Patent Application
20120205306
The present disclosure relates generally to fluid separation devices, systems, and methods, and more particularly, to multi-layered fluid separation devices and systems, and methods employing multi-layered separation components for processing fluids, such as blood.
Blood component exchange devices for medical treatment are known. For example, devices and systems for apheresis, hemodialysis, hemofiltration, adsorbent-based dialysis, apheresis, plasmapheresis, have existed for a long time and continue to be refined. Most of such systems make use of devices such as centrifugation and filter membranes for discrimination between blood components. Recently, systems have been proposed in which blood components are exchanged between blood and another fluid which are permitted to be in direct contact with each other. Also, the present inventors have proposed systems employing cross-flow filtration to provide a number of medical treatment modalities. There remains a need for improvements and alternatives to existing systems including proposals for addressing the attending manufacturing and reliability challenges.
Embodiments will hereinafter be described with reference to the accompanying drawings, wherein like reference numerals represent like elements. The accompanying drawings have not necessarily been drawn to scale. Where appropriate, some features may not be illustrated to assist in the illustration and description of underlying features.
Disclosed embodiments relate to fluid transfer and separation devices, systems, and methods, for example, for the membraneless transfer of fluid components between fluids and for the separation of fluid components. In a particular application, plasma is skimmed from blood for a diagnostic or treatment purpose, for example, ultrafiltration, plasmapheresis, or dialysis. In embodiments, the blood treatment apparatus includes multiple separation channels in which fluids flow in separate adjacent layers in each separation channel. The fluids can flow into the channel in separate layers or separate layers can form due to gravitational effect or fluid dynamic effects such may arise in a high shear microfluidic flow.
In important embodiments, one of the fluids is blood and the other is plasma and/or dialysate. The fluids can flow into the channel in adjacent layers and components of the fluids exchanged between the adjacent layers by one or more mechanisms that include diffusion. In embodiments, blood and plasma are mixed prior to entering the channel and plasma and is extracted from the channel through nanopore filters in one or more walls of the channel by a crossflow filtration process. A layering effect may arise due to the differences in fluid strain (concomitantly, shear) rate across (perpendicular to the direction of) the flow. This layering effect may enhance the separation of plasma through the nanopore filter(s). The layering effect may arise due to fluid dynamic effects, for example, solutes may be exchanged between blood and plasma and cells may concentrate in a low shear part of the flow causing a cell-free plasma fraction to be established in a separate layer of the flow. The layering may occur or be enhanced by gravity, causing the plasma components desired to be drawn through the nanopore filters to concentrate near the nanopore filter and components desired to remain in the channel to be depleted near the nanopore filter.
Although embodiments described herein are aimed at separating plasma from blood, the principles are applicable to other fluids, treatment modalities, or fluid separation processes. For example, the separation channel may be employed for microfluidic crossflow filtration on a chip for analyte separation.
A blood treatment for a patient may include separating blood components into a cytoplasmic body-depleted blood fluid fraction “CBF” (that is, fractions that are depleted of, or free of, cytoplasmic bodies such as leukocytes, erythrocytes, and platelets (thrombocytes)) and a remaining blood fraction using a primary membraneless separation device and performing a treatment on the CBF.
One type of microfluidic channel may be used to isolate from the walls of the channel blood cells in a blood flow by sheathing a cell enriched fraction (or whole blood) between sheaths of a different fluid or a cell depleted fraction (e.g., pure plasma). This may permit the treatment to be done in a manner which is highly biocompatible, reducing or eliminating the need for anti-coagulants and with a reduced level of activation of the complement system. A separation device incorporating these microfluidic channels may thus be considered membraneless in that the blood flow does not pass through a membrane within the microfluidic channels for processing; but, rather, interfaces only with another fluid. In other devices, no sheathing or even laying may occur.
For patients with end stage renal disease (ESRD), the treatments may include one or more of ultrafiltration, hemodialysis, hemofiltration, and hemodiafiltration, sorbent-based dialysis, chemical, mechanical (e.g., centrifugation), or any other type of treatment which may be facilitated or modified by performing it on a CBF rather than blood or a blood component prepared by other means. The primary membraneless separation device may be used in conjunction with an extraction fluid treatment device to provide the desired treatment on the CBF.
The devices, system, and methods described herein may selectively transfer molecular and other components from a sample fluid such as blood by contacting the sample fluid with another fluid or sample fluid fraction. Embodiments of an extraction channel or separation channel are discussed in U.S. patent application Ser. No. 11/814,117 (published as U.S. Publication No. 2009/0139931) to Leonard and filed Jul. 17, 2007, hereby incorporated by reference in its entirety. Flow patterns and species exchanges may occur when blood is flowed as a thin layer adjacent to, or between, concurrently flowing layers of an extraction fluid, without an intervening membrane (i.e., membraneless). The extraction fluid, moreover, is generally miscible with blood and diffusive and convective transport of all components may arise. In embodiments disclosed herein, the sheath fluid (cytoplasmic body-depleted blood fluid fraction or CBF) may be partly or entirely plasma that has undergone a secondary process to remove undesirable components, such as uremic toxins and/or excess water. In further embodiments, the returned sheath (or extraction) fluid that has been processed is mixed directly with blood or other sample fluid before returning to the channel.
As taught in U.S. patent application Ser. No. 11/814,117, a microfluidic flow channel capable of separating cytoplasmic bodies from other components may employ filters such as nanoporous membranes with precise, short pores and high void fractions. The embodiments of microfluidic separation channels with such wall filters described in the '117 application may be employed in, for example, in the walls of, any of the microfluidic separation channels described herein. In embodiments in which blood is mixed directly with plasma treated in the secondary separation as described in the '117 application, the wall filters serve to prevent cytoplasmic bodies from entering the secondary stream enhancing the potential effectiveness of secondary processing. The effectiveness of the wall filters is maintained by the shear rate of the fluid (e.g., blood) passing over it which sweeps particles from the surface helping to ensure against blocking of the pores of the filter(s).
