Search Results (9)

Large segmental bone defects present significant challenges due to the insufficient vascularization of implanted grafts, necessitating advances in vascularized bone tissue engineering. Recent innovations focus primarily on enhancing graft vascularization through advanced biomaterial scaffolds, precise three-dimensional (3D) bioprinting technologies, biochemical interventions, and co-culture techniques. Biomaterial scaffolds featuring microchannels and high-surface-area architectures facilitate endothelial cell infiltration and subsequent vessel formation. Concurrently, sophisticated 3D-bioprinting methods, including inkjet, extrusion, and laser-assisted approaches, enable the precise placement of endothelial and osteogenic cells, promoting anatomically accurate vascular networks. Biochemical strategies that utilize the simultaneous delivery of angiogenic factors (e.g., vascular endothelial growth factor) and osteogenic factors (e.g., bone morphogenetic protein-2) effectively couple angiogenesis and osteogenesis. Additionally, co-culturing mesenchymal stem cells and endothelial progenitors accelerates the development of functional capillary networks. Preclinical studies consistently demonstrate superior outcomes for prevascularized grafts, as evidenced by enhanced vascular inosculation, increased bone formation, and improved mechanical stability compared to non-vascularized controls. These technological advancements collectively represent significant progress toward the clinical translation of engineered vascularized bone grafts capable of addressing complex and previously intractable bone defects. Full article

This study developed electrosprayed deferoxamine (DFO)-loaded poly(lactic-co-glycolic acid) microspheres (DFO-MS) combined with a sucrose acetate isobutyrate (SAIB) depot (DFO-MS@SAIB) for bone-defect repair, targeting the coordinated regulation of angiogenesis and osteogenesis in vascularized bone regeneration—where new blood vessels support functional bone integration. In vitro/in vivo evaluations confirmed its dual pro-angiogenic and pro-osteogenic effects via HIF-1α pathway activation. Background/Objectives: Emerging evidence underscores the indispensability of vascularization in bone-defect repair, a clinical challenge exacerbated by limited intrinsic healing capacity. While autologous grafts and growth-factor-based strategies remain mainstream, their utility is constrained by donor-site morbidity, transient bioactivity, and poor spatiotemporal control over angiogenic–osteogenic coupling. Here, we leveraged DFO, a hypoxia-mimetic HIF-1α stabilizer with angiogenic potential, to engineer an injectable DFO-MS@SAIB depot. This system was designed to achieve sustained DFO release, thereby synchronizing vascular network formation with mineralized tissue regeneration in critical-sized defects. Methods: DFO-MS were fabricated via electrospraying and combined with SAIB (DFO-MS@S) to form an injectable sustained-release depot. Their physicochemical properties, including morphology, encapsulation efficiency, degradation, release kinetics, and rheology, were systematically characterized. In vitro, the angiogenic capacity of HUVECs co-cultured with DFO-MS was evaluated; conditioned HUVECs were then co-cultured with BMSCs to assess the BMSCs’ cytocompatibility and osteogenic differentiation. In vivo bone regeneration in a rat calvarial defect model was evaluated using micro-CT, histology, and immunohistochemistry. Results: The DFO-MS@SAIB system achieved sustained DFO release, stimulating HUVEC proliferation, migration, and tubulogenesis. In a Transwell co-culture model, pretreated HUVECs promoted BMSC migration and osteogenic differentiation via paracrine signaling involving endothelial-secreted factors (e.g., VEGF). HIF-1α pathway activation upregulated osteogenic markers (ALP, Col1a1, OCN), while in vivo experiments demonstrated enhanced vascularized bone regeneration, with significantly increased bone volume/total volume (BV/TV) and new bone area compared with controls. Conclusion: The DFO-MS@SAIB system promotes bone regeneration via sustained deferoxamine release and HIF-1α-mediated signaling. Its angiogenesis–osteogenesis coupling effect facilitates vascularized bone regeneration, thereby offering a translatable strategy for critical-sized bone-defect repair. Full article

