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Long-Term Functional Efficacy of a Novel Electrospun Poly(Glycerol Sebacate)-Based Arterial Graft in Mice

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Abstract

Many surgical interventions for cardiovascular disease are limited by the availability of autologous vessels or suboptimal performance of prosthetic materials. Tissue engineered vascular grafts show significant promise, but have yet to achieve clinical efficacy in small caliber (<5 mm) arterial applications. We previously designed cell-free elastomeric grafts containing solvent casted, particulate leached poly(glycerol sebacate) (PGS) that degraded rapidly and promoted neoartery development in a rat model over 3 months. Building on this success but motivated by the need to improve fabrication scale-up potential, we developed a novel method for electrospinning smaller grafts composed of a PGS microfibrous core enveloped by a thin poly(ε-caprolactone) (PCL) outer sheath. Electrospun PGS–PCL composites were implanted as infrarenal aortic interposition grafts in mice and remained patent up to the 12 month endpoint without thrombosis or stenosis. Many grafts experienced a progressive luminal enlargement up to 6 months, however, due largely to degradation of PGS without interstitial replacement by neotissue. Lack of rupture over 12 months confirmed sufficient long-term strength, due primarily to the persistent PCL sheath. Immunohistochemistry further revealed organized contractile smooth muscle cells and neotissue in the inner region of the graft, but a macrophage-driven inflammatory response to the residual polymer in the outer region of the graft that persisted up to 12 months. Overall, the improved surgical handling, long-term functional efficacy, and strength of this new graft strategy are promising, and straightforward modifications of the PGS core should hasten cellular infiltration and associated neotissue development and thereby lead to improved small vessel replacements.

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Abbreviations

TEVG:

Tissue engineered vascular graft

PGS:

Poly(glycerol sebacate)

PCL:

Poly(ε-caprolactone)

SCPL:

Solvent casted particulate leached

IAA:

Infrarenal abdominal aorta

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Acknowledgements

The Morphology Core at Nationwide Children’s Hospital performed histology stainings. The authors are grateful for the expertise of Dr. Kan Hor, Cardiology, Nationwide Children’s Hospital, for his assistance with μCT data reconstruction and analysis. This work was supported, in part, by Grants from the NIH: R01 HL128602 (JH, CB, YW), R01 HL089658 (YW), and T32 HL076124 (RK). CB receives Grant support from Gunze Limited and Pall Corporation. The authors have no professional or financial conflicts of interest to disclose.

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    Authors and Affiliations

    1. Department of Biomedical Engineering, Yale University, 55 Prospect Street, New Haven, CT, 06511, USA

      Ramak Khosravi, Matthew R. Bersi & Jay D. Humphrey

    2. Tissue Engineering Program and Surgical Research, Nationwide Children’s Hospital, 575 Children’s Crossroads, Research III – WB4151, Columbus, OH, 43215, USA

      Cameron A. Best, Ekene Onwuka, Yong-Ung Lee, Tai Yi, Toshiharu Shinoka & Christopher K. Breuer

    3. Department of Bioengineering, University of Pittsburgh, 3700 O’Hara Street, Pittsburgh, PA, 15261, USA

      Robert A. Allen, Chelsea E. T. Stowell, Jennifer J. Zhuang & Yadong Wang

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    1. Ramak Khosravi
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    Correspondence to Ramak Khosravi.

    Additional information

    Associate Editor Ender Finol oversaw the review of this article.

    Ramak Khosravi, Cameron A. Best, Robert A. Allen, and Chelsea E.T. Stowell have contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    10439_2015_1545_MOESM1_ESM.pdf

    Supplementary Figure 1 PCL sheath circumference throughout the implantation period. Values are mean ± SEM. Supplementary material 1 (PDF 32 kb)

    10439_2015_1545_MOESM2_ESM.pdf

    Supplementary Figure 2. (A) Representative von Kossa staining of PGS-PCL arterial TEVGs at 3, 6, and 12 months post-implantation identifies chronic medial calcification that coincides with an increase in F4/80 positive macrophages per high powered field (B). SMC apoptosis, as quantified by Caspase 3 immunofluorescence staining (C), and SMC osteogenic transdifferentiation, as quantified by Runx-2 expression (D) were observed throughout implantation, with no significant difference detected between time points (E). This suggests that chronic inflammation, coincident with persistent SMC apoptosis and osteogenic transdifferentiation, contributed to late-term TEVG calcification. Four fluorescent photomicrographs were acquired at 63X for each section and cells were manually counted based on the coincidence of positive immunolabeling and nuclear staining. Black arrows indicate medial calcification; white arrows denote double positive cells. Values are mean ± SEM. L indicates the lumen. Supplementary material 2 (PDF 2272 kb)

    10439_2015_1545_MOESM3_ESM.pdf

    Supplementary Figure 3. The energy dissipation ratio (EDR) at 3 months and 12 months for both the graft (TEVG) and the adjacent proximal infrarenal abdominal aorta (PIAA). The EDR of the native IAA in the absence of graft implantation6 is shown for comparison. Values are mean ± SEM. *p < 0.05. Supplementary material 3 (PDF 72 kb)

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    Khosravi, R., Best, C.A., Allen, R.A. et al. Long-Term Functional Efficacy of a Novel Electrospun Poly(Glycerol Sebacate)-Based Arterial Graft in Mice. Ann Biomed Eng 44, 2402–2416 (2016). https://doi.org/10.1007/s10439-015-1545-7

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