The functions of versatile electronics in dental, oral, and craniofacial drugs

Dental, oral, and craniofacial health is closely related to the quality of both physical and social life. Commonly, dental, oral, and craniofacial diseases include caries, periodontal disease, oral mucosal disease, malocclusion, and benign/malignant tumors in the oral/craniofacial region. Treatment of these diseases is not only time-consuming and causes inconvenience and embarrassment in daily life but also induces a great financial burden¹. Given that the progression of most oral and craniofacial diseases is slow, implementing diagnosis and treatment at early pathological stages can effectively prevent exacerbation, significantly improve the prognosis and the quality of life, and also avoid potential time/economy consumption relating to treatment. However, existing diagnostic methods in stomatology mainly rely on artificial examination and imaging technologies and thus have limitations in real-time health monitoring and disease diagnosis regardless of time and place². After sufficient treatment, monitoring therapeutic effects and recovery also challenges patient compliance due to the inconvenience and excessive costs of re-examination in the hospital. The lack of point-of-care diagnosis hinders the implementation of primary prevention to sustain dental, oral, and craniofacial health.

Medical flexible electronics are electric devices fabricated on soft and extensible substrates that fit the human skin to enable non-invasive continuous monitoring of health and even participate in disease treatment/recovery³. These miniaturized devices have the advantages of portability and wearability to realize continuous and prolonged monitoring of biophysical or biochemical signals without limitations in time and places. These benefits help to avoid interference with daily life, alleviate the economic burden, and thus endow the devices with great potential for application in point-of-care diagnosis. Currently, flexible electronics have been widely used in everyday life as well as medical practises⁴. In the field of stomatology, flexible electronics have also been gradually utilized for preventing the progression of dental, oral, and craniofacial diseases and judging the corresponding prognosis. After adjusting the design, construction, and material constituents according to the special biophysical/biochemical properties and environment in dental, oral, and craniofacial areas, flexible electronics can detect the levels of various factors relating to oral hygiene, orthodontic forces, and even cancer biomarkers, and thus help to make predictions of oral health status in time.

In this review, we summarize the mechanisms and applications of flexible electronics applied in teeth, oral cavity, and craniofacial regions, and analyze challenges in the current medical practices of these promising devices. Finally, we discuss the potential strategies to improve the device performance and prospect the future trend of flexible electronics in stomatology.

A brief introduction to flexible electronics and their specificity when applied in stomatology

Generally, flexible electronics are designed as wearable sensors⁵. In daily life, they often present in the form of wireless electronic devices coupled to wristwatches to monitor basic physiological characteristics such as heart rate and skin temperature⁶. With the development of micromachining, electronics, and sensors, the types of flexible electronics expand greatly. These devices can be mainly categorized into two groups according to their functions of monitoring biophysical or biochemical signals: the former examines electrophysiology, motions (e.g., feedback from prosthetics), temperature changes, intrinsic thermal, electrical, or mechanical properties of the skin, and vascular dynamics, while the latter detects metabolites and electrolytes in body fluids such as saliva, sweat, tears, and interstitial fluid⁷. Flexible electronics usually consist of a substrate, stretchable interconnects, and sensing elements. The substrate is required to be both flexible and elastically stretchable to ensure that it fits the human skin perfectly. The materials used for substrate fabrication also need to be durable to maintain their sufficient lifespan. Besides adopting intrinsically-specific or chemically-modified materials for fabricating the substrate and interconnection, deterministic geometries, such as serpentine, rotating square tessellations, nanocurve circuits, and wavy structures, are also utilized to enhance the device flexibility and scalability^3,8,9. Conductive interconnects are fabricated on the substrate to enable electronic functions such as information transmission or electrochemical detection, mainly using micro/nano-fabrication methods to deposit or print either metals or non-metallic but conductive materials (carbon nanotubes (CNTs), graphene, conductive hydrogels, etc.). Sensors used for flexible electronics are either biosensors or electronic sensors¹⁰. Biosensors access biological activities by targeting biomolecules based on immobilized bioactive molecules onto the constructed electrodes. Electronic sensors usually adopt materials with specific electric properties to enable the detection or measurement of the targets. For example, some devices utilize piezo-elastomeric substrates to capture mechanical signals of human tissues, and some other devices use optoelectronic nanohybrids that allow photon absorption, exciton dissociation, and charge-carrier transfer and transport to achieve optical signal acquisition^11,12.

