Biosensors and Sleep: The Future and Beyond

Introduction

The evolution and integration of material sciences, skin electronics or implantable devices, sensing techniques, and information technology as a whole has greatly propelled the progression of medical science.¹ Under the same umbrella of thought, biomedical devices that involve continuous real-time health care monitoring have emerged and drawn huge attention to their potential application. These devices can collect multi-modal physiological and biochemical information from the entire body to its digital components in order to provide a comprehensive overview of human health. This, in turn, can greatly enhance the accuracy of disease diagnosis and outcome of the therapy.²

Biosensors are the ubiquitous devices that have revolutionized the field of nanotechnology and its further application in disease diagnosis, monitoring, drug discovery, treatment and health management. These analytical devices detect changes in biological processes and converts them into electrical signals, via its different components. The recent times have also seen the advent of implantable and wearable biosensors which monitors biological metabolites like glucose, lactate, urea along with vital signs like temperature, pulse, blood pressure, respiratory rate and even oxygen saturation.

Biosensors have gained popularity in the diagnosis of obstructive sleep apnea (OSA) as well. Dentistry is not new to the world of sleep medicine. Loss of few teeth or entire dentition plays a very significant role in terms of respiratory process, body balance and in turn overall health of the stomatognathic system. The management of OSA needs a long-term multi-disciplinary approach. Polysomnography (PSG), the gold standard test, is used to diagnose sleep disorders and sleeping patterns in patients. However, it has been observed that multiple wired-sensors that are attached to the patients while they are asleep, cause discomfort to the patient. Furthermore, many individuals with sleep disorders remain undiagnosed due to the limited availability and high cost of PSG. These limitations are now being overcome by the advent of wearable sensors that have successfully enabled continuous sleep monitoring at home.

Many efforts have been made to translate the complicated, uncomfortable systems used in PSG to monitor various physiological parameters into unobtrusive and easy-to-use systems that every individual can use at home. Dentists, especially Prosthodontists, have a significant role in the early diagnosis of OSA to improve the quality of life of the apneic patients. They are well positioned to identify, evaluate and manage patients at greater risk of OSA thereby providing effective care to the patients reporting to a dental clinic. Their expertise in prosthesis designing and fabrication can amalgamate the oral appliance therapy with sleep sensors. They can convert the huge conventional sleep assessment setup into miniaturized sensors incorporated within dentures for edentate patients and splints for dentate individuals.

This review paper discusses and presents an overview of the biosensors, their types, their potential in oral appliances and how these can help the operators to detect cases of snoring and mild-to-moderate OSA with ease.

Parts of a Biosensor

A typical biosensor measures biological and chemical reactions by the generation of signals, corresponding to the amount of an analyte in the reaction.² The basic design of a biosensor consists of the following components:

• Analyte: An analyte is the substance of interest that is to be detected in the reaction. Example: glucose, adenosine.
• Bio-receptor: It is a molecule that specifically recognizes the analyte. Example: enzymes, cells, antibodies.
• Transducer: An element that converts one form of energy into a measurable signal (optical or electricalenergy). This process of energy conversion is known as signalisation.
• Electronics: The signals being transduced are converted to digital data that is displayed by the electronic system of the biosensors.
• Display: The final output signal of a biosensor can be detected and seen on the display. Based on the requirements of the end user, the output being displayed can be numeric, graphic, tabular or an image.

A typical biosensor is represented in Figure 1.²

Characteristics of a Biosensor²

1. Selectivity: Selectivity of a biosensor is that property which helps its bio-receptor to detect a particular analyte from a given sample consisting of admixtures and contaminants. For a biosensor to be manufactured, it is the selectivity that serves as the main consideration for its bio-receptor selection. 
2. Reproducibility: Reproducibility is the property of a biosensor to generate similar results i.e signals for a testing set-up that uses same method but is performed under different conditions. It signifies the precision of the transducer and electronics used in the biosensor.
3. Stability: Stability corresponds to the extent of susceptibility of a biosensor to the disturbances in and around it. In cases where a biosensor is required to perform continuous monitoring like sleep assessment, stability turns out to be the most crucial characteristic of a biosensor.
4. Sensitivity: Sensitivity corresponds to the limit of detection i.e. the minimum amount of analyte that is perceived by a biosensor defines its sensitivity. Biosensors can detect concentrations that are as low as nanograms per milliliter (ng/mL) or even femtogram per milliliter (fm/mL).
5. Linearity: Linearity is a mathematical function which is represented by a straight line on a graph. Biosensor linearity determines the accuracy of the output signal in response to different concentrations of the analyte. Mathematically it is represented by y = mc (y = output signal, c = concentration of the analyte, m = sensitivity)

Classification of Biosensors

Based either on the sensing components or on the transducer components, these can be broadly classified into following categories:

1. On the basis of biological sensing elements

A. Catalytic biosensors are based on the conversion of non-detectible amount of analyte in a reaction to a measurable form. This category includes enzymes, microbes, organelles, cells and biological tissues.

