Mass transfer device for the treatment of biological fluids and methods of use

Abstract

The present disclosure provides, in part, devices and compositions comprising a dual-cartridge extracorporeal transfer module for removing and / or adding one or more ions to a biological fluid, and methods of using the same.

Description

MASS TRANSFER DEVICE FOR THE TREATMENT OF BIOLOGICAL FLUIDS AND METHODS OF USEFIELD

[0001] The present disclosure relates to, in part, devices comprising an extracorporeal transfer module for removing and adding ionic species and dissolved gases in a biological sample and methods of using the same.CROSS REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 553,237, filed February 14, 2024, the entire contents of which are incorporated by reference herein.BACKGROUND

[0003] Hypercapnia is characterized by the accumulation of carbon dioxide (CO2) in the blood. If left untreated, hypercapnia leads to systemic acidosis, respiratory failure, and even death. Common causes of hypercapnia include various diseases, conditions, as well as respiratory system impairments. The most common diseases and conditions that affect the lungs are chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, obesity hypoventilation syndrome, opioid abuse, and neuromuscular diseases such as amyotrophic lateral sclerosis. The morbidity and mortality caused by chronic conditions arises from acute exacerbations of conditions, which rapidly increase systemic CO2 levels and necessitate immediate hospitalization. Hypercapnia also arises from respiratory system impairments such as acute lung injury (ALI), which may be caused by direct insults like pulmonary infections or aspiration of gastric contents, as well as indirect factors like trauma or sepsis. Severe ALI, known as acute respiratory distress syndrome (ARDS), results in reduced lung compliance and increased work of breathing required to maintain adequate ventilation. This initiates a cycle of progressive lung injury, leading to worsening compliance, insufficient ventilation, and further aggravation of hypercapnia.

[0004] To restore hemostasis for patients with hypercapnia and associated conditions, the standard of care is to employ a mechanical means to enhance ventilation and facilitate CO2 elimination. Mechanical ventilation can be delivered non-invasively through a face mask or helmet, or invasively through endotracheal intubation or tracheostomy. Mechanical ventilation uses positive pressure to cycle delivery of a specified volume of air to the patient’s airway. While mechanical ventilation improves ventilation in injured or impaired lungs, the delivery of positive airway pressure carries the risks of exacerbating underlying injury and promoting further lung damage, which worsens patient survival and lessen the likelihood of full recovery.Mechanical ventilation is also associated with risks of aspiration, complications that derive from the presence of an indwelling foreign body within the airway (such as ventilation-associated pneumonia), and from the use of sedatives, which are often necessary for patient tolerance of intubation or assisted ventilation.

[0005] Alternatively, extracorporeal methods of removing CO2 directly from the blood are a potential means of reducing the ventilatory burden on injured lungs. Extracorporeal membrane oxygenation (ECMO) is a form of lung support in which venous blood is withdrawn via a mechanical pump and passed through a gas exchange device - termed an oxygenator, which serves to both add oxygen and remove CO2 from the blood. The treated blood is then returned to the patient’s circulatory system either through a separate cannulation or through the same insertion site from which the venous blood was withdrawn with the aid of a double lumen cannula.

[0006] Modern oxygenators achieve oxygenation and CO2 removal through diffusion of gaseous molecules across a selectively-permeable hollow fiber membrane. These hollow fiber membranes are composed of hundreds to thousands of individual hollow fibers arranged in configurations such that blood passes on one side of the hollow fiber and a gaseous mixture (referred to as the sweep gas) passes on the other side of the hollow fiber. The sweep gas may vary in composition depending on the patient size, clinical condition, or intended purpose of therapy, but often it is composed of a clinician-determined mixture of medical-grade room air and oxygen. Accordingly, the sweep gas composition facilitates passive diffusion of molecules across the semi-permeable hollow fiber membrane to mimic the physiologic function of the patient’s lungs such that oxygen diffuses into the blood and CO2 diffuses out of the blood along concentration gradients with a continuous flow of sweep gas.

[0007] ECMO is commonly employed to support patients with severe hypoxic respiratory failure in which high blood flow rates (typically 4-6 L / min) through the extracorporeal circuit are required to achieve clinically sufficient oxygen delivery. Extracorporeal CO2 removal (ECCO2R) is a low blood flow adaptation (typically 1- 2 L / min) of the principles of ECMO in which blood is passed through an oxygenator for the primary purpose of achieving physiologically significant CO2 removal to support patients with hypercapnic respiratory failure. Both ECMO and ECCO2R methods of mass transfer are limited solely to the diffusion of gaseous constituents. Therefore, traditional ECMO and ECCO2R technologies are functionally active only on removal of the gaseous CO2 dissolved in the blood, which represents just 5-10% of the total CO2 content per unit volume. The remaining portion of the total CO2 content is predominantly transported in the blood as bicarbonate and is not directly removed by current extracorporeal lung support devices. This mismatchedefficiency is the primary driver for requiring large membrane surface areas (> 1 m2) and high volumetric blood flow rates (> 1 L / min) for extracorporeal therapies to be clinically beneficial in adult patient populations. While ECMO and ECCO2R therapies may mitigate some of the risks with mechanical ventilation, the resulting foreign surface area, together with an extensive tubing circuit, affects biocompatibility and creates secondary areas of risk in patient care, such as the need for controlling anticoagulation and monitoring blood trauma. Moreover, the placement of large bore cannula(s) (such as a 32 Fr double lumen cannula used in ECMO) needed to support the high blood flow rates and the bleeding risks that are introduced relegate traditional ECMO and ECCO2R practices to only highly specialized surgical centers.

[0008] The same principles of diffusion across a membrane have been adopted in filtration and dialysis, where solutes, toxins, and other forms of fluid processing are achieved by passing a liquid solution ( / .e., a dialysate) with specific properties on one side of a semi-permeable membrane, with the target fluid (e.g., blood) passing on the other side of the membrane. In most cases, the dialysate solution is a formulation with an ionic composition and purity designed to maintain (or restore) homeostatic balance, while removing undesirable compounds such as toxins or waste products.

[0009] Adaptation of a dialysis approach in clinical practices to reduce the total CO2 through removal of bicarbonate ions would affect blood chemistries through physiologic principles governing the transport and storage of CO2 within the body. The balance of biologic constituents involving total CO2 content is governed by the bicarbonate buffer system, which modulates concentrations of gaseous CO2 with bicarbonate ions through the intermediary carbonic acid (H2CO3). This system is also one of the most important mechanisms the body uses to maintain pH equilibrium and is represented by the following equation:CO2 + H2O H2CO3 H++ HCO3’

[0010] Under normal physiological conditions, this reversible equation shifts the products and reactants to maintain a constant blood pH. However, a rapid and unbalanced removal of a clinically meaningful amount of CO2 through the clearance of bicarbonate ions would induce significant acidosis of the blood because of an equilibrium re-stabilization that would generate elevated quantities of H+ and severely affect patient health. Conversely, the unbalanced removal of gaseous CO2 has the potential to consume excessive quantities of H+, inducing symptomatic alkalemia.

[0011] There, therefore, remains a need for devices, systems, and methods that meet the clinical requirements of reducing elevated CO2 levels, by accounting for blood pH homeostasis and impaired lungfunction, while minimizing the risks and complications associated with traditional ventilatory and extracorporeal therapies.SUMMARY

[0012] Accordingly, the present disclosure provides, in part, an extracorporeal transfer module for a biological fluid comprising a housing, a first bundle of hollow fiber membranes disposed within the housing, the first bundle having a plurality of hollow fiber membranes, arranged axially or orthogonally relative to the housing, where the first bundle of hollow fiber membranes is configured for laminar extraluminal or intraluminal flow of a dialysate or sweep gas therethrough, at least a second bundle of hollow fiber membranes disposed within the housing, the second bundle having a plurality of hollow fiber membranes, arranged axially or orthogonally relative to the first bundle of hollow fiber membranes, where the second bundle of hollow fiber membranes is configured for laminar extraluminal or intraluminal flow of a dialysate or sweep gas therethrough, a lumen transition region comprising a void space between the first bundle of hollow fiber membranes and the second bundle of hollow fiber membranes configured to flow the biological fluid, extralu min ally to intraluminally, intraluminally to extraluminally, extraluminally to extraluminally, and / or intraluminally to intraluminally, where the housing comprises at least one potting portion that bonds at least one open end of the first bundle of hollow fiber membranes and bonds at least one open end of the second bundle of hollow fiber membranes, such that the first bundle of hollow fiber membranes and the second bundle of hollow fiber membranes are configured to receive a dialysate and / or a sweep gas from outside of the housing.

[0013] In embodiments, the biological fluid is blood. In embodiments, the housing is cylindrical.

[0014] In embodiments, the first bundle of hollow fiber membranes and the second bundle of hollow fiber membranes are comprised of semi-permeable material that is configured to transfer one or more ionic species, dissolved gases, or similar molecules and compounds from and / or to the biological fluid.

[0015] In embodiments, the one or more dissolved gases comprises gaseous carbon dioxide (CO2) and is transferred from the biological fluid. In embodiments, the one or more dissolved ionic species comprises bicarbonate (HCO3’) and is transferred from the biological fluid. In embodiments, the one or more dissolved gases comprises oxygen (O2) and is transferred to the biological fluid. In embodiments, the one or more dissolved ionic species comprises calcium, chloride, sodium, potassium, and / or magnesium, and is transferred to the biological fluid. In embodiments, the one or more similar molecules and compounds comprises urea, ammonia, creatinine, water, and / or plasma, and is transferred from the biological fluid. Inembodiments, the one or more similar molecules and compounds comprises glucose, a pH-buffering agent, and / or water, and is transferred to the biological fluid.

[0016] In embodiments, the first bundle of hollow fiber membranes is configured for laminar extraluminal flow through the hollow fiber membranes, and the second bundle of hollow fiber membranes is configured for laminar intraluminal flow through the hollow fiber membranes; or where the first bundle of hollow fiber membranes is configured for laminar intraluminal flow through the hollow fiber membranes, and the second bundle of hollow fiber membranes is configured for laminar extraluminal flow through the hollow fiber membranes.

[0017] In embodiments, the extracorporeal transfer module is configured for a sweep gas to flow intraluminally through the first bundle of hollow fiber membranes, where the biological fluid is configured to flow extraluminally relative to the first bundle of hollow fiber membranes; and is configured for a dialysate to flow extraluminally through the second bundle of hollow fiber membranes, where the biological fluid is configured to flow intraluminally relative to the second bundle of hollow fiber membranes.

[0018] In embodiments, the second bundle of hollow fiber membranes is arranged substantially orthogonally relative to the first bundle of hollow fiber membranes.

[0019] In embodiments, the extracorporeal transfer module is configured to flow the dialysate with a flow rate of less than about 500 mL / min, less than about 450 mL / min, less than about 400 mL / min, less than about 350 mL / min, less than about 300 mL / min, less than about 250 mL / min, less than about 200 mL / min, less than about 150 mL / min, less than about 100 mL / min, less than about 90 mL / min, less than about 80 mL / min, less than about 70 mL / min, less than about 60 mL / min, less than about 50 mL / min, less than about 40 mL / min, less than about 30 mL / min, less than about 25 mL / min, less than about 20 mL / min, less than about 15 mL / min, or less than about 10 mL / min.

[0020] In embodiments, the extracorporeal transfer module is configured to flow the sweep gas with a flow rate of less than about 20 L / min, less than about 15 L / min, less than about 10 L / min, less than about 5 L / min, less than about 3 L / min, less than about 2 L / min, or less than about 1 L / min.

[0021] In embodiments, the extracorporeal transfer module is configured to flow the biological fluid with a flow rate of less than about 400 mL / min, less than about 350 mL / min, less than about 300 mL / min, less than about 250 mL / min, less than about 200 mL / min, less than about 150 mL / min, less than about 100 mL / min, less than about 90 mL / min, less than about 80 mL / min, less than about 70 mL / min, less than about60 mL / min, less than about 50 mL / min, less than about 40 mL / min, less than about 30 mL / min, less than about 25 mL / min, less than about 20 mL / min, less than about 15 mL / min, or less than about 10 mL / min.

[0022] In embodiments, the dialysate comprises one or more of a pH buffer, calcium, chloride, sodium, potassium, magnesium, sulfate, lactate, gluconate, starch, glucose, and water. In embodiments, the pH buffer comprises one or more of monoethanolamine, phosphate buffer, citrate buffer, acetate buffer, amino acid buffer, hydrochloric acid, and sodium hydroxide.

[0023] In embodiments, the sweep gas comprises oxygen and / or medical room gas.

[0024] In embodiments, the biological fluid flows extralu min ally and / or intraluminally relative to the first bundle of hollow fiber membranes and the second bundle of hollow fiber membranes.

[0025] In embodiments, the extracorporeal transfer module is configured to be in fluid communication with one or more of a cannula, catheter, vascular access tool, or blood withdrawal device.

[0026] In embodiments, the extracorporeal transfer module further comprises a data port. In embodiments, the data port comprises one or more sensors configured to relay information about the biological fluid. In embodiments, the data port comprises one or more connectors configured to couple and / or align channels of direct contact and / or non-contact signal transmission. In embodiments, the non-contact signal transmission is WiFi or BLUETOOTH.

[0027] In embodiments, the extracorporeal transfer module further comprises one or more openings in fluid communication with the void space within the lumen transition region.

[0028] In embodiments, the extracorporeal transfer module further comprises one or more sensors in fluid communication with the one or more openings. In embodiments, the one or more sensors comprises an electrode, optode, and / or device. In embodiments, the electrode, optode, and / or device senses, measures, and / or assesses one or more of conductivity, pH, sodium, potassium, chloride, calcium, oxygen, carbon dioxide, bicarbonate, carbonic acid, metabolic levels, magnesium, urea, creatine, creatinine, glucose, lactate, proteins, metabolites, hormones, lipids, carbohydrates, blood cell content / counts, pathogens, clotting factors, electrolyte balance, intracellular or extracellular compositions, perfusion characteristics, temperature, flow rate, pressure, partial pressure, saturation, resistance, device longevity, and physical, chemical, and / or timedependent variables.

[0029] In embodiments, the proteins comprise serum albumin, hematocrit, hemoglobin, alanine transaminase (ALT), aspartate transferase (AST), fibrinogen, thrombopoietin, tissue-type plasminogenactivator (tPA), hemopexin, calcitonin, thyroxine-binding globulin, von Willebrand factor, haptoglobin, alpha- 1 -proteinase inhibitor, urokinase, transferrin, alpha-2-macroglobulin, transthyretin, ceruloplasmin, complement component 3, apolipoprotein A-V (AP0A5), lecithin-cholesterol acyltransferase, lipopolysaccharide binding protein, mannan-binding lectin, chemokine ligand 18 (CCL18), chemokine ligand 17 (CCL17), transcortin, angiopoietin-1 (CD202B), adiponectin, angiotensin-converting enzyme (ACE), and / or platelet-derived growth factor.

[0030] In embodiments, the cell content / counts comprises red blood cell count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), red cell distribution width (RDW), white blood cell count, lymphocyte count, monocyte counts, eosinophil count, basophil count, neutrophil count, and / or platelet count.

[0031] In embodiments, the pathogens comprise bacteria, viruses, mycoplasmas, parasites, spores, and / or fungus.

[0032] In embodiments, the extracorporeal transfer module further comprises one or more ports in fluid communication with the one or more openings. In embodiments, the one or more ports comprises a sampling port configured to withdraw a volume of the biological fluid and / or infuse a volume into the biological fluid. In embodiments, the one or more ports is configured to supply one or more therapeutic agents to the biological fluid.

[0033] In embodiments, the extracorporeal transfer module has more than two discrete bundles of hollow fiber membranes. In embodiments, extracorporeal transfer module comprises a third bundle of hollow fiber membranes configured to alter the ionic content and / or pH-balance of the biological fluid after passage through the first two bundles of hollow fiber membranes. In embodiments, the extracorporeal transfer module comprises at least a second lumen transition region located between the second bundle of hollow fiber membrane bundles and a third hollow fiber membrane bundles, where the luminal flow orientation relative to the biological fluid changes. In embodiments, a lumen transition region is present between every two hollow fiber bundles.

[0034] In embodiments, the extracorporeal transfer module has two or more bundles of hollow fiber membranes, three or more bundles of hollow fiber membranes, four or more bundles of hollow fiber membranes, or five or more bundles of hollow fiber membranes. In embodiments, the extracorporeal transfer module is configured to be connected in a stackable configuration. In embodiments, the extracorporealtransfer module is connected via Luer connectors, tubing, Hansen connectors, or uniform cross-sectional connectors.

[0035] In aspects, described herein are methods of removing carbon dioxide and bicarbonate from a biological fluid comprising: 1) causing the biological fluid to enter an extracorporeal transfer module comprising a housing, a first bundle of hollow fiber membranes disposed within the housing, the first bundle having a plurality of hollow fiber membranes, arranged axially or orthogonally relative to the housing, where the first bundle of hollow fiber membranes is configured for laminar extraluminal or intraluminal flow of a dialysate or sweep gas therethrough, at least a second bundle of hollow fiber membranes disposed within the housing, the second bundle having a plurality of hollow fiber membranes, arranged axially or orthogonally relative to the first bundle of hollow fiber membranes, where the second bundle of hollow fiber membranes is configured for laminar extraluminal or intraluminal flow of a dialysate or sweep gas therethrough, a lumen transition region comprising a void space between the first bundle of hollow fiber membranes and the second bundle of hollow fiber membranes configured to flow the biological fluid: extraluminally to intraluminally, intraluminally to extraluminally, extraluminally to extraluminally, and / or intraluminally to intraluminally, 2) passing a dialysate through the first bundle of hollow fiber membranes to cause bicarbonate to transfer from the biological fluid into the dialysate, 3) passing a sweep gas through the second bundle of hollow fiber membranes to cause gaseous carbon dioxide to transfer from the biological fluid into the sweep gas, and 4) causing the biological fluid to exit the housing after the bicarbonate and gaseous carbon dioxide are removed from the biological fluid.

[0036] In embodiments, the biological fluid of the method is blood. In embodiments, the method uses sweep gas comprising oxygen and / or medical room gas, optionally where oxygen is transferred from the sweep gas into the biological fluid. In embodiments, the method comprises passing the dialysate through the first bundle of hollow fiber membranes, resulting in one or more ionic species and / or similar molecules and compounds to transfer from the dialysate to the biological fluid and / or to transfer from the biological fluid to the dialysate.

[0037] In embodiments, the dialysate comprises an ionic content that is configured to restore and / or adjust the ionic content and / or pH balance of the biological fluid. In embodiments, the dialysate comprises one or more of pH buffer, calcium, chloride, sodium, potassium, magnesium, sulfate, lactate, gluconate, starch, glucose, and water. In embodiments, the pH buffer comprises one or more of monoethanolamine, phosphate buffer, citrate buffer, acetate buffer, amino acid buffer, hydrochloric acid, and sodium hydroxide.

[0038] In embodiments, methods herein further comprise removing the biological fluid from a subject using a cannula, catheter, vascular access tool, and / or blood withdrawal device in fluid connection with the extracorporeal transfer module. In embodiments, methods herein further comprise returning the biological fluid to a subject after the biological fluid has exited the housing using a cannula, catheter, vascular access tool, and / or blood withdrawal device in fluid connection with the extracorporeal transfer module.

[0039] In embodiments, the one or more dissolved gases comprises gaseous carbon dioxide (CO2) and is transferred from the biological fluid and / or oxygen (O2) and is transferred to the biological fluid. In embodiments, the one or more ionic species comprises bicarbonate (HCO3’) and is transferred from the biological fluid, and / or wherein the one or more ionic species comprises calcium, chloride, sodium, potassium, sulfate, lactate, and / or magnesium, and is transferred to the biological fluid. In embodiments, the one or more similar molecules and compounds comprises urea, ammonia, creatinine, water, and / or plasma, and is transferred from the biological fluid, and / or the one or more similar molecules and compounds comprises glucose, a pH-buffering agent, and / or water, and is transferred to the biological fluid.

[0040] In embodiments, the extracorporeal transfer module is configured for a dialysate to flow extralu min ally through the first bundle of hollow fiber membranes, where the biological fluid is configured to flow intraluminally relative to the first bundle of hollow fiber membranes; and is configured for a sweep gas to flow intraluminally through the second bundle of hollow fiber membranes, where the biological fluid is configured to flow extraluminally relative to the second bundle of hollow fiber membranes.

[0041] In aspects, described herein are methods of treating a disease or disorder in a subject in need thereof using an extracorporeal transfer module comprising: 1) removing a biological fluid from the subject, 2) causing the biological fluid to enter the extracorporeal transfer module comprising a housing, a first bundle of hollow fiber membranes disposed within the housing, the first bundle having a plurality of hollow fiber membranes, arranged axially or orthogonally relative to the housing, where the first bundle of hollow fiber membranes is configured for laminar extraluminal or intraluminal flow of a dialysate or sweep gas therethrough, at least a second bundle of hollow fiber membranes disposed within the housing, the second bundle having a plurality of hollow fiber membranes, arranged axially or orthogonally relative to the first bundle of hollow fiber membranes, where the second bundle of hollow fiber membranes is configured for laminar extraluminal or intraluminal flow of a dialysate or sweep gas therethrough, a lumen transition region comprising a void space between the first bundle of hollow fiber membranes and the second bundle of hollow fiber membranes configured to flow the biological fluid: extraluminally to intraluminally, intraluminally toextralu min ally, extraluminally to extraluminally, and / or intraluminally to intraluminally, 3) passing a dialysate through the first bundle of hollow fiber membranes to cause bicarbonate to transfer from the biological fluid into the dialysate, 4) passing a sweep gas through the second bundle of hollow fiber membranes to cause gaseous carbon dioxide to transfer from the biological fluid into the sweep gas, 5) causing the fluid to exit the housing after the bicarbonate and gaseous carbon dioxide are removed from the biological fluid, and 6) returning the biological fluid into the subject.

[0042] In embodiments, the biological fluid of the method of treatment is blood. In embodiments, the disease or disorder comprises a condition with excess carbon dioxide and / or bicarbonate in the blood, and / or a condition with reduced oxygenation of the blood. In embodiments, the disease or disorder comprises hypercarbic respiratory failure (HRF), lung injury and / or diminished lung function, type 1 respiratory failure, type 2 respiratory failure, increased airways resistance, asthma, suffocation, reduced breathing effort, drug effects, CNS / brain stem lesion, extreme obesity, obesity hypoventilation, decrease in the area of the lung available for gas exchange, chronic bronchitis, decreased neuromuscular function, Guillain— Barre syndrome, motor neuron disease, neurodegeneration, muscular dystrophy, or amyotrophic lateral sclerosis, musculoskeletal deformity and / or rigidity, kyphoscoliosis, ankylosing spondylitis, stroke, pulmonary embolism, lung disease, COPD, interstitial lung disease, lung cancer, flail chest, liver disease and / or cancer, and / or renal disease and / or cancer. In some embodiments, the disease or disorder is HRF.

[0043] In embodiments, the method includes the use of a sweep gas comprising oxygen and / or medical room gas, optionally the oxygen is transferred from the sweep gas into the biological fluid (e.g., oxygenation of blood).

[0044] In embodiments, the method comprises removing the biological fluid from a subject using a cannula, catheter, vascular access tool, and / or blood withdrawal device in fluid connection with the extracorporeal transfer module. In embodiments, the method comprises returning the biological fluid to the subject using a cannula, catheter, vascular access tool, and / or blood withdrawal device in fluid connection with the extracorporeal transfer module.

[0045] In embodiments, the one or more dissolved gases comprises gaseous carbon dioxide (CO2) and is transferred from the biological fluid, and / or the one or more dissolved gases comprises oxygen (O2) and is transferred to the biological fluid. In embodiments, the one or more ionic species comprises calcium, chloride, sodium, potassium, sulfate, lactate, and / or magnesium, and is transferred to the biological fluid. In embodiments, the one or more similar molecules and compounds comprises urea, ammonia, creatinine,water, and / or plasma, and is transferred from the biological fluid, and / or the one or more similar molecules and compounds comprises glucose, a pH-buffering agent, and / or water, and is transferred to the biological fluid.

[0046] In embodiments, the extracorporeal transfer module is configured for a dialysate to flow extralu min ally through the first bundle of hollow fiber membranes, where the biological fluid is configured to flow intraluminally relative to the first bundle of hollow fiber membranes; and is configured for a sweep gas to flow intraluminally through the second bundle of hollow fiber membranes, where the biological fluid is configured to flow extraluminally relative to the second bundle of hollow fiber membranes.

