Vol. 29 No. 4 (2025): Patologiya krovoobrashcheniya i kardiokhirurgiya
EXPERIMENTAL STUDIES

An optogenetic tissue-engineered cardiac pacemaker: demonstration of principle in an isolated rat heart

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  • Vitalii D. Dzhabrailov,
  • Alina A. Brichagina,
  • Daria V. Kononova,
  • Elena A. Turchaninova,
  • Mihail M. Slotvitsky,
  • Valeriya A. Tsvelaya,
  • Konstantin I. Agladze,
  • Alexander B. Romanov
Vitalii D. Dzhabrailov
E. Meshalkin National Medical Research Center of the Ministry of Health of the Russian Federation, Novosibirsk, Russia, Moscow Institute of Physics and Technology (National Research University), Moscow, Russia
Alina A. Brichagina
Moscow Institute of Physics and Technology (National Research University), Moscow, Russia
Daria V. Kononova
Moscow Institute of Physics and Technology (National Research University), Moscow, Russia
Elena A. Turchaninova
E. Meshalkin National Medical Research Center of the Ministry of Health of the Russian Federation, Novosibirsk, Russia, Moscow Institute of Physics and Technology (National Research University), Moscow, Russia
Mihail M. Slotvitsky
E. Meshalkin National Medical Research Center of the Ministry of Health of the Russian Federation, Novosibirsk, Russia, Moscow Institute of Physics and Technology (National Research University), Moscow, Russia, M. F. Vladimirsky Moscow Regional Research Clinical Institute, 129110 Moscow, Russia
Valeriya A. Tsvelaya
E. Meshalkin National Medical Research Center of the Ministry of Health of the Russian Federation, Novosibirsk, Russia, Moscow Institute of Physics and Technology (National Research University), Moscow, Russia, M. F. Vladimirsky Moscow Regional Research Clinical Institute, 129110 Moscow, Russia
Konstantin I. Agladze
E. Meshalkin National Medical Research Center of the Ministry of Health of the Russian Federation, Novosibirsk, Russia, Moscow Institute of Physics and Technology (National Research University), Moscow, Russia, M. F. Vladimirsky Moscow Regional Research Clinical Institute, 129110 Moscow, Russia
Alexander B. Romanov
E. Meshalkin National Medical Research Center of the Ministry of Health of the Russian Federation, Novosibirsk, Russia
DOI: https://doi.org/10.21688/1681-3472-2025-4-33-43

Published 2026-01-21

Keywords

  • biocompatible fibers; biological pacemaker; cardiomyocytes; channelrhodopsin-2; photo-guided stimulation

How to Cite

Dzhabrailov, V. D. D., Brichagina, A. A. B., Kononova, D. V. K., Turchaninova, E. A. T., Slotvitsky, M. M. S., Tsvelaya, V. A. T., Agladze, K. I. A., & Romanov, A. B. R. (2026). An optogenetic tissue-engineered cardiac pacemaker: demonstration of principle in an isolated rat heart. Patologiya Krovoobrashcheniya I Kardiokhirurgiya, 29(4), 33–43. https://doi.org/10.21688/1681-3472-2025-4-33-43

Copyright (c) 2026 Виталий Дмитриевич Джабраилов, Алина Андреевна Бричагина, Дарья Викторовна Кононова, Елена Александровна Турчанинова, Михаил Михайлович Слотвицкий, Валерия Александровна Цвелая, Константин Игоревич Агладзе, Александр Борисович Романов

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Abstract

Background: Heart rhythm disturbances remain a serious problem in modern cardiology. Traditional pacemakers have certain limitations including invasiveness, risk of infection, mechanical complications, and a limited service life. Advances in bioengineering and optogenetics technologies offers new prospects for the production of minimally invasive, biocompatible, and controllable cardiac pacing systems. The combination of cell therapy and optogenetics enables to create a photo-controlled biological pacemaker, free from the key drawbacks of traditional devices.

Objective: The aim of this study was to produce photosensitive cellular patches and to further investigate their functionality as an optogenetic tissue-engineered pacemaker in an ex vivo rat heart model.

Methods: We engineered a cell-based construct using either human cardiomyocytes derived from induced pluripotent stem cells or neonatal rat cardiomyocytes expressing channelrhodopsin-2. These cells were seeded onto fibrous scaffolds made of poly-L-lactic acid and collagen, coated with fibronectin. The testing model was an isolated, temporarily maintained ex vivo rat heart. Optical mapping of calcium activity was used to record cardiac electrophysiology.

