Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
  • A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
  • A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
  • A61M1/1698—Blood oxygenators with or without heat-exchangers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
  • A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
  • A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
  • A61M1/1621—Constructional aspects thereof
  • A61M1/1623—Disposition or location of membranes relative to fluids
  • A61M1/1625—Dialyser of the outside perfusion type, i.e. blood flow outside hollow membrane fibres or tubes
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D63/00—Apparatus in general for separation processes using semi-permeable membranes
  • B01D63/02—Hollow fibre modules
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D63/00—Apparatus in general for separation processes using semi-permeable membranes
  • B01D63/02—Hollow fibre modules
  • B01D63/021—Manufacturing thereof
  • B01D63/0232—Manufacturing thereof using hollow fibers mats as precursor, e.g. wound or pleated mats
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D63/00—Apparatus in general for separation processes using semi-permeable membranes
  • B01D63/02—Hollow fibre modules
  • B01D63/025—Bobbin units
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M2240/00—Specially adapted for neonatal use

Definitions

• Extracorporeal gas exchange therapy would obviate the need for ventilator support and diminish the incidence of the most prevalent EPI morbidity.
• Major limitations with the gas exchange devices currently being used in research are priming volumes greater than normal placental volume, device resistances that vary greatly from normal placental physiology, inefficient gas exchange, and lackluster biocompatibility.
• Others that have successfully completed animal trials using artificial placentas have utilized devices intended for neonates of advanced gestational age.
• a device for use in connection with a premature infant to achieve gas exchange includes a housing, and a fiber bundle positioned within a fiber bundle compartment within the housing.
• the fiber bundle includes a plurality of hollow gas permeable fibers.
• the plurality of hollow gas permeable fibers is adapted to pennit diffusion of gas between blood and an interior of the plurality of hollow gas permeable fibers.
• the plurality of hollow gas permeable fibers is positioned such that blood flows around the plurali ty of hollow gas permeable fibers when flowing through the fiber bundle compartment.
• the plurality of hollow gas permeable fibers of the fiber bundle extend generally perpendicular to the direction of bulk flow of blood through the fiber bundle from the second end of the fiber bundle to the first end of the fiber bundle.
• the plurality of hollow gas permeable fibers may, for example, be formed in at least one generally cylindrical bundle.
• the generally cylindrical bundle is formed from a plurality of layers of fiber fabric, each of the plurality of layers of fiber fabric comprising hollow gas permeable fibers.
• bulk flow of blood through the fiber bundle is in a generally axial direction.
• FIG. I D illustrates a cross-sectional view of the oxygenator of FIG. 1A along section A- A as set forth in FIG. IC.
• FIG. 2 illustrates a resistance apparatus used in studies of oxygenators hereof
• FIG. 4C illustrates CFD analysis results for 165 mL/min flow of velocity magnitude (m/s) through the blood inlet of a device hereof
• FIG. 6 illustrates plasma free hemoglobin (pffib) concentration over time for experimental and control circuits, demonstrating that levels of pffib did not statistically increase over time for either circuit (repeated measures AN'OVA, p :::: 0.24).
• FIG. 7 illustrates in-wtm values of the COa removal rate of the experimental HFM bundle compared to predictions of CO’ removal by the model that accounts for the Haldane effect, and a similar model that, does not, wherein standard deviations are included.
• FIG. 8 illustrates in-vilm values of the oxygenation rate of the experimental HFM bundle compared to predictions of oxygenation by the mode! that accounts for the Haldane effect and a similar mode that does not.
• a number of embodiments hereof provide devices, systems and method for use in connection with a premature infant (for example, in connection with an artificial uterine environment) to achieve gas exchange.
• a premature infant for example, in connection with an artificial uterine environment
• gas exchange for example, in connection with an artificial uterine environment
• the components of the embodiments, as generally described and illustrated in the figures herein, may be arranged and designed in a wide var iety of different configurations in addition to the described example embodiments.
• the following more detailed description of the example embodiments, as represented in the figures, is not intended to limit the scope of the embodiments, as claimed, but is merely representative of example embodiments.
• the terms “approximately” and “generally” when used with respect to a value means within 10% or, more typically, within 5% thereof.
• the term “generally cylindrical” refers to a component having an outer radius which varies by less than 10% (or less than 5%) from an average radius along the axis thereof.
