Echogenic balloon dilation catheter and balloon thereof

Abstract

An echogenic balloon dilation catheter and a balloon thereof. The balloon includes a balloon body, a balloon cone at each side of the balloon body, and a balloon tip extending from the balloon cone and fixed to the catheter, the balloon body and the balloon cone being formed of a plurality of polymer layers in a radial direction of the balloon. The balloon may be of enhanced echogenicity using a variety of disclosed techniques.

Claims

1. A balloon for a dilatation catheter, comprising, along an axial direction of the balloon: a balloon body, a balloon cone at each side of the balloon body; and a balloon tip extending from the balloon cone and fixed to the dilatation catheter, wherein the balloon body and the balloon cone are formed of a plurality of polymer layers in a radial direction of the balloon, wherein the balloon tip comprises metal; and wherein the balloon tip, balloon body and balloon cones are all formed of multiple polymer layers in the radial direction of the balloon, wherein the metal of the balloon tip comprises an integral metal ring provided on the balloon tip, and a body of the ring is provided with a plurality of circumferentially extending through grooves with opening directions opposite to each other and spaced apart from each other in the axial direction.

2. The balloon according to claim 1, wherein an outer surface of the balloon body includes printed scale marks capable of reflecting ultrasonic waves.

3. The balloon according to claim 2, wherein a first scale mark and scale marks at an interval therefrom are different from other scale marks in shape.

4. The balloon according to claim 3, wherein a starting position of the scale marks starts at a distal end of the balloon or at a distance from the balloon tip.

5. A balloon for a dilatation catheter, comprising, along an axial direction of the balloon: a balloon body, a balloon cone at each side of the balloon body; and a balloon tip extending from the balloon cone and fixed to the dilatation catheter, wherein the balloon body and the balloon cone are formed of a plurality of polymer layers in a radial direction of the balloon, wherein the balloon tip comprises metal; and wherein the balloon tip, balloon body and balloon cones are all formed of multiple polymer layers in the radial direction of the balloon, wherein the metal of the balloon tip comprises an integral metal ring provided on the balloon tip, and a body of the ring is provided thereon with a continuously spiral through groove.

6. The balloon according to claim 5, wherein an outer surface of the balloon body includes printed scale marks capable of reflecting ultrasonic waves.

7. The balloon according to claim 6, wherein a first scale mark and scale marks at an interval therefrom are different from other scale marks in shape.

8. The balloon according to claim 7, wherein a starting position of the scale marks starts at a distal end of the balloon or at a distance from the balloon tip.

9. A balloon for a dilatation catheter, comprising, along an axial direction of the balloon: a balloon body, a balloon cone at each side of the balloon body; and a balloon tip extending from the balloon cone and fixed to the dilatation catheter, wherein the balloon body and the balloon cone are formed of a plurality of polymer layers in a radial direction of the balloon, wherein the balloon tip comprises metal; and wherein the balloon tip, balloon body and balloon cone are all formed of multiple polymer layers in the radial direction of the balloon, wherein the metal of the balloon tip comprises an integral metal ring provided on the balloon tip, and a body of the ring is provided thereon with a plurality of axially disposed windows with every two adjacent rows of windows staggered from each other in a circumferential direction.

10. The balloon according to claim 9, wherein an outer surface of the balloon body includes printed scale marks capable of reflecting ultrasonic waves.

11. The balloon according to claim 10, wherein a first scale mark and scale marks at an interval therefrom are different from other scale marks in shape.

12. The balloon according to claim 11, wherein a starting position of the scale marks starts at a distal end of the balloon or at a distance from the balloon tip.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) Other features of the present disclosure will become apparent from the following description of exemplary embodiments with reference to the drawings.

