Abstract:
A soft contact lens comprises a module embedded in a soft contact lens material. The module comprises a hydrophobic material having channels formed therein, such that a surface tension of the aqueous solution within the channels inhibits release of therapeutic agent, such as a drug, through the one or more channels. The surface tension of the aqueous solution within the channel can inhibit diffusion of the therapeutic agent through the channel. The channels may comprise a cross-sectional area and optionally a length, such that therapeutic agent is released through the channels when pressure of the eyelid increases. In many embodiments, the contact lens is configured to inhibit release of the therapeutic agent when the contact lens comprises a free floating configuration, for example when stored in a contact lens solution, such that the storage time of the contact lens can be increased substantially.

Description:
CROSS-REFERENCE 
       [0001]    This application claims the benefit of U.S. Provisional Application No. 61/806,538, filed Mar. 29, 2013, entitled “Drug Delivery from Contact Lens with a Fluidic Module”, [attorney docket number 46282-703.101], the entire disclosure of which application is incorporated herein by reference. 
     
    
     BACKGROUND OF THE INVENTION 
       [0002]    Prior methods and apparatus of delivery of therapeutic agents can be less than ideal in at least some instances. The release mechanisms of the prior devices and be less than ideal, and provide less than ideal drug release profiles. Although contact lenses have been proposed to release therapeutic agents, the prior contact lenses can provide less than ideal amounts of drug and release profiles. 
         [0003]    Administration of drugs to treat eye diseases can be challenging, since normal modes of drug administration fail to deliver therapeutically beneficial doses beyond a short time. 
         [0004]    Drugs delivered via eye drops, for example, can be rapidly washed away by the tear film, and only about 1/104 or less of the total amount of the drug delivered via an eye drop reaches the anterior or the posterior chamber. 
         [0005]    The total bioavailability of a lipophilic drug can be about 10% in the anterior chamber relative to its concentration delivered as eye drops, while that of hydrophilic drugs and large molecules can be less than 5%. 
         [0006]    The total amount that enters the anterior chamber can be further reduced by an order of magnitude since typical eye drops deliver about 60-70 μl, while the eye rapidly removes all fluids in excess of 7 μl. 
         [0007]    There still exists an unmet need of an agent to deliver drugs into the anterior and posterior chambers of the eye in a sustained manner. 
         [0008]    In light of the above, it would be desirable to have improved release of therapeutic agents from contact lenses. Ideally, such devices will provide improved release of therapeutic agents from contact lenses. 
       SUMMARY OF THE INVENTION 
       [0009]    In many embodiments, a fluidic module may be embedded in a soft contact lens that may be filled with a concentrated solution of a drug to be delivered into the eye in a sustained manner. 
         [0010]    In many embodiments, the module comprises a hydrophobic material having channels formed therein, such that a surface tension of the aqueous solution within the channels inhibits release of therapeutic agent, such as a drug, through the one or more channels. The surface tension of the aqueous solution within the channel can inhibit diffusion of the therapeutic agent through the channel, which can be in addition to decreased diffusion through the channel related to the cross-sectional area of the channel. The channels may comprise a cross-sectional area and optionally a length, such that therapeutic agent is released through the channels when pressure of the eyelid increases, and release is inhibited when pressure of the eyelid decreases. In many embodiments, the contact lens is configured to inhibit release of the therapeutic agent when the contact lens comprises a free floating configuration, for example when stored in a contact lens solution, such that the storage time of the contact lens can be increased substantially over contact lenses relying on a diffusion based release of therapeutic agent. The therapeutic agent may comprise one or more of many substances capable of providing a therapeutic benefit to the eye, such as substances capable of treating one or more of dry eye, uveitis. The therapeutic agent may comprise one or more of many therapeutic agents, such as a drug, a surfactant, a solution, a lipid or a component of an artificial tear, for example. 
         [0011]    In many embodiments, the openings are sized to provide a gated release of therapeutic agent in response to pressure of the eyelid, in which surface tension extending across each of the plurality of openings inhibits diffusion of therapeutic agent through the opening, and a pressure of the eyelid urges fluid of the container through the plurality of openings. The gated release has the advantage of inhibiting diffusion through a cross-sectional area of the opening, such that storage life of the contact lens in solution can be extended substantially. The gated release also has the advantage of providing therapeutic agent, such that the wearer receives an amount of therapeutic agent in response to blinking in order for the user to control the amount of therapeutic agent provided. Such embodiments can be particularly well suited for the delivery of therapeutic agents to treat dry eye, for example. 
