Elsevier

Biomaterials

Volume 35, Issue 33, November 2014, Pages 9033-9040
Biomaterials

The performance of a small-calibre graft for vascular reconstructions in a senescent sheep model

https://doi.org/10.1016/j.biomaterials.2014.07.008Get rights and content

Abstract

There is an acute clinical need for small-calibre (<6 mm) vascular grafts for surgery. The aim of this study was to evaluate the long-term performance of a small-calibre graft produced from a nanocomposite biomaterial, polyhedral oligomeric silsesquioxane poly(carbonate-urea)urethane (POSS-PCU), in a large animal model following Good Manufacturing Practice (GMP) and Good Laboratory Practice (GLP) protocols. Grafts were characterised and implanted into the left carotid artery (LCA) of senescent sheep (n = 11) for a period of 9 months. In vivo compliance and blood flow rates were measured using ultrasound wall tracking software and a Transonic flow meter. Graft patency and degree of intimal hyperplasia (IH) were examined at the study end point. Seven of the POSS-PCU grafts were free from thrombosis, IH, calcification and aneurysmal dilation, with 4 occluding within 14 days. All of the ePTFE controls (n = 4) were found to be occluded by day 32. The lumen of the patent POSS-PCU grafts was free from any cellular deposits, whilst perigraft tissue could be seen to be infiltrating into the body of the graft from the adventitia. No significant differences were detected between the blood flow rates (p = 0.3693) and compliance (p = 0.9706) of the POSS-PCU grafts and the native artery, either post-operatively or after 9 months implantation. Small-calibre vascular grafts produced from POSS-PCU offer a viable option for the clinical use in revascularisation procedures with a patency rate of 64%.

Introduction

Occlusion of the blood vessels is a leading cause of morbidity and mortality. Treatment options to restore perfusion are often limited to surgical interventions. In more severe occlusions, 70% or more, or in cases where stenosis is multi-focal or when multiple vessels are involved; bypass surgery is often the only choice. Approximately 600 000 coronary or peripheral artery bypass grafting operations are performed annually in the USA alone [1]. Currently, autologous vessels, such as the saphenous vein, are the conduits of choice for revascularisation. However, up to 30% of patients who require surgery do not have suitable or sufficient blood vessels to be used for transplantation due to vascular disease, amputation or previous harvest [2]. Further, harvesting autologous vessels requires a second surgical procedure, with potential concomitant morbidities.

Developing clinically viable small-calibre vascular grafts, as an alternative to autologous vessels, is the subject of intense research. Whilst a number of prosthetic grafts have been successfully developed for the replacement of large-calibre (>6 mm) vessels, the small-calibre (<6 mm) counterparts fail due to thrombosis and intimal hyperplasia (IH) [3]. The two most common prosthetic grafts used clinically are produced from polyethylene terephthalate (PET) and expanded polytetrafluoroethylene (ePTFE). Both materials are rigid compared to the native artery. In small-diameter, low flow positions, such as the coronary or infrainguinal arteries, viscoelasticity of graft is necessary to minimise the impedance to flow and the risk of stasis and thrombosis [4]. Additionally, the viscoelastic mismatch between graft and host artery has been implicated in the development of IH. Pulsatile stretching at the site of anastomosis can trigger the excessive proliferation of smooth muscle cells (SMC) resulting in the narrowing or stenosis of the graft [5].

Our lab has previously developed a nanocomposite biomaterial, polyhedral oligomeric silsesquioxane poly(carbonate-urea)urethane (POSS-PCU) with the aim of improving the poor in vivo biostability of polyurethanes [6]. Polyurethanes have been proposed as an alternative prosthetic graft material as they have excellent mechanical properties, namely a compliance profile similar to that of the native artery [7]. However, this initial enthusiasm was dampened somewhat due to the lack of long term durability, leading to mechanical and chemical degradation resulting in radial dilation and the formation of aneurysms. By covalently attaching the chemically robust POSS nanocage to the PCU backbone, a highly durable and biostable material was created which was shown to be resistant to hydrolytic and oxidative degradation both in vitro and in vivo [8], [9]. Following subcutaneous implantation in an ovine model for 36 months, no sign of degradation or inflammation was noted. Constructs from POSS-PCU have already found clinical use as a synthetic tracheal transplant [10]. Additionally, POSS-PCU displayed improved anti-thrombogenic properties in vitro compared to ePTFE making it a promising biomaterial for cardiovascular applications [11].

The purpose of this study was to explore the hypothesis that with improved in vivo stability, blood compatibility and a compliance profile similar to the native artery, POSS-PCU grafts will yield superior patency rates compared to PTFE counterparts. The long term performance of the grafts exposed to the arterial circulation was evaluated in a senescent ovine model for a period of 9 months following GMP/GLP protocols. The patency, structural integrity, compliance and perfusion efficiency were assessed as key determinants of graft performance.

Section snippets

Materials and methods

The study was performed in compliance with the GLP Regulations 1999 (S.I. No. 3106) as amended by the 2004 regulations (S.I. 994) which are based on the principles of GLP as adopted by the Organisation for Economic Co-operation and Development (OECD), ENV/MC/CHEM (98) 17.

Graft manufacture and characterisation

Phase separation methodologies are well established in the field of membrane science for producing porous substrates for purification and separation purposes. In the present study, we utilized phase separation and extrusion as a facile method to produce porous vascular conduits from POSS-PCU. The manufacturing process allows the production of porous grafts in a range of diameters and wall thickness' (Fig. 1C and D) depending on the end use.

Prior to implantation, grafts were fully characterised

Discussion

Driven by clinical demand, considerable research effort has been directed at developing alternative, more suitable, small-calibre vascular bypass grafts. In recent years, advances in bioengineering and cell biology has led to the development of a number of tissue engineering and regenerative medicine based solutions being proposed. Whilst admirable progress has been made, a number of challenges remain to be overcome before they become clinically feasible. Tissue engineered blood vessels using

Conclusions

In this study, we describe the long-term performance of a small-calibre vascular graft implanted in the carotid artery of senescent sheep and monitored for a period of 9 months. The patency rate of the POSS-PCU graft was found to be 64% and they were free from IH, aneurysm, and calcification. The grafts displayed comparable functional properties to the native arteries. The data presented here, lead us to believe POSS-PCU vascular grafts are a promising option for clinical use for patients who

Acknowledgements

The authors would like to acknowledge the financial support provided by the Translational grant of the Wellcome Trust “Pre-clinical assessment of small diameter conduit made from nanocomposite polymer for coronary artery bypass graft application” and the Engineering and Physical Sciences Research Council (EPSRC).

References (29)

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