A leading cause of heart failure is left ventricular (LV) remodeling caused by overexpression of matrix metalloproteinases (MMPs) following a myocardial infarction (MI). MMPs are known to degrade numerous extracellular matrix proteins, and this degradation can cause in MI a growth of the infarct accompanied by detrimental increase in LV volume. Doxycycline (DOXY) is a small molecule antibiotic that is also known to inhibit MMP activity. In order for DOXY to be repurposed as an effective MMP inhibitor, DOXY must be present in MI regions at concentrations above what can be expected by safe systemic delivery.
We are designing amphiphilic polymer networks that undergo micro-phase transitions under microscopic local pathologic strain profiles. In order for inhibitors to be released by local microscopic mechanical signals, the synergistic physical interactions in the gel must be finely tuned to balance combined repulsive and attractive forces so that the gel swells under specific pathogenic strain. As strain profiles change from physiological to pathological states in the MI region, the new biomaterials respond by releasing MMP inhibitors into the local surrounding tissue. The gel does not undergo a local swelling transition of the gel network to release DOXY into the surrounding environment until strain profiles consistent with advancing pathologic states are sensed by the gel. Our results use a molecular theory to properly account for the highly non-additive coupling of molecular interactions that all occur cooperatively together inside the gel environment. In order to properly ensure that the strain profiles in the surrounding tissue propagate predicatively into the gel, adhesive interactions are introduced at the gel contact to provide us with a no-slip condition between the tissue and the gel. When viewed in the context of cardiovascular repair, these strain responsive gels are novel drug delivery vehicles whereby release is modulated by the local physical properties of the current disease state.