         [0012]    In a first aspect, embodiments comprise a soft contact lens. The soft contact lens comprises a container comprising a plurality of openings sized to release a therapeutic agent, and a soft contact lens material encapsulating the module. 
         [0013]    In many embodiments, the soft contact lens further comprises a module. The module comprises the container. The module may comprise a plurality of anchors to anchor the module in the soft contact lens material. The module comprises a barrier material to inhibit release of the therapeutic agent. 
         [0014]    In many embodiments, the material of the module comprises an optically transparent material extending across at least a portion of an optically corrective portion of the contact lens, and one or more of the plurality of anchors extends at least partially within the optically used portion of the lens. 
         [0015]    In many embodiments, the material comprises an index of refraction similar to the soft contact lens material in order to inhibit light scatter. 
         [0016]    In many embodiments, the openings are sized to provide a gated release of therapeutic agent in response to pressure of the eyelid, in which surface tension extending across each of the plurality of openings inhibits diffusion of therapeutic agent through the opening, and a pressure of the eyelid urges fluid of the container through the plurality of openings. 
         [0017]    In many embodiments, the container comprises a hydrophobic material, and the openings are sized to release the therapeutic agent in response to pressure of the eyelid and to inhibit release of the therapeutic agent when the contact lens comprises a free floating configuration. 
         [0018]    In many embodiments, the openings are sized to inhibit diffusion of the therapeutic agent through the opening in response to a surface tension of a solution comprising the therapeutic agent. 
         [0019]    In many embodiments, the openings of the container comprise a length extending along a thickness of the container wall and are dimensioned with a cross sectional area in to release therapeutic agent in response to pressure of the eyelid and inhibit diffusion of the therapeutic agent through the cross-sectional area. 
         [0020]    In many embodiments, a maximum dimension across the cross-sectional area comprises no more than about 50 nm, for example no more than about 5 nm. 
         [0021]    In many embodiments, the length is sized to allow a therapeutic amount of fluid comprising the therapeutic agent to be forced through the opening with pressure of the eyelid. 
         [0022]    In many embodiments, the free floating configuration comprises a configuration of the contact lens placed in a solution of a storage container. 
         [0023]    In many embodiments, this fluidic module is comprised of flexible membranes and is matched in refractive index to the lens substrate so that it does not cause any optical disturbance or changes in refractive property of the contact lens. 
         [0024]    In many embodiments, the one or more membranes comprising the wall of the fluidic module is drilled with one or more of a precision drill, a laser, an electron beam, a water jet, or an etching process, in order to form submicron size holes, such as nanometer sized holes. 
         [0025]    In many embodiments, the diameter of the holes is such that the rate of drainage through these holes is negligible under normal conditions of atmospheric pressure and body temperature. 
         [0026]    In many embodiments, the diameter of the holes is sized, for example adjusted, so that the rate of drainage increases when eyelids put pressure on the contact lens in the eye during blinking, for example. 
         [0027]    In many embodiments, the drainage of the drug solution/suspension occurs in pulses during daytime, immediately following blinking, and continuously during down-gaze, at a lower rate. 
         [0028]    In many embodiments, the contact lens bearing the drug eluting module is designed to be removed before going to sleep. 
         [0029]    In many embodiments, the soft contact lens has a diameter of 10-14 mm and the embedded fluidic module has a diameter of 3-12 mm. 
         [0030]    In many embodiments, the fluidic module is barrel shaped, with a height of 10-200 microns, preferably 50-150 microns. Alternatively, the fluidic module may comprise an annular shape, or a plurality of reservoirs located away from an inner optical region of the contact lens. 
         [0031]    In many embodiments, the fluidic module is comprised of membranes that are impermeable to water and other hydrophilic liquids. 
         [0032]    In many embodiments, the wall thickness of the membranes comprising the fluidic module varies from 5-25 microns. 