[0047] In aspects, described herein are methods of measuring one or more fluid parameters of a biological fluid using an extracorporeal transfer module comprising: 1) causing the biological fluid to enter the extracorporeal transfer module comprising a housing, a first bundle of hollow fiber membranes disposed within the housing, the first bundle having a plurality of hollow fiber membranes, arranged axially or orthogonally relative to the housing, where the first bundle of hollow fiber membranes is configured for laminar extraluminal or intraluminal flow of a dialysate or sweep gas therethrough, at least a second bundle of hollow fiber membranes disposed within the housing, the second bundle having a plurality of hollow fiber membranes, arranged axially or orthogonally relative to the first bundle of hollow fiber membranes, where the second bundle of hollow fiber membranes is configured for laminar extraluminal or intraluminal flow of a dialysate or sweep gas therethrough, a lumen transition region comprising a void space between the first bundle of hollow fiber membranes and the second bundle of hollow fiber membranes configured to flow the biological fluid: extraluminally to intraluminally, intraluminally to extraluminally, extraluminally to extraluminally, and / or intraluminally to intraluminally, and 2) measuring one or more fluid parameters of the biological fluid as the biological fluid flows through the extracorporeal transfer module.

[0048] In embodiments, the biological fluid for methods of measuring one or more fluid parameters is blood.

[0049] In embodiments, methods of measuring one or more fluid parameters comprise passing a dialysate through the first bundle of hollow fiber membranes to cause bicarbonate to transfer from the biological fluid into the dialysate. In embodiments, methods of measuring one or more fluid parameters comprise passing a sweep gas through the second bundle of hollow fiber membranes to cause gaseous carbon dioxide to transfer from the biological fluid into the sweep gas.

[0050] In embodiments, methods of measuring one or more fluid parameters comprise removing the biological fluid from a subject using a cannula, catheter, vascular access tool, and / or blood withdrawal device in fluid connection with the extracorporeal transfer module. In embodiments, methods of measuring one or more fluid parameters comprise returning the biological fluid to a subject after the biological fluid has exited the housing using a cannula, catheter, vascular access tool, and / or blood withdrawal device in fluid connection with the extracorporeal transfer module.

[0051] In embodiments, the measuring is via one or more openings in fluid communication with the void space within the lumen transition region, and / or the measuring is via one or more openings in fluid communication after the second bundle of hollow fiber membranes, and / or wherein the measuring is before the first bundle of hollow fiber membranes.

[0052] In embodiments, the one or more fluid parameters comprise conductivity, pH, sodium, potassium, chloride, calcium, oxygen, carbon dioxide, bicarbonate, carbonic acid, metabolic levels, magnesium, urea, creatine, creatinine, glucose, lactate, proteins, metabolites, hormones, lipids, carbohydrates, blood cell content / counts, pathogens, clotting factors, electrolyte balance, intracellular or extracellular compositions, perfusion characteristics, temperature, flow rate, pressure, partial pressure, saturation, resistance, device longevity, and physical, chemical, and / or time-dependent variables.

[0053] In embodiments, the measuring comprises using one or more sensors in fluid communication with the extracorporeal transfer module. In embodiments, the one or more sensors comprises an electrode, optode, and / or device.

[0054] In embodiments, the electrode, optode, and / or device senses, measures, and / or assesses one or more of conductivity, pH, sodium, potassium, chloride, calcium, oxygen, carbon dioxide, bicarbonate, carbonic acid, metabolic levels, magnesium, urea, creatine, creatinine, glucose, lactate, proteins, metabolites, hormones, lipids, carbohydrates, blood cell content / counts, pathogens, clotting factors, electrolyte balance, intracellular or extracellular compositions, perfusion characteristics, temperature, flow rate, pressure, partial pressure, saturation, resistance, device longevity, and physical, chemical, and / or timedependent variables.

[0055] In embodiments, the proteins comprise serum albumin, hematocrit, hemoglobin, alanine transaminase (ALT), aspartate transferase (AST), fibrinogen, thrombopoietin, tissue-type plasminogen activator (tPA), hemopexin, calcitonin, thyroxine-binding globulin, von Willebrand factor, haptoglobin, alpha- 1 -proteinase inhibitor, urokinase, transferrin, alpha-2-macroglobulin, transthyretin, ceruloplasmin,complement component 3, apolipoprotein A-V (APOA5), lecithin-cholesterol acyltransferase, lipopolysaccharide binding protein, mannan-binding lectin, chemokine ligand 18 (CCL18), chemokine ligand 17 (CCL17), transcortin, angiopoietin-1 (CD202B), adiponectin, angiotensin-converting enzyme (ACE), and / or platelet-derived growth factor.

[0056] In embodiments, the cell content / counts comprise red blood cell count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), red cell distribution width (RDW), white blood cell count, lymphocyte count, monocyte counts, eosinophil count, basophil count, neutrophil count, and / or platelet count.

[0057] In embodiments, the pathogens comprise bacteria, viruses, mycoplasmas, parasites, spores, and / or fungus.

[0058] In embodiments, methods of measuring one or more fluid parameters comprise sampling the biological fluid. In embodiments, the sampling is via one or more openings in fluid communication with the void space within the lumen transition region, and / or where the sampling is via one or more openings in fluid communication after the second bundle of hollow fiber membranes, and / or before the first bundle of hollow fiber membranes.

[0059] In embodiments, methods of measuring one or more fluid parameters comprise adjusting one or more parameters of the dialysate, the sweep gas, and / or the biological fluid as one or more are passed through the first bundle of hollow fibers and / or the second bundle of hollow fiber bundles. In embodiments, the adjusting is as a function of the measuring of the one or more parameters of the biological fluid, and / or as a function of the sampling of the biological fluid.

[0060] In embodiments, the adjusting comprises increasing the concentration of one or more components of the dialysate and / or sweep gas, decreasing the concentration of one or more components of the dialysate and / or sweep gas, adding one or more one or more components to the dialysate and / or sweep gas, removing one or more one or more components from the dialysate and / or sweep gas, and / or altering one or more of the perfusion characteristics, temperature, flow rate, pressure, and resistance of the dialysate, sweep gas, and / or biological fluid.

[0061] In embodiments, the one or more components comprises a pH buffer, calcium, chloride, sodium, potassium, sulfate, lactate, gluconate, magnesium, glucose, oxygen, water, and / or a therapeutic agent.DESCRIPTION OF THE DRAWINGS

[0062] Fig. 1 depicts an illustrative, non-limiting diagrammatic representation of a first perspective view of a dual-stage cartridge.

[0063] Fig. 2 depicts an illustrative, non-limiting diagrammatic representation of a second perspective view of a dual-stage cartridge.

[0064] Fig. 3 depicts an illustrative, non-limiting diagrammatic representation of an exploded view of a dual-stage cartridge indicating the assembly of multiple subassembly cores and housing enclosure.

[0065] Fig. 4 depicts an illustrative, non-limiting diagrammatic representation or a cross-sectional view of an assembled dual-stage cartridge with aspects of the device to bind fluid flow through one inlet and one outlet.

[0066] Fig. 5 depicts an illustrative, non-limiting diagrammatic representation of a cross-sectional view of an assembled dual-stage cartridge with aspects of the device to bind a first dialysate or sweep gas flow through a first dialysate or sweep gas inlet and a first dialysate or sweep gas outlet.

[0067] Fig. 6 depicts an illustrative, non-limiting diagrammatic representation of a cross-sectional view of an assembled dual-stage cartridge with aspects of the device to bind a second dialysate or sweep gas flow through a second dialysate or sweep gas inlet and a second dialysate or sweep gas outlet.

[0068] Fig. 7 depicts an illustrative, non-limiting diagrammatic representation of a perspective cross- sectional view of a first treatment stage.

[0069] Fig. 8 depicts an illustrative, non-limiting diagrammatic representation of a perspective cross- sectional view of a second treatment stage.

[0070] Fig. 9 depicts an illustrative, non-limiting diagrammatic representation of a perspective view of a second subassembly core.

[0071] Fig. 10 depicts an illustrative, non-limiting diagrammatic representation of an exploded view and assembly of the second subassembly core.

[0072] Figs. 11 A-11 B depict illustrative, non-limiting diagrammatic representations of partially exploded views and assemblies of alternative configurations of a sensor unit in the second subassembly core.

[0073] Fig. 12 depicts an illustrative, non-limiting diagrammatic representation of a perspective view of another configuration of a sensor unit.DETAILED DESCRIPTION

[0074] The present disclosure provides, in part, devices comprising a multi-modal hollow fiber membrane unit, referred to herein as an “extracorporeal transfer module,” or a “mass transfer device,” (used interchangeably). In embodiments, the terms “device,” “cartridge-based system,” and “cartridge,” are used interchangeably to refer to a system that uses one or more extracorporeal transfer modules. In embodiments, the terms “transfer module,” “treatment stage,” and “subassembly core,” are used interchangeably to refer to a singular membrane unit that is configured to exchange one or more elements to and / or from a fluid. In embodiments, the terms “treatment fluid,” “dialysate,” “reconditioning fluid,” “transfer fluid,” and “biological fluid treatment,” are used interchangeably to refer to a fluid used to exchange one or more elements to and / or from a fluid intended to be treated.

[0075] In embodiments, the extracorporeal transfer module is designed for a stackable configuration, where multiple extracorporeal transfer modules can be connected, e.g., in series or in parallel, to customize methods of treating, measuring, and / or sampling biological fluids {e.g., blood). In embodiments, the present disclosure provides, in part, a mass transfer device that incorporates principles of diffusion across one or more semi-permeable membranes. In embodiments, the mass transfer device is a cartridge-based system and finds use in methods for the removal of molecules and ions using hollow fiber membranes to treat biological fluids in the medical field. In embodiments, the cartridge-based system is intended for extracorporeal handling of fluids, with interfaces for connecting to medical articles such as tubing, syringes, pumps, and other forms of hospital supplies or equipment.

[0076] In aspects, provided herein, are methods of using the extracorporeal transfer module to filter components from biological fluids and / or add components to biological fluids. In embodiments, the biological fluid is blood, and the filtration is to remove carbon dioxide (CO2) and / or bicarbonate (HCO3). In embodiments, the biological fluid is blood, and the added components include one or more of oxygen, sodium, chloride, potassium, calcium, sulfate, lactate, bicarbonate, magnesium, glucose, a pH buffer, etc. In embodiments, this process is performed to treat a disease and / or disorder related to excess carbon dioxide (CO2), bicarbonate (HCO3), and / or carbonic acid (H2CO3) in the blood, and / or for filtration of blood and / or for addition of one or more species into blood. In embodiments, the cartridge-based system is intended to interface with supplies and equipment in proximity to the subject, where blood is withdrawn from the subject, passed through a cartridge where the blood is modified by a transfer fluid through diffusion gradients across one or more semi- permeable membranes, and returned to the patient using a continuous flow loop and / or cannulation methodknown in the art of extracorporeal therapies such as dialysis, extracorporeal membrane oxygenation (ECMO) and renal replacement therapy (RPT).

[0077] In aspects, provided in embodiments herein, are methods of using the extracorporeal transfer module to measure fluid parameters of biological fluids and / or to aseptically sample the biological fluids. In embodiments, the extracorporeal transfer module is compatible with one or more sensors used to measure a variety of biological fluid components. In embodiments, the biological fluid is blood.Extracorporeal Transfer Module

[0078] In aspects, the present disclosure provides, extracorporeal transfer modules for a biological fluid that includes a first bundle of hollow fiber membranes disposed within the housing, the first bundle having a plurality of hollow fiber membranes, arranged axially or orthogonally relative to the housing, where the first bundle of hollow fiber membranes is configured for laminar extraluminal or intraluminal flow of a dialysate or sweep gas therethrough, at least a second bundle of hollow fiber membranes disposed within the housing, the second bundle having a plurality of hollow fiber membranes, arranged axially or orthogonally relative to the first bundle of hollow fiber membranes, where the second bundle of hollow fiber membranes is configured for laminar extraluminal or intraluminal flow of a dialysate or sweep gas therethrough, a lumen transition region comprising a void space between the first bundle of hollow fiber membranes and the second bundle of hollow fiber membranes configured to flow the biological fluid extralumi nally to i ntralumi nally, intral umi nally to extraluminally, extraluminally to extraluminally, and / or intraluminally to intraluminally, where the housing comprises at least one potting portion that bonds at least one open end of the first bundle of hollow fiber membranes and bonds at least one open end of the second bundle of hollow fiber membranes, such that the first bundle of hollow fiber membranes and the second bundle of hollow fiber membranes are configured to receive a dialysate and / or a sweep gas from outside of the housing.

[0079] In reference to Fig. 1, in embodiments, an illustrative perspective view of a dual-stage cartridge 100 is shown. In embodiments, the cartridge 100 comprises three regions, with a first subassembly core 105, a second subassembly core 110, and a third subassembly core 115, with a biological fluid inlet 120 and a biological fluid outlet 125 aligned along a longitudinal axis. The first subassembly core 105 has a first biological fluid treatment inlet 130 and first biological fluid treatment outlet 135. In embodiments, the cartridge 100 is part of an extracorporeal system and the biological fluid passes through the biological fluid inlet 120 and biological fluid outlet 125.

[0080] In embodiments, the biological fluid is blood. In embodiments, the extracorporeal transfer module is configured for sterile manipulation of blood and / or to aseptically transfer the blood to and from a subject, as well as to aseptically sample the blood and / or aseptically measure one or more parameters of the blood in situ.

[0081] Continuing in reference to Fig. 1, in embodiments, a first subassembly core 105 includes a first bundle of hollow fiber membranes and a third subassembly core 115 is comprised of a second bundle of hollow fiber membranes. In embodiments, the first subassembly core 105 and third subassembly core 115 are separated by a lumen transition region within the second subassembly core 110 that contains a sampling port 140 to allow access to the blood flowing between the first and second hollow fiber membrane bundles for analysis, measurement, taking samples, and / or making adjustments to the clinical therapy of the biological fluid and / or subject.

[0082] In embodiments, the first bundle of hollow fiber membranes, the second bundle of hollow fiber membranes, and the lumen transition region are encompassed in a housing, e.g., the components are encapsulated in a housing where the ends are open to be connected to one or more components (e.g., such as tubing, other medical devices / instrumentation). In embodiments, the first bundle of hollow fiber membranes and the second bundle of hollow fiber membranes are located in the housing in series, e.g., where the biological fluid exits the first bundle before entering the second bundle. In embodiments, the housing is substantially cylindrical in shape.

[0083] In reference to Fig. 2, in embodiments, a second illustrative perspective view of a dual-stage cartridge 100 is shown. In embodiments, the cartridge 100 includes a second biological fluid treatment inlet 205 and a second biological fluid treatment outlet 210. In embodiments, the first biological fluid treatment inlet 130 and first biological fluid treatment outlet 135 correspond to the inlet and outlet pathway for a liquid dialysate, and the second biological fluid treatment inlet 205 and second biological fluid treatment outlet 210 correspond to the inlet and outlet pathway of a sweep gas. Accordingly, in embodiments, as a biological fluid (e.g., blood) passes from the biological fluid inlet 120 to the biological fluid outlet 125, the biological fluid (e.g., blood) is first conditioned by a treatment fluid dialysate, followed by a second treatment fluid sweep gas. In embodiments, the influence of each treatment fluid / gas on the blood can be evaluated by comparing blood samples taken proximal to the biological fluid inlet 120, at the mid-cartridge sampling port 140, and distal to the biological fluid outlet 125. In embodiments, the order of the dialysate and sweep gas are reversed - e.g., where the first biological fluid treatment inlet 130 and first biological fluid treatment outlet 135 correspond tothe inlet and outlet pathway for a sweep gas, and the second biological fluid treatment inlet 205 and second biological fluid treatment outlet 210 correspond to the inlet and outlet pathway of a liquid dialysate.

[0084] In embodiments, the first bundle of hollow fiber membranes and the second bundle of hollow fiber membranes are comprised of a semi-permeable material that is configured to transfer one or more ionic species, dissolved gases, or similar molecules and compounds from and / or to the biological fluid. This semi- permeable material, in embodiments, includes fiber types with material properties influenced by manufacturing techniques, such as porosity, surface tension, coatings, impregnated agents, layers, and dimensional parameters, or properties unique to the selective permeability of carbon dioxide, bicarbonate ions, and one or more ionic species, dissolved gases, and / or similar molecules and compounds, as described herein. In embodiments, the semi-permeable material includes epoxy potting compounds, materials used in hollow fiber membrane construction, and materials used in centrifugal potting processes. Persons skilled in the art, with the benefit of this disclosure in its entirety will understand the materials that can be used to construct the hollow fiber bundles herein.

[0085] In embodiments, the one or more dissolved gases includes gaseous carbon dioxide (CO2) and is transferred from the biological fluid. For example, in embodiments, where a sweep gas is passed through a hollow fiber membrane bundle to capture gaseous carbon dioxide from the biological fluid (e.g., blood), which is flowed on the other side of the hollow fiber membranes. In embodiments, such a sweep gas has a substantially lower carbon dioxide concentration relative to the biological fluid (e.g., blood), for example, having about a 10-fold lower to about a 10Mbld lower concentration of carbon dioxide or less, or having no carbon dioxide.

[0086] In embodiments, the one or more ionic species includes bicarbonate (HCO3’), calcium, chloride, sodium, potassium, sulfate, lactate, and / or magnesium, and is transferred from the biological fluid. For example, in embodiments, where a dialysate is passed through a hollow fiber membrane bundle to capture dissolved bicarbonate, calcium, chloride, sodium, potassium, sulfate, lactate, and / or magnesium ions from the biological fluid (e.g., blood), which is flowed on the other side of the hollow fiber membranes. In embodiments, such a dialysate would have a substantially lower bicarbonate, calcium, chloride, sodium, potassium, sulfate, lactate, and / or magnesium concentration relative to the biological fluid (e.g., blood), for example, having about a 10-fold lower to about a 108-fold lower concentration of bicarbonate, calcium, chloride, sodium, potassium, sulfate, lactate, and / or magnesium or less, or having no bicarbonate, calcium, chloride, sodium, potassium, sulfate, lactate, and / or magnesium.

[0087] In embodiments, the one or more similar molecules and compounds includes urea, ammonia, creatinine, water, and / or plasma is transferred from the biological fluid. For example, in embodiments, where a dialysate is passed through a hollow fiber membrane bundle to capture urea, ammonia, creatinine, water, and / or plasma from the biological fluid (e.g., blood), which is flowed on the other side of the hollow fiber membranes. In embodiments, such a dialysate would have a substantially lower urea, ammonia, creatinine, and / or water concentration relative to the biological fluid (e.g., blood), for example, having about a 10-fold lower to about a 108-fold lower concentration urea, ammonia, creatinine, and / or water or less, or having no urea, ammonia, creatinine, and / or water.

[0088] In embodiments, the one or more ionic species includes calcium, chloride, sodium, potassium, and magnesium, and is transferred to the biological fluid (e.g., blood).

[0089] In embodiments, the one or more dissolved gases include oxygen and is transferred to the biological fluid (e.g., blood). In embodiments, the one or more similar molecules and compounds include glucose, a pH-buffering agent, and water, and is transferred to the biological fluid.

[0090] Continuing in reference to Fig. 2, in embodiments, the sampling port 140 includes a Luer connector, while the fluid openings on the cartridge 100 include Luer connectors, Hansen connectors, or uniform cross-sectional connectors. In embodiments, the connectors may be permanently affixed during manufacture to medical tubing and / or integrated into a cassette that configures with hospital equipment containing pumps and interfaces for managing the treatment therapy. In embodiments, fluid openings include a combination of attachable and detachable connectors, as well as some connectors permanently affixed to tubing during manufacture. For example, in embodiments, the first biological fluid treatment inlet 130 and first biological fluid treatment outlet 135 are welded to medical tubing during manufacture, and the biological fluid inlet 120 and the biological fluid outlet 125 are manufactured as Luer connectors. In embodiments, and in reference to Fig. 2, the second treatment fluid inlet 205 and second treatment fluid outlet 210 are recesses on a bottom-facing ledge 220 of the cartridge 100, where tubular prongs from an interfacing equipment establish fluid communion with the cartridge 100.

[0091] In embodiments, there is a transition between the laminar flow of the biological fluid (e.g., blood) between the first bundle of hollow fiber membrane and the second bundle of hollow fiber membrane. For example, in embodiments, the first bundle of hollow fiber membranes is configured for laminar extraluminal flow through the hollow fiber membranes, and the second bundle of hollow fiber membranes is configured for laminar intraluminal flow through the hollow fiber membranes. Alternatively, in embodiments, the firstbundle of hollow fiber membranes is configured for laminar intraluminal flow through the hollow fiber membranes, and the second bundle of hollow fiber membranes is configured for laminar extraluminal flow through the hollow fiber membranes.

[0092] In embodiments, the extracorporeal transfer module is configured for a dialysate to flow extralu min ally through the first bundle of hollow fiber membranes, where the biological fluid is configured to flow intraluminally relative to the first bundle of hollow fiber membranes. In embodiments, the extracorporeal transfer module is configured for a sweep gas to flow intraluminally through the second bundle of hollow fiber membranes, where the biological fluid is configured to flow extraluminally relative to the second bundle of hollow fiber membranes.

[0093] In embodiments, the extracorporeal transfer module has a construction where the second bundle of hollow fiber membranes is arranged substantially orthogonally (90°) relative to the first bundle of hollow fiber membranes. Such a construction, in embodiments, enables a biological fluid to travel longitudinally along a first bundle of hollow fiber membranes, and then transverse along a second bundle of hollow fiber membranes. In embodiments, the extracorporeal transfer module is constructed such that the first and second bundle of hollow fiber membranes adopt variety of angles relative to one another, such as being approx. 45° relative to one another, being approx. 60° relative to one another, or arranged axially or at another angle relative to one another.

[0094] In embodiments, the extracorporeal transfer module is configured to flow the dialysate with a flow rate of < 500 mL / min. In embodiments, the flow rate is less than about 500 mL / min, less than about 450 mL / min, less than about 400 mL / min, less than about 350 mL / min, less than about 300 mL / min, less than about 250 mL / min, less than about 200 mL / min, less than about 150 mL / min, less than about 100 mL / min, less than about 90 mL / min, less than about 80 mL / min, less than about 70 mL / min, less than about 60 mL / min, less than about 50 mL / min, less than about 40 mL / min, less than about 30 mL / min, less than about 25 mL / min, less than about 20 mL / min, less than about 15 mL / min, or less than about 10 mL / min.

[0095] In embodiments, the extracorporeal transfer module is configured to flow the sweep gas with a flow rate of < 20 L / min. In embodiments, the flow rate is less than about 20 L / min, less than about 15 L / min, less than about 10 L / min, less than about 5 L / min, less than about 3 L / min, less than about 2 L / min, or less than about 1 L / min.

[0096] In embodiments, the extracorporeal transfer module is configured to flow the biological fluid (e.g., blood) with a flow rate of < 400 mL / min. In embodiments, the flow rate is less than about 400 mL / min, lessthan about 350 mL / min, less than about 300 mL / min, less than about 250 mL / min, less than about 200 mL / min, less than about 150 mL / min, less than about 100 mL / min, less than about 90 mL / min, less than about 80 mL / min, less than about 70 mL / min, less than about 60 mL / min, less than about 50 mL / min, less than about 40 mL / min, less than about 30 mL / min, less than about 25 mL / min, less than about 20 mL / min, less than about 15 mL / min, or less than about 10 mL / min.

[0097] In embodiments, the dialysate (e.g., also referred to herein as a “treatment fluid”) includes one or more of a pH buffer, calcium, chloride, sodium, potassium, magnesium, and / or glucose. In embodiments, the pH buffer includes one or more of monoethanolamine, phosphate buffer, citrate buffer (e.g., sodium citrate), acetate buffer (e.g., sodium acetate), amino acid buffer (e.g., histidine / histidine monochloride), hydrochloric acid (e.g., at low concentrations useful to buffering in the physiological range of blood), and sodium hydroxide (e.g., at low concentrations useful to buffering in the physiological range of blood).

[0098] In embodiments, the sweep gas includes oxygen and / or medical room gas. In embodiments, medical room gas includes all acceptable medical-grade gases (e.g., for ventilation or ECMO), including 100% oxygen, carbogen (e.g., 95% O2 and 5% CO2), and small percent amounts of other gases (e.g., nitrogen).

[0099] In embodiments, the biological fluid flows extralu min ally and / or intraluminally relative to the first bundle of hollow fiber membranes and to the second bundle of hollow fiber membranes.

[0100] In embodiments, the extracorporeal transfer module is configured to be in fluid communication with one or more of a cannula, catheter, vascular access tool, or blood withdrawal device.

[0101] In reference to Fig. 2, in embodiments, the module includes a data port 215. In embodiments, the cartridge 100 contains sensors which relay information to a system for managing patient care. In embodiments, the data port 215 is in the form of an analog or digital interface for connecting one or more devices in electrical communication, and contains any number of pins or terminals by which data and / or signals can be transmitted. In embodiments, the data port 215 is also designed in the form of a connector that is intended to couple and / or align channels capable of direct contact and / or non-contact signal transmission, such as an optical fiber connector, or scintillator-based wireless connector for example for internet connectivity (e.g., WiFi) or BLUETOOTH.

