Patent Publication Number: US-2020290790-A1

Title: Thermally insulating packaging system

Description:
1. BACKGROUND 
     Thermally insulating packaging can be utilized to store and transport materials while maintaining the materials within a desired temperature range. Several factors can affect the performance of a thermally insulating packaging, for example the thermal characteristics of the transport materials, the insulation materials, and the external temperatures. Packages may be subject to freezing and elevated temperatures during transport, e.g., through different global regions by both surface and air carriers. 
     Veterinary companies, pharmaceutical companies, medical transportation companies and others have need to transport quantities of temperature-sensitive products that must be kept cool in transport but which cannot be allowed to freeze. It has become more common in the pharmaceutical marketplace to transport and/or store medications at refrigerated temperatures, e.g., from manufacturer&#39;s distribution to vendors, during pharmacy and patient transport, etc. Temperature-sensitive products intended for storage may be in liquid or solid form, and the manufacturer and/or distributor are typically responsible for maintaining the transport temperature ranges specified for the product (e.g., drug) stability and use. 
     Prior art packages for transporting such temperature-sensitive materials, including those employing water ice or dry ice in a container with such materials, do not provide extended periods of temperature stability. Such periods cannot be extended by simply adding more water ice or dry ice, as doing so may create issues with freezing the temperature sensitive material, or creating excess water of sublimated carbon dioxide during extended periods. Consequently, shipping such prior art packages often required either expensive expedited shipping so that delivery took place before the temperature limits were exceeded, or active maintenance of the shipping container during the course of shipment to maintain the desired temperature range. In some cases this made it impractical to ship prior art packages over weekends or holidays, in certain climates, or to remote or distant destinations. In addition to excessive shipping cost, unexpected delays in delivery could result in the temperature sensitive materials being ruined or being suspect. Therefore, a relatively inexpensive package system and method is needed to extend the period that a particular temperature range can be maintained for temperature sensitive material for extended periods. 
     2. SUMMARY 
     In an aspect, a thermally insulating packaging system is provided that maintains within a closed environment a target temperature range that is different and/or more uniform than the temperature of the environment external to the system, such as a temperature range that is lower than the temperature of the environment external to the system. Such a system can be used for transport of temperature-sensitive materials within the closed environment for an extended period of time. The packaging system, in some embodiments, includes one or more of the following components: a case having an inner chamber, the case and/or inner chamber having multiple sides and an opening; a lid or other closure sized and shaped for mating with and closing the opening to create the closed environment; a cooling layer having inner and outer surfaces, the outer surface disposed on a surface of the inner chamber; and an insulating layer having inner and outer surfaces, the outer surface disposed on an inner surface of the cooling layer. The cooling and insulating layers each may or may not be removable. The insulating layer may provide cushioning for contents of the inner chamber. 
     In another aspect, the closed environment has the shape of a closed box defined by six substantially planar surfaces and the cooling layer and the insulating layer are disposed on four of the six substantially planar surfaces. In some aspects, the two substantially planar surfaces not disposed with the cooling layer and the insulating layer are non-adjacent to one another. 
     In another aspect, the closed environment is a closed box defined by six substantially planar surfaces and the cooling layer and insulating layer are disposed on two of the six substantially planar surfaces, which may be non-adjacent surfaces. 
     In certain aspects, the cooling layer and insulating layer are disposed on five of the six substantially planar surfaces and the substantially planar surface not disposed with the cooling layer and the insulating layer is the bottom inner surface of the closed box opposite the lid. In particular aspects, one of the substantially planar surfaces disposed with the cooling layer and the insulating layer is the top inner surface of the closed box coinciding with the lid, and four of the substantially planar surfaces disposed with the cooling layer and the insulating layer is the inner surface of the sides of the closed box. 
     In another aspect, the cooling layer comprises multiple panels, each panel having a cooling capacity, wherein each panel is disposed on one of the substantially planar surfaces of an inner surface of the closed box. In certain instances, two panels having the same cooling capacity are placed opposite each other on non-adjacent sides of the inner surface of the closed box. 
     Implementation of the thermally insulating packaging system provided herein may include one or more of the following features. The case and lid may comprise an insulating material, such as polystyrene or polyurethane, and may further comprise a covering, such as polypropylene or polyethylene. The cooling layer can be a ductile pouch that comprises ice or a gel formulation. The insulating layer can be a ductile pouch that comprises a cellulose material. An optional cushioning and/or thermally insulating layer, such as air embedded polyethylene, may be disposed on the inner surface of the insulating layer. And the temperature-sensitive material may be disposed on the insulating layer or, if present, on the cushioning layer. In some instances, the temperature-sensitive material is surrounded or wrapped in the insulating later and/or the cushioning layer. 
     In certain aspects, the temperature-sensitive material can be a perishable food product, a biological material, a human pharmaceutical product, or a veterinary pharmaceutical product. In certain aspects, the temperature-sensitive material is a pharmaceutical or veterinary pharmaceutical product, such as insulin, vaccines, tresaderm, proparicaine, or a human organ for transport. 
     In another aspect, the target temperature for storing and transporting temperature-sensitive materials ranges from about 0.5° C. to about 8° C. for an extended period of time from about 48 hours to about 72 hours, in ambient conditions that may be either higher or lower than that temperature range. 
     Also provided herein is a method for packaging a temperature-sensitive material for storage or transport at a target temperature. The method, in some instances, includes one or more of the following steps: placing a cooling layer within an inner chamber of a case, the inner chamber having multiple sides and an opening, the cooling layer being placed against two adjacent or non-adjacent sides or portions of the inner chamber; placing a temperature-sensitive material into the inner chamber through the opening; and closing the opening to form a closed environment. 
     Also provided herein is a method for packaging a temperature-sensitive material for storage or transport at a target temperature. The method, in some instances, includes one or more of the following steps: wrapping a temperature-sensitive material in a cushioning and/or insulating layer; placing the wrapped temperature-sensitive material within an inner chamber of a case, the inner chamber having the shape of an open box with a bottom and four sides and an opening, the wrapped temperature-sensitive material placed into the inner chamber through the opening; placing an insulating layer against an outer surface of the cushioning layer through the opening; placing a first cooling layer within the inner chamber, an outer surface of the first cooling layer being placed against the four sides of the inner chamber and an inner surface of the first cooling layer being placed against an outer surface of the insulation layer through the opening; placing a second cooling layer within the inner chamber, the second cooling layer being placed on top of the insulation layer through the opening; and closing the opening with a lid to form a closed environment. In some aspects, an additional cushioning layer is placed on top of the second cooling layer to fill the headspace of the closed environment. 
     The methods can further include additional steps, such as placing an insulating layer against an inner surface of the cooling layer and wrapping the temperature-sensitive material in a cushioning layer prior to placing the temperature-sensitive material into the inner chamber. The cooling layer, the temperature-sensitive material, and/or any portion of the packaging system can be pre-cooled to a temperature suitable for achieving the target temperature within the closed environment for the desired extended period of time. In some aspects, the insulating layer can serve as a cushioning layer. 
     The inventors have found, surprisingly, that permitting air circulation in the closed environment of the inner chamber can dramatically increase the length of time that a target temperature range may be maintained. Without wishing to be bound by any particular theory as to the cause of this discovery, the inventors believe that air circulation ensures that any temperature differences between relatively warm and cold areas are reduced, such as where gaps or thermal bridges may be present in the insulating layer, where sides do not include a cooling layer, and/or where the exterior of the package is exposed to different ambient temperatures at different places. Consequently, in some aspects, the various layers described herein may be perforated, or the fit among different components of the layers may allow gaps, to allow convection air currents to flow. 
     The inventors have also found, surprisingly, that condensation of water or the sublimation of frost from moisture in air inside the package onto the cooling elements may increase the length of time that a target temperature range may be maintained. Without wishing to be bound by any particular theory as to the cause of this discovery, the inventors believe that water or frost may serve to insulate the cooling elements and simultaneously prevent freezing, even under freezing external temperatures, while slowing the rate of temperature loss from those elements. Consequently, in some aspects of the invention, the humidity of the air in the inner chamber is controlled to provide sufficient moisture and/or a source of additional moisture may be provided, such liquid water or a damp material or layer(s). Without wishing to be bound by any particular theory as to the cause of these discoveries, the inventors believe that air circulation and condensation/sublimation work in tandem to promote greater thermal stability in the package. 
     The inventors have also surprisingly found that an arrangement of cooling and insulating layers that permits flow of dense cool air passing from the cooling layers through temperature-sensitive material and out the bottom of the case may increase the length of time that a target temperature range may be maintained without over cooling. In some aspects, as cooling layers continue to absorb thermal energy they begin to soften and fluidly deform to each other and to the contours to the outer surface of the temperature-sensitive material, prolonging the cooling process. 
    
