Compact hydraulic manifold structure for shear sensitive fluids

An compact hydraulic manifold for transporting shear sensitive fluids is provided. A channel network can include a trunk and branch architecture coupled to a bifurcation architecture. Features such as tapered channel walls, curvatures and angles of channels, and zones of low fluid pressure can be used to reduce the size while maintaining wall shear rates within a narrow range. A hydraulic manifold can be coupled to a series of microfluidic layers to construct a compact microfluidic device.

BACKGROUND

The wall shear rate for blood travelling through a network of channels must be maintained within a limited range to preserve blood health. Shear rates outside of the acceptable range can lead to clotting or hemolysis. Blood health is important in organ assist devices, which often contain channels carry blood. Patient mobility can also be an important factor in the success of an organ assist device. It is therefore desirable to have a compact channel network architecture that is capable of safely transporting blood and other shear sensitive fluids.

SUMMARY OF THE INVENTION

Aspects and implementations of the present disclosure are directed to a compact hybrid hydraulic manifold structure for shear sensitive fluids.

At least one aspect is directed to a microfluidic device. The microfluidic device includes a first network of channels having a plurality of First Channels. Each First Channel has a height in the range of about 50 microns to about 500 microns, a width in the range of about 50 microns to about 1.5 millimeters, and a length in the range of about 3 centimeters to about 20 centimeters. The microfluidic device includes a second network of channels having at least one Second Channel complementary to one or more of the First Channels. The microfluidic device includes a filtration membrane separating the one or more First Channels from the at least one Second Channel. The plurality of First Channels includes an input channel forming a primary channel, a plurality of secondary channels, and an outlet channel. A first secondary channel connects to the primary channel at a first junction located at a first distance along the primary channel. A second secondary channel connects to the primary channel at a second junction located at a second distance, greater than the first distance, along the primary channel. The primary channel and the first and second secondary channels are configured such that flow of fluid through the primary channel beyond the first junction is substantially greater than flow of fluid into the first secondary channel

In some implementations, the plurality of First Channels is located within a first substrate. The first substrate can have a thickness in the range of about 10 microns to about 10 millimeters.

In some implementations, at least one of the first and second secondary channels of the microfluidic device bifurcates into first and second tertiary channels at a third junction, such that a fluid flow rate through the first tertiary channel is substantially the same as a fluid flow rate through the second tertiary channel, and the total fluid flow rate between the first and second tertiary channels is substantially the same as the fluid flow rate through the portion of the at least one secondary channel between the primary channel and the third junction.

In some implementations, the microfluidic device includes a flow divider for dividing fluid flow between the first and second tertiary channels. The flow divider has a curved surface connecting to the walls of the first and second tertiary channel, and the radius of curvature of the flow divider is not greater than the hydraulic diameter of the at least one secondary channel. In some implementations, the microfluidic device includes third and fourth tertiary channels that converge at a point where they have opposing curvatures to form a third secondary channel, such that all of the fluid flowing through the third and fourth tertiary channels is subsequently transported into the third secondary channel.

In some implementations, the diameter of at least one secondary channel at a portion adjacent to its junction with the primary channel is significantly greater than the diameter of the downstream portion of the at least one secondary channel, such that a zone of low fluid pressure is created at the junction. In some implementations, an angle formed by a centerline of the secondary channel and a downstream portion of the centerline of the primary channel measures in the range of about one to about sixty degrees. In some implementations, the channels are further configured to maintain a shear rate of within a range of about two hundred inverse seconds to about two thousand inverse seconds when blood is transported through the channels. In some implementations, the walls of the primary channel are disposed at an angle of no greater than thirty degrees with respect to the direction of fluid flow through the primary channel.

In some implementations, at least one secondary channel includes a curved portion directing flow away from the primary channel. In some implementations, the curved portion of the at least one secondary channel has a radius of curvature that is not less than its hydraulic diameter.