Example: Glucose oxidase (GOx) based biosensors for glucose monitoring

B. Affinity biosensors are based on the stability of a sensing complex which consists of an analyte and an immobile bioreceptor. This category includes nucleic acids, antibodies or receptors.

Example: ELISA (enzyme-linked immunosorbent assay)

2. On the basis of transduction component

A. Electrochemical: These are based on the conversion of biochemical signals into electric ones and can be of following types:

• i. Potentiometer biosensors: Generates a quantifiable amount of potential or charge accumulation between two electrodes.
• ii. Amperometric biosensors: Generates measurable amount of inter-electrode current.
• iii. Conductimetric biosensors: Generates measurable conductance.
• iv. Impedimetric biosensors: Measures resistive and capacitive changes between the electrodes.

B. Optical: These transducers cause changes in optical properties, like fluorescence, absorbance and chemiluminescence, due to the interaction between the analyte and bioreceptor.

C. Calorimetric: Any change in temperature caused by the binding of the analyte with biorecepetor is detected and measured by calorimetric transducers.

D. Acoustic: They convert acoustic waves into electrical signals using piezoelectric material to quantify any change in mass, elasticity or conductivity.³

Role of Biosensors in Obstructive Sleep Apnea

In order to revamp the quality of life, biosensors now-a-days deal with wide array of applications. This includes their usage for monitoring environmental pollution, veterinary and agricultural applications, defence, general health care monitoring and disease diagnosis, discovery of drugs and lot more.² One of the main application of biosensors in sleep dentistry is the detection of biomolecules that focus on diagnosing OSA or for its management. Studies that have used biosensors to probe sleep–wake transitions have quantified the changes in glucose, lactate, glutamate, and adenosine upon physiologic state change.⁴

Naylor et al., measured the extracellular concentrations of lactate, glucose and glutamate to understand their role in sleep-wake cycle. They concluded that lactate is the most reliable biomarker as its concentration exhibits a rapid and sustained change during onset of sleep, throughout the sleep and after waking.⁵ Its concentration is low in the brain during non-rapid eye movement (NREM) sleep as compared to rapid eye movement (REM) sleep and wakefulness.⁶ However, the extracellular concentration of glucose increases during NREM phase.⁷ Glutamate levels, on the other hand, increases during REM and wakefulness.⁸ Huang et al., found that the levels of Adenosine, a homeostatic regulator of sleep, increases during prolonged wakefulness and diminishes during recovery phase of sleep.⁹

Even though in-lab PSG remains the gold standard for the diagnosis of OSA, the use of at-home biosensor systems has gained popularity. PSG performed at sleep centres may cause disruption of patient’s sleep which we rather intend to monitor. Other limitations of PSG include uncomfortable sleep-setup, high burden of resources and personnel at the sleep centres, use of single-night analysis for clinical decision-making, limited accessibility to sleep laboratories, and lastly the cost.¹⁰

On the contrary, the biosensors used for sleep assessment provide high resolution, continuous over-night tracking,which is critical for any process that exhibits night-tonight variability.^4,10-12 They track autonomic functions of the body like cardiac and respiratory physiology, including electrocardiography (ECG), via limited, sophisticated and non-invasive methods.¹³ They also allow quantification of neuroenergetic and neurotransmitter changes on a time scale that is related to the physiology of most sleep transitions.⁵

Respiratory signals like thoracic movements while sleeping can support the estimation of apnea–hypopnea index (AHI). This is used to quantify the apneic episodes in an individual. Such movements take place throughout the body while a person is sleeping and are called periodic limb movements of sleep (PLMS), known to be vital for sleep assessment.

