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

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.

References

  1. 1.

    O’Neill, H. S. et al. Biomaterial-enhanced cell and drug delivery: lessons learned in the cardiac field and future perspectives.Adv. Mater. 28, 5648–5661 (2016).

    PubMed  Google Scholar 

  2. 2.

    Hastings, C. L. et al. Drug and cell delivery for cardiac regeneration. Adv. Drug Deliv. Rev. 84, 85–106 (2015).

    CAS  PubMed  Google Scholar 

  3. 3.

    Jung, D. W. & Williams, D. R. Reawakening atlas: chemical approaches to repair or replace dysfunctional musculature. ACS Chem. Biol. 7, 1773–1790 (2012).

    CAS  PubMed  Google Scholar 

  4. 4.

    Plowright, A. T., Engkvist, O., Gill, A., Knerr, L. & Wang, Q. D. Heart regeneration: opportunities and challenges for drug discovery with novel chemical and therapeutic methods or agents. Angew. Chem. Int. Ed. 53, 4056–4075 (2014).

    CAS  Google Scholar 

  5. 5.

    Segers, V. F. M. & Lee, R. T. Protein therapeutics for cardiac regeneration after myocardial infarction. J. Cardiovasc. Transl. Res. 3, 469–477 (2010).

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Segers, V. F. M. et al. Local delivery of protease-resistant stromal cell derived factor-1 for stem cell recruitment after myocardial infarction. Circulation 116, 1683–1692 (2007).

    CAS  PubMed  Google Scholar 

  7. 7.

    Ziegler, M. et al. The bispecific SDF1-GPVI fusion protein preserves myocardial function after transient ischemia in mice. Circulation 125, 685–696 (2012).

    CAS  PubMed  Google Scholar 

  8. 8.

    Urbanek, K. et al. Cardiac stem cells possess growth factor-receptor systems that after activation regenerate the infarcted myocardium, improving ventricular function and long-term survival. Circ. Res. 97, 663–673 (2005).

    CAS  PubMed  Google Scholar 

  9. 9.

    Jabbour, A. et al. Parenteral administration of recombinant human neuregulin-1 to patients with stable chronic heart failure produces favourable acute and chronic haemodynamic responses. Eur. J. Heart Fail. 13, 83–92 (2011).

    CAS  PubMed  Google Scholar 

  10. 10.

    Torella, D. et al. Cardiac stem cell and myocyte aging, heart failure, and insulin-like growth factor-1 overexpression. Circ. Res. 94, 514–524 (2004).

    CAS  PubMed  Google Scholar 

  11. 11.

    Hsueh, Y. C., Wu, J. M., Yu, C. K., Wu, K. K. & Hsieh, P. C. Prostaglandin E2 promotes post-infarction cardiomyocyte replenishment by endogenous stem cells. EMBO Mol. Med. 6, 496–503 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Saraswati, S. et al. Pyrvinium, a potent small molecule Wnt inhibitor, promotes wound repair and post-MI cardiac remodeling. PLoS ONE 5, e15521 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    van Brakel, T. J. et al. Intrapericardial delivery enhances cardiac effects of sotalol and atenolol. J. Cardiovasc. Pharmacol. 44, 50–56 (2004).

    PubMed  Google Scholar 

  14. 14.

    Baek, S. H. et al. Augmentation of intrapericardial nitric oxide level by a prolonged-release nitric oxide donor reduces luminal narrowing after porcine coronary angioplasty. Circulation 105, 2779–2784 (2002).

    CAS  PubMed  Google Scholar 

  15. 15.

    Waxman, S., Moreno, R., Rowe, K. A. & Verrier, R. L. Persistent primary coronary dilation induced by transatrial delivery of nitroglycerin into the pericardial space: a novel approach for local cardiac drug delivery. J. Am. Coll. Cardiol. 33, 2073–2077 (1999).

    CAS  PubMed  Google Scholar 

  16. 16.

    Hermans, J. J. R. et al. Pharmacokinetic advantage of intrapericardially applied substances in the rat. J. Pharmacol. Exp. Ther. 301, 672–678 (2002).