By using a microfluidic channel, components of blood may be separated for further processing. Each microfluidic channel may have a height less than 1.5 mm, for example, preferably less than 200 μm, where “height” is the dimension perpendicular to the direction of flow and perpendicular to the interfacial area across which transport occurs. The height of the channel is not limited to the above-mentioned range in all embodiments and other sizes, channel shapes other than flat (e.g., cylindrical), and tapered channels, are possible. By using several microfluidic channels in parallel, a therapeutically effective amount of the blood may be processed. The present application is concerned in large part with effective ways to manufacture such multiple-channel devices. Examples of applications and further embodiments of microfluidic separation channels may be found in International Application No. PCT/US09/33111, filed Feb. 4, 2009.
Sheathing a core of blood with recirculated plasma (referred to herein as a “sheath fluid” or CBF to identify a function thereof), or assuring that the sheath fluid flows between at least a substantial portion of the blood and the enclosing boundaries of the flow path, prevents, or at least reduces contact of the blood with these boundaries. In turn, this configuration of the two fluids prevents, or at least reduces, undesirable activation of factors in the blood, thereby reducing bio-incompatibilities that have been problematic in other techniques of blood processing, including clotting, fouling and activation of the complement system.
Referring now to the drawings, and in particular,
Within the blood-plasma separation module 102, blood may flow at, for example, 30 cc/minute in a thin microfluidic layer between two co-flowing sheath fluid layers. The transit time of the blood within each separation channel 104 may be very short, for example, less than 1 second, during which time contact of the blood with walls of the separation channel 104 is reduced and/or minimized by the co-flowing sheath fluid. The low height of the channel may result in rapid molecular and solute equilibration and/or concentration polarization, thereby enabling osmotic balance to occur, as well as toxins and other undesired components to migrate from the blood and into the sheath fluid for removal during only a brief contact interval. The extracorporeal blood volume may be less than 5 cc.
As discussed in U.S. patent application Ser. No. 11/814,117, the flow of the blood within the separation microchannel 104 is such that blood cells tend to move toward the center of the channel, i.e., away from the channel walls. Each separation microchannel 104 may have dimensions that assure laminar flow conditions are maintained even under conditions of normal use and that permit a large interface area between the sample and extraction fluids in a compact design, as described in the incorporated '117 application. The space adjacent to the channel walls tends to be primarily sheath fluid and plasma. The sheath fluid may then be siphoned from the separated blood components by an appropriate outlet at the microchannel walls. The total height of all three fluid layers (e.g., sheath, blood, sheath) in each microchannel 104 may be approximately 100 μm or less; e.g., 40-80 microns.
In each separation microchannel 104 of the blood-plasma separation module 102, blood does not contact an artificial membrane. Rather, within the separation channel 104, blood is primarily in contact with the sheathing fluid layers. There is minimal boundary wall contact, thereby reducing surface compatibility and coagulation issues. In addition, the rapid flow rate through the separation microchannel 104 ensures that no mixing or stasis of the blood occurs.
To keep stray blood cells and other desirable components from being extracted with the sheath fluid, and to ensure that only CBF leaves the microchannel for subsequent processing, the microchannel wall outlets may be provided with appropriately sized wall-filters. The wall-filter and flow dynamics may be configured such that any cells incident on a surface of the wall-filter are prevented from exiting the channel with the sheath flow outlet, and further that the cells are continuously swept away from the filter surface so as to prevent clogging. For example, a portion of the microchannel wall may be provided with a micro- or nano-pore wall-filter, such as a “microsieve” filter. A surface of the microsieve filter may be coplanar with a wall of the separation microchannel so as to minimize disruption to flow dynamics within the channel as well as to prevent cells from being caught in a protrusion or depression. Thus, sheath fluid (CBF), primarily composed of plasma after sufficient operation time, and any undesirable components contained therein may be removed the separation channel, and thereby the blood flowing therethrough, for further processing. Further processing may include, but is not limited to, treatment modalities associated with ESRD, such as removal of uremic toxins and/or excess water, as well as other blood treatment modalities. Note that the separation channel outlets may also be free of micropore filters in alternative embodiments.
An inlet manifold 110 may be provided to distribute fluid simultaneously to each of the separation microchannels 104. The inlet manifold 110 in the present embodiment provides a transition from the large scale flow of a blood supply to the microscale environment of the microchannel. For example, a blood supply 106, such as a patient, may supply blood to the inlet manifold 110 through one or more blood pumps 108. The inlet manifold 110 receives the blood through a common blood inlet 120 and then apportions (e.g., distributes at an equal rate) the blood to the respective blood inlet of each microchannel 104 via common blood input line 124. A sheath fluid source, such as secondary processor 112, may also supply sheath fluid to the inlet manifold 110 through one or more sheath fluid pumps 114. In
The inlet manifold 110 receives the sheath fluid through a common sheath fluid inlet 122 and then equally distributes the sheath fluid to the respective sheath fluid inlets of each microchannel 104 via a common sheath input line 126. Note that more than one sheath fluid inlet is shown for each microchannel 104, so as to provide a sheath flow on either side of the blood flow within each microchannel 104, thereby isolating the blood flow at its top and bottom from the microchannel walls. However, fewer or additional sheath fluid inlets may be provided. Also, as illustrated in more detailed embodiments, the manifolds 110 and 116 may distribute fluid to common supply and return plenums located between adjacent separation microchannels 104.
An outlet manifold 116 may also be provided simultaneously to collect fluid from each of the separation microchannels 104. For example, the outlet manifold 116 may separately receive sheath fluid and blood which have been processed within each separation microchannel 104. The outlet manifold 116 collects the sheath fluid from each microchannel 104 into a common sheath fluid output line 130 and conveys the collected sheath fluid. Note that the collected sheath fluid, after its interaction with the blood in the microchannel 104, may contain desired and undesired components of the blood, but does not contain any blood cells. The collected sheath fluid may be conveyed from the common sheath fluid output line 130 to a secondary processor 112 for further processing.
