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Alicia anisopetala and Callaeum psilophyllum are two closely related species that belong to the christianelloid clade of the family Malpighiaceae. Both species are pollinated by oil-collecting bees and exhibit variations at specimen and population level in the number of elaiophores per flower. These floral glands that secrete non-volatile oils constitute an ancestral trait for the family. There is evidence that the observed variations in the number of elaiophores can be the result of processes of connation or reduction associated with differences in their vascularization. In order to identify which process occurs in each species, we conducted an anatomical study in natural populations of both species distributed along a wide range of their geographical distributions in Argentina. We collected flowers of different individuals, counted the number of elaiophores per flower, carried out exomorphological observations, and used conventional histological techniques to examine the vascularization of these glands. The floral anatomy of both species does not show any modifications in other whorls related to the fusion or reduction of elaiophores. Our results indicate that the process of loss of elaiophores in A. anisopetala is caused by incomplete connation and in C. psilophyllum by reduction, suggesting that the processes that lead to the loss of elaiophores in Malpighiaceae are homoplastic and would not reflect phylogenetic signals. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this cadaveric study was to further describe the vascular supply of the radial, posterior interosseous and superficial radial nerves. Methods: 11 cadaveric upper limbs, injected with colored latex, were dissected. Vascular afferents to the radial nerve, superficial radial nerve (SRN) and posterior interosseous nerve (PIN) were described and located. Their origin was identified and its distance to interepicondylar line was measured. Results: The radial nerve had an average of 3 vascular afferents (1–5), of septomuscular origin in 54% of cases. 46% came from adjacent arteries. The PIN had an average of 8 vascular afferents (6–14), arising from septomuscular branches in 82% of cases. The PIN was vascularized in 100% of cases by a large arterial plexus originating from the supinator muscle between its two heads. The SRN had an average of 4 vascular afferents (3–7). Before crossing the septum of the brachioradialis, vascularization was predominantly septomuscular; after crossing the septum, the nerve was exclusively vascularized by septocutaneous arteries. Conclusion: This is the first study to describe the vascularization of the radial nerve and its terminal branches along their entire length. Our results are in line with the data available in the literature. An arterial plexus between the two heads of the supinator was surrounding the PIN in all cases. This vascular plexus might be involved in dynamic compression of the posterior interosseous nerve. [ABSTRACT FROM AUTHOR]

Background: Critical limb ischemia (CLI) is a condition characterized by insufficient blood flow to the lower limbs, resulting in severe ischemia and potentially leading to amputation. This study aims to identify novel vasculogenic precursor cells (VPCs) in human bone marrow and evaluate their efficacy in combination with bone marrow-derived mesenchymal stem cells (BM-MSCs) for the treatment of CLI. Methods: Ex vivo cultured VPCs and BM-MSCs from bone marrow were characterized and their effects on neovascularization and long-term tissue regeneration were tested in a mouse CLI model. Results: VPCs, expressing high levels of hepatocyte growth factor and c-MET, were identified from human bone marrow aspirates. These cells exhibited strong vasculogenic capacity in vitro but possessed a cellular phenotype distinct from those of previously reported endothelial precursor cells in circulation or cord blood. They also expressed most surface markers of BM-MSCs and demonstrated multipotent differentiation ability. Screening of 376 surface markers revealed that VPCs uniquely display CD141 (thrombomodulin). CD141+VPCs are present in BM aspirates as a rare population and can be expanded ex vivo with a population doubling time of approximately 20 h, generating an elaborate vascular network even under angiogenic factor-deficient conditions and recruiting BM-MSCs to the network as pericyte-like cells. Intramuscular transplantation of a combination of human CD141+VPCs and BM-MSCs at a ratio of 2:1 resulted in limb salvage, blood flow recovery, and regeneration of large vessels in the femoral artery-removed CLI model, with an efficacy superior to that of singular transplantation. Importantly, large arteries and arterioles in dual cell transplantation expressed human CD31 in the intima and human α-smooth muscle actin in media layer at 4 and 12 weeks, likely indicating their lineage commitment to endothelial cells and vascular smooth muscle, respectively, in vivo. Conclusion: Dual-cell therapy using BM-derived CD141+ VPCs and BM-MSCs holds potential for further development in clinical trials to treat peripheral artery disease and diabetic ulcers. [ABSTRACT FROM AUTHOR]

Addressing a critical challenge in current tissue-engineering practices, this study aims to enhance vascularization in 3D porous scaffolds by incorporating bioceramics laden with pro-angiogenic ions. Specifically, freeze-dried gelatin-based scaffolds were infused with sol-gel-derived powders of Cu-doped akermanite (Ca 2 MgSi2O 7) and bredigite (Ca 7 MgSi 4 O 16) at various concentrations (10, 20, and 30 wt%). The scaffolds were initially characterized for their structural integrity, biodegradability, swelling behavior, impact on physiological pH, and cytocompatibility with human umbilical vein endothelial cells (HUVECs). The silicate incorporation effectiveness in promoting vascularity was then assessed through HUVEC attachment, capillary tube formation, and ex-ovo chick embryo chorioallantoic membrane assays. The findings revealed significant improvements in both in-vitro and ex-ovo vascularity of the gelatin scaffolds upon the addition of Cu-doped akermanite. The most effective concentrations were determined to be 10 and 20 %, which led to notable HUVEC metabolic activity, a well-spread morphology with extensive peripheral filopodia and lamellipodia at 10 % and a cobblestone phenotype indicative of in-vivo endothelium at 20 % during cell attachment, the formation of complex networks of tubular structures, and robust vascularization in chick embryo development. Moving forward, the incorporation of Cu-doped akermanite into tissue-engineering scaffolds shows great potential for addressing the limitations of vascularization, especially for critical-sized bone defects, by facilitating the controlled release of pro-angiogenic and pro-osteogenic ions. [ABSTRACT FROM AUTHOR]

Regeneration of soft tissues, especially those requiring complex vascularization, is a major challenge in the field of tissue engineering. The current types of tissue engineering scaffolds include sponges, electric spinning silk, hydrogels, and 3D printed biomaterials. Among them, hydrogels have the unique property of mimicking extracellular matrix (ECM), which can provide a relatively stable microenvironment for cellular activities and facilitate cell adhesion, proliferation, and differentiation; thus, have become a promising scaffold. In this paper, we present a review of the commonly used types of natural hydrogels and their applications as scaffolds in tissue vascularization. First, we enumerate the importance and advantages of several types of commonly used hydrogels of natural origin in terms of fabricating vascularized tissues or organs. Second, we discuss two different formation modalities of blood vessels, as well as natural hydrogel-based vascularization strategies, including carrying growth factors, stem cell delivery, special scaffold structures and pharmaceutical-enhanced strategy. In addition, we describe the crosslinking strategies of hydrogels as scaffolds for regeneration of vascularized soft tissues, as well as the factors affecting it. Finally, new insights are provided for the development of natural hydrogel-based vascularized soft tissue regeneration research. [ABSTRACT FROM AUTHOR]

Engineering functional, thick tissues with integrated vascular architectures is crucial for advancing regenerative medicine. This study applied a novel 3D bioprinting strategy to construct thick adipose tissues featuring complex, hierarchical vascular networks. Mature adipocytes and endothelial cells are encapsulated within a collagen matrix, with structural integrity and vascular functionality ensured through a combination of bioinks. An innovative approach is utilized to establish millimetric vascular channels that connect to microvascular networks, forming a fully perfusable, hierarchical vasculature throughout the 3D bioprinted tissue. The structural stability and endothelial functionality of the vascularized constructs are assessed under continuous flow. In‐vitro analyses confirmed the integrity of the vascular networks and demonstrated the functional characteristics of the printed mature adipose cells. Direct anastomosis of the bioprinted tissue to a rat femoral artery resulted in effective vascular integration and tissue viability, as evidenced by efficient blood perfusion and significant host vascular ingrowth within the implanted tissues. The findings highlighted the potential of the presented bioprinting technique in the development of fully functional, vascularized adipose tissues suitable for surgical reconstruction and regenerative medicine applications. [ABSTRACT FROM AUTHOR]

