Bone Regeneration In Defects Research Articles

Engineered Magneto-Piezoelectric Nanoparticles-Enhanced Scaffolds Disrupt Biofilms and Activate Oxidative Phosphorylation in Icam1+ Macrophages for Infectious Bone Defect Regeneration.

Infectious bone defects pose significant clinical challenges due to persistent infection and impaired bone healing. Icam1+ macrophages were identified as crucial and previously unrecognized regulators in the repair of bone defects, where impaired oxidative phosphorylation within this macrophage subset represents a significant barrier to effective bone regeneration. To address this challenge, dual-responsive iron-doped barium titanate (BFTO) nanoparticles were synthesized with magnetic and ultrasonic properties. These nanoparticles were further loaded with the anti-inflammatory agent curcumin and coated with engineered mesenchymal stem cell membranes (EMM) modified with γ3 peptide, creating BFTO-Cur@EMM nanoparticles specifically designed to target Icam1+ macrophages. These nanoparticles were shown to disrupt bacterial biofilms under alternating magnetic fields (AMF) and to activate oxidative phosphorylation and osteogenic immune responses in Icam1+ macrophages via low-intensity pulsed ultrasound (LIPUS). Transcriptomic sequencing and validation experiments demonstrated that this approach activates oxidative phosphorylation (OXPHOS) by stimulating the JAK2-STAT3 pathway and inhibiting the MAPK-JNK pathway, thereby promoting the polarization of Icam1+ macrophages toward a pro-reparative phenotype and enhancing the secretion of pro-angiogenic and osteogenic cytokines. These nanoparticles were subsequently integrated into quaternized chitosan (QCS) and tricalcium phosphate (TCP) to create a bioink for three-dimensional (3D) printing anti-infection QT/BFTO-Cur@EMM bone repair scaffolds. In vivo studies indicated that these scaffolds significantly improved the healing of infectious bone defects without causing thermal damage to surrounding tissues. This work highlights the potential of this material and the targeting of Icam1+ macrophages as an effective strategy for simultaneously controlling infection and promoting bone regeneration.

Boron-Doped Nano Hydroxyapatite Grafts for Bone Regeneration in Rat Mandibular Defects.

The aim of this study was to evaluate the potential effects of boron-doped nano hydroxyapatite grafts on craniofacial bone regeneration in critical bone defects in the mandibular corpus of rats, in terms of scintigraphic and histopathological aspects. Forty Wistar albino rats, with an average weight of 200-220g, aged 16-18weeks, and all male, were used in the study. The rats were randomly assigned to five groups, each containing 8 rats, as follows: group C1 (no procedure applied to the mandible), group C2 (surgical defect created in the mandible but no treatment applied), group nHA (nano hydroxyapatite applied to the surgical defect area), group nHA + B1 (nano hydroxyapatite + 1% boron applied to the surgical defect area), and group nHA + B2 (nano hydroxyapatite + 2% boron applied to the surgical defect area). A standard 4 × 4mm full-thickness transosseous bone defect was created in the mandibular corpus of all rats, except for those in group C1. The bone defect in the rats in group C2 was left to heal naturally. Nano hydroxyapatite (nHA), nano hydroxyapatite + 1% boron, and nano hydroxyapatite + 2% boron were applied to the surgical defect areas of the other three groups, respectively. Bone scintigraphy was performed on all rats on days 0 (following the surgical procedure) and 28 of the experimental period. At the end of the 28th day, the animals were sacrificed, and tissue samples were collected for histological examination. A standard grading system was used to evaluate fracture healing. When the groups were compared in terms of bone healing histopathological scores, a statistically significant difference was observed between group C1 and the other groups (p < 0.005). In the statistical evaluation made according to the histopathological mean scores, the least improvement was observed in group C2. No statistically significant difference was observed between group nHA and group nHA + B1 and group C2 and between group nHA and group nHA + B1 in terms of bone healing scores (p > 0.005). A statistically significant difference was found between group nHA + B2 and group C2 (p = 0.026). Although there was no statistically significant difference in histopathological scores, the mean score closest to group C1 was observed in group nHA + B2. A statistically significant difference was observed between the groups in the scintigraphic evaluation performed on the 28th day of the experimental procedure, and the difference was between group C1 and group nHA + B1 and between group nHA and group nHA + B1 (p = 0.004; p = 0.028, p < 0.005). In the comparison of the values obtained on days 0 and 28 within the group, a statistically significant change was observed in group nHA + B1 and group nHA + B2 (p < 0.005). When the results of the present study were evaluated, it was thought that the boron-doped nHA graft biomaterials may have positive effects on bone healing. Providing a different perspective for the development of an alternative new treatment modality that can be locally applied in the treatment of fractures a serious and common health problem can be interpreted as an important outcome of the present study. We believe that this study will serve as a preliminary study for more comprehensive future studies on this subject.

