Patent Description:
Embodiments have been made in light of these and other considerations. However, the relatively specific problems discussed above do not limit the applicability of the embodiments.

The summary is provided to introduce aspects of some embodiments in a simplified form, and is not intended to identify key or essential elements, nor is it intended to limit the embodiments.

Embodiments provide for reducing pathogens in a fluid. The embodiments may include systems, and apparatuses. One embodiment provides for a flow cell with a plurality of channels through which a fluid to be pathogen reduced is flowed. The flow cell, and fluid, may be illuminated from more than one direction to pathogen reduce the fluid. The fluid may include a photosensitizer to aid in the pathogen reduction process.

Other embodiments provide for a system that reduces pathogens in a fluid. The system may include a flow cell with a plurality of channels and an illumination system. Each of the plurality of channels has a depth that is less than <NUM>. The illumination system may be configured to illuminate each of the plurality of channels from a plurality of sides.

Non-limiting and non-exhaustive embodiments are described with reference to the following figures.

The principles of the present invention may be further understood by reference to the following detailed description and the embodiments depicted in the accompanying drawings. It should be understood that although specific features are shown and described below with respect to detailed embodiments, the present invention is defined by the appended claims, and not limited to the embodiments described below or shown in the drawings. It is noted that several embodiments are described with respect to reducing pathogens in whole blood or blood components (e.g., plasma, platelets, red blood cells, leukocytes, buffy coat, or combinations thereof). However, the present invention is not limited to use with any particular fluid. Rather, the specific embodiments may be implemented with other fluids including biological fluids, non-biological fluids, or combinations thereof.

Reference will now be made in detail to the embodiments illustrated in the accompanying drawings and described below. Wherever possible, the same reference numbers are used in the drawings and the description to refer to the same or similar parts.

<FIG> illustrates an embodiment of a system <NUM> that may be used to reduce pathogens in a fluid, according to embodiments. The system <NUM> includes a flow cell system <NUM> and a flow cell holder <NUM>. As described in greater detail below, the flow cell system <NUM> may work with flow cell holder <NUM> to reduce pathogens in a fluid.

Flow cell system <NUM> includes a first container (e.g., bag <NUM>) which in embodiments contains the fluid to be pathogen reduced. Bag <NUM> is connected to flow cell <NUM> through tubing <NUM>. Tubing <NUM> creates a fluid communication path from the bag <NUM> to the flow cell <NUM>. Flow cell <NUM> is connected to a second container (e.g., bag <NUM>) through tubing <NUM>, which creates a fluid communication path between flow cell <NUM> and bag <NUM>.

Flow cell holder <NUM> includes an illumination system <NUM>. In the embodiment shown in <FIG>, illumination system <NUM> includes two light sources <NUM> and <NUM>. As described in greater detail below, flow cell system <NUM> may be used with illumination system <NUM> to reduce pathogens in a fluid. In some embodiments, flow cell system <NUM> may be implemented as a disposable that is used in reducing pathogens in a single volume of fluid and then replaced.

<FIG> illustrates another flow-through pathogen reduction system <NUM> according to another embodiment. As shown in <FIG>, system <NUM> illustrates a flow cell system <NUM> and a flow cell holder <NUM>. Flow cell system <NUM> includes a first container (e.g., bag <NUM>) which in embodiments contains the fluid to be pathogen reduced, for example, blood or a blood component (e.g., red blood cells, plasma, platelets, buffy coat, leukocytes, or combinations thereof). Bag <NUM> is connected to flow cell <NUM> through tubing <NUM>, which creates a fluid communication path from the bag <NUM> to the flow cell <NUM>. Flow cell <NUM> is connected to a second container (e.g., bag <NUM>) through tubing <NUM>, which creates a fluid communication path between flow cell <NUM> and bag <NUM>.

As shown in <FIG>, flow cell <NUM> has been positioned in flow cell holder <NUM>, which includes an illumination system <NUM>. Flow cell <NUM> has been positioned between the two light sources <NUM> and <NUM>. In embodiments, the light source <NUM> and light source <NUM> are configured to illuminate flow cell <NUM> from at least two directions during a process of pathogen reducing a fluid. In embodiments, flow cell holder <NUM> may be configured with features to hold flow cell <NUM> but allow flow cell <NUM> to be removed after a pathogen reduction process has been completed. Some non-limiting examples of features include clips, rails, shelves, biased members, springs, sliding members, locks, etc..

System <NUM> also includes a stand <NUM>. Stand <NUM> may include a base and a pole.

In operation, a user may begin a pathogen reduction process by hanging bag <NUM> from a pole of stand <NUM>. Bag <NUM> may in embodiments contain a fluid to be pathogen reduced. For example, the fluid may be whole blood or a blood component (e.g., red blood cells, plasma, platelets, buffy coat, leukocytes, or combinations thereof). As disclosed below, in some embodiments, the fluid may also contain an additional material, e.g., a photosensitizer, that aids in the pathogen reduction process. The user may then position flow cell <NUM> in flow cell holder <NUM>, between light source <NUM> and light source <NUM>.

The light sources <NUM> and <NUM> may be activated to illuminate flow cell <NUM> from at least two directions. A fluid flow control device <NUM> may be activated, e.g., opened, to allow fluid to flow from bag <NUM> into flow cell <NUM>. In embodiments, fluid flow control device <NUM> may be one or more of a clip, clamp, a frangible, a pump or combinations thereof. In other embodiments, there may be more than one fluid flow control device, e.g., fluid flow control device <NUM> which is located in a different location, e.g., such as along tubing <NUM>. In embodiments, fluid flow control device <NUM> may be a pump that creates negative pressure in flow cell <NUM> drawing fluid through the flow cell <NUM>.

In yet other embodiments, a fluid flow control device may be located on both tubing <NUM> and tubing <NUM> (e.g., <NUM> and <NUM>). A user would activate both fluid flow control devices to allow fluid to flow from bag <NUM> into flow cell <NUM>. In some embodiments, the fluid flow control devices <NUM> and <NUM> may be activated individually, e.g., <NUM> ON and <NUM> OFF; or <NUM> OFF and <NUM> ON.

As the fluid flows through the flow cell <NUM>, the fluid may be illuminated by light sources <NUM> and <NUM> causing a reduction in pathogens. After pathogen reduction, the fluid may flow from flow cell <NUM> into bag <NUM> for storage.

