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Construction of vascular graft with circumferentially oriented microchannels for improving artery regeneration.

ABSTRACT: Design and fabrication of scaffolds with three-dimensional (3D) topological cues inducing regeneration of the neo-tissue comparable to native one remains a major challenge in both scientific and clinical fields. Here, we developed a well-designed vascular graft with 3D highly interconnected and circumferentially oriented microchannels by using the sacrificial sugar microfiber leaching method. The microchannels structure was capable of promoting the migration, oriented arrangement, elongation, and the contractile phenotype expression of vascular smooth muscle cells (VSMCs) in vitro. After implantation into the rat aorta defect model, the microchannels in vascular grafts simultaneously improved the infiltration and aligned arrangement of VSMCs and the oriented deposition of extracellular matrix (ECM), as well as the recruitment and polarization of macrophages. These positive results also provided protection and support for ECs growth, and ultimately accelerated the endothelialization. Our research provides a new strategy for the fabrication of grafts with the capability of inducing arterial regeneration, which could be further extended to apply in preparing other kinds of oriented scaffolds aiming to guide oriented tissue in situ regeneration.

SUBMITTER: Wu P

PROVIDER: S-EPMC7483276 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:AimsIt is well-established that endothelial dysfunction promotes activation of vascular smooth muscle cell (VSMC). Whether decreased accumulation of VSMCs affects endothelial regeneration and functions in arteriovenous graft (AVG) remodelling has not been studied. We sought to identify mechanisms by which the Notch ligand, Jagged1, in VSMCs regulates endothelial cell (EC) functions in AVGs.Methods and resultsAVGs were created in transgenic mice bearing VSMC-specific knockout (KO) or overexpression of Jagged1. VSMC migration, EC regeneration, and its barrier functions as well as AVG remodelling were evaluated. Jagged1 expression was induced in VSMCs of neointima in the AVGs. Jagged1 KO in VSMCs inhibited the accumulation of extracellular matrix as well as VSMC migration. Fewer α-SMA-positive VSMCs were found in AVGs created in VSMC-specific Jagged1 KO mice (VSMCJagged1 KO mice) vs. in WT mice. Decreased VSMCs in AVGs were associated with deterioration of EC functions. In AVGs created in transgenic mice bearing Jagged1 KO in VSMCs exhibited delayed EC regeneration and impaired EC barrier function. Barrier dysfunction of ECs increased inflammatory cell infiltration and dysregulation of AVG remodelling and arterialization. The increased expression of IL-1β in macrophages was associated with expression of adhesion markers in ECs in AVGs created in VSMCJagged1 KO mice. In contrast, AVGs created in mice with overexpression of Jagged1 in VSMCs exhibited improved EC regeneration plus decreased macrophage infiltration. This led to AVG remodelling and arterialization. In co-cultures of ECs and VSMCs, Jagged1 deficiency in VSMCs suppressed N-cadherin and integrin β3 expression in ECs. Inhibition of integrin β3 activation delayed EC spreading and migration. Notably, Jagged1 overexpression in VSMCs or treatment with recombinant Jagged1 stimulated the expression of N-cadherin and integrin β3 in ECs. Jagged1-induced responses were blocked by inhibition of Notch signalling.ConclusionsJagged1 expression in VSMCs maintains EC barrier functions and blocks infiltration of macrophages. These responses promote remodelling and arterialization of AVGs.

Project description:Porous synthetic grafts made of poly (glycerol sebacate) (PGS) can transform into autologous vascular conduits in vivo upon degradation of PGS. A long-held doctrine in tissue engineering is the necessity to match degradation of the scaffolds to tissue regeneration. Here, we tested the impact of degradation of PGS and its derivative in an interposition model of rat common carotid artery (CCA). Previous work indicates a complete degradation of PGS within approximately 2 weeks, likely at the fast end of the spectrum. Thus, the derivation of PGS focuses on delay degradation by conjugating the free hydroxy groups in PGS with a long chain carboxylic acid: palmitic acid, one of the most common lipid components. We evaluated two of the resultant palmitate-PGS (PPGS) in this study: one containing 9% palmitate (9-PPGS) and the other16% palmitate (16-PPGS). 16-PPGS grafts had the highest patency. Ultrasound imaging showed that the lumens of 16-PPGS grafts were similar to CCA and smaller than 9-PPGS and PGS grafts 12 weeks post-operation. Immunohistological and histological examination showed an endothelialized lumens in all three types of grafts within 4 weeks. Inflammatory responses to 16-PPGS grafts were limited to the adventitial space in contrast to a more diffusive infiltration in 9-PPGS and PGS grafts in week 4. Examination of calponin+ and αSMA+ cells revealed that 16-PPGS grafts remodeled into a distinctive bi-layered wall, while the walls of 9-PPGS grafts and PGS grafts only had one thick layer of smooth muscle-like cells. Correspondingly, the expression of collagen III and elastin displayed an identical layered structure in the remodeled 16-PPGS grafts, in contrast to a more spread distribution in 9-PPGS and PGS grafts. All the three types of grafts exhibited the same collagen content and burst pressure after 12 weeks of host remodeling. However, the compliance and elastin content of 16-PPGS grafts in week 12 were closest to those of CCA. Overall, placing the degradation of PGS derived elastomer to a window of 4-12 weeks results in vascular conduits closer to arteries in a rat carotid artery interposition model over a 12-week observation period.

Project description:BackgroundIntraoperative data may improve models predicting postoperative events. We evaluated the effect of incorporating intraoperative variables to the existing preoperative model on the predictive performance of the model for coronary artery bypass graft.MethodsWe analyzed 378 572 isolated coronary artery bypass graft cases performed across 1083 centers, using the national Society of Thoracic Surgeons Adult Cardiac Surgery Database between 2014 and 2016. Outcomes were operative mortality, 5 postoperative complications, and composite representation of all events. We fitted models by logistic regression or extreme gradient boosting (XGBoost). For each modeling approach, we used preoperative only, intraoperative only, or pre+intraoperative variables. We developed 84 models with unique combinations of the 3 variable sets, 2 variable selection methods, 2 modeling approaches, and 7 outcomes. Each model was tested in 20 iterations of 70:30 stratified random splitting into development/testing samples. Model performances were evaluated on the testing dataset using the C statistic, area under the precision-recall curve, and calibration metrics, including the Brier score.ResultsThe mean patient age was 65.3 years, and 24.7% were women. Operative mortality, excluding intraoperative death, occurred in 1.9%. In all outcomes, models that considered pre+intraoperative variables demonstrated significantly improved Brier score and area under the precision-recall curve compared with models considering pre or intraoperative variables alone. XGBoost without external variable selection had the best C statistics, Brier score, and area under the precision-recall curve values in 4 of the 7 outcomes (mortality, renal failure, prolonged ventilation, and composite) compared with logistic regression models with or without variable selection. Based on the calibration plots, risk restratification for mortality showed that the logistic regression model underestimated the risk in 11 114 patients (9.8%) and overestimated in 12 005 patients (10.6%). In contrast, the XGBoost model underestimated the risk in 7218 patients (6.4%) and overestimated in 0 patients (0%).ConclusionsIn isolated coronary artery bypass graft, adding intraoperative variables to preoperative variables resulted in improved predictions of all 7 outcomes. Risk models based on XGBoost may provide a better prediction of adverse events to guide clinical care.

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Construction of vascular graft with circumferentially oriented microchannels for improving artery regeneration.

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