Among all organs, lungs are the last ones to grow and develop fully. As a result, extreme premature neonates may suffer from respiratory failure due to their immature lungs and will require respiratory support in the form of mechanical ventilation or extracorporeal membrane oxygenation (ECMO). In addition, extreme prematurity is recognized as the primary cause of neonatal morbidity and mortality. The conventional standard of care for respiratory support of preterm neonates with respiratory failure are invasive and may lead to long-term morbidities and complications. Hence, a non-invasive respiratory support technique named “Artificial Placenta” has been developed to address the issues and challenges associated with the current technologies. An artificial placenta type device is one designed to provide required oxygenation in room air via non-invasive access to the umbilical vessels without the need of any external pump. In this thesis, microfluidic and microfabrication technologies have been employed in the development of a pumpless neonatal lung assist device (LAD) for preterm neonates in two approaches: 1) design and develop novel microfabrication techniques to fabricate advanced microfluidic blood oxygenators with high gas exchange capacity and reduced form factor and 2) design and construct several modular LADs based on the oxygenators that were developed to fulfill the required gas transfer needs for these babies. The new microfluidic blood oxygenators with double-sided gas transfer channels were found to enhance oxygenation up to 343 % in room air and be easily scaled-up to achieve higher gas exchange capacities without a noticeable increase in priming volume. Furthermore, this microfabrication method has been utilized to make the largest all PDMS ultra-thin double-sided blood oxygenator with higher gas exchange capabilities. Also, a novel composite material made of PDMS and PTFE was introduced that conferred high flexibility to the oxygenator to decrease the form factor of such devices. This device was one of the first microfluidic blood oxygenators with enough flexibility to be deformed, bent, or rolled without limitation and losing its functionality. In order to satisfy the gas transfer need of these preterm neonates, few microfluidic-based modular LADs were constructed to support different birth weights up to 2 kg. The main design criteria for such a LAD in this research was low pressure drops (capable of being operated by a baby’s heart), an oxygen transfer of 1.3 – 1.9 mL min-1 kg-1 of body weight (or an increase in oxygen saturation level from ~ 75 % to ~ 100 % and ideally in room air), and low priming volume (less than 10 % of the total blood volume of a baby). These LADs first were evaluated in vitro to measure their gas exchange capacities and those which could meet needed oxygenation would be tested in vivo. For the first time, it was shown that a pumpless microfluidic-based LAD could support a newborn piglet and provide adequate oxygenation in room air or the oxygen-rich environment. The application of these microfluidic blood oxygenators was not only limited to preterm neonates but also can be used to develop LADs for adult patients. / Thesis / Doctor of Philosophy (PhD)

A novel in vitro membrane oxygenator circuit was developed to test gas exchange where particular elements could be examined whilst keeping other variables constant. The circuit comprises two membrane oxygenators connected to form a continuous blood circuit resembling venous and arterial blood conditions. The effects of Isoflurane, a volatile anaesthetic, on oxygen transfer were investigated. RBC resistance to nitric oxide diffusion (DNO) was tested in this circuit by haemolysis and addition of the haemoglobin-based-oxygen-carrier (HBOC) Oxyglobin. The circuit was primed with equine blood flowing at 2.5 l/min. The oxygenator was ventilated with 5 l/min air/oxygen/N2 mix providing a range of FiO2. The deoxygenator received 5 l/min 5% CO2 in N2 with 0.2-0.3 l/min CO2. Isoflurane 1%, NO 4000-16000 ppb and CO 0.03% were added to the oxygenator gas. Uptake of O2, CO2, CO and NO were calculated by gas inlet and outlet concentrations and flow rates. Arterial and venous oxygen dissociation curve (aODC and vODC) comparisons were made. Isoflurane uptake by the circuit blood was evident and 1% Isoflurane did not affect oxygen uptake (p=0.981), aODC or vODC (p=0.311 and p=0.751). Haemolysis did not affect O2 or CO2 transfer but increased DNO (p<0.001). 250ml free Hb solution addition to the circuit increased DNO by 91% (p<0.0001). Addition of 250ml Oxyglobin increased DNO by 143% from 7.41±2.77 to 17.97±1.83 ml/min/mmHg. Oxyglobin caused a right shift of aODC and vODC (p<0.0001) but NO-bound Oxyglobin caused a left vODC shift (p<0.0001). Conclusion: Isoflurane administered via a membrane oxygenator does not affect O2 uptake or carriage in the blood. RBC surroundings provide significant resistance to DNO in circuit tests. Significant uptake of NO by Oxyglobin supports the potential of HBOCs to scavenge endothelial NO in vivo, causing vasoconstriction.

