Metal-Organic Framework-Based Nanomaterials for Regulation of the Osteogenic Microenvironment.

As the global population ages, bone diseases have become increasingly prevalent in clinical settings. These conditions often involve detrimental factors such as infection, inflammation, and oxidative stress that disrupt bone homeostasis. Addressing these disorders requires exogenous strategies to regulate the osteogenic microenvironment (OME). The exogenous regulation of OME can be divided into four processes: induction, modulation, protection, and support, each serving a specific purpose. To this end, metal-organic frameworks (MOFs) are an emerging focus in nanomedicine, which show tremendous potential due to their superior delivery capability. MOFs play numerous roles in OME regulation such as metal ion donors, drug carriers, nanozymes, and photosensitizers, which have been extensively explored in recent studies. This review presents a comprehensive introduction to the exogenous regulation of OME by MOF-based nanomaterials. By discussing various functional MOF composites, this work aims to inspire and guide the creation of sophisticated and efficient nanomaterials for bone disease management.

Multi-Mechanism Antibacterial Strategies Enabled by Synergistic Activity of Metal-Organic Framework-Based Nanosystem for Infected Tissue Regeneration.

Drug-resistant bacterial infection impairs tissue regeneration and is a challenging clinical problem. Metal-organic frameworks (MOFs)-based photodynamic therapy (PDT) opens up a new era for antibiotic-free infection treatment. However, the MOF-based PDT normally encounters limited photon absorbance under visible light and notorious recombination of photogenerated holes and electrons, which significantly impede their applications. Herein, a MOFs-based nanosystem (AgNPs@MOFs) with enhanced visible light response and charge carrier separation is developed by modifying MOFs with silver nanoparticles (AgNPs) to improve PDT efficiency. The AgNPs@MOFs with enhanced photodynamic performance under visible light irradiation mainly disrupt bacteria translation process and the metabolism of purine and pyrimidine. In addition, the introduction of AgNPs endows nanosystems with chemotherapy ability, which causes destructive effect on bacterial cell membrane, including membrane ATPase protein and fatty acids. AgNPs@MOFs show excellent synergistic drug-resistant bacterial killing efficiency through multiple mechanisms, which further restrain bacterial resistance. In addition, biocompatible AgNPs@MOFs pose potential tissue regeneration ability in both Methicillin-resistant Staphylococcus aureus (MRSA)-related soft and hard tissue infection. Overall, this study provides a promising perspective in the exploration of AgNPs@MOFs as nano antibacterial medicine against drug-resistant bacteria for infected tissue regeneration in the future.

Biomechanical behavior analysis of four types of short implants with different placement depths using the finite element method.

STATEMENT OF PROBLEM: The clinical application of short implants has been increasing. However, studies on the marginal bone loss of short implants are sparse, and clinicians often choose short implants based on their own experience rather than on scientific information. PURPOSE: The purpose of this finite element analysis study was to evaluate the microstrain-stress distribution in the peri-implant bone and implant components for 4 types of short implants at different placement depths of platform switching. MATERIAL AND METHODS: By using short implants as prototypes, 4 short implant models were 1:1 modeled. The diameter and length of the implants were 5×5, 5×6, 6×5, and 6×6 mm. The restoration was identical for all implants. Three different depths of implant platform switching were set: equicrestal, 0.5-mm subcrestal, and 1-mm subcrestal. The models were then assembled and assigned an occlusal force of 200 N (vertical or 30-degree oblique). A finite element analysis was carried out to evaluate the maximum equivalent elastic strain and von Mises stress in the bone and the stress distribution in the implant components. RESULTS: The 5×5 implant group showed the largest intraosseous strain (21.921×103 µÎµ). A 1-mm increase in implant diameter resulted in a 17.1% to 37.4% reduction in maximum intraosseous strain when loaded with oblique forces. The strain in the bone tended to be much smaller than the placement depth at the equicrestal and 0.5-mm subcrestal positions than that at the 1-mm subcrestal position, especially under oblique force loading, with an increase of approximately 37.4% to 81.8%. In addition, when the cortical bone thickness was less than 4 mm, 5×6 implants caused significantly higher intraosseous stresses than 6×6 implants. CONCLUSIONS: Large implant diameters, rather than long implants, led to reduced intraosseous strain, especially under oblique loading. Regarding the implant platform switching depth, the short implant showed small intraosseous strains when the platform switching depth was equicrestal or 0.5-mm subcrestal.

pH-Triggered Size-Tunable Silver Nanoparticles: Targeted Aggregation for Effective Bacterial Infection Therapy.