Compared to devices applied to other parts of the body, flexible electronics used in dental, oral, and craniofacial areas have to address some special situations (Fig. 1):

(1) Due to the frequent motions of both craniofacial muscles and the tongue during speaking, chewing, and swallowing, flexible electronics for dental, oral, and craniofacial applications are subjected to much more times of deformation and friction (e.g., against teeth and tongue) compared to other kinds of wearable devices. Therefore, they require great extensibility and durability, meanwhile, they should keep good adhesion to the craniofacial skin or the moist surface of teeth, tongue, or oral cavity. It is noteworthy that flexible electronics applied inside the oral cavity should avoid the possibility of accidental detachment, which may lead to respiratory tract block. Moreover, comfort should be considered as well, given the long-time wear and frequent facial motions in daily life.

(2) Materials for fabricating flexible electronics in dental, oral, and craniofacial applications should ensure sufficient biocompatibility. Since these devices adhere to the surface of human tissues for a long time, the substrates, as well as adhesives, need to be chemically friendly to the skin or mucosa and would not cause irritation nor immune response^13,14. Especially since that oral cavity directly connects the digestive tract and flexible electronics applied here in long-term contact with various acidic/alkaline substances (from food/drink or microbial metabolism) and enzymes in saliva, materials used for device fabrication should have excellent chemical inertness or been well-encapsulated by other inert and biocompatible materials, or they should be non-toxic and edible (both the materials themselves and their degradation/abrasion products) when intaken into digestive tract¹⁵.

(3) The functions of flexible electronics should be stable enough to endure the complex environment with various pH conditions in the moist oral cavity that contains enzyme-rich saliva, food/drink residue, and abundant bacteria. The abundant bioactive molecules and bacteria in the oral cavity greatly challenge the selectivity and sensitivity for target detection and analysis.

According to these peculiarities, various strategies have been developed to ensure the performance of dental, oral, and craniofacial flexible electronics and also the health of the users, mainly through adopting specific materials for device fabrication. Hydrogels that can be attached to skin and have great self-healing ability and load-bearing performance have been excellent choices for fabricating flexible substrates in stomatology scenarios. For instance, organic resin materials such as polyethylene terephthalate (PET), polyimide (PI), and polydimethylsiloxane (PDMS) are widely used due to their excellent durability and flexibility properties. To adapt to the frequent deformation during speaking, chewing, and swallowing, some additives are mixed into the aforementioned hydrogels to increase their stretchability. Some researchers added gallium (Ga) into hydrogel fabricated from sodium alginate (SA) and polyacrylamide (PAm) and obtained good performance when executing repeated mechanical movements since that the dynamic cross-linking between hydrogel ingredients and Ga ions strengthened mechanical properties^16,17. MXene is another additive that can improve the hydrogel with satisfactory structural stability and excellent deformability^18,19,20. Otherwise, chitosan-rich hydrogel, CNTs, and graphene oxide (GO) nanosheets can also endow flexible electronics with great mechanical properties^17,21,22,23. For fabricating electrodes, adopting Cu/PI organic-inorganic composite can help improve deformability when maintaining essential conductivity^24,25. It is also necessary to design specific structures (e.g., serpentine) of the electrodes to enable the tensile strength²⁶. In order to enhance the adhesion of flexible electronics to facial skin, silk, poly(N-isopropylacrylamide) (PNIPAM), and other materials can be used to modify hydrogels to increase the covalent and non-covalent interactions²¹, while some other flexible electronics used to detect physical and biological signals in the oral cavity are mainly attached to mouth guards by using medical-grade epoxy or pastes^27,28,29. In addition, for moist surfaces, it has been reported that flexible devices using water-soluble tape or silk can closely attach to the tooth surface after being dissolved by saliva^24,30.

