{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T16:40:58Z","timestamp":1780504858743,"version":"3.54.1"},"reference-count":43,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,11,17]],"date-time":"2020-11-17T00:00:00Z","timestamp":1605571200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL089315-7"],"award-info":[{"award-number":["R01HL089315-7"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCDD"],"abstract":"<jats:p>The clinical efficacy of neuregulin (NRG) in the treatment of heart failure is hindered by off-target exposure due to systemic delivery. We previously encapsulated neuregulin in a hydrogel (HG) for targeted and sustained myocardial delivery, demonstrating significant induction of cardiomyocyte proliferation and preservation of post-infarct cardiac function in a murine myocardial infarction (MI) model. Here, we performed a focused evaluation of our hydrogel-encapsulated neuregulin (NRG-HG) therapy\u2019s potential to enhance cardiac function in an ovine large animal MI model. Adult male Dorset sheep (n = 21) underwent surgical induction of MI by coronary artery ligation. The sheep were randomized to receive an intramyocardial injection of saline, HG only, NRG only, or NRG-HG circumferentially around the infarct borderzone. Eight weeks after MI, closed-chest intracardiac pressure\u2013volume hemodynamics were assessed, followed by heart explant for infarct size analysis. Compared to each of the control groups, NRG-HG significantly augmented left ventricular ejection fraction (p = 0.006) and contractility based on the slope of the end-systolic pressure\u2013volume relationship (p = 0.006). NRG-HG also significantly reduced infarct scar size (p = 0.002). Overall, using a bioengineered hydrogel delivery system, a one-time dose of NRG delivered intramyocardially to the infarct borderzone at the time of MI in adult sheep significantly reduces scar size and enhances ventricular contractility at 8 weeks after MI.<\/jats:p>","DOI":"10.3390\/jcdd7040053","type":"journal-article","created":{"date-parts":[[2020,11,17]],"date-time":"2020-11-17T07:23:28Z","timestamp":1605597808000},"page":"53","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A Bioengineered Neuregulin-Hydrogel Therapy Reduces Scar Size and Enhances Post-Infarct Ventricular Contractility in an Ovine Large Animal Model"],"prefix":"10.3390","volume":"7","author":[{"given":"Jeffrey E.","family":"Cohen","sequence":"first","affiliation":[{"name":"Department of Cardiothoracic Surgery, Stanford University, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew B.","family":"Goldstone","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Stanford University, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2367-5591","authenticated-orcid":false,"given":"Hanjay","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Stanford University, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan P.","family":"Purcell","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiro","family":"Shudo","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Stanford University, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John W.","family":"MacArthur","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Stanford University, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda N.","family":"Steele","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Stanford University, Stanford, CA 94305, USA"},{"name":"Department of Bioengineering, Stanford University, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1730-0678","authenticated-orcid":false,"given":"Michael J.","family":"Paulsen","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Stanford University, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan B.","family":"Edwards","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Stanford University, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiaka N.","family":"Aribeana","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Stanford University, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2711-019X","authenticated-orcid":false,"given":"Nicholas C.","family":"Cheung","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Stanford University, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason A.","family":"Burdick","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y. Joseph","family":"Woo","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Stanford University, Stanford, CA 94305, USA"},{"name":"Department of Bioengineering, Stanford University, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e139","DOI":"10.1161\/CIR.0000000000000757","article-title":"American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association","volume":"141","author":"Virani","year":"2020","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1161\/CIR.0b013e31820a55f5","article-title":"Forecasting the future of cardiovascular disease in the United States: A policy statement from the American Heart Association","volume":"123","author":"Heidenreich","year":"2011","journal-title":"Circulation"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2287","DOI":"10.1161\/CIRCULATIONAHA.113.007412","article-title":"Mesenchymal precursor cells as adjunctive therapy in recipients of contemporary left ventricular assist devices","volume":"129","author":"Ascheim","year":"2014","journal-title":"Circulation"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1038\/s41569-018-0013-0","article-title":"Cell therapy trials for heart regeneration\u2014Lessons learned and future directions","volume":"15","year":"2018","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1161\/CIRCRESAHA.117.310599","article-title":"Intravenously Delivered Mesenchymal Stem Cells: Systemic Anti-Inflammatory Effects Improve Left Ventricular Dysfunction in Acute Myocardial Infarction and Ischemic Cardiomyopathy","volume":"120","author":"Luger","year":"2017","journal-title":"Circ. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"208","DOI":"10.3389\/fbioe.2019.00208","article-title":"Vascularization of Engineered Spatially Patterned Myocardial Tissue Derived From Human Pluripotent Stem Cells in vivo","volume":"7","author":"Wanjare","year":"2019","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2130","DOI":"10.1161\/CIRCULATIONAHA.118.035231","article-title":"Rapid Self-Assembly of Bioengineered Cardiovascular Bypass Grafts From Scaffold-Stabilized, Tubular Bilevel Cell Sheets","volume":"138","author":"Wang","year":"2018","journal-title":"Circulation"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1161\/CIRCRESAHA.114.302884","article-title":"Preclinical evaluation of the engineered stem cell chemokine stromal cell-derived factor 1\u03b1 analog in a translational ovine myocardial infarction model","volume":"114","author":"Macarthur","year":"2014","journal-title":"Circ. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.jmbbm.2019.04.014","article-title":"Bioengineered analog of stromal cell-derived factor 1\u03b1 preserves the biaxial mechanical properties of native myocardium after infarction","volume":"96","author":"Wang","year":"2019","journal-title":"J. Mech. Behav. Biomed. Mater."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e1603078","DOI":"10.1126\/sciadv.1603078","article-title":"An innovative biologic system for photon-powered myocardium in the ischemic heart","volume":"3","author":"Cohen","year":"2017","journal-title":"Sci. Adv."},{"key":"ref_11","first-page":"843","article-title":"Photosynthetic symbiotic therapy","volume":"11","author":"Wang","year":"2019","journal-title":"Aging (Albany N. Y.)"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1128.e18","DOI":"10.1016\/j.cell.2018.12.023","article-title":"A unique collateral artery development program promotes neonatal heart regeneration","volume":"176","author":"Das","year":"2019","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Wang, H., Paulsen, M.J., Hironaka, C.E., Shin, H.S., Farry, J.M., Thakore, A.D., Jung, J., Lucian, H.J., Eskandari, A., and Anilkumar, S. (2020). Natural heart regeneration in a neonatal rat myocardial infarction model. Cells, 9.","DOI":"10.3390\/cells9010229"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7319","DOI":"10.1038\/s41598-020-63324-w","article-title":"Multiaxial Lenticular Stress-Strain Relationship of Native Myocardium is Preserved by Infarct-Induced Natural Heart Regeneration in Neonatal Mice","volume":"10","author":"Wang","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1126\/science.1164680","article-title":"Evidence for cardiomyocyte renewal in humans","volume":"324","author":"Bergmann","year":"2009","journal-title":"Science"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.cell.2009.04.060","article-title":"Neuregulin1\/ErbB4 signaling induces cardiomyocyte proliferation and repair of heart injury","volume":"138","author":"Bersell","year":"2009","journal-title":"Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.1016\/j.jacc.2006.05.057","article-title":"Neuregulin-1\/erbB-activation improves cardiac function and survival in models of ischemic, dilated, and viral cardiomyopathy","volume":"48","author":"Liu","year":"2006","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1161\/CIRCHEARTFAILURE.113.001273","article-title":"A bioengineered hydrogel system enables targeted and sustained intramyocardial delivery of neuregulin, activating the cardiomyocyte cell cycle and enhancing ventricular function in a murine model of ischemic cardiomyopathy","volume":"7","author":"Cohen","year":"2014","journal-title":"Circ. Heart Fail"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"H2139\u201347","DOI":"10.1152\/ajpheart.00063.2012","article-title":"The role of neuregulin\/ErbB2\/ErbB4 signaling in the heart with special focus on effects on cardiomyocyte proliferation","volume":"302","author":"Wadugu","year":"2012","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"10261","DOI":"10.1074\/jbc.273.17.10261","article-title":"Neuregulins promote survival and growth of cardiac myocytes","volume":"273","author":"Zhao","year":"1998","journal-title":"J. Bio. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1038\/nrm1962","article-title":"EGF-ERBB signalling: Towards the systems level","volume":"7","author":"Citri","year":"2006","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1161\/CIRCRESAHA.112.267286","article-title":"Neuregulin in cardiovascular development and disease","volume":"111","author":"Odiete","year":"2012","journal-title":"Circ. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1200\/JCO.1999.17.5.1644e","article-title":"Cardiotoxicity associated with paclitaxel\/trastuzumab combination therapy","volume":"17","author":"Jerian","year":"1999","journal-title":"J. Clin. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1161\/CIRCULATIONAHA.107.690487","article-title":"Role of neuregulin-1\/ErbB signaling in cardiovascular physiology and disease: Implications for therapy of heart failure","volume":"116","author":"Lemmens","year":"2007","journal-title":"Circulation"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1016\/j.jacc.2009.12.044","article-title":"A Phase II, randomized, double-blind, multicenter, based on standard therapy, placebo-controlled study of the efficacy and safety of recombinant human neuregulin-1 in patients with chronic heart failure","volume":"55","author":"Gao","year":"2010","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1093\/eurjhf\/hfq152","article-title":"Parenteral administration of recombinant human neuregulin-1 to patients with stable chronic heart failure produces favourable acute and chronic haemodynamic responses","volume":"13","author":"Jabbour","year":"2011","journal-title":"Eur. J. Heart Fail."