Self-Sustained H2O2 and O2 Generation by Calcium Carbonate/Zinc Peroxide Nanocomposite, Enhancing Osteosarcoma Cell Differentiation and Antibacterial Activity

Calcium carbonate nanoparticles (CaCO3 NPs) show promising osteogenic potential due to their ability to release calcium ions and modulate pH. However, their limited bioactivity, potential cytotoxicity, variable degradation rates, poor mechanical properties, and lack of inherent osteoinductivity present significant challenges. In this study, we hypothesized that decorating CaCO3 NPs with another active material, zinc peroxide (ZnO2), can address some of these challenges and enhance the effectiveness of CaCO3 NPs in the treatment of bone cancer and bone regeneration. For this purpose, CaCO3 NPs with the vaterite polymorph were synthesized and decorated with ZnO2 NPs. These nanostructures were thoroughly characterized and thin films with varying layers were fabricated. The CaCO3/ZnO2 films showed greater initial adhesion of osteosarcoma cells (Saos-2 cells) than the CaCO3 films. While CaCO3 NPs promoted cellular proliferation over time, the CaCO3/ZnO2 nanocomposites (NCs) reduced the proliferation of osteosarcoma cells and triggered apoptosis. Analyses of osteogenic markers, including alkaline phosphatase activity, mineralization, and the expression of Runx-2 and osteocalcin, strongly indicated that CaCO3/ZnO2 NCs possess even greater osteogenic potential than CaCO3 NPs alone. The dual effects of CaCO3/ZnO2 on osteosarcoma cells, promoting both osteogenesis and apoptosis, may be attributed to the self-production of H2O2 and O2, along with the controlled release of calcium and zinc ions. Given their osteogenic potential and significant antibacterial activity against Staphylococcus aureus and Escherichia coli, CaCO3/ZnO2 NCs are promising candidates for treating bone tumors and regeneration of bone defects.

Polyphenols and Functionalized Hydrogels for Osteoporotic Bone Regeneration.

Osteoporosis induces severe oxidative stress and disrupts bone metabolism, complicating the treatment of bone defects. Current therapies often have side effects and require lengthy bone regeneration periods. Hydrogels, known for their flexible mechanical properties and degradability, are promising carriers for drugs and bioactive factors in bone tissue engineering. However, they lack the ability to regulate the local pathological environment of osteoporosis and expedite bone repair. Polyphenols, with antioxidative, anti-inflammatory, and bone metabolism-regulating properties, have emerged as a solution. Combining hydrogels and polyphenols, polyphenol-based hydrogels can regulate local bone metabolism and oxidative stress while providing mechanical support and tissue adhesion, promoting osteoporotic bone regeneration. This review first provides a brief overview of the types of polyphenols and the mechanisms of polyphenols in facilitating adhesion, antioxidant, anti-inflammatory, and bone metabolism modulation in modulating the pathological environment of osteoporosis. Next, this review examines recent advances in hydrogels for the treatment of osteoporotic bone defects, including their use in angiogenesis, oxidative stress modulation, drug delivery, and stem cell therapy. Finally, it highlights the latest research on polyphenol hydrogels in osteoporotic bone defect regeneration. Overall, this review aims to facilitate the clinical application of polyphenol hydrogels for the treatment of osteoporotic bone defects.

