Bone Angiogenesis Research Articles

Antioxidant PDA-PEG nanoparticles alleviate early osteoarthritis by inhibiting osteoclastogenesis and angiogenesis in subchondral bone

Accumulating evidence suggests that osteoclastogenesis and angiogenesis in subchondral bone are critical destructive factors in the initiation and progression of osteoarthritis (OA). Herein, methoxypolyethylene glycol amine (mPEG-NH2) modified polydopamine nanoparticles (PDA-PEG NPs) were synthesized for treating early OA. The cytotoxicity and reactive oxygen species (ROS) scavenging ability of PDA-PEG NPs were evaluated. The effects of PDA-PEG NPs on osteoclast differentiation and vessel formation were then evaluated. Further, PDA-PEG NPs were administrated to anterior cruciate ligament transection (ACLT)-induced OA mice. Results demonstrated that PDA-PEG NPs had low toxicity both in vitro and in vivo. PDA-PEG NPs could inhibit osteoclastogenesis via regulating nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. Moreover, PDA-PEG NPs suppressed osteoclast-related angiogenesis via down-regulating platelet-derived growth factor-BB (PDGF-BB). In vivo, PDA-PEG NPs inhibited subchondral bone resorption and angiogenesis, further rescuing cartilage degradation in OA mice. In conclusion, we demonstrated that PDA-PEG NPs deployment could be a potential therapy for OA.Graphical

HIF-1α Regulates Bone Homeostasis and Angiogenesis, Participating in the Occurrence of Bone Metabolic Diseases.

In the physiological condition, the skeletal system's bone resorption and formation are in dynamic balance, called bone homeostasis. However, bone homeostasis is destroyed under pathological conditions, leading to the occurrence of bone metabolism diseases. The expression of hypoxia-inducible factor-1α (HIF-1α) is regulated by oxygen concentration. It affects energy metabolism, which plays a vital role in preventing bone metabolic diseases. This review focuses on the HIF-1α pathway and describes in detail the possible mechanism of its involvement in the regulation of bone homeostasis and angiogenesis, as well as the current experimental studies on the use of HIF-1α in the prevention of bone metabolic diseases. HIF-1α/RANKL/Notch1 pathway bidirectionally regulates the differentiation of macrophages into osteoclasts under different conditions. In addition, HIF-1α is also regulated by many factors, including hypoxia, cofactor activity, non-coding RNA, trace elements, etc. As a pivotal pathway for coupling angiogenesis and osteogenesis, HIF-1α has been widely studied in bone metabolic diseases such as bone defect, osteoporosis, osteonecrosis of the femoral head, fracture, and nonunion. The wide application of biomaterials in bone metabolism also provides a reasonable basis for the experimental study of HIF-1α in preventing bone metabolic diseases.

Exosomal let-7f-5p derived from mineralized osteoblasts promotes the angiogenesis of endothelial cells via the DUSP1/Erk1/2 signaling pathway.

Blood vessel formation is the prerequisite for the survival and growth of tissue-engineered bone. Mineralized osteoblasts (MOBs) have been shown to regulate angiogenesis through the secretion of exosomes containing various pro-angiogenic factors. However, whether the mineralized osteoblast-derived exosomes (MOB-Exos) containing let-7f-5p can regulate the angiogenesis of endothelial cells (ECs) is still unknown. In this study, the angiogenic capabilities of ECs respectively treated with MOB-Exos, let-7f-5p mimicked MOB-Exos (miR mimic group), and let-7f-5p inhibited MOB-Exos (miR inhibitor group) were compared through in vitro and in vivo studies. Moreover, the potential mechanism of MOB-Exo let-7f-5p regulating angiogenesis was explored by verifying the role of the Erk1/2 signaling pathway and target gene DUSP1. The results showed that MOB-Exos could significantly promote the angiogenesis of ECs, which could be enhanced by mimicked exosomal let-7f-5p and attenuated by inhibited exosomal let-7f-5p. Let-7f-5p could suppress the luciferase activity of wide-type DUSP1, and the mutation of DUSP1 could abrogate the repressive ability of let-7f-5p. Furthermore, the expression of DUSP1 exhibited a reversed trend to that of pErk1/2. The expression of pErk1/2 was significantly higher in the miR mimic group and lower in the miR inhibitor group than that in the MOB-Exos group, while inhibition of pErk1/2 could partly impair the angiogenic capabilities of ECs. In conclusion, we concluded that exosomal let-7f-5p derived from MOBs could promote the angiogenesis of ECs via activating the DUSP1/Erk1/2 signaling pathway, which might be a promising target for promoting the angiogenesis of tissue-engineered bone.

