Abstract:
An asymmetric occlusion device for occluding an opening in a body tissue where part of the opening is defined by a partial inadequate rim. The asymmetric occlusion device includes a waist portion having a distal end extending to a proximal end. The waist portion is of non-woven material extending around a longitudinal axis opening. The occlusion device further includes a pair of asymmetric occluder disks attached to the waist. The asymmetric distal and proximal occluder disks are formed of shape memory material. The asymmetric occluder disks include a short arm extending from the waist and an extended arm extending from the waist. The extended arm exceeds the length of the first short arm. The density of the first short arm exceeds the density of the second extended arm.

Description:
CROSS-REFERENCE TO RELATED APPLICATION 
       [0001]    The application claims priority to U.S. Provisional Application entitled “ASYMMETRIC OCCLUDER FOR TRANSCATHETER ATRIAL SEPTAL DEFECT CLOSURE IN PATIENTS WITH SECUNDUM ATRIAL SEPTAL DEFECT AND INADEQUATE RIMS,” Ser. No. 61/828,991, filed May 30, 2013, which is incorporated herein by reference in its entirety. 
     
    
     BIBLIOGRAPHY 
       [0002]    Complete bibliographical citations to the documents cited herein can be found in the Bibliography, immediately preceding the claims. 
       FIELD OF THE INVENTION 
       [0003]    The present invention is directed to a medical device and particularly to a device for closing or occluding atrial septal defects in patients with secundum atrial septal defect and inadequate rims. 
       BACKGROUND 
       [0004]    Atrial septal defect (ASD) is one of the most common congenital heart defects, accounting for 7%-10% of all congenital Heart disease in children and 30%-33% of defects diagnosed in adults with congenital heart disease (Kazmouz et al. 2013). Secundum atrial septal defect (ASD) is a congenital heart defect in the septum between the atria of the heart, which allows blood to flow from the left atrium to the right atrium through a hole or defect in the interatrial septum. This defect is typically caused by deficiency of valve tissue of fossa ovalis, excessive or ectopic resorption of septum primum or deficient growth of septum secundum. Forty years ago, Dr. Terry D. King performed the first transcatheter closure of atrial septal defect using double umbrella disks (King et al. 1976). Since then, many devices have been developed to close such defects (King and Mills 2010). During a cardiac catheterization, a thin catheter is inserted into a blood vessel in the groin of a patient and guided to the heart. Through the catheter, a mesh patch or plug is put into place to close to close the interatrial defect. The heart tissue grows around the mesh permanently sealing the defect. 
         [0005]    However, patients with ASD and inadequate rims are not good candidates for the available devices or may pose significant technical challenges seating the device well (Podnar et al. 2001; Amin 2006; Kannan, et al. 2003). An inadequate rim of tissue around the ASD may not allow for proper device anchoring leading to device malposition. The most common site of deficient rim is the retroaortic area (also called the anterior-superior rim) which may be deficient in up to 45% of patients with ASD (Knirsch et al., 2005; cited in Love, et al., 2012). 
         [0006]    Therefore, currently, many of these patients are referred for traditional surgical closure of their defects (Moore et al. 2013; Gokaslan et al. 2012). However, an inadequate rim is one of the serious challenges for transcatheter closure of ASD, making this treatment modality impossible in many occasions (Li et al. 2012. The purpose of this invention is to modify these defects (defects with deficient or inadequate rims) and to make their defects more feasible for transcatheter closure. 
       SUMMARY OF THE INVENTION 
       [0007]    The present invention is directed to a heart occluder device comprising two separate, uniquely-shaped members separated by a middle portion or waist wherein each member is shaped into two semi-ovoid designs to form two half-discs by the memory-shaping capability of the wires forming the members. The waist area is formed between the two semi-ovoid designs. 
         [0008]    The present invention is further directed to an asymmetric occlusion device for occluding an opening in a body tissue wherein the opening is defined by a partial adequate rim and a partial inadequate rim. The asymmetric occlusion device comprises a waist portion having a distal end extending to a proximal end, the waist portion being formed of non-woven material extending around a longitudinal axis opening. The occlusion device further includes a pair of asymmetric occluder disks, comprising an asymmetric distal occluder disk attached to the distal portion of the waist, the asymmetric distal occluder disk being made of shape memory material, and an asymmetric proximal occluder disk attached to the proximal portion of the waist, the asymmetric proximal occluder disk being made of shape memory material. The asymmetric occluder disks are defined by a first short arm extending from the waist wherein the first short arm includes shape memory material, and a second extended arm extending from the waist, wherein the second extended arm exceeds the length of the first short arm and wherein the second long arm includes shape memory material, wherein the density of the first short arm exceeds the density of the second extended arm. 