A secondary processor 112 may be connected to the inlet manifold 110 to process sheath fluid which is supplied to the blood plasma separation module 102. In an embodiment, the secondary processor 112 removes water and small solutes from the collected sheath fluid (i.e., an ultrafiltration unit). For example, the sheath fluid may be circulated through a hollow fiber secondary processor, by which excess fluid may be removed. An ultrafiltration pump may be provided in the secondary processor so as to remove this excess water from the collected sheath fluid before recirculating the fluid back to the blood-plasma separation module. The excess water may be removed at a rate of, for example, 2 cc/min. The secondary processor, in other embodiments, may be a dialyzer with a dialysate circulation loop (not shown) that is used to cleanse the sheath fluid before circulating the sheath fluid back to the separation microchannels 104.
In other embodiments, the secondary processor 112, additionally or in the alternative, has an adsorbent that removes toxins from the blood. Thus, blood proteins and other precious components within the collected sheath fluid, which are not effectively removed by the secondary processor 112, may be recirculated back to the separation microchannels 104 by way of the inlet manifold 110. After a short time of operation of the blood-plasma separation module 102, the blood components within the sheath fluid will equilibrate with those in the flowing blood such that the sheath fluid flowing in the channels is substantially cell-free blood plasma. In embodiments where secondary processor 112 is an ultrafilter, a reservoir of dialysate or other suitable fluid may be used for priming or as an initial source of sheath fluid, which is recirculated within the blood-plasma separation module 102. In embodiments, the separation microchannels 104 may operate without any external supply of sheath fluid. In such embodiments, plasma separated from the blood during initial passes of the blood through the separation microchannels 104 may serve as sheath fluid for subsequent operation of the blood-plasma separation module 102.
The outlet manifold 116 also collects the blood exiting the microchannels 104 into a common blood output line 128 and conveys the collected blood back to the blood supply 106. For example, when the blood supply 106 is a patient, the collected blood is reintroduced into the body of the patient. In embodiments, flow rates employed by the blood-plasma separation module may be insufficient simultaneously to process an extracorporeal volume of blood from a patient 106. In such cases, it may be beneficial to process only a portion of the blood from the patient with the blood-plasma separation module 102 while a remainder of the blood is returned to the patient 106 without processing. A blood bypass line 118 may be provided which connects the common blood input line 124 of inlet manifold 110 with the common blood output line 128 of outlet manifold 116. Thus, a portion of the blood flow may bypass the blood separation module 102 and be returned to the patient via the common blood output line 128. The blood bypass line 118 may include flow control devices, such as a pump or valve, to regulate the blood flow therethrough and control the amount of blood processed by the blood-plasma separation module, although such regulation is not required. Note that a bypass line may also, or alternatively, be provided between inlet and outlet plenums instead of just the manifold. The blood bypass line is preferably effective to eliminate flow “dead-ends” which might have a negative impact on performance or patient outcomes, such as by permitting stagnation and consequent thrombosis.
Although shown as separate components, various elements of the blood treatment system 100 may be incorporated into a single device. For example, inlet manifold 110 and outlet manifold 116 may be combined into a single unit. Likewise, manifolds 110 and 116 as well as bypass line 118 may also be incorporated with the blood-plasma separation module 102 into a single unit. In other embodiments, the various fluid delivery lines of each manifold 110, 116 may be separated from other fluid delivery lines therein. For example, the sheath fluid delivery lines of inlet manifold 110 may be physically separated into a separated device or component from the blood delivery lines of inlet manifold 110. A similar arrangement is also possible for the fluid and blood lines of the outlet manifold 116. In embodiments, all components of the illustrated blood treatment system 100 may be incorporated into a single unit for use by a patient as a wearable or portable unit for ESRD therapy.
The manifolds are preferably highly polished to prevent coagulation. An alternative is to form the manifold via holes in the succession of layers and lining the resulting channel with Teflon or another material that is biocompatible. Teflon or other such materials can also be used in other areas of the device to smooth edges and transitions, such as the intersection of the plenum and slits.
An alternative arrangement for a blood treatment system 100′ is shown in
Blood treatment system 100′ may thus include a mixer 132 which may combine the inlet blood flow and inlet sheath fluid flow prior to the inlet manifold 110′. The flows may be simply mixed or stirred or the two fluids simply flowed in a common channel without direct mixing. Inlet manifold 110′ may be provided with a single inlet 120′ connected to a single input flow line 124′. The combined flow may then be distributed to each microchannel 104 by the manifold 110′. In an alternative embodiment, the mixer 132 may be combined with the inlet manifold 110′, in which case separate blood and sheath fluid inlets may still be provided. The separation microchannels 104 then cause the combined flow of blood and sheath fluid to form layers in which cytoplasmic bodies are concentrated and layers in which cytoplasmic bodies are depleted permitting a cell free or cell depleted sheath fluid to be extracted from the separation microchannels 104. The configuration of
Referring now to
By segregating the functions of the different plate members, the fabrication of the plates may be simplified, for example, the microfluidic channel (not shown separately) may be defined by a cutout through the channel plate 244 such that the major surfaces of the channel are defined by external surfaces of the adjacent flow control plates 242. The flow control plates can include through-slits, filters, or other flow control elements at appropriate locations in such a manner that these elements are continuous through the plate. For example, a slit may define a channel directly through the plate and thus form a simple two-dimensional feature. Similarly, a filter can be placed in an opening formed in the plate or be provided as a separate element with the same thickness as the flow control plates 242. The flow distribution plates 240, 248 may be formed by simple two-dimensional features as well. For example, plenums (not shown in the present figure) can be defined in the flow distribution plates 240, 248 by cutouts such that the adjacent flow control plates (and/or an end plate for flow distribution plates 240) form opposite walls of the plenums.
The top and bottom walls of a separation channel 202 are formed by a top filter member 210 and a bottom filter member 212, respectively. The top filter member 210 has a sheath fluid inlet 230 through which sheath fluid may enter the separation channel 202. The top filter member 210 also includes a filter 234, through which sheath fluid may exit the separation channel 202, and a blood outlet 242 which allows blood to exit the separation channel 202. Similarly, bottom filter member 210 also has a sheath fluid inlet 230 and a filter 234, through which sheath fluid may exit the separation channel 202. In contrast to the top filter member 210, the bottom filter member may include a blood inlet 226 which allows blood to enter the separation channel 202. Blood may thus enter separation channel 202 through the blood inlet 226 in the bottom filter member 212, flow through the separation channel 202, and exit through the top filter member 210. The sheath fluid may enter the separation channel 202 through both the top filter member 210 and the bottom filter member 212, enter the separation channel 202, and exit the separation channel 202 through the respective filters 234 in the top and bottom filter layers 210, 212.
