Stimulate Bone Regeneration Research Articles

Accelerating Fracture Healing in Delayed Uniting Fractures: A Clinical Study

Background: Delayed union fractures pose a significant clinical challenge, often requiring enhanced treatment modalities to accelerate healing and improve patient outcomes. Various techniques, including autologous bone grafting and biologic agents like platelet-rich plasma (PRP) and bone morphogenetic proteins (BMPs), have been employed to stimulate bone regeneration. However, the optimal approach remains debated. Objective: This study aimed to compare the efficacy of autologous bone grafting, biologic agents, and combined therapies in promoting fracture healing, reducing pain, improving functional outcomes, and enhancing patient satisfaction in delayed union fractures. Methods: A prospective study was conducted on 80 patients with delayed union fractures. Patients were randomly assigned to one of four groups: standard care (control), autologous bone grafting, biologic agents (PRP and BMPs), or a combination of bone grafting and biologic agents. Radiographic healing was assessed at 6, 12, and 24 weeks. Pain intensity was measured using the Visual Analog Scale (VAS), functional outcomes were assessed using the AAOS lower limb function scale, and patient satisfaction was evaluated using a Likert scale. Results: The combined therapy group exhibited significantly faster radiographic healing, with 80% of patients showing callus formation at 6 weeks and 95% achieving complete union at 24 weeks, compared to 35% in the control group. The combined group also reported the greatest reduction in VAS pain scores, with a mean decrease from 7.8 to 1.5 at 24 weeks (p<0.001). Functional outcomes were significantly improved in the combined group, with a mean AAOS score of 100 at 24 weeks, compared to 70 in the control group (p<0.001). Additionally, 90% of patients in the combined group reported high satisfaction, compared to 40% in the control group. Conclusion: The combination of autologous bone grafting and biologic agents, such as PRP and BMPs, significantly accelerates ..........

Tellurium-Doped Bioactive Glass Induces Ferroptosis in Osteosarcoma Cells Regardless of FSP1

Human osteosarcoma (OS) is a rare tumor predominantly affecting long bones and characterized by a poor prognosis. Currently, the first line of intervention consists of the surgical resection of primary tumors combined with radiotherapy and chemotherapy, with a profound impact on the patient’s life. Since the surgical removal of OS frequently results in a large resection of bones, the use of biomaterials to sustain the stability of the remaining tissue and to stimulate bone regeneration is challenging. Moreover, residual neoplastic cells might be responsible for tumor recurrence. Here, we explored the potential of tellurium-ion-doped bioactive glass as a novel therapeutic intervention to both eradicate residual malignant cells and promote bone regeneration. Bioactive glass (BAG) has been extensively studied and employed in the field of regenerative medicine due to its osseointegration properties and ability to improve bone tissue regeneration. We found that the incorporation of tellurium (Te) in BAG selectively kills OS cells through ferroptosis while preserving the viability of hBMSCs and stimulating their osteodifferentiation. However, the mechanism of Te toxicity is still unclear: (i) Te-BAG generates lipid-ROS through LOXs activity but not iron overload; (ii) Te-dependent ferroptosis is mediated by GPX4 down-regulation; and (iii) the anti-ferroptotic activity of FSP1 is abrogated, whose expression confers the resistance of OS to the canonical induction of ferroptosis. Overall, our data show that Te-doped bioglass could represent an interesting biomaterial with both pro-ferroptotic activity towards residual cancer cells and pro-osteoregenerative activity.

Tauroursodeoxycholic acid combined with selenium accelerates bone regeneration in ovariectomized rats.

