Research Progress of Sodium Alginate-Based Hydrogels in Myocardial Infarction Treatment

Abstract

Myocardial infarction (MI), a prevalent critical cardiovascular disease (CVD), poses a severe threat to patients’ lives. Despite the availability of pharmacological, interventional, and surgical treatments in clinical practice, these conventional therapies encounter the bottleneck of difficulty in repairing and reconstructing damaged myocardial tissue. Additionally, novel cardiac repair approaches based on stem cell and cardiomyocyte injections are restricted by the harsh microenvironment of infarcted areas. However, biomaterial hydrogels emerge as promising candidates for MI treatment due to their strong mechanical properties, good biocompatibility, high water absorption capacity, and excellent anti-inflammatory and antioxidant properties. These features enable them to enhance the microenvironment, promote myocardial regeneration, and restore myocardial function. This article delves into the therapeutic effects of sodium alginate (SA) and its composite hydrogel materials in repairing and regenerating myocardial injuries caused by MI. Furthermore, it offers insights into the future research directions of SA and its composite hydrogel materials. It also explores their potential applications in the field of CVDs.

Impact Statement

This review article highlights the significance and potential impact of sodium alginate (SA)-based hydrogels in myocardial infarction (MI) treatment. It effectively communicates the importance of the research, the gap in the current treatments for MI, and how the reviewed SA hydrogels offer a promising solution with their unique properties. It also clearly states the intended contribution to the field and the potential benefits for researchers and clinicians.

Keywords

hydrogels alginate myocardial infarction cardiac repair

Introduction

Myocardial infarction (MI), a common critical cardiovascular disease (CVD), occurs when blood flow to the coronary arteries is significantly reduced or interrupted, causing myocardial cell ischemic necrosis due to ischemia. Globally, it is the leading cause of death, accounting for 42% of CVD-related fatalities, posing a severe threat to patient safety.^1,2 Traditional treatments like drug therapy, interventional procedures, and surgery can alleviate MI symptoms, though they struggle to repair the damaged myocardial tissue due to its limited regenerative potential.^3,4 Cardiac repair therapy using stem cell or cardiomyocyte injections is promising but faces low cell survival and retention in the harsh infarcted microenvironment.^5,6 Thus, cardiac tissue engineering (CTE) techniques, particularly biomaterial hydrogels, have gained attention for repairing and regenerating infarcted hearts. Hydrogels, known for their high water absorption, anti-inflammatory and antioxidant properties, robust mechanical properties, and biocompatibility,^7–9 can modulate the infarcted microenvironment, attenuate ventricular remodeling, and induce myocardial regeneration and function restoration.^10,11

Currently, hydrogels for MI therapy are classified into six types based on their therapeutic mechanisms: Reactive oxygen species (ROS)-scavenging, conductive, matrix metalloproteinases (MMP)-responsive, immune-modulating, angiogenesis-promoting, and three-dimensional (3D)-printed hydrogels.^12–14 They can also be categorized as natural polymer-based (e.g., sodium alginate [SA], cellulose, chitosan, hyaluronic acid, collagen) and artificial polymer-based (e.g., polyacrylic acid, polyacrylamide, poly(vinyl alcohol)) hydrogels.^15,16 Among natural polymer-based hydrogels, SA is a promising scaffold material for tissue engineering. SA, a polysaccharide polymer composed of β-d-mannuronic acid (M-block) and α-l-guluronic acid (G-block) units connected by 1→4 glycosidic linkages, has different physicochemical properties due to its characteristic alternating sequences and specific stoichiometric ratios. As a scaffold material, SA offers advantages including low cost, rapid gelation kinetics, low cytotoxicity, and mild crosslinking requirements. Its exceptional biocompatibility and inherent anti-inflammatory and antioxidant capacities have also made it widely used in regenerative medicine.^17,18 Preparation techniques range from droplet-based injection, spray deposition, and emulsification crosslinking to physical and chemical crosslinking.^19,20 The emergence of 3D bioprinting has further expanded SA’s biomedical applications due to its advantageous rheological properties like shear-thinning behavior, tunable viscoelasticity, and rapid crosslinking capabilities.^21–23

To ensure a stable interfacing between SA hydrogels and beating myocardium, hydrogels matching cardiac tissue biomechanics (e.g., tensile strength, self-healing) and functional properties have been engineered using sol–gel transitions.^24,25 This stabilizes the infarct zone via strategies such as bioadhesive moieties (e.g., dopamine), in situ photochemical/enzymatic crosslinking, micro/nanostructuring, and bioactive mediators.^26,27 Covalent or strong noncovalent interactions with intrinsic tissue components (e.g., collagen, laminin, and transglutaminase) prevent displacement and enable long-term therapeutic integration.⁷ Owing to its superior biocompatibility and injectability, SA hydrogel has been extensively studied for MI repair and functional recovery. SA hydrogel can enhance cardiac function by increasing the thickness of infarct scar, promoting angiogenesis, and inhibiting apoptosis and myocardial fibrosis.^28,29 The therapeutic relationship between the physicochemical characteristics of SA-based hydrogels and MI pathology is summarized in Table 1. As an excellent delivery vehicle, injectable SA-based hydrogels can be loaded with therapeutic cargo (e.g., growth factors, extracellular vesicles [EVs], nanomaterials, or stem cells) to restore cardiac function (Fig. 1). This review aims to provide a comprehensive analysis of the mechanisms and therapeutic efficacy of SA-based hydrogels in MI treatment while highlighting future research directions and potential applications in cardiovascular and other diseases.

Table 1.

The Therapeutic Relationship Between the Physicochemical Characteristics of Sodium Alginate-Based Hydrogels and the Pathological Features of Myocardial Infarction Diseases

Physicochemical characteristics	Pathological features of MI diseases	Therapeutic effect/mechanism	Ref.
Injectability and in situ gelation	Irregular infarct regions, minimally invasive delivery requirements	Through minimally invasive injection, sodium alginate-based hydrogels loaded with therapeutic factors are accurately delivered to the infarct site, in situ forming fillers to provide mechanical support and limit ventricular remodeling	^30–38
Mechanical properties	Tissue softening in the infarcted regions, abnormally elevated ventricular wall stress, and ventricular dilation	Provide mechanical support to match/slightly higher than healthy myocardium, reduce wall stress, and limit pathological expansion; provide cells with a suitable mechanical microenvironment to guide tissue regeneration	^{32,34–37,39,40}
Porosity and pore size	Impaired cell infiltration, insufficient angiogenesis, and limited diffusion of nutrients/metabolic waste	Provide space for cell migration and proliferation; promote the growth of new blood vessels; allow the diffusion of nutrients, oxygen, growth factors, and the discharge of metabolic waste; affect drug/cytokine release kinetics	^{30–34,36,40–43}
Degradation rate	Tissue regeneration requires time, long-term support, and timely exit	The degradation rate matches the ingrowth rate of new tissue: too fast leads to premature loss of temporary support performance of the scaffold, and too slow will hinder regeneration and chronic inflammation	^34,42,43
Biofunctionalization	Apoptosis, excessive inflammatory response, insufficient angiogenesis, and electrical conduction disorder	Loading/sustained-release therapeutic molecules (cells, growth factors); promote cell adhesion/migration/proliferation; the introduction of conductive materials (nanoparticles) to improve electrical signal conduction	^{30–34,37,40,41,43}
Adhesion/integration strength	Sustained cardiac pulsation leads to patch displacement/shedding	Ensure that the hydrogel block formed after injection is firmly combined with the pulsating myocardium, prevent displacement and shedding, and ensure long-term efficacy and stability	^{30,36,38,39,41,44}
Electrical conductivity	The electrical insulation of infarction scars leads to conduction block and arrhythmia	Restore the electrical signal transduction in the infarct area, improve myocardial electrical synchronization, reduce the risk of arrhythmia, and promote electro-mechanical coupling	^38,40,43

MI, myocardial infarction.

FIG. 1.

Schematic representation of sodium alginate and composite hydrogel-mediated delivery of bioactive substances for myocardial infarction therapy.

