RELATED APPLICATIONS PARAGRAPH

[0001] This application claims the benefit of U.S. Provisional Application No. 63/154,470, filed February 26, 2021. The entire teachings of the above application are incorporated herein by reference.

FIELD

[0002] The present disclosure relates generally to apparatus for exchanging small molecules with blood and methods therefor.

BACKGROUND OF THE INVENTION

[0003] In certain blood diffusion systems, such as an artificial lung, it is known to arrange blood and a carrier fluid, such as perfluorodecalin (PFD), such that oxygen diffuses into the blood from the carrier fluid and carbon dioxide diffuses from the blood and into the carrier fluid. Systems for exchanging oxygen and carbon dioxide between blood and a carrier fluid can flow the two fluids side-by-side within a channel or with a physical membrane positioned in the channel between the two fluids to ensure fluid separation (i.e., prevent fluid intermixture). In such systems, the oxygen and carbon dioxide can be exchanged directly between the two fluids or through the membrane, respectively.

[0004] Systems for facilitating the diffusion of oxygen and carbon dioxide into and from blood, which contains proteins, are generally more complex than systems for the diffusion of fluids that do not contain proteins. For example, proteins in blood tend to aggregate along surfaces, thereby impeding diffusion.

[0005] In such systems, blood has a disadvantageous tendency to leave a film on the surface of the channel, which adversely affects the system. In systems having side-by-side flow, it can be difficult to separate the blood from the carrier fluid after the diffusion has occurred. In systems having a membrane positioned between blood and the carrier fluid, it can be difficult to facilitate efficient molecular transport between blood and the second fluid. Additionally, such systems can be subject to biofouling of the physical membrane and thrombogenesis in the blood caused by contact between the blood and the physical membrane.

[0006] There is a need for apparatuses and methods that promote diffusion between the fluids, while also facilitating the separation of the blood from the carrier fluid after diffusion.

SUMMARY OF THE INVENTION

[0007] One aspect of the disclosure relates to an apparatus for exchanging small molecules with blood. The apparatus comprises a channel configured to receive immiscible fluids including blood and a carrier fluid capable of exchanging small molecules with the blood, wherein the channel includes a fluid-contacting surface configured to have an affinity to one of the blood and the carrier fluid. The apparatus further comprises a flow control device configured to control a flow rate of the blood and the carrier fluid through the channel to create a stable bolus flow within the channel. Preferably each bolus is similar in diameter to the width of the channel. Droplet flow is similar to bolus flow but droplets are much smaller than the width of the channel. Ribbon flow, or side by side flow, is the third type of flow possible, and is characterized by continuous flow of both liquids. Each of these three flow regimes can be created with the appropriate combination of liquid viscosities, surface tension, flow rates, and channel size. Once the flow regime is established, the flow will remain stable under those conditions

[0008] Another aspect of the disclosure relates to a method of exchanging small molecules with blood. The method comprises flowing immiscible fluids through a channel, wherein the immiscible fluids include blood and a carrier fluid capable of exchanging small molecules with the blood, and controlling a flow rate of the blood and the carrier fluid through the channel to create a stable bolus flow within the channel.

[0009] Yet another aspect of the disclosure relates to an apparatus for exchanging small molecules with blood. The apparatus comprises a channel configured to receive immiscible fluids including blood and a carrier fluid capable of exchanging small molecules with the blood, wherein the channel includes a portion providing a non-linear flow path for the immiscible fluids that is configured to cause microcirculation and promote the exchange of small molecules.

[0010] Another aspect of the disclosure relates to an apparatus for exchanging small molecules with blood. The apparatus comprises a channel configured to receive immiscible fluids including blood and a carrier fluid capable of exchanging small molecules with the blood, wherein the channel includes a first fluid-contacting surface configured to have an affinity to one of the blood and the carrier fluid. The apparatus further comprises a fluid guide disposed within the channel, wherein the fluid guide includes a second fluid-contacting surface configured to have an affinity to the other of the blood and the carrier fluid, wherein the fluid guide is configured to guide the other of the blood and the carrier fluid to promote the exchange of small molecules between the carrier fluid and the blood.

[0011] Yet another aspect of the disclosure relates to an apparatus for exchanging small molecules with blood. The apparatus comprises a channel configured to receive immiscible fluids having different densities, the immiscible fluids including blood and a carrier fluid capable of exchanging small molecules with the blood. The apparatus further comprises a separation device configured to receive the blood and carrier fluid from the channel and substantially separate the blood and carrier fluid. The separation device includes a gravity separation chamber for receiving the blood and carrier fluids and having a volume configured to permit pooling of the blood and carrier fluid and separation of the blood and carrier fluid due to gravity based on differing densities of the blood and carrier fluid. The separation device further includes an inlet for receiving the blood and carrier fluid from the channel into the gravity separation chamber, a first outlet for removing the blood from the gravity separation chamber, wherein the first outlet is disposed in an upper region of the separation chamber, and a second outlet for removing the carrier fluid from the gravity separation chamber, wherein the second outlet is disposed in a lower region of the separation chamber.

[0012] Another aspect of the disclosure relates to an apparatus for exchanging small molecules with blood. The apparatus comprises a channel configured to receive immiscible fluids including blood and a carrier fluid capable of exchanging small molecules with the blood. The apparatus further comprises a separation section configured to receive the blood and carrier fluid from the channel and substantially separate the blood and carrier fluid. The separation section includes an inlet for receiving the blood and carrier fluid from the channel into the separation section, a first outlet for removing the blood from the separation section, a second outlet for removing the carrier fluid from the separation section. The separation section further includes a fluid guide disposed within the separation section, wherein the fluid guide includes a fluid-contacting surface configured to have an affinity to one of the blood and the carrier fluid, wherein the fluid guide is configured to guide the one of the blood and the carrier fluid to a corresponding one of the first outlet and the second outlet, such that the other of the blood and the carrier fluid flow to a corresponding other one of the first outlet and the second outlet.

