An Integrated Array of Microfluidic Oxygenators as a Neonatal Lung Assist Device: In Vitro Characterization and In Vivo Demonstration

Abstract

A miniaturized oxygenator device that is perfused like an artificial placenta via the umbilical vessels may have significant potential to save the lives of newborns with respiratory insufficiency. Recently we presented the concept of an integrated modular lung assist device (LAD) that consists of stacked microfluidic single oxygenator units (SOUs) and demonstrated the technical details and operation of SOU prototypes. In this article, we present a LAD prototype that is designed to accommodate the different needs of term and preterm infants by permitting changing of the number of parallel-stacked microfluidic SOUs according to the actual body weight. The SOUs are made of polydimethylsiloxane, arranged in parallel, and connected though 3D-printed polymeric interconnects to form the LAD. The flow characteristics and the gas exchange properties were tested in vitro using human blood. We found that the pressure drop of the LAD increased linearly with flow rate. Gas exchange rates of 2.4-3.8 μL/min/cm(2) (0.3-0.5 mL/kg/min) and 6.4-10.1 μL/min/cm(2) (0.8-1.3 mL/kg/min) for O2 and CO2 , respectively, were achieved. We also investigated protein adsorption to provide preliminary information on the need for application of anticoagulant coating of LAD materials. Albumin adsorption, as measured by gold staining, showed that surface uptake was evenly distributed and occurred at the monolayer level (>0.2 μg/cm(2) ). Finally, we also tested the LAD under in vivo conditions using a newborn piglet model (body weight 1.65-2.0 kg). First, the effect of an arteriovenous bypass via a carotid artery-to-jugular vein shortcut on heart rate and blood pressure was investigated. Heart rate and mean arterial blood pressure remained stable for extracorporeal flow rates of up to 61 mL/kg/min (101 mL/min). Next, the LAD was connected to umbilical vessels (maximum flow rate of 24 mL/min [10.4 mL/kg/min]), and O2 gas exchange was measured under hypoxic conditions (Fi O2 = 0.15) and was found to be 3.0 μL/min/cm(2) . These results are encouraging and support the feasibility of an artificial placental design for an LAD.

Evolution of Gas Permeable Membranes for Extracorporeal Membrane Oxygenation

“…As the evolution of extracorporeal membrane oxygenation continues, it is becoming possible to overcome past limitations of blood‐side resistance to gas exchange. PDMS thin films can be produced at less than 20 μm thickness and greatly surpass the low permeability of early polymer membranes , and modern fabrication techniques can reliably produce defect‐free membranes that minimize the risk of gas embolism . The stacked parallel plate blood channels used in the first clinical membrane oxygenators can now be reproduced using soft lithography to yield sub‐10 μm channel heights , significantly reducing plasma boundary layers.…”

“…Meanwhile, Rochow et al used PDMS to define the blood channels, testing both 6 μm thick microporous polycarbonate membranes or 20 μm thick PDMS for gas exchange. This enabled blood channels with 80 μm height and 500 μm width in a stackable design . The high gas permeability of the thin PDMS membranes enabled the use of ambient air as a sweep gas, which could make dedicated pure oxygen supplies and gas mixers unnecessary.…”

Development of a biomimetic microfluidic oxygen transfer device

“…24–25 Most reports of microfluidic oxygenators have been limited to blood flow rates of 5 mL/min or less; 17, 18, 21, 26–29 one has reported blood flow rates as high as 40 mL/min, but the oxygen content of the blood appeared to drop below commercial oxygenator oxygen transfer levels (5 volume percent oxygen relative to the total blood volume) above 10 mL/min blood flow rates. 30 Another recent report from Rieper et al has demonstrated blood oxygen transfer at blood flow rates as high as 60 mL/min, clearly a major advance over most of the microfluidic literature [T. Rieper, C. Muller and H. Reinecke, However, this report does not describe an approach to ensure that blood flow patterns in the channel structures are designed in a manner to avoid sharp corners and non-physiologic and potentially deleterious flow paths. This highlights the need to develop strategies for larger scale devices while retaining the advantages of microfluidic devices in achieving and maintaining blood stability in the flow networks.…”

Translating advances in organ‐on‐a‐chip technology for supporting organs

“…However, its application was limited by the risk of intraventricular hemorrhage that may follow full body anticoagulation, which is usually required in extracorporeal oxygenation. 84 One method to improve hematocompatibility and prevent clotting is the use of ECs. 81 The study provides new ideas and foundations for the development of cell-based organ-on-a-chip systems in a similar way, whether as a respiratory assist device or in other organ optimization device, a concept proposed in the present article.…”