Advanced Cardiac Patches for the Treatment of Myocardial Infarction

Abstract

Myocardial infarction is a cardiovascular disease characterized by a high incidence rate and mortality. It leads to various cardiac pathophysiological changes, including ischemia/reperfusion injury, inflammation, fibrosis, and ventricular remodeling, which ultimately result in heart failure and pose a significant threat to global health. Although clinical reperfusion therapies and conventional pharmacological interventions improve emergency survival rates and short-term prognoses, they are still limited in providing long-lasting improvements in cardiac function or reversing pathological progression. Recently, cardiac patches have gained considerable attention as a promising therapy for myocardial infarction. These patches consist of scaffolds or loaded therapeutic agents that provide mechanical reinforcement, synchronous electrical conduction, and localized delivery within the infarct zone to promote cardiac restoration. This review elucidates the pathophysiological progression from myocardial infarction to heart failure, highlighting therapeutic targets and various cardiac patches. The review considers the primary scaffold materials, including synthetic, natural, and conductive materials, and the prevalent fabrication techniques and optimal properties of the patch, as well as advanced delivery strategies. Last, the current limitations and prospects of cardiac patch research are considered, with the goal of shedding light on innovative products poised for clinical application.

In 2019, cardiovascular diseases resulted in ≈18.6 million global fatalities, accounting for a staggering 49.2% of total deaths,¹ representing the leading cause of mortality worldwide.^2–4 Myocardial infarction (MI) has garnered significant attention owing to its high incidence, mortality, and adverse prognosis, with these concerns becoming more pronounced in our rapidly aging society.⁵ Consequently, MI has emerged as a significant public health threat that jeopardizes the health and well-being of the global population.

Clinical reperfusion therapies such as percutaneous coronary intervention, thrombolysis, and coronary artery bypass grafting can restore blood supply to the ischemic myocardium in the early stages, restrict infarct size, and enhance emergency patient survival rates. However, they fail to stimulate the repair and regeneration of the damaged myocardium. Extensive loss of cardiomyocytes (CMs), resulting in ventricular thinning and increased stress, coupled with aseptic inflammation from tissue necrosis and subsequent scar tissue formation, can contribute to progressive ventricular remodeling, culminating in heart failure (HF). Current interventions for advanced HF remain inadequate, with only a 50% survival rate observed 5 years after treatment across various HF phenotypes.^6,7 Heart transplantation is the only suitable therapeutic option but is constrained by limitations such as scarcity of heart donors, transplant rejection, and adverse reactions such as infections and malignant tumors induced by immunosuppressants. Hence, interventions for adverse developments after MI are pivotal in preventing the onset of HF. Over the past 2 decades, medications such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and β-blockers have been used to counter pathological remodeling after infarction, without significantly improving long-term prognosis.⁸

Cardiac patches provide a beacon of hope for patients with complex cardiovascular ailments. As an adjunct therapy after reperfusion, cardiac patches can avert, decelerate, and even reverse pathological progression after MI; improve prognosis; and prevent terminal HF, and they have the potential to resolve ischemia/reperfusion injury. Cardiac patches comprise scaffolds loaded with therapeutic agents or not. The scaffolds incorporate natural or synthetic materials or a combination thereof, offering mechanical reinforcement to the weakened ventricular wall and, on integrating conductive materials, re-establishing electrical connections of the infarction region. Concurrently, as a platform, cardiac patches can load and deliver “cargo,” including cells, growth factors, exosomes, drugs, genes, and gaseous signaling molecules, to the damaged region, reducing nontargeted side effects. Unlike injectable hydrogels, cardiac patches are usually prefabricated in vitro with controllability and stability. Thus, their design allows personalized treatment tailored to individual patient specifications. Although the current transplantation of patches is performed primarily in surgeries such as coronary artery bypass grafting that require chest opening, advancements in shape-memory materials and adhesion design could pave the way for minimally invasive patch implantation through thoracoscopy, transapical puncture, or even percutaneous coronary intervention.

Cardiac patches exhibit immense potential for clinical applications; however, they are largely confined to laboratory settings with no mature translational products in use. This article provides a comprehensive review of the latest advancements in the treatment of MI with cardiac patches from a clinical perspective (Figure 1). The review aims to provide theoretical underpinnings and guidance for the design, fabrication, and preclinical study of cardiac patch innovations.

Figure 1.

Schematic summary of cardiac patches for myocardial infarction treatment. 3D indicates 3-dimensional.

PATHOLOGICAL MECHANISMS AFTER MI

The pathophysiological progression from MI to HF can be delineated into 4 distinct yet overlapping phases (Figure 2): early acute injury, inflammatory response, tissue proliferation and repair, and adverse remodeling stage.^9,10 Understanding the specific pathophysiological mechanisms of each phase can inform the formulation of treatment targets and strategies.

Figure 2.

Progression of pathological changes after myocardial infarction corresponding to representative therapeutic functions of cardiac patches. I/R indicates ischemia/reperfusion; and ROS, reactive oxygen species.

Early Acute Injury Stage

During the initial stages of MI, coronary artery obstruction culminates in localized cardiac tissue ischemia and hypoxia. This deleterious microenvironment impairs the high-density mitochondria within the CMs, perturbing ATP metabolism. As a result, there is pathological augmentation of reactive oxygen species (ROS) levels and myocardial ischemia/reperfusion injury. Dysfunctional mitochondrial operations also shift cellular metabolism toward anaerobic glycolysis, accumulating metabolites such as lactate, thus lowering the local pH. Elevated ROS not only stimulate the production of high levels of inflammatory cytokines, precipitating an intense subsequent inflammatory response, but also enhance the permeability of the mitochondrial permeability transition pore, exacerbating the loss of cytochrome c. This pathological progression further induces necrosis and programmed apoptosis of CMs. An abrupt reduction in CM number causes ventricular wall thinning and elevates stress, which may lead to chamber dilation or ventricular aneurysm,¹¹ thereby amplifying the risk of cardiac rupture. In addition, myocardial functionality is lost in the infarcted area, leading to alterations in the hemodynamics of the heart. Noninfarcted regions manifest functional hyperactivity, instigating neurohormonal regulation, including the excitation of sympathetic adrenaline and the renin-angiotensin-aldosterone system and secretion of natriuretic peptides (ANP [atrial natriuretic peptide] and BNP [B-type natriuretic peptide]) aimed at stabilizing cardiac output and effecting transient circulatory compensation. However, this early compensation stabilization is “symptomatic.” Precociously activated neurohormonal regulation may initiate the malignant cycle present in long-term adverse ventricular remodeling. At this stage, it is imperative to proactively perform reperfusion therapies to deter further enlargement of the MI region. Concurrently, excess ROS must be cleared, and mitochondrial functionality must be improved to mitigate ischemia/reperfusion injuries resulting from blood perfusion. Responsive cardiac patches could be engineered from the dynamic microenvironment changes to achieve responsive release of loaded substances such as nitric oxide, α-tocopherol, tanshinone, gallic acid, cyclosporine A, and elamipretide (SS-31).^12–14

Inflammatory Response Stage

Necrotic tissue and degraded extracellular matrix (ECM) induce a series of aseptic inflammations involving molecular cascades and cell reactions.^15,16 Primarily, neutrophils infiltrate, and monocytes are recruited from the bloodstream and migrate to the infarcted area, where they differentiate into macrophages to carry out phagocytosis. Concurrently, macrophages secrete growth factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor, which promote neovascularization and ameliorate the microenvironment. At this stage, macrophages exhibit predominantly an M1 proinflammatory phenotype and cause direct inflammation by releasing cytokines. Appropriate inflammation is beneficial for subsequent repair. However, if inflammation becomes excessive and does not subside at the right time, it can further damage the surviving myocardium and surrounding healthy tissue. Modulation of the inflammatory response and promotion of angiogenesis by delivering bioactive agents are common strategies for patch therapy.

