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<p>This review evaluates injectable bioactive hydrogels as localized pharmacological platforms for post-myocardial infarction (MI) cardiac repair, focusing on therapeutic cargo engineering, stimuli-responsive release systems, mechanistic signaling pathways, and translational potential. A critical narrative synthesis was conducted drawing upon the most recent original research published in leading journals in the field, emphasizing hydrogel composition, pharmacological cargo classes, release mechanisms, molecular targets, animal models, and clinical evidence. The review integrates studies involving small molecules, exosomes, conductive nanomaterials, nanobodies, extracellular matrix-derived systems, and gene delivery vectors. Injectable hydrogels demonstrated the capacity to provide spatially localized and temporally controlled therapy within the infarcted myocardium. Stimuli-responsive systems exploiting pH, reactive oxygen species, and enzymatic microenvironments enabled phase-matched therapeutic release. Major pharmacological effects included macrophage immunomodulation, angiogenesis promotion, oxidative stress reduction, fibrosis attenuation, and restoration of electrical conductivity. Convergent signaling pathways across studies included PI3K/AKT, AMPK-mTOR, VEGF, and TGF-β-related networks. Preclinical studies consistently reported improvements in ventricular remodeling and cardiac function, while early clinical translation with VentriGel established feasibility and procedural safety in human patients. Injectable bioactive hydrogels represent a promising pharmacological strategy for post-MI cardiac repair by integrating biomaterial engineering with localized multi-dimensional drug delivery. Despite substantial preclinical progress, challenges including long-term safety, mechanistic standardization, large-animal validation, and regulatory complexity remain critical barriers to clinical translation.</p> Graphical Abstract <p><b>Injectable bioactive hydrogels as multi-cargo pharmacological platforms for post-myocardial infarction (MI) cardiac repair.</b> Zone&#xa0;1 illustrates the post-MI pathological context: an infarcted left ventricular wall progressing through four biochemically distinct phases — acute, inflammatory, proliferative, and remodeling — each defined by specific trigger biochemistry. Zone&#xa0;2 represents the injectable hydrogel as a universal delivery platform loaded with five pharmacologically distinct cargo classes: small molecules, exosomes, electroactive nanomaterials, ECM bioactives, and biological macromolecules. Zone&#xa0;3 depicts stimuli-responsive release, whereby pH-sensitive Schiff base hydrolysis, ROS-triggered thioketal cleavage, and chronologically programmed dual-crosslink degradation enable phase-matched cargo liberation. Zone&#xa0;4 shows the resulting pharmacological outputs — angiogenesis, ROS scavenging, M2 macrophage reprogramming, electrophysiological restoration, and anti-fibrosis — which converge on three master pharmacological nodes (PI3K/AKT axis, M2 polarization, AMPK-mTOR) identified through cross-study mechanistic synthesis. Zone&#xa0;5 represents the cardiac repair endpoint alongside the translational evidence hierarchy from rodent through porcine validation to the first-in-man Phase&#xa0;I clinical trial. AMPK, AMP-activated protein kinase; ECM, extracellular matrix; MI, myocardial infarction; PI3K, phosphoinositide 3-kinase; ROS, reactive oxygen species.</p> <p></p>

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Injectable bioactive hydrogels as pharmacological drug delivery platforms for post-myocardial infarction cardiac repair: therapeutic cargo engineering, stimuli-responsive release mechanisms, and translational perspectives

  • 期刊论文

  • 发表日期：

    2026年7月8日

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  • Amr Ali Mohamed Abdelgawwad El-Sehrawy,
  • Safa Alkhayyat,
  • Mirza R. Baig,
  • Aziz Kubaev,
  • Tushar B. Gajjar,
  • Malathi Hanumanthayya,
  • Laxmidhar Maharana,
  • Irwanjot Kaur,
  • Aseel Smerat,
  • Narges Fereydouni

摘要

This review evaluates injectable bioactive hydrogels as localized pharmacological platforms for post-myocardial infarction (MI) cardiac repair, focusing on therapeutic cargo engineering, stimuli-responsive release systems, mechanistic signaling pathways, and translational potential. A critical narrative synthesis was conducted drawing upon the most recent original research published in leading journals in the field, emphasizing hydrogel composition, pharmacological cargo classes, release mechanisms, molecular targets, animal models, and clinical evidence. The review integrates studies involving small molecules, exosomes, conductive nanomaterials, nanobodies, extracellular matrix-derived systems, and gene delivery vectors. Injectable hydrogels demonstrated the capacity to provide spatially localized and temporally controlled therapy within the infarcted myocardium. Stimuli-responsive systems exploiting pH, reactive oxygen species, and enzymatic microenvironments enabled phase-matched therapeutic release. Major pharmacological effects included macrophage immunomodulation, angiogenesis promotion, oxidative stress reduction, fibrosis attenuation, and restoration of electrical conductivity. Convergent signaling pathways across studies included PI3K/AKT, AMPK-mTOR, VEGF, and TGF-β-related networks. Preclinical studies consistently reported improvements in ventricular remodeling and cardiac function, while early clinical translation with VentriGel established feasibility and procedural safety in human patients. Injectable bioactive hydrogels represent a promising pharmacological strategy for post-MI cardiac repair by integrating biomaterial engineering with localized multi-dimensional drug delivery. Despite substantial preclinical progress, challenges including long-term safety, mechanistic standardization, large-animal validation, and regulatory complexity remain critical barriers to clinical translation.

Graphical Abstract

Injectable bioactive hydrogels as multi-cargo pharmacological platforms for post-myocardial infarction (MI) cardiac repair. Zone 1 illustrates the post-MI pathological context: an infarcted left ventricular wall progressing through four biochemically distinct phases — acute, inflammatory, proliferative, and remodeling — each defined by specific trigger biochemistry. Zone 2 represents the injectable hydrogel as a universal delivery platform loaded with five pharmacologically distinct cargo classes: small molecules, exosomes, electroactive nanomaterials, ECM bioactives, and biological macromolecules. Zone 3 depicts stimuli-responsive release, whereby pH-sensitive Schiff base hydrolysis, ROS-triggered thioketal cleavage, and chronologically programmed dual-crosslink degradation enable phase-matched cargo liberation. Zone 4 shows the resulting pharmacological outputs — angiogenesis, ROS scavenging, M2 macrophage reprogramming, electrophysiological restoration, and anti-fibrosis — which converge on three master pharmacological nodes (PI3K/AKT axis, M2 polarization, AMPK-mTOR) identified through cross-study mechanistic synthesis. Zone 5 represents the cardiac repair endpoint alongside the translational evidence hierarchy from rodent through porcine validation to the first-in-man Phase I clinical trial. AMPK, AMP-activated protein kinase; ECM, extracellular matrix; MI, myocardial infarction; PI3K, phosphoinositide 3-kinase; ROS, reactive oxygen species.