[0013] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only, and are not restrictive of the invention as claimed. The above discussed, and many other features and attendant advantages of the present invention will become better understood by reference to the following detailed description of the invention when taken in conjunction with the accompanying examples. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawings will be provided by the Office upon request and payment of the necessary fee.

[0015] FIG. 1 is a block diagram showing the primary components of a system containing an embodiment of an apparatus for exchanging small molecules with blood within a channel.

[0016] FIG. 2 is a perspective view of an embodiment of a portion of the channel of FIG. 1 between lines I and II of FIG. 1.

[0017] FIG. 3 A is a cross-sectional view of an embodiment in which boluses of blood flow within a carrier fluid.

[0018] FIG. 3B is a cross-sectional view of an embodiment in which boluses of carrier fluid flow within blood.

[0019] FIG. 4 shows data related to oxygenation that can be realized when using bolus flow and ribbon flow.

[0020] FIG. 5A is a cross-sectional view of an embodiment of a serpentine channel including a serpentine flow path.

[0021] FIG. 5B is a cross-sectional view of the serpentine channel of FIG. 5A with two fluids flowing therein.

[0022] FIG. 6 is a perspective view of an embodiment of an apparatus with a plurality of serpentine channels.

[0023] FIG. 7A is a cross-sectional view of an embodiment of a helical channel including a helical flow path. [0024] FIG. 7B is a cross-sectional view of an embodiment of the helical channel of FIG 6A including a helical flow path with two fluids flowing therein.

[0025] FIG. 8 illustrates Dean flow within a channel.

[0026] FIG. 9 shows measured differences in relative oxygenation in straight and helically wound tubing.

[0027] FIG. 10 shows measured differences in relative oxygenation of tubing wound in a helical pattern on mandrels of different sizes.

[0028] FIG. 11 shows measured differences in relative oxygenation for different blood flow rates.

[0029] FIG. 12 shows measured differences in relative oxygenation for different coil lengths.

[0030] FIG. 13 shows measured differences in fluid pressure drop across helical coils with different inner diameters.

[0031] FIG. 14 shows measured difference in pressure drop across helical paths that have different path lengths.

[0032] FIG. 15A is a perspective view of an embodiment of a channel including a ribbon shaped fluid guide.

[0033] FIG. 15B is a cross-sectional view of the portion of the fluid channel and ribbon shaped fluid guide of the apparatus show in in FIG. 15 A.

[0034] FIG. 15C is a cross-sectional view of the embodiment of FIG. 15A perpendicular to the channel and the ribbon shaped fluid guide showing a cross-sectional profile of a ribbon flow path.

[0035] FIG. 16A is a perspective view of an embodiment of a channel including a ribbon shaped fluid guide contacting the channel. [0036] FIG. 16B is a cross-sectional view of the portion of the fluid channel and ribbon shaped fluid guide of the apparatus show in in FIG. 16A.

[0037] FIG. 16C is a cross-sectional view of the embodiment of FIG. 16A perpendicular to the channel and the ribbon shaped fluid guide contacting the channel showing a cross-sectional profile of a ribbon flow path.

[0038] FIG. 17A is a perspective view of an embodiment of a channel including a helical- ribbon- shaped fluid guide contacting the channel.

[0039] FIG. 17B is a cross-sectional view of the portion of the fluid channel and helical-ribbon- shaped fluid guide of the apparatus show in in FIG. 17A.

[0040] FIG. 17C is a cross-sectional view of the embodiment of FIG. 17A perpendicular to the channel and the helical-ribbon- shaped fluid guide contacting the channel showing a cross- sectional profile of a spiral flow path.

[0041] FIG. 18A is a perspective view of an embodiment of a channel including a helical- ribbon- shaped fluid guide.

[0042] FIG. 18B is a cross-sectional view of the portion of the fluid channel and helical-ribbon- shaped fluid guide of the apparatus show in in FIG. 18A.

[0043] FIG. 18C is a cross-sectional view of the embodiment of FIG. 18A perpendicular to the channel and the helical-ribbon- shaped fluid guide showing a cross-sectional profile of a helical flow path.

[0044] FIG. 19A is a perspective view of an embodiment of a channel including a twisted ribbon shaped fluid guide.

[0045] FIG. 19B is a cross-sectional view of the portion of the fluid channel and twisted ribbon shaped fluid guide of the apparatus show in in FIG. 19A.

[0046] FIG. 19C is a cross-sectional view of the embodiment of FIG. 19A perpendicular to the channel and the twisted ribbon shaped fluid guide showing a cross-sectional profile of a twisted ribbon flow path. [0047] FIG. 20A is a perspective view of an embodiment of a channel including a twisted ribbon shaped fluid guide contacting the channel.

[0048] FIG. 20B is a cross-sectional view of the portion of the fluid channel and twisted ribbon shaped fluid guide of the apparatus show in in FIG. 20A.

[0049] FIG. 20C is a cross-sectional view of the embodiment of FIG. 20A perpendicular to the channel and the twisted ribbon shaped fluid guide contacting the channel showing a cross- sectional profile of a twisted ribbon flow path.

[0050] FIG. 21 A is a perspective view of an embodiment of a channel including a rod shaped fluid guide.

[0051] FIG. 2 IB is a cross-sectional view of the portion of the fluid channel and rod shaped fluid guide of the apparatus show in in FIG. 21 A.

[0052] FIG. 21C is a cross-sectional view of the embodiment of FIG. 21 A perpendicular to the channel and the rod shaped fluid guide showing a cross-sectional profile of an annular ribbon flow path.

[0053] FIG. 22 is a side view of an embodiment of an apparatus for separating immiscible fluids.