Respiratory distress syndrome is a major cause of mortality among infants. Current therapies are limited in terms of invasiveness, cost, infrastructure, and leads to long term morbidities such as bronchopulmonary dysplasia. As a result a form of respiratory support termed as “artificial placenta” has been developed that allows natural development of lungs and avoids long term morbidities. The artificial placenta is connected via the umbilical vessels and provide pumpless respiratory support and is characterized by non-invasiveness, low cost and low infrastructure. Our group previously reported on a development of porous PDMS membrane artificial placenta. To build upon its development, one of the objectives of this thesis was to reduce the variation in the oxygen saturation of the input blood for testing the oxygenator. Another objective was to setup a mathematical model to predict the oxygen uptake in an oxygenating unit and use the model to optimize the geometric parameters of a design. The final objective was to improve the oxygen uptake of the oxygenating unit of the artificial placenta by redesigning the blood flow path and the membrane material. The experimental setup was improved to employ an active controller that actively maintained the oxygen saturation of the input blood for testing the oxygenator within a variation of ±3% of the set point for at least an hour. As compared to previous experimental setup the blood deviated from the set point by 9%. Later, the blood flow path in the oxygenator was redesigned from a flat height profile to a sloping height profile; and the PDMS membrane was reinforced with a thin steel mesh. Such changes improved the oxygen uptake at the operating pressure of 30 mmHg from 16 µL/min in case of an oxygenator with flat height profile and PDMS membrane to 26 µL/min in case of an oxygenator with flat profile and composite membrane. Finally, a mathematical model was developed that coupled oxygen uptake, pressure drop and membrane expansion. The model was validated against experimental results and was later used to optimize the configuration of the oxygenator with sloping profile and composite membrane. The predicted oxygen uptake of the optimized configuration at the operating pressure of 30 mmHg was 78.8 µL/min. / Thesis / Master of Applied Science (MASc)

The effects of oxygenation and aeration on water quality, rainbow trout (Oncorhynchus mykiss) production, and economics were compared at the Wytheville State Fish Hatchery (WSFH) for 270 days. Mean dissolved oxygen (DO) concentrations and delta DO were significantly higher (P < 0.001) in the oxygenated raceways (9.5 and 2.75 mg/L, respectively) compared to aerated raceways (7.4 and 0.57 mg/L). Total settleable solids loads were significantly greater (P < 0.001) in aerated raceways (10.3 g/L/day) than in oxygenated raceways (8.8 g/L/day). Dissolved nitrogen (%), total gas pressure, and other water quality parameters (CO2, nitrite nitrogen, alkalinity, pH, and TAN) did not differ significantly between the treatments (P > 0.05). Raceway trout production (kg/day), trout growth rates (grams), feed conversion rate (FCR), and fish survival were not significantly different between treatments (P > 0.05). Blood hematocrit (Hct) and percent visceral mass were significantly elevated (P < 0.001) in oxygenated raceways compared to aerated raceways at 46 and 14.4% and 44 and 