Devices and methods for oxygen supersaturation of human blood in an extracorporeal circuit

Abstract

A system to oxygenate blood may include an inlet channel configured to receive blood in a first state, a microbubble generation interface coupled to the inlet channel, the microbubble generation interface including a first stream of a first portion of the blood in the first state; and an inlet, coupled to a downstream end of the first stream, configured to provide microbubbles to the blood in the first state to cause the blood to change to a second state, and the system further including an outlet channel downstream of the inlet to flow the blood in the second state.

Description

DEVICES AND METHODS FOR OXYGEN SUPERSATURATION OF HUMAN BLOOD IN AN EXTRACORPOREAL CIRCUITCROSS-REFERENCED TO RELATED APPLICATION|0001| This application claims the benefit of U.S. provisional application Serial No. 63 / 575,028 filed April 05, 2024, the disclosure of which is hereby incorporated in its entirety by reference herein.TECHNICAL FIELD

[0002] Disclosed herein are systems and methods for oxygen supersaturation of human blood in an extracorporeal system.BACKGROUND

[0003] Extracorporeal membrane oxygenation (ECMO) is used to remove carbon dioxide from patient blood by pumping the blood outside of the body, removing the carbon dioxide. This, and / or oxygenation may be used to return oxygen rich blood back to the body tissues. Such process allows blood to bypass the heart and lungs, eliminating additional strain on these organs.SUMMARY

[0004] A microfluidic supersaturation circuit may include microbubble generation interface configured to receive deoxygenated blood and pump oxygen into the blood to produce blood having uniform microbubbles therein, wherein the blood is divided into two separate streams and combined with a third stream of pure oxygen to produce the microbubbles.

[0005] A system to oxygenate blood may include an inlet channel configured to receive blood in a first state, a microbubble generation interface coupled to the inlet channel, the microbubble generation interface comprising a first stream of a first portion of the blood in the first state, and an inlet, coupled to a downstream end of the first stream, configured to provide microbubbles tothe blood in the first state to cause the blood to change to a second state, and an outlet channel downstream of the inlet to flow the blood in the second state.(0006] The microbubble generation interface may include a second stream of a second portion of the blood in the first state; and wherein the inlet is coupled to a downstream end of the first stream and a downstream end of the second stream.100071 The first stream and the second stream combine at the inlet.(0008] The inlet comprises a membrane.

[0009] The inlet a pore defined by a membrane, and wherein the pore is coupled to the downstream end of the first stream.

[0010] The inlet is configured to accept a gas to a side of a membrane opposing the first stream; and provide the gas through a pore of the membrane to produce the microbubbles.(0011 ] The membrane defines a plurality of pores tangential to the blood flowing through the interface, the pores configured to allow oxygen to pass to the blood via a pinch-off effect to generate the microbubbles within the blood.

[0012] The membrane includes a surface coating configured to enable bubble generation.(0013] The surface coating includes an alumina membrane.

[0014] The surface coating is a hydrophobic coating.

[0015] At least one pressure sensor is arranged at an input of the interface.

[0016] An oxygen probe is arranged at an output of the interface.

[0017] The membrane divides the interface into a liquid channel and a gas chamber.

[0018] The membrane is configured to receive pressurized oxygen through the gas chamber.

[0019] A method for microbubble generation in a microfluidic supersaturation circuit, may include receiving deoxygenated blood, dividing the blood into two streams, recombining the two streams at a combination point; providing microbubbles to the blood at the combination point with the two blood streams, and outputting the oxygenated blood through an expanded chamber.

[0020] The method may include accepting a gas at one side of the membrane and wherein the flowing oxygen at the combination point includes providing the gas through a pore of the membrane to produce microbubbles.

[0021] The microbubbles are produced via a pinch off effect at the membrane.

