James Kwon

Background: Cardiovascular disease, particularly myocardial infarction (MI), is a leading cause of death worldwide.¹ MI occurs due to a blockage in the coronary artery, leading to tissue damage and impaired heart function. These events trigger various biological changes, exacerbating the detrimental effects of MI.² While existing treatments such as angioplasty with stents addresses the immediate threat, the consequences of MI, such as scar tissue formation and adverse remodeling, still remains. Current research focuses on vascular grafts, cardiac scaffolds, and injectable hydrogels for post-MI cardiac tissue regeneration. Vascular grafts and cardiac scaffolds have shown potential in providing support and self-repair mechanisms, although improvements are needed to prevent restenosis and reduce production times which includes decullarization.⁴ Injectable hydrogels enable controlled release of growth factors and can be prepared relatively quickly.¹ Among these approaches, injectable hydrogels hold promise for urgent post-MI treatment, considering their ability to deliver therapeutic agents and fast preparation time.

Objective: To investigate the ongoing research focused on repairing tissue damage caused by myocardial infarction (MI) utilizing various injectable hydrogels.

Search Methods: An online search in the PubMed database conducted from 2018 to 2023 using the following keywords: “myocardial infarction”, “injectable hydrogel”

Results:  Elastin-like recombinamers-based hydrogels (ELR) have shown promising results in reducing infarct expansion, preserving left ventricular function, and improving cardiac contractility. The average decrease in ejection fraction due to the surgical procedure was completely reversed in the ELRs-treated group with a 16.2% average improvement (P < 0.01) 21 days after the injection time in a sheep model.⁵

Targeting excessive matrix metalloproteinases (MMPs) secreted during myocardial infarction (MI) can provide molecular insights. Smart hydrogels responsive to MMPs enable controlled release of loaded drugs like basic fibroblast growth factor (bFGF). Including tissue inhibitors of metalloproteinases (TIMPs) in the hydrogel inhibits MMP activity and promotes cardiac tissue regeneration. This approach reduces adverse remodeling and improves cardiac function, increasing ejection fraction from 50% to 75% (P<0.001) and wall thickness from 30% to 75% (P<0.001) in a rat MI model.^6,7

Lastly, scavenging reactive oxygen species (ROS) has been proposed as a strategy to mitigate oxidative stress and tissue damage following myocardial infarction (MI). Hydrogels conjugated with ROS scavengers, such as poly(ethylene glycol)-conjugated catalase or Tashinone IIA (TIIA), have demonstrated reducing infarct size, restoring cardiac function and angiogenesis. In a rat model, these hydrogels significantly improved cardiac function, such as by increasing in ejection fraction from 25% to 55% (P<0.01) compared to the MI group.⁸

Conclusions:

This study proposes injectable hydrogels as a promising solution for post-myocardial infarction (MI) damage. Elastin recombinamers-based hydrogels and hydrogels targeting MMPs and ROS have shown significant advancements in reducing infarction size, restoring cardiac functions, and promoting remodeling. These hydrogels hold great potential for urgent post-MI treatment. Additionally, incorporating growth factors like bFGF or VEGF enhances tissue remodeling. The versatility of hydrogels allows for loading various therapeutic drugs, expanding treatment possibilities. However, further research is needed to optimize safety and effectiveness for post-MI patients.

Works Cited:

1. Wu T, Liu W. Functional hydrogels for the treatment of myocardial infarction. NPG Asia Materials. 2022;14(1):9. doi:10.1038/s41427-021-00330-y
2. Saleh M, Ambrose JA. Understanding myocardial infarction. F1000Res. 2018;7:F1000 Faculty Rev-1378. Published 2018 Sep 3. doi:10.12688/f1000research.15096.1
3. Peña B, Laughter M, Jett S, et al. Injectable Hydrogels for Cardiac Tissue Engineering. Macromol Biosci. 2018;18(6):e1800079. doi:10.1002/mabi.201800079
4. Stapleton, L., Zhu, Y., Woo, Y. J., &amp; Appel, E. (2020). Engineered biomaterials for heart disease. Current Opinion in Biotechnology, 66, 246–254. https://doi.org/10.1016/j.copbio.2020.08.008
5. Contessotto, P., Orbanić, D., Da Costa, M., Jin, C., Owens, P., Chantepie, S., Chinello, C., Newell, J., Magni, F., Papy-Garcia, D., Karlsson, N. G., Kilcoyne, M., Dockery, P., Rodríguez-Cabello, J. C., & Pandit, A. (2021). Elastin-Like Recombinamers-Based Hydrogel Modulates Post-Ischemic Remodeling in a Non-Transmural Myocardial Infarction in Sheep. Science translational medicine, 13(581), eaaz5380. https://doi.org/10.1126/scitranslmed.aaz5380
6. Fan C, Shi J, Zhuang Y, et al. Myocardial‐Infarction‐Responsive Smart Hydrogels Targeting Matrix Metalloproteinase For On‐Demand Growth Factor Delivery. Advanced Materials. 2019;31(40):1902900. doi:10.1002/adma.201902900
7. Fan, Z., Fu, M., Xu, Z., Zhang, B., Li, Z., Li, H., Guan, J. (2017). Sustained Release of a Peptide-Based Matrix Metalloproteinase-2 Inhibitor to Attenuate Adverse Cardiac Remodeling and Improve Cardiac Function Following Myocardial Infarction. Biomacromolecules, 18(9), 2820–2829. doi:10.1021/acs.biomac.7b00760\
8. Wang, W., Chen, J., Li, M., Jia, H., Han, X., Zhang, J., Zou, Y., Tan, B., Liang, W., Shang, Y., Xu, Q., A, S., Wang, W., Mao, J., Gao, X., Fan, G., & Liu, W. (2019). Rebuilding Postinfarcted Cardiac Functions by Injecting TIIA@PDA Nanoparticle-Cross-linked ROS-Sensitive Hydrogels. ACS applied materials & interfaces, 11(3), 2880–2890. https://doi.org/10.1021/acsami.8b20158