In embodiments, the light sources <NUM> and <NUM> may radiate light of a particular wavelength that provides a pathogen reducing effect. For example, light sources <NUM> and <NUM> may radiate light in the ultraviolet spectrum such as light with a wavelength of between about <NUM> and about <NUM>. Some embodiments provide for use of light sources that radiate ultraviolet light within more specific ranges. As some non-limiting examples, some embodiments may utilize light sources that radiate UVA (wavelengths from about <NUM> to about <NUM>), UVB (wavelengths from about <NUM> to about <NUM>) and/or UVC (wavelengths from about <NUM> to about <NUM>). Without being bound by theory, it is believed that the energy from the ultraviolet light may destroy nucleic acids and disrupt DNA, which may interfere with cellular processes of microorganisms. As a result, pathogens, such as viruses and bacteria die. Ultraviolet light is merely one example. Other non-limiting examples of possible wavelengths of light that may be used include, visible light such as violet light (wavelengths from about <NUM> to about <NUM>), indigo light (wavelengths from about <NUM> to about <NUM>), blue light (wavelengths from about <NUM> to about <NUM>), and green light (wavelengths from about <NUM> to about <NUM>). In embodiments, light sources <NUM> and/or <NUM> may radiate light in any of the ranges noted above or in any combination of the ranges.

In other embodiments, in addition to light, the fluid may contain an additional material, e.g., a photosensitizer that aids in the pathogen reduction. Without being bound by theory, it is believed that photosensitizers include molecules that may be activated by light energy (e.g., ultraviolet light). The photosensitizer (or reaction products resulting from the activation) may disrupt bonds in DNA. In pathogens, such as viruses and bacteria, the disruption may lead to the death of the pathogen, or an inability to reproduce. Some non-limiting examples of photosensitizers that may be used in some embodiments include: porphyrins, flavins (e.g., riboflavin), psorolens, and combinations thereof.

<FIG> illustrate various views of a flow cell <NUM> and pieces of flow cell <NUM> according to some embodiments. As shown in <FIG>, flow cell <NUM> includes a first piece <NUM> and a second piece <NUM>. Flow cell <NUM> also includes a plurality of channels <NUM>, an inlet manifold <NUM>, an inlet port <NUM>, outlet manifolds <NUM> and <NUM>, and an outlet port <NUM>.

Referring to <FIG>, in operation, a fluid to be pathogen reduced may be introduced into flow cell <NUM> through inlet port <NUM>. The fluid may flow into inlet manifold <NUM> and into the plurality of channel <NUM>. After flowing through the plurality of channels <NUM>, the fluid flows into outlet manifolds <NUM> and <NUM>. Finally, the fluid flows out of flow cell <NUM> through outlet port <NUM>. In embodiments, the fluid may be exposed to light energy throughout the process of flowing through flow cell <NUM>. In other embodiments, the fluid may be exposed to light energy only when passing through channels <NUM>. As described in greater detail below, the features of flow cell <NUM> provide for exposing fluid to light energy (and in some embodiments to a photosensitive material), which reduces pathogens in the fluid. In embodiments, flow cell <NUM> is designed to ensure that fluid processed through flow cell <NUM> has a threshold amount of exposure to light energy to reduce pathogens by a predetermined amount. In other words, the fluid is provided with a minimum dose of light energy to reduce pathogens in the fluid by a predetermined amount. In embodiments, the process may result in a log reduction of about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, or even about <NUM>.

Also, embodiments may be designed to avoid exceeding a maximum threshold amount of exposure to light energy. That is, if the fluid is exposed to an amount of light energy above a threshold amount, other components of the fluid may be negatively affected. For example, too much energy may denature proteins that are desired to be maintained in the fluid.

As noted above, flow cell <NUM> is shown as constructed from two pieces. This is merely one example of how a flow cell may be constructed according to embodiments. In other embodiments, flow cell <NUM> may be constructed from one piece or more than two pieces. For example, <FIG> illustrate an embodiment of a flow cell that is constructed from three pieces.

Referring back to flow cell <NUM>, the first piece <NUM> and second piece <NUM> may be made from materials that are transparent to the light used in processing the fluid, e.g., ultraviolet and/or visible light. For example, the first piece <NUM> and second piece <NUM> may be made from polymers, glass, ceramics, composites, or combinations thereof. In some embodiments, the first piece <NUM> and second piece <NUM> are made from a polymeric material that is transparent to a predetermined wavelength of light (e.g., ultraviolet, violet, indigo, blue, green, etc.).

Examples of polymeric materials that may be used in some embodiments include, but are not limited, to acrylics and polycarbonates. In embodiments, both pieces <NUM> and <NUM> may be made from the same, or similar, material. In other embodiments, pieces <NUM> and <NUM> may be made from different materials. In one embodiment, first piece <NUM> and second piece <NUM> may be made from a polymeric material (e.g., acrylic) that is transparent to ultraviolet light with wavelengths less than or equal to <NUM>. In another embodiment, first piece <NUM> and second piece <NUM> may be made from a polymeric material (e.g., acrylic).

As shown in <FIG>, first piece <NUM> and second piece <NUM> may be attached to create flow cell <NUM>. In some embodiments, pieces <NUM> and <NUM> may be attached around their perimeters. That is, a portion of piece <NUM> around perimeter 204A (<FIG>) may be attached to a portion of piece <NUM> around perimeter 208A (<FIG>), such as for example by an adhesive, solvent welding, RF welding, ultrasonic welding, laser welding, etc. In some embodiments, it may be that only the perimeter of pieces <NUM> and <NUM> are attached, and no portions of the interior of pieces <NUM> and <NUM> are attached together. In these embodiments, a clamping mechanism, as described below, maybe used to apply pressure to flow cell <NUM> to push piece <NUM> and piece <NUM> together particularly in the interior where the two pieces may not be attached. The pressure aids in maintaining the dimension of the channels <NUM>.

Referring now to <FIG>, the plurality of channels creates fluid communication between inlet manifold <NUM> and outlet manifolds <NUM> and <NUM>. In embodiments, the plurality of channels <NUM> may have characteristics that aid in reducing pathogens in a fluid.

