Rat Cranial Defect Model Research Articles

Seamlessly Adhesive Bionic Periosteum Patches Via Filling Microcracks for Defective Bone Healing.

Current artificial designs of the periosteum focus on osteogenic or angiogenic properties, while ignoring the filling and integration with bone microcracks, which trigger a prolonged excessive inflammatory reaction and lead to failure of bone regeneration. In this study, seamless adhesive biomimetic periosteum patches (HABP/Sr-PLA) were prepared to fill microcracks in defective bone via interfacial self-assembly induced by Sr ions mediated metal-ligand interactions among pamidronate disodium-modified hyaluronic acid (HAPD), black phosphorus (BP), and hydrophilic polylactic acid (PLA). In vitro, HABP/Sr-PLA exhibited excellent self-healing properties, seamlessly filled bone microcracks, and significantly enhanced osteogenesis and angiogenesis. Furthermore, in a rat cranial defect model, HABP/Sr-PLA was demonstrated to significantly promote the formation of blood vessels and new bone under mild 808 nm photothermal stimulation (42.8 °C), and the highest protein expression of CD31 and OPN was five times higher than that of the control group and other groups. Therefore, the proposed seamless microcrack-filled bionic periosteum patch is a promising clinical strategy for promoting bone repair.

Bio-inspired Glycosylated Nano-hydroxyapatites Enhance Endogenous Bone Regeneration by Modulating Macrophage M2 Polarization.

A macrophage-associated immune response is vital in bone regeneration. Mannose receptor (MR), a macrophage pattern-recognition receptor, is crucial for the maintenance of immune homeostasis. Here, we designed MR-targeted glycosylated nano-hydroxyapatites (GHANPs) to reprogram macrophages into polarized M2s, promoting bone regeneration by improving the osteoimmune microenvironment. The prepared GHANPs induced macrophage M2 polarization, which then promoted osteoblastic differentiation of stem cells. Further, the mechanistic study showed that GHANPs might influence macrophage polarization by modulating cell metabolism, including enhancing mitochondrial oxidative phosphorylation and activating autophagy. Finally, a rat cranial defect model was used to verify the effect of GHANPs on endogenous bone regeneration in vivo, revealing that GHANPs promoted bone regeneration within the defect and increased the ratio of M2/M1 macrophages in early bone repair. Our results indicate that the MR-targeted macrophage M2 polarization strategy is promising in endogenous bone regeneration. STATEMENT OF SIGNIFICANCE: Macrophage is a pivotal immunity component for bone regeneration. A switch to M2 macrophage has been considered to contribute to osteogenesis. For inducing macrophage M2 polarization, an effective strategy to overcome off-target effects and insufficient specificity is a critical challenge. The mannose receptor on the surface of macrophages has been involved in regulating macrophage directional polarization. The glucomannan presented on the nano-hydroxyapatite rods acts as ligands targeting macrophage mannose receptors to promote their M2 polarization, improving the immunomicroenvironment and achieving bone regeneration. This approach has the advantage of easy preparation, specific regulation, and safety.

3D-Printed Bioactive Scaffold Loaded with GW9508 Promotes Critical-Size Bone Defect Repair by Regulating Intracellular Metabolism.