Results: Functional coupling between the implanted patch and the host myocardium was observed 35 minutes after implantation. Photostimulation reliably increased the heart rate, which was confirmed by stochastic dominance analysis. The experiments in vitro on cell cultures demonstrated the operational capacity of channelrhodopsin-2 upon illumination with 470 nm light.

Conclusion: This study successfully demonstrates a complete technology cycle, from the genetic modification of cells to the control of contractions in a whole organ. It represents a significant step towards developing targeted and safe methods for future temporary cardiac pacing. Our results confirm the fundamental feasibility of a hybrid optogenetic approach and lay the groundwork for further research into creating safe, controllable, and biocompatible next-generation pacemaker systems.

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References

  1. Choi Y.S., Yin R.T., Pfenniger A., Koo J., Avila R., Benjamin Lee K., Chen S.W., Lee G., Li G., Qiao Y., Murillo-Berlioz A., Kiss A., Han S., Lee S.M., Li C., Xie Z., Chen Y.Y., Burrell A., Geist B., Jeong H., Kim J., Yoon H.J., Banks A., Kang S.K., Zhang Z.J., Haney C.R., Sahakian A.V., Johnson D., Efimova T., Huang Y., Trachiotis G.D., Knight B.P., Arora R.K., Efimov I.R., Rogers J.A. Fully implantable and bioresorbable cardiac pacemakers without leads or batteries. Nat Biotechnol. 2021;39(10):1228-1238. PMID: 34183859; PMCID: PMC9270064. https://doi.org/10.1038/s41587-021-00948-x
  2. Zhang J., Das R., Zhao J., Mirzai N., Mercer J., Heidari H. Battery‐ free and wireless technologies for cardiovascular implantable medical devices. Adv Mater Technol. 2022;7(6):2101086. https://doi.org/10.1002/admt.202101086
  3. Li P., Zhang J., Hayashi H., Yue J., Li W., Yang C., Sun C., Shi J., Huberman-Shlaes J., Hibino N., Tian B. Monolithic silicon for high spatiotemporal translational photostimulation. Nature. 2024;626(8001):990-998. PMID: 38383782; PMCID: PMC11646366. https://doi.org/10.1038/s41586-024-07016-9
  4. Zhang Y., Rytkin E., Zeng L., Kim J.U., Tang L., Zhang H., Mikhailov A., Zhao K., Wang Y., Ding L., Lu X., Lantsova A., Aprea E., Jiang G., Li S., Seo S.G., Wang T., Wang J., Liu J., Gu J., Liu F., Bailey K., Li Y.F.L., Burrell A., Pfenniger A., Ardashev A., Yang T., Liu N., Lv Z., Purwanto N.S., Ying Y., Lu Y., Hoepfner C., Melisova A., Gong J., Jeong J., Choi J., Hou A., Nolander R., Bai W., Jin S.H., Ma Z., Torkelson J.M., Huang Y., Ouyang W., Arora R.K., Efimov I.R., Rogers J.A. Millimetre-scale bioresorbable optoelectronic systems for electrotherapy. Nature. 2025;640(8057):77-86. PMID: 40175757. https://doi.org/10.1038/s41586-025-08726-4
  5. Ionta V., Liang W., Kim E.H., Rafie R., Giacomello A., Marbán E., Cho H.C. SHOX2 overexpression favors differentiation of embryonic stem cells into cardiac pacemaker cells, improving biological pacing ability. Stem Cell Reports. 2015;4(1):129-142. PMID: 25533636; PMCID: PMC4297875. https://doi.org/10.1016/j.stemcr.2014.11.004
  6. Shiba Y., Fernandes S., Zhu W.Z., Filice D., Muskheli V., Kim J., Palpant N.J., Gantz J., Moyes K.W., Reinecke H., Van Biber B., Dardas T., Mignone J.L., Izawa A., Hanna R., Viswanathan M., Gold J.D., Kotlikoff M.I., Sarvazyan N., Kay M.W., Murry C.E., Laflamme M.A. Human ES-cell-derived cardiomyocytes electrically couple and suppress arrhythmias in injured hearts. Nature. 2012;489(7415):322-5. PMID: 22864415; PMCID: PMC3443324. https://doi.org/10.1038/nature11317