At least one aspect is directed to a microfluidic device. The microfluidic device includes a first manifold having a primary inlet channel and a plurality of secondary inlet channels, coupled to a first plurality of substrates each having a network of First substrate channels. The microfluidic device includes a plurality of second substrates. Each second substrate corresponds to one of the first substrates and includes at least one Second channel complementary to one or more of the First substrate channels. The microfluidic device includes a plurality of filtration membranes. Each filtration membrane separates the First Channels of one of the plurality of first substrates from the at least one Second channel included in a corresponding second substrate. Each of the First substrate channels has a height in the range of about 50 microns to about 500 microns, a width in the range of about 50 microns to about 1.5 millimeters, and a length in the range of about 3 centimeters to about 20 centimeters. A first secondary inlet channel connects to the primary inlet channel at a first junction located at a first distance along the primary inlet channel. A second secondary inlet channel connects to the primary inlet channel at a second junction located at a second distance, greater than the first distance, along the primary inlet channel. The inlet channels are configured such that flow of fluid through the primary inlet channel beyond the first junction is substantially greater than flow of fluid into the first secondary inlet channel.

In some implementations, the network of First substrate channels in at least one of the first plurality of substrates comprises a primary substrate channel and a plurality of secondary substrate channels. The microfluidic device includes a first secondary substrate channel connecting to the primary substrate channel at a first junction located at a first distance along the primary substrate channel. The microfluidic device includes a second secondary substrate channel connecting to the primary substrate channel at a second junction located at a second distance, greater than the first distance, along the primary substrate channel. The substrate channels in the microfluidic device are configured such that flow of fluid through the primary substrate channel beyond the first junction is substantially greater than flow of fluid into the first secondary substrate channel.

In some implementations, the microfluidic device includes a second manifold having a primary inlet channel and a plurality of secondary inlet channels, coupled to a second plurality of substrates each having a network of Second substrate channels. The microfluidic device includes a first secondary inlet channel connecting to the primary inlet channel at a first junction located at a first distance along the primary inlet channel. The microfluidic device includes a second secondary inlet channel connecting to the primary inlet channel at a second junction located at a second distance, greater than the first distance, along the primary inlet channel. The network of secondary channels of each of the second plurality of substrates connects to a secondary inlet channel at a junction such that fluid can be transported from the second manifold to the network of Second substrate channels of each of the second plurality of substrates.

In some implementations, each of the second plurality of substrates is coupled to a respective one of the first plurality of substrates to form a bilayer. In some implementations, an angle formed by a surface of at least one of the first plurality of substrates and the downstream portion of the primary inlet of the first manifold is in the range of about one to about sixty degrees.

DESCRIPTION OF CERTAIN ILLUSTRATIVE IMPLEMENTATIONS

Following below are more detailed descriptions of various concepts related to, and implementations of, a compact hydraulic manifold structure for shear sensitive fluids. 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.

FIG. 1Adepicts a microfluidic device100composed of eight bilayers, as exemplified by the bilayer102. Each bilayer102consists of a blood substrate layer, such as the blood substrate layer104, and a filtrate substrate layer, such as the filtrate substrate layer106, separated by a permeable membrane, such as the permeable membrane108. A network of channels within the blood substrate104and the filtrate substrate106allows fluid (i.e. blood or filtrate) to be transported. The microfluidic device100also includes a blood inlet manifold110and a blood outlet manifold112, both coupled to the blood substrate layer104. Similarly, a filtrate inlet manifold114and a filtrate outlet manifold116are coupled to the filtrate substrate layer106. Blood enters the blood substrate layer104through the blood inlet manifold110and exits through the blood outlet manifold112. Filtrate enters the filtrate substrate layer106through the filtrate inlet manifold114and exits through the filtrate outlet manifold116.