The process of bone regeneration is complicated, and it is still a major clinical challenge to regenerate critical-size bone defects caused by severe trauma, infection, and tumor resection. Intracellular metabolism has been found to play an important role in the cell fate decision of skeletal progenitor cells. GW9508, a potent agonist of the free fatty acid receptors GPR40 and GPR120, appears to have a dual effect of inhibiting osteoclastogenesis and promoting osteogenesis by regulating intracellular metabolism. Hence, in this study, GW9508 was loaded on a scaffold based on biomimetic construction principles to facilitate the bone regeneration process. Through 3D printing and ion crosslinking, hybrid inorganic-organic implantation scaffolds were obtained after integrating 3D-printed β-TCP/CaSiO3 scaffolds with a Col/Alg/HA hydrogel. The 3D-printed β-TCP/CaSiO3 scaffolds had an interconnected porous structure that simulated the porous structure and mineral microenvironment of bone, and the hydrogel network shared similar physicochemical properties with the extracellular matrix. The final osteogenic complex was obtained after GW9508 was loaded into the hybrid inorganic-organic scaffold. To investigate the biological effects of the obtained osteogenic complex, in vitro studies and a rat cranial critical-size bone defect model were utilized. Metabolomics analysis was conducted to explore the preliminary mechanism. The results showed that 50 μM GW9508 facilitated osteogenic differentiation by upregulating osteogenic genes, including Alp, Runx2, Osterix, and Spp1 in vitro. The GW9508-loaded osteogenic complex enhanced osteogenic protein secretion and facilitated new bone formation in vivo. Finally, the results from metabolomics analysis suggested that GW9508 promoted stem cell differentiation and bone formation through multiple intracellular metabolism pathways, including purine and pyrimidine metabolism, amino acid metabolism, glutathione metabolism, and taurine and hypotaurine metabolism. This study provides a new approach to address the challenge of critical-size bone defects.

In vitro/ in vivo evaluation of double crosslinked bone glue with different degrees

ABSTRACT Successful bone fragment fixation is a crucial factor in bone fracture healing, the fixation of crushed bone fragments could hinder bone fracture healing. Thus, ideal bone glues to effectively adhere and splice comminuted bone fragments are needed in clinical. Herein, an osteoinductive and biodegradable double cross-linked bone glue (GelMA-oDex-AMBGN) was constructed through Schiff’s base reaction between commercial GelMA (with different substitution degrees of amino groups) and Odex mixed with amine-modified mesoporous bioactive glass nanoparticles (AMBGN), followed by crosslink with blue light irradiation. The GelMA-oDex-AMBGN bone glue successfully adhered and spliced the comminuted bone fragments of isolated rat skulls. GelMA-oDex-AMBGN promoted the proliferation of 3T3 cells and enhanced the expression of osteogenic proteins Runx2 and OCN in vitro. In rat cranial critical-sized defect models, GelMA-oDex-AMBGNs with different substitution degrees significantly increased the new bone contents at the fracture defect sites and promoted bone tissue regeneration in vivo. In conclusion, the double cross-linked bone glue (GelMA-oDex-AMBGN) was successfully constructed and can induce bone regeneration. Additionally, there was no significant difference in osteogenic activity among GelMA-oDex-AMBGNs with different substitution degrees and the equal content of AMBGN.

Sericin/Nano-Hydroxyapatite Hydrogels Based on Graphene Oxide for Effective Bone Regeneration via Immunomodulation and Osteoinduction.

Immune responses and osteogenesis differentiation induced by implants are crucial for bone tissue regeneration. Consideration of only one of those properties is not sufficient. To investigate the synergistic actions, we designed alginate/graphene oxide/sericin/nanohydroxyapatite (Alg/GO/Ser/nHAP) nanocomposite hydrogels with both osteoimmunomodulatory and osteoinductive activities. This study aimed to explore the effect of hydrogel with osteoimmunomodulatory properties on promoting osteogenesis of bone marrow stem cells (BMSCs). Alg/GO/Ser/nHAP nanocomposite hydrogel was fabricated and was characterized by SEM, FTIR, XRD, stress-strain, rheology, swelling and degradation. After the impact of sericin on M2 macrophage polarization was identified, the BMSCs viability and adhesion were evaluated by CCK8 assay, live/dead staining, cytoskeleton staining. The cell osteogenic differentiation was observed by ALP/ARS staining, immunofluorescence staining, RT-PCR, and Western blotting, respectively. Rat cranial defect model was used to assess osteoimmunomodulatory effects of scaffolds in vivo by micro‑computed tomographic, histological, and immunohistochemical analyses after 8 weeks of healing. In vitro experiments revealed that the hydrogel presented desirable mechanical strength, stability, porosity, and biocompatibility. Significantly, sericin and nHAP appeared to exert synergistic effects on bone regeneration. Sericin was observed to inhibit the immune response by inducing macrophage M2-type polarization to create a positive osteoimmune microenvironment, contributing to improving osseointegration at the bone-implant interface to promote osteogenesis. However, the osteogenic differentiation in rat BMSCs was further enhanced by combining nHAP and sericin in the nanocomposite hydrogel. Eventually, the hydrogel was implanted into the rat cranial defect model, assisting in the reduction of local inflammation and efficient bone regeneration. The nanocomposite hydrogel stimulated bone formation by the synergistic effects of immunomodulation of macrophage polarization by sericin and direct osteogenic induction by nHAP, demonstrating that such a scaffold that modulates the osteoimmune microenvironment to promote osteogenesis is a promising approach for the development of bone tissue engineering implants in the future.

