WO2025179030A1 - Increasing extracorporeal filtration efficiency of blood using feature-induced fluid rotation - Google Patents

Abstract

Systems, devices, and methods are provided for increasing extracorporeal filtration and/or oxygenation efficiency of blood using feature-induced fluid rotation. The presently-disclosed subject matter includes features patterned on the inside of channel walls to rotate blood flow, moving filtered blood away from a membrane surface and moving fresh, unfiltered blood into its place as it travels down the length of the channel.

Description

INCREASING EXTRACORPOREAL FILTRATION EFFICIENCY OF BLOOD USING FEATURE-INDUCED FLUID ROTATION by Christine Trinkle

Assignee: University of Kentucky Research Foundation

Attorney Docket No.: 13177N/2790WO

RELATED APPLICATIONS

[0001] This application claims priority from U.S. Provisional Application Serial No. 63/555,858 filed February 20, 2024. the entire disclosure of which is incorporated herein by this reference.

TECHNICAL FIELD

[0002] The presently-disclosed subject matter generally relates to extracorporeal blood filtration and oxy genation systems. In particular, certain embodiments of the presently- disclosed subject matter relate to systems that substantially eliminate blood stagnation zones and allow for greater efficiency in oxygenation of blood within a single device.

INTRODUCTION

[0003] Extracorporeal Membrane Oxygenation (ECMO) is an important medical therapy that provides temporary life support for patients with severe respirator}' failure by functioning as an artificial lung. During ECMO, deoxygenated blood is removed from the patient, filtered to remove CO2 and add O2, and then returned to the body. This technology has been especially useful during acute disease outbreaks, such as the COVID-19 pandemic, and serves as a bridge to transplant for patients with chronic lung failure. ECMO offers an alternative to mechanical ventilation, which can damage sensitive lung tissue and requires patient sedation. [0004] Despite its life-saving potential, ECMO systems face significant challenges. The primary’ component, the membrane oxygenator, consists of a dense network of cylindrical micro-porous membrane fibers that separate blood from an oxygen-rich gas mixture. The chaotic blood flow through these fibers results in regions of high shear stress, causing hemolysis and inflammation, and stagnation zones, leading to clot formation. To mitigate clotting, aggressive anticoagulant medications are used, but these can cause severe bleeding complications, including intracranial hemorrhage. Clotting and bleeding issues are the most common complications, with clots being the primary limitation, causing oxygenators to rarely last more than a week.

[0005] Current ECMO systems also involve large thrombogenic surfaces due to the extensive membrane area required for rapid gas exchange. This nonuniform blood flow exacerbates the formation of clots and other complications, limiting the use of ECMOs to the most critical situations. Researchers have proposed microfluidic oxygenator systems with controlled blood flow to eliminate stagnation zones. However, these systems require extremely small channels, making them impractical for clinical use due to the need for hundreds of devices with tens of thousands of channels.

[0006] Additionally, the oxygenator component of ECMO is widely accepted as the primary source of hemocompatibility problems. The large membrane surface area in these devices enables rapid gas exchange but also provides a ripe surface for plasma protein adsorption, activation of platelets and immune cells, and ultimately, thrombus formation. Even with significant efforts to improve membrane antithrombotic properties, thrombogenesis remains the most common reason for oxygenator failure. Post hoc analysis of oxygenators shows consistent locations of clot formation and aggregation that correspond with regions of high stress and fluidic dead zones within the oxygenator. Stagnation and chaotic blood flow alone are sufficient to trigger thrombotic and hemorrhagic events, indicating that serious complications will persist if the mechanics of extracorporeal blood flow are not addressed.

[0007] Another issue with standard ECMO oxygenators is the high fluidic resistance, which requires a large amount of pressure to push blood through the tightly wound hollow fiber nest. This pressure can trigger clotting and inflammation and necessitates the use of an external centrifugal pump to drive blood flow. This pump represents an additional potential failure point in the ECMO system and is also known to cause red blood cell death (hemolysis) and trigger clotting and inflammation.

[0008] In existing ECMO systems, blood is directed through a dense network of hollowfiber membranes, which are filled with an oxygen-rich gas mixture. This chaotic flow results in regions of high shear stress, as well as fluidic dead zones where blood stagnates.

[0009] Regions of chaos and stagnation within the oxygenator promote the formation and aggregation of blood clots. Over time, these clots accumulate and can lead to the failure of the oxygenator, necessitating its replacement and posing significant risks to the patient.

[0010] Standard microfluidic oxygenator designs aim to provide controlled blood flow through a series of small channels. These devices are proposed as an alternative to traditional hollow-fiber oxygenators due to their potential for precise flow control; however, they suffer from diffusion limitations, high internal shear stress, and increased fluidic resistance, which can lead to clot formation and manufacturing complexity.

[0011] The internal structure of existing microfluidic oxygenators use complex networks of microchannels designed to facilitate gas exchange. Typically a series of microscale channels filled with blood run orthogonal to a series of microscale channels filled with oxygen, with a membrane separating the two. The layout aims to optimize oxygenation efficiency by controlling blood flow through the channels; however, the complex geometry can lead to high internal shear stress and fluidic resistance, which may cause blood cell damage and increase the risk of clot formation.

[0012] FIG. 1A depicts the traditional limitation of oxy genation efficiency in microchannels, where oxygen diffusion is only efficient within a short distance (< 100 pm) from the membrane.

