Oral appliance having standardized doses of medicament, methods of use and methods of making

Abstract

An oral appliance for delivering a medicament at a selected standardized dose to an oral cavity is provided. The oral appliance comprises an exterior and an interior, the interior of the oral appliance configured to contour at least a portion of teeth and / or soft tissue of the oral cavity; and a volume of the medicament being disposed in a hydrogel at a selected dose within the interior based on dimensions of the portion of the teeth and / or soft tissue. The method of making the oral appliance and the method of treating a patient with the oral appliance are provided.

Description

ORAL APPLIANCE HAVING STANDARDIZED DOSES OF MEDICAMENT, METHODS OF USE AND METHODS OF MAKING Docket: 1658-30 PCT TITLE: ORAL APPLIANCE HAVING STANDARDIZED DOSES OF MEDICAMENT, METHODS OF USE AND METHODS OF MAKING INVENTORS: Peter John Zegarelli Jarret Scott Fass Dorna HakimimehrORAL APPLIANCE HAVING STANDARDIZED DOSES OF MEDICAMENT, METHODS OF USE AND METHODS OF MAKING BACKGROUND

[0001] Although advances have been made in recent years for the treatment of specific dental diseases, the actual delivery of dental treatment remains a manually intensive process. Oral appliances have been used to deliver certain medicaments, such as for example, tooth whitening compositions when the treatment area is generally throughout the oral cavity. However, with other medicaments, such as for example, antimicrobials, steroids, anesthetics, analgesics, etc., often the medicaments are improperly loaded into the oral appliance, which can cause unwanted off target effects of the medicament, when or if the medicament contacts the wrong treatment area, if there is not enough medicament that contacts the desired treatment area, or if there is too much medicament that contacts the desired treatment area.

[0002] The oral cavity (mouth) is red and pink for a reason; it is highly vascularized with arteries, arterioles, capillaries and veins which are near the surface or just below the surface of the epithelium (mucosal tissues). As such, the oral cavity uniquely presents opportunities to mucosally or transmucosally deliver and / or the absorb various medicaments. This oral cavity is also the only large mucosal tissue, aggregately, which is easily accessible by the individual or a practitioner, who can then self-medicate themselves. Additionally, the terrain of the mouth, especially the dentition, is forensically unique and therefore can accept an individual patient specific device which will fit precisely to that patient and no other patient for the targeted delivery of medications.

[0003] One area of interest of the oral cavity is the gingiva and / or other soft and hard tissues. Even more specifically, the gingival sulcus, which is the V-shaped crevice that surrounds each tooth, bounded by tooth on one side and the epithelium lining free margin of gingiva on the other side; the gingival sulcus can be an area for unwanted microbial growth that is resistant to the cleaning action of saliva and gingival fluid. The gingival sulcus is involved in pathogenic diseases such as gum bleeding, gingivitis, plaque formation, periodontal disease and dental caries.

[0004] The geometric topography of the oral cavity is forensically unique. In other words, no two oral cavities are alike between patients including identical twins. For example, the geometric topographies of the teeth, gingiva, and / or sulcus are unique to that individual patient and the surface areas, sizes, depths, and shapes of the oral cavity are random andforensically unique to that individual. The physical size and development of the patient does not, in general, correspond to the size of the oral cavity. For example, a very large adult may have a smaller mouth (e.g., oral cavity) with a smaller dentition than an undersized adult individual who may have a very large mouth with a large dentition. Thus, the total surface areas of the teeth and the gingiva may not correspond at all to the overall size and weight of the different individuals. To this end, the very large individual with the smaller mouth may actually require less medication than the small individual with the large mouth in order to adequately treat a condition. Currently, oral dosing of medicaments adheres to Clark’s Rule such that for example, a patient will be prescribed chlorhexidine rinse 0.12% at a volume of 15 mL to be used twice per day for 30 seconds each rinse to treat gingivitis. This medicament is standardized based on an arbitrary standard 150 pound universal person and has nothing to do with the number and size of teeth in the mouth, the surface area to be treated and the desired dosage of drug to be applied based on the huge discrepancies of mouth sizes. Ultimately, the patient is either undertreated, overtreated and / or unevenly treated throughout the mouth and non-targeted areas are treated as well as targeted areas.

[0005] Further, not only is the geometric topography of the oral cavity unique to that individual patient, but also the oral microbiome of the oral cavity is also unique to that individual patient. Typically, the oral microbiome is a collective genome of microorganisms (e.g., bacteria, fungi, viruses, protozoa, etc.) that reside throughout the oral cavity. The oral microbiome can contain a core microbiome and a variable microbiome. The core microbiome is common to all the individuals, whereas the variable microbiome is unique to individuals depending on, among other things, the lifestyle, diet, general health of the individual and the total body inflammation level, hygiene or other factors unique to the individual.

[0006] The microbiome in the oral cavity can be found on the hard and the soft tissues of the oral cavity including teeth and the oral mucosa. The teeth, tongue, buccal mucosa (e.g., cheeks), labial mucosa (e.g., lips), gingiva and gingival sulcus, periodontal pockets, tonsils, hard and soft palates and the floor of the mouth provide a rich environment in which microorganisms can flourish. Each of these above different tissues often also harbor and nurture biomes that are specific to that tissue and not the other tissues. For example, bacteria of the tongue can be different from bacteria of the gingiva. Often times, the unique oral microbiome can be found as a biofilm coating throughout the oral cavity.

[0007] Because there is such uniqueness in the oral cavity in the topography and in the microbiome, oral appliances that are provided in one-size-fits-all or universal sizes that are not custom fit to the oral cavity of the patient do not adequately match the contours of the patient’s unique oral cavity. Universal sizes do not fit everyone; and universal sizes fit no one in particular. To complicate matters, when the universal size oral appliance is loaded with medicament, the universal size can lead to poor contact or gaps, for example, between the interior surface of the oral appliance that can have the medicament loaded therein and the soft and hard tissue of the individual patient’s oral cavity. This may cause problems with the medicament delivery to the oral cavity such that the medicament can leak out along the edges of universal appliances with resultant patient swallowing or the saliva can enter and easily dilute the medication. Custom fit or patient specific oral appliances provide a better fit to the patient’s oral cavity since they are made to match the contours of the soft and hard tissue of the individual patient.

[0008] Sometimes loading the medicament, for example, in the interior of the oral appliance so that the medicament properly contacts the treatment area, can be challenging as the medicament may not be loaded at the appropriate location adjacent to the treatment area, which may cause unwanted off target effects depending on the medicament. In addition to improper location of the loaded medicament, there may be other variances in the dose of medicament, where too little medicament will not lead to the desired efficacy or too much medicament may cause leakage outside the oral appliance to the general oral cavity causing off targeted tissues to be exposed, or the gut itself from swallowing or the excess medicaments concentrated in one area can deliver too much medication versus an area with too little medication will be under medicated. All of these scenarios can result in undertreated, overtreated, unevenly treated or off-targeted treatment of tissues causing unwanted side effects. Further, the oral cavity being unique to each individual patient can also cause challenges in customizing the medicament to specifically meet the medicament needs of that particular patient.

[0009] To date, delivery of medicaments in universal appliances and custom fit oral appliances has reflected the same errors as associated with the arbitrary Clark’s Rule. Patients are instructed to arbitrarily fill an oral appliance (e.g., oral tray) with standard doses of medicament such as a capful, or a teaspoon or 5 mL without regard to the very specific topography to be treated. There is no standard delivery of a concentration of a drug to a specific targeted topography that is dosed evenly as applied.

[0010] Therefore, there is a need to improve loading and standardizing doses of a given medicament delivered by a custom-fit oral appliance. Custom-fit oral appliances that can be easily and precisely loaded with standardized doses of medicament specific to the unique topography and / or microbiome of the patient would be beneficial. SUMMARY

[0011] The current application provides custom-fit oral appliances that have standardized doses loaded in them and methods for disposing standardized doses of medicaments in the oral appliances for delivery of medicament either locally or systemically to the patient based on a unique principle of delivering a uniform dose of medicament per square millimeter of a specific targeted tissue. For example, in one embodiment, the custom-fit oral appliance is loaded with medicament and the medicament dose is based on the geometric topography and / or microbiome of the oral cavity (e.g., the surface area, size, depth, shape, and / or biofilm of the tissue). In this way a standardized dose of medicament can be delivered to the oral cavity of the patient. In one embodiment, the unique topography of the treatment area of the oral cavity (e.g., surface area, size, depth, and / or shape), severity of disease, therapeutic index of the medicament, are assigned a score or rating and then the medicament can be loaded into the oral appliance at the appropriate dose and location based on that score or rating. In this way, a precisely loaded oral appliance having a standardized dose of medicament can be made that is specific to the unique characteristics of the oral cavity of the individual patient.

[0012] In various aspects, an oral appliance for delivering a medicament to an oral cavity is provided. The oral appliance comprises an exterior and an interior, the interior of the oral appliance configured to contour at least a portion of teeth and / or soft tissue of the oral cavity; and a volume of the medicament is disposed in a hydrogel at a selected dose within the interior based on dimensions of at least a portion of the teeth and / or soft tissue.

[0013] In various aspects, a method of making an oral appliance for delivering a medicament to an oral cavity is provided. The method comprises providing an oral appliance having an exterior and an interior, the interior of the oral appliance configured to contour at least a portion of teeth and / or soft tissue areas of the oral cavity; calculating a selected dose; providing a volume of the medicament disposed in a hydrogel or other medium at the selected dose; providing a dispensing device having an outlet configured to dispense medicament at discrete regions of the interior based on custom dimensions of at least a portion of the teeth and / or soft tissue of a patient as well as the exterior or both theinterior and the exterior of the oral appliance; disposing the volume of the medicament within the interior based on dimensions of at least a portion of the teeth and / or soft tissue using the dispensing device.

[0014] In other aspects, a method of producing an oral appliance pre-loaded with at least one medicament having a selected dose. The method comprises creating a digital image of at least a portion of the teeth and / or soft tissue areas of the oral cavity to be treated to using an imaging device; generating a surface area of a portion of the teeth and / or soft tissue areas of the oral cavity to be treated based on the digital image; calculating a selected standardized dose for the generated surface area; disposing the selected standardized dose at least at the portion of the teeth and / or soft tissue areas of the oral cavity to be treated; and producing the oral appliance having the medicament with the selected standardized dose disposed in or on at least a portion and / or all of the interior surface of the oral appliance. The medicament dose can be based at a specific area of the oral cavity and the dose can be based on the square millimeters of that specific area.

[0015] In other aspects, a system for dispensing a medicament having a standardized dose into or on an oral appliance is provided. The system comprises a robotic dispensing device having an outlet configured to dispense medicament having a standardized dose at discrete regions of an interior, an exterior or both the interior and the exterior of an oral appliance; one or more sensors mounted on the robotic dispensing device, the one or more sensors configured to detect a marker for registering a position of the oral appliance; a processor configured to receive and process input from the one or more sensors; and a controller operatively connected to the processor and configured to operate the robotic dispensing device, at least in part, on input from the one or more sensors and processed by the processor, wherein the robotic dispensing device is configured to dispense from the outlet the medicament having a standardized dose at discrete regions of an interior, an exterior or both the interior and the exterior of an oral appliance.

[0016] In other aspects, a method of making a standardized dose of a medicament for an oral appliance is provided. The method comprises obtaining a digital image of at least a portion of the teeth and / or soft tissue of the oral cavity; identifying a surface area of the portion of the teeth and / or soft tissue of the oral cavity to be treated; calculating the surface area to be treated with a medicament; generating a virtual model of the oral appliance having the volume of medicament having the standardized dose disposed in the oral appliance; generating a volume of medicament having a standardized dose corresponding to the surface area to be treated; producing an oral appliance and disposing the volume of medicamenthaving the standardized dose on the portion of the teeth and / or soft tissue of the oral cavity to be treated.

[0017] In other aspects, a system for delivering a medicament having a standardized dose to an inflamed tissue of an oral cavity is provided. The system comprises a first set of oral appliance comprising an exterior and an interior, the interior of the oral appliance configured to contour at least a portion of teeth and / or soft tissue of the oral cavity; and a volume of the medicament is disposed in a hydrogel at a selected dose within the interior based on dimensions of at least a portion of the teeth and / or soft tissue; and a second set of oral appliance comprising an exterior and an interior, the interior of the oral appliance configured to contour at least a portion of teeth and / or soft tissue of the oral cavity; and a second volume of the medicament disposed in a hydrogel at a second selected dose within the interior based on a second dimensions of at least a portion of the teeth and / or soft tissue after an application of the first set of oral appliance.

[0018] Additional features and advantages of various embodiments will be set forth in part in the description that follows, and in part will be apparent from the description, or may be learned by practice of various embodiments. The objectives and other advantages of various embodiments will be realized and attained by means of the elements and combinations particularly pointed out in the description and appended claims. BRIEF DESCRIPTION OF THE FIGURES

[0019] In part, other aspects, features, benefits and advantages of the embodiments will be apparent with regard to the following description, appended claims and accompanying drawings.

[0020] FIG.1 illustrates an enlarged side view of an embodiment of the oral appliance that contours the teeth and / or soft tissues of a patient, the oral appliance is shown without teeth and / or soft tissues inserted in the oral appliance.

[0021] FIG. 2 illustrates an enlarged side view of an embodiment of the oral appliance, where the medicament is in a hydrogel that is adjacent to the gingival sulcus region. This view has the teeth and gums loaded in the interior surface of the oral appliance and the oral appliance can be transparent or non-transparent.

[0022] FIG. 2A illustrates an example of a hydrogel or a virtual model of a hydrogel containing the medicament that is configured to contact the unique gingival sulcus of a patient, when it is part of the oral appliance. The virtual model of the hydrogel can, for example, be the desired treatment area and can be the coordinates that the robotic arm willuse to dispense the hydrogel in the appropriate area of the oral appliance. The hydrogel can also be loaded as part of the oral appliance during, for example, additive manufacturing (e.g., 3D printing). The data that is used to dispense the hydrogel from the robotic arm or to print the hydrogel using additive manufacturing can be from, for example, a first digital image of the oral appliance (Dig1) based on a baseline image of a patient’s oral cavity of at least a portion of the patient’s teeth and / or soft tissue, and a computer processor generates a second digital image (Dig2) corresponding to at least a portion of the patient’s oral appliance that requires dispensing medicament, the processor combines the first digital image (Dig1) with the second digital image (Dig2) to form a third digital image (Dig3) for enabling the robotic arm or 3D printer to dispense or print the hydrogel containing the medicament in such a pattern or coordinates as shown in for example, FIG.2A, where the hydrogel will be located adjacent to the gingival sulcus region, which is the specific area to be treated.

[0023] FIG. 2B illustrates an example of a standardized dosing chart based on unique characteristics such as the size of the patient’s sulcus and other parameters, such as for example, surface area, depth, shape, severity of disease, microbiome of the oral cavity, height of the patient, weight of the patient and / or therapeutic index of the medicament. These parameters can be scored or rated and the hydrogel dispensing can be selected according to this scoring or rating to standardize the dose of medicament, dispense and load the hydrogel in the oral appliance. In some embodiments, the height and weight of the patient has nothing to do with the size of the oral cavity and dosing based on parameters such as height and weight of the patient used in Clark’s rule to dose medication is not a relevant parameter in dosing the medicament.

[0024] FIG. 3A illustrates a top view of an embodiment of an oral appliance that has a handle and covers the lower teeth and / or soft tissues of a patient that aids in manufacturing the oral appliance.

[0025] FIG. 3B illustrates a bottom view of an embodiment of an oral appliance that has a handle and covers the lower teeth and / or soft tissues of a patient.

[0026] FIG. 3C illustrates a top view of an embodiment of an oral appliance that has a separatable handle on the exterior surface and allows covering the lower teeth and / or soft tissues of a patient.

[0027] FIG.3D illustrates a bottom view of an oral appliance that has a handle and a barrier that allows covering of the lower teeth and / or soft tissues of a patient. The handle assists the robot during manufacture, for example, or patient in manipulating the oral appliance.

[0028] FIG.4 illustrates an enlarged side cross sectional view of an embodiment of the oral appliance configured to correspond to and cover the tooth and soft tissue areas inside the oral cavity. The interior surface encompasses the hydrogel having the medicament.

[0029] FIG.4A illustrates an enlarged cross-sectional view of the anatomy of the gums and a tooth including free gingiva, attached gingiva, lining mucosa, the periodontal pocket or crevice, the cementoenamel junction (CEJ), periodontal ligament (PDL), cementum, the enamel, dentin, and pulp. In some embodiments, the treatment area is the periodontal pocket that is targeted for delivery. The design of the medicament of the oral appliance is to target the periodontal pocket or crevice of the sulcus and dispose the medicament into the entrance of the sulcus, which leads to the periodontal pocket. In some embodiments, the robotic device can dispense medicament so precisely in the oral appliance to specifically target the sulcus, which is unique to the individual patient.

[0030] FIG. 4B illustrates an enlarged cross-sectional view of a portion of the oral appliance. In the embodiment shown, medicament is disposed in a porous material that is a hydrogel and the robotic device dispenses medicament precisely at a discrete region of the oral appliance. The hydrogel is shown in an uncompressed state and when worn with slight pressure, the hydrogel will be compressed against, among other things, the gingival crevice or sulcus causing a seal of the entrance of the gingival crevice or periodontal pocket, which prevents oral fluids (e.g., saliva, exudate, other foreign liquids, etc.) from entering the crevice or sulcus, which allows release of the medicament in the gingival crevice or sulcus which leads to the periodontal pocket with minimal dilution from other mouth fluids such as saliva and allows the hydrogel to absorb or wick fluid from the crevice, sulcus or pocket.

[0031] FIG.4C illustrates an enlarged cross-sectional view of a portion of the oral appliance that is placed adjacent to the teeth and gums. In the embodiment shown, medicament is disposed in a porous material that is a hydrogel and the robotic device dispenses medicament precisely at a discrete region of the oral appliance. The hydrogel is shown in a compressed state, where the device is worn and the hydrogel is compressed against, among other things, the treatment area, which is the unique gingival crevice, sulcus or periodontal pocket causing a seal of the entrance of the gingival crevice, sulcus or periodontal pocket, which prevents oral fluids (e.g., saliva, exudate, other foreign liquids, etc.) from entering the crevice, sulcus or pocket. The hydrogel allows release of the medicament into the gingival crevice, sulcus or periodontal pocket to treat the inflamed tissue shown by the down arrows. The hydrogel also absorbs or wicks oral fluids from the crevice, sulcus or pocket, which aides healing, shown by the up arrows.

[0032] FIG. 5 illustrates a perspective view of a robotic system having a first and second robotic arms.

[0033] FIG. 6 illustrates a perspective view of a dual arm robot that can have artificial intelligence utilized in, among other things, dispensing the hydrogel containing the medicament at discrete regions of the oral appliance.

[0034] FIG.7 is a diagram showing end effectors attached to the robot shown in FIG.6.

[0035] FIG. 8 is a block diagram of one embodiment of components to a computer- implemented system for producing an oral appliance by 3D printing or additive manufacturing or by a robotic system utilizing a robot.

[0036] FIG. 9 is a flow chart illustrating one embodiment of the computer implemented system and steps that the computer performs to produce the oral appliance, which is then loaded with medicament by a robotic system or a robot or by additive manufacturing.

[0037] FIG 10. is a flow chart showing the flow of one embodiment of the methods and steps to produce the oral appliance using a standardized dose of medicament disposed in or on the oral appliance for delivery to the treatment area. The methods and steps involve conducting a calculation involving scoring or rating of, for example, the unique characteristics of the treatment area such as, for example, the surface area of the patient’s sulcus and other unique parameters of the oral cavity, such as for example, depth, shape, height, width, severity of disease, microbiome of the oral cavity, and / or therapeutic index of the medicament. Once this is calculated and a scoring or rating is assigned, a standardized dose based on that scoring or rating can be dispensed in a particular pattern and location in the oral appliance from the robotic arm or by additive manufacturing. The medicament will be adjacent to the treatment area based on that scoring or rating and when worn will contact that treatment area. In this way, a standardized dose of medicament loaded in the oral appliance can be applied to the patient’s oral cavity based on the scoring or rating of the unique characteristics and dimensions of the topography of the oral cavity. The custom fit oral appliance will have a standardized dose of medicament even though the oral cavity (e.g., gingival sulcus) varies among patients.

