Reprogramming the Myocardial Infarction Conductive Microenvironment with Superconductive Ionic Patch for Cardiac Function Repair
Changyong Wang, Zhuang Zhang, Qi Yin, Changgeng Xu, Linlin Liang, Siwei Li, Yuwei Zhao, Chunlan Wang, Jin Zhou
TL;DR
A new superconductive patch improves heart function after heart attacks by enhancing electrical signals and tissue repair.
Contribution
A superconductive ionic patch is developed for stable electrical coupling and cardiac repair after myocardial infarction.
Findings
The patch enables stable ionic migration and electrical signal transmission in damaged heart tissue.
It enhances conduction velocity and reduces depolarization and repolarization durations in MI models.
The patch reduces infarct size and improves ejection fraction in rat and mini-pig models.
Abstract
Cardiac patches demonstrate promise in the treatment of myocardial infarction (MI). However, their clinical application encounters challenges, particularly electrical coupling instability, impairing myocardial contractility and functional reconstruction. Here, we developed a super‐conductive ionic patch with high electrical stability and biocompatibility based on a choline‐derived bio‐ionic liquid (Bio‐IL). The patch formed multiple interactions with the cardiac interface, including covalent bonds and ionic interactions, achieving rapid and stable adhesion. In the infarcted area, ‐N(CH3)3⁺ in Bio‐IL dynamically interacted with host anions, enabling mutual ionic migration and consistent electrical signal transmission. The electrophysiological integration and reparative effects of the patch were evaluated in rat and mini‐pig MI models. Results demonstrated enhanced electrical signal…
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Taxonomy
TopicsTissue Engineering and Regenerative Medicine · Cardiac electrophysiology and arrhythmias · Cardiac Fibrosis and Remodeling
Introduction
1
Myocardial infarction (MI) typically causes massive death of cardiomyocytes, leading to cardiac dysfunction and ultimately progressing to heart failure.[1, 2] In recent years, cardiac patches, as a therapeutic strategy for replacing and repairing infarcted myocardium, have shown potential in cardiac regeneration.[3, 4] These patches are designed to mimic critical features of myocardial tissue, including extracellular matrix (ECM),[5, 6] mechanical properties,[7] and spatial configuration.[8, 9] While they achieve structural integration with host tissue and partially restore cardiac function, their efficacy in fully recovering physiological cardiac performance remains suboptimal.[10] A key limitation is their failure to adequately replicate the unique excitation‐contraction coupling electrophysiology of the heart, which compromises both the intrinsic electrical activity of the patch and its ability to rebuild stable electrocoupling with host tissue.
To address this issue, the incorporation of conductive components has become a pivotal strategy in cardiac patch design.[11, 12] Gold nanowires were first incorporated into alginate scaffolds and confirmed to enhance intercellular electrical conduction in cardiomyocytes.[13] Subsequently, metal‐based,[14] carbon‐based,[15] and conductive polymers were employed to construct highly conductive patches.[16] Notably, these conductive materials not only improve synchronized contraction with engineered cardiac tissues (ECTs), but also enhance electrocoupling efficiency between ECTs and host myocardium.[17, 18] However, achieving dynamic synchronization and stable electrical conduction at the patch‐host interface during rhythmic cardiac contractions remains challenging. This limitation primarily stems from the fact that electron‐dominated conduction fails to replicate the continuous and stable ion‐mediated signal transmission of native cardiac tissue.[12, 19, 20] Thus, developing ionic conductive patches that mirror the physiological signal propagation of healthy myocardium is a promising solution.
Ionic conductive patches, initially developed as sensors and electrode materials of wearable devices and flexible electronics,[21, 22, 23] offer potential for the simulation of the continuous transmission process of cardiac action potentials through ion transport across interfaces. This approach provides a theoretical and technical foundation for constructing a biomimetic conductive microenvironment similar to the myocardium.[24, 25, 26, 27, 28] In recent years, biomimetic conductive units like polyacrylic acid (PAA) and carboxybetaine methacrylate (CBMA) have been employed in patches for MI treatment, and have shown some promising results on cardiomyocyte maturation, functionalization, and restoration of electrical conduction.[24, 26] Among them, acrylic acid serves as an ion‐conductive monomer to construct cross‐linked networks, and has been proven to facilitate the formation of micro‐ homogeneous ionic channels.[24] It has also been combined with gelatin and AAc‐NHS to prepare double‐sided tape (DST) with robust wet tissue adhesion and mechanical toughness.[29] Despite these advances, PAA‐based patches can hardly achieve the high electrical conductivity required in the infarct area, especially their high interfacial impedance that prevents stable interfacial electrical conduction. Therefore, we engineered a super‐conductive ionic patch by integrating bio‐derived ionic liquid (Bio‐IL) into PAA/gelatin hydrogel, which holds the advantages of high ionic conductivity, low interfacial impedance, biodegradability, and promoting cell directional migration,[27, 28] providing a new insight into the reconstruction of the conductive microenvironment in MI.
In this study, we developed a super‐conductive ionic adhesive patch using gelatin, acrylic acid (AAc), N‐hydroxy succinimide ester of acrylic acid (AAc‐NHS), and Bio‐IL (Figure 1). The patch is easy to prepare and implant, and aviods secondary damage caused by sutures or biological glue. Its robust adhesion originates from the ‐NHS ester and ‐N(CH_3_)3⁺ groups on the patch, forming multiple interactions, including covalent and ionic bonds with cardiac tissue. In addition, the patch can dynamically adapt to cardiac contraction‐relaxation cycles, showing high and stable conductivity and synchronous signal transmission ability. This feature helps to restore the normal function of the myocardium and reduce the occurrence of arrhythmias. Critically, we discovered that the mechanism of reprogramming the conductive microenvironment was through promoting the excitation‐contraction coupling of the myocardium. Additionally, the efficacy and safety were further validated in mini‐pigs.