The rapid spread of drug-resistant pathogens threatens human health. To address the current antibacterial dilemma, the development of antibiotic-free strategies using nanotechnology is imperative. In this study, silver nanoparticles (Ag-P&C NPs) with pH-sensitive charge reversal and self-aggregation capacities are successfully synthesized. In the acidic microenvironment of bacterial biofilms, protonation of the surface peptide enhances the affinity of Ag-P&C NPs for bacteria, which can make Ag-P&C NPs prone to target and penetrate into biofilms, and the self-aggregated capacity helps Ag-P&C NPs remain in biofilms for a long time to disrupt bacterial biofilm formation. In addition, biocompatible Ag-P&C NPs are utilized in three types of bacteria-infected animal models. They exhibit an excellent performance in killing bacteria, inhibiting plaque biofilms, and ameliorating inflammatory responses. In conclusion, this study offers new insights into antibiotic-free antibacterial strategies, and exhibits promising application prospects.

An implant-supported overdenture for a mandibular defect after tumor resection guided by 3-dimensional finite element analysis: A clinical report.

This clinical report describes the rehabilitation of a mandibular defect after tumor resection with an implant-supported overdenture and the attachment selection as guided by 3-dimensional finite element analysis. Autologous bone grafting was declined by the patient who demanded the restoration of lateral appearance and mastication function. Three implants were placed based on the condition of the bone, and a satisfactory definitive prosthesis was provided that corresponded with the results of the finite element analysis.

Comparative analyses of the soft tissue interfaces around teeth and implants: Insights from a pre-clinical implant model.

AIM: To evaluate the similarities and differences in barrier function of a peri-implant epithelium (PIE) versus a native junctional epithelium (JE). MATERIALS AND METHODS: A mouse model was used wherein titanium implants were placed sub-occlusally in healed extraction sites. The PIE was examined at multiple timepoints after implant placement, to capture and understand the temporal nature of its assembly and homeostatic status. Mitotic activity, hemidesmosomal attachment apparatus, and inflammatory responses in the PIE were compared against a JE. Additionally, we evaluated whether the PIE developed a Wnt-responsive stem cell niche like a JE. RESULTS: The PIE developed from oral epithelium (OE) that had, by the time of implant placement, lost all characteristics of a JE. Compared with a JE, an established PIE had more proliferating cells, exhibited lower expression of attachment proteins, and had significantly more inflammatory cells in the underlying connective tissue. Wnt-responsive cells in the OE contributed to an initial PIE, but Wnt-responsive cells and their descendants were lost as the PIE matured. CONCLUSIONS: Although histologically similar, the PIE lacked a Wnt-responsive stem cell niche and exhibited characteristics of a chronically inflamed tissue. Both features contributed to suboptimal barrier functions of the PIE compared with a native JE.

Formation and regeneration of a Wnt-responsive junctional epithelium.

AIM: To identify the molecular mechanisms mediating the persistent defensive functions of the self-renewing junctional epithelium (JE). MATERIALS AND METHODS: Two strains of Wnt reporter mice, Axin2CreErt2/+ ;R26RmTmG/+ and Axin2LacZ/+ , were employed, along with three clinically relevant experimental scenarios where the function of the JE is disrupted: after tooth extraction, after a partial gingivectomy, and after a complete circumferential gingivectomy. RESULTS: Using transgenic Wnt reporter strains of mice, we established the JE is a Wnt-responsive epithelium beginning at the time of its formation and that it maintains this status into adulthood. After tooth extraction, progeny of the initial Wnt-responsive JE population directly contributed to healing and ultimately adopted an oral epithelium (OE) phenotype. In the traditional partial gingivectomy model, the JE completely regenerated and did so via progeny of the original Wnt-responsive population. However, following circumferential gingivectomy, the OE was incapable of re-establishing a functional JE. CONCLUSIONS: A Wnt-responsive niche at the interface between tooth and oral epithelia is required for a functional JE.

Internal adaptation of cobalt-chromium posts fabricated by selective laser melting technology.

