Patent Publication Number: US-2016243165-A1

Title: Processing cell therapy products

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     The application claims benefit under 35 U.S.C. §119(e) of U.S. Provisional Application Ser. No. 61/893,495 filed Oct. 21, 2013, the contents of which are herein incorporated by reference in their entirety. 
    
    
     TECHNICAL FIELD 
     The present disclosure relates generally to systems, methods, and apparatus for processing cell therapy products. More specifically, the present disclosure relates to a closed system for the processing of cell therapy products, such as blood, bone marrow, and stem cells. 
     BACKGROUND 
     Cell therapy includes therapies in which cellular material is injected into a recipient subject. Cell therapy may be used to reverse, minimize, and/or treat diseases and cellular damage by replacing cellular material, repairing damage and/or stimulating the recipient subject&#39;s own immune system. The cellular material may include live or freeze-dried cells or parts of cells, and may be sourced from the recipient subject or from a healthy donor subject. The healthy donor subject may or may not be of the same species. For example, cellular material from an organ, fetus, or embryo of an animal, such as a sheep or cow, may be injected into a human subject. The cellular material is usually processed before being injected into a recipient subject. 
     A blood transfusion is one form of cell therapy that may be used to, for example, replace lost components of a subject&#39;s blood. Whole blood can be collected and then separated by centrifugation into blood components, including red blood cells, plasma, platelets, albumin protein, clotting factor concentrates, cryoprecipitate, fibrinogen concentrate, and immunoglobulins (i.e., antibodies). In addition to testing and other processing steps, one or more components may be isolated. For example, in a luekoreduced blood transfusion procedure, white blood cells (or buffy coat) are removed by filtration to prevent and/or minimize HLA alloimmunization, infections, and other adverse reactions. Following leukoreduction, the remaining components of the blood may be provided intravenously to a recipient subject. 
     Whole blood or blood components are usually collected and stored in plastic transfusion bags. Multiple transfusion bags may be required in procedures like the luekoreduced blood transfusion for different blood components or due to bag damage or processes intended to prevent bag damage. In addition to cost, the use of multiple transfusion bags may increase the risk of contamination, trauma to cellular components, and the residual accumulation and subsequent loss of components in the bags following transfer. 
     SUMMARY 
     The present disclosure provides systems, methods, and apparatus for processing cell therapy products. In an aspect, a system can include a container, an expandable seal, a connector, and a needle for aspirating. The container can include a top. The expandable seal can be fixed to the container top and form a barrier between an external environment and an interior of the container. The connector can be coupled to the expandable seal. The needle can be operatively coupled to the connector and can extend into the interior of the container. The needle can be movable between a first depth in the container and a second depth in the container without exposing the needle to the external environment. 
     In one embodiment, a system includes a container with an interior configured to hold at least one cellular therapy product, an expandable seal coupled to the container and forming a barrier between an external environment and the interior of the container, a connector coupled to the expandable seal, and a needle operatively coupled to the connector. The distal end of the needle can extend from the connector into the interior of the container. The position of the distal end of the needle can be selectively adjustable between a first depth in the interior of the container and a second depth in the interior of the container without exposing the needle to the external environment. The needle can be configured for aspirating one or more of the at least one cellular therapy product. 
     One or more of the following features also can be included. For example, the system can be configured for containing cellular therapy products during centrifugation. The container can be comprised of plastic resistant to puncture by the needle when the needle is moved within the container, for example, when the needle is repositioned within the interior of the container and/or used to aspirate a cellular therapy product from the interior of the container. One or more support elements can be included to support at least a distal portion of the needle, for example, during centrifugation. The expandable seal can include an accordion seal. The connector can be a mechanically-closed device. The mechanically-closed device can be configured to automatically self-seal when not being accessed. A plurality of sterile access tubes can be included, as can at least one port between the interior of the container and the external environment. The at least one port can be one or more of an aspirating needle access port, a vent port, and/or an infusion port. 