[0013] In summary, while ECMO and artificial lung technologies are useful for managing severe respiratory failure and have demonstrated clinical benefits, their current designs are hindered by significant complications, including: clotting complications, hemocompatibility problems, non-uniform blood flow (further increasing risk of clot formation, as well as hemolysis and inflammation), high fluidic resistance (further increasing risk of clotting and inflammation), need for external centrifugal pump (introducing a potential failure point and further increasing the risk of hemolysis, inflammation, and cloting), use large thrombogenic surface area (further increasing risk of clot formation) and impracticability of replacement with microfluidic systems in clinical setting, uncontrolled flow and fluidic dead zones (triggering thrombotic and hemorrhagic events), bleeding complications (resulting from atempts to mitigate cloting), short lifespan of oxygenators, and need for significant management and monitoring. These shortcomings highlight the need for improved ECMO and artificial lung technologies that can provide efficient oxygenation without these drawbacks.

[0014] An oxygenator that does not trigger clot formation or immune activation would dramatically reduce the risk of serious complications associated with ECMO. such as stroke, limb ischemia, and hemorrhage, making this therapy much safer for patients. The reduced risk of complications decreases the chance of readmission or extended ICU stay, leading to significant financial savings, in addition to reduced post-ICU recovery time and beter overall outcomes.

[0015] Accordingly, there remains a need in the art for blood filtration and oxygenation systems that substantially eliminate blood stagnation zones and allow for greater efficiency in oxygenation of blood within a single device.

SUMMARY

[0016] The presently-disclosed subject mater meets some or all of the above-identified needs, as will become evident to those of ordinary skill in the art after a study of information provided in this document.

[0017] This Summary- describes several embodiments of the presently-disclosed subject mater, and in many cases lists variations and permutations of these embodiments. This Summary- is merely exemplary of the numerous and varied embodiments. Mention of one or more representative features of a given embodiment is likewise exemplary. Such an embodiment can ty pically exist with or without the feature(s) mentioned; likewise, those features can be applied to other embodiments of the presently-disclosed subject mater, whether listed in this Summary or not. To avoid excessive repetition, this Summary does not list or suggest all possible combinations of such features.

[0018] In some embodiments of the presently-disclosed subject mater, a blood filtration device is provided, which includes a series of channels having an internal surface presenting paterned surface features to rotate biological fluid flowing through the channels; and a gas- permeable membrane through which oxygen can diffuse into the biological fluid and carbon dioxide can diffuse out of the biological fluid.

[0019] In some embodiments of the presently-disclosed subject mater, a blood filtration device is provided, which includes a first series of channels having an internal surface presenting paterned surface features to rotate biological fluid flowing through the channels; a second series of channels for receiving a dialysate fluid; and a membrane through which components of a dialysate can diffuse into or out of the biological fluid, including wastes, toxins, and other solutes. In some embodiments of the presently-disclosed subject mater, a blood filtration device is provided, in which the channels of the second series have an internal surface presenting patterned surface features to rotate a dialysate fluid flowing through the second series of channels.

[0020] In some embodiments of the presently-disclosed subject mater, a system is provided for blood filtration and/or oxygenation, which includes a microfluidic device having a series of channels with an internal surface presenting paterned surface features to rotate biological fluid flowing through the channels; and a gas-permeable membrane through which oxygen can diffuse into the biological fluid and carbon dioxide can diffuse out of the biological fluid.

[0021] In some embodiments of the presently-disclosed subject mater, a system is provided for blood filtration, which includes a microfluidic device having a first series of channels having an internal surface presenting paterned surface features to rotate biological fluid flowing through the channels; a second series of channels for receiving a dialysate fluid; and a membrane through which components of a dialysate can diffuse into or out of the biological fluid, including wastes, toxins, and other solutes. In some embodiments of the presently-disclosed subject mater, a system is provided for blood filtration including a device, in which the channels of the second series have an internal surface presenting paterned surface features to rotate a dialysate fluid flowing through the second series of channels.

[0022] The presently-disclosed subject mater further includes a method of providing a blood filtration and/or oxygenation treatment to a subject in need thereof, which involves: providing a device or system as disclosed herein; connecting the device to the circulatory' system of the subject; initiating a supply of an oxygen-rich gas mixture to the oxygenation channels: monitoring blood flow and oxygenation levels; and disconnecting the device from the circulatory system of the subject when the treatment is complete.

[0023] The presently-disclosed subject matter further includes a method of providing a blood filtration treatment to a subject in need thereof, which involves providing a device or system as disclosed herein; connecting the device to the circulatory system of the subject; initiating a supply of dialysate to the channels; monitoring blood flow and solute levels; and disconnecting the device from the circulatory system of the subject when the treatment is complete.

[0024] The presently-disclosed subject matter further includes a method of increasing filtration efficiency of blood, which involves providing a device or system as disclosed herein; feeding blood through the channels having the surface features to rotate blood flowing through the channels; and determining the blood oxygenation levels, whereby the higher blood oxygenation level are achieved as compared to a device without the surface features.

[0025] The presently-disclosed subject matter further includes a method of increasing filtration efficiency of blood, which involves providing a device or system as disclosed herein; feeding blood through the channels having the surface features to rotate blood flowing through the channels; and determining the levels of wastes, toxins, and other solutes in the blood, whereby lower levels of these substances are achieved as compared to a device without the surface features.

BRIEF DESCRIPTION OF THE DRAWINGS

[0026] The unique features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are used, and the accompanying drawings of which:

[0027] FIG. 1A. Classical limitation of oxygenation efficiency in microchannels: This image depicts the traditional limitation where oxygen diffusion is only efficient within a short distance (< 100 pm) from the membrane, resulting in the need for complex internal geometry' and numerous microchannels.

