Patent Publication Number: US-2021178148-A1

Title: Systems, apparatus, and methods for delivery of therapeutic substance to nasal cavity

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application claims priority to and the benefit of U.S. Provisional Patent Application No. 62/579,243, filed Oct. 31, 2017 and titled “SYSTEMS, APPARATUS, AND METHODS FOR DELIVERY OF THERAPEUTIC SUBSTANCE TO NASAL CAVITY,” which is incorporated herein by reference in its entirety. 
    
    
     TECHNICAL FIELD 
     The present disclosure relates generally to systems, apparatus, and methods for delivering a substance to a nasal cavity or surrounding regions of a subject. More specifically, the present disclosure relates to systems, apparatus, and methods for accessing and delivering a therapeutic substance, such as an anesthetic, to a region within or proximate to a nasal cavity. 
     BACKGROUND 
     The nasal cavity forms a part of a subject&#39;s respiratory system. As shown in  FIG. 1 , the nasal cavity is an air-filled space disposed behind an exterior portion of the nose. Four pairs of sinuses are disposed around the nasal cavity, including the ethmoid sinuses, the maxillary sinuses, the frontal sinuses, and the sphenoid sinuses. The ethmoid sinuses are located in the ethmoid bone, which separates the nasal cavity from the brain, the maxillary sinuses are located behind the cheekbones near the maxillae or upper jaws, the frontal sinuses are located in the center of the frontal bone or forehead above each eye, and the sphenoid sinuses are located in the sphenoid bone near the optic nerve and the pituitary gland. 
     The nasal cavity is divided by a vertical partition, the nasal septum, into a right and a left side. Both sides of the nasal cavity are hollow and normally filled with air. The nasal cavity is exposed to the atmosphere of the outside environment via the anterior nares of the nose, as shown in  FIG. 1 . The anterior nares allow for the inhalation and exhalation of air through the nasal cavity. The nasal cavity is bounded by sidewalls, which include three pairs of turbinates or nasal concha—the inferior turbinates, the middle turbinates, and the superior turbinates. The turbinates project into the nasal cavity and divide the nasal passage of the nasal cavity into four groove-like air passages. As shown in  FIG. 1 , the inferior turbinates are disposed below the middle turbinates and the superior turbinates on the septum, the middle turbinates are disposed between the inferior turbinates and the superior turbinates, and the superior turbinates are disposed above the middle turbinates and the inferior turbinates. The turbinates are responsible for regulating airflow during inhalation. 
     The nasal cavity opens into the nasopharynx, which forms the upper part of the pharynx or throat. The nasopharynx contains a collection of lymphoid tissue towards the midline known as adenoids. The nasopharynx also includes a Eustachian tube opening, which connects the nasopharynx to the middle ear via the Eustachian tube. The Eustachian tube serves as an air channel between the middle ear and the nasopharynx that helps fill the middle ear with air and equalize the air pressure of the middle ear with the atmosphere. 
     The nasal cavity and the sinuses are lined with tissue known as mucosa that produces mucus. The mucus-covered surfaces of the nasal cavity help filter, humidify, and warm or cool air that is inhaled by a subject. The mucus-covered surfaces also trap harmful particles such as allergens or bacteria. The nasal cavity and its surrounding tissue, however, can become inflamed, infected, or obstructed. To treat these conditions, a physician may need to deliver therapeutic substances to the nasal cavity or its surrounding tissue. For example, a physician can deliver a therapeutic substance such as an anesthetic to tissue surrounding or proximate to the nasal cavity to alleviate pain or other discomfort during a surgical operation (e.g., a skull-based surgery, septoplasty, dental surgery, etc.). The physician can also delivery other therapeutic substances (e.g., analgesics, anti-inflammatories, antibiotics, antivirals, antifungals, antiparasitics, decongestants, mucokinetics, antihistamines, antioxidants, immunosuppressive agents, dissociatives, steroids, sedatives or hypnotics, anticholinergics, antiemetics, antiepiletics) to reduce or treat inflammation, infection, congestion, pressure, and/or other conditions within the nasal cavity and/or other conditions of a patient&#39;s body. 
     Delivery of therapeutic substances, including anesthetics, to the nasal cavity or surrounding tissue regions can be used to treat and/or aid in treatment of allergic or non-allergic rhinitis, nasal obstruction (e.g., an obstruction caused by sinusitis, allergies, etc. or an anatomical factor such as a deviated septum, enlarged adenoids, nasal polyps, foreign objects, turbinate hypertrophy, nasal valve collapse, etc.), nasal polyps, sinusitis (e.g., ostium, intra-sinus, post-sinus surgery), epistaxis, allergies, migraines, and tinnitus, polyposis, etc. Oftentimes, the therapeutic substance may need to be maintained against a tissue surface for an extended period of time to provide effective results. For example, for treating inflammation or applying an anesthetic, a therapeutic substance may need to be applied to a tissue surface within the nasal cavity for a sufficient period of time such that the therapeutic substance can diffuse or perfuse through the surface into the tissue. Additional apparatuses and methods for delivering a therapeutic substance to the nasal cavity or surrounding tissue are desirable. 
     SUMMARY 
     Systems, apparatus, and methods are described for delivering a therapeutic substance to a nasal cavity and/or surrounding tissue regions of a subject. The delivery system preferably provides soft, non-painful contact with the nasal cavity and/or surrounding tissue. In some embodiments, the therapeutic substance may be an anesthetic, such as lidocaine, which may be used to anesthetize the nasal cavity or its surrounding tissue in preparation for a surgical operation. The delivery system and method can enable delivery of the therapeutic substance over a sufficient time to deliver a therapeutically effective dose, without requiring the subject to be still and/or to maintain an awkward head position or orientation, e.g. with their head tilted to allow drops of liquid therapeutic substance to be maintained in position against a tissue surface. In some embodiments, the therapeutic substance can be an anti-hemorrhagic or hemostatic agent, such as an anti-fibrinolytic acid, that reduces bleeding during or after a surgical procedure. The therapeutic substance can be delivered before, during, and/or after a surgical procedure to improve surgical visualization and avoid nasal packing. In some embodiments, the therapeutic substance can be an analgesic, an anti-inflammatory, an antibiotic, an antiviral, an antifungal, an antiparasitic, a decongestant, a mucokinetic, an antihistamine, an antioxidant, an immunosuppressive agent, an dissociative, a steroid, a sedative or hypnotic, an anticholinergic, an antiemetic, an antiepiletic, etc. or any combination of therapeutic substances. 
     In some embodiments, systems and methods described herein can deliver a therapeutic substance to a nasal cavity and/or surrounding tissue regions of a subject using iontophoresis. With iontophoresis, a low-level electric current can be applied to a charged solution (i.e., an iontophoresis fluid) to transport ions of a therapeutic substance (e.g., an anesthetic, an analgesic, an anti-inflammatory, an antibiotic, an antiviral, an antifungal, an antiparasitic, a decongestant, a mucokinetic, an antihistamine, an antioxidant, an immunosuppressive agent, an dissociative, a steroid, a sedative or hypnotic, an anticholinergic, an antiemetic, an antiepiletic, etc.) across skin or other tissue surfaces into the surrounding tissue. The delivery system and method can be configured to maintain an iontophoresis fluid against a tissue surface and to apply an electric current to the fluid to drive delivery of a therapeutic substance in the iontophoresis fluid through the tissue surface. The delivery system and method can include an electrode device that is in fluid communication with the iontophoresis fluid such that an electric current can be supplied to the fluid to perform the iontophoresis procedure. 
     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 the anatomy of a nasal cavity and surrounding regions. 
         FIG. 2  is a schematic illustration of a therapeutic delivery system according to some embodiments. 
         FIG. 3  is a flow diagram illustrating a method for delivering a therapeutic substance to a target area in a nasal cavity of a subject in accordance with some embodiments. 
         FIGS. 4A-4B  are a schematic illustration of a therapeutic delivery system including an electrode device according to some embodiments. 
         FIG. 5  is a flow diagram illustrating a method for delivering a therapeutic substance to a target area in a nasal cavity of a subject in accordance with some embodiments. 
         FIGS. 6A-6B  are schematic illustrations of a therapeutic substance delivery system according to an embodiment. 
         FIGS. 7A-7B  are schematic illustrations of a therapeutic substance delivery system according to an embodiment. 
         FIGS. 8A-8B  are schematic illustrations of a therapeutic substance delivery system according to an embodiment. 
         FIG. 9  is a schematic illustration of a therapeutic substance delivery system according to an embodiment. 
         FIGS. 10A and 10B  are schematic illustrations of a therapeutic substance delivery system according to an embodiment. 
         FIGS. 11A and 11B  are schematic illustrations of a therapeutic substance delivery system according to an embodiment. 
         FIGS. 12A and 12B  are schematic illustrations of a therapeutic substance delivery system according to an embodiment. 
         FIG. 13  is a schematic illustration of a therapeutic substance delivery system according to an embodiment. 
         FIG. 14  is a schematic illustration of a therapeutic substance delivery system according to an embodiment. 