Bioorthogonal "Click Chemistry" Bone Cement with Bioinspired Natural Mimicking Microstructures for Bone Repair.

Current bone cement systems often demand free radical or metal-related initiators and/or catalysts for the crosslinking process, which may cause serious toxicity to the human body. In addition, the resultant dense scaffolds may have a prolonged degradation time and are difficult for cells to infiltrate and form new tissue. In this study, we developed a porous "click" organic-inorganic nanohybrid (PO-click-ON) cement that crosslinks via metal-free biorthogonal click chemistry and forms porous structures mimicking the native bone tissue via particulate leaching. Strain-promoted click reaction enables fast and efficient crosslinking of polymer chains with the exclusion of any toxic initiator or catalyst. The resulting PO-click-ON implants supported exceptional in vitro stem cell adhesion and osteogenic differentiation with a large portion of stem cells infiltrated deep into the scaffolds. In vivo study using a rat cranial defect model demonstrated that the PO-click-ON system achieved outstanding cell adsorption, neovascularization, and bone formation. The porous click cement developed in this study serves as a promising platform with multifunctionality for bone and other tissue engineering applications.

Copper-deposited diatom-biosilica enhanced osteogenic potential in periodontalligamentstemcellsand rat cranium.

This study aimed to establish that copper-deposited Diatom-biosilica have the potential and possibility for clinical applications in repairing bone defects in a state of inflammation, such as periodontitis. Treatment of alveolar bone defects caused by periodontitis is a major challenge for clinicians. To achieve better repair results, the material should not only be bone conductive but also have the ability to stimulate osteogenesis and angiogenesis at the lesion site. Copper (II) and silicon (IV) ions could react to form basic copper silicate, which promoted both osteogenesis and angiogenesis. The mineralized diatom (Cu-DBs) loaded with copper (II) ions were synthesized by processing diatom shells using a hydrothermal method. Periodontal ligament stem cells (PDLSCs) are used to detect the osteogenic properties of Cu-DBs at the gene and protein levels. Using a rat cranial defect model and a full-thickness skin incision model to test the osteogenic properties of Cu-DBs in vivo. Compared with untreated diatoms (DBs), Cu-DBs extractsignificantly promoted the expression of osteogenesis-related factors like ALP, RUNX2, BSP, OCN, and OPN in PDLSCs. In vivo experiments further confirmed that Cu-DBs could effectively stimulate the osteogenesis of a rat skull defect and promote angiogenesis, significantly inhibit the inflammatory responses to bone damages, and reduce the infiltration of inflammatory immune cells to the lesion site. Due to the unique chemical characteristics of Si4+ and Cu2+ ions, the Cu-DBs composite biomaterial could enhance the osteogenic differentiation of PDLSCS in vitro, as well as stimulate the osteogenesis of the rat in vivo.

Thermodynamic 2D Silicene for Sequential and Multistage Bone Regeneration.

