Three-Dimensional Printed BGS Treat a Large Bone Defect in a Rabbit Model.

This study aimed to evaluate if the 3D printed bioactive glass porous scaffolds (BGS) can improve the reconstruction of the large bone defect. A rabbit model of large bone defects was established by making a 1.0 or 1.5 cm segmental defect in the middle of the femur bone. Then a 1.0 or 1.5 cm BGS was implanted into the bone defect. X-ray imaging showed that in both 1.0 and 1.5 cm groups, the newly formed bone tissue could be observed at 4 weeks after implantation, but a strengthened ossification trend could be observed at different time points. In the 1.0 cm group, a larger number of newly formed bone tissues were observed at 4 weeks, and in the 1.5 group, more newly formed bone tissues were found at 8 weeks. Nevertheless, ossified tissue generation on the BGS mainly completed at 12 weeks after implantation in both groups. The H&E staining revealed that the 3D BGS was easily degraded to form osteoid-like material in vivo, where the neo-ossification gradually occurred from the edge to the center. Immunohistochemical analysis showed that in the 1.0 group, protein expressions of three osteogenesis-related genes- BMP, collagen I and RUNX-2-all peaked at 8 weeks, and then gradually decreased at 12 and 18 weeks. In the 1.5 group, BMP and collagen I peaked at 18 weeks.

Sr-Incorporated Bioactive Glass Remodels the Immunological Microenvironment by Enhancing the Mitochondrial Function of Macrophage via the PI3K/AKT/mTOR Signaling Pathway.

The repair of critical-sized bone defects continues to pose a challenge in clinics. Strontium (Sr), recognized for its function in bone metabolism regulation, has shown potential in bone repair. However, the underlying mechanism through which Sr2+ guided favorable osteogenesis by modulating macrophages remains unclear, limiting their application in the design of bone biomaterials. Herein, Sr-incorporated bioactive glass (SrBG) was synthesized for further investigation. The release of Sr ions enhanced the immunomodulatory properties and osteogenic potential by modulating the polarization of macrophages toward the M2 phenotype. In vivo, a 3D-printed SrBG scaffold was fabricated and showed consistently improved bone regeneration by creating a prohealing immunological microenvironment. RNA sequencing was performed to explore the underlying mechanisms. It was found that Sr ions might enhance the mitochondrial function of macrophage by activating PI3K/AKT/mTOR signaling, thereby favoring osteogenesis. Our findings demonstrate the relationship between the immunomodulatory role of Sr ions and the mitochondrial function of macrophages. By focusing on the mitochondrial function of macrophages, Sr2+-mediated immunomodulation sheds light on the future design of biomaterials for tissue regenerative engineering.

Biomimetic Hydrogels as the Inductive Endochondral Ossification Template for Promoting Bone Regeneration.

Repairing critical size bone defects (CSBD) is a major clinical challenge and requires effective intervention by biomaterial scaffolds. Inspired by the fact that the cartilaginous template-based endochondral ossification (ECO) process is crucial to bone healing and development, developing biomimetic biomaterials to promote ECO is recognized as a promising approach for repairing CSBD. With the unique highly hydrated 3D polymeric network, hydrogels can be designed to closely emulate the physiochemical properties of cartilage matrix to facilitate ECO. In this review, the various preparation methods of hydrogels possessing the specific physiochemical properties required for promoting ECO are introduced. The materiobiological impacts of the physicochemical properties of hydrogels, such as mechanical properties, topographical structures and chemical compositions on ECO, and the associated molecular mechanisms related to the BMP, Wnt, TGF-ß, HIF-1α, FGF, and RhoA signaling pathways are further summarized. This review provides a detailed coverage on the materiobiological insights required for the design and preparation of hydrogel-based biomaterials to facilitate bone regeneration.

A bioactive glass functional hydrogel enhances bone augmentation via synergistic angiogenesis, self-swelling and osteogenesis.

