Patent Description:
Oxygenators can be used as lung assist devices to supplement the oxygenation performed by damaged or diseased lungs. Standard configurations for blood oxygenators are configured to maximize the amount of oxygen transferred to the blood without consideration for maximizing the removal of carbon dioxide within the blood.

<CIT> describes a microfluidic device including a first layer defining a first channel therein. The microfluidic device also includes a second layer defining a second channel therein. The second channel overlaps the first channel along a substantial portion of the length of the first channel. A membrane separates the first channel from the second channel.

<CIT> describes a microfluidic oxygenation device including a first polymer layer defining a first oxygen flow channel. The device also includes a second polymer layer defining a first blood flow channel. The first blood flow channel overlaps the first oxygen flow channel, and the two channels are separated by a permeable membrane that allows communication between the channels at overlapping portions.

A microfluidic flow device having the features of claim <NUM> is the object of the invention. The present disclosure discusses a system and method that includes a microfluidic device that can be used in either an extracorporeal or implantable configuration. The device supports efficient and safe removal of carbon dioxide from the blood of patients suffering from respiratory disease or injury. In some implementations, the microfluidic device is configured to remove clinically relevant rates of carbon dioxide from the blood as the blood flows through the microfluidic device at low blood flow rates. The low blood flow rates can increase safety and blood health. The increased safety can enable the device to be used with patients suffering from acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), and other diseases that lead to hypercapnia.

According to one aspect of the disclosure a microfluidic flow device includes a first layer. The first layer includes a plurality of gas channels. The device includes a distensible membrane coupled with the first layer. The device includes a plurality of support structures embedded in the distensible membrane, the plurality of support structures distributed evenly along the length of the plurality of gas channels. The device includes a second layer. The second layer includes a plurality of blood channels. The second layer is coupled with the distensible membrane. The plurality of blood channels is separated from the plurality of gas channels by the distensible membrane. The plurality of blood channels includes a cross-sectional area defined in the second layer. A shape of the cross-sectional area oscillates along a length of the plurality of blood channels by pressurizing, with a gas, the plurality of gas channels to distend the distensible membrane.

The device can also include an inlet manifold that is coupled with an inlet of each of the plurality of blood channels. The device can include an outlet manifold that is coupled with an outlet of each of the plurality of blood channels. The plurality of gas channels can include an open inlet end and an open outlet end.

The device can include a pressure vessel. The pressure vessel can house the first layer and the second layer. The pressure vessel can be configured to flow a gas into an open end of each of the plurality of gas channels. The shape of the cross-sectional area can be controlled by a degree of distension of the distensible membrane. The distensible membrane can be configured to deform a distance responsive to a gas pressure of a gas in the plurality of gas channels.

The plurality of support structures embedded in the membrane can include a plurality of ribs supporting the distensible membrane. The distensible membrane can deflect toward a central axis of the blood channel between each of the plurality of ribs.

The plurality of ribs can be distributed evenly along the length of the plurality of gas channels. In other implementations, the plurality of ribs can be distributed unevenly along the length of the plurality of gas channels. The distensible membrane can include the plurality of ribs.

According to another aspect of the disclosure, a method which does not form part of the claimed invention can include providing a microfluidic device. The device can include a first layer. The first layer can include a plurality of gas channels. The device can include a distensible membrane coupled with the first layer. The device can include a second layer. The second layer can include a plurality of blood channels. The second layer can be coupled with the distensible membrane. The plurality of blood channels can be separated from the plurality of gas channels by the distensible membrane. The plurality of blood channels can have a cross-sectional area defined in the second layer. The method can include flowing blood through into an inlet of each of the plurality of blood channels. The method can include oscillating a shape of the cross-sectional area along a length of the plurality of blood channels by pressurizing, with a gas, the plurality of gas channels to distend the distensible membrane. The method can include collecting the blood from an outlet of each of the plurality of channels.

The method can also include flowing the blood through an inlet manifold coupled with the inlet of each of the plurality of blood channels. The method can include collecting, from an outlet manifold coupled with the outlet of each of the plurality of blood channels, the blood. The method can include flowing the gas into an open inlet end of the plurality of gas channels.

In some implementations, the method can include pressurizing a pressure vessel housing the microfluidic device. The method can include flowing the gas through the plurality of gas channels with a pulsatile flow. The shape of the cross-sectional area is controlled by a degree of distension of the distensible membrane.

The distensible membrane is configured to deform a distance responsive to a gas pressure of the gas in the plurality of gas channels. The method can include distending the distensible membrane between a plurality of ribs. The plurality of ribs can be distributed evenly along the length of the plurality of gas channels. The ribs are distributed unevenly along the length of the plurality of gas channels. The distensible membrane can include the plurality of ribs. The gas can be air.

