The timely establishment of functional neo-vasculature is pivotal for successful tissue development and regen-eration,remaining a central challenge in tissue engineering.In this study,we present a novel(micro)vascular...The timely establishment of functional neo-vasculature is pivotal for successful tissue development and regen-eration,remaining a central challenge in tissue engineering.In this study,we present a novel(micro)vascular-ization strategy that explores the use of specialized“vascular units”(VUs)as building blocks to initiate blood vessel formation and create perfusable,stroma-embedded 3D microvascular networks from the bottom-up.We demonstrate that VUs composed of endothelial progenitor cells and organ-specific fibroblasts exhibit high angiogenic potential when embedded in fibrin hydrogels.This leads to the formation of VUs-derived capillaries,which fuse with adjacent capillaries to form stable microvascular beds within a supportive,extracellular matrix-rich fibroblastic microenvironment.Using a custom-designed biomimetic fibrin-based vessel-on-chip(VoC),we show that VUs-derived capillaries can inosculate with endothelialized microfluidic channels in the VoC and become perfused.Moreover,VUs can establish capillary bridges between channels,extending the microvascular network throughout the entire device.When VUs and intestinal organoids(IOs)are combined within the VoC,the VUs-derived capillaries and the intestinal fibroblasts progressively reach and envelop the IOs.This promotes the formation of a supportive vascularized stroma around multiple IOs in a single device.These findings un-derscore the remarkable potential of VUs as building blocks for engineering microvascular networks,with ver-satile applications spanning from regenerative medicine to advanced in vitro models.展开更多
基金developed under the scope of the EndoSWITCH project(PTDC/BTMORG/5154/2020)supported by the Portuguese Founda-tion for Science and Technology(FCT).The authors thanks FCT for Iasmim Orge’s PhD scholarship SFRH/BD/2020.07458+5 种基金Sílvia Bidarra’s research contract DL 57/2016/CP1360/CT0006 and Silvia Ferreira’s research contract CEECINST/00132/2021/CP1774/CT0001Iasmim Orge thanks the training provided under the scope of the REMODEL project(European Union’s Horizon 2020 research and innovation pro-gramme,grant agreement 7857491)The authors also acknowledge the support of i3S Scientific Platforms:“Bioimaging”member of the PPBI(Grant No:PPBI-POCI-01-0145-FEDER-022122)“Biointerfaces and Nanotechnology”(Grant No:UID/BIM/04293/2019)“BioSciences Screening”(member of the PT-OPENSCREEN(NORTE-01-0145-FEDER-085468)PPBI(PPBI-POCI-01-0145-FEDER-022122)).
文摘The timely establishment of functional neo-vasculature is pivotal for successful tissue development and regen-eration,remaining a central challenge in tissue engineering.In this study,we present a novel(micro)vascular-ization strategy that explores the use of specialized“vascular units”(VUs)as building blocks to initiate blood vessel formation and create perfusable,stroma-embedded 3D microvascular networks from the bottom-up.We demonstrate that VUs composed of endothelial progenitor cells and organ-specific fibroblasts exhibit high angiogenic potential when embedded in fibrin hydrogels.This leads to the formation of VUs-derived capillaries,which fuse with adjacent capillaries to form stable microvascular beds within a supportive,extracellular matrix-rich fibroblastic microenvironment.Using a custom-designed biomimetic fibrin-based vessel-on-chip(VoC),we show that VUs-derived capillaries can inosculate with endothelialized microfluidic channels in the VoC and become perfused.Moreover,VUs can establish capillary bridges between channels,extending the microvascular network throughout the entire device.When VUs and intestinal organoids(IOs)are combined within the VoC,the VUs-derived capillaries and the intestinal fibroblasts progressively reach and envelop the IOs.This promotes the formation of a supportive vascularized stroma around multiple IOs in a single device.These findings un-derscore the remarkable potential of VUs as building blocks for engineering microvascular networks,with ver-satile applications spanning from regenerative medicine to advanced in vitro models.