         FIG. 15  is a schematic illustration of a therapeutic substance delivery system according to an embodiment. 
         FIG. 16  is a schematic illustration of a therapeutic substance delivery system according to an embodiment. 
         FIG. 17  is a schematic illustration of a therapeutic substance delivery system according to an embodiment. 
         FIGS. 18A and 18B  are schematic illustrations of a therapeutic substance delivery system according to an embodiment. 
         FIGS. 19A and 19B  are schematic illustrations of a therapeutic substance delivery system according to an embodiment. 
     
    
    
     DETAILED DESCRIPTION 
     Systems, apparatus, and methods are described herein for delivery of therapeutic substances to the nasal cavity and/or surrounding tissue areas. As illustrated schematically in  FIG. 2 , a delivery system  100  can deliver a therapeutic substance TS to a target area TA in a nasal cavity NC of a subject. Although target area TA is shown as being disposed within nasal cavity NC, in other embodiments, target area TA can be disposed outside of the nasal cavity NC (e.g., target area TA can be proximate to or adjacent to the nasal cavity NC). 
     Delivery system  100  can be an example of a passive delivery system in which a therapeutic substance TS is allowed to elute, diffuse, or otherwise be passively released into a target area TA. Delivery system  100  can include a reservoir  110  that can contain therapeutic substance TS. A delivery interface  120  can be part of, or coupled fluidically to, reservoir  110 , enabling therapeutic substance TS to contact, and enter (e.g., via diffusion), target area TA. Optionally, an inlet  130  can be coupled fluidically to reservoir  110 , enabling reservoir  110  to be filled, or refilled, with the therapeutic substance TS. Delivery system  100  can include a body or housing  140  that supports, or defines, reservoir  110 , delivery interface  120 , and/or inlet  130 . Delivery system  100  may also include a retrieval element  145  by which system  100  can be removed from the nasal cavity NC of the subject. Delivery system  100  may be deployed into an operative position in the nasal cavity NC of the subject with a deployment device  180 , which may be releasably engaged with delivery system  100  in preparation for deployment of delivery system  100 , and released from delivery system  100  after deployment in nasal cavity NC, or alternatively may remain engaged with delivery system  100  during delivery of therapeutic substance TS. 
     Each component of delivery system  100  can be implemented in various ways. Reservoir  110  may be formed by a solid structure within which therapeutic substance TS (in fluid and/or solid form) may be eluted, diffused, or released by other mechanisms. For example, reservoir  110  may be an open cell foam in which therapeutic substance TS in liquid form is contained and from which therapeutic substance TS may be released by osmotic diffusion from a distal surface of the foam reservoir that is in contact with the target area TA (the delivery interface  120 ). That is, delivery or release of therapeutic substance TS may be driven by a differential in concentration of therapeutic substance TS in the foam and in target area TA. The foam reservoir  110  may be delivered by mechanical insertion through the nasal cavity into operative apposition with the target area TA. As needed, therapeutic substance TS may be added to reservoir  110  by supplying it, e.g. in liquid form, to a proximal surface of the foam, serving as inlet  130 . 
     In another embodiment, reservoir  110  may be in the form of a solid structure that biodegrades, i.e. formed of a material that breaks down in contact with tissue, and can release therapeutic substance TS as reservoir  110  biodegrades. In some embodiments, reservoir  110  can be formed of a structure that degrades based on exposure to environmental conditions associated with the nasal cavity NC. For example, reservoir  110  can degrade in response to being subjected to a certain temperature for a predefined period of time. Alternatively or additionally, reservoir  110  can degrade in response to application of pressure (e.g., a user pressing on an outside surface of the nose such that pressure is applied to the reservoir  110  disposed inside the nose), a change in pressure (e.g., based on a user inhaling and/or exhaling), and moisture level associated with air within the nasal cavity and/or a tissue surface, etc. Reservoir  110  can be configured to maintain apposition between delivery interface  120  and target area TA (or a tissue surface above target area TA) until a therapeutically effective amount or dose of therapeutic substance TS has been delivered to the target area TA. Accordingly, reservoir  110  can be configured to degrade over a period of time that enables the delivery interface  120  to be maintained against the target area TA for a sufficient amount of time to enable a therapeutically effective amount of therapeutic substance TS to be delivered to the target area TA. 
     In other embodiments, reservoir  110  may be formed of a carrier material in which therapeutic substance TS in liquid form is mixed, or in solid, particulate form is dissolved, suspended, etc. The carrier material and therapeutic substance TS may be delivered through the nasal cavity NC into operative apposition with target area TA, for example by injection, spray, or other suitable delivery mechanism. Thus, reservoir  110  may be formed in situ on target area TA. The carrier material and therapeutic substance may be delivered as a foam or mousse or a hydrogel. In another embodiment, the carrier may be deliverable in a liquid form that changes to a solid form, e.g. by a change in temperature. Such carriers are known from applications such as liquid bandages. In this embodiment, the carrier, containing therapeutic substance TS, may be injected or sprayed in liquid form against the surface of target area TA and then solidify due to the higher temperature of nasal cavity NC, thus forming reservoir  110  in situ on target area TA. 
     In another embodiment, reservoir  110  may be in the form of a stable / solid thin film that may contain therapeutic substance TS as with the other embodiments described above, and the therapeutic substance TS may be delivered to target area TA by diffusion when the thin film is in apposition with target area TA. Alternatively, the thin film may function as a body  140  on which a reservoir  110  in the form of a foam, hydrogel or other material containing therapeutic substance TS may be carried. In other words, the body  140  may be a thin film substrate, and reservoir  110  may be a layer of material disposed on the distal surface of the body  140 . 
     In another embodiment, reservoir  110  may be in the form of a bundle or other mass of wicking, fibrous material, i.e. a material that can absorb therapeutic substance TS in liquid form, and conduct therapeutic substance TS by capillary action through the body of reservoir  110  to a distal surface of reservoir  110  in contact with target area TA, from which the therapeutic substance TS can diffuse into target area TA. As needed, therapeutic substance TS may be added to reservoir  110  by supplying it, e.g. in liquid form, to a proximal surface or end of the wicking material, serving as inlet  130 . 
     In some embodiments, including those described above, reservoir  110  can be configured to deform, e.g., change configuration and/or shape, once reservoir  110  is disposed within the nasal cavity NC. For example, as depicted in  FIGS. 6A-12B  (further described below), a reservoir can be formed of a material that changes shape such that a delivery interface associated with the reservoir conforms to a shape of a tissue surface. Stated differently, a reservoir can be a deformable structure that includes a delivery interface capable of deforming to conform to a shape of a tissue surface. 
     Although, in the embodiment depicted in  FIG. 2 , delivery system  100  has one delivery interface  120  that can contact and deliver therapeutic substance TS to one target area TA, in other embodiments, delivery system  100  can have multiple delivery interfaces  120  that enable therapeutic substance TS to contact, and enter, multiple target areas TA. In some embodiments, delivery system  100  can deliver therapeutic substance TS to multiple target areas TA simultaneously. 
     A method  200  of delivering therapeutic substance TS to target area TA in nasal cavity NC is illustrated schematically in  FIG. 3 . 
     Initially, therapeutic substance TS may be added to the reservoir, such as reservoir  110  described above, in step  202 . In step  204 , a delivery system, such as delivery system  100  disclosed above, is deployed in nasal cavity NC of the subject. In particular, deployment includes disposing the delivery system with its delivery interface, such as delivery interface  120 , in operative apposition with target area TA within nasal cavity NC of the subject. In step  206 , the delivery system is allowed to be retained in nasal cavity NC of the subject for sufficient time to deliver a therapeutically effective dosage of the therapeutic substance TS to target area TA of the subject. In step  208 , the delivery system is removed from nasal cavity NC of the subject. 
     Optionally, in step  210 , a test may be conducted to evaluate the efficacy of the delivery of therapeutic substance TS. For example, if therapeutic substance TS is an anesthetic, the therapeutically effective dosage to be delivered to target area TA of the subject may be the dosage required to anesthetize target area TA so that a medical procedure may performed, such as a surgery to tissue or bone within nasal cavity NC. The efficacy of delivery of the therapeutic substance TS may thus be a test of anesthetization of target area TA, e.g. by touching target area TA and assessing the subject&#39;s response. In step  212 , if it is determined that the delivery was not effective, the method may revert to step  204  to dispose the, or another, delivery system in nasal cavity NC to deliver more therapeutic substance TS. Alternatively, if it is determined that the delivery was effective, the method may proceed to step  214 , in which a medical procedure, such as a surgical operation, may be started. In another embodiment, therapeutic substance TS can be an antihistamine, a steroid, and/or an antibiotic used to treat an allergy or an infection within nasal cavity NC. The therapeutically effective dosage to be delivered to target area TA of the subject may be a dosage required to treat the condition, and the efficacy of delivery can be tested by examining target area TA and/or evaluating symptoms that are commonly associated with the condition (e.g., inflammation, congestion, nasal discharge, pain, bleeding, sneezing, itching, etc.). In step  212 , if it is determined that the delivery was not effective, then the method may revert to step  204  to apply additional therapeutic substance TS to target area TA. Alternatively, if it is determined that the delivery was effective, then the method can terminate without proceeding to step  214  or, optionally, the method can proceed to step  214 , where another medical procedure can be started. For example, if a delivery system is being used by a subject at home or otherwise outside of a medical facility, the subject can test, at step  210 , the efficacy of the delivery of therapeutic substance TS by evaluating whether certain symptoms of a nasal condition (e.g., inflammation, congestion, nasal discharge, pain, bleeding, sneezing, itching, etc.) remain after removing the delivery system. And at step  212 , if it is determined that the delivery was not effective, the subject can place the delivery system or another delivery system back in the subject&#39;s nasal cavity to apply additional therapeutic substance TS to target area TA. Alternatively, if it is determined that the delivery was effective, method  200  can terminate. 
