A Discrete-Time Control Algorithm Applied to Closed-Loop Pacing of HL-1 Cardiomyocytes

Electrical stimulation represents a useful tool for electrophysiologic investigation of electrically excitable cells such as cardiomyocytes. The stimulation threshold and electrophysiologic response to precisely timed pulses yields valuable information regarding physiologic processes. However, determining these parameters accurately, while simultaneously resolving time-dependent or transient effects has been difficult or impossible with previous methods. This paper presents a discrete-time algorithmic controller used for closed-loop electrical stimulation of HL-1 clonal cardiomyocytes cultured on, and stimulated using, a planar microelectrode array. We introduce the temporal error-controlled algorithm (TECA), that is well-suited to control using capture fraction, a low data rate, highly quantized feedback parameter describing stimulation efficacy. HL-1 cardiomyocytes were electrically stimulated and resulting parameters were used to develop a representative model of partial capture, enabling extensive analysis of the algorithm. The performance of this approach is compared via computer simulation to a previously introduced conditional convergence algorithm to quantify its performance and relative advantages. Operation of the TECA is demonstrated by tracking the real-time biological response of stimulation threshold to a rapid increase in extracellular potassium concentration in four independent cell cultures. This work enables the use of stimulation threshold as a real-time, continuously monitored parameter with considerable utility in cardiac pharmacology, electrophysiology, and cell-based biosensing.