A number of biosensors have been deployed over the years for the assessment and quantification of OSA, both wearable and implantable. Literature provides enough share of evidence that these sensors are tolerable and accurate for capturing signals of respiration, ECG, electromyography (EMG) etc. while sleeping as comparable to that of simultaneous PSG recordings.¹⁰ Few biosensors and their application are discussed in detail below:¹⁴

Biosensors for Monitoring Signals from the Brain¹⁴

Measuring electroencephalogram (EEG) during sleep is vital to begin any sleep assessment by monitoring changes in brain activity.

• i. Sleep profiler provides wireless sleep monitoring in a headband platform equipped with three frontopolar EEG electrodes on the forehead. It also has a photoplethysmography (PPG) sensor, microphone, and a tri-axial accelerometer to simultaneously monitor the pulse rate, snoring, and body movements, respectively.¹⁰
• ii. Dreem headband records EEG from a combination of five electrodes on the forehead, back of the head and scalp by penetrating through the hair. This also includes a PPG sensor to measure heart rate and a tri-axial accelerometer to measure movements, position, and respiration rate.
• iii. Ear-type EEG measurement platform with two fabric-based EEG electrodes integrated with a memory-foam substrate that provides a comfortable fit to the ear, makes reliable skin-electrode contact, and effectively reduces signal artifacts from ear canal movements due to pulsation of blood vessels.
• iv. cEEGrid is a flexible, thin adhesive strip with multiple electrodes embedded within a structure that attaches behind the ear. It allows continuous monitoring of EEG.

Biosensors for Monitoring Heart-Activity¹⁴

Electrocardiogram (ECG) has been accepted as the gold standard for monitoring cardiac activity to the highest level of accuracy during sleep.

1. i. T-REX is a wireless, adhesive, patch-type device made of a fabric-based thin-flexible patch integrated with three electrodes and equipped with a tri-axial accelerometer. Apart from ECG, it can be utilized to measure heart rate, respiration rate, and degree of limb movements.
2. ii. Integrated, portable chest patch device is a singlelead ECG system that is uniquely equipped with an integrated stethoscope used for further cardiac activity monitoring by phonocardiogram (PCG) and tracking of respiration by measuring the lung sound. These parameters are utilized to provide more detailed ECG activity, including a pre-ejection period (PEP) and left ventricular ejection time (LVET) with high accuracy.
3. iii. Movesense are pull-up-pants-type wireless sensors which have two fabric-integrated ECG electrodes designed for sleep monitoring of infants. It is designed to be worn over the diaper, such that the waistband contacts the baby’s abdomen for ECG measurement.
4. iv. MagIC-Space is also a smart garment i.e. a sensory vest designed to wirelessly measure cardiac performance and vital signs of humans during sleep.
5. v. Biostamp RC® is a simple, adhesive, wearable sensor system that provides accurate sensing of heart rate, respiratory rate, and leg EMG. It is advised to be placed on the leg for EMG measurement or on the chest to detect ECG and respiratory changes. It can couple cardio-pulmonary mechanisms which can not only screen OSA, but can even distinguish obstructive and central forms of OSA. ¹⁴ According to Jortberg et al., the EMG based sensors of Biostamp RC®, however, did not turn out to be as accurate as PSG.¹⁰

Biosensors for Monitoring Pulse

The assessment and quantification of pulse wave by PPG is widely accepted as a low-cost, simple, andportable alternative for ECG for heart rate and heart rate variability (HRV) measurements.

• i. Oura Ring provides easy and continuous PPG measurement as a finger ring structure by taking advantage of recording high quality PPG from fingers.
• ii. MORFEA is a nose-mounted wireless device equipped with PPG and tri-axial accelerometer that helps to detect the timing and type of apnea event by the movement of nostrils during sleep. It can be further put into use for pulse oximetry to estimate the blood oxygen saturation (SpO2).
• iii. Smartwatches are capable of measuring SpO2 throughout the day and night.
• iv. Pulse oximeter integrated with an in-ear-type structure: It is unique in the fact that it can detect change in SpO2 12.4 seconds earlier than the average finger pulse oximeter.

Biosensors for Monitoring Respiration

One of the prime ways to monitor respiration during sleep is by measuring nasal airflow to detect any abnormal respiratory behaviour caused by sleep apnea and hypopnea and to evaluate their severity.

