Search Results (123)

Bioactive agents can stimulate osteogenesis, angiogenesis, and cell proliferation; therefore, their application in bone regeneration offers significant therapeutic potential. The aim of this systematic review was to evaluate strategies for applying chitosan-based scaffolds with growth factors in bone regeneration. A structured literature search was conducted in July 2025 across the PubMed, Scopus, and Web of Science databases. Search terms included combinations of (chitosan scaffold) AND (growth factor OR BMP-2 OR VEGF OR FGF OR TGF-beta OR periostin OR PDGF OR IGF-1 OR EGF OR ANG-1 OR ANG-2 OR GDF-5 OR SDF-1 OR osteopontin). The study selection process followed PRISMA 2020 guidelines and the PICO framework. Out of 367 records, 226 were screened, and 17 studies met the eligibility criteria for qualitative analysis. BMP-2 was the most frequently investigated growth factor, studied in both in vitro and in vivo models, with rats and rabbits as the most common animal models. Scaffold compositions varied, incorporating hydroxyapatite, heparin, polyethylene glycol diacrylate, octacalcium phosphate-mineralized graphene, silk fibroin, and aloe vera. Growth factors were introduced using diverse methods, including microspheres, chemical grafting, covalent coupling, protein carriers, and nanohydroxyapatite mesopores. Most studies reported enhanced bone regeneration, although differences in models, scaffold composition, and delivery methods preclude definitive conclusions. The addition of growth factors generally improved osteoblast proliferation, angiogenesis, bone density, and expression of osteogenic markers (RunX2, COL1, OPN, OCN). Combining two bioactive agents further amplified osteoinduction and vascularization. Sustained-release systems, particularly those using heparin or hydroxyapatite, prolonged biological activity and improved regenerative outcomes. In conclusion, functionalization of chitosan-based scaffolds with growth factors shows promising potential for bone regeneration. Controlled-release systems and combinations of different bioactive molecules may offer synergistic effects on osteogenesis and angiogenesis. Further research should focus on optimizing scaffold compositions and delivery methods to tailor bioactive agent release for specific clinical applications. Full article

Heterotopic ossification (HO) is a disease characterized by ectopic bone formation, which can occur following severe traumatic brain injury (TBI). However, the underlying mechanisms remain poorly understood. In this study, we established a stem cell model using adipose-derived stem cells (ADSCs) and skeletal stem cells (SSCs) to examine osteogenic factors present in the sera of TBI patients. Incubation of ADSCs and SSCs with osteoinductive medium supplemented with TBI serum significantly enhanced osteogenic differentiation, particularly in male ADSCs and both female and male SSCs, with male SSCs exhibiting the highest osteogenic potential. Furthermore, we identified TGF-β1 as an important factor involved in these osteogenic processes. Elevated levels of TGF-β1 were detected in the serum of male TBI patients 14 days post-injury. Cellular assays revealed a sexual dimorphism in response to TGF-β1 neutralization: osteogenic differentiation in male SSCs was significantly reduced, while no effect was detectable in female SSCs. These findings, together with the rarity of HO in female patients, suggest that TGF-β1 plays a central role in the development of HO in males. Furthermore, this study highlights the importance of considering sex-specific mechanisms in traumatic HO for the development of sex-specific therapy options. Full article

Successful arthrodesis is a crucial factor in spinal fusion surgery, maximizing the likelihood of improved quality of life. The incorporation of metals into bone grafts has been demonstrated to enhance fusion rates through various osteoinductive and osteoconductive pathways. A systematic review was conducted to investigate the utility of metal composite bone grafts in promoting arthrodesis in spinal fusion preclinical studies. PubMed/MEDLINE was queried to identify studies investigating metal composite bone grafts in animal models of spinal fusion. Non-spinal fusion animal models were excluded. Risk of bias was assessed using the SYRCLE risk of bias tool. After screening a total of 1554 articles, 17 articles were included in our review. Metal composite bone grafts with bioactive agents had significantly greater fusion rates than metal composite only bone grafts (p < 0.001) and similar fusion rates compared to non-metal comparator bone grafts (p = 0.172). Bone grafts containing strontium and magnesium had the greatest fusion rates compared to other metals and had significantly greater fusion rates than those of silicon-containing bone grafts (p = 0.02 and p = 0.04, respectively). Bone quality and bone volume percentages of fusion masses formed by metal composite bone grafts were enhanced via the addition of bioactive agents such as stem cells, rhBMP-2, autograft, and poly (lactic-co-glycolic acid). The adverse event rate was 3.0% in all animal surgeries. Metal composite bone grafts show promise as osteoinductive agents to promote arthrodesis in spinal fusion, and their osteoinductive capability is enhanced with the synergistic addition of osteogenic factors such as stem cells and autograft. Full article