The impact of aging and physical training on angiogenesis in the musculoskeletal system.

Angiogenesis is the physiological process of capillary growth. It is strictly regulated by the balanced activity of agents that promote the formation of capillaries (pro-angiogenic factors) on the one hand and inhibit their growth on the other hand (anti-angiogenic factors). Capillary rarefaction and insufficient angiogenesis are some of the main causes that limit blood flow during aging, whereas physical training is a potent non-pharmacological method to intensify capillary growth in the musculoskeletal system. The main purpose of this study is to present the current state of knowledge concerning the key signalling molecules implicated in the regulation of skeletal muscle and bone angiogenesis during aging and physical training.

The Effect of Angiogenesis-Based Scaffold of MesoporousBioactive Glass Nanofiber on Osteogenesis.

There is still an urgent need for more efficient biological scaffolds to promote the healing of bone defects. Vessels can accelerate bone growth and regeneration by transporting nutrients, which is an excellent method to jointly increase osteogenesis and angiogenesis in bone regeneration. Therefore, we aimed to prepare a composite scaffold that could promote osteogenesis with angiogenesis to enhance bone defect repair. Here, we report that scaffolds were prepared by coaxial electrospinning with mesoporous bioactive glass modified with amino (MBG-NH2) adsorbing insulin-like growth factor-1 (IGF-1) as the core and silk fibroin (SF) adsorbing vascular endothelial growth factor (VEGF) as the shell. These scaffolds were named MBG-NH2/IGF@SF/VEGF and might be used as repair materials to promote bone defect repair. Interestingly, we found that the MBG-NH2/IGF@SF/VEGF scaffolds had nano-scale morphology and high porosity, as well as enough mechanical strength to support the tissue. Moreover, MBG-NH2 could sustain the release of IGF-1 to achieve long-term repair. Additionally, the MBG-NH2/IGF@SF/VEGF scaffolds could significantly promote the mRNA expression levels of osteogenic marker genes and the protein expression levels of Bmp2 and Runx2 in bone marrow mesenchymal stem cells (BMSCs). Meanwhile, the MBG-NH2/IGF@SF/VEGF scaffolds promoted osteogenesis by simulating Runx2 transcription activity through the phosphorylated Erk1/2-activated pathway. Intriguingly, the MBG-NH2/IGF@SF/VEGF scaffolds could also significantly promote the mRNA expression level of angiogenesis marker genes and the protein expression level of CD31. Furthermore, RNA sequencing verified that the MBG-NH2/IGF@SF/VEGF scaffolds had excellent performance in promoting bone defect repair and angiogenesis. Consistent with these observations, we found that the MBG-NH2/IGF@SF/VEGF scaffolds demonstrated a good repair effect on a critical skull defect in mice in vivo, which not only promoted the formation of blood vessels in the haversian canal but also accelerated the bone repair process. We concluded that these MBG-NH2/IGF@SF/VEGF scaffolds could promote bone defect repair under accelerating angiogenesis. Our finding provides a new potential biomaterial for bone tissue engineering.

SIRT6 Prevents Glucocorticoid-Induced Osteonecrosis of the Femoral Head in Rats.