[0022] A method for microbubble generation in a microfluidic supersaturation circuit may include receiving deoxygenated blood, receiving a tangential flow of oxygen via a nano-porous membrane, the membrane defining openings to create a bubble pinch off to generate uniform microbubbles in the blood; and transporting the oxygenated blood to an outlet.

[0023] The method may further include transporting the oxygenated blood through an expanded chamber.

[0024] The method may further include accepting a gas at one side of the membrane to provide gas to the membrane.BRIEF DESCRIPTION OF THE DRAWINGS

[0025] In the accompanying drawings, reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale; emphasis has instead been placed upon illustrating the principles of the invention. Of the drawings:[0026| FIG. 1 illustrates a side view of an example microbubble oxygenation system.

[0027] FIG. 2 illustrates a side view of another example oxygenation system.

[0028] FIG. 3A illustrates an example uncoated membrane of the example oxygenation system of FIG. 2.

[0029] FIG. 3B illustrates an example coated membrane of the example oxygenation system of FIG. 2.

[0030] FIG. 4 illustrates a top view of the example oxygenation system of FIG. 2.

[0031] FIG. 5 illustrates example microfluidic supersaturation circuits simulating an ECMO.

[0032] FIG.6 illustrates an example chart for Surface Area Flux across the active bloodoxygenation interface for device types.

[0033] FIG. 7 illustrates an example diagram of another example microbubble system using a porous membrane.

[0034] FIG. 8 illustrates an exploded view of the example microbubble device of FIG. 7.

[0035] FIG. 9 illustrates images of example microbubbles.

[0036] FIG. 10 illustrates an example flow focusing device.

[0037] FIG. 11 illustrates an image of the example flow focusing device of FIG. 10.

[0038] FIG. 12 illustrates an example of another flow focusing device.

[0039] FIG. 13 illustrates a side view of another example interface.

[0040] FIG. 14 illustrates a top view of another example interface.

[0041] FIG. 15 illustrates a side view of an example acoustic device for generating microbubbles.

[0042] FIG. 16 illustrates a top view of the example acoustic device of FIG. 15.

[0043] FIG. 17A illustrates example microbubbles without ultrasonic application.

[0044] FIG. 17B illustrates example microbubbles with ultrasonic application.

[0045] FIG. 18 illustrates an example chart illustrating radial displacement vs. shear stress in blood.DETAILED DESCRIPTION

[0046] As required, detailed embodiments of the present invention are disclosed herein; however, it is to be understood that the disclosed embodiments are merely exemplary of the invention that may be embodied in various and alternative forms. The figures are not necessarily to scale; some features may be exaggerated or minimized to show details of particular components. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a representative basis for teaching one skilled in the art to variously employ the present invention.

[0047] As explained, extracorporeal membrane oxygenation (ECMO) is used to remove carbon dioxide from patient blood by pumping the blood outside of the body, removing the carbon dioxide, and returning oxygen rich blood back to the body tissues. Such process allows blood to bypass the heart and lungs, eliminating additional strain on these organs. ECMO is typically used in critical care situations, or with patients having lung or heart conditions. It is also used during life support measures. However, certain risks may be associated with ECMO, such as bleeding, blood clots, lung ischemia, seizures and stroke. CO2 may be an easier extraction over processes such as oxygenation.