The skilled artisan will understand that the figures, described herein, are for illustration purposes only. It is to be understood that in some instances various aspects of the described implementations may be shown exaggerated or enlarged to facilitate an understanding of the described implementations. In the drawings, like reference characters generally refer to like features, functionally similar and/or structurally similar elements throughout the various drawings. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the teachings. The system and method may be better understood from the following illustrative description with reference to the following drawings in which:.

The various concepts introduced above and discussed in greater detail below may be implemented in any of numerous ways, as the described concepts are not limited to any particular manner of implementation. Examples of specific implementations and applications are provided primarily for illustrative purposes.

As an overview, this present disclosure describes a microfluidic device which can have a biomimetic flow design. The design supports high efficiency carbon dioxide removal from the blood at very low blood flow rates. Enhanced safety can arise from the reduced reliance on anticoagulants and the reduction in clotting and bleeding relative to current approaches.

The high transfer rates of blood gases are achieved by utilizing thin, gas-permeable membranes, by controlling the gas flow rate and gas composition through the microfluidic device, by controlling the blood channel design to enhance mixing and reduce the build-up of boundary layers, or any combination thereof.

Unlike oxygenation, carbon dioxide removal at clinically relevant rates can be achieved at very low blood flow rates. For example, in some implementations, the present device can achieve the removal of between about <NUM>/min and about <NUM>/min of carbon dioxide at blood flow rates of about <NUM>/min and about <NUM>/min. In contrast, meaningful oxygenation in an adult human may require blood flow rates of several liters per minute.

<FIG> illustrates an example system <NUM> that includes a microfluidic device <NUM> for the extraction of carbon dioxide from blood. As an overview, the system <NUM> includes a microfluidic device <NUM> that is housed within a pressure vessel <NUM>. Fluid pump <NUM> flows a fluid (e.g., blood) through the microfluidic device <NUM>. A gas pump <NUM> flows gas into the pressure vessel <NUM>. One or more pressure regulators <NUM> regulate the pressure within the pressure vessel <NUM>. The pumps <NUM> and <NUM> are controlled by a controller <NUM>, which, in some implementations, receives pressure readings about the pressure vessel <NUM> from the pressure regulator <NUM>. In other implementations, the gas pump <NUM> provides the gas to the gas channels of the microfluidic device <NUM> through a manifold, and the microfluidic device <NUM> is not housed within the pressure vessel <NUM>.

In general, the microfluidic device <NUM> includes a plurality of polymer substrate layers. Each of the polymer substrate layers includes a plurality of gas channels and a plurality of fluid channels, which can also be referred to as blood channels. In some implementations, in each polymer substrate layer, the gas channels and fluid channels alternate such that each of the gas channels and each of the fluid channels (except for the channels on the edges of the polymer substrate layers) are between two fluid channels and two gas channels, respectively. The microfluidic device <NUM> is also configured such that each of the fluid channels of a first polymer substrate layer vertically aligns with and overlaps with a gas channel of a second polymer substrate layer. Similarly, each of the gas channels of the first polymer substrate layer vertically aligns with and overlaps a fluid channel of the second polymer substrate layer. This alignment configuration is referred to as a checkerboard configuration. In the checkerboard configuration, gas channels surround (e.g., are above, below, and on both sides) each interior fluid channel, and fluid channels surround each interior gas channel. In some implementations, the gas channels and fluid channels alternate according to a more complex alternation pattern without departing from the scope of the disclosure.

In other implementations, each of the channels in a given polymer substrate layer include the same type of channel. For example, gas layers that include only gas channels and fluid layers that include only fluid channels. In these implementations, the microfluidic device <NUM> includes stacked, alternating gas layers and fluid layers. Each of the layers is separated by a gas permeable membrane.

The microfluidic device <NUM> of the system can be housed within a pressure vessel <NUM>. To reduce the complexity of a manifold system that routes gas to each of the gas channels of the microfluidic device <NUM>, vents that supply gas to the gas channels of the microfluidic device <NUM> are open and exposed to the ambient, atmospheric conditions created within the pressure vessel <NUM>. In these implementations, the gas channels do not require a complex manifold for the distribution of gas to each of the gas channels. In these implementations, only the fluid channels of the microfluidic device <NUM> are coupled to a manifold. The pressure vessel <NUM> is a pressure resistant housing that includes a hard shell configured to withstand elevated pressures. The pressure vessel <NUM> is manufactured from a gas impermeable plastic, such as polycarbonate, or a metal. The controller <NUM> controls the gas pump <NUM>, which pumps gas, such as oxygen, into the pressure vessel <NUM> to pressurize the pressure vessel <NUM>. In some implementations, the pressure vessel <NUM> is pressured to between about <NUM> atm to about <NUM> atm, between about <NUM> atm and about <NUM> atm, between <NUM> atm and about <NUM> atm, or between about <NUM> atm and about <NUM> atm (<NUM> atm = <NUM>,<NUM> pascals).

