Creation of long-lasting blood vessels

Koike, Naoto; Fukumura, Dai; Gralla, Oliver; Au, Patrick; Schechner, Jeffrey S.; Jain, Rakesh K.

doi:10.1038/428138a

Cited by 649 publications

(512 citation statements)

References 10 publications

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“…[1][2][3][4][5] The vessel walls engineered under these conditions were found to be substantially similar to native vessels at both molecular and cellular levels. [2][3][4][5] These findings have generated considerable interest in the potential application of engineered blood vessels in regenerative medicine and cell-based revascularization therapies.…”

Section: Introductionmentioning

confidence: 84%

Factory neovessels: engineered human blood vessels secreting therapeutic proteins as a new drug delivery system

et al. 2010

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Several works have shown the feasibility of engineering functional blood vessels in vivo using human endothelial cells (ECs). Going further, we explored the therapeutic potential of neovessels after gene-modifying the ECs for the secretion of a therapeutic protein. Given that these vessels are connected with the host vascular bed, we hypothesized that systemic release of the expressed protein is immediate. As a proof of principle, we used primary human ECs transduced with a lentiviral vector for the expression of a recombinant bispecific aCEA/aCD3 antibody. These ECs, along with mesenchymal stem cells as a source of mural cells, were embedded in Matrigel and subcutaneously implanted in nude mice. High antibody levels were detected in plasma for 1 month. Furthermore, the antibody exerted a therapeutic effect in mice bearing distant carcinoembryonic-antigen (CEA)-positive tumors after inoculation of human T cells. In summary, we show for the first time the therapeutic effect of a protein locally secreted by engineered human neovessels.

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Section: Introductionmentioning

confidence: 84%

Factory neovessels: engineered human blood vessels secreting therapeutic proteins as a new drug delivery system

et al. 2010

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“…There are two explicit mechanisms of blood vessel growth: vasculogenesis, the de novo formation of blood vessels by endothelial progenitor cells, and angiogenesis, the sprouting of new vessels from preexisting ones. For engineering of microvasculature within a 3-D cell laden biomaterial construct, many biological extracellular matrix (ECM) materials and cell co-cultures have been studied with respect to their vasculogenic potential [1][2][3][4]. Mimicking the embryonic environment for vasculogenesis is a popular strategy; for example, experiments on encapsulation of vascular progenitor cells within 3-D biological ECM have been undertaken, in which angioblasts and mesenchymal stem cells self-organize into a microvascular network and form a capillary bed [5].…”

Section: Introductionmentioning

confidence: 99%

Hydrogel-based microfluidics for vascular tissue engineering

Koroleva

Deiwick

Nguyen³

et al. 2016

BioNanoMaterials

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Abstract:In this work, we have explored 3-D co-culture of vasculogenic cells within a synthetically modified fibrin hydrogel. Fibrinogen was covalently linked with PEG-NHS in order to improve its degradability resistance and physico-optical properties. We have studied influences of the degree of protein PEGylation and the concentration of enzyme thrombin used for the gel preparation on cellular responses. Scanning electron microscopy analysis of prepared gels revealed that the degree of PEGylation and the concentration of thrombin strongly influenced microstructural characteristics of the protein hydrogel. Human umbilical vein endothelial cells (HUVECs) and human adipose-derived stem cells (hASCs), used as vasculogenic co-culture, could grow in 5:1 PEGylated fibrin gels prepared using 1:0.2 protein to thrombin ratio. This gel formulation supported hASCs and HUVECs spreading and the formation of cell extensions and cell-to-cell contacts. Expression of specific ECM proteins and vasculogenic process inherent cellular enzymatic activity were investigated by immunofluorescent staining, gelatin zymography, western blot and RT-PCR analysis. After evaluation of the optimal gel composition and PEGylation ratio, the hydrogel was utilized for investigation of vascular tube formation within a perfusable microfluidic system. The morphological development of this co-culture within a perfused hydrogel over 12 days led to the formation of interconnected HUVEC-hASC network. The demonstrated PEGylated fibrin microfluidic approach can be used for incorporating other cell types, thus representing a unique experimental platform for basic vascular tissue engineering and drug screening applications.

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“…However, the process of angiogenesis is an inherently slow process (estimates range from 100 mm to 1 mm per day (Mikos et al, 1993;Orr et al, 2003)), and the timely generation of a stable vascular network has long been identified as a fundamental challenge for tissue engineering (Koike et al, 2004). Because of the inherent constraints of vascular ingrowth, constructs of clinically relevant size may progressively become devoid of oxygen and nutrients in their centre upon implantation, which will be detrimental for cellular function and survival (Radisic et al, 2006;Scheufler et al, 2008).…”

Section: Hypoxia In Bone Tissue Engineeringmentioning

confidence: 99%

“…Upon implantation, this network then only has to anastomose to the host vasculature to establish perfusion. Indeed, many studies have shown that implanted endothelial cells can contribute to the blood vessels that are formed inside tissue-engineered constructs (Koike et al, 2004;Ma et al, 2014a;van Gastel et al, 2012). While promising, most approaches are still in an experimental stage with varying degrees of success, even in small defects (Kim and von Recum, 2008).…”

Section: The Potential Of Intrinsic Angiogenesis To Decrease Hypoxiamentioning

confidence: 99%

Targeting the hypoxic response in bone tissue engineering: A balance between supply and consumption to improve bone regeneration

Stiers

Gastel

Carmeliet

2016

Molecular and Cellular Endocrinology

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a b s t r a c tBone tissue engineering is a promising therapeutic alternative for bone grafting of large skeletal defects. It generally comprises an ex vivo engineered combination of a carrier structure, stem/progenitor cells and growth factors. However, the success of these regenerative implants largely depends on how well implanted cells will adapt to the hostile and hypoxic host environment they encounter after implantation. In this review, we will discuss how hypoxia signalling may be used to improve bone regeneration in a tissue-engineered construct. First, hypoxia signalling induces angiogenesis which increases the survival of the implanted cells as well as stimulates bone formation. Second, hypoxia signalling has also angiogenesis-independent effects on mesenchymal cells in vitro, offering exciting new possibilities to improve tissue-engineered bone regeneration in vivo. In addition, studies in other fields have shown that benefits of modulating hypoxia signalling include enhanced cell survival, proliferation and differentiation, culminating in a more potent regenerative implant. Finally, the stimulation of endochondral bone formation as a physiological pathway to circumvent the harmful effects of hypoxia will be briefly touched upon. Thus, angiogenic dependent and independent processes may counteract the deleterious hypoxic effects and we will discuss several therapeutic strategies that may be combined to withstand the hypoxia upon implantation and improve bone regeneration.

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Creation of long-lasting blood vessels

Cited by 649 publications

References 10 publications

Factory neovessels: engineered human blood vessels secreting therapeutic proteins as a new drug delivery system

Factory neovessels: engineered human blood vessels secreting therapeutic proteins as a new drug delivery system

Hydrogel-based microfluidics for vascular tissue engineering

Targeting the hypoxic response in bone tissue engineering: A balance between supply and consumption to improve bone regeneration

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