Promote Bone Repair Research Articles

Nanotherapy for bone repair: milk-derived small extracellular vesicles delivery of icariin

Icariin (ICA) played an important role in the treatment of inflammatory bone defects. However, pharmacokinetic studies have shown that its poor bioavailability limited its application. In this context, we isolated bovine milk-derived sEV and prepared sEV-ICA to improve the osteogenic effect of ICA. In this study, we successfully constructed sEV-ICA. sEV-ICA was found to have significantly higher osteogenic efficiency than ICA in cell culture and cranial bone defect models. Mechanistically, bioinformatics analysis predicted that signal transducers and activators of transcription 5 (STAT5a) may bind to the GJA1 promoter, while luciferase activity assays and chromatin immunoprecipitation (ChIP) experiments confirmed that STAT5a directly binded to the GJA1 promoter to promote osteogenesis. We proved that compared with ICA, sEV-ICA showed a better effect of promoting bone repair in vivo and in vitro. In addition, sEV-ICA could promote osteogenesis by promoting the combination of STAT5a and GJA1 promoter. In summary, as a complex drug delivery system, sEV-ICA constituted a rapid and effective method for the treatment of bone defects and could improve the osteogenic activity of ICA.

L-cysteine aided polyaniline capped SrO2 nanoceramics: Assessment of MC3T3-E1-arbitrated osteogenesis and anti-bactericidal efficacy on the polyurethane 2D nanofibrous substrate

Fabricating bioartificial bone graft ceramics retaining structural, mechanical, and bone induction properties akin to those of native stem-cell niches is a major challenge in the field of bone tissue engineering and regenerative medicine. Moreover, the developed materials are susceptible to microbial invasion leading to biomaterial-centered infections which might limit their clinical translation. Here, we successfully developed biomimetic porous scaffolds of polyurethane-reinforcedL-cysteine-anchored polyaniline capped strontium oxide nanoparticles to improve the scaffold’s biocompatibility, osteo-regeneration, mechanical, and antibacterial properties. The engineered nanocomposite substrate PU/L-Cyst-SrO2 @PANI (0.4 wt%) significantly promotes bone repair and regeneration by modulating osteolysis and osteogenesis. ALP activity, collagen-I, ARS staining, as well as biomineralization of MC3T3-E1 cells, were used to assess the biocompatibility and cytocompatibility of the developed scaffolds in vitro, confirming that the scaffold provided a favorable microenvironment with a prominent effect on cell growth, proliferation, and differentiation. Furthermore, osteogenic protein markers were studied using qRT-PCR with expression levels of runt-related transcription factor 2 (RUNX2), secreted phosphoprotein 1 (Spp-I), and collagen type I (Col-I). The overall results suggest that PU/L-Cyst-SrO2 @PANI (0.4 wt%) scaffolds showed superior interfacial biocompatibility, antibacterial properties, load-bearing ability, and osteoinductivity as compared to pristine PU. Thus, prepared bioactive nanocomposite scaffolds perform as a promising biomaterial substrate for bone tissue regeneration.

The additive effects of bioactive glasses and photobiomodulation on enhancing bone regeneration.

Bioactive glasses (BG) have been generally used in bone defects repair for its good osteoinductivity and osteoconductivity. However, the early angiogenesis of BG in the repair of large-sized bone defects may not be sufficient enough to support new bone formation, resulting in the failure of bone repair. Photobiomodulation (PBM) therapy, which is superior on promoting early angiogenesis, may contribute to the angiogenesis of BG and further enhance the repair of bone defects. Therefore, we applied BG and PBM in combination and preliminarily investigated their additive effects on bone regeneration both in vitro and in vivo. The in vitro results revealed that BG combined with PBM remarkably enhanced human bone marrow mesenchymal stem cells proliferation, osteogenic-related genes expression and mineralization, which was better than applying BG or PBM respectively. For in vivo studies, the histological staining results showed that BG induced new bone formation in the interior of defects and promoted new bone reconstruction at 6 weeks post-operation. The micro-computed tomography results further confirmed that BG combined with PBM accelerated bone formation and maturation, improved the speed and quality of bone regeneration, and promoted bone repair. In conclusion, with the optimum BG and PBM parameters, BG combined with PBM generated additive effects on promoting bone regeneration.

