The overall goal of this project is to examine whether mechanical cues can improve the contractile function of engineered heart tissue (EHT) constructs. EHT constructs are made by tissue engineering approaches that use human cell derived cardiomyocytes. These constructs can serve as an ethical testbed for cardiology and pharmacology studies and can reduce the reliance on animal studies in some cases. EHT constructs are functional tissues for they produce muscle contractions that are visible in vitro. However, in the current state-of-the-art for EHT constructs, their contractility and physiology does not fully resemble that of adult heart tissue. As such, this project will subject EHT constructs to dynamically changing external loads in a novel bioreactor in order to build stronger muscle tissue through cardiac exercise. If successful, this project would achieve a "hearts-in-a-dish" platform for assessing new pharmacological treatments for heart disease, understanding inheritable myopathies, or studying the progression of cardiac pathologies. Research opportunities with this project will be provided to undergraduates and underrepresented minority groups. We will publicize our research to K-12 students at outreach events at the University of Washington to educate them on the innovations that are possible at the intersection of engineering and medicine.

This project will provide a transformative approach to cardiac tissue engineering by magnetically measuring the biomechanical performance of EHT constructs and providing mechanobiological cues that drive their maturation towards adult levels. Real-time measurements of the contractile force and twitch frequency of EHT constructs will be achieved by growing the constructs on magnetic silicone posts, which deflect in portion to the applied force of the constructs. The motion of the magnetic posts will be measured using a novel array of magnetometers underneath a multi-well plate, which enable the EHT constructs to be monitored continually over a long period of time and in a parallel manner. Application of magnetic fields that pull on the magnetic posts will impart external forces on the EHT constructs to forcibly stretch the constructs before their contraction (preload) and forcibly restrain the constructs during a contraction (afterload). Application of fetal loading patterns of preload and afterload using magnetic forces will improve the myofibril structure, maturation markers, and contractile output of hPSC-CM in the EHT constructs through mechanobiological cues that replicate the increasing loads that the human heart experiences during fetal development. In broader terms, the approaches in this project are intended to mimic to the developmental loading patterns of preload and afterload in a developing human heart in order to improve the maturation of hPSC-CM grown in EHT constructs and assess the improvements by monitoring the contractile function of the cells.

Project Start
Project End
Budget Start
2017-08-15
Budget End
2021-07-31
Support Year
Fiscal Year
2016
Total Cost
$459,122
Indirect Cost
Name
University of Washington
Department
Type
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98195