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Diabetic foot ulcers are particularly difficult to treat due to neuropathy and healing deficiencies. Glutathione and adenosine have been studied as possible modulators of diabetic response and would healing. The objective of this in vitro study was to measure the effects of adenosine and glutathione on fibroblast proliferation and collagen synthesis. Further, methods were explored for delivering these compounds locally through chitosan sponges. Elution concentrations of adenosine and glutathione from chitosan sponges were evaluated through HPLC, and activity was evaluated for fibroblast proliferation and viability in vitro. Furthermore, collagen production of normal and hyperglycemic fibroblasts exposed to those compounds individually and in combination was evaluated using a colorimetric collagen assay. Results indicate a dose-dependent increase in fibroblast proliferation, with exposure to concentrations up to 133.6 mg/ml adenosine and 76.8 mg/ml glutathione. Total collagen concentration determination confirmed that adenosine alone at 133.6 mg/ml significantly increases collagen production in low glucose conditions, but not to the same extent in medium and diabetic glucose conditions.  Glutathione at 76.8 mg/ml did not increase collagen production compared to control or adenosine alone, and the combination attenuated increases in collagen production in low glucose conditions. There were no additive or synergistic effects of combining these two small molecule mediators of growth on fibroblast growth or collagen production. Both adenosine and glutathione were released in a burst response from chitosan sponges, and demonstrated activity in increasing proliferation.  These preliminary in vitro evaluations demonstrate that the local delivery of adenosine and glutathione released from chitosan sponges may be a promising strategy for the treatment of diabetic foot ulcers under glucose conditions that are closely managed.