[0028] FIG. IB. Unique approach to increase oxygen transfer: This image shows the approach of the currently-disclosed subject matter for enhancing oxygen transfer by introducing blood flow rotation, improving the efficiency of oxygen diffusion throughout microchannels and addressing the limitations of classical designs.

[0029] FIG. 2. Bar graph presenting the results of experiments comparing blood oxygenation levels. Bar 1 shows the baseline blood oxygenation level before going through any device. Bar 2 represents blood oxygenation after passing through the device with rotational features in accordance with the presently-disclosed subject matter, showing a significant increase in blood oxygenation levels (P O2 (mm Hg)). Bar 3 shows blood oxy genation after passing through a device without the rotational features of the presently- disclosed subject matter, showing significantly lower blood oxygenation levels. Bars 4 and 5 represent negative controls using CO2 instead of oxygen as a sweep gas, with and without rotational features, respectively.

[0030] FIG. 3. Numerical model results demonstrating fluid rotation in microfluidic channels with (right) and without (left) the effects of surface features.

[0031] FIG. 4. Experimental results demonstrating fluid rotation in microfluidic channels using surface features, (a) Example devices, (b) numerical simulation (left) compared to confocal microscope image (right) showing clockwise rotation of fluid

[0032] FIG. 5. Sample device containing internal features that result in rotational fluid flow. Blood path and gas path are separated by a thin gas-permeable membrane.

DESCRIPTION OF EXEMPLARY EMBODIMENTS

[0033] The details of one or more embodiments of the presently-disclosed subject matter are set forth in this document. Modifications to embodiments described in this document, and other embodiments, will be evident to those of ordinary skill in the art after a study of the information provided in this document. The information provided in this document, and particularly the specific details of the described exemplary' embodiments, is provided primarily for clearness of understanding and no unnecessary limitations are to be understood therefrom. In case of conflict, the specification of this document, including definitions, will control.

[0034] The presently-disclosed subject matter includes a system, device, and method for increasing filtration efficiency of blood using feature-induced fluid rotation. The presently- disclosed subject matter includes features patterned on the inside of channel walls to rotate blood flow, moving filtered blood away from a membrane surface and moving fresh, unfiltered blood into its place as it travels down the length of the channel.

[0035] The presently-disclosed subject matter includes a microfluidic filtration and oxygenator device and system that addresses many of the shortcomings of current extracorporeal membrane oxygenation (ECMO) technologies by controlling blood flow. The presently-disclosed subject matter also includes a microfluidic filtration device and system that addresses many of the shortcomings of current kidney dialysis and/or continuous renal replacement therapy (CRRT).

[0036] The design disclosed herein reduces or eliminates known drivers of clot formation and immune activation, significantly decreasing fluid flow' resistance, minimizing the necessary’ membrane surface area, controlling blood flow, and removing stagnant regions that promote coagulation. As a result, the risk of complications that increase the length, risk, and financial cost of hospitalization for patients in need of a blood filtration and/or oxygenation is reduced.

[0037] The presently-disclosed subject matter employs a unique rolling-fluid microfluidic oxygenator design that overcomes the limitations of traditional microfluidic systems. By using asymmetric surface features to rotate blood within microfluidic channels, freshly filtered and/or oxygenated blood is moved away from the membrane, and new blood is brought into contact as it travels through the channel. This method achieves efficient filtration and/or oxygenation in fewer, larger channels, decreasing internal shear and fluidic resistance. Data reflects a significant increase in filtration and/or oxygenation efficiency while maintaining low-force, controlled blood flow throughout the filtration channels. This design represents the lowest flow resistance filter and/or oxygenator available and the first to match the fluidic resistance of the natural lung and/or kidney.

[0038] Embodiments of the device disclosed herein allows for blood flow' through microfluidic channels, providing uniform, well-controlled flow that eliminates high shear regions triggering clotting and low-flow regions that allow for undesirable clot aggregation and growth. This unique rolling-fluid design has several distinct advantages over known commercial and microfluidic filters and/or oxygenators, including lower shear stress, increased uniformity in blood flow, and decreased flow resistance. Calculations show a resistance more than five-fold smaller than the lowest resistance filters and/or oxygenators currently available, eliminating the need for centrifugal pumps in, for example, ECMO and opening the door to true portable ECMO/artificial lung technology. Indeed, in some embodiments of the presently-disclosed subject matter, no pumps are required.

[0039] The presently-disclosed subject matter can be used for all patients who are currently identified to benefit from existing ECMO technology, but with a reduction in complications and a reduced or eliminated need for systemic anticoagulants. As will be appreciated upon study of the present document, the microfluidic rotation in extracorporeal blood flow can be applied to in other contexts, such as continuous renal replacement therapy (CRRT) and kidney hemodialysis, enhancing mass transfer between filtered blood and dialysate.

[0040] Among the benefits of the presently-disclosed subject matter are its ability to trigger less clotting and immune activation in blood, and to require less pumping pressure to operate. The presently-disclosed subject matter includes a system, device, and method for increasing extracorporeal filtration efficiency of blood using feature-induced fluid rotation. Features patterned on the inside of channel walls rotate blood flow, moving filtered blood away from the membrane surface and bringing fresh, unfiltered blood into its place as it travels down the length of the channel. This method significantly decreases the driving pressure necessary to pump blood through the filter and substantially increases the amount of blood that can be filtered in a single device.