Lactoferrin Mediates Enhanced Osteogenesis of Adipose-Derived Stem Cells: Innovative Molecular and Cellular Therapy for Bone Repair.

A prospective source of stem cells for bone tissue engineering is adipose-derived stem cells (ADSCs), and BMP-2 has been proven to be highly effective in promoting the osteogenic differentiation of stem cells. Rarely has research been conducted on the impact of lactoferrin (LF) on ADSCs' osteogenic differentiation. As such, in this study, we examined the effects of LF and BMP-2 to assess the ability of LF to stimulate ADSCs' osteogenic differentiation. The osteogenic medium was supplemented with the LF at the following concentrations to culture ADSCs: 0, 10, 20, 50, 100, and 500 μg/mL. The Cell Counting Kit-8 (CCK-8) assay was used to measure the proliferation of ADSCs. Calcium deposition, alkaline phosphatase (ALP) staining, real-time polymerase chain reaction (RT-PCR), and an ALP activity assay were used to establish osteogenic differentiation. RNA sequencing analysis was carried out to investigate the mechanism of LF boosting the osteogenic development of ADSCs. In the concentration range of 0-100 μg/mL, LF concentration-dependently increased the proliferative vitality and osteogenic differentiation of ADSCs. At a dose of 500 μg/mL, LF sped up and enhanced differentiation, but inhibited ADSCs from proliferating. LF (100 and 500 μg/mL) produced more substantial osteoinductive effects than BMP-2. The PI3 kinase/AKT (PI3K/AKT) and IGF-R1 signaling pathways were significantly activated in LF-treated ADSCs. The in vitro study results showed that LF could effectively promote osteogenic differentiation of ADSCs by activating the PI3K/AKT and IGF-R1 pathways. In our in vitro investigation, an LF concentration of 100 μg/mL was optimal for osteoinduction and proliferation. Our study suggests that LF is an attractive alternative to BMP-2 in bone tissue engineering. As a bioactive molecule capable of inducing adipose stem cells to form osteoblasts, LF is expected to be clinically used in combination with biomaterials as an innovative molecular and cellular therapy to promote bone repair.

Janus-Inspired Core–Shell Structure Hydrogel Programmatically Releases Melatonin for Reconstruction of Postoperative Bone Tumor

At present, surgery is one of the main treatments for bone tumor. However, the risk of recurrence and the large area of bone defects after surgery pose a great challenge. Therefore, a Janus-inspired core-shell structure bone scaffold was designed to achieve the self-programmed release of melatonin at different concentrations, clearing the residual tumor cells at early stage after resection and promoting bone repair later. The layered differential load designs inspired by Janus laid the foundation for the differential release of melatonin, where sufficient melatonin inhibited tumor growth as low dose promoted osteogenesis. Then, the automatically programmed delivery of melatonin is achieved by the gradient degradation of the core-shell structure. In the material characterization, scanning electron microscopy revealed the core-shell structure. The drug release experiment and in vivo degradation experiment reflected the programmed differential release of melatonin. In the biological experiment part, in vivo and in vitro experiments not only confirmed the significant inhibitory effect of the core-shell hydrogel scaffold on tumor but also confirmed its positive effect on osteogenesis. Our Janus-inspired core-shell hydrogel scaffold provides a safe and efficient means to inhibit tumor recurrence and bone repair after bone tumor, and it also develops a new and efficient tool for differential and programmed release of other drugs.

Ultrasound-controlled MXene-based Schottky heterojunction improves anti-infection and osteogenesis properties.

