Balancing Scaffold Degradation and Neo-Tissue Formation in In Situ Tissue Engineered Vascular Grafts.

An essential aspect of cardiovascular in situ tissue engineering (TE) is to ensure balance between scaffold degradation and neo-tissue formation. We evaluated the rate of degradation and neo-tissue formation of three electrospun supramolecular bisurea-based biodegradable scaffolds that differ in their soft-block backbone compositions only. Scaffolds were implanted as interposition grafts in the abdominal aorta in rats, and evaluated at different time points (t = 1, 6, 12, 24, and 40 weeks) on function, tissue formation, strength, and scaffold degradation. The fully carbonate-based biomaterial showed minor degradation after 40 weeks in vivo, whereas the other two ester-containing biomaterials showed (near) complete degradation within 6-12 weeks. Local dilatation was only observed in these faster degrading scaffolds. All materials showed to some extent mineralization, at early as well as late time points. Histological evaluation showed equal and non-native-like neo-tissue formation after total degradation. The fully carbonate-based scaffolds lagged in neo-tissue formation, presumably as its degradation was (far from) complete at 40 weeks. A significant difference in vessel wall contrast enhancement was observed by magnetic resonance imaging between grafts with total compared with minimal-degraded scaffolds.

Calcification in Pulmonary Heart Valve Tissue Engineering: A Systematic Review and Meta-Analysis of Large-Animal Studies.

Tissue-engineered heart valves (TEHVs) are emerging alternatives to current valve prostheses and prospectively a lifelong replacement. Calcification, a pathological complication for biological protheses, has been reported in preclinical TEHV studies. Systematic analysis of its occurrence is missing. This review aims to: 1) systematically review reported calcification of pulmonary TEHVs in large-animal studies; and 2) analyze the influence of engineering methodology (choice of scaffold material, cell preseeding) and animal model (animal species and age) on calcification. Baseline analysis included 80 studies, of which 41 studies containing 108 experimental groups were included in meta-analysis. Inclusion was low because only 55% of studies reported on calcification. Meta-analysis showed an overall average calcification event rate of 35% (95% CI: 28%-43%). Calcification was more prominent (P = 0.023) in the arterial conduit region (34%; 95% CI: 26%-43%) than in the valve leaflets (21%; 95% CI: 17%-27%), and was mostly (42% in leaflets, 60% in conduits) present in a mild form. Time-analysis showed an initial surge within 1 month after implantation, decreased calcification between 1 and 3 months, and then progression over time. There were no significant differences in degree of calcification between TEHV strategy nor animal models. Much variability between individual studies was observed in degree of calcification as well as quality of analysis and reporting thereof, hampering adequate comparisons between studies. These findings underline the need for improved analysis and better reporting standards of calcification in TEHVs. It also necessitates control-based research to further enlighten the risk of calcification for tissue-engineered transplants compared to current options. This can bring the field of heart valve tissue engineering forward toward safe clinical use.

A systematic evaluation on reporting quality of modern studies on pulmonary heart valve implantation in large animals.

OBJECTIVES: Before new heart valves can be implanted safely in humans, animal experiments have to be performed. These animal experiments have to be clearly designed, analysed and reported to assess the accuracy and importance of the findings. We aimed to provide an overview of the reporting and methodological quality of preclinical heart valve research. METHODS: We conducted a systematic literature search on biological and mechanical pulmonary valve implantations in large animals. We used the Animals in Research: Reporting In Vivo Experiments (ARRIVE) guidelines to score the quality of reporting in each article. We compared the scores before and after the introduction of the ARRIVE guidelines (2010). RESULTS: We screened 348 articles, of which 31 articles were included. The included articles reported a mean of 54.7% adequately scored ARRIVE items (95% confidence interval 52.2-57.3%). We did not identify a difference in reporting quality (54.7% vs 54.8%) between articles published before and after 2010. We found an unclear (lack of description) risk of selection bias, performance bias and detection bias. CONCLUSIONS: The reporting quality of studies that implanted bioprosthetic or mechanical valves in the pulmonary position in the large animal model is not on the desired level. The introduction of the ARRIVE guidelines in 2010 did not improve the reporting quality in this field of research. Hereby, we want to emphasize the importance of clearly describing the methods and transparently reporting the results in animal experiments. This is of great importance for the safe translation of new heart valves to the clinic. CLINICAL TRIAL REGISTRATION NUMBER: PROSPERO (CRD42019147895).

In Situ Remodeling Overrules Bioinspired Scaffold Architecture of Supramolecular Elastomeric Tissue-Engineered Heart Valves.

In situ tissue engineering that uses resorbable synthetic heart valve scaffolds is an affordable and practical approach for heart valve replacement; therefore, it is attractive for clinical use. This study showed no consistent collagen organization in the predefined direction of electrospun scaffolds made from a resorbable supramolecular elastomer with random or circumferentially aligned fibers, after 12 months of implantation in sheep. These unexpected findings and the observed intervalvular variability highlight the need for a mechanistic understanding of the long-term in situ remodeling processes in large animal models to improve predictability of outcome toward robust and safe clinical application.

Angiographic fate of side branch dissections in bifurcation lesions treated with a provisional single stenting strategy: a post-hoc analysis of the international multicenter randomized DEBIUT study.

BACKGROUND: The provisional single stenting strategy is currently the preferred treatment strategy in bifurcation lesions. However, in case of nonflow limiting side branch (SB) dissections, it is not clear whether outcomes may be inferior to coronaries without a SB dissection, whether it can be safe to leave a SB dissection untreated, and whether bail-out SB stenting provides benefits over conservative treatment. METHODS: Bifurcation lesions treated with a provisional single stenting in the randomized DEBIUT were screened according to the presence or absence of SB dissections. Additional treatment (with possible stent implantation) or conservative management was left to the discretion of the operator. RESULTS: Out of the 117 lesions included, 18 (15.4%) angiographic SB dissections were seen following intervention (type A = 3, B = 7, C = 6, D/E = 2), 9 (50%) were treated with additional stenting, while 9 (50%) were left untreated. At 6-month follow up, all dissections that were left untreated were healed. The late-luminal loss was similar (P = 0.33) between patients without dissection (0.11 mm [-0.22 to 0.43 mm]) and with dissection (0.29 mm [-0.28 to 0.88 mm]). The late-luminal loss was nonsignificantly lower (P = 0.40) in the nonstented dissection group (-0.01 mm [-0.33 to 0.87 mm]), than in the stented dissection group (0.41 mm [-0.20 to 0.97 mm]), while binary restenosis was 1 (13%) and 2 (25%), respectively. CONCLUSION: Coronary SB dissections have similar 6-month angiographic late-luminal loss as lesions without SB dissection, with complete angiographic healing of the dissections. Moreover, this study suggests that in case of a dissection, if operators consider it safe not to stent the dissection, this can lead to a satisfactory result at mid-term follow-up.