Technical Abstract: The recent article by Koc et al. (2008) reports predictive models for the swelling behavior of calcium-alginate hydrogels in response to changes in pH and temperature. We submit that the reported effect of “pH” on hydrogel swelling is unsupported by the data and is more properly interpreted as the effect of covaried concentrations and proportions of Na+ and Cl-. For a response to be truly “pH-dependent,” that response would have to be the same for any given set of ions that achieve the same pH value; i.e., if hydrogel swelling is pH-dependent then a mixture of NO3-, PO43- and K+ ions and a mixture of SO42-, OAc- and Na+ ions should produce the same swelling if these mixtures are molar equivalents at the same pH. Contrary to the accepted paradigm, pH is a dependent factor (cf. Evens and Niedz, 2008); pH effects cannot be directly determined, are inherently correlative, and have no relevancy outside of the context of the particular ions used in a given experiment. Similarly, the concept of an ‘optimal’ pH is valid only in the context of the ions used in the experiment(s) that identified that particular ‘pH optimum’. Consequently, Koç et al. (2008) have decidedly not established pH-dependency. In addition, because Na+ and Cl- were covaried the experimental design exhibits ion confounding (Niedz and Evens, 2006). Consequently, Koç et al. (2008) cannot quantify either the main or the interactive effects of Na+ and/or Cl-. Without plausible data to ignore the effect of one of these ions the only valid analysis left is to calculate the mean effect of Na+ and Cl- across a range of total ion concentrations. Designing an experiment to determine ion-specific effects requires 1) treating ions as independent factors; 2) defining the dimensions of the design space as mixtures (proportions) of ions across a total ion concentration dimension; and 3) ensuring that the experiment is free of ion confounding.