(2) FIG. 1 shows a metal tip of an echogenic balloon;

(3) FIG. 2 shows an echogenic balloon tip with a notch;

(4) FIG. 3 shows an echogenic balloon tip with a metal sleeve or a cladding layer;

(5) FIG. 4 shows an echogenic balloon tip subjected to surface treatment;

(6) FIG. 5 shows an echogenic balloon tip with a plurality of metal cuffs;

(7) FIGS. 6A, 6B, and 6C each show an echogenic balloon tip with a differently patterned surface of;

(8) FIG. 7A shows a cross-sectional view of a prior art balloon, and FIG. 7B shows a cross-sectional view of an echogenic balloon with metal cuffs according to the present disclosure;

(9) FIG. 8 shows an echogenic balloon tip mounted with a plurality of echogenic rings;

(10) FIGS. 9A (side view), 9B (end view), 9C (perspective view) show an embodiment of an integral echogenic ring;

(11) FIGS. 10A (side view), 10B (end view), 10C (perspective view) show an embodiment of an integral echogenic ring;

(12) FIGS. 11A (side view), 11B (end view), 11C (perspective view) show another embodiment of an integral echogenic ring;

(13) FIG. 12 shows an example of scale marks on a balloon body; and

(14) FIG. 13 shows another example of scale marks on a balloon body.

DETAILED DESCRIPTION

(15) Hereinafter, embodiments of the present disclosure will be described with reference to the accompanying drawings. An echogenic balloon dilatation catheter is an example of an echogenic medical device, such as for PCNL. However, it should be noted that examples of an echogenic medical device are not limited thereto.

(16) Depending on specific applications, the echogenic medical devices may be other medical devices known to those skilled in the art, such as abdominal medical devices, gynecological and obstetric medical devices, cardiac medical devices, and so on.

(17) Embodiments described below serve only as specific examples. However, the present disclosure is not limited to the embodiments described in the description.

(18) In general, as shown in FIG. 1, a balloon for a balloon dilatation catheter is shown. The balloon 10 includes a cylindrical balloon body 11, a balloon cone 12 on each side of the balloon body, and a balloon tip (or balloon neck) 13 extending from the cone and fixed to the catheter. The balloon body merges with the balloon cone through a balloon shoulder 14.

(19) An Echogenic Balloon Having an Echogenic Tip

(20) More specifically, the present disclosure relates to an echogenic tip of a balloon. A balloon with an echogenic tip can be identified from a surrounding tissue and saline injected into a renal pelvis. The present disclosure can enhance the difference in acoustic impedance between the tip of the balloon and the surrounding environment.

Embodiment 1: An Echogenic Balloon Having a Metal Tip

(21) As shown in FIG. 1, a distal tip 13 of the balloon connected to the cone of the balloon may be made of a metal material. Metal has a higher acoustic impedance value (Z value) than an organ tissue and an organ fluid, which helps to construct an interface with a significant Z value difference. Suitable metals include but are not limited to titanium, platinum, and stainless steel. They have excellent biocompatibility and can be used to process metal tubes. The metal tip is connected to the balloon cone by welding or bonding. The metal surface enhances the reflection of sound waves back to the ultrasonic probe.

(22) A further modification is shown in FIG. 2, in which the tip 13 of the balloon is provided with notches 15 to enhance echogenicity, since backscattering of sound waves is enhanced. The notches 15 may be hemispherical, but could take other shapes as well. Each notch 15 may have a diameter of from about 20 μm to about 50 μm. The notches 15 may be formed using laser ablation on a smooth metal tip.

Embodiment 2: An Echogenic Balloon Tip with a Metal Sleeve or Cladding Layer

(23) As shown in FIG. 3, a sleeve or cladding layer 16 on the balloon tip 13 can improve the echogenicity of the balloon tip, since the difference in acoustic impedance at the interface increases. The advantage of the metal sleeve is that it is easy to adhere with an adhesive. Titanium, platinum or gold foil with a thickness of from about 0.01 mm to about 0.05 mm can be selected, since these metals with such a thickness are flexible enough for being wrapped on the balloon tip. All metals with good flexibility can be used. A titanium, platinum or gold tube with a wall thickness of from about 0.02 mm to about 0.05 mm is preferable, because a tube with such a wall thickness is sufficiently rigid to form a sleeve.

(24) FIG. 4 shows a further improvement. Sandblasting (60-120 mesh) or physical deformation or machining is used to process the surface of the metal sleeve 16 or cladding layer so that the surface has a roughness of a few microns to tens of microns. This roughened surface can further improve the echogenicity, since back scattering of the sound is improved.