[0041] The presently-disclosed subject matter provides a unique and beneficial improvement over prior technologies. It allows for increasing extracorporeal filtration efficiency of blood using feature-induced fluid rotation. Patterned surface features are provided in the internal surfaces (floor, ceiling, and/or walls) of a series of oxygenation channels, to rotate blood within the oxygenation channels with respect to its original trajectory. In some embodiments, the features can be asymmetrical. In some embodiments, the features can be symmetrical. Such features can be, for example, topographic features or chemical surface patterns. As the blood or other biological fluid flows through the channels, and rotates due to the features on the internal surfaces of the channels, there is an increased efficiency of dissolved species transport in extracorporeal filtration systems using the device as disclosed herein. Such systems can include ECMO, artificial lung, and kidney dialysis.

[0042] With reference to FIG. IB, the presently-disclosed subject matter provides a unique approach to increasing oxygen transfer by introducing blood flow rotation within the microfluidic channels. This is contrasted with the traditional limitation of oxygenation efficiency in microchannels, as depicted in FIG. 1A, where oxygen diffusion is only efficient within a short distance (< 100 pm) from the membrane.

[0043] The unique design of the presently-disclosed subject matter rotates freshly filtered and/or oxygenated blood away from the membrane and brings new blood into contact as it travels through the channel. As a result, and as contrasted with known microfluidic filter and/or oxygenator technology, the presently-disclosed subject matter provides for efficient filtration and/or oxygenation that can be achieved in fewer, larger channels, decreasing internal shear and fluidic resistance. This approach enhances oxygen and/or dialysate diffusion throughout the microchannels, addressing the limitations of classical designs and significantly improving oxygenation and/or filtration efficiency.

[0044] In some embodiments of the presently-disclosed subject matter, a blood filtration device is provided, which includes a series of channels having an internal surface presenting patterned surface features to rotate biological fluid flowing through the channels; and a gas- permeable membrane through which oxygen can diffuse into the biological fluid and carbon dioxide can diffuse out of the biological fluid.

[0045] In some embodiments of the presently-disclosed subject matter, a blood filtration device is provided, which includes a first series of channels having an internal surface presenting patterned surface features to rotate biological fluid flowing through the channels; a second series of channels for receiving a dialysate fluid; and a membrane through which components of a dialysate can diffuse into or out of the biological fluid, including wastes, toxins, and other solutes. In some embodiments of the presently-disclosed subject matter, a blood filtration device is provided, in which the channels of the second series have an internal surface presenting patterned surface features to rotate a dialysate fluid flowing through the second series of channels. [0046] In some embodiments, the biological fluid is blood. In some embodiments of the device, the channels are microfluidic channels. In some embodiments of the device, the surface features are topographic features or chemical surface patterns.

[0047] In some embodiments, the device include a gas supply system for providing an oxygen-rich gas mixture to the oxygenation channels. In some embodiments, the device includes a dialysate supply system for providing an dialysate to the channels.

[0048] In some embodiments, the device include a heat exchanger for regulating the temperature of the blood. In some embodiments, the device include a pump to facilitate movement of the blood. In some embodiments, the device include a system for monitoring and controlling blood flow, oxygenation levels, and other desired parameters.

[0049] In some embodiments of the presently-disclosed subject matter, a system is provided for blood filtration and/or oxygenation, which includes a microfluidic device having a series of channels with an internal surface presenting patterned surface features to rotate biological fluid flowing through the channels; and a gas-permeable membrane through which oxy gen can diffuse into the biological fluid and carbon dioxide can diffuse out of the biological fluid.

[0050] In some embodiments of the presently-disclosed subject matter, a system is provided for blood filtration, which includes a microfluidic device having a first series of channels having an internal surface presenting patterned surface features to rotate biological fluid flowing through the channels; a second series of channels for receiving a dialysate fluid; and a membrane through which components of a dialysate can diffuse into or out of the biological fluid, including wastes, toxins, and other solutes. In some embodiments of the presently-disclosed subject matter, a system is provided for blood filtration including a device, in which the channels of the second series have an internal surface presenting patterned surface features to rotate a dialysate fluid flowing through the second series of channels.

[0051] In some embodiments, the system further includes a system for monitoring and controlling blood flow, oxygenation levels, dialysate, and/or other desired parameters. In some embodiments, the system further includes one or more of a gas supply system for providing an oxygen-rich gas mixture to the oxygenation channels; a dialysate supply system for providing an dialysate to the channels; a heat exchanger for regulating the temperature of the blood; and a pump to facilitate movement of the blood.

[0052] The presently-disclosed subject matter further includes a method of providing a blood filtration and/or oxygenation treatment to a subject in need thereof, which involves: providing a device or system as disclosed herein; connecting the device to the circulatoiy system of the subject; initiating a supply of an oxygen-rich gas mixture to the oxygenation channels; monitoring blood flow and oxygenation levels; and disconnecting the device from the circulatory system of the subj ect when the treatment is complete.

[0053] The presently-disclosed subject matter further includes a method of providing a blood filtration treatment to a subject in need thereof, which involves providing a device or system as disclosed herein; connecting the device to the circulatory⁷ system of the subject; initiating a supply of dialysate to the channels; monitoring blood flow and solute levels; and disconnecting the device from the circulatory system of the subject when the treatment is complete.

[0054] Some embodiments of the method further involve monitoring the rotation of the blood by the patterned surface features as it flows through the channels.

[0055] Some embodiments of the method further involve activating a pump to facilitate movement of blood through the device. Some embodiments of the method further involve regulating the temperature of the blood using the heat exchanger to maintain optimal conditions for blood filtration and/or oxygenation. Some embodiments of the method further involve adjusting flow rate, gas mixture, dialysate, and/or temperature to facilitate efficient oxygenation and/or filtration of the blood.

