HK1080403B - System for collecting a desired blood component and performing a photopheresis treatment - Google Patents

Description

System for collecting desired blood components and performing photopheresis treatment

Cross reference to related applications

This application is a later series of U.S. patent application 10/375628, filed on day 2/27 of 2003, claiming the benefit of U.S. provisional application serial No. 60/361287, filed on day 3/4 of 2002, both of which are incorporated herein by reference in their entirety.

Technical Field

The present invention relates generally to methods of separating whole blood into blood components and collecting the desired components, and more particularly to methods of treating diseases using photopheresis.

Background

Some disease treatments require that the patient's blood be removed to achieve a therapeutic effect, one or more components of the blood be treated, and the treated blood components be returned. These extracorporeal treatment methods require a system for safely drawing blood from a patient, separating it into components, and returning the blood or blood components back into the patient. With the development of medical technology, it is possible to treat a patient's blood in a closed cycle, thereby returning the patient's own treated blood to the patient in a medical procedure. Examples of such methods include in vitro treatment of diseases that include pathological increases in lymphocytes, such as cutaneous T cell lymphoma, or other diseases that affect leukocytes. In these methods, the patient's blood is irradiated with ultraviolet light in the presence of a chemical or antibody, which will affect the association between the lymphocytes and the chemical or antibody, which can inhibit the growth metabolic processes of the lymphocytes.

Photopheresis systems and methods have been proposed and used, including separation of the buffy coat from the blood, addition of a photo-active drug, and ultraviolet irradiation of the buffy coat prior to reinfusion into the patient. Extracorporeal photopheresis is useful in the treatment of a number of diseases including graft-versus-host disease, rheumatoid arthritis, progressive systemic dermatitis, juvenile onset diabetes, inflammatory bowel disease, and other diseases believed to be mediated by T cells or leukocytes including cancer. Apheresis methods and systems are also presented and used, including the separation of blood into various blood components.

In one of these treatments, a centrifuge cartridge, such as the Latham cartridge shown in U.S. Pat. No. 4303193, the disclosure of which is also expressly incorporated herein by reference in its entirety, is operable to separate whole blood into red blood cells ("RBCs"), plasma, and buffy coat. The Latham cartridge is a blood component separator that has been used in apheresis technology in medicine and in some new medical procedures such as extracorporeal photopheresis (ECP). PCT applications WO97/36581, WO 97/36634, and U.S. Pat. No.4,321,919; 4,398,906, respectively; 4,428,744 and 4,464,166, the disclosures of which are also incorporated herein by reference in their entireties

The Latham tube efficiency is generally measured by using a yield of White Blood Cells (WBCs), which is typically 50%. And yield is defined as the percentage of cells collected to cells treated. The high yield of the Latham cartridge separator compared to other types of whole blood separators allows it to collect more white blood cells while processing less blood samples from donor patients. However, one major disadvantage of the Latham bowl separator is that: once the red blood cells and plasma fill the interior of the separation cartridge, the separation process must be repeatedly stopped in order to remove the accumulated red blood cells and plasma, resulting in an "intermittent" medical procedure. Although Latham bowl separators have high volumetric productivity, the constant filling and emptying of Latham bowls is time consuming and, therefore, the process is inefficient from a time standpoint.

Previous photopheresis and apheresis systems and methods typically require intermittent processing, and thus take several hours to treat a patient or obtain an adequate supply of separated blood samples. Moreover, manufacturing such systems is very complex. The general purpose of performing a complete photopheresis cycle is to reduce the time required, while another purpose is to reduce the amount of blood extracted from the patient, and a closed cycle procedure should be performed for each irradiation treatment cycle. It is also an object to increase the yield of leukocytes or to obtain a cleaner buffy coat per unit volume of whole blood processed.

Disclosure of Invention

It is an object of the present invention to provide an improved method of separating blood or other biological fluids into components. Another object is to improve the efficiency of existing liquid separation processes by reducing the time necessary to separate a desired amount of a component from the liquid. It is also an object to more effectively treat a patient, improve a photopheresis procedure, or improve a platelet removal procedure. Another object is to separate and remove target cells using specific gravity of the target cells. Another object is to eliminate the need to perform the liquid separation process "batch-wise". It is also an object of the present invention to increase the percentage yield of a desired liquid component from a treated liquid.

The present invention overcomes the deficiencies of the prior art by enabling continuous separation of liquid components without interrupting the process to empty the centrifuge bowl and remove the separated components. The present invention therefore eliminates batch processing and other Latham bowl batch techniques. These and other objects are achieved by the present invention which is directed to improving the process of separating whole blood into its components and collecting the desired blood components. The desired blood component may be buffy coat, red blood cells, plasma, or other components, depending on the intended medical treatment. The present invention is also directed to improving existing methods using the optical fractionation and displacement method. More particularly, the present invention provides a continuous process for whole blood separation of sufficient fractions for photopheresis treatment, thereby greatly reducing the irradiation treatment time for the patient.

When it is desired to collect buffy coat from whole blood, one aspect of the invention is a method comprising: providing a separator having an inlet, a first outlet, and a second outlet; drawing whole blood from a source; adding an anticoagulant fluid to the whole blood in a predetermined ratio to form a mixture of whole blood and anticoagulant; pumping a mixture of whole blood and anticoagulant into the separator via the inlet at a selected input rate; separating the mixture into components of different densities; withdrawing plasma and red blood cells from the separator while continuing to pump the whole blood and anticoagulant fluid mixture into the separator, the plasma and red blood cells being withdrawn at a rate such that the buffy coat accumulates in the separator, the plasma being withdrawn through the first outlet and the red blood cells being withdrawn through the second outlet; the buffy coat is collected from the separator when a predetermined amount of buffy coat has accumulated in the separator.

By withdrawing red blood cells and plasma at a rate sufficient to cause the buffy coat to accumulate in the separator, which is preferably a centrifuge bowl, the buffy coat is under the centrifugal force of the separator for a longer period of time. Increasing the time that the buffy coat is subjected to centrifugal forces can result in a purer buffy coat composition, as well as increased white blood cell production. In addition, this prolonged exposure can be used to further separate the buffy coat into its component parts, including platelets and a wide variety of white blood cells.

When pumping a fluid mixture of whole blood and anticoagulant into the separator, the mixture is preferably passed through and arranged to pass through a cassette for controlling fluid flow. More preferably, by stopping the withdrawal of red blood cells from the second outlet, the red blood cells push the buffy coat out of the first outlet as whole blood continues to enter the separator. The withdrawn buffy coat may be collected in a processing bag that is in fluid communication with the separator via an outlet line. In this embodiment, the collection of the buffy coat is preferably interrupted when red blood cells are detected in the outlet tube. This will minimize the red blood cells mixed by the desired buffy coat.

In carrying out the method, it is also preferred that only plasma is removed before a predetermined amount of red blood cells has been detected in the separator. When a predetermined amount of red blood cells is then detected in the separator, the red blood cells will move out of the separator at a rate sufficient to maintain the amount of red blood cells present in the separator at about the predetermined amount. The predetermined level of red blood cells may be determined by a hematocrit sensor that detects the red blood cell lineage in the centrifuge bowl.

When the method is used in a closed loop process where the source of whole blood is a patient, it is important to return the fluid to the patient during the process. To accomplish this, the removed plasma is preferably collected in a plasma reservoir bag, mixed with a priming solution, and then re-infused into the patient when a predetermined amount of plasma has been collected in the plasma reservoir bag. Further preferred are: the withdrawn red blood cells are mixed with a mixture of plasma and infusate from the plasma reservoir, and the red blood cell-plasma-infusate mixture is then infused back into the patient at a rate approximately equal to the infusion rate.

The method can be used in conjunction with photopheresis, in which the method will further include injecting a photoactive chemical into the collected buffy coat and then irradiating the buffy coat in an irradiation chamber until a predetermined amount of energy has been transferred to the buffy coat. To ensure that the appropriate amount of energy is transferred into the buffy coat, e.g., to induce apoptosis, the buffy coat is preferably circulated between the treatment bag and the irradiation chamber. The irradiated buffy coat should be passed through a filter before it is reinjected into the patient for the photopheresis procedure. In this way, enough buffy coat can be collected and irradiated to perform a full photopheresis treatment in less than 70 minutes. More preferably, the total treatment time is less than 45 minutes.

For other types of treatment, it may be desirable to collect red blood cells from the separator. The current method provides a very high packing volume of red blood cells, since the red blood cells can withstand the centrifugal force for a longer period of time. These red blood cells can be removed and collected for other uses, such as apheresis therapy.

In another aspect, the invention is also a method of performing a photopheresis method for ameliorating a disease. This method comprises: withdrawing whole blood from a source; adding an anticoagulant fluid to whole blood in a predetermined ratio, thereby forming a mixture of anticoagulant and whole blood; separating the mixture of whole blood and anticoagulant into a plurality of blood components according to density; mixing a photoactive chemical with at least one blood component to form a mixture of the photoactive chemical and the at least one blood component; irradiating the combination of the photoactive material and at least one blood component; returning the irradiated composition to the patient; wherein the entire photopheresis treatment is completed in less than 70 minutes. More preferably, the entire photopheresis treatment is completed in less than 45 minutes. This is a great improvement over existing photopheresis treatments, which typically require 2 hours or more of treatment time.

In this aspect of the invention, the at least one blood component may be buffy coat, white blood cells, or platelets. Preferably the buffy coat. In performing photopheresis therapy, the whole blood and anticoagulant fluid mixture is preferably pumped into a separator having an inlet, a first outlet, and a second outlet. Since the buffy coat is the desired component during the photopheresis treatment cycle, the plasma and red blood cells are removed from the separator while continuing to pump the whole blood and anticoagulant mixture fluid into the separator. The plasma and red blood cells are preferably discharged at a rate sufficient to accumulate a buffy coat in the separator, thereby allowing the buffy coat to be subjected to centrifugal forces for an extended period of time. Plasma is drawn through the first outlet and red blood cells are drawn through the second outlet. The buffy coat is preferably collected from the separator for irradiation only after a predetermined amount of buffy coat has accumulated in the separator.

The separated buffy coat is preferably collected from the separator through an outlet line in fluid communication with the processing bag. The buffy coat is collected from the separator by interrupting the discharge of red blood cells from the second outlet while continuing to pump whole blood. This causes the red blood cells to push the buffy coat out of the first outlet. The buffy coat preferably stops collecting when the presence of red blood cells in the outlet tube is detected by the hematocrit sensor. The collected buffy coat is preferably irradiated within the irradiation chamber until a predetermined amount of energy has been transferred into the collected buffy coat. The predetermined amount of energy is preferably sufficient to induce apoptosis.

This photopheresis treatment procedure is preferably performed in a closed circulatory system in which the patient is also the source. Finally, in addition to separating only the buffy coat, the cells can be further separated into components such as platelets and leukocytes as desired.

Finally, another aspect of the present invention, which is a method for collecting a desired blood component, realizes an efficient method for collecting red blood cells, comprising: providing a separator having an inlet, a first outlet, and a second outlet; drawing whole blood from a source; adding an anticoagulant fluid to whole blood in a predetermined ratio, thereby forming a mixture of whole blood and anticoagulant fluid; pumping the whole blood and anticoagulant mixture through the inlet into the separator at a selected input rate; separating the mixture into components of different densities; withdrawing the plasma and the buffy coat from the separator while continuing to pump the whole blood and anticoagulant fluid mixture into the separator, the plasma and the buffy coat being withdrawn at a rate that causes red blood cells to accumulate in the separator, the plasma and the buffy coat being withdrawn through the first outlet; when a predetermined amount of red blood cells has accumulated in the separator, the red blood cells are collected from the separator via the second outlet. The method allows red blood cells to be accumulated in the separator and to withstand the maximum centrifugal forces.

Drawings

The invention is described in detail with reference to the accompanying drawings, which illustrate one embodiment of the apparatus, assembly, system, and method of the invention.

FIG. 1 is a schematic diagram of one embodiment of a disposable kit for use in photopheresis apheresis therapy embodying features of the invention.

FIG. 2 is a top perspective view of one embodiment of a cassette for controlling the flow of fluids in the disposable photopheresis kit shown in FIG. 1.

Fig. 3 is an exploded view of the cassette shown in fig. 2.

Fig. 4 is a top view of the cassette of fig. 2 with the top cover removed to show the internal tubular circuitry.

Fig. 5 is a bottom view of the cassette top cover shown in fig. 2.

FIG. 6 is a top perspective view of an embodiment of a filter assembly.

Fig. 7 is a bottom perspective view of the filter assembly shown in fig. 6.

Fig. 8 is an exploded view of the filter assembly shown in fig. 6.

Fig. 9 is a rear perspective view of the filter assembly shown in fig. 6.

FIG. 10 is a schematic view of the filter assembly of FIG. 6 coupled to a pressure sensor and a data processor.

FIG. 11 is a front view of an irradiator cell.

FIG. 12 is a longitudinal side view of the irradiation cell of FIG. 11.

FIG. 13 is a lateral side view of the irradiation chamber of FIG. 11.

FIG. 14 is a cut-away view of the first and second sheets prior to joining to form the cell shown in FIG. 11.

Figure 15 is a spatial end view of a cross-section of the cell shown in figure 11.

Figure 16 is a perspective view of the irradiation chamber of figure 11 positioned in an ultraviolet lamp assembly.

FIG. 17 is a top perspective view of one embodiment of a permanent tower system for attachment to the disposable kit to facilitate photopheresis treatment.

Fig. 18 is a schematic cross-sectional view of an embodiment of a photoactivation chamber without a UVA light assembly for use in the tower system of fig. 17.

FIG. 19 is a cross-sectional view of a centrifugal chamber used in the tower system of FIG. 17.

Fig. 20 is a circuit schematic of a leak detection circuit provided in the photoactive cell of fig. 18.

FIG. 21 is an electrical schematic diagram of a leak detection circuit provided in the centrifugal chamber of FIG. 19.

FIG. 22 is a top perspective view of the liquid flow console in the tower system of FIG. 17.

Fig. 23 is a bottom perspective view of the console shown in fig. 22.

Fig. 24 is an exploded view of the console shown in fig. 22.

FIG. 25 is a top perspective view of the console of FIG. 22 with the cassette of FIG. 2 mounted thereon.

FIG. 26 is a flow chart of an embodiment of a photopheresis treatment process.

Fig. 27 is a fluid flow circuit diagram for performing the treatment procedure shown in fig. 26.

FIG. 28 is a top perspective view of an embodiment of a peristaltic pump.

Fig. 29 is a cross-sectional side view of the peristaltic pump as shown in fig. 28.

FIG. 30A top perspective view of a peristaltic pump rotor as shown in FIG. 29

Fig. 31 is a bottom perspective view of the rotor shown in fig. 30.

Fig. 32 is a top view of the peristaltic pump shown in fig. 28.

FIG. 33 is a top view of the peristaltic pump shown in FIG. 28 in an installed position adjacent to the cassette shown in FIG. 2.

Fig. 34 is a schematic circuit diagram of an infrared communication port.

FIG. 35 is a schematic view of a centrifuge bowl and rotating frame.

Fig. 36 is a spatial structure view of the cartridge shown in fig. 35.

Fig. 37 is an exploded view of the cartridge as shown in fig. 36.

FIG. 38 is a cross-sectional view of the cartridge of FIG. 36 taken along line XIX-XIX.

Fig. 39A is a cross-sectional view of a connection sleeve connected to the lumen connector of the cartridge of fig. 38 taken along line XX.