13%, respectively. Carrying capacity estimates derived from fish loading trials were significantly different (P < 0.001) at 3,355 and 2,217 kg/raceway in oxygenated and aerated raceways, respectively. Estimates of carrying capacity calculated using a fish loading (Ld) equation were also significantly different (P < 0.001) at 1,530 and 990 kg for oxygenated and aerated raceways, respectively. Oxygen injection increased the cost of production by $0.20/kg, however, net present value analysis (NPV) of oxygenated and aerated raceways over 5 years at a 10% discount rate yielded estimates of $50,666.51 and $32,742.15, respectively. Oxygen injection is an effective means of increasing DO concentrations, reducing effluent solids loading, and increasing raceway carrying capacity. / Master of Science

HINTERGUND: Ziel dieser Studie war es, den Einfluss zweier in der klinischen Routine gebräuchlicher Oxygenatoren mit unterschiedlichen Membranen, bestehend aus Polymethylpenten (PMP) oder aus Polypropylen (PPL), auf die Plasmakonzentration von Sevofluran während der extrakorporalen Zirkulation zu untersuchen. Es sollte geprüft werden, ob mittels der PMP-Membran vs. der PPL-Membran eine klinisch relevante Blutplasmakonzentration von vor dem Start der extrakorporalen Zirkulation appliziertem Sevofluran während des gesamten Zeitraums der extrakorporalen Zirkulation erhalten bleibt ohne eine zusätzliche Einspeisung des volatilen Anästhetikums über einen Vapor in den Frischgasfluss des Oxygenators vorzunehmen. METHODIK: Zwanzig Patienten, welche sich einer elektiven koronaren Bypassoperation unterzogen, wurden randomisiert einer der beiden Gruppen mit unterschiedlichem Membranoxygenator zugeordnet. Die Konzentrationen von Sevofluran wurden während der Operation im Plasma der Patienten und am Oygenatorgasauslass der Herz-Lungen-Maschine gemessen. Es wurde ermittelt, wie hoch der Verbrauch von additiv intravenös verabreichten Anästhetika in der jeweiligen Gruppe war, um eine adäquate Narkosetiefe aufrecht zu erhalten. ERGEBNISSE: Der Verlust von Sevofluran war signifikant geringer wenn ein PMP-Membranoxygenator im Vergleich zu einem PPL-Membranoxygenator verwendet wurde. Die Plasmakonzentration von Sevofluran zeigte vor Beginn (PPL 1.15-4.84 (2.49) vs. PMP 1.29-3.97 (3.97) μl×100 ml^-1, p=0.62) und fünf Minuten nach dem Start der extrakorporalen Zirkulation (PPL 0.72-2.32 (1.42) vs. PMP 0.98-2.29 (1.68) µl x 100 ml^-1, p=0.31) keinen signifikanten Unterschied zwischen den beiden Oxygenatoren. Zehn Minuten nach Beginn der extrakorporalen Zirkulation war jedoch die Sevofluranplasmakonzentration in der Patientengruppe mit PPL-Membranoxygenator im Vergleich zu der PMP-Oxygenator-Gruppe signifikant gefallen (PPL 0.48-1.79 (0.93) vs. PMP 0.80-2.15 (1.56) μl×100 ml^-1, p=0.02). Dieser Unterschied hielt bis zehn Minuten nach Beendigung der extrakorporalen Zirkulation an. Zeitweise lag die Sevofluranplasmakonzentration in der Gruppe mit PMP-Membranoxygenator doppelt so hoch. Der Verbrauch von additiv intravenös verabreichten Anästhetika war in der Patientengruppe mit PMP-Membran signifikant geringer. FAZIT: Zusammenfassend konnte gezeigt werden, dass der Gebrauch eines PMP-Membranoxygenators im Vergleich zu einem PPL-Membranoxygenator zu einem signifikant niedrigeren Verlust von Sevofluran über die Membran führt, was in einer höheren, narkoserelevanten Sevofluranplasmakonzentration resultiert.

