From Biomarker to Trigger: Biological Calibration of Stimuli-Responsive Gels Toward Precision Periodontal Therapy

Endogenous stimuli-responsive gels are designed to alter drug release or matrix behavior in periodontal sites, but their responsiveness is often demonstrated under conditions that may not represent the biological compartment encountered after placement. This comprehensive review examined whether proposed periodontal triggers have been biologically calibrated. Targeted searches of PubMed/MEDLINE, publisher websites, and backward and forward citations identified human studies measuring periodontal pH, proteases, redox conditions, oxygen tension, microbial metabolites, and glucose, together with gel studies using the same cues. Human pH measurements ranged from mildly acidic to alkaline and did not support a universal activation window. Protease-responsive systems had the strongest mechanistic rationale, although recombinant-enzyme testing was not equivalent to native-fluid cleavage. Hydrogen peroxide-responsive gels were generally evaluated under challenge conditions above the limited direct gingival crevicular fluid evidence and without physiological antioxidant buffering. Oxygen-generating systems did not directly sense local oxygen tension. Some glucose challenges overlapped reported human GCF measurements, but calibration to defined periodontal sites and treatment conditions remained unverified. Across trigger classes, preclinical efficacy seldom isolated responsiveness from payload and carrier effects. Future studies should use compartment- and treatment-matched measurements, realistic input-output testing under flow and buffering, patient-derived fluids, and controls that isolate cue-dependent material behavior.