Towards improved neonatal care through noninvasive and minimally invasive sensing technologies for hypoxia monitoring

Hypoxia, characterized by inadequate oxygen supply to specific body regions at the tissue level, has significant implications for the fetus during labor and the newborn shortly after delivery. This oxygen deprivation can lead to severe cellular abnormalities, stillbirth, or neonatal mortality. Birth asphyxia, a critical manifestation of hypoxia, leads to significant neonatal morbidity and mortality. Neonates who survive the acute phase of birth asphyxia are at risk of developing long-term neurological sequelae, such as hypoxic-ischemic encephalopathy, cognitive impairment, speech and developmental delays, vision, hearing, and feeding impairments, emotional and behavioral disorders, and learning disabilities. Current clinical practices using biophysical technologies, such as electrocardiography (ECG), cardiotocography (CTG), ST-analysis adjunct to CTG, and Doppler ultrasound, result in high false-positive rates and increased obstetric interventions during labor. Biochemical-based technologies like fetal scalp blood sampling and arterial blood gas sampling identify metabolic acidosis and oxygen deprivation. However, these methods are highly invasive and may not improve clinical outcomes or reduce unnecessary interventions. Therefore, accurate, continuous, affordable, and ideally noninvasive monitoring of hypoxia in neonates is a pressing clinical need. This thesis focuses on two approaches to overcome the limitations of existing hypoxia monitoring methods. The first approach focuses on improving the use of existing biophysical technology, ECG, by identifying hypoxia-related morphological features to predict hypoxia in neonates. This is achieved by analyzing data recorded simultaneously using biochemical (ABG analysis) and biophysical (ECG waveform analysis) methods. The study found that specific ECG features, including T/QRS, T Amplitude, Tslope, Tslope/T, Tslope/|T|, HR, QT, and QTc were significantly different in neonates with asphyxia compared to those without asphyxia. Furthermore, ECG features, Tslope/T, QT, and QTc, exhibited significant differences across all three groups (acidosis, normal, and alkalosis) both before and after the management of neonatal asphyxia. Therefore, this study demonstrated the feasibility of noninvasive, and continuous monitoring of asphyxiated neonates using these ECG features, either individually or in combination. The second approach explores the potential of utilizing interstitial fluid (ISF) pH as a biomarker for hypoxia. This approach is based on two primary factors, ISF pH levels respond quickly to hypoxic events due to the limited buffering capacity of ISF, and monitoring ISF presents a less invasive alternative to blood sampling. To enable the development of novel sensors for ISF pH monitoring, it is essential to create impedance-based pH-representative liquid mimics due to limited access to ISF. This thesis reports the preparation of eight buffers as potential ISF mimics, with pH values ranging from 6.00 to 8.00, standardized to a concentration of 0.1 M, and tested at room temperature. The prepared buffers were evaluated based on their pH profile, electrical conductivity, and dielectric properties compared to human plasma ISF. The experimental findings suggest that the BES buffer, HCl-CBC buffer, CBC buffer, and SP buffer effectively mimic the metabolic acidosis induced by asphyxia. Conversely, the metabolic alkalosis effect can be replicated using the BTP, Trizma, and NaOH-BTP buffers. With the development of these ISF mimics, impedance-based biosensors for noninvasive ISF pH (and potentially hypoxia) monitoring could be developed and reliably tested in the lab. To this end, a study was conducted to select appropriate electrode configurations and measurement techniques for the development of sensitive and accurate impedance-based pH biosensors. This study demonstrated that ITO electrode configuration and mode of operation significantly impact the precision of pH and impedance in EIS measurements. The three-electrode potentiostat probe setup at measured temperatures was selected for its reduced impedance and consistent output, which is essential for developing highly sensitive and precise pH biosensors. The study confirmed the feasibility of utilizing ITO-based EIS for pH sensing by demonstrating the impact of pH variations on impedance. Additionally, the frequency-dependent impedance changes in ISF due to pH variations provide the potential for designing a minimally invasive approach to detect and monitor asphyxia associated with metabolic disorders. The findings of this research underscore the potential of microneedle-based biosensing devices for continuous, long-term hypoxia monitoring in ISF, which could significantly improve healthcare and patient care.

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University of Galway

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Attribution-NonCommercial-NoDerivatives 4.0 International

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University of Galway Theses (PhD Theses)