In one implementation, each bilayer102is parallel to each other bilayer102, as shown inFIG. 1A. AlthoughFIG. 1Adepicts the bilayers102as perpendicular relative to the manifolds110,112,114, and116, this orientation is not essential. For example,FIG. 1Bshows an alternative arrangement, in which the blood inlet manifold110and the blood outlet manifold112are not perpendicular to the bilayers102. This configuration reduces the angle through which the blood flows as it enters into the blood inlet manifold110, flows through the bilayer102, and exits through the blood outlet manifold112. The blood substrate layer104and the filtrate substrate layer106each have a thickness in the range of about 10 microns to about 10 millimeters, and the membrane108has thickness in the range of about 500 nanometers to about 1 millimeter. In some implementations, adjacent bilayers102can be in contact with one another. In other implementations, the bilayers102can be separated by a distance of about 500 microns or more, as shown inFIG. 1.

The device100is designed for use in hemofiltration. The network of channels within the blood substrate layer104and the filtrate substrate layer106divide the fluid (i.e. blood and filtrate) so that a relatively large surface area of each fluid is exposed to the permeable membrane108. Each channel of the blood substrate layer104is aligned with a corresponding channel of the filtrate substrate layer106, so that the corresponding channels are separated by the permeable membrane108. As the blood moves through the channels of the blood substrate layer104, filtrate moves in the opposite direction through the filtrate substrate layer106and waste products and water are removed from the blood via diffusion through the permeable membrane108into the filtrate substrate layer106. Healthy blood remains in the blood substrate layer104and can then be recirculated into the body of a patient.

The blood inlet manifold110has a primary channel118coupled to several secondary channels, as exemplified by the secondary channel120. The other manifolds112,114, and116have primary and secondary channels similar to the primary channel118and secondary channel120. Features of the blood manifolds110and112, such as the curved shape of the channels, help to preserve blood health. These features are described further below. The shape of the filtrate manifolds114and116are less important, because filtrate is typically not a shear sensitive fluid like blood.

The blood substrate layer104and the filtrate substrate layer106can be made of a thermoplastic, such as polystyrene, polycarbonate, polyimide, or cyclic olefin copolymer (COC), biodegradable polyesters, such as polycaprolactone (PCL), or soft elastomers such as polyglycerol sebacate (PGS). The substrate layers104and106may alternatively be made of polydimethylsiloxane (PDMS), poly(N-isopropylacrylamide), or nanotubes or nanowires formed from, for example, carbon or zinc oxide. The substrates104and106are made of an insulating material to maintain temperature stability. In some implementations, the channels can be coated with cytophilic or cytophobic materials to promote or prevent the growth of cells, such as vascular endothelial cells, in the channels. The channels may also be coated with an anticoagulant to help prevent clotting of the blood in the blood substrate layer104.

FIG. 2illustrates a blood substrate layer200suitable for use as the blood substrate layer104ofFIG. 1A. The blood substrate layer200has a network of channels, which includes a primary channel202, secondary channels such as channel204, tertiary channels such as channel206, quaternary channels such as channel208, and an outlet channel210. The blood substrate layer200has a thickness in the range of about 10 microns to 10 millimeters. In some implementations, each channel has a height in the range of about 10 microns to about 1 millimeter and a width in the range of about 50 microns to about 1.5 millimeters. In some implementations, the width of each channel is less than about 900 microns.

As used herein, the term “height” refers to the greatest depth of each channel. The term “width” refers to the greatest distance between interior edges of a channel, as measured in a direction perpendicular to the flow of fluid and within the plane occupied by the substrate layer containing the channel. In some implementations, each channel can have a substantially semi-circular cross-section. In other implementations, the channels may have rectangular or trapezoidal cross sections. In still other implementations, the cross sections of the channels can be irregular in shape. For example, the channel may be generally rectangular with rounded or faceted corners. Each channel is created by etching, milling, stamping, plating, direct micromachining, or injection molding. The top portions of the channels on the blood substrate layer200are open and do not include a top wall. In the final configuration of the microfluidic device100shown inFIG. 1A, the permeable membrane108will be placed in contact with the blood substrate layer200to form enclosed channels.

The blood substrate layer200also includes alignment features212to facilitate alignment of the blood substrate layer200with the permeable membrane108and the filtrate substrate layer106ofFIG. 1Ato form a bilayer, such as the bilayer102. This can ensure the correct orientation of the blood substrate layer200with respect to the permeable membrane108and the filtrate substrate layer106. Characteristics of the network of channels in the blood substrate layer are further discussed below.