STATEMENT OF PROBLEM: Selective laser melting (SLM) has become popular in prosthetic dentistry. However, only limited information is available for the internal adaptation of cobalt-chromium (Co-Cr) posts fabricated by SLM. PURPOSE: The purpose of this in vitro study was to investigate the internal adaptation of Co-Cr metal posts fabricated by SLM technique. MATERIAL AND METHODS: Thirty-six Co-Cr metal posts were fabricated by conventional casting, subtractive computer-aided design and computer-aided manufacturing (CAD-CAM), and additive CAD-CAM, by making an impression from a standardized model of a tooth with a single root canal. Posts and the dies were bonded with cement. Specimens were then sectioned horizontally by using a grinding and polishing machine, and 3 different cross-sections of each post were chosen to represent the apical, middle, and coronal regions. The areas of cement were photographed by using a stereomicroscope at an original magnification of ×32 and measured using image-measuring software. From each group, 1 specimen was randomly selected and observed by using scanning electron microscopy. One-way ANOVA and Tukey honestly significant difference test were performed to identify differences among groups with regard to internal adaptation (α=.05). RESULT: The internal adaptation of the SLM group did not differ from that of the CAD-CAM milling group at 3 cross-section levels (P>.05). At the apical and coronal cross-section levels, the cement area of SLM group was smaller than that of the cast group (P<.05). However, at the middle cross-section level, the cement area of the cast group was significantly smaller than that of the SLM group (P<.05). Use of scanning electron microscopy showed both the SLM group and the CAD-CAM milling group exhibited homogeneous microstructures. However, the cast group showed a typical discontinuous dendritic solidification microstructure. CONCLUSIONS: The internal adaptation of SLM was not inferior to that of the CAD-CAM milling group or the cast group. The SLM technique seems a promising choice for fabricating dental posts.

A Systematic Review of the Survival and Complication Rates of All-Ceramic Resin-Bonded Fixed Dental Prostheses.

PURPOSE: The aim of this systematic review was to investigate the survival and complication rates of all-ceramic resin-bonded fixed dental prostheses (RBFDPs). MATERIALS AND METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were applied. A systematic search was conducted by an electronic search in PubMed, EMBASE, Cochrane Library, and CNKI databases complemented by a manual search. Only clinical studies on all-ceramic RBFDPs with a mean follow-up period of at least 3 years qualified for data analyses. RESULTS: Among 1503 screened articles, one randomized controlled trial (RCT) and seven prospective or retrospective cohort studies were included in this study. The estimated 5-year survival rate of all-ceramic RBFDPs was 91.2%. Debonding and framework fracture were the two most frequent technical complications, and the estimated 5-year debonding rate and fracture rate were 12.2% and 4.8%, respectively. Additionally, cantilevered all-ceramic RBFDPs had a higher survival rate (p < 0.01), lower debonding rate, (p < 0.05), and fracture rate (p < 0.01) compared with two-retainer all-ceramic RBFDPs. Zirconia ceramic RBFDPs had a lower incidence of failure but a higher debonding rate compared with glass-ceramic RBFDPs (p < 0.01). CONCLUSION: Within the limitations of this systematic review, although all-ceramic RBFDPs have a favorable 5-year survival rate, this rate cannot represent the complete success of the treatment, since it may include typical complications such as debonding and fractures. There is an urgent need for long-term clinical studies, especially for well-designed RCTs on all-ceramic RBFDPs.

Practice-based preclinical instruction for gingival displacement with animal models.

STATEMENT OF PROBLEM: Gingival displacement is recognized as a substantive and difficult procedure in fixed prosthodontics. However, a realistic simulation of gingival displacement is unavailable for preclinical dental students. PURPOSE: The purpose of this study was to evaluate whether practice-based preclinical instruction of gingival displacement with animal models could improve students' skill in patient care. MATERIAL AND METHODS: Isolated bovine mandibles (calves were younger than 6 months of age) and isolated porcine hemimandibles were prepared for this study. Twenty-two general dental practitioners with at least 5 years of experience were randomly selected and assigned to perform gingival displacement on both bovine and porcine jaws. Those practitioners were then asked to assess the clinical similarity of gingival displacement between human teeth and animal teeth. The data were analyzed with the paired t test (α=.05). Upon confirmation that the animal jaw provided a similar gingival displacement environment to that of human teeth, 80 predoctoral dental students were enrolled and randomized into 2 groups. Half of them underwent the new practice-based instruction, while the others underwent traditional preclinical teaching only (lectures, online video, or live demonstration). After preclinical learning, clinical performance in gingival displacement was evaluated for all students in terms of the effect of gingival displacement and quality of impression. The data were analyzed with the chi-square test (α=.05). RESULTS: The dentogingival environments of porcine and bovine jaws were similar to those of human jaws, and no significant difference was detected between these 2 animal models (P=.178). A significant increase occurred in the acceptable rate of the effect of gingival displacement (P<.001) and the quality of impression (P<.001) among students who received the practice-based instruction compared with those who received traditional teaching. CONCLUSIONS: These findings suggest that this practice-based instruction of gingival displacement with animal models is an effective method of promoting dental students' learning of gingival displacement.