     In another aspect, a method can include providing a closed system containing cellular therapy products. An adjustable needle of the closed system can be moved from a first depth to a second depth. One or more cellular therapy products can be aspirated through the adjustable needle. The closed system containing cellular therapy products can include a container, an expandable seal, a connector, and a needle for aspirating. The container can include a top. The expandable seal can be fixed to the container top and form a barrier between an external environment and an interior of the container. The connector can be coupled to the expandable seal. The needle can be operatively coupled to the connector and can extend into the interior of the container. The needle can be movable between a first depth in the container and a second depth in the container without exposing the needle to the external environment. 
     In one embodiment, a method includes acquiring a closed system with at least one cellular therapy product, selecting the position of the distal end of the needle to correlate with a location of one or more of the at least one cellular therapy product in the interior of the container, and aspirating the one or more of the at least one cellular therapy product through the needle. In an embodiment, acquiring the closed system with the at least one cellular therapy product includes introducing the at least one cellular therapy product into the interior of the container using at least one of the plurality of access tubes. In an embodiment, the method further includes subjecting the closed system with the at least one cellular therapy product to centrifugation. In an embodiment, the method further includes repositioning the distal end of the needle to correlate with the location of the one or more of the at least one cellular therapy product in the interior of the container. In an embodiment, the method further includes distributing the one or more of the at least one cellular therapy product aspirated from the interior of the container into a freeze bag. 
     The subject matter described herein provides many advantages for the processing of cell therapy products, such as blood, bone marrow, and stem cells. For example, in some embodiments, by providing and using durable systems and apparatus for processing cell therapy products, cell therapy products, which are irreplaceable at time of transplant, are less likely to be damaged or destroyed by debris during centrifugation or inadvertent punctures during sampling and infusion. Additionally, the use of functionally-closed systems and apparatus can reduce the risk of contamination to cell therapy products without the need, in some cases, for costly clean room facilities and maintenance. 
     It should be appreciated that all combinations of the foregoing concepts and additional concepts discussed in greater detail below (provided such concepts are not mutually inconsistent) are contemplated as being part of the inventive subject matter disclosed herein. In particular, all combinations of claimed subject matter appearing at the end of this disclosure are contemplated as being part of the inventive subject matter disclosed herein. It should also be appreciated that terminology explicitly employed herein that also may appear in any disclosure incorporated by reference should be accorded a meaning most consistent with the particular concepts disclosed herein. 
     Other systems, processes, and features will become apparent to those skilled in the art upon examination of the following drawings and detailed description. It is intended that all such additional systems, processes, and features be included within this description, be within the scope of the present invention, and be protected by the accompanying claims. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The skilled artisan will understand that the drawings primarily are for illustrative purposes and are not intended to limit the scope of the inventive subject matter described herein. The drawings are not necessarily to scale; in some instances, various aspects of the inventive subject matter disclosed herein may be shown exaggerated or enlarged in the drawings to facilitate an understanding of different features. In the drawings, like reference characters generally refer to like features (e.g., functionally similar and/or structurally similar elements). 
         FIG. 1  illustrates a closed system for processing cellular therapy products in accordance with some embodiments. 
         FIG. 2A  illustrates a closed system containing blood post-centrifugation with a needle in a down position in accordance with some embodiments. 
         FIG. 2B  illustrates a closed system containing blood post-centrifugation with a needle in a raised position in accordance with some embodiments. 
         FIG. 3  illustrates a cross-sectional view of a closed system in accordance with some embodiments. 
         FIG. 4  illustrates another implementation of a closed system for processing cellular therapy products in accordance with some embodiments. 
         FIG. 5  illustrates a process for performing apheresis cryopreservation of hematopoietic progenitor cells in accordance with some embodiments. 
     
    
    
     DETAILED DESCRIPTION 
       FIG. 1  is a diagram illustrating a system  100  for processing cellular therapy products in accordance with some embodiments. Different embodiments of the system  100  can involve different types of products, different material compositions, and different manufacturing processes. The system can include a container  105 , which can be implemented in a wide variety of different shapes, sizes, and configurations. Different embodiments of the container  105  can be used for the storage, transportation, and/or use of a wide variety of cellular therapy products. Cellular therapy products can include live or freeze-dried cells or parts of cells, such as blood components, bone marrow, stem cells, and the like. 