Objective Glucocorticoid-induced osteonecrosis of the femoral head is one of the most common causes of nontraumatic osteonecrosis of the femoral head, but its exact pathogenesis remains unclear. The aim of this study was to investigate the role of SIRT6 in the maintenance of bone tissue morphology and structure, intravascular lipid metabolism, and its potential molecular mechanism in glucocorticoid-induced osteonecrosis of the femoral head. Methods SIRT6 adenovirus was transfected into GIONFH in rats. The microstructure of rat bone was observed by micro-CT and histological staining, and the expression of bone formation-related proteins and angiogenesis-related factors was determined through western blot and immunohistochemistry. Alkaline phosphatase activity, alizarin red staining, and the expression levels of Runx2 and osteocalcin were used to evaluate the osteogenic potential. And in vitro tube formation assay and immunofluorescence were used to detect the ability of endothelial cell angiogenesis. Results Dexamethasone significantly inhibited osteoblast differentiation, affected bone formation, and destroyed microvessel formation, increased the intracellular Fe2+ and ROS levels and induced the occurrence of ferroptosis. SIRT6 can inhibit ferroptosis and restore the ability of bone formation and angiogenesis. Conclusion SIRT6 can inhibit the occurrence of ferroptosis, reduce the damage of vascular endothelium, and promote osteogenic differentiation, so as to prevent the occurrence of osteonecrosis of the femoral head.

Bioinspired sandwich-like hybrid surface functionalized scaffold capable of regulating osteogenesis, angiogenesis, and osteoclastogenesis for robust bone regeneration.

Recently, strategies that focus on biofunctionalized implant surfaces to enhance bone defect healing through the synergistic regulation of osteogenesis, angiogenesis, and osteoclastogenesis have attracted increasing attention in the bone tissue engineering field. Studies have shown that the Wnt/β-catenin signaling pathway has an imperative effect of promoting osteogenesis and angiogenesis while reducing osteoclastogenesis. However, how to prepare biofunctionalized bone implants with balanced osteogenesis, angiogenesis, and osteoclastogenesis by activating the Wnt/β-catenin pathway has seldom been investigated. Herein, through a bioinspired dopamine chemistry and self-assembly method, BML-284 (BML), a potent and highly selective Wnt signaling activator, was loaded on a mussel-inspired polydopamine (PDA) layer that had been immobilized on the porous beta-tricalcium calcium phosphate (β-TCP) scaffold surface and subsequently modified by a biocompatible carboxymethyl chitosan hydrogel to form a sandwich-like hybrid surface. β-TCP provides a biomimetic three-dimensional porous microenvironment similar to that of natural cancellous bone, and the BML-loaded sandwich-like hybrid surface endows the scaffold with multifunctional properties for potential application in bone regeneration. The results show that the sustained release of BML from the sandwich-like hybrid surface significantly facilitates the adhesion, migration, proliferation, spreading, and osteogenic differentiation of MC3T3-E1 cells as well as the angiogenic activity of human umbilical vein endothelial cells. In addition to osteogenesis and angiogenesis, the hybrid surface also exerts critical roles in suppressing osteoclastic activity. Remarkably, in a critical-sized cranial defect model, the biofunctionalized β-TCP scaffold could potentially trigger a chain of biological events: stimulating the polarization of M2 macrophages, recruiting endogenous stem cells and endothelial cells at the injury site to enable a favorable microenvironment for greatly accelerating bone ingrowth and angiogenesis while compromising osteoclastogenesis, thereby promoting bone healing. Therefore, these surface-biofunctionalized β-TCP implants, which regulate the synergies of osteogenesis, angiogenesis, and anti-osteoclastogenesis, indicate strong potential for clinical application as advanced orthopedic implants.

Vasculogenic gene therapy: No role for revitalization of structural bone allografts.