[0056] Some embodiments of the method further involve collecting data on the performance of the device. In some embodiments, the performance of the device refers to oxygenation efficiency, fluidic resistance, and any signs of clot formation or immune actu ation. Some embodiments of the method further involve adjusting flow rate, gas mixture, dialysate, and/or temperature based on the collected data.

[0057] The presently-disclosed subject matter further includes a method of increasing filtration efficiency of blood, which involves providing a device or system as disclosed herein; feeding blood through the channels having the surface features to rotate blood flowing through the channels; and determining the blood oxygenation levels, whereby the higher blood oxygenation level are achieved as compared to a device without the surface features.

[0058] The presently-disclosed subject matter further includes a method of increasing filtration efficiency of blood, which involves providing a device or system as disclosed herein; feeding blood through the channels having the surface features to rotate blood flowing through the channels; and determining the levels of wastes, toxins, and other solutes in the blood, whereby lower levels of these substances are achieved as compared to a device without the surface features.

[0059] Some embodiments of the method further involve monitoring the rotation of the blood by the patterned surface features as it flows through the oxygenation channels.

[0060] Some embodiments of the method further involve activating a pump to facilitate movement of blood through the device. Some embodiments of the method further involve regulating the temperature of the blood using the heat exchanger to maintain optimal conditions for blood filtration and oxygenation. Some embodiments of the method further involve adjusting flow rate, gas mixture, dialysate, and/or temperature to facilitate efficient oxygenation and filtration of the blood.

[0061] Some embodiments of the method further involve collecting data on the performance of the device. In some embodiments, the performance of the device refers to filtration efficiency and/or oxygenation efficiency, fluidic resistance, and any signs of clot formation or immune activation. Some embodiments of the method further involve adjusting flow rate, gas mixture, and/or temperature based on the collected data.

[0062] The presently-disclosed subject matter provides for a unique and beneficial improvement over prior technologies. The presently-disclosed subject matter allows for increasing extracorporeal filtration efficiency of blood using feature-induced fluid rotation The presently-disclosed subject matter utilizes features on the inside walls of channel-based filters to rotate fluid flow, increasing the efficiency of dissolved species transport in extracorporeal filtration systems, such as ECMO, artificial lung, and kidney dialysis.

[0063] The presently-disclosed subject matter uses features patterned on the inside of channel filter walls to rotate blood flow, moving filtered blood away from the membrane surface and moving fresh, unfiltered blood into its place as it travels dow n the length of the channel. This can be accomplished using, for example, topographic features or chemical surface patterns, and the features can be present on the internal floor, ceiling, and/or walls of the channel. In some embodiments, the features can be asymmetrical features. In some embodiments, the features can be symmetrical features. In some embodiments, the features can be raised asymmetrical features. In some embodiments, the features can be raised symmetrical features. In some embodiments the features can be surface patterns that are not raised.

[0064] While the terms used herein are believed to be well understood by those of ordinary skill in the art, certain definitions are set forth to facilitate explanation of the presently-disclosed subject matter.

[0065] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the invention(s) belong.

[0066] All patents, patent applications, published applications and publications, databases, websites and other published materials referred to throughout the entire disclosure herein, unless noted otherwise, are incorporated by reference in their entirety.

[0067] Where reference is made to a URL or other such identifier or address, it understood that such identifiers can change and particular information on the internet can come and go. but equivalent information can be found by searching the internet. Reference thereto evidences the availability and public dissemination of such information.

[0068] Although any methods, devices, and materials similar or equivalent to those described herein can be used in the practice or testing of the presently-disclosed subject matter, representative methods, devices, and materials are described herein.

[0069] Following long-standing patent law convention, the terms “a’', "an", and ‘‘the” refer to “one or more” when used in this application, including the claims. Thus, for example, reference to “a cell” includes a plurality of such cells, and so forth.

[0070] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and claims are approximations that can vary depending upon the desired properties sought to be obtained by the presently-disclosed subject matter.

[0071] As used herein, the term “about,” when referring to a value or to an amount of mass, weight, time, volume, concentration or percentage is meant to encompass variations of in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, in some embodiments ±0.1%, in some embodiments ±0.01%, and in some embodiments ±0.001% from the specified amount, as such variations are appropriate to perform the disclosed method.

[0072] As used herein, ranges can be expressed as from “about” one particular value, and/or to “about” another particular value. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0073] As used herein, the term “biological fluid” refers to fluids obtained from a subject for which it could be useful to filter or infuse with a particular gas. Examples of such biological fluids include blood, plasma, cerebrospinal fluid, lymph, peritoneal fluid, pleural fluid, synovial fluid, amniotic fluid, gastric fluid, urine, saliva, tears, bile, and semen. The following are non-limiting examples of the manner in w hich filtration of exemplary biological fluids could be supported by the presently-disclosed subject matter. Blood is commonly infused with oxygen during extracorporeal oxygenation or filtered to remove carbon dioxide and waste products. Cerebrospinal fluid, which surrounds the brain and spinal cord, can benefit from oxygen infusion or waste filtration to support neurological health or for research purposes. Lymph, a fluid essential for immune function and w aste removal, could be enhanced by gas infusion to stimulate lymphatic flow. Peritoneal fluid, found in the abdominal cavity, is often exposed to carbon dioxide during laparoscopic surgeries to expand the cavity safely. Pleural fluid, located between the lungs and chest all, could be managed with controlled gas infusion to address pleural effusion or assist in lung expansion. Synovial fluid, which lubricates joints, might benefit from filtering to remove inflammatory mediators, while oxygenation could promote joint health. Amniotic fluid, surrounding the fetus during pregnancy, could be infused with gas to support fetal health during specific medical procedures. Gastric fluid, found in the stomach, is sometimes exposed to carbon dioxide during endoscopic procedures to safely distend the stomach. Urine has been explored for gas infusion, such as ozone, for sterilization purposes in medical research. Saliva, a key component in oral health, could benefit from oxygenation or other gas treatments to promote wound healing and improve hygiene. Tears, which protect and nourish the eyes, might be infused with specific gases to support ocular health or drug deliver}' innovations. Bile, produced by the liver to aid digestion, could theoretically be treated with gas infusion to improve liver function in experimental settings. Lastly, semen might be filtered or oxygenated to enhance fertility’ treatments.

