Restoring cardiac contractility after myocardial infarction with a composite therapy of aligned electrospun polycaprolactone scaffold and engineered human myocardium

Introduction: : During myocardial infarction (MI), up to 1 billion cardiomyocytes (CMs) die, leading to permanent muscle loss and devasting functional outcomes. For decades, biomaterial therapies have been used to restrain the infarcted left ventricle (LV), reduce ventricular wall stress, limit dilation, and maintain global cardiac function. However, how these biomaterials alter regional mechanics and LV remodeling through time is poorly understood, and they fail to directly address contractile deficits due to the loss of CMs. In this study, an optimized therapeutic implant is designed to provide both mechanical support from a biomaterial scaffold and contractile CMs in an engineered tissue to promote cardiac function after MI, informed by computational simulations.

Materials and

Methods: : A finite element model of the LV post-MI was developed in FEbio to assess the role of passive and active implant properties including fiber alignment for optimization of ejection fraction. We then developed a composite therapy by combining engineered human myocardium (EHM) composed of human induced pluripotent stem cell-derived CMs (hiPSC-CMs) in a collagen-1 hydrogel with highly aligned electrospun polycaprolactone (PCL) fibrous scaffolds. Remuscularization (i.e. ECT-only), reinforcement (i.e. PCL-only), and dual therapy (PCL+ECT) were assessed versus no implant (sham) in a rat model of permanent ligation MI with immediate implantation of the therapeutic. Longitudinal 4D ultrasound was captured throughout 4 weeks and explanted hearts assessed by immunofluorescence imaging.

Results, Conclusions, and Discussions:: Computational simulations show that a longitudinally aligned fibrous material (modeled after PCL) and active implant contraction improve calculated LV ejection fraction post-MI by +3.4% and +15.0%, respectively. Implanted hiPSC-CMs significantly mature over 4 weeks, shown by an increase in myofilament area (~7-fold) and ventricular myosin light chain 2 expression (~2-fold). Analysis of regional 3D strain (a measure of contractility) from 4D ultrasound imaging reveals dynamic changes in the injured LV over 4 weeks. PCL alone supports maintenance of almost 80% surface area (SA) strain acutely (day 3) but strain diminishes through 4 weeks. ECT alone enables SA strain recovery from day 3 to >70% of baseline at weeks 1 and 2. The dual PCL+ECT therapy shows preserved SA strain at day 3 and improved strain at 1, 2, and 4 weeks, maintaining higher strain globally at 4 weeks versus all other groups. In conclusion, our high resolution contractility results support the continued development of an aligned PCL scaffold with hiPSC-CM EHM as a cell-based therapy to reinforce, remuscularize and re-engineer the function of the heart post-MI.

Acknowledgements and/or References (Optional):: We gratefully acknowledge funding from a Brown University Division of Research Seed Award.