SA hydrogel

As a nonimmunogenic, water-soluble linear polymer, SA is widely employed in biomedical applications, including drug delivery and wound healing, due to its biodegradability, injectability, and favorable safety profile.^45,46 Its excellent physicochemical and mechanical properties enable mechanical support to reduce cardiomyocyte apoptosis while promoting vascular regeneration and immune regulation, thereby establishing a reparative microenvironment for myocardial tissue. SA hydrogels can further be loaded with bioactive factors,⁴⁷ EVs,⁴⁸ nanomaterials,⁴⁹ and stem cells⁵⁰ to restore cardiac function. In summary, SA hydrogel serves as a safe and versatile therapeutic biomaterial with efficient drug-loading/release capabilities, while its injectability enhances patient comfort and treatment adherence.⁷

Loading of bioactive factors

MI is characterized by massive cardiomyocyte death, inflammation, and fibrotic scar formation, influencing cardiac function. Myocardial fibrosis, a common pathophysiological feature, involves excessive extracellular matrix (ECM) protein deposition, distorting myocardial structure and causing arrhythmias and dysfunction.^51,52 Various growth factors and cytokines, such as tumor necrosis factor-α (TNF-α), interleukin (IL-1), transforming growth factor-β (TGF-β), stromal cell-derived factor-1 (SDF-1), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF), are secreted via paracrine mechanisms, playing a role in myocardial fibrosis activation and cardiac function improvement.^30,53,54 Introducing appropriate bioactive factors is a promising MI treatment strategy. SA hydrogel, with good biocompatibility and ECM-like mechanical properties, serves as an excellent carrier for loading and releasing bioactive factors.

Insulin-like growth factor 1 (IGF-1), a key cytoprotective factor, enhances cardiac function by reducing postinfarction inflammation, increasing cardiomyocyte survival, and inhibiting apoptosis.^31,55 However, its clinical use is limited by its short half-life and low myocardial uptake efficiency. Feng et al. developed an injectable SA hydrogel incorporating IGF-1-loaded silk fibroin (SF) microspheres prepared via coaxial needle technology (Fig. 2a).⁵⁶ The hydrogel with 1.5% SA showed optimal proliferation-promoting and antihypoxia effects on H9C2 cardiomyocytes (CMs). Compared with the Gel/IGF-1 group, SF microspheres enabled sustained IGF-1 release for up to 28 days. Echocardiography revealed the Gel + SF/IGF-1 group had the highest left ventricular ejection fraction (LVEF) and cardiac function improvement. Hematoxylin and eosin and Masson trichrome staining indicated thicker walls and reduced fibrosis. Additionally, this group showed the lowest inflammatory factor expression (IL-6 and TNF-α), leading to smaller infarct sizes and significant cardiac function improvement 28 days postprocedure.

FIG. 2.

Schematic diagram of sodium alginate hydrogel loaded with bioactive factors for myocardial infarction treatment (a and b).^56,57

VEGF promotes endothelial cell proliferation and migration in the infarcted area, accelerating neointimal formation and early infarcted microenvironment improvement.⁵⁸ Bone morphogenetic protein 9 (BMP9), an endogenous myocardial fibrosis inhibitor, protects cardiac function long-term by suppressing TGF-β1 activity.⁵⁹ However, uncontrolled VEGF and BMP9 release limits their application. Wu et al. developed an injectable SA hydrogel loaded with VEGF and BMP9-containing SF microspheres for controlled release (Fig. 2b).⁵⁷ In vitro experiments showed VEGF achieved rapid initial release, while BMP9 released slowly and continuously. ELISA and immunohistochemical staining (α-SMA and CD31) indicated VEGF-containing groups (Gel + V and Gel + B/SF + V) had the highest vessel density, highlighting VEGF’s angiogenesis promotion. The Gel + B/SF + V group demonstrated the best antifibrotic effect in a mouse MI model with smaller infarct areas. In conclusion, SA hydrogels mediate bioactive factor release to promote early angiogenesis and long-term fibrosis suppression post-MI, demonstrating clinical potential. Future work should optimize controlled release kinetics for enhanced therapeutic efficacy.

Loading of EVs

Containing soluble proteins, mitochondrial DNA, mRNA, and noncoding RNAs, EVs play a pivotal role in reducing cardiomyocyte death, promoting vascular regeneration, and repairing myocardial tissue damage.^41,60 EVs can be divided into exosomes (30–150 nm), microvesicles (150–1000 nm), and apoptotic bodies (>1000 nm), with exosomes showing therapeutic potential due to low immunogenicity.⁶¹ EVs mainly mediate intercellular communication by modulating the downstream signaling pathway.^62,63 However, high intracardiac pressure impedes their retention, limiting therapeutic duration. Therefore, SA hydrogel, with its 3D network structure, water absorption, and biocompatibility, has been used as a carrier for EVs.

Stem cell-derived small EVs (sEVs) show antiapoptotic, proangiogenic, and immunomodulatory properties.⁶⁴ Lv et al. proposed loading sEVs from bone marrow mesenchymal stromal cells (MSCs) in SA hydrogel (sEVs-Gel) for MI therapy.³⁹ In vitro fluorescence imaging showed sEVs-Gel enhanced sEVs retention in the heart, reducing cardiomyocyte apoptosis and CD68+ macrophage numbers. CD31 and α-SMA staining showed higher vessel density in the sEVs-Gel group. Also, echocardiography and Masson trichrome staining revealed better cardiac function and neovascularization in the sEVs-Gel group (Fig. 2a). Thus, sEVs loaded in SA hydrogel prolonged their retention time and promoted angiogenesis, decreased cardiomyocyte apoptosis, inhibited myocardial fibrosis, enhanced scar thickness, and improved cardiac function.

Exosomes, the smallest EV subtype, have important roles in tissue repair, immunomodulation, and disease treatment due to their low immunogenicity and excellent biocompatibility.^65–67 Dendritic cell-derived exosomes (DEXs) improve myocardial function by activating CD4⁺ T cells but have a short in vivo half-life.⁶⁸ Zhang et al. constructed a DEXs-Gel delivery system by combining DEXs with SA hydrogel to prolong DEXs’ retention time.⁶⁹ Near-infrared fluorescence imaging showed DEXs-Gel achieved controlled release for 10–12 days. Echocardiography at 14 days postoperatively showed a significant increase in LVEF (69.76% ± 4.16%) and LVFS (34.97% ± 3.04%) in the DEXs-Gel group (Fig. 2b). Immunofluorescence staining showed DEXs reduced proinflammatory M1 macrophage (iNOS⁺) infiltration and increased anti-inflammatory M2 macrophage (CD206⁺) and Treg cell infiltration (Foxp3⁺). In summary, DEXs-Gel effectively improved postinfarction inflammation, cardiomyocyte apoptosis, and neovascularization by prolonging DEXs’ retention time. This study also revealed the potential mechanism of SA hydrogel delivering DEXs to activate Treg cells and regulate macrophage polarization to improve cardiac function.

Loading of nanoparticles

The hypoxic microenvironment in early MI features elevated ROS levels, substantially limiting cardiac repair/regeneration strategies.^70,71 This oxidative stress causes irreversible damage to CMs and vascular cells while activating signaling pathways that induce excessive inflammatory factor secretion via M1 macrophages, triggering severe inflammatory responses.^3,32 Nanomaterials, including metallic nanoparticles, carbon-based structures, and natural nanoparticles, offer tunable, biocompatible platforms exhibiting quantum size effects and high specific surface areas. These properties enable their application as drug delivery carriers that enhance therapeutic stability and facilitate targeted biodistribution.^72,73 Particularly, nanoparticles (NPs) demonstrate significant therapeutic potential through anti-inflammatory/antioxidant effects, promotion of neovascularization, and immune modulation. Therefore, integrating SA hydrogel with multifunctional NPs represents a synergistic strategy for MI therapy.

To address the irreversible damage to CMs and vascular cells caused by elevated ROS in hypoxic microenvironments, new strategies are needed to scavenge ROS, reduce oxidative stress in CMs, and promote macrophage polarization to an anti-inflammatory M2 phenotype, which is crucial for postinfarction repair.^33,71 Zhou et al. used melanin nanoparticles (MNPs) from squid ink and alginate (Alg) from seaweed to form a novel injectable hydrogel (MNPs/Alg) via Ca²⁺ crosslinking, exploring its effects on ROS scavenging and macrophage M2 polarization (Fig. 3a).⁷⁴ The MNPs/Alg hydrogel significantly improved CMs survival in vitro, increasing survival rates by about 30% even in 200 μM H₂O₂-induced oxidative stress. In a rat MI model, the hydrogel increased cardiac LVEF by approximately 20% and reduced infarct size from 54.3% to 20.7%. It also promoted gap junction formation, angiogenesis between CMs, and increased left ventricular (LV) wall thickness, thus improving cardiac remodeling and function. The hydrogel was also found to promote macrophage M2 polarization and attenuate inflammation by modulating the PI3k/Akt1/mTOR signaling pathway. However, the specific signaling pathways and mechanisms by which MNPs regulate macrophage polarization require further exploration. Additionally, future studies should investigate combining the MNPs/Alg hydrogel with other therapies, like stem cell or gene therapy, to enhance cardiac repair.

FIG. 3.