FIG. 39B is another cross-sectional view of a connection cannula connected to the lumen connector of the cartridge of FIG. 38.

Figure 40 is a cross-sectional view of the top core of the cartridge of figure 37.

Figure 41 is a space view of the top kernel and upper plate of figure 37.

Figure 42 is a bottom view of the top core of figure 41.

Figure 43A is a space exploded view of the bottom core and lower plate of the cartridge of figure 37.

Figure 43B is a cross-sectional view of the space of the bottom core and lower plate bonded to each other in the cartridge of figure 43A.

Figure 44 is a side exploded view of the bottom core and lower plate of figure 43A.

FIG. 45 is a perspective view of another embodiment of a conduit assembly.

Fig. 46 is a perspective view of the coupling sleeve of fig. 45.

FIG. 47 is a perspective view of one end of the piping component of FIG. 45.

FIG. 48 is a perspective view of one anchoring tip of the present invention.

Fig. 49 is a side cross-sectional view of the anchor tip.

FIG. 50 is a horizontal cross-sectional view taken along line XXI of an anchor tip

Fig. 51 is a space view of the rotating frame shown in fig. 35.

FIG. 52 is an enlarged view of the outer tube support.

Fig. 53 illustrates an alternative embodiment of the cartridge, having a cross-section similar to that of fig. 38.

FIG. 54 illustrates an alternative embodiment of the top core.

Fig. 55 shows an alternative embodiment of the connection sleeve.

Detailed Description

The technical features of the present invention are embodied in a permanent blood drive apparatus, a disposable photopheresis kit, the many components that make up the kit, and the corresponding therapeutic treatment process. The outline described below is as follows:

I. disposable photoseparation replacement kit

A. Cartridge for controlling liquid flow

1. Filter assembly

B. Irradiation chamber

C. Centrifugal cylinder

1. Driving tube

Permanent tower system

A. Light activated chamber

B. Centrifugal chamber

C. Liquid flow control console

1. Cassette clamping mechanism

2. Self-loading peristaltic pump

D. Infrared communication

Photopheresis treatment protocol

The above outline is summarized to facilitate understanding of the technical features of the present invention. The schema is not intended to be limiting and is not intended to categorize or limit any aspect of the invention. The invention has been described and illustrated in sufficient detail to enable those skilled in the art to readily make or use the invention. It will, however, be evident that various alternatives, modifications, and improvements may be made thereto without departing from the spirit and scope of the invention. In particular, although the present invention is directed to photopheresis treatment using disposable kits and permanent blood drive systems, certain aspects of the present invention are not so limited and may be used with kits and systems for other procedures such as apheresis or other extracorporeal blood treatment methods.

I. Disposable photoseparation replacement kit

FIG. 1 illustrates a disposable photopheresis kit 1000 embodying features of the invention. It is essential that a new disposable sterile kit be used for each treatment cycle. To facilitate circulation of fluids through photopheresis kit 1000, and treatment of blood passing therethrough, photopheresis kit 1000 is installed in a permanent tower system 2000 (FIG. 17). The manner in which photopheresis kit 1000 is installed in permanent tower system 2000 is described in more detail below.

Photopheresis kit 1000 includes cassette 1100, centrifuge bowl 10, irradiation chamber 700, hematocrit sensor 1125, removable data card 1195, processing bag 50, and plasma collection bag 51. Photopheresis kit 1000 also includes saline coupling spike 1190 and anticoagulant coupling spike 1191 for coupling a saline bag and an anticoagulant fluid bag (not shown), respectively. Photopheresis kit 1000 is provided with all necessary tubing and connectors for a photopheresis treatment cycle to fluidly circulate all of the equipment and to route the circulation of fluids. All tubing was sterile, medical grade, flexible tubing. A three port connector 1192 may be located at various locations for introducing fluid into the tubing as necessary.

Needle adapters 1193 and 1194 are provided for respectively connecting photopheresis kit 1000 to a plurality of needles for withdrawing whole blood from a patient and returning blood fluid to the patient. Alternatively, photopheresis kit 1000 may be adjusted to both draw blood from the patient and return blood to the patient using the same needle cannula. However, a two needle cannula set is preferred because it allows for the simultaneous withdrawal of whole blood and the return of blood to the patient. When photopheresis kit 1000 is hung from a patient, a closed circulatory system is formed.

Cassette 1100 acts as both a conduit organizer and a router for fluid flow. Irradiation chamber 700 is used to expose blood to ultraviolet light. The centrifuge bowl 10 separates whole blood into different components according to density. The processing bag 50 is a 1000 ml three-pocket bag. The straight binding port 52 is used to inject photoactive or photosensitive compounds into the processing bag 50. The plasma collection bag 51 is a 1000 ml two port bag. Both the processing bag 50 and the plasma collection bag 51 have a screw-cap syringe 53 for draining fluids when required. Photopheresis kit 1000 also includes hydrophobic filters 1555 and 1556 connected to pressure sensors 1550 and 1551 connected to filter 1500 via vent tubes 1552 and 1553 for monitoring and controlling the pressure in the lines connected to the patient (FIG. 10). Controlling the pressure helps to ensure that the cartridge is operated below safe pressure limits. The individual devices of the kit 1000, and their functions, will be discussed in detail below.

A. Liquid flow control cartridge

FIG. 2 is a top perspective view of a disposable cassette 1100 for valving, pumping, and controlling the flow of blood fluid during a photopheresis treatment cycle. Cassette 1100 has a housing 1101 that defines an interior space that serves as a protective enclosure for its internal components and conduits. The housing 1101 is preferably made of hard plastic, but may be made of any suitable rigid material. Housing 1101 has side walls 1104 and an upper surface 1105. Side wall 1104 of housing 1101 has tabs 1102 and 1103 extending therefrom. During a photopheresis treatment, cassette 1100 needs to be secured to deck 1200 of tower system 2000, as best shown in FIG. 25. Tabs 1102 and 1103 help position and secure cassette 1100 to deck 1200.

Cassette 1100 has inlet tubes 1106, 1107, 1108, 1109, 1110, 1111, and 1112 for receiving fluid into cassette 1100, outlet tubes 1114, 1115, 1116, 1117, 1118, and 1119 for removing fluid from outside of cassette 1100, and fluid inlet/outlet tube 1113 for either introducing fluid into or removing fluid from outside of cassette 1100. These fluid inlet and outlet tubes fluidly connect cassette 1100 to the patient being treated and to a number of devices such as centrifuge bowl 10, irradiation chamber 700, processing bag 50, plasma collection bag 51, and photopheresis kit 1000 including saline, anticoagulant containing bags, thereby forming a closed-loop extracorporeal fluid circulation circuit (fig. 27).

Pump tube loops 1120, 1121, 1122, 1123, and 1124 extend from side wall 1104 of housing 1101. Pump tubing loops 1120, 1121, 1122, 1123, and 1124 are used to help circulate fluid through photopheresis kit 1000 during treatment. More specifically, each of the pump tubing loops 1120, 1121, 1122, 1123, and 1124 is connected to a respective peristaltic pump 1301, 1302, 1303, 1304, and 1305 (FIG. 4) when cassette 1100 is secured to deck 1200 for operation. Peristaltic pumps 1301, 1302, 1303, 1304, and 1305 cause fluid to flow through each pump tubing loop 1120, 1121, 1122, 1123, and 1124 in a predetermined direction, thereby causing fluid to flow through photopheresis kit 1000 (FIG. 1) as desired. The operation and automatic loading and unloading of peristaltic pumps 1301, 1302, 1303, 1304, and 1305 will be discussed in detail below with reference to fig. 28-33.

Referring now to fig. 3, cassette 1100 and housing 1101 are shown in an exploded state. For ease of illustration and explanation, the piping inside the housing 1101 is not shown in FIG. 3. This internal piping is shown in fig. 4 and will be described in relevant part. Cassette 1100 houses a filter assembly 1500 positioned therein that is in fluid communication with inlet tube 1106, outlet tube 1114, and one end of pump tube loops 1120 and 1121. Filter assembly 1500 includes breather chambers 1540 and 1542. The filter assembly 1500 and its function will be described in detail below with reference to fig. 6-10.

Housing 1101 includes cover 1130 and base 1131. Cover 1130 has an upper surface 1105, a lower surface 1160 (FIG. 5), and sidewalls 1104. Cover 1130 also has openings 1132 and 1133 for extending vent chambers 1540 and 1542 of filter assembly 1500 therethrough. The side wall 1104 has a plurality of tube slots 1134 for connecting the inlet tube, outlet tube, and pump tubing loop into the housing 1101 with the tubing within it. To avoid the redundant numbering in the figure, only a few of the tube slots 1134 are labeled in fig. 3. Tabs 1102 and 1103 are located on side walls 1134 so as not to interfere with channel 1134. Cover 1130 has snap strips 1162 and 1162A (fig. 5) extending from lower surface 1160. The snap strips 1162 and 1162A are preferably formed in the lower surface 1160 during the formation of the cover 1130.

Base 1131 has a plurality of U-shaped tube holders 1135 extending from upper surface 1136. The U-tube holder 1135 positions the inlet tube, outlet tube, pump tubing loop, filter assembly and internal piping. In FIG. 3, only a few U-tube holders 1135 are labeled to avoid numerical redundancy. Preferably, U-tube retainers 1135 are provided at each location on base 1131 where the inlet tubes, outlet tubes, or pump tubing loops pass through tube slots 1134 in side walls 1104. Protrusions 1136 on upper surface 1136 of base 1131 mate with recesses 1161 on lower surface 1160 of cover 1130 (fig. 5). Preferably, the projections 1136 are located at or near the four corners of the base 1130 and are located near the filter 1500. The protrusion 1136 mates with the cavity 1161 to form a mating structure and secure the base 1131 to the cover 1130.

Base 1131 also includes a hub 1140. The hub 1140 is a five-way union for connecting 5 lines of internal piping. Preferably, three apertures 1137 are located adjacent to and around the three lines leading into hub 1140. Hub 1140 acts as a central coupling mechanism that, in conjunction with compression actuator 1240 and 1247 (FIG. 22), can direct fluid through photopheresis kit 1000 and into and out of the patient. In addition to hub 1140, suitable tubing connectors, such as T-connector 1141 and Y-connector 1142, are used to obtain the desired elastic tube pathway.

Five openings 1137 are located on the base of base 1130. Each aperture 1137 is surrounded by an aperture wall 1138 having an aperture channel 1139 for passage of the inner conduit portion therethrough. The base of the base 1131 also has an elongate aperture 1157 therein. Apertures 1137 are located on base 1131 and are aligned with corresponding compression actuators 1243 and 1247 on platform 1200 (FIG. 22). Aperture 1157 is located on base 1131 and is aligned with corresponding compression actuators 1240 and 1242 of deck 1200 (FIG. 22). Each aperture 1137 is sized to allow each of the compression actuators 1243 and 1247 to extend therethrough. Aperture 1157 is also sized such that three compression actuators 1240 and 1242 can extend therethrough. Compression actuators 1240 and 1247 are used to close/occlude and open some fluid pathway of the inner conduit to help or prevent the flow of liquid in the desired path. When a passage is desired to be open to allow fluid flow therethrough, compression actuator 1240 and 1247 of that passage are in a low position. Conversely, when a passage closure is desired to prevent fluid flow therethrough, the corresponding compression actuator 1240 and 1247 is raised, extending the compression actuator 1240 and 1247 through either aperture 1137 or 1157, compressing a portion of the resilient conduit toward the bottom surface 1160 (FIG. 5) of the cover 1130, thereby closing the passage. Preferably, snap bars 1163 and 1173 (FIG. 5) are located on bottom surface 1160 and aligned with compression actuators 1240 and 1247 such that a portion of the elastomeric tubing being snapped is compressed relative to snap bars 1163 or 1173. Alternatively, the snap strip may be omitted or located on the compression actuator.

Preferably, cassette 1100 has a unique identifier that enables communication and transfer of signals with permanent tower system 2000. This identifier is used to ensure that the disposable photopheresis kit is compatible with the blood drive set in which it is to be loaded, while ensuring that the photopheresis kit is capable of running the intended course of treatment. This unique identifier can also serve as a means of ensuring that the disposable photopheresis kit is of some sort of merchandise or of some sort of manufacture. In the illustrated embodiment, the unique identifier is embodied in a data card 1195 (FIG. 2) that is inserted into data card receiving slot 2001 of permanent tower system 2000 (FIG. 17). Data card 1195 has read-write capabilities and can store data relevant to the treatment process for future analysis. The unique identifier can also take many other forms, including, for example, a microchip that interacts with the blood-driven device when the kit is loaded, a bar code, or a serial number.

Cover 1130 has a data card holder 1134 for receiving data card 1195 (FIG. 1). The retainer 1134 includes four projecting ridges arranged in a broken rectangular pattern for receiving and retaining a data card to the cassette 1100. Data card holder 1134 holds data card 1195 in a fitted manner (fig. 2).

The internal circuitry of cassette 1100 will now be described with reference to fig. 1 and 4. At least a portion of the internal conduit is preferably made of a resilient plastic tube so that it can be cut by compressing the tube under pressure without compromising the sealing integrity of the tube. The internal circuitry is visible through base 1131 of cassette 1100 as shown in FIG. 4. Inlet tubes 1107 and 1108 and outlet tube 1115 are used to connect cassette 1100 to centrifuge bowl 10 (FIG. 1). More specifically, outlet tube 1115 delivers whole blood from cassette 1100 to centrifuge bowl 10, and inlet tubes 1107 and 1108 return lower density and higher density blood components, respectively, to cassette 1100 for further circulation within photopheresis kit 1000. The lower density blood components may include, for example, plasma, white blood cells, platelets, buffy coat, or combinations thereof, and the higher density blood components may include red blood cells. An outlet pipe 1117 and an inlet pipe 1112 fluidly connect cassette 1100 to irradiation chamber 700. More specifically, outlet tube 1117 delivers untreated lower density blood components, such as buffy coat, to the irradiation chamber for exposure to light energy, while inlet tube 1112 is used to return treated lower density blood components to cassette 1100 for further communication.

An inlet tube 1111 and an outlet tube 1116 connect the processing bag 50 to the cassette 1100. The outlet tube 1116 delivers untreated low density blood components, such as buffy coat, to the processing bag 50. The outlet tube 1116 has a hematocrit sensor ("HCT") operatively connected thereto to control the introduction of high density blood components, such as red blood cells. HCT sensor 1125 is a light sensing component and may be connected to a controller. When red blood cells are detected in outlet 1116, HCT sensor 1125 sends a detection signal to the controller, which takes action accordingly. The inlet tube 1111 returns untreated low density blood components in the treatment bag 50 to the cassette 1100 for further flow communication. Inlet tubes 1109 and 1110 are connected by needles 1190 and 1191, respectively, to saline and anticoagulant bags (not shown) and deliver saline and anticoagulant fluids to cassette 1100 for further fluid communication to the patient.

Inlet/outlet tube 1113 and outlet tube 1118 connect the plasma collection bag 50 to the cassette 1100. More specifically, outlet tube 1118 delivers blood components, such as plasma, to plasma collection bag 51. Inlet/outlet tube 1113 can deliver red blood cells from cassette 1100 to plasma collection bag 51 or return blood components accumulated in plasma collection bag 51 to cassette 1100 for further flow. Both inlet tube 1106 and outlet tubes 1119, 1114 are connected to the patient. In particular, outlet tube 1114 is used to return treated blood, saline, untreated blood components, treated blood components, and other fluids to the patient. Inlet tube 1106 is used to deliver untreated whole blood (and a predetermined amount of anticoagulant fluid) from a patient to cassette 1100 for circulation and processing in photopheresis kit 1000. Outlet tube 1119 is more particularly used to deliver anticoagulant fluid to inlet tube 1106. Preferably, all of the tubes are disposable sterile medical tubes. Most preferred are resilient plastic tubes.