Osteogenesis–angiogenesis coupling, a dynamic and coordinated interaction between skeletal and vascular cells, is essential for fracture healing. However, the effects of these cell ratios and their interactions under microfluidic perfusion and paracrine signaling on osteogenesis–angiogenesis coupling have rarely been reported. In this study, dynamic and static models of osteogenesis–angiogenesis coupling were developed and the osteogenic and angiogenic effects of the two models were compared. Static co-cultures of MC3T3-E1 and bEnd.3 cells in Transwell inserts showed a cell ratio-dependent reciprocal relation: a ratio of 1:1 (MC3T3-E1:bEnd.3) favored osteogenesis, whereas a ratio of 2:1 (MC3T3-E1:bEnd.3) promoted angiogenesis. On that basis, we developed an osteogenesis–angiogenesis coupling chip based on microfluidic technology. The microfluidic perfusion within the chip further enhanced the mineralizing effect of osteoblasts and the angiogenic effect of endothelial cells, respectively, and increased the secretion of vascular endothelial growth factor (VEGF) and bone morphogenetic protein-2 (BMP-2) compared to the static Transwell insert model. The results suggest that the microfluidic chip enhanced the potential of osteogenesis–angiogenesis coupling mediated by paracrine signaling. Overall, the chip is not only a powerful model for understanding bone–vascular interaction but also a scalable platform for high-throughput drug screening and personalized therapy development for fractures. Full article

Biogenic hydroxyapatite is known for its osteoinductive potential due to its similarity to human bone and biocompatibility, but insufficient vascularization compared to autogenous bone during early implantation limits bone integration and osteogenesis. Fluorine has been shown to improve hydroxyapatite’s mechanical properties and the coupling of osteogenic and angiogenic cells. In this study, fluorine-modified biogenic hydroxyapatite (FPHA) with varying fluorine concentrations was prepared and tested for its ability to promote vascularized osteogenesis. FPHA prepared in this study retained the natural porous structure of biological cancellous bone and released F⁻ ions when immersed in cell culture medium. The extraction solutions of FPHA0.25 and FPHA0.50 promoted the formation of capillary-like tubes by human umbilical vein endothelial cells (HUVECs), with FPHA0.25 significantly upregulating vegf mRNA and VEGF protein levels in co-cultured human bone marrow mesenchymal stem cells (HBMSCs). Additionally, FPHA0.25 and FPHA0.50 upregulated pdgf-bb mRNA and PDGF-BB protein levels in HUVECs. In vivo experiments using a rabbit cranial defect model demonstrated that FPHA0.25 promoted early bone formation and angiogenesis in the defect area, enhanced VEGF secretion, and increased PDGFR-β expression in endothelial and mesenchymal cells. These findings suggest that fluorine-modified biogenic hydroxyapatite with an optimal fluorine concentration (FPHA0.25) may offer a promising strategy to enhance the body’s innate bone-healing potential by accelerating vascularization. Full article

Osteonecrosis of the femoral head (ONFH) is a vascular disease of unknown etiology and can be categorized mainly into two types: non-traumatic and traumatic ONFH. Thus, understanding osteogenic–angiogenic coupling is of prime importance in finding a solution for the treatment of ONFH. Hydrogels are biomaterials that are similar to the extracellular matrix (ECM). As they are able to mimic real tissue, they meet one of the most important rules in tissue engineering. In ONFH studies, hydrogels have recently become popular because of their ability to retain water and their adjustable properties, injectability, and mimicry of natural ECM. Because bone regeneration and graft materials are very broad areas of research and ONFH is a complex situation including bone and vascular systems, and there is no settled treatment strategy for ONFH worldwide, in this review paper, we followed a top-down approach by reviewing (1) bone and bone grafting, (2) hydrogels, (3) vascular systems, and (4) ONFH and hydrogel use in ONFH with studies in the literature which show promising results in limited clinical studies. The aim of this review paper is to provide the reader with general information on every aspect of ONFH and to focus on the hydrogel used in ONFH. Full article

Bone fracture healing is an overly complex process in which inflammation, osteogenesis, and angiogenesis are tightly coupled, and delayed fracture repair is a very common health risk. One of the major causes of delayed healing is the formation of insufficient vasculature. Precise regulation of blood vessels in bone and their interplay with especially osteogenic processes has become an emerging topic within the last years; nevertheless, regulation of angiogenesis in (early) diseased fracture repair is still widely unknown. Here, we aim to develop an in vitro model for the analysis of early fracture healing which also enables the analysis of angiogenesis as a main influencing factor. As smoking is one of the main risk factors for bone fractures and developing a delay in healing, we model smoking and non-smoking conditions in vitro to analyze diverging reactions. Human in vitro fracture hematomas mimicking smokers’ and non-smokers’ hematomas were produced and analyzed regarding cell viability, inflammation, osteogenic and chondrogenic differentiation, and angiogenic potential. We could show that smokers’ blood hematomas were viable and comparable to non-smokers. Smokers’ hematomas showed an increase in inflammation and a decrease in osteogenic and chondrogenic differentiation potential. When analyzing angiogenesis, we could show that the smokers’ hematomas secrete factors that drastically reduced HUVEC proliferation and tube formation. With an angiogenesis array and gene expression analysis, we could identify the main influencing factors: Anpgt1/2, Tie2, and VEGFR2/3. In conclusion, our model is suitable to mimic smoking conditions in vitro showing that smoking negatively impacts early vascularization of newly formed tissue. Full article