Schematic representation of the preparation and therapeutic mechanism of MNPs/Alg hydrogel in cardiac repair in vivo (a).⁷⁴ Schematic representation of the therapeutic role of fullerenol/sodium alginate hydrogel in cardiac repair (b).⁷⁵ Alg, alginate; MNPs, melanin nanoparticles.

Carbon-based nanoparticles also show good antioxidant properties for scavenging ROS in the infarcted microenvironment.⁷⁶ Unlike other carbon materials, fullerenol, as a fullerene derivative, has excellent water solubility, antioxidant properties, and low cytotoxicity. It can adsorb ROS to electron-deficient sites on its surface, alleviating oxidative stress in CMs.^77,78 Hao et al. prepared an injectable cell delivery vehicle with antioxidant activity by loading fullerenol nanoparticles into SA hydrogel (Fig. 3b).⁷⁵ The fullerenol/SA hydrogel demonstrated good injectability and mechanical strength and effectively scavenged superoxide anions (O₂⁻) and hydroxyl radicals (·OH). In vitro, it significantly improved the survival and differentiation of brown adipose-derived stem cells (BADSCs) under oxidative stress, with a survival rate of 43.6% versus 1.6% in the control group, and 27.2% of BADSCs still survived four weeks postprocedure. Furthermore, the fullerenol/SA hydrogel group showed significant cardiac function improvement, with LVEF and LVFS higher than other groups (LVEF: 48.3% vs. 32.6%, LVFS: 32.5% vs. 20.1%). In summary, recent studies present a novel antioxidant SA hydrogel with excellent biocompatibility. By modulating the infarcted microenvironment, enhancing stem cell survival, and promoting cardiomyocyte differentiation, this system offers a promising approach for injectable cell delivery in MI treatment.

Bioglass/SA hydrogel

Composed of SiO₂, Na₂O, P₂O₅, and CaO, bioactive glass (BG) is a multifunctional inorganic material with good biocompatibility and biodegradability, with its applications in proangiogenesis, immunomodulation, and regenerating muscle, cartilage, and gastrointestinal tissues increasing.^79–81 In addition, BG ions can downregulate proinflammatory cytokines (e.g., IL-6, TNF-α) and upregulate anti-inflammatory ones (e.g., TGF-β, VEGF) in LPS-stimulated macrophages.^34,82 The SA network serves as a physical barrier, delaying BG dissolution to enable sustained, tunable release of therapeutic ions. Concurrently, Ca²⁺ released from BG maintains the alginate’s cross-linked structure. This self-sustaining synergy establishes the SA-BG composite hydrogel as a promising strategy for continuous myocardial repair.

Cardiac blood flow reestablishment is vital for postinfarction regeneration, since increased local blood flow improves cardiac function.⁸³ VEGF and bFGF, key angiogenic proteins, drive endothelial and smooth muscle cell proliferation, migration, and angiogenesis.^42,84 Qi et al. developed an injectable BG-SA composite hydrogel by mixing BG and SA to promote angiogenesis and improve cardiac function (Fig. 4a).⁸⁵ In vitro, 20 μg/mL BG-SA showed good biocompatibility with H9C2 cells. It increased vascular density to 65.52 ± 1.46/mm² compared with 36.26 ± 3.45/mm² (saline), 38.10 ± 3.87/mm² (SA), and 39.80 ± 3.43/mm² (BG-S groups) by upregulating VEGF and bFGF. Echocardiography confirmed that BG-SA improved cardiac function by reducing infarct area and maintaining wall thickness. This study first proposes BG-SA hydrogel as a minimally invasive, in situ treatment for MI, though future research should focus on improving its biodegradability and tissue permeability.

FIG. 4.

Schematic representation of the preparation and therapeutic effect of BG/SA hydrogel in in vivo cardiac repair (a).⁸⁵ Schematic representation of SA hydrogel grafted with deferoxamine for modulating SA/BG hydrogel degradation and its mechanism of action in wound repair (b).⁸⁶ BG, bioactive glass; SA, sodium alginate.

Traditional hydrogels limit the penetration of cells and new tissues due to the limitation of nanopore size, which hinders tissue regeneration. To overcome this, studies aim to develop hydrogels with macroporous structures or controlled degradation.^87,88 Zhang et al. prepared a novel G-DFO-SA/BG hydrogel by grafting deferoxamine (DFO) onto SA to modulate degradation properties (Fig. 4b).⁸⁶ In vitro, G-DFO-SA/BG showed faster mass loss and structural disintegration than SA/BG. In vivo, it degraded faster, with complete degradation by day 14, compared with SA/BG’s significant degradation starting on day 14. G-DFO-SA/BG also accelerated wound healing, reaching a 99% healing rate on day 14 versus 96% for SA/BG. This study developed a G-DFO-SA/BG hydrogel with rapid degradation and good tissue permeability, whose degradation can be regulated by DFO grafting, showing potential for promoting angiogenesis in myocardial repair. This study developed G-DFO-SA/BG, a novel hydrogel featuring rapid degradation and enhanced tissue permeability. The hydrogel demonstrated significant tissue repair/regeneration capabilities, highlighting its therapeutic potential for promoting angiogenesis in MI repair, warranting further validation.

Chitosan/SA hydrogel

Chitosan (CS), a deacetylated derivative of chitin, is a linear polysaccharide with abundant amine (-NH₂) and hydroxyl (-OH) groups that forms hydrogels with good biocompatibility and mechanical properties.^35,89 CS hydrogels can activate the PI3K/Akt signaling pathway and upregulate the expression of VEGF to promote myocardial regeneration and neovascularization while inhibiting oxidative stress and inflammation.^90,91 Nevertheless, polysaccharide hydrogels formed via Schiff base reaction between CS and SA show promise in drug delivery, wound healing, and myocardial tissue engineering due to their excellent mechanical properties, biocompatibility, and biodegradability.^36,92

Postinfarction LV remodeling is usually caused by inflammation and MMP upregulation. Deng et al. developed a temperature-responsive injectable CS/SA hydrogel to prevent LV remodeling and improve cardiac function.⁹³ In rats injected with the hydrogel, cardiac function improved significantly, with reduced infarct dilatation, fibrosis, and increased scar tissue thickness (0.6 mm) compared with CS (0.33 mm) and SA (0.48 mm) groups. The hydrogel also promoted angiogenesis (vessel density 60% ± 3.2/mm²) and reduced CMs apoptosis (25% ± 1.2%) compared with SA (39% ± 1.4%) and CS (48 ± 2.1%) groups. At 4 weeks posttreatment, LVEF in the CS/SA group was 40.53% ± 4.65%, higher than CS (34.42% ± 3.88%) and PBS (24.84% ± 2.64%) groups. This demonstrates the hydrogel’s potential in reducing LV remodeling and lowering heart failure risk.

Additionally, the ECM is composed of collagen, elastin, and proteoglycans, is crucial for cardiac support, structure, function, and tissue regeneration. After decellularization, ECM-based biomaterials offer low immunogenicity and good biocompatibility.^94,95 Tamimi et al. created high-porosity (>96%) hydrogel scaffolds by mixing decellularized bovine myocardial ECM with CS and SA.⁹⁶ The 75:25 ECM/CS/SA ratio (E75/P25) showed superior mechanical properties (tensile strength >200 kPa vs. pure ECM’s 49.6 kPa) and cell proliferation. It also promoted human bone marrow mesenchymal stem cells (hMSCs) proliferation and cardiomyocyte differentiation, with immunofluorescence showing higher cardiac troponin-T (cTnT) expression (55.5% ± 7.38%) than pure ECM (24% ± 7.17%). This ternary scaffold material shows great potential for CTE due to its biocompatibility, mechanical properties, and pore structure, which facilitate cardiac cell regeneration/repair. This ECM-SA-based ternary scaffold exhibits biocompatibility, suitable mechanical properties, and pore structure conducive to myocardial regeneration, demonstrating promise for CTE.

Hyaluronic acid/SA hydrogel

Hyaluronic acid (HA) is a naturally occurring linear polysaccharide that is widely found in human connective tissue and is biocompatible, biodegradable, and moisturizing.⁹⁷ HA received attention in the treatment of inflammatory diseases and tissue regeneration applications as a key ingredient in the modulation of inflammatory responses.³⁷ The HA/SA composite hydrogel, combining HA and SA, provides an excellent microenvironment for CMs and improves cell survival in infarcted areas, thereby alleviating postinfarction ventricular remodeling and restoring cardiac function.^98,99 This hydrogel’s 3D network can load slow-release growth factors, nanomaterials, and stem cells to enhance therapeutic effects in infarcted regions.

