Biosensors in Neurosurgery: Wearable and Implantable Devices for Monitoring

This chapter includes an accompanying lecture presentation that has been prepared by the authors: .

Full text of this chapter is available online at ExpertConsult.com .

This chapter includes an accompanying lecture presentation that has been prepared by the authors: .

Key Concepts

Traditional diagnostic methods used in medicine are often invasive and intermittent and provide only a “snapshot” of a disease.
Neurosurgical monitoring techniques including electroencephalography and electrocorticography often require specialized equipment and personnel and tethering of the patient to the equipment, substantially reducing patient freedom.
Advancements in miniaturized electronics, biostable materials, and microprocessing technology have permitted realization of a range of wearable and implantable sensor hardware.
These wearable and implantable sensors may be applied in a broad range of neurosurgical tasks including intracranial pressure monitoring, analyte detection, electrophysiologic monitoring, motion detection, and fluid dynamic assessment.
Many prototypical devices permit for integration with commercially available “smart” technology such as smartphones and smartwatches, theoretically permitting increased patient freedom and self-monitoring.
We are likely to see an increasing number of commercially available wearable and implantable biosensors in the near future.

Introduction

Efficacious detection capabilities are essential for the accurate diagnosis and monitoring of neurological conditions. Traditionally, clinical investigations involved intermittent, often invasive data-gathering modalities. although periodic data gathering may provide a necessary clinical “snapshot” from which diagnoses may be formed or informed treatment decisions made, the ability to continuously gather physiologic data without subjecting a patient to repeated invasive testing is a highly desirable capability. Advances in material science technology have permitted the development of sensitive, miniaturized physical and chemical sensors that may be adapted for use in health care. They can permit detection of macro- or micro-scale physiologic changes in healthy and pathologic states. Their diminutive size and use of durable materials allow them to be either implanted within the body or worn continuously on its surfaces. Combined with similarly miniaturized data storage and wireless transmission capabilities (e.g., Bluetooth, Wi-Fi), continuous telemetric monitoring may be permitted. Moreover, the rise of portable computing in the form of smartphones, smartwatches, and tablet devices allows for easy patient or physician monitoring and transmission of measured parameters. Altogether, the use of wearable or implantable sensor technology aims to simultaneously enable real-time clinical data gathering while minimizing physical restriction for the patient.

Neurosurgical monitoring domains include intracranial pressure (ICP), blood and cerebrospinal fluid (CSF) compositions, flow rates, and electrophysiologic activity. Peripherally placed sensors may also be valuable for the monitoring of nerve-muscle activity or the rehabilitation of physically debilitating conditions such as stroke (ischemic or hemorrhagic), tumors, neurodegenerative conditions (e.g., amyotrophic lateral sclerosis), movement disorders (e.g., Parkinson disease [PD]), and epilepsy. Although many of these devices are experimental, with few commercially available at present, it is likely that this sector will grow substantially in the coming years. This chapter aims to provide neurosurgeons with an update on state-of-the-art sensor technology and its current and future adaptations for clinical practice. As the physical properties and mechanisms are diverse and largely beyond the scope of what is required by practicing neurosurgeons (we recommend the recent review by the Rogers group ), the chapter has been organized by clinical domain and provides overviews of the relevant technology.

Intracranial Pressure Monitoring

ICP monitoring is indicated in trauma patients with severe (Glasgow Coma Scale [GCS] score <9) or moderate (GCS 9–12, if anesthetized or with abnormal CT scan) head injuries, who are at increased risk of mortality. Other indications for ICP monitoring include hemorrhagic events, hydrocephalus, malignant infarctions, cerebral edema, infections, and encephalopathy. Sustained ICP values greater than 20 to 25 mm Hg correlate with increased mortality risk. In some instances, evolving metabolic and pathologic processes precede measurable ICP increases, thus highlighting the requirement for sensitive ICP detection and monitoring capabilities. Numerous invasive and noninvasive ICP monitoring methods have been introduced since the mid-20th century. ^,