For flexible electronics in dental, oral, and craniofacial applications, especially those used inside the oral cavity, the biocompatibility of materials used should be good enough when experiencing various enzymes and pH conditions of saliva. Many natural hydrogels that are edible, such as chitosan and cellulose, are adopted for device fabrication^17,19. Another strategy is employing chemically inertial materials (e.g., PDMS, silk film (SF), parylene, and silicone) to embed electric materials^{19,31,32,33,34}. When constructing the electrodes of flexible electronics, metals like Ag, Pt, and Au, and conductive nano-materials such as CNTs and MXene, which have been proven to show little toxicity under limited dosage, are employed to ensure ample biological safety^{19,21,22,31,35}. For sensors that are commonly attached to mouthguards, aligners, or pacifiers, it is crucial to disinfect these items beforehand to ensure their sterility and biosafety²⁹, and their constituents also mainly adopt biocompatible materials such as Prussian-blue (PB) transducer and fluorescent zinc oxide quantum dots (ZnO QDs)^27,28,34,35.

In order to ensure the good working performance of dental, oral, and craniofacial flexible electronics, it is important to encapsulate their electrodes and sensors^31,35,36 to resist the humid and complex environment in the oral cavity or breathing gas. For example, carbon nanofibers mats are added beneath the surface of mask-like sensors to resist humidity³⁶. In other flexible electronics, inert or hydrophobic PDMS, poly(MPC-co-EHMA-co-MBP) (PMEHB), polyvinyl butyral (PVB), polyethylene naphthalate film, and acrylic pressure sensitive adhesive have been used for package. For instance, to minimize biofouling and interference effects from saliva constituents, poly-orthophenylenediamine (PPD) is utilized for packaging an entire oral sensor^27,28, while PMEHB, silicone, Nafion solution, and PVB mainly help to minimize the interference on electrodes^31,35,37,38. Additionally, cellulose acetate (CA) membrane can be specifically employed to combat various bacteria present in the mouth³⁵.

Furthermore, it is necessary to enhance the selectivity of flexible electronics applied in complex oral environments. PPD could be embedded in those devices to enhance the performance of enzymatic, ionophore-based, or electrochemical determination of biochemical signals in saliva and oral gases²⁸. For electrochemical analysis, the utilization of multiple capacitive channels can assist in mitigating interference among diverse analytes, thereby improving the accuracy and reliability of the measurements²⁷. Other highly sensitive materials (e.g., MXene, PNIPAM)^19,32 can be used as well. For example, the modified polyaniline (PANI) and PVB with increased porous structures coated on electrodes can enhance their ability to enrich ions, thereby boosting the sensitivity of the sensing process³¹. In addition, improving the electrode patterns or array shapes can also improve the sensitivity^21,26.

Flexible electronics applied in oral, dental, and craniofacial scenarios

Flexible electronics have the advantages of good sensitivity, short response time, and non-invasiveness³⁹, therefore they can be applied in the dental, oral, and craniofacial areas to realize the real-time monitoring of health state and play an important role in the prevention of disease occurrence/progression, timely feedback of therapeutic effects and finally benefit long-term oral health maintenance.

Detecting biochemical signals

Biochemical signals in the oral cavity coming from saliva or cavity gas can be used as indicators for oral health status (Table 1). Common saliva-based biomarkers include uric acid (UA), glucose, lactic acid (LA), and various electrolytes, while oral cavity gas-based biomarkers are mainly ammonia (NH₃), volatile sulfide compounds (VSCs), and so on.

Saliva-based biomarkers

Metabolites, biomolecules, and a variety of ionic compounds in saliva can reflect the health status of human body^40,41. Measuring levels and changes of various substances in saliva by flexible electronics can guide disease diagnosis and treatment, and is a good alternative to invasive tests such as blood tests.

