Patent Description:
ECP typically involves processing a large volume of whole blood, ranging from <NUM> to <NUM> per treatment based on the number of white blood cells collected. Consequently, ECP has proven more difficult to administer to patients that are small in stature, such as pediatric patients, due to their lower body weight, the limits on the extracorporeal volume of the whole blood withdrawn and accompanying fluid balances that may be safely tolerated by such patients, and the relatively large extracorporeal volumes required for operation of apheresis devices used for separating out the white blood cells from the whole blood. Similarly, some adult patients may not be able to tolerate large changes in fluid balance due to their disease state, or have poor venous access, that make ECP procedures difficult to administer.

Set forth in greater detail below are a number of different embodiments of systems and methods specifically developed for performing low volume (e.g., <NUM> or less) ECP procedures. Each of the different systems and methods eliminates the need for multiple kits and solutions and reduce some of the potential risks inherent in the use of such multiple kits and solutions.

The present disclosure includes five aspects, each having related sub-aspects.

In a first aspect, which is part of the invention, a unitary disposable kit for performing low volume extracorporeal photopheresis is provided. The kit comprises a first container that is configured to receive whole blood from a patient and to be mountable in both a centrifuge and a blood component separator. A second container is provided that is connected to the upper portion of the first container by a first tubing segment for receipt of plasma. Both the first container and second container have an upper portion and a lower portion when mounted in the centrifuge and blood component separator. A third container is provided that is connected to the lower end of the first container by a second tubing segment for receipt of packed red blood cells. Optionally, the third container may be prefilled with a volume of allogenic, ABO packed red blood cells matched to the patient. A fourth container is provided that is connected to the first container by a third tubing segment for receipt of buffy coat and is also configured to be mountable in an irradiation device. Preferably, each of the first, second, third, and fourth containers is configured to be mountable in the centrifuge.

Related to the invention the unitary disposable kit further may further comprise a phlebotomy needle connected to the first container by a fourth tubing segment for introducing whole blood into the first container and wherein the first container is prefilled with a volume of anticoagulant.

According to the invention, the unitary disposable kit comprises a fifth tubing segment connected to the fourth container for introducing a photoactivation agent into the fourth container. Further, the unitary disposable kit comprises a fifth container prefilled with a volume of photoactivation agent and connected to the fourth container by the fifth tubing segment.

According to the invention, the unitary disposable kit comprises a sixth container prefilled with a volume of saline and connected to the first container by a sixth tubing segment for introducing saline into the first container.

Other variations of the invention comprise one or more of any of a flow control clamp, a break-away cannula is associated with at least one of the tubing segments, and an in-line anti-microbial filter associated with the fifth tubing segment.

In another aspect related to the first aspect, and also part of the invention, there is a method for performing a low volume extracorporeal photopheresis procedure utilizing the unitary disposable kit of the invention and the aspects related thereto in combination with a centrifuge, a blood separation device that is separate from said centrifuge and an irradiation device. The method comprises: mounting a first container containing whole blood in the centrifuge; operating the centrifuge to separate the whole blood into separate layers of plasma at the upper end of the first container, packed red blood cells at the lower end of the first container, and buffy coat intermediate the layers of plasma and packed red blood cells; loading the first container onto the blood separation device; expressing plasma from the upper end of the first container through the first tubing segment and into the second container; expressing packed red blood cells from the lower end of the first container through the second tubing segment and into the third container; retaining the buffy coat in the first container; adding plasma from the second container and/or saline to the first container to dilute the buffy coat retained in the first container and to achieve a target hematocrit and volume for the diluted buffy coat; flowing the diluted buffy coat through the third tubing segment and into the fourth container; adding photoactivation agent to the diluted buffy coat; loading the fourth container onto the irradiation device; and irradiating the fourth container.

In a related aspect, photoactivation agent may be added to the diluted buffy coat by flowing photoactivation agent from the fifth container through the fifth tubing segment and into the fourth container.

In a further related aspect, photoactivation agent may be added to the diluted buffy coat by introducing photoactivation agent into the third tubing segment simultaneously with flowing the diluted buffy coat through the third tubing segment and into the fourth container.

In another related aspect, the buffy coat may diluted by flowing saline from the sixth container through the sixth tubing segment and into the first container.

In another related aspect, the irradiated buffy coat is recombined with a portion of the separated plasma and/or packed red blood cells.

In another related aspect, any excess air in the fourth container is flowed into the first container prior to irradiation of the fourth container.

In another related aspect, a label identifying the patient is applied to at least the fourth container prior to collecting whole blood in the first container and separating the fourth container from the unitary kit only after the diluted buffy coat is flowed from the first container into the fourth container. Optionally, the label identifying the patient is applied to at least the fourth container prior to collecting whole blood in the first container and separating the fourth container from the unitary kit only after the fourth container is irradiated.

