Axially Prestretched Elastomeric Graft (APENG) for Lower Extremity Arterial Reconstructions - PROJECT SUMMARY This NHLBI R61/R33 exploratory/developmental project aims to develop and test a novel Axially Prestretched Elastomeric Nanofibrillar Graft (APENG) for lower extremity arterial reconstructions. Lower extremity arterial disease is a substantial public health burden associated with significant morbidity, mortality, and diminished quality of life. Advanced stages of this disease commonly require open surgery with synthetic vascular bypass grafts. While synthetic vascular grafts are generally considered successful, their failure rates in the main artery in the leg, the femoropopliteal artery (FPA), are unacceptably high. Various advancements in existing graft technologies have only shown limited improvements in the clinic as they do not address the underlying cause of complications – the limb flexion-induced kinking and buckling of the graft. Our innovative APENG concept addresses this problem by incorporating a substantial Axial Prestretch (AP) into the graft. AP is the in-built mechanism in healthy young FPAs that counteracts limb flexion-induced compression, thereby preventing arterial buckling and kinking. To achieve physiological levels of AP without inflicting potentially injurious high axial forces or graft overdilation, we will mimic the anisotropic nature of native FPAs with substantially lower axial stiffness by inducing circumferential fiber alignment in electrospun APENG. Our preliminary studies support this concept by showing that APENG prototypes resist buckling and kinking during limb flexion, possess good surgical handling characteristics, and undergo rapid functional regeneration in-vivo. Our team will employ benchtop, human cadaver, computational, and large animal models for evaluation and optimization of APENG prototypes and testing the hypothesis that FPA-tuned APENGs with optimized AP provide reduced limb flexion- induced buckling, improved flow characteristics, and better functional regeneration than conventional stiff ePTFE grafts without AP. Our research strategy is focused on reaching specific sequential milestones in the APENG development and includes measurable deliverables for evaluating progress. Completion of the R61 phase specific aims will provide physiologically justified functional requirements for the APENG device, refined and validated manufacturing process, optimized prototypes and surgical procedures, and in-vivo feasibility assessment. In addition, we will identify an industry Accelerator Partner and secure at least 25% non-Federal cost matching of direct costs before advancing to the R33 phase. Completion of the R33 phase specific aims will produce refined APENG design, finalized and standardized manufacturing process, and safety and efficacy evaluations of the final product against commonly used commercial analogs through standardized in-vitro and chronic in-vivo studies. Reaching these milestones will lay the groundwork for future larger-scale preclinical and clinical studies and support professional development and regulatory approval of APENG. This project will also create new knowledge in arterial and graft biomechanics that can lead to the development of other lower extremity arterial repair devices and intervention methods offering better and more durable treatments.