Cassette 1100 has five pump tubing loops 1120, 1121, 1122, 1123, and 1124 for flowing blood through cassette 1100 and photopheresis kit 1000. More specifically, pump tube loop 1121 is coupled to whole blood pump 1301 and drives whole blood into and out of cassette 1100 through inlet tube 1106 and outlet tube 1115, respectively, and along the lines of filter 1500. Pump loop 1120 engages return pump 1302, forcing blood through filter 1500 and back into the patient through outlet tube 1114. Pump loop 1122 is connected to red blood cell pump 1305, which draws red blood cells from centrifuge bowl 10 and pumps them into cassette 1100 through inlet line 1108. Pump loop 1123 is coupled to anticoagulant pump 1304, pumps anticoagulant fluid into cassette 1100 through inlet pipe 1124, and pumps it out of cassette 1100 through outlet pipe 1119, which outlet pipe 1119 is coupled to inlet pipe 1106. The pump loop 1124 is coupled to a circulation pump 1303, which allows blood fluid, such as plasma, from cassette 1100 to flow through the processing bag 50 and irradiation chamber 700.

Each of the peristaltic pumps 1301-1305 is activated when photopheresis therapy according to embodiments of the method of the present invention described below with reference to FIGS. 26-27 is desired. Peristaltic pumps 1301 and 1305 may be operated together at the same time or in any combination. Pump 1301 + 1305, in conjunction with compression actuator 1240 + 1247, direct the flow of fluid in the desired path within photopheresis kit 1000. Holes 1137 and 1157 are flexibly mounted to base 1131 along the internal lines to facilitate proper routing. Through the use of compression actuators 1240 and 1247, the flow of liquid along any route or combination thereof can be directed.

1. Filter assembly

As mentioned above, the filter 1500 is located within the cartridge 1100, which will be described in detail below with reference to fig. 6-10. Referring first to fig. 6 and 7, an overview of the filter 1500 is shown in full. Filter 1500 includes filter housing 1501. Filter housing 1501 is preferably made of a transparent or translucent medical grade plastic. However, the present invention is not so limited and filter housing 1501 can be constructed of any material that will not contaminate the blood or the remaining fluid flowing therethrough.

Filter housing 1501 has four fluid connection ports protruding therefrom, namely, whole blood inlet port 1502, whole blood outlet port 1503, treated liquid inlet port 1504, and treated liquid outlet port 1505. Ports 1502-1505 are standard medical tubing connections so that medical tubing can be in fluid communication therewith. Port 1502-1505 includes openings 1506, 1507, 1508, and 1509, respectively. Openings 1506, 1507, 1508 and 1509 extend from ports 1502, 1503, 1504 and 1505, creating fluid passageways into filter housing 1501 at desired locations.

Ports 1502, 1503, 1504, and 1505 are also used to secure the filter 1500 in the cassette 1100. In this case, ports 1502, 1503, 1504, and 1505 can engage with U-shaped fasteners 1135 of cassette 1100 (fig. 3). Filter housing 1501 also has a protrusion 1510 extending from the bottom surface of housing floor 1518. The protrusion 1510 is matched with a guide hole of the base 1131 of the cartridge 1100 (fig. 3).

Referring now to fig. 8, filter 1500 is illustrated in an exploded state. Filter housing 1501 is a two-part assembly including a top frame 1511 and a base 1512. The top frame 1511 is attached to the base 1512 by any means known in the art, such as ultrasonic welding, heat welding, the use of an adhesive, or by designing the structure of the top frame 1151 and the base 1512 to form a tight bond. Filter housing 1501 may be two-piece as shown, may be a unitary structure, or may be composed of multiple pieces.

The base 1512 has a housing separation wall 1513 (FIG. 7) extending upwardly from an upper surface of the housing floor 1518. When base 1512 and roof 1511 are assembled, upper surface 1515 of housing separation wall 1513 contacts the lower surface of roof 1511, forming two internal chambers of the filtration chamber, whole blood chamber 1516 and filtration chamber 1517. Fluid cannot flow directly between the whole blood chamber 1516 and the filter chamber 1517.

Whole blood chamber 1516 is a generally L-shaped housing having floor 1514. Whole blood chamber 1516 has a whole blood inlet hole 1519 and a whole blood outlet hole (not shown) in floor 1514. Whole blood inlet hole 1519 and whole blood outlet hole are located at or near the end of the generally L-shaped whole blood chamber 1516. Whole blood inlet hole 1519 forms a channel with opening 1506 of inlet port 1502 so that fluid can flow into whole blood chamber 1516. Similarly, a whole blood outlet hole (not shown) forms a channel with opening 1507 of outlet port 1503 so that fluid can flow out of whole blood chamber 1516.

The filter chamber 1517 has a bottom plate 1520. A protruding ridge 1521 extends from the bottom plate 1520. The protruding ridge 1521 is rectangular and forms a boundary. Although the protruding ridge 1521 is rectangular in the embodiment shown, it may be any other shape as long as it forms a closed boundary. The ridge 1521 is lower in height than the housing separation wall 1513. Thus, when the top 1511 and base 1512 are assembled, the top of the ridge 1521 and the bottom surface of the top 1511 form a gap. A channel 1524 is formed between the ridge 1521 and the housing separation wall 1513.

To assist in the flow of fluid through the filter chamber 1517, the floor 1520 of the filter chamber 1517 has a treated fluid inlet 1522 and a treated fluid outlet 1523. Treated liquid inlet 1522 is located on the outer surface of the boundary defined by ridge 1521 and forms a channel with opening 1508 at inlet end 1504 to allow liquid from outside filter housing 1501 to flow into filter chamber 1517. The treated liquid outlet 1523 is located on the inner surface of the boundary formed by the ridge 1521 and forms a channel with the opening 1509 of the outlet port 1505 to allow liquid to flow out of the filter chamber 1517.

Filter 1500 also includes a filter element 1530. Filter element 1530 includes a frame 1531, and filter media 1532 is located within frame 1531. The frame 1531 has a neck 1534 that forms a filter inlet aperture 1533. Filter element 1530 is positioned within filter chamber 1517 such that frame 1531 is inserted into trench 1524 and neck 1534 surrounds treated liquid inlet hole 1522. Filter inlet hole 1533 is aligned with treated liquid inlet 1522 so that incoming liquid can flow freely through holes 1522 and 1533 into filter chamber 1517. Frame 1531 of filter element 1530 cooperates with protruding ridge 1521 to form a seal. All liquid entering filter chamber 1517 through holes 1522 and 1533 must pass through filter media 1532 before exiting filter chamber 1517 through treated liquid outlet hole 1523. Filter media 1532 preferably has a pore size of about 200 microns. Filter media 1532 may be constructed of a woven web, such as woven polyester.

Filter chamber 1517 also includes a filter vent chamber 1540 within top housing 1511. Filter vent chamber 1540 has a perforated vent 1541 (FIG. 9). Because vent 1541 leads into filter plenum 1540 and filter plenum 1540 leads into filter chamber 1517, gas accumulated in filter chamber 1517 can escape through vent 1541. Similarly, whole blood chamber 1516 includes a blood vent chamber 1542 within roof 1511. Blood vent chamber 1541 has a perforated vent 1543. Since vent 1543 opens into blood vent chamber 1542 and blood vent chamber 1542 opens into whole blood chamber 1517, gas accumulated in whole blood chamber 1516 can be released through vent 1543.

FIG. 10 shows a top view of filter 1500 having pressure sensors 1550 and 1551 coupled to vents 1541 and 1543. Pressure sensors 1550 and 1551 are preferably pressure sensors. Pressure sensor 1550 is coupled to vent 1541 via vent tube 1552. Vent tube 1552 mates with vent hole 1541 to form a tight fit and seal. Since vent 1541 opens into filter plenum 1540 and plenum 1540 opens into filter chamber 1517, the pressure in vent tubing 1552 is the same as in filter chamber 1517. By measuring the pressure on vent tubing 1552, pressure sensor 1550 measures the pressure in filter chamber 1517. Similarly, pressure sensor 1551 is coupled to vent 1543 via vent tubing 1553. Vent tube 1553 mates with vent hole 1543 to form a tight fit and seal, and pressure sensor 1551 measures the pressure of whole blood chamber 1516. When filter 1500 is positioned (fig. 2), filter vent chamber 1540 and blood vent chamber 1542 extend from openings 1132 and 1133 of cassette 1100. This allows monitoring of the pressure within chambers 1516 and 1517 while also protecting filter housing 1500 and its fluid connections.

Pressure sensors 1550 and 1551 are connected to controller 1554, which is a suitably programmed processor. Controller 1554 may be a main processor that drives the entire system or may be a separate processor coupled to the main processor. Pressure sensors 1550 and 1551 generate electrical output signals representative of the pressure readings within chambers 1517 and 1516, respectively. Controller 1554 receives frequently occurring or continuous, fundamental data representative of the pressure within chambers 1516 and 1517. Controller 1554 is programmed with values representing the desired pressures within chambers 1516 and 1517. Controller 1554 continuously analyzes the pressure values received from pressure sensors 1551 and 1550 and determines whether the pressure readings from chambers 1517 and 1516 are within a predetermined range of desired pressure values. Controller 1554 is also coupled to whole blood pump 1301 and return pump 1302. Based on the pressure values received from pressure sensors 1551 and 1550, controller 1554 is programmed to control the speed of whole blood pump 1301 and return pump 1302, thereby regulating the flow rate of liquid through pumps 1301 and 1302. Adjustments to these flow rates, in turn, may adjust the pressure in whole blood chamber 1516 and filter chamber 1517, respectively. In this way, the pressure in the line that draws blood from or returns blood to the patient is maintained within acceptable levels.

The function of filter 1500 during photopheresis treatment cycles will be described in detail with reference to figures 1, 6 and 10. The function of filter 1500 is described in detail by: whole blood is withdrawn from the patient and a processed component of the whole blood is returned to the patient, although the invention is in no way so limited. Filter 1500 may be used with any fluid, including red blood cells, white blood cells, buffy coat, plasma, or combinations thereof.

The whole blood pump 1601 draws whole blood from a patient connected to the photopheresis kit 1000 through a needle connected to port 1193. The rotational speed in an all blood pump is set such that the pressure in the line from which blood is drawn from the patient is at an acceptable level. Once withdrawn from the patient, whole blood flows into the cassette 1100 through the inlet tube 1106. The inlet tube 1106 is in fluid communication with the inlet end 1502 of the filter 1500. Whole blood enters L-shaped whole blood chamber 1516 through opening 1506 of inlet port 1502. Whole blood enters chamber 1516 through inlet aperture 1519 located in floor 1514. As more whole blood enters chamber 1516, it overflows along floor 1514 until it reaches a whole blood outlet port (not shown) at the other end of L-shaped whole blood chamber 1516. As described above, the whole blood outlet port forms a passageway with the opening 1507 of the outlet port 1503. Whole blood in chamber 1516 flows through floor 1514, through the whole blood outlet port, into outlet port 1503, and out of filter 1500 through opening 1507.

As whole blood flows through the whole blood chamber 1516, gases trapped therein escape. These gases collect in blood vent chamber 1542 and subsequently escape through vent 1543. Pressure sensor 1551 continuously monitors the pressure in whole blood chamber 1516 through vent tubing 1553 and transmits corresponding pressure data to controller 1554. Controller 1554 analyzes the received pressure data and adjusts the speed of whole blood pump 1301, if necessary, to adjust the fluid flow rate and pressure within chamber 1516 and inlet tube 1106. Controller 1554 adjusts the speed of the pump to ensure that the pressure is within the desired pressure range.

Whole blood flows out of filter 1500 through outlet port 1503 and out of cassette 1100 through outlet tube 1115. The whole blood is then separated into components and/or processed as described in detail below. The treated fluid (i.e., treated blood or blood components) must be filtered prior to reinfusion into the patient. Untreated liquids, such as red blood cells, must also be filtered and subjected to the following filtration process. Treated liquid is delivered into the filter chamber 1517 through the opening 1508 of the inlet end 1504. The inlet end 1504 is in fluid communication with the pump annulus 1120. The treated liquid enters filter chamber 1517 through inlet hole 1522 and flows through filter inlet hole 1533 of filter element 1530. The treated liquid fills filter chamber 1517 until overflowing frame 1531 of filter element 1530, which is secured over protruding ridge 1521. The treated liquid flows through the filter media 1532. The filter assembly 1532 removes contaminants and other unwanted substances from the treated liquid while also assisting in the release of gases trapped in the treated liquid. Treated liquid passing through the filter media 1532 collects on the floor 1520 of the filter chamber 1517 within the boundaries formed by the ridges 1521. The fluid then flows into the treated fluid outlet hole 1523 and out of the filter 1500 through the opening 1506 of the outlet port 1502. The treated liquid is then infused back into the patient through outlet tube 1114, which is fluidly connected to outlet port 1502. Treated liquid is driven by return pump 1302 to flow through filter chamber 1517 and outlet tube 1114.

As the treated liquid flows through filter chamber 1517, gases trapped in the treated liquid escape and accumulate in filter plenum 1540. This gas then escapes filter 1500 through vent 1541. Pressure sensor 1550 continuously monitors the pressure within filter chamber 1517 through vent 1552 and transmits corresponding pressure data to controller 1554. Controller 1554 analyzes the received pressure data and compares it to the desired pressure value and range. Controller 1554 adjusts the speed of return pump 1302, as necessary, to adjust the liquid flow rate and pressure within chamber 1517 and outlet tube 1114.

B. Irradiation chamber

Fig. 11-16 illustrate the irradiator cell 700 of the photopheresis kit 1000 in detail. Referring first to FIG. 11, an irradiation chamber 700 is formed by joining two plates, a front plate and a back plate, preferably about 0.06 inches to about 0.2 inches thick, preferably made of a material that is ideally transparent at the wavelength of electromagnetic radiation. In the case of ultraviolet a radiation, polycarbonate is most preferred, although acrylic or the like may be used. Similarly, many known attachment methods may be used herein and need not be described in further detail herein.

The first plate 702 has a first surface 712 and a second surface 714. In a preferred embodiment, the first plate 702 has a first port 705 at the first surface 712 from which fluid flows to the second surface 714. The second surface 714 of the first plate 702 has a convex boundary line 726A that defines a boundary. The boundary line 726A preferably extends substantially perpendicular (i.e., 80-100 degrees) to the second surface 714. A protruding partition member 720A extends (preferably, extends substantially perpendicularly) from the second surface 714. The boundary line 726A surrounds the partition member 720A. One end of each partition member 720A extends and contacts the border 726A.

The second plate 701 has a first surface 711 and a second surface 713. In a preferred embodiment, the second plate 701 has a second port 730 in the first surface 711, from which fluid can flow to the second surface 713. The second surface 713 of the backplate 701 has a convex boundary line 726B that defines a boundary. The boundary line 726B preferably extends substantially perpendicular (i.e., 80-100 degrees) to the second surface 713. A protruding partition member (720B) extends (preferably substantially perpendicularly) from the second surface 713. The boundary line 726B surrounds the partition member 720B. One end of each partition member 720B extends and contacts one side of the border 726B.