[0048] A major contributor to ECMO’s poor outcomes is the high rate of blood trauma induced by the extracorporeal circuit due to the high extracorporeal flowrates required to provide sufficient systemic oxygenation. These high flowrates induce blood trauma through high shear rates and significant foreign material exposure which lead to many deleterious conditions, including systemic inflammation, thrombosis, and cellular damage. Conventional ECMO systems necessitate these high flowrates due to hemoglobin oxygen saturation limits throttling the amount of oxygen that can safely be delivered to the patient within a finite volume of blood. Techniques to safely increase the oxygen carrying capacity of blood above this saturation limit would allow a ECMO system to increase the rate of oxygen delivery to the patient while requiring less blood to circulate through the extracorporeal circuit thereby reducing the degree of blood trauma. Some techniques have been developed to provide this capability but require the addition of non-bloodsolutions to the extracorporeal circuit to increase the oxygen capacity. This limits the use case of these technologies to acute or localized oxygenation due to risks of fluid overload.(0049] Disclosed herein are systems and methods that do not require the net addition of fluid to the patient and directly increase the oxygen capacity of the blood. No additional gasses other than oxygen are required, nor any carrier fluids other than whole blood, as well as no additional surfactants or bubbles shell stabilizers. These techniques are enabled by carefully engineered microfluidic channels that provide a high degree of fluid and oxygen control to achieve safe increases in blood oxygen capacity beyond the hemoglobin saturation limit, hereafter referred to as supersaturation.10050] FIG. 1 illustrates a side view of a portion of an example microbubble oxygenation system 100. The microbubble oxygenation system 100 may be applicable to medical applications such as extracorporeal membrane oxygenation (ECMO) used oxygenate patient blood. However, other medical applications, may be appreciated. Other use cases may include generation of bubbles in carrier solutions for use as localized oxygenation injection, use as an acoustic contrast agent, used to generate unique optical properties contrast / scattering in solution, used to generate bubbles to actuate through stable or inertial cavitation to generate localized / controlled shear effects. Generation of oxygen bubbles in non-blood fluids, where shear stresses can be elevated without harming the cells or materials in solution, can be done using simpler devices.

[0051] The system 100 may be used to enhance oxygen transfer to a liquid medium (e.g., blood). The example system discussed herein may be a flow focusing device for generating microbubbles and introducing the bubbles to a liquid, such as blood. Deoxygenated blood Bi enters the system 100 at an inlet channel 101. The blood flow is split into two streams, including a first stream 106A and a second stream 106B. The streams 106 are recombined at a point 108 with gaseous pure oxygen at an interface 102 having an inlet coupled to a downstream end of the deoxygenated blood Bi in the first state. The trifurcation generates a uniform stream of microbubbles in the blood forming a second state. This passes through an expanded chamber 104 for visualization before oxygenated blood Boexits the device through the outlet stream 110.

[0052] Thus, in the example in FIG. 1, the microfluidic supersaturation circuit or system includes the microbubble generation interface 102 configured to receive deoxygenated blood Bi and pump oxygen into the blood to produce blood having uniform microbubbles therein. In this example, the blood is divided into two separate streams and combined with a third stream of pure oxygen to produce the microbubbles. This process and method may include receiving deoxygenated blood, dividing the blood into two streams, flowing oxygen at a combination point with the two blood streams, and outputting the oxygenated blood through an expanded chamber. Such oxygenation is accomplished without additional gasses, liquids or carrier fluids.

[0053] FIG. 2 illustrates a side view of a portion of another example oxygenation system 200 having a nano-porous or microporous membrane 202. This example may include a membrane device, while the example in FIG. 1 illustrates a flow-focused device. In this example the deoxygenated blood Bi enters the device. Gas, such as oxygen, O2 enters the blood via the microporous membrane 202 defining membrane pores 204 tangential to the flowing blood. This is evident at “1” in FIG. 2. The membrane defines pores 204 that facilitate bubble pinch off and transport microbubbles to the blood outlet Bo, as illustrated at “2” and “3” in FIG. 2. Bubble pinch off may refer to the process of gas bubble growing at and eventually detaching from an opening, surface, or other bubble. As the bubble initiates and grows, as best illustrated at “1” in FIG. 2, a neck may form near the origin of the bubble and gradually thin. The neck is best shown at “2” in FIG. 2. Once the neck thins enough, the bubble becomes too “heavy” and forces the neck to break, thus forming and closing the bubble, allowing the bubble to detach and move, as best illustrated at “3” in FIG. 2.