Background: The current clinical treatment of osteomyelitis is limited by the emergence of drug-resistant bacteria, which often leads to the failure of traditional antibiotic treatment and large bone defects. Sonodynamic therapy (SDT) is a new strategy that is widely used to overcome the problem of bacterial resistance to antibiotic therapy as well as poor tissue penetration using near-infrared light in photodynamic therapy (PDT). Therefore, it is necessary to develop a new sonosensitizer that can kill bacteria and promote bone repair. Methods: Herein, we developed a sonosensitizer, porphyrin metal-organic framework (HNTM), with a Schottky junction modified by Ti3C2 nanosheets (HN-Ti3C2) for highly efficient sonodynamic therapy of osteomyelitis and bone regeneration. Results: Ti3C2 greatly improves the acoustic catalytic performance by rapidly transferring the charge carriers generated by HNTM under ultrasound (US) irradiation, which killing drug-resistant bacteria through the generation of large amounts of reactive oxygen species (ROS). And HN-Ti3C2 shows excellent 99.75% antibacterial effectiveness against MRSA. In addition, HN-Ti3C2 generates a sonocurrent under low-intensity US to promote the repair of bone defects for a long time period. Mechanistic research using CCK-8 and RNA-seq showed that HN-Ti3C2 nanocomposites can promote the proliferation of stem cells by regulating the cell cycle, DNA replication, and apoptosis. In addition, after low-intensity US irradiation, HN-Ti3C2 promotes osteogenic differentiation via some key signaling pathways, including the calcium, Wnt, and TGF-beta signaling pathways, according to the Kyoto Encyclopedia of Genes and Genomes (KEGG). In a MRSA-infected rat tibial osteomyelitis model, HN-Ti3C2 successfully eliminated the infection and significantly improved bone regeneration under US irradiation. Conclusion: This study indicates that engineered HN-Ti3C2 is a distinctive nanocomposite for successful osteomyelitis treatment.

Dual-Nozzle 3D Printed Nano-Hydroxyapatite Scaffold Loaded with Vancomycin Sustained-Release Microspheres for Enhancing Bone Regeneration

Successful treatment of infectious bone defect remains a major challenge in the orthopaedic field. At present, the conventional treatment for infectious bone defects is surgical debridement and long-term systemic antibiotic use. It is necessary to develop a new strategy to achieve effective bone regeneration and local anti-infection for infectious bone defects. Firstly, vancomycin / poly (lactic acid-glycolic acid) sustained release microspheres (VAN/PLGA-MS) were prepared. Then, through the dual-nozzle 3D printing technology, VAN/PLGA-MS was uniformly loaded into the pores of nano-hydroxyapatite (n-HA) and polylactic acid (PLA) scaffolds printed in a certain proportion, and a composite scaffold (VAN/MS-PLA/n-HA) was designed, which can not only promote bone repair but also resist local infection. Finally, the performance of the composite scaffold was evaluated by in vivo and in vitro biological evaluation. The in vitro release test of microspheres showed that the release of VAN/PLGA-MS was relatively stable from the second day, and the average daily release concentration was about 15.75 μg/mL, which was higher than the minimum concentration specified in the guidelines. The bacteriostatic test in vitro showed that VAN/PLGA-MS had obvious inhibitory effect on Staphylococcus aureus ATCC-29213. Biological evaluation of VAN/MS-PLA/n-HA scaffolds in vitro showed that it can promote the proliferation of adipose stem cells. In vivo biological evaluation showed that VAN/MS-PLA/n-HA scaffold could significantly promote bone regeneration. Our research shows that VAN/MS-PLA/n-HA scaffolds have satisfying biomechanical properties, effectively inhibit the growth of Staphylococcus aureus, with good biocompatibility, and effectiveness on repairing bone defects. The VAN/MS-PLA/n-HA scaffold provide the clinic with an application prospect in bone tissue engineering.

Gold nanoparticles: promising biomaterials for osteogenic/adipogenic regulation in bone repair.

Bone defects are a common bone disease, which are usually caused by accidents, trauma and tumors. However, the treatment of bone defects is still a great clinical challenge. In recent years, research on bone repair materials has continued with great success, but there are few reports on the repair of bone defects at a high lipid level. Hyperlipidemia is a risk factor in the process of bone defect repair, which has a negative impact on the process of osteogenesis, increasing the difficulty of bone defect repair. Therefore, it is necessary to find materials that can promote bone defect repair under the condition of hyperlipidemia. Gold nanoparticles (AuNPs) have been applied in the fields of biology and clinical medicine for many years and developed to modulate osteogenic differentiation and adipogenic differentiation. In vitro and vivo studies displayed that they promoted bone formation and inhibited fat accumulation. Further, the metabolism and mechanisms of AuNPs acting on osteogenesis/adipogenesis were partially revealed by researchers. This review further clarifies the role of AuNPs in osteogenic/adipogenic regulation during the process of osteogenesis and bone regeneration by summarizing the related in vitro and in vivo research, discussing the advantages and challenges of AuNPs and highlighting several possible directions for future research, with the aim to provide a new strategy for dealing with bone defects in hyperlipidemic patients.

