Coumarin‐Based Photodegradable Hydrogels Enable Two‐Photon Subtractive Biofabrication at 300 mm s−1

Abstract Spatiotemporally controlled two‐photon photodegradation of hydrogels has gained increasing attention for high‐precision subtractive tissue engineering. However, conventional photolabile hydrogels often have poor efficiency upon two‐photon excitation in the near‐infrared (NIR) region and thus require high laser dosage that may compromise cell activity. As a result, high‐speed two‐photon hydrogel erosion in the presence of cells remains challenging. Here we introduce the design and synthesis of efficient coumarin‐based photodegradable hydrogels to overcome these limitations. A set of photolabile coumarin‐functionalized polyethylene glycol linkers are synthesized through a Passerini multicomponent reaction. After mixing these linkers with thiolated hyaluronic acid, semi‐synthetic photodegradable hydrogels are formed in situ via Michael addition crosslinking. The efficiency of photodegradation in these hydrogels is significantly higher than that in nitrobenzyl counterparts upon two‐photon irradiation at 780 nm. A complex microfluidic network mimicking the bone microarchitecture is successfully fabricated in preformed coumarin hydrogels at high speeds of up to 300 mm s −1 and low laser dosage down to 10 mW. Further, we demonstrate fast two‐photon printing of hollow microchannels inside a hydrogel to spatiotemporally direct cell migration in 3D. Collectively, these hydrogels may open new avenues for fast laser‐guided tissue fabrication at high spatial resolution.