The pressure vessel <NUM> of the system <NUM> includes one or more pressure regulators <NUM> to regulate the pressure within the pressure vessel <NUM> and maintain a predetermined pressure within the pressure vessel <NUM>. In some implementations, the pressure regulator <NUM> includes pressure sensors that send pressure readings to the controller <NUM> - enabling a closed loop control of the pressure within the pressure vessel <NUM>. In some implementations, the pressure regulator <NUM> is a pressure release valve that prevents build-up of pressure substantially beyond the predetermined pressure. For example, the pressure regulator <NUM> may be a pressure valve that automatically opens when the pressure within the pressure vessel <NUM> reaches <NUM> atm. In operation, carbon dioxide diffuses out of the blood (e.g., through the polymer layers) and into pressure vessel <NUM>. Venting the pressure within the pressure vessel <NUM> also enables the carbon dioxide to escape the pressure vessel <NUM>, such that carbon dioxide levels do not build up within the pressure vessel <NUM>.

The system <NUM> also includes a fluid pump <NUM> that is controlled by the controller <NUM> and configured to flow a fluid through the microfluidic device <NUM>. For example, the fluid pump <NUM> is configured to flow blood through the fluid channels of the microfluidic device <NUM>. The fluid pump <NUM> is fluidically coupled to a manifold of the microfluidic device <NUM> that distributes the fluid to each of the fluid channels of the microfluidic device <NUM>. The fluid pump <NUM> is configured to flow a fluid through the microfluidic device <NUM> at a rate of between about <NUM>/min and about <NUM>/min, between about <NUM>/min and about <NUM>/min, or between about <NUM>/min and about <NUM>/min.

In some implementations, the controller <NUM> controls, via the fluid pump <NUM> and the gas pump <NUM>, the rate of gas flow and the gas composition entering the microfluidic <NUM> to increase carbon dioxide transfer rates out of the blood. For higher carrier gas flow rates, the removal of carbon dioxide increases, up to an asymptotic value. In some implementations, the system <NUM> modulates the carbon dioxide transfer rate by altering the carrier gas flow rate flowing through the gas channels of the microfluidic device <NUM>. In some implementations, the composition of the carrier gas is substantially pure oxygen. When the carrier gas is substantially pure oxygen, the carbon dioxide transfer rate increases as the carrier gas flow rate is increased, up to an asymptotic value. This relationship is illustrated in the graph illustrated in <FIG>.

In some implementations, the system <NUM> includes a plurality of microfluidic devices <NUM>. The microfluidic devices <NUM> can be coupled together serially. Alternating microfluidic device <NUM> in the series of microfluidic device <NUM> can be configured to increase the amount of carbon dioxide transfer from the blood channels to the gas channels, with the other microfluidic device <NUM> configured to increase the amount of oxygen transferred from the gas channels to the blood channels. For example, a first microfluidic device can remove carbon dioxide from the blood and a second microfluidic device can oxygenate the blood. In some implementations, the microfluidic device described herein can be used to both oxygenate and to remove carbon dioxide from the blood flowing through the microfluidic device.

<FIG> illustrates an exploded view of an example microfluidic device <NUM> that can be used with the system <NUM> illustrated in <FIG>. The microfluidic device <NUM> includes a plurality of polymer layers <NUM>. The polymer layers <NUM> can alternate between including gas channels and blood channels. In some implementations, each of the polymer layers <NUM> can include a plurality of gas channels and a plurality of fluid channels. Neighboring polymer layers <NUM> can be separated from one another by a permeable membrane. The membrane can be a distensible membrane. The membrane can separate the gas channels in one layer from the blood channels in another layer. In some implementations, the membranes can form opposing walls of each of the gas and blood channels. For example, the floor and ceiling of each of the channels can be a membrane. In these implementations, the gas and blood channels are formed as longitudinal gaps in the polymer layers <NUM>. This can give the microfluidic device <NUM> a repeating layer pattern of polymer layer <NUM>, membrane, polymer layer <NUM>, membrane. In other implementations, the gas and blood channels are formed as trenches within polymer layers <NUM>. In these implementations, the polymer layer <NUM> can form the three walls of the channels and the membrane can form the fourth wall (e.g., the ceiling or floor). The microfluidic device <NUM> can include a repeating pattern of polymer layer <NUM>, membrane, polymer layer <NUM>. A variety of alternation patterns can be suitable for the system described herein.