[0038] FIG. 11 is a flow chart illustrating one embodiment of the computer implemented system and steps that the computer performs to produce the oral appliance, which is then loaded with medicament by a robotic system or a robot or by additive manufacturing.

[0039] FIG. 12 is a flow chart illustrating one embodiment of the computer implemented system and steps that the computer performs to produce the oral appliance, which is then loaded with medicament by a robotic system or a robot or by additive manufacturing.

[0040] FIGS.13A, 13B, 13C, 13D, 13E, 13F, 13G and 13H illustrate a cross-sectional view of the virtual image of a treatment surface area (TSA), a second treatment surface area (TSA1) and then a third Treatment surface area (TSA2) to produce a virtual image of the oral appliance (oral tray) and then the computer is given instructions to produce the oral tray containing a hydrogel loaded with medicament at discrete positions of the oral tray by a robotic system or a robot or by additive manufacturing.

[0041] FIGS.14, 15 and 16 illustrate and embodiment of use of the oral appliance that had significant reduction in selected cytokines and / or matrix metalloprotease enzymes (MMPs).

[0042] It is to be understood that the figures are not drawn to scale. Further, the relationship between objects in a figure may not be to scale and may in fact have a reverse relationship as to size. The figures are intended to bring understanding and clarity to the structure of each object shown, and thus, some features may be exaggerated in order to illustrate a specific feature of a structure. DETAILED DESCRIPTION

[0043] For the purposes of this specification and appended claims, unless otherwise indicated, all numbers expressing quantities of ingredients, percentages or proportions of materials, reaction conditions, and other numerical values used in the specification and claims, are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0044] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Moreover, all ranges disclosed herein are to be understood to encompass any and all subranges subsumed therein. For example, a range of “1 to 10” includes any and all subranges between (and including) the minimum value of 1 and the maximum value of 10, that is, any and all subranges having a minimum value of equal to or greater than 1 and a maximum value of equal to or less than 10, e.g., 5.5 to 10.

[0045] It is noted that, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the,” include plural referents unless expressly and unequivocally limited to one referent. Thus, for example, reference to “a medicament” includes one, two, three or more medicaments.

[0046] The term “porous” as used herein, refers to a material which is permeable such that fluids are movable therethrough by way of pores or other passages. An example of a porous material is a hydrogel material, concrete, cellulosic material, ceramics, foams, sponges, combinations thereof and / or derivatives thereof. The porous material may be the result of using a low or high molecular weight polymer. In some embodiments, the polymer may be porous as it is dispensed at a low density on the oral appliance and / or substrate, or is dispensed in a geometric pattern, either as a specific structure or a randomized structure.

[0047] The term “non-porous” as used herein, refers to a material which is impermeable such that fluids cannot move through the material. The non-porous material may be the result of using a low or high molecular weight polymer. In some embodiments, the polymer may be non-porous as it is dispensed at a high density on the oral appliance and / or substrate in a solid form with no structural spacing to hold medicaments, as described above.

[0048] The terms “hydrogel” and “hydrogels” refer to a broad class of polymeric materials, which may be natural or synthetic, which have an affinity for an aqueous medium (e.g., a medicament), and are able to absorb aqueous medium.

[0049] The term “medicament” as used herein is generally meant to refer to any substance that alters in part or in toto the physiology of a patient. The term “medicament” may be used interchangeably herein with the terms “medicine”, “drug”, “therapeutic agent”, “therapeutically effective amount”, or “active pharmaceutical ingredient”. It will be understood that a “medicament formulation” may include more than one therapeutic agent, wherein exemplary combinations of therapeutic agents include a combination of two or more medicaments.

[0050] The terms “treating” and "treatment” include "preventing” or “prevention” of disease. In addition, "treating” or "treatment” does not require complete alleviation of signs or symptoms, does not require a cure, and specifically includes protocols that have only a marginal effect on the patient.

[0051] The term “standardized dose” includes an optimal dose given at one or more times.

[0052] The term “localized” delivery includes delivery where one or more medicaments contact the tooth and / or soft tissue areas, for example, the gingival margins of the teeth or a region inside of the mouth such as the palate, or in close proximity thereto.

[0053] The term “target site” is that specific area to be treated that is then located on the digital image of the patient where a digital manipulation is preformed and onto which the hydrogel will be placed in the oral appliance to treat that target site.

[0054] The term “off target site” or “non-targeted site” are those areas outside of the defined target site which are not treated and the hydrogel will not be placed in the oral appliance adjacent to those sites so that those “off target sites” or “non-targeted sites” are not treated by the one or more medicaments loaded in the oral appliance.

[0055] The term "targeted delivery” includes delivery of one or more medicaments at a target site or sites as needed for treatment of a disease or diseases or condition including cosmetic applications, for example, whitening teeth or removing stains. In some embodiments, the oral appliance can be used to deliver medicament to the soft tissue of the inside of the mouth including, but not limited to, any soft tissue adjacent or between the teeth including, but not limited to, the papilla, tissue of the upper and lower dental arches, marginal gingiva, gingival sulcus, inter-dental gingiva, gingival gum structure on lingual and buccal surfaces up to and including the muco-gingival junction, generalized mucosae of the mouth and / or the palate, tongue and / or the floor of the mouth or to the hard tissues including teeth and bone. In various embodiments, the soft tissue area includes the muco- buccal folds, hard and soft palates, the tongue, lining mucosa, and / or attached gingival tissue.

[0056] The term “custom fit” as used herein, refers to an oral appliance that is specifically made, via molding, 3D printing or any way, to correspond to at least a portion of a tooth, a selected number of teeth, all of the teeth and / or the soft tissues found in the mouth of a specific individual patient. A custom fit oral appliance is not a generic device which is then heated or otherwise manipulated by a consumer (commonly known as boil and bite appliances), inserted into their mouth by themselves and then molded by that consumer to fit their own mouth. The patient image is the result of an action upon that particular individual by another person whereas the consumer is acting upon themselves by manually manipulating the generic material.

[0057] For this application, in some embodiments, Clark's rule or Clark’s rule equation is defined as the weight of the patient in pounds divided by the average standard weight of 150 pounds (68 kg) multiplied by the adult dose of a drug to obtain the pediatric medication dose, as is demonstrated below: (Weight* divided by 150 lbs.) x Adult Dose**.

[0058] Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying drawings. While the invention willbe described in conjunction with the illustrated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the invention as defined by the appended claims.

[0059] The headings below are not meant to limit the disclosure in any way; embodiments under any one heading may be used in conjunction with embodiments under any other heading.

[0060] The current application provides custom-fit oral appliances that have standardized doses loaded in them and methods for disposing standardized doses of medicaments in the oral appliances for delivery of medicament either locally or systemically to the patient. For example, in one embodiment, the custom-fit oral appliance is loaded with medicament and the medicament dose is based on the geometric topography and / or microbiome of the oral cavity (e.g., the surface area, size, depth, shape, and / or biofilm of the sulcus). In this way a standardized dose of medicament can be delivered to the oral cavity of the patient. In one embodiment, the unique topography of the treatment area of the oral cavity (e.g., surface area, size, depth, and / or shape), severity of disease and / or the therapeutic index of the medicament, are assigned a score or rating and then the medicament can be loaded into the oral appliance at the appropriate dose and location based on that score or rating. In this way, a precisely loaded oral appliance having a standardized dose of medicament can be made that is specific to the unique characteristics of the oral cavity of the individual patient. Oral Appliance

[0061] Numerous custom fit oral appliances can be made in a variety of ways including by traditional thermoforming, 3D printing or additive manufacturing, or injection molding or other ways. Unlike orthodontic appliances, the present oral appliance is not designed to move teeth and is not an orthodontic appliance. Therefore, a plurality of oral appliances will be configured to fit the teeth in the same position as was imaged within the oral appliance. The teeth position will not change. However, the medicament disposed in or on the oral appliance will be in the same or different areas at different stages of the treatment regimen with a variety of oral appliances. Thus, kits containing a plurality of oral appliances can be provided with different treatment plans. For example, as the patient’s condition improves, each oral appliance can have a decreasing or increasing amount of medicament or the medicament can change as the treatment progresses. In some embodiments, the area targeted for treatment with a medicament can change based on how the treatment progresses.FIG. 10 illustrates and embodiment of the process steps to make and update the oral appliance based on how the treatment progresses.

[0062] In various embodiments, the oral appliance is monolithic or a single piece and the interior surface custom fit and formed to fit contours of the teeth and / or soft tissue areas inside the oral cavity of a patient in need of treatment. The device of the present application has the medicament dispensed into the device. In some embodiments, the medicament is not removable from it except by diffusion in the mouth. In certain embodiments, the oral appliance comprises, consists essentially of or consists of one, two, three, four, five or more oral appliances.

[0063] In various embodiments, the oral appliance is not monolithic or a single piece. The medicament is disposed on the inside and / or on the outside of the oral appliance, but as a separate component to the oral appliance. For example, the medicament can be disposed in porous material (e.g., polymer or hydrogel) that is configured to allow release of the medicament when the oral appliance is worn.

[0064] In some embodiments, oral appliances include, but are not limited to, oral trays, oral holders, oral covers, or the like that are designed to be placed within the oral cavity. The interior surface and / or exterior surface of the oral appliance contains a medicament disposed inside the porous portion of the hydrogel of the oral appliance and the medicament can be disposed anywhere within or on the oral appliance. In some embodiments, the exterior surface of the oral appliance is porous and allows medicament to be released to adjacent teeth and / or soft or hard tissue, or into the mouth in general. In some embodiments, the medicament and / or porous material (e.g., hydrogel) can be monolithic with the device—that is, the device, medicament and porous material are a single piece.

[0065] Numerous different oral appliances can be made by the methods of the present application, including custom fit oral appliances that correspond to a digital scan taken from the patient’s mouth or impression molds. Custom fit oral appliances are generally described in U.S. Patent No.9,649,182 to Peter J. Zegarelli, filed June 18, 2015. The entire disclosure of this patent is herein incorporated by reference into the present disclosure.

[0066] The oral appliance when worn allows the interior and / or exterior surface of the oral appliance to be adjacent to the teeth and / or gums or other tissue in the oral cavity. In some embodiments, the oral appliance receives one or more teeth including one or more molars, premolars, incisors, cuspids, tooth implants, or combinations or portions thereof.

[0067] The contact of the oral appliance with the tissue, when the oral appliance contains medicament in discrete regions, will allow medicament to be released from the oralappliance to the target tissue areas in the oral cavity (e.g., gum, gum line, teeth, etc.) at the desired regions adjacent to the medicament-containing discrete regions of the oral appliance. In this way, targeted therapy can be directed at the desired regions in the oral cavity. By providing an oral appliance with discrete medicament-containing regions and non- medicament-containing regions, medicament release can be controlled to adjacent tissue or confined to those regions adjacent to the non-medicament-containing material without unwanted dilution or contamination by oral fluids such as saliva or releasing the medicaments onto non-targeted or off targeted areas of the mouth with sometimes deleterious effects.

[0068] In some embodiments, the medicament containing regions are porous and the non- medicament containing regions are non-porous. In some embodiments, the oral appliance is predominantly porous (at least 51% or more) and non-porous material is coated on the oral appliance at discrete regions to make these discrete regions non-porous. In this way, medicament loading of the oral appliance and medicament release from the oral appliance is controlled as medicament will be released from the porous material at discrete regions and can target specific tissues in the oral cavity.

[0069] In some embodiments, the oral appliance is predominantly non-porous (at least 51% or more) and porous material containing medicament is dispensed into the oral appliance at discrete regions to make these discrete regions porous. In this way, medicament loading of the oral appliance and medicament release from the oral appliance is controlled as medicament will be released from the porous material at discrete regions and can target specific tissues in the oral cavity.

[0070] It will be understood that the medicament can be mixed with the polymer or hydrogel before, during or after the manufacture of the oral appliance.

[0071] In some embodiments, the oral appliance is made from a porous material or hydrogel that contains the medicament, and an agent that reduces porosity is applied to one or more discrete regions of the porous material or hydrogel to make the one or more discrete regions of the oral appliance non-porous as more particularly described in U.S. Patent Application No. 15 / 895,554 to Peter J. Zegarelli, filed on February 13, 2018. The entire disclosure of this application is incorporated herein by reference into the present application. For example, a crosslinking agent can be used to reduce porosity of a porous oral appliance and make that region where the crosslinking agent is applied to non-porous region to reduce or eliminate medicament release from that region.

[0072] In some embodiments, the oral appliance can be made by controlling the print density of the polymer during 3D printing or additive manufacturing. For example, the same polymer can be printed (e.g., using the same print head) at a density of, for example, 0.25 g / cm3to 0.5 g / cm3at discrete regions to form the porous regions of the oral appliance and at a higher density for example, 0.8 g / cm3to 1.5 g / cm3to make the oral appliance non- porous at discrete regions. This will be one way to produce the oral appliance without medicament and then the robotic device can dispense the medicament at discrete regions of the oral appliance. In some embodiments, the medicament can be disposed in a porous material such as a hydrogel.

[0073] In some embodiments, the oral appliance can be made by controlling the density of the polymer during 3D printing or additive manufacturing. For example, different polymers can be printed using two or more print heads, each print head having a different polymer. A high-density polymer can be used (e.g., 50,000 MW) and printed at discrete regions to form the non-porous regions of the oral appliance and another print head can use a low- density polymer (e.g., 5,000 MW) to make the oral appliance porous at discrete regions.

[0074] It will be understood that the oral appliance with discrete portions of the porous material and with discrete portions of non-porous material can be monolithic or a single piece having the same or different material. This type of oral appliance, in some embodiments, does not contain a porous insert after the oral appliance is made. Such porous inserts are described in U.S. Patent No.9,579,178, filed July 12, 2013 to Peter J. Zegarelli. The entire disclosure of this patent is herein incorporated by reference into the present disclosure.

[0075] In some embodiments, methods, systems and apparatuses for the generally continuous production of a three-dimensional oral appliance are provided. In these methods, systems, and apparatuses, the three-dimensional oral appliance can be produced from a liquid interface, which is often referred to as “continuous liquid interphase printing”, which are suitable methods, systems, and apparatuses for making the oral appliance. Suitable operation parameters for the continuous production of the oral appliance using 3D printing technology is described in U.S. Patent No.9,205,601 assigned to Carbon3D, Inc. The entire disclosure of this patent is herein incorporated by reference into the present disclosure. This will be one way to produce the oral appliance without medicament and then the robotic device can dispense the medicament at discrete regions of the oral appliance.

[0076] In some embodiments, an oral appliance for delivering a medicament to an oral cavity is provided. The oral appliance comprises an exterior and an interior. The interiorof the oral appliance is configured to contour at least a portion of teeth and / or soft tissue of the oral cavity. A volume of the medicament is disposed in a hydrogel at a selected dose within the interior based on dimensions of at least a portion of teeth and / or soft tissue.

[0077] In some embodiments, the selected dose is a custom dose and the dimensions of at least a portion of the teeth and / or soft tissue of a patient. In one embodiment, the selected dose is a uniform dose that can be universally administered to a patient. In some embodiments, the medicament is disposed in a channel of the interior or at discrete regions of the interior. In some embodiments, the oral appliance comprises a barrier for providing a seal between the channel and at least a portion of the teeth and / or the soft tissue areas of the oral cavity. In another embodiment, each of the discrete regions of the interior contact surfaces of a plurality of gingival sulcus. In some embodiments, the dimensions of at least a portion of the teeth and / or soft tissue include dimensions of a gingival sulcus. In another embodiment, the dimensions include a height, a width and a depth of the teeth, soft tissue and / or a gingival sulcus. In some embodiments, dimensions of the portion of the teeth and / or soft tissue to be treated are measured to calculate and rate or score a surface area to determine the selected dose.

[0078] In some embodiments, the selected dose of the medicament is in a 1:1 ratio with the hydrogel. In other embodiments, the selected dose of the medicament is in a 0.5:1 ratio with the hydrogel. In some embodiments, the medicament disposed in the hydrogel is uniformly disposed within the interior. In some embodiments, the volume of medicament includes a uniform dose that can be a universal dose administered to any patient. In some embodiments, the interior of the oral appliance includes a zero point marker having a width, a depth and a height for loading the oral appliance with the medicament that is disposed in a hydrogel. In some embodiments, the oral appliance can be used by an adult and / or an adolescent or pediatric human patient. In some embodiments, the oral appliance includes a projection and / or recess configured for manipulation of the oral appliance. In another embodiment, the projection and / or recess comprises a handle, a gripping surface, or a combination thereof configured to mate with a robotic arm of a robotic dispensing device or be manually manipulated by hand.

[0079] In some embodiments, a method of making an oral appliance for delivering a medicament to an oral cavity is provided. The method comprises providing an oral appliance having an exterior and an interior. The interior of the oral appliance is configured to contour at least a portion of teeth and / or soft tissue areas of the oral cavity. The method also includes calculating a selected dose based on a rating or score; providing a volume ofthe medicament disposed in a hydrogel at the selected dose; providing a dispensing device having an outlet configured to dispense medicament at discrete regions of the interior based on custom dimensions of at least a portion of the teeth and / or soft tissue of a patient, the exterior or both the interior and the exterior of the oral appliance; disposing the volume of the medicament within the interior based on dimensions of at least a portion of the teeth and / or soft tissue using the dispensing device.

[0080] In some embodiments, the dispensing device comprises a robotic arm coupled to the outlet to dispense a precise dose of the medicament at the discrete regions of the oral appliance. In some embodiments, each of the discrete regions of the interior contact surfaces of a treatment area including a plurality of the gingiva and / or other soft and hard tissues. In some embodiments, the dimensions of at least a portion of the teeth and / or soft tissue include dimensions of a gingival sulcus. In some embodiments, the dimensions include a height, a width and a depth of the teeth, soft tissue and the topography of the gingival sulcus. In some embodiments, the dimensions of the portion of the teeth and / or soft tissue to be treated are measured to calculate a surface area to determine a selected dose of the medicament. In some embodiments, the oral appliance comprises an actual or virtual channel configured to receive the medicament from the outlet of the robotic dispensing device. In one embodiment, the channel is continuous in the interior of the oral appliance and extends along a gum line perimeter. In other embodiments, portions of the oral cavity and / or portions of the oral appliance can be defined by at least Cartesian coordinates X, Y and Z to form a guideline for guiding the robotic arm of the robotic dispensing device to dispense the medicament at discrete regions of the oral appliance. In some embodiments, before the medicament is dispensed, the oral appliance is made by thermoforming, additive manufacturing, 3D printing or injection molding.

[0081] In some embodiments, a method of treating at least a portion of teeth and / or soft tissue of an oral cavity is provided. The method comprises providing an oral appliance, the oral appliance having an exterior and an interior, the interior of the oral appliance configured to contour at least a portion of teeth and / or soft tissue areas of the oral cavity; providing a medicament disposed in a hydrogel at a selected dose, the medicament disposed within the interior based on dimensions of at least a portion of the teeth and / or soft tissue; and inserting the oral appliance within the oral cavity of a patient. In some embodiments, the dimensions of the portion of the teeth and / or soft tissue to be treated are measured to calculate a surface area to determine the target area of a selected dose. In some embodiments, the dimensions of at least a portion of the teeth and / or soft tissue include dimensions of a gingival sulcus.In some embodiments, the dimensions include a height, a width and a depth of the teeth, soft tissue and / or a gingival sulcus. In some embodiments, the image was created by obtaining a baseline digital image of the portion of the teeth and / or soft tissue areas of the oral cavity to be treated using an imaging device.

