Heart failure has a five-year mortality rate approaching 50%. Inducing angiogenesis following a myocardial infarction is hypothesized to reduce cardiomyocyte death and tissue damage, thereby preventing heart failure. Herein, a novel nano-in-gel delivery system for vascular endothelial growth factor (VEGF), composed of star-shaped polyglutamic acid-VEGF nanoparticles in a tyramine-modified hyaluronic acid hydrogel (nano-VEGF-HA-TA), is investigated. The ability of the nano-VEGF-HA-TA system to induce angiogenesis is assessed in vivo using a chick chorioallantoic membrane model (CAM). The formulation is then integrated with a custom-made, clinically relevant catheter suitable for minimally invasive endocardial delivery and the effect of injection on hydrogel properties is examined. Nano-VEGF-HA-TA is biocompatible on a CAM assay and significantly improves blood vessel branching (p < 0.05) and number (p < 0.05) compared to a HA-TA hydrogel without VEGF. Nano-VEGF-HA-TA is successfully injected through a 1.2 m catheter, without blocking or breaking the catheter and releases VEGF for 42 days following injection in vitro. The released VEGF retains its bioactivity, significantly improving total tubule length on a Matrigel® assay and human umbilical vein endothelial cell migration on a Transwell® migration assay. This VEGF-nano in a HA-TA hydrogel delivery system is successfully integrated with an appropriate device for clinical use, demonstrates promising angiogenic properties in vivo and is suitable for further clinical translation.

Department of Chemistry Royal College of Surgeons in Ireland Dublin 2 Ireland

Drug Delivery and Advanced Materials Team School of Pharmacy and Biomolecular Sciences Royal College of Surgeons in Ireland Dublin 2 Ireland

Faculty of Chemistry Institute of Physical Chemistry Brno University of Technology Purkynova 464 118 612 00 Brno Czech Republic

Nursing and Health Sciences Anatomy and Regenerative Medicine Institute Galway Ireland

R and D Department Contipro Dolni Dobrouc 401 561 02 Dolni Dobrouc Czech Republic

SFI Centre for Research in Medical Devices Galway and Dublin 2 Ireland

SFI Research Centre for Advanced Materials and Bioengineering Research Centre Dublin 2 Ireland

Tissue Engineering Research Group Department of Anatomy and Regenerative Medicine Royal College of Surgeons in Ireland Dublin 2 Ireland

Trinity Centre for Bioengineering Trinity College Dublin Dublin 2 Ireland

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Stewart S., MacIntyre K., Hole D., Capewell S., McMurray J.J.V. More ‘malignant’ than cancer? Five-year survival following a first admission for heart failure. Eur. J. Heart Fail. 2001;3:315–322. doi: 10.1016/S1388-9842(00)00141-0. PubMed DOI

Levy D., Kenchaiah S., Larson M.G., Benjamin E.J., Kupka M.J., Ho K.K., Murabito J.M., Vasan R.S. Long-Term Trends in the Incidence of and Survival with Heart Failure. N. Engl. J. Med. 2002;347:1397–1402. doi: 10.1056/NEJMoa020265. PubMed DOI

National Institute for Health and Clinical Excellence . National Clinical Guideline for Diagnosis and Management in Primary and Secondary Care. Royal College of Physicians; London, UK: 2010. Chronic Heart Failure. PubMed

Kemp C.D., Conte J.V. The pathophysiology of heart failure. Cardiovasc. Pathol. 2012;21:365–371. doi: 10.1016/j.carpath.2011.11.007. PubMed DOI

Rouleau J.L. New and Emerging Drugs and Device Therapies for Chronic Heart Failure in Patients with Systolic Ventricular Dysfunction. Can. J. Cardiol. 2011;27:296–301. doi: 10.1016/j.cjca.2011.02.010. PubMed DOI

McMurray J.J., Adamopoulos S., Anker S.D., Auricchio A., Böhm M., Dickstein K., Falk V., Filippatos G., Fonseca C., Gomez-Sanchez M.A., et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur. Heart J. 2012;33:1787–1847. PubMed

Taylor C.J., Ryan R., Nichols L., Gale N., Hobbs F.D.R., Marshall T. Survival following a diagnosis of heart failure in primary care. Fam. Pract. 2017;34:161–168. doi: 10.1093/fampra/cmx040. PubMed DOI PMC