[0054] The process and method for the example in FIG. 2, may include receiving deoxygenated blood, receiving a tangential flow of oxygen via the nano-porous membrane, the membrane having openings to create a bubble pinch off to generate uniform microbubbles in the blood, and transporting the oxygenated blood to an outlet. Again, the pure oxygen is the only necessary gas or fluid. Additional surfactants or bubble shell stabilizers are unnecessary.

[0055] FIG. 3A illustrates an example uncoated membrane 202 of the example oxygenation system 200 of FIG. 2. FIG. 3B illustrates an example coated membrane 202 of the exampleoxygenation system 200 of FIG. 2. In FIG. 3B, the nano-porous membrane 202 may include an alumina membrane having engineered hydrophillic and / or hydrophobic surface coatings to enable bubble generation. While alumina is specifically referenced, other ceramic materials or polymers or metals, may be contemplated as suitable coatings. The use of the hydrophobic coating enables better control of bubble generation. Hydrophilic coatings are more hemocompatible. Both coatings may be used together (e g. one side of the membrane and the pores are hydrophobic and the other side hydrophilic) may produce the best membranes performance.

[0056] As evident by comparing FIG. 3A and FIG. 3B, the bubble pinch off may increase with the use of coatings at the membrane 202 where the coating may facilitate a larger angle between the oxygen Ch and the membrane 202 at the pore 204. Such larger angle facilitates bubble pinch off more effectively, thus oxygenating the blood at a better rate. The coating may cause bubbles to have less contact area with the surface adjacent to the pore 204, thus facilitating a faster and cleaner pinch off, as opposed to bubbles that spread out more on the surface and delaying the pinch off. As explained, the coating may be a hydrophobic or superhydrophobic coating such as silanes, including fluoroSilane.

[0057] FIG. 4 illustrates a top view of an example apparatus housing the example oxygenation system 200 of FIG. 2. Similar to FIG. 2, deoxygenated blood enters the device, oxygen O2 enters the blood via a nano-porous membrane 202 having membrane pores 204 (pores 204 are best illustrated in FIG. 2) tangential to the flowing blood. The device then transports microbubbles to the blood, which leaves the device at outlet Bo,

[0058] FIG. 5 illustrates example microfluidic supersaturation devices simulating an ECMO. Example A illustrates the example system 200 outlined above in FIGs. 2-4 for a membrane device. Example B illustrates the example system 100 outlined in FIG. 1 for a flow focusing design. In these examples, approximately half of the conventional volume of blood is removed from the patient, supersaturated with microbubbles, and delivered back to the patient. The supersaturated blood delivers enough excess oxygen to full oxygenate the venous blood flow to the remaining body without the need for additional gasses or liquids.

[0059] In these examples, deoxygenated blood Bi and pressurized oxygen gas O2 are pumped into the microfluidic devices such they combine at an interface 109, such as at the membrane device in Example A, or the flow focused device in Example B, to generate uniform microbubbles within the blood. Microbubbles dissolve in the deoxygenated blood stream over seconds as oxygen is transported to the plasma and hemoglobin. As blood is supersaturated above normoxic levels in the extracorporeal circuit, the microbubble laden flow is combined 1 : 1 with deoxygenated blood after exiting the microfluidic device. Microbubbles fully dissolve in the venous flow to prove highly efficient blood oxygenation.10060| FIG. 6 illustrates an example chart for measured surface area flux across the active bloodoxygenation interface for various ECMO technologies and examples herein. For example, Hollow Fiber Membrane Oxygenator (HFMO) shows a calculated membrane oxygenation efficiently for a NEONATAL QUADROX hollow fiber membrane oxygenator using the reported total membrane surface area. BLOx is demonstrated in vitro efficiency of microfluidic blood oxygenator using the active oxygen transfer surface area within the microfluidic network. FF1-4 illustrate efficiencies for four experimental conditions for the flow focusing device using the experimental design described above (e.g., FIG. 1 and FIG. 5).