[0082] In some embodiments, a computer implemented method of producing an oral appliance pre-loaded with at least one medicament having a selected dose using a computer is provided. The computer implemented method comprises creating a digital image of the portion of the teeth and / or soft tissue areas of the oral cavity to be treated by using an imaging device; generating a surface area of the portion of the teeth and / or soft tissue areas of the oral cavity to be treated based on the digital image; calculating a selected standardized dose for the generated targeted surface area; generating an instruction to dispose the selected standardized dose at the portion of the teeth and / or soft tissue areas of the oral cavity to be targeted and treated; and producing the oral appliance having the medicament with the selected standardized dose disposed in or on at least a portion and / or all of the interior surface of the oral appliance. In some embodiments, the method comprises directing a 3D printer to produce the oral appliance containing the at least one medicament.

[0083] In some embodiments, a system for dispensing a medicament having a standardized dose into or on an oral appliance is provided. The system comprises a robotic dispensing device having an outlet configured to dispense medicament having a standardized dose at discrete regions of an interior, an exterior or both the interior and the exterior of an oral appliance; one or more sensors mounted on the robotic dispensing device, the one or more sensors configured to detect a marker for registering a position of the oral appliance; a processor configured to receive and process input from the one or more sensors; and a controller operatively connected to the processor and configured to operate the robotic dispensing device, at least in part, on input from the one or more sensors and processed by the processor, wherein the robotic dispensing device is configured to dispense from the outlet the medicament having a standardized dose at discrete regions of an interior, an exterior or both the interior and the exterior of an oral appliance.

[0084] In some embodiments, the robotic dispensing device comprises a robotic arm coupled to the outlet to dispense a precise dose of the medicament at the discrete regions of the oral appliance. In some embodiments, the discrete regions are adjacent to a treatment area (e.g., targeted area) and the medicament is configured to contact the treatment area. In some embodiments, the oral appliance comprises an actual or virtual channel configured to receive the medicament from the outlet of the robotic dispensing device. In otherembodiments, the channel is continuous in the interior of the oral appliance and extends along a gum line perimeter. In some embodiments, the oral appliance comprises a marker for registering the position of the oral appliance with the robotic dispensing device. In some embodiments, the oral appliance comprises a projection and / or recess configured for manipulation of the oral appliance. In other embodiments, the projection and / or recess comprises a handle, a gripping surface, or a combination thereof configured to mate with the robotic arm of the robotic dispensing device or be manually manipulated by hand. In other embodiments, the projection and / or recess is removable from the oral appliance or remains and is configured as a handle for the patient. In some embodiments, the oral appliance comprises a barrier for providing a seal between the channel and at least a portion of the teeth and / or the soft tissue areas of the oral cavity.

[0085] In other embodiments, the marker is a zero-point marker for registering the position of the oral appliance with the robotic dispensing device. In one embodiment, portions of the oral cavity and / or portions of the oral appliance can be defined by at least Cartesian coordinates X, Y and Z to form a guideline for guiding the robotic arm of the robotic dispensing device to dispense the medicament at discrete regions of the oral appliance. In another embodiment, each tooth of the oral cavity and / or oral appliance can be defined (i) by at least 10 Cartesian coordinates or (ii) by one or more Cartesian points. In some embodiments, the one or more sensor comprises a camera or an imaging device. In some embodiments, the processor: (i) creates a first digital image of the oral appliance (Dig1) based on a baseline image of a patient’s oral cavity of at least a portion of the patient’s teeth and / or soft tissue, and the processor generates a second digital image (Dig2) corresponding to at least a portion of the patient’s oral appliance that requires dispensing medicament; and (ii) combines the first digital image (Dig1) with the second digital image (Dig2) to form a third digital image (Dig3) for enabling the robotic dispensing device to dispense the medicament at the discrete regions of the oral appliance. In some embodiments, each tooth and / or other anatomical part of the oral cavity can be defined by from about 1 to about 50 points, each point defined by at least Cartesian coordinates X, Y and Z that are sent to the processor to generate a guideline (Dig2a). In some embodiments, the second digital image (Dig2) of the patient’s oral appliance can be combined with the digital image of the guideline (Dig2a) to facilitate dispensing of the porous material at discrete regions of the oral appliance. In some embodiments, the third digital data (Dig3) is formed by one of (i) subtracting the second digital data (Dig2) fromthe first digital data (Dig1) or (ii) adding the second digital data (Dig2) to the first digital data (Dig1).

[0086] In some embodiments, the third digital data (Dig3) is formed by one of (i) subtracting the second digital data (Dig2) and the digital image of the guideline (Dig2a) from the first digital data (Dig1) or (ii) adding the second digital data (Dig2) and the digital image of the guideline (Dig2a) to the first digital data (Dig1). In other embodiments, creating the first digital record (Dig1) of the patient’s oral cavity comprises taking an impression of the patient’s oral cavity using materials comprising alginate, polyvinyl, silicone or a combination thereof. In one embodiment, obtaining the baseline digital image of at least a portion of the patient’s teeth and / or soft tissue of the patient’s oral cavity further comprises digitally storing a permanent record of the topography or topology of least a portion of the patient’s teeth and / or soft tissue of the patient’s oral cavity for future iterations of oral appliances. In another embodiment, creating the digital record of the patient’s oral cavity comprises utilizing imaging devices including at least one of a digital camera, X-ray device, hand-held 3-D scanner, laser scanner, computed tomography (CT) scanner, magnetic resonance imaging (MRI) scanner, coordinate measuring machine, destructive scanner or ultrasound scanner.

[0087] In some embodiments, the robotic dispensing device is controlled by artificial intelligence. In some embodiments, the medicament is in a hydrogel that is cured during dispensing of the hydrogel or after dispensing the hydrogel. In some embodiments, the outlet of the robotic dispensing device is configured to dispense the medicament in a hydrogel at discrete regions of the interior, the exterior or both the interior and the exterior of the oral appliance.

[0088] In some embodiments, a method of making a standardized dose of a medicament for an oral appliance is provided. The method comprises obtaining a digital image of at least a portion of the teeth and / or soft tissue of the oral cavity; identifying a surface area of at least a portion of the teeth and / or soft tissue of the oral cavity to be treated; calculating the surface area to be treated with a medicament; generating a virtual model of the oral appliance having the volume of medicament having the standardized dose disposed in the oral appliance; generating a volume of medicament having a standardized dose corresponding to the surface area to be treated; producing an oral appliance and disposing the volume of medicament having the standardized dose on the at least a portion of the teeth and / or soft tissue of the oral cavity.

[0089] In some embodiments, the surface area is identified by a processor processing the digital image. In some embodiments, the digital image is obtained through an image analysis of a plurality of images taken in the oral cavity. In some embodiments, the volume of the medicament is calculated based on a weight of the patient. In some embodiments, the volume of the medicament is calculated based on the surface area of at least a portion of the teeth and / or soft tissue of the oral cavity to be treated. In some embodiments, the volume of the medicament is calculated based on the surface area of at least a portion of the teeth and / or soft tissue of the oral cavity to be treated. In some embodiments, the volume of the medicament is calculated based on a past response of a patient.

[0090] In some embodiments, a system for delivering a medicament having a standardized dose to an inflamed tissue of an oral cavity is provided. The system comprises a first oral appliance comprising an exterior and an interior, the interior of the oral appliance configured to contour at least a portion of teeth and / or soft tissue of the oral cavity, and a volume of the medicament disposed in a hydrogel at a selected dose within the interior based on dimensions of at least a portion of the teeth and / or soft tissue; and a second oral appliance comprising an exterior and an interior, the interior of the oral appliance configured to contour at least a portion of teeth and / or soft tissue of the oral cavity, and a second volume of the medicament disposed in a hydrogel at a second selected dose within the interior based on a second dimensions of at least a portion of the teeth and / or soft tissue after an application of the first set of oral appliances. In some embodiments, the selected dose is determined by a surface area of the portion of the teeth and / or soft tissue to be treated. In some embodiments, the portion of the teeth and / or soft tissue. In some embodiments, the height and weight of the patient has nothing to do with the size of the oral cavity and dosing based on parameters such as height and weight of the patient used in Clark’s rule to dose medication is not a relevant parameter in dosing the medicament to be loaded in the oral appliance.

[0091] In some embodiments, the practitioner and / or artificial intelligence can use guidelines such as, for example, the American Academy of Periodontology Staging and Grading guidelines to properly assess and diagnose periodontal disease for case management. (See, for example, AAP 2017 Staging and Grading Periodontitis.) Criteria such as these can be used by practitioners or artificial intelligence to help determine a proper concentration and dose of medicaments in order to properly treat patients taking into account their forensically unique anatomic characteristics to create a therapeutic index of a medicament. These parameters can be scored or rated and the hydrogel dispensing can beselected according to this scoring or rating to standardize the dose of medicament, dispense and load the hydrogel in the oral appliance. As new guidelines are created or updated, these guidelines either created through research, official academy policy or by feedback through usage of the appliance itself may all contribute to changes in dosing, concentration or new medications. These can also be programmed into the computer or artificial intelligence and used in making the oral appliance that contains the medicament at discrete regions of the oral appliance.

[0092] In some embodiments, the height and weight of the patient has nothing to do with the size of the oral cavity and dosing based on parameters such as height and weight of the patient used in Clark’s rule to dose medication is not a relevant parameter in dosing the medicament to be loaded in the oral appliance. In some embodiments, the practitioner and / or artificial intelligence can use guidelines such as, for example, the American Academy of Periodontology Staging and Grading guidelines to properly assess and diagnose periodontal disease for case management. (See, for example, AAP 2017 Staging and Grading Periodontitis.) Criteria such as these can be used by practitioners or artificial intelligence to help determine a proper concentration and dose of medicaments in order to properly treat patients taking into account their forensically unique anatomic characteristics to create a therapeutic index of a medicament. These parameters can be scored or rated and the hydrogel dispensing can be selected according to this scoring or rating to standardize the dose of medicament, dispense and load the hydrogel in the oral appliance. As new guidelines are created or updated, these guidelines either created through research, official academy policy or by feedback through usage of the appliance itself may all contribute to changes in dosing, concentration or new medications. These can also be programmed into the computer or artificial intelligence and used in making the oral appliance that contains the medicament at discrete regions of the oral appliance.

[0093] Referring to FIGS.1-3, an enlarged side view of an embodiment of the oral appliance 10 is illustrated. The oral appliance has an interior surface 12 and exterior surface 14, both comprising, in some embodiments, a polymer or hydrogel containing medicament. The interior surface 12 contacts one or more teeth and / or soft tissue areas of a patient. The interior surface 12 is custom fit to the individual patient's mouth and configured to contour at least a portion of teeth and / or soft tissues of the oral cavity. In this view the interior surface 12 contacts the teeth and soft tissue. Oral appliances include, but are not limited to, oral trays, oral holders, oral covers, or the like that are designed to be placed within the oral cavity. The interior surface 12 and / or exterior surface 14 of the oral appliance contain amedicament 11 disposed in or on the polymer or hydrogel and the medicament can be disposed anywhere within or on the oral appliance.

[0094] For example, the medicament can be disposed at discrete regions adjacent to the treatment area or uniformly disposed throughout the device. As the interior and / or exterior surface of the oral appliance contacts the oral cavity, the medicament is released from the polymer (e.g., hydrogel) by all or parts of the oral appliance contacting the desired treatment site or pressure from the device contacting tissue or fluid at the treatment site (e.g., gums, tissue, teeth, etc.). The medicament disposed has a specific volume containing a selected dose in the interior based on the dimension of the teeth and / or soft tissue. In some embodiments, the selected dose is disposed on the exterior. The select dose can be a standardized dose based on various input factors including, for example, the unique topography of the treatment area of that patient’s oral cavity, such as for example, surface area, size, depth, height, shape, and / or other dimensions of the gingiva and / or other soft and / or hard tissue parameters, severity of disease, constituents in microbiome of the oral cavity, and / or therapeutic index of the medicament. The input factors allow a health professional to calculate a standardized dose. In some embodiments, the input factors rely on artificial intelligence to calculate various combination of factors and then balance each factor to find a suitable dose amount for the individual patient. Thus, the oral appliance can be used to treat diseases in children and adults and the dose can be calculated based on, for example, the dimensions of the gingiva and / or other soft and / or hard tissue parameters.

[0095] In one particular embodiment, the unique microbiome of the oral cavity for the individual patient can be reconstituted based on the constituents of the biofilm in the oral cavity. For example, if the patient was on long term antimicrobial therapy or received chemotherapy, the healthy microbiome or biofilm may be eliminated or reduced because of such therapy, which can lead to gum bleeding, gingivitis, plaque formation, inflammation and worsening of periodontal disease. To reconstitute the healthy microbiome or biofilm at the treatment area, the hydrogel can comprise a probiotic as the medicament alone or with other medicaments. Probiotics are beneficial agents that can be used to repopulate the flora or the oral microbiome with microbes. Probiotics, which are healthy microorganisms that can be ingested, may help to improve oral health. Probiotics, which are defined as live microbes that confer health benefits to a host when consumed in sufficient quantities, may offer a low-risk, easy-to-use treatment option for periodontal diseases. Probiotics are referred to as living microorganisms, principally bacteria, which are safe for humans and have beneficial effects on human health. Oral probiotics maintain a balanced oralmicrobiome, which can prevent cavity development, maintain fresh breath, and keep gum disease at bay.

[0096] In some embodiments, a polymer (e.g., hydrogel) containing medicament can degrade over time by the action of enzymes, by hydrolytic action and / or by other similar mechanisms in the oral cavity. In some embodiments, all or discrete portions of the polymer containing medicament will degrade and release medicament at or near the target site in the oral cavity. The oral appliance will cover at least a portion of the teeth and or gums by applying the device over axis 8-8 to cover the area of the teeth and or gums, and the oral appliance will be adjacent to the gingival sulcus 20, which will allow the medicament, if desired, to be released from the polymer to this area and not onto off target site tissues.

[0097] FIG. 2 is an enlarged side view of an embodiment of an oral appliance. In this embodiment, the oral appliance is transparent, colored, translucent or opaque and holds teeth 16 and or gums, which are covered by it. The oral appliance comprises a surface that contains medicament as part of the hydrogel that in use releases the medicament at or near the gingival sulcus 20.

[0098] FIG.2A illustrates an enlarged view of a hydrogel 11 (e.g., cross linked hydrogel) that can be loaded on the exterior surface, interior surface, or both the interior surface and the exterior surface of the oral appliance. The hydrogel can have one or more medicaments (e.g., antimicrobial, wound healing agent, preservative, probiotic, or a combination thereof) disposed uniformly throughout the hydrogel or, in some embodiments, it can be disposed at a discrete region of the hydrogel and / or discrete regions of the oral appliance. The medicament can be, for example, a preservative, an antimicrobial, a wound healing agent or a combination thereof. In some embodiments, the hydrogel can contain no medicament or preservative. The hydrogel once loaded into the oral appliance at discrete regions of it will contact discrete regions of the oral tissue (e.g., soft tissue and / or hard tissue) that contact the hydrogel and / or the oral appliance where treatment is desired.

[0099] The select dose of medicament in the hydrogel can be a standardized dose based on the unique topography of the treatment area of that patient’s oral cavity, such as for example, surface area, size, depth, height, shape, and / or other dimensions of the gingiva and / or other soft and / or hard tissues, severity of disease, constituents in microbiome of the oral cavity, and / or therapeutic index of the medicament.

[0100] Oral appliance 10 can also include at least a projection 24 and / or recess configured for manipulation of the oral appliance by a robotic device as illustrated in FIGS.3A, 3B, 3C and 3D. In some aspects, projection 24 comprises at least a handle with or without agripping surface 26 or a combination thereof configured to mate with the robotic arm of a robotic dispensing device. In some embodiments, projection or handle 24 can also be used to manipulate oral appliance 10 manually. Incorporating at least a handle with or without a gripping surface into the oral appliance of this disclosure facilitates the robotic maneuvering of the oral appliance so that its geometry and structural integrity does not get compromised by the robot’s squeezing or handling of it.

[0101] In other aspects, projection 24 is removable via a separation assist, for example, indentation 28 as illustrated in FIG. 3B to separate entirely from oral appliance 10 as illustrated in FIG. 3C. In some aspects, the separation assist includes a score line to allow the projection and / or recess to be easily removed from the oral appliance. After the projection is removed, the surface 23 of the exterior of the oral appliance can be smoothed so as not to provide discomfort to the patient when the oral appliance is worn. It will be understood that although the projection 24 is shown on the exterior surface of the oral appliance, the projection can be positioned on the interior surface or a combination of the exterior surface and the interior surface. In some embodiments, the projection can have a different stiffness compared to the other parts of the oral appliance. For example, the projection can be less flexible as compared to the remainder of the oral appliance so that it is easier to break (e.g., break away) or separate the projection from the oral appliance. The projection 24 can also be manually removed or machined off in toto or in part. Further the handle can be left on the oral appliance and serve a second purpose – as an assist to patients as a grabber or handle for the patient to hold onto the oral appliance and an assist to insert the appliance into the mouth and onto the teeth and soft tissues. This handle would be especially valuable to those patients with motor skill deficits and / or neurologic disorders and / or to caregivers of compromised patients.

[0102] In various embodiments, the oral appliance includes channel 30 configured to receive the medicament from the outlet of a robotic dispensing device as illustrated in FIG. 3D. In some embodiments, channel 30 can be continuous in the interior of the oral appliance and extend along a gum line perimeter. In other embodiments, the oral appliance includes barrier 32 for providing a seal between channel 30 and at least a portion of the teeth and / or soft tissue areas of the oral cavity to prevent or reduce leaching of the medicament from the oral appliance, as illustrated in FIG.3D. In some embodiments, medicament 11 is disposed in the channel of the interior or at discrete regions of the interior surface.

[0103] In various embodiments, oral appliance 10 includes a zero point or other reference marker 34 that can be either physically placed on the oral appliance and / or on handle 24 orgripping surface 26 of oral appliance 10 for registering its position relative to the robotic dispensing device or can be a virtual marker that can be optically recognized by position by the robotic dispensing device. Using a zero-point marker facilitates orienting the oral appliance in space in three dimensions during the precision medicament dispensing process. To promote a precise, automated robotic dispensing of hydrogel in oral appliance 10, X, Y, Z Cartesian coordinates of the patient specific customized channel are created along the anatomic geometry of the patient’s oral cavity such that a robot can read the coordinate data points in width, length and depth and create an accurate guideline to precisely dispense a hydrogel strip, bead or reservoir onto or into the oral appliance. Thus, each tooth, gum line and / or other portions of the oral appliance and / or oral cavity can be defined by X, Y, Z Cartesian coordinates to form a guideline for guiding the robotic arm of the robotic dispensing device to dispense the medicament at discrete regions of the oral appliance. For example, in one embodiment, each tooth can be defined by at least 10 Cartesian X, Y, Z coordinates. In some embodiments, the dispensing arm is stationary and the oral appliance is moved in three dimensions in space by the robotic arm attached to the oral appliance such that the dispensing arm is in the vertical position to facilitate the dispensing of material.

[0104] FIG. 4 illustrates an enlarged side cross sectional view of an embodiment of the oral appliance 40 showing an outline of a tooth 42. The oral appliance 40 has an exterior surface 44 and interior surface 46. The interior surface of oral appliance 40 contains a medicament infused polymer gel or hydrogel, which contacts tooth 42 up to gingival area 48. In the embodiment shown, the medicament in the polymer layer extends and contacts the buccal surfaces of the teeth and surrounding gingival tissue and over adjacent gingival tissue on a lingual side of the teeth. In some embodiments, the oral appliance extends over occlusal surfaces of the teeth and / or over lingual surfaces of the teeth in need of treatment. There are several locations 34 on tooth 42 where a zero-point marker can be located. In other aspects, each tooth can have a plurality of reflective markers 36, for example, attached to the tooth image to guide the robotic arm of a robotic dispensing device. Markers can be placed on other sites of the oral cavity, for example, on the buccal side, the lingual side and the occlusal side. More markers can be deployed if the tooth and / or soft geometries are not constant or if required due to a particular situation in a case.