Platelet-rich fibrin (PRF) is a second-generation platelet concentrate that is widely used for angiogenesis and tissue repair because of its safety profile and ability to release growth factors.^43,100 Qian et al. created a novel injectable composite hydrogel by freeze-drying PRF to obtain lyophilized platelet-rich fibrin (Ly-PRF) and combining it with ALG-HA.¹⁰¹ In vitro, the alginate (ALG) hydrogel with 20% HA showed the best mechanical properties. Ly-PRF released growth factors like PDGF-AA more effectively and sustainably (21 days) in the ALG-HA hydrogel than the platelet-rich plasma (PRP) group, with a total release of 10638.55 ± 1577.43 pg/mL compared with 7940.06 ± 910.28 pg/mL in the PRP group. In vivo, rats injected with ALG-HA (Ly-PRF) hydrogel showed a significant increase in LVEF (43.51 ± 2.48%) after 4 weeks, compared with the MI group (24.86 ± 2.82%) and ALG-HA group (34.30 ± 2.46%). This study proposes a new, effective, and safe MI treatment strategy by combining Ly-PRF with ALG-HA hydrogel, achieving sustained growth factor release and promoting neovascularization and myocardial repair (Fig. 5a). It also reveals Ly-PRF’s potential in regulating inflammatory responses and myocardial fibrosis, providing a theoretical basis for future clinical applications.

FIG. 5.

Schematic diagram of the preparation process of composite hydrogel and their use in MI treatment (a).¹⁰¹ Schematic diagram of the synthesis of multifunctional ALG-HA-BP-PDA hydrogel and their use in MI (b).¹⁰²

Black phosphine nanosheets (BPNs) are novel two-dimensional nanomaterials with excellent stability and biocompatibility that control oxidative stress and inflammation by scavenging free radicals.^103,104 Guo et al. prepared an ALG-HA-BP-PDA hydrogel by loading polydopamine-modified BPNs into ALG-HA to inhibit the oxidative stress-inflammatory chain in MI (Fig. 5b).¹⁰² The hydrogel showed good biocompatibility and electrical conductivity (about 0.085 S/m) without negatively affecting H9C2 CMs’ survival and function. It significantly reduced ROS levels, with 2,2-diphenyl-1-picrylhydrazyl radical and -OH scavenging rates of 81% and 89.6%, respectively. Compared with the MI group, ALG-HA-BP-PDA-treated rats showed a smaller infarct area (reduced by about 40%) and higher LVEF values (increased from 24.86% to 43.51%). The hydrogel reduced TNF-α and iNOS expression mainly by inhibiting the NF-κB signaling pathway and increasing M2-type macrophages, alleviating the inflammatory response. Although HA alone cannot form robust hydrogels via ionic crosslinking, its combination with SA creates a supportive primary network where HA undergoes physical entanglement and mild covalent crosslinking. The resulting ALG-HA-BP-PDA hydrogel demonstrated therapeutic efficacy by effectively scavenging ROS, suppressing inflammation and CMs apoptosis, significantly inhibiting LV remodeling, and improving cardiac function.

Gelatin/SA hydrogel

Gelatin hydrogel (GH), a biodegradable and water-soluble polymer derived from hydrolyzed collagen, exhibits excellent biocompatibility, promotes cell adhesion/proliferation, and maintains high cell retention/viability. It serves as an effective delivery platform for transplanted cells such as CMs,¹⁰⁵ MSCs,¹⁰⁶ and ADSCs.¹⁰⁷ It can provide mechanical support to the heart after infarction and promote infarct healing through anti-inflammatory, antioxidant stress, and angiogenesis-promoting properties.⁸⁶ Further studies have shown that GH hydrogels can be used to transport stem cells, organs, and nanoparticles.^5,108 Moreover, combining Gel with SA forms a thermally stable gel network at physiological temperatures, resolving gelatin’s inherent melting and structural collapse issues. This synergy grants the GH/SA composite hydrogel significant advantages for myocardial repair applications.

Mitochondria regulate cell function, scavenge ROS to rescue macrophages, promote the expression of anti-inflammatory and tissue repair factors, and promote the proliferation and activation of myofibroblasts in the infarcted area.^38,109 Hassanpour et al. assessed MSC-derived mitochondria encapsulated in PPy-rich Alg/Gel conductive hydrogel’s therapeutic effect in a rat MI model.¹¹⁰ The Alg/Gel + PPy hydrogel (87.67% ± 0.57% porosity) was more porous than the Alg + PPy group (83.33% ± 1.52%), preserving mitochondrial integrity. Compared with the MI group, the mitochondria-loaded Alg/Gel + PPy hydrogel group showed increased LV wall thickness and more vWF⁺ capillaries and α-SMA⁺ small arteries, indicating proangiogenic and antifibrotic effects. This implies the hydrogel promotes CMs survival/recovery and improves the infarcted area’s microenvironment via neovascularization. Future studies should explore how mitochondria function in CMs and develop advanced delivery platforms for better tissue repair.

In MI, the death of CMs and the deposition of collagen fiber can interfere with the transmission of electrical signals in the myocardium, leading to cardiac dysfunction and arrhythmias. To address this, hydrogels must support the growth of CMs and be electrically conductive.^111,112 Pournemati et al. developed a novel hydrogel with good electrical conductivity and biocompatibility by incorporating gold nanoparticles (AuNPs) into Alg/Gel hydrogel.⁴⁴ The Alg/Gel + AuNPs composite hydrogel had a porous network structure and electrical conductivity of 2.04 × 10⁻⁴ S/cm, much higher than Alg/Gel hydrogel’s 2.38 × 10⁻⁸ S/cm. Methylthiazolyldiphenyl-tetrazolium bromide experiments showed it had no significant toxicity to embryonic mouse CMs and improved cTnT and Cx43 expression. Moreover, Alg/Gel + AuNPs hydrogel encapsulating mECCs significantly increased cell survival in the infarcted area and improved cardiac function while reducing infarcted and fibrotic areas 30 days postoperation. This study presents an injectable hydrogel based on SA and gelatin, enhanced with AuNPs for improved conductivity and biocompatibility, for postinfarction mECCs transplantation and myocardial repair, demonstrating the potential of nanoparticle-loaded composite hydrogels for myocardial repair. These findings demonstrate the significant potential of nanoparticle-loaded GH/SA hydrogels in cardiac regeneration. Future work should establish multifunctional delivery platforms with expanded tissue repair capabilities and broader disease applicability.

Conclusions

SA-based hydrogels exhibit a unique combination of mechanical robustness, exceptional biocompatibility, high hydration capacity, and inherent anti-inflammatory and antioxidant properties, which collectively enhance the therapeutic efficacy for MI. These advanced materials have demonstrated remarkable potential in improving cardiac function by increasing scar thickness, promoting angiogenesis, modulating oxidative stress and immune responses, and inhibiting apoptosis and myocardial fibrosis (Table 2). The injectable nature of SA hydrogels further enables minimally invasive delivery and precise targeting of the infarcted region, providing significant advantages in clinical applications.

Table 2.

Sodium Alginate and Its Composite Hydrogel in the Treatment of Myocardial Infarction