    
     
       3. BRIEF DESCRIPTION OF THE FIGURES 
         FIG. 1  is a perspective view of an outer case and lid of a thermally insulated packaging system in an open position. 
         FIG. 2  is a bottom view of a lid of the thermally insulated packaging system of  FIG. 1 . 
         FIG. 3  is an exploded view of a temperature-sensitive material packaged in the inner chamber of the thermally insulated packaging system of  FIG. 1  having one cooling and insulating layer. 
         FIG. 4  is an exploded view of a temperature-sensitive material packaged in the inner chamber of the thermally insulated packaging system of  FIG. 1  having two cooling and insulating layers. 
         FIG. 5  is an exploded view of a temperature-sensitive material packaged in the inner chamber of the thermally insulated packaging system of  FIG. 1  having three cooling and insulating layers. 
         FIG. 6  is an exploded view of a temperature-sensitive material packaged in the inner chamber of the thermally insulated packaging system of  FIG. 1  having four cooling and insulating layers. 
         FIG. 7  is an exploded view of a temperature-sensitive material packaged in the inner chamber of the thermally insulated packaging system of  FIG. 1  having five cooling and insulating layers. 
         FIG. 8  is an exploded view of a temperature-sensitive material packaged in the inner chamber of the thermally insulated packaging system of  FIG. 1  having six cooling and insulating layers. 
         FIG. 9  is a top view of a case of the thermally insulated packaging system of  FIG. 1  in an open position having no cooling and insulating layers on the side walls of the inner chamber. 
         FIG. 10  is a top view of a case of the thermally insulated packaging system of  FIG. 1  in an open position having one cooling and insulating layer on the side walls of the inner chamber. 
         FIG. 11  is a top view of a case of the thermally insulated packaging system of  FIG. 1  in an open position having two non-adjacent or opposite facing cooling and insulating layers on the side walls of the inner chamber. 
         FIG. 12  is a top view of a case of the thermally insulated packaging system of  FIG. 1  in an open position having two adjacent facing cooling and insulating layers on the side walls of the inner chamber. 
         FIG. 13  is a top view of a case of the thermally insulated packaging system of  FIG. 1  in an open position having three cooling and insulating layers on the side walls of the inner chamber. 
         FIG. 14  is a top view of a case of the thermally insulated packaging system of  FIG. 1  in an open position having four cooling and insulating layers on the side walls of the inner chamber. 
         FIG. 15  is a cross section about the xz-plane of the packaged temperature-sensitive material of  FIG. 7  with an additional cooling layer. 
         FIG. 16  is a variant of the packaged temperature-sensitive material of  FIG. 15  stowed in the inner chamber of the case in closed position. 
         FIG. 17  is a cross section about the xy-plane of the packaged temperature-sensitive material of  FIG. 7 . 
         FIG. 18  is a variant of the packaged temperature-sensitive material of  FIG. 17  stowed in the inner chamber of the case. 
         FIG. 19  is the stowed and packaged temperature-sensitive material of  FIG. 16  showing the flow of cooling air. 
         FIGS. 20A-C  are graphical representations of the results of the six panel summer temperature testing depicting temperature (° C.)(y-axis) and time (hours)(x-axis) with Distemper (A), Parainfluenza (B), and VETSULIN® (C) as temperature-sensitive materials, respectively. 
         FIG. 21  is a graphical representation of the results of the four panel summer temperature testing depicting temperature (° C.)(y-axis) and time (hours)(x-axis). 
         FIG. 22  is a graphical representation of the results of the single panel winter temperature testing depicting temperature (° C.)(y-axis) and time (hours)(x-axis). 
         FIG. 23  is a graphical representation of the results of the four panel cooler live temperature testing depicting temperature (° C.)(y-axis) and time (hours)(x-axis). 
     
    
    