Filters 234 may be micro- or nano-pore filters incorporated into the respective filter member to form a continuous and smooth surface so as to minimize disruption to the flow in the separation channel and help prevent thrombosis or activation of clotting factors. For example, the filter may be mounted in an appropriate receptacle of the filter member with a surface of the filter 234 being coplanar with a channel-side surface of the filter member. The filters may be any suitable filter capable of preventing blood cells, platelets, or other blood components from exiting the separation microchannel through the filter. For example, the filters 234 may be nanoporous filters fabricated using lithographic techniques. Preferably, the filter and the separation microchannel are configured such that any blood cells incident on the surface of the filter 234 are swept by maintaining a minimum shear rate across the entire surface of the filter.
To supply and remove blood and sheath fluid simultaneously to each of the separation channels 202, 204, 206, the blood-plasma separation module 200 includes a manifold/plenum system. A plenum member 214 is provided between each top filter member 210 and bottom filter member 212. In effect, each plenum member 214, other than those at the ends of the blood-plasma separation module, are shared between a top filter member of one separation channel and a bottom filter member of an adjacent separation channel. Blood from a common blood inlet line 216 enters distribution line 224 in plenum member 214. The distribution line 224 is fluidly connected to the blood inlet 226 so as to introduce blood into the separation channel 202 in the shim member 208. Similarly, sheath fluid from a common sheath fluid inlet line 218 enters distribution lines 228 in plenum member 214. As the plenum member 214 is located between the top filter member 210 and bottom filter member 212 of adjacent separation channels, the sheath fluid distribution line 228 is connected to inlets 230 of top filter member 210 and bottom filter 212 so as simultaneously to provide sheath fluid to the respective adjacent separation channels. Thus, a top plenum member 214 provides sheath fluid to the inlet 230 in the top filter member 210 while a bottom plenum member 214 provides sheath fluid to the inlet 230 in the bottom filter member 210. Filter layers 210, 212 may also be fabricated with the filter 234 monolithically formed therein. For example, the filter layers 210, 212 may be provided with an array of appropriately sized pores or outlets to function as filter 234. Such a wall structure may be fabricated using photolithographic techniques as used currently to fabricate the nanopore filter “chips.” The slits and nanopore filters may be fabricated in a single block of material to form the filter layer. For example, the filter layer may be of Silicon with thin layers (e.g., silicon nitrite) deposited and lithographically machined thereon.
Plenum member 214 further includes a filter outlet line 240. Sheath fluid that passes through the filter 234 of the top filter member 210 or which passes through the filter 234 of the bottom filter member 212 enters the filter outlet line 240. The filter outlet line 240 of the plenum member 214 is fluidly connected to a common sheath fluid outlet line, so as to remove the sheath fluid that has interacted with the blood in the separation channel. Plenum member 214 also includes a blood outlet line 244. Blood exiting the separation channel from 202 from blood outlet 242 is conveyed to the blood outlet line 244, where it joins with a common blood outlet line 220. Blood outlet line 220 may be connected to, for example, a patient for reintroduction back into the patient.
Within the separation channel 202, blood flow is sheathed by the sheath fluid so as to isolate the blood flow at its top and bottom from a substantial portion of the separation channel walls. That is, blood entering through blood inlet 226 in bottom filter member 212 enters the separation channel within the shim member and is combined with sheath flows entering through sheath fluid inlet 230 in top filter member 210 and bottom filter member 212. Within channel portion 232, the top sheath fluid flow 236a isolates the blood flow between the top filter member 210 and the blood flow 238 while the bottom sheath flow 236b isolates the blood flow between the bottom filter member 212 and the blood flow 238. As the sheath fluid passes by filters 234 in the top filter member 210 and the bottom filter member 212, portions of the sheath fluid layers 236a, 236b, pass therethrough. All or a portion of the sheath fluid layers 236a, 236b may be removed through the filters 234 by appropriate control of flow rates (e.g., pumping rates) in the blood-plasma separation module. The blood along with any sheath fluid remaining in the separation channel 202 after the filters 234 exit through blood outlet 242 to the blood outlet line 244 in plenum member 214, whereby it is conveyed back to the patient or blood supply via blood outlet line 220.
Although shown in the
It is further noted that the configurations for the blood-plasma separation module are for illustration purposes only. Other configurations for the layers and/or flow patterns within the blood-plasma separation module are possible according to one or more contemplated embodiments. For example, the blood outlet 242 may be provided in the bottom filter member 212 rather than the top filter member 210. Similarly, the blood inlet 226 may be provided in the top filter member 210 rather than the bottom filter member 212. In another example, the blood inlet 226 and the blood outlet 242 may be provided in the same filter member. In still another example, each of the top filter member 210 and the bottom filter member 212 may be provided with a blood inlet 226 and a blood outlet 242, such that blood flow may flow from/to two different plenum layers 214.
Referring now to
Each of the separation channel modules 402a-402e may include an arrangement of layers, in particular a plenum layer 514, a top filter layer 510, a shim layer 508 (i.e., separation channel layer), and a bottom filter layer 512. The shim layer 508 is located between the top filter layer 510 and the bottom filter layer 512. The surfaces of the top filter layer 510 and the bottom filter layer 512 thus define the top and bottom walls of the separation microchannel. One plenum layer 514 is provided adjacent to the top filter layer 510. The plenum layer 514 from an adjacent separation channel module 402 (for example, channel module 402b for channel module 402a) is provided adjacent to the bottom filter layer 512. Thus, the plenum layer 514 may be shared between the top filter layer 510 of one separation channel module (e.g., 402b) and the bottom filter layer 512 of another separation channel module (e.g., 402a).