     Therapeutic substance TS can be any suitable substance or combination of substances, in any suitable dosage form or combination of dosage forms. Non-limiting examples include analgesics (e.g., non-steroidal anti-inflammatory drugs (NSAIDs) like acetaminophen, COX-2 inhibitors, opioids, flupirtine, cannabinoids, capsaicinoids, etc.), anesthetics (e.g. lidocaine, benzocaine, procaine, amethocaine, cocaine, tetracaine, prilocaine, bupivicaine, levobupivacaine, ropivacaine, mepivacaine, dibucaine, etidocaine, etc.), anti-inflammatories (e.g. NSAIDs like aspirin, ibuprofen, and naproxen, peptides, steroids or glucocorticosteroids like dexamethasone, etc.), antibiotics (e.g., ciprofloxacin, ciprofloxacin otic suspension, amoxicillin, amoxicillin-clavulanate, beta lactamase inhibitor, etc.), antivirals, antifungals, antiparasitics, decongestants (e.g., ephedrine, levomethamphetamine, naphazoline, oxymetazoline, phenylephrine, phenylpropanolamine, propylhexedrine, synephrine, tetrahydrozoline, xylometazoline, pseudoephedrine, tramazoline, etc.), mucokinetics (e.g., mucolytics like acetylcysteine, expectorants like guaifenesin, surfactants, etc.), antihistamines, antioxidants, immunosuppressive agents, and dissociatives (e.g., NMDA receptor antagonists like gacyclidine, κ-opioid receptor agonists, etc.). Suitable dosage form(s) can include liquids (including solutions, suspensions, and colloids) delivered (e.g., sprayed) as a liquid, liquid aerosol, foam, emulsion, sol, etc.; gases (including solutions, suspensions, and colloids) delivered as a vapor; and solids (including solutions, suspensions, and colloids) delivered as solid aerosols, solid foam, gel, sol, etc., including solids that are incorporated into or onto a solid or porous substrate for elution or release by biodegradation of the substrate. The therapeutic substance can include small molecules that can penetrate through mucosa, skin, or other tissue surfaces. 
     Suitable biodegradable solids may include, but are not limited to, agro-polymers, including polysaccharides and proteins, or biopolyesters including natural monomers (e.g., polyhydroxyalkanoates (PHAs) like poly-3-hydroxybutyrate (PHB), polyhydroxyvalerate (PHV) and polyhydroxyhexanoate (PHH), etc.), renewable monomers (e.g., polylactic acid (PLA)), and synthetic monomers (e.g., polybutylene succinate (PBS), polycaprolactone (PCL), etc.). Additional examples of biodegradable solids include polyglycolic acid, poly(lactic-co-glycolic) acid, poly-ε-caprolactone, polydioxanone, chitosan, hyaluronic acid, poly(2-hydroxyethyl-methacrylate), poly(ethylene glycol), polyurethanes, poly(ester amide)s, polyanhydrides, polyvinyl alcohol, cellulose esters, polyethylene terephthalate, and hydrogels. In some embodiments, a normal plastic polymer such as polyethylene or polypropylene may be incorporated with an additive which causes degradation (e.g., due to oxidation). Biodegradable materials may include films, fibers, extruded or molded products, laminates, foams, powders, nonwovens, adhesives, and/or coatings. 
       FIGS. 4A and 4B  are schematic illustrations of a delivery system  300  according to another embodiment. Delivery system  300  can be an example of an active delivery system in which a therapeutic substance is driven via iontophoresis (e.g., using an electric current) into a target area TA. 
     Similar to delivery system  100 , delivery system  300  can include a reservoir  310 , a delivery interface  320 , and a body  340 . As illustrated in  FIG. 4A , delivery system  300  can be disposed within a nasal cavity NC of a subject and be brought into operative apposition with a target area TA within nasal cavity NC. Alternatively, delivery system  300  can be positioned outside of nasal cavity NC (e.g., outside of the subject&#39;s nose) and be brought into operative apposition with external tissue ET (e.g., the external skin of a subject&#39;s nose) located proximate or adjacent to target area TA. Delivery system  300  can be configured to deliver a therapeutic substance to a single target area TA or to multiple target areas TA. For example, delivery system  300  can have multiple reservoirs  310  and delivery interfaces  320  such that delivery system  300  can deliver a therapeutic substance to multiple target areas TA within and/or proximal to nasal cavity NC at substantially the same time. In other embodiments, delivery system  300  can deliver a therapeutic substance to multiple target areas TA in a sequential manner. 
     Reservoir  310  can contain an iontophoresis fluid IF, including an ionic therapeutic substance that can be driven (e.g., transported) into tissue by applying an electric current to iontophoresis fluid IF. The iontophoresis fluid IF can contain the ionic therapeutic substance, e.g., iontophoresis fluid IF can be an ionic solution with ions of the therapeutic substance. The therapeutic substance can include small molecules that can penetrate through mucosa, skin, or other tissue surfaces. Iontophoresis can be used to deliver a wide range of relatively small molecules. For example, iontophoresis can be used to deliver anesthetics, anti-histamines, and anti-inflammatory drugs to target tissue. Examples of these molecules that have been successfully delivered via iontophoresis include lidocaine with a molecular weight of approximately 234 Da, epinephrine with a molecular weight of approximately 183 Da, anti-histamines with a molecular weight of approximately 380 Da, and steroids with a molecular weight of approximately 400-500 Da. Iontophoresis has also been used to deliver small ions such as lithium with a molecular weight of approximately 7 Da to target areas to treat gouty arthritis. Iontophoresis can also be used to enhance transdermal delivery of larger molecules such as insulin having a molecular weight of approximately 6000 Da. In some embodiments, iontophoresis fluid IF can also include a buffering solution for maintaining the pH of the iontophoresis fluid IF at biologically appropriate levels. In some embodiments, iontophoresis fluid IF can also include inactive ingredients suitable for nasal applications. In some embodiments, iontophoresis fluid IF can include more than one therapeutic substance. 
     Advantages of iontophoresis include quicker delivery rates and deeper local penetration of a therapeutic substance into surrounding tissue. For example, in certain applications, it may be desirable to have a therapeutic substance penetrate deeper into tissue such that the therapeutic substance can have an effect on nerve endings found in deeper tissue structures. Alternatively or additionally, it may be desirable to increase the rate of delivering a therapeutic substance into tissue, e.g., to produce a stronger and/or faster drug effect, to avoid breakdown of a drug delivery interface prior to effective drug delivery, etc. For example, when a delivery system and/or delivery interface is designed to break down over time (e.g., in the case of a degradable carrier material), iontophoresis can be used to increase drug uptake prior to breakdown of the delivery system and/or delivery interface. 
     Delivery interface  320  can be part of, or coupled fluidically to, reservoir  310 , enabling iontophoresis fluid IF to come into contact with a tissue surface. Delivery interface  320  and/or reservoir  310  can be implemented in various ways, including, for example, a solid structure (e.g., a container or cup, a flexible bag, a sponge), a carrier material (e.g., a foam, a mousse, a hydrogel), a thin film or membrane, or a bundle or mass of fibrous material. Optionally, an inlet  330  can be coupled fluidically to reservoir  310 , enabling reservoir  310  to be filled, or refilled, with iontophoresis fluid IF. Body  340  can support, or define, reservoir  310 , delivery interface  320 , and/or inlet  330 . Delivery system  300  optionally can include a retrieval element  345  for removing delivery system  300  from nasal cavity NC and/or another location proximate to the nasal cavity NC and a deployment device  380  for deploying delivery system  300  in nasal cavity NC and/or another location proximate to the nasal cavity NC. In some embodiments, a single component or mechanism such as, for example, a flexible shaft, beam, bar, wire, etc. can serve as both retrieval element  345  and deployment device  380 . 