[0105] FIG.4A illustrates an enlarged cross-sectional view of the anatomy of the gums and a tooth including free gingiva, attached gingiva, lining mucosa, the periodontal pocket or crevice, the cementoenamel junction (CEJ), periodontal ligament (PDL), cementum, the enamel, dentin, and pulp. In some embodiments, the treatment area is the periodontal pocketthat is targeted for delivery. The design of the medicament of the oral appliance is to target the periodontal pocket or crevice of the sulcus and place the medicament onto the entrance of the periodontal pocket. In some embodiments, the robotic device can dispense medicament so precisely in the oral appliance to specifically target the periodontal pocket or crevice. A dimension of at least a portion of the teeth and / or soft tissue includes dimensions of a gingival sulcus are also shown in FIG. 4A. A sulcus has a height, HH; a width, WW; and a depth (DD). In some embodiments, the measurement of these dimensions allows a calculation of the surface area of the sulcus. In turns, the surface area allows a calculation of the selected dose for the patient.

[0106] FIG. 4B illustrates an enlarged cross-sectional view of a portion of the oral appliance 400 that has medicament dispensed via a robotic outlet into the oral appliance. In the embodiment shown, medicament is disposed in a porous material 402 that is a hydrogel 404 and is dispensed precisely from the outlet of the robotic device at a discrete region of the oral appliance. The hydrogel is shown in an uncompressed state 405 and when worn with slight pressure, the hydrogel will be compressed against, among other things, the gingival crevice, sulcus or periodontal pocket causing a seal of the entrance of the gingival crevice, sulcus or periodontal pocket, which prevents oral fluids (e.g., saliva, exudate, other foreign fluids, etc.) from entering the crevice, sulcus or pocket, which allows release of the medicament in the gingival crevice, sulcus or periodontal pocket and allows the hydrogel to absorb or wick fluid from the crevice, sulcus or pocket. In this embodiment, the hydrogel is dispensed from the robotic device and disposed at a discrete region of the oral appliance and is sized to be greater than the height, width, and length of the entrance of the crevice, sulcus or periodontal pocket. In some embodiments, the ratio of the medicament to the hydrogel is from about 1:4 to about 2:1. In some embodiments the ratio is from about 1:4, 1:3.5, 1:3, 0.5:1, 1:1, 1.5:1, to about 2:1.

[0107] FIG. 4C illustrates an enlarged cross-sectional view of a portion of the oral appliance 400 being worn that is placed adjacent to the teeth and gums using the top down approach to treating periodontal disease as described in International application No. PCT / US2020 / 059440 filed on November 6, 2020, incorporated herein by reference in its entirety. In the embodiment shown, medicament has been precisely dispensed via a robotic outlet into the oral appliance and the medicament is disposed in a porous material 402 that is a hydrogel 404 at a discrete region of the oral appliance. The hydrogel is shown in a compressed state 407, where the device is worn and the hydrogel is compressed against, among other things, the gingival crevice, sulcus or periodontal pocket causing a seal 413 ofthe entrance of the gingival crevice, sulcus or periodontal pocket, which prevents oral fluids (e.g., saliva, exudate, other foreign fluids, etc.) from entering the crevice, sulcus or pocket. There is a gap 415 between the junctional epithelium and the entrance 411 of the crevice, sulcus or pocket, which is now sealed by the hydrogel. This gap allows the hydrogel to release medicament in the gingival crevice, sulcus or periodontal pocket to treat deep down into the inflamed tissue. The medicament release is shown by the down arrows 406. The hydrogel also absorbs or wicks oral fluids from the crevice or pocket which aides healing, shown by the up arrows 408. The hydrogel has dual ability to deliver medicament and wicking action to remove crevicular / sulcular fluids from the environment. This dual action of wicking, which then creates a negative crevicular fluid flow, allows the medicaments under pressure, shown by pressure points A, B and C, to enter the top portion of the pocket to fill the resultant negative pressure void, thus inserting the medicaments further into the pockets. Oral Appliance Materials

[0108] The oral appliance can be made of any materials that can hold and release the medicament. In various embodiments, the material from which the oral appliance can be made from includes swellable polymers, such as, for example, hydrogels, gels, polymer brushes or combinations thereof.

[0109] In some embodiments, suitable polymers for use to make the oral appliance include, for example, polyacrylates, polyamide-imide, phenolic, nylon, nitrile resins, petroleum resins, fluoropolymers, copolyvidones (copovidones), epoxy, melamine- formaldehyde, diallyl phthalate, acetal, coumarone-indene, acrylics, acrylonitrile- butadiene-styrene, alkyds, cellulosics, polybutylene, polycarbonate, polycaprolactones, polyethylene, polyimides, polyphenylene oxide, polypropylene, polystyrene, polyurethanes, polyvinyl acetates, polyvinyl chloride, poly(vinyl alcohol-co ethylene), styrene acrylonitrile, sulfone polymers, saturated or unsaturated polyesters or combinations thereof. In some embodiments, the polymer can be ethylene-vinyl acetate (EVA), which is the copolymer of ethylene and vinyl acetate. The weight percent vinyl acetate usually varies from 10 to 40%, with the remainder being ethylene

[0110] In some embodiments, the polymer comprises, consists essentially of or consists of an amount from about 5% to about 100% by weight, from about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% to about 100% by weight, from about 10% to about 15% by weight, from about 15% to about20% by weight, from about 20% to about 25% by weight, from about 25% to about 30% by weight, from about 30% to about 35% by weight, from about 35% to about 40% by weight, from about 40% to about 45% by weight, from about 45% to about 50% by weight, from about 50% to about 55% by weight, from about 55% to about 60% by weight, from about 60% to about 65% by weight, from about 65% to about 70% by weight, from about 70% to about 75% by weight, from about 75% to about 80% by weight, from about 80% to about 85% by weight, from about 85% to about 90% by weight, from about 90% to about 95% by weight, or from about 95% to about 100% by weight of the oral appliance. In some embodiments, the oral appliance is substantially all polymer from about 80% to about 99.9% by weight. The medicament comprises, consists essentially of or consists of an amount from about 0.01% to about 50%, from about 0.1% to about 20% by weight, from about 0.5% to about 10%, or from about 1% to about 7% by weight of the oral appliance.

[0111] In various embodiments, the molecular weight of the polymer can be a wide range of values. The average molecular weight of the polymer can be from about 1000 to about 10,000,000 g / mol; or about 1,000 to about 1,000,000; or about 5,000 to about 500,000; or about 10,000 to about 100,000; or about 20,000 to about 50,000 g / mol.

[0112] In some embodiments, when the oral appliance is made from one polymer, the density of the polymer can vary such that the non-porous and porous regions are formed in the oral appliance from a single material.

[0113] In some embodiments, when different molecular weight polymers are used, the polymer can be dense and have a higher molecular weight such that the polymer is non- porous. In some embodiments, the polymer can be less dense and have a lower molecular weight such that the polymer is porous. In some embodiments, the oral appliance can be made from multiple polymers, as described above. The multiple polymers can have the same or different densities. The polymers can have an average molecular weight of from about 1000 to about 10,000,000 g / mol; or about 1,000 to about 1,000,000; or about 5,000 to about 500,000; or about 10,000 to about 100,000; or about 20,000 to about 50,000 g / mol.

[0114] The polymer can have a modulus of elasticity (Young’s modulus) in the range of about 1 x 10-2to about 6 x 105dynes / cm2, or 2 x 104to about 5 x 105dynes / cm2, or 5 x 104to about 5 x 105dynes / cm2.

[0115] The polymer may optionally have a viscosity enhancing agent such as, for example, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, carboxymethylcellulose and salts thereof, Carbopol, poly- (hydroxyethylmethacrylate), poly-(methoxyethylmethacrylate), poly(methoxyethoxyethylmethacrylate), polymethylmethacrylate (PMMA), methylmethacrylate (MMA), gelatin, polyvinyl alcohols, propylene glycol, mPEG, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, PEG 700, PEG 800, PEG 900, PEG 1000, PEG 1450, PEG 3350, PEG 4500, PEG 8000 or combinations thereof.

[0116] In various embodiments, the polymer can comprise a hydrogel that is or is not infused with at least one medicament. Suitable hydrogels for use in the oral appliance include natural hydrogels, such as for example, gelatin, collagen, silk, elastin, fibrin and polysaccharide-derived polymers like agarose, and chitosan, glucomannan gel, hyaluronic acid, polysaccharides, such as cross-linked carboxyl-containing polysaccharides, or a combination thereof. Synthetic hydrogels include, but are not limited to those formed from polyvinyl alcohol, acrylamides such as polyacrylic acid and poly(acrylonitrile-acrylic acid), polyurethanes, polyethylene glycol (for example, PEG 3350, PEG 4500, PEG 8000), silicone, polyolefins such as polyisobutylene and polyisoprene, copolymers of silicone and polyurethane, neoprene, nitrile, vulcanized rubber, poly(N-vinyl-2-pyrolidone), acrylates such as poly(2-hydroxy ethyl methacrylate) and copolymers of acrylates with N-vinyl pyrolidone, N-vinyl lactams, polyacrylonitrile or combinations thereof.

[0117] In some embodiments, cross-linking agents used to make the porous material non- porous include, but are not limited to, glutaraldehyde, formaldehyde, epoxy, compounds, dialdehyde, sodium borate / boric acid, glyoxal, oxidized dextrins, epichlorohydrin, endogen polyamine spermidine, oxidized alginate, zinc, borax, ethylene glycol dimethacrylate (EGDMA), N, N′-methylenebisacrylamide, derivatives of ethylene glycol di(meth)acrylate, derivatives of methylenebisacrylamide, formaldehyde-free crosslinking agent including N- (1-Hydroxy-2,2-dimethoxyethyl)acrylamide, or a combination thereof.

[0118] In some embodiments, it may be difficult for the medicament to move in and out of the oral appliance. In some embodiments, a porosity reducing agent such as a cross- linking agent is used to generate a non-porous region on the polymer oral appliance.

[0119] In some embodiments, the oral appliance can be transparent, colored, translucent or opaque so that a user can see the teeth. The oral appliance may be disposable and sterilizable. In various embodiments, one or more components of the oral appliance are sterilized by radiation in a terminal sterilization step in the final packaging. Terminal sterilization of a product provides greater assurance of sterility than from processes such as an aseptic process, which require individual product components to be sterilized separately and for the final package to be assembled in a sterile environment. Other methods may also be used to sterilize one or more components of the oral appliance, including, but not limitedto, E-beam radiation, gamma radiation, gas sterilization, such as, for example, with ethylene oxide or steam sterilization. Automated Dispensing Systems

[0120] FIG.5 depicts an embodiment of an image-guided robotic dispensing system 300. The image-guided robotic dispensing system 300 is shown with a robotic dispensing device 301, including a first robotic arm 302 with a delivery tool assembly 304 attached to a distal tool plate 306 of the first robotic arm 302. The delivery tool assembly 304 includes dispensing tool 308 extending from a tubular body 310, which in turn extends from a delivery tool housing 312 attached to the tool plate 306. In some embodiments, the zero point marker and / or the guideline can assist dispensing tool 308 in orienting the oral appliance so that the dispensing outlet shown as a dispensing tip 324 of dispensing tool 308 is frequently placed in a vertically down position relative to the oral appliance so as to maximize the natural gravitational flow and lessen the pressure needed to dispense the hydrogel from dispensing tip 324. In this manner, the oral appliance is continually advanced along a guideline or guidelines through the continued multi-angled rotation of the oral appliance while the dispensing tip 324 remains static on its vertical axis. The oral appliance can also be rotated such that the dispensing tip 324 is frequently perpendicular to the surface of the oral appliance that the dispensing tip is dispensing onto. The dispensing tip may move slightly, but this is a desirable position. It is recognized that other orientations are also possible. In some embodiments, the dispensing tip and the robotic arms orient the oral appliance to facilitate dispensing of the materials.

[0121] The first robotic arm 302 has a base 314 mounted on a stable platform 316. An oral appliance 320 having a channel 322 is positioned relative to the first robotic arm 302, so that a targeted channel 322 and / or targeted discrete regions into or onto oral appliance 320 is directly underlying the dispensing tip 324 of the dispensing tool 308. The actual dimensions of dispensing tool 308 (e.g., its respective inner and out diameters) may vary in accordance with different embodiments of this application, depending, for example, on the particular therapeutic dispensing procedure to be performed and / or the particular substances to be delivered into or onto the targeted region(s) of oral appliance 320. In various embodiments, the robotic dispensing system 300 includes one or more sensors 328 (e.g., cameras or other special relationship devices) (two are visible in FIG. 5) mounted on the delivery tool housing 312 (which in turn is mounted on the distal end tool plate 306 of the first robotic arm 302).

[0122] In particular, the first robotic arm 302 is maneuverable so that the dispensing tool 308 may be positioned proximate a targeted location on the oral appliance, wherein one or both of the processor and controller are configured to cause dispensing tip 324 of dispensing tool 308 to dispense a controlled delivery of desired material along the coordinates chosen and precisely the quantitative amounts to be dispensed at discrete regions or in channel 322 of oral appliance 320. In some embodiments, robotic dispensing system 300 preferably includes a user interface (not shown) that allows a system operator to input instructions relating to one or more of a location, an orientation and a depth of the dispensing tool 308. Such a user interface, additionally or alternatively, preferably allows a system operator to input instructions relating to a type, a quantity, or both of the therapeutic substance to be delivered into a targeted region of oral appliance 320.

[0123] Various embodiments of the robotic dispensing system 300 may be configured for delivery of therapeutic substances including, but not limited to, all of the therapeutic substances described in this application, into or onto target regions of oral appliance 320. Towards this end, under image guidance and verification, at a desired location, embodiments of the robotic dispensing system 300 precisely (and repeatedly) position the oral appliance 320 at respective desired locations and in desired orientation(s) relative to dispensing tip 324 of the dispensing tool 308. Further, due to the continued guiding and orientation of the oral appliance relative to the generally vertical robotic arm and perpendicular orientation of the dispenser, the dispensed hydrogel may be in such gravitational positions that the hydrogel may flow away from the Dig2 channel it was dispensed in. Therefore, the viscosity of the hydrogel must be formulated such that it can flow out of the dispensing nozzle but remain in place without distortion according to the Dig2 data points. The hydrogel is then cured using curing lights, heat, or other means such that it hardens and binds to the oral appliance. The curing may occur simultaneously to the dispensing or cured after the dispensing is finished. In some embodiments, curing can be initiated by heat, radiation, electron beams, or chemical additives. In other embodiments, curing can occur by thermosetting in the absence of additives.

[0124] A number of differing delivery tool assemblies 304 may be housed in delivery tool housing 312, with each delivery tool assembly 304 configured for operating in conjunction with, and under the common control of, robotic dispensing system 300. Relative motion of the dispensing tool 308 may be provided by movement of first robotic arm 302 relative to oral appliance 320. Additionally, or alternatively, relative motion of the dispensing tool 308 to oral appliance 320 may be provided by embodiments of the delivery tool assembly 304.Regardless of how such relative motion of the dispensing tool 308 is accomplished, the respective delivery tool assemblies 304 are configured to deliver precisely metered doses or amounts of flowable substances into the targeted regions of the oral appliance.

[0125] In various embodiments, robotic dispensing system 300 illustrated in FIG. 5 also includes a second robotic arm 350 for holding and / or manipulating oral appliance 320 in position(s) effective to receive material from a dispensing tool 308. Second robotic arm 350 is supported on base 354 located on platform 352. Second robotic arm 350 has several articulated joints and arms configured to precisely maneuver second robotic arm 350 in at least six degrees of freedom, and / or a six-axis robot. Second robotic arm 350 includes a gripper or hand 358 that can grip projection or handle 330 of oral appliance 320. Gripper 358 is connected to a wrist 356, which in turn is connected to elbow 362 and shoulder 360 through forearm 364 and upper arm 366, respectively. In various embodiments, second robotic arm 350 includes one or more sensors 370 (e.g., cameras) mounted between gripper 358 and wrist 356. It is also recognized that the gripper may grab the tray directly without a projection or handle.

[0126] A processor (not shown in FIG. 5) associated with the robotic dispensing system 300 receives and processes images acquired by the one or more sensors. The robotic dispensing system 300 includes a controller (also not shown in FIG. 5) that is operatively associated with the processor and configured to precisely maneuver the first and second robotic arms 302 and 350 in six degrees of freedom and gripper 358 based, at least in part, on images acquired by the one or more sensors 328 and / or 370 and processed by the processor. It will be understood that although two robotic arms are shown, the dispensing and oral appliance manipulation can be accomplished with one robotic dispensing device 301 having one robotic arm.

[0127] In another embodiment, a two-arm robot as described in U.S. Patent No. 10,300,597 assigned to Seiko Epson Corporation can be used, incorporated herein by reference, and configured to use one robotic arm for holding an oral appliance and the other robotic arm for dispensing a therapeutic formulation into or onto the oral appliance. FIG.6 illustrates robot 100 which has a main body 200, and a robot control device 900 for controlling the action of the robot main body 200. The robot main body 200 has a base 210, a body 220 connected to the base 210, a pair of articulated arms 230, 240 connected to both sides of the body 220, a first sensor 250 (e.g., stereo camera) and a second sensor 260 (e.g., signal light) provided to the body 220, a hand camera (not shown) provided to each of the articulated arms 230, 240, and a monitor 270 disposed on a rear side of the body 220.

[0128] The base 210 is provided with a plurality of wheels (rotating members) for making the movement of the robot 100 easy, a lock mechanism (not shown) for locking each of the wheels, and a handle (a grip section) 211 to be gripped when moving the robot 100. By releasing the lock mechanism and then gripping the handle 211 to push or pull the handle 211, the robot 100 can be moved at will, and by locking the wheels with the lock mechanism, the robot 100 can be fixed at a predetermined position. Base 210 is also provided with an emergency stop button 214. Body 220 is connected to the base 210 through an elevating mechanism 800 which enables body 220 to move up and down in a vertical direction. In some embodiments, body 220 is connected to base 210 via a joint mechanism which enable the body to be also rotatable around its vertical axis.

[0129] As shown in FIG. 6, articulated arm 230 includes a first shoulder section (a first arm) 231 connected to the body 220 via a joint mechanism (not shown), a second shoulder section (a second arm) 232 connected to the first shoulder section 231 via another joint mechanism (not shown), an upper arm section (a third arm) 233 connected to the tip of the second shoulder section 232 via a twist mechanism (not shown), a first lower arm section (a fourth arm) 234 connected to the tip of the upper arm section 233 via a joint mechanism (not shown), a second lower arm section (a fifth arm) 235 connected to the tip of the first lower arm section 234 via another twist mechanism (not shown), a wrist section (a sixth arm) 236 connected to the tip of the second lower arm section 235 via a joint mechanism (not shown), and a connector section (a seventh arm) 237 connected to the tip of the wrist section 236 via a twist mechanism (not shown). Further, the connector section 237 is provided with a hand section 238, and an end effector 610 corresponding to the operation to be performed by the robot 100 is attached to the hand section 238 via a kinesthetic sensor 740 as shown in FIG.7.

[0130] The articulated arm 240 has substantially the same configuration as the configuration of the articulated arm 230 described above. Specifically, as shown in FIG.6, the articulated arm 240 includes a first shoulder section (a first arm) 241 connected to the body 220 via a joint mechanism (not shown), a second shoulder section (a second arm) 242 connected to the first shoulder section 241 via another joint mechanism (not shown), an upper arm section (a third arm) 243 connected to the tip of the second shoulder section 242 via a twist mechanism (not shown), a first lower arm section (a fourth arm) 244 connected to the tip of the upper arm section 243 via a joint mechanism (not shown), a second lower arm section (a fifth arm) 245 connected to the tip of the first lower arm section 244 via another twist mechanism (not shown), a wrist section (a sixth arm) 246 connected to the tipof the second lower arm section 245 via a joint mechanism 560, and a connector section 247 connected to the tip of the wrist section 246 via a twist mechanism (not shown). Further, the connector section 247 is provided with a hand section 248, and an end effector 620 corresponding to the operation to be performed by the robot 100 is attached to the hand section 248 via a kinesthetic sensor 750 as shown in FIG.7.