More recently, increased studies have revealed that antioxidants can cure osteoporosis by inhibiting oxidative stress. Tauroursodeoxycholic acid (TUDCA) and Selenium (Se) have been confirmed to possess potent anti-oxidative effects and accelerate bone regeneration. In addition, very little is currently known about the effects of a combination with Se and TUDCA on bone defects in osteoporotic states. We, therefore, aimed to assess the protective effect of combination with Se and TUDCA on bone regeneration and investigate the effect and underlying mechanisms. When MC3T3-E1 was cultured in the presence of H2H2, Se, TUDCA and Se/TUDCA therapy could increase the matrix mineralization and promote expression of anti-oxidative stress markers in MC3T3-E1, while reducing intracellular reactive oxygen species (ROS) and mitochondrial ROS levels. Meanwhile, silent information regulator type 1 (SIRT1) was upregulated in response to Se, TUDCA and Se/TUDCA exposures in H2H2 treated-MC3T3-E1. In the OVX rat model, Se, TUDCA and Se/TUDCA showed a clear positive effect against impaired bone repair in osteoporosis. The results above demonstrate that Se/TUDCA exhibits superior efficacy in both cellular and animal experiments, as compared to Se and TUDCA. In conclusion, combination with Se and TUDCA stimulates bone regeneration and is a promising candidate for promoting bone repair in osteoporosis.

Incorporating Microbial Stimuli for Osteogenesis in a Rabbit Posterolateral Spinal Fusion Model.

Autologous bone grafts are commonly used to repair defects in skeletal tissue, however, due to their limited supply there is a clinical need for alternatives. Synthetic ceramics present a promising option but currently lack biological activity to stimulate bone regeneration. One potential approach to address this limitation is the incorporation of immunomodulatory agents. In this study, we investigate the application of microbial stimuli to stimulate bone formation. Three different microbial stimuli were incorporated in a biphasic calcium phosphate (BCP) ceramic: Bacille Calmette-Guérin (BCG), gamma-irradiated Staphylococcus aureus (γi-S. aureus), or Candida albicans (γi-C. Albicans). The constructs were then implanted in both a rabbit posterolateral spinal fusion (PLF) and an intramuscular implant model for 10 weeks and compared to a non-stimulated control construct. For the PLF model, the formation of a bony bridge was evaluated by manual palpation, micro-CT, and histology. While complete fusion was not observed, the BCG condition was most promising with higher manual stiffness and almost twice as much bone volume in the central fusion mass compared to the control (9±4.4% bone area vs 4.6±2.3%, respectively). Conversely, the γi-S. aureus or γi-C. albicans appeared to inhibit bone formation (1.4±1.4% and 1.2±0.6% bone area). Bone induction was not observed in any of the intramuscular implants. This study indicates that incorporating immunomodulatory agents in ceramic bone substitutes can affect bone formation, which can be positive when selected carefully. The readily available and clinically approved BCG showed promising results, which warrants further research for clinical translation.

Injectable, oxygen-releasing, thermosensitive hydrogel promotes vascularized bone formation with prolonged oxygen delivery and improved osteoinductivity

The failure or delay in healing of critical bone defects is primarily due to early local anoxic conditions and reduced osteogenic activity. In this research, we integrated calcium peroxide (CPO) embedded polycaprolactone (PCL) microspheres and osteoinductive nanoparticles (Hydroxyapatite/Laponite) into a thermosensitive hydrogel (Pluronic F127), thereby formulating an injectable oxygen-releasing osteogenic thermosensitive hydrogel. Notably, the oxygen-releasing microspheres (ORMs) within the composite hydrogel provide stable oxygen release for up to 21 days, ensuring the survival, migration, and bioactivity of both mesenchymal stem cells and endothelial cells under anoxic conditions. Additionally, the composite hydrogel significantly augments the osteogenic potential of bone marrow mesenchymal stem cells by providing a biomimetic microenvironment with the incorporation of nano-hydroxyapatite/laponite. Ultimately, the injectable composite hydrogel successfully stimulated bone regeneration within a cranial defect in a rat model after 8 weeks, with enhanced vascularization and bone quality. The engineered hydrogel provides a minimally invasive approach to stimulate bone regeneration with a sustained oxygen supply and osteogenic microenvironment provision, underlining its potential for treating critical bone defects.