Joining the second surfaces of the first and second panels results in a fluid-tight connection between boundaries 726A and 726B to form boundary 726. The partition members 720A and 720B also form a liquid-tight sealed joint, thereby forming the partition member 720. Boundary 726 forms irradiation chamber 700 and, together with partition 720, provides channel 710 with channel 715 for transport of liquid. The channel may be curved, zig-zag, or dove-tail. A curved channel is preferred here.

Referring to fig. 11 and 12, irradiation chamber 700 contains a tortuous path 710 for conveying patient fluid, such as buffy coat or white blood cells, from inlet end 705 to outlet end 730, i.e., tortuous path 710 is a path for liquid transport between inlet end 705 of front plate 702 and outlet end 730 of back plate 701. Patient fluid passes from cassette 1100 to inlet port 705 through outlet tube 1117. After being activated by light and passing through the tortuous path 710, the treated patient fluid is returned to the cassette 1100 through the inlet tube 1112 (fig. 1 and 4). The flow of patient fluid is driven by the circulation pump 1303. The cells are activated by light through the radiation impact of both walls of the irradiation chamber 700, so that the self-shielding effect of the cells is reduced.

Figure 11 shows pins 740 and grooves 735 aligning the two panels of the cell before they are sealingly joined together by high frequency welding, heat pulse welding, solvent welding or adhesive bonding. It is more preferable to combine the two plates by adhesive bonding and high-frequency welding. The combination of the front and back plates is most preferably high frequency welding, since the design of the protruding partition member 720 and the perimeter 725 minimizes arcing and even allows the use of high frequency energy. The pin 740 and groove 735 may be located within or outside the curved channel 710. Figure 12 also shows a view of the cell along the L-axis. By rotating the cell 700 180 degrees about the L-axis, the original profile of the irradiation cell is given. Irradiation Chamber of the invention about the L-axis C₂And (4) symmetry.

Referring to fig. 11, 13, and 16, leukocyte enriched blood, plasma, and infusate are fed into channel 715 from inlet port 705 in front plate 702 of irradiation chamber 700. To enable the leukocyte enriched blood to be exposed to radiation over a large area and to reduce self-shielding effects due to low surface area to volume ratios, the channel 715 in the irradiation chamber 700 is relatively "thin" (e.g., the distance between the two plates is about 0.04 "). The cross-sectional shape of the channel 715 is substantially rectangular (e.g., rectangular, diamond-shaped, or trapezoidal), the distance between the partition members 720 being the long side, and the distance between the two plates being the short side. The cross-sectional shape is designed to optimize radiation to the cells flowing through the channel 715. Although the tortuous passage 710 is employed to avoid or minimize fluid entrapment zones, other arrangements may be employed.

By irradiation from optical components, e.g. PHOTOSTETE for activationTwo sets of ultraviolet lamps (758) (fig. 16), the cell 700 provides effective activation of the light activated reagents. The irradiation plate and uv lamp assembly (759) are designed for use in a device where rim 706 is oriented downward and rim 707 is oriented upward. In this orientation, liquid entering the outlet port 705 is able to flow out of the outlet port 730 under the force of gravity. In the most preferred embodiment, irradiation of both sides of the irradiation chamber occurs simultaneously while still allowing the chamber to be easily disassembled. The UV light assembly 759 is located within the UV light chamber 750 of the 59 permanent tower system 2000 (FIGS. 17 and 18).

The fluid flow path of the irradiation chamber is cycled to form two or more channels that circulate leukocyte-enriched blood during photoactivation with UVA light. Preferably, cell 700 has between 4 and 12 channels. More preferably, the cell has 6 to 8 channels. Most preferably, the cell has 8 channels.

FIG. 14 is a cut-away sectional view of an irradiation chamber. The channels 715 of the meandering channel 710 are formed by a combination of protruding partition members 720 and plate borders 726.

The irradiation chamber of the present invention may be made of biocompatible materials and may be sterilized by known methods such as heating, radiation exposure or ethylene oxide treatment (ETO).

A method of irradiating cells using irradiation chamber 700 during in vitro treatment of cells with electromagnetic radiation (uv-a) while treating a patient, such as inducing apoptosis and controlling the entry of cells into a patient, will now be discussed. Preferably, the cells treated are leukocytes.

In one embodiment of the method, the light-activatable or light-sensitive compound is first added to at least a portion of the recipient's blood prior to the in vitro treatment of the cells. Light-activatable or light-sensitive compounds may be incorporated in vivo (e.g., orally or intravenously). While oral administration may be employed, the photosensitive compound may be administered intravenously and/or by other conventional means. Oral doses of the photosensitive compound may range from about 0.3 to about 0.7mg/kg, more specifically about 0.6 mg/kg.

When administered orally, the photosensitive compound may be administered at least one hour prior to the photopheresis treatment, but not three hours prior to the treatment. If intravenous administration is used, the time should be shorter. Alternatively, the light-sensitive compound may be applied prior to or simultaneously with exposure to ultraviolet light. The light-sensitive compound may be used in whole blood or a portion of whole blood, so long as the target blood cells or blood components receive the light-sensitive compound. A portion of the blood is first treated in a known manner to substantially remove red blood cells, and then a photoactivatable compound is added to the resulting leukocyte-enriched blood fraction. In one embodiment, the blood cells comprise leukocytes, particularly T cells.

Psoralen, a photoactivatable or photosensitive compound, is capable of binding to nucleic acids when activated by exposure to electromagnetic radiation of a specified spectrum (e.g., ultraviolet light).

Compounds having photoactivity may include, but are not limited to, psoralens (or furocoumarins) and psoralen derivatives as described, for example, in U.S. patent nos. 4321919 and 5399719. According to the present invention, the light activatable or photosensitive compound includes, but is not limited to, the following: psoralen and psoralen derivatives; 8-methoxypsoralen; 4, 5', 8-trimethylpsoralen; 5-methoxypsoralen; 4-methylpsoralen; 4, 4-dimethylpsoralen; 4-5' -dimethylpsoralen; 4 'aminomethyl-4, 5', 8-trimethylpsoralen; 4 '-hydroxymethyl-4, 5', 8-trimethylpsoralen; 4', 8-methoxypsoralen; and 4 '- (omega-amino-2-oxo) alkyl-4, 5', 8-trimethylpsoralen, including but not limited to 4 '- (4-amino-2-oxo) butyl-4, 5', 8-trimethylpsoralen. In one embodiment, the light-sensitive compounds used include psoralen derivatives, amotosalen (S-59) (Cerus, concord, ca), as described in U.S. patent No. 6552286; 6469052, respectively; and 6420570. In another embodiment, light-sensitive compounds comprising 8-methoxypsoralen may also be used in the present invention.

Methoxypsoralen is a natural substance with photoactivity, and is derived from Ammi maju (a plant of Umbelliferae) seed. It belongs to a psoralen or furocoumarin compound. Its chemical name is 9-methoxy 7 hydrogen-furan [3, 2-g][1]-benzopyran-7-one. The drug was formed by filling sterile liquid at a concentration of 20mcg/mL in a 10 mL vial. Reference may be made to http:// www.therakos.com/TherakosUS/pdf/uvadexpi. The investigator's manual contains in vitro photopheresis and UVADEXToxicology studies of uv light in various doses and beagle dogs.

Subsequently, the host, acceptor, or donor blood fraction to which the photoactive compound has been added is subjected to photopheresis treatment by ultraviolet light. The photopheresis treatment may be performed by long-wave Ultraviolet (UVA) light having a wavelength of 320 nm to 400 nm. This wavelength range is described here as an example only, however the range is not limited thereto. During the photopheresis treatment, the exposure time to ultraviolet light should be long enough to deliver, for example, approximately 1-2 joules per square centimeter of irradiation energy to the blood.

The photopheresis step is performed ex vivo by installing cell 700 into photoactivation chamber 750 of permanent tower system 2000 (FIGS. 17 and 18). In one embodiment, when the photopheresis step is performed ex vivo, at least a portion of the treated blood is returned to the subject, recipient, or donor. The treated blood or leukocyte enriched blood fraction (as may occur in the present invention) may then be returned to the subject, recipient, or donor.

The photopheresis process consists of three stages, including: 1) collection of the buffy coat fraction (enriched with white blood cells), 2) irradiation of the collected buffy coat fraction, and 3) return of the treated white blood cells. This process will be described in more detail below. In general, whole blood is centrifuged and separated in the separation cartridge 10. A total of approximately 240 ml of buffy coat and 300 ml of plasma were separated and stored for the uv irradiation process.

Collected plasma and buffy coat with heparinized normal saline and UVADEX(8-methoxypsoralen dissolved in water) were mixed. The mixture was passed through the cell of the invention in a 1.4 mm thick layer. Irradiation chamber 700 at PHOTOSTEEThe two sets of UVA lamps (fig. 15) are embedded in optically activated chamber 750 of tower system 2000. PHOTOSTEEThe uv lamp of (a) irradiates both walls of the uv-transparent irradiation chamber 700 so that the irradiation chamber is exposed to uv-rays a, resulting in an average exposure energy per lymphocyte of 1-2 joules/square centimeter. After the light activation process, the cells are removed from irradiation chamber 700.

In a preferred embodiment of the invention, the cells are removed by gravity and any cells remaining in the irradiation chamber are replaced by additional fluid selected from the group consisting of saline, plasma and combinations thereof. For small patients, such as small children (e.g. less than 30 kg) or those whose vascular system is easily overloaded, the additional fluid used for the irradiation chamber preferably does not exceed 2 times the volume of the chamber, more preferably does not exceed 1 time the volume of the chamber, more preferably does not exceed 0.5 times, more preferably is 0.25 times. The treated cell solvent is reinjected into the patient.

Similar light separation displacement systems and methods are described in U.S. patent application serial No. 09/480893, the disclosure of which is incorporated herein by reference. Equally useful systems and methods are described in U.S. patent nos. 5951509, 5985914, 5984887, 4464166, 4428744, 4398906 and 4321919; PCT publication Nos. WO 97/36634 and WO97/36581 are also described in PCT applications, all of which are incorporated herein by reference.

An effective amount of light energy to be delivered to a biological fluid can be determined using the method and system described in U.S. patent No. 6219584, which is also incorporated herein by reference in its entirety. Of course, the application of extracorporeal photopheresis to the various diseases described herein requires the adjustment of the light energy values to optimize the treatment process.

In addition, the photosensitizing factors used in extracorporeal photopheresis may be removed prior to returning the treated biological fluid to the patient. Such as methoxsalen (UVADEX)) Is used in extracorporeal photopheresis. Methoxsalen belongs to one of psoralen compounds. Exposure to methoxsalen or other psoralen compounds may have adverse effects on the subject, recipient or donor, such as phototoxicity or other toxic effects associated with psoralens and their breakdown products. Therefore, psoralen derivatives, or psoralen decomposition products that may remain in the biological fluid may be removed after being irradiated with ultraviolet light. U.S. patent No. 6228995, the disclosure of which is incorporated herein by reference in its entirety, describes a psoralen biological fluid removal process.

C. Centrifugal cylinder

In a particular embodiment, the present invention relates to methods and apparatus for separating liquid components, for example, according to density or weight of biological fluids. Biological fluids include those fluids that contain, exist in, or are applied to, or delivered to, living organisms. Of course, the biological fluid may be a body fluid and its components, such as blood cells, plasma, but also other fluids containing biological components, such as bacteria, cells or other cellular components. The biological fluid may be whole blood or a specific whole blood component, including red blood cells, platelets, white blood cells, and precursor cells. Particularly during procedures such as extracorporeal treatments, blood needs to be removed from the patient for treatment. It should be understood, however, that the present invention may be practiced with many centrifugal processing apparatuses and that the specific embodiments presented herein are for illustrative purposes only. Other uses for the separation techniques and devices of the present invention may include other medical procedures such as dialysis, chemotherapy, platelet separation and removal, and the separation and removal of remaining specialized cells. Furthermore, the invention may be used to separate other types of liquids, including many liquids having non-medical uses such as oil and liquid components. All of the components used in the present invention should not have a negative effect on biological fluids or render them unsuitable for their intended use, such as those described herein, and may be made of any suitable and compatible material for use herein, including but not limited to plastics, such as polycarbonate, methacrylate, styrene-acrylonitrile, acrylic, styrene, acrylonitrile, or other plastics. Where the components of the invention are to be bonded together and form a liquid-tight seal, any suitable, conventional means of joining the components may be used, including: using adhesives, ultrasonic welding, or high frequency welding, but not limited to the above.

The present invention has several advantages for using a conventional Latham bowl centrifuge. UVARXTS^TMThe Latham bowl in the system has an inlet port for whole blood into the centrifuge bowl and an outlet port for plasma and buffy coat to flow out of the centrifuge bowl. This limits the number of buffy coats collected per cycle, since there are only two ports. Each cycle includes injecting whole blood into the centrifuge bowl; 2) rotating the centrifuge bowl to thereby separate whole bloodSeparating into plasma, buffy coat, and red blood cells; 3) collecting the buffy coat for treatment, 4) stopping the operation of the centrifuge bowl; and 5) returning the collected plasma and red blood cells. This buffy coat collection method can be characterized as "batch-wise" because the desired amount of buffy coat for irradiation treatment can only be obtained by several cycles of buffy coat collection. Because the accumulated red blood cells linger within the centrifuge bowl, only a limited number of buffy coats can be collected per cycle. Therefore, the accumulated red blood cells can only be emptied at the end of each buffy coat collection cycle, which is an inherent limitation of the Latham cartridge.

The centrifuge bowl of the present invention has three separate liquid tubes as one inlet end and two outlet ends. This additional liquid conduit has the following functions: 1) by continuing to spin throughout the buffy coat collection process without stopping the centrifuge bowl from spinning to remove accumulated red blood cells, the patient's treatment time is reduced; 2) patients with low blood counts can be treated by continuously returning collected red blood cells to the patient, who are more likely to receive medical procedures requiring the use of the buffy coat or a portion thereof, such as extracorporeal photopheresis; 3) due to the increased spin centrifugation time, the different cellular components in the buffy coat are better separated; and 4) the ability to separate high density red blood cell components from whole blood. The centrifuge bowl also allows for reduced processing time for any medical procedure requiring collection of a buffy coat fraction substantially free of red blood cells from a patient, such as extracorporeal photopheresis.

To the accomplishment of the foregoing and related ends, the invention, then, is particularly and broadly described and illustrated in FIGS. 35 and 36, respectively. The embodiment shown in FIG. 35 includes a centrifuge bowl 10A, duct assembly 860A, frame 910A, and stationary restrictor 918A. Fluid is communicated between the centrifuge bowl 10A and the outer tube 20A of the tube assembly 860A. Lower end 832A (fig. 46) of connecting sleeve 500A is secured to cartridge 10A. Upper end 831A of coupling sleeve 500A is secured to outer tube 20A, coupling outer tube 20A with cartridge 10A, placing outer tube 20A in fluid-coupling communication with the interior of cartridge 10A. This communicative coupling enables the supply of liquid 800 to cartridge 10A through outer tube 20A. Likewise, this fluid communication also enables the separated liquid components 810 and 820 to be removed from cartridge 10A through outer tube 20A. The adjustment cylinder 10A and the frame 910A rotate about the central axis 11A.