  7. Kanani S., Pumir A., Krinsky V. Genetically engineered cardiac pacemaker: Stem cells transfected with HCN2 gene and myocytes–A model. Physics Letters A. 2008;372(2):141-7. https://doi.org/10.1016/j.physleta.2007.07.075
  8. Wolfson D.W., Kim N.K., Lee K.H., Beyersdorf J.P., Langberg J.J., Fernandez N., Choi D., Zureick N., Kim T.Y., Bae S., Gu J.M., Kirschman J.L., Fan J., Sheng C.Y., Gottlieb Sen D., Mettler B., Sung J.H., Yoon Y.S., Park S.J., Santangelo P.J., Cho H.C. Transient pacing in pigs with complete heart block via myocardial injection of mRNA coding for the T-box transcription factor 18. Nat Biomed Eng. 2024;8(9):1124-41. PMID: 38698155; PMCID: PMC11410671. https://doi.org/10.1038/s41551-024-01211-9
  9. Bruegmann T., Malan D., Hesse M., Beiert T., Fuegemann C.J., Fleischmann B.K., Sasse P. Optogenetic control of heart muscle in vitro and in vivo. Nat Methods. 2010;7(11):897-900. PMID: 20881965. https://doi.org/10.1038/nmeth.1512
  10. Nussinovitch U., Gepstein L. Optogenetics for in vivo cardiac pacing and resynchronization therapies. Nat Biotechnol. 2015;33(7):750-4. PMID: 26098449. https://doi.org/10.1038/nbt.3268
  11. Joshi J., Xu B., Rubart M., Chang Y., Bao X., Chaliki H.P., Scott L.R., Zhu W. Optogenetic control of engrafted human induced pluripotent stem cell-derived cardiomyocytes in live mice: A proof-of-concept study. Cells. 2022;11(6):951. PMID: 35326403; PMCID: PMC8946017. http://dx.doi.org/10.3390/cells11060951
  12. Alex A., Li A., Tanzi R.E., Zhou C. Optogenetic pacing in Drosophila melanogaster. Sci Adv. 2015;1(9):e1500639. PMID: 26601299; PMCID: PMC4646813. https://doi.org/10.1126/sciadv.1500639
  13. Aitova A., Scherbina S., Berezhnoy A., Slotvitsky M., Tsvelaya V., Sergeeva T., Turchaninova E., Rybkina E., Bakumenko S., Sidorov I., Popov M.A., Dontsov V., Agafonov E.G., Efimov A.E., Agapov I., Zybin D., Shumakov D., Agladze K. Novel molecular vehicle-based approach for cardiac cell transplantation leads to rapid electromechanical graft-host coupling. Int J Mol Sci. 2023;24(12):10406. PMID: 37373555; PMCID: PMC10299342. https://doi.org/10.3390/ijms241210406
  14. Григорьева Е.В., Валетдинова К.Р., Устьянцева Е.И., Шевченко А.И., Медведев С.P., Мазурок Н.А., Маретина М.А., Куранова М.Л., Киселев А.В., Баранов В.С., Закиян С.М. Дифференцировка в нейральном направлении пациент-специфичных индуцированных плюрипотентных стволовых клеток от больных с наследственной формой спинальной мышечной атрофии. Гены и Клетки. 2016;11(2):70-81. https://doi.org/10.23868/gc120584 Grigor’eva E.V., Valetdinova K.R., Ustyantseva E.I., Shevchenko A.I., Medvedev S.P., Mazurok N.A., Maretina M.A., Kuranova M.L., Kiselev A.V., Baranov V.S., Zakian S.M. Neural differentiation of patient-specific induced pluripotent stem cells from patients with a hereditary form of spinal muscular atrophy. Genes Cell. 2016;11(2):70-81. (In Russ.) https://doi.org/10.23868/gc120584
  15. Lian X., Zhang J., Azarin S.M., Zhu K., Hazeltine L.B., Bao X., Hsiao C., Kamp T.J., Palecek S.P. Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/β-catenin signaling under fully defined conditions. Nat Protoc. 2013;8(1):162-75. PMID: 23257984; PMCID: PMC3612968. https://doi.org/10.1038/nprot.2012.150
  16. Slotvitsky M.M., Tsvelaya V.A., Podgurskaya A.D., Agladze K.I. Formation of an electrical coupling between differentiating cardiomyocytes. Sci Rep. 2020;10(1):7774. PMID: 32385315; PMCID: PMC7210299. https://doi.org/10.1038/s41598-020-64581-5