         [0009]    The present invention is further directed to an asymmetric atrial septum occlusion device for occluding an atrial septum defect, wherein the atrial septum defect is defined by a partial adequate rim and a partial inadequate rim. The occlusion device comprises a waist portion having a distal end extending to a proximal end, the waist portion being formed of non-woven material extending around a longitudinal axis opening, wherein the waist comprises a hub and a channel passing through the hub. The occlusion device further includes a pair of ovoid asymmetric occluder disks, comprising an asymmetric distal occluder disk attached to the distal portion of the waist, the asymmetric distal occluder disk being made of shape memory material, and an asymmetric proximal occluder disk attached to the proximal portion of the waist, the asymmetric proximal occluder disk being made of shape memory material, wherein the distal disk and larger in size than the proximal disk to prevent dislodgement of the occluder device from the body tissue opening, wherein further the asymmetric occluder disks comprise a first short arm extending from the waist wherein the first short arm includes shape memory material, and a second extended arm extending from the waist, wherein the second extended arm exceeds the length of the first short arm and wherein the second long arm includes shape memory material. The density of the first short arm exceeds the density of the second extended arm. 
         [0010]    The design and deployment of this device is easy and very similar to conventional Amplatzer ASD occluder. 
         [0011]    The objects and advantages of the invention will appear more fully from the following detailed description of the preferred embodiment of the invention made in conjunction with the accompanying drawings. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0012]      FIG. 1  is a schematic representation of a human heart illustrating an atrial septal defect (ASD). 
           [0013]      FIG. 2  is a schematic representation of the heart septum separating the right atrium (RA) from the left atrium (LA) and illustrating an ASD. 
           [0014]      FIG. 3  is a top plan view illustrating the distinctions between the occluder device of the present invention and the prior art occluder device. 
           [0015]      FIG. 4  is a top plan view of the occluder device of the present invention. 
           [0016]      FIG. 5  is a perspective view of the occluder device of the present invention. 
           [0017]      FIG. 6  is a top plan view illustrating the placement of the occluder device on the ASD. 
           [0018]      FIG. 7  is a side plan view illustrating the placement of the occluder device on the ASD. 
           [0019]      FIG. 8  is schematic view illustrating the initial placement of the occluder device through the ASD between the right atrium and the left atrium. 
           [0020]      FIG. 9  is a close up side plan view illustrating the opening of the distal occluder disk in the region of the left atrium. 
           [0021]      FIG. 10  is a close up side plan view illustrating the opening of the waist portion of the occluder disk. 
           [0022]      FIG. 11  is a close up side plan view illustrating the opening of the proximal occluder disk in the region of the right atrium. 
           [0023]      FIG. 12  is a close up side plan view illustrating the removal of the deployment cable and catheter from the occluder device. 
           [0024]      FIG. 13  is a close up side plan view illustrating the attachment of guide wires and a snare for the removal of the occluder device from the ASD. 
           [0025]      FIG. 14  is a side plan view illustrating the removal of the occluder device from the ASD. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0026]    The present invention provides a device for occluding an aperture within body tissue wherein the aperture includes an area of adequate rim and an area of inadequate rim. 
         [0027]      FIG. 1  illustrates a human heart  10 , having a right atrium  12 , a left atrium  14 , a right ventricle  16 , and a left ventricle  18 . Shown at  20  is an ASD anatomical anomaly or aperture in the atrial septum  22 . The presence of an ASD  20  could permit blood to travel through septum  22 , such as that schematically illustrated by aperture  20 . A ventricle septal defect (“VSD”) is similar to an ASD, except that an aperture would exist in the septum  24  between the right ventricle  16  and the left ventricle  18 . Unless specifically described otherwise, the term “aperture” will refer to the specific heart defect described above, i.e., the ASD. 
         [0028]    Occluder (or occlusion) devices are known for occluding ASDs. Reference is made to U.S. Patent Publication 2009/0228038 to Amin for one such heart occluder device. However, such devices are typically symmetrical occluders which are able to repair a defect having adequate rim structure completely encircling the defect. By “adequate rim structure,” it is meant that there is a sufficient amount of tissue making up the rim and surrounding tissue of the heart wall to accept an occluder device. 