         [0033]    In many embodiments, the posterior (cornea facing) wall of the fluidic module is penetrated with a number of submicron sized holes, of diameter in the range 100-500 nm, designed to allow minimal drainage under normal handling and storage conditions, but allow enhanced drainage when the module is pressurized. In many embodiments, the diameter of the holes is within a range from about 0.5 nm to about 5 nm, in order to provide decreased drainage and inhibit diffusion of the therapeutic agent. 
         [0034]    In many embodiments, the number of the submicron holes is in the range of 10 2  (100) to 10 6  (1,000,000) per module. 
         [0035]    In many embodiments, the volume of the fluidic module is in the range 1-10 microliter, preferably, 3-8 microliter. 
         [0036]    In many embodiments, the holes are only placed on the wall of the module in contact with the cornea in order to deliver the drug into the post tear film, that persists for up to 20-30 minutes before being drained into the sub-conjunctival nasolacrimal glands. 
         [0037]    In many embodiments, this module is filled with a solution of an ocular drug at a concentration in the range 1-100 g/L (grams per liter), or 1-300×10 −3  M/L (moles per liter). 
         [0038]    In many embodiments, the loading of drugs in a single module prior to encapsulation into the contact lens is in the range 50-500 micrograms. 
         [0039]    In many embodiments, it is estimated that approximately 6 micrograms of Timolol (timolol maleate) is required to be delivered on the cornea every day for treatment of glaucoma caused by enhancement of intraocular pressure. 
         [0040]    In many embodiments, a drug eluting lens comprising a fluidic module may be used for up to 1 month or longer for sustained delivery of this drug. 
         [0041]    In many embodiments, it is also expected that 80% or more of the drug eluted from the contact lens is actually delivered on the cornea, because of the specific placement of the drainage holes. 
         [0042]    In many embodiments, the force exerted by eyelids on the contact lens during blinking is in the range of 4-50 millinewtons, preferably, 8-30 millinewtons. 
         [0043]    The diameter of the drain holes on the wall of the fluidic module is adjusted so that proper drainage rate is achieved when the module is placed under this pressure. 
       INCORPORATION BY REFERENCE 
       [0044]    All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0045]    The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which: 
           [0046]      FIG. 1  shows a top view of the fluidic module, comprising an optically centered chamber, in accordance with embodiments; 
           [0047]      FIG. 2  shows a side view of the contact lens as in  FIG. 1 , comprising the fluidic module embedded in a soft contact lens, in accordance with embodiments; and 
           [0048]      FIG. 3  shows a contact lens comprising a drug delivery module having an annular reservoir container, in accordance with embodiments; 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0049]    The embodiments disclosed herein are well suited for combination with many prior contact lenses and therapeutic agents. 
         [0050]      FIG. 1  shows a top view of the fluidic module, comprising an optically centered chamber, and  FIG. 2  shows a side view of the contact lens as in  FIG. 1 , comprising the fluidic module embedded in a soft contact lens, in accordance with embodiments. 
         [0051]    In many embodiments, a soft hydrogel contact lens comprises a reservoir module embedded inside the contact lens to release a therapeutic agent such as drug. The therapeutic agent may comprise lipid to inhibit evaporation of the tear film, in order to treat dry eye, for example. The soft hydrogel material may comprise a silicone hydrogel material that readily releases the therapeutic agent to the eye, for example to the tear film, when release from the module. The reservoir module comprises a wall to contain and inhibit release of the drug, and holes sized to release the drug. The holes can be sized large, e.g. greater than 500 nm to release the drug with diffusion or when the eyelid blinks and applies pressure to the module. Alternatively, the holes can be sized smaller than 500 nm, for example smaller than 50 nm, for further example smaller than 5 nm, such that drug is only released when the user blinks and in response to the blinking pressure, depending on the molecular size of the therapeutic agent. In many embodiments, the module comprises a hydrophobic barrier material, such that the surface tension of water within the small holes inhibits diffusion of the drug molecules through the openings. The barrier material may comprise one or more of many materials capable of inhibiting release of the therapeutic agent through the material itself. Once released through the holes, the drug diffuses through the hydrogel material to the eye. The module comprises a transparent material, and may comprise a plurality of outer anchors to hold the module in the soft hydrogel material. The anchors comprise loops of materials or openings in a flange of the module sized to receive hydrogel material of the contact lens and anchor the module when embedded within the lens. The contact lens has a diameter from about 10-14 mm and the module has a diameter within a range from about 3-12 mm. 