     4. DETAILED DESCRIPTION 
     4.1. Definitions 
     As used herein, the following terms are intended to have the following meanings: 
     The articles “a” and “an” are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. 
     The term “and/or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise. 
     “About” refers to an approximate value. For example, “about” can include a value ±0.5° C. of the recited value. 
     The term “cooling capacity” refers to a measure of the ability of a cooling layer or panel, as described herein, to remove heat from a closed environment, as described herein. The cooling capacity of a particular layer or panel may be varied by, for example, freezing the layer or panel at different temperatures. 
     The term “substantially planar” refers to a surface that may be uneven, e.g., including localized depressions, bumps, or divots, but is generally flat or two-dimensional in shape with regard to the whole surface. A “substantially planar” surface may also not be precisely flat over its whole surface. For example, a “substantially planar” surface can include a slightly concave or convex surface that deviates from flatness by less than about 10 degrees. 
     Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. 
     4.2. Thermally Insulating Packaging System 
     Provided herein is a thermally insulating packaging system to store and transport temperature-sensitive materials within a temperature-controlled environment (e.g., a cooled or refrigerated environment with respect to the environment external to the system). In particular, certain embodiments provide techniques for storing and transporting temperature-sensitive materials in a relatively stable, refrigerated environment for extended periods of time using one or more cooling layers such as ice packs, cooling gel packs, etc. and one or more thermal insulating layers comprising a one or more insulating materials (such as a cellulose material), closed or open cell insulators, thermal breaks, a reflective layer, etc. 
     For example, a thermally insulating packaging system for transporting temperature-sensitive materials in a cool environment may include an insulated case having an inner chamber with removable cooling and insulating layers. The cooling and insulation layers may be arranged in such a way as to maintain a target temperature or temperature range isolated from outside ambient temperature conditions, for example a target temperature that ranges from about 0.5° C. to about 8° C. for about 48 hours to about 72 hours. Other embodiments are within the scope of the present disclosure. 
     The thermally insulating packaging system provided herein can be fabricated in various shapes and forms. In some embodiments, the thermally insulating packaging system includes a case that can be provided as a hard or soft square or rectangular box of various dimensions having pointed or rounded edges and corners. In some embodiments, the case can be provided as an envelope, bag, or pouch that is either soft and flexible or rigid or semi-rigid in shape. 
     In some embodiments, the thermally insulating packaging system is that shown in 
       FIGS. 1-2 . Referring to  FIGS. 1-2 , the thermally insulating packaging system includes insulated case  1  and lid  3  that operably covers an opening to inner chamber  5  that provides a temperature-controlled environment for a temperature-sensitive material. The opening can be any shape or size that allows insertion of the temperature-sensitive materials through the opening into the inner chamber. In some embodiments, the opening to the inner chamber may be triangular, square, hexagonal, or rectangular with pointed or rounded corners, or oval or circular. In some embodiments the underside of lid  3  includes an appropriately sized and shaped raised area  6  that both increases the insulating performance of lid  3  and provides snug mating with case  1 . In some embodiments, the snug mating of lid  3  and case  1  creates a closed environment providing further insulating performance by reducing heat loss. In some embodiments, lid  3  can be permanently or reversibly attached or tethered to case  1  using one or more hinges, fasteners, zippers, straps, and the like. In some embodiments, the lid is separate and removable. In some embodiments, the lid is connected, e.g., via a hinge or strap, and closed via fasteners, Velcro, adhesive, etc. In other embodiments, there is no lid and the case is a pouch, bag, or envelope that closes by ziplock, Velcro, adhesive, etc. In another embodiment, in lieu of or in addition to a lid for creating a closed environment, the opening may be covered by a door or flap, or the opening may be closed by deforming one or more side(s) of the case or chamber. In some embodiments, the opening may closed and be folded or rolled to form the closed environment. In another embodiment, the thermally insulating packaging system may be integrally manufactured such that some or all portions are not removable in ordinary operation. In some embodiments, the closed environment may have the shape of a closed box, round cylinder, a hexagonal cylinder, or any other closed form, including a bag, envelope, or pouch. In some embodiments, case  1  and lid  3  are fabricated from one or more types of insulation materials such as a vacuum insulated material, silica aerogel, expanded polyurethane, expanded polyisocyanurate, closed-cell polyurethane, phenolic foam, thinsulate™, urea foam, urea-formaldehyde foam, icynene foam, open-cell polyurethane, extruded polystyrene, polyurethane foam, polyethylene foam, expanded polystyrene, cardboard, laminated polyurethane foam, laminated expanded polystyrene, molded plastics, etc. In some embodiments, case  1  and lid  3  further comprise one or more coverings or films on outer surfaces of the case and the lid, such as various plastic coverings, including a polypropylene or polyethylene covering and/or thermally reflective materials such as metallized mylar. The one or more coverings or films may also cover the inner surface of the inner chamber. In further embodiments, mated case  1  and lid  3  forming a closed environment can be placed into a cellulose container, such as a cardboard box, and prepped and sealed for shipment. In some embodiments, the mated case  1  and lid  3  fits into the cellulose container with a snug fit. 
     In further aspects, the thermally insulating packaging system provided herein includes an arrangement of removable cooling and/or insulating layers disposed on the inner surface of the inner chamber of the case of the thermally insulating packaging system. In some embodiments, the removable cooling layer comprises inner and outer surfaces, the outer surface disposed on a surface of the inner chamber. In some embodiments, the removable insulating layer comprises inner and outer surfaces, the outer surface disposed on the inner surface of the cooling layer. Referring to  FIGS. 3-8 , temperature-sensitive material  9  (shown having a cube shape in exploded view for clarity, but not necessarily having a cube shape in practice) can be stowed in the inner chamber of the case of the thermally insulating packaging system including one to six cooling and insulating layers disposed upon six substantially planar surfaces. In particular embodiments when the closed environment has the shape of a closed box, one substantially planar surface includes the bottom of the closed box, one substantially planar surface includes the top of the closed box, and four substantially planar surfaces include the sides of the closed box. In some embodiments, the one or more of the six substantially planar surfaces may be comprised of a curved surface. In some embodiments, the thermally insulating packaging system can include temperature-sensitive material  9  and one insulating layer  11  and cooling layer  12 . In some embodiments, the thermally insulating packaging system can include temperature-sensitive material  9  and two insulating layers  11  and  13 , and cooling layers  12  and  14 . In some embodiments, the thermally insulating packaging system can include temperature-sensitive material  9  and three insulating layers  11 ,  13 , and  15 , and cooling layers  12 ,  14 , and  16 . In some embodiments, the thermally insulating packaging system can include temperature-sensitive material  9  and four insulating layers  11 ,  13 ,  15 , and  17 , and cooling layers  12 ,  14 ,  16 , and  18 . In some embodiments, the thermally insulating packaging system can include temperature-sensitive material  9  and five insulating layers  11 ,  13 ,  15 ,  17 , and  19 , and cooling layers  12 ,  14 ,  16 ,  18 , and  20 . In some embodiments, the thermally insulating packaging system can include temperature-sensitive material  9  and six insulating layers  11 ,  13 ,  15 ,  17 ,  19 , and  21 , and cooling layers  12 ,  14 ,  16 ,  18 ,  20 , and  22 . In certain embodiments, the one or more cooling layers are disposed between the one or more insulating layers and the one or more surfaces of the inner chamber of the case. In some embodiments, the one or more insulating layers are disposed between the one or more cooling layers and the temperature-sensitive material. 
     In another embodiment, any two or more of the cooling layers, the insulating layers, or both the cooling layers and the insulating layers are permanently or reversibly/releasably connected. In some embodiments, two or more of the cooling layers are permanently or reversibly/releasably connected, such that the outer surfaces of the two or more cooling layers are disposed on two or more surfaces of the inner chamber. In some embodiments, two, three, four, or five cooling layers are permanently or reversibly/releasably connected forming a multi-surfaced cooling structure that surrounds the temperature-sensitive material while providing one or more surfaces of the inner chamber not covered with cooling layers in order to permit increased air circulation. 
     In certain embodiments, with respect to  FIGS. 3-8  above, temperature-sensitive material  9  and the associated insulating and cooling layers are stowed in the inner chamber of the case of the thermally insulating packaging system as depicted or rotated in 90 degree increments about the x-, y-, or z-axis, with the x- and y-axes corresponding to the x-axis (i.e., horizontal) and y-axis (i.e., vertical) of the page, respectively, and the z-axis corresponding to the z-axis with respect to the page (i.e., perpendicular to the x- and y-axes and extending perpendicularly into and out of the page). The x- and y-axes together define a vertically- and horizontally-extending plane that coincides with the page (“xy-plane”); the x- and z-axes together define a plane that extends horizontally and perpendicularly into and out of the page (“xz-plane”); and the y- and z-axes together define a plane that extends vertically and perpendicularly into and out of the page (“yz-plane”). For example, insulating layer  11  and cooling layer  12  of  FIG. 3  may be on the bottom (e.g., as depicted), top (e.g., rotated 180 degrees about the x- or z-axis), or a side (e.g., rotated 90 degrees about the x- or z-axis) of temperature-sensitive material  9 . In particular embodiments, temperature-sensitive material  9  and the associated insulating and cooling layers are orientated in the inner chamber of the case of the thermally insulating packaging system as shown in  FIG. 4 , having insulating layer  11  and cooling layer  12  on the bottom of the inner chamber and insulating layer  13  and cooling layer  14  on the top of the inner chamber. In particular embodiments, temperature-sensitive material  9  and the associated insulating and cooling layers are orientated in the inner chamber of the case of the thermally insulating packaging system as shown in  FIG. 7  rotated 90 degrees about the x-axis, having five insulating layers  11 ,  13 ,  15 , and  17 , and cooling layers  12 ,  14 ,  16 , and  18 , comprising the four sides of the inner chamber, and insulating layer  19  and cooling layer  20  comprising the top of the inner chamber. 
     In some embodiments, two or more of the insulating layers are permanently or reversibly/releasably connected, such that the inner surfaces of the two or more insulating layers are disposed on two or more outer surfaces of the cooling layer. In some embodiments, two or more of the insulating layers are permanently or reversibly/releasably connected, such that the outer surfaces of the two or more insulating layers are disposed on two or more inner surfaces of the cooling layer. In some embodiments, three, four, or five insulating layers are permanently or reversibly/releasably connected forming a multi-surfaced insulating structure that surrounds the temperature-sensitive material while providing one or more surfaces of the inner chamber and/or outer surfaces of the cooling layers not covered with insulating layers in order to permit increased air circulation. In some embodiments, the any two or more of the cooling layers, the insulating layers, or both the cooling layers and the insulating layers can be permanently or reversibly/releasably attached or tethered together using one or more hinges, snaps, fasteners, Velcro, zippers, straps, and the like. 