         [0029]    Unfortunately, there are times when the heart defect does not occur in a more centrally located area of the septum  22 , but rather at the edge of the septum  22  as illustrated in  FIG. 2 . In these occurrences, the heart defect rim  25  is defined by a rim  26  of adequate surface structure to accept the heart occluder device and a rim  28  of inadequate surface structure, where it will be difficult to accept the clamping mechanism of the heart occluder device with enough force to fix the heart occluder to the entire rim  25  structure of the heart defect. This situation requires a specialized form of heart occluder device as described in the present application. 
         [0030]    As used herein, “distal” refers to the direction away from the delivery catheter and “proximal” refers to the direction nearer the delivery catheter. 
         [0031]    As used herein, “memory” or “shape memory” refers to a property of materials to resume and maintain an intended shape despite being distorted for periods of time, such as during storage or during the process of delivery in vivo. 
         [0032]    Reference is now made to  FIG. 3 , which illustrates the distinction between a standard, prior-art Amplatzer-type septal occluder  102 , which is typically a self-centering device that consists of two circular retaining discs  104  (one shown in  FIG. 3 ) made of nitinol wire mesh and linked together by a short connecting waist  106  surrounding a hub  107 . The waist  106  centers the device  102  in the ASD and occludes it with the retaining discs  104  providing equal stability of the rim of the defect (Kasmouz, et al., 2013). 
         [0033]    Unlike the prior art occluder device  102  described above, the septal occluder device  100  of the present invention is distinguished by extended distal and proximal disks  120 ,  122  which include an extended arm  110  thereby giving each disk  120 ,  122  an ovoid or oval appearance. In addition, the waist  105  separating the disks  120 ,  122  is ovoid in shape to accommodate the shape of the disks  120 ,  122 . The disks  120 ,  122  are further defined by having the hub area  107  offset thus forming a short arm  112  opposing the extended arm  110 . As illustrated by arrows  114  and  116 , the length or radius of the short arm  112  is shorter than the length or radius of the extended arm  110 . As will be illustrated and described in this disclosure, the extended arm  110  in combination with the unique features of the short arm  112  will create a device for adequately occluding an aperture  20  in the heart septum  22  which is characterized by an inadequate rim structure  28 . As illustrated in  FIGS. 3 ,  4  and  7 , the hub  107  is preferably defined by an extension  108  which includes a channel  109  passing through the extension  108 . The usefulness of the channel  109  will become apparent in the description of the deployment, attachment and removal of the occluder device  100 . 
         [0034]    Referring now to  FIGS. 4 and 5 , the occluder device  100  of the present invention comprises two separate uniquely shaped ovoid disks, distal disk  120  and proximal disk  122 , formed of shape memory material, such as wire or other specialized material. The material can be formed of biocompatible metals or polymers, such as bioresorbable polymers, shape memory polymers, shape memory metal alloys, biocompatible metals, bioresorbable metals, or combinations thereof. Specific examples include but are not limited to iron, magnesium, stainless steel, nitinol, or combinations of these and similar materials. A preferred metal for the present invention is a nitinol alloy. Nitinol (an acronym for Nickel Titanium Naval Ordnance Laboratory) is a family of intermetallic materials, which contain a nearly equal mixture of nickel (55 wt. %) and titanium. Other elements can be added to adjust or “tune” the material properties. Nitinol exhibits unique behavior, specifically, a well-defined “shape memory” and super elasticity. In general, any biocompatible material with a memory capability can be used with the present invention. The thermal shape memory and/or superelastic properties of shape memory polymers and alloys permit the occluder  100  to resume and maintain its intended shape in vivo despite being distorted during the delivery process. 
         [0035]    In certain embodiments, the memory may also assist in pressing the aperture  20  closed. The diameter or thickness of the wire depends on the size and type of the device, i.e., the larger the device, the larger the diameter of the wire. In general, wire having a diameter between about 0.2 mm and 0.8 mm can be used. 
         [0036]    Each disk  120 ,  122  in the occluder device  100  includes a rim  124 ,  126 , also made of shaped memory material to create and hold the ovoid shape of each disk  120 ,  122  as illustrated. While the ovoid shape is illustrated and is the preferred shape for the device  100  of the present invention, it is within the scope to have other shapes as desired. Ideally, the shape of the disks  120 ,  122  is customized to approximate the size and shape of the ASD. 