In a second aspect, not part of the invention, a method for performing low volume extracorporeal photopheresis with a syringe having a needle, a barrel transparent to UVA light; and a stopper slidably received in the barrel having a plunger removably secured thereto in which the syringe contains a volume of whole blood. In the method, the operator performs the steps of: removing the needle from the syringe and attaching a tip cap to the syringe; removing the plunger from the stopper; placing the syringe in a centrifuge; spinning the centrifuge to separate the whole blood into layers comprising red blood cells, plasma and buffy coat; removing the syringe form the centrifuge; reattaching the plunger to the stopper; removing the tip cap and connecting a return container to the syringe; evacuating the layer of red blood cells from the syringe into the return container, leaving only the layer of buffy coat and plasma in the syringe; disconnecting the return container from the syringe and reattaching the tip cap to the syringe; resuspending the buffy coat remaining in the syringe; placing the syringe with the resuspended buffy coat in a UVA irradiation device; irradiating the resuspended buffy coat with UVA light; removing the syringe from the irradiation device; removing the tip cap from the syringe and reattaching the return container to the syringe; and dispensing the entire contents of the syringe into the return container.

In a further aspect, not part of the invention, related to the second aspect, the method of may further comprise withdrawing whole blood from a patient into the syringe prior to removing the needle from the syringe, and/or infusing the contents of the return container into the patient after dispensing the entire contents of the return container into the patient.

In a further aspect, not part of the invention, related to the second aspect, the method may include the steps of pre-filling the syringe with a pre-determined volume of photoactivation agent or drawing a pre-determined volume of photoactivation agent into the syringe after removing the needle from the syringe and attaching a tip cap.

In another aspect, not part of the invention, related to the second aspect, the method may include evacuating the layer of red blood cell from the syringe using an optical scanning device to identify an interface between the layers of red blood cells and buffy coat. Alternatively, the method may comprise evacuating the layer of red blood cells from the syringe with the operator making a visual determination to identify an interface between the layers of red blood cells and buffy coat.

In another aspect, not part of the invention, related to the second aspect, the method may further comprise drawing air and/or a diluent into the syringe prior to resuspending the buffy coat remaining in the syringe.

In another aspect, not part of the invention, related to the second aspect, the buffy coat remaining in the syringe is resuspended by means of the operator shaking the syringe. Alternatively, the buffy coat remaining in the syringe is resuspended by means of the operator loading the syringe in to a mechanical shaker and activating the shaker.

In a third aspect, not part of the invention, a system for performing extracorporeal photopheresis including a single use disposable fluid flow circuit and a reusable hardware component. The disposable single-use fluid flow circuit comprises: a separation chamber; a first tubing segment in fluid communication with the separation chamber for flowing whole blood from a patient or blood source and into the separation chamber; a second tubing segment in fluid communication with the separation chamber for flowing separated plasma and red blood cells from the separation chamber and to the patient or to a separate container for later reinfusion to the patient; a third tubing segment in fluid communication with the separation chamber for flowing separated, UV-treated MNCs from the separation chamber and to the patient or to the separate container for later reinfusion to the patient; a source of anticoagulant in fluid communication with the first tubing segment through a fourth tubing segment; and a source of photoactivation agent in fluid communication with the first tubing segment through a fifth tubing segment.

The reusable hardware component comprises: a housing; a centrifuge mounted within the housing having a UV-A transmissive bowl configured to mount the separation chamber of the fluid flow circuit therein; a UV-A emitting light source mounted in the housing configured to deliver UV-A light to the bowl of the centrifuge; an interface detector associated with the second tubing segment of the fluid flow circuit configured to detect an interface between separated plasma, red blood cells and MNCs; a first pump associated with the first tubing segment for flowing whole blood from the patient through the first tubing segment and into the separation chamber; a second pump associated with the second tubing segment for flowing separated plasma and red blood cells from the separation chamber through the second tubing segment and back to the patient or to the separate container for later reinfusion to the patient; a third pump associated with the fourth tubing segment for flowing anticoagulant through the forth tubing segment and into the first tubing segment; a fourth pump associated with the fifth tubing segment for flowing photoactivation agent through the fifth tubing segment and into the first tubing segment; and a programmable controller programmed to automatically operate the first, second, third and fourth pumps, the centrifuge, and the UV-A emitting light source.

In a further aspect, not part of the invention, related to the third aspect, the controller is further programmed to control operation of the second pump based upon a signal received from the interface detector.