     When multiple cooling layers are discussed herein in association with a particular embodiment, it is to be understood that collectively these multiple cooling layers can be described as a single cooling layer. For instance, with reference to  FIG. 7 , cooling layers  12 ,  14 ,  16 ,  18 , and  20  can be considered a single cooling layer in aggregate. Relatedly, individual cooling layers may also be referred to as “panels” of the aggregate cooling layer, particularly when discussing the cooling capacities of the individual cooling layers. For example with reference again to  FIG. 7 , cooling layers  12 ,  14 ,  16 ,  18 , and  20  can be described as individual panels of the cooling layer that they form in aggregate, particularly when discussing their respective cooling capacities. In some instances, cooling layer  20  represents a panel of the cooling layer made up of cooling layers  12 ,  14 ,  16 ,  18 , and  20  in aggregate. 
     In further aspects, the thermally insulating packaging system provided herein includes an arrangement of cooling and insulating layers disposed on the inner side walls of the inner chamber of the case of thermally insulating packaging system. Referring to  FIGS. 9-14 , the thermally insulating packaging system having case  1  in open position provides inner chamber  5  having from zero to four cooling and insulating layers disposed upon the substantially planar inner side walls of the inner chamber. In some embodiments, case  1  in open position includes zero cooling and insulating layers disposed on the inner side walls of inner chamber  5 . In some embodiments, case  1  in open position includes at least one insulating layer  31  and cooling layer  32  disposed on the inner side walls of inner chamber  5 . In some embodiments, case  1  in open position includes two insulating layers  31  and  33 , and cooling layers  32  and  34 , disposed opposite to each other on the inner side walls of inner chamber  5 . In some embodiments, case  1  in open position includes two insulating layers  31  and  35 , and cooling layers  32  and  36 , disposed adjacent to each other on the inner side walls of inner chamber  5 . In some embodiments, case  1  in open position includes three insulating layers  31 ,  33 , and  35 , and cooling layers  32 ,  34 , and  36 , disposed on the inner side walls of inner chamber  5 . In some embodiments, case  1  in open position includes four insulating layers  31 ,  33 ,  35 , and  37 , and cooling layers  32 ,  34 ,  36 , and  38 , disposed on the side inner walls of inner chamber  5 . Case  1  in is pictured in the open position in  FIGS. 9-14  for clarity and in no way limits these embodiments from having additional insulating and cooler layers. 
     In some of the above embodiments, case  1  can be in an open or closed position having additional insulating and cooling layers on the bottom of the inner chamber, or on the top of the inner chamber (e.g., under the lid if in the closed position), or on both the bottom and the top of the inner chamber. In some embodiments, the arrangement of cooling and insulations layers permits efficient air circulation and condensation of air moisture in the closed environment on the inner chamber. For instance, in some configurations, air circulation is facilitated by not placing a cooling layer on an inner sidewall of the inner chamber (an open side). In some embodiments, open sides can be opposite one another in the inner chamber, such as when all four inner side walls of the inner chamber include a cooling layer, but the bottom and top of the inner chamber do not, or when only two of the inner side walls of the inner chamber (opposite each other) include a cooling layer and the other two inner side walls of the inner chamber (opposite each other) do not. In some embodiments, efficient air circulation and condensation of air moisture can increase the amount of time temperature-sensitive materials can be stored in the closed environment without freezing, even with freezing external temperatures, using cooling layers such as ice and/or gel packs. In some embodiments, an air circulating device, such as an intermittently battery-powered fan, may be incorporated in the closed environment to actively promote efficient air circulation. 
     In particular embodiments following from those above, an xz-plane cross section of the packaged temperature-sensitive material of  FIG. 7  is shown in  FIG. 15 , having temperature-sensitive material  9 , insulating layers  15 ,  17 , and  19 , and cooling layers  16 ,  18 , and  20 . In certain embodiments, the insulating layer  19  and the cooling layers  20  are located on top of the temperature-sensitive material, i.e., the packaged temperature-sensitive material of  FIG. 7  is rotated 90 degrees about the x-axis in  FIG. 15 .  FIG. 15  shows cooling layer  20  as two cooling layers in stacked configuration used as a single cooling layer on top of insulation layer  19 . In certain embodiments, such as shown in  FIG. 15 , temperature-sensitive material  9  is stowed in the inner chamber of the case of the thermally insulating packaging system having no insulation or cooling layers on the bottom of the inner chamber.  FIG. 16  depicts a variant of the packaged temperature-sensitive material of  FIG. 15  showing temperature-sensitive material  9 , insulating layer  40 , and cooling layers  16 ,  18 , and  20  stowed in the inner chamber of case  1  in closed position secured with lid  3 .  FIG. 16  shows insulation layers  15 ,  17 , and  19  of  FIG. 15  attached together as single insulation layer  40 . Insulation layers  15 ,  17 , and  19  maybe permanently (e.g., a unitary structure) or reversibly (e.g., separate panels) attached together to form single insulation layer  40 . 
     Insulation and cooling layers or panels may be reusable. Cooling layers may require exposure to freezing temperatures to recharge their cooling capacity, Insulation and cooling layers may be prefabricated in particular configurations (e.g. different sizes, shapes, and along different sides of a closed box). 
     Where the ambient temperature is low and the inner chamber is to be maintained above a certain temperature, for example when the inner chamber is not to reach freezing temperatures where the ambient temperature is expected to be below freezing, the cooling layers may be omitted and/or substituted with layer(s) comprising a thermal mass whose temperature is above the anticipated ambient temperature, with or without additional insulation to shield such thermal mass from the ambient temperature. 
     In particular embodiments following from those above, an xy-plane cross section of the packaged temperature-sensitive material of  FIG. 7  is shown in  FIG. 17 , having temperature-sensitive material  9 , insulating layers  11 ,  13 ,  15 , and  17 , and cooling layers  12 ,  14 ,  16 , and  18 . In certain embodiments, the insulating layers and cooling layers are located on the sides of the temperature-sensitive material, i.e., the packaged temperature-sensitive material of  FIG. 7  is rotated 90 degrees about the x-axis in  FIG. 18 .  FIG. 18  depicts a variant of the packaged temperature-sensitive material of  FIG. 17  showing temperature-sensitive material  9 , insulating layer  40 , and cooling layers  12 ,  14 ,  16 , and  18  stowed in the inner chamber of case  1 .  FIG. 18  shows insulation layers  11 ,  13 ,  15 , and  17  of  FIG. 17  attached together as single insulation layer  40 . Insulation layers  11 ,  13 ,  15 , and  17  maybe permanently (e.g., a unitary structure) or reversibly (e.g., separate panels) attached together to form single insulation layer  40 . 
     In certain embodiments, the thermally insulating packaging system of the present disclosure is provided as shown in  FIG. 19  having temperature-sensitive material  9 , insulating layer  40 , and cooling layers  16 ,  18 , and  20  stowed in the inner chamber of case  1  in closed position secured with lid  3 . Arrows  50  show the flow of dense cool air passing from the cooling layers through temperature-sensitive material  9  and out the bottom of case  1 . In some embodiments, as cooling layers  16 ,  18 , and  20  continue to absorb thermal energy over a period of time they begin to soften and fluidly deform to the contours of temperature-sensitive material  9 . This action provides prolonged cooling of the temperature-sensitive material as the cooling layers come into closer contact with each other and the temperature-sensitive material. In certain embodiments, the time taken for the cooling layers to soften and fluidly deform advantageously provides a target temperature for storing and transporting temperature-sensitive materials for an extended period of time. 
     In certain aspects, temperature-sensitive material  9  in the  FIGS. 15-18  above is depicted having a cube shape, but this is merely for clarity and in no way limits the shape of the wrapped temperature-sensitive material stowed in the inner chamber of the case of the thermally insulating packaging system described herein. In particular embodiments, temperature-sensitive material  9  wrapped in a cushioning layer may have rounded corners and edges or have the shape of a cylinder or sphere or pouch, and insulation layer  40  and cooling layers  12 ,  14 ,  16 ,  18  and  20  deform to the shape of the wrapped temperature-sensitive material. 
     In further aspects, storing and transporting temperature-sensitive materials in a relatively stable, refrigerated environment for extended periods of time requires the use of one or more cooling layers. In some embodiments, the cooling layers are flexible and can include an outer thermally-reflective layer. In some embodiments, the cooling layers are ductile pouches that can be bent and/or flattened. In some embodiments, the ductile pouches comprise an ice or a gel formulation that has the capacity to absorb thermal energy. The ductile pouches can include re-usable gel packs. The gel packs described herein may contain, e.g., from about 10 to about 100 oz. of gel, and have a flattened square, oval, circular or rectangular shape, although other volumes and sizes may also be used. In certain embodiments, each cooling layer comprises a cooling capacity. Alternatively, a cooling layer can be described as having multiple panels, each with a cooling capacity. The cooling capacity of a cooling layer or panel thereof may be a result of the type of ice or gel formulation used, the amount of ice or gel formulation used, additives used in the ice or gel formulation, or combinations of these. In some embodiments, gel formulations may include, e.g., water with additives, food grade cellulose gum (e.g., carboxymethyl cellulose; CMC), food grade propylene glycol or salt (e.g. to help prevent freezing), super absorbers (e.g., polyacrylamides), gelatin, starch or other thickening agents, etc., with preservatives such as benzoic acid. Gel packs that use non-toxic materials and are reusable are particularly useful cooling materials for long term temperature-sensitive material refrigeration. The gel packs can be conveniently pre-chilled (e.g., frozen) under freezing conditions (e.g., freezer) for a period of time before use and can be re-chilled, e.g., after the chilling effects are no longer needed or are reduced or the temperature of the packs has stabilized to the ambient surrounding temperature, or the packs have phase transitioned from a solid to a liquid state. 
     In some embodiments, materials other than ice or gel formulations may be used. For example, certain phase-change material (PCM) that can change state at a specific temperature from a solid to a liquid or gas and can be frozen at a specific temperature and that have a phase change at a specific temperature can be used as a cooling layer. In some embodiment, one or more cooling layers (e.g. ice packs) can be included in stacked configuration and be used as a single cooling layer. 
