I-Wire Heart-on-a -Chip I: Three-dimensional cardiac tissue constructs for physiology and pharmacology

摘要

Engineered 3D cardiac tissue constructs (ECTCs) can replicate complex cardiac physiology under normal and pathological conditions. Currently, most measurements of ECTC contractility are either made isometrically, with fixed length and without control of the applied force, or auxotonically against a variable force, with the length changing during the contraction. The "I-Wire" platform addresses the unmet need to control the force applied to ECTCs while interrogating their passive and active mechanical and electrical characteristics. A six-well plate with inserted PDMS casting molds containing neonatal rat cardiomyocytes cultured with fibrin for 13-15 days is mounted on the motorized mechanical stage of an inverted microscope equipped with a fast sCMOS camera. A calibrated flexible probe provides strain load of the ECTC via lateral displacement, and the microscope detects the deflections of both the probe and the ECTC. The ECTCs exhibited longitudinally aligned cardiomyocytes with well-developed sarcomeric structure, recapitulated the Frank-Starling force-tension relationship, and demonstrated expected transmembrane action potentials, electrical and mechanical restitutions, and responses to both beta-adrenergic stimulation and blebbistatin. The I-Wire platform enables creation and mechanical and electrical characterization of ECTCs, and hence can be valuable in the study of cardiac diseases, drug screening, drug development, and the qualification of cells for tissue-engineered regenerative medicine.