[0054] FIG. 23 is a side view of another embodiment of an apparatus for separating immiscible fluids

[0055] FIG. 24 is a side view of another embodiment of an apparatus for separating immiscible fluids.

DETAILED DESCRIPTION

[0056] Aside from the preferred embodiment or embodiments disclosed below, this invention is capable of other embodiments and of being practiced or carried out in various ways. Thus, it is to be understood that the invention is not limited in its application to the details of construction and the arrangements of components set forth in the following description or illustrated in the drawings. If only one embodiment is described herein, the claims hereof are not to be limited to that embodiment. Moreover, the claims hereof are not to be read restrictively unless there is a clear and convincing evidence manifesting a certain exclusion, restriction, or disclaimer.

[0057] For ease of reference, embodiments in the present disclosure are described specifically with respect to oxygenating and removing carbon dioxide from a physiological fluid. However, it is to be understood that the apparatus and methods described herein apply to and can be used for other applications for facilitating the transfer of small molecules between a first fluid and a second fluid.

[0058] Embodiment of System for Use with Apparatus for Exchanging Small Molecules with Blood

[0059] FIG. 1 shows an exemplary embodiment of a system 10 that that can be used with an apparatus 100 for exchanging small molecules with blood. The system 10 includes a blood source or reservoir 113 configured to provide blood 111, a blood channel 115 that carries blood

111 from the blood reservoir 113 to the apparatus 100, a carrier fluid source or reservoir 114 configured to provide a carrier fluid 112, and a carrier fluid channel 116 that carries carrier fluid

112 from the carrier fluid source 114 to the apparatus 100. The carrier fluid 112 preferably is perfluorocarbon and more preferably is perfluorodecalin (PFD). The system 10 could be used, for example, to operate as an artificial lung by causing oxygen to diffuse into the blood from the carrier fluid and carbon dioxide to diffuse from the blood and into the carrier fluid.

[0060] Embodiment of Apparatus for Exchanging Small Molecules with Blood Using Flow Control Device to Establish Bolus Flow

[0061] FIGS. 1 to 3B show an embodiment of an apparatus 100 for exchanging small molecules with blood using stable bolus flow. The apparatus 100 includes a channel 120 configured to receive immiscible fluids 110, including blood and the carrier fluid. Apparatus 100 further includes a blood flow control device 150, and a carrier fluid flow control device 108, configured to control the flow of each fluid. The flow control devices 150 and 108 may each be an active device such as a pump or a passive device such as an aperture. [0062] The apparatus 100 can be used, for example, in the system 10 shown in FIG. 1. The blood reservoir 113 provides blood 111, which is transported along the blood channel 115 to the apparatus 100. Similarly, the carrier fluid source 114 provides carrier fluid 112, which is transported via the carrier fluid channel 116 to the apparatus 100. The blood 111 and the carrier fluid 112 each flow into channel 120 such that the flow of both immiscible fluids 110 are joined and transported along the channel 120 together to cause diffusion.

[0063] It has been determined that creating stable bolus flow (as contrasted with ribbon flow and droplet flow) within the channel 120 can enhance diffusion. In this embodiment, the channel

120 and the flow control devices 150 and 108 of the apparatus 100 are configured to create stable bolus flow within the channel 120. FIG. 4 shows the increase in relative oxygenation that can be realized when bolus flow is used instead of ribbon flow. Data in FIG. 4 were collected in straight channels of approximately 1.5mm diameter and approximately 800mm in length, with the two liquids flowing at 1.5 mL/min each. In this and other graphical illustrations of test data herein: Relative Oxygenation (%) = ( S02 outlet - S02% inlet ) / ( 100% - S02% inlet ).

[0064] The channel 120 can be formed as or in a tube, block of material with a passage, or other structures and configurations that will provide the channel 120 for guiding fluid. FIG. 2 illustrates a perspective view of a portion of the channel 120 formed as a tube.

[0065] The channel 120 includes a fluid-contacting surface 121. The fluid-contacting surface

121 is provided, disposed, positioned, formed, etc. along an inner surface of the channel 120 that contacts the fluid. The fluid-contacting surface 121 is configured to have an affinity to one of the blood 111 and the carrier fluid 112. The fluid-contacting surface 121 may be the same material(s) as the remaining (non-fluid-contacting) portions of the channel 120. Alternatively, the fluid-contacting surface 121 may be comprised of one or more materials different from the remaining portions of the channel 120, such as a coating or a sleeve, and may cover a portion or the entire surface area of the inner surface of the channel 120.

[0066] The mode of a bolus flow can be affected by the fluid-contacting surface 121 of the channel 120. In particular, bolus flow of a first fluid in a second fluid is promoted if the first fluid has a stronger affinity to the fluid-contacting surface 121 than the second fluid. Alternatively, bolus flow of the second fluid in the first fluid is promoted when the second fluid has a stronger affinity to the fluid-contacting surface 121 than the first fluid.

[0067] As seen in FIG 3A, the fluid-contacting surface 121a of the channel 120a may be hydrophobic. If the fluid-contacting surface 121a is hydrophobic, the flow control device 150 and/or the carrier fluid flow control device 108 may be configured to control the flow rate of the immiscible fluids 110 to form boluses of blood 111 in the carrier fluid 112. More specifically, a hydrophobic fluid-contacting surface 121a may be used, in the case of blood 111 and PFD as the carrier fluid 112, to promote a bolus flow of blood 111 in the carrier fluid 112. The hydrophobic fluid-contacting surface 121a may comprise, for example, at least one of polytetrafluoroethylene (PTFE) or perfluoroalkoxy (PFA) alkanes. Perfluoroalkoxy alkane, in particular, has superior hydrophobicity and blood 111 compatibility for use in the apparatus 100 for longer term use with blood 111 flow. Blood-in-PFD bolus flow 130a can have low surface tension of PFD 112 which results in little to no film of PFD 112 around the blood 111, allowing the blood 111 boluses to coalesce into a clean stream. Additionally, blood-in-PFD flow can reduce or eliminate the tendency of blood 111 to lay down a protein film on a foreign surface such as the fluid contacting surface 121. The laying down of a protein film can be problematic because it creates a barrier to diffusion and may create clogging within the channel 120.

