Triple-Scale Endothelialized Tubular Networks via Hybrid Biofabrication for Scalable Vascular Tissue Engineering

Abstract

The human vascular system is a sophisticated hierarchical network branching from large-diameter vessels to fine capillaries. Recapitulating this hierarchy remains a major biofabrication challenge, as oxygen diffusion from the nearest capillary is limited to ≈200 µm in native tissues, while current vascularized constructs struggle to maintain stable perfusion and functional multiscale architectures. To address this, a hybrid fabrication strategy is introduced that combines top-down microfabrication of tubular scaffolds via electrospinning with bottom-up bioprinting of cell-laden bioinks. This approach enables the engineering of spatially programmable endothelialized tubular networks across three scales: macrovessels (≈3 mm), mesovessels (500–2000 µm), and capillaries (10–25 µm). Electrospun macrovessels exhibit artery-like mechanical properties in longitudinal and circumferential directions. Bioprinting enables precise control over meso- and capillary-scale vessels, facilitating the hierarchical patterning of complex architectures. Integrated triple-scale endothelialized tubular networks formed interconnected, perfusable architectures comprising spatially patterned capillaries and enhanced diffusive transport by more than fivefold. Dynamic culture within endothelialized tubular networks of 5 mm thick tissue constructs supports high cell viability, rapid capillary formation, and in vivo-like endothelial phenotypes under moderate flow. This work uniquely enables scalable vascular–mimetic architectures with artery-like mechanical properties and spatially defined capillaries, representing a previously unattainable integration in angiogenesis, bioprinting, electrospinning, scaled-up tissue constructs, vascular tissue engineeringlarge-scale vascular constructs.