Bone healing is a multistage process involving the recruitment of cells, revascularization, and osteogenic differentiation, all of which are modulated in the temporal sequence to maximize cascade bone regeneration. However, insufficient osteoblast cells, poor blood supply, and limited bone induction at the site of critical-sized bone defect broadly impede bone repair. 2D SiO2 -silicene@2,2'-,azobis(2-[2-imidazolin-2-yl] propane) (SNSs@AIPH) with inherent thermodynamic property and osteoinductive activity is therefore designed and engineered for sequentially efficient bone repair. By means of controllable NIR-II irradiation, the integrated SNSs@AIPH stimulates the generation of appropriate intracellular reactive oxygen species, which accelerates early bone marrow mesenchymal stem cells (BMSCs) proliferation and angiogenesis remarkably. Importantly, as silicon-based 2D nanoparticles, the engineered SNSs@AIPH with high biocompatibility features distinct bioactivity to significantly promote BMSCs osteogenesis differentiation by activating TGFβ and BMP pathways. In a rat cranial defect model, SNSs@AIPH-NIR-II leads to a comparable increase of BMSCs proliferation and local vascularization at an early stage, followed by significant osteogenic differentiation, synergically resulting in a highly effective bone repair. Collectively, the fascinating characteristics and exceptional bone repair efficiency of NIR-II-mediated SNSs@AIPH allow it to be a promising bionic-oriented strategy for bone regeneration, broadening a new perspective in the application of cell-instructive biomaterials in bone tissue engineering.

Compromised osteogenic effect of exosomes internalized by senescent bone marrow stem cells via endocytoses involving clathrin, macropinocytosis and caveolae.

Stem cell senescence leads to progressive functional declines and disrupts the physiological homeostasis of bone environment. Stem cell-derived exosomes are emerging as promising therapeutical approaches to treat diverse aging-related osseous diseases. Herein, a previously reported osteoinductive exosome (OI-exo) was applied as a therapeutic agent for bone repair in aging individuals and its internalization mechanisms in senescent bone marrow stem cells (BMSCs) were explored. The results demonstrated that OI-exos derived from young BMSCs could partially rescue the proliferation, osteogenic differentiation and alleviate aging phenotypes in vitro. OI-exo-delivered hierarchical mesoporous bioactive glass (MBG) scaffold effectively promote in vivo bone formation in aging rat cranial defect model. However, the osteogenic effects of OI-exo both in vitro and in vivo were compromised in senescent individuals and for aging BMSCs compared to younger ones. This study revealed that non-senescent BMSCs internalized exosomes exclusively via clathrin-mediated endocytosis, while senescent BMSCs additionally evoked macropinocytosis and caveolae-mediated endocytosis to mediate the internalization of exosomes. The alteration of endocytic manner of senescent BMSCs and the involvement of macropinocytosis might be responsible for the compromised effects of therapeutical exosomes. The phenomena discovered in this study could also be extended to other scenarios where drugs or treatments exerted compromised effects in aging individuals. The influence of endocytic manner, avoidance of macropinocytosis-related negative effects should be taken into considerations in future therapeutic design for aging populations.

Functionalized Collagen/Elastin-like Polypeptide Hydrogels for Craniofacial Bone Regeneration.