<FIG> illustrates a cross-section of flow cell <NUM> taken along line AA-AA (<FIG>). As shown in <FIG> each of the plurality of channels <NUM> include a depth 212A and a width 212B. In embodiments, the depth 212A of the channels <NUM> may be one of a plurality of parameters (e.g., depth, flow rate, energy dose, etc.) that is selected to ensure that the fluid being pathogen reduced is exposed to the necessary dose of light energy to provide a predetermined log reduction of at least one pathogen.

In embodiments depth 212A may be selected based on the fluid that may be processed. Without being bound by theory, it is believed that to reduce pathogens effectively using light energy, the light should penetrate through a depth of the fluid being pathogen reduced and expose the fluid to a minimum dose of light energy. As can be appreciated, the penetration of the light may depend, among other things, on the type of fluid, fluid transmissivity, and the thickness of the fluid, e.g., the depth of channels through which the fluid flows (212A). Additionally, the dose of light energy that a fluid receives may be affected by the amount of time that the fluid is exposed to the light energy. In other words, how much time the fluid may spend in a zone where it is exposed to the light energy, e.g., a flow rate of the fluid.

<FIG> illustrates a graph <NUM> showing a possible relationship between minimum energy dose and depth size that may affect the pathogen reduction of a fluid flowing through a flow cell, e.g., flow cell <NUM>. By minimum energy dose, it is meant the total amount of energy exposure (per area) received by a fluid element located at the midpoint of the channel depth. In the embodiment shown in <FIG>, the fluid may be flowing at a predetermined flow rate, e.g., <NUM>/min. Without being bound by theory, it is believed that at small depth sizes, the fluid element may flow through the channel too quickly, e.g., at high velocity. That is, the amount of time (e.g., dwell time) spent in the zone where it is exposed to light is too short for the fluid element to receive much energy exposure. As the depth size increases, the velocity decreases, which increases the dwell time and consequently the amount of light energy that reaches fluid element. As the depth increases further, the amount of light energy transmitted through to the midpoint of the channel depth decreases exponentially. Accordingly, even though the dwell time may increase, the amount of light energy exposure received by the fluid element begins to decrease. As shown in <FIG>, there may be an optimal depth <NUM> at which the maximum amount of light energy may reach a fluid element located at the midpoint to effect the pathogen reduction. In embodiments, the optimal depth <NUM> is selected as the depth 212A of channels <NUM>.

In some embodiments, where the fluid to be pathogen reduced includes red blood cells (whole blood or packed red cells), the depth 212A (<FIG>) may be selected based on a predetermined range of flow rates and a minimum dose to achieve a predetermined pathogen reduction (e.g., log reduction). In these embodiments, the depth 212A may be between about <NUM> and about <NUM>, such as between about <NUM> and about <NUM>, between about <NUM> and about <NUM>, or even between about <NUM> and about <NUM>. In embodiments depth 212A may be less than about <NUM>, less than about <NUM>, less than about <NUM>, less than about <NUM>, less than about <NUM>, or even less than about <NUM>. In other embodiments, depth 212A may be greater than about <NUM>, greater than about <NUM>, greater than about <NUM>, greater than about <NUM>, or even greater than about <NUM>. In embodiments, where fluid to be pathogen reduced includes whole blood, the depth 212A may be between about <NUM> and about <NUM> or even between about <NUM> and about <NUM>. In embodiments, where fluid to be pathogen reduced includes packed red blood cells, the depth 212A may be between about <NUM> and about <NUM> or even between about <NUM> and about <NUM>.

In some embodiments, where the fluid to be pathogen reduced includes platelets and/or plasma, the depth 212A may be selected based on a predetermined range of flow rates and a minimum dose to achieve a predetermined pathogen reduction (e.g., log reduction). In these embodiments, the depth 212A may be between about <NUM> and about <NUM>, such as between about <NUM> and about <NUM>, between about <NUM> and about <NUM>, or even between about <NUM> and about <NUM>. In embodiments depth 212A may be less than about <NUM>, less than about <NUM>, less than about <NUM>, less than about <NUM>, less than about <NUM>, less than about <NUM>, less than about <NUM>, less than about <NUM>, less than about <NUM> or even less than about <NUM>. In other embodiments, depth 212A may be greater than about <NUM>, greater than about <NUM>, greater than about <NUM>, greater than about <NUM>, greater than about <NUM>, greater than about <NUM>, greater than about <NUM>, greater than about <NUM>, greater than about <NUM>, greater than about <NUM>, or even greater than about <NUM>. In embodiments, where fluid to be pathogen reduced includes plasma and/or platelets, the depth 212A may be between about <NUM> and about <NUM> or even between about <NUM> and about <NUM>.

In other embodiments, width 212B may be selected to increase the flow rate of fluid that may be processed through a flow cell. In other words, the larger the width 212B, the larger the flow rate of fluid through flow cell <NUM>. In embodiments, the width 212B may be between about <NUM> and about <NUM>, between about <NUM> and about <NUM>, between about <NUM> and about <NUM>, between about <NUM> and about <NUM>, or even between about <NUM> and about <NUM>. In embodiments, the width 212B may be greater than about <NUM>, greater than about <NUM>, greater than about <NUM>, greater than about <NUM>, or even greater than about <NUM>. In other embodiments, width 212B may be may be less than about <NUM>, less than about <NUM>, less than about <NUM>, less than about <NUM>, or even less than about <NUM>.

In embodiments, the width 212B may be no wider than a predetermined ratio of width 212B to depth 212A. For example, in embodiments the ratio of width 212B to depth 212A may be less than about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM> or even less than about <NUM>. In other embodiments, the ratio of width 212B to depth 212A may be greater than about <NUM>, than about <NUM>, than about <NUM>, or even greater than about <NUM>.

In some embodiments, to increase flow rate of fluid through flow cell <NUM>, instead of having width 212B larger, flow cell <NUM> may in embodiments include more channels <NUM>. In some embodiments, flow cell <NUM> may include more than about <NUM> channels, about <NUM> channels, about <NUM> channels, about <NUM> channels, about <NUM> channels, about <NUM> channels, about <NUM> channels, about <NUM> channels, or even more than about <NUM> channels. In some embodiments, flow cell <NUM> may include less than about <NUM> channels, about <NUM> channels, about <NUM> channels, about <NUM> channels, about <NUM> channels, or even less than about <NUM> channels.