Tissue Proliferation and Repair Stage

This phase is the key to determining the potential progression to HF. Necrotic CMs, together with macrophages, locally produce abundant transforming growth factor-β1 to induce the chemotaxis of fibroblasts. These fibroblasts migrate to the central necrotic region, proliferate, and transdifferentiate into myofibroblasts, which synthesize and secrete type I and III collagen and other ECM components. Over several weeks, these restorative collagen fibers undergo continuous crosslinking, maturation, and aging, forming scars that replace the infarcted tissue. Although fibrous scars exhibit tensile strength, distribute augmented stress, and provide mechanical support, they lack normal contractile function and conductivity of the healthy myocardium. Under physiological conditions, myofibroblasts undergo programmed apoptosis to prevent excessive collagen synthesis and deposition. Furthermore, matrix metalloproteinases such as matrix metalloproteinase-2 and -9 are markedly upregulated in the infarcted region and can mediate left ventricular remodeling by degrading specific ECM components. In summary, therapeutic strategies at this phase aim to induce a shift in macrophage polarization (from the M1 to M2 anti-inflammatory phenotype), facilitate the regression of inflammation, inhibit matrix metalloproteinases, and regulate collagen deposition.

Adverse Remodeling Stage

If the scar tissue fails to counterbalance the increased stress or force of ventricular deformation, myofibroblasts may remain persistently activated, leading to the overproduction of collagen. This collagen appears in the infarcted region, but excessive collagen can also spread to the peri-infarct border and even to the healthy myocardium, rendering the lesion and surrounding ventricular wall stiff. Long-standing fibrous scars are electromechanically isolated from native myocardium, leading to compromised cardiac function, anomalous conduction, and arrhythmias.¹⁷ To adapt to localized dysfunction, the body can compensate through neurohumoral regulation. However, prolonged compensation intensifies the mechanical load of the heart, exacerbating fibrosis adjacent to the infarct and resulting in myocardial hypertrophy. These imbalances intensify cardiac dysfunction and further activate neurohumoral regulation. A persistent, vicious cycle caused by disparities in mechanical structure, conduction, and excessive neurohumoral compensatory responses develops, leading to sustained ventricular remodeling and eventually HF. At this stage, the cardiac patch could be used for ventricular restraint and electrocoupling therapy to improve the patient’s symptoms or provide a temporal respite pending heart transplantation.

CLASSIFICATION OF CARDIAC PATCHES

Currently, hydrogel patches, fibrous films, elastomer patches, cell sheets, and microneedle patches are the most promising types of patch for MI treatment. Hydrogel patches, the most prevalent type, are crafted from materials such as decellularized ECM (dECM), collagen, alginate, and poly(ethylene glycol). They exhibit superior biocompatibility, tunable mechanical properties, and porous structures due to crosslinking. Cells, other active agents, and conductive materials can be integrated into hydrogel matrices to realize diverse therapeutic strategies. Fibrous films are synthesized from polymers such as polycaprolactone, polyurethane, and gelatin by electrospinning and are segmented into specified dimensions from electrospun mats. These films are elastic and nanofibrous and can be modified for enhanced conductivity,¹⁸ bioactivity, and controlled therapeutic delivery through grafting and layer-by-layer assembly.¹⁹ Elastomer patches, derived from materials such as poly(glycerol sebacate) (PGS) and polyurethane, are known for their exceptional elasticity and deformation capacities. Recently, researchers have amalgamated these patches with other approaches to construct comprehensive therapeutic systems.²⁰ Cell sheets, predominantly cultivated and organized from CMs or stem cells, exhibit minimal in vivo rejection reactions and fully harness the therapeutic potential of cells. However, mechanical stress and the lack of a scaffold often lead to the rapid rupture and loss of cell sheets. Last, microneedle patches are assembled from arrays of microneedles with heights ranging from 10 to 2000 μm and widths of 10 to 50 μm,^21,22 manufactured from materials like poly(vinyl alcohol), hyaluronic acid, and gelatin methacryloyl using molding or 3-dimensional (3D) printing methods. The ventricular walls are much thicker in large animal models and humans than in small animals. Permeation from the epicardium may be insufficient for delivery, particularly to deep infarcts within the myocardium. The microneedle tips, capable of penetrating the epicardium, can establish microscale channels between the patch and the myocardial tissue, which allows the precise delivery of cells, regenerative factors, or pharmacological agents to deep myocardial tissue. Compared with intramyocardial injections, minuscule tips are less likely to cause cardiac structural injury and inflammation. In summary, these distinct cardiac patch types have unique characteristics and merits and offer broad prospective applications.

TYPICAL FABRICATION TECHNIQUES

Building on the prevailing patch types, the principal fabrication methodologies include molding, electrospinning, 3D printing, spray drying, and in situ crosslinking (eg, injection and painting). In this review, we focus on the 3 foremost approaches and compare their strengths and limitations, as listed in Table 1.

Table 1.

Common Techniques for Preparing Cardiac Patches

Molding

Molding, which is the epitome of simplicity in patch production, is versatile for fabricating an array of patch types. However, molding is ill equipped to create intricate patch systems owing to the limited precision. Polydimethylsiloxane, silicone, and Teflon molds are the predominant types. Predesigned molds are infused and filled with the materials, and the patch is then shaped with self-assembly, photocuring, freezing, and drying, followed by demolding to obtain the patch. With advances in microfabrication techniques such as soft lithography, electron beam lithography, and deep reactive ion etching, researchers can etch microstructures onto molds, including grooves, micropatterns, and complex microneedle-negative molds.