[0061] Active membrane surface area is estimated as the total oxygen-blood interface prior to bubble pinch-off A0M1 -4may be conditions for the tangential flow membrane device using the system described above (e.g., FIGs. 2-4 and FIG. 3). Active membrane surface area is estimated as the total membrane surface area where bubble nucleation was visualized.

[0062] Hyperbaric Oxygenation is when air pressure allows oxygen to continue to dissolve into the blood up to the plasma saturation limit (760mmHg). This may be achieved via an oxygen compartment adjacent to microfluidic blood channels, separated by a non-porous membrane or a porous membrane with a high bubble point, that allows oxygen to diff use into the blood. Pressurization of the oxygen compartment increases the rate of oxygen transfer to blood at lower partial pressures of blood oxygenation and increases the maximum partial pressure achievable by the microfluidic device. This results in increases in the dissolved oxygen contained in the blood plasma increasing the total oxygen carrying capacity of the blood. High partial pressures of oxygenin the blood presents a risk for uncontrolled nucleation of gas bubbles. The flow can be engineered to increase convective transport of the oxygen away from the surface to control this phenomenon. Pressurization may refer to oxygen pressures above lOOmmHg and up to or exceeding 760mmHg.

[0063] Surface area efficiencies are important as they indicate that a future device may be smaller than other options. This may result in reduced blood contact area and a smaller device that would indicate improved hemocompatibility and be more user friendly.

[0064] FIG. 7 illustrates an example diagram of the oxygenation system 300 including microbubble device 304 using the porous membrane 302.

[0065] Direct infusion of microbubbles to the blood act as ‘temporary’ oxygen transporters above the oxygen saturation limit. Oxygen diffuses from the bubbles, and they collapse as supersaturated blood is mixed with deoxygenated venous blood or dissolved oxygen is transported out of the blood during cellular metabolism. Microbubble generation occurs by flowing oxygen through a porous membrane with blood flowing tangentially over the membrane surface causing bubble nucleation.

[0066] The device 304 includes a microfluidic channel integrated with a porous membrane 302 such that the porous membrane 302 forms an interface between oxygen gas O2 in a gas chamber 314 and a liquid in a liquid channel 312. The oxygen gas pressure is tuned to overcome the bubble point of the membrane 302 and liquid to create microbubbles in the liquid. Wall shear stress of the liquid channel is controlled by flow rate and channel dimensions. Tuning shear stress and oxygen gas pressure or mass flow rate serve as mechanisms to control the bubble size. Further, pressurizing the membrane with oxygen prior to starting the liquid flow avoids fluid leak across the membrane 302. Membrane pore size, pore density and membrane coatings including creation of hydrophilic and hydrophobic surfaces are other parameters that can be tuned to control bubble size and density.

[0067] The system 300 may include a pressure sensor 320 arranged at the input of the interface / device 304. An oxygen probe 322 may be arranged on at least one of the input or the output of the interface 304. The oxygen probes 322 may measure the oxygen concentration in theinputs and outputs. This may allow for baselines and comparisons between the blood before the interface and after.(0068] FIG. 8 illustrates an exploded view of the example microbubble device 304 of FIG. 7. The device 304 may include a pair of covers 310 on each end of the device 304. A first acrylic cover 310A may include liquid inlet and outlet ports for receiving liquid, e.g., blood Bi. A second acrylic cover 310B may include a gas inlet port for receiving oxygen. The covers may be made of acrylic, polycarbonate, and other plastics. The membrane 302 may bifurcate the chamber formed by the acrylic covers 310, creating the liquid channel 312 and the gas chamber 314.

[0069] FIG. 9 illustrates images of example microbubbles. These example bubbles are distributed between ~10um and -lOOum. Smaller bubbles may rapidly dissolve. Oxygen microbubble solutions may produce increased dissolved oxygen content in solution from 100-760mmHg. Smaller bubbles may dissolve rapidly due to high surface tension / internal pressures.