*Schematic of the fabrication, application, and function of the ionic conductive adhesive patch. The ionic conductive adhesive patch is prepared by one‐pot synthesis, composed of gelatin, AAc, AAc‐NHS, GelMA, and Bio‐IL. The patch provides migration channels for counter‐ions, exhibiting stable conductivity during the cardiac systole‐diastole cycle. Simultaneously, the ‐NHS and ‐N(CH3)3
- groups within the patch can form multiple interactions with the heart surface, including covalent bonds and ionic bonds. After implantation for 28 days, the patch promoted infarct size reduction and cardiac electrical integration and inhibited excitation‐contraction decoupling, thereby restoring cardiac function.*
Results
2
Construction and Mechanical Property Characterization of Super‐Conductive Ionic Patches
2.1
The hydrogel precursor was prepared according to a previously reported protocol by dissolving AAc, AAc‐ NHS, gelatin, etc. in distilled water [29]. Then, Bio‐IL was incorporated at 0, 2%, 4%, or 6% (w/w), named as PGN (polyacrylic acid‐gelatin‐AAc‐NHS), PGNB1 (polyacrylic acid‐gelatin‐AAc‐NHS‐Bio‐IL‐1), PGNB2, and PGNB3, respectively. These patches were transparent, with a diameter of 10 mm and a thickness of 0.2 mm (Figure S1A, PGNB2). Upon hydration, the patch transformed into an elastic hydrogel. Fourier‐transform infrared (FTIR) spectroscopy revealed a carboxyl C═O stretching vibration at 1,700 cm^−1^ in all patches, confirming polyacrylic acid (PAA). The symmetric and asymmetric C─N─C stretching vibration at 1,170 and 1,230 cm^−1^, respectively, confirmed the presence of NHS‐ester in PGN and PGNB patches. Additionally, the conductive Bio‐IL units were evidenced by the C─N stretching vibration at 960 cm^−1^ and the ‐N(CH_3_)3 ^+^ methyl peak at 3,190 cm^−1^ in PGNB patches (Figure S1B). All patches exhibited interconnected porous structures, facilitating ion penetration and nutrient transport, cell growth, and migration (Figure 2A). The pore size decreased with increasing Bio‐IL content, attributed to increased cross‐linking from ionic interactions (Figure 2B). The patches rapidly absorb water and swell, maintaining a relatively moist environment on the cardiac surface (Figure S1C).
Characterization of the mechanical properties and adhesion properties of the patches. (A) Microtopography of the patches obtained by SEM. The scale bars are 20 µm. (B) Pore size calculated from SEM images. Values represent the means ± SD (n = 12). (C) Stress–strain curves and tensile modulus of the patches. (D) Stress–strain curves and compressive modulus of the patches. (E) Settings for measurement of tensile strength, based on the standard tensile test (ASTM F2258). (F) Tensile force curves and tensile strength. (G) Settings for measurement of shear strength, based on the standard lap‐shear test (ASTM F2255). (H) Shear force curves and shear strength. (I) Settings for measurement of interfacial toughness, based on the standard 180° peel test (ASTM F2256). (J) Peel force curves and interfacial toughness. F, force; L, length; W, width. P values are determined by one‐way ANOVA followed by Tukey's post‐hoc test: * p < 0.05, ** p < 0.01, *** p < 0.001.
Given that excessive swelling can lead to damage to the molecular chain structure, thus causing a decrease in mechanical properties and elastic modulus, these changes may hamper the ability to cope with the left ventricle.[30, 31, 32] However, in this work, the tensile modulus increased from 22.35 ± 2.29 to 60.39 ± 4.83 kPa, and the compressive modulus increased from 40.29 ± 3.98 to 115.89 ± 10.54 kPa with the increase of Bio‐IL, showing a remarkable enhancement in mechanical properties (Figure 2C,D). The elastic modulus of the patches was consistent with the natural myocardium (0.02–0.5 MPa),[33] which aids in reducing left ventricular wall stress and enhances mechanical coupling with cyclically deforming myocardium.[7, 34] Additionally, rheological analysis showed that G′ consistently exceeded G″ across all frequencies (Figure S2A), indicating that the patches exhibit stable viscoelastic solid properties.
Upon being attached to the heart surface, the dry patch rapidly hydrated, forming a hydrogel that adhered strongly to tissue. To detect the patch's adhesive properties, the tensile, shear, and 180° peeling tests were performed between patches and cardiac tissue. (Figure 2E,G,I).[29] The tensile strength of PGN was 19.04 ± 1.90 kPa, whereas that of the PGNB patch increased from 25.68 ± 1.78 to 38.78 ± 3.31 kPa with the addition of Bio‐IL (Figure 2F), indicating that Bio‐IL enhances adhesion of the patch. This improvement may be attributed to the formation of multiple interactions between the patch and cardium, including ionic bonds and covalent bonds via ‐N(CH_3_)3 ^+^ and NHS‐esters, respectively.[27, 29, 35] To confirm that AAc‐NHS in the hydrogel formed covalent bonds with heart tissue, PG, PGN, and PGNB patches were incubated with amino‐grafted fluorescent microspheres. Only PGN and PGNB patches exhibited strong fluorescence, demonstrating that NHS‐esters facilitate covalent bonding with amino groups (Figure S2B,C). Furthermore, shear strength and interfacial toughness increased with Bio‐IL content (Figure 2H,J), indicating that the adhesive capability of the patches improves with the increase of Bio‐IL, likely due to ionic bonds between the negatively charged tissue and the positively charged patch. In addition, the patch is initially in a dry state, which enables long‐term storage, improving the practicality and convenience.
Super‐Conductive Ionic Patches Showing Compatible Conductivity and Stability with Myocardium
2.2
The ‐N(CH_3_)3 ^+^ groups of Bio‐IL imparted inherent positive charges to the hydrogel patches, enabling the migration of oppositely charged ions and resulting in high ionic conductivity. The light‐emitting diodes (LEDs) circuit tests showed brightness increased with Bio‐IL (Figure S3A), indicating PGNB3 had maximal conductivity. The electrochemical performance was further evaluated using a three‐electrode electrochemical workstation (Figure S3B). Cyclic voltammetry (CV) demonstrated that Bio‐IL significantly enhanced patch conductivity, as evidenced by an increase in the hysteresis loop area, with PGNB3 showing the largest hysteresis loop area (Figure 3A). The conductivity of the PGN patch was the lowest (1.66 ± 0.39 × 10^−2^ S m^−1^) by four‐probe conductivity measurements, while the conductivity increased with the increase of Bio‐IL content, with the PGNB3 patch achieving the highest conductivity of 2.05 ± 0.04 × 10^−1^ S m^−1^ (Figure 3B). All PGNB patches matched the electrical conductivity of native myocardium (5 × 10^−3^ to 1.6 × 10^−1^ S m^−1^). [33, 36] To further evaluate the capability to transmit biological electrical signals, action potential (AP) amplitudes and response threshold voltages were recorded using an electrophysiological recorder for both contralateral and unilateral muscle stimulation tests [37]. The AP amplitude in unstimulated muscle on the PGNB patch was significantly higher than on the PGN patch by the contralateral muscle stimulation, with amplitude increasing with Bio‐IL content (Figure 3C,D). Unilateral muscle stimulation indicated that the threshold voltage for muscle contraction was significantly lower on the PGNB patch compared to the PGN patch (Figure S3C). Therefore, it was demonstrated that PGNB patches hold superior bioelectrical signal transmission capabilities compared to the PGN patches, with a positive correlation to Bio‐IL content through both bioelectrical conductivity tests.
