collagen sponge containing BMP-2 into mouse muscle tissue, FK506 was found to promote ectopic ossification and enhance BMP-2-induced osteoblast differentiation in vitro. Our findings also revealed that FK506 increased the number of immature osteoblasts in the absence of BMP-2 without affecting osteoblast differentiation. Furthermore , direct effects were observed, reducing the ability of osteoblasts to support osteoclastogenesis. These results indicate that FK506 increases new bone formation during bone repair and influences the proliferation of immature osteoblasts, as well as osteoblast-supported osteoclastogenesis. [Display omitted] • FK506 increases new bone formation during bone repair. • BMP-2-induced ectopic ossification is promoted by FK506. • FK506 enhances BMP-2-induced osteoblast differentiation. • FK506 increases osteoblasts in the absence of BMP-2. • FK506 has effects on osteoblast-supported osteoclastogenesis. [ABSTRACT FROM AUTHOR]

A composite bone cement based on α-TCP with self-reinforcing characteristics is prepared by compounding cellulose whiskers and polyvinyl alcohol in different proportions. In this system, we are inspired by the sea cucumber, which can alter the stiffness of their inner dermis reversibly. Through the formation of hydrogen bonds between the hydroxyl groups on the cellulose whiskers and PVA, the bone cement matrix can be strengthened during the curing process of cement. In the process of bone cement blending, there is more water, the hydrogen bond connection is destroyed, so the slurry has better fluidity at this time. As the hydration of the bone cement progresses, the reduction of the water phase leads to the formation of a permeable network structure of hydrogen bond connections between the whiskers. The dual-phase action of PVA and whiskers greatly increases the mechanical strength of the bone cement system (5.5 to 23.8 MPa), while the presence of polyvinyl alcohol improves the toughness of the bone cement system. This work was supposed to explore whether the chemoresponsive materials can be adapted to biomedical materials, for example, bone repair. [ABSTRACT FROM AUTHOR]

The repair of bone defects necessitates the establishment of sophisticated gradients. However, most strategies for gradient casting require specialized apparatus and have high equipment requirements. Therefore, there is a strong desire to develop a simple method for constructing gradient scaffolds that mimic the hierarchical structure of native bone. In this study, we prepared poly (vinyl alcohol)/bacterial cellulose (PVA/BC) scaffolds with gradient hydroxyapatite (HAp) content using the buoyancy-driven gradient (BG) method. Scanning electron microscopy characterization revealed that HAp gradient scaffold exhibited the gradient microstructure and HAp content. Furthermore, HAp gradient scaffold demonstrated enhanced adhesion, spreading, and proliferation of MC3T3-E1 cells and displayed excellent osteogenic ability. Additionally, when applied in subcutaneous implantation models in mice, HAp gradient scaffold showed superior biocompatibility compared to other scaffolds tested in vitro. These results present a straightforward approach for fabricating gradient HAp bone scaffolds that hold great potential as candidate materials for bone regeneration. [ABSTRACT FROM AUTHOR]

Abstract The treatment of infected bone defects (IBDs) needs simultaneous elimination of infection and acceleration of bone regeneration. One mechanism that hinders the regeneration of IBDs is the iron competition between pathogens and host cells, leading to an iron deficient microenvironment that impairs the innate immune responses. In this work, an in situ modification strategy is proposed for printing iron‐active multifunctional scaffolds with iron homeostasis regulation ability for treating IBDs. As a proof‐of‐concept, ultralong hydroxyapatite (HA) nanowires are modified through in situ growth of a layer of iron gallate (FeGA) followed by incorporation in the poly(lactic‐co‐glycolic acid) (PLGA) matrix to print biomimetic PLGA based composite scaffolds containing FeGA modified HA nanowires (FeGA‐HA@PLGA). The photothermal effect of FeGA endows the scaffolds with excellent antibacterial activity. The released iron ions from the FeGA‐HA@PLGA help restore the iron homeostasis microenvironment, thereby promoting anti‐inflammatory, angiogenesis and osteogenic differentiation. The transcriptomic analysis shows that FeGA‐HA@PLGA scaffolds exert anti‐inflammatory and pro‐osteogenic differentiation by activating NF‐κB, MAPK and PI3K‐AKT signaling pathways. Animal experiments confirm the excellent bone repair performance of FeGA‐HA@PLGA scaffolds for IBDs, suggesting the promising prospect of iron homeostasis regulation therapy in future clinical applications.

Abstract Angiogenesis is crucial for successful bone defect repair. Co‐transplanting Bone Marrow Stromal Cells (BMSCs) and Endothelial Cells (ECs) has shown promise for vascular augmentation, but it face challenges in hostile tissue microenvironments, including poor cell survival and limited efficacy. In this study, the mitochondria of human BMSCs are isolated and transplanted to BMSCs from the same batch and passage number (BMSCsmito). The transplanted mitochondria significantly boosted the ability of BMSCsmito‐ECs to promote angiogenesis, as assessed by in vitro tube formation and spheroid sprouting assays, as well as in vivo transplantation experiments in balb/c mouse and SD rat models. The Dll4‐Notch1 signaling pathway is found to play a key role in BMSCsmito‐induced endothelial tube formation. Co‐transplanting BMSCsmito with ECs in a rat cranial bone defect significantly improves functional vascular network formation, and improve bone repair outcomes. These findings thus highlight that mitochondrial transplantation, by acting through the DLL4‐Notch1 signaling pathway, represents a promising therapeutic strategy for enhancing angiogenesis and improving bone repair. Hence, mitochondrial transplantation to BMSCS as a therapeutic approach for promoting angiogenesis offers valuable insights and holds much promise for innovative regenerative medicine therapies.