[0102] In reference to Fig. 3, in embodiments, an exploded view of a dual-stage cartridge and assembly of components is shown. In embodiments, the cartridge 300 includes a first subassembly core 305 and athird subassembly core 315, with a second subassembly core 310 disposed therebetween. In embodiments, the first subassembly core 305 is enclosed in a housing 330, and the second subassembly core 310 and third subassembly core 315 are laterally enclosed by covers 325, with a top 320 completing the assembly. In embodiments, the housing 330 and top 320 define a longitudinal axis along which a biological fluid passes through subassembly cores 305, 310, and 315.

[0103] In reference to Fig. 4, in embodiments, a cross-sectional view of an assembled dual-stage cartridge 400 and aspects of the device useful to bind biological fluid flow along a longitudinal axis passing through a fluid inlet 405 and a fluid outlet 415 is shown. In embodiments, the dual-stage cartridge 400 includes a first conditioning stage, defined by the boundaries of a first potted region 430, a second potted region 435, and a generally cylindrical wall 450, with a first bundle of hollow fiber membranes 420 disposed therebetween. In embodiments, a second conditioning stage is defined by the boundaries of a transition region 410, an outlet region 445, and a generally annular potted region 440, with a second bundle of hollow fiber membranes 425 disposed therebetween.

[0104] In embodiments, the extracorporeal transfer module has more than two discrete bundles of hollow fiber membranes, for example, where additional reconditioning of the biological fluid (e.g., blood) is performed. For example, the first bundle of hollow fiber membranes removes bicarbonate, a second bundle of hollow fiber membranes removes carbon dioxide and / or adds oxygen, and a third bundle of hollow fiber membranes alters the ionic content and / or pH-balance of the biological fluid after passage through the first two bundles of hollow fiber membranes. I n embodiments, a second lumen transition region is located between the second and third hollow fiber membrane bundles, where the luminal flow (e.g., extraluminal / intralumi nal) orientation relative to the biological fluid changes. In embodiments, a lumen transition region is present between every two hollow fiber bundles, e.g., where extraluminal / intraluminal flow is switchable. In embodiments, the extracorporeal transfer module has two or more bundles of hollow fiber membranes, three or more bundles of hollow fiber membranes, four or more bundles of hollow fiber membranes, or five or more bundles of hollow fiber membranes. In embodiments, the extracorporeal transfer module is configured to be connected in a stackable configuration, for example, where multiple extracorporeal transfer modules can be connected via Luer connectors, tubing, etc.

[0105] In reference to Fig. 4, in embodiments, fluid flows from a fluid inlet 405 through the first conditioning stage comprising a first bundle of hollow fiber membranes 420, into a transition region 410, through a second conditioning stage comprising a second bundle of hollow fiber membranes 425, into anoutlet region 445, and through the fluid outlet 415. In embodiments, the transition region 410 maintains a uniform cross-sectional area between the two conditioning stages such that the fluid flow exiting the first conditioning stage has approximately the same cross-section as the fluid flow entering the second conditioning stage. In embodiments, it is desirable that the fluid flow within the transition region 410 does not undergo any expansion or constriction affecting the local superficial velocity (e.g., flow rate divided by cross- sectional area) along the longitudinal axis of the cartridge 400 thereby achieving uniform perfusion into the second conditioning stage. However, in embodiments, the transition region 410 may alternatively be non- rigid and not have a uniform cross-section between the two conditioning stages, or may not be aligned with the longitudinal axis of the cartridge 400.

[0106] Continuing in reference to Fig. 4, in embodiments, a cross-sectional view of the first subassembly core 305 is shown, where manufacture of the first subassembly core 305 is achieved using known methods, e.g., for the manufacture of dialyzer cartridges. In embodiments, a first bundle of hollow fiber membranes 420 are restrained within a cylindrical wall 450 and generally aligned along the longitudinal axis of the cylindrical wall 450. In embodiments, the subassembly is placed in a centrifugal apparatus, where liquid resin is injected, deposited, or otherwise delivered to the end(s) of the fiber bundle by centrifugal force, where the subassembly is exposed to continual centrifugal forces until the liquid resin is immobilized via a curing process. In embodiments, the type of material, centrifugation time and force, among other factors, are altered to achieve different thickness of hollow fiber membranes. In embodiments, the fiber ends, oriented along the longitudinal axis and extending beyond the wall 450, are sealed with the cylindrical wall 450 by the potted resin. In embodiments, a cutting process removes a distal layer of the potted resin and encapsulated fiber ends, thereby maintaining a seal between the cylindrical wall 450 and the extraluminal fiber surface, and exposing a continuous hollow intraluminal space between the first potted region 430 and second potted region 435. Alternatively, in embodiments, the first potted region 430 and second potted region 435 are manufactured without centrifugal forces, but placed in a reservoir containing a liquid epoxy, which will produce a similar sealing of the extraluminal fiber surfaces with the cylindrical wall 450, where fiber lumens can be exposed using a similar cutting process described above. In embodiments, the generally cylindrical wall 450 has other cross-sectional geometries suitable for manufacturing and fluid flow.

[0107] In embodiments, the first and second bundle of hollow fiber membranes are composed of one or more materials that are semi-permeable to one or more ionic species, dissolved gases, or similar molecules or compounds herein (e.g., bicarbonate, carbon dioxide, oxygen, sodium, chloride, potassium, magnesium, glucose, a pH buffering agent, etc.), including for example, silicone, polysulfone (PSU; UDEL),polyethersulfone (PES; VERADEL), PES with polyvinylpyrrolidone (PVP) fibers (e.g., PUREMA fiber manufactured by 3M Deutschland GmbH), polyamide, polyacryl-polyamide acrylate (PMNA), AN69 polyacrylonitrile, cellulose-based membranes (e.g., CUROPHAN, cellulose acetate, or HEMOPHAN), and / or low molecular weight cutoff (LMWCO) dialysis filters.

[0108] Continuing in reference to Fig. 4, in embodiments, a cross-sectional view of the third subassembly core 315 is shown, where manufacture of the third subassembly core 315 is achieved using a centrifugal potting process where a second bundle of hollow fiber membranes 425 are restrained within an enclosure 455. In embodiments, the subassembly is placed in a centrifugal apparatus, where liquid resin is injected, deposited, or otherwise delivered to the subassembly such that the resin is forced to the edges of the enclosure 455, leaving a cylindrically shaped center that is void of any resin. In embodiments, the subassembly is exposed to continual centrifugal forces until the liquid resin is immobilized via a curing process. In embodiments, the fiber ends, extending beyond the enclosure 455, are sealed with the enclosure 455 by the potted resin. In embodiments, a cutting process removes a distal layer of the potted resin and encapsulated fiber ends, thereby maintaining a seal between the enclosure 455 and the extraluminal fiber surface and exposing a continuous hollow intraluminal space extending between the ends of each hollow fiber membrane.

[0109] In embodiments, the first bundle of hollow fiber membranes 420 is generally aligned along the longitudinal axis extending between a fluid inlet 405 and a fluid outlet 415, and the second bundle of hollow fiber membranes 425 is generally aligned orthogonal to the same longitudinal axis, such that the fiber lumens of the first bundle of hollow fiber membranes 420 forms a passageway from the fluid inlet 405 to the transition region 410, but the fiber lumens of the second bundle of hollow fibers 425 forms a passageway inaccessible to the fluid in the transition region 410. Therefore, in embodiments, the biological fluid enters the first conditioning stage from the fluid inlet 405, passes intraluminally through the lumens of the first bundle of hollow fiber membranes 420 into the transition region 410, and then passes extral umi n ally through the second conditioning stage by traveling along the extraluminal surface of the second bundle of hollow fiber membranes 425 into the outlet region 445, exiting the cartridge 400 through the fluid outlet 415. Accordingly, in embodiments, the lumen transition region 410 is the space where the biological fluid changes from intraluminal flow to extraluminal flow within the cartridge 400. Although the figure illustrates a preferred embodiment where the transition region 410 redirects flow from intraluminal to extraluminal flow through bundles of hollow fiber membranes, in embodiments, there are configurations in which the lumen transitionregion 410 facilitates biological fluid flow extraluminally to intraluminally, intraluminally to intraluminally, or extralu min ally to extraluminally through separate bundles of hollow fiber membranes.

[0110] Without wishing to be bound by theory, in embodiments, the redirection in flow between intraluminal flow and extraluminal flow through the hollow fiber membranes increases the efficiency of ionic transfer between the biological fluid and the dialysate and / or sweep gas. Without wishing to be bound by theory, in embodiments, the redirection in flow between intraluminal to extraluminal flow through the hollow fiber membranes decreases one or more of the time, surface area, and / or length of the fiber membranes required to achieve ionic transfer in comparison to systems with uniform hollow fiber membrane construction, e.g., where ionic transfer is only extraluminal and / or only intraluminal.

[0111] In reference to Fig. 5, in embodiments, a cross-sectional view of an assembled dual-stage cartridge 500 with aspects of the device to bind a first treatment fluid flow through a first treatment fluid inlet 505 and a first treatment fluid flow outlet 510 is shown. In embodiments, a fluid or gas (e.g., a dialysate or sweep gas) flows from the first treatment fluid inlet 505 through an aperture 515 and into a cavity 535. Flow is then circumferentially distributed through the cavity 535 with the aid of one or more baffles 520, allowing uniform perfusion through a series of radially distributed inlet apertures 525 into the first bundle of hollow fiber membranes 420. In embodiments, the first treatment fluid or sweep gas perfuses towards a series of radially distributed outlet apertures 530 while mass is transported across the semi-permeable membrane of the first bundle of hollow fiber membranes 420 with the biological fluid passing from fluid inlet 405 toward the lumen transition region 410.

[0112] In embodiments, the terms “treatment fluid,” “reconditioning fluid,” and “dialysate,” are used interchangeably. In embodiments, the terms “gas,” “sweep gas,” and “exchange gas,” are used interchangeably. In embodiments, where a “treatment fluid,” “reconditioning fluid,” or “dialysate,” are used, a “gas,” “sweep gas,” or “exchange gas,” is also compatible for use.

[0113] Continuing in reference Fig. 5, in embodiments, the direction of flow illustrated in Fig. 5 between the first treatment fluid and biological fluid flowing from fluid inlet 405 to the transition region 410 is countercurrent. In embodiments, the direction of flow includes concurrent flow, which is achieved by either reversal of the first treatment fluid flow inlet 505 with the first treatment fluid flow outlet 510 or by reversal of flow from the fluid outlet 415 to the biological fluid inlet 405. In embodiments, the baffle 520 and cavity 535 adopt a variety of different shapes and different positional arrangements conducive to fluid perfusion of the first treatment fluid and / or the fluid entering through the fluid inlet 405.

[0114] In reference to Fig. 6, in embodiments, a cross-sectional view of an assembled dual-stage cartridge 600 with aspects of the device to bind a second treatment fluid flow is shown. In embodiments, the direction of the second bundle of hollow fiber membranes 425 are aligned orthogonally to the direction of biological fluid flow from the lumen transition region 410 to the fluid outlet 415. In embodiments, by means of the cutting process of the annular potting 440, the lumens of the second bundle of hollow fiber membranes form a passageway from a left cavity 605 to a right cavity 610, which are in fluid communication with a second treatment fluid inlet and a second treatment fluid outlet. Accordingly, in embodiments, the second treatment fluid passes from the left cavity 605 through the intraluminal space of the second bundle of hollow fiber membranes 425 and into the right cavity 610, while biological fluid in the lumen transition region 410 passes along the extraluminal surface of the second bundle of hollow fiber membranes 425 and exits the cartridge 600 through the fluid outlet 415. In embodiments, mass transport between the second treatment fluid (or treatment gas) and the biological fluid occurs across the semi-permeable hollow fibers when both fluids are within the region of the second bundle of hollow fiber membranes 425 defined by the thickness and inner diameter of the annular potting 440.

[0115] In reference to Fig. 7, in embodiments, a perspective cross-sectional view of a first treatment stage 700 is shown. In embodiments, the first treatment stage 700 includes a first bundle of hollow fiber membranes 705 potted within a generally cylindrical wall 720 and sealed with an upper potted region 715 and a lower potted region 710. In embodiments, following a potting and cutting process described previously, the first bundle of hollow fiber membranes 705 is generally aligned along a longitudinal axis, with an upper surface 755 of exposed fiber lumens and a lower surface (not visible from perspective view) of exposed fiber lumens. In embodiments, the first treatment stage 700 further includes a housing 725, a first treatment fluid inlet 730, a first treatment fluid outlet 735, and a biological fluid inlet 770. In embodiments, the first treatment fluid (e.g., a liquid dialysate) enters the first treatment stage 700 through the first treatment fluid inlet 730, passes through inlet aperture 740, and uniformly perfuses through one or more radially distributed inlet apertures 760, with distribution of flow aided by one or more baffles 750. In embodiments, due to the upper potted region 715, the first treatment fluid flows towards the lower potted region 710 along the extraluminal surface of a first bundle of hollow fiber membranes 705 and disperses through one or more radially distributed outlet apertures 765. In embodiments, the first treatment fluid is collected through the outlet aperture 745 and exits the first treatment stage 700 through the first treatment fluid outlet 735. In embodiments, simultaneous biological fluid (e.g., blood) flows from the biological fluid inlet 770, through the intraluminal space of the firstbundle of hollow fiber membranes 705, and out of the first treatment stage 700 though the upper surface 755 of exposed fiber lumens.

[0116] Continuing in reference to Fig. 7, in embodiments, the first treatment stage 700 defines five different fluid regions within the housing 725: a first region where the first treatment fluid enters the housing 725 through the first treatment fluid inlet 730; a second region where the first treatment fluid passes along the extraluminal surface (or intraluminal surface) of the first bundle of hollow fiber membranes 705; a third region where the first treatment fluid exits the housing 725 through the first treatment fluid outlet 735; a fourth region where a biological fluid enters the housing 725 through the biological fluid inlet 770; and a fifth region where a biological fluid passes along the intraluminal surface (or extraluminal surface) of the first bundle of hollow fiber membranes 705. Accordingly, in embodiments, mass transfer occurs between two fluids (or a fluid and a gas) within the second and fifth regions of the first treatment stage 700.

[0117] In reference to Fig. 8, in embodiments, a perspective cross-sectional view of the second treatment stage 800 is shown. In embodiments, the second treatment stage 800 includes a second bundle of hollow fiber membranes 805 potted within an enclosure 815 and sealed with a generally annular potted region 810, such that the potted region 810 defines a generally cylindrical area in the non-potted region of the second bundle of hollow fiber membranes 805. In embodiments, the second treatment stage 800 has a front end 820, a back end 825, a left cover 830, and a right cover 835. In embodiments, the back end 825 is partitioned into a left chamber 840 and a right chamber 850, through which the second treatment fluid respectfully enters and exits the second treatment stage 800.

[0118] Continuing in reference to Fig. 8, in embodiments, the second treatment fluid (e.g., a dialysate or a sweep gas) enters the second treatment stage 800 through an inlet chamber 840 and passes through an inlet opening 845 to fill the cavity formed between the left cover 830 and the hollow fiber membrane enclosure 815. In embodiments, following the potting and cutting process described herein, the second treatment fluid is forced through the passageway formed by the intraluminal space of the second bundle of hollow fiber membranes 805 and into the cavity formed between the right cover 835 and the enclosure 815. In embodiments, the second treatment fluid passes through the outlet opening 855 and into the outlet chamber 850 where it exits the second treatment stage 800. In embodiments, while the second treatment fluid (e.g., a dialysate or a sweep gas) is passed through the second treatment stage 800, biological fluid (e.g., blood) is simultaneously passed through the cylindrical area in the non-potted region of the second bundle of hollow fiber membranes 805 around the extraluminal surface of the hollow fiber membranestowards the outlet region (not shown in the cross-section; refer to Fig. 4), and then out of the second treatment stage 800.

[0119] In embodiments, the extracorporeal transfer module is configured to flow the dialysate with a flow rate of < 500 mL / min. In embodiments, the extracorporeal transfer module is configured to flow the sweep gas < 20 L / min. In embodiments, the extracorporeal transfer module is configured to flow the biological fluid with a flow rate of < 400 mL / min. In embodiments, the efficiency in mass transport of the extracorporeal transfer module is high due to the low flow rates (e.g., less than about 400 mL / min of the biological fluid), which provides therapeutic benefit. In embodiments, the physical velocity (e.g., the macroscopic flow through porous, hollow fiber media) of the extraluminal fluid flowing through the cylindrical area in the non-potted region of the second bundle of hollow fiber membranes 805 is characterized as laminar pipe flow.

[0120] Continuing in reference to Fig. 8, in embodiments, the second treatment stage 800 defines five different fluid regions: a first region where the second treatment fluid enters the inlet chamber 840; a second region where the second treatment fluid passes along the intraluminal surface (or extraluminal surface) of the second bundle of hollow fiber membranes 805; a third region where the second treatment fluid exits the second treatment stage 800 through the outlet chamber 850; a fourth region where a biological fluid passes along the extraluminal surface (or intraluminal surface) of the second bundle of hollow fiber membranes 805; and a fifth region where a biological fluid enters an outlet region of the second treatment stage 800. Accordingly, in embodiments, mass transfer occurs between the biological fluid and the second treatment fluid / gas within the second and fourth regions of the second treatment stage 800.

[0121] In reference to Fig. 9, in embodiments, a perspective view of a second subassembly core 310 is shown. In embodiments, the second subassembly core 310 is disposed between the two treatment stages of the dual-stage cartridge and establishes a lumen transition region 905 between the two treatment stages. In embodiments, the lumen transition region 905 allows a biological fluid passing through the dual-stage cartridge to transition between intraluminal and extraluminal flow, extraluminal and intraluminal flow, intraluminal and intraluminal flow, and extraluminal and extraluminal flow through the neighboring bundles of hollow fiber membranes.

[0122] Continuing in reference to Fig. 9, in embodiments, the lumen transition region 905 permits analysis of the biological fluid between the two treatment stages, enabling real-time adjustments to the clinical therapy. For example, in embodiments, if the first treatment stage results in an undesirable increase or decrease in hydronium ions, hydrogen ions, and / or hydroxide ions (e.g., a shift in pH), the rate of masstransfer is decreased or increased in the first treatment stage, and / or decreased or increased in the second treatment stage. In embodiments, the flow rates and / or compositions are changed in response to the analysis of the biological fluid. In embodiments, a sampling port 910 is located within second subassembly core 310 in fluid communication with the one or more openings 915 to enable the withdrawal of biological fluid from within the lumen transition region 905 for analysis. In embodiments, the sampling port 910 is useful for retrieval of larger volumes of infusion or withdrawal of biological fluids, as appropriate for clinical therapy or use. For example, in embodiments, additional dialysate, sweep gas, or therapeutic agents are continuously administered through the sampling port 910 (or another port located within the subassembly core) into the transition region 905, thereby bypassing the first treatment stage; or a continuous withdrawal of fluids from the lumen transition region 905 through the sampling port 910, thereby bypassing the second treatment stage; or for additional modes of therapy.

[0123] Continuing in reference to Fig. 9, in embodiments, openings for the second treatment fluid inlet 920 and second treatment fluid outlet 925 are shown.

[0124] Continuing in reference to Fig. 9, in embodiments, analysis of one or more fluid properties or parameters within the lumen transition region 905 of the second subassembly core 310 are achieved through a data port 930. In embodiments, the data port is used to collect information from one or more sensors (e.g., one or more electrodes, optodes, and / or devices) and send the information collected or measured by the one or more sensors within the second subassembly core 310 to an external processor and / or display. In embodiments, the one or more electrodes, optodes, and / or devices collects information for clinical therapy, including sensing, measuring, and / or assessing one or more of conductivity, pH, sodium, potassium, chloride, calcium, oxygen, carbon dioxide, bicarbonate, carbonic acid, metabolic levels, magnesium, urea, creatine, creatinine, glucose, lactate, proteins, metabolites, hormones, lipids, carbohydrates, blood cell content / counts, pathogens, clotting factors, electrolyte balance, intracellular or extracellular compositions, perfusion characteristics, temperature, flow rate, pressure, partial pressure, saturation, resistance, device longevity, and / or physical, chemical, or time-dependent variables of interest. In embodiments, one or more sensors includes electrolyte sensors which are configured to measure the electrolytic content.

[0125] In embodiments, sensing includes a qualitative assessment of the presence of a variable or component, such as an indication that a metabolite is present, that a medication was detected in the blood, etc. In embodiments, measuring includes a quantitative assessment of the presence of a variable or a component, such as a concentration of one or more ions, fluid / gas pressure, flow rate measurement, etc. Inembodiments, assessing includes a measurement compared against a setpoint or threshold, for example, if a pressure exceeds a pressure alarm, if an ion concentration is above or below a threshold concentration, where an output includes a determination, or assessment, of a next step (e.g., to increase, decrease, or alter a component in a dialysate and / or sweep gas, increase / decrease flow rate, etc.}.

[0126] In embodiments, the proteins that are sensed, measured, and / or assessed include serum albumin, hematocrit, hemoglobin, alanine transaminase (ALT), aspartate transferase (AST), fibrinogen, thrombopoietin, tissue-type plasminogen activator (tPA), hemopexin, calcitonin, thyroxine-binding globulin, von Willebrand factor, haptoglobin, alpha-1 -proteinase inhibitor, urokinase, transferrin, alpha-2- macrog Io bul i n, transthyretin, ceruloplasmin, complement component 3, apolipoprotein A-V (APOA5), lecithin- cholesterol acyltransferase, lipopolysaccharide binding protein, mannan-binding lectin, chemokine ligand 18 (CCL18), chemokine ligand 17 (CCL17), transcortin, angiopoietin-1 (CD202B), adiponectin, angiotensinconverting enzyme (ACE), and / or platelet-derived growth factor. In embodiments, proteins relevant to blood clotting, proteins relevant to organ damage (e.g., liver damage, cirrhosis, scarring, heart damage from infarctions, heart attack, stroke, pulmonary embolism, etc. , proteins relevant to dyslipidemia, obesity, diabetes, and / or proteins relevant to metabolism are sensed, measured, and / or assessed via the data port and / or sampling port of the extracorporeal transfer module.

[0127] In embodiments, the cell content / counts includes red blood cell count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), red cell distribution width (RDW), white blood cell count, lymphocyte count, monocyte counts, eosinophil count, basophil count, neutrophil count, and / or platelet count.

[0128] In embodiments, the pathogens include bacteria, viruses, mycoplasmas, parasites, spores, and / or fungus. In embodiments, the pathogen includes common bloodborne pathogens, such as Staphylococcus aureus, Group A streptococcus (GAS), Group B streptococcus (GBS), Enterococci spp. , E. coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Proteus mirabilis, Salmonella spp., Enterobacter spp., hepatitis B (HBV), hepatitis C (HCV), human immunodeficiency virus (HIV), Haemoproteus spp., Leucocytozoon spp., Trypanosoma spp., Plasmodium spp. (malaria), and microfilaria, Candida spp., etc.

[0129] In reference to Fig. 10, in embodiments, an exploded view and assembly of the second subassembly core is shown. In embodiments, the second subassembly core includes a top cover 1005, a bottom cover 1015, and a sensor unit 1010. In embodiments, the sensor unit 1010 includes one or more data ports 1025 and one or more sensor elements 1055. In embodiments, the fluid ports 1035 are used for the passage of the second treatment fluid, and join to the openings 1020, which interface with the secondtreatment stage. In embodiments, the bottom cover 1015 also provides an opening 1030 for the data port 1025 to interface with external equipment.

[0130] Continuing in reference to Fig. 10, in embodiments, a sampling port 1045 is in fluid communication with one or more internal openings 1050 to enable the withdrawal of biological fluid from the lumen transition region 1040. In embodiments, one or more sampling ports 1045 are used for infusion and / or withdrawal of any volume of fluid into or out of the lumen transition region of the dual-stage cartridge.

[0131] In embodiments, the extracorporeal transfer module includes one or more ports in fluid communication with the one or more openings. In embodiments, the one or more ports includes a sampling port configured to withdraw a volume of the biological fluid and / or infuse a volume into the biological fluid. In embodiments, the one or more ports is configured to supply one or more therapeutic agents to the biological fluid, as described herein.

[0132] In reference to Figs. 11A-11B, in embodiments, partially exploded views of alternate configurations of a sensor unit in the second subassembly core are shown. In embodiments, the sensor unit 1110 is housed between a bottom cover 1115 and a top cover 1105. In embodiments, the sensor unit 1110 uses a non-contact sensor element(s) 1120 to measure and / or analyze biological fluid within the lumen transition region 1130. Accordingly, in embodiments, the inner wall 1125 of the transition region 1130 is continuous such that biological fluid passing through the transition region 1130 experiences no interruptions in flow. In embodiments, the sensor element(s) detect, analyze, and / or measure all information necessary for clinical use such that no sampling port for direct fluid access is needed (see, e.g., Fig. 10).