Bone augmentation materials usually cannot provide enough new bone for dental implants due to the material degradation and mucosal pressure. The use of hydrogels with self-swelling properties may provide a higher bone augmentation, although swelling is generally considered to be a disadvantage in tissue engineering. Herein, a double-crosslinked gelatin-hyaluronic acid hydrogels (GH) with self-swelling properties were utilized. Meanwhile, niobium doped bioactive glasses (NbBG) was dispersed in the hydrogel network to prepare the GH-NbBG hydrogel. The composite hydrogel exhibited excellent biocompatibility and the addition of NbBG significantly improved the mechanical properties of the hydrogel. In vivo results found that GH-NbBG synergistically promoted angiogenesis and increased bone augmentation by self-swelling at the early stage of implantation. In addition, at the late stage after implantation, GH-NbBG significantly promoted new bone formation by activating RUNX2/Bglap signaling pathway. Therefore, this study reverses the self-swelling disadvantage of hydrogels into advantage and provides novel ideas for the application of hydrogels in bone augmentation.

PBAT/PLA humic acid biodegradable film applied on solar greenhouse tomato plants increased lycopene and decreased total acid contents.

This work aims to resolve residual film pollution in farmlands and improve tomato quality. The mechanical properties and degradation of PBAT/PLA lignin (MZS) and PBAT/PLA humic acid (FZS) composite biodegradable film were analyzed, and its effect on soil temperature and humidity, soil microorganisms, soil physical and chemical properties, tomato yield, and quality was studied. Polyethylene film (PE) was used as a control. The results demonstrate a higher degradation degree of FZS film than of MZS film. The degradation degree of FZS and MZS films reached level 2 and level 1, respectively, after 131 days of film covering. The weight loss rate of FZS and MZS films reached 52.74 % and 57.82 %, respectively, when buried for 160 days. Compared to the coverings of PE and MZS films, FZS film could significantly increase the soil's electric conductivity and organic matter content (p < 0.05). The relative abundance of soil fungi Chaetomium also increased. The yield, soluble solids, vitamin C (Vc), soluble sugar, and lycopene of tomato plants covered with FZS film significantly increased by 6.74 %, 8.75 %, 15.41 %, 8.30 %, and 27.27 % compared to plants covered with PE film, and the total acid and hardness significantly decreased by 24.95 % and 8.46 %, respectively (p < 0.05). Using 10 µm PBAT/PLA humic acid biodegradable film for tomato cultivation in autumn and winter increased the lycopene and decreased the total acid content by changing the soil's physical and chemical characteristics and increasing the content of Chaetomium soil.

Graphene-Based Material-Mediated Immunomodulation in Tissue Engineering and Regeneration: Mechanism and Significance.

Tissue engineering and regenerative medicine hold promise for improving or even restoring the function of damaged organs. Graphene-based materials (GBMs) have become a key player in biomaterials applied to tissue engineering and regenerative medicine. A series of cellular and molecular events, which affect the outcome of tissue regeneration, occur after GBMs are implanted into the body. The immunomodulatory function of GBMs is considered to be a key factor influencing tissue regeneration. This review introduces the applications of GBMs in bone, neural, skin, and cardiovascular tissue engineering, emphasizing that the immunomodulatory functions of GBMs significantly improve tissue regeneration. This review focuses on summarizing and discussing the mechanisms by which GBMs mediate the sequential regulation of the innate immune cell inflammatory response. During the process of tissue healing, multiple immune responses, such as the inflammatory response, foreign body reaction, tissue fibrosis, and biodegradation of GBMs, are interrelated and influential. We discuss the regulation of these immune responses by GBMs, as well as the immune cells and related immunomodulatory mechanisms involved. Finally, we summarize the limitations in the immunomodulatory strategies of GBMs and ideas for optimizing GBM applications in tissue engineering. This review demonstrates the significance and related mechanism of the immunomodulatory function of GBM application in tissue engineering; more importantly, it contributes insights into the design of GBMs to enhance wound healing and tissue regeneration in tissue engineering.

Easily attainable and low immunogenic stem cells from exfoliated deciduous teeth enhanced the in vivo bone regeneration ability of gelatin/bioactive glass microsphere composite scaffolds.

Repair of critical-size bone defects remains a considerable challenge in the clinic. The most critical cause for incomplete healing is that osteoprogenitors cannot migrate to the central portion of the defects. Herein, stem cells from exfoliated deciduous teeth (SHED) with the properties of easy attainability and low immunogenicity were loaded into gelatin/bioactive glass (GEL/BGM) scaffolds to construct GEL/BGM + SHED engineering scaffolds. An in vitro study showed that BGM could augment the osteogenic differentiation of SHED by activating the AMPK signaling cascade, as confirmed by the elevated expression of osteogenic-related genes, and enhanced ALP activity and mineralization formation in SHED. After implantation in the critical bone defect model, GEL/BGM + SHED scaffolds exhibited low immunogenicity and significantly enhanced new bone formation in the center of the defect. These results indicated that GEL/BGM + SHED scaffolds present a new promising strategy for critical-size bone healing.