Referring to fig. 36, cartridge 10A includes housing 100A, coupling sleeve 500A, top core 200A, bottom core 201A, and housing floor 180A. Outer shell 100A may be made of any biocompatible material as previously described, and as shown in FIG. 36, outer shell 100A is made of a clear plastic, so that inner cores 200A and 201A are visible in this view. The housing 100A is adhered to a base plate 180A that includes a projection 150A for locking the cartridge 10A to a rotating device such as a rotating apparatus 900A. Cartridge 10A is preferably a device that is simple in construction and easy to produce by molding or other known manufacturing processes, for example, it may be disposable or used only for a limited number of treatments, and most preferably contains 125 ml of liquid, which may be pressure-sealed. In another embodiment, the throughput of the cartridge may vary depending on the patient's condition and the amount of extracorporeal blood he or she is allowed to. The throughput of the cartridge may also vary depending on the use of the cartridge or depending on the particular treatment process for which the cartridge is used. Furthermore, to avoid contamination of the biological fluid, or to avoid contact with the biological fluid by persons involved in the treatment operation, the transfer process is preferably carried out in a sealed fluid system, possibly hermetically pressurized, preferably formed of a resilient plastic or similar material which is convenient to handle after each use.

As shown in fig. 36 and 37, the housing 100A is substantially conical in shape having an upper housing end 110A, a housing wall 120A and a lower housing end 190A. The housing 100A may be made of plastic (such as those listed above), or other suitable material. The upper shell end 110A has an outer surface 110B, an inner surface 110C and an outlet 700A in the shell that forms a passageway between the surfaces. Preferably, the upper shell also defines a neck 115A corresponding to the shell outlet 700A. The shell outlet 700A and neck 115A are sized to allow the body 830A of the coupling sleeve 500A to pass therethrough while at the same time retaining the sleeve flange 790A extending from the body 830A of the coupling sleeve 500A. In one embodiment of the present invention, an O-ring 791A may be inserted between sleeve flange 790A and inner surface 110C of housing end 110A to provide a liquid-tight seal. In another embodiment of the present invention as shown in fig. 53, a second sleeve flange 790B extends from the body 830A of the coupling sleeve 500B at the end of the sleeve flange 790A. Both sleeve flanges 790A and 790B fit within neck 115A and retain O-ring 791A therein. In this embodiment, a liquid-tight seal is formed by the O-ring in contact with the body 830A and the inner surface 110C of the shell end 110A adjacent the neck 115A. However, the adapter sleeve 500A may be secured to the barrel 10A by any suitable means, including, for example, by a flange, groove, or close fit, and bonded to one of the components of the barrel 10A with an adhesive. A housing wall joins upper housing end 110A and lower housing end 190A. Lower housing end 190A is attached to housing floor 180A at a diameter greater than upper housing end 110A. Housing floor 180A mates with lower housing end 190A and forms a liquid-tight seal therewith. Any conventional means may be used to secure lower shell end 190A to shell floor 180A, including but not limited to adhesives, ultrasonic welding, or high frequency welding. Housing floor 180A may have a serrated recess 185A for collecting more concentrated liquid 810. The diameter of the housing 100A increases from the superior housing end 110A to the inferior housing end 190A.

The housing 100A may be adapted to rotatably couple to a rotating device 900 (fig. 35), such as a rotor drive system or a rotating bracket 910. The rotatable connection may be, for example, a bearing that allows the cartridge 10A to rotate freely. Preferably, the housing 100A has a locking mechanism. The locking mechanism may be one or more projections 150A designed to interact with corresponding indentations in the centrifuge container, or other suitable interconnection or locking mechanisms or similar structures known in the art. The locking mechanism may also include a keyway 160 (fig. 51).

Referring to FIG. 37, outer shell 100A and base 180A define an interior chamber 710A within which inner cores 200A and 201A mate with one another when cartridge 10A is assembled. When fully installed, inner cores 200A and 201A are disposed entirely within lumen 710A of shell 100A, occupying a coaxial volume of lumen 710A along axis 11A.

Referring to fig. 38, 40 and 44, top core 200A and bottom core 201A are substantially conical and have respective core top ends 205A, 206A; the outer nuclear wall 210A, 211A; and a nucleus bottom end 295A, 296A. Cores 200A and 201A occupy a coaxial volume of interior 710A of cartridge 10A and form a separation space 220A between core top end 205A and core outer wall 210A of top core 200A, core outer wall 211A and core bottom end 296A of bottom core 201A, and shell 100A. Separation space 220A is the void of lumen 710A between cores 200A and 201A and outer wall 100A.

As shown in fig. 40 and 41, the apical nucleus 200A includes a nucleus apical end 205A and a nucleus basolateral end 295A connected by a nucleus outer wall 210A. The core outer wall 210A has an outer surface 210B, an inner wall surface 210C, and a bottom edge 210D. Preferably, the diameter of the apical nucleus 200A increases from the nucleus apical end 205A to the nucleus basolateral end 295A. The core tip end 205A also includes an outer surface 205B and an inner surface 205C. Located on the central axis and extending perpendicularly from the upper surface 205B is the lumen connector 481A. Lumen connector 481A has an upper surface 482A and a wall 482B. The upper surface 482A has two channels 303B and 325D that allow fluid flow between the core tip end 205A and the second bowl channel 410A and the first bowl channel 420A, respectively. Second barrel inner passage 410A is a conduit having a wall 325A extending perpendicularly from an inner surface 481C of lumen connector 481A.

39B, 39A and 40, second cartridge channel 410 and catheter channel 760A communicate through a conduit 321A having a first end 321B and a second end 321C adapted to be inserted into conduit lumen connection 481A. In operation, liquid is communicated between conduit 760A of outer tube 20A and bowl channel 410A. The first intra-barrel channel 420A is an auxiliary conduit having a channel wall 401A extending substantially perpendicularly from the inner surface 481C of lumen connector 481A. 39A, 39B and 40, fluid is communicated between the first bowl channel 420A and the conduit 780A of the outer tube 20A through a hollow cylindrical cavity 322A having a first end 322B and a second end 322C that mates with the opening 303B of the upper surface 482A. As described in one embodiment of the present invention, the second in-barrel channel 410A is disposed in the first in-barrel channel 420A. In another embodiment of the present invention as illustrated in FIG. 53, duct wall 325A may be comprised of an upper member 325F and a lower member 325G, and may merge with duct walls 401A and 402A.

The upper surface 482A also has indentations 483A that allow it to communicate with the chamber 740A. When assembled, chamber 740A is defined by lumen mount recess 851A, which is smaller in volume than hollow cylinder lumens 321A and 322A to which coupling sleeve 500A and lumen connector 481A are coupled. The chamber 740A is fluidly connected to the conduit 770A and communicates with the separation space 220A adjacent the neck 115A via the serrated grooves 483A. The channels formed by the indentations 483A allow the second separated liquid component 820 to be removed through the chamber 740A. A plurality of pads 207A extending from the outer surface and contacting the inner surface 110C of the upper housing end 110A are optionally present on the outer surface 205B to provide fluid communication between the separation space 220A and the passage formed by the indentations 483A.

In another embodiment as shown in fig. 53, 54 and 55, 321A and 322A may be attached to openings 325D and 303B in upper surface 482A of lumen connector 481A. In addition, the serrated grooves 483A may form a large number of channels in the lumen connector 481A and may be used to form the chamber 740B when connected to the cannula 500A or 500B. The chamber 740B is adapted to have one or more surfaces 742A that mate with the protruding end 853A of the connection sleeve 500A (the protruding end 853 surrounds the end 861 of the outer tube 20A). To assist in proper positioning of the connection sleeve to lumen connector 481A, the shape of the raised end 853A and chamber 740B may be asymmetrical, or as illustrated in FIGS. 53, 54 and 55, a guide member 855A is provided that extends from the upper surface of lumen connector 481A and mates with opening 857A of sleeve flange 790A.

Referring again to FIG. 40, the bottom core end 295A is formed by an upper plate 299A having an upper surface 298A, a lower surface 297A, and an edge 299B which is attached to and in direct contact with the bottom edge 210D of the outer core wall 210A. The edge 299B of the upper plate 299A is adapted to engage the bottom edge 210D on the outer core wall 210A and form a liquid-tight seal thereat. Extending perpendicularly from the upper surface 298A of the upper plate 299A is a channel wall 402A having an upper end 402B and a lower end 402C and surrounding an opening 303A located substantially in the center of the upper plate 299A. A plurality of tabs 403A are attached to the outer surface of wall 402A and upper surface 298A for supporting shaft cavity wall 402A. This wall 402A is adapted to mate with wall 401A to form a liquid-tight seal and provide lumen 400A. Liquid is communicated between first bowl channel 420A and conduit 780A of outer tube 20A via conduit 322A. Opening 303A allows liquid to flow from lumen 400A into separation space 220A, as will be further described below. The first bowl channel 420A also surrounds the second bowl channel 410A.

Referring to fig. 43A, 43B and 44, bottom core 201A is comprised of upper core end 206A, outer core wall 211A and bottom core end 296A. The outer core wall 211A has an outer surface 211B, an inner wall 211C and a bottom edge 211D. The diameter of bottom core 201A preferably increases from upper core end 206A to lower core end 296A. Bottom core 201A also has an upper surface 309A and a lower surface 309B. The upper core end 206A has a serrated recess 186A in its surface 309A substantially at its center, preferably substantially circular. The indentation 186A has an upper surface 186B and an inner surface 186C. The upper surface 186B of the indentation 186A has an opening 324D extending to the inner surface 186C. In another embodiment of the invention as shown in FIG. 53, the upper surface 186B may also have a recess 186D for receiving an O-ring to form a liquid-tight seal around the bottom end 325B of the tube wall 325A. Extending perpendicularly from the inner surface 186C around the opening 324D is a tubular wall 324A having a distal end 324B. Above the upper surface 309A, one or more channels 305A extend from the indentation 186A to the outer surface 211B of the outer core wall 211A. The upper surface 309A may be horizontal or sloped upward or downward from the serrated recess 186A. If upper surface 309A slopes upward or downward from indented notch 186A to nucleus end 206A, one skilled in the art can adjust the shape of upper plate 299A and upper nucleus end 295A accordingly. The channel 305A may have an equal depth throughout its length. However, the channel 305A is radially inclined upward or downward from the center. This should be understood by those skilled in the art to be the case: if the upper surface 309A is sloped upward or downward and the channel 305A is of constant depth, then the channel 305A should also slope upward or downward accordingly.

Referring to fig. 38, when fully assembled, the bottom surface 29A of the upper plate 299A directly contacts the upper surface 309A of the bottom core 201A. This contact forms a liquid-tight seal bond between the two surfaces and forms an opening 305B between the serrated groove 186A to the channel 305A. A second opening 305C from the channel 305A is formed in the outer surface 211B of the outer core wall 211A. The openings 305B allow liquid to flow from the serrated groove 186A into the separation space 220A through the channels 305A and openings 305C (FIGS. 38 and 40). The liquid 800 thus flows through conduit 780A and then through the first bowl channel 420A. After exiting the first bowl channel 420A, the liquid 800 flows through channel 305 into separation space 220A.

Referring to FIGS. 43A and 44, the bottom core end 296A has a bottom plate 300A with an upper surface 300B, a lower surface 300C and an outer edge 300D. One or more protruding members 301A extend from the lower surface 300C of the base plate 300. The outer rim 300D is adapted to be attached to the bottom edge 211D of the outer core wall 211A and provide a liquid-tight, sealed bond therewith. The bottom plate 300A sits on top of the housing bottom plate 180A, is circular in shape and curves radially upward from its center (as shown in fig. 44). Alternatively, the base plate 300A may be flat. When seated on housing floor 180A, a space 220C is present between floor 300A and housing floor 180A, as shown in fig. 38. Liquid can flow between this space 220C and the separation space 220A. The base plate 300A may be made of plastic or other suitable material. Further, the duct 320A extends substantially vertically from the lower surface 300C of the base plate 300A. Conduit 320A has a first end 320B extending into space 220C between base plate 300A and housing floor 180A and a second end 320C extending above upper surface 300B of base plate 300A. The diameter of conduit 320A is suitably sized to form a tight fit with the end 324B of the conduit wall. The space between tube walls 324A and 325A includes a lumen 400B. The space defined by the bottom plate 300A, the inner surface 211C, and the top plate 253A of the bottom core 201A, excluding the second bowl channel 410A, may contain gas or solid matter (see fig. 43B and 44).

In another embodiment of the invention as shown in FIG. 53, support walls 405A and 407A may optionally be present in a centrifuge bowl. Support wall 405A extends perpendicularly from lower surface 309B. Support wall 407A extends perpendicularly from the upper surface 300B of base plate 300A and is connected to support wall 405A when the base core 201A is assembled. Tube wall 324A may be joined to tube 320A to form a liquid-tight seal, and tubes 324A, 320A may be fused together with support walls 405A and 407A, respectively. Also extending from the lower surface 300C of the base plate 300A are one or more locating pads 409A that fit snugly into the serrated recess 185A.

As will be apparent to those of ordinary skill in the art, the cartridge 10A needs to be balanced with respect to the central axis 11A. Thus, to assist in balancing the cartridge 10A, a counterbalance needs to be added as part of the apparatus, such as counterbalance 408A shown in FIG. 53.

Referring to FIG. 38, cartridge 10A is adapted so that outer shell 100A, inner cores 200A and 201A, bottom plate 300A and upper plate 299A of the cores, bottom plate 180A of the shells, outer tube 20A and coupling sleeve 500A, and lumens 400A and 400B are connected to one another and rotate together. The case bottom plate 180A of the case 100A includes recesses 181A on the upper surface thereof, and the recesses are shaped to engage with the protruding parts 301A of the bottom plate 300A. As shown, bottom surface 300C of bottom plate 300A has a rounded protrusion 301A for limiting movement of bottom plate 300A relative to housing bottom plate 180A. When assembled, each of the protruding members 301A on the bottom surface of the base plate 300A is tightly coupled to the recess 181A on the base plate 180A. Thus, as outer tube 20A and coupling sleeve 500A, top core 200A, upper plate 299A, bottom core 201A, lower plate 300A, housing bottom plate 180A, and lumens 400A and 400B rotate as well, as outer tube 100A rotates.

As shown in FIG. 38, lumen 400A allows whole blood 800 to flow into cartridge 10A through first in-cartridge passage 20A. First bowl channel 420A provides a path for influent 800 to zigzag grooves 186A through lumen 400A and then to separation space 220A through channel 305A. Lumen 400A is located within upper core 200A. Lumen 400A has a height from lumen upper end 480A to lumen lower end 402C. Lumen 400A is formed by the connection of channel wall 401A extending from inner surface 481C of lumen connector 481A and channel wall 402A extending from upper surface 298A of upper plate 299A. Channel wall 401A is supported by a plurality of fins 251A attached to inner wall surface 210C of core outer wall 210A and inner wall surface 205C of upper core end 205A, and channel wall 402A is supported by a plurality of fins 403A (FIG. 40). It is apparent that the height of lumen 400A can be adjusted by varying the size and shape of core 200A, channel wall 401A, channel wall 402A, duct wall 325A, and varying the height of duct wall 324A.