Apoptotic Extracellular Vesicles Derived from Human Umbilical Vein Endothelial Cells Promote Skin Repair by Enhancing Angiogenesis: From Death to Regeneration.

Purpose: The promotion of angiogenesis is an effective strategy for skin wound repair. While the transplantation of endothelial cells has shown promise in vascularization, the underlying mechanism remains unclear. Recent studies have suggested that transplanted cells undergo apoptosis in a short period and release apoptotic extracellular vesicles (ApoEVs) that may have therapeutic potential. Methods: In this study, we isolated ApoEVs from human umbilical vein endothelial cells (HUVECs) and characterized their properties. In vitro, we assessed the effects of ApoEVs on the proliferation, migration, and differentiation of endothelial cells and fibroblasts. In vivo, we investigated the therapeutic role of ApoEVs-AT in full-thickness skin wounds, evaluating wound closure rate, re-epithelialization, granulation tissue formation, vascularization, scar area, and collagen 3(Col3)/collagen 1(Col 1) ratio. Results: ApoEVs derived from HUVECs displayed typical characteristics. In vitro, ApoEVs significantly enhanced the proliferation, migration, tube formation, and expression of angiogenic-related genes in endothelial cells and slightly promoted the proliferation and migration of fibroblasts. In vivo, ApoEVs improved the wound closure rate, re-epithelialization, the formation of granulation tissue, and vascularization. Besides, ApoEVs reduced scar formation, accompanied by an increase in the Col 3/ Col 1 ratio. Conclusion: Given their abundant source and effectiveness, this study provided a novel approach for angiogenesis in tissue regeneration and deepened the understanding of from death to regeneration.

The development of magnesium-based biomaterials in bone tissue engineering: A review.

Bone regeneration is a vital clinical challenge in massive or complicated bone defects. Recently, bone tissue engineering has come to the fore to meet the demand for bone repair with various innovative materials. However, the reported materials usually cannot satisfy the requirements, such as ideal mechanical and osteogenic properties, as well as biocompatibility at the same time. Mg-based biomaterials have considerable potential in bone tissue engineering owing to their excellent mechanical strength and biosafety. Moreover, the biocompatibility and osteogenic activity of Mg-based biomaterials have been the research focuses in recent years. The main limitation faced in the applications of Mg-based biomaterials is rapid degradation, which can produce excessive Mg2+ and hydrogen, affecting the healing of the bone defect. In order to overcome the limitations, researchers have explored several ways to improve the properties of Mg-based biomaterials, including alloying, surface modification with coatings, and synthesizing other composite materials to control the degradation rate upon implantation. This article reviewed the osteogenic mechanism and requirement for appropriate degradation rate and focused on current progress in the biomedical use of Mg-based biomaterials to inspire more clinical applications of Mg in bone regeneration in the future.

Recent advances of hydrogels as smart dressings for diabetic wounds.

Chronic diabetic wounds have been an urgent clinical problem, and wound dressings play an important role in their management. Due to the design of traditional dressings, it is difficult to achieve adaptive adhesion and on-demand removal of complex diabetic wounds, real-time monitoring of wound status, and dynamic adjustment of drug release behavior according to the wound microenvironment. Smart hydrogels, as smart dressings, can respond to environmental stimuli and achieve more precise local treatment. Here, we review the latest progress of smart hydrogels in wound bandaging, dynamic monitoring, and drug delivery for treatment of diabetic wounds. It is worth noting that we have summarized the most important properties of smart hydrogels for diabetic wound healing. In addition, we discuss the unresolved challenges and future prospects in this field. We hope that this review will contribute to furthering progress on smart hydrogels as improved dressing for diabetic wound healing and practical clinical application.