     Container  105  can be comprised of a durable material, such as polyethylene terephthalate (PET) and/or polypropylene (PP). PET is a thermoplastic polymer resin of the polyester family and can be used in liquid containers, thermoforming applications, and engineering resins, often in combination with glass fiber. PP is also a thermoplastic polymer that can be rugged and resistant to many chemical solvents, bases, and acids. In preferred embodiments, container  105  is resistant to puncture by a needle and has sufficient durability to withstand centrifugal forces applied at a wide range of centrifuge speeds and sample densities. For example, container  105  can have sufficient durability to withstand about 4000 rpm centrifugation in a Beckman JS-4.2 Swinging-Bucket Rotor (4539.5×g) centrifuge (available from Beckman Coulter, Inc. (Brea, Calif.)). 
     The container  105  includes a body  106 , a top portion  107 , and a conical bottom portion  109  opposite the top portion  107 . In some embodiments, one or both of the top portion  107  and the conical bottom portion  109  can be configured to be detachable/removable from the body  106 , for example, as a screw cap. In other embodiments, two or more of the body  106 , the top portion  107 , and the conical bottom portion  109  are integral to each other and are not configured to be separable from each other. The top portion  107  can be the means by which a container  105  is closed and, in some cases, sealed. The top portion  107  can be in an open position, a closed position, or in some instances, a partially open/partially closed position. The top portion  107  can be comprised of the same material as the body  106 . 
     The shape of container  105  can vary. For example, in  FIG. 1  the container  105  is substantially cylindrical in shape. According to some embodiments, the body  106  of the container  105  constitutes the majority of the surface area of the container  105 . The body  106  of the container  105  also typically defines the shape, size, and contours of the container  105 ; however, the length-to-diameter ratio of the container  105  can vary. In some embodiments, the container  105  is a centrifuge tube. The conical bottom portion  109 , which can have a more rounded bottom shape, typically serves as the base of the container  105  with the top portion  107  being placed in a vertical position that is higher than most or even all of the body  106 , depending on the particular embodiment and application of the container  105 . 
     The size of the container  105  can also vary. For example, the volume capacity of the container  105  can be approximately 50, 250, 500, or 1000 mL. In one embodiment, the container  105  is a cylinder with a volume of about 50 mL, a diameter of about 30 mm, and a height of about 115 mm. In another embodiment, the container  105  has a volume of about 500 mL. In some embodiments, the size and shape of the container  105  is configured to be compatible with one or more standard centrifuges. 
     The system  100  can include a needle  110  (e.g., an aspirating hypodermic needle with one or more sheaths  112 ). The needle  110  can be double sheathed, singled sheathed, or unsheathed and can be comprised of metal, plastic, or other suitable material. The distal end of the needle  110  can be blunt. The size of the needle  110  can vary, both in length and in gauge. The diameter of the needle  110  is indicated by the needle gauge. As illustrative examples, needles in common medical use can range from 7 gauge (larger) to 33 gauge (smaller) on the Stubs scale, including 21-gauge needles, which are commonly used for drawing blood for testing purposes, and 16- or 17-gauge needles, which are commonly used for blood donation. In a preferred embodiment of the closed system  100 , the needle  110  is 16 gauge. 
     The needle  110  can be coupled to a connector  115  (e.g., an adapter). The connector  115  can be a needleless closed device, such as an end cap, injection cap, luer-activated device, injection port, and/or mechanical valve. The connector  115  can be adapted to interface with any desired syringe or tubing. In a preferred embodiment, the connector  115  is a mechanically-closed device, which is automatically self-sealing when not accessed, such as a CLAVE® connector (available from ICU Medical, Inc. (San Clemente, Calif.)). 