[0068] FIG. 3B shows another alternative, in which the fluid-contacting surface 121b of the channel 120b may be a hydrophilic fluid-contacting surface 121b. The hydrophilic fluid contacting surface 121 may comprise, for example, at least one of silicone or acrylic. In this alternate embodiment, in which the fluid-contacting surface 121 is hydrophilic, the flow control device 150 and/or the carrier fluid flow control device 108 may be configured to control the flow rate of the immiscible fluids 110 to form boluses of the carrier fluid 112 in the blood 111. A hydrophilic fluid-contacting surface 121b may be used, in the case of blood 111 and PFD as the carrier fluid 112, to promote a bolus flow of PFD in the blood 111. A PFD-in-blood bolus flow 130b exhibits superior diffusion of oxygen and carbon dioxide as a thin film of blood 111 is left on the fluid-contacting surface 121b. The surface film of blood 111 is renewed with each passing bolus furthering circulation in the blood 111 and enhancing diffusion.

[0069] The blood flow control device 150 and/or the carrier fluid flow control device 108 is preferably configured to control a flow rate of the blood 111 and the carrier fluid 112 through the channel 120 to create a stable bolus flow within the channel 120 as depicted in FIGS. 3 A and 3B . As referenced above, flow control device 150 and/or the carrier fluid flow control device 108 may control the flow rate to either form boluses of blood 111 in the carrier fluid 112 (blood-in- PFD bolus flow 130a) or to form boluses of the carrier fluid 112 in the blood 111 (PFD-in-blood bolus flow 130b). The mode of bolus flow (PFD-in-blood or blood-in-PFD) is largely dependent upon the type of fluid-contacting surface 121 that is contained within the channel 120.

[0070] A method of exchanging small molecules with blood 111 may, in a preferred embodiment, be performed using the system 10 and apparatus 100 described above. However, the method of the present invention is not so limited, but will be described in the context of such system 10 and apparatus 100.

[0071] The method comprises flowing, through a channel 120, immiscible fluids 110 that include blood 111 and a carrier fluid 112 capable of exchanging small molecules with the blood 111. The immiscible fluids 110 can be the same type as described above with regard to the first embodiment. The method further comprises controlling a flow rate of the blood 111 and the carrier fluid 112 through the channel 120 to create a stable bolus flow within the channel 120. The method may make use of a flow control device 150 to control the flow rate of the blood 111 and/or a carrier fluid flow control device 108 to control the flow rate of the carrier fluid 112, or any combination of the two or other means could be utilized to provide appropriate control to the flow rate.

[0072] Embodiment of Apparatus for Exchanging Small Molecules with Blood Using a Non-Linear Flow Path [0073] Another embodiment of the present disclosure relates to an apparatus 300 for exchanging small molecules with blood 111, which includes a channel 320 configured to receive immiscible fluids 110 including blood 111 and a carrier fluid 112 capable of exchanging small molecules with the blood 111. The immiscible fluids 110 can be, for example, the same as those described above with regard to the first embodiment. The channel 320 includes a portion 320a, 320b providing a non-linear flow path for the immiscible fluids. The portion 320a, 320b with the non linear flow path is configured to cause microcirculation and promote the exchange of small molecules. The non-linear flow path provides changes flow direction that improve diffusion by, for example, disrupting the formation of a pseudo-membrane due to the changing directions of the flow. A pseudo-membrane is a barrier that can form between the immiscible fluids 110, which reduces the rate of diffusion. Specifically, a pseudo-membrane is a layer of lipids, proteins, and other molecules in the blood which aggregate at the surface of a blood bolus.

[0074] The channel 320 may be used, for example, in the apparatus 100 shown in FIG. 1 and replace the channel 120 shown in FIG. 1. The channel 320 may positioned between lines I and II shown in FIG. 1.

[0075] According to a configuration shown in FIGS. 5A-6, the channel 320 may include, for example, a serpentine portion 320a that provides a serpentine flow path 330a. The serpentine flow path 330a can provide a plurality of turns 33 la. The serpentine flow path 330a may be configured such that such that the blood 111 and the carrier fluid 112 pass through consecutive turns 331a. The turns 331a are preferably configured such that the frequency of the turns will induce microcirculation in the blood at a preferred flow rate or range of flow rates, without creating coagulation issues with the blood. See also the disclosure related to FIG. 10.

[0076] The serpentine flow path 330a preferably is configured to limit coagulation issues with the blood 111. The serpentine flow path 330a is also preferably configured to disrupt the formation of a pseudo membrane and enable better diffusion of the small molecules into the blood 111. [0077] While a single channel 320a is shown in FIGS. 5A and 5B, it is understood that a device can be configured to have multiple channels 320a, as shown in FIG. 6. For example, the use of multiple channels 320a allows for higher throughput.

[0078] The flow control device 150 and/or the carrier fluid flow control device 108 may be configured to control a flow rate of the blood 111 and the carrier fluid 112 through the serpentine portion 320a of the channel 320a with the serpentine flow path 330a such that the blood 111 and the carrier fluid 112 pass through consecutive turns 33 la at a frequency that is equal to or less than one turn 331a per quarter second or a similar frequency which induces microcirculation in the blood at a faster rate than the aggregation of a significant pseudo-membrane, which takes about half a second.