Components	Ingredients	Action mechanism	Therapeutic outcome	Ref.
Alginate and gelatin	BIO and IGF-1	The corelease of BIO and IGF-1 promotes cardiomyocyte proliferation and angiogenesis	Proliferation of cardiomyocytes and blood vessels was promoted, LVEF, FS, LVSD, and LVDD were improved	⁷
Sodium alginate and collagen	EVs	Hydrogel encapsulates and releases EVs	Increase EVs retention rate, reduce infarct size, and improve cardiac function	²⁸
Sodium alginate	ZIF-8	Clear ROS, promote macrophage M2 phenotype polarization, and reduce inflammatory response	Reduce cardiomyocyte apoptosis, promote angiogenesis, and improve cardiac function	²⁹
Sodium alginate and collagen type I	hUC-MSCs	The hydrogel improved the cell retention rate and survival rate of hUC-MSCs, and promoted the secretion and release of growth factors and anti-inflammatory factors	Accelerate wound closure, promote tissue remodeling, enhance angiogenesis, and reduce inflammatory response	⁴⁵
Sodium alginate	SF microspheres containing IGF-1	The sustained release of IGF-1 promotes cardiomyocyte survival and reduces apoptosis, and improves the local microenvironment in the infarcted area	Reduce infarct size, improve cardiac function, and promote tissue repair and regeneration after myocardial infarction	³⁰
Sodium alginate	SF microspheres containing VEGF and BMP9	The hydrogel rapidly releases VEGF to promote angiogenesis and continuously releases BMP9 to inhibit myocardial fibrosis	Reduce infarct size, promote angiogenesis, and inhibit myocardial fibrosis	³¹
Sodium alginate	sEVs	Slow release of sEVs exerts antiapoptotic, proangiogenic and anti-inflammatory effects	Reduce cardiomyocyte apoptosis, increase angiogenesis, and improve cardiac function	⁴¹
Sodium alginate	DEXs	The sustained release of DEXs activates Treg cells and promotes M2 transformation of macrophages	Increase the retention rate of DEXs and angiogenesis, reduce the infarct size, and improve cardiac function	³⁹
Sodium alginate	MNPs	Scavenging ROS, activating PI3k/Akt1/mTOR signaling pathway, and promoting macrophage M2 transformation	The survival rate of cardiomyocytes was increased, the infarct size was decreased, and the thickness of left ventricular wall was increased	³²
Sodium alginate	Fullerenol	Scavenge superoxide anion and hydroxyl radical, inhibit oxidative stress damage of BADSCs	The survival rate of BADSCs was increased, the infarct size was reduced, and LVEF and LVFS were significantly increased	³³
Bioglass and sodium alginate	BG	Release of Ca, Si, and P ions, upregulation of VEGF and bFGF expression stimulated angiogenesis and inhibited cardiomyocyte apoptosis	Cardiac function was improved, LVEF and LVFS were increased, infarct size was decreased, and angiogenesis in infarct area was increased	³⁴
Sodium alginate and bioglass	DFO	Release of Ca, Si, and P ions, upregulation of VEGF expression, promote neovascularization and guide tissue regeneration	Accelerate wound healing, improve tissue penetration, and enhance angiogenesis	⁴²
Alginate and chitosan	Chitosan	Provide mechanical support, promote angiogenesis, reduce inflammation, and reduce cardiomyocyte apoptosis	Reduce infarct size, increase scar thickness, enhance the recruitment of endogenous repair cells, and improve cardiac function	³⁵
ECM/chitosan/alginate	ECM and chitosan	Promote cell proliferation and expression of myocardial markers	Significantly enhance cardiomyocyte proliferation and improve cardiac function	³⁶
Alginate and hyaluronic acid	Ly-PRF	Hydrogel provides mechanical support, and Ly-PRF releases growth factors to promote angiogenesis and reduce cardiomyocyte apoptosis	Improve cardiac function, reduce infarct size, enhance angiogenesis, and inhibit myocardial fibrosis	³⁷
Aginate and hyaluronic acid	PDA-modified BPNs	Provide mechanical support, remove ROS, inhibit NF-κB signaling pathway, promote angiogenesis, and improve mitochondrial function	Reduces infarct size, reduces cardiomyocyte apoptosis, promotes angiogenesis, and improves cardiac function	⁴³
Alginate and gelatin	PPy	The hydrogel provides mechanical support and drug release, and the loaded mitochondria produce ATP, neutralize ROS, and promote angiogenesis	Improve cardiac function, increase infarct wall thickness, reduce fibrosis, and promote angiogenesis	⁴⁰
Alginate/gelatin hydrogel	AuNPs	Support the growth of myocardial cells and enhance the transmission of electrical signals between tissues	Increase the expression of α-SMA and cTnT, reduce the infarct size and fibrosis area	³⁸

ATP, Adenosine triphosphate; AuNPs, gold nanoparticles; BADSCs, brown adipose-derived stem cells; BIO, 6-Bromoindirubin-3-oxime; BG, bioactive glass; DEXs, dendritic cell-derived exosomes; DFO, deferoxamine; ECM, extracellular matrix; EVs, extracellular vesicles; hUC, Human umbilical cord; IGF-1, insulin-like growth factor 1; LVDD, Left ventricular end-diastolic diameter; LVEF, Left ventricular ejection fraction; Ly-PRF, Lyophilized platelet-rich fibrin; MNPs, melanin nanoparticles; MSCs, mesenchymal stromal cells; PDA, Polydopamine; ROS, Reactive oxygen species; sEVs, small EVs; SF, silk fibroin; VEGF, vascular endothelial growth factor; ZIF, Zeolitic Imidazolate Framework.

The field of cardiac repair and regeneration is continuously evolving, and SA hydrogels have emerged as a promising solution to address the limitations of conventional therapies. However, several challenges remain to be addressed to fully harness their potential. These include the need for more precise control over the mechanical strength and degradation kinetics of the hydrogels to match the dynamic environment of the myocardium. Additionally, the development of multifunctional delivery platforms capable of spatiotemporal control and sustained release of multiple bioactive substances is critical to achieve coordinated improvements in mechanical properties, electrical conductivity, angiogenesis, and immunomodulation.

Future research should focus on optimizing material compositions and structure–property relationships to enhance the robustness, tunable degradation profiles, and biocompatibility of these hydrogels. Furthermore, rigorous clinical efficacy validation, mechanistic elucidation, and the establishment of standardized protocols are essential to ensure the safe and effective translation of these therapies into clinical practice. Addressing these challenges will not only accelerate the adoption of SA hydrogels as viable clinical therapeutics for MI but also pave the way for broader applications in cardiovascular and other regenerative medicine fields.

Authors’ Contributions

Z.C.: Conceptualization; writing, reviewing, and editing—original draft; and visualization. X.L. and E.Z.: Conceptualization, writing, reviewing, and supervision. J.L. and C.Z.: Writing, reviewing, and editing—original draft.

Footnotes

Author Disclosure Statement

The authors declare no competing interests.

Funding Information

This work was supported by Tianjin Municipal Science and Technology Commission Grant, No. 24ZXRKSY00010; and Program for Innovative Research Team in Peking Union Medical College, CAMS Initiative for Innovative Medicine, Nos. 2022-I2M-1-023, 2023-I2M-2-008, and 2021-I2M-1-065.

References

Zhang

, Wang

, et al. Signaling pathways and targeted therapy for myocardial infarction. Signal Transduct Target Ther, 2022; 7(1):78; doi: 10.1038/s41392-022-00925-z

Zhang

, Guo

, Bai

, et al. Application of biomedical materials in the diagnosis and treatment of myocardial infarction. J Nanobiotechnology, 2023; 21(1):298; doi: 10.1186/s12951-023-02063-2

Zhang

, Bei

, Li

, et al. An injectable conductive hydrogel with dual responsive release of rosmarinic acid improves cardiac function and promotes repair after myocardial infarction. Bioact Mater, 2023; 29:132–150; doi: 10.1016/j.bioactmat.2023.07.007

Sampaio‐Pinto

, Janssen

, Chirico

, et al. A roadmap to cardiac tissue‐engineered construct preservation: Insights from cells, tissues, and organs. Adv Mater, 2021; 33(27):e2008517; doi: 10.1002/adma.202008517

Zhu

, Yu

, Liu

, et al. Injectable conductive gelatin methacrylate/oxidized dextran hydrogel encapsulating umbilical cord mesenchymal stem cells for myocardial infarction treatment. Bioact Mater, 2022; 13:119–134; doi: 10.1016/j.bioactmat.2021.11.011

Ding

, Ding

, Liu

, et al. Mesenchymal stem cells encapsulated in a reactive oxygen species-scavenging and O₂-generating injectable hydrogel for myocardial infarction treatment. Chem Eng J, 2022; 433:133511; doi: 10.1016/j.cej.2021.133511

Zheng

, Tan

, Li

, et al. Biotherapeutic-loaded injectable hydrogel as a synergistic strategy to support myocardial repair after myocardial infarction. J Control Release, 2021; 335:216–236; doi: 10.1016/j.jconrel.2021.05.023

Deng

, Hua

, Gao

, et al. Thermosensitive hydrogel with programmable, self‐regulated HIF‐1α stabilizer release for myocardial infarction treatment. Adv Sci (Weinh), 2024; 11(43):e2408013; doi: 10.1002/advs.202408013

Zhang

, Gao

, Wang

, et al. Bioenergetic metabolism modulatory peptide hydrogel for cardiac protection and repair after myocardial infarction. Adv Funct Materials, 2024; 34(24):2312772; doi: 10.1002/adfm.202312772

10.

Yoshizumi

, Zhu

, Jiang

, et al. Timing effect of intramyocardial hydrogel injection for positively impacting left ventricular remodeling after myocardial infarction. Biomater, 2016; 83:182–193; doi: 10.1016/j.biomaterials.2015.12.002

11.

Matsumura

, Zhu

, Jiang

, et al. Intramyocardial injection of a fully synthetic hydrogel attenuates left ventricular remodeling post myocardial infarction. Biomater, 2019; 217:119289; doi: 10.1016/j.biomaterials.2019.119289

12.

Zheng

, Lei

, Liu

, et al. A ROS‐Responsive liposomal composite hydrogel integrating improved mitochondrial function and pro‐angiogenesis for efficient treatment of myocardial infarction. Adv Healthcare Materials, 2022; 11(19):2200990; doi: 10.1002/adhm.202200990

13.