Critical-sized cranial bone defects fail to re-ossify and require the surgical intervention of cranioplasty. To achieve superior bone healing in such cases, a hydrogel consisting of an interpenetrating network of collagen and elastin-like polypeptide to encapsulate bone morphogenetic protein-2 (BMP-2), doxycycline, and 45S5 Bioglass is developed. This hydrogel has an appropriate elastic modulus of 39 ± 2.2kPa to allow proper handling during implantation. The hydrogel promotes human adipose-derived stem attachment, proliferation, and differentiation toward the osteogenic lineage, including the deposition of hydroxyapatite particles embedded within a collagenous fibrillar structure after 21 days of in vitro culture. After eight weeks of implantation of the acellular hydrogel in a critical-sized rat cranial defect model, only a small quantity of various pro-inflammatory (< 20 pgmg-1 ) and anti-inflammatory (< 10 pgmg-1 ) factors in the adjacent cranial tissue is noticed, indicating the overall biocompatibility of the hydrogel. Scanning electron microscopy evidenced the presence of new fibrous extracellular matrix and mineral aggregates at the defect site, with calcium/phosphorus ratio of 0.5 and 2.0 by eight and twelve weeks, respectively. Microcomputed tomography (Micro-CT) and histological analyses showed formation of mature mineralized tissue that bridged with the surrounding bone. Taken together, the acellular composite hydrogel shows great promise for superior bone healing after cranioplasty.

Ultrafine-grained Nb-Cu immiscible alloy implants for hard tissue repair: Fabrication, characterization, and in vitro and in vivo evaluation

The biocompatible metallic implants with strong osteointegration often lack the ability of anti-infection. The biocompatible niobium (Nb) containing the antibacterial copper (Cu), the obtained Nb-Cu alloy, could be a potential candidate to solve this issue. To test this hypothesis, ultrafine-grained Nb-Cu immiscible alloys were fabricated via mechanical alloying and spark plasma sintering. The aim of this study was to investigate the microstructure, mechanical properties, magnetic susceptibility, corrosion behavior, ion release, and the bactericidal activity, biocompatibility and osteogenic potential of the Nb-Cu alloys in vitro and their osteogenesis and osteointegration ability in vivo with a comparison with pure Nb. The rat cranial defect model and the bone screws insertion in rabbit femoral bone were used to evaluate the osteogenesis and osteointegration ability, respectively. The results showed that after the addition of 3 wt.% of Cu, the compressive strength was significantly improved from 1.57 GPa to 2.21 GPa and the magnetic susceptibility slightly decreased. The Nb-3 wt.% Cu (Nb-3Cu) alloy exhibited higher corrosion resistance than pure Nb in Hank's solution and strong bactericidal activity against both E. coli and S. aureus. In vitro, the Nb-3Cu alloy showed comparable biocompatibility with pure Nb. The addition of 3 wt.% Cu also significantly enhanced the expression of osteogenesis-related genes (RUNX2, ALP, COLA1 and OCN) of pre-osteoblasts. In vivo, the Nb-3Cu alloy promoted bone regeneration at the defect sites and showed enhanced osteointegration after 12 weeks of implantation. Such a good combination of high mechanical strength and corrosion resistance, strong antibacterial activity and improved osteogenesis and osseointegration ability enables the present Nb-3Cu alloy a promising candidate for heavy load-bearing hard tissue repair.

Spatiotemporal Regulation of the Bone Immune Microenvironment via Dam-Like Biphasic Bionic Periosteum for Bone Regeneration.

The bone immune microenvironment (BIM) regulates bone regeneration and affects the prognosis of fractures. However, there is currently no effective strategy that can precisely modulate macrophage polarization to improve BIM for bone regeneration. Herein, a hybridized biphasic bionic periosteum, inspired by the BIM and functional structure of the natural periosteum, is presented. The gel phase is composed of genipin-crosslinked carboxymethyl chitosan and collagen self-assembled hybrid hydrogels, which act as the "dam" to intercept IL-4 released during the initial burst from the bionic periosteum fiber phase, thus maintaining the moderate inflammatory response of M1 macrophages for mesenchymal stem cell recruitment and vascular sprouting at the acute fracture. With the degradation of the gel phase, released IL-4 cooperates with collagen to promote the polarization towards M2 macrophages, which reconfigure the local microenvironment by secreting PDGF-BB and BMP-2 to improve vascular maturation and osteogenesis twofold. In rat cranial defect models, the controlled regulation of the BIM is validated with the temporal transition of the inflammatory/anti-inflammatory process to achieve faster and better bone defect repair. This strategy provides a drug delivery system that constructs a coordinated BIM, so as to break through the predicament of the contradiction between immune response and bone tissue regeneration.

