Engineered Prevascularization for Oral Tissue Grafting: A Systematic Review

Abstract

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.

Human Periodontal Ligament Stem Cell and Umbilical Vein Endothelial Cell Co-Culture to Prevascularize Scaffolds for Angiogenic and Osteogenic Tissue Engineering

“…In the present study, the ratio of hPDLSCs and hUVECs was fixed at 1:3. Several studies indicated that a 1:1 ratio of MSCs and hUVECs provided robust and stable vascular networks while enabling bone-like tissue formation [7,22]. However, other studies used higher proportion of hUVECs in co-culture with MSCs, such as 3:1 and 5:1, as MSCs are larger and more proliferative [23,24].…”

Acceleration of ligamentization and osseointegration processes after anterior cruciate ligament reconstruction with autologous tissue-engineered polyethylene terephthalate graft

“…Despite such a positive effect, overstimulation of vascularization at the late healing stage is not appropriate, as it may cause pathological fibrosis (35)(36)(37)(38). "Pre-vascularization," as a newly emerged concept in tissue engineering, emphasizes the pre-formed functional vascular networks with grafts or scaffolds embedded prior to their implantation, which enhances the graft connection to the host vascular system (22). The novelty of our study lies in the fact that a PET graft, with preliminary subcutaneous implantation, underwent an autologous tissue engineering process and became highly pre-vascularized.…”

“…Rapid pre-vascularization based on tissue engineering is very important for the survival of transplanted scaffolds and grafts. It has been reported that an in vivo engineered pre-vascularization strategy can utilize the body itself as a bioreactor to form new blood vessels within the implanted scaffolds for skin and bone tissue regeneration, which is promising for clinical applications (21,22).…”

Transforming one organ into another to overcome challenges in tissue engineering

“…This is evidenced by the fact that thromboembolism in any part of the circulation will always lead to severe outcomes 22–24 . Indeed, in the practice of TE, the vascularization of engineered tissue is both crucial and challenging 25–28 . Without a mature large‐scale blood vessel network, it is not possible to construct an organ with physiological functions even if the difficulties regarding seeded cells and immune rejection are overcome.…”