Excellent conductivity of ionic conductive adhesive patches. (A) CV curves of ionic conductive patches recorded by a three‐electrode electrochemical workstation. (B) The conductivity of ionic conductive patches was measured by the four‐probe method. For each group, n = 3, * p < 0.05, ** p < 0.01, *** p < 0.001. (C) Schematic of the two‐muscle recording method and the AP amplitude of the unstimulated muscle at all tested voltages. (D) AP amplitude of ionic conductive patches with stimulation voltage 1 V at 0.2 V intervals. For each group, n = 6, * p < 0.05, ** p < 0.01, *** p < 0.001. (E) The conductivity of ionic and electronic conductive patches with tensile deformation was detected by the four‐probe method. (F) Resistivity of ionic and electronic conductive patches with tensile deformation detected by the four‐probe method. (G) Resistivity rate of change of ionic and electronic conductive patches with tensile deformation detected by the four‐probe method. (H) The SAXS profile of PGNB1. (I) Schematic of the method for characterizing the conductivity continuity of the patches. (J) The field potential signal before and after the patches are 100% stretched. (K) Electrical signal propagation heat map on the patches.
Ionic conductive hydrogels were found to maintain stable conductivity during deformation [23, 24], which may be attributed to the integration of conductive and elastic domains to form a continuous ionic conductive network, thus overcoming the mismatch of conductive homogeneity. To assess PGNB conductive stability during deformation, hydrogels doped with hydrophobic carbon nanotubes (CNTs) and poly (3,4‐ethylenedioxythiophene)‐poly (styrenesulfonate) (PEDOT: PSS) (PGNC and PGNP) were set as control groups, and the changes in conductivity were evaluated by stretching the hydrogel patches. When stretched to 50% strain, PGNB patches exhibited little variation compared to PGNC and PGNP in conductivity, resistivity, and the rate of resistivity change, indicating more stable conductive properties (Figure 3E–G). The stable conductivity may be related to the homogeneous dispersion of conductive units within the hydrogel. To evaluate the dispersion of Bio‐IL, Small‐angle X‐ray scattering (SAXS) was employed to reveal the nanoscale structure of PGNB1, and the results indicated a mass fractal dimension z of 1.0 for PGNB1 (Figure 3H), suggesting the presence of a mass fractal and homogeneous dispersion of ions within the hydrogel. Therefore, the conduction of electrical signals would not be significantly affected by deformation when the patches are applied to the surface of a beating heart. To further assess the bioelectrical signals conducted by the patch, one end of a rectangular patch was placed in contact with a Langendorff‐perfused rat heart, while the other end was connected to an electrode to collect the field potential. (Figure 3I). After 100% strain, the amplitude decay of the field potentials in the PGNC and PGNP was more pronounced than that of the PGNB, and the increase of Bio‐IL led to a decrease in the potential amplitude change, indicating that the signal transmission capability of PGNB were more stable (Figure 3J and Figure S4A). Heat maps of activation time and absolute indices demonstrated the conductivity uniformity after stretching. Aggregation of CNTs and PEDOT: PSS and increased interparticle distances during stretching led to signal propagation disorder and discontinuities in PGNC and PGNP, which could lead to discontinuous electrical signal conduction and arrhythmias in vivo. In contrast, PGNB maintained orderly signal propagation, and conductivity homogeneity improved with the increase of Bio‐IL (Figure 3K and Figure S4B). This homogeneous integration of elastic and conductive domains enables significant conductivity retention even under substantial deformation, ensuring continuous and stable bioelectrical signal transmission during cardiac contraction and relaxation. Additionally, the dynamic network conferred the patches excellent self‐healing properties (Figure S5A,B).
The interfacial impedance between patches and tissue plays a crucial role in electrical conduction coupling. Ionic or electronic hydrogels were utilized to replace the original commercial Ag/AgCl hydrogels, and subsequently, the impedance between different patches and porcine hearts was measured by an electrochemical workstation (Figure S6A,B). These results demonstrated that the ionic conductive patch exhibited a lower interfacial impedance in comparison with the electronic conductive patch and a superior performance to that of the commercial Ag/AgCl hydrogel (Figure S6C).
Ionic Conductive Patches Facilitating Cardiomyocytes Functionalization and Synchronous Contraction
2.3
The acrylic acid monomer residues were analyzed before transplantation, and results showed that only trace amounts of residual monomer were detected (Figure S7A,B). Neonatal rat cardiomyocytes (NRCMs) were cultured on PGN or PGNB patches for 1, 3, 5, and 7 days, and cell viability was assessed using the CCK‐8 assay. The results demonstrated that PGN, PGNB1, and PGNB2 had no significant impact on cell viability, with survival rates consistently exceeding 90%. However, PGNB3 exhibited noticeable cytotoxicity, with a progressive decline in cell viability over time (Figure S7C). Consequently, PGNB3 was excluded from subsequent in vitro and in vivo studies.
To investigate the impact of the patches on sarcomere structure, the maturation of cardiomyocytes was examined and revealed that cardiomyocytes on the PGNB2 patch exhibited a more mature sarcomere (Figure 4A). To evaluate whether the patch effectively facilitated synchronized contraction of cardiomyocytes, Fluo‐4AM was employed to assess the contraction behavior of the cardiomyocytes. Cardiomyocytes on the PGNB2 patch demonstrated more synchronized Ca^2+^ transients and higher fluorescence intensity compared with cardiomyocytes on other patches (Figure 4B). Quantitative analysis of Ca^2+^ transients showed that cardiomyocytes cultured on PGNB2 reached the peak values faster and had higher transient frequencies (Figure 4C and Figure S8). Furthermore, the temporal synchronization of Ca^2+^ transients across different regions indicated superior synchronization of cells cultured on PGNB2. Additionally, A 64‐channel microelectrode array (MEA) system was employed to measure the field potential frequency and amplitude of cardiomyocytes. The electrical pulse frequency and field potential amplitude of cardiomyocytes on PGNB2 patches increased significantly (Figure 4D–F). In contrast, cardiomyocytes on PGNC and PGNP hydrogels exhibited lower field potential amplitudes and AP frequencies. These results highlight that the PGNB2 patch enhanced signal transmission between cardiomyocytes and induced a more synchronized contractile behavior.