α-Hemihydrate calcium sulfate/n-hydroxyapatite combined with metformin promotes osteogenesis in vitro and in vivo.

This study aimed to examine the effects of loading different concentrations of metformin onto an α-hemihydrate calcium sulfate/nano-hydroxyapatite (α-CSH/nHA) composite. The material characteristics, biocompatibility, and bone formation were compared as functions of the metformin concentration. X-ray diffraction results indicated that the metformin loading had little influence on the phase composition of the composite. The hemolytic potential of the composite was found to be low, and a CCK-8 assay revealed only weak cytotoxicity. However, the metformin-loaded composite was found to enhance the osteogenic ability of MC3T3-E1 cells, as revealed by alkaline phosphate and alizarin red staining, real-time PCR, and western blotting, and the optimal amount was 500 µM. RNA sequencing results also showed that the composite material increased the expression of osteogenic-related genes. Cranial bone lacks muscle tissue, and the low blood supply leads to poor bone regeneration. As most mammalian cranial and maxillofacial bones are membranous and of similar embryonic origin, the rat cranial defect model has become an ideal animal model for in vivo experiments in bone tissue engineering. Thus, we introduced a rat cranial defect with a diameter of 5 mm as an experimental defect model. Micro-computed tomography, hematoxylin and eosin staining, Masson staining, and immunohistochemical staining were used to determine the effectiveness of the composite as a scaffold in a rat skull defect model. The composite material loaded with 500 µM of metformin had the strongest osteoinduction ability under these conditions. These results are promising for the development of new methods for repairing craniofacial bone defects.

Black phosphorus nanosheets-enabled DNA hydrogel integrating 3D-printed scaffold for promoting vascularized bone regeneration.

The classical 3D-printed scaffolds have attracted enormous interests in bone regeneration due to the customized structural and mechanical adaptability to bone defects. However, the pristine scaffolds still suffer from the absence of dynamic and bioactive microenvironment that is analogous to natural extracellular matrix (ECM) to regulate cell behaviour and promote tissue regeneration. To address this challenge, we develop a black phosphorus nanosheets-enabled dynamic DNA hydrogel to integrate with 3D-printed scaffold to build a bioactive gel-scaffold construct to achieve enhanced angiogenesis and bone regeneration. The black phosphorus nanosheets reinforce the mechanical strength of dynamic self-healable hydrogel and endow the gel-scaffold construct with preserved protein binding to achieve sustainable delivery of growth factor. We further explore the effects of this activated construct on both human umbilical vein endothelial cells (HUVECs) and mesenchymal stem cells (MSCs) as well as in a critical-sized rat cranial defect model. The results confirm that the gel-scaffold construct is able to promote the growth of mature blood vessels as well as induce osteogenesis to promote new bone formation, indicating that the strategy of nano-enabled dynamic hydrogel integrated with 3D-printed scaffold holds great promise for bone tissue engineering.

Tissue engineered bone via templated hBMSCs mineralization and its application for bone repairing.

To develop bone implants, a novel tissue-engineered bone was constructed via templated human bone mesenchymal stem cells (hBMSCs) mineralization. Firstly, an osteoid-like template (Os-template) with aligned collagen fibers was prepared and followed by seeding hBMSCs to mimic the process of bone formation. After being cultured over weeks, the cells produced collagen fibers in an orderly aligned osteomorphic fashion. Further, a novel tissue-engineered bone with mineralized collagen fiber (mOs-ECM) was subsequently achieved after cell mineralization, showing a high degree of osteomimicry in terms of both composition and structure. When applied to the rat cranial bone defect model, the mOs-ECM significantly promoted the new bone formation and fused with the host bone. The study indicated that microscopic cell mineralization could be guided by artificially designed templates and successfully fabricated a macroscopic implant with a pronounced effect on bone repairing.