[0131] As illustrated in FIG. 7, end effectors 610, 620 are attached to the tips of the respective articulated arms 230, 240 and have a function of, for example, gripping an object, for example, oral appliance 611. The configuration of each of the end effectors 610, 620 varies by the operation to be performed. For example, it is possible to adopt a configuration at end effector 620, having a first finger 621 and a second finger 622 configured to grip oral appliance 611. At end effector 610, the configuration can be changed and adapted to contain a dispensing outlet 614 to deliver hydrogel and / or a medicament to channel 612.

[0132] The kinesthetic sensors 740, 750 respectively disposed between the hand sections 238, 248 and the end effectors 610, 620 each have a function of detecting an external force applied to the end effectors 610, 620. Further, by feeding back the force detected by the kinesthetic sensors 740, 750 to the robot control device 900, the robot 100 can more precisely perform the operation. Further, contact between the end effectors 610, 620 and an obstacle can be detected using the force and the moment detected by the kinesthetic sensors 740, 750.

[0133] The robotic system, in some embodiments, can be a platform for the oral appliance to be laid upon that is part of a robotic arm, which has a vacuum system which holds the oral appliance in place when the vacuum is on while the other robotic arm is dispensing the hydrogel and then the oral appliance is released onto a surface when the vacuum is off. In this manner, there is no robotic arm or other mechanism to distort the appliance shape. Medicaments

[0134] The oral appliance contains one or more medicaments coated or layered on it or impregnated within it at the same or different areas to form a monolithic oral appliance. In various embodiments, some areas of the polymer material of the oral appliance do not contain one or more medicaments, and the polymer material may function to hold or lock a portion of the polymer material in place so that other portions of the polymer material can contact the appropriate target site. Thus, in some embodiments, the polymer material may contain one or more medicaments disposed in or on it throughout the whole polymer material of the oral appliance. In other embodiments, one or more portions of the oralappliance do not contain any medicament disposed in or on it (e.g., the non-porous regions of the oral appliance). The term “medicament” as used herein is generally meant to refer to any substance that alters in part or in toto the physiology of a patient. The term “medicament” may be used interchangeably herein with the terms “medicine”, “drug” “therapeutic agent”, “therapeutically effective amount”, or “active pharmaceutical ingredient”. It will be understood that a “medicament formulation” may include more than one therapeutic agent, wherein exemplary combinations of therapeutic agents include a combination of two or more medicaments. The medicament can also include cells, where the device (e.g., oral appliance) can be seeded with the cells, for example, gingival cells or gingival tissue, bone cells, cartilage cells, probiotics or bone tissue so that the device can repair or replace tissue in the treatment area.

[0135] The medicament may be in powder, liquid, solid, solution, or suspension (e.g., gel) form and disposed on or impregnated in the oral appliance. This may occur during manufacture of the oral appliance or it may occur after the oral appliance is made. For example, on the core polymer material of the oral appliance, the medicament may be layered by solution or suspension layering or powder layering techniques. In solution or suspension layering, the medicament and any inactive ingredients (e.g. excipients, binders, etc.) are suspended or dissolved in water or an organic solvent. The resulting liquid is sprayed onto the outside of the oral appliance to make the polymer material have the desired potency. Solution or suspension layering may be conducted using a wide variety of process techniques, for example, by fluidized bed, Wurster bottom spray techniques, or the like. When the desired potency has been achieved, the polymer material is dried to the desired residual moisture content. Powdered layering involves the application of a dry powder to the oral appliance. The powder may contain the drug, or may include excipients such as a binder, flow aid, inert filler, and the like. In the powder layering technique, a pharmaceutically acceptable liquid, which may be water, organic solvent, with or without a binder and / or excipient, is applied to the oral appliance while applying the dry powder until the desired potency is achieved. When the desired potency has been achieved, the oral appliance may be dried to the desired moisture content.

[0136] In various embodiments, the medicament is in liquid form and is capable of diffusing through and within the oral appliance comprising a polymer material. In various embodiments, the liquid medicament may flow or diffuse from one portion of the oral appliance to another portion. In some embodiments, the liquid medicament may not flow or diffuse within the oral appliance. In some embodiments, the liquid medicament isconfined within the regions of the oral appliance corresponding to the treatment area. The liquid medicament is not capable of flowing or diffusing into the non-porous regions of the oral appliance. In some embodiments, the liquid medicament may flow or diffuse into the non-porous regions; however, the medicament cannot easily flow or diffuse out of the non- porous regions.

[0137] Examples of medicaments include, but are not limited to, anti-inflammatory agents, anti-infective agents (e.g., antiviral, antibacterial, antifungal agents, etc.), tissue and bone growth factors, pain management medication (e.g., analgesics, anesthetics, etc.) antineoplastic agents, tooth whitening agents, breath fresheners, anticalculus agents, antineoplastic agents, oral dermatologics, selective H-2 antagonists, anticaries agents, nutrients, vitamins, minerals, herbal products, opioids, or mixtures thereof.

[0138] In various embodiments, the oral appliance may contain more than one medicament. However, in another embodiment, combination therapy will involve use of a single, safe and effective amount of the medicament. For example, the method may further comprise subsequently administering one or more additional oral appliances, each containing a medicament that is different from the medicament contained in the earlier oral appliance. In this way, a series of customized treatment regimens can be provided to the patient. This provides for a "mix and match" medicament regimen with dose adjustment capability and provides the added advantage of allowing the health professional complete control to administer only those medicaments at the desired strength believed to be appropriate for the disease or condition being treated in a particular individual.

[0139] In various embodiments, the oral appliance can contain an antimicrobial agent, an anti-inflammatory agent, an antiseptic agent, a probiotic, an immunologic agent, an astringent agent, a preservative or a mixture thereof. In some aspects, the antiseptic agent is chlorhexidine digluconate disposed in a porous material comprising a polymer, for example hydrogel.

[0140] The amount of medicament contained within the oral appliance, will vary widely depending on the effective dosage required and rate of release from the polymer material and the length of the desired delivery interval. The dosage administered to the patient can be single or multiple doses and will vary depending upon a variety of factors, including the agent’s pharmacokinetic properties, patient conditions and characteristics (sex, age, body weight, health, size, etc.), extent of symptoms, concurrent treatments, frequency of treatment and the effect desired. These factors can readily be determined by those of ordinary skill in the art. In some embodiments, the surface area can be calculated to treat aspecific targeted area which corresponds to the surface area of the channel such that the treated area is precisely calculated to a specific individual based on that person’s specific geometries and not based on the size or weight of the patient.

[0141] In various embodiments, the polymer material of the oral appliance is designed to release the medicament as a bolus dose of the medicament, a single dose of the medicament, or multiple doses of the medicament all preloaded with a specific dosage at the manufacturing facility.

[0142] In some embodiments, the medicament described herein is in the oral appliance in an amount of from about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, to about 50% by weight of the oral appliance.

[0143] The oral appliance may comprise a safe and effective amount of one or more whitening agents such as bleaching agents or abrasive agents. Generally, the level of the bleaching agent is dependent on the available oxygen or chlorine respectively that the molecule is configured for providing to bleach the stain. The bleaching agent may be present at levels from about 0.1% to about 20%, in another embodiment from about 0.5% to about 9% and in another embodiment from about 3% to about 8%, and in yet another embodiment from about 4% to about 6%, by weight of the bleaching agent composition.

[0144] In some embodiments, the medicament can be disposed anywhere in or on the interior or exterior surface of the oral appliance adjacent to the gum and / or other soft tissue areas of the oral cavity including the buccal, lingual, palatal, mesial, distal, occlusal surfaces of one or more teeth. Some portions of teeth that do not require the medicament are sealed with the non-porous material which can be a coating, cross-linked with porosity reducing agent or comprise non-porous material such that the medicament cannot penetrate said portions. In some embodiments, the medicament may be disposed in or may enter the non- porous region. However, the medicament disposed in the non-porous region will not release the medicament or will release the medicament at a reduced rate.

[0145] In some embodiments, the medicament may enter the non-porous regions, but the medicament will release slowly from these regions. For example, the medicament can be disposed at discrete non-porous regions adjacent to the treatment area or uniformly disposed throughout the device. In this example, the medicament will not be released to other regions that do not correspond with the treatment area.

[0146] In some embodiments, the unique biomarkers and / or cytokines of the individual patient can be targeted by the oral appliance. The medicament in the hydrogel, for example, can inhibit, reduce, or modify proinflammatory cytokines. “Cytokine(s)” as used herein, include for example, a polypeptide(s) / glycoprotein(s) derived from a natural lymphokine (cytokines made by lymphocytes), monokine (cytokines made by monocytes), chemokine (cytokines with chemotactic activities), an interleukin (cytokines made by one leukocyte and acting on other leukocytes), or modification thereof or a combination thereof. The modified cytokine may be a fragment of the naturally occurring cytokine. In one embodiment, the modified cytokine has at least 70%, 75%, 80%, 85%, 90%, 95% or 98% amino acid sequence identity to a naturally occurring cytokine. In one embodiment, the modified cytokine is a mutant where at most 10% of the amino acids are deleted, substituted, and / or added based on a naturally occurring cytokine.

[0147] Examples of cytokines include, but are not limited to, interleukin (IL) including over 30 type such as IL-1α, IL-1β, IL-2, -3, -4, -5, -6, -7, -8, -9, -10, -11, -12, -13, -14, -15, -16, -17 to -37; interferon (IFN) such as IFN-α, IFN-5 β and IFN-γ; tumor necrosis factor (TNF) such as TNF-α and TNF-β; transforming growth factor (TGF) such as TGF-α and TGF-β; colony stimulating factor (CSF) such as granulocyte-colony stimulating factor (G- CSF), granulocyte-macrophage-colony 10 stimulating factor (GM-CSF), macrophage- colony Stimulating factor (M-CSF), erythropoietin (EPO), stem cell factor (SCF) and monocyte chemotactic and activating factor (MCAF); growth factor (GF) such as epidermal growth factor (EGF), fibroblast growth factor (FGF), insulin like growth 15 factor (IGF), nerve growth factor (NGF), Brain-derived neurotrophic factor (BONE), platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), keratinocyte growth factor (KGF), thrombopoietin (TPO), and bone morphogenic protein 20 (BMP); and other polypeptide factors including LIF, kit ligand (KL), MPO (Myeloperoxidase) and CRP (C-reactive protein); COX (Cyclooxygenase) such as COX-1, COX-2 and COX-3, NOS (Nitric oxide synthase) such as NOS-1, NOS-2 and NOS-3; and modifications thereof or a combination thereof.

[0148] Cytokines also include, for example, chemokines which are cytokines that induce chemotaxis. There are two major classes of chemokines, CXC and CC. The CXC chemokines, such as neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulatory activity 5 protein (MGSA) are chemotactic primarily for neutrophils and T lymphocytes, whereas the CC chemokines, such as RANTES, Macrophage inflammatory protein (MIP) including MIP-1α and MIP-1β, keratinocyte-derived chemokine (KC), themonocyte 10 chemotactic proteins (MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (-1 and -2) are chemotactic for, among other cell types, macrophages, T lymphocytes, eosinophils, neutrophils, dendritic cells, and basophils. There also exist the chemokines lymphotactin-1, lymphotactin-2 (both C15 chemokines), and fractalkine (a CX3C chemokine) that do not fall into either of the major chemokine subfamilies and modifications thereof or a combination thereof.

[0149] The medicament in the hydrogel, for example, can inhibit, reduce, or modify matrix metalloprotease enzymes (MMPs). The MMPs are divided into classes with some members having several different names in common use. Examples are: collagenase I (MMP-1, fibroblast collagenase), collagenase II (MMP-8, neutrophil collagenase), collagenase III (MMP-13), stromelysin 1 (MMP-3), stromelysin 2 (MMP-10), proteoglycanase, matrilysin (MMP-7), gelatinase A (MMP-2, 72 kDa gelatinase, basement membrane collagenase), gelatinase B (MMP-9, 92 kDa gelatinase), stromelysin 3 (MMP- 11), metalloelastase (MMP-12, HME, human macrophage elastase), membrane MMP (MMP-14), and combinations thereof.

[0150] In one embodiment, the oral appliance reduces, inhibits, or modifies proinflammatory mediators including cytokines / chemokines (IL-1 beta, IL-6, IL-8, IL-17A, TNF-alpha), matrix metalloproteinases (MMPs) including MMP-8 and MMP-9. FIGS.14, 15 and 16 illustrate and embodiment of use of the tray that had significant reduction in selected cytokines and / or matrix metalloprotease enzymes (MMPs). Methods of Making the Oral Appliance

[0151] The oral appliance is custom made to fit a specific patient. The custom-made oral appliance may be prepared by a health care professional including, but not limited to a dentist, oral surgeon, medical doctor, technician or manufacturer. The oral appliance can be made from an impression mold, or by using an analog or digital image capturing device. The oral appliance disclosed herein is not a boil and bite prefabricated device or a stock tray which can be manipulated by the consumer himself / herself with fingers to shape it against the teeth and gums. The oral appliance disclosed herein is custom fit, disposable, and monolithic such that it is pre-loaded with medicament in or on at least a portion of the interior and / or exterior surfaces of the appliance and can deliver medicaments to a patient in a targeted fashion to specific tissues. The medicament can be pre-loaded as part of the oral appliance or infused into the polymer of the oral appliance after the oral appliance is made.

[0152] In some embodiments, as shown in FIG.10, a method of making an oral appliance for delivering a medicament to an oral cavity, the method comprising providing an oral appliance 1012 having an exterior and an interior, the interior of the oral appliance configured to contour at least a portion of teeth and / or soft tissue areas of the oral cavity; calculating a selected dose; providing a volume of the medicament 1014 disposed in a hydrogel at the selected dose; providing a dispensing device 1016 having an outlet configured to dispense medicament at discrete regions of the interior based on custom dimensions of at least a portion of the teeth and / or soft tissue of a patient, the exterior, the interior or both the interior and the exterior of the oral appliance; and disposing the volume of the medicament 1018 within the interior based on dimensions of at least a portion of the teeth and / or soft tissue using the dispensing device.

[0153] In one embodiment, also as shown in FIG. 10, the method 1000 comprises obtaining a digital image of at least a portion of the teeth and / or soft tissue of the oral cavity 1002; identifying a surface area of at least a portion of the teeth and / or soft tissue of the oral cavity to be treated 1004; calculating the surface area to be treated with a medicament 1006; generating a virtual model of the oral appliance having the volume of medicament having the standardized dose disposed in the oral appliance 1011a; generating a volume of medicament having a standardized dose corresponding to the surface area to be treated 1011b; and producing an oral appliance and disposing the specific volume of medicament having the standardized dose on at least a portion of the teeth and / or soft tissue of the oral cavity 1011c. In some embodiments, an oral appliance is produced without medicament 1012 and a volume of medicament is produced separately 1014. A dispensing device is used to dispose the medicament onto or into the oral appliance 1018. In some embodiments, an oral appliance and the medicament are produced together as one monolithic piece with or without a dispensing device 1011. The oral appliance with the customized or universal standardized dosage is then applied to the patient 1020. Depending on the medicament and type of the treatment, the oral appliance is applied throughout a treatment period 1022. Also depending on the type of the treatment and the medicament, a health professional, a processor, or an artificial intelligence assisted health professional would calculate the standardized dosage for the second set of oral appliance for the patient 1024. In some embodiments, the method comprises a series of treatments and treatment periods. An artificial intelligence assisted health professional can predict the standardized dose for each treatment in the series. In some embodiments, the input factors may change during the treatment or the treatment period such that the health professional, a processor, or anartificial intelligence assisted health professional can adjust and re-calculate the standardized dose. Once the standardized dose is calculated, a second or a second set of oral appliances will be produced with the updated dose 1026. A patient according to the instruction of the health professional will be able to apply the second or the second set of oral appliances 1028. In some embodiments, three, four or more sets of oral appliances can be implemented the same way as the second set of the oral appliances. Each set can have just one or more oral appliances.

[0154] In some embodiments, the surface area is identified by a processor processing the digital image. An artificial intelligence is used to assist a health professional to identify the surface that has sufficient space allowing the medicament to be in contact with. In some embodiments, the digital image needed for image analysis is not the same as base image for producing an oral appliance. An artificial intelligence when conducting image analysis may require multiple images from different angles for a particular area. The calculation of the surface area where the medicament will be administered can be done in real time by an artificial intelligence, while this calculation may be difficult or sometimes impossible for a health professional to complete.

[0155] The processes described herein can produce oral appliances with a variety of different properties. Hence in some embodiments the oral appliances are rigid; in other embodiments the products are flexible or resilient. In some embodiments, the oral appliances are a solid; in other embodiments, the oral appliances are a gel such as a hydrogel or have layers of such. In some embodiments, the oral appliances have a shape memory (that is, return substantially to a previous shape after being deformed, so long as they are not deformed to the point of structural failure). Computer Implemented System

[0156] In various embodiments, the present disclosure provides a computer implemented method of making an oral appliance. The method comprises creating a digital record of a patient’s oral cavity, the Base Image (BI), by obtaining a digital image of at least a portion of the teeth and / or soft tissue of the oral cavity by using an imaging device. The Base Image is additively overlaid to create a first digital image, Dig1. Subsequently, a second digital image, Dig2, comprising at least a portion of the teeth and / or soft tissue of the oral cavity in need of treatment is subtractively generated. Thereafter, the first digital image, Dig1, and the second digital image, Dig2, are combined to form a third digital image, Dig3, of the oral cavity treatment area and the third digital image is then stored in the computer and used formanufacture. In other embodiments, the oral appliance is made by traditional vacuum based methods using thermoplastic materials which are softened with heat and then vacuum formed over a model of the patient’s mouth including all areas of interest to be treated as described in U.S. Patent No.6,386,869 to Zegarelli, P. J.

[0157] In some embodiments, there is a computer implemented method of producing an oral appliance pre-loaded with at least one medicament using a computer, comprising: using the Base Image of the digital image of the patient's mouth, generating first digital data representing an overlay of at least a portion of the teeth and / or soft tissues areas of the oral cavity of a patient, generating second digital data by performing a digital segmentation of at least a portion of the teeth and / or soft tissues areas of the oral cavity to determine discrete regions of the oral cavity in need of treatment, combining the first digital data and the second digital data to form a third digital data from which the oral appliance can be produced, wherein the third digital data comprises positions for at least one medicament to be placed at the discrete regions in the oral cavity in need of treatment.

[0158] In other embodiments, a computer implemented method is provided for creating a treatment plan for delivering a medicament to at least a portion of the teeth and / or soft tissue areas inside the oral cavity. The computer implemented method comprises generating a first digital data, Dig1, representing at least a portion of the teeth and / or soft tissues areas of the oral cavity of a patient from the Base Image. Subsequently, a second digital data, Dig2, is generated by performing via the computer a digital segmentation of at least a portion of the teeth and / or soft tissues areas of the oral cavity comprising discrete regions of the oral cavity in need of treatment. The first digital data, Dig1, and the second digital data, Dig2, are then combined via computer to form the third digital data, Dig3, from which the oral appliance can be produced, wherein the oral appliance has at least one medicament positioned at the discrete regions requiring treatment in the oral cavity.

