Cell-guiding microporous hydrogels by photopolymerization-induced phase separation

Monica Z. Müller, Margherita Bernero, Chang Xie, Wanwan Qiu, Esteban Oggianu, Lucie Rabut, Thomas C. T. Michaels, Robert W. Style, Ralph Müller and Xiao-Hua Qin ()
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Monica Z. Müller: ETH Zurich
Margherita Bernero: ETH Zurich
Chang Xie: ETH Zurich
Wanwan Qiu: ETH Zurich
Esteban Oggianu: ETH Zurich
Lucie Rabut: ETH Zurich
Thomas C. T. Michaels: ETH Zurich
Robert W. Style: ETH Zurich
Ralph Müller: ETH Zurich
Xiao-Hua Qin: ETH Zurich

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Microporous scaffolds facilitate solute transport and cell-material interactions, but materials allowing for spatiotemporally controlled pore formation in aqueous solutions are lacking. Here, we propose cell-guiding microporous hydrogels by photopolymerization-induced phase separation (PIPS) as instructive scaffolding materials for 3D cell culture. We formulate a series of PIPS resins consisting of two ionic polymers (norbornene-functionalized polyvinyl alcohol, dextran sulfate), di-thiol linker and water-soluble photoinitiator. Before PIPS, the polymers are miscible. Upon photocrosslinking, they demix due to the increasing molecular weight and form a microporous hydrogel. The pore size is tunable in the range of 2-40 μm as a function of light intensity, polymer composition and molecular charge. Unlike conventional methods to fabricate porous hydrogels, our PIPS approach allows for in situ light-controlled pore formation in the presence of living cells. We demonstrate that RGD-functionalized microporous hydrogels support high cell viability (>95%), fast cell spreading and 3D morphogenesis. As a proof-of-concept, these hydrogels also enhance the osteogenic differentiation of human mesenchymal stromal cells, matrix mineralization and collagen secretion. Collectively, this study presents a class of cell-guiding microporous hydrogels by PIPS which may find applications in complex tissue engineering.

Date: 2025
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DOI: 10.1038/s41467-025-60113-9

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