In another aspect, not part of the invention, related to the third aspect, a method for performing extracorporeal photopheresis using the system of the third aspect is provided comprising: introducing whole blood from a patient or a blood source into the first tubing segment; introducing anticoagulant and photoactivation agent into the first tubing segment to mix with the whole blood; flowing the mixture of whole blood, anticoagulant and photoactivation agent from the first tubing segment into the separation chamber; activating the centrifuge to separate the whole blood in the separation chamber into a first layer comprising plasma, a second layer comprising red blood cells, and a third layer comprising MNCs; controlling the centrifuge to flow the plasma and red blood cells out of the separation chamber and into the second tubing segment and to retain the MNCs in the separation chamber; returning the separated plasma and red blood cells to the patient or to the separate container for later reinfusion to the patient; activating the UV-A emitting light source to provide a prescribe dose of UV-A light to the MNCs retained in the separation chamber; operating the centrifuge to flow UV-A treated MNCs from the separation chamber into the third tubing segment; and flowing the UV-A treated MNCs from the third tubing segment back to the patient or to the separate container for later reinfusion to the patient.

In a fourth aspect, not part of the invention, a single-use disposable kit for performing low volume extracorporeal photopheresis is provided that comprises: a first container holding photoactivation agent having a first tubing segment connected thereto; a second container holding saline having a second tubing segment connected thereto; a third tubing segment having a first portion and a second portion, the first portion in fluid communication with both the first tubing segment and the second tubing segment; a mixing container having a fourth tubing segment connected thereto in fluid communication with the first portion of the third tubing segment, a fifth tubing segment connected thereto in fluid communication with the second portion of the third tubing segment, and a sixth tubing segment connected thereto; an irradiation container in fluid communication with the mixing container through the sixth tubing segment and having a seventh tubing segment connected thereto in fluid communication with the second portion of the third tubing segment; and an eighth tubing segment in fluid communication with the irradiation container.

In an aspect, not part of the invention, related to the fourth aspect, the mixing container is pre-filled with whole blood.

In a further aspect, not part of the invention, related to the fourth aspect, a patient access device is connected to the eighth tubing segment.

In a further aspect, not part of the invention, related to the fourth aspect, a treated product container is connected to the eighth tubing segment.

In a further aspect, not part of the invention, related to the fourth aspect, the irradiation container further comprises a fan-shaped cartridge.

In a further aspect, not part of the invention, related to the fourth aspect, the single-use disposable kit further comprises a container of whole blood having a ninth tubing segment connected thereto, a tenth tubing segment in fluid communication with both the first portion of the third tubing segment and the ninth tubing segment, and an eleventh tubing segment in fluid communication with both the second portion of the third tubing segment and the ninth tubing segment.

In a further aspect, not part of the invention, related to the fourth aspect, a system for performing low volume extracorporeal photopheresis is provided that comprises the single-use disposable kit of the fourth aspect, as set forth above, and a reusable hardware component to which the single-use disposable kit is mounted. The reusable hardware component comprises one or more of: a first fluid flow control device associated with the first tubing segment; a second fluid flow control device associated with the second tubing segment; a third fluid flow control device associated with the third tubing segment; a fourth fluid flow control device associated with the fourth tubing segment; a fifth fluid flow control device associated with the fifth tubing segment; a sixth fluid flow control associated with the sixth tubing segment; a seventh fluid flow control device associated with the seventh tubing segment; and an eighth fluid flow control device associated with the eighth tubing segment. The hardware component further comprises: an agitation device configured to receive the mixing container; an irradiation device having a UV light source configured to receive the irradiation container; and a programmable controller for automatically operating the fluid flow control devices, the agitation device and the irradiation device.

In a further aspect, not part of the invention, of the fourth aspect, the third fluid flow control device of the system comprises a pump interposed between the first and second portions of the third tubing segment.

In a further aspect, not part of the invention, of the fourth aspect, each of the first, second, fourth, fifth, sixth, seventh, and eighth fluid flow control devices of the system comprises a valve or a clamp.

In a further aspect, not part of the invention, related to the fourth aspect, a system for performing low volume extracorporeal photopheresis is provided that comprises the single-use disposable kit of the fourth aspect, as set forth above, in which the single-use disposable kit further comprises a container of whole blood having a ninth tubing segment connected thereto, a tenth tubing segment in fluid communication with both the first portion of the third tubing segment and the ninth tubing segment, and an eleventh tubing segment in fluid communication with both the second portion of the third tubing segment and the ninth tubing segment, and a reusable hardware component to which the single-use disposable kit is mounted. The reusable hardware component comprises one or more of: a first fluid flow control device associated with the first tubing segment; a second fluid flow control device associated with the second tubing segment; a third fluid flow control device associated with the third tubing segment; a fourth fluid flow control device associated with the fourth tubing segment; a fifth fluid flow control device associated with the fifth tubing segment; a sixth fluid flow control associated with the sixth tubing segment; a seventh fluid flow control device associated with the seventh tubing segment; an eighth fluid flow control device associated with the eighth tubing segment; a ninth fluid flow control device associated with the ninth tubing segment; an agitation device for receiving the mixing container; an irradiation device having a UV light source for receiving the irradiation container; and a programmable controller for automatically operating the fluid flow control devices, the agitation device and the irradiation device. The third fluid flow control device may comprise a pump interposed between the first and second portions of the third tubing segment, and each of the first, second, fourth, fifth, sixth, seventh, eighth and ninth fluid flow control devices may comprise a valve or a clamp.