         [0052]    In many embodiments, the module comprises a sufficient number of openings to release a therapeutic amount of therapeutic agent over the time the lens is worn, in order to provide a therapeutic benefit. The volume of the reservoir, and the size and number of openings can be configured to release the therapeutic amount in response to blinking of the eye. The reservoir can be sized to provide the therapeutic amount over a predetermined time, for a number of blinks each day, for example. 
         [0053]    In many embodiments, each of the plurality of openings comprises a subnanometer hole in a hydrophobic membrane film, such that one or more of a permeation rate or a diffusion is substantially lower than a corresponding permeation rate of a similar hole in a similar hole in a hydrophilic membrane film. In many embodiments, the permeation of diffusion rate is at least about one order of magnitude lower, such as at least about two orders of magnitude lower and can be within a range from about 1-4 orders of magnitude lower, for example 3 to 4 orders of magnitude lower. 
         [0054]    In many embodiments, each of the plurality of openings is sized to a therapeutic agent to be delivered through said each opening. 
         [0055]    For example, the hole size to stop diffusion of pure water is about 0.5, which can be referred to as a critical size of the hole for pure water. In many embodiments, the critical size of the gate is larger for therapeutic agents having a bigger molecular size. A larger therapeutic agent can have a larger diameter hole than pure water in order to deliver therapeutic amounts as described herein. 
         [0056]    The membrane of the module comprises a biocompatible compatible material, and has an index preferably substantially the same as the fluid and the contact lens itself, in the range 1.44-1.55, or within the range from 1.40 to 1.55, for example. 
         [0057]    The membrane may be of the same thickness throughout, or it may have a thickness profile, contoured to control its rigidity or flexibility along the dimensions of the membrane. 
         [0058]    The membrane is preferably a fluorocarbon, a polyester, a polyurethane, a polyether, a polyimide, a polyamide, an acrylate or methacrylate ester, or a copolymer bearing these functionalities. 
         [0059]    The module may comprise on or more of many optically transmissive materials, such as one or more of a plastic, a polymer, a thermo plastic, a fluoropolymer a non-reactive thermoplastic fluoropolymer, or polyvinylidene difluoride (hereinafter “PVDF”), for example. In many embodiments, the material comprises an optically transmissive hydrophobic material, for example. 
         [0060]    The walls of the module may either be composed of the same material as the membrane on the two sides, or it may be made of a different material. 
         [0061]      FIG. 3  shows a contact lens comprising a drug delivery module having an annular reservoir container. In many embodiments, the module comprises an annular shape with the reservoir located away from an optical axis of the eye and entrance pupil of the eye, in order to inhibit refractive changes of the contact lens when fluid is released from the module. Alternatively, the module may comprise a plurality of reservoirs located away from a central optical axis of the lens that approximately corresponds to an optical axis of the eye. The outer reservoir chamber located away from the optical axis may comprise an annular ring shaped chamber, or a plurality of chambers arranged with a substantially annular profile, for example. Each of the plurality of reservoir chambers may comprise a plurality of holes as described herein, for example. 
         [0062]    In many embodiments, the one or more reservoir containers located away from the optical axis comprises an inner boundary wall located toward the optical axis and an outer boundary wall located away from the optical axis. A first plurality of inwardly located anchors can be located inward from the inner boundary wall, and a second plurality of outwardly located anchors can be located outward from the outer boundary wall. Each of the anchors may comprise an opening formed in a layer of material such that the soft contact lens material extends through the opening. The anchors may comprise loops, apertures or other structures such as branches or struts of configured to contact the soft contact lens material and anchor the module to the soft contact lens material. The anchors and modules may comprise optically transparent materials having an index of refraction that substantially corresponds to the index of refraction of the soft contact lens hydrogel material, in order to inhibit light scatter. 
         [0063]    In many embodiments, and inner portion of the module extends between the inner module wall extending circumferentially around the inner portion. 
         [0064]    The module may comprise one or more of many materials, for example. 
