No systemic exposure of transtympanic heparin-binding epidermal growth factor like growth factor

Abstract

Context: Heparin-binding epidermal growth factor like growth factor (HB-EGF) is an emerging therapeutic for the regeneration of the tympanic membrane (TM). Objective: Our aim was to determine whether the doses of HB-EGF delivered in a sustained release hydrogel into a middle ear mouse model, would be measurable in the systemic circulation. We also aimed to observe, in the scenario that the intended dose was absorbed directly into the circulation, whether these levels could be measured above the background levels of HB-EGF in the circulation. Methods: A total of 12 mice had transtympanic injections of 5 μg/ml of HB-EGF contained within a previously described novel hydrogel vehicle, while another 12 mice had intravenous delivery of 10 μg/kg of HB-EGF. Intravenous blood samples were collected at 0-, 3-, 24-, 168-, 288- and 720-h post-injection. A double-antibody sandwich one-step process enzyme-linked immunosorbent assay (ELISA) was used to determine the level of HB-EGF in the serum. Results: No mice in the transtympanic administration group and no mice in the intravenous administration group were found to have blood level measured above that in the controls. Discussion: The inability of the positive control to measure levels above background, suggest the total dose used in our studies, even if 100% absorbed into the system circulation is insignificant. Conclusions: HB-EGF at the doses and delivery method proposed for treatment of chronic TM perforation in a mouse model are likely to have no measurable systemic effect.

• Tympanic membrane
• regeneration
• tympanic perforation

Acknowledgements

The authors acknowledge Garnett Passe and Rodney Williams Memorial Foundation, Stanford’s SPARK, Stanford Child Health Research Institute, Wallace H. Coulter Foundation and DOD W81XWH-10-1-0966 (PRORP).

Declaration of interest

The authors disclose the potential conflict of interest. Filed patents: U.S. Non-Provisional No. 61/823 749, April 2014: P.L.S.M., S.K. and Y.P.Y. U.S. Non-Provisional No. 61/810 101, April 2014: S.K. and Y.P.Y. Founding stock in Auration biotech: P.L.S.M. NIH funding: NIH R01AR057837 (NIAMS) and NIH R01DE021468 (NIDCR).