, Liu

. Functional hydrogel for the treatment of myocardial infarction. NPG Asia Mater, 2022; 14(1):9; doi: 10.1038/s41427-021-00330-y

14.

Chen

, Wang

, Liu

, et al. A matrix‐metalloproteinase‐responsive hydrogel system for modulating the immune microenvironment in myocardial infarction. Adv Mater, 2023; 35(13):e2209041; doi: 10.1002/adma.202209041

15.

Allen

, Hindley

, Baxani

, et al. Hydrogel as functional components in artificial cell systems. Nat Rev Chem, 2022; 6(8):562–578; doi: 10.1038/s41570-022-00404-7

16.

Catoira

, Fusaro

, Di Francesco

, et al. Overview of natural hydrogel for regenerative medicine applications. J Mater Sci: Mater Med, 2019; 30(10); doi: 10.1007/s10856-019-6318-71

17.

, Hu

, Wang

, et al. The role of hydrogel in cardiac repair and regeneration for myocardial infarction: Recent advances and future perspectives. Bioengineering (Basel), 2023; 10(2):165; doi: 10.3390/bioengineering10020165

18.

Rakshit

, Giri

, Mukherjee

. Progresses and perspectives on natural polysaccharide based hydrogel for repair of infarcted myocardium. Int J Biol Macromol, 2024; 269(Pt 2):132213; doi: 10.1016/j.ijbiomac.2024.132213

19.

Zheng

, Zuo

. Functional silk fibroin hydrogel: Preparation, properties and applications. J Mater Chem B, 2021; 9(5):1238–1258; doi: 10.1039/D0TB02099K

20.

Bao

, Xian

, Yuan

, et al. Natural polymer‐based hydrogel with enhanced mechanical performances: Preparation, structure, and property. Adv Healthcare Mater, 2019; 8(17):1900670; doi: 10.1002/adhm.201900670

21.

Wei

, Zhou

, An

, et al. Modification, 3D printing process and application of sodium alginate based hydrogel in soft tissue engineering: A review. Int J Biol Macromol, 2023; 232:123450; doi: 10.1016/j.ijbiomac.2023.123450

22.

Zhang

, Qian

, Deng

, et al. 3D printed double-network alginate hydrogel containing polyphosphate for bioenergetics and bone regeneration. Int J Biol Macromol, 2021; 188:639–648; doi: 10.1016/j.ijbiomac.2021.08.066

23.

Mallakpour

, Azadi

, Hussain

. State-of-the-art of 3D printing technology of alginate-based hydrogel—An emerging technique for industrial applications. Adv Colloid Interface Sci, 2021; 293:102436; doi: 10.1016/j.cis.2021.102436

24.

Mousavi

, Mashayekhan

, Baheiraei

, et al. Biohybrid oxidized alginate/myocardial extracellular matrix injectable hydrogels with improved electromechanical properties for cardiac tissue engineering. Int J Biol Macromol, 2021; 180:692–708; doi: 10.1016/j.ijbiomac.2021.03.097

25.

Chen

, Zhu

, Wang

, et al. Insight into heart-tailored architectures of hydrogel to restore cardiac functions after myocardial infarction. Mol Pharm, 2023; 20(1):57–81; doi: 10.1021/acs.molpharmaceut.2c00650

26.

Zhao

, Chen

, Qin

, et al. Adhesive and conductive hydrogels for the treatment of myocardial infarction. Macromol Rapid Commun, 2025; 46(5):e2400835; doi: 10.1002/marc.202400835

27.

Liu

, Li

, Bao

, et al. Pericardial delivery of sodium alginate-infusible extracellular matrix composite hydrogel promotes angiogenesis and intercellular electrical conduction after myocardial infarction. ACS Appl Mater Interfaces, 2024; 16(34):44623–44635; doi: 10.1021/acsami.4c12593

28.

Curley

, Dolan

, Otten

, et al. An injectable alginate/extra cellular matrix (ECM) hydrogel towards acellular treatment of heart failure. Drug Deliv Transl Res, 2019; 9(1):1–13; doi: 10.1007/s13346-018-00601-2

29.

Zhang

, Shao

, Li

, et al. Annexin A1-loaded alginate hydrogel promotes cardiac repair via modulation of macrophage phenotypes after myocardial infarction. ACS Biomater Sci Eng, 2024; 10(5):3232–3241; doi: 10.1021/acsbiomaterials.4c00146

30.

Liberale

, Ministrini

, Carbone

, et al. Cytokines as therapeutic targets for cardio-and cerebrovascular diseases. Basic Res Cardiol, 2021; 116(1):23; doi: 10.1007/s00395-021-00863-x

31.

Troncoso

, Ibarra

, Vicencio

, et al. New insights into IGF-1 signaling in the heart. Trends Endocrinol Metab, 2014; 25(3):128–137; doi: 10.1016/j.tem.2013.12.002

32.

Xiong

, Wang

, Guan

, et al. A vascularized conductive elastic patch for the repair of infarcted myocardium through functional vascular anastomoses and electrical integration. Adv Funct Materials, 2022; 32(19):2111273; doi: 10.1002/adfm.202111273

33.

Liao

, Song

, Li

, et al. An injectable co-assembled hydrogel blocks reactive oxygen species and inflammation cycle resisting myocardial ischemia-reperfusion injury. Acta Biomater, 2022; 149:82–95; doi: 10.1016/j.actbio.2022.06.039

34.

Zhu

, Ma

, Kong

, et al. Modulation of macrophages by bioactive glass/sodium alginate hydrogel is crucial in skin regeneration enhancement. Biomater, 2020; 256:120216; doi: 10.1016/j.biomaterials.2020.120216

35.

, Li

, Wang

, et al. An injectable chitosan/dextran/β-glycerophosphate hydrogel as cell delivery carrier for therapy of myocardial infarction. Carbohydr Polym, 2020; 229:115516; doi: 10.1016/j.carbpol.2019.115516

36.

You

, Xie

, Jiang

. Injectable and biocompatible chitosan-alginic acid hydrogel. Biomed Mater, 2019; 14(2):025010; doi: 10.1088/1748-605X/aaff3d

37.

Marinho

, Nunes

, Reis

. Hyaluronic acid: A key ingredient in the therapy of inflammation. Biomolecules, 2021; 11(10):1518; doi: 10.3390/biom11101518

38.

Ramachandra

CJA

, Hernandez-Resendiz

, Crespo-Avilan

, et al. Mitochondria in acute myocardial infarction and cardioprotection. EBioMedicine, 2020; 57:102884; doi: 10.1016/j.ebiom.2020.102884

39.

, Li

, Zhang

, et al. Incorporation of small extracellular vesicles in sodium alginate hydrogel as a novel therapeutic strategy for myocardial infarction. Theranostics, 2019; 9(24):7403–7416; doi: 10.7150/thno.32637

40.

Wang

, Zhang

, Liu

, et al. A physically cross-linked sodium alginate–gelatin hydrogel with high mechanical strength. ACS Appl Polym Mater, 2021; 3(6):3197–3205; doi: 10.1021/acsapm.1c00404

41.

, Wang

, Tan

WLW

, et al. Extracellular vesicles from human embryonic stem cell-derived cardiovascular progenitor cells promote cardiac infarct healing through reducing cardiomyocyte death and promoting angiogenesis. Cell Death Dis, 2020; 11(5):354; doi: 10.1038/s41419-020-2508-y

42.

Lee

, Peters

, Mooney

. Comparison of vascular endothelial growth factor and basic fibroblast growth factor on angiogenesis in SCID mice. J Control Release, 2003; 87(1–3):49–56; doi: 10.1016/S0168-3659(02)00349-8

43.

Miron

, Fujioka-Kobayashi

, Bishara

, et al. Platelet-rich fibrin and soft tissue wound healing: A systematic review. Tissue Eng Part B Rev, 2017; 23(1):83–99; doi: 10.1089/ten.teb.2016.0233

44.

Pournemati

, Tabesh

, Mehdinavaz Aghdam

, et al. An Alginate/Gelatin injectable hydrogel containing au nanoparticles for transplantation of embryonic mouse cardiomyocytes in myocardial repair. Macromol Biosci, 2025; 25(2):e2400301; doi: 10.1002/mabi.202400301

45.

Ahmad

, Mubarak

, Jannat

, et al. A critical review on the synthesis of natural sodium alginate based composite materials: An innovative biological polymer for biomedical delivery applications. Processes, 2021; 9(1):137; doi: 10.3390/pr9010137

46.