Surface Modification of Titanium Implants by Metal Ions and Nanoparticles for Biomedical Application.

Implant surface modification can improve osseointegration and reduce peri-implant inflammation. Implant surfaces are modified with metals because of their excellent mechanical properties and significant functions. Metal surface modification is divided into metal ions and nanoparticle surface modification. These two methods function by adding a finishing metal to the surface of the implant, and both play a role in promoting osteogenic, angiogenic, and antibacterial properties. Based on this, the nanostructural surface changes confer stronger antibacterial and cellular affinity to the implant surface. The current paper reviews the forms, mechanisms, and applications of nanoparticles and metal ion modifications to provide a foundation for the surface modification of implants.

Zinc-based biomaterials for bone repair and regeneration: mechanism and applications.

Zinc (Zn) is one of the most important trace elements in the human body and plays a key role in various physiological processes, especially in bone metabolism. Zn-containing materials have been reported to enhance bone repair through promoting cell proliferation, osteogenic activity, angiogenesis, and inhibiting osteoclast differentiation. Therefore, Zn-based biomaterials are potential substitutes for traditional bone grafts. In this review, the specific mechanisms of bone formation promotion by Zn-based biomaterials were discussed, and recent developments in their application in bone tissue engineering were summarized. Moreover, the challenges and perspectives of Zn-based biomaterials were concluded, revealing their attractive potential and development directions in the future.

Alkaline earth metals for osteogenic scaffolds: From mechanisms to applications.

Regeneration of bone defects is a significant challenge today. As alternative approaches to the autologous bone, scaffold materials have remarkable features in treating bone defects; however, the various properties of current scaffold materials still fall short of expectations. Due to the osteogenic capability of alkaline earth metals, their application in scaffold materials has become an effective approach to improving their properties. Furthermore, numerous studies have shown that combining alkaline earth metals leads to better osteogenic properties than applying them alone. In this review, the physicochemical and physiological characteristics of alkaline earth metals are introduced, mainly focusing on their mechanisms and applications in osteogenesis, especially magnesium (Mg), calcium (Ca), strontium (Sr), and barium (Ba). Furthermore, this review highlights the possible cross-talk between pathways when alkaline earth metals are combined. Finally, some of the current drawbacks of scaffold materials are enumerated, such as the high corrosion rate of Mg scaffolds and defects in the mechanical properties of Ca scaffolds. Moreover, a brief perspective is also provided regarding future directions in this field. It is worth exploring that whether the levels of alkaline earth metals in newly regenerated bone differs from those in normal bone. The ideal ratio of each element in the bone tissue engineering scaffolds or the optimal concentration of each elemental ion in the created osteogenic environment still needs further exploration. The review not only summarizes the research developments in osteogenesis but also offers a direction for developing new scaffold materials.

Alginate-based biomaterial-mediated regulation of macrophages in bone tissue engineering.

Many studies in the bone tissue engineering field have focused on the interactions between materials and bone marrow stem cells. With the development of osteoimmunology, the immune cells' essential role in biomaterial-mediated osteogenesis has increasingly been recognized. As a promising therapeutic candidate for bone defects due to their prominent biocompatibility, tuneability, and versatility, it is necessary to develop alginate-based biomaterials that can regulate immune cells, especially macrophages. Moreover, modified alginate-based biomaterials may facilitate better regulation of macrophage phenotypes by the newly endowed physicochemical properties, including stiffness, porosity, hydrophilicity, and electrical properties. This review summarizes the role of macrophages in bone regeneration and the recent research progress related to the effects of alginate-based biomaterials on macrophages applied in bone tissue engineering. This review also emphasizes the strategies adopted by material design to regulate macrophage phenotypes, the corresponding macrophage responses, and their contribution to osteogenesis.

Vascular and lymphatic heterogeneity and age-related variations of dental pulps.