Segmental bone defects are often performed with cryopreserved allografts. They provide immediate stability, but risk nonunion, infection and late stress fracture. Improving the rate and extent of bone revitalization may improve results. Angiogenesis from surgically placed arteriovenous (AV) bundles improves bone blood flow and vitality in cryopreserved rat femora, augmented by vasculogenic growth factors. This study tests the same principal in Yucatan mini-pigs with a tibial diaphyseal defect, combining surgical angiogenesis with angiogenic gene therapy within cryopreserved orthotopically-placed allografts. Tibial diaphyseal defects were reconstructed with cryopreserved allografts and rigid internal fixation in 16 mini pigs. Half of the cranial tibial AV bundles placed within the allograft medullary canal were transfected with an adeno-associated virus containing vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) genes (AAV9.VEGF.PDGF). Bone remodeling, angiogenesis, and allograft healing were assessed. During the postoperative survival period 5 of 8 transfected animals developed cutaneous benign vascular lesions at sites remote from the operated hindlimb, causing excessive bleeding. Within the allograft, both medullary (p = 0.013) and cortical (p = 0.009) vascular volumes were higher and vessels more mature than nontransfected allografts. Bone turnover (p = 0.013), bone mineralization (p = 0.018), bone healing (p = 0.008) and graft incorporation (p = 0.006) were all significantly higher in the gene therapy group. In a large animal tibial defect model, gene therapy of implanted AV bundles improved revascularization, remodeling and healing of cryopreserved allografts used for limb reconstruction. However, benign vascular lesions causing excessive bleeding developed in 5 out of 8 pigs transfected with AAV containing genes for VEGF and PDGF. This unforeseen complication makes vasculogenic gene therapy unacceptable for clinical use.

Co‐delivery of tauroursodeoxycholic acid and dexamethasone using electrospun ultrafine fibers to induce early coupled angiogenesis and osteogenic differentiation

AbstractIn the complicated process of bone regeneration, osteogenic differentiation and angiogenesis are crucial. In this study, a novel dual small molecule composite electrospun scaffold was prepared using polycaprolactone embedded with angiogenic factor tauro‐ursodeoxycholic acid and osteogenic factor dexamethasone to promote early angiogenesis and osteogenesis. Additionally, the related properties, angiogenic activity, and osteogenic activity analyses were conducted for the scaffold. The results demonstrated that the composite scaffold possessed proper mechanical properties and hydrophilicity. During the initial drug release, the release rate of the hydrophilic drug tauro‐ursodeoxycholic acid was higher compared to the hydrophobic drug dexamethasonethe. The drugs were slowly sustained released for more than 528 h. The composite scaffold boosted cell proliferation and accelerated osteogenic differentiation up to 21 days. The alkaline phosphatase activity and mineral deposition were comparatively higher on dual drug‐releasing fibers compared to control scaffolds. Wound healing migration assay and tube formation assay for further in vitro revealed that the composite scaffold exhibited higher efficiency in promoting cell migration and the angiogenesis ductive. Hence, the composite scaffold had a high potential for promoting bone regeneration by enhancing angiogenesis.

MiR-210-3p protects against osteoarthritis through inhibiting subchondral angiogenesis by targeting the expression of TGFBR1 and ID4.

Excessive subchondral angiogenesis is a key pathological feature of osteoarthritis (OA), as it alters the balance of subchondral bone remodeling and causes progressive cartilage degradation. We previously found that miR-210-3p correlates negatively with angiogenesis, though the specific mechanism of miR-210-3p-related angiogenesis in subchondral bone during OA progression remains unclear. This study was conducted to identify the miR-210-3p-modulating subchondral angiogenesis mechanism in OA and investigate its therapeutic effect. We found that miR-210-3p expression correlated negatively with subchondral endomucin positive (Emcn+) vasculature in the knee joints of OA mice. miR-210-3p overexpression regulated the angiogenic ability of endothelial cells (ECs) under hypoxic conditions in vitro. Mechanistically, miR-210-3p inhibited ECs angiogenesis by suppressing transforming growth factor beta receptor 1 (TGFBR1) mRNA translation and degrading DNA-binding inhibitor 4 (ID4) mRNA. In addition, TGFBR1 downregulated the expression of ID4. Reduced ID4 levels led to a negative feedback regulation of TGFBR1, enhancing the inhibitory effect of miR-210-3p on angiogenesis. In OA mice, miR-210-3p overexpression in ECs via adeno-associated virus (AAV) alleviated cartilage degradation, suppressed the type 17 immune response and relieved symptoms by attenuating subchondral Emcn+ vasculature and subchondral bone remodeling. In conclusion, we identified a miR-210-3p/TGFBR1/ID4 axis in subchondral ECs that modulates OA progression via subchondral angiogenesis, representing a potential OA therapy target.

