Exploring the role of hydrogel scaffolds in cardiac regeneration: emphasis on natural extracellular matrix components

Cardiovascular diseases remain the leading cause of death worldwide, with myocardial infarction (MI) being a significant contributor to heart failure [1]. The aftermath of the MI colloquially known as a heart attack involves the replacement of damaged tissue by scar, leading to often irreversible loss of cardiac function [2]. Traditional therapeutic strategies, including pharmacological treatments and surgical interventions, are aimed at managing symptoms rather than reversing the damage caused by cardiac injury. Nonetheless, to engage at the root of the problem, the field of tissue engineering offers a promising new avenue for cardiac regeneration [3]. These are hydrogel scaffolds that mimic the natural extracellular matrix (ECM). These hydrogels have gained significant attention as a potential to repair damaged cardiac tissue. Particularly, those compositions involving natural ECM components (biopolymers) have shown great promise [4].

1. Hydrogels: the backbone of tissue engineering

Hydrogels are hydrophilic, three-dimensional cross linked polymeric networks capable of retaining substantial amounts of water, making them attractive candidates for mimicking the natural ECM. Hydrogels are biocompatible, with tunable mechanical properties, and the ability to support cell proliferation and differentiation [5–7]. They can serve as scaffolds offering structural support to the heart, particularly adding components such as carriers for cells, growth factors, and other bioactive molecules that promote regeneration [7].

In cardiac regeneration, hydrogels play a crucial role in the healing of damaged tissue. The heart is a mechanically active organ, and its ECM withstands the constant mechanical stress of contractions. Therefore, suitable hydrogels must closely replicate these properties to support cardiac cell function. The suitability of a hydrogel depends on several criteria, including biocompatibility, biodegradability, mechanical properties, and the ability to mimic the ECM [5–7]. Additionally, the materials used to form the hydrogel scaffold, whether synthetic or natural, must provide the necessary structural support while maintaining a balance between elasticity and stiffness to facilitate cardiac cell adhesion, proliferation, and differentiation [6].

Synthetic polymers, such as polyglycerol sebacate, polycaprolactone, polylactic acid, and poly D,L-lactic-co-glycolic acid, are known for their remarkable mechanical resistance and durability [6,8]. Natural polymers, such as gelatin, collagen, alginate, elastin, fibronectin, laminin, and decellularized ECM derived from various organs are favored for their bioactivity, low immunogenicity, and biodegradability. Among these, decellularized ECM has progressed to clinical stages in the form of injectable hydrogels and patches, due to its ability to recreate a native-like microenvironment. This is achieved by preserving the tissue-specific composition of structural proteins, proteoglycans, and bioactive molecules which not only provide structural support but also promote tissue remodeling and vascularization. Consequently, decellularized ECM-based hydrogels closely mimic the natural ECM, offering significant potential in cardiac repair [8] Decellularized ECM hydrogels have demonstrated potential as a bioink for three-dimensional bioprinting applications in vitro. Their use has yielded encouraging outcomes in tissue engineering, particularly in cardiac regeneration. Studies indicate that hydrogels derived from decellularized human-derived ECM (hdECM) significantly enhance the maturation of cardiomyocytes when compared to traditional collagen-based hydrogel matrices. This suggests that hdECM bioinks provide a more biomimetic microenvironment conducive to promoting functional tissue development [9].

2. Hydrogel patches: direct application repair

Hydrogel patches are developed from semisolid materials that permit encapsulation; thus, patches can be directly applied typically by suturing to the surface of the affected area. However, it is important to consider that suturing can induce an inflammatory reaction or oxidative stress, negatively impacting the regeneration process. To mitigate these drawbacks, biocompatible adhesives, such as fibrin glue, are used to secure the patch to the infarcted area [10]. This strategy has proven highly effective, resulting in significant improvements in cardiac function and tissue repair [6]. However, the use of fibrin glue also has limitations, including the potential risk of infection due to its plasma-derived nature, the elicitation of immune responses, allergic reactions, thrombogenesis, and other complications [11]. Therefore, its application must be carefully assessed in clinical settings to minimize risks and ensure optimal outcomes.

3. Injectable hydrogels: a minimal invasive approach

Injectable hydrogels have appeared as a minimal invasive alternative for cardiac repair [12,13]. Once injected, these liquid base state polymers can undergo solution-to-gel transition allowing for targeted treatment, which may further incorporate cells and/or bioactive compounds [4,8,14]. These hydrogels can facilitate localized and sustained release of therapeutic agents, significantly enhancing their efficacy in treating cardiac injuries [15]. Currently, two alginate-based hydrogels (Algisyl-LVR^TMand IK-5001) have entered clinical trials, demonstrated safety and improved left ventricular ejection fraction in patients with heart failure, marking a significant advancement in hydrogel-based cardiac therapies [15].

4. Bioactive components

The inclusion of bioactive components plays a vital role in boosting the therapeutic efficacy of hydrogel scaffolds in cardiac tissue engineering. Bioactive molecules include growth factors, cytokines, and peptides, are incorporated within the hydrogel structure in order to create an environment conducive to healing and tissue regeneration [6,8,14].

In cardiac applications, bioactive components include growth factors known to promote proangiogenic effects, essential for salvaging ischemic myocardium post-MI. Growth factors such as fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor (VEGF) play a crucial role in stimulating the formation of new blood vessels (neovascularization), ensuring that the damaged myocardium receives sufficient oxygen and nutrients for recovery [16]. In addition, other compounds such as insulin-like growth factor 1 (IGF-1) and platelet-derived growth factor (PDGF) can support cell proliferation and survival, which are critical for regenerating myocardial tissue [17,18].