The polymer layers <NUM> and membranes can be coupled together by clamping the layers together or by bonding the layers together with a glue or heat welding the layers together. Coupled together, the polymer layers <NUM> can create a separate fluid flow network and a separate gas flow network. In some implementations, the coupled polymer layers <NUM> create a fluid flow network and two separate gas flow networks.

The microfluidic device <NUM> can include a fluid inlet manifold <NUM> and a fluid outlet manifold <NUM>. Fluid, such as blood, flows to each of the fluid channels of the different polymer layers <NUM> through the fluid inlet manifold <NUM>. The fluid outlet manifold <NUM> collects the fluid as the fluid exits each of the polymer layers <NUM> (or the polymer layers <NUM> including the blood channels). The microfluidic device <NUM> includes vents <NUM>(a) and <NUM>(b) within the top layer <NUM> and bottom layer <NUM>, respectively. In some implementations, the top layer <NUM> and bottom layer <NUM> do not include gas and fluid channels, and the vents <NUM> provide the inlets to the gas channels in the top most and bottom most polymer layers. That is, the gas channels can have open inlets that are exposed to the environment external to the microfluidic device <NUM>. The vents provide access to the inlets of the gas channels to enable access to the ambient environment. The ambient environment can be the environment within the pressure vessel housing the microfluidic device <NUM>. The vent <NUM>(a) provides access to the gas channels of a first gas flow network and the vent <NUM>(b) provides access to the gas channels of a second gas flow network. In some implementations, each polymer layer <NUM> that includes gas channels can include open inlets to enable ambient gas flow directly the gas channels of the respective polymer layers <NUM>.

The inlet manifold <NUM> and the outlet manifold <NUM> can be configured to introduce and receive blood from each of the polymer layers <NUM> without causing substantial damage to the blood. For example, both the inlet manifold <NUM> and the outlet manifold <NUM> include gradual curving channels rather than right angles. In some implementations, the channels within the manifold mimic vascular channels. For example, the channels split at bifurcations. After a bifurcation, the size of the channel is reduced according to Murray's Law.

Each of the polymer layers <NUM> of microfluidic device <NUM> can be stacked upon one another such that the channels in a fist polymer layer <NUM> substantially overlap and run parallel with the channels of polymer layers <NUM> on either side of the first polymer layer <NUM>. In some implementations, the microfluidic device <NUM> includes between <NUM> and <NUM>, between <NUM> and <NUM>, or between <NUM> and <NUM> stacked polymer layers <NUM>. The polymer layers <NUM> can include between about <NUM> and about <NUM> channels, between about <NUM> and about <NUM> channels, and between about <NUM> and about <NUM> channels.

In some implementations, the polymer layers <NUM> are manufactured from Poly(DiMethylSiloxane) (PDMS) and are directly stacked upon one another without a separate membrane between each of the polymer layers <NUM>. For example, when the channels of the polymer layers <NUM> can be defined within a PDMS layer, oxygen can saturate from the gas channels and into the PDMS. The PDMS then serves as a source of oxygen for the fluid channels aligned horizontally and vertically with the gas channel. In other implementations, the polymer layers <NUM> are manufactured from thermoplastics, such as polystyrene, polycarbonate, polyimide, or cyclic olefin copolymer (COC), biodegradable polyesters, such as polycaprolactone (PCL), or soft elastomers such as polyglycerol sebacate (PGS). In these implementations, each of the polymer layers <NUM> can be separated from one another by a semi-porous membrane selected to permit diffusion of oxygen or other gas between the fluid channels and the gas channels.

<FIG> illustrates a graph of the volume percent of carbon dioxide transfer versus the carrier gas flow rate. The graph illustrates the relationship between the carbon dioxide transfer and the carrier gas flow rate for three different blood flow rates. In each experiment, the carrier gas was <NUM>% oxygen. As illustrated in the graph, the transfer efficiency reaches an asymptotic value at <NUM>/min for all three blood flow rates, with the sharpest rise occurring between about <NUM>/min and about <NUM>/min blood flow rate.

In some implementations, the carrier gas includes a reduced oxygen concentration to increase the carbon dioxide transfer rate. <FIG> illustrates a graph comparing carbon dioxide transfer using pure oxygen as the carrier gas versus air as the carrier gas. The circles illustrate the volume percent transfer of carbon dioxide with respect to different blood flow rates using air as the carrier gas, and the diamonds illustrate the volume percent transfer of carbon dioxide with respect to different blood flow rates using pure oxygen as the carrier gas. As illustrated by the graph, the volume percent transfer of carbon dioxide is enhanced for several of the blood flow rates, indicating a boost in performance obtained by using air as the carrier gas. In other implementations, the carrier gas is pure nitrogen.

