One of the principal challenges in artificial lung technology has been the ability to provide levels of oxygen and carbon dioxide exchange that rival those of the natural human lung, while mitigating the deleterious interaction between blood and the surface of the synthetic gas exchange membrane. This interaction is exacerbated by the large oxygenator surface area required to achieve sufficient levels of gas transfer. In an effort to address this challenge, microfluidics-based artificial lung technologies comprising stacked microchannel networks have been explored by several groups. Here we report the design, fabrication and initial testing of a parallel plate multilayered silicone-based microfluidic construct containing ultrathin gas exchange membranes, aimed at maximizing gas transfer efficiency while minimizing membrane-blood contact area. The device comprises a branched microvascular network that provides controlled wall shear stress and uniform blood flow, and is designed to minimize blood damage, thrombosis and inflammatory responses seen in current oxygenators. Initial testing indicates that flow distribution through the multilayer structure is uniform and that the thin membrane can withstand pressures equivalent to those expected during operation. Oxygen transfer using phosphate buffered saline as the carrier fluid has also been assessed, demonstrating a sharp increase in oxygen transfer as membrane thickness is reduced, consistent with the expected values of oxygen permeance for thin silicone membranes.

A microfluidic respiratory assist device with high gas permeance for artificial lung applications.

We have utilized soft lithography techniques to create three-dimensional arrays of blood microchannels and gas pathways in poly(dimethylsiloxane) (PDMS) that approach the microvascular scale of the natural lung. The blood microchannels were lined with endothelial cells in an effort to provide a non-thrombogenic surface that might ultimately reduce the need for systemic anticoagulation. A novel design and fabrication method were developed to create prototype modules for gas permeance and cell culture testing. The gas permeance modules contained 6 layers, four gas and two blood, while the modules for cell culture testing contained two layers of blood channels. The gas permeance of the modules was examined and maximum values of 9.16 × 10−6 and 3.55 × 10−5 mL/s/cm2/cmHg, for O2 and CO2 respectively, were obtained. Finally, endothelial cells were seeded and dynamically cultured in prototype cell culture modules. Confluent and viable cell monolayers were achieved after 10 days of perfusion.

Towards microfabricated biohybrid artificial lung modules for chronic respiratory support.

Assisted venous drainage presents the risk of undetected air microembolism.

Characterization of membrane blood oxygenation devices using computational fluid dynamics

Importance of the field: Pharmacokinetic–pharmacodynamic (PK-PD) modeling enables quantitative prediction of the dose–response relationship. Recent advances in microscale technology enabled researchers to create in vitro systems that mimic biological systems more closely. Combination of mathematical modeling and microscale technology offers the possibility of faster, cheaper and more accurate prediction of the drug's effect with a reduced need for animal or human subjects.Areas covered in this review: This article discusses combining in vitro microscale systems and PK-PD models for improved prediction of drug's efficacy and toxicity. First, we describe the concept of PK-PD modeling and its applications. Different classes of PK-PD models are described. Microscale technology offers an opportunity for building physical systems that mimic PK-PD models. Recent progress in this approach during the last decade is summarized.What the reader will gain: This article is intended to review how microscale technology c...

Integration of in silico and in vitro platforms for pharmacokinetic-pharmacodynamic modeling.

An artificial lung is used during cardiopulmonary bypass to oxygenate blood and control blood temperature. The oxygen transfer rate-flow rate characteristics of three hollow fiber membrane artificial lungs (Sarns Turbo 440, Cobe Optima, Dideco Compactflo) were determined in vitro to characterize design features. Results are presented as a unique dimensionless relationship between Sherwood number, NSh (ratio of convective to diffusive mass transfer), Schmidt number, NSc (ratio of momentum to diffusive transport), and Reynolds number, NRe (ratio of inertial to viscous forces). This relationship is a function of device porosity, epsilon, and characteristic device length, xi, defined as the ratio of the mean blood path and manifold length: Nsh/NSc(1/3) x xi(1/2) = phi x (epsilon(1/m) x NRe)(m) where phi = 0.26 and m = 1.00 for NPe 3,200 where NPe is the dimensionless Peclet number defined as NRe x NSc. We found good correspondence between the model predictions and in vitro blood oxygen transfer rates. We conclude that this dimensionless approach allows us (1) to compare artificial lungs independently, (2) to relate water tests to blood, and (3) to predict the oxygen transfer rate of a new artificial lung design.

Mass transfer characteristics of artificial lungs.

At present, air handling of a membrane oxygenator is generally studied by using an ultrasonic sound bubble counter. However, this is not a quantitative method and it does not give any information on where air was entrapped in the oxygenator and if it eventually was removed through the membrane for gas exchange. The study presented here gives a novel technique for the determination of the air-handling characteristics of a membrane oxygenator. The study aimed at defining not only the amount of air released by the oxygenator, but also the amount of air trapped within the oxygenator and/or removed through the gas exchange membrane. Two neonatal membrane oxygenators without the use of an arterial filter were investigated: the Polystan Microsafe and the Dideco Lilliput. Although the air trap function of both oxygenators when challenged with a bolus of air was similar, the Microsafe obtained this effect mainly by capturing the air in the heat exchanger compartment while the Lilliput did remove a large amount of air through the membrane. In conclusion, the difference in trap function was most striking during continuous infusion of air. Immediate contact with a microporous membrane, avoidance of high velocities within the oxygenator, pressure drop, transit time and construction of the fibre mat all contribute to the air-handling characteristics of a membrane oxygenator.

Can an oxygenator design potentially contribute to air embolism in cardiopulmonary bypass? A novel method for the determination of the air removal capabilities of neonatal membrane oxygenators:

An artificial lung is used during cardiopulmonary bypass to oxygenate blood and to control blood temperature. The pressure drop-flow rate characteristics of the membrane compartment in three hollow fiber membrane oxygenators were determined in vitro to characterize design features. Results are presented in a unique dimensionless relationship between Euler number, N Eu (ratio of pressure drop to kinetic energy), and Reynolds number, N Re (ratio of inertial to viscous forces), and are a function of the device porosity, e, and a characteristic device length, ξ, defined as the ratio of the mean blood path and manifold length: N Eu .ξ/e 2 = α + β/N Re .e.(1-e) This dimensionless approach allows us (1) to compare oxygenators independently, and (2) to relate water tests to blood.

Peter Dierickx

Papers

Mass transfer characteristics of artificial lungs.

Can an oxygenator design potentially contribute to air embolism in cardiopulmonary bypass? A novel method for the determination of the air removal capabilities of neonatal membrane oxygenators:

Hydrodynamic characteristics of artificial lungs.

A numerical model for blood flow through hollow fiber banks.

Towards a pressure volume controlled physical model of the cardiovascular system