     Delivery system  300  can include an electrode device  350  that is configured to apply an electric current to iontophoresis fluid IF to transport the therapeutic substance within iontophoresis fluid IF across the tissue surface into the surrounding tissue (e.g., target area TA, external tissue ET). Electrode device  350  can include a control unit for powering and controlling application of the electric current, an electrode for applying the electric current, and a return electrode for providing an electrical return path to the control unit. The electrode for applying the electric current can be positioned in contact with iontophoresis fluid IF, and the return electrode can be distanced from that electrode e.g., at a location on a patient&#39;s skin (e.g., back of neck, shoulder, etc.). In some embodiments, electrode device  350  can be coupled to and/or integrally formed with body  340  and/or reservoir  310 . In other embodiments, electrode device  350  can be brought into engagement with reservoir  310  such that a tip (e.g., an electrode tip) of electrode device  350  is in contact with iontophoresis fluid IF and can apply an electric current to iontophoresis fluid IF. Electrode device  350  can be designed to deliver a low-level current such that patient discomfort is reduced. For example, electrode device  350  can include an electrode with a relatively large conductive surface that helps reduce current density. In some embodiments, electrode device  350  can deliver a current with a current profile that reduces discomfort during delivery. For example, the current profile can gradually ramp-up and/or ramp-down, or have an alternating profile (e.g., pulsed, sine-wave, etc.). In some embodiments, electrode device  350  can also include insulating components and/or portions (e.g., an insulating sheath or sleeve) that can surround parts of the conductive surface of the electrode and help direct current flow toward the tissue surface when in use. In some embodiments, electrode device  350  can have a portion that is flexible or malleable. 
     In some embodiments, iontophoresis systems and/or electrode devices described in U.S. Pat. No. 8,452,392 to Morriss, et al., entitled “Systems and methods for anesthetizing ear tissue,” the disclosure of which is incorporated herein by reference, can be used and/or adapted for use in delivering a therapeutic substance to a subject&#39;s nasal cavity NC or surrounding tissue regions. For example, the dimensions, shape, or other configuration of an electrode device, such as electrode device  350  and/or electrode devices disclosed in U.S. Pat. No. 8,452,392, can be designed according to the anatomy of a subject&#39;s nasal cavity NC. 
     In some embodiments, electrode device  350  is configured to provide a direct current (DC) signal. For example, electrode device  350  can provide a constant current (e.g., approximately 1 mA) for a period of time. In some embodiments, electrode device  350  is configured to provide an alternating current (AC) signal with a DC offset. For example, a DC signal can be modulated by a circuit with an AC signal to produce a modulated current signal. The modulated current signal can be any one of a pulsed square waveform, a sinusoidal waveform, a sawtooth waveform, a trapezoidal waveform, etc. In some embodiments, electrode device  350  is configured to ramp up and/or ramp down the current. For example, electrode device  350  can gradually ramp up a constant current or a modulated current until the current reaches a predefined value (e.g., approximately  1  mA) and/or to gradually ramp down the current from a predefined value to zero. In some embodiments, current profiles such as those described in U.S. application Ser. No. 13/804,491, entitled “System and method for providing iontophoresis at tympanic membrane, published as U.S. Patent Publication No. 2014/0276352, the disclosure of which is incorporated herein by reference, can be used and/or adapted to deliver a therapeutic substance to a subject&#39;s nasal cavity NC or surrounding tissue regions. 
     Similar to delivery system  100 , each component of delivery system  300  can be implemented in various ways. Reservoir  310  may be formed by a solid structure that contains iontophoresis fluid IF and provides an outlet (e.g., delivery interface  320 ) through which a therapeutic substance in iontophoresis fluid IF can be delivered to a tissue region (e.g., target area TA). For example, reservoir  310  may be an open cell foam in which iontophoresis fluid IF is contained and from which a therapeutic substance within iontophoresis fluid IF can be delivered via an iontophoresis procedure to a tissue region. That is, delivery of the therapeutic substance may be driven by an electric current that is applied to the iontophoresis fluid IF. The foam reservoir  310  may be delivered by mechanical insertion through nasal cavity NC into operative apposition with a tissue surface. As needed, iontophoresis fluid IF and/or therapeutic substance may be added to reservoir  310  by supplying it, e.g. in liquid form, to a proximal surface of the foam, serving as inlet  330 . 
     In other embodiments, reservoir  310  may be formed of a carrier material (e.g., a foam, a mousse, a hydrogel) that contains iontophoresis fluid IF. For example, the carrier material can be saturated and/or mixed with iontophoresis fluid IF. In some embodiments, the carrier material can be electrically conductive, e.g. capable of conducting an electric current supplied from an electrode device, such as electrode device  350 . The carrier material and iontophoresis fluid IF may be delivered through the nasal cavity into operative apposition with a tissue surface, for example, by injection, spray, or other suitable delivery mechanism. Thus, reservoir  310  may be formed in situ on a tissue surface. In some embodiments, the carrier may be deliverable in a liquid form that changes to a solid form (e.g., a solid porous material). 
     In other embodiments, reservoir  310  may be in the form of a thin film or membrane that contains iontophoresis fluid IF. The thin film or membrane can be electrically conductive, e.g. capable of conducting an electric current supplied from an electrode device, such as electrode device  350 . The thin film or membrane can be placed in contact with or proximate to the electrode device. In some embodiments, the thin film or membrane can function as a body  320  on which a reservoir  310  in the form of a foam, hydrogel, or other material containing iontophoresis fluid IF may be carried. 
     In another embodiment, reservoir  310  may be in the form of a bundle or other mass of wicking, fibrous material, i.e. a material that can absorb iontophoresis fluid IF, and conduct iontophoresis fluid IF by capillary action through the body of reservoir  310  to a distal surface of reservoir  310  in contact with a tissue surface, from which a therapeutic substance within iontophoresis fluid IF can be delivered via an iontophoresis procedure into a tissue region. An electrode device (e.g., electrode device  350 ) can be placed in contact with the wicking, fibrous material to supply an electric current to the iontophoresis fluid IF to drive the therapeutic substance into the tissue region. As needed, iontophoresis fluid IF and/or therapeutic substance may be added to reservoir  310  by supplying it, e.g. in liquid form, to a proximal surface or end of the wicking material, serving as inlet  330 . 
     A method  400  of delivering a therapeutic substance via an iontophoresis procedure to a target area TA is illustrated schematically in  FIG. 5 . In step  402 , iontophoresis fluid IF containing a therapeutic substance can be added to the reservoir, such as reservoir  310  described above. In step  404 , a delivery system, such as delivery system  300  disclosed above, is disposed proximate or adjacent to a target area TA of the subject. For example, the delivery system can be disposed with its delivery interface, such as delivery interface  320 , in operative apposition with target area TA of the subject. Alternatively, the delivery system can be disposed with its delivery interface in operative apposition with a tissue surface, such as external tissue ET. In particular, the delivery system can be disposed outside of a subject&#39;s nose but in operative apposition with an external skin surface of the nose and/or surrounding area (e.g., surrounding facial area). 
     In step  405 , an electrode device, such as electrode device  350 , can be used to deliver the therapeutic substance within iontophoresis fluid IF to target area TA using iontophoresis. For example, the electrode device can be brought into contact with the reservoir and/or iontophoresis fluid IF and used to supply a current to iontophoresis fluid IF to transport the therapeutic substance into target area TA. In step  406 , the delivery system is allowed to be retained proximate to target area TA for sufficient time to deliver a therapeutically effective dosage of the therapeutic substance to target area TA of the subject. In step  408 , the delivery system is removed, e.g. from nasal cavity NC or an area proximate to nasal cavity NC. 
     Similar to method  200  described above, method  400  may also include optional steps  410 ,  412 , and  414 . In step  410 , a test may be conducted to evaluate the efficacy of the delivery of therapeutic substance. In step  412 , if it is determined that the delivery was not effective, the method may revert to step  404  to dispose the, or another, delivery system proximate to target area TA to deliver more therapeutic substance to target area TA. Alternatively, if it is determined that the delivery was effective, the method may proceed to step  414 , in which a medical procedure, such as a surgical operation, may be started. In some embodiments, similar to that described above with respect to method  200 , where a therapeutic substance, such as, for example, an antihistamine, a steroid, and/or an antibiotic, is delivered to treat a condition in nasal cavity NC, the method  400  may terminate after step  412  when it is determined that the delivery of the therapeutic substance was effective. 
     In addition or alternatively, delivery systems described herein can be used to deliver a therapeutic substance via electroosmosis. For example, a delivery system (e.g., delivery system  300 ) can be used to deliver a therapeutic substance to target area TA via electroosmosis in addition to iontophoresis. The delivery system can include a reservoir (e.g., reservoir  310 ), which can contain a fluid including non-ionic molecules that can pass into target area TA via a concentration gradient. The delivery can occur under the influence of an electric field via the application of an electric current to the fluid, which can include an ionic component that delivers the applied electric current to a tissue membrane to open channels in the tissue membrane. After the channels in the tissue membrane are opened, the non-ionic drug molecules can be delivered to target area TA via a concentration gradient. 
     Various non-limiting, exemplary embodiments are described below. 
       FIGS. 6A and 6B  schematically illustrate a delivery system  500  according to a first embodiment. In this embodiment, delivery system  500  includes a reservoir  510  implemented as a unitary solid structure formed of a foam material. Therapeutic substance TS is disposed within the foam material of reservoir  510 , and can move through the foam material to delivery interface  520 , which is the distal surface of the foam structure. 
