Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Jul 12:29:132-150.
doi: 10.1016/j.bioactmat.2023.07.007. eCollection 2023 Nov.

An injectable conductive hydrogel with dual responsive release of rosmarinic acid improves cardiac function and promotes repair after myocardial infarction

Linghong Zhang  1 , Zhongwu Bei  1 , Tao Li  2 , Zhiyong Qian  1
Affiliations

An injectable conductive hydrogel with dual responsive release of rosmarinic acid improves cardiac function and promotes repair after myocardial infarction

Linghong Zhang et al. Bioact Mater. .

Abstract

Myocardial infarction (MI) causes irreversible damage to the heart muscle, seriously threatening the lives of patients. Injectable hydrogels have attracted extensive attention in the treatment of MI. By promoting the coupling of mechanical and electrical signals between cardiomyocytes, combined with synergistic therapeutic strategies targeting the pathological processes of inflammation, proliferation, and fibrotic remodeling after MI, it is expected to improve the therapeutic effect. In this study, a pH/ROS dual-responsive injectable hydrogel was developed by modifying xanthan gum and gelatin with reversible imine bond and boronic ester bond double crosslinking. By encapsulating polydopamine-rosmarinic acid nanoparticles to achieve on-demand drug release in response to the microenvironment of MI, thereby exerting anti-inflammatory, anti-apoptotic, and anti-fibrosis effects. By adding conductive composites to improve the conductivity and mechanical strength of the hydrogel, restore electrical signal transmission in the infarct area, promote synchronous contraction of cardiomyocytes, avoid induced arrhythmias, and induce angiogenesis. Furthermore, the multifunctional hydrogel promoted the expression of cardiac-specific markers to restore cardiac function after MI. The in vivo and in vitro results demonstrate the effectiveness of this synergistic comprehensive treatment strategy in MI treatment, showing great application potential to promote the repair of infarcted hearts.

Keywords: Combined treatment; Conductivity; Myocardial infarction; Responsive hydrogel; Rosmarinic acid.

PubMed Disclaimer

Conflict of interest statement

Zhiyong Qian is an editorial board member for Bioactive Materials and was not involved in the editorial review or the decision to publish this article. All authors declare that there are no competing interests.