As shown in FIG. 38, shaft lumen 400A, from upper end 480A to lower end 402C of the shaft lumen, encloses a shaft inner housing 400B. The lower end 402C of the lumen has an opening 303A which communicates with the separation space 220A through a plurality of channels 305A. In the illustrated embodiment, shaft cavity 400A includes a first barrel passage 420A. The second bowl channel 410A is located within the first bowl channel 420A of the upper core 200A and is surrounded by a shell from the lumen upper end 480A to the lower end 402C. Moreover, to remove first liquid separation component 810 that collects in serrated groove 185A of housing floor 180A, second bowl channel 410A forms a pathway from beneath floor 300A through housing 400B. Second bowl channel 410A extends from shell floor 180A of outer shell 100A, through shaft housing 400B, to conduit 760A of outer tube 20A.

Referring to FIG. 38 (conduit 321C not shown), shaft lumen 400B allows red blood cells 810 to exit cartridge 10A through second cartridge interior channel 410A, which allows fluid communication between the bottom of the shell above serrated groove 185A and opening 324E. Lumen 400B has an upper conduit end 325C and a lower conduit end 324B and includes two conduit walls 324A and 325A which are joined in a fluid-tight manner and form a second bowl channel 410A which is smaller in diameter than first bowl channel 420A and which is separate from the first bowl channel. Duct wall 325A is supported by fins 251A that extend through duct wall 401A and attach to duct wall 325A. Unlike shaft lumen 400A, which has a distal end adjacent to indented notch 186A, shaft lumen 400B extends distally of indented notch 186A and through base plate 300A. First tubular wall 325A has an upper end 325C with an opening 325D in the upper surface 482A of lumen connector 481A, and a lower end 325B with an opening 325E for mating with upper end 324C of tubular wall 324A. Upper end 324C of tube wall 324A is above indentation 186A and has an opening 324D. Tube wall 324A also has a bottom end 324B and is supported by a plurality of fins 252A. Bottom end 324B having opening 325E is adapted to be connected to conduit 20A having opening 302A located near the center of bottom plate 300A. The connection of openings 325E and 302A allows fluid communication between interior chamber 400B and space 220C, which is located between bottom plate 300A and housing bottom plate 180A. And space 220C between bottom plate 300A and housing bottom plate 180A has a fluid path with separation space 220A.

Conduit 320A forms a tight fit with bottom end 324B, thereby supporting second bowl channel 410A. Each of the in-barrel passages 420A and 410A may be formed by: any flexible or rigid tube (e.g., medical tubing), or other device that provides a sealed passageway for fluids that may or may not be pressurized, for example, and is preferably disposable and sterilizable, i.e.: is convenient for simple and effective production.

1, driving the tube

As shown in fig. 39A and 39B, the conduit assembly 860A is attached to the cartridge 10A by a coupling sleeve 500A that is attached over the first end 861A of the outer conduit 20A, which has a first conduit 780A, a second conduit 760A, and a third conduit 770A. Fluid may be communicated between each conduit and first bowl channel 420A, second bowl channel 410A, and bowl chamber 740A. The three pipes are spaced apart from each other at an angle of 120 degrees in the outer pipe 20A and have the same diameter (see fig. 50). When fluidly coupled to outer tube 20A and cartridge 10A, conduit 780A is fluidly coupled to first cartridge passage 420A for introducing liquid 800 from outer tube 20A to cartridge 10A for separation. Similarly, second conduit 760A is fluidly connected to second bowl channel 410A for moving the first separated liquid component from bowl 10A to outer tube 20A. Finally, third conduit 770A is connected to cartridge chamber 740A to remove second separated liquid component 820 from cartridge 10A.

As shown in FIG. 45, the outer tube 20A has a connection sleeve 500A at a first end 861A and an anchor sleeve 870A at a second end 862A. Optionally, between the connection sleeve 500A and the anchor sleeve 870A on the outer tube 20A may be a first shoulder 882 and a second shoulder 884 extending perpendicularly from the outer tube 20A and having a larger diameter. Between the connection sleeve 500A and the anchor sleeve 870A (or the first and second shoulders 882, 884 if they are present) are first and second bearing rings 871A and 872A. The outer tube 20A, anchor sleeve 870A, and connector sleeve may be made of the same or different biocompatible materials, which should have suitable strength and flexibility for use as tubing in a centrifuge (one such preferred material is HYTREL @)). The connection sleeve 500A and anchor sleeve 870A may be joined by any suitable means, such as with an adhesive, welding, etc., however, for ease of manufacture, the connection sleeve 500A and anchor sleeve 870A are preferably molded over the outer tube 20A.

Referring to fig. 45, 48 and 49, anchor sleeve 870A includes a body 877B having a first anchor end 873A and a second anchor end 874A. Anchor sleeve 870A is attached to second tube end 862A of outer tube 20A (preferably by molding) and increases in diameter from first collar 873A to collar 874A. Positioned distally of the second end 874A is a collar 886A extending perpendicularly from the body 877B and having a larger diameter than the body 877B of the anchor sleeve 870A. Attached to the body 877B is a plurality of reinforcing ribs 877A having a first rib end 877B located between the collar 886A and the second anchor end 873A and a second rib end 877C extending distally of the first anchor end 873A. The second anchor ends 877C are joined together by a loop 880A, which is also attached to the outer tube 20A. The ribs 877A are parallel to the outer tube 20A and are preferably located above where the conduits 760A, 770A, and 780A are closest to the surface of the outer tube 20A (FIG. 50). If no reinforcement is applied to the tubes 760A, 770A, and 780A proximate the outer diameter of the outer tube 20A, the tubes are prone to failure at high rotational speeds. The provision of ribs parallel to the conduit beyond the anchoring sleeve end 873A provides a reinforced structure there to prevent conduit failure at high rotational speeds. In one aspect, the ribs prevent deformation of the outer tube 20A thereat and act as a structural element to transfer torsional stresses to the anchor sleeve 870A.

The coupling sleeve 500A includes a tubular body 830A having an upper sleeve end 831A and a lower sleeve end 832A (fig. 46 and 47). Lower sleeve end 832A has a sleeve flange 790A and a plurality of projections 843A sized to engage serrated recesses 484A on wall 482A of housing connector 481A. When the cartridge 10A is assembled, a liquid-tight seal may be formed by surrounding the body 830A with the O-ring 791A and compressing the O-ring 791A between the flange 790A and the housing 100A. The upper sleeve end 831A is adapted to be secured to the outer tube 20A. Referring to FIGS. 46, 39A and 39B, a coupling sleeve 500A is secured to the cartridge 10A by a sleeve flange 790A and is adapted to communicate fluid between the passages 780A, 760A, 770A of the outer tube 20A and the channels 420A and 410A within the cartridge, as well as the chamber 740A within the cartridge 10A. When the connection sleeve 500A is assembled, it is mounted to the lumen connector 481A (FIGS. 39A and 39B).

Preferably, the coupling sleeve 500A increases in diameter from the upper sleeve end 831A to the lower sleeve end 832A and is molded over the first conduit end 861A of the outer tube 20A. Coupling sleeve 500A couples barrel 10A to outer tube 20A without the use of a rotatable seal arrangement that would otherwise be conventionally positioned between barrel 10A and coupling sleeve 500A. The sealless arrangement between the barrel 10A and the adapter sleeve 500A may be as set forth above, or may be by use of, for example, an O-ring, groove, or flange, metal oil seal type connection, welding, or the use or absence of an adhesive within the barrel 10A or adapter sleeve 500A to form a tight bond.

As shown in fig. 46 and 39B, sleeve flange 790A has a bottom surface 847A that contacts upper surface 482A of lumen connector 481A to form a tight seal. However, lumen connector 481A has a plurality of saw-tooth shaped grooves 483A that allow fluid communication between separation chamber 220A and cartridge chamber 740A, which communicates with conduit 770A. Cartridge chamber 740A is defined by chamber mounting recess 851A, the upper surface 482A of chamber connector 481A, excluding the space occupied by hollow cylinders 321A and 322A. A plurality of projections 843A on the bottom surface 847A of sleeve flange 790A engage and slide into serrated grooves 484A on wall 482B of lumen connector 481A, thereby providing a tight fit.

Coupling sleeve 500A assists in securing outer tube 20A to barrel 10A, and thus outer tube 20A is fluidly coupled to barrel 10A. This flow-through connection allows liquid 800 to be supplied to cartridge 10A through outer tube 20A. Likewise, this flow-through connection also allows the separated liquid component b, 820 to be removed from the cartridge 10A through the outer tube 20A.

The outer tube 20A has a substantially constant diameter which should help to reduce the rigidity of the tube. The outer tube 20A having too high rigidity will heat up more quickly to cause a failure. Furthermore, fixed diameter pipes are inexpensive and easy to manufacture, and the dimensions of the connection sleeve 500A and the anchor sleeve 870A can be easily tested, and also allows the bearing rings 871A, 872A to slide in. Preferably, the sliding movement of the bearing rings 871A and 872A is inhibited by the first and second shoulders 882A and 884A. The outer tube 20A is formed of any form of flexible tubing (e.g., medical tubing), or device such as a device that provides a sealed passageway for the flow of liquid, which may be pressurized into or out of any form of reservoir, and is preferably disposable and sterilizable.

II, permanent tower system

Fig. 17 illustrates a permanent tower system 2000. Tower system 2000 is constructed of a durable (i.e., non-disposable) metal component that houses a number of devices of photopheresis kit 1000, such as cassette 1100, irradiation chamber 700, and centrifuge bowl 10 (FIG. 1). Tower system 2000 performs the following operations: the fluid passing through the disposable photopheresis kit is controlled by a valve, conveyed by a pump and comprehensively controlled and driven. Permanent tower system 2000 automatically performs all necessary control functions by coupling to all necessary components using a suitably programmed controller, such as a processor or integrated circuit. Tower system 2000 is reusable, as opposed to a new disposable kit that must be discarded after each photopheresis treatment cycle. Tower system 2000 may be adapted to perform a number of extracorporeal blood circulation procedures, such as apheresis, by suitably programming the controller or changing certain components thereof.

Tower system 2000 has a body with an upper portion 2100 and a base portion 2200. Base portion 2200 has a top 2201 and a bottom 2202. Wheels 2203 are located at or near the bottom 2202 of base 2200 so tower system 2000 is mobile and easily moved from room to room in the hospital. Preferably, front wheel 2203 is rotatable about a vertical axis to facilitate maneuvering tower system 2000. The top 2201 of the base 2200 has an upper surface 2204 with a console 1200 constructed on the upper surface (see fig. 22), which is best illustrated in fig. 22. In fig. 17, the cassette 1100 is loaded into the console 1200. The base 2200 also has hooks (not shown), or other connectors, for hanging the plasma collection bag 51 and processing bag 50 therefrom. Such hooks may be located anywhere on tower system 2000 so long as their location does not interfere with the function of the system during treatment. Base 2200 has light activated chamber 750 (fig. 18) located behind door 751. Additional hooks (not shown) are provided in tower system 2000 for hanging saline and anticoagulant bags. Preferably, these hooks are positioned on the upper portion 2100.

Optically activated chamber 750 (FIG. 18) in base 2200 of tower system 2000 is located between base top 2201 and bottom 2202 behind door 751. Door 751 is hingedly attached to base 2200 and provides access to optically active chamber 750, through which an operator may close optically active chamber 750 so that ultraviolet light does not escape into the surrounding space during treatment. Recess 752 is used to allow tubes 1112, 1117 (FIG. 1) to pass into photoactivation chamber 750 when irradiation chamber 700 is loaded and door 751 is closed. The light activated chambers will be described in detail below with reference to fig. 16 and 18.

The upper portion 2100 is positioned above the base 2200. Centrifuge chamber 2101 (fig. 19) is located within upper portion 2100 behind centrifuge chamber door 2102. Centrifuge chamber door 2102 has a window 2103 so that the operator can see inside centrifuge chamber 2101 and monitor for any problems. The window 2103 is constructed of thick glass having a thickness sufficient to withstand the pressure exerted thereon by an accident that may occur during centrifugation at centrifuge bowl speeds greater than 4800 RPMs. Preferably, window 2103 is constructed of shock resistant glass. Hatch 2102 is hinged to upper portion 2100 and has an automatic locking mechanism that is activated by the system controller during system operation. Centrifuge chamber 2101 is described in more detail below with reference to FIG. 19.

Preferably, console 1200 is located on upper surface 2204 of base portion 2200 at or adjacent a front portion of tower 2000, while upper portion 2100 extends upwardly from base portion 2200 at or adjacent a rear portion of tower 2000. This allows the operator to easily manipulate console 1200 while at the same time allowing the operator to manipulate centrifuge chamber 2101. By designing tower system 2000 with centrifuge chamber 2101 in upper portion 2100 and photoactivation chamber 750 and console 1200 in base 2200, an upright configuration is achieved. Thus, tower system 2000 has a reduced footprint and occupies less floor space in the hospital. The tower system 2000 is kept below 60 inches in height so that the perspective of the mover is not obscured when the machine is later moved through the hospital. In addition, the console 1200 is located in a fairly flat position so that the operator has room to place the devices of the photopheresis kit 1000 when loading other facilities, which facilitates ease of installation. Tower system 2000 is sufficiently robust to withstand the shock and impact of the centrifugation process. ,

monitor 2104 sits above centrifuge chamber door 2102 above window 2103. Monitor 2104 has a display area 2105 for displaying such data to an operator as a user side of data entries, installed instruments, charts, warnings, alarms, treatment data, or treatment procedures. Monitor 2104 is coupled to and controlled by the system controller. The data card receiving slot 2001 is located at one side of the monitor 2104. Data card receiving slot 2001 is for slidably receiving data card 1195 provided by each disposable photopheresis kit 1000 (FIG. 1). As described above, data cards 1195 may be pre-programmed to store the large amount of data that needs to be provided to tower system 2000. For example, data card 1195 can be programmed to communicate information such that the system controller can determine: (1) the disposable photopheresis kit is compatible with the blood driving device in which the kit is installed; (2) the photopheresis kit can operate the required treatment process; (3) the disposable photopheresis kit is of some commercial product or construction. Data card receiving slot 2001 has the necessary components and circuitry to read and write data card 1195. Preferably, data card receiving slot 2001 records treatment data to data card 1195. Such data information includes, for example, collection time, collection volume, processing time, volumetric flow rate, any alarms in the process, faults, disturbances, or any other desired data. Data card receiving slot 2001 is located on monitor 2104, but it may be located anywhere on tower system 2000, so long as it is coupled to a system controller or other suitable control means.

A, a light activation chamber for receiving an irradiation chamber

Referring to fig. 16 and 18, optically activated chamber 750 is illustrated in cross-section. Optically activated chamber 750 is formed by housing 756. Enclosure 756 is within base 2200 of tower system 2000, behind door 751 (FIG. 17). A number of electrical connections 753 are provided on the back wall 754 of the chamber 750. Electronic connection 753 is coupled to a power source. Optically activated chamber 750 is designed to receive ultraviolet light assembly 759 (fig. 16). When fully enclosed in light activated chamber 750, electrical contacts (not shown) located on contact wall 755 of uv light assembly 759 form an electrical path with electrical connection terminals 753. This electrical path allows electrical energy to be supplied to the ultraviolet lamp 758 to activate it. Preferably, each set of ultraviolet lamps 758 has three electrical connections. More preferably, the uv lamp assembly 759 has two sets of uv lamps 758, thereby forming a space in which the irradiation chamber 700 can be recessed. The supply of electrical energy to the ultraviolet lamp 758 is controlled by a suitably programmed system controller via a switch. During photopheresis treatment, the controller activates or deactivates the ultraviolet lamp 758 as needed.

