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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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).
Hastings, C. L. et al. Drug and cell delivery for cardiac regeneration. Adv. Drug Deliv. Rev. 84, 85–106 (2015).
Jung, D. W. & Williams, D. R. Reawakening atlas: chemical approaches to repair or replace dysfunctional musculature. ACS Chem. Biol. 7, 1773–1790 (2012).
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).
Segers, V. F. M. & Lee, R. T. Protein therapeutics for cardiac regeneration after myocardial infarction. J. Cardiovasc. Transl. Res. 3, 469–477 (2010).
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).
Ziegler, M. et al. The bispecific SDF1-GPVI fusion protein preserves myocardial function after transient ischemia in mice. Circulation 125, 685–696 (2012).
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).
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).
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).
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).
Saraswati, S. et al. Pyrvinium, a potent small molecule Wnt inhibitor, promotes wound repair and post-MI cardiac remodeling. PLoS ONE 5, e15521 (2010).
van Brakel, T. J. et al. Intrapericardial delivery enhances cardiac effects of sotalol and atenolol. J. Cardiovasc. Pharmacol. 44, 50–56 (2004).
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).
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).
Hermans, J. J. R. et al. Pharmacokinetic advantage of intrapericardially applied substances in the rat. J. Pharmacol. Exp. Ther. 301, 672–678 (2002).
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).
Ashraf, M. et al. Systems approaches to preventing transplanted cell death in cardiac repair. J. Mol. Cell. Cardiol. 45, 567–581 (2008).
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).
Clifford, D. M. et al. Stem cell treatment for acute myocardial infarction.Cochrane Datab. System. Rev. 2, CD006536(2012).
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).
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).
Gnecchi, M., Zhang, Z., Ni, A. & Dzau, V. J. Paracrine mechanisms in adult stem cell signaling and therapy. Circ. Res. 103, 1204–1219 (2008).
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).
Hamdi, H. et al. Cell delivery: intramyocardial injections or epicardial deposition? A head-to-head comparison. Ann. Thorac. Surg. 87, 1196–1203 (2009).
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).
Qian, L. et al. Hemodynamic contribution of stem cell scaffolding in acute injured myocardium. Tissue Eng. Part A 18, 1652–1663 (2012).
Habib, M. et al. A combined cell therapy and in-situ tissue-engineering approach for myocardial repair. Biomaterials 32, 7514–7523 (2011).
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).
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).
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).
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).
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).
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).
Martens, T. P. et al. Percutaneous cell delivery into the heart using hydrogels polymerizing in situ. Cell Transplant. 18, 297–304 (2009).
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).
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).
Bolli, R. Repeated cell therapy: a paradigm shift whose time has come. Circ. Res. 120, 1072–1074 (2017).
Menasche, P. Cardiac cell therapy: lessons from clinical trials. J. Mol. Cell. Cardiol. 50, 258–65 (2011).
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).
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).
Koshy, S. T., Ferrante, T. C., Lewin, S. A. & Mooney, D. J. Injectable, porous, and cell-responsive gelatin cryogels. Biomaterials 35, 2477–2487 (2014).
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).
Laham, R. J., Hung, D. & Simons, M. Therapeutic myocardial angiogenesis using percutaneous intrapericardial drug delivery. Clin. Cardiol. 22, 6–9 (1999).
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).
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).
Hatzistergos, K. E. et al. Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circ. Res. 107, 913–922 (2010).
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).
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).
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).
Assmus, B. et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI).Circulation 106, 3009–3017 (2002).
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).
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).
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).
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).
Pilla, J. J. et al. Early postinfarction ventricular restraint improves borderzone wall thickening dynamics during remodeling. Ann. Thorac. Surg. 80, 2257–2262 (2005).
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).
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).
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).
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
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).
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).
Maisch, B., Ristić, A. D., Pankuweit, S. & Seferovic, P. Percutaneous therapy in pericardial diseases. Cardiol. Clin. 35, 567–588 (2017).
Li, J. et al. Tough adhesives for diverse wet surfaces. Science 357, 378–381 (2017).
Cannata, A. et al. Postsurgical intrapericardial adhesions: mechanisms of formation and prevention. Ann. Thorac. Surg. 95, 1818–1826 (2013).
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).
Imazio, M. et al. Drainage or pericardiocentesis alone for recurrent nonmalignant, nonbacterial pericardial effusions requiring intervention. J. Cardiovasc. Med. 15, 510–514 (2014).
Chaudhry, P. A. et al. Passive epicardial containment prevents ventricular remodeling in heart failure. Ann. Thorac. Surg. 70, 1275–1280 (2000).
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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