• i. Surface acoustic wave sensor is a thin, flexible sensor placed around the nostrils that monitors breathing via its sensitivity to changes in humidity. It is a passive wireless system that does not require a battery or direct power input to the system.
• ii. Respiratory inductance plethysmograph (RIP) belts measures the chest and abdomen’s physical expansion to monitor respiration while a patient is asleep.
• iii. Tattoo-like strain sensor is a stretchable chest-worn sensor which deforms physically due to inhalation and exhalation by the patient.
• iv. Magnetometer chest belt:Milici et al.,made a batterypowered chest belt with an embedded magnetometer to measure the change in its orientation caused by breathing motion. This can also detect apnea when a pause in breathing is observed.

Biosensors for Monitoring Body Movements

Body or the limb movements are used to identify when the patients are awake and when they are not and also to detect various sleep disorders.

• i. Biostamp RC® is used to sense leg EMG.
• ii. Actigraphy (ACT) is an at-home sleep monitoring method that measures body movements with a wearable accelerometer, usually in a wristband form. The accelerometer also incorporates an ambient light sensor, along with other sensors for temperature, sound, and finger-PPG detection.
• iii. Wireless sleep position sensor for infants is a low-power, flexible, wearable device with an accelerometer to monitor a baby’s sleep posture, alerting the caregivers when a prone position is detected.

Biosensors in Oral Appliances

Several companies are in the quest for developing oral appliances having inherent biosensors that can assess the sleep parameters such as AHI and brain activity while being snugly fit inside the oral cavity. Achaemenid Innovations have recently applied for an FDA approval for one such biosensor which is equipped with SpO₂, PPG and EEG sensors that can record the blood oxygen saturation, heart rate, and brain waves, respectively. It is a modification of pulse oximeter wearable on finger, except it is customized for an intraoral use.¹⁵

Another company, named SomnoMed, is working on ‘Rest Assure’ technology which is a smart oral appliance designed to transfer AHI score and adherence data to a cloud-based server every morning after an overnight usage. Then dentist, physician as well as the patient can review the result on an app-bases system. By 2023, the company is determined to incorporate Rest Assure technology to its commercially available oral appliances like Herbst Advance Elite.^15,16

Conclusion

Over the last few decades, the literature suggests that the field of biosensors is attractive not only for the academicians, but has gained huge popularity in clinical practice as well. In addition, it has opened new frontiers in the field of nanotechnology to draw the attention of the researchers towards development of biosensors with relatively simple design and mechanism. Continuous sleep monitoring at home will be a point of start for maintaining good sleep quality. There is plenty of data available today that addresses the role of oral appliances in sleep apnea patients. Despite the promising advancements in wearable sleep monitoring systems, we still need further technological advancements in electronics miniaturization, sensor technology, device integration and packaging within these oral appliances.

According to Indian initiative on Obstructive Sleep Apnea Guidelines (INOSA) guidelines, the gold standard or level 1 PSG mandates the estimation of ≥7 channels in a laboratory setting for evaluation of OSA. These include EEG, electrooculography (EOG), EMG, ECG-heart rate, airflow, respiratory effort, oxygen saturation. On the other hand, a combination of at least three channels or a combination of airflow, oxygen saturation and respiratory effort is sufficient for portable monitoring. This brings us to the conclusion that every biosensor mentioned in the review is equipped to record three or more sleep metrics. A combination of one or more biosensors can be used to provide real-time data of all the seven channels.

There is a vast space that is left unexplored in the world of biosensors when it comes to oral appliances. Further exploration in this direction becomes important for dental practitioners who can play a pivotal role in diagnosing the undetected sleep apneic patients at a very early stage. As oral health professionals, we are at a position to identify the factors that can be detrimental to one’s health, such as edentulism, either partial or complete, in relation to OSA. By restoring the vertical dimension of an edentulous patient, we can diagnose and limit the symptoms in undetected sleep apneic patients at a very primitive stage. These biosensors are portable tools that can be put into judicious use for identifying such patients and further referring them to other sleep specialists. The presence of teeth prevents unnecessary movement of the sensor, which is usually a problem in case of extra-oral sensors. They are also superior in terms of speed and accuracy of recording data as compared to their extra-oral counterparts. Oral biosensors are core arteriolar tone sensors which provide the most accurate and the fastest result during any disturbance or arousal from sleep.¹⁵ When in use, oral sensors can be masked easily by being present inside the mouth unlike other biosensors that are visible outside the body.

Since most of the oral appliances incorporating biosensors are already under trial phase, there is a paucity of long-term studies. Their mass accessibility to the general population and practitioners will help overcome the demerits in the coming years. Hope we continue this quest to explore the unanswered areas in the field of sleep dentistry to generate evidence in the right direction.

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Conflict of Interest

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