[0074] The present application can “comprise” (open ended) or “consist essentially of’ the components of the present invention as well as other ingredients or elements described herein. As used herein, “comprising” is open ended and means the elements recited, or their equivalent in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended unless the context suggests otherwise.

[0075] The term “microfluidic” refers to systems that contain channels with dimensions of tens of micrometers to several millimeters. In some embodiments the channels can have dimensions of about 1 to about 2 millimeters. These systems leverage the unique properties of fluids at the micro- and millimeter-scale to achieve precise control and manipulation.

[0076] As used herein, “optional” or “optionally” means that the subsequently described event or circumstance does or does not occur and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, an optionally variant portion means that the portion is variant or non-variant.

[0077] As used herein, the term “subject” includes both human and animal subjects. Thus, veterinary therapeutic uses are provided in accordance with the presently disclosed subject matter. As such, the presently disclosed subject matter provides for the treatment of mammals such as humans, as well as those mammals of importance due to being endangered, of economic importance, and/or animals of social importance to humans, such as animals kept as pets, as race horse, or in zoos. [0078] The presently-disclosed subject matter is further illustrated by the following specific but non-limiting examples. The following include some examples that are prophetic. The following examples may include compilations of information that are representative of information gathered at various times during the course of development related to the presently-disclosed subject matter.

EXAMPLES

[0079] Example 1: Blood Oxygenation Study

[0080] A study was conducted that demonstrates the efficacy of a microfluidic oxygenator design with rotational features for enhancing blood oxygenation levels, in accordance with the presently-disclosed subject matter. The results of this study are provided in FIG. 2

[0081] Microfluidic oxygenator devices were fabricated using polydimethylsiloxane (PDMS) casting on 3D printed molds. Membranes were made from thin layers of PDMS spin-coated on a flexible substrate. Membranes and channels were bonded together using oxy gen plasma bonding.

[0082] Whole blood samples were obtained and oxygen saturation levels were measured using an FDA-approved device (iSTAT, Abbot). Blood was fed through the microfluidic oxygenator devices using a syringe pump to control blood speed in the devices. Devices with and without rotational features were tested. Negative controls were conducted using CO2 instead of oxygen as the sweep gas.

[0083] Blood oxygenation levels were measured pre- and post-device using an FDA- approved device (iSTAT, Abbott). The partial pressure of oxygen (P O2) was recorded for each condition.

[0084] The results of the study are provided in FIG. 2, which is a bar graph showing the partial pressure of oxygen (P O2_? mmHg) for each condition: Bar 1: Baseline (blood oxygenation levels before going through any device); Bar 2: O2, Features (blood oxygenation levels after going through the device with rotational features in accordance with the presently-disclosed subject matter); Bar 3: O2, No Features (blood oxygenation levels after going through a device without rotational features); Bar 4: CO2, Features (negative control using CO2 as the sweep gas with rotational features); and Bar 5: CO2, No Features (negative control using CO2 as the sweep gas without rotational features).

[0085] The results indicate that the device with rotational features (Bar 2) achieved significantly higher blood oxygenation levels compared to the baseline (Bar 1) and the device without rotational features (Bar 3). The negative controls (Bars 4 and 5) showed no significant increase in blood oxygenation levels, confirming the efficacy of the oxygen-rich gas mixture and the rotational features in enhancing oxygen transfer.

[0086] This study demonstrates that the presently-disclosed microfluidic oxygenator design with rotational features significantly improves blood oxygenation levels compared to devices without such features.

[0087] Example !: Embodiment of Device

[0088] With reference to FIG. 3, numerical model results demonstrating fluid rotation in microfluidic channels are presented. The left panel illustrates fluid flow in the absence of surface features, characterized by a predominantly linear flow' profile. The right panel demonstrates the introduction of surface features within the microfluidic channel, resulting in pronounced rotational flow patterns, as indicated by the streamlines and velocity gradients.

[0089] With reference to FIG. 4, experimental results validating fluid rotation within microfluidic channels using engineered surface features are presented. Panel (a) presents example devices designed for inducing rotational flow through patterned microstructures. Panel (b) compares numerical simulations (left) predicting clockwise fluid rotation with confocal microscope images (right) capturing the corresponding experimental results, confirming the simulated rotational flow direction and intensity.

[0090] With reference to FIG. 5, a sample device comprising internal features configured to generate rotational fluid flow is presented. The device includes distinct blood and gas flow' paths separated by a thin gas-permeable membrane. This configuration facilitates controlled gas exchange while maintaining independent flow circuits, with the internal surface structures promoting rotational fluid dynamics within the blood path for enhanced mixing and exchange efficiency. [0091] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference, including the references set forth in the following list:

REFERENCES

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11. Betit, P., Technical Advances in the Field of ECMO. Respiratory Care, 2018. 63(9): p. 1162-1173.

