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Electrical Impedance Tomography (EIT) is a fast, portable imaging technique that produces tomographic images of the internal impedance of an object from surface electrode measurements. This thesis reports the first use of EIT to image evoked brain activity in adults and neonates and determines whether accurate EIT images could be obtained from the adult and neonatal brain. In addition, a realistic head-tank phantom was developed to test the performance of EIT with known impedance changes placed within a real human skull. Two EIT systems were used. Images were obtained using 31 or 21 Ag/AgCl EEG scalp electrodes in adults and neonates, respectively, with either 256 or 187 individual impedance measurements from different electrode combinations: 2 applied a safe, alternating current and 2 measured the resultant scalp voltage. Imaging was performed using a block design with 6-15 stimulation periods of between 10-75s during either: 1) Visual, 2) Somatosensory or 3) Motor stimuli. Impedance changes were detected in 38/39 adults and 9/9 neonates within 0.6-5.8s after stimulus onset, and returned to baseline 7.6-36s after stimulus cessation. Reconstructed images were noisy: -20-70% images showed correct localisation to the expected area of cortex stimulated by the visual, motor or somatosensory paradigms. As EIT images from the head-tank localised changes within 10% of the impedance perturbation, this indicated that poor localisation in humans was not due to the head-shape or the skull, but may be related to unknown physiological factors. An improved EIT reconstruction algorithm, using a computerised finite-element model of the head, showed improved localisation for the adult images. This is the first demonstration that EIT can detect and image impedance changes in the head, probably due to increased regional cerebral blood volume in the activated cortex. Improvements may enable more accurate neuroimaging of the adult and neonatal brain for use in clinical practice.

The aimso f this thesisa ret o outlinet he ethicalc hallengesp osedb y neonatarl esearch, to propose solutions to these challenges and to consider whether Scanlon's contractualism can accommodate these solutions. The thesis does not offer a comprehensive appraisal of contractualism, but applies important contractualist ideas, particularlyr easonablere jectabilitya ndj ustifiability to others,t o neonatarl esearch. The circumstances in which neonatal research is conducted pose constraints on equipoise and parental consent, particularly when promising experimental treatment is accessible only through trial participation. While randomised trials generally produce more rigorous evidence than uncontrolled studies, they raise concerns about the use of sick infants to glean this evidence. Participation in relevant research cannot be guaranteed to serve the best interests of sick infants. Whether conducting neonatal researchis imperativeo r optionald ependso n the moral statusa ccordedto futurehumans. Compromisesa ren eededto reconcilet he conflicting ethicali mperatives.T hese include developing alternative forms of parental authorisation, providing access to promising new treatment before there is definitive evidence supporting its safety and efficacy, and using observational studies when randomised trials are impractical or unethical. Pro-triallist approaches, emphasising the benefits of research and sceptical approaches, emphasising individual rights and interests, offer inadequate moral justification for these compromises.The pluralism and mutual consideration espoused by contractualism render it a more promising theory of the ethics of neonatal research than pro-triallist and sceptical accounts.T he priority accordedb y contractualismto justifiability andr easonable acceptability to others could allow the theory to justify the compromises needed to reconcile these conflicting standpoints. To meet this challenge, however, contractualism must provide more specific guidance to determine whether or not moral disagreement is reasonable, and it must offer a more defensible account of the moral status of future humans.

Continuing improvements in neonatal care have allowed significant progress in the clinical outcome of prematurity, with improvement t in both survival and neurological outcome. Although the incidence of intraventricular haemorrhage associated with prematurity has been lowered, it still represents a significant source of neurological morbidity. Several management strategies have attempted to reduce the neurological impact of IVH and its progression to post-haemorrhagic ventricular dilatation (PHVD). Studies have evaluated the impact of serial withdrawal of cerebrospinal fluid (CSD) by lumbar puncture, fontanelletap or through a ventricular access device, yet none of these interventions have reduced progression to PHVD. The use of agents that reduce production of CSF have actually led to worse clinical outcomes for unclear reasons. A new technique involving intraventricular fibrinolysis, drainage and irrigation, while not reducing the need for CSF diversion, has improved cognitive outcome at 2 years.

