as acellular matrices to support endogenous repair, an approach that relies on the body's innate regenerative capacity and stem cell pool. [3] For an endogenous repair strategy to succeed, host cells and blood vessels must invade and populate the injected hydrogel to create a bioactive microenvironment. [4,5] However, traditionally used bulk hydrogels are often rigid and nonporous, which prevents host cells from invading. [6] Strategies to overcome this include incorporating enzymatically or hydrolytically degradable sites within the hydrogel, [7,8] fabricating hydrogels from decellularized extracellular matrices (dECMs) with inherent degradability, [9] or combining with fast-degrading or dissolving porogens to introduce porosity over time. [10] Despite improvements, the degradation of synthetic hydrogels or the inclusion of porogens are associated with weakening of mechanical properties and may additionally compromise structural features that provide instructive physical signals to host cells, while batch inconsistencies and a limited ability to manipulate properties affect the utility of natural dECMs.To overcome these limitations, granular hydrogels have been developed in recent years to allow decoupling of material degradability from microporosity. In addition, granular hydrogels present other desirable features including injectability, modularity, and ease of tuning physical properties. [11] Granular hydrogels are assembled through the packing of smaller Granular hydrogels have emerged as a new class of injectable and porous biomaterials that improve integration with host tissue when compared to solid hydrogels. Granular hydrogels are typically prepared using spherical particles and this study considers whether particle shape (i.e., isotropic spheres vs anisotropic rods) influences granular hydrogel properties and cellular invasion. Simulations predict that anisotropic rods influence pore shape and interconnectivity, as well as bead transport through granular assemblies. Photo-cross-linkable norbornene-modified hyaluronic acid is used to produce spherical and rod-shaped particles using microfluidic droplet generators and formed into shear-thinning and self-healing granular hydrogels, with particle shape influencing mechanics and injectability. Rod-shaped particles form granular hydrogels that have anisotropic and interconnected pores, with pore size and number influenced by particle shape and degree of packing. Robust in vitro sprouting of endothelial cells from embedded cellular spheroids is observed with rod-shaped particles, including higher sprouting densities and sprout lengths when compared to hydrogels with spherical particles. Cell and vessel invasion into granular hydrogels when injected subcutaneously in vivo are significantly greater with rod-shaped particles, whereas a gradient of cellularity is observed with spherical particles. Overall, this work demonstrates potentially superior functional properties of granular hydrogels with rodshaped particles for tissue repair.

Granular hydrogels are an exciting class of microporous and injectable biomaterials that are being explored for many biomedical applications, including regenerative medicine, 3D printing, and drug delivery. Granular hydrogels often possess low mechanical moduli and lack structural integrity due to weak physical interactions between microgels. This has been addressed through covalent inter‐particle crosslinking; however, covalent crosslinking often occurs through temporal enzymatic methods or photoinitiated reactions, which may limit injectability and material processing. To address this, a hyaluronic acid (HA) granular hydrogel is developed with dynamic covalent (hydrazone) inter‐particle crosslinks. Extrusion fragmentation is used to fabricate microgels from photocrosslinkable norbornene‐modified HA, additionally modified with either aldehyde or hydrazide groups. Aldehyde and hydrazide‐containing microgels are mixed and jammed to form adhesive granular hydrogels. These granular hydrogels possess enhanced mechanical integrity and shape stability over controls due to the covalent inter‐particle bonds, while maintaining injectability due to the dynamic hydrazone bonds. The adhesive granular hydrogels are applied to 3D printing, which allows the printing of structures that are stable without any further post‐processing. Additionally, the authors demonstrate that adhesive granular hydrogels allow for cell invasion in vitro. Overall, this work demonstrates the use of dynamic covalent inter‐particle crosslinking to enhance injectable granular hydrogels.

Tissue Repair In article number 2109194, Jason A. Burdick and co‐workers report the fabrication of anisotropic rod‐shaped microparticles through a microfluidics approach and their assembly into injectable and porous granular hydrogels for tissue repair. Interconnected and anisotropic pores within these hydrogels support both robust endothelial cell sprouting in vitro and rapid invasion of endogenous cells and blood vessels in vivo.

Granular hydrogels are an emerging class of biomaterials formed by jamming hydrogel microparticles (i.e., microgels). These materials have many advantageous properties that can be tailored through microgel design and extent of packing. To enhance the range of properties, granular composites can be formed with a hydrogel interstitial matrix between the packed microgels, allowing for material flow and then stabilization after crosslinking. This approach allows for distinct compartments (i.e., microgels and interstitial space) with varied properties to engineer complex material behaviors. However, a thorough investigation of how the compositions and ratios of microgels and interstitial matrices influence material properties has not been performed. Herein, granular hydrogel composites are fabricated by combining fragmented hyaluronic acid (HA) microgels with interstitial matrices consisting of photocrosslinkable HA. Microgels of varying compressive moduli (10–70 kPa) are combined with interstitial matrices (0–30 vol.%) with compressive moduli varying from 2–120 kPa. Granular composite structure (confocal imaging), mechanics (local and bulk), flow behavior (rheology), and printability are thoroughly assessed. Lastly, variations in the interstitial matrix chemistry (covalent vs guest–host) and microgel degradability are investigated. Overall, this study describes the influence of granular composite composition on structure and mechanical properties of granular hydrogels towards informed designs for future applications.

Granular hydrogels have emerged as a new class of injectable and porous biomaterials that improve integration with host tissue when compared to solid hydrogels. Granular hydrogels are typically prepared using spherical particles and this study considers whether particle shape (i.e., isotropic spheres versus anisotropic rods) influences granular hydrogel properties and cellular invasion. Simulations predict that anisotropic rods influence pore shape and interconnectivity, as well as bead transport through granular assemblies. Photocrosslinkable norbornene- modified hyaluronic acid is used to produce spherical and rod-shaped particles using microfluidic droplet generators and formed into shear-thinning and self-healing granular hydrogels at low and high particle packing. Rod-shaped particles form granular hydrogels that have anisotropic and interconnected pores, with pore number and size, storage moduli, and extrusion forces influenced by particle shape and packing. Robust in vitro sprouting of endothelial cells from embedded cellular spheroids is observed with rod-shaped particles, including higher sprouting densities and sprout lengths when compared to hydrogels with spherical particles. Cellular invasion into granular hydrogels when injected subcutaneously in vivo is significantly greater with rod-shaped particles, whereas a gradient of cellularity is observed with spherical particles. Overall, this work demonstrates potentially superior functional properties of granular hydrogels with rod-shaped particles for tissue repair.

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