Abourehab

MAS

, Rajendran

, Singh

, et al. Alginate as a promising biopolymer in drug delivery and wound healing: A review of the state-of-the-art. Int J Mol Sci, 2022; 23(16):9035; doi: 10.3390/ijms23169035

47.

Fang

, Qiao

, Liu

, et al. Sustained co-delivery of BIO and IGF-1 by a novel hybrid hydrogel system to stimulate endogenous cardiac repair in myocardial infarcted rat hearts. Int J Nanomedicine, 2015; 10:4691–4703; doi: 10.2147/IJN.S81451

48.

Gil-Cabrerizo

, Saludas

, Prósper

, et al. Development of an injectable alginate-collagen hydrogel for cardiac delivery of extracellular vesicles. Int J Pharm, 2022; 629:122356; doi: 10.1016/j.ijpharm.2022.122356

49.

Zhong

, Yang

, Xu

, et al. Design of a Zn-based nanozyme injectable multifunctional hydrogel with ROS scavenging activity for myocardial infarction therapy. Acta Biomater, 2024; 177:62–76; doi: 10.1016/j.actbio.2024.01.015

50.

Zhang

, Li

, et al. Sodium alginate/collagen hydrogel loaded with human umbilical cord mesenchymal stem cells promotes wound healing and skin remodeling. Cell Tissue Res, 2021; 383(2):809–821; doi: 10.1007/s00441-020-03321-7

51.

, Zhao

, Kong

. Extracellular matrix remodeling and cardiac fibrosis. Matrix Biol, 2018; 68–69:490–506; doi: 10.1016/j.matbio.2018.01.013

52.

Frangogiannis

. The extracellular matrix in myocardial injury, repair, and remodeling. J Clin Invest, 2017; 127(5):1600–1612; doi: 10.1172/JCI87491

53.

Frangogiannis

. Cardiac fibrosis: Cell biological mechanisms, molecular pathways and therapeutic opportunities. Mol Aspects Med, 2019; 65:70–99; doi: 10.1016/j.mam.2018.07.001

54.

Frangogiannis

. Cardiac fibrosis. Cardiovasc Res, 2021; 117(6):1450–1488; doi: 10.1093/cvr/cvaa324

55.

Higashi

, Gautam

, Delafontaine

, et al. IGF-1 and cardiovascular disease. Growth Horm IGF Res, 2019; 45:6–16; doi: 10.1016/j.ghir.2019.01.002

56.

Feng

, Wu

, Chen

, et al. Sustained release of bioactive IGF-1 from a silk fibroin microsphere-based injectable alginate hydrogel for the treatment of myocardial infarction. J Mater Chem B, 2020; 8(2):308–315; doi: 10.1039/C9TB01971E

57.

, Chang

, Chen

, et al. Release of VEGF and BMP9 from injectable alginate based composite hydrogel for treatment of myocardial infarction. Bioact Mater, 2021; 6(2):520–528; doi: 10.1016/j.bioactmat.2020.08.031

58.

Braile

, Marcella

, Cristinziano

, et al. VEGF-A in cardiomyocytes and heart diseases. Int J Mol Sci, 2020; 21(15):5294; doi: 10.3390/ijms21155294

59.

Morine

, Qiao

, York

, et al. Bone morphogenetic protein 9 reduces cardiac fibrosis and improves cardiac function in heart failure. Circulation, 2018; 138(5):513–526; doi: 10.1161/CIRCULATIONAHA.117.031635

60.

Barile

, Lionetti

, Cervio

, et al. Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction. Cardiovasc Res, 2014; 103(4):530–541; doi: 10.1093/cvr/cvu167

61.

, Zhang

, Li

, et al. Extracellular vesicles in cardiovascular diseases. Cell Death Discov, 2020; 6(1):68; doi: 10.1038/s41420-020-00305-y

62.

Kervadec

, Bellamy

, El Harane

, et al. Cardiovascular progenitor–derived extracellular vesicles recapitulate the beneficial effects of their parent cells in the treatment of chronic heart failure. J Heart Lung Transplant, 2016; 35(6):795–807; doi: 10.1016/j.healun.2016.01.013

63.

Gabisonia

, Khan

, Recchia

. Extracellular vesicle-mediated bidirectional communication between heart and other organs. Am J Physiol Heart Circ Physiol, 2022; 322(5):H769–H784; doi: 10.1152/ajpheart.00659.2021

64.

Chen

, Wang

, Fan

, et al. Targeted delivery of extracellular vesicles in heart injury. Theranostics, 2021; 11(5):2263–2277; doi: 10.7150/thno.51571

65.

Hade

, Suire

, Suo

. Mesenchymal stem cell-derived exosomes: Applications in regenerative medicine. Cells, 2021; 10(8):1959; doi: 10.3390/cells10081959

66.

Zou

, Li

, et al. Restoring cardiac functions after myocardial infarction–ischemia/reperfusion via an exosome anchoring conductive hydrogel. ACS Appl Mater Interfaces, 2021; 13(48):56892–56908; doi: 10.1021/acsami.1c16481

67.

, Hao

, Wang

, et al. Mesenchymal stromal exosome–functionalized scaffolds induce innate and adaptive immunomodulatory responses toward tissue repair. Sci Adv, 2021; 7(20):eabf7207; doi: 10.1126/sciadv.abf7207

68.

, Gao

, Yao

, et al. Roles of exosomes derived from immune cells in cardiovascular diseases. Front Immunol, 2019; 10:648; doi: 10.3389/fimmu.2019.00648

69.

Zhang

, Cai

, Shen

, et al. Hydrogel-load exosomes derived from dendritic cells improve cardiac function via Treg cells and the polarization of macrophages following myocardial infarction. J Nanobiotechnology, 2021; 19(1):271–216; doi: 10.1186/s12951-021-01016-x

70.

Ding

, Yao

, Li

, et al. A reactive oxygen species scavenging and O₂ generating injectable hydrogel for myocardial infarction treatment in vivo. Small, 2020; 16(48):e2005038; doi: 10.1002/smll.202005038

71.

Guan

, Niu

, Wen

, et al. Rescuing cardiac cells and improving cardiac function by targeted delivery of oxygen-releasing nanoparticles after or even before acute myocardial infarction. ACS Nano, 2022; 16(11):19551–19566; doi: 10.1021/acsnano.2c10043

72.

Zhao

, Wu

, Sui

, et al. Reactive oxygen species-based nanomaterials for the treatment of myocardial ischemia reperfusion injuries. Bioact Mater, 2022; 7:47–72; doi: 10.1016/j.bioactmat.2021.06.006

73.

Ashtari

, Nazari

, Ko

, et al. Electrically conductive nanomaterials for cardiac tissue engineering. Adv Drug Deliv Rev, 2019; 144:162–179; doi: 10.1016/j.addr.2019.06.001

74.

Zhou

, Liu

, Zhao

, et al. Natural melanin/alginate hydrogel achieve cardiac repair through ROS scavenging and macrophage polarization. Adv Sci, 2021; 8(20):2100505; doi: 10.1002/advs.202100505

75.

Hao

, Li

, Yao

, et al. Injectable fullerenol/alginate hydrogel for suppression of oxidative stress damage in brown adipose-derived stem cells and cardiac repair. ACS Nano, 2017; 11(6):5474–5488; doi: 10.1021/acsnano.7b00221

76.

Jalilinejad

, Rabiee

, Baheiraei

, et al. Electrically conductive carbon‐based (bio)‐nanomaterials for cardiac tissue engineering. Bioeng Transl Med, 2023; 8(1):e10347; doi: 10.1002/btm2.10347

77.

Veerubhotla

, Lee

. Emerging trends in nanocarbon‐based cardiovascular applications. Adv Ther, 2020; 3(7):1900208; doi: 10.1002/adtp.201900208

78.

Wei

, Wang

, Jiang

, et al. Fullerenol reduces vascular injury caused by ischemia-reperfusion. Carbon, 2025; 234:119949; doi: 10.1016/j.carbon.2024.119949

79.

Barabadi

, Azami

, Sharifi

, et al. Fabrication of hydrogel based nanocomposite scaffold containing bioactive glass nanoparticles for myocardial tissue engineering. Mater Sci Eng C Mater Biol Appl, 2016; 69:1137–1146; doi: 10.1016/j.msec.2016.08.012

80.

Zeimaran

, Pourshahrestani

, Fathi

, et al. Advances in bioactive glass-containing injectable hydrogel biomaterials for tissue regeneration. Acta Biomater, 2021; 136:1–36; doi: 10.1016/j.actbio.2021.09.034

81.

Zhu

, Zhang

, Chang

, et al. Bioactive glass in tissue regeneration: Unveiling recent advances in regenerative strategies and applications. Adv Mater, 2025; 37(2):e2312964; doi: 10.1002/adma.202312964

82.

