This study examined the interrelated effect of environmental pH, gelatin backbone modification and crosslinking modality on hydrogel morphology, surface hydrophilicity, in vitro swelling/degradation kinetics, in vitro drug release kinetics and in vivo degradation, inflammatory response and drug release activity. The percent glutaraldehyde fixation had a greater impact on the morphology of the dehydrated hydrogels than gelatin modification. Any decrease in percent glutaraldehyde fixation and/or modification of gelatin with polyethylene glycol dialdehyde (PEG-dial) and/or ethylenediaminetetraacetic dianhydride (EDTAD) increased hydrogel surface hydrophilicity. Swelling/degradation studies showed that modification of gelatin with PEG-dial generally increased the time to reach the maximum swelling weight ratio (T(max)) and the time to failure by hydrolysis (T(fail)), but had little effect on the maximum swelling weight ratio (R(max)) and the weight ratio at failure (R(fail)). Modification of gelatin with EDTAD generally had no effect on T(max) and T(fail), but increased R(max) and R(fail). Modification of gelatin with PEG-dial and EDTAD increased R(max), but had no effect on T(max), R(fail), or T(fail). Decreasing percent glutaraldehyde fixation generally increased R(max) and R(fail) but decreased T(max) and T(fail). Decreasing environmental pH from 7.4 to 4.5 had no effect on any swelling/degradation properties. In vitro drug release studies showed that modification of gelatin with PEG-dial and/or EDTAD generally decreased the maximum mass ratio of drug released (D(max)) and the time to reach D(max) (T(dmax)). Percent glutaraldehyde fixation did not significantly affect D(max) or T(dmax) (except for EDTAD-modified gelatin hydrogels). In vivo studies showed that gelatin-based hydrogels elicited comparable levels of acute and chronic inflammatory response as that of the empty cage control by 21 d.