[0159] In various embodiments, the X, Y, Z coordinates of the hydrogel channel and / or reservoir are created (Dig2) digitally in such a way that a robot can "read" the coordinate datapoints in order to create a precise guideline (Dig2a) for the dispensing robotic arm to precisely dispense the hydrogel strip, bead or reservoir onto or into the oral appliance according to the Dig2 mapping system. In some embodiments, Dig2a is a digital coordinate imprint onto Dig3 to specifically guide the robot in dispensing the medicament into the Dig2 portion of Dig3. By using the series of XYZ coordinate as a guideline (Dig2a), the robotic arm can dispense the hydrogel bead along the proper line(s) or point(s) and does so in the prescribed widths, lengths and depths in a smooth way so that the medicament is distributedevenly and precisely. Each tooth and / or anatomical part of the oral cavity can be defined by from about 1 to about 50 points, each point defined by at least Cartesian coordinates X, Y and Z that are sent to the processor to generate a guideline (Dig2a). For example, in one embodiment, each tooth can be defined by at least 10 Cartesian X, Y, Z coordinates or approximately at least about 160 per guideline. Moreover, by using the zero-point marker reference, the robotic dispensing arm can then orient where the guideline is in three dimensions to calibrate exactly where to begin to dispense hydrogel or other porous material. The guideline Dig2a can be a real line or another marker on the oral appliance itself utilizing a modification of the image of the oral appliance or may only be a digital representation of a line. Thus, guideline Dig2a can be a line or a series of points along the anatomic geometries of the mouth, such as points on the teeth, the gum line or other place markers.

[0160] In other embodiments, a computer-based system further comprises creating a virtual 3D image of the oral appliance indicating the discrete regions requiring treatment in the oral cavity; displaying on a display the virtual 3D image and performing interactive treatment plans including the selection of the at least one medicament. Imaging devices utilized to generate the various digital data sets include, without limitations, a digital camera, X-ray device, hand-held 3-D scanner, laser scanner, computerized tomography (CT) scanner, magnetic resonance imaging (MRI) scanner, coordinate measuring machine, destructive scanner or ultrasound scanner, generating first digital data, Dig1, representing at least a portion of the teeth and / or soft tissues areas of the oral cavity of a patient based on an imaging device image (Base Image), generating second digital data, Dig2, by performing via the computer a digital segmentation of at least a portion of the teeth and / or soft tissues areas of the oral cavity comprising discrete regions of the oral cavity in need of treatment, combining via the computer the first digital data, Dig1, and the second digital data, Dig2, to form a third digital data, Dig3, from which the oral appliance can be produced having at least one medicament positioned at the discrete regions requiring treatment in the oral cavity. In some aspects, obtaining the baseline digital image of at least a portion of the patient’s teeth and / or soft tissue of the patient’s oral cavity or Dig1 further comprises digitally storing a permanent record of the topography of least a portion of the patient’s teeth and / or soft tissue of the patient’s oral cavity for future iterations of oral appliances.

[0161] In other embodiments, the three-dimensional representation of the third digital data, Dig3, is stored in a format suitable for use by a manufacturer to produce the oral appliance pre-loaded with at least one medicament at areas targeted for treatment. Astereolithography apparatus comprising at least two print heads can be used to manufacture the oral appliances described in this disclosure. As discussed above, the first print head can be configured to deliver a first chemical composition according to the first digital data, Dig1, and the second print head can be configured to deliver a second chemical composition according to the second digital data, Dig2. The two combined merge and represent the image of the third digital data, Dig3. At least one of the chemical compositions includes a medicament while the other can be a polymer gel, hydrogel, brush polymer, another medicament or combinations thereof.

[0162] FIG. 8 illustrates an embodiment of the computer-implemented system for producing an oral appliance. An input device or scanner 60 is used to scan the oral cavity of and thus generate a digital record of the patient’s mouth, a Base Image (BI). The scanner can be an MRI scanner, a CT scanner, a PET scanner, a digital scanner, an X-Ray machine, or an intra-oral scanner, for example. In various embodiments, scanner 60 can scan the patient’s teeth, soft tissue, or both to obtain a digital data set of the teeth and / or soft tissue areas inside the mouth from which the base image is generated. The digital data can be stored in a database, such as for example, a computer that has a processor or CPU 62, which sends the digital data to its memory 64 and / or can display it in a virtual 3D image display 66 of processor 62. In some aspects, CPU 62 can be included in robotic dispensing system 300 and is in communication with first robotic arm 302 and second robotic arm 350. In other aspects, CPU 62 can be included in robot 100 as was discussed above. The database and / or processor can comprise an input device (e.g., keyboard, touch screen, voice activation, etc.) to allow a user to enter, display, edit, and / or transmit one or more images from Dig1, Dig2, Dig2a and Dig3. The processor 62 comprises logic to execute one or more instructions to carry instructions of the computer system (e.g., transmit instructions to the 3D printer and / or the robotic system). The logic for executing instructions may be encoded in one or more tangible media for execution by the processor 62. For example, the processor 62 may execute codes stored in a computer-readable medium such as memory 64. The computer-readable medium may be, for example, electronic (e.g., RAM (random access memory), ROM (read-only memory), EPROM (erasable programmable read-only memory)), magnetic, optical (e.g., CD (compact disc), DVD (digital video disc)), electromagnetic, semiconductor technology, or any other suitable medium. Based on memory 64, processor 62 can generate Dig2, Dig2a and Dig3 and thereafter send a 3D image to the 3D printer 68 of a stereolithography apparatus or robotic dispensing system 300 orrobot 100. Based on memory 64, processor 62 can receive image files from sensors 328 and 370 of robotic dispensing system 300 or sensors 250, 270, 740 and 750 of robot 100.

[0163] In various embodiments, an authorized user can input, edit data and approve or prescribe a treatment plan based on the virtual 3D images displayed at the user interface of the computer processor 62 and / or another treating computer networked with computer processor 62. Although the components of the system of FIG.8 are shown as separate, they may combine in one or more computer systems. Indeed, they may be one or more hardware, software, or hybrid components residing in (or distributed among) one or more local or remote computer systems. It also should be readily apparent that the components of the system as described herein may be merely logical constructs or routines that are implemented as physical components combined or further separated into a variety of different components, sharing different resources (including processing units, memory, clock devices, software routines, logic commands, etc.) as required for the particular implementation of the embodiments disclosed. Indeed, even a single general-purpose computer (or other processor-controlled device) executing a program stored on an article of manufacture (e.g., recording medium or other memory units) to produce the functionality referred to herein may be utilized to implement the illustrated embodiments. It also will be understood that a plurality of computers or servers can be used to allow the system to be a network based system having a plurality of computers linked to each other over the network or Internet, or that the plurality of computers can be connected to each other to transmit, edit, and receive data via cloud computers.

[0164] The computer (e.g., memory, processor, storage component, etc.) may be accessed by authorized users. Authorized users may include at least one dentist or dental specialist, dental hygienist, oral surgeon, physician, surgeon, nurse, patient, and / or health care provider, manufacturer, etc.).

[0165] The user can interface with the computer via a user interface that may include one or more display devices (e.g., CRT, LCD, or other known displays) or other output devices (e.g., printer, etc.), and one or more input devices (e.g., keyboard, mouse, stylus, touch screen interface, or other known input mechanisms) for facilitating interaction of a user with the system via user interface. The user interface may be directly coupled to database or directly coupled to a network server system via the Internet or cloud computing. In accordance with one embodiment, one or more user interfaces are provided as part of (or in conjunction with) the illustrated systems to permit users to interact with the systems.

[0166] The user interface device may be implemented as a graphical user interface (GUI) containing a display or the like, or may be a link to other user input / output devices known in the art. Individual ones of a plurality of devices (e.g., network / stand-alone computers, personal digital assistants (PDAs), WebTV (or other Internet-only) terminals, set-top boxes, cellular / phones, screen phones, pagers, blackberry, smart phones, iPhone, iPad, table, peer / non-peer technologies, kiosks, or other known (wired or wireless) communication devices, etc.) may similarly be used to execute one or more computer programs (e.g., universal Internet browser programs, dedicated interface programs, etc.) to allow users to interface with the systems in the manner described. Database hardware and software can be developed for access by users through personal computers, mainframes, and other processor-based devices. Users may access data stored locally on hard drives, CD-ROMs, stored on network storage devices through a local area network, or stored on remote database systems through one or more disparate network paths (e.g., the Internet).

[0167] The database can be stored in storage devices or systems (e.g., Random Access Memory (RAM), Read Only Memory (ROM), hard disk drive (HDD), floppy drive, zip drive, compact disk-ROM, DVD, bubble memory, flash drive, redundant array of independent disks (RAID), network accessible storage (NAS) systems, storage area network (SAN) systems, etc.), CAS (content addressed storage) may also be one or more memory devices embedded within a CPU, or shared with one or more of the other components, and may be deployed locally or remotely relative to one or more components interacting with the memory or one or more modules. The database may include a data storage device, a collection component for collecting information from users or other computers into centralized database, a tracking component for tracking information received and entered, a search component to search information in the database or other databases, a receiving component to receive a specific query from a user interface, and an accessing component to access centralized database. A receiving component is programmed for receiving a specific query from one of a plurality of users. The database may also include a processing component for searching and processing received queries against a data storage device containing a variety of information collected by the collection device.

[0168] The disclosed system may, in some embodiments, be a computer network-based system. The computer network may take any wired / wireless form of known connective technology (e.g., corporate or individual LAN, enterprise WAN, intranet, Internet, Virtual Private Network (VPN), combinations of network systems, etc.) to allow a server to provide local / remote information and control data to / from other locations (e.g., other remotedatabase servers, remote databases, network servers / user interfaces, etc.). In accordance with one embodiment, a network server may be serving one or more users over a collection of remote and disparate networks (e.g., Internet, intranet, VPN, cable, special high-speed ISDN lines, etc.). The network may comprise one or more interfaces (e.g., cards, adapters, ports) for receiving data, transmitting data to other network devices, and forwarding received data to internal components of the system (e.g., 3D printers, printer heads, etc.).

[0169] In accordance with one embodiment of the present application, the data may be downloaded in one or more textual / graphical formats (e.g., RTF, PDF, TIFF, JPEG, STL, XML, XDFL, TXT etc.), or set for alternative delivery to one or more specified locations (e.g., via e-mail, fax, regular mail, courier, etc.) in any desired format (e.g., print, storage on electronic media and / or computer readable storage media such as CD-ROM, etc.). The user may view the search results and underlying documents at the user interface, which allows viewing of one or more documents on the same display.

[0170] In various embodiments, the computer software can create a 2D or 3D digital image of the patient's oral cavity to allow the treatment provider to review and discuss the proposed treatment with the patient. In another embodiment, the software can process the scanned data and provide the user / operator with useful data including tooth measurements (e.g. arch width, arch length, tooth size, angulations, sulcus size, etc.) to assist the user in fine-tuning the treatment plan. The computer can then provide the operator with options in staging the treatment plan from one stage to another stage, or it can completely generate all the stages ranging from the initial to the final desired stage. The staging can be done automatically.

[0171] FIG. 9 is a flow chart illustrating the logic steps followed by processor 62. The first step 70 comprises generating a Base Image (BI) of at least a portion of the teeth and / or soft tissues by using an imaging device. In step 72, the BI is stored in the memory of the processor. In step 74, a first data set (Dig1) is generated by the computer additively layering over the BI of at least a portion of the teeth and / or soft tissues. The Dig1 is stored.

[0172] In step 76, a second data set (Dig2) is generated by digitally segmenting at least a portion of the teeth and / or soft tissues from the Base Image. Thereafter, in step 78, the processor can decide if all discrete regions of the oral cavity in need of treatment have been identified or if they have not been, then the digital segmentation step will occur again. Dig2 will also be checked for accuracy. In some embodiments, in step 76a, the second set of data is defined by a guideline Dig2a. Dig2a is generated by defining each tooth and / or anatomical part of the oral cavity from about 1 to about 50 points, each point defined by atleast Cartesian coordinates X, Y and Z and which are sent to processor 62. In step 78a, Dig2a is checked for accuracy and then stored in step 80a. In other aspects, the second digital image (Dig2) of the patient’s oral appliance can be combined with the digital image of the guideline (Dig2a) to facilitate dispensing of the porous material at discrete regions of the oral appliance.

[0173] If all the desired discrete regions have been identified, then in step 80, the processor stores the data, which includes the discrete regions in need of treatment as a separate set corresponding to Dig2. The first and second data sets are combined in step 82 to generate a third data set corresponding to Dig3. In some aspects, the third digital data (Dig3) is formed by one of (i) subtracting the second digital data (Dig2) and the digital image of the guideline (Dig2a) from the first digital data (Dig1) or (ii) adding the second digital data (Dig2) and the digital image of the guideline (Dig2a) to the first digital data (Dig1) as illustrated in step 82a. The third data set Dig3 is stored in step 84 and then sent to a 3D printer in step 86, or for manufacturing of the oral appliance without medicament in step 87 or with medicament in step 88, wherein steps 86, 87 and 88 are accomplished with the help of a robotic system or robot. In yet other embodiments, the software manipulation can be performed by the robotic system(s) and / or robot(s) described in this application using artificial intelligence. For example, in one embodiment, Dig2a can be created by artificial intelligence. In yet another embodiment, the Dig1 image is modified to create the handle in a specific location on the oral appliance either incorporating a zero-point marker on the handle or designating a zero-point marker on another aspect of the oral appliance. Still another embodiment is to modify the Dig2 image and have the handle and / or the zero-point marker created digitally and have that image additively attached to generate the final Dig3 image. In other embodiments, Dig2a is a digital coordinate imprint onto Dig3 to specifically guide the robot in dispensing the medicament into the Dig2 portion of Dig3.

[0174] In some embodiments, using the data from Dig1, Dig2 and Dig3, there is a Base Image (BI) from which most modifications are drawn from. An overlay oral appliance image is digitally designed to follow the anatomy and contours of parts of or the entire surface area of the upper and lower jaws including teeth and soft tissues and this is called Dig1. Dig2 is a process where a segment or a continuous line of soft and / or hard tissues are subtracted from the BI. The Dig2 is then added to a surface of the Dig1 to create a Dig3 on the inner surface of the Dig1. In process, in some embodiments, there can be a bulge protruding from the tray onto the tissues of the mouth that were originally targeted.

[0175] In another process, FIG.11 is a flow chart illustrating the logic steps followed by processor 62. The first step 600 comprises generating a Base Image (BI) of at least a portion of the teeth and / or soft tissues by using an imaging device. In step 602, the BI is stored in the memory of the processor. From the BI, there are digital manipulations that create a first digital data set that has structures over the targeted areas to be treated, such as the teeth and / or gumline. This can be a scaffolding or a virtual “preformed solid line” of specific spatial dimensions or other such methodology with lateral walls and a roof of the area to be treated in the oral cavity. These forms are added to the BI and are termed Form1, which is the first data set that has specific dimensions of height, width and length. The data set for Form1 is generated and stored in step 604.

[0176] In step 606, onto Form1 there is layered a solid digital roof or covering which corresponds to the dimensions of the targeted area to be treated, for example, the gumline. This is a second digital data set or Form2 that is generated in step 606. The digital data in Form2 is checked for accuracy in step 608 and stored in the database at step 610.

[0177] The system can do random guideline and accuracy checks of the digital images of Form1 and Form2. For example, in some embodiments, in step 606a, the second set of data is defined by a guideline Form2a that is generated by defining each tooth and / or anatomical part of the oral cavity from about 1 to about 50 points, each point defined by at least Cartesian coordinates X, Y and Z and which are sent to processor 62. In step 608a, Form2a is checked for accuracy and then stored in step 610a. In 612a, digital data sets Form1 and Form2 are combined and the data stored.

[0178] In step 612, from the combination of the digital data sets in Form1 and Form2, Form1 is subtracted from the combinations of Form1 and Form2 to generate the third digital data set Form3, which is a digital tunnel over the targeted area to be treated. In step 614, the digital data set for Form3 is stored in the database and then sent to a 3D printer and / or robotic manufacturing system in step 616 for manufacturing the oral appliance. If no medicament in the oral appliance is needed at this time, manufacturing of the oral appliance without medicament can be done in step 618. In some embodiments, the medicament can be added to an already formed oral appliance with the help of a robotic system or robot in 620. In yet other embodiments, the software manipulation can be accomplished by the robotic system(s) and / or robot(s) described in this application using artificial intelligence. For example, in one embodiment, Form2 can be created by artificial intelligence. In yet another embodiment, the Form1 image is modified to create the handle in a specific location on the oral appliance either incorporating a zero-point marker on the handle or designatinga zero-point marker on another aspect of the oral appliance. Still another embodiment is to modify the Form2 image and have the handle and / or the zero-point marker created digitally and have Form1 subtracted from Form1 and Form2 to obtain the digital image of Form3.

[0179] In some embodiments, Form3 would be the digital image that would be 3D printed where the oral appliance would be configured to be placed over the jaws and teeth and a tunnel would be incorporated into the tray and would bulge out into the mouth of the patient. In some embodiments, if the oral appliance is to be thermoformed, then a 3D model would be printed with a bulge over the targeted areas and the oral appliance would be thermoformed over that.

[0180] In some embodiments, for delivering medicament from the outside of the tray, the surface would be away from the teeth and gums. BI is again taken. Form1 is additively created utilizing digital walls of specific height, width and length over the surfaces from which the medicament will be eluted. This is Form1. Onto Form1 there is layered a covering, again creating Form2. Form1 is digitally subtracted leaving Form3 leaving open channels where medicament can be placed. It will be understood that there can be other manipulations and geometric forms which can enhance the delivery of the medicaments, e.g., open boxes, squares, rectangles, etc.

[0181] In general, in FIG.9 above, the digital image Dig1 uses additive, subtractive and additive digital manipulations and the oral appliance can be formed first where, in some embodiments, bulges are formed inside the oral appliance that extend outwardly.

[0182] In general, in FIG.11 above, the digital image Form1 uses additive, additive and subtractive digital manipulations and the oral appliance can be formed first where, in some embodiments, bulges are formed outside of oral appliance that extend outwardly.

[0183] FIG.12 is a flow chart illustrating one embodiment of the computer implemented system and steps that the computer performs to produce the oral appliance, which is then loaded with medicament by a robotic system or a robot or by additive manufacturing.

[0184] In the embodiment shown in FIG.12, the practitioner or artificial intelligence first identifies the area(s) to be treated (e.g., the target tissue). The target tissue identified can be, for example, some or all of various soft tissues such as the gingiva or the dorsum of the tongue or the hard tissues such as the teeth or bone or a combination of soft and hard tissues of the mouth. The entire dentition as well as any or all adjacent soft tissues are then 3D scanned to create a Base Image (BI) 700, which is a permanent record of the clinical presentation of the oral cavity that is stored in the computer database. The area to be treated, the Target Area Map (TAM) 710, is identified by the processor and outlined. For instance,if the TAM is along the gum line to treat gingivitis, then the length of the gumline to be treated is a constant that can be measured by simply following the line created by the junction of the cervical areas of the teeth with the soft tissues of the gingiva (free gingival margin) (FIG. 13A). The processor now has a calculable length to create a virtual image. The width of the TAM can also be calculated by the processor following along the gumline as before and it can create a treatment belt of a given width, or a variable width, overlaid on that gumline or above or below it topographically, which is shown visually as a virtual image. The processor now has a calculable width. Using these calculable lengths and widths, the processor can then determine the entire surface area to be treated in square millimeters or other standard measuring scales. This is similar to Dig1 discussed above. The TAM, for example, can be applied to other areas of the mouth to treat dental caries, oral dermatologic lesions or other conditions that can be identified mapped and treated using the medicament loaded in the oral appliance based on the virtual image and the robot can make the oral appliance loaded with medicament or it can be made by additive manufacturing. Since the topography of the mouth is curvilinear, this surface is irregular in shape. Now every individual has not only a forensically unique TAM but also a forensically unique Topographical Pharmacologic Map (TPM) 720 for treating various oral maladies or for the systemic delivery of drugs that can be treated with the oral appliance loaded with medicament. This combination of BI, TAM and TPM is unique to no other organ of the body and allows for the ultimate in personalized delivery of drugs or medicaments. This information can be saved and reused as the target tissue topography changes with treatment.