Fabrication of 3D microfibrous composite polycaprolactone/hydroxyapatite scaffolds loaded with piezoelectric poly (lactic acid) nanofibers by sequential near-field and conventional electrospinning for bone tissue engineering

Near-field electrospinning (NFES) has recently gained considerable interest in fabricating tissue engineering scaffolds. This technique combines the advantages of both 3D printing and electrospinning. It allows for the production of fibers with smaller resolution and the ability to make regular structures with suitable pores. In this study, a microfibrous composite scaffold of polycaprolactone (PCL)/hydroxyapatite (HA) was prepared by NFES in the first step. The microfibrous scaffold had a fiber spacing of 414.674 ± 24.9 μm with an average fiber diameter of 94.695 ± 16.149 μm. However, due to the large fiber spacing, the surface area was insufficient for cell adhesion. Therefore, the hybrid scaffold was prepared by adding aligned and random electrospun poly (L-lactic acid) (PLLA) nanofibers to the microfibrous scaffold. Cellular studies showed that cell adhesion to the hybrid scaffold increased by 334 % compared to the microfibrous scaffold. These nanofibers also exhibited piezoelectric properties, which helped stimulate bone regeneration. Aligned nanofibers in the hybrid scaffold enhanced alkaline phosphatase activity and the intensity of alizarin red staining 1.5 and 1.6 times, respectively, compared to the microfibrous scaffold. Furthermore, the elastic modulus and ultimate tensile strength increased by 268 % and 130 %, respectively, by adding aligned nanofibers to the microfibrous scaffold. Therefore, the hybrid microfibrous composite scaffold of PCL/HA containing aligned electrospun PLLA nanofibers with improved properties showed the potential for bone regeneration.

The Role of Mesenchymal Stem Cells in Dentistry: A Review

Mesenchymal stem cells (MSCs) have garnered significant attention in regenerative dentistry due to their remarkable ability to differentiate into various cell types and their immunomodulatory properties. This review provides a comprehensive overview of recent advancements in MSC research relevant to dentistry, focusing on their potential applications in periodontal tissue regeneration, dental pulp regeneration, and maxillofacial bone repair. Periodontal diseases, which affect the tissues surrounding and supporting the teeth, are a significant challenge in dentistry. Current treatments often involve surgical intervention and tissue grafting. MSCs have shown promise as a potential alternative for periodontal tissue regeneration, as they can differentiate into periodontal ligament cells, cementoblasts, and osteoblasts. Several preclinical and clinical studies have demonstrated the efficacy of MSC-based therapies in periodontal regeneration. Dental pulp regeneration is another area where MSCs hold promise. Damaged or infected dental pulp can lead to pulpitis or pulp necrosis, necessitating root canal treatment. MSCs have been studied for their ability to regenerate dental pulp tissue and promote pulp healing. They can differentiate into odontoblast-like cells and regenerate dentin-like tissue, making them a potential treatment option for dental pulp regeneration. In maxillofacial bone repair, MSCs have been investigated for their osteogenic differentiation potential and ability to stimulate bone regeneration. Studies have shown promising results, suggesting that MSC-based therapies could be a viable treatment option for maxillofacial bone defects. The mechanisms underlying MSC-based therapies in dentistry are not fully understood but are thought to involve a combination of paracrine effects, immunomodulation, and differentiation into specific cell types. Future research should focus on addressing these challenges and exploring novel approaches for enhancing the regenerative potential of MSCs in dentistry.

Effect of various admixtures on selected mechanical properties of medium viscosity bone cements: Part 1 – α/β tricalcium phosphate (TCP)