         [0037]    As illustrated primarily in  FIG. 7 , the size and shape of the distal occluder disk  120  is larger than the proximal occluder disk  122 . Because the flow of blood naturally passes from the left atrium  14  to the right atrium  15 , referred to  FIG. 1 , it is preferred but not absolutely necessary to enlarge the size of the distal occluder disk  120  to assist in blocking the flow of fluid and to prevent the occluder disk  100  from dislodging and passing into the right atrium  120  and possibly to the right ventricle  16  or pulmonary artery  202 . For this reason, it is preferred to increase the overall size of the distal disk  120 , in comparison to the proximal disk  122 , to further secure the occluder disk  100  in position over the ASD. 
         [0038]    The disks  120 ,  122  are shaped and constructed of a dense mesh of tightly woven wire material, such as nitinol. The form of the distal disk  120  opposes the form of the proximal disk  122  and is connected by a 3-4 mm short ovoid waist  105 , illustrated in  FIG. 7 . The shape and relative size of the waist  105  preferably conforms to the shape and the size of the ASD  20 . The disks  120 ,  122  are larger than the waist  105 . 
         [0039]    As illustrated in  FIGS. 3 and 7 , the waist portion  105  of the occluder device  100  is extended, ovoid and follows the contour of the disks  120 ,  122 . The dimensions of the waist are variable, ranging from small to large, and are typically selected based on the size and shape of the ASD. Ideally, the waist  105  is formed to completely fill the ASD  20 . The size of the waist  105  typically ranges between about 1 and 4 mm larger in size than the ASD  20 , preferably between about 2 and 4 mm larger than the ASD. In this manner, the waist  105  can provide a stopper-like plug to the ASD  20  opening. 
         [0040]    In addition to acting as a stopper for the ASD  20 , the waist acts to retain the occluder disks  120 ,  122  in place on the ASD  20  for maximum sealing. Further, the waist  105  assists in preventing the inadvertent or accidental displacement of the occluder device  100 . 
         [0041]    The short arm  112  of each disk  120 ,  122  is defined by an arcuate portion  126 ,  128  in each rim  124 ,  125 , and is designed to attach or clamp onto the rim  25  of the aperture  20  defined by the adequate rim  26 . 
         [0042]    Likewise, the extended arm  110  of each disk  120 ,  122  is defined by an arcuate portion  130 ,  132  in each rim  124 ,  125 . This arm is intended to attach or clamp onto the rim  25  of the aperture  20  defined by the inadequate rim  28 . 
         [0043]    To assist in accomplishing this task, the short arm  112  is characterized by increased bulk or thickness density of memory material, illustrated by the dense mesh of memory material  134 , to increase the size, structure, strength and tension of each disk  120 ,  122  at the region of the short arm  112 . The added bulk can be accomplished by adding more memory material, such as memory wire, thicker wire, or a combination of both. Without wishing to be restricted to any set dimensions, the preferred thickness of the short arm, illustrated by arrow  136  in  FIG. 7 , is approximately twice the thickness of the extended arm  110 , illustrated by arrow  138 . The less dense memory material in extended arm  110  is designated by reference number  135 . 
         [0044]    Referring now to  FIG. 7 , the provision of a thicker, stronger, denser material  134  adds tension to the disks  120 ,  122  at the short arm  112 . Clamping the disks  120 ,  122  onto the septum  22  at the area of the adequate rim  26  will then create a torsional rotation of the extended arms  110  of each disk  120 ,  122  along arrows  140 ,  142  in order to assist in a more secure attachment of the disks  120 ,  122  at the arcuate portion  130 ,  132  or precisely at the location of the inadequate rim  28 . The torsional clamping effect will seat the occluder device  100  onto the rim  25  of the aperture  20  in a manner to prevent the device  100  from slipping off the aperture  20  at the area of the inadequate rim  28 . In this manner, the occluding device  100  provides a firm gripping seal on the aperture  20  at the location of the adequate rim surface  26  and an enhanced gripping seal on the aperture  20  at the location of the inadequate rim surface  28 . The “asymmetry” in thickness is therefore helpful in preventing the occluder device  100  from dislodging from the aperture  20 . 
         [0045]    It is also within the scope of the present invention to add a mild magnetic property to occluder device  100  at the short arm  112  of each disk  120 ,  122 . The magnetic property is specifically placed on the wire mesh on the interior surfaces  150 ,  152  adjacent the adequate rim  26  area of the septum  20 . Applying a mild magnetic property to each disk  120 ,  122  will aid in attracting each disk  120 ,  122  to each other for more secure closure over the adequate rim  26 . This in turns adds closure pressure at the extended arm  110  portion of the disk thereby assisting the ends  130 ,  132  in a proper sealing closure on the inadequate rim  28 . This effectively seals the aperture  20  without any displacement. Therefore, when both of the disks  120 ,  122  are deployed, the magnetic property causes the two disks  120 ,  122  to be kept attached to each other at the safe and firm part of the septum  22 . As illustrated in  FIG. 7 , the mild magnetic property will be applied bilaterally to the atrial sides of both discs at the location of the short arm covering the adequate and firm rim. Therefore, after deployment, they will gently attach to each other. 