Invasive Intracranial Pressure Monitoring

Invasive ICP monitoring requires placement of a sensor device into fluid-filled or intraparenchymal spaces to detect pressure changes. Invasive ICP monitoring provides a direct measurement of ICP from within the skull and is considered the “gold standard.” Nevertheless, there is controversy as to the optimal anatomic location of the catheter. Because a craniotomy is required, along with placement of a foreign object, risks inherent to invasive ICP monitoring include infection, hemorrhage, sensor dislodgement, malfunction, need for ex vivo recalibration, device migration, and inaccurate positioning. Another shortcoming of invasive ICP measurement includes inability to leave the device in situ for prolonged periods owing to infection risk. Moreover, invasive ICP monitoring requires specialized staff, equipment, and facilities, making it more expensive and labor-intensive than noninvasive approaches. Certain conditions such as trauma necessitate long-term ICP measurement, and therefore implantable, or internally contained, devices with ability to transmit data wirelessly are called for. Currently, the gold standard of ICP measurement involves measuring ICP from within the ventricles via an external ventricular drain (EVD). Most EVD designs also permit fluid drainage, thus serving dual monitoring and therapeutic purposes. EVDs are not suitable for long-term monitoring, however, because of risk of infection or blockage. Other suitable locations for placement of ICP devices include the subarachnoid space (via bolts, screws, or catheters) or intraparenchymally; however, these do not permit drainage of CSF.

Most invasive ICP measuring systems incorporate a fixed external transducer, connected to an air- or fluid-filled catheter, which is inserted intracranially. ICP changes equilibrate with air or fluid within the catheter system, and changes within the catheter pressure-sensing medium are subsequently detected and amplified for measurement. The predominant transducer design used in commercially available ICP devices is the strain gauge, which is a conducting material attached to a flexible plastic material. When the strain gauge is deformed by external forces (i.e., pressure changes) the conducting material is also deformed, thus altering its structure and its electrical conductance.

EVDs commonly possess an externally located transducer held at a fixed point (at the level of either the tragus or the foramen of Monro). More compact designs include miniaturized transducers contained within the catheter system itself. These systems may also use alternative solid-state methods for transduction, such as piezoresistive, capacitive, or fiberoptic materials. Fiberoptic transduction involves use of a pressure-sensitive diaphragm that is attached to a displaceable mirror contained within the sensory apparatus. Pressure-induced changes in mirror position cause alterations in the intensity of light reflected from the mirror apparatus. ^, The sensitivity of an internally located ICP measuring device is inversely proportional to its size; thus the advent of miniaturized piezoresistive transducers located on microchips permits the development of very accurate self-contained ICP monitors. Moreover, these designs may demonstrate greater robustness by dispensing with fluid-filled catheters, which are prone to dislodgement, infection, and blockage and cannot be recalibrated without removal.

Novel invasive ICP devices may also permit simultaneous, multiparametric data gathering, permitted by miniaturized sensor hardware. The Neurovent-PTO (Raumedic, Helmbrechts, Germany) is capable of simultaneous ICP (via a strain gauge), temperature (via a thermocouple), and tissue oxygenation monitoring, along with CSF drainage capability, all within a single device ( Fig. 74.1A ). Leidorf et al. (2014) conducted in vivo trials of a device manufactured by Oxford Optronix (Abingdon, Oxford, United Kingdom) capable of simultaneously measuring tissue perfusion (via laser Doppler flowmetry), tissue oxygenation (using light fluorescence), ICP (using a piezoresistive bridge), and temperature. The limitations of tethered, implantable ICP monitors have been previously stated. Nevertheless, continuous ICP monitoring following traumatic brain injury, subarachnoid hemorrhage, shunt insertion, or neuroendoscopic procedures may be necessary. Telemetric ICP monitoring has been proposed for this purpose, with use of miniaturized and biostable hardware enclosed intracranially. Although pressure sensing and transduction technology may be similar to traditional ICP monitoring devices, telemetric ICP devices also contain a method of wirelessly transmitting data to an external receiver. The device may also be combined with shunt systems, the flow rates of which may be manipulated using externally transmitted signals. Experimental designs have included passive devices that are activated by an external electromagnetic signal (see also “Fluid Flow in Shunts”), or active devices with a self-contained battery. Nevertheless, only recently has technology permitted a clinically viable telemetric ICP monitor, such as the Raumedic Neurovent-P-tel (Raumedic), to be implanted on a long-term (up to 10 months) basis ( Fig. 74.1B ). Readings are obtained wirelessly by placing a radiofrequency coil ( Fig. 74.1C ) on or near the scalp enclosing the sensor. Shortcomings of implantable telemetric ICP monitoring include zero drift (i.e., deviation from an initially calibrated baseline), chronic host rejection, infections, and necessity for a surgical procedure to remove malfunctioning devices.