[0133] Continuing in reference to Figs. 11A-11 B, in embodiments, a sensor unit 1140 housed between a bottom cover 1145 and a top cover 1135 is shown. In embodiments, the sensor unit 1140 uses a sensor element(s) 1150 with contact probe(s) 1165 passing through the inner wall 1155 to measure and / or analyze biological fluid within the lumen transition region 1160. In embodiments, the sensor element(s) detect, analyze, and / or measure all information necessary for clinical use such that no sampling port for direct fluid access is needed (see, e.g., Fig. 10).

[0134] In reference to Fig. 12, in embodiments, a perspective view of a sensor unit 1200 is shown. In embodiments, the sensor unit 1200 has a body 1215, data port 1220, and sensor element(s) 1205. In embodiments, the contact probe(s) 1210 directly contact the biological fluid in the lumen transition region of the second subassembly core, but appear as shortened nubs that have minimal effect on the fluid flow path.

[0135] In embodiments, the sensor unit and / or one or more ports (e.g, data port and / or sampling ports) are located after the second bundle of hollow fiber membranes, for example to measure and / or analyze the biological fluid after the dual-stage cartridge of the extracorporeal transfer module. This is done, in embodiments, to ensure the biological fluid (e.g., blood) meets the clinical criteria to be returned to the subject. In embodiments, the sensor unit and / or one or more ports (e.g., data port and / or sampling ports) are located before the first bundle of hollow fiber membranes, for example to determine the proper treatment of the biological fluid and / or to adjust components of the dialysate and / or sweep gas before entering the extracorporeal transfer module.Methods of Removing and / or Adding Components to a Biological Fluid

[0136] In aspects, described herein are methods of removing carbon dioxide and bicarbonate from a biological fluid, where the methods include 1) causing the biological fluid to enter the extracorporeal transfer module, which includes a housing, a first bundle of hollow fiber membranes disposed within the housing, the first bundle having a plurality of hollow fiber membranes arranged axially or orthogonally relative to the housing, where the first bundle of hollow fiber membranes is configured for laminar extraluminal or intraluminal flow of a dialysate or sweep gas therethrough, at least a second bundle of hollow fiber membranes disposed within the housing, the second bundle having a plurality of hollow fiber membranes, arranged axially or orthogonally relative to the first bundle of hollow fiber membranes, where the second bundle of hollow fiber membranes is configured for laminar extraluminal or intraluminal flow of a dialysate or sweep gas therethrough, a lumen transition region comprising a void space between the first bundle of hollow fiber membranes and the second bundle of hollow fiber membranes configured to flow the biological fluid: extralu min ally to intraluminally, intraluminally to extraluminally, extraluminally to extraluminally, intraluminally to intraluminally, 2) passing a dialysate through the first bundle of hollow fiber membranes to cause bicarbonate to transfer from the biological fluid into the dialysate, 3) passing a sweep gas through the second bundle of hollow fiber membranes to cause gaseous carbon dioxide to transfer from the biological fluid into the sweep gas, and 4) causing the biological fluid to exit the housing after the gaseous carbon dioxide and bicarbonate are removed from the biological fluid.

[0137] In embodiments, methods for removing carbon dioxide and / or bicarbonate are performed as part of an ex vivo and / or in vitro process, for example, in treating samples for clinical, diagnostic, therapeutic, or manufacturing purposes (e.g., preparing blood and / or blood plasma), and / or to aseptically add one or morecomponents and / or filter out one or more components in instances that are not directly related to a method of treatment or in vivo uses.

[0138] In embodiments, the biological fluid is blood and / or blood plasma. Methods herein, in embodiments, include the use of the extracorporeal transfer module for sterile manipulation of blood and / or to aseptically transfer the blood to and / or from a subject, as well as to aseptically sample the blood and / or aseptically measure one or more parameters of the blood in situ.

[0139] In blood, CO2 exists in the forms of (1) dissolved gas (about 5%), (2) bound to hemoglobin (about 5%), and (3) as a component of the bicarbonate (HCO3) ion (about 90%) produced via the hydration of CO2 in a reaction catalyzed by the carbonic anhydrase enzyme in human red blood cells. Due to the small fraction of total CO2 present as dissolved gas in the blood, a traditional ECCO2R approach necessitates the use of a blood withdrawal cannula having a large bore size, so that adequate blood flow is generated to achieve clinically significant CO2 removal that can lower total CO2 content at a rate faster than accumulation and in a timescale that would be therapeutically feasible. The safe and proper placement of such cannulae requires specialized clinical expertise. Highly trained, specialized medical professionals, however, may not always be available in hospitals with ECCO2R systems, or hospitals may not have the resources for implementing such clinical programs. For this and other reasons, clinical use of ECCO2R systems remains limited.

[0140] Accordingly, in embodiments, to address these disadvantages, the device and methods described herein provide sufficient removal of carbon dioxide by removing both gaseous CO2 dissolved in the blood, as well as bicarbonate ions, which represent the largest (about 90%) physiological store of effective CO2 in venous blood. In embodiments, this hybrid approach allows the subject’s blood to be drawn at flow rates of < 400 mL / min, and using catheters having a smaller diameter (which are less invasive and both safer and easier to position). In embodiments, the gaseous CO2 and bicarbonate are removed from the subject’s blood while maintaining homeostasis and preventing undesirable local variation and / or derangement in blood pH levels and / or ionic content. In embodiments, local pH control at the ECCO2R device and reducing CO2 load of the entire body back to physiologic levels drives restoration of homeostatic pH levels.

[0141] Accordingly, in embodiments, removal of bicarbonate ions across a semi-permeable membrane with the aid of a specific dialysate formulation is feasible; however, unlike the transport of gaseous molecules along concentration gradients with a sweep gas, diffusion via dialysate is subject to influences of both concentration and ionic charges. As such, in embodiments, the removal of the bicarbonate ion is accompanied by either the co-transport ( / .e., co-removal) of a positively charged (ionic) specie(s) or thecounter-transport ( / .e., blood uptake) of a negatively charged (ionic) specie(s) to maintain a net charge neutrality and balance free energy of the system.

[0142] In embodiments, passing the dialysate through the first bundle of hollow fiber membranes results in one or more ionic species and / or similar molecules and compounds to transfer from the dialysate to the biological fluid and / or to transfer from the biological fluid to the dialysate. In embodiments, the dialysate comprises an ionic content that is configured to restore and / or adjust the ionic content and / or pH balance of the biological fluid. In embodiments, the dialysate includes a composition that is configured to restore the ionic content of one or more concentrations of calcium, chloride, sodium, potassium, sulfate, lactate, bicarbonate, gluconate, magnesium, and / or glucose to about or at least about 80%, about or at least about 85%, about or at least about 90%, about or at least about 95%, about or at least about 96%, about or at least about 97%, about or at least about 98%, about or at least about 99%, or about or at least about 100% of a normal, physiological level / concentration of human blood. In embodiments, the dialysate includes a composition that is configured to restore and / or adjust the pH to about or at least about 80%, about or at least about 85%, about or at least about 90%, about or at least about 95%, about or at least about 96%, about or at least about 97%, about or at least about 98%, about or at least about 99%, or about or at least about 100% of a normal, physiological pH of human blood.

[0143] In embodiments, passing the sweep gas through the second bundle of hollow fiber membranes results in one or more dissolved gases to transfer from the sweep gas to the biological fluid and / or to transfer from the biological fluid to the sweep gas. In embodiments, the sweep gas comprises oxygen and / or medical room gas. In embodiments, the sweep gas includes oxygen, and the oxygen is transferred from the sweep gas into the biological fluid, e.g., for oxygenation of blood. In embodiments, the sweep gas includes a composition that is configured to restore the concentrations of dissolved carbon dioxide and / or dissolved oxygen to about or at least about 80%, about or at least about 85%, about or at least about 90%, about or at least about 95%, about or at least about 96%, about or at least about 97%, about or at least about 98%, about or at least about 99%, or about or at least about 100% of a normal, physiological level / concentration of human blood.

[0144] Bicarbonate is a charged ion and any diffusion of bicarbonate against a concentration gradient across a membrane (e.g., a semi-permeable membrane) will act to create an electrical field that counteracts further net diffusion of bicarbonate. Accordingly, in embodiments, net charge neutrality between two compartments or areas within the extracorporeal transfer module separated by a semi-permeable membrane(e.g., hollow fiber membrane) is maintained to enable sufficient diffusion of bicarbonate across the semi- permeable membrane for adequate bicarbonate removal of a biological fluid (e.g., blood). In embodiments, coupling bicarbonate transport with transport of another ion, either a positive ion moving in the same direction or a negative ion moving in the opposite direction provides for maintenance of charge balance or charge neutrality.

[0145] In embodiments, the dialysate for removing bicarbonate from blood includes one or more ions, e.g., sodium, chloride, etc., in concentrations that facilitate removal of bicarbonate in a manner that maintains charge neutrality. In embodiments, the transfer of the negatively charged bicarbonate ions from blood into a dialysate remain electrically neutral by transfer of positively charged ions into the dialysate from the blood, or transfer of negatively charged ions into the blood from the dialysate. Thus, in embodiments, one or more ions (e.g., as described herein) function as co-transport or counter-transport ions, which exhibit different transportation kinetics and membrane transport implications, are utilized with the described methods herein as necessary.

[0146] In embodiments, methods herein use one or more dialysate, e.g., also referred to herein as a “treatment fluid,” which includes one or more of a pH buffer, calcium, chloride, sodium, potassium, sulfate, lactate, bicarbonate, gluconate, magnesium, and / or glucose. In embodiments, the pH buffer includes one or more pH-buffering agent such as monoethanolamine, phosphate buffer, citrate buffer (e.g., sodium citrate), acetate buffer (e.g., sodium acetate), amino acid buffer (e.g., histidine / histidine monochloride), hydrochloric acid (e.g., at low concentrations useful to buffering in the physiological range of blood), and sodium hydroxide (e.g., at low concentrations useful to buffering in the physiological range of blood). In embodiments, the pH buffer includes one or more pH buffering agents that are suitable for use intravenously, such as pharmaceutically acceptable excipients useful as buffering agents intended to be injected into the bloodstream.

[0147] In embodiments, the dialysate includes a concentration of sodium of about 0 mmol / L to about 200 mmol / L, e.g., or about 10 mmol / L, or about 20 mmol / L, or about 30 mmol / L, or about 40 mmol / L, or about 50 mmol / L, or about 60 mmol / L, or about 70 mmol / L, or about 80 mmol / L, or about 90 mmol / L, or about 100 mmol / L, or about 110 mmol / L, or about 120 mmol / L, or about 130 mmol / L, or about 140 mmol / L, or about 150 mmol / L, or about 160 mmol / L, or about 170 mmol / L, or about 180 mmol / L, or about 190 mmol / L, including all values of sodium concentration therein.

[0148] In embodiments, the dialysate includes a concentration of chloride of about 0 mmol / L to about 150 mmol / L, e.g., or about 10 mmol / L, or about 20 mmol / L, or about 30 mmol / L, or about 40 mmol / L, or about 50 mmol / L, or about 60 mmol / L, or about 70 mmol / L, or about 80 mmol / L, or about 90 mmol / L, or about 100 mmol / L, or about 110 mmol / L, or about 120 mmol / L, or about 130 mmol / L, or about 140 mmol / L, including all values of chloride concentration therein.

[0149] In embodiments, the dialysate includes a concentration of calcium of about 0 mmol / L to about 3.0 mmol / L, e.g., or about 0.25 mmol / L, or about 0.50 mmol / L, or about 0.75 mmol / L, or about 1 .00 mmol / L, or about 1.25 mmol / L, or about 1.50 mmol / L, or about 1.75 mmol / L, or about 2.00 mmol / L, or about 2.25 mmol / L, or about 2.50 mmol / L, or about 2.75 mmol / L, including all values of calcium concentration therein.

[0150] In embodiments, the dialysate includes a concentration of potassium of about 0 mmol / L to about 7.0 mmol / L, e.g., or about 0.5 mmol / L, or about 1.0 mmol / L, or about 1.5 mmol / L, or about 2.0 mmol / L, or about 2.5 mmol / L, or about 3.0 mmol / L, or about 3.5 mmol / L, or about 4.0 mmol / L, or about 4.5 mmol / L, or about 5.0 mmol / L, or about 5.5 mmol / L, or about 6.0 mmol / L, or about 6.5 mmol / L, including all values of magnesium concentration therein.

[0151] In embodiments, the dialysate includes a concentration of magnesium of about 0 mmol / L to about 1.50 mmol / L, e.g., or about 0.25 mmol / L, or about 0.50 mmol / L, or about 0.75 mmol / L, or about 1.00 mmol / L, or about 1.25 mmol / L, including all values of magnesium concentration therein.

[0152] In embodiments, the dialysate includes a concentration of sulfate of about 0 mmol / L to about 5 mmol / L, e.g., or 0.1 mmol / L, or 0.2 mmol / L, or 0.3 mmol / L, or 0.4 mmol / L, or 0.5 mmol / L, or 1.0 mmol / L, or 2.0 mmol / L, or 3.0 mmol / L, or 4.0 mmol / L, or 5.0 mmol / L, including all values of sulfate concentration therein.

[0153] In embodiments, the dialysate includes a concentration of lactate of about 0 mmol / L to about 30 mmol / L, e.g., or about 1 mmol / L, or about 2 mmol / L, or about 3 mmol / L, or about 4 mmol / L, or about 5 mmol / L, or about 10 mmol / L, or about 15 mmol / L, or about 20 mmol / L, or about 25 mmol / L, or about 30 mmol / L, including all values of lactate concentration therein.

[0154] In embodiments, the dialysate includes a concentration of bicarbonate of about 0 mmol / L to about 30 mmol / L, e.g., or about 1 mmol / L, or about 2 mmol / L, or about 3 mmol / L, or about 4 mmol / L, or about 5 mmol / L, or about 10 mmol / L, or about 15 mmol / L, or about 20 mmol / L, or about 25 mmol / L, or about 30 mmol / L, including all values of bicarbonate concentration therein.

[0155] In embodiments, the dialysate includes a concentration of glucose of about 0 mmol / L to about 10.0 mmol / L, e.g., or about 0.5 mmol / L, or about 1.0 mmol / L, or about 1.5 mmol / L, or about 2.0 mmol / L, or about 2.5 mmol / L, or about 3.0 mmol / L, or about 3.5 mmol / L, or about 4.0 mmol / L, or about 4.5 mmol / L, or about 5.0 mmol / L, or about 5.5 mmol / L, or about 6.0 mmol / L, or about 6.5 mmol / L, or about 7.0 mmol / L, or about 7.5 mmol / L, or about 8.0 mmol / L, or about 8.5 mmol / L, or about 9.0 mmol / L, or about 9.5 mmol / L, including all values of glucose concentration therein.

[0156] In embodiments, the dialysate has a composition that is configured to restore and / or adjust the pH to about or at least about 80%, about or at least about 85%, about or at least about 90%, about or at least about 95%, about or at least about 96%, about or at least about 97%, about or at least about 98%, about or at least about 99%, or about or at least about 100% of a normal, physiological pH of human blood.

[0157] In embodiments, the dialysate includes a concentration of a pH buffering agent of about 0 mmol / L to about 100 mmol / L, e.g., or about 10 mmol / L, or about 20 mmol / L, or about 30 mmol / L, or about 40 mmol / L, or about 50 mmol / L, or about 60 mmol / L, or about 70 mmol / L, or about 80 mmol / L, or about 90 mmol / L, including all values of pH buffering agent concentration therein.

[0158] Methods herein, in embodiments, further comprise removing the biological fluid from a subject using a cannula, catheter, vascular access tool, and / or blood withdrawal device in fluid connection with the extracorporeal transfer module. For example, in embodiments, the cannula, catheter, vascular access tool, and / or blood withdrawal device are in fluid connection with the biological fluid inlet 120 (e.g., as shown in Figs. 1-2), or the biological fluid inlet 405 (e.g., as shown in Figs. 4-6), or as the biological fluid inlet 770 (e.g., as shown in Fig. 7).

[0159] Methods herein, in embodiments, further comprise returning the biological fluid to a subject after the biological fluid has exited the housing using a cannula, catheter, vascular access tool, and / or blood withdrawal device in fluid connection with the extracorporeal transfer module. For example, in embodiments, the cannula, catheter, vascular access tool, and / or blood withdrawal device are in fluid connection with the biological fluid outlet 125 (e.g., as shown in Figs. 1-2), or the biological fluid outlet 415 (e.g., as shown in Figs. 4-6).

[0160] In embodiments, the first bundle of hollow fiber membranes and the second bundle of hollow fiber membranes are comprised of semi-permeable material that is configured to transfer one or more ionic species, dissolved gases, or similar molecules and compounds from and / or to the biological fluid. In embodiments, the one or more ionic species includes bicarbonate (HCO3) and is transferred from thebiological fluid. In embodiments, the one or more dissolved gases includes carbon dioxide (CO2) and is transferred from the biological fluid. In embodiments, the one or more dissolved gases includes oxygen and is transferred to the biological fluid (e.g., oxygenation of blood). In embodiments, the one or more similar molecules and compounds includes urea, ammonia, creatinine, water, and / or plasma, and is transferred from the biological fluid (e.g., such as is done in traditional hemodialysis).

[0161] In embodiments, carbon dioxide (CO2) is filtered out of the biological fluid (e.g., blood) via diffusion using a sweep gas, which has a lower concentration of gaseous carbon dioxide relate to the biological fluid (e.g., blood). In embodiments, bicarbonate (HCO3) is filtered out of the biological fluid (e.g., blood) via diffusion using a dialysate, which has a lower concentration of bicarbonate relate to the biological fluid (e.g., blood).

[0162] In embodiments, the one or more ionic species, dissolved gases, or similar molecules and compounds includes calcium, chloride, sodium, potassium, oxygen, magnesium, glucose, and / or a pH- bufferi ng agent, and is transferred to the biological fluid. In embodiments, removal of gaseous carbon dioxide (CO2) and / or dissolved bicarbonate (HCO3) results in a derangement in one of more ionic species of blood (for example, one or more of pH, chloride, calcium, sodium, and potassium are altered relative to before the carbon dioxide (CO2) and / or dissolved bicarbonate (HCO3) are removed). In embodiments, the dialysate supplies a pH-buffering agent, chloride, calcium, sodium, and / or potassium to restore and / or adjust the blood such that it is suitable to be re-infused in the subject.

[0163] In embodiments, the first bundle of hollow fiber membranes is configured for laminar extraluminal flow through the plurality of fiber membranes, and the second bundle of hollow fiber membranes is configured for laminar intraluminal flow through the plurality of fiber membranes; or where the first bundle of hollow fiber membranes is configured for laminar intraluminal flow through the plurality of fiber membranes, and the second bundle of hollow fiber membranes is configured for laminar extraluminal flow through the plurality of fiber membranes.

[0164] In embodiments, the extracorporeal transfer module is configured for a dialysate to flow extraluminally through the first bundle of hollow fiber membranes, where the biological fluid is configured to flow intraluminally relative to the first bundle of hollow fiber membranes; and is configured for a sweep gas to flow intraluminally through the second bundle of hollow fiber membranes, where the biological fluid is configured to flow extraluminally relative to the second bundle of hollow fiber membranes.

[0165] In embodiments, one or more treatment parameters are altered as a function of sensing, measuring, and / or assessing one or more proteins relevant to blood clotting, organ damage (e.g., liver damage, cirrhosis, scarring, heart damage from infarctions, heart attack, stroke, pulmonary embolism, etc.), dyslipidemia, obesity, diabetes, and / or to metabolism. In embodiments, the sensing, measuring, and / or assessing is performed via the data port and / or sampling port of the extracorporeal transfer module.

[0166] In embodiments, the second bundle of hollow fiber membranes is arranged axially or orthogonally relative to the first bundle of hollow fiber membranes.

[0167] Methods herein, in embodiments, include passing the dialysate through the extracorporeal transfer module at a flow rate of < 500 mL / min. In embodiments, the flow rate is less than about 500 mL / min, less than about 450 mL / min, less than about 400 mL / min, less than about 350 mL / min, less than about 300 mL / min, less than about 250 mL / min, less than about 200 mL / min, less than about 150 mL / min, less than about 100 mL / min, less than about 90 mL / min, less than about 80 mL / min, less than about 70 mL / min, less than about 60 mL / min, less than about 50 mL / min, less than about 40 mL / min, less than about 30 mL / min, less than about 25 mL / min, less than about 20 mL / min, less than about 15 mL / min, or less than about 10 mL / min.

[0168] Methods herein, in embodiments, include passing the sweep gas through the extracorporeal transfer module with a flow rate of < 20 L / min. In embodiments, the flow rate is less than about 20 L / min, less than about 15 L / min, less than about 10 L / min, less than about 5 L / min, less than about 3 L / min, less than about 2 L / min, or less than about 1 L / min.

[0169] Existing approaches to removing carbon dioxide depend on a vascular-access flow rate of greater than 500 mL / min. Methods herein, in embodiments, include passing the biological fluid (e.g., blood) through the extracorporeal transfer module at a flow rate of < 400 mL / min. In embodiments, the flow rate is less than about 400 mL / min, less than about 350 mL / min, less than about 300 mL / min, less than about 250 mL / min, less than about 200 mL / min, less than about 150 mL / min, less than about 100 mL / min, less than about 90 mL / min, less than about 80 mL / min, less than about 70 mL / min, less than about 60 mL / min, less than about 50 mL / min, less than about 40 mL / min, less than about 30 mL / min, less than about 25 mL / min, less than about 20 mL / min, less than about 15 mL / min, or less than about 10 mL / min.

[0170] As a result, the devices, systems, and methods according to some embodiments employ a catheter or access cannula used to withdraw blood from the subject that has a size of from about 8 Fr to about 13 Fr (e.g, from about 8 Fr to about 12 Fr, from about 8 Fr to about 11 Fr, or from about 8 Fr to about10 Fr, or from about 8 Fr to about 9 Fr, or from about 9 Fr to about 13 Fr, or from about 9 Fr to about 12 Fr, or from about 9 Fr to about 11 Fr, or from about 9 Fr to about 10 Fr, or from about 10 Fr to about 13 Fr, or from about 10 Fr to about 12 Fr, or from about 10 Fr to about 11 Fr, or from about 11 Fr to about 13 Fr, from about 11 Fr to about 12 Fr, or from about 12 Fr to about 13 Fr, or about 8 Fr, or about 9 Fr, or about 10 Fr, or about 11 Fr, or about 12 Fr, or about 13 Fr). In embodiments, the catheters of a reduced size that are used to acquire blood at low flow rates are positioned at a subject’s body in a less traumatic manner, such that a likelihood of clinical error is reduced or eliminated.Methods of Treating Diseases or Disorders

[0171] In aspects, described herein are methods of treating a disease or disorder in a subject in need thereof using an extracorporeal transfer module, where the methods include 1) removing a biological fluid from the subject, 2) causing the biological fluid to enter the extracorporeal transfer module, where the extracorporeal transfer module includes a housing, a first bundle of hollow fiber membranes disposed within the housing, the first bundle having a plurality of hollow fiber membranes, arranged axially or orthogonally relative to the housing, where the first bundle of hollow fiber membranes is configured for laminar extraluminal or intraluminal flow of a dialysate or sweep gas therethrough, at least a second bundle of hollow fiber membranes disposed within the housing, the second bundle having a plurality of hollow fiber membranes, arranged axially or orthogonally relative to the first bundle of hollow fiber membranes, where the second bundle of hollow fiber membranes is configured for laminar extraluminal or intraluminal flow of a dialysate or sweep gas therethrough, a lumen transition region comprising a void space between the first bundle of hollow fiber membranes and the second bundle of hollow fiber membranes configured to flow the biological fluid extralu min ally to intraluminally, intraluminally to extraluminally, extraluminally to extraluminally, and / or intraluminally to intraluminally, 3) passing a dialysate through the first bundle of hollow fiber membranes to cause bicarbonate to transfer from the biological fluid into the sweep gas, 4) passing a sweep gas through the second bundle of hollow fiber membranes to cause gaseous carbon dioxide to transfer from the biological fluid into the dialysate, 5) causing the biological fluid to exit the housing after the gaseous carbon dioxide and bicarbonate are removed, and 6) returning the biological fluid into the subject.

[0172] Without wishing to be bound by theory, in embodiments, the redirection in flow between intraluminal flow and extraluminal flow through the hollow fiber membranes increases the efficiency of ionic transfer, decreasing one or more of the time, surface area, and / or length of the fiber membranes required toachieve comparable ionic transfer in a system lacking the lumen transition region(s), where damage to cells in the biological fluid is minimized such that patient outcome is improved.

[0173] In embodiments, the biological fluid is blood. Methods herein, in embodiments, include the use of the extracorporeal transfer module for sterile manipulation of blood and / or aseptic transfer of blood to and from a subject to treat one or more diseases and / or disorders. Methods herein, in embodiments, include aseptically sampling the blood and / or aseptically measuring one or more parameters of the blood in situ. For example, in embodiments, sampling and / or measuring one or more parameters is useful in monitoring treatment and / or the disease state.

