Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Injectable and conductive cardiac patches repair infarcted myocardium in rats and minipigs

Nature Biomedical Engineering volume 5, pages 1157–1173 (2021)Cite this article

Subjects

Abstract

Cardiac patches can help to restore the electrophysiological properties of the heart after myocardial infarction. However, scaffolds for the repair of heart muscle typically require surgical implantation or, if they are injectable, they are not electrically conductive or do not maintain their shape or function. Here, we report the performance, as demonstrated for the repair of infarcted heart muscle in rats and minipigs, of injectable and conductive scaffolds consisting of methacrylated elastin and gelatin, and carbon nanotubes that display shape-memory behaviour, a hierarchical porous structure and a negligible Poisson’s ratio. In rats, the implantation of cell-free patches or patches seeded with rat cardiomyocytes onto the myocardium after ligation of the left anterior descending coronary artery led to functional repair after 4 weeks, as indicated by increases in fractional shortening and the ejection fraction, and by a decrease in the infarcted area. We also observed measures of functional recovery in minipigs with infarcted hearts after the delivery of cell-free patches or patches incorporating cardiomyocytes differentiated from human pluripotent stem cells.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Fabrication of injectable conductive cardiac patches.
Fig. 2: The mechanical and electrical performance of the EGC scaffolds.
Fig. 3: The injectability of the EGC20 scaffolds.
Fig. 4: Calcium transients in RCMs, and electrical responses in a rat model of MI.
Fig. 5: Evaluation of cardiac function through echocardiography analysis, and histological observations of heart sections in a rat model of MI.
Fig. 6: Histological assessment after HCM injection and after the implantation of EGC20 and HECP in minipigs.
Fig. 7: Assessment of myocardial regeneration in infarcted hearts of minipigs.
Fig. 8: Cardiac repair after MI in minipigs.

Similar content being viewed by others

Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during the study are too large to be publicly shared, yet they are available for research purposes from the corresponding authors on reasonable request.

References

  1. McMurray, J. J. & Pfeffer, M. A. Heart failure. Lancet 365, 1877–1889 (2005).

    Article  PubMed  Google Scholar 

  2. Matsa, E., Sallam, K. & Wu, J. C. Cardiac stem cell biology: glimpse of the past, present, and future. Circ. Res. 114, 21–27 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Cates, A. W., Smith, W. M., Ideker, R. E. & Pollard, A. E. Purkinje and ventricular contributions to endocardial activation sequence in perfused rabbit right ventricle. Am. J. Physiol. Heart Circ. Physiol. 281, H490–H505 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Karikkineth, B. C. & Zimmermann, W. H. Myocardial tissue engineering and heart muscle repair. Curr. Pharm. Biotechnol. 14, 4–11 (2013).

    CAS  PubMed  Google Scholar 

  5. Zimmermann, W. H., Melnychenko, I. & Eschenhagen, T. Engineered heart tissue for regeneration of diseased hearts. Biomaterials 25, 1639–1647 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Breckwoldt, K., Weinberger, F. & Eschenhagen, T. Heart regeneration. Biochim. Biophys. Acta 1863, 1749–1759 (2016).

    Article  CAS  PubMed  Google Scholar 

  7. Rodness, J. et al. VEGF-loaded microsphere patch for local protein delivery to the ischemic heart. Acta Biomater. 45, 169–181 (2016).

    Article  CAS  PubMed  Google Scholar 

  8. Ye, L., Zimmermann, W. H., Garry, D. J. & Zhang, J. Y. Patching the heart cardiac repair from within and outside. Circ. Res. 113, 922–932 (2013).

    Article  CAS  PubMed  Google Scholar 

  9. Xiong, Q. et al. Bioenergetic and functional consequences of cellular therapy activation of endogenous cardiovascular progenitor cells. Circ. Res. 111, 455–468 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Xiong, Q. et al. Functional consequences of human induced pluripotent stem cell therapy myocardial ATP turnover rate in the in vivo swine heart with postinfarction remodeling. Circulation 127, 997–1008 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yang, J.-A., Yeom, J., Hwang, B. W., Hoffman, A. S. & Hahn, S. K. In situ-forming injectable hydrogels for regenerative medicine. Prog. Polym. Sci. 39, 1973–1986 (2014).