     In some further aspects, storing and transporting temperature-sensitive materials in a relatively stable, refrigerated environment for extended periods of time may use of one or more insulating layers. In some embodiments, the insulating layer is a ductile pouch that is flat or can be flattened. Various insulation materials can be used as the insulation layers, either alone or in combination, and can be combined in a pouch. In some embodiments, the insulating layer is constructed from a single sheet of layered materials that is cut into a square or rectangular shape. The insulation material may be disposable. In some embodiments, the disposable material can be made, e.g., of a non-woven cellulose fiber or hydrospun material that is optionally laminated with a foil liner. Other cellulose materials including recycled paper, shredded recycled paper, glass fiber or polyester fiber fill and/or polyethylene and foil laminated bubble wrap can be configured and/or combined to make a disposable insulation material. In some embodiments, the ductile pouch may be fabricated to include an outer plastic material (e.g., polypropylene or polyethylene) and filled with a single sheet or multiple pieces of a disposable insulation materials as desired, e.g., for economic and/or ease of manufacturing. In some embodiments, the insulation layer can be constructed from one or more types of insulation materials such as a vacuum insulated material, silica aerogel, expanded polyurethane, expanded polyisocyanurate, closed-cell polyurethane, phenolic foam, thinsulate™, urea foam, urea-formaldehyde, icynene foam, open-cell polyurethane, extruded polystyrene, polyurethane foam, polyethylene foam, expanded polystyrene, cardboard, laminated polyurethane foam, laminated expanded polystyrene, molded plastics, etc. In some embodiments, the ductile pouch comprising a disposable cellulose insulation material may be perforated to increase ductility and/or allow increase air circulation in the closed environment of the inner chamber. In some embodiments, efficient air circulation can increase the amount of time that temperature-sensitive materials can be stored in the closed environment without freezing, even under freezing external temperatures, using cooling layers such as ice and/or gel packs. In some embodiments, the insulation layer is a non-woven material, e.g., of polypropylene fabric, spun cellulose fiber, etc., to help absorb moisture (e.g., due to condensation) and promote temperature stability in the inner chamber. For example, the insulation layer placed between the cooling layer and the temperature-sensitive material can provide insulation and moisture retention to help stabilize temperature and prevent over cooling and freezing, even under freezing external temperatures, of the temperature-sensitive material. In other embodiments, there may be provided seals or sealant at joints in the cooling layer, the insulating layer, or between layers. 
     In further aspects, storing and transporting temperature-sensitive materials in a relatively stable, refrigerated environment for extended periods can further include the use of one or more cushioning layers. In some instances, the cushioning layer can act to prevent damage to the temperature-sensitive material. In other instances, the cushioning layer can act to prevent disturbance of the cooling and insulating layers within the inner chamber that may decrease the efficiency of thermally insulating packaging system. The amount of cushioning layer can vary based on the size of the temperature-sensitive material used. In some embodiments, the cushioning layer can be disposed on the inner surface of the insulating layer. In some embodiments, the cushioning layer is wrapped around the temperature-sensitive material before insertion of the wrapped temperature-sensitive material into the inner chamber of the case of the thermally insulating packaging system. The cushioning layer can be fabricated from a range of typical packaging materials known in the art, such as air imbedded polyethylene (bubble pack), expanded polystyrene peanuts, cellulose wadding, etc. 
     In further aspects, the thermally insulating packaging system provided herein is capable of maintaining the temperature-sensitive material or the closed environment containing the temperature-sensitive material at a target temperature or temperature range for an extended period of time. The target temperature or temperature range of the temperature-sensitive material or the closed environment containing the temperature-sensitive material may be measured using a temperature measuring device (e.g., a modular thermocouple, etc.). In some embodiments, the temperature measuring device measures the temperature of the closed environment surrounding the temperature-sensitive material (e.g., by wrapping and securing a thermocouple wire around a container housing the temperature-sensitive material) or by measuring the temperature of the temperature-sensitive material directly (e.g., by inserting and securing a thermocouple into the temperature-sensitive material). In some instances, the temperature of the temperature-sensitive material or the closed environment containing the temperature-sensitive material are the same. In other instances, the temperatures are different, for example the closed environment containing the temperature-sensitive material may be ±0.1, ±0.2, ±0.3, ±0.4, ±0.5, ±0.6, ±0.7, ±0.8, ±0.9, ±1, ±1.2, ±1.5, ±1.7, ±2, ±2.5, ±3, ±3.5, ±4, ±4.5, ±5, or ±5.5° C. different than the temperature of the temperature-sensitive material. In some embodiments, the temperatures may vary due to the thermal insulation properties of the container housing the temperature-sensitive material or the temperature-sensitive material itself. 
     In some embodiments, the thermally insulating packaging system is capable of maintaining the temperature-sensitive material or the closed environment containing the temperature-sensitive material at a target temperature or temperature range that is greater than 0° C., such as ranging from greater than 0° C. to about 10° C. or about 8° C. for greater than 24, 36, or 48 hours. In some embodiments, the thermally insulating packaging system is capable of maintaining the temperature-sensitive material or the closed environment containing the temperature-sensitive material at a target temperature ranging from about 0.5° C. to about 10° C., from about 1° C. to about 10° C., from 1.5° C. to about 10° C., from about 2° C. to about 10° C., from about 0.5° C. to about 9° C., from about 1° C. to about 9° C., from 1.5° C. to about 9° C., from about 2° C. to about 9° C., from about 0.5° C. to about 8° C., from about 1° C. to about 8° C., from 1.5° C. to about 8° C., or from about 2° C. to about 8° C., for an extended period of time from about 24 hours to about 84 hours, from about 36 to about 84 hours, from about 48 hours to about 84 hours, from about 24 hours to about 72 hours, from about 36 to about 72 hours, from about 48 hours to about 72 hours, from about 24 hours to about 60 hours, from about 36 to about 60 hours, or from about 48 hours to about 60 hours. In some embodiments, the thermally insulating packaging system is capable of maintaining the temperature-sensitive material or the closed environment containing the temperature-sensitive material at a target temperature ranging from about 0.5° C. to about 8° C. for an extended period of time from about 36 hours to about 72 hours. In some embodiments, the thermally insulating packaging system is capable of maintaining the temperature-sensitive material or the closed environment containing the temperature-sensitive material at a target temperature ranges from about 2° C. to about 8° C. for an extended period of time from about 36 hours to about 72 hours. In some embodiments, the thermally insulating packaging system is capable of maintaining the temperature-sensitive material or the closed environment containing the temperature-sensitive material at a target temperature range for certain periods of time within in a larger temperature range. For instance, in a 72 hour period, the temperature range may be from about 0.5° C. to about 2° C. for 0-24 hours, from about 0.5° C. to about 4° C. for 24-48 hours, and from about 1° C. to about 8° C. for 48-72 hours, or from about 1° C. to about 2° C. for 0-24 hours, from about 1° C. to about 4° C. for 24-48 hours, and from about 2° C. to about 8° C. for 48-72 hours 
     In some aspects, the thermally insulating packaging system may be manufactured and/or the configuration of the system may be specified with a target interior temperature range, a target exterior ambient temperature range, and/or a target duration for interior temperature maintenance. The manufacture or configuration of the packaging system may be varied to meet such target(s). Consequently, in some embodiments, the insulating and/or cooling layers may be disposed on one or more than one side of the inner chamber, depending upon these targets. Configurations may therefore change on the basis of the climate of the source location, the climate of the destination, the time of year, the route of shipping, the method of shipping, the anticipated duration of shipping, the possibility of a delay in shipping, and the needs of the temperature-sensitive material. In other embodiments, the type or thickness of insulating materials, the type or thermal mass or temperature of cooling layer material, or the surface area of the case, inner chamber, cooling or insulating layers may all be varied according to these variables. 
     In some aspects, the thermally insulating packaging system provided herein is capable of maintaining the temperature-sensitive material or the closed environment containing the temperature-sensitive material at a target temperature or temperature range for an extended period of time independent of external ambient temperatures. For example, the thermally insulating packaging system is capable of maintaining target temperatures in the closed environment from about 0.5° C., about 1° C., or about 2° C. to about 8° C. for an extended period of time from about 48 hours to about 72 hours when the average daily external ambient temperature ranges from about −10° C. to about 30° C., from about 0° C. to about 30 ° C., from about −10° C. to about 20° C., from about 0° C. to about 25° C., or from about 5° C. to about 25° C., or from about 10° C. to about 25° C. 
     4.3. Temperature-Sensitive Materials 
     The thermally insulating packaging system provided herein may be used to store and/or transport temperature-sensitive materials. In some embodiments, the thermally insulating packaging system can accept various amounts, sizes, and shapes of temperature-sensitive materials, for example, from nanoliters to several liters of liquid or nanograms to several kilograms of solid material in single or in multiple containers. Temperature-sensitive materials can include, for example, chemicals, perishable food products, biological materials (e.g., vaccines, living cells, tissue samples, specimens, human organ for transplant, etc.), human pharmaceutical products, veterinary pharmaceutical products, etc. In some embodiments, the temperature sensitive material is a veterinary pharmaceutical product, such as insulin (e.g., VETSULIN®), tresaderm, proparicaine, etc. VETSULIN® is an FDA approved insulin for cats and dogs that is recommended to be stored under refrigeration at 2-8° C. and not frozen. 
     In some instances, the temperature-sensitive material is solid or semi-solid. In other embodiments, the temperature-sensitive material is a liquid formulation, suspension, dispersion, gel or hydrogel. In certain examples, the temperature-sensitive material is an aqueous composition, such as an aqueous human pharmaceutical or veterinary pharmaceutical composition. 
     In certain embodiments, the thermally insulating packaging system maintains the closed environment at a temperature below that of the environment external to the system without freezing the temperature-sensitive material. In other embodiments, the thermally insulating packaging system maintains the closed environment at a temperature above external environment conditions that are freezing (e.g., below 0° C.) without freezing the temperature-sensitive material. 
     In some embodiments, the thermally insulating packaging system may include a thermometer or other device to sense temperature, a device to record interior or ambient temperature(s) at one or more times, a device to indicate if a particular maximum or minimum temperature was maintained, a device to determine the temperature inside the chamber without opening the chamber, or a telemetry device to send temperature information to a remote location. In certain embodiments said temperature sensing device, or a portion thereof, is disposed in the inner chamber with the temperature sensitive material. In some embodiments, a probe or sensor of the temperature sensing device is disposed in the inner chamber with the temperature sensitive material, and the remainder of the device is located outside the inner chamber. In some embodiments, the system may include a means to detect whether the inner chamber has been opened. In certain embodiments, the thermally insulating packaging system benefits from remaining in a particular orientation during transport (e.g., upright with no cooling or insulation layers on the bottom of the inner chamber inside the case). As such, the system may further include an accelerometer or other device for sensing axis-based motion to indicate whether or not a particular orientation is maintained and/or recording or reporting such orientations. 
