Granular hydrogels: emergent properties of jammed hydrogel microparticles and their applications in tissue repair and regeneration

Abstract

Granular hydrogels are emerging as a versatile and effective platform for tissue engineered constructs in regenerative medicine. The hydrogel microparticles (HMPs) that compose these materials exhibit particle jamming above a minimum packing fraction, which results in a bulk, yet dynamic, granular hydrogel scaffold. These injectable, microporous scaffolds possess self-assembling, shear-thinning, and self-healing properties. Recently, they have been utilized as cell cultures platforms and extracellular matrix mimics with remarkable success in promoting cellular infiltration and subsequent tissue remodeling in vivo. Furthermore, the modular nature of granular hydrogels accommodates heterogeneous HMP assembly, where varying HMPs have been fabricated to target distinct biological processes or deliver unique cargo. Such multifunctional materials offer enormous potential for capturing the structural and biofunctional complexity observed in native human tissue.

Figure 1.

Overview of granular hydrogels. A) Defining characteristics of granular materials. These contrast other particulate matter, such as colloids (size < 10 μm; thermal forces > gravitational forces), foams (particles of air), and emulsions (particles of water). B) Particle jamming occurs when particles are packed above a minimum particle-volume fraction (and under suitable conditions of stress and temperature). Particles configured here are closer to random close packing with a particle-volume fraction of 0.64. The network of contact forces between neighboring particles is indicated by black lines. C) Inherent and tunable properties of granular hydrogel scaffolds. Microporosity: Micron-sized particles result in micron-sized pores that are similar to cell size. Interlinking: Particles can be interlinked in a variety of ways to form a stable structure. Heterogeneity: Granular scaffolds can incorporate a heterogeneous mix of particle species, such as porous particles, layered particles, particles encapsulating cells or small molecules, or particles of varying shapes.

Figure 2.

Experimental applications of granular hydrogels. A) Three-dimensional rendering of cellular infiltration and spreading in a granular hydrogel scaffold. Source: dapted from [15]. B) (Top) Heterogenous mixture of two microparticle species: (green) cleavable hydrogel loaded with FITC-BSA, (red) stable hydrogel loaded with rhodamine-dextran; (Bottom) Payload release study in the presence (+) or not in the presence (−) of collagenase. Source: Adapted from []. C) Three different hydrogel microparticle species sequentially-loaded in a syringe and injected subcutaneously, retaining spatial distribution in vivo. Source: Adapted from []. D) Cell-laden hydrogel microparticles with controlled, three-dimensional geometric shapes generated by flow lithography. Source: Adapted from []. Scale bar = 100 μm for all figures.