Abstract:
The present invention relates to a method and/or apparatus suitable for use in reduction of any pathogens in a fluid such as a biological fluid, or a fraction or component thereof, which may contain pathogens. The device may include a vessel having an inlet and an outlet and a passage which extends therebetween. The passage may have a wall which is substantially transparent to a pathogen reduction radiation. The passage contains a static mixer system which is formed and arranged for thoroughly mixing the fluid in use of the device so as to bring substantially the whole of the fluid into an irradiation zone extending along and in substantially direct proximity to the passage walls during passage between the inlet and the outlet to be expose the fluid to a similar substantial level of irradiation. The static mixer may include light transmissive blades.

Description:
RELATED APPLICATIONS  
       [0001]    This application claims the benefit of priority from provisional patent application 60/377697 filed May 3, 2002. 
     
    
     
       INTRODUCTION  
         [0002]    The present invention relates to the treatment of fluids, especially biological or body fluids, such as human blood and fractions or components thereof to inactivate or reduce selected components, e.g. pathogens which may include microorganisms, viruses, bacteria and/or the like, and in particular relates to a fluid mixing and irradiation device or method suitable for use in such a pathogen reduction procedure.  
         BACKGROUND  
         [0003]    Large amounts of body fluids such as blood and plasma and various fractions or components thereof are used in the treatment of patients suffering from a variety of conditions. However, contamination of such fluids with various pathogens such as viruses and other microorganisms can give rise to serious new conditions in the patients receiving transfusion of these fluids and may even result in their death.  
           [0004]    It has been found that fluids containing certain substances or agents are susceptible to be activated to reduce viruses, bacteria, and other microorganisms or pathogens. Some of these substances and agents are activatable by light radiation or irradiation for the reduction of pathogens. This light or photo-activation can be hindered somewhat by the opacity of the fluid into which the light is radiated. Thus, mixing of the fluid can be performed during irradiation to enhance radiation exposure. Frequently such mixing is done in a batch-wise procedure using a shaker table. Also, a flow-through system for pathogen reduction can be used. A pathogen reduction procedure and system is shown in U.S. Pat. No. 6,277,337.  
           [0005]    Visible and/or ultra-violet (UV) irradiation can thus be used to activate certain substances or agents which thereby, when activated, work to reduce pathogens such as bacteria and viruses. However, this has been less practical with blood products because of the very low transmissibility of light into blood and hence the difficulty of ensuring a complete irradiation and inactivation or reduction. This problem is particularly pronounced with respect to a blood product or component having red blood cells.  
           [0006]    In the past static mixers or flow splitters have been used for such industrial processes as epoxy mixing. Also, static mixers or flow splitters have been used for fluid flow mixing with an irradiation area. It is against this background that the instant invention was conceived.  
         BRIEF SUMMARY OF THE INVENTION  
         [0007]    In one aspect, the present invention provides a device suitable for use in the sterilization of, or reduction of any pathogens in a fluid, for example, a biological fluid or a component thereof potentially containing pathogens perhaps including lymphocytes and/or microorganisms. Such a device may include a vessel having an inlet and an outlet and a passage extending substantially directly therebetween to form a flow-through system, the passage having a wall which is substantially transparent to pathogen reduction radiation. A static mixer device may be formed and arranged in the passage for thoroughly mixing a fluid in use of the device, so as to bring substantially the whole of the fluid into an irradiation relationship with the wall extending along and between the inlet and the outlet. The static mixer may also include light transmissive blades or protrusions which may provide light penetration into the fluid flow path. Thus, in use of the device, substantially the whole of a body of the fluid passed through the vessel may be exposed to a similar substantial level of irradiation.  
           [0008]    Hence, with a device of the present invention, a particularly uniform treatment of the fluid with respect to irradiation thereof may be achieved thereby avoiding under-exposure to pathogen reduction radiation whether as a result of screening by an excessive depth of relatively opaque fluid components or otherwise. Substantial mixing of the fluid to be treated with a pathogen reduction agent such as photosensitizers, if used to provide the pathogen reduction reaction, may also be provided. Either or both of these will then maximize reduction of any pathogens in the fluid.  