Self-Adhesive Hydrogel Biomimetic Periosteum to Promote Critical-Size Bone Defect Repair via Synergistic Osteogenesis and Angiogenesis.

The periosteum plays an important role in the regeneration of critical-size bone defects, with functions of recruiting multiple cells, accelerating vascular network reconstruction, and guiding bone tissue regeneration. However, these functions cannot be easily implemented by simply simulating the periosteum via a material structure design or by loading exogenous cytokines. Herein, inspired by the periosteal function, we propose a biomimetic periosteum preparation strategy to enhance natural polymer hydrogel membranes using inorganic bioactive materials. The biomimetic periosteum having bone tissue self-adhesive functions and resembling an extracellular matrix was prepared using dopamine-modified gelatin and oxidized hyaluronan (GA/HA), and micro/nanobioactive glass (MNBG) was further incorporated into the hydrogel to fabricate an organic/inorganic co-crosslinked hydrogel membrane (GA/HA-BG). The addition of MNBG enhanced the stability of the natural polymer hydrogel membrane, resulting in a sustained degradation time, biomineralization, and long-term release of ions. The Ca2+ and SiO44- ions released by bioactive glass were shown to recruit cells and promote the differentiation of bone marrow stromal cells into osteoblasts, initiating multicentric osteogenic behavior. Additionally, the bioactive ions were able to continuously stimulate the endogenous expression of vascular endothelial growth factor from human umbilical vein endothelial cells through the PI3K/Akt/HIF-1α pathway, which accelerated vascularization of the defect area and synergistically promoted the repair of bone defects. This organic-inorganic biomimetic periosteum has been proved to be effective and versatile in critical-size bone defect repair and is expected to provide a promising strategy for solving clinical issues.

Design and evaluation of a novel sub-scaffold dental implant system based on the osteoinduction of micro-nano bioactive glass.

Alveolar ridge atrophy brings great challenges for endosteal implantation due to the lack of adequate vertical bone mass to hold the implants. To overcome this limitation, we developed a novel dental implant design: sub-scaffold dental implant system (SDIS), which is composed of a metal implant and a micro-nano bioactive glass scaffold. This implant system can be directly implanted under mucous membranes without adding any biomolecules or destroying the alveolar ridge. To evaluate the performance of the novel implant system in vivo, SDISs were implanted into the sub-epicranial aponeurosis space of Sprague-Dawley rats. After 6 weeks, the SDIS and surrounding tissues were collected and analysed by micro-CT, scanning electron microscopy and histology. Our results showed that SDISs implanted into the sub-epicranial aponeurosis had integrated with the skull without any mobility and could stably support a denture. Moreover, this design achieved alveolar ridge augmentation, as active osteogenesis could be observed outside the cortical bone. Considering that the microenvironment of the sub-epicranial aponeurosis space is similar to that of the alveolar ridge, SDISs have great potential for clinical applications in the treatment of atrophic alveolar ridges. The study was approved by the Animal Care Committee of Guangdong Pharmaceutical University (approval No. 2017370).

3D-printed photoluminescent bioactive scaffolds with biomimetic elastomeric surface for enhanced bone tissue engineering.

Three dimensional (3D) printed porous bioactive glass nanoparticles scaffolds (BGNS) exhibit excellent bone integration and bone regeneration capacities, but the early rapid ion release, brittle mechanical properties and lack of functions limit their application. In this work, photoluminescent biomimetic elastomeric BGNS were fabricated by directly assembling poly(citrate-siloxane) (PCS) on the surface of BGNS (BGNS@PCS). The morphologies, mechanical behavior, photoluminescent ability, ions release, biomineralization activity, biocompatibility and osteogenic properties of BGNS@PCS were evaluated in detail. The results indicated that BGNS@PCS presented superior elasticity and outstanding compressive strength compared with BGNS. The controlled release of the Si and Ca ions in BGNS@PCS was achieved and enhanced biomineralization ability was also observed. In addition, the modified scaffolds have the photoluminescent ability which has the potential application for bioimaging. BGNS@PCS could significantly promote cells attachment, proliferation and enhance osteogenic differentiation of mouse bone marrow stromal cells (BMSCs). Therefore, the BGNS@PCS with the multifunctional properties including elastomeric surface, enhanced photoluminescent, controlled ions release and biomineralization, reinforced osteogenic activity, would be a promising candidate for bone tissue regeneration. This study probably provides a novel strategy to design biomimetic elastomeric bioceramic scaffolds for hard tissue regeneration.

