Hydrogel-based drug delivery systems for localized eradication of bacterial biofilms: Advances, challenges and future directions

Bacterial biofilms pose a significant clinical challenge due to their intrinsic resistance to antibiotics and immune clearance. Traditional systemic antibiotic therapies are often ineffective against the structured microbial communities, emphasizing the urgent need for localized and targeted drug delivery systems. Hydrogels are three-dimensional, water-rich polymeric networks, and have emerged as a versatile platform for localized delivery of antimicrobial agents, offering controlled release, biocompatibility and the potential for functionalization with bioactive components. This review explores recent advancements in hydrogel-based strategies for biofilm eradication, including systems with mucoadhesive, thermosensitive, bactericidal, and stimuli-responsive properties. Special emphasis is placed on hydrogels responsive to the microenvironment of the biofilm such as pH, enzymes and reactive oxygen species (ROS), enabling on-demand release of a drug at the infection site. Additionally, we highlight the incorporation of synergistic agents such as antimicrobial peptides (AMPs), biofilm-disrupting enzymes, and bacteriophages to enhance antibiofilm efficacy. Despite promising preclinical research, challenges remain in translating these findings into clinical applications. Most preclinical evaluations rely on planktonic bacterial evaluation or in some cases static biofilm models, which fail to replicate the dynamic conditions of in vivo infections. This review identifies a critical need for improved biofilm models simulating physiological conditions, particularly those involving flow of liquid and complex tissue interfaces. In conclusion, hydrogel-based drug delivery systems offer significant promise for localized biofilm eradication. However, future studies must address the limitations of current models and provide mechanistic validation of responsiveness and efficacy under clinically relevant conditions to advance these systems toward therapeutic implementation.