     In use, delivery interface  520  is placed in apposition with a target area TA to permit therapeutic substance TS to be absorbed into target area TA, such as by osmotic transport. In the embodiment depicted in  FIGS. 6A and 6B , target area TA can be a subject&#39;s adenoid or tissue proximate to the adenoid. In other embodiments, target area TA can be another region in nasal cavity NC. Reservoir  510  can be filled, and/or refilled, with therapeutic substance TS, via inlet  530 , which is the proximal surface of the foam structure. 
     Delivery system  500  can be deployed by inserting the foam structure into nasal cavity NC until delivery interface  520  is in apposition with target area TA. Optionally, delivery system  500  can include a retrieval element  545 , coupled to reservoir  510 , by which a user can remove delivery system  500  from nasal cavity NC of the subject by pulling delivery system  500  through nasal cavity NC. 
       FIGS. 7A and 7B  schematically illustrate a delivery system  600  according to another embodiment. Delivery system  600  can be similar to delivery system  500  but include an electrode device  650 . For example, delivery system  600  includes a reservoir  610  implemented as a unitary solid structure formed of a foam material. An iontophoresis fluid IF containing a therapeutic substance can be disposed within the foam material of reservoir  610 , e.g. the foam material of reservoir  610  can be saturated with iontophoresis fluid IF. The therapeutic substance within iontophoresis fluid IF can be transported via a delivery interface  620  (e.g., a distal surface of the foam structure) to a target area TA. 
     Delivery system  600  includes electrode device  650 . Electrode device  650  can include an electrode tip  654 , an elongate shaft  656 , and a proximal connector  652 . Electrode device  650  can also include a return electrode (not shown) that can be placed on the subject at a distance from electrode tip  654 . Electrode tip  654  can be coupled to or separate from but engageable with reservoir  610 . For example, electrode tip  654  can be coupled to reservoir  610  via a friction fit and/or an adhesive or other coupling mechanism. Electrode device  650  can be dimensioned such that it can be inserted into nasal cavity NC of the subject. In some embodiments, electrode device  650  can have smooth or rounded edges to reduce trauma to the subject as the electrode device  650  is inserted into nasal cavity NC. In some embodiments, electrode device  650  can be flexible. Electrode tip  654  can be constructed from a conductive material, such as, for example, a conductive metal. For example, electrode tip can be constructed from pure silver (e.g., 99.9% silver) and/or include a pure silver coating (e.g., a pure silver coating over a stainless steel electrode), which can provide reduced levels of electrolysis and changes in pH value when compared to other conductive materials such as, for example, stainless steel or gold. Electrode tip  654  can be disposed adjacent to an external surface of reservoir  610  or disposed within reservoir  610 . Electrode tip  654  can have any general shape (e.g., cylindrical, rectangular, etc.). 
     In some embodiments, electrode tip  654  can have different configurations to increase surface area and promote iontophoresis. For example, electrode tip  654  can include one or more of: a plurality of wires configured similar to a brush head, a plurality of concentric tubes with staggered diameters that are nested within one another, a silver mesh mass configured similar to steel wool, a molded polymer matrix plug with a sponge-like structure and a metal plating or deposition (e.g., a pure silver plating or deposition), a metal-coated woven fabric, a honeycomb structure, a coil structure, a mass with a plurality of petals or branches (e.g., flower shaped), a flexible bag structure, one or more cavities or recesses with metal-coated surfaces, a textured surface (e.g., cross-hatched, etched, sandblasted), a laser-cut tube with cavities or recesses, etc. Electrode tip  654  can have a configuration that increases surface area but also minimizes a risk that a conductive region of electrode tip  654  comes into contact with tissue within nasal cavity NC. For example, electrode tip  654  can be formed of conductive and non-conductive regions, where the conductive regions are recessed within non-conductive regions and therefore prevented from coming into contact with a tissue surface within nasal cavity NC. Additionally or alternatively, electrode tip  654  can also be recessed within a non-conductive, insulating material (e.g., an outer sheath or sleeve) such that electrode tip  654  does not come into contact with a tissue surface. In some embodiments, electrode tip  654  can be attached to and disposed within reservoir  610  before being inserted into nasal cavity NC. Reservoir  610  can then prevent electrode tip  654  from directly contacting tissue within nasal cavity NC. In other embodiments, electrode device  650  can include a controller (not shown) that supplies power to electrode device  650  and controls when electrode device  650  applies a current to iontophoresis fluid IF. The controller can include safety features that prevent the electrode device  650  from activating and applying a current until the electrode device  650  is properly positioned within nasal cavity NC. For example, electrode device  650  can include a sensor that informs the controller of when electrode tip  654  of electrode device  650  is disposed within reservoir  610  before allowing a user to actuate the controller and apply an electric current. 
     In some embodiments, electrode tip  654  can include multiple metals with one metal (e.g., zinc) serving as a galvanic or sacrificial anode. In some embodiments, electrode device  650  can include a conveyor system (e.g., a flexible belt) that can be actuated to supply a fresh electrode surface during an iontophoresis procedure. In some embodiments, electrode device  650  can include wiping or cleaning mechanisms that can be actuated to clean the surface of electrode tip  654  to supply a new electrode surface. In some embodiments, electrode tip  654  can include a protective coating to help prevent corrosion. 
     Electrode tip  654  may be attached to the elongate shaft  656 , e.g. by soldering or welding or by using a conductive adhesive. Elongate shaft  656  can be constructed from a conductive material. In some embodiments, elongate shaft  656  can be constructed from the same material as electrode tip  654 . Elongate shaft  656  can be disposed within an outer sheath or sleeve  658 . Outer sheath  658  can be formed of a non-conductive, insulating material. In some embodiments, portions of electrode device  650  (e.g., elongate shaft  656 , outer sheath  658 , or portions thereof) can be flexible or malleable such that a user can pre-shape electrode device  650  before inserting it into nasal cavity NC. Elongate shaft  656  can be attached to proximal connector  652 , which can be electrically connected to a source for providing energy to electrode device  650 . In other embodiments, electrode device  650  can be wirelessly energized, e.g. using a magnetic field that can induce an electric current in one or more coils disposed on electrode device  650 . 
     Electrode device  650  can optionally include a fluid delivery channel  632  configured to supply iontophoresis fluid IF to reservoir  610 . Fluid delivery channel  632  can be used to fill or refill reservoir  610  with iontophoresis fluid IF, as needed. In the embodiment shown in  FIG. 7B , fluid delivery channel  632  is integrally formed in outer sheath  658 . In other embodiments, fluid delivery channel  632  can be formed separately from outer sheath  658  but be coupleable (e.g., via an adhesive or other attachment mechanism) to outer sheath  658  and/or elongate shaft  656 . 
     In operation, reservoir  610  and electrode device  650  can be deployed in nasal cavity NC. In some embodiments, electrode device  650  can be coupled to reservoir  610  (e.g., electrode tip  654  can be coupled to reservoir  610 ) and be used to deploy reservoir  610  into an operative position in nasal cavity (e.g., into operative apposition with target area TA). In other embodiments, reservoir  610  can be deployed in nasal cavity NC, e.g., via a deployment device, after which electrode device  650  can be inserted into nasal cavity NC and brought into engagement with reservoir  610 . In other embodiments, electrode device  650  can be inserted into nasal cavity NC such that electrode tip  654  is disposed proximate to target area TA, after which reservoir  610  can be deployed in nasal cavity NC in operative apposition with TA and in engagement with electrode tip  654  of electrode device  650 . Electrode device  650  can be used to perform an iontophoresis procedure to deliver the therapeutic substance to target area TA. As needed, additional iontophoresis fluid IF and/or therapeutic substance can be added to reservoir  610  by supplying it, e.g. via fluid delivery channel  632 , to reservoir  610 . After an iontophoresis procedure is performed, reservoir  610  and electrode device  650  can be removed from nasal cavity NC. In some embodiments, electrode device  650  can be coupled to reservoir  610 , and a user can grasp a proximal end of electrode device  650  disposed outside of nasal cavity NC to remove the electrode device  650  and reservoir  610  from the nasal cavity. In other embodiments, electrode device  650  can be removed from nasal cavity NC (e.g., by a user grasping the proximal end of electrode device  650 ) and a retrieval element (not shown) coupled to reservoir  610  can be used to remove reservoir  610  from nasal cavity NC. 
     In addition or alternatively, reservoir  610  can include a fluid with non-ionic molecules that can be delivered to target area TA via electroosmosis. Electrode device  650  can be used to apply an electric current to a porous material, a capillary tube, or other fluid channel to induce the delivery of the non-ionic molecules through the fluid channel to target area TA. 
