3D Construction of Shape-Controllable Tissues through Self-Bonding of Multicellular Microcapsules

Designed microtissues that replicate highly ordered three-dimensional (3D) multicellular in vivo structures have shown huge potential in biomedical research and drug discovery. Through microencapsulation and microfluidic techniques, cell-laden microcapsules have been widely used as pathological or pharmacological models. However, most conventional microtissue construction strategies can only engineer simply predefined microcapsules with monotonous biological components in two dimensions. Here, we propose a flexible 3D microtissue construction method through self-bonding of real-time shape-programmable microcapsules. The microcapsules are prepared by photo-induced electrodeposition of cell-laden alginate hydrogel and flexibly tailored into tissue-specific shapes, sizes, and arbitrary biocomponents. With the local fluidics-guided assembly, the microcapsules are spatially organized into 3D perfectly aligned microtissues. To mimic in vivo intercellular connection, the aligned microcapsules are precoated with fibroblasts to self-bond the adjacent layers into a robust assemblage through fibroblast-extracellular matrix interactions, which highly reproduces the tissue morphogenesis in natural organisms. As a typical complex tissue model, the 3D hepatic lobule was engineered utilizing HepG2 cells seeded into microcapsules with a fibroblast coating, and its biofunction including albumin and urea secretion was improved by nearly two-fold compared with cells seeded without a fibroblast coating. We anticipate that our method will be capable of regenerating more complex multicellular constructs with unprecedented possibilities for future tissue engineering applications.