Feasibility of Leadless Cardiac Pacing Using Injectable Magnetic Microparticles

A noninvasive, effective approach for immediate and painless heart pacing would have invaluable implications in several clinical scenarios. Here we present a novel strategy that utilizes the well-known mechano-electric feedback of the heart to evoke cardiac pacing, while relying on magnetic microparticles as leadless mechanical stimulators. We demonstrate that after localizing intravenously-injected magnetic microparticles in the right ventricular cavity using an external electromagnet, the application of magnetic pulses generates mechanical stimulation that provokes ventricular overdrive pacing in the rat heart. This temporary pacing consistently managed to revert drug-induced bradycardia, but could only last up to several seconds in the rat model, most likely due to escape of the particles between the applied pulses using our current experimental setting. In a pig model with open chest, MEF-based pacing was induced by banging magnetic particles and has lasted for a longer time. Due to overheating of the electromagnet, we intentionally terminated the experiments after 2 min. Our results demonstrate for the first time the feasibility of external leadless temporary pacing, using injectable magnetic microparticles that are manipulated by an external electromagnet. This new approach can have important utilities in clinical settings in which immediate and painless control of cardiac rhythm is required.


Particle size assessment
To assess the particle size needed to enable capture in the RV using our electromagnet, the magnetic and drag force applied on IMPs were calculated by equations number 3 and 4, respectively. F m =4/3•π•R 3 •ρ•m•∇B Equation 3 3 A= π•R 2 Equation 5 P=F m /A Equation 6 Where A is the area of aggregate cross-section, R is its radius, m F is the magnetic force given by eq. 3, and P is the mean local pressure. The values calculated for different distances from the electromagnet tip, and different current through the coil are given in Table S1.

Isolated Pig Heart Model
Ex-vivo pacing of pig hearts was initially performed on isolated hearts from ventilated deeply anesthetized pigs (60 kg) through median thoracotomy. 1.3, Glucose 11.2, 2,3-Butanedione monoxime 30, and insulin 10 IE/L) and transferred to our laboratory in Ben-Gurion university. In addition, 1 L of autologous blood was taken from the pig prior to removing the heart. Recovering the heart was done by perfusing warm (~35ºC) blood, diluted with perfusion solution (the same modified krebs-henseleit solution containing without the 2,3-Butanedione monoxime) in a 1:1 ratio. O 2 and CO 2 gas mixture (95:5 volume ratio) was used for oxygenation and buffering the pH of the diluted blood by an oxygenator (affinity fusion oxygenation system, Medtronic, USA).
Perfusion rate was controlled by a peristaltic pump to obtain perfusion pressure of 80-120 inflated to an end-diastolic pressure of 5-10 mmHg. After the isolated heart setting was performed, the RV was approached via the superior vena cava and the tricuspid valve. In order to prevent the heart from moving due to the magnetic pulses, it was held in place in a glass funnel, which also pretected the heart from touching the electromagnet tip. IMPs (150 mg, suspended in 10 ml PBS) were administered while the electromagnet was on DC mode, until the IMPs were accumulated (~20 s). Here, we used a low duty cycle (5%) square waveform, where the current in the coil shifted from 0 to 20 A.

Supplementary Fig. 1
Comparing the magnetic force to the drag force applied on IMPs. By plotting the two forces according to equations 3 and 4, one can see that a particle size that exceeds ~10µm will be subjected to a magnetic force that is larger than the drag force applied by the blood flow. It is important to note that the assumptions taken under consideration are the 'worst case scenario'. The blood velocity taken here is the maximal in the whole RV (30), however, most of the volume of the RV, which will homogenously contain IMPs, has lower velocities. Moreover, the reported velocity is for systole, which is the time of blood exiting the heart and therefore, the blood velocity is the highest during a full heartbeat. In addition, this theoretical assessment does not consider the interactions between particles.
Under a magnetic field, each IMP becomes magnetized; therefore, the particles tend to aggregate when they are subjected to an external magnetic field. This aggregation results in larger particles, so they will be dominated by the magnetic force even if each particle alone is smaller than the theoretical limit of 10µm.
Moreover, it is important to realize that this model was performed according to the electromagnet we designed and according to its current settings. The magnetic induction generated by our electromagnet is in the range of ~1 T, which is far less than the FDA approved level of 8 T in adults. This means that the magnetic properties of the electromagnet may be further increased without raising any safety issues.
In addition to Comparing the effect of high vs. low duty cycle. A detailed illustration of the experiment performed in Fig. 5 B. An overall view before the high duty cycle pulses were applied and the mild effect it had on heart rate. After ~20s of high duty pulses, the pulses were stopped, and switched to DC so that IMPs that are still located in the RV will remain there. Then, it was switched to low duty pulses so that IMPs that are still located in the RV can stimulate the heart and provoke MEF-induced pacing. The blue line indicates the arterial pressure (AP), and the red line indicates the current through the electromagnet coil. Plus (+) signs indicate heart beats that are synchronized with the magnetic pulses. The perfusion setting of the isolated pig heart model. The modified Krebs-Henseleit solution and whole blood (1:1 ratio) was heated and oxygenated by the oxygenator, 5% CO 2 was used to buffer the solution. The perfusion flow was set by the peristaltic pump to give perfusion pressure of 80-100mmHg. The left ventricular pressure was measured by a pressure transducer connected to a water filed balloon.

Supplementary Fig. 6B
MEF-induced pacing in an isolated pig heart. Bradycardia was induced by addition of verapamil to the perfusate. The IMPs were injected directly to RV while the electromagnet was set on DC, and then magnetic pulses (with 1.5Hz frequency) were applied. Upon application of pulses the heart rate synchronizes with the pulses to give 90 bpm. The blue line indicates the LVP, and the red line indicates the current through the electromagnet coil, which correlates with the magnetic induction generated by the electromagnet. Plus signs indicate heart beats that are synchronized with the magnetic pulses.
Supplementary Table 1 Calculation of mean local pressure using eq. 3, 5, and 6. These values were calculated for an accumulated IMP aggregate with a radius of 1 mm.