In native skeletal muscle, capillaries reside in close proximity to muscle stem cells (satellite cells, SCs) and regulate SC numbers and quiescence through partially understood mechanisms that are difficult to study in vivo. This challenge could be addressed by the development of a 3-dimensional (3D) in vitro model of vascularized skeletal muscle harboring both a pool of quiescent SCs and a robust network of capillaries. Still, studying interactions between SCs and endothelial cells (ECs) within a tissue-engineered muscle environment has been hampered by the incompatibility of commercially available EC media with skeletal muscle differentiation. In this study, we first optimized co-culture media and cellular ratios to generate highly functional vascularized human skeletal muscle tissues ("myovascular bundles") with contractile properties (∼10 mN/mm2) equaling those of avascular, muscle-only tissues ("myobundles"). Within one week of muscle differentiation, ECs in these tissues formed a dense network of capillaries that co-aligned with muscle fibers and underwent initial lumenization. Incorporating vasculature within myobundles increased the total SC number by 82%, with SC density and quiescent signature being increased proximal (≤20μm) to EC networks. In vivo , at two weeks post-implantation into dorsal window chambers in nude mice, vascularized myobundles exhibited improved calcium handling compared to avascular implants. In summary, we engineered highly functional myovascular tissues that enable studies of the roles of EC-SC crosstalk in human muscle development, physiology, and disease. In native skeletal muscle, intricate relationships between vascular cells and muscle stem cells ("satellite cells") play critical roles in muscle growth and regeneration. Current methods for in vitro engineering of contractile skeletal muscle do not recreate capillary networks present in vivo. Our study for the first time generates in vitro robustly vascularized, highly functional engineered human skeletal muscle tissues. Within these tissues, satellite cells are more abundant and, similar to in vivo , they are more dense and less proliferative proximal to endothelial cells. Upon implantation in mice, vascularized engineered muscles show improved calcium handling compared to muscle-only implants. We expect that this versatile in vitro system will enable studies of muscle-vasculature crosstalk in human development and disease. [Display omitted] [ABSTRACT FROM AUTHOR]

Complexation with sulfated glycosaminoglycans (GAGs) regulates the signaling of pro‐angiogenic growth factors in vivo. To use this principle in modulating microvascular network formation and stability in vitro, a library of biohybrid hydrogels containing heparin, a highly sulfated GAG, or its selectively desulfated derivatives, is prepared. The hydrogels are applied to systematically investigate the effects of GAG concentration and sulfation patterns on embedded cultures of human umbilical vein endothelial cells (HUVECs) and cocultures of HUVECs with mesenchymal stromal cells (MSCs). Formation and morphology of microvascular networks, stromal cell expansion, and extracellular matrix (ECM) protein deposition are found to be significantly influenced by the hydrogel's GAG concentrations and sulfation patterns, presumably through differences in the resulting availability and bioactivity of GAG‐binding growth factors. In particular, cocultures in hydrogels with either low heparin concentration (500 µm) or higher concentrations of heparin desulfated at the 6O or N position resulted in the formation of dense, stable microvascular networks. The respective conditions also displayed enhanced stromal cell proliferation and ECM protein deposition, leading to increased matrix stiffness. Therefore, precisely tuning the affinity of biohybrid materials for pro‐angiogenic factors effectively enhances the vascularization of engineered tissue constructs in vitro. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases, particularly ischemic heart disease, area leading cause of morbidity and mortality worldwide. Myocardial infarction (MI) results in extensive cardiomyocyte loss, inflammation, extracellular matrix (ECM) degradation, fibrosis, and ultimately, adverse ventricular remodeling associated with impaired heart function. While heart transplantation is the only definitive treatment for end-stage heart failure, donor organ scarcity necessitates the development of alternative therapies. In such cases, methods to promote endogenous tissue regeneration by stimulating growth factor secretion and vascular formation alone are insufficient. Techniques for the creation and transplantation of viable tissues are therefore highly sought after. Approaches to cardiac regeneration range from stem cell injections to epicardial patches and interposition grafts. While numerous preclinical trials have demonstrated the positive effects of tissue transplantation on vasculogenesis and functional recovery, long-term graft survival in large animal models is rare. Adequate vascularization is essential for the survival of transplanted tissues, yet pre-formed microvasculature often fails to achieve sufficient engraftment. Recent studies report success in enhancing cell survival rates in vitro via tissue perfusion. However, the transition of these techniques to in vivo models remains challenging, especially in large animals. This review aims to highlight the evolution of cardiac patch and stem cell therapies for the treatment of cardiovascular disease, identify discrepancies between in vitro and in vivo studies, and discuss critical factors for establishing effective myocardial tissue regeneration in vivo. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigated how pulmonary metastases in the lungs can be assessed using a special imaging technique called contrast-enhanced ultrasound (CEUS). We analyzed data from 54 patients with confirmed cancer spread to the lungs. Our goal was to identify patterns of blood flow in the lung tumors and to compare these with the findings from tissue samples stained to highlight blood vessels. The results showed that most lung tumors had a blood supply from the bronchial arteries, with a few showing a supply from the pulmonary arteries. Additionally, most tumors showed a rapid reduction in contrast enhancement. This research helps improve the understanding of blood flow in lung tumors and could aid in developing better diagnostics strategies. Purpose: Description of the perfusion of pulmonary metastasis by contrast-enhanced ultrasound (CEUS) and their correlation with vascularization patterns represented by immunohistochemical CD34 endothelial staining. Patients and methods: The data of 54 patients with histologic proven peripheral pulmonary metastasis, investigated between 2004 and 2023 by CEUS. These CEUS parameters were evaluated: time to enhancement (TE), categorized as early pulmonary-arterial (PA) or delayed bronchial-arterial (BA) patterns; extent of enhancement (EE), either marked or reduced; homogeneity of enhancement (HE), homogeneous or inhomogeneous; and decrease of enhancement (DE), rapid washout (<120 s) or late washout (≥120 s). Additionally, tissue samples in 45 cases (83.3%) were stained with CD34 antibody for immunohistochemical analysis. Results: In total, 4 lesions (7.4 %) exhibited PA enhancement, and 50 lesions (92.6%) demonstrated BA enhancement. Furthermore, 37 lesions (68.5%) showed marked enhancement, while 17 lesions (31.5%) exhibited reduced enhancement. The enhancement was homogeneous in 28 lesions (51.86%) and inhomogeneous in 26 lesions (48.14%). Additionally, 53 lesions (98.1%) displayed a rapid washout. A chaotic vascular pattern indicative of a bronchial arterial blood supply was identified in all cases (45/45, 100%), including all 4 lesions with PA enhancement. Conclusion: Pulmonary metastases in CEUS predominantly reveal bronchial arterial enhancement and a rapid washout. Regarding EE and HE, pulmonary metastases show heterogeneous perfusion patterns. A PA enhancement in CEUS does not exclude BA neoangiogenesis. [ABSTRACT FROM AUTHOR]

Developing microphysiological cell culture platforms with a three-dimensional (3D) microenvironment has been a significant advancement from traditional monolayer cultures. Still, most of the current microphysiological platforms are limited in closed designs, i.e. are not accessible after 3D cell culture loading. Here, we report an open-top microfluidic chip which enables the generation of two sequentially loaded 3D cell cultures without physical barriers restricting the nurture, gas exchange and cellular communication. As a proof-of-concept, we demonstrated the formation of two 3D vasculatures, one in the upper and the other in the lower compartment, under three distinct flow conditions: asymmetric side-to-center, symmetric side-to-center and symmetric center-to-side. We used computational modelling to characterize initial flow pressures in cell culture compartments. We showed prominent vessel formation and branched vasculatures in upper and lower cell culture compartments with interconnecting, lumenized vessels with in vivo-relevant diameter in all flow conditions. With advanced image processing, we quantified and compared the overall vascular network volume and the total length formed in asymmetric side-to-center, symmetric side-to-center and symmetric center-to-side flow conditions. Our results indicate that the developed chip can house two distinct 3D cell cultures with merging vessels between compartments and by providing asymmetric side-to-center or symmetric center-to-side flow vascular morphogenesis is enhanced in terms of overall network length. The developed open-top microfluidic chip may find various applications in generation of tissue-specific 3D-3D co-cultures for studying cellular interactions in vascularized tissues and organs. [ABSTRACT FROM AUTHOR]

Skin tissue engineering is undergoing tremendous expansion as a result from clinical needs, mandatory replacement of animal models and development of new technologies. Many approaches have been used to produce vascularized skin substitutes for grafting purposes showing the presence of capillary-like structures but with limited analysis of their in vitro maturation and plasticity. Such knowledge is however important for the development of tissue substitutes with improved implantation success as well as for validation of vascularization in vitro models, including as a readout in pharmacological analyses. For optimal interactions of cells with microenvironment and vasculature, we here used a cell sheet approach consisting in the sole production of matrix by the cells. In this context, we limited the density of endothelial cells seeded for self-assembly and rather relied on the stimulation of angiogenesis for the development of an extensive connected microvascular-like network. After detailed characterization of this network, we challenged its plasticity both during and after establishment of the skin substitute. We show that fine tuning of VEGF concentration and time of application differentially affects formation of capillary-like structures and their perivascular coverage. Furthermore, we performed a deep wound assay that displayed tissue repair and angiogenesis with unique characteristics of the physiological process. These studies demonstrate the importance of cell-derived microenvironment for the establishment of mature yet dynamic vascularized skin models allowing a wide range of pharmacological and basic investigations. The significant advancements in organ-on-chips and tissue engineering call for more relevant models including microvascularization with remodeling potential. While vascularized skin substitutes have been developed for years, focus has primarily been on the impact of microvascularization on implantation rather than on its in vitro characterization. We here developed a cell sheet-based vascularized skin substitute relying on angiogenesis, i.e. growth of vessel-like structures within the 3D model, rather than solely on endothelial cell self-assembly. We then characterized :1/ vascularization after modulation of angiogenic factor VEGF during the substitute construction; -2/ angiogenesis associated to tissue repair after deep mechanical wounding. These studies establish a solid physiologically relevant model for further investigation of skin cell interactions and in vitro wound healing. [Display omitted] [ABSTRACT FROM AUTHOR]