           [0009]    A cylindrical form of vessel may be used, where in one embodiment, there may be an outer wall substantially transparent to pathogen reduction radiation and, in another embodiment, an inner wall being the substantially transparent wall or both the inner and outer walls may be transparent. Any or all of these may then be used with light transmissive static mixing elements or blades in a light communication relationship therewith.  
           [0010]    In another aspect of the invention the device may include at least one pathogen reduction radiation source mounted in more or less closely spaced proximity to the transparent wall. Note that transparency for the transparent wall and/or the static mixing elements is intended to indicate substantial transmission of radiation at a desired photo-activation wavelength, which may or may not be accompanied by significant transparency at other wavelengths, e.g., visible or UV light. The mounting of the radiation source may generally be arranged to maximize the radiation intensity in the irradiation zone. Indeed high transmissivity may also be made or further maximized through the static mixer blades as well.  
           [0011]    One or various pathogen reduction radiation wavelengths may be used and this may depend upon a particular pathogen reduction agent or photosensitizer, if used, or may depend on the blood component or bodily fluid to be irradiated. For example, riboflavin may be used and this may suggest using radiation having a wavelength range from about 300 nm to about 500 nm, for example, or perhaps more appropriately at about 447 nm for red blood cells. Another example of a photo-activatable agent that may be used is a psoralen, e.g., 8-methoxy psoralen, which upon exposure to UV radiation of from about 320 to about 400 nm wavelength may become capable of forming photoadducts with DNA in lymphocytes to thereby reduce or inactivate these. Various light source types may be used whether of the fluorescent type, incandescent lamps or LED&#39;s, inter alia.  
           [0012]    Where light radiation is used to effect inactivation or reduction of pathogens, then the vessel side wall (inner or outer or both) and/or the static mixer blades may be made of various light transmissive materials including for example silica and other glasses; silicones; quartz, cellulose products and plastics materials such as polytetrafluoroethylene (PTFE), fluorinated ethylenepropylene (FEP), and/or low density polyethylene (LDPE) or polyvinyl chloride (PVC).  
           [0013]    Other inactivating or reducing radiation wavelengths that may be used include microwave radiation used in conjunction with a glass or ceramic vessel wall or blades; infrared radiation used in conjunction with a quartz vessel wall or blades. The duration of irradiation required will depend on various factors such as the intensity, disposition and number of sources used, the transmission characteristics of the vessel side wall or blade material, the vessel configuration and hence the mixing efficiency therein and the surface area of the thin layer of fluid adjacent the vessel side wall and/or mixing blades, the length of the passage in the vessel and the flow rate of the fluid being treated, and hence the residence time of the fluid in the irradiation zone, as well as the nature of the fluid itself. In general, the residence time in the vessel, the material and thickness of the vessel side wall and/or blades and the radiation sources may be chosen and arranged to provide an effective reducing or inactivating dosage of radiation within such a period.  
           [0014]    The required irradiation time can be achieved in a number of different ways including one or more of the following: use of vessels with irradiation zones of different length, varying the flow rate of the fluid, using a plurality of devices in series or parallel, and recycling the fluid through the device(s) a number of times.  
           [0015]    It will also be understood that the degree of mixing desired to achieve complete irradiation may depend on various factors such as the transmissibility or permeability of the fluid to the radiation and the total depth of fluid in the vessel from the wall or blades through which radiation is received. In general the lower the transmissibility/permeability and the greater the fluid depth, the greater will be the number of mixer blade elements and mixing stages desired for effective irradiation.  