[0185] Since the concentration of the drug to be delivered can be a constant, the main variable left is the dosage of drug to be delivered. In some embodiments, the oral appliance can deliver a standard dose of medicament for each individual patient based, for example, not on some arbitrary sizing, such as the weight of the individual (e.g., Clark’s Rule), but it can apply a constant dose per square millimeter for the individual being treated based on their individual TAM. As such, one way to standardize the dosage is to regulate the thickness or depth of the medicament in a hydrogel or other medium to be applied creating a uniform volume of medicament over a given surface area of the total TAM. Since the TAM is length times width, adding a uniform depth will result in a calculable volume of TAM times depth. This calculable volume is the Target Volume (TV) 730 that can be calculated and stored in the database, for example, in cubic millimeters. For instance, if the total TAM equals 600 sq mm and the uniform depth is 2 mm, then the Total Volume is 1200 cubic millimeters.

[0186] The TV, having a uniformity of depth, assures an evenly dispersed dosage of the same concentration of medicaments per square millimeter and since the shortest distance between two points is a straight line and drugs will diffuse from an area of high concentration to an area of low concentration based on that straight line effect, the drug delivery uniformity of depth assures the same amount of the same concentration of drug is delivered per square millimeter. Since the total depth is constant, the base of the depth of hydrogel infused medicament can mirror the topography of the curvilinear TAM map. Therefore, a second TAM can be duplicated off the original TAM on the Base Image. Thus, two TAM maps are created and stored in the database, the original, (TAM1) 740, which is the surface to be targeted and treated and a second (TAM2) 750, which is a virtual TAM map. Here TAM1 equals TAM2 and are identical. More particularly, in some embodiments, TAM2 is a copy of TAM1 and is virtually overlaid and placed parallel to the original TAM1 and uniformly spaced over it when the virtual image is generated. To create a channel over the original TAM, the processor will create virtually walls along the outside width perimeters at the same predetermined depth and / or lengths and these are generally geometrically perpendicular to both TAM1 and TAM2. A channel is thus created of uniform depth and width (Dig2, for example discussed above) from which a total volume is calculated and the dose is the forensically identified TPM based on that volume. With this design, the Dig3 image presents a uniform amount of medicament delivered per square millimeter to any targeted tissue per square millimeter of surface and per depth above the surface. The processor stores data for the TAM, TPM, TV and optionally TAM1 and TAM2 in the database at 760. The processor can execute the instruction to produce the oral appliance 770 by, for example, the robot or by additive manufacturing.

[0187] U.S. Patent No.9,649,182 to Peter J. Zegarelli, filed June 18, 2015, describes that there is a Base Image but then there is a digital segmentation creating a unique Dig1, followed by a unique Dig2 and a combination of the two subtractive and additive steps to create a final and unique Dig3. The entire disclosure of this patent is herein incorporated by reference into the present disclosure. The embodiment in the current application in FIG.12 is utilizing similar concepts of Dig1, Dig2 and Dig3 but creating parallel topographies to deliver drugs in a consistent measured way and creating a channel to hold the medicaments. From these virtual digital manipulations, an overlay oral appliance can be either 3D printed directly based on the outline of the original surface topography of the BI minus TAM1 but including the parallel TAM2 with the outer width walls or a model can be manufacturedbased on Dig3 and a thermoforming step can be made over the model to create the oral appliance.

[0188] The medicament is then loaded into this channel and can be loaded to the top of the channel or overloaded to a consistent height so as to maintain uniformity in depth and thus in dosage of medicament delivered.

[0189] One of ordinary skill in the art will understand that one can adjust the TAM1 and TAM2 images to make one different from the other or vice versa or can make them not parallel or manipulate them in other ways to create areas where there is a desire to have more medicaments delivered to a specific area of a TAM that is more diseased or to decrease the dose of medicaments to an area where there is less need to treat. Or one could construct the walls first perpendicular to the contours of TAM1 and then place TAM2 on top of the walls as a quality control check for parallelism.

[0190] In some embodiments, to confirm that the correct amount by weight of hydrogel is added to the oral appliance, an empty oral appliance (without hydrogel) can be weighed and a known quantity of hydrogel (with or without medicament) can be loaded in the oral appliance and the hydrogel loaded oral appliance can be weighed. The target weight or control weight of the hydrogel loaded in the oral appliance and the actual weight of the hydrogel loaded oral appliance should match or, for example, be substantially similar that is plus or minus 10% of the target weight of the hydrogel loaded oral appliance. This is one way to provide quality assurance to the hydrogel loaded oral appliance and ensure that medicament delivery will be substantially precise.

[0191] FIGS. 13A, 13B, 13C, 13D, 13E, 13F, 13G and 13H illustrate a cross-sectional view of the virtual image of a treatment surface area (TSA), a second treatment surface area (TSA1) and then a third Treatment surface area (TSA2) to produce a virtual image of the oral appliance (oral tray) and then the computer is given instructions to produce the oral tray containing a hydrogel loaded with medicament at discrete positions of the oral tray by a robotic system or a robot or by additive manufacturing.

[0192] In some embodiments, the virtual image of the target treatment area can be manipulated, increased and / or decreased by + / – 10%, + / - 15%, or + / - 20% so as to allow for the varied potency of the medicament concentration that can vary in the hydrogel. For example, the virtual image of the target treatment area can be decreased or manipulated by -10% to offset a medicament that has a potency of +10% of that which is on the label. Methods of Delivering a Medicament with the Oral Appliance

[0193] A method of treating at least a portion of teeth and / or soft tissue of an oral cavity is provided. As shown in FIG.10, the method comprises providing an oral appliance 1012, the oral appliance having an exterior and an interior, the interior of the oral appliance configured to contour at least a portion of teeth and / or soft tissue areas of the oral cavity; providing a medicament 1014 disposed in a hydrogel at a selected dose, the medicament disposed within the interior based on dimensions of at least a portion of the teeth and / or soft tissue; and inserting 1020 the oral appliance within the oral cavity of a patient.

[0194] Also referring to FIG. 10, in some embodiments, the method 1000 comprises scanning the oral cavity of a patient 1002. The scanning of the oral cavity will generate a base image allowing a health professional, a computer, or an artificial intelligence assisted health professional to identify a region to be treated 1004. The region to be treated is not necessarily the same as the area where the medicament is administered. For example, the region to be treated can extend into a pocket under or behind a tooth where the medicament cannot be applied or contacted directly. In other scenarios, the medicament can be applied around the region to be treated to prevent further infection. A health professional, a computer, or an artificial intelligence assisted health professional in 1006 can calculate a surface area based on the area to be treated that will receive the medicament. Once the surface area is calculated, the specific dosage for contacting the treatment region can be determined. The determination of the dosage is based on various factors. In some embodiments, the dosage of a medicament is based on the clinical test results, medical guidelines, and recommendations. In other embodiments, the dosage of a medicament in the hydrogel can be a standardized dose based on the unique topography of the treatment area of that patient’s oral cavity, such as for example, surface area, size, depth, height, shape, and / or other dimensions of the gingiva and / or other soft and / or hard tissues of the oral cavity, severity of disease, constituents in microbiome of the oral cavity, and / or therapeutic index of the medicament. In the calculation there can be an assigning a score or rating and then the medicament can be loaded into the oral appliance at the appropriate dose and location based on that score or rating. In this way, a precisely loaded oral appliance having a standardized dose of medicament can be made that is specific to the unique characteristics of the oral cavity of the individual patient and is not based on Clark’s Rule but based on the topography of the specific patient for which the dose has been prescribed.

[0195] FIG. 2B illustrates an example of a standardized dosing chart based on unique characteristics such as the size of the patient’s sulcus and other parameters, such as for example, surface area, depth, shape, severity of disease, microbiome of the oral cavityand / or therapeutic index of the medicament. These parameters can be scored or rated and the hydrogel dispensing can be selected according to this scoring or rating to standardize the dose of medicament, dispense and load the hydrogel in the oral appliance. All these dosage factors are input into the computer or a processor for a final calculation or determination of the dosage in 1008 based on the rating or scoring.

[0196] Once all the input factors or variables are considered, a health professional, a processor or an artificial intelligence assisted health professional will balance each factor to generate a standardized dose 1010. The standardized dose can be generated for an individual patient based on if a patient belongs to certain categories such as an age group, a weight group, or a height group, have certain co-morbidities which can aggravate their oral condition such as chronic inflammatory diseases (diabetes, for example as well as others) or other aggravating systemic conditions, a certain surface area of sulcus or other factors. In some embodiments, a universal standardized dose can be generated for the oral appliance. Based on all the information gathered, an oral appliance is produced without medicament 1012 and a volume of medicament is produced separately 1014. A dispensing device is used to dispose the medicament onto or into the oral appliance 1018. In some embodiments, an oral appliance and the medicament are produced together as one monolithic piece with or without a dispensing device 1011. The oral appliance with the customized or universal standardized dosage is then applied to the patient 1020. Depending on the medicament and type of the treatment, the oral appliance is applied throughout a treatment period 1022. Also depending on the type of the treatment and the medicament, a health professional, a processor, or an artificial intelligence assisted health professional can calculate the standardized dosage for the second set of oral appliances for the patient 1024. In some embodiments, the method comprises a series of treatments and treatment periods, wherein an artificial intelligence assisted health professional can predict the standardized dose for each treatment in the series. In some embodiments, the input factors may change during the treatment or the treatment period such that the health professional, a processor, or an artificial intelligence assisted health professional can make adjustment and re-calculate the standardized dose. Once the standardized dose is calculated, a second or a second set of oral appliances will be produced with the updated dose 1026. This update dose will have a change in dose of medicament and / or location of medicament as the condition progresses. A patient according to the instruction of the health professional will be able to apply the second or the second set of oral appliances in step 1028. In some embodiments, three, fouror more oral appliances can be implemented the same way as the first and second set of the oral appliances. Artificial Intelligence

[0197] The scanning of the oral cavity, calculation of the surface area, calculation and determination of the standardized dose and many other features in the present application can rely on an artificial intelligence. The artificial intelligence (AI) stems from the application of a computer system that intends to replicate human capability in electronics. Specifically, the computer system that can replicate human cognitive abilities that allows the computer system to learn, reason, and make decisions. The computer system that utilizes the AI involves creating and developing algorithm that allow machines to process data, recognize patterns, and adapt to new situations. In various embodiments, the scanning of the oral cavity involves the image analysis aspect of the AI. For example, AI automates repetitive tasks in taking images and comparing images and refining the images by repeatedly retaking or repairing the image to enhance the quality in both accuracy and consistency of the final image. The AI model will be trained prior to the application on a patient through a data preparation, a model selection and an evaluation process. The AI will then be retrained when implemented on a specific patient to further improve its algorithm for a customized oral appliance and a standardized dose. The AI also reduces a significant amount of manual time overhead that was previously required of health professionals. Some tasks such as the immediate comparing and retaking the image would be nearly impossible as this would require a patient to come in multiple times just to have a clear base image. The travel and time burden of such practice may not be worth the cost, not to say, the accuracy of the images may not be superior than the one produced by an AI.

[0198] In various embodiments, the AI also assists in calculation of the surface area that is suitable and capable of receiving a medicament. The AI can simulate a virtual model of the oral appliance implemented on a virtual model of the oral cavity as well as build and create a dispersing or a distributing model of the medicament for the implementation. In such learning model, the AI is able to determine the surface area that can receive the medicament. The AI allows the calculation of the surface area to be repeated for unlimited times while limiting the patient’s exposure to an x-ray or other scanning devices. The AI, via its image analysis is also capable of identifying deliverable surface area independent of a health professional’s identification such that a health profession with AI’s assistance canhave a more accurate and consistent identification of the deliverable surface area where the medicament can be received by the patient. The AI can further assist in calculation of changing in sulcus size as the treatment progresses. As the treatment progresses, the diseased inflamed area would hopefully decrease in size. The AI can utilize the algorithm or previous training to re-calculate or predict the new surface area. In some embodiments, the AI also assists in the calculation and determination of the standardized dose. The AI, based on the conversion chart or other input factors, can determine the maximum effective dose and the minimum effective dose for a medicament. With the previously calculated surface area, the AI can assist the health professional in arriving at a standardized dose per surface area of the sulcus. For example, if a medicament requires 1 unit dose to treat 10 cm2of diseased or infected tissue(s), the AI can calculate the total available deliverable surface area, for example 10 unit doses for 100 cm2. When such standardized dose is determined, the AI can further direct a dispensing machine to dispense a total of 10 unit doses onto the oral appliance at the discrete region where, when implemented, matches the treatment region and the contact area.

[0199] Artificial intelligence (AI) can be in the form of an independent processor, a computer system similar to the system shown in FIG.8. The AI can also be in the form of a scanning device, dispensing device or other electronic device involving a processor. In various embodiments, the processor is an independent computer connecting and instructing a scanning device and / or other input devices and is capable of instructing a 3D printer, robotic system, robot and / or other dispensing device. Dosage Selection Based on Input Factors

[0200] FIG. 2B illustrates an example of a standardized dosing chart based on unique characteristics such as the size of the patient’s gingiva, sulcus, and / or other soft and / or hard tissues and other parameters, such as for example, surface area, depth, shape, severity of disease, microbiome of the oral cavity, biomarkers of the patient, cytokines of the patient, height of the patient, weight of the patient other systemic diseases which may aggravate the oral condition or the general inflammatory condition of the patient based on such factors as the patient’s cytokine levels and / or therapeutic index of the medicament. The parameters can include, for example, whether transmucosal delivery of drugs for systemic diseases is desired, or if mucosal delivery for oral diseases is desired or a combination thereof. These parameters can be scored or rated and the hydrogel dispensing can be selected according to this scoring or rating to standardize the dose of medicament, dispense and load the hydrogelin the oral appliance. All these dosage factors are input into the computer or a processor for a final calculation or determination of the dosage based on the rating or scoring. In some embodiments, these parameters do not include the height and weight of a patient and they can be excluded.

[0201] To increase the accuracy and consistency of the standardized dose, more input factors can be used. Different medicaments have various therapeutic drug indexes where the medicament dosage range is usually expected to achieve the desired therapeutic effect. Thus, to account for possible deviance and errors from a pure weight-based dosage, in various embodiments, a conversion chart with multiple factors is used. Multiple factors include dose, formulation form, route, frequency, administration time, drug–drug interaction, food–drug interaction, genetics, sex, age, body weight, pregnancy, circadian rhythms, comorbidities, pathophysiology status, smoking, prior treatments, drug resistance, biofilm constituents, and other patient activity associated with the treatment region. In some embodiments, a dosage table based on various factors can be generated via a scoring or rating system using factors as described below. Tables 1-3, each demonstrates a prophetic scenario of a scoring or rating system based on weight, age, creatinine and sulcus surface area to be treated. In one embodiment, the scoring system has a rating between 0 to 10, where 0 indicates no dosage at all, while 10 allows a full 1 unit dosage. Table 4. demonstrates a weighted score. After calculation and compilation of all scores from all the scoring systems based on each factor, a health professional, a processor, or an artificial intelligence assisted health professional will weigh each system with medical judgment and consideration to arrive at a final weighted score. The weighted score will then be used to determine a dosage amount. In some embodiments, 1 unit of standardized dosage is based on a male patient with height of 6 feet, and weight of 200 pounds. In other embodiments, 1 unit of a standardized dosage is based on a creatinine level of 1.5 or lower. In some embodiments, 1 unit of a standardized dose can be discretionary by a health professional or the convenience of the manufacturer. For example, if a standardized dosage is based on the surface area of a treatment region per 1 mm2, a health professional may at their discretion and judgment set 1 unit per 1 mm of treatment area, so as to avoid confusion of a large numerical number or accidental errors.

[0202] Table 1. Rating or Scoring System Based on Weight Weight (lb) <10 lb 10-30 lb 20-30 lb 30-50 lb >50 lb

[0203] Table 2. Rating or Scoring System Based on Surface Area of the Sulcus 2 <1 1-100 101-200 201-400 >500 Area (mm)Weighted 0 1-3 4-6 7-10 >10 Scorea es a eo e os aes ao e sco g syse a e sa a zed dose based on a prophetic use of minocycline gel for the treatment of periodontal disease.

[0207] Table 5. Rating or Scoring System Based on Surface Area of the Sulcus 2 <1 1-100 101-200 201-400 >500 Area (mm)

[0208] Table 6. Rating or Score and Standardized dose Conversion Chart Weighted 0 1-3 4-6 7-10 >10

[0209] Table 5 shows an example of a medicament loaded in a hydrogel, for example, minocycline 2% (2 gm / 100 mL) of hydrogel that can be used to treat the sulcus, which has periodontal disease (PD). If the infected sulcus is relatively small at 4 mm, andthere are no other factors, the treatment area can be scored as between 1-3 in Table 5 and half the standardized dose can be given or 0.5 dosage units in Table 6. If later, the health professional discovers that the surface area of the infected sulcus area has increased, the weighted score can increase and 1 dosage unit can now be loaded in a second oral appliance where the discrete treatment region is increased and the second oral appliance is worn so that the increased dosage of hydrogel contacts the increased treatment region. In this way, treatment based on the infected surface area of the sulcus evolves as the treatment progresses and the dose of medicament is based on the unique sulcus surface area of that individual patient. The scoring or rating system can also incorporate current diagnostic and treatment guidelines such as guidelines from the American Academy of Periodontology Staging and Grading guidelines to properly assess and diagnose periodontal disease for case management as described above. (See, for example, AAP 2017 Staging and Grading Periodontitis.)

[0210] In some embodiments, the oral appliance can have a dose of medicament therein that is based on patient specific biomarkers and / or cytokines (e.g., a medicament dose is a standardize dose to specific biomarkers like inflammatory biomarkers or cytokines). This can allow repeatability during manufacturing of the oral appliance and will allow quality control.

[0211] Having now generally described the invention, the same may be more readily understood through the following reference to the following example, which are provided by way of illustration and are not intended to limit the present invention unless specified. EXAMPLE

[0212] Pro-inflammatory mediators in gingival crevicular fluid (GCF) in the Emanate oral appliance. The Emanate oral appliance (e.g., oral tray), in some embodiments, has the following composition in Table 7 and is further described in U.S. Serial No. 18 / 114,559 entitled Polyvinyl alcohol compositions and methods of making and using them, which was filed on February 27, 2023. The entire contents of this application is hereby incorporated by reference into the present disclosure.. Table 7 Entitled Material Content (w / w) Range (w / w) PurposeGlycerol 7.3% 2%-9% Humectant CHG (chlorhexidine)005% 0005%-1% Preservative[002(GCF) levels of proinflammatory mediators and enzymes that are known to play a role in the tissue destruction, analysis of GCF were performed at the Forsyth Institute Multiplexing Core according to Standard Operating Procedures and established protocols. For this purpose, proinflammatory mediators including cytokines / chemokines (IL-1beta, IL-6, IL-8, IL-17A, TNF-alpha), matrix metalloproteinases (MMPs) including MMP-8 and MMP-9 were analyzed.

[0214] Crevicular fluid samples were obtained from 8 teeth with deepest pocket depths and bleeding on probing distributed between maxilla and mandible, with at least 2 sites in one arch at baseline and repeated on Day 56. GCF samples was collected using paper strips (PerioPaper). The sample strip was snap frozen in liquid nitrogen, and stored at -80°C until analysis.