Mechanism and application of 3D-printed degradable bioceramic scaffolds for bone repair.

Bioceramics have attracted considerable attention in the field of bone repair because of their excellent osteogenic properties, degradability, and biocompatibility. To resolve issues regarding limited formability, recent studies have introduced 3D printing technology for the fabrication of bioceramic bone repair scaffolds. Nevertheless, the mechanisms by which bioceramics promote bone repair and clinical applications of 3D-printed bioceramic scaffolds remain elusive. This review provides an account of the fabrication methods of 3D-printed degradable bioceramic scaffolds. In addition, the types and characteristics of degradable bioceramics used in clinical and preclinical applications are summarized. We have also highlighted the osteogenic molecular mechanisms in biomaterials with the aim of providing a basis and support for future research on the clinical applications of degradable bioceramic scaffolds. Finally, new developments and potential applications of 3D-printed degradable bioceramic scaffolds are discussed with reference to experimental and theoretical studies.

Strategies of Macrophages to Maintain Bone Homeostasis and Promote Bone Repair: A Narrative Review.

Bone homeostasis (a healthy bone mass) is regulated by maintaining a delicate balance between bone resorption and bone formation. The regulation of physiological bone remodeling by a complex system that involves multiple cells in the skeleton is closely related to bone homeostasis. Loss of bone mass or repair of bone is always accompanied by changes in bone homeostasis. However, due to the complexity of bone homeostasis, we are currently unable to identify all the mechanisms that affect bone homeostasis. To date, bone macrophages have been considered a third cellular component in addition to osteogenic spectrum cells and osteoclasts. As confirmed by co-culture models or in vivo experiments, polarized or unpolarized macrophages interact with multiple components within the bone to ensure bone homeostasis. Different macrophage phenotypes are prone to resorption and formation of bone differently. This review comprehensively summarizes the mechanisms by which macrophages regulate bone homeostasis and concludes that macrophages can control bone homeostasis from osteoclasts, mesenchymal cells, osteoblasts, osteocytes, and the blood/vasculature system. The elaboration of these mechanisms in this narrative review facilitates the development of macrophage-based strategies for the treatment of bone metabolic diseases and bone defects.

Electroactive Biomaterials for Facilitating Bone Defect Repair under Pathological Conditions.

Bone degeneration associated with various diseases is increasing due to rapid aging, sedentary lifestyles, and unhealthy diets. Living bone tissue has bioelectric properties critical to bone remodeling, and bone degeneration under various pathological conditions results in significant changes to these bioelectric properties. There is growing interest in utilizing biomimetic electroactive biomaterials that recapitulate the natural electrophysiological microenvironment of healthy bone tissue to promote bone repair. This review first summarizes the etiology of degenerative bone conditions associated with various diseases such as type II diabetes, osteoporosis, periodontitis, osteoarthritis, rheumatoid arthritis, osteomyelitis, and metastatic osteolysis. Next, the diverse array of natural and synthetic electroactive biomaterials with therapeutic potential are discussed. Putative mechanistic pathways by which electroactive biomaterials can mitigate bone degeneration are critically examined, including the enhancement of osteogenesis and angiogenesis, suppression of inflammation and osteoclastogenesis, as well as their anti-bacterial effects. Finally, the limited research on utilization of electroactive biomaterials in the treatment of bone degeneration associated with the aforementioned diseases are examined. Previous studies have mostly focused on using electroactive biomaterials to treat bone traumatic injuries. It is hoped that this review will encourage more research efforts on the use of electroactive biomaterials for treating degenerative bone conditions.

