Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Oregon Health Sciences University on 10/06/14 For personal use only.

Review

Electrospinning of biomimetic scaffolds for tissue-engineered vascular grafts: threading the path Expert Rev. Cardiovasc. Ther. 12(7), 815–832 (2014)

Ian Woods and Thomas C Flanagan* School of Medicine & Medical Science, Health Sciences Centre, University College Dublin, Belfield, Dublin 4, Ireland *Author for correspondence: Tel.: +353 1716 6631 Fax: +353 1716 6649 [email protected]

Tissue-engineered vascular grafts (TEVGs) offer an alternative to synthetic grafts for the surgical treatment of atherosclerosis and congenital heart defects, and may improve graft patency and patient outcomes after implantation. Electrospinning is a versatile manufacturing process for the production of fibrous scaffolds. This review aims to investigate novel approaches undertaken to improve the design of electrospun scaffolds for TEVG development. The review describes how electrospinning can be adapted to produce aligned nanofibrous scaffolds used in vascular tissue engineering, while novel processes for improved performance of such scaffolds are examined and compared to evaluate their effectiveness and potential. By highlighting new drug delivery techniques and porogenic technologies, in addition to analyzing in vitro and in vivo testing of electrospun TEVGs, it is hoped that this review will provide guidance on how the next generation of electrospun vascular graft scaffolds will be designed and tested for the potential improvement of cardiovascular therapies. KEYWORDS: atherosclerosis • congenital heart defect • electrospinning • nanotechnology • tissue engineering • vascular graft

Clinical background

Ever since the first coronary artery bypass surgeries were performed in 1960 by Robert Goetz and his team, the number and type of materials available to surgeons for grafting has rapidly expanded and evolved, as have the nature of the conditions to which grafting can be applied. Today, vascular grafting is used to treat conditions ranging from atherosclerosis to aortic aneurysms and congenital heart defects. In adult patients, saphenous veins, internal mammary and radial arteries are considered to be the gold standard for arterial bypass and replacement surgery [1]. However, autologous vessels are unavailable in many patients or are unsuitable for grafting due to previous surgical harvest or peripheral vascular disease [2]. In neonatal care and pediatric applications, synthetic graft materials are often used as patches and/or vascular conduits for reconstructive surgeries in the treatment of congenital heart defects. The diameter of vascular grafts used in both adult and pediatric applications ranges between 4 and 20 mm. For coronary artery bypass surgery, the diameter of an informahealthcare.com

10.1586/14779072.2014.925397

implanted graft is approximately 3–5 mm, while a Blalock-Taussig shunt, used in the Fontan procedure for correction of congenital heart defects, also has a small diameter of approximately 4–6 mm. Long-term patency of implanted synthetic small-caliber grafts with a lumen diameter in this range (70% porosity) environment, which allows the seeded cells to bridge voids and attach at multiple sites [41]. The morphology of the scaffold is an important factor that influences a multitude of cellular variables and functions, such as cell phenotype, ECM deposition and cellular infiltration [34,42,43]. For example, a number of studies comparing the performance of cells on aligned and non-aligned electrospun scaffolds demonstrate a significant increase in the mechanical properties of tissue that has been engineered using aligned scaffolds [35,44]. The aligned scaffold microstructure is indicated to have led to an improvement in the mechanical properties of the tissue without an increase in matrix deposition. This is theorized to be due to the alignment of structural proteins parallel to the aligned scaffold fibers.

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Woods & Flanagan

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Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Oregon Health Sciences University on 10/06/14 For personal use only.

Horizontal actuator

Polymer solution High voltage power source

Mandrel actuator

Figure 4. A schematic diagram of a standard electrospinning apparatus. The polymer of interest is dissolved into solution, and discharged via a jet from a needle tip as a fine (micro- to nano-scale) polymer fiber through an electric field. The fiber is deposited on a grounded collector, in this case a spinning mandrel, producing a tubular, cylindrical scaffold via a spooling effect.

A number of different approaches have been employed to create aligned, electrospun nanofibrous scaffolds, which may better mimic the anisotropic, biomechanical properties of the native vascular ECM. By the very nature of electrospinning onto a rotating cylindrical mandrel, a certain level of fiber alignment can be attained by the natural spooling effect of the electrospun fibers onto the substrate. However, it is not a trivial task to generate highly-aligned nanofibrous structures using the electrospinning technique. Conveniently, the ECM of the medial layer of an artery is primarily arranged in a circumferential manner, that is, perpendicular to flow of blood through the lumen. Therefore, the most straightforward approach to increase the circumferential fiber alignment for the synthesis of TEVG scaffolds is to simply increase the speed of rotation of the collecting mandrel. By using large diameter collectors, much higher linear surface velocities can be generated at a particular mandrel rotation speed, which will naturally increase alignment of fibers collecting on the surface. Lee and colleagues produced highly-aligned polyurethane fibers using a collector with a diameter of 40 mm (linear surface velocity: 2.6 m/s) [45], while Xu and colleagues reported the synthesis of highlyaligned poly(L-lactid-co-e-caprolactone) (P(LLA-CL)) scaffolds using a collector with a diameter of 200 mm (linear surface velocity: 11 m/s) [32]. However, such scaffolds would not be 820

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Electrospinning of biomimetic scaffolds for tissue-engineered vascular grafts: threading the path.

Tissue-engineered vascular grafts (TEVGs) offer an alternative to synthetic grafts for the surgical treatment of atherosclerosis and congenital heart ...
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