In a fifth aspect, not part of the invention, a single-use fluid flow circuit for performing low volume extracorporeal photopheresis is provided, comprising: a separation chamber configured to be received in a centrifuge; a first tubing segment connected to the separation chamber for flowing whole blood thereto; a collection container for receipt of buffy coat separated from the whole blood in the separation chamber by operation of the centrifuge and configured to be received in a treatment chamber of an irradiation device; and a second tubing segment for flowing buffy coat from the separation chamber onto the collection container.

In a further aspect, not part of the invention, related to the fifth aspect, the fluid flow circuit further comprises a container of photoactivation agent connected to the collection container.

In another aspect, not part of the invention, related to the fifth aspect, the collection container of the fluid flow circuit comprises a syringe.

In a still further aspect, not part of the invention, related to the fifth aspect, the first tubing segment comprises one of a phlebotomy device for flowing whole blood directly from a patient through the first tubing segment and to the separation chamber and a sterile connector for connecting a container of previously-collected whole blood to the first tubing segment.

In another aspect, not part of the invention, related to the fifth aspect, a system for performing low volume extracorporeal photopheresis comprising the single-use fluid flow circuit of the fifth aspect and a durable hardware component. The durable hardware component further comprises a centrifuge configured to receive the separation chamber of the fluid flow circuit; one or more pumps for flowing whole blood through the first tubing segment to the separation chamber and flowing buffy coat through the second tubing segment into the collection container; an irradiation device having a treatment chamber configured to receive the collection container, and a programmable controller for automatically operating the one or more pumps, the centrifuge and the irradiation device. In a further embodiment, not part of the invention, the one or more pumps are associated with each of the first and second tubing segments.

The embodiments disclosed herein are for the purpose of providing and exemplary description of the present subject matter. They are, however, only exemplary, and the present subject matter may be embodied in various forms. Therefore, specific details disclosed herein are not to be interpreted as limiting the subject matter defined in the accompanying claims.

In a first aspect, part of the invention, and with reference to <FIG>, an all-in-one disposable fluid flow circuit or kit for performing a low volume ECP procedure generally designated <NUM> is disclosed. The kit includes a number of different containers that are interconnected by tubing segments. More particularly, the kit <NUM> includes a first container <NUM> into which a volume of whole blood is collected. The whole blood collection container <NUM> is optionally pre-filled with a volume of anticoagulant, if anticoagulant was not added to the whole blood upon withdrawing it from the patient. The whole blood collection container <NUM> also serves as the separation chamber and is thus configured to be received in the bowl of a centrifuge used for separating the components of the whole blood. Typically, separation is performed in a large, floor-standing, high capacity blood banking centrifuge, such as the Sorvall™ centrifuge available from Thermo Fisher Scientific Inc. Alternatively, an apheresis centrifuge may be used, such as the Amicus® Separator, available from Fenwal, Inc. , the details of which may be found in, e.g., <CIT>.

The kit further includes a second collection container <NUM> and a third collection container <NUM> for the plasma and packed red blood cells, respectively, separated out from the whole blood during centrifugation. In instances where the patient is not able to donate a full unit of whole blood, the collection container <NUM> for the packed red blood cells may contain a volume of allogenic, ABO-matched red blood cells, which can be added to the whole blood collection container <NUM> prior to buffy coat separation. A fourth collection container <NUM> which serves as an irradiation container is provided into which the buffy coat remaining in the whole blood collection container <NUM> is transferred. The irradiation container <NUM> is configured to be received in the treatment chamber of an irradiation device. An exemplary irradiation device is described in <CIT>. The kit also optionally includes pre-attached fifth and sixth containers <NUM>, <NUM> of photoactivation agent (<NUM>-MOP) and saline, respectively.

