Organs-on-a-Chip in Dental, Oral, and Craniofacial Research (DOC-OoCs)

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  1. Goal
  2. Background
  3. Gaps and Opportunities
  4. Specific Areas of Interest
  5. References

September 2023

Integrative Biology and Infectious Diseases Branch
Division of Extramural Research

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Goal

This initiative seeks to advance the validation of organ-on-a-chip (OoC) toward disease modelling and pre-clinical efficacy studies in dental, oral, and craniofacial (DOC) research. It is expected that outcomes will advance the use of validated reproducible, three-dimensional microfluidic systems into the framework of clinical trials with demonstrated usefulness as new approach methodologies for DOC clinical research. An essential feature will be a multidisciplinary approach including experts in DOC biology and clinical science, pathology, microfluidics, bioengineering, material science, computational biology, pharmacology, and biostatistics.

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Background

Over the past decade OoCs or organ chips have been used increasingly to model a wide range of human conditions across multiple organ systems to study biological mechanisms. Per the 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 modelling 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. Organ chips 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 modelled 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.

These advances create 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. 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. 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 organ chips 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 organ chips 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.

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Gaps and Opportunities

NIDCR currently funds model development of tooth-on-chip, oral epithelial barrier, oral mucosa perfusion model with gingival keratinocytes, dental pulp, vascularized and innervated mineralized rat calvarial bone in microgels, and salivary gland on microbubbles. Trans-agency efforts between NIH and FDA have resulted in the development and translation of organ chips in lung, liver, heart, kidney, bone, intestine, eye, reproductive organs, blood vessels and lymphoid organs. While DOC chips have shown initial promise in replicating relevant tissue and organ functions, the challenge of demonstrating equivalence or superiority relative to animal models remains to be addressed.

Importantly, this initiative builds on NIDCR’s contributions as part of the trans-agency efforts and the NIH MPS program led by NCATS to move organ chips toward disease modelling, efficacy testing, and clinical trials. Secondly, the recent FDA update on alternate platforms presents an opportunity for DOC-OoC models to move toward demonstration of utility and integration in the DOC clinical framework. Thirdly, the NIH Common Fund is in the early stages of developing a concept to advance complementary new approach methodologies in complex in vitro systems including MPS/tissue chips. Lastly, the NIH Advisory Committee to the Director working group on Novel Alternative Methods (NAMs) is involved in framing recommendations to the NIH on high-priority areas for future investment in NAMs.

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Specific Areas of Interest

DOC chips must mimic the dynamic nature of mechanical and functional processes, interfaces of the oral environment, and inter-organ crosstalk of DOC tissues in the context of the whole body. Synergies with other organ chips and integration with vasculature, neural and immune components will enable the DOC platforms to move toward pre-clinical equivalence. This initiative will encourage studies to move the DOC chips to validated alternate testing platforms, including:

  • Developing multi-array, serial, and parallel-chamber designs of DOC tissues
  • Developing OoCs that capture the dynamic nature, mechanical forces, and interfaces of the DOC environment
  • Demonstrating utility of DOC OoCs using iPSC and/or primary tissues derived from patients to create patient-specific preclinical models
  • Demonstrating functional validation and standardization of DOC OoCs’ equivalence or superiority to preclinical animal models
  • Demonstrating functional utility in disease models for identification of novel treatment mechanisms including drug screening, assessment of candidate therapies for efficacy, and safety assessments
  • Establishing the preclinical foundation that will inform clinical trial design
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References

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Last Reviewed
December 2024