Electrospinning

Electrospinning capitalizes on charge interactions to extrude polymer materials in solution or molten form through an orifice. These extrusions stretch into fine filaments in a high-voltage electric field and rapidly solidify under ambient conditions to form nanoscale or microscale continuous fibers. Modulating the electrospinning parameters facilitates the fine-tuning of the nanofiber diameter, spacing, and alignment. Electrospinning is routinely used to fabricate nanofibrous films and elastomer patches from materials such as polyesters (polyurethane and polycaprolactone), gelatin, and chitosan. Electrospun fibers with a commendable surface-to-volume ratio and porosity offer an abundance of niches and ensure the diffusion of nutrients and metabolites. The orientation of the electrospun fibers closely mimics that of the natural epicardium (with type I and III collagen fibers), providing cells with physical cues. However, to form stable fibers, electrospinning has some requirements for the processability of the material such as a specific high molecular weight, melting point, and glass transition temperature.

3D Printing

In recent years, 3D printing, using biomaterials as inks and complemented with computer-assisted software design of digital models, has enabled the preparation of patches with intricate architectures,²³ catering to most fabrication needs.²⁴ For example, 3D printing enables the fabrication of patch scaffolds that mimic cardiac tissue structures²⁵ or cellular spatial organization,²⁶ enhancing cell adhesion and microvascular infiltration, thereby allowing the formation of prevascularized cardiac patches. Printing techniques commonly used in cardiac tissue engineering include inkjets (thermal and piezoelectric), extrusion (fused deposition modeling, free-form reversible embedding, and mechanical and pneumatic pressures), and light-based printing (stereolithography, 2-photon polymerization, and digital light processing). The prerequisites for 3D printing include materials that are amenable to printing and undergo rapid solidification. Among these, certain hydrogel materials, including dECM, alginate, gelatin, collagen, and poly(ethylene glycol), which exhibit properties resembling those of native ECM, have emerged as essential bioink candidates. However, owing to the prohibitive cost of 3D printing apparatus and a suboptimal fabrication pace, large-scale production of patches by 3D printing remains difficult in both ordinary laboratories and clinical settings, and the approach is still in the foundational stage of applied research. The realization of clinical translation necessitates further optimization of 3D printing materials and techniques.

MATERIALS

Patch scaffolds include synthetic, natural, and composite materials that can meet various therapeutic needs by adjusting their combinations and ratios. The advantages, disadvantages, and common characteristics of these materials are listed in Table 2. There has been a growing trend for the addition of conductive materials to patches to improve their electrical conductivity. This section highlights the materials used in recent patch fabrication alongside the prevalent conductive materials.

Table 2.

Comparison Between Synthetic and Natural Materials

Synthetic Materials

Synthetic materials, because of their controllable origins and superior mechanical properties coupled with reduced immunogenicity, have been used extensively in cardiac patches. Prominent among these are polycaprolactone, polyurethane, poly(ethylene glycol), poly(vinyl alcohol), PGS, poly(N-isopropylacrylamide), poly(l-lactide-co-ε-caprolactone), and poly(lactic-co-glycolic acid). Researchers have introduced polycaprolactone into cardiac patches to improve the mechanical strength and adapt to the dynamic stress of the heart. Although polycaprolactone has commendable toughness,¹⁸ elasticity, and stiffness, similar to those of natural myocardial tissue, it tends to undergo plastic deformation under prolonged cyclic forces. The cost-effective elastomer material PGS, first reported by Wang et al²⁷ in 2002, exhibits impressive stiffness (0.056–1.5 megapascals) and rubber-like elastic behavior and demonstrates an aptitude for deformation, retention, and recovery, making it particularly suitable for dynamic mechanical environments. Patches composed of PGS elastomers synthesized by Chen et al²⁸ by molding exhibited stiffness values ranging from several tens of kilopascals to 1 megapascal. Although PGS manifests no pronounced cytotoxicity in vitro, its degradation products could potentially lead to an acidic environment and affect cell viability. Polyurethane, a polymer composed of repetitive triadic structural units, can be endowed with specific biodegradability and responsiveness by modulating its ternary structural components. Xie et al²⁹ used poly(thioketal) dithiol as a soft segment chain and, based on thioketal groups, synthesized ROS-responsive polyurethane to fabricate electrospun polyurethane/gelatin patches that exhibited robust ROS-scavenging and antioxidant capabilities (Figure 3A). Synthetic materials are characterized by their tunable mechanical properties and processability. Because of the mechanical support, synthetic material patches can function without the load of cells or other active substances.

Figure 3.

Application of synthetic, natural, and conductive material-derived patches in the treatment of MI. A, Schematic diagram of the mechanism of reactive oxygen species-responsive polyurethane/gelatin (PFTU/Gt) fibrous film in treating myocardial infarction (MI) with its effectiveness in enhancing cardiac function in MI rats. Adapted with permission from Xie et al.²⁹ Copyright © 2022, John Wiley & Sons. B, The second-generation CorMatrix-extracellular matrix patch was implanted in the left ventricular infarct area during surgery and steadily improved scar tissue postoperatively. Adapted with permission from Bhatt et al.³⁷ Copyright © 2023, Springer Nature. C, Schematic illustration of the electrocoupling treatment for MI with conductive patches, capable of bridging the infarct area to improve electrical conduction. Adapted with permission from Yu et al.³⁹ Copyright © 2023, Springer Nature. D, Characterization of the conductive properties of MXene patches. Adapted with permission from Lee et al.⁴² Copyright © 2023, American Chemical Society. E, Polyaniline-based conductive patches for monitoring of infarct area pulsation amplitude and rhythm. Adapted with permission from Yu et al.³⁹ Copyright © 2023, Springer Nature. PPFU/Gt indicates a non-reactive oxygen species-responsive polyurethane/gelatin.

Natural Materials

Natural materials are derived from polymers found in the environment, including proteins (fibrin, collagen, and gelatin), polysaccharides (hyaluronic acid, chitosan, and alginates), and dECM from various tissues. Consequently, these materials maintain their natural structure and biology, exhibit excellent biocompatibility, and promote cell adhesion and proliferation. Fibrin scaffolds can directly ameliorate cardiac function after MI but are commonly used as cellular scaffolds³⁰ because of the lack of bioactives.³¹ Gelatin is produced by the partial hydrolysis of collagen and is primarily fabricated into cardiac patches through chemical modifications such as methacrylic anhydride and dopamine to obtain gelatin methacryloyl and dopamine-modified gelatin, respectively, coelectrospinning with other materials and crosslinking to form gelatin sponges.³² Chen et al³³ created a microneedle patch laden with galunisertib from gelatin methacryloyl through molding. The mechanical strength of the microneedle tips reached up to 0.4 N per needle, enabling myocardial penetration without breaking. This patch enabled the sustained release of galunisertib for >15 days, inhibiting the transforming growth factor-β/Smad2 signaling pathway and controlling fibroblast differentiation and collagen deposition. The rich active growth factors and matricellular proteins in the dECM and their natural degradation products drive endogenous cardiac repair and angiogenesis through bioinductive mechanisms. Sarig et al³⁴ used porcine cardiac dECM to produce acellular cardiac patches. They demonstrated the ability to attract and recruit endogenous progenitor cells, showing a linear infiltration rate, and cellular density increased with ECM degradation time. dECM patches have received clinical approval from departments of medical device supervision for epicardial MI repair, including the CorMatrix CorPatch,³⁵ derived from porcine small intestine submucosa, and PeriCord,³⁶ which is obtained from allogeneic human pericardium. Although clinical use has not been widespread, case reports have demonstrated encouraging therapeutic outcomes such as reduced scar, enhanced cardiac function, and improved myocardial perfusion without arrhythmias or the requirement for immunosuppression, indicating long-term safety in humans. The development of the CorMatrix material focused primarily on reducing antigenicity. A recent case report documents the successful implantation of the second-generation CorMatrix-ECM patch in the infarct zone during a total arterial coronary artery bypass grafting procedure (Figure 3B), serving as an adjunctive therapy, which effectively restored the postoperative left ventricular ejection fraction in a young patient with cardiogenic shock and left ventricular dysfunction.³⁷ As a result of the challenges of clinical translational costs and sourcing, researchers are exploring alternative dECM sources such as medical waste from placentas, umbilical arteries, and even plant tissues such as spinach leaves. Natural materials are ideal carriers of bioactive compounds. From a translational perspective, individual variability in biological sources causes heterogeneity across batches, challenging standardized production. In addition, considering their high storage requirements, further development is required before more frequent use of natural materials in clinical applications.