[0079] This serpentine flow path 330a is compatible with any flow regime, i.e., any of ribbon flow, bolus flow, or droplet flow.

[0080] According to an alternative configuration shown in FIGS. 7A-7B, the channel 320 may include, for example, a helical portion 320b that provides a helical flow path 330b that is configured to induce Dean flow. As shown in FIG. 7 A, the fluids follow a flow path through the helical portion 320b. As illustrated in FIG. 8, Dean flow is a secondary circulation, perpendicular to the axial flow lines, which occurs in circular flow. When the bulk flow path is directed down a helical channel 320b, the streamlines are not parallel to the axis, but rather they form a tighter helix within the flow path. See also the discussion related to FIG. 10.

[0081] The flow control device 150 and/or the carrier fluid flow control device 108 may be configured to control a flow rate of the blood 111 and the carrier fluid 112 through the helical portion 320b of the channel 320 with the helical flow path 330b such that the blood and the carrier fluid 112 pass through consecutive turns 33 lb at a frequency that is equal to or less than one turn 331b per quarter second or a similar frequency which induces microcirculation in the blood. [0082] The helical flow path 330b is compatible with any flow regime, i.e., any of ribbon flow, bolus flow, or droplet flow.

[0083] Testing indicates parameters of and general advantages of using a channel with a helical portion.

[0084] FIG. 9 shows measured differences in relative oxygenation of the same length of tubing when the tubing is maintained straight (left-side data or “1”) versus when the tubing is wound in around a mandrel in a helical pattern (right-side data or “2”). The data for the tubing wound in a helical pattern extends over a broader range because it includes winding on mandrels of different sizes (i.e. different inner diameter of the coil). These data show that helical tubing exhibits better diffusion than straight tubing.

[0085] FIG. 10 shows the difference in relative oxygenation of the same length of tubing when the tubing is wound in a helical pattern on mandrels of different sizes (i.e. different inner diameter of the coil, as measured in millimeters). These data show that there is an optimum radius for the helical flow, although the exact size will depend on the fluid flow rates, radius of the tubing, and possibly other factors.

[0086] FIG. 11 shows the difference in relative oxygenation for different blood flow rates within the same flow regime. These data show that with a faster fluid flow rate, there is less diffusion for the same length channel.

[0087] FIG. 12 shows the difference in relative oxygenation based on changes in the coil length (i.e., the length of the flow path of the helical coil). Longer coil length may provide increased oxygenation. These data show that there is greater diffusion for greater path length, although that increase tapers off as the concentration of oxygen reaches saturation.

[0088] FIG. 13 shows the difference in fluid pressure drop across helical paths of the same length, but wound on different mandrels having different diameters and thus providing helical coils with different inner diameters. Some of this difference may be attributable to the coil flattening out (i.e., the tubing inner diameter decreasing) with a smaller diameter mandrel. However, it is believed that at least some of this difference is attributable to the flow profile in the different helical shapes. This may be an important consideration in designing a practical blood processing device.

[0089] FIG. 14 shows the difference in pressure drop across helical paths that have different path lengths. This may be an important consideration in designing a practical blood processing device.

[0090] Embodiment of Apparatus for Exchanging Small Molecules with Blood Using a

Fluid Guide

[0091] Another aspect of the present disclosure relates to an apparatus for exchanging small molecules with blood using a fluid guide. Presently preferred embodiments of such an apparatus are shown in FIGS. 15A-21C. The apparatus can have a channel 420 configured to receive immiscible fluids 110. The immiscible fluids 110 can be the same as those described above, and preferably include blood and a carrier fluid capable of exchanging small molecules with the blood. The channel 420 preferably includes a first fluid-contacting surface configured to have an affinity to one of the blood and the carrier fluid. The apparatus also can have the fluid guide 440 disposed within the channel 420. The fluid guide includes a second fluid-contacting surface 441 configured to have an affinity to the other of the blood and the carrier fluid. The fluid guide 440 is configured to guide the other of the blood and the carrier fluid to promote the exchange of small molecules between the carrier fluid and the blood. In exemplary embodiments, different flow patterns promoted by the fluid guide 440 may include, but are not limited to, a ribbon flow path 430a, spiral flow path 430b, twisted ribbon flow path 430c, an annular flow path 430d, and a helical flow path 430e. This second surface may be of a different type than the main flow channel 420.

[0092] Guiding the flow of one fluid in another in this manner enables embodiments to be configured that can provide enhancements with regard to one or more of the following aspects: maintaining flow stability, increasing the surface area between the two immiscible fluids 110 to improve diffusion, and causing at least one of the fluids to follow a rotating flow path (for blood this disrupts the formation of the pseudo-membrane and further improves diffusion). Moreover, guiding flow in this manner may enhance or enable the ability to separate the two immiscible fluids 110 after diffusion.

[0093] The channel 420 can be of the same type described above with regard to the embodiments described above. In one embodiment, the channel 420 further includes a first fluid contacting surface 421. The first fluid-contacting surface 421 is configured to have an affinity to one of the blood 111 and the carrier fluid 112. The first fluid-contacting surface 421 can be of the same type as described above with regard to the fluid-contacting surface 121 of the first embodiment. More specifically, the first fluid-contacting surface can be the same type as described above with regard to either the hydrophobic fluid-contacting surface 121a or the hydrophilic fluid-contacting surface 121b as described above.

[0094] The fluid guide 440 of the apparatus 400 is configured to be disposed within the channel 420. The fluid guide 440 is configured to guide the other of the blood 111 and the carrier fluid 112 along the channel 420 to promote the exchange of small molecules between the carrier fluid 112 and the blood 111 by employing hydrophilic surfaces where blood is to be guided, and hydrophobic surfaces to guide the carrier fluid.

