Combining mechanical and pharmacological support to redirect post-MI wound healing towards regeneration

The limited regenerative capacity of the human myocardium after myocardial infarction (MI) remains a major barrier for effective cardiac repair. The massive loss of cardiomyocytes and activation of resident fibroblasts into myofibroblasts result in the formation of a protective but non-contracting scar, ultimately impairing heart function. We hypothesize that controlled dampening of post-MI scarring promotes more effective repair. However, reducing scar formation may increase the risk of ventricular rupture. To address this challenge, we are developing a synthetic elastic supramolecular adhesive patch that provides mechanical support to the vulnerable myocardium post-MI and simultaneously serves as a drug-delivery platform.

The overall aim of this study is to modulate post-MI remodeling and promote effective cardiac repair by using a supramolecular adhesive patch to deliver small-molecule TGFβ-pathway inhibitors while providing mechanical support.

Small molecule inhibitors of the TGFβ-pathway (SB431542 and SB505124) were incorporated into the biomaterial and tested in vitro for functional efficacy. The conditioned media from the loaded patches were applied to HT1080-TGFβ/Smad-reporter cells to measure luciferase activity. To examine patch adherence and release properties, the patches were loaded with SB431542 and SB505124 and applied to mouse hearts ex vivo. Immunohistochemistry followed by light-sheet microscopy were used to determine pSmad2 expression as a readout of TGFβ-pathway activation.

Preliminary in vivo experiments confirmed the technical feasibility of the adhesive patch, which remained attached to the myocardium for up to one week. Both SB431542 and SB505124 released from the patches reduced TGFβ-reporter activity in HT1080-TGFβ/Smad-reporter cells for at least four days, demonstrating a prolonged release profile with sustained bioactivity. Ex vivo studies confirmed compound delivery, showing reduced pSmad2 expression specifically at the side of patch application.

We developed a synthetic elastic supramolecular adhesive patch that adheres to cardiac tissue for up to one week and enables sustained release of SB431542 and SB505124 for at least four days with preserved functional activity in vitro and ex vivo. Future work will focus on identifying the optimal combination and dosing of compounds to modulate cardiac remodeling and enhance myocardial repair.