[0174] In embodiments, the disease or disorder comprises a condition with excess carbon dioxide and / or bicarbonate in the blood, and / or a condition with reduced oxygenation of the blood. In embodiments, the disease or disorder includes one or more of hypercarbic respiratory failure (HRF), lung injury and / or diminished lung function, type 1 respiratory failure, type 2 respiratory failure, increased airways resistance (e.g., asthma, suffocation), reduced breathing effort (e.g., drug effects, CNS / brain stem lesion, extreme obesity, obesity hypoventilation), decrease in the area of the lung available for gas exchange (e.g., in chronic bronchitis), decreased neuromuscular function (e.g., Guillain— Barre syndrome, motor neuron disease, neurodegeneration, muscular dystrophy, or amyotrophic lateral sclerosis), cystic fibrosis, musculoskeletal deformity and / or rigidity (e.g., kyphoscoliosis, ankylosing spondylitis), stroke, pulmonary embolism, lung disease (e.g., COPD, interstitial lung disease, lung cancer), flail chest, liver disease (e.g., cancer) and / or renal disease (e.g., cancer). In some embodiments, the disease or disorder is hypercarbic respiratory failure (HRF).

[0175] Methods herein, in embodiments, include passing the sweep gas through the second bundle of hollow fiber membranes to result in one or more dissolved gases to transfer from the sweep gas to the biological fluid and / or to transfer from the biological fluid to the sweep gas. In embodiments, the sweep gas comprises oxygen and / or medical room gas. In embodiments, the sweep gas includes oxygen, and the oxygen is transferred from the sweep gas into the biological fluid, e.g., for oxygenation of blood.

[0176] In embodiments, the physiologic range of blood-dissolved carbon dioxide (CO2) concentrations includes about or at least about 20 mmol / L to about or at least about 120 mmol / L. In embodiments, the sweep gas includes a composition configured to remove carbon dioxide from blood such that it results in a blood- dissolved concentration of carbon dioxide of about 20 mmol / L to about 120 mmol / L of carbon dioxide (e.g., about 20 mmol / L, or about 30 mmol / L, or about 40 mmol / L, or about 50 mmol / L, or about 60 mmol / L, or about70 mmol / L, or about 80 mmol / L, or about 90 mmol / L, or about 100 mmol / L, or about 110 mmol / L, or about 120 mmol / L of carbon dioxide), and / or to return the content of carbon dioxide in the subject’s blood to a baseline level of from about 20 mmol / L to about 30 mmol / L (e.g., about 21 mmol / L, or about 22 mmol / L, or about 23 mmol / L, or about 24 mmol / L, or about 25 mmol / L, or about 26 mmol / L, or about 27 mmol / L, or about 28 mmol / L, or about 29 mmol / L).

[0177] In embodiments, the sweep gas includes a composition that is configured to restore the concentrations of dissolved carbon dioxide and / or dissolved oxygen to about or at least about 80%, about or at least about 85%, about or at least about 90%, about or at least about 95%, about or at least about 96%, about or at least about 97%, about or at least about 98%, about or at least about 99%, or about or at least about 100% of a normal, physiological level / concentration of human blood.

[0178] In embodiments, passing the dialysate through the first bundle of hollow fiber membranes results in one or more ionic species and / or similar molecules and compounds to transfer from the dialysate to the biological fluid and / or to transfer from the biological fluid to the dialysate.

[0179] In embodiments, the dialysate is used to capture and / or remove blood-dissolved bicarbonate. In embodiments, the physiologic range of blood-dissolved bicarbonate concentrations includes about or at least about 20 mmol / L to about or at least about 38 mmol / L. In embodiments, the dialysate includes a composition configured to remove bicarbonate from blood such that it results in a blood-dissolved concentration of carbon dioxide of about 20 mmol / L to about 38 mmol / L of carbon dioxide (e.g., about 20 mmol / L, or about 22 mmol / L, or about 24 mmol / L, or about 26 mmol / L, or about 28 mmol / L, or about 30 mmol / L, or about 32 mmol / L, or about 34 mmol / L, or about 36 mmol / L, or about 38 mmol / L of bicarbonate), and / or to return the content of bicarbonate in the subject’s blood to a baseline level of from about 20 mmol / L to about 38 mmol / L (e.g., about 23 mmol / L, or about 24 mmol / L, or about 25 mmol / L, or about 26 mmol / L, or about 27 mmol / L, or about 28 mmol / L, or about 29 mmol / L, or about 30 mmol / L, or about 31 mmol / L).

[0180] In embodiments, the dialysate includes a composition that is configured to restore the ionic content and concentration of dissolved bicarbonate ions to about or at least about 80%, about or at least about 85%, about or at least about 90%, about or at least about 95%, about or at least about 96%, about or at least about 97%, about or at least about 98%, about or at least about 99%, or about or at least about 100% of a normal, physiological level / concentration of human blood.

[0181] In embodiments, by removing both bicarbonate and dissolved gaseous carbon dioxide, at least partially simultaneously, a removal of a larger amount of effective CO2, which is not dependent on gaseousC02 concentration, is achieved. In embodiments, this shifting focus to a larger scope and whole-body pH balance and CO2 removal, capture of both bicarbonate ion and dissolved CO2, allows lower flow rates of therapy and / or reduced length of therapy.

[0182] In embodiments, the dialysate has an ionic content that is configured to restore and / or adjust the ionic content and / or pH balance of the biological fluid. In embodiments, the dialysate has a composition that is configured to restore the ionic content of one or more concentrations of calcium, chloride, sodium, potassium, sulfate, lactate, bicarbonate, gluconate, magnesium, and / or glucose to about or at least about 80%, about or at least about 85%, about or at least about 90%, about or at least about 95%, about or at least about 96%, about or at least about 97%, about or at least about 98%, about or at least about 99%, or about or at least about 100% of a normal, physiological level / concentration of human blood.

[0183] In embodiments, the physiologic range of blood-dissolved sodium concentrations includes about or at least about 130 mmol / L to about or at least about 150 mmol / L. In embodiments, the dialysate includes a composition configured to adjust the sodium content of the blood such that it results in a blood-dissolved concentration of sodium of about 130 mmol / L to about 150 mmol / L of sodium (e.g., about 132 mmol / L, or about 134 mmol / L, or about 136 mmol / L, or about 138 mmol / L, or about 140 mmol / L, or about 142 mmol / L, or about 144 mmol / L, or about 146 mmol / L, or about 148 mmol / L, of sodium), and / or to return the content of sodium in the subject’s blood to a baseline level of from about 130 mmol / L to about 150 mmol / L (e.g., to about 136 mmol / L, or about 137 mmol / L, or about 138 mmol / L, or about 139 mmol / L, or about 140 mmol / L, or about 141 mmol / L, or about 142 mmol / L, or about 143 mmol / L, or about 144 mmol / L).

[0184] In embodiments, the physiologic range of blood-dissolved chloride concentrations includes about or at least about 90 mmol / L to about or at least about 110 mmol / L. In embodiments, the dialysate includes a composition configured to adjust the chloride content of the blood such that it results in a blood-dissolved concentration of chloride of about 90 mmol / L to about 110 mmol / L of chloride (e.g., about 92 mmol / L, or about 94 mmol / L, or about 96 mmol / L, or about 98 mmol / L, or about 100 mmol / L, or about 102 mmol / L, or about 104 mmol / L, or about 106 mmol / L, or about 108 mmol / L, of chloride), and / or to return the content of chloride in the subject’s blood to a baseline level of from about 90 mmol / L to about 110 mmol / L (e.g., to about 97 mmol / L, about 98 mmol / L, or about 99 mmol / L, or about 100 mmol / L, or about 101 mmol / L, or about 102 mmol / L, or about 103 mmol / L, or about 104 mmol / L, or about 105 mmol / L).

[0185] In embodiments, the physiologic range of blood-dissolved calcium concentrations includes about or at least about 2.1 mmol / L to about or at least about 2.6 mmol / L. In embodiments, the dialysate includes acomposition configured to adjust the calcium content of the blood such that it results in a blood-dissolved concentration of calcium of about 2.1 mmol / L to about 2.6 mmol / L of calcium (e.g., about 2.15 mmol / L, or about 2.2 mmol / L, or about 2.25 mmol / L, or about 2.3 mmol / L, or about 2.35 mmol / L, or about 2.4 mmol / L, or about 2.45 mmol / L, or about 2.5 mmol / L, or about 2.55 mmol / L, of calcium), and / or to return the content of calcium in the subject’s blood to a baseline level of from about 2.1 mmol / L to about 2.6 mmol / L (e.g., to about 2.2 mmol / L, about 2.25 mmol / L, or about 2.3 mmol / L, or about 2.35 mmol / L, or about 2.4 mmol / L, or about 2.45 mmol / L, or about 2.5 mmol / L, or about 2.55 mmol / L).

[0186] In embodiments, the physiologic range of blood-dissolved potassium concentrations includes about or at least about 3.0 mmol / L to about or at least about 6.0 mmol / L. In embodiments, the dialysate includes a composition configured to adjust the potassium content of the blood such that it results in a blood- dissolved concentration of potassium of about 3.0 mmol / L to about 6.0 mmol / L of potassium (e.g., about 3.5 mmol / L, or about 4.0 mmol / L, or about 4.5 mmol / L, or about 5.0 mmol / L, or about 5.5 mmol / L of potassium), and / or to return the content of calcium in the subject’s blood to a baseline level of from about 3.0 mmol / L to about 6.0 mmol / L (e.g., to about 4.0 mmol / L, about 4.5 mmol / L, or about 5.0 mmol / L).

[0187] In embodiments, the physiologic range of blood-dissolved magnesium concentrations includes about or at least about 0.80 mmol / L to about or at least about 1 .20 mmol / L. In embodiments, the dialysate includes a composition configured to adjust the magnesium content of the blood such that it results in a blood- dissolved concentration of magnesium of about 0.80 mmol / L to about 1 .20 mmol / L of magnesium (e.g., about 0.85 mmol / L, or about 0.90 mmol / L, or about 0.95 mmol / L, or about 1.00 mmol / L, or about 1.05 mmol / L, or about 1.10 mmol / L, or about 1.15 mmol / L, of magnesium), and / or to return the content of magnesium in the subject’s blood to a baseline level of from about 0.80 mmol / L to about 1.20 mmol / L (e.g., to about 0.86 mmol / L, about 0.88 mmol / L, or about 0.90 mmol / L, or about 0.92 mmol / L, or about 0.94 mmol / L, or about 0.96 mmol / L, or about 0.98 mmol / L, or about 1.00 mmol / L, or about 1.02 mmol / L, or about 1.04 mmol / L, or about 1 .06 mmol / L, or about 1 .08 mmol / L).

[0188] In embodiments, the physiologic range of blood-dissolved glucose concentrations includes about or at least about 3.5 mmol / L to about or at least about 8.0 mmol / L. In embodiments, the dialysate includes a composition configured to adjust the glucose content of the blood such that it results in a blood-dissolved concentration of glucose of about 3.5 mmol / L to about 8.0 mmol / L of glucose (e.g., about 4.0 mmol / L, about 4.5 mmol / L, or about 5.0 mmol / L, or about 5.5 mmol / L, or about 6.0 mmol / L, or about 6.5 mmol / L, or about 7.0 mmol / L, or about 7.5 mmol / L of glucose), and / or to return the content of glucose in the subject’s blood toa baseline level of from about 3.5 mmol / L to about 8.0 mmol / L (e.g., to about 4.0 mmol / L, about 4.5 mmol / L, or about 5.0 mmol / L, or about 5.5 mmol / L, or about 6.0 mmol / L, or about 6.5 mmol / L, or about 7.0 mmol / L, or about 7.5 mmol / L).

[0189] In embodiments, the dialysate has a composition that is configured to restore and / or adjust the pH to about or at least about 80%, about or at least about 85%, about or at least about 90%, about or at least about 95%, about or at least about 96%, about or at least about 97%, about or at least about 98%, about or at least about 99%, or about or at least about 100% of a normal, physiological pH of human blood.

[0190] In embodiments, the physiologic range of blood pH includes about or at least about pH 7.30 to about or at least about pH 7.50. In embodiments, the dialysate includes a composition configured to adjust the pH of the blood such that it results in a pH of about 7.30 to about pH 7.50 mmol / L (e.g., about pH 7.32, or about pH 7.34, or about pH 7.36, or about pH 7.38, or about pH 7.40, or about pH 7.42, or about pH 7.44, or about pH 7.46, or about pH 7.48), and / or to return the blood pH in the subject to a baseline level of from about pH 7.30 to about pH 7.50 (e.g., or about pH 7.36, or about pH 7.37, or about pH 7.38, or about pH 7.39, or about pH 7.40, or about pH 7.41 , or about pH 7.42, or about pH 7.43, or about pH 7.44).

[0191] In embodiments, methods herein use one or more dialysate, e.g., also referred to herein as a “treatment fluid,” which includes one or more of a pH buffer, calcium, chloride, sodium, potassium, sulfate, lactate, bicarbonate, gluconate, magnesium, and / or glucose. In embodiments, the pH buffer includes one or more of pH-buffering agent, including for example, monoethanolamine, phosphate buffer, citrate buffer (e.g., sodium citrate), acetate buffer (e.g., sodium acetate), amino acid buffer (e.g., histidine / histidine monochloride), hydrochloric acid (e.g., at low concentrations useful to buffering in the physiological range of blood), and sodium hydroxide (e.g., at low concentrations useful to buffering in the physiological range of blood).

[0192] Methods herein, in embodiments, further comprise removing the biological fluid from a subject using a cannula, catheter, vascular access tool, and / or blood withdrawal device in fluid connection with the extracorporeal transfer module. For example, in embodiments, the cannula, catheter, vascular access tool, and / or blood withdrawal device are in fluid connection with the biological fluid inlet 120 (e.g., as shown in Figs. 1-2), or the biological fluid inlet 405 (e.g., as shown in Figs. 4-6), or as the biological fluid inlet 770 (e.g., as shown in Fig. 7).

[0193] Methods herein, in embodiments, further comprise returning the biological fluid to a subject after the biological fluid has exited the housing using a cannula, catheter, vascular access tool, and / or bloodwithdrawal device in fluid connection with the extracorporeal transfer module. For example, in embodiments, the cannula, catheter, vascular access tool, and / or blood withdrawal device are in fluid connection with the biological fluid outlet 125 (e.g., as shown in Figs. 1-2), or the biological fluid outlet 415 (e.g., as shown in Figs. 4-6).

[0194] In embodiments, the first bundle of hollow fiber membranes and the second bundle of hollow fiber membranes are comprised of semi-permeable material that is configured to transfer one or more ionic species, dissolved gases, or similar molecules and compounds from and / or to the biological fluid. In embodiments, the one or more ionic species includes bicarbonate (HCO3) and is transferred from the biological fluid. In embodiments, the one or more dissolved gases includes carbon dioxide (CO2) and is transferred from the biological fluid. In embodiments, the one or more dissolved gases includes oxygen and is transferred to the biological fluid (e.g., oxygenation of blood). In embodiments, the one or more similar molecules and compounds includes urea, ammonia, creatinine, water, and plasma, and is transferred from the biological fluid (e.g., such as is done in traditional hemodialysis).

[0195] In embodiments, carbon dioxide (CO2) is filtered out of the biological fluid (e.g., blood) via diffusion using a sweep gas, which has a lower concentration of gaseous carbon dioxide related to the biological fluid (e.g., blood). In embodiments, bicarbonate (HCO3) is filtered out of the biological fluid (e.g., blood) via diffusion using a dialysate, which has a lower concentration of bicarbonate relate to the biological fluid (e.g., blood).

[0196] In embodiments, the one or more ionic species, dissolved gases, or similar molecules and compounds includes calcium, chloride, sodium, potassium, oxygen, magnesium, glucose, and pH-buffering agent, and is transferred to the biological fluid. In embodiments, removal of gaseous carbon dioxide (CO2) and / or dissolved bicarbonate (HCOs) results in a derangement in one of more ionic species of blood (for example one or more of pH, chloride, calcium, sodium, and potassium are altered relative to before the carbon dioxide (CO2) and / or dissolved bicarbonate (HCO3) was removed). In embodiments, the dialysate supplies a pH-buffering agent, chloride, calcium, sodium, and / or potassium to restore and / or adjust the blood such that it is suitable to be re-infused in the subject.

[0197] In embodiments, the first bundle of hollow fiber membranes is configured for laminar extraluminal flow through the plurality of fiber membranes, and the second bundle of hollow fiber membranes is configured for laminar intraluminal flow through the plurality of fiber membranes; or where the first bundle of hollow fiber membranes is configured for laminar intraluminal flow through the plurality of fiber membranes, and thesecond bundle of hollow fiber membranes is configured for laminar extraluminal flow through the plurality of fiber membranes.

[0198] In embodiments, the extracorporeal transfer module is configured for a dialysate to flow extraluminally through the first bundle of hollow fiber membranes, where the biological fluid is configured to flow intraluminally relative to the first bundle of hollow fiber membranes; and is configured for a sweep gas to flow intraluminally through the second bundle of hollow fiber membranes, where the biological fluid is configured to flow extraluminally relative to the second bundle of hollow fiber membranes.

[0199] In embodiments, one or more treatment parameters are altered as a function of sensing, measuring, and / or assessing one or more proteins relevant to blood clotting, organ damage e.g., liver damage, cirrhosis, scarring, heart damage from infarctions, heart attack, stroke, pulmonary embolism, etc.), dyslipidemia, obesity, diabetes, and / or to metabolism. In embodiments, the sensing, measuring, and / or assessing is performed via the data port and / or sampling port of the extracorporeal transfer module.

[0200] In embodiments, the second bundle of hollow fiber membranes is arranged substantially orthogonally relative to the first bundle of hollow fiber membranes.

[0201] Methods herein, in embodiments, include passing the dialysate through the extracorporeal transfer module at a flow rate of < 500 mL / min. In embodiments, the flow rate is less than about 500 mL / min, less than about 450 mL / min, less than about 400 mL / min, less than about 350 mL / min, less than about 300 mL / min, less than about 250 mL / min, less than about 200 mL / min, less than about 150 mL / min, less than about 100 mL / min, less than about 90 mL / min, less than about 80 mL / min, less than about 70 mL / min, less than about 60 mL / min, less than about 50 mL / min, less than about 40 mL / min, less than about 30 mL / min, less than about 25 mL / min, less than about 20 mL / min, less than about 15 mL / min, or less than about 10 mL / min.

[0202] Methods herein, in embodiments, include passing the sweep gas through the extracorporeal transfer module at a flow rate of < 20 L / min. In embodiments, the flow rate is less than about 20 L / min, less than about 15 L / min, less than about 10 L / min, less than about 5 L / min, less than about 3 L / min, less than about 2 L / min, or less than about 1 L / min.

[0203] Methods herein, in embodiments, include passing the biological fluid (e.g., blood) through the extracorporeal transfer module at a flow rate of < 400 mL / min. In embodiments, the flow rate is less than about 400 mL / min, less than about 350 mL / min, less than about 300 mL / min, less than about 250 mL / min,less than about 200 mL / min, less than about 150 mL / min, less than about 100 mL / min, less than about 90 mL / min, less than about 80 mL / min, less than about 70 mL / min, less than about 60 mL / min, less than about 50 mL / min, less than about 40 mL / min, less than about 30 mL / min, less than about 25 mL / min, less than about 20 mL / min, less than about 15 mL / min, or less than about 10 mL / min.Methods of Sampling and / or Measuring Fluid Parameters of a Biological fluid

[0204] In aspects, devices and / or methods herein are suitable for use in sampling and / or measuring one or more fluid parameters of a biological fluid (e.g., blood). In embodiments, the sampling and / or measuring is performed substantially contemporaneously alongside gaseous carbon dioxide and bicarbonate removal. In embodiments, the sampling and / or measuring is performed sequentially, in between the removal of gaseous carbon dioxide and / or bicarbonate. In embodiments, methods of sampling and / or measuring of the one or more fluid parameters of a biological fluid are compatible with any of the devices and / or other methods, as described herein.

[0205] In embodiments, the sampling and / or measuring is performed during the treatment of one or more diseases and / or disorders, e.g., in a subject in need thereof.

[0206] In embodiments, the sampling and / or measuring is performed as part of an ex vivo and / or in vitro process, for example, in treating samples for clinical, diagnostic, therapeutic, or manufacturing purposes (e.g., preparing blood and / or blood plasma), and / or to aseptically add one or more components and / or filter out one or more components.

[0207] In embodiments, the sampling and / or measuring of the one or more fluid parameters of the biological fluid is performed as the biological fluid flows through the extracorporeal transfer module.

[0208] In embodiments, the sampling and / or measuring is via one or more openings in fluid communication with a void space within the lumen transition region, e.g., as depicted in the non-limiting illustrations of Figs. 1, 4-6, and 9-12. In embodiments, the sampling and / or measuring is via one or more openings in fluid communication before the first bundle of hollow fiber membranes (e.g., sampling prior to any filtration), for example to evaluate fluid parameters before removal of gaseous carbon dioxide and bicarbonate. In embodiments, the sampling and / or measuring is via one or more openings in fluid communication after the first bundle of hollow fiber membranes but before the second bundle of hollow fiber membranes, for example to evaluate fluid parameters after removal of one of gaseous carbon dioxide or bicarbonate. In embodiments, the sampling and / or measuring is via one or more openings in fluidcommunication after the second bundle of hollow fiber membranes, for example to evaluate fluid parameters after removal of both gaseous carbon dioxide and bicarbonate.

[0209] In embodiments, the sampling and / or measuring includes using one or more sensors in fluid communication with the extracorporeal transfer module. In embodiments, the one or more sensors include one or more electrodes, optodes, and / or devices.

[0210] In embodiments the one or more fluid parameters includes pH (e.g., [H+], change in pH, detection of acidosis, etc.), sodium (e.g., [Na+], change in sodium concentration, etc.), potassium (e.g., [K+], change in potassium concentration, etc.), chloride (e.g., [CI-], change in chloride concentration, etc.), calcium (e.g., [Ca2+], change in calcium concentration, etc.), blood-gas analysis (e.g., gas content, concentration, change in concentration, etc.), oxygen (e.g., dissolved oxygen concentration, change in oxygen concentration, detection of hypoxia, etc.), carbon dioxide (e.g., dissolved carbon dioxide concentration, change in carbon dioxide concentration, etc.), bicarbonate (e.g., bicarbonate concentration, change in bicarbonate concentration, etc.), carbonic acid (e.g., carbonic acid concentration, change in carbonic acid concentration, etc.), metabolic levels (e.g., concentration of one or more biomarkers indicative of metabolism of carbohydrates, lipids, and amino acid metabolism, such as co-factors, ammonia, and triglycerides, change in concentration of such biomarkers, etc.), magnesium (e.g., [Mg2+], change in magnesium concentration, etc.), urea (e.g., urea concentration, change in urea concentration, etc.), creatine (e.g., creatine concentration, change in creatine concentration, etc.), creatinine (e.g., creatinine concentration, change in creatinine concentration, etc.), glucose (e.g., glucose concentration, change in glucose concentration, etc.), lactate (e.g., lactate concentration, change in lactate concentration, indications of Type B lactic acidosis, etc.), proteins (e.g., protein concentration, presence or absence of one or more proteins, change in the concentration of one or more proteins, etc.), metabolites (e.g., concentration of one or more metabolites of carbohydrate, lipids, amino acid metabolism, change in concentration of such biomarkers, etc.), hormones (e.g., concentration of one or more hormones, change in concentration of hormones, etc.), lipids (e.g., blood lipid concentration, change in blood lipid concentration, etc.), carbohydrates (e.g., blood sugar concentration, change in blood sugar concentration, etc.), blood cell content / counts (e.g., blood cell absolute counts by cell types, changes in blood cell count, etc.), pathogens (e.g., presence or absence of blood pathogens, pathogen identification, etc.), clotting factors (e.g., concentration of clotting factors, changes in clotting factor concentration, etc.), electrolyte balance (e.g., concentration of one or more electrolytes, ratio of electrolyte concentration, changes in electrolyte concentration, etc.), intracellular or extracellular compositions (e.g.,presence of and / or concentration of one or more intracellular or extracellular components, DNA, RNA, chromatin, cytosolic proteins, secreted proteins, and changes in concentrations thereof, etc.), perfusion characteristics (e.g., clinical evaluation of heart rate (HR), heart rhythm, mean arterial blood pressure (MAP), skin perfusion, capillary refill, urine output, etc.), temperature, flow rate, pressure (e.g., back pressure of blood, dialysate, and / or sweep gas being passed through the device, pressure differences due to changes in in liquid viscosity, etc.), partial pressures (e.g., of dissolved gasses), saturation (e.g., concentration of oxygen and carbon dioxide bound to hemoglobin), resistance (e.g., electrical resistivity and conductivity, volume resistivity or specific electrical resistance, etc.), device longevity (e.g., one or more metrics indicative of hollow fiber membrane health, power, etc.), and / or physical, chemical, and / or time-dependent variables of interest.