The effects of morphology and electrophysiology of ionic conductive patches on cardiomyocytes. (A) Immunostaining images of cTnT and Cx43 in cardiomyocytes on the patches after 7‐day culture. Scale bars: 20 µm. (B) Calcium transients and Ca2+ signal intensity and frequency of cardiomyocytes cultured on the patch. Scale bars: 50 µm. (C) Time taken from baseline to peak in one contraction‐relaxation process. (D) Representative MEA electrograms of cardiomyocytes grown on different patches. (E) Field potential amplitude of cardiomyocytes grown on different patches. (F) Field potential frequency of cardiomyocytes grown on different patches. For each group, n = 3, * p < 0.05, ** p < 0.01, *** p < 0.001.
Ionic Conductive Patches Promoting Myocardial AP Conduction in MI Rats
2.4
The reconstruction of cardiac electrical conduction pathways is critical for MI repair. In this study, a combination of optical and electrical mapping systems was used to systematically assess the effects of the ionic conductive patches on electrophysiological signals post MI.[32, 38, 39] Local AP was recorded within an 8 × 8 matrix electrode under 5 Hz electrical stimulation in the left ventricle (LV) one week after myocardial infarction (Figure S9A). The earliest response regions were marked in red, while the adjacent active regions were marked in blue, and the color change from red to blue indicated the direction of propagation of the excitation. Compared to healthy hearts, myocytes that underwent apoptosis or necrosis one week after infarction restricted AP conduction and prolonged activation times. The implantation of PGNB2 ionic conductive patches accelerated excitation propagation in the infarcted myocardium (Figure S9B). Compared with the PGNC and PGNP groups, the PGNB2 group demonstrated the most significant improvement in local electrical signal conduction speed. After 4 weeks of patch implantation, the lateral conduction velocities for the PGN, PGNB2, PGNC, and PGNP groups were found to be 0.415, 0.586, 0.443, and 0.482 mm/ms, respectively (Figure 5A and Figure S10A–C).
Conductive remodeling and excitation‐contraction coupling recovery of ionic conductive adhesive patches. (A) Representative activation time heat maps of the border area in different groups detected by electrical mapping at 4 weeks post MI. Red: earliest activation, blue: latest activation, numbers: activation time (ms). (B) Representative AP conducting heat maps of the heart in different groups detected by optical mapping at 4 weeks post MI. From left to right are the fluorescence grayscale map, AP propagation map, and AP dispersion map. Red: earliest activation, blue: latest activation, numbers: activation time (ms). (C) Computation diagram of Vm‐Ca2+ Delay. (D) Representative curves of AP and Ca2+ signal in different groups. (E) Vm‐Ca2+ Delay Calculation in different groups. For each group, n = 6, * p < 0.05, ** p < 0.01, *** p < 0.001. (F) KEGG pathway enrichment analysis of differentially expressed genes (DEGs) of environmental information processing assessed by RNA‐seq. (G) Heatmap of DEGs in the calcium signaling pathway in the infarct region between the MI group and the PGNB2 group. (H) qPCR analysis of gene expression related to calcium signaling pathways. For each group, n = 3, * p < 0.05, ** p < 0.01, *** p < 0.001.
The rapid dye perfusion technique was further used to observe the propagation of electrical signals in healthy and infarcted areas. AP and calcium transient (CT) were labeled with RH237 and Rhod2‐AM, respectively, and electrical stimulation time heat maps and activation time dispersion were analyzed. As illustrated in Figure 5B, in a healthy heart, electrical stimulation propagates from the apex to the atrium with comparable velocities in both ventricles. However, in the MI rat, although signals from the apex were conducted generally to the right ventricle, the infarcted LV region (mainly marked in blue) severely obstructed the AP propagation. The color distribution of the infarcted LV and right ventricle in the PGNB2 group was the most similar, and the activation time was the shortest, about 15 ms, indicating that PGNB2 was most effective in reconstructing the conductive microenvironment, preserving the electrophysiological function of myocardial cells. PGNB2 group exhibited shorter activation durations and higher conduction velocities across the entire heart (Figure S11A–D). Moreover, PGNB2 group exhibited minimal repolarization dispersion, indicating its potential to regulate the rhythm of electrical signal conduction. The signals in the infarct and border zones revealed that the PGNB2 group demonstrated elevated AP amplitudes and reduced depolarization and repolarization duration. We postulate that the electrophysiological repair efficacy may be attributed not only to the role of PGNB2 as a bridge in reconstructing the conductive pathway but also potentially to the infiltration of ions within the patch into the infarcted region. Therefore, X‐ray photoelectron spectroscopy (XPS) was used to detect N⁺ and Cl^−^ ions in the superficial, intermediate, and deep layers of myocardial infarction, and it was found that 48 h after the implantation of PGNB2, more Cl^−^ was observed in all three layers of the infarct area, while N⁺ did not change. This suggests that N⁺ was grafted onto the hydrogel network, allowing Cl^−^ to migrate between the hydrogel and the heart (Figure S12).
These results highlight the remarkable effect of PGNB2 in promoting the electrophysiological remodeling of the damaged myocardium. Subsequently, the effects of structural integration and functional recovery were assessed in MI rats. For instance, during the PGNB2 implantation, the patch was applied to the infarcted heart's surface and pressed for 5 s to ensure rapid adhesion (Figure S13). The retention of fluorescent dye = coupled patches on the cardiac surface was evaluated using the IVIS imaging system. The images showed that after 2 weeks, the patches remained securely adhered with no significant positional changes (Figure S14A). After 4 weeks, while partial degradation was observed, the images confirmed that a portion of the patch was still retained on the cardiac surface (Figure S14B). This finding was corroborated by H&E staining, which also verified the presence of a residual PGNB2 patch at week 4 (Figure S14C).
