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Delivery of targeted gene therapies using a hybrid cryogel-coated prosthetic vascular graft
Beth Israel Deaconess Med Ctr, Div Vasc & Endovasc Surg, Boston, MA 02215 USA;SUNY Syracuse, Dept Surg, Syracuse, NY USA.ORCID iD: 0000-0002-8505-2680
Harvard Univ, John A Paulson Sch Engn & Appl Sci, Cambridge, MA 02138 USA;Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Beth Israel Deaconess Med Ctr, Div Vasc & Endovasc Surg, Boston, MA 02215 USA;Harvard Univ, John A Paulson Sch Engn & Appl Sci, Cambridge, MA 02138 USA.
Beth Israel Deaconess Med Ctr, Div Vasc & Endovasc Surg, Boston, MA 02215 USA.
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2019 (English)In: PeerJ, ISSN 2167-8359, E-ISSN 2167-8359, Vol. 7, article id e7377Article in journal (Refereed) Published
Abstract [en]

Objectives. The 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. Methods. Hybrid 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. Results. SEM 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. Conclusions. 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 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.

Place, publisher, year, edition, pages
PEERJ INC , 2019. Vol. 7, article id e7377
Keywords [en]
Vascular surgery, Peripheral arterial disease, Prosthetic graft material, Intimal hyperplasia, Biomaterials, Cryogel, Polymer
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:uu:diva-398860DOI: 10.7717/peerj.7377ISI: 000482714500001PubMedID: 31497383OAI: oai:DiVA.org:uu-398860DiVA, id: diva2:1377299
Available from: 2019-12-11 Created: 2019-12-11 Last updated: 2019-12-11Bibliographically approved

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