Sustainable Hydrogel-Forming Microneedle-Reservoir Patches for Transdermal Delivery of Hydrophilic Macromolecules: Biopolymers, Green Manufacturing and Translation.

Hydrophilic biomacromolecules, including insulin, peptides, proteins and vaccine antigens, have transformed modern therapeutics, yet their delivery remains dominated by injections because the stratum corneum (SC) severely restricts passive transport of large and polar molecules. Microneedles have created a route through this barrier, but many existing systems remain limited by low loading capacity, burst release, weak dose control, microbiological quality requirements, short-term stability, and poor manufacturing scalability. This review critically examines hydrogel-forming microneedle (HFMN)-reservoir patches as an emerging architecture for controlled transdermal biomacromolecule delivery. Rather than treating microneedles as isolated projections, it positions the patch as an integrated multilayer device comprising a skin-interfacing hydrogel conduit, a drug reservoir, a diffusion-control layer, and a protective backing. Particular emphasis is placed on sustainable polymers, including cellulose derivatives, alginate, chitosan (CS), polyethylene oxide (PEO), carboxymethyl chitosan (CMCS) and oxidized polysaccharides, together with scalable manufacturing routes such as pressurized gyration (PG). The review also evaluates fluorescein isothiocyanate (FITC)-dextran and other model macromolecules, highlighting what they prove about physical transport and what they cannot prove about therapeutic bioactivity. Finally, design rules are proposed for next-generation microneedle-reservoir patches that integrate biomaterial selection, release control, green manufacturing, and translational requirements.