       FIGS. 8A and 8B  schematically illustrate a delivery system  700  according to another embodiment. In this embodiment, delivery system  700  includes a reservoir  710  disposed within nasal cavity NC. In this embodiment, reservoir  710  is formed in situ by injecting from a deployment device  780  a foamable carrier, or foam forming agent, mixed with therapeutic substance TS through nasal cavity NC into a region adjacent to target area TA. As best depicted in  FIG. 8B , target area TA can be a region of a subject&#39;s superior turbinate, which can become inflamed due to infection, allergies, or other nasal conditions. In other embodiments, target area TA can be another region in nasal cavity NC. The foam-based reservoir  710  enables delivery of therapeutic substance TS to target area TA as the foam evaporates over time. The foam may also dissipate without leaving any residue, stains, or odor. The foam also provides a relatively uniform concentration of therapeutic substance TS at the surface of reservoir  710 , such as at the delivery interface  720 . The foam (or mousse) can be a lightweight material in cellular form that is made by introducing gas bubbles into a liquid phase. The carrier, or foam forming agent, can include foam producing agents and compounds that are able to generate a foamable composition when mixed with a liquid or gel composition. The foamable composition can generate a foam within deployment device  780  or upon dispensing from deployment device  780 . 
     Deployment device  780  can have an elongate shaft  782 . The elongate shaft  782  can be malleable or have a portion that is malleable such that the elongate shaft  782  can be configured to deliver reservoir  710  to a specific region of nasal cavity NC (e.g., a region adjacent to target area TA). For example, a user can configure (e.g., bend, shape, adjust) elongate shaft  782  such that a dispensing end  784  of deployment device  780  can be positioned in a specific region of nasal cavity NC, such as depicted in  FIG. 7A , when deployment device  780  is inserted into nasal cavity NC. Elongate shaft  782  and dispensing end  784  can have rounded edges and/or have a soft or compressible external layer to reduce patient discomfort. 
     Suitable carrier compositions and techniques for delivering the foam are disclosed in U.S. Pat. No. 8,030,362 to Eliat, entitled “Compositions for Treatment of Ear Disorders and Methods of Use Thereof,” and in U.S. Patent Application Publication No. 2015/0342965 to Lozinsky et al, entitled “Foamable Otic Pharmaceutical Compositions,” the disclosures of which are incorporated herein by reference. An exemplary, suitable formulation for a foamable composition can include: (a) an oil-in-water emulsion that includes (i) the therapeutic agent in an effective concentration or amount, for example lidocaine in a 4% concentration solution; (ii) water in an amount of, for example, 75% or more (w/w), (iii) mineral oil in an amount of, for example, 15% or less (w/w); (iv) a synthetic surfactant pharmaceutically acceptable for nasal applications; (v) a foaming agent; and (vi) white petrolatum; and (b) a compressed propellant gas. 
     In some embodiments, an electrode device  750  can be used to deliver a therapeutic substance to target area TA with delivery system  700 , as schematically illustrated in  FIG. 9 . Reservoir  710  can include a foamable carrier mixed with iontophoresis fluid IF containing a therapeutic substance. For example, reservoir  710  can include a foamable composition (e.g., a liquid oil mixture) with an electrically charged therapeutic substance, such as, for example, lidocaine. Electrode device  750  can be similar to electrode device  650 . For example, electrode device  750  can have an electrode tip  754 , an elongate shaft  756 , a proximal connector (not shown), an outer sleeve  758 , and a return electrode (not shown). Optionally, electrode device  750  can also have a delivery channel  732 , which can be used to deliver iontophoresis fluid IF and/or foam including iontophoresis fluid IF into nasal cavity NC. 
     In operation, deployment device  780  can be used to dispense reservoir  710  in an operative position within nasal cavity (e.g., in apposition with target area TA), and electrode device  750  can be inserted into nasal cavity NC such that electrode tip  754  of electrode device  750  is operatively engaged with reservoir  710 , e.g. disposed in foam-based reservoir  710 . Electrode device  750  can then supply an electric current to drive therapeutic substance within iontophoresis fluid IF into target area TA. After an effective dose of therapeutic substance has been delivered to target area TA, electrode device  750  can be removed from nasal cavity NC. Reservoir  710  can also be removed from nasal cavity NC or, alternatively, reservoir  710  can be left in nasal cavity NC to dissipate. In other embodiments, electrode device  750  can be inserted into nasal cavity NC such that its distal end is proximate to target area TA, and delivery channel  732  can be used to deliver foam including iontophoresis fluid IF into nasal cavity NC to form reservoir  710 . After sufficient foam has been delivered into nasal cavity NC and a surface (e.g., delivery interface  720 ) is in operative apposition with target area TA, electrode device  750  can supply an electric current to deliver the therapeutic substance to target TA. Once an effective dose of therapeutic substance has been delivered, electrode device  750  can be removed from nasal cavity NC. 
     In addition or alternatively, reservoir  710  can include a fluid with non-ionic molecules that can be delivered to target area TA via electroosmosis similar to other delivery systems described herein. 
       FIGS. 10A and 10B  schematically illustrate a delivery system  800  according to another embodiment. Delivery system  800  is similar to delivery system  700 , except that reservoir  810  can be formed in situ by injecting from a suitable deployment device (not shown) a hydrogel mixed with therapeutic substance TS through nasal cavity NC into the region adjacent to target area TA. The hydrogel-based reservoir  810  enables delivery of therapeutic substance TS to target area TA by osmotic transport and/or an iontophoresis procedure, as further described below. 
     A variety of hydrogel compositions may be suitable for delivery of different compositions of therapeutic substance TS. For example, photopolymerizable hydrogels disclosed in U.S. Pat. No. 5,410,016 to Hubbell et al, entitled “Photopolymerizable biodegradable hydrogels as tissue contacting materials and controlled-release carriers,” the disclosure of which is incorporated herein by reference may be used. The method of use may include mixing the therapeutic substance TS with an aqueous solution including a light-sensitive free-radical polymerization initiator and a macromer to form a coating mixture. The coating mixture can be applied to target area TA (by any suitable means, such as a syringe) and then exposed to light sufficient to polymerize the macromer. 
     In other embodiments, the compositions and methods described in U.S. Pat. No. 6,201,065 to Pathak, et al., entitled “Multiblock biodegradable hydrogels for drug delivery and tissue treatment,” the disclosure of which is incorporated herein by reference, may be used. In these embodiments, macromers may be crosslinked reversibly or irreversibly to form gels for controlled delivery of therapeutic substance TS. The composition and properties of the macromers can be selected and fabricated to produce hydrogels with desired delivery properties. The therapeutic substance TS may be provided in the macromer solution prior to or after administration, and either before or after gel formation, depending on the macromer composition. For example, the gels can be designed to have a selected rate of release of therapeutic substance TS, such as first order or zero order release kinetics. For specific therapeutic substances, such as peptides, the composition of the gel may be designed to result in pulsatile or mixed wave release characteristics in order to obtain maximum efficacy and to minimize side effects and tolerance development. The release profiles can be selected by the use of macromers and gels formed therefrom that respond to specific external stimuli such as ultrasound, temperature, pH or electric current. For example, the extent of swelling and size of these hydrogels can be modulated. Changes induced in the swelling directly correlate to the rate of release of the incorporated therapeutic substances. Through this, a particular release profile may be obtained. The hydrogels may be biodegradable so that removal is not required after administration or delivery. The gels permit controlled delivery and release of a biologically active therapeutic substance TS in a predictable and controlled manner locally at target area TA. 
     In other embodiments, rather than a hydrogel, reservoir  810  may be implemented with any non-Newtonian fluid that can be mixed with therapeutic substance TS and delivered through nasal cavity NC into the region adjacent to target area TA. That is, the material can flow under the shear forces produced by the delivery device, and then not flow under the lower shear forces imposed by gravity and normal movement of the subject, and thus can be retained in appropriate apposition with target area TA and deliver therapeutic substance TS, e.g. by osmotic transport and/or an iontophoresis procedure. Suitable materials may be shear thinning, i.e. apparent viscosity decreases with increased stress. 
     In other embodiments, rather than a hydrogel, reservoir  810  may be implemented with a fluid that can be mixed with therapeutic substance TS and delivered through nasal cavity NC into the region adjacent to target area TA and that can thicken, gel, or solidify in place. That is, the material can be delivered in liquid form (by any suitable device, such as a syringe, sprayer, etc.) and then be retained on target area TA and deliver therapeutic substance TS, e.g. by osmotic transport and/or an iontophoresis procedure. Suitable compositions can include those similar to compositions employed for “liquid bandages,” e.g. polymers dissolved in solvents, which form a thin film when the solvent evaporates. Suitable polymers can include water-soluble polymers such as polyvinylpyrrolidone, alcohol-soluble polymers such as ethyl cellulose, pyroxylin/nitrocellulose, or poly(methactcrylate-isobutene-monoisopropylmaleate, and hexamethyldisoloxane- or isooctane-soluble polymers such as acrylate or siloxane. 