In alternative embodiments, each separation channel module 402 may include a plenum layer 514 for the top filter layer 510 and a plenum layer 514 for the bottom filter layer 512. Thus, the plenum layer 514 for the bottom filter layer 512 for one separation channel module (e.g., 402a) may be adjacent to and in communication with the plenum layer 514 for the top filter layer 510 of an adjacent separation channel module (e.g., 402b), in effect creating a plenum layer 514 that is shared between adjacent separation channel modules.
The separation channel modules 402a and 402e are illustrated in
Referring now to
In operation, blood and sheath fluid are provided to each plenum layer 514 via inlet blood manifold 406 and inlet sheath manifold 408, respectively. The plenum layer 514 may be configured with a blood inlet line 516 and a sheath fluid inlet line 518. Blood entering blood inlet line 516 flows from an end 516a proximal to the manifold 406 to an end 516b distal from the manifold 406. As the blood flows in the blood inlet line 516 of the plenum layer 514, it is incident on one or more inlet slits 524 in the bottom filter layer 512. The blood may thus enter the separation channel 530 in shim layer 508 through respective slits 524 where it flows along the separation channel. Sheath fluid entering sheath fluid inlet lines 518 flows from an end 518a proximal to the manifold 408 to an end 518b distal from the manifold 408. As the sheath fluid flows in the sheath fluid inlet line 518 of the bottom plenum layer 514, it is incident on one or more inlet slits 526 in the bottom filter layer 512. Sheath fluid flow in the sheath fluid inlet line 518 of the top plenum layer 514 is also incident on one or more inlet slits 534 in the top filter layer 510. Thus, sheath fluid enters the separation channels 530 through slits in both the top filter layer 510 and the bottom layer 512, thereby sheathing the blood flow from the separation microchannel walls (i.e., the surfaces of the top and bottom filter layers) in the microchannels 530.
In general, the inlet slits in the filter layers 510, 512 may be sized and shaped to achieve laminar flow in the separation microchannel with no or a minimal number of stagnation regions. For example, the inlet slits for the blood flow and/or the sheath fluid flow may have parallel sidewalls through the thickness of the filter layers 510, 512. In another example, the inlet slits for the blood flow and/or the sheath fluid flow may be tapered in a thickness direction of the filter layers 510, 512. In still another example, the slits may be tapered in at least one of the thickness direction and the width direction of the filter layer. Of course, although only one slit is shown for each fluid inlet on each respective filter layer, more than one slit may also be employed. Further, other shapes and configurations are also possible for the fluid inlets in the respective filter layers.
Filters 532 are provided in the top filter layer 510 and filters 528 are provided in the bottom filter layer 512. Sheath flow adjacent to the top filter layer 510 in the separation microchannel 530 may exit the microchannel through the filter 532 and enter into the sheath flow outlet line 520 in the top plenum layer 514. Similarly, sheath flow adjacent to the bottom filter layer 512 in the separation microchannel 530 may exit the microchannel through the filter 528 and enter into the sheath flow outlet line 520 in the bottom plenum layer 514. The exiting sheath flow from both microchannels 530 in shim layer 508 may be combined in the sheath flow outlet line 520 in the plenum layer 514. Sheath fluid collected in the sheath flow outlet line progresses from an end 520a distal from the manifold 410 to an end 520b proximal to the manifold 410, whereby the collected sheath fluid is conveyed by manifold 410 out of the plenum layer 514.
The top filter layer 510 may include a blood outlet slit 536, by which the remaining blood flow in the separation channel 530 exits therefrom into the blood outlet line 522 of the plenum layer 514. The exiting blood flow from both microchannels 530 in shim layer 508 may be combined in the blood outlet line 522 in the plenum layer 514. Blood collected in the blood outlet line 522 through slit 536 progresses from an end 522a distal from the manifold 412 to an end 522b proximal to the manifold, whereby the collected blood is conveyed by manifold 412 out of the plenum layer 514.
In general, the blood outlet slits in the filter layer 510 (or alternately in filter layer 512) may be sized and shaped to achieve laminar flow in the separation microchannel with no or a minimal number of stagnation regions. For example, the outlet slit for the blood flow may have parallel sidewalls through the thickness of the filter layer. In another example, the outlet slit for the blood flow may be tapered in a thickness direction of the filter layer. In still another example, the outlet slit may be tapered in at least one of the thickness direction and the width direction of the filter layer. Of course, although only one slit is shown for each blood outlet on the top filter layer 510, more than one slit may also be employed. Further, other shapes and configurations are also possible for the fluid outlets in the respective filter layers.
Referring now to
Manifolds 406, 408, 410, and 412 may be eliminated if smooth surfaces can be created for holes 538. The aligned holes 538 may form a smooth fluid passage and thus serve, in effect, as the manifold distributing fluid to the various layers. Appropriate inlet and outlet connections may be provided to convey fluid to the fluid passage formed in by the holes 538. In such a case, each layer may be appropriately redesigned to have flow channel features that prevent, or at least reduce the number of, stagnation regions in the fluid flows. For example, holes 538 can be machined and coated, before or after stacking of the various layers, to provide a smooth fluid pathway connecting the multiple plenum layers.
In another example, the various layers forming the blood-plasma separation device 400 can be assembled together, after which the various holes 538 can be precision machined to form a smooth fluid pathway connecting the multiple plenum layers. Such precision machining may include, but is not limited to, laser machining and semiconductor manufacturing techniques.
The inlet manifolds are arranged such that the openings 902 point away from the length of the respective inlet line. For example, as shown in
Similarly, the blood inlet manifold 406 has an opening which points away from the length of the blood inlet line 516. As the blood exits through the opening of the manifold 406, the blood is forced to wrap around the manifold before proceeding down the length of the blood inlet line 516. The blood inlet line 516 in the area around the manifold 406 may be rounded so as to minimize any potential stagnation regions. The blood inlet line 516 may also be tapered to allow for reduced blood volume at the distal end 516b of the blood inlet line 516. The opening slits in the manifold may be smaller than the height of the plenum. Alternatively the manifold may be formed such that their width is the same as the plenum height. The coating described above may be used to ameliorate sharp edges or imperfections in the matching of the opening to the surfaces of the plenums.