Tubing segments interconnect the various containers. Specifically, a first tubing segment <NUM> connects the plasma collection container <NUM> to the upper end of the whole blood collection container/separation chamber <NUM>. A second tubing segment <NUM> connects the lower end of the whole blood collection container/separation chamber <NUM> to the red blood cell collection container <NUM>. A third tubing segment <NUM> connects the whole blood collection container/separation chamber <NUM> to the irradiation container <NUM>. Optionally, a fourth tubing segment <NUM> having a phlebotomy needle <NUM> on the end thereof may be connected to the whole blood collection container/separation chamber <NUM> for introducing whole blood into the whole blood collection container/separation chamber <NUM>. A fifth tubing segment <NUM> is connected to the irradiation container <NUM> for introducing photoactivation agent from the container <NUM> of photoactivation agent into the irradiation container. The tubing segment <NUM> may connect the container <NUM> directly to the irradiation container or may connect the container <NUM> to tubing segment <NUM>. A sixth tubing segment <NUM> connects the saline container <NUM> to the whole blood collection container/separation chamber <NUM>.

Variations of the kit <NUM> include providing the tubing segments interconnecting the containers with means for controlling the flow between the containers, such as clamps, valves, and/or break-away cannulas. Further, a sampling pouch <NUM> may be connected to the irradiation container.

The fluid flow circuit/kit may <NUM> be used in the following manner. First, whole blood is collected into the whole blood collection container <NUM>. The whole blood collection container <NUM> is then loaded into the bowl of a centrifuge, and the entire kit <NUM> is centrifuged to separate the whole blood into plasma, buffy coat and packed red blood cell layers.

The kit <NUM> is removed from the centrifuge and loaded onto an automated separation device, such as the CompoMat® G5 automated blood component separator available from Fresenius Kabi, which expresses the plasma layer into the plasma collection container <NUM> and the packed red blood cells to the packed red blood cell collection container <NUM>, while the buffy coat is retained in the whole blood collection container <NUM>. A target hematocrit and volume of the buffy coat required for irradiation is achieved by adding some of the separated plasma back into the whole blood collection container <NUM> and/or adding saline to the whole blood collection container <NUM>.

The diluted buffy coat is then transferred (by, e.g., draining or gravity feed) into the irradiation container <NUM>. The photoactivation agent (<NUM>-MOP) may be added in line with the transfer of the diluted buffy coat into the irradiation container. Alternatively, the photoactivation agent may be added directly to the irradiation container. Any excess air in the irradiation container <NUM> after the introduction of the diluted buffy coat and photoactivation agent may be flowed back into the whole blood collection container <NUM> by burping the irradiation container <NUM>.

The irradiation container <NUM> is then loaded into the treatment chamber of an irradiation device, where the container <NUM> is then irradiated to provide an effective dose of light energy to the diluted buffy coat.

After irradiation, the treated buffy coat may either be directly reinfused to the patient, in which case the irradiation container may be detached from the remainder of the kit. Alternatively, the treated buffy coat may be recombined with the remaining plasma and packed red blood cells and then reinfused.

In a second aspect, not part of the invention, and with reference to <FIG>, a method is depicted for performing a low volume ECP procedure utilizing a syringe-like container, generally designated <NUM>, that can be centrifuged, UVA treated, and then ready for injection into the patient. The depicted method shows the use of a single syringe-like container <NUM>. However, as can be readily appreciated, multiple syringes <NUM> may be used to achieve the desired total volume of treated buffy coat.

The syringe <NUM> comprises a barrel <NUM> made of a UVA transparent material, such as glass or a cyclic-olefin polymer/copolymer. A needle <NUM> is removably attached to the syringe <NUM>. A stopper <NUM> having a plunger handle <NUM> removably secured thereto is slidably received in the barrel <NUM>.

Initially, whole blood from the patient is manually drawn into the barrel <NUM> of the syringe <NUM> (<FIG> and <FIG>). The syringe may be pre-filled with the photoactivation agent (<NUM>-MOP). Alternatively, the photoactivation agent may be drawn into the syringe from a separate source at the start of the procedure either before or after the whole blood is drawn into the syringe. Alternatively, the photoactivation agent may be drawn into the syringe <NUM> after centrifugation (<FIG>, described below) and prior to irradiation (<FIG>, also described below).

The needle <NUM> is then removed from the syringe <NUM> and replaced with a tip cap <NUM>, and the plunger handle <NUM> removed (<FIG>). The syringe <NUM> is then placed in a centrifuge <NUM>, which is then operated to spin the syringe <NUM> and separate the whole blood into layers comprising red blood cells <NUM>, plasma <NUM> and buffy coat <NUM> (<FIG>). The centrifuge <NUM> may be provided with a custom holder compatible with the standard centrifuge buckets for holding the syringe in the appropriate orientation.