FIG. 3depicts a network of channels300. The network of channels300includes a trunk channel302, branch channels304A-304C, and bifurcation channels310A-310F. In one implementation, portions of the network of channels300represent the network of channels within the blood substrate layer200shown inFIG. 2. For example, the trunk302ofFIG. 3can correspond to the primary channel202ofFIG. 2, the branch channel304A can correspond to the secondary channel204, the bifurcation channel310A can correspond to the tertiary channel206, and the bifurcation channel310C can correspond to the quaternary channel208. In another implementation, the network of channels300represents the channels in the blood inlet manifold110and the blood outlet manifold112ofFIG. 1A. For example, the trunk302can represent the primary channel118and the branch304C can represent the secondary channels120. In this example, each branch304A-304C couples to a single blood substrate layer104ofFIG. 1A. Generally, the network of channels300would not need to be used for the filtrate inlet manifold114, the filtrate substrate layer106, or the filtrate outlet manifold116because filtrate is not a shear sensitive fluid. In some implementations, in which the blood inlet manifold110includes a trunk channel and branch channels similar to the trunk302and branch channels304A-304C, the branch channels couple to the primary channel of a blood substrate layer. The primary channels of the blood substrate layers then branches into secondary and tertiary channels.

In one implementation, a volume of fluid enters the trunk302at its widest point. As the fluid travels along the trunk302, a portion of the fluid is redirected through the branch channels304A-304C. Although only three branch channels304A-304C are shown inFIG. 3, it should be appreciated that the network of channels300is illustrative only, and that the trunk302may be coupled to any number of the branch channels304. In some implementations, the trunk302couples to additional branch channels (not shown inFIG. 3) on other sides of the trunk302. Such additional channels can branch off the trunk302on the same side or opposite side of the trunk302as the branch channels304A-304C.

The channels are configured such that the volume of fluid redirected into a single branch channel304(other than the last branch channel, i.e. branch channel304C) is significantly less than the total volume of fluid flowing through the trunk302at the point at which the branch304meets the trunk302. For example, as fluid enters the widest portion of the trunk302and travels along the trunk302, a relatively small percentage of the fluid is redirected into the first branch channel304A. In various implementations, the percentage of fluid diverted into the branch channel304A is less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% of the total fluid at the junction. A larger percentage of the fluid continues to flow through the trunk302and is then redirected into the branch channels304B-304C. The percentage redirected is a function of the number of branch channels and is controlled by varying the dimensions of each branch channel.

These flow characteristics are achieved by selecting hydraulic diameters for the branch channels304A-304C that are significantly smaller than the hydraulic diameter of the trunk302. The hydraulic diameters of the branch channels304A-304C may not necessarily be equal. In one example, the hydraulic diameters of the trunk302and the branch channels304A-304C are selected according to Murray's Law. Murray's Law provides a technique for selecting the radius of channels in a network in order to balance the energy required to circulate fluid (e.g. blood) and the energy required to metabolically support the fluid. Generally, Murray's Law indicates that for a primary channel having a radius of rpand branch channels having radii of rb1, rb2, etc., the relationship between the radii of all of the channels should be:

rp3=rb13+rb23+ . . . +rbn3. Murray's Law can also be used to select the relationships between the hydraulic diameters of a primary channel and branch channels in a network with non-circular cross sections. For example, for a primary channel having a hydraulic diameter dpand branch channels having hydraulic diameters of db1, db2, etc., Murray's Law indicates that the relationship between the hydraulic diameters of all of the channels should be:

In some implementations, and as shown inFIG. 3, the diameter of the trunk302is varied along its length to adhere to Murray's Law. The variation of the diameter is smooth, giving the trunk302a tapered shape in the direction of fluid flow. In some implementations, the angle306formed by the centerline of the trunk304(i.e., the direction of fluid flow through the trunk304) and the tapered wall of the trunk304is less than about 45°. In some implementations, the angle306is less than about 30°. In some implementations, the angle306is less than about 20°. Other walls of the trunk may also be tapered (e.g., the trunk may have a tapered height instead of, or in addition to, a tapered width).