     In some embodiments, after hydrogel-based reservoir  810  is placed in operative apposition against target area TA, therapeutic substance TS within hydrogel-based reservoir  810  can be delivered to target area TA via diffusion (e.g., osmosis, perfusion, etc.). In other embodiments, after hydrogel-based reservoir  810  is placed in operative apposition against target area TA, an electrode device similar to electrode device  750  can be inserted into nasal cavity NC into operative engagement with reservoir  810 . In these embodiments, reservoir  810  can include an iontophoresis fluid IF with the therapeutic substance, and the electrode device can be used to perform an iontophoresis procedure to deliver the therapeutic substance into target area TA, e.g. to supply an electric current that drives the therapeutic substance into target area TA. In other embodiments, hydrogel-based reservoir  810  can include non-ionic molecules that can be delivered to target area TA via electroosmosis similar to other delivery systems described herein. In some embodiments, therapeutic substance TS can be supplied to target area TA via both diffusion and an iontophoresis and/or electroosmosis procedure. 
       FIG. 11A  schematically illustrates a delivery system  900  according to another embodiment. Delivery system  900  includes a reservoir  910  implemented as stable, solid, relatively thin film that may contain therapeutic substance TS, and that may be delivered through nasal cavity NC and secured to target area TA. Reservoir  910  can thus can be retained in appropriate apposition with target area TA and deliver therapeutic substance TS, e.g. by osmotic transport and/or an iontophoresis procedure. As depicted in  FIG. 11A , target area TA can be a region of a subject&#39;s inferior turbinate, which can become inflamed due to infection, allergies, or another nasal condition. In other embodiments, target area TA can be another region in nasal cavity NC. Delivery system  900  may optionally include a retrieval element  945 , such as a long tab, that is secured at its distal end to reservoir  910  and that can extend to a proximal end near or outside of the entrance to nasal cavity NC where it can be grasped by a user to retrieve reservoir  910  after the therapeutically effective amount of therapeutic substance TS has been delivered to target area TA. 
     In another embodiment, shown in  FIG. 11B , a delivery system  900 ′ can include a stable, relatively thin film that is devoid of therapeutic substance, and instead form a body or substrate  940  supporting a reservoir  910 ′. In this embodiment, reservoir  910 ′ can be a thin layer of any suitable material, including those discussed above, that can contain therapeutic substance TS. Similar to delivery system  900 , delivery system  900 ′ may optionally include a retrieval element  945 ′, such as a long tab, that is secured at its distal end to the thin film body  940 . 
       FIGS. 12A and 12B  schematically illustrate a delivery system  1000  according to another embodiment. Similar to delivery systems  900  and  900 ′, delivery system  1000  can include a reservoir  1010  implemented as a stable, solid, relatively thin film. Delivery system  1000  also includes an electrode device  1050  with a proximal connector  1052 , an elongate shaft  1056 , and an electrode  1054 . Reservoir  1010  can support electrode  1054 , which can be configured as a thin plate or pad. Reservoir  1010  can include an iontophoresis fluid IF, e.g. reservoir  1010  can be formed of a composition including a stable gel-based carrier and iontophoresis fluid IF or, alternatively, reservoir  1010  can be formed of a stable porous material that can hold iontophoresis fluid IF. 
     Electrode device  1050  can be similar to other electrode devices described herein. For example, elongate shaft  1056  of electrode device  1050  can be connected at its distal end to electrode  1054  and at its proximal end to proximal connector  1052 . Electrode device  1050  can include a return electrode (not shown) that can be placed on the subject at a distance from electrode  1054 . Elongate shaft  1056  and electrode  1054  can be constructed from conductive materials, such as, for example, one or more of a conductive metal, a conductive polymer, etc. Proximal connector  1052  can be electrically connected to a source for providing energy to electrode device  1050 . In other embodiments, electrode device  1050  can be wirelessly energized, e.g. using a magnetic field that can induce an electric current in one or more coils disposed on electrode device  1050 . Elongate shaft  1056  can be disposed within an outer sheath  1058 , which can be formed of an insulating, non-conductive material. In some embodiments, portions of electrode device  1050  (e.g., elongate shaft  1056 , outer sheath  1058 , or portions thereof) can be flexible or malleable such that it can be adjusted by a user into multiple configurations (e.g., a straight configuration, a curved configuration, etc.). In particular, a user can adjust a portion of electrode device  1050  such that a distal end of electrode device  1050  (i.e., an end of electrode device  1050  with electrode  1054 ) can be positioned within nasal cavity NC in an operative location (e.g., an area adjacent to target area TA). 
     In operation, reservoir  1010  and electrode  1056  can be positioned proximate to target area TA such that a delivery interface  1020  is in operative apposition with target area. Proximal connector  1052  of electrode device  1050  can be connected to an energy source, and electrode device  1050  can be supplied with energy to perform an iontophoresis procedure. In particular, electrode device  1050 , via electrode shaft  1056  and electrode  1054 , can supply an electric current to reservoir  1010  to drive a therapeutic substance within iontophoresis fluid IF into target area TA. After an effective dose of therapeutic substance has been supplied to target area TA, electrode device  1050  and reservoir  1010  can be removed from nasal cavity NC. 
     In addition or alternatively, reservoir  1010  can include a fluid with non-ionic molecules that can be delivered to target area TA via electroosmosis similar to other delivery systems described herein. 
       FIG. 13  schematically illustrates a delivery system  1100  according to another embodiment. Delivery system  1100  includes a reservoir  1110  implemented as stable, solid, relatively thin film that may contain an iontophoresis fluid IF with a therapeutic substance. Similar to delivery system  1010 , delivery system  1100  also includes an electrode device  1150  with an electrode  1154  formed as a thin plate or pad. Electrode  1154  can be supported on reservoir  1110 . Electrode device  1150  also includes a shaft  1152  that is connected at its distal end to electrode  1154 . Electrode device  1150  can be configured to supply an electric current to reservoir  1110  to perform an iontophoresis procedure. 
     Delivery system  1100  can be positioned outside of a subject&#39;s nasal cavity NC. For example, as depicted in  FIG. 13 , delivery system  1100  can be positioned on skin adjacent to a subject&#39;s nose. Delivery system  1100  can be used to supply a therapeutic substance to a target area TA within or proximate to nasal cavity NC by delivering the therapeutic substance through the skin. In operation, reservoir  1110  and electrode  1154  can be secured to the subject&#39;s skin, and the electrode device  1150  can be used to supply an electric current to the reservoir  1110  to drive the therapeutic substance within iontophoresis fluid IF into and through the skin tissue to a target area TA beneath the skin. Additionally or alternatively, in some embodiments, electrode device  1150  can be used to supply an electric current to the reservoir  1110  to induce delivery of non-ionic molecules within a fluid into and through skin tissue. Since delivery system  1100  is not inserted into nasal cavity NC, delivery system  1100  is not restricted in size or shape by the anatomy of nasal cavity NC or the passageways or openings into nasal cavity NC (e.g., nostril openings or nasal nares). Thus, delivery system  1100  can have components that are dimensioned and configured differently from other delivery systems described herein. For example, electrode  1154  can be larger in size and have an increased surface area for promoting iontophoresis. Reservoir  1110  can have a larger delivery interface (e.g., delivery interface  320 ) for delivering therapeutic substance to a larger target area TA. Delivery system  1100  may also reduce patient discomfort by being disposed outside of nasal cavity NC. 
       FIG. 14  schematically illustrates a delivery system  1200  according to another embodiment. In this embodiment, reservoir  1210  is implemented as a bundle or other mass of wicking, fibrous material, i.e. a material that can absorb therapeutic substance TS in liquid form, and conduct therapeutic substance TS by capillary action through the body of reservoir  1210  to a distal surface of reservoir  1210 , defining a delivery interface  1220 , in operative apposition with target area TA, from which therapeutic substance TS can be delivered to target area TA by osmotic transport. In this embodiment, target area TA can be a region of a subject&#39;s middle turbinate, which can become inflamed due to infection, allergies, or other nasal conditions. In other embodiments, target area TA can be another region within nasal cavity NC. Delivery system  1200  may include a body  1240 , such as a tube of material, that radially constrains the fibrous material and increases its stiffness to facilitate insertion through nasal cavity NC. As needed, therapeutic substance TS can be added to reservoir  1210  by supplying, or resupplying, it, e.g. in liquid form, to a proximal surface or end of the wicking material, serving as an inlet. 
       FIG. 15  schematically illustrates a delivery system  1300  according to another embodiment. Similar to delivery system  1200 , delivery system  1300  can include a reservoir  1310  that is implemented as a bundle or other mass of wicking, fibrous material. Reservoir  1310  can absorb an iontophoresis fluid IF containing therapeutic substance and conduct iontophoresis fluid IF by capillary action through body of reservoir  1310  to a distal surface of reservoir  1310 , defining a delivery interface  1320 , in operative apposition with target area TA. As needed, iontophoresis fluid IF and/or therapeutic substance can be added to reservoir  1310  by supplying, or resupplying, it, e.g. in liquid form, to a proximal surface or end of the wicking material, serving as an inlet. 
