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One specific capillary subtype, termed type H vessel, has been found with unique functional characteristics in coupling angiogenesis with osteogenesis. Researchers have fabricated a variety of tissue engineering scaffolds to enhance bone healing and regeneration through the accumulation of type H vessels. However, only a limited number of reviews discussed the tissue engineering strategies for type H vessel regulation. The object of this review is to summary the current utilizes of bone tissue engineering to regulate type H vessels through various signal pathways including Notch, PDGF-BB, Slit3, HIF-1α, and VEGF signaling. Moreover, we give an insightful overview of recent research progress about the morphological, spatial and age-dependent characteristics of type H blood vessels. Their unique role in tying angiogenesis and osteogenesis together via blood flow, cellular microenvironment, immune system and nervous system are also summarized. This review article would provide an insight into the combination of tissue engineering scaffolds with type H vessels and identify future perspectives for vasculized tissue engineering research., (© 2023 Wiley Periodicals LLC.)

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 Zn 2+ , 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 Zn 2+ -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.

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.

Owing to the insufficient guidance of new bone formation in orthopedic and craniomaxillofacial surgery, construction of a guided bone regeneration membrane to support vascularized bone regeneration remains a challenge. Herein, an electrospun asymmetric double-layer polycaprolactone/collagen (PCL/Col) membrane modified by metal-organic framework (MOF) crystals is developed. The optimization of the PCL/Col weight ratio (1:1 and 1:1.5) enables the composite membrane with a balanced tensile strength (only fell by 49.9% in wet conditions) and a controlled degradation rate (completely degraded at 12 weeks). The MOF crystals can provide a pH-responsive release of Zn 2+ ions. In vitro experiments indicate that the barrier layer functions to prevent the infiltration of fibrous connective tissue. The MOF crystal layer functions to enhance osteogenesis and angiogenesis in vitro. Using a rat calvarial defect model, the MOF crystals exhibit a sign of osteoinductivity along with blood vessel formation after 8 weeks post-surgery. Strikingly, when assessed in a chick chorioallantoic membrane model, the MOF modified membrane demonstrates a significant angiogenic response, which can be envisaged as its outstanding merits over the commercially Col membrane. Therefore, the MOF crystals represent an exciting biomaterial option, with neovascularization capacity for bone tissue engineering and regenerative medicine., (© 2021 Wiley-VCH GmbH.)

Bone substitute biomaterials, whose compositions and structures both play vital roles in bone defect healing, hold promising prospects in the clinical treatment of bone defects. Three-dimensional (3D) printed porous scaffolds incorporating osteoinductive components are considered as ideal bone grafts, because of the accurate control of structure parameters and the capacity to enhance bone tissue regeneration. Our previous studies demonstrated that nanoscale zeolitic imidazolate framework-8 (nanoZIF-8), a subclass of metal organic frameworks (MOFs), presented minimal cytotoxicity, inhibited bacterial activities, and promoted osteogenesis both in vitro and in vivo. However, the application of nanoZIF-8 in the 3D printed scaffold system remains unknown. In this study, nanoZIF-8 was incorporated into composite scaffolds composed of polycaprolactone (PCL) and dicalcium phosphate dihydrate (DCPD) via extrusion-based 3D printing technology. The results revealed that the composite scaffolds possessed increased mechanical strength and exhibited homogeneous structure with highly interconnected macropores. In vitro studies indicated that scaffolds showed biocompatibility to bone mesenchymal stem cells (BMSCs), significantly up-regulated the expression of osteogenesis-related genes and proteins, and facilitated the extracellular matrix mineralization. In vivo results showed that 3D printed porous scaffolds promoted new bone formation and enhanced micro-architecture at the critical defect sites (Φ10 mm) in rabbits, compared with the blank control group. Moreover, composite scaffolds significantly improved calvarial defect healing in comparison with scaffolds without nanoZIF-8 incorporation. In summary, nanoZIF-8 modified 3D printed porous composite scaffolds demonstrated great potential in the treatment of critical-sized bone defects, proving the effectiveness of MOF incorporation in 3D printed composite scaffolds to promote osteogenesis in the field of bone tissue engineering.

