Abstract
ObjectivesThe success of prosthetic vascular grafts in the management of peripheral arterial disease is frequently limited by the development of anastomotic neointimal hyperplasia (ANIH), with the host response to prosthetic grafts beginning soon after implantation. To address this, we combine a platform of polyethylene terephthalate (PET) fabric with an applied cryogel layer containing biologic agents to create a bioactive prosthetic graft system, with the ability to deliver therapeutics targeting modulators of the ANIH-associated transcriptome response, along with antithrombotic agents.MethodsHybrid graft materials were synthesized by cryopolymerization of methacrylated alginate and heparin onto electrospun (ePET), knitted PET (kPET), or woven PET (wPET). Arg-Gly-Asp (RGD) peptides were added to increase cell adhesion. Scanning electron microscopy (SEM) was used to study the microstructure at 1 day, and 2, 4, and 8 weeks. Physical properties such as swelling ratio, pore connectivity, shape recovery, and stiffness were evaluated. Human aortic endothelial cell (HAoEC) adherence was visualized using confocal microscopy after 24 hours and proliferation was evaluated with a resazurin-based assay for 7 days. Confocal microscopy was used to assess delivery of adeno-associated virus (AAV-GFP) after incubation of hybrid grafts with HAoECs. Heparin activity of the materials was measured using an anti-Xa assay.ResultsSEM demonstrated large interconnected pores throughout the entire structure for all graft types, with minimal degradation of the cryogel after 8 weeks. Hybrid materials showed a trend towards increased shape recovery, increased stiffness, decreased swelling ratio, and no difference in pore connectivity. HAoECs incorporated, adhered, and proliferated over 7 days on all materials. HAoECs were successfully transduced with AAV-GFP from the hybrid graft materials. Anti-Xa assay confirmed continued activity of heparin from all materials for over 7 days.ConclusionsWe have developed a bioactive prosthetic graft system with a cryogel coating capable of delivering biologic agents with antithrombotic activity. By applying the cryogel and selected agents onto PET prior to graft implantation, this study sets the stage for the system to be individualized and tailored to the patient, with bioengineering and targeted gene therapy strategies dovetailing to create an improved prosthetic graft adaptable to emerging knowledge and technologies.
Highlights
Peripheral arterial disease (PAD) affects more than eight million Americans and, despite advances in endovascular technologies, open surgical revascularization using vein or prosthetic graft is a key component in management of these patients (Mozaffarian et al, 2015)
We have developed a bioactive prosthetic graft system with a cryogel coating capable of delivering biologic agents with antithrombotic activity
By applying the cryogel and selected agents onto polyethylene terephthalate (PET) prior to graft implantation, this study sets the stage for the system to be individualized and tailored to the patient, with bioengineering and targeted gene therapy strategies dovetailing to create an improved prosthetic graft adaptable to emerging knowledge and technologies
Summary
Peripheral arterial disease (PAD) affects more than eight million Americans and, despite advances in endovascular technologies, open surgical revascularization using vein or prosthetic graft is a key component in management of these patients (Mozaffarian et al, 2015). Anastomotic neointimal hyperplasia (ANIH) is one of the limiting factors in the long-term success of prosthetic grafts and is especially pronounced at the distal anastomosis, in part due to increased contact activation of blood proteins and platelets in transit through the graft (LoGerfo et al, 1983; Ito et al, 1991; LoGerfo, 1991). Decades of research elucidating the biology and pathophysiology leading to neointimal hyperplasia and graft failure have established several fundamental factors critical in predicting the success of a prosthetic vascular graft, such as adequate runoff, technical aspects in constructing the anastomoses, contact activation, and the thrombogenic potential of the graft material. Understanding of the molecular mechanisms involved in the host response to prosthetic grafts has allowed for development of a bioactive material that can deliver viral vectors and modulators of the ANIH-associated transcriptome response, along with antithrombotic agents
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