Figure 74.1, Intracranial pressure (ICP) monitoring.

Noninvasive Intracranial Pressure Monitoring

Because of the risks and logistical drawbacks of invasive ICP monitoring, several noninvasive ICP measurements have been devised. These primarily involve taking surrogate measurements of ICP from external body areas including the ocular, skin, or auditory systems. Other methods may use noninvasive electromagnetic waves to obtain measurements. At present, direct (invasive) rather than indirect (noninvasive) ICP measurement is considered the most accurate method of ICP monitoring. ^,

Surrogate anatomic areas providing ICP measurements are the tympanic membrane and optic nerve sheath, as these are in direct (optic nerve sheath) or indirect (tympanic membrane) communication with the central nervous system. The optic nerve remains surrounded by the dural sheath within the orbit. It encloses a subarachnoid space that is continuous with the intracranial subarachnoid and CSF spaces. ICP changes are therefore transmitted via the optic nerve, causing reciprocal changes in optic nerve sheath diameter, which can be measured using an ultrasound apparatus. Likewise, tympanic membrane displacement secondary to the stapedial reflex has been shown to correlate with ICP. Tympanic membrane displacement may be measured via a sensor probe hermetically sealed within the external auditory meatus, which can detect nanoliter-scale changes in meatal air volume caused by membrane displacement.

Transcranial Doppler measurements of cerebral blood flow taken by insonating intracranial vessels may, if combined with appropriate deductive algorithms, be able to provide a reasonable measurement of ICP. Nevertheless, the measurement process is technique dependent and may be prone to interobserver variability, rendering it less accurate or reliable than invasive methods. Other limitations of using sound waves for ICP measurement are conferred by the bony skull or other tissues impeding transmission of sound waves, and impracticality for use as a continuous screening tool due to constant presence of sensory hardware, which is yet to be reliably miniaturized.

A potentially wearable method of noninvasive ICP measurement may include measuring the impedance mismatch between the carotid arteries and cerebral vessels. As described by Swoboda et al., the pulse-pressure waveform of the carotid artery is partially influenced by the backflow of blood moving from large-caliber arteries to smaller-diameter vessels contained intracranially. Changes in ICP not only affect overall ICP, but, owing to inherent autoregulation mechanisms, also affect cerebrovascular calibers. Consequently, the degree of “reflection” on the carotid pulse-pressure waveform may vary and be quantitatively measured to provide a surrogate measurement of ICP.

Skull deformation by ICP changes may also be measured to provide a surrogate measurement of the ICP waveform. Oliveira et al. proposed a system utilizing a strain-gauge type transducer affixed to a band encircling the head. Changes in ICP transmitted through the cranium and scalp alter the tension on the headband, which is subsequently measured by the strain gauge and amplified to produce a waveform. This technique has been studied in animals and humans. ^, If reliably validated, it may be ideal for situations requiring continuous ICP measurement without sacrifice of mobility, such as during spaceflight, wherein the microgravity environment produces ICP increases secondary to fluid redistribution ( Fig. 74.1D ).