Dermal substitutes require sufficient tissue integration and vascularization to be successfully covered with split-thickness skin grafts. To rapidly achieve this, we provide the proof of principle for a novel vascularization strategy with high translational potential. Nanofat was generated from subcutaneous adipose tissue of green fluorescence protein (GFP)+ C57BL/6J donor mice and seeded onto small samples (4 mm in diameter) of the clinically approved dermal substitute Integra®. These samples and non-seeded controls were then implanted into full-thickness skin defects in the dorsal skinfold chamber of C57BL/6J wild-type mice and analyzed by intravital fluorescence microscopy, histology and immunohistochemistry over a 14-day period. Nanofat-seeded dermal substitutes exhibited an accelerated vascularization, as indicated by a significantly higher functional microvessel density on days 10 and 14 when compared to controls. This was primarily caused by the reassembly of GFP+ microvascular fragments inside the nanofat into microvascular networks. The improved vascularization promoted integration of the implants into the surrounding host tissue, which finally exhibited an increased formation of a collagen-rich granulation tissue. There were no marked differences in the inflammatory host tissue reaction to nanofat-seeded and control implants. These findings demonstrate that nanofat significantly improves the in vivo performance of dermal substitutes without affecting their biocompatibility. [ABSTRACT FROM AUTHOR]

Background This study aims to address challenges in dental pulp regeneration therapy. The heterogeneity of DPSCs poses challenges, especially in stem cell transplantation for clinical use, particularly when sourced from donors of different ages and conditions. Methods Pseudotime analysis was employed to analyze single-cell sequencing data, and immunohistochemical studies were conducted to investigate the expression of fibronectin 1 (FN1). We performed in vitro sorting of PDGFRβ+ DPSCs using flow cytometry. A series of functional assays, including cell proliferation, scratch, and tube formation assays, were performed to experimentally validate the vasculogenic capabilities of the identified PDGFRβ+ DPSC subset. Furthermore, gene-edited mouse models were utilized to demonstrate the importance of PDGFRβ+ DPSCs. Transcriptomic sequencing was conducted to compare the differences between PDGFRβ+ DPSCs and P1-DPSCs. Results Single-cell sequencing analysis unveiled a distinct subset, PDGFRβ+ DPSCs, characterized by significantly elevated FN1 expression during dental pulp development. Subsequent cell experiments demonstrated that this subset possesses remarkable abilities to promote HUVEC proliferation, migration, and tube formation. Gene-edited mouse models confirmed the vital role of PDGFRβ+ DPSCs in dental pulp development. Transcriptomic sequencing and in vitro experiments demonstrated that the PDGFR/PI3K/AKT signaling pathway is a crucial factor mediating the proliferation rate and pro-angiogenic properties of PDGFRβ+ DPSCs. Conclusion We defined a new subset, PDGFRβ+ DPSCs, characterized by strong proliferative activity and pro-angiogenic capabilities, demonstrating significant clinical translational potential. [ABSTRACT FROM AUTHOR]

Currently, an increasing number of patients are undergoing extensive surgeries to restore the mucosa of the gums in the area of recessions. The use of a connective tissue graft from the palate is the gold standard of such surgical treatment, but complications, especially in cases of extensive defects, have led to the development of approaches using xenogeneic collagen matrices and methods to stimulate their regenerative and vasculogenic potential. This study investigated the potential of a xenogeneic scaffold derived from porcine skin Mucoderm and injections of the pCMV-VEGF165 plasmid ('Neovasculgen') to enhance soft gingival tissue volume and vascularization in an experimental model in rabbits. In vitro studies demonstrated the biocompatibility of the matrix and plasmid with gingival mesenchymal stem cells, showing no toxic effects and supporting cell viability and metabolic activity. In the in vivo experiment, the combination of Mucoderm and the pCMV-VEGF165 plasmid (0.12 mg) synergistically promoted tissue proliferation and vascularization. The thickness of soft tissues at the implantation site significantly increased with the combined application (3257.8 ± 1093.5 µm). Meanwhile, in the control group, the thickness of the submucosa was 341.8 ± 65.6 µm, and after the implantation of only Mucoderm, the thickness of the submucosa was 2041.6 ± 496.8 µm. Furthermore, when using a combination of Mucoderm and the pCMV-VEGF165 plasmid, the density and diameter of blood vessels were notably augmented, with a mean value of 226.7 ± 45.9 per 1 mm2 of tissue, while in the control group, it was only 68.3 ± 17.2 per 1 mm2 of tissue. With the application of only Mucoderm, it was 131.7 ± 37.1 per 1 mm2 of tissue, and with only the pCMV-VEGF165 plasmid, it was 145 ± 37.82 per 1 mm2 of the sample. Thus, the use of the pCMV-VEGF165 plasmid ('Neovasculgen') in combination with the xenogeneic collagen matrix Mucoderm potentiated the pro-proliferative effect of the membrane and the pro-vascularization effect of the plasmid. These results indicate the promising potential of this innovative approach for clinical applications in regenerative medicine and dentistry. [ABSTRACT FROM AUTHOR]

Scaffolds for bone defect treatment should ideally support vascularization and promote bone formation, to facilitate the translation into biomedical device applications. This study presents a novel approach utilizing 3D-printed water-dissolvable polyvinyl alcohol (PVA) sacrificial molds to engineer polymerized High Internal Phase Emulsion (polyHIPE) scaffolds with microchannels and distinct multiscale porosity. Two sacrificial mold variants (250 µm and 500 µm) were generated using fused deposition modeling, filled with HIPE, and subsequently dissolved to create polyHIPE scaffolds containing microchannels. In vitro assessments demonstrated significant enhancement in cell infiltration, proliferation, and osteogenic differentiation, underscoring the favorable impact of microchannels on cell behavior. High loading efficiency and controlled release of the osteogenic factor BMP-2 were achieved, with microchannels facilitating release of the growth factor. Evaluation in a mouse critical-size calvarial defect model revealed enhanced vascularization and bone formation in microchanneled scaffolds containing BMP-2. This study not only introduces an accessible method for creating multiscale porosity in polyHIPE scaffolds but also emphasizes its capability to enhance cellular infiltration, controlled growth factor release, and in vivo performance. The findings suggest promising applications in bone tissue engineering and regenerative medicine, and are expected to facilitate the translation of this type of biomaterial scaffold. This study holds significance in the realm of biomaterial scaffold design for bone tissue engineering and regeneration. We demonstrate a novel method to introduce controlled multiscale porosity and microchannels into polyHIPE scaffolds, by utilizing 3D-printed water-dissolvable PVA molds. The strategy offers new possibilities for improving cellular infiltration, achieving controlled release of growth factors, and enhancing vascularization and bone formation outcomes. This microchannel approach not only marks a substantial stride in scaffold design but also demonstrates its tangible impact on enhancing osteogenic cell differentiation and fostering robust bone formation in vivo. The findings emphasize the potential of this methodology for bone regeneration applications, showcasing an interesting advancement in the quest for effective and innovative biomaterial scaffolds to regenerate bone defects. [Display omitted] [ABSTRACT FROM AUTHOR]

Tissue self‐assembly relies on the interplay between structural cues imparted by the extracellular matrix (ECM) and instructive chemical factors that guide cellular signaling pathways. Here, it is reported that endothelial cell‐laden gelatin‐based hydrogels with optimized mechanical and chemical properties facilitate de novo vasculogenesis and recruitment of endogenous blood vessels in vivo. It is demonstrated that these engineered matrices, with tailored viscoelastic features and stiffness, drive vascular self‐assembly in a yes‐associated protein (YAP) mechanosensing‐dependent manner through integrin alpha V beta 3 (αvβ3) and matrix metalloproteinase 2 activity (MMP2). This research highlights how the ECM, in the form of gelatin‐based hydrogels with adjustable stress relaxation rates, drives vascular morphogenesis in the absence of growth factor supplementation, lending to a minimalistic platform for discretizing features of the microenvironment niche. Collectively, these results demonstrate a testbed that enables mechanistic evaluation of morphogenetic processes. Specifically, the results show how mechanical cues impact signaling pathways that modulate vascular remodeling, a critical tissue engineering paradigm needed for the translational application of vascularized grafts for regenerative medicine applications. [ABSTRACT FROM AUTHOR]