Vascular Endothelial Growth Factor Mimetic Peptide and Parathyroid Hormone (1-34) Delivered via a Blue-Light-Curable Hydrogel Synergistically Accelerate Bone Regeneration.

Safe and effective biomaterials are in urgent clinical need for tissue regeneration and bone repair. While numerous advances have been made on hydrogels promoting osteogenesis in bone formation, co-stimulation of the angiogenic pathways in this process remains to be exploited. Here, we have developed a gelatin-based blue-light-curable hydrogel system, functionalized with an angiogenic vascular endothelial growth factor (VEGF) mimetic peptide, KLTWQELYQLKYKGI (KLT), and an osteoanabolic peptide, parathyroid hormone (PTH) 1-34. We have discovered that the covalent modification of gelatin scaffold with peptides can modulate the physical properties and biological activities of the produced hydrogels. Furthermore, we have demonstrated that those two peptides orchestrate synergistically and promote bone regeneration in a rat cranial bone defect model with remarkable efficacy. This dual-peptide-functionalized hydrogel system may serve as a promising lead to functional biomaterials in bone repair and tissue engineering.

Effects of pre-osteogenic differentiation on the bone regeneration potentiality of marrow mesenchymal stem cells/poly(ethylene glycol)-diacrylate hydrogel using a rat cranial defect model

Transplanting cell/hydrogel constructs into a bone defect site is an effective strategy to repair the damaged tissues. However, before transplantation, there are various methods to culture cell/hydrogel constructs. Especially, the preferred pre-osteogenic differentiation period to achieve satisfied bone regeneration should be determined. To this end, Bone marrow mesenchymal stem cells (BMSCs) were firstly photo-encapsulated into poly(ethylene glycol)-diacrylate (PEGDA) hydrogel. Then the constructs were implanted in rat calvarial defects after being osteogenically induced for 0, 7, 14, and 21days. In vitro experiments demonstrated that the proliferation of BMSCs in the hydrogels deceased significantly from 0day to 7days. The activity and the gene expression of alkaline phosphatase, besides the gene expression of bone morphogenetic protein-2 peaked at day 14, whereas the gene expression of osteocalcin and the formation of calcium nodules increased with the prolongation of differentiation time. In vivo results showed that limited areas of newly formed bone were found in the day0 and day21 groups. In the day7 group, obvious new bone with bone marrow space was found, while the day14 group nearly achieved complete bone healing. Our data suggested that the period of in vitro pre-osteogenic differentiation played a crucial role for the osteogenesis of BMSCs/PEGDA hydrogels. Furthermore, we found that a pre-differentiation for 14days is preferable for bone regeneration in the rat cranial defects.

A Novel Calcium Phosphate-Based Nanocomposite for Augmentation of Cortical Bone Trajectory Screw Fixation.

PurposeTo evaluate the effect of cement augmentation of cortical bone trajectory (CBT) screws using a novel calcium phosphate–based nanocomposite (CPN).Material and MethodsCBT screws were placed into cadaveric lumbar vertebrae. Depending on the material used for augmentation, they were divided into the following three groups: CPN, polymethylmethacrylate (PMMA), and control. Radiological imaging was used to evaluate the cement dispersion. Biomechanical tests were conducted to measure the stability of CBT screws. A rat cranial defect model was used to evaluate biodegradation and osseointegration of the CPN.ResultsAfter cement augmentation, the CPN tended to disperse into the distal part of the screws, whereas PMMA remained limited to the proximal part of the screws (P < 0.05). As for cement morphology, the CPN tended to form a concentrated mass, whereas PMMA arranged itself as a scattered cement cloud, but the difference was not significant (P > 0.05). The axial pullout test showed that the average maximal pullout force (Fmax) of CPN-augmented CBT screws was similar to that of the PMMA group (CPN, 1639.56 ± 358.21 N vs PMMA, 1778.45 ± 399.83 N; P = 0.745) and was significantly greater than that of the control group (1019.01 ± 371.98 N; P < 0.05). The average torque value in the CPN group was higher than that in the control group (CPN, 1.51 ± 0.78 N∙m vs control, 0.97 ± 0.58 N∙m) and lower than that in the PMMA group (1.93 ± 0.81 N∙m), but there were no statistically significant differences (P > 0.05). The CPN could be biodegraded and gradually replaced by newly formed bone tissue after 12 weeks in a rat cranial defect model.ConclusionThe biocompatible CPN could be a valuable augmentation material to enhance CBT screw stability.

