VEGF-loaded microsphere patch for local protein delivery to the ischemic heart
Abstract
Background Revascularization of the heart after myocardial infarction (MI) using growth factors delivered by hydrogel-based microspheres represents a promising therapeutic approach for cardiac regeneration. Microspheres have tuneable degradation properties and support the prolonged release of soluble factors. Cardiac patches provide mechanical restraint, preventing dilatation associated with ventricular remodelling.Methods We combined these approaches and produced a compacted calcium-alginate microsphere patch, restrained by a chitosan sheet, to deliver vascular endothelial growth factor (VEGF) to the heart after myocardial injury in rats.Results Microspheres had an average diameter of 3.2μm, were nonporous, and characterized by a smooth dimpled surface. Microsphere patches demonstrated prolonged in vitro release characteristics compared to non-compacted microspheres and VEGF supernatants obtained from patches maintained their bioactivity for the 5day duration of the study in vitro. In vivo, patches were assessed with magnetic resonance imaging following MI, and demonstrated 50% degradation 25.6days after implantation. Both VEGF(-) and VEGF(+) microsphere patch-treated hearts had better cardiac function than unpatched (chitosan sheet only) controls. However, VEGF(+) microsphere-patched hearts had thicker scars characterized by higher capillary density in the border zone than did those treated with VEGF(-) patches. VEGF was detected in the patches 4weeks post-implantation.Conclusion The condensed microsphere patch represents a new therapeutic platform for cytokine delivery and could be used as an adjuvant to current biomaterial and cell-based therapies to promote localized angiogenesis in the infarcted heart.Statement of significance Following a heart attack, a lack of blood flow to the heart results in loss of heart cells. Growth factors may facilitate growth of blood vessels and heart tissue repair and prevent the onset of heart failure. Determining a way to deliver these growth factors directly to the heart is vital. Here, we combined two biomaterial-based approaches to deliver vascular endothelial growth factor (VEGF) to rat hearts after heart attack: a microsphere for prolonged release of VEGF, and a cardiac patch for mechanical restraint to prevent heart dysfunction. The feasibility of this microsphere patch was demonstrated by surgically implanting it over the infarct region of the heart post-injury. VEGF-patched hearts had better blood vessel growth, tissue repair, and heart function.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Heart patch can be used as carrier to slowly release growth factors such as VEGF and bFGF to promote angiogenesis and tissue regeneration.
“it can be used as a carrier to slowly release growth factors such as VEGF and bFGF to promote angiogenesis and tissue regeneration [165].”
From Application of PLCL as a biodegradable polymer in biomedical engineering (2026) · cites this paper as [165]
Cites
Paracrine Mechanisms in Adult Stem Cell Signaling and Therapy
Gnecchi, M., Zhang, Z., Ni, A., & Dzau, V. J. (2008) · Circulation Research · doi:10.1161/circresaha.108.176826 · Cited by 2,030 · see citing works
Henry, T. D., Annex, B. H., McKendall, G. R., Azrin, M., López, J. J., Giordano, F. J., Shah, P. K., Willerson, J. T., Benza, R. L., Berman, D. S., et al. (2003) · Circulation · doi:10.1161/01.cir.0000061911.47710.8a · Cited by 1,025 · see citing works
Challenges in Cardiac Tissue Engineering
Vunjak-Novakovic, G., Tandon, N., Godier, A. F. G., Maidhof, R., Marsano, A., Martens, T., & Radišić, M. (2009) · Tissue engineering. Part B, Reviews · doi:10.1089/ten.teb.2009.0352 · Cited by 521 · see citing works
Pasparakis, G., & Bouropoulos, N. (2006) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2006.05.054 · Cited by 488 · see citing works
Landa, N., Miller, L., Feinberg, M. S., Holbová, R., Shachar, M., Freeman, I., Cohen, S., & Leor, J. (2008) · Circulation · doi:10.1161/circulationaha.107.727420 · Cited by 449 · see citing works
Xu, H., Silva, E. A., Månsson‐Broberg, A., Grinnemo, K., Siddiqui, A. J., Dellgren, G., Wärdell, E., Brodin, L., Mooney, D. J., & Sylvén, C. (2007) · Cardiovascular Research · doi:10.1016/j.cardiores.2007.03.028 · Cited by 377 · see citing works