As illustrated in <FIG>, carbon dioxide transfer rate is increased when the carrier gas is changed from pure oxygen to air. At some blood flow rates, the transfers are increased by as much as <NUM>%. In some implementations, air can include a mixture of gasses. Air can be, by volume, about <NUM>% oxygen, <NUM>% nitrogen, with the remaining portion being a mix of other gases. In some implementations, the air (or other gas) can be dried or humidified based on the ambient conditions prior to use in the microfluidic devices described herein. The carrier gas can be pure oxygen or contain between about <NUM>% and about <NUM>%, between about <NUM>% and about <NUM>%, between about <NUM>% and about <NUM>%, or between about <NUM>% and about <NUM>% oxygen.

In some implementations, the blood channels of the microfluidic device include mixing elements to mix the blood as the blood flows along the length of the blood channels. In some implementations, the mixing elements can also disrupt boundary layers that can form along the blood side of the membrane. The mixing elements can be incorporated into a channel wall of the microfluidic device <NUM>. The mixing elements can be included on one, two, or three walls of the channels. The mixing elements can also be included on a face of the membrane. The mixing elements can be distributed along the length of the blood flow channels. The mixing elements can mix the blood, such that blood near the floor of a channel is pushed toward the membrane. For example, under laminar flow conditions in a horizontal direction, there is little movement of the blood particles in a vertical direction. This can hinder the transfer of carbon dioxide across the membrane because the same portion of the blood remains near the membrane along the length of the channel. Under such circumstances, the amount of carbon dioxide in the blood near the membrane diminishes while the blood near the floor of the channel (e.g., the blood farthest away from the membrane) remains rich in carbon dioxide. The mixing elements push carbon dioxide rich blood towards the membrane from the floor of the blood channels.

The mixing elements can include a plurality of chevron-like mixing features disposed in a wall of the blood channels. The mixing elements can include other mixing elements such as ridges, channels, protrusions, or a combination thereof. Mixing elements formed in the membrane or walls of the blood channels can be referred to as passive mixing elements. The mixing elements can be spread along substantially the entire length of a blood channels. In other implementations, the mixing elements cover only a sub-portion of the total length of the blood channels. In yet other implementations, the mixing elements can be grouped together. For example, the blood channels can include a first type of mixing element along a first portion of the channels and then a second type of mixing element along a second portion of the channels. The distribution of the mixing elements can be equal along the length of the channels. Or, the distribution of the mixing elements can change along the length of the channels. For example, channels can include a higher density of mixing elements towards the outlet end of the channels when compared to the inlet end.

In some implementations, the height or depth of the mixing elements is between about <NUM>% and about <NUM>%, between about <NUM>% and about <NUM>%, or between about <NUM>% and <NUM>% of the total height of the blood channels. In some implementations, each of the mixing elements in a channel is the same height or depth. While, in other implementations, the height or depth of the mixing elements changes along the length of the channel. The blood and gas channels of the microfluidic device can be between about <NUM> and about <NUM>, between about <NUM> and about <NUM>, between about <NUM> and about <NUM>, and between about <NUM> and about <NUM> deep.

In some implementations, the mixing elements are dynamic. The mixing elements can be formed by the distension of the membrane toward (or away from) the central, longitudinal axis of the respective blood channels. In some implementations, the gas pump <NUM> is configured to enhance mixing of the blood, and to increase carbon dioxide transfer, by supplying pulsed mechanical waves of gas to the gas channels that modulate the channel geometry in an oscillatory fashion. The increased pressure within the gas channels causes the membrane to distend toward the central, longitudinal axis of the respective blood channels. In some implementations, the flow of blood can be pulsed to generate pressure waves through the blood channels that distend the membrane and cause oscillations in the blood channels' geometry. In some implementations, the microfluidic device can include a mixture of passive and dynamic mixing elements. For example, the floor of the blood channels can include chevron mixing elements and a pulsed gas flow can be used to distend the membrane in an oscillatory fashion to modulate the blood channels' geometry (e.g., the shape of the cross-sectional area).

In other implementations, the blood is supplied to the blood flow channels in a pulsatile fashion to modulate the channel geometry. In these implementations, the pressure of the blood flowing through the blood channels can distend the membrane away from the central, longitudinal axis of the respective blood channels.

