Improving cardiovascular implants to reduce thrombosis and other confounds has been a long-term goal of medical science. Grafts and endovascular stents have been recently modified to include new materials, attached cells or drug-eluting polymers to make them more biocompatible. While these efforts represent substantial progress, the progression from inflammation to coagulation and eventual thrombosis still remains despite these interventions. Interference with the health and continuity of the vascular endothelium is a challenging problem introduced by all cardiovascular implants. Any interruption of contact between terminally differentiated endothelial cells (ECs) and blood flow is likely to produce an undesirable prothrombotic response. Thus far, improved cardiovascular implants have employed materials such as expanded polytetrofluoroethylene (ePTFE), which provides a non-adherent surface and therefore inhibits coagulation. While an initial benefit, non-adherent surfaces also prevent endothelial cells from attaching to the endovascular surface, hampering the development of a protective endothelium. An unmet need therefore exists, to generate functionalized cardiovascular implants which encourage the development of endothelium on synthetic surfaces. Affinergy Inc. has developed bifunctional peptide linkers, called interfacial biomaterials (IFBMs) that help promote biology at the critical interface between a synthetic and a biologic. Attaching one peptide designed to bind endothelial cells; to another designed to bind a cardiovascular implant material would specifically encourage EC attachment to the endovascular surface. This approach is modular, allowing the guidance of multiple biological targets to various medical device materials. Here we propose the development of an IFBM to encourage the endothelialization of expanded PTFE grafts. Previously, we have observed encouraging in vivo results, using an IFBM for improved endothelialization of stainless steel stents. We are therefore eager to extend our work, and initiate the development of an EC: ePTFE IFBM. The overall goal of this project is to develop multifunctional adapter molecules that can mediate efficient recruitment, survival, and terminal differentiation of endothelial cells (ECs) on cardiovascular implants to promote their integration with the body. Efficient growth and coverage of ECs on ePTFE represents the proof of concept focus for this Phase I SBIR application. To accomplish the Aims proposed here, we will first optimize ePTFE binding peptides and synthesize EC: ePTFE IFBMs. We will then verify IFBM stability and function in static biological fluids and under shear flow conditions. Second, building on the work we have done on stainless steel surfaces, we will evaluate EC migration and attachment on peptide coated ePTFE. Finally, we will evaluate the effect of IFBM-mediated cell attachment on EC phenotype. Project Narrative improving cardiovascular implants to reduce thrombosis and other confounds has been a long-term goal of medical science. Grafts and endovascular stents have been recently modified to include new materials, attached cells or drug-eluting polymers to make them more biocompatible. While these efforts represent substantial progress, the progression from inflammation to coagulation and eventual thrombosis still remains despite these interventions. Interference with the health and continuity of the vascular endothelium is a challenging confound introduced by all cardiovascular implants. Any interruption of contact between terminally differentiated endothelial cells (ECs) and blood flow is likely to produce an undesirable prothrombotic response. The overall goal of this project is to develop multifunctional adapter molecules that can mediate efficient recruitment, survival, and terminal differentiation of endothelial cells (ECs) onto cardiovascular implants to promote their integration with the body. Efficient growth and coverage of ECs on ePTFE represents the proof of concept focus for this Phase I SBIR application. ? ? ?