Leor, J., Tuvia, S., Guetta, V., Manczur, F., Castel, D., Willenz, U., Petneházy, Ö., Landa, N., Feinberg, M. S., Konen, E., et al. (2009) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2009.06.010 · Cited by 347 · see citing works
Ruvinov, E., Leor, J., & Cohen, S. (2010) · Biomaterials · doi:10.1016/j.biomaterials.2010.08.097 · Cited by 278 · see citing works
Edelman, E. R., Nugent, M. A., & Karnovsky, M. J. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.4.1513 · Cited by 266 · see citing works
Mihic, A., Li, J., Miyagi, Y., Gagliardi, M., Li, S.-H., Zu, J., Weisel, R. D., Keller, G., & Li, R.-K. (2014) · Biomaterials · doi:10.1016/j.biomaterials.2013.12.052 · Cited by 248 · see citing works
Self-citationSustained delivery of vascular endothelial growth factor with alginate beads
Gu, F., Amsden, B. G., & Neufeld, R. J. (2004) · Journal of Controlled Release · doi:10.1016/j.jconrel.2004.02.021 · Cited by 246 · see citing works
Biodegradable collagen patch with covalently immobilized VEGF for myocardial repair
Miyagi, Y., Chiu, L. L. Y., Cimini, M., Weisel, R. D., Radisic, M., & Li, R. (2010) · Biomaterials · doi:10.1016/j.biomaterials.2010.10.007 · Cited by 232 · see citing works
Self-citationElçin, Y. M., Dixit, V., & Gitnick, G. (2001) · Artificial Organs · doi:10.1046/j.1525-1594.2001.025007558.x · Cited by 225 · see citing works
Formiga, F. R., Pelacho, B., Garbayo, E., Abizanda, G., Gavira, J. J., Simón‐Yarza, T., Mazo, M. M., Tamayo, E., Jauquicoa, C., & Ortíz-de-Solórzano, C. (2010) · Journal of Controlled Release · doi:10.1016/j.jconrel.2010.07.097 · Cited by 206 · see citing works
Controlled delivery of VEGF via modulation of alginate microparticle ionic crosslinking
Jay, S. M., & Saltzman, W. M. (2008) · Journal of Controlled Release · doi:10.1016/j.jconrel.2008.10.019 · Cited by 195 · see citing works
Cardiac remodeling by fibrous tissue after infarction in rats
Sun, Y., Zhang, J. Q., Zhang, J., et al. (2000) · Journal of Laboratory and Clinical Medicine · doi:10.1067/mlc.2000.105971 · Cited by 178 · see citing works
Injectable Acellular Hydrogels for Cardiac Repair
Tous, E., Purcell, B. P., Ifkovits, J. L., & Burdick, J. A. (2011) · Journal of Cardiovascular Translational Research · doi:10.1007/s12265-011-9291-1 · Cited by 164 · see citing works
Infarct stabilization and cardiac repair with a VEGF-conjugated, injectable hydrogel
Wu, J., Zeng, F., Huang, X., Chung, J. C.-Y., Konecny, F. A., Weisel, R. D., & Li, R. (2010) · Biomaterials · doi:10.1016/j.biomaterials.2010.08.098 · Cited by 162 · see citing works
Self-citationAranda, E., & Owen, G. I. (2009) · Biological Research · doi:10.4067/s0716-97602009000300012 · Cited by 135 · see citing works
Temporal Response and Localization of Integrins β1 and β3 in the Heart After Myocardial Infarction
Sun, M., Opavsky, M. A., Stewart, D. J., Rabinovitch, M., Dawood, F., Wen, W.-H., & Liu, P. P. (2003) · Circulation · doi:10.1161/01.cir.0000051363.86009.3c · Cited by 129 · see citing works
Extended release of high pI proteins from alginate microspheres via a novel encapsulation technique
Wells, L. A., & Sheardown, H. D. (2006) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2006.10.018 · Cited by 109 · see citing works
Efficacy of intracoronary or intravenous VEGF165in a pig model of chronic myocardial ischemia
Sato, K., Wu, T., Laham, R. J., et al. (2001) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(00)01144-x · Cited by 108 · see citing works
Sabbah, H. N., Wang, M., Gupta, R. C., Rastogi, S., Ilsar, I., Sabbah, M. S., Kohli, S., Helgerson, S. L., & Lee, R. J. (2013) · JACC Heart Failure · doi:10.1016/j.jchf.2013.02.006 · Cited by 102 · see citing works
Dhingra, S., Li, P., Huang, X., Guo, J., Wu, J., Mihic, A., Li, S., Zang, W., Shen, D., Weisel, R. D., et al. (2013) · Circulation · doi:10.1161/circulationaha.112.000324 · Cited by 80 · see citing works
Self-citationLee, J., Bhang, S. H., Park, H., Kim, B., & Lee, K. Y. (2010) · Pharmaceutical Research · doi:10.1007/s11095-010-0067-0 · Cited by 59 · see citing works
Cittadini, A., Monti, M. G., Petrillo, V., et al. (2011) · European Journal of Heart Failure · doi:10.1093/eurjhf/hfr143 · Cited by 58 · see citing works