As noted above, and shown in <FIG>, flow cell <NUM> may be constructed, in embodiments, by attaching first piece <NUM> and second piece <NUM>. Each of pieces <NUM> and <NUM> may include different features that when attached to each other forms the structure of flow cell <NUM>, as described above. <FIG> illustrate various views of pieces <NUM> and <NUM>.

<FIG> illustrates a bottom view of piece <NUM> of flow cell <NUM>. As shown in <FIG>, piece <NUM> may include channels that create manifolds <NUM>, <NUM>, and <NUM> in flow cell <NUM>. Manifolds <NUM>, <NUM>, and <NUM>, in embodiments, have particular structural features that aid in the flow of fluid through flow cell <NUM>.

In embodiments, flow cell <NUM> may include features that reduce the pressure drop as fluid flows through flow cell <NUM>. A drop in pressure may create short circuit situations in which the fluid does not flow through all of the channels, but rather flows only through a few of the first channels where fluid begins to flow. Also, the features may address the possible issue of stagnant fluid being over exposed to light energy.

Some of these features (of the manifolds) include the shape and structure of manifolds <NUM>, <NUM>, and <NUM>. As can be seen in <FIG>, manifolds <NUM>, <NUM>, and <NUM> have a tapered structure. That is, the cross-sectional area of the manifold is larger in some locations and gets smaller along a length of the manifold.

For example, manifold <NUM> has a larger cross-sectional area at a proximal end 216A than at a distal end 216B. <FIG> illustrates a cross-section of piece <NUM> taken along line BB-BB (<FIG>). <FIG> illustrates a cross-section of piece <NUM> taken along line CC-CC (<FIG>). <FIG> illustrates a cross-section of piece <NUM> taken along line DD-DD (<FIG>). As shown in <FIG>, as cross-sectional areas are taken from the proximal end 216A to the distal end 216B along the length of manifold <NUM>, the cross-sectional areas get progressively smaller.

Similarly, manifold <NUM> has a proximal end 224A and a distal end 224B, and manifold <NUM> has a proximal end 228A and a distal end 228B. As shown in <FIG>, manifolds <NUM> and <NUM> have their distal ends 224B and 228B on a same side of piece <NUM> as the proximal end 216A of manifold <NUM>. As shown in <FIG>, as cross-sectional areas are taken from the distal ends 224B and 228B to the proximal ends 224A and 224B along the length of manifolds <NUM>, the cross-sectional areas get progressively larger.

It is noted that although <FIG>, illustrate the cross-sections of manifolds <NUM>, <NUM>, and <NUM> in particular shapes, other embodiments may have different cross-sectional shapes. As some non-limiting examples, the manifolds <NUM>, <NUM>, and <NUM> may have square, rectangular, triangular, elliptical, diamond, or other cross-sectional shape.

In addition to features of the actual manifold, flow cell <NUM> may also utilize other features to manage pressure within the flow cell <NUM>. For example, the number of manifolds, the pattern of the manifolds (i.e., locations), lengths of manifolds, lengths of channels, may all be modified to control pressure drop and fluid flow in flow cell <NUM>.

<FIG> illustrates a top view of piece <NUM> of flow cell <NUM>. As shown in <FIG>, piece <NUM> includes features, namely a plurality of walls <NUM> that create channels <NUM> in flow cell <NUM>. <FIG> illustrates a cross-sectional view of piece <NUM> taken along line EE-EE (<FIG>). As illustrated in <FIG>, the number, width, and depth of channels <NUM> may be created by the dimensions of walls <NUM>.

Referring again to <FIG>, when pieces <NUM> and <NUM> are attached, e.g., along their perimeters 204A and 204B for example, the structures (including manifolds <NUM>, <NUM>, and <NUM>; channels <NUM>) of flow cell <NUM> are created. As shown in <FIG>, walls <NUM> create channels <NUM> between manifold <NUM> and <NUM> and between manifold <NUM> and <NUM>. As illustrated in <FIG>, at least one of the plurality of channels <NUM> creates fluid communication between the proximal end 216A of manifold <NUM> and the distal end 224B of manifold <NUM>. Similarly, at least a second one of the plurality of channels <NUM> creates fluid communication between the proximal end 216A of manifold <NUM> and the distal end 228B of manifold <NUM>. In some embodiments, only the perimeters 204A and 208A are attached and the interiors of pieces <NUM> and <NUM> are not attached (e.g., bonded) together.

<FIG> illustrates a perspective view of a flow cell holder <NUM> according to an embodiment. Flow cell holder <NUM> may be configured to hold a flow cell (e.g., flow cell <NUM>) during illumination of the flow cell while fluid is flowing through the flow cell. As described below, flow cell holder <NUM> may in embodiments include other features/mechanisms to aid in the pathogen reduction process.

Flow cell holder <NUM> may include a first portion <NUM> and a second portion <NUM>. Flow cell holder <NUM> may also include features of a clamping mechanism that allows first portion <NUM> and/or second portion <NUM> to move to create a space between first portion <NUM> and second portion <NUM>. The clamping mechanism may also allow first portion <NUM> and/or second portion <NUM> to move to clamp a flow cell between the first portion <NUM> and the second portion <NUM>.

The clamping mechanism may include a number of structures. For example, the clamping mechanism may include springs 1012A-D, hinges 1016A & 1016B, alignment blocks 1020A & 1020B, handles 1024A & 1024B, and plates <NUM> and <NUM>.

<FIG> illustrates a side view of the flow cell holder <NUM> with a clamping mechanism in a closed position. <FIG> illustrates flow a side view of the flow cell holder with a clamping mechanism in an open position. As illustrated in <FIG>, when the clamping mechanism is in an open position, plates <NUM> and <NUM> have a space <NUM> between them. A flow cell (e.g., flow cell <NUM>) may be positioned in space <NUM>. <FIG> illustrates the clamping mechanism in an open position with space <NUM>, reduced or eliminated. As noted above, a flow cell may be clamped between plates <NUM> and <NUM> when the clamping mechanism is in the closed position (<FIG>).

<FIG> illustrates portions of a clamping mechanism, namely plates <NUM> and <NUM> (and space <NUM> between plates <NUM> and <NUM>) and portions of an illumination system <NUM>, namely light source <NUM> and light source <NUM> according to an embodiment. <FIG> illustrates the interaction and spatial relationship between plates <NUM> and <NUM> and light sources <NUM> and <NUM>.

