Understanding blood oxygenation in a microfluidic meander double side membrane contactor

Lung disease is one of the most important causes of high morbidity in preterm infants. In this work, we study a simple and easy to fabricate microfluidic device that demonstrates a great potential for blood oxygenation. A meander type architecture with double side vertical membrane arrangement has been selected as reference model to investigate the oxygenation process. The design criteria for the fabricated devices has been to maximize the oxygen saturation level while ensuring the physiological blood flow in order to avoid thrombus formation and channel blockage during operation. A mathematical model for the oxygen transfer has been developed and validated by the experimental study. The obtained results demonstrate that blood was successfully oxygenated up to approximately 98% of O-2 saturation and that the oxygen transfer rate at 1 mL/min blood flow rate was approximately 92 mL/minm(2). Finally, a sensitivity analysis of the key parameters, i.e. size of the channel, oxygen concentration in the gas phase and oxygen permeation properties of the membrane, is carried out to discuss the performance limits and to settle the guidelines for future developments.The authors would like to acknowledge the financial support from the Government of Aragón and the Education, Audiovisual and Culture Executive Agency (EU-EACEA) within the EUDIME - 'Erasmus Mundus Doctorate in Membrane Engineering' program (FPA 2011-0014, SGA 2012-1719, http://eudime.unical.it). CIBER-BBN is an initiative funded by the VI National R&D&i Plan 2008-2011 financed by the Instituto de Salud Carlos III with the assistance of the European Regional Development Fund. Authors acknowledge the LMA-INA for offering access to their instruments and expertise

Silicon Membranes for Extracorporeal Membrane Oxygenation (ECMO)

In cases of severe lung or heart failure, extracorporeal membrane oxygenation (ECMO) is a life-saving therapy in which a patient’s blood is passed into a circuit outside of their body to provide respiratory support. The circuit’s main component is the membrane oxygenator that drives oxygen into the blood from a sweep gas source and removes excess carbon dioxide from the blood. At present, clinical use of ECMO is limited by its high risk profile, owing to two intertwined risks: thrombosis from the large circuit, and bleeding from the anticoagulation needed to prevent thrombosis. Improvements to the gas exchange efficiency and hemocompatibility of the oxygenator could enable the development of a longer-term supportive ECMO therapy, intended as a bridge-to-transplant or destination therapy for chronic lung failure. Here we describe a novel blood oxygenator concept based on parallel plate silicon membranes developed for high precision geometry, mechanical rigidity, and high efficiency membrane transport. Using these membranes, we create blood oxygenator prototypes consisting of arrays of silicon membranes, and endeavor to improve the efficiency and hemocompatibility of this concept.First, multiple types of silicon membranes were evaluated systematically for mechanical rigidity and oxygen exchange efficiency, indicators of suitability for a future oxygenator. The combination of a silicon micropore membrane (SµM) and a 5 µm-thick polydimethylsiloxane (PDMS) layer maximized both qualities, withstanding over 260 cmHg of applied pressure and producing 0.03 mL/min of O2 flux. These membranes were then assembled into prototype flow cells, and tested for in vitro and in vivo oxygenation, successfully yielding an oxygen permeability of 1.92 ± 1.04 ml O2 STP/min/m2/cmHg. From this benchmark, we then attempted to optimize the surface hemocompatibility of the Si-PDMS composite through application of multiple polyethylene glycol (PEG)-based coatings. Although successful application of PEG to the surfaces was demonstrated, none of the coatings appeared to reduce protein adhesion to the SµM -PDMS membranes. Finally, we inserted turbulence-inducing spacer meshes into the channels of the SµM-PDMS prototypes to disrupt the transport boundary layer adjacent to the membranes, with the goal of substantially improving oxygenation. Though a threefold increase in oxygen flux was observed in vitro with the spacer meshes, the disruptive turbulence resulted in thrombosis and channel occlusion within the channels despite heavy anticoagulation of the blood. In summary, the work in this dissertation demonstrates the successful construction and testing of SµM-PDMS oxygenator prototypes, laying the foundation for future work to optimize this concept and create a large-scale blood oxygenator that can expand the clinical use of this life-saving therapy

On the improvement of alveolar-like microfluidic devices for efficient blood oxygenation