<FIG> illustrates a cross-sectional view of an example microfluidic device <NUM> configured to modulate the channel geometry in an oscillatory fashion. The microfluidic device <NUM> includes two gas channels <NUM> and a blood channel <NUM>. The blood channel <NUM> is separated from each of the gas channels <NUM> by a respective membrane <NUM>. The membranes <NUM> include a plurality of support structures <NUM>, which can also be referred to as ribs <NUM>.

Also referring to <FIG>, gas flows through the gas channels <NUM> in a pulsatile manner. The controller <NUM> controls the pulsatile pressure of the gas flowing through the gas channels <NUM>. The controller <NUM> can flow the gas through the gas channels <NUM> at a rate between about <NUM> cycles/min to about <NUM> cycles/min, between about <NUM> cycles/min to about <NUM> cycles/min, or between about <NUM> cycles/min to about <NUM> cycles/min.

During a cycle of relatively high pressure, as illustrated in <FIG>, the high gas pressure distends the membrane <NUM> toward the central axis of the blood channel <NUM>, which temporarily constricts the blood channel <NUM>. As illustrated, the support structures <NUM> keep the membrane stationary and the membrane <NUM> distends between the support structures <NUM>. When the gas flow cycles to a relatively low pressure (e.g., a pressure less than or equal to the pressure of the blood in the blood channel <NUM>), the membrane <NUM> returns to its original position. When the gas pressure causes the membrane <NUM> to distend toward the central axis of the blood channel <NUM>, a shape of the blood channel's cross-sectional area changes along the length of the blood channel. For example, in the example illustrated in <FIG>, the blood channel <NUM> is the widest at the cross-sections taken at one of the support structures <NUM>. The blood channel <NUM> is the narrowest at the cross-sections taken half way between neighboring support structures <NUM>. As illustrated the changing shape of the channel's cross-sectional area along the length of the blood channel <NUM> can be one form of oscillation. The shape of the cross-sectional area can also oscillate from default position (where the membrane <NUM> is not distended) to the constricted (or dilated) positions where the membrane <NUM> is distended toward (or away) from the blood channel's central axis.

In some implementations, the blood is flowed through the blood channel <NUM> with a pulsatile waveform. The pulsatile waveform may mimic the hemodynamic waveform of the cardiac pumping of blood in the body. Pulsation of the blood can be generated using a shuttle pump.

The distension of the membrane <NUM> creates small undulations in the surface of the membrane <NUM> facing the blood channel <NUM>. The undulations can appear in an oscillatory fashion with the pulsatile gas flow. The undulations can provide a natural means to disturb and disrupt boundary layers along the membrane <NUM>. The undulations also mix the blood and stir the carbon dioxide remaining in the blood to enhance mixing and transfer.

As illustrated in <FIG>, the support structures <NUM> are embedded within the membrane <NUM> of the microfluidic device <NUM>. The membranes described herein can be between about <NUM> and about <NUM>, between about <NUM> and about <NUM>, or between about <NUM> and about <NUM>.

According to the invention, the ribs are distributed evenly along the length of the plurality of gas channels. For example, the distance between neighboring ribs can be constant along the length of the gas channels. In other implementations which do not form part of the claimed invention, the ribs are distributed unevenly along the length of the plurality of gas channels. For example, the distance between neighboring ribs can change along the length of the gas channels. The ribs can be more tightly spaced toward the outlet of the gas channels, can be more tightly spaced toward the inlet of the gas channels, or the distribution of the ribs can be random.

In other implementations, the support structures <NUM> are not embedded within the membrane <NUM>. For example, <FIG> illustrates a microfluidic device <NUM> that includes support structures <NUM> that are coupled to the gas channel surface of the membranes <NUM>. The support structure <NUM> can include a material that is stiffer than the material of the membrane <NUM>. In some implementations, the support structure <NUM> can be manufactured in PDMS that has a different composition than the PDMS of the membrane <NUM> to make the support structure <NUM> stiffer than the membrane <NUM>.

<FIG> illustrates a microfluidic device that includes support structures that are posts <NUM>. The posts <NUM> are another example of a support structure that are coupled to the gas surface of the membranes <NUM>. The posts <NUM> enable gas to flow along the length of the gas channels <NUM>. The posts <NUM> couple a portion of the membrane406 to an opposite wall of the gas channels <NUM>. The posts <NUM> substantially prevent the membranes <NUM> from flexing near the portion of the membrane <NUM> where they are coupled.

<FIG> illustrates a microfluidic device <NUM>. The microfluidic device <NUM> includes support structures <NUM>, similar to those described above in relation to <FIG>. The microfluidic device <NUM> illustrates one example where blood flows through the blood flow channels <NUM> in a pulsatile manner. The pulsatile flow of the blood causes the membranes <NUM> to flex outward toward the gas channels <NUM>.