[0211] In embodiments, the one or more electrodes, optodes, and / or devices collects information for clinical therapy, including sensing, measuring, and / or assessing one or more of conductivity, pH, sodium, potassium, chloride, calcium, oxygen, carbon dioxide, bicarbonate, carbonic acid, metabolic levels, magnesium, urea, creatine, creatinine, glucose, lactate, proteins, metabolites, hormones, lipids, carbohydrates, blood cell content / counts, pathogens, clotting factors, electrolyte balance, intracellular or extracellular compositions, perfusion characteristics, temperature, flow rate, pressure, partial pressure, saturation, resistance, device longevity, and / or physical, chemical, or time-dependent variables of interest. In embodiments, one or more sensors includes electrolyte sensors which are configured to measure the electrolytic content.

[0212] In embodiments, the one or more electrodes, optodes, and / or devices is coupled with one or more assays for sensing, measuring, and / or assessing one or more of the fluid parameters. Such assays, in embodiments, include immunohistochemical staining, western blotting, in cell western, immunofluorescence staining, enzyme-linked immunosorbent assay (ELISA), flow cytometry, polymerase chain reaction (PCR), nucleic acid sequencing, cell cultures, or a combination thereof. In embodiments, assays useful for detecting blood ions include assay kits for electrolytes (e.g., sodium, chloride, potassium, etc.). In embodiments, assays useful for protein and / or analyte detection include immunoassays and antibody-based detection (e.g, western blotting, dot blotting, ELISA, multiplex assays, etc.), mass spec analyses of analytes, fluorescencebased detection in situ, flow cytometry of cell surface markers relating to protein secretion, etc. In embodiments, assays useful for cell counting and / or detection include immunofluorescence staining, cell sorting (e.g, fluorescence-activated cell sorting (FACS)), flow cytometry, confocal microscopy, etc. In embodiments, assays useful for detecting pathogens include blood cultures from samples taken from thetransfer module, antibody-based detection of pathogen or infection (e.g., detection of lipopolysaccharide (LPS), viral products, blood titers indicative of an active or previous infection, etc.).

[0213] In embodiments, sensing includes a qualitative assessment of the presence of a variable or component, such as an indication that a metabolite is present, that a medication was detected in the blood, etc. In embodiments, measuring includes a quantitative assessment of the presence of a variable or a component, such as a concentration of one or more ions, fluid / gas pressure, flow rate measurement, etc. In embodiments, assessing includes a measurement compared against a setpoint or threshold, for example, if a pressure exceeds a pressure alarm, if an ion concentration is above or below a threshold concentration, where an output includes a determination, or assessment, of a next step (e.g., to increase, decrease, or alter a component in a dialysate and / or sweep gas, increase / decrease flow rate, etc.).

[0214] In embodiments, the proteins that are sensed, measured, and / or assessed include serum albumin, hematocrit, hemoglobin, alanine transaminase (ALT), aspartate transferase (AST), fibrinogen, thrombopoietin, tissue-type plasminogen activator (tPA), hemopexin, calcitonin, thyroxine-binding globulin, von Willebrand factor, haptoglobin, alpha-1 -proteinase inhibitor, urokinase, transferrin, alpha-2- macrog Io bul i n, transthyretin, ceruloplasmin, complement component 3, apolipoprotein A-V (APOA5), lecithin- cholesterol acyltransferase, lipopolysaccharide binding protein, mannan-binding lectin, chemokine ligand 18 (CCL18), chemokine ligand 17 (CCL17), transcortin, angiopoietin-1 (CD202B), adiponectin, angiotensinconverting enzyme (ACE), and / or platelet-derived growth factor. In embodiments, proteins relevant to blood clotting, proteins relevant to organ damage (e.g., liver damage, cirrhosis, scarring, heart damage from infarctions, heart attack, stroke, pulmonary embolism, etc.), proteins relevant to dyslipidemia, obesity, diabetes, and / or proteins relevant to metabolism are sensed, measured, and / or assessed via the data port and / or sampling port of the extracorporeal transfer module.

[0215] In embodiments, the cell content / counts includes red blood cell count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), red cell distribution width (RDW), white blood cell count, lymphocyte count, monocyte counts, eosinophil count, basophil count, neutrophil count, and / or platelet count.

[0216] In embodiments, the pathogens include bacteria, viruses, mycoplasmas, parasites, spores, and / or fungus. In embodiments, the pathogen includes common bloodborne pathogens, such as Staphylococcus aureus, Group A streptococcus (GAS), Group B streptococcus (GBS), Enterococci spp. , E. coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Proteus mirabilis, Salmonella spp., Enterobacterspp., hepatitis B (HBV), hepatitis C (HCV), human immunodeficiency virus (HIV), Haemoproteus spp., Leucocytozoon spp., Trypanosoma spp., Plasmodium spp. (malaria), and microfilaria, Candida spp., etc.

[0217] In embodiments, methods herein include sampling the biological fluid, such as diverting a small amount of the flow of the biological fluid (e.g., blood) to be aseptically transferred into one or more tubes, vials, cryovials, centrifugal tubes, wells, plates, aliquots, etc. In embodiments, sampling the biological fluid enables one or more additional tests to be performed with a subject’s blood, for example for blood tests or panels, to check for blood-borne pathogens / diseases, and / or to check for one or more biomarkers of disease. In embodiments, the sampling is via one or more openings in fluid communication with the void space within the lumen transition region, for example, to sample blood after removal of carbon dioxide or bicarbonate. In embodiments, the sampling is via one or more openings in fluid communication before the first bundle of hollow fiber membranes, after the first bundle of hollow fiber membranes and before the second bundle of hollow fiber membranes, and after the second bundle of hollow fiber membranes, for example, to sample blood after removal of both carbon dioxide and bicarbonate.

[0218] In embodiments, methods herein include adjusting one or more parameters of the dialysate, the sweep gas, and / or the biological fluid as each are passed through the first bundle of hollow fibers and / or the second bundle of hollow fiber bundles. In embodiments, the adjusting of the one or more parameters is as a function of the measuring of the one or more parameters of the biological fluid, and / or as a function of the sampling. In embodiments, “as a function of the measuring and / or sample,” refers to adjustment in response to measuring one or more fluid parameters of the dialysate, the sweep gas, and / or the biological fluid, for example, as performed in real time.

[0219] In embodiments, the adjusting includes increasing the concentration of one or more components of the dialysate and / or sweep gas, for example, where measuring and / or sampling indicates that the subject’s blood has a lower than normal physiological concentration of one or more components, as described herein. In embodiments, the adjusting includes decreasing the concentration of one or more components of the dialysate and / or sweep gas, for example, where measuring and / or sampling indicates that the subject’s blood has a higher than normal physiological concentration of one or more components, as described herein.

[0220] In embodiments, the adjusting includes adding one or more one or more components to the dialysate and / or sweep gas, for example, where measuring and / or sampling indicates that the subject’s blood is substantially missing one or more components, a described herein (e.g., a therapeutic agent or medication to treat and / or prevent a disease and / or disorder). In embodiments, the adjusting includes removing one ormore one or more components from the dialysate and / or sweep gas, for example, where measuring and / or sampling indicates that the subject’s blood no longer requires the addition of one or more components.

[0221] In embodiments, the adjusting includes altering one or more of the perfusion characteristics, temperature, flow rate, pressure, and resistance of the dialysate, sweep gas, and / or biological fluid, for example, where measuring and / or sampling indicates that the flow rates need to be increased / decreased, or that the back pressure indicates potential damage to blood cells, etc.

[0222] In embodiments, the one or more components that is increased, decreased, added, and / or removed includes any of the components described herein, including a pH buffer, calcium, chloride, sodium, potassium, magnesium, glucose, oxygen, and / or a therapeutic agent.

[0223] In embodiments, the therapeutic agent includes one or more therapeutic agents suitable for a subject undergoing dialysis, including for one or more diseases and / or disorders selected from hypercarbic respiratory failure (HRF), lung injury and / or diminished lung function, type 1 respiratory failure, type 2 respiratory failure, increased airways resistance (e.g., asthma, suffocation), reduced breathing effort (e.g., drug effects, CNS / brain stem lesion, extreme obesity, obesity hypoventilation), decrease in the area of the lung available for gas exchange (e.g., in chronic bronchitis), decreased neuromuscular function (e.g., Guillain— Barre syndrome, motor neuron disease, neurodegeneration, muscular dystrophy, or amyotrophic lateral sclerosis), musculoskeletal deformity and / or rigidity (e.g., kyphoscoliosis, ankylosing spondylitis), stroke, pulmonary embolism, lung disease (e.g., COPD, interstitial lung disease, lung cancer), flail chest, liver disease (e.g., cancer) and / or renal disease (e.g., cancer).

[0224] In embodiments, the various parameters of the extracorporeal transfer module are controlled based on a user input, which is performed using the controller or via other device(s). For example, in embodiments, the controller has or is associated with one or more input devices (e.g., control panel(s), buttons, knobs, scroll wheels, computer mouse, touch screens, user interfaces, etc.) configured to receive user input instructing the controller or other component(s) of the extracorporeal transfer module to adjust operating parameter(s). In embodiments, the control is performed such that some of the parameters are controlled automatically by the controller, e.g., by selecting a set point or threshold value for one or more fluid parameters measured by one or more sensors.

[0225] In embodiments, the controller used for adjusting the one or more fluid parameters is connected via one or more data ports located on the extracorporeal transfer module, for example as shown in Figs. 2, 9-10, and 12. In embodiments, the data port relays information to a system for managing the dialysate, sweepgas, and / or biological fluid. In embodiments, the data port is in the form of an analog or digital interface for connecting one or more devices in electrical communication, and contains any number of pins or terminals by which data and / or signals can be transmitted. In embodiments, the data port is also designed in the form of a connector that is intended to couple and / or align channels capable of direct contact and / or non-contact signal transmission, such as an optical fiber connector, or scintillator-based wireless connector for example for internet connectivity (e.g., WiFi) or BLUETOOTH.

[0226] In embodiments, the controller is associated with a computing device having at least one processor and memory storing computer-executable instructions for execution by the at least one processor, such as a laptop computer, desktop computer, or a smartphone. In embodiments, the controller includes or is associated with a display configured to provide a user interface that presents information to a user (e.g., a clinician, researcher, or the subject of the treatment) during a treatment of the subject, or at any other suitable time. For example, in embodiments, the user interface displays, in any suitable visual, audio, etc. format, information to the user indicating progress and / or status of the treatment. In embodiments, the display is a touch panel display configured to receive user input for controlling operation of the extracorporeal transfer module, user input for controlling the way in which data is presented on the display, and / or any other type of user input.Kits

[0227] The present disclosure provides, in embodiments, kits including one or more extracorporeal transfer modules, Luer connectors, Hansen connectors, needles, tubing, tubes, vials, cryovials, centrifugal tubes, wells, plates, and / or additional components for carrying out methods described herein. In embodiments, the components of the present disclosure are assembled into a kit.

[0228] In embodiments, the kit comprises various containers for handling samples of biological samples, for example tubing, tubes, vials, cryovials, centrifugal tubes, wells, and / or plate. In embodiments, the tubing, tubes, vials, cryovials, centrifugal tubes, wells, and / or plate are resealable, e.g, for transporting samples to a laboratory. In embodiments, kits include one or more sterile solutions (e.g, dialysate) useful for performing one or more methods described herein. In embodiments, the kit comprises various items that are sealed and / or sterilized, for example by using high temperature, ionizing radiation, and / or UV radiation.

[0229] In embodiments, the kit has a shelf life that enables storage and use over time, where the extracorporeal transfer module and / or components thereof are stably stored and effective for about or at least about 6 months, about or at least about 1 year, about or at least about 2 years, about or at least about 5years, about or at least about 10 years, or about or at least about 20 years, without an appreciable degradation in efficiency. In embodiments, extracorporeal transfer module can be stored at a range of temperatures, including at about or at least about -80°C, about or at least about -20°C, about or at least about 0°C, about or at least about 4°C, about or at least about 25°C, about or at least about 37°C, without an appreciable degradation in efficiency.

[0230] The kits described herein, in embodiments, can include one or more containers housing components for performing the methods described herein and optionally instructions for use. Any of the kits described herein, in embodiments, can further include components needed for assembling and / or connecting the components described herein, e.g., for incorporating the extracorporeal transfer module into a dialysis machine. Alternatively, in embodiments, each component of the kit can be pre-assembled and ready for use, for example, where the extracorporeal transfer module is already assembled into a larger device, and the module and device is sealed and primed for use.

[0231] In embodiments, the kits may optionally include instructions and / or promotion for use of the components provided. As used herein, "instructions" can define a component of instruction and / or promotion, and typically involve written instructions on or associated with packaging of the disclosure. Instructions also can include any oral or electronic instructions provided in any manner such that a user will clearly recognize that the instructions are to be associated with the kit, for example, audiovisual (e.g., videotape, DVD, etc.), Internet, and / or web-based communications, etc. As used herein, "promoted" includes all methods of doing business including methods of education, engineering instruction, scientific inquiry, discovery or development, academic research, manufacturing, chemical, cosmetic, and pharmaceutical industry activity including sales, and any advertising or other promotional activity including written, oral, and electronic communication of any form, associated with the disclosure. Additionally, the kits may include other components depending on the specific application, as described herein.

[0232] The kits may have a variety of forms, such as a blister pouch, a shrink-wrapped pouch, a vacuum sealable pouch, a sealable thermoformed tray, or a similar pouch or tray form, with the accessories loosely packed within the pouch, one or more tubes, containers, a box, or a bag.

[0233] Without further elaboration, it is believed that one skilled in the art can, based on the above description, utilize the present disclosure to its fullest extent. The following specific embodiments are, therefore, to be construed as merely illustrative, and not limiting of the remainder of the disclosure in anyway whatsoever.EXAMPLESExample 1: In vivo and ex vivo testing of mass transfer device.

[0234] The mass transfer devices herein are testable using, inter alia, an acute hypercarbic pig model. For example, induction of hypercarbic conditions in vivo, is achievable by slowing ventilator settings to approximately 5 breaths or fewer per minute and using a positive end expiratory pressure to maintain adequate oxygenation. Serial blood gas is analyzable using an OPTI CCA blood bas and electrolyte analyzer device, performed at approx. 10 minute intervals to titrate an effect and indicate a stable level of hypercarbia. The mass transfer device is then usable with a variety of sweep gases and / or liquids, such as approx. 125 mM concentration ionic solution as a sweep liquid containing sodium, potassium, and / or chloride ions. The mass transfer device is connectable using an approx. 13 Fr dialysis catheter for venous access for withdrawal and return of blood. Flows are maintainable at approx. 400 mL / min or lower and are pumpable using standard cardiopulmonary bypass roller pumps. Serial measurements of arterial, venous pre-device, and venous-post device blood samples are measurable at set intervals.

[0235] An illustrative time course from an in vivo usage shows CO2 and / or bicarbonate capture efficiency in pre-device, post-device, and / or arterial blood flows. Carbon dioxide and / or bicarbonate load in vivo consistently increases under hypercarbic conditions. The CO2 and / or bicarbonate decreases as the blood is flowed through the mass transfer device. A rapid decrease in CO2 load is observable in the arterial side from the mass transfer device. Pre-device measurements are obtainable from the flow prior to mass transfer device conditioning and post-device measurements are obtainable from the flow after mass transfer device conditioning. Membrane capture efficiency is measurable based on these differences. Pre-device and post-device pH balance is also obtainable before and after subjecting to the mass transfer device. Due to the nature of the intervention to induce the disease state, there is a consistent drop in pH (acidemia) that is independent of the mass transfer device. Pre-device and post-device measurements of blood pH show an increase in pH (more alkaline) from the mass transfer device caused by the hybrid removal of constituent CO2 and / or bicarbonate and / or addition of ions. This prevents an increased drop in pH that would have occurred with isolated bicarbonate removal. Overall the device tempers the drop in pH induced by the highly acute intervention. The mass transfer device provides both an improvement to pH and reduction of overall CO2 and / or bicarbonate load.

[0236] An in vivo (or ex vivo) experiment is performable using the mass transfer device with three of more bundles of hollow fiber membranes, and / or with a reconditioning fluid. The starting blood samples areenriched with CO2 to a concentration that equals approx. 110 ± 1 mmHg. The mass transfer device is usable with blood samples and / or a reconditioning fluid at an approximate 250 mLPM flow rate by a positive displacement roller pump to ensure consistent flow. The flow across a first bundle of hollow fiber membranes is extraluminal or intraluminal to capture bicarbonate. An illustrative first bundle hollow fiber membranes (e.g., dialyzer membrane) is made from a polycarbonate housing and a plurality of hollow polysulfone low-flux fibers, with an illustrative total surface area of approx. 0.4 m2

[0237] The flow across a second bundle of hollow fiber membranes is intraluminal or extraluminal to capture dissolved CO2 gas. An illustrative second bundle of hollow fiber membranes (e.g., carbon dioxide membrane) is made from layered woven matts of hollow polymethylpentene fibers, with an illustrative total gas surface area of 0.1 m2, and with an illustrative sweep gas at a flow rate of 1 LPM of gas flow.

[0238] The flow across a third membrane component is intraluminal or extraluminal to address electrolyte derangement, pH, and / or ionic content. An illustrative third bundle of hollow fiber membranes (e.g., reconditioning fluid membrane) is made from a polycarbonate housing and a plurality of hollow polysulfone low-flux membrane, having an illustrative total membrane surface area of 0.4 m2, with an illustrative dialysate flow rate of 250 mLPM. Sample of blood gas are measure able after CO2 loading (pre-device), and / or after dialysis with the first bundle of hollow fiber membranes, after gas capture with the second bundle of hollow fiber membranes, and / or after a second dialysis with the third bundle of hollow fiber membranes.

[0239] CO2 is removable using the mass transfer device throughout the duration of the fluid treatment, pH was largely modifiable distinct from bicarbonate and CO2 removal. Traditional CO2 and bicarbonate capture systems result in a change in pH, i.e., increased acidity, which can exacerbate conditions that necessitate CO2 removal. The mass transfer device is suitable for efficient CO2 capture with concomitant pH derangement toward acidification (i.e., toward pH 7.0), where the pH is adjusted toward a physiological blood pH of ~7.4. Overall the mass transfer device tempers the drop in pH induced by the highly acute intervention.DEFINITIONS

[0240] The following definitions are used in connection with the disclosure disclosed herein. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of skill in the art to which this disclosure belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0241] As used herein, “a,” “an,” or “the” can mean one or more than one and can be intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0242] As used herein, the term “and / or” includes any and all combinations of one or more of the associated listed items.

[0243] The directional terminology used herein is for the purpose of describing particular embodiments and / or illustrated orientations and is not intended to be limiting. As used herein, the terms “up”, “down”, “left”, “right”, “top”, “bottom”, and similar directional terminologies are intended to be relative to the orientation in which the embodiment is illustrated or described, but do not preclude other orientations.

[0244] Further, the term “about” when used in connection with a referenced numeric indication means the referenced numeric indication plus or minus up to 10% of that referenced numeric indication. For example, the language “about 50” covers the range of 45 to 55. Unless otherwise clear from the context, numerical values provided herein are modified by the term “about.”

[0245] As referred to herein, all compositional percentages are by weight of the total composition, unless otherwise specified. As used herein, the word “include,” and its variants, is intended to be non-limiting, such that recitation of items in a list is not to the exclusion of other like items that may also be useful in the compositions and methods of this technology. Similarly, the terms “can” and “may” and their variants are intended to be non-limiting, such that recitation that an embodiment can or may comprise certain elements or features does not exclude other embodiments of the present technology that do not contain those elements or features.

[0246] Although the open-ended term “comprising,” as a synonym of terms such as including, containing, or having, is used herein to describe and claim the disclosure, the present disclosure, or embodiments thereof, may alternatively be described using alternative terms such as “consisting of” or “consisting essentially of.” The terms “comprises” and / or “comprising,” can specify the presence of stated features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof.

[0247] In embodiments, as used herein, the words “preferred” and “preferably” refer to embodiments of the technology that afford certain benefits, under certain circumstances. However, other embodiments may also be preferred, under the same or other circumstances. Furthermore, the recitation of one or morepreferred embodiments does not imply that other embodiments are not useful, and is not intended to exclude other embodiments from the scope of the technology.

[0248] In embodiments, the disclosure is directed to the following embodiments:

[0249] Embodiment 1 . An extracorporeal transfer module for a biological fluid comprising a housing, a first bundle of hollow fiber membranes disposed within the housing, the first bundle having a plurality of hollow fiber membranes and arranged axially or orthogonally relative to the housing, and wherein the first bundle of hollow fiber membranes is configured for laminar extraluminal or intraluminal flow of a dialysate or sweep gas therethrough, at least a second bundle of hollow fiber membranes disposed within the housing, the second bundle having a plurality of hollow fiber membranes, arranged axially or orthogonally relative to the first bundle of hollow fiber membranes, and wherein the second bundle of hollow fiber membranes is configured for laminar extraluminal or intraluminal flow of a dialysate or sweep gas therethrough, a lumen transition region comprising a void space between the first bundle of hollow fiber membranes and the second bundle of hollow fiber membranes configured to flow the biological fluid: extraluminally to intraluminally, intraluminally to extraluminally, extraluminally to extraluminally, and / or intraluminally to intraluminally, wherein the housing comprises at least one potting portion that bonds at least one open end of the first bundle of hollow fiber membranes and bonds at least one open end of the second bundle of hollow fiber membranes, such that the first bundle of hollow fiber membranes and the second bundle of hollow fiber membranes are configured to receive the dialysate and / or sweep gas from outside of the housing.

[0250] Embodiment 2. The extracorporeal transfer module of embodiment 1 , wherein the biological fluid is blood.

[0251] Embodiment 3. The extracorporeal transfer module of embodiment 1 or 2, wherein the housing is cylindrical, or substantially cylindrical in shape.

[0252] Embodiment 4. The extracorporeal transfer module of any one of embodiments 1-3, wherein the first bundle of hollow fiber membranes and the second bundle of hollow fiber membranes are comprised of semi-permeable material that is configured to transfer one or more ionic species, dissolved gases, or similar molecules and compounds from and / or to the biological fluid.

[0253] Embodiment 5. The extracorporeal transfer module of embodiment 4, wherein the one or more dissolved gases comprises gaseous carbon dioxide (CO2) and is transferred from the biological fluid.

[0254] Embodiment 6. The extracorporeal transfer module of embodiment 4, wherein the one or more ionic species comprises bicarbonate (HCO3’) and is transferred from the biological fluid.

[0255] Embodiment 7. The extracorporeal transfer module of embodiment 4, wherein the one or more dissolved gases comprises oxygen (O2) and is transferred to the biological fluid.

[0256] Embodiment 8. The extracorporeal transfer module of embodiment 4, wherein the one or more ionic species comprises calcium, chloride, sodium, potassium, sulfate, lactate, and / or magnesium, and is transferred to the biological fluid.

[0257] Embodiment 9. The extracorporeal transfer module of embodiment 4, wherein the one or more similar molecules and compounds comprises urea, ammonia, creatinine, water, and / or plasma, and is transferred from the biological fluid; and / or wherein the one or more similar molecules and compounds comprises glucose, a pH-buffering agent, and / or water, and is transferred to the biological fluid.

[0258] Embodiment 10. The extracorporeal transfer module of any one of the preceding embodiments, wherein the first bundle of hollow fiber membranes is configured for laminar extraluminal flow through the hollow fiber membranes, and the second bundle of hollow fiber membranes is configured for laminar intraluminal flow through the hollow fiber membranes; or wherein the first bundle of hollow fiber membranes is configured for laminar intraluminal flow through the hollow fiber membranes, and the second bundle of hollow fiber membranes is configured for laminar extraluminal flow through the hollow fiber membranes.

[0259] Embodiment 11 . The extracorporeal transfer module of any one of the preceding embodiments, wherein the extracorporeal transfer module is configured for a dialysate to flow extraluminally through the first bundle of hollow fiber membranes, where the biological fluid is configured to flow intraluminally relative to the first bundle of hollow fiber membranes; and is configured for a sweep gas to flow intraluminally through the second bundle of hollow fiber membranes, where the biological fluid is configured to flow extraluminally relative to the second bundle of hollow fiber membranes.

[0260] Embodiment 12. The extracorporeal transfer module of any one of the preceding embodiments, wherein the second bundle of hollow fiber membranes is arranged orthogonally relative to the first bundle of hollow fiber membranes.

[0261] Embodiment 13. The extracorporeal transfer module of any one of the preceding embodiments, wherein the extracorporeal transfer module is configured to flow the dialysate with a flow rate of less than about 500 mL / min, less than about 450 mL / min, less than about 400 mL / min, less than about 350 mL / min,less than about 300 mL / min, less than about 250 mL / min, less than about 200 mL / min, less than about 150 mL / min, less than about 100 mL / min, less than about 90 mL / min, less than about 80 mL / min, less than about 70 mL / min, less than about 60 mL / min, less than about 50 mL / min, less than about 40 mL / min, less than about 30 mL / min, less than about 25 mL / min, less than about 20 mL / min, less than about 15 mL / min, or less than about 10 mL / min; and / or wherein the extracorporeal transfer module is configured to flow the sweep gas with a flow rate of less than about 20 L / min, less than about 15 L / min, less than about 10 L / min, less than about 5 L / min, less than about 3 L / min, less than about 2 L / min, or less than about 1 L / min.