The outlet manifolds are also arranged such that the openings 902 of each manifold points away from the central area of the respective outlet line. For example, as shown in
Similarly, the blood outlet manifold 412 has an opening which points away from the length of the blood outlet line 522. As the blood enters the plenum layer 512 through slit 536 in the top filter layer 510, it fills the blood outlet line 522 and proceeds to the opening 902 in the outlet manifold 412. Because of the orientation of the opening in the outlet manifold 412, the exiting blood is forced to wrap around the manifold 412 before entering the opening of the manifold 412. The blood outlet line 522 in the area around the manifold 412 may be rounded so as to minimize any potential stagnation regions. The blood outlet line 522 may also be tapered to allow for increased blood volume at the proximal end 522b of the blood outlet line 522. Referring now to
All openings between adjacent layers, such as the openings that define the separation channels and the openings that define the plenums, may be sealed by any suitable mechanism. For example, a gasket ridge may be printed around each opening to concentrate pressure and form a seal. A frame constructed around the stack of plates may be used to provide such a compression seal. Instead of a structured clamping frame, potting material be molded to an outside of the layers and cured under compression to ensure a seal. Also, instead of a manifold, the openings may be sealed between adjacent plates so as to form effectively the same device without a separate manifold component. In all embodiments, the number of edges that may cause fluid acceleration, particularly blood, may be minimized to reduce the risk of thrombogenesis.
Openings 1114 may be provided in the surface of the body portion 1102 and communicating with the interior fluid pathway 1112. The final opening 1116 in the manifold 1100 may be formed by fitting and sealing the end cap 1104 to the body portion 1102, such that the bottom and sides of the opening 1116 is formed by the body portion 1102 and the top of the opening 1116 is formed by the end cap 1104. The openings 1114 and 1116 may be precision machined at locations that are precisely aligned with the respective input or output lines of the plenum layer 514.
An annular protrusion 1108 may be provided on an exterior surface of the body portion 1102. This annular protrusion 1108 may serve to align openings 1114 and 1116 with respective inlet or outlet lines of the plenum layers in the blood-plasma separation module 400 by sampling abutting the protrusion 1108 with a bottom surface of the blood-plasma separation module 400. Of course, other mechanisms for alignment are also possible according to one or more contemplated embodiments.
The blood-plasma separation device 400 may be constructed so as to minimize device size while providing precision control of device size and alignment. For example, holes 538 may be provided in the filter layers 510, 512 and the shim layer 508 so as to provide alignment therebetween. Holes 538 also serve as access points through which manifolds are inserted and interface with respective inlet and outlet lines in the plenum layer 514. Moreover, the configuration of the blood-plasma separation device 400 is such that the number of layers and overall device size can be minimized, or arranged, so as to provide the desired fluid distribution functions to each separation microchannel and to handle the desired blood flow rates in a compact size. The blood-plasma separation device 400 may be sized so as to be portable and/or preferably wearable by a patient. Contemplated embodiments of the blood-plasma separation device 400 can also provide for an assembly process with a minimal number of parts and assembly steps.
For example, referring to
Moreover, various layers may be combined to minimize fabrication steps of the complete device. A top filter layer 510, a plenum layer 514, and a bottom filter layer 512 may be combined into a single unit. The plenum layer 514 may formed from a glass plate of an appropriate thickness, for example, 300 μm thick. The top and bottom filter layers 510, 512 may also be formed from a glass plate or silicon plate which may have integral nanoport filters. The plenum layer 514 may be sandwiched between the top and bottom filter layers 510, 512 and appropriately aligned, after which the layers may be joined together via anodic bonding or any other technique which strengthens the overall combined unit. The resulting combined filter/plenum layer may be assembled with shim layers, made of glass, steel or formed by etching, machining or buildup in the filter layer, and other combined filter/plenum layers to form one or more separation modules 402 of the blood-plasma separation device 400.
The shim layer 508 may also be formed from a glass plate of an appropriate thickness, for example, 80 μm thick. The features defining the microchannel 530 may be formed within the glass plate by any suitable means, such as, but not limited to, microfabrication or laser machining. A polymer coating may be applied to the surfaces of the top filter layer 510 and the bottom filter layer 512 adjacent to the shim layer 508. The shim layer 508 may thus be sandwiched between the top filter layer 510 and the bottom filter layer 512, with the polymer coating serving to bond the shim layer with the surfaces of the filter layers.
In other embodiments, other processes for sealing and securing the various layers to each other are used. For example, optical contact bonding may be used to bond the layers together. In such a process, the surface of each layer may be highly polished and then brought into contact, whereby intermolecular forces bond the two layers together.
After assembly of the various layers of the blood-plasma separation module 400, the manifolds may be installed through the holes 538 in the shim and filter layers and respective lines 516, 518, 520, and 522 in the plenum layers. The device may be compressed to bring the manifold openings 902 into alignment with the respective lines of the plenum layers 514 and to further bond the shim layer 508 to the adjacent filter layers. After compression, a potting material may be applied to the exterior of the entire blood-plasma separation module 400 so as to seal the device from the environment.
Referring to
Referring to
Manifold 1464 supplies blood to tapered channels 1414A (also 1414B which is in the adjacent mirror image flow distribution layer 1434R). Tapered channels 1414A and 1414B form a distribution channel 1414 that conveys sheath fluid across the width of the separation channel 1420. Manifold 1468 conveys blood leaving the separation channels 1419 and 1420 from tapered channels 1444A (also 1444B which is in the adjacent mirror image flow distribution layer 1434R). Tapered channels 1444A and 1444B form a distribution channel 1444 that conveys blood fluid from across the width of the separation channel 1420 (1419).
A nanopore filter 1440A is provided in each of the flow distribution layers 1434 in an arrangement similar to that of the above embodiments. A plenum 1426 for uptake of withdrawn sheath fluid is formed by adjacent opposing recesses 1426A and 1426B in flow distribution layers 1434 and 1434R.
