DESIGN OPTIMIZATION AND PRECLINICAL TESTING OF PEDIATRIC ROTARY BLOOD PUMPS AND COMPONENTS: TOWARDS THE PEDIAFLOW® VAD

Limited options exist for children (BSA<1.5 m2) requiring long-term mechanical circulatory support (MCS). Unlike adults where compact, 3rd generation, continuous-flow, implantable rotary blood pumps (RBPs) are now the standard for ventricular assist device (VAD)-indications, the only pediatric-approved chronic MCS device is the Berlin Heart® EXCOR®: a 1st generation pulsatile, pneumatically-driven, paracorporeal life-saving technology albeit with a substantial risk profile associated with frequent neurological and coagulation-related serious adverse events. In support of the smallest and most vulnerable patients, the goal of this research is to facilitate the development and translation of next-generation pediatric RBPs, including the University of Pittsburgh-led Consortium’s PediaFlow®: a miniature, implantable, rotodynamic, fully magnetically levitated, continuous-flow pediatric VAD intended to support patients between 3 to 15 kg at a flow rates of 0.3-1.5 L/min for up to six months. Presented here is the i) development of a standardized method for in vitro mechanical blood trauma testing of pediatric MCS devices; ii) design and ex vivo evaluation of a novel, pediatric-appropriate, suction resistant, placement insensitive, left ventricular drainage cannula; iii) creation of an MCS-tailored monitoring software for preclinical testing; iv) development of a PediaFlow®-specific flow estimation algorithm; and v) hemocompatibility findings in vitro and in vivo of the 4th generation PediaFlow® (PF4) VAD. The PF4, comparable in size to an AA battery, is the embodiment of more than a decade of extensive computational and experimental efforts over the span of four device iterations to minimize size, optimize performance, and maximize safety. This dissertation represents the work and results to date of PediaFlow® PF4 on the path to preclinical testing to submit an Investigation Device Exception (IDE) application in anticipation of eventual clinical trials

Intraoperative Fourier domain optical coherence tomography for microsurgery guidance and assessment

In this dissertation, advanced high-speed Fourier domain optical coherence tomography (FD-OCT)systems were investigated and developed. Several real-time, high resolution functional Spectral-domain OCT (SD-OCT) systems capable of imaging and sensing blood flow and motion were designed and developed. The system were designed particularly for microsurgery guidance and assessment. The systems were tested for their ability to assessing microvascular anastomosis and vulnerable plaque development. An all fiber-optic common-path optical coherence tomography (CP-OCT) system capable of measuring high-resolution optical distances, was built and integrated into di fferent imaging modalities. First, a novel non-contact accurate in-vitro intra-ocular lens power measurement method was proposed and validated based on CP-OCT. Second, CP-OCT was integrated with a ber bundle based confocal microscope to achieve motion-compensated imaging. Distance between the probe and imaged target was monitored by the CP-OCT system in real-time.The distance signal from the CP-OCT system was routed to a high speed, high resolution linear motor to compensate for the axial motion of the sample in a closed-loop control. Finally a motion-compensated hand-held common-path Fourier domain optical coherence tomography probe was developed for image-guided intervention. Both phantom and ex vivo models were used to test and evaluate the probe. As the data acquisition speed of current OCT systems continue to increase, the means to process the data in real-time are in critically needed. Previous graphics processing unit accelerated OCT signal processing methods have shown their potential to achieve real-time imaging. In this dissertation, algorithms to perform real-time reference A-line subtraction and saturation artifact removal were proposed, realized and integrated into previously developed FD-OCT system CPU-GPU heterogeneous structure. Fourier domain phase resolved Doppler OCT (PRDOCT) system capable of real-time simultaneous structure and flow imaging based on dual GPUs was also developed and implemented. Finally, systematic experiments were conducted to validate the system for surgical applications. FD-OCT system was used to detect atherosclerotic plaque and drug effi ciency test in mouse model. Application of PRDOCT for both suture and cu ff based microvascular anastomosis guidance and assessment was extensively stuided in rodent model