[0215] 4 of the 8 sites were selected for GCF analysis. To optimize the GCF volume for all cytokines and MMPs (2 separate panels), samples collected from 2 maxillary sites (Site #2 and 3) and 2 mandibular sites (Sites #6 and 7) were pooled. Strips were eluted in 90 microliters of calibrator diluent RD6-

[0216] 40. Fifty (50) microliters were used per well and levels of pro-inflammatory mediators ( IL-1β, IL-6, IL-8, IL17A and TNF-α in GCF were determined using a Human Cytokine High Performance Kit (R&D Systems) and levels of matrix-metalloproteases (MMP)-8 and (MMP)-9 using Human High Sensitivity MMP kit (R&D Systems) by multiplexing immunoassay (Luminex). Raw data were obtained based on standard curves and cleaned for extrapolations, based on the assay sensitivity and presented as pg / mL

[0217] Statistical Analysis: Data for all GCF cytokines and matrix metalloproteinases were significantly non normal, thus analyses were conducted on log-transformed data. After log transformation MMP-8, MMP-9, IL- 1β, and TNF-α were not significantly non-normal by Kolmogorov-Smirnov normality test. The cytokines IL-6, IL- 8, IL-17A, were non- normal by Kolmogorov-Smirnov testing as well as Shapiro-Wilk tests, whereas TNF-α was significantly non-normal by Shapiro-Wilk tests, but not Kolmogorov-Smirnov, observation of the detrended Q-Q plot revealed that the highest 5 values disproportionately contributed to the non-normality. Thus, IL-6, IL-8, IL- 17A, and TNF-α were analyzed withnonparametric Wilcoxon rank sum tests. Mean cytokine levels were calculated by patient and by visit, collapsing across the two pooled sites. In paired t-tests only TNF-α was significantly different by pooled site, t(43) = 2.758, p=.009, the other cytokine levels did not differ by pooled site.

[0218] Results: Linear modeling, for variables that approximated a normal distribution, showed that participant metalloproteinase and cytokine levels significantly decreased from baseline to Visit 5, F(1,43)=13.62, p=.0007 for MMP-8, F(1, 43)=22.81, p<.0001 for MMP- 9, F(1,43)=21.30, p<0.001 for IL1β in Emanate Tray group.

[0219] Emanate Tray group and control group significantly differed for IL1β, F(1, 43)=15.94 p=.0003, with participants in Emanate Tray group having 0.18 ± 0.05 (SEM) log units (or an average of 324.4 ± 7.3 pg / mL original units), greater decrease from baseline to Visit 5, than controls. Test and control groups also significantly differed for MMP-9, F(1, 43)=4.40, p=0.04, with participants in the Emanate Tray group having a 0.13 ± 0.06 log unit greater decrease from baseline to Visit 5, or 72591.4 ± 121.4 pg / mL original units. MMP- 8 did not significantly differ between experimental groups, p=.13, ns.

[0220] Due to their non-normal distribution before and after log transformation, Wilcoxon signed-rank tests were performed for the cytokines IL-6, IL-8, IL-17, and TNF- α. All cytokine levels significantly decreased from baseline to Visit 5 for IL-6, z=3.98, p<.001, IL-8, z=3.57, p<.001, IL-17 z=3.47, p=.001, and TNF-α z=2.10, p=.036 in Emanate Tray group. Wilcoxon rank-sum tests showed that the difference between baseline and Visit 5 significantly differed for cytokines IL-6, z=1.97, p=.049 (Emanate Tray group had a 3.67 pg / mL greater decrease), and IL17A, z=2.34, p=.019 (Emanate Tray group had a 1.02 pg / mL greater decrease from baseline to Visit 5), with participants in the Emanate Tray group having a greater reduction in cytokine levels. Levels of IL-8, z=1.70, p=.09, and TNF- α, z=1.15, p=.25 did not significantly differ between the experimental groups. FIGS.14, 15 and 16 illustrate and embodiment of use of the oral appliance that had significant reduction in selected cytokines and / or matrix metalloprotease enzymes (MMPs). FIG. 14 shows the change in IL-1β and IL-8 in the GCF on day 56 compared to a control. FIG. 15 shows the change in TNF-α, IL-6 and IL-17 in the GCF on day 56 compared to a control. FIG. 16 shows the change in MMP-8 and MMP-9 in the GCF on day 56 compared to a control.

[0221] While particular embodiments of the present disclosure have been shown and described, it will be appreciated by those skilled in the art that, based upon the teachings herein, changes and modifications may be made without departing from this disclosure and its broader aspects and, therefore, the appended claims are to encompass within their scopeall such changes and modifications as are within the true spirit and scope of this disclosure. The true spirit and scope is considered to encompass devices and processes, unless specifically limited to distinguish from known subject matter, which provide equivalent functions as required for interaction with other elements of the claims and the scope is not considered limited to devices and functions currently in existence where future developments may supplant usage of currently available devices and processes yet provide the functioning required for interaction with other claim elements.

Claims

WHAT IS CLAIMED IS:

1. An oral appliance for delivering a medicament to an oral cavity, the oral appliance comprising an exterior and an interior, the interior of the oral appliance configured to contour at least a portion of teeth and / or soft tissue of the oral cavity; and a volume of the medicament being disposed in a hydrogel at a selected dose within the interior based on dimensions of at least a portion of the teeth and / or soft tissue.

2. The oral appliance of claim 1, wherein the selected dose is a custom dose and the dimensions are custom dimensions of at least a portion of the teeth and / or soft tissue of a patient.

3. The oral appliance of claim 1, wherein the selected dose is a uniform dose that can be universally administered to a patient.

4. The oral appliance of claim 1, wherein the medicament is disposed in a channel of the interior or at discrete regions of the interior.

5. The oral appliance of claim 4, wherein the oral appliance comprises a barrier for providing a seal between the channel and at least a portion of the teeth and / or the soft tissue areas of the oral cavity.

6. The oral appliance of claim 4, wherein each of the discrete regions of the interior contact surfaces of a plurality of gingival sulcus when the oral appliance is worn.

7. The oral appliance of claim 1, wherein the dimensions of at least a portion of the teeth and / or soft tissue include dimensions of a gingival sulcus.

8. The oral appliance of claim 1, wherein the dimensions include a height, a width and a depth of the teeth, soft tissue and / or a gingival sulcus.

9. The oral appliance of claim 1, wherein the dimensions of the portion of the teeth and / or soft tissue to be treated are measured to calculate a surface area to determine theselected dose and have at least a portion of the dose in an amount to contact the portion of the teeth and / or soft tissue.

10. The oral appliance of claim 1, wherein the selected dose of the medicament is in a 1:1 ratio with the hydrogel.

11. The oral appliance of claim 1, wherein the selected dose of the medicament is in a 0.5:1 ratio with the hydrogel.

12. The oral appliance of claim 1, wherein the medicament disposed in the hydrogel is uniformly disposed within the interior.

13. The oral appliance of claim 1, wherein the volume of medicament includes a uniform dose that can be a universal dose administered to any patient.

14. The oral appliance of claim 1, wherein the interior of the oral appliance includes a zero point marker having a width, a depth and a height for loading the oral appliance with the medicament.

15. The oral appliance of claim 1, wherein the oral appliance can be worn by an adult and / or an adolescent patient.

16. The oral appliance of claim 1, wherein the oral appliance includes a projection and / or recess configured for manipulation of the oral appliance.

17. The oral appliance of claim 16, wherein the projection and / or recess comprises a handle, a gripping surface, or a combination thereof configured to mate with a robotic arm of a robotic dispensing device or be manually manipulated by hand.

18. A method of making an oral appliance for delivering a medicament to an oral cavity, the method comprising providing an oral appliance having an exterior and an interior, the interior of the oral appliance configured to contour at least a portion of teeth and / or soft tissue areas of the oral cavity; calculating a selected dose; providing a volume of the medicament disposed in a hydrogel at the selected dose; providing a dispensingdevice having an outlet configured to dispense medicament at discrete regions of the interior based on custom dimensions of at least a portion of the teeth and / or soft tissue of a patient, the exterior or both the interior and the exterior of the oral appliance; and disposing the volume of the medicament within the interior based on dimensions of at least a portion of the teeth and / or soft tissue using the dispensing device.

19. The method of claim 18, wherein the dispensing device comprises a robotic arm coupled to the outlet to dispense a precise dose of the medicament at the discrete regions of the oral appliance.

20. The method of claim 18, wherein each of the discrete regions of the interior contact surfaces of a treatment area including a plurality of gingival sulcus for a human patient.

21. The method of claim 18, wherein the dimensions of at least a portion of the teeth and / or soft tissue include dimensions of a gingival sulcus.

22. The method of claim 18, wherein the dimensions include a height, a width, a depth, and a surface of the teeth, soft tissue and / or a gingival sulcus.

23. The method of claim 18, wherein the dimensions of the portion of the teeth and / or soft tissue to be treated are measured to calculate a surface area to determine a selected dose of the medicament.

24. The method of claim 18, wherein the oral appliance comprises an actual or virtual channel configured to receive the medicament from the outlet of the robotic dispensing device.

25. The method of claim 18, wherein the channel is continuous in the interior of the oral appliance and extends along a gum line perimeter.

26. The method of claim 18, wherein portions of the oral cavity and / or portions of the oral appliance can be defined by at least Cartesian coordinates X, Y and Z to form a guideline for guiding the robotic arm of the robotic dispensing device to dispense the medicament at discrete regions of the oral appliance.

27. The method of claim 18, wherein before the medicament is dispensed, the oral appliance is made by thermoforming, additive manufacturing, or injection molding.

28. A method of treating at least a portion of teeth and / or soft tissue of an oral cavity, the method comprising providing an oral appliance, the oral appliance having an exterior and an interior, the interior of the oral appliance configured to contour at least a portion of teeth and / or soft tissue areas of the oral cavity; providing a medicament disposed in a hydrogel at a selected dose, the medicament disposed within the interior based on dimensions of at least a portion of the teeth and / or soft tissue; and inserting the oral appliance within the oral cavity of a patient.

29. The method of claim 28, wherein the dimensions of the portion of the teeth and / or soft tissue to be treated are measured to calculate a surface area to determine the selected dose.

30. The method of claim 28, wherein the dimensions of at least a portion of the teeth and / or soft tissue include dimensions of a gingival sulcus.

31. The method of claim 28, wherein the dimensions include a height, a width, a depth, and a surface area of the teeth, soft tissue and / or a gingival sulcus.

32. A computer implemented method of producing an oral appliance pre-loaded with at least one medicament having a selected dose using a computer, the computer implemented method comprising creating a digital image of at least a portion of the teeth and / or soft tissue areas of the oral cavity to be treated using an imaging device; generating a surface area of the portion of the teeth and / or soft tissue areas of the oral cavity to be treated based on the digital image; calculating a selected standardized dose for the generated surface area; generating an instruction to dispose the selected standardized dose at the portion of the teeth and / or soft tissue areas of the oral cavity to be treated; and producing the oral appliance having the medicament with the selected standardized dose disposed in or on at least a portion and / or all of the interior surface of the oral appliance.

33. The computer implemented method of claim 32, wherein the image was created by obtaining a baseline digital image of the portion of the teeth and / or soft tissue areas of the oral cavity to be treated using an imaging device.

34. The computer implemented method of claim 33, wherein the method further comprises obtaining a first digital image of the oral appliance corresponding to at least a portion of the teeth and / or soft tissue areas of the oral cavity to be treated, creating a second digital image based on a baseline image corresponding to the portion of the teeth and / or soft tissue areas of the oral cavity to be treated with the medicament; combining the first digital image and the second digital image to form a third digital image of the oral appliance that comprises a treatment area for treatment with the medicament and storing the third digital image in the computer; instructing the computer to produce the oral appliance from at least the stored third digital image; and producing the oral appliance layering each layer of the oral appliance and layering the medicament in or at least a portion and / or all of the interior surface of the oral appliance so that the medicament is disposed in or on at least a portion and / or all of the interior surface of the oral appliance.

35. The computer implemented method of claim 32, wherein the calculating includes assigning a rating or score of select parameters to the treatment area including, a surface area, a size, a depth, a shape, severity of disease, and / or a therapeutic index of the medicament and wherein the layering of the medicament is in a pattern of the interior of the oral appliance based on the assigned rating or score.

36. The computer implemented method of claim 32, wherein the method further comprises directing a 3D printer to produce the oral appliance containing the at least one medicament.

37. A system for dispensing a medicament having a standardized dose into or on an oral appliance, the system comprising a robotic dispensing device having an outlet configured to dispense medicament having a standardized dose at discrete regions of an interior, an exterior or both the interior and the exterior of an oral appliance; one or more sensors mounted on the robotic dispensing device, the one or more sensors configured to detect a marker for registering a position of the oral appliance; a processor configured to receive and process input from the one or more sensors; and a controller operativelyconnected to the processor and configured to operate the robotic dispensing device, at least in part, on input from the one or more sensors and processed by the processor, wherein the robotic dispensing device is configured to dispense from the outlet the medicament having a standardized dose at discrete regions of an interior, an exterior or both the interior and the exterior of an oral appliance.

38. The system of claim 37, wherein the robotic dispensing device comprises a robotic arm coupled to the outlet to dispense a precise dose of the medicament at the discrete regions of the oral appliance.

39. The system of claim 37, wherein the discrete regions are adjacent to a treatment area and the medicament is configured to contact the treatment area.

40. The system of claim 37, wherein the oral appliance comprises an actual or virtual channel configured to receive the medicament from the outlet of the robotic dispensing device.

41. The system of claim 38, wherein the channel is continuous in the interior of the oral appliance and extends along a gum line perimeter.

42. The system of claim 37, wherein the oral appliance comprises a marker for registering the position of the oral appliance with the robotic dispensing device.

43. The system of claim 37, wherein the oral appliance comprises a projection and / or recess configured for manipulation of the oral appliance.

44. The system of claim 43, wherein the projection and / or recess comprises a handle, a gripping surface, or a combination thereof configured to mate with the robotic arm of the robotic dispensing device or be manually manipulated by hand.

45. The system of claim 43, wherein the projection and / or recess is removable from the oral appliance or remains and is configured as a handle for the patient.

46. The system of claim 37, wherein the oral appliance comprises a barrier for providing a seal between the channel and at least a portion of the teeth and / or the soft tissue areas of the oral cavity.

47. The system of claim 42, wherein the marker is a zero-point marker for registering the position of the oral appliance with the robotic dispensing device.

48. The system of claim 38, wherein portions of the oral cavity and / or portions of the oral appliance can be defined by at least Cartesian coordinates X, Y and Z to form a guideline for guiding the robotic arm of the robotic dispensing device to dispense the medicament at discrete regions of the oral appliance.

49. The system of claim 39, wherein each tooth of the oral cavity and / or oral appliance can be defined (i) by at least 10 Cartesian coordinates or (ii) by one or more Cartesian points.

50. The system of claim 37, wherein the one or more sensor comprises a camera or an imaging device.

51. The system of claim 37, wherein the processor: (i) creates a first digital image of the oral appliance (Dig1) based on a baseline image of a patient’s oral cavity of at least a portion of the patient’s teeth and / or soft tissue, and the processor generates a second digital image (Dig2) corresponding to at least a portion of the patient’s oral appliance that requires dispensing medicament; and (ii) combines the first digital image (Dig1) with the second digital image (Dig2) to form a third digital image (Dig3) for enabling the robotic dispensing device to dispense the medicament at the discrete regions of the oral appliance.

52. The system of claim 51, wherein each tooth and / or other anatomical part of the oral cavity can be defined by from about 1 to about 50 points, each point defined by at least Cartesian coordinates X, Y and Z that are sent to the processor to generate a guideline (Dig2a).

53. The system of claim 52, wherein the second digital image (Dig2) of the patient’s oral appliance can be combined with the digital image of the guideline (Dig2a) to facilitate dispensing of the porous material at discrete regions of the oral appliance.

54. The system of claim 52, wherein the third digital data (Dig3) is formed by one of (i) subtracting the second digital data (Dig2) from the first digital data (Dig1) or (ii) adding the second digital data (Dig2) to the first digital data (Dig1).

55. The system of claim 52, wherein the third digital data (Dig3) is formed by one of (i) subtracting the second digital data (Dig2) and the digital image of the guideline (Dig2a) from the first digital data (Dig1) or (ii) adding the second digital data (Dig2) and the digital image of the guideline (Dig2a) to the first digital data (Dig1).

56. The system of claim 52, wherein creating the first digital record (Dig1) of the patient’s oral cavity comprises taking an impression of the patient’s oral cavity using materials comprising alginate, polyvinyl, silicone or a combination thereof.

57. The system of claim 52, wherein obtaining the baseline digital image of at least a portion of the patient’s teeth and / or soft tissue of the patient’s oral cavity further comprises digitally storing a permanent record of the topography of least a portion of the patient’s teeth, and / or soft tissue of the patient’s oral cavity for future iterations of oral appliances.

58. The system of claim 52, wherein creating the digital record of the patient’s oral cavity comprises utilizing imaging devices including at least one of a digital camera, X- ray device, hand-held 3-D scanner, laser scanner, computed tomography (CT) scanner, magnetic resonance imaging (MRI) scanner, coordinate measuring machine, destructive scanner or ultrasound scanner.

59. The system of claim 37, wherein the robotic dispensing device is controlled by artificial intelligence.

60. The system of claim 37, wherein the medicament is in a hydrogel that is cured during dispensing of the hydrogel or after dispensing the hydrogel.

61. The system of claim 37, wherein the outlet of the robotic dispensing device is configured to dispense the medicament in a hydrogel at discrete regions of the interior, the exterior or both the interior and the exterior of the oral appliance.

62. A method of making a standardized dose of a medicament for an oral appliance, the method comprising obtaining a digital image of at least a portion of the teeth and / or soft tissue of the oral cavity; identifying a surface area of at least a portion of the teeth and / or soft tissue of the oral cavity to be treated; calculating the surface area to be treated with a medicament; generating a virtual model of the oral appliance having the volume of medicament having the standardized dose disposed in the oral appliance; generating a volume of medicament having a standardized dose corresponding to the surface area to be treated; and producing an oral appliance and disposing the volume of medicament having the standardized dose on the at least a portion of the teeth and / or soft tissue of the oral cavity.

63. The method of 62, wherein the surface area is identified by a processor configured to process the digital image.

64. The method of 62, wherein the digital image is obtained through an image analysis of a plurality of images taken in the oral cavity.

65. The method of 62, wherein the volume of the medicament is calculated based on a therapeutic index of the medicament, size, width, depth of the surface area to be treated, weight of the patient, and / or severity of disease.

66. The method of 62, wherein the volume of the medicament is calculated based on the surface area of at least a portion of the teeth and / or soft tissue of the oral cavity to be treated.

67. The method of 62, wherein the volume of the medicament is calculated based on a scoring or rating which includes the surface area of at least a portion of the teeth and / or soft tissue of the oral cavity to be treated.

68. The method of 62, wherein the volume of the medicament is calculated based on a topography of the oral appliance custom made to an oral cavity.

69. The method of 62, wherein the volume of the medicament is calculated based on a past response of a patient.

70. A system for delivering a medicament having a standardized dose to an inflamed tissue of an oral cavity, the system comprising a first oral appliance comprising an exterior and an interior, the interior of the oral appliance configured to contour at least a portion of teeth and / or soft tissue of the oral cavity; and a volume of the medicament being disposed in a hydrogel at a selected dose within the interior based on first dimensions of at least a portion of the teeth and / or soft tissue; and a second oral appliance comprising an exterior and an interior, the interior of the oral appliance configured to contour at least a portion of teeth and / or soft tissue of the oral cavity; and a second volume of the medicament being disposed in a hydrogel at a second selected dose within the interior based on second dimensions of at least a portion of the teeth and / or soft tissue after an application of the first oral appliance.

71. The system of claim 70, wherein the selected dose is determined by a surface area of the at least a portion of the teeth and / or soft tissue.

72. The system of claim 70, wherein the portion of the teeth and / or soft tissue to be treated is sulcus.

73. The oral appliance of any one of claims 1-17, wherein the oral appliance is used to treat an adult or pediatric human patient.

74. The method of any one of claims 18-31 or 62-69, wherein the oral appliance is used to treat an adult or pediatric human patient.

75. The system of any one of claims 37-61 or 70-72, wherein the oral appliance is used to treat an adult or pediatric human patient.

76. The computer implemented method of any one of claims 32-36, wherein the oral appliance is used to treat an adult or pediatric human patient.

77. The oral appliance of any one of claims 1-17, wherein the medicament is in a dose based on a patients biomarker or cytokine level.

78. The oral appliance of any one of claims 1-17, wherein the medicament and / or hydrogel can be added to one or more oral appliances in a repeatable manner so as to provide repeatability in the manufacturing of the one or more oral appliances.

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