Conductive Materials

The electrical conductivity of the native cardiac tissue is ≈1.5 to 1.7×10⁻³ S/cm.³⁸ However, the necrotic myocardium and scar tissue lack conduction. Conductive patches with electrical conductivity similar or superior to that of native myocardium can, by electrocoupling treatment (Figure 3C), clear electrical conduction, reduce arrhythmias, and limit ventricular remodeling that can result from long-term heterogeneous conduction. Common conductive materials used in cardiac patches include polypyrrole, polyaniline, carbon nanotube, graphene, graphene oxide, nanogold, and MXene. Polypyrrole is biocompatible and has a simple fabrication process. However, the hydrophobic nature of conducting polymers (polypyrrole and polyaniline) can lead to aggregation within the aqueous solution, influencing their conductive properties. Researchers primarily use chemical modifications such as catechol and carboxyl to ensure uniform distribution in hydrogel patches and fibrous films.¹⁸ Wu et al⁴⁰ copolymerized pyrrole with the hydrophilic compound dopamine (DA) in an HCl/FeCl₃ solution. The resultant dopamine-polypyrrole exhibited enhanced dispersibility in water and a distinct rod-like morphology. MXene, a 2-dimensional conductive material with an excellent electrical conductivity similar to that of graphene, was first reported in 2011 by Naguib et al.⁴¹ MXene nanoflakes exhibit good hydrophilicity and stable dispersion because of their surface-active chemical groups (-OH, -F). A conductive hydrogel patch was developed by combining 2-dimensional titanium carbide (Ti₃C₂T_x) MXene with natural materials such as gelatin, which imparts high electrical conductivity (18.3×10^-3 S/cm; Figure 3D) and cardiac tissue-like elasticity (30.4 kPa) to the patch.⁴² Ti₃C₂ MXene nanosheets have also been reported to effectively scavenge ROS and mitigate oxidative stress injuries.⁴³ Shape-memory materials based on conductive materials are under development such as water-driven shape-memory patches incorporating carbon nanotubes with a hierarchical porous structure⁴⁴ and photothermal-driven shape-memory patches embedded with graphene oxide,⁴⁵ capable of being delivered through a catheter to the epicardial surface where they can unfold. However, most inorganic conductive materials are nondegradable and are eliminated exclusively through excretion. The potential toxicity arising from prolonged accumulation in the body necessitates long-term safety evaluations. Recent studies have used the electrical signals from resistance changes in conductive patches^39,46 induced by ventricular strain and deformation, thereby allowing real-time monitoring of the diastolic-systolic amplitude, heart rate, and rhythm (Figure 3E). The combination of electrocoupling and monitoring is a promising approach for fabricating conductive patches.

OPTIMAL PROPERTIES FOR CARDIAC PATCHES

When cardiac patches are being designed and developed, it is essential to define the properties of the scaffold material, including its mechanical performance, adhesion, biocompatibility, degradability, conductivity, and vascularization. As we transition toward clinical implementation, considerations related to cost, source challenges, large-scale producibility, and storage have become equally pivotal.

Mechanical Properties

Given that cardiac patches endure the dynamic stress generated by prolonged cardiac contractions on the epicardium, they should possess specific mechanical characteristics, including a good fracture elongation rate, toughness, flexibility, and fatigue resistance, thereby preventing breakage and adapting to dynamics. Simultaneously, a patch of appropriate stiffness facilitates mechanical integration with the heart and provides physical support to the ventricular wall. However, excessive stiffness may influence the cardiac output, potentially leading to severe ventricular deformities and restricted filling. Drawing on the law of Laplace, sustained left ventricular restraint in treating MI reduces stress and early ventricular dilation, suppresses long-term ventricular remodeling, and conserves cardiac function. Consequently, the ideal mechanical properties of the patches include suitable stiffness, toughness, and flexibility. Previous findings suggest that the Young’s modulus (slope of the elastic stage in the stress-strain curve) of the epicardial patch that benefits cardiac tissue regeneration should range from tens of kilopascals to tens of megapascals (between the 2 red lines in Figure 4A).^47,48 The Young’s modulus of natural cardiac tissue is within the range of 10 to 15 kPa.⁴⁹ However, the exact values of myocardial stiffness are influenced by various factors such as species, age, sex, and pathological states. For instance, ischemia-induced myocardial fibrosis increases the ventricular wall stiffness to 30 to 50 kPa.⁵⁰ More than a decade ago, the Acorn trial indicated that ventricular restraint therapy relying solely on mechanical support should be used only as symptomatic treatment and was not as effective as expected, with failure to prevent progression to end-stage HF⁵¹ and improve mortality.⁵² This failure may be attributed to an inadequate understanding of the mechanisms underlying the mechanical benefits from a physiological perspective, coupled with the challenge of adapting a specific static elasticity to varying degrees of myocardial stiffness. In response to the continual morphological changes in the heart, Lin et al⁵³ developed an ionically crosslinked transparent starch hydrogel, called the gel-point adhesive patch. In contrast to traditional hydrogel patches, the gel-point adhesive patch displays specific mechanical and rheological properties under cardiac contraction stress, self-adapting to cyclical deformations of the myocardium and exerting sustained support, ultimately mitigating ventricular dilation and effectively counteracting the decline in cardiac output.

Figure 4.