Studies of lung function

This thesis outlines the candidate's contribution to the study of Respiratory Physiology in two main areas 1. The effect of lung morphometry on lung function and 2. Reflex control of pattern of breathing.The work that makes up this thesis is laid out in largely chronological order describing the evolution of the investigations.The effect of bronchial tree structure on function was investigated using a number of new techniques developed by the author. These include a method of modelling the bronchial tree to previously unobtained detail in the form of a hollow cast. This enabled gas transit times to airways of 2-3 mm diameter to be measured and the contribution made by architecture, tissue compliance and the gradient of pleural pressure to the distribution of ventilation to be apportioned. This was the first time transit times to individual airways had been measured. Using these techniques the effect of bronchial tree structure on the phenomenon of separation of gas mixtures into their components during breathing, and the effect of the beating heart on the mixing of gases during breathing was quantified. The author's contributions to the investigation of neural control of breathing follow. A fortuitous observation that SO₂ blocks pulmonary stretch receptors (PSR) in rabbits, which took place while developing an animal model of bronchitis, lead to the observation of a non PSR mechanism determining inspiratory time (ti). Investigation of the action of rapidly adapting pulmonary receptors (RAR) using SO₂ confirmed their role in provoking sighs or augmented breaths and demonstrated that they terminated expiratory duration (tn) with a constant latency. A consistent effect of RARs on inspiration proved elusive until it was discovered that after provoking an augmented breath ft is refractory to the direct effects of RAR activity for about 2 minutes. This observation lead to the development of a theoretical model of control of ft via a central linking. This explained our observation of a non-PSR effect restricting ft after SO₂ block. Further investigations confirmed a role for RAR in control of breathing in conscious dogs. The action of RAR in initiating inspiration was demonstrated using PSR block. The same technique was used to elucidate the role played by PSR in shifts in functional residual capacity during changes in posture. An interesting observation made at this time is that although cough is primarily associated with RAR activity it can not be triggered from the lungs. The results of experiments demonstrating a similar role for RAR in conscious animals are presented.The influence of high frequency ventilation, on pulmonary receptors, the reflexes they produce and on the non-Newtonian properties of bronchial mucus is described.The way in which different species control their very different frequencies of breathing is included and the way pulmonary receptor activity is changed in some models of lung disease. The effects of modern anaesthetics on receptor activity and the effect of acupuncture as a respiratory stimulant are reported. The results of some investigations of human movement and tremor are presented. The candidates contributions to books and books published are described

High Frame Rate Ultrasound Velocimetry of Fast Blood Flow Dynamics

In this thesis we develop and validate high frame rate ultrasound sequences for use with echo-particle image velocimetry (in 2D and 3D), with the aim of measuring the high velocity blood flow patterns in the left ventricle and abdominal aorta

Cerebral Hemodynamics in High-Risk Neonates Probed by Diffuse Optical Spectroscopies

Advances in medical and surgical care of the critically ill neonates have decreasedmortality, yet a significant number of these neonates suffer from neurodevelopmentaldelays and failure in school. Thus, clinicians are now focusing on prevention ofneurologic injury and improvement of neurocognitive outcome in these high-risk infants. Assessment of cerebral oxygenation, cerebral blood volume, and the regulation of cerebral blood flow (CBF) during the neonatal period is vital for evaluating brain health. Traditional CBF imaging methods fail, however, for both ethical and logistical reasons. In this dissertation, I demonstrate the use of non-invasive optical modalities, i.e., diffuse optical spectroscopy and diffuse correlation spectroscopy, to study cerebral oxygenation and cerebral blood flow in the critically ill neonatal population. The optical techniques utilize near-infrared (NIR) light to probe the static and dynamic physiological properties of deep tissues. Diffuse correlation spectroscopy (DCS) employs the transport of temporal correlation functions of diffusing light to extract relative changes in blood flow in biological tissues. Diffuse optical spectroscopy (DOS) employs the wavelength-dependent attenuation of NIR light to assess the concentrations of the primary chromophores in the tissue, namely oxy- and deoxy-hemoglobin. This dissertation presents both validation and clinical applications of novel diffuse optical spectroscopies in two specific critically ill neonatal populations: very-low birth weight preterm infants,and infants born with complex congenital heart defects. For validation of DCS in neonates, the blood flow index quantified by DCS is shown to correlate well with velocity measurements in the middle cerebral artery acquired by transcranial Doppler ultrasound. In patients with congenital heart defects DCS-measured relative changes in CBF due to hypercapnia agree strongly with relative changes in blood flow in the jugular veins as measured by phase-encoded velocity mapping magnetic resonance. For applications in the clinic, CO2 reactivity in patients with congenital heart defects prior to various stages of reconstructive surgery was quantified; our initial results suggest that CO2 reactivity is not systematically related to brain injury in this population. Additionally, the cerebral effects of various interventions, such as blood transfusion and sodium bicarbonate infusion, were investigated. In preterm infants, monitoring with DCS reveals a resilience of these patients to maintain constant CBF during a small postural manipulation

Aerospace Medicine and Biology: A continuing bibliography with indexes, supplement 192

This bibliography lists 247 reports, articles, and other documents introduced into the NASA scientific and technical information system in March 1979

Preclinical MRI of the kidney : methods and protocols

This Open Access volume provides readers with an open access protocol collection and wide-ranging recommendations for preclinical renal MRI used in translational research. The chapters in this book are interdisciplinary in nature and bridge the gaps between physics, physiology, and medicine. They are designed to enhance training in renal MRI sciences and improve the reproducibility of renal imaging research. Chapters provide guidance for exploring, using and developing small animal renal MRI in your laboratory as a unique tool for advanced in vivo phenotyping, diagnostic imaging, and research into potential new therapies. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Cutting-edge and thorough, Preclinical MRI of the Kidney: Methods and Protocols is a valuable resource and will be of importance to anyone interested in the preclinical aspect of renal and cardiorenal diseases in the fields of physiology, nephrology, radiology, and cardiology. This publication is based upon work from COST Action PARENCHIMA, supported by European Cooperation in Science and Technology (COST). COST (www.cost.eu) is a funding agency for research and innovation networks. COST Actions help connect research initiatives across Europe and enable scientists to grow their ideas by sharing them with their peers. This boosts their research, career and innovation. PARENCHIMA (renalmri.org) is a community-driven Action in the COST program of the European Union, which unites more than 200 experts in renal MRI from 30 countries with the aim to improve the reproducibility and standardization of renal MRI biomarkers

