Engineering Polymeric Hydrogels, Nanogels, and Microgels for Next-Generation Tissue Regeneration: Materials, Mechanisms, and Translational Perspectives

Tissue engineering (TE) has emerged as a transformative discipline aiming to restore, maintain, or improve damaged tissues and organs through a combination of scaffolds, cells, and bioactive molecules. Among the loads of materials explored for scaffold development, polymeric hydrogels have gathered exceptional interest due to their high-water content, biomimetic mechanical properties, and versatile functionalization potential. Hydrogels provide a three-dimensional (3D) hydrated environment conducive to cellular activities such as adhesion, proliferation, and differentiation, making them ideal candidates for regenerative applications . Over time, the hydrogel platform has expanded into nanoscale and microscale domains, giving rise to nanogels and microgels—engineered particles that offer advantages such as injectability, controlled drug release, and tailored microenvironments While traditional bulk hydrogels are excellent as static scaffolds, nanogels and microgels provide dynamic interactions, injectable formulations, and customizable architectures, enabling a shift toward minimally aggressive TE strategies. Recent innovations in polymer chemistry, such as click chemistry, controlled radical polymerizations (e.g., Reversible Addition Fragmentation chain Transfer (RAFT), Atom Transfer Radical Polymerization (ATRP)), Michael addition, and enzymatic crosslinking, have allowed the precise fabrication of hydrogels with tunable properties. Emerging fabrication techniques, including microfluidics, 3D printing, and electrospinning, have further expanded the design flexibility, enabling spatially organized, heterogeneous constructs resembling the complex architecture of native tissues. Furthermore, stimuli-responsive hydrogels that react to pH, temperature, enzymes, or mechanical forces have been developed to achieve on-demand therapeutic delivery, adaptive mechanical performance, and self-healing capabilities. The evolution from simple passive hydrogels to intelligent and interactive systems marks a pivotal shift in the field, aligning more closely with the dynamic nature of living tissues. Comparatively, nanogels and microgels bridge critical gaps in hydrogel technologies by offering enhanced surface area, controlled porosity, modularity, and precision in therapeutic delivery. Nanogels, owing to their small size, easily penetrate biological barriers and can be engineered for targeted delivery, while microgels can assemble into macroscopic scaffolds, allowing cell encapsulation and modular tissue construction. Hybrid systems, combining nanogels and microgels within bulk hydrogels, represent a cutting-edge strategy to achieve multifunctional tissue scaffolds. Though researchers are exploring the individual advancement of bulk hydrogels as well as nano and micro gels in tissue engineering applications , an integration of the roles of hydrogels, nanogels, and microgels within a unified framework for tissue regeneration has not been discussed till now. In this review, I comprehensively explored the synthetic evolution and biomedical applications of polymeric hydrogels, nanogels, and microgels, with a particular emphasis on their comparative efficacy in tissue engineering. Furthermore, we systematically divided the synthetic strategies employed for each class of material, analyzed key performance metrics such as biocompatibility, mechanical strength, degradation, and therapeutic efficacy, and offer a visionary outlook toward emerging technologies such as 4D printing, bioinspired hybrid gels, and personalized regenerative platforms. The intent is to bridge material innovation with clinical translation, providing insights to accelerate the development of next-generation scaffolds for regenerative medicine.