Meniscal lesions in vascularized regions are known to regenerate while lack of vascular supply leads to poor healing. Here, we developed and validated a novel methodology for three‐dimensional structural analysis of meniscal vascular structures with high‐resolution microcomputed tomography (µCT). We collected porcine medial menisci from 10 neonatal (not‐developed meniscus, n‐) and 10 adults (fully developed meniscus, a‐). The menisci were cut into anatomical regions (anterior horn (n‐AH and a‐AH), central body (n‐CB and a‐CB), and posterior horn (n‐PH and a‐PH). Specimens were cut in half, fixed, and one specimen underwent critical point drying and µCT imaging, while other specimen underwent immunohistochemistry and vascularity biomarker CD31 staining for validation of µCT. Parameters describing vascular structures were calculated from µCT. The vascular network in neonatal spread throughout meniscus, while in adult was limited to a few vessels in outer region, mostly on femoral side. n‐AH, n‐CB, and n‐PH had 20, 17, and 11 times greater vascular volume fraction than adult, respectively. Moreover, thickness of blood vessels, in three regions, was six times higher in adults than in neonatal. a‐PH appeared to have higher vascular fraction, longer and thicker blood vessels than both a‐AH and a‐CB. Overall, neonatal regions had a higher number of blood vessels, more branching, and higher tortuosity compared to adult regions. For the first time, critical point drying‐based µCT imaging allowed detailed three‐dimensional visualization and quantitative analysis of vascularized meniscal structures. We showed more vascularity in neonatal menisci, while adult menisci had fewer and thicker vascularity especially limited to the femoral surface. [ABSTRACT FROM AUTHOR]

Ovarian cancer is high recurrence and mortality malignant tumor. The most common ovarian cancer was High‐Grade Serous Ovarian Cancer. However, High‐Grade Serous Ovarian Cancer organoid is rare, which organoid with patient immune microenvironment and blood vessels even absence. Here, we report a novel High‐Grade Serous Ovarian Cancer organoid system derived from patient ovarian cancer samples. These organoids recapitulate High‐Grade Serous Ovarian Cancer organoids' histological and molecular heterogeneity while preserving the critical immune microenvironment and blood vessels, as evidenced by the presence of CD34+ endothelial cells. Whole exome sequencing identifies key mutations (CSMD3, TP53, GABRA6). Organoids show promise in testing cisplatin sensitivity for patients resistant to carboplatin and paclitaxel, with notable responses in cancer proteoglycans and p53 (TP53) signaling, like ACTG/ACTB1/AKT2 genes and BBC3/MDM2/PERP. Integration of immune microenvironment and blood vessels enhances potential for novel therapies like immunotherapies and angiogenesis inhibitors. Our work may provide a new detection system and theoretical basis for ovarian cancer research and individual therapy. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus is a complex condition with high prevalence in the global population, implying multiple complications for the entire organism. It is essential to understand its implications in the development and evolution of other pathologies in order to manage efficiently their complications thus decreasing overall mortality. A surgical pathology potentially associated with type 2 diabetes is acute mesenteric ischemia. Although it has a decreased prevalence in the global population, mesenteric infarction is related to an extremely high mortality rate due to its elusive clinical presentation and rapid progression. The difficult diagnosis emphasizes the need to make associations between acute mesenteric ischemia and other pathologies involved in its evolution, such as type 2 diabetes mellitus. This metabolic disease raises the risk of macro and microvascular complications, therefore disturbing the vascularization of the bowel. The purpose of this review is to describe how diabetes is particularly involved in all four types of mesenteric infarction by modulating different physiopathological mechanisms based on the process of atherosclerosis and other endothelial molecular processes.

Abstract Developing microphysiological cell culture platforms with a three-dimensional (3D) microenvironment has been a significant advancement from traditional monolayer cultures. Still, most of the current microphysiological platforms are limited in closed designs, i.e. are not accessible after 3D cell culture loading. Here, we report an open-top microfluidic chip which enables the generation of two sequentially loaded 3D cell cultures without physical barriers restricting the nurture, gas exchange and cellular communication. As a proof-of-concept, we demonstrated the formation of two 3D vasculatures, one in the upper and the other in the lower compartment, under three distinct flow conditions: asymmetric side-to-center, symmetric side-to-center and symmetric center-to-side. We used computational modelling to characterize initial flow pressures in cell culture compartments. We showed prominent vessel formation and branched vasculatures in upper and lower cell culture compartments with interconnecting, lumenized vessels with in vivo-relevant diameter in all flow conditions. With advanced image processing, we quantified and compared the overall vascular network volume and the total length formed in asymmetric side-to-center, symmetric side-to-center and symmetric center-to-side flow conditions. Our results indicate that the developed chip can house two distinct 3D cell cultures with merging vessels between compartments and by providing asymmetric side-to-center or symmetric center-to-side flow vascular morphogenesis is enhanced in terms of overall network length. The developed open-top microfluidic chip may find various applications in generation of tissue-specific 3D-3D co-cultures for studying cellular interactions in vascularized tissues and organs.

Bioactive hydrogel materials have great potential for applications in bone tissue engineering. However, fabrication of functional hydrogels that mimic the natural bone extracellular matrix (ECM) remains a challenge, because they need to provide mechanical support and embody physiological cues for angiogenesis and osteogenesis. Inspired by the features of ECM, we constructed a dual-component composite hydrogel comprising interpenetrating polymer networks of gelatin methacryloyl (GelMA) and deoxyribonucleic acid (DNA). Within the composite hydrogel, the GelMA network serves as the backbone for mechanical and biological stability, whereas the DNA network realizes dynamic capabilities (e.g., stress relaxation), thereby promoting cell proliferation and osteogenic differentiation. Furthermore, functional aptamers (Apt19S and AptV) are readily attached to the DNA network to recruit bone marrow mesenchymal stem cells (BMSCs) and achieve sustained release of loaded vascular endothelial growth factor towards angiogenesis. Our results showed that the composite hydrogel could facilitate the adhesion of BMSCs, promote osteogenic differentiation by activating focal adhesion kinase (FAK)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/β-Catenin signaling pathway, and eventually enhance vascularized bone regeneration. This study shows that the multifunctional composite hydrogel of GelMA and DNA can successfully simulate the biological functions of natural bone ECM and has great potential for repairing bone defects.

BACKGROUND: We have successfully established an animal model of small ear pig in southern Yunnan province with internal tension relieving technique combined with autologous Achilles tendon for anterior cruciate ligament reconstruction, and verified the stability and reliability of the model. However, whether internal tension relieving technique can promote the ligamentalization process of autologous Achilles tendon graft has not been studied. OBJECTIVE: To investigate the differences in the process of ligamentalization between conventional reconstruction and internal reduction reconstruction of the anterior cruciate ligament by gross view, histology and electron microscopy. METHODS: Thirty adult female small ear pigs in southern Yunnan province were selected. Anterior cruciate ligament reconstruction was performed on the left knee joint with the ipsilateral knee Achilles tendon (n=30 in the normal group), and anterior cruciate ligament reconstruction was performed on the right knee joint with the ipsilateral knee Achilles tendon combined with the internal relaxation and enhancement system (n=30 in the relaxation group). The autogenous right forelimb was used as the control group; the anterior cruciate ligament was exposed but not severed or surgically treated. At 12, 24, and 48 weeks after surgery, 10 animals were sacrificed, respectively. The left and right knee joint specimens were taken for gross morphological observation to evaluate the graft morphology. MAS score was used to evaluate the excellent and good rate of the ligament at each time point. Hematoxylin-eosin staining was used to evaluate the degree of ligament graft vascularization. Collagen fibers and nuclear morphology were observed, and nuclear morphology was scored. Ultrastructural remodeling was evaluated by scanning electron microscopy and transmission electron microscopy. RESULTS AND CONCLUSION: (1) The ligament healing shape of the relaxation group was better at various time points after surgery, and the excellent and good rate of MAS score was higher (P < 0.05). Moreover, the relaxation group could obtain higher ligament vascularization score (P < 0.05). (2) The arrangement of collagen bundles and fiber bundles in the two groups gradually tended to be orderly, and the transverse fiber connections between collagen gradually increased and thickened, suggesting that the strength and shape degree of the grafts were gradually improved, but the ligament remodeling in the relaxation group was always faster than that in the normal group at various time points after surgery. (3) The diameter, distribution density, and arrangement degree of collagen fibers in the relaxation group were better than those in the normal group at all time points, especially in the comparison of collagen fiber diameter between and within the relaxation group (P < 0.05). [ABSTRACT FROM AUTHOR]