Embodiment 3: An Echogenic Balloon Tip with a Plurality of Metal Cuffs

(25) As shown in FIG. 5, a plurality of metal cuffs 17 adhered to the balloon tip in the winding direction (that is, the circumferential direction) and spaced apart in the axial direction can improve the echogenicity of the tip, since the interface between the metal and the surrounding environment has a large difference in acoustic impedance. The metal may be titanium, platinum, gold, stainless steel or other metals with excellent biocompatibility. It is easy to adhere the cuffs on the surface of the balloon tip. It is only required that the adhesive is used to adhere the metal cuffs to the tip of the balloon, no matter whether an adhesive is applied densely or intermittently. Such a balloon tip can improve identifiability, because the adhered cuffs can appear as bright and dark intervals in the ultrasound image. The cuff has a thickness in range of from about 0.01 mm to about 0.05 mm, a width in range of from about 0.7 mm to about 2 mm, and an interval between adjacent cuffs of from about 0.5 mm to about 2 mm.

Embodiment 4: An Echogenic Balloon Tip with a Patterned Surface

(26) There is a determined pattern on a surface of the metal balloon tip.

(27) In addition, the patterned surface the balloon tip can also be covered with a heat-shrinkable polymer coating. Due to an air gap on the patterned surface, air can be trapped between the balloon tip surface and the polymer coating so as to form an air/polymer interface, the interface having a large difference in acoustic impedance, thereby improving echogenicity.

(28) Surface patterning can be achieved by machining on the final metal balloon tip, including laser lithography, etching, stamping or ball milling after the balloon tip is molded. As shown in FIGS. 6A, 6B, 6C, the surface pattern 18 can be in any shape, such as a rectangular array, a triangular array, a hemispherical array, a diamond array, a cylindrical array, or a plurality of parallel grooves extending in the circumferential direction.

Embodiment 5: An Echogenic Balloon Tip Wound with a Metal Fiber

(29) According to this embodiment, the tip of the echogenic balloon is wound with a metal fiber. The advantage thereof is that, on one hand, as compared to the interface between the polymer surface and the surrounding tissue, it provides an interface with a higher difference in acoustic impedance between the surface of the metal fiber and the surrounding tissue, and on the other hand, the irregular arrangement of the metal fiber layer provides an irregular surface with convexes and concaves. The fiber has a circular or rectangular shaped cross section, with a diameter of from about 0.05 mm to about 0.5 mm (for a circular cross section) or a side length of from about 0.01 mm to about 0.05 mm and from about 0.05 mm to about 0.25 mm. Metals include but are not limited to silver, platinum, gold, stainless steel, or silver-stainless steel composite material. Any metal that has good biocompatibility and can be extruded into a fiber can be used.

(30) A Balloon Having an Echogenic Body and Cones

(31) The present disclosure also relates to an echogenic balloon having an echogenic balloon body and balloon cones, used for percutaneous nephrolithotomy surgery.

(32) As shown in FIG. 7A, as an example, the balloon may be composed of multiple layers, including a polymer base layer 20, a polymer adhesive layer 21, a polymer membrane layer 22, a polymer fiber layer 23, a polymer cladding layer 24 and an outermost polymer protective layer 25.

(33) According to the present disclosure, an echogenic element can be added to the balloon so as to improve ultrasound echogenicity.

Embodiment 1: An Echogenic Balloon Having an Echogenic Functional Modification as a Metal Echogenic Layer

(34) As shown in FIG. 7B, as compared to the prior art, a metal echogenic layer 26 is added as an additional layer between the polymer cladding layer 24 and the outermost polymer protective layer 25. As an alternative, it will be sufficient that a metal echogenic layer is provided under the outermost layer of the balloon. Further, in such a case, the metal echogenic layer includes a plurality of metal cuffs spaced apart in the axial direction and extending in the circumferential direction of the balloon. The metal of the cuff may include, but is not limited to, silver, gold, platinum, titanium or stainless steel, etc., so as to provide enhanced sound wave reflection. Any metal that has good biocompatibility can be used. The metal cuff on the balloon body or cones has the advantage that it can be used as a scale mark to indicate the balloon position in ultrasound diagnosis. The cuff on the area of the balloon cone can indicate whether the balloon cone is correctly placed in the renal pelvis, which is important for the surgeon to judge whether the dilation is effective. Width of the cuff on the balloon body may be from about 0.8 mm to about 3 mm, and width of the cuff on the balloon cone area may be from about 0.8 mm to about 2 mm.