Uric acid is a biomarker for a variety of diseases such as gout and hyperuricemia. Kim et al. fabricated a mouthguard biosensor to monitor UA in saliva using a well-established method by screen-printing the sensor on a flexible polyethylene terephthalate substrate (Fig. 2a)²⁷. A working electrode, PB transducer, was made by crosslinking the uricase enzyme and electropolymerizing o-phenylenediamine. A Bluetooth low energy chipset was integrated to achieve wireless connectivity with smartwatches, cell phones, or computers. The device employed the uricase to implement high selectivity, sensitivity, and stability to measure salivary UA and avoid interference from ascorbic acid. It could respond stably to 300 μM UA, showing sufficient sensitivity when the abnormal UA value usually exceeded greater than 400 μM. Diabetes is a common cardiovascular disease whose diagnosis mostly depends on blood sugar detection (with fasting blood sugar (FBS) higher than 7 mmol L⁻¹)⁴². Researches reveal that salivary glucose levels of healthy people (ranging from 0.5 to 4.8 mg dL⁻¹) are statistically lower than diabetic patients (ranging from 1.26 to 11 mg dL⁻¹)^43,44, and the correlation of saliva glucose and blood glucose in individuals can be quantitatively determined as previously reported: FBS = 76.548 + (0.423 × saliva glucose) for healthy people, FBS = 106.35 + (0.116 × saliva glucose) for pre-diabetic patients, and FBS = 51.064 + (2.964 × saliva glucose) for diabetic patients⁴⁵. Accordingly, Arakawa et al. invented a cavity sensor to measure glucose in saliva, thus avoiding conventional invasive blood glucose testing and facilitating continuous dynamic monitoring of diabetes (Fig. 2b)³⁸. The measurement of salivary glucose was mainly implemented by detecting the concentration of hydrogen peroxide produced by the enzymatic reaction of glucose oxidase (GOD). GOD was embedded within poly(2-methacryloyloxyethyl phosphorylcholine-co-2-ethylhexyl methacrylate) (poly(MPC-co-EHMA) or PMEH) and fixed on a customized monolithic mouthguard bracket with a wireless transmitter. This device ensured the specific monitoring of salivary glucose concentrations ranging from 1 to 1000 μmol L⁻¹, covering the concentration variation of 20–200 μmol L⁻¹ required for medical monitoring. Afterward, they attached a CA coating to this sensor to prevent contamination from saliva (Fig. 2c)³⁵. Kim et al. developed a mouthguard sensor based on a printable PB transducer and a PPD/lactate oxidase (LOx) reagent layer (Fig. 2d)²⁸. This miniaturized and integrated device could be worn without professional guidance, enabling continuous noninvasive monitoring of lactate levels in a point-of-care manner for widespread scenarios. PB is highly selective for the products of LOx to detect lactate with a sensitivity of 0.1–1.0 mM. Newborns usually have difficulty in cooperating with invasive blood tests, and routine blood tests may lead to infections and even pediatric blood clots, sepsis, etc.⁴⁶. Lim et al. developed a smart pacifier that continuously monitors salivary electrolytes in real-time. Several miniature ionic sensors made of fine metal wires were mounted in a microfluidic channel and inserted into a commercial pacifier. The microfluidic device was able to continuously draw saliva from the baby’s mouth to monitor sodium (5.7–9.1 mM) and potassium (4.2–5.2 mM) levels in newborns (Fig. 2e)²⁹. This device avoided the pain and risks associated with skin pricking during traditional blood tests, enabled continuous monitoring of the salivary electrolyte status of infants, and increased the cooperation of newborns with essential diagnosis.

Biomacromolecules in saliva can indicate the physiological/pathological status of the oral cavity as well. Mannoor et al. designed graphene nanosensors coupled with silk membranes and self-assembled antimicrobial peptides onto graphene monolayers to achieve biorecognition³⁰. This device could monitor Helicobacter pylori in the oral cavity and thus prevent gastric ulcers. Li et al. designed a flexible conducting polymer electrode that could monitor salivary steroid hormones with low concentrations to reflect the female menstrual cycle⁴⁷. The sensitivity of this device could reach 11 ± 4 fM and eliminate a series of interferences in saliva such as urea, LA, glucose, and ascorbic acid.