Background: The Harderian gland in domestic birds is a major paraocular excretory gland that has an important role in tear production as well as in the immune protection of the conjunctiva surface. Aim: The aim of this research was to investigate the arterial and venous supply of the gland in hens and provide valuable and useful information for future research. Methods: The research was conducted on 26 adult hens, provenience of Lohmann Brown. For the identification and determination of blood vessels, we used the vascular corrosion cast technique in conjunction with the transmission electron microscope (TEM). Results: The casts showed that the gland receives the arterial supply via branches of a. ophthalmotemporalis and a. nasalis communis and these arteries are accompanied by the corresponding veins. Ultrastructural analyses showed the presence of fenestrated capillaries, which indicates the possibility for permeability of larger molecules. Conclusion: The present research gives important and detailed information about the arterial and venous supply of the Harderian gland in hens that may serve as guidelines for future vascular and morphological investigations. [Open Vet J 2024; 14(7.000): 1553-1560]

Abstract Vascularization plays a significant role in promoting the expedited process of bone regeneration while also enhancing the stability and viability of artificial bone implants. Although titanium alloy scaffolds were designed to mimic the porous structure of human bone tissues to facilitate vascularization in bone repair, their biological inertness restricted their broader utilization. The unique attribute of Metal-organic framework (MOF) MIL-53(Fe), known as “breathing”, can facilitate the efficient adsorption of extracellular matrix proteins and thus provide the possibility for efficient interaction between scaffolds and cell adhesion molecules, which helps improve the bioactivity of the titanium alloy scaffolds. In this study, MIL-53(Fe) was synthesized in situ on the scaffold after hydrothermal treatment. The MIL-53(Fe) endowed the scaffold with superior protein absorption ability and preferable biocompatibility. The scaffolds have been shown to possess favorable osteogenesis and angiogenesis inducibility. It was indicated that MIL-53(Fe) modulated the mechanotransduction process of endothelial cells and induced increased cell stiffness by promoting the adsorption of adhesion-mediating extracellular matrix proteins to the scaffold, such as laminin, fibronectin, and perlecan et al., which contributed to the activation of the endothelial tip cell phenotype at sprouting angiogenesis. Therefore, this study effectively leveraged the intrinsic “breathing” properties of MIL-53 (Fe) to enhance the interaction between titanium alloy scaffolds and vascular endothelial cells, thereby facilitating the vascularization inducibility of the scaffold, particularly during the sprouting angiogenesis phase. This study indicates that MIL-53(Fe) coating represents a promising strategy to facilitate accelerated and sufficient vascularization and uncovers the scaffold-vessel interaction from a biomechanical perspective. Graphical Abstract

Abstract Endothelial cells (ECs) are widely used as donor cells in tissue engineering, organoid vascularization, and in vitro microvascular model development. ECs are invaluable tools for disease modeling and drug screening in fundamental research. When treating ischemic diseases, EC engraftment facilitates the restoration of damaged blood vessels, enhancing therapeutic outcomes. This article presents a comprehensive overview of the current sources of ECs, which encompass stem/progenitor cells, primary ECs, cell lineage conversion, and ECs derived from other cellular sources, provides insights into their characteristics, potential applications, discusses challenges, and explores strategies to mitigate these issues. The primary aim is to serve as a reference for selecting suitable EC sources for preclinical research and promote the translation of basic research into clinical applications. Graphical abstract

Sunir J Garg,1 Majda Hadziahmetovic2 1Retina Service, Wills Eye Hospital, Philadelphia, PA, USA; 2Department of Ophthalmology, Duke University, Durham, NC, USACorrespondence: Sunir J Garg, Retina Service, Wills Eye Hospital, 840 Walnut Street, Suite 1020, Philadelphia, PA, 19107, USA, Tel +1-215-928-3444, Email sgarg@midatlanticretina.com Majda Hadziahmetovic, Department of Ophthalmology, Duke University, 5321 Erwin Road, Durham, NC, 27710, USA, Tel +1-919-684-0275, Email majda.hadziahmetovic@duke.eduAbstract: Photodynamic therapy (PDT) with verteporfin involves intravenous administration of a photosensitizer followed by its laser light activation at the target site to inhibit aberrant choroidal vascularization. This narrative review provides an overview of the role verteporfin PDT plays in the management of chorioretinal conditions. A PubMed literature review of all English-language articles published through October 19, 2023, was conducted to identify relevant references. Verteporfin PDT has been shown to be safe and effective for the treatment of patients with choroidal neovascularization (CNV) due to neovascular age-related macular degeneration and is often used in combination with a vascular endothelial growth factor (VEGF) inhibitor. Additionally, patients with polypoidal choroidal vasculopathy, a subtype of neovascular age-related macular degeneration, also benefit from verteporfin PDT combined with a VEGF inhibitor for improving visual acuity. Verteporfin PDT has also been effective in treating patients with peripapillary CNV, as well as eyes with CNV due to ocular histoplasmosis and pathologic myopia. Reduced dose and/or fluence PDT protocols have been effective in patients with central serous chorioretinopathy while reducing adverse effects. In eyes with choroidal hemangioma, tumor regression and visual outcomes have been improved with verteporfin PDT treatment. Photodynamic therapy with verteporfin continues to play an important role in the management of chorioretinal conditions.Keywords: choroid, retina, macular degeneration, vascularization, VEGF inhibitor

Tissue‐engineered extraction products, such as apoptotic extracellular vesicles (ApoEVs), significantly promote tissue regeneration, endowing them with the potential to improve osseointegration. However, there is an urgent need to determine how to effectively load these materials onto a material surface to maximize their function. Considering that all such products have a phospholipid bilayer, a phospholipid‐modified implant coating is designed that can effectively load tissue‐engineered products with a phospholipid bilayer structure. ApoEVs are effectively loaded onto the surface and the osteogenic effect improved, achieving good osseointegration. In vitro experiments show that this material improves angiogenesis by promoting macrophage M1 polarization and NO secretion in the early stages. In vivo experiments show that after implantation, it effectively improve the peri‐implant vascularization of the implant, thereby improving the new bone formation ability and osseointegration. This study provides a universal solution for loading vesicular tissue‐engineered products onto an implant surface and validates its ability to improve bone fusion using ApoEVs as an example while exploring its mechanism. [ABSTRACT FROM AUTHOR]

Antifibrotic drug screening requires evaluating the inhibitory effects of drug candidates on fibrotic cells while minimizing any adverse effects on normal cells. It is challenging to create organ-specific vascularized organoids that accurately model fibrotic and normal tissues for drug screening. Our previous studies have established methods for culturing primary microvessels and epithelial cells from adult tissues. In this proof-of-concept study, we used rats as a model organism to create a two-dimensional vascularized liver organoid model that comprised primary microvessels, epithelia, and stellate cells from adult livers. To provide appropriate substrates for cell culture, we engineered ECMs with defined stiffness to mimic the different stages of fibrotic tissues and normal tissues. We examined the effects of two TGFβ signaling inhibitors, A83-01 and pirfenidone, on the vascularized liver organoids on the stiff and soft ECMs. We found that A83-01 inhibited fibrotic markers while promoting epithelial genes of hepatocytes and cholangiocytes. However, it inhibited microvascular genes on soft ECM, indicating a detrimental effect on normal tissues. Furthermore, A83-01 significantly promoted the expression of markers of stem cells and cancers, increasing the potential risk of it being a carcinogen. In contrast, pirfenidone, an FDA-approved compound for antifibrotic treatments, did not significantly affect all the genes examined on soft ECM. Although pirfenidone had minor effects on most genes, it did reduce the expression of collagens, the major components of fibrotic tissues. These results explain why pirfenidone can slow fibrosis progression with minor side effects in clinical trials. In conclusion, our study presents a method for creating vascularized liver organoids that can accurately mimic fibrotic and normal tissues for drug screening. Our findings provide valuable insights into the potential risks and benefits of using A83-01 and pirfenidone as antifibrotic drugs. This method can be applied to other organs to create organ-specific vascularized organoids for drug development. [ABSTRACT FROM AUTHOR]

The subcutaneous tissue of rats after implantation of polypropylene materials with adsorbed bone marrow-derived mesenchymal multipotent stromal cells (MMSCs) was studied using light microscopy. Inflammation in response to implantation was mild, and the foreign material was encapsulated into a thin strip of dense fibrous connective tissue with multinucleated macrophages. By 1 year after introduction of the monofilament and 6 and 12 months after implantation of the mesh product, some threads were deformed, broken, and had sharp edges. Small fragments of foreign material appeared in the adjacent tissues surrounded by their own relatively thick acellular capsule. As a result of preliminary adsorption of MMSCs on polypropylene, the thickness of the connective tissue capsule decreased, its vascularization increased, and the severity of inflammatory infiltration decreased. However, all effects of MMSCs adsorption in rats were transient and disappeared within 1 week. [ABSTRACT FROM AUTHOR]

