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US 12,503,717 B2Granted
Systems and methods for modeling disease and assessing adverse side effects of therapeutics therefor
AssigneeNovoheart International Limited
InventorRonald A. Li
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Abstract
The disclosure provides a substrate for the ordered growth and development of cardiomyocytes such as ventricular cardiomyocytes derived from pluripotent stem cells along with methods of culturing the cells on the substrates for use in assays such as cardiotoxicity assays. Further provided are methods for assessing cardiotoxicity using one or more criteria disclosed herein.
Claims13
A method of assessing whether a compound exhibits cardiotoxicity comprising:
- (a) contacting an anisotropic layer of ventricular cardiac cells comprising at least 70% troponin T+ cardiomyocytes on a microfabricated substrate comprising microgrooves oriented along a single axis of the substrate with a compound, wherein microgrooves have a width of 15 μm and a depth 5 μm and wherein spacing between microgrooves is 5 μm;
- (b) electrically stimulating the anisotropic layer of cardiac cells at one or more points by a programmed electrical stimulation comprising delivering a train of eight S1 stimuli at 1.5 Hertz, followed by a premature extra stimulus S2 with an S1-S2 interval initiated at 550 milliseconds (ms) and consecutively shortened in steps of 50 ms until capture fails, at which point the S1-S2 interval is increased by 20 ms, followed by 2 ms decrements until an effective refractory period is achieved when the maximum S1-S2 interval fails to lead to action potential propagation and a radiating conduction pattern with an anisotropic ratio of at least 1.8 in response to electrical point stimulation;
- (c) detecting an electrical signal propagation in the anisotropic layer of cardiac cells;
- (d) determining whether the electrical signal propagation is an arrhythmic reentrant event;
- and
- (e) identifying the compound as exhibiting cardiotoxicity if the electrical signal propagation is an arrhythmic reentrant event.
3 more elements
A method for assessing whether a compound is cardiotoxic, the method comprising
- (a) contacting an anisotropic layer of ventricular cardiac cells comprising at least 70% troponin T+ cardiomyocytes on a microfabricated substrate comprising microgrooves oriented along a single axis of the substrate with a compound, wherein microgrooves have a width of 15 μm and a depth 5 μm and wherein spacing between microgrooves is 5 μm;
- and
- (b) determining the compound is cardiotoxic if the compound induces an arrhythmic reentrant event in the cardiac cells after administering a programmed electrical stimulation comprising a train of eight S1 stimuli delivered at 1.5 Hertz followed by a premature extra stimulus S2 with S1-S2 interval initiated at 550 milliseconds (ms) and consecutively shortened in steps of 50 ms until capture fails, at which point the S1-S2 interval is increased by 20 ms, followed by 2 ms decrements until the effective refractory period is achieved when the maximum S1-S2 interval fails to lead to action potential propagation.
Dependencies are inferred from the claim text.