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0016]    Further features and advantages of the invention will appear from the following detailed description given by way of examples and illustrated with reference to the accompanying drawings in which: FIG. 1 is a partly schematic, partly cross-sectional view of an irradiation apparatus according to the present invention;  
         [0017]    [0017]FIG. 2 is a partly schematic, partly cross-sectional view of an alternative embodiment according to the present invention;  
         [0018]    [0018]FIG. 3 is a transverse section of an alternative embodiment of the invention using LED&#39;s;  
         [0019]    [0019]FIG. 4 is a schematic view of an alternative apparatus according to the present invention;  
         [0020]    [0020]FIG. 5 is a cut-away, cross-sectional view of the apparatus of FIG. 4;  
         [0021]    [0021]FIG. 6 is an isometric view of an apparatus such as that shown in FIG. 4; and  
         [0022]    [0022]FIG. 7 is a schematic view showing flow through a further alternative apparatus according to the present invention. 
     
    
     DETAILED DESCRIPTION  
       [0023]    [0023]FIG. 1 shows an apparatus  10  comprising a vessel  12  in the form of a cylindrically walled tube  13 . In one embodiment (see FIG. 2), tube walls  13  may be of a light transmissible material. Vessel  12  also has an inlet  14  and an outlet  15 , with an axially extending static mixer device  16  disposed within the walls  13  thereof. In more detail the static mixer device  16  comprises an axially extending series of angularly offset helical “screw” or paddle or blade elements  18  defining pairs of flow paths which are divided equally and mixed at the junctions  19  between successive elements  18  thereby providing a degree of mixing which increases with the number of elements used. Blades  18  may also be referred to as flow splitting elements wherein they may split flow streams in a repeating fashion. Another effect of the blades  18  is to move the streams adjacent an outer wall  13  or walls (of a core  20 ), as will be described.  
         [0024]    The “screw” or blade elements  18  may be, as shown in FIG. 1, mounted on a hollow core  20  which defines one embodiment of light transmission. In particular, a passage  21  in core  20  forms a container for light source(s)  22  (shown schematically). In more detail, the light system  17  may include an electrical light circuit  24  provided with power supply  23  for circulating electricity for the lights  22  mounted inside the hollow core  20 .  
         [0025]    The walls of core  20 , and in one embodiment, also the screw elements  18 , may be made of an inert physiologically acceptable light conductive material such as transparent plastic in order to facilitate efficient light transfer from the light circuit  17  to the fluid being treated  27  to thereby maximize the exposure of the fluid to light by “turning over” fluid closely adjacent the core  20  and screw elements  18 , so as to thereby maximize the efficiency of the sterilization/pathogen reduction treatment of the fluid. Light may thus be transmitted from a bulb or bulbs  22  through the walls of core  20  and into the flow passages between core  20  and walls  13  as well as, in one embodiment, into and through blades  18 . The walls of core  20  represent the inner walls of the fluid flow passage of vessel  12  with walls  13  representing the outer walls.  
         [0026]    Irradiation (not separately shown in FIG. 1) may be effected by means of one or a plurality of light sources  22  (represented schematically in FIG. 1) inside the core  20 . These light sources may be incandescent or fluorescent bulbs or tubes, or they may be a number of LED light sources (see FIG. 3).  
         [0027]    In another embodiment, as shown in apparatus  30  of FIG. 2, additional or alternative exterior light sources  31  may be alternatively or additionally used. These may also be incandescent or fluorescent tubes or bulbs  31  (also shown schematically) and may extend parallel to and/or may be closely spaced from the vessel walls  13  and distributed there around. The light or irradiation sources could also be LED&#39;s or light emitting diodes arranged around and along the length of vessel walls  13  as shown in FIG. 3. Vessel walls  13  could then also be light transmissive, and in one embodiment, light transmissive screw blades  18  may be in light conduction communication herewith to convey light from sources  31  through walls  13  into the interior of mixer  16 . Exterior reflectors  32  may also be provided to help concentrate the radiation  40  onto and through the vessel walls  13 . The vessel walls  13  may be made of any of a number of light transmissive materials to maximize transmission of the radiation  40  into the fluid  27  being treated. Note, the inner core  20  with interior light source(s)  22  may continue to be used in addition as well. In this or any of the embodiments herein, flow through the system may be affected by movement of the system by a number of methods such as by vibration or gyration or nutation or gravity or pumping, including pumping in opposite directions, inter alia, to further increase mixing.  