Segers V.F.M., Lee R.T. Protein Therapeutics for Cardiac Regeneration after Myocardial Infarction. J. Cardiovasc. Transl. Res. 2010;3:469–477. doi: 10.1007/s12265-010-9207-5. PubMed DOI PMC

Liau B., Zhang D., Bursac N. Functional cardiac tissue engineering. Regen. Med. 2012;7:187–206. doi: 10.2217/rme.11.122. PubMed DOI PMC

Thygesen K., Alpert J.S., Jaffe A.S., Simoons M.L., Chaitman B.R., White H.D. ESC/ACCF/AHA/WHF Expert Consensus Document Third Universal Definition of Myocardial Infarction. Circulation. 2012;126:2020–2035. doi: 10.1161/CIR.0b013e31826e1058. PubMed DOI

Ibanez B., James S., Agewall S., Antunes M.J., Bucciarelli-Ducci C., Bueno H., Caforio A.L.P., Crea F., Goudevenos J.A., Halvorsen S., et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevationThe Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC) Eur. Heart J. 2018;39:119–177. PubMed

Ertl G., Frantz S. Healing after myocardial infarction. Cardiovasc. Res. 2005;66:22–32. doi: 10.1016/j.cardiores.2005.01.011. PubMed DOI

Shah A.M., Mann D.L. In Search of New Therapeutic Targets and Strategies for Heart Failure: Recent Advances in Basic Science. Lancet. 2011;378:704–712. doi: 10.1016/S0140-6736(11)60894-5. PubMed DOI PMC

Cochain C., Channon K.M., Silvestre J.-S. Angiogenesis in the Infarcted Myocardium. Antioxid. Redox Signal. 2013;18:1100–1113. doi: 10.1089/ars.2012.4849. PubMed DOI PMC

Neufeld G., Cohen T., Gengrinovitch G., Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors. Off. J. Fed. Am. Soc. Exp. Biol. 1999;13:9–22. doi: 10.1096/fasebj.13.1.9. PubMed DOI

Simon-Yarza T., Formiga F.R., Tamayo E., Pelacho B., Prosper F., Blanco-Prieto M.J. Vascular endothelial growth factor-delivery systems for cardiac repair: An overview. Theranostics. 2012;2:541–552. doi: 10.7150/thno.3682. PubMed DOI PMC

Hendel R.C., Henry T.D., Rocha-Singh K., Isner J.M., Kereiakes D.J., Giordano F.J., Simons M., Bonow R.O. Effect of Intracoronary Recombinant Human Vascular Endothelial Growth Factor on Myocardial Perfusion. Circulation. 2000;101:118–121. doi: 10.1161/01.CIR.101.2.118. PubMed DOI

Henry T.D., Annex B.H., McKENDALL G.R., Azrin M.A., Lopez J.J., Giordano F.J., Shah P., Willerson J.T., Benza R.L., Berman D.S., et al. The VIVA Trial. Circulation. 2003;107:1359–1365. doi: 10.1161/01.CIR.0000061911.47710.8A. PubMed DOI

O’Dwyer J., Murphy R., Dolan E.B., Kovarova L., Pravda M., Velebny V., Heise A., Duffy G.P., Cryan S.A. Development of a nanomedicine-loaded hydrogel for sustained delivery of an angiogenic growth factor to the ischaemic myocardium. Drug Deliv. Transl. Res. 2020;10:440–454. doi: 10.1007/s13346-019-00684-5. PubMed DOI

Nowak-Sliwinska P., Alitalo K., Allen E., Anisimov A., Aplin A.C., Auerbach R., Augustin H.G., Bates D.O., Van Beijnum J.R., Bender R.H.F., et al. Consensus guidelines for the use and interpretation of angiogenesis assays. Angiogenesis. 2018;21:425–532. doi: 10.1007/s10456-018-9613-x. PubMed DOI PMC

Wells D.J. Animal welfare and the 3Rs in European biomedical research. Ann. N. Y. Acad. Sci. 2011;1245:14–16. doi: 10.1111/j.1749-6632.2011.06335.x. PubMed DOI

Kue C.S., Tan K.Y., Lam M.L., Lee H.B. Chick embryo chorioallantoic membrane (CAM): An alternative predictive model in acute toxicological studies for anti-cancer drugs. Exp. Anim. 2015;64:129–138. doi: 10.1538/expanim.14-0059. PubMed DOI PMC

