Wireless, battery-free optoelectronic systems as subdermal implants for local tissue oximetry

Monitoring regional tissue oxygenation in animal models and potentially in human subjects can yield insights into the underlying mechanisms of local O2-mediated physiological processes and provide diagnostic and therapeutic guidance for relevant disease states. Existing technologies for tissue oxygenation assessments involve some combination of disadvantages in requirements for physical tethers, anesthetics, and special apparatus, often with confounding effects on the natural behaviors of test subjects. This work introduces an entirely wireless and fully implantable platform incorporating (i) microscale optoelectronics for continuous sensing of local hemoglobin dynamics and (ii) advanced designs in continuous, wireless power delivery and data output for tether-free operation. These features support in vivo, highly localized tissue oximetry at sites of interest, including deep brain regions of mice, on untethered, awake animal models. The results create many opportunities for studying various O2-mediated processes in naturally behaving subjects, with implications in biomedical research and clinical practice.Center for Bio-Integrated Electronics at Northwestern University; Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF) [ECCS-1542205]; Materials Research Science and Engineering Center [DMR-1720139]; State of Illinois; Northwestern University; Developmental Therapeutics Core at Northwestern University; Robert H. Lurie Comprehensive Cancer Center [NCI CA060553]Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Monte Carlo Analysis of Optical Interactions in Reflectance and Transmittance Finger Photoplethysmography

Photoplethysmography (PPG) is a non-invasive photometric technique that measures the volume changes in arterial blood. Recent studies have reported limitations in developing and optimising PPG-based sensing technologies due to unavailability of the fundamental information such as PPG-pathlength and penetration depth in a certain region of interest (ROI) in the human body. In this paper, a robust computational model of a dual wavelength PPG system was developed using Monte Carlo technique. A three-dimensional heterogeneous volume of a specific ROI (i.e., human finger) was exposed at the red (660 nm) and infrared (940 nm) wavelengths in the reflectance and transmittance modalities of PPG. The optical interactions with the individual pulsatile and non-pulsatile tissue-components were demonstrated and the optical parameters (e.g., pathlength, penetration depth, absorbance, reflectance and transmittance) were investigated. Results optimised the source-detector separation for a reflectance finger-PPG sensor. The analysis with the recorded absorbance, reflectance and transmittance confirmed the maximum and minimum impact of the dermis and bone tissue-layers, respectively, in the formation of a PPG signal. The results presented in the paper provide the necessary information to develop PPG-based transcutaneous sensors and to understand the origin of the ac and dc components of the PPG signal

Opto-physiological modeling applied to photoplethysmographic cardiovascular assessment

This paper presents opto-physiological (OP) modeling and its application in cardiovascular assessment techniques based on photoplethysmography (PPG). Existing contact point measurement techniques, i.e., pulse oximetry probes, are compared with the next generation noncontact and imaging implementations, i.e., non-contact reflection and camera-based PPG. The further development of effective physiological monitoring techniques relies on novel approaches to OP modeling that can better inform the design and development of sensing hardware and applicable signal processing procedures. With the help of finite-element optical simulation, fundamental research into OP modeling of photoplethysmography is being exploited towards the development of engineering solutions for practical biomedical systems. This paper reviews a body of research comprising two OP models that have led to significant progress in the design of transmission mode pulse oximetry probes, and approaches to 3D blood perfusion mapping for the interpretation of cardiovascular performance

The 2023 wearable photoplethysmography roadmap

Photoplethysmography is a key sensing technology which is used in wearable devices such as smartwatches and fitness trackers. Currently, photoplethysmography sensors are used to monitor physiological parameters including heart rate and heart rhythm, and to track activities like sleep and exercise. Yet, wearable photoplethysmography has potential to provide much more information on health and wellbeing, which could inform clinical decision making. This Roadmap outlines directions for research and development to realise the full potential of wearable photoplethysmography. Experts discuss key topics within the areas of sensor design, signal processing, clinical applications, and research directions. Their perspectives provide valuable guidance to researchers developing wearable photoplethysmography technology

Phantom with Pulsatile Arteries to Investigate the Influence of Blood Vessel Depth on Pulse Oximeter Signal Strength