In some implementations, the support structures of the microfluidic device can be any of the support structures described herein or a combination thereof. Additionally, the support structures can include a mesh that spans a surface of the membrane <NUM>. The ribs, bars, or meshes can include a metal or a plastic that is stiffer than the membrane <NUM>.

<FIG> illustrates a microfluidic device <NUM>. The microfluidic device <NUM> illustrated in <FIG> is similar to the microfluidic device <NUM> illustrated in <FIG>. As illustrated in <FIG>, the membranes <NUM> are not distended toward the blood channel <NUM>. For example, the pressure within the gas channels <NUM> may not be great enough to force a deflection of the membrane <NUM>. In some implementations, the pulsatile flow in the gas channels <NUM> can cause the cross-sectional area to oscillate between the cross-sectional area illustrated in <FIG> and the cross-sectional area illustrated in <FIG>. The shape of the cross-sectional area can oscillate over time (e.g., the membrane can distend and then recover). The shape of the cross-sectional area can also oscillate over a distance. For example, as illustrated in <FIG>, the pressurized gas channels <NUM> cause the cross-sectional area of the blood channel <NUM> to change in a sinusoidal fashion. That is, at least one of the height or width of the blood channel <NUM> changes in a sinusoidal fashion along the length of the blood channel <NUM>. In other implementations, the shape of the cross-sectional area can oscillate in a non-sinusoidal fashion. The shape of the cross-sectional area can also oscillate over both over time and distance (such as when a pulsatile gas flow causes the microfluidic device <NUM> to oscillate between the state illustrated in <FIG> and <FIG>.

<FIG> illustrates a block diagram of an example method <NUM> of removing carbon dioxide from blood. The method <NUM> can include providing a microfluidic device (ACT <NUM>). The method <NUM> can include flowing blood through an inlet of the device's blood channels (ACT <NUM>). The method <NUM> can include oscillating a shape of a cross-sectional area along a length of the device's blood channels (ACT <NUM>). The method <NUM> can include collecting the blood from the outlet of the device's blood channels (ACT <NUM>).

As set forth above, the method <NUM> can include providing a microfluidic device (ACT <NUM>). The microfluidic device can be any of the microfluidic devices described herein. The microfluidic device can include multiple polymer layers. A first layer can include a plurality of gas channels. A second layer can include a plurality of blood channels. The blood and gas channels can be separated from one another by a distensible membrane coupled between the layers. The plurality of blood channels can include a cross-sectional area defined in the second layer. In the default state (or initial state) the cross-sectional area can be substantially uniform along the length of the blood channels. The blood channels can be fluid channels that are capable or otherwise configured to flow fluids in addition to or in place of blood.

The method <NUM> can include flowing blood through an inlet of the device's blood channels (ACT <NUM>). In some implementations, the blood channels are coupled with a manifold system. The blood can be flowed through an inlet manifold coupled with the inlet of each of the plurality of blood channels. The manifold can include channels with smooth and gradual bifurcations and bends that can reduce trauma to the blood. In some implementations, the gas channels are coupled to a gas manifold. In other implementations, the gas channels are not coupled to a gas manifold. The gas channels' inlets can be open to expose the gas channels to the ambient environment.

The method <NUM> can include oscillating a shape of a cross-sectional area along a length of the device's blood channels (ACT <NUM>). Oscillating the shape of the cross-sectional area along the length of the device's blood channels can include changing the cross-sectional area in a pulsatile manner (e.g., constricting and then relaxing the blood channels), changing the cross-sectional area along the length of the blood channels (e.g., constricting the blood channels at points along the length of the blood channels), or a combination thereof (e.g., constricting the blood channels at points in a pulsatile manner).

The shape of the cross-sectional area can be changed by distending the membrane into the blood channels. The membrane can be distended into the blood channels by pressurizing the gas channels. When the pressure in the gas channels is greater than the pressure in the blood channels, the membrane can distend into the blood channels. In some implementations, the membrane can be distended into the gas channels.

In some implementations, the microfluidic device is placed into a pressure vessel. The inlets to the device's gas channels can be open to the ambient environment such that the pressure within the gas channels is substantially that of the pressure within the pressure vessel. By pressurizing the pressure vessels, the gas channels pressurize and distend the membrane. The level of pressure in the pressure vessel can be controlled to be greater than or less than the pressure of the blood within the blood channels. The gas can be flowed through the gas channels with a pulsatile flow. The pulsatile flow can be generated by oscillating the pressure within the pressure vessel between a relatively low and a relatively high-pressure value. The relatively low pressure can be a pressure less than or about equal to the pressure within the blood channels and the relatively high pressure can be a pressure greater than the pressure in the blood channels. The pressure controls the amount the membrane distends. The membrane distension can control the shape of the cross-sectional area of the blood channels. The amount of the membrane's distension can be relative to the gas pressure of the gas in the plurality of gas channels.