    Article  CAS  Google Scholar 

  12. Zhao, S. et al. Bioengineering of injectable encapsulated aggregates of pluripotent stem cells for therapy of myocardial infarction. Nat. Commun. 7, 13306 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Shin, M., Song, K.H., Burrell, J. C., Cullen, D. K. & Burdick, J. A. Injectable and conductive granular hydrogels for 3D printing and electroactive tissue support. Adv. Sci. 6, 1901229.

  14. Wang, L. L. et al. Sustained miRNA delivery from an injectable hydrogel promotes cardiomyocyte proliferation and functional regeneration after ischaemic injury. Nat. Biomed. Eng. 1, 983–992 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhou, J. et al. Injectable OPF/graphene oxide hydrogels provide mechanical support and enhance cell electrical signaling after implantation into myocardial infarct. Theranostics 8, 3317–3330 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cui, Z. et al. Polypyrrole-chitosan conductive biomaterial synchronizes cardiomyocyte contraction and improves myocardial electrical impulse propagation. Theranostics 8, 2752–2764 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bencherif, S. A. et al. Injectable preformed scaffolds with shape-memory properties. Proc. Natl Acad. Sci. USA 109, 19590–19595 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Montgomery, M. et al. Flexible shape-memory scaffold for minimally invasive delivery of functional tissues. Nat. Mater. 16, 1038–1046 (2017).

    Article  CAS  PubMed  Google Scholar 

  19. Liu, J. et al. Syringe-injectable electronics. Nat. Nanotechnol. 10, 629–636 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lee, J. M. et al. Nanoenabled direct contact interfacing of syringe-injectable mesh electronics. Nano Lett. 19, 5818–5826 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Shah, N. J. et al. An injectable bone marrow–like scaffold enhances T cell immunity after hematopoietic stem cell transplantation. Nat. Biotechnol. 37, 293–302 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kim, I., Lee, S. S., Bae, S., Lee, H. & Hwang, N. S. Heparin functionalized injectable cryogel with rapid shape-recovery property for neovascularization. Biomacromolecules 19, 2257–2269 (2018).

    Article  CAS  PubMed  Google Scholar 

  23. Kim, M., Choe, Y. & Kim, G. Injectable hierarchical micro/nanofibrous collagen-based scaffolds. Chem. Eng. J. 365, 220–230 (2019).

    Article  CAS  Google Scholar 

  24. Zhao, X., Guo, B., Wu, H., Liang, Y. & Ma, P. X. Injectable antibacterial conductive nanocomposite cryogels with rapid shape recovery for noncompressible hemorrhage and wound healing. Nat. Commun. 9, 2784 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Qiu, Y. et al. A role for matrix stiffness in the regulation of cardiac side population cell function. Am. J. Physiol. Heart Circ. Physiol. 308, H990–H997 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Annabi, N. et al. Highly elastic and conductive human-based protein hybrid hydrogels. Adv. Mater. 28, 40–49 (2016).

    Article  CAS  PubMed  Google Scholar 

  27. Kharaziha, M. et al. Tough and flexible CNT-polymeric hybrid scaffolds for engineering cardiac constructs. Biomaterials 35, 7346–7354 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hwang, J. Y., Kim, H. S., Kim, J. H., Shin, U. S. & Lee, S. H. Carbon nanotube nanocomposites with highly enhanced strength and conductivity for flexible electric circuits. Langmuir 31, 7844–7851 (2015).

    Article  CAS  PubMed  Google Scholar 

  29. Martinelli, V. et al. Carbon nanotubes instruct physiological growth and functionally mature syncytia: nongenetic engineering of cardiac myocytes. ACS Nano 7, 5746–5756 (2013).

    Article  CAS  PubMed  Google Scholar 

  30. Martinelli, V. et al. Carbon nanotubes promote growth and spontaneous electrical activity in cultured cardiac myocytes. Nano Lett. 12, 1831–1838 (2012).

    Article  CAS  PubMed  Google Scholar 

  31. Shin, S. R. et al. Carbon-nanotube-embedded hydrogel sheets for engineering cardiac constructs and bioactuators. ACS Nano 7, 2369–2380 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Shin, S. R. et al. Carbon nanotube reinforced hybrid microgels as scaffold materials for cell encapsulation. ACS Nano 6, 362–372 (2012).

    Article  CAS  PubMed  Google Scholar 

  33. Wu, Y., Wang, L., Guo, B. & Ma, P. X. Interwoven aligned conductive nanofiber yarn/hydrogel composite scaffolds for engineered 3D cardiac anisotropy. ACS Nano 11, 5646–5659 (2017).