Piezoresistive MXene/Silk fibroin nanocomposite hydrogel for accelerating bone regeneration by Re-establishing electrical microenvironment.

The electrical microenvironment plays an important role in bone repair. However, the underlying mechanism by which electrical stimulation (ES) promotes bone regeneration remains unclear, limiting the design of bone microenvironment–specific electroactive materials. Herein, by simple co-incubation in aqueous suspensions at physiological temperatures, biocompatible regenerated silk fibroin (RSF) is found to assemble into nanofibrils with a β-sheet structure on MXene nanosheets, which has been reported to inhibit the restacking and oxidation of MXene. An electroactive hydrogel based on RSF and bioencapsulated MXene is thus prepared to promote efficient bone regeneration. This MXene/RSF hydrogel also acts as a piezoresistive pressure transducer, which can potentially be utilized to monitor the electrophysiological microenvironment. RNA sequencing is performed to explore the underlying mechanisms, which can activate Ca2+/CALM signaling in favor of the direct osteogenesis process. ES is found to facilitate indirect osteogenesis by promoting the polarization of M2 macrophages, as well as stimulating the neogenesis and migration of endotheliocytes. Consistent improvements in bone regeneration and angiogenesis are observed with MXene/RSF hydrogels under ES in vivo. Collectively, the MXene/RSF hydrogel provides a distinctive and promising strategy for promoting direct osteogenesis, regulating immune microenvironment and neovascularization under ES, leading to re-establish electrical microenvironment for bone regeneration.

Promoting lacunar bone regeneration with an injectable hydrogel adaptive to the microenvironment.

Injectable hydrogel is suitable for the repair of lacunar bone deficiency. This study fabricated an injectable, self-adaptive silk fibroin/mesoporous bioglass/sodium alginate (SMS) composite hydrogel system. With controllable and adjustable physical and chemical properties, the SMS hydrogel could be easily optimized adaptively to different clinical applications. The SMS hydrogel effectively showed great injectability and shapeability, allowing defect filling with no gap. Moreover, the SMS hydrogel displayed self-adaptability in mechanical reinforcement and degradation, responsive to the concentration of Ca2+ and inflammatory-like pH value in the microenvironment of bone deficiency, respectively. In vitro biological studies indicated that SMS hydrogel could promote osteogenic differentiation of bone marrow mesenchymal stem cells by activation of the MAPK signaling pathway. The SMS hydrogel also could improve migration and tube formation of human umbilical vein endothelial cells. Investigations of the crosstalk between osteoblasts and macrophages confirmed that SMS hydrogel could regulate macrophage polarization from M1 to M2, which could create a specific favorable environment to induce new bone formation and angiogenesis. Meanwhile, SMS hydrogel was proved to be antibacterial, especially for gram-negative bacteria. Furthermore, in vivo study indicated that SMS could be easily applied for maxillary sinus elevation, inducing sufficient new bone formation. Thus, it is convincing that SMS hydrogel could be potent in a simple, minimally invasive and efficient treatment for the repair of lacunar bone deficiency.

An artificial bone window for long-term photoacoustic monitoring of bone recovery.

Blood vessels that deliver nutrients and oxygen over the entire body is essential for bone homeostasis. Especially, for the bone recovery, long-term in vivo vascular imaging is desirable. Here, we propose an optical and ultrasonic transparent bone window, which allows repeated, chronic monitoring of bone angiogenesis in mouse tibia defect. A metal ring with an outer diameter of 2 mm and an inner diameter of 1 mm is bonded with a silicone-based polydimethylsiloxane (PDMS) film and cover the bone surface, which can effectively eliminate the inflammation caused by repeated wound opening before imaging. We make a bone defect model in mouse tibia, and employ an optical resolution photoacoustic microscopy (ORPAM) to provide a high-resolution, label-free, long-term, in vivo observation of the bone vascularization during the bone defect healing. The results suggest that the artificial bone window can remain stable for inspection and play positive role for bone repair.

