(68i) Anisotropic, Acellular, Silk-ECM Patches for Treatment of Myocardial Infarction

Heart failure is a major clinical issue that plagues both young patients born with congenital heart defects and older patients who have suffered from a myocardial infarction. These patients undergo reconstructive heart surgery or bypass surgery with positive short-term prognosis, but the disease often results in detrimental scar formation often limiting long-term patient outcomes due to the progression to heart failure. To ameliorate some of these complications natural, bioactive, degradable, and implantable biomaterial systems have been considered. The objective of this study was to improve current cell-free biomaterial designs for cardiac repair by utilizing silk fibroin scaffolds with uniaxially aligned pore architecture containing decellularized cardiac extracellular matrix (cECM) derived from adult or fetal porcine heart tissue (adult cECM and fetal cECM, respectively) with the goal of promoting a better healing response that limited or prevented the progression towards heart failure following MI.

To achieve these goals, silk sponges were formed as previously described,^1,2 with 5 study groups: sham (no repair), silk alone, silk + adult cECM, and silk + fetal cECM, and a commercially available collagen I (control). Briefly, Bombyx mori silkworm cocoons were used to obtain pure silk solutions, which was then mixed with ECM proteins derived from decellularized adult or fetal porcine heart tissue (adult or fetal cECM). Adult or fetal cECM was added to 3% wt/vol silk solution at 0.2 mg/mL prior to aligned sponge formation via directional freezing.¹ To generate the animal model, myocardial infarctions (MIs) were induced in 7-week old Sprague Dawley rats via permanent ligation of the coronary artery (Tufts IACUC approved). One week following MI, patches were implanted over the surface of the infarct, starting just below the infarct suture. Animals were monitored 1, 3, 5, 7, 9-, and 11-weeks post-implantation via echocardiography. Pressure-volume loops were acquired at 3- and 11-weeks post-implantation, in addition to analysis of tissue composition via immunohistochemistry, western blot, and qPCR.

Hemodynamics results from PV loops demonstrate that addition of the silk patch containing fetal cECM led to higher ejection fractions and larger stroke volumes at 11-weeks post-implant. Immunohistochemistry analysis showed that silk-fetal cECM patches led to a reduction in infarct expansion and ventricular wall thinning as compared to shams. Cell infiltration and degradation of the original material was improved in patches containing cECM at 11-weeks post-implant. Current work includes analyzing data from a second study of the same groups and also addressing mechanism by looking at cellular identity and gene/ protein expression to understand the role of cECM composition on the infiltrating cell population and the subsequent functional data.

Implantation of silk-cECM patches 1-week post-myocardial infarction appears to limit the progression to heart failure following MI as compared to sham controls. Ongoing work will increase the number of samples per group as well as compare to collagen sponge scaffolds in order to elucidate the role of cECM composition on patch integration, immune response, and maintenance of cardiac function. Future work will also assess whether silk-fetal cECM scaffolds seeded with human-derived induced pluripotent stem cells have greater potential for cardiac repair as compared to the cell-free approach via evaluation in a rodent model of heart disease.

References:

1. Stoppel, W. L., et al., Biomed Mat 2015, 10 (3).
2. Rnjak-Kovacina, J., et al., ACS Biomater Sci Eng 2015, 1 (4), 260-70.