Every year millions of people around the world suffer from joint and bone diseases and require orthopaedic surgery. Owing to its unique properties such as biocompatibility and ability to bond bones with orthopaedic implants, poly methyl-methacrylate (PMMA) is among the most widely used polymer composites for bone cements in orthopaedic and trauma surgery. On the other hand, this material is characterized by low mechanical properties, which can lead to accelerated implant loosening in aggressive environments, such as the human body. Over the years, researchers have studied PMMA, especially its failure mechanism. Various additives to PMMA have been proposed to enhance the mechanical properties of this material. This study investigated the effect of mixing PMMA with α-TCP (PMMA/α-TCP bone cement composite) and β-TCP (PMMA/β-TCP bone cement composite) on its mechanical properties. The study was conducted on commercially available PMMA (Haraeus Palamed) mixed with α-TCP and β-TCP in different concentrations. TCP has bacteriostatic properties and, as a bone compatible material, it stimulates bone regeneration and bone ingrowth, which highly increases the survival rate of PMMA bonding. However, the addition of particles to PMMA can affect mechanical properties of bone cements. In this study, the effects of 0, 1, 2, 3, 5, 8 and 10% dry mass concentration of TCP in bone cement on the mechanical properties of PMMA were investigated. Samples were subjected to compressive loading. This loading mode is typical of the human body after joint prosthesis implantation. The analysis involved comparing selected mechanical parameters of samples prepared according to manufacturer’s instructions and of samples prepared with the addition of α-TCP and β-TCP. Results demonstrated that the addition of β-TCP, whose crystals are triangular, did not affect the mechanical properties of PMMA. On the other hand, the addition of more than 3% dry mass α-TCP, the inner structure of which is hexagonal, led to a slight yet significant decrease in the compressive strength of PMMA.

Sustainable biomaterials for tissue engineering: electrospun polycaprolactone fibers enriched with freshwater snail calcium carbonate and waste human hair keratin

AbstractThis study focuses on developing a sustainable and biocompatible polycaprolactone (PCL)‐based scaffold for bone tissue engineering through electrospinning, utilizing calcium carbonate (CaCO3) from Pomacea canaliculata shells and keratin from human hair, known for stimulating bone regeneration. The isolated CaCO3 has been identified to demonstrate two polymorphs, vaterite and calcite, as determined by X‐ray diffraction. The isolation of keratin from human hair was confirmed through sodium dodecyl sulfate polyacrylamide gel electrophoresis and Fourier transform infrared spectroscopy analysis, revealing the presence of α‐keratin structures around 45–50 kDa and β‐keratin structures around 55–60 kDa. According to scanning electron microscope observations, the addition of keratin to PCL fibers reduced their diameter from 457 ± 345 to 371 ± 103 nm. Further addition of calcium carbonate led to a mean diameter of 258 ± 76 nm. The melting temperature of PCL fibers containing keratin and CaCO3 was determined to be 76.17 °C via differential scanning calorimetry, while thermogravimetric analysis, conducted at temperatures up to 600 °C, revealed a remaining ash content of 9.59%. Calcium phosphate accumulation was observed to initiate on PCL fibers containing keratin and CaCO3 following a 7‐day exposure to simulated body fluid. The fibers exhibit cytocompatibility, showing no toxicity while supporting the growth and proliferation of Saos‐2 osteosarcoma cells. The results suggest that the innovative incorporation of keratin and CaCO3 into PCL nanofibers could serve as a bioactive matrix compared to pure PCL matrices, thereby offering enhanced potential for bone tissue engineering applications. © 2024 The Author(s). Polymer International published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Translational Experimental Basis of Indirect Adenosine Receptor Agonist Stimulation for Bone Regeneration: A Review.

Bone regeneration remains a significant clinical challenge, often necessitating surgical approaches when healing bone defects and fracture nonunions. Within this context, the modulation of adenosine signaling pathways has emerged as a promising therapeutic option, encouraging osteoblast activation and tempering osteoclast differentiation. A literature review of the PubMed database with relevant keywords was conducted. The search criteria involved in vitro or in vivo models, with clear methodological descriptions. Only studies that included the use of indirect adenosine agonists, looking at the effects of bone regeneration, were considered relevant according to the eligibility criteria. A total of 29 articles were identified which met the inclusion and exclusion criteria, and they were reviewed to highlight the preclinical translation of adenosine agonists. While preclinical studies demonstrate the therapeutic potential of adenosine signaling in bone regeneration, its clinical application remains unrealized, underscoring the need for further clinical trials. To date, only large, preclinical animal models using indirect adenosine agonists have been successful in stimulating bone regeneration. The adenosine receptors (A1, A2A, A2B, and A3) stimulate various pathways, inducing different cellular responses. Specifically, indirect adenosine agonists act to increase the extracellular concentration of adenosine, subsequently agonizing the respective adenosine receptors. The agonism of each receptor is dependent on its expression on the cell surface, the extracellular concentration of adenosine, and its affinity for adenosine. This comprehensive review analyzed the multitude of indirect agonists currently being studied preclinically for bone regeneration, discussing the mechanisms of each agonist, their cellular responses in vitro, and their effects on bone formation in vivo.