Super‐Conductive Ionic Patches Facilitating Conductive Remodeling by Restoring Excitation‐Contraction Coupling
2.5
Myocardial contraction depends on the generation and propagation of AP. Post‐MI, the formation of collagen and scar tissue severely impedes AP conduction, particularly across the infarcted region, decoupling electrochemical signals from mechanical contraction. Therefore, the mechanisms of conductive patches that facilitate conductive remodeling in infarcted areas were investigated. The coupling between excitation and mechanical contraction was assessed by analyzing the intervals between AP and calcium transients, known as Vm‐Ca^2+^ Delay (Figure 5C).[40, 41] The Vm‐Ca^2+^ Delay in healthy hearts is approximately 9.0 ms; however, post‐MI, this delay was prolonged to 19.5 ms. Implantation of PGN, PGNB2, PGNC, and PGNP patches shortened the interval to 17.8, 10.6, 16.4, and 16.0 ms, respectively. The delay of PGNB2 was the shortest, close to that of healthy myocardium, indicating that the PGNB2 patch could effectively restore the excitation‐contraction coupling of infarcted myocardium (Figure 5D,E).
To further explore the molecular mechanisms of the repair process, RNA sequencing (RNA‐Seq) was performed on infarcted tissues of the MI and PGNB2 groups. Compared to the MI group, 760 genes were significantly upregulated in the PGNB2 group, mainly including genes related to the mitogen‐activated protein kinase (MAPK) signaling pathway, phosphatidylinositol‐3‐kinase‐protein kinase B (PI3K‐Akt) signaling pathway, and calcium signaling pathway (Figure 5F). Additionally, 915 genes were downregulated, involving cell adhesion and cytokine‐receptor interaction processes. Given the performance of PGNB2 in regulating excitation‐contraction coupling, genes related to Ca^2+^ signaling pathways, including CACNA1D, NOS3, TPCN2, ATP2A3, and ADCY4, were further analyzed by heatmap between the MI and PGNB2 groups (Figure 5G). Quantitative PCR confirmed that PGNB2 upregulates CACNA1D, which encodes the α1 subunit of the voltage‐gated CaV1.3L channel (Figure 5H). Compensatory increases in CaV1.3 expression have been documented in heart failure, resulting in a positive inotropic effect [42]. Therefore, it is hypothesized that the PGNB2 may modulate L‐type calcium channels to enhance calcium influx and prevent calcium and AP decoupling.
Ionic Conductive Patches Recovering the Structural and Functional of Infarcted Myocardium
2.6
To evaluate the myocardial cytoskeleton and gap junctions in the infarcted area, cardiac tissues were subjected to immunofluorescence staining (Figure 6A). At 4 weeks post MI, cTnT and Cx43 levels markedly decreased in the MI group. Conversely, the levels of these markers were significantly higher in the PGNB2 group, indicating that PGNB2 effectively inhibited myocardial cell necrosis and protected gap junctions in the infarcted area.
The ionic conductive adhesive patches recover the heart structure and function of MI rats. (A) Immunofluorescent staining of cTnT (green) and Cx43 (red) proteins in the infarct area in different groups at 4 weeks post MI. Scale bars: 50 µm. (B) Masson's Trichrome staining for cardiac sections in different groups. Blue: fibrotic tissue; red: myocardium. Scale bars: 2 mm. (C) The infarct size of the LV wall in different groups. (D) Echocardiograms of LV contraction in different groups. (E,F) EF and FS were determined by echocardiography at 4 weeks post MI. (G,H) + dp/dt and LVSP determined by hemodynamic assessment at 4 weeks post MI. For each group, n = 6, * p < 0.05, ** p < 0.01, *** p < 0.001.
To further explore the effect of PGNB2 on the repair of myocardial tissue, Masson staining was used to analyze myocardial fibrosis and collagen deposition. The MI group exhibited extensive collagen deposition (Figure 6B), whereas the PGNB2 group showed reduced scar area and increased LV wall thickness (Figure 6C and Figure S15), and more effectively inhibited fibrosis and LV expansion. By 4 weeks, PGNB2 maintained superior efficacy with minimized infarct size and maximal wall thickness.
Angiogenesis, essential for myocardial repair, was assessed via α‐smooth muscle actin (α‐SMA) and von Willebrand factor (vWF) immunofluorescence (Figure S16). Compared to the MI group, the PGNB2 patches significantly promoted new blood vessels formation with the highest density of arterioles and vWF‐positive cells, which may be due to the effective stimulation of angiogenesis in the infarct area by Bio‐IL. Although the PGNC and PGNP patches also promoted angiogenesis, PGNB2 was more effective, especially in enhancing the formation of vWF‐positive blood vessels. These findings suggest that the improved effect of PGNB2 treatment may be partly due to the increased blood supply to the infarct area, highlighting the synergistic role of PGNB2 in regulating the MI environment and promoting angiogenesis.
The functional recovery and therapeutic effects of the PGNB2 in MI rats were further measured by echocardiography (Figure 6D). At 1 week post‐implantation, the LV ejection fraction (LVEF) and shortening fraction (LVFS) of the PGNB2 group were significantly higher than those of the MI group, with an increase of approximately 20.3% and 16.1%, respectively. The LV end‐diastolic diameter (LVIDd) and end‐systolic diameter (LVIDs) decreased in the PGNB2 group (Figure 6E, F and Figure S17A,B), indicating that PGNB2 effectively inhibited LV dilatation by providing mechanical support. In addition, the PGNB2 patch significantly improved LV systolic pressure (LVSP), maximum LV pressure rise/fall rate (± dp/dt max), and reduced LV end‐diastolic pressure (LVEDP) (Figure 6G,H and Figure S17C,D).
Finally, to verify the stability of the patches, in vitro and subcutaneous retention of them over time was evaluated. Results showed that all patches degraded by approximately 20% weekly in DPBS (Dulbecco's Phosphate Buffered Saline) and nearly fully degraded within 7 days in collagenase‐supplemented DPBS (Figure S18A). Subcutaneous degradation experiments showed that approximately 25% of the initial patch material remained after 28 days (Figure S18B), indicating that the patch could provide sustained electrical conduction and repair effects at the infarct site for up to four weeks.