As shown in <FIG>, plate <NUM> is opposite plate <NUM> and as noted above, the plates <NUM> and <NUM> are configured to hold a flow cell between them. As also shown, light source <NUM> is adjacent plate <NUM> and light source <NUM> is adjacent plate <NUM>. In embodiments, plates <NUM> and <NUM> are transparent to the light emitted by light sources <NUM> and <NUM>. As can be appreciated, in a pathogen reduction process, a flow cell may be clamped between plates <NUM> and <NUM>. When light sources <NUM> and <NUM> are activated, the flow cell may be illuminated from more than one direction, namely from the top by light source <NUM> and the bottom by light source <NUM>.

<FIG> illustrates a cross-sectional view of flow cell holder <NUM> taken along line FF-FF. <FIG> illustrates the clamping mechanism in a closed position and holding a flow cell <NUM> between plates <NUM> and <NUM>. As shown in <FIG>, light sources <NUM> and <NUM> may be implemented using a plurality of bulbs. This is merely for illustrative purposes and embodiments may implement light sources <NUM> and <NUM> using any type of illumination device(s) non-limiting examples including: LEDs, incandescent bulbs, fluorescent bulbs, halogen bulbs, xenon bulbs, and/or combinations thereof.

As noted above with respect to <FIG>, embodiments provide for light sources to emit light with wavelengths that have a pathogen reducing effect, which may include ultraviolet light. It is noted that in addition to illumination devices, light sources <NUM> and <NUM> may have additional components that aid in the illumination of flow cell <NUM>. For example, light sources <NUM> and <NUM> may include components such as: filters, wave guides, lenses, mirrors and/or combinations thereof.

As noted above, plates <NUM> and <NUM> are transparent to at least a predetermined wavelength of light e.g., ultraviolet light, violet light, indigo light, blue light, and/or green light. By transparent, it is meant that at least about <NUM> % of light of a particular wavelength is transmitted through plates <NUM> and/or <NUM>. In embodiments, greater than about <NUM> %, greater than about <NUM> % or even greater than about <NUM> % of light of a particular wavelength may be transmitted through plates <NUM> and/or <NUM>.

In embodiments, plates <NUM> and <NUM> may be made from any suitable material that has transparency to a particular wavelength of light. Further, because the plates <NUM> and <NUM> may clamp down on a flow cell, they may be made from materials with the necessary structural integrity to withstand pressure used in clamping the flow cell without failing (e.g., fracturing). For example, plates <NUM> and <NUM> may be made from polymers, glass, ceramics, composites, or combinations thereof. In some embodiments, plates <NUM> and <NUM> may be made from a glass material that is transparent to the predetermined wavelength of light. Some non-limiting examples of glass that may be used include: fused quartz, borosilicate glass, and soda-lime glass. In other embodiments, polymeric materials may be used. Non-limiting examples of polymers that may be used include acrylics and polycarbonates. In embodiments, both plates <NUM> and <NUM> may be made from the same material. In other embodiments, both plates <NUM> and <NUM> may be made from different materials.

In addition to materials properties, plates <NUM> and <NUM> may also include other structural features. <FIG> illustrates a plate <NUM> which may be part of a clamping mechanism according to an embodiment. Plate <NUM> includes gaskets <NUM> and <NUM>. In embodiments, when plate <NUM> clamps a flow cell, gaskets <NUM> and <NUM> may contact the flow cell.

Gaskets <NUM> and <NUM> may provide a number of functionalities. For example, in some embodiments, the gaskets <NUM> and <NUM> may provide cushion when clamping the flow cell. In other embodiments, gaskets <NUM> and <NUM> may, in addition to other functions, aid in holding the flow cell and preventing the flow cell from moving during a pathogen reduction process.

In other embodiments, the gaskets <NUM> and <NUM> may be located on plate <NUM> to correspond to edges (e.g., portions of a perimeter) of the flow cell, holding the flow cell in place. In other embodiments, gaskets <NUM> and <NUM> may be made of materials (e.g., polymer, rubber, and/or combinations thereof) that grip the flow cell to hold it in place. In some embodiments, the material may be somewhat transparent to a particular wavelength of light in order not to interfere with the pathogen reduction process.

In the embodiment shown in <FIG>, gaskets <NUM> and <NUM> are shaped to correspond to manifolds; for example, manifolds <NUM>, <NUM>, and <NUM> of flow cell <NUM>. The gaskets may be designed to align with manifolds <NUM>, <NUM>, and <NUM> when plate <NUM> clamps flow cell <NUM>. In some embodiments, gaskets <NUM> and <NUM> may be somewhat transparent to a particular wavelength of light in order not to interfere with the pathogen reduction process. In other embodiments, gaskets <NUM> and <NUM> may not be transparent to a particular wavelength of light but not affect the pathogen reduction process because the necessary light energy dose may be provided while flowing through the channels (e.g., channels <NUM>) of the flow cell. In other embodiments, the gaskets may be designed to intentionally shield portions of the flow cell from the light to avoid overexposing the fluid to light energy.

In other embodiments, the gasket that are not attached to plate <NUM> may be used. For example, in some embodiments, the gaskets may be a separate piece (or pieces). In these embodiments, the gaskets may be positioned between plates and a flow cell. The gaskets may include a relatively soft polymeric material (e.g. rubber) attached to a frame, which itself may be made from a polymer, metal, and/or a composite material. These are merely examples provided for illustrative purposes.

<FIG> illustrates an exploded view of a clamping mechanism that includes plate <NUM>. As shown in <FIG>, portions of gaskets <NUM> and <NUM> may be aligned with flow cell <NUM>. When flow cell <NUM> is clamped, e.g., in contact with gaskets <NUM> and <NUM> and plate <NUM>, gaskets <NUM> and <NUM> may be aligned with specific features of flow cell <NUM>, such as manifolds <NUM>, <NUM>, and/or <NUM>. In embodiments, having gaskets <NUM> and <NUM> may allow additional pressure to be used when clamping flow cell <NUM>. As described above, in embodiments flow cell <NUM> may be constructed by two pieces that may be attached along their perimeter. Having the clamping mechanism maintain a moderate amount of pressure on the flow cell <NUM> may aid in maintaining the channels <NUM> dimensions during fluid flow.