         [0028]    A cross-sectional view of another embodiment is shown in FIG. 3. In this FIG. 3 embodiment, another view of an apparatus is depicted in which the parts mostly correspond to those shown in the embodiment of FIG. 2. However, the light source(s) in this apparatus may include an array of light emitting diodes, LED&#39;s  24  (either or both inner and/or outer) each providing a desirable wavelength of electromagnetic radiation. The LED&#39;s  24  may be arranged so that angularly distributed LED&#39;s are positioned around the vessel tube  13  and along its length, as well as or alternatively may so be disposed inside the hollow core  20  along its length. Light rays  40  are shown here also, from both inner and outer LED&#39;s  24  as well as emanating from light transmissive blades  18 , penetrating deeper into the fluid flow.  
         [0029]    [0029]FIG. 4 shows an alternative apparatus  100  of the present invention comprising a tubular vessel  120  having a first end with an inlet  140  and a second end having an outlet  150 . Arrow A shows the direction of flow of the liquid into the device and arrow B indicates the direction of the flow of the liquid exiting the device during use. A fluid flow supply  170  may be provided to pass fluid through the tubular vessel  120  in use of the apparatus. The fluid supply  170  may typically be a pump  171  which can pump the fluid through the device at a desired flow rate, for example, a peristaltic pump or a gear pump. In an alternative arrangement, the fluid may be supplied to the device  100  by arranging a reservoir  172  (reservoir discretely shown as a box) of the fluid to be held at a level substantially above the level of the inlet  140  and outlet  150  of the device  100 . This arrangement may then allow the fluid to flow under the influence of gravity from the reservoir  172  through the tubular vessel  120  to the outlet  150  positioned below the level of the reservoir  172 . Supply  170  may thus include one or the other or both pump  171  and/or reservoir  172 . A receiver/container  175  is shown at the receiving end past outlet  150  of device  100 . Reservoir  172  and receiver  175  may be conventional containers such as bags.  
         [0030]    Although fluid is shown flowing through apparatus  100  in one direction it is also understood that the direction of fluid flow could be reversed to provide fluid flow in the opposite direction. Also, fluid flow could alternatively change direction periodically over time to provide further mixing and additional irradiation.  
         [0031]    The tubular vessel  120  of the apparatus  100  may be in the form of a transparent tube wall  130 . The tubular vessel may thus be substantially cylindrical. A static flow mixer  160  may be disposed in and extend along the length of the vessel  120  and may include a series of mixer elements  180  arranged longitudinally therein with pairs of alternatively handed screw elements or blades angularly offset from each other by some degrees, for example ninety degrees (90°). The mixer device  160  and blades  180  may be transparent and may have an outside diameter which meets the inner diameter of the tube walls  130 , and may thus be push-fit inside the transparent tube vessel  120 . A tight fit between the tube wall  130  and the blades  180  is desired such that fluid does not flow between the wall  130  and blade  180  and so that light can pass through the wall  130  and into the blade  180 . Such a tight fit is desirable in all embodiments.  
         [0032]    The mixer elements  180  in such devices may be formed and arranged such that in use the fluid may be thoroughly mixed so that different portions of the main body of the fluid are successively brought within a more or less shallow irradiation zone  210  adjacent the wall  130  of the vessel  120  to be light- irradiated. In this way substantially all of the fluid is exposed to a similar pathogen reduction level of light irradiation. With substantially light transmissive mixer elements  180 , light may be transmitted deeper into the fluid flow and thereby provide greater exposure of the fluid to light.  
         [0033]    Various angularly distributed light lamps  220  mounted inside a reflective housing  225  are positioned more or less closely adjacent around the vessel wall  130 . In relation to control of the exposure of the fluid to visible or UV radiation, this is conveniently monitored in terms of the residence time of a fluid within any part of the transparent wall tubular vessel  120  between the opposed lamps  220 , referred to herein as the irradiation area though it will be appreciated that the actual period of time during which any part of the fluid is actually irradiated—corresponding to residence time within the irradiation zone adjacent the walls of the vessel may be rather less than the residence time in the irradiation area, the difference depending on factors such as the outside diameter (OD) of the fluid and the diameter of the vessel as discussed hereinbefore.  