Polyetheretherketone microspheres loaded with cerium dioxide nanoparticles mitigate damage from cellular oxidative stress and promote bone repair

The imbalance of oxidative and antioxidant effects in the bone repair process can lead to insufficient osseointegration of orthopedic implants and cause failure regeneration. In this study, cerium (IV) sulfate (Ce(SO4)2) was introduced into polyetheretherketone (PEEK) to prepare composite microspheres containing Ce(SO4)2 (Ce(SO4)2/PEEK microspheres). A hydrolysis method assisted by hydrothermal treatment enabled the successful in-situ convertion of Ce(SO4)2 to cerium dioxide nanoparticles (CeO2NPs) which were uniformly loaded in the microspheres and fulfilled a unique “topological” structure on the surface of the microspheres. In addition, CeO2NPs in the PEEK microspheres had catalase-like activity, which reduced the amount of hydrogen peroxide (H2O2) in the micro-environment of bone injury. Concurrently, the CeO2NPs/PEEK microspheres directly promoted cell proliferation and osteogenic differentiation and showed excellent promotion of bone regeneration in a rat-skull-defect repair model. In summary, we prepared CeO2NPs that were uniformly distributed in PEEK microspheres using a hydrothermal method to act as antioxidants and improve the osteogenic activity of PEEK microspheres.

Histological and Immunohistochemical Analysis of the Effects of Topical Melatonin Treatment Associated with Collagen Sponge and rhBMP-2 Protein on Bone Remodeling.

Extensive bone defect healing is an important health issue not yet completely resolved. Different alternative treatments have been proposed but, in face of a critical bone defect, it is still very difficult to reach a complete regeneration, with the new-formed bone presenting all morphological and physiological characteristics of a normal, preinjury bone. Topical melatonin use has shown as a promising adjuvant for bone regeneration due to its positive effects on bone metabolism. Thus, to search for new, safe, biological techniques that promote bone repair and favor defect healing, we hypothesized that there is a synergistic effect of melatonin treatment associated with rhBMP-2 to guide bone regeneration. This study aimed to investigate bone repair effects of topical melatonin administration in different concentrations (1, 10, and 100 µg), associated or not with rhBMP-2. Surgical-induced bone defect healing was qualitatively evaluated through histopathological analysis by light microscopy. Additionally, quantitative stereology was performed in immunohistochemistry-prepared tissue to identify angiogenic, osteogenic, and osteoclastogenic factors. Quantification data were compared between groups by the ANOVA/Tukey test and differences were considered significant when p < 0.05. Our results showed that the presence of the scaffold in the bone defect hindered the process of bone repair because in the group treated with "blood clot + scaffold" the results of bone formation and immunolabeling were reduced in comparison with all other groups (treated with melatonin alone or in association with rhBMP-2). Statistical analysis revealed a significant difference between the control group (bone defect + blood clot), and groups treated with different concentrations of melatonin in association with rhBMP-2, indicating a positive effect of the association for bone repair. This treatment is promising once it becomes a new safe alternative technique for the clinical treatment of fractures, bone defects, and bone grafts. Our results support the hypothesis of the safe use of the association of melatonin and rhBMP-2 and have established a safe and effective dose for this experimental treatment.

Functionalized Microscaffold-Hydrogel Composites Accelerating Osteochondral Repair through Endochondral Ossification.

Osteochondral regeneration remains a key challenge because of the limited self-healing ability of the bone and its complex structure and composition. Biomaterials based on endochondral ossification (ECO) are considered an attractive candidate to promote bone repair because they can effectively address the difficulties in establishing vascularization and poor bone regeneration via intramembranous ossification (IMO). However, its clinical application is limited by the complex cellular behavior of ECO and the long time required for induction of the cell cycle. Herein, functionalized microscaffold-hydrogel composites are developed to accelerate the developmental bone growth process via recapitulating ECO. The design comprises arginine-glycine-aspartic acid (RGD)-peptide-modified microscaffolds loaded with kartogenin (KGN) and wrapped with a layer of RGD- and QK-peptide-comodified alginate hydrogel. These microscaffolds enhance the proliferation and aggregation behavior of the human bone marrow mesenchymal stem cells (hBMSCs); the controlled release of kartogenin induces the differentiation of hBMSCs into chondrocytes; and the hydrogel grafted with RGD and QK peptide facilitates chondrocyte hypertrophy, which creates a vascularized niche for osteogenesis and finally accelerates osteochondral repair in vivo. The findings provide an efficient bioengineering approach by sequentially modulating cellular ECO behavior for osteochondral defect repair.

Thermosensitive hydrogel loaded with concentrated growth factors promote bone repair in segmental bone defects.

