Bioprinting, the process of printing living cells into functional tissues, presents a complex set of challenges. In a remarkable achievement, the Levato lab of UMC Utrecht, in collaboration with colleagues, has successfully combined two promising printing techniques to enhance cell density, cell survival, and specialization in bioprinted constructs. The key lies in the utilization of granular biogels or resins, as described in their publication in the journal Advanced Materials.

While bioprinting holds promise for creating functional tissues using stem cells, the integration of this intricate technology with delicate cells poses significant challenges. To ensure cell survival and tissue functionality, printed cells must receive optimal conditions for growth, mobility, and intercellular communication.

Various printing strategies have been explored to address these challenges, each with its own advantages and limitations. 3D extrusion printing allows for the deposition of cells in various types and large quantities, but it is time-consuming, subjects cells to mechanical stress, and is gravity-dependent, all of which negatively impact cell viability and function. On the other hand, fast volumetric bioprinting solves the speed and gravity issues, but it results in random cell distribution in the resin and lower cell numbers. Additionally, the solid resin structure hampers proper cell functioning and communication. To overcome this limitation, the materials used for bioprinting must provide an environment that enables self-organization and cell communication. Although achievable with soft hydrogels, ensuring high printing resolution and shape fidelity remains challenging, especially with conventional layer-by-layer fabrication techniques.

In their study, first author Davide Ribezzi investigated the use of granular resins as a solution to these challenges. Ribezzi explains that granular gels consist of tightly packed gel microparticles, each possessing properties similar to bulk hydrogel counterparts. However, the packed microgel particles can be tailored to exhibit a wide range of additional beneficial properties.

Harnessing particulate biomaterials proves to be a promising strategy for overcoming limitations associated with bulk cell encapsulation and material processability in printing processes. The granulated resins allowed the researchers to combine extrusion and volumetric printing techniques. With extrusion printing, specific cells or chemicals can be precisely deposited within the resin, optimizing the balance between volumetric printing speed and extrusion printing accuracy.

The gel behaves fluidly around the printing nozzle, akin to custard around a finger, enabling rapid layering of cells without compromising the structural strength. Volumetric printing then refines and shapes the extruded cells, completing the process.

The team faced challenges during this endeavor. Ribezzi notes that processing biological materials demands meticulous attention and planning. In their research, they harnessed the thermal properties of the microgel, allowing precise tuning of mechanical and optical properties. This enabled the embedded cells to perceive tunable stimuli. However, this heightened level of customization required increased precision and attention during the printing process. Experimental results with cells confirmed that the granulated resins significantly enhanced biological activity post-printing, surpassing the performance of solid gels. Within eight days of being printed into the resin, stem cells exhibited increased spreading, epithelial cells formed more junctions, and neuron-like cells established more connections with one another.

Looking ahead, Ribezzi envisions the mixing and local patterning of microgels derived from different materials. This approach would enable the creation of composite constructs with unique properties or bioactive pockets capable of controlled drug release. These advancements will augment tissue functionality and unlock additional possibilities in tissue engineering, regenerative medicine, and the emerging field of engineered living materials.

By Impact Lab