Clinical Observations of the Effectiveness of the Masquelet Induced Membrane Technique in the Treatment of Critical Long-Bone Defects of the Lower and Upper Extremities

Background and Objectives: Successful treatment of severe trauma and fractures of the long bones with successful healing and bone union is still a significant challenge for surgeons. Unfortunately, up to 10% of long-bone fractures develop bone healing disorders. The aim of this study was to evaluate the results of treating bone defects with different etiologies in the upper and lower extremities using the induced membrane technique. Materials and Methods: We prospectively evaluated the radiological and clinical outcomes of 45 patients with severe bone defects treated with the induced membrane technique during the period from May 2021 to October 2023. The time to bone defect regeneration, size of the bone defect, and the cost of treatment were evaluated. Functional outcomes were assessed using the Disabilities of the Arm Shoulder and Hand (DASH) scale, SF-36, and the Lower Limb Functional Index (LLFI). Results: The mean follow-up time was 31 months (12–35). There were 20 patients with upper extremity bone defects and 25 with lower extremity bone defects. The mean defect length was 7.9 cm for the upper extremity (3.5–18) and 5.3 cm for the lower extremity (3–11). The mean times to achieve bone union and remodeling were 6.0 months (3–12) and 9 months (3–13) for the upper and lower limbs, respectively. Clinical evaluation at the end of treatment (achieving bone union) showed statistically significant improvements in the DASH, SF-36, and LLFI scales for pre- and postoperative outcomes. There was no statistical significance in the SF-36 clinical scale scores after surgical treatment compared to reconstructive treatment of upper and lower extremity bone defects. Results: The presented reconstructive approach to the treatment of bone defects and healing disorders and extensive analysis demonstrate the effectiveness of the induced membrane technique in a short follow-up period, with a relatively high level of patient comfort and good clinical results in the treatment of severe bone defects with particularly infectious etiologies.

Microenvironment-optimized gastrodin-functionalized scaffolds orchestrate asymmetric division of recruited stem cells in endogenous bone regeneration

The regeneration of osteoporotic bone defects remains challenging as the critical stem cell function is impaired by inflammatory microenvironment. Synthetic materials that intrinsically direct osteo-differentiation versus self-renewal of recruited stem cell represent a promising alternative strategy for endogenous bone formation. Therefore, a microenvironmentally optimized polyurethane (PU) /n-HA scaffold to enable sustained delivery of gastrodin is engineered to study its effect on the osteogenic fate of stem cells. It exhibited interconnected porous networks and an elevated sequential gastrodin release pattern to match immune-osteo cascade concurrent with progressive degradation of materials. In a critical-sized femur defect model of osteoporotic rat, 5% gastrodin-PU/n-HA potently promoted neo-bone regeneration by facilitating M2 macrophage polarization and CD146+ host stem cell recruitment to defective site. The implantation time-dependently increased the bone marrow mesenchymal stem cell (BMSC) population, and further culture of BMSCs showed a robust ability of proliferation, migration, and mitochondrial resurgence. Of note, some of cell pairs produced one stemness daughter cell while the other committed to osteogenic lineage in an asymmetric cell division (ACD) manner, and a much more compelling ACD response was triggered when 5% gastrodin-PU/n-HA implanted. Further investigation revealed that one-sided concentrated presentation of aPKC and β-catenin in dividing cells effectively induced asymmetric distribution, which polarized aPKC biased the response of the daughter cells to Wnt signal. The asymmetric cell division in skeletal stem cells (SSCs) was mechanically comparable to BMSCs and also governed by distinct aPKC and β-catenin biases. Concomitantly, delayed bone loss adjacent to the implant partly alleviated development of osteoporosis. In conclusion, our findings provide insight into the regulation of macrophage polarization combined with osteogenic commitment of recruited stem cells in an ACD manner, advancing scaffold design strategy for endogenous bone regeneration.Graphical abstract

Strontium-Substituted Nanohydroxyapatite Containing Biodegradable 3D Printed Composite Scaffolds for Bone Regeneration.