Medication Related Osteonecrosis of the Jaw: A Conservative Approach

Medication-related osteonecrosis of the jaw is a well-known condition to the oral and maxillofacial surgeon despite being considered rare. In recent epidemiologic studies, the incidence of MRONJ was found to be between < 0.05% among patient taking antiresorptive medications for osteoporosis and ∼1.5% for cancer therapy. The pathophysiology is believed to be multifactorial involving bone remodeling inhibition, inflammation/infection, angiogenesis inhibition, dysfunctional immunity and genetics. Most recently, the American Association of Oral and Maxillofacial surgeons (AAOMS) released an updated position paper (2022) for guidelines regarding diagnosis and management of this condition.

Effect of tibial cortex transverse transport in patients with recalcitrant diabetic foot ulcers: A prospective multicenter cohort study.

BackgroundManagement of recalcitrant diabetic foot ulcer (DFU) remains difficult. Distraction osteogenesis mediates new bone formation and angiogenesis in the bone itself and the surrounding tissues. Recently it was reported that tibial cortex transverse transport (TTT) was associated with neovascularization and increased perfusion at the foot in patients with recalcitrant DFUs and facilitated healing and limb salvage. However, the findings were from several single-center studies with relatively small populations, which need to be confirmed in multicenter cohort studies with relatively large populations. Furthermore, the effect of this technique on patient's health-related quality of life is still unclear.MethodsWe treated patients with recalcitrant (University of Texas wound grading system 2-C to 3-D and not responding to prior routine conservative and surgical treatments for at least 8 weeks) DFUs from seven centers using TTT (a 5 ​cm ​× ​1.5 ​cm corticotomy followed by 4 weeks of medial and lateral distraction) between July 2016 and June 2019. We analyzed ulcer healing, major amputation, recurrence, health-related quality of life (physical and mental component summary scores), and complications in the 2-year follow-up. Foot arterial and perfusion changes were evaluated using computed tomography angiography and perfusion imaging 12 weeks postoperatively.ResultsA total of 1175 patients were enrolled. Patients who died (85, 7.2%) or lost to follow-up (18, 1.7%) were excluded, leaving 1072 patients for evaluation. Most of the patients were male (752, 70.1%) and with a mean age of 60.4 ​± ​9.1 years. The mean ulcer size was 41.0 ​± ​8.5 ​cm2 and 187 (16.6%) ulcers extended above the ankle. During the follow-up, 1019 (94.9%) patients healed in a mean time of 12.4 ​± ​5.6 weeks, 53 (4.9%) had major amputations, and 33 (3.1%) experienced recurrences. Compared to preoperatively, the patients had higher physical (26.2 ​± ​8.3 versus 41.3 ​± ​10.6, p ​= ​0.008) and mental (33.6 ​± ​10.7 versus 45.4 ​± ​11.3, p ​= ​0.031) component summary scores at the 2-year follow-up. Closed tibial fracture at the corticotomy site was found in 8 (0.7%) patients and was treated using external fixation and healed uneventfully. There were 23 (2.1%) patients who had pin site infections and were treated successfully with dressing changes. Compared to preoperatively, the patients had more small arteries and higher foot blood flow (8.1 ​± ​2.2 versus 28.3 ​± ​3.9 ml/100 ​g/min, p ​= ​0.003) and volume (1.5 ​± ​0.3 versus 2.7 ​± ​0.4 ml/100 ​g, p ​= ​0.037) 12 weeks postoperatively.ConclusionTTT promotes healing, limb salvage, and health-related quality of life in patients with recalcitrant DFUs as demonstrated in this multicenter cohort study. The surgical procedure was simple and straightforward and the complications were few and minor. The effect of this technique was associated with neovascularization and improved perfusion at the foot mediated by the cortex distraction. The findings are required to confirm in randomized controlled trials.The Translational Potential of this Article: TTT can be used as an effective treatment in patients with recalcitrant DFUs. The mechanism is associated with neovascularization and consequently increased perfusion in the foot after operation.