In this work, we study alveolar-like microfluidic devices with a horizontal membrane arrangement that demonstrate a great potential as small-scale blood oxygenator. The design criteria for the fabricated devices were to maximize the oxygen saturation level and minimize liquid chamber volume while ensuring the physiological blood flow in order to avoid thrombus formation and channel blockage during operation. The liquid chamber architecture was iteratively modified upon analysis of the fluid dynamics by computer modelling. Accordingly, two alveolar type architectures were fabricated, Alveolar Design 1 (AD1) and Alveolar Design 2 (AD2), and evaluated for oxygenation of sheep blood. The attained O2 transfer rate at 1 mL/min of blood flow rate for both devices was rather similar: 123 mL·min-1 ·m-2 and 127 mL·min-1 ·m-2 for AD1 and AD2 microfluidic devices, respectively. Among the studied, AD2 type geometry would lead to the lowest pressure drop and shear stress value upon implementation in a scaled microfluidic artificial lung (µAL) to satisfy oxygenation requirements of a 2.0 kg neonate.Government of Aragon and the Education, Audiovisual and Culture Executive Agency (EU-EACEA) within the EUDIME – ‘Erasmus Mundus Doctorate in Membrane Engineering’ program (FPA 2011-0014, SGA 2012-1719, http://eudime.unical.it). CIBER-BBN is an initiative funded by the VI National R&D&i Plan 2008–2011 financed by the Instituto de Salud Carlos III with the assistance of the European Regional Development Fund

Membrane integration in biomedical microdevices

The present work has been performed under the Erasmus Mundus Doctorate in Membrane Engineering (EUDIME) program. The home institute was the Chemical and Environmental Engineering Department at the University of Zaragoza, within the Nanostructured Films and Particles (NFP) group. The NFP is a member of the Nanoscience Institute of Aragon (INA). Two host universities were: Faculdade de Ciências e Tecnologia at the University Nova de Lisboa (Portugal) and Mesoscale Chemical Systems group at the University of Twente (The Netherlands). This research has been carried out for approximately 4 years (2013-2017) and it was part of the EUDIME (FPA 2011-0014, SGA 2012-1719), which was funded by the European Union. The target of the research presented in this thesis is a design, development and fabrication of a microfluidic device with integrated membrane in the form of a membrane contactor for various biological applications. The microfluidic devices are fabricated and tested for oxygenation of blood and separation of anaesthetic gas. In the first part of the work, the microfluidic system for blood oxygenation, so called lungon- a-chip, is introduced. In such system, one chamber is devoted to pure oxygen, and the other chamber is designed for blood and they are separated by a dense permeable membrane. Computer modelling is performed in order to design the liquid chamber with homogenous liquid flow, low pressure drop of the system and low shear stress without compensation of high oxygenation. Two different microdevice geometries are proposed: alveolar and meander type design with vertical membrane arrangement. Fabricated devices as well as integrated membranes are made of PDMS by soft-lithography and their surface is modified in order to make them more hydrophilic. The experiments of blood oxygenation are performed and the oxygen concentration is measured by an oximeter electrode and compared to the mathematically modelled values. The sensitivity analysis of the key parameters and the possible improvements of the proposed architectures based on the mathematical simulations are presented as well. The second part of the thesis, introduces the concept of an alveolar microfluidic device as gas-ionic liquid micro-contactor for removal of CO2 from anaesthesia gas, containing Xe. The working principle involves the transport of CO2 through a flat PDMS membrane followed by the capture and enzymatic bioconversion in the ionic liquid solvent. As proof of concept demonstration, simple gas permeability experiments are performed followed by the experiments with ionic liquid and ionic liquid with the enzyme. Finally, an alternative concept of a silicon/glass microfluidic device with an integrated membrane in the form of a fractal geometry with nanonozzles as pores at the vertices of the third-level octahedra for the controlled addition of gaseous species is introduced. Fractal geometry, that is a three-dimensional repetitive unit, is fabricated by a combination of anisotropic etching of silicon and corner lithography. As a proof of concept, simple gas permeation experiments are performed, and the achieved results reveal the potentialities of the chip for high temperature gas-liquid contactors

Gas Transfer in Cellularized Collagen-Membrane Gas Exchange Devices

Chronic lower respiratory disease is highly prevalent in the United States, and there remains a need for alternatives to lung transplant for patients who progress to end-stage lung disease. Portable or implantable gas oxygenators based on microfluidic technologies can address this need, provided they operate both efficiently and biocompatibly. Incorporating biomimetic materials into such devices can help replicate native gas exchange function and additionally support cellular components. In this work, we have developed microfluidic devices that enable blood gas exchange across ultra-thin collagen membranes (as thin as 2 μm). Endothelial, stromal, and parenchymal cells readily adhere to these membranes, and long-term culture with cellular components results in remodeling, reflected by reduced membrane thickness. Functionally, acellular collagen-membrane lung devices can mediate effective gas exchange up to ~288 mL/min/m[superscript 2] of oxygen and ~685 mL/min/m[superscript 2] of carbon dioxide, approaching the gas exchange efficiency noted in the native lung. Testing several configurations of lung devices to explore various physical parameters of the device design, we concluded that thinner membranes and longer gas exchange distances result in improved hemoglobin saturation and increases in pO[subscript 2]. However, in the design space tested, these effects are relatively small compared to the improvement in overall oxygen and carbon dioxide transfer by increasing the blood flow rate. Finally, devices cultured with endothelial and parenchymal cells achieved similar gas exchange rates compared with acellular devices. Biomimetic blood oxygenator design opens the possibility of creating portable or implantable microfluidic devices that achieve efficient gas transfer while also maintaining physiologic conditions.National Institute of General Medical Sciences (U.S.) (MSTP T32GM007753