• the oxygenator included a fiber bundle formed from representative polymethylpentene (PMP) fibers (OXYPLUSTM, 3MTM MEMBRANATM).
• PMP polymethylpentene
• the fiber bundle had a diameter of approximately 2.5 cm, a length of approximately 3.2 cm, a surface area of approximately 0.1 mfi and a porosity of 0.48.
• the fiber bundles hereof may, for example, be a generally cylindrical bundles of hollow fiber membranes stacked in layers at, for example, 5-15 degree angles (as rotated around the axis thereof) to one another and aligned generally perpendicular to the principal direction of blood flow (that is, generally perpendicular to the axis A of fiber bundle compartment 22 and fiber bundle 100: see, FIGS ID and IE) to maximize gas exchange.
• the fiber bundle was a generally cylindrical bundle of hollow fiber membranes stacked in layers at approximately 1-4 degree angles io one another.
• the fibers were cut into round sheets and stacked at a 14 degree angle between adjacent sheets into a poting mold.
• the fiber bundle is formed by stacking hollow fiber membrane fabric into a three-piece reusable mold made from Delrin® (a high-perfonnance acetal resin also known as Polyoxymethylene). The mold/fixtire helps to ensure consistency between all devices throughout the fabrication process,
• the ends of the hollow fibers were poted into semi-circular gas manifold channels (a. gas inlet manifold channel and a gas outlet manifold channel).
• a polyurethane or other glue may be injected into the mold by using centrifugal force generated by spinning the mold in a lathe. The glue binds all the fibers into the fiber bundle. The thickness of the potting glue may be readily determined to provide adequate mechanical support.
• the fibers were potted and molded around the periphery by centrifugally injecting a two-part polyurethane adhesive (Cas Chem, Bayonne, NJ ) into the mold as described above.
• the mold was removed after the adhesive dried, and the poted fibers were exposed and tomed in a custom fixture to establish a common pathway between all fibers.
• the poted bundle was assembled into a main housing that creates separate blood and gas pathways. Aligning the hollow fibers generally perpendicular (for example, within no more 5 degrees from perpendicular or within no more than 2.5 degrees of perpendicular) to the axis of the fiber bundle can significantly decrease volume (that is, improve compactness) as compared to systems in which hol low fibers are generally parallel to the axis of the housing and bulk blood flow through the fiber bundle. This design allows for a highly compact extracorporeal life support device that closely mimics the nati ve placenta in terms of priming volume, resistance, blood flow, and gas exchange performance.
• the stacked-type fabrication method described above in connection with PMP fibers allows for a highly compact form factor with efficient gas exchange. This provides a technological advantage over other utilized hollow fiber membranes as the extremely premature infant is significantly smaller and more fragile than current pediatric ECMO patients.
• the bundle housing was designed to generate frilly developed flow through the bundle to prevent stasis and increase hemocompatibitity. These design advantages result in a hollow fiber membrane gas exchanging device that is more comparable to the human placenta when compared to other devices.
• a zwitterionic coating may be formed on all blood-contacting surfaces to increase the hemocompatibility of the device.
• the device hereof enables the native vasculature to control flow through the device rather than requiring the use of a peristaltic or other pump.
• a representative oxygenator 10 hereof includes a housing 20, A fiber bundle compartment 22 (see, for example, FIG. ID) is formed within housing 20.
• Fiber bundle compartment 22 houses a fiber bundle 100 (see FIG. ID) and provides a gas pathway designed to uniformly perfuse the gas side of fiber bundle 100 with a sweep gas which may be oxygen or a gas mixture including oxygen.
• a first end of fiber bundle compartment 22 includes an inlet blood manifold or volume 30 which is in fluid connection with a blood inlet 40 via which blood enters housing 20.
• a second end of fiber bundle compartment 22 includes outlet blood manifold or volume 32 which is in fluid connection with a blood outlet 42 via which blood exits housing 20.
• a gas inlet port 60 into a channel on one side of fiber bundle 100 and out through a gas outlet port 62 in fluid connection with a channel on the other side of fiber bundle 100.
• Cannula system 200 is connected to blood inlet 40 of oxygenator 10 via tubing 210.
• Cannula/catheter system 202 may be used to connected to the infant umbilical vein.
• Cannula 210 is connected to blood outlet 42 of oxygenator 10 via tubing 212.