         [0065]    A soft contact lens comprised of a hydrogel that may be a cross-linked polyhydroxy ethyl methacrylate network or a silicone-hydrogel copolymer is embedded with a sealed fluidic module comprised of impermeable walls penetrated with a plurality of through holes, each of diameter in the range of 100 nm to 500 nm. 
         [0066]    Preferably, the holes are drilled exclusively on the surface of the fluidic module that faces the corneal surface. 
         [0067]    These holes may be drilled by reactive ion etching or by etching using a solution, through a mask to control the hole size. 
         [0068]    The fluidic module is filled with a solution of a desired ophthalmic drug that is required to be administered on the surface of the cornea, so that it may be transported across the cornea into the aqueous humor of the eye. 
         [0069]    The solution has a viscosity in the range of 10-100 cps, preferably in the range 20-80 cps. 
         [0070]    Preferably, the drug solution is miscible with the tear fluid, so that the mixture remains clear. 
         [0071]    The viscosity of the solution is adjusted so that transport of this solution through the holes is minimized by external air pressure when the lens comprising the embedded fluidic module is stored under normal conditions of atmospheric pressure and temperature. 
         [0072]    The concentration of the drug in the solution is in the range of 1-300 millimoles/L. 
         [0073]    Preferably, the concentration of the drug in the solution is in the range 50-100 millimoles/L 
         [0074]    The fluidic module is embedded in the soft contact lens such that the module is close to the bottom of the contact lens. 
         [0075]    Preferably there is a thin layer of contact lens material below the fluidic module, its thickness being in the range of 5-10 microns. 
         [0076]    Pressurization of the fluidic module due to blink applied pressure by the eyelids causes forced ejection of fluid from the fluidic module that then diffuses through the contact lens material and enters the post tear film and stays in contact with the cornea for a period of up to 20-30 minutes. 
         [0077]    An incremental volume of drug laden solution is thus delivered on the cornea by every blink. 
         [0078]    As the pressure on the contact lens is relieved after the blink, the fluidic module comes under negative pressure, since some of the fluid has been ejected from the module during the blink period. 
         [0079]    The negative pressure induces tear fluid to enter into the fluidic module and equalize the pressure difference created by ejection of the drug solution 
         [0080]    The tear fluid causes the drug solution to become diluted. 
         [0081]    This process reduces the incremental amount of drug delivered per blink as more drug is delivered. 
         [0082]    The trans-corneal transport of the drug competes with the delivery of the drug via blinks, so that an equilibrium drug concentration is established in the post tear film in contact with the cornea, underneath the contact lens 
         [0083]    The diameter of the fluidic module is in the range 3-12 mm, preferably 8-10 mm. 
         [0084]    The thickness of the fluidic module is 10-200 microns, preferably 50-150 microns 
         [0085]    The thickness of the membrane comprising the wall of the membrane is in the range of 5-25 microns. 
         [0086]    The volume of the fluidic module is 3-12 microliters, preferably 5-8 microliters. 
         [0087]    The drug loading per module is therefore in the range of 75-240 micrograms 
         [0088]    The amount of drug solution ejected out of the fluidic module per blink is approximately 5-10 pL, depending on the viscosity of the solution and the diameter of the holes. 
         [0089]    The amount of drug delivered per blink is 75-300 picograms. 
         [0090]    Approximately 0.025 to 0.1 micrograms will be delivered before the post tear film is cleared by the eye. 
         [0091]    Since the average blink rate is about 10 blinks per minute, there are approximately 1.2×104 blinks per 20 hours, delivering about 0.06-0.12 microliters of fluid per day. 
         [0092]    This means that the drug reservoir will be diluted by as much as 15% or as little as 5% per day, depending on the number of hours of wear of the contact lens and its design, as well as the blink rate of the individual. 
         [0093]    The drug concentration will therefore be reduced to 85-95% per day of use. 
         [0094]    This rate of dilution translates to an effective use period of 2-7 days, assuming that a dosage variation of 25-30% is acceptable. 
         [0095]    This variation will produce a corresponding variation in bioavailability of the drug in the anterior chamber 
         [0096]    Such a variation is substantially less than that achieved by twice daily topical applications 
         [0097]    Thus a broad range of delivery dosages and use periods will be achieved by this device. 
