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Changes in structure and function of small muscular arteries play a major role in the pathophysiology of pulmonary hypertension, a burgeoning public health challenge. Improved anatomically mimetic in vitro models of these microvessels are urgently needed because nonhuman vessels and previous models do not accurately recapitulate the microenvironment and architecture of the human microvascular wall. Here, we describe parallel biofabrication of photopatterned self-rolled biomimetic pulmonary arterial microvessels of tunable size and infrastructure. These microvessels feature anatomically accurate layering and patterning of aligned human smooth muscle cells, extracellular matrix, and endothelial cells and exhibit notable increases in endothelial longevity and nitric oxide production. Computational image processing yielded high-resolution 3D perspectives of cells and proteins. Our studies provide a new paradigm for engineering multicellular tissues with precise 3D spatial positioning of multiple constituents in planar moieties, providing a biomimetic platform for investigation of microvascular pathobiology in human disease. 

Multicellular organization with precise spatial definition is essential to various biological processes, including morphogenesis, development, and healing in vascular and other tissues. Gradients and patterns of chemoattractants are well‐described guides of multicellular organization, but the influences of 3D geometry of soft hydrogels are less well defined. Here, the discovery of a new mode of endothelial cell self‐organization guided by combinatorial effects of stiffness and geometry, independent of protein or chemical patterning, is described. Endothelial cells in 2 kPa microwells are found to be ≈30 times more likely to migrate to the edge to organize in ring‐like patterns than in stiff 35 kPa microwells. This organization is independent of curvature and significantly more pronounced in 2 kPa microwells with aspect ratio (perimeter/depth) < 25. Physical factors of cells and substrates that drive this behavior are systematically investigated and a mathematical model that explains the organization by balancing the dynamic interaction between tangential cytoskeletal tension, cell–cell, and cell–substrate adhesion is presented. These findings demonstrate the importance of combinatorial effects of geometry and stiffness in complex cellular organization that can be leveraged to facilitate the engineering of bionics and integrated model organoid systems with customized nutrient vascular networks.

 

Interfacing nano/microscale elements with biological components in 3D contexts opens new possibilities for mimicry, bionics, and augmentation of organismically and anatomically inspired materials. Abiotic nanoscale elements such as plasmonic nanostructures, piezoelectric ribbons, and thin film semiconductor devices interact with electromagnetic fields to facilitate advanced capabilities such as communication at a distance, digital feedback loops, logic, and memory. Biological components such as proteins, polynucleotides, cells, and organs feature complex chemical synthetic networks that can regulate growth, change shape, adapt, and regenerate. Abiotic and biotic components can be integrated in all three dimensions in a well‐ordered and programmed manner with high tunability, versatility, and resolution to produce radically new materials and hybrid devices such as sensor fabrics, anatomically mimetic microfluidic modules, artificial tissues, smart prostheses, and bionic devices. In this critical Review, applications of small scale devices in 3D hybrid integration, biomicrofluidics, advanced prostheses, and bionic organs are discussed.