A vent 757 is located at the top of the housing 756 near the back wall 754 of the photoactive chamber 750. Vent 757 is connected to vent tube 760 that extends out of the rear of tower system 2000. During a treatment procedure, as heat generated by the ultraviolet lamp 758 builds up within the light activated chamber 750, the heat escapes the light activated chamber 750 through the vent 757 and the vent channel 760. This heat escapes the tower 2000 from the holes 761 in the tower shell located at the rear of the tower, away from the patient and operator.

The light activation cell 750 also includes a slot 762 for receiving the irradiation cell 700 and maintaining irradiation in a vertical position between the ultraviolet lamps 758. The slot 762 is located at or near the bottom of the photoactive chamber 750. Preferably, a leak detection circuit 763 is located below slot 762 for detecting fluid leaking out of cell 700 during, before or after operation. The leak detection circuit 762 has two electrodes in a U-shaped pattern on an adhesive backed flex circuit. The electrode is designed to allow the use of a short circuit to test for an interruption of the electrical circuit. Each electrode end may be routed to an integrated circuit, while the other end of each electrode is tied to a solid state switch. The solid state switch can be used to check the continuity of the electrodes. By closing the switch, the electrodes are short-circuited to each other. The short is then detected in the integrated circuit. Closing the switch causes the same situation as electrode-to-wet (e.g., leakage). If any damage occurs to the electrodes, the continuity check will fail. This is a positive indication that one electrode is not damaged. This test may be performed each time the system is started or periodically during normal operation to ensure that the leak detection circuit 762 is operating properly. The leak detection circuit 762 helps to ensure that leakage does not leak unnoticed because the leak detection circuit is broken throughout the treatment cycle. Fig. 20 provides a circuit schematic of the leak detection circuit 762.

B. Centrifugal chamber

FIG. 19 illustrates a section of centrifuge chamber 2101 with the housing of tower system 2000 removed. A turning device 900 (also shown in cross-section) capable of utilizing 1- ω 2- ω rotation technology is located inside the centrifuge chamber 2101. The turning device 900 includes a turning bracket 910 and a barrel support plate 919 for rotatably securing a centrifugal barrel 10 (FIG. 1). The housing 2107 of centrifuge chamber 2101 is preferably made of aluminum or other lightweight yet strong metal. Alternatively, other rotation systems may be used within tower system 2000, such as the rotation device described in U.S. patent No. 3986442, the disclosure of which is also incorporated herein by reference in its entirety.

The leak detection circuit 2106 is located on the rear wall 2108 of the housing 2107. The leak detection circuit 2106 is used to detect any leaks in the centrifuge bowl 10 or in the connecting tubing during processing. The leak detection circuit 2106 is identical to the leak detection circuit 762 described above. Fig. 21 provides a circuit schematic of a leak detection circuit 2106.

C. Liquid flow control console

Fig. 22 illustrates a console 1200 of tower system 2000 (fig. 17) without cassette 1100 mounted thereon. Console 1200 performs valving and pumping operations to drive and control the flow of fluids through photopheresis kit 1000. Preferably, console 1200 is a separate plate 1202 that is fastened to base 2200 of tower system 2000 by screws or other fastening means, such as bolts, nuts, or clamps. The plate 1202 may be made of steel, aluminum, or other durable metal or material.

Console 1200 has five peristaltic pumps extending from plate 1202, whole blood pump 1301, return pump 1302, recirculation pump 1303, anticoagulant pump 1304, and red blood cell pump 1305. The pumps 1301 & 1305 are mounted on the plate 1202 such that the pump tubing loop 1120 & 1124 extends from and around the pumps 1301 & 1305 (FIG. 25) when the cassette 1100 is mounted on the console for operation.

A bubble sensing assembly 1204 and HCT sensing assembly 1205 are located above the plate 1202. Bubble sensing assembly 1204 has three passages 1206 for receiving tubes 1114, 1106, and 1119 (FIG. 25). Bubble sensing assembly 1204 uses ultrasonic energy to monitor the difference in density in tubes 1114, 1106, and 1119, which would reveal the presence of air in the liquid fluid normally passing through the tubes. Since tubes 1114, 1106, and 1119 lead to the patient, these tubes need to be monitored. The bubble sensing assembly 1204 is operatively coupled to the system controller and transmits data thereto for analysis. If a bubble is detected, the system controller will interrupt operation and close conduits 1114, 1106, and 1109 by moving compression actuator 1240 and 1242 to the high position, thereby compressing conduits 1114, 1106, and 1119 relative to cassette 1100 and/or turning off the respective pumps as previously described to prevent fluid flow into the patient. HCT sensor assembly 1205 has a channel 1207 for receiving HCT element 1125 of tube 1116. HCT sensing assembly 1205 monitors tube 1116 for the presence of red blood cells via a photosensor. The HCT sensing assembly 1205 is also operably coupled to and transmits data to the system controller. When red blood cells are detected in the exit tube 1116, the controller will take action to prevent fluid flow through the tube 1116, such as turning off the corresponding pump or activating one of the compression actuators 1243 and 1247.

Console 1200 also has five compression actuators 1243-1247 and three compression actuators 1240-1242 strategically positioned over plate 1202 such that each compression actuator 1240-1247 is associated with a respective aperture 1137 and 1157 when cassette 1100 is loaded into console 1200 for operation. Compression actuators 1240 and 1247 are movable between an upper position and a lower position. As shown in FIG. 22, compression actuators 1243 and 1247 are in the low position and compression actuator 1240 and 1242 are in the high position. When compression actuator 1240 and 1247 are in the raised position and cassette 1100 is loaded onto console 1200 as shown in fig. 25, compression actuator 1240 and 1247 will extend out of the respective aperture 1137 or 1157 and compress a portion of the elastomeric tube connected thereto, thereby compressing the elastomeric tube closed so that liquid cannot pass therethrough. When compression actuator 1240 and 1247 are in the low position, holes 1139 and 1157 cannot be extended and thus the elastomeric tube cannot be compressed.

Compression actuators 1243 and 1247 are retracted springs so their default positions are moved to the low position unless activated. Compression actuators 1243 and 1247 are individually controlled and can be raised or lowered independently of each other. And, on the other hand, compression actuators 1240 and 1242 are coupled to each other. Thus, when one compression actuator 1240-. In addition, compression actuators 1240 and 1242 are springs that are compressed so their default position is moved to a high position. Thus, if the system is powered down during treatment, compression actuator 1240 and 1242 will automatically move to the high position, closing tubes 1114, 1106, and 1119, and preventing fluid flow into or out of the patient.

Referring now to fig. 23 and 24, the console 1200 further includes a system controller 1210, a cylinder assembly 1211, a manifold assembly 1213, a pump cable 1215, a pump motor cable 1216, and a speed control belt assembly 1217. System controller 1210 is an integrated circuit suitably programmed and operatively coupled to the necessary components of the system to perform all of the functions, interactions, decisions, and responses necessary for the photopheresis treatment of the present invention, as described above. Cylinder assembly 1211 couples each compression actuator 1240-1247 to the pneumatic cylinder. Air ports 1212 are located on many elements of the console 1200 for connecting gas lines to each device and to a corresponding one of the manifold assemblies 1213. In this manner, the gas is delivered to the desired equipment to activate the desired components, such as compression valve 1240 and 1247. All functions and timing are controlled by the system controller 1210. A speed drive belt assembly 1217 is used to adjust the rotation of rotating clamp 1203. Finally, plate 1202 includes a plurality of holes 1215, 1219, 1220, 1221, and 1218 such that a plurality of components of console 1200 can be properly loaded into the plate and console 1200 can be secured to tower system 2000. Specifically, the pump 1301 + 1305 is inserted into the bore 1314, the HCT sensor 1205 is inserted into the bore 1220, the bubble probe assembly 1204 is inserted into the bore 1219, the compression actuator 1240 + 1247 extends from the bore 1218, and a screw extends from the bore 1221 to secure the console 1200 to the tower apparatus 2000.

1. Cassette clamping mechanism

A method by which the cassette 1100 is loaded into and secured to the console 1200 will now be described with reference to fig. 22 and 25. In order for system 2000 to perform a photopheresis treatment procedure, cassette 1100 must be properly loaded onto console 1200. Since the compression actuator valve system is incorporated into the present invention, the cassette 1100 must be properly secured to the console 1200 and the cassette 1100 will not be dislocated or moved when the compression actuator 1240 and 1247 closes the resilient tube by compressing it relative to the lid 1130 of the cassette 1100 (FIG. 3). However, such a demand is in conflict with the purpose of conveniently loading the cassette 1100 into the console 1200 and reducing operator's mistake. The following described cassette clamping mechanism will achieve all of the above objectives.

To embed the convenience box 1100 in the console 1200, the console 1200 uses two detents 1208 and two rotating clamps 1203 and 1223. The catch 1208 has a slot 1228 adjacent the middle of the top plate. The detents 1208 are secured to the plate 1202 in predetermined positions so that they are spaced apart a distance substantially equal to the distance between the tabs 1102 and 1103 on the cassette 1100 (fig. 2). Rotating clamps 1203 and 1223 are illustrated in a closed position. However, the rotating clamps 1203 and 1223 can be rotated to an open position (not shown) either manually or by automatic activation of a pneumatic cylinder. Rotating clamps 1203 and 111223 are equipped with torque springs so that the rotating clamps automatically return to the closed position when no additional torque is applied. The rotating clamps 1203 and 1223 are connected to each other by a timing belt assembly 1217 (fig. 24).

Referring to fig. 23, the speed drive belt assembly 1217 includes a speed drive belt 1226, a torque spring housing 1224, and a tension assembly 1225. The speed regulation belt assembly 1217 regulates the rotation of the rotating clamps 1203 and 1223 so that if one rotates, the other also rotates in the same direction and speed. In other words, rotating clamps 1203 and 1223 are coupled. Tension assembly 1217 ensures that speed belt 1226 is under sufficient tension to rotate its adjusted rotating clamps 1203 and 1223. The torque spring housing 1224 provides a protective housing for the torque spring that twists the rotating clamps 1203 and 1223 to the closed position.

Referring again to fig. 22 and 25, when the cassette 1100 is loaded onto the console 1200, the cassette 1100 is positioned at an angle above the console 1200 and the tabs 1102 and 1103 (fig. 2) are aligned with the detents 1208. The cartridge 1100 is moved so that the tabs 1102 and 1103 can slide into the detents 1208. Rotating clamps 1203 and 1223 are now in the closed position. When the tabs 1102 and 1103 are inserted into the detents 1208, the rear of the cassette 1100 (i.e., the opposite side of the tabs 1102 and 1103) contacts the rotating clamps 1203 and 1223. When a downward force is applied to cassette 1100, rotating clamps 1203 and 1223 will be rotated to the open position such that the rear of cassette 1100 moves downward to a position below edges 1231 of rotating clamps 1203 and 1223. Once cassette 1100 is in this position, rotating clamps 1203 and 1223 spring back against the force exerted by the torque spring and rotate back to the closed position, locking cassette 1100 in this position. With the cassette 1100 in this locked position, upward and lateral forces are resisted.

To remove the cassette 1100 after the treatment cycle is complete, the rotating clamps 1103 and 1123 are rotated, either manually or automatically, to the open position. Automatic rotation is achieved by a pneumatic cylinder coupled to the air line and system controller 1210. Once the rotating clamps 1203, 1223 are in the open position, the cassette 1100 can be removed by simply lifting and sliding the tabs 1102, 1103 out of the detents 1208.

2. Automatic loading peristaltic pump

Referring to FIG. 24, peristaltic pumps 1301 and 1305 are located above console 1200 for moving fluid through light separation kit 1000 (FIG. 1) along the desired path. Activation, deactivation, speed regulation, acceleration, coordination, and all other functions of peristaltic pump 1301-. Peristaltic pumps 1301 and 1305 are identical in structure. However, the position of the peristaltic pumps 1301 1305 on the console 1200 indicates the function of each peristaltic pump 1301 1305 with respect to driving and flowing the respective fluid along the respective path. This is because the position of the peristaltic pump 1301 + 1305 indicates where the corresponding pump tubing loop 1220 + 1224 is installed.

Referring now to fig. 28 and 29, whole blood pump 1301 is illustrated in detail. The function and structure of the whole blood pump will be described, and the peristaltic pump 1302-1305 also has exactly the same function and structure. The whole blood pump 1301 has a motor 1310, a position sensor 1311, a pneumatic cylinder 1312, a pneumatic actuator 1313, a rotor 1314 (best shown in FIG. 30), and a housing 1315.

A rotor 1314 is rotatably mounted within a casing 1315 and is operatively connected to a drive shaft 1316 of the motor 1310. Specifically, rotor 1314 is mounted on curved wall 1317 of housing 1315 and is thus rotatable about the A-A axis by motor 1310. When rotor 1314 is mounted in housing 1315, a space 1318 is formed between rotor 1314 and curved wall 1317. This space 1318 is the tubing pumping area of the whole blood pump 1301 into which the pump tubing loop 1211 (FIG. 33) fits when installed for pumping. A position sensor 1316 is coupled to a drive shaft 1316 of the motor 1310 so that the rotational position of the rotor 1314 can be detected by monitoring the drive shaft 1316. The position sensor 1311 is operably connected to and transmits data to the system controller 1210 (fig. 24). By analyzing the data, system controller 1210, which is also coupled to motor 1310, can activate motor 1310 to position rotor 1314 at any desired rotational position.

The housing 1315 also includes a housing flange 1319. The housing flange 1319 is used to secure the whole blood pump 1310 over the plate 1202 of the console 1200 (FIG. 22). More specifically, a screw extends through screw hole 1320 of housing flange 1319 to threadingly engage a hole in plate 1202. The housing flange 1319 also includes an aperture (not shown) through which the pneumatic actuator 1313 may extend. The size of the hole is such that the pneumatic activator 1313 can move up and down without too much resistance. The pneumatic cylinder 1312 activates or deactivates the pneumatic activator 1313 in a piston-like manner by using gas. Pneumatic cylinder 1312 includes a gas inlet port 1321 for connecting a gas supply line. When gas is supplied to pneumatic cylinder 1312, the pneumatic actuator extends upwardly through housing flange 1319 to a high position. When the gas stops replenishing to pneumatic cylinder 1312, the pneumatic actuator retracts into pneumatic cylinder 1312. And back to the low position. The system controller 1210 (fig. 22) controls the supply of gas to the gas inlet port 1321.

Curved wall 1317 of housing 1315 contains two slots 1322 (only one of which is visible). Slots 1322 are located on diametrically opposite sides of curved wall 1317. Slots 1322 are used to allow pump tube loop 1121 (fig. 33) to pass into tube pumping region 1318. More specifically, pump inlet portion 1150 and outlet portion 1151 (FIG. 33) of pump loop tube 1121 pass through slots 1322. referring now to FIGS.

Referring to fig. 30 and 31, rotor 1314 is illustrated removed from housing 1315 so that its components are more clearly visible. Rotor 1314 has an upper surface 1323, angled guide 1324, rotor flange 1325, two guide rollers 1326, two drive rollers 1327, and rotor floor 1328. Guide rollers 1326 and drive rollers 1327 are rotatably secured to core 1330 between rotor floor 1328 and bottom surface 1329 of rotor flange 1325. As best shown in FIG. 29, core 1330 fits within aperture 1331 of rotor floor 1328 and recess 1332 of bottom surface 1329. Guide rollers 1326 and drive rollers 1327 fit around the core 1330 and can rotate therein. Preferably, there are two guide rollers 1326 and two drive rollers 1327. More preferably, the guide rollers 1326 and the drive rollers 1327 are positioned on the rotor 1314 to form an alternating pattern.