• Such an embodiment of a cannulation method eases the strain on the EPFs underdeveloped heart and mirrors the native placenta’s vascular access route.
• flow of blood through system 5 may be driven solely by the fetal heart, in certain embodiments an optional pump may be provided in the flow path of system 5 as illustrated schematically in FIG. IF.
• oxygenator 10 further includes ports 70 and 72 which function as both de-airing and pressure monitoring ports. Further, a drainage port 80 was provided in case there was an accumulation of condensation in the outlet sweep gas plenum.
• manifold diameter was based solely on the diameter of hollow fiber membrane bundle 100.
• Manifold depth (for example, 7 mm in a number of studied embodiments) was serially modified in models hereof until fully developed and straightened flow resulted at the bundle face. Manufacturing considerations also drove manifold depth as proper wall thickness is required to prevent material warping or damage.
• inlet channel 40 (that is, the flow channel defined by the inner wall/diameter of blood inlet 40) of blood inlet manifold 30 was selected to be the largest inner diameter 3/16” connector commercially available.
• the inlet flow channel was tangent to the deepest (that is, the axially outermost) portion of manifold 30 to prevent recirculation or fluid movement divergent from bulk flow (see, for example, FIGS. 4A through 4D).
• the outer wall or rim of the manifold was filleted (fillet FI having radius of, for example, 6.35 mm in a number of embodiments; see FIGS. 4A and 4C) to direct flow from the inlet channel toward the face of fiber bundle 100.
• the flow conduit of blood inlet 40 enters manifold 40 in a generally radial direction relative to axis A of fiber bundle compartment 22 and fiber bundle 100 and is generally horizontally oriented (that is, generally perpendicular to the gravitation vector represented by arrow G) in the illustrated embodiment.
• Blood outlet.42 is oriented generally parallel to blood inlet 40 (that is, generally perpendicular to the gravitation vector represented by arrow G) but is offset downward from axis A (relative to the orientation of the gravity vector G). Such an offset of blood outlet 42 assists in preventing the settling of red blood cells under the force of gravity.
• ln(hj/hf) in FIG. 5 was 51 ⁇ 0 mmHg/L/min across all tested fluid column height changes.
• Total priming volume of the device was 15 mL.
• the measured resistance of the oxygenator was thus approximately 33% less (as determined by the equation Vt- V2/(avg(Vj,V2)) than the requirement of 71 mmHg/L/min, minimizing the chance of heart failure due to supraphysiologic resistance of the artifi cial placenta circui t.
• a low resistance device minimizes fetal heart afterload and decreases the likelihood of hypertensive heart, failure tn an tn-v/w setting.
• a one-way Analysis of Variance (ANOVA; which is a statistical formula used to compare variances across the means (or average) of different groups) showed that the vCOa was stati stically equivalent between the three sweep gas flow rates tested (data not shown, p :::: 0,22).
• Mean vCO2 averaged over ail three sweep gas flow rates was 12.7 ⁇ 0.9 mL/min at a blood flow rate of 163 ⁇ 2 mL/min (n :::: 9). This is within 4% of computational predictions. Hemoglobin was completely oxygen saturated in all three cases (SO2 ⁇ 99.4 ⁇ 0.4).
• FIG. 6 shows pfHb over time for the control and experimental circuit. Levels of pfHb did not change over time according to a repeated measured ANOVA (p - 0.24).
• the data of FIG. 6 demonstrates that no hemolysis was detected in either the control or experimental circuit over six hours. Therefore values of a normalized index of hemolysis (NIH) and a therapeutic index of hemolysis (TIH) could not be calculated.
• NIH normalized index of hemolysis
• TIH therapeutic index of hemolysis
• a potential limitation of the i/i-rifm analysis of the oxygenator is the use of adult bovine blood for hemolysis and gas exchange experiments.
• Pediatric patients treated with ECMO show trends of increasing hemolysis as patients decrease in age and weight.
• Fetal red blood cells (RBCs) are known to have a shorter lifespan, a larger size, less deformability, and are more fragile than adult RBCs.
• EPIs also typically suffer from anemia of prematurity resulting from a lack of maternal iron, a delayed EPO response, and phlebotomy losses from clinical testing. As a result, of these factors, patients receive an increase in the number of adult blood transfusions correlating with a decrease in GA.