Seamless route of self-assembly and 3D printing to fabricate hierarchical mesoporous bioactive glass scaffold for customized bone regeneration with enhanced efficacy

Mesoporous bioactive glass (MBG) was one of the most promising bone regenerative materials for its well-acknowledged bioactivity, biodegradability, and osteoinductivity, as well as its potential for drug delivery. However, it remained a challenge to fabricate MBG scaffold with precisely controllable macro-structure and robust mechanical strength meanwhile to maintain uncompromised composition and mesoporosity. Herein, a fabricating route incorporating self-assembly and 3D printing (SAP) via acryloylating F127 (mesoporous template) was proposed and successfully realized directly printing MBG sol into hierarchical macro-/mesoporous SAP-MBG scaffold with compact and integral structure. Compared to traditional polyurethane (PU) templated MBG scaffold, SAP-MBG scaffold exhibited significantly enhanced mechanical strength meanwhile maintained non-composite component and mesoporous structure. SAP-MBG presented improved macropore interconnectivity and faster calcium dissolution, resulting in superior cellular penetration, in vitro osteogenic performances and in vivo bone regenerative efficacy in a critical-size rat cranial defect model. The SAP fabricating route represented an available approach to overcome the drawbacks of conventional manufacturing methods and realized individualized manufacturing of MBG scaffold. The synthetic design of this study might be extended to the fabricating process improvement of other mesoporous inorganic materials and shed light on future clinical translation of MBG scaffold in bone regeneration.

Preparation of photothermal-sensitive PDGF@ZIF-8-PDA@COL/PLGA-TCP composite scaffolds for bone defect repair

The repair of bone defects has long been a challenging and significant health question. Here, collagen hydrogel incorporating platelet-derived growth factor (PDGF)-loaded photopolymerizable ZIF-8-PDA nanoparticles (PDGF@ZIF-8-PDA@COL hydrogel) was prepared and perfused into 3D printed poly (lactide-co-glycolide)-tricalcium phosphate (PLGA-TCP) scaffolds. The resulting PDGF@ZIF-8-PDA@COL/PLGA-TCP composite scaffolds were applied as a bone substitute for cranial bone defect repair. The photopolymerizable ZIF-8-PDA nanoparticles had a mean size of 226.2 ± 5.3 nm with photothermal conversion capacity. PDGF@ZIF-8-PDA@COL/PLGA-TCP composite scaffolds showed a slower release of PDGF compared to PDGF release from collagen hydrogels. The composite scaffolds exhibited excellent antibacterial properties and good in vitro osteoconductive capacity. The osteoconductive activities of PDGF@ZIF-8-PDA@COL/PLGA-TCP composite scaffolds were also investigated in a rat cranial bone defect model in vivo by micro-CT imaging, hematoxylin and eosin staining, Masson’s trichrome staining, and immunohistochemical staining of osteogenesis-related markers. The PDGF@ZIF-8-PDA@COL/PLGA-TCP composite scaffolds accelerated cranial bone formation and gradually degraded over time. All these results provided strong evidence that PDGF@ZIF-8-PDA@COL/PLGA-TCP composite scaffolds might be a promising system for bone defect repair.