Over 26 million Americans suffer from pulmonary disease, resulting in more than 150,000 deaths annually. Lung transplantation remains the only definitive treatment for many patients, but has meager survival rates and only approximately 1,700 of the 2,200 patients added to the lung transplant wait list each year are transplanted. Extracorporeal gas exchangers have been used as an alternative to mechanical ventilation in acute respiratory failure and as a bridge to transplantation in chronic respiratory failure. Current gas exchangers are limited by their high resistance and low biocompatibility that lead to patient complications and device clot formation. Therefore, there exists a dire need for improved devices that can act as destination therapy. To accomplish the goal of destination therapy, this dissertation discusses three studies that were performed to pave the way. First, I examined clot formation and failure patterns of two common clinical devices (Maquet’s CardioHelp (CH) and Quadrox (Qx)) to further our understanding of their limitations with respect to long-term support. Overall, it was demonstrated that the Qx devices fail earlier and more frequently than CH devices and result in a significantly greater reduction in platelet count, and that a four-inlet approach is beneficial. Next, I determined the optimal sweep gas nitric oxide (NO) concentration that minimizes platelet binding and activation while ensuring that blood methemoglobin (metHb) concentrations increase less than 5%. Miniature artificial lungs were attached to rabbits in a pumped veno-venous configuration and run for 4 h with NO added to the sweep gases in concentrations of 0, 100, 250, and 500 ppm (n=8 ea.). 100 ppm significantly reduced the amount of platelet consumption (p < 0.05), reduced platelet activation as measured by soluble p-selectin (p < 0.05), and had negligible increases in metHb and will thus be used in future experiments. Last, I tested the Pulmonary Assist Device (PAD) which was designed for long term use as a bridge to transplantation and destination therapy. Benchtop experiments were performed that confirmed that it meets our design and performance goals. From here, we are equipped to commence with 30-day PAD testing in sheep.

<p>Respiratory distress syndrome is a major cause of mortality among pre-term and term neonatal population. To overcome the limitations of current therapies, a new form of respiratory support termed the, “Artificial Placenta” has been proposed. The Artificial Placenta is a type of oxygenator that is attached postnatally via the umbilical vessels to provide pumpless respiratory support to pre-term and term neonates. To develop this concept, our group previously reported on a novel polycarbonate membrane lung assist device (LAD). To build upon its development, the objectives of this thesis are to determine the optimal interface for gas exchange, and characterize the gas exchange properties of the LAD under ambient and oxygen rich atmosphere. Subsequently, its feasibility was determined by studying the effects of extracorporeal flow rates on cardiovascular parameters and gas exchange performance was assessed in a newborn piglet model.</p> <p>In vitro testing demonstrated that PDMS based membrane is the optimal interface for gas exchange in the LAD. In vitro testing of the LAD demonstrated 2.4 µL/min/cm² -3.8 µL/min/cm² and 6.4 µL/min/cm²- 10.1 µL/min/cm² of O₂ and CO₂ transfer respectively under ambient air and oxygen rich atmospheric conditions. Based on these results, the LAD theoretically could provide 6-11% of metabolic O₂ while eliminating 18-26% of CO₂in a newborn healthy pre term infant. Experiments in newborn piglet models achieved pumpless configuration with flow rates up to 60.9ml/kg/min without presenting decompensation. Preliminary, in vivo gas exchange experiments demonstrated O₂ transfer of 3ul/min/cm², which matches closely to in vitro data.</p> <p>A novel pumpless LAD is reported, which provides sufficient respiratory support. High extracorporeal flow rates with stable cardiovascular parameters demonstrate feasibility of the artificial placenta concept. This novel LAD could potentially serve as a rescue device when all other therapies such as nasal continuous positive airway and mechanical ventilation fail.</p> / Master of Applied Science (MASc)