Embodiment 2: An Echogenic Balloon Having an Echogenic Functional Modification as a Metal Echogenic Layer Formed by Mixing a Metal Component in the Adhesive Between Different Layers

(35) According to this embodiment, it is also possible to mix metal powder in the polymer adhesive, which can increase the density of the entire composite. According to the present disclosure, in the polymer cladding layer 24 (which also serves as an adhesive layer) for adhering the polymer fiber layer 23 to the outermost polymer protective layer 25 or in the polymer adhesive layer 21 for adhering the polymer base layer 20 to the polymer film layer 22, metal powder is mixed, especially silver, titanium, nitinol, and gold powder, the metal powder having a particle size of from about 1 μm to about 10 μm, and a content of approximately 50% to approximately 80% such that density of the entire balloon is increased, thereby enhancing the echogenicity of the balloon body or cones.

Embodiment 3: An Echogenic Balloon Having an Echogenic Functional Modification as an Echogenic Layer Having Bubbles in an Adhesive Layer

(36) According to this embodiment, it is also possible to use expansion/volatility effect of a poor solvent on a solvent-based adhesive so as to create pores in a polymer base layer of a balloon. In particular, the adhesive layer (for example, the polymer cladding layer 24 or the polymer adhesive layer 21) can be expanded by volatilization of the poor solvent. The solvent molecules penetrate into the polymer chain, but do not dissolve the polymer chain. Then, when the solvent volatilizes from the adhesive layer, the underlying polymer base layer of the balloon will shrink irregularly to form an irregular (e.g., convex and concave) surface, thereby forming echogenic gas pores. An interface between the polymer and gas pores provides a high acoustic impedance, which helps to improve echogenicity.

(37) Further, the outermost polymer protective layer 25 may be omitted. In such a case, the polymer cladding layer 24 itself may be an adhesive. As such, it is advantageous to avoid the loss of adhesiveness caused by the formation of pores.

(38) The following are some specific examples made according to the above embodiments:

(39) 1. Examples of an Echogenic Balloon Tip

(40) 1.1 In an example of an echogenic balloon, the tip of the balloon connected to the cone of the balloon is made of a metal material, in particular, titanium. The titanium tip of the balloon is adhered to the balloon cone. A large acoustic impedance difference between the titanium tip of the balloon and an organ tissue builds an interface on the tip with large acoustic wave backscattering, such that brightness of the titanium tip of the balloon is increased.

(41) Another way to improve the echogenicity of the metal tip of the balloon is to form a hemispherical notch with a diameter of about 45 μm on the balloon tip by laser ablation. This also enhances the echogenicity of the balloon tip.

(42) 1.2 A metal cladding layer can be provided on the balloon tip. A stainless steel foil and a titanium foil with a thickness of about 0.05 mm are used to cover the balloon tip with the help of an adhesive so as to enhance the echogenicity.

(43) Another way is to blast the titanium foil with a thickness of 0.05 mm and the stainless steel foil with a thickness of about 0.07 mm so as to form a rough surface with a roughness of 60-120 mesh. This rough cladding layer also enhances the echogenicity of the balloon tip.

(44) 1.3 A platinum, gold or silver cuff with a width of 1.0 mm and a thickness of 0.038 mm is adhered to the entire periphery of the balloon tip. Due to the enhanced backscattering of sound waves, brightness of the entire balloon tip is improved.

(45) 1.4 A stainless steel-silver composite fiber is used to wind around the balloon tip. A stainless steel-silver composite fiber with a diameter of about 0.076 mm is used to wind around the tip of the balloon as closely as possible. The wound composite fiber helps to greatly improve the echogenicity of the balloon tip.

(46) 1.5 A patterned balloon tip is made by machining. For example, a circle of groove is machined. As a result, an improved tip image identification is obtained, and the brightness in the grooved area is enhanced.

(47) 2. Examples of an Echogenic Balloon Body or Cone

(48) 2.1 A metal cuff is adhered to the balloon body. Particularly, a gold cuff can be adhered to the balloon body or cone to cover the entire cone. The gold cuff has a thickness of about 10 μm, and a width of about 1 mm. Echogenicity of the body or cone is improved.