Background: Injury of peripheral nerve capable of regeneration with much poorer prognosis affects people's life quality. The recovery of nerve function after transplantation for peripheral nerve injury remain a worldwide problem. Silicon-induced biofilms as vascularized biological conduits can promote nerve regeneration by encapsulating autologous or allogeneic nerve graft. Objective: We proposed to explore the effect of silicon-induced biofilms on nerves regeneration and whether the VEGF/VEGFR2/ERK pathway was involved in the present study. Methods: Biofilms around the transplanted nerves in peripheral nerve injury rats were induced by silicon. Vascularization and proteins related to VEGF/VEGFR2/ERK were measured. Pathology and morphology of nerves were investigated after encapsulating the transplanted nerves by silicon-induced biofilms. Results: Our results indicated that the biofilms induced by silicon for 6 weeks showed the most intensive vascularization and the optimal effect on nerve regeneration. Moreover, silicon-induced biofilms for 4, 6 and 8 weeks could significantly secrete VEGF with the highest content at week 6 after induction. VEGFR2, VEGF, p-VEGFR2, ERK1, ERK2, p-ERK1 and p-ERK2 were expressed in the biofilms. p-VEGFR2, p-ERK1 and p-ERK2 expression were different at each time point and significantly increased at week 6 compared with that at week 4 or week 8 which was consistent with that 6 week of was the optimum time for biofilms induction to improve the nerve repair after peripheral nerve injury. Conclusion: Our results suggested that combination of silicon-induced autologous vascularized biofilm and autologous transplantation may promote the repair of rat sciatic nerve defect quickly through VEGF/VEGFR2/ERK pathway. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Reducing side effects in non-cancerous tissue is a key aim of modern radiotherapy. Here, we assessed whether the use of the antioxidants hydroxytyrosol (HT) and thioredoxin-mimetic peptide CB3 (TMP) attenuated radiation-induced normal tissue toxicity in vitro. We used primary human umbilical vein endothelial cells (HUVECs) and human epidermal keratinocytes (HaCaT) as normal tissue models. Cells were treated with HT and TMP 24 h or immediately prior to irradiation. Reactive oxygen species (ROS) were assessed via luminescent- and fluorescence-based assays, migration was investigated using digital holographic microscopy, and clonogenic survival was quantified by colony formation assays. Angiogenesis and wound healing were evaluated via time-dependent microscopy. Secreted cytokines were validated in quantitative polymerase chain reaction (qPCR) studies. Treatment with HT or TMP was well tolerated by cells. The application of either antioxidant before irradiation resulted in reduced ROS formation and a distinct decrease in cytokines compared to similarly irradiated, but otherwise untreated, controls. Antioxidant treatment also increased post-radiogenic migration and angiogenesis while accelerating wound healing. HT or TMP treatment immediately before radiotherapy increased clonogenic survival after radiotherapy, while treatment 24 h before radiotherapy enhanced baseline proliferation. Both antioxidants may decrease radiation-induced normal tissue toxicity and deserve further pre-clinical investigation. [ABSTRACT FROM AUTHOR]

As the conversion rate of preclinical studies for cancer treatment is low, user-friendly models that mimic the pathological microenvironment and drug intake with high throughput are scarce. Animal models are key, but an alternative to reduce their use would be valuable. Vascularized tumor-on-chip models combine great versatility with scalable throughput and are easy to use. Several strategies to integrate both tumor and vascular compartments have been developed, but few have been used to assess drug delivery. Permeability, intra/extravasation, and free drug circulation are often evaluated, but imperfectly recapitulate the processes at stake. Indeed, tumor targeting and chemoresistance bypass must be investigated to design promising cancer therapeutics. In vitro models that would help the development of drug delivery systems (DDS) are thus needed. They would allow selecting good candidates before animal studies based on rational criteria such as drug accumulation, diffusion in the tumor, and potency, as well as absence of side damage. In this review, we focus on vascularized tumor models. First, we detail their fabrication, and especially the materials, cell types, and coculture used. Then, the different strategies of vascularization are described along with their classical applications in intra/extravasation or free drug assessment. Finally, current trends in DDS for cancer are discussed with an overview of the current efforts in the domain. [ABSTRACT FROM AUTHOR]

3D bioprinting enables the fabrication of human organ models that can be used for various fields of biomedical research, including oncology and infection biology. An important challenge, however, remains the generation of vascularized, perfusable 3D models that closely simulate natural physiology. Here, a novel direct ink writing (DIW) approach is described that can produce vascularized organ models without using sacrificial materials during fabrication. The high resolution of the method allows the one‐step generation of various sophisticated hollow geometries. This sacrificial‐free DIW (SF‐DIW) approach is used to fabricate hepatic metastasis models of various cancer types and different formats for investigating the cytostatic activity of anti‐cancer drugs. To this end, the models are incorporated into a newly developed perfusion system with integrated micropumps and an agar casting step that improves the physiological features of the bioprinted tissues. It is shown that the hepatic environment of the tumor models is capable of activating a prodrug, which inhibits breast cancer growth. This versatile SF‐DIW approach is able to fabricate complicated perfusable constructs or microfluidic chips in a straightforward and cost‐efficient manner. It can also be easily adapted to other cell types for generating vascularized organ tissues or cancer models that may support the development of new therapeutics. [ABSTRACT FROM AUTHOR]

Insulin-like Growth Factor-Binding Protein 7 (IGFBP7) is an extracellular matrix (ECM) glycoprotein, highly enriched in activated vasculature during development, physiological and pathological tissue remodeling. Despite decades of research, its role in tissue (re-)vascularization is highly ambiguous, exhibiting pro- and anti-angiogenic properties in different tissue remodeling states. IGFBP7 has multiple binding partners, including structural ECM components, cytokines, chemokines, as well as several receptors. Based on current evidence, it is suggested that IGFBP7's bioactivity is strongly dependent on the microenvironment it is embedded in. Current studies indicate that during physiological angiogenesis, IGFBP7 promotes endothelial cell attachment, luminogenesis, vessel stabilization and maturation. Its effects on other stages of angiogenesis and vessel function remain to be determined. IGFBP7 also modulates the pro-angiogenic properties of other signaling factors, such as VEGF-A and IGF, and potentially acts as a growth factor reservoir, while its actual effects on the factors' signaling may depend on the environment IGFBP7 is embedded in. Besides (re-)vascularization, IGFBP7 clearly promotes progenitor and stem cell commitment and may exhibit anti-inflammatory and anti-fibrotic properties. Nonetheless, its role in inflammation, immunomodulation, fibrosis and cellular senescence is again likely to be context-dependent. Future studies are required to shed more light on the intricate functioning of IGFBP7. [ABSTRACT FROM AUTHOR]

Vascularization plays a significant role in promoting the expedited process of bone regeneration while also enhancing the stability and viability of artificial bone implants. Although titanium alloy scaffolds were designed to mimic the porous structure of human bone tissues to facilitate vascularization in bone repair, their biological inertness restricted their broader utilization. The unique attribute of Metal-organic framework (MOF) MIL-53(Fe), known as "breathing", can facilitate the efficient adsorption of extracellular matrix proteins and thus provide the possibility for efficient interaction between scaffolds and cell adhesion molecules, which helps improve the bioactivity of the titanium alloy scaffolds. In this study, MIL-53(Fe) was synthesized in situ on the scaffold after hydrothermal treatment. The MIL-53(Fe) endowed the scaffold with superior protein absorption ability and preferable biocompatibility. The scaffolds have been shown to possess favorable osteogenesis and angiogenesis inducibility. It was indicated that MIL-53(Fe) modulated the mechanotransduction process of endothelial cells and induced increased cell stiffness by promoting the adsorption of adhesion-mediating extracellular matrix proteins to the scaffold, such as laminin, fibronectin, and perlecan et al., which contributed to the activation of the endothelial tip cell phenotype at sprouting angiogenesis. Therefore, this study effectively leveraged the intrinsic "breathing" properties of MIL-53 (Fe) to enhance the interaction between titanium alloy scaffolds and vascular endothelial cells, thereby facilitating the vascularization inducibility of the scaffold, particularly during the sprouting angiogenesis phase. This study indicates that MIL-53(Fe) coating represents a promising strategy to facilitate accelerated and sufficient vascularization and uncovers the scaffold-vessel interaction from a biomechanical perspective. [ABSTRACT FROM AUTHOR]