       Examples of Therapeutic Agents and Studies Suitable for Incorporation in Accordance with Embodiments Disclosed Herein 
       [0098]    A person of ordinary skill in the art can modify prior therapeutic agents and delivery devices in accordance with the teachings disclosed herein. 
         [0099]    Clinical Applications 
         [0100]    Among clinical applications are as follows. 
         [0101]    Bacterial of Fungal Keratitis 
         [0102]    Sight-threatening conditions, such as microbial keratitis, require rapid and sustained delivery of high levels of medication to the affected tissues. Currently, patients with severe microbial keratitis are hospitalized to ensure continuous delivery of therapeutic levels of antibiotic through round-the-clock dosing. Management of these patients could be dramatically improved through the use of an effective drug delivery system, ensuring continuously high antibiotic levels. Contact lens delivery of antibiotics has been investigated, showing some improvement over delivery via eyedrops. Fungal keratitis is a major cause of blindness in tropical developing countries, and requires sustained delivery of antifungal agents for their management and cure 
         [0103]    Glaucoma 
         [0104]    A feasibility study investigating efficacy and toxicity of contact lenses that were passively impregnated with timolol maleate and brimonidine tartrate found IOP reductions equivalent to conventional therapy and no toxicity. 
         [0105]    Dry Eye 
         [0106]    Myobium gland dysfunction has been associated with a deficiency of phospholipids in the tear film. Drug-eluting contact lenses have been used to provide controlled release of phospholipids. Phospholipid-eluting contact lenses may provide an effective treatment for some forms of dry eye, and possibly can improve end-of-day dryness in contact lens wearers by stabilizing the tear film and enhancing lens wettability. This may be especially helpful in wearers of silicone hydrogel lenses, which sequester lipids due to the hydrophobic nature of their surfaces 
         [0107]    Allergy or Uveitis 
         [0108]    The eye is especially vulnerable to auto-immune disorders such as uveitis, requiring sustained administration of immuno-modulators or immuno-suppresants for their control. These are required to be administered topically or via sustained drug delivery, because of their systemic toxicity. The use of ketotifen-containing contact lenses for the management of ocular allergy has been investigated experimentally, and has also undergone several clinical trials addressing safety and efficacy. 
         [0109]    Based on the teachings disclosed herein, a person of ordinary skill in the art can determine dimensions of the openings, the thickness of the container wall, the number of openings, and the reservoir volume in order to provide therapeutic amounts of the therapeutic agent over a predetermined amount of time. For example, a pressure of the eyelid with a blink can be determined, and amounts of therapeutic agent released through each opening with each blink determined. The number of times a person blinks during a day can be used to determine the amount of therapeutic agent released per day. 
         [0110]    The amount of therapeutic agent released through the plurality of openings during non-blink times can be determined based on Fick&#39;s law of diffusion for channels appropriately sized to allow diffusion, for example having a diameter across of at least about 50 nm. Alternatively or in combination, the amount of therapeutic agent released through the plurality of openings during non-blink times can be determined for channels appropriately sized to inhibit diffusion through the channels and to release therapeutic agent in response to eyelid pressure, for example channels having a diameter across of no more than about 50 nm, for example, depending on the molecular size of the therapeutic agent. The gated release of therapeutic agent in response to each eye blink can be studied in human subjects with known study designs suitable for incorporation in accordance with embodiments disclosed herein. 
         [0111]    In many embodiments, a therapeutic agent can be identified, and the molecular size of the therapeutic agent determined based on published data. Based on this published size, a plurality of holes as described herein can be formed in a barrier material, in which each of the holes comprises a diameter corresponding to the therapeutic agent, for example slightly larger than a molecular diameter of the therapeutic agent, and studies conducted with known materials and apparatus to determine the amount of therapeutic agent released. 
         [0112]    An example of molecular gating with hydrophobic surfaces suitable for incorporation in accordance with embodiments described herein is described in Principles of Gating Mechanisms of Ion Channels, by Oliver Beckstein, a thesis submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at the University of Oxford, Michelmas 2004, available on the world wide web at (sbcb.bioch.ox.ac.uk/users/oliver/download/Thesis/OB_thesis — 2sided.pdf). 
         [0113]    While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.