Ionic Conductive Patches Repairing Cardiac Function in MI Pigs
2.7
The above findings indicate that PGNB2 could effectively rescue the damaged myocardium in rats, inhibit LV remodeling, and reverse electrical remodeling by providing mechanical and electrical support. To further explore the clinical potential of the PGNB2 patch, pigs with cardiac anatomy and beating characteristics similar to humans were selected (Figure 7A,B). After permanent ligation of the LAD, the wall motion of the infarcted ventricle was weakened, accompanied by a sharp increase in serum cardiac troponin I (cTnI) (Figure 7C), and abnormal Q waves and ST‐segment elevation on electrocardiography (ECG) (Figure 7D), confirming successful modeling of acute MI. The PGNB2 patch with a diameter of 8 cm was applied to the infarct area to allow it to adhere quickly. Blood samples were collected at 14 and 30 days post‐implantation to assess the liver and kidney toxicity. No significant differences in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were observed between the PGNB2 and MI groups at either time point, indicating PGNB2 did not damage the liver. In addition, no significant differences were found in the creatinine and blood urea nitrogen (BUN) concentrations between the PGNB2 group and the MI group after 30 days, indicating that PGNB2 had no significant nephrotoxicity (Figure 7C and Figure S19).
Effect of the ionic conductive adhesive patch on MI repair in pigs. (A) Flow chart of pig experiments. After permanent LAD ligation, the patch was adhered to the infarct zone. Blood sample test and ECG were performed at 4 time points (Before MI, after occlusion, 14 and 30 days after transplantation). Echocardiography was carried out at 2 time points (14 and 30 days after implantation). Thirty days after implantation, pigs were sacrificed, and heart histology and morphology were studied. (B) Photographs of the LAD ligation, patch grafting, and suturing process. (C) The concentration of cTnI and ALT in blood samples. (D) ECG recordings of pigs at 4 time points. (E) Representative images of Masson's trichrome staining of heart sections. IZ: infarct zone, BZ: border zone, red: muscle fibers, blue: collagen fibers. The scale bars are 500 µm. (F) Immunofluorescence staining of α‐actinin and Cx43 in the infarct and border zone. Green: α‐actinin, red: Cx43. The scale bars are 40 µm. (G) Quantitative expression area of α‐actinin and Cx43 in IZ. (H) Echocardiographic images and LVEF, LVFS, LVIDd, LVIDs, LVEDV, and LVESV were determined by echocardiography. For each group, n = 3, * p < 0.05, ** p < 0.01, *** p < 0.001.
Q‐wave abnormalities and ST‐segment elevations were reduced at 14 and 30 days after PGNB2 patch treatment compared with those in the MI group (Figure 7D), indicating effective suppression of myocardial necrosis by PGNB2. Compared with the MI group, the infarct size of PGNB2‐treated pigs was smaller (less white area), the ventricular wall was thicker, and fibrosis was reduced by Masson staining (Figure S20). Myocardial tissue in both the infarct and border zones of the PGNB2 group was protected to a certain extent (Figure 7E). In addition, the expression levels of α‐actinin and Cx43 in the infarct and border zones of the PGNB2 group were higher than those in the MI group (Figure 7F,G), indicating that PGNB2 helped preserve functional myocardial tissue and promoted myocardial regeneration in the infarct and peri‐infarct zones. These results support the positive therapeutic effects of PGNB2 on MI pigs and indicate its potential for clinical translation. The echocardiographic assessment revealed a significant increase in LVEF and a significant decrease in LVIDd and LVIDs, LV end‐diastolic volume (LVEDV), and LV end‐systolic volume (LVESV) in the PGNB2 group (Figure 7H), demonstrating that PGNB2 initiates cardiac function restoration at 14 days and maintains at 30 days.
Discussion
3
As an emerging strategy in tissue engineering and regenerative medicine, conductive patches have become a focal point in myocardial tissue repair research over the past decade.[11] These patches are usually composed of conductive components and hydrogel scaffold materials. Their efficacy mainly depends on the incorporation of conductive components, which provide electrical conduction and functional benefits to the damaged tissues. However, electronic conductive components can be adversely affected by the cardiac contraction‐relaxation cycle, leading to conductivity instability. Therefore, it remains a significant interest to develop super‐conductive patches that can maintain stable conductivity and adhere effectively to the cardiac interface. Ionic conductive patches that incorporate biocompatible ionic conductive components have emerged as an alternative to electronic conductive patches. In recent years, a variety of ionic conductive hydrogels have been developed for myocardial infarction repair. For example, hydrogels based on PAA and zwitterionic methacrylate monomers such as CBMA have demonstrated beneficial effects in restoring electrical conduction after MI. [24, 25, 26] Other studies have engineered ionic conductive hydrogels by leveraging the synergistic interactions between conductive zwitterionic nanochannels and dynamic hydrogen‐bonding networks, resulting in materials with high optical transparency, ultrahigh stretchability, and enhanced mechanical modulus, further highlighting the intrinsic stability of ion‐based conductivity [43]. Among these strategies, choline‐derived bio‐ionic liquids are particularly attractive because their functional groups resemble those of endogenous acetylcholine, conferring excellent biocompatibility. These features suggest that choline‐based ionic components hold significant potential for cardiac injury repair. In this study, we crosslinked AAc‐NHS and Bio‐IL into a PAA/gelatin network to create a super‐conductive ionic adhesive cardiac patch. The stable conductivity of the patch not only mimics the conductivity of a natural myocardium but also addresses the secondary damage risks associated with suturing or biological glues during implantation, demonstrating promising application prospects.