The syringe <NUM> is then removed from the centrifuge <NUM> (<FIG>), the plunger handle <NUM> reattached to the stopper <NUM> (<FIG>), and the tip cap <NUM> removed. Care is to be taken in removing the tip cap <NUM> so as to not disturb the interface between the layers of red blood cells <NUM>, buffy coat <NUM> and plasma <NUM>. The syringe <NUM> is then connected to a return container <NUM> (<FIG>). The layer of red blood cells <NUM> is evacuated into the return container <NUM> (<FIG>) leaving only the buffy coat and plasma in the syringe.

The evacuation of the red blood cells may be done "manually," with the unaided vision of the operator being used to judge the position of the red blood cell-buffy coat interface in the syringe <NUM>, or an optical sensor may be associated with the tubing segment connecting the return container to the syringe to determine when the interface exits the syringe.

The return container is then detached from the syringe <NUM> and the tip cap <NUM> reattached (<FIG>). The buffy coat and any residual red blood cells remaining in the syringe are then resuspended in the plasma (<FIG>). It may be necessary to draw some additional diluent (such as saline) and/or some air into the syringe <NUM> to sufficiently dilute the buffy coat for irradiation. The resuspension may be performed manually by the operator simply shaking the syringe <NUM>. Alternatively, the syringe <NUM> may be placed in a mechanical shaker to resuspend the buffy coat.

The syringe <NUM> is then placed in a UVA radiation device <NUM>, where the syringe is subjected to a prescribed dose of UVA light to photoactivate the MNCs in the buffy coat and the <NUM>-MOP (<FIG>). After illumination, the syringe <NUM> is removed from the irradiation device (<FIG>). The tip cap <NUM> is removed and the return container <NUM> reattached to the syringe <NUM> (<FIG>). The entire contents of the syringe <NUM> are then dispensed into the return container <NUM>, where it is recombined with the separated red blood cells (<FIG>). The contents of the return container <NUM> may then be reinfused into the patient directly from the container <NUM>. As can be appreciated, the process may be aided by the use of custom disposable tubing sets and/or automated syringes for syringe control.

In a third aspect, not part of the invention, and with reference to <FIG>, a system for performing low volume ECP generally designated <NUM> is disclosed in which the system <NUM> receives blood either directly from a patient or a container of previously collected blood, both of which are indicated by <NUM>, adds <NUM>-MOP in line, and sends it to a separation chamber that is positioned in a centrifuge <NUM>. Upon centrifugation, the blood in the separation chamber separates into its components. A pump controls the level of plasma and red cells within the separation chamber by means of an interface detector within the centrifuge chamber, so that the level of red cells and plasma in the separation chamber is kept low. Consequently, the buffy coat layer is thin and takes up most of the volume in the separation chamber. When the optimal interface position is reached, UV-A lights <NUM> positioned within the centrifuge chamber are activated. Therefore, the MNCs will be treated in the centrifuge, and then can be immediately returned to the patient or to a separate container from which the treated MNCs will be reinfused to the patient, both of which are indicated by <NUM>.

Returning to <FIG>, the system includes a single-use disposable fluid flow circuit that is mounted on to a reusable hardware component. The fluid flow circuit comprises a separation chamber having a first tubing segment <NUM> connected thereto to provide fluid communication between the separation chamber and the patient or blood source <NUM>, so that whole blood may be flowed through the first tubing segment <NUM> into the separation chamber. A second tubing segment <NUM> is in fluid communication with the separation chamber for flowing plasma and red blood cells that are separated from the whole blood from the separation chamber back to the patient or to a separate container <NUM>. A third tubing segment <NUM> is in fluid communication with the separation chamber for flowing separated, UV-treated MNCs from the separation container and back to the patient or to the separate container <NUM>. A container <NUM> holding anticoagulant is in fluid communication with the first tubing segment <NUM> through a fourth tubing segment <NUM> to add anticoagulant to the whole blood withdrawn from the patient or from the blood source <NUM> as it is flowing through the first tubing segment <NUM>. Further, a container <NUM> holding a photoactivation agent is in fluid communication with the first tubing segment <NUM> through a fifth tubing segment <NUM> to add photoactivation agent in the appropriate volume to the contents of the separation chamber prior to irradiation.

The reusable hardware component comprises a housing within which a centrifuge is mounted. The centrifuge includes a UV-transmissive bowl in which the separator of the fluid flow circuit is mounted, and the UV-A emitting light source <NUM> configured to deliver UV-A light to the bowl of the centrifuge. An interface detector is provided configured to detect an interface between separated plasma, red blood cells and MNCs. The interface detector is mounted on the housing to be in association with the second tubing segment <NUM> of the fluid flow circuit.