The branch channels304A-304C are coupled to the trunk302and are used to carry fluid in a direction away from the trunk302. In some implementations, the branch channels304A-304C are straight channels. In other implementations, the branch channels304A-304C curve away from the trunk302, as shown inFIG. 3. Curvature of the branch channels304A-304C allows for smoother fluid flow and helps to maintain wall shear rate within an acceptable range. The radius of curvature308of the branch channels304A-304C also affects the shear rate of fluid flowing through the network of channels300. The network of channels300is configured such that the radius of curvature308of each branch channel304A-304C is no less than the hydraulic diameter of the corresponding branch channel304A-304C.

The network of channels300also includes bifurcations, as illustrated by bifurcation channels310A-310F. A bifurcation channel directs fluid flow from a first channel (e.g., branch channel304A) into one of two additional channels (e.g. bifurcation channels310A and310B). The bifurcation channels310A-310F are configured to substantially evenly split the fluid flow from the channels to which they are coupled. For example, branch channel304A and bifurcation channels310A and310B are configured such that the fluid flow rate through bifurcation channel310A is substantially the same as the fluid flow rate through bifurcation channel310B, and the total fluid flow rate through bifurcation channels310A and310B is the same as the fluid flow rate through branch channel304A. In some implementations, the bifurcation channels are designed in accordance with Murray's Law. For example, the cube of the radius of branch channel304A can be selected to equal the sum of the cubes of the radii of bifurcation channels310A and310B.

A flow divider314, formed by the junction of the trunk302and the branch304A, has a rounded surface, as shown inFIG. 3. The rounded surface of the flow divider314helps to maintain smooth fluid flow through the trunk302and the branch channel304A. In some implementations, the radius of curvature of the flow divider314is no greater than the hydraulic diameter of the portion of the trunk302proximate to the flow divider. The flow divider feature is described further below in connection withFIG. 4.

The network of channels300can contain any number of bifurcations. In some implementations, there are multiple bifurcations in a single path through the network of channels300. For example, the fluid flow through the branch channel304A bifurcates into bifurcation channels310A and310B, and then further bifurcates into the bifurcation channels310C-310F. Fluid flow can also be recombined after a bifurcation, as shown in a bifurcation subnetwork312depicted at the top ofFIG. 3.

The features described above, such as the taper of the trunk302, the curvature of the branches304A-304C, and the bifurcation channels310A-310F, are selected to maintain a wall shear rate within a specified range substantially throughout the entire channel network300. In a device that will be used to transport blood, such as the microfluidic device100ofFIG. 1Aor the blood substrate layer200ofFIG. 2, the features of the channel network300can be selected to maintain a wall shear rate in the range of about 200 s−1-2000 s−1. In other implementations, the channel network300can be designed to allow for shear rate ranges outside of this range. Additional features that can be used to maintain blood health are further described below in connection withFIG. 4andFIG. 5.

The selection of features described above in connection withFIG. 3for use in a microfluidic device can be optimized for various applications. For example, the bifurcation channels310A-F are useful for maintaining wall shear rate and smooth fluid flow, but multiple bifurcations will occupy a relatively large volume of space, requiring a large overall device size. Coupling a bifurcation network, such as the bifurcation channels310A-310F, to a trunk and branch network, such as the trunk302and the branch channels304A-304C, results in a smaller overall device while preserving wall shear rates within an acceptable range throughout.

The direction of fluid flow in the examples described above is illustrative only. For example, the channel network300could be used to transport fluid first through the bifurcation channels310A-310F, then into the branch channel304A, and finally into the trunk302. Further, the features depicted inFIG. 3and described above may apply to any type of channel in the channel network300. For example, althoughFIG. 3shows a taper only along the trunk302, any other channel in the network300can also be tapered. Similarly, the curved structure shown on the branch channels304A-304C could be applied to any other channel in the network300, such as the trunk302or the bifurcations310A-310F.