As a new class of crystalline nanoporous materials, metal-organic frameworks (MOFs) have recently been used for biomedical applications due to their large surface area, high porosity, and theoretically infinite structures. To improve the biological performance of titanium, MOF films were applied to surface modification of titanium. Zn-based MOF films composed of zeolitic imidazolate framework-8 (ZIF-8) crystals with nanoscale and microscale sizes (nanoZIF-8 and microZIF-8) were prepared on porous titanium surfaces by hydrothermal and solvothermal methods, respectively. The ZIF-8 films were characterized by powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR), and scanning electron microscopy (SEM). The nanoZIF-8 film exhibited good biocompatibility, whereas the microZIF-8 film showed obvious cytotoxicity to MG63 cells. Compared to pure titanium and alkali- and heat-treated porous titanium, the nanoZIF-8 film not only enhanced alkaline phosphatase (ALP) activity, extracellular matrix mineralization, and expression of osteogenic genes (ALP, Runx2) in MG63 cells but also inhibited the growth of Streptococcus mutans. These results indicate that MOF films or coatings may be promising candidates for bone tissue engineering. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 834-846, 2017., (© 2016 Wiley Periodicals, Inc.)

Nanoscale zeolitic imidazolate framework-8 coating with certain density can significantly improve the osteogenic activity of titanium implants both in vitro and in vivo. In this study, we loaded dimethyloxalylglycine into zeolitic imidazolate framework-8-modified implants (Z-AHT) to enhance the angiogenic activity, and the obtained products were denoted as D-AHT. Firstly, we characterized the specimens via scanning electron microscopy, Fourier transform infrared spectroscopy, powder X-ray diffraction, and surface contact angle. Then, the release kinetics of both zinc ions and dimethyloxalylglycine were investigated. To illustrate the combined effects of surface topography and chemistry (zeolitic imidazolate framework-8 and dimethyloxalylglycine) on osteogenic and angiogenic activity, MC3T3-E1 preosteoblast cells and human umbilical vein endothelial cells were respectively cultured on D-AHT. Pure Ti and Z-AHT were designated as control groups. As evidenced by the expression of osteogenic genes (Alp, Col1, Opg, and Runx2) and the secretion of ALP protein, D-AHT showed comparable osteogenic activity to Z-AHT which was better than that of Ti. Further angiogenesis assay revealed a better human umbilical vein endothelial cell migration on D-AHT, suggesting that D-AHT can be an attractive candidate for application in implant surface modification. [ABSTRACT FROM AUTHOR]

Piezoelectric biomaterials are advantageous in terms of easy generation of transduced bioelectrical signals to skeleton systems in response to body movements or external stimulations. In the bone formation process, the coupling of angiogenesis-osteogenesis is crucial but the effect of piezoelectric biomaterials on angiogenesis and mechanism of stress-transformed electrical signals affecting vascular cells remain elusive. In this work, hierarchically architected polyvinylidene fluoride (PVDF) foam fabricated by solid-state shearing milling was further decorated with ZIF-8 nanocrystals. The unique hierarchical porous structure realizes stable voltage outputs up to 10 V without polarization. The electric potential of piezoelectric PVDF affected molecular trajectory of Zn2+ released from ZIF-8, leading to Zn2+ enrichment around the PVDF surface. Under piezoelectric condition, PVDF/ZIF-8 foams promoted in-vitro angiogenic and osteogenic activity as well as antibacterial effect. Upon calvarium and femur defect repair, PVDF/ZIF-8 piezoelectric foams also guided vascularized bone regeneration through micro-current stimulation and Zn2+ enrichment. RNA-seq demonstrated PVDF/ZIF-8 piezoelectric foam mainly up-regulated ATP coupled cation transmembrane transportation in vascular endothelial cells, which enhanced cellular uptake of Zn2+, indicating the synergistic effect of piezoelectric PVDF and bioactive ZIF-8. This work offers a preliminary explanation for mechanism of angiogenesis-osteogenesis coupling of PVDF/ZIF-8 foam nanogenerator and provides a valuable complement to clinical treatment strategies for bone defect repair. [Display omitted] • Hierarchically architected PVDF foams affect the molecular trajectory of Zn2+. • PVDF/ZIF-8 foams reconstruct the physiological potential of bone defect sites and promote angiogenesis and osteogenesis. • PVDF/ZIF-8 piezoelectric foams up-regulate ATP coupled cation transmembrane transportation in vascular endothelial cells. [ABSTRACT FROM AUTHOR]