     The needle  110  and connector  115  can form a channel for aspiration of particular material residing within the container  105 . The needle  110  can have an adjustable position. The needle  110  can be moved to a desired position or level in the container  105 ; and aspiration can be performed by, for example, coupling the connector  115  to a syringe, pump, or other suction-based device in order to withdraw particular material residing within the container  105  through the needle  110  and connector  115 . 
     The system  100  can further include an expandable seal (or covering)  120 . The expandable seal  120  can form a seal with the connector  115  and container  105  to form a barrier between the interior of the container  105  and an external environment. The expandable seal  120  can be, for example, adhered to and/or mechanically coupled to the container  105  and connector  115 , and can be composed of a suitable rubber, plastic, or other material. Additionally, the expandable seal  120  can be formed such that its elasticity and/or shape (e.g., similar to an accordion) allows the needle  110  to be manipulated within the container  105 . For example, the needle  110  can be lowered and raised within and relative to the container  105 . Together, the expandable seal  120 , connector  115 , and container  105  can form a functionally-closed system such that during use of the system  100 , the needle  110  cannot be exposed to the external environment and/or sterility of the system can be improved and/or maintained. Thus, a functionally-closed system can reduce the risk of sample contamination. 
     Some embodiments of the container  105  include one or more additional openings configured to receive one or more access tubes  125 . The access tubes  125  can be included for sterile docking of the system  100 , particularly when functionally-closed. For example, the access tubes  125  can provide for introduction of a sample or other product into the container  105 . For example, blood can be transferred into the container  105  through a first one of the access tubes  125 , while additional solution (e.g., in an apheresis cryopreservation procedure, Plasma-Lyte® A (available from Baxter (Deerfield, Ill.)) may be added to processed blood product) can be transferred into the container  105  through a second and different one of the access tubes  125 . Any number of access tubes  125  can be included in the system  100 . In one preferred embodiment, six access tubes are included. Additionally, the access tubes  125  can be manufactured with various sizes, lengths, and diameters. In one preferred embodiment, each access tube is about 6 cm in length with an inner diameter of about 1.15 mm and an outer diameter of about 1.6 mm. According to some embodiments, the system  100  includes support elements or features to secure a length of one or more access tubes  125  during centrifugation. For example, clips and/or clasps can be located on and affixed to the container  105  to support a distal portion of one or more access tubes  125 . 
     According to some embodiments, the system  100  can be used for processing cellular therapy products, for example, for blood reduction (e.g., leukoreduction). In the example of reducing blood, blood can be transferred into a closed system  100  through one or more access tubes  125  by sterile docking of the one or more access tubes  125  with a blood supply. The closed system  100  can then be input into a centrifuge. Centrifugation separates the blood into components, including the plasma (supernatant), white cells (buffy coat), and red blood cells (erythrocytes). 
       FIG. 2A  illustrates a closed system  100  containing post-centrifugation blood with the needle  110  in a down position in accordance with some embodiments. Included within the container  105  are the plasma  205 , white blood cells  210 , and red blood cells  215 . The needle  110  can be manipulated by, for example, pulling the connector  115  and/or expandable seal  120  upwards.  FIG. 2B  illustrates the closed system  100  with the needle  110  in a raised position. The expandable seal  120  is expanded, allowing the distal end of the needle  110  to be in a different position relative to the container  105 . The expansion of the expandable seal  120  allows the distal end of the needle  110  to move in the container  105  without having to remove the needle  110  from the sterile internal environment of the closed system  100 . In this manner, the depth by which the needle  110  extends into the container  105  can be controlled. Removal of one or more of the plasma  205 , white blood cells  210 , and/or red blood cells  215  can be performed by manipulating the needle  110  such that the end of the needle  110  is positioned at a similar level as the material to be removed, and withdrawing the material to be removed through the needle  110  and connector  115 , with, for example, a syringe. In the example of leukoreduction, the white blood cells  210  are removed, and the plasma  205  and red blood cells  215  remaining in the container  105  can be used for transfusion. 