Optimal properties for cardiac patches. A, The stress-strain curve of the mechanical performance of the epicardial patch. B, Bio-inspired microneedle arrays for fixation. Created with BioRender. C, Schematic diagram of a Janus adhesive double-layer hydrogel (named CPAMC/PCA Janus hydrogel) with the inner layer adhering to the epicardium and the outer layer that exhibits antipostoperative synechia. Adapted with permission from He et al.⁶⁰ Copyright © 2022, Springer Nature. D, Organized vascular networks formed by spheroids of early vascular cells derived from human embryonic stem cells within the 3-dimensional (3D) printed cardiac patches displayed continual development over time. Adapted with permission from Liu et al.⁶⁵ Copyright 2022, John Wiley & Sons. cTnT indicates cardiac troponin T.

Adhesion Properties

Most cardiac patches lack adhesiveness and require conventional methods such as suturing or fibrin glue to fix them on the epicardium. Although suturing can exacerbate cardiac injury, manifesting as edema, inflammation, bleeding, or even infections, fibrin glues offer suboptimal fixation with associated detachment risks.⁵⁴ In recent years, the adhesive design of cardiac patches has encompassed both physical fixation and chemical adhesion. Physical fixation is represented primarily by microneedle patches that penetrate the myocardium. However, traditional microneedle tips, which are smoothly conical, exhibit suboptimal fixation. Lu et al⁵⁵ drew inspiration from the intricacies of honeybee stingers to devise a patch with unidirectional backward-facing barbs of hard polymer microneedles that self-interlocked on hearts. Intriguing biomimetic microneedle designs also include octopus suction cups, snake fangs, and shark teeth (Figure 4B). Chemical adhesion involves the introduction of certain chemical groups into the scaffold material to form hydrogen, ionic, Schiff base,⁵⁶ Michael-type addition,⁵⁷ or covalent bonds⁵⁸ with myocardial tissue surface groups (eg, -NH₂ and -SH), represented by the catechol of dopamine and other mussel derivatives.⁵⁹ However, the adhesive properties on both sides of the patch may cause adhesion to the pericardium, surrounding tissues, and chest wall during surgical procedures. He and colleagues⁶⁰ developed an asymmetrically adhesive Janus hydrogel, wherein the basal hydrogel layer established multiplex dynamic noncovalent interactions with tissues, with the top layer exhibiting anticell adhesion and nonfouling properties, thereby ensuring that only the inner side (adjacent to the epicardium) remained highly adhesive (Figure 4C). Developing stable and robust adhesion methods will be the foundation for the minimally invasive delivery of patches⁴⁵ and the cornerstone for high-quality cardiac signal sensing.⁶¹

Biocompatibility and Degradability

Biocompatibility is the premise for translating the patch materials and their degradation products. On interaction with the human body, cardiac patches should demonstrate minimal foreign-body reactions (thereby preventing severe inflammation, ECM deposition, fibrous capsule formation, and tissue adhesion) and low toxicity (avoiding damage to the liver and kidneys).⁶² Optimal biocompatibility standards would require little or no initial acute postimplantation inflammation that would subside during follow-up without notable impairment of liver and kidney functions. Consequently, it is essential to focus on evaluating material-induced immune responses,⁶³ monitoring inflammatory responses (particularly in large-animal models), and assessing clinical biochemical markers, including liver function (alanine aminotransferase, aspartate aminotransferase, and albumin/globulin) and kidney function (blood urea nitrogen and creatinine). Autologous materials are promising in minimizing the risk of immune rejection. The degradability of patches in clinical translation should be customizable for different patients and disease stages. For patients with HF of advanced functional class, age, and frailty (ineligible for heart transplantation or left ventricular assist devices), continuous mechanical support is essential to ameliorate the symptoms. In such cases, nondegradable polymer materials should be selected to prevent the loss of mechanical integrity. Conversely, patches composed of degradable materials can release preloaded substances and provide ventricular support before degradation. Appropriate degradability prevents potential secondary surgeries to separate the patch from the heart. However, an excessively rapid degradation rate (as observed in certain natural materials such as dECM) may lead to premature patch loss and failure. Researchers have manipulated the degradation kinetics by using composite materials, thereby prolonging the mechanical effects of the patch⁶⁴ and allowing the time-dependent release of loaded bioactives in synchrony with scaffold degradation, achieving sustained and controlled treatment.¹³

Vascularization

Vascularization of cardiac patches can enhance the survival of loaded cells, facilitate inward diffusion and release of reparative factors, and ameliorate the hostile microenvironment of the infarcted area. Given that current patch studies are conducted primarily on small animals with relatively small patch sizes, the impact of vascularization on the therapeutic efficacy is somewhat diminished. However, in terms of the future applications of cardiac patches in larger animals and clinical trials, the dimensions are expected to be substantially larger and thicker. The increased volume of biomaterials may pose challenges to internal oxygen diffusion and nutrient exchange, hindering cell survival. Recently, strategies for vascularizing cardiac patches can be categorized into cell- and scaffold-based approaches. Cell-based strategies encompass the self-assembly or cocultivation of various vessel-forming cells such as endothelial cells, fibroblasts, progenitors, and stem cells to achieve vascularization. Among these, cell sheets, cell spheroids⁶⁵ (Figure 4D), or microtissues with cellular spatial organization²⁶ have been reported to successfully construct vascularized patches. Moreover, endothelial cells have been used to directly construct microvessels within patches with 3D printing⁶⁶ or microfabrication technologies. Su et al⁶⁷ achieved the construction of freestanding biomimetic microvessels within fibrin gel scaffolds through microfluidic hydrodynamic focusing with internal and external diameters of ≈250 and 550 μm, respectively. It is important to note that patches of clinically relevant dimensions (5 cm×5 cm×1 mm) prepared with this method were safe and effective in a porcine MI model. In addition, cell-derived growth factors such as VEGF, basic fibroblast growth factor, platelet-derived growth factor, and hepatocyte growth factor (HGF) have been shown to activate endothelial (progenitor) cells and stimulate their migration toward factor gradients. Scaffold-based strategies primarily involve the construction of porous architectures within a patch, which facilitates the survival and migration of loaded or in situ cells and vascularization after implantation. Materials with pore sizes exceeding 50 μm can enhance long-term vascular survival, although excessively large pores may inhibit vasculogenesis, possibly rooted in the interaction between pore size and endothelial diameter.⁶⁸ The formation of a porous architecture and its parameters such as porosity are influenced by the intrinsic properties of the material, the aforementioned fabrication technologies, and other processing methods such as thermally induced phase separation, freeze-drying, and gas foaming. Natural materials, which generally exhibit superior biocompatibility and more cell adhesion sites, are more advantageous than synthetic polymers for the formation of internal vascular networks. Among these, dECM, which retains the morphological characteristics and some provascular active factors of the original tissue, is a popular material for cardiac tissue vascular engineering. Nevertheless, the current challenges in the vascularization of cardiac patches persist. Construction of high-density vascular networks is technically difficult. Theoretically, constrained by the limits of oxygen diffusion, the distance between internal vessels in engineered tissue should be <200 μm. In addition, the vascular density in current engineered cardiac tissue is ≈7-fold lower than in the human heart (which ranges from 2000 to 3000 capillaries/mm²).⁶⁹ Furthermore, most existing vascularization strategies for patches rely on the natural process of vasculogenesis within the body, which may span weeks. In contrast, because of the lack of microsurgical connections, in vitro vascularization faces challenges in anastomosing with the marginal host cardiac vascular system after implantation, which may influence the stability of efficacy. Consequently, further research on the vascularization of cardiac patches is required.