In regenerative medicine, orthobiologics, particularly platelet-rich plasma (PRP), are widely used due to their ability to enhance natural tissue repair mechanisms. PRP contains a concentrated pool of growth factors and cytokines that enhance regeneration while also acting as a biomimetic scaffold, thereby optimizing the microenvironment for tissue healing. In bone tissue engineering, PRP is commonly combined with synthetic or natural biomaterials, as its fibrin matrix alone lacks sufficient mechanical stability. However, even such composite systems frequently exhibit limited osteoinductive capacity, necessitating further supplementation with bioactive components. This review evaluates the regenerative potential of PRP in bone defect healing when combined with osteoinductive agents in preclinical in vivo models. We present compelling experimental evidence supporting the efficacy of this combined therapeutic approach. Full article

This review article provides a comprehensive evaluation of Infuse^® and InductOs^®, two ground-breaking recombinant human Bone Morphogenetic Protein-2 (rhBMP-2)-based bone graft products, focusing on their tissue-level regenerative responses, clinical applications, and associated costs. Preclinical and clinical studies demonstrate that rhBMP-2 induces strong osteoinductive activity, effectively promoting mesenchymal stem cell differentiation and vascularized bone remodeling. While generally well-tolerated, these osteoinductive effects are dose-dependent, and excessive dosing or off-label use may result in adverse outcomes, such as ectopic bone formation or soft tissue inflammation. Histological and imaging analyses in craniofacial, orthopedic, and spinal fusion models confirm significant bone regeneration, positioning rhBMP-2 as a viable alternative to autologous grafts. Notably, advances in delivery systems and scaffold design have enhanced the stability, bioavailability, and targeted release of rhBMP-2, leading to improved fusion rates and reduced healing times in selected patient populations. These innovations, alongside its proven regenerative efficacy, underscore its potential to expand treatment options in cases where autografts are limited or unsuitable. However, the high initial cost, primarily driven by rhBMP-2, remains a critical limitation. Although some studies suggest overall treatment costs might be comparable to autografts when factoring in reduced complications and operative time, autografts often remain more cost-effective. Infuse^® has not substantially reduced the cost of bone regeneration and presents additional safety concerns due to the rapid (burst) release of growth factors and limited mechanical scaffold support. Despite representing a significant advancement in synthetic bone grafting, further innovation is essential to overcome limitations related to cost, mechanical properties, and controlled growth factor delivery. Full article

Healing large bone defects remains challenging. Gelatin scaffolds are biocompatible and biodegradable, but lack osteoinductive activity. Plant-derived exosomes carry miRNAs, growth factors, and proteins that modulate osteogenesis, but free exosomes suffer from poor stability, limited targeting, and low bioavailability in vivo. We developed a 3D GelMA hydrogel loaded with Epimedium-derived exosomes (“GelMA@Exo”) to improve exosome retention, stability, and sustained release. Its effects on MC3T3-E1 preosteoblasts—including proliferation, osteogenic differentiation, migration, and senescence—were evaluated via in vitro assays. Angiogenic potential was assessed using HUVECs. Underlying mechanisms were examined at transcriptomic and protein levels to elucidate GelMA@Exo’s therapeutic osteogenesis actions. GelMA@Exo exhibited sustained exosome release, enhancing exosome retention and cellular uptake. In vitro, GelMA@Exo markedly boosted MC3T3-E1 proliferation, migration, and mineralized nodule formation, while reducing senescence markers and promoting angiogenesis in HUVECs. Mechanistically, GelMA@Exo upregulated key osteogenic markers (RUNX2, TGF-β1, Osterix, COL1A1, ALPL) and activated the PI3K/Akt pathway. Transcriptomic data confirmed global upregulation of osteogenesis-related genes and bone-regeneration pathways. This study presents a GelMA hydrogel functionalized with plant-derived exosomes, which synergistically provides osteoinductive stimuli and structural support. The GelMA@Exo platform offers a versatile strategy for localized delivery of natural bioactive molecules and a promising approach for bone tissue engineering. Our findings provide strong experimental evidence for the translational potential of plant-derived exosomes in regenerative medicine. Full article