Treatment of large-size bone defects is difficult, and acquiring autografts may be challenging due to limited availability. A synthetic patient-specific bone substitute can be developed by using 3D printing technologies in such cases. In the present study, we have developed photocurable composite resins with poly(trimethylene carbonate) (PTMC) containing a high percentage of biodegradable bioactive strontium-substituted nanohydroxyapatite (SrHA, size 30-70 nm). These photocurable resins have then been employed to develop high-surface-area 3D-printed bone substitutes using the digital light processing (DLP) technique. To enhance the surface area of the 3D-printed substitute, cryogels alone and functionalized with bioactive components of bone morphogenetic protein (BMP) and zoledronic acid (ZA) were filled within the 3D-printed scaffold/substitute. The scaffolds were tested in vitro for biocompatibility and functionality in vivo in two therapeutically relevant rat models with large bone defects (4 mm). The porosities of 3D printed scaffolds were found to be 60.1 ± 0.9%, 72.9 ± 0.5%, and 74.3 ± 1.6% for PTMC, PTMC-HA, and PTMC-SrHA, respectively, which is in the range of cancellous bone (50-95%). The thermogravimetric analysis demonstrated the fabrication of 3D printed composites with HA and SrHA concentrations of 51.5 and 57.4 wt %, respectively, in the PTMC matrix. The tensile Young's modulus (E), compressive moduli, and wettability increased post incorporation of SrHA and HA in the PTMC matrix. In vitro and in vivo results revealed that SrHA integrated into the PTMC matrix exhibited good physicochemical and biological properties. Furthermore, the osteoactive molecule-functionalized 3D printed composite scaffolds were found to have an adequate osteoconductive and osteoinductive surface that has shown increased bone regeneration and defect repair in both tibial and cranial bone defects. Our findings thus support the use of PTMC-SrHA composites as next-generation patient-specific synthetic bioactive biodegradable bone substitutes.

Effect of nHA/CS/PLGA delivering adipose stem cell-derived exosomes and bone marrow stem cells on bone healing—in vitro and in vivo studies

Adipose stem cell-derived exosomes (ADSC-EXO) have been demonstrated to promote osteogenic differentiation of bone marrow stem cells (BMSCs) and facilitate bone regeneration. The present study aims to investigate the effect of ADSC-EXO-loaded nano-hydroxyapatite/chitosan/poly-lactide-co-glycolide (nHA/CS/PLGA) scaffolds on maxillofacial bone regeneration using tissue engineering. ADSC-EXO was isolated and co-cultured with BMSCs, and the osteogenic differentiation of BMSCs was assessed through the detection of mineralized nodule formation, alkaline phosphatase (ALP) activity, and mRNA expression of COL1A1 and runt-related transcription factor 2 (RUNX2). The nHA/CS/PLGA scaffolds were fabricated and loaded with ADSC-EXO and BMSCs, and these tissue engineering complexes were applied to the maxillofacial bone defect region of rabbits to elucidate their bone regeneration effect. The osteogenic differentiation of BMSCs was markedly enhanced when they were co-cultured with ADSC-EXO. This was evidenced by an increase in the formation of mineralized nodule formation, ALP activity, and mRNA expression of COL1A1 and runt-related transcription factor 2 (RUNX2). In vivo experiments demonstrated that the application of ADSC-EXO and BMSCs loaded nHA/CS/PLGA scaffolds effectively repaired maxillofacial bone defects in rabbits. ADSC-EXO has been demonstrated to promote the osteogenic differentiation of BMSCs. The ADSC-EXO and BMSCs loaded nHA/CS/PLGA scaffolds have been shown to facilitate the regeneration of maxillofacial bone defects. This may serve as a potential therapeutic strategy for large-scale bone defects.

