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Hydrogels with tailored porosity and microstructure are essential for biomedical applications such as drug delivery and tissue engineering. However, controlling their internal architecture remains a challenge. A promising approach leverages polymer phase separation in water to create hydrogels with large interconnected pores, enhancing cell growth or migration, nutrient transport, and cellular waste removal.
This work presents a straightforward strategy to regulate the phase separation of gelatin methacryloyl (GelMA) and dextran in water to produce hydrogels with tunable interconnected pores. By introducing glucono delta-lactone (GDL) into the aqueous two-phase system (ATPS), a gradual pH decrease is triggered, inducing segregative phase separation between the two biopolymers. The in-situ acidification delays and moderates phase separation kinetics. UV photo-crosslinking of the GelMA-rich phase at different time points arrests the microstructure at different stages of phase separation, allowing fine control over the length scales of the interconnected GelMA-dextran channels. After washing out dextran, porous GelMA-based hydrogels are obtained.
The approach is effective for both casting and inkjet 3D printing. Initially, the GelMA-dextran mixture is in solution state at 37°C, with GDL delaying phase separation to ensure that the system is fully mixed and that there is sufficient time to set up and calibrate the printer before inkjet printing. The delay duration is tunable by adjusting GDL concentration, and the higher the GDL concentration, the faster the pH drops. Additional parameters such temperature, ionic strength and viscosity have also been investigated to optimize ATPS ink.
In figure (A), confocal laser scanning microscopy (CLSM) is used to monitor the in-situ evolution of the GelMA-dextran solution at 37 °C. Labeled GelMA appears red, while dextran-rich regions are dark. With 5 mg/mL GDL, bicontinuous GelMA-dextran interconnected channels begin forming after a 26-minute delay, and spinodal decomposition is complete within 4 minutes. Photo-crosslinking during this time window allows the formation of permanent hydrogels with varied microporosity. In figure (B), the temporal evolution of the width of the elongated interwoven channels of GelMA and dextran is shown. The quantitative analysis was performed with the software “Aquami” and depicts the distinct parallel growth of GelMA (orange symbols) and dextran (black symbols) domains.
The proposed method is simple and the production of these unique porous hydrogels is easily scalable. It provides enhanced reproducibility and control over spinodal decomposition, which is typically sensitive to experimental procedures. Importantly, the printing process does not interfere with phase separation or disrupt the targeted microstructure. The tailored design of the length scales of the interconnected GelMA-dextran channels, hence the resulting porosity of the hydrogels, is promising for biomedical applications with different requirements regarding cell types or sizes.
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