THERAPEUTIC STRATEGIES

Some patches rely solely on their intrinsic mechanical and conductive properties to confer cardioprotective effects. Numerous studies have used patches as a platform to load and deliver cells (Table S1) and other bioactive compounds (Table S2), including cellular derivatives such as growth factors and exosomes, genes, drugs, and gaseous signaling molecules, thereby improving cardiac repair. Particularly for patients with defective endogenous cardiac repair such as those with diabetes, chronic kidney disease, or advanced age, sustained provision of exogenous therapeutic agents through patches may improve prognosis.

Cellular Therapy

Preclinical and clinical studies have indicated that cellular therapy alleviates myocardial injury after MI and reduces the incidence of HF. Cardiac patches provide the requisite 3D microenvironment for cells, significantly enhancing the retention rate within the infarcted area. Although cellular therapies are currently beset with numerous challenges for clinical applications, including US Food and Drug Administration approval, immune rejection, tumorigenicity, risk of arrhythmia, and ethical considerations, their advantage lies in constant therapy through the multifunctionality of cells. Therefore, the development of cell-loaded patches should be considered. Currently, stem cells are the main cells loaded into patches and can be categorized into multipotent/adult stem cells (cardiac stem/progenitor cells and mesenchymal stem cells [MSCs]) and pluripotent stem cells (embryonic stem cells [ESCs] and induced pluripotent stem cells [iPSCs]) according to their differentiation potential.

Cardiac Stem/Progenitor Cells

In 2003, researchers identified a stem cell population within the heart, but the origins and abundance remain ambiguous; it includes c-kit⁺ cells, cardiosphere-derived cells, and stem cell antigen-1⁺ cells. Studies have categorized these cell populations, according to membrane surface markers, into specific cardiac stem cells (CSCs) or cardiac progenitor cells.⁷⁰ However, the expression of most of these markers often overlaps, suggesting that such cells could result from a 1-cell phenotype shift. Although there are significant confusion and debate over the reparative role of CSCs/cardiac progenitor cells as cardiomyogenic precursors, a plethora of studies over the past 2 decades have indicated that the cardioprotective effects of CSCs/cardiac progenitor cells after MI depend mainly on their paracrine activities,⁷¹ involving VEGF, angiogenin, and basic fibroblast growth factor. The atrial appendage is a natural reservoir of cardiac progenitor cells. Xie et al⁷² constructed a patch consisting of autologous atrial appendage micrografts covered with ECM. After anchoring to the epicardium of ischemic regions, it salvaged functional cardiac tissue and limited postinfarction fibrosis by activating the cardiogenic and cardioprotective pathways. Subsequent preliminary clinical trials confirmed the feasibility and safety of atrial appendage micrografts in cardiac surgery in patients with stable coronary artery disease or chronic HF.⁷³ However, because of the unique challenges in harvesting atrial appendage micrografts and the time required for intraoperative preparation, its application in acute MI or HF cases is limited. Future exploration of allogeneic sources as alternatives could broaden their applicability; however, issues related to donor availability and immunogenicity remain significant challenges. Su et al⁷⁴ prepared patch-loaded CSCs combined with biomimetic microvessels (biomimetic microvessel–CSC patch). Four weeks after treatment in the acute MI rat model, biomimetic microvessel–CSC patch therapy significantly stimulated mitotic activity in endogenous CMs around the infarct zone and enhanced their proliferation, which may be attributed to the cell-cycle reentry mechanism of CMs stimulated by CSCs. This suggests the potential of the patches to trigger and modulate the proliferation of endogenous CMs to mediate regenerative therapies through the delivery of pertinent signaling factors. However, current research on CM regeneration is still controversial, and there is uncertainty about its efficacy, molecular mechanisms, and oncogenic risks.⁷⁵

Mesenchymal Stem Cells

MSCs are among the most commonly used multipotent stem cells in clinical research and are renowned for their paracrine effect, low immunogenicity, and diverse origins, including bone marrow, adipose tissue, placenta, and umbilical cord blood. Gene engineering of loaded MSCs has recently emerged as a potent strategy in cardiac patch research. The commonly used strategy is the overexpression of specific factors within MSCs to increase their paracrine efficiency in ischemic regions. Park et al⁷⁶ developed gene-engineered MSCs that continuously released HGF through lentiviral transduction, which were coencapsulated with unedited bone marrow–derived MSCs within hydrogel-dECM to fabricate cardiac patches. Persistent HGF stimulation primed and amplified the paracrine functions of the unedited bone marrow–MSCs, effectively improved cardiac function, and reduced adverse remodeling in MI rats, and most gene-engineered cells seemed to be fixed within patches without migration to the myocardium. In addition, to further enhance therapeutic efficacy, loaded MSCs can be predifferentiated into CM-like cells by gene editing–mediated signaling pathways (eg, the typical Wnt/β-catenin pathway) and electrical or mechanical stimulation before transplantation.⁷⁷ Compared with MSCs dispersed in a 2-dimensional fashion on cardiac patches, MSC aggregates, spheroids, or microtissues exhibit improved angiogenesis, anti-inflammatory and immunomodulatory effects, better ischemic tolerance, and greater oxidative stress resilience,⁷⁸ which may facilitate a more stable and sustained performance of the MSCs in the infarcted region.⁷⁹ Numerous clinical studies have been conducted on MSCs; however, several pivotal issues remain unresolved, including the obscurity of paracrine therapeutic mechanisms and variability in individual efficacy. As platforms, patches appear to offer a standardized approach. Containing MSCs within the internal network structure enhances survival and retention rates, allowing constant or controllable paracrine signaling at the site of implantation.

Embryonic Stem Cells

ESCs are derived from the embryonic inception of the blastocyst inner cell mass. Human ESCs were first isolated in 1998 by Thomson et al.⁸⁰ Over the past 2 decades, CMs derived from human ESCs have exhibited promising therapeutic potential in rodent MI models and have reduced both spontaneous and induced ventricular arrhythmias.⁸¹ However, ventricular arrhythmias in nonhuman primate models hamper the clinical translation of CMs derived from human ESCs.⁸² In 2018, 6 patients with severe ischemic left ventricular dysfunction underwent the implantation of fibrin patches loaded with human ESC-derived cardiovascular progenitors onto the epicardium during a coronary artery bypass grafting procedure.⁸³ In a 1-year follow-up, no arrhythmias or tumors were observed. One patient had HF after 22 months, whereas echocardiographic assessments revealed significant improvements in the wall motion of the ventricular segments treated with the patches. In addition, there was a notable improvement in the patients’ New York Heart Association functional class (III to I/II), and left ventricular ejection fraction increased (26% to 38.5%). These findings provide evidence of the feasibility and short-term safety of patch-loaded clinical-grade human ESCs. However, ethical concerns about ESC sources present a pivotal impediment to their widespread short-term clinical application.

