Computationally Optimizing the Compliance of Multilayered Biomimetic Tissue Engineered Vascular Grafts

Abstract

Coronary artery bypass grafts used to treat coronary artery disease (CAD) often fail due to compliance mismatch. In this study, we have developed an experimental/computational approach to fabricate an acellular biomimetic hybrid tissue engineered vascular graft (TEVG) composed of alternating layers of electrospun porcine gelatin/polycaprolactone (PCL) and human tropoelastin/PCL blends with the goal of compliance-matching to rat abdominal aorta, while maintaining specific geometrical constraints. Polymeric blends at three different gelatin:PCL (G:PCL) and tropoelastin:PCL (T:PCL) ratios (80:20, 50:50, and 20:80) were mechanically characterized. The stress–strain data were used to develop predictive models, which were used as part of an optimization scheme that was implemented to determine the ratios of G:PCL and T:PCL and the thickness of the individual layers within a TEVG that would compliance match a target compliance value. The hypocompliant, isocompliant, and hypercompliant grafts had target compliance values of 0.000256, 0.000568, and 0.000880 mmHg−1, respectively. Experimental validation of the optimization demonstrated that the hypercompliant and isocompliant grafts were not statistically significant from their respective target compliance values (p-value = 0.37 and 0.89, respectively). The experimental compliance values of the hypocompliant graft were statistically significant than their target compliance value (p-value = 0.047). We have successfully demonstrated a design optimization scheme that can be used to fabricate multilayered and biomimetic vascular grafts with targeted geometry and compliance.

Optimization of Tissue-Engineered Vascular Graft Design Using Computational Modeling

“…While the clinical trials arose from trial-anderror empirical approaches, computational models have also become increasingly sophisticated and recognized as tools for guiding the design of implants for tissue engineering applications. 22,30 Thus, we sought to exploit the advances in computational modeling to establish a new approach to scaffold design. We previously showed that computational models can describe 6 and predict 9 in vivo neovessel development that starts from a biodegradable polymeric scaffold implanted as an IVC-interposition model, a reasonable surrogate for an extracardiac Fontan conduit.…”

“…with R 2 the luminal radius at pressure P 2 and R 1 that at P 1 , is an important clinical and previously identified computational metric 22 that can be used to minimize the mechanical mismatch between graft and adjacent vessels and thus promote normal hemodynamics. Since evolving thickness affects radial changes during loading, compliance quantifies the structural stiffness of the construct.…”

Strategies to counteract adverse remodeling of vascular graft: A 3D view of current graft innovations

“…Such endothelialization modality requires a strong binding between the circulating cell and the graft surface, which may be offered by progenitor-specific antibodies or ligand (Lu et al, 2013;Hao et al, 2020) or adhesive peptides (Choi et al, 2016;Hao et al, 2017;Liu et al, 2021) immobilized on the lumen surface. Since all three in situ mechanisms are still insufficient to create a continuous endothelium throughout a long vascular graft in human patients, ex vivo or in vitro seeding of matured vascular cells (Dahan et al, 2017), progenitor/stem cells (Olausson et al, 2012;Ardila et al, 2019), or genetically modified autologous cells expressing fibulin-5 and VEGF, onto the graft lumen have been employed (Sánchez et al, 2018).…”

“…The neotissue growth and graft remodeling in turn change the flow-graft interactions. Therefore, computational models simulate such interactions as well as advanced statistical analyses of a parametric cause-effect relationship have been exploited to accelerate the rational optimization of vascular grafts ( Keshavarzian et al, 2019 ; Tamimi et al, 2019 ; Khosravi et al, 2020 ). Recently, data-informed models have been developed to improve graft designs, even toward patient-specific design ( Best et al, 2018 ), for desired graft performances in terms of lumen diameter, extracellular matrix (ECM) production, and levels of inflammation ( Best et al, 2019 ; Drews et al, 2020 ).…”

Effects of Braiding Parameters on Tissue Engineered Vascular Graft Development

“…Computational modeling has shown promise for accelerating the optimization process of vascular grafts by determining potential mechanisms of neotissue formation and effects of altering scaffold parameters. [17,18] Recent models informed by experimental data have suggested that in vivo neovessel formation is an inflammation-driven, mechano-mediated process. [15] Therefore, altering the design of the scaffold provides a twofold means for optimizing in vivo performance.…”