     Delivery system  1300  also includes a body  1340 , such as a tube of material, that radially constrains the fibrous material and increases its stiffness to facilitate insertion through nasal cavity NC. Body  1340  can support an electrode device  1350 , which can be engaged with reservoir  1310  and be used to deliver an electric current to reservoir  1310 . Electrode device  1350  can be supplied with energy, e.g. via a wired connection and/or wirelessly. For example, electrode device  1350  can be connected to an energy source via a wire (not shown) that is supported on body  1340 . Additionally or alternatively, electrode device  1350  can include a harvesting coil that can be wirelessly energized using a magnetic field. 
     In addition or alternatively, reservoir  1310  can include a fluid with non-ionic molecules that can be delivered to target area TA via electroosmosis similar to other delivery systems described herein. 
       FIG. 16  schematically illustrates a delivery system  1400  according to another embodiment. Delivery system  1400  can be similar to other delivery systems described herein but include a plurality of reservoirs  1420 . Reservoirs  1420  can be implemented as, for example, a foam, a hydrogel, a thin film, a fibrous material, or other material containing therapeutic substance TS. Reservoirs  1420  can be implemented in the same form, or some of reservoirs  1420  can be implemented in a first form (e.g., a foam) and others of reservoirs  1420  can be implemented in a second form (e.g., a hydrogel). Reservoirs  1420  can be supported on a body  1440 . In the embodiment shown in  FIG. 16 , reservoirs  1420  are supported on body  1440  spaced from one another, but in other embodiments, reservoirs  1420  can be disposed adjacent to one another. Reservoir  1420  can provide increased surface area and multiple delivery interfaces such that therapeutic substance TS can be delivered to a larger target area TA and/or multiple target areas TA. 
       FIG. 17  schematically illustrates a delivery system  1500  according to another embodiment. Similar to delivery system  1400 , delivery system  1500  can include a plurality of reservoirs  1520 . Reservoirs  1520  can be implemented as, for example, a foam, a hydrogel, a thin film, a fibrous material, or other material containing iontophoresis fluid IF with a therapeutic substance. Reservoirs  1520  can be implemented in the same form, or some of reservoirs  1520  can be implemented in a first form (e.g., a foam) and others of reservoirs  1520  can be implemented in a second form (e.g., a hydrogel). Reservoir  1520  can provide increased surface area and multiple delivery interfaces such that the therapeutic substance can be delivered to a larger target area TA and/or multiple target areas TA. 
     Delivery system  1500  can include an electrode device  1550 . Electrode device  1550  can be similar to other electrode devices described herein but include a plurality of electrodes  1554  for applying electric current to iontophoresis fluid IF. For example, electrode device  1550  can have a proximal connector  1552 , an elongate shaft  1556 , and an outer sheath  1558 . Electrode device  1550  can also include a return electrode (not shown) that is disposed on the subject at a distance from the plurality of electrodes  1554 , e.g., on the subject&#39;s neck, shoulder, etc. Elongate shaft  1556  and electrodes  1554  can be formed of a conductive material, e.g. stainless steel and/or silver. Elongate shaft  1556  can be disposed within outer sheath  1558 , which can be formed of an insulating, non-conductive material. Proximal connector  1552  can connect to a source for supplying energy to electrode device  1550 . Each of electrodes  1554  can be operatively engaged with a reservoir  1520 . Thus, electrodes  1554  can supply an electrical current to reservoirs  1520 . As depicted in  FIG. 17 , electrodes  1554  and/or reservoirs  1520  can be supported on a distal portion of electrode device  1550  spaced apart from one another. In other embodiments, electrodes  1554  and/or reservoirs  1520  can be disposed adjacent to one another on electrode device  1550  and have different configurations (e.g., have different sizes, shapes, or structures). In some embodiments, elongate shaft  1556  and outer sheath  1558 , or portions of elongate shaft  1556  and outer sheath  1558 , can be flexible or malleable such that a user can configure electrode device  1550  to position electrodes  1554  and reservoirs  1520  in specific regions within nasal cavity NC. 
     In addition or alternatively, reservoirs  1520  can include a fluid with non-ionic molecules that can be delivered to target area TA via electroosmosis similar to other delivery systems described herein. 
       FIGS. 18A and 18B  schematically illustrate a delivery system  1600  according to another embodiment. Delivery system  1600  is similar to other delivery systems described herein. Delivery system  1600  includes a body  1640  implemented as a nasal plug. The nasal plug can be inserted into a subject&#39;s nasal nares or nostrils. The nasal plug can prevent fluid discharge or the discharge of other material from the subject&#39;s nasal cavity NC. Body  1640  can support, define, and/or be coupled to a reservoir  1610  that can be implemented as a foam or other material (e.g., a liquid, a mousse, a hydrogel). In some embodiments, reservoir  1610  can be implemented as a solid material (e.g., a foam) that can change into a liquid once positioned within nasal cavity NC, e.g., due to a change in temperature. Reservoir  1610  can be configured to change shape (e.g., expand) once positioned within nasal cavity NC. In some embodiments, body  1640  and reservoir  1610  can be formed as a single integrated unit. For example, body  1640  and reservoir  1610  can be formed of a foam material that can be inserted into the subject&#39;s nostrils such that a portion of the material is disposed within nasal cavity NC. In other embodiments, body  1640  can be formed as a separate component (e.g., a plastic plug or stop, a packed fibrous material, etc.) on which reservoir  1610  can be supported. 
     Reservoir  1610  can expand to occupy the space within nasal cavity NC. For example, as depicted in  FIG. 18B , reservoir  1610  can expand to fill the middle meatus and come into contact with anterior portions of the middle and inferior turbinates and a portion of the nasal wall. Reservoir  1610  can expand in response to changes in various conditions such as, for example, temperature, moisture level, etc. In some embodiments, reservoir  1610  can be positioned within nasal cavity NC, and a therapeutic substance TS such as a liquid can be added to reservoir  1610  via an inlet  1630  to cause reservoir  1610  to expand within nasal cavity NC. In other embodiments, reservoir  1610  can expand within nasal cavity NC in response to being positioned within nasal cavity NC, e.g., due to a temperature change. 
     Reservoir  1610  can contain a therapeutic substance TS and enable therapeutic substance TS to be eluted, diffused, or released by other mechanisms to one or more target areas TA within nasal cavity NC. For example, once reservoir  1610  has expanded within nasal cavity NC, as depicted in  FIG. 18B , reservoir  1610  can enable therapeutic substance TS to diffuse into anterior portions of the middle and inferior turbinates. As needed, therapeutic substance TS may be added to reservoir  1610  by supplying it, e.g. in liquid form, to a proximal surface of reservoir  1610 , serving as inlet  1630 . 
     In some embodiments, reservoir  1610  can be implemented as a liquid containing therapeutic substance TS or a solid material that is configured to change into a liquid once positioned within nasal cavity NC. Body  1640 , which is implemented as a nasal plug, can prevent the liquid from discharging from nasal cavity NC via the subject&#39;s nostrils. And the subject may lean forward or lie on the subject&#39;s stomach to contain the fluid within an anterior region of nasal cavity NC and to prevent it from draining out of nasal cavity NC via the throat. 
       FIGS. 19A and 19B  schematically illustrate a delivery system  1700  according to another embodiment. Delivery system  1700  can be similar to delivery system  1600  but include an electrode device  1750 . For example, delivery system  1700  includes a body  1740  implemented as a nasal plug, and a reservoir  1710  implemented as a foam. An iontophoresis fluid IF containing a therapeutic substance can be disposed within the foam of reservoir  1710 , e.g. the foam of reservoir  1710  can be saturated with iontophoresis fluid IF. The therapeutic substance within iontophoresis fluid IF can be driven via iontophoresis to one or more target areas TA. 
     Electrode device  1750  can be similar to other electrode devices described herein. For example, electrode device  1750  can include a conductive tip or electrode  1754 , an elongate shaft  1756 , and a proximal connector  1752 . Electrode device  1750  also includes a return electrode (not shown) that can be placed on the subject at a distance from electrode  1754 . Electrode device  1750  can be coupled to or separate from by engageable with body  1740  and reservoir  1710 . Body  1740  can be designed to prevent conductive regions of electrode device  1750  (e.g., electrode  1754 ) from coming into direct contact with a tissue surface of the subject&#39;s nasal cavity NC. For example, body  1740  can form an enclosure or surrounding around a portion of electrode device  1750  such that electrode  1754  and/or other conductive regions of electrode device  1750  are spaced from the nasal wall and other tissue surfaces within nasal cavity NC. 
     Electrode  1754  can be disposed within reservoir  1710  such that electrode  1754  can deliver an electric current to reservoir  1710  in order to deliver the therapeutic substance within iontophoresis fluid IF into target areas TA. Optionally, electrode device  1750  can also have a delivery channel  1732 , which can be used to deliver iontophoresis fluid IF and/or foam including iontophoresis fluid IF into nasal cavity NC. 
     In addition or alternatively, reservoir  1710  can include a fluid with non-ionic molecules that can be delivered to target area TA via electroosmosis similar to other delivery systems described herein. 
     Conclusion 
     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. 
     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 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, 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.