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PeerJ. 2019 Aug 20;7:e7377. doi: 10.7717/peerj.7377. eCollection 2019.

Delivery of targeted gene therapies using a hybrid cryogel-coated prosthetic vascular graft.

Author information

1
Division of Vascular and Endovascular Surgery, Beth Israel Deaconess Medical Center, Boston, MA, United States of America.
2
Department of Surgery, State University of New York (SUNY), Syracuse, NY, United States of America.
3
John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, United States of America.
4
Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States of America.
5
Division of Pharmacology, Department of Pharmaceutical Biosciences, Uppsala Universitet, Uppsala, Sweden.
6
BioSurfaces, Inc, Ashland, MA, United States of America.
#
Contributed equally

Abstract

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.

KEYWORDS:

Biomaterials; Cryogel; Intimal hyperplasia; Peripheral arterial disease; Polymer; Prosthetic graft material; Vascular surgery

Conflict of interest statement

Saif G. Pathan is employed by BioSurfaces, Inc; David W. Nelson was formerly employed by BioSurfaces, Inc.

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