This paper describes a three-layer head phantom with artificial pulsating arteries at five different depths (1.2 mm, 3.7 mm, 6.8 mm, 9.6 mm and 11.8 mm). The structure enables formation of spatially and temporally varying tissue properties similar to those of living tissues. In our experiment, pressure pulses were generated in the arteries by an electronically controlled pump. The physical and optical parameters of the layers and the liquid in the artificial arteries were similar to those of real tissues and blood. The amplitude of the pulsating component of the light returning from the phantom tissues was measured at each artery depth mentioned above. The build-up of the in-house-developed pulse oximeter used for performing the measurements and the physical layout of the measuring head are described. The radiant flux generated by the LED on the measuring head was measured to be 1.8 mW at 910 nm. The backscattered radiant flux was measured, and found to be 0.46 nW (0.26 ppm), 0.55 nW (0.31 ppm), and 0.18 nW (0.10 ppm) for the 1.2 mm, 3.7 mm and 6.8 mm arteries, respectively. In the case of the 9.6 mm and 11.8 mm arteries, useful measurement data were not obtained owing to weak signals. We simulated the phantom with the arteries at the above-mentioned five depths and at two additional ones (2.5 mm and 5.3 mm in depth) using the Monte Carlo method. The measurement results were verified by the simulation results. We concluded that in case of 11 mm source-detector separation the arteries at a depth of about 2.5 mm generate the strongest pulse oximeter signal level in a tissue system comprising three layers of thicknesses: 1.5 mm (skin), 5.0 mm (skull), and >50 mm (brain)

Criteria for the design of tissue-mimicking phantoms for the standardization of biophotonic instrumentation

A lack of accepted standards and standardized phantoms suitable for the technical validation of biophotonic instrumentation hinders the reliability and reproducibility of its experimental outputs. In this Perspective, we discuss general criteria for the design of tissue-mimicking biophotonic phantoms, and use these criteria and state-of-the-art developments to critically review the literature on phantom materials and on the fabrication of phantoms. By focusing on representative examples of standardization in diffuse optical imaging and spectroscopy, fluorescence-guided surgery and photoacoustic imaging, we identify unmet needs in the development of phantoms and a set of criteria (leveraging characterization, collaboration, communication and commitment) for the standardization of biophotonic instrumentation

Investigation of fontanelle photoplethysmographs and oxygen saturations in intensive care neonates and infants utilising miniature photometric sensors

In children and newborn babies on intensive care, information regarding blood oxygen saturation (SpO2) is determined non-invasively by a device called a pulse oximeter. Sensors are usually placed on a hand or foot where their operation relies on the presence of pulsatile arterial blood. Light shines at two or more wavelengths (usually red and infrared) into the tissue where the pulsatile blood modulates, absorbs and scatters the different wavelengths of light in varying amounts and is detected by a photo-detector as a photoplethysmograph (PPG). The spectral information received is then processed electronically and digitally to determine the amount of haemoglobin present. In the sickest of children blood supply can become compromised to these sensor locations and the pulsatile component of the blood may diminish and pulse oximeter readings may become unreliable, especially at times when accurate blood oxygen information would be vital. Currently the alternative is to take blood from an arterial line and run a relatively lengthy analysis (pulse oximeters are near-instantaneous in their operation) that may be unnecessary if the pulse oximeter could be relied upon at these critical moments. In the smallest of babies invasive sampling of blood becomes even more of an issue as any blood loss could lead to hypovolaemia and introduce extra sites of infection plus it causes a lot of stress to the neonate. Since central blood flow may be preferentially preserved, the anterior fontanelle was investigated as an alternative monitoring site. Custom reflectance fontanelle and reference PPG sensors have been designed and built to investigate the fontanelle in those children at risk of peripheral supply compromise. Dedicated instrumentation and software has also been successfully developed for the control of the sensor electronics and the data-logging of PPG signals for retrospective analysis. Sixteen neonates were recruited for fontanelle monitoring; all were ASA 1 – 3 (ASA ranges from 1 to 5 where 1 is the least sick and 5 is the most critically ill). As part of the approved protocol the delivered oxygen to the patients was artificially altered to look for corresponding changes in PPG signal amplitudes. Amplitude results reveal strong correlations (R > 0.5) between the reference sensor (placed on the foot) and the fontanelle sensor. This suggests that the fontanelle sensor is sensitive to changes in amplitude when oxygen in the blood alters. Correlation of the health of the child, using the ASA score, and the difference in amplitudes of PPGs between the sensors reveals that the fontanelle sensor does detect increasing fontanelle PPG amplitudes when compared to the PPGs from the reference sensor the sicker the child is, confirming that pulsatile flow is being preferentially preserved at the fontanelle in those children who are the most at risk from peripheral supply compromise. SpO2 estimation at the fontanelle reveals a mean difference of 2.2 % to the SpO2 as read by the commercial device and a 1.7 % difference to the blood gas results. These results confirm that the anterior fontanelle may be used as an alternative location for SpO2 measurement in those who are at most risk of peripheral supply compromise

Influence of blood pulsation on diagnostic volume in pulse oximetry and photoplethysmography measurements

