In-Vivo Assessment of a Tissue Engineered Vascular Graft Computationally Optimized for Target Vessel Compliance
25 Pages Posted: 13 Jul 2020 Publication Status: Accepted
Compliance mismatch between a bypass graft and the host vasculature can lead to in-vivo graft failure. Specifically, hypocompliant (stiff) grafts are believed to provide a hemodynamic environment that promotes graft failure via thrombus formation and the development of intimal hyperplasia. Tissue engineered vascular grafts(TEVGs) offer an opportunity to control the compliance of a graft to match that of the native target vasculature and minimize these undesirable outcomes. Our group has recently developed a technique to computationally and experimentally optimize the compliance of a TEVG to a wide range of target values. In this work, acellular TEVGs were created using our validated computational optimization approach that were either compliance matched (CMgel- high gelatin content) or hypocompliant (HYPOpcl- high polycaprolactone content) relative to rat abdominal aorta.A third acellular hypocompliant graft (HYPOgen- increased genipin crosslinking) was also fabricated using the CMgel material composition but crosslinked with an increased genipin concentration such that it's compliance matched that of HYPOpcl grafts. All TEVGs were implanted interpositionally into the abdominal aorta of 21 Sprague Dawley rats(n=7 for each group, males=11, females=10) for 28 days, imaged in-vivo using ultrasound, explanted, and assessed for cellular/extracellular markers using immunofluorescence and two photon excitation fluorescence imaging. In-vivo ultrasound demonstrated that CMgel grafts remained compliance-matched while hypocompliant grafts remained stiff throughout the 4 week implantation period (p<0.05). Overall, the constructs with higher gelatin content (CMgel & HYPOgen) showed increased cellular infiltration and degradation compared to the HYPOpcl grafts. The compliance matched grafts showed an increase in the amount of contractile smooth muscle cell markers in the proximal portion of the graft compared to hypocompliant grafts (0.058±0.015 CMgel vs 0.033±0.009 HYPOpcl(p=0.007) & 0.022±0.018 HYPOgen, p=0.04). The middle section (along the axial length) of compliance matched grafts displayed an increase in the ratio of CD163 to CD68 macrophages (CMgel=1.83±1.82) compared to the HYPOpcl grafts (0.13±0.06, p=0.03)suggesting a reduced pro-inflammatory response in these optimized grafts. Our results suggest that computational optimization may improve the acute (28 day) in-vivo remodeling of a biopolymer TEVG. To the authors' knowledge,this is the first in-vivo rat study comparing electrospun acellular grafts that have been computationally optimized for target levels of compliance.
Suggested Citation: Suggested Citation