• HbA Human hemoglobin con tains two alpha and two beta chains each associated with a heme group.
• Fetal hemoglobin (fHb) structurally differs from HbA as it contains two alpha and two gamma chains. Gamma chains have an increased affinity for oxygen compared to the Beta chains present in HbA. In-utero this adaptation allows fetuses to achieve adequate gas exchange despite the relatively low (compared to atmospheric) oxygen content of placental blood.
• the gas exchanging circuit component of ECMO or ECCO2R therapy is a structure composed of microporous hollow fiber membranes (HFM) woven into sheets and folded into bundle structures (HFM bundle); blood flows through the bundle around the fibers while a sweep gas, usually pure O2, flows through the fiber lumens.
• a sweep gas usually pure O2
• the juxtaposition of pure oxygen gas and venous blood creates a concentration gradient, causing O2 to diffuse from the sweep gas across the membrane and into the blood and CO3 to diffuse across the membrane from the blood to the sweep gas.
• the efficiency of a HFM bundles can be refined by iteratively modifying bundle characteristics, performing in-vitro testing, and comparing experimental results. This trial-and-error method is cosily in terms of money, materials, and manpower.
• Computational fluid dynamics or CFD has thus evolved to be the primary method by which researchers design and compare HFM bundles before prototyping and testing.
• FIG. 8 illustrates m-vim values of the oxygenation rate of the experimental HFM bundle compared to predictions of oxygenation by the model that accounts for the Haldane effect and a similar mode that does not. Given the identity in the manner of such predictions of oxygenation, those values are identical.
• the constant curve used by the model that does not account for the Haldane effect assumes blood is at an oxygen saturation of 100% and a Hb ⁇ 15 g (dL blood)* 1 . Testing conditions for oxygenators, however, typically dictate venous oxygen saturation to be 65% and blood hemoglobin to be 12 g (dL blood) 1 .
• Oxyhemoglobin is a stronger acid than both unbound hemoglobin and protonated hemoglobin. As hemoglobin becomes oxygenated, protonated hemoglobin is forced to dissociate into unbound hemoglobin and a proton Carbaminohenioglobin is also forced to dissociate, displacing additional intxaerythrocytic CO2 into the plasma.
• a total of 7,8 g (dL blood) ⁇ ! of Hb are present in the form of oxyhemoglobin.
• the increased presence of oxyhemoglobin forces a greater amount of protonated hemoglobin and carbaminohemoglobin to dissociate.
• the overall content of CO2 in the 15 g (dL blood )' ! of Hb system is smaller than the alternative, a greater amount of it is stored within the plasma and there is a higher partial pressure gradient present to drive CO2 exchange mass transfer.
• CO2 partial pressure values experienced during the collection of the presented in-vitro data ranged from 9- 45 mmHg.
• CO3 partial pressure values that were the farthest outside of the validated empirical range were experienced at a blood flow rate of 250 mL min* I This correlates to the highest experienced percent error, 16%, between code predictions and experimental data.
• the code without the Haldane Effect also experienced a 16% error at a blood flow rate of 250 mLmin' 1 , but the highest experienced percent error was 30% at a blood flow rate of 753 mL min* 1 .
• the inclusion of the Haldane Effect may therefore still provide more accurate predictions of CO2 removal, when used outside of the validated ranges, when compared to the code without the Haldane effect.
• the mass transport coefficient, k co , ⁇ is a constant that relates mass transfer rate, mass transfer area, and the difference in partial pressure gradient that drives the movement of CCh from the sweep gas to the blood .
• the mass transport coefficient of CO? in blood can be determined from an analogous heat transfer correlation for flow perpendicular to a bundle of tubes in the form:
• the Sherwood number, Sh relates the ratio of convective mass transfer to the rate of diffusive mass transport.
• the Reynold’s number, Re is a ratio of inertial to viscous forces, and the Schmidt number. Sc, is the ratio of momentum to mass diffusivity.
• the coefficients a and b are dependent on the geometry of the HFM bundle and can be found in Table 2 below.
• the Reynold’s number describing flow conditions of a fluid within a packed bed takes the general form: where lf 0 is the superficial velocity through the HFM bundle and y is the fluid viscosity.
• Superficial velocity is a hypothetical fluid flow that is calculated by dividing the volumetric flow rate of fluid through the bundle by the cross-sectional area of the HFM bundle.