     4.4. Methods for Packing Temperature-Sensitive Materials 
     In some aspects, a method for packaging a temperature-sensitive material for storage and/or transport within a temperature-controlled environment (e.g., a refrigerated environment) is provided herein. The method includes placing one or more cooling layers within an inner chamber of a case. The case may be fabricated from an insulating material (e.g., polystyrene or polyurethane) and have a plastic (e.g., polypropylene or polyethylene) covering on the outer surface of the case. In some embodiments, the plastic covering on the outer surface of the case may extend into the inner chamber creating a plastic liner. The inner chamber may have multiple sides and an opening. In some embodiments, the inner chamber has the shape of an open box with a floor and four sides and an opening. The floor and four side of the inner chamber can be substantially planar. In some embodiments, cooling layers (e.g., gel packs) having inner and outer surfaces are placed on two non-adjacent or opposite sides of the inner surface of inner chamber, the outer surface disposed on the surface of the inner chamber. In some embodiments, the cooling layers are placed on one side of the inner chamber. In some embodiments, the cooling layers are placed on three sides of the inner chamber. In some embodiments, the cooling layers are placed on four sides of the inner chamber. In some embodiments, the cooling layers are placed on the bottom and two non-adjacent or opposite sides of the inner chamber. In some embodiments, the cooling layers are placed on the bottom and two adjacent sides of the inner chamber. In some embodiments, the cooling layers are placed on the bottom and three sides of the inner chamber. In some embodiments, the cooling layers are placed on the bottom and four sides of the inner chamber. 
     The method can further include placing one or more insulating layers (e.g., a cellulose material) having inner and outer surfaces on the cooling layer such that the outer surface of the insulating layer is disposed on the inner surface of the cooling layer. In some embodiments, the method includes placing a temperature-sensitive material into the inner chamber through the opening and closing the opening to form a closed environment. In other embodiments, a second cooling layer and a second insulating layer can be placed on top of the temperature-sensitive material through the opening. In some embodiments, the opening is closed with a lid sized and shaped for mating with an opening. Efficient mating of the case and lid to achieve a snug fit can improve the insulation properties of the thermally insulating packaging system. In some embodiments, the temperature-sensitive material can be wrapped in a cushioning layer (e.g., an air embedded polyethylene) prior to placing the temperature-sensitive material into the inner chamber. The methods for packaging temperature-sensitive materials in the thermally insulating packaging systems provided herein are capable of maintaining target temperatures in the closed environment as described herein, such as ranging from greater than 0° C. to about 10° C. for extended periods of time described herein, such as greater than 24, 36, or 48 hours. In some embodiments, the method is capable of maintaining target temperatures from about 0.5° C., about 1° C., or about 2° C. to about 8° C. for an extended period of time from about 48 hours to about 72 hours. In further embodiments, the closed case can be placed into a cellulose container, such as cardboard box, and prepped and sealed for shipment. In some embodiments, the closed case fits into the cellulose container with a snug fit. 
     In particular embodiments following from those above, the temperature-sensitive material is wrapped in a cushioning layer and placed into the inner chamber of the case. An insulating layer is placed against an outer surface of the cushioning layer and first cooling layers are inserted into the case against on four sides of the inner chamber such that the inner surfaces of the cooling layers are placed against an outer surface of the insulation layer. Alternatively, the insulating layer may be used to provide cushioning and/or the cushioning layer may provide insulation. A second cooling layer can be a single cooling layer or multiple cooling layers in stacked configuration. Additional cushioning material can then be placed in the headspace of the inner chamber and the case closed with a lid. 
     The specific embodiments discussed herein are exemplary only and not limiting as other embodiments, including modifications and adaptations of the described embodiments are within the scope of the present disclosure. 
     4.5. Numbered Embodiments 
     Embodiment 1. A thermally insulating packaging system comprising: a case having an inner chamber, the inner chamber having multiple sides and an opening; a lid sized and shaped for mating with and closing the opening to create a closed environment; a removable cooling layer having inner and outer surfaces, the outer surface disposed on a surface of the inner chamber; and a removable insulating layer having inner and outer surfaces, the outer surface disposed on the inner surface of the cooling layer; the system configured to maintain within the closed environment a target temperature that is lower than the temperature of the environment external to the system for transport of a temperature-sensitive material within the closed environment for an extended period of time. 
     Embodiment 2. The system of embodiment 1, wherein the closed environment has the shape of a closed box defined by six substantially planar surfaces. 
     Embodiment 3. The system of embodiment 2, wherein the cooling layer and the insulating layer are disposed on four of the six substantially planar surfaces. 
     Embodiment 4. The system of embodiment 3, wherein the two substantially planar surfaces not disposed with the cooling layer and the insulating layer are non-adjacent to one another. 
     Embodiment 5. The system of any one of embodiments 1-4, wherein the case and lid comprise an insulating material. 
     Embodiment 6. The system of any one of embodiments 1-5, wherein the case and lid comprise polystyrene or polyurethane. 
     Embodiment 7. The system of embodiment 6, wherein the case and lid further comprise a polypropylene or polyethylene covering on outer surfaces of the case and the lid. 
     Embodiment 8. The system of any one of embodiments 1-7, wherein the cooling layer is a ductile pouch. 
     Embodiment 9. The system of embodiment 8, wherein the ductile pouch comprises ice or a gel formulation. 
     Embodiment 10. The system of any one of embodiments 1-9, wherein the insulating layer is a ductile pouch. 
     Embodiment 11. The system of embodiment 10, wherein the ductile pouch comprises a cellulose material. 
     Embodiment 12. The system of any one of embodiments 1-11, further comprising a cushioning layer disposed on the inner surface of the insulating layer. 
     Embodiment 13. The system of embodiment 12, wherein the cushioning layer comprises air imbedded polyethylene. 
     Embodiment 14. The system of any one of embodiments 1-13, wherein the temperature sensitive material is a perishable food product, a biological material, a human pharmaceutical product, or a veterinary pharmaceutical product. 
     Embodiment 15. The system of embodiment 14, wherein the temperature sensitive material is a veterinary pharmaceutical product. 
     Embodiment 16. The system of embodiment 15, wherein the veterinary pharmaceutical product is insulin. 
     Embodiment 17. The system of any one of embodiments 1-16, wherein the target temperature ranges from about 0.5° C. to about 8° C. and the extended period of time is from about 48 hours to about 72 hours. 
     Embodiment 18. The system of any one of embodiments 1-17, wherein the cooling layer is pre-cooled to a temperature suitable for achieving the target temperature within the closed environment. 
     Embodiment 19. A method for packaging a temperature-sensitive material, the method comprising: placing a cooling layer within an inner chamber of a case, the inner chamber having multiple sides and an opening, the cooling layer being placed against two non-adjacent sides of the inner chamber; placing a temperature-sensitive material into the inner chamber through the opening; and closing the opening to form a closed environment. 
     Embodiment 20. The method of embodiment 19, further comprising placing an insulating layer against an inner surface of the cooling layer. 
     Embodiment 21. The method of embodiment 19, further comprising wrapping the temperature-sensitive material in a cushioning layer prior to placing the temperature-sensitive material into the inner chamber. 
     Embodiment 22. The method of embodiment 19, wherein the temperature-sensitive material is wrapped in a cushioning layer. 
     Embodiment 23. The method of any one of embodiments 19-22, wherein the opening is closed with a lid sized and shaped for mating with the opening. 
     Embodiment 24. A method for packaging a temperature-sensitive material, the method comprising: placing a first cooling layer within an inner chamber of a case, the inner chamber having the shape of an open box with a floor and four sides and an opening, the cooling layer being placed on the bottom and against two non-adjacent sides of the inner chamber; placing an insulating layer against an inner surface of the cooling layer; wrapping a temperature-sensitive material in a cushioning layer; placing the wrapped temperature-sensitive material into the inner chamber through the opening; placing a second cooling layer and a second insulating layer on top of the wrapped temperature-sensitive material through the opening; and closing the opening with a lid to form a closed environment. 
     Embodiment 25. The method of embodiment 24, wherein the case and lid comprise polystyrene or polyurethane. 
     Embodiment 26. The method of embodiment 25, wherein the case and lid further comprise a polypropylene or polyethylene covering on outer surfaces of the case and the lid. 
     Embodiment 27. The method of any one of embodiments 24-26, wherein the first and second cooling layers are ductile pouches comprising ice or a gel formulation. 
     Embodiment 28. The method of any one of embodiments 24-27, wherein the first and second insulating layers are ductile pouches comprising a cellulose material. 
     Embodiment 29. The method of any one of embodiments 24-28, wherein the cushioning layer comprises air imbedded polyethylene. 
     Embodiment 30. The method of any one of embodiments 24-29, wherein the temperature sensitive material is a perishable food product, a biological material, a human pharmaceutical product, or a veterinary pharmaceutical product. 
     Embodiment 31. The method of embodiment 30, wherein the temperature sensitive material is a veterinary pharmaceutical product. 
     Embodiment 32. The method of embodiment 31, wherein the veterinary pharmaceutical product is insulin. 
     Embodiment 33. The method of any one of embodiments 24-32, wherein the closed environment is maintained at a target temperature ranging from about 0.5° C. to about 8° C. 
     Embodiment 34. The method of embodiment 33, wherein the cooling layer is pre-cooled to a temperature suitable for achieving the target temperature within the closed environment. 
     Embodiment 35. A method for packaging a temperature-sensitive material, the method comprising placing a temperature-sensitive material into the inner chamber of the thermally insulating packaging system of any one of embodiments 1-18. 
     5. EXAMPLES 
     The following Examples, which highlight certain features and properties of embodiments of thermally insulating packaging system described herein are provided for purposes of illustration and not limitation. 
     Example 1 
     Six Panel Cooler Summer Temperature Testing 
     Testing was designed and performed to document the thermal performance of a 14″×14″ corrugated box with 1.5#/pcf (density) expanded polystyrene (EPS) panels for the six sides. Trials 1 and 2 coolers had a carton of twenty-five vials containing 1 mL of saline solution. The Trial 3 cooler contained three vials containing 10 mL saline solution. A layer of ½″ bubble wrap was placed in the bottom of the cooler and above the simulated product. All the test samples had four 24 oz. frozen gel packs (Creative ICE) placed above the product. All the six-panel coolers were subjected to summer temperature conditions (ISTA 7E Summer Temperature Profile). Thermocouple wires were inserted into and secured to the payload vials and recorded the internal temperature throughout the test. The results are shown in  FIGS. 20A -20C and are summarized in Table 1-3 below. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Results of Summer Temperature Testing 
               