Vascular restoration through local delivery of angiogenic factors stimulates bone regeneration in critical size defects

Critical size bone defects represent a significant challenge worldwide, often leading to persistent pain and physical disability that profoundly impact patients’ quality of life and mental well-being. To address the intricate and complex repair processes involved in these defects, we performed single-cell RNA sequencing and revealed notable shifts in cellular populations within regenerative tissue. Specifically, we observed a decrease in progenitor lineage cells and endothelial cells, coupled with an increase in fibrotic lineage cells and pro-inflammatory cells within regenerative tissue. Furthermore, our analysis of differentially expressed genes and associated signaling pathway at the single-cell level highlighted impaired angiogenesis as a central pathway in critical size bone defects, notably influenced by reduction of Spp1 and Cxcl12 expression. This deficiency was particularly pronounced in progenitor lineage cells and myeloid lineage cells, underscoring its significance in the regeneration process. In response to these findings, we developed an innovative approach to enhance bone regeneration in critical size bone defects. Our fabrication process involves the integration of electrospun PCL fibers with electrosprayed PLGA microspheres carrying Spp1 and Cxcl12. This design allows for the gradual release of Spp1 and Cxcl12 in vitro and in vivo. To evaluate the efficacy of our approach, we locally applied PCL scaffolds loaded with Spp1 and Cxcl12 in a murine model of critical size bone defects. Our results demonstrated restored angiogenesis, accelerated bone regeneration, alleviated pain responses and improved mobility in treated mice.

Poly(dl-lactide) Polymer Blended with Mineral Phases for Extrusion 3D Printing-Studies on Degradation and Biocompatibility.

A promising therapeutic option for the treatment of critical-size mandibular defects is the implantation of biodegradable, porous structures that are produced patient-specifically by using additive manufacturing techniques. In this work, degradable poly(DL-lactide) polymer (PDLLA) was blended with different mineral phases with the aim of buffering its acidic degradation products, which can cause inflammation and stimulate bone regeneration. Microparticles of CaCO3, SrCO3, tricalcium phosphates (α-TCP, β-TCP), or strontium-modified hydroxyapatite (SrHAp) were mixed with the polymer powder following processing the blends into scaffolds with the Arburg Plastic Freeforming 3D-printing method. An in vitro degradation study over 24 weeks revealed a buffer effect for all mineral phases, with the buffering capacity of CaCO3 and SrCO3 being the highest. Analysis of conductivity, swelling, microstructure, viscosity, and glass transition temperature evidenced that the mineral phases influence the degradation behavior of the scaffolds. Cytocompatibility of all polymer blends was proven in cell experiments with SaOS-2 cells. Patient-specific implants consisting of PDLLA + CaCO3, which were tested in a pilot in vivo study in a segmental mandibular defect in minipigs, exhibited strong swelling. Based on these results, an in vitro swelling prediction model was developed that simulates the conditions of anisotropic swelling after implantation.

An In Vitro Study on the Application of Silver-Doped Platelet-Rich Plasma in the Prevention of Post-Implant-Associated Infections.