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/j.jacbts.2016.09.005","article-title":"A Phase I, Single Ascending Dose Study of Cimaglermin Alfa (Neuregulin 1\u03b23) in Patients With Systolic Dysfunction and Heart Failure","volume":"1","author":"Lenihan","year":"2016","journal-title":"JACC Basic Transl. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"S79","DOI":"10.1161\/CIRCULATIONAHA.112.000343","article-title":"Sustained release of engineered stromal cell-derived factor 1-\u03b1 from injectable hydrogels effectively recruits endothelial progenitor cells and preserves ventricular function after myocardial infarction","volume":"128","author":"MacArthur","year":"2013","journal-title":"Circulation"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e1801147","DOI":"10.1002\/adhm.201801147","article-title":"A Biocompatible Therapeutic Catheter-Deliverable Hydrogel for In Situ Tissue Engineering","volume":"8","author":"Steele","year":"2019","journal-title":"Adv. Healthc. Mater."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"154974","DOI":"10.1016\/j.cyto.2019.154974","article-title":"Multi-phase catheter-injectable hydrogel enables dual-stage protein-engineered cytokine release to mitigate adverse left ventricular remodeling following myocardial infarction in a small animal model and a large animal model","volume":"127","author":"Steele","year":"2020","journal-title":"Cytokine"},{"key":"ref_31","unstructured":"National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals (2011). The National Academies Collection: Reports funded by National Institutes of Health. Guide for the Care and Use of Laboratory Animals, National Academies Press (US). [8th ed.]."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"7849","DOI":"10.1016\/j.biomaterials.2012.07.005","article-title":"Synergistic effects of SDF-1\u03b1 chemokine and hyaluronic acid release from degradable hydrogels on directing bone marrow derived cell homing to the myocardium","volume":"33","author":"Purcell","year":"2012","journal-title":"Biomaterials"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1038\/s41551-019-0442-z","article-title":"Use of a supramolecular polymeric hydrogel as an effective post-operative pericardial adhesion barrier","volume":"3","author":"Stapleton","year":"2019","journal-title":"Nat. Biomed. Eng."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Wang, H., Paulsen, M.J., Imbrie-Moore, A.M., Tada, Y., Bergamasco, H., Baker, S.W., Shudo, Y., Ma, M., and Woo, Y.J. (2020). In vivo validation of restored chordal biomechanics after mitral ring annuloplasty in a rare ovine case of natural chronic functional mitral regurgitation. J. Cardiovasc. Dev. Dis., 7.","DOI":"10.3390\/jcdd7020017"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1017\/S0021859600086469","article-title":"Regional body surface area of sheep","volume":"81","author":"Bennett","year":"1973","journal-title":"J. Agric. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3738","DOI":"10.1161\/CIRCULATIONAHA.105.561423","article-title":"Candesartan in Heart Failure Reduction in Mortality (CHARM) Investigators Influence of ejection fraction on cardiovascular outcomes in a broad spectrum of heart failure patients","volume":"112","author":"Solomon","year":"2005","journal-title":"Circulation"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Camacho, P., Fan, H., Liu, Z., and He, J.-Q. (2016). Large mammalian animal models of heart disease. J. Cardiovasc. Dev. Dis., 3.","DOI":"10.3390\/jcdd3040030"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1642","DOI":"10.1093\/eurheartj\/ehv510","article-title":"Beyond ejection fraction: An integrative approach for assessment of cardiac structure and function in heart failure","volume":"37","author":"Cikes","year":"2016","journal-title":"Eur. Heart J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1161\/01.RES.32.3.314","article-title":"Load independence of the instantaneous pressure-volume ratio of the canine left ventricle and effects of epinephrine and heart rate on the ratio","volume":"32","author":"Suga","year":"1973","journal-title":"Circ. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1161\/01.RES.35.1.117","article-title":"Instantaneous pressure-volume relationships and their ratio in the excised, supported canine left ventricle","volume":"35","author":"Suga","year":"1974","journal-title":"Circ. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1016\/0002-9149(77)90192-8","article-title":"End-systolic pressure\/volume ratio: A new index of ventricular contractility","volume":"40","author":"Sagawa","year":"1977","journal-title":"Am. J. Cardiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1674","DOI":"10.1016\/j.jacc.2016.01.069","article-title":"Relationship Between Infarct Size and Outcomes Following Primary PCI: Patient-Level Analysis From 10 Randomized Trials","volume":"67","author":"Stone","year":"2016","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e004058","DOI":"10.1161\/CIRCINTERVENTIONS.116.004058","article-title":"Injectable Shear-Thinning Hydrogels for Minimally Invasive Delivery to Infarcted Myocardium to Limit Left Ventricular Remodeling","volume":"9","author":"Rodell","year":"2016","journal-title":"Circ. Cardiovasc. Interv."}],"container-title":["Journal of Cardiovascular Development and Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2308-3425\/7\/4\/53\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:34:28Z","timestamp":1760178868000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2308-3425\/7\/4\/53"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,17]]},"references-count":43,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["jcdd7040053"],"URL":"https:\/\/doi.org\/10.3390\/jcdd7040053","relation":{},"ISSN":["2308-3425"],"issn-type":[{"value":"2308-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,17]]}}}