Injectable hydrogel electrodes as conduction highways to restore native pacing

Ventricular arrhythmias (VAs) are a major cause of sudden cardiac death. Current treatments, including antiarrhythmic drugs and ablation, are insufficient due to their high toxicity and failure rates. These methods fail to address the underlying issue of delayed conduction in scarred myocardium, leading to wave break, re-entry, and fibrillation. Implantable cardioverter-defibrillators (ICDs) are often the only option, but they are painful and negatively impact quality of life. This study aims to develop a novel pacing modality that targets the pathophysiology of re-entry by restoring native conduction patterns. The researchers hypothesize that an injectable hydrogel electrode, delivered via minimally invasive catheter delivery and integrated into standard pacemaker technologies, will fill the epicardial coronary veins and their tributaries, effectively converting them into flexible electrodes that can access the previously inaccessible mid-myocardium. The simultaneous pacing from multiple sites along the electrode will stimulate broad areas of ventricular tissue, normalizing conduction and eliminating regions of delayed activation responsible for re-entry.

Current pacing modalities are insufficient to address the underlying pathophysiology of ventricular arrhythmias, which is delayed conduction in scarred myocardium. Antiarrhythmic drugs, while widely used, have significant toxicity and can be pro-arrhythmic. Ablation strategies, although common, have high failure rates (18-40%) due to recurrent arrhythmias. Implantable cardiac defibrillators (ICDs), which deliver high-energy shocks, are used as a last resort, but cause pain and negatively impact patient quality of life. The existing technologies do not address the root cause of re-entry, which is the delayed conduction.

The researchers developed a biocompatible, injectable hydrogel with high ionic conductivity. This was achieved by synthesizing a polyether urethane diacrylamide (PEUDAm) macromer, resistant to hydrolysis, and combining it with redox chemistry (ammonium persulfate and iron gluconate) for rapid in situ cure without external stimuli. Ionic species were added to enhance conductivity. The hydrogel's injectability, conductivity, and biostability were tested in a porcine model. In vivo gel formation and retention were characterized, and safety was assessed by examining cardiac function, cardiac enzymes, and histology. The ability of the hydrogel electrode to pace the heart was evaluated by measuring pacing thresholds and analyzing surface ECG tracings. Electroanatomical mapping was performed in a porcine cardiac ablation model to assess conduction in heterogeneous tissue. The study involved three main parts: 1. **Hydrogel Development and Characterization:** This involved synthesizing the PEUDAm macromer and NAGA crosslinker, optimizing the redox initiation system for rapid in situ cure, and measuring the conductivity of the resulting hydrogel. 2. **In Vivo Deployment and Safety Assessment:** This involved injecting the hydrogel precursor solutions into the anterior intraventricular vein (AIV) and middle cardiac vein (MCV) of porcine models, assessing hydrogel homogeneity, and performing histological analysis to evaluate the host response. Cardiac function and troponin levels were monitored. 3. **Electrophysiological Assessment:** This included measuring pacing thresholds with different electrode configurations (metal electrode, hydrogel point source, hydrogel line source, and hydrogel in the AIV), analyzing QRS morphology from surface ECGs, and performing electroanatomical mapping in an ablation model to assess wavefront propagation.

The researchers successfully synthesized and characterized a biocompatible, injectable hydrogel with high ionic conductivity suitable for use as a cardiac electrode. The hydrogel exhibited rapid in situ cure, excellent segmental uniformity, and maintained its integrity in the coronary veins of a porcine model for at least four weeks. Histological analysis showed mild perivascular and interstitial fibrosis, with chronic inflammation and foreign body giant cell reaction near the injection site, but no myocardial necrosis. Cardiac function and troponin levels remained within normal ranges. The injectable hydrogel electrode successfully paced the porcine heart, achieving pacing thresholds comparable to metal electrodes and other hydrogel configurations. Notably, pacing through the AIV hydrogel resulted in a QRS morphology remarkably similar to native sinus rhythm, suggesting capture of the deep septal bundle branches and Purkinje fibers. Electroanatomical mapping in an ablation model demonstrated that the hydrogel electrode significantly increased the area of tissue activation and resulted in much earlier activation of the mid-myocardium and endocardium compared to point pacing. This finding suggests that the hydrogel electrode can potentially normalize tissue activation across heterogeneous myocardium, thus minimizing the delayed conduction that underpins re-entry. The hydrogel electrode's ability to achieve near-native QRS morphology and its superior wavefront propagation compared to point stimulation indicate that the technology has the potential to prevent and treat ventricular arrhythmias, particularly those that originate in the mid-myocardium.

This study demonstrates the feasibility of using an injectable hydrogel electrode to directly pace the mid-myocardium, a region previously inaccessible to conventional pacing modalities. The hydrogel's ability to mimic physiological conduction by capturing the deep septal bundle branches and Purkinje fibers represents a significant advancement. The normalization of tissue activation across heterogeneous myocardium shown in the ablation model suggests a novel approach to preventing re-entry, the underlying mechanism of many lethal arrhythmias. The use of coronary veins as delivery pathways is advantageous, as it avoids arterial occlusion and takes advantage of existing clinical practices for catheter-based interventions. The observed mild inflammatory response, lack of myocardial necrosis, and preservation of cardiac function suggest a good safety profile, although long-term studies are necessary. The integration of the hydrogel electrode with current pacing systems offers a significant translational advantage.

This research successfully developed and tested an injectable hydrogel electrode capable of pacing the mid-myocardium, resulting in QRS morphology similar to native sinus rhythm and improved wavefront propagation compared to conventional methods. The findings support the potential of this technology to prevent and treat ventricular arrhythmias and pave the way for painless defibrillation. Future studies should focus on long-term safety assessment, optimization of catheter design, and clinical trials to confirm the efficacy and broad applicability of this novel pacing modality in patients with various forms of cardiac disease and scar formation.

The study was conducted in a porcine model, which may not perfectly replicate the complexities of human cardiac physiology and disease. The sample size was relatively small. The ablation model, while useful for demonstrating the effect of tissue heterogeneity, does not completely mimic the scarring that occurs after a myocardial infarction. Long-term studies are needed to fully assess the chronic host response to the hydrogel and potential vessel remodeling. The development of a suitable clinical catheter is ongoing and requires further refinement.