Bone has the intrinsic capacity to regenerate itself, as long as the damage is small, through the sequential stimulation of specific phases, such as angiogenesis followed by osteogenesis. However, when the damage is extensive it is unable to regenerate and bone tissue engineering is used as an alternative. In this study, we developed a platform to allow the triple ion delivery with sequential delivery capacity to potentially stimulate antibacterial, angiogenic and osteogenic processes. The scaffold-based platform consisted of alginate/hydroxyapatite (HA) microparticles embedded in alginate fibers. Firstly, microparticles were developed using different ratios of alginate:HA using the spraying method, resulting in a high reproducibility of the technique. Microparticle size between 100–300 µm and ratio 1:40 resulted in a more spherical morphology and were selected for their incorporation into alginate fiber. Different amounts of copper and cobalt were added with the microparticles and alginate fiber, respectively, were used as model ions which could eventually modulate and mimic antimicrobial and angiogenic processes. Moreover, calcium ion was also incorporated in both, in order to provide the system with potential osteogenic properties together with HA. The multiple delivery of copper, cobalt and calcium released were in the therapeutic range as measured by induced coupled plasma (ICP), providing a promising delivery strategy for tissue engineering. Full article

Bone formation and regeneration is a multistep complex process crucially determined by the formation of blood vessels in the growth plate region. This is preceded by the expression of growth factors, notably the vascular endothelial growth factor (VEGF), secreted by osteogenic cells, as well as the corresponding response of endothelial cells, although the exact mechanisms remain to be clarified. Thereby, coordinated coupling between osteogenesis and angiogenesis is initiated and sustained. The precise interplay of these two fundamental processes is crucial during times of rapid bone growth or fracture repair in adults. Deviations in this balance might lead to pathologic conditions such as osteoarthritis and ectopic bone formation. Besides VEGF, the recently discovered important regulatory and modifying functions of microRNAs also support this key mechanism. These comprise two principal categories of microRNAs that were identified with specific functions in bone formation (osteomiRs) and/or angiogenesis (angiomiRs). However, as hypoxia is a major driving force behind bone angiogenesis, a third group involved in this process is represented by hypoxia-inducible microRNAs (hypoxamiRs). This review was focused on the identification of microRNAs that were found to have an active role in osteogenesis as well as angiogenesis to date that were termed “CouplingmiRs (CPLGmiRs)”. Outlined representatives therefore represent microRNAs that already have been associated with an active role in osteogenic-angiogenic coupling or are presumed to have its potential. Elucidation of the molecular mechanisms governing bone angiogenesis are of great relevance for improving therapeutic options in bone regeneration, tissue-engineering, and the treatment of bone-related diseases. Full article

Angiogenesis and osteogenesis coupling processes are essential for bone regeneration, and human bone marrow stromal cells (hBMSCs) along with endothelial cells (ECs) are crucial participants. Deferoxamine (DFO), a hypoxia-mimetic agent, could activate the hypoxia-inducible factor (HIF)-1α signaling pathway and trigger angiogenic and osteogenic effects in these cells. However, the lifetime of DFO is very short, thus a suitable delivery system is urgently needed. In this study, we encapsulated DFO in Poly(lactide-co-glycolide)-Poly(ethylene glycol)-Poly(lactide-co-glycolide) (PLGA-PEG-PLGA) nanoparticles (DFO-loaded NPs) to realize its long-term angiogenic and osteogenic bioactivities. Surface morphology, size, size distribution of DFO-loaded NPs as well as DFO loading content (LC), encapsulation efficiency (EE) and release profile were systematically evaluated. When hBMSCs were exposed to the vehicle with DFO concentration of 100 μM, cells showed good viability, increased HIF-1α expression and enhanced vascular endothelial growth factor (VEGF) secretion. The transcriptional levels of the angiogenic and osteogenic genes were also upregulated. Moreover, promoted alkaline phosphatase (ALP) activity further confirmed better osteogenic differentiation. Similarly, angiogenic activity of human umbilical vein endothelial cells (HUVECs) were enhanced after the addition of DFO-loaded NPs, evidenced by increased angiogenic genes expressions and tube formation. Taken together, DFO-loaded NPs could provide a sustained supply of DFO, with its angiogenic and osteogenic coupling effects preserved, which extends the potential of this system for bone defect repair. Full article