FIG. 4depicts a bifurcation network of channels400for dividing and recombining fluid flow, similar to the bifurcation subnetwork312ofFIG. 3. The bifurcation network400includes an inlet channel402, bifurcation channels404A-404B, and an outlet channel406. The bifurcation network400also includes a flow divider408for dividing the fluid flow from the inlet channel402into the bifurcation channels404A-404B, and a convergence point410for recombining the fluid flow from the bifurcation channels404A-404B into the outlet channel406.

The flow divider408is formed by the junction of the walls of the bifurcation channels404A-404B. Fluid traveling through the inlet channel402is redirected into either the bifurcation channel404A or the bifurcation channel404B by the flow divider408. The flow divider408and the bifurcation channels404A-404B are configured to substantially evenly divide the total fluid flow from the inlet channel402into the bifurcation channels404A and404B. In some implementations, the walls of the bifurcation channels404A and404B join at a sharp point, such that the radius of curvature412of the flow divider408is effectively zero. In other implementations, the flow divider408has a rounded surface connecting to the walls of the bifurcation channels404A and404B to allow fluid to flow more uniformly into the bifurcation channels404A-404B. In some implementations, the flow divider408is designed with a radius of curvature408that is no greater than the hydraulic diameter of the inlet channel402. This helps to maintain even flow and keeps the shear rate within a specified range for a shear sensitive fluid, such as blood.

Fluid flow through the bifurcation channels404A and404B is recombined into the outlet channel406at the convergence point410, defined by the downstream junction of the walls of the bifurcation channels404A and404B. In some implementations, the bifurcation channels404A and404B each have substantially straight walls at the convergence point410. In other implementations, the bifurcation channels404A and404B are curved at the convergence point410. For example, the bifurcation channels404A and404B shown inFIG. 4have opposing curvatures at the convergence point410. Like the curved flow divider408, opposing curvatures at the convergence point410reduce eddie currents and vortices and maintain shear rate within a specified range, which promotes blood health when the channels are used in an medical device.

FIG. 5depicts a network of channels500for transporting fluid. The network500includes a trunk channel502and branch channels504A-C. The branch channels504A and504B include low pressure zones506A and506B, respectively. In one implementation, the network500represents the network of channels within the blood substrate layer200shown inFIG. 2. For example, the trunk502ofFIG. 5corresponds to the primary channel202ofFIG. 2, and the branch channels504A-504C correspond to the secondary channels204ofFIG. 2. The network of channels500can also represent the channels in the manifolds110,112,114, and116and bilayers102ofFIG. 1A. For example, the trunk502can represent the primary channel118and the branches504A-504C can represent the secondary channels120of the blood inlet manifold110.

In one implementation, a volume of fluid enters the trunk502at its widest point. The fluid travels along the trunk502and is redirected through the branch channels504A-504C. Low pressure zones506A and506B facilitate redirection of fluid from the trunk502into the branch channels504A and504B. The low pressure zones506A and506B are located at the junction of the trunk502and the branch channels504A and504B. Low fluid pressure is created by increasing the diameter of the branch channels504A and504B at the junction point relative to the diameter of the downstream portion of the branch channels504A and504B. Fluid flowing through the trunk is more easily redirected into the branch channels504A and504B due to the low pressure zones506A and506B. As depicted inFIG. 5, the low pressure zones506A and506B have a rounded shape.

The angle of the junction between the branch channels504A-504C and the trunk502is selected to allow for smooth flow of fluid from the trunk502into the branch channels504A-C. As shown in theFIG. 5, the angle508formed by the junction of the branch channel504A and the trunk502, and measured proximate to the junction, is acute. In some implementations, the network of channels500is designed so that the angle508measures less than about 60°. A smaller value for angle508allows fluid flow to avoid turning at a sharp angle as fluid is redirected from the trunk502into the branch channel504A. Such a configuration helps to maintain the wall shear rate within a specified range, which can be useful if the fluid is shear sensitive (e.g., blood).