Bone integrity is maintained through continuous remodeling, orchestrated by the coordinated actions of osteocytes, osteoblasts, and osteoclasts. Once considered passive bystanders, osteocytes are now recognized as central regulators of this process, mediating biochemical signaling and mechanotransduction. Malfunctioning osteocytes contribute to serious skeletal disorders such as osteoporosis. Mesenchymal stromal cells (MSCs), multipotent stem cells capable of differentiating into osteoblasts, have emerged as promising agents for bone regeneration, primarily through the paracrine effects of their secreted exosomes. MSC-derived exosomes are nanoscale vesicles enriched with proteins, lipids, and nucleic acids that promote intercellular communication, osteoblast proliferation and differentiation, and angiogenesis. Notably, they deliver osteoinductive microRNAs (miRNAs) that influence osteogenic markers and support bone tissue repair. In vivo investigations validate their capacity to enhance bone regeneration, increase bone volume, and improve biomechanical strength. Additionally, MSC-derived exosomes regulate the immune response, creating pro-osteogenic and pro-angiogenic factors, boosting their therapeutic efficacy. Due to their cell-free characteristics, MSC-derived exosomes offer benefits such as diminished immunogenicity and minimal risk of off-target effects. These properties position them as promising and innovative approaches for bone regeneration, integrating immunomodulatory effects with tissue-specific regenerative capabilities. Full article

Heterotopic ossification (HO) refers to the pathological formation of bone in soft tissues, typically following trauma, surgical procedures, or as a result of genetic disorders. Notably, injuries to the central nervous system significantly increase the risk of HO, a condition referred to as neurogenic HO (NHO). This review outlines the cellular and molecular mechanisms driving HO, focusing on the inflammatory response, progenitor cell reprogramming, and current treatment strategies. HO is primarily fuelled by a prolonged and dysregulated inflammatory response, characterized by sustained expression of osteoinductive cytokines secreted by M1 macrophages. These cytokines promote the aberrant differentiation of fibro-adipogenic progenitor cells (FAPs) into osteoblasts, leading to ectopic mineralization. Additional factors such as hypoxia, BMP signalling, and mechanotransduction pathways further contribute to extracellular matrix (ECM) remodelling and osteogenic reprogramming of FAPs. In the context of NHO, neuroendocrine mediators enhance ectopic bone formation by influencing both local inflammation and progenitor cell fate decisions. Current treatment options such as nonsteroidal anti-inflammatory drugs (NSAIDs), radiation therapy, and surgical excision offer limited efficacy and are associated with significant risks. Novel therapeutic strategies targeting inflammation, neuropeptide signalling, and calcium metabolism may offer more effective approaches to preventing or mitigating HO progression. Full article

Alveolar bone loss due to trauma, extraction, or periodontal disease often requires bone grafting prior to implant placement. Although human allograft bone is widely used as an alternative to autograft, it has limited osteoinductive potential and a prolonged healing time. Mesenchymal stem cell–conditioned media (MSC-CM), rich in paracrine factors, has emerged as a promising adjunct to enhance bone regeneration. This study evaluated the regenerative effect of MSC-CM combined with human allograft bone in a rabbit calvarial defect model. Bilateral 8 mm defects were created in eight rabbits. Each animal received a human allograft alone (HB group) on one side and an allograft mixed with MSC-CM (HB+GF group) on the other. Histological and histomorphometric analyses were performed at 2 and 8 weeks postoperatively. Both groups showed new bone formation, but the HB+GF group demonstrated significantly greater bone regeneration at both time points (p < 0.05). New bone extended into the defect center in the HB+GF group. Additionally, greater graft resorption and marrow formation were observed in this group at 8 weeks. These findings suggest that MSC-CM enhances the osteogenic performance of human allograft bone and may serve as a biologically active adjunct for bone regeneration. Full article