Induced Pluripotent Stem Cells

In a landmark study in 2006, Takahashi and Yamanaka⁸⁴ reprogrammed murine fibroblasts, culminating in the derivation of iPSCs. CMs derived from iPSCs (iPSC-CMs) aim to integrate with the grafted heart and not only replace those lost as a result of MI but also secrete some paracrine factors such as VEGF and HGF. Compared with ESCs, iPSCs can be procured autologously, avoiding the ethical and legal difficulties of ESCs. Nevertheless, a challenge in directly delivering iPSC-CMs in cardiac patches is their immature differentiation and functionality, which manifests a phenotype akin to that of fetal CMs and might induce electrical conduction disturbances. Incompletely differentiated iPSCs harbor in vivo tumorigenic risks. Cardiac patches, as carriers for iPSC-CMs, provide the possibility of a diverse array of preimplantation preprocessing steps to facilitate their maturation, including structural induction, exogenous stimuli (electrical and cyclic stress), coculturing,⁸⁵ and the introduction of conductive materials. English et al⁸⁶ used molding to introduce micropatterning on fibrin gel patch surfaces, mirroring the anisotropic microtopographical characteristics of the native epicardium (Figure 5A), facilitating the organized arrangement of iPSC-CMs and the expression of connexin-43. Gao et al⁸⁷ used fibrin scaffolds to culture the trilineage differentiation of iPSCs, including iPSC-CMs, smooth muscle cells derived from iPSCs, and endothelial cells derived from iPSCs, crafting a cardiac patch with a clinically relevant size and thickness (4 cm×2 cm×1.25 mm). After a 7-day dynamic coculture using cyclic shaking, the stimulated cardiac patch demonstrated maturation of the myoplasmic reticulum, exhibiting superior force generation and calcium-handling capabilities. In addition, scaffolds modified with graphene oxide enhanced the relative maturation and conduction uniformity of loaded iPSC-CMs,⁸⁸ indicating that conductive patches have the potential to reduce the risk of arrhythmias induced after the transplantation of cells. For clinical translation, patch-mediated delivery of iPSC-CMs is promising, with better standardization from improved survival rates and cell quantity control and reduced risk of arrhythmias by promoting maturation and uniform orientation of CMs to avoid uneven propagation of action potentials. However, challenges such as tumorigenicity (due to potential genetic alterations during the reprogramming process), uncertain optimal time of differentiation, technical approval and regulation (including genetic engineering or preconditioning), and economic considerations remain to be addressed for future iPSC therapies.

Figure 5.

Application of cardiac patches for the delivery of therapeutic components. A, Schematic illustration of the fabrication of micropatterned scaffolds using photolithography techniques, followed by the seeding of human induced pluripotent stem cell–derived cardiomyocytes to improve alignment and electrical response. Adapted with permission from English et al.⁸⁶ Copyright © 2023, John Wiley & Sons. B, The artificial cardiac patch (artCP) was transplanted into the epicardium of Yorkshire pig hearts to cover infarcted areas. Compared with the control group, the artCP-treated group exhibited a smaller infarct size and less severe fibrosis. Adapted with permission from Huang et al.⁹⁰ Copyright © 2020, American Association for the Advancement of Science. C, In situ formation of hyaluronic acid (HA) hydrogel patches loaded with exosomes within the pericardial cavity by intrapericardial injection prolongs the retention time of the exosomes. Adapted with permission from Zhu et al.⁹² Copyright © 2021, Springer Nature. D, Schematic illustration of the preparation of nitrate-functionalized fibrous film and the release of nitric oxide (NO) at the infarction site. Adapted with permission from Zhu et al.⁹⁹ Copyright © 2021, Springer Nature. MA indicates methacryloyl; MI, myocardial infarction; MSC, mesenchymal stem cell; and PCL, polycaprolactone.

Growth Factors

Due to the inherent limitations of cellular therapies, some researchers have emphasized the delivery of crucial reparative factors. Because of the degradation properties of the material, cardiac patches can locally and sustainably release regenerative factors such as neuregulin-1,³¹ platelet-derived growth factor, insulin-like growth factor, and VEGF. Huang et al⁸⁹ constructed a perfusable, multifunctional epicardial device embedded with a permeable hierarchical microchannel network for drug storage and a subcutaneously implanted drug pump, enabling consistent, targeted, and stable release of platelet-derived growth factor-BB in infarcted regions, thereby promoting local angiogenesis. Some researchers have proposed delivering various factors for synergistic modulation, potentially offering superior reparative outcomes compared with single factors. Huang et al⁹⁰ encapsulated myriad factors secreted by CSCs, including VEGF, HGF, and insulin-like growth factor, into poly(lactic-co-glycolic acid) and assembled them into synthetic CSCs, which were integrated with a decellularized porcine myocardium scaffold to fabricate acellular artificial cardiac patches. It is notable that the artificial cardiac patch was functional in the porcine MI model after 7 days of treatment (Figure 5B). Moreover, because of the complexity of MI repair, a single-patch system that enables multiprocess modulation strategies is worth exploring. However, the practicality of achieving a synergistic effect wherein the “muti” exceeds the “mono” in clinical settings and the potential adverse impacts of excessive exogenous regenerative factors remain to be validated. Susceptibility to deactivation, low-temperature storage requirements, and high costs limit the clinical application of growth factor therapy.

Exosomes

Exosomes are extracellular vesicles with diameters ranging from 40 to 120 nm and a lipid bilayer structure that encapsulates a diverse array of growth factors, mRNAs, and microRNAs. They function effectively in adverse ischemic and hypoxic microenvironments. Several studies have used extracellular vesicles as vectors of microRNAs using patches for gene therapy delivery.⁹¹ Whereas exosomes have demonstrated promising cardiac regenerative potential, their therapeutic efficacy is compromised owing to their brief plasma half-life. Direct injection into the infarcted region results in rapid metabolic clearance. Cardiac patches serve as platforms, allowing localized and sustained exosome storage and release. Zhu et al⁹² devised an innovative cardiac patch preparation and minimally invasive transplant strategy, using the pericardial cavity as a natural mold and using in situ gelation after intrapericardial injection. Accordingly, a hyaluronic acid hydrogel containing MSC-derived exosomes was introduced into the pericardial cavity of MI mice (Figure 5C), which prolonged the retention time of exosomes. Extended follow-up revealed morphological improvements in the mouse hearts and the concurrent inhibition of the onset of HF. Although exosomes are a popular topic for tissue repair, the difficulty in preparation and the challenge of large-scale production hinder their clinical translation.

