Oral tissue spheroid, organoid, and organ-on chip microphysiological modeling strategies towards enhanced emulation of health and disease.

Diseases and disorders of dental, oral, and craniofacial (DOC) tissues represent a significant global health burden and have been found to have the greatest age-standardized prevalence and incidence of all reported diseases worldwide. While the application of novel therapies has been suggested to address the different types of oral health diseases, only a limited number of interventional regenerative therapies have been reported to improve clinical therapeutic outcomes. The lack of novel therapies in DOC tissue regeneration may be in part attributed to the highly resource-intensive translational path from preclinical models to clinical trials. Recently, stakeholders and regulatory agencies have begun to encourage the use of alternative preclinical models using human tissues for testing therapeutic interventions in place of animal models. This advocacy may provide an opportunity to reduce or eliminate animal testing, ultimately limiting resource expenditure and providing a more efficient regulatory pathway for the approval of novel DOC therapies. While the complexity of DOC physiology, defects, and diseases is not effectively recapitulated in traditional 2D or 3D in vitro culture models, the emergence of more sophisticated in vitro models (or so-called microphysiological systems that include spheroid, organoid and organ on-chip (OoC) systems) has enabled effective modeling of clinically simulated disease states in several DOC tissue and organ systems. Here, we aim to provide an overview and collective comparison of these microphysiological systems, outline their current uses in DOC research, and identify important gaps in both their utilization and abilities to recapitulate essential features of native oral-craniofacial physiology, towards enabling the therapeutic performance of de novo interventions targeted at regeneration outcomes in vivo.