Table 1.

Biological Pacemaker Design Criteria, Current and Future Work

Design Criteria	Current Progress	Future Work
Generate spontaneous action potentials with a coupled clock	Most studies verify spontaneous generation of pacemaker-like action potentials.	Measure expression and maintenance of calcium and membrane clock proteins.
Overcome source-sink mismatch	In vivo studies aim to prove pacing is possible, and various mapping techniques have shown electrical propagation.	Electromechanical integration should be demonstrated. Incorporate design features such as electrical insulation and exit pathways.
Provide reliable pacing over long periods of time	Most in vivo studies are days to two weeks long. The longest study was 13 weeks.83	Monitor for at least 6 months for potential failure or arrhythmias.
Contain heterogeneous nodal cell types	Studies using embryoid bodies contain multiple cell types, but this concept is not otherwise addressed.	A reliable method for generating nodal cells, as well as transitional cells, will need to be developed. Co-culture with multiple cell types may yield new insights.
Replicate the nodal tissue architecture	No design studies address the role of ECM,* cell environment, or culture substrates.	Determine the effect of cell patterning and incorporate ECM to tissue-engineered scaffolds. Further characterization of SAN† ECM is necessary.
Demonstrate autonomic responsiveness	Response to isoproterenol is frequently shown in vitro, and two in vivo studies monitor heart rate during daily activity.78,83	Chronotropic competence must be studied thoroughly, particularly under high stress, such as exercise stress testing.

^*extracellular matrix

^†sinoatrial node