Brooks P.C., Montgomery A.M.P., Cheresh D.A. Use of the 10-Day-Old Chick Embryo Model for Studying Angiogenesis. In: Howlett A., editor. Integrin Protocols. Humana Press; Totowa, NJ, USA: 1999. pp. 257–269. PubMed

Deryugina E.I., Quigley J.P. Chick embryo chorioallantoic membrane model systems to study and visualize human tumor cell metastasis. Histochem. Cell Biol. 2008;130:1119–1130. doi: 10.1007/s00418-008-0536-2. PubMed DOI PMC

Ribatti D. The chick embryo chorioallantoic membrane (CAM). A multifaceted experimental model. Mech. Dev. 2016;141:70–77. doi: 10.1016/j.mod.2016.05.003. PubMed DOI

Auerbach R., Lewis R., Shinners B., Kubai L., Akhtar N. Angiogenesis Assays: A Critical Overview. Clin. Chem. 2003;49:32–40. doi: 10.1373/49.1.32. PubMed DOI

Staton C.A., Reed M., Brown N.J. A critical analysis of current in vitro and in vivo angiogenesis assays. Int. J. Exp. Pathol. 2009;90:195–221. doi: 10.1111/j.1365-2613.2008.00633.x. PubMed DOI PMC

Tahergorabi Z., Khazaei M. A Review on Angiogenesis and Its Assays. Iran J. Basic Med. Sci. 2012;15:1110–1126. PubMed PMC

Banovic M., Ostojic M.C., Bartunek J., Nedeljkovic M., Beleslin B., Terzic A. Brachial Approach to NOGA-Guided Procedures Electromechanical Mapping and Transendocardial Stem-Cell Injections. Texas Heart Inst. J. 2011;38:179–182. PubMed PMC

O’Dwyer J., Cullen M., Fattah S., Murphy R., Stefanovic S., Kovarova L., Pravda M., Velebny V., Heise A., Duffy G.P., et al. Development of a Sustained Release Nano-In-Gel Delivery System for the Chemotactic and Angiogenic Growth Factor Stromal-Derived Factor 1α. Pharmaceutics. 2020;12:513. doi: 10.3390/pharmaceutics12060513. PubMed DOI PMC

Luo J., Redies C. Ex ovo electroporation for gene transfer into older chicken embryos. Dev. Dyn. 2005;233:1470–1477. doi: 10.1002/dvdy.20454. PubMed DOI

do Amaral R.J.F.C., Zayed N.M.A., Pascu E.I., Cavanagh B., Hobbs C., Santarella F., Simpson C.R., Murphy C.M., Sridharan R., González-Vázquez A. Functionalising Collagen-Based Scaffolds With Platelet-Rich Plasma for Enhanced Skin Wound Healing Potential. Front. Bioeng. Biotechnol. 2019;7:371. doi: 10.3389/fbioe.2019.00371. PubMed DOI PMC

Hamburger V., Hamilton H.L. A series of normal stages in the development of the chick embryo. Dev. Dyn. 1992;195:231–272. doi: 10.1002/aja.1001950404. PubMed DOI

Anderson S.M., Siegman S.N., Segura T. The effect of vascular endothelial growth factor (VEGF) presentation within fibrin matrices on endothelial cell branching. Biomaterials. 2011;32:7432–7443. doi: 10.1016/j.biomaterials.2011.06.027. PubMed DOI PMC

Dolan E.B., Kovarova L., O’Neill H., Pravda M., Sulakova R., Scigalkova I., Velebny V., Daro D., Braun N., Cooney G.M., et al. Advanced Material Catheter (AMCath), a minimally invasive endocardial catheter for the delivery of fast-gelling covalently cross-linked hyaluronic acid hydrogels. J. Biomater. Appl. 2018;33:681–692. doi: 10.1177/0885328218805878. PubMed DOI

Dunn L.K., Gruenloh S.K., Dunn B.E., Reddy D.S., Falck J.R., Jacobs E.R., Medhora M. Chick chorioallantoic membrane as an in vivo model to study vasoreactivity: Characterization of development-dependent hyperemia induced by epoxyeicosatrienoic acids (EETs) Anat. Rec. Part A. 2005;285:771–780. doi: 10.1002/ar.a.20212. PubMed DOI