Pumps <NUM>, <NUM>, <NUM> and <NUM> are respectively associated with each of the first, second, fourth and fifth tubing segments <NUM>, <NUM>, <NUM> and <NUM>. The first pump106 associated with the first tubing segment <NUM> flows whole blood from the patient or blood source <NUM> through the first tubing segment <NUM> and into the separation chamber. The second pump <NUM> is associated with the second tubing segment <NUM> for controlled removal of separated plasma and for flowing red blood cells from the separation chamber through the second tubing segment <NUM> and back to the patient or to the separate container for later reinfusion to the patient <NUM>. The third pump <NUM> is associated with the fourth tubing segment <NUM> for flowing anticoagulant through the fourth tubing segment <NUM> and into the first tubing segment <NUM>. The fourth pump <NUM> is associated with the fifth tubing segment <NUM> for flowing photoactivation agent through the fifth tubing segment <NUM> and into the first tubing segment <NUM>.

The system also includes a programmable controller <NUM> that is programmed to automatically operate the first, second, third and fourth pumps, <NUM>, <NUM>, <NUM> and <NUM>, the centrifuge <NUM>, and the UV-A emitting light source <NUM>. Further, the programmable controller may be programmed to control the operation of the second pump <NUM>, based on a signal received from the interface detector.

In a fourth aspect, not part of the invention, and with reference to <FIG>, a system, generally designated <NUM>, is illustrated comprising a single-use disposable kit and a reusable hardware component. The single-use kit includes a series of containers interconnected by tubing segments and an irradiation cartridge, while the hardware component at least one pump engaging one of the tubing segments for moving fluid through the kit, flow control devices, such as clamps, valves, pumps, associated with the tubing segments, an agitation device, for mixing the contents of one of the containers, an irradiation device including a UV light source configured to receive the irradiation cartridge, and a programmable controller to automatically operate the fluid flow control devices, the agitation device, and the irradiation device.

More specifically, and with reference to <FIG>, there is seen the combination of the single-use disposable kit and a reusable hardware component. The kit comprises a first container <NUM> holding a volume of photoactivation agent ("<NUM>-MOP Source") having a first tubing segment <NUM> connected thereto and a second container <NUM> holding a volume of saline having a second tubing segment <NUM> connected thereto, the first and second tubing segments merging together in a third tubing segment <NUM>.

A mixing container <NUM> is provided that has fourth, fifth and sixth tubing segments <NUM>, <NUM> and <NUM>, respectively, connected thereto The fourth tubing segment <NUM> is connected to a first portion 130a of the third tubing segment <NUM>, while the fifth tubing segment <NUM> is connected to a second portion130b of the third tubing segment <NUM>.

The sixth tubing segment <NUM> connects the mixing container <NUM> to an irradiation container or cartridge <NUM> that connects back to the second portion 130b of the third tubing segment <NUM> by a seventh tubing segment <NUM>. An eighth tubing segment <NUM> is also connected to the irradiation container <NUM> through which the final product is flowed either to reinfuse directly to the patient through a patient access device <NUM>, or to a treated product container <NUM> (<FIG>) for reinfusion at a later time.

With reference to <FIG>, the irradiation container <NUM> may have a fan-shaped configuration to enhance exposure of the blood to UV radiation as it flows through the cartridge. As illustrated, the cartridge divides the flow into six channels <NUM>. By way of example, each channel may have a width WC of approximately <NUM> and a straight length LC of approximately <NUM>, with the overall dimensions of the cartridge being <NUM> in width, WOA, and <NUM> in length, LOA. The cartridge <NUM> has a fluid capacity of approximately <NUM>, and provides for a fluid thickness of approximately <NUM> on average.

As shown in <FIG>, the kit may include a separate container <NUM> of previously collected whole blood having a ninth tubing segment <NUM> connected thereto through which flow is established with the first portion130a of the third tubing segment <NUM> through a tenth tubing segment <NUM> and with the second portion 130b of the third tubing segment <NUM> through an eleventh tubing segment <NUM>. Alternatively, mixing container <NUM> may be prefilled with anticoagulated whole blood, as shown in <FIG>.

The reusable hardware component includes an agitation device <NUM> configured to receive the mixing container <NUM> and an irradiation device <NUM> having a UV light source <NUM> configured to receive the irradiation container <NUM>. Flow control devices are associated with one or more of the first, second, third, fourth, fifth, sixth, seventh and eighth tubing segments. As illustrated, flow control devices <NUM>, <NUM>, <NUM>, <NUM>, <NUM>,<NUM>, <NUM> and <NUM> associated with, respectively, the first, second, fourth, fifth, sixth, seventh, eighth and ninth tubing segments <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>, comprise a valve or clamp, while the third fluid flow control <NUM> device is a pump interposed between the first and second portions 130a, 130b of the third tubing segment <NUM>.