     The vertical range of motion of the needle  110  can vary between implementations. In some embodiments, the vertical range of motion of the needle  110  can be between approximately 25 and 50 percent of the height of the container  105 . In other embodiments, the vertical range of motion of the needle  110  is greater than the height of the container  105  (i.e., the distal end of the needle  110  can be adjusted to any desired level within the container  105 ). Additionally, in some embodiments, one or more of the needle  110 , connector  115 , and expandable seal  120  can be integral with the container  105 . In other embodiments, the needle  110 , connector  115 , and/or expandable seal  120  can be disconnected (e.g., unfastened) from the container  105 . 
       FIG. 3  is a cross-section view of a closed system  100  in accordance with some embodiments. The levels of the plasma  205 , white blood cells  210 , and red blood cells  215  are evident in  FIG. 3 . The needle  110  is in a position suitable for removal of the red blood cells  215  from the closed system  100 . 
     Also illustrated in  FIG. 3  are support elements or features  305  extending inward from the conical bottom portion  109  of the container body  106 . One or more support elements  305  can be configured to support the needle  110  during centrifugation. Centrifugation provides a lateral force on the needle  110 . Some centrifuges used to process biological material are spun at maximum angular speeds of 12,000-13,000 rpm, or even greater. One or more support elements  305  can provide support or reinforcement of at least a distal portion of the needle  110  to prevent deformation or significant lateral movement of the needle  110 . In the embodiment shown in  FIG. 3 , prior to centrifugation, the needle  110  can be manipulated such that the distal end of the needle  110  resides within or between the support elements  305 . The support elements  305  can, for example, take the form of posts or a cylinder. The support elements  305  can take other forms, for example, as arms or as a disk extending from the body  106 , including the conical bottom portion  109 , of the container  105  toward the needle  110 . The support elements  305  can include one or more apertures, slots, or perforations for allowing passage of material (e.g., blood components) within the container  105 . 
       FIG. 4  illustrates another embodiment of a closed system  100  for processing cellular therapy products in accordance with some embodiments. In the embodiment illustrated in  FIG. 4 , one or more ports  405  can be included on the container  105 , for example, on the top portion  107 , as shown in  FIG. 4 . The one or more ports  405  can include a needle access port to allow a second aspirating needle to access the material within the container  105 . A second needle access port can be useful, for example, should the needle  110  become disabled. Alternatively or in addition, the one or more ports  405  can include a vent port for stabilizing a pressure differential between the interior of the container  105  and the external environment. 
     Alternatively or in addition, an infusion port  410  can be included on the container  105 , for example, on the conical bottom portion  109 , as shown in  FIG. 4 . The infusion port  410  can include a twist cap or seal that, when removed, allows an infusion line to be attached to the conical bottom  109 . The closed system  100  can operate similar to a bedside infusion bag (e.g., an intravenous bag). The closed system  100  can further include an intravenous pole attachment  420  allowing the closed system  100  to be hung on a standard bedside intravenous pole. The closed system  100  can further include a partially or fully removable end cap  425  to protect the infusion port  410  and/or provide a self-standing skirt or structure to the closed system  100 . The end cap  425  can connect to the container  105  as, for example, a screw cap, a clip, and the like. 
     System  100  can include additional aspects. For example, a locking mechanism can be included to secure the connector  115  and/or the expandable seal  120  relative to the container  105  during centrifugation. System  100  can include an integral filter (e.g., about 0.20-0.24 μm membrane) for separating product components. System  100  can be disposable (e.g., intended for a single use) or reusable. Different types of coatings can be used with respect to parts of system  100 . For example, the needle  110  and/or the container  105  can include a coating of a silicon gel that separates blood cells from plasma. When blood is centrifuged, the silicone gel forms a layer on top of the buffy coat, allowing the blood plasma to be removed more effectively. 
     The present disclosure can be applied to many different clinical procedures, including but not limited to the following procedures: cryopreservation; bedside infusion; plasma depletion; red cell reduction; thaw and wash; donor lymphocyte processing; stem cell transplant; hematopoietic transplants; and the like. 