Wang

, Li

, Xie

, et al. Multi-layer-structured bioactive glass nanopowder for multistage-stimulated hemostasis and wound repair. Bioact Mater, 2023; 25:319–332; doi: 10.1016/j.bioactmat.2023.01.019

83.

Guan

, Zhu

, Tian

, et al. Evaluation of the effect of nano-sodium alginate-bioglass on cardiac function of myocardial infarction based on cardiac ultrasound. Cell Mol Biol (Noisy-le-Grand), 2022; 68(3):67–76; doi: 10.14715/cmb/2022.68.3.9

84.

Yamamoto

, Oyaizu

, Enomoto

, et al. VEGF and bFGF induction by nitric oxide is associated with hyperbaric oxygen-induced angiogenesis and muscle regeneration. Sci Rep, 2020; 10(1):2744; doi: 10.1038/s41598-020-59615-x

85.

, Zhu

, Liu

, et al. Local intramyocardial delivery of bioglass with alginate hydrogel for post-infarct myocardial regeneration. Biomed Pharmacother, 2020; 129:110382; doi: 10.1016/j.biopha.2020.110382

86.

Zhang

, Li

, Ma

, et al. Modulating degradation of sodium alginate/bioglass hydrogel for improving tissue infiltration and promoting wound healing. Bioact Mater, 2021; 6(11):3692–3704; doi: 10.1016/j.bioactmat.2021.03.038

87.

, Zeng

, Geng

, et al. Macroporous methacrylated hyaluronic acid hydrogel with different pore sizes for in vitro and in vivo evaluation of vascularization. Biomed Mater, 2022; 17(2):025006; doi: 10.1088/1748-605X/ac494b

88.

Griveau

, Lafont

, Le Goff

, et al. Design and characterization of an in vivo injectable hydrogel with effervescently generated porosity for regenerative medicine applications. Acta Biomater, 2022; 140:324–337; doi: 10.1016/j.actbio.2021.11.036

89.

Pellá

MCG

, Lima-Tenório

, Tenório-Neto

, et al. Chitosan-based hydrogel: From preparation to biomedical applications. Carbohydr Polym, 2018; 196:233–245; doi: 10.1016/j.carbpol.2018.05.033

90.

Liu

, Li

, Qiao

, et al. Chitosan hydrogel enhances the therapeutic efficacy of bone marrow–derived mesenchymal stem cells for myocardial infarction by alleviating vascular endothelial cell pyroptosis. J Cardiovasc Pharmacol, 2020; 75(1):75–83; doi: 10.1097/FJC.0000000000000760

91.

Beltran-Vargas

, Peña-Mercado

, Sánchez-Gómez

, et al. Sodium alginate/chitosan scaffolds for cardiac tissue engineering: The influence of its three-dimensional material preparation and the use of gold nanoparticles. Polymers (Basel), 2022; 14(16):3233; doi: 10.3390/polym14163233

92.

Ghauri

, Islam

, Qadir

, et al. Novel pH-responsive chitosan/sodium alginate/PEG based hydrogel for release of sodium ceftriaxone. Mater Chem Phys, 2022; 277:125456; doi: 10.1016/j.matchemphys.2021.125456

93.

Deng

, Shen

, Wu

, et al. Delivery of alginate‐chitosan hydrogel promotes endogenous repair and preserves cardiac function in rats with myocardial infarction. J Biomed Mater Res A, 2015; 103(3):907–918; doi: 10.1002/jbm.a.35232

94.

Efraim

, Sarig

, Anavy

, et al. Biohybrid cardiac ECM-based hydrogel improve long term cardiac function post myocardial infarction. Acta Biomater, 2017; 50:220–233; doi: 10.1016/j.actbio.2016.12.015

95.

Wang

, Shi

, Huang

, et al. Localized delivery of anti-inflammatory agents using extracellular matrix-nanostructured lipid carriers hydrogel promotes cardiac repair post-myocardial infarction. Biomater, 2023; 302:122364; doi: 10.1016/j.biomaterials.2023.122364

96.

Tamimi

, Rajabi

, Pezeshki-Modaress

. Cardiac ECM/chitosan/alginate ternary scaffolds for cardiac tissue engineering application. Int J Biol Macromol, 2020; 164:389–402; doi: 10.1016/j.ijbiomac.2020.07.134

97.

Tan

, Wang

, Chen

, et al. Hyaluronate supports hESC‐cardiomyocyte cell therapy for cardiac regeneration after acute myocardial infarction. Cell Prolif, 2020; 53(12):e12942; doi: 10.1111/cpr.12942

98.

Dorsey

, McGarvey

, Wang

, et al. MRI evaluation of injectable hyaluronic acid-based hydrogel therapy to limit ventricular remodeling after myocardial infarction. Biomater, 2015; 69:65–75; doi: 10.1016/j.biomaterials.2015.08.011

99.

Dahlmann

, Krause

, Möller

, et al. Fully defined in situ cross-linkable alginate and hyaluronic acid hydrogel for myocardial tissue engineering. Biomater, 2013; 34(4):940–951; doi: 10.1016/j.biomaterials.2012.10.008

100.

Bilgen

, Ural

, Bekerecioglu

. Platelet-rich fibrin: An effective chronic wound healing accelerator. J Tissue Viability, 2021; 30(4):616–620; doi: 10.1016/j.jtv.2021.04.009

101.

Qian

, Yang

, Wang

, et al. Encapsulation of lyophilized platelet-rich fibrin in alginate-hyaluronic acid hydrogel as a novel vascularized substitution for myocardial infarction. Bioact Mater, 2022; 7:401–411; doi: 10.1016/j.bioactmat.2021.05.042

102.

Guo

, Huang

, Zhang

, et al. Injectable conductive hydrogel containing black phosphorus nanosheets inhibits the oxidative stress-inflammation chain during myocardial infarction. ACS Appl Nano Mater, 2023; 6(18):16749–16767; doi: 10.1021/acsanm.3c02956

103.

Luo

, Fan

, Zhou

, et al. 2D black phosphorus–based biomedical applications. Adv Funct Materials, 2019; 29(13):1808306; doi: 10.1002/adfm.201808306

104.

Wang

, Gui

, Chen

, et al. Black-Phosphorus-Reinforced injectable conductive biodegradable hydrogel for the delivery of ADSC-Derived exosomes to repair myocardial infarction. ACS Appl Mater Interfaces, 2024; 16(43):58286–58298; doi: 10.1021/acsami.4c12285

105.

Nakajima

, Fujita

, Matsui

, et al. Gelatin hydrogel enhances the engraftment of transplanted cardiomyocytes and angiogenesis to ameliorate cardiac function after myocardial infarction. PLoS One, 2015; 10(7):e0133308; doi: 10.1371/journal.pone.0133308

106.

Kim

, Kim

, Park

, et al. MSC-encapsulating in situ cross-linkable gelatin hydrogel to promote myocardial repair. ACS Appl Bio Mater, 2020; 3(3):1646–1655; doi: 10.1021/acsabm.9b01215

107.

Liang

, Chen

, Li

, et al. Conductive hydrogen sulfide-releasing hydrogel encapsulating ADSCs for myocardial infarction treatment. ACS Appl Mater Interfaces, 2019; 11(16):14619–14629; doi: 10.1021/acsami.9b01886

108.

Chen

, Li

, et al. Tailorable hydrogel improves retention and cardioprotection of intramyocardial transplanted mesenchymal stem cells for the treatment of acute myocardial infarction in mice. J Am Heart Assoc, 2020; 9(2):e013784; doi: 10.1161/JAHA.119.013784

109.

Cai

, Zhao

, Zhou

, et al. Mitochondrial dysfunction in macrophages promotes inflammation and suppresses repair after myocardial infarction. J Clin Invest, 2023; 133(4):e159498; doi: 10.1172/JCI159498

110.

Hassanpour

, Sadeghsoltani

, Haiaty

, et al. Mitochondria-loaded alginate-based hydrogel accelerated angiogenesis in a rat model of acute myocardial infarction. Int J Biol Macromol, 2024; 260(Pt 2):129633; doi: 10.1016/j.ijbiomac.2024.129633

111.

Zhang

, Li

, Yu

, et al. An injectable conductive hydrogel restores electrical transmission at myocardial infarct site to preserve cardiac function and enhance repair. Bioact Mater, 2023; 20:339–354; doi: 10.1016/j.bioactmat.2022.06.001

112.

Chen

, Hsieh

, Li

, et al. A conductive cell-delivery construct as a bioengineered patch that can improve electrical propagation and synchronize cardiomyocyte contraction for heart repair. J Control Release, 2020; 320:73–82; doi: 10.1016/j.jconrel.2020.01.027