<FIG> illustrate views of a flow cell <NUM> according to another embodiment. As shown in <FIG>, flow cell <NUM> is constructed from three pieces. Piece <NUM> which may include a number of pathways that create manifolds 1516A-D. Piece <NUM> may be a top piece positioned above piece <NUM>. Piece <NUM> may be positioned between piece <NUM> and <NUM> and provide walls that create a plurality of channels <NUM>. The plurality of channels <NUM> may create fluid communication between one or more manifolds 1516A-F. Similar to flow cell <NUM> (<FIG>) fluid flowing through flow cell <NUM> may be illuminated with light energy to pathogen reduce the fluid.

Pieces <NUM> and <NUM> may be made from materials that are transparent to a predetermined wavelength of light. For example, pieces <NUM> and <NUM> may be made from materials such as polymers, glass, ceramics, composites, or combinations thereof. In some embodiments, pieces <NUM> and/or <NUM> may be made from a glass material that is transparent to the predetermined wavelength of light. Some non-limiting examples of glass that may be used include: fused quartz, borosilicate glass, and soda-lime glass. In other embodiments, polymeric materials may be used. Non-limiting examples of polymers that may be used include acrylics and polycarbonates. In embodiments, pieces <NUM> and <NUM> may be made from the same type of material. In other embodiments, pieces <NUM> and <NUM> may be made from different materials.

<FIG> illustrates a flow chart <NUM> of a process of reducing pathogens in a fluid according to an embodiment. Although features of flow cells (e.g., flow cells <NUM> and/or <NUM>), flow cell holders (e.g., flow cell holder <NUM>), clamping mechanisms (e.g., plates <NUM> and <NUM>) and/or systems (e.g., system <NUM>) may be described as part of performance of the steps of the flow chart <NUM>, embodiments are not limited thereto. Indeed, other types of flow cells, holders, clamping mechanisms, and/or systems may be used (with different structures) in the process of flow chart <NUM>.

Flow chart <NUM> starts at <NUM>, and passes to step <NUM> where a fluid to be pathogen reduced is introduced into a flow cell at a flow rate. In embodiments, the flow cell may include a plurality of channels with a depth and a width. In one embodiment, the flow cell is similar to flow cell <NUM> noted above. The plurality of channels may correspond to channels <NUM> which provide fluid communication between an inlet manifold and one or more outlet manifolds. In embodiments, the plurality of channels may be relatively straight channels that provide a direct line-of-sight between an inlet manifold and an outlet manifold. That is, the channels are not serpentine or curved channels. The channels may have the dimensions, depth and width, described above with respect to flow cell <NUM>.

In embodiments, the flow rate may be selected to process a volume of fluid within a predetermined period of time. For example, in some embodiments, it may be desirable to process between about <NUM> liters and about <NUM> of the fluid through the flow cell in less than about <NUM> hours, less than about <NUM> hours, less than about <NUM> hour, less than about <NUM> hours, less than about <NUM> hours, or even less than about <NUM> hours. In these embodiments, the flow rate may be selected to be between about <NUM>/min and about <NUM>/min, such as between about <NUM>/min and about <NUM>/min. In embodiments, the flow rate may be greater than about <NUM>/min, about <NUM>/min, about <NUM>/min, about <NUM>/min, about <NUM>/min, about <NUM>/min, about <NUM>/min, about <NUM>/min, or even greater than about <NUM>/min. In other embodiments, the flow rate may be less than about <NUM>/min, about <NUM>/min, about <NUM>/min, about <NUM>/min, about <NUM>/min, about <NUM>/min, about <NUM>/min, about <NUM>/min, about <NUM>/min, or even less than about <NUM>/min. These flow rates may be selected in combination with one or more dimensions (e.g., depth, width, etc.) of channels <NUM>, described above with respect to flow cell <NUM>.

After step <NUM>, flow <NUM> passes to step <NUM>, where the fluid is illuminated while it passes through the channels. In embodiments, the fluid may be illuminated from at least two directions. In some embodiments, step <NUM> may be performed while the flow cell (e.g., flow cell <NUM>) is in a cell holder, such as cell holder <NUM>. The cell holder may include a lighting system (e.g., system <NUM> or system <NUM>) that illuminates the flow cell and the fluid while the fluid flows through the plurality of channels. For example, the fluid may be illuminated from a top and a bottom of the plurality of channels.

Flow <NUM> passes from step <NUM> to step <NUM>, where the fluid is pathogen reduced. In embodiments, the reduction in pathogens may be effected by the illumination of the fluid as it passes through the channels. In some embodiments, the light alone may create the pathogen reducing effect. In other embodiments, an additional material, may work in combination with the light energy to effect the pathogen reduction. For example, a photosensitizer may be added to the fluid before or during step <NUM>. The photosensitizer may be activated when illuminated. The activated photosensitizer (or reaction products from the activation) result in disruption of the genetic material and death, or an inability to replicate, of the pathogen. Flow <NUM> ends at <NUM> where the pathogen reduced fluid is collected.

Although flow chart <NUM> has been described with steps listed in a particular order, the embodiments are not limited thereto. In other embodiments, steps may be performed in different order, in parallel, or any different number of times, e.g., before and after another step. Also, flow chart <NUM> may include some optional steps or substeps. However, those steps above that are not indicated as optional should not be considered as essential to the invention, but may be performed in some embodiments of the present invention and not in others.

<FIG> illustrates example components of a basic computer system <NUM> upon which embodiments of the present invention may be implemented. Computer system <NUM> may perform some steps in the methods for introducing fluid into a flow cell or illuminating fluid in a flow cell. System <NUM> may be a controller for controlling features, e.g., flow control devices, pumps, valves, rotation of bioreactors, motors, lighting systems, clamping mechanisms etc., of systems such as systems <NUM>, <NUM>, and/or <NUM> shown above.

Computer system <NUM> includes output device(s) <NUM>, and/or input device(s) <NUM>. Output device(s) <NUM> may include one or more displays, including CRT, LCD, and/or plasma displays. Output device(s) <NUM> may also include a printer, speaker, etc. Input device(s) <NUM> may include a keyboard, touch input devices, a mouse, voice input device, etc..