Gene Therapy

Cardiac patches enable platforms to deliver therapeutic genes loaded into nonviral or viral vectors to the infarct zone. Nonviral vectors, including naked DNA, liposomes, and nanoparticles, have superior nucleic acid loading efficiency, cost-effectiveness, straightforward synthesis, and mass production. Yuan et al⁹³ used exosomes derived from human umbilical cord MSCs as gene vectors and introduced a microRNA-29b mimic through electroporation, which was subsequently absorbed onto a gelatin-based microneedle patch with a soaking method. By leveraging the internalization of exosomes by fibroblasts in the infarct zone, miR-29 expression was amplified, resulting in the downregulation of the transforming growth factor-β/Smad3 signaling pathway and target genes coding for ECM, thus inhibiting myocardial fibrosis. Unlike nonviral vectors, viral vectors often exhibit higher delivery and transgene expression efficiencies. Recombinant adeno-associated virus (AAV) vectors have attracted considerable attention owing to their minimal immunogenicity prolonged gene expression and attenuated pathogenicity. AAV1, AAV6, and AAV9 were able to transduce CMs in the heart, with AAV9 exhibiting the highest transfection efficiency.⁹⁴ Shi et al⁹⁵ uniformly coated a poly(vinyl alcohol)–fabricated microneedle patch with an AAV vector encoding VEGF, which effectively reduced infarct area and improved cardiac function in a rat MI model. However, genetic engineering is currently controversial in many areas, including the medical and food industries, where obtaining US Food and Drug Administration approval is difficult and validation of its safety is critical.

Gas Therapy

Gaseous signaling molecules, including nitric oxide and H₂S, are involved in mitigating post-MI injuries and aiding repair. The primary role of nitric oxide is in mitochondrial protection and curbing the excessive production of ROS, thereby modulating subsequent inflammation.⁹⁶ H₂S can modify macrophage phenotypes and regulate signaling pathways that facilitate cardiac fibrosis induced by MI and hypertension.⁹⁷ However, the clinical application of these gas molecules is limited by their short retention times, poor target specificity, and significant systemic side effects. Patches can be a safe platform for the localized delivery of these molecules in prodrug form.⁹⁸ Zhu et al⁹⁹ synthesized a nitrate-functionalized fibrous film by covalently modifying both ends of the low-molecular-weight polymer polycaprolactone with nitrates to form polycaprolactone-ONO₂ using electrospinning. On transplantation, the nitrate functional groups underwent nonenzymatic hydrolysis and locally released nitric oxide (Figure 5D). This nitrate-functionalized fibrous film improved survival rate, reduced infarct size, and enhanced vascular regeneration in a clinically relevant porcine model of cardiac ischemia/reperfusion injury. These patch-mediated, localized, smart gas signaling molecular delivery strategies require further investigation.

LIMITATIONS AND FUTURE PROSPECTS

Here, we describe both short- and long-term perspectives on the future development of cardiac patches. In the short term, the aim is to expedite clinical translation, which requires the consideration of 3 aspects. First, there is a shortage of large-animal model studies because current research focuses predominantly on small animals, with only a few pig models assessing implantability and short-term efficacy. Comprehensive efficacy and safety evaluations in large-animal models such as pigs, sheep, and nonhuman primates are crucial before clinical trials. Moreover, the significant difference in ventricular wall thickness between large and small animals, which affects the penetration of active substances, should not be overlooked. Although the efficacy of microneedle patches has been validated in several studies, exploring other methods to enhance myocardial permeability is advisable. Ultrasonography, which has been reported to enhance transdermal drug delivery efficiency through acoustic porosification (opening mechanical channels in the skin), could be a possible strategy for the heart. Second, there needs to be acceleration of bioactive substances research. Given the challenges of US Food and Drug Administration approval, large-scale production, and storage of bioactive compounds such as cells, growth factors, exosomes, and genes, autologous substances appear more readily translatable but may not be suitable for short-term scenarios. The immediate priority is to develop well-defined allogeneic products that are standardized in production with high batch-to-batch consistency and minimal rejection responses. Third, multimodal therapies should be explored. Cardiac patches that integrate various therapies may be more adaptable to multiple complex clinical scenarios, including phototherapy, photothermal therapy, sonodynamic therapy, pulsed electromagnetic field therapy, microwave therapy, and magnetic therapy. Furthermore, a forward-looking trajectory for the cardiac patches involves integration with intelligence. The first step is to integrate stable and highly sensitive biosensors into the patch for real-time monitoring. If specific local cardiac biochemical markers, strain, stress, and temperature fluctuations are detected, there is a potential for effective post-MI prognosis management, enabling medical personnel to be promptly informed of the patient’s condition such as coronary restenosis, malignant arrhythmias, progressive cardiac dysfunction, and HF. With the use of monitoring, implementing signal feedback for intelligent adjustment of drug delivery schemes could minimize ineffective medication while achieving precision treatment, especially for patients with underlying conditions that necessitate long-term monitoring and management.

CONCLUSIONS

Cardiac patches aim to enhance reparative processes after MI and mitigate ventricular remodeling, thereby preventing progressive HF. With continuous advancements in tissue engineering, various types of cardiac patches have shown promising therapeutic effects and clinical potential in numerous in vivo and in vitro studies. In terms of materials, researchers have experimented with a combination of synthetic, natural, and conductive materials to engineer patches with good mechanical properties, adhesion ability, conductivity, biocompatibility, degradability, and vascularization. As materials science progresses and the mechanisms underlying reparative promotion from mechanical support are further explored, future patches are expected to mimic or surpass the properties of the native myocardium. On the basis of postinfarction pathophysiology, using cardiac patches as a platform for the localized delivery of cells and their derivatives (growth factors and exosomes), genes, and gaseous signaling molecules constitutes the primary therapeutic strategy. This review has addressed the current limitations in clinical translation and provided an outlook on cardiac patch research to illustrate innovative patch designs and developments poised for clinical application.

ARTICLE INFORMATION

Sources of Funding

This work was supported by the National Natural Science Foundation of China (U23A20395, 82170375, 32101134, 32101161); Key Research and Development Project of Science & Technology Department of Sichuan Province (2022ZDZX0020); Program of Science and Technology Department of Sichuan Province (23NSFSC0884, 2022YFS0203); Technology Innovation Project of Science and Technology Bureau of Chengdu (2022-YF05-01468-SN, 2022-YF05-01724-SN); Chinese Medical Association Cardiovascular Branch (CSC) Clinical Research Special Fund Project (CSCF2020B04); Institutional Research Fund from Sichuan University (2023SCUH0030); 1· 3· 5 Project for Disciplines of Excellence–Clinical Research Fund, West China Hospital, Sichuan University (2023HXFH009).

Disclosures

None.

Supplemental Material

Tables S1 and S2

References 100–150