Traditional tissue engineering skin are composed of living cells and natural or synthetic scaffold. Besize the time delay and the risk of contamination involved with cell culture, the lack of autologous cell source and the persistence of allogeneic cells in heterologous grafts have limited its application. This study shows a novel tissue engineering functional skin by carrying minimal functional unit of skin (MFUS) in 3D-printed polylactide-co-caprolactone (PLCL) scaffold and collagen gel (PLCL + Col + MFUS). MFUS is full-layer micro skin harvested from rat autologous tail skin. 3D-printed PLCL elastic scaffold has the similar mechanical properties with rat skin which provides a suitable environment for MFUS growing and enhances the skin wound healing. Four large full-thickness skin defects with 30 mm diameter of each wound are created in rat dorsal skin, and treated either with tissue engineering functional skin (PLCL + Col + MFUS), or with 3D-printed PLCL scaffold and collagen gel (PLCL + Col), or with micro skin islands only (Micro skin), or without treatment (Normal healing). The wound treated with PLCL + Col + MFUS heales much faster than the other three groups as evidenced by the fibroblasts migration from fascia to the gap between the MFUS dermis layer, and functional skin with hair follicles and sebaceous gland has been regenerated. The PLCL + Col treated wound heals faster than normal healing wound, but no skin appendages formed in PLCL + Col-treated wound. The wound treated with micro skin islands heals slower than the wounds treated either with tissue engineering skin (PLCL + Col + MFUS) or with PLCL + Col gel. Our results provide a new strategy to use autologous MFUS instead “seed cells” as the bio-resource of engineering skin for large full-thickness skin wound healing.

Engineered implantable functional thick tissues require hierarchical vasculatures within cell‐laden hydrogel that can mechanically withstand the shear stress from perfusion and facilitate angiogenesis for nutrient transfer. Yet current extrusion‐based 3D printing strategies are unable to recapitulate hierarchical networks, highlighting the need for bioinks with tunable properties. Here, we introduce an approach whereby crosslinkable microgels enhance mechanical stability and induce spontaneous microvascular networks comprised of human umbilical cord vein endothelial cells (HUVECs) in a soft gelatin methacryoyl (GelMA)‐based bioink. Furthermore, we successfully implanted the 3D printed multi‐branched tissue, being connected from the rat carotid artery to the jugular vein direct surgical anastomosis. The work represents a significant step toward in the field of large vascularized tissue fabrication and may have implications for the treatment of organ failure in the future.

Bioprinting is a promising technology focusing on tissue manufacturing, whose vital problem is the precise assembly of multiple materials. As the primary solution, the extrusion-based multi-printhead bioprinting (MPB) method requires printhead switching during the printing process, which induces inefficient motion time and material interface defects. We present a valve-based consecutive bioprinting (VCB) method to resolve these problems, containing a precise integrated switching printhead and a well-matched voxelated digital model. The rotary valve built-in the VCB printhead guarantees the precise assembling of different materials at the interface isolated from the viscoelastic inks’ elastic potential energy in the cartridge. We study the coordinated control approach of the valve rotation and pressure adjustment to achieve the seamless switching, leading to a controllable multimaterial interface, including boundary and suture structure. Furthermore, we compare the VCB method and MPB method, quantitatively and comprehensively, indicating that the VCB method obtained greater mechanical strength (maximum tensile deformation increased by 44.37%) and higher printing efficiency (effective time ratio increased by 29.48%). As an exemplar, we fabricate a muscle-like tissue with a vascular tree, suture interface encapsulating C2C12, and human dermal fibroblasts (HDFB) cells, then placed it in complete medium with continuous perfusion for 5 d. Our study suggests that the VCB method is sufficient to fabricate heterogeneous tissues with complex multimaterial interfaces.

Over the past two decades, 3D bioprinting has become a popular research topic worldwide, as it is the most promising approach for manufacturing vascularized organs in vitro. However, transitioning from bioprinting of simple tissue models to real biomedical applications is still a challenge due to incomplete interdisciplinary theoretical knowledge and imperfect multi‐technology integration. This review examines the goals of vasculature manufacturing and proposes new strategic objectives in three stages. We then outline a bidirectional manufacturing strategy consisting of top‐down reconstruction (bioprinting) and bottom‐up regeneration (cellular behaviour). We also provide an in‐depth analysis of the four aspects of design, ink, printing and culture. Furthermore, we present the ‘construction‐comprehension cycle’ research paradigm and the ‘math‐model‐based batch insights generator’ research paradigm for the future, which may have the potential to revolutionize the biomedical field.