Referring to fig. 29 and 31, as rotor 1314 rotates about axis a-a, drive roller 1327 squeezes a portion of pump tube loop 1121, which is loaded into tube pumping region 1318, against the interior of curved wall 1317, thereby deforming the tube and forcing liquid through the tube. Varying the rotational speed of rotor 1314 will correspondingly vary the rate of liquid flow through the conduit. Guide rollers 1326 are used to maintain the proper alignment of the portion of pump loop tube 1121 that is loaded into tube suction region 1318 during pumping. In addition, guide rollers 1326 help properly load pump tube loop 1121 into tube pumping region 1318. Although the guide rollers 1326 are shown as having the same cross-section, it is preferred that the top plate of the guide rollers be tapered to achieve a sharper edge at their outer diameter. Tapering the top results in a guide roller having an asymmetric cross-sectional profile. This tapered embodiment helps to ensure that the tubing fits properly into the tube suction area.

Rotor 1314 also includes a cavity 1328 extending from its center. The cavity 1328 is used to connect the rotor to the drive shaft 1316 of the engine 1310.

Referring to fig. 30 and 32, the rotor flange has an opening 1333. The aperture 1333 is defined by a leading edge 1334 and a trailing edge 1335. It is assumed that rotating rotor 1314 in a clockwise direction is a forward direction and rotating rotor 1314 in a counter-clockwise direction is a rearward direction, and thus the terms leading windward edge and trailing leeward edge are used. However, the invention is not so limited and changes may be made to a counter-clockwise pump. The leading edge 1334 slopes downwardly into the bore 1333, and the trailing edge 1335 extends upwardly from the upper surface of the rotor flange 1325 above the leading edge 1334. Once rotor 1314 is rotated in the forward direction, the leading edge of the windward side serves as the trailing edge of the leeward side to feed pump loop tube 1121 into tube pumping region 1318 and lock it in place.

Rotor 1314 also has angled guides 1324 extending upward at an opposite angle from rotor flange 1325. Angled guide 1324 is used to move pump loop 1121 toward rotor flange 1325 once rotor 1314 is rotated in the forward direction. Preferably, angled guide 1324 has a raised ridge 1336 that is manually movable along upper surface 1323 by an operator, if necessary. More preferably, angled guide 1324 is positioned before leading edge 1334.

Referring to fig. 28 and 33, whole blood pump 1301 can automatically install and unload pump tube loop 1121 into tube pumping region 1318. Using position sensor 1311, rotor 1314 is rotated to a mounting position where angled guide 1324 will face cartridge 1100 when cartridge 1100 is mounted to console 1200 (FIG. 25). More specifically, rotor 1314 is pre-adjusted to a position such that angled guide 1324 is positioned between inlet portion 1150 and outlet portion 1151 of pump loop 1121 when cassette 1100 is secured to the console, as shown in FIG. 13. When cassette 1100 is secured to console 1200, pump tube loop 1121 extends over and around rotor 1314. Pneumatic activator 1313 is now in the low position.

When cassette 1100 is secured and the system is ready, rotor 1314 is rotated in a clockwise direction (i.e., the forward direction). As rotor 1314 rotates, pump tube loop 1121 is in contact with angled guide 1324 and is displaced relative to the upper surface of rotor flange 1325. The portion of pump tube loop 1121 displaced relative to the upper surface of rotor flange 1325 is then brought into contact with trailing edge 1335 and fed into tube pumping region 1318 through opening 1333. A guide roller 1326 is located directly behind the opening 1333 to further properly position the tubing within the tube pumping chamber for pumping by the drive roller 1327. When assembled, inlet portion 1150 and outlet portion 1151 of pump loop 1121 pass through slots 1322 of curved wall 1317. Complete loading of the tube required 1.5 revolutions.

To automatically unload pump tube loop 1121 from whole blood pump 1301 after treatment is complete, rotor 1314 is rotated to the point where opening 1333 connects with slot 1322 through which outlet portion 1151 passes. Once attached, pneumatic actuator 1313 is activated and extends to an elevated position, contacting outlet portion 1151 and raising it above trailing edge 1335. Rotor 1314 is then rotated in a counter-clockwise direction so that trailing edge 1335 contacts pump tube loop 1121 and displaces it from tube pumping region 1318 through opening 1333.

D. Infrared communication device

Referring to FIG. 34, tower system 2000 (FIG. 17) preferably also includes a wireless infrared ("IR") communication interface (not shown). The wireless infrared communication interface is comprised of three main components, a system controller 1210, an IRDA protocol integrated circuit 1381, and an IRDA transponder (transceiver) port 1382. The IR communication interface is capable of transmitting and receiving data via IR signals from a remote computer or other IR capable device. When sending data, the system controller 1210 sends continuous communication data to the IRDA protocol chip 1381 to buffer the data. IRDA protocol chip 1381 adds additional data and other communication information to the transmission line and sends it to IRDA transponder 1382. The transponder 1382 converts the electronically transmitted data into encoded optical pulses and transmits them to a remote device via optical transmission means.

Upon receiving the data, the IR data pulses are received by a photodetector located on the transponder chip 1382. The transponder chip 1382 converts the optical pulses into electronic data and sends the data stream to the IRDA protocol chip 1381 where the electronic signals of the control and additional IRDA protocol content are filtered. The retained data is then sent to the system controller 1210 where the data stream is parsed by a communication protocol.

By incorporating an IR communication interface into tower system 2000, real-time and timely data from the treatment process can be transmitted to a remote device for recording, analysis, or further transmission. Data may be sent to tower system 2000 via IR signals to control therapy or allow protocols to be changed in a state that operates with instrumentation without visual inspection. Furthermore, the IR signal does not interfere with other hospital equipment, such as other wireless transmission means, e.g. radio frequency.

Photopheresis treatment procedure

Referring to fig. 26, a flow chart illustrates one embodiment of the present invention including the light activation of the buffy coat, and fig. 27 is a schematic of the apparatus that can be used with the embodiment starting 1400 from a patient 600 connected through a needle adapter 1193 with a needle for drawing blood and a needle adapter 1194 with another needle for back-filling the treated blood and other components. Saline bag 55 is connected by connector 1190 and anticoagulant bag 54 is connected by connector 1191. Actuators 1240, 1241 and 1242 are turned on, anticoagulant pump 1304 is activated, and saline activator 1246 is turned on so that the entire disposable tubing set is infused 1401 with saline 55 and anticoagulant 54. Centrifuge 10 is opened 1402 and the blood-anticoagulant mixture is pumped 1403 to centrifuge bowl 10 by A/C pump 1304 and WB pump 1301 at a rate ratio of 1: 10.

When the collected volume reaches 150ml1404, the return pump 1302 is set to the rate 1405 of the collection pump 1301 until red blood cells are detected 1406 by the HCT (not shown) sensor in the centrifuge chamber 1201 (FIG. 19). Packed red blood cells and buffy coat accumulate in the rotating centrifuge bowl and are pumped out slowly at a rate controlled by a processor that maintains the red blood cell line at the level of the sensor port.

The red cell pump 1305 is then set 1407 to 35% of the inlet pump rate while controlling 1408 the speed to maintain the cell line at the sensor port level until 1409 the volume of the collection cycle is reached, at which point the red cell pump 1305 is turned off 1410 and the fluid path through the HCT sensor 1125 to the processing bag 50 is opened by the descending actuator 1244 and closed when the HCT sensor 1125 detects 1411 red cells. The "volume of a collection cycle" is defined as the target value of whole blood processed divided by the number of collection cycles, e.g., a 1500 ml leukocyte processing target may require 6 cycles, so 1500/6 is a 250 ml collection cycle volume. As whole blood continues 1410 to be delivered from the patient to the cartridge and the red blood cell pump is turned off, red blood cells will accumulate and push the buffy coat out of the cartridge 10. The red blood cells are used to push out the buffy coat and will be detected by a Hematocrit (HCT) sensor in the outlet channel, indicating that the buffy coat has been collected.

If another cycle is required 1412, the centrifuge 10 effluent path is returned 1413 to the plasma bag 51 and the red blood cell pump 1305 rate is increased 1413 to the inlet pump 1301 rate until red blood cells are detected 1414, which is the beginning of the second cycle. If another cycle 1412 is not needed, the centrifuge 10 is shut down 1415 and the inlet pump 1301 and anticoagulant pump 1304 are set at KVO rate, which in this embodiment is 10 ml/hr. The outlet channel leads 1416 to the plasma bag 51, the red cell pump 1305 rate is set 1417 to 75 ml/min, the recirculation pump 1303 and light activated lamp are turned on 1418 so that there is enough time to treat the buffy coat, and the controller calculates the treatment time based on the type and amount of disease being treated.

After the cartridge 10 is emptied 1419, the red blood cell pump 1305 is turned off 1420 and the plasma bag 51 is emptied 1421 by opening the actuator 1247 and continuing the return pump 1302. After the plasma bag 51 is emptied and when photoactivation is complete 1423, the return pump 1302 is turned off 1422 and the treated cells are reinfused 1424 from the plate 700 into the patient via the return pump 1302. The saline is used to purge the system and the purge is returned to the patient, completing the entire process 1425.

The anticoagulant, blood from the patient, and fluid returning to the patient are all monitored by bubble detectors 1204 and 1202, and the fluid returning to the patient passes through a settling chamber and filter 1500. The rotation of pumps 1304, 1301, 1302, 1303 and 1305, actuators 1240, 1241, 1242, 1243, 1244, 1245, 1246 and 1247, and drum 10 are all controlled by programmed processors within the tower.

The process and related equipment have significant advantages over previous processes and devices in that: the present invention allows the buffy coat to remain in the bowl for a longer period of time since the buffy coat is collected in the bowl at the time of centrifugation while the red blood cells are being withdrawn, so that more buffy coat remains in the bowl until the desired amount of buffy coat cells are collected before the collected buffy coat is removed. Platelets, white blood cells, and other buffy coat debris can also be separated or red blood cells collected rather than being returned to the patient with plasma as described in the above-described procedures.

Increasing the time that the buffy coat 810 is in rotational motion within the centrifuge bowl 10 creates a "cleaner cut" for the buffy coat 820. "cleaner cut" means that the hematocrit count (HCT%) is reduced. HCT% refers to the number of red blood cells per unit volume of buffy coat. The time that the buffy coat 820 is in rotational motion in the centrifuge bowl 10 can be maximized as follows. First, whole blood 800 is fed into the first bowl channel 420 as the centrifuge bowl 10 rotates, and as the whole blood 800 moves outward on top of the bottom plate 300, it is separated into a buffy coat 820 and red blood cells 810, as described above. The second bowl channel 410 and the third bowl channel 740 are now closed. Whole blood 800 continues to flow until the separation space 200 is filled with buffy coat 820 adjacent the top and red blood cells 810 adjacent the bottom of centrifuge bowl 10. By removing red blood cells 810 from centrifuge bowl 10 only from second bowl channel 410, additional space is created for the influent whole blood 800 and the unremoved buffy coat 820 remains under the force of the spinning centrifugal force for a longer period of time. As centrifuge bowl 10 continues to rotate, those portions of red blood cells 810 trapped in buffy coat 820 are pulled to the bottom of centrifuge bowl 10 and away from third bowl channel 740 and buffy coat 820. Thus, when third bowl channel 740 is opened, the buffy coat 820 removed has a lower HCT%. By controlling the inflow rate of whole blood 800 and the outflow rate of buffy coat 820 and red blood cells 810, a steady state can be achieved that produces a buffy coat with approximately constant HCT%.

The elimination of the intermittent production process and improved throughput are achieved by the present invention, reducing the treatment time required to properly treat the patient. For a medium-sized adult, 90-100 ml of buffy coat/white blood cells are collected for a full photopheresis treatment. To collect this amount of buffy coat/white blood cells, the present invention requires processing about 1.5 liters of blood. With the present invention, the desired amount of buffy coat/white blood cells can be removed from 1.5 liters of whole blood in about 30-45 minutes, collecting about 60% or more of the total amount of buffy coat/white blood cells in the separation process. The collected buffy coat/white blood cells have an HCT of 2% or less. By contrast, one existing device, the UVAR XTS, requires approximately 90 minutes to process 1.5 liters of whole blood to obtain sufficient amounts of bloodLayer/white blood cells. Uvarx can only collect about 50% of the total amount of buffy coat/white blood cells in the process of separation. The HCT of buffy coat/leukocytes collected by the UVAR XTS was approximately 2%, but not significantly below this value. Another prior art apparatus, the Cobe Spectra of Gambro^TM10 liters of whole blood must be processed to collect a sufficient number of buffy coats/leukocytes. Typically, it takes about 150 minutes, and only 10-15% of the total buffy coat/white blood cells in the separation process can be collected, with an HCT value of about 2%. Thus, the present invention is capable of performing the same function in less than 70 minutes, as opposed to the conventional devices and systems that require, in any event, 152-225 minutes to separate, process, treat and reinject the requisite number of white blood cells or buffy coat. These times do not include patient preparation or start-up times. This time represents only the total time that the patient is connected to the system.

Claims (3)

1. A disposable photopheresis kit comprising:

a cassette (1100) that acts as both a tubing organizer and a router for fluid flow;

a centrifuge bowl (10) for separating whole blood into its different components according to density, wherein the centrifuge bowl has three separate liquid tubes as one inlet end and two outlet ends; and a conduit assembly (860A); wherein fluid is circulated between the centrifuge bowl (10) and an outer tube (20A) of the tube assembly (860A), wherein the outer tube (20A) has a first tube (780A), a second tube (760A), and a third tube (770A), wherein the first tube (780A) is in fluid communication with a first bowl channel (420A) for introducing fluid from the outer tube (20A) to the centrifuge bowl (10) for separation, the second tube (760A) is in fluid communication with a second bowl channel (410A) for removing a first separated fluid component from the centrifuge bowl (10) to the outer tube (20A), and the third tube (770A) is in fluid communication with a bowl chamber (740A) for removing a second separated fluid component from the centrifuge bowl (10), wherein the second bowl channel (410A) and the second tube (760A) are connected through a fluid conduit having a first end (321B) and a second end (321C), A conduit (321A) adapted to be inserted into the conduit lumen connector (481A) for communication and fluid communication between the first bowl channel (420A) and the first conduit (780A) of the outer tube (20A) through a hollow cylindrical lumen (322A) having a first end (322B) and a second end (322C);

an irradiation chamber (700) for exposing blood to ultraviolet light;

a hematocrit sensor (1125);

a removable data card (1195);

a disposal bag (50); and

a plasma collection bag (51).

2. The disposable photopheresis kit of claim 1, further comprising:

a system controller (1210) which is an integrated circuit programmed to operatively couple the necessary elements of the system to perform the photopheresis treatment.

3. A disposable photopheresis kit according to claim 1 or 2, further comprising:

an anticoagulant pump (1304) for driving anticoagulant fluid into the cassette (1100) and out of the cassette (1100);

a whole blood pump (1301) for driving whole blood into and out of the cassette (1100);

a return pump (1302) for driving blood back to the patient;

a controller (1554) coupled to the full blood pump (1301) and the return pump (1302) and programmed to control the speed of the full blood pump (1301) and the return pump (1302);

a circulation pump (1303) that drives blood fluid from the cassette (1100) through the processing bag (50) and the irradiation chamber (700); and

a red blood cell pump (1305) for pumping out red blood cells from the centrifuge bowl (10) and pumping them into the cassette (1100).