[0262] Embodiment 14. The extracorporeal transfer module of any one of the preceding embodiments, wherein the extracorporeal transfer module is configured to flow the biological fluid with a flow rate of less than about 400 mL / min, less than about 350 mL / min, less than about 300 mL / min, less than about 250 mL / min, less than about 200 mL / min, less than about 150 mL / min, less than about 100 mL / min, less than about 90 mL / min, less than about 80 mL / min, less than about 70 mL / min, less than about 60 mL / min, less than about 50 mL / min, less than about 40 mL / min, less than about 30 mL / min, less than about 25 mL / min, less than about 20 mL / min, less than about 15 mL / min, or less than about 10 mL / min.

[0263] Embodiment 15. The extracorporeal transfer module of any one of the preceding embodiments, wherein the dialysate comprises one or more of a pH buffer, calcium, chloride, sodium, potassium, magnesium, sulfate, lactate, gluconate, starch, glucose, and water.

[0264] Embodiment 16. The extracorporeal transfer module of any one of the preceding embodiments, wherein the pH buffer comprises one or more of monoethanolamine, phosphate buffer, citrate buffer, acetate buffer, amino acid buffer, hydrochloric acid, and sodium hydroxide, hydrochloric acid, and sodium hydroxide.

[0265] Embodiment 17. The extracorporeal transfer module of any one of the preceding embodiments, wherein the sweep gas comprises oxygen and / or medical room gas.

[0266] Embodiment 18. The extracorporeal transfer module of any one of the preceding embodiments, wherein the biological fluid flows extral umi nally and / or intral uminally relative to the first bundle of hollow fiber membranes and to the second bundle of hollow fiber membranes.

[0267] Embodiment 19. The extracorporeal transfer module of any one of the preceding embodiments, wherein the extracorporeal transfer module is configured to be in fluid communication with one or more of a cannula, catheter, vascular access tool, or blood withdrawal device.

[0268] Embodiment 20. The extracorporeal transfer module of any one of the preceding embodiments, further comprising a data port.

[0269] Embodiment 21. The extracorporeal transfer module of embodiment 20, wherein the data port comprises one or more sensors configured to relay information about the biological fluid.

[0270] Embodiment 22. The extracorporeal transfer module of embodiment 20, wherein the data port comprises one or more connectors configured to couple and / or align channels of direct contact and / or noncontact signal transmission.

[0271] Embodiment 23. The extracorporeal transfer module of embodiment 20, wherein the non-contact signal transmission is WiFi or BLUETOOTH.

[0272] Embodiment 24. The extracorporeal transfer module of any one of the preceding embodiments, further comprising one or more openings in fluid communication with the void space within the lumen transition region.

[0273] Embodiment 25. The extracorporeal transfer module of embodiment 24, further comprising one or more sensors in fluid communication with the one or more openings.

[0274] Embodiment 26. The extracorporeal transfer module of embodiment 25, wherein the one or more sensors comprises an electrode, optode, and / or device.

[0275] Embodiment 27. The extracorporeal transfer module of embodiment 26, wherein the electrode, optode, and / or device senses, measures, and / or assesses one or more of conductivity, pH, sodium, potassium, chloride, calcium, oxygen, carbon dioxide, bicarbonate, carbonic acid, metabolic levels, magnesium, urea, creatine, creatinine, glucose, lactate, proteins, metabolites, hormones, lipids, carbohydrates, blood cell content / counts, pathogens, clotting factors, electrolyte balance, intracellular or extracellular compositions, perfusion characteristics, temperature, flow rate, pressure, partial pressure, saturation, resistance, device longevity, and physical, chemical, and / or time-dependent variables.

[0276] Embodiment 28. The extracorporeal transfer module of embodiment 27, wherein the proteins comprise one or more of serum albumin, hematocrit, hemoglobin, alanine transaminase (ALT), aspartate transferase (AST), fibrinogen, thrombopoietin, tissue-type plasminogen activator (tPA), hemopexin, calcitonin, thyroxine-binding globulin, von Willebrand factor, haptoglobin, alpha-1 -proteinase inhibitor, urokinase, transferrin, alpha-2-macroglobulin, transthyretin, ceruloplasmin, complement component 3, apolipoprotein A-V (APOA5), lecithin-cholesterol acyltransferase, lipopolysaccharide binding protein,mannan-binding lectin, chemokine ligand 18 (CCL18), chemokine ligand 17 (CCL17), transcortin, angiopoietin-1 (CD202B), adiponectin, angiotensin-converting enzyme (ACE), and platelet-derived growth factor.

[0277] Embodiment 29. The extracorporeal transfer module of embodiment 27, wherein the cell content / counts comprise one or more of red blood cell count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), red cell distribution width (RDW), white blood cell count, lymphocyte count, monocyte counts, eosinophil count, basophil count, neutrophil count, and platelet count.

[0278] Embodiment 30. The extracorporeal transfer module of embodiment 27, wherein the pathogens comprise one or more of bacteria, viruses, mycoplasmas, parasites, spores, and fungus.

[0279] Embodiment 31 . The extracorporeal transfer module of any one of embodiments 24-30, further comprising one or more ports in fluid communication with the one or more openings.

[0280] Embodiment 32. The extracorporeal transfer module of embodiment 31 , wherein the one or more ports comprises a sampling port configured to withdraw a volume of the biological fluid and / or infuse a volume into the biological fluid.

[0281] Embodiment 33. The extracorporeal transfer module of embodiment 31 or 32, wherein the one or more ports is configured to supply one or more therapeutic agents to the biological fluid.

[0282] Embodiment 34. The extracorporeal transfer module of any one of embodiments 1-33, wherein the extracorporeal transfer module has more than two discrete bundles of hollow fiber membranes.

[0283] Embodiment 35. The extracorporeal transfer module of embodiment 34, comprising a third bundle of hollow fiber membranes configured to alter the ionic content and / or pH-balance of the biological fluid after passage through the first two bundles of hollow fiber membranes.

[0284] Embodiment 36. The extracorporeal transfer module of embodiment 34 or 35, wherein the extracorporeal transfer module comprises at least a second lumen transition region located between the second bundle of hollow fiber membrane bundles and a third hollow fiber membrane bundles, wherein the luminal flow orientation relative to the biological fluid changes.

[0285] Embodiment 37. The extracorporeal transfer module of any one of embodiments 34-36, wherein a lumen transition region is present between every two hollow fiber bundles.

[0286] Embodiment 38. The extracorporeal transfer module of any one of embodiments 34-37, wherein the extracorporeal transfer module has two or more bundles of hollow fiber membranes, three or more bundles of hollow fiber membranes, four or more bundles of hollow fiber membranes, or five or more bundles of hollow fiber membranes.

[0287] Embodiment 39. The extracorporeal transfer module of any one of embodiments 1-38, wherein the extracorporeal transfer module is configured to be connected in a stackable configuration.

[0288] Embodiment 40. The extracorporeal transfer module of embodiment 39, wherein the extracorporeal transfer module is connected via Luer connectors, tubing, Hansen connectors, or uniform cross-sectional connectors.

[0289] Embodiment 41. A method of removing carbon dioxide and bicarbonate from a biological fluid comprising 1) causing the biological fluid to enter an extracorporeal transfer module comprising a housing, a first bundle of hollow fiber membranes disposed within the housing, the first bundle having a plurality of hollow fiber membranes and arranged axially or orthogonally relative to the housing, and wherein the first bundle of hollow fiber membranes is configured for laminar extraluminal or intraluminal flow of a dialysate or sweep gas therethrough, at least a second bundle of hollow fiber membranes disposed within the housing, the second bundle having a plurality of hollow fiber membranes, arranged axially or orthogonally relative to the first bundle of hollow fiber membranes, and wherein the second bundle of hollow fiber membranes is configured for laminar extraluminal or intraluminal flow of a dialysate or sweep gas therethrough, a lumen transition region comprising a void space between the first bundle of hollow fiber membranes and the second bundle of hollow fiber membranes configured to flow the biological fluid: extraluminally to intraluminally, intraluminally to extraluminally, extraluminally to extraluminally, and / or intraluminally to intraluminally, 2) passing a dialysate through the first bundle of hollow fiber membranes to cause bicarbonate to transfer from the biological fluid into the dialysate, 3) passing a sweep gas through the second bundle of hollow fiber membranes to cause gaseous carbon dioxide to transfer from the biological fluid into the sweep gas, and 4) causing the biological fluid to exit the housing after the bicarbonate and gaseous carbon dioxide are removed from the biological fluid.

[0290] Embodiment 42. The method of embodiment 41 , wherein the biological fluid is blood.

[0291] Embodiment 43. The method of embodiment 41 or 42, wherein the sweep gas comprises oxygen and / or medical room gas, optionally wherein oxygen is transferred from the sweep gas into the biological fluid.

[0292] Embodiment 44. The method of any one of embodiments 41-43, wherein passing the dialysate through the first bundle of hollow fiber membranes results in one or more ionic species and / or similar molecules and compounds to transfer from the dialysate to the biological fluid and / or to transfer from the biological fluid to the dialysate.

[0293] Embodiment 45. The method of any one of embodiments 41-44, wherein the dialysate comprises an ionic content that is configured to restore and / or adjust the ionic content and / or pH balance of the biological fluid.

[0294] Embodiment 46. The method of any one of embodiments 41-45, wherein the dialysate comprises one or more of pH buffer, calcium, chloride, sodium, potassium, magnesium, sulfate, lactate, gluconate, starch, glucose, and water.

[0295] Embodiment 47. The method of embodiment 46, wherein the pH buffer comprises one or more of monoethanolamine, phosphate buffer, citrate buffer, acetate buffer, amino acid buffer, hydrochloric acid, and sodium hydroxide.

[0296] Embodiment 48. The method of any one of embodiments 41-47, further comprising removing the biological fluid from a subject using a cannula, catheter, vascular access tool, and / or blood withdrawal device in fluid connection with the extracorporeal transfer module.

[0297] Embodiment 49. The method of any one of embodiments 41 -48, further comprising returning the biological fluid to a subject after the biological fluid has exited the housing using a cannula, catheter, vascular access tool, and / or blood withdrawal device in fluid connection with the extracorporeal transfer module.

[0298] Embodiment 50. The method of any one of embodiments 41-49, wherein the first bundle of hollow fiber membranes and the second bundle of hollow fiber membranes are comprised of semi-permeable material that is configured to transfer one or more ionic species, dissolved gases, or similar molecules and compounds from and / or to the biological fluid.

[0299] Embodiment 51. The method of embodiment 50, wherein the one or more dissolved gases comprises gaseous carbon dioxide (CO2) and is transferred from the biological fluid and / or oxygen (O2) and is transferred to the biological fluid.

[0300] Embodiment 52. The method of embodiment 50, wherein the one or more ionic species comprises bicarbonate (HCOs’) and is transferred from the biological fluid, and / or wherein the one or moreionic species comprises calcium, chloride, sodium, potassium, sulfate, lactate, and / or magnesium, and is transferred to the biological fluid.

[0301] Embodiment 53. The method of embodiment 50, wherein the one or more similar molecules and compounds comprises urea, ammonia, creatinine, water, and / or plasma, and is transferred from the biological fluid; and / or wherein the one or more similar molecules and compounds comprises glucose, a pH- bufferi ng agent, and / or water, and is transferred to the biological fluid.

[0302] Embodiment 54. The method of any one of embodiments 41-53, wherein the first bundle of hollow fiber membranes is configured for laminar extraluminal flow through the plurality of fiber membranes, and the second bundle of hollow fiber membranes is configured for laminar intraluminal flow through the plurality of fiber membranes; or wherein the first bundle of hollow fiber membranes is configured for laminar intraluminal flow through the plurality of fiber membranes, and the second bundle of hollow fiber membranes is configured for laminar extraluminal flow through the plurality of fiber membranes.

[0303] Embodiment 55. The method of any one of embodiments 41-54, wherein the extracorporeal transfer module is configured for a dialysate to flow extraluminally through the first bundle of hollow fiber membranes, where the biological fluid is configured to flow intraluminally relative to the first bundle of hollow fiber membranes; and is configured for a sweep gas to flow intraluminally through the second bundle of hollow fiber membranes, where the biological fluid is configured to flow extraluminally relative to the second bundle of hollow fiber membranes.

[0304] Embodiment 56. The method of any one of embodiments 41-55, wherein the second bundle of hollow fiber membranes is arranged orthogonally relative to the first bundle of hollow fiber membranes.

[0305] Embodiment 57. The method of any one of embodiments 41-56, wherein the extracorporeal transfer module is configured to flow the dialysate with a flow rate of less than about 500 mL / min, less than about 450 mL / min, less than about 400 mL / min, less than about 350 mL / min, less than about 300 mL / min, less than about 250 mL / min, less than about 200 mL / min, less than about 150 mL / min, less than about 100 mL / min, less than about 90 mL / min, less than about 80 mL / min, less than about 70 mL / min, less than about 60 mL / min, less than about 50 mL / min, less than about 40 mL / min, less than about 30 mL / min, less than about 25 mL / min, less than about 20 mL / min, less than about 15 mL / min, or less than about 10 mL / min; and / or wherein the extracorporeal transfer module is configured to flow the sweep gas with a flow rate of less than about 20 L / min, less than about 15 L / min, less than about 10 L / min, less than about 5 L / min, less than about 3 L / min, less than about 2 L / min, or less than about 1 L / min.

[0306] Embodiment 58. The method of any one of embodiments 41-57, wherein the extracorporeal transfer module is configured to flow the biological fluid with a flow rate of less than about 400 mL / min, less than about 350 mL / min, less than about 300 mL / min, less than about 250 mL / min, less than about 200 mL / min, less than about 150 mL / min, less than about 100 mL / min, less than about 90 mL / min, less than about 80 mL / min, less than about 70 mL / min, less than about 60 mL / min, less than about 50 mL / min, less than about 40 mL / min, less than about 30 mL / min, less than about 25 mL / min, less than about 20 mL / min, less than about 15 mL / min, or less than about 10 mL / min.

[0307] Embodiment 59. A method of treating a disease or disorder in a subject in need thereof using an extracorporeal transfer module comprising 1) removing a biological fluid from the subject, 2) causing the biological fluid to enter the extracorporeal transfer module comprising a housing, a first bundle of hollow fiber membranes disposed within the housing, the first bundle having a plurality of hollow fiber membranes and arranged axially or orthogonally relative to the housing, and wherein the first bundle of hollow fiber membranes is configured for laminar extraluminal or intraluminal flow of a dialysate or sweep gas therethrough, at least a second bundle of hollow fiber membranes disposed within the housing, the second bundle having a plurality of hollow fiber membranes, arranged axially or orthogonally relative to the first bundle of hollow fiber membranes, and wherein the second bundle of hollow fiber membranes is configured for laminar extraluminal or intraluminal flow of a dialysate or sweep gas therethrough, a lumen transition region comprising a void space between the first bundle of hollow fiber membranes and the second bundle of hollow fiber membranes configured to flow the biological: extralu min ally to intralumi nally, intraluminally to extralu min ally, extraluminally to extraluminally, and / or intraluminally to intraluminally, 3) passing a dialysate through the first bundle of hollow fiber membranes to cause gaseous carbon dioxide to transfer from the biological fluid into the sweep gas, 4) passing a sweep gas through the second bundle of hollow fiber membranes to cause bicarbonate to transfer from the biological fluid into the dialysate, 5) causing the fluid to exit the housing after the gaseous carbon dioxide and bicarbonate are removed from the biological fluid; and 6) returning the biological fluid into the subject.

[0308] Embodiment 60. The method of embodiments 59, wherein the biological fluid is blood.

[0309] Embodiment 61. The method of embodiments 59 or 60, wherein the disease or disorder comprises a condition with excess carbon dioxide and / or bicarbonate in the blood, and / or a condition with reduced oxygenation of the blood.

[0310] Embodiment 62. The method of embodiments 61 , wherein the disease or disorder comprises hypercarbic respiratory failure (HRF), lung injury and / or diminished lung function, type 1 respiratory failure, type 2 respiratory failure, increased airways resistance, asthma, suffocation, reduced breathing effort, drug effects, CNS / brain stem lesion, extreme obesity, obesity hypoventilation, decrease in the area of the lung available for gas exchange, chronic bronchitis, cystic fibrosis, decreased neuromuscular function, Guillain- Barre syndrome, motor neuron disease, neurodegeneration, muscular dystrophy, or amyotrophic lateral sclerosis, musculoskeletal deformity and / or rigidity, kyphoscoliosis, ankylosing spondylitis, stroke, pulmonary embolism, lung disease, COPD, interstitial lung disease, lung cancer, flail chest, liver disease and / or cancer, and / or renal disease and / or cancer.

[0311] Embodiment 63. The method of embodiments 62, wherein the disease or disorder comprises hypercarbic respiratory failure (HRF).

[0312] Embodiment 64. The method of any one of embodiments 59-63, wherein the sweep gas comprises oxygen and / or medical room gas, optionally wherein oxygen is transferred from the sweep gas into the biological fluid.

[0313] Embodiment 65. The method of any one of embodiments 59-64, wherein passing the dialysate through the first bundle of hollow fiber membranes results in one or more ionic species and / or similar molecules and compounds to transfer from the dialysate to the biological fluid and / or to transfer from the biological fluid to the dialysate.

[0314] Embodiment 66. The method of any one of embodiments 59-65, wherein the dialysate comprises an ionic content that is configured to restore and / or adjust the ionic content and / or pH balance of the biological fluid.

[0315] Embodiment 67. The method of any one of embodiments 59-66, wherein the dialysate comprises one or more of a pH buffer, calcium, chloride, sodium, potassium, magnesium, sulfate, lactate, gluconate, starch, glucose, and water.

[0316] Embodiment 68. The method of any one of embodiments 59-67, wherein the pH buffer comprises one or more of monoethanolamine, phosphate buffer, citrate buffer, acetate buffer, amino acid buffer, hydrochloric acid, and sodium hydroxide.

[0317] Embodiment 69. The method of any one of embodiments 59-68, wherein removing the biological fluid from a subject comprises using a cannula, catheter, vascular access tool, and / or blood withdrawal device in fluid connection with the extracorporeal transfer module.

[0318] Embodiment 70. The method of any one of embodiments 59-69, wherein returning the biological fluid to the subject comprises using a cannula, catheter, vascular access tool, and / or blood withdrawal device in fluid connection with the extracorporeal transfer module.

[0319] Embodiment 71. The method of any one of embodiments 59-70, wherein the first bundle of hollow fiber membranes and the second bundle of hollow fiber membranes are comprised of semi-permeable material that is configured to transfer one or more ionic species, dissolved gases, or similar molecules and compounds from and / or to the biological fluid.

[0320] Embodiment 72. The method of embodiment 71 , wherein the one or more dissolved gases comprises gaseous carbon dioxide (CO2) and is transferred from the biological fluid; and / or wherein the one or more dissolved gases comprises oxygen (O2) and is transferred to the biological fluid.

[0321] Embodiment 73. The method of embodiment 71 , wherein the one or more ionic species comprises calcium, chloride, sodium, potassium, sulfate, lactate, and / or magnesium, and is transferred to the biological fluid.

[0322] Embodiment 74. The method of embodiment 71 , wherein the one or more similar molecules and compounds comprises urea, ammonia, creatinine, water, and / or plasma, and is transferred from the biological fluid; and / or wherein the one or more similar molecules and compounds comprises glucose, a pH- bufferi ng agent, and / or water, and is transferred to the biological fluid.

[0323] Embodiment 75. The method of any one of embodiments 59-74, wherein the first bundle of hollow fiber membranes is configured for laminar extraluminal flow through the plurality of fiber membranes, and the second bundle of hollow fiber membranes is configured for laminar intraluminal flow through the plurality of fiber membranes; or wherein the first bundle of hollow fiber membranes is configured for laminar intraluminal flow through the plurality of fiber membranes, and the second bundle of hollow fiber membranes is configured for laminar extraluminal flow through the plurality of fiber membranes.

[0324] Embodiment 76. The method of any one of embodiments 59-75, wherein the extracorporeal transfer module is configured for a dialysate to flow extraluminally through the first bundle of hollow fiber membranes, where the biological fluid is configured to flow intraluminally relative to the first bundle of hollowfiber membranes; and is configured for a sweep gas to flow intraluminally through the second bundle of hollow fiber membranes, where the biological fluid is configured to flow extraluminally relative to the second bundle of hollow fiber membranes.

[0325] Embodiment 77. The method of any one of embodiments 59-76, wherein the second bundle of hollow fiber membranes is arranged orthogonally relative to the first bundle of hollow fiber membranes.

[0326] Embodiment 78. The method of any one of embodiments 59-77, wherein the extracorporeal transfer module is configured to flow the dialysate with a flow rate of less than about 500 mL / min, less than about 450 mL / min, less than about 400 mL / min, less than about 350 mL / min, less than about 300 mL / min, less than about 250 mL / min, less than about 200 mL / min, less than about 150 mL / min, less than about 100 mL / min, less than about 90 mL / min, less than about 80 mL / min, less than about 70 mL / min, less than about 60 mL / min, less than about 50 mL / min, less than about 40 mL / min, less than about 30 mL / min, less than about 25 mL / min, less than about 20 mL / min, less than about 15 mL / min, or less than about 10 mL / min; and / or wherein the extracorporeal transfer module is configured to flow the sweep gas with a flow rate of less than about 20 L / min, less than about 15 L / min, less than about 10 L / min, less than about 5 L / min, less than about 3 L / min, less than about 2 L / min, or less than about 1 L / min.

[0327] Embodiment 79. The method of any one of embodiments 59-78, wherein the extracorporeal transfer module is configured to flow the biological fluid with a flow rate of less than about 400 mL / min, less than about 350 mL / min, less than about 300 mL / min, less than about 250 mL / min, less than about 200 mL / min, less than about 150 mL / min, less than about 100 mL / min, less than about 90 mL / min, less than about 80 mL / min, less than about 70 mL / min, less than about 60 mL / min, less than about 50 mL / min, less than about 40 mL / min, less than about 30 mL / min, less than about 25 mL / min, less than about 20 mL / min, less than about 15 mL / min, or less than about 10 mL / min.

[0328] Embodiment 80. A method of measuring one or more fluid parameters of a biological fluid using an extracorporeal transfer module comprising 1) causing the biological fluid to enter the extracorporeal transfer module comprising a housing, a first bundle of hollow fiber membranes disposed within the housing, the first bundle having a plurality of hollow fiber membranes and arranged axially or orthogonally relative to the housing, and wherein the first bundle of hollow fiber membranes is configured for laminar extraluminal or intraluminal flow of a dialysate or sweep gas therethrough, at least a second bundle of hollow fiber membranes disposed within the housing, the second bundle having a plurality of hollow fiber membranes, arranged axially or orthogonally relative to the first bundle of hollow fiber membranes, and wherein the secondbundle of hollow fiber membranes is configured for laminar extraluminal or intraluminal flow of a dialysate or sweep gas therethrough, a lumen transition region comprising a void space between the first bundle of hollow fiber membranes and the second bundle of hollow fiber membranes configured to flow the biological fluid: extralu min ally to intraluminally, intraluminally to extraluminally, extraluminally to extraluminally, and / or intraluminally to intraluminally, and 2) measuring one or more fluid parameters of the biological fluid as the biological fluid flows through the extracorporeal transfer module.

[0329] Embodiment 81 . The method of embodiment 80, wherein the biological fluid is blood.

[0330] Embodiment 82. The method of embodiment 80 or 81 , further comprising passing a dialysate through the first bundle of hollow fiber membranes to cause bicarbonate to transfer from the biological fluid into the sweep gas.

[0331] Embodiment 83. The method of embodiment 82, wherein passing the dialysate through the first bundle of hollow fiber membranes results in one or more ionic species and / or similar molecules and compounds to transfer from the dialysate to the biological fluid.

[0332] Embodiment 84. The method of embodiment 82 or 83, wherein the dialysate comprises an ionic content that is configured to restore and / or adjust the ionic content and / or pH balance of the biological fluid.

[0333] Embodiment 85. The method of any one of embodiments 80-84, wherein the dialysate comprises one or more of a pH buffer, calcium, chloride, sodium, potassium, magnesium, sulfate, lactate, gluconate, starch, glucose, and water.

[0334] Embodiment 86. The method of embodiment 85, wherein the pH buffer comprises one or more of monoethanolamine, phosphate buffer, citrate buffer, acetate buffer, amino acid buffer, hydrochloric acid, and sodium hydroxide.

[0335] Embodiment 87. The method of any one of embodiments 80-86, further comprising passing a sweep gas through the second bundle of hollow fiber membranes to cause gaseous carbon dioxide to transfer from the biological fluid into the dialysate.

