Continuously Quantifying Oral Chemicals Based on Flexible Hybrid Electronics for Clinical Diagnosis and Pathogenetic Study

Abstract

Simultaneous monitoring of diverse salivary parameters can reveal underlying mechanisms of intraoral biological processes and offer profound insights into the evolution of oral diseases. However, conventional analytical devices with bulky volumes, rigid formats, and discrete sensing mechanisms deviate from the requirements of continuous biophysiological quantification, resulting in huge difficulty in precise clinical diagnosis and pathogenetic study. Here, we present a flexible hybrid electronic system integrated with functional nanomaterials to continuously sense Ca²⁺, pH, and temperature for wireless real-time oral health monitoring. The miniaturized system with an island-bridge structure that is designed specifically to fit the teeth is only 0.4 g in weight and 31.5 × 8.5 × 1.35 mm³ in dimension, allowing effective integration with customized dental braces and comfort attachment on teeth. Characterization results indicate high sensitivities of 30.3 and 60.6 mV/decade for Ca²⁺ and pH with low potential drifts. The system has been applied in clinical studies to conduct Ca²⁺ and pH mappings on carious teeth, biophysiological monitoring for up to 12 h, and outcome evaluation of dental restoration, providing quantitative data to assist in the diagnosis and understanding of oral diseases. Notably, caries risk assessment of 10 human subjects using the flexible system validates the important role of saliva buffering capacity in caries pathogenesis. The proposed flexible system may offer an open platform to carry diverse components to support both clinical diagnosis and treatment as well as fundamental research for oral diseases and induced systemic diseases.

Figure 1

Modularized flexible electronic systems for real-time oral health monitoring. (a) A schematic of an implantable flexible system modified with functional materials for monitoring intraoral Ca²⁺, pH, and temperature simultaneously. (b) An exploded view of a sensor integrated with multiple functional nanomaterials. Insets: SEM images showing the surface morphology of the (I) PANI, (II) PVB/NaCl, and (III) PEDOT layers modified on corresponding electrodes. (c) An image of a modularized system that includes three electrochemical electrodes for chemical sensing, a flexible circuit for data transmission, and two batteries connected in series for power supply. (d) A system-level diagram showing the electrical components of the system. (e) A flexible dental brace embedded with a system for oral health monitoring. Inset: a flexible system fixed on teeth. (f) A panoramic X-ray image of an oral cavity showing the deployment of a system on teeth.

Figure 2

The sensing performance of ion-selective sensors. (a) The open-circuit potential response of a Ca²⁺ sensor with concentrations ranging from 0.25 to 4 mM. Inset: a linear fitting result of the Ca²⁺ sensing. (b) Selectivity and (c) reversibility of Ca²⁺ sensors. (d) The open-circuit potential response of a pH sensor with pH values ranging from 4 to 8. Inset: a linear fitting result of the pH sensing. (e) Selectivity and (f) reversibility of pH sensors. (g) Long-term stability of Ca²⁺ sensors and pH sensors with varying Ca²⁺ concentrations and pH values. The sensing performance of (h) Ca²⁺ sensors and (i) pH sensors in artificial saliva and daily beverages compared with a commercial calcium meter and a commercial pH meter, respectively.

Figure 3

Mechanical, thermal, and long-term stability of the system. (a) Sensing results of a Ca²⁺ sensor and a pH sensor under bending with a curvature radius of 0.6 cm. Thermal stability of (b) a pH sensor and (c) a Ca²⁺ sensor upon different temperatures ranging from 25 to 50°C. (d) The linear fitting result of temperature sensing using embedded temperature sensors. n = 5; error bars indicate means ± SD. (e) Wireless, simultaneous monitoring of Ca²⁺, pH, and temperature in vitro under room temperature using the flexible system. (f) The lifespan of a Ca²⁺ sensor and a pH sensor. (g) Received signal strength measurements of the system under mouth opening and mouth closing conditions. (h) The power consumption of the system. (i) The temperature distribution of the circuit and batteries in nonworking and working modes.

Figure 4

Ca²⁺ and pH mappings on extracted teeth and biocompatibility of the system. (a) Images of a tooth with active caries for Ca²⁺ and pH mappings. Insets: SEM images of the distribution of bacteria at a caries site (position 4) and a caries-affected site (position 3). (b) Ca²⁺ and pH measurements at different positions on tooth surfaces. (c) Dynamic changes in pH at the caries site (position 4) when the tooth was cultured in the artificial saliva. (d) The demineralization process of a tooth immersed in an acidic solution with a pH value of 4.3. (e) Simulation of bacterially produced lactic acid diffusing on tooth surfaces over time. (f) Fluorescent images obtained by Calcein-AM/PI double-stain assay showing the dyed viable (green) and dead (red) HGF-1 cells cocultured with batteries, circuits, Ca²⁺ sensors, pH sensors, and PVB/NaCl-coated reference electrodes. (g) Cell viability of HGF-1 cells obtained by CCK-8 assay after coculturing with different samples for 24 h and 48 h. n = 3; error bars indicate means ± SD.

Figure 5

Real-time, in vivo analysis of oral microenvironment using the flexible system. (a) An image of the in vivo testing setup with a user interface and a human subject wearing a flexible system. (b) Simultaneous monitoring of Ca²⁺ concentration, pH value, and temperature when ingesting drinks and food additives with different Ca²⁺ concentrations and pH values. (c) Real-time, continuous monitoring of a healthy subject during asleep and awake periods. (d) Results of intraoral Ca²⁺ concentration, pH value, and temperature over 12 h. (e) A 3D reconstruction model of teeth based on CBCT images that shows the position of the caries cavity. (f) Analysis of salivary Ca²⁺, pH, and temperature of a patient before and after dental restoration treatment.

Figure 6

Caries risk assessment based on clinical conditions and salivary buffering capacity. (a) A schematic illustrating the relationship between salivary buffering capacity and dental caries. (b) Caries risk assessment for 10 subjects based on general health and clinical conditions. Representative sensing results of salivary (c) Ca²⁺ concentration, (d) pH value, and (e) temperature in different caries risk populations when applied to the same acid stimulation. n = 3; error bars indicate means ± SD. Corresponding buffering speeds of (f) Ca²⁺ concentration, (g) pH value, and (h) temperature in different caries risk populations. (i) Saliva recovery time after acid stimulation and risk classification of 10 human subjects. n = 3; error bars indicate means ± SD. Comparison of the resting (j) Ca²⁺ concentration, (k) pH value, and (l) temperature in different caries risk populations. n = 3; error bars indicate means ± SD.