Implant therapy is a common treatment option in dentistry and orthopedics, but its application is often associated with an increased risk of microbial contamination of the implant surfaces that cause bone tissue impairment. This study aims to develop two silver-enriched platelet-rich plasma (PRP) multifunctional scaffolds active at the same time in preventing implant-associated infections and stimulating bone regeneration. Commercial silver lactate (L) and newly synthesized silver deoxycholate:β-Cyclodextrin (B), were studied in vitro. Initially, the antimicrobial activity of the two silver soluble forms and the PRP enriched with the two silver forms has been studied on microbial planktonic cells. At the same time, the biocompatibility of silver-enriched PRPs has been assessed by an MTT test on human primary osteoblasts (hOBs). Afterwards, an investigation was conducted to evaluate the activity of selected concentrations and forms of silver-enriched PRPs in inhibiting microbial biofilm formation and stimulating hOB differentiation. PRP-L (0.3 µg/mm2) and PRP-B (0.2 µg/mm2) counteract Staphylococcus aureus, Staphylococcus epidermidis and Candida albicans planktonic cell growth and biofilm formation, preserving hOB viability without interfering with their differentiation capability. Overall, the results obtained suggest that L- and B-enriched PRPs represent a promising preventive strategy against biofilm-related implant infections and demonstrate a new silver formulation that, together with increasing fibrin binding protecting silver in truncated cone-shaped cyclic oligosaccharides, achieved comparable inhibitory results on prokaryotic cells at a lower concentration.

Multifunctional platform for future applications in cell and tissue engineering based on silicate phosphate hydroxyapatite co-doped with Li+, Eu3+ and Gd3+ ions

Although hydroxyapatite has established itself as a promising biomaterial for the simultaneous diagnosis and treatment of bone defects, several physicochemical properties can be further refined to achieve a specialized theranostic platform for cell and tissue engineering. In this context, we synthesized silicate-substituted hydroxyapatites co-doped with Li+, Eu3+, and Gd3+ ions (abbr. as Si-HAp-LEG) using a microwave-assisted hydrothermal method. The aim was to create a combination of dopants to stimulate bone regeneration (Li+ ion) while enabling bioimaging (Eu3+ and Gd3+ ions). Structural and morphological assessments included, e.g., XRPD (X-ray Powder Diffraction), HR-TEM (High-resolution Transmission Electron Microscopy) imaging, and BET (Brauner-Emmet-Teller) analysis. Unit-cell parameters were estimated via Rietveld refinement. The luminescence properties (emission, excitation spectra, and emission kinetics) were recorded depending on the varying Li+-ion concentration. The cytocompatibility of biomaterials was tested using hBMSCs (multipotent human bone-marrow mesenchymal stromal cells). In vitro assays evaluated biomaterials’ effects on morphology, metabolic activity (Alamar blue assay), and transcriptomic activity (RT-qPCR). The results indicate that co-doping with Li+, Eu3+, and Gd3+ ions introduces distortions while preserving the crystal structure of hydroxyapatite. Additionally, the cells maintained proper morphology and ultrastructure, internalizing biomaterials without significant cytotoxicity. The biomaterials also triggered the expression of key transcriptional factors. Si-HAp-LEG biomaterials, particularly LEG-222 and LEG-221, exhibit desired physicochemical and biological features, rendering them highly bioactive and promising for cell and tissue engineering applications.

DIFFERENT APPROACHES IN BONE TISSUE ENGINEERING: ADVANTAGES AND DISADVANTAGES

Human bone tissue damage arises due to defects, injury, tumors, aging, and traffic accidents. It is one of the most challenging issues that need surgical development and advanced bone implants. Biocomposite-based bone has insufficient blood supply restricting the utilization for bone regeneration. It is often overcome by including scaffold having angiogenic factor delivery, in vitro and in vivo pre-vascularization. Bone and endothelial cell development and proliferation are stimulated by magnetic responsive scaffolds containing magnetic nanoparticles. Its porous structure allows cells to communicate and develop in all directions, which improves osteointegration. Scaffolds without seeded cells might have applications in bone tissue engineering (BTE) and it is mandatory to estimate in vitro and in vivo biocompatibility and degradation behavior. Three-dimensional (3D) printing opens the door to the creation of one-of-a-kind shapes and structures with specific properties. It helps to minimize the spread of germs during synthesis stage. The gamma rays minimize the infection communicated during transplantation but also damage the graft. When it comes to choosing biomaterials for cancellous and cortical bones, an artificial neural network has the highest recognition rate. This review paper explores the different potential approaches for bone grafting. Different techniques have been developed to create hydrogels with desirable properties for BTE, including non-toxicity, biocompatibility, controllability, and performance. A cell-free framework is used to stimulate bone regeneration, which helps in the bone the self-healing processes of bone fractures. The recent approach combines TE, material science, and genetic engineering for enhanced vascularization, restoring blood flow, and preventing cell death.

