Injectable Biomaterials for Transplantation of Cardiac Cell-Based Therapies

Abstract

The global burden of heart disease, as well as the heart’s inability to regenerate, continues to account for 1 in 5 deaths in the developed world. This makes progressive heart failure the number one killer worldwide. On average, 1 billion cardiomyocytes (CMs) are lost during a myocardial infarction (MI). The heart’s inability to regenerate these lost CMs significantly diminishes its function. As a result, once-healthy regions of CMs are now filled with a fibrotic scar tissue that does not exhibit the same electrophysiological capacity of normal adults CMs. Current treatment options are limited to palliative drug regimens (ACE inhibitors, beta blockers, etc.) or ventricular assist devices (risk of infection, thrombosis, power supply), and the only real cure historically has been a heart transplant (limited supply). Thus, the Murry lab has shown that injection of human-stem-cell-derived-Cardiomyocytes (hSC-CMs) can enhance overall cardiac function to a degree better than any other therapy developed to date. However, despite this progress, there are still several outstanding limitations keeping this stem cell therapy from being effective. Notably, single-cell-suspensions are the current delivery method to the heart, making engraftment a challenge: <10% of injected cells persist as a long-term, stable graft, thus, lending to high manufacturing costs and limiting the amount of new myocardium (heart muscle) that can form. Cell survival and retention could be significantly improved with the use of a biomaterial platform. In the past, biomaterial options for engineered heart tissues (EHTs) have been cardiac patches or cell sheets, but their geometries limit these constructs from electrically coupling with host myocardium and must be directly sutured onto the myocardium (more invasive). However, the use of an injectable biomaterial, such as a hydrogel that can gel in situ (directly mixed with cells), is appealing. They can be delivered directly through a catheter into the myocardium, provide easy support and dispersion of transplanted cells directly at the site of MI, and provide a scaffold for cells. Here, we investigated the use of a Zwitterionic Injectable Pellet (ZIP) microgel system that ultimately had a systematic flaw in its design – embolization downstream of dislodged particles throughout the body. We used lessons learned from the ZIP system to then create the Coil-XTEN-Coil (PXP) system to (1) promote cell survival, proliferation, and engraftment histologically, and (2) improve overall functional output of an infarcted heart (confirmed via echocardiography). By exploiting the non-covalent self-association of monomeric recombinant proteins to yield stable hydrogels, the simple design of XTEN is modular and tunable, whereby a single point mutation to the protein primary sequence can macroscopically change the material behavior (seen by significant changes in self-healing behavior and biodegradation). Overall, the PXP biomaterial platform offers an exciting opportunity towards promoting patient outcomes after an MI.