Surgical ventricular restoration with a cell- and cytokine-seeded biodegradable scaffold
Miyagi, Y., Zeng, F., Huang, X., Foltz, W. D., Wu, J., Mihic, A., Yau, T. M., Weisel, R. D., & Li, R. (2010) · Biomaterials · doi:10.1016/j.biomaterials.2010.06.048 · Cited by 52 · see citing works
Self-citationKang, K., Sun, L., Xiao, Y., Li, S., Wu, J., Guo, J., Jiang, S.-L., Yang, L., Yau, T. M., Weisel, R. D., et al. (2012) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2012.08.985 · Cited by 45 · see citing works
Self-citationGürsoy, A. (2000) · Journal of Microencapsulation · doi:10.1080/026520400417621 · Cited by 39 · see citing works
Laham, R. J., Post, M. J., Rezaee, M., et al. (2005) · Drug Metabolism and Disposition · doi:10.1124/dmd.104.002774 · Cited by 37 · see citing works
Yan, P., Gong, H., Zhai, X., Feng, Y., Wu, J., he, S. T., Guo, J., Wang, X., Guo, R., Xie, J., et al. (2016) · American Journal Of Pathology · doi:10.1016/j.ajpath.2015.11.012 · Cited by 35 · see citing works
Self-citationXu, S., Lü, Y., Li, J., et al. (2006) · Journal of Biomaterials Science Polymer Edition · doi:10.1163/156856207779146141 · Cited by 34 · see citing works
Modification of alginate degradation properties using orthosilicic acid
Birdi, G., Bridson, R. H., Smith, A. M., et al. (2011) · Journal of the mechanical behavior of biomedical materials/Journal of mechanical behavior of biomedical materials · doi:10.1016/j.jmbbm.2011.10.001 · Cited by 24 · see citing works
GURSOY, D. K. A. (1999) · Journal of Microencapsulation · doi:10.1080/026520499288906 · Cited by 20 · see citing works
Yang, Y., Gruwel, M., de Gervai, P. D., Sun, J., Jilkina, O., Gussakovsky, E. E., & Kupriyanov, V. V. (2011) · NMR in Biomedicine · doi:10.1002/nbm.1736 · Cited by 12 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Injectable and conductive cardiac patches repair infarcted myocardium in rats and minipigs
Wang, L., Liu, Y., Ye, G., He, Y., Li, B., Guan, Y., Gong, B., Mequanint, K., Xing, M. M. Q., & Qiu, X. (2021) · Nature Biomedical Engineering · doi:10.1038/s41551-021-00796-9 · Cited by 207 · see citing works
Alginate Formulations: Current Developments in the Race for Hydrogel-Based Cardiac Regeneration
Cattelan, G., Guerrero Gerbolés, A., Foresti, R., Pramstaller, P. P., Rossini, A., Miragoli, M., & Caffarra Malvezzi, C. (2020) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2020.00414 · Cited by 152 · see citing works
Application of PLCL as a biodegradable polymer in biomedical engineering
Zhao, Y., & Liu, H. (2026) · Journal of Materials Science Materials in Medicine · doi:10.1007/s10856-026-07016-3 · Cited by 7 · see citing works
“At the same time, it can be used as a carrier to slowly release growth factors such as VEGF and bFGF to promote angiogenesis and tissue regeneration [165].”
- Authors
- Rodness, J., Mihic, A., Miyagi, Y., Wu, J., Weisel, R. D., & Li, R.-K.
- Affiliations
- University Health Network (CA)
- Corresponding author
- Li, Ren-Ke
- Venue
- Acta Biomaterialia
- Publisher
- Elsevier BV
- Published
- 2016-11
- Volume
- 45
- Pages
- 169-181
- ISSN
- 1742-7061 (ISSN-L)
- OpenAlex
- W2519983187
- Cited by
- 84
- References
- 35
- Citations by year
- 2026: 9 · 2025: 8 · 2024: 8 · 2023: 6 · 2022: 7 · 2021: 12 · 2020: 12 · 2019: 12 · 2018: 6 · 2017: 4
- FWCI
- 8.11
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Acta Biomaterialia (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Heart and Stroke Foundation of Canada (G140005765)
- Topics
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Hydrogels: synthesis, properties, applications
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Keywords
- vascular endothelial growth factor, calcium alginate microspheres, myocardial infarction, local growth factor delivery, cardiac regeneration, angiogenesis, ventricular remodeling, sustained drug release, cardiac patch, infarct border zone, cardiac function
- MeSH terms
- Alginates, Animals, Biocompatible Materials, Calcium, Female, Hexuronic Acids, Humans, Microspheres, Pericardium, Drug Delivery Systems, Myocardial Ischemia, Rats, Sprague-Dawley, Neovascularization, Physiologic, Implants, Experimental, Glucuronic Acid, Vascular Endothelial Growth Factor A
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
