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A Hydrogel Construct and Fibrin-based Glue Approach to Deliver Therapeutics in a Murine Myocardial Infarction Model.
Published on: June 14, 2015
Celastrol-Loaded Conductive Hydrogel Mitigates Myocardial Ischemia-Reperfusion Injury and Restores
Shixin Wang1, Shaojie Chen1, Chengzong Li2
1Department of Cardiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, P. R. China.
Insights
This study developed a novel conductive hydrogel (FGPC) for localized delivery of celastrol (CLT) to treat myocardial ischemia-reperfusion injury (MIRI). FGPC reduces oxidative stress and inflammation, improving cardiac function and repair without systemic toxicity.
Area of Science:
- Biomaterials Science
- Cardiovascular Research
- Regenerative Medicine
Background:
- Myocardial ischemia-reperfusion injury (MIRI) poses a significant clinical challenge, impacting patient outcomes after revascularization.
- Celastrol (CLT), a potent antioxidant, shows promise for MIRI treatment but faces limitations due to poor solubility and potential toxicity.
- Localized and sustained drug delivery systems are needed to overcome CLT's limitations and enhance therapeutic efficacy.
Purpose of the Study:
- To develop an injectable, conductive hydrogel platform (FGPC) for localized and sustained delivery of celastrol (CLT).
- To evaluate the efficacy of FGPC in mitigating MIRI through antioxidant and anti-inflammatory mechanisms.
- To assess the potential of FGPC for promoting cardiac repair and improving cardiac function post-MIRI.
Main Methods:
- Fabrication of an injectable FGPC hydrogel composed of F127DA, GelMA, PEDOT:PSS, and CLT.
- In vitro assessment of FGPC's physical properties, biocompatibility, and antioxidant capacity.
- In vivo evaluation of FGPC in a rat MIRI model, including histological, transcriptomic, and functional analyses.
Main Results:
- FGPC hydrogel demonstrated favorable mechanical properties, electrical conductivity, local retention, and controlled CLT release.
- In vitro studies showed FGPC effectively reduced reactive oxygen species (ROS) and supported cardiomyocyte health.
- In vivo, FGPC treatment attenuated MIRI-induced oxidative stress, inflammation, and neutrophil extracellular trap formation, leading to improved cardiac function, reduced fibrosis, and enhanced angiogenesis without systemic toxicity.
Conclusions:
- The developed FGPC hydrogel platform enables localized and sustained delivery of CLT, effectively addressing MIRI.
- FGPC combines CLT's antioxidant effects with electrical support, offering a promising therapeutic strategy for myocardial repair.
- This approach presents a potential solution for improving outcomes in patients suffering from myocardial ischemia-reperfusion injury.
Abstract:
Myocardial ischemia-reperfusion injury (MIRI) remains an unresolved clinical challenge that severely limits the prognosis of patients undergoing revascularization. Through a phenotype-guided antioxidant screening workflow, celastrol (CLT) was selected as a bioactive compound for integration into a locally retained conductive hydrogel platform. However, the clinical translation of CLT is limited by poor aqueous solubility and potential systemic toxicity. To overcome these limitations, we developed an injectable F127DA/GelMA/PEDOT:PSS/celastrol hydrogel (FGPC) for the localized and sustained delivery of CLT. The FGPC hydrogel, composed of Gelatin methacryloyl (GelMA), Pluronic F127 diacrylate (F127DA) , and conductive poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS), exhibits favorable mechanical properties, enhanced electrical conductivity, local retention, and controlled drug release. In vitro, FGPC effectively reduced reactive oxygen species (ROS), supported cardiomyocyte structural organization, and enhanced gap-junction coupling. In a rat MIRI model, local FGPC delivery attenuated acute oxidative stress, suppressed inflammatory activation, and reduced neutrophil extracellular trap formation. Transcriptomic analysis further revealed downregulation of inflammatory pathways, including the IL-17 signaling pathway and S100a8/S100a9-related inflammatory mediators. During the chronic repair phase, FGPC improved cardiac function, reduced fibrosis, restored connexin 43 expression, reduced inducible ventricular arrhythmia susceptibility, and promoted angiogenesis without obvious systemic toxicity. This study presents a locally retained conductive hydrogel platform that combines CLT-mediated microenvironment modulation with electrical support, providing a potential strategy for myocardial repair after reperfusion.
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