Implantation of electronic pacemakers is the primary therapy for patients with sinus node dysfunction. Because of various limitations, the development of biological pacemakers is of great interest. For this the transfer of genes or cells with pacemaking potential to the native myocardium is required and this should be ideally locally restricted. Therefore we have developed a technology for localized cell therapy and gene transfer in vitro using magnetic nanoparticles (MNPs) and confined magnetic fields.

Local gene targeting (~1mm diameter) was performed by magnetic complexes of lentiviruses and the MNP SO-Mag5 in the presence of confined magnetic fields generated by permanent magnets and specially designed soft iron tips. To generate a local pacemaking site, we have used this method to locally express the light-gated ion channel channelrhodopsin2 on a monolayer of HL-1 cardiomyocytes. Functional expression was proven by application of blue light pulses, which reliably paced the monolayer. Latency analysis of local field potentials from micro-electrode arrays proved the origin of pacing from the transduced area.

To perform local pacemaking by cell delivery we generated and purified channelrhodopsin2 expressing cardiomyocytes from mouse embryonic stem cells. By localized magnetic fields only 5000 cells loaded with MNPs were positioned on a monolayer of HL-1 cardiomyocytes and formed a cell cluster (~1mm diameter). Importantly, global light stimulation paced the monolayer and pacing started from the site of cell transfer.

Taken together, MNP-aided gene and cell transfer will be useful to investigate the generation of biological pacemakers and potentially enable the MNP-aided generation of pacemakers in vivo.