The reconstruction of a severely resorbed alveolar bone is a significant challenge in dental implantology and maxillofacial surgery. Traditional bone grafting materials, including autogenous, allogeneic, xenogeneic, and alloplastic materials, have limitations such as donor site morbidity, limited availability, and prolonged maturation periods. To address these challenges, recombinant human bone morphogenetic protein-2 (rhBMP-2) has emerged as a potent osteoinductive factor that facilitates bone regeneration without the need for additional donor site surgery. This study introduces a box technique which combines rhBMP-2 (CowellBMP^®, Cowellmedi, Busan, Republic of Korea) with a 3D-preformed titanium mesh (3D-PFTM), utilizing a mixture of allografts and xenografts for horizontal and vertical alveolar ridge augmentation. The technique leverages the structural stability provided by the OssBuilder^® (Osstem, Seoul, Republic of Korea), a preformed titanium mesh, that allows for simultaneous implant placement and vertical ridge augmentation. This technique not only reduces the treatment time compared to traditional methods but also minimizes post-operative discomfort by eliminating the need for autogenous bone harvesting. Clinical outcomes from this technique demonstrate successful bone regeneration within a shorter period than previously reported techniques, with excellent bone quality and implant stability being observed just four months after vertical augmentation. In conclusion, the so called BOXAM (BMP-2, Oss-builder, Xenograft, Allograft, Maintenance) technique presents a promising therapeutic strategy for alveolar bone reconstruction, particularly in cases of severe bone resorption. Further studies are needed to evaluate the long-term outcomes and potential limitations of this approach, especially in scenarios where the inferior alveolar nerve proximity poses challenges for fixture placement. Full article

The aim of this in vitro study is to investigate the adhesion, proliferation, and differentiation of human adipose-derived mesenchymal stem cells (hASC) on Trabecular Titanium scaffolds manufactured with different manufacturing processes (EBM and SLM). The in vitro adhesion and proliferation of hASC on titanium scaffolds with WST assays have been carried out. The comparison of the gene expression profiles of typical bone genes (Alp, Bglap, Col1a1, and Osx) through real-time PCR assays and the evaluation of extracellular matrix composition with immunofluorescence and SEM analysis have been performed. In addition, the possible osteoinductive properties of the two scaffolds have been investigated through real-time PCR and ALP assays. Data showed that Trabecular Titanium supports human adipose-derived mesenchymal stem cell colonization and induces differentiation in bone with the deposition of the abundant extracellular mineralized matrix regardless of the manufacturing process, proving that the micro- and macro-design features are the key factors responsible for the osteoinduction behavior. These features can only be achieved through tailored 3D printing process parameters. Full article

Every year, millions of people worldwide suffer from bone tissue damage caused by bone trauma and surgical operations, as well as diseases such as osteoporosis, osteoarthritis, osteomyelitis, and periodontitis. Bone defect repair is one of the major challenges in the field of regenerative medicine. Although bone grafts are the gold standard for treating bone defects, factors such as donor sources and immune responses limit their application. Functionalized nanomaterials have become an effective means of treating bone diseases due to their good biocompatibility and osteoinductivity, anti-inflammatory, and antibacterial properties. Metal–organic frameworks (MOFs) are porous coordination polymers composed of metal ions and organic ligands, featuring unique physical properties, including a high surface area–volume ratio and porosity. In regenerative medicine, MOFs function as the functions of drug carriers, metal ion donors, nanozymes, and photosensitizers. When combined with other functional materials, they regulate cellular reactive oxygen species, macrophage phenotypic transformation, bone resorption, osteogenesis, and mineralization, providing a new paradigm for bone tissue engineering. This study reviews the classification of functionalized MOF composites in biomedicine and the application of their synthesis techniques in bone diseases. The unique in vivo and in vitro applications of MOFs in bone diseases, including osteoarthritis, osteoporosis, bone tumors, osteomyelitis, and periodontitis, are explored. Their properties include excellent drug loading and sustained release abilities, high antibacterial activity, and bone induction abilities. This review enables readers to better understand the cutting-edge progress of MOFs in bone regeneration applications, which is crucial for the design of and functional research on MOF-related nanomaterials. Full article