Besides, salivary Ca²⁺ concentration and pH values, as a reflection of the degree of enamel demineralization, can also indicate the situation and risk of individual caries^48,49. Ling et al. designed a Ca²⁺ and pH sensor electrode fabricated using Ca²⁺ ionophore II (ETH 129) and polyaniline, supplemented with a temperature sensor to reflect the effect of temperature fluctuation on electrochemistry (Fig. 2f)³¹. This sensor enabled the monitoring of the distribution of Ca²⁺ and pH values on the tooth surface. The Ca²⁺ sensor exhibited a linear response from 0.25 to 4 mM with a sensitivity of 30.3 mV decade⁻¹, and the pH sensor exhibited a linear response to pH values from 4 to 8 with a sensitivity of 60.6 mV decade⁻¹ based on electrochemical measurement. The device contained PVB to enhance stability and electrodeposited gold nanoparticles (AuNPs) on the electrodes to improve the sensing performance, whose lifetime could last more than 20 days. In addition, the monitoring of pH variation in the oral microenvironment using a dental patch was realized⁵⁰. Some flexible electronics could detect ion variation caused by dental caries during orthodontic treatment^51,52. Liu et al. designed an integrated multiplex sensing clear aligner system that could attach to transparent aligners³⁷. The device could reflect the varied Ca²⁺, pH, and PO₄³⁻ in the oral environment in a real-time manner with electrochemical sensitivity of 29.52 mV decade⁻¹ of concentration for the Ca²⁺ sensor, −10.52 nA mM⁻¹ for the PO₄³⁻ sensor, and 54.38 mV pH⁻¹ for the pH sensor, so as to prompt tooth demineralization.

In order to detect more than a single metabolite, Liu et al. proposed a dual-channel electrochemical biosensor for the simultaneous detection of lactose (with a sensitivity of 21.8 μA mM⁻¹ cm⁻²) and glucose (with a sensitivity of 18.7 μA mM⁻¹ cm⁻²) in saliva⁵³. Since lactate is an intermediate product of glucose metabolism, simultaneous detection of dynamic trends of both lactate and glucose levels is important for preventing diabetic complications. This dual-channel biosensor was based on a flexible screen-printed PET-based electrode with two working electrodes so that the sensitivity and linear range of the two substances could be distinguished, thus avoiding interference between the two channels.

Cavity gas-based biomarkers

Detection of gases from the oral cavity, when dental caries or periodontitis occurs, is helpful for early diagnosis of these diseases. Pathogenic anaerobes potentially inducing periodontal disease and dental caries produce NH₃ and VSCs when consuming food residues^54,55. Jin et al. utilized a degradable bacterial cellulose/Ti₃C₂T_x MXene (BC/MXene) bioaerogel sandwiched between the patterned Au/PET substrates to design a multifunctional flexible sensing platform, which could detect the localized release of NH₃ (Fig. 3a)¹⁹. The 3D porous structure of BC/MXene bioaerogels ensured good gas sensitivity, and this material was easy to degrade to achieve environmental protection. Experiments proved that the device could use gas signals to reveal imperceptible dental lesions. Li et al. designed a transparent, wearable fluorescent mouthguard consisting of the zinc oxide–poly(dimethylsiloxane) (ZnO-PDMS) nanocomposite to detect the local release of VSCs (Fig. 3b)³⁴. Through observing fluorescence brightness variation, the device not only located VSCs to screen hidden dental lesion sites but also reflected the degree of the lesion. Although this research ruled out the influence of VSCs in gas and liquid states, factors such as different food residues would impact the results and the detection accuracy still needed to be improved for oral flexible electronics.

Detecting biophysical signals

Dental, oral, and craniofacial biophysical signals mainly cover mechanics, temperature, humidity, and fluid dynamics (Table 2). Appropriate stress on oral tissues is vital to maintain the health of teeth and periodontal tissues, and the mechanical movements of craniofacial muscles are related to functions such as pronunciation, facial expression, and swallowing. In addition, the dynamic temperature, humidity, and gas flow can reflect the state of breathing as well.