[0095] The fluid guide 440 includes a second fluid-contacting surface 441. The second fluid contacting 441 surface is configured to have an affinity to the other of the blood 111 and the carrier fluid 112. In one embodiment, the second fluid-contacting surface 441 is disposed on all surfaces of the fluid guide 440. In an alternate embodiment, the second fluid-contacting surface 441 may be disposed on a predetermined portion of the fluid guide 440 surface. For example, in one embodiment the second fluid-contacting surface 441 may be disposed on one surface of a flat fluid guide 440 but not on the other side surface of a flat fluid guide 440. [0096] In one embodiment, the first fluid-contacting surface 421 may be hydrophobic and the second fluid-contacting surface 441 is hydrophilic. In such an embodiment, the second fluid contacting surface 441 may comprises at least one of silicone or acrylic. When the fluid contacting surface 421 is hydrophobic and the second fluid-contacting surface 441 is hydrophilic, the flow of the carrier fluid 112 is drawn to the fluid-contacting surface 421 and the blood 111 is drawn to second fluid-contacting surface 441.

[0097] Alternatively, the first fluid-contacting surface 421 may be hydrophilic and the second fluid-contacting surface 441 may be hydrophobic. In such an embodiment, the second fluid contacting surface 441 may comprises at least one of polytetrafluoroethylene (PTFE) or perfluoroalkoxy (PFA) alkanes. The second fluid-contacting surface 441 may be of the same types described above with respect to the first fluid-contacting surface 142. When the fluid contacting surface 421 is hydrophilic and the second fluid-contacting surface 441 is hydrophobic, the flow of the blood 111 is drawn to the fluid-contacting surface 421 and the carrier fluid 112 is drawn to second fluid-contacting surface 441.

[0098] According to the embodiments illustrated in FIGS. 15A-16C, the fluid guide 440 may be a ribbon-shaped fluid guide 440a. The ribbon shaped fluid guide 440a may be configured in a ribbon shape that extends in a direction of a longitudinal axis (x) of the channel 420 and is configured to promote a ribbon flow path 430a for the other of the blood 111 and the carrier fluid 112.

[0099] In one embodiment, such as the embodiment depicted in FIGS. 15A-15C, the ribbon shaped fluid guide 440a does not contact the first fluid-contacting surface 421 of the channel 420. A cross-sectional view perpendicular to the channel 420 and the ribbon-shaped fluid guide 440a, as seen in FIG. 15C, shows a cross-sectional profile of the ribbon flow path 430a wherein the blood 111 is drawn toward the second fluid-contacting surface 441 and the carrier fluid 112 is drawn toward the first fluid-contacting surface 421. [0100] In an alternate embodiment, such as that of FIGS. 16A-16C, the ribbon-shaped fluid guide 440a contacts the first fluid-contacting surface 421 of the channel 420. A cross-sectional view perpendicular to the channel 420 and the ribbon-shaped fluid guide 440a, as seen in FIG. 16C, similarly shows a cross-sectional profile of the ribbon flow path 430a wherein the blood 111 is drawn toward the second fluid-contacting surface 441 and the carrier fluid 112 is drawn toward the first fluid-contacting surface 421.

[0101] In the embodiments represented in FIGS. 17A-18C, the fluid guide 440 may be a helical shaped fluid guide 440b. The helical-ribbon- shaped fluid guide 440b may be configured in a helical-ribbon-shape that extends in a direction of a longitudinal axis (x) of the channel 420 and is configured to promote a helical flow path 430b for the other of the blood 111 and the carrier fluid 112

[0102] In one embodiment depicted in FIGS. 17A-17C, the helical-ribbon-shaped fluid guide 440b is provided, at least in part, on the channel 420 adjacent the first fluid-contacting surface 421 of the channel 420 and is configured to promote a spiral flow path 430b for the other of the blood 111 and the carrier fluid 112. A cross-sectional view perpendicular to the channel 420 and the helical-ribbon- shaped fluid guide 440b, as seen in FIG. 17C, shows a cross-sectional profile of the spiral flow path 430b wherein the blood 111 is drawn toward the second fluid-contacting surface 441 and the carrier fluid 112 is drawn toward the first fluid-contacting surface 421.

[0103] In an alternate embodiment shown in FIGS. 18A-18C, the helical-ribbon- shaped fluid guide 440b does not contact the first fluid-contacting surface 421 of the channel 420 and is configured to promote a helical flow path 430e for the other of the blood 111 and the carrier fluid 112. A cross-sectional view perpendicular to the channel 420 and the helical ribbon-shaped fluid guide 440b, as seen in FIG. 18C, shows a cross-sectional profile of the helical flow path 430e wherein the blood 111 is drawn toward the second fluid-contacting surface 441 and the carrier fluid 112 is drawn toward the first fluid-contacting surface 421. [0104] In yet another embodiment shown in FIGS. 19A-20C, the fluid guide 440 may be a twisted ribbon shaped fluid guide 440c. The twisted ribbon shaped fluid guide 440c may be configured in a twisted ribbon shape that extends in a direction of a longitudinal axis (x) of the channel 420 and is configured to promote a twisted ribbon flow path 430c for the other of the blood 111 and the carrier fluid 112.

[0105] In the embodiment depicted in FIGS. 19A-19C, the twisted ribbon shaped fluid guide 440c does not contact the first fluid-contacting surface 421 of the channel 420. A cross-sectional view perpendicular to the channel 420 and the twisted ribbon shaped fluid guide 440c, as seen in FIG. 19C, shows a cross-sectional profile of the twisted ribbon flow path 430c wherein the blood 111 is drawn toward the second fluid-contacting surface 441 and the carrier fluid 112 is drawn toward the first fluid-contacting surface 421.