The electrical stability of the patch is crucial for maintaining effective coupling with the host myocardium during cardiac contraction.[44, 45] The heart relies on coordinated electrical and mechanical activity, and stable signal propagation is essential for synchronous myocardial excitation and contraction. After a myocardial infarction, disrupted electrical signaling leads to desynchronized contraction and increases arrhythmia risk. Implanting a conductive patch aims to restore stable conduction in the infarcted region, enhancing electrical coupling and reducing arrhythmias.[46] In contrast, materials with unstable conductivity may cause intermittent signal propagation, further promoting desynchrony and arrhythmic events. Our design achieved the electrical integration and therapeutic efficacy of the ionic conductive patch after 28 days of implantation. Compared with electronically conductive patches, ionic conductive patches exhibit more stable electrical conductivity during the cardiac systole‐diastole cycle, thus improving the therapeutic effects. The underlying mechanism may be due to the conductivity of electronic conductive hydrogels achieved through the mixing or embedding of conductive polymers, carbon‐based conductive nanomaterials, and metal conductive nanomaterials. However, their rigidity and heterogeneous distribution or aggregation lead to reduced stability and synchrony of conductivity. In contrast, ionic conductive hydrogels, through the cross‐linking of their ionic conductive components, attract counter‐ions and form ion mobility channels, thus more closely resembling the conductive manner of natural myocardial ionic conduction at the microscopic level. Additionally, unlike electronic conductive hydrogels, ionic conductive hydrogels combine elastic domains with conductive domains, ensuring stable conductivity during deformation, which is crucial for the constantly beating heart. Moreover, ionic conductive hydrogels generally have better biocompatibility due to their excellent metabolizability. In particular, the Bio‐IL used in our study offers unique advantages. As a choline‐based ionic liquid derived from an endogenous nutrient, Bio‐IL exhibits inherently lower cytotoxicity and better biosafety compared with exogenous ionic conductive components such as PAA alone or CBMA. These endogenous‐like molecular features make Bio‐IL more suitable for long‐term application in cardiac repair.
Electrical mapping and optical mapping are important tools for assessing cardiac electrophysiology. Electrical mapping uses microelectrodes in direct contact with the epicardium to quantitatively record local field potentials, conduction velocity, and rhythm stability in specific regions such as the infarct and border zones. Optical mapping, based on voltage or calciumsensitive dyes, provides high‐resolution visualization of action potential propagation across the entire heart and enables simultaneous evaluation of excitation–contraction coupling. In this study, both electrical and optical mapping were applied to assess the effects of the ionic conductive patch on electrical conduction in the infarcted region as well as throughout the whole heart. The results demonstrated that the PGNB2 ionic conductive patch not only enhanced electrical conduction between the infarct and border zones but also effectively restored action potential propagation across the entire heart while reducing conduction heterogeneity. Moreover, PGNB2 significantly shortened the time lag between myocardial action potentials and calcium transients, effectively suppressing the decoupling phenomenon induced by myocardial infarction (MI) and restoring overall excitation–contraction coupling in the heart. The main mechanisms leading to excitation‐contraction uncoupling may be due to abnormal calcium ion handling, dysfunctions in troponin, and issues with the electrical conduction system. RNA‐seq analysis revealed significant activation of L‐type Ca^2+^ channels (such as CaV1.3) in the infarcted area, while calcium ion pump of the sarcoplasmic reticulum showed no significant changes. Therefore, we propose that the PGNB2 may promote electrical conduction in the infarcted area by regulating the CaV1.3 channels encoded by CACNA1D. Previous studies have shown that Cav1.3 is primarily expressed in the atria, but in patients with heart failure, the ventricles compensate by increasing Cav1.3 expression to make up for the functional deficiency of Cav1.2.[42] We speculate that after myocardial infarction, there is a dysfunction in the Cav1.2 of myocardial cells, and the choline‐based ionic components in the ionic conductive hydrogel can activate the expression of Cav1.3 in myocardial cells, increasing the influx of extracellular Ca^2+^ into the cytoplasm, achieving calcium triggering, and thus restoring the excitationcontraction coupling in the heart post‐MI.
Indeed, this study also has certain limitations. First, the sample size of pigs is limited. Before clinical translation, further studies in larger animals with larger sample sizes and longer follow‐up times are needed to further confirm the efficacy and biosafety. Second, the underlying mechanism of myocardial electrical integration needs to be further studied. Although we explored the possible mechanisms of super‐conductive ionic hydrogels in regulating electrical integration by RNA‐seq, it is still unclear whether the hydrogel regulates CACNA1D expression or the transmembrane transport of Ca^2+^. Understanding how PGNB2 patches modulate the CaV1.3 ion channels may help clarify their therapeutic effects. Third, the hydrogel patch was implanted immediately after LAD ligation, when the myocardium was still in the acute ischemic phase, and mature scar tissue had not yet formed. Consequently, it was not feasible to quantitatively evaluate scar size prior to implantation, nor to perform a longitudinal comparison of scar evolution within the same animal (i.e., before vs after implantation). Future studies incorporating paired longitudinal imaging strategies would enable more accurate tracking of dynamic scar remodeling and provide a more comprehensive assessment of the material's therapeutic effects on cardiac repair. Additionally, future transplantation efforts may focus on developing minimally invasive delivery methods for the patches to reduce damage associated with open‐chest surgery. Nevertheless, the current research indicates that the super‐conductive ionic patches with stable conductivity and adhesion have potential therapeutic value for myocardial regeneration.
Materials and Methods
4
Study Design
4.1
The aim of this study was to develop a super‐conductive ionic patch that adheres to the heart surface for conductive remodeling and cardiac function repair following myocardial infarction. The patch is designed as a ready‐to‐use, thin, flexible, and transparent film that allows for rapid adhesion to the infarcted area, reducing secondary trauma caused by sutures and biological adhesives. Upon adhesion, the patch hydrates in bodily fluids to form ionic migration channels. The choline‐based ionic liquid might regulate Ca^2+^ channels in the heart, which is crucial for late‐phase myocardial function protection. The patch was subsequently characterized using scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), mechanical testing, rheological testing, and fluorescence microsphere adhesion experiments. The conductivity was assessed by electrochemical analysis, conductivity measurements, small‐angle X‐ray scattering (SAXS), and multi‐channel electrophysiological mapping. The effects of the patches on cardiomyocytes were evaluated through toxicity assays, immunofluorescence staining for cTnT and Cx43, calcium transient measurements, and multi‐electrode array (MEA) assays. Optical/electrical mapping was used to detect changes in AP and calcium transients across the healthy area and infarcted area, exploring the mechanisms of electrical integration. Cardiac function repair and regeneration effects of the patch were assessed in rat and pig MI models using echocardiography, immunofluorescence, Masson's trichrome staining, and hemodynamic measurements. Sample sizes for each experiment were determined based on similar evaluations in the literature. All experiments were conducted in randomly assigned experimental groups, with no data excluded from the analysis. All animal experiments complied with the regulations of the Animal Care and Use Committee of the Beijing Institute of Basic Medical Sciences.