3D-printed bioactive scaffolds: an emerging strategy for the regeneration of infectious bone defects

3D-printed bioactive scaffolds: an emerging strategy for the regeneration of infectious bone defects

GelMA-based moldable and rapid-curable osteogenic paste inspired by ceramic craft for alveolar bone defect regeneration

Alveolar bone defects pose a significant challenge in oral clinical treatments, impacting procedures such as dental implants, orthodontics, and oral restoration. Despite their frequent occurrence due to various causes, the effective restoration and reconstruction of alveolar bone defects remain a significant clinical challenge in dentistry. Existing treatments often rely on intrinsic blood coagulation to stabilize bone grafts, but they present limitations such as gradual clotting and reduced effectiveness in patients with coagulation dysfunction. Injectable gel holds promise as an alternative to coagulation-dependent bone graft matrices, but it also faces challenges, including low initial viscosity and dependence on the natural formation of the defect area during the curing process. Here, we present a ceramic-craft-inspired osteogenic (CIO) hydrogel, designed to achieve moldable and curable properties for bone defect regeneration. This injectable paste, composed of gelatin methacrylate (GelMA), nanoclay, and bone grafts, allows for local injection and manual shaping without the need for molds. The shaped hydrogel rapidly crosslinks within 15 s under UV irradiation, providing malleability, strength, and coagulation-independent bone graft stabilization. This approach offers a potential breakthrough in addressing the persistent clinical challenge of alveolar bone defect restoration.

Constructing bone organoids based on endochondral ossification model via endogenous enzyme-induced mineralization

Regenerative strategies based on the utilization of bone organoids have been effective. The mineralization of bone organoids, in particular, is a crucial step that not only validates their functionality but also their potential for clinical applications in bone regeneration and disease modeling. However, the mechanisms underlying mineralization in bone organoids is unclear. Here, we recapitulated the differentiation and mineralization processes of natural bone development, through the mineralization of cartilaginous pellets (CPs) by utilizing the concept of endogenous enzyme-induced mineralization. An endogenous enzyme-induced mineralization system based on the encapsulation of CPs, calcium glycerophosphate (CaGP), and 6,8-dimethyl-3-(4-phenyl-1H-imidazol-5-yl)-quinolin-2(1H)-one (DIPQUO) in a methacrylated gelatin (GelMA) hydrogel was reconstructed. DIPQUO significantly enhanced the expression of alkaline phosphatase (ALP) in CPs, hydrolyzed CaGP to provide calcium and phosphate ions, and synchronously accelerated the mineralization of CPs and the hydrogel. The mineralization of CPs exhibited a stage-specific gene expression pattern highly consistent with the process of endochondral ossification, which was mediated by the Wnt/β-catenin and MAPK/ERK signaling pathways confirmed by RNA sequencing. Electron microscopy-based ultrastructural analysis showed that the number of mitochondria, lysosomes, and vesicles increased markedly during mineralization. Furthermore, bone organoids constructed via endogenous enzyme-induced mineralization led to rapid bone healing within 4 weeks in a rat model with a distal femoral condyle defect. Our findings have important implications for elucidating the bone formation process and bone-defect regeneration.

Recent Advances in Biomaterial‐Based Scaffolds for Guided Bone Tissue Engineering: Challenges and Future Directions

ABSTRACTBone tissue engineering (BTE) has emerged as a promising approach for the regeneration and repair of bone defects caused by trauma, disease, or aging. This review provides an overview of recent advancements in BTE, with a focus on the development and application of biomaterial‐based scaffolds, including natural (e.g., collagen, chitosan), synthetic (e.g., polylactic acid [PLA], polycaprolactone [PCL]), and composite materials (e.g., hydroxyapatite‐based composites). It discusses their properties, benefits, and limitations. Additionally, this review examines innovative fabrication strategies such as 3D printing, electrospinning, and freeze‐drying, which enhance scaffold customization and performance. This review aims to provide insights into future directions of BTE research and its potential applications in regenerative medicine. Functionalization strategies, including surface modifications, coating, and the incorporation of growth factors and cells, are reviewed for their roles in improving scaffold bioactivity. In vivo and in vitro research have demonstrated the therapeutic promise of these scaffolds, while current clinical trials offer insights into their translational use. Challenges facing the translation of these technologies into clinical practice are also highlighted.