Figures

Image 1
Graphical abstract
Scheme 1
Scheme 1
Schematic illustration of the preparation of a pH/ROS dual-responsive conductive hydrogel encapsulating PDA-RA NPs and its use in MI treatment.
Fig. 1
Fig. 1
Preparation and characterization of the nanoparticles and hydrogels. (A) Synthesis of PDA and PDA-RA NPs. (B, C) Particle size distribution (B) and zeta potential (C) of PDA and PDA-RA NPs. (D) UV absorption spectra of RA, PDA, and PDA-RA NPs. (E) TEM images of PDA and PDA-RA NPs. Scale bars: 100 nm. (F) Gelation time of different hydrogels. (G) Photographs of the OGDPR hydrogel before (left) and after (right) gelation. (H) Photograph of the injectability of the OGDPR hydrogel. (I) SEM images of different hydrogels. Scale bar: 1 mm.
Fig. 2
Fig. 2
Properties of multifunctional hydrogels. (A) Swelling ratio of hydrogels in PBS (n = 5). (B, C) Release profiles of RA from OGDR (B) and OGDPR (C) hydrogels under different conditions (n = 3). (D) Rheological measurements of hydrogels in time-sweep mode. (E) Viscosity of hydrogels as a function of shear rate. (F) G′ and G″ of the hydrogels under different oscillatory strains. (G) Self-healing properties of hydrogels under alternating strain. (H) Conductivity of different hydrogels (n = 3). (I, J) CV curves (I) and EIS (J) curves of different hydrogels. (K, L) Stress-strain curves (K) and elastic moduli (L) of the hydrogels (n = 3).
Fig. 3
Fig. 3
In vitro cytocompatibility and antioxidant activity of hydrogels. (A) Live/dead staining of H9C2 and RCF incubated with different hydrogel extracts. Green dots: living cells; red dots: dead cells. Yellow arrows indicate dead cells. Scale bars: 100 μm. (B, C) CCK-8 assay for cell viability of H9C2 (B) and RCF (C) co-incubated with hydrogel extracts, untreated cells were used as control (n = 6). (D) Cell viability of H9C2 cells treated with H2O2 (200 μM) and different hydrogel extracts for 24 h (n = 5). (E) Images of CD86 and CD206 immunofluorescent staining in macrophages stimulated with LPS and treated with different hydrogel extracts. (F–H) Representative flow cytometry analysis images (F) of different groups and the proportion of M1 (G) and M2 (H) macrophages (n = 3). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.
Fig. 4
Fig. 4
Hydrogels promote HUVECs migration and tube formation. (A) Representative images of HUVECs cultured with different hydrogel extracts for 0, 6, 12, and 18 h. Scale bar: 200 μm. (B) Quantitative results of wound cell migration at different time points (n = 3). (C) Images of HUVECs forming tubes in vitro. (D–F) Quantitative results of the number of nodes (D), the number of junctions (E), and the number of branches (F) of different hydrogel groups (n = 4). Scale bar: 100 μm *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.
Fig. 5
Fig. 5
Injection of hydrogel after MI improves cardiac function. (A) Critical time points of animal experiments. (B) ECG before (left) and after (right) modeling. (C) Echocardiograms before (left) and after (right) modeling. (D) Gross pictures of rat hearts injected with different biomaterials. (E) Representative echocardiographic images of each group at 4 weeks after injection. (F) Cardiac function indicators were determined by echocardiography after 0 (before injection), 2, and 4 weeks of treatment (n = 6). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.
Fig. 6
Fig. 6
Protective effects of hydrogels on the electrophysiology of infarcted hearts. (A) ECG of each group 4 weeks after treatment. (B) ECG of arrhythmias induced by PES 4 weeks after injection. (C, D) Effects on QRS (C) and QT (D) intervals after injection of different biomaterials (n = 6). (E) Arrhythmia susceptibility characterized by inducibility quotient (n = 6). (F) Tissue resistivity of the infarct scar areas (n = 6). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.
Fig. 7
Fig. 7
Hydrogels attenuate pathological remodeling of the LV. (A) Masson's trichrome staining was performed on multiple cardiac slices from the apex to the atrium 4 weeks after treatments. The image at high magnification comes from the black box of the low magnification image. Scale bars: low magnification = 1 mm, high magnification = 200 μm. (B–D) Quantitative analysis of the wall thickness (B), infarct size (C), and fibrosis area (D) in each group after 4 weeks of treatment according to Masson's trichrome staining (n = 6). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.
Fig. 8
Fig. 8
Hydrogels resist oxidation, inhibit inflammation, and reduce apoptosis. (A) ROS expression in infarcted hearts after different treatments. (B) Immunofluorescence images of CD86+ and CD206+ macrophages in the area of MI. Scale bar: 100 μm. (C) Representative TUNEL staining images of the infarct area. Scale bar: 100 μm. (D–F) Quantitative analysis of relative ROS fluorescence intensity (D), M2/M1 (CD206+/CD86+) ratio (E), and TUNEL positive cells (F) in the infarct area of the heart (n = 4). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.
Fig. 9
Fig. 9
Hydrogels promote cell proliferation and angiogenesis. (A) The expression of Ki67 in the MI area after 4 weeks of different treatments. Scale bar: 100 μm. (B) Representative images of α-SMA/vWF double staining in different treatment groups at 4 weeks. Scale bar: 100 μm. (C–E) Quantitative analysis of Ki67 positive cells (C), α-SMA positive vessels (D), and vWF positive vessels (E) in the infarct regions (n = 4). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.
Fig. 10
Fig. 10
Hydrogels facilitate the expression of cardiac-specific markers. (A, B) Representative images of α-actinin (A) and CX-43 (B) staining 4 weeks after different treatments. (C, D) Quantitative analysis of α-actinin (C) and CX-43 (D) area coverage in the infarct region (n = 4). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Vos T., Lim S.S., Abbafati C., Abbas K.M., Abbasi M., Abbasifard M., Abbasi-Kangevari M., Abbastabar H., Abd-Allah F., Abdelalim A. Global burden of 369 diseases and injuries in 204 countries and territories. 1990–2019: A systematic analysis for the global burden of disease study 2019, The Lancet. 2020;396(10258):1204–1222. - PMC - PubMed
    1. Zhou M., Wang H., Zeng X., Yin P., Zhu J., Chen W., Li X., Wang L., Wang L., Liu Y., Liu J., Zhang M., Qi J., Yu S., Afshin A., Gakidou E., Glenn S., Krish V.S., Miller-Petrie M.K., Mountjoy-Venning W.C., Mullany E.C., Redford S.B., Liu H., Naghavi M., Hay S.I., Wang L., Murray C.J.L., Liang X. Mortality, morbidity, and risk factors in China and its provinces, 1990–2017: a systematic analysis for the global burden of disease study 2017. Lancet. 2019;394(10204):1145–1158. - PMC - PubMed
    1. Jiao L., Li M., Shao Y., Zhang Y., Gong M., Yang X., Wang Y., Tan Z., Sun L., Xuan L., Yu Q., Li Y., Gao Y., Liu H., Xu H., Li X., Zhang Y., Zhang Y. LncRNA-ZFAS1 induces mitochondria-mediated apoptosis by causing cytosolic Ca2+ overload in myocardial infarction mice model. Cell Death Dis. 2019;10(12):942. - PMC - PubMed
    1. Sutton M.G.S.J., Sharpe N. Left ventricular remodeling after myocardial infarction. Circulation. 2000;101(25):2981–2988. - PubMed
    1. Taimeh Z., Loughran J., Birks E.J., Bolli R. Vascular endothelial growth factor in heart failure. Nat. Rev. Cardiol. 2013;10(9):519–530. - PubMed

LinkOut - more resources