    CAS  PubMed  Google Scholar 

  17. 17.

    Laflamme, Ma, Zbinden, S., Epstein, S. E. & Murry, C. E. Cell-based therapy for myocardial ischemia and infarction: pathophysiological mechanisms. Annu. Rev. Pathol. 2, 307–339 (2007).

    CAS  PubMed  Google Scholar 

  18. 18.

    Ashraf, M. et al. Systems approaches to preventing transplanted cell death in cardiac repair. J. Mol. Cell. Cardiol. 45, 567–581 (2008).

    Google Scholar 

  19. 19.

    Gavira, J. J. et al. Repeated implantation of skeletal myoblast in a swine model of chronic myocardial infarction. Eur. Heart J. 31, 1013–1021 (2010).

    PubMed  Google Scholar 

  20. 20.

    Clifford, D. M. et al. Stem cell treatment for acute myocardial infarction.Cochrane Datab. System. Rev. 2, CD006536(2012).

    Google Scholar 

  21. 21.

    Gnecchi, M. et al. Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J. 20, 661–669 (2006).

    CAS  PubMed  Google Scholar 

  22. 22.

    Kinnaird, T. et al. Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ. Res. 94, 678–685 (2004).

    CAS  PubMed  Google Scholar 

  23. 23.

    Gnecchi, M., Zhang, Z., Ni, A. & Dzau, V. J. Paracrine mechanisms in adult stem cell signaling and therapy. Circ. Res. 103, 1204–1219 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Wang, X., Zachman, A. L., Haglund, N. A., Maltais, S. & Sung, H. J. Combined usage of stem cells in end-stage heart failure therapies. J. Cell. Biochem. 115, 1217–1224 (2014).

    CAS  PubMed  Google Scholar 

  25. 25.

    Hamdi, H. et al. Cell delivery: intramyocardial injections or epicardial deposition? A head-to-head comparison. Ann. Thorac. Surg. 87, 1196–1203 (2009).

    PubMed  Google Scholar 

  26. 26.

    Smith, R. R., Marbán, E. & Marbán, L. Enhancing retention and efficacy of cardiosphere-derived cells administered after myocardial infarction using a hyaluronan-gelatin hydrogel.Biomatter 3, e24490 (2013).

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    Qian, L. et al. Hemodynamic contribution of stem cell scaffolding in acute injured myocardium. Tissue Eng. Part A 18, 1652–1663 (2012).

    CAS  PubMed  Google Scholar 

  28. 28.

    Habib, M. et al. A combined cell therapy and in-situ tissue-engineering approach for myocardial repair. Biomaterials 32, 7514–7523 (2011).

    CAS  PubMed  Google Scholar 

  29. 29.

    Christman, K. L. et al. Injectable fibrin scaffold improves cell transplant survival, reduces infarct expansion, and induces neovasculature formation in ischemic myocardium. J. Am. Coll. Cardiol. 44, 654–660 (2004).

    CAS  PubMed  Google Scholar 

  30. 30.

    Singelyn, J. M. & Christman, K. L. Injectable materials for the treatment of myocardial infarction and heart failure: the promise of decellularized matrices. J. Cardiovasc. Transl. Res. 3, 478–486 (2010).

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    Liu, Z. et al. The influence of chitosan hydrogel on stem cell engraftment, survival and homing in the ischemic myocardial microenvironment. Biomaterials 33, 3093–3106 (2012).

    CAS  PubMed  Google Scholar 

  32. 32.

    Lu, W.-N. et al. Functional improvement of infarcted heart by co-injection of embryonic stem cells with temperature-responsive chitosan hydrogel. Tissue Eng. Part A 15, 1437–47 (2009).

    CAS  PubMed  Google Scholar 

  33. 33.

    Yu, J. et al. The use of human mesenchymal stem cells encapsulated in RGD modified alginate microspheres in the repair of myocardial infarction in the rat. Biomaterials 31, 7012–7020 (2010).

    CAS  PubMed  Google Scholar 

  34. 34.