Retinopathy of prematurity (ROP) is a posterior eye disorder found in prematurely born infants, that can result in blindness. In this thesis a delivery system, for the prophylactic management of the disease was designed and tested based on the hypothesis that delivery of a hypoxia inducible plasmid to the posterior eye might prevent the pathogenesis of the ROP. Major challenges identified for the project included: characterisation of the hypoxia inducible plasmid, efficient transfection of the target cells and delivering the DNA to the posterior eye with a minimally invasive route. To meet these requirements it was proposed to encapsulate a hypoxia responsive plasmid condensed with a cationic peptide (RALA) within PLA-PEG nanoparticles that can deliver the DNA to the posterior eye via transscleral route for efficient transfection of the retinal endothelial cells. In order to pursue this hypothesis the DNA condensation with RALA was optimized to give nanoparticies (RNPs) with a z-average diameter of 58.7±10.3 nm and PDI of 0.252±0.050. These nanoparticies efficiently transfected a variety of cell lines. A series of PLA-PEG block copolymers were synthesized with various PEG chain length and LA/EG ratio, and formulated into composite nanoparticles (diameters <200 nm and PDI <0.200) containing the RNPs. TEM was used for the first time to confirm the presence of a nanoparticle-in-nanoparticle system by TEM. Furthermore, an in vitro DNA release study demonstrated that the composite nanoparticles were able to release DNA, with faster DNA release in the first 24 hrs comprising 10% of the DNA content, followed by a slow continuous release for a prolonged duration. Among the studied formulations PLA25-PEG5 exhibited the fastest release where >30% of DNA content was released over 6 weeks. Finally these nanoparticles were evaluated for their ability to cross the sclera and the results demonstrated that > 1 0% of PLA20-PEG2 and 8% of PLA25-PEG5 . nanoparticles crossed the sclera in a 4 hrs, whereas PLGA nanoparticles exhibited permeation of just 3.2% in this time. While the selected hypoxia responsive plasmid, pE9/GFP, failed to show its specificity to express only in hypoxia conditions the work presented herein demonstrates that the proposed delivery system is viable. Thus, this thesis demonstrates the preparation of a composite nanoparticle system where inner RNPs demonstrated their efficiency to condense the DNA and enable them express inside cells and outer PLA-PEG nanoparticles demonstrated their efficiency to cross the sclera. This system is a promising candidate for the prophylactic management of ROP and may be suited to other gene therapies.

An optimal thermal environment is regarded as a priority in the medical care of newborn infants (neonatology). Survival of each neonate (newborn infant) depends on the ability to regulate its temperature. Preterm and small neonates often cannot respond to the environmental temperature changes. For this reason, maintenance of neonates bodies within a narrow temperature range is essential for their survival and growth. However, there is one major concern when using radiant warmers, namely the neonates often become severely dehydrated when nursed in these devices. For this reason, the major objective of this thesis is to find a solution to this difficulty. In order to achieve this goal, numerical techniques including Computational Fluid Dynamics and conjugate heat transfer were employed. Mathematical mod- els applied to living organisms can provide a better understanding of the thermal processes occurring i~side a human body, together with their interactions with the surrounding environment. Therefore, in this thesis we focus on developing a model of a neonate under a radiant warmer that incorporates both heat and mass transfer processes in order to provide a better understanding of how a radiative heat source interacts with a neonate. The numerical models were prepared in ANSYS FLUENT and ANSYS CFX commercial softwares. The flow was assumed to be turbulent, and radiation cal- culations were performed as they are a crucial part of this analysis. Moreover, a semi-analytical ray tracking method was developed for the purpose of validating the numerical results. A good general agreement was observed when comparing the ray tracking results with the numerical ones. Next, a heat generation within the newborn was considered, and the numerical data was validated against the analytical calculations, and this comparison showed a good agreement of the results obtained using these two different techniques. Finally, several modifications to the geometry and operation of the radiant warmer are introduced in order to assist with the difficulty of high temperature gradients being obtained on the skin of the newborns nursed under the radiant warmer. It was found that the proposed modifications reduce the large temperature differences on the skin of the newborn. A more uniform temperature field on the skin will result in decreasing the evaporative loss. The proposed modifications in- clude to different approaches. Namely, the first solution, being a high conductivity blanket, can be easily implemented by the staff of the hospital. The second solution introduces modifications to the design of the radiant warmer, and it could be of interest to the producer of the device. Therefore, the main goal of this project, namely to find a solution to newborns becoming dehydrated when nursed under radiant warmers, has been successfully achieved.

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