(G-273) Model-Direct Design and Optimization of Kink-Resistant Vascular Grafts with High-Compliance

Introduction:: Approximately 1.4 million patients require arterial grafts in the U.S. each year. When autografts are unavailable, synthetic vascular grafts are required and implanted in ~10-20% of patients. However, synthetic small-diameter vascular grafts (SDVG, ID < 6 mms) are associated with a 40-50% reduction in patency after 2 years and a 40% failure rate at 5 years [1]. This loss of patency due to intimal hyperplasia is attributed, in part, to poor compliance-matching with native arterial tissue [2]. Data demonstrate that the high compliance of native vessels (e.g., coronary artery, 10-15%/mmHg*10^-2) permits expansion and contraction during the cardiac cycle, whereas current synthetic SDVG (e.g., ePTFE, 1-2%/mmHg*10^-2) resist such dilation, causing a difference in luminal diameter at the graft-artery interface.



Recently, a graft was developed consisting of a hydrogel-electrospun mesh composite that provides arterial compliance-matching mechanical properties [3]. These grafts have been shown to reduce cellular markers for intimal hyperplasia. However, the increased compliance resulted in grafts prone to kinking (i.e., buckling). To improve kink-resistance, a polymeric coil was added, but negatively impacted compliance [4]. The ideal graft (i.e., high compliance and high kink-resistance) requires a balance between multiple biomechanical properties that are in opposition (e.g., methods to increase graft kink-resistance reduce its compliance). Between geometric and material property tunability, the number of design parameter combinations for coil-reinforced graft manufacturing via a trial-and-error approach is nearly limitless and prohibitively time-consuming. Herein, we developed a novel finite element (FE) framework to inform and identify graft designs that enhance kink-resistance without sacrificing high compliance.


Materials and Methods:: To advise and accelerate the graft design process, a batch-processing scheme via GibbonCode was used to sweep the multi-dimensional design space (Fig. 1A, [5]). The grafts were modeled as an axisymmetric cylinder with a reinforced coil wrapped helically around the outer surface (Fig. 1B). Two FE models were created for each of the 100 unique coil-reinforced graft parameter combinations (200 models in total) to quantify compliance and kink resistance. To quantify compliance, physiologic pressure loads of 80 and 120mmHg were applied to the inner graft surface. Graft compliance (C_graft) was calculated as the change in graft diameter due to change in pressure (Fig. 2A, Eq. 1). To quantify kink-resistance, the graft was pressurized to 100mmHg, and compressed axially by application of a displacement. Kink-resistance was calculated by measuring the critical buckling load (F_graft, i.e., the maximum compressive force the graft can withstand before bending or buckling; Fig. 2B). FE simulations were performed using FEBio, and solved using a high-performance computational system, containing 192 Intel Xeon Platinum 8360H CPUs @ 3.00-4.20GHz, and 3TB of RAM [6].



To identify optimal parameter combinations for grafts with target compliance and kink-resistance, an optimization function (φ, Eq. 2) was defined to balance the contribution of the competing mechanical responses. Function values were calculated for each combination of design parameters and sought to be minimized across the parameter search space. A minimum φ value indicates the modeled graft compliance and kink-resistance are both comparable to native arterial tissue and ePTFE grafts, respectively.


Results, Conclusions, and Discussions:: Across the 100 parameter combinations, graft compliance displayed a wide range of values from 1.03 to 7.91%/mmHg*10^-2 (Fig. 3A). Compliance values were dependent on both coil diameter and spacing, with minimal changes due to coil modulus, and increased across the parameter space from coil diameter/spacing of 0.5mm/1mm to 0.1mm/10mm. In addition, critical buckling load across the parameter space varied from 0.18 to 0.42N (Fig. 3B). Buckling loads were dependent on coil diameter and spacing, and increased from a coil spacing of 3 to 10mm. Notably, however, the buckling load increased sharply at coil spacings of 1 and 2 mm. Specifically, for coil spacing of 3mm, the mean buckling load was 0.23±0.04N, but for coil spacings of 2 and 1mm, the mean buckling load was 0.30±0.02N, and 0.39±0.03N, respectively, indicating higher kink-resistance. Based on an α value equal to 0.5 (equal weighting for compliance and kink-resistance), predicted compliance and kink-resistance led to diverse values for the optimization function (Fig. 3C). The minimum value of φ = 0.15 resulted from the combination of a coil diameter = 0.1mm, coil modulus = Bionate® 80A, and coil spacing = 1mm. For this parameter combination, the compliance and critical buckling load were 7.01%/mmHg*10^-2 and 0.35N, respectively. The maximum optimization value of φ = 0.61 had a combination of a coil diameter = 0.5mm, coil modulus = Bionate® 55D, and coil spacing = 1mm.



Our investigation demonstrates the success of implementing a model-directed framework to accelerate the design of tissue-engineered SDVG with optimal mechanical properties. Results suggest that smaller coil spacing improves kink-resistance of the graft but reduces compliance, whereas, both compliance and kink-resistance are independent of coil moduli. Furthermore, the data suggest that coil spacings < 2mm should be refined to explore and improve optimization values. It should be emphasized that the model-directed design process took ~9 hours to complete, whereas experimental fabrication and testing of 100 grafts would take 5-6 months. We anticipate that this model-directed design approach will provide a kink-resistant SDVG with high compliance. Ultimately, these unique grafts have the potential to improve clinical outcomes by addressing failures of current synthetic SDVG.


Acknowledgements (Optional): : This research was supported, in part, by the National Institutes of Health (R01 HL150608). The authors thank DSM Biomedical for providing Bionate^® 80A and Bionate^® 55D used in graft development and mechanical testing.


References (Optional): : [1] Salacinski, HJ et al., J Biomater Appl, 15(3):241-278, 2001.

[2] Burkel, W. E., Med Prog Technol, 14(3-4):165-175, 1989.

[3] Post, A et al., Acta biomater, 89:84-94, 2019.

[4] Li, X., MS Thesis, University of California Los Angeles, 2018.

[5] Moerman. KM et al., J Open Source Softw,3(22): 506, 2018.

[6] Maas, SA et al., J Biomech Eng, 134(1):011005, 2012.