A pH-responsive, poly(2-hydroxyethyl methacrylate) [poly(HEMA)]-based hydrogel has been fashioned into an impedimetric pH sensor for the continual measurement and monitoring of tissue acidosis that can arise due to hemorrhaging trauma. Four hydrogel systems molecularly engineered to influence water distribution and ionic abundance were studied: a cationogenic primary amine, N-(2-aminoethyl) methacrylate (AEMA), a tertiary amine moiety, N,N-(2-dimethylamino)ethyl methacrylate (DMAEMA), and a combined AEMA−DMAEMA formulation. Electrochemical impedance spectroscopy (EIS) of hydrogel discs held between platinized Type 304 stainless steel mesh electrodes in pH-adjusted 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid sodium salt (HEPES) buffer and equivalent circuit modeling indicated that the AEMA hydrogel had the highest sensitivity containing the relevant pathophysiological range (pH 7.0− 8.0). Thus, the AEMA formulation was studied at 0, 1, 3, 4.4, and 30 mol % AEMA. The 1 mol % AEMA was found to significantly (p < 0.05) discern nominal pH (7.35, 7.40, 7.45). The Taguchi Design of Experiments approach was employed and confirmed composition as a factor and 1 mol % AEMA to be the most robust. DMAEMA (0, 4.4, 14, 30 mol %) and AEMA−DMAEMA (0, 4.4, 14, 30 mol %) allowed the use of the one-factor Response Surface Methodology optimizer to confirm the AEMA 1 mol % system to be most robust, sensitive, and possessing optimal sensitivity in the pathophysiological pH sensing range (7.35−7.45) for hemorrhagic trauma. This composition was fashioned as a responsive membrane on a microlithographically fabricated interdigitated microsensor electrode and the sensitivity was determined using R(QR)(QR) analysis. Water distribution within the AEMA (0, 1, 4.4, 30 mol %), determined by gravimetric analysis and differential scanning calorimetry, revealed a strong anticorrelation between nonfreezable bound water and pH sensitivity (−0.82) and was in good agreement with the total hydration (−0.70). Nonfreezable bound water was found to be the most strongly correlated factor that governs the pH response of hydrogels.