Finally, it is worth mentioning near-infrared spectroscopy (NIRS), a novel method of ICP measurement. Near-infrared radiation is an electromagnetic energy source with wavelength of approximately 600 to 1000 nm. Biologic tissues of varying composition (e.g., bone, fat, blood) each possess key chromophores, or light-absorption properties. At near-infrared wavelengths, tissues permit passage of light rather than absorption, with significant absorption occurring only at wavelengths >1000 nm. NIRS uses the quantitative detection of light scattering caused by interaction with tissues of variable molecular composition. An apparatus consisting of a near-infrared light source together with a detection element may be placed externally on the head. The light is detected after it exits the cranium and intracranial tissues. This signal can then be reconstructed using appropriate algorithms to deduce the concentrations of target chromophores. NIRS may be used to study local changes in cerebral blood volume by measuring regional oxygen saturation (rS o ₂ ). A study by Kampfl et al. demonstrated that patients with ICP values >25 mm Hg had lower rS o ₂ values at baseline and after treatment with 50% O ₂ . Another method using NIRS may involve measurement of ICP slow waves, which are thought to be caused by vasomotor and blood flow changes associated with underlying pathology. NIRS techniques may be able to detect these slow waves from which ICP may be deduced. Nevertheless, NIRS remains an indirect surrogate of ICP measurement, and further clinical evaluation is required to validate this technique.

Body Fluid Composition

Traditional laboratory investigations involve removal of a sample of fluid or tissue from the body for analysis using benchtop devices. Although indwelling catheters capable of providing repeated sample withdrawal are available (e.g., central lines, EVDs), these cannot be left in place for prolonged periods owing to risk of infection or blockage. Moreover, investigators must determine opportune times at which to obtain body fluid samples for analysis for diagnosis or monitoring purposes. Advances in microfluidic and biosensor technology have permitted development of miniaturized “lab-on-a-chip” designs capable of implantation into various visceral or solid body compartments, thus potentially offering continuous monitoring of desired physiologic parameters. Biosensors are defined as analytic devices capable of detecting chemical substances. They use a biologic sensory component (e.g., enzymes, microbes, cells, or antibodies) with particular affinity for the tested analyte, and a detection element that senses the conformational change. ^, The detection element produces a physicochemical signal output (electrical, optical, piezoelectric, and so on) following binding of the detection molecule. Implantable biosensors for clinical purposes involve a miniaturized device capable of detecting single or multiple analytes in real time. Because these devices are not physically continuous with the external environment, they require both a power source and a means to transmit data to external sensors for analysis. A prototypic example is the CytoComm Platform, a miniaturized injectable biosensor (Efferent Labs, Buffalo, NY). It uses living cells as sensory components, which emit light following interaction with the desired analyte (proteins, biomarkers, or medications). The device wirelessly transmits these data to be picked up by an externally located sensor ( Fig. 74.2A ). Another battery-powered implantable device was developed by Carrara and De Micheli, consisting of several separate, enzyme-coated sensors, a control unit and a radio-transmission module. The 14-mm-long device is powered by an external battery placed on the skin (much like todays wireless cellular phone chargers which utilize electromagnetic induction principles) ( Fig. 74.2B ). Nevertheless, as the enzymatic sensory components are susceptible to denaturation, the sensor has a finite lifespan in the human body. Heat, pH, toxins and other host elements may cause erosion of the organic or inorganic components of these chips.

As most of these designs are either experimental or first generation, they have yet to be widely implemented. Due to the significant global burden of diabetes, implantable glucose biosensors were the focus of much of the pioneering work in this field and have subsequently become the first commercially available examples of this technology. The Eversense device (Senseonics, Germantown, MD) has been trialed in humans and can be worn on the upper arm for up to 90 days. This system incorporates an external transmitter device, which can send information to smartphones and other smart devices (e.g., watches, tablets) for real-time analysis and monitoring. Further development of this technology and the impending introduction of similar technologies for broader diagnostic capabilities may permit continuous rather than intermittent monitoring of physiologic, prodromic, and pathologic states, thus providing clinicians with a wealth of readily obtainable data. At present, these devices have not been adapted for neurosurgical purposes. Nevertheless, development of lactate and glutamate biosensors may prove useful for certain neurological conditions. Another area to be considered is the adaptation of this technology for implantation in the spine or intracranially for monitoring purposes in chronic neurological conditions such as CSF analysis, epilepsy, or neurodegeneration, among many others.

Intraoperative Monitoring

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