Engineered Prevascularization for Oral Tissue Grafting: A Systematic Review

Extensive dental and periodontal defects are frequent and with a limited regenerative potential. Tissue engineering could be a promising tool to obtain personalized oral grafts. However, current research shows a lack of in vitro engineered oral tissues. This is explained by the difficulty to engineer blood vessel systems, impairing the connection to the host tissue and the graft success. Various strategies were used to engineer vascularized tissues and reported successful results, thus needing a clear analysis of the current state of art in oral tissue engineering. This systematic review aimed at studying the critical factors and techniques used to engineer a prevascularized oral tissue graft. PubMed, Cochrane Library, and SCOPUS databases were searched over the last 5 years following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Out of 638 screened studies, 24 were included in the systematic review according to strict inclusion and exclusion criteria and focusing on higher connection to the host vasculature. Animal models were all rodents, and subcutaneous implantation was the most used intervention. Studies presented low-to-unclear risk of bias according to the Systematic Review Center for Laboratory Animal Experimentation tool. Endothelial cells were mainly human umbilical vein endothelial cells, while stromal cells were most of the time oral or mesenchymal stem cells. Coculture of both types of cells at a 1:1 ratio was the most common technique used to obtain vascular networks, and some studies precultured grafts up to 3 weeks to enable network formation before implantation. Prevascularized grafts were produced by various tissue engineering technologies, including cell seeding and/or embedding, cell sheets, and spheroids. All studies reported a statistically significant faster and higher connection to host of prevascularized constructs compared to controls. Vessel networks were indeed denser, with a higher portion of lumen containing erythrocytes and blood flow increased. By assessing the relevant studies on the subject, this systematic review showed that engineered prevascularization proved to be an interesting approach to improve graft connection to the host vasculature and respective specific cell and scaffold criteria. Further studies on enhanced scaffolds and larger animals seem necessary to confirm these promising results with more voluminous grafts and get closer to native human tissues and applications. Impact statement Autologous oral grafts display limitations in terms of revascularization and morbidity of donor sites, despite being the gold standard. This systematic review aimed at clarifying existing data regarding techniques to engineer prevascularized oral grafts. Tissue engineering techniques, using cocultures of endothelial and oral stromal cells, proved to be an efficient way to enhance and accelerate the connection of the graft to the host vasculature. Engineered prevascularization appears to be a promising way to improve the connection to the host and the vascularization of grafts, especially when voluminous. Large animal and human studies are necessary to allow clinical translation.