OPTICAL COHERENCE TOMOGRAPHY FOR NEUROSURGEY AND CANCER RESEARCH

Optical Coherence Tomography (OCT) provides non-labeling, real-time and high resolution images, which has the potential to transform the paradigm of surgical guidance and preclinical animal studies. The design and development of OCT devices for neurosurgery guidance and novel imaging algorithms for monitoring anti-cancer therapy have been pursued in this work. A forward-imaging needle-type OCT probe was developed which can fit into minimally invasive tools (I.D. ~ 1mm), detect the at-risk blood vessels, and identify tissue micro-landmarks. This promising guidance tool improves the safety and the accuracy of needle-based procedures, which are currently performed without imaging feedback. Despite the great imaging capability, OCT is limited by the shallow imaging depth (1-2 mm). In order to address this issue, the first MRI compatible OCT system has been developed. The multi-scale and multi-contrast MRI/OCT imaging combination significantly improves the accuracy of intra-operative MRI by two orders (from 1mm to 0.01 mm). In contrast to imaging systems, a thin (0.125 mm), low-cost (1/10 cost of OCT system) and simple fiber sensor technology called coherence gated Doppler (CGD) was developed which can be integrated with many surgical tools and aid in the avoidance of intracranial hemorrhage. Furthermore, intra-vital OCT is a powerful tool to study the mechanism of anti-cancer therapy. Photo-immunotherapy (PIT) is a low-side-effect cancer therapy based on an armed antibody conjugate that induces highly selective cancer cell necrosis after exposure to near infrared light both in vitro and in vivo. With novel algorithms that remove the bulk motion and track the vessel lumen automatically, OCT reveals dramatic hemodynamic changes during PIT and helps to elucidate the mechanisms behind the PIT treatment. The transformative guidance tools and the novel image processing algorithms pave a new avenue to better clinical outcomes and preclinical animal studies

The design and evaluation of discrete wearable medical devices for vital signs monitoring

The observation, recording and appraisal of an individual’s vital signs, namely temperature, heart rate, blood pressure, respiratory rate and blood oxygen saturation (SpO2), are key components in the assessment of their health and wellbeing. Measurements provide valuable diagnostic data, facilitating clinical diagnosis, management and monitoring. Respiratory rate sensing is perhaps the most under-utilised of all the vital signs, being routinely assessed by observation or estimated algorithmically from respiratory-induced beat-to-beat variation in heart rate. Moreover there is an unmet need for wearable devices that can measure all or most of the vital signs. This project therefore aims to a) develop a device that can measure respiratory rate and b) develop a wearable device that can measure all or most of the vital signs. An accelerometer-based clavicular respiratory motion sensor was developed and compared with a similar thoracic motion sensor and reference using exhalatory flow. Pilot study results established that the clavicle sensor accurately tracked the reference in monitoring respiratory rate and outperformed the thoracic device. An Ear-worn Patient Monitoring System (EPMS) was also developed, providing a discrete telemonitoring device capable of rapidly measuring tympanic temperature, heart rate, SpO2 and activity level. The results of a comparative pilot study against reference instruments revealed that heart rate matched the reference for accuracy, while temperature under read (< 1°C) and SpO2 was inconsistent with poor correlation. In conclusion, both of the prototype devices require further development. The respiratory sensor would benefit from product engineering and larger scale testing to fully exploit the technology, but could find use in both hospital and community-based The design and evaluation of discrete wearable medical devices for vital signs monitoring DG Pitts ii Cranfield University monitoring. The EPMS has potential for clinical and community use, having demonstrated its capability of rapidly capturing and wirelessly transmitting vital signs readings. Further development is nevertheless required to improve the thermometer probe and resolve outstanding issues with SpO2 readings

Gas-Liquid Two-Phase Flow in the Pipe or Channel

The main goal of this Special Issue was to contribute to, highlight and discuss topics related to various aspects of two-phase gas–liquid flows, which can be used both in fundamental sciences and practical applications, and we believe that this main goal was successfully achieved. This Special Issue received studies from Russia, China, Thailand, ROC-Taiwan, Saudi Arabia, and Pakistan. We were very grateful to see that all the papers presented findings characterized as unconventional, innovative, and methodologically new. We hope that the readers of the journal Water can enjoy and learn about the experimental and numerical study of two-phase flows from the published material, and share these results with the scientific community, policymakers and stakeholders. Last but not least, we would like to thank Ms. Aroa Wang, Assistant Editor at MDPI, for her dedication and willingness to publish this Special Issue. She is a major supporter of the Special Issues, and we are indebted to her