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14. Evseev. A., et al., Membranes in extracorporeal blood oxygenation technology. Membranes and Membrane Technologies, 2019. 1: p. 201-211.

15. Birkenmaier, C., et al., Analysis of Thrombotic Deposits in Extracorporeal Membrane Oxygenators by High-resolution Microcomputed Tomography: A Feasibility Study. ASAIO Journal, 2020. 66(8): p. 922-928.

16. Sharifi, A. and D. Bark, Mechanical forces impacting cleavage of Von Willebrand factor in laminar and turbulent blood flow. Fluids. 2021. 6(2): p. 67.

17. Bortot, M., et al., Turbulent flow promotes cleavage of VWF (von Willebrand factor) by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type-1 motif, member 13). Arteriosclerosis, thrombosis, and vascular biology, 2019. 39(9): p. 1831-1842.

18. Nobili, M., et al., Platelet activation due to hemodynamic shear stresses: damage accumulation model and comparison to in vitro measurements. ASAIO journal (American Society for Artificial Internal Organs: 1992), 2008. 54(1): p. 64.

19. Roka-Moiia, Y., et al., Platelet activation via shear stress exposure induces a differing pattern of biomarkers of activation versus biochemical agonists. Thrombosis and haemostasis, 2020. 120(05): p. 776-792.

20. Mazzeffi, M., et al., Variation in Hospitalization Costs, Charges, and Lengths of Hospital Stay for Coronavirus Disease 2019 Patients Treated With Venovenous Extracorporeal Membrane Oxygenation in the United States: A Cohort Study. J Cardiothorac Vase Anesth. 2023. 37(8): p. 1449-1455.

21. Thompson, A.J., et al., Design analysis and optimization of a single-layer PDMS microfluidic artificial lung. IEEE Transactions on Biomedical Engineering, 2018. 66(4): p. 1082-1093.

22. Astor, T.L. and J.T. Borenstein, The microfluidic artificial lung: Mimicking nature's blood path design to solve the biocompatibility paradox. Artificial Organs, 2022. 46(7): p. 1227-1239.

23. Orizondo, R.A., et al., Artificial lungs: current status and future directions. Current Transplantation Reports, 2019. 6: p. 307-315.

24. Thompson. A., et al.. A small-scale, rolled-membrane microfluidic artificial lung designed towards future large area manufacturing. Biomicrofluidics, 2017. 11(2).

25. Kovach, K., et al., In vitro evaluation and in vivo demonstration of a biomimetic, hemocompatible, microfluidic artificial lung. Lab on a Chip, 2015. 15(5): p. 1366-1375.

26. Dabaghi, M., et al., An ultra-thin highly flexible microfluidic device for blood oxygenation. Lab on a Chip, 2018. 18(24): p. 3780-3789.

27. Matharoo, H., et al., Steel reinforced composite silicone membranes and its integration to microfluidic oxygenators for high performance gas exchange. Biomicrofluidics, 2018. 12(1).

28. Rieper, T., C. Muller, and H. Reinecke, Novel scalable and monolithically integrated extracorporeal gas exchange device. Biomedical microdevices, 2015. 17: p. 1-10.

29. Stroock, A.D., et al., Chaotic mixer for microchannels. Science. 2002. 295(5555): p. 647-651.

30. Hama, B., et al., Evolution of mixing in a microfluidic reverse-staggered herringbone micromixer. Microfluidics and Nanofluidics, 2018. 22: p. 1-14. 31. Shigemura, N., Extracorporeal lung support for advanced lung failure: a new era in thoracic surgery and translational science. Gen Thorac Cardiovasc Surg, 2018. 66(3): p. 130- 136.

32. Dabaghi, M., et al., An artificial placenta ty pe microfluidic blood oxygenator with double-sided gas transfer microchannels and its integration as a neonatal lung assist device. Biomicrofluidics, 2018. 12(4).

33. Toomasian, J.M. and R.H. Bartlett, Hemolysis and ECMO pumps in the 21st century'. Perfusion, 2011. 26(1): p. 5.

34. Halaweish, I., et al., Roller and centrifugal pumps: a retrospective comparison of bleeding complications in extracorporeal membrane oxygenation. Asaio Journal, 2015. 61(5): p. 496-501.

35. Paudel, R., et al., Mechanical Power: A New Concept in Mechanical Ventilation. The American Journal of the Medical Sciences, 2021. 362(6): p. 537-545.

36. Trinkle, C.A., et al., Simple, accurate calculation of mechanical power in pressure controlled ventilation (PCV). Intensive Care Medicine Experimental, 2022. 10(1): p. 22.

37. Doyle, A.J. and B.J. Hunt, Current understanding of how extracorporeal membrane oxygenators activate haemostasis and other blood components. Frontiers in medicine, 2018. 5: p. 352.

38. Boes, S., et al., Control of the fluid viscosity in a mock circulation. Artificial organs, 2018. 42(1): p. 68-77.

[0092] It will be understood that various details of the presently disclosed subject matter can be changed without departing from the scope of the subject matter disclosed herein. Furthermore, the foregoing description is for the purpose of illustration only, and not for the purpose of limitation.

Claims

CLAIMS What is claimed is:

1. A filtration device for biological fluid, comprising: a series of channels having an internal surface presenting patterned surface features to rotate biological fluid flowing through the channels; and a gas-permeable membrane through which oxygen can diffuse into the biological fluid and carbon dioxide can diffuse out of the biological fluid.

2. The device of claim 1, wherein the biological fluid is blood.

3. The device of claim 2, and further comprising a gas supply system for providing an oxygen-nch gas mixture to the channels.