[0106] In an alternate embodiment depicted in FIGS. 20A-20C, the twisted ribbon shaped fluid guide 440c contacts the first fluid-contacting surface 421 of the channel 420. A cross-sectional view perpendicular to the channel 420 and the twisted ribbon shaped fluid guide 440c, as seen in FIG. 20C, shows a cross-sectional profile of the twisted ribbon flow path 430c wherein the blood 111 is drawn toward the second fluid-contacting surface 441 and the carrier fluid 112 is drawn toward the first fluid-contacting surface 421.

[0107] In another embodiment, the fluid guide 440 may be a rod shaped fluid guide 440d. The rod shaped fluid guide 440d may be configured in a rod shape that extends in a direction of a longitudinal axis (x) of the channel 420 and is configured to promote an annular flow path 430d for the other of the blood 111 and the carrier fluid 112. In one embodiment, the rod shaped fluid guide 440d may be suspended within the channel 420 without contacting the first fluid contacting surface 421. In an alternate embodiment, the rod shaped fluid guide 440d may first fluid-contacting surface 421.

[0108] A cross-sectional view perpendicular to the channel 420 and the rod shaped fluid guide 440d, as seen in FIG. 21C, shows a cross-sectional view of the annular flow path 430d wherein the blood 111 is drawn toward the second fluid-contacting surface 441 and the carrier fluid 112 is drawn toward the first fluid-contacting surface 421.

[0109] Embodiment of Apparatus for Exchanging Small Molecules with Blood Having a Separation Device or Separation Section

[0110] As seen in FIGS. 22-23, one embodiment of the present disclosure relates to an apparatus 500 for exchanging small molecules between immiscible fluids 110 comprising a channel 520 and a separation device 560. The immiscible fluids 110 can be the same type as described above with regard to the prior embodiments.

[0111] Effective separation of immiscible fluids 110, including a carrier fluid 112, is important to ensure that the blood 111 is suitable for patient use. One embodiment, such as that of apparatus 500 in FIG. 22, serves to allow multiple immiscible fluids 110, including blood 111 and a carrier fluid 112, to flow in a single channel 520 to facilitate diffusion between the immiscible fluids 110 while also providing a mechanism for fluid separation - a separation device 560. More specifically, the apparatus 500 serves to increases the efficiency of separability of the two immiscible fluids 110 by way of gravity after the transfer of the molecules has taken place within the channel 520.

[0112] If the two immiscible fluids 110 have at least a density difference, they may be separated by using gravity. For example, PFD (carrier fluid 112) has a density greater than that of blood 111, and so a mixed immiscible fluid flow 510 can be separated in a gravity separation chamber 561 with blood 111 coming out at a top side in a blood flow 511 and PFD (carrier fluid 112) coming out at a bottom side in a carrier fluid flow 512.

[0113] The channel 520 can be of the same type as described above with regard to the prior embodiments. The channel 520 may be further be configured to receive an immiscible fluid flow 510 having fluids of different densities. The immiscible fluids 110 including blood 111 and a carrier fluid 112 are capable of exchanging small molecules with the blood 111. In one embodiment, such as that of FIG. 23, the apparatus 500 may further includes a plurality of channels (520a, 520b, 520c, 520d) configured to transport immiscible fluids 110.

[0114] As seen in FIGS. 22-23, the separation device 560 is configured to receive the blood 111 and carrier fluid 112, in the form of an immiscible fluid flow 510, from the channel 520 and substantially separate the blood 111 and carrier fluid 112. The separation device 560 comprises a gravity separation chamber 561, an inlet 562, a first outlet 563, and a second outlet 564.

[0115] The separation device 560 includes a gravity separation chamber 561 for receiving the immiscible fluid flow 510. The separation device 560 further has a volume that is capable of holding the blood 111 and carrier fluid 112. The volume of the separation chamber 561 is configured to permit pooling of the blood 111 and carrier fluid 112 such that the less dense fluid is situated above the denser fluid within the separation chamber 561. More specifically, the volume of the separation chamber 561 is configured to permit separation of the blood 111 and carrier fluid 112 due to gravity based on differing densities of the blood 111 and carrier fluid 112.

[0116] In one embodiment, the gravity separation chamber 561 may be subdivided into at least two regions - an upper region 565 and a lower region 566. The boundaries of each respective region correspond to one of the blood 111 or the carrier fluid 112 and the size of each respective boundary is dependent upon the amount of each immiscible fluid 110 present in the gravity separation chamber 561. The upper region 565 of the gravity separation chamber 561 is configured to be adjacent to a first outlet 563 and to include the volume of the separation chamber 561 containing less to the less dense fluid - blood 111. The lower region 566 of the gravity separation chamber 561 is configured to be adjacent to a second outlet 564 and to include the volume of the separation chamber 561 containing the denser fluid - the carrier fluid 112.

[0117] In one embodiment, the separation device 560 further includes an inlet 562 for receiving the blood 111 and carrier fluid 112 from the channel 520 into the gravity separation chamber 561. The separation device 560 may be configured to further include a plurality of corresponding inlets (562a, 562b, 562c, 562d) of the gravity separation chamber 561 for receiving the blood 111 and carrier fluid 112 from the respective channels (520a, 520b, 520c, 520d) such as the separation device 560 depicted in FIG. 23.

[0118] In one embodiment, the separation device 560 further includes a first outlet 563 for removing the blood 111 from the gravity separation chamber 561, wherein the first outlet 563 is disposed in an upper region 565 of the gravity separation chamber. The first outlet 563 is configured to transport the blood flow 511 out of the separation device 560. Generally the carrier fluid is set up in a closed loop, so the pump that drives it in also serves as the pump to pull it out of the system. Gravity pulls the carrier fluid to the bottom of the separator but it flows out because of the pump. Gravity otherwise has less relevance as the fluid has to go somewhere in a fixed volume system.

