REVIEW: Gradient Hydrogels: Fabrication Strategies and Biomedical Applications

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Nikita G. Yabbarov^1,2,a*, Ivan V. Romashkin², Vasilina A. Zakharova^2,3, Darya N. Zinovieva², Mariia R. Mollaeva¹, Maria B. Sokol¹, Margarita V. Chirkina¹, Ivan A. Gulyaev¹, Maksim A. Klimenko¹, and Elena D. Nikolskaya^1,2,b*

¹Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, 119334 Moscow, Russia

²National University of Science and Technology MISIS, Institute of Biomedical Engineering, 119049 Moscow, Russia

³Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow, Russia

^* To whom correspondence should be addressed.

Received: August 29, 2025; Revised: October 2, 2025; Accepted: October 15, 2025

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Gradient hydrogels represent a unique class of biomaterials capable of mimicking the spatial heterogeneity of native tissues and providing targeted effects on cells through mechanical, chemical, and biophysical gradients. In recent years, numerous fabrication strategies have been developed to generate gradient hydrogels, including layer-by-layer formation, photopolymerization, microfluidic techniques, and 3D/4D printing. This review summarizes current methodologies for the characterization of gradient hydrogels and highlights their emerging biomedical applications, such as controlled drug delivery, tissue engineering, regenerative medicine, organ-on-chip systems, and soft bioelectronic devices. Furthermore, the review discusses critical challenges related to the protocol standardization, manufacturing scalability, integration with additive manufacturing technologies, and potential regulatory barriers.

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KEY WORDS: gradient hydrogels, biomimetic matrices, tissue engineering, microfluidic technologies, 3D/4D bioprinting, regenerative medicine, organ-on-a-chip platforms

DOI: 10.1134/S0006297925604137

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