Basic computer system <NUM> may also include a processing unit <NUM> and/or a memory <NUM>, according to embodiments of the present invention. The processing unit <NUM> may be a general purpose processor operable to execute instructions stored in memory <NUM>. Processing unit <NUM> may include a single processor or multiple processors, according to embodiments. Further, in embodiments, each processor may be a multi-core processor having one or more cores to read and execute separate instructions. The processors may include general purpose processors, application specific integrated circuits (ASICs), field programmable gate arrays (FPGAs), other integrated circuits.

The memory <NUM> may include any tangible medium for short-term or long-term storage for data and/or processor executable instructions, according to embodiments. The memory <NUM> may include, for example, Random Access Memory (RAM), Read-Only Memory (ROM), or Electrically Erasable Programmable Read-Only Memory (EEPROM). Other storage media may include, for example, CD-ROM, tape, digital versatile disks (DVD) or other optical storage, tape, magnetic disk storage, magnetic tape, other magnetic storage devices, etc. In embodiments, system <NUM> may be used to control activation of a light source and/or various flow control devices, pumps, valves, etc. of a pathogen reducing system. Memory <NUM> can store protocols <NUM> and procedures <NUM>, such as protocols and procedures for introducing fluid into a flow cell and/or illuminating fluid in a flow cell, which would control operation of pumps, valves, clamping mechanisms, etc..

Storage <NUM> may be any long-term data storage device or component. Storage <NUM> may include one or more of the systems described in conjunction with memory <NUM>, according to embodiments. Storage <NUM> may be permanent or removable. In embodiments, system <NUM> is part of a system for reducing pathogens in a fluid and storage <NUM> may store various procedures for utilizing the system to pathogen reduce a fluid.

Described below are some examples of embodiments. However, it is noted that although specific methods, apparatuses, and systems are described below, these are provided merely for illustrative purposes, and the present invention is not limited to the specific details in the examples below.

This example provides information on the PhiX174 (pathogen) reduction in whole blood with riboflavin at three different flow rates in five different prototype flow-through flow cells.

This study is designed to obtain insight into the correlation between flow rate, channel thickness and pathogen reduction of whole blood. The flow cells in this study have thin channels and different flow configurations. Thin channels are used because whole blood is less transmissive than plasma.

The flow cell mounts in a fixture (e.g. a flow cell holder) which maintains channel thickness by applying pressure from both the top and bottom. The fixture houses eight illumination lamps driven at <NUM> mA with four on top and four on bottom producing an irradiance of <NUM> mW/cm<NUM>. Product can be flowed through the flow-cell, which is mounted adjacent to the light source, and then samples can be taken on the back end. Whole blood combined with riboflavin and PhiX174 (pathogen) may be used as the test medium (product).

A peristaltic pump to control flow rate is used with the pump will located after the flow cell so that negative pressure is applied to the flow cell by the pump instead of positive pressure. The pump is calibrated prior to use to ensure flow rate accuracy.

Two flow cell configurations being tested may be referred to as "8p" and "4sx2p". The 8p configuration has all the channels in parallel; therefore the fluid crosses one channel before exiting the flow cell. The 4sx2p configuration requires the fluid to cross four channels in series before exiting the flow cell. All the flow cells have the same channel surface area regardless of channel configuration; therefore dwell time is only proportional to channel thickness and flow rate. See Table <NUM> and Table <NUM>.

Table <NUM> below summarizes the results of the study. Cells highlighted are samples that are beyond the limit of detection. Flow cells A and B may clog making some of the samples unobtainable. The data for flow cells C, D and E is included below (other than C6 which is at the limit of detection).

<FIG> plots log reduction vs dwell time. Pathogen reduction in flow cells C, D and E is linearly related to dwell time as expected. The 8p channel configuration results in the greatest pathogen reduction and the greatest rate of pathogen reduction (slope of pathogen reduction vs dwell time). It is not known why the 8p flow cell configuration is better than the 4px2s configuration.

Flow cell E results in less pathogen reduction than flow cell D likely because of the difference in channel thickness. The slope of pathogen reduction vs dwell time of flow cells D and E is the same as expected because both have the same channel configuration.

<FIG> plots log reduction vs flow rate. With respect to flow rate, flow cells C and E have similar performance with the best log reduction per flow rate. Flow cell E has thicker channels and a different cell configuration than flow cell C. Given that flow cell E has only a little less pathogen reduction for the same dwell time than flow cell D it may be that the same would hold true for flow cells with the 8p cell configuration. Therefore it may be that a flow cell with an 8p cell configuration and channel thickness of <NUM>" (<NUM>) could outperform all flow cells tested in this study.

Hemolysis data is summarized in Table <NUM> above. Hemolysis for flow cells C, D and E is the same as the hold control or within <NUM>% hemolysis of the hold control. Sample A2 shows no hemolysis but sample A4 has considerable hemolysis. This infers that the main cause of hemolysis is not shearing because sample A2 was at a higher flow rate than A4. The predicted cause of hemolysis is temperature because when flow cell A is removed from the fixture it was over <NUM>. The effects of hemolysis due to over dosage cannot be ruled out because A4 received a higher dose than A2.

Flow cells are tested from thickest channel thickness to thinnest channel thickness. All flow cells are tested from low flow rate to high flow rate except for flow cell A. During flow cell A samples are taken from high flow rate to low flow rate to attempt to avoid clogging.

Two of the lamps do not turn on when the fixture is warming up for flow cell C. This error is fixed but it is unknown if the two lamps are operational for flow cell D.

Sample A6 is unobtainable because of flow cell clogging and breaks that leak air into the system. When the flow cell is removed from the illuminator it is <NUM>. This high temperature may explain the flow cell clogging.

Flow cell B clogs early on. The only sample collected is B2. Sample B2 has many little bubbles in it and has visible hemolysis.

It is predicted that pathogen reduction is inversely exponentially related to channel thickness due to the transmittance of whole blood (light decays exponentially in a homogenous medium). This may be why the <NUM>" (<NUM>) flow cell has less pathogen reduction than the <NUM>" (<NUM>) flow cell for the same dwell time but the difference is small inferring that we are early on the exponential decay curve. Therefore, it is suggested to test <NUM>" (<NUM>), <NUM>" (<NUM>) and <NUM>" (<NUM>) channel flow cells. The thicker flow cells allow for higher flow rates and may be more manufacturable with injection molding. Theoretically there is an ideal channel thickness that optimizes flow rate and pathogen reduction.

