Organs-on-a-Chip in Dental, Oral, and Craniofacial Research (DOC-OoCs) (R21 Clinical Trial Not Allowed)

This funding opportunity issued by the National Institute of Dental and Craniofacial Research solicits exploratory/developmental Research Grant (R21) applications from institutions/organizations that will develop organ-on-a-chip (OoC) towards disease modeling and pre-clinical efficacy studies in dental, oral, and craniofacial (DOC) research. Over the past decade OoCs have increasingly been used to model a wide range of human conditions across multiple organ systems to study biological mechanisms. Per the U.S. Food and Drug Administration (FDA) definition, OoC is a subset class of microphysiological systems (MPS) consisting of a miniaturized physiological environment engineered to yield and/or analyze functional tissue units capable of modeling specified/targeted organ-level responses. There are notable examples of microfluidic devices and on-chip products, with early adoption in various research and development level projects. OoCs have demonstrated clinical mimicry in the lung, liver, heart, kidney, bone, intestine, eye, reproductive organs, blood vessels and lymphoid organs. Alternative cardiomyocyte platforms can now measure contractile forces of cardiac tissue, monitor drug toxicity, model diseases like drug-induced valvular heart disease, and dilated cardiomyopathy. Blood–brain barrier platforms have successfully modeled the interface between vascular and brain tissues. Vascularized microtumors have recreated physiologically relevant vascularized tumorigenesis in vitro, dynamic interactions between tissues and tumors, and effects of chemotherapeutics on healthy and cancerous tissues. Other platforms include blood vessel vasculature from blood and iPSC-derived endothelial cells, liver platforms that metabolize drugs, produce albumin, and show immune-mediated toxicity, kidney proximal tubule model which displays secretory and reabsorption properties, subchondral bone, adipose tissue, and bone marrow. In addition, multi-organ physiological coupling to model drug disposition in the whole-body context has demonstrated a potential for these methodologies to guide clinical trial design. The development of OoC technologies for DOC tissues has accelerated in recent years including bio-fabricated chip models of tooth, oral mucosa, dental pulp, oral epithelium, and salivary glands. These advances create further opportunities to draw parallels to examine similarities and differences with the tissues in the oral environment, such as OoCs representing tonsils, tongue, lip, alveolar bone, suture, temporomandibular joint, and periodontal ligament. Advances in stem cell technology, such as induced pluripotent stem cells and organoids, have enabled sourcing of patient-specific stem cells that can now be integrated and differentiated within OoCs to create patient-specific preclinical models. The 2022 change to the FDA Modernization Act allows for alternatives to animal testing for purposes of drug and biological product applications. The ultimate promise for these alternate platforms is the potential to be used as an accepted drug testing platform, which, when validated and standardized, can largely reduce animal testing, and limit the problems seen in drug candidate attrition due to inadequacy of the two-dimensional cell culture models and variability from pre-clinical animal models from different genetic backgrounds. If human OoCs are found to perform better than existing models, then in addition to reducing animal testing, they may be used to develop or select therapeutics that are personalized for individual patients, distinct genetic subpopulations or even subgroups with specific disease comorbidities, that could revolutionize clinical trials design.