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The management of avulsed teeth undergoing delayed replantation remains a clinical challenge as there are currently no effective interventions that can improve periodontal healing and prevent replacement root resorption. While several preclinical studies have reported varied success using cell-based tissue engineering to improve periodontal healing, a consensus is required before further clinical translation. Therefore, this systematic review seeks to evaluate the efficacy of cell-based therapy in promoting periodontal healing following delayed replantation in animal models. MEDLINE (PubMed) and Embase were searched on September 27, 2020. Ten studies involving rodent and dog models met the inclusion criteria. Cell sources included gingiva, periodontal ligament (PDL), bone marrow, and adipose tissues. Generally, cell-based therapy had increased the proportion of root surfaces displaying periodontal healing and concomitantly reduced the proportion presenting with replacement root resorption and ankylosis. The best outcomes were observed following treatment with PDL-derived cells of various potency. Future preclinical studies will benefit from adopting measures to minimize bias during the conduct of animal experiments and the standardization of the outcome measures reporting. This will facilitate future reviews with possible pooling of results in the form of meta-analyses, allowing a consensus to be obtained from the literature. In addition, further research will be required to shed light on the implications of using allogeneic cells as well as the optimization of cell delivery protocols. The findings of this systematic review demonstrated the therapeutic potential of certain cell-based therapies in promoting periodontal healing following delayed replantation, thus highlighting their prospective clinical benefits and translational value. Impact statement Current therapies cannot predictably promote periodontal healing following delayed replantation of an avulsed tooth, especially when there is already significant root surface damage. This review systematically assessed the literature for preclinical studies employing cell-based therapies to promote periodontal healing following delayed replantation. The results showed that certain cell-based therapies significantly increased the formation of new periodontal ligament and reduced adverse healing outcomes of replacement root resorption and ankylosis. This highlights the potential clinical benefits and translational value of cell-based therapy for the replantation of avulsed teeth.

Clinical and animal studies have demonstrated efficacy of mesenchymal stem/stromal cells (MSCs) in cartilage repair. Although MSCs were originally predicated to mediate tissue repair through cellular differentiation and cell replacement, it is now recognized that MSCs exert most of their paracrine effects on tissue repair through the release of extracellular vesicles (EVs). In particular, 50-200 nm small EVs that also include exosomes carry a rich cargo of lipids, nucleic acids, and proteins, and have been reported to be therapeutically efficacious in various disease indications, including osteochondral injuries and osteoarthritis (OA). This systematic review aimed to assess the preclinical studies that used MSC exosomes for cartilage repair. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, PubMed and Cochrane Library databases were searched for relevant controlled preclinical animal studies. A total of 13 studies were identified, with the total sample size being 434. This included 378 (87.1%) mice or rats and 56 (12.9%) rabbits. According to Systematic Review Centre for Laboratory Animal Experimentation risk of bias assessment, all the studies presented with unclear-to-low risk in bias. In general, MSC exosomes were found to be efficacious in promoting repair and regeneration of osteochondral defects and alleviating OA degeneration. In most studies, exosome-treated animals displayed increased cellular proliferation, enhanced matrix deposition, and improved histological scores. Having assessed the relevant preclinical animal studies reported to date, this systematic review shows the therapeutic benefit of MSC exosome therapy in cartilage repair. Standardization of animal models and outcome measurements would be needed to facilitate more robust analysis and improve the validity of the results in future studies.