(49) 2.2 A metal cuff is adhered to the balloon body. Particularly, a gold cuff can be adhered to the balloon body or cone to cover the entire cone. The gold cuff has a thickness of about 30 μm, and a width of about 1 mm. Echogenicity of the body or cone is improved.

(50) 2.3 A metal cuff is adhered to the balloon body. Particularly, a gold cuff can be adhered to the balloon body or cone to cover the entire cone. The gold cuff has a thickness of about 10 μm, and a width of about 2 mm. Echogenicity of the body or cone is improved.

(51) 2.4 Metal cuffs are adhered to the balloon body. Particularly, gold cuffs can be adhered to the balloon body or cone. The gold cuffs has a thickness of about 10 μm, and a width of about 1 mm, and an interval between adjacent gold cuffs is about 1 mm. Echogenicity of the body or cone is improved.

(52) 2.5 Metal cuffs are adhered to the balloon body. Particularly, gold cuffs can be adhered to the balloon body or cone. The gold cuffs has a thickness of about 30 μm, and a width of about 1 mm, and an interval between adjacent gold cuffs is about 1 mm. Echogenicity of the body or cone is improved.

(53) 2.6 A metal foil is adhered to the balloon body. Particularly, a stainless foil can be adhered to the balloon body or cone. The stainless cuff has a thickness of about 0.02 mm, and a width of about 1 cm. Echogenicity of the cone or body is improved.

(54) 2.7 A metal foil is adhered to the balloon body. Particularly, a titanium foil can be adhered to the balloon cone or body. The titanium foil has a thickness of about 0.05 mm, and a width of about 1 cm. Echogenicity of the cone or body is improved.

(55) 2.8 Metal powder is mixed in an adhesive between the layers. In particular, silver powder with a particle size of 6 μm is mixed into the adhesive at a content of about 50%. Echogenicity of the entire body or cone of the balloon is improved.

(56) 2.9 A layer of polyurethane adhesive is applied over a first polymer layer of the balloon (i.e. the layer that needs to be adhered to a second polymer layer). Then, a thin layer of dichloromethane or trichlormethane poor solvent is applied on top of the polyurethane adhesive to make it volatilize. Due to formation of pores in the polymer layer below the adhesive layer, echogenicity of the balloon is improved.

(57) The above embodiments and examples improve the echogenicity of the balloon tip, balloon cone, or balloon body.

(58) According to the present disclosure, the echogenicity of the balloon tip can also be improved by the following modifications.

(59) A plurality of echogenic rings are mounted on the balloon tip at an axial interval. This is easy to manufacture and easy to perform ultrasonic examination.

(60) A material for manufacturing the echogenic ring can be: a metal material with or without surface treatment; an alloy material with or without surface treatment; an polymer material with or without surface treatment and containing micro-bubbles; or any combination thereof.

(61) Similar to the embodiment of FIG. 5, as shown in FIG. 8, the echogenic ring 30 is mounted on the tip of the balloon outside the balloon cone, which helps to ensure a high burst pressure of the balloon and does not reduce the burst pressure of the balloon pressure.

(62) Compared to the mounting of a single ring on the balloon tip, since multiple echogenic rings are mounted on the balloon tip at an axial interval and the surface reflection of the echogenic ring material is stronger than the surface reflection of the balloon tip material 32, more echogenic surfaces can be obtained, such that ultrasound visibility and detectability of the balloon tip can be enhanced. Further, the balloon tip material in the interval between the rings helps to trap some air during use, which also helps to enhance the ultrasound visibility of the balloon tip.

(63) On the other hand, due to the clinical requirements, the balloon tip is usually designed to be very short. Therefore, the echogenic ring should also be small so as to engage the balloon tip without excessively increasing an outer diameter and length of the balloon tip. However, it is difficult to engage multiple rings to the balloon tip at an axial interval. This problem can be solved by an integral echogenic ring.

(64) (1) As shown in FIGS. 9A (side view), 9B (end view), and 9C (perspective view), the ring body 30 is provided thereon with a plurality of circumferentially extending through grooves with opening directions opposite to each other and axially spaced from each other;

(65) (2) As shown in FIGS. 10A (side view), 10B (end view), and 10C (perspective view), the ring body is provided thereon with a continuously spiral through groove;

(66) (3) As shown in FIGS. 11A (side view), 11B (end view), and 11C (perspective view), the ring body is provided thereon with a plurality of axially disposed windows in which every two adjacent rows of windows are staggered from each other in the circumferential direction.