         [0034]    The amount of fluid in contact with or close proximity to the vessel wall  130  may usually be relatively small compared to the total volume of fluid present in the tubular vessel  120  at any given time. The fluid may be very thoroughly remixed as it passes from one mixer element  180  to the next. This may heighten the exposure of the components of the fluid to irradiation. A close-up example of what the blades  180  may look like in the device of FIG. 4 is shown in FIG. 5, and a further more isometric view with cut away portion is shown in FIG. 6 with like elements having like numbers with FIG. 4.  
         [0035]    [0035]FIG. 7 shows an alternative embodiment which may also provide for mixing the fluid of interest with a gas (such as oxygen (O 2 ), nitric oxide (NO 2 ), or air, inter alia). The system  300  of FIG. 7 includes a flow vessel  320  with a vessel wall  330  having an inlet  340  and an outlet  350 . A mixing device  360  is disposed inside the vessel  320  and may be adjacent the vessel wall  330 . The mixing device  360  may have a plurality of blades  380  as shown and described in the embodiments of either FIGS.  1 - 3  and/or FIGS. 4 and 5. A further gas container  325  may be disposed as shown downstream of the flow-through vessel  320  (it may alternatively be disposed upstream thereof (not shown)). Also, the fluid flow may be orientated downward (either by gravity as shown or by pump) from a reservoir system  370 , e.g., a reservoir  372  and as the fluid flow is downward, for example, the gas may be flowing or trickling upward, see flow arrow C, to provide enhanced mixing of the gas and fluid. This may be beneficial for certain uses such as where a pathogen reduction agent may be aided in operation by chemical combination of the gas therewith. For example, riboflavin as a pathogen inactivation or reduction agent may be further activated by combination with an oxygen product (e.g., oxygen (O 2 ), nitric oxide (NO 2 ), or air, inter alia). Thus fluid containing a photosensitizer may flow from one direction while the gas or oxygen flows into core or vessel  320  from another direction. Alternatively, both the gas and fluid can flow in the same direction. Horizontal or other  3 -D space orientations may also be provided. Irradiated fluid may then be collected in a container  375  (though, it may alternatively be collected in the same chamber/container from which the gas was/is released, e.g., container  325 ).  
         [0036]    In this embodiment, as was described for the previous embodiments above, the blades  380  may be of a light transmissive material to provide good penetration of light radiation into the fluid flow. Light radiation  40  may thus emit from source(s)  440  and irradiate fluid in an irradiation zone  410 . Another alternative usable herewith may be to have a hollow core (not shown) such as that shown in FIGS.  1 - 3  with light source(s) disposed therein to irradiate the inner surface of fluid flow.  
         [0037]    As noted relative to gas mixing, the static mixers of the present invention may also be used for mixing an agent, such as a pathogen reduction agent, with the fluid of interest (e.g., blood or a component thereof). Very thorough mixing of the agent with the fluid of interest may then provide enhanced exposure of all or substantially all of the fluid of interest with the agent. Thorough pathogen reduction may then result. Note, irradiation may be performed simultaneously, or before or after such agent mixing. Further, a pathogen reduction agent may originally be disposed in one or more discrete parts prior to use (for sterilization reasons, inter alia), and these may then be appropriately mixed using devices or systems of the present invention, before, simultaneously with or after mixture with the fluid of interest (e.g., blood or a component thereof).  
         [0038]    The examples of the above-described systems, methods, and apparatuses are for illustrative purposes only. For example, although a cylindrical or annular vessel is described, it is understood that the outer vessel can be any shape, particularly if the static mixer is arranged in an inner passage. Because other variations will become apparent to those skilled in the art, the present invention is not intended to be limited to the particular embodiments described above. Any such variations and other modifications, adaptations or alterations are included within the scope and intent of the invention.