            
           
           
               
               
               
            
               
                 Description 
                 Low Temperature (° C.) 
                 High Temperature (° C.) 
               
               
                   
               
            
           
           
               
               
               
            
               
                 Trial 1 
                   
                   
               
               
                 #1 (25 × 1 mL) 
                 2.9 
                 10.6 
               
               
                 #2 (25 × 1 mL) 
                 1.6 
                 8.9 
               
               
                 #3 (25 × 1 mL) 
                 2.1 
                 9.8 
               
               
                 Trial 2 
               
               
                 #4 (25 × 1 mL) 
                 1.8 
                 9.5 
               
               
                 #5 (25 × 1 mL) 
                 1.1 
                 8.4 
               
               
                 #6 (25 × 1 mL) 
                 0.4 
                 8.1 
               
               
                 Trial 3 
               
               
                 #7 (3 × 10 mL) 
                 1.7 
                 9.0 
               
               
                 #8 (3 × 10 mL) 
                 2.3 
                 9.3 
               
               
                 #9 (3 × 10 mL) 
                 1.2 
                 8.7 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Summer Test Temperature Excursion below 2° C. (1.5° C. limit) 
               
            
           
           
               
               
               
            
               
                 Description 
                 Time of Excursion 
                 Length of Excursion 
               
               
                   
               
               
                 Trial 1 
                   
                   
               
               
                 #1 (25 × 1 mL) 
                 None 
                 None 
               
               
                 #2 (25 × 1 mL) 
                 None 
                 None 
               
               
                 #3 (25 × 1 mL) 
                 None 
                 None 
               
               
                 Trial 2 
               
               
                 #4 (25 × 1 mL) 
                 None 
                 None 
               
               
                 #5 (25 × 1 mL) 
                 3 Hours 45 Minutes 
                 22 Hours 50 Minutes 
               
               
                 #6 (25 × 1 mL) 
                 0 Hours 15 Minutes 
                 30 Hours 25 Minutes 
               
               
                 Trial 3 
               
               
                 #7 (3 × 10 mL) 
                 None 
                 None 
               
               
                 #8 (3 × 10 mL) 
                 None 
                 None 
               
               
                 #9 (3 × 10 mL) 
                 4 Hours 45 Minutes 
                 16 Hours 05 Minutes 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Summer Test Temperature Excursion above 7.2° C. 
               
            
           
           
               
               
               
            
               
                 Description 
                 Time of Excursion 
                 Length of Excursion 
               
               
                   
               
               
                 Trial 1 
                   
                   
               
               
                 #1 (25 × 1 mL) 
                 40 Hours 00 Minutes 
                 Balance of Test 
               
               
                 #2 (25 × 1 mL) 
                 45 Hours 00 Minutes 
                 Balance of Test 
               
               
                 #3 (25 × 1 mL) 
                 42 Hours 10 Minutes 
                 Balance of Test 
               
               
                 Trial 2 
               
               
                 #4 (25 × 1 mL) 
                 42 Hours 55 Minutes 
                 Balance of Test 
               
               
                 #5 (25 × 1 mL) 
                 45 Hours 35 Minutes 
                 Balance of Test 
               
               
                 #6 (25 × 1 mL) 
                 46 Hours 00 Minutes 
                 Balance of Test 
               
               
                 Trial 3 
               
               
                 #7 (3 × 10 mL) 
                 44 Hours 50 Minutes 
                 Balance of Test 
               
               
                 #8 (3 × 10 mL) 
                 43 Hours 35 Minutes 
                 Balance of Test 
               
               
                 #9 (3 × 10 mL) 
                 45 Hours 00 Minutes 
                 Balance of Test 
               
               
                   
               
            
           
         
       
     
     Example 2 
     Insulated Cooler Summer Temperature Testing 
     Testing was designed and performed to document the thermal performance of a medium corrugated regular slotted container (RSC) with gusseted 1 Mil polybag using 16 oz. gel ice packs (KODIAKOOLER®) and natural fiber liner and insulation (KODIAKOTTON®). Payload consisted of three 5 mL vials conditioned to 5.0° C. placed in a SBS box within a re-sealable plastic bag. Ice packs were removed from freezer and allowed to rest until −5.0° C. Corrugate container pack-out was performed in the following order: RSC; 1 Mil polybag; plastic lined 1.5″ natural fiber liner; two gel ice packs; 1/2″ plastic lined natural fiber insulation; payload; ½″ plastic lined natural fiber insulation; two gel ice packs; two gel ice pack on sides; and ½″ bubble wrap to fill void. A vial probe data logger (InTemp CX402-T405) was used to record temperature. The RSC cooler was then subjected to the summer temperature conditions (ISTA 7E Summer Temperature Profile). The results are shown in  FIG. 21 . 
     Example 3 
     Insulated Cooler Winter Temperature Testing 
     Testing was developed to identify the performance results of using a molded shipping container (CCC14, Creative Packaging Company in Shelbyville, Ky.) with a single 24 oz. frozen gel pack (Creative ICE) out with simulated product payloads. Each product box contained three 5 mL vials of saline solution, for a total of 15 mL each. The results of each container were charted to determine the effectiveness of maintaining the simulated product payload within a temperature range of 2-8° C. for a minimum of 48 hours. Thermocouple wires were inserted into and secured to the payload vials and recorded the internal temperature throughout the test. The testing was performed under winter temperature conditions (ISTA 7E Winter Temperature Profile). The results are shown in  FIG. 22  and are summarized in Tables 4-6 below. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Results of Winter Temperature Testing 
               
            
           
           
               
               
               
            
               
                 Description 
                 Low Temperature (° C.) 
                 High Temperature (° C.) 
               
               
                   
               
            
           
           
               
               
               
            
               
                 #1 
                 2.1 
                 7.1 
               
               
                 #2 
                 2.6 
                 7.9 
               
               
                 #3 
                 2.3 
                 7.6 
               
               
                 Ambient 
                 1.2 
                 16.0 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Winter Test Temperature Excursion below 2° C. (1.5° C.) 
               
            
           
           
               
               
               
            
               
                 Description 
                 Low Temperature (° C.) 
                 High Temperature (° C.) 
               
               
                   
               
               
                 #1 
                 None 
                 None 
               
               
                 #2 
                 None 
                 None 
               
               
                 #3 
                 None 
                 None 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Winter Test Temperature Excursion above 8° C. (8.5° C.) 
               
            
           
           
               
               
               
            
               
                 Description 
                 Low Temperature (° C.) 
                 High Temperature (° C.) 
               
               
                   
               
               
                 #1 
                 None 
                 None 
               
               
                 #2 
                 None 
                 None 
               
               
                 #3 
                 None 
                 None 
               
               
                   
               
            
           
         
       
     
     Example 4 
     Insulated Cooler Live Temperature Testing 
     Testing was performed using the following: Sealed Air Chil-Pak Cooler (12″×12″×12″); four 24 oz. Nordic Ice frozen gel packs (on bottom, top, and two opposite sides); four Kodiak Kooler inserts on top of gel packs; and 2 sheets of ½″ Sealed Air bubble wrap wrapped around two 5 mL vials of saline solution. The thermocouple logger (onset® HOBO®) was programmed to read over a 72 hour period. The thermocouple logger wire was wrapped tightly around the vials of saline solution before being wrapped with the bubble wrap. The coolers were shipped in sealed MD18 boxes (12″×12″×18″) between August and October from Louisville, KY to Boca Raton, Fla. and Davie, Fla. to replicate a live test via Fed-ex ground and left outside at arrival to complete the 72 hours. Results from eight separate trials (Trials 1-8) are shown in  FIG. 23  and in Table 7 below. 
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 Results of Live Testing 
               
            
           
           
               
               
            
               
                   
                 Temperature (° C.) 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 Hour 
                 Trial 1 
                 Trial 2 
                 Trial 3 
                 Trial 4 
                 Trial 5 
                 Trial 6 
                 Trial 7 
                 Trial 8 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 1 
                 4.9 
                 5.7 
                 4.5 
                 3.6 
                 4.1 
                 4.5 
                 3.4 
                 3.3 
               
               
                 2 
                 0.6 
                 1.2 
                 0.7 
                 0.4 
                 0.9 
                 0.6 
                 −0.1 
                 −0.1 
               
               
                 3 
                 0.2 
                 0.7 
                 0.2 
                 0.2 
                 0.4 
                 0.2 
                 −0.3 
                 −0.2 
               
               
                 4 
                 0.2 
                 0.6 
                 0.3 
                 0.1 
                 0.4 
                 0.2 
                 −0.2 
                 −0.2 
               
               
                 5 
                 0.3 
                 0.9 
                 0.5 
                 0.4 
                 0.5 
                 0.4 
                 0.0 
                 −0.1 
               
               
                 6 
                 0.2 
                 0.7 
                 0.5 
                 0.3 
                 0.6 
                 0.3 
                 0.0 
                 0.0 
               
               
                 7 
                 0.2 
                 0.7 
                 0.4 
                 0.3 
                 0.5 
                 0.4 
                 −0.1 
                 0.1 
               
               
                 8 
                 0.4 
                 0.9 
                 0.4 
                 0.5 
                 0.7 
                 0.4 
                 0.0 
                 0.0 
               
               
                 9 
                 0.4 
                 0.9 
                 0.4 
                 0.5 
                 0.7 
                 0.4 
                 −0.1 
                 0.2 
               
               
                 10 
                 0.4 
                 0.9 
                 0.4 
                 0.5 
                 0.7 
                 0.4 
                 0.0 
                 0.3 
               
               
                 11 
                 0.4 
                 0.9 
                 0.5 
                 0.5 
                 0.7 
                 0.4 
                 0.0 
                 0.3 
               
               
                 12 
                 0.4 
                 0.9 
                 0.5 
                 0.5 
                 0.7 
                 0.4 
                 0.0 
                 0.4 
               
               
                 13 
                 0.5 
                 0.9 
                 0.5 
                 0.5 
                 0.7 
                 0.4 
                 0.1 
                 0.3 
               
               
                 14 
                 0.5 
                 0.9 
                 0.5 
                 0.6 
                 0.7 
                 0.4 
                 0.1 
                 0.3 
               
               
                 15 
                 0.5 
                 0.9 
                 0.5 
                 0.6 
                 0.7 
                 0.4 
                 0.1 
                 0.3 
               
               
                 16 
                 0.5 
                 0.9 
                 0.5 
                 0.6 
                 0.7 
                 0.4 
                 0.1 
                 0.3 
               
               
                 17 
                 0.5 
                 0.9 
                 0.5 
                 0.5 
                 0.7 
                 0.4 
                 0.1 
                 0.3 
               