Treating critical-size bone defects beyond the body's self-healing capacity is a challenging clinical task. In this study, we investigate the effect of concentrate growth factors (CGFs) loaded Poloxamer 407 hydrogel on the viability and osteogenic differentiation potential of bone marrow mesenchymal stem cells (BMSCs) and reconstruction of critical-size bone defects. In vitro, this CGFs-loaded thermosensitive hydrogel can significantly promote proliferation, maintain cell viability, and induce osteogenic differentiation of BMSCs by up-regulating the mineralization and alkaline phosphatase (ALP) activity, as well as gene markers, including runt-related transcription factor-2 (Runx-2), type I collagen (Col-1), osteocalcin (OCN), as well as osteopontin (OPN). In vivo, Micro-CT radiography analysis and histological detection demonstrated that the CGFs-loaded hydrogel significantly induced bone healing and reconstructed the medullary cavity structure in critical-size bone defect models. In conclusion, this strategy of transplantation of CGFs-loaded hydrogel promoted bone regeneration and prevented bone nonunion, so as to provide basis for clinical treatment for repairing critical-size bone defects.

Distinct osteogenic effect of different periosteum derived cells via Hippo-YAP cascade signaling

ABSTRACT Periosteum is expected for bone repairing due to excellent regenerative potential. PDCs are the main source of cells for promoting bone repair. However, PDCs from different sites have been confirmed to be site specific due to their distinct embryonic origin and the methods of bone formation. Hippo-YAP pathway is proved to play a critical role in fate decision of mesenchymal stem cells. The effect of Hippo-YAP on PDCs has not been reported so far. Hence, we aim to explore the differences of PDCs from mandible and femur along with their possible responses to YAP signaling. mPDCs and fPDCs were obtained and tested through flow cytometry for identification. Follow-up results illustrated mPDCs was cubic shape and with better proliferation while fPDCs preferred slender cell shape with worse cell viability compared with mPDCs. mPDCs was superior to fPDCs in ALP activity, related mRNA expression and calcium deposits in late stage. Interestingly, downregulation of YAP promoted the ALP activity, related mRNA expression and calcium deposits of fPDCs while hindered that of mPDCs in vitro. Moreover, implant animal model in mandible and femur were constructed for evaluation in vivo. Histological results were similar to the results in vitro. We speculate this may result from their different embryonic origin and the way of bone formation. Taken together, results available suggested that mPDCs may serve as more optimal seed cells for tissue engineering compared with fPDCs; however, considering their different response to YAP signaling, to ensure sufficient YAP expression in mPDCs and appropriate declining YAP expression in fPDCs may establish better osteogenesis.

Biomaterial-induced macrophage polarization for bone regeneration

As the main target cells of immune regulation, macrophages play an important role in the bone regeneration process. Macrophages can be polarized into the M1 and M2 types under the stimulation of different factors. They have proinflammatory and anti-inflammatory effects, respectively, and play key roles in different stages of bone regeneration. The ratio of M1 to M2 macrophages can be regulated by immunomodulatory biomaterials to promote bone repair and regeneration. In this paper, we review the recent literature on the chemical, physical and biological properties of biomaterials and the regulation of macrophage polarization under the influence of other factors. We also cover new methods for preparing immunomodulatory biomaterials for bone regeneration. This paper will provide new design ideas for the development of biomaterials with immunological properties and will support the clinical translation of bone-related medical biomaterials.

The Potential Therapeutic Role of Metformin in Diabetic and Non-Diabetic Bone Impairment.

Metformin is a widely-used anti-diabetic drug in patients with type 2 diabetic mellitus (T2DM) due to its safety and efficacy in clinical. The classic effect of metformin on lowering blood glucose levels is to inhibit liver gluconeogenesis that reduces glucose production as well as increases peripheral glucose utilization. However, the factors such as hyperglycemia, insulin deficiency, reduced serum levels of insulin-like growth factor-1 (IGF-1) and osteocalcin, accumulation of advanced glycation end products (AGEs), especially in collagen, microangiopathy, and inflammation reduced bone quality in diabetic patients. However, hyperglycemia, insulin deficiency, reduced levels of insulin-like growth factor-1 (IGF-1) and osteocalcin in serum, accumulation of advanced glycation end products (AGEs) in collagen, microangiopathy, and inflammation, reduce bone quality in diabetic patients. Furthermore, the imbalance of AGE/RAGE results in bone fragility via attenuating osteogenesis. Thus, adequate glycemic control by medical intervention is necessary to prevent bone tissue alterations in diabetic patients. Metformin mainly activates adenosine 5′ -monophosphate-activated protein kinase (AMPK), and inhibits mitochondrial respiratory chain complex I in bone metabolism. In addition, metformin increases the expression of transcription factor runt-related transcription factor2 (RUNX2) and Sirtuin protein to regulate related gene expression in bone formation. Until now, there are a lot of preclinical or clinical findings on the application of metformin to promote bone repair. Taken together, metformin is considered as a potential medication for adjuvant therapy in bone metabolic disorders further to its antidiabetic effect. Taken together, as a conventional hypoglycemia drug with multifaceted effects, metformin has been considered a potential adjuvant drug for the treatment of bone metabolic disorders.