Development of degradable magnesium-based metal implants and their function in promoting bone metabolism (A review).

BackgroundUse of degradable magnesium (Mg)-based metal implants in orthopaedic surgeries can avoid drawbacks associated with subsequent removal of the non-degradable metallic implants, reducing cost and trauma of patients. Although Mg has been applied in the clinic for orthopaedic treatment, the use of Mg-based metal implants is largely in the research phase. But its application is potentially beneficial in this context as it has been shown that Mg can promote osteogenesis and inhibit osteoclast activity.MethodsA systematic literature search about “degradable magnesium (Mg)-based metal implants” was performed in PubMed and Web of Science. Meanwhile, relevant findings have been reviewed and quoted.ResultsIn this review, we summarize the latest developments in Mg-based metal implants and their role in bone regeneration. We also review the various molecular mechanisms by which Mg ions regulate bone metabolic processes, including osteogenesis, osteoclast activity, angiogenesis, immunity, and neurology. Finally, we discuss the remaining research challenges and opportunities for Mg-based implants and their applications.ConclusionCurrently, establishment of the in vitro and in vivo biological evaluation systems and phenotypic modification improvement of Mg-based implants are still needed. Clarifying the functions of Mg-based metal implants in promoting bone metabolism is beneficial for their clinical application.The Translational potential of this articleAll current reviews on Mg-based implants are mainly concerned with the improvement of Mg alloy properties or the progress of applications. However, there are few reviews that provides a systematic narrative on the effect of Mg on bone metabolism. This review summarized the latest developments in Mg-based metal implants and various molecular mechanisms of Mg ions regulating bone metabolism, which is beneficial to further promote the translation of Mg based implants in the clinic and is able to provide a strong basis for the clinical application of Mg based implants.

Safety of terminally gamma-ray-sterilized screws coated with fibroblast growth factor 2-calcium phosphate composite layers in non-human primates.

Screws coated with fibroblast growth factor 2 (FGF-2)-calcium phosphate (CP) composite layers exhibit enhanced soft tissue and bone formation and angiogenesis because of the biological activity of FGF-2. Furthermore, the mitogenic activity of the FGF-2 within the composite layers remains unchanged after gamma-ray sterilization, which may improve the storage stability prior to clinical use. However, the in vivo safeties of these screws as spinal implants remain unknown. Here, a randomized controlled trial, involving non-human primates, investigated the safety of using FGF-2-CP composite layer-coated screws after either gamma-ray sterilization or aseptic processing. Titanium alloy screws coated with FGF-2-CP composite layers and subjected to either gamma-ray sterilization at 25kGy (GS group) or aseptic storage (AS group) were implanted into the vertebral bodies of two cynomolgus monkeys exceeding 12weeks (day 99). Physiological, histological, and radiographic investigations were performed to evaluate the safeties of the screws. There were no serious adverse events, such as surgical site infection, significant loss of body weight, or abnormal blood test results. No radiolucent areas were observed around the screws from the GS or AS group throughout the study. In the intraosseous region, no significant differences were observed in bone and fibrous tissue apposition rates and rate of bone formation between the two groups (p = 0.49, 0.77, and 0.11, respectively). Neither tumor lesions nor accumulation of lymphocytes and neutrophils were observed in either group. Our data suggest that FGF-2-CP composite layer-coated screws subjected to terminal gamma-ray sterilization are as safe as those fabricated in aseptic processing.