[0119] The separation device 560 further includes a second outlet 564 for removing the carrier fluid 112 from the gravity separation chamber 561, wherein the second outlet 564 is disposed in a lower region 566 of the gravity separation chamber 560. The second outlet 564 is configured to transport the carrier fluid flow 512 out of the separation device 560.

[0120] Another embodiment of the present disclosure, as seen in FIG. 24, relates to an apparatus 600 for exchanging small molecules between immiscible fluids 110 comprising a channel 620 and a separation section 670 including a fluid guide 640. The immiscible fluids 110 can be the same type as described above with regard to the prior embodiments. The channel 620 can be of the same type described above with regard to previous embodiments.

[0121] Effective separation of immiscible fluids 110, including a carrier fluid 112, is important to ensure that the blood 111 is suitable for patient use. One embodiment, such as that of apparatus 600 in FIG. 24, serves to allow multiple immiscible fluids 110, including blood 111 and a carrier fluid 112, to flow in a single channel 620 to facilitate diffusion between the immiscible fluids 110 while also providing a mechanism for fluid separation - a separation section 670. [0122] The separation section 670 is configured to receive the blood 111 and carrier fluid 112 by way of an immiscible fluid flow 610 from the channel 620 and substantially separate the blood 111 and carrier fluid 112 into a blood flow 611 and a carrier fluid flow 612. The separation section 670 includes an inlet 671, a first outlet 672, a second outlet 673, and a fluid guide 640.

[0123] In one embodiment, the separation section 670 includes an inlet 671 for receiving the immiscible fluid flow 610 of blood 111 and carrier fluid 112 from the channel 620 into the separation section 670. The separation section 670 further includes a first outlet 672 for removing the blood 111 from the separation section 670 by way of a blood flow 611. The separation section 670 further includes a second outlet 673 for removing the carrier fluid 112 from the separation section 670 by way of a carrier fluid flow 612.

[0124] In one embodiment, the separation section 670 further includes a fluid guide 640 disposed within the separation section 670. The fluid guide 640 includes a fluid-contacting surface 641. The fluid-contacting surface 641 can be of the same type as described above with regard to the second-fluid contacting surface 441 described with respect to a prior embodiment. The fluid guide 640 is configured to guide one of the blood 111 and the carrier fluid 112 to a corresponding one of the first outlet 672 and the second outlet 673, such that the other of the blood 111 and the carrier fluid 112 flows to a corresponding other one of the first outlet 672 and the second outlet 673.

[0125] This separation section 670 serves to increase the efficiency of separability between the two immiscible fluids 110 due, in part, to differences in surface affinity between the immiscible fluids 110. If two immiscible fluids 110 have at least a difference in surface affinity, they may be separated by guiding at least one flow, the blood flow 611 or the carrier fluid flow 612, along the fluid guide 640 through the first outlet 672 and allowing the other fluid to flow through the second outlet 673 by substantially excluding it from the path including the fluid guide 640. In a preferred embodiment, fluid guide 640 is configured such that one of the two immiscible fluids 110 is attracted to the fluid guide due to the surface affinity of one of the two immiscible fluids 110. [0126] In an exemplary embodiment, the fluid-contacting surface 641 may be hydrophobic and the fluid guide 640 configured to guide the blood 111 to the first outlet 673. In such an embodiment, the fluid-contacting surface 641 may comprise at least one of polytetrafluoroethylene or perfluoroalkoxy alkanes. In an alternative embodiment, the fluid contacting surface 641 may be hydrophilic and the fluid guide 640 configured to guide the carrier fluid 112 to the second outlet 673. In such an embodiment, the fluid-contacting surface 641 may comprise at least one of silicone or acrylic.

[0127] In one embodiment, the fluid guide 640 is configured in a helical ribbon shape that extends in a direction toward the corresponding one of the first outlet 672 and the second outlet 673. In the separation section 670 depicted in FIG. 24, the fluid guide 640 extends in the direction of the first outlet 672 and is configured to guide the flow of blood 611 through the outlet 672. More specifically, the surface affinity of the fluid-contacting surface 641 of the fluid guide 640 causes the flow of one of the blood 611 to flow along the fluid guide 640 through the corresponding first outlet 672.

[0128] Although specific features of the invention are shown in some drawings and not others, this is fore convenience only as each feature may be combined with any or all of the other features in accordance with the invention. The words “including”, “comprising”, “having”, and “with” as used herein are to be interpreted broadly and comprehensively and are not limited to any physical interconnection. Moreover, any embodiments disclosed in the subject of the application are not to be taken as the only possible embodiments.

[0129] The construction and arrangement of the apparatuses and methods as shown in the various exemplary embodiments are illustrative only. Although only a few embodiments have been described in detail in this disclosure, many modifications are possible (e.g. variations in sizes, dimensions, structures, shapes and proportions of the various elements, values of parameters, mounting arrangements, use of materials, colors, orientations, etc.). For example, the position of elements may be reversed or otherwise varied, and the nature or number of discrete elements or positions may be altered or varied. Accordingly, all such modifications are intended to be included within the scope of the present disclosure. The order or sequence of any process or method steps may be varied or re-sequenced according to alternative embodiments. Other substitutions, modifications, changes, and omissions may be made in the design, operating conditions, and arrangement of the exemplary embodiments without departing from the scope of the patent disclosure.

[0130] In addition, any amendment presented during the prosecution of the patent application for this patent is not a disclaimer of any claim element presented in the application as filed: those skilled in the art cannot reasonably be expected to draft a claim that would literally encompass all possible equivalents, many equivalents will be unforeseeable at the time of the amendment and are beyond a fair interpretation of what is to be surrendered (if anything), the rationale underlying the amendment may bear no more than a tangential relation to many equivalents, and/or there are many other reasons the applicant cannot be expected to describe certain insubstantial substitutes for any claim element amended.