Bone morphogenetic protein-2 loaded triple helix recombinant collagen-based hydrogels for enhancing bone defect healing

The development of efficacious bone substitute biomaterials remains a major challenge for research and clinical surgical. Herein, we constructed triple helix recombinant collagen (THRC) -based hydrogels loading bone morphogenetic protein-2 (BMP-2) to stimulate bone regeneration in cranial defects. A series of in situ forming hydrogels, denoted as THRC-oxidized carboxymethylcellulose (OCMC)-N-succinyl-chitosan (NSC) hydrogels, was synthesized via a Schiff base reaction involving OCMC, THRC and NSC. The hydrogels underwent rapid formation under physiological pH and temperature conditions. The composite hydrogel exhibits a network structure characterized by uniform pores, the dimensions of which can be tuned by varying THRC concentrations. The THRC-OCMC-NSC and THRC-OCMC-NSC-BMP2 hydrogels display heightened mechanical strength, substantial biodegradability, and lower swelling properties. The THRC-OCMC-NSC hydrogels show exceptional biocompatibility and bioactivity, accelerating cell proliferation, adhesion, and differentiation. Magnetic resonance imaging, computed tomography and histological analysis of rat cranial defects models revealed that the THRC-OCMC-NSC-BMP2 hydrogels substantially promote new bone formation and expedite bone regeneration. The novel THRC-OCMC-NSC-BMP2 hydrogels emerge as promising candidates for bone substitutes, demonstrating substantial potential in bone repair and regeneration applications.

Favorable osteogenic activity of vericiguat doped in β-tricalcium phosphate: In vitro and in vivo studies.

Recently, more and more studies have shown that guanylate cyclase, an enzyme that synthesizes cyclic guanosine monophosphate (cGMP), plays an important role in bone metabolism. Vericiguat (VIT), a novel oral soluble guanylate cyclase stimulator, directly generates cyclic guanosine monophosphate and reduce the death incidence from cardio-vascular causes or hospitalization. Recent studies have shown beneficial effects of VIT in animal models of osteoporosis, but very little is currently known about the effects of VIT on bone defects in the osteoporotic states. Therefore, in this study, β-tricalcium phosphate (β-TCP) was used as a carrier to explore the effect of local VIT administration on the repair of femoral metaphyseal bone defects in ovariectomized (OVX) rats. When MC3T3-E1 was cultured in the presence of H2H2, VIT, similar to Melatonin (MT), therapy could increase the matrix mineralization and ALP, SOD2, SIRT1, and OPG expression, reduce ROS and Mito SOX production, RANKL expression, Promote the recovery of mitochondrial membrane potential. In the OVX rat model, VIT increases the osteogenic effect of β-TCP and better results were obtained at a dose of 5mg. Local use of VIT can inhibit increased OC, BMP2 and RUNX2 expressions in bone tissue, while decreased SOST and TRAP expressions by RT-PCR and immunohistochemistry. Thereby, VIT stimulates bone regeneration and is a promising candidate for promoting bone repair in osteoporosis.

Enhanced bone formation of rat mandibular bone defects with collagen membranes loaded on bone morphogenetic protein-9