The method <NUM> can include collecting the blood from the outlet of the device's blood channels (ACT <NUM>). The outlets of the blood channels can be coupled with an outlet manifold. The outlet manifold can collect the blood exiting the blood channels without causing damage to the blood. In some implementations, the blood exiting the microfluidic device can be passed to an oxygenator device that can oxygenate the blood. In other implementations, the blood can pass through an oxygenator prior to entry into the microfluidic device.

The above-described embodiments can be implemented in any of numerous ways. For example, the embodiments may be implemented using hardware, software or a combination thereof. When implemented in software, the software code can be executed on any suitable processor or collection of processors, whether provided in a single computer or distributed among multiple computers.

Such computers may be interconnected by one or more networks in any suitable form, including a local area network or a wide area network, such as an enterprise network, an intelligent network (IN) or the Internet. Such networks may be based on any suitable technology and may operate according to any suitable protocol and may include wireless networks, wired networks or fiber optic networks.

A computer employed to implement at least a portion of the functionality described herein may comprise a memory, one or more processing units (also referred to herein simply as "processors"), one or more communication interfaces, one or more display units, and one or more user input devices. The memory may comprise any computer-readable media, and may store computer instructions (also referred to herein as "processor-executable instructions") for implementing the various functionalities described herein. The processing unit(s) may be used to execute the instructions. The communication interface(s) may be coupled to a wired or wireless network, bus, or other communication means and may therefore allow the computer to transmit communications to and/or receive communications from other devices. The display unit(s) may be provided, for example, to allow a user to view various information in connection with execution of the instructions. The user input device(s) may be provided, for example, to allow the user to make manual adjustments, make selections, enter data or various other information, and/or interact in any of a variety of manners with the processor during execution of the instructions.

The various methods or processes outlined herein may be coded as software that is executable on one or more processors that employ any one of a variety of operating systems or platforms. Additionally, such software may be written using any of a number of suitable programming languages and/or programming or scripting tools, and also may be compiled as executable machine language code or intermediate code that is executed on a framework or virtual machine.

In this respect, various concepts may be embodied as a computer readable storage medium (or multiple computer readable storage media) (e.g., a computer memory, one or more floppy discs, compact discs, optical discs, magnetic tapes, flash memories, circuit configurations in Field Programmable Gate Arrays or other semiconductor devices, or other non-transitory medium or tangible computer storage medium) encoded with one or more programs that, when executed on one or more computers or other processors, perform methods that implement the various embodiments of the invention discussed above. The computer readable medium or media can be transportable, such that the program or programs stored thereon can be loaded onto one or more different computers or other processors to implement various aspects of the present invention as discussed above.

The terms "program" or "software" are used herein in a generic sense to refer to any type of computer code or set of computer-executable instructions that can be employed to program a computer or other processor to implement various aspects of embodiments as discussed above. Additionally, it should be appreciated that according to one aspect, one or more computer programs that when executed perform methods of the present disclosure need not reside on a single computer or processor, but may be distributed in a modular fashion amongst a number of different computers or processors to implement various aspects of the present disclosure.

Typically, the functionality of the program modules may be combined or distributed as desired in various embodiments.

Such relationships may likewise be achieved by assigning storage for the fields with locations in a computer-readable medium that conveys relationship between the fields.

As used herein, the term "about" and "substantially" will be understood by persons of ordinary skill in the art and will vary to some extent depending upon the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, "about" will mean up to plus or minus <NUM>% of the particular term.

As used herein in the specification and in the claims, the phrase "at least one" in reference to a list of one or more elements should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.

Only the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section <NUM>.

Claim 1:
A microfluidic flow device (<NUM>) comprising:
(a) a first layer (<NUM>) comprising a plurality of gas channels (<NUM>);
(b) a distensible membrane (<NUM>) coupled with the first layer;
(c) a plurality of support structures (<NUM>) embedded in the distensible membrane, the plurality of support structures distributed evenly along the length of the plurality of gas channels; and
(d) a second layer (<NUM>) comprising a plurality of blood channels (<NUM>) and coupled with the distensible membrane, the plurality of blood channels separated from the plurality of gas channels by the distensible membrane, the plurality of blood channels comprising:
(i) a cross-sectional area defined in the second layer, a shape of the cross-sectional area being configured to oscillate along a length of the plurality of blood channels by pressurizing, with a gas, the plurality of gas channels to distend the distensible membrane.