Stimuli-responsive hydrogels: smart state of-the-art platforms for cardiac tissue engineering

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TL;DR

This review comprehensively examines stimuli-responsive hydrogels (SRHs) as advanced platforms for cardiac tissue engineering (CTE), highlighting their ability to respond to physical, chemical, and biological cues to mimic the native extracellular matrix. The paper details various SRH types—including temperature, pH, enzyme, and redox-responsive systems—and their applications in myocardial infarction repair, drug delivery, and cell therapy. The clinical significance lies in the potential of these smart hydrogels to improve cardiac function, reduce fibrosis, and promote angiogenesis, offering a promising alternative to conventional treatments for cardiovascular diseases.

Full summary

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**Background:** Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide, and the limited regenerative capacity of human cardiac cells necessitates innovative tissue engineering (TE) approaches. Conventional hydrogels, while useful, suffer from limitations such as inadequate mechanical strength, poor biocompatibility, and lack of responsiveness to physiological changes. Stimuli-responsive hydrogels (SRHs) have emerged as a promising solution, as they can dynamically alter their properties in response to specific triggers (e.g., temperature, pH, enzymes, light, magnetic fields), thereby better mimicking the native extracellular matrix (ECM) and enhancing cardiac repair. This review aims to provide a comprehensive overview of SRHs for cardiac tissue engineering (CTE), covering their design, mechanisms, and therapeutic applications.

**Methods:** This is a narrative review that synthesizes findings from a wide range of preclinical studies, including in vitro experiments and in vivo animal models (primarily rat and mouse myocardial infarction (MI) models). The review categorizes SRHs based on the type of stimulus they respond to: physical (temperature, light, electro, magnetic, pressure, ultrasound), chemical (pH, ionic strength, redox), and biological (enzyme, antigen/antibody). For each category, the review summarizes key studies, detailing the hydrogel composition, the specific stimulus, the study model, and the reported outcomes. The paper also discusses the role of SRHs in 4D printing and future perspectives.

**Key Results:** The review presents a wide array of SRH systems with demonstrated efficacy in CTE. Key findings include: - **Temperature-responsive hydrogels:** Poly(N-isopropylacrylamide) (PNIPAAm)-based hydrogels, often combined with carbon nanotubes or gold nanoparticles, improved cell proliferation and engraftment at MI sites. For example, a PNIPAAm/SWCNTs hydrogel enhanced the delivery of brown adipose-derived stem cells (BASCs) to the infarct myocardium in vivo. A chitosan/dextran/β-glycerophosphate hydrogel loaded with umbilical cord mesenchymal stem cells (UCMSCs) promoted cardiac marker expression (cTnI, Cx43) and activated p-Akt and p-ERK1/2 pathways. A colchicine-loaded PLGA-PEG-PLGA hydrogel (Col@Gel) reduced macrophage viability and migration in vitro, and in a rat MI model, it ameliorated cardiac inflammatory response, hindered myocardial necrosis, improved cardiac performance, and enhanced mouse viability. - **Light/photo-responsive hydrogels:** Near-infrared (NIR)-sensitive polydopamine nanoparticles in collagen foams regulated the electrical activity of cardiac cells. Carbon nanotube (CNT)-incorporated gelatin methacrylate (GelMA) hydrogels led to more elongated cardiac cells and more stable beating frequencies over 6 days compared to pure GelMA. Reduced graphene oxide (rGO)-GelMA hydrogels improved cell survival, proliferation, and contractility, with a faster natural beating rate. - **Electro-responsive hydrogels:** Poly-3-amino-4-methoxy benzoic acid (PAMB) crosslinked gelatin hydrogels (PAMB-G) were compatible with cardiomyocytes in vitro and effectively conducted electrical impulses ex vivo, showing significantly higher amplitude in non-beating cardiac muscle compared to non-conductive gelatin. Polyacrylic acid (PAA) mixed with oxidized alginate/gelatin (POG) hydrogels exhibited self-healing properties and improved functional recovery in a rat MI model. - **Magnetic-responsive hydrogels:** Magnetic alginate scaffolds stimulated with a weak alternating magnetic field (1.5 mT, 40 Hz) promoted the formation of early capillary-like structures in endothelial cells. Magnetic iron oxide (Fe3O4) nanoparticles in collagen hydrogels enabled micropatterning to mimic the electroconductive properties of cardiac tissue. - **Pressure/mechano-responsive hydrogels:** A polyaniline (PAni) hybrid hydrogel supported cardiomyocyte organization into a spontaneously contracting system and exhibited pressure-responsive and self-healing properties. - **Ultrasound/acoustic-responsive hydrogels:** A secretome-encapsulated Fe2O3-silk sericin (Sec@MSS) hydrogel was proposed for reducing doxorubicin-induced cardiotoxicity. An ultrasound-sensitive CaO2@MSN-HE-PEG (CMHP) nanosystem generated oxygen at the infarct site, reducing hypoxia and oxidative stress, and markedly enhancing cardiac cell survival under hypoxic conditions. - **pH-responsive hydrogels:** A PNIPAAm-BA-PAA hydrogel, liquid at pH 7.4 but gelling at pH 6.8 and 37°C, increased growth factor retention time in infarcted rat myocardium by 10-fold, promoting 30-40% raised capillary and arteriolar densities. - **Ionic strength-responsive hydrogels:** Polypyrrole-chitosan (PPY-CH) hydrogels improved Ca2+ conduction in rat cardiomyocytes in vitro, depressed the QRS interval, and improved electrical signal transmission and heart function after MI. A POG hydrogel drastically minimized left ventricular remodeling and recovered myocardial performance in vivo. - **Redox-responsive hydrogels:** A poly(arginine)-based injectable hydrogel (NO-RIG) scavenged reactive oxygen species (ROS) and sustained nitric oxide (NO) release, significantly slowing the progression of MI and enhancing cardiac functions and angiogenesis in both major and mild MI models. A basic fibroblast growth factor (bFGF)-loaded ROS-responsive PVA hydrogel (Gel-bFGF) injected into the pericardial cavity of rats released bFGF on-demand, preserving cardiac function and reducing fibrosis post-ischemia/reperfusion. - **Enzyme-responsive hydrogels:** A hydrogel formed by cyclic self-assembling peptides with a PLGLAG polypeptide gelled in situ in response to matrix metalloproteinases (MMP-2) and elastase in a rat MI model. A recombinant protein GST-TIMP-bFGF entrapped in a collagen-GSH hydrogel released bFGF in response to MMP-2/9, decreasing MMP activity, boosting angiogenesis, and promoting MI healing. - **Antigen/antibody-responsive hydrogels:** An injectable hydrogel loaded with artificial apoptotic cells (AACs) and VEGF achieved spatiotemporal release, reducing inflammatory response and cardiomyocyte death in a rat MI model, and leading to considerable improvement in cardiac function and reduced pathological remodeling.

**Clinical Implications:** The review underscores the transformative potential of SRHs for CTE. By enabling on-demand, localized delivery of therapeutic agents (cells, growth factors, drugs) and providing a conductive, mechanically supportive scaffold, SRHs can address key challenges in cardiac repair, such as poor cell survival, arrhythmias, and fibrosis. The ability to respond to specific pathological cues (e.g., low pH in ischemia, elevated ROS, upregulated MMPs) allows for targeted and controlled therapy, minimizing systemic side effects. While most studies are preclinical, the results are promising for future clinical translation, particularly for treating myocardial infarction and preventing heart failure. The review also highlights the need for further research to overcome challenges related to biodegradation, immune response, toxicity, and scalability before SRHs can be widely adopted in clinical settings.