A programmable controller <NUM> automatically operates the fluid flow control devices, the agitation device, and the irradiation device in accordance with an algorithm that provides for optimal dilution of the whole blood needed to achieve the target UVA dose.

The use of the system of <NUM> is illustrated in <FIG>. With reference to <FIG>, photoactivation agent is flowed from the first container <NUM> by means of the pump <NUM> though the various tubing segments and flow control devices and into the container of previously collected whole blood <NUM>. Then, with reference to <FIG>, saline is flowed form the second container <NUM> by means of the pump <NUM> through the various tubing segments and flow control devices and into the container of previously collected whole blood <NUM> to dilute the whole blood.

Then, with reference to <FIG>, the contents of the container of the previously collected whole blood <NUM> are flowed by means of the pump <NUM> through the various tubing segments and into the mixing container <NUM>. The agitation device <NUM> is then activated to oscillate or otherwise move the mixing container <NUM> to mix the whole blood, photoactivation agent, and saline together.

The contents of the mixing container <NUM> are then returned to the container <NUM> that originally held the previously collected whole blood (<FIG>) and then flowed back to the mixing container for further mixing (<FIG>). The contents of the mixing container is then circulated through the irradiation container, with the UV light source activated, and back to the mixing container until the target light dose has been delivered (<FIG>). The treated blood may then be directly reinfused to the patient (as shown in <FIG>). Alternatively, the treated blood can be flowed into a treated product container <NUM> (such as that shown in <FIG>) for later reinfusion to the patient.

In a fifth aspect, not part of the invention, a further system for performing low volume extracorporeal photopheresis, generally designated <NUM>, is provided comprising a durable, reusable hardware component and a single-use fluid flow circuit. The fluid flow circuit comprises a separation chamber <NUM> having a first tubing segment <NUM> connected thereto for flowing whole blood into the separation chamber and a collection container <NUM> in fluid communication with the separation chamber by a second tubing segment <NUM>.

The first tubing segment <NUM> may also comprise a phlebotomy device <NUM>, such as a needle, for flowing whole blood directly from a patient through the first tubing segment and into the separation chamber. Alternatively, the first tubing segment may include a sterile connector for connecting a container <NUM> of previously collected whole blood to the first tubing segment <NUM>. Optionally, a container <NUM> of photoactivation agent may be connected to the collection container <NUM> so that photoactivation agent may be introduced into the collection container <NUM>. Further, the collection container <NUM> may be a syringe in order to facilitate reinfusion of the treated product into the patient.

The durable hardware component comprises a centrifuge <NUM> configured to receive the separation chamber <NUM> of the fluid flow circuit, and one or more pumps <NUM> for flowing whole blood through the first tubing segment <NUM> into the separation chamber <NUM> and for flowing buffy coat separated out of the whole blood by action of the centrifuge <NUM> through the second tubing segment <NUM> and into the collection container <NUM>. As illustrated, a pump <NUM> is associated with each of the tubing segments <NUM>, <NUM> for flowing fluid through the circuit. Alternatively, a single pump may be associated with either of the first and second tubing segments <NUM>, <NUM>.

The durable hardware component also includes an irradiation device <NUM> having a treatment chamber configured to receive the collection container <NUM> to deliver a prescribed dose of radiation to the contents of the collection container <NUM>. A programmable controller <NUM> associated with the hardware component automatically controls the operation of the pump(s) <NUM>, the centrifuge <NUM>, and the irradiation device <NUM>.

Claim 1:
A unitary disposable kit (<NUM>) for performing low volume extracorporeal photopheresis comprising:
a) a first container (<NUM>) configured to receive whole blood from a patient and to be mountable in both a centrifuge and an automated blood component separator device that is separate from said centrifuge;
b) a second container (<NUM>) connected to the upper portion of the first container (<NUM>) by a first tubing segment (<NUM>) for receipt of plasma configured to be mountable in both a centrifuge and a blood component separator, the first container (<NUM>) and second container (<NUM>) each having an upper portion and a lower portion when mounted in the centrifuge and blood component separator;
c) a third container (<NUM>) connected to the lower end of the first container (<NUM>) by a second tubing segment (<NUM>) for receipt of packed red blood cells;
d) a fourth container (<NUM>) connected to the first container (<NUM>) by a third tubing segment (<NUM>) for receipt of buffy coat and configured to be mountable in an irradiation device.
e) a fifth container (<NUM>) connected to said fourth container (<NUM>) by a fifth tubing segment (<NUM>), said fifth container (<NUM>) prefilled with a volume of photoactivation agent; and
f) a sixth container (<NUM>) connected to said first container (<NUM>) by a sixth tubing segment (<NUM>), said sixth container (<NUM>) prefilled with a volume of saline solution.