Harnessing hydrogen sulfide in injectable hydrogels that guide the immune response and osteoclastogenesis balance for osteoporosis treatment

Elevated levels of oxidative stress, inflammation, and a dysregulated osteoclastogenesis balance frequently characterize the microenvironment of osteoporosis, which impedes the processes of healing and repair. Existing treatment approaches are limited in scope and rely primarily on factors and drugs. An injectable hydrogel designed for the ROS-responsive release of H2S gas is presented in this study. The first network of the hydrogel comprises sodium alginate (SA-SATO) chelated with S-aroylthiooxime (SATO) and an H2S-generating group, while the second network is composed of photocrosslinkable PEGDA. Through the integration of Cys-releasing microspheres that are reactive with ROS, a composite hydrogel was developed that exhibited advantageous mechanical characteristics and biosafety. The composite hydrogel effectively promoted osteogenic differentiation of mesenchymal stem cells, modulated macrophage polarization, decreased inflammatory responses, and halted cell apoptosis, as evidenced by in vitro experiments. Additionally, it released H2S gas and mitigated excess ROS in cells. The efficacy of the composite hydrogel in promoting bone defect repair and regeneration in an osteoporotic model was further validated by in vivo findings. In summary, the composite hydrogel exhibits potential as a viable approach to address osteoporotic bone defects by harmonizing osteogenesis and osteoclast activity, modulating the microenvironment of bone injuries, and reducing inflammation. Consequently, it presents a viable strategy for the efficient repair of bone defects.

Structural and material double mechanical enhancement of HAp scaffolds promote bone defect regeneration

Critical bone defects caused by trauma, bone tumors, and infections are still challenges in clinical surgery. Digital light processing printing of hydroxyapatite (HAp) scaffolds can fabricate high-resolution personalized bone repair scaffolds. However, creating load-bearing bone regeneration HAp scaffolds with satisfactory mechanical property remain challenging. This study investigated the enhancement of the HAp scaffold mechanical properties from both structural and material perspectives. Structurally, the diamond structure model was optimized to Triply Periodic Minimal Surface structures, increasing the compressive strength of scaffolds from 2.2 to 7.2 MPa. Material-wise, ZnO was incorporated as second-phase particle, improved the compressive strength of HAp scaffolds from 7.2 to 13.7 MPa. Additionally, the incorporation of zinc ions enhanced the bioactivity of the HAp scaffolds. Animal mechanical testing revealed that the enhanced scaffolds effectively supported load-bearing. The HAp/ZnO-TPMS scaffolds exhibited excellent mechanical properties and promoted cellular osteogenic differentiation, showing potential for clinical development and application.

Three-Dimensional Scaffolds Designed and Printed Using CAD/CAM Technology: A Systematic Review