[0070] FIG. 10 illustrates an example flow focusing device 400. The device 400 may include a microfluidic channel 402 containing a nozzle / orifice / intersection 404 with an upstream intersection at a blood stream 406 and an oxygen stream 408, receiving two fluids (e.g., oxygen and blood). The two fluids are infused into the device 400 pneumatically or via syringe pump (not shown in FIG. 10). At the intersection 404, a fluid interface is formed followed by the formation of an oxygen-rich bubble which is carried along the microfluidic outlet channel 402 by the surrounding blood. Device geometry and surface treatments can be modified to create bubbles of desired size and monodispersity. During bubble generation, infusion rates can be adjusted to achieve a target bubble size and monodispersity. Additionally, blood viscosity can be modulated via temperature to alter bubble generation.

[0071] FIG. 11 illustrates an image of the example device 400 of FIG. 10.

[0072] FIG. 12 illustrate an example of another flow focusing device 500, which may function similarly to the example device 400 of FIG. 10. The device 500 may include a microfluidic droplet generator 502 configured to receive fluid from a blood inlet 504 and oxygen from an oxygen inlet506. At the droplet generator 502, a fluid interface is formed followed by the formation of an oxygen-rich bubble which is carried along the generator 502 to the outlet 510.(0073] FIG. 13 illustrates a side view of another example device 600 or interface. In this example, buoyancy is used for indirect bubble introduction into the blood without fluid transfer. The device 600 may include a carrier stream 602 carrying microbubbles and a blood stream 604 carrying blood. The carrier stream 602 and the blood stream 604 may meet at an intersection 606 or interface, the microbubbles transferring from the carrier stream 602 to the blood stream 604 at the interface 606 to combine with the blood. The blood stream 604 and the carrier stream 602 then separating after the interface 606 where the blood stream 604 carries the oxygenated blood. As explained, in this example, the microbubbles transfer from the carrier stream 602 to the blood stream 604 via buoyancy.(0074) The process and method for the examples in FIG. 12 may include receiving deoxygenated blood via a blood stream, receiving a microbubbles via a carrier stream, combining the deoxygenated blood with the microbubbles at the interface intersection of the blood stream and carrier stream, dividing the oxygenated blood into one output and the carrier stream into another outlet after the interface intersection.

[0075] FIG. 14 illustrates a side view the example device 600 of FIG. 14, but with using acoustic radiation force for indirect bubble introduction into the blood without fluid transfer. Similar to the example of FIG. 13, the device 600 may include a carrier stream 602 carrying microbubbles and a blood stream 604 carrying blood. The carrier stream 602 and the blood stream 604 may meet at an intersection 606 or interface, the microbubbles transferring from the carrier stream 602 to the blood stream 604 at the interface 606 to combine with the blood. The blood stream 604 and the carrier stream 602 then separating after the interface 606 where the blood stream 604 carries the oxygenated blood. As explained, in this example, the microbubbles transfer from the carrier stream to the blood stream via acoustic radiation.|0076| In these examples, the method for microbubble application into a blood stream in a microfluidic supersaturation circuit includes, receiving deoxygenated blood via the blood stream, receiving the microbubbles via the separate carrier stream, combining the deoxygenated bloodwith the microbubbles at the interface intersection of the blood stream and carrier stream, and then dividing the oxygenated blood into one output and the carrier stream into another outlet after the interface intersection. The microbubbles may be transferred via buoyancy and / or ultrasonic radiation.

[0077] FIG. 15 illustrates a side view of an example acoustic device 700 for generating microbubbles. FIG. 16 illustrates a top view of the example acoustic device 700 of FIG. 15. The device 700 may include a pair of posts 702 configured to rest on an optical breadboard. The device 700 may also include a glass coverslip 704 adjacent a polymer channel 706 configured to receive liquid at an inlet 710 and output liquid at an outlet 712. A piezo 714 may be arranged on the channel 706 to generate acoustic radiation force on the channels.