Materials
4.2
Pigskin gelatin (Type A), acrylic acid (AAc), (2‐(acryloyloxy) ethyl) trimethylammonium chloride (Bio‐IL), acrylic acid N‐hydroxysuccinimide ester (AAc‐NHS), gelatin methacryloyl (GelMA; Type A; degree of substitution 60%), and α‐ketoglutaric acid were obtained from Sigma–Aldrich. Double‐distilled water was purified using a Milli‐Q Simplicity system. All other chemicals were purchased from Sigma–Aldrich and used without further purification.
Preparation of Patches
4.3
Patches with varying conductivities (PGNB1, PGNB2, PGNB3) were prepared by adjusting the Bio‐IL content. Gelatin (10% w/w), AAc (30% w/w), AAc‐NHS (1% w/w), α‐ketoglutaric acid (0.2% w/w), GelMA (0.1% w/w), and Bio‐IL (2% w/w, 4% w/w, or 6% w/w) were dissolved in deionized water to obtain precursor solutions. The solutions were poured into glass molds and photocured under UV light (365 nm, 20 W output) for 15 min. The resulting patches were completely dried in a nitrogen environment and stored at −20°C until use. PGN was prepared similarly to PGNB but without Bio‐IL. PG was prepared similarly to PGN but without AAc‐NHS. For the PGNC and PGNP, the Bio‐IL component was replaced with either CNTs (0.8 mg/mL) or PDEOT:PSS (0.5 mg/mL), respectively. The choice of these concentrations aimed to prepare control hydrogel patches with electrical conductivities comparable to that of PGNB2.
Characterization of the Physical Properties of Patches
4.4
Fourier transform infrared (FTIR) spectra of the patches were obtained using a PerkinElmer Spectrum 400 FTIR spectrometer in ATR mode, covering the range of 4000–400 cm^−1^. After freeze–drying, SEM (S‐3000N, Hitachi, Japan) was used to observe the microstructure of the hydrated patches at an accelerating voltage of 20 kV. SAXS detection was conducted on a Xenocs XeUSS2.0 at an X‐ray energy of 70 kV.
The swelling and degradation behavior were tested according to a previous study [24, 47] (see Supplementary Materials and Methods). The adhesion properties of the patches were conducted using an Instron 68SC‐1 mechanical tester (1 kN load cell) (see Supplementary Materials and Methods). Electrical conductivity was tested by an electrochemical workstation (CHI660e, CH Instruments), four‐point probe tester (ST2242, China), and multi‐channel matrix electrophysiological mapping system (EMS64‐USB‐1003, Mapping Lab) (see Supplementary Materials and Methods).
Primary Cardiomyocytes Isolation, Culture, and Test
4.5
Primary cardiomyocytes were isolated from 0–1 day‐old Sprague‐Dawley rats. Briefly, rats were anesthetized with isoflurane, and the heart was quickly excised from the aortic root and placed in 4°C sterile PBS to remove blood. The blood vessels, atria, and pericardium were carefully removed, and the remaining tissue was cut into small pieces. The minced tissue was digested into a single‐cell suspension using 0.05% trypsin and 0.25% type IV collagenase. The suspension was collected in DMEM containing 15% fetal bovine serum (FBS) and centrifuged at 100 ×g for 5 min. The cells were resuspended and pretreated for 2 h to remove non‐cardiomyocytes. The isolated cardiomyocytes were then seeded onto different patches at a density of 105 cells/mm^2^. The cardiomyocytes on various scaffolds were cultured in a 37°C, 5% CO_2_ humidified environment for 7 days, with media changes every 2 days.
The measurement of cardiomyocytes Ca^2+^ transient and cardiomyocytes‐specific proteins expression was captured using a fluorescence microscope (Nikon, Ti2) (see Supplementary Materials and Methods). The electrical activity of cardiomyocytes was detected by the MEA electrode (EGMA064200700A, Mapping Lab) (see Supplementary Materials and Methods).
Rat Myocardial Infarction Model Preparation, Patch Implantation, and Detection
4.6
Male SD rats, weighing 250 ± 20 g, were divided into six groups: Sham, MI, PGN, PGNC, PGNP, and PGNB2. Rats were anesthetized with isoflurane, and the LAD was permanently ligated using 6‐0 polypropylene sutures. In the patch groups, a 10 mm diameter patch was placed on the heart surface to cover the infarct area. Rats in all groups were evaluated from the perspectives of cardiac histology, function, and electrophysiology (see Supplementary Materials and Methods).
Pig Myocardial Infarction and Patch Implantation Models
4.7
Six male pigs weighing 25–30 kg were randomly divided into MI (n = 3) and PGNB2 (n = 3) groups. Prior to surgery, animals were anesthetized with 15 mg/kg of ketamine hydrochloride via intramuscular injection. Then, a left anterior thoracotomy was performed between the fourth and fifth ribs, with the pericardium carefully opened to directly view the LAD. The LAD was permanently ligated with 5‐0 polypropylene sutures. Ischemic white surface and abnormal ventricular wall motion were observed in the infarcted area, and ST‐segment elevation was detected on the ECG. A diameter 8 cm PGNB2 patch was placed on the infarcted area and gently pressed for less than 5 s to ensure firm tissue adhesion. The MI group pigs did not receive any cardiac patches. All animals were closely monitored by veterinary staff following these procedures. Pigs in different groups were evaluated from the perspectives of cardiac histology, function, and electrophysiology (see Supplementary Materials and Methods).
Ethics Statement
All animal experiments were performed in accordance with the National Institutes of Health (NIH Publications) and approved by the Institutional Animal Care and Use Committee (IACUC) of Beijing Institute of Basic Medical Sciences (IACUC‐DWZX‐2022‐644).
Statistical Analysis
Results were analyzed using SPSS 22.0 and Origin 8.0. All data are expressed as mean ± standard deviation (s.d.). Comparisons between two groups were performed using a two‐tailed Student's t‐test. One‐way ANOVA with Tukey's post‐hoc test was used to analyze differences among multiple groups. A p‐value of < 0.05 was considered statistically significant.
Author Contributions
C.W. and J.Z. conceptualized and designed the study. Z.Z., and Q.Y. conducted the in vivo experiments and analyzed the data. Z.Z., Q.Y., L.L., C.X., S.L., and Y.Z. performed the in vitro experiments and analyzed the data. C.W., J.Z., Z.Z., and Q.Y. wrote the manuscript. All co‐authors revised the manuscript.
Funding
The Joint Fund Project of the National Natural Science Foundation of China (Grant Nos. U21A20394).
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Supporting File: advs73446‐sup‐0001‐SuppMat.docx.
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