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Hydrogels are commonly used materials in tissue engineering and organ-on-chip devices. This study investigated the nanomechanical properties of monolithic and multilayered poly(ethylene glycol) diacrylate (PEGDA) hydrogels manufactured using bulk polymerization and layer-by-layer projection lithography processes, respectively. An increase in the number of layers (or reduction in layer thickness) from 1 to 8 and further to 60 results in a reduction in the elastic modulus from 5.53 to 1.69 and further to 0.67 MPa, respectively. It was found that a decrease in the number of layers induces a lower creep index (CIT) in three-dimensional (3D) printed PEGDA hydrogels. This reduction is attributed to mesoscale imperfections that appear as pockets of voids at the interfaces of the multilayered hydrogels attributed to localized regions of unreacted prepolymers, resulting in variations in defect density in the samples examined. An increase in the degree of cross-linking introduced by a higher dosage of ultraviolet (UV) exposure leads to a higher elastic modulus. This implies that the elastic modulus and creep behavior of hydrogels are governed and influenced by the degree of cross-linking and defect density of the layers and interfaces. These findings can guide an optimal manufacturing pathway to obtain the desirable nanomechanical properties in 3D printed PEGDA hydrogels, critical for the performance of living cells and tissues, which can be engineered through control of the fabrication parameters.

Three-dimensional (3D) printed hydrogels fabricated using light processing techniques are poised to replace conventional processing methods used in tissue engineering and organ-on-chip devices. An intrinsic potential problem remains related to structural heterogeneity translated in the degree of cross-linking of the printed layers. Poly(ethylene glycol) diacrylate (PEGDA) hydrogels were used to fabricate both 3D printed multilayer and control monolithic samples, which were then analyzed using atomic force microscopy (AFM) to assess their nanomechanical properties. The fabrication of the hydrogel samples involved layer-by-layer (LbL) projection lithography and bulk crosslinking processes. We evaluated the nanomechanical properties of both hydrogel types in a hydrated environment using the elastic modulus (E) as a measure to gain insight into their mechanical properties. We observed that E increases by 4-fold from 2.8 to 11.9 kPa transitioning from bottom to the top of a single printed layer in a multilayer sample. Such variations could not be seen in control monolithic sample. The variation within the printed layers is ascribed to heterogeneities caused by the photo-cross-linking process. This behavior was rationalized by spatial variation of the polymer cross-link density related to variations of light absorption within the layers attributed to spatial decay of light intensity during the photo-cross-linking process. More importantly, we observed a significant 44% increase in E, from 9.1 to 13.1 kPa, as the indentation advanced from the bottom to the top of the multilayer sample. This finding implies that mechanical heterogeneity is present throughout the entire structure, rather than being limited to each layer individually. These findings are critical for design, fabrication, and application engineers intending to use 3D printed multilayer PEGDA hydrogels for in vitro tissue engineering and organ-on-chip devices.

In this brief review, we discuss the recent advancements in using poly(ethylene glycol) diacrylate (PEGDA) hydrogels for tissue engineering applications. PEGDA hydrogels are highly attractive in biomedical and biotechnology fields due to their soft and hydrated properties that can replicate living tissues. These hydrogels can be manipulated using light, heat, and cross-linkers to achieve desirable functionalities. Unlike previous reviews that focused solely on material design and fabrication of bioactive hydrogels and their cell viability and interactions with the extracellular matrix (ECM), we compare the traditional bulk photo-crosslinking method with the latest three-dimensional (3D) printing of PEGDA hydrogels. We present detailed evidence combining the physical, chemical, bulk, and localized mechanical characteristics, including their composition, fabrication methods, experimental conditions, and reported mechanical properties of bulk and 3D printed PEGDA hydrogels. Furthermore, we highlight the current state of biomedical applications of 3D PEGDA hydrogels in tissue engineering and organ-on-chip devices over the last 20 years. Finally, we delve into the current obstacles and future possibilities in the field of engineering 3D layer-by-layer (LbL) PEGDA hydrogels for tissue engineering and organ-on-chip devices.