TGFβ1-modified MSC-derived exosome attenuates osteoarthritis by inhibiting PDGF-BB secretion and H-type vessel activity in the subchondral bone

BackgroundGreater bone resorption increases TGF-β1 release and nestin-positive BMSC recruitment to the subchondral bone marrow, leading to excessive subchondral osteophyte formation and severe wear to articular cartilage. Our previous research demonstrated that BMSCs-ExoTGF-β1 attenuated cartilage damage in osteoarthritis (OA) rats through carrying highly expressed miR-135b. MethodsThe bone marrow mesenchymal stem cells (BMSCs) were isolated from mouse bone marrow, and BMSC-derived exosomes (BMSCs-Exo) were isolated from BMSCs. OA mouse models were established by anterior cruciate ligament transection (ACLT) surgery on the left knee of mice. Then we explored the therapeutic effect of BMSCs-ExoTGF-β1 on ACLT mice. ResultsBMSCs-ExoTGF-β1 attenuated cartilage damage in OA mice in vivo by ameliorating articular cartilage degeneration and suppressing calcification of the cartilage zone. BMSCs-ExoTGF-β1 also inhibited osteoclastogenesis by suppressing the MAPK pathway in vitro. Micro-computed tomography indicated that BMSCs-ExoTGF-β1 impeded uncoupled subchondral bone remodeling. BMSCs-ExoTGF-β1 also reduced CD31hiEmcnhi vessel activity in the subchondral bone and attenuated OA pain behaviors. ConclusionsIn conclusion, BMSCs-ExoTGF-β1 maintains the microarchitecture, inhibits abnormal angiogenesis in subchondral bone and exerts protective effect against OA-induced pain and bone resorption on ACLT mice. Data availabilityThe datasets are available from the corresponding author on reasonable request.

Copper-containing titanium alloys promote angiogenesis in irradiated bone through releasing copper ions and regulating immune microenvironment.

Poor vascularization was demonstrated as a factor inhibiting bone regeneration in patients receiving radiotherapy. Various copper-containing materials have been reported to increase angiogenesis, therefore might improve bone formation. In this study, a Ti6Al4V-1.5Cu alloy was prepared using selective laser melting (SLM) technology. The immunomodulatory and pro-angiogenic effects of the Ti6Al4V-1.5Cu alloys were examined. In vitro, Ti6Al4V-1.5Cu stimulated vascular formation by restraining inflammatory factors and provoking angiogenic factors in non-irradiated and irradiated macrophages. In vivo, the angiogenic effects of the Ti6Al4V-1.5Cu alloy were confirmed using an irradiated rat femur defect model. Moreover, we found that the biological effects of the Ti6Al4V-1.5Cu alloy were partially due to the release of copper ions and associated with PI3K-Akt signaling pathway. In conclusion, this study indicated the potential of the Ti6Al4V-1.5Cu alloy to promote angiogenesis by releasing copper ions and inhibiting inflammation in normal and irradiated tissues.

Gelatin/sodium alginate composite hydrogel with dynamic matrix stiffening ability for bone regeneration

Bone regeneration is largely affected by mechanical cues in the surrounding microenvironment, and natural new bone formation is an uninterrupted stiffening physiological process. Although cells biological behaviors can be regulated by the dynamic mechanical microenvironment, it is still unclear how dynamic matrix stiffening influences mesenchymal stem cells (MSCs) differentiation and bone formation. In this study, static and dynamic stiffening hydrogels were prepared to evaluate the activity and osteogenic differentiation of MSCs in vitro and the repair ability of calvarial defects in vivo. It was found that the dynamic hydrogel (Dynamic) could be uninterrupted stiffened from 14.63 ± 1.18 kPa to 68.37 ± 4.99 kPa within 7 days. The stiffness of static hydrogels was 10.20 ± 2.39 kPa (Low) and 66.30 ± 4.40 kPa (High). The results indicated that the Dynamic hydrogel promoted the osteogenic differentiation of MSCs compared with the Low and High hydrogels. Notably, in calvarial defect model, the Dynamic group could enhance bone regeneration and promote angiogenesis. The dynamic stiffening hydrogel can promote the bone formation and angiogenesis by activating the extracellular matrix remodeling, which is a potential regeneration composite material for bone defect repair. This strategy for mechanically modifying hydrogel with dynamic stiffening may help to understand how dynamic matrix mechanics guide stem cell fate and bone regeneration.