The objective of this work is to review the literature on the use of three-dimensional scaffolds obtained by printing for the regeneration of bone defects in the maxillofacial area. The research question asked was: what clinical experiences exist on the use of bone biomaterials manufactured by CAD/CAM in the maxillofacial area? Prospective and retrospective studies and randomized clinical trials in humans with reconstruction area in the maxillofacial and intraoral area were included. The articles had to obtain scaffolds for bone reconstruction that were designed by computer processing and printed in different materials. Clinical cases, case series, in vitro studies and those that were not performed in humans were excluded. Six clinical studies were selected that met the established inclusion criteria. The selected studies showed heterogeneity in their objectives, materials used and types of regenerated bone defects. A high survival rate was found for dental implants placed on 3D-printed scaffolds, with rates ranging from 94.3% to 98%. The materials used included polycaprolactone, coral-derived hydroxyapatite, biphasic calcium phosphate (BCP) and bioceramics. The use of CAD/CAM technology is seen as key for satisfying variations in the shapes and requirements of different fabrics and size variations between different individuals. Furthermore, the possibility of using the patient’s own stem cells could revolutionize the way bone defects are currently treated in oral surgery. The results indicate a high survival rate of dental implants placed on 3D-printed scaffolds, suggesting the potential of this technology for bone regeneration in the maxillofacial mass.

Collagen-Platelet-Rich Plasma Mixed Hydrogels as a pBMP2 Delivery System for Bone Defect Regeneration.

Background/Objectives: The replenishment of bone deficiency remains a challenging task in clinical practice. The use of gene-activated matrices (GAMs) impregnated with genetic constructs may be an innovative approach to solving this problem. The aim of this work is to develop collagen-based matrices with the addition of platelet-rich plasma, carrying polyplexes with the BMP2 gene, to study their biocompatibility and osteogenic potential in vitro and in vivo. Methods: The cytocompatibility of the materials during incubation with adipose-derived stem cells (ADSCs) was studied using the MTT test and fluorescent microscopy. Biocompatibility was assessed during intramuscular implantation, followed by histological analysis. Osteogenic differentiation was determined by the expressions of Alpl and Bglap using real-time PCR and extracellular matrix (ECM) mineralization by alizarin red staining. The efficiency of bone regeneration was studied using micro-CT and analysis of histological sections stained according to Masson. Results: After the incubation of ADSCs with GAS, significant increases in the expressions of the Alpl and Bglap genes by 3 ± 0.1 and 9.9 ± 0.6 times, relative to the control, as well as mineralization of the ECM, were observed. The volume of newly formed bone was 37.2 ± 6.2% after implantation of GAS, 20.9 ± 1.2%-non-activated Col/PRP, and 2.6 ± 1.5% in an empty defect. Conclusions: The use of Col/PRP-based matrices is an effective method for delivering of the osteoinductor gene to the site of bone tissue damage. The highest degree of healing was observed after the implantation of Col/PRP-TF/pBMP2 into the critical size defect compared to the other groups.

Concrete-Inspired Bionic Bone Glue Repairs Osteoporotic Bone Defects by Gluing and Remodeling Aging Macrophages.

Osteoporotic fractures are characterized by abnormal inflammation, deterioration of the bone microenvironment, weakened mechanical properties, and difficulties in osteogenic differentiation. The chronic inflammatory state characterized by aging macrophages leads to delayed or non-healing of the fracture or even the formation of bone defects. The current bottleneck in clinical treatment is to achieve strong fixation of the comminuted bone fragments and effective regulation of the complex microenvironment of aging macrophages. Inspired by cement and gravel in concrete infrastructure, a biomimetic bone glue with poly(lactic-co-glycolic acid) microspheres is developed and levodopa/oxidized chitosan hydrogel stabilized on an organic-inorganic framework of nanohydroxyapatite, named DOPM. DOPM is characterized via morphological and mechanical characterization techniques, in vitro experiments with bone marrow mesenchymal stromal cells, and in vivo experiments with an aged SD rat model exhibiting osteoporotic bone defects. DOPM exhibited excellent adhesion properties, good biocompatibility, and significant osteogenic differentiation. Transcriptomic analysis revealed that DOPM improved the inflammatory microenvironment by inhibiting the NF-κB signaling pathway and promoting aging macrophage polarization toward M2 macrophages, thus significantly accelerating bone defect repair and regeneration. This biomimetic bone glue, which enhances osteointegration and reestablishes the homeostasis of aging macrophages, has potential applications in the treatment of osteoporotic bone defects.

