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G. P. Misra, H. Imai, T. W. Gardner, T. L. Lowe; Regulating Insulin Release from Subconjunctivally Implantable Hydrogels for Potential Treatment of Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3486.
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© ARVO (1962-2015); The Authors (2016-present)
To develop novel subconjunctivally implantable hydrogels for delivering low doses of insulin to rescue neuronal cells from death in diabetic retinas.
Novel hydrogels consisting of thermoresponsive and hydrolytically degradable properties were tailored for long-term release of insulin. The hydrogels were formulated by synthesizing in dimethyl formamide medium under UV irradiation. FITC-labeled insulin or Humalog was loaded during the process of hydrogel synthesis. FITC-labeled insulin from the hydrogels was released in phosphate buffered saline, PBS, at 37 °C and was monitored by measuring fluorescence intensity. Hydrogels loaded with FITC-labeled insulin or Humalog® were implanted subconjunctivally in normal rats. Confocal microscopy was used to detect the presence of FITC-labeled insulin in the retina. Humalog-specific radioimmunoassay (RIA) was used to detect the Humalog® in the retina. Ex-vivo retinal cultures were performed to check if the insulin released from hydrogels still has bio-activity. Whole retinas were treated with hydrogels loaded with Humalog® for 5 minutes. Retinal protein were extracted and used for Western blot analysis for Akt and immunoprecipitation for insulin receptor beta (IRß) and insulin-like growth factor receptor (IGF1R) of released Humalog was tested by Akt and IRß, and IGF1R tyrosine phosphorylations in the retina ex vivo.
The designed novel hydrogels released FITC-labeled insulin for more than 5 months in phosphate buffered saline at 37° C. Composition of the hydrogels and their formulation strategies regulated the release of inulsin. Confocal microscopy confirmed the presence of FITC-labeled insulin after one day, one week, and one month of subconjunctival implantation. RIA also confirmed the presence of Humalog in the retina one day and one week after subconjunctival implantation. Phosphorylation of.Akt and tyrosine kinase of IRß, and IGF1R were increased by the treatment with hydrogel loaded with Humalog® in ex-vivo retinas. These data indicated that the released Humalog was active.
The designed hydrogels have ability to regulate insulin release kinetics and dosages, and have potential to deliver low dose insulin delivery to prevent or treat diabetic retinopathy.
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