Muscle activities

Beyond applications for detecting the above biochemical signals, flexible electronics also have a wide range of applications for monitoring physical signals from dental, oral, and craniofacial muscle functions⁵⁶. Cao et al. prepared a composite hydrogel with covalently crosslinked polyacrylamide as flexible “elastin”, Ca²⁺ crosslinked SA as rigid “collagen” and Ga as active conductive soft “filler”, whose properties were very similar to the human skin (Fig. 4a)¹⁶. The SA/PAm/Ga hydrogel strain sensors made from this material could monitor the subtle changes in facial muscles and generate and transmit signals through the resistance variety corresponding to different pronunciations. This device could help people with speech disorders to recover their speech function. Lee et al. designed a skin-like electrode that could reduce motion artifacts compared to rigid electrodes and assist patients suffering from dysphagia in swallowing training (Fig. 4b)²⁴. This electrode had a significantly lower false-positive detection rate for sub-chin muscle monitoring than rigid electrodes and could distinguish swallowing from other movements. Song et al. fabricated a structurally stable and highly sensitive hollow structure of MXene-polydimethylsiloxane composites (MPCs) (Fig. 4c)¹⁸. MPCs were piezoresistive pressure sensors allowing fine measurement of the vibration of facial muscles by detecting the resistance change of compressive strain, which might help facial paralysis patients to practice more effectively in their rehabilitation exercises. Du et al. utilized functionalized adenine molecules and chitosan-grafted polyaniline copolymer (chi-g-PANI) to form conductive hydrogels to sensitively measure the activity of facial muscles for a long period. Polyaniline endowed the material with electrical conductivity, and chitosan compensated for the brittleness of PANI (Fig. 4d)¹⁷. The quaternate adenine here not only acted as an adhesive modulator by breaking the hydrogen bond between PANI and chitosan but also promoted the dispersion of the rigid polymer network to avoid the deterioration of mechanical and electrochemical properties.

Orthodontic forces

Traditional orthodontic treatment requires patients to make regular follow-up visits and adjust their orthodontic plan several times, which is likely to cause a decrease in patient compliance, leading to poor treatment results or even failure⁵⁷. Wang et al. integrated a piezoelectric electret field generator into a personalized mechanical orthodontic aligner, which could stimulate the proliferation and differentiation of osteoclasts and osteoblasts through electrostimulation (Fig. 5a)²⁶. This device could promote orthodontic tooth movement through a piezoelectric-excited alternating electric field for bone remodeling. Furthermore, the six-dimensional force sensors could help orthodontists refine their protocols, given that the device could keep directional tracking and precise monitoring while applying complex multiaxial stimuli. Hu et al. mimicked mortise and tenon structures to fabricate flexible sensors that could be interlocked between the upper and lower structures by concave and convex interlocking and integrated them with an orthodontic aligner (Fig. 5b)⁵⁸. This device could effectively detect the magnitude and direction of orthodontic forces on the teeth to minimize potential side effects and treatment periods. Lee et al. developed a flexible hemispherical sensor that could be affixed between the tooth surface and a clear aligner (Fig. 5c)³³. The thermoplastic hemispherical sensor fixed its semicircular bottom on the tooth surface, and its top side touched the clear aligner. When the aligner was stressed, the contact area between the top of the hemispherical sensor and the aligner surface changed, which could be measured by a portable microscope to quantify orthodontic forces. In order to measure the large loads of biting force and ensure the sensitivity, Lin et al. utilized a combination of multilayer ceramic capacitors (MLCCs) that had good piezoelectric properties and flexible small force sensors made of polyimide to form an MLCC force sensor (Fig. 5d)⁵⁹. This device could be tightly attached to the teeth and was able to measure the force distribution on the occlusion surface or the force response during actual food chewing, which would be beneficial in aiding dental treatment.