Several patient groups undergoing small‐diameter (<6 mm) vessel bypass surgery have limited autologous vessels for use as grafts. Tissue‐engineered vascular grafts (TEVG) have been suggested as an alternative, but the ideal TEVG remains to be generated, and a systematic overview and meta‐analysis of clinically relevant studies is lacking. We systematically searched PubMed and Embase databases for (pre)clinical trials and identified three clinical and 68 preclinical trials ([>rabbit]; 873 TEVGs) meeting the inclusion criteria. Preclinical trials represented low to medium risk of bias, and binary logistic regression revealed that patency was significantly affected by recellularization, TEVG length, TEVG diameter, surface modification, and preconditioning. In contrast, scaffold types were less important. The patency was 63.5%, 89%, and 100% for TEVGs with a median diameter of 3 mm, 4 mm, and 5 mm, respectively. In the group of recellularized TEVGs, patency was not improved by using smooth muscle cells in addition to endothelial cells nor affected by the endothelial origin, but seems to benefit from a long‐term (46–240 hours) recellularization time. Finally, data showed that median TEVG length (5 cm) and median follow‐up (56 days) used in preclinical settings are relatively inadequate for direct clinical translation. In conclusion, our data imply that future studies should consider a TEVG design that at least includes endothelial recellularization and bioreactor preconditioning, and we suggest that more standard guidelines for testing and reporting TEVGs in large animals should be considered to enable interstudy comparisons and favor a robust and reproducible outcome as well as clinical translation.

Myocardial infarction (MI) is a worldwide condition that affects millions of people. This is mainly caused by the adult human heart lacking the ability to regenerate upon injury, whereas zebrafish have the capacity through cardiomyocyte proliferation to fully regenerate the heart following injury such as apex resection (AR). But a systematic overview of the methods used to evidence heart regrowth and regeneration in the zebrafish is lacking. Herein, we conducted a systematical search in Embase and Pubmed for studies on heart regeneration in the zebrafish following injury and identified 47 AR studies meeting the inclusion criteria. Overall, three different methods were used to assess heart regeneration in zebrafish AR hearts. 45 out of 47 studies performed qualitative (37) and quantitative (8) histology, whereas immunohistochemistry for various cell cycle markers combined with cardiomyocyte specific proteins was used in 34 out of 47 studies to determine cardiomyocyte proliferation qualitatively (6 studies) or quantitatively (28 studies). For both methods, analysis was based on selected heart sections and not the whole heart, which may bias interpretations. Likewise, interstudy comparison of reported cardiomyocyte proliferation indexes seems complicated by distinct study designs and reporting manners. Finally, six studies performed functional analysis to determine heart function, a hallmark of human heart injury after MI. In conclusion, our data implies that future studies should consider more quantitative methods eventually taking the 3D of the zebrafish heart into consideration when evidencing myocardial regrowth after AR. Furthermore, standardized guidelines for reporting cardiomyocyte proliferation and sham surgery details may be considered to enable inter study comparisons and robustly determine the effect of given genes on the process of heart regeneration.Cells 2020, 9, 548 2 of 16 the compensatory mechanism after ischemia or injury, are assumed to favor fibrotic healing and hypertrophy instead of regeneration and cardiomyocyte proliferation [2,5]. Unfortunately, fibrotic healing may result in loss of heart contractility, leading to various complications and symptoms such as arrhythmias that also contribute to an increase in morbidity and mortality [5]. Today, only heart transplantation and palliative medication is offered as treatment of MI. Thus, a substantial effort is ongoing worldwide to develop regenerative therapies that can reduce mortality and improve life quality for millions of people [6].