As can be seen best in
The tapering of the channels 1422A, 1414A, and 1444A (and similar instances in other layers) provides space for low flow resistance distribution of fluid (blood or sheath fluid) and restriction of flow to provide for equalization of the flow. The precise shapes of the channels may be a wedge shaped channel or some variation thereof. An optimal design would provide for equalized flow across the fluid inlets to the separation channels. In alternative embodiments, the tapered channels may be tapered on both sides of the flow distribution layers 1434 (1434R) so that a minimal width flow restriction exists between the opposite faces of the flow distribution layer 1434. The three-dimensional shapes of the flow distribution layers may be formed by lithographic techniques. Filters (e.g., 1440A) may be formed by the same technique and made integral to the flow distribution layers 1434.
A shim layer may or may not be used to provide the separation channel 1420 as indicated at 1404 (1406 showing a separation channel formed by recesses 1418A-1418D) in a flow distribution layer 1434. Note that the embodiments of
The embodiments of
Referring to
Sheath fluid inlet headers are formed by stacks of openings 1519 and 1586 which form header channels and open to respective plenums (not shown in the present drawing) and enter the sheath channel through narrow slits 1511 and 1513. Sheath fluid outlet headers are formed by stacks of openings 1558 and 1530 which form header channels and open to respective plenums underneath the microporous filters (not shown in the present drawing) which collect sheath fluid from the microfluidic separation channel via the microporous filters 1548.
The openings 1530 and 1558 are sealed by the mating of a land surface 1559 with a surface 1528. The surface 1528 is coplanar with the plane of the surface 1507 of a flow distribution channel member 1500. The land surface 1559 is elevated slightly above the surface 1529 of the microfluidic separation channel member 1501. A secondary seal is formed by the mating of a raised ridge 1560 which compresses an elastomer-filled channel 1524. The features of this seal, which is provided elsewhere in the current embodiments, is now described with reference to
Referring now to
The ridge 1824 compresses an elastomer 1811 that partially fills a channel 1810. The quantity of the elastomer is such that the volume displaced by the penetration of the of the ridge 1824 as the members 1813 and 1814 are brought together and pressed together just barely is such that no elastomer is forced between the mating surfaces 1808 and 1806.
Surfaces 1808 lie in a plane 1842 while the remainder of the facing surface of member 1813 lies in a plane 1840. Thus, surfaces 1808 are slightly elevated from the main surface 1812 of the member 1813. Also, lands 1852 are provided proximate fastener openings 1819 and the lands 1852 have surfaces that are in the same elevated plane 1842. As a result of the structure shown, the volume 1871 is sealed by the direct compression of surfaces 1808 and 1806, which are preferably polished flat with a back-up seal provided by the elastomer 1811 and ridge 1824. The lands 1852 surrounding the fastener openings 1819 prevent the creation of any distortion inducing moments in the members 1813 and 1814 while permitting much of the force applied by the fasteners 1818 to be applied to the seals between land surfaces 1808 and opposite surfaces 1806 to form seals.
In an alternative embodiment, the elastomer 1811 may protrude from the channel 1810 forming a bead and the ridge 1824 may be reduced, omitted, or replaced by a recess. The embodiment of
Returning now to
A well 1551 formed in microfluidic separation channel member 1501 has a perimeter seal of the structure of
Locator pin openings 1584 may be provided to facilitate alignment and assembly of the flow distribution and microfluidic separation channel members 1500 and 1501. The locator pins may extend through as many layers of the distribution and microfluidic separation channel members 1500 and 1501 as desired. Fastener openings 1582 are provided with lands 1540 as described with reference to
Surfaces 1912 and 1916 are facing surfaces at the bottom of wells 1913 and 1917 formed in members 1922 and 1920, respectively. Together the wells enclose a plenum volume when the members 1922 and 1920 are brought together. A recess 1924 in the member 1020 creates a microfluidic separation channel 1940. Sheath fluid plenums 1938 formed in each of the members 1920 and 1922 taper along a length that goes into the page of the drawing and also have a section that tapers to a small slit 1906 in member 1922 (1910 in member 1920). Blood flows into the header 1926 and is distributed into each of one or multiple blood plenums 1936. The slits 1906 and 1910 inject sheath fluid into the blood forming a layered flow in the microfluidic separation channel 1940.
Referring to
The plenum formed by recesses 1618 and 1680 are sealed by polished surfaces of a land 1678 and a surrounding surface 1622. This seal is backed up by a channel filled with elastomer 1620 into which a ridge 1676 is urged as described. Similarly, the groove 1664 is closed and sheath fluid outlet opening 1668 is sealed to sheath fluid outlet opening 1613 by a circumnavigating land surface 1666 which is urged against an opposite surface 1612 and backed up by a ridge 1667 and elastomer filled channel 1610 as discussed. Blood outlet header opening 1662 is sealed to blood outlet header opening 1606 by means of a land surface 1663 that mates with a surface 1608. This seal is backed up by the seal formed by a ridge 1660 that engages an elastomer filled channel 1605. Blood inlet header opening 1630 is sealed to blood inlet header opening 1674 by means of a land surface 1675 which mates with a surface 1628. This seal is backed up by the seal formed by a ridge 1672 which engages an elastomer filled channel 1626.
Preferably, the end block is stiffer than the distribution and microfluidic separation channel members 1500 and 1501 in order to provide predictable and firm pressure to form all the seals.
Locator pin openings 1652 and 1624 may be provided to facilitate alignment and assembly of the flow distribution 1500 and end block 1600 members. Fastener openings 1650 and 1604 are provided to hold the members together. Ports 1654 are provided to permit the injection of elastomer (prior to hardening or polymerization) into the channels on the opposite face of the microfluidic separation channel member 1500.
Referring now to
The plenum formed by recesses 1734 and 1766 are sealed by polished surfaces of a land 1765 and a surrounding surface 1738. This seal is backed up by a channel filled with elastomer 1720 into which a ridge 1764 is urged as described. Similarly, the groove 1760 is closed and sheath fluid outlet opening 1758 is sealed to sheath fluid outlet opening 1714 by a circumnavigating land surface 1761 which is urged against an opposite surface 1710 and backed up by a ridge 1756 and elastomer filled channel 1756 as discussed. Blood outlet header opening 1727 is sealed to blood outlet header opening 1772 using similar structure as is blood inlet header opening 1732 sealed to blood inlet header opening 1776.