         [0046]    Referring now the hub  107  located in the center of the waist  105 , the hub  107  is defined by an extension  108 , located on both surfaces of the distal occluder disk  120  and proximal occluder disk  122 . As illustrated in  FIGS. 5 ,  7  and  13 , the extension  108  includes a channel  109  extending through the extension  108 . The channel  109  in the extension  109  is provided in order to remove the occluder device  100  if necessary. For example, the flow of blood from the left atrium  14  to the right atrium  12  in the heart  10  can dislodge the occluder device  100  if the device  100  is not adequately secure. This is called “embolism.” Typically, the device  100  is dislodged toward the left atrium  14  and subsequently to the left ventricle  18  and aorta (not shown). Additionally, it is possible for the device  100  to be dislodged to the right ventricle  16  and the pulmonary artery  202 . If the occluder device  100  becomes dislodged, causing an embolism, it will be necessary to remove the occluder device  100  from the heart  10 . This can be accomplished by means of the channel  109  in the extension  108  as will be described later. 
         [0047]    The occluder device  100  may also include a scaffold or sealed covering  111 , illustrated in  FIG. 7 , over each of the distal and proximal disks  120 ,  122 , wherein the covering provides a seal to occlude the ASD  20  wherein the coverings comprise a flexible, biocompatible material capable of promoting tissue growth and/or act as a sealant, including but not limited to polyester fabrics, Teflon-based materials or polyvinyl alcohol. 
         [0048]    The deployment of the occluder device  100  is well-known to the art and similar to standard Amplatzer-type deployment steps. It is typically a percutaneous procedure which does not require major surgery. 
         [0049]    Referring to  FIG. 8 , the catheter  33  containing the occluder device  100  attached to the deployment cable  32 , is fed via a needle stick (not shown) through a large vein in the groin which feeds into the heart  100 . The catheter  33  locates the ASD  20  and is passed through the ASD  20 . 
         [0050]    Referring to  FIG. 9 , the catheter  33  is withdrawn which allows the distal disk  120  to open and reform its memory shape in the left atrium  14 . The distal disk  120  is then placed against the ASD  20  to seal off the ASD  20 . The larger size of the distal disk  120 , compared to the size of the proximal disk  122 , assists in the proper placement of the distal disk  120  over the ASD  20 . The radiomarker  300 , housed within the occluder device  100 , assists in the proper placement of the distal disk  120 , by means known to the art. The distal disk  120  is positioned such that the arcuate portion  126  of the rim  124  in the short arm  112  is placed over the adequate rim  26  area of the ASD  20 . As a result of this positioning the arcuate portion  130  of the distal disk is in proper placement over the inadequate rim area  28  of the ASD. 
         [0051]    Referring to  FIGS. 6 and 10 , once the distal disk  120  is properly positioned and secured against the rim  25  of the ASD  20 , the catheter  33  is further withdrawn thereby revealing the waist  105  of the occluder  100 . The waist  105  preferably fills and further plugs the entirety of the ASD  20 . 
         [0052]    Referring to  FIG. 11 , once both the distal disk  120  and the waist  105  are adequately secured over the ASD  20 , the catheter  33  is further withdrawn revealing the proximal disk  122  in the right atrium  12 . The proximal disk  122  is secured to the ASD  20  in the same position as the distal disk  120 , such that the short arm  112  of the proximal disk  122  aligns with the short arm  112  of the distal disk  120 . As illustrated in  FIG. 7 , a significant portion of the septum  22  at the adequate rim  26  area is positioned and essentially clamped between the short arms  112  of the distal and proximal disks  120 ,  122 . Because of the unique properties of the short arms  112 , i.e., its layer of denser memory material  134 , the short arms  112  of both disks  120 ,  122  secure the occluder disk  100  to the ASD  20 . In addition, the secured attachment of the short arms  112  assists in properly securing the extended arms  110  of each disk  120 ,  122  to the ASD  20  at the area of inadequate rim structure  28 . Furthermore and as discussed previously, the short arms  112  of the disks  120 ,  122  can be provided with magnetic attraction at the interior surfaces  150 ,  152  of the short arms  112  to further assist in the clamping action of the short arms  112  of both disks  120 ,  122  on the ASD  20  at the area of adequate rim  26 . 
