Cell Co-transplantation Strategies in Craniofacial Bone Tissue Engineering: A Systematic Review

Objectives: To systematically assess the literature to answer the focused question: does co-culture and co-transplantation of angiogenic endothelial cells (EC) and osteogenic mesenchymal stem cells (MSC) enhance the regenerative potential of bone tissue engineering constructs compared to MSC alone in animal defect-models?
Methods: Electronic databases (MEDLINE, EMBASE, Google) were searched in duplicate for English literature until June 2104 based on the following inclusion criteria:
- randomized or non-randomized controlled animal studies reporting on healing of critical-size defects (CSD) in calvarial or alveolar bone models,
- inclusion of a control group receiving MSC-scaffold implantation,
- assessment of new bone formation (histologic, histomorphometric or micro-CT) and new vessel formation (histologic or immunohistochemical),
- an observation period of 4 weeks or longer.
Study-quality was assessed according to the ARRIVE guidelines.
Results: Of 576 search-identified studies, 11 were included. Ten studies reported on calvarial and one on mandibular CSD in rodents and rabbits. Random allocation of animals/defects to treatment groups was done in 5 studies; overall methodological quality was lacking. Use of human-derived bone marrow or adipose tissue MSC and dermal or umbilical EC (5 studies), and of MSC-derived EC (5 studies) was reported. Co-culture for 2–14 days prior to implantation enhanced MSC osteogenic differentiation (8 studies); the optimal MSC:EC seeding ratio was 1:1. Alloplastic copolymer scaffolds were most often used (7 studies) for in vivo transplantation. New bone formation was significantly enhanced in co-transplantation versus MSC-only groups (7 studies) with likely better vascularization (4 studies). However, this was not always the case when human-derived cells were used. No complications or adverse-reactions were reported in association with new tissue formation after co-transplantation of MSC-EC cells.
Conclusions: Limited evidence from small-animal models suggests that co-culture and co-transplantation of MSC and EC seeded on appropriate biomaterial scaffolds may enhance bone regeneration in craniofacial defects compared to the use of only MSC-seeded constructs.