Cell‐Laden Multiple‐Step and Reversible 4D Hydrogel Actuators to Mimic Dynamic Tissue Morphogenesis

Abstract

Shape‐morphing hydrogels bear promising prospects as soft actuators and for robotics. However, they are mostly restricted to applications in the abiotic domain due to the harsh physicochemical conditions typically necessary to induce shape morphing. Here, multilayer hydrogel actuator systems are developed using biocompatible and photocrosslinkable oxidized, methacrylated alginate and methacrylated gelatin that permit encapsulation and maintenance of living cells within the hydrogel actuators and implement programmed and controlled actuations with multiple shape changes. The hydrogel actuators encapsulating cells enable defined self‐folding and/or user‐regulated, on‐demand‐folding into specific 3D architectures under physiological conditions, with the capability to partially bioemulate complex developmental processes such as branching morphogenesis. The hydrogel actuator systems can be utilized as novel platforms for investigating the effect of programmed multiple‐step and reversible shape morphing on cellular behaviors in 3D extracellular matrix and the role of recapitulating developmental and healing morphogenic processes on promoting new complex tissue formation.

4D biofabrication via instantly generated graded hydrogel scaffolds

“…4D biofabricated scaffolds capable of undergoing dynamic shape transformations may enable the engineering of tissues with complex geometries and replication of critical morphodynamic evolutions that occur during native tissue development [ 43 , 54 ]. Design of conventional inductive hydrogel scaffolds for tissue engineering that are geometrically static often primarily focuses on controlling microenvironmental physiochemical niches for guiding cell behavior and new tissue formation and generally neglects important macroscopic morphing.…”

“…Note that to minimize the potential impact of HMAP on the cell behaviors, culture medium for cell-laden constructs was changed 4 times during the first 2 h (every 30 min) to remove as much of the UV absorber as possible. The details about the definition of bending angle and the angle measurements can be found in the literature [ 43 ].…”

Programmable and Contractile Materials Through Cell Encapsulation in Fibrous Hydrogel Assemblies

“…The potential application of fibrous assemblies in biofabrication techniques is explored by printing tissues that shrink to improve resolution and have programmable bending in 3D. A major goal in the biofabrication field is to create tissues that undergo morphological changes over time to mimic developmental processes or yield functional tissues (53)(54)(55). Our findings highlight how the microscale architecture and force responsive properties of the ECM influence macroscopic changes in tissue shape over time, and provide methods to program tissue bending.…”

Induction of Four‐Dimensional Spatiotemporal Geometric Transformations in High Cell Density Tissues via Shape‐Changing Hydrogels

“…By recreating the spatiotemporal changes during native development and repair processes, it also may find utility in the development of artificial tissue models for drug screening. [ 4 ] In this study, we exploited the differential swelling of OMA and GelMA, which are widely used biocompatible, biodegradable hydrogel materials, to form constructs that can change their geometry over time when placed in aqueous solutions. [ 19–22 ] Importantly, 4D high cell density constructs were fabricated by incorporating cells into the photocrosslinkable OMA/GelMA hydrogels at high densities of up to 1.0 × 10 8 cells mL –1 .…”

“…In this respect, the ability to induce defined 4D geometric changes in cytocompatible materials may endow engineered tissues with the capacity to dynamically change their shape in concert with those of neighboring tissues. [ 4 ] Since developing and healing tissues often begin as cellular condensations with minimal ECM, [ 5 ] 4D material constructs capable of incorporating high concentrations of cells and enabling extensive cell–cell interactions while still exhibiting tailored geometric shape changes would be valuable in studying and understanding these biological phenomena.…”