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Sustained release of targeted cardiac therapy with a replenishable implanted epicardial reservoir

Nature Biomedical Engineering volume 2, pages 416–428 (2018)Cite this article

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Abstract

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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Fig. 1: An overview of the vision for the clinical translation of Therepi and its realization for pre-clinical evaluation.
Fig. 2: Pre-clinical implementation and demonstration of targeted small-molecule delivery.
Fig. 3: The Therepi system allows for sustained viability, cell localization, protein release and cell refills in vitro.
Fig. 4: Demonstration of fibrous capsule penetration and 3D distribution of macromolecules in the myocardium.
Fig. 5: Cell refill from the simplified Therepi device in vivo.
Fig. 6: Pre-clinical safety and efficacy of the replenishable cell delivery device.
Fig. 7: Histological analysis of the Therepi device in vivo.

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Acknowledgements

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.

Author information

Author notes

  1. These authors contributed equally to this work: William Whyte, Ellen T. Roche.

  2. These authors jointly supervised this work: Garry P. Duffy, Conor J. Walsh, David J. Mooney.

Authors and Affiliations

  1. John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA

    William Whyte, Ellen T. Roche, Keegan Mendez, James C. Weaver, Conor J. Walsh & David J. Mooney

  2. Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA, USA

    William Whyte, Ellen T. Roche, Keegan Mendez, James C. Weaver, Conor J. Walsh & David J. Mooney

  3. Tissue Engineering Research Group, Department of Anatomy, Royal College of Surgeons in Ireland, Dublin, Ireland

    William Whyte, Hugh O’Neill & Garry P. Duffy

  4. Trinity Centre for Bioengineering, Trinity College Dublin, Dublin, Ireland

    William Whyte, Bruce Murphy & Garry P. Duffy

  5. Advanced Materials and BioEngineering Research (AMBER) Centre, Royal College of Surgeons in Ireland, National University of Ireland Galway and Trinity College Dublin, Dublin, Ireland

    William Whyte, Bruce Murphy & Garry P. Duffy

  6. Biomedical Engineering, College of Engineering and Informatics, National University of Ireland, Galway, Ireland

    Ellen T. Roche, Fiona Weafer, Reyhaneh Neghabat Shirazi & Peter E. McHugh

  7. Department of Anatomy, School of Medicine, College of Medicine Nursing and Health Sciences, National University of Ireland, Galway, Ireland

    Ellen T. Roche & Garry P. Duffy

  8. Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA

    Ellen T. Roche & Claudia E. Varela

  9. Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    Ellen T. Roche & Shahrin Islam

  10. Harvard-MIT Program in Health Sciences and Technology, Cambridge, MA, USA

    Ellen T. Roche & Claudia E. Varela

  11. Department of Cardiac Surgery, Boston Children’s Hospital, Boston, MA, USA

    Nikolay V. Vasilyev

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Contributions

W.W., E.T.R., G.P.D., C.J.W. and D.J.M. designed the study. W.W., E.T.R., C.E.V., K.M., S.I., H.O.N., F.W., R.N.S. and J.C.W. performed the experiments. W.W., E.T.R., N.V.V., B.M., P.E.McH., G.P.D, C.J.W. and D.J.M. analysed and reviewed the data. W.W., E.T.R., G.P.D., C.J.W. and D.J.M. wrote the manuscript. All authors reviewed and edited the manuscript.

Corresponding authors

Correspondence to Garry P. Duffy, Conor J. Walsh or David J. Mooney.

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Competing interests

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 information

Supplementary Information

Supplementary methods, figures and tables.

Reporting Summary

Supplementary Video 1

Device-manufacturing process.

Supplementary Video 2

Minimally invasive delivery.

Supplementary Video 3

Refill of therapy.

Supplementary Video 4

Overview of the surgery.

Supplementary Video 5

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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