Background/purposeBone morphogenetic protein-9 (BMP-9) has demonstrated multiple advantages in promoting osteogenesis. Our previous findings have indicated that the use of an absorbable collagen membrane (ACM) as a carrier for growth factors is effective in stimulating bone regeneration. The objective of this study was to assess the synergistic impact of BMP-9 incorporated into ACM (ACM/BMP-9) on bone formation within rat mandibular bone defects. Materials and methodsCircular bone defects of critical size were surgically induced on both sides of the rat mandibular bone, with subsequent random allocation into distinct groups: control, ACM alone, and ACM loaded with low (0.5 μg) or high (2.0 μg) concentrations of BMP-9. We conducted real-time in vivo micro-computerized tomography scans at the baseline and at 2, 4, and 6 weeks, and measured the volume of newly formed bone (NFB), bone mineral density (BMD) of NFB, and the closure percentage of the NFB area. Histological and histomorphometric analyses were performed at 6 weeks. ResultsReal-time assessment revealed notably higher levels of bone volume, BMD, and closure percentage in the NFB area for the groups treated with ACM/BMP-9 compared to the control and ACM groups. Within the high concentration of BMP-9 group, the volume and BMD of NFB exhibited a significant increase at 6 weeks compared to baseline. Histological examination confirmed the existence of osteoblasts, osteocytes, and blood vessels within the NFB. ConclusionConsidering the limitations of this research, the real-time evaluation finding indicates that ACM/BMP-9 effectively promotes bone formation in critical-size mandibular defects in rats.

Nanocomposite magnetic hydrogel with dual anisotropic properties induces osteogenesis through the NOTCH-dependent pathways

Physical factors in the cellular microenvironment have critical effects on stem cell differentiation. The utilization of physical factors to promote the osteogenic differentiation of stem cells has been established as a new strategy for developing bone tissue engineering scaffolds. In this context, scaffolds with multiscale anisotropy are considered to possess biomimetic properties, which are advantageous for their biological performance. In the present study, a novel magnetic anisotropic hydrogel (MAH) with magnetic and topographic anisotropy was designed by combining static magnetic field-induced magnetic nanomaterials and a hydrogel. In in vitro studies, the MAH exhibited excellent biocompatibility and osteogenic bioactivity. The alkaline phosphatase activity and the expression of osteogenic-related genes and proteins induced by the MAH were greater than those induced by the pure PEGDA–GelMA hydrogel (PGH) and the magnetic isotropic hydrogel (MIH). In addition, the present study revealed that the dual anisotropic properties of the MAH activated the NOTCH1/2 pathway by upregulating SNHG5 and downstream SIRT6, which modulates the level of NOTCH1/2 by antagonizing DNMT1 protein stability, ultimately inducing the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Furthermore, the MAH, MIH, and PGH were tested for in vivo bone regeneration in rabbits with femur defects, and the results demonstrated that the MAH effectively stimulated bone regeneration. Taken together, these findings suggest that this magnetically and topographically anisotropic biomimetic hydrogel might be a promising candidate for application in the field of bone tissue regeneration.

Three-Dimensional Printing Methods for Bioceramic-Based Scaffold Fabrication for Craniomaxillofacial Bone Tissue Engineering.

Three-dimensional printing (3DP) technology has revolutionized the field of the use of bioceramics for maxillofacial and periodontal applications, offering unprecedented control over the shape, size, and structure of bioceramic implants. In addition, bioceramics have become attractive materials for these applications due to their biocompatibility, biostability, and favorable mechanical properties. However, despite their advantages, bioceramic implants are still associated with inferior biological performance issues after implantation, such as slow osseointegration, inadequate tissue response, and an increased risk of implant failure. To address these challenges, researchers have been developing strategies to improve the biological performance of 3D-printed bioceramic implants. The purpose of this review is to provide an overview of 3DP techniques and strategies for bioceramic materials designed for bone regeneration. The review also addresses the use and incorporation of active biomolecules in 3D-printed bioceramic constructs to stimulate bone regeneration. By controlling the surface roughness and chemical composition of the implant, the construct can be tailored to promote osseointegration and reduce the risk of adverse tissue reactions. Additionally, growth factors, such as bone morphogenic proteins (rhBMP-2) and pharmacologic agent (dipyridamole), can be incorporated to promote the growth of new bone tissue. Incorporating porosity into bioceramic constructs can improve bone tissue formation and the overall biological response of the implant. As such, employing surface modification, combining with other materials, and incorporating the 3DP workflow can lead to better patient healing outcomes.