4. The device of claim 2, and further comprising a heat exchanger for regulating the temperature of the blood.

5. The device of claim 2, and further comprising a pump to facilitate movement of the blood.

6. The device of claim 2, and further comprising a system for monitoring and controlling blood flow, oxygenation levels, and/or other desired parameters.

7. The device of claim 6, and further comprising a gas supply system for providing an oxygen-rich gas mixture to the oxygenation channels.

8. The device of claim 6, and further comprising a heat exchanger for regulating the temperature of the blood.

9. The device of claim 6, and further comprising a pump to facilitate movement of the blood.

10. The device of claim 2, and further comprising: a system for monitoring and controlling blood flow, oxygenation levels, and other desired parameters; a gas supply system for providing an oxygen-rich gas mixture to the oxygenation channels: a heat exchanger for regulating the temperature of the blood; and a pump to facilitate movement of the blood.

11. The device of claim 2, wherein the oxygenation channels are microfluidic channels.

12. The device of claim 2, wherein the surface features are topographic features or chemical surface patterns.

13. A method of providing a blood filtration treatment to a subject, comprising: a) providing a device according to any one of claims 2-12; b) connecting the device to the circulatory system of the subject; c) initiating a supply of an oxygen-rich gas mixture to the channels; d) monitoring blood flow and oxygenation levels; and e) disconnecting the device from the circulatory system of the subject when the treatment is complete.

14. The method of claim 13, and further comprising monitoring the rotation of the blood by the patterned surface features as it flows through the channels.

15. The method of claim 13, and further comprising activating a pump to facilitate movement of blood through the device.

16. The method of claim 13, and further comprising regulating the temperature of the blood using the heat exchanger to maintain optimal conditions for blood filtration and oxygenation.

17. The method of claim 13, and further comprising adjusting flow rate, gas mixture, and/or temperature to facilitate efficient oxygenation and filtration of the blood.

18. The method of claim 13, and further comprising collecting data on the performance of the device.

19. The method of claim 18, wherein the performance of the device includes oxygenation efficiency, fluidic resistance, and any signs of clot formation or immune activation.

20. The method of claim 18, and further comprising adjusting flow rate, gas mixture, and/or temperature based on the collected data.

21. A method of increasing filtration efficiency of blood, comprising: a) providing a device according to any one of claims 2-12; b) feeding blood through the oxygenation channels having the surface features to rotate blood flowing through the channels; and c) determining the blood oxygenation levels, whereby the higher blood oxygenation level are achieved as compared to a device without the surface features.

22. A filtration device for biological fluid, comprising: a first series of channels having an internal surface presenting patterned surface features to rotate biological fluid flowing through the channels; a second series of channels for receiving a dialysate fluid; and a membrane through which components of a dialysate can diffuse into or out of the biological fluid, including wastes, toxins, and other solutes.

23. The device of claim 22, wherein the channels of the second series have an internal surface presenting patterned surface features to rotate the dialysate fluid flowing through the second series of channels.

24. The device of claim 22, wherein the biological fluid is blood.

25. The device of claim 24, and further comprising a dialysate supply system for providing a dialysate to the channels.

26. The device of claim 24, and further comprising a heat exchanger for regulating the temperature of the blood.

27. The device of claim 24, and further comprising a pump to facilitate movement of the blood.

28. The device of claim 24, and further comprising a system for monitoring and controlling blood flow and/or other desired parameters.

29. The device of claim 28. and further comprising a dialysate supply system for providing an dialysate to the channels.

30. The device of claim 28, and further comprising a heat exchanger for regulating the temperature of the blood.

31. The device of claim 28, and further comprising a pump to facilitate movement of the blood.

32. The device of claim 24. and further comprising: a system for monitoring and controlling blood flow, dialysate flow, and other desired parameters; a dialysate supply system for providing dialysate to the channels; a heat exchanger for regulating the temperature of the blood; and a pump to facilitate movement of the blood.

33. The device of claim 24, wherein the oxygenation channels are microfluidic channels.

34. The device of claim 24, wherein the surface features are topographic features or chemical surface patterns.

35. A method of providing a blood filtration treatment to a subject, comprising: a) providing a device according to any one of claims 24-34; b) connecting the device to the circulatory system of the subject; c) initiating a supply of dialysate to the channels; d) monitoring blood flow and solute levels; and e) disconnecting the device from the circulatory' system of the subject when the treatment is complete.

36. The method of claim 35, and further comprising monitoring the rotation of the blood by the patterned surface features as it flows through the channels.

37. The method of claim 35, and further comprising activating a pump to facilitate movement of blood through the device.

38. The method of claim 35, and further comprising regulating the temperature of the blood using the heat exchanger to maintain optimal conditions for blood filtration and oxygenation.

39. The method of claim 35, and further comprising adjusting flow rate, dialysate, and/or temperature to facilitate efficient filtration of the blood.

40. The method of claim 35, and further comprising collecting data on the performance of the device.

41. The method of claim 40, wherein the performance of the device includes filtration efficiency, fluidic resistance, and any signs of clot formation or immune activation.

42. The method of claim 40, and further comprising adjusting flow rate, dialysate, and/or temperature based on the collected data.

43. A method of increasing filtration efficiency of blood, comprising: a) providing a device according to any one of claims 24-34; b) feeding blood through the channels having the surface features to rotate blood flowing through the channels; and c) determining the levels of wastes, toxins, and other solutes in the blood, whereby lower levels of these substances are achieved as compared to a device without the surface features.