               
                 18 
                 0.5 
                 0.9 
                 0.5 
                 0.6 
                 0.7 
                 0.4 
                 0.1 
                 0.3 
               
               
                 19 
                 0.5 
                 0.9 
                 0.5 
                 0.6 
                 0.7 
                 0.4 
                 0.1 
                 0.3 
               
               
                 20 
                 0.5 
                 0.9 
                 0.5 
                 0.6 
                 0.7 
                 0.5 
                 0.1 
                 0.3 
               
               
                 21 
                 0.5 
                 0.9 
                 0.6 
                 0.6 
                 0.8 
                 0.5 
                 0.1 
                 0.3 
               
               
                 22 
                 0.5 
                 1.0 
                 0.6 
                 0.6 
                 0.8 
                 0.5 
                 0.2 
                 0.3 
               
               
                 23 
                 0.6 
                 1.0 
                 0.6 
                 0.6 
                 0.8 
                 0.5 
                 0.2 
                 0.3 
               
               
                 24 
                 0.6 
                 1.1 
                 0.7 
                 0.6 
                 0.9 
                 0.5 
                 0.2 
                 0.3 
               
               
                 25 
                 0.6 
                 1.3 
                 0.7 
                 0.7 
                 0.9 
                 0.5 
                 0.3 
                 0.4 
               
               
                 26 
                 0.9 
                 1.5 
                 0.7 
                 0.6 
                 0.8 
                 0.6 
                 0.4 
                 0.4 
               
               
                 27 
                 1.0 
                 1.6 
                 0.8 
                 0.6 
                 0.9 
                 0.5 
                 0.3 
                 0.4 
               
               
                 28 
                 0.9 
                 1.5 
                 0.8 
                 0.6 
                 1.0 
                 0.4 
                 0.3 
                 0.4 
               
               
                 29 
                 0.8 
                 1.5 
                 0.6 
                 0.6 
                 1.1 
                 0.3 
                 0.2 
                 0.4 
               
               
                 30 
                 0.8 
                 1.4 
                 0.6 
                 0.7 
                 1.1 
                 0.3 
                 0.3 
                 0.7 
               
               
                 31 
                 0.8 
                 1.4 
                 0.6 
                 0.7 
                 1.2 
                 0.5 
                 0.6 
                 1.1 
               
               
                 32 
                 0.7 
                 1.7 
                 1.5 
                 0.7 
                 2.5 
                 0.5 
                 0.4 
                 1.2 
               
               
                 33 
                 0.7 
                 1.8 
                 1.3 
                 1.1 
                 2.1 
                 0.6 
                 0.7 
                 1.2 
               
               
                 34 
                 0.6 
                 1.7 
                 0.8 
                 1.0 
                 2.1 
                 0.6 
                 0.7 
                 1.3 
               
               
                 35 
                 0.5 
                 1.6 
                 0.7 
                 1.0 
                 2.1 
                 0.6 
                 0.7 
                 1.3 
               
               
                 36 
                 0.6 
                 1.7 
                 0.7 
                 1.1 
                 2.1 
                 0.6 
                 0.7 
                 1.2 
               
               
                 37 
                 0.6 
                 1.7 
                 0.8 
                 1.1 
                 2.2 
                 0.6 
                 0.7 
                 1.1 
               
               
                 38 
                 0.6 
                 1.7 
                 0.8 
                 1.1 
                 2.2 
                 0.7 
                 1.0 
                 1.0 
               
               
                 39 
                 0.6 
                 1.7 
                 0.8 
                 0.9 
                 1.9 
                 0.7 
                 1.0 
                 0.9 
               
               
                 40 
                 0.6 
                 1.6 
                 0.7 
                 1.0 
                 1.8 
                 0.7 
                 1.0 
                 0.9 
               
               
                 41 
                 0.6 
                 3.3 
                 0.7 
                 1.0 
                 1.8 
                 1.1 
                 2.1 
                 1.0 
               
               
                 42 
                 2.7 
                 6.4 
                 1.5 
                 3.1 
                 3.6 
                 1.1 
                 2.0 
                 1.0 
               
               
                 43 
                 2.8 
                 6.9 
                 1.6 
                 3.7 
                 3.6 
                 1.2 
                 1.7 
                 1.0 
               
               
                 44 
                 2.7 
                 7.3 
                 1.6 
                 3.3 
                 4.8 
                 1.4 
                 1.7 
                 1.0 
               
               
                 45 
                 2.9 
                 8.2 
                 1.7 
                 3.1 
                 5.0 
                 1.6 
                 1.8 
                 0.9 
               
               
                 46 
                 3.5 
                 9.8 
                 2.0 
                 3.4 
                 5.5 
                 1.9 
                 2.2 
                 1.3 
               
               
                 47 
                 4.5 
                 10.8 
                 2.3 
                 3.8 
                 6.7 
                 2.3 
                 2.4 
                 1.6 
               
               
                 48 
                 4.7 
                 12.7 
                 2.6 
                 4.3 
                 7.3 
                 2.5 
                 3.2 
                 1.7 
               
               
                 49 
                 2.9 
                 13.1 
                 2.1 
                 4.0 
                 9.0 
                 6.4 
                 3.1 
                 1.8 
               
               
                 50 
                 2.2 
                 12.3 
                 1.3 
                 4.5 
                 9.1 
                 6.3 
                 3.2 
                 2.1 
               
               
                 51 
                 2.1 
                 12.4 
                 1.4 
                 4.6 
                 7.9 
                 6.5 
                 3.3 
                 2.0 
               
               
                 52 
                 2.2 
                 13.8 
                 1.5 
                 5.3 
                 7.5 
                 7.8 
                 3.8 
                 2.9 
               
               
                 53 
                 2.3 
                 13.2 
                 1.8 
                 6.3 
                 7.8 
                 8.2 
                 3.2 
                 2.8 
               
               
                 54 
                 1.8 
                 11.9 
                 1.8 
                 5.4 
                 8.3 
                 8.2 
                 2.9 
                 1.7 
               
               
                 55 
                 1.6 
                 11.2 
                 2.0 
                 5.0 
                 8.1 
                 8.0 
                 2.8 
                 1.6 
               
               
                 56 
                 1.5 
                 10.7 
                 2.3 
                 4.8 
                 7.8 
                 7.9 
                 2.8 
                 1.7 
               
               
                 57 
                 1.6 
                 10.5 
                 2.5 
                 4.8 
                 7.5 
                 7.8 
                 2.8 
                 2.0 
               
               
                 58 
                 1.6 
                 10.3 
                 2.8 
                 4.8 
                 7.4 
                 7.8 
                 2.8 
                 1.9 
               
               
                 59 
                 1.7 
                 10.1 
                 3.1 
                 4.9 
                 7.3 
                 7.7 
                 2.9 
                 1.8 
               
               
                 60 
                 1.8 
                 9.9 
                 3.5 
                 4.9 
                 7.2 
                 7.7 
                 3.0 
                 1.8 
               
               
                 61 
                 1.9 
                 9.9 
                 3.8 
                 5.0 
                 7.1 
                 7.7 
                 3.1 
                 1.8 
               
               
                 62 
                 2.1 
                 9.8 
                 4.1 
                 5.1 
                 7.1 
                 7.7 
                 3.2 
                 1.9 
               
               
                 63 
                 2.3 
                 9.6 
                 4.3 
                 5.2 
                 7.1 
                 7.8 
                 3.3 
                 2.0 
               
               
                 64 
                 2.7 
                 9.5 
                 4.6 
                 5.3 
                 7.1 
                 7.8 
                 3.5 
                 2.1 
               
               
                 65 
                 3.0 
                 9.5 
                 4.7 
                 5.5 
                 7.1 
                 7.8 
                 3.7 
                 2.2 
               
               
                 66 
                 3.3 
                 9.5 
                 5.0 
                 5.6 
                 7.1 
                 7.7 
                 3.5 
                 2.4 
               
               
                 67 
                 3.7 
                 10.9 
                 5.3 
                 5.9 
                 7.3 
                 8.7 
                 4.8 
                 2.6 
               
               
                 68 
                 4.7 
                 8.9 
                 5.6 
                 5.5 
                 8.2 
                 9.3 
                 5.2 
                 2.9 
               
               
                 69 
                 5.3 
                 8.5 
                 5.9 
                 5.5 
                 8.2 
                 9.1 
                 5.1 
                 3.3 
               
               
                 70 
                 5.8 
                 8.5 
                 6.2 
                 5.7 
                 8.2 
                 9.1 
                 5.1 
                 3.8 
               
               
                 71 
                 6.3 
                 8.8 
                 6.4 
                 6.0 
                 8.4 
                 9.4 
                 5.3 
                 4.5 
               
               
                 72 
                 6.8 
                 9.2 
                 6.7 
                 6.3 
                 8.7 
                 9.7 
                 5.5 
                 5.6 
               
               
                   
               
            
           
         
       
     
     All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications referred to in this specification are incorporated herein by reference in their entireties, including U.S. provisional application No. 62/805,599, filed Feb. 14, 2019. 
     Although specific embodiments of the present disclosure have been described in detail herein with reference to the accompanying drawings, it is to be understood that the disclosure is not limited to those precise embodiments, and that various changes and modifications may be effected therein by one skilled in art without departing from the spirit and scope of the disclosure.