    Article  CAS  PubMed  Google Scholar 

  34. Kucheyev, S. O. et al. Super-compressibility of ultralow-density nanoporous silica. Adv. Mater. 24, 776–780 (2012).

    Article  CAS  PubMed  Google Scholar 

  35. Sun, J. Y. et al. Highly stretchable and tough hydrogels. Nature 489, 133–136 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lv, S. et al. Designed biomaterials to mimic the mechanical properties of muscles. Nature 465, 69–73 (2010).

    Article  CAS  PubMed  Google Scholar 

  37. Yeo, G. C. et al. Fabricated Elastin. Adv. Healthc. Mater. 4, 2530–2556 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Liu, Y. et al. Highly flexible and resilient elastin hybrid cryogels with shape memory, injectability, conductivity, and magnetic responsive properties. Adv. Mater. 28, 7758–7767 (2016).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  40. He, S. et al. Preservation of conductive propagation after surgical repair of cardiac defects with a bio-engineered conductive patch. J. Heart Lung Transpl. 37, 912–924 (2018).

    Article  Google Scholar 

  41. Kong, W. et al. Optical measurements of intramural action potentials in isolated porcine hearts using optrodes. Heart Rhythm 4, 1430–1436 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Pleger, S. T. et al. Cardiac AAV9-S100A1 gene therapy rescues post-ischemic heart failure in a preclinical large animal model. Sci. Transl. Med. 3, 92ra64 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wang, L. Y. et al. Mussel-Inspired conductive cryogel as cardiac tissue patch to repair myocardial infarction by migration of conductive nanoparticles. Adv. Funct. Mater. 26, 4293–4305 (2016).

    Article  CAS  Google Scholar 

  44. Li, X. et al. A PNIPAAm-based thermosensitive hydrogel containing SWCNTs for stem cell transplantation in myocardial repair. Biomaterials 35, 5679–5688 (2014).

    Article  CAS  PubMed  Google Scholar 

  45. Kapnisi, M. et al. Auxetic cardiac patches with tunable mechanical and conductive properties toward treating myocardial infarction. Adv. Funct. Mater. 28, 1800618 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Liang, S. et al. Paintable and rapidly bondable conductive hydrogels as therapeutic cardiac patches. Adv. Mater. 30, e1704235 (2018).

    Article  PubMed  Google Scholar 

  47. He, Y. T. et al. Mussel-inspired conductive nanofibrous membranes repair myocardial infarction by enhancing cardiac function and revascularization. Theranostics 8, 5159–5177 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hulsmans, M. et al. Macrophages facilitate electrical conduction in the heart. Cell 169, 510–522 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Dick, S. A. et al. Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction. Nat. Immunol. 20, 664–664 (2019).

    Article  CAS  PubMed  Google Scholar 

  50. Ong, S. B. et al. Inflammation following acute myocardial infarction: multiple players, dynamic roles, and novel therapeutic opportunities. Pharmacol. Ther. 186, 73–87 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Zhang, F. X. et al. Transplantation of iPSc ameliorates neural remodeling and reduces ventricular arrhythmias in a post-infarcted swine model. J. Cell. Biochem. 115, 531–539 (2014).

    Article  CAS  PubMed  Google Scholar 

  52. Arana, M. et al. Epicardial delivery of collagen patches with adipose-derived stem cells in rat and minipig models of chronic myocardial infarction. Biomaterials 35, 143–151 (2014).

    Article  CAS  PubMed  Google Scholar 

  53. Gao, L. et al. Large cardiac muscle patches engineered from human induced-pluripotent stem cell-derived cardiac cells improve recovery from myocardial infarction in swine. Circulation 137, 1712 (2018).

    Article  PubMed  Google Scholar 

  54. Perea-Gil, I. et al. A cell-enriched engineered myocardial graft limits infarct size and improves cardiac function: pre-clinical study in the porcine myocardial infarction model. JACC Basic Transl. Sci. 1, 360–372 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Kawamura, M. et al. Feasibility, safety, and therapeutic efficacy of human induced pluripotent stem cell-derived cardiomyocyte sheets in a porcine ischemic cardiomyopathy model. Circulation 126, S29–S37 (2012).

    Article  CAS  PubMed  Google Scholar 

  56. Nichol, J. W. et al. Cell-laden microengineered gelatin methacrylate hydrogels. Biomaterials 31, 5536–5544 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Harsdorf, R., von., Li, P. F. & Dietz, R. Signaling pathways in reactive oxygen species-induced cardiomyocyte apoptosis. Circulation 99, 2934–2941 (1999).