Referring now to
Referring now to
An opening 2144 in the upper intermediate plate 2006, which opens at opening 2134B in a reverse surface of the same plate (shown from above and below in the same drawing as indicated) mates with opening 2134A in the lower intermediate plate 2008. The opening 2134A opens at 2136 on the opposite face of the latter plate 2008 and communicates with opening 2139 and return line 2012.
The above openings above and elsewhere may be sealed by seal ribbons such as indicated at 2125 and which run around all the recesses and openings that are sealed between the plates and can have the characteristic structures described with reference to
Sample fluid flowing into the supply line 2016 enters a spreading plenum defined between recesses 2126A and 2126B which distributes the sample fluid to a settling channel defined between flat recesses 2128A and 2128B. The channel continues to a portion defined between the two nanopore filters 2130A and 2130B. The sample fluid then flows into an exiting plenum defined between recesses 2132A and 2132B and then exits through opening 2134A where it meets the bypass flow from the bypass line 2010.
The extractate passes out of the sample fluid through the nanopore filters 2130A and 2130B into narrow plenums beneath each one (not visible in the present figure) where the extract exits the plenums from the openings 2146 in the lower intermediate 2008 plate and 2154 in the upper intermediate plate 2006. The extractate is gathered through a takeoff channel 2156 and flows through an opening 2158 which opens below the upper intermediate plate 2006 at 2160. The extractate from opening 2160 and passing through opening 2162, which opens at 2164 in an opposite face of the lower intermediate plate 2008, joins extractate that leaves the lower plenum through opening 2146 which is conveyed along takeoff channel 2156. Both extractate streams exit through opening 2152 which opens to the extractate line 2014.
Openings 2104 are for fasteners. Referring to
To provide for multiple channels, the intermediate plates 2006 and 2008 are replicated to create a higher stack of plates. The flows of sample fluid and extractate are distributed and gathered by manifolds that extend through the multiple plate layers.
In an assembly method, the nanopore filters may be adhered to the intermediate plates. Sealant material may be distributed to form the seals in the plates. Then the intermediate and end plates are stacked and fastened together such that a compression force is applied to the seals.
The module of
In any of the embodiments, surfaces that may be in contact with blood and/or blood components may be coated with materials that are more biocompatible and smoother. Surfaces that may be in contact with any fluid (e.g., blood or sheath fluid) may be coated. Coatings may be chosen so as to reduce surface roughness relative to the underlying material or junctions between elements. Coatings may be selected to be effective to reduce, blood protein adsorption and to and/or fouling of layer surfaces. Coatings applied to the filter layers may be chosen and applied such that the pores or holes of filters, such as the filters 532, are not blocked or substantially reduced in size. For example, a suitable coating may include polyethylene glycol (PEG) or other organic polymer coatings. The coating may be applied before or after assembly of the various layers.
Although specific materials and arrangements have been disclosed herein, materials for the various layers of the blood-plasma separation module are not limited to those materials. Other materials are also possible according to one or more contemplated embodiments. Furthermore, although specific fabrication methodologies are discussed above, such fabrication techniques are illustrative only. Other fabrication techniques are also possible, especially when working with different materials.
Cleaning of the blood-plasma separation device and its various components is possible using any means sufficient to remove blood or blood components from the flow channels of the blood-plasma separation device and to sterilize the device for its next use. One or more cleaning processes described herein or known in the art may be used alone or in tandem to clean the blood-plasma separation module and thereby prepare it for use by a patient. For example, an appropriate detergent may be flushed through the blood-plasma separation device for a period of time sufficient to remove organic substances from the flow channels in the blood-plasma separation device. After the period of time has expired, a rinse may be performed to purge the device of any remaining detergent. In another example, the device may be filled with a cleaner/sterilizer, such as germicide or sulfuric acid, and maintained with the cleaner/sterilizer therein for a set period of time, for example, 12 hours. After the set time, the blood-plasma separation device may be purged by flowing a solvent through the flow channels therein so as to clear the blood-plasma separation device of any cleaner. In still another example, water at an elevated temperature, such as 80° C., may be flushed through the device for a period of time sufficient to kill germs or bacteria that may be present in the device. Ultrasonic cleaning methods may also be employed. Accordingly, materials for the blood-plasma separation device may be chosen to minimize the potential for surface fouling as well as to be compatible with the desired cleaning process or processes.
Note that as used herein, the term “extracorporeal” is not necessarily limited to the removal of blood from the patient body envelope. Microfluidic extraction channels that are implanted in the bodies of patients are not intended to be excluded from the scope of the present disclosure.
Features of the disclosed embodiments may be combined, rearranged, omitted, etc., within the scope of the invention to produce additional embodiments. Furthermore, certain features may sometimes be used to advantage without a corresponding use of other features.
Note that although in the embodiments described throughout, channel widths much greater than the examples given may also be used to generate the diffusion and cytoplasmic body-polarization effects described herein. For example, it is possible to have separation channels that are 1000 microns or more. In embodiments, channel thickness of about 500 microns or less are employed.
It is, thus, apparent that there is provided, in accordance with the present disclosure, multi-layered fluid separation devices, systems, and methods employing multi-layered separation components for processing fluids. Many alternatives, modifications, and variations are enabled by the present disclosure. While specific embodiments have been shown and described in detail to illustrate the application of the principles of the invention, it will be understood that the invention may be embodied otherwise without departing from such principles. Accordingly, Applicants intend to embrace all such alternatives, modifications, equivalents, and variations that are within the spirit and scope of the present invention.
| Number | Date | Country | Kind |
|---|---|---|---|
| 61238068 | Aug 2009 | US | national |
| 61293956 | Jan 2010 | US | national |
The present application claims the benefit of U.S. Provisional Application No. 61/238,068, filed Aug. 28, 2009, and U.S. Provisional Application No. 61/293,956, filed Jan. 11, 2010, both of which are hereby incorporated by reference herein in their entireties.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/US10/47041 | 8/27/2010 | WO | 00 | 5/4/2012 |
