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

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.

Implantation of VEGF‐functionalized cell‐free vascular grafts: regenerative and immunological response

“…Prior to this study, a polymer‐based graft composed of an inner core of poly(glycerol sebacate) and a nondegrading outer sheath of thin poly(ε‐caprolactone) implanted in mice was patent over a 12‐mo period. However, the polymeric outer sheath did not degrade during that time, indicating a lack of integration and long‐term remodeling (19).…”

“…It is important to note that these vessels, although successful, still require intensive culture times-a key issue when considering the ability of a graft to be truly off-the-shelf ready. In addition to devitalized and decellularized grafts, nonbiologic grafts composed of various polymeric biomaterials have also been used to engineer cell-free vascular grafts (15)(16)(17)(18)(19)(20)(21)(22)(23). Besides biocompatibility, lack of immunogenicity, and mechanical properties matching those of native vessels, these materials must promote endothelialization of the lumen to achieve patency and promote development of the vascular wall through extensive, long-term remodeling.…”

Quickening: Translational design of resorbable synthetic vascular grafts

“…Though it may seem that a slower-degrading graft would give more time for neotissue to mature, the rate of tissue formation seems to positively correlate with that of material degradation. (92,115,120) The foundational design requirement is that at any given moment, the material and neotissue combined must bear arterial pressure stably. [Fig.…”

“…(122) As discussed previously, slowly resorbing graft materials like PCL or PLA can face similar challenges. (123,96,120)…”

<p>Microporous elastomeric membranes fabricated with polyglycerol sebacate improved guided bone regeneration in a rabbit model</p>

“…Furthermore, it is difficult to adjust the thickness, pore size, or external shape of fabricated scaffolds and to maintain architectural consistency. [19][20][21] As a kind of heat-resistant cross-linking polyester, polyglycerol sebacate (PGS) is characterized by biocompatibility, elasticity to resist tissue compression, and flexible fabrication styles, including salt leaching and electrospinning. We therefore proposed that PGS could be an ideal biomaterial for GBR applications.…”