The extracellular matrix of native human tissues is complex, in terms of biochemical composition, multi-scale architecture, mechanical properties and cellular population. To artificially reproduce and to control the growth’s direction of such tissue, scientists try to insert adapted guiding cues for the cells to follow. If healthy cells – autologous or allogeneic – were to be inserted alone onto the injury site of a patient, cells could leak to the rest of the body and their survival won’t be insured as they arrive in a degraded environment. That’s why there is currently a consensus in the tissue engineering community to provide the transplanted cells a healthy 3D-environment, so the cell’s healing potential is optimized .
Hydrogel microparticles typically ranging from 1 to 350 µm are called microgels. In the last decade, microgels have drawn increasing attention in the scientific community, due to their tailorable size and viscoelasticity, their high water content, and their ability to encapsulate bioactive factors. Relative to a classic bulk hydrogel, they display a high specific surface area with space between each hydrogel microparticle. This feature allows (i) cells to more easily colonize the designed scaffold, as they have more space to grow into; (ii) a more efficient nutrient and waste transfer and thus (iii) improved cell-cell and cell-matrix interactions. Moreover, microgels are easily injectable in vivo. By avoiding invasive surgical procedures and associated complications, they are more pertinent for clinical uses .
Microgels can be implemented as an autonomous system, with microparticles linked together either through a chemical bond (permanent), a physical bond (reversible), via cell interaction, or by applying an external force, such as a magnetic field if the microgels contain a paramagnetic compound. “Click chemistry” is an example of recently developed techniques that support the precise tailoring of the designed biomaterial properties. Click chemistry supplies unique mild bioorthogonal reactions with a high reactivity and selectivity. Thus, fine-tuned biomaterials can achieve both spatial and temporal control over cellular behaviors with a large variety of microgels morphology: classic spherical, rod-shaped, cylindrical, etc. depending on the desired application .
Microgels can also be incorporated inside a “carrier” bulk hydrogel, in a “Hydrogel-Microgel” composite macroscopic system (see illustration below). Our last Article of the Month published last week presented e.g. magneto-responsive, rod-shaped, peptide-modified and PEG-based microgels, encapsulated into a fibrin hydrogel for various anisotropic tissue regeneration, depending on the concentration used and on the associated viscoelasticity of the produced scaffold .
Scientists are also able to produce smaller hydrogels, with particles typically ranging from 20 to 250 nm, or so called nanogels . As an example, Dr. Sahiner’s team (both working in Turkey and in the USA) developed blood-compatible polysaccharides micro/nanogels as nanocarriers for targeted drug delivery, using poly-lactose or poly-laminarin .
As microgels can easily be injected in vivo, they can also be used as inks for 3D- and 4D-Bioprinting to create complex scaffolds (schema below). They can either contain cells before printing (bioinks) or be seeded with cells afterwards. The former method is especially adapted for in vivo applications, when the latter provides an alternative for in vitro cell culture . Composite microgels can be extruded. Seymour et al. did extrude gelatin microbeads mixed together with methacrylated gelatin (GelMA) microgels. After printing, the raw gelatin was melted and removed by heating the system at 37 °C, once the crosslinked GelMA was stable. Using gelatin as a sacrificial ink, the authors were able to produce a GelMA-microgel, with a multi-scale porosity that favors the migration of cells inside the scaffold .
Altogether, microgels are promising tools for the regeneration of various native tissues, from the mechanically soft neuronal tissue to the stiffer bones, through cardiac, hepatic, vascular and cartilage tissues. Microgels pertain to bioactive factors encapsulation and release, in vitro cell proliferation as well as cell-cell and cell-matrix interaction, and in vivo tissue regeneration. As a versatile tool, microgels provide optimized support for the cell to rely on.
 Rose, J.C., Gehlen, D.B., Haraszti, T., Köhler, J., Licht, C.J., De Laporte, L., (2018). Biofunctionalized aligned microgels provide 3D cell guidance to mimic complex tissue matrices. Biomaterials, 163, 128–141.
 Newsom, J.P., Payne, K.A., Krebs, M.D., 2019. Microgels: Modular, tunable constructs for tissue regeneration. Acta Biomaterialia, 88, 32–41.
 Nguyen, T.P.T., Li, F., Shrestha, S., Tuan, R.S., Thissen, H., Forsythe, J.S., Frith, J.E., (2021). Cell-laden injectable microgels: Current status and future prospects for cartilage regeneration. Biomaterials, 279, 121214.
 Jiang, Y., Chen, J., Deng, C., Suuronen, E.J., Zhong, Z., (2014). Click hydrogels, microgels and nanogels: Emerging platforms for drug delivery and tissue engineering. Biomaterials, 35, 4969–4985.
 Feng, Q., Li, D., Li, Q., Cao, X., Dong, H., (2022). Microgel assembly: Fabrication, characteristics and application in tissue engineering and regenerative medicine. Bioactive Materials, 9, 105–119.
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