4D bioprinting is promising to build cell‐laden constructs (bioconstructs) with complex geometries and functions for tissue/organ regeneration applications. The development of hydrogel‐based 4D bioinks, especially those allowing living cell printing, with easy preparation, defined composition, and controlled physical properties is critically important for 4D bioprinting. Here, a single‐component jammed micro‐flake hydrogel (MFH) system with heterogeneous size distribution, which differs from the conventional granular microgel, has been developed as a new cell‐laden bioink for 4D bioprinting. This jammed cytocompatible MFH features scalable production and straightforward composition with shear‐thinning, shear‐yielding, and rapid self‐healing properties. As such, it can be smoothly printed into stable 3D bioconstructs, which can be further cross‐linked to form a gradient in cross‐linking density when a photoinitiator and a UV absorber are incorporated. After being subject to shape morphing, a variety of complex bioconstructs with well‐defined configurations and high cell viability are obtained. Based on this system, 4D cartilage‐like tissue formation is demonstrated as a proof‐of‐concept. The establishment of this versatile new 4D bioink system may open up a number of applications in tissue engineering.

We employed a multiplexed microvasculature-on-a-chip platform to investigate the impact of stromal cell identity on microvascular network formation and perfusion.

Extracellular matrix (ECM) remodeling is essential for the process of capillary morphogenesis. Here we employed synthetic poly(ethylene glycol) (PEG) hydrogels engineered with proteolytic specificity to either matrix metalloproteinases (MMPs), plasmin, or both to investigate the relative contributions of MMP‐ and plasmin‐mediated ECM remodeling to vessel formation in a 3D‐model of capillary self‐assembly analogous to vasculogenesis. We first demonstrated a role for both MMP‐ and plasmin‐mediated mechanisms of ECM remodeling in an endothelial‐fibroblast co‐culture model of vasculogenesis in fibrin hydrogels using inhibitors of MMPs and plasmin. When this co‐culture model was employed in engineered PEG hydrogels with selective protease sensitivity, we observed robust capillary morphogenesis only in MMP‐sensitive matrices. Fibroblast spreading in plasmin‐selective hydrogels confirmed this difference was due to protease preference by endothelial cells, not due to limitations of the matrix itself. In hydrogels engineered with crosslinks that were dually susceptible to MMPs and plasmin, capillary morphogenesis was unchanged. These findings highlight the critical importance of MMP‐mediated degradation during vasculogenesis and provide strong evidence to justify the preferential selection of MMP‐degradable peptide crosslinkers in synthetic hydrogels used to study vascular morphogenesis and promote vascularization. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B:2507–2516, 2019.

There is a critical need for biomaterials that support robust neovascularization for a wide-range of clinical applications. Here we report how cells alter tissue-level mechanical properties during capillary morphogenesis using a model of endothelial-stromal cell co-culture within poly(ethylene glycol) (PEG) based hydrogels. After a week of culture, we observed substantial stiffening in hydrogels with very soft initial properties. Endothelial cells or stromal cells alone, however, failed to induce hydrogel stiffening. This stiffening tightly correlated with degree of vessel formation but not with hydrogel compaction or cellular proliferation. Despite a lack of fibrillar architecture within the PEG hydrogels, cell-generated contractile forces were essential for hydrogel stiffening. Upregulation of alpha smooth muscle actin and collagen-1 was also correlated with enhanced vessel formation and hydrogel stiffening. Blocking cell-mediated hydrogel degradation abolished stiffening, demonstrating that matrix metalloproteinase (MMP)-mediated remodeling is required for stiffening to occur. These results highlight the dynamic reciprocity between cells and their mechanical microenvironment during capillary morphogenesis and provide important insights for the rational design of materials for vasculogenic applications.

4D Bioprinting For bioprinting of 4D living tissues, in article number 2109394, Eben Alsberg and co‐workers devise a cell‐laden bioink featuring high‐resolution printing, physiological‐trigger‐enabled shape morphing, and long‐term cell viability and function. With this system, they demonstrate that the printed cell‐rich bioconstructs can exert multidirectional reshaping in a controlled manner and transform and develop into tissues with sophisticated structures. The system is anticipated to advance bioprinting to a horizon that enables 4D biomimetic tissue engineering.