    Wang, T. et al. Bone marrow stem cells implantation with α-cyclodextrin/MPEG–PCL–MPEG hydrogel improves cardiac function after myocardial infarction. Acta. Biomater. 5, 2939–2944 (2009).

    CAS  PubMed  Google Scholar 

  35. 35.

    Martens, T. P. et al. Percutaneous cell delivery into the heart using hydrogels polymerizing in situ. Cell Transplant. 18, 297–304 (2009).

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    Gaffey, A. C. et al. Injectable shear-thinning hydrogels used to deliver endothelial progenitor cells, enhance cell engraftment, and improve ischemic myocardium.J. Thorac. Cardiovasc. Surg. 150, 1268–1276 (2015).

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Tokita, Y. et al. Repeated administrations of cardiac progenitor cells are markedly more effective than a single administration: a new paradigm in cell therapy. Circ. Res. 119, 635–651 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Bolli, R. Repeated cell therapy: a paradigm shift whose time has come. Circ. Res. 120, 1072–1074 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Menasche, P. Cardiac cell therapy: lessons from clinical trials. J. Mol. Cell. Cardiol. 50, 258–65 (2011).

    CAS  PubMed  Google Scholar 

  40. 40.

    Malliaras, K. & Marban, E. Cardiac cell therapy: where we’ve been, where we are, and where we should be headed.Br. Med. Bull. 98, 161–185 (2011).

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    O’Cearbhaill, E. D., Ng, K. S. & Karp, J. M. Emerging medical devices for minimally invasive cell therapy. Mayo Clin. Proc. 89, 259–273 (2014).

    PubMed  Google Scholar 

  42. 42.

    Koshy, S. T., Ferrante, T. C., Lewin, S. A. & Mooney, D. J. Injectable, porous, and cell-responsive gelatin cryogels. Biomaterials 35, 2477–2487 (2014).

    CAS  PubMed  Google Scholar 

  43. 43.

    Roche, E. T. et al. Comparison of biomaterial delivery vehicles for improving acute retention of stem cells in the infarcted heart. Biomaterials 35, 6850–6858 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Laham, R. J., Hung, D. & Simons, M. Therapeutic myocardial angiogenesis using percutaneous intrapericardial drug delivery. Clin. Cardiol. 22, 6–9 (1999).

    Google Scholar 

  45. 45.

    Ujhelyi, M., Hadsall, K., Euler, D. & Mehra, R. Intrapericardial therapeutics: a pharmacodynamic and pharmacokinetic comparison between pericardial and intravenous procainamide delivery. J. Cardiovasc Electro. 13, 605–611 (2002).

    Google Scholar 

  46. 46.

    Moreno, R., Waxman, S., Rowe, K. & Verrier, R. L. Intrapericardial β-adrenergic blockade with esmolol exerts a potent antitachycardic effect without depressing contractility. J. Cardiovasc. Pharmacol. 36, 722–727 (2000).

    CAS  PubMed  Google Scholar 

  47. 47.

    Hatzistergos, K. E. et al. Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circ. Res. 107, 913–922 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Zhang, Z. et al. Selective inhibition of inositol hexakisphosphate kinases (IP6Ks) enhances mesenchymal stem cell engraftment and improves therapeutic efficacy for myocardial infarction. Basic Res. Cardiol. 109, 417 (2014).

    PubMed  Google Scholar 

  49. 49.

    Mathieu, E. et al. Intramyocardial delivery of mesenchymal stem cell-seeded hydrogel preserves cardiac function and attenuates ventricular remodeling after myocardial infarction. PLoS ONE 7, e51991 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Tendera, M. et al. Intracoronary infusion of bone marrow-derived selected CD34+ CXCR4+ cells and non-selected mononuclear cells in patients with acute STEMI and reduced left ventricular ejection fraction: results of randomized, multicentre myocardial Regeneration by Intracoronary Infusion of Selected Population of Stem Cells in Acute Myocardial Infarction (REGENT) trial. Eur. Heart J. 30, 1313–1321 (2009).

    PubMed  Google Scholar 

  51. 51.

    Assmus, B. et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI).Circulation 106, 3009–3017 (2002).