         [0053]    Referring to  FIG. 12 , once the position of the occluder disk  100  is verified, the deployment cable  32 , which secures the occluder device  100  to the catheter  33 , is released by means known to the art, and the catheter  33  is removed by means known to the art. 
         [0054]    Properly placed, the occluder device  100  will stay in place for the life of the patient. As the occluder device  100  becomes further embedded into the septum  22  tissue, new tissue will grow over the occluder device  100  further securing the occluder device  100  to the septum  22 . 
         [0055]    The occluder device  100  is connected to a hub  107 , which includes a delivery attachment mechanism for attachment to a deployment cable  32  housed within a delivery catheter sheath or catheter  33 . 
         [0056]    Therefore, one, two or three of the following parameters can help the occluder device  100  seat properly in place without prolapse into the right atrium  12 :
       a. The extra length of the distal and proximal disks  120 ,  122  on the side with inadequate rim  28 ;   b. The added thickness or density of the short arms  112  of both the distal and proximal disks  120 ,  122 ; and   c. The equal size of the distal and proximal disk members  120 ,  122  which provides better support, especially considering the firmer wire mesh and the larger retention disc member on part of the disc member that seats on the part of the septum  22  with the adequate rim  28 .       
 
         [0060]    In the event, the occluder device  100  must be removed for any reason, such as an inadvertent embolism, the channel  109  within the extension in the hub  108  in the occluder device  100  is useful for this process. The channel  109  within the extension  108  facilitates retrieving the occluder device  100  on both the left atrium  12  and right atrium  14  sides by passing an appropriate guide wire through the channel  109  and snaring the proximal disk  122 . 
         [0061]    Referring to  FIG. 13 , the extension  108  of either the distal disk  120  or the proximal disk  122  can receive a guide wire  250  which is threaded to the occluder device  100  via an appropriate blood vessel. The guide wire  250  is snared by a snare wire  260 , according to methods well known to the art, for retrieval of the occluder device  100 . 
         [0062]    Referring to  FIG. 14 , the snare wires  260 , connected to the hubs  107  of both the distal and proximal disks  120 ,  122  can then be pulled along the direction of arrows  270  thereby stretching and pulling the occluder device  100  free from the ASD. In this stretched position, the occluder device  100  can be reinserted into a catheter  33  for removal from the heart  10  by means known to the art. Hydrophilic guide wires are preferred for this step. 
         [0063]    Any version of any component or method step of the invention may be used with any other component or method step of the invention. The elements described herein can be used in any combination whether explicitly described or not. 
         [0064]    All combinations of method steps as used herein can be performed in any order, unless otherwise specified or clearly implied to the contrary by the context in which the referenced combination is made. 
         [0065]    As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. 
         [0066]    Numerical ranges as used herein are intended to include every number and subset of numbers contained within that range, whether specifically disclosed or not. Further, these numerical ranges should be construed as providing support for a claim directed to any number or subset of numbers in that range. For example, a disclosure of from 1 to 10 should be construed as supporting a range of from 2 to 8, from 3 to 7, from 5 to 6, from 1 to 9, from 3.6 to 4.6, from 3.5 to 9.9, and so forth. 
         [0067]    All patents, patent publications, and peer-reviewed publications (i.e., “references”) cited herein are expressly incorporated by reference in their entirety to the same extent as if each individual reference were specifically and individually indicated as being incorporated by reference. In case of conflict between the present disclosure and the incorporated references, the present disclosure controls. 
         [0068]    The devices, methods, compounds and compositions of the present invention can comprise, consist of, or consist essentially of the essential elements and limitations described herein, as well as any additional or optional steps, ingredients, components, or limitations described herein or otherwise useful in the art. 
         [0069]    While this invention may be embodied in many forms, what is described in detail herein is a specific preferred embodiment of the invention. The present disclosure is an exemplification of the principles of the invention is not intended to limit the invention to the particular embodiments illustrated. It is to be understood that this invention is not limited to the particular examples, process steps, and materials disclosed herein as such process steps and materials may vary somewhat. It is also understood that the terminology used herein is used for the purpose of describing particular embodiments only and is not intended to be limiting since the scope of the present invention will be limited to only the appended claims and equivalents thereof. 
       BIBLIOGRAPHY 
       [0000]    
       
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