The clinical translation of regenerative therapy for the diseased heart, whether in the form of cells, macromolecules or small molecules, is hampered by several factors: the poor retention and short biological half-life of the therapeutic agent, the adverse side effects from systemic delivery, and difficulties with the administration of multiple doses. Here, we report the development and application of a therapeutic epicardial device that enables sustained and repeated administration of small molecules, macromolecules and cells directly to the epicardium via a polymer-based reservoir connected to a subcutaneous port. In a myocardial infarct rodent model, we show that repeated administration of cells over a four-week period using the epicardial reservoir provided functional benefits in ejection fraction, fractional shortening and stroke work, compared to a single injection of cells and to no treatment. The pre-clinical use of the therapeutic epicardial reservoir as a research model may enable insights into regenerative cardiac therapy, and assist the development of experimental therapies towards clinical use.
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The authors would like to thank R. Liao, S. Fisch and S. Ngoy from the Brigham and Women’s Hospital (BHW) Rodent Cardiovascular Physiology core for their technical support (echocardiographic assessment and rodent surgery) during our 28-day animal studies; R. Padera from BWH for his histological assessment; J. W. Shin and A. Mao for providing us with luciferase-expressing cells; D. Connolly and the CT scanning core at the Department of Biomedical Engineering, NUI Galway, Ireland; N. Phipps and P. Allen for designing scientific illustrations; Y. Narang, F. Connolly and C. Payne for their technical input; A. Grodzinsky and E. Frank for their generous help and guidance with the diffusion test set-up; and finally T. Ferrante from the Wyss Institute for his imaging expertise. Funding was provided by the Wyss Institute for Biologically Inspired Engineering at Harvard University. E.T.R. was funded by the Institute for Medical Engineering Science at the Massachusetts Institute of Technology, Wellcome Trust/Science Foundation Ireland/Health Research Board Seed Award in Science and a Government of Ireland Postdoctoral Award from the Irish Research Council. W.W and G.P.D. acknowledge support from Science Foundation Ireland under grant SFI/12/RC/2278, Advanced Materials and Bioengineering Research (AMBER) Centre, Royal College of Surgeons in Ireland and Trinity College Dublin, Ireland.
Patents describing the device documented in this article have been filed with the US Patent Office. W.W., E.T.R., H.O.N., G.P.D., C.J.W. and D.J.M. are inventors of the following patent application: U.S. 15/557,353. The other authors declare no competing interests.
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Supplementary methods, figures and tables.
Minimally invasive delivery.
Refill of therapy.
Overview of the surgery.
Overview of the terminal surgery with a pressure–volume catheter.
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Whyte, W., Roche, E.T., Varela, C.E. et al. Sustained release of targeted cardiac therapy with a replenishable implanted epicardial reservoir. Nat Biomed Eng 2, 416–428 (2018). https://doi.org/10.1038/s41551-018-0247-5
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