(67) For example, the specific design requirements of the above integral echogenic ring can be as follows: There are 2 to 5 ring bodies between the openings; The ring body between the openings has a width of from about 0.3 mm to about 4 mm; The opening has a width of from about 0.5 mm to about 2 mm; The ring has a thickness of from about 0.01 mm to about 2 mm.

(68) Scale Marks

(69) According to another aspect of the disclosure, scale marks 40 may be printed on an outer surface of the body of the balloon 10. The scale marks 40 are visible in fluoroscopy or ultrasound, and also visible to naked eyes. The scale marks can be used to measure an insertion depth of balloon, locate an effective portion of the balloon body, and measure an affected area during surgery. The scale marks may have an internal that may be from about 1 mm to about 20 mm, for example 10 mm.

(70) For different application purposes, a starting position of the scale marks can start at a distal shoulder 14 of the balloon 10 so as to identify a position of the effective portion of the balloon. Alternatively, they can also start at a distance D from the tip 13 of the balloon, such as about 5 mm, so as to determine the catheter insertion depth.

(71) For easy identification, a first scale mark and another scale mark at an interval (for example, about 50 mm) are different from other scale marks, for example, one is thicker than the other.

(72) A material for the scale mark can be: a metal material with or without surface treatment; an alloy material with or without surface treatment; a polymer material with or without surface treatment and containing micro-bubbles; or any combination thereof.

(73) Example 1 of Scale Marks:

(74) As shown in FIG. 12, scale marks are added on an outer surface of the balloon body, the first scale mark is located at a distal balloon shoulder and the last scale mark is located at a proximal balloon shoulder. The scale marks have an interval of 1 cm. The scale marks are visible in fluoroscopy or ultrasound, and are also visible to naked eyes.

(75) The number of scale marks is 16 in total. The first, sixth, eleventh and sixteenth scale marks are thicker than other scale marks.

(76) In PCNL surgery, the doctor can measure the size of calculi by comparing the size of the calculi with these scale marks in fluoroscopy or ultrasound.

(77) In aneurysm embolization using a balloon catheter, the doctor can measure a size of a tumor neck by comparing the size of the tumor neck with these scale marks in fluoroscopy or ultrasound.

(78) Example 2 of Scale Marks:

(79) As shown in FIG. 13, scale marks are added on an outer surface of the balloon body, the first scale mark is about 5 mm away from a distal tip of the balloon, and the last scale mark is located adjacent a proximal end of the balloon body. The scale marks have an interval of about 1 cm. These scale marks are visible to naked eyes.

(80) The number of scale marks is 12 in total. The first, sixth, and eleventh scale marks are thicker than other scale marks.

(81) During PCNL surgery, the doctor needs to place the balloon in an appropriate position in the human body. The scale marks added on the outer surface of the balloon body can be used as scales to record an insertion depth of balloon. The doctor can insert the balloon and balloon catheter into the human body to a depth with naked eyes.

(82) As used herein, the following terms have the following meanings:

(83) “A”, “an”, and “the” as used herein refers to both singular and plural referents unless the context clearly dictates otherwise. By way of example, “a compartment” refers to one or more than one compartment.

(84) “About,” “substantially,” or “approximately,” as used herein referring to a measurable value, such as a parameter, an amount, a temporal duration, and the like, is meant to encompass variations of +/−20% or less, preferably +/−10% or less, more preferably +/−5% or less, even more preferably +/−1% or less, and still more preferably +/−0.1% or less of and from the specified value, in so far such variations are appropriate to perform in the disclosed invention. However, it is to be understood that the value to which the modifier “about” refers is itself also specifically disclosed.

(85) “Comprise”, “comprising”, and “comprises” and “comprised of” as used herein are synonymous with “include”, “including”, “includes” or “contain”, “containing”, “contains”, and are inclusive or open-ended terms that specifies the presence of what follows e.g. component and do not exclude or preclude the presence of additional, non-recited components, features, element, members, steps, known in the art or disclosed therein.

(86) Although the invention has been described in conjunction with specific embodiments, many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, it embraces all such alternatives, modifications, and variations that fall within the appended claims' spirit and scope. All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present disclosure.