Impaired bone healing is a significant complication observed in individuals with type 2 diabetes mellitus (T2DM), leading to prolonged recovery, increased risk of complications, impaired quality of life, and increased risk of patient morbidity. Oxidative stress, resulting from an imbalance between the generation of reactive oxygen species (ROS) and cellular/tissue antioxidant defence mechanisms, has been identified as a critical contributor to the pathogenesis of impaired bone healing in T2DM. Antioxidants have shown promise in mitigating oxidative stress and promoting bone repair, particularly non-enzymic antioxidant entities. This comprehensive narrative review aims to explore the underlying mechanisms and intricate relationship between oxidative stress, impaired bone healing and T2DM, with a specific focus on the current preclinical and clinical evidence advocating the potential of antioxidant therapeutic interventions in improving bone healing outcomes in individuals with T2DM. From the ever-emerging evidence available, it is apparent that exogenously supplemented antioxidants, especially non-enzymic antioxidants, can ameliorate the detrimental effects of oxidative stress, inflammation, and impaired cellular function on bone healing processes during uncontrolled hyperglycaemia; and therefore, hold considerable promise as novel efficacious therapeutic entities. However, despite such conclusions, several important gaps in our knowledge remain to be addressed, including studies involving more sophisticated enzymic antioxidant-based delivery systems, further mechanistic studies into how these antioxidants exert their desirable reparative effects; and more extensive clinical trial studies into the optimisation of antioxidant therapy dosing, frequency, duration and their subsequent biodistribution and bioavailability. By enhancing our understanding of such crucial issues, we can fully exploit the oxidative stress-neutralising properties of these antioxidants to develop effective antioxidant interventions to mitigate impaired bone healing and reduce the associated complications in such T2DM patient populations.

Biphasic calcium phosphate (BCP) ceramics are valued for their osteoconductive properties but have limited osteogenic and angiogenic activities, which restricts their clinical utility in bone defect repair. Silicon doping has emerged as an effective strategy to enhance these biological functions of BCP. However, the biological impact of BCP is influenced by the level of silicon doping, necessitating determination of the optimal concentration to maximize efficacy in bone repair. This study investigated the effects of silicon doping on both the physicochemical and biological properties of BCP, with a specific focus on osteogenic and angiogenic potentials. Results indicated that silicon doping exceeding 4 mol.% led to the formation of α-TCP, accelerating BCP degradation, enhancing silicon ion release, and promoting mineralization product formation. Simultaneously, silicon doping increased the porosity of BCP scaffolds, which typically reduces their compressive strength. Nevertheless, scaffolds doped with ≤4 mol.% silicon maintained compressive strengths exceeding 2 MPa. In vitro biological experiments indicated that higher levels of silicon doping (≥6 mol.%) partially inhibited the successful differentiation of stem cells and the vascularization of endothelial cells. Optimal conditions for promoting osteogenic differentiation and angiogenesis were identified between 2 and 4 mol.% silicon doping, with an optimal level of approximately 4 mol.%. Subsequent in vivo experiments confirmed that BCP scaffolds doped with 4 mol.% silicon effectively promoted vascularization and new bone formation, highlighting their potential for clinical bone defect repair.

Introduction3D-printed scaffolds have emerged as an alternative for addressing the current limitations encountered in bone reconstruction. This study aimed to systematically review the feasibility of using 3D bio-printed scaffolds as a material for bone grafting in animal models, focusing on femoral and tibial defects. The primary objective of this study was to evaluate the efficacy, safety, and overall impact of these scaffolds on bone regeneration.MethodsElectronic databases were searched using specific search terms from January 2013 to October 2023, and 37 relevant studies were finally included and reviewed. We documented the type of scaffold generated using the 3D printed techniques, detailing its characterization and rheological properties including porosity, compressive strength, shrinkage, elastic modulus, and other relevant factors. Before incorporating them into the meta-analysis, an additional inclusion criterion was applied where the regenerated bone area (BA), bone volume (BV), bone volume per total volume (BV/TV), trabecular thickness (Tb. Th.), trabecular number (Tb. N.), and trabecular separation (Tb. S.) were collected and analyzed statistically.Results3D bio-printed ceramic-based composite scaffolds exhibited the highest capacity for bone tissue regeneration (BTR) regarding BV/TV of femoral and tibial defects of animal models. The ideal structure of the printed scaffolds displayed optimal results with a total porosity >50% with a pore size ranging between 300- and 400 µM. Moreover, integrating additional features and engineered macro-channels within these scaffolds notably enhanced BTR capacity, especially observed at extended time points.DiscussionIn conclusion, 3D-printed composite scaffolds have shown promise as an alternative for addressing bone defects.

Magnesium (Mg) is abundant in humans. Studies have shown that Mg2+ significantly affects physiological processes such as osteogenesis, osteoblast adhesion and motility, immunomodulation, and angiogenesis. Mg-based alloy porous scaffolds have attracted increasing attention because of their degradability and mechanical properties. Hence, wire-cut EDM was used to fabricate porous scaffolds. In addition, fluoride treatment afforded an MgF2 coating, and racemic polylactic acid PDLLA was used as the carrier of rhBMP-2, which was evenly coated on the surface of the passivated porous alloy scaffold to slowly release growth factors and slow down the degradation rate. The rat femoral condyle defect model experiment was performed to study the in vivo bone regeneration capacity of porous scaffolds and compare the differences in the healing effect with or without rhBMP-2. The enhanced corrosion resistance of the porous scaffold was confirmed through in vitro immersion experiments. Micro-CT implied that porous scaffold with rhBMP-2 induced new bone formation and the new bone formation along the pores, as well as the histological examination in vivo. In summary, the porous scaffold promotes bone formation and has great potential for clinical translation.