Natural loofah sponge inspired 3D printed bionic scaffolds promote personalized bone defect regeneration

Critical-sized bone defects pose serious health concerns for patients. Clinically, the use of functionalized bone implants has emerged as an effective solution. However, the rapid advancement in drug and biomaterials has led to an increasing design cost, triggering discussions in the field about how to efficiently create customized functional bone implants. Inspired by the unique structure of natural loofah sponges that effectively deliver nutrients to seeds, we designed a functionalized bone implant emulating this structure. Drug-release gradients were achieved through the application of different concentrations of hydrogels within the composite scaffold. This approach allowed active substances to be released outwardly during the early stage of bone repair, sustaining a local drug micro-environment within the implant scaffold that promotes angiogenesis and osteogenic differentiation in damaged areas. In vivo experiments showed that our loofah sponge bionic scaffold outperformed traditional hydroxyapatite scaffolds by promoting both bone and vascular regeneration. We expect the design of loofah sponge bionic scaffold could potentially deliver an effective strategy in the development of functionalized bone implants.

Periosteum-bone inspired hierarchical scaffold with endogenous piezoelectricity for neuro-vascularized bone regeneration

The development of scaffolds for repairing critical-sized bone defects heavily relies on establishing a neuro-vascularized network for proper penetration of nerves and blood vessels. Despite significant advancements in using artificial bone-like scaffolds infused with various agents, challenges remain. Natural bone tissue consists of a porous bone matrix surrounded by a neuro-vascularized periosteum, with unique piezoelectric properties essential for bone growth. Drawing inspiration from this assembly, we developed a periosteum-bone-mimicking bilayer scaffold with piezoelectric properties for regeneration of critical-sized bone defects. The periosteum-like layer of this scaffold features a double network hydrogel composed of chelated alginate, gelatin methacrylate, and sintered whitlockite nanoparticles, emulating the viscoelastic and piezoelectric properties of the natural periosteum. The bone-like layer is composed of a porous structure of chitosan and bioactive hydroxyapatite created through a biomineralization process. Unlike conventional bone-like scaffolds, this bioinspired bilayer scaffold significantly enhances osteogenesis, angiogenesis, and neurogenesis combined with low-intensity pulsed ultrasound-assisted piezoelectric stimulation. Such a scheme enhances neuro-vascularized bone regeneration in vivo. The results suggest that the bilayer scaffold could serve as an effective self-powered electrical stimulator to expedite bone regeneration under dynamic physical stimulation.

Biomimetic non-collagenous proteins-calcium phosphate complex with superior osteogenesis via regulating macrophage IL-27 secretion

Traumatic defects or non-union fractures presents a substantial challenge in the fields of tissue engineering and regenerative medicine. Although synthetic calcium phosphate-based biomaterials (CaPs) such as dibasic calcium phosphate anhydrate (DCPA) are commonly employed for bone repair, their inadequate cellular immune responses significantly impede sustained degradation and optimal osteogenesis. In this study, drawing inspiration from the key structure of an acidic non-collagenous protein-CaP complex (ANCPs-CaP) essential for natural bone formation, we prepared biomimetic mineralized dibasic calcium phosphate (MDCPA). This preparation utilized plant-derived non-collagenous protein Zein as the organic template and acidic artificial saliva as the mineralization medium. Physicochemical property analysis revealed that MDCPA is a complex of Zein and DCPA, which mimics the composite of the natural ANCP-CaP. Moreover, MDCPA exhibited enhanced biodegradability and osteogenic potential. Mechanistic insight revealed that MDCPA can be phagocytized and degraded by macrophages via the FCγRIII receptor, leading to the release of interleukin 27 (IL-27), which promotes osteogenic differentiation by osteoimmunomodulation. The critical role of IL-27 in osteogenesis is further confirmed using IL-27 gene knockout mice. Additionally, MDCPA demonstrates effective healing of critical-sized defects in rat cranial bones within only 4 w, providing a promising basis and valuable insights for critical-sized bone defects regeneration.