Therapeutic effect of human umbilical cord mesenchymal stem cells in early traumatic osteonecrosis of the femoral head.

BackgroundOsteonecrosis of the femoral head (ONFH) is a refractory disease due to its unclear pathomechanism. Therapies during the early stage of ONFH have not achieved satisfactory results. Therefore, this study aims to explore the available evidence for the therapeutic effect of human umbilical cord mesenchymal stem cells (HUCMSCs) on early-stage traumatic ONFH.MethodsEarly-stage traumatic ONFH was established. The femoral heads of rats were then locally administered HUCMSCs. Four weeks and eight weeks after surgery, bone repair of the necrotic area in the femoral head was analyzed to evaluate the therapeutic effect of HUCMSCs using micro-CT, histopathological staining, immunofluorescence staining, Luminex.ResultsHUCMSCs were still present in the femoral head four weeks later, and the morphological, micro-CT and histopathological outcomes in the 4-week HUCMSC-treated group were better than those in the model, NS and 8-week HUCMSC-treated groups. Local transplantation of HUCMSCs promoted bone repair and prevented bone loss in the necrotic area of the femoral head.ConclusionsHUCMSCs can survive and positively affect the femoral head through local transplantation in early-stage traumatic ONFH. The conclusions of this study can provide a treatment option for patients who have ONFH and can serve as basic research on the advanced development of this disease.The Translational potential of this articleThe study indicated that the positive effect of exogenous HUCMSCs in the treatment of early-stage traumatic ONFH provides the solid basis and guidance for the clinical application of HUCMSCs.

Application of Bone Marrow-Derived Macrophages Combined with Bone Mesenchymal Stem Cells in Dual-Channel Three-Dimensional Bioprinting Scaffolds for Early Immune Regulation and Osteogenic Induction in Rat Calvarial Defects.

The host immune response to biomaterials is critical for determining scaffold fate and bone regeneration outcomes. Three-dimensional (3D) bioprinted scaffolds encapsulated with living cells can improve the inflammatory microenvironment and further accelerate bone repair. Here, we screened and adopted 8% methacrylamidated gelatin (GelMA)/1% methacrylamidated hyaluronic acid (HAMA) as the encapsulation system for rat bone marrow-derived macrophages (BMMs) and 3% Alginate/0.5 mg/mL graphene oxide (GO) as the encapsulation system for rat bone mesenchymal stem cells (BMSCs), thus forming a dual-channel bioprinting scaffold. The 8% GelMA/1% HAMA/3% Alginate/0.5 mg/mL GO (8/1/3/0.5) group could form a scaffold with a stable structure, good mechanical properties, and satisfied biocompatibility. When exploring the crosstalk between BMMs and BMSCs in vitro, we found that BMSCs could promote the polarization of BMMs to M2 type at the early stage, reduce the pro-inflammatory gene expression, and increase anti-inflammatory gene expression; conversely, BMMs can promote the osteogenic differentiation of BMSCs. In addition, in the model of rat calvarial defects, the dual-channel scaffold encapsulated with BMMs and BMSCs was more effective than the single-cell scaffold and the acellular scaffold. The paracrine of BMMs and BMSCs in the biodegradable dual-channel scaffold effectively promoted the M2-type polarization of macrophages in the microenvironment of early bone defects, avoided excessive inflammatory responses, and further promoted bone repair. In conclusion, our findings suggested that using 3D bioprinting to simultaneously encapsulate two primary cells of BMMs and BMSCs in a dual-channel system may be an effective way to promote bone repair from the perspective of early immune regulation and late induction of osteogenesis.