Design and development / Respiratory distress syndrome (RDS) is a major cause of mortality and long-term morbidity annually affecting 14% preterm infants worldwide. Therapies have been developed to overcome this common disorder; however, limitations exist with these treatments that often lead to complications including bronchopulmonary dysplasia (BPD). One approach to address RDS is to implement a microfluidic oxygenator that serves as a respiratory support system for preterm neonates while the lungs fully develop, extra-uterine. This artificial lung assist device (LAD) is characterised by its non-invasiveness (given that it is connected via umbilical vessels), pumpless configuration, ambient air operation, portability and low priming volume. Furthermore, the LAD is formed by single oxygenator units (SOU) that are stacked in a parallel array which allows for usage on different body weights. The objective of this thesis is to design an electrochemical system to provide an in-situ enriched O2 environment able to supply 1.9 ml O2/min for use in the SOU while maintaining the simplicity of operation of the oxygenator. An inexpensive, electrically powered and compact device was envisioned allowing for a higher permeation flux to fully oxygenate the blood. Moreover, the system would be easy to manufacture, low maintenance and avoid the risk of gas contamination. In the initial work, different designs of electrolytic cells were developed and tested. The two- chamber design connected by a gel membrane showed an O2 production 10 times higher than with previous designs with 42 mg O2/L. Subsequently, different supporting electrolytes were tested. NaOH demonstrated a better performance and no degradation of the electrode in contrast to NaCl and Na2SO4. Stainless steel mesh (SSM) and graphite sheet electrodes were then tested; it was observed that stainless steel produced 3.4 times more dissolved oxygen (DO) than graphite with 28.3 mg O2/L. Experimentation with electrolysis of water showed that the DO in water reached stability 3 min after the electrolysis process was initiated measuring a change of DO of 29 mg/L at 3 A. Furthermore, an active oxygenation (AO) system was developed for in-vitro experiments via electrolysis of water and compared to a passive oxygenation (PO) system exposing blood to enriched O2 air and ambient air, respectively. It was demonstrated that AO provided 300% greater oxygenation to blood than PO. The electrolysis chamber designed for the microfluidic oxygenator allows the oxygenator to maintain its essential characteristics of simplicity and low cost while increasing the rate of oxygenation of blood. Preterm neonates suffering from RDS need an artificial lung that can partially support the oxygenation of their blood. Thus, combining the oxygenator with the O2 generation in-situ system enables a greater blood O2 uptake of 300% making possible the development of an efficient artificial lung. / Thesis / Master of Applied Science (MASc)

Made available in DSpace on 2016-01-26T12:51:32Z (GMT). No. of bitstreams: 1 renatageronfinoti_dissert.pdf: 2240331 bytes, checksum: e80f129b0db02c473d3a9c4f5162e004 (MD5) Previous issue date: 2011-11-29 / To analyze the security and efficacy of a new membrane oxygenator, the so-called OXM 1500. Methods: From May 2005 to September 2006, six sheep of Santa Inês breed (5 male and 1 female, respectively) were studied. The average body weight was 14.1 (±5) kg, body surface 0.6 (±0.2) m2 and a mean age 3.8 (±1.5) months. All of them were submitted to extracorporeal circulation (CEC) with evaluation at 10, 30, 60, 120, 180 and 240 minutes. The following values were obtained: values of oxygen transference (TTO2) and carbon dioxide transference (TTCO2), haemoglobin (HBS) and free haemoglobin (HBL), the score of platelets and of leucocytes, and heat transference rate. Results: TTO2 and TTCO2 were adequate. Lesion of the majority formed blood elements was insignificant; there no modifications in HBS, HBL levels; platelets and leucocytes decreased over time. Heat exchange was effective (p &#8804; 0.05). Conclusions: The membrane OXM 1500 infant oxygenator, tested in sheep, showed adequate oxygenation capacity, CO2 removal capacity, and small alteration of haemoglobin and platelets without significant decrease of leucocytes, as expected. Heat exchanger connected to the oxygenator was efficient in temperature changes. / Analisar a segurança e a eficácia de um novo oxigenador de membrana denominado OXM -1500. Métodos: No período de maio de 2005 a setembro de 2006, foram estudados seis ovinos da raça Santa Inês, sendo cinco machos e uma fêmea, com peso corpóreo médio de 14,1 (±5) kg, superfície corpórea de 0,6 (±0,2) m2 e idade média de 3,8 (±1,5) meses. Todos foram submetidos à circulação extracorpórea (CEC) com avaliação nos tempos 10, 30, 60, 120, 180 e 240 minutos, obtendo-se os valores de taxa de transferência de oxigênio (TTO2) e de taxa de transferência de gás carbônico (TTCO2), hemoglobina sérica (HBS) e livre (HBL), plaquetometria, leucometria e taxa de transferência de calor. Resultados: Houve adequadas TTO2 e TTCO2. A lesão da maioria dos elementos figurados do sangue foi insignificante, sem alterações dos níveis de HBS, HBL, plaquetas e o número de leucócitos diminuíram com o tempo. A troca de calor foi efetiva (p &#8804; 0,05). Conclusão: O oxigenador de membrana infantil OXM-1500, testado em ovinos, mostrou-se com capacidade adequada de oxigenação, remoção de gás carbônico e pequena alteração da hemoglobina e plaquetas, com diminuição do número de leucócitos de forma esperada. O trocador de calor acoplado ao oxigenador foi eficaz nas variações de temperatura.