Frontiers in microfluidics, a teaching resource review

This is a literature teaching resource review for biologically inspired microfluidics courses or exploring the diverse applications of microfluidics. The structure is around key papers and model organisms. While courses gradually change over time, a focus remains on understanding how microfluidics has developed as well as what it can and cannot do for researchers. As a primary starting point, we cover micro-fluid mechanics principles and microfabrication of devices. A variety of applications are discussed using model prokaryotic and eukaryotic organisms from the set of bacteria (Escherichia coli), trypanosomes (Trypanosoma brucei), yeast (Saccharomyces cerevisiae), slime molds (Physarum polycephalum), worms (Caenorhabditis elegans), flies (Drosophila melangoster), plants (Arabidopsis thaliana), and mouse immune cells (Mus musculus). Other engineering and biochemical methods discussed include biomimetics, organ on a chip, inkjet, droplet microfluidics, biotic games, and diagnostics. While we have not yet reached the end-all lab on a chip, microfluidics can still be used effectively for specific applications

Micro/nanofluidic and lab-on-a-chip devices for biomedical applications

Micro/Nanofluidic and lab-on-a-chip devices have been increasingly used in biomedical research [1]. Because of their adaptability, feasibility, and cost-efficiency, these devices can revolutionize the future of preclinical technologies. Furthermore, they allow insights into the performance and toxic effects of responsive drug delivery nanocarriers to be obtained, which consequently allow the shortcomings of two/three-dimensional static cultures and animal testing to be overcome and help to reduce drug development costs and time [2–4]. With the constant advancements in biomedical technology, the development of enhanced microfluidic devices has accelerated, and numerous models have been reported. Given the multidisciplinary of this Special Issue (SI), papers on different subjects were published making a total of 14 contributions, 10 original research papers, and 4 review papers. The review paper of Ko et al. [1] provides a comprehensive overview of the significant advancements in engineered organ-on-a-chip research in a general way while in the review presented by Kanabekova and colleagues [2], a thorough analysis of microphysiological platforms used for modeling liver diseases can be found. To get a summary of the numerical models of microfluidic organ-on-a-chip devices developed in recent years, the review presented by Carvalho et al. [5] can be read. On the other hand, Maia et al. [6] report a systematic review of the diagnosis methods developed for COVID-19, providing an overview of the advancements made since the start of the pandemic. In the following, a brief summary of the research papers published in this SI will be presented, with organs-on-a-chip, microfluidic devices for detection, and device optimization having been identified as the main topics.info:eu-repo/semantics/publishedVersio

Cells and Organs on Chip—A Revolutionary Platform for Biomedicine

Lab‐on‐a‐chip (LOC) and microfluidics are important technologies with numerous applications from drug delivery to tissue engineering. LOC integrates fluidic and electronic components on a single chip and becomes very attractive due to the possibility of their state‐of‐art implementation in personalized devices for the point‐of‐care treatments. Microfluidics is the technique that deals with small (10-9 to 10-18 L) amounts of fluids, using channels with dimensions of 10 to 100 μm. These LOC and microfluidics devices enable the development of next‐generation portable and implantable bioelectronics devices. Superior chip‐based technologies are emerging with the advances in microfluidics and motivating various chip‐based methods for rapid low‐cost analysis as compared to traditional laboratory method.An organ‐on‐chip (OOC) is on‐chip cell culture device created with microfabrication techniques and contains continuously perfused chambers inhabited by living cells that simulate tissue‐ and organ‐level physiology. In vitro models of cells, tissues and organ based on LOC devices are a major breakthrough for research in biologic systems and mechanisms. The recapitulations of cellular events in OOC devices provide them an edge over two‐dimensional (2D) and three‐dimensional (3D) cultures and open a gateway for their newer applications in biomedicine such as tissue engineering, drug discovery and disease modeling. In this chapter, the advancement and potential applications of OOC devices are discussed