• the characteristic length, 1/ipa considers a correction factor for the geometry of the packing the bed, I/J ⁇ 0.91, and the surface area of the fibers per unit volume of the bundle: where E is the bundle porosity and is the particle diameter.
• the HFM fibers the particle diameter is expressed as: where is the total surface area of the gas exc hanging portion of the hollow fiber membranes.
• the Sherwood number describing the flux of a gas into a fluid takes the general form: where k is the mass transport coefficient of the gaseous species, L is the characteristic length of the system, a is the solubility of the gas in the fluid, and D is the diffusivity of the gas into the fluid.
• k is the mass transport coefficient of the gaseous species
• L is the characteristic length of the system
• a is the solubility of the gas in the fluid
• D the diffusivity of the gas into the fluid.
• the diffusivity, D must consider the diffusion of CO2 dissolved in the plasma and the diffusion of CO3 stored as bicarbonate. This value will be referred to as the facilitated diffusivity* and is represented mathematically by:
• D C Q is the diffusivity of CO2 in blood
• a co is the solubility of CO2 in blood
• dCff C Q /d s the change in bicarbonate ion concentration with respect to partial pressure of CO2 in the blood
• /dP co is the slope of the CO2 dissociation curve, Eq. 2, as the majority of carbon dioxide in the blood is stored as bicarbonate.
• the Schmidt number takes the dimensionless form: where iy ? is the kinematic viscosity of blood.
• the diffusivity. D must account for the convection of COs .stored as carbaminohemoglobin and bicarbonate. This value will be referred to as the effective diffusivity, and is represented mathematically by:
• the total concentration of O2 in blood is a combination of oxygen dissolved in the plasma and bound to hemoglobin. This can mathematically be represented as: the solubility of O2 in blood, C r is the oxygen binding capacity of hemoglobin, Hb is the total hemoglobin le vel in the blood, and SO 2 is die percent of hemoglobin present in the form of oxyhemoglobin. Substituting the derivative of Eq. 14 into Eq, 13 gives:
• S0 2 is a function of the partial pressure of oxygen in blood, approximated well by the Hill equation; where n and P 50 are constants dependent on the age and species of animal blood being tested and can be found in Table 2 below.
• Eq. 4 can also be used to derive the mass transport coefficient of (>2, however the appropriate values for oxygen must be substituted into the general dimensionless values of the Reynolds, Sherwood, and Schmidt numbers. The Reynold’s number, Eq. 5, applies for both the CO2 and O2 mass balance as it is not dependent on any gaseous species-specific values.
• This equation is derived from a linear fit of any whole blood COe dissociation curve when plotted on logarithmic coordinates.
• the mathematical model that does not include the Haldane effect assumed a constant q and t value to define the COs dissociation curve throughout the entirety of the bundle. While this assumption greatly simplifies the mathematical calculations made within the model, it does not accurately reflect the compensatory mechanisms blood uses to achieve efficient COa removal. It is within this section that an iteratively updating CO2 dissociation curve will be included into the model to incorporate the Haldane effect.
• the HEMO includes polymethy I pentene (PMP) fibers (OXYPLUSTM, 3MTM MEMBRANATM) and has a diameter of 2.5 cm, a length of 3.2 cm, a surface area of -0.1 n? (FIG. 1), and a porosity of 0.48.
• PMP polymethy I pentene
• FIG. 1 The HEMO includes polymethy I pentene (PMP) fibers (OXYPLUSTM, 3MTM MEMBRANATM) and has a diameter of 2.5 cm, a length of 3.2 cm, a surface area of -0.1 n? (FIG. 1), and a porosity of 0.48.
• Computational fluid dynamic analysis of the flow distribution in the device was completed using the Free and Porous Media Flow physics of COMSOL Multiphysics (COMSOL INC., Sweden). Blood was modeled as an incompressible fluid with a density of 1050 kg/nri with a dynamic viscosity of
• the tubing clamp was removed from the device outlet, and the passage of fluid through the column and the device was video recorded.
• the time from an inframe stopwatch (Traceable Stopwatch, Thomas Scientific, Swedesboro, NJ) was used to calculate the elapsed time for the blood analogue to pass from each height increment to the final height.
• the protocol was performed in triplicate.

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• 2023
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