Nowak-Sliwinska P., Segura T., Iruela-Arispe M.L. The chicken chorioallantoic membrane model in biology, medicine and bioengineering. Angiogenesis. 2014;17:779–804. doi: 10.1007/s10456-014-9440-7. PubMed DOI PMC

Yla-Herttuala S., Rissanen T.T., Vajanto I., Hartikainen J. Vascular endothelial growth factors: Biology and current status of clinical applications in cardiovascular medicine. J. Am. Coll. Cardiol. 2007;49:1015–1026. doi: 10.1016/j.jacc.2006.09.053. PubMed DOI

Koch S., Yao C., Grieb G., Prével P., Noah E.M., Steffens G.C.M. Enhancing angiogenesis in collagen matrices by covalent incorporation of VEGF. J. Mater. Sci. Mater. Electron. 2006;17:735–741. doi: 10.1007/s10856-006-9684-x. PubMed DOI

Kornowski R., Leon M.B., Fuchs S., Vodovotz Y., Flynn M.A., Gordon D.A., Pierre A., Kovesdi I., Keiser J.A., Epstein S.E. Electromagnetic guidance for catheter-based transendocardial injection: A platform for intramyocardial angiogenesis therapy: Results in normal and ischemic porcine models. J. Am. Coll. Cardiol. 2000;35:1031–1039. doi: 10.1016/S0735-1097(99)00642-7. PubMed DOI

Bastings M.M.C., Koudstaal S., Kieltyka R.E., Nakano Y., Pape A.C.H., Feyen D.A.M., van Slochteren F.J., Doevendans P.A., Sluijter J., Meijer E.W., et al. A Fast pH-Switchable and Self-Healing Supramolecular Hydrogel Carrier for Guided, Local Catheter Injection in the Infarcted Myocardium. Adv. Health Mater. 2014;3:70–78. doi: 10.1002/adhm.201300076. PubMed DOI

Lee L.C., Wall S.T., Klepach D., Ge L., Zhang Z., Lee R.J., Hinson A., Gorman J.H., Gorman R.C., Guccione J.M. Algisyl-LVR™ with coronary artery bypass grafting reduces left ventricular wall stress and improves function in the failing human heart. Int. J. Cardiol. 2013;168:2022–2028. doi: 10.1016/j.ijcard.2013.01.003. PubMed DOI PMC

Lee F., Chung J.E., Kurisawa M. An injectable enzymatically crosslinked hyaluronic acid–tyramine hydrogel system with independent tuning of mechanical strength and gelation rate. Soft Matter. 2008;4:880–887. doi: 10.1039/b719557e. PubMed DOI

Lee F., Chung J.E., Kurisawa M. An injectable hyaluronic acid–tyramine hydrogel system for protein delivery. J. Control. Release. 2009;134:186–193. doi: 10.1016/j.jconrel.2008.11.028. PubMed DOI

des Rieux A., Ucakar B., Mupendwa B.P.K., Colau D., Feron O., Carmeliet P., Préat V. 3D systems delivering VEGF to promote angiogenesis for tissue engineering. J. Control. Release. 2011;150:272–278. doi: 10.1016/j.jconrel.2010.11.028. PubMed DOI

Briquez P.S., Clegg L.E., Martino M.M., Mac Gabhann F., Hubbell J.A. Design principles for therapeutic angiogenic materials. Nat. Rev. Mater. 2016;1:15006. doi: 10.1038/natrevmats.2015.6. DOI

Silva E.A., Mooney D.J. Effects of VEGF temporal and spatial presentation on angiogenesis. Biomaterials. 2010;31:1235–1241. doi: 10.1016/j.biomaterials.2009.10.052. PubMed DOI PMC

Minguell J.J., Lorino R., LaSala G.P. Myocardial implantation of a combination stem cell product by using a transendocardial MYOSTAR injection catheter: A technical assessment. Acute Card. Care. 2011;13:40–42. doi: 10.3109/17482941.2010.551134. PubMed DOI

Fu K., Klibanov A.M., Langer R. Protein stability in controlled-release systems. Nat. Biotechnol. 2000;18:24–25. doi: 10.1038/71875. PubMed DOI

Mitragotri S., Burke P.A., Langer R. Overcoming the challenges in administering biopharmaceuticals: Formulation and delivery strategies. Nat. Rev. Drug Discov. 2014;13:655–672. doi: 10.1038/nrd4363. PubMed DOI PMC