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)

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)

Preterm infants are at risk for respiratory distress syndrome (RDS) due to immature lungs, leading to notable neonatal mortality. About 10% of US births are premature. While mechanical ventilation is a common RDS treatment, it can cause complications. If it fails, extracorporeal membrane oxygenation (ECMO) is employed, but standard ECMO devices are not suited for preterm babies. The limitations of hollow fiber membrane oxygenators used in ECMO have spurred interest in an artificial placenta that connects to the umbilical cord and supports lung growth. Microfluidic blood oxygenators, with their biomimetic designs, have being explored for this purpose. This thesis advances microfabrication techniques for Lung Assist Devices (LADs), focusing on two main objectives: I. Improving Throughput for Elevated Blood Flow Rates: This section delves into refining Microfluidic Blood Oxygenators (MBOs) to accommodate greater blood flow rates. By combining parallel units, we increased throughput and optimized LAD designs. Newly designed MBOs, with an expanded gas exchange surface area, can manage blood flow rates up to 60 mL/min. Using these enhanced MBOs, we constructed a novel LAD achieving superior oxygenation compared to predecessors. Our in vitro tests confirmed that this LAD can sustain blood flow rates of up to 150 ml/min, elevating oxygen saturation by approximately 20%—equivalent to an oxygen transfer of 7.48 mL/min, a leading figure for AP-type devices. II. Hierarchically Designed Microchannels: The second objective revolves around developing microchannels with a hierarchical layout to mitigate stagnation and high shear stress regions. Traditional photolithography poses challenges at channel intersections, inducing clotting risks. We pioneered alternative microfabrication methods, yielding diverse microchannels and intricate hierarchical designs that emulate natural vascular networks devoid of dead zones. These advancements have propelled the microfabrication domain for artificial placenta-like LADs. Utilizing our method, we produced channels varying from hundreds to a few microns in height with a single exposure and an opal diffuser. Thin membranes (~60 µm top and ~45 µm bottom) were amalgamated, culminating in a total depth of about 200 µm. Such oxygenators excel in oxygenating blood even at intense flow rates of up to 15 mL/min per unit. Leveraging these hierarchically designed MBOs, we crafted a LAD supporting a flow rate of 100 mL/min, offering an oxygen transfer of 5.21 mL/min. Both LADs developed in this research proficiently support premature neonates weighing up to 2 kg. Notably, the priming volume of the LAD using the enhanced MBOs has been substantially minimized, underscoring its advancements over earlier models. Realizing these objectives can transform neonatal care, addressing respiratory challenges in premature neonates and bolstering their chances for a healthier life. / Thesis / Master of Science (MSc)

<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)