    PubMed  Google Scholar 

  52. 52.

    Janssens, S. et al. Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet 367, 113–121 (2006).

    PubMed  Google Scholar 

  53. 53.

    Klinker, M. W. & Wei, C.-H. Mesenchymal stem cells in the treatment of inflammatory and autoimmune diseases in experimental animal models. World J. Stem Cells 7, 556–567 (2015).

    PubMed  PubMed Central  Google Scholar 

  54. 54.

    Hodgkinson, C. P., Bareja, A., Gomez, J. A. & Dzau, V. J. Emerging concepts in paracrine mechanisms in regenerative cardiovascular medicine and biology. Circ. Res. 118, 95–107 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Guo, Y. et al. Repeated doses of cardiac mesenchymal cells are therapeutically superior to a single dose in mice with old myocardial infarction. Basic Res. Cardiol. 112, 18 (2017).

    PubMed  PubMed Central  Google Scholar 

  56. 56.

    Pilla, J. J. et al. Early postinfarction ventricular restraint improves borderzone wall thickening dynamics during remodeling. Ann. Thorac. Surg. 80, 2257–2262 (2005).

    PubMed  Google Scholar 

  57. 57.

    Blom, A. S. et al. Ventricular restraint prevents infarct expansion and improves borderzone function after myocardial infarction: a study using magnetic resonance imaging, three-dimensional surface modeling, and myocardial tagging. Ann. Thorac. Surg. 84, 2004–2010 (2007).

    PubMed  Google Scholar 

  58. 58.

    Kwon, M. H., Cevasco, M., Schmitto, J. D. & Chen, F. Y. Ventricular restraint therapy for heart failure: a review, summary of state of the art, and future directions. J. Thorac. Cardiovasc. Surg. 144, 771–777 (2012).

    PubMed  Google Scholar 

  59. 59.

    Naftali-Shani, N. et al. Left ventricular dysfunction switches mesenchymal stromal cells toward an inflammatory phenotype and impairs their reparative properties via Toll-like receptor-4. Circulation 135, 2271–2287 (2017).

    CAS  PubMed  Google Scholar 

  60. 60.

    JDRF. Sernova Corp. announces collaboration with Massachusetts General Hospital to develop novel diabetes treatment with funding support from JDRF (accessed 16 October 2015); go.nature.com/2IEDbB6

  61. 61.

    Makkar, R. R. et al. Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet 379, 895–904 (2012).

    PubMed  PubMed Central  Google Scholar 

  62. 62.

    Killu, A. M. et al. Trends in percutaneous pericardial access during catheter ablation of ventricular arrhythmias: a single-center experience. J. Interv. Card. Electrophysiol. 47, 109–115 (2016).

    PubMed  Google Scholar 

  63. 63.

    Maisch, B., Ristić, A. D., Pankuweit, S. & Seferovic, P. Percutaneous therapy in pericardial diseases. Cardiol. Clin. 35, 567–588 (2017).

    PubMed  Google Scholar 

  64. 64.

    Li, J. et al. Tough adhesives for diverse wet surfaces. Science 357, 378–381 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Cannata, A. et al. Postsurgical intrapericardial adhesions: mechanisms of formation and prevention. Ann. Thorac. Surg. 95, 1818–1826 (2013).

    PubMed  Google Scholar 

  66. 66.

    Melfi, F. M. A., Menconi, G. F., Chella, A. & Angeletti, C. A. The management of malignant pericardial effusions using permanently implanted devices. Eur. J. Cardiothorac. Surg. 21, 345–347 (2002).

    PubMed  Google Scholar 

  67. 67.

    Imazio, M. et al. Drainage or pericardiocentesis alone for recurrent nonmalignant, nonbacterial pericardial effusions requiring intervention. J. Cardiovasc. Med. 15, 510–514 (2014).

    CAS  Google Scholar 

  68. 68.

    Chaudhry, P. A. et al. Passive epicardial containment prevents ventricular remodeling in heart failure. Ann. Thorac. Surg. 70, 1275–1280 (2000).

    CAS  PubMed  Google Scholar 

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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.

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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 or 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 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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