[0078] FIG. 17A illustrates example microbubbles without ultrasonic application. FIG. 17B illustrates example microbubbles with ultrasonic application. In the example of ultrasonic application, the bubbles may be up to 200x200um, or as small as lOxlOum. Without ultrasonic application, the bubbles may be up to 860x380um or as small as 280 / 380um.

[0079] FIG. 18 illustrates an example ultrasound pressure wave. FIG. 19 illustrates an example chart illustrating radial displacement vs. shear stress in blood. These figures illustrate stable and inertial acoustic cavitation effects. Nominally there are two regimes of acoustic cavitation, stable having oscillation about an equilibrium size, and inertial having rapid growth followed by violent inertial collapse. Inertial cavitation may be preferred for bubble fragmentation.(0080] If bubbles cannot be formed directly into the blood for any reason, it may be possible to generate bubbles in a carrier fluid first prior to transferring the bubbles to the patient. However, injecting with large volumes of carrier fluid may be problematic and could require significant fluid management of the patient. Transferring only the bubbles to the blood would circumvent this issue. While the concept is not limited to the examples in the diagrams, it may be possible to transfer bubbles into the blood without overloading the patient with excess fluid by pushing or pulling the bubbles out of the carrier stream and into the blood stream.

[0081] A laminar carrier fluid stream containing preformed microbubbles is brought in contact with a parallel laminar blood stream in a fluidic device. Bubbles are transported across the interface without exchanging bulk fluid between the two streams. The two streams exit the device separately only with the bubble exiting with the blood, which is returned to the patient. The carrier fluid can be disposed of or recycled through the system to pick up more bubbles. The mechanism of transporting the bubbles between streams can be any force that would primarily act on the bubbles. Examples include, but are not limited to, buoyancy to move the bubbles upwards and across the interface from a carrier stream running beneath a parallel flow (FIG. 8) and acoustic radiation force (FIG. 9).

[0082] With each of the mechanisms, systems, and methods described herein, such techniques could be multiplexed or replicated in parallel to handle the large quantities of blood required for full adult ECMO. Further, integrating an extracorporeal CO2 removal (ECCOR) membrane as one of the microfluidic walls may be contemplated.

[0083] While exemplary embodiments are described above, it is not intended that these embodiments describe all possible forms of the invention. Rather, the words used in the specification are words of description rather than limitation, and it is understood that various changes may be made without departing from the spirit and scope of the invention. Additionally, the features of various implementing embodiments may be combined to form further embodiments of the invention.

[0084] Concepts:|0085] A microfluidic supersaturation circuit, comprising: a microbubble generation interface configured to receive deoxygenated blood and pump oxygen into the blood to produce blood having uniform microbubbles therein, wherein the blood is divided into two separate streams and combined with a third stream of pure oxygen to produce the microbubbles.

[0086] A microfluidic supersaturation circuit, comprising: a microbubble generation interface configured to receive deoxygenated blood and pump oxygen into the blood to produce bloodhaving uniform microbubbles therein, wherein the microbubble generation interface includes a nano-porous or microporous membrane configured to produce the microbubbles.(0087] A method for microbubble generation in a microfluidic super saturation circuit, comprising: receiving deoxygenated blood, dividing the blood into two streams, flowing oxygen at a trifurcation point with the two blood streams, and outputting the oxygenated blood through an expanded chamber.(0088| A method for microbubble generation in a microfluidic super saturation circuit, comprising: receiving deoxygenated blood, receiving a tangential flow of oxygen via a nano- porous membrane, the membrane having openings to create a bubble pinch off to generate uniform microbubbles in the blood; transport the oxygenated blood to an outlet.