     As an example,  FIG. 5  is a process flow diagram illustrating a process  500  for performing apheresis cryopreservation of hematopoietic progenitor cells using a closed system  100  in accordance with some embodiments. At step  510 , closed system  100  is provided; and cellular matter is transferred into container  105  of the closed system  100  using a first one or more of a plurality of access tubes  125 . Following step  510 , initial quality control samples can be withdrawn from the container  105  via needle  110 ; and the entire system  100  with the cellular material can be subjected to centrifugation. 
     At step  520 , the cellular matter is volume reduced by removing the plasma supernatant. The volume reduction can occur by moving the needle  110  of the closed system  100  such that a distal end of the needle  110  is at an appropriate level to withdraw the plasma supernatant. The plasma supernatant may then be withdrawn through the needle  110  and connector  115  (using, e.g., a syringe). 
     At step  530 , a plasma substitute, such as Plasma-Lyte® A (available from Baxter (Deerfield, Ill.)), is added to the container  105  of the closed system  100  using another one or more of the plurality of access tubes  125 , different from the first one or more of the plurality of access tube(s)  125  used to introduce the cellular material at step  510 . The plasma substitute can be added to increase the cellular therapy product volume to a desired pre-freeze volume. Following step  530 , quality control samples can be removed using the needle  110 . 
     At step  540 , the closed system  100  and a freezing solution are sterile docked to a harness for distribution of both the freezing solution and the cellular therapy product contained in the closed system  100  into a freeze bag, which can then be frozen. 
     While various inventive embodiments have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and/or structures for performing the function and/or obtaining the results and/or one or more of the advantages described herein, and each of such variations and/or modifications is deemed to be within the scope of the inventive embodiments described herein. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the inventive teachings is/are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific inventive embodiments described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, inventive embodiments may be practiced otherwise than as specifically described and claimed. Inventive embodiments of the present disclosure are directed to each individual feature, system, article, material, kit, and/or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and/or methods, if such features, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the inventive scope of the present disclosure. 
     The above-described embodiments can be implemented in any of numerous ways. Also, various inventive concepts may be embodied as one or more methods, of which an example has been provided. The acts performed as part of the method may be ordered in any suitable way. Accordingly, embodiments may be constructed in which acts are performed in an order different than illustrated, which may include performing some acts simultaneously, even though shown as sequential acts in illustrative embodiments. 
     All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. 
     All definitions, as defined and used herein, should be understood to control over dictionary definitions, definitions in documents incorporated by reference, and/or ordinary meanings of the defined terms. 
     The indefinite articles “a” and “an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean “at least one.” 
     The phrase “and/or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and/or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and/or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and/or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc. 
     As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and/or” as defined above. For example, when separating items in a list, “or” or “and/or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of” or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e. “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law. 
     As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and/or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc. 
     In the claims, as well as in the specification above, the terms “about,” “approximately,” and the like are to be understood to mean+/−10% of the total amount stated, e.g., about 5 would include 4.5 to 5.5, about 10 would include 9 to 11, and about 100 would include 90-110. 
     In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of” and “consisting essentially of” shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03. 
     It is to be understood that the disclosed subject matter is not limited in its application to the details of construction and to the arrangements of the components set forth in the following description or illustrated in the drawings. The disclosed subject matter is capable of other embodiments and of being practiced and carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein are for the purpose of description and should not be regarded as limiting. 
     As such, those skilled in the art will appreciate that the conception, upon which this disclosure is based, may readily be utilized as a basis for the designing of other structures, methods, and systems for carrying out the several purposes of the disclosed subject matter. For example, the logic flow depicted in the accompanying figures and described herein does not require the particular order shown, or sequential order, to achieve desirable results. It is important, therefore, that the claims be regarded as including such equivalent constructions insofar as they do not depart from the spirit and scope of the disclosed subject matter. 
     Although the disclosed subject matter has been described and illustrated in the foregoing exemplary embodiments, it is understood that the present disclosure has been made only by way of example, and that numerous changes in the details of implementation of the disclosed subject matter may be made without departing from the spirit and scope of the disclosed subject matter, which is limited only by the claims which follow.