This study shows the feasibility of flow through whole blood pathogen reduction. The data aligns with theory further validating the approach for whole blood flow through pathogen reduction. Pathogen reduction of the virus under test was within the acceptable pathogen reduction range. Further studies into thicker channels and other flow paths may be performed to optimize the system.

This example provides information on the PhiX174 (pathogen) reduction observed in plasma with riboflavin at four different flow rates in four different prototype flow-through flow cells.

The goal of this study is to obtain insight into the correlation between flow rate, channel thickness and pathogen reduction. The flow cells in this study have a relatively thicker channel and different flow configurations.

The flow cell mounts in a fixture (e.g., flow cell holder) which maintains channel thickness by applying pressure from both the top and bottom. The fixture houses eight illumination lamps driven at <NUM> mA with four on top and four on bottom producing an irradiance of <NUM> mW/cm2. Product can be flowed through the flow-cell, which is mounted adjacent to the light source, and then samples are taken on the back end. Plasma combined with riboflavin and PhiX174 is the test medium (product).

The increased channel thickness results in decreased fluidic impedance requiring the use of a peristaltic pump to control flow rate instead of by gravity. The pump is calibrated prior to use to ensure flow rate accuracy.

Ensure the lamps are warmed up and have been running for <NUM> minutes. Purge the system and take sample.

Ensure that the pump is programmed with the correct flow rate from Table <NUM>. Open all the clamps to allow flow from the plasma pool to the waste bag. Turn on the pump and start the stop watch (approximately simultaneously). Monitor fluid progress through the disposable. After the purge time from Table <NUM> has elapsed (allowing at least <NUM> of plasma to flow into the waste bag) open the clamp to the corresponding sample bag then close the clamp to the waste bag. After the sample time from Table <NUM> has elapsed (allowing at least <NUM> of plasma to flow into the sample bag) open the clamp to the waste bag then close the clamp to the sample bag. Open the clamp from the saline then close the clamp from the plasma bag. Repeat from step <NUM>. <NUM> for each flow rate in Table <NUM>. Seal and remove all sample bags. Aseptically remove three <NUM> samples from each bag and transfer into three sample tubes labeled as indicated in Table <NUM>. Submit one sample tube for each sample for viral titer and save the other two samples for later analysis. Repeat from step <NUM> for each flow cell. Use the same plasma pool for the entire study. Aseptically remove three <NUM> samples from the plasma pool and transfer into three sample tubes labeled "HC". These samples will be used as hold controls for the study. Submit one HC sample tube for viral titer and save the other two for later analysis.

Below are the pathogen reduction results. In Table <NUM>, cells with bold text indicate a sample that is within the limit of detection and cells with an asterisk indicate a sample that has six or less PhiX174 colonies at a one log dilution and is outside the limit of detection. Cells with underlined text indicate a sample is technically outside the limit of detection but has PhiX174 colonies allowing for the inferred calculation of pathogen reduction. Each cell also has dwell time in seconds and predicted dose. The lower predicted dose value takes into account the transmissivity of the plasma and flow cell. Transmissivity measurements of the plasma and flow cells are graphed and shown in <FIG>. The higher predicted dose assumes that all light incident on the flow cell is absorbed by the plasma.

With respect to <FIG>, samples are prepared by mixing one unit of plasma with one <NUM> pouch of riboflavin and then diluting the samples with saline. The percentages above denote the concentration of plasma. Concentration and transmission distance are taken into account when the <NUM>% transmission distance is calculated. The Beer-Lambert law is used to determine <NUM>% transmission distance using the equations below.

Greater pathogen reduction than anticipated is achieved resulting in the majority of the data points being beyond the limit of detection. Therefore, no major conclusions about the correlation between channel thickness, flow rate and pathogen reduction are made. The data points that are within the method detection limits have a correlation between dwell time and pathogen reduction. The greater the dwell time the greater the pathogen reduction.

The <NUM>" (<NUM>) thick channel flow cell has opaque deposits on certain sections of the flow cell on the inside of the flow cell after illumination. This indicates that the plasma is overdosed possibly due to the flow stopping in certain regions of the flow cell. It is observed that the <NUM>" (<NUM>) thick flow cell has the most issues with priming due to bubbles in the system.

All flow cells achieve adequate pathogen reduction demonstrating the feasibility of flow through pathogen reduction of plasma and riboflavin. Much of the data is beyond the limit of detection limiting the conclusions that can be drawn from the data in terms of effects of channels thickness and flow rate on pathogen reduction.

It may be apparent to those skilled in the art that various modifications and variations can be made to the embodiments of the present invention described above without departing from the scope of the claims. Thus it should be understood that the invention is not be limited to the specific examples given, the embodiments described, or the embodiments shown in the figures. Rather, the invention is intended to cover modifications and variations within the scope of the appended claims.

Claim 1:
A flow cell (<NUM>) for reducing one or more pathogens in a fluid, the flow cell (<NUM>) comprising:
a plurality of channels (<NUM>), each of the plurality of channels (<NUM>) comprising:
a depth (212A) of less than <NUM>;
a first wall transparent to ultraviolet light;
a second wall transparent to ultraviolet light;
an inlet port (<NUM>), wherein fluid enters the flow cell (<NUM>) through the inlet port (<NUM>);
at least one inlet manifold (<NUM>) in fluid communication with the inlet port (<NUM>) and the plurality of channels (<NUM>), wherein a cross section of the at least one inlet manifold (<NUM>) tapers from a proximal end (216A) of the at least one inlet manifold (<NUM>) to a distal end (216B) of the at least one inlet manifold (<NUM>);
an outlet port (<NUM>) wherein fluid exits the flow cell (<NUM>) through the outlet port (<NUM>);
at least one outlet manifold (<NUM>, <NUM>) in fluid communication with the outlet port (<NUM>) and the plurality of channels, (<NUM>) wherein a cross section of the at least one outlet manifold (<NUM>, <NUM>) tapers from a proximal end (224A, 228A) of the at least one outlet manifold (<NUM>, <NUM>) to a distal end (224B, 228B) of the at least one outlet manifold (224A, 228A).