By embedding bioactive molecules, hydrogels can facilitate a sequential release profile that mirrors the natural healing process initially reducing inflammation, then stimulating tissue repair, and finally promoting remodeling. This multi-phase release is vital in addressing the progressive stages of healing post-MI, aligning with the cardiac tissue’s intrinsic repair mechanisms.

5. The role of ECM components

Decellularized ECM serves as a naturally occurring polymeric biomaterial derived from native tissue, comprising various proteins, proteoglycans, glycosaminoglycans (GAGs), and other matrix proteins. Decellularized ECM provides a foundational structure for myocardial regeneration, repair, and remodeling because of its ability to mimic the ECM [8,19,20].

• Glycosaminoglycans (GAGs), such as hyaluronic acid and heparan sulfate contribute to tissue hydration, facilitating nutrient diffusion and providing a gel-like environment that supports cell migration and proliferation [5]. In hydrogels, GAGs are often incorporated to enhance their water retention and bioactivity. Hyaluronic acid has been shown to promote angiogenesis e.g., the formation of new blood vessels, a vital process in the healing of infarcted cardiac tissue. GAGs also bind growth factors and cytokines, helping regulate their availability to cells, further promoting tissue repair [20,21].

• Elastin is an important component of the ECM, which provides elasticity and allows tissues to stretch and recoil under mechanical stress. In the heart, elastin ensures that the myocardium can expand and contract effectively. Hydrogels incorporating elastin or elastin-like peptides are particularly attractive for cardiac applications because they could mimic these properties, restoring the mechanical function of damaged heart tissue. Additionally, elastin’s ability to endure repeated cycles of stretching and contraction makes it ideal for applications in dynamic tissues including the heart [20].

• Fibronectin and laminin are glycoproteins that play key roles in cell adhesion, migration, and differentiation. They are vital in wound healing and tissue remodeling processes, providing binding sites for integrins and other cell surface receptors. In the heart, they help organize cardiomyocytes and endothelial cells into functional structures [6,22]. By incorporating fibronectin and laminin into hydrogel scaffolds enhances their ability to support the attachment, survival, and organization of cells. Laminin is important for the differentiation of progenitor cells into cardiomyocytes, making it a valuable component in scaffolds aimed at promoting heart tissue regeneration [20–22].

6. Drug therapy

A wide range of medications can be used in combination with hydrogels for treating myocardial infarction. Natural bioactive drugs, such as tanshinone and colchicine, alongside synthetic compounds, are explored for their therapeutic benefits [23]. Bioactive drugs, such as curcumin and quercetin, possess strong anti-inflammatory, anti-apoptotic, and tissue repair properties [18]. However, their limited solubility in water hinders effective delivery through conventional methods.

Recent research has shown the potential of incorporating selenium-containing PEG-PPG hydrogels to reduce pro-inflammatory cytokine secretion, improve myocardial fibrosis, and enhance left ventricular remodeling [24]. The synergy between bioactive drugs and hydrogels enables sustained drug release, enhancing localized pharmacological benefits while minimizing systemic side effects, which is crucial for addressing the prolonged and complex pathological environment following MI [6,23,24].

7. Advances in hydrogel design for cardiac regeneration

Recent advancements in hydrogel scaffold design have a focus on enhancing their ability to mimic the complex structure and function of the native cardiac ECM [6,7]. This includes developing hybrid hydrogels that combine natural ECM components with synthetic polymers to achieve optimal mechanical properties, bioactivity, and degradation rates. Such strategic designs allow hydrogels to provide temporary support to the heart while new tissue forms [6–8,19].

Incorporating bioactive molecules as growth factors and peptides into hydrogel scaffolds shows great promise. Controlled release of these molecules can facilitate the survival and growth of cardiomyocytes, promote new blood vessel development, and mitigate inflammation. For instance, scientists have enhanced blood vessel formation and tissue repair after MI by integrating VEGF and FGF into hydrogels [16].

Furthermore, researchers are investigating the co-culture of stem cells and other cell types, such as endothelial cells and fibroblasts, within hydrogels to enhance cardiac regeneration [25]. Enclosing stem cells in hydrogels, as well as multi-cellular approaches provide a workable and nurturing environment that enhances their viability and specialization within the injured cardiac tissue.

8. Challenges to overcome

Despite all the aforementioned potential, there are important hurdles to address. One critical challenge is achieving the appropriate mechanical properties which can be accomplished by enhancing their structural integrity and elasticity to mimic the properties of native heart tissue. This is possible by modifying the crosslinking density, adding bioactive molecules or nanoparticles, and choosing appropriate natural or synthetic polymer matrices; hydrogels must be strong enough to withstand the heart’s beating forces while maintaining the flexibility needed for contraction and relaxation [6,8].

Delivery issues also create challenges in the effective utilization of hydrogels for treating cardiac injuries. Existing techniques, such as direct injection or surgical implantation, can be invasive and may not guarantee uniform distribution throughout the injured tissue. Researchers are exploring alternative delivery methods, including catheter-based approaches, to enhance the viability and effectiveness of hydrogel-based treatments [26].

Before clinical application, researchers must address regulatory and manufacturing challenges, ensuring hydrogels undergo rigorous preclinical and clinical testing and developing scalable production processes for consistent, high-quality materials. Hence, continuous research on hydrogel scaffolds, integrating bioactive molecules, and developing less invasive delivery methods is crucial for advancing this promising field. Overcoming these challenges will revolutionize the treatment of heart disease, offering a hopeful outlook for patients with cardiac injuries.

Funding Statement

This paper was not funded.

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Author contributions

Conceptualization: MGS-S, JFI, investigation: MGS-S, ENG-T, JFI, writing – original draft preparation: MGS-S, ENG-T, JFI, writing – review editing: MGS-S, ENG-T supervision: JFI.