(334b) Growth Factor Delivery from Silk-Extracellular Matrix Composite Sponges for Modulating Congenital Heart Defect Repair

Congenital heart defects are the leading cause of death in live-born infants and the most severe CHDs require surgery within the first few days of life.^1-2 While these surgical procedures extend the life of the patient, they do not provide a complete correction of the defect. For example, in the case of Tetralogy of Fallot, the standard repair utilizes a patch made of polytetrafluorethylene (PTFE) or polyethylene terephthalate (Dacronâ„¢) to widen the right ventricular outflow tract (RVOT). These synthetic patch materials do not mimic the native mechanical properties of the heart, do not degrade over reasonable time periods, and do not promote new tissue formation. In particular, the Dacronâ„¢ patches interfere with proper patient growth, impede electrical conduction in the heart, and are inert and non-contractile. Thus, these synthetic patch materials do not meet the needs of the organ during physiologic heart development. In addition, Dacronâ„¢ patches are prone to aneurysm, calcification, and infection.^3-5 Therefore, there exists a clinical need to develop a patch or construct that promotes the growth of the patient’s own tissue to minimize the cost and risks associated with the re-operative procedures necessitated by the inadequacies of currently available synthetic materials. To address these issues, functional, cellularized silk-extracellular matrix (ECM) composite cardiac grafts⁶are under development.

In the work presented here, we aim to utilize growth factor (GF) loaded silk-ECM patches to promote functional restoration of the right ventricular heart wall while minimizing scarring at the injury site in a rodent model system of RVOT repair. We have optimized silk-ECM patches with tunable growth factor release, evaluating the role of heparin, ECM, and GF concentration in release kinetics following protease degradation in vitro and via subcutaneous implantation. In vitro and subcutaneous analyses of these GF delivering silk-ECM materials provide key data regarding the importance of timing, concentration, and GF specificity that we hypothesize to lead to improved repair, delivered cell viability/retention, vascular ingrowth, and native cell infiltration. Pilot studies are underway to evaluate the GF delivering silk-ECM cardiac grafts in a full thickness RVOT defect in a rodent model, where we aim to evaluate functional recovery and histological outcomes compared to a standard Dacronâ„¢ patch.

References

1.Stumper, O., Hypoplastic left heart syndrome. Postgraduate Medical Journal 2010, 86(1013), 183-188.

2.Jonsson, H.; Ivert, T.; Jonasson, R.; Holmgren, A.; Bjork, V. O., Work capacity and central hemodynamics thirteen to twenty-six years after repair of tetralogy of Fallot. J Thorac Cardiovasc Surg 1995, 110(2), 416-26.

3.Parks, W. J.; Ngo, T. D.; Plauth, W. H., Jr.; Bank, E. R.; Sheppard, S. K.; Pettigrew, R. I.; Williams, W. H., Incidence of aneurysm formation after Dacron patch aortoplasty repair for coarctation of the aorta: long-term results and assessment utilizing magnetic resonance angiography with three-dimensional surface rendering. J Am Coll Cardiol 1995, 26(1), 266-71.

4.Wainwright, J. M.; Hashizume, R.; Fujimoto, K. L.; Remlinger, N. T.; Pesyna, C.; Wagner, W. R.; Tobita, K.; Gilbert, T. W.; Badylak, S. F., Right ventricular outflow tract repair with a cardiac biologic scaffold. Cells Tissues Organs 2012, 195(1-2), 159-70.

5.Fujimoto, K. L.; Guan, J.; Oshima, H.; Sakai, T.; Wagner, W. R., In vivo evaluation of a porous, elastic, biodegradable patch for reconstructive cardiac procedures. Ann Thorac Surg 2007, 83(2), 648-54.

6.Stoppel, W. L.; Hu, D.; Domian, I. J.; Kaplan, D. L.; Black, L. D., 3rd, Anisotropic silk biomaterials containing cardiac extracellular matrix for cardiac tissue engineering. Biomed Mater 2015, 10 (3), 034105.