Hydrogels are widely used as wound healing dressings to repair wound tissues because of their good biocompatibility. However, issues of excessive swelling and the disordered release of loaded drugs remain to be addressed in practical wound-healing applications. In this study, we designed a near-infrared- (NIR-) responsive composite nanofiber-based hydrogel patch (NIR-NFHP). The nanofibers embedded in the hydrogel inhibited its swelling, such that the swelling rate of the composite was only 1.3. Meanwhile, during the proliferative phase of wound healing, the orderly and stable release of deferoxamine through the on/off NIR response achieved a controlled and hierarchical release of drugs. During the acute inflammatory phase of wound healing, the fast release of valsartan provided a strong anti-inflammatory environment. The synergistic effects of anti-inflammatory and vascularization responses achieved improved the wound healing rate up to 95%. Based on its antiswelling effects as well as the controlled and hierarchical release of drugs, we believed that this NIR-responsive nanofiber hydrogel patch has broad prospects for applications as a dressing in the field of wound healing. [ABSTRACT FROM AUTHOR]

Adipose tissues, particularly beige and brown adipose tissue, play crucial roles in energy metabolism. Brown adipose tissues' thermogenic capacity and the appearance of beige cells within white adipose tissue have spurred interest in their metabolic impact and therapeutic potential. Brown and beige fat cells, activated by environmental factors like cold exposure or by pharmacology, share metabolic mechanisms that drive non-shivering thermogenesis. Understanding these two cell types requires advanced, yet broadly applicable in vitro models that reflect the complex microenvironment and vasculature of adipose tissues. Here we present mouse vascularized adipose spheroids of the stromal vascular microenvironment from inguinal white adipose tissue, a tissue with 'beiging' capacity in mice and humans. We show that adding a scaffold improves vascular sprouting, enhances spheroid growth, and upregulates adipogenic markers, thus reflecting increased adipocyte maturity. Transcriptional profiling via RNA sequencing revealed distinct metabolic pathways upregulated in our vascularized adipose spheroids, with increased expression of genes involved in glucose metabolism, lipid metabolism, and thermogenesis. Functional assessment demonstrated increased oxygen consumption in vascularized adipose spheroids compared to classical 2D cultures, which was enhanced by β-adrenergic receptor stimulation correlating with elevated b-adrenergic receptor expression. Moreover, stimulation with the naturally occurring adipokine, FGF21, induced Ucp1 mRNA expression in the vascularized adipose spheroids. In conclusion, vascularized inguinal white adipose tissue spheroids provide a physiologically relevant platform to study how the stromal vascular microenvironment shapes adipocyte responses and influence activated thermogenesis in beige adipocytes. [ABSTRACT FROM AUTHOR]

Background: The Harderian gland in domestic birds is a major paraocular excretory gland that has an important role in tear production as well as in the immune protection of the conjunctiva surface. Aim: The aim of this research was to investigate the arterial and venous supply of the gland in hens and provide valuable and useful information for future research. Methods: The research was conducted on 26 adult hens, provenience of Lohmann Brown. For the identification and determination of blood vessels, we used the vascular corrosion cast technique in conjunction with the transmission electron microscope (TEM). Results: The casts showed that the gland receives the arterial supply via branches of a. ophthalmotemporalis and a. nasalis communis and these arteries are accompanied by the corresponding veins. Ultrastructural analyses showed the presence of fenestrated capillaries, which indicates the possibility for permeability of larger molecules. Conclusion: The present research gives important and detailed information about the arterial and venous supply of the Harderian gland in hens that may serve as guidelines for future vascular and morphological investigations. [ABSTRACT FROM AUTHOR]

The anterior chamber of the eye (ACE) is distinct in its anatomy, optics, and immunology. This guarantees that the eye perceives visual information in the context of physiology even when encountering adverse incidents like inflammation. In addition, this endows the ACE with the special nursery bed iris enriched in vasculatures and nerves. The ACE constitutes a confined space enclosing an oxygen/nutrient-rich, immune-privileged, and less stressful milieu as well as an optically transparent medium. Therefore, aside from visual perception, the ACE unexpectedly serves as an excellent transplantation site for different body parts and a unique platform for noninvasive, longitudinal, and intravital microimaging of different grafts. On the basis of these merits, the ACE technology has evolved from the prototypical through the conventional to the advanced version. Studies using this technology as a versatile biomedical research platform have led to a diverse range of basic knowledge and in-depth understanding of a variety of cells, tissues, and organs as well as artificial biomaterials, pharmaceuticals, and abiotic substances. Remarkably, the technology turns in vivo dynamic imaging of the morphological characteristics, organotypic features, developmental fates, and specific functions of intracameral grafts into reality under physiological and pathological conditions. Here we review the anatomical, optical, and immunological bases as well as technical details of the ACE technology. Moreover, we discuss major achievements obtained and potential prospective avenues for this technology. [ABSTRACT FROM AUTHOR]

Background: Teeth and supporting oral tissues are attractive and accessible sources of stem cells. Periodontal ligament stem cells (PDLSC) are readily isolated from extracted third molars, and exhibit the ability to self‐renew and differentiate into multiple mesodermal cell fates. Clinical experience suggests that the exact location of periodontal defects affects the oral bone remodeling and wound healing. Compared to the mandible, the maxilla heals quicker and more efficiently. Angiogenesis is key in tissue regeneration including dental tissues, yet few studies focus on the angiogenic potential of PDLSC, none of which considered the differences between upper and lower jaw PDLSC (u‐PDLSC and l‐PDLSC, respectively). Methods: Here we studied the angiogenic potential of u‐PDLSC and l‐PDLSC and compared the results to well‐established mesenchymal stem cells (MSC). Cells were characterized in terms of surface markers, proliferation, and vascular endothelial growth factor (VEGF) secretion, and angiogenic assays were performed. Newly formed capillaries were stained with CD31, and their expression of platelet endothelial cell adhesion molecule (PECAM‐1), angiopoietin 2 (ANGPT2), and vascular endothelial growth factor receptor 1 and 2 (VEGFR‐1, VEGFR‐2) were measured. Results: Periodontal stem cells from the upper jaw showed a higher proliferation capacity, secreted more VEGF, and formed capillary networks faster and denser than l‐PDLSC. Gene expression of angiogenesis‐related genes was significantly higher in u‐PDLSC than in l‐PDLSC or MSC, given that culture conditions were suitable. Conclusion: The oral cavity is a valuable source of stem cells, particularly PDLSC, which are promising for oral tissue engineering due to their robust growth, lifelong accessibility, low immunogenicity, and strong differentiation potential. Notably, u‐PDLSC exhibit higher VEGF secretion and accelerate capillary formation compared to l‐PDLSC or MSC. This study suggests a potential molecular mechanism in capillary formation, emphasizing the significance of precise location isolation of PDLSC. [ABSTRACT FROM AUTHOR]

A high sodium (HS) diet is believed to affect bone metabolism processes. Clarifying its impact on osseointegration of titanium (Ti) implants holds significant implications for postoperative dietary management of implanted patients. This investigation probed the impact of sodium ions (Na+) on neovascularization and osteogenesis around Ti implants in vivo , utilizing micro-computed tomography, hematoxylin and eosin staining, and immunohistochemical analyses. Concurrently, in vitro experiments assessed the effects of varied Na+ concentrations and exposure durations on human umbilical vein endothelial cells (HUVECs) and MC3T3-E1 cells. In vivo , increased dietary sodium (0.8%–6.0%) led to a substantial decline in CD34 positive HUVECs and new bone formation around Ti implants, alongside an increase in inflammatory cells. In vitro , an increase in Na+ concentration (140–150 mmol/L) adversely affected the proliferation, angiogenesis, and migration of HUVECs, especially with prolonged exposure. While MC3T3-E1 cells initially exhibited less susceptibility to high Na+ concentrations compared to HUVECs during short-term exposure, prolonged exposure to a HS environment progressively diminished their proliferation, differentiation, and osteogenic capabilities. These findings suggest that HS diet had a negative effect on the early osseointegration of Ti implants by interfering with the process of postoperative vascularized bone regeneration. [ABSTRACT FROM AUTHOR]

Using two independent speckle imaging systems based on the recently published LSOCI method operating in contact mode on the skin, we assess the reproducibility of in vivo measurements and conduct an inter-instrument comparison. To this aim, we propose a calibration method to handle each imaging system as a comprehensive unit, which includes the laser source, optics, and camera. Key to our method is the introduction of a new index that quantifies the departure of the temporal contrast observed in vivo from the spatial contrast scattered from a reference static element generating a circular Gaussian speckle field. Using such near-real-time calibration method, we demonstrate that the microcirculation images produced by 2 different instruments exhibit high accuracy and stability, with microcirculation activity values in excellent agreement, thereby paving the way for clinical applications. [ABSTRACT FROM AUTHOR]

Endothelial cells (ECs) are widely used as donor cells in tissue engineering, organoid vascularization, and in vitro microvascular model development. ECs are invaluable tools for disease modeling and drug screening in fundamental research. When treating ischemic diseases, EC engraftment facilitates the restoration of damaged blood vessels, enhancing therapeutic outcomes. This article presents a comprehensive overview of the current sources of ECs, which encompass stem/progenitor cells, primary ECs, cell lineage conversion, and ECs derived from other cellular sources, provides insights into their characteristics, potential applications, discusses challenges, and explores strategies to mitigate these issues. The primary aim is to serve as a reference for selecting suitable EC sources for preclinical research and promote the translation of basic research into clinical applications. [ABSTRACT FROM AUTHOR]