    Article  Google Scholar 

  58. Lin, B. et al. Culture in glucose-depleted medium supplemented with fatty acid and 3,3′,5-triiodo-l-thyronine facilitates purification and maturation of human pluripotent stem cell-derived cardiomyocytes. Front. Endocrinol. 8, 253 (2017).

    Article  Google Scholar 

Download references

Acknowledgements

This research was supported by the National Natural Science Foundation of China (nos U1601221, 31922043 and 31572343), Guangdong Province Science and Technology Projects (2016B090913004). M.M.Q.X. and K.M thank NSERC Discovery grants and NSERC Discovery Accelerator Supplements (DAS) Awards for supporting this work.

Author information

Author notes

  1. These authors contributed equally: Leyu Wang, Yuqing Liu, Genlan Ye.

Authors and Affiliations

  1. Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, School of Basic Medical Science; Biomaterials Research Center, School of Biomedical Engineering, Southern Medical University, Guangzhou, China

    Leyu Wang, Genlan Ye, Yutong He & Xiaozhong Qiu

  2. Department of Mechanical Engineering, University of Manitoba and Children’s Hospital Research Institute of Manitoba, Winnipeg, Manitoba, Canada

    Leyu Wang, Yuqing Liu & Malcolm M. Q. Xing

  3. Department of Orthopaedics, School of Medicine, West Virginia University, Morgantown, WV, USA

    Bingyun Li

  4. Guangdong Laboratory Animals Monitoring Institute, Guangdong Provincial Key Laboratory of Laboratory Animals, Guangzhou, China

    Yezhi Guan & Baoyong Gong

  5. Department of Chemical and Biochemical Engineering, The University of Western Ontario, London, Ontario, Canada

    Kibret Mequanint

  6. School of Biomedical Engineering, The University of Western Ontario, London, Ontario, Canada

    Kibret Mequanint

Authors
  1. Leyu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuqing Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Genlan Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yutong He
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bingyun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yezhi Guan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Baoyong Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kibret Mequanint
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Malcolm M. Q. Xing
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xiaozhong Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.M.Q.X. and X.Q. conceived the research. X.Q. and M.M.Q.X. supervised the project and provided research direction, including all experimental designs. Y.L., M.M.Q.X. and L.W. synthesized and characterized the materials. L.W., Y.L., X.Q., M.M.Q.X., B.L., G.Y. and Y.H. performed the in vitro experiments of the engineered cardiac patches. L.W., G.Y., Y.H., Y.G., B.G. and X.Q. performed the in vivo experiments. K.M. provided critical input that shaped the research, data analysis and manuscript revision. L.W., Y.L., X.Q. and M.M.Q.X. verified data integrity and performed the statistical analyses. M.M.Q.X., L.W., Y.L., K.M., B.L. and X.Q. interpreted the data and co-wrote the manuscript. All of the authors reviewed the manuscript.

Corresponding authors

Correspondence to Malcolm M. Q. Xing or Xiaozhong Qiu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature Biomedical Engineering thanks Milica Radisic and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Figs. 1–23, Tables 1–17 and References, and the captions for Supplementary Videos 1–10.

Reporting Summary

Supplementary Video 1

Rigid CNTs bridged by extremely flexible biomacromolecular coils.

Supplementary Video 2

The compressive elasticity and water-driven shape memory behaviour of the EGC20 scaffold.

Supplementary Video 3

The loading, injection and instant-recovery process of an EGC20 patch injected out of the pipette tip.

Supplementary Video 4

Minimally invasive delivery of an EGC20 patch onto porcine heart through a catheter.

Supplementary Video 5

Fibrin-glue delivery under a simulative thoracoscope trainer.

Supplementary Video 6

Calcium transients in rat CMs cultured in different scaffolds on day 7.

Supplementary Video 7

Synchronous contraction of an EGC20 cardiac patch seeded with rat cardiomyocytes in vitro on day 7.

Supplementary Video 8

HECP injected and fixed on the infarcted heart of a porcine MI model.

Supplementary Video 9

LV at the papillary-muscle level in the study groups, captured by echocardiography.

Supplementary Video 10

Beating activity of hPSC-differentiated cardiomyocytes.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, L., Liu, Y., Ye, G. et al. Injectable and conductive cardiac patches repair infarcted myocardium in rats and minipigs. Nat Biomed Eng 5, 1157–1173 (2021). https://doi.org/10.1038/s41551-021-00796-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41551-021-00796-9

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research