OBJECTIVES: Dental pulp tissue is highly vascularized. However, age-related vascular changes of the dental pulp in mice and humans remain poorly understood. We modified a novel tissue clearing method, mapped the vasculature, pericytes, and perivascular matrix in the dental pulp via high-resolution 3D imaging. METHODS: We isolated young and aged pulps from mouse teeth, and mapped vasculature through a high-resolution thick frozen sections imaging method and a modified tissue clearing method. Human dental pulps were also mapped for vasculature studying. Furthermore, young and aged human dental pulps were collected and were compared with mouse pulps through RNA- sequencing. RESULTS: Five vascular subtypes of blood vessels were found in the mouse dental pulp, which constituted the arterioles-capillaries-venules network. The density of capillaries and venules of molars declined obviously in aged mice. Among the age-dependent changes in the perivascular pulp matrix, the perivascular macrophages remarkably increased, lymphatic capillaries increased, while the nerves and extracellular matrix remained unchanged. Furthermore, the vascular patterns of human formed a complex vascular network. Both mouse and human dental pulps exhibited an inflammaging state. TNF pathway and Rap1 pathway might become promising targets for combating inflammaging and promoting angiogenesis. CONCLUSIONS: Five subtypes of blood vessels were identified within the dental pulp of mice. Notably, the density of capillaries and venules in pulps of aged mice was reduced. Furthermore, partial similarities were observed in the vascular patterns between the dental pulps of humans and mice. RNA-sequencing analysis revealed that both mouse and human dental pulps exhibit indications of an inflammaging state. CLINICAL SIGNIFICANCE: This study may contribute to unraveling potential therapeutic targets in the pulp regeneration and treatment of relevant diseases in the elderly.

Blue-ringed octopus-inspired microneedle patch for robust tissue surface adhesion and active injection drug delivery.

Intratissue topical medication is important for the treatment of cutaneous, mucosal or splanchnic diseases. However, penetrating surface barriers to providing adequate and controllable drug delivery while guaranteeing adhesion in bodily fluids remains challenging. Here, the predatory behavior of the blue-ringed octopus inspired us with a strategy to improve topical medication. For effective intratissue drug delivery, the active injection microneedles were prepared in a manner inspired by the teeth and venom secretion of blue-ringed octopus. With on demand release function guided by temperature-sensitive hydrophobic and shrinkage variations, these microneedles can supply adequate drug delivery at an early stage and then achieve the long-term release stage. Meanwhile, the bionic suction cups were developed to facilitate microneedles to stay firmly in place (>10 kilopascal) when wet. With wet bonding ability and multiple delivery mode, this microneedle patch achieved satisfactory efficacy, such as accelerating the ulcers' healing speed or halting early tumor progression.

Drug-Delivery Nanoplatform with Synergistic Regulation of Angiogenesis-Osteogenesis Coupling for Promoting Vascularized Bone Regeneration.

It has been confirmed that substantial vascularization is an effective strategy to heal large-scale bone defects in the field of bone tissue engineering. The local application of deferoxamine (DFO) is among the most common and effective methods for promoting the formation of blood vessels, although its short half-life in plasma, rapid clearance, and poor biocompatibility limit its therapeutic suitability. Herein, zeolitic imidazolate framework-8 (ZIF-8) was selected as a vehicle to extend the half-life of DFO. In the present study, a nano DFO-loaded ZIF-8 (DFO@ZIF-8) drug delivery system was established to promote angiogenesis-osteogenesis coupling. The nanoparticles were characterized, and their drug loading efficiency was examined to confirm the successful synthesis of nano DFO@ZIF-8. Additionally, due to the sustained release of DFO and Zn2+, DFO@ZIF-8 NPs were able to promote angiogenesis in human umbilical vein endothelial cells (HUVECs) culture and osteogenesis in bone marrow stem cells (BMSCs) in vitro. Furthermore, the DFO@ZIF-8 NPs promoted vascularization by enhancing the expression of type H vessels and a vascular network. The DFO@ZIF-8 NPs promoted bone regeneration in vivo by increasing the expression of OCN and BMP-2. RNA sequencing analysis revealed that the PI3K-AKT-MMP-2/9 and HIF-1α pathways were upregulated by DFO@ZIF-8 NPs in HUVECs, ultimately leading to the formation of new blood vessels. In addition, the mechanism by which DFO@ZIF-8 NPs promoted bone regeneration was potentially related to the synergistic effect of angiogenesis-osteogenesis coupling and Zn2+-mediation of the MAPK pathway. Taken together, DFO@ZIF-8 NPs, which were demonstrated to have low cytotoxicity and excellent coupling of angiogenesis and osteogenesis, represent a promising strategy for the reconstruction of critical-sized bone defects.