The Application of Organs-on-a-Chip in Dental, Oral, and Craniofacial Research

Abstract

The current development of microfluidics-based microphysiological systems (MPSs) will rapidly lead to a paradigm shift from traditional static 2-dimensional cell cultivation towards organized tissue culture within a dynamic cellular milieu. Especially organs-on-a-chip (OoCs) can very precisely re-create the mechanical and unique anatomical structures of the oral environment. This review provides an introduction to such technology, from commonly used chip materials and fabrication methods to the application of OoC in in vitro culture. OoCs are advantageous because of their small-scaled culture environment, the highly controlled dynamic experimental conditions, and the likeness to the in vivo structure. We specifically focus on current chip designs in dental, oral, and craniofacial (DOC) research. Also, future perspectives are discussed, like model standardization and the development of integrated platforms with advanced read-out functionality. By doing so, it will be possible for OoCs to serve as an alternative for animal testing and to develop highly predictive human models for clinical experiments and even personalized medicine.

Mechanical Regulation of Oral Epithelial Barrier Function

“…A deeper understanding of oral pathophysiology requires the development of 3D culture systems that can recapitulate the oral ECM structures, mechanics, and complex cell-cell and cell-matrix interactions that occur in vivo [51][52][53]. Recent studies have demonstrated the development of 3D microfluidic platforms that have been widely used in oral, dental, and craniofacial areas [54]. Specific efforts related to oral mucosa include the Gingival Crevice-On-Chip platform, which recapitulates host-oral microbiome interactions [55]; oral mucosa-on-a-chip, which has been applied to evaluate the responses of bacteria to dental materials [56]; and oral mucositis-on-a-chip, which investigates the role of chemo-and radiation treatments in oral tissue [56].…”

Microphysiological Modeling of Gingival Tissues and Host‐Material Interactions Using Gingiva‐on‐Chip

“…However, such a configuration limits the ability to achieve the necessary air‐liquid interface culture required for the stratification and differentiation of keratinocytes, and the attainment of epithelial barrier function. [ 18 ] In contrast, the vertically stacked design combined with open access feature presented in this study, helps mimic the lumen of the oral cavity, and achieve the required air‐liquid interface for efficient differentiation of keratinocytes, and the formation of protective barrier.…”

“…Fluid control systems provide continuous nutrient supply, controlled delivery, and mechanical stimulation through active flow, resulting in a superior representation of the in vivo microenvironment. [16][17][18] Further, miniaturization helps to minimize sample size and reagent volumes needed for the assays. [19] Recent advancements in oral and dental barrier tissue emulation using microfluidic systems are gaining significant traction with platforms such as oral mucosa-on-chip, [20][21][22][23] gingival creviceon-chip, [24] gingival epithelial-capillary interface-on-chip [25] and tooth-on-chip.…”

“…[15,26,27] Integration of fluid dynamics and organotypic cultures using perfusion bioreactors, [28,29] oral mucosa-on-chip, [20][21][22][23]30] gingival crevice-on-chip, [24,30] and gingival epithelial-capillary interfaceon-chip [25] provided unprecedented opportunities to emulate microanatomical features of the gingiva and oral mucosa such as interstitial fluid flow, and controlled exposure to dental materials and bacteria. [18] These features provided more insights into the host-material and host-microbiome interactions under microphysiological flow conditions. However, design features such as horizontally stacked configuration of the microchannels and collagen matrix contraction limited the long-term culture capabilities, [22,23] epithelial stratification, and the formation of cornified barrier layers, [21,[23][24][25]30] which can only be achieved through an air-liquid interface culture.…”

Micropillars in Biomechanics: Role in Guiding Mesenchymal Stem Cells Differentiation and Bone Regeneration

“…Promising novel fabrication techniques include 3D printing, [98,99] nanofabrication, [100,101] and microfluidics-based methods. [102,103] In summary, micropillars hold great promise in the field of stem cell research and tissue engineering. While the innovative techniques involving PDMS micropillar arrays and microfluidic chips have found success in other areas of regenerative medicine, their direct application to bone regeneration may necessitate further customization and exploration to effectively address the complex demands of bone tissue engineering.…”