  17. Glukhov A.V., Flagg T.P., Fedorov V.V., Efimov I.R., Nichols C.G. Differential K(ATP) channel pharmacology in intact mouse heart. J Mol Cell Cardiol. 2010;48(1):152-60. PMID: 19744493; PMCID: PMC2813353. https://doi.org/10.1016/j.yjmcc.2009.08.026
  18. Laughner J.I., Ng F.S., Sulkin M.S., Arthur R.M., Efimov I.R. Processing and analysis of cardiac optical mapping data obtained with potentiometric dyes. Am J Physiol Heart Circ Physiol. 2012;303(7):H753-65. PMID: 22821993; PMCID: PMC3469699. https://doi.org/10.1152/ajpheart.00404.2012
  19. Lin J.Y., Knutsen P.M., Muller A., Kleinfeld D., Tsien R.Y. ReaChR: a red-shifted variant of channelrhodopsin enables deep transcranial optogenetic excitation. Nat Neurosci. 2013;16(10):1499-508. PMID: 23995068; PMCID: PMC3793847. https://doi.org/10.1038/nn.3502
  20. Ausra J., Madrid M., Yin R.T., Hanna J., Arnott S., Brennan J.A., Peralta R., Clausen D., Bakall J.A., Efimov I.R., Gutruf P. Wireless, fully implantable cardiac stimulation and recording with on- device computation for closed-loop pacing and defibrillation. Sci Adv. 2022;8(43):eabq7469. PMID: 36288311; PMCID: PMC9604544. https://doi.org/10.1126/sciadv.abq7469
  21. Chong J.J.H., Yang X., Don C.W., Minami E., Liu Y.W., Weyers J.J., Mahoney W.M., Van Biber B., Cook S.M., Palpant N.J., Gantz J.A., Fugate J.A., Muskheli V., Gough G.M., Vogel K.W., Astley C.A., Hotchkiss C.E., Baldessari A., Pabon L., Reinecke H., Gill E.A., Nelson V., Kiem H.P., Laflamme M.A., Murry C.E. Human embryonic-stem-cell-derived cardiomyocytes regenerate non- human primate hearts. Nature. 2014;510(7504):273-7. PMID: 24776797; PMCID: PMC4154594. https://doi.org/10.1038/nature13233
  22. Liu Y.W., Chen B., Yang X., Fugate J.A., Kalucki F.A., Futakuchi- Tsuchida A., Couture L., Vogel K.W., Astley C.A., Baldessari A., Ogle J., Don C.W., Steinberg Z.L., Seslar S.P., Tuck S.A., Tsuchida H., Naumova A.V., Dupras S.K., Lyu M.S., Lee J., Hailey D.W., Reinecke H., Pabon L., Fryer B.H., MacLellan W.R., Thies R.S., Murry C.E. Human embryonic stem cell-derived cardiomyocytes restore function in infarcted hearts of non-human primates. Nat Biotechnol. 2018;36(7):597-605. PMID: 29969440; PMCID: PMC6329375. https://doi.org/10.1038/nbt.4162
  23. Alagarsamy K.N., Yan W., Srivastava A., Desiderio V., Dhingra S. Application of injectable hydrogels for cardiac stem cell therapy and tissue engineering. Rev Cardiovasc Med. 2019;20(4):221-30. PMID: 31912713. https://doi.org/10.31083/j.rcm.2019.04.534
  24. Slotvitsky M., Berezhnoy A., Scherbina S., Rimskaya B., Tsvelaya V., Balashov V., Efimov A.E., Agapov I., Agladze K. Polymer kernels as compact carriers for suspended cardiomyocytes. Micromachines (Basel). 2022;14(1):51. PMID: 36677111; PMCID: PMC9865253. https://doi.org/10.3390/mi14010051
  25. Engelmayr G.C. Jr, Cheng M., Bettinger C.J., Borenstein J.T., Langer R., Freed L.E. Accordion-like honeycombs for tissue engineering of cardiac anisotropy. Nat Mater. 2008;7(12):1003-10. PMID: 18978786; PMCID: PMC2613200. https://www.nature.com/articles/nmat2316
  26. Deng C., Zhang P., Vulesevic B., Kuraitis D., Li F., Yang A.F., Griffith M., Ruel M., Suuronen E.J. A collagen-chitosan hydrogel for endothelial differentiation and angiogenesis. Tissue Engineering Part A. 2010;16(10):3099-109. PMID: 20586613. https://doi.org/10.1089/ten.tea.2009.0504
  27. Lin J., Keener J.P. Ephaptic coupling in cardiac myocytes. IEEE Trans Biomed Eng. 2013;60(2):576-82. PMID: 23335235. https://doi.org/10.1109/tbme.2012.2226720