Sequentially-crosslinked biomimetic bioactive glass/gelatin methacryloyl composites hydrogels for bone regeneration.

In recent years, gelatin-based composites hydrogels have been intensively investigated because of their inherent bioactivity, biocompatibility and biodegradability. Herein, we fabricated photocrosslinkable biomimetic composites hydrogels from bioactive glass (BG) and gelatin methacryloyl (GelMA) by a sequential physical and chemical crosslinking (gelation + UV) approach. The results showed that the compressive modulus of composites hydrogels increased significantly through the sequential crosslinking approach. The addition of BG resulted in a significant increase in physiological stability and apatite-forming ability. In vitro data indicated that BG/GelMA composites hydrogels promoted cell attachment, proliferation and differentiation. Overall, the BG/GelMA composites hydrogels combined the advantages of good biocompatibility and bioactivity, and had potential applications in bone regeneration.

Synergistic effect of strontium and silicon in strontium-substituted sub-micron bioactive glass for enhanced osteogenesis.

Strontium-substituted sub-micron bioactive glasses (Sr-SBG) have been reported to have enhanced osteogenic differentiation capacity compared to sub-micron bioactive glasses (SBG) in our previous study. However, the underlying molecular mechanisms of such beneficial effect of Sr-SBG are still not fully understood. In this study, we synthesized Sr-SBG, studied the effects of Sr-SBG on proliferation and osteogenic differentiation of mouse mesenchymal stem cells (mMSCs), and identified the molecular mechanisms of the enhancement effect of Sr-SBG on mMSCs. The results demonstrated that Sr-SBG had more profound promotion effect on proliferation and osteogenic differentiation of mMSCs than SBG and SrCl2 group which containing identical Sr concentration with Sr-SBG group. RT-qPCR and western blot analysis showed that the mRNA expressions and protein expressions involved in NFATc and Wnt/ß-catenin signaling pathways were all upregulated mediated by Sr-SBG, while only Wnt/ß-catenin signaling pathway related genes upregulated in SBG group and only NFATc signaling pathway activated in SrCl2 group, suggesting that NFATc and Wnt/ß-catenin signaling pathways played important roles in osteogenesis enhancement induced by Sr-SBG. To conform the above conclusion, cyclosporin A (CSA) was applied to inhibit NFATc signaling pathway. It was found that the enhanced osteogenic differentiation of mMSCs induced by Sr-SBG was partially abrogated and the activated Wnt/ß-catenin signaling pathway was also inhibited in part. However, the effects of SBG on proliferation and osteogenesis of mMSCs were unimpaired, yet the effects of SrCl2 were greatly suppressed. Taken together, these results indicated that strontium activated NFATc signaling pathway and silicate activated Wnt/ß-catenin signaling pathway might synergistically mediated the enhanced osteogenesis induced by Sr-SBG.

Characterization of the mechanical behaviors and bioactivity of tetrapod ZnO whiskers reinforced bioactive glass/gelatin composite scaffolds.

The purpose of this study is to construct bone tissue engineering scaffold with high porosity, good mechanical properties, and biological activities. Bioactive glass/gelatin composite scaffolds with different amounts of tetrapod zinc oxide whiskers were produced. The morphology, mechanical properties and in vitro bioactivity of the composite scaffolds were investigated. Results showed that, the composite scaffolds had open pores with a high degree of interconnectivity, and the porosity was higher than 80%. With the amount of ZnO whiskers increased, the mechanical properties of scaffolds increased. However, the reinforcing effect began to decrease when the addition is higher than 2wt%, which was resulted by the aggregation of the ZnO whiskers. In vitro test showed that, the composite scaffolds processed good biodegradability, and in vitro apatite-forming ability. The release of zinc ions retarded the growth of the HCA, so the HCA deposited on the scaffolds with ZnO was amorphous and worm-like. Furthermore, the composite scaffolds had good biocompatibility assessed by in vitro cell tests using rMSCs. All results are promising for the application of the composite scaffolds in bone repair.