Granular Hydrogels in Biofabrication: Recent Advances and Future Perspectives

Abstract

Granular hydrogels, which are formed by densely packing microgels, are promising materials for bioprinting due to their extrudability, porosity, and modularity. However, the multidimensional parameter space involved in granular hydrogel design makes material optimization challenging. For example, design inputs such as microgel morphology, packing density, or stiffness can influence multiple rheological properties that govern printability and the behavior of encapsulated cells. This review provides an overview of fabrication methods for granular hydrogels, and then examines how important design inputs can influence material properties associated with printability and cellular responses across multiple scales. Recent applications of granular design principles in bioink engineering are described, including the development of granular support hydrogels for embedded printing. Further, the paper provides an overview of how key physical properties of granular hydrogels can influence cellular responses, highlighting the advantages of granular materials for promoting cell and tissue maturation after the printing process. Finally, potential future directions for advancing the design of granular hydrogels for bioprinting are discussed.

Ionically annealed zwitterionic microgels for bioprinting of cartilaginous constructs

“…In that study, at day 21, there was a decreasing trend in the elastic modulus of cultured crosslinked granular hydrogels as the grid aperture for fragmentation was increased from 40 µm to 500 µm. According to the literature, mechanical properties of crosslinked granular hydrogels are influenced by the size, shape, and packing density relative to the surrounding interstitial phase [44,70,71]. Smaller microgels have a greater surface area and packing density, leading to more interlinking points, which enhances the scaffold's mechanical strength.…”

The microparticulate inks for bioprinting applications

“…We refer the reader to other remarkable reviews for a more detailed overview of microfabrication techniques [ 35 , [50] , [51] , [52] , [53] ]. These microgels can be densely packed to form granular hydrogels, which exhibit the shear-thinning behavior of ‘solid-like’ at low strain and ‘fluid-like’ at high strain, and these properties are ideal for extrusion bioprinting [ 20 , 21 ]. Jammed microgels have also been employed as supporting baths for 3D printing structures (Embedded bioprinting) made from diverse soft matter components [ 19 , 54 ].…”

“…In addition, Anseth and colleagues have given the idea that microgels uniquely provide highly tunable microenvironments for manipulating cell fate, as well as a building block to recapitulate tissue mimics [ 17 ]. Therefore, these cell-laden microgels have been explored as inks to print complex tissues [ 20 , 55 ]. More in-depth discussions of granular gel inks are presented below.…”

“…Compared to hard-spherical particles, soft microgels have complicated rheological properties due to the physicochemical properties of microgels, such as shape, concentration, interparticle interactions, composition, size, and stiffness ( Fig. 4 A) [ 20 ]. When the low concentration of microgels is suspended in the continuous phase, the particle-to-volume fraction Φ is tiny.…”

Cation-crosslinked κ-carrageenan sub-microgel medium for high-quality embedded bioprinting

“…Particularly, embedded 3D bioprinting deposits bioink into a matrix composed of granular hydrogels, which provides structural support throughout the printing process [7][8][9][10]. The granular hydrogels consist of jammed hydrogel microparticles that exhibit a shear-yielding response [11][12][13]. During the embedded 3D bioprinting process, the jammed microgels behave as viscous fluids under shearing forces, facilitating the smooth movement of the printing nozzle within the bath, and enabling precise bioink deposition.…”