[0336] Embodiment 88. The method of embodiment 87, wherein the sweep gas comprises oxygen and the oxygen is transferred from the sweep gas into the biological fluid.

[0337] Embodiment 89. The method of any one of embodiments 80-88, further comprising removing the biological fluid from a subject using a cannula, catheter, vascular access tool, and / or blood withdrawal device in fluid connection with the extracorporeal transfer module.

[0338] Embodiment 90. The method of any one of embodiments 80-89, further comprising returning the biological fluid to a subject after the biological fluid has exited the housing using a cannula, catheter, vascular access tool, and / or blood withdrawal device in fluid connection with the extracorporeal transfer module.

[0339] Embodiment 91. The method of any one of embodiments 80-90, wherein the first bundle of hollow fiber membranes and the second bundle of hollow fiber membranes are comprised of semi-permeable material that is configured to transfer one or more ionic species, dissolved gases, or similar molecules and compounds from and / or to the biological fluid.

[0340] Embodiment 92. The method of embodiment 91 , wherein the one or more dissolved gases comprises gaseous carbon dioxide (CO2) and is transferred from the biological fluid.

[0341] Embodiment 93. The method of embodiment 91 , wherein the one or more ionic species comprises bicarbonate (HCC ’) and is transferred from the biological fluid.

[0342] Embodiment 94. The method of embodiment 91 , wherein the one or more dissolved gases comprises oxygen (O2) and is transferred to the biological fluid.

[0343] Embodiment 95. The method of embodiment 91 , wherein the one or more ionic species comprises calcium, chloride, sodium, potassium, sulfate, lactate, and / or magnesium, and is transferred to the biological fluid.

[0344] Embodiment 96. The method of embodiment 91 , wherein the one or more similar molecules and compounds comprises urea, ammonia, creatinine, water, and / or plasma, and is transferred from the biological fluid; and / or wherein the one or more similar molecules and compounds comprises glucose, a pH- bufferi ng agent, and / or water, and is transferred to the biological fluid.

[0345] Embodiment 97. The method of any one of embodiments 80-96, wherein the first bundle of hollow fiber membranes is configured for laminar extraluminal flow through the plurality of fiber membranes, and the second bundle of hollow fiber membranes is configured for laminar intraluminal flow through the plurality of fiber membranes; or wherein the first bundle of hollow fiber membranes is configured for laminar intraluminal flow through the plurality of fiber membranes, and the second bundle of hollow fiber membranes is configured for laminar extraluminal flow through the plurality of fiber membranes.

[0346] Embodiment 98. The method of any one of embodiments 80-97, wherein the extracorporeal transfer module is configured for a dialysate to flow extraluminally through the first bundle of hollow fiber membranes, where the biological fluid is configured to flow intraluminally relative to the first bundle of hollowfiber membranes; and is configured for a sweep gas to flow intraluminally through the second bundle of hollow fiber membranes, where the biological fluid is configured to flow extraluminally relative to the second bundle of hollow fiber membranes.

[0347] Embodiment 99. The method of any one of embodiments 80-98, wherein the second bundle of hollow fiber membranes is arranged orthogonally relative to the first bundle of hollow fiber membranes.

[0348] Embodiment 100. The method of any one of embodiments 80-99, wherein the extracorporeal transfer module is configured to flow the dialysate with a flow rate of less than about 500 mL / min, less than about 450 mL / min, less than about 400 mL / min, less than about 350 mL / min, less than about 300 mL / min, less than about 250 mL / min, less than about 200 mL / min, less than about 150 mL / min, less than about 100 mL / min, less than about 90 mL / min, less than about 80 mL / min, less than about 70 mL / min, less than about 60 mL / min, less than about 50 mL / min, less than about 40 mL / min, less than about 30 mL / min, less than about 25 mL / min, less than about 20 mL / min, less than about 15 mL / min, or less than about 10 mL / min; and / or wherein the extracorporeal transfer module is configured to flow the sweep gas with a flow rate of less than about 20 L / min, less than about 15 L / min, less than about 10 L / min, less than about 5 L / min, less than about 3 L / min, less than about 2 L / min, or less than about 1 L / min.

[0349] Embodiment 101 . The method of any one of embodiments 80-100, wherein the extracorporeal transfer module is configured to flow the biological fluid with a flow rate of less than about 400 mL / min, less than about 350 mL / min, less than about 300 mL / min, less than about 250 mL / min, less than about 200 mL / min, less than about 150 mL / min, less than about 100 mL / min, less than about 90 mL / min, less than about 80 mL / min, less than about 70 mL / min, less than about 60 mL / min, less than about 50 mL / min, less than about 40 mL / min, less than about 30 mL / min, less than about 25 mL / min, less than about 20 mL / min, less than about 15 mL / min, or less than about 10 mL / min.

[0350] Embodiment 102. The method of any one of embodiments 80-101 , wherein the measuring is via one or more openings in fluid communication with the void space within the lumen transition region, and / or wherein the measuring is via one or more openings in fluid communication after the second bundle of hollow fiber membranes, and / or wherein the measuring is before the first bundle of hollow fiber membranes.

[0351] Embodiment 103. The method of any one of embodiments 80-102, wherein the one or more fluid parameters comprise conductivity, pH, sodium, potassium, chloride, calcium, oxygen, carbon dioxide, bicarbonate, carbonic acid, metabolic levels, magnesium, urea, creatine, creatinine, glucose, lactate, proteins, metabolites, hormones, lipids, carbohydrates, blood cell content / counts, pathogens, clotting factors,electrolyte balance, intracellular or extracellular compositions, perfusion characteristics, temperature, flow rate, pressure, partial pressure, saturation, resistance, device longevity, and physical, chemical, and / or timedependent variables.

[0352] Embodiment 104. The method of any one of embodiments 80-103, wherein the measuring comprises using one or more sensors in fluid communication with the extracorporeal transfer module.

[0353] Embodiment 105. The method of embodiment 104, wherein the one or more sensors comprises an electrode, optode, and / or device.

[0354] Embodiment 106. The method of embodiment 105, wherein the electrode, optode, and / or device senses, measures, and / or assesses one or more of conductivity, pH, sodium, potassium, chloride, calcium, oxygen, carbon dioxide, bicarbonate, carbonic acid, metabolic levels, magnesium, urea, creatine, creatinine, glucose, lactate, proteins, metabolites, hormones, lipids, carbohydrates, blood cell content / counts, pathogens, clotting factors, electrolyte balance, intracellular or extracellular compositions, perfusion characteristics, temperature, flow rate, pressure, partial pressure, saturation, resistance, device longevity, and / or physical, chemical, and / or time-dependent variables.

[0355] Embodiment 107. The method of embodiment 106, wherein the proteins comprise one or more of serum albumin, hematocrit, hemoglobin, alanine transaminase (ALT), aspartate transferase (AST), fibrinogen, thrombopoietin, tissue-type plasminogen activator (tPA), hemopexin, calcitonin, thyroxine-binding globulin, von Willebrand factor, haptoglobin, alpha-1 -proteinase inhibitor, urokinase, transferrin, alpha-2- macrog Io bul i n, transthyretin, ceruloplasmin, complement component 3, apolipoprotein A-V (APOA5), lecithin- cholesterol acyltransferase, lipopolysaccharide binding protein, mannan-binding lectin, chemokine ligand 18 (CCL18), chemokine ligand 17 (CCL17), transcortin, angiopoietin-1 (CD202B), adiponectin, angiotensinconverting enzyme (ACE), and platelet-derived growth factor.

[0356] Embodiment 108. The method of embodiment 106, wherein the cell content / counts comprise one or more of red blood cell count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), red cell distribution width (RDW), white blood cell count, lymphocyte count, monocyte counts, eosinophil count, basophil count, neutrophil count, and platelet count.

[0357] Embodiment 109. The method of embodiment 106, wherein the pathogens comprise bacteria, viruses, mycoplasmas, parasites, spores, and / or fungus.

[0358] Embodiment 110. The method of any one of embodiments 80-109, further comprising sampling the biological fluid.

[0359] Embodiment 111. The method of embodiment 110, wherein the sampling is via one or more openings in fluid communication with the void space within the lumen transition region, and / or wherein the sampling is via one or more openings in fluid communication after the second bundle of hollow fiber membranes, and / or before the first bundle of hollow fiber membranes.

[0360] Embodiment 112. The method of any one of embodiments 80-111 , further comprising adjusting one or more parameters of the dialysate, sweep gas, and / or biological fluid as one or more thereof are passed through the first bundle of hollow fibers and / or the second bundle of hollow fiber bundles.

[0361] Embodiment 113. The method of embodiment 112, wherein the adjusting is as a function of the measuring the one or more parameters of the biological fluid, and / or as a function of the sampling of the biological fluid.

[0362] Embodiment 114. The method of embodiment 112 or 113, wherein the adjusting comprises: increasing the concentration of one or more components of the dialysate and / or sweep gas, decreasing the concentration of one or more components of the dialysate and / or sweep gas, adding one or more one or more components to the dialysate and / or sweep gas, removing one or more one or more components from the dialysate and / or sweep gas, and / or altering one or more of the perfusion characteristics, temperature, flow rate, pressure, and resistance of the dialysate, sweep gas, and / or biological fluid.

[0363] Embodiment 115. The method of embodiment 114, wherein the one or more components comprises a pH buffer, calcium, chloride, sodium, potassium, sulfate, lactate, gluconate, magnesium, glucose, oxygen, water, and / or a therapeutic agent.EQUIVALENTS

[0364] While the disclosure has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the disclosure following, in general, the principles of the disclosure and including such departures from the present disclosure as come within known or customary practice within the art to which the disclosure pertains and as may be applied to the essential features hereinbefore set forth and as follows in the scope of the appended claims.

[0365] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.INCORPORATION BY REFERENCE

[0366] All patents and publications referenced herein are hereby incorporated by reference in their entireties.

[0367] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present disclosure is not entitled to antedate such publication by virtue of prior disclosure.

[0368] As used herein, all headings are simply for organization and are not intended to limit the disclosure in any manner. The content of any individual section may be equally applicable to all sections.

Claims

CLAIMSWhat is claimed is:1 . An extracorporeal transfer module for a biological fluid comprising: a housing; a first bundle of hollow fiber membranes disposed within the housing, the first bundle having a plurality of hollow fiber membranes and arranged axially or orthogonally relative to the housing, and wherein the first bundle of hollow fiber membranes is configured for laminar extraluminal or intraluminal flow of a dialysate or sweep gas therethrough; at least a second bundle of hollow fiber membranes disposed within the housing, the second bundle having a plurality of hollow fiber membranes, arranged axially or orthogonally relative to the first bundle of hollow fiber membranes, and wherein the second bundle of hollow fiber membranes is configured for laminar extraluminal or intraluminal flowof a dialysate or sweep gas therethrough; a lumen transition region comprising a void space between the first bundle of hollow fiber membranes and the second bundle of hollow fiber membranes configured to flow the biological fluid: i. extraluminally to intraluminally; ii. intraluminally to extraluminally; ill. extraluminally to extraluminally; and / or iv. intraluminally to intraluminally; wherein the housing comprises at least one potting portion that bonds at least one open end of the first bundle of hollow fiber membranes and bonds at least one open end of the second bundle of hollow fiber membranes, such that the first bundle of hollow fiber membranes and the second bundle of hollow fiber membranes are configured to receive the dialysate and / or sweep gas from outside of the housing.

2. The extracorporeal transfer module of claim 1 , wherein the biological fluid is blood.

3. The extracorporeal transfer module of claim 1 , wherein the housing is cylindrical.

4. The extracorporeal transfer module of claim 1 , wherein the first bundle of hollow fiber membranes and the second bundle of hollow fiber membranes are comprised of semi-permeable material that is configured to transfer one or more ionic species, dissolved gases, or similar molecules and compounds from and / or to the biological fluid.

5. The extracorporeal transfer module of claim 4, wherein the one or more dissolved gases comprises gaseous carbon dioxide (CO2) and is transferred from the biological fluid.

6. The extracorporeal transfer module of claim 4, wherein the one or more ionic species comprises bicarbonate (HCOa-) and is transferred from the biological fluid.

7. The extracorporeal transfer module of claim 4, wherein the one or more dissolved gases comprises oxygen (O2) and is transferred to the biological fluid.

8. The extracorporeal transfer module of claim 4, wherein the one or more ionic species comprises calcium, chloride, sodium, potassium, sulfate, lactate, and / or magnesium, and is transferred to the biological fluid.

9. The extracorporeal transfer module of claim 4, wherein the one or more similar molecules and compounds comprises urea, ammonia, creatinine, water, and / or plasma, and is transferred from the biological fluid; and / or wherein the one or more similar molecules and compounds comprises glucose, a pH-buffering agent, and / or water, and is transferred to the biological fluid.

10. The extracorporeal transfer module of any one of the preceding claims, wherein the first bundle of hollow fiber membranes is configured for laminar extraluminal flow through the hollow fiber membranes, and the second bundle of hollow fiber membranes is configured for laminar intraluminal flow through the hollow fiber membranes; or wherein the first bundle of hollow fiber membranes is configured for laminar intraluminal flow through the hollow fiber membranes, and the second bundle of hollow fiber membranes is configured for laminar extraluminal flow through the hollow fiber membranes.

11. The extracorporeal transfer module of any one of the preceding claims, wherein the extracorporeal transfer module is configured for a dialysate to flow extraluminally through the first bundle of hollow fiber membranes, where the biological fluid is configured to flow intraluminally relative to the first bundle of hollow fiber membranes; and is configured for a sweep gas to flow intraluminally through the second bundle of hollow fiber membranes, where the biological fluid is configured to flow extraluminally relative to the second bundle of hollow fiber membranes.

12. The extracorporeal transfer module of any one of the preceding claims, wherein the second bundle of hollow fiber membranes is arranged orthogonally relative to the first bundle of hollow fiber membranes.

13. The extracorporeal transfer module of any one of the preceding claims, wherein the extracorporeal transfer module is configured to flow the dialysate with a flow rate of less than about 500 mL / min, less than about 450 mL / min, less than about 400 mL / min, less than about 350 mL / min, less than about 300 mL / min, less than about 250 mL / min, less than about 200 mL / min, less than about 150 mL / min, less than about 100 mL / min, less than about 90 mL / min, less than about 80 mL / min, less than about 70 mL / min, less than about 60 mL / min, less than about 50 mL / min, less than about 40 mL / min, less than about 30 mL / min, less than about 25 mL / min, less than about 20 mL / min, less than about 15 mL / min, or less than about 10 mL / min; and / or wherein the extracorporeal transfer module is configured to flow the sweep gas with a flow rate of less than about 20 L / min, less than about 15 L / min, less than about 10 L / min, less than about 5 L / min, less than about 3 L / min, less than about 2 L / min, or less than about 1 L / min.

14. The extracorporeal transfer module of any one of the preceding claims, wherein the extracorporeal transfer module is configured to flow the biological fluid with a flow rate of less than about 400 mL / min, less than about 350 mL / min, less than about 300 mL / min, less than about 250 mL / min, less than about 200 mL / min, less than about 150 mL / min, less than about 100 mL / min, less than about 90 mL / min, less than about 80 mL / min, less than about 70 mL / min, less than about 60 mL / min, less than about 50 mL / min, less than about 40 mL / min, less than about 30 mL / min, less than about 25 mL / min, less than about 20 mL / min, less than about 15 mL / min, or less than about 10 mL / min.

15. The extracorporeal transfer module of any one of the preceding claims, wherein the dialysate comprises one or more of a pH buffer, calcium, chloride, sodium, potassium, magnesium, sulfate, lactate, gluconate, starch, glucose, and water.

16. The extracorporeal transfer module of claim 15, wherein the pH buffer comprises one or more of monoethanolamine, phosphate buffer, citrate buffer, acetate buffer, amino acid buffer, hydrochloric acid, and sodium hydroxide, hydrochloric acid, and sodium hydroxide.

17. The extracorporeal transfer module of any one of the preceding claims, wherein the sweep gas comprises oxygen and / or medical room gas.

18. The extracorporeal transfer module of any one of the preceding claims, wherein the biological fluid flows extraluminally and / or i ntraluminally relative to the first bundle of hollow fiber membranes and to the second bundle of hollow fiber membranes.

19. The extracorporeal transfer module of any one of the preceding claims, wherein the extracorporeal transfer module is configured to be in fluid communication with one or more of a cannula, catheter, vascular access tool, or blood withdrawal device.

20. The extracorporeal transfer module of any one of the preceding claims, further comprising a data port.

21. The extracorporeal transfer module of claim 20, wherein the data port comprises one or more sensors configured to relay information about the biological fluid.

22. The extracorporeal transfer module of claim 20, wherein the data port comprises one or more connectors configured to couple and / or align channels of direct contact and / or non-contact signal transmission.

23. The extracorporeal transfer module of claim 20, wherein the non-contact signal transmission is WiFi or BLUETOOTH.

24. The extracorporeal transfer module of any one of the preceding claims, further comprising one or more openings in fluid communication with the void space within the lumen transition region.

25. The extracorporeal transfer module of claim 24, further comprising one or more sensors in fluid communication with the one or more openings.

26. The extracorporeal transfer module of claim 25, wherein the one or more sensors comprises an electrode, optode, and / or device.

27. The extracorporeal transfer module of claim 26, wherein the electrode, optode, and / or device senses, measures, and / or assesses one or more of conductivity, pH, sodium, potassium, chloride, calcium, oxygen, carbon dioxide, bicarbonate, carbonic acid, metabolic levels, magnesium, urea, creatine, creatinine, glucose, lactate, proteins, metabolites, hormones, lipids, carbohydrates, blood cell content / counts, pathogens, clotting factors, electrolyte balance, intracellular or extracellular compositions, perfusion characteristics, temperature, flow rate, pressure, partial pressure, saturation, resistance, device longevity, and physical, chemical, and / or time-dependent variables.

28. The extracorporeal transfer module of claim 27, wherein the proteins comprise one or more of serum albumin, hematocrit, hemoglobin, alanine transaminase (ALT), aspartate transferase (AST), fibrinogen, thrombopoietin, tissue-type plasminogen activator (tPA), hemopexin, calcitonin, thyroxine-binding globulin, von Willebrand factor, haptoglobin, alpha-1 -proteinase inhibitor,urokinase, transferrin, alpha-2-macroglobulin, transthyretin, ceruloplasmin, complement component 3, apolipoprotein A-V (APOA5), lecithin-cholesterol acyltransferase, lipopolysaccharide binding protein, mannan-binding lectin, chemokine ligand 18 (CCL18), chemokine ligand 17 (CCL17), transcortin, angiopoietin-1 (CD202B), adiponectin, angiotensin-converting enzyme (ACE), and platelet-derived growth factor.

29. The extracorporeal transfer module of claim 27, wherein the cell content / counts comprise one or more of red blood cell count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), red cell distribution width (RDW), white blood cell count, lymphocyte count, monocyte counts, eosinophil count, basophil count, neutrophil count, and platelet count.

30. The extracorporeal transfer module of claim 27, wherein the pathogens comprise one or more of bacteria, viruses, mycoplasmas, parasites, spores, and fungus.

31. The extracorporeal transfer module of any one of claims 24-30, further comprising one or more ports in fluid communication with the one or more openings.

32. The extracorporeal transfer module of claim 31 , wherein the one or more ports comprises a sampling port configured to withdraw a volume of the biological fluid and / or infuse a volume into the biological fluid.

33. The extracorporeal transfer module of claim 31 or 32, wherein the one or more ports is configured to supply one or more therapeutic agents to the biological fluid.

34. The extracorporeal transfer module of any one of claims 1-33, wherein the extracorporeal transfer module has more than two discrete bundles of hollow fiber membranes.

35. The extracorporeal transfer module of claim 34, comprising a third bundle of hollow fiber membranes configured to alter the ionic content and / or pH-balance of the biological fluid after passage through the first two bundles of hollow fiber membranes.

36. The extracorporeal transfer module of claim 34 or 35, wherein the extracorporeal transfer module comprises at least a second lumen transition region located between the second bundle of hollow fiber membrane bundles and a third hollow fiber membrane bundles, wherein the luminal flow orientation relative to the biological fluid changes.

37. The extracorporeal transfer module of any one of claims 34-36, wherein a lumen transition region is present between every two hollow fiber bundles.

38. The extracorporeal transfer module of any one of claims 34-37, wherein the extracorporeal transfer module has two or more bundles of hollow fiber membranes, three or more bundles of hollow fiber membranes, four or more bundles of hollow fiber membranes, or five or more bundles of hollow fiber membranes.

39. The extracorporeal transfer module of any one of claims 1-38, wherein the extracorporeal transfer module is configured to be connected in a stackable configuration.

40. The extracorporeal transfer module of claim 39, wherein the extracorporeal transfer module is connected via Luer connectors, tubing, Hansen connectors, or uniform cross-sectional connectors.

41. A method of removing carbon dioxide and bicarbonate from a biological fluid comprising:1) causing the biological fluid to enter an extracorporeal transfer module comprising: a housing; a first bundle of hollow fiber membranes disposed within the housing, the first bundle having a plurality of hollow fiber membranes and arranged axially or orthogonally relative to the housing, and wherein the first bundle of hollow fiber membranes is configured for laminar extraluminal or intraluminal flow of a dialysate or sweep gas therethrough; at least a second bundle of hollow fiber membranes disposed within the housing, the second bundle having a plurality of hollow fiber membranes, arranged axially or orthogonally relative to the first bundle of hollow fiber membranes, and wherein the second bundle of hollow fiber membranes is configured for laminar extraluminal or intraluminal flow of a dialysate or sweep gas therethrough; a lumen transition region comprising a void space between the first bundle of hollow fiber membranes and the second bundle of hollow fiber membranes configured to flow the biological fluid: i. extraluminally to intraluminally; ii. intraluminally to extraluminally; ill. extraluminally to extraluminally; and / or iv. intraluminally to intraluminally;2) passing a dialysate through the first bundle of hollow fiber membranes to cause bicarbonate to transfer from the biological fluid into the dialysate;3) passing a sweep gas through the second bundle of hollow fiber membranes to cause gaseous carbon dioxide to transfer from the biological fluid into the sweep gas; and4) causing the biological fluid to exit the housing after the bicarbonate and gaseous carbon dioxide are removed from the biological fluid.

42. A method of treating a disease or disorder in a subject in need thereof using an extracorporeal transfer module comprising:1) removing a biological fluid from the subject;2) causing the biological fluid to enter the extracorporeal transfer module comprising: a housing; a first bundle of hollow fiber membranes disposed within the housing, the first bundle having a plurality of hollow fiber membranes and arranged axially or orthogonally relative to the housing, and wherein the first bundle of hollow fiber membranes is configured for laminar extraluminal or intraluminal flow of a dialysate or sweep gas therethrough; at least a second bundle of hollow fiber membranes disposed within the housing, the second bundle having a plurality of hollow fiber membranes, arranged axially or orthogonally relative to the first bundle of hollow fiber membranes, and wherein the second bundle of hollow fiber membranes is configured for laminar extraluminal or intraluminal flow of a dialysate or sweep gas therethrough; a lumen transition region comprising a void space between the first bundle of hollow fiber membranes and the second bundle of hollow fiber membranes configured to flow the biological: i. extraluminally to intraluminally; ii. intraluminally to extraluminally; ill. extraluminally to extraluminally; and / or iv. intraluminally to intraluminally;3) passing a dialysate through the first bundle of hollow fiber membranes to cause gaseous carbon dioxide to transfer from the biological fluid into the sweep gas;4) passing a sweep gas through the second bundle of hollow fiber membranes to cause bicarbonate to transfer from the biological fluid into the dialysate;5) causing the fluid to exit the housing after the gaseous carbon dioxide and bicarbonate are removed from the biological fluid; and6) returning the biological fluid into the subject.

43. A method of measuring one or more fluid parameters of a biological fluid using an extracorporeal transfer module comprising:1) causing the biological fluid to enter the extracorporeal transfer module comprising: a housing; a first bundle of hollow fiber membranes disposed within the housing, the first bundle having a plurality of hollow fiber membranes and arranged axially or orthogonally relative to the housing, and wherein the first bundle of hollow fiber membranes is configured for laminar extraluminal or intraluminal flow of a dialysate or sweep gas therethrough; at least a second bundle of hollow fiber membranes disposed within the housing, the second bundle having a plurality of hollow fiber membranes, arranged axially or orthogonally relative to the first bundle of hollow fiber membranes, and wherein the second bundle of hollow fiber membranes is configured for laminar extraluminal or intraluminal flow of a dialysate or sweep gas therethrough; a lumen transition region comprising a void space between the first bundle of hollow fiber membranes and the second bundle of hollow fiber membranes configured to flow the biological fluid: i. extraluminally to intraluminally; ii. intraluminally to extraluminally; ill. extraluminally to extraluminally; and / or iv. intraluminally to intraluminally; and2) measuring one or more fluid parameters of the biological fluid as the biological fluid flows through the extracorporeal transfer module.

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