BACKGROUND: Graphene is the thinnest, strongest, and toughest type of two-dimensional new crystal material, demonstrating significant advantages in biomedical applications. Angiogenesis and vascularization of bone are key factors in tissue repair and regeneration, and are effective ways to address vascular and osteogenic issues. OBJECTIVE: To review the characteristics and mechanisms of graphene and its derivatives in promoting angiogenesis activity and vascularizing bone, in order to provide a reference for their clinical application in vascular tissue repair and regeneration. METHODS: Using a computer to search for relevant literature included in PubMed, ScienceDirect, CNKI, and Wanfang databases, the Chinese search terms were “grapheme”, “angiogenesis, vascularization”, “vascularized bone”, and “endothelial cells”, while the English search terms were “graphene” “angiogenesis OR vascularization” “vascularized bone” “endothelial cells”. After excluding literature unrelated to the topic of the article, according to the inclusion and exclusion criteria, 62 articles were ultimately included for result analysis. RESULTS AND CONCLUSION: (1) At present, graphene oxide has been studied more and is the most widely used in graphene and its derivatives. (2) Graphene and its derivatives are suitable for heart, bone, nerve, and wound healing related diseases. (3) Graphene and its derivatives have excellent physical and chemical properties and biological properties, but they have potential cytotoxicity. We should pay attention to its biological safety in application. (4) The application of graphene and its derivatives requires further research to demonstrate the optimal size and concentration and measures to reduce toxicity. (5) On the cellular level, graphene and its derivatives can promote angiogenic activity by tip endothelial cell phenotype, mesenchymal stem cell adhesion and proliferation, and vascular smooth muscle cell growth. (6) On the molecular level, graphene and its derivatives can increase the expression of vascular endothelial growth factor, basic fibroblast growth factor, hepatocyte growth factor and activate reactive oxygen species/nitric oxide synthase/nitric oxide signaling pathway, lysophosphatilate R6/Hippo-YAP pathway, stromal cell-derived factor-1/vascular endothelial growth factor and ZEB 1/Notch1 pathway. (7) Grapheme oxide and graphene oxide-copper phosphorylated extracellular regulatory protein kinase and activated hypoxia-inducible factor-1, thereby promoting the up-regulation of vascular endothelial growth factor and bone morphogenetic protein-2 expression, and promoting angiogenesis and vascularized bone. (8) In summary, graphene and its derivatives, especially graphene oxide, have great application prospects in the repair and regeneration of vascularized tissues due to their excellent biological properties, good angiogenesis and vascularized bone ability. [ABSTRACT FROM AUTHOR]

The tissue‐specific heart decellularized extracellular matrix (hdECM) demonstrates a variety of therapeutic advantages, including fibrosis reduction and angiogenesis. Consequently, recent research for myocardial infarction (MI) therapy has utilized hdECM with various delivery techniques, such as injection or patch implantation. In this study, a novel approach for hdECM delivery using a wet adhesive paintable hydrogel is proposed. The hdECM‐containing paintable hydrogel (pdHA_t) is simply applied, with no theoretical limit to the size or shape, making it highly beneficial for scale‐up. Additionally, pdHA_t exhibits robust adhesion to the epicardium, with a minimal swelling ratio and sufficient adhesion strength for MI treatment when applied to the rat MI model. Moreover, the adhesiveness of pdHA_t can be easily washed off to prevent undesired adhesion with nearby organs, such as the rib cages and lungs, which can result in stenosis. During the 28 days of in vivo analysis, the pdHA_t not only facilitates functional regeneration by reducing ventricular wall thinning but also promotes neo‐vascularization in the MI region. In conclusion, the pdHA_t presents a promising strategy for MI treatment and cardiac tissue regeneration, offering the potential for improved patient outcomes and enhanced cardiac function post‐MI. [ABSTRACT FROM AUTHOR]

Background and Objective: The embryo and the fetus develop in a physiologically hypoxic environment, where vascularization is sustained by HIF-1, VEGF, and the β-adrenergic system. In animals, β3-adrenoceptors (β3-ARs), up-regulated by hypoxia, favor global fetal wellness to such an extent that most diseases related to prematurity are hypothesized to be induced or aggravated by a precocious β3-AR down-regulation, due to premature exposure to a relatively hyperoxic environment. In animals, β3-AR pharmacological agonism is currently investigated as a possible new therapeutic opportunity to counteract oxygen-induced damages. Our goal is to translate the knowledge acquired in animals to humans. Recently, we have demonstrated that fetuses become progressively more hypoxemic from mid-gestation to near-term, but starting from the 33rd–34th week, oxygenation progressively increases until birth. The present paper aims to describe a clinical research protocol, evaluating whether the expression level of HIF-1, β3-ARs, and VEGF is modulated by oxygen during intrauterine and postnatal life, in a similar way to animals. Materials and Methods: In a prospective, non-profit, single-center observational study we will enroll 100 preterm (group A) and 100 full-term newborns (group B). We will collect cord blood samples (T0) and measure the RNA expression level of HIF-1, β3-ARs, and VEGF by digital PCR. In preterms, we will also measure gene expression at 48–72h (T1), 14 days (T2), and 30 days (T3) of life and at 40 ± 3 weeks of post-menstrual age (T4), regardless of the day of life. We will compare group A (T0) vs. group B (T0) and identify any correlations between the values obtained from serial samples in group A and the clinical data of the patients. Our protocol has been approved by the Pediatric Ethical Committee for Clinical Research of the Tuscany region (number 291/2022). Expected Results: The observation that in infants, the HIF-1/β3-ARs/VEGF axis shows similar modulation to that of animals could suggest that β3-ARs also promote fetal well-being in humans. [ABSTRACT FROM AUTHOR]

Purpose: The tensor fasciae latae (TFL) muscle is supplied by the lateral femoral circumflex artery (LCFA), arising from the deep femoral artery. However, it has been noted that there is also a consistent vascular anastomotic network. The aim of this study was to describe the accessory vascularization of the TFL muscle through a descriptive anatomical study, in order to hypothesize the feasibility of harvesting a TFL flap in the event of an injury to the main pedicle. In addition, we illustrate this hypothesis with a successful clinical case of Scarpa freconstruction following ligature of the deep femoral artery. Methods: The description of the accessory vascularization was obtained by injecting dye into seven lateral femoral circumflex arteries (LCFA), six superficial circumflex iliac arteries (SCIA), and three inferior gluteal arteries (IGA). Results: The TFL muscle was vascularized primarily by the LCFA. A vascular anastomotic network with the SCIA and the IGA was observed. After selective injection to the SCIAs and IGAs, the subsequent injection to the LCFA showed a diffusion of the TFL skin paddle with a perforasome overlapping between the different vascular territories. Conclusion: The ascending branch of the lateral femoral circumflex plays a dominant role in the vascularization of the TFL muscle. As a result of a periarticular anastomotic network of the hip, this artery establishes several connections with the proximal arteries. Consequently, in cases where blood flow through the LCFA is interrupted, it should be equally possible to harvest the TFL flap through its accessory vascularization. [ABSTRACT FROM AUTHOR]

Background: We previously reported that metastases are generally characterized by a core program of gene expression that activates tissue remodeling/vascularization, alters ion homeostasis, induces the oxidative metabolism, and silences extracellular matrix interactions. This core program distinguishes metastases from their originating primary tumors as well as from their destination host tissues. Therefore, the gene products involved are potential targets for anti‐metastasis drug treatment. Methods: Because the silencing of extracellular matrix interactions predisposes to anoiks in the absence of active survival mechanisms, we tested inhibitors against the other three components. Results: Individually, the low‐specificity VEGFR blocker pazopanib (in vivo combined with marimastat), the antioxidant dimethyl sulfoxide (or the substitute atovaquone, which is approved for internal administration), and the ionic modulators bumetanide and tetrathiomolybdate inhibited soft agar colony formation by breast and pancreatic cancer cell lines. The individual candidate agents have a record of use in humans (with limited efficacy when administered individually) and are available for repurposing. In combination, the effects of these drugs were additive or synergistic. In two mouse models of cancer (utilizing 4T1 cells or B16‐F10 cells), the combination treatment with these medications, applied immediately (to prevent metastasis formation) or after a delay (to suppress established metastases), dramatically reduced the occurrence of disseminated foci. Conclusions: The combination of tissue remodeling inhibitors, suppressors of the oxidative metabolism, and ion homeostasis modulators has very strong promise for the treatment of metastases by multiple cancers. [ABSTRACT FROM AUTHOR]