Background and Objectives: Demineralized bone matrix (DBM) is a widely used bone graft substitute due to its osteoconductive and osteoinductive properties. However, its efficacy varies due to differences in donor, processing, and storage conditions. Synthetic alternatives, such as iFactor^®, combine non-organic bone mineral and a small peptide (P-15) to enhance the cellular attachment and osteogenesis. To compare the osteogenic potential and bone matrix maturity of iFactor^® and a commercial DBM scaffold through calcium nodule formation and Fourier transform infrared spectroscopy (FTIR) analysis. Materials and Methods: Human mesenchymal stem cells (hMSCs) were cultured and exposed to iFactor^® or DBM in paracrine culture conditions for 21 days. Calcium nodule formation was assessed using alizarin red staining and quantified spectrophotometrically. The FTIR analysis of hMSCs exposed to the scaffolds for three months evaluated the biomolecular composition and bone matrix maturity. Results: Calcium nodules formed in both groups but in smaller quantities than in the positive control (p < 0.05). The biomolecular components of the DBM were similar to healthy bone (p > 0.05) than those of the iFactor^® group (p < 0.005). A different rate of bone regeneration was observed through the formation of a greater number of calcium nodule aggregates identified in the extracellular matrix of mesenchymal stem cell cultures exposed to iFactor^® compared to those cultures enriched with DBM. Conclusions: Both experimental matrices demonstrated similar osteogenic potential at the 3-month follow-up. Although DBM has a closer biomolecular composition and carbonate substitution compared to healthy bone, iFactor^® showed faster matrix maturity expressed through the formation of a greater number of calcium nodule aggregates and higher hMSCs proliferation. Full article

A novel parameter optimization method for additively manufacturing nickel–titanium (NiTi) alloys using laser powder bed fusion (LBPF) was developed. Compared with the conventional NiTi alloy and the previously reported LPBF-NiTi alloy, the LBPF-NiTi alloy prepared with these parameters exhibits excellent tensile properties and an anisotropic microstructure. Since distinct regions of orthopedic implants have specific functional requirements, we investigated the anisotropy of this LPBF-NiTi in terms of its osteoinductive capacity to determine the appropriate building direction for prosthesis fabrication. The biosafety of the transverse (XY-NiTi) and longitudinal (XZ-NiTi) planes was assessed through cytotoxicity assays. Comparative analyses of the biological activities of these planes were conducted by evaluating the adherent cell counts, the adhesion morphology, and the expression of osteogenic-related genes and factors in adherent cells. Compared with XZ-NiTi, XY-NiTi exhibited superior cell adhesion properties. Additionally, the expression levels of osteogenic markers (RUNX2, ALP, OPG, and OCN) were significantly greater in bone marrow mesenchymal cells (BMMCs) adhered to XY-NiTi than in those adhered to XZ-NiTi. These results indicate a greater osteogenic potential in the XY-NiTi group. XY-NiTi was more advantageous as an implant–bone contact surface. Building implant products in the direction perpendicular to the load-bearing axis enhances biofixation; thus, this is the preferred orientation for manufacturing orthopedic implants. Full article

The purpose of this study was to evaluate in vitro whether the type of tooth preservation before treatment with the Tooth Transformer^® (TT) device affects the osteoinductive characteristics of the extracted tooth. Forty extracted teeth from healthy non-smoking patients were selected. All teeth were cleaned of caries, tartar, and filling material and then roughly sectioned and divided into four experimental groups according to storage type: room-temperature (RT) tooth samples, frozen tooth samples, RIPA tooth samples, and fresh tooth samples. Each sample was minced, demineralized, and disinfected using the TT device. The Enzyme-Linked ImmunoSorbent Assay (ELISA) test revealed the presence of bone morphogenetic protein-2 (BMP-2) and collagen type-I (COL-I) in all of the samples, demonstrating that the fresh teeth retained the most significant amount of osteoinductive protein. In contrast, the tooth samples stored at room temperature (RT) showed the most important loss of BMP-2 and COL-I. A Western Blot analysis demonstrated the presence of the Mineralization Protein LIM-1 (LMP-1) and Transforming Growth Factor-β (TGF-β) in all of the dental samples analyzed. The fresh and frozen dental samples showed significantly higher levels of LMP-1 than those in the other samples. In contrast, the levels of TGF-β were similar in all of the dental samples examined, regardless of the type of storage. These experimental results suggest that an extracted tooth should be treated with the TT device as soon as possible to maximize its osteoinductive potential in surgical bone preservation and regeneration procedures. Full article