Recent advances in the development of ultra-compact semiconductor lasers and technology of printed flexible hybrid electronics have opened broad perspectives for the design of new pulse oximetry and photoplethysmography devices. Conceptual design of optical diagnostic devices requires careful selection of various technical parameters, including spectral range; polarization and intensity of incident light; actual size, geometry, and sensitivity of the detector; and mutual position of the source and detector on the surface of skin. In the current study utilizing a unified Monte Carlo computational tool, we explore the variations in diagnostic volume due to arterial blood pulsation for typical transmitted and back-scattered probing configurations in a human finger. The results of computational studies show that the variations in diagnostic volumes due to arterial pulse wave are notably (up to 45%) different in visible and near-infrared spectral ranges in both transmitted and back-scattered probing geometries. While these variations are acceptable for relative measurements in pulse oximetry and/or photoplethysmography, for absolute measurements, an alignment normalization of diagnostic volume is required and can be done by a computational approach utilized in the framework of the current study

Monitoring Cellular Metabolism with Near-infrared Spectroscopy

Aims: Although NIRS oximetry has been widely used in clinical and research settings to monitor oxygen consumption in muscles (1), it is not necessarily able to obtain cellular metabolic levels directly. Oxygen saturation will only change with aerobic metabolism (2); however, anaerobic metabolism cannot be assessed by monitoring oxygen saturation. This work aims to measure cell oxygenation and blood oxygenation, simultaneously, by applying oximetry to hemoglobin/deoxyhemoglobin and to cytochrome c oxidase (CCOX). A custom build NIRS device called the cytoximeter was constructed to achieve this goal. This work could have important impacts on monitoring neurological diseases, Postural Tachycardia Syndrome (POTS), and epilepsy. Introduction: CCOX is the terminal enzyme in the electron transport chain (ETC) and as such will be responsive in changes in either aerobic or anaerobic metabolism (3). CCOX transports a number of electrons over a single cycle of the ETC. As the enzyme accepts electrons, it enters a reduced state. Monitoring the redox state of CCOX in a given tissue will reflect the amount of metabolic activity in that tissue (9). We developed a novel device that monitors the changes in optical densities of a tissue. Using Beer’s law and the difference in absorption spectra of reduced and oxidized CCOX, it is possible to measure the relative changes in concentration of these chemicals (4). Methods: In order to observe and separate the CCOX signals from absorption changes due to whole blood changes, a six wavelength absorption spectroscopy device is constructed. This device uses the optimal source detector separations, obtained by numerical photon migration simulations, for monitoring superficial muscles and cortical brain tissue. In order to validate the device performance, several phantom studies are conducted followed by clinical investigations. In the clinical setting, the device was applied to the gastrocnemius muscles of patients undergoing a tilt table test during a standard of care neurological examination. Results: The phantom studies showed that the device was able to obtain changes in the concentration and the redox state of CCOX in a medium with optical properties similar to the tissues found in the calf and skull. When applied in a clinical setting, the device produced reproducible and predictable results. The clinical results are partially verified by the use of a commercially available oximeter, which validates the changes in hemoglobin and oxy hemoglobin obtained by our custom-made cytoximeter. Conclusion: This work is a novel approach to the non-invasive monitoring of CCOX simultaneously with blood oxygen saturation by use of NIR spectroscopy. While there is currently no gold standard with which to compare these results to, the ability to separate cellular metabolism in the presence of large changes in blood volume during a clinical procedure is a promising first step toward clinically monitoring the energy expenditure of tissues. Further work is underway to correlate changes in CCOX redox state to the level muscular exertion. This will allow the researchers to quantitatively monitor CCOX redox changes during different levels of exercise

Absolute quantification of cerebral tissue oxygen saturation with multidistance broadband NIRS in newborn brain

Tissue oximetry with near-infrared spectroscopy (NIRS) is a technique for the measurement of absolute tissue oxygen saturation (StO2). Offering a real-time and non-invasive assessment of brain oxygenation and haemodynamics, StO2 has potential to be used for the assessment of newborn brain injury. Multiple algorithms have been developed to measure StO2, however, issues with low measurement accuracy or extracranial tissue signal contamination remain. In this work, we present a novel algorithm to recover StO2 in the neonate, broadband multidistance oximetry (BRUNO), based on a measurement of the gradient of attenuation against distance measured with broadband NIRS. The performance of the algorithm was compared to two other published algorithms, broadband fitting (BF) and spatially resolved spectroscopy (SRS). The median error when recovering StO2 in light transport simulations on a neonatal head mesh was 0.4% with BRUNO, 4.2% with BF and 9.5% with SRS. BRUNO was more sensitive to brain tissue oxygenation changes, shown in layered head model simulations. Comparison of algorithm performance during full oxygenation-deoxygenation cycles in a homogeneous dynamic blood phantom showed significant differences in the dynamic range of the algorithms; BRUNO recovered StO2 over 0–100%, BF over 0–90% and SRS over 39–80%. Recovering StO2 from data collected in a neonate treated at the neonatal intensive care showed different baseline values; mean StO2 was 64.9% with BRUNO, 67.2% with BF and 73.2% with SRS. These findings highlight the effect of StO2 algorithm selection on oxygenation recovery; applying BRUNO in the clinical care setting could reveal further insight into complex haemodynamic processes occurring during neonatal brain injury