[0089] A microfluidic supersaturation circuit, comprising: a carrier stream carrying microbubbles and a blood stream carrying blood, the carrier stream and the blood stream meeting at an interface, the microbubbles transferring from the carrier stream to the blood stream at the interface to combine with the blood, the blood stream and the carrier stream separating after the interface wherein the blood stream carries oxygenated blood.|0090] Wherein the microbubbles transfer from the carrier stream to the blood stream via buoyancy.|0091| Wherein the microbubbles transfer from the carrier stream to the blood stream via ultrasonic radiation.

[0092] A method for microbubble application into a blood stream in a microfluidic supersaturation circuit, comprising: receiving deoxygenated blood via a blood stream, receiving a microbubbles via a carrier stream, combining the deoxygenated blood with the microbubbles at an interface intersection of the blood stream and carrier stream, dividing the oxygenated blood into one output and the carrier stream into another outlet after the interface intersection.

[0093] Wherein the microbubbles transfer from the carrier stream to the blood stream via buoyancy.

[0094] Wherein the microbubbles transfer from the carrier stream to the blood stream via ultrasonic radiation.

Claims

WHAT IS CLAIMED IS:

1. A system to oxygenate blood, comprising: an inlet channel configured to receive blood in a first state; a microbubble generation interface coupled to the inlet channel, the microbubble generation interface comprising: a first stream of a first portion of the blood in the first state; and an inlet, coupled to a downstream end of the first stream, configured to provide microbubbles to the blood in the first state to cause the blood to change to a second state; and an outlet channel downstream of the inlet to flow the blood in the second state.

2. The system of claim 1, wherein the microbubble generation interface comprises: a second stream of a second portion of the blood in the first state; and wherein the inlet is coupled to a downstream end of the first stream and a downstream end of the second stream.

3. The system of claim 2, wherein the first stream and the second stream combine at the inlet.

4. The system of claim 1, wherein the inlet comprises a membrane.

5. The system of claim 1, wherein the inlet a pore defined by a membrane, and wherein the pore is coupled to the downstream end of the first stream.

6. The system of claim 1, wherein the inlet is configured to: accept a gas to a side of a membrane opposing the first stream; and provide the gas through a pore of the membrane to produce the microbubbles.

7. The system of claim 4, wherein the membrane defines a plurality of pores tangential to the blood flowing through the interface, the pores configured to allow oxygen to pass to the blood via a pinch-off effect to generate the microbubbles within the blood.

8. The system of claim 4, wherein the membrane includes a surface coating configured to enable bubble generation.

9. The system of claim 8, wherein the surface coating includes an alumina membrane.

10. The system of claim 8, wherein the surface coating is a hydrophobic coating.

11. The system of claim 1, further comprising at least one pressure sensor arranged at an input of the interface.

12. The system of claim 1, further comprising an oxygen probe arranged at an output of the interface.

13. The system of claim 4, wherein the membrane divides the interface into a liquid channel and a gas chamber.

14. The system of claim 13, wherein the membrane is configured to receive pressurized oxygen through the gas chamber.

15. A method for microbubble generation in a microfluidic supersaturation circuit, comprising: receiving deoxygenated blood, dividing the blood into two streams, recombining the two streams at a combination point; providing microbubbles to the blood at the combination point with the two blood streams, and outputting the oxygenated blood through an expanded chamber.

16. The method of claim 15, further comprising accepting a gas at one side of the membrane and wherein the flowing oxygen at the combination point includes providing the gas through a pore of the membrane to produce microbubbles.

17. The method of claim 16, wherein the microbubbles are produced via a pinch off effect at the membrane.

18. A method for microbubble generation in a microfluidic supersaturation circuit, comprising: receiving deoxygenated blood, receiving a tangential flow of oxygen via a nano-porous membrane, the membrane defining openings to create a bubble pinch off to generate uniform microbubbles in the blood; and transporting the oxygenated blood to an outlet.

19. The method of claim 16, further comprising transporting the oxygenated blood through an expanded chamber.

20. The method of claim 18, further comprising accepting a gas at one side of the membrane to provide gas to the membrane.

Images